Conditions: Breast Cancer
Keywords: stage IV breast cancer recurrent breast cancer male breast cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 28
Healthy volunteers: no

Brief summary:
RATIONALE: Androgens can cause the growth of breast cancer cells. Antihormone therapy, such as bicalutamide, may stop the adrenal glands from making androgens.

PURPOSE: This phase II trial is studying how well bicalutamide works in treating patients with metastatic breast cancer.

Detailed description:
OBJECTIVES:

Primary

* Determine the 6-month efficacy rate of bicalutamide as first-, second-, or third-line therapy in patients with androgen receptor-positive and estrogen receptor- and progesterone receptor-negative metastatic breast cancer.

Secondary

* Determine the 6-month progression-free survival of patients treated with this drug.
* Evaluate the safety of this drug in these patients.
* Evaluate changes in estradiol, total and free testosterone, and sex-hormone binding globulin in response to androgen blockade in patients treated with this drug.
* Evaluate tissue, including cytokeratins 5/6 and 17, SPDEF, ALCAM, ERBB2, FGFR4, and prostate-specific antigen (PSA), using immunohistochemical analysis in patients treated with this drug.

OUTLINE: This is a open-label study.

Patients receive oral bicalutamide once daily for 4 weeks. Treatment repeats every 4 weeks for 6 months in the absence of disease progression or unacceptable toxicity. Patients achieving complete response, partial response, or stable disease may continue to receive bicalutamide as above at the discretion of the investigator.

Patients undergo blood and tissue sample collection for correlative studies. Samples are analyzed for hormonal levels, including estradiol, total testosterone, free testosterone, and sex-hormone binding globulin, and proteins, including ALCAM, SPEDF, and CK 5/6, by immunohistochemical analysis at baseline, after course 1, and at the end of the study.

After completion of study treatment, patients are followed every 3 months.

PROJECTED ACCRUAL: A total of 28 patients will be accrued for this study.

Arms:
arm 1: This is a multicenter, open-label, phase II study to evaluate the antitumor activity and safety of bicalutamide administered orally daily to patients with ER(-)/PR(-)/AR(+) metastatic breast cancer. Eligible patients who have consented to trial participation will receive bicalutamide at a dose of 150mg PO daily.

Interventions: intervention 1: bicalutamide intervention 2: diagnostic laboratory biomarker analysis intervention 3: immunohistochemistry staining method
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol document:
Prot_SAP_000.pdf: 
Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 07-022A (13) 
Amended:  8/22/12 
 
 
 
Bicalutamide for the Treatment of Androgen Receptor Positive (AR(+)), Estrogen Receptor 
Negative, Progesterone Receptor Negative (ER(-)/PR(-)) Metastatic Breast Cancer  
Patients:  A Phase II Feasibility Study 
 
 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
 
Principal Investigator: 
Tiffany Traina, MD 
Medicine/Breast 
 
Co-Principal 
Investigator(s)/Department: 
Clifford A. Hudis, MD 
Medicine/Breast 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Ave. 
New York, NY 10021 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 07-022A (13) 
Amended:  8/22/12 
 
 
 
Investigator(s)/Department: 
Mark E. Robson, MD 
Maura N. Dickler, MD 
Larry Norton, MD 
Mary Ellen Moynahan, MD 
Teresa Ann Gilewski, MD 
Nancy T. Sklarin, MD 
Andrew D. Seidman, MD 
Gabriella D'Andrea, MD 
Maria Theodoulou, MD 
Jacqueline F. Bromberg, MD, 
PhD. 
Diana Lake, MD 
Chau Dang, MD 
Monica Fornier, MD 
Shanu Modi, MD 
Victoria Blinder, MD, MSc 
Shanu Modi, MD 
Sarat Chandarlapaty, MD, 
PhD 
Heather McArthur, MD, MPH 
Shari Goldfarb, MD 
Devika Gajria, MD, MPH 
Elizabeth Comen, MD 
Ayca Gucalp, MD 
 
Dilip Giri, MD 
Kimberly Feigin, MD 
Sujata Patil, PhD 
Medicine/Human Genetics 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
Medicine/Breast 
 
Pathology 
Radiology 
Epidemiology-Biostatistics 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 07-022A (13) 
Amended:  8/22/12 
 
 
 
Consenting 
Professional(s)/Department: 
Clifford A. Hudis, MD 
Tiffany A. Traina, MD 
Mark E. Robson, MD 
Medicine/Breast 
Medicine/Breast 
Medicine/Human Genetics 
Maura N. Dickler, MD 
Medicine/Breast 
Larry Norton, MD 
Medicine/Breast 
Mary Ellen Moynahan, MD 
Medicine/Breast 
Teresa Ann Gilewski, MD 
Medicine/Breast 
Nancy T. Sklarin, MD 
Medicine/Breast 
Andrew D. Seidman, MD 
Medicine/Breast 
Gabriella D'Andrea, MD 
Medicine/Breast 
Maria Theodoulou, MD 
Medicine/Breast 
Jacqueline F. Bromberg, MD, PhD. 
Medicine/Breast 
Diana Lake, MD 
Medicine/Breast 
Chau Dang, MD 
Medicine/Breast 
Monica Fornier, MD 
Medicine/Breast 
Shanu Modi, MD 
Medicine/Breast 
Victoria Blinder, MD, MSc 
Medicine/Breast 
Sarat Chandarlapaty, MD, PhD 
Medicine/Breast 
Heather McArthur, MD, MPH 
Medicine/Breast 
Shari Goldfarb, MD 
Medicine/Breast 
Devika Gajria, MD, MPH 
Medicine/Breast 
Elizabeth Comen, MD 
Medicine/Breast 
Deena Atieh Graham, MD 
Medicine/Basking-Ridge 
Ephraim Casper, MD 
Medicine/Basking-Ridge 
Audrey Hamilton, MD 
Medicine/Basking-Ridge 
Mila Gorsky, MD 
Medicine/Basking-Ridge 
Han Xiao, MD 
Medicine/Basking-Ridge 
Stuart Lichtman, MD 
Medicine/Commack 
Philip Schulman, MD 
Medicine/Commack 
Steven Sugarman, MD 
Medicine/Commack 
Julie Fasano,MD 
Medicine/Commack 
John Fiore, MD 
Medicine/Commack 
Arlyn Apollo, MD 
Medicine/Rockville-Center 
Pamela Drullinsky,  MD 
Medicine/Rockville-Center 
Zoe Goldberg,  MD 
Medicine/Rockville-Center 
Kenneth Ng,  MD 
Medicine/Rockville-Center 
Tiffany Troso-Sandoval, MD 
Medicine/Rockville-Center 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 07-022A (13) 
Amended:  8/22/12 
 
 
 
Michelle Boyar, MD 
Philip Caron, MD, PhD 
Nancy Mills, MD 
Carolyn Wasserheit-Lieblich, MD 
Stephanie Smith-Marrone, MD 
Medicine/Phelps 
Medicine/Phelps 
Medicine/Phelps 
Medicine/Phelps 
Medicine/Phelps 
 
 
 
 
 
 
Collaborating Institutions: 
PI’s Name 
Site’s Role 
Dana Farber Cancer 
Institute 
Sarah Tolaney, MD 
Data Collection 
Duke University 
Kimberly Blackwell, MD 
Data Collection 
Georgetown 
Minetta Liu, MD 
Data Collection 
Mayo Clinic 
James Ingle, MD 
Data Collection 
University of Alabama 
Lisle Nabell, MD 
Data Collection 
University of California, 
San Francisco 
Hope Rugo, MD 
Data Collection 
University of North 
Carolina 
Lisa Carey, MD 
Data Collection 
 
 
 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 


Amended:  8/22/12 
Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#:07-022A( 13  ) 
 
 
 
Table of Contents 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL ........................................................................................ 1 
PHILIP SCHULMAN, MD ......................................................................................................................................... 3 
1.0 
PROTOCOL ABSTRACT AND SUMMARY ................................................................................................. 2 
1.1 
PROTOCOL ABSTRACT ...................................................................................................................................... 2 
1.2 
PROTOCOL SUMMARY ...................................................................................................................................... 2 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ........................................................................................................ 3 
2.1 
PRIMARY OBJECTIVE ........................................................................................................................................ 3 
2.2 
SECONDARY OBJECTIVES ................................................................................................................................. 3 
3.0 
BACKGROUND AND RATIONALE .............................................................................................................. 4 
3.1 
STUDIES OF BICALUTAMIDE IN MEN WITH PROSTATE CANCER ..................................................................... 5 
3.2 
STUDIES OF BICALUTAMIDE IN WOMEN ........................................................................................................... 7 
3.3 
RATIONALE FOR BICALUTAMIDE STUDY DOSE SELECTION ................................................................................ 8 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION .................................................................................. 8 
4.1 
DESIGN ............................................................................................................................................................. 8 
4.2 
INTERVENTION ............................................................................................................................................... 9 
4.3 
CORRELATIVE STUDIES .................................................................................................................................. 9 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ................................................................................................... 11 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY .................................................................................................. 12 
6.1 
SUBJECT INCLUSION CRITERIA .................................................................................................................. 12 
6.2 
SUBJECT EXCLUSION CRITERIA ................................................................................................................. 13 
7.0 
RECRUITMENT PLAN .................................................................................................................................. 14 
8.0 
PRETREATMENT EVALUATION .............................................................................................................. 15 
9.0 
TREATMENT/INTERVENTION PLAN ...................................................................................................... 15 
9.1 
AGENT ADMINISTRATION ............................................................................................................................... 15 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION ................................................................. 16 
11.0 
TOXICITIES/SIDE EFFECTS .................................................................................................................. 19 
11.1 DEFINITIONS .................................................................................................................................................... 19 
11.2 
DOSING DELAYS/DOSE MODIFICATIONS .................................................................................................... 21 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ..................................... 23 
12.1 
DEFINITIONS .............................................................................................................................................. 23 
12.2 GUIDELINES FOR EVALUATION OF MEASURABLE DISEASE ............................................................................... 24 
12.3 RESPONSE CRITERIA ........................................................................................................................................ 26 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ......................................................................................... 27 
14.0 
BIOSTATISTICS ........................................................................................................................................ 27 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES .......... 28 
15.1 
RESEARCH PARTICIPANT REGISTRATION ................................................................................................... 28 
16.0 
DATA  MANAGEMENT ISSUES ............................................................................................................. 30 
17.0 
PROTECTION OF HUMAN SUBJECTS ................................................................................................ 37 


Amended:  8/22/12 
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IRB Protocol 
IRB#:07-022A( 13  ) 
 
 
18.0 
INFORMED CONSENT PROCEDURES ................................................................................................ 40 
18.1 FOR PARTICIPATING SITES ........................................................................................................................ 41 
19.0 
REFERENCES ............................................................................................................................................ 42 
20.0 
APPENDICES.............................................................................................................................................. 43 
APPENDIX A – BICALUTAMIDE (DRUG INSERT INFORMATION PROVIDED BY ASTRAZENECA) ............................ 43 
APPENDIX B: BICALUTAMIDE MEDICATION DIARY .............................................................................................. 53 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 07-022A (13) 
 
 
 
Amended:  8/22/12 


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IRB Protocol 
IRB#: 07-022A(13 ) 
Amended:  8/22/12 
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1.1 
PROTOCOL ABSTRACT AND SUMMARY 
 
1.2 
Protocol Abstract 
 
Estrogen receptor negative (ER(-)), progesterone receptor-negative (PR(-)) breast cancer 
represents approximately 25 – 30% of all breast cancers.  Unlike estrogen receptor-positive 
(ER(+)) breast cancer, patients with ER(-)/PR(-) disease are not candidates for current anti- 
hormonal strategies.  The biology of ER(-) disease is poorly understood and with the exception 
of trastuzumab for Her2/neu-positive tumors, targeted therapy options are limited. Genome-wide 
expression analysis has revealed a subset of ER(-)/PR(-) breast cancers that share a gene 
expression profile with hormone receptor-positive tumors1.  Among these shared genes is the 
androgen receptor (AR).  In-vitro studies of androgen blockade demonstrated a reduction in 
growth of ER(-)/PR(-)/AR(+) breast cancer cells.  Clinical investigation of androgen blockade in 
breast cancer patients is therefore a rational therapeutic strategy. 
 
The primary objective of this Phase II study is to evaluate the efficacy of bicalutamide 
(CasodexTM, Astrazeneca), a well-tolerated anti-androgen used in prostate cancer, in women with 
ER(-)/PR(-)/AR(+) metastatic breast cancer.  Efficacy will be measured by the response rate 
(RR), including those patients with a demonstrated complete response (CR), partial response 
(PR), or stable disease (SD) after 6 months from the first day of therapy. Secondary objectives 
include progression-free survival (PFS), safety and correlative studies. Correlative studies, 
including peripheral blood hormone levels and selected immunohistochemical markers, will 
further characterize the biology of this novel subtype of breast cancer. This is an important study 
for the field of breast cancer research because bicalutamide may allow a greater number of 
patients with breast cancer the option of treatment with hormonal therapy instead of, or in 
addition to, chemotherapy. 
 
1.3 
Protocol Summary 
 
This is a multicenter, open-label, phase II study to evaluate the antitumor activity and safety of 
bicalutamide administered orally daily to patients with ER(-)/PR(-)/AR(+) metastatic breast 
cancer.  Patients with measurable or non-measurable, metastatic breast cancer are eligible. Prior 
neo-adjuvant or adjuvant chemotherapy is permitted.   There is no restriction on prior 
chemotherapy or hormonal therapy. Prior therapy with trastuzumab is allowed but may not be 
administered while on study. 
 
Patients with metastatic, ER(-), PR(-) breast cancer may consent to androgen receptor testing 
while on breast cancer-directed treatment. If they are found to have AR(+) disease, they will be 
considered potentially eligible for treatment on study. At the time their treating physician 
determines they require a change in therapy, they may consent to participate in this study if they 
meet remaining eligibility criteria. 
 
Eligible patients who have consented to trial participation will receive bicalutamide at a dose of 
150mg PO daily.  Up to two dose reductions of 50mg each will be allowed for grade 3 or 4 
toxicity as specified by the protocol. The primary aim of the study is to evaluate the efficacy of 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 07-022A(13 ) 
Amended:  8/22/12 
- 3 - 
 
 
bicalutamide after 6 months of therapy. The study is a phase II design with a planned enrollment 
of 28 patients.  If 4 or more patients demonstrate a response (defined as either a CR, PR or SD) 
after 6 months of therapy, bicalutamide will be considered a feasible and potentially promising 
therapy.  Patients with progression of disease will be withdrawn from the study. Treatment may 
continue after 6 months in the absence of progression of disease or unacceptable toxicity. 
 
Based on studies of bicalutamide in men with prostate cancer, an oral daily dose of 150 mg per 
day has been selected for this study. In men, the pharmacodynamic, pharmacokinetic, safety and 
efficacy data support this dose for monotherapy. Studies of doses up to 600 mg failed to show 
dose-related increases in adverse events. This study will not aim to provide extensive 
pharmacokinetic and pharmacodynamic data on different dose levels.  It will not aim to 
recapitulate data from previous studies performed in men.  Rather, this is a straightforward 
extrapolation of studies performed in men, to test this hormonal agent in women based on a 
rational biologic hypothesis.   While there may be differences seen with its use in women, this 
study has been designed with a dose reduction schema and early stopping rules for toxicity. 
Additionally, correlative studies will include serum hormonal levels to further characterize 
differences seen in women. 
 
2.1 
OBJECTIVES AND SCIENTIFIC AIMS 
 
2.2 
Primary Objective 
 
The primary objective of this study is to: 
 
• 
Evaluate the efficacy of treatment with bicalutamide at 6 months for patients with 
ER(-) /PR(-)/AR(+) metastatic breast cancer in terms of response (CR, PR) and SD. 
 
2.3 
Secondary Objectives 
 
The secondary objectives of this study are to: 
 
• 
Estimate the progression-free survival (PFS) at 6 months for patients with ER(-)/PR(-)/AR(+) 
metastatic breast cancer 
• 
Evaluate the safety of bicalutamide for patients with ER(-)/PR(-)/AR(+) metastatic breast 
cancer. 
• 
Perform correlative studies including: 
 
- 
Monitoring of changes in estradiol, total and free testosterone and sex-hormone binding 
globulin in response to androgen blockade in women with breast cancer 
- 
Immunohistochemical analysis of tissue including cytokeratins 5/6 and 17, SPDEF, 
ALCAM, ERBB2, FGFR4 and PSA 
- 
Collection and storage of AR+ paraffin embedded tissue samples from primary or 
metastatic site, if available. These samples will be used to further investigate the biology 
of AR+ breast cancer (ie, by building a tissue microarray). 


Memorial Sloan-Kettering Cancer Center 
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Amended:  8/22/12 
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3.1 
BACKGROUND AND RATIONALE 
 
Breast cancer remains one of the most common diseases affecting women with a lifetime risk of 
approximately 13% (or 1 in 7 women) 2.   It is estimated that in 2008 over 180,000 women will 
develop breast cancer and ~40,400 will die of their disease3.  Approximately 70% of patients 
with breast cancer have tumors that express estrogen receptors or progesterone receptors, or 
both, and are candidates for hormonal therapy. 
 
Estrogen receptor-negative, progesterone receptor-negative (ER(-)/PR(-)) breast cancer 
represents approximately 25 to 30% of all breast cancers and generally has a more aggressive 
clinical course than hormone receptor-positive disease.  Therapeutic options for these patients 
are limited.  Patients with ER(-)/PR(-) tumors gain little or no benefit from anti-estrogen therapy 
and targeted therapy is limited to trastuzumab in those patients with tumors that overexpress 
Her2/neu. 
 
In addition to ER and PR, breast cancer cells express other nuclear hormone receptors.  The 
androgen receptor (AR) is expressed in 60 to 80% of breast cancers and implicated in breast 
cancer biology4.  Among postmenopausal women, high androgen levels are associated with an 
increased risk of developing breast cancer5.  Furthermore, androgens can induce proliferation in 
breast tissue, and initiate tumor formation via the AR in animal models6. 
 
A recent analyses of gene expression profiles of primary breast cancers from investigators at 
MSKCC identified a subset of ER(-)/PR(-) tumors with a molecular signature that suggests an 
active hormonally regulated transcriptional program1.  Gene expression signatures were used to 
develop a predictive model that can identify molecularly similar breast cancers in an independent 
human breast cancer data set and among breast cancer cell lines. A cell line with this signature 
demonstrated a proliferative response to androgen in an androgen receptor dependent manner 
that was inhibited by anti-androgens. This subset of breast cancers (ER(-) Class A) characterized 
by a hormonally related transcriptional program and proliferative response to androgen, suggests 
the potential for therapeutic strategies targeting the androgen signaling pathway.  This trial is 
designed to test this hypothesis. 
 
Admittedly, the mechanisms by which androgens contribute to increased risk of breast cancer are 
not well understood. In an older literature, androgens appeared to have a growth inhibitory effect 
in animal and cell-line experiments. However, this idea has not been supported in studies of 
human populations. Recent studies of CAG-repeat length in androgen receptor polymorphisms 
suggest that differing AR polymorphisms may modulate a woman’s risk of breast cancer. It has 
been postulated that an association exists between AR CAG-repeat length and BRCA1-related 
breast cancer risk. Androgens may have both direct and indirect effects on breast tissue and 
ultimately breast cancer risk. As the mechanism by which androgens influence breast cancer risk 
remain unclear, we have designed this trial to test the hypothesis derived from our preclinical 
work that targeting androgen receptor signaling in the subset of ER(-) Class A tumors will be of 
benefit. 


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Amended:  8/22/12 
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3.2 
Studies of Bicalutamide in men with prostate cancer 
 
Bicalutamide is an orally active, nonsteroidal anti-androgen that competitively inhibits the action 
of androgens by binding to cytosol androgen receptors in target tissues. Studies have 
demonstrated tolerability and efficacy of bicalutamide in men with locally advanced and 
metastatic prostate cancer. 
 
Bicalutamide was initially evaluated in patients with prostate cancer at the 50 mg per day dose 
for use in combination with castration in combined androgen blockage (CAB) therapy. CAB 
therapy consists of an antiandrogen with either surgical castration or medical castration with a 
luteinizing hormone-releasing hormone analogue (LHRH-A). 
 
Subsequently, studies evaluated bicalutamide at a dose of 50 mg per day (licensed for use in 
CAB) as monotherapy in patients with previously untreated, advanced prostate cancer. After 
bicalutamide 50 mg per day was shown to be inferior to castration in terms of survival, dose- 
finding phase II studies were performed to evaluate whether higher doses of bicalutamide would 
be more effective.  Pharmacodynamic studies showed an increasing prostate specific antigen 
(PSA) response with increasing dose that reached a plateau at 150 – 200 mg per day, with the 
PSA response seen with 150 mg per day similar to that seen with castration. The use of 
bicalutamide in doses higher than 150 mg per day was not limited by safety concerns, as doses of 
up to 600 mg per day did not cause dose-related increases in adverse events7. 
 
A dose of bicalutamide 150 mg per day was selected for development as monotherapy based on 
pharmacodynamic results that showed the PSA response after 3 months of treatment at this dose 
level (>92% reduction) was comparable to that seen in patients who had undergone surgical 
castration. Bicalutamide 150 mg per day was subsequently evaluated against castration in two 
large randomized Phase III studies in men with M0 or M1 disease.   Bicalutamide 150 mg per 
day demonstrated good tolerability in these studies8.  6% of bicalutamide-treated patients 
withdrew from treatment due to an adverse event.  The reported side effect profile included 
gynecomastia and breast pain (35 – 40%), hot flashes (6-13%) and diarrhea (4-5%). 
 
The corresponding pharmacokinetic data for the relationship between (R)-bicalutamide (the 
active enantiomer) steady-state concentration (Css) and dosage shows a departure in linearity at 
doses >50 mg/day and a clear plateau for doses > 300mg/day9.  Pharmacokinetics are unaffected 
by age, body-weight, renal impairment and mild-to-moderate hepatic impairment.  Bicalutamide 
does not demonstrate any clinically relevant interaction with other drugs. 
 
A dose of bicalutamide 150 mg/day was selected for the ongoing bicalutamide (‘Casodex’) Early 
Prostate Cancer (EPC) Program.  This program was designed to evaluate whether the addition of 
bicalutamide 150 mg to standard care can reduce the risk of disease progression, as well as 
improve overall survival in patients with localized or locally advanced prostate cancer. 
Consisting of three randomized, double-blind, placebo-controlled trials, it is the largest prostate 
cancer study to date. Following standard care, 8113 men with localized or locally advanced 
prostate cancer were randomized to receive oral bicalutamide 150 mg once daily or oral placebo. 
At a median follow-up of 7.4 years, the data suggest that adjuvant hormonal therapy for patients 


Memorial Sloan-Kettering Cancer Center 
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at low risk of disease progression (ie localized disease) is currently not appropriate. For patients 
with locally advanced disease, however, the addition of bicalutamide to standard care 
significantly increases PFS and shows a trend towards improved OS10. 
 
For safety and tolerability, the most common adverse events reported with bicalutamide were 
breast pain (73.6%) and gynecomastia (68.8%). Symptoms were reported as mild to moderate in 
over 90% of cases.   Symptoms typically developed within the first 6 to 9 months of treatment. 
Other adverse events were infrequent and included impotence (9.3% with bicalutamide and 6.5% 
with standard care alone), decreased libido (3.6% and 1.2%, respectively), hotflushes (9.2% and 
5.4% respectively), and abnormal liver function tests (3.1% and 1.7%, respectively). Withdrawal 
rates from the study due to adverse events were 29.3% with bicalutamide and 10.0% with 
standard care alone.  Withdrawal rates secondary to breast pain and/or gynecomastia were 16.8% 
and 0.7% respectively. In the bicalutamide group, fewer patients died from prostate cancer than 
those receiving standard care alone (6.4% vs 7.5%).  Deaths from heart failure and 
gastrointestinal carcinoma were higher in the bicalutamide group, though there were no 
consistent patterns to suggest that these were due to drug toxicity. 


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IRB Protocol 
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The most common adverse events and causes of death, as number (%) of patients10 
Variable 
Bicalutamide 150 mg + 
standard care 
N=4022 
Standard care alone 
N=4031 
Adverse Event 
Breast pain 
2962 (73.6%) 
308 (7.6%) 
Gynecomastia 
2766 (68.8%) 
334 (8.3%) 
Pharyngitis 
448 (11.1%) 
470 (11.7%) 
Asthenia 
442 (11.0%) 
315 (7.8%) 
Back pain 
420 (10.4%) 
490 (12.2%) 
Rash 
404 (10.0%) 
337 (8.4%) 
Constipation 
380 (9.4%) 
314 (7.8%) 
Impotence 
375 (9.3%) 
263 (6.5%) 
Hot flushes 
370 (9.2%) 
216 (5.4%) 
Arthralgia 
355 (8.8%) 
405 (10.0%) 
Cause of death 
Prostate cancer 
257 (6.4%) 
302 (7.5%) 
Myocardial infarction 
81 (2.0%) 
76 (1.9%) 
Cause unknown 
68 (1.7%) 
63 (1.6%) 
Gastrointestinal carcinoma 
54 (1.3%) 
38 (0.9%) 
Heart failure 
49 (1.2%) 
25 (0.6%) 
Cerebrovascular accident 
47 (1.2%) 
45 (1.1%) 
Lung carcinoma 
44 (1.1%) 
47 (1.2%) 
Heart arrest 
37 (0.9%) 
33 (0.8%) 
Pneumonia 
34 (0.8%) 
45 (1.1%) 
 
 
The most common side effects of gynecomastia and breast pain reflect the pharmacology of 
bicalutamide.  Gynecomastia, the proliferation of the glandular component of the male breast, 
occurs because of an increase in the ratio of estrogen to androgen. Bicalutamide treatment 
causes gynecomastia because of blockade of androgenic activity and the increase in peripheral 
aromatization of androgens to estrogens.  The reported rates of gynecomastia and breast pain 
were lower in trials of bicalutamide in metastatic patients than in the EPC study of patients with 
localized or locally advanced disease.   The toxicity profile of bicalutamide 50 mg in 
combination with an LHRH analogue (as included in the AstraZeneca package insert) is included 
in Appendix A. 
 
3.3 
Studies of Bicalutamide in Women 
 
In two small studies bicalutamide has been given at a dose of 25 mg per day to women with 
polycystic ovary disease and for treatment of hirsuitism11,12 . To date, there have been no studies 
of bicalutamide as an anti-cancer therapy in women, or using doses above 25 mg per day. 


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3.4 
Rationale for bicalutamide study dose selection 
 
Though bicalutamide has not been well tested in women, the extensive studies of this drug in 
men with prostate cancer demonstrating good tolerability provide support for its use in women. 
The selection of a dose of 150 mg per day is based on pharmacokinetic, pharmacodynamic and 
safety data from studies performed in men with prostate cancer.  Notably, studies of doses above 
150 mg (up to 600 mg) failed to show dose-limiting toxicity. The dose of 150 mg reflects an 
optimal steady-state concentration and PSA-lowering effect in men with prostate cancer. 
 
Because there may be differences seen with the use of bicalutamide in women, this study has 
been designed with a dose reduction schema for toxicity.   Correlative studies include a panel of 
serum hormonal studies that will provide information on differences seen in the 
hormonal/metabolic pathways in women.  The goal of this study is to test the hypothesis that 
androgen blockade in women with ER(-)/PR(-)/AR(+) breast cancer (ER(-) Class A) is an 
effective hormonal treatment.   This study will not perform pharmacokinetic and 
pharmacodynamic studies. 
 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.2 
Design 
 
This is a multicenter, open-label, one-stage, phase II study to evaluate the antitumor activity and 
safety of bicalutamide administered orally daily to patients with ER(-)/PR(-)/AR(+) metastatic 
breast cancer.  Patients with non-measurable or measurable, metastatic breast cancer are eligible. 
Prior neo-adjuvant or adjuvant chemotherapy is permitted. Prior therapy with trastuzumab is 
necessary for patients with Her-2/neu positive disease (3+ IHC or FISH > 2.0). There is no 
limitation on prior treatment with chemotherapy or hormonal therapies. 
 
After signing the protocol consent form for androgen receptor testing, the patient’s tumor will be 
evaluated for androgen receptor status using a commercially available immunohistochemical 
analysis.  Androgen receptor testing may occur on primary breast tumor or tissue from biopsy of 
a metastatic site. Participating centers may send unstained slides to MSKCC for ER, PR and AR 
testing. Participating sites may instead choose to perform androgen receptor testing themselves 
however, estrogen receptor, progesterone receptor and androgen receptor status will be centrally 
confirmed at Memorial Sloan-Kettering Cancer Center by the Department of Pathology for 
tumors which test ER(-)/PR(-)/AR(+) locally.  If this patient  meets the remaining eligibility 
criteria for study participation, they may later consent to treatment on study. Patients with ER(- 
)/PR(-)/AR(+) breast cancer on local testing may begin bicalutamide if otherwise eligible while 
confirmation of receptor status at MSKCC takes place. If the patient’s tumor is AR(-) at 
MSKCC, or if either estrogen or progesterone receptors are positive at MSKCC, the patient may 
continue on treatment with bicalutamide if the tumor tested ER(-), PR(-), AR(+) locally. 


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Amended:  8/22/12 
- 9 - 
 
 
The primary aim of the study is to evaluate the efficacy of bicalutamide in terms of response 
(CR+PR) and SD at 6 months.  The study has a projected enrollment of 28 patients. If 4 or more 
patients demonstrate a response (defined as a CR, PR or SD by RECIST criteria) after 6 months 
of treatment, bicalutamide will be considered a feasible and promising therapy. 
 
4.3 
Intervention 
 
Patients will receive bicalutamide at a dose of 150mg PO daily. Patients will be seen monthly for 
an assessment by a care provider familiar with the protocol. Clinical assessment and serum 
studies will be performed per protocol (See Time and Events Schedule, Section 10) . Patients 
may be seen before their scheduled monthly follow-up if they are experiencing any adverse 
effects or symptoms that may be consistent with progression of disease. Patients will undergo a 
radiologic extent of disease evaluation (EOD) every 3 months.  An EOD may be performed 
earlier than a 3 month interval if progression of disease is suspected. Response will be evaluated 
using RECIST criteria as complete response (CR), partial response (PR), stable disease (SD) or 
progressive disease (PD). 
 
If a patient experiences unacceptable toxicity at the initial dose level, up to two dose reductions 
of 50mg each will be permitted.  Dose reduction of bicalutamide from the initial dose of 150mg 
PO daily to100mg PO daily will occur for an individual patient if that patient experiences 
unacceptable toxicity. A second dose reduction of 50mg is acceptable. Toxicities will be graded 
using the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 3. 
Treatment may be delayed no more than 2 weeks to allow recovery from acute toxicity. In the 
event of a treatment delay exceeding 2 weeks, the patient will be withdrawn from the study. 
 
A patient will be withdrawn from the study in the following situations: 
 
• For an unacceptable toxicity, defined as a Grade 3 or 4 non-hematologic toxicity after 2 
(50 mg) dose reductions (see Section 11.2.5); or 
• For unacceptable toxicity that fails to resolve after a maximum treatment delay of 2 
weeks; or 
• Progression of disease 
 
Treatment with bicalutamide will continue until one or more of the criteria for withdrawal from 
study are met. After 6 months of treatment, patients will be considered responders if they 
achieve a CR, PR or SD by RECIST criteria.   At the investigator’s discretion, and in the absence 
of disease progression by RECIST criteria, treatment with bicalutamide may continue beyond 6 
months. Study drug is provided by AstraZeneca. 
 
4.4 
Correlative Studies 
 
As a secondary objective, correlative studies will be performed to further elucidate the biology of 
this potentially novel subtype of ER(-)/PR(-)/AR(+) (ER(-) Class A) breast cancer and to 
measure the effect of androgen blockade on peripheral hormonal levels. 


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In patients with prostate cancer, the use of bicalutamide leads to increased testosterone and 
estrogen levels.  Little data is available for women treated with androgen blockade, but changes 
in hormonal levels are anticipated. A serum hormone panel will be drawn at baseline, after one 
month and at the end of study . This serum hormonal panel will include: estradiol, total and free 
testosterone, and sex-hormone binding globulin. 
 
Doane and colleagues describe a panel of IHC markers that identifies ER(-) class A breast 
cancers.  A combination of ER, PR, SPDEF and ALCAM was estimated to predict ER(-)/PR(-) 
samples as ER(-) Class A with a sensitivity approaching 100% (95% CI 69 -100%) and a 
specificity of 94% (95% CI 79-99%)1.   Other genes that are overexpressed in ER(-) Class A will 
also be evaluated for their protein expression with IHC including Her2/neu and FGFR4. 
Her2/neu has been previously shown to stabilize AR protein levels and optimize binding of AR 
to promoters of androgen-regulated genes in prostate cancer cells14. FGFR4 is overexpressed in 
ER(-) Class A tumors, and previous research has demonstrated molecular ‘cross-talk’ between 
FGFR4 and Her2/neu leading to activation of the mTOR translational pathway and subsequent 
cyclin D1 activation15. This convergence of data suggests that further investigation into the role 
of FGFR4, Her2/neu and AR in ER(-) Class A breast cancers is warranted. 
 
The ER(-) Class A subtype was noted by Doane and colleagues to be distinct from the ‘basal 
subtype’ previously identified by Perou and colleagues16. The basal subtype generally 
corresponds to a proportion  of ER(-) breast cancers.  Cytokeratins 5/6 and 17 are expressed in 
the basal subtype but not in the ER(-) Class A subtype. Correlative studies of CK 5/6 and 17 will 
be performed to further explore these previously noted differences in expression patterns 
between the ER(-) Class A and a basal subtypes. 
 
Paraffin embedded tissue from primary tumor or metastatic sites which have tested AR+, will be 
requested from patients. Specimens will be collected, if available and at stored for the purpose of 
future correlative studies on the biology of AR+ breast cancer (ie, creation of tissue microarray 
of ER(-)/PR(-)/AR(+) breast cancer). 
 
Based on the preclinical data demonstrating a response to androgen blockade in a subset of ER(-) 
/PR(-)/AR(+) breast cancer, further study of androgen blockade is warranted. A feasibility study 
to evaluate the efficacy of bicalutamide in women with ER(-)/PR(-)/AR(+) breast cancer is 
therefore rational, and a logical next step.  This is an important study for the field of breast 
cancer research because bicalutamide may allow a greater number of patients with breast cancer 
the option of treatment with hormonal therapy instead of, or in addition to, chemotherapy. 


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IRB Protocol 
IRB#: 07-022A(13 ) 
Amended:  8/22/12 
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5.1 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
 
CASODEX® (bicalutamide) 
Drug Composition: 
CASODEX® (bicalutamide) Tablets for oral administration contain 50 mg of bicalutamide, a 
non-steroidal antiandrogen with no other known endocrine activity. The chemical name is 
propanamide, N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2- 
methyl-,(+-). The structural and empirical formulas are: 
 
 
 
 
Bicalutamide has a molecular weight of 430.37. The pKa' is approximately 12. Bicalutamide is a 
fine white to off-white powder which is practically insoluble in water at 37°C (5 mg per 1000 
mL), slightly soluble in chloroform and absolute ethanol, sparingly soluble in methanol, and 
soluble in acetone and tetrahydrofuran. 
 
CASODEX is a racemate with its antiandrogenic activity being almost exclusively exhibited by 
the R-enantiomer of bicalutamide; the S-enantiomer is essentially inactive. 
 
The inactive ingredients of CASODEX Tablets are lactose, magnesium stearate, 
methylhydroxypropylcellulose, polyethylene glycol, polyvidone, sodium starch glycollate, and 
titanium dioxide. 
 
Drug is supplied as 50 mg Tablets by AstraZeneca: 
(NDC 0310-0705) White, film-coated tablets (identified on one side with "CDX50" and on the 
reverse with the "CASODEX logo") are supplied in unit dose blisters of 30 tablets per carton 
(0310-0705-39), bottles of 30 tablets (0310-0705-30) and bottles of 100 tablets (0310-0705-10). 
 
Store at controlled room temperature, 20°-25°C (68°-77°F). 


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IRB#: 07-022A(13 ) 
Amended:  8/22/12 
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Pharmacokinetics: 
 
Bicalutamide has good oral absorption (though the absolute oral bioavailability is not known). 
Taking the drug with food has no significant effect on absorption.   Both the parent drug and its 
metabolites have renal and hepatic clearance.  Renal impairment has no significant effect on 
clearance.  Patients with severe hepatic disease have increased plasma half-life of a metabolite of 
bicalutamide.  In-vitro protein binding studies have shown that bicalutamide can displace 
coumarin anticoagulants from binding sites.  Patients already on coumarin anticoagulants should 
have closely monitored Prothrombin times while taking bicalutamide.  In men, the mean half-life 
of the drug is 5.8 days (standard deviation 2.29). 
 
Contraindications: 
 
Bicalutamide is contraindicated in any patient who has shown a hypersensitivity reaction to the 
drug or any of the tablet’s components.  It is contraindicated for use in pregnant women. 
 
Toxicity: 
 
Bicalutamide has not been tested in women at the intended doses for this study. Toxicities that 
have been reported in men with prostate cancer are listed above, in section 3.1 (with further 
details in Appendix A). 
 
The anticipated toxicities of bicalutamide in women at doses of 50 – 150 mg include (listed in 
order of most likely to least likely to occur): 
 
• Breast pain/tenderness 
• Hot flashes 
• Diarrhea 
• Abnormal Hepatic Function 
• Anemia 
• Constipation 
• Nausea 
• Abdominal pain 
 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.2 
Subject Inclusion Criteria 
 
A patient will be eligible for androgen receptor expression testing if the following criteria are 
met: 
 
• 
Pathologically confirmed adenocarcinoma of the breast which is ER(-) and PR(-). 
• 
Non-measurable or Measurable, metastatic disease 


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A patient will be eligible for participation in the therapeutic trial if the following criteria are 
met: 
 
• 
Androgen receptor expression testing confirms that the patient’s tumor is ER(-)/PR(-) 
/AR(+). ER, PR and AR are considered positive if greater than 10% of cell nuclei are 
immunoreactive. Receptor testing may be performed on either primary tumor specimen 
or tissue from a metastatic site. 
• 
Prior neo-adjuvant or adjuvant chemotherapy is allowed.  Any number of chemotherapy 
regimens are allowed for metastatic disease.   There is no restriction on prior treatment 
with hormonal agents. 
• 
Prior treatment with trastuzumab must have been given if patient has Her2/neu positive 
disease (defined as IHC=3+ or FISH amplified). 
• 
At least 2 weeks since prior cytotoxic chemotherapy.  Patients should have recovered 
from all acute effects of such therapy. 
• 
Absence of active brain metastatic disease or leptomeningeal disease. If patient has a 
history of brain metastases, lesions must be stable for at least 3 months (as documented 
by either head CT or brain MRI). 
• 
At least 4 weeks from major surgery with full recovery 
• 
ECOG performance status 0-1 
• 
Age 18 years or greater 
• 
Laboratory parameters as follows: 
 
o ANC ≥ 1.5 x 109 cells/L 
o Platelets ≥ 100 x 109 cells/L 
o Hgb ≥ 9g/dL 
 
o AST (SGOT), ALT (SGPT)  ≤  2.5 x upper limit of normal range (ULN); total 
bilirubin ≤ 1.5 x ULN; alkaline phosphatase ≤ 2.5 x ULN (unless bone metastases 
are present in the absence of liver metastases), creatinine ≤ 1.5 mg/dL 
 
• 
If female of childbearing potential, pregnancy test is negative 
 
• 
If fertile, the patient agrees to use an effective method to avoid pregnancy for the duration 
of the study 
• 
Informed consent has been obtained 
 
6.3 
Subject Exclusion Criteria 
 
A patient will not be eligible for treatment on this study if any of the following criteria apply: 
 
• 
Concurrent chemotherapy, hormonal therapy or biologic therapy is being administered to 
treat breast cancer. 
• 
Serious intercurrent medical or psychiatric illness, including serious active infection. 


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• 
History of other malignancy within the last five years, which could affect the diagnosis or 
assessment of breast cancer (except non-melanomatous skin carcinoma). 
• 
Patients who have received an investigational drug within the previous 3 weeks. 
• 
Patient is currently enrolled in another clinical study in which investigational therapies 
are administered.  In addition, a patient may not enroll in such clinical trials while 
participating in this study. 
 
7.1 
RECRUITMENT PLAN 
 
Patients will be recruited for enrollment on this trial primarily through referrals from their 
primary oncologists.  Efforts will be made to enroll women from a diversity of ethnic and socio- 
economic backgrounds. There will be no payments made to participants or physicians for 
participation in this study.  Prior to enrollment on the study, the physician will discuss the study 
protocol in detail with the patient, including possible toxicities. An informed consent will be 
reviewed by the physician with the patient. 
 
Androgen Receptor Testing: 
If a patient wishes to undergo androgen receptor testing on the protocol, an informed consent 
will be signed prior to reviewing pathologic specimens for AR status. Androgen receptor testing 
may be performed using the Dako antibody, catalog number M3562, Animal/Clone AR441 
(antibody dilution of 1:300 with citrate buffer pretreatment). The pathology specimen submitted 
for AR testing can be from either the primary or the metastatic site. 
 
Dr. Dilip Giri and team at MSKCC Department of Pathology will verify the invasive breast 
cancer is AR positive. Fewer than 10 unstained slides or a tumor block will be accepted if that is 
all that is available. I 
 
7.2 
For participating sites sending pathology specimens to MSKCC for AR testing 
Participating sites must  send unstained slides to MSKCC for AR testing.  All specimens 
submitted to MSKCC for AR testing must have previously tested ER(-)/PR(-) locally. ER, PR 
and AR are considered positive if greater than 10% of cell nuclei are immunoreactive. Dr. Dilip 
Giri and team at MSKCC Department of Pathology will verify the invasive breast cancer is AR 
positive. If the patient is AR (+), the MSKCC Department of Pathology will verify the specimen 
is ER(-)/PR(-).If the patient is AR (-), the patient is ineligible and the study staff will take steps 
to register the patient as ineligible. 
 
Pathology specimens may be requested from either the primary or the metastatic site. Sites must 
request 10 unstained slides to send to MSKCC. Fewer than 10 unstained slides or a tumor block 
will be accepted if that is all that is available. Specimen submissions are to be shipped with an 
accompanying pathology report and the tumor tissue shipment form provided by the 07-022 
MSKCC research staff using the MSKCC issued patient ID. The MSKCC study staff must be 
notified of all shipments. Shipments cannot be accepted on weekends. All shipments should be 
directed to the address listed on the tissue sample shipment form.This tissue will also be used for 


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Amended:  8/22/12 
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correlative studies as discussed in section 10.0 
 
8.1 
PRETREATMENT EVALUATION 
 
Baseline evaluations will be performed for ER(-)/PR(-)/AR(+) patients to determine study 
eligibility. Patients who have received any chemotherapy must have a washout period of 2 
weeks before the first dose of study drug is administered.  The investigator will document the 
designated washout period in the patient’s source documentation. 
 
The following must be completed within 28 days of initiation of study drug: 
 
• 
Medical history including history of prior therapy 
• 
Medication list (include medications taken within 30 days of baseline visit) 
• 
Physical exam, height and weight. 
 
• Vital signs 
 
• 
ECOG performance status. 
• 
CBC with differential and platelet count, comprehensive blood panel (including 
chemistries and liver function tests), tumor markers (Ca15-3 & CEA, or CA 27.29) 
 
• 
Estradiol, total testosterone, free testosterone, sex-hormone binding globulin, 
• 
Serum pregnancy test (for women of childbearing-potential) will be conducted within 
72h of first study drug administration (negative results required for study drug 
administration). 
 
• 
CT scan of chest, abdomen and pelvis 
• 
Bone scan or PET scan 
 
9.1 
TREATMENT/INTERVENTION PLAN 
 
9.2 
Agent Administration 
 
Treatment will be administered on an outpatient basis.  Bicalutamide is administered orally at 
150 mg (three 50mg tablets) on a continuous daily schedule. A cycle length consists of 4 weeks 
of therapy. Please refer to the Time and Events Calendar (Section 10) for a detailed description 
of required tests. Radiographic tumor assessment will take place every 3 cycles. 
 
Expected adverse events for bicalutamide are described in Section 5.0. Appropriate dose 
modifications for bicalutamide are described in Section 4.2 and Section 11.2. Two 50mg dose 
reductions are permitted per protocol. A treatment delay of up to 2 weeks is permitted. Therapy 
will continue until disease progression or unacceptable toxicity. 


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10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
 
Day 0 and every 4 weeks (+/- 5 days), the following clinical and laboratory assessments must be 
done prior to continuation of treatment with bicalutamide: 
 
• History and physical examination, including: 
o Vital signs 
o ECOG performance status 
o Weight 
o Concomitant medications 
• Laboratory assessments, including: (screening labs can be used as Day 0 labs) 
o CBC with differential and platelet count 
o Comprehensive metabolic panel (Na, K, Cl, CO2, BUN, Creatinine,  Ca, Glucose, 
Total Protein, Albumin, Alkaline Phosphatase, Total Bilirubin, AST and ALT) 
• Adverse Event Evaluation (toxicity assessment using the NCI CTC version 3) 
• Blood for correlative study of hormonal levels including estradiol, total testosterone, free 
testosterone, and sex-hormone binding globulin will be performed at baseline, after Cycle 
#1 and at the end of study. (See further description below) 
 
Every 12 weeks (+/- two weeks), tumor assessments will be performed. Patients with measurable 
disease will be evaluated for complete response (CR), partial response (PR), stable disease (SD) 
or progressive disease (PD) using RECIST criteria, using the same modality of imaging 
performed at baseline. Patients with non-measurable disease will be evaluated for either stable 
disease or progressive disease. Responders and stable disease patients will continue on study 
unless they develop unacceptable toxicity.  Progressive disease or unacceptable toxicity (after a 
maximum of two dose reductions) will be the criteria for treatment failure and discontinuation 
from the study. 
 
Response assessment will include: 
o Radiologic scans of disease sites (e.g. CT scan of chest, abdomen and pelvis and 
PET or  bone scan if there are bone lesions identified on pre-study bone imaging) 
o Measurement of all target lesions that are followed by physical examination 
o Patients achieving a CR or PR must have confirmation of response at least 4 
weeks following the initial response determination. 
 
• 
End-of-Study (EOS) Evaluation:  At the time patients are removed from study, laboratory 
and clinical evaluations to assess adverse events (AEs) will be performed.  Serum 
hormone panel including estradiol, free and total testosterone and serum hormone binding 
globulin will be collected. Radiologic studies for antitumor response will be repeated if 
they have not been performed within the previous 28 days. 
• 
Adverse Event Resolution Follow-up:  Any AE that started anytime beginning from the 


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time the patient has registered, and up to 30 days after the last dose of bicalutamide, must 
be followed until the AE has resolved or stabilized. 
 
Correlative study methods: 
All correlative studies will be performed for the purpose of exploratory analysis. Correlative 
study will include immunohistochemical (IHC) analysis of proteins representing the ER(-) 
Class A and Basal subtypes, including ALCAM, SPDEF and CK 5/6.  IHC analysis will be 
performed using preexisting formalin fixed paraffin embedded biopsy or excision tissue from 
cancer sites. An exploratory analysis will be performed to correlate IHC expression profile 
and response to bicalutamide.  In addition, the effect of bicalutamide administration on serum 
hormone level will be investigated. Estradiol, free and total testosterone and serum hormone 
binding globulin will be measured at baseline, after cycle #1 and at the end of study to 
describe changes in these circulating hormones in response to androgen blockade in women. 
 
Paraffin embedded tissue from primary tumor or metastatic site which has tested AR+ will be 
requested from participating patients. These tumor blocks, if available, will be collected and 
stored for the purpose of future correlative studies to understand the biology of AR+ breast 
cancer. 


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Time and Events Schedule 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a one cycle is equal to 4 weeks 
b after study consent form has been signed, pathological testing of tumor for androgen receptor (AR) status will be 
performed.  If patient’s tumor is AR+ then they will be eligible to participate in the therapeutic study. If AR- they 
will not be permitted to participate in study. 
c  body weight only 
d   by physical exam 
e   confirm response 28 days 
f   females of childbearing potential only, within 72 hours of drug initiation 
g   bone scan or PET must be repeated if bone disease is known from baseline scans. If patient does not have bone 
disease, follow-up bone or PET scans are at the discretion of the treating physician. If PET/CT scans are being 
performed and can monitor for bone lesions, then no further bone scans are necessary. 
* after Cycle 1 
h   Comprehensive blood panel may include the following: Na, K, Cl, CO2, BUN, Creatinine, Ca, Glucose, Total 
Protein, Albumin, Alkaline Phosphatase, Total Bilirubin, AST and ALT 
Study Parameter 
Prestudy 
Every 
cyclea 
Every 3 
cycles 
Study 
Termination 
(EOS) 
AE 
resolution 
Informed consentb 
X 
History 
X 
Concomitant medications 
X 
X 
X 
Physical examination 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
Height and body weight 
X 
Xc 
Xc 
ECOG performance status 
X 
X 
X 
X 
Adverse Event Evaluation 
X 
X 
Disease Status 
Tumor assessment (clinical) 
Xd 
Tumor assessment with CT scan 
X 
Xe 
X 
Tumor assessment with PET or Bone scang 
X 
X 
X 
Toxicity assessment (by patient and by 
physician) 
X 
X 
CBC with differential and platelet count 
X 
X 
X 
Comprehensive blood panel (including 
chemistries and liver function tests) h 
X 
X 
X 
X 
Tumor Markers (Ca 15-3 & CEA, or CA 27- 
29) 
X 
X 
X 
Estradiol, total testosterone, free 
testosterone, sex-hormone binding globulin 
*Only after Cycle #1. 
X 
X* 
X 
Pregnancy test 
Xf 


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11.1 
TOXICITIES/SIDE EFFECTS 
 
These adverse event management guidelines are intended to ensure the safety of each patient 
while attempting to characterize the safety and tolerability of the test products. In agreeing to the 
provisions of this protocol, the investigator accepts all legal responsibilities for prompt 
notification of SAEs to the SAE manager in the Office of Clinical Research and to AstraZeneca 
as per section 11.4. 
 
Adverse events occurring during the study will be graded according to the NCI CTCAE Scale 
Version 3.0 (see http://ctep.cancer.gov/forms/CTCAEv3.pdf) where applicable. Adverse events 
that are not included on the toxicity scale will be designated as Grade 1 = mild, Grade 2 = 
moderate, Grade 3 = severe, Grade 4 = life-threatening, and Grade 5 = death. 
 
The investigator should evaluate all adverse events and should make an immediate effort to 
determine their etiology. Adverse events that are determined not to be possibly, probably, or 
definitely related to study drug may not require further evaluation but will need to be recorded on 
the CRFs.  Study medication may be interrupted for an adverse event at the discretion of the 
investigator. Patients requiring toxicity management should be assessed and evaluated at least 
weekly as indicated by the severity of the event. 
 
11.2 Definitions 
 
The definitions of adverse events (AEs) and serious adverse events (SAEs) are given below. It is 
of the utmost importance that all staff involved in the study is familiar with the content of this 
section.  The principal investigator is responsible for ensuring this. 
11.2.1 Adverse event 
An adverse event is the development of an undesirable medical condition or the deterioration of 
a pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product.  An undesirable medical condition can 
be symptoms (eg, nausea, chest pain), signs (eg, tachycardia, enlarged liver) or the abnormal 
results of an investigation (eg, laboratory findings, electrocardiogram).  In clinical studies, an AE 
can include an undesirable medical condition occurring at any time, including run-in or washout 
periods, even if no study treatment has been administered. In cancer clinical trials, many AEs are 
in fact related to progression of the patient’s underlying malignancy. 
 
An adverse event includes: 
• 
An exacerbation of a pre-existing illness; 
• 
An increase in frequency or intensity of a pre-existing episodic event or condition; 
• 
A condition detected or diagnosed after study drug administration even though it may 
have been present prior to the start of the study; 
• 
Continuously persistent disease or symptoms that were present at baseline and worsen 
following the start of the study. 


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An adverse event does not include: 
 
• 
Medical or surgical procedures (eg, surgery, endoscopy, tooth extraction, or transfusion); 
however, the condition that leads to the procedure is an adverse event (Procedures that 
occur during the trial should be recorded on the Concurrent Procedure CRF); 
• 
Pre-existing diseases, conditions or laboratory abnormalities present or detected at the 
start of the study that do not worsen; 
• 
Hospitalizations or procedures that are done for elective purposes not related to an 
untoward medical occurrence (eg, hospitalizations for cosmetic or elective surgery or 
social/convenience admissions); 
• 
The disease being studied or signs/symptoms associated with the disease unless more 
severe than expected for the patient’s condition; 
• 
Overdose of study drug without any clinical signs or symptoms. 
 
11.2.2 Serious adverse event 
A serious adverse event is an AE occurring during any study phase (eg, run-in, treatment, 
washout, follow-up), and at any dose of the investigational product, comparator or placebo, that 
fulfills one or more of the following criteria: 
 
• 
results in death 
 
• 
is immediately life-threatening (defined as an immediate risk of death from the event as it 
occurred) 
 
• 
requires in-patient hospitalization or prolongation of existing hospitalization (Exception: 
hospitalization for elective treatment of a pre-existing condition that did not worsen 
during the study is not considered an adverse event.  NOTE:  Complications that occur 
during hospitalization are adverse events and if a complication prolongs hospitalization, 
then the event is serious) 
 
• 
results in persistent or significant disability or incapacity 
 
• 
is a congenital abnormality or birth defect 
 
• 
is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above. 
 
• 
Is a Grade 4 laboratory abnormality. 
 
The causality of SAEs (their relationship to study treatment) will be assessed by the 
investigator(s). 


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11.3 
Dosing Delays/Dose Modifications 
 
Dose reductions are to be made according to the system showing the greatest degree of toxicity. 
Toxicities will be graded using the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) Version 3. 
 
Dose reductions for toxicity should be made according to guidelines, which follow.  A maximum 
of two 50mg (bicalutamide) dose reductions will be allowed per patient. 
 
11.3.1 Gastrointestinal Toxicity 
 
If ≥ grade 3 diarrhea occurs, that is not controlled with anti-diarrheal agents (eg. loperamide), 
bicalutamide should be withheld until resolution to ≤ grade 1, then reinstituted at the next lower 
dose level. 
 
11.3.2 Breast Pain/Tenderness 
 
If ≥ grade 3 breast pain occurs, that is not controlled with non-opioid pain medications (NSAIDs, 
Tylenol), bicalutamide should be withheld until resolution to ≤ to grade 1, then reinstituted at the 
next lower dose level.  If ≥ grade 3 breast pain occurs at a reduced dose level, and is not 
controlled with non-opioid pain medications, bicalutamide should be withheld until resolution to 
≤ grade 1, then reinstituted at the next lower dose level. If, after 2 dose reductions (to 50mg PO 
daily), ≥ grade 3 breast pain persists, opioid pain medicine is encouraged. If symptoms persist, 
patient may be referred to a radiation oncologist (if no breast irradiation previously administered, 
and at discretion of treating radiation oncologist) for breast irradiation to palliate symptoms.  If 
none of these interventions successfully alleviates symptoms, and if ≥ grade 3 breast pain 
persists, then patient will be discontinued from study. Toxicity will be reported, and patient will 
be evaluated as unable to tolerate bicalutamide.  If ≤ grade 2 breast pain persists, patient may 
elect to stop treatment on study, or to continue. If patient chooses to discontinue study treatment, 
toxicity will be noted; however, this will not constitute unacceptable toxicity for purposes of 
adverse event reporting. 
 
11.3.3 Hot flashes 
 
If ≥ grade 3 hot flashes occur, bicalutamide may be reduced to the next lower dose level, at the 
discretion of the treating physician. Pharmacologic intervention with low-dose SSRI (or an 
alternative oral therapy that has been demonstrated to have beneficial effect for treatment of hot 
flashes greater than that reported for placebo eg. clonidine, buproprion) may be administered. If 
≥ grade 3 hot flashes persist at lower dose level, a second dose reduction may be instituted. If ≥ 
Grade 3 hot flashes persist at lowest treatment dose (50mg), patient will be taken off study, and 
adverse effect will be reported as intolerable toxicity. If ≤ grade 2 hot flashes persist at lowest 
treatment dose (50mg), patient may be taken off study at discretion of treating physician. 
Toxicity will be reported; however, it will not constitute unacceptable toxicity for purposes of 
adverse event reporting. 


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11.3.4 Abnormal Hepatic Function 
 
Bicalutamide should only be administered if hepatic function is within the parameters established 
in the eligibility criteria. Hepatic toxicity from bicalutamide may occur but it is uncommon. 
Therefore, hepatic dysfunction that occurs while the patient is on study should prompt an 
evaluation to determine the cause, including the possibility of progressive metastatic disease and 
hepatotoxicity from concurrent medications.  A maximum of 2 weeks will be permitted for liver 
enzymes to return to within normal range for the institution. 
 
If transaminases (ALT/AST) are elevated > 2.5x normal levels, treatment should be withheld 
until levels fall to ≤ 2.5 x normal levels.  If total bilirubin is elevated > 1.5 x normal level, 
treatment should be withheld until level falls to ≤ 1.5 x normal levels. If alkaline phosphatase is 
elevated > 2.5 x normal value, treatment should be withheld until levels fall to ≤ 2.5 x normal 
level (unless bone metastases are present in the absence of liver metastases).  A dose reduction 
should then be administered following resolution of any or all of these liver enzyme 
abnormalities. 
 
If transaminases are subsequently elevated > 2.5 x normal; or, if total bilirubin is elevated > 1.5 x 
normal value, or if alkaline phosphatase is elevated > 2.5 x normal value (unless bone metastases 
are present in the absence of liver metastases), treatment will again be withheld until AST/ALT 
decrease to ≤ 2.5 x normal, total bilirubin decreases to ≤ 1.5 x normal value and alkaline 
phosphatase decreases to ≤ 2.5 x normal value.  A second dose reduction should then be 
administered. 
 
If, after 2 dose reductions, AST, ALT, total bilirubin and/or alkaline phosphatase remain 
elevated, patient should be taken off study, and laboratory abnormalities should be reported as an 
unacceptable toxicity. 
 
11.3.5 Other toxicities 
 
If toxicities are ≤ grade 2, manage symptomatically if possible and retreat without dose 
reduction. 
 
If toxicities are ≥ grade 3, except for anemia, treatment should be withheld until resolution to ≤ 
grade 1 or baseline if baseline was greater than grade 1, then reinstituted, if medically 
appropriate, at the next lower dose level. 
 
For any grade 3 or 4 toxicity not mentioned above, treatment should be withheld until the patient 
recovers completely or to grade 1 toxicity.  The treatment should then be resumed at the next 
dose level. For grade 1 or 2 toxicities, no dose reduction should be made. 
 
A maximum of two weeks will be permitted for resolution of grade 3 or 4 toxicities. If toxicity 
has not resolved by the end of two weeks, patient will be taken off study. 


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Dose Modification Table 
 
 
Dose Level 
(starting dose) 
Bicalutamide (mg) 
0 
150 
-1 
100 
-2 
50 
 
11.3 Concomitant Treatment/ Medications for Symptom Relief 
 
Irradiation is permitted during the study for treatment of symptomatic breast pain, as outlined 
above, if it is deemed feasible and appropriate care. Administration of other chemotherapy, 
immunotherapy, biologic therapy or anti-tumor hormonal therapy during the study is not 
allowed.  Supportive care, including but not limited to antiemetic medications, may be 
administered at the discretion of the investigator. Concurrent treatment with bisphosphonates is 
allowed.  All concomitant treatments, including blood and blood products, must be reported on 
the case report form.  Granulocyte stimulating factor and/or erythropoietin may be administered 
at the discretion of the investigator, consistent with institution guidelines. 
 
12.1 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
Efficacy, defined as the response rate (CR, PR or SD by RECIST criteria) is the primary 
endpoint of this trial, and patients with measurable disease will be assessed by standard criteria. 
Patients with non-measurable disease will be evaluated for SD or progressive disease only. For 
the purposes of this study, patients should be evaluated radiographically every 12 weeks. In 
addition to a baseline scan, confirmatory CT scan will also be obtained at least 4 weeks 
following initial documentation of an objective response. 
 
A radiologist will review all of the scans with non-measurable and measurable sites 
of disease (e.g. CT scans). Target lesions will be identified prospectively, and recorded on a data 
collection form. These lesions will be followed over the duration of the study as discussed 
below. The use of a designated study radiologist and data collection forms should ensure quality 
assurance and verification of tumor response. At participating sites, staff radiologists may 
evaluate study scans and the principal investigator will calculate response for prespecified target 
lesions. 
 
12.2 
Definitions 
 
Response and progression will be evaluated in this study using the international 
criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) 
Committee [JNCI 92(3):205-216, 2000]. Changes in only the largest diameter (uni 
dimensional measurement) of the tumor lesions are used in the RECIST criteria. 


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Note: Lesions are either measurable or non-measurable using the criteria provided 
below. The term “evaluable” in reference to measurability will not be used because it 
does not provide additional meaning or accuracy. 
 
Measurable Disease: Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as >20 mm with 
conventional techniques (CT, MRI, x-ray) or as >10 mm with spiral CT scan. 
All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
 
Non-measurable Disease: All other lesions (or sites of disease), including small lesions (longest 
diameter <20 mm with conventional techniques or <10 mm using spiral CT scan), are 
considered non-measurable disease. Bone lesions, leptomeningeal disease, 
ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory 
breast disease, abdominal masses (not followed by CT or MRI), and cystic 
lesions are all non-measurable. 
 
Target Lesions: All measurable lesions up to a maximum of five lesions per organ and 10 
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) and their suitability 
for accurate repeated measurements (either by imaging techniques or clinically). 
A sum of the longest diameter (LD) for all target lesions will be calculated and 
reported as the baseline sum LD. The baseline sum LD will be used as reference 
by which to characterize the objective tumor response. 
 
Non-target Lesions:  All other lesions (or sites of disease) should be identified as non-target 
lesions and should also be recorded at baseline. Non-target lesions include measurable 
lesions that exceed the maximum numbers per organ or total of all involved 
organs as well as non-measurable lesions. Measurements of these lesions are not 
required but the presence or absence of each should be noted throughout followup. 
 
12.3 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 and never more than 4 weeks before the beginning of the 
treatment. 
 
Tumor lesions that are situated in a previously irradiated area are considered 
measurable if there is clear disease progression following radiation therapy. 
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 antitumor effect of a treatment. 


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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:  These techniques should be performed with cuts of 10 
mm or less in slice thickness contiguously. Spiral CT 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 (US):   When the primary endpoint of the study is objective response 
evaluation, US 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. US might also be useful to confirm the 
complete disappearance of superficial lesions usually assessed by clinical 
examination. 
 
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor 
evaluation has not yet been fully and widely validated. Their uses in this specific 
context require sophisticated equipment and a high level of expertise that may only be 
available in some centers. Therefore, the utilization of such techniques for objective 
tumor response should be restricted to validation purposes in reference centers. 
However, such techniques can be useful to confirm 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 normal limit, they must normalize for a patient 
to be considered in complete clinical response. 
 
Cytology, Histology. These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in 
tumor types such as germ cell tumors, where known residual benign tumors can 
remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response 
or stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 


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12.4 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 
 
Progressive Disease (PD): At least a 20% increase in the sum of the LD of 
target lesions, taking as reference the smallest sum LD recorded since the treatment started or the 
appearance of one or more new lesions 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR 
nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the 
treatment started 
 
Evaluation of Non-target Lesions 
 
Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level Incomplete Response/ 
Stable Disease (SD): Persistence of one or more non-target lesion(s) 
or/and maintenance of tumor marker level above the normal limits 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Although a clear progression of “non- 
target” lesions only is exceptional, in such circumstances, the opinion of the treating physician 
should prevail, and the progression status should be confirmed at a later time by the review panel 
(or study chair). 
Note: If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the treatment 
started). The patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 


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Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Incomplete 
response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as 
having “symptomatic deterioration.” Every effort should be made to document the 
objective progression, even after discontinuation of treatment. 
 
In some circumstances, it may be difficult to distinguish residual disease from normal 
tissue. When the evaluation of complete response depends on this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) before 
confirming the complete response status. 
Non-measurable disease: Patients with non-measurable disease (ie, bone only disease) will be 
evaluated only as either stable disease or progressive disease. 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
Patients will be removed from the study if any of the following conditions apply: 
 
• 
intercurrent illness which would in the judgment of the investigator effect assessments of 
clinical status to a significant degree or require discontinuation of drug; 
• 
unacceptable toxicity; 
• 
progressive disease; 
• 
request by the patient to withdraw; 
• 
patient non-compliance with protocol; 
• 
irradiation of an indicator lesion during the trial; 
• 
if at the discretion of the investigator continued treatment would be harmful or 
ineffective. 
 
14.0 
BIOSTATISTICS 
 
This is a multicenter, open-label, phase II study to evaluate the efficacy of bicalutamide 
administered orally daily to patients with ER(-)/PR(-)/AR(+) metastatic breast cancer. The 
primary endpoint of this trial is the response rate (RR), defined as the total number of patients 
who demonstrate a complete response (CR), partial response (PR) or stable disease (SD) (after 6 
months from the first day of treatment) divided by the total number of patients treated. Upon 


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completion of the study, the RR will be estimated via the observed response rate and an exact 
confidence interval will be constructed. The response rate for patients with only measurable 
disease will be reported separately as the number of patients who demonstrate a CR, PR or SD 
>6months divided by the number of patients with measurable disease treated with bicalutamide. 
For this trial, a target response rate of 20% or higher is considered promising. A target response 
rate below 5% is considered unacceptable. 
 
This study is designed as a single-stage, phase II which requires a total of 28 patients. If 4 or 
more patients have a CR, PR or SD after 6 months from the first day of treatment, bicalutamide 
will be considered feasible and will merit further clinical study.  With 28 patients, this design 
discriminates between true response rates of ≤ 5% and ≥ 20% at a Type I error of 5% and a Type 
II error of 16%. 
 
Secondary objectives of this study include estimating median progression-free survival at 6 
months and describing the rate of selected non-hematologic and hematologic toxicities. 
Progression-free survival will be estimated by the Kaplan-Meier method.  Selected toxicities will 
be described by frequency and grade, by cycle and overall cycles, with the maximum grade over 
all cycles used as the summary measure per patient.  The safety endpoint will also be measured 
as the percentage of patients who are able to tolerate daily treatment with bicalutamide after a 
maximum of 2 (50mg) dose reductions from the starting dose of 150mg, for 6 months from the 
first day of treatment. 
 
Data analysis plan: 
Upon completion of the study, response rate will be estimated via the observed response rate and 
an exact confidence interval will be constructed. Categorical variables (such as toxicities, 
responses) will be summarized by counts, percentages or contingency tables and confidence 
intervals.  Continuous variables and changes in continuous variables will be summarized by 
means, medians and standard deviations. For the correlative studies, analysis is exploratory in 
nature and hypothesis generating. The relationship between immunohistochemical expression 
and response will be explored using graphical methods. Similarly, changes in hormone levels 
over time during treatment with bicalutamide will be described. 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION 
PROCEDURES 
 
15.1 
Research Participant Registration 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
 
Obtain informed consent, by following procedures defined in section entitled Informed Consent 
Procedures. 
 
During the registration process registering individuals will be required to complete a protocol 
specific Eligibility Checklist. 


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All participants must be registered through the Protocol Participant Registration (PPR) Office at 
Memorial Sloan-Kettering Cancer Center. PPR is available Monday through Friday from 8:30am 
– 5:30pm at 646-735-8000. The PPR fax numbers are (646) 735-0008 and (646) 735-0003. 
Registrations can be phoned in or faxed. The completed signature page of the written 
consent/verbal script and a completed Eligibility Checklist must be faxed to PPR. 
 
15.2 For Participating Centers: 
 
Central registration for this study will take place at Memorial Sloan Kettering Cancer Center 
(MSKCC). 
 
To complete registration and enroll a participant from another institution, the study staff at that 
site must contact the designated research staff at MSKCC to notify him/her of the participant 
registration. The site staff then needs to fax registration/eligibility documents to the 07-022 
Research Staff at MSKCC 646-227-2482. 
 
The following documents must be sent for each enrollment within 24 hours of the informed 
consent form being signed: 
• The completed or partially completed MSKCC eligibility checklist 
• The signed informed consent and HIPAA Authorization form (Research 
Authorization) 
• Supporting source documentation for eligibility questions (laboratory results, 
pathology report, radiology reports, MD notes, physical exam sheets, medical history, 
prior treatment records, and EKG report). 
Upon receipt, the research staff at Memorial Sloan Kettering Cancer Center will conduct an 
interim review of all documents.   If the eligibility checklist is not complete, the patient will be 
registered PENDING and the site is responsible for sending a completed form within 30 days of 
the consent. 
 
If the eligibility checklist is complete, participant meets all criteria, all source documentation is 
received, the participating site IRB has granted approval for the protocol, and the site is in good 
standing with MSKCC, the MSKCC research staff will send the completed registration 
documents to the MSKCC Protocol Participant Registration (PPR) Office to be enrolled as stated 
in section 15.1.  The participant will be registered. 
 
Once eligibility has been established and the participant is registered, the participant will be 
assigned an MSKCC Clinical Research Database (CRDB) number (protocol participant number). 
This number is unique to the participant and must be written on all data and correspondence for 
the participant.  This protocol participant number will be relayed back to study staff at the 
registering site via e-mail and will serve as the enrollment confirmation. 


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16.1 
DATA MANAGEMENT ISSUES 
A Research Study Assistant (RSA) will be assigned to the study. The responsibilities of 
the RSA include project compliance, data collection, abstraction and entry, data reporting, 
regulatory monitoring, problem resolution and prioritization, and coordination of the activities of 
the protocol study team. 
The data collected for this study will be entered into the Clinical Research Database 
(CRDB). Source documentation will be available to support the computerized patient 
record. 
16.1.1 Data Management Requirements for Participating Sites 
Data 
Standardized Case Report Forms (CRFs) and directions for use and sign off requirements have 
been generated for this study. Blank case report forms will be sent to the study staff at each 
participating site for use. The participating Site PI is responsible for ensuring these forms are 
completed accurately, legibly and in a timely manner. 
 
Source Documentation 
 
Source documentation refers to original records of observations, clinical findings and evaluations 
that are subsequently recorded as data. Source documentation should be consistent with data 
entered into CRFs. Relevant source documentation to be submitted throughout the study 
includes: 
 
For Step 1: 
 
o Pathology report confirming ER/PR/AR status. 
 
For Step 2:  
o Baseline measures to assess pre–protocol disease status 
o Medical history 
o Physical examination, including height and weight measurement 
o ECOG performance status 
o Vital signs 
o Prior medication evaluation 
o Laboratory tests (CBC, comprehensive panel, tumor markers) 
o Bone scan or PET Scan 
o CT Chest/Abdomen/Pelvis 
o Pathologic confirmation of breast cancer and hormone receptor status 
o Laboratory records 
o Treatment records 
o Toxicities/adverse events not previously submitted with SAE Reports 
o Response designation 


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16.1.2 Data and Source Documentation Submission for Participating Sites 
 
Participating sites should fax CRFs and source documentation to MSKCC to the contact 
provided below. Submissions should include a cover page listing all CRFs enclosed per 
participant. 
 
FAX: 646-227-2482 to the attention of Protocol 07-022 Research Staff 
 
16.1.3 Data and Source Documentation Submission Timelines for Participating Sites 
 
Data and source documentation to support data should be transmitted to MSKCC according to 
chart 16.0.3.1: 
 
 
Data and Source Submission Requirements and Timelines for Therapeutic Studies 


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Baseline 
Visit 
1 
Visit 2 
Visit 3 
Visit 4 
SAE 
Off 
Study 
SUBMISSION SCHEDULE
Source Documentation 
Within 24 hours 
(see section 
15.1.1) 
within 14 days of the end of cycle 
Within 3 days of 
event (see section 
17.2.1); updates to 
be submitted as 
available 
Within 
14 
days of 
visit 
CRFs 
Within 7 days of 
visit 
Required Forms 
Demographics/Disease 
Form1 
X 
Patient Disease 
X 
Concomitant 
Medications 
Form 
X 
X 
X 
X 
X 
X 
Diagnostic Test Form 
X 
Physical Exam Form 
X 
X 
X 
X 
X 
X 
Pathology Form 
X 
Treatment Form 
X 
X 
X 
X 
X 
Laboratory Form 
X 
X 
X 
X 
X 
X 
Treatment 
Modification Form 
X 
X 
X 
X 
Past Treatment Form 
X 
Comorbidity 
X 
Lesion/EOD Form 
X1 
X 
Toxicity Form 
X 
X 
X 
X 
X 
X 
X 
Serious Adverse Event 
Form 
X 
Hospitalization Form 
X 
Protocol Outcome 
X 
X 
Patient Status Form 
X 
1 For step 1 ineligible patients, this is the only form required. 
 
16.1.4 Data Review and Queries for Participating Site Data 
 
Research staff at MSKCC will review data and source documentation as it is submitted. Data 
will be monitored against source documentation and discrepancies will be sent as queries to 
the participating sites. Queries will be sent by MSKCC Research staff twice a month. 
 
Participating sites should respond to data queries within 14 days of receipt. 


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16.1 
Quality Assurance 
 
Weekly registration reports will be generated to monitor patient accruals and completeness of 
registration data. Routine data quality reports will be generated to assess missing data and 
inconsistencies.  Accrual rates and extent and accuracy of evaluations and follow-up will be 
monitored periodically throughout the study period and potential problems will be brought to the 
attention of the study team for discussion and action.  Random-sample data quality and protocol 
compliance audits will be conducted by the study team, at a minimum of two times per year, 
more frequently if indicated. 
 
16.1.1 Quality Assurance for Participating Sites 
Each site participating in the accrual of participants to this protocol will be audited by the staff of 
the MSKCC study team for protocol and regulatory compliance, data verification and source 
documentation. Audits may be accomplished in one of two ways: (1) selected participant 
records can be audited on-site at participating sites or (2) source documents for selected 
participants will be sent to MSKCC for audit. Audits will usually be determined by participant 
accrual numbers and rate of accrual, but can also be prompted by reported SAEs or request of 
MSKCC PI. 
 
Audits will be conducted at least once shortly after initiation of participant recruitment at a site, 
annually during the study (or more frequently if indicated), and at the end or closeout of the trial. 
The number of participants audited will be determined by available time and the complexity of 
the protocol. 
 
The audit will include a review of source documentation to evaluate compliance for: 
• Informed consent documents and procedures 
• Adherence to eligibility criteria 
• Protocol defined treatment 
• Required baseline, on study and follow-up protocol testing 
• IRB documents (submitted amendments, annual continuing review reports, SAEs) 
• Required specimen submission 
• Pharmacy review, if applicable 
• Case Report Form submissions to MSKCC: timelines and accuracy 
 
A wrap-up session will be conducted at the participating site and preliminary findings will be 
discussed with the participating site PI and research team. The preliminary results will be sent to 
the MSKCC PI. 
 
Each audit will be summarized and a final report will be sent to the PI at the audited participating 
site within 30 days of the audit. The report will include a summary of findings, participant by 
participant case review, specific recommendations on any performance and/or shortcomings and 
request for corrective action, when necessary. When corrective action is required, the 
participating site must reply within 45 days of receipt of audit report with their corrective action 
plan. 


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A copy of the audit report and corrective action plan (if applicable) submitted by the 
participating site must be sent to the MSKCC IRB/PB, CRQA and maintained in the 
department’s protocol regulatory binder. 
 
16.1.2 Response Review 
 
Since therapeutic efficacy is a stated primary objective, all sites participant’s responses are 
subject to review by MSKCC’s Therapeutic Response Review Committee (TRRC).  Radiology, 
additional lab reports and possibly bone marrow biopsies and/or aspirates will need to be 
obtained from the participating sites for MSKCC TRRC review and confirmation of response 
assessment. These materials must be sent to MSKCC promptly upon request. 
 
16.1.3 Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center were 
approved by the National Cancer Institute in September 2001.  The plans address the new 
policies set forth by the NCI in the document entitled “Policy of the National Cancer Institute for 
Data and Safety Monitoring of Clinical Trials” which can be found at:  
http://cancertrials.nci.nih.gov/researchers/dsm/index.html. The DSM Plans at MSKCC were 
established and are monitored by the Office of Clinical Research. The MSKCC Data and Safety 
Monitoring Plans can be found on the MSKCC Intranet at:  
http://mskweb2.mskcc.org/irb/index.htm. 
 
There are several different mechanisms by which clinical trials are monitored for data, safety and 
quality.  There are institutional processes in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff education on 
clinical research QA) and departmental procedures for quality control.  Additionally, two 
institutional committees are responsible for monitoring the activities of our clinical trials 
programs.  The committees, Data and Safety Monitoring Committee (DSMC) for Phase I and II 
clinical trials and the Data and Safety Monitoring Board (DSMB) for Phase III clinical trials, 
report to the Center’s Research Council and Institutional Review Board.  Patients treated 
collaborating institutions will also be included in these reviews. 
 
During the protocol development and review process, each protocol will be assessed for its level 
of risk and degree of monitoring required. Every type of protocol (e.g., NIH sponsored, in-house 
sponsored, industrial sponsored, NCI cooperative group, etc.) will be addressed, and the 
monitoring procedures will be established at the time of protocol activation. 


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16.2 
Regulatory Documentation 
 
Prior to implementing this protocol at MSKCC, the protocol, informed consent form, HIPAA 
authorization and any other information pertaining to participants must be approved by the 
MSKCC Institutional Review Board/Privacy Board (IRB/PB). Prior to implementing this 
protocol at the participating sites, approval for the MSKCC IRB/PB approved protocol must 
be obtained from the participating site’s IRB. 
 
The following documents must be provided to MSKCC before the participating site can be 
initiated and begin enrolling participants: 
• Participating Site IRB approval(s) for the protocol, appendices, informed consent form 
and HIPAA authorization 
• Participating Site IRB approved consent form 
• Participating Site IRB membership list 
• Participating Site IRB’s Federal Wide Assurance number and OHRP Registration number 
• Curriculum vitae and medical license for each investigator and consenting professional 
• Documentation of Human Subject Research Certification training for investigators and 
key staff members at the Participating Site 
• Participating site laboratory certifications and normals 
 
Upon receipt of the required documents, MSKCC will formally contact the site and grant 
permission to proceed with enrollment. 
 
16.2.1 Amendments 
 
Each change to the protocol document must be organized and documented by MSKCC and first 
approved by the MSKCC IRB/PB. Upon receipt of MSKCC IRB/PB approval, MSKCC will 
immediately distribute all non-expedited amendments to the participating sites, for submission to 
their local IRBs. 
 
Participating sites must obtain approval for all non-expedited amendments from their IRB within 
90 calendar days of MSKCC IRB/PB approval. If the amendment is the result of a safety issue or 
makes the eligibility criteria more restrictive, sites will not be permitted to continuing enrolling 
new participants until the participating site IRB approval has been granted. 
 
The following documents must be provided to MSKCC for each amendment within the stated 
timelines: 
• Participating Site IRB approval 
• Participating Site IRB approved informed consent form and HIPAA authorization 


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16.2.2 Additional IRB Correspondence 
Continuing Review Approval 
The Continuing Review Approval letter from the participating site’s IRB and the most current 
approved version of the informed consent form should be submitted to MSKCC within 7 days 
of expiration. Failure to submit the re-approval in the stated timeline will result in suspension 
of study activities. 
 
Deviations and Violations 
A protocol deviation on this study is defined as a request to treat a research participant who 
does not meet all the eligibility criteria, pretreatment evaluation, or who requires alteration in 
their study plan. If a deviation from this protocol is proposed for a potential or existing 
participant at MSKCC or a participating site, approval from the MSKCC IRB/PB is required 
prior to the action. Participating sites should contact the MSKCC PI who will in turn seek 
approval from the MSKCC IRB/PB. 
 
A protocol violation is anything that occurs with a participant, which deviated from the 
protocol without prior approval from the MSKCC IRB/PB. For protocol violations that are 
identified after they occur, the participating site should report to MSKCC as soon as possible. 
The MSKCC PI will in turn report the violation to the MSKCC IRB/PB. 
 
Participating sites should report deviations and violations to their institution’s IRBs as soon as 
possible per that site’s institutional guidelines. Approvals/acknowledgments from the 
participating site IRB for protocol deviations and violations should be submitted to MSKCC 
as received. 
 
Other correspondence 
Participating sites should submit other correspondence to their institution’s IRB according to 
local guidelines, and submit copies of that correspondence to MSKCC. 
 
16.2.3 Document maintenance 
 
The MSKCC PI and the Participating Site PI will maintain adequate and accurate records to 
enable the implementation of the protocol to be fully documented and the data to be 
subsequently verified. 
 
The participating sites will ensure that all participating site IRB correspondence (IRB approval 
letters referencing protocol version date and amendment number, IRB approved protocol, 
appendices, informed consent forms, deviations, violations, and approval of continuing reviews) 
is maintained in the regulatory binder on site and sent to MSKCC. 
 
A regulatory binder for each site will also be maintained at MSKCC; this binder may be paper or 
electronic. 
After study closure, the participating site will maintain all source documents, study related 
documents and CRFs for 3 years. 


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16.3 Noncompliance 
 
If a participating site is noncompliant with the protocol document, accrual privileges may be 
suspended and/or contract payments maybe withheld (if applicable), until the outstanding issues 
have been resolved. 
 
17.1 
PROTECTION OF HUMAN SUBJECTS 
 
Prior to the enrollment of each patient, the risks, benefits and objectives of the study will 
be reviewed with the participant, including a discussion of the possible toxicities and side 
effects. Alternative options for treatment will be reviewed, including chemotherapy or 
hormonal therapy, as appropriate. Financial costs and burdens of the trial will be 
reviewed, including a detailed discussion of the tests that will be the financial 
responsibility of the study, and the tests which will be the financial responsibility of the 
patient. 
 
17.2 Privacy 
 
MSKCC’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
 
17.3 
Serious Adverse Event (SAE) Reporting 
 
Any SAE must be reported to the IRB/PB as soon as possible but no later than 5 calendar days. 
The IRB/PB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office at sae@mskcc.org.  The report should contain the following 
information: 
 
Fields populated from CRDB: 
• Subject’s name (generate the report with only initials if it will be sent outside of 
MSKCC) 
• Medical record number 
• Disease/histology (if applicable) 
• Protocol number and title 
 
Data needing to be entered: 
• The date the adverse event occurred 
• The adverse event 
• Relationship of the adverse event to the treatment (drug, device, or intervention) 
• If the AE was expected 
• The severity of the AE 


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• The intervention 
• Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent form. 
The PI’s signature and the date it was signed are required on the completed report. 
 
17.2.1 Physician Reporting of Adverse Events 
 
Patients in the treatment population will be followed for the development of AEs from study 
drug initiation through the end of study or 30 days after the end of treatment, whichever is 
longer. AEs and SAEs that develop during this period are followed until resolution or 
stabilization (resolved with sequelae). Only patients with clear documentation that no study drug 
was administered may be excluded from the treated population. 
 
The safety/tolerability will be evaluated for treatment-emergent adverse events and serious 
adverse events, laboratory abnormalities, physical examinations, vital signs and patients 
experiencing dose modifications, dose interruptions, and/or premature discontinuation of study 
drug. 
 
The investigator or designee must completely and promptly record each adverse event in the 
source documentation and in the appropriate CRF, regardless of relationship to study drug as 
determined by the investigator.  The Principal Investigator must assess AE/SAE causality for any 
patients treated at his/her site and for any patients treated under the direct care of his/her sub- 
investigators.  The investigator should attempt, if possible, to establish a diagnosis based on the 
patient’s signs and symptoms.  When a diagnosis for the reported signs or symptoms is known, 
the investigator should report the diagnosis, not the symptoms, as the adverse event. 
 
Clinically significant laboratory abnormalities present at the Baseline visit will be recorded as 
pre-treatment signs and symptoms. Clinical Chemistry liver and renal function will be 
summarized using the NCI CTCAE for alkaline phosphatase, AST, ALT, total bilirubin, and 
creatinine. The number and percentage of patients that have each NCI CTCAE grade will be 
summarized using the most severe grade for the first cycle of therapy and for anytime during the 
study. The incidence of patients with clinically significant chemistry values (NCI CTCAE 
toxicity Grades of 3 or 4) that occurred after the first dose of study drug will be presented. Data 
for patients with clinically significant values will also be listed. 
 
AEs and SAEs should be reported on the appropriate Case Report Forms.  In addition, all SAEs 
must be reported promptly to AstraZeneca after the investigator recognizes/classifies the event as 
a SAE. The specific reporting time frame depends on the type of SAE.  For life-threatening or 
fatal events, the investigator must report initial information on the SAE no later than the next 
business day, preferably by fax or alternatively by phone or email; at a minimum, a description 
of the event and the investigator’s judgment of causality must be provided at the time of the 


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initial report.  If a SAE is reported by phone or by e-mail, the investigator must fax a completed 
SAE report form to AstraZeneca within 24 hours. For an event that is not life-threatening or 
fatal, the investigator must fax a completed SAE report form within 2 business days after he/she 
recognizes/classifies the event as a SAE. 
 
SAE reports should be faxed to AstraZeneca at: 1-866-984-7229. 
 
 
“Lack of efficacy” (progressive disease) is not considered an adverse event. The signs and 
symptoms or clinical sequelae resulting from lack of efficacy should be reported if they fulfill 
the adverse event of SAE definitions. 
 
17.2.2 Serious Adverse Event (SAE) Reporting for Participating Sites 
Responsibility of Participating Sites 
• Participating sites are responsible for reporting all SAEs to the MSKCC PI via fax or 
e-mail within 3 calendar days of learning of the event. 
• Participating sites should notify the MSKCC PI of any grade 5 event immediately. 
• Participating sites should use the SAE Report Template (appendix C) to report SAEs 
to MSKCC. 
 
SAE contact information for the Coordinating Center is listed below: 
FAX: 646-227-2482 to the attention of Dr. Traina/07-022 Research Staff at MSKCC 
Responsibility of MSKCC 
• The MSKCC Research Staff is responsible for submitting all SAEs to the MSKCC IRB/PB 
as specified in 17.1 and to AstraZeneca as described in 17.2.1. 
• The MSKCC PI is responsible for informing all participating sites about unexpected SAEs 
and fatalities within 30 days of receiving the stamped SAE from the MSKCC IRB/PB. 
• Any report pertaining to a grade 5 event will be distributed to the participating sites as soon 
as possible. 
 
17.2.3 Safety Reports 
• MSKCC will distribute outside safety reports to the participating sites immediately upon 
receipt. 
• MSKCC must submit safety reports to the MSKCC IRB/PB according to institutional 
guidelines. 
• Participating sites must submit safety reports to their institution’s IRBs within 30 days of 
receipt from MSKCC or per participating site guidelines. 


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17.2.4 Additional Investigator Responsibilities for Follow-up of Serious Adverse Events 
 
The investigator and supporting personnel responsible for patient care should institute any 
supplemental investigations of SAEs based on their clinical judgment of likely causative factors. 
This may include extra clinical laboratory tests, physical examinations or consulting an 
appropriate specialist. Astrazeneca may also request the investigator to conduct supplemental 
assessments.  The results of any additional assessments conducted must be reported to 
Astrazeneca.  If a patient dies during participation in the study and an autopsy is performed, a 
copy of the report must be submitted to Astrazeneca.  If during the follow-up period for an SAE 
a patient dies due to another event unrelated to the SAE being followed, the event causing the 
death will be reported as a separate SAE. 
 
17.2.5 Sponsor Notification of Post-Study Serious Adverse Events 
 
The investigator should notify AstraZeneca of any death or SAE occurring after a patient has 
withdrawn from the study, when such death or SAE may reasonably be related to medication 
used in the study. However, investigators are not obligated to actively seek adverse events in 
former study participants. 
 
Adverse events will be recorded on the case report forms by the investigator using verbatim 
terms that best describe the event.  Grading of severity will be based upon the NCI CTCAE 
version 3.0. All adverse events will be coded to a MedDRA term by the sponsor. All MedDRA 
terms will then be mapped into the appropriate NCI CTCAE version 3.0 term. 
 
Adverse events will be analyzed in terms of treatment-emergent AEs defined to be any AEs that 
begin or worsen in intensity after study drug initiation through 30 days after the last dose of 
study drug. 
 
The incidence of all adverse events (all AEs regardless of causality) and all treatment related 
adverse events (those AEs thought to be possibly, probably or definitely related to study drug) 
will be summarized by NCI CTCAE version 3.0 term and maximum grade. The incidence of 
Serious Adverse Events (SAEs) and AEs that lead to discontinuation of study drug will also be 
summarized.  Listings of patients that discontinued study drug due to an adverse vent, patients 
with SAEs and deaths will be presented.  Patients with SAEs will be described by narrative. 
 
18.1 INFORMED CONSENT PROCEDURES 
Before protocol-specified procedures are carried out, consenting professionals will explain full 
details of the protocol and study procedures as well as the risks involved to participants prior to 
their inclusion in the study. Participants will also be informed that they are free to withdraw from 
the study at any time. All participants must sign an IRB/PB-approved consent form indicating 
their consent to participate. This consent form meets the requirements of the Code of Federal 
Regulations and the Institutional Review Board/Privacy Board of this Center. The consent form 
will include the following: 


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1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of 
supportive care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and 
to withdraw from participation at any time. 
Before any protocol-specific procedures can be carried out, the consenting professional will fully 
explain the aspects of patient privacy concerning research specific information.  In addition to 
signing the IRB Informed Consent, all patients must agree to the Research Authorization 
component of the informed consent form. 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
If modifications are made according to local requirements, the new version has to be approved 
by AstraZeneca. 
 
18.1 For Participating Sites 
 
The investigators listed on the protocol cover page and their qualified designees at each 
participating site may obtain informed consent and care for the participants according to good 
clinical practice and protocol guidelines. 
 
Signed copies of the informed consent should be distributed as follows: One copy will be given 
to the participant to be retained for their personal records. One copy will be maintained on file at 
the MSKCC. The third copy will be confidentially maintained by the participating institution. 
 
A note will be placed in the medical record documenting that informed consent was obtained for 
this study, and that the participant acknowledges the risk of participation. 


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19.0 
REFERENCES 
 
1. Doane AS, Danso M, Lal P, et al. An estrogen-negative breast cancer subset characterized 
by a hormonally regulated transcriptional program and proliferative response to androgen. 
Oncogene, 1-15 [epub ahead of print], Feb 20, 2006 
2. SEER Cancer Statistics Review 1975 - 2001, National Cancer Institute, Joinpoint Regression 
Program Version 2.7, September 2003. 
3. Jemal A, Murray T, Ward E, et al. Cancer statistics, 2005. CA Cancer J Clin 2005;55(1):10- 
30. 
4. Isola JJ.  Immunohistochemical demonstration of androgen receptor in breast cancer and its 
relationship to other prognostic factors.  J Pathol 1993;170(1):31-5. 
5. Agoff SN, Swanson PE, Linden H, Hawes SE, Lawton TJ.  Androgen receptor expression in 
estrogen receptor-negative breast cancer.  Immunohistochemical, clinical, and prognostic 
associations. Am J Clin Pathol 2003;120(5):725-31. 
6. Wong YC, Xie B. The role of androgens in mammary carcinogenesis. Ital J Anat Embryol 
2001;106(2 Suppl 1):111-25. 
7. Kolvenbag GJCM, Blackledge GRP, Gotting-Smith K.  Bicalutamide (Casodex) in the 
treatment of prostate cancer:  history of clinical development. Prostate 1998; 34:61 – 72. 
8. Tyrrell CJ, Kaisary AV, Iversen P et al. A randomized trial of Casodex (bicalutamide) 150 
mg monotherapy versus castration in the treatment of metastatic and locally advanced 
prostate cancer.  Eur Urol 1998; 33:447 – 456. 
9. Cockshott I, Bicalutamide:  Clin Pharmacokinet 2004: 43 (13): 855 – 878. 
10. McLeod D, Iversen P, See W, et al (on behalf of the Casodex Early Prostate Cancer Trialists’ 
Group).  Bicalutamide 150 mg plus standard care vs standard care alone for early prostate 
cancer.  Urol Onc 97, 247 – 254, 2005. 
11. Bahceci M, Alpaslan T, Canoruc N, et al.  Serum C-Reactive Protein (CRP) Levels and 
Insulin Resistance in Non-Obese Women with Polycystic Ovarian Syndrome, and Effect of 
Bicalutamide on Hirsutism, CRP Levels and Insulin Resistance. Horm Res 2004;62:283-287. 
12. Muderris II, Bayram F, Ozcelik B, Guven M, New Alternative Treatment in Hirsuitism 
25mg/day.  Gynecol Endocrinol 2002 Feb; 16(1):63-6. 
13. Narita D, Cimpean AM, Anghel A et al. Prostate-specific antigen value as a marker in breast 
cancer.  Neoplasma 2006;53(2): 161-7. 
14. Mellinghoff IK, Vivanco I, Kwon A et al. 2004 Cancer Cell 6:517-527). 
15. Koziczak M, Hynes NE 2004 J Biol Chem 279:50004-50011. 
16. Perou CM, Sorlie T, Eisen MB et al 2000 Nature 406:747-752. 


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20.0 
APPENDICES 
 
Appendix A – Bicalutamide (drug insert information provided by AstraZeneca) 
 
 
DRUG INFORMATION 
 
CASODEX® 
(bicalutamide) 
TABLETS 
 
 
CLINICAL PHARMACOLOGY 
 
Mechanism of Action 
 
CASODEX is a non-steroidal antiandrogen. It competitively inhibits the action of androgens by 
binding to cytosol androgen receptors in the target tissue. 
 
In clinical trials with CASODEX as a single agent for prostate cancer, rises in serum 
testosterone and estradiol have been noted. 
Pharmacokinetics 
Absorption: 
Bicalutamide is well-absorbed following oral administration, although the absolute 
bioavailability is unknown. Co-administration of bicalutamide with food has no clinically 
significant effect on rate or extent of absorption. 
 
Distribution: 
Bicalutamide is highly protein-bound (96%). See Drug-Drug Interactions below. 
 
Metabolism/Elimination: 
Bicalutamide undergoes stereospecific metabolism. The S (inactive) isomer is metabolized 
primarily by glucuronidation. The R (active) isomer also undergoes glucuronidation but is 
predominantly oxidized to an inactive metabolite followed by glucuronidation. Both the parent 
and metabolite glucuronides are eliminated in the urine and feces. The S-enantiomer is rapidly 
cleared relative to the R-enantiomer, with the R-enantiomer accounting for about 99% of total 
steady-state plasma levels. 


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Special Populations: 
 
Geriatric: 
In two studies in patients given 50 or 150 mg daily, no significant relationship between age and 
steady-state levels of total bicalutamide or the active R-enantiomer has been shown. 
 
Hepatic Insufficiency: 
No clinically significant difference in the pharmacokinetics of either enantiomer of bicalutamide 
was noted in patients with mild-to-moderate hepatic disease as compared to healthy controls. 
However, the half-life of the R-enantiomer was increased approximately 76% (5.9 and 10.4 days 
for normal and impaired patients, respectively) in patients with severe liver disease (n=4). 
 
Renal Insufficiency: 
Renal impairment (as measured by creatinine clearance) had no significant effect on the 
elimination of total bicalutamide or the active R-enantiomer. 
 
Women, Pediatrics: 
Bicalutamide has not been extensively studied in women or pediatric subjects. 
 
Drug-Drug Interactions: 
There is no evidence that bicalutamide induces hepatic enzymes. In vitro protein-binding studies 
have shown that bicalutamide can displace coumarin anticoagulants from binding sites. 
Prothrombin times should be closely monitored in patients already receiving coumarin 
anticoagulants who are started on CASODEX. 
 
Pharmacokinetics of the active enantiomer of CASODEX in normal males and patients with 
prostate cancer are presented in Table 1. 


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Clinical Studies: 
In a multicenter, double-blind, controlled clinical trial, 813 patients with previously untreated 
advanced prostate cancer were randomized to receive CASODEX 50 mg once daily (404 
patients) or flutamide 250 mg (409 patients) three times a day, each in combination with LHRH 
analogues (either goserelin acetate implant or leuprolide acetate depot). 
 
In an analysis conducted after a median follow-up of 160 weeks was reached, 213 (52.7%) 
patients treated with CASODEX-LHRH analogue therapy and 235 (57.5%) patients treated with 
flutamide-LHRH analogue therapy had died. There was no significant difference in survival 
between treatment groups (see Figure 1). The hazard ratio for time to death (survival) was 0.87 
(95% confidence interval 0.72 to 1.05). 


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Figure 1 - The Kaplan-Meier probability of death for both antiandrogen treatment groups. 
 
 
 
 
There was no significant difference in time to objective tumor progression between treatment 
groups (see Figure 2). Objective tumor progression was defined as the appearance of any bone 
metastases or the worsening of any existing bone metastases on bone scan attributable to 
metastatic disease, or an increase by 25% or more of any existing measurable extraskeletal 
metastases. The hazard ratio for time to progression of CASODEX plus LHRH analogue to that 
of flutamide plus LHRH analogue was 0.93 (95% confidence interval, 0.79 to 1.10). 
 
Figure 2 - Kaplan-Meier curve for time to progression for both antiandrogen treatment groups 
 
 


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Quality of life was assessed with self-administered patient questionnaires on pain, social 
functioning, emotional well-being, vitality, activity limitation, bed disability, overall health, 
physical capacity, general symptoms, and treatment related symptoms. Assessment of the 
Quality of Life questionnaires did not indicate consistent significant differences between the two 
treatment groups. 
 
INDICATIONS AND USAGE 
CASODEX is indicated for use in combination therapy with a luteinizing hormone-releasing 
hormone (LHRH) analogue for the treatment of Stage D2 metastatic carcinoma of the prostate. 
 
CONTRAINDICATIONS 
CASODEX is contraindicated in any patient who has shown a hypersensitivity reaction to the 
drug or any of the tablet’s components. 
 
CASODEX has no proven indication for women. Further, CASODEX should not be used by 
women who are or may become pregnant. If this drug is used during pregnancy, or if the patient 
becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to 
the fetus. CASODEX may cause fetal harm when administered to pregnant women. The male 
offspring of rats receiving doses of 10 mg/kg/day (plasma drug concentrations in rats equal to 
approximately 2/3 human therapeutic concentrations*) and above were observed to have reduced 
anogenital distance and hypospadias in reproductive toxicology studies. These pharmacological 
effects have been observed with other antiandrogens. No other teratogenic effects were observed 
in rabbits receiving doses up to 200 mg/kg/day (approximately 1/3 human therapeutic 
concentrations*) or rats receiving doses up to 250 mg/kg/day (approximately 2 times human 
therapeutic concentrations*). 
 
*Based on a maximum dose of 50 mg/day of bicalutamide for an average 70 kg patient. 
 
WARNINGS 
Hepatitis: 
Rare cases of death or hospitalization due to severe liver injury have been reported 
postmarketing in association with the use of CASODEX. Hepatotoxicity in these reports 
generally occurred within the first three to four months of treatment. Hepatitis or marked 
increases in liver enzymes leading to drug discontinuation occurred in approximately 1% of 
CASODEX patients in controlled clinical trials. 
 
Serum transaminase levels should be measured prior to starting treatment with CASODEX, at 
regular intervals for the first four months of treatment, and periodically thereafter. If clinical 
symptoms or signs suggestive of liver dysfunction occur (e.g., nausea, vomiting, abdominal pain, 
fatigue, anorexia, “flu-like” symptoms, dark urine, jaundice, or right upper quadrant tenderness), 
the serum transaminases, in particular the serum ALT, should be measured immediately. If at 
any time a patient has jaundice, or their ALT rises above two times the upper limit of normal, 
CASODEX should be immediately discontinued with close follow-up of liver function. 


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PRECAUTIONS 
General: 
1. CASODEX should be used with caution in patients with moderate-to-severe hepatic 
impairment. CASODEX is extensively metabolized by the liver. Limited data in subjects 
with severe hepatic impairment suggest that excretion of CASODEX may be delayed and 
could lead to further accumulation. Periodic liver function tests should be considered for 
hepatic-impaired patients on long-term therapy (See WARNINGS). 
 
2. In clinical trials with CASODEX as a single agent for prostate cancer, gynecomastia and 
breast pain have been reported in up to 38% and 39% of patients, respectively. 
 
Drug Interactions: 
In vitro studies have shown CASODEX can displace coumarin anticoagulants, such as warfarin, 
from their protein-binding sites. It is recommended that if CASODEX is started in patients 
already receiving coumarin anticoagulants, prothrombin times should be closely monitored and 
adjustment of the anticoagulant dose may be necessary (see CLINICAL PHARMACOLOGY, 
Drug-Drug Interactions). 
 
Carcinogenesis, Mutagenesis, Impairment of Fertility: 
Two-year oral carcinogenicity studies were conducted in both male and female rats and mice at 
doses of 5, 15 or 75 mg/kg/day of bicalutamide. A variety of tumor target organ effects were 
identified and were attributed to the antiandrogenicity of bicalutamide, namely, testicular benign 
interstitial (Leydig) cell tumors in male rats at all dose levels (the steady-state plasma 
concentration with the 5 mg/kg/day dose is approximately 2/3 human therapeutic 
concentrations*) and uterine adenocarcinoma in female rats at 75 mg/kg/day (approximately 1 
1/2 times the human therapeutic concentrations*). There is no evidence of Leydig cell 
hyperplasia in patients; uterine tumors are not relevant to the indicated patient population. A 
small increase in the incidence of hepatocellular carcinoma in male mice given 75 mg/kg/day of 
bicalutamide (approximately 4 times human therapeutic concentrations*) and an increased 
incidence of benign thyroid follicular cell adenomas in rats given 5 mg/kg/day (approximately 
2/3 human therapeutic concentrations*) and above were recorded. These neoplastic changes were 
progressions of non-neoplastic changes related to hepatic enzyme induction observed in 
animal toxicity studies. Enzyme induction has not been observed following bicalutamide 
administration in man. There were no tumorigenic effects suggestive of genotoxic 
carcinogenesis. 
 
A comprehensive battery of both in vitro and in vivo genotoxicity tests (yeast gene conversion, 
Ames, E. coli, CHO/HGPRT, human lymphocyte cytogenetic, mouse micronucleus, and rat bone 
marrow cytogenetic tests) has demonstrated that CASODEX does not have genotoxic activity. 
 
Administration of CASODEX may lead to inhibition of spermatogenesis. The long-term effects 
of CASODEX on male fertility have not been studied. 


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In male rats dosed at 250 mg/kg/day (approximately 2 times human therapeutic concentrations*), 
the precoital interval and time to successful mating were increased in the first pairing but no 
effects on fertility following successful mating were seen. These effects were reversed by 7 
weeks after the end of an 11-week period of dosing. 
 
No effects on female rats dosed at 10, 50 and 250 mg/kg/day (approximately 2/3, 1 and 2 times 
human therapeutic concentrations, respectively*) or their female offspring were observed. 
Administration of bicalutamide to pregnant females resulted in feminization of the male 
offspring leading to hypospadias at all dose levels. Affected male offspring were also impotent. 
*Based on a maximum dose of 50 mg/day of bicalutamide for an average 70 kg patient. 
 
Pregnancy: 
 
Pregnancy Category X: 
(See CONTRAINDICATIONS) 
 
Nursing Mothers: 
 
CASODEX is not indicated for use in women. It is not known whether this drug is excreted in 
human milk. Because many drugs are excreted in human milk, caution should be exercised when 
CASODEX is administered to a nursing woman. 
 
Pediatric Use: 
Safety and effectiveness of CASODEX in pediatric patients have not been established. 
 
 
ADVERSE REACTIONS 
In patients with advanced prostate cancer treated with CASODEX in combination with an LHRH 
analogue, the most frequent adverse experience was hot flashes (53%). 
In the multicenter, double-blind, controlled clinical trial comparing CASODEX 50 mg once daily 
with flutamide 250 mg three times a day, each in combination with an LHRH analogue, the 
following adverse experiences with an incidence of 5% or greater, regardless of causality, have 
been reported. 
 
Side effects that have been reported in men taking bicalutamide with an LHRH analogue on 
clinical trial (regardless of causality) are listed in the following table: 


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Toxicity (by system) 
>5% Frequency  (with % 
frequency, regardless of 
toxicity) 
>/= 2% and < 5% Frequency 
(listed in order of decreasing frequency in 
each system, regardless of causality) 
Abnormal Laboratory 
Values 
AST, ALT, bilirubin, BUN and creatinine, 
decreased hemoglobin and white blood cell 
count 
Constitutional/general 
Pain (general) (35%) 
Back Pain (25%) 
Asthenia (22%) 
Pelvic Pain (21%) 
Infection (18%) 
Abdominal Pain (11%) 
Chest Pain (8%) 
Headache (7%) 
Flu Syndrome (7%) 
Fever 
Chills 
Neoplasm 
Neck Pain 
Sepsis 
Hernia 
Cyst 
Cataract 
Cardiovascular 
Hot Flashes (53%) 
Hypertension (8%) 
Angina Pectoris 
Congestive Heart Failure 
Myocardial Infarct 
Coronary Artery Disorder 
Syncope 
Dermatologic 
Rash (9%) 
Sweating (6%) 
Dry Skin 
Alopecia 
Pruritis 
Herpes Zoster 
Skin Carcinoma 
Skin Disorder 
Gastrointestinal 
Constipation (22%) 
Nausea (15%) 
Diarrhea (12%) 
Increased Liver Enzymes (7%) 
Dyspepsia (7%) 
Flatulence (6%) 
Anorexia (6%) 
Vomiting (6%) 
Melena 
Rectal Hemorrhage 
Dry Mouth 
Dysphagia 
Gastrointestinal Disorder 
Periodontal Abscess 
Gastrointestinal Carcinoma 
Hematologic 
Anemia (11%) 
Metabolic and 
Nutritional 
Peripheral edema (13%) 
Weight loss (7%) 
Hyperglycemia (6%) 
Increased Alkaline Phosphatase 
(5%) 
Weight Gain (5%) 
Edema 
BUN increased 
Creatinine increased 
Dehydration 
Gout 
Hypercholesteremia 
Musculoskeletal 
Bone Pain (9%) 
Myasthenia (7%) 
Arthritis (5%) 
Pathological Fracture (4%) 
Myalgia 
Leg Cramps 
Neurologic 
Dizziness (10%) 
Parasthesia (8%) 
Insomnia (7%) 
Anxiety (5%) 
Depression (4%) 
Hypertonia 
Confusion 
Somnolence 
Libido decreased 
Neuropathy 
Nervousness 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 07-022A(13 ) 
Amended:  8/22/12 
- 51 - 
 
 
 
Respiratory 
Dyspnea (13%) 
Cough increased (8%) 
Pharyngitis (8%) 
Bronchitis (6%) 
Pneumonia (4%) 
Rhinitis (4%) 
Lung disorder 
Asthma 
Epistaxis 
Sinusitis 
Urogenital 
Nocturia (12%) 
Hematuria (12%) 
Urinary Tract 
Infection (9%) 
Gynecomastia (9%) 
Impotence (7%) 
Breast Pain (6%) 
Urinary Frequency (6%) 
Urinary Retention (5%) 
Urinary Impairment (5%) 
Urinary Incontinence (4%) 
Dysuria 
Urinary Urgency 
Hydronephrosis 
Urinary Tract Disorder 
 
The most common side effects reported by men taking bicalutamide with an LHRH analogue 
include hot flashes (53%), breast tenderness (39%) and gynecomastia (38%). 
 
Rare cases of death or hospitalization due to severe liver injury have been reported in association 
with the use of bicalutamide.  Hepatotoxicity in these reports generally occurred within the first 
three to four months of treatment.  Hepatitis or marked increases in liver enzymes leading to 
drug discontinuation occurred in approximately 1% of patients taking bicalutamide on a clinical 
trial.  If clinical symptoms or signs suggestive of liver dysfunction occur (e.g., nausea, vomiting, 
abdominal pain, fatigue, anorexia, “flu-like” symptoms, dark urine, jaundice, or right upper 
quadrant tenderness), the serum transaminases should be measured immediately. 
 
Other adverse experiences (greater than or equal to 2%, but less than 5%) reported in the 
CASODEX-LHRH analogue treatment group are listed below by body system and are in order of 
decreasing frequency within each body system regardless of causality. 
 
Body as a Whole: Neoplasm; Neck pain; Fever; Chills; Sepsis; Hernia; Cyst 
 
Cardiovascular: Angina pectoris; Congestive heart failure; Myocardial infarct; Heart arrest; 
Coronary artery disorder; Syncope 
 
Digestive: Melena; Rectal hemorrhage; Dry mouth; Dysphagia; Gastrointestinal disorder; 
Periodontal abscess; Gastrointestinal carcinoma 
 
Metabolic and Nutritional: Edema; Bun increased; Creatinine increased; Dehydration; Gout; 
Hypercholesteremia 
 
Musculoskeletal: Myalgia; Leg cramps 
 
Nervous: Hypertonia; Confusion; Somnolence; Libido decreased; Neuropathy; Nervousness 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 07-022A(13 ) 
Amended:  8/22/12 
- 52 - 
 
 
Respiratory: Lung disorder; Asthma; Epistaxis; Sinusitis 
 
Skin and Appendages: Dry skin; Alopecia; Pruritus; Herpes zoster; Skin carcinoma; Skin 
disorder 
 
Special Senses: Cataract specified 
 
Urogenital: Dysuria; Urinary urgency; Hydronephrosis; Urinary tract disorder 
 
Abnormal Laboratory Test Values:  Laboratory abnormalities including elevated AST, ALT, 
bilirubin, BUN, and creatinine and decreased hemoglobin and white cell count have been 
reported in both CASODEX-LHRH analogue treated and flutamide-LHRH analogue treated 
patients. 
 
Postmarketing Experience: Rare cases of interstitial pneumonitis and pulmonary fibrosis have 
been reported with CASODEX. 
 
OVERDOSAGE 
Long-term clinical trials have been conducted with dosages up to 200 mg of CASODEX daily 
and these dosages have been well tolerated. A single dose of CASODEX that results in 
symptoms of an overdose considered to be life-threatening has not been established. There is no 
specific antidote; treatment of an overdose should be symptomatic.  In the management of an 
overdose with CASODEX, vomiting may be induced if the patient is alert. It should be 
remembered that, in this patient population, multiple drugs may have been taken. Dialysis is not 
likely to be helpful since CASODEX is highly protein bound and is extensively metabolized. 
General supportive care, including frequent monitoring of vital signs and close observation of the 
patient, is indicated. 
 
DOSAGE AND ADMINISTRATION 
The recommended dose for CASODEX therapy in combination with an LHRH analogue is one 
50 mg tablet once daily (morning or evening), with or without food. It is recommended that 
CASODEX be taken at the same time each day. Treatment with CASODEX should be started at 
the same time as treatment with an LHRH analogue. 
 
Dosage Adjustment in Renal Impairment: 
No dosage adjustment is necessary for patients with renal impairment (see CLINICAL 
PHARMACOLOGY, Special Populations, Renal Insufficiency). 
 
Dosage Adjustment in Hepatic Impairment: 
No dosage adjustment is necessary for patients with mild to moderate hepatic impairment. 
Although there is a 76% (5.9 and 10.4 days for normal and impaired patients, respectively) 
increase in the half-life of the active enantiomer of bicalutamide in patients with severe liver 
impairment (n=4), no dosage adjustment is necessary (see CLINICAL PHARMACOLOGY, 
Special Populations, Hepatic Impairment, PRECAUTIONS and WARNINGS sections). 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 07-022A(13 ) 
Amended:  8/22/12 
- 53 - 
 
 
Appendix B:  Bicalutamide medication diary 
 
Patient Name:    
 
MRN:   
 
 
Cycle 
Day 
Was study 
drug taken 
(circle Y or 
N) 
Date study 
drug taken 
Time study 
drug taken 
AM/PM 
# of 50 mg 
tablets 
taken 
If no study drug taken, 
please explain reason for 
missing dose 
1 
Yes  No 
2 
Yes  No 
3 
Yes  No 
4 
Yes  No 
5 
Yes  No 
6 
Yes  No 
7 
Yes  No 
8 
Yes  No 
9 
Yes  No 
10 
Yes  No 
11 
Yes  No 
12 
Yes  No 
13 
Yes  No 
14 
Yes  No 
15 
Yes  No 
16 
Yes  No 
17 
Yes  No 
18 
Yes  No 
19 
Yes  No 
20 
Yes  No 
21 
Yes  No 
22 
Yes  No 
23 
Yes  No 
24 
Yes  No 
25 
Yes  No 
26 
Yes  No 
27 
Yes  No 
28 
Yes  No 
 
 
MD/RN Signature: 
 
 
Date: 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 07-022A(13 ) 
Amended:  8/22/12 
- 54 - 
 
 
Appendix C: SAE Reporting Form for Multicenter Studies 
 
 
 
 
 
Protocol Title:   
 
 
 
 
 
Participating Site Name:   
 
 
Date of Report:           /        /                   
m    m 
d 
d 
y 
y 
y 
y 
 
Check one: 
 Initial Report 
 Follow-up Report  → 
Date of original Report 
/        /                  
 
m    m 
d 
d 
y 
y 
y 
y 
 
 
 
 
 
 
 
Participant Initials:   
   
 
 
Participant ID:    
 
 
Treatment 
Last Protocol 
Start Date:          /        /                   
Treatment Date:          /        /                   
m    m 
d 
d 
y 
y 
y 
y 
m    m 
d 
d 
y 
y 
y 
y 
 
Participant Status: (check one) 
 Alive 
 Deceased 
 
 
PARTICIPANT INFORMATION 
SERIOUS ADVERSE EVENT REPORT FORM FOR NON-MSKCC SITES 
FOR MSKCC USE ONLY 
MSKCC IRB PROTOCOL #          - 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 07-022A(13 ) 
Amended:  8/22/12 
- 55 - 
 
 
 
 
 
 
Type of Protocol Therapy (circle one): 
 
 Multiple 
 Radiation 
 Transplant 
 Drug 
 Nutrition 
 Alternative Med 
 Surgery 
 Non-Treatment 
 Adoptive Cell 
 
Radiation Therapy 
Surgery Procedure 
Type:  N/A or   
 
Type: N/A or   
 
 
Drug Therapy Agents:  N/A or 
1.   
 
 
 
2.  
 
 
3.   
 
4.  
 
 
 
 
 
Generic Name 
Start Date 
mm/dd/yyyy 
End Date 
mm/dd/yyyy 
 
 
CONCOMINANT MEDICATIONS 
(IF ADMINISTERED WHILE ADMITTED OR POTENTIALLY RELATED TO THE SAE) 
PROTOCOL INFORMATION 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 07-022A(13 ) 
Amended:  8/22/12 
- 56 - 
 
 
 
 
 
SAE 
Start Date 
mm/dd/yyyy 
Event 
Grade1 
SAE 
End Date 
mm/dd/yyyy 
Relationship2 
Expected3 
Severity4 
Intervention5 
 
 
 
1 Grades per CTCAE v.3.0 = 1- Mild, 2-Moderate, 3-Severe, 4-Life Threatening or Disabling, 5-Death 
2 Relationship = 1-Unrelated, 2-Unlikely, 3-Possible, 4-Probable, 5-Definite, 6-Likely, 9-Unknown 
3 Expected= Y-Yes, N-No, U-Unknown, N/E-Not Evaluable 
4 Severity= 1-Life Threatening, 2-Disabling, 3-Hospitalized, 4-Congential Anomaly, 5-Secondary 
Cancer, 
6-Overdose, 7-Serious (other), 8-Not Serious 
5 Intervention= 1-None, 2-Interrupted, 3-Reduced, 4-Discontinued, 5-Med Given, 6-Not Applicable, 7- 
Surgery, 8-Hospitalized, 9-Unknown, 10-Other, 11-Transfusion, 12-Dose Not Escalated, 
13-Pain Meds Lowered,14-Interrupted/Meds Given, 15-Interrupted/Reduced 
 
 
 
 
 
 
 
Lab Test 
Lab Date 
mm/dd/yyyy 
Lab Value 
Baseline 
Value 
Baseline 
Date 
mm/dd/yyyy 
Recovery 
Value 
Recovery 
Date 
mm/dd/yyyy 
 
 
 
 
SAE HEMATOLOGIC INFORMATION 
SAE INFORMATION 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 07-022A(13 ) 
Amended:  8/22/12 
- 57 - 
 
 
 
 
 
 
Brief description of event, including relevant findings:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complications and sequelae (including death):  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient’s past medical history related to this event:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NON HEMATOLOGIC/UNEXPECTED REACTION DETAIL 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 07-022A(13 ) 
Amended:  8/22/12 
- 58 - 
 
 
REPORTING INFORMATION 
 
 
SAE Reported By:    
 
 
Participating Site PI Name (print):  
 
 
Participating Site PI Signature:  
 
 
Date:          /        /                   
m    m 
d 
d 
y 
y 
y 
y