Alternative Dosing of Exemestane in Postmenopausal Women With Stage 0-II ER-Positive Breast Cancer: A Randomized Presurgical Trial
Phase: PHASE2
Conditions: Stage 0 Breast Cancer AJCC v6 and v7, Stage I Breast Cancer AJCC v7, Stage IA Breast Cancer AJCC v7, Stage IB Breast Cancer AJCC v7, Stage II Breast Cancer AJCC v6 and v7, Stage IIA Breast Cancer AJCC v6 and v7, Stage IIB Breast Cancer AJCC v6 and v7
Sponsor: National Cancer Institute (NCI)

DCP Protocol Number MDA2014-04-01 
Protocol Version 11, Amendment 3, Dated 2/10/2018 
 
COVER PAGE 
 
DCP Protocol #: 
MDA2014-04-01  
Local Protocol #: IEO 370; MDACC 2016-0276; CUMC IRB-AAAQ5054; Moffitt Cancer Center 
MCC 18899; Galliera 24 UCS 2017 
 
EudraCT number: 2015-005063-16 
 
Alternative Dosing of Exemestane in Postmenopausal Women with Stage 0-II ER-Positive Breast 
Cancer: a Randomized Presurgical Trial 
 
 
 
Consortium Name:  
 
University of Texas MD Anderson Early Phase Clinical Research 
 
 
 
 
Consortium 
 
MD Anderson Consortium 
Powel H. Brown, MD, PhD 
Principal Investigator:  
Professor and Chair, Department of Clinical Cancer Prevention 
 
 
 
 
University of Texas MD Anderson Cancer Center 
 
 
 
 
1515 Holcombe Boulevard, Unit 1360 
 
 
 
 
Houston, TX 77030-4009 
 
 
 
 
Telephone: (713)-792-4509 
 
 
 
 
Fax: (713) 794-4679 
 
 
 
 
E-mail: phbrown@mdanderson.org 
 
MD Anderson Consortium  
Lana A. Vornik, MHA, MS 
Administrative Director:  
Administrative Director, Protocol Research 
 
 
 
 
Department of Clinical Cancer Prevention 
 
 
 
 
University of Texas MD Anderson Cancer Center 
 
 
 
 
1515 Holcombe Boulevard, Unit 1360 
 
 
 
 
Houston, TX 77030-4009 
 
 
 
 
Telephone: (713) 792-9594 
 
 
 
 
Fax: (713) 745-4230 
 
 
 
 
E-mail: lavornik@mdanderson.org  
 
MD Anderson Consortium 
Saba Abutaseh, BS 
Lead Org Coordinator: 
CLO Coordinator 
 
 
 
 
Department of Clinical Cancer Prevention 
 
 
 
 
University of Texas MD Anderson Cancer Center 
 
 
 
 
1515 Holcombe Boulevard, Unit 1360 
Houston, TX 77030-4009 
Telephone: (713)-745-8181 
Fax: (713) 745-4230 
 
 
 
 
E-mail: sgabutas@mdanderson.org 
 
Consortium Lead Statistician: J. Jack Lee, Ph.D. 
 
1515 Holcombe Boulevard, Unit 447 
Houston, TX 77230 
 
Telephone: (713) 794-4158 
 
Fax: (713) 563-4242 
E-mail: jjlee@mdanderson.org  
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DCP Protocol Number MDA2014-04-01 
Protocol Version 11, Amendment 3, Dated 2/10/2018 
 
Organization:  
 
European Institute of Oncology (IEO) 
 
Protocol Principal Investigator: Bernardo Bonanni, MD 
 
 
 
 
Division of Cancer Prevention and Genetics 
 
 
 
 
Via Ripamonti, 435 
 
 
 
 
20141 Milan, Italy 
 
 
 
 
Telephone: +39-0257489022 
 
 
 
 
Fax: +39-0294379225 
 
 
 
 
E-mail: bernardo.bonanni@ieo.it 
 
Investigator:   
 
Davide Serrano, MD 
  
 
 
Division of Cancer Prevention and Genetics 
 
 
 
 
Via Ripamonti, 435 
 
 
 
 
20141, Milan, Italy 
 
 
 
 
Telephone:+39-0294379653 
 
 
 
 
Fax+39-0294379225 
 
 
 
 
E-mail: davide.serrano@ieo.it 
 
Investigator:   
 
Massimiliano Cazzaniga, MD 
 
Division of Cancer Prevention and Genetics 
 
Via Ripamonti, 435 
20141, Milan, Italy 
 
Telephone:+39-0294379656 
 
Fax+39-0294379225 
 
E-mail: massimiliano.cazzaniga@ieo.it  
 
Investigator:  
Matteo Lazzeroni, MD 
 
Division of Cancer Prevention and Genetics 
 
Via Ripamonti, 435 
20141, Milan, Italy 
 
Telephone:+39-0294379652 
 
Fax+39-0294379225 
 
E-mail: matteo.lazzeroni@ieo.it 
 
Investigator:  
Clara Varricchio, MD 
 
Division of Cancer Prevention and Genetics 
 
Via Ripamonti, 435 
20141, Milan, Italy 
 
Telephone:+39-0257489863 
 
Fax+39-0294379225 
 
E-mail: clara.varricchio@ieo.it 
 
Statistician: 
Sara Gandini, PhD 
 
Division of Epidemiology and Biostatistics,  
 
Via Ripamonti, 435 
20141, Milan, Italy 
Telephone: +39-0257489819 
Fax: +39-0257489813 
E-mail: sara.gandini@ieo.it 
 
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DCP Protocol Number MDA2014-04-01 
Protocol Version 11, Amendment 3, Dated 2/10/2018 
 
Investigator:   
 
Paolo Veronesi, MD 
 
Division of Breast Surgery 
 
Via Ripamonti, 435 
20141, Milan, Italy 
 
Telephone:+39-0257489656 
 
E-mail: paolo.veronesi@ieo.it  
 
Counselor: 
 
 
Irene Feroce, RN 
 
Division of Cancer Prevention and Genetics 
 
Via Ripamonti, 435 
20141, Milan, Italy 
 
Telephone: +39-0257489551 
 
Fax: +39-0294379225 
 
E-mail: Irene.feroce@ieo.it  
 
Investigator:   
 
GiuseppeViale; MD, FRCPath 
 
Division of Pathology 
 
Via Ripamonti, 435 
20141, Milan, Italy 
 
Telephone: +39-0257489420 
 
Fax: +39-0294379225 
 
E-mail: Giuseppe.viale@ieo.it  
 
Pharmacist: 
 
 
Emanuela Omodeo Salè; PhD 
 
Pharmacy Service 
 
Via Ripamonti, 435 
20141, Milan, Italy 
 
Telephone: +39-0257489051 
 
Fax: +39-0294379225 
 
E-mail: eomodeo@ieo.it 
 
Lab Investigator: 
 
Harriet Johansson, MSc, PhD 
 
 
 
 
Division of Cancer Prevention and Genetics 
 
 
 
 
European Institute of Oncology 
 
 
 
 
Via Ripamonti, 435 
 
 
 
 
20141, Milan, Italy 
 
 
 
 
Telephone: +39-0294379654 
 
 
 
 
Fax: +39-0257489809 
 
 
 
 
E-mail: harriet.johansson@ieo.it 
 
Study Coordinator: 
 
Aliana Guerrieri-Gonzaga, MSc 
 
 
 
 
Division of Cancer Prevention and Genetics 
 
 
 
 
European Institute of Oncology 
 
 
 
 
Via Ripamonti, 435 
 
 
 
 
20141, Milan, Italy 
 
 
 
 
Telephone: +39-0257489893 
 
 
 
 
Fax: +39-0294379225 
 
 
 
 
Email: aliana.guerrieri-gonzaga@ieo.it  
 
 
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DCP Protocol Number MDA2014-04-01 
Protocol Version 11, Amendment 3, Dated 2/10/2018 
 
Organization:   
 
E.O. Galliera 
 
Investigator#*:  
 
Andrea De Censi, MD 
 
 
 
 
Medical Oncology Unit 
Mura Cappuccine, 14 
16128 Genoa 16100 
Telephone: +39-0105634501 
Fax: +39-01057481090 
 
E-mail: andrea.decensi@galliera.it 
 
 
Investigator:  
 
Mauro D’Amico, MD 
 
 
 
 
Medical Oncology Unit 
Mura Cappuccine, 14 
16128 Genoa 16100 
Telephone: +39-0105634506 
Fax: +39-01057481405 
 
E-mail: mauro.damico@galliera.it 
 
 
Organization:   
 
Ospedale Villa Scassi-Genova ASL3-Regione Liguria* 
 
Investigator:  
 
Nicoletta Gandolfo, M.D. 
 
 
 
 
Imaging Department 
 
 
 
 
Corso Scassi, 1 
16149 Genova Sampierdarena 
Italy 
 
 
 
 
Telephone:  +39-0108492651  
Fax:  +39-0108492647  
E-mail: nicoletta.gandolfo@asl3.liguria.it  
 
Investigator:  
 
Flavio Guasone, M.D. 
 
 
 
 
Thoracic Surgery Unit 
Corso Scassi, 1 
16149 Genova Sampierdarena 
Telephone: +39-0108492402 
Fax: +39-010849 2511 
E-mail: flavio.guasone@asl3.liguria.it 
*Not an accruing site.  Investigators working in collaboration with E.O. 
Galliera 
 
 
Organization:   
 
Columbia University Medical Center 
 
Investigator#:  
 
Katherine D. Crew, MD, MS 
Medical Oncology 
161 Fort Washington Ave, Room 10-1072 
New York, NY 10032 
Telephone: (212) 305-1732 
Fax: (212) 305-0178 
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Protocol Version 11, Amendment 3, Dated 2/10/2018 
 
E-mail: kd59@cumc.columbia.edu 
 
Investigator:  
  
Emily Chen, PhD  
Department of Pharmacology  
1130 St. Nicholas 
New York NY 10032 
United States   
Telephone: (212) 851-4677  
E-mail: ec2974@columbia.edu  
 
Investigator:   
 
Dawn L. Hershman, MD, MS 
Medical Oncology 
161 Fort Washington Ave, Room 10-1068 
New York, NY 10032 
Telephone: (212) 305-1945 
Fax: (212) 305-0178 
E-mail: dlh23@cumc.columbia.edu 
 
 
Organization:   
 
Moffitt Cancer Center, University of South Florida 
 
Investigator#:   
 
Nagi B. Kumar, PhD, RD, FADA 
Cancer Epidemiology 
12902 Magnolia Drive  
Tampa, FL 33612  
Telephone: (813) 745-6885  
Fax: (813) 745-7183  
E-mail: nagi.kumar@moffitt.org  
 
Investigator:  
 
Heather Han, MD 
 
 
 
 
Oncologic Sciences [Breast Oncology] 
12902 Magnolia Drive 
Tampa, FL 33612 
Telephone: (813) 745-4673 
Fax: (813) 745-7183 
E-mail: Heather.han@moffitt.org 
 
 
Organization:   
 
University of Texas MD Anderson Cancer Center 
 
Investigator#:  
 
Parijatham (Priya) Thomas, MD 
 
 
 
 
Department of Clinical Cancer Prevention 
 
 
 
 
1515 Holcombe Boulevard, Unit 1360 
 
 
 
 
Houston, TX 77030-4009 
 
 
 
 
Telephone: (713) 745-1075 
 
 
 
 
Fax: (713)-745-4218 
 
 
 
 
E-mail: PSThomas@mdanderson.org  
 
Investigator:  
 
Powel H. Brown, MD, PhD 
 
 
 
 
Department of Clinical Cancer Prevention 
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Protocol Version 11, Amendment 3, Dated 2/10/2018 
 
 
 
 
 
1515 Holcombe Boulevard, Unit 1360 
 
 
 
 
Houston, TX 77030-4009 
 
 
 
 
Telephone: (713) 792-4509 
 
 
 
 
Fax: (713) 794-4679 
 
 
 
 
E-mail: phbrown@mdanderson.org 
 
 
Organization@:  
 
Haukeland Hospital 
 
Investigator:  
 
Gunnar Mellgren, MD, PhD 
Laboratory Medicine and Pathology 
 
 
 
 
Haukeland Hospital 
 
 
 
 
Haukelandsveien 22 
 
 
 
 
N-5021 Bergen, Norway 
 
 
 
 
Telephone:   +47-55-974366  
fax:  +47-55-975814  
E-mail: gunnar.mellgren@med.uib.no 
 
 
Organization:   
 
Division of Cancer Prevention, National Cancer Institute 
 
Medical Monitor: 
 
Eva Szabo, MD 
Lung and Upper Aerodigestive Cancer Research Group 
9609 Medical Center Drive, Rm 5E-102 
Bethesda, MD 20892 (For FedEX, Rockville, MD 20850) 
Telephone: +1 (240) 276-7011 
Fax: +1 (240) 276-7848 
E-mail: szaboe@mail.nih.gov 
 
Scientific Monitor: 
 
Brandy Heckman-Stoddard, PhD, MPH 
Breast and Gynecologic Cancer Research Group 
9609 Medical Center Dr. 
Room 5E326 MSC 9783 
Bethesda, MD 20892-9783 
Telephone: (240)276-7048 
Fax: (240)276-7828 
E-mail: heckmanbm@mail.nih.gov 
 
*   Protocol Co-Principal Investigator 
#   Site Principal Investigator 
@  Biomarker Site; No participant accrual occurs at this site 
 
IND Sponsor:  
NCI/Division of Cancer Prevention  
 
IND#  
 
IND# 52662 
Agent(s)/Supplier: 
Exemestane/NCI DCP 
NCI Contract # 
HHSN26120120034I 
 
Protocol Version Date: February 10, 2018 
Protocol Revision or   
Amendment #  
Version 11, Amendment 3 
DCP Protocol Template 
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DCP Protocol Number MDA2014-04-01 
Protocol Version 11, Amendment 3, Dated 2/10/2018 
 
SCHEMA 
 
Alternative Dosing of Exemestane in Postmenopausal Women with Stage 0-II ER-Positive Breast Cancer: a 
Randomized Presurgical Trial 
 
Screening visit (Italian sites only) 
For women with prior histopathologic biopsy diagnosis of in-situ or invasive carcinoma without ER assessment, 
consent to obtain material for ER staining to determining eligibility 
For women without a prior histopathologic biopsy, obtain consent to perform core needle biopsy with requisite 
guidance (palpation or imaging) to assess eligibility criteria based on a diagnosis of ER-positive in-situ or invasive 
breast carcinoma. 
 
Baseline clinic visit (within 14 days prior to randomization)* 
Postmenopausal women with cT0-2, cN0-1, Mx, histologically confirmed ER-positive primary breast cancer or 
women with larger tumors who refuse neo-adjuvant therapy before surgery. No previous treatment for breast cancer. 
Baseline medical history, physical exam, concomitant medication, baseline symptoms, tobacco/alcohol use 
assessment and blood collection for clinical lab tests and circulating biomarkers 
 
Randomization (day 0) 
Eligibility confirmation, randomization (stratification by center and by BMI <25 versus >25 kg/m2) 
 
Intervention (N=180) 
 
For at least four up to six weeks 
Arm 1: Exemestane 25 mg/daily  
Arm 2: Exemestane 25 mg/ 3 times a week (3 active tablets and 4 placebo tablets) 
Arm 3: Exemestane 25 mg/once a week (1 active tablet and 6 placebo tablets) 
 
Treatment start (day 1) 
The participant starts treatment, a telephone contact will be performed only if different from the randomization day 
 
Telephone contact (a week before surgery +3 days) 
Review of self-reported compliance, concomitant medications, toxicity assessment. 
 
Final clinical visit (the day of surgery or the day before)  
Physical exam, toxicity assessment, concomitant medications, blood collection for clinical lab tests and circulating 
biomarkers, compliance/review pill diary. The blood withdrawn for biomarkers will be at 12 hours, 1.5-2.5 days and 
5.5-6.5 days from last active dose respectively for arm 1, 2 and 3 depending on scheduled final visit. Participants 
continue intervention until the night before surgery 
 
Surgery (4 to 6 weeks; ideally at day 29) 
Surgery performed; Surgical specimens collected 
 
* After identifying the pool of 180 potentially eligible women with ER-positive in-situ or invasive breast cancer, 
women in Italy and the U.S. undergo identical procedures. Specifically, consent for blood draw, laboratory testing, 
completion of questionnaire, etc. -as outlined under baseline clinic visit- will be performed.  
 
Endpoints 
Primary endpoint: Percentage change in time of serum estradiol concentration at alternative dosing schedules 
compared to daily dose. 
Secondary endpoints: Safety and toxicity, change in Ki-67 and PgR expression, tissue estradiol, exemestane and 
17-dihydroxyexemestane concentration. 
Circulating estrogens (including ultrasensitive estradiol measurement), androgens and sex hormone binding 
globulin, exemestane and 17-dihydroxyexemestane, adipokines, glucose, insulin and lipid profile. Further secondary 
endpoints will be proteomics and UGT2B17 genotype and measurement of crown-like structures in non-cancerous 
breast fat tissue. 
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TABLE OF CONTENTS 
 
COVER PAGE.............................................................................................................................................. 1 
SCHEMA ...................................................................................................................................................... 7 
1. 
OBJECTIVES ................................................................................................................................ 10 
1.1 
Primary Objective ......................................................................................................................................... 10 
1.2 
Secondary Objectives .................................................................................................................................... 10 
2. 
BACKGROUND ........................................................................................................................... 10 
2.1 
Breast Cancer ................................................................................................................................................ 10 
2.2 
Exemestane ................................................................................................................................................... 10 
2.3 
Rationale ....................................................................................................................................................... 11 
3. 
SUMMARY OF STUDY PLAN ................................................................................................... 14 
4. 
PARTICIPANT SELECTION ....................................................................................................... 15 
4.1 
Inclusion Criteria ........................................................................................................................................... 15 
4.2 
Exclusion Criteria .......................................................................................................................................... 15 
4.3 
Inclusion of Women and Minorities .............................................................................................................. 16 
4.4 
Recruitment and Retention Plan .................................................................................................................... 16 
5. 
AGENT ADMINISTRATION ...................................................................................................... 16 
5.1 
Dose Regimen and Dose Groups ................................................................................................................... 16 
5.2 
Exemestane Administration .......................................................................................................................... 17 
5.3 
Run-in Procedures ......................................................................................................................................... 17 
5.4 
Contraindications .......................................................................................................................................... 17 
5.5 
Concomitant Medications .............................................................................................................................. 17 
5.6 
Dose Modification ......................................................................................................................................... 17 
5.7 
Adherence/Compliance ................................................................................................................................. 18 
6. 
PHARMACEUTICAL INFORMATION ...................................................................................... 19 
6.1 
Exemestane (IND# 52662, IND Sponsor: NCI, DCP) .................................................................................. 19 
6.2 
Reported Adverse Events and Potential Risks ............................................................................................... 19 
6.3 
Availability .................................................................................................................................................... 20 
6.4 
Agent Distribution ......................................................................................................................................... 20 
6.5 
Agent Accountability .................................................................................................................................... 20 
6.6 
Packaging and Labeling ................................................................................................................................ 21 
6.7 
Storage........................................................................................................................................................... 21 
6.8 
Registration/Randomization .......................................................................................................................... 21 
6.9 
Blinding and Unblinding Methods ................................................................................................................ 22 
6.10 Agent Destruction/Disposal .......................................................................................................................... 23 
7. 
CLINICAL EVALUATIONS AND PROCEDURES ................................................................... 23 
7.1 
Schedule of Events ........................................................................................................................................ 23 
7.2 
Pre-study Testing at Italian Sites ................................................................................................................... 25 
7.3 
Baseline Testing/Pre-study Evaluation .......................................................................................................... 25 
7.4 
Evaluation During Study Intervention ........................................................................................................... 26 
7.5 
Evaluation at Completion of Study Intervention ........................................................................................... 26 
7.6 
Post-intervention Follow-up Period .............................................................................................................. 27 
7.7 
Methods for Clinical Procedures ................................................................................................................... 27 
8.  
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITION ........................................... 28 
8.1 
Primary Endpoint .......................................................................................................................................... 28 
8.2 
Secondary Endpoints ..................................................................................................................................... 28 
8.3 
Off-Agent Criteria ......................................................................................................................................... 29 
8.4 
Off-Study Criteria ......................................................................................................................................... 29 
8.5 
Study Termination ......................................................................................................................................... 29 
9. 
CORRELATIVE/SPECIAL STUDIES ......................................................................................... 29 
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9.1 
Rationale for Methodology Selection ............................................................................................................ 30 
9.2 
Comparable Methods .................................................................................................................................... 32 
10. 
SPECIMEN MANAGEMENT ...................................................................................................... 33 
10.1 Laboratories ................................................................................................................................................... 33 
10.2 Collection and Handling Procedures ............................................................................................................. 35 
10.3 Shipping Instructions ..................................................................................................................................... 36 
10.4 Specimen Banking ......................................................................................................................................... 37 
11. 
REPORTING ADVERSE EVENTS ............................................................................................. 37 
11.1 Adverse Events .............................................................................................................................................. 37 
11.2 Serious Adverse Events ................................................................................................................................. 39 
12. 
STUDY MONITORING ............................................................................................................... 40 
12.1 Data Management ......................................................................................................................................... 40 
12.2 Case Report Forms ........................................................................................................................................ 41 
12.3 Source Documents ......................................................................................................................................... 41 
12.4 Data and Safety Monitoring Plan .................................................................................................................. 41 
12.5 Sponsor or FDA Monitoring ......................................................................................................................... 41 
12.6 Record Retention ........................................................................................................................................... 41 
12.7 Cooperative Research and Development Agreement (CRADA)/Clinical Trials Agreement (CTA) ............ 42 
13. 
STATISTICAL CONSIDERATIONS ........................................................................................... 42 
13.1 Study Design/Description .............................................................................................................................. 42 
13.2 Randomization/Stratification ......................................................................................................................... 42 
13.3 Accrual and Feasibility .................................................................................................................................. 42 
13.4 Primary Objective, Endpoint(s), Analysis Plan ............................................................................................. 42 
13.5 Secondary Objectives, Endpoints, Analysis Plans ........................................................................................ 43 
13.6 Reporting and Exclusions .............................................................................................................................. 45 
13.7 Evaluation of Toxicity ................................................................................................................................... 45 
13.8 Evaluation of Response ................................................................................................................................. 45 
13.9 Interim Analysis ............................................................................................................................................ 45 
13.10 Ancillary Studies ........................................................................................................................................... 46 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS ............................................................. 46 
14.1 Form FDA 1572 ............................................................................................................................................ 46 
14.2 Other Required Documents ........................................................................................................................... 46 
14.3 Institutional Review Board Approval ............................................................................................................ 46 
14.4 Informed Consent .......................................................................................................................................... 47 
14.5 Submission of Regulatory Documents .......................................................................................................... 47 
14.6 Other .............................................................................................................................................................. 47 
15. 
FINANCING, EXPENSES, AND/OR INSURANCE ................................................................... 48 
REFERENCES ........................................................................................................................................... 49 
APPENDIX A ............................................................................................................................................. 54 
Appendix B ................................................................................................................................................. 55 
Appendix C ................................................................................................................................................. 58 
 
 
 
 
 
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Protocol Version 11, Amendment 3, Dated 2/10/2018 
 
1. 
OBJECTIVES 
 
1.1 
Primary Objective 
 
It has been shown that exemestane reduces estradiol levels both at the standard dose (25 mg/day) and at 
lower doses. We expect to achieve with 25 mg three times a week and 25 mg/week similar effects in 
estradiol reductions to the standard dose of 25 mg daily.  
Non-inferiority of percent change in time of serum estradiol levels, adjusted for baseline levels, following 
four up to six weeks of exemestane 25 mg given three times per week or one time per week compared 
with exemestane 25 mg daily dosing. 
 
1.2 
Secondary Objectives 
 
Secondary objectives are:  
- To assess safety and toxicity. 
- To support the preventive activity of exemestane we will investigate the change in Ki-67 and 
PgR levels in tumor cells and the adjacent intraepithelial neoplasia or benign histologic 
structures. 
- To assess possible association of estradiol level with tissue and circulating biomarkers. 
- To investigate possible pharmacogenetic markers. 
- To assess drug levels on tissue samples. 
- To investigate tissue and circulating proteomics profiling. 
 
 
2. 
BACKGROUND 
 
2.1 
Breast Cancer 
 
Breast cancer is the most common cancer in women and its incidence is rapidly increasing, largely 
because of an ageing population and several lifestyle changes, such as decreases in physical activity, 
increase in obesity, later age at first childbirth, and reductions in breastfeeding. Estrogen is a key factor in 
breast cancer carcinogenesis, and reductions in its synthesis can decrease breast cancer risk. Estrogen 
production is driven by the aromatase enzyme, which converts androgens to estrogens. Trials in the 
adjuvant setting have shown that aromatase inhibitors effectively prevent breast cancer recurrence (1) and 
breast cancer events in at-risk women (2,3). 
 
The pre-surgical - window of opportunity - trial design has been successfully used to streamline drug 
development, check tumor sensitivity to a given drug and shape up new preventive strategies (4). The 
change in Ki-67 labeling index is considered an appropriate endpoint biomarker for preoperative studies 
(5,6). The post-treatment tumor expression of Ki-67 has been shown to be correlated with disease-free 
survival and overall survival (7). In addition the Ki-67 analysis on adjacent IEN or atypical hyperplasia 
can assess the potential preventive activity of the tested agent (8,9).  
 
2.2 
Exemestane 
 
Exemestane is an irreversible aromatase inhibitor. This drug is highly specific and inhibits peripheral 
conversion of androstenedione to estrogen down to 98%. The drug was recently approved for the adjuvant 
setting, and the placebo–controlled phase III MAP.3 chemoprevention trial showed an overall 65% 
reduction in breast cancers and a specific ER-positive breast cancer reduction of 73% in the intervention 
arm compared to the placebo group (3). 
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Exemestane is in fact a steroidal aromatase inactivator with a long-lasting effect attributable to a tight 
covalent binding to the enzyme. The estradiol suppression persists for at least 5 days after administration 
of a single dose (10). This suggests, especially in a prevention setting, the possibility to reduce the dose 
and change the time schedule, while still maintaining a significant estradiol reduction. A study of 10 
patients found that women who took a daily dose of 10 mg of exemestane achieved equivalent estradiol 
suppression as women who took a dose of 25 mg daily (11). 
The exemestane steroidal structure suggests it may have androgenic properties that could potentially 
counteract any anti-estrogenic properties in bone and possibly sexual function and menopausal symptoms. 
The favorable profile on bone may represent an advantage of this agent in prevention settings in 
unaffected women at increased risk for breast cancer. 
 
2.3 
Rationale 
 
Despite the strong positive findings in breast cancer prevention with tamoxifen, the attitude towards 
chemoprevention remains ambivalent, and the associated side effects hamper the drug uptake by high-risk 
women who could benefit from its preventive effects.  
Among the strategies to overcome tamoxifen side effects, we have intensively investigated alternative low 
doses of tamoxifen in several phase II studies (12-14), and in two phase III studies (15,16). 
More recently AIs have proven their capability to lower cancer incidence in high risk women. The 
Mammary Protocol 3 (MAP.3) trial (3) was a randomized, placebo-controlled, double-blind trial of 
exemestane 25 mg/day administered to postmenopausal women 35 years or older with at least one of the 
following risk factors: 60 years or older; Gail 5-year risk score greater than 1.66%; prior atypical ductal or 
lobular hyperplasia or LCIS; or DCIS with mastectomy. A total of 4,560 women (median age 62.5 years, 
median Gail risk score 2.3%) were randomly assigned to either exemestane or placebo. At a median 
follow-up of 35 months, 11 invasive breast cancers were detected in those given exemestane and 32 in 
those given placebo, with a 65% relative reduction in the annual incidence of invasive breast cancer 
(0.19% vs 0.55%; HR 0.35, 95% CI 0.18-0.70; p = 0.002). 
The IBIS II Prevention trial included 1,920 women randomly assigned to receive anastrozole 1 mg daily 
and 1,944 assigned to placebo. After a median follow-up of 5 years, 2% of women in the anastrozole 
group vs. 4% in the placebo group have developed breast cancer (HR 0.47 95% CI 0.32, 0.68; p < 
0.0001). The predicted cumulative incidence of all breast cancers after 7 years has been 5.6% in the 
placebo group and 2.8% in the anastrozole group (2). Musculoskeletal adverse events were common in 
the anastrozole group, but mostly of moderate severity. Vasomotor symptoms were common in both 
groups but the incidence was higher in women on anastrozole. No increases in fractures, myocardial 
infarction, or cardiac failure were observed between the groups. 
However we might expect that an AI would achieve low acceptability similar to the SERMs by high risk 
women for the undesirable symptoms, bone density loss, musculoskeletal ache, climacteric syndrome, and 
ultimate possible impact on QoL, significantly compromising their motivation and adherence to a 
preventive treatment. Therefore, a significant step forward to promote breast cancer prevention in 
postmenopausal women is to ameliorate QoL issues by seeking for the minimally active AI dose and an 
intermittent schedule. A lighter schedule, compared to the standard regimen, may be much more 
appealing to a healthy at-risk woman. 
 
For this purpose we are proposing a pre-surgical phase IIb, randomized, double-blind, multi-center study 
for postmenopausal women with histologically confirmed ER-positive breast cancer (Stage 0-II) 
comparing the exemestane standard daily dose regimen versus two alternative, less frequent dose 
regimens. 
 
Rationale for Biomarkers 
Estradiol: Overall, a strong positive association between breast cancer risk and circulating levels of 
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estrogens is now well confirmed among postmenopausal women; the top 20% hormone levels versus 
bottom 20% have a two- to three-fold higher risk of breast cancer (17). Interestingly, circulating estradiol 
levels can predict risk of hormone receptor positive breast cancer for up to 16-20 years. Top versus 
bottom quartile contrast RR was 2.0 (95% CI: 1.4-2.7; p trend<0.001) for <10 years, 2.0 (95%CI: 1.3-3.1; 
p trend=0.002) for >10-20 years before diagnosis (18). 
The direct consequence of AIs in postmenopausal women is a steep decrease in circulating estrogens and 
their metabolites. For the assessment of exemestane activity at different doses and schedules the most 
appropriate biomarker appears to be circulating estradiol concentrations (19-21). In postmenopausal 
women, estradiol levels are low and their assessment is technically challenging as routine labs generally 
lack standardized sensitive methods. During estrogen suppression with AIs for breast cancer treatment 
and prevention, the accuracy of estradiol assay becomes of paramount importance as plasma levels are 
very low (<5 pmol/L). Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) 
provides greater sensitivity and specificity than radio immunoassays (RIA). 
 
Ki-67: Several studies indicate that staining with the Ki-67 antibody may be useful in monitoring 
response to anti-estrogen therapy. We previously conducted a presurgical trial assessing tamoxifen dose 
escalation. Our study showed that the effects of tamoxifen on breast cancer cell proliferation, as assessed 
by the change in the percentage of cells expressing Ki-67, was comparable among women who received a 
daily tamoxifen dose of 1 mg, 5 mg, or 20 mg administered for 4 weeks (22). These results led us to focus 
on low dose tamoxifen in several chemoprevention trials. Ki-67 proliferation index has hence increasingly 
been used as a surrogate endpoint. Additional evidences from neoadjuvant trials pointed to a prognostic 
value of Ki-67. Measurements of tumor Ki-67 level after only 2 weeks treatment with either tamoxifen or 
anastrozole or their combination improved the prediction of recurrence-free survival over baseline Ki-67 
after a median of 3 years in postmenopausal women (6,23).  
Our findings on standard and low dose tamoxifen confirmed this observation, Ki-67 expression after 4 
weeks of tamoxifen predicted recurrence-free and overall survival significantly better than baseline Ki-67. 
Post-tamoxifen Ki-67 point increase predicted a 5% significant increased risk of breast cancer recurrence. 
Likewise, overall mortality, mostly due to breast cancer, was better predicted by post-tamoxifen Ki-67 
(7).  
More recently, we conducted a WOP trial in postmenopausal women with exemestane (25 mg/day) 
demonstrating a significant reduction in Ki-67 (a 10 point decrease) without any significant toxicity(24). 
To support the hypothesis of an alternative dose , the Ki-67 was reduced at the same extent irrespective of 
time since last drug intake (<24 hours or >24 hours) and serum concentrations of exemestane (10 nM vs 2 
nM), according to time since last drug intake (25). 
 
Progesterone Receptor (PgR): Compared to Ki-67 the role of PgR is less clear, at least with tamoxifen 
treatment (26). Its modulation by tamoxifen is controversial, some studies showed no significant effect on 
PgR expression. In a low percentage of participants a decreased expression after short tamoxifen 
treatment has been observed, and these participants showed a worse response to the treatment, but the 
data were more informative if both pre and post treatment PgR expression was taken into account (27). 
Moreover, this receptor may change in time also with no treatment. Similarly to Ki-67 exemestane can 
significantly reduce PgR expression after 6 weeks of treatment (24). It will be useful to compare the 
modulating effect by exemestane dose and eventually correlate it to Ki-67 changes. 
 
Sex Hormones: Similarly to estradiol, other circulating sex hormones are involved in breast 
carcinogenesis, and their analysis can contribute to a better understanding of their role in the tumor 
pathogenesis and drug efficacy through their modulation. Among postmenopausal women, higher levels 
of endogenous sex hormones and lower levels of sex hormone binding globulin (SHBG) are associated 
with increased risk of breast cancer. Literature data clearly show the AIs activity on these hormones is 
due to the direct enzyme inactivation. We have recently published data in premenopausal women that 
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showed in a multivariable analysis that SHBG had an HR = 2.26 (95 %CI 1.04-4.89) for the lowest versus 
the highest tertile (28). Endocrine effects of exemestane standard treatment in postmenopausal breast 
cancer patients result in suppression of estrone, estradiol and estrone sulfate and lowering of SHBG 
levels, and it increases testosterone, DHEAS and FSH levels. In this study it will be useful to compare the 
modulation of such hormones to evaluate the drug activity at different schedules. Their evaluation may 
help to understand the activity of the different proposed doses, and eventually provide an indication to 
response prediction (19,29,30). 
 
Insulin – Insulin resistance: There is evidence of an association of androgen excess and insulin 
resistance, glucose intolerance and dyslipidemia in animal models as well as in women. Insulin resistance 
is considered an important feature of the metabolic syndrome, and is a risk factor for cardiovascular 
diseases, type 2 diabetes and cancer (31,32).  
In aromatase deficient mice, in association with the increased levels of androgens, increased abdominal 
adiposity and higher insulin levels has been described. Several polymorphisms of the aromatase gene 
CYP19 (rs1008805, rs2446405 and rs2414096) are associated with increased risk for insulin sensitivity 
and diabetes in African Americans, Caucasians and Japanese(33). Based on these observations, we will 
measure insulin, glucose levels and insulin sensitivity (HOMA) to assess whether there is a different 
effect among the three exemestane doses.  
 
Lipid profile: A concern with the use of aromatase inhibitors relates to an increased risk of 
cardiovascular events. It has been reported that, in postmenopausal women, the increase in cardiovascular 
risk may be ascribed to changes in lipid metabolism and, above all, to the elevation of low-density 
lipoprotein (LDL) cholesterol. Amongst aromatase inhibitors, exemestane may potentially have a more 
neutral effect on circulating lipid changes compared to letrozole and anastrozole. After 6 weeks treatment 
of exemestane (24), total and HDL cholesterol decreased by -10 mg/dL (IQR -21 to –2) and _-7 mg/dL, 
(IQR -14 to -2), respectively. Triglycerides were reduced by -8 mg/dL (IQR -28 to –9). Similar results 
were previously described, however associated with an increase in LDL-cholesterol(34,35). Based on 
these observations, we will measure total, LDL,HDL cholesterol and triglyceride levels to assess whether 
there is a different effect among the three exemestane doses. 
 
 
Adipokines: In the global picture of breast carcinogenesis, adipose tissue has been shown to play an 
important role. In particular, two adipokines, leptin and adiponectin, have been studied as risk biomarkers 
for breast cancer associated with obesity in postmenopausal breast cancer patients. Leptin may influence 
breast cancer through enhancing expression of aromatase providing a link between body weight (adipose 
tissue), estrogen levels and the risk for breast cancer development as well as poor prognosis (36). 
Adiponectin appears to have anti-inflammatory, antiatherogenic, anti-angiogenic and anti-diabetic 
properties. Serum adiponectin levels are reduced in obese women and they increase after relevant weight 
loss. Low levels of adiponectin are also closely linked to insulin resistance and hyperinsulinemia, which 
were demonstrated to be positively associated with breast cancer risk (37). 
In a few subjects, it has been reported that exemestane can reduce leptin plasma level (38); if this effect 
can be confirmed on a larger population it can be considered an additional activity and potential effect for 
cancer treatment as well as prevention. 
 
Proteomics: Proteomic analyses have been studied, with varying success, to identify on breast cancer 
tissue an expression profiling in order to discover protein biomarkers/signatures suitable for: 
characterization and subtyping of tumors, early diagnosis, and both prognosis and prediction of outcome 
(39). This dataset will allow us to run spectra network analysis for protein identification and 
comprehensive characterization of post-translational modifications, in addition to the traditional database 
search approach. It will also allow us to further develop the spectra network analysis algorithm for higher 
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charged peptides using multiple fragmentation capability of the new Fusion Tribrid mass spectrometer in 
Dr. Chen’s Proteomics Shared Resource for the Herbert Irving Comprehensive Cancer Center (HICCC) at 
CUMC (40,41). 
 
UGT2B17: Exemestane and its major metabolite 17-dihydroexemestane are metabolized by UGT 
enzyme. UGT genetic variations play a role in altered 17-dihydroexemestane glucuronidation and overall 
exemestane metabolism. The prevalence of the polymorphic UGT2B17 whole-gene deletion is 
approximately 30% in Caucasians. In vitro studies UGT2B17 gene deletion correlates with a significant 
decrease of 17-dihydroexemestane excretion and consequently increasing circulating levels (42). This 
could reflect an increased exemestane activity. We have data from a pre-surgical study, consistent with 
these observations, showing a significant association of the UGT2B17 deletion with increased serum 
concentration of 17-dihydroexemestane (25). Interestingly, Ki-67 decreased equally irrespective of time 
since last drug intake supporting the rationale of testing differential drug schedules. 
 
Crown-like structures: The potential links between obesity, inflammation, and aromatase expression are 
still unclear. In both dietary and genetic models of obesity, necrotic adipocytes surrounded by 
macrophages forming crown-like structures (CLS) in the mammary glands and visceral fat have been 
observed. The presence of CLS was associated with activation of NF-κB and increased levels of 
proinflammatory mediators (TNF-α, IL-1β, Cox-2), which were paralleled by elevated levels of aromatase 
expression and activity in the mammary gland and visceral fat of obese mice (43). These preclinical 
findings were further assessed in 30 women undergoing breast surgery (44). CLS of the breast (CLS-B) 
was found in nearly 50% (14 of 30) of patient samples. The severity of breast inflammation, defined as 
the CLS-B index, correlated with both body mass index (P < 0.001) and adipocyte size (P = 0.01). 
Increased NF-κB binding activity and elevated aromatase expression and activity were found in the 
inflamed breast tissue of overweight and obese women. 
 
 
3. 
SUMMARY OF STUDY PLAN 
 
We will conduct a multicenter, pre-surgical double-blind non-inferiority phase IIb study in which 
participants will be randomized to receive either exemestane 25 mg/day or 25 mg/ three times a week or a 
single dose of 25 mg/week for a minimum of 4 up to 6 weeks. 
 
A total of 180 post-menopausal women will be accrued; 60 per arm, enrolled in 35 months and treated for 
a minimum of 4 up to 6 weeks. 
 
Participants will be histologically-confirmed ER-positive (ER >10%) primary breast cancer patients who 
are candidates for breast surgery. Postmenopausal women younger than 76 years of age with cT0-2, cN0-1, 
Mx or women with larger tumors who refuse neo-adjuvant therapy before surgery are eligible. No 
previous treatment for breast cancer is allowed. 
 
Complete physical exam and safety lab tests will be performed at baseline and at end of treatment (28+1, 
35+1, 42+1 days). Phone contact will occur at day 1 and a week before surgery (+3 days). 
 
Biomarkers: blood samples will be collected at baseline and the end of treatment (fasting blood for 
biomarkers will be collected prior to randomization and either on the day of surgery or the day before; 
fasting is strongly recommended but is not mandated), tissue samples will be collected from the 
diagnostic or research biopsy and at the time of surgery.  
 
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Duration of study will be four years: 35 months for accrual, 4-6 weeks of treatment, and one year for 
biomarkers measurement. 
 
 
4. 
PARTICIPANT SELECTION 
 
4.1 
Inclusion Criteria 
 
4.1.1 
Postmenopausal women (* postmenopausal: age >60 years, or amenorrhea ≥ 12 months, or 
bilateral oophorectomy, or - in women with hysterectomy only - FSH in the menopausal levels as per 
local institutional guidelines if < 60 years old) with histologically-confirmed ER-positive (≥ 10%) 
primary breast cancer stage cT0-2, cN0-1, Mx. Women with larger tumors who refuse chemo and/or 
endocrine neoadjuvant therapy can be eligible. 
 
 
4.1.2 
ECOG performance status ≤1 (Karnofsky ≥70%; see Appendix A). 
 
4.1.3 
Participants must have normal organ and marrow function as defined below: 
 
Leukocytes 
 
 
≥3,000/microliter 
Absolute neutrophil count 
≥1,500/microliter 
Platelets 
 
 
≥100,000/microliter 
Total bilirubin  
 
< 2 x institutional ULN   
AST (SGOT)/ALT (SGPT) 
≤1.5 × institutional ULN 
Serum creatinine 
 
< 1.5 times institutional ULN 
 
4.1.4  Ability to understand and the willingness to sign a written informed consent document. 
 
4.2 
Exclusion Criteria 
 
4.2.1 
BMI < 18.5 Kg/m2. 
 
4.2.2 
Previous treatment for breast cancer including chemotherapy, endocrine therapy and 
radiotherapy. Women with prior DCIS who were treated with surgery only and whose treatment ended >2 
years prior to enrollment are eligible for the trial. 
 
4.2.3 
Women who are planned to receive neoadjuvant therapy. 
 
4.2.4 
Participants may not be receiving investigational agents. 
 
 
4.2.5 
History of allergic reactions attributed to compounds of similar chemical or biologic composition 
to exemestane. 
 
4.2.6 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric 
illness/social situations that would limit compliance with study requirements. 
 
4.2.7  Other co-existing invasive malignancies (with the exclusion of basal cell carcinoma or skin 
squamous cell carcinoma) diagnosed during the last 2 years before randomization. 
 
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4.2.8 
History of severe osteoporosis (T score < -4 either spine or hip), or presence of vertebral fracture. 
 
4.2.9 
Use of systemic Hormone Replacement Therapy (HRT) in the last 30 days prior to the 
randomization. The use of non-systemic estrogen (such as vaginal estrogen use) is allowed. 
 
4.2.10 Use of any chemopreventive agents (SERM) in the last 3 months. 
 
4.2.11 Concomitant use of CYP3A4 inducer medication (rifampicin, phenytonin, carbamazepine, 
phenobarbital, and St. John’s wort).  
 
4.3 
Inclusion of Women and Minorities 
 
Participants will be adult women of all races and ethnic groups. Breast cancer is extremely rare in men 
and men have limited amounts of normal breast tissue; therefore, male participants will not be recruited to 
this trial. Children will not be recruited to the trial because breast cancer is not relevant to the child 
population. Every attempt will be made to recruit minority women at the Italian sites. However, given that 
the distribution of the Italian population mainly consists of white Caucasians (about 93%), we expect very 
few participants of different ethnic background to be enrolled at the Italian sites. At the US sites efforts 
will be made to enroll women from a diversity of ethnic and socio-economic backgrounds. 
 
4.4 
Recruitment and Retention Plan 
 
This multicenter protocol will be conducted at the following five sites: the European Institute of 
Oncology (IEO), Milan, Italy; the E.O. Galliera, Genoa, Italy; the Columbia University Medical Center 
(CUMC), New York, NY; the UT MD Anderson Cancer Center, Houston, TX; and the Moffitt Cancer 
Center, University of South Florida, Tampa, FL. The IEO will be the Lead Site. The high rate of breast 
cancer surgeries at these sites will allow the recruitment of the required samples size. Efforts will be made 
to enroll women from a diversity of ethnic and socio-economic backgrounds. Recruitment and retention 
effort will be evaluated routinely by the site coordinator and the study staff. The study recruitment and 
retention plan will be modified as necessary to promote rapid accrual and to assure 100% recruitment rate 
of participants. Please refer to the study-specific recruitment and retention plan for more details. 
 
 
5. 
AGENT ADMINISTRATION 
 
Intervention will be distributed on an outpatient basis. Reported adverse events (AEs) and potential risks 
are described in Section 6.2.  
 
5.1 
Dose Regimen and Dose Groups 
 
Arm 1 
Agent: Exemestane 
Doses: one dose of 25 mg once a day 
Duration: 4 to 6 weeks 
 
Arm 2 
Agent: Exemestane 
Dose: 25 mg three times a week 
Duration: 4 to 6 weeks 
 
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Arm 3 
Agent: Exemestane 
Doses: 25 mg once a week 
Duration: 4 to 6 weeks 
 
5.2 
Exemestane Administration 
 
Investigational drug pharmacy will be responsible for drug distribution. Dr. Bonanni (PI) and the local 
Site Investigators or their designees will be responsible for drug administration. They can delegate to 
other study investigators (MDs and research nurses) to distribute the agent on their behalf. 
 
Participants will receive a 6-week supply (2 wallets containing 3 blisters each) of the drug/placebo as 
outlined in the clinical procedure schema (see Section 7.1 for a detailed description). Each wallet will 
consist of 3 blisters, each blister for 7 days of treatment. Each blister will have 7 tablets numbered from 1 
to 7 to clearly mark the order to be taken by the participants. Based on the arm, the blister will contain 7 
active tablets 1 through 7, or three active tablets corresponding to days 1, 3 and 5 and four placebo tablets 
at days 2, 4, 6 and 7, or one active tablet placed at day 1 and 6 placebo in the remaining 6 days. The 
participant will be advised to take one tablet per day after dinner, always at approximately 8 PM, starting 
from day 1 till the night before surgery. If for any reason they will skip a tablet they will be instructed to 
leave it behind and take the one for the corresponding day. Participants will be asked to contact the study 
coordinator the first time they miss a dose. 
 
5.3 
Run-in Procedures  
 
No run-in procedure will take place in the present protocol. 
 
5.4 
Contraindications 
 
Eligible participants should not have specific contraindication to exemestane, considering also the short 
period of treatment. Any pre-existing musculoskeletal disorder should be carefully evaluated before 
enrolling the participants. Furthermore, medications that may impact participant safety or scientific 
integrity of the study are non-allowed, such as the following: strong CYP 3A4 inducers (e.g., rifampicin, 
phenytoin, carbamazepine, phenobarbital, or St. John’s wort). 
 
5.5 
Concomitant Medications 
 
All medications (prescription and over-the-counter), vitamin and mineral supplements, and/or herbs taken 
by the participant will be documented on the concomitant medication CRF and will include: 1) start and 
stop date, dose and route of administration, and indication. Medications taken for a procedure (e.g., 
biopsy) should also be included.  
 
5.6 
Dose Modification 
 
Participants will be asked to maintain the full dose throughout the treatment period. Due to the short time 
of treatment no dose modification will be applied. 
 
Toxicity will be evaluated using the NCI terminology criteria (CTCAE version 4.0.3, published 
06/14/2010). 
 
If grade 1 or 2 toxicity occurs, the participant will be maintained on treatment irrespective of attribution to 
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the study drug. In case of grade 3 toxicity unrelated or unlikely to be related to study treatment, 
participant may remain on treatment as per physician judgment, women who experience other grade 3 or 
more severe adverse events will be removed from the study.  
 
 
Toxicity 
Attribution to study drug 
Grade 
Unrelated 
Unlikely 
Possible 
Probable 
Definite 
1 
C 
C 
C 
C 
C 
2 
C 
C 
C 
C 
C 
3 
C1 
C1 
W 
W 
W 
4 
W 
W 
W 
W 
W 
 
C =  
Continue drug 
 
C1 =  
Continue drug as per physician judgment 
 
W =  
Withdrawal 
 
5.7 
Adherence/Compliance 
 
5.7.1 
 
There is no “gold standard” yet on how to measure participant compliance. Recent data from ongoing 
chemoprevention studies have estimated compliance to be between 60% and 100%, and this disparity can 
be attributed to adherence methodology assessment.  
Compliance estimates will be limited to pills that fall within the required dosing period (depending on 
total number of days between first dose and surgery). To be compliant, a participant has to take ≥ 80% of 
the active scheduled pills overall and also specifically, ≥ 80% compliant in the last 7 days before surgery. 
We propose the use of multiple methods of adherence monitoring: subject self-reporting, pill diary and 
tablets count. Drug and its metabolite will be also measured, but due to different schedules and the half-
life of exemestane, these measurements may not be indicative of compliance for arms 2 and 3.  
 
5.7.2 
 
Pill diary completion: Each participant will receive a 42 days diary to facilitate tracking and recording of 
pill intake (Appendix B). Each participant will be asked to write Yes/No in the corresponding day of the 
diary and to register the time of drug intake. Participants are asked to fill the diary and some additional 
space will be left for participant’s notes. Participants will be asked to contact the study coordinator the 
first time they miss a dose. Each pill diary will be returned at the final scheduled visit. The amount of pills 
and the pill diary are for the total admitted period of treatment. 
 
Dose count: Each participant will receive a 42 day supply of the drug / placebo and will be asked to return 
both wallets with full and empty blisters. Overall compliance will be measured by blinded staff as 
follows: 
number of tablets taken (i.e., number of tablets given-number of tablets returned)/number of tablets that 
should have been taken during that period of time. 
Any missed pill in each blister will be recorded in order to collect the compliance of active pills at a later 
stage (unblinded statistician). 
 
In cases where the tablets are not returned, the compliance will be calculated only from the pill diary. 
 
Drug/metabolite plasma levels: Circulating levels of exemestane and 17-dihydroxyexemestane will be 
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measured using LC-MS/MS technology. 
 
 
6. 
PHARMACEUTICAL INFORMATION 
 
6.1 
Exemestane (IND# 52662, IND Sponsor: NCI, DCP) 
 
Exemestane is a steroidal, suicide inhibitor of aromatase, the principal enzyme that converts androgens to 
estrogens. Exemestane is approved for adjuvant treatment of postmenopausal women with estrogen 
receptor-positive early breast cancer after receiving 2−3 years of prior tamoxifen therapy and for 
treatment of advanced breast cancer in postmenopausal women whose disease has progressed following 
tamoxifen therapy. The usual dose is 25 mg once daily after a meal since drug bioavailability is increased 
40% with food. Though not approved for breast cancer prevention, exemestane administered to 
postmenopausal women with a moderately increased risk of breast cancer (≥60 years; Gail five-year risk 
score >1.66%; prior atypical ductal or lobular hyperplasia or lobular carcinoma in situ; or ductal 
carcinoma in situ with mastectomy) resulted in a 65% relative risk reduction of invasive breast cancer 
compared with placebo treatment after three years of follow-up in the MAP.3 trial (3). NCI, DCP is 
continuing to evaluate exemestane for breast cancer prevention.  
 
Film-coated 25 mg exemestane tablets are provided as white, round, lenticular tablets with uniform 
appearance and intact edges for once daily oral administration after a meal (Actavis Group PTC ehf, 
initial United Kingdom (UK) approval in 2010. Full prescribing information is in the summary of product 
characteristics (SPC) available at: www.medicines.org.uk/emc/medicine/24704). Each tablet contains 25 
mg exemestane and the following excipients in its core: povidone K30, maize starch (bleached), starch 
(partially pregelatinized), sodium starch glycolate type A, cellulose microcrystalline type 101, talc, silica 
(colloidal anhydrous), magnesium stearate, and polysorbate 80. The tablet film coating contains: partly 
hydrolyzed polyvinyl alcohol (PVA), titanium dioxide (E171), macrogol 3350, and talc.  
 
Matching placebo tablets are round, lenticular, film-coated tablets containing partially pregelatinized 
maize starch (Starch 1500), microcrystalline cellulose (Avicel PH102), sodium starch glycolate 
(Explotab), colloidal silicon dioxide (Aerosil 200), and magnesium stearate (Ligamed MF-2-V). The film 
coating is Opadry II white, which is PVA based.  
 
Blinded blister packages of study medication (exemestane and placebo tablets) for the three different 
dosing regimens will be provided: Arm 1) 25 mg exemestane qd (once daily, seven exemestane tablets 
per week); Arm 2), 25 mg exemestane 3 times a week (three exemestane tablets and four placebo 
tablets per week); and Arm 3), 25 mg exemestane qw (once weekly, one exemestane tablet and six 
placebo tablets per week). 
 
6.2 
Reported Adverse Events and Potential Risks 
 
According to the UK SPC for 25 mg exemestane film-coated tablets from Actavis UK Ltd., the most 
commonly reported adverse events (AEs) by early breast cancer patients treated with exemestane were (in 
order of frequency): hot flushes (22%), arthralgia (18%) and fatigue (16%). AEs similarly or less 
commonly reported by early breast cancer patients treated with exemestane compared to tamoxifen were 
headache (14%), insomnia (13%), sweating increased (12%), gynecological disorders (11%), and 
dizziness (10%). Similar to early breast cancer, in advanced BC hot flushes were the most common AE 
(14%), followed by nausea (12%). Other common AEs (≥1% to <10%) seen in clinical studies and 
postmarketing reports were: anorexia, alopecia, carpal tunnel syndrome, constipation, depression, 
diarrhea, dyspepsia, fracture, osteoporosis, other primary cancer, pain, paresthesia, peripheral edema, 
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pruritis, reduction in bone mineral density, rash, urticaria, vaginal haemorrhage, visual disturbance, and 
vomiting. Uncommon AEs (≥0.1% to <1%) were: acute generalized exanthematous pustulosis, asthenia, 
gastric ulcer, hepatitis (including cholestatic hepatitis, hepatic enzyme increased, blood bilirubin 
increased, and blood alkaline phosphatase increased), leucopenia, lymphocyte count decreased, 
somnolence, thrombocytopenia, and thromboembolism. Though rare, ischemic cardiac events were not 
significantly different with exemestane compared to tamoxifen (4.5% vs. 4.2%), including individual AEs 
hypertension (9.9% vs. 8.4%), myocardial infarction (0.6% vs. 0.2%), and cardiac failure (1.1% vs. 0.7%) 
(Full prescribing information in the SPC is available at: www.medicines.org.uk/emc/medicine/24704). 
 
6.3 
Availability 
 
Exemestane and matching placebo tablets in blister packages will be supplied by NCI, DCP. 
 
6.4 
Agent Distribution 
 
The European Institute of Oncology will be responsible for the distribution to the Italian sites. 
Exemestane will only be released by NCI, DCP after documentation of IRB approval of the 
DCP­approved protocol and consent is provided to DCP and the collection of all Essential Documents 
is complete (see DCP website for description of Essential Documents). 
 
NCI, DCP-supplied agents may be requested by the Investigator (or their authorized designees) at 
each Organization. DCP guidelines require that the agent be shipped directly to the institution or 
site where the agent will be prepared and administered. DCP does not permit the transfer of agents 
between institutions (unless prior approval from DCP is obtained). DCP does not automatically ship 
agents; the site must make a request. Agents are requested by completing the DCP Clinical Drug 
Request form (NIH-986) (to include complete shipping contact information) and faxing or emailing 
the form to the DCP agent repository contractor: 
 
John Cookinham 
MRIGlobal 
DCP Repository 
1222 Ozark Street 
North Kansas City, MO 64116 
Phone: (816) 360-3805 
FAX: (816) 753-5359 
Emergency Telephone: (816) 360-3800 
Email: NCI.DCP@mriglobal.org 
 
6.5 
Agent Accountability 
 
The Investigator, or a responsible party designated by the Investigator, must maintain a careful record 
of the inventory and disposition of all agents received from DCP using the NCI Drug Accountability 
Record Form (DARF) or an institutionally-approved accountability system. The Investigator is required 
to maintain adequate records of receipt, dispensing and final disposition of study agent. This 
responsibility has been delegated to the local pharmacist. Include on receipt record from whom the 
agent was received and to whom study agent was shipped, date, quantity and batch or lot number. On 
dispensing record, note quantities and dates study agent was dispensed to and returned by each 
participant. 
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6.6 
Packaging and Labeling 
 
Exemestane and matching placebo tablets for the three dosing arms will be packaged in blinded blister 
packages and distributed by NCI, DCP or its authorized designee. 
 
Tablets will be packaged in blister card packaging. Each blister card will contain 7 tablets. Participants 
will receive two wallets of 3 blister cards each (6 blister cards for up to 6 weeks of treatment). 
 
A three-part label will be used for blinding provided by the NCI DCP Repository. 
 
The fixed part of the label will remain attached to the blister cards wallet and will identify the following: 
 
Exemestane 25 mg or Placebo   
21 Tablets  
Expiration Date: XX-XXXX  
Protocol: MDA2014-04-01  
Patient ID: _________________________  
Rand #: ___________________________  
Dispensed Date: ___________________________  
 
Take one tablet once a day at the same time each day.  
Store at Controlled Room temperature 59°F - 77°F (15°C - 25°C)  
Keep Out of Reach of Children  
 
Distributed by MRIGlobal for NCI  
1222 Ozark Street  
North Kansas City, MO 64116  
 
CAUTION: NEW DRUG – LIMITED BY FEDERAL LAW TO INVESTIGATIONAL USE 
ONLY 
 
 
The first tear-off portion of the label will be removed from the wallet at the time of dispensing and will be 
affixed to the Compliance Drug Labels form (Appendix C). This portion of the label will be identical to 
the first portion of the label, except that it will contain a scratch off area with the unblinding information 
should the PI need to be unblinded in case of emergency (See Section 6.9). 
 
The second tear-off portion of the label will be removed from the wallet by the pharmacist at the time of 
dispensing. This portion of the label will contain unblinded information and will be maintained by the 
pharmacist following institutional guidelines or maybe destroyed if this portion of the label is not needed 
for drug accountability purposes. 
 
6.7 
Storage 
 
Study drug will be stored in a secure location at controlled room temperature, with excursions permitted 
between l5°-25°C (59°-77°F). 
 
6.8 
Registration/Randomization 
 
Screening and Registration into the DMI Database:  
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Once informed consent has been signed, participants will be registered into the DMI database. The DMI 
database will assign a participant’s PID upon completion of the registration process. 
 
Randomization:  
Participants will be assigned a randomization number once the following has been accomplished: 
eligibility has been verified at the site level, eligibility has been confirmed by the site PI, eligibility CRF 
has been entered into the DMI web application and the randomization process has been completed by 
CLO staff. Once eligibility has been verified and confirmed by the CLO staff, the randomization number 
will be generated by the database and assigned to the participant. Refer to Section 13.2 for details of 
randomization.  
 
Screening/Registration/Randomization into site-specific databases: 
The DMI is the database of record for the study. Registration and randomization should occur per the 
procedures outlined above. If the site staff need to enter study data into site-specific electronic databases 
per their institutional requirements, they should do so in accordance with their institutional policies and 
procedures. 
 
Appropriate CRFs must be completed for any participant who signs an informed consent. If a consented 
participant is a screen failure and deemed ineligible, the following CRFs must be completed: 1) the 
Registration CRF; 2) the Randomization CRF with the eligibility box checked “no”, 3) the Inclusion and 
Exclusion CRFs showing why the participant is ineligible, 4) the Off-Study CRF, 5) the Adverse Event 
CRF, 6) the Concomitant Medication CRF and 7) the Verification CRF. If no Adverse Event and/or 
Concomitant Medications were assessed by the time the participant is deemed ineligible, the “NONE” 
box will be checked to complete both CRFs. All participants who sign an informed consent must formally 
go off study. All participant registration information will be entered into DMI. If a participant experiences 
a serious adverse event during the screening process, an SAE form must be completed. 
 
6.9 
Blinding and Unblinding Methods 
 
• 
Participants will be blinded to exemestane schedule. 
• 
The Statistician and the Site Study Pharmacist will not be blinded to exemestane schedule. 
• 
All other Investigators will be blinded to exemestane schedule. 
• 
All participants will take 1 tablet per day.  
• 
Study assignments will be unblinded to the Study Investigators and Site Coordinators after all of the 
data are collected and the study database has been locked. Unblinding will also occur if the participant’s 
physician deems that unblinding is necessary, such as in the case of unacceptable toxicity thought to be 
related to the study agent or progressive disease.  
• 
The Data and Safety Monitoring Board will also be blinded unless unblinding is warranted (if the 
participant’s physician deems that unblinding is necessary, if the participant becomes pregnant, or after all 
of the data are collected and the study database has been locked). 
• 
Unblinding will only take place after consultation with the NCI, DCP Task Order Monitor (Medical 
Monitor). Unblinding will be conducted as follows: 
1) 
The Site Investigator contacts the Protocol Principal Investigator and requests the participant’s 
treatment status be unblinded. 
2) 
The Protocol Principal Investigator contacts the NCI, DCP Task Order Monitor (Medical 
Monitor) and requests the participant’s treatment status be unblinded. The Protocol Principal Investigator 
then conveys the Task Order Monitor’s decision to the Site Investigator. The Site Investigator then 
proceeds with unblinding as written out below.  
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3) 
If the NCI Task Order Monitor cannot be reached and the participant requires emergency care, 
the Protocol Principal Investigator may authorize the Site Investigator to break the blind. 
4) 
If the Site Investigator is unable to reach the Protocol Principal Investigator and the participant 
requires emergency care, then the Site Investigator must proceed with unblinding as written out below.  
5) 
The Site Investigator requests the participant’s treatment status be unblinded by the research 
pharmacist (or designated individual responsible for dispensing drug). 
6) 
The Site Investigator officially takes the participant off-study.  
7) 
The date and reason for breaking the blind must be submitted by the Site Investigator to the 
Protocol Principal Investigator, Bernardo Bonanni, MD, as soon as possible.  
8) 
It is the responsibility of the Protocol Principal Investigator to report the date and reason for 
breaking the blind to the NCI Medical Monitor, Eva Szabo, MD, via email to szaboe@mail.nih.gov, as 
soon as possible after receiving this information from the Site Investigator. 
9) 
The date and reason for breaking the blind must be submitted by the Protocol Principal 
Investigator to the MD Anderson Consortium Principal Investigator, Powel H. Brown, MD, PhD, or 
designee as soon as possible via email to phbrown@mdanderson.org or lavornik@mdanderson.org or 
phone at (713) 792-4509. 
10) 
The date and the reason for breaking the blind will be reported by the MD Anderson Consortium 
Principal Investigator or designee to the MD Anderson DSMB as soon as possible. 
 
6.10 
Agent Destruction/Disposal 
 
At the completion of investigation, all unused study agent will be returned to NCI, DCP Repository 
according to the DCP “Guidelines for AGENT RETURNS” and using the DCP form “Return Drug List”.  
 
The guidelines and the form are available on the DCP website. 
 
 
7. 
CLINICAL EVALUATIONS AND PROCEDURES 
 
7.1 
Schedule of Events 
 
The possibility of taking part in a pre-surgical trial will be presented to incoming postmenopausal women 
with a highly suspicious palpable lesion or a newly diagnosed ER-positive DCIS or breast cancer. The 
baseline visit will be scheduled for interested potential participants after histological confirmation.  
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SCHEDULE OF EVENTS 
 
Evaluation/ Procedure 
Screening 
Visit1 
Baseline 
Visit/ 
Registration 
(within 14 days 
prior to 
randomization) 
Randomization 
Phone 
call 
(Day 1) 
Phone call 
(1 week 
+3 days 
prior to 
surgery)2 
Final Visit 
(Days 
28+1, 
35+1, or 
42+1)3 
Surgery 
(Days 29, 
36 or 43) 12 
Screening Informed 
Consent 
X 
 
 
 
 
 
 
Tru-cut biopsy 
(Eligibility ER + 
breast cancer) 
X 
 
 
 
 
 
 
Informed Consent 
 
X 
 
 
 
 
 
Assess eligibility 
 
X 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
Physical exam/ 
height/weight/vital 
signs 
 
X 
 
 
 
X9,10 
 
Tobacco / alcohol use 
assessment 
 
X 
 
 
 
 
 
 
Fasting blood lab 
tests4 
 
X 
 
 
 
X 
 
Blood lab tests that 
may not be fasting5 
 
X 
 
 
 
X10 
 
Fasting blood for 
biomarkers 6 
 
X 
 
 
 
X 
 
Tissue for biomarkers 
(FFPE blocks or 
slides) 
 
X 
 
 
 
 
X 
Frozen tissue for 
biomarkers 
 
 
 
 
 
 
X 
Frozen tissue for 
proteomics11 
 
 
 
 
 
 
X11 
Concomitant 
medications 
 
X 
 
 
X 
X 
 
Baseline symptoms 
 
X 
 
 
 
 
 
Confirm eligibility 
 
(X) 
X 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
Dispense study 
agent13 
 
 
X13 
 
 
 
 
Treatment initiation 
 
 
 
X 7 
 
 
 
Collect study agent 
 
 
 
 
 
X 
X 
Compliance 
 
 
 
 
X 
X 
 
Review agent 
diary/record 
 
 
 
 
 
X 
 
Adverse events 
 
 
 
 
X 
X 
 
QoL questionnaire8 
 
X 
 
 
 
X 
 
 
1 For the Italian sites only 
2 If the participant is seen on site for the physical exam and blood safety tests on Day 7 prior to surgery, perform all procedures in 
person rather than as a phone call. In all other cases call the participant on the phone 1 week +3 days prior to surgery 
3 Based on institutional procedure, the final visit may occur on the same day as surgery or the day before. The Final Visit must be 
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conducted on Days 28+1, 35+1, or 42+1.  
4 Fasting blood lab tests (local lab): Glucose, total cholesterol, HDL cholesterol and triglycerides. Fasting is strongly 
recommended, but is not mandated.  Every effort should be taken to draw these labs fasting.  
5 Blood tests for safety that do not require fasting: complete blood count (CBC), AST, ALT, Na, K, BUN, total bilirubin, Cl, Ca, 
alkaline phosphatase, creatinine, and FSH if needed 
6 Fasting blood collection for biomarkers: estradiol, exemestane, 17-dihydroxyexemestane, estrone, estrone-sulphate, 
androstenedione, testosterone, SHBG, insulin, leptin, adiponectin. Fasting is strongly recommended, but is not mandated.  Every 
effort should be taken to draw these labs fasting. 
7 The first phone call is not performed if the day of call coincides with the day of the baseline visit 
8 Quality of Life questionnaire 
9 Do not repeat the height assessment at the Final Visit. Height measurement will be used from the baseline visit 
10 May be done within 7 days prior to surgery or the day of surgery 
11 US Sites Only 
12 Surgery must occur on Days 29, 36 or 43.  For this study coordinators are advised to count back from the day of surgery so that 
participants can either have 28, 35 or 42 days of study agent (ending on the 7th day of blister pack). Study agent can be dispensed 
in advance of starting agent on Day 1, However, coordinators must remind the participants not to start the study agent until the 
agent start date is provided to them by the coordinating center, in most cases via a telephone call from the coordinating site to the 
participant, indicating when to start the agent. 
13 In person or by mail. 
 
Unresolved AEs with a “possibly”, “probably” or “definitely” attribution to study agent at final visit will 
be monitored via telephone call at 20-30 days after surgery. AEs occurred after surgery will not be 
recorded. 
 
7.2 
Pre-study Testing at Italian Sites 
 
At the Italian sites, women who wish to consider participating in the trial but have not received a 
confirmed diagnosis of ER-positive in-situ or invasive breast cancer will require consent for additional 
evaluations to determine eligibility. Specifically, women who have undergone a histopathologic biopsy 
diagnosed as in-situ or invasive cancer that has not been stained for ER will be consented to provide 
access to archival tissue for immunohistochemistry. This may require access to samples from non-study 
sites. Among women who have not undergone a histopathologic biopsy, consent will be sought to 
perform core needle biopsies (guided by palpation or imaging) to establish a diagnosis of ER-positive in-
situ or invasive cancer.  
 
7.3 
Baseline Testing/Pre-study Evaluation 
 
Pre-study evaluation is: 
• 
ER positive (ER >10%) breast cancer histologically confirmed 
 
Baseline exams are:  
• Fasting blood lab tests that are performed at the local lab (glucose, total cholesterol, HDL 
cholesterol and triglycerides).  Fasting is strongly recommended, but is not mandated.  Every 
effort should be taken to draw these labs fasting. 
 
• Blood lab tests for safety that do not require fasting (complete blood count (CBC), AST, 
ALT, Na, K, BUN, total bilirubin, Cl, Ca, alkaline phosphatase, creatinine, and FSH if 
needed) 
 
• Fasting blood sample collection for biomarkers. Fasting is strongly recommended, but is not 
mandated.  Every effort should be taken to draw these labs fasting. 
 
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• Physical exam and medical history, vital signs, alcohol and tobacco assessment, 
anthropometric measurement (height, weight, waist measurement, hip measurement) and 
quality of life assessment; for the purpose of the present study, minimal requirement for the 
physical exam visit include the following body/system sites: breasts/ cardiovascular/ 
gastrointestinal/ lymphnodes 
 
For any participant who is deemed as screen failure, blood samples collected at Baseline are to be 
destroyed locally at the respective Participating Organization (PO). A Note to File detailing the 
destruction procedure and associated information is to be generated and documented in the participant’s 
research folder or electronic health record. 
 
At the baseline clinic visit, participants will be instructed on the importance of drug compliance. 
Participants will be provided and instructed on the use of a pill diary to be completed daily, signed and 
dated by the participant. Participants will be informed that a pill count will be conducted on their study 
medication use so that their study medication blisters with remaining tablets must accompany them to the 
subsequent clinic visit.  
 
Plan the beginning of drug administration according to the day fixed for surgery.  Surgery must occur on 
Days 29, 36 or 43.  For this study coordinators are advised to count back from the day of surgery so that 
participants can either have 28, 35 or 42 days of study agent (ending on the 7th day of blister pack). Study 
agent can be dispensed in advance of starting agent on Day 1, However, coordinators must remind the 
participants not to start the study agent until a specific day set for the start of study drug. 
 
 
7.4 
Evaluation During Study Intervention 
 
A phone contact on day one for treatment initiation will occur. If day one is on weekend or holiday the 
participants will be contacted the previous working day, if randomization and day one coincide, no phone 
call will be performed.  
 
A phone call a week (+3 days) before surgery to monitor safety and compliance will occur. If the 
participant is seen on site for the physical exam and non-fasting blood safety tests on Day 7 prior to 
surgery, perform all procedures in person rather than as a phone call. In all other cases call the participant 
on the phone 1 week +3 days prior to surgery. 
 
7.5 
Evaluation at Completion of Study Intervention 
 
At the final visit, participants will undergo physical exam, vital signs, and anthropometric measurements 
(weight, waist measurement, hip measurement). These procedures may be done within 7 days prior to 
surgery or on the day of surgery. Do not repeat the height assessment at the Final Visit. Height 
measurement will be used from the baseline visit.  
 
Blood tests for safety that do not require fasting may be done within 7 days prior to surgery or on the 
day of surgery:  
• complete blood count (CBC), AST, ALT, Na, K, BUN, total bilirubin, Cl, Ca, alkaline 
phosphatase, and creatinine 
 
All other procedures are performed the day of surgery or the day before surgery: 
 
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Fasting blood lab tests that are performed at the local lab (glucose, total cholesterol, HDL cholesterol and 
triglycerides).  Fasting is strongly recommended, but is not mandated.  Every effort should be taken to 
draw these labs fasting. 
 
Fasting blood for biomarkers will be collected. Fasting is strongly recommended, but is not mandated.  
Every effort should be taken to draw these labs fasting. 
 
The date and time of blood draw, the date and time of surgery, and the date and time of last pill intake 
will be recorded. 
 
The use of concomitant medications, adverse events, compliance, and quality of life assessment will be 
assessed. Study agent will be collected. A review of agent diary will be performed. 
 
Any kind of surgery will be allowed from simple lumpectomy to total mastectomy. Tissue samples will 
be collected from the surgical specimen and processed according to Section 10. A detailed Manual of 
Operations and Procedures will be implemented with the specific procedures for each specimen.  
 
7.6 
Post-intervention Follow-up Period 
 
• 
The follow up visit is a telephone contact to follow up on previously reported unresolved AEs 
with a “possibly”, “probably” or “definitely” attribution to study agent. 
• 
Only those participants who have reported unresolved AEs with a “possibly”, “probably” or 
“definitely” attribution to study agent at the previous visit need to be contacted.  
• 
Telephone call should occur at 20-30 days after Surgery. Any AE occurring between surgery 
and the phone call will not be reported 
• 
The study coordinator will attempt to contact the participant as many times as needed to reach 
the participant during the “20-30 days after Surgery” window, but a minimum of two 
attempts must be made. If the coordinator is not able to reach the participant by phone 
within the study visit window, a protocol deviation is filed. 
  
7.7 
Methods for Clinical Procedures 
 
Assessment of ER positive breast cancer (Italian sites only) 
A tru-cut diagnostic biopsy of the primary tumor will be performed percutaneously with a 14 gauge 
needle after the administration of local anaesthetic. A single skin incision serving both biopsies with the 
tip of an n.11 scalpel will be performed. Among women who require a biopsy to determined eligibility, 
the method used to guide the biopsy (guidance with palpation or radiological imaging) will vary with 
clinical presentation.   
The biopsy will be fixed in 10% neutral-buffered formalin for 6-8 hours before being embedded in 
paraffin. Sections (4-micron thick) are cut, de-waxed and stained with hematoxylin and eosin for 
conventional histopathological examination (presence and prevalence of normal, hyperplastic, in situ and 
cancer tissue, grading of the tumor and occurrence of peritumoral vascular invasion) and IHC for the 
assessment of the ER (mandatory), PgR (optional), Ki-67 labeling index (optional), HER-2 expression 
(optional). 
 
 
IEO centralized evaluation of immunohistochemical (IHC) biomarker analyses (All Sites) 
Pathology reports of breast biopsy and definitive surgery will be collected by each site.  
 
Tissue samples will be required from both the initial diagnostic breast biopsy (US sites) and the 
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subsequent surgical excisional procedure. A formalin-fixed and paraffin-embedded (FFPE) block or 6 
unstained slides from each time point will be stored locally before shipping to IEO at the end of the study 
(or more frequently in the case of unstained slides – please refer to the Manual of Operations and 
Procedures for complete instructions).  
 
It is advised that whenever possible FFPE blocks should be stored locally, and slides to be used for IHC 
biomarker analyses should be prepared not earlier than one week before shipping in order to avoid antigen 
decay potentially affecting the IHC procedures. If that is not possible, slides may be cut per institutional 
practice and stored. Six 5-micron thick sections will be cut from FFPE block and mounted on charged 
slides, kept in the dark (i.e., in a covered box) and kept at room temperature (18-22°C, 64-71°F) till 
shipment. 
 
At IEO, every set of slides will be stained by H&E and evaluated for expression of ER, PgR, Her-2 and 
Ki-67. The IHC analysis will run by using an automated immunostainer (Dako) and the FDA-approved 
kits Pharm-DX (for ER and PgR) and Herceptest (both by Dako). For Ki-67, we will use the MIB-1 
antibody from Dako. The extent of immunostaining will be evaluated strictly following the ASCO-CAP 
guidelines and the recommendations of the Ki-67 working group (45). 
 
Procedures at the time of surgery (all sites) 
At the time of surgery a small but representative sample of the excised cancerous tissue will be obtained, 
as well as a specimen of adjacent and distant grossly benign tissue for study biomarkers. 
 
 
8.  
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITION 
 
8.1 
Primary Endpoint 
 
For the purpose of the main endpoint, percent change in serum estradiol concentrations, we will refer to 
an outsource laboratory (Quest Diagnostics, San Juan Capistrano, CA), that has obtained a CLIA 
certificate for their high sensitivity estradiol test and will perform estradiol measurements. The method 
applied is based on LC-MS/MS technology, able to measure down to 2 pg/ml. 
We expect to achieve with 25 mg three times a week and 25 mg once a week similar effects in estradiol 
reductions to the standard dose of 25 mg daily. 
 
8.2 
Secondary Endpoints 
 
We will investigate the effects of alternative dosing of exemestane on the following secondary endpoints: 
(see Section 13.5 for a detailed statistical analysis): 
 
• 
Exemestane safety and toxicity will be evaluated at the clinic visit according to the Common 
Terminology Criteria for Adverse Events v4.0 (CTCAE) and by a self-administered Quality of 
Life questionnaire (MENQOL). 
• 
Change in Ki-67 expression comparing pre-treatment versus post-treatment specimen to compare 
the antiproliferative effect among the different doses. 
• 
Serum drug measurements of exemestane and 17-dihydroxyexemestane at the end of treatment. 
• 
Additional validated method of estradiol measurement. This method has a lower detection limit (1 
pg/ml) than the CLIA certified estradiol test (Quest) and will serve as a quality control since it has 
proven to more effectively detect estradiol concentrations at the very low level, which is 
characteristic of older postmenopausal women. 
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• 
Serum concentrations of estrone, estrone-sulfate, will be measured by LC-MS/MS while 
androstenedione and testosterone will be measured by RIA. Sex hormone binding globulin serum 
levels will be measured by a chemiluminescent microparticle immunoassay (CMIA) on the 
ARCHITECT i System (Abbott Laboratories, Weisbaden, Germany). 
• 
Insulin concentrations will be measured with the Architect Immunoassay analyzer (Abbott 
Laboratories, Abbott Park, IL, US). Glucose will be measured at each local lab 
• 
Adipokines: change in leptin and adiponectin serum concentrations will be analyzed and 
compared among the different treatments arms. These measurements will be performed by the use 
of commercially available enzyme linked immunoassays purchased from R&D systems (SPACE 
Import-Export Srl, Milan, Italy). 
• 
Lipid profile (total cholesterol, HDL and triglycerides) will be determined locally at baseline and 
before surgery.Measurement of breast tissue estradiol concentration in tumor and normal breast at 
time of surgery. 
• 
Centralized evaluation of ER, PgR, Her2 and Ki67 expression in tumor comparing pre-treatment 
levels (tru-cut biopsy) to post-treatment level expression (surgical specimen).  
• 
Centralized evaluation of Ki-67 in adjacent intraepithelial neoplasia and or grossly benign tissue. 
• 
Drug measurements of exemestane and 17-dihydroxyexemestane on frozen tissue samples, when 
available. 
• 
Proteomic analysis will be performed with the new Fusion Tribrid mass spectrometer in Dr. 
Chen’s Proteomics Shared Resource for the Herbert Irving Comprehensive Cancer Center 
(HICCC) at CUMC. 
• 
To analyze the UGT2B17 gene we will use Taqman copy number variation assay (Life 
Technologies, Monza, Italy). 
• 
Crown like structures in mammary fat tissue by IHC (CD68), comparing pre-treatment (tru-cut 
biopsy) versus post-treatment (surgical specimens). 
 
8.3 
Off-Agent Criteria  
 
Participants may stop taking study agent for the following reasons: completed the protocol-prescribed 
intervention, adverse event or serious adverse event, inadequate agent supply, non-compliance, 
concomitant medications, medical contraindications. Participants will continue to be followed, if possible, 
for safety reasons and in order to collect endpoint data according to the schedule of events. Participants 
will not be replaced. 
 
8.4 
Off-Study Criteria 
 
Participants may go ‘off-study’ for the following reasons: the protocol intervention and any protocol-
required follow-up period is completed, adverse event/serious adverse event, lost to follow-up, non-
compliance, concomitant medication, medical contraindication, withdraw consent, death, determination of 
ineligibility (including screen failure).  
 
8.5 
Study Termination 
 
NCI, DCP as the study sponsor has the right to discontinue the study at any time.  
 
 
9. 
CORRELATIVE/SPECIAL STUDIES 
 
We will collect and process flash frozen tissue, paraffin-embedded tissue, serum and whole blood for 
evaluation of biomarkers.  
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9.1 
Rationale for Methodology Selection 
 
Estradiol 
Serum estradiol concentrations will be determined by use of a CLIA certified test, according to MD 
Anderson policies for primary endpoint analyses. This test is based on a non-derivatized LC-MS/MS 
technology that has a detection limit of 2 pg/ml, a limit that may not be sufficient to detect estradiol levels 
in all postmenopausal women . Any samples that have estradiol results below the detection limit will be 
assigned to have a concentration of ½ the value of the detection limit. 
 
Because of the critical issue of sensitivity of the method, we have decided to include an additional 
validated bioanalytical method performed in a CLIA certified laboratory for steroid testing. Estradiol will 
be measured by a two-dimensional liquid chromatography with mass spectrometry detection LC-MS/MS) 
after liquid-liquid extraction. Duplicate standard curves, water blanks and four assay control pools are 
processed with samples to assess accuracy and precision of the assay. This method has a lower detection 
limit (1 pg/ml) than the CLIA certified estradiol test (Quest) and will serve as a quality control since it has 
proven to more effectively detect estradiol concentrations at the very low level, characteristic of older 
postmenopausal women. The functional sensitivity of the test is 1 pg/ml and the within assay precision of 
two control samples were 13% at 1.0 pg/mL and 8.8% at 5 pg/mL, respectively.  
 
Ki-67 
Ki-67 labeling index modulation in preoperative studies has proven to be an appropriate surrogate marker 
for outcome in participants who are administered antiestrogen therapies. 
 
The Division of Pathology at IEO is in strict compliance with the recommendations of the International 
Working Group for Ki-67 assessment in breast cancer (45) and performs central revision of Ki67 within 
the International Breast Cancer Study Group. Ki-67 labeling index expression will be evaluated by IHC, 
as previously described (46). Specifically, Ki-67 is assessed by IHC according to recent international 
recommendations (45) using the Mib-1 monoclonal antibody (1:50 dilution; Dako, Denmark), using an 
automated immunostainer (Dako). We will evaluate all the cells in the diagnostic biopsies, and 2000 cells 
from three high power (×400) microscopic fields randomly selected at the periphery of the tumor in 
surgical samples, as previously reported (46). The Ki-67 labeling index is calculated as the percentage of 
Ki-67 immunoreactive cells over the total number of counted cells. 
 
ER, PgR and HER2 
Centralized analyses of ER, PgR (PharmDX) and Her2 (herceptest) expression will be determined by IHC 
on tumor sections from biopsy and surgical samples, as previously described(45).  
 
Estrone, estrone-sulfate 
Estrone will be measured by a two-dimensional liquid chromatography with mass spectrometry detection 
LC-MS/MS) after liquid-liquid extraction. Duplicate standard curves (2.5-00 pg/mL), water blanks and 
four assay control pools are processed with samples to assess accuracy and precision of the assay. The 
detection limit of the assay is 2.5 pg/mL and the intra and inter-assay coefficient of variation of a pooled 
human serum sample of 21 pg/mL were 4.8% and 9.0%, respectively.  
 
Estrone-sulfate will be measured by a two-dimensional liquid chromatography (HPLC) with triple 
quadrupole mass spectrometry detection. Estrone-sulfate from serum is first partially purified by protein 
precipitation, and then further purified by gradient reverse phase HPLC. Duplicate standard curves (10-
1000 ng/dL), water blanks and four assay control pools are processed with samples to assess accuracy and 
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precision of the assay. The detection limit of the assay is 10 ng/dL and the intra and inter-assay 
coefficient of variation of a pooled human serum sample of 25 ng/dL were 3.6% and 9.3%, respectively.  
 
Androstenedione 
Serum concentrations of androstenedione will be measured by a radioimmunoassay kit (DSL-3800 
ACTIVE, Beckman Coulter S.r.l., Rome, Italy), contining androstenedione coated tubes. The procedure 
follows the basic principle of radioimmunoassays where there is competition between a radioactive and a 
non-radioactive antigen for a fixed number of antibody binding sites. The amount of I125-labeled 
androstenedione bound to the antibody is inversely proportional to the concentration of androstenedione 
present in the sample. The separation of free and bound antigen is achieved by decanting the antibody-
coated tubes. The sensitivity of the assay is 0.03 ng/mL and the intra and inter-assay coefficients of 
variation of a control provided with the kit (0.5 ng/mL) were 10% and 14% respectively. Interassay 
coefficients of variation of our in-house prepared serum pool (1.6 ng/mL) was 14% for androstenedione. 
 
Testosterone 
Serum testosterone will be determined by an electrochemiluminescent immunometric assay (Roche 
Diagnostics S.p.A., Monza, Italy) designed for the Cobas e411 automated analyzer. The sensitivity of the 
assays was 2.5 ng/dL and the inter-assay coefficient of variation of our in-housed pooled serum sample 
(18 ng/dL) was 4.6.  
 
Sex hormone binding globulin (SHBG) 
Serum concentrations of SHBG will be determined by a chemiluminescent microparticle immunoassay 
(CMIA) on the ARCHITECT i System (Abbott Laboratories, Weisbaden, Germany). This assay shows 
very good agreement with our previously adopted platforms and the assay performance in terms of 
reproducibility were improved. Sensitivity of the method is < 0.01nmol/L and intra and inter-assay 
coefficient of variation were below 5.5% at 3 different control levels (low, median, high). 
 
Insulin 
Serum concentrations of insulin will be determined by a chemiluminescent microparticle immunoassay 
(CMIA) on the ARCHITECT i System (Abbott Laboratories, Weisbaden, Germany). This assay shows 
very good agreement with our previously adopted platforms and the assay performance in terms of 
reproducibility were improved. The sensitivity of the method is ≤ 1.0 μU/mL, and inter-assay coefficient 
of variation are below 2% at 3 different control levels (low, median, high) produced by Abbott. Interassay 
coefficient of variation of our in-house prepared serum pool (mean: 4.9 μU/mL) is 3.9%. 
 
Adiponectin and leptin 
Serum adiponectin and leptin will be measured using a commercial enzyme-linked immunosorbent assay 
kit (R&D Systems, Minneapolis, MN). Serum samples should not undergo freeze and thaw cycles before 
adiponectin and leptin measurements. Particularly, leptin is very sensitive to freeze-thaw cycles and will 
be determined after first thaw. 
The minimum detectable dose of adiponectin is 0.25 ng/mL and the inter-assay coefficient of variation of 
our in-house prepared serum pool (mean: 12.5 μg/mL) was 6.9%. The minimum detectable dose of leptin 
is 7.8 pg/mL. and the inter-assay coefficient of variation of our in-house prepared serum pool (mean: 9.7 
ng/mL) was 6.6%. 
 
Pharmocokinetics 
EXE and 17-dihydroEXE concentrations will be determined by mass spectrometry (MS) using Waters® 
Xevo™ TQ MS in electrospray positive ionization mode (Waters, Manchester, UK), optimized by 
multiple reaction monitoring mode. We used Zorbax Eclipse Plus C18 columns and mobile phase 
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MeOH/H2O with 0.1% formic acid. EXE pure substance was provided by Pfizer Inc., 17β-hydroxy EXE 
and EXE-19-d3 were purchased from Toronto Research Chemicals (Toronto, Ontario, Canada). 
 
Proteomic Analysis 
Fresh frozen tumor tissues will be homogenized and quantified using the standard operating protocols 
established in HICCC Proteomics Shared Resource. Exosomes will be isolated from serum using SBI’s 
ExoQuick exosome kit (47-49), and the enrichment of exosomes will be verified by Western blot. 100 µg 
of exosomes from each time point of the same participant will be proteolytically cleaved with trypsin and 
then chemically labeled with mass spectrometer detectable quantification reagent, TMT isobaric mass 
tags (TMT126, 127, 128, 129)(50,51) separately for quantification. 10 µg from each TMT labeled sample 
(4plex) will be mixed per LC-MS/MS run. Three technical replications will be performed per sample. For 
the LC-MS/MS analysis, 40 µg of TMT-labeled peptide mixture will be separated by nano-HPLC and 
analyzed by the new Orbitrap Fusion Tribrid mass spectrometer. The proposed proteomic studies will 
take advantage of its vastly improved sensitivity, as well as other features that can be optimized for 
complex samples. For example, parallelization of the newly designed instrument maximizes the amount 
of high-quality data acquired by synchronizing operations of several different mass analyzers. Dynamic 
scan management enables selection, sorting, and routing of precursors to different fragmentation modes, 
enabling us to optimize the instrument for PTM characterization. Also, synchronous MS3 precursor 
selection significantly increases the number of peptides accurately quantified in isobaric mass tagging 
experiments. The new Orbitrap Fusion Tribrid mass spectrometer has increased sensitivity for detecting 
lower abundant proteins, which allows us to use less starting material and increase the number of 
biological replications for analysis. 
 
Pharmacogenetics 
DNA will be extracted from whole blood EDTA treated samples (Qiagen, Italy). We will use Taqman 
copy number variation assay (Life Technologies, Monza, Italy) for the UGT2B17 genotyping. The 
expected minor allele frequency (UGT2B17 deletion) in the Caucasian population is 0.26. We recently 
demonstrated a statistically significant association of the UGT2B17 gene deletion with increased serum 
concentrations of 17-dihydroxyEXE (Johansson et al. SABCS 2014) in a pre-surgical trial involving 47 
participants randomized to exemestane 25 mg/daily for six weeks, exemestane levels were also higher, 
although the difference was not statistically significant between groups (homozygous wt versus 
heterozygous and homozygous UGT2B17 deleted). 
 
Crown like structures (CLS) 
We will use CD68 (mouse monoclonal KP1 antibody; Dako; dilution 1:4,000) to identify CLS in 
mammary fat tissue in FFPE sections stained by H&E. All cases will be reviewed by the same breast 
histopathologist. Light microscopy will be used to assess for evidence of CLS. 
 
Biorepository 
Leftover specimens will be stored for future unspecified analyses. Leftover samples will be retained at 
IEO Central Biobank if informed consent for biobanking is signed. 
 
Biologic specimens collected during the conduct of the trial that are not used during the course of the 
study will be considered deliverables under the contract and thus the property of the NCI. At study 
completion, NCI reserves the option to either retain or relinquish ownership of the unused biologic 
specimens. If NCI retains ownership of specimens, the Contractor shall collect, verify and transfer the 
requested biologic specimens from the site to a NCI-specified repository or laboratory at NCI’s expense. 
 
9.2 
Comparable Methods 
 
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We will use established and validated assays for determination of changes in biomarkers expression in 
this study. We plan to evaluate biomarkers in serum, tissue and DNA for secondary endpoints evaluation.  
 
As to the primary endpoint, the method has been validated and already described in peer-reviewed 
publications (52). 
 
For secondary serum biomarkers we will utilize standardized protocols of commercially available kits 
already described in peer-reviewed publications. Standard control samples as well as an in-house pooled 
serum sample will be analyzed in each run to monitor for inter- and intra assay coefficient of variation. 
We will pair samples obtained from the same participant (pre and post-treatment) and run samples in 
batches to reduce analytical variability. As to SHBG (28,53), HOMA index (53,54) and adipokines 
(37,55) our group has already published several papers involving these biomarkers. 
 
 
10. 
SPECIMEN MANAGEMENT  
 
10.1 
Laboratories 
 
Planned analysis of biomarkers will be centralized to specialized laboratories as outlined below. 
 
10.1.1 Blood samples  
 
Specimen (amount) 
 
Laboratory 
Serum 1 aliquot (1 mL) 
Estradiol, Estrone and estrone-sulfate levels 
 
Nigel Clarke, PhD 
Quest Diagnostics Nichols Institute 
 
Serum 1 aliquot (1 mL) 
Ultra sensitive estradiol levels 
 
inVentiv Health, Princeton, NJ 
Serum, 6 aliquots (1 mL each) 
Androstenedione, Testosterone, SHBG levels and 
Insulin levels 
Adiponectin and Leptin levels 
 
Harriet Johansson, MSc, PhD 
Division of Cancer Prevention and Genetics 
European Institute of Oncology 
Serum 1 aliquot (1 mL) 
EXE and 17-dihydroEXE Levels 
Prof. Gunnar Mellgren, MD, PhD 
Director, Laboratory Medicine and Pathology 
Haukeland University Hospital and University of 
Bergen 
Serum 1 aliquot (1 mL) 
Proteomic Biomarker Discovery 
Emily Chen, PhD 
Proteomics Shared Resource  
Herbert Irving Comprehensive Cancer Center 
Columbia University Medical Center  
 
Whole Blood EDTA-treated, 2 aliquots (1 mL 
each) 
DNA extraction and UGT2B17 copy number 
variation analysis 
Harriet Johansson, MSc, PhD 
Division of Cancer Prevention and Genetics 
European Institute of Oncology 
 
 
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10.1.2 Tissue samples 
 
Specimen 
 
Laboratory 
Tru-cut Biopsy 1 (FFPE) – Italian Sites 
Histological evaluation prior to randomization 
Pathology staff at institution where diagnosis was 
performed 
 
Tru-cut FFPE sections from Biopsy 1 – Italian 
Sites 
Six consecutive 5-micron thick sections from 
FFPE tru-cut biopsy for centralized analyses of 
Ki67 (and ER, PGR HER2) 
 
Prof. Giuseppe Viale, MD 
Division of Pathology 
European Institute of Oncology 
FFPE block or 6 unstained slides from the 
initial diagnostic biopsy – US Sites 
Prof. Giuseppe Viale, MD 
Division of Pathology 
European Institute of Oncology 
Surgical specimen 1: Breast Tumor Tissue 
(FFPE) 
Histological evaluation of surgical specimen 
 
Pathology staff at each institution where definitive 
diagnosis was performed 
 
Surgical specimen 1: FFPE sections from breast 
tumor Six consecutive 5-micron thick sections 
from each FFPE block mounted on charged slides 
[preferably within 7 days prior to shipping] 
 
Prof. Giuseppe Viale, MD 
Division of Pathology 
European Institute of Oncology 
Surgical specimen 2: Flash Frozen Breast 
Tumor (minimal wet weight: 200 mg) 
 
Estradiol/exemestane measurements 
 
 
Surgical specimen 3: Flash Frozen Normal Breast 
(minimal wet weight: 200 mg) 
 
Estradiol/exemestane measurements 
 
 
Prof. Gunnar Mellgren, MD, PhD 
Director, Laboratory Medicine and Pathology 
Haukeland University Hospital and University of 
Bergen 
 
Surgical specimen 4: Flash Frozen Breast 
Tumor (minimal wet weight: 50 mg) 
Proteomic Biomarker Discovery 
US Sites only 
Emily Chen, PhD 
Proteomics Shared Resource  
Herbert Irving Comprehensive Cancer Center 
Columbia University Medical Center 
 
Surgical specimen 5: FFPE sections from 
normal breast fat Crown like structures (IHC 
staining) 
Potential Anxillary Study  
Investigator to be defined 
 
 
The analysis of serum concentrations of estradiol, estrone and estrone-sulfate will be performed at the 
Quest Diagnostics Nichols Institute, San Juan Capistrano, CA, US under the supervision of Nigel Clarke. 
 
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The analysis of serum concentrations of ultrasensitive estradiol will be performed at inVentiv Health lab, 
Princeton, NJ, USA. 
 
The analysis of serum concentrations of exemestane and its main metabolite 17-dihydroxy-exemestane 
will be performed by the Hormone Laboratory, Haukeland University, Bergen, Norway under the 
supervision of Prof. Gunnar Mellgren MD, PhD. 
 
The analysis of serum concentrations of androstenedione, testosterone, SHBG, insulin, adiponectin and 
leptin will be performed at the IEO Cancer Prevention Lab, Milan, Italy under the supervision of Harriet 
Johansson, MSC, PhD. The IEO Cancer Prevention Lab is also responsible DNA extraction, UGT2B17 
copy number variation analysis, and for Centralized Biobanking of leftover specimens. 
 
The evaluation of IHC biomarker analyses will be centralized to the Division of Pathology, IEO, Milan, 
Italy under the supervision of Professor Giuseppe Viale. 
 
Proteomic profiling will be centralized to Dr. Chen’s Proteomics Shared Resource for the Herbert Irving 
Comprehensive Cancer Center (HICCC) at Columbia University Medical Center (CUMC). 
 
10.2 
Collection and Handling Procedures 
 
Specific instructions about specimen handling and storage will be provided in a separate Manual of 
Operations and Procedures. 
 
10.2.1 Blood 
 
It is strongly recommended for all blood samples for biomarkers to be drawn under fasting condition (at 
least 6 hours) preferably between 8 a.m. and 10 a.m. at baseline and the day of surgery (or the day before, 
depending on the local institutional procedures). 
 
A total of 10 ml of blood will be withdrawn for safety lab exams and lipid profile at baseline and before 
surgery. 
 
At baseline and before surgery a total of 20 ml of blood will be collected into vacuum blood collection 
tubes containing beads coated with clotting activator for serum separation to be employed for circulating 
biomarker analysis. Accordingly with specific tubes adopted at your hospital, please refer to the 
manufacture instructions. Allow the blood to clot at room temperature for 30 minutes. Then, spin in 
centrifuge for 10 minutes.  Sarstedt Serum Monovettes tubes require 10 min centrifugation at 2000 x g at 
room temperature, while BD Vacutainer® SST™ and PST™ gel tubes should be spun at a speed of 1300 
x g. Swing-out buckets best option for both systems. . After centrifugation, the yellow top layer, which 
corresponds to serum, is pipetted using the disposable transfer pipettes in 10 even aliquots (about 1.0 mL 
each) into the polypropylene cryotubes (Thermo Fisher Scientific), specifically labeled according to the 
Instructions in the Manual of Operations and Procedures. Tubes are tightly capped and stored in a 
dedicated – 80°C freezer equipped with a temperature control and temperature log chart or an alarm 
monitoring system per institutional standards. 
 
At baseline and before surgery a total 3 ml whole blood will be collected in tubes containing EDTA-K2 
as anti-coagulant agent. The tube is gently mixed and blood is pipetted using disposable transfer pipettes 
in 2 even aliquots (about 1.5 mL each) into the polypropylene cryotubes (Thermo Fisher Scientific), 
specifically labeled according to the Instructions in the Manual of Operations and Procedures . Tubes are 
tightly capped and stored in a dedicated –80°C freezer equipped with a temperature control and 
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temperature log chart or an alarm monitoring system per institutional standards. 
 
Specimen collection kits for storage of serum and blood samples will be provided by the Central 
Laboratory, at the Division of Cancer Prevention and Genetics, European Institute of Oncology in Milan, 
Italy (See the Instructions in the Manual of Operations and Procedures for requesting kits). Briefly, they 
will provide labels and polypropylene cryotubes and rack (Thermo Fisher Scientific) and instructions for 
specimen handling, processing, labeling, tracking and storage.  
 
Each local site must be equipped with a -80°C (range -70 °C to -80 °C) freezer provided with temperature 
control 24 hours a day, 7 days a week and temperature log charts or an alarm monitoring system, better if 
electronic. The Center should also be equipped with a back-up freezer.  
 
10.2.2 Tissue 
Breast tissue fixation with neutral buffered formalin for 4–48 hours has been shown to be adequate. 
Thus, when tissue is fixed in neutral buffered formalin, IHC for Ki-67 is robust across a wide range of 
fixation times. Tissue handling guidelines that are already in place for ER (8–72 hours of neutral buffered 
formalin fixation) are therefore more than adequate for Ki-67. Once tissue is properly fixed and 
embedded in paraffin, antigenicity is well preserved, potentially for decades.  
 
FFPE sections from breast tumor (baseline and surgical specimens) will be cut locally by each site and 
shipped for centralized evaluation of immunohistochemical biomarker analyses at IEO. Six 
consecutive 5-micron thick sections will be cut from each FFPE block and mounted on charged slides, 
preferably within 7 days prior to shipping. 
 
Flash frozen specimen from surgical resections (minimal wet weight: 200 mg) both from the tumor and 
the macroscopically negative normal tissue will be collected within 20-30 minutes, frozen on liquid 
nitrogen and stored in freezer at –80°C. 
 
There could be some cases of insufficient tumor tissue available to be snap frozen (in situ histology, small 
size of invasive cancer, etc). However, any effort should be made to collect and freeze normal breast 
tissue for secondary endpoint measurements. 
 
 
Note for the US Sites: Additional Flash Frozen Breast Tumor tissue from the surgical specimen 
(minimal wet weight: 50 mg) will be collected at the US Sites only for Proteomic Biomarker Discovery at 
the Proteomics Shared Resource, Herbert Irving Comprehensive Cancer Center, Columbia University 
Medical Center.  This specimen is only collected by the US sites, stored in local freezers at –80°C until 
the end of the study, and shipped to CUMC per the shipping instructions in the Manual of Operations and 
Procedures.  
 
10.3 
Shipping Instructions 
 
In order to keep shipping costs at an affordable level, Participating Centers are requested to store blood 
samples at -80°C until pick-up by a courier will be arranged by and to the Central Laboratory at the 
Division of Cancer Prevention and Genetics, European Institute of Oncology in Milan, Italy. Samples will 
be shipped on dry ice in compliance with the International Air Transport Association (IATA) Dangerous 
Goods Regulations. Specific instructions about specimen shipping will be provided in a dedicated Manual 
of Operations and Procedures. 
 
Tissue specimens will be stored locally until shipment the Central Laboratory at the Division of Cancer 
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Prevention and Genetics, European Institute of Oncology in Milan, Italy. Storage and shipment 
instructions are outlined in the Manual of Operations and Procedures. 
 
Note to the US Sites: Tissue collected for Proteomic Biomarker Discovery will be stored locally and 
shipped to the Proteomics Shared Resource, Herbert Irving Comprehensive Cancer Center, Columbia 
University Medical Center. Storage and shipment instructions are outlined in the Manual of Operations 
and Procedures.  
 
10.4 
Specimen Banking 
 
Leftover specimens will be stored at IEO Central Biobank for optional studies. 
 
Biologic specimens collected during the conduct of the trial that are not used during the course of the 
study will be considered deliverables under the contract and thus the property of the NCI. At study 
completion, NCI reserves the option to either retain or relinquish ownership of the unused biologic 
specimens. If NCI retains ownership of specimens, the Contractor shall collect, verify and transfer the 
requested biologic specimens from the site to a NCI-specified repository or laboratory at NCI’s expense. 
 
 
11. 
REPORTING ADVERSE EVENTS  
 
DEFINITION: AE means any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related. An AE can therefore be any unfavorable and unintended sign, 
symptom, or disease temporally associated with participation in a study, whether or not related to that 
participation. This includes all deaths that occur while a participant is on a study. 
 
Please note that all abnormal clinical laboratory values that are determined to be of clinical significance 
based on a physician’s assessment are to be reported as AEs. Those labs determined to be of no clinical 
significance or of unknown clinical significance (per the physician’s assessment) should not be reported 
as AEs. Any lab value of unknown clinical significance should continue to be investigated/followed-up 
further for a final determination, if possible. 
 
A list of AEs that have occurred or might occur (Reported Adverse Events and Potential Risks) can be 
found in §6.2, Pharmaceutical Information, as well as the Investigator Brochure or package insert.  
 
11.1 
Adverse Events 
 
11.1.1 Reportable AEs 
 
All AEs that occur after the informed consent is signed and baseline assessments are completed must be 
recorded on the AE CRF (paper and/or electronic) whether or not related to study agent. 
 
11.1.2 AE Data Elements: 
 
The following data elements are required for adverse event reporting. 
• 
AE verbatim term 
• 
NCI Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0) AE term 
(MedDRA lowest level term) 
• 
CTCAE (MedDRA) System Organ Class (SOC) 
• 
Event onset date and event ended date 
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• 
Treatment assignment code (TAC) at time of AE onset 
• 
Severity grade 
• 
Attribution to study agent (relatedness) 
• 
Whether or not the event was reported as a serious adverse event (SAE) 
• 
Whether or not the subject dropped due to the event 
• 
Outcome of the event 
 
11.1.3  Severity of AEs 
 
 
 
11.1.3.1 
Identify the AE using the CTCAE version 4.0. The CTCAE provides descriptive 
terminology (MedDRA lowest level term) and a grading scale for each AE listed. A copy of the CTCAE 
can be found at http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
AEs will be assessed according to the grade associated with the CTCAE term. AEs that do not have a 
corresponding CTCAE term will be assessed according to the general guidelines for grading used in the 
CTCAE v4.0 as stated below.  
 
CTCAE v4.0 general severity guidelines:  
 
Grade 
Severity 
Description  
1 
Mild 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
2 
Moderate 
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living 
(ADL)*. 
3 
Severe 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; 
disabling; limiting self-care ADL**. 
4 
Life-threatening 
Life-threatening consequences; urgent intervention indicated. 
5 
Fatal 
Death related to AE. 
 
ADL 
 
*Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
 
**Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
 
11.1.4 Assessment of relationship of AE to treatment 
 
 
The possibility that the adverse event is related to study agent will be classified as one of the following: 
not related, unlikely, possible, probable, definite. 
  
11.1.5 Follow-up of AEs 
 
All AEs, including lab abnormalities that in the opinion of the investigator are clinically significant, will 
be followed according to good medical practices and documented as such. AEs with a “possibly”, 
“probably” or “definitely” attribution to study agent will be monitored up to 20-30 days after surgeryvia 
phone call. 
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11.2 
Serious Adverse Events  
 
11.2.1 DEFINITION: Regulations at 21 CFR §312.32 (revised April 1, 2014) defines an SAE as any 
untoward medical occurrence that at any dose has one or more of the following outcomes: 
• 
Death 
• 
A life-threatening AE 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions 
• 
A congenital anomaly or birth defect 
• 
Important medical events that may not be immediately life-threatening or result in death or 
hospitalization should also be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical intervention to 
prevent one of the other outcomes. 
 
11.2.2 Reporting SAEs to DCP 
The organization that experiences the serious adverse event (SAE) should report the SAE to the 
following 3 entities: 1) NCI DCP, 2) DCP’s regulatory contractor CCSA, and 3) MDACC, the 
CLO.  Detailed reporting instructions are provided below.  In addition, all participating 
organizations will follow their IRB requirements for SAE reporting. 
 
11.2.2.1 
The Lead Organization and all Participating Organizations will report SAEs on the DCP 
SAE 
Report 
Form 
found 
at 
http://prevention.cancer.gov/clinical-trials/clinical-trials-
management/protocol-information-office/pio-instructions-and-tools/2012-consortia.  
 
11.2.2.2 Reporting within 24 hours of knowledge of the event.  
 
11.2.2.2(A) Report to the NCI DCP Medical Monitor within 24 hours: 
Contact the DCP Medical Monitor by phone within 24 hours of knowledge of the event.   
 
Eva Szabo, MD 
NCI/Division of Cancer Prevention 
9609 Medical Center Drive, Rm 5E-102 
Bethesda, MD 20892 (For FEdEX, Rockville, MD 20850) 
Phone: (240) 276-7011 
Fax: (240) 276-7848 
Email: szaboe@mail.nih.gov 
 
Include the following information when calling the Medical Monitor: 
• 
Date and time of the SAE 
• 
Date and time of the SAE report 
• 
Name of reporter 
• 
Call back phone number 
• 
Affiliation/Institution conducting the study 
• 
DCP protocol number 
• 
Title of protocol 
• 
Description of the SAE, including attribution to drug and expectedness 
 
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11.2.2.2(B) Report to the Consortium Lead Organization (CLO) PI (Dr. Powel Brown) 
within 24 hours of knowledge of the event: 
Report all SAEs to the Consortium Lead Organization PI (Dr. Powel Brown) within 24 
hours of knowledge of the event.  The same information reported to the DCP Medical 
Monitor should be provided to the CLO Coordinator via email, phone or fax within 24 
hours of knowledge of the event.  
 
11.2.2.3 Reporting within 48 hours of knowledge of the event: 
11.2.2.3 (A) Email the written SAE reports to the DCP Medical Monitor within 48 hours 
of learning of the event using the paper SAE form. The SAE forms should be obtained at 
http://prevention.cancer.gov/clinical-trials/clinical-trials-management/protocol-
information-office/pio-instructions-and-tools/2012-consortia.  
 
11.2.2.3 (B) The written SAE reports will also be emailed to DCP’s Regulatory 
Contractor, CCS Associates, at safety@ccsainc.com. 
 
11.2.2.3 (C) The written SAE report will also be faxed to the Consortium Lead 
Organization 
PI 
(Dr. 
Powel 
Brown), 
at 
(713) 
792-4003 
or 
emailed 
at 
PHBrown@mdanderson.org.  
 
It is the responsibility of the CLO to inform the Lead Protocol PI upon receipt of the 
report from the organization experiencing the event.  
 
11.2.2.4 The DCP Medical Monitor and regulatory staff will determine which SAEs require FDA 
submission. 
 
11.2.2.5 The Lead Organization and all Participating Organizations will comply with applicable 
regulatory requirements related to reporting SAEs to the IRB/IEC.  
 
11.2.2.6 Follow-up of SAE 
Site staff should send follow-up reports as requested when additional information is available. Additional 
information should be entered on the DCP SAE form in the appropriate format. Follow-up information 
should be sent to DCP as soon as available. SAEs will be monitored up to 30 days after post-treatment 
with a visit or a phone call based on the severity of the SAE  
 
 
12. 
STUDY MONITORING 
 
12.1 
Data Management 
 
This study will report clinical data using the Data Management Initiative (DMI) web-based application 
managed by the Consortium Biostatistics and Data Management Core. Data Management Initiative (DMI) 
infrastructure has been developed in the Division of Quantitative Sciences (DQS), MD Anderson Cancer 
Center. This infrastructure supplies integrated database and software services for web-based data 
collection, randomized treatment assignment, reporting, query, data download, and data quality 
management. The DMI will be the database of record for the protocol and subject to NCI and FDA audit. 
All DMI users will be trained to use the DMI system and will comply with the instructions in the 
protocol-specific “DMI User Manual” as well as applicable regulatory requirements such as 21 CFR; Part 
11. Data management procedures for this protocol will adhere to the Data Management Plan (DMP) on 
file at the DCP for contract HHSN261201200034I.  
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12.2 
Case Report Forms 
 
Participant data will be collected using protocol-specific case report forms (CRF) developed from the 
standard set of DCP Chemoprevention CRF Templates and utilizing NCI-approved Common Data 
Elements (CDEs). The approved CRFs will be used to create the electronic CRF (e-CRF) screens in the 
DMI application. Site staff will enter data into the e-CRF. Amended CRFs will be submitted to the DCP 
Protocol Information Office for review and approval. Approved changes will be programmed into the 
DMI database by the Consortium Biostatistics and Data Management Core. 
 
12.3 
Source Documents 
 
Source documentation will include only those documents containing original forms of data, including 
clinic charts, shadow files, hospital charts, and physician notes. Data recorded directly on the CRFs 
designated as source documents (i.e., no prior written or electronic record of data) will be considered 
source data. All other data recorded on the CRFs will not be considered source documentation. 
 
12.4 
Data and Safety Monitoring Plan 
 
The Data and Safety Monitoring Plan for the MD Anderson Consortium is on file at the DCP.  This study 
will be monitored by the MDACC Data and Safety Monitoring Board, the data and safety monitoring 
board of record for this study.  The Data Safety and Monitoring Board (DSMB) reports to the President, 
or his designee, as the on-campus representative of The University of Texas Board of Regents. It oversees 
the data and patient safety issues for randomized clinical trials that originate at MD Anderson; that are 
coordinated or analyzed by MD Anderson and are not being monitored by any other DSMB; or have been 
designated as requiring DSMB monitoring at the request of the IRB, the CRC, or institution. The primary 
objectives of the DSMB are to ensure that patients' rights pertaining to participation in a research study 
are protected, and that patients' interests are prioritized over the interests of the scientific investigation. 
Responsibilities include: 
(a) Review interim analyses of outcome data (prepared by the study statistician or other 
responsible person at the time points defined in the study) approved by the IRB and 
additional time points as determined by the DSMB, and to recommend, if necessary, whether 
the study needs to be changed or terminated based on these analyses; 
(b) Determine whether, and to whom, outcome results should be released prior to the reporting of 
study results; 
(c) Review interim toxicity data and efficacy of treatment; 
(d) Review major research modifications proposed by the investigator or appropriate study 
committee prior to implementation (e.g., termination, dropping an arm based on toxicity 
results from the study or results of other studies, increasing target sample size). 
 
Refer to the Data and Safety Monitoring Plan for the MD Anderson Consortium on file at the DCP for 
further details. 
 
12.5 
Sponsor or FDA Monitoring 
 
The NCI, DCP (or their designee), pharmaceutical collaborator (or their designee), or FDA may 
monitor/audit various aspects of the study. These monitors will be given access to facilities, databases, 
supplies and records to review and verify data pertinent to the study.  
 
12.6 
Record Retention 
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Clinical records for all participants, including CRFs, all source documentation (containing evidence to 
study eligibility, history and physical findings, laboratory data, results of consultations, etc.), as well as 
IRB records and other regulatory documentation will be retained by the Investigator in a secure storage 
facility in compliance with Health Insurance Portability and Accountability Act (HIPAA), Office of 
Human Research Protections (OHRP), Food and Drug Administration (FDA) regulations and guidances, 
and NCI/DCP requirements, unless the standard at the site is more stringent. For NCI/DCP, records will 
be retained for at least three years after the completion of the research. NCI will be notified prior to the 
planned destruction of any materials. The records should be accessible for inspection and copying by 
authorized persons of the Food and Drug Administration, the Italian Ministry of Health representative and 
Italian Agency of Drug (AIFA). If the study is done outside of the United States, applicable regulatory 
requirements for the specific country participating in the study also apply. 
 
12.7 
Cooperative Research and Development Agreement (CRADA)/Clinical Trials Agreement 
(CTA) 
 
N/A  
 
 
13. 
STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Description 
 
The trial is a randomized, double-blind, non-inferiority phase IIb study. Participants will be randomized 
to receive exemestane as one dose of 25 mg once a day; or 25 mg three times a week; or 25 mg once a 
week for at least four up to six weeks. Analysis will be performed according to intention to treat principle 
and then according to efficacy. 
 
13.2 
Randomization/Stratification  
 
In order to keep at minimum the imbalance in treatments a stratified blocked randomization strategy will 
be used considering only the relevant prognostic factors. Participants will be stratified according to center 
and BMI (<25 kg/m2 versus > 25 kg/m2). Subjects with a BMI <25 kg/m2 will be limited to 50% per site. 
A fixed block randomization will be carried out with a block size of 6 patients. 
 
13.3 
Accrual and Feasibility 
 
We expect to screen 300 potential participants to randomize 180 women, 60 per arm. We assume the 
drop-out rate to be 10%. Our goal is to achieve a total sample size of 162 evaluable participants (54 
participants per arm). 
 
13.4 
Primary Objective, Endpoint(s), Analysis Plan 
 
Primary objective and primary endpoint 
Since the primary objective of this study is to assess if the reduction in estradiol with the standard dose is 
comparable with the other lower doses, we will measure the estradiol before and after treatment. Thus, the 
primary endpoint is the percentage change of serum estradiol concentration from baseline and we will 
compare the median change and percentage changes among arms. 
 
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We choose the percentage change as the primary endpoint because it will improve generalization of 
results, given the wide variability among different assays, and because we predict that a large percentage 
of participants will have the final values of estradiol below the detectable level. 
 
Analysis plan  
We will present full distribution and median values of estradiol at baseline (before treatment), at post 
(after treatment), and changes and percentage changes (with interquartile ranges) of estradiol level, from 
baseline to post, by arms. Differences by arms of % change, change and final values will be tested 
considering t-test and ANCOVA models. Estradiol at baseline will be included as explanatory variable 
together with other possible confounders such as BMI, age and time since last dose. Normal distribution 
of residuals from full model will be checked and, if needed, a transformation will be considered.  
 
We will also compare percentages of participants with final values of estradiol below the detectable level 
by arms with Chi-square tests and logistic models.   
 
We will carry out the two comparisons with the standard dose considering alfa=0.025.  
 
Power analysis 
Given the expected reduction of at least 80% change with exemestane at 25 mg daily (56) considered as 
reference group (control arm) against 25 mg 3 times a week, or 25 mg weekly, for the power calculation 
we assume a non-inferiority difference of 6% in percentage changes of estradiol after treatment from 
baseline, using a one-sided, two-sample t-test. A total sample size of 162 participants (54 participants per 
arm), enables us to achieve 80% power with a margin of equivalence of -6% in the mean percentage 
changes from baseline at the lower dose compared to the standard dose. The true difference between the 
means percentage changes is assumed to be 0.0%.  
 
The significance level of the test is 0.025 to take into account of multiple comparisons (we will compare 
the changes at the two low doses with the standard dose)(57).  
 
The data are drawn from populations with common standard deviations of 11% (58). 
 
Assuming a 10% drop-out rate while on study, we would need to randomize 180 participants (60 
participants per arm) to achieve the total sample size of 162 evaluable participants (54 participants per 
arm). 
 
13.5 
Secondary Objectives, Endpoints, Analysis Plans 
We will attempt to understand the mechanism of action of exemestane on the primary endpoint of the 
study. More specifically, we will assess the effects of exemestane on the secondary endpoint biomarkers 
to see whether the effects of different doses on the primary endpoint is through the secondary endpoint 
biomarkers or independent of them. This will entail exploratory analysis of the primary endpoint by the 
secondary endpoint biomarkers while accounting for the effect of treatment. 
 
Secondary objectives:  
- To assess safety and toxicity. 
- To support the preventive activity of exemestane we will investigate the change in Ki-67 and 
PgR level on the tumor adjacent intraepithelial neoplasia and/or grossly benign tissue. 
- To assess possible association of estradiol level with tissue and circulating biomarkers. 
- To investigate possible pharmacogenetic markers. 
- To assess drug levels on tissue samples. 
- To investigate tissue and circulating proteomics profiling. 
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Secondary endpoints: 
 
• 
Exemestane safety and toxicity will be evaluated at the clinic visit according to the Common 
Terminology Criteria for Adverse Events v4.0 (CTCAE) and by a self-administered Quality of 
Life questionnaire (MENQOL). 
• 
Change in Ki-67 expression comparing pre-treatment versus post-treatment specimen to compare 
the antiproliferative effect among the different dosages. 
• 
Serum drug measurements of exemestane and 17-dihydroxyexemestane at the end of treatment. 
• 
Additional validated method of estradiol measurement. This method has a lower detection limit (1 
pg/ml) than the CLIA certified estradiol test (Quest) and will serve as a quality control since it has 
proven to more effectively detect estradiol concentrations at the very low level, which is 
characteristic of older postmenopausal women. 
• 
Serum concentrations of estrone, estrone-sulfate, will be measured by LC-MS/MS while 
androstenedione and testosterone will be measured at baseline and at surgery. Sex hormone 
binding globulin serum levels will be measured by a chemiluminescent microparticle 
immunoassay (CMIA) on the ARCHITECT i System (Abbott Laboratories, Weisbaden, 
Germany). 
• 
Change in concentrations of insulin, glucose (HOMA index) and lipid profile (total cholesterol, 
HDL cholesterol and triglycerides will be evaluated. 
• 
Adipokines: change in leptin and adiponectin serum concentrations will be analyzed and 
compared among the different treatments arms. These measurements will be performed by the use 
of commercially available enzyme linked immunoassays purchased from R&D systems (SPACE 
Import-Export Srl, Milan, Italy). 
• 
Measurement of breast estradiol concentration in tumor and normal breast tissue at time of 
surgery. 
• 
Centralized evaluation of ER, PgR, Her2 expression in tumor comparing pre-treatment levels 
(tru-cut biopsy) to post-treatment level expression (surgical specimen). Centralized evaluation of 
Ki-67 in adjacent intraepithelial neoplasia and or grossly benign tissue. 
• 
Drug measurements of exemestane and 17-dihydroxyexemestane on frozen tissue samples, when 
available. 
• 
Proteomic analysis will be performed with the new Fusion Tribrid mass spectrometer in Dr. 
Chen’s Proteomics Shared Resource for the Herbert Irving Comprehensive Cancer Center 
(HICCC) at CUMC. 
• 
To analyze the UGT2B17 gene we will use Taqman copy number variation assay (Life 
Technologies, Monza, Italy). 
• 
Crown like structures in mammary fat tissue by IHC (CD68), comparing pre-treatment (tru-cut 
biopsy) versus post-treatment (surgical specimens). 
 
Analysis plan 
We will present full distributions and median values of circulating biomarkers, Ki-67, exemestane and 17-
dihydroxyexemestane in tissue at baseline, after treatment and also of changes and percentage changes 
(with interquartile ranges) of all continuous variable, by arms. ANCOVA models will evaluate the 
associations of post values (after treatment) and changes from baseline by study arms adjusting for 
baseline values, explanatory variables and possible confounders (such as age and BMI). Normal 
distribution of residuals from full models will be checked and, if needed, a transformation will be 
considered.  
 
For binary variables, when we need to assess differences in frequencies, Chi-squares tests and Odds ratios 
(ORs) will be calculated. Multivariate logistic models will be considered to assess differences between 
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arms, adjusting for possible confounders. We will report nominal P-values and we will highlight 
associations that meet a false discovery rate adjusted P less than or equal to .05 by the Benjamini and 
Hochberg method. 
 
Analyses on secondary endpoints will be considered as exploratory since we will not have enough power 
to draw definitive conclusions. 
 
13.6 
Reporting and Exclusions 
 
The primary analysis will employ an intention-to-treat approach, which includes all women irrespective 
of compliance. An according-to-protocol subgroup analysis will be restricted to women who are 
“compliant”, such as participants who have taken ≥ 80% of the active scheduled pills, and notably, due to 
the different arm schedule, ≥ 80% of the active pills has to be reached also in the last 7 days before 
surgery. 
 
Due to limitations of estradiol analysis procedures, small concentrations cannot be precisely measured. 
These concentrations are said to be below the limit of detection (LOD). We will consider a statistical 
method that uses the characteristics of the distribution of the values above the LOD to estimate the values 
below the LOD. This can be done with an extrapolation technique or maximum likelihood estimation that 
has smaller error rates than all the standard replacement techniques (Methods of Dealing with Values 
Below the Limit of Detection using SAS. Croghan et al.).  
 
Patterns of observations for covariates will be classified as complete cases (no missingness), terminal 
(monotone) dropouts, intermittent (non-monotone) dropouts, mixed and no-data. Kendall’s τb will be 
computed in order to test the correlation between a dichotomous indicator of missing observations and 
treatment assigned as well as any possible baseline covariates.  
 
13.7 
Evaluation of Toxicity 
 
All participants will be evaluable for toxicity from the time of their first dose of exemestane. 
 
13.8 
Evaluation of Response 
 
All participants included in the study who have taken at least one dose of study agent will be assessed for 
response to study treatment even if there are major protocol deviations or if they are ineligible. All of the 
participants who met the eligibility criteria (with the possible exception of those who did not receive 
study agent) will be included in the main analysis. All conclusions regarding efficacy will be based on all 
eligible participants. 
 
All randomized participants who received at least one dose will be included in the study analysis with an 
intent-to-treat approach. A secondary analysis will also be carried out after excluding non-compliers and 
participants who will drop-out and who will refuse treatment after randomization. Using a more 
conservative approach, participants who drop-out will be considered in the failure group. Both the intent-
to-treat and efficacy analyses will be conducted on a per-participant basis.  
 
Reasons for excluding participants from the analysis will be clearly reported and sub analyses may not 
serve as the basis for drawing conclusions concerning efficacy. For all measurements of response, the 
95% confidence intervals will also be provided. 
 
13.9 
Interim Analysis 
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There is no interim analysis planned.  
 
13.10 Ancillary Studies 
 
No ancillary studies are planned. 
 
 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
14.1 
Form FDA 1572 
 
Prior to initiating this study, the Protocol Lead Investigator at the Lead or Participating Organization(s) 
will provide a signed Form FDA 1572 stating that the study will be conducted in compliance with 
regulations for clinical investigations and listing the investigators, at each site that will participate in the 
protocol. All personnel directly involved in the performance of procedures required by the protocol and 
the collection of data should be listed on Form FDA 1572. 
 
14.2 
Other Required Documents 
 
14.2.1 Current (within two years) CV or biosketch for all study personnel listed on the Form FDA 1572 
and Delegation of Tasks form for the Lead Organization and all Participating Organizations.  
 
14.2.2 Current medical licenses (where applicable) for all study personnel listed on Form FDA 1572 and 
Delegation of Tasks form for the Lead Organization and all Participating Organizations. 
 
14.2.3 Lab certification (e.g., CLIA, CAP) and lab normal ranges for all labs listed on Form FDA 1572 
for the Lead Organization and all Participating Organizations. 
 
14.2.4 Documentation of training in “Protection of Human Research Subjects” for all study personnel 
listed on the FDA Form 1572 and Delegation of Tasks form for the Lead Organization and all 
Participating Organizations. 
 
14.2.5 Documentation of Federalwide Assurance (FWA) number for the Lead Organization and all 
Participating Organizations. 
 
14.2.6 Signed Investigator’s Brochure/Package Insert acknowledgement form. 
 
14.2.7 Delegation of Tasks form for the Lead Organization and all Participating Organizations signed by 
the Principal Investigator for each site and initialed by all study personnel listed on the form 
 
14.2.8 Signed and dated NCI, DCP Financial Disclosure Form for all study personnel listed on Form 
FDA 1572 for the Lead Organization and all Participating Organizations 
 
14.3 
Institutional Review Board Approval 
 
Prior to initiating the study and receiving agent, the Investigators at the Lead Organization and the 
Participating Organization(s) must obtain written approval to conduct the study from the appropriate IRB. 
Should changes to the study become necessary, protocol amendments will be submitted to the DCP PIO 
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according to DCP Amendment Guidelines. The DCP-approved amended protocol must be approved by 
the IRB prior to implementation 
 
14.4 
Informed Consent 
 
All potential study participants will be given a copy of the IRB-approved Informed Consent to review. At 
the Italian sites, potentially eligible women who would like to participate in the trial will sign an IRB-
approved screening Informed Consent. If they are eligible based on the ER status of their breast cancer, 
the Italian women will then sign the main study Informed Consent. The investigator will explain all 
aspects of the study in lay language and answer all questions regarding the study. If the participant 
decides to participate in the study, she will be asked to sign and date the Informed Consent document. The 
study agent(s) will not be released to a participant who has not signed the Informed Consent document.  
 
Those who refuse to participate or who withdraw from the study will be treated without prejudice.  
 
Participants must be provided the option to allow the use of blood samples, other body fluids, and tissues 
obtained during testing, operative procedures, or other standard medical practices for further research 
purposes. If applicable, statement of this option is included within the informed consent documents. 
 
Prior to study initiation, the informed consent document must be reviewed and approved by NCI, DCP, 
the Consortium Lead Organization, and the Central IRB for the US sites and the Ethics Committees in 
Italy. Any subsequent changes to the informed consent must be approved by NCI, DCP, the Central IRB, 
and then submitted to each organization’s IRB for approval prior to initiation.” 
 
14.5 
Submission of Regulatory Documents 
 
All regulatory documents are collected by the Consortia Lead Organization and reviewed for 
completeness and accuracy. Once the Consortia Lead Organization has received complete and accurate 
documents from a participating organization, the Consortium Lead Organization will forward the 
regulatory documents to DCP’s Regulatory Contractor: 
 
 
Paper Document/CD-ROM Submissions: 
 
Regulatory Affairs Department 
 
CCS Associates, Inc. 
 
2001 Gateway Place, Suite 350 West 
 
San Jose, CA 95110 
 
Phone: 650-691-4400 
 
 
E-mail Submissions: 
 
regulatory@ccsainc.com 
 
Regulatory documents that do not require an original signature may be sent electronically to the 
Consortium Lead Organization for review, which will then be electronically forwarded to the DCP 
Regulatory Contractor. 
 
14.6 
Other 
 
This trial will be conducted in compliance with the protocol, Good Clinical Practice (GCP), and the 
applicable regulatory requirements. 
 
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15. 
FINANCING, EXPENSES, AND/OR INSURANCE 
 
Participants will not be responsible for the costs of this study. Study agent will be provided at no cost to 
the participants. If, as a result of participation in this study, an individual experiences injury from known 
or unknown risks of the research procedures as described in the informed consent, immediate medical 
care and treatment, including hospitalization, if necessary, will be available. No monetary compensation 
is available for the costs of medical treatment for an injury, thus, the participant will be responsible for the 
costs of such medical treatment, either directly or through their medical insurance and/or other forms of 
medical coverage.  
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2010;82(15):6549-6558. 
51. Ross PL, Huang YN, Marchese JN et al. Multiplexed protein quantitation in Saccharomyces 
cerevisiae using amine-reactive isobaric tagging reagents. Mol Cell Proteomics. 2004;3(12):1154-1169. 
52. Lee JS, Ettinger B, Stanczyk FZ et al. Comparison of methods to measure low serum estradiol levels 
in postmenopausal women. J Clin Endocrinol Metab. 2006;91(10):3791-3797. 
53. Bonanni B, Puntoni M, Cazzaniga M et al. Dual Effect of Metformin on Breast Cancer Proliferation 
in a Randomized Presurgical Trial. J Clin Oncol. 2012;30(21):2593-2600. 
54. Johansson H, Gandini S, Guerrieri-Gonzaga A et al. Effect of fenretinide and low-dose tamoxifen on 
insulin sensitivity in premenopausal women at high risk for breast cancer. Cancer Res. 2008;68(22):9512-
9518. 
55. Macis D, Gandini S, Guerrieri-Gonzaga A et al. Prognostic effect of circulating adiponectin in a 
randomized 2 x 2 trial of low-dose tamoxifen and fenretinide in premenopausal women at risk for breast 
cancer. J Clin Oncol. 2012;30(2):151-157. 
56. Geisler J, King N, Anker G et al. In vivo inhibition of aromatization by exemestane, a novel 
irreversible aromatase inhibitor, in postmenopausal breast cancer patients. Clin Cancer Res. 
1998;4(9):2089-2093. 
57. Chow SC, Shao J, and Wang H. Sample Size Calculations in Clinical Research. New York: 2003. 
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58. Hus J.C. Multiple Comparisons: Theory and Methods. London: Chapman & Hall, 1996. 
 
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APPENDIX A 
 
Performance Status Criteria 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade Descriptions 
Percent 
Description 
0 
Normal activity. Fully active, able to 
carry on all pre-disease performance 
without restriction. 
100 
Normal, no complaints, no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
1 
Symptoms, but ambulatory. Restricted in 
physically 
strenuous 
activity, 
but 
ambulatory and able to carry out work of 
a light or sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some signs 
or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time. Ambulatory and 
capable of all self-care, but unable to 
carry out any work activities. Up and 
about more than 50% of waking hours. 
60 
Requires occasional assistance, but is 
able to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time. Capable of only 
limited self-care, confined to bed or chair 
more than 50% of waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely 
disabled, 
hospitalization 
indicated. Death not imminent. 
4 
100% bedridden. Completely disabled. 
Cannot carry on any self-care. Totally 
confined to bed or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes progressing 
rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
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Appendix B 
Exemestane Pill Diary 
 
PID: __ __ __ __ __ __ __ __ __ __ 
     Site: __ __ __ __ __      Visit#: ______ 
 
Number of Pills Given: _______  
 
      Agent Returned:  □ Yes □ No 
        
Total Daily Dose:            25 mg                                       Number of Pills Returned: ________ 
1. Please complete daily.  You should take 1 tablet once a day, preferably at dinner. 
2. Please do not take an extra dose to “make up” for the missed dose.  Take your next dose as scheduled. The 
first time you miss a dose, please contact the study coordinator at:________________ 
3. DRUG INTERACTION Please report as soon as possible to the study doctor if you will be prescribe on of 
these medicaments:  rifampicin, phenytonin, carbamazepine, phenobarbital, and St. John’s wort  
 
Day 
Date 
Took 1 tablet – 
Yet/No and Time 
Notes 
Wallet 1 
Blister 1 
1 
 
 
 
2 
 
 
 
3 
 
 
 
4 
 
 
 
5 
 
 
 
6 
 
 
 
7 
 
 
 
Blister 2 
8 
 
 
 
9 
 
 
 
10 
 
 
 
11 
 
 
 
12 
 
 
 
13 
 
 
 
14 
 
 
 
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Blister 3 
15 
 
 
 
16 
 
 
 
17 
 
 
 
18 
 
 
 
19 
 
 
 
20 
 
 
 
21 
 
 
 
Day 
Date 
Took 1 tablet – 
Yet/No and Time 
Notes 
Wallet 2 
Blister 1 
22 
 
 
 
23 
 
 
 
24 
 
 
 
25 
 
 
 
26 
 
 
 
27 
 
 
 
28 
 
 
 
Blister 2 
29 
 
 
 
30 
 
 
 
31 
 
 
 
32 
 
 
 
33 
 
 
 
34 
 
 
 
35 
 
 
 
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Blister 3 
36 
 
 
 
37 
 
 
 
38 
 
 
 
39 
 
 
 
40 
 
 
 
41 
 
 
 
42 
 
 
 
 
 
Patient’s Signature: ___________________________________________ 
 
Date: ________________ 
 
Reviewer’s Signature:______________________________________________ 
 
Date: ________________ 
 
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APPENDIX C 
 
COMPLIANCE DRUG LABELS 
(Used for Randomization) 
 
INSTITUTION CODE 
 
_______________________ 
PARTICIPANT ID 
 
______________________ 
VISIT TYPE 
 
__________________________ 
VISIT DATE 
(MM/DD/YYYY)  
___ ___ / ___ ___ / ___ ___ ___ ___ 
 
 
Affix Labels Here: 
 
 
 
 
 
Were Labels Affixed?   
 
 Yes  
 
 No  
 
 
 
Investigator’s Signature: __________________          Date of Investigator’s Signature: _ _ / _ _ / _ _ _ _  
                                                                                                                                          (MM/DD/YYYY) 
 
 
Investigator’s Name (Please Print): ________________________________________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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