Conditions: Prostatic Neoplasms Prostate Cancer Neoplasm, Prostate Neoplasm,Prostatic
Keywords: Anti-Angiogenesis Ang 1 Ang 2 Peptide-Fc fusion protein Small Molecule
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 36
Healthy volunteers: no

Brief summary:
Background:

* Advanced prostate cancer is treated with surgery or drugs that lower the levels of androgens (male hormones) in the body. However, some cancers become resistant to this treatment. These types of cancers are known as castration-resistant prostate cancers.
* Interfering with the growth of blood vessels that feed tumors can slow prostate cancer growth. Trebananib (AMG 386), a new anticancer drug, targets the blood vessels that feed tumors. It has been tested for different types of cancer, but not for prostate cancer. Researchers want to see if AMG 386 can slow disease progression in men with castration-resistant prostate cancer. AMG 386 will be given with abiraterone and prednisone, two drugs that are also used to treat advanced prostate cancer.

Objectives:

\- To test the safety and effectiveness of AMG 386 with abiraterone for castration-resistant prostate cancer.

Eligibility:

\- Men at least 18 years of age with castration-resistant prostate cancer.

Design:

* Participants will be screened with a physical exam, medical history, and imaging studies. Blood and urine samples will also be collected.
* Participants will be separated into two groups.
* The first group will have AMG 386 once per week for a total of four doses during a 28-day cycle. They will also take abiraterone once a day and prednisone twice a day, every day of the cycle.
* The second group will not have AMG 386. They will take abiraterone once a day and prednisone twice a day, every day of the 28-day cycle.
* Treatment will be monitored with frequent blood tests and imaging studies.
* Participants will continue to take the study drugs as long as the disease does not progress and there are no severe side effects.

Detailed description:
Background:

* Inhibition of angiogenesis, either as a stand-alone approach or in combination with chemotherapy, has demonstrable antitumor efficacy against castration-resistant prostate cancer (CRPC) and there are several antiangiogenic agents that are now in clinical trials in this population of patients.
* AMG 386 is a novel peptide-Fc fusion protein. The molecule is a non-glycosylated homodimer engineered by fusing an Immunoglobulin gamma-1 heavy chain constant region, partial (IgG1 Fc) domain to 4 copies of an anti-angiopoietin 2 (Ang2) peptide. AMG 386 sequesters Ang1 and Ang2, thereby preventing their interaction with Tie2 and inhibiting tumor endothelial cell (EC) proliferation and tumor growth.
* Abiraterone acetate is a small molecule that irreversibly inhibits Cytochrome P450 17A1 (CYP17), a rate-limiting enzyme in androgen biosynthesis, to block residual androgen synthesis in the adrenal gland and tumor cells.
* Previous studies have demonstrated that in vivo alterations of testosterone levels regulate the expression of vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and angiopoietin family members. Dual targeting of the androgen and angiogenic axis represents a novel approach as a potential targeted therapy for patients with metastatic castration-resistant prostate cancer (CRPC).

Objectives:

-To estimate the treatment effect as measured by progression free survival (PFS) in patients treated with AMG 386 plus abiraterone/prednisone relative to abiraterone/prednisone alone.

Eligibility:

-Patients with progressive, metastatic CRPC with radiographic evidence of progression after primary therapy (surgery or radiotherapy) and adequate androgen deprivation therapy.

Design:

* This is an open-label, randomized, phase II multicenter trial with a two-part design and a planned accrual of 88 patients.
* An initial run-in phase of AMG 386 will be conducted with 15mg/kg weekly escalating to 30mg/kg weekly to establish the MTD. The decision on declaration of a safe and tolerable dose during this run-in phase will lead to the second part of the study consisting of a randomized comparison of abiraterone/prednisone plus AMG 386 (at the established maximum tolerated dose (MTD)) vs. abiraterone/prednisone alone.
* AMG 386 will be administered intravenously every week, on days 1, 8, 15 and 22 of each 28-day cycle. Abiraterone acetate will be self-administered once daily by mouth and prednisone will be self-administered by mouth either twice per day at 5 mg per dose or once per day at 10 mg per dose as the patient prefers.

Arms:
arm 1: Abiraterone and prednisone will be given with maximum tolerated dose (MTD) of Trebananib (AMG) arm 2: Abiraterone and prednisone only arm 3: Dose escalation phase to determine MTD of AMG

Interventions: intervention 1: AMG 386 intervention 2: Abiraterone intervention 3: Prednisone
Intervention descriptions: intervention 1: AMG 386 dose will be calculated using the subjects actual body weight (Kg). Supplied in 240 mg v will be administered as an intravenous (IV) infusion using an intravenous infusion pump given over a 60-minute period. intervention 2: A 1,000 mg dose of abiraterone should be taken orally once daily intervention 3: Prednisone should be taken orally either, at 5mg twice a day for each dose or 10 mg once a day a patients preference.

Protocol document:
Prot_SAP_ICF_000.pdf: 
Amendment
Protocol Number:
12C0079-R
Principal Investigator: Ravi Madan 
NCI 
GMB 
301.480.7168 
madanr@mail.nih.gov
(NIH Employee Name, Institute/Branch, Telephone and e-mail)
Reference Number:
365732
Protocol Title:
A Phase II Multicenter Study of AMG 386 and Abiraterone in Metastatic Castration Resistant Prostate Cancer 
SIGNATURES
Principal Investigator (*): 
William Dahut - applied signature on 01/12/2017 4:52 PM EST 
Ravi Madan - applied signature on 01/11/2017 5:32 PM EST
Accountable Investigator:
PI is the Accountable Investigator
Branch Chief/CC Department Head (**):
James L Gulley, MD PhD - applied signature on 01/11/2017 4:37 PM EST
Medical Advisory Investigator (if applicable):
N/A
Lead Associate Investigator signature:
N/A
Referral Contact signatures:
N/A
Associate Investigators signatures:
William Dahut - applied signature on 01/12/2017 4:52 PM EST
For Institute/Center Scientific Review Committee:
N/A
Other IC Clinical Director signatures:
N/A
APPROVALS
IRB Chair:
Michael Hamilton - applied signature on 01/18/2017 9:55 AM EST
Clinical Director:
N/A
CONCURRENCE
OPS Protocol Specialist:
Signature
Print Name
Date
* Signature signifies that investigators on this protocol have been informed that the collection and use of personally identifiable information at
the NIH are maintained in a system of record governed under provisions of the Privacy Act of 1974. The information provided is mandatory for
employees of the NIH to perform their assigned duties as related to the administration and reporting of intramural research protocols and
used solely for those purposes.  Questions may be addressed to the Protrak System Owner.
** I have reviewed this research project and considered the NIH Policy for Inclusion of Women and Minorities in Clinical Research. Taking into 
account the overall impact that the project could have on the research field involved, I feel the current plans adequately includes both sex/
gender, minorities, children, and special populations, as appropriate. The current enrollment is in line with the planned enrollment report for 
inclusion of individuals on the basis of their sex/gender, race, and ethnicity and is appropriate and of scientific and technical merit. 
IRB Meeting Date:
Expedited
DEC Clearance Date:
01/03/2017
Protocol Version Date:11/15/2016
Lemuel Clayborn                                                                         
AM R                                                    01/27/2017


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
Confidential                                                                                                                                      1 
 
Abbreviated Title: AMG 386 + abiraterone in mCRPC 
CTEP Protocol #: 9068 
CC Protocol #: 12C0079 R 
 
Title: A Phase II Multicenter Study of AMG 386 and Abiraterone in Metastatic Castration Resistant 
Prostate Cancer  
 
Coordinating Center: 
Center for Cancer Research, NCI, NIH 
 
NCI Principal Investigator: 
Ravi A. Madan, M.D.A-F 
Genitourinary Malignancies Branch 
Center for Cancer Research 
National Cancer Institute 
10 Center Drive, Room 13N240B 
Bethesda, MD 20892 
Phone: 301-480-7168 
 
Email: madanr@mail.nih.gov 
NIH Co-Investigators:  
 
Fatima Karzai, M.D., NIMHDA-F 
10 Center Drive, Room 2N204 
Bethesda, MD 20892 
Phone: 301-402-9134 
Email: Fatima.karzai@nih.gov 
 
William L. Dahut, M.D., GMB, CCR, NCIA-F 
10 Center Drive, Room 3-2571 
Bethesda, MD 20892 
Phone: 240-760-6187 
Email: dahut@mail.nih.gov 
Andrea Apolo, M.D., GMB, CCR, NCIA-F 
10 Center Drive, Room 12N226 
Bethesda, MD 20892 
Phone: 301-480-0536 
Email: andrea.apolo@nih.gov 
James Gulley, M.D., Ph.D., GMB, CCR,A-F 
10 Center Drive, Room 13N208 
Bethesda, MD 20892 
Phone: 301-435-2956 
Email: gj50i@nih.gov 
Howard Parnes, M.D.A-F 
Prostate and Urologic Cancer Research Group 
Division of Cancer Prevention, NCI 
9609 Medical Center Dr, Room 5E302 
Rockville MD 20850 Phone: 240-276-7045 
Email: parnesh@mail.nih.gov 
 
John Wright, M.D., Ph.D. 
Investigational Drug Branch, CTEP, 
CTD,NCIA-F 
9609 Medical Center Dr, Room 5W454 
Rockville MD 20850 Phone: 240-276-6565 
Email: wrightj@ctep.nci.nih.gov 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                                                                                                                                      2 
 
*William 
Figg, 
Pharm.D., 
GMB, 
CCR, 
NCIA,B,E,F 
10 Center Drive, Room 5A01 
Bethesda, MD 20892 
Phone: 240-760-6179 
Fax: 301-402-8606 
Email: wdfigg@mail.nih.gov 
*Cindy Chau, Pharm. D., Ph.D., GMB, CCR, 
NCIA,B,E,F 
10 Center Drive, Room 5A01 
Bethesda, MD 20892 
Phone: 301-402-3622 
Email: chauc@mail.nih.gov 
*Liang Cao, Ph.D. Genetics Branch, CCR, NCI 
37 Convent Drive, Room 6134B,E,F 
Bethesda, MD 20892-1906 
Phone: 301-435-9039  
E-mail: caoli@mail.nih.gov 
*Douglas Price, Ph.D., GMB, CCR, NCIB,E,F 
10 Center Drive, Room 5A01 
Bethesda, MD 20892 
Phone: 301-451-5860 
Fax: 301-402-8606 
Email: dkprice@mail.nih.gov 
*Jane Trepel, Developmental Therapeutics 
Branch, CCR, NCIA,B,E 
10 Center Drive, Room 2N230 
Bethesda MD, 20892 
Phone: 301 496 1547 
Email: trepelj@mail.nih.gov  
*Zhigang Kang, M.D., Ph.D. GB, CCR, NCI 
37 Convent Drive, Room 6134A,B,E,F  
Bethesda, MD 20892-1906 
Phone: 301-443-2817 
E-mail: Zhigang.Kang@nih.gov  
Anna Couvillon, N.P., GMB, CCR, NCIA,B,C 
10 Center Drive, Room 13N224 
Bethesda, MD 20892 
Phone: 301 443 6211 
Fax: 201 480 0884 
Email: couvilla@mail.nih.gov 
 
 
Statistician: 
*Seth Steinberg, Ph. D., OCD, CCR, NCIB,E,F 
Office of the Clinical Director 
National Cancer Institute 
9609 Medical Center Drive, Room 2W-334 
Bethesda, MD 20892 
Phone: 240-276-5563 
Fax: 240-276-7885 
Email: steinbes@mail.nih.gov 
 
Responsible Research Nurse(s):  
 
 
Guinevere Chun, R.N., OCD, CCR, NCIA-C 
10 Center Drive, Room 13N220 
Phone: 240-760-6065 
Fax: 301-480-2590 
Email: gchun@mail.nih.gov 
 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                                                                                                                                      3 
 
Research Contact/Study Coordinator:  
Guinevere Chun, R.N., OCD, CCR, NCIA-C 
10 Center Drive, Room 12N226 
Bethesda, MD 20892-1906 
Phone: 240-760-6065 
Email: gchun@mail.nih.gov 
 
Investigator Roles 
A. Obtain information by intervening or interacting with living individuals for research 
purposes 
B. Obtaining identifiable private information about living individuals 
C. Obtaining the voluntary informed consent of individuals to be subjects 
D. Makes decisions about subject eligibility 
E. Studying, interpreting, or analyzing identifiable private information or data/specimens for 
research purposes 
F. Studying, interpreting, or analyzing de-identified data or specimens for research purposes 
G. Some/all research activities performed outside NIH 
 
 
 
Participating Institution: 
Fox Chase Cancer Center 
FWA Number: 
00003846 
Institutional PI: 
Daniel Geynisman, M.D. 
  
Fox Chase Cancer Center 
  
333 Cottman Avenue 
  
Philadelphia, PA 19111 
  
Phone: 215-214-4284 
  
Fax: 215-728-3639 
  
Email: daniel.geynisman@fccc.edu 
 
Associate Investigators: 
 Elizabeth Plimack, M.D. 
 Assistant Professor, Medical Oncology 
 Fox Chase Cancer Center 
 333 Cottman Ave, Suite C307 
 Philadelphia, PA 19111 
 Phone: 215-728-3889 
 Fax: 215-728-3639 
 Email:  Elizabeth.Plimack@fccc.edu 
 
  


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                                                                                                                                      4 
 
   
 
IRB Contacts: 
Joanne Ley 
Regulatory Manager 
Fox Chase Cancer Center 
333 Cottman Ave, CRU 2nd Floor 
Philadelphia, PA 19111 
Phone: 215-214-1724 
Fax: 215-728-2914 
Email: Joanne.Ley@fccc.edu 
 
Keith Salador  
Regulatory Asst. Manager 
Fox Chase Cancer Center 
333 Cottman Ave, CRU 2nd Floor 
Philadelphia, PA 19111 
Phone: 215-214-3769 
Fax: 215-214-1023 
Email:  Keith.Salador@fccc.edu  
 
IRB of Record: 
Fox Chase Cancer Center IRB 
 
Pharmacy Contact: 
Richard Needleman, RPh 
Investigational Drug Pharmacist 
Fox Chase Cancer Center 
333 Cottman Ave, W08 
Philadelphia, PA 19111 
Phone: 215-728-3075 
Fax:  215-728-3875 
Email: Richard.Needleman@fccc.edu 
 
Nuclear Medicine:  
*Michael Yu, M.D. 
Associate Professor, Director of Nuclear 
Medicine 
Fox Chase Cancer Center 
333 Cottman Ave, C121 
Philadelphia, PA 19111 
Phone: 215-728-3865 
Fax:  215-728-4755 
Email: Michael.Yu@fccc.edu 
 
 
Protocol Contact:  
Alycia Corrigan, CRA 
Fox Chase Cancer Center 
333 Cottman Ave, CRU 2nd Floor 
Philadelphia, PA 19111 
Phone: 215-214-1604 
Fax:  215-728-2687 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                                                                                                                                      5 
 
Email: Alycia.Corrigan@fccc.edu 
Study Coordinators: 
Charlotte Cione, RN, BS, CCRP 
Fox Chase Cancer Center 
333 Cottman Ave, CRU 2nd Floor 
Philadelphia, PA 19111 
Phone: 215-728-3614 
Fax:  215-728-2687 
Email: Charlotte.Cione@fccc.edu 
Lois Malizzia, RN, CCRP 
Fox Chase Cancer Center 
333 Cottman Ave, CRU 2nd Floor 
Philadelphia, PA 19111 
Phone: 215-728-5311 
Fax:  215-728-2687 
Email:  Lois. Malizzia@fccc.edu   
*not responsible for patient care 
Participating Institution:  
 
 
       Rutgers Cancer Institute of New Jersey 
FWA #:  
 
 
 
 
       00003913 
Institutional PI:  
 
 
                  Tina Mayer, M.D. 
 
 
 
 
 
 
       Medical Oncologist 
 
 
 
 
 
 
       195 Little Albany Street 
       New Brunswick, NJ 08901 
       Phone: 732-235-2465 
       Fax: 732-235-7355 
       Email: tina.mayer@rutgers.edu 
 
IRB of Record:  
 
 
 
        Rutgers Health Sciences IRB 
 
IRB Contact:    
 
 
 
        Donna Hoagland 
        335 George St., Suite 3100 
        New Brunswick, NJ 08901 
        Phone: 732-235-9807 
        Fax: 732-235-9810 
        Email: donna.hoagland@rutgers.edu 
 
Pharmacy Contact 
 
 
 
        Michael Kane, RPh, BCOP 
        Director of Pharmacy 
        Rutgers Cancer Institute of New Jersey 
        195 Little Albany St., Room 1602 
        New Brunswick, NJ 08901 
        Phone: 732-235-7407 
        Fax: 72-235-8090 
        Email: kanemp@cinj.rutgers.edu  
 
Study Contact:  
 
 
 
        Joanne Onyschak 
 
 
 
 
 
 
        Program Development Analyst 
        195 Little Albany St., Room 2005 
        New Brunswick, NJ 08901 
        Phone: 732-235-5632 
        Fax: 732-235-6797 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                                                                                                                                      6 
 
        Email: Joanne.onyschak@rutgers.edu  
 
 
NCI Supplied Investigational Agent: 
Drug Name: 
AMG 386 
IND Number: 
114215 
NSC Number 
751173 
Sponsor: 
CTEP 
Manufacturer: 
Amgen 
 
Commercially Available Agents: 
Abiraterone and prednisone may be supplied by the NIH Clinical Center pharmacy.  Prednisone and 
abiraterone, if not being provided by the NIH Clinical Center, will be supplied by the local site 
pharmacy. 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                                                                                                                                      7 
 
PRÉCIS  
Background: 
 Inhibition of angiogenesis, either as a stand-alone approach or in combination with 
chemotherapy, has demonstrable antitumor efficacy against castration-resistant prostate 
cancer (CRPC) and there are several antiangiogenic agents that are now in clinical trials 
in this population of patients.   
 AMG 386 is a novel peptide-Fc fusion protein.  The molecule is a non-glycosylated 
homodimer engineered by fusing an IgG1 Fc domain to 4 copies of an anti-angiopoietin 2 
(Ang2) peptide.  AMG 386 sequesters Ang1 and Ang2, thereby preventing their 
interaction with Tie2 and inhibiting tumor endothelial cell (EC) proliferation and tumor 
growth.   
 Abiraterone acetate is a small molecule that irreversibly inhibits CYP17, a rate-limiting 
enzyme in androgen biosynthesis, to block residual androgen synthesis in the adrenal 
gland and tumor cells. 
 Previous studies have demonstrated that in vivo alterations of testosterone levels regulate 
the expression of VEGF, FGF, and angiopoietin family members. Dual targeting of the 
androgen and angiogenic axis represents a novel approach as a potential targeted therapy 
for patients with metastatic CRPC.   
Objectives: 
 To estimate the treatment effect as measured by progression free survival (PFS) in 
patients 
treated 
with 
AMG 
386 
plus 
abiraterone/prednisone 
relative 
to 
abiraterone/prednisone alone. 
Eligibility: 
 Patients with progressive, metastatic CRPC with radiographic evidence of progression 
after primary therapy (surgery or radiotherapy) and adequate androgen deprivation 
therapy.   
Design: 
 This is an open-label, randomized, phase II multicenter trial with a two-part design and a 
planned accrual of 88 patients. 
 An initial run-in phase of AMG 386 will be conducted with 15mg/kg weekly escalating 
to 30mg/kg weekly to establish the MTD. The decision on declaration of a safe and 
tolerable dose during this run-in phase will lead to the second part of the study consisting 
of a randomized comparison of abiraterone/prednisone plus AMG 386 (at the established 
MTD) vs. abiraterone/prednisone alone. 
 AMG 386 will be administered intravenously every week, on days 1, 8, 15 and 22 of each 
28-day cycle.  Abiraterone acetate will be self-administered once daily by mouth and 
prednisone will be self-administered by mouth either twice per day at 5 mg per dose or 
once per day at 10 mg per dose as the patient prefers. 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                                                                                                                                      8 
 
SCHE MA 
Run-in phase: 
 
Dose Escalation Schedule 
Dose Level 
Dose of AMG 386 
Level 1 
15 mg/kg IV weekly 
Level 2 
30 mg/kg IV weekly 
At all dose levels, subjects will take: 
1000 mg abiraterone daily + prednisone 5 mg twice per day or 10 mg once per day 
 
Treatment: 
Patients will be randomized in a 1:1 distribution to receive: 
A: 1000 mg abiraterone PO once daily + prednisone PO 5 mg twice per day or 10 mg once per 
day 
B: 1000 mg abiraterone PO once daily + prednisone PO 5 mg twice per day or 10 mg once per 
day + AMG 386 IV weekly at the MTD established in the run-in phase 
 
Baseline screening evaluations are to be conducted within 16 days prior to protocol enrollment. 
Baseline scans and x-rays must be performed 4 weeks prior to protocol enrollment. Patients must 
be evaluated at the NCI clinic each cycle for treatment continuation. 
 
 
 
 
 
 
 
 
 
 
 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                                                                                                                                      9 
 
TABLE OF CONTE NTS 
SUMMARY OF PROTOCOL CHANGES ............... ERROR! BOOKMARK NOT DEFINED. 
PRÉCIS ............................................................................................................................................7 
SCHEMA .........................................................................................................................................8 
1 
OBJECTIVES .........................................................................................................................14 
1.1 
Primary Objective ............................................................................................................14 
1.2 
Secondary Objectives ......................................................................................................14 
2 
BACKGROUND ....................................................................................................................14 
2.1 
Castration-Resistant Prostate Cancer ..............................................................................14 
2.1.1 Angiogenesis in CRPC .............................................................................................15 
2.2 
AMG  386 ........................................................................................................................15 
2.3 
Abiraterone/Prednisone ...................................................................................................26 
2.4 
Rationale ..........................................................................................................................27 
2.4.1 CHAARTED Trial (Rationale for Modification of Exclusion Criteria) ..................28 
2.5 
Correlative Studies Background ......................................................................................29 
2.5.1 Genetic Biomarkers ..................................................................................................29 
2.5.2 Angiogenic Biomarkers ............................................................................................29 
2.5.3 Predictive biomarkers: Circulating tumor cells (CTCs) and AR signaling ..............29 
3 
PATIENT SELECTION .........................................................................................................30 
3.1 
Eligibility Criteria ............................................................................................................30 
3.1.1 Inclusion Criteria ......................................................................................................30 
3.1.2 Exclusion Criteria .....................................................................................................31 
3.1.3 Inclusion of Women and Minorities .........................................................................33 
3.1.4 Accrual Targets ........................................................................................................33 
3.2 
Screening Evaluation .......................................................................................................33 
4 
REGISTRATION AND RANDOMIZATION PROCEDURES ............................................34 
4.1 
Randomization (or Stratification) Procedures .................................................................34 
5 
TREATMENT PLAN .............................................................................................................35 
5.1 
Agent Administration ......................................................................................................36 
5.1.1 AMG 386 ..................................................................................................................36 
5.1.2 Abiraterone ...............................................................................................................39 
5.1.3 Prednisone ................................................................................................................39 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
10 
 
5.2 
Definition of Dose-Limiting Toxicity .............................................................................39 
5.3 
General Concomitant Medication and Supportive Care Guidelines ...............................40 
5.4 
Duration of Therapy ........................................................................................................41 
5.5 
Duration of Follow Up ....................................................................................................41 
5.6 
Criteria for Removal from Protocol Therapy and Off Study Criteria .............................41 
5.6.1 Criteria for removal from protocol therapy ..............................................................41 
5.6.2 Off Study Criteria .....................................................................................................42 
5.6.3 Off-Study Procedure ................................................................................................42 
6 
DOSING DELAYS/DOSE MODIFICATIONS ....................................................................42 
6.1 
Abiraterone dose modification ........................................................................................42 
6.1.1 Hematologic Toxicities ............................................................................................43 
6.1.2 Non-Hematologic Toxicities ....................................................................................43 
6.2 
AMG 386 Dose Modification ..........................................................................................43 
7 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS /DATA AND 
SAFETY MONITORING PLAN ...........................................................................................48 
7.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) ..............................49 
7.1.1 CAEPR for AMG 386 (Trebananib, NSC 751173) .................................................49 
7.1.2 Adverse Event List(s) for Commercial Agent(s) .....................................................52 
7.2 
Definitions .......................................................................................................................53 
7.2.1 Adverse Event ..........................................................................................................53 
7.2.2 Suspected adverse reaction .......................................................................................54 
7.2.3 Unexpected adverse reaction ....................................................................................54 
7.2.4 Serious ......................................................................................................................54 
7.2.5 Serious Adverse Event (SAE) ..................................................................................54 
7.2.6 Disability ..................................................................................................................54 
7.2.7 Life-threatening adverse drug experience ................................................................55 
7.2.8 Protocol Deviation (NIH Definition) .......................................................................55 
7.2.9 Non-compliance (NIH Definition) ...........................................................................55 
7.2.10 Unanticipated Problem .............................................................................................55 
7.3 
Expedited Adverse Event Reporting to CTEP ................................................................55 
7.3.1 Reporting via CTEP-AERS ......................................................................................55 
7.3.2 In the event of lost internet connectivity ..................................................................55 
7.3.3 Multi-institutional studies ........................................................................................56 
7.3.4 Expedited Reporting Guidelines ..............................................................................56 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
11 
 
7.4 
Routine Adverse Event Reporting to CTEP ....................................................................57 
7.5 
NCI IRB and NCI Clinical Director Adverse Event Reporting ......................................57 
7.5.1 NCI-IRB and NCI Clinical Director Expedited Reporting of Unanticipated 
Problems and Deaths ................................................................................................57 
7.5.2 NCI-IRB Requirements for PI Reporting at Continuing Review ............................58 
7.5.3 NCI-IRB Reporting of IND Safety Reports .............................................................58 
7.6 
NCI Guidance for Reporting Expedited Adverse Events for Multi-Center Trials ..........58 
7.7 
Secondary Malignancy ....................................................................................................58 
7.8 
Second Malignancy .........................................................................................................59 
7.9 
Data and Safety Monitoring Plan ....................................................................................59 
7.9.1 Principal Investigator/Research Team .....................................................................59 
7.9.2 Sponsor Monitoring Plan .........................................................................................59 
8 
PHARMACEUTICAL INFORMATION ..............................................................................59 
8.1 
AMG 386 (NSC 751173) ................................................................................................59 
8.1.1 Agent Ordering and Agent Accountability ..............................................................62 
8.2 
Commercial Agent(s) ......................................................................................................62 
8.2.1 Abiraterone ...............................................................................................................62 
8.2.2 Prednisone ................................................................................................................63 
9 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES .............................................63 
9.1 
Laboratory Correlative Studies ........................................................................................63 
9.1.1 Evaluation of genetic biomarkers of efficacy...........................................................63 
9.1.2 Evaluation of pharmacokinetics (NCI Site only) .....................................................65 
9.1.3 Determine the biological effects of AMG 386: molecular markers of 
angiogenesis .............................................................................................................66 
9.1.4 Predictive biomarkers for abiraterone: Measurement of circulating tumor cells & 
androgen receptor pathway analysis ........................................................................68 
9.2 
Sample Storage, Tracking and Disposition .....................................................................70 
9.2.1 Clinical Pharmacology Program ..............................................................................70 
10 STUDY CALENDAR ............................................................................................................71 
11 MEASUREMENT OF EFFECT ............................................................................................74 
11.1 Antitumor Effect – Solid Tumors ....................................................................................74 
11.1.1 Definitions ................................................................................................................74 
11.1.2 Disease Parameters ...................................................................................................75 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
12 
 
11.1.3 Methods for Evaluation of Measurable Disease ......................................................76 
11.1.4 Response Criteria .....................................................................................................78 
11.1.5 Duration of Response ...............................................................................................81 
11.1.6 Progression-Free Survival ........................................................................................82 
11.1.7 Radiographic Progression-Free Survival .................................................................82 
12 DATA COLLECTION / DATA REPORTING / REGULATORY 
REQUIREMENTS .................................................................................................................82 
12.1 Data Collection ................................................................................................................82 
12.2 Data Reporting .................................................................................................................83 
12.2.1 Method .....................................................................................................................83 
12.2.2 Responsibility for Data Submission .........................................................................83 
12.3 CTEP Multicenter Guidelines .........................................................................................83 
12.4 Collaborative Agreements Language ..............................................................................84 
13 STATISTICAL CONSIDERATIONS ...................................................................................86 
13.1 Study Design/Endpoints ..................................................................................................86 
13.2 Sample Size/Accrual Rate ...............................................................................................87 
13.3 Stratification Factors .......................................................................................................87 
13.4 Analysis of Secondary Endpoints ....................................................................................87 
13.5 Reporting and Exclusions ................................................................................................88 
13.5.1 Evaluation of toxicity ...............................................................................................88 
13.5.2 Evaluation of response .............................................................................................88 
13.5.3 Evaluation of DLT ...................................................................................................88 
14 HUMAN SUBJECTS PROTECTIONS .................................................................................88 
14.1 Rationale For Subject Selection ......................................................................................88 
14.1.1 NCI IRB Multi-Institutional Guidelines ..................................................................89 
14.2 Participation of Children .................................................................................................89 
14.3 Participation of NIH Subjects Unable to Give Consent ..................................................89 
14.4 Evaluation of Benefits and Risks/Discomforts ................................................................89 
14.5 Risks/Benefits Analysis ...................................................................................................89 
14.6 Consent Process and Documentation ..............................................................................90 
14.6.1 Informed Consent of Non-English Speaking Subjects .............................................90 
15 REFERENCES .......................................................................................................................92 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
13 
 
16 APPENDICES ........................................................................................................................98 
16.1 Appendix A: Performance Status Criteria .......................................................................98 
16.2 Appendix B:  Dose calculation tables for after depletion of 240 mg supply ..................99 
16.3 Appendix C: List of drugs that may have potential CYP2D6 interactions ...................102 
16.4 Appendix D: NCI IRB Problem Form ...........................................................................104 
16.5 Appendix E:  CTEP Multicenter Guidelines .................................................................109 
 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
14 
 
1 
OBJE CTIVE S 
1.1 
PRIM ARY OBJECTIVE 
 To estimate the treatment effect as measured by progression free survival (PFS) in 
patients 
treated 
with 
AMG 
386 
plus 
abiraterone/prednisone 
relative 
to 
abiraterone/prednisone alone. 
1.2 
SECONDARY OBJECTIVES 
 To evaluate the overall survival of the enrolled patients and the safety and toxicity 
profile of the combination 
 To assess changes in genetic biomarkers related to androgen and angiogenesis signaling 
axis and to correlate that with efficacy 
 To assess changes in the molecular markers of angiogenesis and circulating tumor cells 
before (CTCs) and after administration of the combination. 
 To determine whether there are changes in AR signaling status in CTCs before and 
after treatment. 
 To determine radiographic progression free survival (rPFS) 
2 
BACKGROUND 
2.1 
CASTRATI ON-RESISTANT PROSTATE CANCER 
Prostate adenocarcinoma is the most common malignancy in American men and the second 
leading cause of cancer-related deaths. Approximately 30-35% of patients will have regional or 
metastatic disease and an additional 25% will develop metastasis.  Androgen-deprivation therapy 
is the mainstay of treatment for metastatic prostate cancer but nearly all men with metastatic 
prostate cancer will progress to a castrate-resistant phenotype and exhibit progression of 
disease.1,2 Once castrate-resistant prostate cancer (CRPC) develops, responses to second-line 
treatment with alternative hormonal therapy or chemotherapies are limited, with a median overall 
survival of approximately 12–18 months. CRPC causes significant morbidity, especially with 
symptoms of pain from bony metastasis and mortality 3. Chemotherapies have been studied 
extensively in the field of prostate cancer and have been disappointing until recently, with the 
demonstration of improved overall survival of 18.9 months with the use of docetaxel and 
prednisone over mitoxantrone and prednisone with 16.5 months 4. The search continues for 
delivering chemotherapy regimens that yield the best survival outcomes while offering the most 
palliation in these groups of patients where cure is as yet unattainable.  It is for this reason that 
although the combination of docetaxel and estramustine showed similar survival advantage to 
docetaxel and prednisone 5, based on fewer side effects, docetaxel and prednisone has become 
the standard of care in patients with metastatic CRPC (mCRPC) 6, although both treatments are 
currently FDA-approved for CRPC. The past year saw the addition of two therapies to the CRPC 
treatment armamentarium. First, therapy with the autologous vaccine sipuleucel-T yielded an 
improvement in overall survival (OS) compared to placebo in a cohort of docetaxel-naïve 
mCRPC patients 7.  Second, a study in mCRPC patients with docetaxel-refractory disease 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
15 
 
demonstrated an improvement in OS with the novel taxane cabazitaxel compared to 
mitoxantrone 8. While cabazitaxel represents the only approved regimen in the second-line 
treatment setting, the median time to PSA progression with most taxane therapy is limited to 
about 6-8 months, with many patients progressing thereafter when resistance to therapy ensues 9. 
The fact remains that men with this disease are not cured and clearly, new therapeutic strategies 
are needed in patients with advanced CRPC.  
 
2.1.1 Angiogenesis in CRPC 
Inhibition of angiogenesis, either as a stand-alone approach or in combination with 
chemotherapy, has demonstrable antitumor efficacy against CRPC and there are several 
antiangiogenic agents that are now in clinical trials in this population of patients. The vast 
majority of antiangiogenic agents being utilized in the clinical setting are based on strategies that 
either interfere with pro-angiogenic ligands or block signaling of pro-angiogenic receptor 
tyrosine kinases. An open-label phase II study of thalidomide in CRPC showed a total of 28% of 
the patients having a greater than 40% decline in PSA 10. In a subsequent phase II trial of 
thalidomide plus docetaxel versus docetaxel alone in metastatic CRPC 11, the combination arm 
showed improvements in PSA response, median progression-free survival (PFS) and median OS 
11,12. At the NCI, a phase II trial using combination therapy with bevacizumab, thalidomide, 
docetaxel and prednisone in patients with metastatic CRPC has resulted in a 90% biochemical 
response rate, overall response rate in measurable disease of 64% and a median OS rate of 28.4 
months 13. When considered in the context of historical data showing a median OS of 19.2 
months with docetaxel and prednisone alone in patients with CRPC 14, this data suggests that the 
addition of angiogenesis-targeted agents would be beneficial in this patient population. However, 
recent results from the phase III CALGB 90401 trial investigating bevacizumab in combination 
with docetaxel and prednisone in treatment-naïve mCRPC showed improvements in PFS not OS; 
however, the combination therapy was associated with greater morbidity and mortality. 
Moreover, a phase IIIa trial of the tyrosine kinase inhibitor sunitinib (plus prednisone), which 
targets intracellular signaling triggered by the VEGF and PDGF receptors, in patients with 
advanced CRPC has been halted for lack of efficacy. While these studies validate the potential 
for an antiangiogenic approach to CRPC, they also indicate the need to investigate alternative 
ways to target the tumor vasculature and the need for a combination treatment approach. Of 
particular interest are agents that can target unique mechanisms for tumor angiogenesis, have a 
better risk-benefit profile, have activity in tumors resistant to existing therapies, and could even 
be combined with other novel targeted therapies to enhance efficacy and limit the development 
of resistance.   
2.2 
AMG  386 
AMG 386 (previously named 2XCon4[C]) is a novel peptide-Fc fusion protein, or peptibody.  
The molecule is a non-glycosylated homodimer engineered by fusing an IgG1 Fc domain to 4 
copies of an anti-angiopoietin (Ang2) peptide.  AMG 386 sequesters Ang1 and Ang2, thereby 
preventing their interaction with the Tie2 receptor and inhibiting tumor endothelial cell (EC) 
proliferation and tumor growth.  The neutralization potency of AMG 386 is greater against Ang2 
(50% inhibitory concentration [IC50]=0.023 nM) than Ang1 (IC50=0.9 nM).  The potency against 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
16 
 
Ang2 is similar across species between humans, mice, rats, and cynomolgous monkeys, while 
the potency against Ang1 is similar between mice and humans.15 
 
Angiopoietins as targets of anticancer therapy 
The Ang family has four members (Ang 1-4), with Ang1 and 2 being the best understood.16-19  
Ang1 and Ang 2 are ligands of Tie2, a tyrosine kinase (TK) receptor expressed on ECs.  Ang1 is 
mainly derived from perivascular cells (pericytes or smooth muscle cells); it acts as an agonist of 
Tie2 and promotes vascular maturation and stabilization.  Ang2 is primarily produced in 
activated ECs, and is thought to be an antagonist of Tie2.  By displacing Ang1 from Tie2, Ang2 
induces vascular plasticity and renders ECs more responsive to angiogenic signals such as 
vascular endothelial growth factor (VEGF).20  In certain contexts, Ang2 may also act as an 
agonist of Tie2.  The precise signal transduction pathway downstream of Ang-Tie2 interaction is 
unknown; the PI3K-AKT-mTOR pathway has been implicated in most studies.  While the two 
angiopoietins may seem to have contradictory effects on Tie2, they act complementarily in the 
angiogenesis process, from vascular formation to vascular maturation:  Ang2 promotes EC 
proliferation, sprouting, and neoangiogenesis, while Ang1 maintains EC survival, pericyte 
coverage, and vascular integrity.  Angiopoietins are also required for the formation of lymphatic 
vessels.  Ang2 ablation in mice was compatible with live birth, but most mice died within 2 
weeks with severe chylous ascites and peripheral lymphedema.21  Overexpression of Ang was 
found to be associated with lymph node metastases in early gastric22 or breast cancers.23  In 
addition, Ang1 and Ang2 have been shown to interact with integrin (α5vβ3 or α5β1) on ECs or 
nonvascular cells; these interactions were implicated in the survival of certain neuronal cells,24,25 
cardiomyocytes, and tumor cells,26 but the precise mechanisms have not be elucidated. 
 
Preclinical studies with Ang1- and Ang2-specific antagonists have suggested that Ang2 is 
involved in EC proliferation and angiogenesis in cancers, and that inhibition of Ang2 may have 
therapeutic benefit.27  Angiopoietins may also promote tumor growth through non-vascular 
mechanisms.  Recent studies reported that Tie2-expressing monocytes (TEMs) can be recruited 
to tumor sites through the chemo-attractant action of angiopoietins.28  In tumor xenograft 
models, TEMs purified from human tumor specimens markedly promoted angiogenesis, 
suggesting a potentially critical role of TEMs in human cancer progression.28-30 
 
Studies with anti-VEGF agents in tumor models suggest that Ang1 and Ang2 may play a role in 
tumor survival under VEGF inhibition.  In an orthotopic tumor model,31 while an Ang1 agonist 
did not alter tumor growth by itself, it was found to attenuate the antitumor effect of VEGF Trap 
and protect the tumor vessels from regression.  In the U87 glioma model, ectopic expression of 
Ang2 increased vascular density without impact on tumor growth; however, the presence of 
Ang2 compromised the activity of a VEGFR2 inhibitor, suggesting that blocking Ang2 along 
with VEGF may lead to enhanced therapeutic effect.32  In patients with renal cell cancer (RCC), 
circulating Ang2 levels were initially decreased after treatment with sunitinib but subsequently 
increased at the time of tumor progression.33 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
17 
 
 
Overexpression of Ang1, Ang2, or Tie2 can be found in tumor tissues, but the levels and sites of 
expression (ECs, stromal cells, or tumor cells) are highly variable among individual patients and 
tumor types.  Increased levels of Ang2 in the tumor or in circulation have been associated with 
higher grade, later stage, and poorer survival in several malignancies, including melanoma,34,35 
glioma, gastric cancer,22,36 breast cancer, bladder cancer,37,38 and acute myeloid leukemia 
(AML).39,40  In general, Ang2 or Tie2 expression is confined to ECs or stromal cells, but ectopic 
expression in tumor cells has also been reported (e.g., gastric cancer, inflammatory breast cancer, 
and thyroid cancer).  The functional relevance of Tie2 expression on tumor cells is unclear.  A 
summary of Ang1, Ang2, and Tie2 expression data in various human cancers has been 
published.16 
 
Nonclinical Studies of AMG 386 
In vitro efficacy:  AMG 386 does not alter the in vitro growth of human cancer cell lines, 
including A431 (uterine epidermoid carcinoma) and Colo205 (colon carcinoma), indicating that 
the mechanism of action of AMG 386 is not likely to be through a direct antitumor effect.15 
 
In vivo efficacy:  As a single agent, AMG 386 significantly inhibited VEGF-induced rat corneal 
angiogenesis and inhibited the growth of multiple tumor xenografts in nude mice, including 
Colo205, A341, OVCAR-3 SQ3 (ovarian carcinoma), and HT29 (colon carcinoma).  The 
antitumor effect in the Colo205 model was associated with a reduction of EC proliferation and 
significant increases in tumor cell apoptosis and necrotic tumor fraction; no increase in EC 
apoptosis suggests that AMG 386 prevents tumor growth via inhibition of angiogenesis.  
Maximum efficacy in Colo205 tumor-bearing mice occurred at 0.6 mg/kg administered 
subcutaneously (SC) twice weekly, which resulted in a minimum observed serum concentration 
(Cmin) of 3 mcg/mL.  No delay in tumor growth was observed with AMG 386 treatment in 
several tumor models, including U-87 MG (glioblastoma), Calu6 (lung carcinoma), Daudi (B-
cell lymphoma), and MesSa/Dx5 (uterine sarcoma).15 
 
The combination of AMG 386 with VEGF/VEGFR inhibitors was associated with greater 
antitumor activities when compared with each agent alone.  In the HT29 model, AMG 386 in 
combination with motesanib (a multi-kinase inhibitor against VEGFR/PDGFR/cKit) showed 
superior antitumor activity in the HT29 model.  Similarly, the combination of AMG 386 with 
bevacizumab in Colo205 xenografts also resulted in significantly improved efficacy.  In another 
experiment in the Colo205 model, combination of bevacizumab and an Ang2-specific peptide 
(L1-7[N]) demonstrated that the enhanced antitumor effect was associated with significantly 
lower vascular sprouting and more profound vascular regression.41 
 
Combinations of AMG 386 with irinotecan, fluorouracil (5-FU), and docetaxel have also been 
tested in the Colo205 model.  Preliminary data suggest neither antagonism of single-agent 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
18 
 
efficacy nor gross evidence of increased toxicity upon combining the agents, but the study design 
did not allow for conclusions regarding additive activity to be made.15 
 
Preclinical pharmacology:  Pharmacokinetics (PK) studies were conducted in Sprague-Dawley 
rats and cynomolgus monkeys.15  Single-dose intravenous (IV) administration of AMG 386 
exhibited dose-linear PK over dose ranges of 1 to 100 mg/kg (rats) and 5 to 100 mg/kg 
(monkeys).  The mean terminal elimination half-life (t1/2) was 97.5 and 49.5 hours in rats and 
monkeys, respectively.  The mean volume of distribution value after the first dose (V0) was 
similar to the plasma volume but increased by 4-5 fold steady state (Vss), suggesting that AMG 
386 distributes extravascularly. 
 
No accumulation of AMG 386 was observed after twice-weekly IV administration to rats (3 to 
300 mg/kg) and monkeys (25 to 300 mg/kg) for 4 weeks.  After 13 weeks, however, moderate 
accumulation (accumulation ratio [AR] range, 2.03 to 2.77) was observed in rats; low 
accumulation (AR range, 1.19 to 2.09) was observed in monkeys. 
 
Unlike full length IgG antibodies, the kidneys may contribute to the overall clearance of AMG 
386.  PK profiles in splenectomized rats indicate that the spleen is not involved in the elimination 
of AMG 386.  In nephrectomized rats, total clearance was decreased by approximately 30%.  
These values were 14-18 fold higher in the neonatal constant region fragment (Fc) receptor (Fc-
Rn) knockout mice, indicating the Fc-Rn receptor contributes to the sustainability of circulating 
AMG 386 levels after IV administration of 3 and 10 mg/kg to mice.15 
 
Preclinical toxicology:   
In preclinical toxicology studies, in adult monkeys and dogs, AMG 386 was well tolerated, with 
findings consistent with the mechanisms of action (see Investigator’s Brochure, 2011, Section 
5.3 for details). 
As with other antiangiogenic agents, administration of AMG 386 in developing monkeys has 
shown dose-dependent, premature closure of the physeal growth plate.  AMG 386 is also 
detrimental to fetal growth and has potential impact on the reproductive system (see 
Investigator’s Brochure, 2011, Section 5.3 for details). 
 
Clinical Studies of AMG 386 
There are a total of 16 studies sponsored by Amgen with AMG 386 as monotherapy or in 
combination regimens.  Two studies have been completed, while 14 are ongoing.  The trials (six 
phase 1, seven phase 2, two phase 3, and one unspecified) have included:  1) phase 1 trials for 
single agent, combination with anti-VEGF agents (AMG 706 [motesanib], sorafenib, sunitinib, 
and bevacizumab), or combination with chemotherapy (carboplatin/paclitaxel, docetaxel, 
paclitaxel/trastuzumab, capecitabine/lapatinib, topotecan, and pegylated liposomal doxorubicin 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
19 
 
[PLD]); 2) phase 2 trials for combination with chemotherapy in ovarian, gastric, colorectal, and 
breast cancer; 3) phase 2 trials in combination with VEGFR tyrosine kinase inhibitors (TKIs) in 
RCC and hepatocellular carcinoma (HCC); and 4) phase 3 trials in combination with 
chemotherapy in ovarian cancer.15 
 
PK, immunogenicity, and maximum tolerated dose (MTD) in humans:  In the phase 1 Study 
2004016942, 32 patients with advanced solid tumors received AMG 386 monotherapy in 
escalating dose cohorts from 0.3 to 30 mg/kg IV weekly.  AMG 386 exposure was dose 
proportional, and the total serum clearance appeared to be similar across doses, suggesting that 
AMG 386 exhibited linear PK.  The mean t1/2 was 3.1 to 6.3 days, and the serum steady state 
level (Css) was reached after four weekly doses.  The average minimum observed concentration 
(Cmin) increased approximately proportionately with increasing dose.  At the initially selected 
phase 2 doses of 3 and 10 mg/kg IV weekly, the mean Css was 10.2 mcg/mL and 26.6 mcg/mL, 
respectively.  Across studies, exposure to weekly IV doses of AMG 386 at 3 and 10 mg/kg (and 
15 mg/kg, based on more limited experience) has been consistent with the approximately dose-
proportional PK and minimal accumulation observed in Study 2004016942.  Population PK 
modeling in several studies has identified baseline creatinine clearance (CrCl) as a significant 
covariate for AMG 386 clearance. 
 
No PK alterations of AMG 386 at 10 mg/kg have been demonstrated in coadministration with 
other agents, including VEGF inhibitors (motesanib, sorafenib, sunitinib, and bevacizumab) 
and/or chemotherapeutic agents (FOLFOX-4 [oxaliplatin, leucovorin, and infusional 5-
fluorouracil [5-FU], FOLFIRI [5-FU, leucovorin, and irinotecan], paclitaxel, docetaxel, 
carboplatin, cisplatin, PLD, topotecan, and capecitabine).  Linear interpolation to compare 15 
mg/kg of AMG 386 with monotherapy data additionally suggests no evidence of drug 
interaction.  There has been no conclusive evidence of a marked PK interaction between AMG 
386 and other targeted or chemotherapeutic agents after co-administration. 
 
As of March 30, 2011, no patients have developed neutralizing antibodies in any open-label or 
blinded AMG 386 studies.  Of the 703 patients across nine studies who had serum samples tested 
for immunogenicity, 32 patients developed binding antibodies to AMG 386. 
 
At doses up to 30 mg/kg weekly in the first-in-human phase 1 Study 2004016942 and Japanese 
phase 1 Study 20060212, the MTD was not reached. 
 
Pharmacodynamics in humans:  There have been limited pharmacodynamic studies with AMG 
386.  In the completed phase 1 single agent trial (Study 20040169),42,43 the post-treatment effects 
of AMG 386 were assessed by DCE-MRI and 18F-FDG PET, and angiogenic cytokine and 
apoptosis marker levels in blood.  Of the 12 patients with interpretable serial DCE-MRIs, 10 
patients were treated at 30 mg/kg and the others at 1 mg/kg and 3 mg/kg.  Vascular response, as 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
20 
 
measured by volume transfer constant (Ktrans) and initial area under the curve (IAUC) changes, 
were demonstrated in all patients, but a dose-effect correlation (or lack thereof) cannot be made 
due to small numbers.  A significant vascular effect (i.e., ≥20% reduction in median Ktrans) was 
seen in 7/12 patients on Day 2, 3/6 patients at Week 4, and 5/8 patients at Week 8. 
 
Serial blood levels of several angiogenic cytokines (e.g., VEGF and placental growth factor 
[PlGF], serum VCAM-1 [sVCAM-1], Ang1, and Ang 2) are being assessed in ongoing phase 1b 
and 2 studies.  Small but significant changes in PlGF and sVCAM-1 have been observed in 
response to treatment with AMG 386.  The correlation of these and other potential markers with 
clinical response will require larger studies and more optimal sampling time. 
 
Clinical activity of AMG 386: 
Phase 1 study of single agent AMG 386 in solid tumors (Study 20040169)42.  In the primary 
analysis (September 6, 2006), 29 patients were evaluable for tumor response.  One patient with 
advanced, refractory ovarian cancer treated at 30 mg/kg achieved a partial response (PR) after 68 
weeks that lasted up to 156 weeks when she withdrew from study; CA125 response occurred 
earlier, at week 4.  Four patients had stable disease (SD) for >16 weeks:  one each with soft 
tissue sarcoma, thyroid cancer, pseudomyxoma, and submandibular adenocarcinoma. 
 
Phase 1 study of single agent AMG 386 in Japanese patients with advanced solid tumors 
(Study 20060212).  Preliminary data have recently been presented.44  Among the 18 patients 
enrolled in three dose cohorts (3, 10, or 30 mg/kg), two patients achieved PR (one patient with 
colon cancer treated at 3 mg/kg, and one patient with bladder cancer treated at 30 mg/kg); these 
two patients were continuing the study treatment for 56 weeks and 24 weeks, respectively.  Two 
patients had a best response of SD, and 14 patients experienced PD. 
 
Phase 1b dose-escalation study of AMG 386 (3-10 mg/kg weekly) in combination with 
standard phase 2 doses of bevacizumab (15 mg/kg every 3 weeks), sunitinib (50 mg daily for 
4 out of 6 weeks), or sorafenib (400 mg twice daily [BID]) (Study 20050170).  A preliminary 
analysis of efficacy among 30 patients with metastatic RCC was conducted using data available 
as of March 19, 2010.  Of the 15 patients who received sorafenib in combination with AMG 386, 
5 patients had PRs, 9 patients had SD, and 1 patient experienced PD.  Of the 15 patients who 
received sunitinib in combination with AMG 386, 1 patient had a CR, 7 patients had PRs, 6 
patients had SD, and 1 patient experienced PD.  Two patients with advanced squamous cell 
carcinoma of the head and neck treated with AMG 386 and bevacizumab combination developed 
fatal arterial hemorrhage and tumor hemorrhage; the events were thought to be due to 
bevacizumab or the combination. 
 
Phase 2 randomized, double-blind, placebo-controlled study in recurrent ovarian cancer 
patients combining paclitaxel (80 mg/m2 weekly) and AMG 386 (3 or 10 mg/kg weekly) or 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
21 
 
placebo (Study 20060342).  The primary analysis (for data as of October 21, 2009) showed a 
strong trend toward progression-free survival (PFS) improvement for the paclitaxel + AMG 386 
arms (combined) vs. paclitaxel + placebo (hazard ratio [HR], 80% CI:  0.761 [0.59, 0.98]; 
P=0.165); median PFS was 5.7, 7.2, and 4.6 months in the AMG 386 3 mg/kg, 10 mg/kg, and 
placebo groups, respectively.  Of the 16 subjects from the paclitaxel + placebo arm who crossed 
over, median PFS was 2.6 months.  The overall response rate (ORR) was 19%, 37%, and 27% in 
the AMG 386 3 mg/kg, 10 mg/kg, and placebo groups, respectively.45  PK analysis revealed a 
significant correlation between AMG 386 exposure and efficacy.46  While patients with low 
steady state AUC (AUCss) (<9.6 mg•h/mL) of AMG 386 had a modest difference in PFS 
compared to the control (5.7 vs. 4.6 months, HR 0.81, P=0.31), those with high AUCss (≥9.6 
mg•h/mL) exhibited greater PFS improvement above chemotherapy alone (8.1 vs. 4.6 months, 
HR 0.76, P=0.14).  The apparent dose-efficacy and exposure-efficacy relationships observed 
here prompted the exploration of higher doses of AMG 386 in subsequent trials.  Subsequently, a 
dose of 15 mg/kg has been selected to begin the phase 3 trials of AMG 386 and chemotherapy in 
first line ovarian cancer. 
Phase 2 randomized, double-blind, multi-center phase 2 study combining sorafenib 400 mg 
orally (PO) BID and weekly AMG 386 (3 or 10 mg/kg) or placebo in RCC (Study 20060159).  
The primary analysis (for data as of February 22, 2010) showed no difference in median PFS 
between individual treatment groups (median PFS:  8.5, 9, and 9 months for the AMG 386 3 
mg/kg, 10 mg/kg, and placebo groups, respectively).  However, the ORR was higher for AMG 
386 at 3 mg/kg (37%) and 10 mg/kg (38%) vs. placebo (24%).  For the 30 subjects who received 
open-label AMG 386 in the crossover arm of the study, median PFS was 3.5 months.  
 
Phase 2 randomized, double-blind, placebo-controlled study in gastric cancer (Study 
20060439).  The primary analysis (for data as of December 15, 2009) showed no improvement in 
PFS for patients on cisplatin 80 mg/m2 and capecitabine 1000 mg/m2 BID with AMG 386 (3 or 
10 mg/kg) or placebo.  Earlier discontinuation of study drugs in the AMG 386 arms due to poor 
tolerability of the combination is likely to have contributed to the observed lack of efficacy and 
decreased median OS observed for the chemotherapy + AMG 386 3 mg/kg and chemotherapy + 
AMG 386 10 mg/kg arms (9.4 and 9.1 months, respectively) vs. the chemotherapy + placebo arm 
(12.8 months).  Common adverse events leading to discontinuation of investigational product 
included pulmonary embolism (2%, 5%, 4% of patients in the groups receiving AMG 386 3 
mg/kg, AMG 386 10 mg/kg, and placebo, respectively), diarrhea (5%, 2%, 0%), and nausea (3%, 
4%, 0%).  No single specific toxicity appeared to account for the reduced tolerability of regimens 
containing AMG 386, and no synergistic toxicities were observed between AMG 386 and 
chemotherapy. 
 
Results from run-in part of current trial   
Enrollment in the run in phase of this study was completed as of Amendment F.  Nine patients 
with mCRPC were enrolled to receive AMG 386 at 2 escalating dose levels (dose level 1 – 15 
mg/kg IV weekly; dose level 2 – 30 mg/kg IV weekly) in combination with 1000 mg abiraterone 
PO once daily + 5mg PO prednisone twice daily.  Three patients were enrolled at dose level 1 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
22 
 
with no DLTs.  Of the 6 patients enrolled at dose level 2, one patient experienced a DLT of grade 
3 confusion of 1 week duration.  After resolution to baseline, the event did not recur.  There were 
no other grade 3 or greater adverse events attributed to the study agent. 
 
AMG 386 Safety Profile 
At the time of study-respective data cutoff dates for safety and efficacy data,15 a total of 1190 
patients had been exposed to either AMG 386 or placebo in open-label (343 patients) and 
unblinded (847 patients) phase 1 and phase 2 studies.  Analysis pools for potential and identified 
risks associated with AMG 386 administration were comprised of 32 patients from monotherapy 
studies; 293 patients from open label, combination therapy studies; and 847 patients (582 
administered AMG 386, and 265 administered placebo) from unblinded, placebo-controlled, 
combination therapy studies.15   
Overall, AMG 386 up to 10 mg/kg weekly is well tolerated as monotherapy or in combination 
with VEGF inhibitors or chemotherapy.  Single agent use at 30 mg/kg also appeared tolerable in 
the phase 1 trials with a total of 22 patients treated at this dose level (Study 2004016942 and 
Study 20060212). 
A unique adverse effect of AMG 386 is edema, which is believed to be due to the target effect on 
the lymphatic system.  AMG 386 does not appear to cause hypertension as typically observed 
with anti-VEGF agents.  Adverse events of proteinuria were not observed in the monotherapy 
setting, and were reported in 3% and 2% of patients who received AMG 386 in combination with 
other agents in open-label and blinded studies, respectively.  Proteinuria was mild to moderate, 
non-serious, and did not result in discontinuation of AMG 386. 
 
Safety data for higher doses of AMG 386 (15 and 30 mg/kg) in combination regimens are 
pending. 
 
A Comprehensive Adverse Events and Potential Risks (CAEPR) list using NCI Common 
Terminology Criteria for Adverse Events (CTCAE) terms is included in Section 7.1 of the 
protocol. 
 
Details of identified risks (edema, ascites, and pleural effusion) and potential risks are described 
below. 
Edema (identified risk):  Ang1 and Ang2 contribute to the normal development of the 
lymphatic system; Ang2 knockout mice display defects in the lymphatic system, including 
chylous ascites, hypoplasia of the lymphatic vasculature, and peripheral lympedema.21  Edema 
events occurred in 34% of patients receiving AMG 386 monotherapy and in 46% of patients 
who received AMG 386 in combination with other agents in open-label studies.  In each of the 
five unblinded studies, a higher incidence of edema was observed in the AMG 386 arms 
(combined) vs. the placebo arms (Table 2-1). 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
23 
 
 
The most common manifestation is peripheral edema, although facial edema, periorbital 
edema, and penile edema were also reported.  Most cases were mild to moderate in severity 
and did not result in permanent discontinuation of investigational product.  Current toxicity 
management guidelines are for investigators to continue AMG 386 for grades 1 and 2 edema, 
and to discontinue AMG 386 only for Grade 3 edema. 
 
Ascites (identified risk):  Approximately 10% of all cases of ascites are due to cancer, with the 
most common primary tumor types being ovarian (37%), pancreaticobiliary (21%), gastric 
(18%), esophageal (4%), colorectal (4%), and breast (3%).  Ascites adverse events have been 
observed for 3% of patients receiving AMG 386 monotherapy, and 8% of patients receiving 
AMG 386 in combination with other agents in open-label studies.  The incidence of ascites in 
the five unblinded studies is shown in Table 2-1.  None of the events of ascites have had fatal 
outcomes. 
 
Pleural effusion (identified risk):  Historically, pleural effusion has been observed in cancer 
patients with advanced disease.  Pleural effusion has been reported for 6% of patients receiving 
AMG 386 monotherapy, and 6% of patients receiving AMG 386 in combination with other 
agents in open-label studies; 1% of patients in open-label studies had events of “malignant 
pleural effusion.”  The incidence of pleural effusion in unblinded studies is shown in Table 
2-1.  One fatal event of pleural effusion occurred in a patient with RCC and bilateral 
lymphangitic carcinomatosis (Study 20080579); the investigator did not consider the event to 
be related to AMG 386 treatment. 
 
A number of potential risks have been analyzed in AMG 386 trials.  The findings are as follows: 
Infusion reaction or allergic response:  Adverse events consistent with possible infusion 
reaction were observed in 6% of patients receiving AMG 386 monotherapy, and 2% of subjects 
who received AMG 386 in combination with other agents in open-label studies; these events 
included hypersensitivity, infusion-related reaction, and dyspnea and were of grade 1 or 2 
severity.  In the five unblinded studies, the incidence of adverse events consistent with possible 
infusion reaction was similar or less in the AMG 386 (combined) arms vs. the placebo arms; 
the events included bronchospasm, chills, infusion related reaction, pyrexia, dyspnea, 
hypersensitivity, and drug hypersensitivity.  No fatal infusion reactions have been reported.  
One patient developed grade 3 hypotension as part of a possible infusion reaction (Study 
20080579).  That patient received concomitant methylprednisolone for laryngeal spasms and 
hot flushes. 
 
Proteinuria:  Treatment-emergent adverse events of proteinuria have been observed in clinical 
studies of AMG 386.  Proteinuria was observed in 4% of patients who received AMG 386 in 
combination with other agents in open-label studies.  The incidence of proteinuria in the five 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
24 
 
unblinded studies is shown in Table 2-1.  The majority of proteinuria events were mild to 
moderate, nonserious, and did not result in discontinuation of the investigational product. 
 
Gastrointestinal perforation:  No patients receiving AMG 386 monotherapy, and 2% of 
patients who received AMG 386 in combination with other agents in open-label studies, 
experienced gastrointestinal perforation events.  In the five unblinded studies, the incidence of 
gastrointestinal perforation was similar between the AMG 386 arms (combined) vs. the 
placebo arms (Table 2-1). 
 
One event of gastrointestinal perforation occurred in a patient enrolled in a study of AMG 102 
(anti-hepatocyte growth factor/scatter factor neutralizing antibody) who was misdosed by a 
clinical site and received AMG 386 in addition to AMG 102.  Another patient with advanced 
ovarian cancer who was receiving AMG 386 10 mg/kg in combination with pegylated 
liposomal doxorubicin (PLD) had a fatal event of intestinal perforation. 
Hemorrhage:  No subjects receiving AMG 386 monotherapy, and 14% of patients who 
received AMG 386 in combination with other agents in open-label studies, had hemorrhagic 
events.  In the five unblinded studies, the incidence of hemorrhage was similar or lower in the 
AMG 386 arms (combined) vs. the placebo arms (Table 2-1).  The majority of events were 
mild to moderate in severity.  However, fatal hemorrhage has been observed on the AMG 386-
containing arms (see below). 
The hemorrhagic event with the highest incidence overall was epistaxis; incidence varied 
among studies, from 0% in Study 2004016942 (AMG 386 monotherapy) to 49% in the blinded 
arms of Study 20060341 (AMG 386 or placebo in combination with paclitaxel and 
bevacizumab). 
 
Five fatal hemorrhagic events of have occurred.  Two of the events (hematemesis and gastric 
hemorrhage, in gastric cancer patients receiving chemotherapy + AMG 386 in Study 
20060439) were not considered by the investigator to be related to AMG 386.  The other three 
events were considered possibly related to the study drug:  two patients with advanced 
squamous cell carcinoma of the head and neck treated with AMG 386 and bevacizumab 
combination developed fatal arterial hemorrhage and tumor hemorrhage (Study 20050170); 
and the other patient with metastatic breast cancer in the lungs treated with AMG 386, 
paclitaxel, and bevacizumab combination developed fatal hemoptysis (Study 20060341).  
Since hemorrhage is a recognized adverse event of agents targeting VEGF,47 interpreting the 
relationship of these events to AMG 386 is confounded. 
 
Pulmonary embolism:  No subjects receiving AMG 386 monotherapy, and 1% of patients who 
received AMG 386 in combination with other agents in open-label studies, had pulmonary 
embolism.  In most of the five unblinded studies, the incidence of pulmonary embolism was 
lower in the AMG 386 arms (combined) vs. the placebo arms (Table 2-1).


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                                                                                                                                      25 
 
 
Table 2-1:  Incidence of selected AEs (all grades) of interest in five randomized phase 2 trials that have been unblinded 
 
 
Study 20060342 
(ovarian ca) 
Study 20060159 
(RCC) 
Study 20060439 
(gastric ca) 
Study 20060341 
(Her2- breast ca) 
Study 20070307 
(colorectal ca) 
 
Paclitaxel  
+ AMG 386 
(3 or 10 mg/kg) 
Paclitaxel 
Sorafenib  
+ 
AMG 386 
(3 or 10 
mg/kg) 
Sorafenib Cisplatin/ gemcitabine  
+ 
AMG 386 
(3 or 10 mg/kg) 
Cisplatin / 
gemcitabine 
Paclitaxel 
+ 
Bevacizumab 
+ 
AMG 386 
(3 or 10 mg/kg)
 
Paclitaxel 
+ 
Bevacizumab 
 
FOLFIRI 
+ 
AMG 386 
(10 mg/kg) 
FORFIRI 
Edema 
71% 
35% 
32% 
20% 
32% 
15% 
62% 
29% 
26% 
6% 
Ascites 
10% 
4% 
1% 
0% 
5% 
2% 
2% 
3% 
2% 
4% 
Pleural effusion 
6% 
0% 
6% 
0% 
4% 
0% 
7% 
0% 
0% 
0% 
Proteinuria 
7% 
4% 
15% 
8% 
1% 
2% 
4% 
2% 
1% 
0% 
GI perforation 
0% 
2% 
2% 
2% 
1% 
2% 
1% 
2% 
1% 
0% 
Hemorrhage 
28% 
24% 
13% 
20% 
12% 
15% 
48% 
55% 
5% 
6% 
Pulmonary 
embolism 
4% 
5% 
2% 
0% 
6% 
15% 
1% 
2% 
1% 
4% 
 
 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
26 
 
2.3 
ABIRATE RONE/PREDNISONE 
Abiraterone acetate, a pregnenolone analog, is a small molecule that irreversibly inhibits CYP17, 
a rate-limiting enzyme in androgen biosynthesis, to block residual androgen synthesis in the 
adrenal gland and tumor cells. CYP17 plays a key role in testosterone biosynthesis, functioning 
in the conversion of pregnenolone to 17-alpha-hydroxypregnenolone (via a 17-alpha-
hydroxylase), and in the subsequent conversion of this moiety to dehydroepiandrosterone 
(DHEA) via a 17, 20-lyase 48. In its early development, abiraterone was noted to block 
testosterone biosynthesis in in vivo models at nanomolar concentrations 49. In a series of phase II 
studies, abiraterone demonstrated clinical efficacy in both chemotherapy-naïve and docetaxel-
treated patients 50-54. The encouraging data from these early trials resulted in the design of phase 
III studies.  
COU-AA-301, a phase III trial in CRPC, was initiated in April 2008 and randomized a total of 
1195 patients with docetaxel-refractory CRPC to either abiraterone or placebo in a 2:1 fashion 
(both arms received concomitant prednisone therapy) 55. Patients were stratified by ECOG 
performance status (0-1 vs. 2), number of lines of prior chemotherapy (1 vs. 2), pain score, and 
the nature of progression (defined by prostate-specific antigen, radiograph, or both). The primary 
endpoint of the study was OS, and secondary endpoints included time to PSA progression 
(TTPP), PSA response rate (PSA RR), and radiographic progression-free survival (rPSF). On 
August 2010, following the first planned interim analysis, an independent data monitoring 
committee recommended that the study be unblinded.56 At this point, abiraterone-treated patients 
had received a median of 8 cycles of therapy, compared to a median of 4 cycles of placebo in the 
control arm. Treatment with abiraterone resulted in an improvement of OS from 10.9 to 14.8 
months (HR 0.65, 95%CI 0.54–0.77; P < 0.0001), and this benefit appeared across multiple 
subgroups. Abiraterone therapy also yielded superior outcomes with respect to TTPP 
(10.2months vs. 6.6 months, P < 0.0001), rPFS (5.6 months vs. 3.6 months, P < 0.0001), and 
PSA RR (confirmed: 29.1% vs. 5.5%, P < 0.0001). The overall frequency of adverse events 
amongst placebo-treated patients exceeded that amongst abiraterone-treated patients. However, 
several grade 3/4 toxicities did occur more frequently with abiraterone therapy, including fluid 
retention (2.3% vs. 1.0%), hypokalemia (3.8% vs. 0.8%), hypertension (1.3% vs. 0.3%), and 
cardiac disorders, defined as ischemic heart disease, myocardial infarction, supra-ventricular 
tachyarrythmias, ventricular tachyarrythmias, cardiac failure and possible arrhythmia related 
signs and symptoms (4.1% vs. 2.3%). 
The phase III mCRPC trial, COU-AA-302, randomized 1088 pre-docetaxel mCRPC patients to 
either abiraterone or placebo in a 1:1 fashion (both arms received concomitant prednisone 
therapy). The co-primary endpoints of the study were radiographic progression-free survival 
(rPFS) and OS.  At an interim analysis (43% of total events) the Independent Data Monitoring 
Committee concluded that the OS, rPFS favored the abiraterone arm and unanimously 
recommended unblinding the study and crossing patients from placebo to abiraterone57.  At this 
time, the median follow up was 22.2 months.  The median rPFS (HR 0.43, P<0.0001) and OS 
(HR 0.75, P<0.0097) were not reached in the abiraterone arm but they were 8.3 months and 27.2 
months in the placebo arm, respectively.  Several grade 3 or grade toxicities occurred more 
frequently in the abiraterone arm than in the placebo arm, including: hypertension (3.9% vs. 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
27 
 
3.0%); hypokalemia (2.4% vs. 1.9%); ALT increased (5.4% vs. 0.7%); AST increased (3.0% vs. 
0.9%.)  
 
Several ongoing trials are examining the agent in earlier settings (i.e., small studies in 
combination with radiation therapy or as neoadjuvant pre-surgery for localized disease). 
 
2.4 
RATIONALE 
Ang2 is expressed in prostate cancer bone, liver, and lymph node metastases.58  In preclinical 
studies, the administration of L1-10, a peptide-Fc fusion that inhibits interactions between Ang2 
and its receptor Tie2, decreased tumor volume and serum prostate-specific antigen (PSA), and 
increased survival in SCID mice bearing subcutaneous LuCaP 23.1 tumors. Histomorphometric 
analysis showed a further significant decrease in tumor epithelial area within the L1-10 treated 
LuCaP 23.1 subcutaneous tumors (P=0.0063), suggesting that inhibiting Ang2 activity impedes 
angiogenesis and growth of LuCaP 23.1 PCa xenografts.59  Ang2 expression was significantly 
correlated to histological grade, vascular density, metastases, and to cancer specific survival in 
prostate cancer tissues.60  Moreover, Ang1 induced sprouting angiogenesis in PC3 tumors. Ang1 
enhanced angiogenesis and resulted in tumor growth in the case of PC3 tumors.61  Based on 
these data, the angiopoietin signaling axis is an important regulator of angiogenesis in prostate 
cancer. Indeed, in the phase I study of AMG 386, a peptibody that binds to and inhibits Ang1 
and Ang2, in combination with chemotherapy in patients with advanced solid tumors, one patient 
with prostate cancer achieved a partial response in the AMG 386/docetaxel cohort.62 
Previous studies have demonstrated that in vivo alterations of testosterone levels regulate the 
expression of VEGF, FGF, and angiopoietin family members.63  VEGF-A and angiopoietins are 
required for the vascular response to androgens. Androgens stimulate the expression of VEGF 
through activation of hypoxia inducible factor (HIF). Androgen deprivation therapy (ADT) is 
associated with lower HIF1a gene expression in human prostate cancer tissue.64 Another study 
found a significant decrease in Ang1 and Ang2 following radical prostatectomy in prostate 
cancer patients.65  Recent studies examined the effect of androgen deprivation therapy (ADT) on 
angiogenic factors and showed that CRPC is associated with elevated levels of VEGF and 
Ang2.66 Plasma levels of VEGF decreased after ADT, and increased again at time of tumor 
relapse. In preclinical studies of mice that were xenografted with LNCaP cells, castrated, and 
administered bicalutimide, our laboratory found that following castration and AR blockade, a 
very strong correlation existed between the expression of genes involved in hypoxia (i.e., VEGF, 
HIF1A) and genes involved in androgen receptor signaling (i.e. AR, FKBP5, and PSA) via 
quantitative PCR (R2=0.82; P<0.00001) (Figg and Dahut; unpublished observations). Thus, it 
appears that ADT induces a relationship between factors involved in AR signaling and hypoxia-
mediated tumor angiogenesis. As such, inhibition of persistent androgen production and AR-
mediated signaling are relevant therapeutic strategies for CRPC.  
Dual targeting of the androgen and angiogenic axis represents a novel approach as a potential 
targeted therapy for patients with metastatic CRPC.  We hypothesize that AMG 386 in 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
28 
 
combination with abiraterone will be safe, well-tolerated, and effective in patients with 
metastatic CRPC. 
To date, a total of 34 of patients have been accrued.  In the randomized portion of the study, 25 
patients have been accrued (14 patients at the NCI and 11 patients at Fox Chase Cancer Center).  
Eleven patients have been randomized to abiraterone/prednisone and 14 patients have been 
randomized to abiraterone/prednisone plus AMG 386.  The MTD of AMG386 is 30 mg/kg IV 
weekly in combination with abiraterone.  
2.4.1 CHAARTED Trial (Rationale for Modification of Exclusion Criteria)  
High-volume hormone-sensitive metastatic prostate cancer has historically been treated using 
hormonal therapy followed by chemotherapy.  The disease however remained poorly prognostic 
in nature.  A shift in the treatment paradigm of these patients occurred with the results of the 
Eastern Cooperative Oncology Group (ECOG) phase III randomized CHAARTED trial, which 
looked at whether the addition of upfront chemotherapy to hormonal therapy improved overall 
survival in patients with hormone-sensitive metastatic prostate cancer.  
A retrospective subanalysis from this trial was reported by Dr. Christopher Sweeney from the 
Dana Farber Cancer Institute, at the 2014 American Society of Clinical Oncology (ASCO) 
Plenary Session.67  In the CHAARTED trial, men with metastatic castrate-sensitive prostate 
cancer were randomized 1:1 to receive androgen deprivation therapy (ADT) alone or to ADT 
with chemotherapeutic drug docetaxel at 75 mg/m2 every 3 for 6 cycles to be started within 4 
months of starting ADT.   ADT plus docetaxel resulted in a median overall survival of 57.6 
months (HR= 0.61; P = .0003) compared to 44 months in the ADT arm1. Patients were stratified 
according to high-volume vs low-volume disease and the benefit for docetaxel therapy was 
found to be more apparent in the high-volume metastatic group vs the low-volume metastatic 
group.   In the ADT plus docetaxel arm of the trial (n=397), common grade 3 non-hematologic 
toxicities include allergic reaction (3%) and fatigue (4%); common grade 4 toxicities include 
thrombo-emobolism (1%) and allergic reaction (<1%). Common grade 3 hematologic toxicities 
include neutropenia (3%) and febrile neutropenia (4%); common grade 4 toxicities include 
neutropenia (9%) and febrile neutropenia (2%).    
Given the very positive results of the CHAARTED trial and current shift towards initial 
treatment with docetaxel for high-volume hormone-sensitive metastatic disease, we propose 
amending protocol 12-c-0079 to address this change in the treatment paradigm.  Patients may be 
enrolled onto protocol 12-c-0079, if they received docetaxel chemotherapy for metastatic 
castrate-sensitive prostate cancer.  Patients are excluded if they have been treated with docetaxel 
chemotherapy for metastatic castrate-resistant prostate cancer.  A patient will not be enrolled if 
he progressed during docetaxel chemotherapy, as this represents a different population of 
patients than those being evaluated in this trial.  A time period of 6 months will be required 
between a patient’s completion of the 6th cycle of docetaxel until the first dose of study 
treatment (cycle 1, day 1). This time period is based upon data seen in other solid tumor types, 
such as retreatment in ovarian cancer with platinum based chemotherapies, and this is a 
reasonable amount of time for patients to have recovered from toxicity from docetaxel.   
 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
29 
 
2.5 
CORREL ATIVE STUDIES BACKGROUND 
2.5.1 Genetic Biomarkers  
Polymerase-chain reaction (PCR) followed by either restriction fragment length polymorphism 
(RFLP) or direct sequencing will be used to genotype a single nucleotide polymorphism (SNP) 
in Ang2 (variant T allele in rs1868554), which was shown to be associated with a variation in 
plasma ANG2 isoforms.68 We will characterize this ANG2 isoform variation and expression and 
investigate its effects in CRPC and in response to AMG 386 therapy. Genotyping will also be 
performed on a specific CYP17 lyase SNP (variant A allele in rs10883783) which was shown to 
be associated with a 56% reduction in prostate cancer-specific mortality.69  
2.5.2 Angiogenic Biomarkers 
Plasma will be obtained to measure changes in the molecular markers of angiogenesis before and 
after administration of the combination since previous studies have found a significant decrease 
in Ang1 and Ang2 following radical prostatectomy in prostate cancer patients. 65 In patients 
treated with pre-operative ADT, significant correlation was noted among AR, HIF1a, VEGF-A, 
and VEGF-C, demonstrating that ADT is associated with lower HIF1a gene expression in 
prostate cancer tissues and documents prognostic value for VEGF-A and VEGF-C expression 
levels.64  Induction of plasma angiogenic factors, VEGF and PlGF, is characteristic for anti-
angiogenic agents targeting VEGF or VEGFR2.  In this study, the effects of AMG 386 on both 
plasma VEGF and PlGF will be evaluated, which serve as the pharmacodynamics markers. We 
will thus elucidate the relationship between biomarker expression, treatment response, and 
biologic behavior. We will assess the effect of AMG 386 on modulating these angiogenic factors 
in the CRPC setting in hopes of identifying a biomarker signature and determine whether 
abiraterone and AMG 386 produce a synergistic or additive effect in modulating plasma levels of 
these angiogenic factors. 
2.5.3 Predictive biomarkers: Circulating tumor cells (CTCs) and AR signaling  
CTCs will be evaluated before and after drug administration as changes in CTC counts were 
shown to correspond with changes in PSA for patients treated with abiraterone.53 CTC 
enumeration at baseline and post-treatment is prognostic of survival and the shedding of cells 
into the circulation represents an intrinsic property of the tumor, distinct from extent of disease. 
Molecular determinants can be identified and characterized in CTCs as potential predictive 
biomarkers of tumor sensitivity to therapeutic treatments. CTC will also be isolated pre-drug and 
immediately following the initial doses of abiraterone.  Genetic analysis will be performed to 
determine the relative levels of androgen receptor (AR), an indicator of gene amplification; the 
relative activity of AR, a marker for AR activity that may infer functional change and gene 
mutations; and the ability of abiraterone to regulate the transcription activity of AR in the 
circulating tumor cells.  These markers directly inform the nature of genetic changes on AR in 
CRPC and the ability for abiraterone to affect AR activity and associated pathway.  Also, as 
TMPRESS2-ERG is the most common driver oncogene translocation downstream of AR, 
occurring in nearly half of the CRPC patients, this translocation will be examined.  Correlative 
studies will be performed between the above biomarkers and clinical responses including PFS to 
delineate the biomarkers predictive of response to abiraterone. 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
30 
 
3 
PATIE NT SELECTIO N 
3.1 
ELIGIBILITY CRIT ERIA  
3.1.1 Inclusion Criteria 
3.1.1.1 Must have metastatic, progressive, castrate-resistant prostate cancer (CRPC) with 
radiographic evidence of disease that has continued to progress radiographically or 
biochemically (rising PSA levels on successive measurements) despite adequate 
androgen-deprivation therapy.  If patients had been on flutamide, disease progression is 
documented  4 weeks or more after withdrawal.  For patients on bicalutamide or 
nilutamide disease progression is documented 6 or more weeks after withdrawal. 
Flutamide, nilutamide and bicalutamide disease progression requirements only apply to 
patients who have been on these drugs for at least the prior 6 months. 
3.1.1.2 Histopathological confirmation of prostate cancer by the Laboratory of Pathology of the 
NCI or Walter Reed National Military Medical Center prior to entering this study.  
Patients enrolled at  participating sites may have histopathological confirmation  at the 
enrolling centerprior to entering the study. Patients whose pathology specimens are no 
longer available may be enrolled if the patient has a clinical course that is consistent 
with prostate cancer and available documentation from an outside pathology laboratory 
of the diagnosis.  All efforts should be made to have the material forwarded to the 
research team for use in correlative studies in cases where original tissue blocks or 
archival biopsy material is available. 
3.1.1.3 Patients must have metastatic disease, defined as at least one lesion on bone scan or at 
least one lesion that can be accurately measured in at least one dimension (longest 
diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >20 
mm with conventional techniques or as >10 mm with spiral CT scan, MRI, or calipers 
by clinical exam.  See Section 11 for the evaluation of measurable disease. 
3.1.1.4 Patients participating in the study must have mCRPC. 
3.1.1.5 Patients who have received docetaxel plus ADT for metastatic castrate sensitive 
prostate cancer are eligible for the study. (Patients may enroll as long as they did not 
have progressive disease while on docetaxel and are 6 months removed from treatment, 
with all treatment related toxicities resolving to at least grade 1.) 
3.1.1.6 Patients may not have had more than 7 days of treatment with ketoconazole by mouth in 
the past 6 months. 
3.1.1.7 Males ≥18 years of age.  Because no dosing or adverse event data are currently 
available on the use AMG 386 in combination with abiraterone in patients <18 years of 
age, children are excluded from this study, but will be eligible for future pediatric trials. 
3.1.1.8 ECOG performance status ≤ 2 for run-in phase; ECOG ≤ 1 for randomized phase (see 
Appendix A) 
3.1.1.9 Life expectancy of > 3 months for the run in phase and > 6 months for the randomized 
phase 
3.1.1.10 Adequate bone marrow, hepatic, and renal function with: 
leukocytes  
≥ 3000/µL 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
31 
 
ANC  
≥ 1500/µL 
Platelets 
≥ 100000/µL 
Total bilirubin  
≤ 1.5 X institutional upper limits of normal 
AST (SGOT)/ALT (SGPT) ≤ 2.5 X institutional upper limits of normal 
PTT or aPTT 
≤ 1.5 X ULN per institutional laboratory range and INR ≤5 
creatinine   
≤ 1.5 X institutional upper limits of normal  
      OR 
creatinine clearance of  
>40 mL/min per 24 h urine collection or calculated 
according to the Cockcroft-Gault formula 
 
CrCl (mL/min) = 
(140-age) x actual body weight (kg) 
(x 0.85 for females) 
72 x serum creatinine (mg/dL) 
 
    
urinary protein  
 
 
≤30 mg/dL in urinalysis or ≤1+ on dipstick, unless  
  
 
 
 
 
 
 
quantitative protein is <1000 mg in a 24h urine sample 
3.1.1.11 Generally well-controlled blood pressure with systolic blood pressure ≤ 140 mmHg 
AND diastolic blood pressure ≤ 90 mmHg prior to enrollment.  The use of anti-
hypertensive medications to control hypertension is permitted 
3.1.1.12 Must have recovered from any acute toxicity related to prior therapy, including surgery.  
Toxicity should be ≤ grade 1 CTCAE version 4 or has returned to baseline.  Alopecia > 
grade 1 is permitted. 
3.1.1.13 The effects of AMG 386 on the developing human fetus are unknown.  For this reason 
and because inhibitors of angiogenesis as well as other therapeutic agents used in this 
trial are known to be teratogenic, men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry and for the 
duration of study participation.  Should a woman become pregnant or suspect she is 
pregnant while her partner is participating in this study, she should inform her treating 
physician immediately.  Men treated or enrolled on this protocol must agree to use 
adequate contraception prior to the study, for the duration of study participation, and 6  
months after completion of AMG 386 administration. 
3.1.1.14 Must have the ability to understand and the willingness to sign a written informed 
consent document. 
 
3.1.2 Exclusion Criteria 
3.1.2.1 Patients who have had chemotherapy for metastatic castration-resistant prostate cancer. 
3.1.2.2 History or presence of known central nervous system metastases. 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
32 
 
3.1.2.3 History of venous or arterial thromboembolism within 12 months prior to 
enrollment/randomization. 
3.1.2.4 History of clinically significant bleeding within 6 months of enrollment/randomization. 
3.1.2.5 Currently or previously treated with AMG 386, or other molecules that primarily inhibit 
the angiopoietins or Tie2 receptor. 
3.1.2.6 Clinically 
significant 
cardiovascular 
disease 
within 
12 
months 
prior 
to 
enrollment/randomization, including myocardial infarction, unstable angina, grade 2 or 
greater peripheral vascular disease, cerebrovascular accident, transient ischemic attack, 
congestive heart failure, or arrhythmias not controlled by outpatient medication or 
placement of percutaneous transluminal coronary angioplasty/stent. 
3.1.2.7 Major surgery within 28 days prior to enrollment or still recovering from prior surgery. 
3.1.2.8 Minor surgical procedures, placement of tunneled central venous access device within 3 
days  prior to randomization/enrollment. 
3.1.2.9 Treatment within 30 days prior to enrollment with the following: cyclosporine, 
tacrolimus, sirolimus, mycophenolate mofetil, methotrexate, azathioprine, rapamycin, 
and targeted immune modulators such as abatacept (CTLA-4-Ig), adalimumab, 
alefacept, anakinra, belatacept (LEA29Y), efalizumab, etanercept, infliximab, or 
rituximab. 
3.1.2.10 Patients who have had large field radiotherapy must wait 2 weeks prior to entering the 
study. 
3.1.2.11 Non-healing wound, ulcer (including gastrointestinal), or fracture. 
3.1.2.12 Contraindication to steroid use or history of allergic reactions attributable to the study 
compounds. 
3.1.2.13 History of allergic reactions to bacterially-produced proteins. 
3.1.2.14 Previously diagnosed with another malignancy, within the past two years with the 
exception of non-melanoma skin cancers or non-invasive bladder cancer. 
3.1.2.15 Patients who have not yet completed at least 28 days (30 days for prior monoclonal 
antibody therapy) since receiving other investigational drugs.   
3.1.2.16 Inability to absorb abiraterone after oral administration (i.e., previous major 
gastrointestinal surgery or gastrointestinal disease resulting in malabsorption). 
3.1.2.17 Use of ketoconazole, itraconazole, ritonavir, cyclosporine, carbamazepine, phenytoin, 
phenobarbital within 2 weeks prior to and while on study therapy. 
3.1.2.18 HIV-positive patients on combination antiretroviral therapy are ineligible because of the 
potential for pharmacokinetic interactions with the study agents. In addition, these 
patients are at increased risk of lethal infections when treated with marrow-suppressive 
therapy.  Appropriate studies will be undertaken in patients receiving combination 
antiretroviral therapy when indicated. 
3.1.2.19 Uncontrolled intercurrent illness or infections, unstable angina pectoris, cardiac 
arrhythmias, renal dysfunction, or psychiatric illness/social situations that would limit 
compliance with study requirements. 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
33 
 
3.1.2.20 Have had treatment with docetaxel for the treatment of metastatic castrate-sensitive 
prostate cancer within 6 months before the first dose of study enrollment. 
3.1.2.21 Have had progression of prostate cancer on prior docetaxel treatment for castrate 
sensitive disease.  
3.1.3 Inclusion of Women and Minorities 
Men of all races and ethnic groups are eligible for this trial.  Women are excluded as prostate 
cancer does not exist in this population. 
3.1.4 Accrual Targets 
 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
0 
+ 
  4 
= 
  4 
Not Hispanic or Latino 
0 
+ 
84 
= 
84 
Ethnic Category: Total of all subjects 
0 
(A1) 
+ 
88 (B1) 
= 
88 (C1) 
Racial Category 
 
American Indian or Alaskan Native 
0 
+ 
  1 
= 
  1 
Asian 
0 
+ 
  2 
= 
  2 
Black or African American 
0 
+ 
13 
= 
13 
Native Hawaiian or other Pacific Islander 
0 
+ 
  1 
= 
  1 
White 
0 
+ 
71 
= 
71 
Racial Category: Total of all subjects 
0 
(A2) 
+ 
88 (B2) 
= 
88 (C2) 
 
(A1 = A2) 
 
(B1 = B2) 
 
(C1 = C2) 
 
Accrual Rate: 
3 
pts/month 
Total 
Expected 
Accrual:   
76 
Min 
88 
Max 
 
3.2 
SCREE NING EVALUATION 
This does not include the baseline correlative studies that will only be performed after the patient 
has signed the consent form. 
 
 To be performed 1 week prior to enrollment  
 History and physical exam including weight and vital signs 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
34 
 
 Tumor marker profile: PSA 
 
 To be performed within 16 days prior to enrollment  
 CBC with differential and platelet count, prothrombin time, activated partial 
thromboplastin time 
 urine analysis with dipstick 
 Electrolytes, BUN, creatinine, urine protein-creatinine ratio (UPC), glucose, AST, ALT, 
bilirubin, calcium, phosphorous, albumin, magnesium, alkaline phosphatase, LDH 
 
 To be performed within 4 weeks prior to enrollment 
 CT scan of chest, abdomen, and pelvis 
 Technetium 99 bone scintigraphy scan 
4 
REG ISTRATION AND RANDOMIZATIO N PROCE DURES 
Authorized staff must register an eligible candidate with NCI Central Registration Office (CRO) 
within 24 hours of signing consent.  A registration Eligibility Checklist from the web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) must be completed and faxed to 301-
480-0757.  After confirmation of eligibility at Central Registration Office, CRO staff will call 
pharmacy to advise them of the acceptance of the patient on the protocol prior to the release of 
any investigational agents.  Verification of Registration will be forwarded electronically via e-
mail to the research team. A recorder is available during non-working hours.  
For participating site Registration:  
All patients must be registered through the NCI Central Registration Office (CRO). The CRO is 
open from 8:30am to 5:30pm EST Monday through Friday, excluding federal holidays.  A 
protocol registration form and cover memo will be supplied by the Coordinating Center, NCI 
CCR and updates will be provided as needed. Subject eligibility and demographic information is 
required for registration. To initially register a subject after the participant has signed consent, 
complete the top portion of the form and fax to the CRO at 301-480-0757. Once eligibility is 
confirmed, complete the remainder of the form which is the eligibility checklist and fax the 
completed registration checklist to the CRO at 301-480-0757.  The CRO will notify you either 
by e-mail or fax that the protocol registration form has been received. The CRO will assign a 
unique patient/subject ID number for each eligible subject that will be used to enter data into the 
C3D data base. Questions about eligibility should be directed to the Coordinating Center’s 
Research Nurse, Guinevere Chun, 301-443-4147, gchun@mail.nih.gov. Technical questions 
about the form should be directed to the Central Registration Office (301-402-1732). 
4.1 
RANDOMIZATION (OR STRATI FICATI ON) PROCEDURES 
Patients participating in the treatment part will be randomized in a 1:1 distribution to receive: 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
35 
 
A: 1000 mg abiraterone PO once daily + PO prednisone 5 mg twice per day or 10 mg once per 
day B: 1000 mg abiraterone PO once daily + PO prednisone 5 mg twice per day or 10 mg once 
per day + AMG 386 IV weekly at 30 mg/kg, the MTD established as of Amendment F. 
 
Randomization will be stratified according to prior ketoconazole or enzalutamide use.  
Stratification will be performed by the Central Registration Office. 
5 
TREATMENT P LAN 
This study will be performed in two parts. In the first part, a safety run-in of AMG 386 will be 
conducted with 15mg/kg weekly escalating to 30mg/kg weekly. The decision on declaration of a 
safe and tolerable dose during part 1 will lead to part 2 consisting of a 70- patient randomized 
comparison of abiraterone/prednisone plus AMG 386 to abiraterone/prednisone.  As of 
amendment F, the randomized dose of AMG 386 was established as 30 mg/kg. 
The first part of this study is a standard 3+3 dose escalation with the primary objective of 
establishing the MTD for AMG 386 when given in combination with standard-dose abiraterone 
acetate/prednisone. Abiraterone acetate will be taken orally at a dose of 1000 mg once daily and 
prednisone will be taken orally at a dose of either 5 mg twice per day or 10 mg once per day. 
AMG 386 will be administered as an intravenous infusion every week. The AMG 386 dose will 
be escalated in cohorts of 3 to 6 patients up to a maximum of 30 mg/kg weekly (see table below).   
Each cohort in the run-in part of the study is planned to have at least 3 patients to evaluate for 
toxicity.  Three patients will be treated at a given dose level and observed for acute toxicity for 
one course of treatment before any more patients are entered. Toxicities will be graded using the 
CTEP Active Version of the NCI Common Terminology Criteria for Adverse Events (CTCAE). 
 If none of the three patients at a given dose level experience dose-limiting toxicity 
(DLT), accrual will proceed to the next cohort.  
 If one of three patients treated at a dose level experiences DLT that is considered to be at 
least possibly related to AMG 386, then three more patients will be enrolled at that same 
level. If the incidence of DLT among those six patients is one in six, then the next cohort 
of three patients will be treated at the next higher dose.  
 In general, if two or more of the six patients treated at a dose level experience DLT, then 
the MTD is considered to have been exceeded. The MTD is defined as the highest dose 
studied for which the incidence of DLT was less than 33%.  However, data from the run 
in part will be reviewed by the study team and the sponsor (CTEP) before initiation of the 
second part to finalize the determination of the phase 2 dose. 
 For MTD determination, dose-limiting toxicities will be evaluated throughout the first 28 
days of treatment (Cycle 1). Patients who exit the study for reasons other than drug-
related toxicity prior to completion of the 28-day DLT evaluation period will be replaced 
to ensure an adequate safety assessment of each cohort.  If at the first dose level more 
than two DLTs in six subjects are observed, then the study will be stopped.  
 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
36 
 
5.1 
AGENT ADMINISTRATI ON 
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. 
Run in part to establish MTD: 
Dose Escalation Schedule 
Dose Level 
Dose of AMG 386 
Level 1 
15 mg/kg 
Level 2 
30 mg/kg 
 
REGIMEN DESCRIPTION 
Agent 
Premedication; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
AMG 386  
none 
 
** in 50 or 100 cc 0.9% 
Normal saline 
(see sections 5.1.1 & 8.1) 
IV infusion 
pump 
over 
60 minutes 
Days 1, 8, 
15, 22*  
28 days  
(4 weeks) 
Abiraterone 
No food should 
be 
consumed 
for at least 2 
hours 
before 
and for at least 
1 
hour 
after 
dose 
1000 mg (4 tablets) 
PO 
Daily  
Prednisone 
Take with food 
or with milk to 
reduce stomach 
irritation. 
5mg 
or 
10 mg 
PO  
Twice per 
day 
or 
Once 
per 
day 
* +/- 5 days 
**Doses as appropriate for assigned dose level. 
 
5.1.1 AMG 386 
AMG 386 dose will be calculated using the subject’s actual body weight (Kg).  The baseline 
weight (Kg) of a subject should be taken prior to the first dose of AMG 386 and subsequent 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
37 
 
weights will be taken on Day 1 of each cycle.  Currently, the 240 mg vials are being used in all 
CTEP-sponsored protocols.  Once the NCI has depleted the 240 mg supply, stop using the dosing 
tables that are currently available in the protocol (directly below this paragraph).  All calculated 
dose in dose levels 10 mg/kg, 15 mg/kg and 30 mg/kg will be rounded to the nearest vial size 
using 150 mg or/and 600 mg vials.  Please refer to  


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
38 
 
Appendix B for dose rounding guidelines that use 150 mg and 600 mg vials.  AMG 386 
calculated doses are based on weight strata as outlined in the table below until the 240 mg supply 
has been depleted.  The actual doses of AMG 386 based on the subject’s weight will be given in 
increments of 150 mg (300 mg [for 30 mg/kg dosing]) as outlined in the table below: 
 
Subject’s actual 
weight 
AMG 15 mg/kg 
AMG 30 mg/kg 
Weight in kilograms 
(kg) 
AMG 386 dose in 
milligrams (mg) 
AMG 386 dose in 
milligrams (mg) 
35 to 44.9 
600 mg 
1200 mg 
45 to 54.9 
750 mg 
1500 mg 
55 to 64.9 
900 mg 
1800 mg 
65 to 74.9 
1050 mg 
2100 mg 
75 to 84.9 
1200 mg 
2400 mg 
85 to 94.9 
1350 mg 
2700 mg 
95 to 104.9 
1500 mg 
3000 mg 
105 kg and above 
Add 150 mg AMG 
386 for each 
additional 10 kg in 
subject’s weight 
Add 300 mg AMG 
386 for each 
additional 10 kg in 
subject’s weight 
 
Every effort should be made to keep the weekly AMG 386 infusions exactly 7 days apart; 
however, occasionally a weekly dose may need to be given off schedule due to logistical reasons.  
Appropriate documentation of AMG 386 dosing must be maintained in the source documents 
and CRF. 
Subjects will be monitored in the clinic for at least 1 hour after the completion of AMG 386 
infusions for any signs of adverse events for the first dose of therapy.  For all subsequent dosing, 
subjects will be monitored for at least 30 minutes after the completion of AMG 386.  
The first dose of AMG 386 will be administered as an IV infusion using an intravenous infusion 
pump given over a 60-minute period.  Administration of AMG 386 by methods other than 
infusion pump must be discussed and approved by the sponsor prior to administration.  If the 
initial dose administration is well tolerated, future administrations of AMG 386 should be given 
in no less than 30 minutes at the discretion of the investigator. 
Before and after each IV infusion, the IV access will be flushed with a minimum of 5 mL of 
sterile 0.9% NaCl suitable for injection.  AMG 386 may be given through a peripheral IV or 
through a central catheter (including but not limited to a port-a-cath, Hickman, triple lumen 
catheter, or PICC line).  Subjects must be monitored throughout and immediately after the 
administration of AMG 386.  If AMG 386 extravasates during IV administration, the infusion 
must be immediately stopped.  The subject may develop a reddened area around the site of 
infiltration which is caused by accumulation of investigational product in the surrounding tissues 
(depot effect).  There is no specific treatment for extravasation of AMG 386.  Supportive 
therapies may be indicated at the discretion of the investigator.  The remaining volume of AMG 
386 may be administered through a separate IV well away from the area of extravasation. 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
39 
 
 
5.1.2 Abiraterone 
A 1,000 mg dose of abiraterone should be taken orally once daily.  Abiraterone must be taken on 
an empty stomach, preferably in the morning.  If a dose of abiraterone is missed, patients should 
be instructed to take the dose at any time during the day.  No food should be consumed for at 
least two hours before the dose of abiraterone is taken and for at least one hour after the dose of 
abiraterone is taken.  Patients should not take two doses on the same day.   
Pill counts will be maintained by study personnel. 
5.1.3 Prednisone 
Prednisone should be taken orally either, at 5mg twice a day for each dose or 10 mg once a day 
as is the patient’s preference.  Prednisone should be taken at approximately the same time every 
day.  The doses should be taken about 12 or 24 hours apart ± 2 hours depending on which dosing 
regimen is used.  Gastric irritation may be reduced if taken before, during, or immediately after 
meals or with milk.  If a dose of prednisone is missed (more than 14 hours [twice daily regimen] 
or 36 hours [once daily regimen] have passed since the last dose), patients should be instructed 
not to make up the dose and to resume taking prednisone at the next scheduled dose.  
 
5.2 
DEFINITION OF DOSE-LIMITING TOXICIT Y 
Dose limiting toxicities (DLTs) are defined as any grade 3 or higher hematologic (excluding 
anemia) or non-hematologic toxicity considered to be possibly related to AMG 386.  
Furthermore, any treatment related AEs that lead to reduction of dose exposure of either agent 
(duration or dose) by > 50% in cycle 1 will be considered a DLT.  Anemia will not be considered 
as a DLT.  Three patients must complete at least 1 cycle of therapy prior to considering dose 
escalation in the next cohort of patients. Determination of DLT for the purpose of dose escalation 
enrollment will be based on toxicities observed in the first 28 days of treatment (cycle 1) and 
must be considered as at least possibly related to study drug. Evaluation for toxicity will continue 
throughout the study and should dose limiting toxicities occur beyond the cycle one, 
consideration will be given to halting the dose escalation and studying the lower dose level. 
 
Management and dose modifications associated with the above adverse events are outlined in 
Section 6. 
 
Dose escalation will proceed within each cohort according to the following scheme.  Dose-
limiting toxicity (DLT) is defined above.   
 
Number of Patients with DLT 
at a Given Dose Level 
Escalation Decision Rule 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
40 
 
Number of Patients with DLT 
at a Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next dose level. 
>2 
Dose escalation will be stopped.  This dose level 
will be declared the maximally administered 
dose (highest dose administered).  Three (3) 
additional patients will be entered at the next 
lowest dose level if only 3 patients were treated 
previously at that dose. 
1 out of 3 
Enter at least 3 more patients at this dose level. 
 If 0 of these 3 patients experience DLT, 
proceed to the next dose level. 
 If 1 or more of this group suffer DLT, then 
dose escalation is stopped, and this dose is 
declared the maximally administered dose.  
Three (3) additional patients will be entered at 
the next lowest dose level if only 3 patients 
were treated previously at that dose. 
<1 out of 6 at highest dose level 
below 
the 
maximally 
administered dose 
This is generally the recommended phase 2 dose. 
At least 6 patients must be entered at the 
recommended phase 2 dose. 
 
If >2 patients experience a DLT at any dose level, at any time in during the run-in part, then 
subsequent patients will be enrolled at the next lower dose level. 
5.3 
GENERAL CONCOMITANT MEDICAT ION AND SUPPORTIVE CARE GUIDELINES 
Because there is a potential for interaction of abiraterone acetate 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. 
Abiraterone acetate 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.  (See Appendix C for list of CYP2D6 
substrates). 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
41 
 
Abiraterone acetate is metabolized by the P450 CYP3A enzyme and has been shown in preclinical 
studies to inhibit multiple CYP isoforms. The following medications will be excluded prior to and 
during the study if indicated: ketoconazole, itraconazole, ritonavir, products containing 
grapefruit juice, cyclosporine, carbamazepine, phenytoin, phenobarbital and prophylactic use of 
G-CSF, GM-CSF. 
Abiraterone acetate has the ability to inhibit a variety of liver metabolic enzymes in vitro. The 
clinical impact of this inhibition in humans taking drugs metabolized by these enzymes is 
unknown. Therefore, all patients enrolled onto this trial who are taking concomitant medications 
that are known to be metabolized by the liver should be closely observed for side effects of these 
concomitant medications. Furthermore, patients taking narrow therapeutic index medications, 
(e.g. warfarin, quinidine, or digoxin) should be monitored proactively.  
5.4 
DURATI ON OF THERAPY 
In the absence of treatment delays due to adverse event(s), may continue study treatment until 
one of the following criteria applies: 
 
Disease progression 
 
Intercurrent illness that prevents further administration of treatment 
 
Unacceptable adverse event(s) 
 
Patient decides to withdraw from the study, or 
 
General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
5.5 
DURATI ON OF FOLLOW UP 
Patients will be followed for overall survival only after removal from study treatment or until 
death, whichever occurs first. Follow-up will be annual telephone contact to assess survival 
status and to collect available information on post study anti-cancer therapy. Every attempt will 
be made to contact patient/subject including: contacting referring physician, contacting 
emergency contact patient identified on admission, checking SSDI (Social Security Death 
Index). Patients removed from study therapy for unacceptable adverse event(s) will be followed 
until resolution or stabilization of the adverse event. 
5.6 
CRIT ERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRIT ERIA 
Prior to removal from study, effort must be made to have all subjects complete a safety visit 
approximately 30 days following the last dose of study therapy. 
5.6.1 Criteria for removal from protocol therapy 
 
Progressive disease 
 
Intercurrent illness that prevents further administration of treatment 
 
Participant requests to be withdrawn from active therapy 
 
Toxicity 
 
Investigator discretion 
 
Death 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
42 
 
5.6.2 Off Study Criteria 
 
Participant requests to be withdrawn from study 
 
Investigator discretion 
 
Death 
5.6.3 Off-Study Procedure 
Authorized staff must notify Central Registration Office (CRO) when a subject is taken off-
study. An off-study form from the web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be completed and 
sent via encrypted email to:  NCI Central Registration Office (HOIS) ncicentralregistration-
l@mail.nih.gov. 
 
5.6.3.1 For Participating Sites 
All subjects must be registered through the NCI Central Registration Office (CRO). The CRO is 
open from 8:30am to 5:30pm EST Monday through Friday, excluding federal holidays.  An off-
study form will be supplied by the CCR study coordinator.  Send the completed off-study form 
to the CCR study coordinator. 
6 
DOSING DELAYS/DOSE MODIF ICATIONS 
Toxicities will be graded according to NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 unless otherwise indicated. The following adjustments will only apply if 
the toxicities reported are attributed by the investigator to be at least probably related to 
abiraterone or AMG 386. Dose delay and dose reduction will be according to the following rules:  
6.1 
ABIRATE RONE DOSE MODIFICATI ON 
Dose reduction and interruptions will be allowed during the study. Patients who experience a 
dose-limiting toxicity (DLT) probably related to abiraterone will have their dose held until the 
toxicities have resolved as outlined in the tables below. Recovery is defined as improvement to 
grade 1, eligibility value, or baseline value. For selected DLTs, upon re-initiation of treatment 
with abiraterone, the patient will have their dose reduced to the next lower dose level.  
Abiraterone may not be held for more than 28 consecutive days.   The dose of abiraterone may 
not be reduced below 750 mg once daily.  Should abiraterone be held longer or should any 
toxicity requiring a dose level reduction occur more than once, the subject will be removed from 
study therapy. 
Table 6-1: Abiraterone dose levels 
 
Dose Level 1 
1000 mg PO qd 
Dose Level -1 
750 mg PO qd 
 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
43 
 
6.1.1 Hematologic Toxicities 
In the event of grade 3 or grade 4 hematologic toxicity (excluding anemia) deemed to be related 
to abiraterone, abiraterone should be suspended until the adverse event resolves to ≤ grade 2.  
CBC will be checked weekly.  Abiraterone will be resumed at the next lower dose level. 
6.1.2 Non-Hematologic Toxicities 
Treatment with abiraterone should continue uninterrupted for grade 1 non-hematologic toxicities. 
However, if the symptoms last for more than 7 days and are significantly intolerable to the 
patient, the dose of abiraterone may be reduced to the next lower dose level. 
 
Grade 2 Non-Hematologic Toxicities 
Maintain the dose of abiraterone but treat symptomatically for nausea, vomiting, or diarrhea. The 
administration of abiraterone may be interrupted in patients with intolerable grade 2 events. 
Abiraterone should be re-initiated at the same dose when the adverse event resolves to grade 1 or 
baseline. If the nausea, vomiting, or diarrhea is persistent and intolerable despite symptomatic 
management, the dose of abiraterone may be reduced to the next dose level. For any other grade 
2 toxicity, the dose of abiraterone need not be reduced unless the adverse event is intolerable to 
the patient.  
Grade 3 Edema (as defined in Table 6-2 below) 
In the event of grade 3 edema, abiraterone will be held.  Abiraterone should be re-initiated at the 
same dose level when edema resolves to grade 1 or baseline. 
Grade 3 or 4 Other Non-Hematologic Toxicity 
Suspend treatment with abiraterone until toxicity improves to grade 1 or pre-treatment baseline 
then re-initiate treatment at a lower dose. Patients with intolerable or limiting toxicity after one 
dose reduction will have abiraterone discontinued.  
6.2 
AMG 386 DOSE MODIFI CATI ON 
Patients who experience dose-limiting toxicities (DLT) possibly related to AMG 386 will have 
their AMG 386 treatment modified as outlined in the tables below. Edema is a known adverse 
event of AMG 386 and the etiology, which may include, but is not limited to, tumor obstruction 
of lymphatic or blood vessels, congestive heart failure, iatrogenic fluid overload, renal 
insufficiency, nephrotic syndrome or other significant hypoalbuminemic states, should be 
ascertained. 
To provide a common framework for reporting edema (including lymphedema), investigators 
should report edema and manage their subjects as defined in this section. 
 Reporting of Edema/lymphedema: Edema should be classified, graded and reported on the 
adverse event eCRF as follows: 
1. Classify the extent of edema:  
 LOCALIZED (confined to a single body area, e.g., lower extremities only), or  


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
44 
 
 GENERALIZED (extending to more than a single body area) 
2. Grade the AE (whether localized and generalized edema/lymphedema) as follows: 
Table 6-2: Edema 
Edema/lymphedema 
(grade based on this 
table, 
NOT 
per 
CTCAE v4.0) 
Grade 1 (MILD) 
Trace 
thickening 
or 
faint 
discoloration of the affected area 
Grade 2 (MODERATE) 
Marked discoloration; leathery 
skin texture; papillary formation 
Grade 3 (SEVERE) 
Severe 
symptoms 
that 
may 
involve skin blistering or skin 
breakdown; 
limitations 
to 
activities of daily living (ADL) 
Edema of a visceral organ or body cavity (such as pulmonary congestion, ascites, or 
pleural effusion): grading based on CTCAE v4.0 but NOT per this section. 
 
 Pleural Effusion and Ascites: Since AMG 386 is known to cause or worsen pre-existing 
pleural effusions and ascites, these adverse events should be managed as in the table below 
for AMG 386 dose modification guidelines. 
NOTE: Each invasive procedure required for interventional treatment of pleural effusion or 
ascites should be documented on the appropriate eCRFs. 
 
In subjects without a documented history of malignant pleural effusion or ascites, investigators 
should attempt to exclude disease progression as the cause of any new onset, or substantially 
worsening ascites or pleural effusion.  In some settings, cytology of aspirated fluid may help in 
this determination (RECIST v1.1, cytology and histology section). 
 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
45 
 
Dose modification of AMG 386 for edema and other AEs should follow the table below: 
Treatment Modification for AMG 386-Related Adverse Events (Based on CTCAE V4.0) 
Event 
CTCAE V4 Grade 
(unless 
noted 
otherwise) 
Action to be Taken 
 There will be no dose reductions for AMG 386, only dose delays.     
 In the event that AMG 386 is held for >28 days, AMG 386 will be permanently discontinued.   
 AMG 386 may be held for a maximum of 2 times for treatment-related toxicity.  If AMG 386 
needs to be held for treatment-related toxicity for a third time, AMG 386 will be permanently 
discontinued. 
 
Edema/lymphedema Edema should be classified and graded as per instructions above 
 
Grades 1:   
(Trace thickening or 
faint discoloration of 
the affected area) 
Continue AMG 386 dosing per protocol and treat 
per institutional guidelines   
 
 
Grade 2: 
(Marked 
discoloration; 
leathery skin texture; 
papillary formation) 
 
Grade 3:   
[(Severe 
symptoms 
that may involve skin 
blistering 
or 
skin 
breakdown; 
limitations 
to 
activities 
of 
daily 
living (ADL)] 
 Permanently Discontinue AMG386 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
46 
 
Treatment Modification for AMG 386-Related Adverse Events (Based on CTCAE V4.0) 
Event 
CTCAE V4 Grade 
(unless 
noted 
otherwise) 
Action to be Taken 
Pleural effusion and 
ascites 
Non-life-threatening 
pleural effusion or 
ascites 
 Treat per institutional guidelines which may 
include: 
non-investigational 
diuretics, 
thoracentesis, chest tube drainage, paracentesis or 
pleurodesis 
 If chest tube drainage or pleurodesis is required, 
AMG 386 should be held until at least two days 
after chest tube removal and the patient’s condition 
is stable. 
 If AMG 386 is interrupted more than two times or 
beyond 28 days for pleural effusion/ascites, but 
continuation of AMG386 is clinically warranted, 
consultation with the study chair and sponsor 
(CTEP) is required before resuming AMG386 
(Each invasive procedure for pleural effusion or 
ascites should be documented on CRFs). 
 
Grade 
4 
or 
Life 
threatening 
pleural 
effusion or ascites 
 Institute emergency measures per institutional 
guidelines  
 Permanently discontinue AMG 386  
 
Hemorrhage (CNS) Any grade 
Permanently discontinue AMG 386. 
Hemorrhage  
≥ Grade 3 
Permanently discontinue AMG 386. 
 
Arterial 
thromboembolic 
event (CVA, 
myocardial 
ischemia or 
infarction, arterial 
thrombosis) 
Any grade 
Permanently discontinue AMG 386. 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
47 
 
Treatment Modification for AMG 386-Related Adverse Events (Based on CTCAE V4.0) 
Event 
CTCAE V4 Grade 
(unless 
noted 
otherwise) 
Action to be Taken 
Venous 
Thromboembolic 
events 
Grade 1 or 2 
Continue AMG 386 
Subjects who, while on anticoagulation, develop a 
second venous thromboembolic event of Grade 2 or 
higher, should permanently discontinue AMG 386. 
 
Grade 3 or 
asymptomatic Grade 
4 
Hold AMG 386.   
 If the planned duration of the full-dose 
anticoagulant is ≤2 weeks, AMG 386 should be 
held until the full-dose anticoagulation period is 
over.   
 If the planned duration of full-dose 
anticoagulation is >2 weeks, AMG 386 may be 
resumed (at the same dose) during the period of 
full-dose anticoagulation if the following 
criterion is met:  the subject must have an in-
range INR (usually between 2 and 3) on a stable 
dose of a coumarin-type anticoagulant OR at 
least 1 week of therapy on a low molecular 
weight heparin (or similar non-coumarin-type 
anticoagulant) prior to restarting AMG 386. 
If VTE recurred or worsened on anti-coagulation: 
discontinue AMG 386 
 
Symptomatic Grade 
4 VTE 
Discontinue AMG 386 
Infusion 
reactions 
and 
delayed 
infusion-related 
reactions:   
Any potential infusion reaction should be classified based upon severity 
and time of onset relative to the infusion and reported as an infusion 
reaction and the underlying symptoms on the AE CRF. 
 
Mild or moderate 
Temporally 
hold 
AMG386, 
and 
treat 
per 
institutional guidelines.  AMG 386 dosing may 
resume; however, all subsequent doses of AMG 386 
should be administered no faster than over 60 
minutes. 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
48 
 
Treatment Modification for AMG 386-Related Adverse Events (Based on CTCAE V4.0) 
Event 
CTCAE V4 Grade 
(unless 
noted 
otherwise) 
Action to be Taken 
 
Severe 
or 
life-
threatening:   
Treat per institutional guidelines.  Discontinue 
AMG386. 
 
*NOTE: infusional reactions usually occur during or within 24 hours of the 
drug administration.  If infusional reactions are suspected more than 24 
hours after the dosing of AMG 386, the patients should be treated as per 
institutional guidelines and decision on subsequent treatment should be 
discussed with the study chair. 
Hypokalemia:   
Subjects should have their serum potassium checked and managed as per 
local medical practice.  If hypokalemia is present, replacement should be 
managed with either oral and/or parenteral replacement, according to 
institutional practice and to the degree of hypokalemia present.  It is 
recommended that the subject’s serum potassium level should be 
maintained within the normal range, as much as possible, during study 
treatment.   
Other toxicities not 
specified:   
Grade 3 
When a subject experiences a Grade 3 toxicity 
considered to be related to AMG 386, AMG386 will 
be held until the toxicity resolves to ≤ Grade 1 or the 
subject’s baseline.   
 
Grade 4 
If a grade 4 event is considered to be related to 
AMG 386, the study should be discontinued.   
 
Resuming AMG 386 may be considered in patients 
who have shown benefit from the protocol and the 
toxicities have resolved to < grade 2, however, 
approval by the study chair and the sponsor is 
required. 
 
7 
ADVERSE  EVENTS:  LIST AND REP ORT ING REQ UIREMENT S /DATA AND 
SAFETY MONIT ORING  PLAN 
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 7.2.1.1) 
will determine whether the event requires expedited reporting (via CTEP-AERS) in addition to 
routine reporting.   


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
49 
 
7.1 
COMPREHENSIVE ADVERSE EVENTS AND POTENTIAL RISKS LIST (CAEPR) 
7.1.1 CAEPR for AMG 386 (Trebananib, NSC 751173) 
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 1422 patients. Below is the CAEPR for 
AMG 386 (trebananib). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses 
next to the AE in the SPEER. If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades 
to determine if expedited reporting is required. 
 
 Version 2.5, April 18, 20161 
 
 Adverse Events with Possible  
 Relationship to AMG 386 (Trebananib) 
 (CTCAE 4.0 Term) 
[n= 1422] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting  
(SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
CARDIAC DISORDERS 
  
 
 
Myocardial infarction2 
  
EYE DISORDERS 
  
 
 
Blurred vision 
  
 
 
Eye disorders - Other 
(retinal vascular 
thrombosis)2,3  
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 3) 
 
 
 Ascites 
  
 
Diarrhea2 
 
 Diarrhea2 (Gr 3) 
 
Nausea 
 
 Nausea (Gr 3) 
 
Vomiting 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Edema face2 
 
 Edema face2 (Gr 2) 
 
Edema limbs 
 
 Edema limbs (Gr 2) 
 
Fatigue2 
 
 Fatigue2 (Gr 3) 
 
Infusion related reaction2,4 
 
 Infusion related reaction2,4 (Gr 
2) 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
50 
 
 
 Adverse Events with Possible  
 Relationship to AMG 386 (Trebananib) 
 (CTCAE 4.0 Term) 
[n= 1422] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting  
(SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
 
Pain 
 
 Pain (Gr 3) 
IMMUNE SYSTEM DISORDERS 
  
 
Allergic reaction4 
 
 Allergic reaction4 (Gr 2) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 3) 
 
Hypokalemia 
 
  
RENAL AND URINARY DISORDERS 
  
 
Proteinuria2 
 
 Proteinuria2 (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
 
Pleural effusion 
  
 
 
Respiratory failure2 
  
VASCULAR DISORDERS 
  
 
 
Hemorrhage5 
  
 
Hypertension 
 
  
 
 
Thromboembolic event3   
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
2These adverse events attributable to AMG 386 (trebaninib) have been reported primarily in studies of 
AMG 386 (trebaninib) in combination with VEGF- and/or tyrosine kinase-inhibitors and/or with 
chemotherapy.  Retinal vascular thrombosis (arterial or venous) may result in permanent impairment of 
vision. 
 
3Thromboembolic events, including Cerebral venous thrombosis, Jugular vein thrombosis, Peripheral 
artery thrombosis, Subclavian vein thrombosis, Deep vein thrombosis, Pulmonary embolism, Retinal 
vascular thrombosis, and Intracardiac thrombus have been observed in AMG 386 (trebananib) trials. 
 
4Symptoms of allergic reactions and/or infusion related reactions may include, Fever, Chills, Headache, 
Rash, Flushing, Swelling, and Shortness of breath.  Severe allergic reactions can cause Dizziness, 
Hypotension, or Difficulty swallowing and may be life-threatening. 
 
5Hemorrhage events, some of which may be serious, including Cerebral hemorrhage, Esophageal varices, 
Hemorrhage, Intracranial hemorrhage, Eye hemorrhage, Gastrointestinal hemorrhage, Arterial 
hemorrhage, Bronchopulmonary hemorrhage, Bladder hemorrhage, Rectal hemorrhage, and Tumor 
hemorrhage have been observed in AMG 386 (trebananib) trials. 
 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
51 
 
6Gastrointestinal obstruction includes Colonic obstruction, Duodenal obstruction, Esophageal obstruction, 
Ileal obstruction, Jejunal obstruction, Obstruction gastric, Rectal obstruction, and Small intestinal 
obstruction under the GASTROINTESTINAL DISORDERS SOC. 
 
7Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal perforation, 
Gastric perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small intestinal 
perforation under the GASTROINTESTINAL DISORDERS SOC. 
 
 
Adverse events reported on AMG 386 (trebananib) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that AMG 386 (trebananib) caused the 
adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Anemia; Febrile neutropenia 
CARDIAC DISORDERS - Acute coronary syndrome; Atrial fibrillation; Atrioventricular block 
complete; Cardiac arrest; Cardiac disorders - Other (atrioventricular block second degree); Heart failure; 
Mitral valve disease; Pericarditis; Restrictive cardiomyopathy; Sinus tachycardia 
EAR AND LABYRINTH DISORDERS - Ear and labyrinth disorders - Other (inner ear fluid); Tinnitus; 
Vertigo 
ENDOCRINE DISORDERS - Hypothyroidism 
EYE DISORDERS - Eye disorders - Other (blindness); Eye disorders - Other (central arterial occlusion); 
Eye disorders - Other (eye edema); Glaucoma; Papilledema; Uveitis; Watering eyes 
GASTROINTESTINAL DISORDERS - Abdominal distension; Bloating; Colitis; Constipation; 
Dysphagia; Enterocolitis; Flatulence; Gastric ulcer; Gastrointestinal disorders - Other (intestinal 
ischemia); Gastrointestinal fistula; Gastrointestinal obstruction6; Gastrointestinal perforation7; Ileus; 
Mucositis oral; Pancreatitis; Rectal pain 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS – Chills4; Fever4; 
General disorders and administration site conditions - Other (generalized edema); Localized edema; 
Malaise; Multi-organ failure; Non-cardiac chest pain 
HEPATOBILIARY DISORDERS - Cholecystitis; Hepatic failure; Hepatobiliary disorders - Other 
(hepatitis toxic) 
INFECTIONS AND INFESTATIONS - Abdominal infection; Anorectal infection; Appendicitis; 
Kidney infection; Lung infection; Sepsis; Skin infection; Upper respiratory infection; Urinary tract 
infection; Wound infection 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Spinal fracture; Wound 
complication; Wound dehiscence 
INVESTIGATIONS - Alanine aminotransferase increased; Alkaline phosphatase increased; Aspartate 
aminotransferase increased; Blood bilirubin increased; Creatinine increased2; GGT increased; INR 
increased; Investigations - Other (granulocyte count decreased); Lymphocyte count decreased; Neutrophil 
count decreased; Platelet count decreased; Weight gain; Weight loss; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hyperglycemia; Hyperkalemia; 
Hypernatremia; Hypoalbuminemia; Hypocalcemia; Hypomagnesemia; Hyponatremia; 
Hypophosphatemia; Metabolism and nutrition disorders - Other (electrolyte imbalance) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Back pain; Bone 
pain; Generalized muscle weakness; Musculoskeletal and connective tissue disorder - Other (muscle 
spasms); Myalgia; Neck pain 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Treatment related secondary malignancy; Tumor pain 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
52 
 
NERVOUS SYSTEM DISORDERS – Dizziness4; Dysgeusia; Dysphasia4; Edema cerebral; 
Encephalopathy; Headache4; Ischemia cerebrovascular; Nervous system disorders - Other (hemiplegia); 
Nervous system disorders - Other (left-sided hemineglect); Paresthesia; Peripheral sensory neuropathy; 
Seizure; Stroke; Syncope; Transient ischemic attacks; Tremor 
PSYCHIATRIC DISORDERS - Confusion; Insomnia; Mania; Personality change 
RENAL AND URINARY DISORDERS - Acute kidney injury2; Hematuria; Urinary tract obstruction 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Apnea; Chylothorax; Cough; 
Dyspnea4; Epistaxis; Hypoxia; Laryngopharyngeal dysesthesia; Pneumonitis; Pulmonary edema; 
Respiratory, thoracic and mediastinal disorders - Other (nasal septum perforation); Respiratory, thoracic 
and mediastinal disorders - Other (obstructive airways disorder); Respiratory, thoracic and mediastinal 
disorders - Other (runny nose)  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Hyperhidrosis; Nail 
discoloration; Nail loss; Palmar-plantar erythrodysesthesia syndrome; Pruritus; Rash acneiform; Rash 
maculo-papular4; Skin and subcutaneous tissue disorders - Other (abnormal hair growth); Skin ulceration 
VASCULAR DISORDERS – Flushing4; Hypotension4; Lymphedema; Peripheral ischemia; Vascular 
disorders - Other (vascular rupture) 
 
 
Note: AMG 386 (trebananib) 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. 
 
 
7.1.2 Adverse Event List(s) for Commercial Agent(s) 
7.1.2.1 Abiraterone 
(See package insert for complete list of side effects) 
Serious adverse events include heart palpitations, lightheadedness, headache, confusion, muscle 
weakness, edema, leg pain, shortness of breath, blood in urine or problems urinating, liver 
problems, allergic reaction.   
The most common adverse events (≥ 5%) are joint swelling or discomfort, hypokalemia, 
edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, 
arrhythmia, urinary frequency, nocturia, dyspepsia, and upper respiratory tract infection. 
 
7.1.2.2 Prednisone 
(See package insert for complete list of side effects) 
Serious side effects of prednisone include hypertension, hyperglycemia, infections, ruptured 
tendons, psychotic reactions, glaucoma, severe edema, gastrointestinal bleeding and allergic 
reactions.  Short term side effects may include headaches and insomnia while long term side 
effects may cause weight gain, exopthalmos, osteoporosis, acne and truncal fat distribution. 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
53 
 
7.2 
DEFINITIONS 
7.2.1 Adverse Event  
An adverse event is defined as any reaction, side effect, or untoward event that occurs during the 
course of the clinical trial associated with the use of a drug in humans, whether or not the event 
is considered related to the treatment or clinically significant. For this study, AEs will include 
events reported by the patient, as well as clinically significant abnormal findings on physical 
examination or laboratory evaluation. A new illness, symptom, sign or clinically significant 
laboratory abnormality or worsening of a pre-existing condition or abnormality is considered an 
AE.  All AEs must be recorded on the AE case report form unless otherwise noted. 
An abnormal laboratory value will be considered an AE if the laboratory abnormality is 
characterized by any of the following: 
 
Results in discontinuation from the study 
 
Is associated with clinical signs or symptoms  
 
Requires treatment or any other therapeutic intervention 
 
Is associated with death or another serious adverse event, including hospitalization.  
 
Is judged by the Investigator to be of significant clinical impact 
 
If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the patient’s 
outcome. 
 
7.2.1.1 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 4.0 will be utilized for AE reporting.  All appropriate treatment 
areas should have access to a copy of the CTCAE version 4.0.  A copy of the 
CTCAE version 4.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.   
 
 
For expedited reporting purposes only:   
o AEs for the agent that are bold and italicized in the CAEPR (i.e., those 
listed in the SPEER column, Section 7.1.1) should be reported through 
CTEP-AERS only if the grade is above the grade provided in the SPEER. 
 
 
Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
54 
 
- 
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. 
7.2.2 Suspected adverse reaction 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. For the purposes of IND safety reporting, ‘reasonable 
possibility’ means there is evidence to suggest a causal relationship between the drug and the 
adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug. 
7.2.3 Unexpected adverse reaction 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in 
the investigator brochure or is not listed at the specificity or severity that has been observed; or, 
if an investigator brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application. 
"Unexpected”, also refers to adverse events or suspected adverse reactions that are mentioned in 
the investigator brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation. 
7.2.4 Serious  
An Unanticipated Problem or Protocol Deviation is serious if it meets the definition of a Serious 
Adverse Event or if it compromises the safety, welfare or rights of subjects or others. 
7.2.5 Serious Adverse Event (SAE) 
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following: 
 
Death, 
 
A life-threatening adverse drug experience 
 
Inpatient hospitalization or prolongation of existing hospitalization 
 
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
 
A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
7.2.6 Disability 
A substantial disruption of a person’s ability to conduct normal life functions. 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
55 
 
7.2.7 Life-threatening adverse drug experience 
Any adverse event or suspected adverse reaction that places the patient or subject, in the view of 
the investigator or sponsor, at immediate risk of death from the reaction as it occurred, i.e., it 
does not include a reaction that had it occurred in a more severe form, might have caused death. 
7.2.8 Protocol Deviation (NIH Definition) 
Any change, divergence, or departure from the IRB-approved research protocol. 
7.2.9 Non-compliance (NIH Definition) 
The failure to comply with applicable NIH Human Research Protections Program (HRPP) 
policies, IRB requirements, or regulatory requirements for the protection of human research 
subjects. 
7.2.10 Unanticipated Problem 
Any incident, experience, or outcome that: 
  Is unexpected in terms of nature, severity, or frequency in relation to  
(a) the research risks that are described in the IRB-approved research protocol and 
informed consent document; Investigator’s Brochure or other study documents, and 
(b) the characteristics of the subject population being studied; AND 
 Is related or possibly related to participation in the research; AND 
 Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
7.3 
EXPEDITED ADVERSE EVENT REPORTING TO CTE P 
7.3.1 Reporting via CTEP-AERS 
Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event Reporting 
System), accessed via the CTEP Web site (https://eapps-ctep.nci.nih.gov/ctepaers).  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/protocolDevelopment/electronic_applications/adverse_events.htm).  
These requirements are briefly outlined in the tables below (Section 7.3.4). 
7.3.2 In the event of lost internet connectivity 
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. 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
56 
 
7.3.3 Multi-institutional studies 
CTEP-AERS is programmed for automatic electronic distribution of reports to the following 
individuals:  Study Coordinator of the Coordinating Center, Principal Investigator, and the local 
treating physician.  CTEP-AERS provides a copy feature for other e-mail recipients.  
7.3.4 Expedited Reporting Guidelines  
Note:  A death on study requires both routine and expedited reporting regardless of 
causality, unless as noted below.  Attribution to treatment or other cause must be provided. 
 
Death due to progressive disease should be reported as Grade 5 “Neoplasms benign, malignant 
and unspecified (incl cysts and polyps) - Other (Progressive Disease)” under the system 
organ class (SOC) of the same name.  Evidence that the death was a manifestation of underlying 
disease (e.g., radiological changes suggesting tumor growth or progression: clinical deterioration 
associated with a disease process) should be submitted.  
 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 
Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration 
of the Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not they are 
considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be 
considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH 
E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-AERS 
within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
57 
 
Resulting in 
Hospitalization       ≥ 
24 hrs 
10 Calendar Days 
24-Hour 5 Calendar Days 
Not resulting in 
Hospitalization       ≥ 
24 hrs 
Not required 
NOTE:   Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific Protocol 
Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of learning of 
the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar days of 
learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational agent/intervention 
and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
 All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
 Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
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 
 
7.4 
ROUTINE ADVERSE EVENT REPORTING TO CTE P 
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. 
7.5 
NCI IRB AND NCI CLINICAL DIRECTOR ADVERSE EVENT REPORTING 
7.5.1 NCI-IRB and NCI Clinical Director Expedited Reporting of Unanticipated Problems 
and Deaths 
The Protocol PI will report in the NIH Problem Form to the NCI-IRB and NCI Clinical Director: 
 All deaths, except deaths due to progressive disease  
 All Protocol Deviations 
 All Unanticipated Problems 
 All non-compliance 
Reports must be received within 7  days of PI awareness via iRIS. 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
58 
 
7.5.2 NCI-IRB Requirements for PI Reporting at Continuing Review 
The protocol PI will report to the NCI-IRB:  
1. A summary of all protocol deviations in a tabular format to include the date the deviation 
occurred, a brief description of the deviation and any corrective action. 
2. A summary of any instances of non-compliance 
3. A tabular summary of the following adverse events: 
 
All Grade 2 unexpected events that are possibly, probably or definitely related to the 
research;  
 
All Grade 3 and 4 events that are possibly, probably or definitely related to the research;  
 
All Grade 5 events regardless of attribution;  
 
All Serious Events regardless of attribution.  
NOTE: Grade 1 events are not required to be reported.  
7.5.3 NCI-IRB Reporting of IND Safety Reports 
Only IND Safety Reports that meet the definition of an unanticipated problem will need to be 
reported to the NCI IRB. 
7.6 
NCI GUIDANCE FOR REPORTING EXPEDITED ADVERSE EVENTS FOR MULTI-CENTER 
TRIAL S 
The site PI must immediately report to the coordinating center PI any serious adverse event, 
whether or not considered drug related, including those listed in the protocol or investigator 
brochure and must include an assessment of whether there is a reasonable possibility that the 
drug caused the event within 48 hours of PI awareness of the event.  The Site PI must also report 
any protocol deviations to the coordinating center PI within 7 days of PI awareness. Participating 
centers must also submit the report to their IRB in accordance with their institutional policies.  
A copy of this form is found in Appendix D. 
7.7 
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  


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
59 
 
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
7.8 
SECOND MALIGNANCY 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine reporting 
via CDUS unless otherwise specified.  
7.9 
DATA AND SAFETY MONITORING  PLAN 
7.9.1 Principal Investigator/Research Team  
The clinical research team will meet on a regular basis when patients are being actively treated 
on the trial to discuss each patient. Decisions about dose level enrollment and dose escalation if 
applicable will be made based on the toxicity data from prior patients.  
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Adverse events will be reported as required above. Any safety concerns, 
new information that might affect either the ethical and or scientific conduct of the trial, or 
protocol deviations will be immediately reported to the IRB using iRIS and if applicable to the 
Sponsor.  
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff.  
7.9.2 Sponsor Monitoring Plan 
It is understood that the responsible monitor will contact and visit the investigator regularly and 
will be allowed, on request, to inspect the various records of the trial including CRFs and other 
pertinent data, provided that subject confidentiality is maintained, and in accord with local 
requirements. 
It will be the monitor’s responsibility to inspect the CRF’s at regular intervals throughout the 
study to verify the adherence to the protocol and the completeness, consistency and accuracy of 
the data being entered on them.  The monitor should have access to laboratory test reports and 
other subject records needed to verify the entries on the CRF.  The investigator or his/her deputy 
agrees to cooperate with the monitor to ensure that any problems detected in the course of these 
monitoring visits are resolved. 
8 
PHARMACEUTICAL INFORMATIO N 
A list of the adverse events and potential risks associated with the investigational or commercial 
agents administered in this study can be found in Section 7.1. 
8.1 
AMG 386 (NSC 751173) 
Classification:  Anti-angiopoietin peptibody 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
60 
 
M.W.:  63.5 kD 
Mode of Action:  AMG 386 selectively inhibits angiopoietins, thereby blocking the 
interaction between Ang1 and Ang2 with their receptor Tie-2.  By inhibiting Ang1 and 
Ang2 from binding to Tie2 receptors, AMG 386 results in an anti-tumor effect.  In 
nonclinical studies, AMG 386 reduced proliferation of tumor endothelial cells and inhibited 
the growth of human xenograft tumors in mice, while having minimal effects on normal 
tissues. 
Description:  A non-glycosylated homodimer consisting of IgG1 Fc domain with 4 copies 
of an anti-Ang2 peptide.  Each monomeric unit contains 10 cysteine residues that are 
involved in 4 intrachain disulfide bonds and 2 interchain disulfide bonds.  AMG 386 
contains 287 amino acids. 
How Supplied:   
Amgen, Inc., supplies and CTEP/DCTD distributes AMG 386 as a 150 mg, 240 mg, and 600 
mg lyophilized powder for Injection vials packaged in a 20 mL and 50 mL vials sizes. AMG 
386 is a single-use vial, sterile, preservative-free, and contains 10 mM histidine, 4% (w/v) 
mannitol, 2% (w/v) sucrose, 10 mM arginine hydrochloride, and 0.01% (w/v) polysorbate 20 
to a pH of 7.1. 
 
AMG 386 (mg) per vial 
Volume SWFI for reconstitution (mL) 
150 
5 
240 
8 
600 
20 
Preparation:  Take the vial(s) out of the refrigerator only when ready to prepare the drug 
for patients. 
Note: Amgen Inc. does not classify AMG 386 as cytotoxic; however, if and only if your 
site requires the use of vial adaptors, a 0.2 µm PES (polyethersulfone) in-line filter must be 
used during the IV administration to reduce the risk of stopper particles in the IV solution. 
 
Step 1:  Make 30 mg/mL stock solution 
1. Reconstitute vial within 3 hours once removed from the refrigerator.  If it is not 
reconstituted within 3 hours, discard the drug. 
2. Inject the required volume of sterile Water for Injection as indicated in the table above 
into the drug vial with the needle directed toward the side of the vial to avoid foaming.  
This results in a 30 mg/mL solution.  Do not use bacteriostatic water.  
3. Swirl gently until all lyophilized powder is dissolved.  Dissolution usually takes 2 
minutes or less.  The diluted solution is clear, colorless to slightly yellow. 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
61 
 
4. Do not shake. 
5. This stock solution is stable up to 1 hour when stored at ambient temperature and up 
to 24 hours when refrigerated at 2˚ to 8˚C, protected from light. 
 
Step 2:  Reconstitute the final IV product: 
Withdraw the calculated amount of the drug from the stock solution (30 mg/mL) and 
further dilute it in 0.9% Sodium Chloride Injection, USP to a final concentration between 
1.2 mg/mL – 30 mg/mL.  The prepared IV bag can be stored at ambient temperature, 
protected from light for up to 6 hours (i.e., from the time the drug is diluted in 0.9% NS to 
the time the IV infusion is completed).  The final IV bag must be protected from light if not 
used immediately. 
 
Do not use vial adaptors when preparing AMG 386 IV solution  
 
Storage:  Refrigerate the intact vials at 2 to 8˚C upon receipt.  Protect the vials from light.  
Do not freeze.   
The prepared IV bag can be stored at ambient temperature, protected from light for up to 6 
hours (this does not include the 1 hour preparation of the stock solution) before 
administration.   
Stability:  Shelf-life studies of AMG 386 are ongoing.  The stock solution (30 mg/mL) is 
stable up to 1 hour at ambient temperature and up to 24 hours refrigerated at 2 to 8˚C, 
protected from light.  The final IV solution is stable up to 6 hours (i.e., from the time the 
drug is diluted in 0.9% NS to the time the IV infusion is completed) at ambient temperature, 
protected from light and must be used within that time. 
Route(s) of Administration:  Intravenous. 
Method of Administration:  Infuse over 60 minutes via an infusion pump.  If well 
tolerated, subsequent infusions can be given over 30 minutes.  Flush the IV line with 0.9% 
NS (minimum volume is 5 mL) before and after each IV infusion. 
Patient Care Implications:  If extravasation occurs follow your institutional guidelines for 
treatment.  Mild to moderate edema, usually in the upper and/or lower extremities, has 
occurred when AMG 386 is given concomitantly with other drugs. 
Availability 
AMG 386 is an investigational agent supplied to investigators by the Division of Cancer 
Treatment and Diagnosis (DCTD), NCI. 
AMG 386 is provided to the NCI under a Collaborative Agreement between the 
Pharmaceutical Collaborator and the DCTD, NCI (see Section 12.4). 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
62 
 
8.1.1 Agent Ordering and Agent Accountability 
8.1.1.1 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 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.  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. 
 
8.1.1.2 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  AGENT(S) 
8.2.1 Abiraterone 
(Please see package insert for complete drug information) 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
63 
 
8.2.1.1 Source: For patient administration oral tablets will be purchased by the local site from 
commercial sources or may be supplied by the NIH Clinical Center pharmacy.   
8.2.1.2 Toxicity:  See section 7.1.2.1 
8.2.1.3 Formulation and preparation:  Abiraterone is supplied as 250 mg tablets. 
8.2.1.4 Stability and storage: Store at 20˚C to 25˚C (68˚F to 77˚F); excursions permitted to 
15˚C to 30˚C (59˚F to 86˚F)  
8.2.1.5 Administration procedures:  See section 5.1.2.  
8.2.1.6 Incompatibilities: Abiraterone is an inhibitor of the hepatic drug-metabolizing enzyme 
CYP2D6. Avoid co-administration of abiraterone with CYP2D6 substrates that have a 
narrow therapeutic index. If an alternative treatment cannot be used, exercise caution 
and consider a dose reduction of the concomitant CYP2D6 substrate. 
Furthermore, 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. 
8.2.2 Prednisone 
(Please see package insert for complete drug information) 
8.2.2.1 Source: For patient administration oral tablets will be purchased by the local site from 
commercial sources or may be supplied by the NIH Clinical Center pharmacy. 
8.2.2.2 Toxicity:  See section 7.1.2.2 
8.2.2.3 Formulation and preparation:  Prednisone is supplied as 5 mg tablets. 
8.2.2.4 Stability and storage: Store at 15 - 30˚C, protected from moisture and light. 
8.2.2.5 Administration procedures: See section 5.1.3. 
8.2.2.6 Incompatibilities:  Systemic fungal infections and known hypersensitivity to 
components. 
9 
BIOMA RKER, CORR ELATIVE, AND SPECIAL STUDIES 
9.1 
LABORATOR Y CORREL ATIVE STUDIES 
9.1.1 Evaluation of genetic biomarkers of efficacy  
Exploratory genetic studies will be performed to identify alleles of known variants such as Ang2 
variant T allele and CYP17 lyase variant A allele as well as genes involved in the metabolic 
pathways of the study drugs as proposed in detail section 2.5.1. There is substantial germline 
genetic variability within angiogenesis pathway genes, which may be an important contributor to 
the heterogeneity of response seen with antiangiogenic therapy.  Specifically, this variability has 
the potential to be used for better selection of patients for future studies evaluating anti-Ang1/2 
therapy. Dr. Figg’s laboratory has extensive experience and expertise in performing 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
64 
 
pharmacogenetic analyses of genes involved in angiogenesis and drug metabolism pathways. 
Towards this end, polymerase-chain reaction (PCR) followed by either restriction fragment 
length polymorphism (RFLP), direct sequencing, or gene array analysis will be used to genotype 
the single nucleotide polymorphism (SNP) in Ang2 (variant T allele in rs1868554), which was 
shown to be associated with a variation in plasma Ang2 isoforms.68 We will characterize this 
Ang2 isoform variation and expression and investigate its effects in CRPC and in response to 
AMG 386 therapy as this potentially could be a resistance mechanism to AMG 386 if the Ang2 
variant is not effectively targeted by this agent. 
Previous studies have shown that genetic variations in the CYP17 gene led to increased PCa-
specific survival. For example, the CYP17 lyase SNP (variant A allele in rs10883783) has shown 
to be associated with a 56% reduction in prostate cancer-specific mortality.69 If these variants 
alter enzyme activity, then this may have an important impact on the action of CYP17 inhibitors 
such as abiraterone. Since CYP17 is a crucial enzyme in the testosterone biosynthesis pathway, it 
remains to be determined whether variant CYP17 alleles may impair this process, thereby 
affecting local intracrine testosterone production and subsequent response to anti-androgen 
therapy. We will determine genetic variants of CYP17 and correlate with clinical outcomes. 
Other laboratory correlates will evaluate genotyping of genes involved in the metabolic pathway 
of these agents to correlate with efficacy. 
Pharmacogenetic studies will also be performed to analyze the genomic DNA and assess 
genotype of the most relevant drug metabolizing enzymes and transporters (DMET). DNA will 
be analyzed on a DMET Plus (Affymetrix) genotyping platform that tests for 1,936 genetic 
variations in 225 drug disposition genes, including 47 CYP (phase I metabolism) genes, 13 non-
CYP (phase I metabolism) genes, 78 phase II metabolizing genes (including UGTs), 63 
transporters, 4 genes involved in facilitation of drug transporters, 9 genes involved in global 
regulation of drug metabolizing/transporting proteins, 4 drug binding proteins, and 4 drug 
targets. 
9.1.1.1 Collection of Specimen(s) 
One 10ml EDTA tube (BD, Franklin Lakes, NJ) will be collected from patients at baseline (after 
consent, prior to treatment initiation). The sample may be collected at a subsequent visit if 
missed at baseline.  
9.1.1.2 Handling and Processing of Specimens(s) 
Immediately after collection, invert the blood tube 8-10 times. Place the tube on wet ice and then 
store at 4C in the refrigerator.  
The following information should be provided with each sample.  If not on the label, the 
information may be provided on an inventory sheet linked to the specimen label.   
 Patient study ID# 
 Sample type 
 Date/time of draw (dd/mm/yy 24:00) 
 Time point (e.g. C1D1 pre, C1D1 24 hr post) 
 Any collection issues (short draw, delayed processing, etc.) 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
65 
 
 Protocol title/number 
 Institute name 
 Contact information 
Participating sites should store samples at 4°C until ready for batch shipping (every 4 months).   
At NCI site, please e-mail Julie Barnes at Julie.barnes@nih.gov and Paula Carter 
pcartera@mail.nih.gov at least 24 hours before transporting samples (the Friday before is 
preferred). 
For sample pickup, page 102-11964. 
For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 
240-760-6190 (main clinical pharmacology lab number). 
For questions regarding sample processing, contact Julie Barnes by e-mail or at 240-760-6044. 
Upon arrival in the BPC, genomic DNA will be extracted and analyzed for genetic 
polymorphisms.  
9.1.1.3 Shipping of Specimen(s) 
Please email Kathy Compton at comptok@mail.nih.gov prior to shipping on ice to the following 
address: 
NIH/NCI/Molecular Pharmacology Section 
Attn: Dr. Figg’s Lab 
10 Center Drive, Room 5A01 
Bethesda, MD 20892 
Batched samples should be shipped every 4 months 
9.1.1.4 Site(s) Performing Correlative Study 
The genotyping will be performed on a research basis in the Molecular Pharmacology Section 
(Bldg. 10 Room 5A01; William Figg, Pharm D.). 
9.1.2 Evaluation of pharmacokinetics (NCI Site only) 
Pharmacokinetic (PK) measurements can be correlated with clinical response and toxicity as well 
as pharmacodynamic (PD) and pharmacogenetic data to possibly identify the plasma 
concentrations that achieve the best response with least toxicity and to determine if genetics 
plays a role. CYP17 is the pharmacological target of abiraterone. OATP1B3 is a transporter 
believed to transport many steroid-based molecules and genotyping may help to shed light on 
whether abiraterone is a potential substrate. 
Bioanalytical measurements will be conducted on an ultra HPLC-MSMS system using a 
validated assay. The plasma concentration-time data will be analyzed with non-compartmental 
methods using Phoenix WinNonlin software (Pharsight, Mountain View, CA). The maximum 
concentration, time to maximum concentration, the area under the curve extrapolated to infinity, 
volume of distribution and clearance will be calculated. These pharmacokinetic measurements 
can be correlated with clinical response and toxicity as well as pharmacodynamic (PD) and 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
66 
 
pharmacogenetic data to possibly identify the plasma concentrations that achieves the best 
response with least toxicity and if genetics plays a role. 
 
9.1.2.1 Collection of Specimen(s) 
PK samples will be collected at the NCI Clinical Center site only.  One 6mL sodium heparin tube 
(BD, Franklin Lakes, NJ) for the determination of steady-state plasma levels of abiraterone is 
collected from each patient at the Cycle 2 day 1 visit and the following three visits. The timing of 
dose administration does not matter in regard to the blood draw. It is important to record the time 
of blood draw as well as the time the patient took their most recent dose.  
9.1.2.2 Handling and Processing of Specimen(s) 
Immediately after collection, invert the blood tube 8-10 times. Place the tube on wet ice and then 
store at 4°C in the refrigerator. The exact time of each blood draw should be recorded on the 
tube.  
Please e-mail Julie Barnes at Julie.barnes@nih.gov and Paula Carter pcartera@mail.nih.gov at 
least 24 hours before transporting samples (the Friday before is preferred). 
For sample pickup, page 102-11964. 
For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 
240-760-6190 (main clinical pharmacology lab number). 
For questions regarding sample processing, contact Julie Barnes by e-mail or at 240-760-6044. 
Upon arrival in the BPC, blood samples will be centrifuged for 5 minutes at 1200 x g at 4°C. 
Plasma will be aliquoted into 2 cryovials and stored at -80°C until the time of analysis.  
 
 
9.1.2.3 Site(s) Performing Correlative Study 
The PK measurement and analysis will be performed on a research basis by the Clinical 
Pharmacology Program (Bldg 10 Rm 5A01; William D. FiggPharm D.). 
 
9.1.3 Determine the biological effects of AMG 386: molecular markers of angiogenesis 
Exploratory studies will be performed to determine the impact of AMG 386 combination therapy 
on serial levels of markers of angiogenesis in order to elucidate the relationship between 
biomarker expression, treatment response, and biologic behavior as described in further detail in 
section 2.5.2.  Fluctuations in the levels of angiogenic factors have been detected following an 
array of anti-angiogenic therapies including bevacizumab, VEGFR2 inhibitors, and their 
combinations in clinical studies. Recent studies examined the effect of androgen deprivation 
therapy (ADT) on angiogenic factors and showed that CRPC is associated with elevated levels of 
VEGF and Ang2.66 Plasma levels of VEGF decreased after ADT, and increased again at time of 
tumor relapse, while Ang2 levels were unaffected. It is therefore important to determine the 
effect of AMG 386 combination therapy on these parameters. Plasma levels of angiogenic 
factors will be assessed for VEGF, PlGF, bFGF and sVEGFR1 (soluble VEGF receptor 1/sFlt1) 
as well as Ang1, Ang2, and soluble Tie2. The analyses will be performed with assays developed 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
67 
 
in Dr. Liang Cao’s laboratory using electrochemiluminescence technology that provides ultra-
high sensitivity and very large signal dynamic range.  Dr. Cao has extensive experience in 
biomarker assay development and validation. Purified protein standard will be used for 
generating standard curves for concentration determination. The currently available ELISA 
assays do not distinguish AMG 386-bound vs. free Ang1/2; thus, our platform will be tested to 
detect total Ang1/2 levels in plasma. Data analysis will be performed with Prism (GraphPad, San 
Diego, CA) to determine the medium value, interquartile range, and P value in paired t test. 
Correlative studies will be performed between the baseline levels of the angiogenic factors and 
the degree of their change over time with clinical response. 
9.1.3.1 Collection of Specimen(s) 
One 5mL EDTA plasma tube (BD, Franklin Lakes, NJ) is collected from each patient prior to 
AMG 386 drug administration at the following four time points: Day 1 of Cycle 1 (baseline, 
C1D1), Day 15 of Cycle 1 (C1D15), Day 1 of Cycle 2 (C2D1), and Day 1 of Cycle 3 (C3D1). 
9.1.3.2 Handling and Processing of Specimens(s) 
Immediately after collection, invert the blood tube 8-10 times. Place the tube on wet ice and then 
store at 4C in the refrigerator.  
The following information should be provided with each sample.  If not on the label, the 
information may be provided on an inventory sheet linked to the specimen label.   
 Patient study ID# 
 Sample type 
 Date/time of draw (dd/mm/yy 24:00) 
 Time point (e.g. C1D1 pre, C1D1 24 hr post) 
 Any collection issues (short draw, delayed processing, etc.) 
 Protocol title/number 
 Institute name 
 Contact information 
Participating sites should store samples at 4°C until ready for batch shipping (every 4 months).   
At NCI site, please e-mail Julie Barnes at Julie.barnes@nih.gov and Paula Carter 
pcartera@mail.nih.gov at least 24 hours before transporting samples (the Friday before is 
preferred). 
For sample pickup, page 102-11964. 
For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 
240-760-6190 (main clinical pharmacology lab number). 
For questions regarding sample processing, contact Julie Barnes by e-mail or at 240-760-
6044. 
Upon arrival in the BPC, blood samples will be centrifuged for 5 minutes at 1200 x g at 
4C.  Plasma will be aliquoted into 2 cryovials and stored at -80C until the time of 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
68 
 
analysis.  The samples will be transferred to Dr. Liang Cao’s lab at Bldg 37/Rm6134 (301-
435-9039) for analysis. 
9.1.3.3 Shipping of Specimen(s) 
Please email Julie Barnes at julie.barnes@nih.gov prior to shipping on ice to the following 
address: 
NIH/NCI/Molecular Pharmacology Section 
Attn: Dr. Figg’s Lab 
10 Center Drive, Room 5A01 
Bethesda, MD 20892 
Batched samples should be shipped every 4 months 
9.1.3.4 Site(s) Performing Correlative Study 
The angiogenic biomarker analysis studies will be performed on a research basis in the 
laboratory of Dr. Liang Cao (Bldg 37/Rm6134). 
9.1.4 Predictive biomarkers for abiraterone: Measurement of circulating tumor cells & 
androgen receptor pathway analysis  
Exploratory studies will be performed to evaluate the levels of circulating tumor cells (CTC) 
before and after drug administration based on previous abiraterone studies in which CTC counts 
corresponded with prostate-specific antigen (PSA) levels.  (See section 2.5.3) The clinical utility 
of monitoring CTC changes with treatment has been demonstrated to be an efficacy-response 
surrogate biomarker of survival. CTC enumeration is currently being tested in several large 
phase III trials, including the novel antiandrogen therapies such as abiraterone acetate. Molecular 
determinants can be identified and characterized in CTCs as potential predictive biomarkers of 
tumor sensitivity to therapeutic treatments. Recent studies report a significant association 
between ERG rearrangements in therapy-naive tumors, CRPCs, and CTCs and magnitude of 
prostate-specific antigen decline (P=0.007) in CRPC patients treated with abiraterone acetate.76 
These data confirm that CTCs are malignant in origin and indicate that hormone-regulated 
expression of ERG persists in CRPC. CTCs will be investigated as an experimental endpoint 
using immunofluorescence techniques and CTC identification by positive expression of 
epithelial markers and a viability marker and negative expression of hematopoietic markers. Dr. 
Jane Trepel has extensive experience in working with CTC technology and has developed a 
platform for accurate detection of CTC enumeration. Dr. Liang Cao is currently developing new 
CTC technologies capable of isolating live CTC for cancer genetic profiling. His expertise will 
be needed in this portion of our biomarker studies to assess AR signaling status in CTCs before 
and after drug treatment and involve cancer genetic profiling that will include the analysis of AR 
level, activity, and the downstream oncogene TMPRESS2-ERG. We will perform the following 
statistical analyses: evaluation of the effects of abiraterone in regulating AR activity; correlative 
analysis between baseline AR activity and clinical outcome; correlative analysis between the 
reduction of AR activity and clinical outcome; and correlative analysis between TMPRESS2-
ERG and clinical outcome. 
9.1.4.1 Collection of Specimen(s) 
9.1.4.1.1 CTC Enumeration 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
69 
 
NCI Site Tubes: Two 7mL EDTA plasma tube (BD, Franklin Lakes, NJ) 
Participating Sites Tubes:  One 10 mL EDTA plasma tube (BD, Franklin Lakes, NJ) and one 
7.5 mL CellSave Preservation tube  
Tubes are collected from each patient at the following two time points: prior to AMG 386 drug 
administration on Day 1 of Cycle 1 (baseline, pre-drug C1D1) and before AMG 386 drug 
administration on Day 15 of Cycle 1 (pre-drug C1D15).  Immediately after collection, invert the 
blood tubes 8-10 times.  
The following information should be provided with each sample.  If not on the label, the 
information may be provided on an inventory sheet linked to the specimen label.   
 Patient study ID# 
 Sample type 
 Date/time of draw (dd/mm/yy 24:00) 
 Time point (e.g. C1D1 pre, C1D1 24 hr post) 
 Any collection issues (short draw, delayed processing, etc.) 
 Protocol title/number 
 Institute name 
 Contact information 
 
9.1.4.1.2 AR analysis in CTCs (NCI site only) 
Two 5 mL EDTA plasma tube (BD, Franklin Lakes, NJ) is collected from each patient at the 
following two time points: prior to AMG 386 drug administration and before 2pm on Day 1 of 
Cycle 1 (baseline, pre-drug C1D1) and before AMG 386 drug administration and before 2pm on 
Day 15 of Cycle 1 (pre-drug C1D15). Immediately after collection, invert the blood tubes 8-10 
times. The date and time of each blood draw should be recorded on the tube. 
9.1.4.2 Handling and Processing of Specimens(s)  
9.1.4.2.1 CTC enumeration:  
As soon as possible after the patient is scheduled please send email notification to the Trepel lab: 
Jane Trepel at trepel@helix.nih.gov; Min-Jung Lee at leemin@mail.nih.gov that the sample is 
scheduled. After the sample is drawn at the NCI site please call the Trepel lab at 301-496-1547 
to communicate that the sample is ready. Keep the sample on the unit at room temperature. The 
sample will be picked up by the lab and processed for CTC enumeration.  Participating should 
ship the samples immediately after collection.  See section 9.1.4.3 for shipping instructions.  
9.1.4.2.2 AR analysis in CTCs (NCI site only) 
As soon as possible after the patient is scheduled please send email notification to the Cao lab: 
Liang Cao caoli@mail.nih.gov that the sample is scheduled. After the sample is drawn please 
call the Cao lab (Mr. Yunkai Yu at 301.443.2799) to communicate that the sample is ready. Keep 
the sample on the unit at room temperature. The sample needs to be picked up by the lab within 4 
hours. The blood will be processed for CTC isolation. 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
70 
 
9.1.4.3 Shipping of Specimen(s) 
Specimens for CTC enumeration from participating sites should be shipped immediately at room 
temperature via FedEx overnight delivery.  Please email the Trepel lab: Jane Trepel at 
trepelj@mail.nih.gov; Min-Jung Lee at leemj@mail.nih.govwith the FedEx shipment tracking 
number as soon as it is available. 
The samples should be sent to the address below: 
Jane Trepel 
Developmental Therapeutics Branch, NCI 
Building 10, Room 12N218 
Bethesda, MD 20892 
Phone: 301-496-1547 
 
Ship specimens to NCI Laboratory Monday through Thursday only.  Do not ship on Fridays, 
weekends or Federal holidays. 
9.1.4.4 Site(s) Performing Correlative Study 
The assays will be performed by Dr. Liang Cao’s laboratory in the Molecular Targets Core, 
Genetics Branch, Building 37, Rm 6134 and Dr. Jane Trepel’s laboratory Developmental 
Therapeutics Branch, Building 10, Room 12N230. 
9.2 
SAMPLE STORAGE, TRACK ING AND DISPOSITION 
Samples will be ordered and tracked through the CRIS Screens.  Should a CRIS screen not be 
available, the NIH form 2803-1 will be completed and will accompany the specimen and be filed 
in the medical record.  Samples will not be sent outside NIH without IRB notification and an 
executed MTA.  
9.2.1 Clinical Pharmacology Program 
All samples sent to the Clinical Pharmacology Program (CPP) will be barcoded, with data 
entered and stored in the Patient Sample Data Management System (PSDMS) utilized by the 
CPP (the Blood Processing Core is part of the CPP). This is a secure program, with access to the 
PSDM System limited to defined CPP personnel, who are issued individual user accounts. 
Installation of PSDMS is limited to computers specified by Dr. Figg. These computers all have a 
password restricted login screen. All CPP personnel with access to patient information annually 
complete the NIH online Protection of Human Subjects course.  
PSDMS creates a unique barcode ID for every sample and sample box, which cannot be traced 
back to patients without PSDMS access. The data recorded for each sample includes the patient 
ID, name, trial name/protocol number, time drawn, cycle time point, dose, material type, as well 
as box and freezer location. Patient demographics associated with the clinical center patient 
number are provided in the system. For each sample, there are notes associated with the 
processing method (delay in sample processing, storage conditions on the ward, etc.). 
Barcoded samples are stored in barcoded boxes in a locked freezer at either -20 or -80C 
according to stability requirements.  These freezers are located onsite in the CPP and offsite at 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
71 
 
NCI Frederick Central Repository Services  in Frederick, MD. Visitors to the laboratory are 
required to be accompanied by laboratory staff at all times.  
Access to stored clinical samples is restricted. Samples will be stored until requested by a 
researcher named on the protocol. All requests are monitored and tracked in the PSDM System. 
All researchers are required to sign a form stating that the samples are only to be used for 
research purposes associated with this trial (as per the IRB approved protocol) and that any 
unused samples must be returned to the CPP. It is the responsibility of the NCI Principal 
Investigator to ensure that the samples requested are being used in a manner consistent with IRB 
approval. 
Following completion of this study, samples will remain in storage as detailed above. Access to 
these samples will only be granted following IRB approval of an additional protocol, granting 
the rights to use the material.  
If, at any time, a patient withdraws from the study and does not wish for their existing samples to 
be utilized, the individual must provide a written request. Following receipt of this request, the 
samples will be destroyed (or returned to the patient, if so requested), and reported as such to the 
IRB. Any samples lost (in transit or by a researcher) or destroyed due to unknown sample 
integrity (i.e. broken freezer allows for extensive sample thawing, etc.) will be reported as such 
to the IRB. 
Sample barcodes are linked to patient demographics and limited clinical information. This 
information will only be provided to investigators listed on this protocol, via registered use of the 
PSDMS. It is critical that the sample remains linked to patient information such as race, age, 
dates of diagnosis and death, and histological information about the tumor, in order to correlate 
genotype with these variables. 
10 STUDY CALENDAR 
Screening evaluations, x-rays, and scans are to be conducted within the timeframe established in 
section 3.2.  On study evaluations/procedures with the exception of cycle 1 day 1 (see footnote h) 
may be performed within ± 5 days of day indicated on calendar. 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. 
All follow-up evaluations can be performed during the last week of the prior cycle. 
 
Pre- 
Study 
Cycle 1 
Cycle 2 
Cycle 3+ 
Off Therapy 
Evaluationk 
Day 
 
1h 8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
 
AMG 386 a 
 
X 
X 
X 
X 
X X 
X 
X 
X X 
X 
X 
 
Abiraterone 
acetate/prednisone 
 
Daily continuous self-administration 
 
 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
72 
 
 
Pre- 
Study 
Cycle 1 
Cycle 2 
Cycle 3+ 
Off Therapy 
Evaluationk 
Day 
 
1h 8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
NIH Advanced Directives 
Formj 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
X  
 
 
X  
 
 
 
Concurrent meds 
X 
X-------------------------------------------------------------------X  
Physical exam 
X 
X 
 
 
 
X  
 
 
X  
 
 
X 
Vital signs 
X 
X 
Xg 
Xg 
Xg 
X Xg 
Xg 
Xg 
X Xg 
Xg 
Xg 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
X  
 
 
X  
 
 
 
Performance status 
X 
X 
 
 
 
X  
 
 
X  
 
 
X 
CBC w/diff, plts 
X 
 
 
 
 
X  
 
 
X  
 
 
X 
INR and PTT (or aPTT) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum chemistryb 
X 
X 
 
 
 
X  
 
 
X  
 
 
X 
Urinalysis with dipstickc 
X 
X 
 
 
 
X  
 
 
X  
 
 
 
Urine protein-creatinine 
ratio (UPC) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
PSA 
X 
X 
 
 
 
X  
 
 
X  
 
 
X 
EKG (as indicated) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event evaluation 
 
 X----------------------------------------------------------------X 
X 
Restaging radiologic 
evaluationd 
X 
Evaluations should be performed after every 3 cycles. 
 
Correlative studies e 
X 
X 
 
X 
 
X Xi 
Xi 
Xi 
X  
 
 
 
Survival and post study 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xf 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
73 
 
 
Pre- 
Study 
Cycle 1 
Cycle 2 
Cycle 3+ 
Off Therapy 
Evaluationk 
Day 
 
1h 8 
15 
22 
1 
8 
15 
22 
1 
8 
15 
22 
 
anti-cancer therapy 
assessment 
a:  AMG 386: Dose as assigned; administered I.V. every week without planned rest/break. One cycle = 28 days 
b:  Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, 
LDH, phosphorus, potassium, total protein, SGOT [AST], SGPT [ALT], sodium, magnesium.  
c:  If the urine protein is 2+ a 24-hour urine collection for total protein should be obtained 
d:  CT chest, abdomen, pelvis; radionuclide bone scintigraphy; refer to section 11 for frequency of imaging 
studies 
e:  See section 9 for details as to pharmacodynamic/pharmacogenetic/pharmacokinetic timepoints/biomarkers to 
be drawn. 
f:  Will occur once every year until subject is off study or has died 
g:  Only subjects assigned to the AMG386 arm will have this assessment 
h:  Screening assessments may be used for Cycle 1 day as long as they are performed within the established 
screening timeframe indicated in section 3.2. 
i: Non AMG 386 patients will have these assessments on the 3 visits following cycle 2 day 1 (i.e. day 1 of cycle 
3, 4 and 5)  
j: As indicated in section 14.3, all NIH Clinical Center subjects will be offered the opportunity to complete an 
NIH advanced directives form.  This should be done preferably at baseline but can be done at any time during 
the study as long as the capacity to do so is retained.  The completion of the form is strongly recommended, but 
is not required. 
k: End of treatment visit will occur approximately 30 days after the last dose of study drug. If the patient cannot 
return to the Clinical Center for this visit, a request will be made to collect required clinical labs from a local 
physician or laboratory.  If this is not possible, patients may be assessed by telephone for symptoms.   
 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
74 
 
11 MEASUREM ENT OF EFFECT 
11.1 ANTITUMOR EFFECT – SOLID TUMORS 
Re-staging bone scans and CT scan of chest, abdomen, and pelvis will be after every three cycles 
of treatment.  If screening CT scan is negative for soft tissue disease, repeat CT imaging will not 
be required. 
 
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.  For exploratory purpose, changes in PSA and measurable 
lesions will be analyzed for efficacy according to the PCWG2 recommendations [JCO 26: 1148-
1159, 2008]. The recommended PSA progressions criteria will not be applied to the study as the 
criteria are arbitrarily proposed and do not necessarily reflect overall disease status. PSA values 
will be captured at each visit and PSA declines and progression will be followed. PSA is not 
sufficient in the evaluation of disease progression in this patient population. This is consistent 
with the recent recommendations by the Prostate Cancer Clinical Trials Working Group 2. [J 
Clin Oncol. 26(7), 2008]. Progression will be determined by radiographic evidence as discussed 
below or by clinical symptoms (symptomatic clinical progression). 
 
11.1.1 Definitions 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their first 
treatment with study agents. 
 
Evaluable for objective response.  All of the patients who met the eligibility criteria (with the 
possible exception of those who received no study medication) are evaluable for response.  
Patients that have: progressive disease, early death from malignant disease, early death from 
toxicity, early death because of other cause, or unknown (not assessable, insufficient data)  
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.    
 
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 one cycle 
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.  
 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
75 
 
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 or as >10 mm 
with CT scan, MRI, or calipers by clinical exam.  All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). 
 
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 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.  


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
76 
 
 
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 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
Metastatic bone lesions Disease progression is considered if a minimum of two new lesions is 
observed on bone scan. New lesions seen by the end of cycle 3 or before cycle 4 (after the first 
staging bone scan) may represent disease that was not detected on the pre-study scan, and a 
confirmatory scan will be required in the next scheduled staging bone scan unless clinically not 
indicated. If confirmed, progression should be dated by the initial time when the lesions are first 
detected. If new lesions are seen after cycle 3, but no additional lesions are seen on confirmatory 
scans, the scans from after cycle 3 would serve as the baseline scan to evaluate for disease 
progression [J Clin Onc, 26 (7), 2008] 
 
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 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.  


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
77 
 
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence.  It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases.  Ideally, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
PET-CT  At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements.  However, if 
the site can document that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be 
used for RECIST measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time.  Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not routinely or serially 
performed.   
 
Ultrasound  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next.  If new lesions are identified by ultrasound in the course of the study, confirmation by CT 
or MRI is advised.  If there is concern about radiation exposure at CT, MRI may be used instead 
of CT in selected instances. 
 
Endoscopy, Laparoscopy  The utilization of these techniques for objective tumor evaluation is 
not advised.  However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence following 
complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers  Tumor markers alone cannot be used to assess response.  If markers are initially 
above the upper normal limit, they must normalize for a patient to be considered in complete 
clinical response.  Specific guidelines for both CA-125 response (in recurrent ovarian cancer) 
and PSA response (in recurrent prostate cancer) have been published [JNCI 96:487-488, 2004; J 
Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008].  In addition, the 
Gynecologic Cancer Intergroup has developed CA-125 progression criteria which are to be 
integrated with objective tumor assessment for use in first-line trials in ovarian cancer [JNCI 
92:1534-1535, 2000]. 
 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
78 
 
Cytology, Histology  These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
 
FDG-PET  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm:  
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based on a 
new lesion. 
a. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this 
is PD.  If the positive FDG-PET at follow-up is not confirmed as a new site of 
disease on CT, additional follow-up CT  scans are needed to determine if there is 
truly progression occurring at that site (if so, the date of PD will be the date of the 
initial abnormal FDG-PET scan).  If the positive FDG-PET at follow-up 
corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD. 
b. FDG-PET may be used to upgrade a response to a CR in a manner similar to a 
biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring.  The use of FDG-PET in this circumstance should be 
prospectively described in the protocol and supported by disease-specific medical 
literature for the indication.  However, it must be acknowledged that both 
approaches may lead to false positive CR due to limitations of FDG-PET and 
biopsy resolution/sensitivity.  
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
 
11.1.4 Response Criteria 
11.1.4.1 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. 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
79 
 
Partial Response (PR): 
At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum of 
diameters. 
Progressive Disease (PD): 
At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on 
study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase 
of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm.  (Note:  the appearance of 
one or more new lesions is also considered 
progressions). 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as 
reference the smallest sum of diameters while on 
study. 
 
11.1.4.2 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. 
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.     
Non-CR/Non-PD: 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal 
limits. 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
80 
 
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). 
11.1.4.3 Clinical Disease Progression 
 Radiographic progression by CT scan or bone scan 
 The need for palliative radiotherapy for pain  
 The need for chemotherapy or other change in therapy based on increased cancer related 
symptoms 
 Worsening ECOG PS to a PS of 3 or 4 based on cancer (not treatment) related symptoms 
11.1.4.4 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 
SD 
Non-
CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least 
once >4 wks. from 
baseline** 
PD 
Any 
Yes 
or PD 
no prior SD, PR or CR 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
81 
 
No 
Any 
PD*** 
Yes 
or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is 
evidence of a new lesion. 
** 
Only for non-randomized trials with response as primary 
endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-
target lesions may be accepted as disease progression. 
 
Note: Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease 
progression at that time should be reported as “symptomatic 
deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease 
since SD is increasingly used as an endpoint for assessment of efficacy in 
some trials so to assign this category when no lesions can be measured is not 
advised 
 
11.1.5 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 or death is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the treatment started). 
 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
82 
 
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.  
11.1.6 Progression-Free Survival 
Progression free survival (PFS) is defined as the duration of time from start of treatment to time 
of progression or death, whichever occurs first. 
11.1.7 Radiographic Progression-Free Survival 
Radiographic progression free survival (rPFS is defined as the duration of time from start of 
treatment to time of radiographic progression by CT scan (or MRI) or bone scan. 
12 DATA COLLECTIO N / DATA REPORT ING / REG ULATO RY REQ UIREMENTS 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7 
(Adverse Events: List and Reporting Requirements). 
12.1 DATA COLLECTION 
Data will be collected prospectively and entered into NCI CCR C3D database.  The NCI 
principal investigator is responsible for the collection, maintenance and quality control of study 
data. 
 
Quality assurance complete records must be maintained on each patient treated on the protocol.  
These records should include primary documentation (e.g.: laboratory report slips, X-ray reports, 
scan reports, pathology reports, physician notes, etc.) which confirm that: 
 The patient met all eligibility criteria 
 Signed informed consent was obtained prior to treatment 
 Treatment was given according to protocol (dated notes about doses given, 
complications, and clinical outcomes) 
 Toxicity was assessed according to protocol (laboratory report slips, etc) 
 Response was assessed according to protocol (X-ray, scan, lab reports, date noted on 
clinical assessment, as appropriate) 
 
The PI will be responsible for overseeing entry of data into an in-house password protected 
electronic system and ensuring data accuracy, consistency and timeliness. The principal 
investigator, associate investigators/research nurses and/or a contracted data manager will assist 
with the data management efforts.. All data obtained during the conduct of the protocol will be 
kept in secure network drives or in approved alternative sites that comply with NIH security 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
83 
 
standards. Primary and final analyzed data will have identifiers so that research data can be 
attributed to an individual human subject participant. 
 
End of study procedures: Data will be stored according to HHS, FDA regulations and NIH 
Intramural Records Retention Schedule as applicable.  
 
Loss or destruction of data: Should we become aware that a major breech in our plan to protect 
subject confidentiality and trial data has occurred, the IRB will be notified.  
 
12.2 DATA REPORTING 
12.2.1 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. 
 
12.2.2 Responsibility for Data Submission 
Study participants are responsible for submitting CDUS data and/or data forms to either the 
Coordinating Center quarterly.  The date for submission to the Coordinating Center will be set by 
them.  CDUS does not accept data submissions from the participants on the study.  When setting 
the dates, allow time for Coordinating Center compilation, Principal Investigator review, and 
timely submission to CTEP by the quarterly deadlines (see Section 12.2.1).  
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.   
12.3 CTE P 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 Coordinating Center (Study 
Coordinator) and the procedures for auditing are presented in Appendix E. 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
84 
 
 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. 
12.4  COLLABORATI VE AGREEMENTS LANGUAGE 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA) between the Pharmaceutical Company(ies) 
(hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer Treatment and 
Diagnosis.  Therefore, the following obligations/guidelines, in addition to the provisions in the 
“Intellectual 
Property 
Option 
to 
Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and 
shall be maintained as such by the investigators.  The protocol documents for studies 
utilizing 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”): 
 
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 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
85 
 
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 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  


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
86 
 
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 
13 STATISTICAL CONSI DERATIO NS 
13.1 STUDY DESIGN/ENDPOINTS 
The primary objective of the trial is to determine if there is a difference in progression free 
survival (PFS) among patients with metastatic prostate cancer without prior chemotherapy for 
metastatic castrate resistant disease who are randomized to receive either abiraterone/prednisone 
alone or in combination with AMG 386.  PFS will be based on metastatic disease (measurable or 
non-measurable but not PSA), using clinical and radiographic criteria. 
The study will be conducted with a two-part design. In the initial run-in part of the trial, the study 
will evaluate patients in two cohorts of escalating dose levels from 15mg/kg to 30mg/kg. Based 
on a standard 3 to 6 per cohort dose escalation, the first 3 patients would be treated at a 15mg/kg 
dose, and then the next cohort of 3 patients will be treated at 30mg/kg provided there are 0 of 3 
patients with unacceptable toxicity at the 15mg/kg dose. If 1 of 3 patients has a dose limiting 
toxicity at 15mg/kg, then 3 more patients will be enrolled at that dose. If 1 of 6 has unacceptable 
toxicity, then accrual would escalate to the 30mg/kg dose. If 1 of 3 patients has dose limiting 
toxicity at 30mg/kg, then 3 more patients will be enrolled at that dose. Three to 6 patients will be 
tested at the 30mg/kg dose. The dose selected for evaluation will be determined after review by 
the sponsor (CTEP and the study team). The maximum dose at with 6 patients are treated and no 
more than 1/6 has dose limiting toxicity will strongly factor into this decision. 
In the second part of the trial, patients without prior chemotherapy for metastatic castrate 
resistant disease will be enrolled at the AMG 386 dose level of 30 mg/kg, established in the run 
in phase as of Amendment F. 
In patients who have not received chemotherapy for metastatic castrate resistant disease based on 
preliminary results reported from ASCO in 2012, patients with this disease but treated with 
abiraterone/prednisone alone would be expected to have an estimated, approximate10 month 
median progression free survival from the date of randomization, using both clinical and 
radiologic determinants of progression. This is based on the published results showing what may 
become a median 12 month PFS by radiologic criteria alone, and allowing for earlier progression 
by clinical determinations. The goal of this study will be to determine if the use of AMG 386 in 
addition to abiraterone/prednisone will result in an 8 month increase in median progression free 
survival from randomization, to a median of 18 months. Kaplan-Meier curves and a one-tailed 
log-rank test will be the primary analysis methods. Assuming exponential progression free 
survival curves, the hazard rate for the abiraterone/prednisone alone arm will be 0.0693, or 
approximately a 6.9% probability of progression each month when the median progression free 
survival is 10 months. If we assume that the combination arm has a median progression free 
survival of 18 months, this corresponds to a hazard rate of 0.0385 and the resulting hazard ratio 
for the comparison of the two overall progression free survival curves would be 1.80. To 
compare these curves and detect a difference with a 0.10 one-tailed log-rank test, following a 
phase 2.5 design, a total of 36 evaluable subjects per arm (72 total) will need to be enrolled 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
87 
 
without prior chemotherapy for metastatic castrate resistant disease in the part 2 portion of the 
study over a three year period and followed for an additional year from the date of entry of the 
last patient, with observation of 52 total progressions, in order to have 80% power to compare 
the curves. In order to allow for early termination of the randomized portion of the trial in the 
event that the AMG 386 arm is not associated with improvement in PFS, the following stopping 
rule will be implemented: if after 50% of the information has been observed (26 events), the 
observed hazard ratio (AMG/non-AMG) exceeds 1.0, no further patients will be enrolled. 
In addition, for each randomized arm of the trial, an early stopping rule for evidence of 
unacceptable toxicity will be implemented. If after 18 patients have been treated on a given arm, 
if 6 patients experience a DLT, then no further patients will be enrolled on the trial. For a given 
arm, 5 of 18 with a DLT has an upper one-sided 90% confidence interval of 45.5% while 6 of 18 
has an upper one-sided 90% confidence interval of 51.2%. Thus, 5 of 18 with toxicity is likely to 
be inconsistent with 50% having severe toxicity while 6 of 18 would potentially be consistent 
with 50% or greater having severe toxicity. 
Patients will be stratified according to prior ketoconazole or enzalutamide use versus no prior 
ketoconazole or enzalutamide use. At the conclusion of the trial, patients will be evaluated for 
outcome (response, OS, PFS) according to prior use of ketoconazole or enzalutamide, but as a 
secondary evaluation and without formal adjustment for multiple comparisons. 
13.2 SAMPLE SIZE/ACCRUAL RATE 
It is anticipated that this trial may enroll approximately 3 patients per month; thus accrual is 
expected to be completed within 2-3 years for both the phase I and randomized phase II portions. 
Up to 12 patients may be required for the run-in part plus 72 without prior chemotherapy for 
metastatic castrate resistant disease in the randomized part. In order to allow for the possibility 
that there may be a very small number of patients who are inevaluable, the accrual ceiling will be 
set at 88 patients. 
The accrual rate is expected to be rapid since there will be a desire for patients to receive 
abiraterone, which will be supplied by the clinical center. Also, there is a local GU consortium 
that could assist in accrual by sending patients to the clinical center. 
 
13.3 STRATI FICATI ON FACTORS 
Randomization will be stratified according to prior ketoconazole use or enzalutamide use versus 
no prior ketoconazole or enzalutamide use.   
 
13.4 ANALYSIS OF SECONDARY ENDPOINTS 
Overall survival will also be evaluated using Kaplan-Meier curves, and a one-tailed log rank test, 
as a secondary endpoint.  
Evaluation of circulating tumor cells will also be performed as an exploratory analysis, 
comparing values between arms relative to changes from baseline. Angiogenic and genetic 
biomarkers will also be explored in relation to evaluating the impact of treatments on outcome. 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
88 
 
Monthly PSA, testosterone, CBC, and serum chemistries will be performed at baseline and 
monthly thereafter, with CT scans and bone scans to be performed at baseline and every 8 weeks 
of treatment until progression. The comparisons will be made without any correction for multiple 
comparisons because of the exploratory and secondary nature of the evaluations. 
Toxicity of the agent will also be tabulated for all patients taken as a group, and potentially by 
type of polymorphism genotype expression in the event that this may have some association. The 
distributions of toxicity identified will be compared informally to data from the same agent in 
other trials. 
 
 
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 AMG 386 and/or abiraterone  
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.  Precise 
definitions for categories 4-9 will be protocol specific.  
All conclusions should 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 deviations, etc.).  However, these 
subanalyses may 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 should also be provided.  
13.5.3 Evaluation of DLT    For MTD determination, dose-limiting toxicities will be evaluated 
throughout the first 28 days of treatment. 
 
14 HUMAN SUBJE CTS PROTECTIO NS  
14.1 RATIONALE FOR SUBJECT SELECTION 
Subjects treated on this study, will be individuals with metastatic progressive, castrate-resistant 
prostate cancer with radiographic evidence of disease after primary treatment with surgery or 
radiotherapy which has continued to progress despite adequate androgen-deprivation therapy.  


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
89 
 
Individuals of any race or ethnic group will be eligible for this study.  Eligibility assessment will 
be based solely on the patient’s medical status.  Recruitment of patients onto this study will be 
through standard CCR mechanisms. No special recruitment efforts will be conducted. 
14.1.1 NCI IRB Multi-Institutional Guidelines 
14.1.1.1 IRB Approvals  
The PI will provide the NCI IRB and Central Registration Office with a copy of the participating 
institution’s approved yearly continuing review.  Registration will be halted at any participating 
institution in which a current continuing approval is not on file at the NCI IRB. 
14.1.1.2 Amendments and Consents 
The CCR PI will provide the NCI IRB with copies of all amendments, consents and approvals 
from each participating institution. 
14.2 PARTI CIP ATION OF CHILDREN 
Individuals under the age of 18 will not be eligible to participate in this study because they are 
unlikely to have prostate cancer, and because of unknown toxicities in the pediatric population. 
14.3 PARTI CIP ATION OF NIH SUBJECTS UNABLE TO GIVE CONSENT 
Adults unable to give consent are excluded from enrolling in the protocol.  However, re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because there is a prospect of direct benefit from 
research participation (section 14.5), all NIH Clinical Center subjects will be offered the 
opportunity to fill in their wishes for research and care, and assign a substitute decision maker on 
the “NIH Advance Directive for Health Care and Medical Research Participation” form so that 
another person can make decisions about their medical care in the event that they become 
incapacitated or cognitively impaired during the course of the study. Note: The PI or AI will 
contact the NIH Ability to Consent Assessment Team for evaluation.  For those subjects that 
become incapacitated and do not have pre-determined substitute decision maker, the procedures 
described in MEC Policy 87-4 for appointing a surrogate decision maker for adult subjects who 
are (a) decisionally impaired, and (b) who do not have a legal guardian or durable power of 
attorney, will be followed. 
14.4 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS 
Subjects participating in this protocol may potentially benefit from an improvement in metastatic 
lesions, reduction in tumor bulk, which may or may not favorably impact symptoms and 
survival.  Potential risks include the range of side effects listed in section 7.1.1.  Subjects will be 
evaluated medically throughout the protocol in order to minimize risk. 
14.5 RISKS/BENEFITS ANALYSIS 
For patients with castration resistant prostate cancer, median survival is in the range of 12-18 
months. The agents administered in this trial have shown activity against prostate cancer in vitro 
and in vivo.  Although possible toxicities from the proposed therapy are serious, given the nature 
of the underlying disease, they are reasonable.  Additionally, we do not anticipate toxicities 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
90 
 
significantly more severe than those observed with other, approved agents.  For these reasons, 
the risk/benefit ratio of this protocol is favorable; therefore, this protocol involves greater than 
minimal risk to patients, but presents the potential for direct benefit to individual subjects. 
14.6 CONSENT PROCESS AND DOCUMENTATION 
Patients will meet with an associate or principal investigator on the trial in the Prostate Cancer 
Clinic, during the initial evaluation for this study.  During that meeting, the investigator will 
inform patients of the purpose, alternatives, treatment plan, research objectives and follow-up of 
this trial.  The investigator will then provide a copy of the IRB-approved informed consent 
document that is included in this protocol.  The patient will be allowed to take as much time as 
he wishes, in deciding whether or not he wishes to participate.  If a prolonged period of time 
expires during the decision making process (several weeks, as an example), it may be necessary 
to reassess the patient for protocol eligibility. The original signed consent goes to Medical 
Records; copy placed in research record (NIH policy). 
If re-consent is required, an informed consent document will be sent to the subject.  An 
explanation of the study will be provided over the telephone after the subject has had the 
opportunity to read the consent form.  The subject will sign and date the informed consent. A 
witness to the subject’s signature will sign and date the consent. 
The original informed consent document will be sent back to the consenting investigator who 
will sign and date the consent form with the date the consent was obtained via telephone.   
A fully executed copy will be returned via mail for the subject’s records. 
The informed consent process will be documented on a progress note by the consenting 
investigator and a copy of the informed consent document and note will be kept in the subject’s 
research record.  
All patients must have a signed informed consent form and an on-study (confirmation of 
eligibility) form filled out and signed by a participating investigator before entering on the study. 
 
14.6.1 Informed Consent of Non-English Speaking Subjects 
If there is an unexpected enrollment of a research participant for whom there is no translated 
extant IRB approved consent document, the principal investigator and/or those authorized to 
obtain informed consent will use the Short Form Oral Consent Process as described in MAS 
Policy M77-2, OSHRP SOP 12, 45 CFR 46.117 (b) (2), and 21 CFR 50.27 (b) (2).  The 
summary that will be used is the English version of the extant IRB approved consent document.  
Signed copies of both the English version of the consent and the translated short form will be 
given to the subject or their legally authorized representative and the signed original will be filed 
in the medical record. 
 
Unless the PI is fluent in the prospective subject’s language, an interpreter will be present to 
facilitate the conversation (using either the long translated form or the short form). Preferably 
someone who is independent of the subject (i.e., not a family member) will assist in presenting 
information and obtaining consent. Whenever possible, interpreters will be provided copies of 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
91 
 
the relevant consent documents well before the consent conversation with the subject (24 to 48 
hours if possible).  
 
We request prospective IRB approval of the use of the short form process for non-English 
speaking subjects and will notify the IRB at the time of continuing review of the frequency of the 
use of the Short Form. 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
92 
 
15 REF ERENC ES 
1. 
Goktas S, Crawford ED. Optimal hormonal therapy for advanced prostatic carcinoma. 
Semin Oncol. 1999;26(2):162-173. 
2. 
Klotz L. Hormone therapy for patients with prostate carcinoma. Cancer. 2000;88(12 
Suppl):3009-3014. 
3. 
Berthold DR, Sternberg CN, Tannock IF. Management of advanced prostate cancer after 
first-line chemotherapy. Journal of clinical oncology : official journal of the American 
Society of Clinical Oncology. 2005;23(32):8247-8252. 
4. 
Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus 
prednisone for advanced prostate cancer. The New England journal of medicine. 
2004;351(15):1502-1512. 
5. 
Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine compared with 
mitoxantrone and prednisone for advanced refractory prostate cancer. The New England 
journal of medicine. 2004;351(15):1513-1520. 
6. 
Gulley J, Dahut WL. Chemotherapy for prostate cancer: finally an advance! Am J Ther. 
2004;11(4):288-294. 
7. 
Kantoff PW, Higano CS , Shore ND, et al. Sipuleuce l-T immunotherapy for 
ca stra tion-resist ant prosta te cancer. N Engl J Med. 2010;363 (5):411 -422 . 
8. 
de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone 
for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a 
randomised open-label trial. Lancet. 2010;376(9747):1147-1154. 
9. 
Savarese DM, Halabi S, Hars V, et al. Phase II study of docetaxel, estramustine, and low-
dose hydrocortisone in men with hormone-refractory prostate cancer: a final report of 
CALGB 9780. Cancer and Leukemia Group B. Journal of clinical oncology : official 
journal of the American Society of Clinical Oncology. 2001;19(9):2509-2516. 
10. 
Figg WD, Dahut W, Duray P, et al. A randomized phase II trial of thalidomide, an 
angiogenesis inhibitor, in patients with androgen-independent prostate cancer. Clin 
Cancer Res. 2001;7(7):1888-1893. 
11. 
Dahut WL, Gulley JL, Arlen PM, et al. Randomized phase II trial of docetaxel plus 
thalidomide in androgen-independent prostate cancer. J Clin Oncol. 2004;22(13):2532-
2539. 
12. 
Figg WD, Ret ter A, Steinberg SM, Dah ut WL. In rep ly. J Clin Oncol. 
2005;23(9):2113-2114. 
13. 
Ning YM, Gulley JL, Arlen PM, et al. Phase II trial of bevacizumab, thalidomide, 
docetaxel, and prednisone in patients with metastatic castration-resistant prostate cancer. 
Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology. 2010;28(12):2070-2076. 
14. 
Berthold DR, Pond GR, Soban F, de Wit R, Eisenberger M, Tannock IF. Docetaxel plus 
prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated 
survival in the TAX 327 study. Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology. 2008;26(2):242-245. 
15. 
Investigator's Brochure AMG 386. 7.0 ed. Thousand Oaks, CA: Amgen, Inc.; 2011. 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
93 
 
16. 
Augustin HG, Koh GY, Thurston G, Alitalo K. Control of vascular morphogenesis and 
homeostasis through the angiopoietin-Tie system. Nat Rev Mol Cell Biol. 
2009;10(3):165-177. 
17. 
Eklund L, Olsen BR. Tie receptors and their angiopoietin ligands are context-dependent 
regulators of vascular remodeling. Exp Cell Res. 2006;312(5):630-641. 
18. 
Huang H, Bhat A, Woodnutt G, Lappe R. Targeting the ANGPT-TIE2 pathway in 
malignancy. Nat Rev Cancer. 2010;10(8):575-585. 
19. 
Yancopoulos GD, Davis S, Gale NW, Rudge JS, Wiegand SJ, Holash J. Vascular-specific 
growth factors and blood vessel formation. Nature. 2000;407(6801):242-248. 
20. 
Maisonpierre PC, Suri C, Jones PF, et al. Angiopoietin-2, a natural antagonist for Tie2 
that disrupts in vivo angiogenesis. Science. 1997;277(5322):55-60. 
21. 
Gale NW, Thurston G, Hackett SF, et al. Angiopoietin-2 is required for postnatal 
angiogenesis and lymphatic patterning, and only the latter role is rescued by 
Angiopoietin-1. Dev Cell. 2002;3(3):411-423. 
22. 
Jo MJ, Lee JH, Nam BH, et al. Preoperative serum angiopoietin-2 levels correlate with 
lymph node status in patients with early gastric cancer. Ann Surg Oncol. 
2009;16(7):2052-2057. 
23. 
Sfiligoi C, de Luca A, Cascone I, et al. Angiopoietin-2 expression in breast cancer 
correlates with lymph node invasion and short survival. Int J Cancer. 2003;103(4):466-
474. 
24. 
Dallabrida SM, Ismail N, Oberle JR, Himes BE, Rupnick MA. Angiopoietin-1 promotes 
cardiac and skeletal myocyte survival through integrins. Circ Res. 2005;96(4):e8-24. 
25. 
Lee OH, Xu J, Fueyo J, et al. Expression of the receptor tyrosine kinase Tie2 in 
neoplastic glial cells is associated with integrin beta1-dependent adhesion to the 
extracellular matrix. Mol Cancer Res. 2006;4(12):915-926. 
26. 
Imanishi Y, Hu B, Jarzynka MJ, et al. Angiopoietin-2 stimulates breast cancer metastasis 
through the alpha(5)beta(1) integrin-mediated pathway. Cancer Res. 2007;67(9):4254-
4263. 
27. 
Oliner J, Min H, Leal J, et al. Suppression of angiogenesis and tumor growth by selective 
inhibition of angiopoietin-2. Cancer Cell. 2004;6(5):507-516. 
28. 
De Palma M, Mazzieri R, Politi LS, et al. Tumor-targeted interferon-alpha delivery by 
Tie2-expressing monocytes inhibits tumor growth and metastasis. Cancer Cell. 
2008;14(4):299-311. 
29. 
Lewis CE, De Palma M, Naldini L. Tie2-expressing monocytes and tumor angiogenesis: 
regulation by hypoxia and angiopoietin-2. Cancer Res. 2007;67(18):8429-8432. 
30. 
Venneri MA, De Palma M, Ponzoni M, et al. Identification of proangiogenic TIE2-
expressing monocytes (TEMs) in human peripheral blood and cancer. Blood. 
2007;109(12):5276-5285. 
31. 
Huang J, Bae JO, Tsai JP, et al. Angiopoietin-1/Tie-2 activation contributes to vascular 
survival and tumor growth during VEGF blockade. Int J Oncol. 2009;34(1):79-87. 
32. 
Chae SS, Kamoun WS, Farrar CT, et al. Angiopoietin-2 interferes with anti-VEGFR2-
induced vessel normalization and survival benefit in mice bearing gliomas. Clin Cancer 
Res. 2010;16(14):3618-3627. 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
94 
 
33. 
Bullock AJ, Zhang L, O'Neill AM, et al. Plasma angiopoietin-2 (ANG2) as an angiogenic 
biomarker 
in 
renal 
cell 
carcinoma 
(RCC). 
ASCO 
Meeting 
Abstracts. 
2010;28(15_suppl):4630. 
34. 
Helfrich I, Edler L, Sucker A, et al. Angiopoietin-2 levels are associated with disease 
progression in metastatic malignant melanoma. Clin Cancer Res. 2009;15(4):1384-1392. 
35. 
Mouawad R, Spano J, Conforti R, Vignot S, de La Motte Rouge T, Khayat D. Evaluation 
of circulating angiopoietin levels with prognosis and disease progression in metastatic 
malignant melanoma. ASCO Meeting Abstracts. 2010;28(15_suppl):8522. 
36. 
Etoh T, Inoue H, Tanaka S, Barnard GF, Kitano S, Mori M. Angiopoietin-2 is related to 
tumor angiogenesis in gastric carcinoma: possible in vivo regulation via induction of 
proteases. Cancer Res. 2001;61(5):2145-2153. 
37. 
Oka N, Yamamoto Y, Takahashi M, Nishitani M, Kanayama HO, Kagawa S. Expression 
of angiopoietin-1 and -2, and its clinical significance in human bladder cancer. BJU Int. 
2005;95(4):660-663. 
38. 
Szarvas T, Jager T, Totsch M, et al. Angiogenic switch of angiopietins-Tie2 system and 
its prognostic value in bladder cancer. Clin Cancer Res. 2008;14(24):8253-8262. 
39. 
Hou HA, Chou WC, Lin LI, et al. Expression of angiopoietins and vascular endothelial 
growth factors and their clinical significance in acute myeloid leukemia. Leuk Res. 
2008;32(6):904-912. 
40. 
Loges S, Heil G, Bruweleit M, et al. Analysis of concerted expression of angiogenic 
growth factors in acute myeloid leukemia: expression of angiopoietin-2 represents an 
independent prognostic factor for overall survival. J Clin Oncol. 2005;23(6):1109-1117. 
41. 
Hashizume H, Falcon BL, Kuroda T, et al. Complementary actions of inhibitors of 
angiopoietin-2 and VEGF on tumor angiogenesis and growth. Cancer Res. 
2010;70(6):2213-2223. 
42. 
Clinical 
Study 
Report: 
20040169. 
2007; 
http://download.veritasmedicine.com/REGFILES/amgen/08D_FDAMA_113_Posting_Su
mmary_65_AMG_386_20040169.pdf. 
43. 
Herbst RS, Hong D, Chap L, et al. Safety, pharmacokinetics, and antitumor activity of 
AMG 386, a selective angiopoietin inhibitor, in adult patients with advanced solid 
tumors. J Clin Oncol. 2009;27(21):3557-3565. 
44. 
Toshihiko D, Ohtsu, N, Fuse, et al. Phase I study of AMG 386, an anti-angiogenic Fc 
fusion protein targeting angiopoietin-1 and -2, in Japanese patients with advanced solid 
tumors. Paper presented at: AACR Annual Meeting2011. 
45. 
Karlan BY, Oza AM, Hansen VL, et al. Randomized, double-blind, placebo-controlled 
phase II study of AMG 386 combined with weekly paclitaxel in patients (pts) with 
recurrent ovarian carcinoma. ASCO Meeting Abstracts. 2010;28(15_suppl):5000. 
46. 
Lu J, Rasmussen E, Navale L, et al. Exposure-response relationships of AMG 386 in 
combination with weekly paclitaxel in advanced ovarian cancer: Population 
pharmacokinetic/pharmacodynamic (PK/PD) modeling to facilitate phase III dose 
selection. ASCO Meeting Abstracts. 2010;28(15_suppl):5042. 
47. 
Avastin 
Prescibing 
Information. 
2009; 
http://www.gene.com/gene/products/information/oncology/avastin/index.html. Accessed 
September 2, 2011, 2011. 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
95 
 
48. 
Soucy P, Luu-The V. Conversion of pregnenolone to DHEA by human 17alpha-
hydroxylase/17, 20-lyase (P450c17). Evidence that DHEA is produced from the released 
intermediate, 17alpha-hydroxypregnenolone. Eur J Biochem. 2000;267(11):3243-3247. 
49. 
Barrie SE, Potter GA, Goddard PM, Haynes BP, Dowsett M, Jarman M. Pharmacology 
of novel steroidal inhibitors of cytochrome P450(17) alpha (17 alpha-hydroxylase/C17-
20 lyase). J Steroid Biochem Mol Biol. 1994;50(5-6):267-273. 
50. 
Attard G, Reid AH, A'Hern R, et al. Selective inhibition of CYP17 with abiraterone 
acetate is highly active in the treatment of castration-resistant prostate cancer. J Clin 
Oncol. 2009;27(23):3742-3748. 
51. 
Attard G, Reid AH, Yap TA, et al. Phase I clinical trial of a selective inhibitor of CYP17, 
abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains 
hormone driven. J Clin Oncol. 2008;26(28):4563-4571. 
52. 
Dan ila DC, Morris MJ, de Bono JS, et al. Phase II multicenter study of abiraterone 
ace tate plus prednisone therap y in patients with doce taxel-treated ca stration-
resista nt prost ate ca ncer. J Clin Oncol. 2010;28(9):1496-1501. 
53. 
Reid  AH, Attard G, Danila DC, et al. Significant and su stained antitumor activity in 
post-docetaxel, ca stration-resista nt prost ate ca nce r with the CYP17 inhibitor 
abiraterone ace tate. J Clin Oncol. 2010;28(9):1489-1495. 
54. 
Ryan CJ , Smith MR, Fong L, et al. Phase I clinical trial of the CYP17 inhibitor 
abiraterone ace tate demonstra ting clinical activity in patients with ca stration-
resista nt prost ate ca ncer who rece ived prior ketoconazole therapy. J Clin Oncol. 
2008;28(9):1481-1488. 
55. 
de Bono JS , Logothetis C, Fizazi K. Abiraterone ace tate plus low dose  
pred nisone improves overall su rvival in patients with metastatic ca stra tion-
resista nt pros tate ca nce r (CRPC)  who have progresse d after doce taxel-base d 
chemotherap y: resu lts of COU-AA-301, a ran domized double-blind place bo-
controlled phase  3 study. . Paper presented at: Prese nted at the 2010 European 
Society for Medical Oncology (ES MO) a nnual meeting2010. 
56. 
de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in 
metastatic prostate cancer. N Engl J Med. 2011;364(21):1995-2005. 
57. 
Ryan CJ, Smith MR, de Bono JS, et al. Interim analysis (IA) results of COU-AA-302, a 
randomized, phase III study of abiraterone acetate (AA) in chemotherapy-naive patients 
(pts) with metastatic castration-resistant prostate cancer (mCRPC). ASCO Meeting 
Abstracts. 2012;30(supplement):LBA4518. 
58. 
Morrissey C, True LD, Roudier MP, et al. Differential expression of angiogenesis 
associated genes in prostate cancer bone, liver and lymph node metastases. Clin Exp 
Metastasis. 2008;25(4):377-388. 
59. 
Morrissey  C, Dowell A, Koreckij TD, et al. Inhibition of angiopoietin-2 in LuCaP  
23.1 pros tate cancer tumors decrease s tumor growth and viability. Prost ate. 
2010;70(16):1799-1808. 
60. 
Lind AJ, Wikstrom P, Granfors T, Egevad L, Stattin P, Bergh A. Angiopoietin 2 
expression is related to histological grade, vascular density, metastases, and outcome in 
prostate cancer. Prostate. 2005;62(4):394-399. 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
96 
 
61. 
Satoh N, Yamada Y, Kinugasa Y, Takakura N. Angiopoietin-1 alters tumor growth by 
stabilizing blood vessels or by promoting angiogenesis. Cancer Sci. 2008;99(12):2373-
2379. 
62. 
Mita AC, Takimoto CH, Mita M, et al. Phase 1 study of AMG 386, a se lective 
angiopoietin 1/2-neutralizing peptibody, in combination with chemotherapy in 
adults with advanced solid tumors. Clin Can cer Res. 2010;16(11):3044-3056. 
63. 
Wang GM, Kovalenko B, Huang Y, Moscatelli D. Vascular endothelial growth factor and 
angiopoietin are required for prostate regeneration. Prostate. 2007;67(5):485-499. 
64. 
Mori R, Dorff TB, Xiong S, et al. The rela tionsh ip between proangiogenic gene 
expression  levels in prost ate cance r and their prognostic value for clinical 
outcomes. Prost ate. 2010;70(15):1692-1700. 
65. 
Caine GJ, Ryan P, Lip GY, Blann AD. Significant decrease in angiopoietin-1 and 
angiopoietin-2 after radical prostatectomy in prostate cancer patients. Cancer Lett. 
2007;251(2):296-301. 
66. 
Tomic TT, Gustavsson H, Wang W, Jennbacken K, Welen K, Damber JE. Castration 
resistant prostate cancer is associated with increased blood vessel stabilization and 
elevated levels of VEGF and Ang-2. Prostate. 2011. 
67. 
Sweeney CC, Y. H.; Carducci, M; Liu, G; . CHAARTED: ChemoHormonal Therapy 
Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer. 
ASCO abstract #2. 2014. 
68. 
Meyer NJ, Li M, Fe ng R, et al. ANGP T2 Ge netic Variant is Asso ciated with 
Trau ma-Ass ociated Acute Lung Injury and Altered  Plasma 
Angiopoietin-2 
Isoform Ra tio. Am J Resp ir Crit Care  Med. 2011. 
69. 
Wright JL, Kwon EM, Lin DW, et al. CYP17 polymorphisms and prosta te ca ncer 
outcomes. Prost ate. 2010;70(10):1094-1101. 
70. 
Cohen HT, McGovern FJ. Renal-cell carcinoma. The New England journal of medicine. 
2005;353(23):2477-2490. 
71. 
Gordon MS, Hussey M, Nagle RB, et al. Phase II study of erlotinib in patients with 
locally advanced or metastatic papillary histology renal cell cancer: SWOG S0317. 
Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology. 2009;27(34):5788-5793. 
72. 
Choueiri TK, Vaishampayan U, Rosenberg JE, et al. Phase II and biomarker study of the 
dual MET/VEGFR2 inhibitor foretinib in patients with papillary renal cell carcinoma. 
Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology. 2013;31(2):181-186. 
73. 
Dharmawardana PG, Giubellino A, Bottaro DP. Hereditary papillary renal carcinoma 
type I. Current molecular medicine. 2004;4(8):855-868. 
74. 
Bottaro DP, Rubin JS, Faletto DL, et al. Identification of the hepatocyte growth factor 
receptor as the c-met proto-oncogene product. Science. 1991;251(4995):802-804. 
75. 
Athauda G, Giubellino A, Coleman JA, et al. c-Met ectodomain shedding rate correlates 
with malignant potential. Clinical cancer research : an official journal of the American 
Association for Cancer Research. 2006;12(14 Pt 1):4154-4162. 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
97 
 
76. 
Attard G, Swennenhuis JF, Olmos D, et al. Characterization of ERG, AR and PTEN gene 
status in circulating tumor cells from patients with castration-resistant prostate cancer. 
Cancer Res. 2009;69(7):2912-2918.  


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
98 
 
16 APPENDICES 
16.1 APPENDIX A: PERFORMANCE STATUS CRIT ERIA 
 
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. 
 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
99 
 
16.2 APPENDIX B:  DOSE CALCULAT ION TABLES FOR AFTER DEPLETION OF 240 MG SUPPLY 
 
Table 3: Dose Level: 15 mg/kg  
Subject’s Actual 
Weight 
AMG 386  
Weight 
in 
kilograms (kg) 
AMG 386 dose in 
milligrams (mg) 
Number of Vials to Dispense 
150 mg 
600 mg 
Total number 
of vials to 
dispense 
25 to 34.9 
450 
3 
0 
3 
35 to 44.9 
600 
0 
1 
1 
45 to 54.9 
750 
1 
1 
2 
55 to 64.9 
900 
2 
1 
3 
65 to 74.9 
1050 
3 
1 
4 
75 to 84.9 
1200 
0 
2 
2 
85 to 94.9 
1350 
1 
2 
3 
95 to 104.9 
1500 
2 
2 
4 
105 to 114.9 
1650 
3 
2 
5 
115 to 124.9 
1800 
0 
3 
3 
125 to 134.9 
1950 
1 
3 
4 
135 to 144.9 
2100 
2 
3 
5 
145 to 154.9 
2250 
3 
3 
6 
155 to 164.9 
2400 
0 
4 
4 
165 to 174.9 
2550 
1 
4 
5 
175 to 184.9 
2700 
2 
4 
6 
185 to 194.9 
2850 
3 
4 
7 
195 to 204.9 
3000 
0 
5 
5 
 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
100 
 
 
Table 4: Dose Level 30 mg/kg 
Subject’s Actual 
Weight 
AMG 386  
Weight 
in 
kilograms (kg) 
AMG 386 dose in 
milligrams (mg) 
Number of Vials to Dispense 
150 mg 
600 mg 
Total number 
of vials to 
dispense 
25 to 34.9 
900 
2 
1 
3 
35 to 44.9 
1200 
0 
2 
2 
45 to 54.9 
1500 
2 
2 
4 
55 to 64.9 
1800 
0 
3 
3 
65 to 74.9 
2100 
2 
3 
5 
75 to 84.9 
2400 
0 
4 
4 
85 to 94.9 
2700 
2 
4 
6 
95 to 104.9 
3000 
0 
5 
5 
105 to 114.9 
3300 
2 
5 
7 
115 to 124.9 
3600 
0 
6 
6 
125 to 134.9 
3900 
2 
6 
8 
135 to 144.9 
4200 
0 
7 
7 
145 to 154.9 
4500 
2 
7 
9 
155 to 164.9 
4800 
0 
8 
8 
165 to 174.9 
5100 
2 
8 
10 
175 to 184.9 
5400 
0 
9 
9 
185 to 194.9 
5700 
2 
9 
11 
195 to 204.9 
6000 
0 
10 
10 
 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
101 
 
 
Table 5:  Dose Level 10 mg/kg 
Subject’s Actual 
Weight 
AMG 386  
Weight 
in 
kilograms (kg) 
AMG 386 dose in 
milligrams (mg) 
Number of Vials to Dispense 
150 mg 
600 mg 
Total number 
of vials to 
dispense 
25 to 34.9 
300 
2 
0 
2 
35 to 44.9 
400 
0 
1 
1 
45 to 54.9 
500 
0 
1 
1 
55 to 64.9 
600 
0 
1 
1 
65 to 74.9 
700 
1 
1 
2 
75 to 84.9 
800 
2 
1 
3 
85 to 94.9 
900 
2 
1 
3 
95 to 104.9 
1000 
3 
1 
4 
105 to 114.9 
1100 
0 
2 
2 
115 to 124.9 
1200 
0 
2 
2 
125 to 134.9 
1300 
1 
2 
3 
135 to 144.9 
1400 
2 
2 
4 
145 to 154.9 
1500 
2 
2 
4 
155 to 164.9 
1600 
3 
2 
5 
165 to 174.9 
1700 
0 
3 
3 
175 to 184.9 
1800 
0 
3 
3 
185 to 194.9 
1900 
1 
3 
4 
195 to 204.9 
2000 
2 
3 
5 
 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
102 
 
 
16.3 APPENDIX C: LIST OF DRUGS THAT MAY HAVE POTENTIAL CYP2D6 INTERACTI ONS 
CYP2D6 Substrates 
Amitriptyline 
Amoxapine 
Aripiprazole 
Atomoxetine 
Betaxolol 
Captopril 
Carvedilol 
Chloroquine 
Chlorpromazine 
Clomipramine 
Codeine 
Desipramine 
Dextroamphetamine 
Dextromethorphan 
Dihydrocodeine 
Doxepin 
Doxorubicin 
Duloxetine 
Flecainide 
Fluoxetine 
Fluphenazine 
Fluvoxamine 
Haloperidol  
Hydrocodone 
Imipramine 
Labetalol 
Lidocaine 
Lomustine 
Maprotiline 
Methamphetamine 
Methylphenidate 
Metoprolol 
Mexiletine 
Mirtazapine 
Moclobemide 
Nefazodone 
Nortriptyline 
Oxycodone 
Paroxetine 
Perphenazine 
Pindolol 
Pipotiazine 
Procainamide 
Promethazine 
Propafenone 
Propranolol 
Protriptyline 
Risperidone 
Sertraline 
Tamoxifen 
Tamsulosin 
Thioridazine 
Timolol 
Tolterodine 
Tramadol 
Trimipramine 
Venlafaxine 
Zuclopenthixol 
 
CYP2D6 Inhibitors 
Acebutolol 
Amiodarone 
Amitriptyline 
Amlodipine 
Amphetamine 
Azelastine 
Bepridil 
Betaxolol 
Biperiden 
Bortezomib 
Buprenorphine 
Bupropion 
Celecoxib 
Chloroquine 
Chlorpheniramine 
Chlorpromazine 
Cholecalciferol/Vitamin D3 
Dolasetron 
Doxorubicin 
Duloxetine 
Entacapone 
Escitalopram 
Felodipine 
Fexofenadine 
Flecainide 
Fluoxetine 
Fluphenazine 
Fluvastatin 
Fluvoxamine 
Gefitinib 
Halofantrine 
Haloperidol 
Hydroxyzine 
Imatinib 
Metoclopramide 
Metoprolol 
Miconazole 
Mifepristone 
Moclobemide 
Nefazodone 
Nelfinavir 
Nevirapine 
Nicardipine 
Nifedipine 
Nortriptyline 
Olanzapine 
Omeprazole 
Ondansetron 
Orphenadrine 
Oxprenolol 
Oxybutynin 
Quinine  
Rabeprazole 
Ranitidine 
Risperidone 
Ritonavir 
Ropinirole 
Rosiglitazone 
Saquinavir 
Selegiline 
Sertraline 
Sildenafil 
Simvastatin  
Sulconazole 
Telithromycin 
Terbinafine 
Thioridazine 
Thiothixene 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
103 
 
Cimetidine 
Cinacalcet 
Cisapride 
Citalopram 
Clemastine 
Clomipramine 
Clotrimazole 
Clozapine 
Cocaine 
Codeine 
Delavirdine 
Desipramine 
Dexmedetomidine 
Dextromethorphan 
Diltiazem 
Diphenhydramine 
Disulfiram 
Imipramine 
Indinavir 
Irbesartan 
Isoniazid 
Ketoconazole 
Labetalol 
Lansoprazole 
Lidocaine 
Lomustine 
Loratadine 
Lovastatin 
Mefloquine 
Methadone 
Methimazole 
Methotrimeprazine 
Methoxsalen 
Methylphenidate 
Paroxetine 
Pentamidine 
Pergolide 
Perphenazine 
Pimozide 
Pindolol 
Pioglitazone 
Pravastatin 
Praziquantel 
Primaquine 
Promethazine 
Propafenone 
Propofol 
Propoxyphene 
Propanolol 
Pyrimethamine 
Quinidine 
Ticlopidine 
Timolol 
Tioconazole 
Tranylcypromine 
Trazodone 
Tripelennamine 
Triprolidine 
Valproic acid 
Venlafaxine 
Verapamil 
Vinblastine 
Vinorelbine 
Yohimbine 
Zafirlukast 
Ziprasidone 
 
When drugs classified as ‘substrates’ are co-administered with abiraterone, there is the potential for higher 
concentrations of the ‘substrate’. When abiraterone is co-administered with compounds classified as ‘inhibitors’, 
increased plasma concentrations of abiraterone is the potential outcome. The co-administration of ‘inducers’ 
would potentially lower plasma abiraterone concentrations. 
Note: Adapted from Cytochrome P450 Enzymes: Substrates, Inhibitors, and Inducers. In: Lacy CF, Armstrong LL, 
Goldman MP, Lance LL eds. Drug Information Handbook 15TH ed. Hudson, OH; LexiComp Inc. 2007: 1899-1912.   
There are no known CYP2D6 inducers. Only major substrates are listed.  
Additional information for drug interactions with cytochrome P450 isoenzymes can be found at 
http://medicine.iupui.edu/flockhart/. 
 
Updated on May 1, 2007 
 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
104 
 
16.4 APPENDIX D: NCI IRB PROBLEM FORM  
NCI Protocol #:  
Protocol Title:  
 
 
Report version: (select one) 
____Initial Report  
____Revised Report 
____Follow-up  
Site Principal Investigator: 
 
  
Date of problem:     
Location of problem: (e.g.,  patient’s home, 
doctor’s office ) 
 
 
Who identified the problem? (provide role (not name of person): nurse, investigator, monitor, 
etc…) 
 
Brief Description of Subject (if 
applicable)  
(Do 
NOT 
include 
personal 
identifiers)  
Sex:  ___ Male  ___ Female 
Age:   
 ___ Not applicable (more than subject is involved) 
 
Diagnosis under study:   
Name the problem: (select all that apply)   
[  ] Adverse drug reaction   
[  ] Abnormal lab value   
[  ] Death   
[  ] Cardiac Arrest/ code  
[  ] Anaphylaxis  
[  ] Sepsis/Infection   
[  ] Blood product reaction 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
105 
 
[  ] Unanticipated surgery/procedure   
[  ] Change in status (e.g. increased level of care required)    
[  ] Allergy (non-medication)  
[  ] Fall  
[  ] Injury/Accident (not fall)  
[  ] Specimen collection issue   
[  ] Informed consent issue   
[  ] Ineligible for enrollment   
[  ] Breach of PII  
[  ] Tests/procedures not performed on schedule  
[  ]  Other, brief  1-2 word description: _________________________ 
 
Detailed Description of the problem: (Include any relevant treatment, outcomes or pertinent 
history): 
 
 
*Is this problem unexpected? (see the definition of unexpected in the protocol))  __YES __NO  
Please explain: 
 
 *Is this problem related or possibly related to participation in the research?  __YES __NO  
Please explain: 
 
*Does the problem suggest the research places subjects or others at a greater risk of 
harm than was previously known or recognized?    __YES __NO      Please explain: 
 
 
Is this problem? (select all that apply) 
[  ] An Unanticipated Problem* that is:       [  ] Serious        [  ] Not Serious  
[  ] A Protocol Deviation that is:                [  ] Serious        [  ] Not Serious 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
106 
 
[  ] Non-compliance 
*Note if the 3 criteria starred above are answered, “YES”, then this event is also a UP. 
Is the problem also (select one)  [  ] AE  [  ] Non-AE 
Have similar problems occurred on this protocol at your site? __YES __NO       
If “Yes”, how many? ____      Please describe: 
Describe what steps you have already taken as a result of this problem: 
 
 
In addition to the NCI IRB, this problem is also being reported to: (select all that apply) 
[  ] Local IRB 
[  ] Study Sponsor 
[  ] Manufacturer : ____________________  
[  ] Institutional Biosafety Committee  
[  ] Data Safety Monitoring Board 
[  ] Other: ____________________________________  
[  ] None of the above, not applicable 
INVESTIGATOR’S SIGNATURE:  
 
DATE:   


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                                                                                                                                      107 
 
Adverse Event Information: 
CTCAE Term 
Date of Event 
Location of 
Event 
CTCAE 
Version 
CTCAE 
Grade 
Attribution 
to Research 
Attribution 
to IND Agent Expected 
 
Click here for 
date. 
Location of 
Event 
Version No 
Grade No 
Attribution 
Attribution 
Yes/No 
 
Click here for 
date. 
Location of 
Event 
Version No 
Grade No 
Attribution 
Attribution 
Yes/No 
 
Click here for 
date. 
Location of 
Event 
Version No 
Grade No 
Attribution 
Attribution 
Yes/No 
 
Click here for 
date. 
Location of 
Event 
Version No 
Grade No 
Attribution 
Attribution 
Yes/No 
 
Click here for 
date. 
Location of 
Event 
Version No 
Grade No 
Attribution 
Attribution 
Yes/No 
 
Click here for 
date. 
Location of 
Event 
Version No 
Grade No 
Attribution 
Attribution 
Yes/No 
 
Click here for 
date. 
Location of 
Event 
Version No 
Grade No 
Attribution 
Attribution 
Yes/No 
 
Click here for 
date. 
Location of 
Event 
Version No 
Grade No 
Attribution 
Attribution 
Yes/No 
 
REPORTED BY: 
 
Printed Name 
 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                                                                                                                                      108 
 
Date 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
109 
 
16.5 APPENDIX E:  CTE P 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. 
 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 


Abbreviated Title: AMG386 + abiraterone in mCRPC 
CTEP # 9068 
Version Date: 11/15/2016 
 
Confidential                        
110 
 
IRB approval documents, NCI Drug Accountability Record forms, patient registration 
lists, response assessments scans, x-rays, etc. available for the audit. 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
INSTITUTE: 
National Cancer Institute 
STUDY NUMBER: 
12-C-0079 
PRINCIPAL INVESTIGATOR: 
Ravi Madan, M.D. 
STUDY TITLE:  
A Phase II Multicenter Study of AMG 386 and Abiraterone in Metastatic Castration Resistant 
Prostate Cancer 
 
Continuing Review Approved by the IRB on 07/25/16 
Amendment Approved by the IRB on 01/18/17 (R) 
 
                                    Date Posted to Web: 01/28/17  
Standard 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent (1) 
 
INTRODUCTION 
We invite you to take part in a research study at the National Institutes of Health (NIH). 
First, we want you to know that: 
Taking part in NIH research is entirely voluntary.  
You may choose not to take part, or you may withdraw from the study at any time.  In 
either case, you will not lose any benefits to which you are otherwise entitled.  However, 
to receive care at the NIH, you must be taking part in a study or be under evaluation for 
study participation. 
You may receive no benefit from taking part.  The research may give us knowledge that 
may help people in the future. 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of 
medical or research treatments they would want to receive (such as blood transfusions).  If you 
have such beliefs, please discuss them with your NIH doctors or research team before you agree 
to the study. 
Now we will describe this research study.  Before you decide to take part, please take as much 
time as you need to ask any questions and discuss this study with anyone at NIH, or with family, 
friends or your personal physician or other health professional.   
Why is this study being done?  
Prostate cancer is the most common cancer among American men and the second leading cause 
of cancer related death.  The majority of these deaths occur among men with metastatic disease 
(disease that has spread to distant locations in the body).  Because androgens (male hormones) 
stimulate prostate cancer cells to grow, and because lowering androgen levels often leads to 
slower growth in prostate cancer, androgen-deprivation therapy (reducing the level of androgens 
in the body) is the mainstay of treatment for metastatic prostate cancer.  However, nearly all men 
with metastatic prostate cancer eventually become resistant to androgen deprivation and 
experience progression of their disease.  These types of cancers are referred to as castration-


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
12-C-0079 
CONTINUATION: page 2 of 16 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent (1) 
 
resistant. Once castration-resistant prostate cancer develops, most patients do not live more than 
18 – 24 months. 
It has been shown that interfering with the formation of blood vessels that feed the tumor can 
reduce tumor growth in prostate cancer cells.  AMG 386 is an investigational or experimental 
anticancer agent that targets the blood vessels that feed the tumor.  It has not been approved by 
the Food and Drug Administration for use in prostate cancer.  AMG 386 has to date been used in 
a total of 1190 subjects in clinical trials of the agent for a variety of tumor types.  None however 
was focused on prostate cancer.  Side effects occurring during these trials are listed in the risks 
and side effects section below.  The purpose of this study is to first establish a safe dose of AMG 
386 to be used in the study and then to determine whether adding this dose of AMG 386 to an 
androgen deprivation regimen of abiraterone and prednisone in men with castration-resistant 
prostate cancer improves the amount of time it takes for the disease to progress.   
Why are you being asked to take part in this study? 
You are being asked to take part in this study because you have been diagnosed with metastatic 
(distantly spread) prostate cancer that does not respond to therapy designed to lower the 
androgen levels in your body. 
How many people will take part in this study?  
88 subjects will be enrolled in this study at the NIH Clinical Center and at other centers in the 
United States.  Of these, a maximum of 12 subjects will be enrolled to the first stage of the study 
for determining the appropriate dose of AMG 386. 
Description of Research Study 
What will happen if you take part in this research study?   
Before you begin the study: 
You will need to have the following exams, tests or procedures to find out if you can be in the 
study.  These exams, tests or procedures are part of regular cancer care and may be done even if 
you do not join the study.  If you have had some of them recently, they may not need to be 
repeated.  This will be up to the study team. 
These tests include: 
• A complete medical history will be taken from you, a history of your cancer, and 
prior cancer treatments you have taken. 
• You will be asked to give information about all drugs (including over the counter 
drugs, vitamins and herbal supplements) that you are currently taking. 
• Your doctor will do a complete physical examination; assess your ability to do 
physical activities, measure your blood pressure, heart rate, and respiration rate. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
12-C-0079 
CONTINUATION: page 3 of 16 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent (1) 
 
• You will be asked to have a 12-lead electrocardiogram (ECG) and a chest x-ray  
• A sample of your blood (approximately 2 tablespoon) will be taken for laboratory 
testing including PSA measurements. 
• A urine sample for measurement of protein in the urine. 
• An evaluation of your cancer will be done. This will include a CT scan and bone 
scan. 
 
During the study: 
If the exams, tests and procedures show that you can be in the study, and you choose to take part, 
then you will need the following tests and procedures.  They are part of regular cancer care.   
• 
PSA measurements  
• 
Blood tests including blood counts and chemistries 
 
You will need these tests and procedures that are part of regular cancer care.   They are being 
done more often because you are in this study.  If these tests were done at screening, they will 
not be repeated for day 1 of cycle 1. 
• 
Bone scan and CT scan of the chest, abdomen, and pelvis after every 3 cycles 
• Vital signs - every week in lead in and group 1 patients, day 1 (+/- 5 days) of each 
cycle for group 2 patients 
• History and physical examination - day 1 (+/- 5 days) of each cycle 
• Blood tests to evaluate toxicities- every 4 weeks 
You will need these tests and procedures that are either being tested in this study or being done 
to see how the study is affecting your body. (Blood may be collected within +/- 5 days of what is 
indicated below) 
• 10 mL (~ 2 teaspoons) of blood collected once after you have enrolled but before 
you have received any study drug  
• 5 mL (~ 1 teaspoon) blood collected before you receive the study drug on the 
following days: day 1 of cycle 1, day 15 of cycle 1, day 1 of cycle 2 and day 1 of 
cycle 3 
• 10 mL (~ 2 teaspoons) of blood at the following times:  days 1 and 15 of cycle 1 
before you have received the study drug 
• 14 mL (~2.8 teaspoons) of blood at the following times: days 1 and 15 of cycle 1 
before you have received the study drug 
• 6 mL (~ 1.2 teaspoons) of blood collected on the following times: cycle 2 day 1 
and the next 3 visits 
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
12-C-0079 
CONTINUATION: page 4 of 16 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent (1) 
 
This study will be conducted on an outpatient basis in two stages.   
In stage 1, or the lead-in phase, a maximum of 12 subjects (up to 6 at each dose) will be assigned 
to take either a 15 mg/kg dose or, if there are no serious side-effects at 15 mg/kg, a 30 mg/kg 
dose of AMG 386.  Subjects will receive the assigned dose through an IV catheter (a plastic tube 
in your vein) once per week for a total of 4 doses during a 28-day cycle.  Subjects will also take 
1000 mg of abiraterone once a day by mouth and depending on your preference, either 5 mg 
twice per day or 10 mg once per day of prednisone by mouth on each day of the cycle.  If 2 or 
more subjects experiences serious side-effects at the 15 mg/kg dose the study will end.  If no 
more than 1 person experiences serious side-effects, another group of up to 6 subjects will be 
enrolled to take a dose of 30 mg/kg of AMG 386.  If 2 or more subjects experience serious side-
effects, the dose for stage 2 of the study will be established at 15 mg/kg.  If no more than 1 
person experiences serious side-effects at the 30 mg/kg dose, the dose for stage 2 of the study 
will be established at 30 mg/kg.  Unless you experience serious side-effects or your disease 
progresses, there is no limit to the number of cycles you may remain on the study regimen.  
Therapy may be stopped, however, for any of the reasons listed in the stopping therapy section 
below. 
If you are enrolled for stage 2 of the study, you will be "randomized" into one of the study 
groups described below.  Randomization means that you are put into a group by chance.  A 
computer program will place you in one of the study groups.  Neither you nor your doctor can 
choose the group you will be in.  You will have an equal chance of being placed in any group. 
 
If you are in group 1 (often called "Arm A"), you will be assigned to take a 1000 mg of 
abiraterone once a day by mouth and depending on your preference either 5 mg twice per 
day or 10 mg once per day of prednisone by mouth on each day of the 4 week cycle. You 
will be evaluated for serious side-effects and your response to therapy on the schedule 
described above. Unless you experience serious side-effects or your disease progresses, 
there is no limit to the number of cycles you may remain on the study regimen.  Therapy 
will be stopped, however, for any of the reasons listed in the stopping therapy section 
below. 
 
If you are in group 2 (often called "Arm B"), you will be assigned to take a weekly dose 
of AMG 386 that was established in stage 1 by IV along with 1000 mg of abiraterone 
once a day by mouth and depending on your preference, either 5 mg twice per day or 10 
mg once per day of prednisone by mouth on each day of the 4 week cycle. The AMG 386 
dose for stage 2 of the study was established at 30 mg/kg. 
You will be evaluated for serious side-effects and your response to therapy on the 
schedule described above. Unless you experience serious side-effects or your disease 
progresses, there is no limit to the number of cycles you may remain on the study 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
12-C-0079 
CONTINUATION: page 5 of 16 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent (1) 
 
regimen.  Therapy will be stopped, however, for any of the reasons listed in the stopping 
therapy section below.        
You should take abiraterone in the morning.  However, if that dose is missed, you should 
make up the dose during the remainder of the day.  Do not take two doses of abiraterone 
on the same day.  Do not have any food for at least 2 hours before and 1 hour after taking 
the abiraterone.   
You should take prednisone at around the same time every day with the doses 
approximately 12 hours apart, give or take two hours if you are taking prednisone twice 
per day or approximately 24 hours apart give or take two hours if you are taking 
prednisone once per day.  Prednisone should, if possible, be taken with food or milk to 
reduce stomach irritation.  If you miss a dose of prednisone, that is, if more than 14 hours 
(or 36 hours in case of once a day dosing) have passed since the previous dose, you should 
not make up that dose.  Instead, you should resume taking the drug at the next scheduled 
dose. 
We ask that you avoid eating or drinking grapefruit and grapefruit products including 
grapefruit juice while enrolled on study as this may adversely interact with one of the study 
drugs (abiraterone). 
 
When you are finished receiving the drugs (treatment): 
Your participation in this study will continue until either you or your study team decides that this 
medication is not beneficial to you. Your participation is voluntary; so you may stop receiving 
the study drugs at any time, but we ask that you speak to your study team before stopping. Your 
study team will be monitoring you and your cancer while you are receiving the study treatment. 
If your prostate cancer is clearly worsening, then your study team will stop treatment with the 
study drugs. At the end of the study, no additional testing will be required outside of the routine 
blood work for regular cancer care. If you stop the drug because of side effects, the study team 
may request that you continue follow-up and/or testing for this until resolution. In addition, we 
will contact you and or your primary care physician by telephone once per year to determine 
your survival status. 
 
Study Chart 
A cycle in this study = 28 days.  The cycle will be repeated until any of the stopping therapy 
criteria are met.  Each cycle is numbered in order.  The chart below shows what will happen to 
you during Cycle 1 and future treatment cycles as explained previously.  The left-hand column 
shows the day in the cycle (+/- 5 days) and the right-hand column tells you what to do on that 
day. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
12-C-0079 
CONTINUATION: page 6 of 16 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent (1) 
 
 
 
Cycle 1 
Within 4 weeks 
before study 
enrollment 
• CT scan and bone scan 
 
Within 16 days 
before enrollment 
• Routine blood tests and urinalysis 
Within 1 week 
before enrollment 
• PSA, medical history and physical exam 
At enrollment (stage 
2 only) 
• Get randomized to take AMG 386 along with abiraterone and prednisone 
or to take abiraterone and prednisone alone 
After enrollment but 
before starting study 
regimen 
• ~1 - 2 teaspoons of blood drawn for research tests 
Day 1 
Prior to taking AMG 386 
• ~7 teaspoons of blood drawn for research tests 
• History and physical exam 
• Vital signs   
• Urinalysis 
• Routine blood tests 
Study drugs 
• Begin receiving AMG 386 by IV once per week (lead in and group 1 
only) 
• Begin taking abiraterone once a day 
• Begin taking prednisone twice per day 
Keep taking the medications until you are told to stop by your health care 
team. 
Day 8 
• Vital signs (lead in and group 1 patients only) 
Day 15 
• Get vital signs taken (lead in and group 1 patients only) 
• ~6 teaspoons blood drawn for research tests  
Day 22 
• Vital signs (lead in and group 1 patients only) 
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
12-C-0079 
CONTINUATION: page 7 of 16 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent (1) 
 
 
 
Future cycles 
Days 1-28 
Study drugs 
• Continue receiving AMG 386 by IV once per week. (lead in and group 1 
patients only) 
• Keep taking abiraterone once a day 
• Keep taking prednisone twice per day 
Routine assessments 
• Vital signs– days 1 for all patients and also days 8, 15 & 22 of each cycle 
for patients lead in and group 1 patients 
• History and physical exam (including weight) – day 1 of each cycle 
• Urinalysis and routine blood tests – day 1 of each cycle 
• Bone scan and CT-scan – day 1 after  every 3 cycles 
Research blood tests 
• ~ 1 teaspoon of blood drawn for research tests on day 1 of cycle 2 and day 
1 of cycle 3 
• ~1.2 teaspoon of blood drawn for research tests on cycle 2 day 1 and the 
next 3 visits 
 
Birth Control 
Because the effects of AMG 386 on the developing human fetus are unknown, men participating 
in this study must agree to practice an effective form of birth control before starting study 
treatment, during study treatment, and for 6 months after you finish study treatment.  If you think 
that your partner is pregnant, you should tell your study doctor or nurse at once.   
Effective forms of birth control include:  
• Abstinence  
• intrauterine device (IUD) 
• hormonal [birth control pills, injections, or implants] 
• tubal ligation 
• vasectomy 
You should recognize that no method of birth control besides abstinence provides 100% 
protection from pregnancy. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
12-C-0079 
CONTINUATION: page 8 of 16 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent (1) 
 
Risks or Discomforts of Participation 
What side effects or risks can I expect from being in this study?  
Risks and side effects in this study are mainly due to the side effects of the study agents: 
AMG 386  
If you choose to take part in this study, there is a risk that: 
• You may lose time at work or home and spend more time in the hospital or doctor’s 
office than usual 
• You may be asked sensitive or private questions which you normally do not discuss 
The AMG 386 used in this study may affect how different parts of your body work such as your 
liver, kidneys, heart, and blood. The study doctor will be testing your blood and will let you 
know if changes occur that may affect your health. 
 
There is also a risk that you could have side effects from the study drug(s)/study approach. 
 
Here are important points about side effects: 
• The study doctors do not know who will or will not have side effects. 
• Some side effects may go away soon, some may last a long time, or some may never go 
away. 
• Some side effects may interfere with your ability to have children. 
• Some side effects may be serious and may even result in death. 
 
Here are important points about how you and the study doctor can make side effects less of a 
problem: 
• Tell the study doctor if you notice or feel anything different so they can see if you are 
having a side effect. 
• The study doctor may be able to treat some side effects. 
• The study doctor may adjust the study drugs to try to reduce side effects. 
 
The tables below show the most common and the most serious side effects that researchers know 
about. There might be other side effects that researchers do not yet know about. If important new 
side effects are found, the study doctor will discuss these with you.” 
 
 
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
12-C-0079 
CONTINUATION: page 9 of 16 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent (1) 
 
Table of Possible Side Effects for AMG 386 
 
COMMON, SOME MAY BE SERIOUS                                           
In 100 people receiving AMG 386, more than 20 and up to 100 may have: 
• Pain 
• Diarrhea, nausea, vomiting 
• Swelling of the body 
• Tiredness 
• Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of 
breath, swelling of the face or throat 
• Loss of appetite 
• High blood pressure which may cause headaches, dizziness 
 
OCCASIONAL, SOME MAY BE SERIOUS   
In 100 people receiving AMG 386, from 4 to 20 may have: 
• Heart attack  
• Blurred vision 
• Blood clot which may cause blindness, swelling, pain, or shortness of breath 
• Fluid in the body 
• Damage to the lungs which may cause shortness of breath 
• Bleeding 
 
Abiraterone  
 (Table Version Date: May 28, 2013) 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Abiraterone Acetate, more than 20 and up to 100 may have: 
• Swelling of the body 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Abiraterone Acetate, from 4 to 20 may have: 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
12-C-0079 
CONTINUATION: page 10 of 16 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent (1) 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Abiraterone Acetate, from 4 to 20 may have: 
• Heartburn, diarrhea 
• High blood pressure which may cause headaches, dizziness, blurred vision 
• Flushing 
 
RARE, AND SERIOUS 
In 100 people receiving Abiraterone Acetate, 3 or fewer may have: 
• None 
Prednisone 
(Table Version Date: June 24, 2013) 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Prednisone, more than 20 and up to 100 may have: 
• In children and adolescents: decreased height 
• Loss of bone tissue 
• Mood swings 
• Skin changes, acne 
• Swelling of the body, tiredness, bruising 
• High blood pressure which may cause headaches, dizziness, blurred vision 
• Pain in belly 
• Increased appetite and weight gain 
• Weight gain in the belly, face, back and shoulders 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Prednisone, from 4 to 20 may have: 
• Cloudiness of the eye, visual disturbances 
• Glaucoma 
• Infection 
• Non-healing wound 
• Diabetes 
• Damage to the bone which may cause joint pain and loss of motion 
• Kidney stones 
• Heartburn 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
12-C-0079 
CONTINUATION: page 11 of 16 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent (1) 
 
 
RARE, AND SERIOUS 
In 100 people receiving Prednisone, 3 or fewer may have: 
• Bleeding from sores in the stomach 
• Broken bones 
 
Potential Benefits of Participation 
Are there benefits to taking part in this study?  
The aim of this study is to see if this experimental treatment will prolong the time that it takes for 
your disease to progress. We do not know if you will receive personal, medical benefit from 
taking part in this study.  These potential benefits could include shrinking of your tumor or 
lessening of your symptoms, such as pain, that are caused by the cancer.  Because there is not 
much information about the drug’s effect on your cancer, we do not know if you will benefit 
from taking part in this study, although the knowledge gained from this study may help others in 
the future who have cancer.   
Alternative Approaches or Treatments 
What other choices do I have if I do not take part in this study?  
Instead of being in this study, you have these options: 
• Getting treatment or care for your cancer without being in a study 
• Taking part in another study 
• Getting comfort care, also called palliative care.  This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer.  It does not treat 
the cancer directly.  Instead, it tries to improve how you feel.  Comfort care tries to keep 
you as active and comfortable as possible. 
Please talk to your doctor about these and other options. 
 
Research Subject’s Rights 
What are the costs of taking part in this study?  
If you choose to take part in the study, the following will apply, in keeping with the NIH policy: 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
12-C-0079 
CONTINUATION: page 12 of 16 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent (1) 
 
• 
The study agents, AMG 386, abiraterone and prednisone will be provided 
by the NIH Clinical Center pharmacy.  In some cases, the NIH Clinical 
Center may not supply abiraterone or prednisone but it can also be 
obtained from a local site pharmacy.  You or your insurance company 
may have to pay for medications that are not provided at the NIH 
Clinical Center.  You will receive study treatment at no charge to you. 
This may include surgery, medicines, laboratory testing, x-rays or scans 
done at the Clinical Center, National Institutes of Health (NIH), or 
arranged for you by the research team to be done outside the Clinical 
Center, NIH if the study related treatment is not available at the NIH.  
• 
There are limited funds available to cover the cost of some tests and 
procedures performed outside the Clinical Center, NIH.  You may have 
to pay for these costs if they are not covered by your insurance company. 
• 
Medicines that are not part of the study treatment will not be provided or 
paid for by the Clinical Center, NIH. 
• 
Once you have completed taking part in the study, medical care will no 
longer be provided by the Clinical Center, NIH. 
Stopping Therapy  
Your doctor may decide to stop your therapy for the following reasons: 
• if he/she believes that it is in your best interest 
• if your disease progresses during treatment 
• if you have side effects from the treatment that your doctor thinks are too severe 
• if new information shows that another treatment would be better for you 
 
In this case, you will be informed of the reason therapy is being stopped. 
You can stop taking part in the study at any time. However, if you decide to stop taking part in 
the study, we would like you to talk to the study doctor and your regular doctor first. 
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to Amgen or designated 
representatives. If you withdraw your consent and leave the trial, any samples of yours that have 
been obtained for the study and stored at the NCI can be destroyed upon request. However, any 
samples and data generated from the samples that have already been distributed to other 
researchers or placed in the research databases cannot be recalled and destroyed. 
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
12-C-0079 
CONTINUATION: page 13 of 16 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent (1) 
 
Will my medical information be kept private?  
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Your personal information may be 
given out if required by law.  If information from this study is published or presented at scientific 
meetings, your name and other personal information will not be used.  
Organizations that may look at and/or copy your medical records for research, quality assurance, 
and data analysis include: 
• Amgen or any subsequent pharmaceutical collaborator 
• National Cancer Institute Institutional Review Board 
• The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), involved in keeping research safe for people 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of study results.  You can search this Web site at any time. 
 
Conflict of Interest 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  This process is detailed in a Protocol Review Guide.  You may ask your research 
team for a copy of the Protocol Review Guide or for more information.  Members of the research 
team who do not work for NIH are expected to follow these guidelines but they do not need to 
report their personal finances to the NIH. 
 
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study.  This is allowed under federal rules and is not a 
conflict of interest.  
 
The National Institutes of Health and the research team for this study are using a drug, AMG 
386, developed by Amgen through a joint study with your researchers and the company.  The 
company also provides financial support for this study. 
 
Use of Specimens and Data for Future Research 
To advance science, it is helpful for researchers to share information they get from studying 
human samples.  They do this by putting it into one or more scientific databases, where it is 
stored along with information from other studies. A researcher who wants to study the 
information must apply to the database and be approved.  Researchers use specimens and data 
stored in scientific databases to advance science and learn about health and disease.  
  


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
12-C-0079 
CONTINUATION: page 14 of 16 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent (1) 
 
We plan to keep some of your specimens and data that we collect and use them for future 
research and share them with other researchers. We will not contact you to ask about each of 
these future uses.  These specimens and data will be stripped of identifiers such as name, address 
or account number, so that they may be used for future research on any topic and shared broadly 
for research purposes. Your specimens and data will be used for research purposes only and will 
not benefit you.  It is also possible that the stored specimens and data may never be used.  
Results of research done on your specimens and data will not be available to you or your doctor.  
It might help people who have cancer and other diseases in the future.   
 
If you do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data.  Then any 
specimens that have not already been used or shared will be destroyed and your data will not be 
used for future research. However, it may not be possible to withdraw or delete materials or data 
once they have been shared with other researchers. 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER: 
12-C-0079 
CONTINUATION: page 15 of 16 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY  
(Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
OTHER PERTINENT INFORMATION 
1. 
Confidentiality.  When results of an NIH research study are reported in medical journals 
or at scientific meetings, the people who take part are not named and identified.  In most cases, 
the NIH will not release any information about your research involvement without your written 
permission.  However, if you sign a release of information form, for example, for an insurance 
company, the NIH will give the insurance company information from your medical record.  This 
information might affect (either favorably or unfavorably) the willingness of the insurance 
company to sell you insurance. 
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you 
should know that the Act allows release of some information from your medical record without 
your permission, for example, if it is required by the Food and Drug Administration (FDA), 
members of Congress, law enforcement officials, or authorized hospital accreditation 
organizations. 
2. 
Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-
term medical care for any injury resulting from your participation in research here.  In general, 
no long-term medical care or financial compensation for research-related injuries will be 
provided by the National Institutes of Health, the Clinical Center, or the Federal Government.  
However, you have the right to pursue legal remedy if you believe that your injury justifies such 
action. 
3. 
Payments.  The amount of payment to research volunteers is guided by the National 
Institutes of Health policies.  In general, patients are not paid for taking part in research studies at 
the National Institutes of Health.  Reimbursement of travel and subsistence will be offered 
consistent with NIH guidelines. 
4. 
Problems or Questions.  If you have any problems or questions about this study, or 
about your rights as a research participant, or about any research-related injury, contact the 
Principal Investigator, Ravi A. Madan, M.D., Building 10, Room 13N240B, Telephone:  301-
480-7168. You may also call the Clinical Center Patient Representative at (301) 496-2626. If you 
have any questions about the use of your specimens or data for future research studies, you may 
also contact the Office of the Clinical Director, Telephone:  240-760-6070. 
5. 
Consent Document.  Please keep a copy of this document in case you want to read it 
again. 
 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER: 
12-C-0079 
CONTINUATION: page 16 of 16 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY  
(Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
COMPLETE APPROPRIATE ITEM(S) BELOW: 
A. Adult Patient’s Consent 
B. Parent’s Permission for Minor Patient. 
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions.  I hereby consent to 
take part in this study. 
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions.  I hereby give 
permission for my child to take part in this 
study.   
(Attach NIH 2514-2, Minor’s Assent, if 
applicable.) 
 
  
  
 
 
 
Signature of Adult Patient/ 
Legal Representative 
Date 
Signature of Parent(s)/ Guardian Date 
 
 
Print Name 
 
 
Print Name 
C. Child’s Verbal Assent (If Applicable) 
The information in the above consent was described to my child and my child agrees to 
participate in the study. 
 
  
  
 
Signature of Parent(s)/Guardian 
Date 
Print Name 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM JULY 25, 2016 THROUGH JULY 24, 2017.  
 
 
 
 
 
 
 
 
Signature of Investigator 
Date 
Signature of Witness 
Date 
 
 
Print Name 
 
 
Print Name