Clinical trial NCT01990209
Conditions: Metastatic Breast Cancer
Keywords: triple-negative breast cancer orteronel TAK-700 metastatic breast cancer
Sponsor: SCRI Development Innovations, LLC
Start date: 2014-03-01; Completion date: 2021-05-01
Enrollment: 71 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The androgen receptor (AR) is expressed in 70-90 percent of primary breast tumors and in 75 percent of breast metastases. There is evidence to suggest that Androgen Receptor (AR) may be a target in patients with advanced breast cancer. Breast cancer patients whose tumors do not express the ER, PR or HER2 (triple negative) have very few options for treatment. Orteronel is being developed as an endocrine therapy for relevant hormone-sensitive cancers such as prostrate cancer and breast cancer. Triple-negative metastatic breast cancer patients with AR expression could potentially benefit from anti-androgen therapy like orteronel.

Detailed description:
This open-label multicenter study will be conducted in 2 stages.

* Lead-in Phase: The first 6 patients treated will be evaluated to confirm the safety and feasibility of this regimen. After all 6 patients complete at least 4 weeks of treatment, and if no prohibitive toxicities are identified, continuous study treatment will begin.
* Continuous Study Treatment: Patients will continue to be enrolled into both cohorts based on their tumor specificities with an anticipated total of 31 patients in Cohort 1 (ER-/PR-/HER2-/AR+) and an anticipated total of 55 patients in Cohort 2 (ER+ and/or PR+/AR+).

Patients will be evaluated every eight weeks for response to treatment. All patients who respond to treatment (complete response \[CR\] or partial response \[PR\]) or have stable disease (SD) will continue to receive orteronel until they develop progressive disease (PD) or unacceptable toxicity.

Arms: arm 1: The planned dose of orteronel is 300mg orally (PO) twice daily (BID), for a total daily dose of 600mg.
Interventions: intervention 1: Orteronel
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 
CONFIDENTIAL 
This document is confidential and is the property of the Sarah Cannon Research Institute (SCRI) Development 
Innovations, LLC.  No part of this document may be transmitted, reproduced, published, or used by other persons 
without prior written authorization from SCRI Development Innovation, LLC. 
 
 
 
 
 
BRE 203 
 
A Phase II Study with Orteronel as Monotherapy in Patients with Metastatic 
Breast Cancer (MBC) that Expresses the Androgen Receptor (AR) 
SCRI DEVELOPMENT 
INNOVATIONS STUDY NUMBER: 
BRE 203 
 
STUDY DRUG: 
 
 
Orteronel 
SPONSOR: 
SCRI Development Innovations, LLC   
(SCRI Innovations) 
3322 West End Avenue, Suite 900 
Nashville, TN  37203 
1-877-MY-1-SCRI 
 
STUDY CHAIR 
Howard A Burris, III, MD 
Sarah Cannon Research Institute   
3322 West End Avenue, Suite 900 
Nashville, TN  37203 
1-877-MY-1-SCRI 
asksarah@scresearch.net 
 
MEDICAL MONITOR: 
John D Hainsworth, MD 
Sarah Cannon Research Institute (SCRI) 
3322 West End Avenue, Suite 900 
Nashville, TN  37203 
1-877-MY-1-SCRI 
asksarah@scresearch.net 
 
DATE FINAL: 
01 October 2013  
Version 2.0 
AMENDMENT NUMBER: 
1 
AMENDMENT DATE: 
30 October 2013 
 
 
 
 
 


 
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STUDY DRUG: Orteronel 
SCRI INNOVATIONS STUDY NUMBER:  BRE 203 
DATE OF PROTOCOL:  Version 3.0 30 October 2013 
Page 2 of 80 
 
BRE 203 Clinical Study Protocol Statement of Compliance 
 
 
This clinical study shall be conducted in compliance with the protocol, as referenced herein, 
and all applicable local, national, and international regulatory requirements to include, but 
not be limited to: 
 
• 
International Conference on Harmonization (ICH) Guidelines on Good Clinical 
Practice (GCP) 
• 
Ethical principles that have their origins in the Declaration of Helsinki  
• 
Food and Drug Administration (FDA) Code of Federal Regulation (CFR): 
o 
Title 21CFR Part 50 & 45 CFR Part 46, Protection of Human Subjects 
o 
Title 21CFR Part 54, Financial Disclosure by Clinical Investigators 
o 
Title 21CFR Part 56, Institutional Review Boards 
o 
Title 21CFR Part 312, Investigational New Drug Application 
o 
Title 45 CFR Parts 160, 162, and 164, Health Insurance Portability and 
Accountability Act 
 
As the Study Chair, I understand that my signature on the protocol constitutes my 
agreement and understanding of PI responsibilities to conduct the research trial in 
accordance to the protocol and applicable regulations.  Furthermore, it constitutes my 
understanding and agreement that any changes initiated by myself, without prior 
agreement in writing from the Sponsor, shall be defined as a deviation from the protocol, 
and shall be formally documented as such. 


 
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Clinical Study Protocol Approval Page 
A Phase II Study with Orteronel as Monotherapy in Patients with Metastatic Breast 
Cancer (MBC) that Expresses the Androgen Receptor (AR) 
SCRI INNOVATIONS STUDY NUMBER: 
BRE 203 
STUDY DRUG: 
Orteronel 
DATE FINAL: 
01 October 2013 
AMENDMENT NUMBER: 
1 
AMENDMENT DATE:        30 October 2013 
 
 
__________________________         _________________________   
______________ 
Study Chair 
 
Study Chair Signature 
 
Date 
 
 
__________________________ 
__________________________         ______________  
SCRI Development Innovations, LLC 
Representative 
 
SCRI Development Innovations, LLC 
Representative Signature 
  
Date 
Howard A. Burris, III, MD,  
Sheetal Khedkar 


 
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STUDY DRUG: Orteronel 
SCRI INNOVATIONS STUDY NUMBER:  BRE 203 
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Page 4 of 80 
 
Clinical Study Principal Investigator Signature Form 
A Phase II Study with Orteronel as Monotherapy in Patients with Metastatic Breast 
Cancer (MBC) that Expresses the Androgen Receptor (AR) 
 
SCRI INNOVATIONS STUDY NUMBER: 
BRE 203 
DATE FINAL: 
01 October 2013 
AMENDMENT NUMBER: 
1 
AMENDMENT DATE:        30 October 2013 
 
By signing this protocol acceptance page, I confirm I have read, understand, and agree to conduct the 
study in accordance with the current protocol. 
 
 
 
__________________________ _            _______________________________     _______  
Principal Investigator Name 
(Please Print) 
 
Principal Investigator Signature 
 
Date 
 
Please retain a copy of this page for your study files and return the original signed and dated 
form to: 
 
SCRI Development Innovations, LLC 
3322 West End Avenue, Suite 900 
Attn:  BRE 203 Study Team  
Nashville, TN 37203 


 
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BRE 203 Summary of Change 
 
AMENDMENT NUMBER: 
1 
AMENDMENT DATE:        30 October 2013 
 
Global Changes 
Patients who experience Grade 4 non-hematologic toxicity will permanently discontinue study 
drug. 
Section 3.1 Inclusion Criteria 
4) 
In addition to having AR+ tumors, patients must fit into 1 of the 2 following categories: 
• 
Triple negative (ER-/PR-/HER2-) (Note:  This group of patients must have received at 
least 1 and up to 3 prior chemotherapy regimens in the advanced setting.) 
• 
ER+ and/or PR+ (Note:  This group of patients must have received at least 1 and up to 3 
prior hormonal therapies and at least one prior chemotherapy treatment in the advanced 
setting.  HER2+ patients in this group must have received a minimum of 2 lines of 
HER2-directed therapy in the advanced setting at least 1 trastuzumab-containing 
regimen for metastatic disease.) This group of patients may be pre-menopausal with 
ovarian suppression or post-menopausal.  LHRH agonists maybe used to render ovarian 
suppression with post-menopausal ranges of estradiol or FSH per institutional guidelines. 
Section 3.2 Exclusion Criteria 
19) 
Use of a prohibited concomitant medication (see Section 5.3.2 and Appendix D) that 
cannot be safely discontinued or substituted. 
Section 5.3.2 Prohibited Concomitant Medications 
• Concomitant treatment with any medication that may cause QT prolongation or Torsades 
de Pointes (see Appendix D).  If a patient, after study enrollment, requires use of a 
medication that may cause QT prolongation and/or Torsades de Pointes that cannot be 
safely substituted, the patient must be removed from the study. 


 
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BRE 203 CLINICAL PROTOCOL SYNOPSIS 
Title of Study: 
A Phase II Study with Orteronel as Monotherapy in Patients with Metastatic Breast Cancer 
(MBC) that Expresses the Androgen Receptor (AR) 
SCRI Innovations 
Protocol Number: 
BRE 203 
Sponsor: 
SCRI Development Innovations, LLC 
Study Duration: 
The total duration of the study is planned to be 48 months 
(enrollment and active treatment). 
Phase of Study:  II 
Study Centers: 
This is a multicenter study to be conducted in the United States at approximately 15 sites. 
Patient Population 
This study will enroll patients with MBC who have progressed on prior hormonal/ 
chemotherapy regimens and whose cancer expresses AR.  Patients will be enrolled onto one 
of the 2 following cohorts based on their tumor specificity: 
• 
Cohort 1:  Patients with estrogen receptor negative (ER-)/progesterone receptor 
negative (PR-)/ human epidermal growth factor receptor 2 negative (HER2-)/AR 
positive (+) MBC with 1 to 3 previous treatments for metastatic disease 
• 
Cohort 2:  Postmenopausal women with ER+ and/or PR+/AR+ refractory MBC who 
have progressed after at least one, and up to 3, previous hormonal treatments for 
metastatic disease. 
Objectives: 
Primary Objectives 
The primary objectives of this study are to evaluate: 
• 
Response rate (RR) and disease control rate (DCR) following treatment with 
orteronel in patients with refractory metastatic triple-negative breast cancer 
expressing AR (ER-/PR-/HER2-/AR+) 
• 
Response rate and disease control rate (DCR) following treatment with orteronel in 
patients with refractory ER+ and/or PR+/AR+ breast cancer. 
Secondary Objectives 
The secondary objectives of this study are to evaluate: 
• 
Safety and tolerability of the regimen 
• 
Measurement of changes in serum estradiol levels, total and free testosterone levels, 
and sex hormone binding globulin (SHBG) during treatment with orteronel 
• 
Measurement of changes in adrenocorticotropic hormone (ACTH), 
dehydroepiandrosterone sulfate (DHEA-S), and cortisol levels during treatment with 
orteronel 
• 
Progression-free survival (PFS) 
• 
Overall survival (OS). 
Exploratory Objective 
As an exploratory objective of this trial: 
• 
Archived tumor tissue will be assayed for the following biomarkers:  loss of 
phosphatase and tensin homolog (PTEN) and phosphatidylinositol 3-kinase 
(PIK3CA) mutation. 
Number of 
Patients: 
Up to 86 patients are planned to be enrolled in this study (6 for the lead-in phase and 80 for 
continuous study treatment). 
Study Design: 
This is an open-label multicenter study to be conducted in 2 stages.  All patients will receive 
orteronel orally (PO) at a dose of 300 mg twice daily (BID). 
• Lead-in Phase:  The first 6 patients treated will be evaluated to confirm the safety and 
feasibility of this regimen.  After all 6 patients complete at least 4 weeks of 
treatment, and if no prohibitive toxicities are identified, continuous study treatment 
will begin. 


 
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BRE 203 CLINICAL PROTOCOL SYNOPSIS 
Study Design 
(continued): 
• 
Continuous Study Treatment:  Patients will continue to be enrolled into both cohorts 
based on their tumor specificities with a total of 31 patients in Cohort 1 (ER-/PR-
/HER2-/AR+) and 55 patients in Cohort 2 (ER+ and/or PR+/AR+). 
Patients will be evaluated every eight weeks for response to treatment. 
All patients who respond to treatment (complete response [CR] or partial response [PR]) or 
have stable disease (SD) will continue to receive orteronel until they develop progressive 
disease (PD) or unacceptable toxicity. 
Study Drug(s), 
Dose, and Mode 
of 
Administration: 
Orteronel will be supplied to SCRI Innovations by Millennium Pharmaceuticals, Inc. 
The planned oral dose of orteronel is 300 mg BID.  In the event of prohibitive toxicity, the 
orteronel dose may be reduced by one level to 200 mg BID. 
Inclusion 
Criteria: 
1. Voluntary written informed consent before performance of any study-related procedure not 
part of normal medical care 
2. Patients must have MBC that is measurable or evaluable as defined by Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria (see Section 9).  Patients with 
metastases limited to the bones are eligible. 
3. Patients with breast tumors that are AR+ (≥10% staining by immunohistochemistry).  
Archived tumor tissue from a primary biopsy or metastatic lesion for centralized 
determination of AR expression is mandatory.  If tissue is limited, the additional correlative 
testing is optional.  If tissue is not available, a patient will not be eligible for enrollment 
into the study.  Patients may enroll based on local laboratory AR assessment, but will need 
to submit tissue for confirmation at the central laboratory. 
4. In addition to having AR+ tumors, patients must fit into 1 of the 2 following categories: 
• 
Triple negative (ER-/PR-/HER2-) (Note:  This group of patients must have received at 
least 1 and up to 3 prior chemotherapy regimens in the advanced setting.) 
• 
ER+ and/or PR+ (Note:  This group of patients must have received at least 1 and up to 
3 prior hormonal therapies and at least one prior chemotherapy treatment in the 
advanced setting.  HER2+ patients in this group must have received a minimum of 2 
lines of HER2-directed therapy in the advanced setting.)  This group of patients may 
be pre-menopausal with ovarian suppression or post-menopausal.  LHRH agonists 
maybe used to render ovarian suppression with post-menopausal ranges of estradiol or 
FSH per institutional guidelines. 
5. Female or male patients ≥18 years-of-age 
6. Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2 (see 
Appendix A) 
7. Patient has recovered (to Grade ≤1) from all clinically significant toxicities related to prior 
antineoplastic therapies (with the exception of alopecia) 
 
8. Adequate hematological function, defined as: 
• 
Absolute neutrophil count (ANC) ≥1.25 x 109/L 
• 
Platelets ≥75 x 109/L 
• 
Hemoglobin ≥9 g/dL 
9. Adequate liver function, defined as: 
• 
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x the 
upper limit of normal (ULN), if no liver involvement or ≤5 x ULN with liver 
involvement 
• 
Total bilirubin ≤1.5 times the upper limit of normal (ULN) (in patients with known 
Gilbert Syndrome, a total bilirubin ≤3.0 x ULN, with direct bilirubin ≤1.5 x ULN) 


 
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BRE 203 CLINICAL PROTOCOL SYNOPSIS 
Inclusion 
Criteria 
(continued): 
10. Adequate renal function, defined as: 
• 
Creatinine ≤1.5 x ULN or creatinine clearance ≥40 mL/min as calculated by the 
Cockcroft-Gault method 
11. Screening calculated LVEF of ≥50% by echocardiogram (ECHO) or multiple-gated 
acquisition (MUGA) scan 
12. Ability to swallow and retain oral medication 
13. Male patients (even those post vasectomy) who are willing to use adequate contraceptive 
measures (see Appendix B) or abstain from heterosexual intercourse during the entire study 
treatment period and for 4 months after the last dose of study drug 
14. Female patients who are not of child-bearing potential and female patients of child-bearing 
potential who agree to use adequate contraceptive measures (see Appendix B) or abstain 
from heterosexual intercourse during the entire study treatment period and for 4 months 
after the last dose of study drug, who are not breastfeeding, and who have had a negative 
serum/urine pregnancy test ≤7 days prior to dosing 
15. Life expectancy of ≥3 months 
16. Willingness and ability to understand the nature of this study and to comply with the study 
and follow-up procedures. 
Exclusion 
Criteria: 
1. Known hypersensitivity to orteronel or to orteronel excipients, which are listed by 
formulation in the Investigator Brochure 
2. Patients receiving other treatment for breast cancer (includes standard hormonal 
therapy, chemotherapy, biologic therapy, immunotherapy, or radiation therapy).  
Patients receiving chronic bisphosphonate or denosumab therapy are eligible. 
3. Female patients who are both lactating and breastfeeding or have a positive serum 
pregnancy test during the screening period. 
4. Prior anti-androgen therapy 
5. Use of an investigational drug ≤21 days or 5 half-lives (whichever is shorter) prior 
to the first dose of orteronel, or concurrent treatment.  For investigational drugs for 
which 5 half-lives is less than 21 days, a minimum of 10 days between termination 
of the investigational drug and administration of orteronel is required. 
6. Active brain metastases or leptomeningeal disease.  Previously treated brain 
metastases are allowed provided lesions are stable for at least 3 months as 
documented by head CT scan or magnetic resonance imaging (MRI) of the brain.  
Patients must be off steroids, but anti-convulsants are allowed. 
7. Patients with known adrenal insufficiency, or patients receiving treatment with 
ketoconazole, abiraterone, or aminoglutethimide. 
8. Wide field radiotherapy (including therapeutic radioisotopes such as strontium 89) 
administered ≤28 days or limited field radiation for palliation ≤7 days prior to 
starting study drug or has not recovered from side effects of such therapy. 
9. Major surgical procedures ≤28 days of beginning study treatment or minor 
surgical procedures ≤7 days.  No waiting is required following port-a-cath 
placement. 
10. Presence of active gastrointestinal (GI) disease or other condition that will 
interfere significantly with the absorption, distribution, metabolism, or excretion 
of oral therapy (eg, ulcerative disease, uncontrolled nausea, vomiting, diarrhea ≥ 
Grade 2, and malabsorption syndrome). 


 
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BRE 203 CLINICAL PROTOCOL SYNOPSIS 
Exclusion 
Criteria: 
(continued) 
11. History of myocardial infarction, unstable symptomatic ischemic heart disease, 
ongoing arrhythmias > Grade 2 (National Cancer Institute [NCI] Common 
Terminology Criteria for Adverse Events [CTCAE], Version 4.0), 
thromboembolic events (eg, deep vein thrombosis, pulmonary embolism, or 
symptomatic cerebrovascular events), or any other cardiac condition (eg, 
pericardial effusion restrictive cardiomyopathy) within 6 months prior to first dose 
of study drug.  Chronic stable atrial fibrillation on stable anticoagulant therapy is 
allowed. 
12. New York Heart Association (NYHA) Class III or IV heart failure (Appendix C) 
13. Electrocardiogram (ECG) abnormalities of Q-wave infarction, unless identified 6 
or more months prior to screening or QTc Fridericia (F) interval >460 msec 
14. Inadequately controlled hypertension (ie, systolic blood pressure [SBP] 
>160 mmHg or diastolic BP [DBP] >90 mmHg) at 2 separate measurements no 
more than 60 minutes apart during the Screening visit.  Note:  patients may be 
rescreened after adjustment of antihypertensive medications. 
15. Known diagnosis of human immunodeficiency virus, active chronic hepatitis B, or 
C, life-threatening illness unrelated to cancer, or any serious medical or 
psychiatric illness that could, in the investigator’s opinion, potentially interfere 
with participation in this study 
16. Uncontrolled diabetes mellitus.  Patients with Type II diabetes are eligible if they 
require only oral hypoglycemic agents and fasting blood glucose level is ≤120.  
Patients with Type I diabetes are eligible if their glycosylated hemoglobin (HbAlc) 
is ≤7. 
17. Diagnosis or treatment for another malignancy within 2 years of enrollment, with 
the exception of adequately treated in-situ carcinoma of the cervix, uteri, basal or 
squamous cell carcinoma or non-melanomatous skin cancer 
18. Inability or unwillingness (including psychological, familial, sociological, or 
geographical conditions) to comply with study and/or follow-up procedures as 
outlined in the protocol. 
19. Use of a prohibited concomitant medication (see Section 5.3.2 and Appendix D) 
that cannot be safely discontinued or substituted. 
 
Correlative 
Testing: 
The following correlative testing will included: 
• 
Measurement of changes in serum estradiol levels, total and free testosterone levels, 
and SHBG 
• 
Measurement of changes in ACTH, DHEA-S, and cortisol levels 
• 
Biomarker testing of archived tumor tissue for loss of PTEN and PIK3CA mutations. 
 


 
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BRE 203 CLINICAL PROTOCOL SYNOPSIS 
Statistical 
Methodology: 
For patients with ER-/PR-/HER2-/AR+ tumors (Cohort 1), the expected response rate with 
standard anti-estrogen therapy is expected to be zero.  Therefore, a response rate of at least 10% 
with orteronel therapy would indicate activity and would lead to further investigation.  
Assuming an evaluable population of 28 patients, the exact 95% confidence intervals (CIs) for a 
hypothesized response rate of 11% is (2.4%, 28.6%).  In order to incorporate an early stopping 
rule, Simon’s two-stage design is applied using alpha = 0.10 and power = 0.80 with comparison 
of the hypothesized response rate of 11% versus a conservative value of 2%.  Initially, 
19 patients will be enrolled in this cohort, and if no responses are observed, recruitment to this 
cohort will stop.  Otherwise, enrollment in this cohort will continue to full accrual of 
28 patients.  To account for an unevaluable rate of 10%, a total of 31 patients will be enrolled in 
this cohort. 
 
For patients with ER+ and/or PR+/AR+ tumors (Cohort 2), published data on exemestane as 
third-line hormonal therapy in postmenopausal women indicate a response rate of 13% and a 
clinical benefit rate (CR, PR, or SD >24weeks) of 30%.  It is hypothesized that treatment with 
orteronel in this patient population will produce similar results.  Assuming an evaluable 
population of 50 patients, the exact 95% CIs for a hypothesized response rate of 14% is (5.8%, 
26.7%).  In order to incorporate an early stopping rule, Simon’s two-stage design is applied 
using alpha = 0.10 and power = 0.80 with comparison of the hypothesized response rate of 14% 
versus a conservative value of 5.1%.  Initially, 26 patients will be enrolled in this cohort, and if 
one or no responses are observed, recruitment into this cohort will stop.  Otherwise, enrollment 
in this cohort will continue to full accrual of 50 patients.  To account for an unevaluable rate of 
10%, a total of 55 patients will be enrolled in this cohort. 


 
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BRE 203 CONTACT INFORMATION: 
SCRI Innovations Contact Information: 
SCRI Development Innovations, LLC 
3322 West End Avenue, Suite 900 
Nashville, TN  37203 
1-877-MY-1-SCRI 
asksarah@scresearch.net 
 
Principal Investigator: 
Howard A. Burris, III, MD 
Sarah Cannon Research Institute   
3322 West End Avenue, Suite 900 
Nashville, TN  37203 
1-877-MY-1-SCRI 
asksarah@scresearch.net 
 
Medical Monitor: 
John D. Hainsworth, MD 
Sarah Cannon Research Institute 
3322 West End Avenue, Suite 900 
Nashville, TN  37203 
1-877-MY-1-SCRI 
asksarah@scresearch.net 
 
Safety Dept. Phone # / Fax #: 
Safety Dept Email: 
1-615-329-7358/1-866-807-4325 
CANN.SAE@scresearch.net 
Regulatory Phone # / Fax #: 
1-877-MY-1-SCRI /1-615-524-4518 
SCRI Innovations Enrollment  Phone #: 
SCRI Innovations Enrollment Fax #: 
1-877-MY-1-SCRI 
1-866-699-0258 
Central Pharmacy Facsimile 
Central Pharmacy Email 
1-866-325-9364 
Centralpharmacy@scresearch.net 
 


 
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List of Abbreviations 
ACTH 
adrenocorticotropic hormone 
ADL 
activity of daily living 
AKT 
protein kinase B 
AE 
adverse event 
ALT 
alanine aminotransferase 
ALP 
alkaline phosphatase 
ANC 
absolute neutrophil count 
AR (+) 
androgen receptor (positive) 
AST 
aspartate aminotransferase 
BP 
blood pressure 
BID 
twice daily 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CMP 
comprehensive metabolic profile 
CR 
complete response 
CRPC 
castration-resistant prostate cancer 
eCRF 
electronic case report form 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DBP 
diastolic blood pressure 
DCR 
disease control rate 
DDI 
drug-drug interactions 
DHEA-S 
dehydroepiandrosterone sulfate 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
EGFR 
epidermal growth factor receptor 
ER+ or - 
estrogen receptor positive or negative 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HbA1c 
glycosylated hemoglobin 
HER2– 
human epidermal growth factor receptor 2 negative 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
IRB 
Institutional Review Board 
LAR 
luminal androgen receptor 
LFT 
liver function tests 
LVEF 
left ventricular ejection fraction 
MBC 
metastatic breast cancer 
MRI 
magnetic resonance imaging 
MUGA 
multi-gated acquisition scan 


 
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List of Abbreviations (Continued) 
NYHA 
New York Heart Association 
OS 
overall survival 
PD 
progressive disease 
PFS 
progression-free survival 
PI 
Principal Investigator 
PI3K 
phosphatidylinositol 3-kinase 
PO 
per os (orally, by mouth) 
PR 
partial response 
PR+ or - 
progesterone receptor positive or negative 
PTEN 
phosphatase and tensin homolog 
PSA 
prostate specific antigen 
QA 
quality assurance 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RR 
response rate 
SAE 
serious adverse event 
SBP 
systolic blood pressure 
SCRI 
Sarah Cannon Research Institute 
SD 
stable disease 
SHBG 
sex hormone binding globulin 
TNBC 
triple-negative breast cancer 
ULN 
upper limit of normal 


 
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Table of Contents 
  
1. 
INTRODUCTION ............................................................................................................... 16 
1.1. 
Background ........................................................................................................ 16 
1.2. 
Orteronel ............................................................................................................ 16 
1.2.1. 
Summary of Non-clinical Findings ...................................................... 16 
1.2.2. 
Summary of Clinical Findings ............................................................. 17 
1.3. 
Rationale for the Study ...................................................................................... 18 
2. 
STUDY OBJECTIVES ........................................................................................................ 19 
2.1. 
Primary Objectives............................................................................................. 19 
2.2. 
Secondary Objectives......................................................................................... 19 
2.3. 
Exploratory Objective ........................................................................................ 19 
3. 
STUDY PATIENT POPULATION AND WITHDRAWAL .............................................. 20 
3.1. 
Inclusion Criteria ............................................................................................... 20 
3.2. 
Exclusion Criteria .............................................................................................. 21 
3.3. 
Discontinuation from Study Treatment ............................................................. 23 
3.4. 
Pregnancy ........................................................................................................... 23 
4. 
STUDY REGISTRATION .................................................................................................. 24 
5. 
STUDY DESIGN................................................................................................................. 25 
5.1. 
Treatment Plan ................................................................................................... 26 
5.2. 
Correlative Studies ............................................................................................. 26 
5.2.1. 
Blood samples for measuring serum hormone levels .......................... 27 
5.3. 
Concomitant Medications .................................................................................. 27 
5.3.1. 
Permitted Concomitant Medications .................................................... 27 
5.3.2. 
Prohibited Concomitant Medications ................................................... 28 
6. 
DOSE MODIFICATIONS .................................................................................................. 28 
6.1. 
Dose Modifications and Reductions .................................................................. 28 
6.1.1. 
Criteria for Orteronel Dose Reduction ................................................. 29 
6.1.2. 
Dose Modifications Due to Hematologic Toxicity .............................. 30 
6.1.3. 
Dose Modifications Due to Non-Hematologic Toxicity ...................... 30 


 
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7. 
STUDY ASSESSMENTS AND TREATMENT................................................................. 41 
7.1. 
Overview ............................................................................................................ 41 
7.2. 
Pre-Screening ..................................................................................................... 41 
7.3. 
Full Screening .................................................................................................... 41 
7.4. 
Treatment Assessments ...................................................................................... 42 
7.4.1. 
Day 1 of Each Cycle............................................................................. 42 
7.4.2. 
Day 1 of Cycle 3 and Every Other Cycle Following (Cycles 5, 7, 9, 
etc), except where noted .................................................................................... 43 
7.5. 
End of Study Treatment ..................................................................................... 43 
7.6. 
Follow-Up .......................................................................................................... 44 
7.6.1. 
Follow-Up After Discontinuing Study Treatment ............................... 44 
7.6.2. 
Follow-Up After Disease Progression.................................................. 44 
7.6.3. 
Comprehensive Metabolic Profile ........................................................ 44 
8. 
DRUG FORMATULATION, AVAILABILITY, ADMINISTRATION AND TOXICITY 
INFORMATION........................................................................................................................... 45 
8.1. 
Orteronel ............................................................................................................ 45 
8.1.1. 
Labeling, Packaging, and Supply ......................................................... 45 
8.1.2. 
Preparation and Administration of Investigational Products ............... 45 
8.1.3. 
Accountability of Investigational Products .......................................... 46 
9. 
RESPONSE EVALUATIONS AND MEASUREMENTS ................................................. 46 
9.1. 
Definitions.......................................................................................................... 46 
9.2. 
Baseline Eligibility............................................................................................. 47 
9.2.1. 
Guidelines for Evaluation of Measurable Disease ............................... 47 
9.2.2. 
Response Criteria ................................................................................. 49 
10. STATISTICAL CONSIDERATIONS................................................................................. 51 
10.1. 
Statistical Design ............................................................................................... 51 
10.2. 
Analysis Population ........................................................................................... 51 
10.3. 
Sample Size Considerations ............................................................................... 51 
10.4. 
Planned Interim Analyses .................................................................................. 52 
10.5. 
Statistical Analyses ............................................................................................ 52 
10.6. 
Efficacy Measures .............................................................................................. 52 
10.6.1. 
Primary Endpoints.............................................................................. 52 


 
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10.6.2. 
Secondary Endpoints.......................................................................... 53 
10.7. 
Safety Review .................................................................................................... 53 
10.8. 
Biomarkers ......................................................................................................... 53 
11. SAFETY REPORT AND ANALYSES .............................................................................. 53 
11.1. 
Safety Analyses .................................................................................................. 53 
11.2. 
Adverse Events .................................................................................................. 54 
11.2.1. 
Definitions of Adverse Events ........................................................... 54 
11.2.2. 
Recording of Adverse Events ............................................................ 54 
11.2.3. 
Handling of Adverse Events .............................................................. 54 
11.3. 
Serious Adverse Events ..................................................................................... 55 
11.3.1. 
Definitions of Serious Adverse Events .............................................. 55 
11.3.2. 
Serious Adverse Event Reporting by Investigators ........................... 56 
11.3.3. 
Sponsor SAE Reporting Requirements .............................................. 57 
11.4. 
Recording of Adverse Events and Serious Adverse Events .............................. 57 
11.4.1. 
Diagnosis versus Signs and Symptoms .............................................. 57 
11.4.2. 
Persistent or Recurrent Adverse Events ............................................. 57 
11.4.3. 
Abnormal Laboratory Values ............................................................. 58 
11.4.4. 
Deaths................................................................................................. 58 
11.4.5. 
Hospitalization, Prolonged Hospitalization, or Surgery .................... 58 
11.4.6. 
Pre-Existing Medical Conditions ....................................................... 58 
11.4.7. 
Pregnancy, Abortion, or Birth Defects/Congenital Anomalies.......... 58 
11.4.8. 
New Cancers ...................................................................................... 58 
11.4.9. 
Lack of Efficacy ................................................................................. 59 
11.5. 
Protocol-Defined Events of Special Interest ...................................................... 59 
11.6. 
Product Complaints ............................................................................................ 60 
12. ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS .......................... 60 
12.1. 
IRB Approval ..................................................................................................... 60 
12.2. 
Regulatory Approval .......................................................................................... 61 
12.3. 
Insurance and Indemnity .................................................................................... 61 
12.4. 
Informed Consent............................................................................................... 61 
12.5. 
Confidentiality ................................................................................................... 61 
12.5.1. 
Patient Confidentiality ....................................................................... 61 


 
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12.5.2. 
Investigator and Staff Information ..................................................... 62 
12.6. 
Financial Information......................................................................................... 62 
13. RECORD RETENTION AND DOCUMENTATION OF THE STUDY ........................... 62 
13.1. 
Amendments to the Protocol .............................................................................. 62 
13.2. 
Documentation Required to Initiate Study ........................................................ 63 
13.3. 
Study Documentation and Storage ..................................................................... 64 
13.4. 
Data Collection .................................................................................................. 65 
13.5. 
Study Monitoring, Auditing, and Inspecting ..................................................... 66 
13.6. 
Quality Assurance and Quality Control ............................................................. 66 
13.7. 
Disclosure and Publication Policy ..................................................................... 66 
REFERENCES ............................................................................................................................. 67 
 


 
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List of Tables 
Table 1. 
Orteronel Dose Level Modifications ................................................................. 32 
Table 2 
CTCAE Criteria and Appropriate Actions for Fatigue ...................................... 34 
Table 3 
CTCAE Criteria and Appropriate Actions for Nausea ...................................... 35 
Table 4 
CTCAE Criteria and Appropriate Actions for Vomiting ................................... 35 
Table 5 
CTCAE Criteria and Appropriate Actions for Diarrhea .................................... 36 
Table 6 
CTCAE Criteria and Appropriate Actions for Hyperglycemia ......................... 38 
Table 7 
Criteria and Appropriate Actions for Hypertension........................................... 39 
Table 8 
Criteria and Appropriate Actions for Adrenal Insufficiency ............................. 40 
Table 9 
CTCAE Criteria and Appropriate Actions for Rash (Acneiform or Maculo-
papular, Localized or Generalized) .................................................................... 41 
Table 10 
Orteronel Treatment Modification for Acute Renal Disorder ........................... 43 
Table 11 
Management of Abnormal AST and ALT Bearing a ≥ Possible Relationship to 
Orteronel Treatment ........................................................................................... 44 
 
 
List of Figures 
Figure 1. 
BRE 203 Treatment Schema  
 
 
 
 
 
       29 
 
 
List of Appendices 
Appendix A: 
ECOG Performance Status Criteria ................................................................... 73 
Appendix B: 
Guidelines for Female Subjects of Child-Bearing Potential and Sexually-Active 
Male Subjects 
............................................................................................................................ 74 
Appendix C: 
New York Heart Association (NYHA) Classifications ..................................... 75 
Appendix D: 
List of QT Prolonging Drugs ............................................................................. 76 
Appendix E: 
Schedule of Assessments for BRE 203 .............................................................. 79 


 
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1. 
INTRODUCTION 
1.1. 
Background 
The androgen receptor (AR) is expressed in 70% to 90% of primary breast tumors and in 75% of 
breast cancer metastases.  It is the sole sex steroid receptor expressed in 35% of metastases 
(Birrell et al. 1998). 
Triple-negative breast cancer (TNBC), which is estrogen-receptor negative (ER-), progesterone-
receptor negative (PR-), and human epidermal-growth-factor-receptor-2 negative (HER2-) 
constitutes 20% of all new breast cancers diagnosed.  The patients who experience this disease 
do not benefit from standard hormone or HER2-targeted therapies, and there are no optimal 
standard treatment regimens for the management of metastatic TNBC. 
Although survival is more favorable in the ER+ group of patients, there are few non-toxic 
treatments available once anti-estrogen therapies are exhausted.  Hence, there is an impetus to 
develop novel hormonal agents in refractory metastatic breast cancer (MBC).  Clinical interest is 
currently being directed to the role of the AR as a potential therapeutic target for treatment of 
MBC in the ER-/AR+ and the ER+/AR+ subsets of patients (Gucalp and Traina, 2010). 
The effects of androgen inhibition and stimulation on ER+/AR+ cancers are variable.  
Approximately 30% of patients with refractory MBC will respond to androgen therapy.  It is 
clear that androgens do not always act as growth promoters in breast cancer in the same ways 
that estrogens do.  In fact, preliminary work has shown that, for estrogen-dependent growth in a 
cancer cell, there is a functional interaction of ER and AR signaling.  Certain cell lines, when 
given testosterone, show inhibition of ER activity in a dose-dependent fashion.  Also, when a 
constitutively active AR is introduced to certain cell lines (T-47D), estrogen-induced 
proliferation is inhibited.  It is thought that this AR is recruited to specific estrogen response 
elements and prevents activation of target genes that mediate stimulatory effects of estrogen on 
breast cancer cells (Gucalp and Traina, 2010).  In other breast cancer cell lines, androgens have 
been shown to promote growth and proliferation.  MCF 7 cells (ER+/PR+ and AR+) and MDA-
MB453 cells (ER-/PR- and AR+) are both stimulated by androgens in vitro (Birrell et al. 1998).  
We hypothesize that patients with breast cancers expressing similar receptor profiles might 
respond when androgen levels are lowered by blockade of adrenal androgen synthesis. 
1.2. 
Orteronel 
Orteronel, a novel, orally active, selective, nonsteroidal inhibitor of 17, 20-lyase, is being 
developed as an endocrine therapy for relevant hormone-sensitive cancers such as prostate 
cancer and breast cancer.  Orteronel is expected to suppress sex hormone levels in both 
circulation and relevant hormone-dependent malignant tissue. 
1.2.1. 
Summary of Non-clinical Findings 
In vitro and in vivo pharmacology studies indicate that orteronel is a reversible inhibitor of 
human and monkey 17,20-lyase activity. Absorption, distribution, metabolism, and excretion 
(ADME) studies, showed that the bioavailability of orteronel in rats and monkeys was 41.0% and 
70.5%, respectively.  14C-labeled parent compound and metabolites were distributed widely into 


 
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the tissues of male and female rats, with relatively high concentrations in the liver and adrenal 
gland.  Orteronel is metabolized into M-I (also known as M1) via hydrolysis of the amide bond 
and other minor metabolites via lucuronidation of both orteronel and M-I (in human plasma 
samples).  Additionally, T-1358043 (TAK-700 dehydrate) is a minor metabolite of orteronel that 
is also a process impurity and drug product degradant.  In vitro testing demonstrated minimal 
involvement of cytochrome P450 (CYP) isozymes in the metabolism of orteronel.  Orteronel is 
not an inducer of CYP2B6 and 3A4/5, but is a moderate inducer of CYP1A2.  Based on the 
results of CYP isozyme and transporter inhibition studies, orteronel is unlikely to cause CYP 
isozyme- or transporter-mediated drug-drug interactions (DDIs).  In addition, a physiologically 
based pharmacokinetic DDI modeling study showed that orteronel, as an inhibitor, is unlikely to 
cause CYP isozyme-mediated clinical DDI.  Orteronel and its metabolites were eliminated 
primarily in the feces in rats and urine in monkeys. 
The safety of orteronel has been assessed in a battery of single and repeat-dose oral (PO) toxicity 
studies in mice, rats, dogs, and/or monkeys; reproductive toxicity studies in rats and rabbits; and 
genotoxicity studies; as well as additional toxicology studies with T-1358043.  Effects noted in 
toxicology studies were consistent with the pharmacologic inhibition of 17,20-lyase activity and 
included atrophy of the epididymis, prostate, and seminal vesicle; delay in the development of 
spermatogenesis; increased fetal mortality; and decreased fetal weights. In chronic 6-month rat 
and 9-month monkey toxicity studies, the no observed adverse effect levels (NOAELs) were 3 
and 1 mg/kg, respectively, which corresponded with area under the concentration-versus-time 
curves (AUC) from 0 to 24 hours (AUC0-24hr) values of 1649 and 1016 hr*ng/mL in males, 
respectively. 
Orteronel itself was not mutagenic or clastogenic in genotoxicity tests and did not elicit changes 
indicative of cutaneous or ocular phototoxicity.  However, T-1358043 was positive for 
genotoxicity in vitro and when dosed neat, positive for genotoxicity in Muta™Mice dosed with 
T-1358043 at ≥15 mg/kg (mean T-1358043 AUC0-24hr of 7950 hr*ng/mL).  However, T-1358043 
was negative for genotoxicity when dosed at 5 mg/kg (AUC0-24hr of 1050 hr*ng/mL) in 
Muta™Mice.  Therefore, T-1358043 could potentially pose a risk to human subjects by leading 
to a secondary malignancy if plasma exposure in humans approaches the levels noted at 
15 mg/kg in the Muta™Mice.  The mean T-1358043 AUC values in the Muta™Mouse study at 
the no observed effect level (5 mg/kg) were approximately 7 times greater than the estimated 
mean steady-state level of T-1358043 formed in patients with CRPC administered the clinical 
dose of 400-mg orteronel PO twice daily (BID) in Study C21003. 
For a complete discussion of the nonclinical data, please refer to the TAK-700 Investigator’s 
Brochure (IB). 
1.2.2. 
Summary of Clinical Findings 
Based on the clinical development experience to date, the overall risk/benefit of orteronel 
therapy in patients with CRPC is favorable.  For the most current summary of the studies 
conducted to date, please refer to the current IB. 
The most commonly reported treatment-emergent adverse events (TEAEs) in patients enrolled in 
orteronel clinical studies include fatigue, nausea, constipation, diarrhea, and headache.  Typical 


 
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adverse events (AEs) associated with androgen-deprivation therapy and with orteronel can be 
monitored and managed with supportive care or dose modification. 
Orteronel has dose-proportional, single-dose and multiple-dose pharmacokinetics (PK).  
Excretion of parent drug and M-I occurs primarily via the kidney.  The steady state PK profile of 
orteronel administered twice daily allows for fairly consistent inhibition of adrenal androgen and 
testosterone production throughout the day. 
Review of the available nonclinical pharmacology and toxicology findings, the Phase I clinical 
data in healthy male subjects and the Phase 1 through 2 clinical data in men with CRPC supports 
the continued clinical development of orteronel for the treatment of CRPC.  Phase III clinical 
studies are ongoing to further evaluate the safety and efficacy of orteronel in this population. 
1.2.2.1. 
Identified and Potential Risks with Orteronel 
Single and multiple doses of orteronel up to 600 mg appeared to be safe and well tolerated in 
Phase II studies conducted in healthy male subjects.  The most common AE observed in the 
completed Phase I studies in healthy subjects was headache. 
Orteronel appears to have an acceptable tolerability profile in patients with prostate cancer, 
across all doses tested thus far.  The most commonly reported TEAEs are fatigue, nausea, 
constipation, diarrhea, and headache. 
Other identified risks associated with orteronel treatment include: 
• Effects of androgen deprivation 
• Left ventricular ejection fraction (LVEF) decreased 
• Adrenal insufficiency 
• Compensatory elevated adrenocorticotropic hormone concentrations, which may result in 
increased mineralocorticoid activity 
• Hepatotoxicity 
• Genotoxicity, that could potentially lead to carcinogenesis and second malignancies 
For a complete discussion of the safety data, please refer to the current IB. 
1.3. 
Rationale for the Study 
To date, there have been no investigations of Orteronel in AR+ patients with MBC.  However, 
preliminary results of a Phase I study with abiraterone acetate (an inhibitor of adrenal androgen 
synthesis, similar to orteronel), including 25 patients with MBC expressing ER+ or ER-/AR+, 
were encouraging and toxicities were manageable (Basu et al. 2011).  Although the median time 
on treatment was short for this group of patients with resistance to at least 2 prior hormone 
therapies, two patients (both ER+/AR+) continued on treatment beyond 11 months (Basu et al. 
2011).  There are also positive preliminary results in an ongoing study of bicalutamide, a non-
steroidal anti-androgen that competitively inhibits AR, in patients with ER-/PR-/AR+ tumors 
(Traina et al. 2009, Gucalp et al. 2012). 


 
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In addition, Lehmann et al. have recently identified a luminal androgen receptor (LAR) subtype, 
one of six distinct subsets of TNBC identified by transcriptome analysis (Lehmann et al. 2011).  
In vitro and in vivo assays have shown the LAR subtypes to be sensitive to bicalutamide, a potent 
anti-androgen.  Therefore, TNBC patients with AR expression could potentially benefit from 
effective anti-androgen therapy like orteronel. 
Substantial evidence therefore suggests that the AR is a potential therapeutic target in selected 
patients with MBC.  Two subsets of patients with MBC will be studied separately in this study: 
• ER-/PR-/HER2-/AR+ 
• ER+ and/or PR+/AR+ 
This trial will be conducted in accordance with the International Conference on Harmonization 
(ICH) guideline on Good Clinical Practice (GCP) (E6), Title 21 of the Code of Federal 
Regulations (CFR) parts 50, 54, 56, and 312, and any other applicable local regulatory 
requirements. 
2. 
STUDY OBJECTIVES 
2.1. 
Primary Objectives 
The primary objectives of this study are to evaluate: 
• Response rate (RR) and disease control rate (DCR) following treatment with orteronel in 
patients with refractory metastatic triple-negative breast cancer expressing AR (ER-/PR-
/HER2-/AR+) 
• Response rate and disease control rate (DCR) following treatment with orteronel in 
patients with refractory ER+ and/or PR+/AR+ breast cancer. 
2.2. 
Secondary Objectives 
The secondary objectives of this study are to evaluate: 
• Safety and tolerability of the regimen 
• Measurement of changes in serum estradiol levels, total and free testosterone levels, and 
sex hormone binding globulin (SHBG) during treatment with orteronel 
• Measurement of changes in ACTH, DHEA-S, and cortisol levels during treatment with 
orteronel 
• Progression-free survival (PFS) 
• Overall survival (OS) 
2.3. 
Exploratory Objective 
As an exploratory objective of this trial: 


 
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• Archived tumor tissue will be assayed for the following biomarkers:  loss of phosphatase 
and tensin homolog (PTEN) and phosphatidylinositol 3-kinase (PIK3CA) mutations. 
3. 
STUDY PATIENT POPULATION AND WITHDRAWAL  
This study will enroll patients with MBC who have progressed on prior hormonal/ chemotherapy 
regimens and whose cancer expresses AR.  Patients will be enrolled onto one of the 2 following 
cohorts based on their tumor specificity: 
• Cohort 1:  Patients with estrogen receptor negative (ER-)/ progesterone receptor negative 
(PR-)/ human epidermal growth factor receptor 2 negative (HER2-)/AR positive (+) 
MBC with 1 to 3 previous treatments for metastatic disease 
• Cohort 2:  Postmenopausal women with ER+ and/or PR+/AR+ refractory MBC who have 
progressed after at least one, and up to 3, previous hormonal treatments for metastatic 
disease. 
3.1. 
Inclusion Criteria 
Patients must meet the following criteria in order to be included in this clinical study: 
1. Voluntary written informed consent before performance of any study-related procedure 
not part of normal medical care 
2. Patients must have MBC that is measurable or evaluable as defined by Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria (see Section 9).  Patients with 
metastases limited to the bones are eligible. 
3. Patients with breast tumors that are AR+ (>10% staining by immunohistochemistry). 
Archived tumor tissue from a primary biopsy or metastatic lesion for centralized 
determination of AR expression is mandatory.  If tissue is limited, the additional 
correlative testing is optional.  If tissue is not available, a patient will not be eligible for 
enrollment into the study.  Patients may enroll based on local laboratory AR assessment, 
but will need to submit tissue for confirmation at the central laboratory. 
4. In addition to having AR+ tumors, patients must fit into 1 of the 2 following categories: 
• Triple negative (ER-/PR-/HER2-) Note: This group of patients must have received at 
least 1 and up to 3 prior chemotherapy regimens in the advanced setting. 
• ER+ and/or PR+ Note: This group of postmenopausal patients must have received at 
least 1 and up to 3 prior hormonal therapies and at least one prior chemotherapy 
treatment in the advanced setting.  HER2+ patients in this group must have received 
a minimum of 2 lines of HER2-directed therapy in the advanced setting.  This group 
of patients may be pre-menopausal with ovarian suppression or post-menopausal.  
LHRH agonists maybe used to render ovarian suppression with post-menopausal 
ranges of estradiol or FSH per institutional guidelines. 
5. Female or male patients ≥18 years-of-age 


 
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6. Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2 (see 
Appendix A) 
7. Patient has recovered (to Grade ≤1) from all clinically significant toxicities related to 
prior antineoplastic therapies (with the exception of alopecia) 
8. Adequate hematological function, defined as: 
• Absolute neutrophil count (ANC) ≥1.25 x 109/L 
• Platelets ≥75 x 109/L 
• Hemoglobin ≥9 g/dL 
9. Adequate liver function, defined as: 
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x the 
upper limit of normal (ULN), if no liver involvement or ≤5 x ULN with liver 
involvement 
• Total bilirubin ≤1.5 times the upper limit of normal (ULN) (in patients with known 
Gilbert Syndrome, a total bilirubin ≤3.0 x ULN, with direct bilirubin ≤1.5 x ULN) 
10. Adequate renal function, defined as: 
• Creatinine ≤1.5 x ULN or creatinine clearance ≥40 mL/min, as calculated by the 
Cockcroft-Gault method 
11. Screening calculated LVEF of ≥50% by echocardiogram (ECHO) or by multiple-gated 
acquisition (MUGA) scan 
12. Ability to swallow and retain oral medication 
13. Male patients, even post vasectomy, who are willing to use adequate contraceptive 
measures (see Appendix B) or abstain from heterosexual intercourse during the entire 
study treatment period and for 4 months after the last dose of study drug 
14. Female patients who are not of child-bearing potential and female patients of child-
bearing potential who agree to use adequate contraceptive measures (see Appendix B) or 
abstain from heterosexual intercourse during the entire study treatment period and for 
4 months after the last dose of study drug, who are not breastfeeding, and who have had a 
negative serum/urine pregnancy test ≤7 days prior to dosing 
15. Life expectancy of ≥3 months 
16. Willingness and ability to understand the nature of this study and to comply with the 
study and follow-up procedures. 


 
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3.2. 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
1. Known hypersensitivity to orteronel or to orteronel excipients, which are listed by 
formulation in the IB 
2. Patients receiving other treatment for breast cancer (includes standard hormonal therapy, 
chemotherapy, biologic therapy, immunotherapy, or radiation therapy).  Patients 
receiving chronic bisphosphonate or denosumab therapy are eligible. 
3. Female patients who are both lactating and breastfeeding or have a positive serum/urine 
pregnancy test during the screening period. 
4. Prior anti-androgen therapy 
5. Use of an investigational drug ≤21 days or 5 half-lives (whichever is shorter) prior to the 
first dose of orteronel, or concurrent treatment.  For investigational drugs for which 
5 half-lives is less than 21 days, a minimum of 10 days between termination of the 
investigational drug and administration of orteronel is required. 
6. Active brain metastases or leptomeningeal disease.  Previously treated brain metastases 
are allowed provided lesions are stable for at least 3 months as documented by head 
CT scan or magnetic resonance imaging (MRI) of the brain.  Patients must be off 
steroids, but anti-convulsants are allowed. 
7. Patients with known adrenal insufficiency, or patients receiving treatment with 
ketoconazole, abiraterone, or aminoglutethimide. 
8. Wide field radiotherapy (including therapeutic radioisotopes such as strontium 89) 
administered ≤28 days or limited field radiation for palliation ≤7 days prior to starting 
study drug or has not recovered from side effects of such therapy. 
9. Major surgical procedures ≤28 days of beginning study treatment or minor surgical 
procedures ≤7 days.  No waiting is required following port-a-cath placement. 
10. Presence of active gastrointestinal (GI) disease or other condition that will interfere 
significantly with the absorption, distribution, metabolism, or excretion of oral therapy 
(eg, ulcerative disease, uncontrolled nausea, vomiting, diarrhea ≥ Grade 2, and 
malabsorption syndrome). 
11. History of myocardial infarction, unstable symptomatic ischemic heart disease, ongoing 
arrhythmias > Grade 2 (National Cancer Institute [NCI] Common Terminology Criteria 
for Adverse Events [CTCAE], Version 4.0), thromboembolic events (eg, deep vein 
thrombosis, pulmonary embolism, or symptomatic cerebrovascular events), or any other 
cardiac condition (eg, pericardial effusion restrictive cardiomyopathy) within 6 months 
prior to first dose of study drug.  Chronic stable atrial fibrillation on stable anticoagulant 
therapy is allowed. 
12. New York Heart Association (NYHA) Class III or IV heart failure (Appendix B) 


 
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13. Electrocardiogram (ECG) abnormalities of: 
o Q-wave infarction, unless identified 6 or more months prior to screening 
o QTc Fridericia (F) interval > 460 msec 
14. Inadequately controlled hypertension (ie, systolic blood pressure [SBP] >160 mmHg or 
diastolic BP [DBP] >90 mmHg) at 2 separate measurements no more than 60 minutes 
apart during the Screening visit.  Note:  patients may be rescreened after adjustment of 
antihypertensive medications. 
15. Known diagnosis of human immunodeficiency virus, active chronic hepatitis B, or C, 
life-threatening illness unrelated to cancer, or any serious medical or psychiatric illness 
that could, in the investigator’s opinion, potentially interfere with participation in this 
study 
16. Uncontrolled diabetes mellitus.  Patients with Type II diabetes are eligible if they require 
only oral hypoglycemic agents and fasting blood glucose level is ≤120.  Patients with 
Type I diabetes are eligible if their glycosylated hemoglobin (HbAlc) is ≤7. 
17. Diagnosis or treatment for another malignancy within 2 years of enrollment, with the 
exception of adequately treated in-situ carcinoma of the cervix, uteri, basal or squamous 
cell carcinoma or non-melanomatous skin cancer 
18. Inability or unwillingness (including psychological, familial, sociological, or 
geographical conditions) to comply with study and/or follow-up procedures as outlined in 
the protocol. 
19. Use of a prohibited concomitant medication (see Section 5.3.2 and Appendix D) that 
cannot be safely discontinued or substituted. 
3.3. 
Discontinuation from Study Treatment 
Patients will be discontinued from study treatment for any of the following reasons: 
• Disease progression 
• Irreversible or intolerable toxicity or abnormal laboratory values thought to be related to 
drug toxicity 
• Patient requests to withdraw from the study and discontinue treatment 
• Patient requests to discontinue treatment 
• Pregnancy 
• Inability of the patient to comply with study requirements 
• Conditions requiring therapeutic intervention not permitted by the protocol 
• Intercurrent illness (this will be at the investigator’s discretion) 
• Non-compliance/lost to follow-up. 


 
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After withdrawal from protocol treatment, patients must be followed for AEs for 30 calendar 
days after their last dose of study drug.  All new AEs occurring during this period must be 
reported and followed until resolution, unless, in the opinion of the investigator, these values are 
not likely to improve because of the underlying disease.  In this case, the investigators must 
record his or her reasoning for this decision in the patients’ medical records and as a comment on 
the electronic Case Report Form (eCRF). 
All patients who have Grade 3 or 4 laboratory abnormalities (CTCAE, Version 4.0) at the time of 
discontinuation must be followed until the laboratory values have returned to Grade 1 or 2, 
unless it is, in the opinion of the investigator, not likely that these values are to improve.  In this 
case, the investigator must record his or her reasoning for making this decision in the patients’ 
medical records and as a comment on the eCRF. 
3.4. 
Pregnancy 
Male patients, even if surgically sterilized, and female patients of child-bearing potential must: 
• Agree to practice effective barrier contraception during the entire study treatment period 
and for 4 months after the last dose of study drug, or 
• Agree to completely abstain from heterosexual intercourse. 
During the course of the study, all female patients of childbearing potential (the definitions of 
“women of childbearing potential” are listed in Appendix B) must contact the treating 
investigator immediately if they suspect that they may be pregnant (a missed or late menstrual 
period should be reported to the treating investigator), despite following the precautions listed 
above. 
If an investigator suspects that a patient may be pregnant prior to administration of study drug, 
the study drug must be withheld until the result of the pregnancy test is confirmed.  If a 
pregnancy is confirmed, the patient must not receive any study drug, and must be discontinued 
from the study. 
If an investigator suspects that a patient may be pregnant after the patient has been receiving 
study drug, the study drug must immediately be withheld until the result of the pregnancy test is 
confirmed.  If a pregnancy is confirmed, the study drug must be immediately and permanently 
stopped, the patient must be discontinued from the study, and the investigator must notify the 
Medical Monitor as soon as possible.  If a patient becomes pregnant while enrolled in the study, 
a Pregnancy Form (a paper report form) should be completed and faxed to SCRI Innovations 
Safety Department.  For more details regarding handling and reporting of pregnancies that occur 
during treatment, see Section 11.5. 
4. 
STUDY REGISTRATION 
The patient must willingly consent after being informed of the procedures to be followed, the 
experimental nature of the treatment, potential benefits, alternatives, side-effects, risks and 
discomforts.  Human protection committee approval of this protocol and informed consent form 
are required. 


 
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Patients will sign a pre-screen informed consent form (ICF) for centralized determination of AR 
expression in an archived tumor sample from a primary biopsy or metastatic lesion.  Patients 
whose tumors have an AR expression ≥10% will then sign and date the main ICF and will be 
screened to determine eligibility for enrollment into the study.  Eligible patients who wish to 
participate in the study will be enrolled into the study.  Patients with ≥10% AR expression in 
their tumor tissue based on local lab assessment may enroll on the study, but will be required to 
provide tumor tissue for confirmation at the central laboratory. 
Registration must occur prior to the initiation of protocol therapy.  Patients eligible to participate 
in the study may be enrolled through the SCRI Innovations by calling (877) MY-1-SCRI.  
Registration may be done via fax (866) 699 0258 Monday through Friday, 8:30 a.m. to 4:30 
p.m., Central Standard Time.  Patient registration will be confirmed within 24 hours, or by the 
next business day. 
 
5. 
STUDY DESIGN 
This is an open-label, multicenter, Phase II study to be conducted in 2 stages.  All patients will 
receive orteronel PO at a dose of 300 mg twice daily (BID) (600 mg total daily dose). 
• Lead-in Phase:  The first 6 patients treated will be evaluated every week to confirm the 
safety and feasibility of this regimen.  After all 6 patients complete at least 4 weeks of 
treatment, and if no prohibitive toxicities are identified, continuous study treatment will 
begin. 
• Continuous Study Treatment:  Patients will continue to be enrolled into both cohorts 
based on their tumor specificities up to a total of 31 patients in Cohort 1 (ER-/PR-/HER2-
/AR+) and 55 patients in Cohort 2 (ER+ and/or PR+/AR+).  These numbers include the 
patients that are participating in the lead-in phase. 
Up to 86 patients are planned to be enrolled in this study (6 for the lead-in phase and 80 for 
continuous study treatment). 
Patients will be evaluated every eight weeks for response to treatment. 
All patients who respond to treatment (complete response [CR] or partial response [PR]) or have 
stable disease (SD) will continue to receive orteronel until they develop progressive disease (PD) 
or unacceptable toxicity. 
The study design schema is presented in Figure 1.


 
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Figure 1. 
BRE 203 Treatment Schema 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.1. 
Treatment Plan 
All patients entering this study will receive continuous 300 mg orteronel PO BID as 
monotherapy.  In the event of prohibitive toxicity, the orteronel dose may be reduced by one 
level to 200 mg BID. 
5.2. 
Correlative Studies 
The PI3Ks are a family of lipid kinases that regulate an intracellular signal transduction network, 
which in turn controls many features of cell behavior including growth, survival, motility, 
metabolism, and additional specialized functions.  Several activating mutations in the PIK3CA 
gene encoding p110 alpha have been identified.  In addition, the PI3K pathway is activated in 
Lead-in Phase  
(Following Pre-Screening for AR Expression) 
N = 6 
Orteronel 300 mg PO BID Continuous 
Patients will be followed weekly 
Continuous Study Treatment  
(Following Pre-Screening for AR Expression) 
Orteronel 300 mg PO BID Continuous 
N = 31 (Cohort 1: ER-/PR-/HER2-/AR+) 
N = 55 (Cohort 2: ER+ and/or PR+/AR+) 
Treatment cycles will be repeated every 4 weeks. 
Patients will be evaluated with CT scans every 2 treatment 
cycles (every 8 weeks).  Treatment will continue until disease 
progression or unacceptable toxicity occurs. 
After all 6 patients complete at least 4 weeks of 
treatment, and if no prohibitive toxicities are 
identified, the study will continue to enroll patients 
until full enrollment has been achieved 
(a total of 86 patients) 


 
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cancers with mutations causing inactivation or silencing of the PTEN, a tumor suppressor gene. 
Breast cancers frequently harbor molecular/genomic aberrations that increase activation of the 
PI3K signaling pathway including loss of PTEN function or activating PIK3CA mutations 
(Engelman, 2009).  Recent studies have found that AR is expressed in 60% to 70% of breast 
cancers regardless of ER status (Niemeier et al. 2010).  Studies have also shown that there were 
significant differences in AR expression levels by PIK3CA mutation status (Gonzalez-Angulo et 
al. 2009).  Interestingly, prostate cancer is characterized by its dependence on AR and frequent 
activation of PI3K signaling.  A recent study has shown that these two oncogenic pathways 
cross-regulate each other by reciprocal feedback.  Inhibition of one activates the other, thereby 
maintaining tumor cell survival (Carver et al. 2011).  We proposed to test the PIK3CA mutation 
status and PTEN loss in patients in this study to investigate whether the activation of PI3K 
pathway correlates with the response to orteronel treatment. 
PIK3CA mutation at codons 88, 539-549, 1020-1025, 1043-1049 will be tested by 
pyrosequencing and the results will be signed off by a molecular pathologist.  PTEN loss will be 
determined by immunohistochemical staining using Ventana systems and the report will be 
signed off by a pathologist.  Both assays will to be performed at a CLIA/CAP certified lab.  
These analyses are exploratory, and will not be used to guide treatment decisions. 
5.2.1. 
Blood samples for measuring serum hormone levels 
Blood samples will be collected at baseline, on Cycle 2 Day 1, on Cycle 4 Day 1, and at the End-
of-Treatment Visit to test for serum levels of estradiol, total and free testosterone, SHBG, 
ACTH, DHEA-S, and cortisol.  A blood sample will be collected for this purpose from each 
patient at the noted time points (see Appendix E) and submitted to a laboratory for testing.  
Details of the laboratory will be provided to the site by the study team.  When the results are 
received by the site, they will be entered into the appropriate eCRF page. 
5.3. 
Concomitant Medications 
Patients will be instructed not to take any additional medications during the course of the study 
without prior consultation with the research team.  At each visit, the patient will be asked about 
any new medications he/she is taking or has taken after the start of the study drug. 
5.3.1. 
Permitted Concomitant Medications 
• Use of erythropoietin replacement or bisphosphonates or denosumab is considered 
supportive care, and their use is permitted, if initiated >2 weeks prior to study treatment. 
• Patients are permitted to receive palliative radiation therapy on study to pre-existing, 
symptomatic lesions at the discretion of the treating physician. 
All other drugs are allowed with the exception of those listed in Section 5.3.2. 


 
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5.3.2. 
Prohibited Concomitant Medications 
The following treatments are prohibited while in this study: 
• 
Other investigational drug treatments or study participation 
• 
Other treatment for breast cancer including hormonal therapy, chemotherapy, biologic 
therapy, immunotherapy, or radiation therapy (except as described in Section 5.3.1).  
Specific excluded hormonal therapies include estrogens, progestins, or herbal products.  
Patients with HER2+ tumors should have completed trastuzumab therapy. 
• 
Concomitant treatment with any medication that may cause QT prolongation or Torsades 
de Pointes (see Appendix D).  If a patient, after study enrollment, requires use of a 
medication that may cause QT prolongation and/or Torsades de Pointes that cannot be 
safely substituted, the patient must be removed from the study. 
• Ketoconazole 
• Aminoglutethimide  
• Abiraterone (Zytiga®)  
• Enzalutamide (MDV-3100) 
• 5-alpha reductase inhibitors (eg, finasteride or dutasteride) 
• Chronic systemic corticosteroids.  If mineralocorticoid-related AEs occur and cannot be 
managed by supportive care (e.g., potassium, antihypertensives) and/or dose 
modification, low-dose corticosteroids (≤20 mg/day prednisone or its equivalent) can be 
given at the discretion of the investigator. 
• Over-the-counter products such as vitamins, minerals, herbal preparations/medications 
and other dietary supplements are not allowed throughout the study; over-the-counter 
multivitamins without antioxidants are allowed.  Patients should stop using these herbal 
medications at least 7 days prior to the first dose of study drug. 
6. 
DOSE MODIFICATIONS 
Toxicity will be assessed utilizing the NCI CTCAE v4.0 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE), unless otherwise specified. 
6.1. 
Dose Modifications and Reductions 
Orteronel, at the dose used in this protocol, is expected to be well tolerated.  Substantial acute 
toxicities should be managed as medically indicated and with temporary suspension of study 
drug, as appropriate.  Dose reductions or holds and initiation of supportive care are allowed as 
clinically indicated by the treating physician.  For each patient, a maximum of 1 dose reduction 
will be allowed.  The reduced dose level is presented in Table 1.  Should the patient not tolerate 
the lowest possible dose, he/she must discontinue treatment with orteronel. 


 
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Table 1. Orteronel Dose Level Modifications 
Dose Level 
Orteronel BID/Daily 
Starting Dose Level  
0 
300 mg/ 600 mg 
Reduced Dose Level  
-1 
200 mg/ 400 mg 
 
6.1.1. 
Criteria for Orteronel Dose Reduction 
Sections 6.1.1.1 and 6.1.1.2 give management guidelines for treatment-related Grade 2, 3, and 4 
toxicities.  Subsequent sections present additional details regarding management of specific 
toxicities (Sections 6.1.3.1 through 6.1.3.8). 
6.1.1.1. 
Grade 3 and 4 Toxicities 
 
Dose modifications for acute renal insufficiency and abnormal liver function tests are presented 
separately in Sections 6.1.3.7 and 6.1.3.8, respectively. 
Grade 4 non-hematologic toxicity: Discontinue orteronel 
Grade 3 toxicities: 
Grade 3 AEs that are considered at least possibly related to study drug require a dosing hold for a 
minimum of 2 weeks. 
Once the dose is reduced, reassessment is required at least every 2 weeks until the event is 
resolved or stabilized.  However, the frequency of reassessment should be increased as clinically 
indicated.  If the grade worsens at any time, the dose should be decreased in accordance with the 
guidelines for the worst grade. 
After the toxicity has improved to ≤ Grade 1, orteronel should be restarted with a dose reduction.  
If the Grade 3 toxicity recurs on the reduced orteronel dose, the drug should be discontinued.  
Dose reduction for a Grade 3 toxicity is permanent; orteronel should not be re-escalated.  Any 
patient who requires a treatment delay of more than 3 weeks due to treatment-related toxicity 
will be discontinued from study treatment, unless the treating physician and the Medical Monitor 
or Study Chair agree that continued treatment at lower doses is in the best interest of the patient. 
Asymptomatic Grade 3 or 4 laboratory findings may not require dose modification (ie, dose hold 
or reduction) especially if these are not considered to be clinically significant or related to study 
drug.  The decision to modify the dose should be based on the investigator’s clinical judgment.  
Dose modifications for Grade 3 hyperglycemia should follow the guidelines in Table 6. 
6.1.1.2. 
Grade 2 Clinically Intolerable Toxicities 
Dose modifications for acute renal insufficiency and abnormal liver function tests are presented 
separately in Sections 6.1.3.7 and 6.1.3.8, respectively. 


 
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For a clinically intolerable Grade 2 AE that is considered at least possibly related to study drug, 
the dose should be decreased by 1 dose level for 2 weeks.  The investigator should identify other 
potential causes of any AE or laboratory abnormality, and consult with the Medical Monitor for 
any questions regarding the need for dose modification. 
Once the dose is reduced, reassessment is required at least every 2 weeks until the event is 
resolved or stabilized.  However, the frequency of reassessment should be increased as clinically 
indicated. 
Subsequent dosing of orteronel should be based on the following guidelines: 
• If the AE grade improves to Grade 0 or 1, re-escalate to the full dose (300 mg BID).  If 
the intolerable Grade 2 toxicity recurs, the orteronel dose should be reduced 
permanently. 
• If the AE remains at Grade 2 and is still intolerable after 2 weeks, hold administration 
of orteronel.  If the AE grade improves to ≤ Grade 1 within 3 weeks, and continued 
treatment is thought to be in the patient’s best interest, orteronel may be restarted at the 
same (reduced) dose. 
• If the event worsens to ≥ Grade 3, hold orteronel for 2 weeks followed by a 
reassessment.  If the AE grade improves to ≤ Grade 1 within 3 weeks, and continued 
treatment is thought to be in the patient’s best interest, orteronel may be restarted at the 
same (reduced) dose. 
Reassess the AE after 2 weeks, or sooner, if the AE worsens.  Continue to reassess at least every 
2 weeks until the event is improved or stabilized.  If the dose has been withheld for 3 weeks, 
orteronel will be discontinued permanently, unless the treating physician and the Medical 
Monitor or Study Chair agree that continued treatment at the minimum-allowed dose (200 mg 
BID) is in the best interest of the patient. 
6.1.2. 
Dose Modifications Due to Hematologic Toxicity 
It is not expected that the dose will need to be held or modified due to hematologic toxicity in 
this study.  If a Grade 1 or 2 hematologic toxicity does occur, hold orteronel and re-evaluate the 
patient in 1 week.  Absolute neutrophil count and platelets should be monitored weekly until 
recovery.  If ANC and/or platelets do not recover within 3 weeks to ≤ Grade 1, the patient will be 
discontinued from the study. 
6.1.3. 
Dose Modifications Due to Non-Hematologic Toxicity 
Due to its mechanism of action, treatment with orteronel may elicit expression of adverse 
reactions typically associated with androgen deprivation.  Risks associated with androgen 
deprivation include hot flushes, decreased libido, loss of energy, QTc interval prolongation, or 
mood swings.  Long-term effects of testosterone suppression may also occur, including effects 
on bone mineral density, muscle mass, hyperglycemia, or lipid or energy metabolism. 
Adverse events commonly recorded during clinical trials with orteronel include fatigue, nausea 
and vomiting, rash, and worsening hypertension.  Pancreatitis and/or elevated amylase/lipase 
have also been reported, occurring in <5% of patients in studies conducted with orteronel.  


 
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Pancreatic enzymes will be measured during scheduled serum chemistries for patients receiving 
long-term administration of orteronel. 
For fatigue, mild or intermittent nausea and vomiting, or rash, dose modifications of orteronel 
should follow the guidelines in Section 6.1.1, depending on the severity. 
For ≥ Grade 3 QTc interval prolongation (QTcF >500 ms or >60 ms change from baseline on at 
least two separate ECGs), orteronel should be held until recovery to ≤ Grade 1 (<480 ms).  The 
patient’s chemistries should be checked, as well as concomitant medication usage.  Once QTc 
interval prolongation has resolved, orteronel may be restarted at the reduced dose level.  For a 
second occurrence of ≥ Grade 3 QTc interval prolongation, orteronel should be discontinued. 
In the event of any grade 4 non-hematologic toxicity, orteronel should be discontinued. 
6.1.3.1. 
Fatigue 
Fatigue is defined as a disorder characterized by a state of generalized weakness with a 
pronounced inability to summon sufficient energy to accomplish daily activities. 
Grade 2 to Grade 3 fatigue has occurred in some patients receiving TAK 700 without 
concomitant prednisone.  Less severe Grade 1 or Grade 2 fatigue has been reported in some men 
receiving concomitant prednisone; other factors such as acute androgen deprivation may also be 
contributing to symptoms.  Table 2 presents the CTCAE Criteria (Version 4.0) for fatigue and 
the appropriate actions to be followed. 
Table 2 
CTCAE Criteria and Appropriate Actions for Fatigue 
CTCAE Grade 
Event Definition 
Action Required 
1 
Fatigue relieved by rest 
No action required 
2 
Fatigue not relieved by rest, 
limits instrumental Activity 
of Daily Living (ADL) 
Dose modification is optional;  
If Grade 2 fatigue is intolerable, dose 
reduction and re-escalation should follow 
guidelines in Section 6.1.1.2. 
3 
Fatigue not relieved by rest, 
limiting self care ADL 
Dose reduction follows guidelines in 
Section 6.1.1.1. 
Source:  CTCAE Version 4.0 
Abbreviations:  ADL = activity of daily living 
 
6.1.3.2. 
Gastrointestinal Adverse Events 
Nausea 
Nausea is defined as a disorder characterized by a queasy sensation and/or the urge to vomit.  
Table 3 summarizes the CTCAE Criteria (Version 4.0) for nausea and the appropriate actions to 
be followed. 
 


 
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Table 3 
CTCAE Criteria and Appropriate Actions for Nausea 
CTCAE 
Grade 
Event Definition 
Action Required 
1 
Loss of appetite without alteration in 
eating habits 
No action required 
2 
Oral intake decreased without 
significant weight loss, dehydration, 
or malnutrition 
Concomitant anti-emetics may initially be 
administered without dose reduction.  If 
Grade 2 nausea persists and is intolerable, 
dose reduction and re-escalation should 
follow Grade 2 Dose Reduction and Dose Re-
escalation guidelines 
3 
Inadequate oral caloric or fluid 
intake; tube feeding, TPN, or 
hospitalization indicated 
Supportive care regimen should follow local 
standard of care.  Follow Dose Reduction and 
Dose Re-escalation guidelines 
Source:  NCI CTCAE Version 4.0 
Abbreviation: CTCAE = Common Terminology Criteria for Adverse Events; TPN = total parenteral nutrition 
 
Vomiting 
Vomiting is defined as a disorder characterized by the reflexive act of ejecting the contents of the 
stomach through the mouth.  Table 4 summarizes the CTCAE Criteria (Version 4.0) for vomiting 
and the appropriate actions to be followed. 
Table 4 
CTCAE Criteria and Appropriate Actions for Vomiting 
CTCAE 
Grade 
Event Definition 
Action Required 
1 
Vomiting 1 to 2 episodes (separated 
by 5 minutes) in a 24-hour period 
No action required 
2 
Vomiting 3 to 5 episodes (separated 
by 5 minutes) in a 24-hour period 
Concomitant anti-emetics may initially be 
administered without dose reduction.  If Grade 2 
vomiting persists and is intolerable, dose reduction 
should follow Grade 2 Dose Reduction and Dose 
Re-escalation guidelines  
3 
Vomiting ≥ 6 episodes (separated by 
5 minutes) in a 24-hour period; tube 
feeding, TPN, or hospitalization 
indicated 
Dose reduction follows Grade 3 Dose Reduction 
and Dose Re-escalation guidelines 
4 
Life-threatening consequences; 
urgent intervention indicated 
Discontinue orteronel  
Source:  CTCAE Version 4.0 
Abbreviation: CTCAE = Common Terminology Criteria for Adverse Events; TPN = total parenteral nutrition 
 


 
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Note:  It is possible that nausea and vomiting could be secondary to acute adrenal insufficiency, 
e.g., caused by sudden cessation of prednisone dosing.  If nausea and vomiting occur in the 
setting of severe fatigue, prostration, or hypotension, blood should be obtained to check the 
electrolytes.  Institutional standard of care should be followed in the presence of electrolytes 
imbalance.  Even if the vomiting occurs shortly following the study drug dose, no re-dosing of 
study drug will be done. 
Diarrhea 
Patients should be treated according to institutional standard of care.  Fluid intake should be 
maintained to avoid dehydration. 
Diarrhea is defined as a disorder characterized by frequent and watery bowel movements.  Table 
5 summarizes the CTCAE Criteria (Version 4.0) for diarrhea and the appropriate actions to be 
followed. 
 
Table 5 
CTCAE Criteria and Appropriate Actions for Diarrhea 
CTCAE 
Grade 
Event Definition 
Action Required 
1 
Diarrhea increase of < 4 stools per 
day over baseline; mild increase in 
ostomy output compared to baseline 
No action needed 
2 
Increase of 4 to 6 stools per day over 
baseline; moderate increase in ostomy 
output compared to baseline 
Concomitant anti-diarrheal agents may initially 
be administered without dose reduction.  If 
Grade 2 diarrhea persists, dose reduction should 
follow Grade 2 Dose Reduction and Dose 
Re-escalation guidelines 
Supportive care regimen should follow local 
standard of care 
3 
Increase of ≥ 7 stools per day over 
baseline; incontinence ~ 
hospitalization indicated; severe 
increase in ostomy output compared 
to baseline; limiting self care ADL 
Dose reduction follows Grade 3 Dose 
Reduction and Dose Re-escalation guidelines 
4 
Life-threatening consequences; 
urgent intervention indicated 
Discontinue orteronel  
Source:  CTCAE Version 4.0 
Abbreviation: CTCAE = Common Terminology Criteria for Adverse Events; TPN = total parenteral nutrition 
 
6.1.3.3. 
Hyperglycemia 
Androgen deprivation has been associated with the new onset of diabetes. 


 
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If the patient has a medical history of diabetes mellitus (type I or type II), the patient’s diabetes 
should be followed frequently per local standard of care.  A physician experienced in the 
management of diabetes should be involved in the patient’s care.  Patients should be counseled 
for the importance of diet and compliance with diabetic treatment throughout the study; any 
change in symptoms or home glucose monitoring results should be reviewed at each scheduled 
visit, and the patient should be encouraged to follow up as required with the physician managing 
the patient’s diabetes.  The physician managing the patient’s diabetes should be informed 
whether the patient is on or has recently started any prednisone therapy. 
Changes in diabetic medication should be supervised by or be based on consultation with the 
physician managing the patient’s diabetes. 
At baseline, if the HbA1c concentration is >7%, the patient should be referred for further 
assessment to ensure adequate or improved diabetes control while on study.  During the study 
treatment, if there is an increase in HbA1c of 1.5% above baseline or to >8.0%, the patient should 
be referred to the physician managing the patient’s diabetes for additional management support.  
The management of hyperglycemia or diabetes should be addressed before considering study 
drug reduction or hold. 
Worsening of diabetic control is often associated with acute or chronic infection, other acute 
illness, new medication (diuretics or beta blockers), or electrolyte abnormalities (hypokalemia).  
Assessment for these underlying precipitating factors should always be considered in addition to 
adjusting the diabetes treatment regimen. 
Table 6 presents the guidelines that apply to either new onset or previously diagnosed diabetes. 


 
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Table 6 
CTCAE Criteria and Appropriate Actions for Hyperglycemia 
Grade 
Event Definition 
Action Required 
1 
Fasting glucose value > 130 up to 160 
mg/dL;  
Fasting glucose value > 6.0 up to 8.9 mmol/L 
Review compliance with diabetic medications, check 
HbA1c.  Refer the patient to a physician experienced 
with management of the diabetes if HbA1c is > 7.0%.  
No dose modification is required.  
2 
Fasting glucose value > 160-250 mg/dL;  
Fasting glucose value > 8.9-13.9 mmol/L 
Check HbA1c.  If > 7.0%, make sure that the patient 
is currently under care of a physician experienced 
with management of the diabetes and refer the patient 
to that physician for evaluation.  Seek precipitating 
cause(s).  Reassess after 2 weeks.  No dose 
modification is required. 
3 
> 250-500 mg/dL;  > 13.9-27.8 mmol/L; 
hospitalization indicated 
Review and assure treatment of precipitating causes, 
including new infections or hypokalemia.  If blood 
glucose does not improve to Grade ≤ 2, hold orteronel 
for 2 weeks then reassess.  Monitor patient for signs 
and symptoms of adrenal insufficiency.  If the 
hyperglycemia event was precipitated by a well-
defined intercurrent event, orteronel may be resumed 
at the same dose, if blood glucose improves to Grade 
≤2.  Otherwise, orteronel should be resumed at the 
reduced dose (200 mg BID). 
4 
> 500 mg/dL; > 27.8 mmol/L;  
life-threatening consequences 
Discontinue orteronel.  
Source:  CTCAE Version 4.0 
Abbreviations:  BID = twice daily; HbA1c = glycosylated hemoglobin 
 
6.1.3.4. 
Hypertension 
Management of orteronel dosing for different stages of hypertension is outlined in Table 7. 
Worsening or new onset hypertension may be part of the natural history of the patients’ 
hypertensive disease, but may also be related to increased adrenal mineralocorticoid activity as a 
result of increased ACTH secretion induced by relatively nonspecific inhibition of 17-
hydroxylase.  Reduced potassium or increased serum sodium may be additional indicators of 
increased mineralocorticoid effect. 
If new onset or worsening of established hypertension occurs and the potassium level is 
<3.5 mEq/L in the absence of other causes such as new diuretic therapy, it suggests a 
orteronel-related mineralocorticoid syndrome.  A plasma renin activity that is undetectable or 
low also suggests such a syndrome rather than a secondary cause.  While addressing either 
underlying factors or compliance with current antihypertensives, dosing of orteronel should be 
followed as outlined in Table 7. 
 


 
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Table 7 
Criteria and Appropriate Actions for Hypertension 
CTCAE 
Grade 
Event Definition 
Action Required 
1 
Pre-hypertension (systolic BP 120 to 
139 mmHg or diastolic BP 80 to 89 mmHg) 
No dose modification needed; increase 
the frequency of BP monitoring as 
necessary 
2 
Stage 1 hypertension (systolic BP 140 to 
159 mmHg or diastolic BP 90 to 99 mmHg); 
medical intervention indicated;  
recurrent or persistent (≥24 hrs); 
symptomatic increase by >20 mmHg 
(diastolic) or to >140/90 mmHg if previously 
within normal limits (WNL); monotherapy 
indicated. 
Concomitant anti-hypertensive agents 
may initially be administered without 
dose reduction.  If Grade 2 hypertension 
persists, dose reduction should follow 
guidelines in Section 6.1.1.2. 
Supportive care regimen should follow 
local standard of care 
3 
Stage 2 hypertension (systolic BP 
≥160 mmHg or diastolic BP ≥100 mmHg); 
medical intervention indicated;  
more than 1 drug or more intensive therapy 
than previously used indicated 
Interrupt orteronel treatment and follow 
the guidelines in Section 6.1.1.1. 
Supportive care regimen should follow 
local standard of care 
4 
Life-threatening consequences (eg, 
malignant hypertension, transient or 
permanent neurologic deficit, hypertensive 
crisis); urgent intervention indicated 
Discontinue orteronel 
Supportive care regimen should follow 
local standard of care 
Source:  CTCAE Version 4.0 
Abbreviations:  BP = blood pressure; WNL = within normal limits 
 
6.1.3.5. 
Possible or Suspected Adrenal Insufficiency 
If patients experience adrenal insufficiency, the adrenal insufficiency will have the more 
nonspecific manifestations of glucocorticoid insufficiency, rather than the more specific 
electrolyte abnormalities of mineralocorticoid insufficiency.  Patients experiencing severe 
physiological stress (eg, surgery, severe infection) should be carefully monitored for adrenal 
insufficiency.  Concomitant medications may complicate the picture of adrenal insufficiency, in 
particular in patients who are on beta-blockers or diuretics.  Concomitant illness such as 
infection might similarly trigger or worsen symptoms of otherwise mild adrenal insufficiency. 
Grading of adrenal insufficiency, the clinical manifestations associated with the specific grade, 
and management and dosing modifications of orteronel are provided in Table 8.  In all cases, 
actions should include a thorough review for other possible causes or contributors to the 
presenting symptoms (eg, infection, anemia, or newly introduced concomitant medications). 
 


 
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Table 8 
Criteria and Appropriate Actions for Adrenal Insufficiency 
Severity 
Symptoms/Signs 
Action Required/Study Drug Modifications 
Possible mild 
insufficiency 
Chronic Grade 1 or Grade 2 fatigue, 
anorexia 
<5% weight loss 
BP normal, possible mild orthostatic 
hypotension 
Weight loss 
Review medications, check electrolytes, cortisol, 
and ACTH concentrations 
Continue study drug as per protocol  
Possible or 
probable moderate 
adrenal 
insufficiency, 
acute or chronic 
Grade 2 or 3 fatigue, anorexia, 
intermittent nausea and vomiting, 
orthostatic lightheadedness, or weakness 
Weight loss 
Definite orthostatic hypotension or 
below baseline supine BP 
Possible hyponatremia 
Interrupt dosing of orteronel 
Review medications, check electrolytes, cortisol, 
and ACTH concentrations 
Review medications and new diuretic use 
Dose reduction follows Grade 3 guidelines in 
Section 6.1.1.1. 
Discuss with Medical Monitor before restarting 
orteronel 
Possible or 
probable severe 
chronic or acute 
adrenal 
insufficiency 
Grade 3 fatigue, definite anorexia, 
nausea and vomiting,  
Severe orthostatic symptoms 
Prostration 
Nausea and/or vomiting 
Hypotension at rest and unable to stand 
due to orthostatic hypotension, possible 
hyponatremia 
Interrupt dosing of orteronel 
Manage in an acute care facility 
Administer IV hydrocortisone and 
electrolyte/volume replacement 
Review medications, check electrolytes, cortisol, 
and ACTH concentrations 
Dose reduction follows Grade 3 guidelines 
(Section 6.1.1.1) if a reversible precipitating cause 
can be identified and reversed.  Discuss with 
Medical Monitor before restarting orteronel 
Discontinue orteronel permanently if a reversible 
precipitating cause cannot be identified and 
reversed or in the event of Grade 4 toxicity 
Sources:  Arlt and Allolio, 2003, Fauci, 2008, and Salvatori, 2005 
Abbreviations:  ACTH = adrenocorticotropic hormone; BP = blood pressure; IV = intravenous. 
 
6.1.3.6. 
Rash (Acneiform or Maculopapular, Localized or Generalized) 
Acneiform rash is defined as a disorder characterized by an eruption of papules and pustules, 
typically appearing in face, scalp, upper chest, and back.  Maculopapular rash is defined as a 
disorder characterized by the presence of macules (flat) and papules (elevated).  Also known as 
morbilliform rash, it is one of the most common cutaneous AEs. 
Other types of dermatitis may occur during study treatment; some may require dose modification 
and supportive care. 
Orteronel should be immediately discontinued in a patient experiencing Grade 3 or 4 Stevens-
Johnson Syndrome. 


 
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Table 9 presents the CTCAE Criteria (Version 4.0) for rash and the appropriate actions to be 
followed. 
Table 9 
CTCAE Criteria and Appropriate Actions for Rash (Acneiform or 
Maculo-papular, Localized or Generalized) 
CTCAE 
Grade 
AE 
Event Definition 
Action Required 
1 
Acneiform Rash 
Papules and/or pustules 
covering < 10% BSA, 
which may or may not be 
associated with 
symptoms of pruritus or 
tenderness 
No dose reduction is necessary. 
Topical steroids and/or antibiotics as 
necessary.  Reassess after 2 weeks. 
 
Maculo-papular 
Rash 
Macules/papules covering 
< 10% body surface area 
(BSA) with or without 
symptoms (eg, pruritus, 
burning, tightness) 
No dose reduction is necessary. 
Topical steroids and/or antibiotics as 
necessary.  Reassess after 2 weeks. 
2 
Acneiform Rash 
Papules and/or pustules 
covering 10% to 30% 
BSA, which may or may 
not be associated with 
symptoms of pruritus or 
tenderness; associated 
with psychosocial impact; 
limiting instrumental 
ADL 
Follow guidelines for intolerable Grade 2 
toxicity (Section 6.1.1.2). 
Topical steroids and/or antibiotics as 
necessary.  Other types of systemic 
treatment such as antihistamine may be 
required.  Repeat incidence of Grade 2 
skin rash may require prophylactic 
antihistamine treatment. 
 
Maculo-papular 
Rash 
Macules/papules covering 
10% to 30% BSA with or 
without symptoms (eg, 
pruritus, burning, 
tightness); limiting 
instrumental ADL 
Follow guidelines for intolerable Grade 2 
toxicity (Section 6.1.1.2). 
Topical steroids and/or antibiotics as 
necessary.  Other types of systemic 
treatment such as antihistamine may be 
required.  Repeat incidence of Grade 2 
skin rash may require prophylactic 
antihistamine treatment. 


 
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CTCAE 
Grade 
AE 
Event Definition 
Action Required 
3 
Acneiform Rash 
Papules and/or pustules 
covering >30% BSA, 
which may or may not be 
associated with 
symptoms of pruritus or 
tenderness; limiting self 
care ADL; associated 
with local super-infection 
with oral antibiotics 
indicated 
Follow guidelines for Grade 3 toxicities 
in Section 6.1.1.1. 
Systemic treatment may be considered, 
including the use of short-term oral 
steroid (eg, prednisone up to 20 mg), 
tapering over 7 to 10 days.  Monitor 
signs of GI AEs when prednisone dose is 
increased.  Before adding another oral 
steroid, consider other options including 
a combination of topical and oral 
treatment. 
3 
Maculo-papular 
Rash 
Macules/papules covering 
>30% BSA with or 
without associated 
symptoms; limiting self 
care ADL 
Follow guidelines for Grade 3 toxicities 
in Section 6.1.1.1. 
Systemic treatment may be considered, 
including the use of short-term oral 
steroid (eg, prednisone up to 20 mg), 
tapering over 7 to 10 days.  Monitor 
signs of GI toxicity when prednisone 
dose is increased.  Before adding an oral 
steroid, consider other options including 
a combination of topical and oral 
treatment. 
4 
Acneiform Rash 
Papules and/or pustules 
covering any % BSA, 
which may or may not be 
associated with 
symptoms of pruritus or 
tenderness and are 
associated with extensive 
super-infection with IV  
antibiotics indicated life-
threatening consequences  
Discontinue orteronel.   
 
Maculo-papular 
Rash 
Not applicable 
 
Source:  CTCAE Version 4.0 
Abbreviations:  ADL = activities of daily living; BSA = body surface area; GI = gastrointestinal; 
IV = intravenous 
 
6.1.3.7. 
Renal Disorders 
The toxicity grade of acute renal injury will be assessed based on the serum creatinine level.  
Other clinical signs and symptoms, including proteinuria and hematuria, as detected by 
qualitative or quantitative laboratory tests, may be monitored in addition to creatinine value. 


 
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Table 10 presents the appropriate actions to be followed in the event of increased creatinine. 
 
Table 10 
Orteronel Treatment Modification for Acute Renal Disorder 
CTCAE 
Grade 
Event Definition 
Action Required 
1 
Creatinine level increase of 
>0.3 mg/dL; creatinine 1.5 to 2 times 
above baseline 
Evaluate patient for urinary tract infection, 
volume depletion or sub (acute) obstruction.  
If creatinine remains ≤2 times above 
baseline, no dose adjustment is required. 
2 
Creatinine >2 to 3 times above 
baseline 
Evaluate patient for urinary tract infection, 
volume depletion or sub(acute) obstruction.  
Hold study drug for 2 weeks.  Resume at 
reduced dose level (200 mg BID) once 
creatinine is ≤2 times baseline.  If the event 
recurs, discontinue orteronel. 
3 
Creatinine >3 times baseline or 
>4.0 mg/dL; hospitalization indicated 
Hold study drug until the patient is 
discharged from the hospital and creatinine 
level has recovered to <2 times baseline.  
Follow guidelines for Grade 3 toxicities in 
Section 6.1.1.1. 
4 
Life-threatening consequences;  
dialysis indicated 
Discontinue orteronel permanently. 
Source:  CTCAE Version 4.0 
 
6.1.3.8. 
Abnormal Liver Function Tests 
The incidence of liver function abnormalities is expected to be low.  Grade 2 or 3 abnormal liver 
function tests (LFTs) that are considered by the investigator to be possibly related to orteronel 
administration should be managed as appropriate, using Table 11 as a guide.  A decision to re-
challenge and/or resume dosing at a lower dose should be reviewed with the Monitor in all cases. 


 
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Table 11 
Management of Abnormal AST and ALT Bearing a ≥ Possible Relationship 
to Orteronel Treatment 
AST and/or ALT 
Elevation Grade 
(per NCI CTCAE) 
Concurrent 
Bilirubin Level 
Required Orteronel Dose Modification 
Grade 1 
≥1.5 × ULN 
Hold until bilirubin resolves to <1.5 X ULN 
Reduce dose to 200 mg BID, if receiving 
300 mg BID, otherwise discontinue orteronel 
Grade 2 
<1.5 × ULN 
Hold until ALT/AST resolve to Grade 1 
Reduce dose to 200 mg BID, if receiving 
300 mg BID, otherwise discontinue orteronel 
Grade 2 
≥1.5 × ULN 
Discontinue orteronel 
Grade 3/4 
Any 
Discontinue orteronel 
Note:  Following orteronel dose de-escalation due to AST/ALT and/or bilirubin abnormalities, no re-escalation is permitted. 
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; BID = twice daily; NCI CTCAE = National 
Cancer Institute Common Terminology Criteria for Adverse Events; ULN = upper limit of normal 
 
7. 
STUDY ASSESSMENTS AND TREATMENT 
7.1. 
Overview 
All patients should visit the study center on the days specified within this protocol.  The 
complete schedule of assessments is presented in Appendix E. 
7.2. 
Pre-Screening 
Patients must sign a pre-screening ICF and provide an archived tumor sample from a primary 
biopsy or metastatic lesion for centralized testing of AR expression.  Those with AR expression 
≥10% are eligible for entry into the main study.  Patients may enroll based on local laboratory 
AR assessment, but will need to submit tissue for confirmation at the central laboratory. 
7.3. 
Full Screening 
Consent for the main study must be obtained ≤28 days prior to the initiation of study treatment.  
The baseline assessments described in Appendix E will be collected prior to the initiation of 
treatment.  Baseline ECHO/MUGA should be within 28 days of treatment. 
The physical examination, ECOG performance status, serum/urine pregnancy test (for women of 
child-bearing potential only), and complete blood counts (CBCs) should be done ≤7 days prior to 
initiation of treatment.  All other assessments should be performed ≤4 weeks prior to initiation of 
treatment. 
• Signed informed consent prior to any other study-related procedures 
• Medical history (including assessment of baseline signs and symptoms) 


 
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• Physical examination including measurements of height, weight, and vital signs 
(resting heart rate, blood pressure, respiratory rate, and oral temperature) 
• Eastern Cooperative Oncology Group Performance Status (ECOG) performance 
status (Appendix A) 
• Concomitant medication review at the time of informed consent 
• Complete blood count (CBC) including 3-part differential and platelets ) (may be 
done up to 72 hours prior to treatment) 
• Comprehensive metabolic profile (CMP) (Section 7.6.3) (may be done up to 
72 hours prior to treatment) 
• Fasting plasma glucose, insulin, c-peptide, and HbA1c (only in patients with a 
history of diabetes) 
• Serum amylase, lipase 
• Serum hormone levels:  estradiol, total and free testosterone, SHBG, ACTH, 
DHEA-S, and cortisol 
• Serum/urine pregnancy test (for women of childbearing potential only).  If done 
within 72 hours prior to treatment, this test need not be repeated on Cycle 1 Day 1. 
• 12-lead ECG 
• ECHO/MUGA 
• Urinalysis 
• CT scan of the chest/abdomen/pelvis 
• Bone scan, if clinically indicated 
• CT/MRI of the brain, if clinically indicated 
7.4. 
Treatment Assessments 
Study treatment will be given in 4-week (28-day) cycles (±5 days) for all patients. 
7.4.1. 
Day 1 of Each Cycle 
The following assessments will be performed on Day 1 of each cycle: 
• Medical history 
• Physical examination including measurements of weight and vital signs (resting 
heart rate, blood pressure, respiratory rate, and oral temperature) (weekly during 
Cycle 1 for Lead-in patients) 
• ECOG performance status 
• AE assessment (weekly during Cycle 1 for Lead-in patients) 
• Concomitant medication review (weekly during Cycle 1 for Lead-in patients) 
• CBC, including 3-part differential and platelets (Day 1 of each cycle ±3 days) 
(weekly during Cycle 1 for Lead-in patients)(need not be done on Cycle 1 Day 1 
if baseline was taken within 72 hours of that day) 


 
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• CMP (Day 1 of each cycle ±3 days) (weekly during Cycle 1 for Lead-in 
patients)(need not be done on Cycle 1 Day 1 if baseline was taken within 72 hours 
of that day) 
• Serum hormone levels:  estradiol, total and free testosterone, SHBG, ACTH, 
DHEA-S, and cortisol (Day 1 of Cycles 2, 4 and End of Treatment only [see 
Section 7.5]) 
• Serum amylase/lipase 
• Serum/urine pregnancy test (for women of childbearing potential only).  If the 
baseline reading was done within 72 hours of Cycle 1 Day 1, this test need not be 
repeated on that day. 
• Study drug compliance assessment 
7.4.2. 
Day 1 of Cycle 3 and Every Other Cycle Following (Cycles 5, 7, 9, etc), except 
where noted 
• Fasting plasma glucose, insulin, c-peptide, and HbA1c (only in patients with a 
history of diabetes) 
• 12-lead ECG 
• CT scan of the chest /abdomen/pelvis (only those scans abnormal at baseline need 
to be repeated) 
• Bone scan (if clinically indicated) 
• CT/MRI of the brain (if clinically indicated) 
7.5. 
End of Study Treatment 
Patients are permitted to continue treatment with orteronel until disease progression, or the 
patient is discontinued due to unacceptable toxicity or a decision to discontinue treatment by the 
patient or the study physician.  Patients will return to the study center ≤30 days after treatment 
ends for the following assessments: 
• Update of medical history 
• Physical examination including measurement of weight and vital signs 
• ECOG performance status 
• AE assessment 
• Concomitant medication review 
• Study drug compliance assessment 
• CBC, including 3-part differential and platelets 
• CMP 
• Fasting plasma glucose, insulin, c-peptide, and HbA1c (only in patients with a 
history of diabetes) 
• Serum hormone levels:  estradiol, total and free testosterone, SHBG, ACTH, 
DHEA-S, and cortisol 


 
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• Serum amylase/lipase 
• Urinalysis 
• CT scan of the chest /abdomen/pelvis, if no documented progressive disease and 
the last assessment was >8 weeks prior (only those scans abnormal at baseline 
need to be repeated) 
If treatment is discontinued because of toxicity or any other reason(s) at a treatment visit and no 
study treatment is administered, that visit may fulfill the End-of-Treatment Visit. 
After withdrawal from protocol treatment, patients must be followed for AEs for 30 calendar 
days after the last dose of study drug. 
7.6. 
Follow-Up 
7.6.1. 
Follow-Up After Discontinuing Study Treatment 
Patients discontinuing treatment for any reason other than progressive disease will be monitored 
for evidence of disease progression.  Disease progression will be assessed every 6 months for 
2 years and annually thereafter, up to a maximum of 5 years after the last patient has enrolled on 
the study.  Imaging scans will be done as clinically indicated for evaluation of any new 
symptoms and assessment for disease progression.  After disease progression is documented, 
patients will be followed as specified in Section 7.6.2. 
7.6.2. 
Follow-Up After Disease Progression 
After disease progression is documented, survival will be monitored every 6 months for 2 years 
and annually thereafter, up to a maximum of 5 years after the last patient has enrolled on the 
study.  Patients may be contacted during outpatient visits or by telephone. 
7.6.3. 
Comprehensive Metabolic Profile 
The following laboratory tests should be performed for each patient for assessment of CMP: 
• glucose 
• blood urea nitrogen (BUN) 
• creatinine 
• sodium 
• potassium 
• chloride 
• calcium 
• carbon dioxide (CO2) 
• alkaline phosphatase (ALP) 
• AST 
• ALT 
• total bilirubin 
• total protein 


 
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• albumin 
8. 
DRUG FORMATULATION, AVAILABILITY, ADMINISTRATION AND 
TOXICITY INFORMATION 
8.1. 
Orteronel 
Investigational Product 
Dosage Form and Strength 
Manufacturer 
Orteronel 
100 mg tablets 
Takeda Pharmaceutical 
Company, Ltd 
Orteronel (chemical name, 6-[(7S)-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl]-N-
methyl-2-naphthamide) is manufactured by Takeda Pharmaceutical Company, Ltd, Osaka, 
Japan. 
Additional information can be found in the IB. 
8.1.1. 
Labeling, Packaging, and Supply 
Orteronel will be packaged in a round, white, high-density polyethylene (HDPE) bottles with a 
child-resistant cap and induction seal. Each bottle of active orteronel will be labeled with either a 
single-panel or multi-language booklet label containing pertinent study information, country-
specific requirements, and a caution statement. 
Orteronel will be supplied as pale red film-coated tablets.  Each bottle will contain 64 tablets and 
each tablet will contain 100 mg of orteronel. 
On Day 1 of each cycle, patients will be dispensed sufficient supplies until the next visit. 
All study drugs must be kept in a secure place under appropriate storage conditions.  Storage 
conditions for orteronel are included in the IB and on the product label. 
8.1.2. 
Preparation and Administration of Investigational Products 
Orteronel 
300 mg PO BID continuous daily dosing 
Patients will be instructed to take 300 mg orteronel (consisting of three 100-mg tablets at each 
administration) twice a day with or without food until discontinuation of study treatment/patient 
withdrawal.  The doses of study drug should be taken at the same time each day, approximately 
12 hours apart, but not less than 6 hours apart. 
Missed doses of study drug may be taken later, provided that the time of dosing is at least 
6 hours before the next scheduled dose.  Otherwise, patients should resume dosing at the next 
scheduled time with the prescribed dose.  Patients who experience Grade 1 or 2 nausea or 
vomiting may be advised to take the study drug with or following meals. 
On Day 1 of each Cycle, patients will be asked about any missed doses.  If a dose is missed, the 
missed dose will be recorded as “not taken.” 


 
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8.1.3. 
Accountability of Investigational Products 
The Principal Investigator (or designee) must maintain accountability for all study medication 
received and dispensed during his or her entire participation in the study.  Proper drug 
accountability includes, but is not limited to: 
• Continuously monitoring expiration dates if retest date is provided to the investigator 
• Frequently verifying that actual inventory matches documented inventory 
• Verifying that the drug accountability log is completed for the drug lot used to prepare 
each dose 
• Verifying that all containers used are documented accurately on the log 
• Verifying that required fields are completed accurately and legibly 
If any dispensing errors or discrepancies are discovered, SCRI Innovations must be notified 
immediately. 
The investigator must maintain a current inventory (drug accountability log) of all study 
medication delivered to the site, inventory at the site, and patients’ use records.  This log must 
accurately reflect the drug accountability of the study medication at all times.  The log should 
include all required information as a separate entry for each patient to whom study medication is 
dispensed. 
The sites should destroy any unused product at the end of the study (or expired product, if any, 
during the study), per the site's SOPs for doing so.  A certificate of destruction that includes a 
description of the supplies, quantity destroyed, and method of destruction should be returned to 
the Sponsor. 
9. 
RESPONSE EVALUATIONS AND MEASUREMENTS 
9.1. 
Definitions 
Response and progression will be evaluated in this study using the RECIST Version 1.1 
(Eisenhauer et al. 2009).  Lesions are either measurable or non-measurable using the criteria 
provided below.  The term “evaluable” in reference to measurability will not be used, as it does 
not provide additional meaning or accuracy. 


 
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9.2. 
Baseline Eligibility 
Measurable Disease: 
Tumor lesions:  Must be accurately measured in at least one dimension 
(longest diameter in the plane of measurement is to be recorded) with a 
minimum size of: 
• 
10 mm by CT scan (CT scan slice thickness no greater than 5 mm). 
• 
10 mm caliper measurement by clinical exam (lesions that cannot be 
accurately measured with calipers should be recorded as non-
measurable). 
• 
20 mm by chest x-ray. 
 
Skin lesions:  Documentation by color photography, including a ruler to 
estimate the size of the lesion, is recommended. 
 
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.  At baseline and in follow-up, only the short axis will be measured 
and followed.  
Non-Measurable Disease: 
All other lesions, including small lesions (longest diameter <10 mm or 
pathological lymph nodes with >10- to <15-mm short axis) as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include: 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory 
breast disease, lymphangitic involvement of skin or lung, abdominal masses, 
abdominal organomegaly identified by physical exam that is not measurable 
by reproducible imaging requirements.  
Target Lesions: 
The most reproducible 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), should be representative of all involved organs, and in 
addition should be those that lend themselves to reproducible repeated 
measurements.  Pathological nodes which are defined as measurable and that 
may be identified as target lesions must meet the criterion or a short axis of 
>15 mm by CT scan. 
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 as noted 
above, only the short axis is added into the sum.  The baseline sum diameters 
will be used as reference to further characterize any objective tumor 
response. 
Non-Target Lesions: 
All other lesions should be identified as non-target lesions at baseline.  
Measurements of these lesions are not required, but the presence or 
absence of each should be noted throughout follow-up. 
 
9.2.1. 
Guidelines for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation, using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment, as 
per protocol screening requirements. 


 
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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 when both methods have been 
used to assess the anti-tumor effect of a treatment. 
 
Clinical Lesions: 
Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes).  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: 
CT and MRI are the best currently available and reproducible methods to 
measure target lesions selected for response assessment.  Conventional CT 
and MRI should be performed with cuts of 10 mm or less in slice thickness, 
contiguously.  Spiral CT scan should be performed using a 5-mm contiguous 
reconstruction algorithm.  This applies to tumors of the chest, abdomen, and 
pelvis.  Head and neck tumors and those of extremities usually require 
specific protocols. 
Ultrasound: 
When the primary trial endpoint is objective response, ultrasound should not 
be used to measure tumor lesions.  It is, however, a possible alternative to 
clinical measurements of superficial palpable lymph nodes, subcutaneous 
lesions, and thyroid nodules.  Ultrasound may also be useful to confirm the 
complete disappearance of superficial lesions usually assessed by clinical 
examination. 
Endoscopy and Laparoscopy: 
Use of endoscopy and laparoscopy for objective tumor evaluation has not yet 
been fully and widely validated.  Therefore, use of these techniques for 
objective tumor response should be restricted to validation purposes in 
specialized centers.  Such techniques can be useful in confirming complete 
pathological response when biopsies are obtained. 
Tumor Markers: 
Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper limit of normal, they must normalize for a patient to 
be considered in complete clinical response when all lesions have 
disappeared. 
Cytology and Histology: 
Cytology and histology can be used to differentiate between PR and CR in 
rare cases (e.g., after treatment to differentiate between residual benign 
lesions and residual malignant lesions in tumor types such as germ cell 
tumors). 
 


 
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9.2.2. 
Response Criteria 
Evaluation of Target Lesions 
Complete Response (CR):  
Disappearance of all target lesions.   
Partial Response (PR):  
 
At least a 30% decrease in the sum of the longest diameter (LD) 
of target lesions, taking as reference the baseline sum LD. 
Stable Disease (SD):   
 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest 
(nadir) sum LD since the treatment started. 
Progressive Disease (PD):   
 
At least a 20% increase in the sum of the LD of target lesions, 
taking as reference the smallest (nadir) sum since the treatment 
started, or the appearance of one or more new lesions.  Requires 
not only 20% increase, but absolute increase of a minimum of 5 
mm over sum. 
 
Evaluation of Non-Target Lesions 
Complete Response (CR): 
Disappearance of all non-target lesions and normalization of 
tumor markers.  All lymph nodes must be non-pathological in 
size (<10 mm short axis). 
Stable Disease (SD):    
 
Persistence of one or more non-target lesions and/or persistence 
of tumor marker level above the normal limits. 
Progressive Disease (PD):  
 
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  When the patient 
also has measurable disease, to achieve “unequivocal 
progression” on the basis of the non-target disease, there must 
be an overall level of substantial worsening in non-target 
disease such that, even in presence of SD or PR in the target 
disease, the overall tumor burden has increased sufficiently to 
merit discontinuation of therapy. 
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).  In general, the patient’s best response 
assignment will depend on the achievement of both measurement and confirmation criteria.   
Confirmation of response (by repeat scans after 4 weeks or as specified in the protocol) is 
required for trials in which response rate is the primary endpoint, but is not required in 
randomized trials or trials with primary survival endpoints (i.e., where response is not a primary 
endpoint). 
 


 
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Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
NO 
CR 
CR 
SD 
NO 
PR 
CR 
NE 
NO 
PR 
PR 
SD OR NE 
NO 
PR 
SD 
SD OR NE 
NO 
SD 
PD 
ANY 
YES OR NO 
PD 
ANY 
PD 
YES OR NO 
PD 
ANY 
ANY 
YES 
PD 
 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue.  
When the evaluation of a CR depends upon this determination, it is recommended that the 
residual lesion be investigated by fine needle aspirate or biopsy to confirm the CR status.  
When nodal disease is included in the sum of target lesions, and the nodes decrease to “normal” 
size (<10 mm), they may still have a measurement reported on scans.  This measurement should 
be recorded even though the nodes are normal in order not to overstate progression, should it be 
based on increase in size of the nodes.  As noted earlier, this means that patients with CR may 
not have a total sum of “zero” on the eCRF. 
Non-Measurable Disease Only 
When a patient only has non-measurable disease:  this circumstance arises in some trials when it 
is not a criterion of study entry to have measurable disease.  The same general concepts apply 
here as noted above, however, in this instance; there is no measureable disease assessment to 
factor into the interpretation of an increase in non-measurable disease burden.  Because 
worsening in non-target disease cannot be easily quantified (by definition: if all lesions are truly 
non-measurable) a useful test that can be applied when assessing patients for unequivocal 
progression is to consider if the increase in overall disease burden based on the change in non-
measurable disease is comparable in magnitude to the increase that would be required to declare 
PD for measurable disease: i.e. an increase in tumor burden representing an additional 73% 
increase in ‘volume’ (which is equivalent to a 20% increase diameter in measurable lesion).  
Examples include an increase in a pleural effusion from ‘trace’ to ‘large’, an increase in 
lymphangitic disease from localized to widespread, or may be described in protocols as 
‘sufficient to require a change in therapy’.  If ‘unequivocal progression’ is seen, the patient 
should be considered to have had overall PD at that point.  While it would be ideal to have 
objective criteria to apply non-measureable disease, the very nature of that disease makes it 
impossible to do so; therefore the increase must be substantial. 


 
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10. 
STATISTICAL CONSIDERATIONS 
10.1. Statistical Design 
This is an open-label multicenter study to be conducted in 2 clinical stages.  All patients will 
receive orteronel PO at a dose of 300 mg twice daily (BID). 
Lead-in Phase:  The first 6 patients treated will be evaluated to confirm the safety and feasibility 
of this regimen.  All 6 patients will be followed weekly for toxicities during the first 4 weeks of 
treatment.  After all 6 patients complete at least 4 weeks of treatment, and if no prohibitive 
toxicities are identified, continuous study treatment will begin. 
Continuous Study Treatment:  Patients will continue to be enrolled into their respective cohorts, 
based on their tumor specificities, to either Cohort 1 (ER-/PR-/HER2-/AR+) or Cohort 2 (ER+ 
and/or PR+/AR+). 
10.2. Analysis Population 
The intent-to-treat (ITT) population will consist of all patients enrolled in the trial. Screen 
failures will not be included in the ITT population. 
The Safety population will consist of all patients receiving at least one dose of study drug. 
10.3. Sample Size Considerations 
Up to 86 patients will be enrolled into this study. 
Sample size computations are as follows for each patient cohort. 
Cohort 1:  For patients with ER-/PR-/HER2-/AR+ tumors, the expected response rate with 
standard anti-estrogen therapy is expected to be zero.  Therefore, a response rate of at least 10% 
with orteronel therapy would indicate activity and would lead to further investigation.  Assuming 
an evaluable population of 28 patients, the exact 95% confidence interval (CI) for a hypothesized 
response rate of 11% is (2.4%, 28.6%).  In order to incorporate an early stopping rule, Simon’s 
two-stage design is applied using alpha = 0.10 and power = 0.80 with comparison of the 
hypothesized response rate of 11% versus a conservative estimate of 2%.  Initially, 19 patients 
will be enrolled in this cohort, and if no responses are observed, recruitment to this cohort will 
stop.  Otherwise, enrollment in Cohort 1 will continue to full accrual of 28 evaluable patients.  
To account for an unevaluable rate of 10%, a total of 31 patients will be enrolled in this cohort. 
Cohort 2:  For patients with ER+ and/or PR+/AR+ tumors, published data on exemestane as 
third-line hormonal therapy in postmenopausal women indicate a response rate of 13% and a 
clinical benefit rate (CR, PR, or SD >24weeks) of 30%.  It is hypothesized that treatment with 
orteronel in this patient population will produce similar results.  Assuming an evaluable 
population of 50 patients, the exact 95% CI for a hypothesized response rate of 14% is (5.8%, 
26.7%).  In order to incorporate an early stopping rule, Simon’s two-stage design is applied using 
alpha = 0.10 and power = 0.80 with comparison of the hypothesized response rate of 14% versus 
a conservative estimate of 5.1%.  Initially, 26 patients will be enrolled in this cohort, and if one 
or no responses are observed, recruitment into this cohort will stop.  Otherwise, enrollment in 


 
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Cohort 2 will continue to full accrual of 50 evaluable patients.  To account for an unevaluable 
rate of 10%, a total of 55 patients will be enrolled in this cohort. 
10.4. Planned Interim Analyses 
Based on Simon’s two-stage design, each cohort individually will undergo an interim analysis 
for efficacy. 
Cohort 1: After enrollment of the first 19 evaluable patients and if no responses are observed, 
recruitment to this cohort will stop due to lack of efficacy.  Otherwise, enrollment will continue 
to full accrual of 28 evaluable patients.  If two or more patients exhibit response at the final 
analysis, the trial will be considered successful with respect to this patient population. 
Cohort 2: After enrollment of the first 26 evaluable patients and if one or no responses are 
observed, recruitment to this cohort will stop due to lack of efficacy. Otherwise, enrollment will 
continue to full accrual of 50 evaluable patients.  If five or more patients exhibit response at the 
final analysis, the trial will be considered successful with respect to this patient population. 
10.5. Statistical Analyses 
All statistical analyses will be performed using SAS 9.1.3 or the current version of SAS available 
at the time of analysis. 
In general, data will be listed and/or summarized and tabulated.  Descriptive statistics, such as 
means, median, standard deviation, minimum and maximum for continuous variables, and counts 
and percentages for discrete variables, will be used to summarize data as appropriate. 
10.6. Efficacy Measures 
The primary efficacy endpoints for both Cohort 1 and Cohort 2 are the RR and DCR. 
Secondary efficacy endpoints are PFS and OS.  
Efficacy analyses will include all patients in the ITT population. 
10.6.1. 
Primary Endpoints 
The RR is defined as the percentage of responders (CR+PR) among those patients who are 
evaluable for response. Response rate will be presented as the point estimate along with 95% 
confidence intervals calculated using both asymptotic normal approximation and exact binomial 
methods. 
The DCR is defined as the percentage of patients who do not exhibit progression (CR+PR+SD) 
among those patients who are evaluable for response at 6 months.  Disease control rate will be 
presented as the point estimate along with 95% confidence intervals calculated using both 
asymptotic normal approximation and exact binomial methods. 


 
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10.6.2. 
Secondary Endpoints 
Progression-free survival (PFS) and OS will be analyzed using Kaplan-Meier methods. Each of 
these endpoints will be presented graphically and further reported using the respective median 
time point estimate along with its 95% CI. 
PFS will be measured from the date of first protocol treatment until the date of objective disease 
progression or date of death is documented (event), or date of last adequate tumor assessment 
(censored). If a patient receives non-protocol therapy for the study indication prior to incurring 
an event, the earliest date of non-protocol treatment recorded will be used (censored). If no post-
treatment tumor assessment has been performed, PFS for the patient will be censored at time 
zero. 
OS will be measured from the date of first protocol treatment until the date of death is 
documented (event), or date last known alive (censored). If a patient receives non-protocol 
therapy for the study indication prior to incurring an event, the earliest date of non-protocol 
treatment recorded will be used (censored). 
10.7. Safety Review 
Treatment-related toxicity is the safety end point. 
All patients who received at least one dose of orteronel and who had at least one post baseline 
safety assessment will be evaluated for toxicity.  Patients enrolled, but never treated, will not be 
included in any of the safety analyses.  The actual dose and duration in days of orteronel as well 
as the dose intensity will be listed and summarized by descriptive statistics.  Assessment of 
safety will be based on the frequency of AEs and on the number of laboratory events that fall 
outside of predetermined ranges as assessed by the investigator.  The incidence of treatment-
emergent AEs will be summarized by system organ class, severity (NCI CTCAE, Version 4.0), 
type of AE, and relationship to study drug.  Any other pertinent information collected will be 
listed, as appropriate. 
Observed levels and changes from baseline will be examined for the following hormones at 
scheduled time point assessments (baseline, at Cycle 2 Day 1, Cycle 3 Day 1, and at the End-of-
Treatment Visit): serum estradiol, total and free testosterone, SHBG, ACTH, DHEA-S, and 
cortisol. 
10.8. Biomarkers 
Exploratory analysis will be conducted on archived tumor tissue for loss of PTEN and PIK3CA 
mutations (Section 5.2). 
11. 
SAFETY REPORT AND ANALYSES 
11.1. Safety Analyses 
Safety assessments will consist of monitoring and recording protocol-defined AEs and SAEs; 
measurement of protocol specified hematology, clinical chemistry, and urinalysis variables; 


 
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measurement of protocol-specified vital signs; and other protocol-specified tests that are deemed 
critical to the safety evaluation of the study drug. 
Investigators must report SAEs and follow-up information to their responsible Institutional 
Review Board (IRB) according to the policies of the responsible IRB. 
11.2. Adverse Events 
11.2.1. 
Definitions of Adverse Events 
An AE is the development of an undesirable medical condition, or the deterioration of a pre-
existing medical condition following or during exposure to a medicinal product, whether or not 
considered causally related to the product. 
An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs 
(e.g., tachycardia, enlarged liver), or the abnormal results of an investigation (e.g., laboratory 
findings). 
11.2.2. 
Recording of Adverse Events 
All AEs of any patient during the course of the trial will be reported in the case report form, and 
the investigator will give his or her opinion as to the relationship of the AE to study drug 
treatment (i.e., whether the event is related or unrelated to study drug administration).  If the AE 
is serious, it should be reported immediately to SCRI Innovations Safety Department.  Other 
untoward events occurring in the framework of a clinical trial are also to be recorded as AEs 
(i.e., AEs that occur prior to assignment of trial treatment that are related to a protocol-mandated 
intervention, including invasive procedures such as biopsies, medication washout, or no 
treatment run-in). 
All AEs regardless of seriousness or relationship to orteronel treatment (called trial treatment), 
spanning from the initiation of trial treatment, until 30 calendar days after discontinuation or 
completion of protocol-specific treatment as defined by the protocol for that patient, are to be 
recorded in the eCRF. 
11.2.3. 
Handling of Adverse Events 
All AEs resulting in discontinuation from the trial should be followed until resolution or 
stabilization.  Patients must be followed for AEs for 30 calendar days after discontinuation or 
completion of protocol-specific treatment (e.g., chemotherapy, radiation, oral medications, 
targeted therapy, and surgery).  All new AEs occurring during this period must be reported and 
followed until resolution unless, in the opinion of the investigator, the AE or laboratory 
abnormality/ies are not likely to improve because of the underlying disease.  In this case, the 
investigators must record his or her reasoning for this decision in the patient’s medical record 
and as a comment on the eCRF.  After 30 days of completion of protocol-specific treatment or 
discontinuation, only AEs, SAEs, or deaths assessed by the investigator as treatment related are 
to be reported. 


 
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11.3. Serious Adverse Events 
11.3.1. 
Definitions of Serious Adverse Events 
The definitions of SAEs are presented in this section.  The Principal Investigator is responsible 
for ensuring that all staff members involved in the study are familiar with the content of this 
section. 
An SAE or reaction is defined as any untoward medical occurrence that at any dose: 
• Results in death 
• Is immediately life-threatening (Refers to an AE in which the patient was at risk of 
death at the time of the event.  It does not refer to an event that hypothetically might 
have caused death, if it were more severe.) 
• Requires at least a 24-hour in-patient hospitalization or prolongation of existing 
hospitalization 
• Results in persistent or significant disability/incapacity (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions.) 
• Is a congenital anomaly/birth defect 
• Is a medically important event. 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the patient or may 
require intervention to prevent one of the other outcomes listed in the previous definition.  These 
should also usually be considered serious.  Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do 
not result in hospitalization; or development of drug dependency or drug abuse.  Progression of 
malignancy (including fatal outcomes), if documented by use of appropriate method (for 
example, as per RECIST criteria for solid tumors), should not be reported as an SAE. 
Treatment within or admission to the following facilities is not considered to meet the criteria of 
“in-patient hospitalization” (although if any other SAE criteria are met, the event must still be 
treated as an SAE and immediately reported): 
• Emergency Department or Emergency Room 
• Outpatient or same-day surgery units 
• Observation or short-stay unit 
• Rehabilitation facility 
• Hospice or skilled nursing facility 
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Hospitalization during the study for a pre-planned surgical or medical procedure (one which was 
planned prior to entry in the study), does not require reporting as a SAE to the SCRI Innovations 
Safety Department. 
11.3.2. 
Serious Adverse Event Reporting by Investigators 
It is important to distinguish between “serious” and “severe” AEs, as the terms are not 
synonymous.  Severity is a measure of intensity; however, an AE of severe intensity need not 
necessarily be considered serious.  For example, nausea which persists for several hours may be 
considered severe nausea, but may not be considered an SAE.  On the other hand, a stroke which 
results in only a limited degree of disability may be considered only a mild stroke, but would be 
considered an SAE.  Severity and seriousness should be independently assessed when recording 
AEs on the eCRF and SAEs on the SAE Report Form. 
Adverse events classified by the treating investigator as serious require expeditious handling and 
reporting to SCRI Innovations in order to comply with regulatory requirements.  Serious AEs 
occurring during the course of the study (spanning from the initiation of orteronel treatment 
through 30 days following the last dose of study medication) will be reported by the Investigator 
to SCRI Innovations Safety Department via fax or email, and are to be recorded in the eCRF.  If 
a patient experiences an SAE after signing the informed consent, but prior to receiving study 
drug, the event does not need to be recorded as an SAE unless the investigator feels the event 
may have been caused by a protocol procedure.  The SCRI Innovations Safety Department must 
be notified of all SAEs, regardless of causality, within 1 business day of the first knowledge of 
the event by the treating physician or research personnel.   
To report an SAE, the SAE Report Form should be completed with the necessary information.  
All SAEs occurring from the signing of consent until 30 calendar days of last study treatment 
must be reported to the Sponsor as SAEs on the SAE Report and followed until resolution (with 
autopsy report if applicable). 
Deaths and other SAEs occurring >30 calendar days after last study treatment that are deemed 
‘possibly’ or ‘probably’ related to orteronel must be reported as SAEs on the SAE Report within 
1 business day of first knowledge of the event by the treating physician or research personnel 
(with an autopsy report if available). 
Deaths occurring >30 calendar days after last study treatment and not attributed to study 
treatment (e.g., disease progression) need not be reported as SAEs, but simply captured on the 
appropriate eCRF. 
The SAE report should be sent to the SCRI Innovations Safety Department via fax or e-mail 
using the contact information listed below: 
SCRI Innovations Safety Department 
Fax #:  866-807-4325 
Safety Dept. Email:  CANN.SAE@scresearch.net 
Transmission of the SAE report should be confirmed by the site personnel submitting the report. 
Follow-up information for SAEs and information on non-serious AEs that become serious should 
also be reported to SCRI Innovations Safety Department as soon as it is available; these reports 


 
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should be submitted using the SCRI Innovations SAE Report Form.  The detailed SAE reporting 
process will be provided to the sites in the SAE reporting guidelines contained in the study 
reference manual. 
Investigators must report SAEs and follow-up information to their responsible Institutional 
Review Board (IRB) according to the policies of the responsible IRB. 
11.3.3. 
Sponsor SAE Reporting Requirements 
SCRI Development Innovations, LLC will forward SAE and pregnancy information to 
Millennium Pharmacovigilance within 1 business day of SCRI Innovations Safety Department 
personnel becoming aware of the SAE. 
Millennium Pharmacovigilance 
SAE and Pregnancy Reporting Contact Information: 
North America PPD, Inc. 
Safety and Medical Management, US 
Fax:  +1 888-488-9697 
Hotline number (available 24/7):  1-800-201-8725 
The Sponsor (SCRI Development Innovations, LLC) is responsible for reporting relevant SAEs 
to the competent authority, other applicable regulatory authorities, and participating 
investigators, in accordance with ICH guidelines, FDA regulations, and/or local regulatory 
requirements. 
11.4. Recording of Adverse Events and Serious Adverse Events 
Investigators should use correct medical terminology/concepts when recording AEs or SAEs on 
the SAE Report Forms and AE eCRF.  Avoid colloquialisms and abbreviations. 
All AEs, including those that meet SAE reporting criteria, should be recorded on the AE eCRF; 
AEs that meet the definition of an SAE should additionally be reported following the procedures 
noted in Section 11.3.2. 
11.4.1. 
Diagnosis versus Signs and Symptoms 
All AEs should be recorded individually in the patient’s own words (verbatim) unless, in the 
opinion of the Principal Investigator or designated physician, the AEs constitute components of a 
recognized condition, disease, or syndrome.  In the latter case, the condition, disease, or 
syndrome should be named rather than each individual sign or symptom.  If a constellation of 
signs and/or symptoms cannot be medically characterized as a single diagnosis or syndrome at 
the time of reporting, each individual event should be recorded as an AE or SAE as appropriate 
on the relevant form(s) (SAE Report Form and/or AE eCRF).  If a diagnosis is subsequently 
established, it should be reported as follow-up information is available.  If a diagnosis is 
determined subsequent to the reporting of the constellation of symptoms, the signs/symptoms 
should be updated to reflect the diagnosis. 
11.4.2. 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between patient evaluation 
time points.  Such events should only be recorded once on the SAE Report Form and/or the 


 
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AE eCRF.  If a persistent AE becomes more severe or lessens in severity, it should be recorded 
on a separate SAE Report Form and/or AE eCRF. 
A recurrent AE is one that occurs and resolves between patient evaluation time points, and 
subsequently recurs.  All recurrent AEs should be recorded on an SAE Report Form and/or 
AE eCRF. 
11.4.3. 
Abnormal Laboratory Values 
Any Grade 3 or 4 laboratory abnormalities or any clinically significant Grade 1 or 2 hematology 
or biochemistry laboratory value(s) should be recorded as an AE.  If an abnormal laboratory 
value or vital sign is associated with clinical signs and/or symptoms, the sign or symptom should 
be reported as an AE, and the associated laboratory value or vital sign should be considered 
additional information that must be collected on the relevant eCRF.  If the laboratory 
abnormality is a sign of a disease or syndrome, only the diagnosis needs to be recorded on the 
SAE Report Form or AE eCRF. 
11.4.4. 
Deaths 
For this protocol, observation of the clinical and laboratory AEs produced by orteronel is the 
primary efficacy endpoint. 
Deaths that occur during the protocol-specified AE reporting period that are attributed by the 
investigator solely to progression of disease will be recorded on the “Study Discontinuation” 
eCRF.  All other on-study deaths, regardless of attribution, will be recorded on an SAE Report 
and expeditiously reported to the SCRI Innovations Safety Department. 
When recording a SAE with an outcome of death, the event or condition that caused or 
contributed to the fatal outcome should be recorded as the single medical concept on the SAE 
report and Adverse Event page of the eCRF.  If the cause of death is unknown and cannot be 
ascertained at the time of reporting, record “Death NOS” on the eCRF Adverse Event page. 
11.4.5. 
Hospitalization, Prolonged Hospitalization, or Surgery 
Any AE that results in hospitalization of >24 hours or prolonged hospitalization should be 
documented and reported as an SAE unless specifically instructed otherwise in this protocol.  
There are some hospitalization scenarios that do not require reporting as an SAE when there is 
no occurrence of an AE (see Section 11.3.2). 
11.4.6. 
Pre-Existing Medical Conditions 
A pre-existing medical condition is one that is present at the start of the study.  Such conditions 
should be recorded on the General Medical History eCRF. A pre-existing medical condition 
should be recorded as an AE or SAE only if the frequency, severity, or character of the condition 
worsens during the study.  When recording such events on an SAE Report Form and/or 
AE eCRF, it is important to convey the concept that the pre-existing condition has changed by 
including applicable descriptors. 
11.4.7. 
Pregnancy, Abortion, or Birth Defects/Congenital Anomalies 
Pregnancy, abortion, birth defects, and congenital anomalies are events of special interest.  
Please refer to Section 11.5 for specific instructions. 


 
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11.4.8. 
New Cancers 
The development of a new primary cancer should be regarded as an AE and will generally meet 
at least one of the serious criteria (see Section 11.3).  New primary cancers are those that are not 
the primary reason for the administration of the study treatment and have developed after the 
inclusion of the patient into the study.  They do not include metastases of the original cancer.  
Symptoms of metastasis or the metastasis itself should not be reported as an AE/SAE, as they are 
considered to be disease progression. 
11.4.9. 
Lack of Efficacy 
When there is deterioration in the condition for which the study treatment is being used, there 
may be uncertainty as to whether this is lack of efficacy or an AE.  In such cases, unless the 
Sponsor or reporting physician considers the study treatment contributed to the deterioration of 
the condition, the deterioration should be considered lack of efficacy and not an AE. 
11.5. Protocol-Defined Events of Special Interest 
The following are events of special interest, and will need to be reported expeditiously (see 
Section 11.3.1): 
Pregnancy, Abortion, Birth Defects/Congenital Anomalies: 
If a patient becomes pregnant while enrolled in the study, a Pregnancy Form (a paper report 
form) should be completed and faxed to SCRI Innovations Safety Department.  SCRI 
Innovations Safety Department should be notified expeditiously, irrespective of whether or not it 
meets the criteria for expedited reporting.  Abortions (spontaneous, accidental, or therapeutic) 
must also be reported to SCRI Innovations Safety Department. 
If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, this must be reported to the SCRI Innovations Safety Department immediately.  Every 
effort should be made to follow the pregnancy for the final pregnancy outcome. 
Congenital anomalies/birth defects always meet SAE criteria, and should therefore be 
expeditiously reported as an SAE, using the previously described process for SAE reporting.  A 
Pregnancy Form should also have been previously completed, and will need to be updated to 
reflect the outcome of the pregnancy. 
Any of these events will be reported to Millennium Pharmacovigilance as presented in 
Section 11.3.3 
Orteronel Overdose 
Symptomatic and non-symptomatic overdose must be reported in the eCRF.  Any accidental or 
intentional overdose with the study treatment that is symptomatic, even if not fulfilling a 
seriousness criterion, is to be reported to the SCRI Innovations Safety Department immediately 
(within one day) using the corresponding screens in the eCRF, and following the same process 
described for SAE reporting (see Section 11.3.2) if the overdose is symptomatic. 
An overdose is defined as a dose of orteronel administered to a patient that is greater than the 
protocol-defined dose for the patient.  There is no experience with clinically significant 


 
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overdosage of orteronel.  In the event of drug overdose, the patient should be treated 
symptomatically, as appropriate.  Patients with possible manifestations of adrenal insufficiency 
may be treated acutely with parenteral or oral glucocorticoids as required and/or tolerated. 
11.6. Product Complaints 
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product.  Individuals who 
identify a potential product complaint situation should immediately contact MedComm Solutions 
(see below) and report the event.  Whenever possible, the associated product should be 
maintained in accordance with the label instructions pending further guidance from a Millennium 
Quality representative. 
For Product Complaints, 
call MedComm Solutions at 
877-674-3784 (877 MPI DRUG) 
(US and International) 
 
Product complaints in and of themselves are not AEs.  If a product complaint results in an SAE, 
an SAE form should be completed and sent to the SCRI Innovations Safety Department (refer to 
Section 11.3.2). 
12. 
ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS 
This study will be conducted according to the standards of Good Clinical Practice outlined in the 
ICH E6 Tripartite Guideline and CFR Title 21 part 312, applicable government regulations, 
institutional research policies and procedures and any other local applicable regulatory 
requirement(s). 
12.1. IRB Approval 
The study protocol, ICF, IB, available safety information, patient documents (e.g., study diary), 
patient recruitment procedures (e.g., advertisements), information about payments (i.e., PI 
payments) and compensation available to the patients and documentation evidencing the PI’s 
qualifications should be submitted to the IRB for ethical review and approval if required by local 
regulations, prior to the study start. 
The PI/Sponsor/CRO and/or designee will follow all necessary regulations to ensure appropriate, 
initial, and ongoing, IRB study review.  The PI/Sponsor (as appropriate) must submit and, where 
necessary, obtain approval from the IRB for all subsequent protocol amendments and changes to 
the informed consent document.  Investigators will be advised by the Sponsor or designee 
whether an amendment is considered substantial or non-substantial and whether it requires 
submission for approval or notification only to an IRB. 
Safety updates for orteronel will be prepared by Millennium or its representative as required, for 
submission to the relevant IRB. 


 
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12.2. Regulatory Approval 
As required by local regulations, the Sponsor will ensure all legal aspects are covered, and 
approval of the appropriate regulatory bodies obtained, prior to study initiation.  If required, the 
Sponsor will also ensure that the implementation of substantial amendment to the protocol and 
other relevant study documents happen only after approval by the relevant regulatory authorities. 
12.3. Insurance and Indemnity 
Details of insurance and/or indemnity will be contained within the written agreement between 
the PI or site and the Sponsor. 
12.4. Informed Consent 
Informed consent is a process by which a subject voluntarily confirms his or her willingness to 
participate in a particular study, after having been informed of all aspects of the study that are 
relevant to the subject's decision to participate.  Informed consent is documented by means of a 
written, signed, and dated informed consent form. 
The informed consent form will be submitted for approval to the IRB that is responsible for 
review and approval of the study.  Each consent form must include all of the relevant elements 
currently required by the FDA, as well as local county authority or state regulations and national 
requirements. 
Before recruitment and enrollment into the study, each prospective candidate will be given a full 
explanation of the study.  Once the essential information has been provided to the prospective 
candidate, and the investigator is sure that the individual candidate understands the implications 
of participating in this study, the candidate will be asked to give consent to participate in the 
study by signing an informed consent form.  A notation that written informed consent has been 
obtained will be made in the patient’s medical record.  A copy of the informed consent form, to 
include the patient’s signature, will be provided by the investigator to the patient. 
If an amendment to the protocol substantially alters the study design or the potential risks to the 
patients, the patient’s consent to continue participation in the study should be obtained. 
12.5. Confidentiality 
12.5.1. 
Patient Confidentiality 
Confidentiality of patient’s personal data will be protected in accordance with the Health 
Insurance Portability and Accountability Act of 1996 (HIPAA) and national data protection laws, 
as applicable.  HIPAA regulations require that, in order to participate in the study, a patient must 
sign an authorization from the study that he or she has been informed of following:  
• What protected health information (PHI) will be collected from patients in this study; 
• Who will have access to that information and why; 
• Who will use or disclose that information;  


 
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• That health information may be further disclosed by the recipients of the information, and 
that if the information is disclosed the information may no longer be protected by federal 
or state privacy laws;  
• The information collected about the research study will be kept separate from the 
patient’s medical records, but the patient will be able to obtain the research records after 
the conclusion of the study; 
• Whether the authorization contains an expiration date; and 
• The rights of a research patient to revoke his or her authorization.  
In the event that a patient revokes authorization to collect or use his or her PHI, the investigator, 
by regulation, retains the ability to use all information collected prior to the revocation of patient 
authorization.  For patients that have revoked authorization to collect or use PHI, attempts should 
be made to obtain permission to collect at least vital status (i.e., that the patient is alive) at the 
end of their scheduled study period. 
In compliance with ICH GCP guidelines and applicable parts of 21 CFR it is a requirement that 
the investigator and institution permit authorised representatives of Sponsor, the regulatory 
authorities and the IRB direct access to review the patient’s original medical records at the site 
for verification of study-related procedures and data.  
Measures to protect confidentiality include: only a unique study number and initials will identify 
patients on the eCRF or other documents submitted to the Sponsor.  This information, together 
with the patient’s date of birth, will be used in the database for patient identification.  Patient 
names or addresses will not be entered in the eCRF or database.  No material bearing a patient’s 
name will be kept on file by Sponsor.  Patients will be informed of their rights within the ICF. 
12.5.2. 
Investigator and Staff Information 
Personal data of the investigators and sub-investigators may be included in the SCRI Innovations 
database, and shall be treated in compliance with all applicable laws and regulations.  When 
archiving or processing personal data pertaining to the investigator or sub-investigator, SCRI 
Innovations shall take all appropriate measures to safeguard and prevent access to this data by 
any unauthorized party. 
12.6. Financial Information 
The finances for this study will be subject to a separate written agreement between the Sponsor 
and applicable parties.  Any Investigator financial disclosures as applicable to 21CFR Part 54 
shall be appropriately provided. 
13. 
RECORD RETENTION AND DOCUMENTATION OF THE STUDY 
13.1. Amendments to the Protocol 
Amendments to the protocol shall be planned, documented and signature authorized prior to 
implementation.   


 
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If an amendment to the protocol is required, the amendment will be originated and documented 
by the Sponsor.  All amendments require review and approval of all pharmaceutical companies 
and the Principal Investigator supporting the study.  The written amendment must be reviewed 
and approved by the Sponsor, and submitted to the IRB at the investigator’s facility for the 
board’s approval. 
Amendments specifically involving change to study design, risk to patient, increase to dosing or 
exposure, subject number increase, addition or removal of new tests or procedures, shall be 
reviewed and approved by the IRB at the Investigator’s facility. 
The amendment will be submitted formally to the FDA or other regulatory authorities by SCRI 
Innovations as applicable, after IRB approval and specifically when an increase to dosing or 
patient exposure and/or subject number has been proposed; or, when the addition or removal of 
an Investigator is necessitated. 
Items requiring a protocol amendment with IRB and/or FDA approval include, but are not 
limited to, the following: 
• Change to study design  
• Risk to patient 
• Increase to dose or patient exposure to drug  
• Subject number increase  
• Addition or removal of tests and / or procedures  
• Addition/removal of a new Investigator  
It should be further noted that, if an amendment to the protocol substantially alters the study 
design or the potential risks to the patients, their consent to continue participation in the study 
should be obtained. 
13.2. Documentation Required to Initiate Study 
Before the study may begin, certain documentation required by FDA regulations must be 
provided by the Investigator.  The required documentation should be submitted to: 
SCRI Innovations 
Attn:  Regulatory Affairs 
3322 West End Avenue, Suite 900 
Nashville, Tennessee  37203 
Regulatory Questions:  1-877-MY-1-SCRI 
Documents at a minimum required to begin a study in the US include, but are not limited to, the 
following: 
• A signature-authorized protocol and contract; 
• A copy of the official IRB approval of the study and the IRB members list; 
• Current Curricula Vita for the principal investigator and any associate investigator(s) 
who will be involved in the study; 


 
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• Indication of appropriate accreditation for any laboratories to be used in the study and a 
copy of the normal ranges for tests to be performed by that laboratory; 
• Original Form FDA 1572 (Statement of Investigator), appropriately completed and 
signed; 
• A copy of the IRB-approved consent form containing permission for audit by 
representatives of SCRI Innovations,   Novartis, the IRB, and the FDA;  
• Financial disclosure forms for all investigators listed on Form FDA 1572; 
• Site qualification reports, where applicable; 
• Verification of Principal Investigator acceptability from local and/or national debarment 
list(s). 
13.3. Study Documentation and Storage 
The Principal Investigator (PI) must maintain a list of appropriately qualified persons to whom 
he/she has delegated study duties and should ensure that all persons assisting in the conduct of 
the study are informed of their obligations.  All persons authorised to make entries and/or 
corrections on the eCRFs are to be included on this document.  All entries in the patient’s eCRF 
are to be supported by source documentation. 
Source documents are the original documents, data, records and certified copies of original 
records of clinical findings, observations and activities from which the patient’s eCRF data are 
obtained. These can include, but are not limited to, hospital records, clinical and office charts, 
laboratory, medico-technical department and pharmacy records, diaries, microfiches, ECG 
traces, copies or transcriptions certified after verification as being accurate and complete, 
photographic negatives, microfilm or magnetic media, X-rays, and correspondence. 
The PI and each study staff member is responsible for maintaining a comprehensive and 
centralized filing system (e.g., regulatory binder or investigator study file [ISF]) of all study-
related (essential) documentation, suitable for inspection at any time by representatives from the 
Sponsor and/or applicable regulatory authorities.  The ISF must consist of those documents that 
individually or collectively permit evaluation of the conduct of the study and the quality of the 
data produced.  The ISF should contain as a minimum all relevant documents and 
correspondence as outlined in ICH GCP Section 8 and 21 CFR Part 312.57, including key 
documents such as the IB and any amendments, protocol and any amendments, signed ICFs, 
copies of completed eCRFs, IRB approval documents, Financial Disclosure forms, patient 
identification lists, enrollment logs, delegation of authority log, staff qualification documents, 
laboratory normal ranges, records relating to the study drug including accountability records.  
Drug accountability records should, at a minimum, contain information regarding receipt, 
shipment, and disposition.  Each form of drug accountability record, at a minimum, should 
contain PI name, date drug shipped/received, date, quantity and batch/code, or lot number for 
identity of each shipment.  In addition, all original source documents supporting entries in the 
eCRF must be maintained and be readily available. 
The Sponsor shall maintain adequate investigational product records and financial interest 
records as per 21CFR Part 54.6 and Part 312.57 for no less than 2 years after the last marketing 
application has been approved by FDA; or, in the event that the marketing application has not 


 
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been approved by FDA, for no less than 2 years after the last shipment / delivery of the drug for 
investigational use is discontinued and FDA has been notified of the discontinuation. 
The Investigator shall maintain adequate records of drug disposition, case histories and any other 
study-related records as per 21 CFR Part 312.62 for no less than 2 years after the last marketing 
application has been approved by FDA; or, in the event that the marketing application has not 
been approved by FDA, for no less than 2 years after the last shipment / delivery of the drug for 
investigational use is discontinued and FDA has been notified of the discontinuation. 
To enable evaluations and/or audits from regulatory authorities or from the Sponsor or its 
representative, the investigator additionally agrees to keep records, including the identity of all 
participating patients (sufficient information to link records e.g., eCRFs and medical records), all 
original, signed informed consent forms, and copies of all eCRFs, SAE Reporting forms, source 
documents, detailed records of treatment disposition, and related essential regulatory documents.  
The documents listed above must be retained by the investigator for as long as needed to comply 
with national and international regulations (generally 2 years after discontinuing clinical 
development or after the last marketing approval).  SCRI Innovations will notify the 
investigator(s)/institutions(s) when the study-related records are no longer required. 
If the investigator relocates, retires, or for any reason withdraws from the study, both SCRI 
Innovations and its representative should be prospectively notified.  The study records must be 
transferred to an acceptable designee, such as another investigator, another institution, or to 
Sponsor.  The investigator must obtain the Sponsor’s written permission before disposing of any 
records, even if retention requirements have been met. 
13.4. Data Collection 
The electronic CRF is the primary data collection instrument for the study.  Case report forms 
will be completed using the English language and should be kept current to enable the Sponsor to 
review the patients’ status throughout the course of the study. 
In order to maintain confidentiality, only study number, patient number, initials and date of birth 
will identify the patient in the CRF.  If the patient’s name appears on any other document 
(e.g., laboratory report), it must be obliterated on the copy of the document to be supplied to 
SCRI Innovations and replaced instead with the patient number and patient’s initials.  The 
investigator will maintain a personal patient identification list (patient numbers with 
corresponding patient identifiers) to enable records to be identified and verified as authentic.  
Patient data/information will be kept confidential, and will be managed according to applicable 
local, state, and federal regulations. 
All data requested on the eCRF must be supported by and be consistent with the patient’s source 
documentation.  All missing data must be explained.  When a required laboratory test, 
assessment, or evaluation has not been done or an “Unknown” box is not an option on the eCRF, 
a note should be created verifying that the field was “Not Done” or “Unknown”.  For any entry 
errors made, the error(s) must be corrected, and a note explaining the reason for change should 
be provided. 


 
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The investigator will electronically sign and date the patient eCRF casebook indicating that the 
data in the eCRF has been assessed.  Each completed eCRF will be signed and dated by the PI, 
once all data for that patient is final. 
13.5. Study Monitoring, Auditing, and Inspecting 
The investigator will permit study-related monitoring, quality audits, and inspections by the 
Sponsor or its representative(s), government regulatory authorities, and the IRB of all study-
related documents (e.g., source documents, regulatory documents, data collection instruments, 
case report forms).  The investigator will ensure the capability for inspections of applicable 
study-related facilities.  The investigator will ensure that the study monitor or any other 
compliance or Quality Assurance reviewer is given access to all study-related documents and 
study-related facilities. 
At the Sponsor’s discretion Source Document Verification may be performed on all data items or 
a percentage thereof. 
Participation as an investigator in this study implies the acceptance of potential inspection by 
government regulatory authorities, the Sponsor or its representative(s). 
13.6. Quality Assurance and Quality Control 
Each study site shall be required to have Standard Operating Procedures (SOP’s) to define and 
ensure quality assurance/control processes for study conduct, data generation & collection, 
recording of data/documentation and reporting according to the protocol, GCP and any 
applicable local, national or international regulations. 
13.7. Disclosure and Publication Policy 
All information provided regarding the study, as well as all information collected/documented 
during the course of the study, will be regarded as confidential.  The Sponsor reserves the right 
to release literature publications based on the results of the study.  Results from the study will be 
published/presented as per the Sponsor’s publication strategy. 
Inclusion of the investigator in the authorship of any multicenter publication will be based upon 
substantial contribution to the design, analysis, interpretation of data, drafting and/or critically 
revising any manuscript(s) derived from the study.  The investigator acknowledges that the study 
is part of a multicenter study and agrees that any publication by the investigator of the results of 
the study conducted at research site shall not be made before the first multicenter publication.  In 
the event there is no multicenter publication within fifteen (15) months after the study has been 
completed or terminated at all study sites, and all data has been received, the investigator shall 
have the right to publish its results from the study, subject to the notice requirements described 
herein and subject to acknowledgement of the Sponsor as appropriate.  Investigator shall provide 
the Sponsor thirty (30) days to review a manuscript or any poster presentation, abstract or other 
written or oral material which describes the results of the study for the purpose only of 
determining if any confidential or patentable information is disclosed thereby.  If the Sponsor 
requests in writing, the investigator shall withhold any publication or presentation an additional 


 
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sixty (60) days solely to permit the Sponsor to seek patent protection and to remove any SCRI 
Innovations Confidential Information from all publications. 
  


 
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REFERENCES 
Arlt and Allolio, 2003 
Arlt W, Allolio B. Adrenal insufficiency. Lancet 2003;361(9372):1881-93. 
Basu et al. 2011 
Basu B, Ang JE, Crawley D, et al. Phase I study of Abiraterone Acetate in patients with estrogen 
receptor or androgen receptor postive advanced breast carcinoma resistant to standard endocrine 
therapies. J. Clin. Oncol. 2011. 29 (suppl; abstract 2525) 
Birrell et al. 1998 
Birrell SN, Hall RE, and Tilley WD.  Role of the Androgen Receptor in Human Breast Cancer.  J 
of Mammary Gland Biology and Neoplasia, 1998. 3(1):95-103. 
Carver et al. 2011 
Carver B, Chapinski C, Wongvipat J, Hieronymus H, Chen Y, et al. Reciprocal Feedback 
Regulation of PI3K and Androgen Receptor Signaling in PTEN-Deficient Prostate Cancer. 
Cancer Cell. 2011;19(5):575-86. 
Eisenhauer et al. 2009 
Eisenhauer E.A., et al. New response evaluation criteria in solid tumours; revised RECIST 
guideline (version 1.1). Eur J Cancer. 2009; 45 p. 228-47. 
Engelman, 2009 
Engelman JA. Targeting PI3K signaling in cancer: opportunities, challenges and limitations. Nat 
Rev Cancer. 2009;9:550–62. 
Fauci, 2008 
Fauci A, Kasper D, Longo D, Braunwald E, Hauser S, Jameson J, et al. Harrison's Principles of 
Internal Medicine, 17th Edition. Columbus, OH: McGraw-Hill; 2008. 
Gonzalez-Angulo et al. 2009 
Gonzalez-Angulo AM, Stemke-Hale K, Pall SL, Carey M, Anarwal, R, et al. Androgen Receptor 
Levels and Association with PIK3CA Mutations and Prognosis in Breast Cancer. Clin Cancer 
Res 2009;15:2472-8. 
Gucalp and Traina, 2010 
Gucalp A and Traina T.  Triple-negative Breast Cancer, Role of the Androgen Receptor. The 
Cancer Journal, 2010. 16(1):62-65. 
Gucalp et al. 2012 
Gucalp A, Tolaney SM, Isakoff SJ, et al. Targeting the androgen receptor (AR) in women with 
AR+ ER-/PR- metastatic breast cancer (MBC). J Clin Oncol 30, 2012 (suppl; abstr 1006). 


 
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Lehmann et al. 2011 
Lehmann, BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, et al.  Identification 
of human triple-negative breast cancer subtypes and preclinical models for selection of targeted 
therapies.  J Clin Invest. 2011;121(7):2750–67. 
Niemeier et al. 2010 
Niemeier LA, Dabbs DJ, Beriwal S, Striebel JM, and Bhargava R. Androgen receptor in breast 
cancer: expression in estrogen receptor-positive tumors and in estrogen receptor-negative tumors 
with apocrine differentiation. Mod Pathol. 2010;23:205–12. 
Salvatori, 2005 
Salvatori R. Adrenal insufficiency. JAMA 2005;294(19):2481-8. 
Traina et al. 2009 
Traina TA, Wolff AC, Giri D, Feigin K, Patil S, Yuan J, et al.  Androgen receptor inhibition can 
stabilize disease in patients with AT+, ER-/PR- metastatic breast cancer. ASCO 2009 Breast 
Cancer Symposium, Abstract 251. 


 
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APPENDICES 
 
Appendix A: 
ECOG Performance Status Criteria 
 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity. Fully active, able to carry on all pre-disease performance without restriction. 
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). 
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. 
3 
In bed >50% of the time.  Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  Totally confined to 
bed or chair. 
5 
Dead 
 


 
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Appendix B: Guidelines for Female Subjects of Child-Bearing Potential and 
Sexually-Active Male Subjects 
Women of Child-Bearing Potential are Defined as:  any female who has experienced 
menarche and does not meet the criteria for “Women Not of Childbearing Potential”. 
Women Not of Childbearing Potential are Defined as: 
• Women who are permanently sterilized (eg, tubal occlusion, hysterectomy, 
bilateral salpingectomy, bilateral oophorectomy) 
• Women who are >45 years-of-age, not using hormone-replacement therapy 
and who have experienced total cessation of menses for at least 1 year OR 
who have a follicle stimulating hormone (FSH) value >40 mIU/mL and an 
estradiol value <40 pg/mL (140 pmol/L) 
• Women who are >45 years-of-age, using hormone-replacement therapy and 
who have experienced total cessation of menses for at least 1 year OR who 
have had documented evidence of menopause based on FSH >40 mIU/mL 
and estradiol <40 pg/mL prior to initiation of hormone-replacement therapy 
Acceptable Contraception Methods:  Male patients with female partners of child-bearing 
potential and women patients of childbearing potential are required to use two forms of 
acceptable contraception, including one barrier method, during their participation in the trial and 
for 4 months following discontinuation of orteronel.  Male patients must also refrain from 
donating sperm for 4 months following discontinuation of orteronel. 
The following are acceptable forms of barrier contraception: 
• Latex condom, diaphragm or cervical/vault cap when used with spermicidal 
foam/gel/film/cream/suppository 
The following are acceptable forms of secondary contraception, when used with a barrier 
method and spermicide: 
• True abstinence.  Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception 
• Male sterilization (with the appropriate post-vasectomy documentation of the 
absence of sperm in the ejaculate) 
• Placement of an intrauterine device (IUD) or intrauterine system, with the 
exception of IUD progesterone T 
• Established use of oral, injected, or implanted hormonal methods of 
contraception 
Unacceptable Contraception Methods: for women of childbearing potential include: 
• IUD progesterone T 
• Female condom 
• Natural family planning (rhythm method) or breastfeeding 
• Fertility awareness 
• Withdrawal 
• Cervical shield 


 
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Appendix C: 
New York Heart Association (NYHA) Classifications 
Class 
Functional Capacity 
Objective Assessment 
I 
Patients with cardiac disease but without resulting limitations of 
physical activity.  Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain. 
No objective evidence of 
cardiovascular disease. 
II 
Patients with cardiac disease resulting in slight limitation of 
physical activity.  They are comfortable at rest.  Ordinary physical 
activity results in fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of minimal 
cardiovascular disease. 
III 
Patients with cardiac disease resulting in marked limitation of 
physical activity.  They are comfortable at rest.  Less than 
ordinary activity causes fatigue, palpitation, dyspnea, or anginal 
pain. 
Objective evidence of 
moderately severe 
cardiovascular disease. 
IV 
Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort.  Symptoms of heart failure 
or the anginal syndrome may be present even at rest.  If any 
physical activity is undertaken, discomfort is increased. 
Objective evidence of severe 
cardiovascular disease. 
Source:  The Criteria Committee of New York Heart Association.  Nomenclature and Criteria for Diagnosis of 
Diseases of the Heart and Great Vessels.  9th Ed. Boston, MA:  Little, Brown & Co; 1994:253-256. 


 
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Appendix D: 
List of QT Prolonging Drugs 
Drug 
QT risk(*) 
Comment 
Amiodarone 
known risk for TdP 
TdP risk regarded as low 
Arsenic trioxide 
known risk for TdP 
 
Astemizole 
known risk for TdP 
CYP3A4 substrate with narrow therapeutic index. 
Bepridil 
known risk for TdP 
 
Chloroquine 
known risk for TdP 
 
Chlorpromazine 
known risk for TdP 
 
Cisapride 
known risk for TdP 
CYP3A substrate with narrow therapeutic index. 
Disopyramide 
known risk for TdP 
 
Dofetilide 
known risk for TdP 
 
Domperidone 
known risk for TdP 
 
Droperidol 
known risk for TdP 
 
Halofantrine 
known risk for TdP 
 
Haloperidol 
known risk for TdP 
When given intravenously or at higher-than- 
recommended doses, risk of sudden death, QT 
prolongation and torsades increases. 
Ibutilide 
known risk for TdP 
 
Levomethadyl 
known risk for TdP 
Sensitive CYP3A substrate 
Mesoridazine 
known risk for TdP 
 
Methadone 
known risk for TdP 
 
Pentamidine 
known risk for TdP 
 
Pimozide 
known risk for TdP 
Sensitive CYP3A substrate with narrow therapeutic 
index 
Probucol 
known risk for TdP 
 
Procainamide 
known risk for TdP 
 
Quetiapine 
possible risk for TdP 
Sensitive CYP3A substrate 
Quinidine 
known risk for TdP 
Sensitive CYP3A substrate  
Sotalol 
known risk for TdP 
 
Sparfloxacin 
known risk for TdP 
 
Tacrolimus 
possible risk for TdP 
Sensitive CYP3A substrate with narrow therapeutic 
index 
Terfenadine 
Known risk for TdP 
Sensitive CYP3A substrate with narrow therapeutic 
index 
Thioridazine 
Known risk for TdP 
 
Vardenafil 
possible risk for TdP 
Sensitive CYP3A substrate 
(*) Classification according to the QTdrugs.org Advisory Board of the Arizona CERT 
Sensitive substrates: Drugs whose plasma AUC values have been shown to increase 5-fold or 
higher when co-administered with a potent inhibitor of the respective enzyme. 
 


 
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Appendix D: List of QT Prolonging Drugs (continued) 
Drug 
QT risk 
Alfuzosin 
possible risk for Torsades de Pointes 
Amantadine 
possible risk for Torsades de Pointes 
Amitriptyline 
conditional risk for Torsades de Pointes 
Azithromycin 
possible risk for Torsades de Pointes 
Chloral hydrate 
possible risk for Torsades de Pointes 
Citalopram 
conditional risk for Torsades de Pointes 
Clomipramine 
conditional risk for Torsades de Pointes 
Clozapine 
possible risk for Torsades de Pointes 
Desipramine 
conditional risk for Torsades de Pointes 
Diphenhydramine 
conditional risk for Torsades de Pointes 
Dolasetron 
possible risk for Torsades de Pointes 
Doxepin 
conditional risk for Torsades de Pointes 
Dronedarone 
possible risk for Torsades de Pointes 
Felbamate 
possible risk for Torsades de Pointes 
Flecainide 
possible risk for Torsades de Pointes 
Fluoxetine 
conditional risk for Torsades de Pointes 
Foscarnet 
possible risk for Torsades de Pointes 
Fosphenytoin 
possible risk for Torsades de Pointes 
Galantamine 
conditional risk for Torsades de Pointes 
Gatifloxacin 
possible risk for Torsades de Pointes 
Gemifloxacin 
possible risk for Torsades de Pointes 
Granisetron 
possible risk for Torsades de Pointes 
Imipramine 
conditional risk for Torsades de Pointes 
Indapamide 
possible risk for Torsades de Pointes 
Isradipine 
possible risk for Torsades de Pointes 
Levofloxacin 
possible risk for Torsades de Pointes 
Lithium 
possible risk for Torsades de Pointes 
Mexiletine 
conditional risk for Torsades de Pointes 
Moexipril/HCTZ 
possible risk for Torsades de Pointes 
Moxifloxacin 
possible risk for Torsades de Pointes 
Nicardipine 
possible risk for Torsades de Pointes 
Nortriptyline 
conditional risk for Torsades de Pointes 
Octreotide 
possible risk for Torsades de Pointes 
Ofloxacin 
possible risk for Torsades de Pointes 
Ondansetron 
possible risk for Torsades de Pointes 
Oxytocin 
possible risk for Torsades de Pointes 


 
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Appendix D: List of QT Prolonging Drugs (continued) 
Drug 
QT risk 
Paliperidone 
possible risk for Torsades de Pointes 
Paroxetine 
conditional risk for Torsades de Pointes 
Perflutren lipid microspheres 
possible risk for Torsades de Pointes 
Protriptyline 
conditional risk for Torsades de Pointes 
Ranolazine 
possible risk for Torsades de Pointes 
Risperidone 
possible risk for Torsades de Pointes 
Roxithromycin* 
possible risk for Torsades de Pointes 
Sertindole 
possible risk for Torsades de Pointes 
Sertraline 
conditional risk for Torsades de Pointes 
Solifenacin 
conditional risk for Torsades de Pointes 
Tizanidine 
possible risk for Torsades de Pointes 
Trazodone 
conditional risk for Torsades de Pointes 
Trimethoprim-Sulfa 
conditional risk for Torsades de Pointes 
Trimipramine 
conditional risk for Torsades de Pointes 
Venlafaxine 
possible risk for Torsades de Pointes 
Ziprasidone 
possible risk for Torsades de Pointes 
(*) Classification according to the QTdrugs.org Advisory Board of the Arizona CERT 


 
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Appendix E: 
Schedule of Assessments for BRE 203 
 
 
Procedures 
Pre-Treatment 
STUDY TREATMENT 
Cycle = 28 days 
End of 
Treat 
mentn 
 
Follow Up 
Prior to 
Progres 
siono 
 
 
Follow Up 
After 
Progres 
sionp 
 
 
Pre-
Screening 
Full 
Screeningg 
All 
Cycles  
Cycle 1 
Cycle 1 
Cycle 1 
Cycle 3 and Every 
Other Subsequent 
Cycle (5, 7, 9, etc) 
Day 1 
Day 8l 
Day 15l 
Day 22l 
Day 1 
Tests and Observations 
Informed Consent 
 
X 
 
 
 
 
 
 
 
 
Medical history 
 
X 
X 
 
 
 
 
X 
 
 
Physical examination, vital signs, height, weighta 
 
X 
X 
Xl 
Xl 
Xl 
 
X 
 
 
ECOG Performance Status 
 
X 
X 
 
 
 
 
X 
 
 
Adverse event evaluation 
 
 
X 
Xl 
Xl 
Xl 
 
X 
X 
 
Concomitant medication review 
 
X 
X 
Xl 
Xl 
Xl 
 
X 
 
 
Survival 
 
 
 
 
 
 
 
 
 
X 
Study Drug Compliance assessment 
 
 
Xi 
 
 
 
 
X 
 
 
Dispense Study Drug 
 
 
X 
 
 
 
 
 
 
 
Laboratory tests 
CBC, including 3-part differential and plateletsb 
 
X 
X 
Xl 
Xl 
Xl 
 
X 
 
 
CMPc 
 
X 
X 
Xl 
Xl 
Xl 
 
X 
 
 
Fasting plasma glucose, insulin, c-peptide, and 
HbA1c (for diabetic patients only)d 
 
X 
 
 
 
 
X 
X 
 
 
Serum Amylase/lipase 
 
X 
X 
 
 
 
 
X 
 
 
Serum Hormones: estradiol, total and free 
testosterone, SHBG, ACTH, DHEA-S, and cortisol 
 
X 
Xj 
 
 
 
 
X 
 
 
Pregnancy test (serum/urine) 
 
X 
Xk 
 
 
 
 
 
 
 
12-lead ECGe 
 
X 
 
 
 
 
X 
 
 
 
ECHO/MUGA 
 
X 
 
 
 
 
 
 
 
 
Urinalysis 
 
X 
 
 
 
 
 
        X 
 
 
Archived tumor tissuef 
X 
 
 
 
 
 
 
 
 
 
Disease Assessments 
CT scan of the chest, abdomen, pelvis 
 
X 
 
 
 
 
Xm 
Xm 
 
 
Bone scan 
 
       Xh 
 
 
 
 
Xh 
 
 
 
CT/MRI of the brain 
 
Xh 
 
 
 
 
Xh 
 
 
 


 
CONFIDENTIAL 
STUDY DRUG: Orteronel 
SCRI INNOVATIONS STUDY NUMBER:  BRE 203 
DATE OF PROTOCOL:  Version 3.0 30 October 2013 
Page 80 of 80 
Appendix E: Schedule of Assessments for BRE 203 (continued) 
a 
Physical examinations will include measurements of vital signs (resting heart rate, blood pressure, respiratory 
rate, oral temperature).  At the baseline visit only, height will also be recorded and weight will be recorded only 
on Day 1 of each cycle. 
b 
Hematological parameters include the following laboratory tests: complete blood count consisting of red blood 
cell count (RBCs), hemoglobin, total white blood count (WBC) with differential, and platelet count.  Do not 
repeat on C1D1, if baseline within 72 hours. 
c 
CMP assessment includes the following laboratory tests:  glucose, BUN, creatinine, sodium, potassium, chloride, 
calcium, CO2, alkaline phosphatase (ALP), AST, ALT, total bilirubin, total protein, and albumin.  Do not repeat 
on C1D1, if baseline within 72 hours. 
d 
Fasting plasma glucose, insulin, and c-peptide will be drawn at screening, predose on Day 1 of odd-numbered 
cycles (Cycles 3, 5, 7, etc), and at study completion for patients with a history of diabetes. 
e 
A single ECG will be obtained at baseline for QTcF interval assessment for all patients.  A single ECG will also 
be obtained predose on Cycle 3 Day 1 and then every 2nd cycle (Cycles 5, 7, 9, etc). 
f 
Archived tumor tissue from a primary biopsy or metastatic lesion is required for centralized testing of AR 
expression.  Patients with AR expression ≥10% will be screened for enrollment into the study.  Additional tumor 
tissue, if available from the patients enrolled on study, will be retained to perform correlative testing (15 to 20, 
4 um unstained slides).  Patients may enroll based on local laboratory AR assessment, but will need to submit 
tissue for confirmation at the central laboratory. 
g 
Informed consent must be obtained ≤28 days prior to the initiation of trial treatment.  The physical examination, 
ECOG performance status, serum/urine pregnancy test (for women of child-bearing potential only), and 
complete blood counts (CBCs) should be done ≤7 days prior to initiation of treatment. 
h 
If clinically indicated. 
i 
Day 1 of each cycle following Cycle 1 
j 
Serum hormone levels will be drawn at screening, on Day 1 of Cycles 2 and 4, and at the end of study visit. 
k 
Do not repeat on Cycle 1 Day 1, if baseline was done within 72 hours. 
l 
Lead-in patients only 
m If no documented progressive disease and the last assessment was >8 weeks prior.  Only abnormal scans at 
baseline need to be repeated. 
n 
All patients will undergo the end-of-treatment assessments listed within 30 days after treatment ends.  Patients 
must be followed for AEs for 30 calendar days after the last dose of study drug. 
o 
Patients discontinuing treatment for any reason other than progressive disease will be monitored for evidence of 
disease progression.  Disease progression will be assessed every 6 months for 2 years and annually thereafter, up 
to a maximum of 5 years after the last patient has enrolled on the study. Imaging scans will be done as clinically 
indicated for evaluation of any new symptoms and assessment for disease progression. 
p 
After disease progression is documented, survival will be monitored every 6 months for 2 years and annually 
thereafter, up to a maximum of 5 years after the last patient has enrolled on the study.  Patients may be contacted 
during outpatient visits or by telephone.