Clinical trial NCT01576172
Conditions: Castration-Resistant Prostate Carcinoma Recurrent Prostate Carcinoma Stage IV Prostate Cancer AJCC v7
Sponsor: National Cancer Institute (NCI)
Start date: 2012-03-30; Completion date: 2020-04-23
Enrollment: 159 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized phase II trial studies abiraterone acetate and prednisone together with veliparib to see how well it works compared to abiraterone acetate and prednisone alone in treating patients with castration-resistant prostate cancer that has spread from the primary site to other places in the body. Androgens can cause the growth of prostate cancer cells. Antiandrogen drugs, such as abiraterone acetate, may lessen the amount of androgens made by the body. Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving abiraterone acetate together with prednisone and veliparib may work better than abiraterone acetate and prednisone alone in treating patients with castration-resistant prostate cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To evaluate the role of v-ets erythroblastosis virus E26 oncogene (ETS) gene fusion as a predictive biomarker for response to hormone therapy (abiraterone \[abiraterone acetate\]) alone or hormone therapy plus poly adenosine diphosphate-ribose polymerase 1 (PARP-1) targeted therapy (ABT-888 \[veliparib\]) in patients with metastatic castration resistant prostate cancer.

II. To evaluate whether the addition of PARP-1 targeted therapy is superior to hormone therapy alone based on ETS gene fusion status.

SECONDARY OBJECTIVES:

I. Rate of prostate-specific antigen (PSA) declines. II. Objective response rate. III. Progression-free survival. IV. Evaluate the qualitative and quantitative toxicity of abiraterone acetate with and without ABT-888.

TERTIARY OBJECTIVES:

I. To determine the concordance in fusion status among prostate cancer samples from the primary site, biopsied metastasis, and circulating tumor cells (CTCs).

II. To assess if ETS fusion status in the CTCs, at baseline, 12 weeks, and disease progression (or when off study) is associated with response to therapy.

III. To evaluate if the number of CTCs, as well as the expression levels of androgen receptor, RAD51 recombinase (RAD51), and gamma-H2A histone family, member X (H2aX) foci in the CTCs at baseline, at 12 weeks, and at disease progression in all patients is associated with response to therapy.

IV. To determine the role of phosphatase and tensin homolog (PTEN) loss as a predictive biomarker of response to abiraterone, alone or in combination with ABT-888.

V. To determine the role of PARP1 activity as a predictive biomarker of response to abiraterone, alone or in combination with ABT-888.

VI. To perform next-generation sequencing for discovery of novel gene fusions in prostate cancers negative for ETS fusions.

VII. To perform germline single nucleotide polymorphism (SNP) analysis of genes involved in hormone synthesis, transport, binding, metabolism, and degradation for discovery of novel SNPs predictive of response to abiraterone, alone or in combination with ABT-888.

VIII. To determine if ETS fusion ribonucleic acid (RNA) levels in blood are predictive of response to abiraterone, alone or in combination with ABT-888.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive abiraterone acetate orally (PO) once daily (QD) and prednisone PO twice daily (BID) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive veliparib PO BID on days 1-28. Patients also receive abiraterone acetate PO QD and prednisone PO BID on day 1 (day 8 of course 1). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for up to 2 years.

Arms: arm 1: Patients receive abiraterone acetate PO QD and prednisone PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive veliparib PO BID on days 1-28. Patients also receive abiraterone acetate PO QD and prednisone PO BID on day 1 (day 8 of course 1). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Abiraterone Acetate intervention 2: Laboratory Biomarker Analysis intervention 3: Prednisone intervention 4: Veliparib
Intervention descriptions: intervention 1: Given PO intervention 2: Correlative studies intervention 3: Given PO intervention 4: Given PO

Protocol documents:
Prot_SAP_001.pdf: 
UCIRB # 12-0109 
 
 
 
Protocol Amendment #  11 
NCI # 9012 
 
 
Version Date:    5/24/2018 
 
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SUMMARY OF CHANGES 
 
For Protocol Amendment #11 to: 
 
NCI Protocol #: 9012 
Local Protocol #:  12-0109 
 
NCI Version Date:   2/26/2018 (last NCI approved version)  
Protocol Date:  5/24/2018 (current version) 
 
# 
Section 
Page 
Change 
1. 
 Title Page 
1 
Updated protocol amendment number and protocol version date 
 
2. 
Protocol 
history 
4 
Updated protocol  history section 
3. 
3.0 
29 
3.1 Eligibility (inclusion criteria) 
3.2 Exclusion criteria  
4. 
6.0 
40 
Dose delay modifications; Management of Investigational Product related 
toxicities; hematologic toxicity- Management of neutropenia and 
thrombocytopenia; management of anemia; Management of prolonged 
hematological toxicities while on study treatment; Management of ABT-
888 associated toxicity-Management of MDS/AML 
 
 
5. 
7.1 
44 
Revised CAPER for ABT-888 version 2.4, May 13, 2018 
  
 


UCIRB # 12-0109 
 
 
 
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Version Date:    5/24/2018 
 
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NCI Protocol #:  
 9012 
Local Protocol #:  
 12-0109  
 
TITLE:  A Randomized Gene Fusion Stratified Phase 2 Trial of Abiraterone With 
Or Without ABT-888 For Patients With Metastatic Castration-Resistant Prostate 
Cancer 
 
 
Coordinating Center: 
 
 
The University of Chicago Phase II Consortium 
 
Overall Lead PI: 
Maha Hussain, M.D. FACP 
 
Genevieve Teuton Professor of Medicine 
                                                      Northwestern University (Current address) 
 
Robert H. Lurie Comprehensive Cancer Center 
 
Clinical Center Galter Pavilion 
 
675 North St. Clair, 21st floor 
 
Chicago, IL-60611 
 
Telephone: 312-695-0990 
 
E-mail: maha.hussain@northwestern.edu 
 
Principal Investigator: 
David Smith, M.D., F.A.C.P. 
 
University of Michigan 
 
7314 Cancer Center 
 
1500 E. Medical Center Drive 
 
Ann Arbor, MI 48109-5946 
 
Telephone: 734-763-6537 
 
Fax: 734-936-7376 
 
Email: dcsmith@umich.edu 
 
Co-Principal Investigator: 
Felix Feng, M.D. 
 
University of Michigan 
 
Department of Radiation Oncology and 
 
Michigan Center for Translational Pathology 
 
University of Michigan Medical Center 
 
1500 E Medical Center Drive 
 
UHB2C490, SPC 5010 
 
Ann Arbor, MI 48109-5010 
 
Telephone: 734-936-4302 
 
Fax: 734-763-7371 
 
Email: ffeng@med.umich.edu 
 
 


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Site Specific and Other Co-Investigators 
Emmanuel Antonarakis, M.D 
Sidney Kimmel Comprehensive 
Cancer Center at Johns Hopkins 
Orleans Street, Rm 1M45 
The Bunting-Blaustein Cancer 
Research Building 
Baltimore, MD 21231 
Telephone: 410-502-7528 
Email: eantona1@jhmi.edu 
David I. Quinn, MBBS (Hons) PhD FRACP  
Kenneth J. Norris Jr. Comprehensive Cancer 
Keck School of Medicine 
University of Southern California 
1441 Eastlake Ave Suite 3453 
Los Angeles, CA 90033 
Telephone: 323-865-3956 
Fax: 323-865-0061 
Email: diquinn@usc.edu 
Glenn Liu, M.D. 
University of Wisconsin Carbone 
Cancer Center 
Wisconsin Institute for Medical Research, 
Room 7051 
1111 Highland Avenue 
Madison, WI 53075 
Telephone: 608-265-8689 
Email: gxl@medicine.wisc.edu 
Paul Corn, M.D., PhD 
The University of Texas 
MD Anderson Cancer Center 
Pressler Street, CPB7.3481 
Houston, Texas 77030 
Telephone: 713-792-2830 
Email: pcorn@mdanderson.org 
Walter Stadler, M.D. 
University of Chicago 
5841 S. Maryland, MC 2115 
Telephone: 773-702-4150 
Fax: 773-702-3163 
Email: wstadler@medicine.bsd.uchicago.edu 
Bruce Montgomery, MD 
University of Washington 
1959 NE Pacific St. SP 1301 
Box 356158 
Seattle, WA 98195 
Telephone: 206-598-0860 
Fax:.206-598-6986 
E-mail: rbmontgo@u.washington.edu 
 
Sumanta Pal, M.D. 
City of Hope Cancer Center 
1500 E. Duarte Road 
Duarte, CA 91010 
Telephone: 626-256-4673  
Fax: 626-301-8233 
Email: spal@coh.org 
 
 Mark Stein, M.D.  
The Cancer Institute of New Jersey 
195 Little Albany Street 
New Brunswick, NJ 08901 
Telephone: 732-235-3336 
Email: steinmn@umdnj.edu 
 
 
Costantine Albany, MD 
Assistant Professor of Medicine  
Medical Oncology 
Indiana University Health 
Simon Cancer Center 
535 Barnhill Drive, RT 473, 
 Indianapolis, IN 46202 
Telephone: 317-948-8310 
E-mail: calbany@iupui.edu 
Young E. Whang, M.D. PhD 
University of North Carolina at Chapel Hill 
Lineberger Comprehensive Cancer Center 
CB #7295, Room 22-016 
Chapel Hill, NC 27599 
Telephone: 919-843-9983 
Fax: 919-966-8212 
Email: ywhang@med.unc.edu 


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Daniel Shevrin, M.D. 
NorthShore University HealthSystem 
2650 Ridge Ave. 
Evanston, IL 60201 
Telephone: 847-570-2515 
Email: DShevrin@northshore.org 
 
Stephen Koehler, MD 
City of Hope Medical Group, Inc. 
209 Fair Oaks Avenue 
South Pasadena, CA  91030 
Phone: 626-396-2900 
Fax: 626-396-2770 
Email: skhoehler@cohmg.com  
 
Biostatistician: 
Stephanie Daignault-Newton, M.S. 
N18D11 NIB  
300 North Ingalls 
Ann Arbor, MI, 48109-0473 
Telephone: 734-647-3271 
Email: sfaruzzi@umich.edu 
 
Radiology Co-Investigators  
Jon A. Jacobson, M.D. 
University of Michigan 
Taubman Center, Room 2910L 
1500 East Medical Center Dr., SPC 5326 
Ann Arbor, MI 48109 
Telephone: 734-936-4365 
Fax: 734-936-9723 
Email: jjacobsn@umich.edu 
 
Matthew S. Davenport, M.D. 
University of Michigan 
Department of Radiology 
1500 E. Medical Center Drive, B1 G505 
Ann Arbor, MI 48109-5030 
Telephone: 734/615-9016 
Email: matdaven@umich.edu 
Study Pathologist 
Lakshmi P. Kunju, M.D. 
University of Michigan Hospital 
Department of Pathology 
1500 E. Medical Center Drive 
2G332 University Hospital, SPC 5054 
Ann Arbor, MI 48109-5054 
Telephone: 734-647-9125 
Email: lkunju@umich.edu 
Study Pathologist 
Arul Chinnaiyan, M.D. 
University of Michigan Hospital 
Department of Pathology/Urology Surgery 
1500 E. Medical Center Drive 
5316 Cancer Center, SPC 5940 
Ann Arbor, MI 48109-5940 
Telephone: 734-615-4062 
Email: arul@umich.edu 
 
Administrative Personnel 
Responsible Research Nurse: 
Tamara Huebner, RN, BSN, OCN 
B1-245 Cancer Center 
1500 E. Medical Center Drive 
Ann Arbor, MI 48109-5913 
Telephone: 734-763-4992 
Email: thuebner@umich.edu 
Phase II Regulatory Manager: 
Sheila Dertz, CCRA 
Regulatory Affairs Manager  
The University of Chicago Comprehensive 
Cancer Center 
Cancer Clinical Trials Office  
5841 S. Maryland, MC1140 


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Chicago, IL 60637 
Phone: 773-702-8751 
Fax: 773-702-1561 
email: sdertz@bsd.uchicago.edu 
 
Group Chairman: 
Walter M. Stadler, M.D.  
University of Chicago 
5841 S. Maryland Ave., MC 2115 
Chicago, IL 60637 
Telephone: (773) 702-4150 
Fax: (773)834-0188 
Email:wstadler@medicine.bsd.uchicago.edu 
 
Responsible Data Manager: 
Jaclyn D. Peterson, MBA 
The University of Chicago 
Section of Hematology/Oncology 
5841 S. Maryland Ave. MC2115 
Chicago, IL 60637 
Phone: 773-834-1746; Fax: 773-702-4889 
Email: jdpeterson@medicine.bsd.uchicago.edu 
OR contact the phase 2 CRA general e-mail at 
phaseIIcra@medicine.bsd.uchicago.edu 
 
 
Technical Director, Michigan Center for 
Translational Pathology 
Javed Siddiqui, MS, MT(ASCP, CLsp (MB)) 
Room 1138  
2900 Huron Parkway Suite 100 
Ann Arbor, MI 48105 
Phone : (734) 232-0829; Fax : (734) 232-0805 
Email: siddiqui@med.umich.edu 
University of Michigan Multi-Site Coordinator 
Kathleen Granlund, CCRP 
Cancer Center Clinical Trials Office 
North Campus Research Complex (NCRC) 
Building 300  Main 
Ann Arbor, MI 48109-2800 
Phone: 734-936-0563 
Fax: 734-232-0744 
Email: kemarsh@med.umich.edu 
 
 
 
 
 
Contract #  
  
NCI Supplied Agent: 
 
ABT-888 (NSC # 737664; IND # 
) 
 
 
Commercially Supplied Agent  
Abiraterone (NSC #748121)   
NCI Approval: 
3/30/2012 
UM Protocol Approval: 
4/16/2012 
 
 
Protocol History 
Version Date 
Description of Action 
12/23/10 
Original Submission to NCI 
11/9/11 
Consensus Response / Version 2  
12/13/11 
Follow-up Review/Version 3 and incorporation of ABT-888 CAEPR  v. 2.0,  10/28/11  in 


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Version Date:    5/24/2018 
 
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response to RA received from Dr. Chen on 11.18.11 
1/09/12  
Follow-up Review /Version 4 and updated Section 5.5 Duration of Follow Up. 
6/26/12 
Amendment 1: added several participating institutions to the protocol, updated site 
information/personnel, and corrected/clarified several technical and patient scheduling 
issues within the protocol. 
8/17/12 
Amendment 2: being submitted in response to an Action Letter for ABT-888 from Dr. 
Alice Chen. Removed one participating site and added two patient scheduling windows in 
the study calendar. Updated the exclusion criteria for patients with history of active 
seizures in Section 3.2.3. Changed FedEx shipping priority in Appendix F from First 
Overnight to Priority Overnight. 
5/29/13 
Amendment 3: Added Dr. Stephen Koehler, MD, City of Hope Medical Group, Inc. 
Updated the University of Chicago regulatory manager. Corrected/clarified several 
technical and patient scheduling issues within the protocol; increased the number of biopsy 
samples needed and clarified the SOPs for obtaining these samples (Appendix C and D); 
updated the eligibility criteria in Section 3.1.8 to indicate that patients with prior exposure 
to ketoconazole are eligible for this trial. Serum Creatinine level was corrected under 
Section 3.1.10. Clarified that patients who had been on prednisone prior to registration 
may continue it during the lead-in ABT-888 therapy in Section 5.1 for Arm 1 and Arm II 
B. Clarified that the dose of ABT-888 was changed from 300 mg to 200 mg at start and 
then escalate to 300 mg after the 1st cycle if patient tolerates 200mg in Section 5.2-under 
agent administration. In section 6.0, dose delays and dose modifications were updated. 
Dose levels of prednisone and ABT-888 also were changed under sections 6.4 and 6.5, 
respectively. Added Appendix G: Standard Operating Procedure for Shipment of CTC 
Clinical Samples to indicate that change to Epic Sciences in the CTC handling and 
shipping procedures and added that these blood/CTC samples would also be collected at 
week 12 and at clinical progression. Added the enumeration and molecular 
characterization of the CTC samples to the correlative analysis plan (section 13.4). 
Revised the approach from detecting ETV1 fusions from FISH to ISH. 
2/10/14 
Amendment 4: Updated Indiana University site PI.  Updated Adverse Event Expedited 
Reporting System (AdEERS) with CTEP Adverse Event Reporting System (CTEP-AERS) 
throughout the protocol. 
3/17/16 
Amendment 5: Updated version date throughout the protocol. Updated Administrative 
Personnel. Section 10.0- updated the study calendar. 
4/27/16 
Amendment 6: Updated version date throughout the protocol. Replaced CAPER for ABT-
888 version 2.2, March 22, 2013 with version 2.3, March 4, 2016 per RA letter dated 
April 19, 2016. 
7/1/16 
Amendment 7: Administrative amendment to update designation and contact info for DR. 
Hussain and to include DR. Smith as the new Principal Investigator at Univ. of Michigan.. 
7/20/17 
Amendment 8: Administrative amendment to replace COH site PI, Twardowski with Pal.  
2.19.18 
Amendment 9: Disapproved  


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2.26.18 
Amendment 10: Updated the lead site regulatory manager from Supriya Perambakam to 
Sheila Dertz; Per CTEP request updated CTCAE v4.0 to v5.0 throughout the document 
5.24.2018 
Amendment 11: Section 3.1- Eligibility (inclusion) criteria; 3.2 Exclusion criteria; Section 
6.0: Dose Delay Modifications; Management of Investigational Product related toxicities; 
Section 7.1: Revised CAPER for ABT-888 version 2.4, May 13, 2018;  
 
 
STUDY SCHEMA 
Registration 
Current metastatic tissue biopsy 
adequate for ETS fusion status 
evaluation 
Arm 1: ETS gene fusion positive 
Arm 2: ETS gene fusion negative 
Stratification/Baseline Evaluation/ 
Randomization 
1A: Abiraterone 
1B: Abiraterone + ABT-888 
2A: Abiraterone 
2B: Abiraterone + ABT-888 
Metastatic tissue biopsy NOT 
adequate for ETS fusion status 
Off Protocol 
Preexisting 
metastatic tissue 
biopsy adequate 
for ETS fusion 
status evaluation 


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TABLE OF CONTENTS 
 
 
Page 
SCHEMA ..................................................................................................................................6 
 
1.  OBJECTIVES ...................................................................................................................10 
 
1.1 Primary Objectives ....................................................................................................10 
 
1.2 Secondary Objectives ................................................................................................10 
 
1.3 Correlative Objectives ...............................................................................................10 
 
2.  BACKGROUND 
 
2.1 Prostate Cancer and Androgen Signaling ...............................................................11 
 
2.2 ETS Gene Fusions in Prostate Cancer .....................................................................11 
 
2.3 ABT-888 ......................................................................................................................15 
 
2.4 Abiraterone Acetate ...................................................................................................23 
     2.5 Rationale for Combining Abiraterone and ABT-888 .............................................23 
 
      2.6 Correlative Studies Background ..............................................................................24 
 
3.  PATIENT SELECTION ..................................................................................................29 
 
3.1 Eligibility Criteria  .....................................................................................................29 
 
3.2 Exclusion Criteria ......................................................................................................30 
 
3.3 Inclusion of Women and Minorities .........................................................................32 
 
4. REGISTRATION PROCEDURES ................................................................................32 
     4.1 Initial Registration .....................................................................................................32 
     4.2 Biopsy and Randomization  ......................................................................................33 
     4.3 Drug Ordering ...........................................................................................................34 
     4.4 Registration Process & Data Submission  ...............................................................34 
 
5.  TREATMENT PLAN .......................................................................................................35 
 
5.1 Stratification and Randomization ............................................................................35 
 
5.2 Agent Administration ................................................................................................36 
     5.3 General Concomitant Medication and Supportive Care Guidelines ....................37 
 
5.4 Duration of Therapy ..................................................................................................39 
 
5.5 Duration of Follow Up ...............................................................................................39 
 
6.  DOSING DELAYS/DOSE MODIFICATIONS .............................................................40 
     6.1 CTCAE……………………………………………………………………………… 40 
     6.2 Guidance Regarding Dose Adjustments for Adverse Event Based on Attribution..40 
     6.3 PI contact number………………………………………………………………….. ..40 
     6.4 Abiraterone and Prednisone dose levels are defined below…………………………40 
     6.5 ABT-888 dose levels are defined below………………………………………………41 
 
7.  ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS………………42 


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     7.1 Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) ..................43 
     7.2 Adverse Event list(s) for Abiraterone  ......................................................................45 
     7.3 Adverse Event Characteristics ………………………………………………………46 
7.4 Expedited Adverse Event Reporting .........................................................................46 
     7.5 Routine Adverse Event Reporting .............................................................................48 
     7.6 Secondary Malignancy ...............................................................................................48 
 
 
8.  PHARMACEUTICAL INFORMATION .......................................................................49 
 
8.1  CTEP IND Agent ......................................................................................................49 
 
8.2 Commercial Agents ....................................................................................................51 
  
8.3 Prednisone ...................................................................................................................53 
 
9.  CORRELATIVE/SPECIAL STUDIES ..........................................................................54 
9.1 Laboratory Correlative Studies ................................................................................54 
 
10.  STUDY CALENDAR .....................................................................................................65 
 
11.  MEASUREMENT OF EFFECT ...................................................................................66 
11.1 Definitions .................................................................................................................66 
11.2 Evaluation of Best Overall Response .....................................................................72 
11.3 Duration of Response ...............................................................................................73 
 
12.  DATA REPORTING / REGULATORY REQUIREMENTS ....................................75 
 
12.1 Data Reporting .........................................................................................................75 
 
12.2 CTEP Multicenter Guidelines .................................................................................75 
 
12.3 Data and Safety Monitoring Procedures................................................................76 
 
12.4 Quality Assurances and Audits ...............................................................................76 
 
12.5 Collaborative Agreements Language .....................................................................77 
 
13.  STATISTICAL CONSIDERATIONS ..........................................................................80 
 
13.1 Study Design/Endpoints ..........................................................................................80 
 
13.2 Sample Size/Accrual Rate ........................................................................................82 
 
13.3 Stratification Factors ...............................................................................................82 
 
13.4 Analysis of Secondary Endpoints ...........................................................................82 
 
13.5 Reporting and Exclusions ........................................................................................85 
 
REFERENCES .......................................................................................................................86 
APPENDICES 
APPENDIX A 
Performance Status Criteria ........................................................................................92 
APPENDIX B 
CTEP Multicenter Guidelines ....................................................................................93 
APPENDIX C 


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Standard Operating Procedure (SOP) for Biopsy of Metastatic Prostate Cancer Lesion 
 
in Bone………………………………………………………………………………        94 
APPENDIX D 
Standard Operating Procedure (SOP) for Biopsy of Metastatic Prostate Cancer Lesion in 
Soft Tissue……………………………………………………………………………….95 
APPENDIX E 
Standard Operating Procedure (SOP) for Handling Samples .................................... 97 
APPENDIX F 
Standard Operating Procedure (SOP) for Shipment of non-CTC Clinical Samples  100 
 APPENDIX G 
Standard Operating Procedure (SOP) for Shipment of CTC Clinical Samples ...... 103 
 APPENDIX H 
Patient Medication Diary ABT-888 ........................................................................ 105 
 
APPENDIX I 
Patient Medication Diary Abiraterone/Prednisone Cycle 1 ..................................... 106 
 
APPENDIX J 
Patient Medication Diary Abiraterone/Prednisone (not for Cycle 1) ...................... 108   
 
 


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1. OBJECTIVES 
 
 
1.1    Primary Objectives 
 
1.1.1 To evaluate the role of ETS gene fusion as a predictive biomarker for response to 
hormone therapy (abiraterone) alone or hormone therapy plus PARP-1 targeted 
therapy (ABT-888) in patients with metastatic castration resistant prostate cancer.  
1.1.2 To evaluate whether the addition of PARP-1 targeted therapy is superior to hormone 
therapy alone based on ETS gene fusion status. 
 
1.2  
Secondary Objectives 
 
1.2.1 Rate of PSA declines. 
1.2.2 Objective response rate. 
1.2.3 Progression-free survival. 
1.2.4 Evaluate the qualitative and quantitative toxicity of abiraterone acetate with and  
without ABT-888.   
 
1.3  
Correlative Objectives  
 
1.3.1 To determine the concordance in fusion status among prostate cancer samples from 
the primary site, biopsied metastasis, and CTCs. 
1.3.2    To assess if ETS fusion status in the CTCs, at baseline, 12 weeks, and at disease 
progression (or when off study) is associated with response to therapy.  
1.3.3 To evaluate if the number of circulating tumor cells (CTCs), as well as the expression 
levels of androgen receptor, RAD51, and gamma-H2aX foci in the CTCs at baseline, 
at 12 weeks, and at disease progression in all patients is associated with response to 
therapy. 
1.3.4 To determine the role of PTEN loss as a predictive biomarker of response to 
abiraterone, alone or in combination with ABT-888. 
1.3.5 To determine the role of PARP1 activity as a predictive biomarker of response to 
abiraterone, alone or in combination with ABT-888. 
1.3.6   To perform next-generation sequencing for discovery of novel gene fusions in 
prostate cancers negative for ETS fusions. 
1.3.7 To perform germline single nucleotide polymorphism (SNP) analysis of genes 
involved in hormone synthesis, transport, binding, metabolism, and degradation for 
discovery of novel SNPs predictive of response to abiraterone, alone or in 
combination with ABT-888. 
1.3.8 To determine if ETS fusion RNA levels in blood are predictive of response to 
abiraterone, alone or in combination with ABT-888. 
 
 


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2. 
BACKGROUND  
 
2.1  
Prostate Cancer and Androgen Signaling  
 
In the United States, metastatic castration-resistant prostate cancer (mCRPC) resulted in 32,050 
deaths in 2010.1  Mounting evidence indicates that mCRPC remains sensitive to androgen 
signaling through multiple different mechanisms which, in part, is androgen receptor-mediated, 
including androgen receptor gene amplification and mutations in addition to up-regulation of 
steroidogenic enzymes (such as CYP17) that lead to increased androgen production. 2-6  
 
Abiraterone acetate is a selective androgen biosynthesis inhibitor that blocks CYP17 and potently 
inhibits persistent androgen synthesis from adrenal and potentially intratumoral 
(autocrine/paracrine) sources. 7-9  In a randomized phase III trial, abiraterone + prednisone 
significantly improved median overall survival (14.8 months in the abiraterone acetate group and 
10.9 months in the placebo group), progression-free survival (5.6 month vs. 3.6 months), and 
confirmed PSA response rate (29% vs. 6%, P<0.001) in patients with chemotherapy-refractory 
metastatic CRPC as compared to prednisone and placebo. 10,11 The benefit was consistent 
irrespective of number of prior chemotherapies (1 vs. 2).  This led the FDA to approve 
abiraterone and confirmed the biologic observation on the continued androgen sensitivity of 
mCRPC.  
 
While significant survival improvement is seen with abiraterone, the effect is relatively modest 
(4 months). The latter coupled with a confirmed PSA response rate of 29% suggests that a 
significant percentage of patients may not be benefiting or have minor benefits from such 
therapy; hence the need for a potential predictive biomarker to personalize therapy and improve 
the therapeutic efficacy of abiraterone-based therapy. 
 
2.2 
 The Role of ETS Gene Fusions in Prostate Cancer 
 
Several years ago, our research team discovered the presence of ETS gene fusions in prostate 
cancers. These gene rearrangements typically involve the fusion of the promoter of an androgen-
responsive gene, such as TMPRSS2, to a gene encoding an ETS transcription factor.12,13  They 
appear to be present in approximately 50%-60% of all prostate cancers, including metastases, 
making them the most common genetic translocations associated with any solid malignancy.12-14 
These fusions typically result in the androgen-driven overexpression of ETS transcription factors, 
such as ERG or ETV1.14   
 
The predominant ETS fusion, TMPRSS2: ERG, results in a 20-120 fold overexpression of ERG, 
with a relatively sharp demarcation in expression levels between prostate cancers containing 
versus lacking the fusion (Fig. 1).  As comparison, EGFR, another commonly investigated 
biomarker, is overexpressed only 3-10 fold across all prostate cancers, with no clear demarcation 
between negative versus positive cases.  Prostate cancer cells are addicted to ETS fusions in 
preclinical models, meaning that knockdown of the specific oncogene results in abrogation of the 
malignant phenotype and overexpression of the oncogene reconstitutes the malignant features14-


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17. These alterations are dominant oncogenes, as reflected by their mutual exclusivity.  
Specifically, ETS fusions are found in approximately 50%-60% (including metastases) of all 
prostate cancers, respectively with no overlap between subtypes.12-14 Finally, and possibly most 
importantly, prostate cancer subtypes determined by ETS fusions are reproducible across 
multiple cohorts from different institutions. 14,15,18-21 
 
Once an ETS gene fusion is formed through genomic rearrangement, the subsequent 
overexpression of an ETS gene fusion protein can contribute to cancer progression through 
several different mechanisms. For example, we and others have demonstrated that TMPRSS2-
ERG gene fusion expression is required for cell growth in cell line models that harbor an 
endogenous gene fusion both in vitro and in vivo; knockdown of the ETS protein ablates the 
ability of these cells to form tumors.15,22-24  Likewise, ETS proteins are active transcription 
factors that drive cellular invasion through the induction of a transcriptional program highly 
enriched for invasion-associated genes 15,22,24-26 as reflected by the distinct gene expression 
signature seen in ETS fusion-positive cancers.27 Genetically-engineered mice expressing ERG or 
ETV1 under androgen regulation exhibit prostate intraepithelial neoplasia (PIN)-like 
lesions.13,15,26,28-30  Clinically, ERG-positive high-grade PIN is frequently found in close 
proximity with ERG-rearranged cancers. 31,32  This data suggests that ETS gene fusions are an 
early driving event in prostate carcinogenesis.  Additionally, high levels of ERG and ETV1 gene 
expression continue to be maintained in advanced or metastatic disease.14  In fact, one recent 
study has suggested that metastases may be relatively enriched for ERG positivity; the authors 
found that in a cohort of prostate cancer patients with multifocal disease containing both ERG- 
positive and ERG-negative foci, the positive foci have a greater predilection for metastases.33  
Figure 1: Relative levels of ERG and EGFR expression across a wide range of prostate cancer samples The 
predominant ETS fusion, TMPRSS2:ERG, results in a 20-120 fold level of ERG overexpression, with a relatively sharp 
demarcation in expression levels between prostate cancers containing versus lacking the fusion (1A).  As comparison, 
EGFR, another commonly investigated biomarker, is overexpressed only 3-10 fold across all prostate cancers, with no clear 
demarcation between negative versus positive cases (1B).   Note: This cohort was purposely enriched for ETS fusion-
negative prostate cancer cases (as a discovery set for non-ETS molecular subtypes).  In a population-based cohort of 
prostate cancer, the frequency of ETS fusions would be expected to be around 50%. 


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Together, this data suggests that ETS fusions are addicting oncogenes which contribute to both 
carcinogenesis and progression, and therefore represent a promising target for oncologic therapy 
in prostate cancer.  
 
2.2.1 Rationale for Targeting ETS Fusion-Positive Prostate Cancers with    
Abiraterone Based Therapy  
 
The fact that ETS gene fusions are predominantly driven by an androgen-sensitive promoter, 
14,16,34,35 coupled with the continued sensitivity of mCRPC to androgen signaling, provides a 
strong rationale to selectively target mCRPC that harbor such fusions with anti-androgen 
approaches.  
 
Emerging clinical data provide additional support for this approach. In 150 radical 
prostatectomy patients, the response to adjuvant androgen deprivation therapy was associated 
with ERG status, showing more significant treatment effect in ERG(+) patients.36  In phase 
I/II studies of mCRPC patients treated with abiraterone, the presence of the predominant ETS 
fusion, the TMPRSS2:ERG rearrangement, has been demonstrated to correlate with PSA 
response.  Specifically, Attard et al. found that 32 of 77 (41%) of men with CRPC had ERG 
rearrangements that could be detected in circulating tumor cells (CTCs) prior to treatment; 
7,37 12 of the 32 patients (38%) with ERG-fusion-positive CTCs had a >90% decline in PSA 
level with abiraterone, compared to 3 of 45 patients (7%) with ERG-fusion-negative CTCs.  
In this cohort, a decline in PSA level was associated with decreased CTCs and an increased 
survival rate.   
 
These findings suggest that Abiraterone may have greater therapeutic effect in ETS-fusion 
positive prostate cancer.   
 
2.2.2  Rationale for Combining Abiraterone and ABT-888   
 
A.  The role of Poly(ADP-ribose)-Polymerase 1 (PARP1) in Prostate Cancer 
 
• 
Preliminary observations indicate that castration-resistant tumor cells exhibit 
increased PARP1 activity. 38 
• 
PARP1 function is critical to the pro-tumorigenic functions of the androgen 
receptor (AR): Specifically, new data strongly support the use of ABT-888 as a 
means to antagonize PARP1-dependent AR function in prostate cancer cells, 
especially in tumor models with intrinsically high AR activity or which have 
achieved castration resistance.  Preclinical findings in a number of models 
demonstrate that: i) PARP1 positively regulates AR activity; ii) ABT-888 inhibits 
expression of  AR target genes that are of clinical importance (such as PSA and 
TMPRSS2);  iii) cells with genetic deletion of PARP1 do not support AR 
function;  and iv) ABT-888 markedly represses AR-dependent cellular 
proliferation  in CRPC cells (including those that are ETS fusion negative).38   
• 
Since AR-mediated transcription is directly coupled with the induction of 
DNA damage,39,40 it is proposed that in metastatic prostate cancer, a combination 


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approach of hormone-directed therapy with inhibitors of DNA repair (such as 
PARP inhibitors) "could overwhelm cancer cells with transcription-associated 
double-strand breaks" and should therefore be used as a therapeutic strategy. 41  
• 
Additionally, published data from the Knudsen and Feng labs (Fig. 2) confirm 
that the addition of the PARP inhibitor ABT888 improves the response to 
hormone therapy in preclinical prostate cancer models.38 
• 
Preclinical data from the Chinnaiyan lab (unpublished) has suggested that a 
short lead-in period of PARP1 inhibition prior to androgen deprivation therapy 
may modestly improve xenograft control compared to initiation of both therapies 
at the same time.  While the efficacy of abiraterone cannot be well-assessed in 
preclinical models, we hypothesize that a short lead-in period of PARP1 
inhibition, prior to initiation of abiraterone within the relevant treatment arms of 
this trial, may also confer a benefit.  Therefore, the abiraterone + ABT-888 arms 
of this trial are designed with a short lead-in period of PARP1 inhibition with 
ABT-888.  
 
 
 
Fig. 2 
 
B. The Interaction of ERG and PARP1 in Prostate Cancer 
 
We recently discovered that, in both preclinical prostate cancer models and clinical 
prostate cancer specimens, ETS transcription factors, such as ERG, physically interact 
with poly(ADP-ribose) polymerase-1 (PARP1), a key nuclear enzyme that regulates 
transcription and facilitates DNA repair through the base excision repair pathway. 42 In 
addition, we found that PARP1 is required for the malignant phenotype conferred by ETS 
transcription factors, including ETS-mediated invasion, transcription, and metastasis. 42 
Most significantly, we found that PARP1 activity is required to drive the metastatic 


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spread of ETS positive cells.  In preclinical models, PARP1 inhibition blocked the 
formation of liver metastases in an ETS-positive cell line but not an ETS-negative cell 
line.  Moreover, using 8 different prostate cancer xenograft models (4 positive for ETS 
fusions, 4 negative for ETS fusions), PARP1 inhibition had a much more significant 
effect on xenograft growth in all of the ETS fusion-positive xenografts compared to the 
ETS fusion-negative xenografts.  (Fig. 3) 
 
 
 
Fig. 3 
 
 
Taken together, this data suggests that ETS-mediated oncogenic features, such as  
metastasis and tumor growth, depend on PARP1, and that inhibition of PARP1 can 
inhibit these phenotypes and specifically target ETS- positive prostate cancers.   
 
 
 
2.3  
ABT-888 (Veliparib) 
 
ABT-888 is an orally available, small molecule inhibitor of poly(ADP-ribose) polymerase 
(PARP).  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 sensitizing agents 
for chemotherapy and radiation therapy that are designed to cause DNA damage. 
 
 
 
 


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Mechanism of Action 
 
Poly (ADP-ribosylation) (PAR) occurs after single or double-stranded DNA damage and 
represents the posttranslational modification of histones and other nuclear proteins by PARP.  
Based on conserved genetic sequences, encoded for by 18 different genes, 18 nuclear proteins 
have been classified as members of the PARP superfamily. The superfamily is further subdivided 
into three branches, the PARP-1 group, the tankyrase group, and other PARP enzymes.  The 
PARP-1 group of NAD+-dependent enzymes has been extensively studied, and its members 
PARP-1 and PARP-2 are generally considered as the primary enzymes involved in DNA repair. 
43 
 
PAR has been implicated in many cellular processes including replication, transcription, 
differentiation, gene regulation, protein degradation, and spindle maintenance.  Enhanced 
PARP-1 expression and/or activity in tumor cells, as compared to normal cells, has been 
demonstrated in malignant lymphomas ,44 hepatocellular carcinoma, 45 cervical carcinoma, 46 
colorectal carcinoma, 47 non-Hodgkin's lymphoma, 48 leukemic lymphocytes, 49 and colon 
adenomatous polyps.50  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.51-53  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. 54-56 
 
The zinc finger domain of PARP binds to both single- and double-stranded DNA breaks, 
resulting in increased catalytic activity. 54,56,57  Once activated, PARP cleaves NAD+ and attaches 
multiple ADP-ribose units to the target nuclear protein. This results in a highly negative charge 
on the target protein and affects its function.  Overactivation of PARP can be induced by DNA 
damage, leading to the depletion of NAD+ and energy stores and, thus, cellular demise by 
necrosis.  An alternate mechanism has been identified where PARP overactivation can induce 
cell death through apoptosis by releasing the Apoptosis Inducing Factor (AIF) from 
mitochondria.58 Consequently, multiple mechanisms to prevent overactivation of PARP exist.  
First, auto-PAR negatively regulates PARP activity. 59  In addition, the cleavage of PARP by 
caspases yields a peptide fragment that acts as a trans-dominant negative inhibitor for uncleaved 
PARP.  PAR of proteins is a dynamic process with a short half-life (t1/2) of <1 min.  The 
enzymes responsible for degrading these polymers are poly(ADP-ribose) glycohydrolase 
(PARG), which cleaves ribose-ribose bonds, and ADP-ribosyl protein lyase, which removes the 
protein proximal to the ADP-ribose monomer. 
 
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.56,60 Therefore, inhibition of PARP 
sensitizes tumor cells to cytotoxic agents (e.g. alkylators [temozolomide, cyclophosphamide, 
BCNU] and topoisomerase I inhibitors [irinotecan, camptothecin, topotecan]) which induce 


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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.   
 
Ionizing radiation induces both double- and single-stranded DNA breaks.  While part of the 
radiosensitization caused by PARP inhibition is through the inhibition of the single-stranded 
break repair pathways, it appears likely that repair of double-stranded breaks, which are thought 
to be more cytotoxic, is also affected.  Double-stranded breaks are strong activators of PARP-1, 
resulting in PARP-1 mediated activation of DNA-PK and Ku80, important components of the 
non-homologous end-joining (NHEJ) double-stranded break repair pathway. 61,62  Also, small 
molecule inhibitors of PARP can directly inhibit the repair of double-stranded breaks. 51,63 Thus, 
it is likely that PARP activity is important for repair of both the single- and double-stranded 
stranded DNA breaks caused by ionizing radiation and other agents. 
 
Nonclinical Activity 
 
In vitro, ABT-888 inhibited PARP-1 and PARP-2 with Ki values of 3.6 nM and 2.9 nM, 
respectively.  These values were observed in enzyme assays measuring the incorporation of [3H]-
NAD+ into histone H1, an important physiological substrate of PARP.  In assays measuring 
inhibition of H2O2-induced poly(ADP-ribosyl)ation in C-41 cervical carcinoma cells, ABT-888 
inhibited PARP with an EC50 value of 2.4 nM.  The extent of DNA damage in cells was 
indicated by γ-H2AX levels.  To determine the effect of ABT-888 in combination with cytotoxic 
agents on DNA damage, the cellular content of γ-H2AX in C-41 cells was assayed by flow 
cytometry using an anti-γ-H2AX antibody.  Addition of 1 mM of temozolomide alone resulted in 
increased numbers of γ-H2AX foci, a result which was further potentiated by ABT-888 in a 
dose-dependent manner.  When cell survival was measured by an AlamarBlue assay, ABT-888 
potentiated cytotoxicity in the same concentration range as used in the γ-H2AX assay, 
demonstrating that ABT-888 potentiates cytotoxicity of temozolomide by delaying DNA repair.  
ABT-888 achieved a maximal potentiation of approximately 15-fold.  ABT-888 also potentiates 
the DNA damage cause by irinotecan. 
 
The combination of PARP inhibitors with different classes of chemotherapeutics was examined.  
Cisplatin-induced potentiation was observed in a long-term clonogenic assay, but not in the 
short-term cytotoxicity assay.  The potentiation of cisplatin by ABT-888 in vitro is consistent 
with the potent enhancement of the efficacy of platinum agents (cisplatin and carboplatin) 
observed in vivo. PARP inhibition was shown to sensitize cells that are mismatch repair (MMR)-
deficient to a greater extent than cells that are MMR competent. 64  Alkylating agents such as 
temozolomide form methyl adducts in DNA and resistance is frequently encountered in the clinic 
with either the overexpression of O6-alkylguanine DNA alkyltransferase (AGT) or functional 
defects in the MMR system.  However, when PARP was inhibited, cells were sensitized to 
methylpurine formation, regardless of their resistance factors. 65 
 
There are data to suggest that PARP inhibitors have activity against some BRCA-deficient cells 
in the absence of any DNA damaging agent. 66,67  These inhibitors did not demonstrate single 
agent activity in BRCA-competent cells, and restoring functional BRCA to deficient cells 


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abrogated single agent cytotoxicity.  It is possible that, in BRCA-deficient cells, PARP inhibition 
stops the BER pathway, and thus single-stranded breaks are carried through DNA synthesis, 
resulting in double-stranded breaks.  The increase in double-stranded breaks cannot be repaired 
by homologous recombination (HR), due to the lack of BRCA1 or 2, resulting in increased cell 
death.  However, since not all BRCA deficient cells are sensitive to the PARP inhibitors, it is 
unclear why single agent cytotoxicity is observed in some BRCA-deficient cells. 
 
Consistent with PARP-1 being a radiosensitization target, PARP-1 knockout mice showed 
enhanced sensitivity to γ-radiation. 68,69  There is evidence to suggest that PARP inhibitors 
sensitize cancer cells to radiation, both in vitro and in vivo. 70-72 Furthermore, a PARP inhibitor 
in the same class as ABT-888 potentiated radiation in the HCT116 colon carcinoma model.  
ABT-888 was tested, in combination with cytotoxic agents, in several tumor models and 
demonstrated a similar profile of antitumor activity to that seen in the literature (See table 
below).  ABT-888 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) 
Glioblastom
a muliforme 
(rat 9L) 
B 
cell 
lymphoma 
(human 
DOHH2) 
Melanoma 
(murine 
B16F10) 
Carboplatin 
Yes 
 
 
 
Cisplatin 
Yes 
 
No 
 
Cyclophosphami
de 
Yes 
 
 
 
Irinotecan 
 
 
 
Yes 
Temozolomide 
 
Yes 
 
Yes 
 
ABT-888 potentiated cytotoxic therapy when administered either parenterally or orally (PO).  
When administered parenterally, significant efficacy was observed at doses as low as 1 
mg/kg/day, and maximal efficacy was achieved at approximately 12.5 mg/kg/day.  3.1 mg/kg/day 
PO (divided, twice daily) provided significant potentiation, with maximal potentiation achieved 
at approximately 25 mg/kg/day.  No increased toxicity was observed at any of these ABT-888 
doses, either parenteral or PO. Supratherapeutic doses of ABT-888 (50 mg/kg/day), administered 
via osmotic minipump (OMP), resulted in skin toxicity at the pump implantation site.  The 
observation that supratherapeutic doses of PARP inhibitors may potentiate toxicity is consistent 
with preclinical and clinical observations.  It is also consistent with the results from a two-week 
ABT-888/cisplatin combination study.  When administered as a continuous infusion, an ABT-
888 Css (plasma concentration at steady-state) of 70 ng/mL was maximally efficacious (area 
under the curve [AUC]=1.7 µg•hr/mL).  Comparable efficacy was seen in oral studies at a 25 
mg/kg/day (divided, twice daily) dose that yielded AUCs between 1.6 and 3.0 µg•hr/mL.  At this 
dose, the plasma concentrations were above 70 ng/mL for only 2-4 hours per dose, demonstrating 
that 24 hour/day coverage above 70 ng/mL was not required for efficacy. 
 


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An enzyme-linked immunosorbent assay (ELISA) that can measure PAR formation was used to 
demonstrate PARP inhibition in murine tumors in vivo and human peripheral blood mononuclear 
cells (PBMCs) ex vivo at clinically relevant doses.  This ELISA was used as the primary assay for 
PARP biomarker analysis.  The degree of PARP inhibition was assessed in B16F10 syngeneic 
flank tumors from mice treated in vivo using tumor efficacy schedules.  In this study, PAR 
formation was measured in tumors treated with ABT-888 alone.  Two hours after administration, 
ABT-888 inhibited PAR formation in B16F10 tumors in a dose-dependent manner. The same 
response was reflected in a parallel efficacy experiment, where temozolomide (50 mg/kg/day, 
PO, daily × 5) was administered with ABT-888.  In another study, PAR formation was measured 
in tumors treated simultaneously with temozolomide and ABT-888.  As in the ABT-888 only 
study, tumor PAR levels in the combination study were also inhibited.  Inhibition of PARP 
activity was significant at 12.5, 5 and 1 mg/kg/day in both the vehicle and temozolomide treated 
groups.  Overall, these results indicate the ability of ABT-888 to inhibit both baseline and 
cytotoxic-induced PARP activity in tumors treated in vivo and provide evidence of the ability of 
ABT-888 to target PARP in vivo. 
 
Nonclinical Pharmacology and Toxicology 
 
The pharmacokinetics (PK) of ABT-888 was evaluated in CD-1 mice, Sprague-Dawley rats, 
beagle dogs and cynomolgus monkeys.  The non-clinical PK profile of ABT-888 was 
characterized by high plasma clearance (CL) values, ranging from a high of 4.1 L/hr•kg in the 
mouse to a low of 0.57 L/hr•kg in the dog.  ABT-888 exhibits moderate volumes of distribution 
(Vss) in all species (Vss > 2.0 L/kg), with terminal elimination t1/2 in the 1.2-2.7 hr range.  In rats 
and dogs, [3H]ABT-888 was rapidly absorbed and cleared primarily in the urine as intact parent 
drug.  A-925088 (M8), a lactam derivative and the major product of ABT-888 metabolism, was 
also cleared primarily in the urine.  In both rats and dogs, parent drug was the major component 
in systemic circulation, followed by M8.  Elimination of total radioactivity was rapid, with most 
(>80%) of the dose recovered within 24 hours post-dose, indicating that parent drug and the 
major metabolites are not likely to accumulate.  Bioavailability following an oral dose was high 
(F>50%) in all species, with values ranging from a low of 56.1% in the monkey to a high of 
92.0% in the mouse, and low animal-to-animal variability across all species. 
 
The bioavailability from a non-formulated capsule was only slightly lower than from the solution 
formulation with values of 59.7% and 65.5% in fasted and non-fasted dogs, respectively.  This 
suggests that there are no major food effects.  The compound has high solubility at physiological 
pH and high permeability.  Protein binding values in plasma (assessed in vitro as % bound at 5 
µM) for ABT-888 were moderate in all species averaging 42% in dog, 41% in monkey, 43% in 
mouse, 49% in rat and 51% in human.  The stability of ABT-888 was evaluated in rat, dog, 
monkey and human plasma and the drug was found to be very stable, with minimal degradation 
over the 8-hour incubation interval.  In vitro metabolism studies indicated that several CYPs 
(1A1, 1A2, 2C9 and 2C19) have the potential to mediate the formation of M8.  However, ABT-
888 is not a potent inhibitor of the major human CYPs in vitro, indicating a low risk for drug-
drug interactions at the anticipated therapeutic concentrations.  ABT-888 partitioned slowly into 
and out of the brain, in both mouse and rat, with high plasma to brain ratios (~3:1) during the 


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first 3-6 hours after dosing.  The plasma to brain ratios approached 1:1 in samples obtained 12 
hours after dosing. 
 
PK parameters in humans were estimated by a variety of methods.  The oral clearance (CL/F) of 
ABT-888 was estimated as a function of the projected clearance after IV administration (CL) and 
the fraction of the dose systemically available after oral administration (F).  Clearance 
predictions were based on allometric scaling.  Bioavailability was estimated by simulations with 
sensitivity analyses using software which took into account human gastrointestinal physiology 
and the drug’s physicochemical characteristics. Vss was estimated either from an average of 
values observed in animal species, a method averaging the fraction unbound in animal tissues, or 
by allometric scaling.  Terminal phase t1/2 values were estimated either by regression 
relationships between animal and human t1/2 values 73, or from the estimates of CL and Vss.  The 
human PK profile is projected to have CL=26 L/hr, with oral bioavailability of ~ 70%.  The 
predicted human t1/2 of ABT-888 is ~4 hrs.  Simulations of 50 mg twice daily dosing in humans 
mimic a maximally efficacious dosing regimen in mouse (12.5 mg/kg, twice daily), with 
concentrations above 71 ng/mL for 8 of 24 hours and an AUC24 of 3 µg•hr/mL at steady state. 
ABT-888 was tested in receptor-binding, CNS/neurobehavioral, cardiovascular, cardiac 
electrophysiological and gastrointestinal assays.  In 74 receptor-binding assays at a concentration 
of 10 µM (2.4 µg/mL), ABT-888 displaced control-specific binding at the human H1 (61%), the 
human 5-HT1A (91%), and the human 5-HT7 (84%) sites only, with IC50 values of 1.2-5.3 µM. 
 
ABT-888 did not display clear adverse CNS effects in the rat and mouse between 3-30 mg/kg 
PO.  At 100 mg/kg PO, mild sedation-like effects were observed, followed in time by mild 
excitation.  At 300 mg/kg PO, more moderate to marked CNS effects were observed, including 
abnormal gait and sedation.  Further, at 100 mg/kg, PO, there was an increased incidence of 
death after electrically-induced tonic convulsions in mice.  Death was also noted in a second 
convulsant model (audiogenic seizures in mice).  In a repeated dosing mini-Irwin observational 
test, in which rats were dosed with ABT-888 at 30, 100, and 300 mg/kg intraperitoneally (IP) 
every day for 5 days, tonic-clonic seizures/death were observed in approximately 50% of the 
animals treated at the highest dose on day 1.  A similar incidence of seizures was observed after 
dosing the remaining animals at the same dose on each of the subsequent days.  In an acute 
follow-up study with rats dosed with ABT-888 300 mg/kg IP, protection against seizures was not 
provided by pretreatment with either valproic acid (300 mg/kg IP, 15 min prior to ABT-888) or 
diphenylhydantoin (75 mg/kg IP, 100 min prior to ABT-888).  In a 2-week toxicology study, 
seizures were also noted in dogs treated with ABT-888 at either 60 mg/kg/day, 30 mg/kg twice 
daily, or 30 mg/kg every day.  Plasma concentrations in dogs with seizures were in excess of 5.4 
µg/mL (26-fold the predicted clinical Cmax of 0.21 µg/mL). 
In the anesthetized dog, ABT-888 produced no physiologically relevant changes in mean arterial 
pressure, heart rate, dP/dtmax, pulmonary arterial pressure, or systemic or pulmonary vascular 
resistance compared to vehicle controls at mean plasma concentrations as high as 4.45 ± 0.13 
µg/mL (21-fold the predicted clinical Cmax of 0.21 µg/mL).  As mean plasma concentrations 
increased to 12.96 ± 0.92 µg/mL (62-fold), ABT-888 produced a modest reduction in mean 
arterial pressure (–16 ± 5% below baseline) and systemic vascular resistance (–10 ± 7% below 
baseline). 
 


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ABT-888 blocked hERG current with an IC50 value of 57.6 ± 1.7 µg/mL (236 ± 7 µM), a value 
278-fold higher than the predicted clinical Cmax.  The M8 metabolite of ABT-888 (A-925088) 
minimally affected hERG at the highest concentration tested (81.5 µg/mL).  While no effect on 
repolarization (in vitro action potential duration measures) was noted at the lowest measured 
concentration of ABT-888 (0.42 µg/mL, 2-fold higher than the predicted clinical Cmax), ABT-
888 prolonged the action potential duration at the intermediate and highest measured 
concentrations (4.8% and 18.6% prolongation at 4.22 ± 0.02 and 39.49 ± 0.70 µg/mL 
respectively), suggesting delayed repolarization risk between 20- and 190-times the Cmax.  There 
was a trend (7%) towards delayed repolarization in the anesthetized dog model (QTc intervals) at 
plasma concentrations 21-fold higher than the predicted clinical Cmax; greater concentrations 
elicited prolongation (15 ± 3% above baseline [QTcV] at 12.96 ± 0.92 µg/mL).  In humans, QTc 
prolongation is predicted to be less than 3 msec at the anticipated dose of 50 mg twice daily.  
These cardiac effects need to be monitored during clinical trials. 
 
Gavage administration of ABT-888 up to 10 mg/kg was generally well tolerated in the ferret 
emesis model.  No emesis was noted at this dose (resulting in mean plasma concentrations of 
3.80 ± 0.11 µg/mL, a value 18-fold greater than the predicted Cmax), with significant emesis 
noted in response to the 20 mg/kg dose (resulting in mean plasma concentrations of 6.61 ± 0.26 
µg/mL, a value 31-fold greater than predicted Cmax).  Parenteral (subcutaneous) dosing of ABT-
888 at doses and plasma concentrations similar to those used in the gavage study revealed a 
similar emetic dose-response relationship, suggesting a centrally-mediated emetic response.  
ABT-888 had no significant effect on gastrointestinal transit up to 100 mg/kg (resulting in a 
mean plasma concentration of 1.63 ± 0.14 µg/mL, a value 7-fold greater than the predicted 
clinical Cmax). 
 
ABT-888 dihydrochloride was evaluated in repeated dose toxicity studies in rats and dogs.  
When administered as a sole agent to rats, the compound did not result in adverse effects at Cmax 
values that were greater than 19-fold the estimated therapeutic peak plasma drug concentration 
(highest dose tested).  When rats were administered ABT-888 dihydrochloride in conjunction 
with a cytotoxic agent (cisplatin), no clinically meaningful exacerbations of cisplatin-associated 
toxicity were apparent at Cmax values that were up to 8-fold greater for ABT-888 than the 
estimated therapeutic value.  Exacerbation of cisplatin-associated toxicity was limited to rats that 
received ABT-888 dihydrochloride in conjunction with cisplatin at the highest dose that yielded 
Cmax values 22-fold greater than the estimated therapeutic peak plasma drug concentration.  In 
dogs, emesis, body weight losses related to anorexia, and convulsions were observed at doses of 
30 mg base/kg/day with Cmax values 26-fold greater than the estimated therapeutic peak plasma 
concentration.  ABT-888 dihydrochloride was found to be negative in vitro for both mutagenicity 
and clastogenicity. 
 
The non-toxic dose observed in the most sensitive mammalian species (beagle dogs) was 300 
mg/m2.  Emesis and QT prolongation were observed in animal models, at 31-fold and 21-fold 
higher concentrations than the predicted clinical Cmax (0.21 μg/mL), respectively.  Based on 
different sensitivities to seizures between rodents and dogs, the plasma concentration that would 
be associated clinically with pro-convulsant activity will be difficult to define. 
 


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Clinical Investigations 
 
A single-dose pharmacokinetic and pharmacodynamic endpoint study in cancer patients was 
initiated under an exploratory IND by the National Cancer Institute as the initial study in their 
phase 0 program (Kummar et al., 2009).  In this study, participants had baseline assessments of 
PAR in peripheral blood mononuclear cells (PBMCs) and at higher dose levels, in tumor from 
needle biopsies, assessed by a validated immunoassay.  Participants received a single dose of 
ABT-888 at 10, 25, or 50 mg.  PBMCs were collected over a 24 hour period at all dose levels, 
and tumor biopsies were obtained at the 25 mg dose level, approximately 3 to 6 hours after 
administration of ABT-888. A total of 6 patients have been studied so far, 3 each for the 10 mg 
and 25 mg cohorts. No treatment related adverse events have been observed. The target plasma 
Cmax of 210 nM was exceeded in 2 of 3 patients at the 10 mg dose level, and in all three patients 
for at least 4 hours at the 25 mg dose level.  Levels of PAR were reduced 80-99% from baseline 
levels after administration of ABT-888 in both the PBMCs and tumor samples at the 25 mg dose 
level. Thus, there is reason to believe that target inhibition is seen at least at the 25 mg dose 
level, and may be occurring at doses lower than 25 mg. 
 
Currently, several combination phase I trials are underway.  Also, a single agent trial had been 
initiated in the BRCA-deficient population. 


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2.4  
Abiraterone Acetate 
 
Abiraterone acetate and its metabolite abiraterone are potent and selective inhibitors of CYP17 
α-hydrxylase and C17,20–lyase activites, both essential steps in androgen biosynthesis.74  In the 
two Phase III studies, COU-AA-301 and COU-AA-302, subjects have been exposed to 
abiraterone acetate and placebo in a 2:1 ratio, and 1:1 ratio, respectively. 10,11,75  Overall, 
abiraterone acetate has been very well tolerated with no dose limiting toxicity observed in several 
trials treating patients with up to 2,000 mg daily. Some evidence of secondary mineralocorticoid 
excess (hypertension, hypokalemia and edema) has been observed in the initial studies; it is now 
recommended that abiraterone acetate be given with a low dose of glucocorticoid such as 
prednisone 5 mg PO twice daily to abrogate these symptoms, while others have advocated the 
use of a mineralocorticoid receptor antagonist. 74,76    Based on the PK profile and the overall 
toxicity pattern, the recommended Phase II testing dose of abiraterone acetate was 1,000 mg 
daily and this regimen in combination with prednisone of 5 mg twice a day was tested in the 
Phase III trials.  
Several trials involving mCRPC have been recently reported.77  COU-301 randomized mCRPC 
patients with prior docetaxel therapy in a 2:1 ratio to abiraterone + prednisone vs placebo + 
prednisone. 1,195 men were enrolled and treated. There was a statistically significant 
improvement in median overall survival (14.8 versus 10.9 months) favoring the abiraterone arm 
(p<0.001). There was also improvement in the time to PSA progression, progression-free 
survival and PSA response rate in the abiraterone acetate treatment arm. 11   Abiraterone with 
prednisone was approved by the FDA in April 2011 for use in mCRPC following docetaxel. The 
most common adverse events, which were associated with increased mineralocorticoid levels, 
included hypokalemia, fluid retention, and hypertension; these events were largely abrogated by 
coadministering low-dose glucocorticoids.11  
Recently this agent also received FDA approval for use in patients with mCRPC and no prior 
chemotherapy based on improvement in progression-free survival. 78 
 
2.5  
Rationale for Combination Abiraterone and ABT-888 Therapy Irrespective of 
ETS Gene Fusions Status  
 
This biomarker stratified and randomized phase II trial will evaluate the role of ETS gene fusion 
as a predictive biomarker for response to hormone therapy alone or hormone therapy plus PARP-
1 targeted therapy in patients with mCRPC.  The study will also evaluate whether the addition of 
PARP-1 targeted therapy is superior to hormone therapy based on gene fusion status. The 
scientific rational for this study is supported by: 
1. 
Abiraterone is FDA approved based on prolonging survival in patients with mCRPC 
post docetaxel and progression free survival in patients with no prior docetaxel therapy; 
however the effect is modest and not all patients benefit.    
2. 
ETS gene fusions are predominantly driven by an androgen-sensitive promoter. Data 
from radical prostatectomy series suggest that ETS fusion status predicts for response to 
adjuvant androgen deprivation therapy36 and preliminary data from phase I/II studies of 


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mCRPC patients suggest that abiraterone may have greater therapeutic effect in ETS-
fusion positive prostate cancer patients. 7,37 
3. 
There is interaction of PARP1 with the androgen signaling cascade, regardless of 
ETS fusion status and with ETS fusions; our data indicate that ERG-positive xenografts 
are preferentially sensitive to PARP-1 inhibitors. 
4. 
ABT-888 has been demonstrated to have efficacy across a wide range of tumor types 
in preclinical studies.79 ABT-888 has been demonstrated to inhibit PARP1 in a clinical 
phase 0 study, and is currently being assessed as a component of combination therapy 
across a range of tumor types clinically, including breast, liver, and ovarian cancer, as 
well as an unselected metastatic prostate cancer population.   We have conducted in 
collaboration with Abbott a clinical trial with ABT-888: M11-070 Protocol A Pilot Study 
Combining ABT-888 (an Oral PARP Inhibitor) + Temozolomide in Patients with 
Metastatic Castration Resistant Prostate Cancer Who Have Failed Up to Two Non-
hormonal Systemic Therapies.  The interim data suggests its feasible to administer ABT-
888 in combination and that there is a signal of clinical activity.    
 
2.6  
Correlative Studies Background 
 
2.6.1 
The Role of ETS Gene Fusions (in Metastases) as a Predictive Biomarker 
for Response to Abiraterone, Alone or in Combination with the PARP1 
Inhibitor ABT-888, in Patients with Metastatic Castration-Resistant Prostate 
Cancer (CRPC) (Primary Objective #1) 
 
2.6.2 
The Role of ETS Gene Fusions (in Metastases) as a Predictive Biomarker 
for Treatment Benefit for the Addition of ABT-888 to Abiraterone 
(Primary Objective #2) 
 
Correlative Studies 2.6.1 and 2.6.2 represent the primary objectives of this 
biomarker-based translational clinical trial--to determine whether ETS fusion status 
predicts for outcome following abiraterone alone and abiraterone in combination with 
ABT-888, and to determine whether ETS fusion status predicts which patients will 
specifically benefit from the addition of ABT-888 to abiraterone.  The background 
and rationale for these two correlative studies have been described in section 2.2. 
 
2.6.3 Concordance in ETS Fusion Status among Primary Tumor, Metastases, 
and Circulating Tumor Cells in Patients  
 
The concordance of ETS fusion status among primary tumors, metastases and 
circulating tumor cells (CTCs) is not well known at this time. In one limited study 
conducted at the time of autopsy, there was complete concordance among samples 
from metastases and primary tumor from 10 patients in which both these samples 
were available at the time of autopsy (5 ETS-positive, 5 ETS-negative)80 and from 11 
similar patients on a second study (5 ETS-positive, 6 ETS-negative).37,81 However, 
the concordance between metastases and primary tumor is unknown in the context of 
multifocal primary disease in the prostate.  As the correct assignment of ETS fusion 


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status in the metastases is critical in this study, as it will dictate assignment to 
treatment arms, ETS fusion status will be assessed in metastatic samples, unless an 
interim analysis planned after accrual of 38 patients to each ETS strata (see Section 
13.1, Interim Analysis Plan) demonstrates sufficient concordance between the 
primary and metastatic samples. 
 
Of note, in the previously mentioned autopsy study, of the 20 patients who had 
multiple metastases from which ETS fusion status could be determined, it was noted 
that all metastases had the same ETS status, and when an ETS rearrangement was 
present in one metastases within a patient, the exact same rearrangement was present 
in all assessable metastases within the same patient, supporting a clonal origin to the 
metastases.80 This finding supports the rationale for biopsying only one metastatic 
site (and not more) in this trial. 
 
The concordance of ETS status between primary tumor and CTCs has also not been 
extensively studied. However, a recent study demonstrated that the concordance of 
ETS status between primary tumor and CTCs was only 65% (concordant in 15 out of 
23 cases).81 The concordance of ETS status between CTCs and metastases has also 
been studied in limited patients, with 100% concordance (7 ETS positive, 4 ETS 
negative).37 Therefore, a secondary correlative objective of this study is to establish 
the concordance among ETS fusion status, in a significantly larger study than any 
previously conducted, among primary tumors, metastases, and CTCs.  If the 
concordance between primary tumor and metastases, or CTCs and metastases, is 
confirmed to be high, then ETS status in the primary tumor or CTCs may serve as a 
surrogate for ETS status in the metastases, on future studies of ETS fusion-directed 
therapy. 
 
To assess ETS fusion status in the circulating tumor cell study, we will utilize a 
platform developed by Epic Sciences for CTC isolation and identification, which has 
previously been described.82-86  This platform allows for analysis of specific 
biomarkers, such as analysis of the status of ERG, in CTCs.  The remainder of the 
CTC studies described below and in this protocol will utilize these same assays.  
 
2.6.4 The Role of ETS Gene Fusions (in Circulating Tumor Cells) as a 
Predictive Biomarker of Response to Abiraterone, Alone or in 
Combination with the PARP1 Inhibitor ABT-888, in Patients with 
Metastatic CRPC 
 
2.6.5 Circulating Tumor Cell Count and Biomarker Status as a Predictive 
Biomarkers of Response to Abiraterone, Alone or in Combination with 
the PARP1 Inhibitor ABT-888, in Patients with Metastatic CRPC 
 
Based on the results of a small study,37 ETS fusion status in CTCs may predict for 
PSA response in mCRPC patients treated with abiraterone based on the results of a 
89 patient phase I/II study, though this association was not found to be statistically 


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significant on a smaller 41 patient study.81  We hypothesize that ETS fusion status in 
CTCs, as well as CTC count, may predict for longer-term PSA responses, and will 
explore this in the larger cohort proposed for this study.  In addition, given the 
previously demonstrated relationships (in preclinical models) between ETS fusions 
and the androgen receptor,14,87 as well as ETS fusions and DNA damage,88 we 
hypothesize that treatment sensitivity to abiraterone +/- a PARP1 inhibitor may also 
correlate to the status of the androgen receptor and markers of DNA damage/repair 
(such as gamma H2aX and RAD51 foci).   
 
2.6.6 The Role of PTEN Loss as a Predictive Biomarker for Response to 
Abiraterone, Alone or in Combination with the PARP1 Inhibitor ABT-
888, in Patients with Metastatic Castration-Resistant Prostate Cancer 
(CRPC)  
 
In addition to ETS fusion status, PTEN loss is a promising predictive biomarker of 
response to abiraterone alone or in combination with PARP1 inhibition.  Specifically, 
preclinical work from Sawyers laboratory in Memorial Sloan Kettering Cancer 
Center demonstrated that, in genetically engineered mouse models of prostate cancer, 
conditional loss of PTEN reduced expression of androgen receptor target genes.89 
Using these models, they further demonstrated that PTEN-loss renders prostate 
cancers less androgen-dependent, and unresponsive to combined androgen 
blockade.89 Additionally, using transcriptomic analyses of 218 primary prostate 
tumors, this group confirmed that prostate cancers with PTEN loss demonstrated 
decreased androgen-receptor transcriptional output.89 Therefore, PTEN loss is a 
promising predictor of resistance to next-generation anti-androgens, such as 
abiraterone. 
Additionally, PTEN deletion has been demonstrated to confer a defect in homologous 
recombination, which can result in synthetic lethality with PARP1 inhibition, 
analogous to BRCA mutations.90,91  Moreover, PTEN deletion has been demonstrated 
to confer sensitivity to PARP1 inhibition in multiple preclinical cancer models.90,92 
Thus, PTEN loss may also predict response to PARP1 inhibition.  Based on a recent 
abstract demonstrating extremely high concordance between PTEN status in the 
CTCs and the metastases from a limited number of patients, we will assess for PTEN 
loss, by FISH, in both CTCs and metastases. 93 
 
2.6.7 The Role of PARP1 Activity (in Metastases) as a Predictive Biomarker for 
Response to Abiraterone, Alone or in Combination with the PARP1 
Inhibitor ABT-888, in Patients with Metastatic Castration-Resistant 
Prostate Cancer (CRPC) 
 
Similar to PTEN deletion, increased PARP1 activity may predict resistance to 
abiraterone and sensitivity to ABT-888.  Unpublished data from Karen Knudsen at 
Thomas Jefferson University show a correlation between PARP1 activity (as detected 
by PAR levels) and castration resistance in cell line models of prostate cancer.  
Specifically, the androgen-sensitive cell lines VCaP, LAPC4, and LnCAP 


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demonstrated no or low PAR levels, but the androgen-resistant cell lines C42 and 
LnCAP-abl demonstrated increased PAR levels.  This increased PAR levels was 
coincident with heightened, differential AR activity, consistent with castration-
resistance. Therefore, PARP1 activity, as reflected in PAR levels, may be a 
biomarker of resistance to abiraterone.  Conversely, increased PARP1 activity may 
suggest a dependence on the PARP1 pathway for a malignant phenotype, and 
therefore may predict for sensitivity to PARP1 inhibition. 
 
2.6.8 
Discovery of Novel Gene Fusions Through Paired-End Transcriptome 
Sequencing of Metastases 
 
While ETS gene fusions are the most common gene fusions found in prostate cancer, 
there are other gene fusions, such as RAF fusions17 that can also be found. 
Additionally, there are molecular alterations, such as massive overexpression of 
SPINK1, for which the underlying genetic cause has not yet been discovered.94 The 
ETS fusions, RAF fusions, and SPINK1 overexpression are unique molecular events, 
in the sense that, in hundreds of patients analyzed by our group to date, there is no 
overlap between these alterations--they are mutually exclusive.17,94  Thus, there is 
rationale to suggest that they may be unique molecular subtypes of prostate cancer, 
and potentially targetable defining alterations.  The goal of this discovery-based 
correlative aim is to perform next-generation sequencing approaches to identify novel 
targetable gene fusions in prostate cancer management. 
 
2.6.9 
Discovery of novel SNPs Predictive of Response to Abiraterone, Alone or 
in Combination with the PARP1 Inhibitor ABT-888, in Patients with 
Metastatic Castration-Resistant Prostate Cancer (CRPC) 
 
Single nucleotide polymorphisms (SNPs) are single nucleotide base pair changes in 
DNA sequences which occur in at least 1% of the population.95  SNPs can affect gene 
function through multiple mechanisms including: missense mutations causing 
conformational changes in protein structure, nonsense mutations creating aberrant 
stop codons and premature truncation of RNA transcription, and mutations in non-
coding gene regulatory regions causing abnormal gene splicing and transcription. 
Due their high frequency and the availability of high-throughput multiplex SNP array 
platforms, SNPs have been a frequent target of cancer biomarker investigations. 
 
In metastatic prostate cancer patients, SNPs in genes critical to hormone synthesis, 
transport, binding, metabolism, and degradation have been analyzed to identify 
subsets of patients with favorable therapy outcomes.  Specifically, investigators from 
the Dana Farber Cancer Institute have reported an improved time to progression in 
CRPC patients treated with ketoconazole (an older, less potent CYP17-lyase inhibitor 
than abiraterone) in association with a germline SNP in the SLCO1B3 gene, a gene 
involved in steroid transport.96  Similarly, investigators at the Indiana University 
Simon Cancer Center have recently reported an improved overall survival in CRPC 
patients treated with ketoconazole in association with additional germline SNPs 


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involved in hormone pathway genes including: AKR1C3, CYP19A1, CYP11B1, and 
HSD17B4.97  Taken together, these studies provide preliminary evidence that 
common variations in genes critical to hormone synthesis, signaling, and degradation 
may impact clinical efficacy of additional hormonal therapies in CRPC patients.  No 
investigations of SNPs associated with favorable clinical outcomes to abiraterone 
therapy in CRPC patients have been reported.  The goal of this correlative aim will 
be to identify candidate germline SNPs associated with improved clinical outcomes 
to abiraterone therapy in CRPC patients. 
 
2.6.10 The Role of ETS fusion RNA levels (in blood) as Predictive Biomarkers 
for Response to Abiraterone, Alone or in Combination with the PARP1 
Inhibitor ABT-888, in Patients with Metastatic Castration-Resistant 
Prostate Cancer (CRPC) 
 
As described in Section 2.2, ETS gene fusions result in androgen-dependent over-
expression of ETS transcription factors. Messenger RNA (mRNA) levels of the 
predominant ETS fusion, TMPRSS2:ERG (found in 50% of all prostate cancers)  can 
be measured in blood from patients with CRPC.98 The goals of this study will be to 
determine the correlation between TMPRSS2:ERG mRNA levels in the blood and 
TMPRSS2:ERG fusion status in metastatic and primary tumors, and to determine of 
TMPRSS2:ERG levels may predict for therapeutic response to abiraterone +/- ABT-
888 in patients with TMPRSS2:ERG-positive tumors. 
 
 


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3. 
PATIENT SELECTION 
 
In calculating days of tests and measurements, the day a test or measurement is done is 
considered Day 0. Therefore, if a test is done on a Monday, the Monday 4 weeks later would be 
considered Day 28. This allows for efficient patient scheduling without exceeding the guidelines. 
If Day 28, 42, or 56 falls on a weekend or holiday, the limit may be extended to the next working 
day. 
 
3.1  
Eligibility Criteria  
 
At registration all patients must: 
 
3.1.1 Have a histologic or cytologic diagnosis of prostate cancer. 
3.1.2 Have progressive metastatic castration resistant prostate cancer, on androgen 
deprivation therapy, based on at least one of the following criteria:    
a) PSA progression defined as 25% increase over baseline value with an increase in 
the absolute value of at least 2 ng/mL that is confirmed by another PSA level 
with a minimum of a 1 week interval with a minimum PSA of 2 ng/ml. 
 
b) Progression of bidimensionally measurable soft tissue (nodal metastasis) assessed 
within one month prior to registration by a CT scan or MRI of the abdomen and 
pelvis (please refer to section 11.1.2 for definitions of measurable disease). 
 
c) Progression of bone disease (evaluable disease) (new bone lesion(s)) by bone scan. 
(please refer to section 11.1.2 for definitions of evaluable disease).  
 
3.1.3 Agree to undergo a biopsy of at least one metastatic site for gene fusion status 
analysis (Please refer to Appendices C and D for specific procedures).  Adequate 
metastatic tissue from prior biopsy/resection can be used if available in lieu of a 
biopsy.  Patients will only be eligible for protocol therapy if the biopsy has tumor and 
the tissue is evaluable for ETS fusion status.  
3.1.4 ECOG performance status of 0-2.  
3.1.5 Age ≥ 18 years.   
3.1.6 Have testosterone < 50 ng/dL. Patients must continue primary androgen deprivation 
with an LHRH analogue if they have not undergone orchiectomy.   
3.1.7 Patients must discontinue antiandrogen therapy for at least 4 weeks (e.g. flutamide, 
bicalutamide, nilutamide) prior to registration with no evidence of a falling PSA after 


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washout.  Patients on steroids are eligible as long as they will be switched to 
prednisone as outlined in the Treatment Plan, Section 5.  
3.1.8 Have no prior exposure to CYP-17 (other than ketoconazole) or PARP inhibitors for 
prostate cancer. Patients with prior exposure to ketoconazole are eligible.      
3.1.9 Patients with up to 2 prior chemotherapy regimens are eligible. 
3.1.10 Patients must have normal organ and marrow function as defined below obtained 
within 14 days prior to registration: 
WBC 
≥ 3,000/µl 
ANC 
≥ 1,500/µl 
Platelet count 
≥ 100,000/µl 
Serum Creatinine 
≤ 1.5 x the institutional upper limits of 
normal 
or 
corrected 
creatinine clearance of  ≥ 50 
mg/ml/hr/1.73 m2 BSA 
Potassium 
> 3.5 mmol/L 
Bilirubin 
within the institutional limits of normal 
SGOT (AST) 
SGPT (ALT) 
≤ 2 x upper limits of normal 
≤ 2 x upper limits of normal 
                   
                  In addition, patients must have adequate organ and marrow function measured within 28 
days prior to administration of ABT-888 as defined below: 
                   
                    ≥10.0 g/dL Hb with no blood transfusion in the past 28 days 
 
3.1.13 The effects of ABT888 and Abiraterone on the developing human fetus at the 
recommended therapeutic dose are unknown, and may cause fetal harm or loss of 
pregnancy.  Men must agree to use effective contraception during treatment and for at 
least 1 week after the last administration of therapy.   
 
3.1.14 Patients must be able to take oral medication without crushing, dissolving or chewing 
tablets. 
 
3.1.15 Patients may have received prior radiation therapy or surgery. However, at least 21 
days must have elapsed since completion of radiation therapy or surgery and patient 
must have recovered from all side effects at the time of registration.  
 
3.1.16 Ability to understand and the willingness to sign a written informed consent 
document that is approved by the local institutional review board. 
 
3.2  
Exclusion Criteria 
 


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3.2.1 Patients may not be receiving any other investigational agents. Any prior 
investigational products must be stopped at least 14 days (2 week washout) prior to 
registration. 
 
3.2.2 Patients who have had chemotherapy, radiotherapy or oral antifungal agents 
(Ketoconazole, itraconazole, fluconazole) within 3 weeks prior to entering the study 
or those who have not recovered (e.g. back to baseline or grade 1) from adverse 
events due to agents administered more than 3 weeks earlier.    
 
There is a potential drug interaction when abiraterone is concomitantly used with a 
CYP2D6 substrate narrow therapeutic index (e.g., thioridazine, dextromethorphan), 
or strong CYP3A4 inhibitors (e.g., atazanavir, erythromycin, indinavir, itraconazole, 
Ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and 
voriconazole) or strong inducers (e.g., carbamazepine, Phenobarbital, phenytoin, 
rifabutin, rifampin, rifapentine). 
Caution should be used when patients are on one of these drugs. 
 
3.2.3 Patients with history of active seizures are not eligible. 
 
3.2.4 Patients with a history of pituitary or adrenal dysfunction, active or symptomatic viral 
hepatitis or chronic liver disease are not eligible. 
 
3.2.5 Patients with known brain metastases should be excluded from this clinical trial 
because of their poor prognosis and because they often develop progressive 
neurologic dysfunction that would confound the evaluation of neurologic and other 
adverse events. 
 
3.2.6 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to ABT-888 or Abiraterone.   
 
3.2.7 Patients may continue on a daily Multi-Vitamin, calcium and Vitamin D, but all other 
herbal, alternative and food supplements (i.e. PC-Spes, Saw Palmetto, St John’s 
Wort, etc.) must be discontinued before registration.  Patients must not be planning to 
receive any concurrent cytotoxic chemotherapy, surgery, or radiation therapy during 
protocol treatment. Hormonal-acting agents (including diethylstilbestrol/DES, 
aldosterone, and spironolactone) are forbidden during the trial and must be stopped 
prior to registration. No washout period will be required for any of these agents.  
Patients on megesterol acetate for hot flashes are allowed to continue therapy. 
 
3.2.8 Patients on stable doses of bisphosphonates or denosumab which have been started 
prior to registration may continue on this medication, patients who are not on 
bisphosphonates or denosumab are eligible as long as they initiate therapy prior to 
registration. 
 


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3.2.9 Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure (New York Heart Association Class 
III and IV heart failure), unstable angina pectoris, cardiac arrhythmia, or psychiatric 
illness/social situations that would limit compliance with study requirements or 
concurrent medications that alter cardiac conduction. 
 
3.2.10 Patients with a "currently active" second malignancy other than non-melanoma skin 
cancers are not eligible. Patients are not considered to have a "currently active" 
malignancy if they have completed all therapy and are now considered without 
evidence of disease for 1 year.  
 
3.2.11 HIV-positive patients on combination antiretroviral therapy are ineligible because of 
the potential for pharmacokinetic interactions with ABT-888.  In addition, these 
patients are at increased risk of lethal infections when treated with marrow-
suppressive therapy.  
 
3.2.12  Patients with treatment-related AML (t-AML)/MDS or with features suggestive of 
AML/MDS. Prior allogeneic bone marrow transplant or double umbilical cord blood 
transplantation 
 
3.3 
Inclusion of Women and Minorities 
 
This study applies only to men. All races and ethnic groups are eligible for this trial. 
The anticipated accrual in the ethnicity/race categories is shown in the table below.  
 
   Ethnic Category 
Males 
Total 
Hispanic or Latino 
16 
16 
Not Hispanic or Latino 
132 
132 
Total Ethnic 
148 
148 
   Racial Category 
 
 
American Indian or Alaskan Native 
1 
1 
Asian 
4 
4 
Black or African American 
27 
27 
Native Hawaiian or other Pacific Islander 
0 
0 
White  
116 
116 
Racial Category: Total of all Subjects 
148 
148 
 
 
4.0 
REGISTRATION PROCEDURES 
 
4.1  
Initial Registration 
 
All patients must be registered with the University of Chicago (UC) Registrar Jeffrey 
Bozeman at 773-834- 3095 or jbozema1@.bsd.uchicago.edu at least 2 business days prior to 
any planned biopsy.  Because a Multi-Site Study Coordinator of the Clinical Trials Office at 


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the University of Michigan will work collaboratively with the UC registrar, to review the 
submitted documents and process the registration, participating sites should inform the UC 
registrar Mon-Fri, 8:15am-4:00pm CST of a potential registration. Same day registrations 
cannot be guaranteed.   
 
Confirm all selection criteria listed in Section 3.0, and then call the UC Registrar with the 
following information: 
 
Copy of required laboratory tests 
Signed patient consent form 
Completed Eligibility checklist 
Provider of information 
            Study # and Institution 
Treating Physician 
Patient name and hospital ID number 
Patient's zip code of residence 
Date of signed informed consent 
Race, gender, date of birth of patient 
Diagnosis and date of initial diagnosis 
 
As noted, the UC Registrar will work collaboratively with Dr. Hussain and her research team 
at the University of Michigan to verify each patient’s eligibility and then issue a confirmation 
of registration. To complete the registration process, the UC registrar will: 
 
• Assign a patient study number 
• Register the patient on the study 
• Fax or e-mail the patient study number to the participating site and to the Michigan 
Center for Translational Pathology (see section 9) 
• 
Call the research nurse or data manager at the participating site and 
verbally confirm registration. 
• 
Fax a copy of the completed Section Two of the Eligibility Worksheet 
signed and dated by the UC registrar to the requesting site. 
• 
Patients found to be ineligible for participation after being consented will be 
considered screen failures, and documented as such in the Screening and Enrollment 
Log. These patients will not have study identification number assigned to them, and 
will not undergo a biopsy and not receive study treatment. 
 
4.2  
Biopsy and randomization 
 
Following registration, patient biopsies must be performed within 10 calendar days.  Issues 
that would cause treatment delays should be discussed with the Principal Investigator.  If a 
patient is eligible for treatment, therapy must start within three weeks from the biopsy dates.   
 
Biopsy tissue should be processed and shipped to the Michigan Center for Translational 
Pathology as specified in section 9. The coordinator for the Michigan Center for 


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Translational Pathology will inform University of Chicago (UC) Registrar Jeffrey Bozeman 
at 773-834- 3095 or jbozema1@.bsd.uchicago.edu as well as the participating site whether 
the patient has adequate tissue for fusion analysis. 
 
If the patient does not have adequate tissue for fusion analysis, he will be removed from 
protocol unless the patient is willing to undergo another biopsy. Repeat biopsy will need to 
be done within 10 calendar days as long as patient still fulfills other eligibility criteria.  No 
study labs are needed but safety labs can be done as deemed necessary by the managing 
oncologist.  Patients will be randomized if on repeat biopsy tissue is adequate for ETS fusion 
status evaluation. 
 
If the patient has adequate tissue for fusion analysis, the coordinator for the Michigan Center 
for Translational Pathology will also inform the statistician, Stephanie Daignault-Newton at 
734-647-3271 or sfaruzzi@umich.edu of the fusion status so appropriate randomization 
stratified by ETS gene fusion status can be performed.  (See Section 5, Treatment Plan).  
Randomization will be conducted using pre-printed cards and sealed envelopes. 
 
Randomized patients should begin protocol treatment within 7 working days from 
randomization.  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.  University of Chicago (UC) 
Registrar Jeffrey Bozeman should be notified of cancellations as soon as possible. 
 
4.3  
Drug ordering 
 
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 Coordinating Center to the 
CTEP PIO (PIO@ctep.nci.nih.gov).  
 
 
4.4 
Registration Process & Data Submission for all Participating Sites 
 
Registration  
 
 
Submit the Clinical Trial Patient Registration Form and all source documentation for the 
protocol required eligibility criteria and pre-study procedures.  
 
All required forms and source documentation should be faxed or mailed to:  
 
UC Phase II Clinical Research Associates 
 
5841 S. Maryland Avenue MC 2115 
 
Chicago, IL 60637 
 
Fax: (773) 702-4889 
 
Weekly: 
  
 
Submit the Clinical Trial Patient Weekly Treatment Summary Form with supporting 
source documentation by noon on Friday of each week, for review at the weekly Phase II 


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Conference.  All other source documentation for protocol required procedures should be 
submitted within a week after it is created or modified. 
 
Evaluations: 
  
 
At each response evaluation as specified in the protocol, submit supporting source 
documentation for the response.  
 
Off-study: 
Submit the Clinical Trial Patient Off Treatment Form with the appropriate source 
documentation 
 
Follow-up: 
 
Submit the Phase II Consortium Affiliate Clinical Trial Patient Follow-Up Form with 
appropriate source documentation. 
 
5. TREATMENT PLAN 
 
5.1 Stratification and Randomization 
 
 
 
 
 All eligible patients with adequate tissue for fusion analysis will be stratified by their 
prior ketoconazole therapy (Yes/No) and ETS gene fusion status (Positive or Negative) 
and then randomized to receive Abiraterone alone or Abiraterone +ABT-888 as follows. 
As noted above, treatment must start within 7 working days of randomization, and 
patients must continue to meet the noted eligibility criteria specified in section 3: 
 
Arm 1:  ETS Fusion-Positive Prostate Cancer 
Patients will be randomized to one of the following arms: 
 
Arm IA: Abiraterone + Prednisone  
Abiraterone 1000 mg orally once daily and prednisone 5 mg orally twice daily, days 
1-28 in 28 day cycles.  
 
Arm IB: Abiraterone + Prednisone + ABT-888  
Abiraterone 1000 mg orally once daily and Prednisone 5 mg orally twice daily.  Only 
for cycle 1, Abiraterone and Prednisone* will start on day 8 to allow lead-in 
with ABT-888 and will continue through day 28. All subsequent cycles 
Abiraterone/prednisone will start on day 1 and continue daily in 28 days cycle.  
ABT-888 200 mg will be given BID orally on days 1-28 in 28 day cycles. If after the 
first cycle of therapy the patient tolerates therapy well then the ABT-888 dose can be 
escalated to 300 mg BID for cycle 2 and thereafter. 
* patients who have been on prednisone prior to registration may continue it during 
the lead in ABT-888 therapy.  
 
 
 Arm II: ETS Fusion-Negative Prostate Cancer  
Patients will be randomized to one of the following arms: 
    


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Arm IIA: Abiraterone + Prednisone  
Abiraterone 1000 mg orally once daily and prednisone 5 mg orally twice daily, days 
1-28 in 28 day cycles.  
 
Arm IIB: Abiraterone + Prednisone + ABT-888  
Abiraterone 1000 mg orally once daily and Prednisone 5 mg orally twice daily.  Only 
for cycle 1, Abiraterone and Prednisone will start on day 8 to allow lead-in with 
ABT-888 and will continue through day 28. All subsequent cycles 
Abiraterone/prednisone will start on day 1 and continue daily in 28 days cycle. ABT-
888 200 mg will be given BID orally on days 1-28 in 28 day cycles. If after the first 
cycle of therapy the patient tolerates therapy well then the ABT-888 dose can be 
escalated to 300 mg BID for cycle 2 and thereafter.  
 
* patients who have been on prednisone prior to registration may continue it during 
the lead in ABT-888 therapy.  
 
5.2 
Agent Administration 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks are described in Section 7.  Appropriate dose modifications 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. 
 
 
*Abiraterone acetate: Four (250 mg) tablets (total dose /day 1,000 mg) orally on an empty 
stomach, 1 hour before or 2 hours after a meal.  The tablets are to be swallowed whole with 
water.  Tablets cannot be broken, crushed, or chewed. Abiraterone acetate therapy must be 
accompanied by prednisone. 
** Prednisone: Predisone 5 mg to be taken with food twice daily. 
#: For patients randomized to Arms IB and IIB:  For Cycle 1 only Abiraterone and 
Prednisone will start on day 8 daily to allow lead in ABT888 therapy.  For all subsequent 
REGIMEN DESCRIPTION 
Agent 
Dose 
Route Schedule 
Cycle 
Length 
Abiraterone*# 
1000mg 
 Oral 
Once daily,  
Days1-28 # 
28 days  
(4 weeks) 
Prednisone**# 
5 mg 
Oral 
Twice daily. 
Days 1-28 # 
ABT-888*** 
Start 
at 200 mg 
escalate to 300 mg 
after the 1st cycle if 
patient tolerates 200 
mg 
Oral  
BID, 
Days1-28 


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cycles Abiraterone/prednisone will start on day 1 and continue daily in 28 day cycles.  
***ABT888: Take the capsules to be taken orally twice daily with or without meals. Tablets 
are not to be crush, broken, or chewed 
• Patients will continue treatment until disease progression or other reason for 
discontinuation of protocol treatment. 
Intake Calendar:  Abiraterone acetate, prednisone and ABT- 888 compliance will be recorded on 
the Intake Calendar (see Appendix F and G). Institutional staff will review and ascertain patient 
adherence with protocol treatment. If a dose is missed, patients are to take the normal dose on the 
following day.  If more than one daily dose is missed, the study doctor or study team must be 
informed5.3  General Concomitant Medication and Supportive Care Guidelines 
 
5.3.1 Several medications are specifically disallowed. Antiandrogens (e.g. flutamide, 
bicalutamide, and nilutamide) may not be used. Five-alpha reductase inhibitor (e.g. 
finasteride and dutasteride) are not permitted. Other excluded therapies include 
ketoconazole, diethylstilbestrol/DES, aldosterone, spironolactone, and PC-SPES. 
Other excluded treatments include chemotherapy, immunotherapy, and 
radiopharmaceuticals or any other therapy intended to treat prostate cancer. 
Oral antifungal medication such as ketoconazole, fluconazole and itraconazole (or related 
antifungal medication) are not allowed.  
 
5.3.2 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 supportive care medications is allowed according to institutional standards.  
 
5.3.3 Because there is a potential for interaction of Abiraterone with other concomitantly 
administered drugs through the cytochrome P450 system, the case report form must capture 
the concurrent use of all other drugs, over-the-counter medications, or alternative therapies.   
The Principal Investigator should be alerted if the patient is taking any agent known to affect 
or with the potential to affect selected CYP450 isoenzymes.   
 
Potential Drug Interaction with Abiraterone Acetate 
 
Effects of Abiraterone on Drug Metabolizing Enzymes  
 
Abiraterone is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. In a 
CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan 
(CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when 
dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 
5 mg twice daily.  
 
Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a 
narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, 
exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate 
drug  
 
Drugs that Inhibit or Induce CYP3A4 Enzymes  
 


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Based on in vitro data, Abiraterone is a substrate of CYP3A4. The effects of strong 
CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, 
nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) 
or inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, 
phenobarbital) on the pharmacokinetics of abiraterone have not been evaluated, in 
vivo. Avoid or use with caution, strong inhibitors and inducers of CYP3A4 during 
Abiraterone treatment  
 
While abiraterone acetate exhibited inhibition of P450 CYPs 2C19, 2D6, and 1A2 in 
the in vitro enzyme interaction studies, these inhibitory effects were an order of 
magnitude weaker than those for classic inhibitors of 1A2 and 2D6,  and 5 fold 
weaker than for classic inhibitors of 2C19. 
 
There have been no reports of clinically significant drug-drug interactions 
involving abiraterone.  Table below identifies medications that could potentially 
be affected in subjects receiving abiraterone acetate.  
  
 
 
 
 
 
 
Drug Name 
P450 Mechanism 
Possible Effect 
Clopidogrel 
2C19 needed for prodrug activation 
Decreased efficacy 
Ticlopidine 
2C19 needed for prodrug activation 
Decreased efficacy 
Metoprolol 
Metabolized by 2D6 
Increased drug levels 
Propranolol 
Metabolized by 2C19 
Increased drug levels 
Flecainide 
Metabolized by 2D6 
Increased drug levels 
Propafenone 
Metabolized by 2D6 
Increased drug levels 
Haloperidol 
Metabolized by 2D6 
Increased drug levels 
Fluoxetine 
Metabolized by 2C19 
Increased drug levels 
Paroxetine 
Metabolized by 2C19 
Increased drug levels 
Sertraline 
Metabolized by 2D6 
Increased drug levels 
Amoxapine 
Metabolized by 2C19 
Increased drug levels 
Clomipramine 
Metabolized by 2D6 
Increased drug levels 
Desipramine 
Metabolized by 2D6 
Increased drug levels 
Doxepin 
Metabolized by 2D6 
Increased drug levels 
Imipramine 
Metabolized by 2D6 
Increased drug levels 
Nortriptyline 
Metabolized by 2D6 
Increased drug levels 
Protriptyline 
Metabolized by 2D6  
Increased drug levels 
Oxycodone 
Metabolized by 2D6 
Increased drug levels 
Codeine 
Prodrug activated by 2D6 to form 
Morph
ine 
Decreased efficacy 
Tamoxifen 
Prodrug activated by 2D6 
Decreased efficacy 
Theophylline 
Metabolized by 1A2 
Increased drug levels 
Cimetidine 
Metabolized by 2C19 
Increased drug levels 


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5.3.4 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.  
Specifically, ABT-888 (veliparib) is not a potent inhibitor of CYP1A2, CYp2A6, CYP2C9, 
CYP2Ci19, CYP2D6, CYP2E1, CYP2B6, CYP2C8, or CYP3A4 in human liver 
microsomes, (IC50 > 30 µM), suggesting that ABT-888 is not likely to inhibit the 
metabolism of drugs that are substrates of the aforementioned CYPs at the projected 
therapeutic concentration (≈1 µM).    
 
ABT-888 did not significantly induce the activities of CYP1A2, 2B6, 2C9, or 3A4 in human 
hepatocytes from 4 donors at the drug concentrations up to 10 µM. 
 
5.3.5 Several medications are specifically allowed. LHRH agonist or antagonist must be continued 
throughout the study and are considered a standard of care treatment for this patient 
population. Conventional multi-vitamins and additional glucocorticoid use, beyond 
prednisone 5 mg twice daily, is allowed as deemed medically necessary. 
 
5.3.6 Transfusions and hematologic growth factors are allowed in accordance with institutional 
guidelines. 
 
 
5.4 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue until one 
of the following criteria applies: 
 
• 
Disease progression, 
 
• 
Intercurrent illness that prevents further administration of treatment, 
 
• 
Unacceptable adverse event(s) (see section 6),  
 
• 
Therapy delay for more than 4 weeks 
 
• 
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. 
 
5.5     Duration of Follow Up 
 
Patients removed from study for progression will be followed for 4 weeks or resolution 
or stabilization of any therapy related adverse events.    
 


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Patients removed from study for unacceptable adverse event(s) will be followed until 
resolution or stabilization of the adverse event. Once off study for any reason, follow-up 
visits to assess progression will be completed every 6 months, until objective progression 
or 2 years, whichever occurs first.  
 
6. 
DOSING DELAYS/DOSE MODIFICATIONS 
 
6.1  
CTCAE  
 
 
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse 
Events) Version 5.0 for toxicity and Serious Adverse Event reporting.  A copy of the 
CTCAE Version 5.0 can be downloaded from the CTEP home page 
(http://ctep.cancer.gov).  All appropriate treatment areas should have access to a copy of 
the CTCAE Version 5.0. 
 CTCAE v5.0 documents, including a mapping document, are available on the CTEP website: 
https://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm 
 
6.1.1 Expedited Reporting of Toxicities 
Toxicities (including suspected reactions) that meet the expedited reporting criteria as 
outlined in section 7.0 of the protocol must be reported to the Coordinating Center, Study 
Coordinator and NCI via CTEP-AERS, and to the IRB per local IRB requirements. 
 
6.2  
Guidance Regarding Dose Adjustments for Adverse Event Based on Attribution 
For laboratory or clinical Adverse events (AEs) that warrant a dose reduction, the 
dose-reduction of the drug will be based on the attribution of the AE. If the event is 
related to one drug the dose-reduction will be made to only that drug, if AE is related 
to both then both drugs should be dose reduced.  
 
6.3  
PI contact number 
 
 
For treatment or dose modification related questions, please contact Dr. Maha 
Hussain at 734/936-8906.  
 
6.4  
Abiraterone and Prednisone dose levels are defined below: 
 
 Dose Level 
Abiraterone acetate 
Prednisone 
 0      
1,000 mg daily 
5 mg twice daily  
-1 
750 mg daily 
5 mg twice daily 
-2 
500 mg daily  
5 mg twice daily 
 
o 
A dose reduction will be pursued for any serious adverse event, defined as any 
Grade 4 toxicity and also for any Grade 3 toxicity that is believed to potentially 
impact the safety of the participant.  The dose of abiraterone will not be re-escalated 
once a dose reduction has occurred. Abiraterone will be held and the subjects 
followed until resolution of any Grade 3 or 4 adverse event to ≤ Grade 1.   
 
o 
Asymptomatic laboratory abnormalities would not be considered a serious 


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adverse event unless the investigator believes it may potentially impact the 
participant’s safety or unless it is specifically addressed separately in the protocol 
(e.g. hypokalemia and liver test abnormalities). 
 
o 
Due to the known side effect of hypokalemia, oral replacement of potassium is to 
be started with grade 1 hypokalemia.  With Grade 3 or 4 hypokalemia, abiraterone 
acetate is to be held until it resolves to ≤ Grade 1 and IV potassium replacement is to 
be given with appropriate monitoring.   
 
o 
If Grade 2 or higher liver function test abnormalities (AST, ALT or bilirubin) 
develop, the liver function tests should be followed at least weekly until they resolve 
to ≤ Grade 1.  If Grade 3 liver test abnormities (AST, ALT or bilirubin) develop, 
abiraterone acetate and any other hepatotoxic drugs should be held until they resolve 
to ≤ Grade 1.  In the specific case of Grade 3 AST, ALT or bilirubin abnormalities, a 
mandatory dose reduction of abiraterone acetate to 500 mg daily must be undertaken, 
with every 2 week assessments of the liver function tests for at least 3 months.  If 
Grade 4 liver test abnormalities (AST, ALT or bilirubin) occur, the drug should be 
permanently discontinued.  The Multi-site study coordinator should also be notified 
with any Grade 3 or 4 liver function test abnormality.   
 
o 
If abiraterone acetate is delayed more than 4 weeks for any reason, or if a dose 
reduction of abiraterone acetate below 500 mg daily is required, patients will be 
removed from protocol treatment.   
 
o 
Prednisone is included in this regimen primarily as a safety medication to reduce 
the potential incidence of mineralocorticoid excess from abiraterone acetate.  For this 
reason, the prednisone cannot be dose reduced or held without holding the 
abiraterone acetate. If Grade 3 or 4 toxicity develops which is known to be related to 
prednisone (e.g. hyperglycemia) and this is believed to potentially impact the safety 
of participation and if the toxicity cannot be managed with medical therapy while 
maintaining the dose of the prednisone, then the prednisone dose may be reduced to 
75% of the starting dose (7.5 mg/day).   If Prednisone cannot be tolerated by the 
patient and therapy is deemed unsafe by the treating physician then patient will be 
removed from protocol. 
 
6.5   ABT-888 dose levels are defined below (*At the time of RRA request on May 24, 2018, the 
study was already closed to accrual and so, Table 6.5 has not been changed) 
 
 Dose Level 
ABT888 
+1 
300 mg BID 
 0  starting 
dose level    
200 mg BID 
-1 
150 mg BID 
-2 
100 mg BID 


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Patients randomized to ABT-888 will be started at 200 mg bid.  If after the first cycle of 
therapy the patient tolerates therapy well then the dose can be escalated to 300 mg BID for 
cycle 2 and thereafter. 
 
Note:  All treatment modifications must be expressed as a specific dose or amount rather 
than as a percentage of the starting or previous dose.  ABT-888 will be available in 10 and 
50 mg increment capsules. 
 
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 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 
 
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. 
 
*At the time of RRA request on May 24, 2018, the study was already closed to accrual and so, Table 6.5.1 has 
not been changed) 
6.5.1 Dose reductions based on hematologic nadirs: Dosage adjustments to be implemented at the 
beginning of each treatment cycle will be based upon the nadir counts as follows: 
 
 
 
Granulocytes 
 
Platelets 
 
ABT888 Dose Adjustment                 
                 
 
 
ANC > 500       and 
>20,000 
 
Full dose 
 
 
ANC < 500     and/or 
<20,000 
 
Decrease ABT888 by 1 dose level 
 
• If the ANC nadir is <500 and/or the platelet nadir is <20,000 after a 1 dose 
level reduction of ABT888, then the next cycle will be started at -2 dose 
level.   
• Patients requiring more than two dose reductions should discontinue ABT888 
 
 
Management of anemia 
 
Anemia is a common adverse drug reaction related to ABT-888.   Management of anemia is in 
accordance with Table 3: 
 
 
6.5.1.1: 
Management of anemia 
 


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CTCAE Grade 
Definition 
ABT-888 Dose 
2 
Hb <10 but ≥8 g/dL 
Give appropriate supportive treatment and 
investigate causality.  Investigator judgement to 
continue ABT-888 or interrupt dose for a 
maximum of 3 weeks.  If repeat Hb <10 but ≥8 
g/dL, dose interrupt until Hb ≥10 g/dL for 
maximum of 3 weeks and upon recovery dose 
reduce to 150 mg BID as a first step and to 100 
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 to 150 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, will require ABT-888 dose 
reductions to 150 mg twice daily (BID) as a first step and to 100 mg BID as a second step. 
 
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: 
 
• 
≥2 week interruption/delay in velaparib due to CTCAE Grade ≥3 anemia (Hb <8 g/dL) 
and/or development of blood transfusion dependence 
 
• 
≥2 week interruption/delay in ABT-888 due to CTCAE Grade ≥3 neutropenia (ANC <1 x 109/L) 
 
• 
≥2 week interruption/delay in ABT-888 due to CTCAE Grade ≥3 thrombocytopenia and/or 
development of platelet transfusion dependence (Platelets <50 x 109/L) 
 
Check weekly differential blood counts including reticulocytes and peripheral blood smear.   If any blood 
parameters remain clinically abnormal after 3 weeks of dose interruption, the patient should be referred to 
a hematological oncologist for further investigations.   Bone marrow for evaluation and cytogenetics 
should be considered at this stage according to standard hematological oncology practice.   ABT-888 
should be discontinued if blood counts do not recover to CTCAE Grade ≤1 within 3 weeks of dose 
interruption. 
 
Management of ABT-888 associated toxicity 
 
Management of MDS/AML 
 
Patients who develop MDS/AML on treatment should discontinue ABT-888 treatment and be 


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managed appropriately. 
 
 
 6.5.2  General Non-Hematological Toxicities: 
 
   
Patients requiring more than two dose reductions (3 if they were treated at the +1 dose level) should 
discontinue ABT888.    
 
   
 
  General Non-Hematological Toxicities including Nausea, Vomiting, and Diarrhea:   
• For Grade 1 and 2 toxicities there will be no routine requirement for a dose 
reduction and appropriate medical therapy is to be given accordingly.  
 
• If patients develop intolerable G1 or G2 toxicities (per patient) then they can 
undergo a dose reduction. 
• > Grade 3 toxicities despite optimal medical therapy:  Hold ABT-888 until ≤ 
Grade 1.  Resume at one dose level reduction.  
  
General Non-Hematological Toxicities excluding nausea, vomiting, and diarrhea:  
Grade > 3: delay until recovery to grade ≤ 1 and reduce one dose level.  
 
 
7. 
ADVERSE EVENTS:  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 reporting (viaCTEP-AERS) in addition to 
routine reporting.   
7.1 Comprehensive Adverse Events and Potential Risks list (CAEPR) 
For Veliparib (ABT-888, NSC 737664) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized text. 
This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited reporting 
to NCI (except as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic applications/docs/aeguidelines.pdf 
for further clarification. Frequency is provided based on 2310 patients. Below is the CAEPR for ABT-888 
(Veliparib). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the 
AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple investigational 
agents and has an AE listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
 
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Adverse events reported on ABT-888 (Veliparib) trials, but for which there is insufficient evidence 
to suggest that there was a reasonable possibility that ABT-888 (Veliparib) caused the adverse 
event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Bone marrow hypocellular; Blood and lymphatic 
system disorders - Other (pancytopenia) 
CARDIAC DISORDERS - Cardiac disorders - Other (Takotsubo cardiomyopathy); Heart failure; Left 
ventricular systolic dysfunction; Palpitations; Sinus bradycardia; Sinus tachycardia 
EAR AND LABYRINTH DISORDERS - Vertigo 
EYE DISORDERS - Blurred vision 
GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites; Colitis; Colonic obstruction; Dental 
caries; Dry mouth; Duodenal ulcer; Dyspepsia; Dysphagia; Enterocolitis; Esophagitis; Flatulence; Gastritis; 
Gastroesophageal reflux disease; Lower gastrointestinal hemorrhage; Mucositis oral; Obstruction gastric; 
Rectal hemorrhage; Rectal pain; Small intestinal obstruction 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema limbs; Fever; Flu 
like symptoms; Malaise; Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Hepatic failure; Hepatobiliary disorders - Other (cirrhosis) 
INFECTIONS AND INFESTATIONS - Appendicitis; Catheter related infection; Infections and infestations - 
Other (peritonsillar abscess); Lung infection; Lymph gland infection; Mucosal infection; Sepsis; Shingles; 
Skin infection; Upper respiratory infection; Urinary tract infection 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising; Dermatitis radiation; Radiation 
recall reaction (dermatologic) 
INVESTIGATIONS - Alanine aminotransferase increased; Alkaline phosphatase increased; Aspartate 
aminotransferase increased; Blood bilirubin increased; Cardiac troponin I increased; Creatinine increased; 
Electrocardiogram QT corrected interval prolonged; Lipase increased 
METABOLISM AND NUTRITION DISORDERS - Hyperglycemia; Hypernatremia; Hypoalbuminemia; 
Hypocalcemia; Hypokalemia; Hypomagnesemia; Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Arthritis; Back pain; Bone 
pain; Generalized muscle weakness; Muscle cramp; Myalgia; Neck pain; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) -Tumor pain 
NERVOUS SYSTEM DISORDERS - Ataxia; Cognitive disturbance; Depressed level of consciousness; 
Dysarthria; Extrapyramidal disorder; Intracranial hemorrhage; Lethargy; Memory impairment; Movements 
involuntary; Paresthesia; Peripheral motor neuropathy; Peripheral sensory neuropathy; Presyncope; 
Reversible posterior leukoencephalopathy syndrome; Stroke; Syncope; Tremor 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression; Insomnia; Psychiatric disorders 
- Other (emotional instability); Psychosis; Restlessness 
RENAL AND URINARY DISORDERS - Dysuria; Hematuria; Proteinuria  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Cough; Dyspnea; Epistaxis; Hypoxia; 
Nasal congestion; Pharyngolaryngeal pain; Pleural effusion; Pneumonitis; Respiratory failure 
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. 
 
 
 
7.2 Adverse Event List(s) for Abiraterone 
 
Please refer to Section 8.3 for detailed information regarding reported toxicities for Abiraterone 


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and the Physician Desk Reference and package insert for complete information. 
 
 
 
 
7.3 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.  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.   
 
• 
‘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 7.1.1). 
 
• 
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. 
 
7.4 Expedited Adverse Event Reporting 
 
7.3.1 
Expedited AE reporting for this study must use CTTEP-AERS  (Adverse 
Event Expedited Reporting System), accessed via the CTEP Web site 
(http://ctep.cancer.gov).  The reporting procedures to be followed are presented in 
the “NCI Guidelines for Investigators: Adverse Event Reporting Requirements 
for DCTD (CTEP and CIP) and DCP INDs and IDEs” which can be downloaded 
from the CTEP Web site (http://ctep.cancer.gov).  These requirements are briefly 
outlined in the tables 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. 
 
7.3.2 
Since this is a multicenter trial 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.  




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NOTE   Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of learning 
of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar days 
of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• Grade 3 adverse events 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
 
 
7.5 
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. 
 
7.6 
Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm.  
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported via CTEP-AERS. Three options are available to describe the event:  
 
• 
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
• 
Myelodysplastic syndrome (MDS)  
• 
Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
 
7.6.1 
Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine reporting 


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via CDUS unless otherwise specified.  


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8. 
PHARMACEUTICAL INFORMATION 
 
8.1  
CTEP IND Agent:  
 
8.1.1 
Veliparib (ABT-888) (NSC 737664) 
 
Chemical Name:  1H-Benzimidazole-7-carboxamide, 2-[(2R)-2-methyl-2-pyrrolidinyl]- 
 
Other Names: 
Veliparib, A-861695.0 
 
Classification:  Poly (ADP-ribosome) polymerase (PARP) Inhibitor 
 
CAS Registry Number:  912444-00-9 
 
Molecular Formula: 
C13H16N4O 
 
M.W.:  244.29 
 
Approximate Solubility:  A-861695.0 is freely soluble at pH < 6.9, soluble at pH 6.9 to 
7.1, and slightly soluble at pH > 7.1. 
 
Mode of Action:  ABT-888 inhibits the formation of poly (ADP-ribose) (PAR) polymers 
in vitro and in vivo.  It inhibits the repair of DNA when the DNA is damaged by cytotoxic 
agents.  ABT-888 increases antitumor efficacy when added to DNA-damaging therapies 
such as temozolomide, cisplatin, carboplatin, cyclophosphamide, irinotecan, or radiation 
therapy. 
 
 
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 at 200C to 250C (680F to 770 F).  
 
Stability:  Excursions permitted to 150 C to 300 C (590F to 860 F).  


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Route(s) of Administration:  Oral 
 
Method of Administration:  Administer ABT-888 orally without regards to meals.   
Potential Drug Interactions:  Clinical studies evaluating the metabolism of ABT-888 
have not been conducted.  However, results from the in vitro analysis reveal that this agent 
is metabolized by multiple isoenzymes – CYP1A1, 2D6, 2C19 and 3A4.  ABT-888 is 
neither a potent inhibitor nor a potent inducer of the CYP-450 isoenzymes.  Use caution 
when concomitantly administer with drugs that are substrate, inhibitor, inducer of 
CYP1A1, 2D6, 2C19 and 3A4. 
 
ABT-888 clears primarily in the urine as intact parent drug along with metabolites 
suggesting that renal function plays an important role in the drug clearance and its 
metabolites. Use caution when concomitantly administer with oxalipaltin, carboplatin, 
cisplatin, and topotecan in patients with pre-existing renal impairment.  
 
Special Handling:  Handle ABT-888 according to your institutional guideline for 
hazardous drugs. 
 
Patient Care Implications:  Patients may feel fatigue or tiredness. Loss of appetite and 
losing weight are common.  Provide appropriate supportive care for diarrhea.  Avoid long-
sun exposure as it might exacerbate skin rash. 
 
i. Availability 
 
ABT-888 is an investigational agent supplied to investigators by the Division of Cancer 
Treatment and Diagnosis (DCTD), NCI. 
 
ABT-888 is provided to the NCI under a Collaborative Agreement between Abbott 
Laboratories and the DCTD, NCI (see Section 12.3). 
 
 
8.1.2 
Agent Ordering and Agent Accountability 
 
8.1.2.1 NCI-supplied agents may be requested by the Principal Investigator (or their 
authorized designee) at each participating institution.  Pharmaceutical 
Management Branch (PMB) policy requires that agent be shipped directly to 
the institution where the patient is to be treated.  PMB does not permit the 
transfer of 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 


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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. 
 
Active CTEP-registered investigators and investigator-designated shipping 
designees and ordering designees can submit agent requests through the 
PMB Online Agent Order Processing (OAOP) application (https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx).  Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account 
(https://eapps-ctep.nci.nih.gov/iam/) and the maintenance of an “active” 
account status and a “current” password.  Alternatively, site personnel can 
fax completed Clinical Drug Requests (NIH-986) to the Pharmaceutical 
Management Branch at (240) 276 7893.  For questions about drug orders, 
transfers, returns, or accountability, call (240) 276 6575 Monday through 
Friday 
between 
8:30 
am 
and 
4:30 
pm 
(ET) 
or 
email 
PMBAfterHours@mail.nih.gov anytime. 
 
8.1.2.2 Agent Inventory Records – 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 (DARF).  (See the NCI Investigator’s Handbook 
for Procedures for Drug Accountability and Storage.) 
 
 
 
8.2 
 
Commercial Agents 
 
8.2.1 
Abiraterone Acetate (CB7630) (NSC #748121) (IND-111552) 
 
a. DESCRIPTION 
 
General:  Abiraterone acetate is a pro-drug of abiraterone.  Abiraterone inhibits the conversion 
of pregnenolone or progesterone into DHEA or androstenedione, which are 2 precursors of 
testosterone in the adrenal glands and testes.  Testosterone is further converted to the more potent 
androgen dihydrotestosterone (DHT).  Both testosterone and DHT stimulate prostatic growth.  
Current therapies (orchiectomy and GNRH) ablate androgen production by the testes but do not 
affect androgen production by the adrenals.  Since the steroid hormones upstream of aromatase 
and downstream of CYP17 could be important in the activation of ER-α and possibly other 
nuclear steroid hormone receptors in breast cancer growth, abiraterone may impact breast cancer 
cell proliferation and survival by virtue of its estrogen suppressing activity. 
 
Molecular Formula:  C26H33NO2 
 


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Molecular Weight:  391 Daltons 
 
PHARMACOLOGY:  
 
Mechanism of Action:  Abiraterone is a selective irreversible steroidal inhibitor of 17α 
hydroxylase/C17, 20-lyase (cytochrome P450c17 [CYP17]).  Inhibition of CYP17 inhibits the 
conversion of pregnenolone or progesterone into DHEA or androstenedione, respectively, which 
are two precursors of testosterone in the adrenal glands and testes.   
  
Pharmacokinetics 
 
Data indicate that the pharmacokinetics of abiraterone acetate administered orally in either tablet 
or capsule formulations were very similar.  Abiraterone acetate is rapidly converted to 
abiraterone after oral administration.  Time to reach maximum plasma concentration is 
approximately 2 to 4 hours.  The terminal half-life is estimated to be between 5 to 16 hours.  
Following a single oral tablet dose of abiraterone acetate, up to 25 – fold variation was observed, 
while up to 9 – fold variation was observed following administration with a capsule formulation. 
 Although there is a variation in plasma levels between the formulations, there is no significant 
difference between the Cmax observed in each group.   Food increases bioavailability of 
abiraterone acetate, however, to minimize the variability in drug exposure as a result of dietary 
variations, abiraterone is to be administered under the fasting condition. 
 
TOXICOLOGY  
 
Human: 
Reported Adverse Events and Potential Risks: 
Hypertriglyceridemia (62.5%) 
Aspartate aminotransferase increased (30.6%) 
Arthritis (29.5%) 
Hypokalemia (28.3%) 
Edema limbs (26.7%) 
Arthralgia (26.2%) 
Investigations – Other, specify (low phosphorus) (23.8%) 
Flushing (19.0%) 
Diarrhea (17.6%) 
Urinary tract infection (11.5%) 
Alanine aminotransferase increased (11.1%) 
Cough (10.6%) 
Hypertension (8.5%) 
Ventricular arrhythmia (7.2%) 
Urinary frequency (7.2%) 
Blood bilirubin increased (6.6%) 
Renal and urinary disorders –Other, specify (nocturia) (6.2%) 
Dyspepsia (6.1%) 


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Upper respiratory infection (5.4%) 
Chest pain - cardiac (3.8%) 
Heart failure (2.3%) 
Adrenal insufficiency (<1%) 
 
Pregnancy and lactation:  Abiraterone acetate has not been tested in pregnant or lactating women. 
As abiraterone acetate affects the levels of androgens and estrogens, fetal abnormalities or 
miscarriage may occur if the drug is administered during pregnancy. 
 
Drug interactions:  Please refer to Physician Desk Reference and package insert for complete 
information. 
  
 
 
ADMINISTRATION (DOSING): 
 
See Section 5.0 Treatment Plan. 
 
STORAGE/STABILITY 
 
Bottles of abiraterone acetate tablets should be stored at room temperature (15-30o C; 59-86o F) 
in the original container/closure with the cap sealed tightly.  Do not refrigerate. 
 
HOW SUPPLIED  
 
Abiraterone acetate is standard agent for this study and is commercially available as 250 mg 
strength tablet and should be purchased by a third party.  The tablets are oval, and white to off-
white. 
 
Please refer to the Physician Desk Reference and package insert for complete information 
 
8.3  
Prednisone (NSC-10023) 
 
DESCRIPTION 
 
Prednisone is a glucocorticoid which is rapidly absorbed from the GI tract. 
 
TOXICOLOGY 
 
Human Toxicology:  Possible adverse effects associated with the use of prednisone are:  fluid 
and electrolyte disturbances, congestive heart failure in susceptible persons, hypertension, 
euphoria, personality changes, insomnia, mood swings, depression, exacerbation of infection 
(e.g., tuberculosis), exacerbation or symptoms of diabetes, psychosis, muscle weakness, 
osteoporosis, vertebral compression fractures, pancreatitis, esophagitis, peptic ulcer disease, 


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dermatologic disturbances, convulsions, vertigo and headache, endocrine abnormalities, 
ophthalmic changes, and metabolic changes.  Some patients have experienced itching and other 
allergic, anaphylactic or other hypersensitivity reactions.  Withdrawal from prolonged therapy 
may result in symptoms of adrenal insufficiency including fever, myalgia and arthralgia.  
Phenytoin, phenobarbitol, and ephedrine enhance metabolic clearance of corticosteroids. 
 
Corticosteroids should be used cautiously in patients with hypothyroidism, cirrhosis, ocular 
herpes simplex, existing emotional instability or psychotic tendencies, nonspecific ulcerative 
colitis, diverticulitis, fresh intestinal anastomoses, peptic ulcer disease, renal insufficiency, 
hypertension, osteoporosis and myasthenia gravis.  Immunization procedures (especially 
smallpox vaccination) should not be undertaken in patients on corticosteroids. 
 
PHARMACOLOGY 
 
Pharmacokinetics:  Natural and synthetic glucocorticoids are readily and completely absorbed 
from the GI tract.  Prednisone is slightly soluble in water.  Glucocorticoids have salt-retaining 
properties.  The anti-inflammatory property of this drug is due to a down-regulation of the body's 
immune system and as a consequence it can suppress the body's response to viral as well as 
bacterial infections. 
Formulation:  Prednisone is available in 2.5 mg, 5 mg, 10 mg, 20 mg and 50 mg tablets. 
 
Storage and Stability:  Prednisone should be stored at room temperature. 
 
Administration:  Prednisone is administered orally. 
Supplier:  Prednisone is commercially available and should be purchased by third party.  
Prednisone will not be supplied by the NCI. 
 
Please refer to the Physician Desk Reference and package insert for complete information.  
 
 
9. 
CORRELATIVE/SPECIAL STUDIES 
 
9.1 Laboratory Correlative Studies 
 
9.1.1  Collection and Handling of Specimens 
 
From each patient, specimens will be collected from three sources: 
 a) A metastatic site of disease (via biopsy) or adequate metastatic tissue from prior 
biopsy or resection. 
 
b) The primary tumor site (via retrieval of previously archived specimens) 
 c) Blood/circulating tumor cells (pre-treatment, week 12, and at clinical progression 
or when off study, whichever is first) 
 
d) Blood/pharmacogenomic SNP analysis (pre-treatment) 
 
e) Blood/TMPRSS2:ERG mRNA(pre-treatment and at weeks 5 and 9) 


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The rationale, and a brief overview, for collection and handling of these specimens is as 
described below. Further technical details regarding biopsies of metastastic sites and 
handling of these biopsy specimens can be found in Appendices C and D, respectively.   
 
9.1.1a: Biopsy of metastatic site: Rationale and Procedure (Appendices C and D) 
 
a).  The primary objectives of this study, and the subsequent assignment of patients to 
treatment arms, depend on determination of ETS fusion status in each patient's 
metastases. The concordance of ETS fusion between primary tumor and metastases has 
been assessed on only limited samples80 and is not well known at this point in time.  
Thus, all patients registered on this study, will undergo a biopsy from a metastatic site 
unless they have adequate available metastatic tissue from prior biopsy or resection. If the 
ETS fusion status of the metastatic tissue is known from previous testing, the ETS fusion 
status of this tissue will be reconfirmed by immunohistochemistry (IHC) for ERG testing 
and ISH-based assays detailed in Section 9.1.5a and 9.1.5b. Biopsies must be scheduled 
for Monday to Thursday to allow for overnight shipping to be received by Friday. 
 
b).  Patients will be scheduled for a CT-guided biopsy of a bone or soft tissue 
abnormality consistent with prostate cancer metastasis. The site of biopsy will be 
determined by the radiologist after review of available radiographs, CT, MRI, and/or 
bone scan, and will be selected based whatever site is expected to result in the best access 
and best yield.   
 
• An ultrasound (US) can be used for lymph node or soft tissue biopsies provided 
that the target lymph node or soft tissue mass is visible with the US and can be 
properly accessed. 
 
Verbal and written informed consent will be obtained after discussion of risks (bleeding, 
infection, soft tissue and bone injury, inconclusive biopsy results) of the procedure.   
 
Standard laboratory tests to assess coagulation and bleeding will also be completed prior 
to the procedure. A standard operating procedure for bone biopsy is provided in 
Appendix C.  A standard operating procedure for soft tissue biopsy is provided in 
Appendix D. 
 
In order to ensure adequate tumor sample as long as it is deemed safe and based on 
accessibility, target lesion size, specimen integrity, specimen appearance, intra-
procedural bleeding, tumor biopsy should attempt to obtain: 
1. Bone biopsy: 2-8 bone biopsy samples.   In addition, at the time of biopsy, it will be 
determined if a bone marrow aspirate is feasible, and if performed, the bone marrow 
aspirate will be sent to University of Michigan for analysis.   


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2. Lymph node or soft tissue: If obtaining a 1-cm-long 18-gauge core specimen, 
attempts should be made to obtain at least 6 cores.  If obtaining a 2-cm-long 18-gauge 
core specimen, attempts should be made to obtain at least 4 cores.  
 
 
c).  The biopsy of the metastases, and any accompanying aspirate, will be obtained 
exclusively for research purposes.  The biopsy specimens and the aspirate will be 
collected and will be immediately frozen in dry-ice ethanol bath in Tissue-Tek O.C.T 
Compound (Sakura Finetek, Torrance, CA) to ensure the integrity of tissue and proteins 
for both immunoblotting and immunohistological analysis of samples.  Upon enrollment 
of each patient on study, a sample kit containing necessary reagents for tissue collection 
(Tissue-Tek standard-size cryomolds, Tissue-Tek OCT, blue pads, markers, and an 
insulated bucket) will be shipped to the enrolling site coordinator.  It is expected that dry 
ice will be provided by the enrolling site.  In addition, written SOPs, with specific details 
regarding tissue collection with this kit, along with a contact sheet with mailing addresses 
for sample shipment, will be mailed to each site coordinator. 
 
d).  Each Tissue-Tek cryomold will be labeled with the clinical protocol number, the 
patient’s study registration number, and the tissue type and the biopsy time and date.  In 
addition, a separate information sheet accompanying each specimen will be filled out.  
This information sheet will include various details necessary for quality assurance of the 
specimen, including: 
1) Date of collection 
2) Specimen ID 
3) Site from which biopsy obtained (bone versus soft tissue, and then location) 
4) Type of biopsy device 
5) Biopsy diameter: gauge, and length: cm 
6) Time biopsy needle introduced 
7) Time biopsy snap-frozen on dry ice 
8) Time aspirate performed (if applicable) 
9) Time aspirate snap-frozen on dry ice 
 
A standard operating procedure for handling of the biopsy and aspirate 
specimens has been attached to this protocol as Appendix D. 
 
Following biopsy, samples from metastatic sites need to be immediately frozen prior to 
shipment within 24 hours to the University of Michigan, per shipping directions 
described in 9.1.2. 
 
9.1.1b:  Archived samples from the primary tumor site: Rationale and Procurement 
Procedure 
 
Archived primary tumor samples, where available, will be requested from the enrolling 
institution.  These primary tumor samples should consist of either radical prostatectomy 


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specimens or biopsies from the prostate.  Archived primary tumor samples can be 
maintained at room temperature.  Either a block from the primary tissue sample, OR 
1 H&E stained slide and 8 unstained charged slides (4 micron thickness) (4 of the 
unstained slides to be used for ISH should be sent without baking the slides) should 
be shipped at room temperature to the University of Michigan, per shipping 
directions described in 9.1.2. 
 
9.1.1c:  Circulating Tumor Cells: Rationale and Sample Collection Procedure 
 
Blood will be collected  pre-treatment,  week 12, and at disease progression or when off 
study. Blood samples will be drawn into three 10-mL evacuated blood draw tubes (Cell-
Free DNA; Streck) (one at each time point).  These blood samples can be maintained at 
room temperature, but must be shipped to Epic Sciences within 48 hours after 
collection, per shipping directions described in 9.1.2.           
  
         9.1.1d: Blood/Pharmacogenomic SNP Analysis: Rationale and Sample Collection 
                      Procedure 
 
Blood for pharmacogenomic SNP analysis will be collected at pre-treatment.  Blood 
samples will be drawn into a single 10-mL EDTA lavender top tube. These blood 
samples need no processing, can be maintained at room temperature, but need to be 
shipped to the University of Michigan within 24 hours after collection, per 
shipping directions described in 9.1.2. 
 
9.1.1e:  Blood/TMPRSS2:ERG mRNA Analysis: Rationale and Sample Collection 
                 Procedure 
 
Blood will be collected at pre-treatment, and at 5 and 9 weeks post-treatment.  At 
each time point, 2.5 mL blood samples will be drawn into two 10-mL PAXgene 
Blood RNA Tubes (Becton Dickinson, Cat# 762165) containing 7.5 mL of solution.  
These blood samples can be maintained at room temperature, but need to be shipped 
to the University of Michigan within 24 hours after collection, per shipping 
directions described in 9.1.2. 


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9.1.2: 
 Shipping of Specimens after Collection 
 
All samples, except the blood samples for CTC analysis, must be shipped to the 
University of Michigan, at the following address: 
 
Javed Siddiqui, MS, MT (ASCP, CLsp (MB)) 
Technical Director 
Michigan Center for Translational Pathology 
Room 1138  
2900 Huron Parkway Suite 100 
Ann Arbor, MI 48105 
Phone: (734) 232-0829 
Fax: (734) 232-0805 
siddiqui@med.umich.edu 
 
Shipping must occur only Monday-Thursday, and an e-mail or phone call to the 
contact listed on the laboratory contact sheet, alerting her to the shipment, is 
required.  
 
9.1.2a Biopsies and aspirates from metastatic sites: If biopsies are performed on 
metastatic sites on Monday through Thursday, the biopsy and aspirate samples should 
be shipped overnight, on dry ice, to the University of Michigan.  
9.1.2b Primary tumor samples: The primary tumor samples can be shipped via 
standard mail, at room temperature, to the University of Michigan.  It is requested that 
efforts be made to ship the primary tumor samples within a month of patient 
enrollment onto the trial. 
9.1.2c Blood samples NOT for CTC analysis: The blood samples should be shipped 
overnight, at room temperature, to the University of Michigan.    
 
9.1.2d Blood samples for CTC analysis: The blood samples should be shipped 
overnight, at room temperature, to Epic Sciences, at the following address:  
 
Epic Sciences 
10975 N Torrey Pines Rd 
La Jolla, CA 92037 
858-356-6610 
 
Shipping must occur only Monday-Thursday, and an e-mail should be 
sent to partners@epicsciences.com, alerting to the shipment, the inclusion 
of the sample ID, number of samples, tracking number, and time of blood 


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draw, is required.  Please note that the Epic Sciences shipping address is 
to be used ONLY FOR THE CTC SAMPLES, and that the remainder of 
the samples (metastases, primary tumor, other blood samples) should be 
sent to the University of Michigan address listed above section 9.1.2a.   
 
 
 
For further details regarding shipping, please refer to Appendix E, F & G which 
are the standard operating procedures for the shipment of samples. 
 
 
9.1.3 Sites Performing Correlative Studies  
 
Aside from the circulating tumor cell studies, all correlative studies will be performed at 
the University of Michigan, within the Michigan Center for Translational Pathology 
(MCTP). Dr. Felix Feng, co-Principal Investigator, and Dr. Arul Chinnaiyan, head of the 
MCTP, will oversee these correlative studies. The circulating tumor cell studies will be 
performed by Epic Sciences. 
 
9.1.4 Processing of Specimens after Receipt at the University of Michigan 
 
a. With the receipt of each biopsy specimen, Javed Siddiqui at the University of 
Michigan (or a pre-specified designee) will place the samples in the -80˚C tissue 
repository described below and will record two additional items for further quality 
assurance: 
 
1) The date/time of receipt of the biopsy specimen at the University of Michigan 
 
2) The date/time that the biopsy specimen is placed at -80°C 
 
b. Biopsies from metastatic sites: The frozen tissue samples from either biopsy or from 
preexisting metastatic tissue, obtained for research from patients taking part in this 
protocol will be held in the University of Michigan Prostate Oncology Program Tissue 
Bank.  The Tissue Bank is located in Room 1143, 2900 Huron Parkway, Suite 100,   
University of Michigan, Ann Arbor, Michigan 48105. This laboratory has multiple -80˚C 
freezers, one of which will be devoted to the biopsies from this trial. The freezers have an 
alarm system and self-dialing emergency system. It is anticipated that at least two 
samples will be obtained from each metastatic biopsy.  From bone biopsies, these 
metastases may consist of two biopsies or a biopsy and an aspirate. One sample from 
each metastatic biopsy (the biopsy sample in cases where there is a biopsy sample and an 
aspirate) will be fixed in formalin shortly after receipt at the University of Michigan.  Six 
5 um section slides will be cut from this formalin fixed sample -- one for H&E staining to 
confirm the presence of tumor, two for determination of ETS fusion status, one for 
analysis of PTEN status, one for analysis of PAR (indicative of PARP1 activity), and one 
for analysis of PARP1 levels. The determination of ETS status for the primary objectives 
will be prioritized above all others, both in schedule and in cases of limited tissue 


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availability, as these studies are necessary to complete the primary objectives of this 
clinical trial. In cases where two samples are available from a metastatic biopsy, the 
second sample will be preserved at -80˚C for subsequent transcriptome sequencing, as 
described below.  For samples in which the biopsies contain insufficient tumor samples 
for analysis, the collected aspirates (if available) will be used for analysis. 
 
c. Primary tumor samples: Retrieved primary tumor samples will be stored at room 
temperature in the University of Michigan Prostate Oncology Program Tissue Bank 
 
d. Blood samples for circulating tumor cell studies:  
The Epic Sciences platform will be utilized for circulating tumor cell analyses. 82-86 
Peripheral blood samples will be drawn at accruing sites following informed consent 
and processed following standard operating procedures. Using a standardized and 
ISO-certified shipping process, samples are transferred to the Epic Sciences central 
laboratory using Federal Express as a carrier. Samples are then processed after 48 
hours of blood draw. The red blood cells are lysed and the remaining nucleated cells 
are plated on custom glass slides and frozen for storage. As needed, blood sample 
slides are thawed and processed to bind the appropriate cell markers with 
fluorescently labeled antibodies.  Depending on peripheral blood counts, up to 16 
slides are generated from each subject. Two to four processed slides, representing one 
patient test, the identification of CTCs consists of three markers (DAPI-nucleus, 
cytokeratin – epithelial marker, and CD-45 – white blood cell marker) and are imaged 
on custom-built automated slide imagers. The resulting images are then automatically 
processed to produce data for technical analysis which consists of removing imaging 
artifacts and selecting potential CTC candidates which are then presented in a web-
based report to a pathologist for final review. Remaining slides are stored for 
subsequent analysis.  These subsequent analyses will include immunofluorescence or 
FISH assays for both ERG and ETV1 fusions, androgen receptor, androgen receptor 
splice variants, RAD51, γH2AX and PTEN biomarkers.  
 
e. Blood samples for SNP and mRNA analysis: Germline DNA from patient peripheral 
blood mononuclear cells will be extracted from blood collected in EDTA lavender top 
tubes using Qiagen DNAEasy assay (Qiagen, Valencia, CA) according to manufacturer 
methods. TMPRSS2:ERG mRNA levels in PAXgene tubes will be quantified using a 
transcription-mediated amplification assay.99 The target RNA is captured onto magnetic 
microparticles and amplified. Amplification products are then detected using 
chemiluminescent DNA probes, and the raw signal is converted to RNA copies using 
calibrators of known TMPRSS2:ERG copy levels. The assay is specific for the 
TMPRSS2(Exon1)-ERG(Exon4) RNA isoform. To verify the presence and integrity of 
prostate RNA in the blood samples, PCA3 (prostate cancer gene 3) and PSA (prostate 
specific antigen) mRNAs will also be quantified using the same methodology.100 
 
 
9.1.5 Description of Correlative Studies  


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9.1.5a. The Role of ETS Gene Fusions (in Metastases) as a Predictive Biomarker for 
Response to Abiraterone, Alone or in Combination with the PARP1 Inhibitor ABT-888, 
in Patients with Metastatic Castration-Resistant Prostate Cancer (CRPC) (Primary 
Objective #1) 
 
and 
 
9.1.5b. The Role of ETS Gene Fusions (in Metastases) as a Predictive Biomarker for 
Treatment Benefit for the Addition of ABT-888 to Abiraterone (Primary Objective #2) 
 
To determine gene fusion status in metastatic biopsies or metastatic prexisting tissue 
samples, our trial will utilize the following assays: 
• 
immunohistochemistry for ERG (the TMPRSS2:ERG gene fusion is the 
predominant ETS gene fusion, and comprises close to 90% of all ETS fusions) 
• 
ISH-based assays for ETV1 fusions (the second most common ETS fusions) 
Together, the ERG and ETV1 fusions comprise approximately 97% of all ETS fusions. 
Until recently, fluorescence in situ hybridization (FISH) approaches have been primarily 
used for the detection of gene fusions involving ERG.  However, recently, a rabbit anti-
ERG antibody has been demonstrated to exhibit extremely high concordance with FISH 
approaches for the detection of ERG fusions, with a sensitivity of approximately 96% 
and a specificity of approximately 97%.101  The diagnostic performance of this ERG 
antibody was independently evaluated in two large patient cohorts from two different 
institutions.101  Given the increased ease and decreased cost of performing 
immunohistochemistry compared to FISH, evaluation of ERG with this antibody 
approach is now offered in our CLIA lab at the University of Michigan, starting in March 
2011, and is the assay of choice, for detection of ERG fusions, in this gene-fusion guided 
clinical trial. 
 
While a robust antibody approach has been successfully been developed for detection of 
ERG, FISH approaches were, until recently, the gold standard for the detection of ETV1 
fusions. However, recently, using 329 samples of both metastatic and localized prostate 
cancer, our team has demonstrated the RNA-ISH (in-situ hybridization) is a good 
approach for detecting ETV1 rearrangements, with benefits in detection compared to the 
DNA-based FISH (fluorescence-in-situ-hybridization approaches).  The primary benefit 
of ETV1 RNA-ISH over ETV1 DNA-FISH is in the ability to detect rearrangements 
using a smaller amount of tissue, as is often the case with bone biopsies.102 Of the first 25 
patients enrolled on this trial, 13 have had assessment for ETV1 fusions by both ETV1 
FISH and ETV1 ISH.  Two cases were positive by both FISH and ISH assays; 10 were 
negative by both assays.  The thirteenth case was inconclusive for ETV1 fusions by 
FISH, but positive for ISH, confirming that even within this initial sample set, ETV1 ISH 
was superior to ETV1 FISH in performance.  Thus, moving forward, ETV1 ISH will be 
used as the gold standard for ETV1 fusion detection. 
 


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As noted, our research team has significant experience and competence with the ERG 
IHC and ETV1 ISH assays.  Our study pathologist, Dr. Arul Chinnaiyan and his team, 
discovered both ERG and ETV1 gene fusions several years ago14,15 and has helped 
develop the ISH assays used to detect ETS fusions.14,15,102  In addition, Dr. Chinnaiyan's 
group has helped perform the preliminary studies validating the performance of the ERG 
antibody.101 Based on our experience, we expect a 7-9 days from receipt of tissue to 
reporting of read-out of ETS fusion assays.  
The impact of ETS fusion status upon treatment outcome following abiraterone vs 
abiraterone + ABT888 will be determined, as described in section 13.1.  In addition, the 
role of ETS fusion in predicting benefit of the addition of ABT888 to abiraterone will 
also be determined, per section 13.1. 
 
 
9.1.5c Concordance in ETS Fusion Status among Primary Tumor, Metastases, and 
Circulating Tumor Cells in Patients 
 
 
ETS fusion status will be evaluated in metastases, primary tumor, and CTCs for 
assessment of concordance.  
• To determine gene fusion status in formalin-fixed metastatic and primary 
tumor biopsies, our trial will utilize the following assays: 
a) immunohistochemistry for ERG (the TMPRSS2:ERG gene fusion 
is the predominant ETS gene fusion, and comprises close to 90% of 
all ETS fusions) 
b) ISH-based assays for ETV1 fusions (the second most common 
ETS fusions) 
• 
To 
determine 
gene 
fusion 
status 
in 
isolated 
CTCs, 
immunofluorescence-based assays for ERG fusions will be performed.   
• 
Statistical assessment for concordance among metastases, primary 
tumor, and CTCs is described in Section 13.4.  
 
9.1.5d The Role of ETS Gene Fusions (in Circulating Tumor Cells) as a Predictive 
Biomarker of Response to Abiraterone, Alone or in Combination with the PARP1 
Inhibitor ABT-888, in Patients with Metastatic CRPC 
 
 
9.1.5e Circulating Tumor Cell Count, and biomarker status of androgen receptor, PTEN, 
RAD51, and gammaH2aX, at baseline, 12 weeks post-therapy, and at progression, as a 
Predictive Biomarkers of Response to Abiraterone, Alone or in Combination with the 
PARP1 Inhibitor ABT-888, in Patients with Metastatic CRPC 
 


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To determine gene fusion status in isolated CTCs, immunofluoresence-based 
assays for ERG will be performed utilizing the Epic Sciences System. The CTCs 
will be enumerated using the Epic Sciences System utilizing automated 
fluorescence- based microscopy systems that permit computer-generated 
reconstruction of cellular images. Associations between outcome, and CTC count 
and percent CTCs harboring ETS fusions, will be performed as per Section 13.4. 
In addition, immunofluoresence-based approaches will be used to assess levels of 
the androgen receptor, RAD51, and gammaH2aX in thte CTCs.  All CTC assays 
will be performed at baseline, at 12 weeks, and at time of progression. 
 
9.1.5f The Role of PTEN Loss (in Metastases) as a Predictive Biomarker for Response to 
Abiraterone, Alone or in Combination with the PARP1 Inhibitor ABT-888, in Patients 
with Metastatic Castration-Resistant Prostate Cancer (CRPC) 
 
We will assess for PTEN loss in metastatic samples using immunohistochemistry 
for a PTEN antibody (138G6–Cell Signaling Technology–Rabbit Monoclonal 
Ab) which has been validated in a CLIA certified lab with excellent performance 
characteristics103 and is also offered in our CLIA-certified lab. We will also 
assess for PTEN loss in CTCs using a FISH-based assay.93 CRPC samples from 
metastases and CTCs will be stratified by PTEN status, and the impact of PTEN 
loss on PSA response following treatment with abiraterone +/- ABT-888 will be 
assessed statistically, as described in Section 13.4.  
 
9.1.5g The Role of PARP1 Activity (in Metastases) as a Predictive Biomarker for 
Response to Abiraterone, Alone or in Combination with the PARP1 Inhibitor ABT-888, 
in Patients with Metastatic Castration-Resistant Prostate Cancer (CRPC) 
 
We will use immunohistochemical approaches to quantitate PAR and PARP1 
levels, as previously published, in metastases and determine the association 
between PAR levels with PSA response to abiraterone, alone and in combination 
with PARP1 inhibition. 
 
9.1.5h Discovery of Novel Gene Fusions Through Paired-End Transcriptome Sequencing 
of Metastases 
 
In frozen biopsy samples from the metastatic lesion, we propose to perform next-
generation sequencing, for discovery of novel targetable gene fusions distinct 
from ETS fusions.  The cancer genome is often highly aneuploid (aberrant 
chromosome numbers) or polyploid (with aberrant sets of chromosomes), and almost 
always highly rearranged, with several areas of gains and losses. To adequately 
analyze these complex sequences, requires extra deep coverage of the genome that is 
not yet routinely feasible (or economical) over large sample sizes. To circumvent 
these formidable sequencing needs we have considered a complementary approach of 
focusing on the ‘expressed’ component of the genome, namely the transcriptome. 
Sequencing the transcriptome not only provides an in depth coverage of entire 


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genomic coding sequences, but also serves as a direct readout of gene expression, 
alternatively spliced isoforms, gene fusions (including RNA chimeras) and 
SNPs/mutations, thus enriching the data for ‘functional’ aberrations with 
considerably reduced sequencing resources and time as compared to genomic 
sequencing. We have recently applied transcriptome sequencing to discover multiple 
novel gene fusions and RNA chimeras in prostate cancer, including the discovery of a 
recurrent chimera, SLC45A3-ELK4 in a subset of prostate cancer tissues11. 
Subsequently, in a proof of concept study we have improved our technique by 
developing the method of ‘paired end transcriptome sequencing’ to systematically 
identify gene fusions and chimeric transcripts in cancers.17,104,105 
 
We will now focus on applying transcriptome sequencing to characterize recurrent 
gene fusions and other transcript aberrations in prostate cancer biospecimens 
collected by this protocol. Two types of next-generation sequencing libraries will 
be constructed and sequenced from the sample RNA.  Specifically, paired-end 
transcriptome libraries from polyadenylated RNA, as well as from ribosomal 
RNA depleted samples (Ribominus), will be sequenced. The aim will be to 
discover novel cancer-specific, recurrent gene fusions and other signature genetic 
aberrations in these prostate cancer samples. The specific aims are to 1. Generate 
high throughput transcriptome sequencing data from these prostate cancer samples 2. 
Bioinformatically identify cancer-specific, recurrent gene fusions, SNPs and 
alternatively spliced (AS) transcript isoforms in prostate cancer. 3. Experimentally 
validate candidate transcript aberrations and screen big sample cohorts to determine 
recurrence and to 4. Functionally characterize novel, recurrent aberrations with 
clinical implications.  These sequencing approaches, and the required bio-
informatic pipelines necessary to analyze the sequencing data, have previously 
been established by our research team, led by Dr. Arul Chinnaiyan.14,15,104,105 
 
9.1.5i   Discovery of novel SNPs Predictive of Response to Abiraterone, Alone or in 
Combination with the PARP1 Inhibitor ABT-888, in Patients with Metastatic Castration-
Resistant Prostate Cancer (CRPC) 
 
Germline DNA will be extracted from patient peripheral blood mononuclear cells 
using Qiagen DNAEasy assay (Qiagen, Valencia, CA) according to manufacturer 
methods.  The extracted DNA will be genotyped for 128 SNPs utilizing a TaqMan 
OpenArray GT Kit (Applied Biosystems, Carlsbad, CA) according to manufacturer 
specifications.  SNPs have been chosen to include previously implicated SNPs of 
interest (i.e. SLCO1B3 (rs4149117)) as well as SNPs in genes with critical roles in 
the metabolism, transport, elimination, and mechanism of action of hormonally 
targeted therapies.  Details regarding the 128 SNPs of interest have been previously 
reported.106 
 
9.1.5j The Role of blood TMPRSS2:ERG RNA as a Predictive Biomarker of Response 
to Abiraterone, Alone or in Combination with the PARP1 Inhibitor ABT-888, in Patients 
with Metastatic CRPC 
 


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Blood TMPRSS2:ERG mRNA levels will quantified at baseline and after initiation of 
treatment. PCA3 and PSA mRNA levels will also be measured as controls, and may 
be used to normalize TMPRSS2:ERG RNA levels for the amount of prostate-specific 
RNA in blood. Associations between outcome, and baseline TMPRSS2:ERG mRNA 
levels (or changes in TMPRSS2:ERG mRNA levels) will be performed per Section 
13.4. 
 
10. 
STUDY CALENDAR 
 
Pre-Study evaluations are to be conducted within 3 weeks prior to registration.   Biopsy must be done within 10 calendar 
days post registration and results will be reported within 10 calendar days.  Patients who are eligible and randomized must have 
Cycle 1 Day 1 evaluations and procedures completed and begin therapy within 7 working days from randomization. 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.  Please refer to # below for Abiraterone + Prednisone Cycle 1 schedule for patients 
randomized to Arms IB and II B (Abiraterone + ABT888). 
 
Return visits after initiation of therapy can be done within ± 4 days from actual due date and lab draws (CBC w/diff, 
plts and Serum chemistry) on day 8 and 15 can be done ± one day. Correlative blood samples to be collected post-
randomization but before starting treatment on day 1. 
 
 
 
Cycle 1 
Cycle 2  
Cycle 3 
 
 
Required Treatment or 
Studies 
Pre- 
Study 
Day 
1 
Day 
8 
Day 
15 
Day 
22 
Day 
1 
Day 
8 
Day 
15 
Day 
22 
Day 
1 
Day 
8 
Day 
15 
Day 
22 
Subsequent 
Courses 
 
Off Studyc 
 
ABT-888 
 
 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
A 
 
 
Abiraterone+ 
Prednisone # 
 
 
# B 
B 
B 
B 
B 
B 
B 
B 
B 
B 
B 
B 
B 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History & Physical 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X& 
 
X 
Weight & PS 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X& 
 
X 
 
Concurrent meds 
X 
 
X----------------------------------------------------------------------------------------X 
 
X 
 
 
 
Metastatic disease 
biopsy*  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
     
 
Serum PSA 
X 
Xe 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
 
CBC w/diff, plts 
X 
Xd 
 
X 
 
X 
 
X 
 
Xd 
 
 
 
X 
 
X 
 
Serum chemistrya 
X 
Xe 
X 
X 
X 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
EKG (as indicated) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Testosterone 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PTT/ PT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event 
evaluation 
 
 
 
X---------------------------------------------------------------------------------------X 
 
X 
 
Tumor measurements 
X 
Tumor measurements are repeated every 12 weeks.  Documentation 
(radiologic) must be provided for patients removed from study for progressive 
disease. 
 
 
 
 
Radiologic evaluationb  
X 
Radiologic measurements should be performed every 12  weeks +/-1  week 
 
& 
 


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Blood samples for ETS 
fusion mRNA studies 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Blood samples for CTC 
studies f 
 
  X 
 
 
 
 
 
 
 
 
 
 
 X 
X 
X 
Blood samples for SNP 
studies 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A: ABT-888:  Dose as assigned; administration schedule 
B: Abiraterone / Prednisone:   Dose as assigned; administration schedule 
#  For patients randomized to Arms IB and IIB:  For Cycle 1 only Abiraterone and Prednisone will start on day 8 to allow lead in ABT888 therapy  
For all subsequent cycles Abiraterone/prednisone will start on day 1 and continue daily in 28 days cycle  
*  Biopsy must be done after patient has consented and registered to the study  (unless prexisiting metastatic tissue is available)  
& After the first 3 months if patients are tolerating therapy well and clinically stable clinic visit for H&P can be done every three months  
Chemistry and PSA will be done on D1 of each cycle as specified  For patients coming every 3 months a 3 month supply of ABT-888 can be 
provided per institutional guidelines  Imaging will be done every 3 months until disease progression or removal from study for patients on 
study for < 1 year  For patients who have completed ≥ 1 year of therapy, imaging can be done every 4 months   For patients who have 
completed ≥ 2 years of therapy, imaging can be done every 6 months  Irrespective of duration on therapy imaging can be done sooner than the 
specified intervals as clinically indicated   a:Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, 
glucose, phosphorus, potassium, total protein, SGOT [AST], SGPT [ALT], sodium  
b   Include bone scan, CT/MRI abdomen and pelvis, CT chest or C XR as appropriate    All disease sites must be reassessed  
c: 30 day off study follow-up for adverse event assessment    
d  CBC w/diff, plts will be monitored on Day 1 only of each cycle after Cycle 1 and 2 if no hematologic toxicity is observe on  Day 15 of cycle 1 
and 2  CBCw/diff after cycle 2 can be done as otherwise clinically indicated  
e  Cycle 1 Day 1 labs will always be reviewed prior to dosing  
f  Pretreatment, end of C#3 and disease progression or removal from study 
 
 
 
11. 
MEASUREMENT OF EFFECT 
 
• For the purposes of this study, patients should be reevaluated for objective (radiologic) 
response every 3 cycles (ideally, every 12 weeks +/- 1 week).   
• Patients demonstrating evidence of objective progression by bone scan but no objective 
measurable disease progression or PSA progression at the first tumor assessment after 3 
cycles should continue on treatment and repeat scans should be done in 6 weeks: 
o If no additional objective progression is noted (SD), then patients will continue on 
therapy.  
o If additional objective progression is demonstrated, then patients are removed from 
study. The date of the imaging at 3 cycles (12 weeks) will be recorded as the date of 
progressive disease.   
 
• 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) [Eur J Ca 45:228-247, 2009].  Changes in 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. 
 
• Pain is a criteria for progression. Please refer to section 11.1.5.5 for specific definitions. 
 
11.1 
Definitions 


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Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of 
their first treatment with Abiraterone +/-ABT-888. 
 
Evaluable for objective response.  Only those patients who have measurable disease 
present at baseline, have received at least two cycles of therapy, and have had their 
disease re-evaluated will be considered evaluable for response.  These patients will 
have their response classified according to the definitions stated below.  (Note:  
Patients who exhibit objective disease progression prior to the end of cycle 1 will 
also be considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at 
baseline that are evaluable but do not meet the definitions of measurable disease, 
have received at least two cycles of therapy, and have had their disease re-evaluated 
will be considered evaluable for non-target disease.  The response assessment is 
based on the presence, absence, or unequivocal progression of the lesions.  
 
 
11.1.2 Disease Parameters 
 
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 CT scan, MRI, or 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 might or might 
not be considered measurable.  If the investigator thinks it appropriate to include 
them, the conditions under which such lesions should be considered must be defined 
in the protocol. 
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be >15 mm in short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm).  At baseline and in follow-
up, only the short axis will be measured and followed. 
 
Non-measurable 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 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 


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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. 
 
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. 
 
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.  
 
11.1.3 Methods 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 
beginning of treatment and never more than 6 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 ≥10 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 


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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. 
 
 
11.1.4 Methods of Evaluation of Bone disease: 
 
 
 
Bone disease will be evaluated using Radionuclide bone scan. 
 
 
11.1.5 Response Criteria 
 
11.1.5.1 
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. 
 


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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. 
 
11.1.5.2 
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). 
 
11.1.5.3   Outcomes based on Radionuclide bone scans:  
 


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The subjectivity in interpreting serial changes in a radionuclide bone scan is well recognized.  
Thus, the primary outcome will be whether the scan is stable or improved, vs. worse or 
progression.  Changes in intensity will not be used as an outcome measure. 
 
Stable or Improved: A stable or improved classification requires that no new 
lesions appear at the 3rd cycle (12 weeks) ± 1 week assessments, or that new pain 
has not developed in an area that was previously visualized. 
 
Progression (Non-Response): Appearance of two or more new skeletal lesions. 
An increase in the size or intensity of known skeletal lesions will not be 
considered progression. 
    
11.1.5.4  Outcomes based on post-therapy PSA changes:  
These definitions are intended to characterize the PSA changes on study for the purpose of 
reporting of results.    
 
Complete Response  (CR): Undetectable PSA (<0.2 ng/ml) that is confirmed by 
another PSA level at no less than 4 weeks interval. 
 
Partial Response (PR): Decrease in PSA value by > 50% that is confirmed by 
another PSA level at no less than 4 weeks interval. 
 
Stabilization (SD): Patients who do not meet the criteria for PR or PD for at least 90 
days on study (2 cycles of treatment) will be considered stable 
 
Progression (PD): 25% increase over baseline or nadir whichever is lower and an 
increase in the absolute value of PSA level by 2 ng/ml that is confirmed by another 
PSA level at no less than 4 weeks interval. 
 
 


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11.1.5.5   Definition of Progression Based on Pain:  
 
Progression by pain criteria is based on pain due to prostate cancer requiring one or more 
of the following palliative interventions: 
 
o Opioid Therapy: Intravenous, intramuscular or subcutaneous opioid therapy 
administered as a single dose; oral or transdermal opioid analgesic use 
administered for 10 out of 14 consecutive days, and/or requiring Radionuclide or 
Radiation therapy.   
 
o Evidence of disease at the site of pain is required.  Pain requiring only non-opioid 
analgesics will not be considered disease progression. 
 
 
11.1.6 Progression-Free Survival 
 
Progression-free survival (PFS) is (PFS) is defined as the duration of time from start of treatment 
to time of progression or death, whichever occurs first. 
 
11.2 
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. 
 
 
 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 
>4 wks. Confirmation** 
CR 
Non-
CR/Non-PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not 
evaluated 
No 
PR 
PR 
Non-
CR/Non-
PD/not 
evaluated 
No 
PR 


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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) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11.3 
Duration of Response 
 
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). 
 
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 category when no lesions can be measured is not advised 


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The duration of overall CR is measured from the time measurement criteria are first 
met for CR until the first date that progressive disease is objectively documented.  
 
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.  


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12. 
 
DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
 
12.1  Data Reporting 
 
 
 
12.1.1 Method 
 
This study will be monitored by the Clinical Data Update System (CDUS) Version 
3.0.  Cumulative protocol- and patient-specific CDUS data will be submitted 
electronically to CTEP on a quarterly basis, either by FTP burst of data or via the 
CDS web application.  Reports are due January 31, April 30, July 31, and October 
31.  Instructions for submitting data using the CDUS can be found on the CTEP Web 
site (http://ctep.cancer.gov/reporting/cdus.html).    
 
 
Note:  If your study has been assigned to CDUS-Complete reporting, all adverse 
events (both routine and expedited) that have occurred on the study and meet the 
mandatory CDUS reporting guidelines must be reported via the monitoring method 
identified above.  If your study has been assigned to CDUS-Abbreviated reporting, no 
adverse event reporting (routine or expedited) is required to be reported via CDUS. 
 
12.1.2 Responsibility for Data Submission 
 
Study participants are responsible for submitting CDUS data and/or data forms to 
the Coordinating Center quarterly by January 31, April 30, July 31, and October 31 
to allow time for Coordinating Center compilation, Principal Investigator review, 
and timely submission to CTEP (see Section 12.1.1).  For trials monitored by CTMS, 
the monthly data submission to CTEP from Theradex should be copied to the 
Coordinating Center. 
 
The 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.   
 
 
12.2 
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 


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Coordinating Center (Study Coordinator) and the procedures for auditing are presented 
in Appendix B. 
 
• The Principal Investigator/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 Coordinating Center to the CTEP PIO (PIO@ctep.nci.nih.gov) except for 
Group studies. 
 
 
12. 3  Data and Safety Monitoring Procedures 
 
Data Safety and Monitoring will occur as specified by the University of Chicago Phase 2 
Consortium Procedure Manual.  Adverse event and serious adverse event reporting is discussed 
in Section 7.  As per the University of Chicago Comprehensive Cancer Center NCI approved 
DSM Plan, routine data and safety monitoring will occur at the weekly University of Chicago 
Phase II Consortium meetings, which are led by Phase 2 Consortium Chairman, Dr. Stadler or a 
senior level medical oncologist designee.  The meeting is held by tele- and web conferencing for 
participation by the protocol PI or her designate.  At each meeting, all active Phase II Consortium 
studies are reviewed for safety and progress toward completion. Toxicities and adverse events 
are reviewed as well and a Data Safety and Monitoring form is completed for each protocol and 
signed by either the principal investigator, the Chairman of the Phase II Consortium or by his 
designate if neither is available. 
 
In addition, a formal review of all collected data will be conducted by the PI after the initial 3 
subjects have completed 2 months of therapy and quarterly thereafter.  Formal accrual reports 
will be generated for PI review on a quarterly basis as well. 
 
12. 4  Quality Assurance and Audits 
 
The Cancer Therapy Evaluation Program (CTEP), as the sponsor of clinical trials of 
investigational agents on behalf of the Division of Cancer Treatment and Diagnosis (DCTD), 
requires that all institutions conducting clinical trials involving NCI-sponsored investigational 
agents be site visited at least once every three years.  The Clinical Trials Monitoring Branch 
(CTMB), in CTEP, is responsible for monitoring and overseeing the site visit program. 
Theradex, a Clinical Trials Monitoring Service (CTMS) contractor, administers the site visit 
audit program on behalf of CTMB. Theradex is a pharmaceutical consulting and development 
company based in Princeton, New Jersey. The audit teams who conduct the audit are composed 
of experienced clinical research associates, pharmacists and outside physicians, as necessary, 
who have specialized experience and expertise relevant to the types of protocols being reviewed.  
 
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period will be eligible for an audit at least every thirty-six months but may be selected for audit 
at any time. The objectives of the audit are to bring to the attention of the individual 
investigators, the Food and Drug Administration regulatory requirements which affect various 
aspects of the conduct of clinical studies. The items reviewed will include: 
 
1. Full and non-contingent Institutional Review Board approval. 
2. Copies of the Institutional Review Board approval to be available, including 
approvals for al amendments. 
3. Copies of the annual reports on the progress of the study and copies of Institutional 
Review Board re-approval.  
4. An IRB approved informed consent for all patients entered on study. 
5. Adherence to the protocol. 
6. Classification of adverse experiences and the reporting to the NCI drug monitor of 
unusual or unexpected events. 
7. Follow up on drop outs with due diligence. 
8. The regulatory requirements as they affect record keeping and record retention. 
9. Test article or investigational drug accountability. This involves a discussion with 
pharmacy the methods of record keeping which best satisfies the federal regulations 
and NCI guidelines and requirements. 
 
12.5 
Collaborative Agreements Language 
 
ABT-888 supplied by CTEP, DCTD, NCI in this protocol is provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between Abbott (hereinafter 
referred to as “Collaborator(s)”) and the NCI Division of Cancer Treatment and 
Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained 
within the terms of award, apply to the use of the Agent(s) in this study: 
 
1.   ABT-888 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 Agents contain confidential information and should not be shared or 
distributed without the permission of the NCI.  If a copy of this protocol is requested 
by a patient or patient’s family member participating on the study, the individual 
should sign a 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 Agent(s), each the subject of different Collaborative Agreements, the 
access to and use of data by each Collaborator shall be as follows (data pertaining to 
such combination use shall hereinafter be referred to as "Multi-Party Data”): 


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a.  
NCI will provide all Collaborators with prior written notice regarding the 
existence and nature of any agreements governing their collaboration with NCI, 
the design of the proposed combination protocol, and the existence of any 
obligations 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 Agent. 
 
c.  
Any Collaborator having the right to use the Multi-Party Data from these 
trials must agree in writing prior to the commencement of the trials that it will 
use the Multi-Party Data solely for development, regulatory approval, and 
commercialization of its own Agent. 
 
3.   Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available to Collaborator(s), the NCI, and the FDA, as 
appropriate and unless additional disclosure is required by law or court order as 
described in the IP Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used 
and disclosed consistent with all applicable federal statutes and regulations for the 
protection of human subjects, including, if applicable, the Standards for Privacy 
of Individually Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4.   When a Collaborator wishes to initiate a data request, the request should first be sent 
to the NCI, who will then notify the appropriate investigators (Group Chair for 
Cooperative Group studies, or PI for other studies) of Collaborator's wish to contact 
them. 
 
5.   Any data provided to 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 
by the Group office for Cooperative Group studies or by the principal investigator for 
non-Cooperative Group studies for immediate delivery to Collaborator(s) for 
advisory review and comment prior to submission for publication.  Collaborator(s) 
will have 30 days from the date of receipt for review.  Collaborator shall have the 
right to request that publication be delayed for up to an additional 30 days in order to 
ensure that Collaborator’s confidential and proprietary data, in addition to 
Collaborator(s)’s intellectual property rights, are protected.  Copies of abstracts must 


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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: 
 
Email: ncicteppubs@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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13. 
STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
 
The goal of this phase II study is to assess the role of the ETS fusion biomarker on efficacy of 
Abiraterone + ABT-888 in comparison to Abiraterone alone in mCRPC patients. The primary 
endpoint will be the confirmed PSA response rate. Overall comparison of treatments and comparison 
of treatments within strata will describe the role of the ETS fusion biomarker on the endpoint by 
treatment. 
 
The biomarker-stratified design107 will be used to determine if there is a difference in PSA response 
between the ETS gene fusion-positive and fusion-negative strata in PSA response to Abiraterone 
compared to Abiraterone + ABT-888.  An overall improvement of 20% in PSA response, from 30% 
expected with Abiraterone versus 50% with Abiraterone + ABT-888, is detectable with 80% power 
at a one-sided 5% significance level assuming 148 total patients are randomized 1:1 to Abiraterone 
vs Abiraterone + ABT-888.  Thus, there will be 74 patients per treatment.  Enrollment will continue 
until 148 patients have been randomized and are response evaluable.  Response evaluable patients 
are defined as patients receiving at least 2 cycles of therapy or patients removed from study due to 
toxicity before completing 2 cycles. It is estimated that 55% of patients enrolled will be ETS fusion-
positive and 45% ETS fusion-negative which results in 81 fusion-positive in the ETS fusion-positive 
stratum and 67 patients in the ETS fusion-negative stratum.  In addition, 81 fusion-positive patients 
randomized provide 87% power to detect a 30% difference in PSA response rates between 
Abiraterone versus Abiraterone + ABT-888 at a 5% one-sided significance level in this stratum; 67 
fusion-negative patients randomized provides 80% power to detect a 30% difference in response 
between treatments at a 5% one-sided significance level in this stratum. 
 
Primary Endpoint Analysis Plan:  Confirmed PSA response rates and the corresponding binomial 
confidence intervals will be reported for each arm.  A logistic model including treatment group, 
fusion status, and prior ketoconazole use will be used to determine the interaction between the rates 
of PSA response between Abiraterone and Abiraterone + ABT-888 and ETS fusion status.  The 
interaction will be tested with a significance threshold of 0.15.  If the interaction is not significant, 
the overall PSA response rates will be compared overall.  Four pair-wise comparisons will be made 
between treatment arms.  These comparisons will be: 
1) ETS fusion-positive Abiraterone vs  ETS fusion-positive Abiraterone + ABT-888. 
2) ETS fusion-negative Abiraterone vs ETS fusion-negative Abiraterone + ABT-888 
3) ETS fusion-positive Abiraterone vs ETS fusion-negative Abiraterone 
4) ETS fusion-positive Abiraterone + ABT-888 vs ETS fusion-negative Abiraterone + ABT-
888                                                                                                                                               
   
 
• 
Using αint=0.15, the interaction test has 85% power when there is a 40% increase in 
PSA response between treatments in ETS fusion-positive patients and no treatment effect 


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in ETS fusion-negative patients and 67% power when there is a 30% increase in PSA 
response in ETS fusion-positive patients and no treatment effect in ETS fusion-negative 
patients. 
• 
Probability of Significant Treatment Effect in ETS Fusion-Positive Patients: 
 
 
 
 
 
 
 
 
 
 
 
Interim Analysis Plan and Early Stopping: 
 
After accrual of 34 response evaluable patients in each ETS stratum, accrual will be halted and an 
interim analysis will be completed.  The results of the interim futility analysis will be discussed with 
CTEP to determine the arms that will be re-opened for enrollment. A comparison within each 
stratum will be made.  If the observed PSA response is the same or worse in the Abiraterone + ABT-
888 treatment arm compared to Abiraterone alone then the Abiraterone + ABT-888 treatment arm in 
that stratum will be stopped.  Under the null, the early stopping probability is 57% and under the 
alternative, has probability of 15.7%.  
 
In addition, each Abiraterone alone arm will be tested for efficacy.  If we have evidence in either 
stratum that Abiraterone alone has a response rate < 5% then we would want to stop treating patients 
in that arm.  Using a binomial comparison with the null hypothesis of PSA response of 30% 
compared to a 5% PSA response rate this treatment arm will close with less than 2 PSA responses 
out of the 17 patients.  If the fusion positive cohort crosses a futility boundary and the fusion 
negative cohort has not crossed the futility boundary, the data will be jointly reviewed by CTEP and 
the investigators to determine whether accrual to the study will continue. If both combination arms 
are closed for futility the trial will close regardless of futility in the single agent arms. 
 
 
Concordance in ETS fusion status between the primary and metastatic biopsies will be examined 
during the interim analysis if there is more than half of the patients have both tissue types available 
for analysis.  The binomial confidence interval will be used to assess concordance with a requirement 
that the lower confidence limit be greater than 80% to consider allowing the requirement of 
metastatic biopsies to be relaxed.  
 
Safety Assessment: 
 
PSA Response 
Difference in ETS+ 
Probability of Significant Treatment 
Effect in ETS Fusion-Positive 
Stratum 
0.2 
0.58 
0.25 
0.74 
0.3 
0.87 
0.35 
0.95 
0.40 
0.98 


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Review of the dose of the combination treatment of Abiraterone + ABT-888 will be conducted after 
the first 10 and again after the first 20 patients who receive the combination treatment.  If toxicity, 
defined as Grade 4 or greater that is at least possibly related to the study drug(s), in the first cycle is 
greater than 33% at either assessment, then an amendment for dose adjustments will be 
recommended.  The dose recommended will be based upon final phase I data and dose reduction data 
from this trial.  The table below outlines the probability of such adjustments based upon a range of 
true toxicity probabilities. 
 
 
P(Tox in 4 or more out of 10) 
P(Tox in 4 or more out of 20) 
True toxicity rate = 10% 
0.013 
0.002 
True toxicity rate = 20% 
0.121 
0.087 
True toxicity rate = 30% 
0.350 
0.392 
True toxicity rate = 40% 
0.618 
0.750 
True toxicity rate = 50% 
0.828 
0.942 
 
 
13.2 
Sample Size/Accrual Rate 
 
Proposed Sample Size:  148 gene fusion assessable and response evaluable patients will be stratified 
based on gene fusions and randomized.  Assuming that 55% of patients harbor ETS fusion-positive 
prostate cancers, 81 patients will be randomized amongst two proposed treatments for ETS fusion-
positive cancer.  The 67 remaining patients (ETS fusion negative) will be randomized between the 
same two treatments as the ETS fusion positive patients.  We plan to accrue 8 – 10 patients per 
month.  Thus this trial will take approximately 15-19 months to accrue.  It is expected that the trial 
will be halted to accrual for interim efficacy analysis for 4 months.  Final follow-up for the primary 
endpoint will be approximately 6 months for the last enrolled patients.  Final trial time will be 
approximately 2 to 3 years. 
 
This timeline will change if arms close at the interim due to efficacy.  If one arm is closed after the 
interim analysis, the final sample size will be at most 132 patients; two arms closed will have a 
maximum of 116 patients. 
 
13.3 
 
Stratification Factors 
 
Patients will be stratified by ETS gene fusion status into ETS positive and ETS negative groups 
and by use of ketoconazole (yes/no) prior to enrollment. 
 
13.4 
 
Analysis of Secondary Endpoints 
 
Secondary endpoints:  Secondary aims will include rates of PSA decline, objective response rates, 
progression free survival, and toxicity of Abiraterone and Abiraterone + ABT-888. 


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• Rates of PSA decline will be exhibited using waterfall plots of 12 week PSA decline and 
maximum PSA decline by treatment arm.  Additionally, the rate of PSA decline will be 
explored using a repeated measures mixed model with the natural log of PSA as the outcome. 
 Fixed effects likely will include treatment, Fusion status, time and the interactions.  A 
second order of time may be necessary as PSA will increase with progression after the 
decline. 
• Objective response proportions with corresponding binomial confidence intervals will be 
reported by treatment. 
• Progression-free survival (PFS) events are defined as the first event of disease progression or 
death.  Patients who do not have an event will be censored at their last disease assessment.  
Kaplan-Meier methods will be used to describe progression free survival by arm. 
• Toxicity will be described by type, grade and frequency for each treatment and arm. 
 
Correlative Analysis Plan: 
Correlative aims include evaluating circulating tumor cells (CTCs) at baseline, during therapy,  and 
at progression in all patients, concordance in fusion status among prostate cancer samples from the 
primary site, biopsied metastasis, and CTCs, ability of expression levels of ETS fusion products in 
the primary tumor, metastasis, and CTCs to predict response to ETS-directed therapies, and next-
generation sequencing for discovery of novel gene fusions in prostate cancers negative for ETS 
fusions. 
 
• CTCs at baseline will be described by treatment arm and strata.  Models may be used to 
explore early baseline CTCs enumeration and molecular characterization to predict response 
and PFS. 
• Concordance of the ETS fusion status between samples (primary, metastatic, and CTCs) 
from each patient will be described and tested between the three populations using a 
generalized kappa. The three pairwise comparisons will also be investigated and McNemar’s 
test and kappa statistic for each will be reported. 
• Logistic models with response as the outcome and loss of PTEN in the specimen will be used 
to determine if PTEN loss predict response to Abiraterone +/- ABT-888 Treatment arm may 
be controlled for or used as a stratification factor in the model. 
• Logistic models with response as the outcome and expression levels of PAR in the specimen 
will be used to determine if PARP activity predict response to Abiraterone +/- ABT-888 
Treatment arm may be controlled for or used as a stratification factor in the model. 
• Next-generation sequencing for discovery of novel gene fusions in prostate cancers negative 
for ETS fusions will be performed.  In general, genes fusions that are highest and are found 
in 2 or more patients will be explored further.  The best methods that are recommended for 
this exploration at the time that all tissue is collected and available will be used.  As these 
methods are rapidly changing, this is difficult to predict at this time.  


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• Standard quality control statistical analyses (i.e. Hardy-Weinberg Equilibrium testing) will be 
performed to analyze SNP assay results.  Univariable analyses will be performed to identify 
candidate SNPs associated with favorable abiraterone outcomes.  SNPs identified in the 
univariable analyses will be tested for significance in a multivariable analysis with inclusion 
of relevant clinical patient parameters (i.e. ETS fusion status, ABT-888 treatment status, 
performance status, prior ketoconazole therapy, etc.). 
•  Blood TMPRSS2:ERG mRNA levels at baseline and change from baseline during therapy 
will be described by treatment arm and strata.  Logistic and Cox regression models may be 
used to explore baseline RNA levels or early changes in RNA levels to predict response and 
PFS respectively. 
 
  


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13.5 
 
Reporting and Exclusions 
 
13.5.1 Evaluation of toxicity – All patients will be evaluable for toxicity from the time of 
their first treatment with Abiraterone or Abiraterone + ABT-888. 
 
13.5.2 Evaluation of response – All patients included in the study must be assessed for 
response to treatment, even if there are major protocol treatment deviations or if 
they are ineligible.  Each patient will be assigned one of the following categories:  
1) complete response, 2) partial response, 3) stable disease, 4) progressive disease, 
5) early death from malignant disease, 6) early death from toxicity, 7) early death 
because of other cause, or 9) unknown (not assessable, insufficient data).  [Note:  
By arbitrary convention, category 9 usually designates the “unknown” status of any 
type of data in a clinical database.] 
 
All of the patients who met the eligibility criteria (with the possible exception of 
those who received no study medication) should be included in the main analysis of 
the response rate.  Patients in response categories 4-9 should be considered to have 
a treatment failure (disease progression).  Thus, an incorrect treatment schedule or 
drug administration does not result in exclusion from the analysis of the response 
rate.   
 
All conclusions will be based on all eligible patients.  Subanalyses may then be 
performed on the basis of a subset of patients, excluding those for whom major 
protocol deviations have been identified (e.g., early death due to other reasons, 
early discontinuation of treatment, major protocol violations, etc.).  However, these 
subanalyses will not serve as the basis for drawing conclusions concerning 
treatment efficacy, and the reasons for excluding patients from the analysis should 
be clearly reported.  The 95% confidence intervals will be provided.  
 


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APPENDICES: 
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 MULTICENTER 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 
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. 
 


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• 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 
 
Standard Operating Procedures for CT-guided Biopsy of Metastatic Prostate Cancer 
Lesion in Bone 
 
Patients will be scheduled for a CT-guided biopsy of a bone or soft tissue abnormality consistent 
with prostate metastasis.  The site of biopsy will be determined after review of available 
radiographs, CT, MRI, and/or bone scan (where applicable).  The decision regarding which 
metastatic lesion to biopsy should depend on three main factors: 
1) 
Size of lesion (with preference towards the largest lesion) 
2) 
Safety (with obvious preference towards least risk to the patient) 
3) 
For bone lesions, the intensity of lesion activity on bone scan (with preference 
towards the most intense activity) 
Verbal and written informed consent will be obtained after discussion of risks (bleeding, 
infection, soft tissue and bone injury, inconclusive biopsy results) of the procedure.  Standard 
laboratory tests to assess coagulation and bleeding will also be completed prior to the procedure. 
 Conscious sedation will be used as necessary using intravenous Fentanyl and Midazolam with 
appropriate nursing support. In order to ensure adequate tumor sample as long as it is deemed 
safe and based on accessibility, target lesion size, specimen integrity, specimen appearance, intra-
procedural bleeding, tumor biopsy should attempt to obtain   2-8 bone biopsy samples in addition 
to possible bone marrow aspirate, to be determined at the time of biopsy. 
 
 
The patient will be initially scanned with a clinically-available multislice CT scanner for the 
purpose of biopsy planning.  Biopsies will be performed using sterile technique and lidocaine 
local anesthetic. For bone lesions, a clinically-available 11-to-14 gauge bone cutting needle, with 
or without a co-axial trocar, will be used to obtain two to eight biopsy samples of the selected 
lesion.  Options for obtaining multiple samples of the biopsy can include: 
a) 
Sequential advancement of needle passes through a fixed trocar, such that each 
needle pass progresses more deeply into the bone lesion 
b) 
Re-insertion and re-direction of the needle and/or trocar through another region of 
the bone lesion  
c) 
Aspiration of the lesion will be attempted in conjunction with biopsy, by attaching 
a 20 cc sterile syringe to the cannula of the biopsy needle and aspirating into this 
syringe, with repeat aspirations as needed. 
 
 
At the completion of the procedure, CT imaging will be repeated to assess for immediate 
complications.  The patient will be observed for 2 – 4 hours before discharge. 
  


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APPENDIX D 
 
Standard Operating Procedures for CT-guided Biopsy of Metastatic Prostate Cancer 
Lesion in Soft Tissue 
 
The patient’s imaging will be reviewed and all soft tissue or nodal lesions deemed suspicious for 
metastasis will be considered.  A target for sampling will be selected based on: 1) perceived 
percutaneous access with respect to safety and technical feasibility, and 2) suspected likelihood 
of obtaining malignant tissue.  In the cases where both bone and soft tissue lesions are safely 
accessible and have high likelihoods of containing malignant tissue, it would be preferable to 
biopsy the soft tissue lesion.  
 
• For lymph nodes or soft tissue lesions a CT scan will be utilized.  An ultrasound may be 
utilized, provided that the target lymph node or soft tissue mass is visible and accessible. 
    
• In order to ensure adequate tumor sample as long as it is deemed safe and based on 
accessibility, target lesion size, specimen integrity, specimen appearance, intra-procedural 
bleeding, tumor biopsy should attempt to obtain: 
o  at least 6 cores if obtaining a 1-cm-long 18-gauge core specimen.   
or 
o at least 4 cores if obtaining a 2-cm-long 18-gauge core specimen.  The needle 
should be directed into the center of the lesion.  
 
Options for obtaining multiple samples include similar principles as described for bone lesions, 
including sequential advancement through the lesion, re-insertion/re-direction, or aspiration 
where appropriate. 
 
Mitigating factors may include but are not limited to: 1) safety of obtaining multiple core 
specimens, 2) friability of the core specimens on visual inspection, 3) target size, 4) perceived 
likelihood of obtaining additional diagnostic tissue by continued sampling.  After biopsy is 
performed, the biopsy would be snap frozen, as described in Appendix E.  No aspirate will be 
performed for soft tissue biopsies. 
 
 


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APPENDIX E:  
 
Standard Operating Procedure (SOP) for Handling Samples  
 
1.0 PURPOSE  
 
To standardize the method for handling frozen needle tumor biopsies, to optimize specimen use 
for molecular analyses. 
 
2.0 MATERIALS AND EQUIPMENT REQUIRED  
 
2.1 Sample kit containing: 
Dual sample kit will be sent to each enrolling site immediately following patient 
registration 
A) Cell Free DNA 1 tube 
B) EDTA 1 tube 
C) PAXgene tubes 2 
D) Sheet for recording biopsy details 
This sample kit will be sent to each enrolling site immediately following patient 
registration. 
 
2.2 Other materials which will be sent to each enrolling site at the initiation of the clinical trial 
(to be kept for use over serial cases):  
a) One box Tissue Tek™ cryomolds 
b) Large bottle of Tissue Tek™ OCT 
c) Blue Pads, Markers 
d) 
Sterile tweezers  
e) 
Shipping labels 
f) 
A supply of additional Cell-Free DNA tubes (for CTC samples at the end of cycle 
3 and at disease progression) (see Appendix G for handling of CTC samples) 
g) 
Boxes for shipment of CTC sample (see Appendix G) 
 
2.3 Materials that will be provided by the enrolling site: 
a) Dry ice  
b) -80°C freezer (particularly in the case of Friday biopsies) 
 
3.0 OPERATING PROCEDURES  
 
3.1 At least 24 hours prior to the biopsy, the research coordinator is to notify the institutional 
research team involved in this protocol, of the scheduled sample collections.  A laboratory 
technician should pick up the sample kit (see 2.1 above), and prepare cryomolds prior to the 
biopsy, by labeling them, using the provided alcohol-proof marker, with the following 


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information:  
             Clinical protocol number 
             Specimen ID  
             Biopsy time and Date       
The research coordinator and the laboratory technician should also confirm, on the day prior to 
biopsy, the availability of materials needed for handling the biopsies, as specified in Section 2 
above. 
3.2 The laboratory technician should arrive at the biopsy collection site at least 15 min ahead of 
the scheduled biopsy to allow sufficient time to set up laboratory supplies and ensure rapid 
transport of specimens to the laboratory after collection.  He or she should also re-confirm, at that 
time, the availability of all specimens from Section 2.  He should also, immediately before the 
biopsy, fill the insulated bucket with dry ice and isopentane. 
 
3.3  Immediately after the biopsy is performed, the freshly collected specimen should be 
placed in the cryomold.  A single drop of Tissue Tek™ OCT should be placed on the 
specimen, and the sterile tweezers should be used to gently hold one end of the freshly 
collected needle biopsy and to push the biopsy to the bottom of the cryomold cassette with 
forceps.  Make sure biopsy is as flat as possible. The cryomold should then be filled with 
OCT, and the cryomold should be immediately placed in direct contact with the dry 
ice/isopentane cocktail until the bottom of the OCT freezes and turns white.  Only the 
bottom of the cryomold should contact the dry ice/isopentane--none of the dry 
ice/isopentane should spill inside the cryomold itself and contact the specimen.   
This process can be repeated using separate cryomold cassettes for separate biopsy 
samples. 
3.4 Once frozen, place cryomolds on dry ice for transport.  The used isopentane should be 
poured back into its bottle using funnel.     
3.5 For bone lesions, an aspirate of the site of bone biopsy may be performed, as described 
in Section C, using a 20 cc sterile syringe.  The contents of this syringe (clotted aspirate) 
should be transferred into a 1.7 mL eppendorf tube.  Several drops of Tissue Tek™ OCT 
should be added to the tube, such that the clotted aspirate is covered by OCT.  The 
eppendorf tube should then be closed, and placed on dry ice for snap freezing. 
3.6 The cryopreserved biopsy and aspirate specimen(s) should be stored at -80°C until shipment. 
 Ideally, shipment should occur on the same day as the biopsy, unless the biopsy occurs on a 
Friday, in which case the specimen should be preserved at -80°C until shipment on the following 
Monday. 
  
4. Quality Assurance Process 
After completion of each biopsy, the following information should be recorded on the 
information sheet shipped with each sample kit: 
Biopsy collection 
Date:  
Specimen ID:  
Time guide needle placement confirmed:  


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Needle Type:  
Needle diameter: gauge; and length: cm  
Time biopsy needle introduced:  
Time biopsy snap-frozen on dry ice:  
Number of specimens: 
Time aspirate performed (for bone lesions): 
Time aspirate snap-frozen on dry ice: 
Date/time of biopsy specimen(s) (and aspirate specimens, if applicable) placed at -80°C:  
Date/time of biopsy specimen(s) (and aspirate specimens, if applicable) shipped:  
Notes, including any deviations from the standard operating procedure:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX F:  
Standard Operating Procedure for Shipment of non-CTC Clinical Samples 
 
I.  Preparing for Shipment 
A. Send an e-mail to Siddiqui@med.umich.edu  prior to shipping to advise recipient of 
scheduled shipping time.  
B. Generate a shipping list recording the number of samples being shipped, type of 
sample (frozen biopsy, blood, or archived formalin-fixed biopsy), and clinical protocol 
number of the patient 
C.  Make sure that the following packing materials are available: 
• Cardboard shipping box with Styrofoam insert.  
--Shipper Boxes 13.38L x 9.25W x 6 in.D; Outside Dimensions: 15.5L x 
11.5W x 8 in.H;  Wall Thickness: 1 in. Fischer Scientific Catalog # 03-
528-27 
• Dry ice (amount varies depending on size of Styrofoam insert; usually about 15 
kg’s) 
• 6 in x 6 in cardboard specimen box, with fiberboard box dividers- holds 81, 
16mm vials  
--Revco Fiberboard Storage Boxes, 12/PAK 
--Revco Fiberboard Box Dividers, Holds 81 16mm vials, 12/PAK 
Fischer Scientific Catalog # 11-678-24A, 13-989-218 (resp.) 
• Plastic bag (to go over the cardboard box –in case of leakage) 
• Absorbent strip (to go inside the plastic bag that the boxes are in; can soak up to 
250 cc of liquid) 
--Absorbent Strips 250/Cs 
--Fischer Scientific Catalog # NC9193000 
• UN 3373 label (2 in x 2 in)  
--Labelmaster UN3373 Labels > 2W x 2.75 In. L 
--Labels; Biological Substance; 2W x 2.75 In. L; Paper; 500/RL 
Fischer Scientific Catalog # NC9493045 
• Dry Ice Label with designated UN 1845 diamond (can also be ordered from 
Fischer Scientific) 
--5 1/2 x 5 1/2 in.; complies with DOT (49 CFR 173.217) and IATA 
(Packing Instructions 904)  
--Fischer Scientific Catalog #22-130-065  
• Packing tape 
 
II.  Packaging the specimens 
1. Pull sample tubes from temporary storage freezers and place in dry ice, make sure the 
labels are securely placed on the tube and tubes properly labeled and easy to read. 
2. Ensure that caps are tightly secured and place in 6 in x 6 in cardboard specimen box 
(which should be kept on dry ice during this transfer). 


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3. Be sure to check off EACH specimen being shipped and verify the contents of the 
package match the shipping list 
4. Label the top of the cardboard specimen box with number of samples; clinical 
protocol/specimen number, and contact information of sender, as well as contact of 
receiver. 
5. Cover the specimen box, and either tape the sides down or place a rubber band around 
the box, to ensure that the cover will not come off. 
6. Place inside the plastic Ziploc bag with the absorbent strip and seal. Keep on dry ice 
until ready to transfer to the larger shipping box. (can fit two of these specimen boxes 
in a shipper box that is the designated size above) 
7. Fill the shipper box about half way with dry ice (about 1-2 inches in height) and place 
the specimen box inside with shipper. 
8. Add more dry ice to cover the specimen boxes. (about 1 or 2 inches in height again 
and 1-2 inches on the sides the boxes as well).  Note: there should be sufficient dry 
ice to maintain the samples at -20°C for at least 72 h. 
9. DO NOT place dry ice inside the specimen boxes or inside the plastic bag. 
10. Close the Styrofoam box, and tape the packing list to the top. DO NOT seal the 
Styrofoam box with tape.  
11. Ship the specimens with a copy of the shipping list and the completed quality 
assurance record (see Appendix D) for all specimens. Retain copies of the completed 
shipping list and quality assurance record in your records. 
12. Seal the shipping box by taping the flaps of the insulated box along the top edges. 
13. At this point, you should check that your final packaging consists of three components 
(triple packaging): 
 
(a) a primary receptacles (the specimen tubes)  
 
(b) a secondary packaging (6 in x 6 in cardboard specimen box) 
 
(c) a rigid outer packaging (larger cardboard shipping box) 
14. Should you decide to use alternative packaging materials instead of those listed in IC 
above, please note the following requirements: 
The primary receptacles must be packed in secondary packaging in such a way 
that, under normal conditions of transport, they cannot break, be punctured or leak 
their contents into the secondary packaging. Secondary packagings must be 
secured in outer packaging with suitable cushioning material. Any leakage of the 
contents must not compromise the integrity of the cushioning material or of the 
outer packaging. The primary container (i.e. test tube) must be leak proof, as 
should the secondary container. The outer packaging (tertiary container) does not 
have to be leak proof.  Packaging must comply with the IATA packing 
instructions 650 which are summarized below; for further questions, please refer 
to the IATA website: 
http://www.iata.org/SiteCollectionDocuments/DGR51_PI650_EN.pdf 
 
III.  Labelling and sending the shipping box 
A. Fill out the black and white dry ice label to reflect the weight of the dry ice in the box, 
note 2lbs= 1kg. Place completed black and white dry ice label on the shipping box 


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B. All shipping boxes must be affixed with two labels: 
“DIAGNOSTIC SPECIMENS PACKED IN COMPLIANCE WITH IATA 
PACKING INSTRUCTION 650” 
and 
“UN 3373 Biological Substance Category B”  
C. Complete the Fed Ex air bill online and attach packing labels to the outside of the 
shipper. Schedule a pick up time and ship overnight to: 
Javed Siddiqui, MS, MT(ASCP, CLsp (MB)) 
Michigan Center for Translational Pathology 
Room 1138  
2900 Huron Parkway Suite 100 
Ann Arbor, MI 48105 
Phone: (734) 232-0829 
Fax: (734) 232-0805 
siddiqui@med.umich.edu 
D. All shipping boxes are required to ship out FedEx Priority Overnight (or another 
comparable shipping service that results in delivery by 10:30 AM the following day). 
E. Biopsies on Monday through Thursday should be shipped on the same day as the 
biopsy.  Biopsies on Friday should be stored at -80 degrees Celsius until the following 
Monday, and then should be shipped via FedEx Priority Overnight (or a comparable 
service).   
F.  The sender would need to complete an "air waybill" form 
G.  All diagnostic or investigational specimens shipped on this trial should be classified 
as “Diagnostic Specimens” not “Infectious Substances” when shipping via a standard 
carrier.  (i.e. UPS, FED-EX, DHL/AIRBORNE). Diagnostic Specimens DO NOT 
require a Shipper’s Declaration of Dangerous Goods form.  
 
IV.  Questions 
For any questions regarding shipping, please contact Javed Siddiqui at 
siddiqui@med.umich.edu or phone: (734) 232-0829. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX G: Standard Operating Procedure for Shipment of CTC Clinical Samples 
 


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APPENDIX H 
PATIENT’S MEDICATION DIARY 
 
Today’s date _____________________     
Agent: ABT-888  
Patient Name_____________________(initials acceptable)  
 Patient Study ID __________________________ 
INSTRUCTIONS TO THE PATIENT: 
1. 
Complete one form for each cycle of treatment. 
2. 
You will take ABT-888  
         Dose:  ABT-888  ___50 mg tablets and ABT-888  ___ 100 mg tablets.  Take ABT888 twice daily. Take it with or without meals.                              Do not crush, 
break, or chew it. 
3. 
Record the date, the number of tablets of each size of tablet that you took, and when you took them.   
4. 
If you have any comments or notice any side effects, please record them in the Comments column.   
5. 
Please bring this form and your bottles of ABT-888 tablets when you return for each appointment. 
6.      Please record missed or skipped doses.  Do not share your study drug supply, and wash your hands after touching the pills 
 
Day 
 
Date 
Time of AM 
dose ABT-888 
# of tablets taken 
ABT-888 
Time of PM dose 
ABT-888 
# of tablets taken ABT-
888 
Comments 
 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
 
 
6 
 
 
 
 
 
 
7 
 
 
 
 
 
 
8 
 
 
 
 
 
 
9 
 
 
 
 
 
 
10 
 
 
 
 
 
 
11 
 
 
 
 
 
 
12 
 
 
 
 
 
 
13 
 
 
 
 
 
 
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15 
 
 
 
 
 
 
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17 
 
 
 
 
 
 
18 
 
 
 
 
 
 
19 
 
 
 
 
 
 
20 
 
 
 
 
 
 
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 tablets taken this month  _________________________________________________________________
5. Physician/Nurse/Data Manager’s Signature  _______________________________________________________________
 
CTEP-assigned Protocol # 9012  
 
Local Protocol # _ 




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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 tablets taken this month  _______________________________________________________________________________
5. Physician/Nurse/Data Manager’s Signature  
 


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APPENDIX J 
PATIENT’S MEDICATION DIARY 
Agent:  Abiraterone/Prednisone (Not for Cycle 1 Arm IB or IIB) 
 
 
 
 
 Today’s date _____________________                                
Patient Name_____________________(initials acceptable)             Patient Study ID __________________________ 
INSTRUCTIONS TO THE PATIENT: 
1. 
Complete this form for each cycle of treatment. 
2. 
You will take Abiraterone and Prednisone  
         Dose:  Abiraterone ___ 250 mg tablets. You should take the Abiraterone tablets on an empty stomach (1 hour before or 2 hours after a meal) at approximately the same 
time each day.  
Swallow the tablets whole with water.  Do not break, crush, or chew it. 
                      Prednisone  ___5 mg tablets.  Take Prednisone twice daily with food. 
3. 
Record the date, the number of tablets of each size of tablet that you took, and when you took them.   
4. 
If you have any comments or notice any side effects, please record them in the Comments column.   
5. 
Please bring this form and your bottles of Abiraterone/Prednisone tablets when you return for each appointment. 
6.      Please record missed or skipped doses.  Do not share your study drug supply, and wash your hands after touching the pills 
 
Day 
 
Date 
Time of AM 
dose 
Prednisone 
# of tablets 
taken 
Prednisone 
Time of PM 
dose 
Prednisone 
# of tablets 
taken 
Prednisone 
Time of dose 
Abiraterone 
# of tablets 
taken 
Abiraterone 
Comments 
 
1 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
 
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9 
 
 
 
 
 
 
 
 
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Patient’s signature_________________________________________________________________________ 
 
 
CTEP-assigned Protocol #9012 
 
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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 tablets taken this month  _________________________________________________________________
5. Physician/Nurse/Data Manager’s Signature