Quality of life in MAP.3: A randomized, placebo-controlled trial evaluating exemestane for prevention of breast cancer

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1 The following protocol information is provided solely to describe how the authors conducted the research underlying the published report associated with the following article: Quality of life in MAP.3: A randomized, placebo-controlled trial evaluating exemestane for prevention of breast cancer Maunsell, et al DOI: /JCO The information provided may not reflect the complete protocol or any previous amendments or modifications. As described in the Information for Contributors ( protocol.xhtml) only specific elements of the most recent version of the protocol are requested by JCO. The protocol information is not intended to replace good clinical judgment in selecting appropriate therapy and in determining drug doses, schedules, and dose modifications. The treating physician or other health care provider is responsible for determining the best treatment for the patient. ASCO and JCO assume no responsibility for any injury or damage to persons or property arising out of the use of these protocol materials or due to any errors or omissions. Individuals seeking additional information about the protocol are encouraged to consult with the corresponding author directly.

2 Amendment #1: 2004-JAN-07 Amendment #2: 2004-MAY-25 Revision #1: 2004-JUL-21 Amendment #3: 2005-JAN-24 Amendment #4: 2006-JUL-20 Consent Amendment #1: 2007-JAN-17 Amendment #5: 2009-APR-07 NCIC CLINICAL TRIALS GROUP (NCIC CTG) A PHASE III RANDOMIZED STUDY OF EXEMESTANE VS PLACEBO IN POSTMENOPAUSAL WOMEN AT INCREASED RISK OF DEVELOPING BREAST CANCER NCIC CTG Protocol Number: MAP.3 Pfizer Protocol Number: EXEAPO STUDY CHAIR: TRIAL COMMITTEE: PROJECT COORDINATOR: BIOSTATISTICIAN: QUALITY OF LIFE COORDINATOR: STUDY COORDINATOR: SPONSOR: SUPPORTED BY: PAUL GOSS JAMES INGLE ROWAN CHLEBOWSKI GLORIA SARTO JUDY GARBER CAROL FABIAN JOSÉ E. ALÉS-MARTÍNEZ PASCAL PUJOL HARRIET RICHARDSON DONGSHENG TU ELIZABETH MAUNSELL DIANNE JOHNSTON NCIC CTG PFIZER, INC CONFIDENTIAL CONFIDENTIAL

3 Amendment #3: 2005-JAN-24; Amendment #4: 2006-JUL-20; Amendment #5: 2009-APR-07 TABLE OF CONTENTS TREATMENT SCHEMA OBJECTIVES Primary Secondary BACKGROUND INFORMATION AND RATIONALE Breast Cancer Chemoprevention Aromatase Inhibitors As Potential Chemopreventatives Aromatase Inhibitors and Bone Health Aromatase Inhibitors and Cardiovascular Health Study Rationale BACKGROUND THERAPEUTIC INFORMATION Exemestane TRIAL DESIGN Stratification Randomization STUDY POPULATION Eligibility Criteria Ineligibility Criteria PRE-TREATMENT EVALUATION ENTRY/RANDOMIZATION PROCEDURES Entry Procedures Stratification Treatment Allocation TREATMENT PLAN Treatment Plan Concomitant Medications Unblinding EVALUATION DURING AND AFTER PROTOCOL TREATMENT Evaluation During Protocol Treatment Evaluation After Protocol Treatment CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS Definitions Response and Evaluation Endpoints SERIOUS ADVERSE EVENT REPORTING Definition of a Reportable Serious Adverse Event Serious Adverse Event Reporting Instructions Reporting Secondary Malignancies or Myeloid Dysplasia NCIC CTG Responsibility for Reporting Serious Adverse Events to Health Canada (Office of Clinical Trials) NCIC CTG Reporting Responsibility to Pfizer Inc Reporting Serious Adverse Events to Local Research Ethics Boards CONFIDENTIAL i CONFIDENTIAL

4 12.0 PROTOCOL TREATMENT DISCONTINUATION AND THERAPY AFTER STOPPING Criteria for Discontinuing Protocol Treatment Therapy After Protocol Treatment is Stopped Off Protocol Treatment Visit CENTRAL REVIEW PROCEDURES Breast Density, Serum Hormone and DNA Samples Breast Events Tissue Collection STATISTICAL CONSIDERATIONS Objectives and Design Endpoints and Analysis Sample Size and Duration of Study Safety Monitoring Interim Analysis PUBLICATION POLICY Authorship of Papers, Meeting Abstracts, Etc Responsibility for Publication Submission of Material for Presentation or Publication ETHICAL, REGULATORY AND ADMINISTRATIVE ISSUES Institution Eligibility for Participation Investigator Qualifications Regulatory Requirements REB/IRB (Research Ethics Board) Approval for Protocols Informed Consent Retention of Subject Records and Study Files Centre Performance Monitoring On-Site Monitoring/Auditing Case Report Forms REFERENCES APPENDIX I - SUBJECT EVALUATION FLOW SHEET APPENDIX II - BREAST CANCER RISK ASSESSMENT APPENDIX III - DRUG DISTRIBUTION, SUPPLY AND CONTROL APPENDIX IV - DOCUMENTATION FOR STUDY APPENDIX V - NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS V APPENDIX VI - NCIC CTG DATA SAFETY MONITORING COMMITTEE APPENDIX VII - QUALITY OF LIFE QUESTIONNAIRE APPENDIX VIII - DECLARATION OF HELSINKI APPENDIX IX - SAMPLE CONSENT FORMS ENGLISH Sample Consent Form Exemple de formulaire de consentement en FRANÇAIS APPENDIX X - PARTICIPATION OF GEICAM APPENDIX XI - PARTICIPATION OF FNCLCC LIST OF CONTACTS LIST OF CONTACTS... Final Page CONFIDENTIAL ii CONFIDENTIAL

5 TREATMENT SCHEMA PROTOCOL DATE: 2003-OCT-29 Amendment #2: 2004-MAY-25; Amendment #3: 2005-JAN-24; Amendment #4: 2006-JUL-20 Postmenopausal women at increased risk for the development of breast cancer are eligible for this study. Stratification: Subjects will be stratified by current low dose (< 100 mg/day) aspirin use (Yes vs No) and Gail score < 2.0 vs > 2.0 Arm Dose Route Frequency a.m. Duration exemestane one 25 mg tablet oral 5 years placebo one tablet oral 5 years Planned sample size: 4560 (90% power) Endpoints Primary incidence of invasive breast cancer. Secondary total incidence of invasive and non-invasive (DCIS) breast cancer incidence of receptor negative invasive breast cancer LCIS, Atypical Ductal Hyperplasia and Atypical Lobular Hyperplasia events number of clinical breast biopsies clinical skeletal fractures cardiovascular events - Myocardial Infarct - coronary heart disease resulting in death quality of life (SF-36) and menopause-specific quality of life (MENQOL) tolerability and safety incidences of other malignancies CONFIDENTIAL 1 CONFIDENTIAL

6 1.0 OBJECTIVES Amendment #3: 2005-JAN-24; Amendment #4: 2006-JUL Primary To determine if exemestane reduces the incidence of invasive breast cancer compared with placebo 1.2 Secondary To determine if exemestane reduces the total incidence of invasive and non-invasive (DCIS) breast cancer compared with placebo To compare the incidence of LCIS, atypical ductal hyperplasia and atypical lobular hyperplasia events in the different treatment groups To compare the number of clinical breast biopsies in the different treatment groups To compare the incidence of all clinical fractures and specifically hip and vertebral fractures in the different treatment groups. (In a specific number of centres a sub-study evaluating bone mineral density will be conducted. A separate companion protocol has been written to encompass this study.) To determine whether there are differences between exemestane or and placebo with respect to the incidence of clinically relevant cardiac events (i.e. significant coronary heart disease, which includes myocardial infarctions and angina requiring percutaneous transluminal coronary angioplasty or coronary artery bypass graft, fatal and nonfatal strokes and all vascular deaths) To assess the impact, in comparison to placebo, of exemestane on menopausal symptoms (as assessed by the MENQOL) and quality of life (as assessed by the SF-36) To determine whether there are significant differences in adverse events between the treatment arms To determine whether exemestane in comparison with placebo reduces the incidences of other malignancies To assess the significance of serum/blood biomarkers in samples collected and stored in central repositories i) At baseline, 1 year and 5 year blood samples will be sent to the Department of Pathology at Queen s University. Part of these samples will be used to analyze serum hormone levels which have been associated with breast cancer risk and the other to establish a DNA database. Proposals for analyses of these stored specimens will be developed according to the guidelines of the Breast Intergroup Correlative Science Committee CONFIDENTIAL 2 CONFIDENTIAL

7 2.0 BACKGROUND INFORMATION AND RATIONALE Amendment #4: 2006-JUL-20 Breast cancer is the most common malignancy in Western women, representing about 30% of all cancers and about 20% of all cancer-related deaths. There are more than and newly diagnosed cases per year in the United States and Canada respectively and, since the 1980 s, the incidence has been rising at a rate of approximately 3% per year (NIH Consensus Statement: Adjuvant Treatment for Breast Cancer, 2000). To date, in addition to optimizing surgical and radiation therapy, clinical approaches to improving patient outcome have included: i) systemic treatment of clinically detectable disease ii) earlier diagnosis of disease by population-based mammographic screening. Mammographic screening has led to a greater number of small tumours and low stage disease being diagnosed. In addition, in the adjuvant setting, both chemotherapy and hormonal interventions have been shown to reduce systemic disease recurrence. These advances have led to a decrease in patient mortality, however, results have been modest as one quarter to one third of breast cancer patients continue to experience systemic disease relapse and death (NIH Consensus Statement: Adjuvant Treatment for Breast Cancer, 2000). It is thus logical to investigate agents capable of interfering with the initiation and/or promotion of breast cancer, i.e. breast cancer chemoprevention. Attention has focused on strategies directed towards antagonizing the effects of estrogens as they are known to play a key role both in the development of the normal breast and in the pathogenesis of breast cancer (Clemons, 2001; The Endogeneous Hormones and Breast Cancer Collaborative Group, 2002). In principle, at least two pharmacologic approaches may be used to antagonize the effects of estrogen in the breast. The first is to inhibit estrogen binding to its receptor using Selective Estrogen Receptor Modulators (Tamoxifen and Raloxifene). This approach has led to the approval of tamoxifen by the FDA for the short-term reduction in the incidence of breast cancer in women at increased risk. In fact, tamoxifen and raloxifene appear effective in reducing breast cancer risk in all risk individuals as well but approval for tamoxifen was granted by the FDA only for use in high risk women because of its therapeutic index. In particular, tamoxifen caused serious and potentially fatal toxicities including endometrial cancer and thromboembolic disease especially in older postmenopausal women. It also caused significant symptoms in women with recent onset and established menopause with an aggravation of vasomotor symptoms and urogenital complications (Day, 1999). More recently the NSABP-P2- STAR trial comparing tamoxifen to raloxifene, has been concluded. Its results are summarized in section 2.1. An alternative strategy of antagonizing (reducing) estrogen s effects is to inhibit its synthesis with an aromatase (estrogen synthetase) inhibitor (see section 2.2). 2.1 Breast Cancer Chemoprevention Breast Cancer Prevention Completed Trials Tamoxifen NSABP P1 The P1 trial of tamoxifen (20 mg) vs. placebo conducted by the NSABP enrolled 13,388 well women at increased risk of breast cancer. Increased risk was defined as being over the age of 60 years or having a five-year predicted risk for breast cancer of at least 1.66% (as determined by the Gail model) or having had a history of LCIS or atypical hyperplasia. P1 demonstrated that tamoxifen reduced the risk of invasive breast cancer by 43% (RR=0.57; 95% CI= ) with a cumulative CONFIDENTIAL 3 CONFIDENTIAL

8 Amendment #4: 2006-JUL-20 incidence (over 7 years of follow-up) of 42.5 cases versus 24.8 cases per 1000 women in the placebo and tamoxifen groups, respectively. This risk reduction occurred in all age groups < 49 (36%), (43%) and 60+ (51%). Tamoxifen was also shown to reduce the incidence of non-invasive breast cancer (DCIS & LCIS) by 37% (RR=0.63; 95% CI= ) (Fisher, 2005). The incidence of a number of benign conditions of the breast including adenosis, cysts, duct ectasia, fibrocystic disease, hyperplasia, and hyperplasia with atypia was also reduced in the tamoxifen group (Tan-Chiu, 2003). Tamoxifen reduced the occurrence of ER-positive tumours by 62% (RR=0.38; 95% CI= ) but did not affect the occurrence of ER-negative tumours (Fisher, 2005). There is no survival difference reportable in this trial population at this time. Tamoxifen does have a beneficial effect on osteoporotic hip, radius and spine fractures with a 32% reduction in overall fractures (RR=0.68; 95% CI= ). However, it increased the risk of endometrial cancer (RR=3.28; 95% CI= ). This increased risk was observed predominantly in women age > 50. The rates of stroke (RR=1.42; 95% CI= ), pulmonary embolism (RR=2.15; 95% CI= ), and deep vein thrombosis (RR=1.44; 95% CI= ) were also elevated in the tamoxifen treatment arm - also predominantly in women age > 50 (Fisher, 2005). It appears, however, that the increased risk for venous thromboembolic events (VTE) may only be apparent for the first 3 years of tamoxifen use but not in the 4th and 5th years of treatment, based on results from a recent analysis of VTE, tamoxifen use and the presence of Factor V leiden (FVL) and prothrombin (PT20210) genetic abnormalities (Abramson 2006). The Royal Marsden Study In the Royal Marsden trial 2494 women were randomized to receive either tamoxifen 20 mg or placebo once daily for up to eight years. Premenopausal women taking oral contraceptives were excluded whereas postmenopausal women on hormone replacement therapy (HRT) at the time of trial entry were eligible. After a median follow-up of 70 months there was no difference in the incidence of breast cancer between the two groups (RR=1.06 [95% CI ], p=0.8){powles, 1998}. The results of this trial have been criticized because it was under powered to detect a significant difference in the time frame of the trial analysis. However, recently an updated analysis has shown a reduction in incidence of invasive breast cancer in the tamoxifen treated patients (Chlebowski, 2002). The Italian Tamoxifen Prevention Study This study included 5408 hysterectomized women, aged years, randomized to tamoxifen 20 mg per day versus placebo for 5 years. There was no reduction in the incidence of breast cancer in women on tamoxifen compared to placebo (19 cases on tamoxifen arm and 22 cases on placebo, p=0.6358) {Veronesi, 1998}. Interestingly however, the incidence of invasive breast cancer was reduced in women taking HRT plus tamoxifen compared with women taking HRT plus placebo. A recent update of the data has concluded that a reduction in invasive breast cancer in the tamoxifen treated women compared with placebo was also seen (Chlebowski, 2002) (Veronesi, 2002). The International Breast Cancer Intervention Study IBIS 1 The international breast cancer intervention study (IBIS 1) was a recently completed multinational study. The population (n=7000) included: women ages 45 to 70 years with a risk of breast cancer at least twice that of the general population. Women were randomized to receive either tamoxifen 20 mg or placebo daily for 5 years. This study was conducted outside of North America and has recently had the results reported (see ref below). Tamoxifen showed a reduction in the incidence of breast cancer of approximately 33% and an overview and meta-analysis of all the tamoxifen related trials to date shows an overall reduction in incidence of approximately 38% in favour of tamoxifen {IBIS Investigators, 2002}. The IBIS 2 trial is now open (see below). CONFIDENTIAL 4 CONFIDENTIAL

9 Raloxifene Amendment #3: 2005-JAN-24; Amendment #4: 2006-JUL-20 In the multiple outcomes of raloxifene evaluation (MORE) trial 7705 postmenopausal women up to 80 years of age who had osteoporosis were randomized to receive raloxifene (60 mg or 120 mg), or placebo, daily for 4 years. Raloxifene is a benzothiophene derivative that appears to act as an estrogen antagonist in uterine and breast tissues but as an estrogen agonist with respect to its effects on circulating lipids and bone. Raloxifene markedly reduced the incidence of ER-positive invasive breast cancer by 84% [RR=0.16; 95% CI ] but not ER-negative invasive breast cancer [RR=1.13; 95% CI ]. Although raloxifene did not increase the risk of endometrial cancer a greater than two fold increased risk of venous thromboembolic disease (p=0.003) was observed in the raloxifene group compared to the placebo group. (Cauley, 2001; Black, 1994; Ashby, 1997; Draper, 1996; Delmas, 1997; Cummings, 1998; Cummings, 1999; Lupu, 1991). Continuing Outcomes Relevant to Evista Study (CORE) The CORE study investigated the effect of 4 additional years of raloxifene (60 mg/day) compared to placebo in a subset of the MORE cohort that agreed to participate (n=4011). Those women on placebo in the MORE study stayed on placebo in the CORE trial (n=1286) and those women originally on raloxifene (60 mg/day or 120 mg/day) were allocated to the raloxifene (60 mg/day) arm in the CORE trial. During the 4 year CORE study the incidence of ER-positive invasive breast cancer was reduced by 59% (HR=0.41; 95% CI: ) in the raloxifene group compared to the placebo group. No difference in the incidence of ER-negative invasive breast cancers was observed between the two groups. Over the 8 years of both trials (MORE and CORE combined) the incidence of invasive breast cancer and ER-positive invasive breast cancer were reduced by 66% (HR=0.34; 95% CI: ) and 76% (HR=0.24; 95% CI: ) respectively, in the raloxifene group compared to the placebo group. The two-fold increase in thromboembolic events ((DVT and pulmonary embolism) observed in the MORE study persisted over the 8 years of both trials. During the CORE study, the RR for thromboembolism in the raloxifene group compared to the placebo group was 2.17 (95% CI: ) (Martino, 2004). Raloxifene Use for The Heart Study (RUTH) RUTH was a 7 year double blind, placebo-controlled, randomized clinical trial of 10,101 postmenopausal women age 55 or older with known heart disease or at high risk for a heart attack. The study was designed to investigate the effect of raloxifene (60 mg/day) compared to placebo in the reduction of coronary events (coronary death, nonfatal MI, or hospitalized acute coronary syndromes other than MI); and the reduction in risk of invasive breast cancer (Mosca, 2001). A recent analysis of the two primary endpoints indicate that Evista (raloxifene) does reduce the incidence of invasive breast cancer (HR=0.56; 95% CI: ) but does not prevent coronary events (HR=0.95; 95% CI: ). In particular, there was a small increase in stroke mortality and an increase in venous thromboembolic events for women who took raloxifene (Barrett-Connor, 2006). CONFIDENTIAL 5 CONFIDENTIAL

10 Amendment #4: 2006-JUL-20 The NSABP P2: Study of Tamoxifen and Raloxifene Study (STAR) Based on the results of P1 and the MORE data, the NSABP STAR study, conducted in North America, compared raloxifene 60 mg versus tamoxifen 20 mg daily for five years in postmenopausal women, age >35 years, who are at increased risk of breast cancer, as defined by the NSABP-P1 eligibility criteria in North America in July There were 19,747 women recruited to the trial before it closed in mid After a median follow-up of 4 years there was no difference between the effect of tamoxifen and the effect of raloxifene on the incidence of invasive breast cancer. The rate per 1000 was 4.3 in the tamoxifen group and 4.41 in the raloxifene group (p-value=0.83). In contrast, there were fewer noninvasive breast cancers in the tamoxifen group than in the raloxifene group. The rate per 1000 was 1.51 for tamoxifen and 2.11 for raloxifene (p-value=0.052). There was a trend toward a decreased incidence of uterine cancer in the raloxifene group, but the difference was not statistically significant (RR=0.62; 95% CI ).There was, however, a significant difference between the groups in the incidence of uterine hyperplasia. The rates were 84% less in the raloxifenetreated group (14 cases) than in the tamoxifen-treated group (84 cases). No differences were found for other invasive cancer sites, for ischemic heart disease events or for stroke. Thromboembolic events (DVT and pulmonary embolism) occurred less often in the raloxifene group (RR=0.70; 95% CI ). The number of osteoporotic fractures in the two treatment groups was similar. There were fewer cataracts (RR=0.79; 95% CI ) in the women taking raloxifene. {Vogel, 2006} There were no significant differences between the two treatment groups with regards to primary QOL endpoints, though effects on vasomotor symptoms were worse and sexual side effects less pronounced with tamoxifen compared to raloxifene (Land, 2006). Ongoing Trials The International Breast Cancer Intervention Study IBIS 2 A follow-up trial to the IBIS-1 trial has begun. The trial design consists of a two arm study of anastrozole versus placebo in postmenopausal women considered at risk by the same criteria as were used for the IBIS I study and in addition a number of new criteria which were not in the original IBIS I study. These include; women treated within 6 months with a mastectomy for DCIS, women with > 50% density on screening mammogram and women at an equivalent risk (> 2x population normal ) as assessed by the study committee. The sample size calculated is 6,000 postmenopausal women. The rationale for employing an aromatase inhibitor is outlined below. CONFIDENTIAL 6 CONFIDENTIAL

11 2.2 Aromatase Inhibitors As Potential Chemopreventatives Amendment #4: 2006-JUL-20 Targeting and reducing estrogen synthesis is a way of preventing estradiol from stimulating the receptor as well as reducing the formation of cancer-causing catechol metabolites of estrogen. To this end estrogen synthetase (aromatase) inhibitors have been developed. Aromatase is the enzyme complex responsible for the final step in estrogen biosynthesis: the conversion of androgens to estrogens. Preclinical experiments have been conducted to determine the chemopreventive efficacy of new, potent and selective aromatase inhibitors. For example, vorozole decreased tumour incidence from 100% to 10% and tumour multiplicity from 5 tumours to 0.1 tumours per animal in the NMUinduced rat mammary tumour model (Lubet, 1994) and showed similar effects in the DMBA-induced tumour model (De Coster, 1992). Similarly, letrozole inhibited new mammary tumour development in the DMBA rat model (Bhatnagar, 1990; Schieweck, 1993). The third-generation aromatase inhibitors letrozole, anastrozole and exemestane are all approved for use in postmenopausal women with ER positive metastatic breast cancer that have progressed after tamoxifen, have failed to respond to tamoxifen (Buzdar, 1996; Domberowsky, 1998; Scott, 1999; Kaufmann, 2000) or as initial therapy in treatment naïve women with receptor positive metastatic disease. In addition letrozole has been shown to be significantly superior to tamoxifen as primary medical (neoadjuvant) therapy in locally advanced or inoperable breast cancer (Eirmann, 2001; Ellis, 2001). There are at least eight ongoing adjuvant trials testing aromatase inhibitors in early stage postmenopausal receptor positive breast cancer. To date published data are available on four large phase III double blind randomized adjuvant trials comparing 3rd generation aromatase inhibitors with tamoxifen or to a placebo following 5 or fewer years of tamoxifen. In the Arimidex, Tamoxifen Alone or in Combination (ATAC) trial 9366 patients were randomly assigned to receive anastrozole and placebo, tamoxifen and placebo or anastrazole and tamoxifen combined. Disease free survival was significantly lengthened when the anastrozole group were compared to the tamoxifen group (absolute risk reduction was 2.7%, p=0.013) after a median follow-up of 47 months. Importantly, the incidence of contralateral new primary breast cancer was significantly lower in the anastrozole group compared to the tamoxifen group (OR=0.42, p=0.007) (The ATAC Trialists, 2002). The intergroup Exemestane Study (IES) randomly assigned 4742women who had received 2-3 years of tamoxifen to continue tamoxifen for a total of 5 years or to switch to exemestane to complete a 5 year course of hormonal therapy. After a median follow-up of 58 months there was a significant improvement in disease free survival in the exemestane group (HR=0.76; 95% CI: ) and a significant reduction in contralateral breast cancer events (HR=0.56, 95%CI: ) (Coombes, 2006). The NCIC CTG MA.17 trial involved 5,187 postmenopausal women who had taken tamoxifen for 5 years and who were disease free at time of study entry and randomly assigned to receive 5 years of letrozole or 5 years of placebo. The study was halted by the Data Safety Monitoring Committee after a median of 2.4 years because of a significant reduction in breast cancer events (Goss, 2003). More recently, the study demonstrated an overall benefit in distant disease free survival and a survival advantage in the subset of women on the trial who had node-positive disease. The incidence of contralateral cancers was also lower in the letrozole group although the difference was not statistically significant (Goss, 2005). The Breast Cancer International Study Group (BIG I-98) involved approximately 8000 women and has 4 treatment arms, tamoxifen alone for 5 years, letrozole alone for 5 years, tamoxifen for 3 years followed by letrozole for 2 years and letrozole for 3 years followed by tamoxifen for 2 years. A recent analysis comparing letrozole to tamoxifen treatment showed that the reduction in risk of recurrence or death was 19% lower in the letrozole group, after a median of 28 months of follow-up. Comparisons of the switched arms are not yet available (Thurlimann, 2005). Based on results from these large trials and other smaller randomized trials the ASCO Technology Assessment of Aromatase Inhibitors Status Report (2004) recommends that adjuvant therapy for postmenopausal women with hormone receptor positive breast cancer should include aromatase inhibitors in order to lower the risk of recurrence. The optimal timing and duration of aromatase inhibitor therapy has yet to be established (Winer, 2005). CONFIDENTIAL 7 CONFIDENTIAL

12 Amendment #4: 2006-JUL-20 Given the convincing evidence, thus far, that the aromatase inhibitors are superior to tamoxifen in the treatment of breast cancer it is highly suggestive that they will also be superior in the chemopreventive setting. Exemestane is a third generation steroidal irreversible aromatase inhibitor, structurally related to the natural substrate androstenedione. The compound has been shown to be a potent, competitive and irreversible inhibitor of human placental aromatase, both in vitro and in vivo. In postmenopausal women, it is capable of inhibiting aromatase action by >95%. The reduction in contralateral breast cancer incidence in the ATAC and IES trials is especially promising in this regard. In addition to the clinical studies, a significant body of data on the chemopreventive properties of aromatase inhibitors comes from preclinical studies. In 7,12-dimethylbenzathracene (DMBA)-induced mammary tumours in ovariectomized (OVX), testosterone-treated rats (an estrogen dependent postmenopausal tumour model) exemestane exerts potent antitumour activity by both subcutaneous and oral routes. In the N-nitrosomethylurea (NMU)- and DMBA-carcinogen-induced mammary tumour models, inhibition of both the appearance of new tumours and their multiplicity has been shown with the aromatase inhibitors letrozole, aminoglutethimide, fadrozole and vorozole, the last three of which are not widely used in breast cancer therapy any longer (Gunson, 1995; Moon, 1994; DeCoster, 1992; Lubet, 1994; Schieweck, 1988; Schieweck, 1993; Bhatnagar, 1990). 2.3 Aromatase Inhibitors and Bone Health Estrogen depletion associated with AIs is responsible for their impressive anti-tumour effect but has led to concerns about negative effects on bone health. Estrogen is one of the principal hormonal regulators of bone turnover in women. Estrogen depletion, however, can lead to negative changes in bone turnover (bone resorption and formation) which can lead to increased loss of bone mineral density (BMD) and an increased risk of clinical fractures (Chien, 2006). However, based on the current data on the effects of AIs on bone, it appears as if each aromatase inhibitor may have its own distinct pharmacodynamic effects on bone metabolism. Exemestane, a steroidal inactivator, and its principal metabolite, 17 hydroexemestane, appears to have a positive effect in preclinical models on bone. Because of the lower level of moderate to severe hot flashes, the suppression of Sex Hormone Binding Globulin (SHBG) and the known androgenicity of 17-hydroexemestane, one of the chief metabolites of exemestane, it is hypothesized that bone may be protected despite potent estrogen suppression when receiving exemestane. In a preclinical model in mature, cycling Sprague Dawley rats, it was demonstrated that complete protection against the adverse changes in bone (pyridinoline bone resorption and osteocalcin bone formation) and lipid (serum cholesterol and LDL cholesterol) metabolism evoked by castration can be afforded by simultaneous administration of exemestane (Goss, 2001). In contrast there are data regarding early markers of bone (Harper-Wynne, 2001) metabolism to show that the non-steroidal inhibitors (anastrozole and letrozole) adversely affect these parameters. In a study of exemestane versus letrozole versus placebo in OVX rats Goss et al (San Antonio 2002 Abstract #267) demonstrated that exemestane showed effects similar to placebo in short term markers of bone turnover whereas letrozole had a negative effect on these biomarkers. Large adjuvant trials of AIs in combination with tamoxifen, instead of tamoxifen and in sequence with tamoxifen have reported clinical fracture rates in the entire study population, and a number of sub-studies measuring BMD and bone turnover biomarkers have been reported (Chien & Goss, 2006). Briefly, the ATAC trial reported a reduction in BMD in the anastrozole group while the tamoxifen group experienced an improvement in BMD in both the lumber spine (LS) and the total hip (TH) after 1 and 2 years of therapy, when compared to controls. The anastrozole group also had a significantly higher incidence of long bone fractures than those taking tamoxifen (11% vs. 7.7%) after a median of 68 months of follow-up (ATAC Trialists Group, 2002). Similarly, the BIG I-98 trial reported a significant increase in bone fractures in the letrozole group compared with the tamoxifen group (5.7% vs. 4%) after 26 months of follow-up. The ABCSG 8 / ARNO 95 study was a combined CONFIDENTIAL 8 CONFIDENTIAL

13 Amendment #4: 2006-JUL-20 analysis of two trials in which anastrozole was randomly assigned to women with early breast cancer following 2-3 years of tamoxifen therapy. After a median follow-up of 28 months, there were twice as many fractures in women who had switched to anastrozole (2%) compared to those who only received tamoxifen (1%) for 5 years (Jakesz, 2005). In a similar design, the Intergroup Exemestane Study (IES) compared 5 years of tamoxifen use with an initial 2-3 years of tamoxifen use followed by 3-2 years of exemestane. After a median of 30.6 months of follow-up there was a non-significant increase in the incidence of osteoporosis (7.4% vs. 5.7% for tamoxifen) and a slight but non-significant increase in the incidence of fractures in the exemestane group (3.1%) than in the tamoxifen group (2.3%) (Coombes, 2004). In a bone sub-study of IES, patients switching to exemestane had a slight decrease in BMD and evidence of increased bone turnover in the first year of therapy. However, it is speculated that these changes were due to tamoxifen withdrawal, since there was no further reduction in BMD in the exemestane group after these initial changes in the first year (Coleman, 2004; Coleman, 2006). In the NCIC CTG MA.17 trial, after a median of 30.6 months of follow-up, significantly more women receiving letrozole (8.1%) reported a new diagnosis of osteoporosis compared to women on placebo (6%). However, the difference in fracture rates between the letrozole group (5.3%) and the placebo group (4.6%) was not significantly different (Goss, 2005). The MA.17 bone sub-study observed a significant increase in biomarkers of bone resorption and a significant decrease in BMD in the letrozole group compared to the placebo group after a median of 1.6 years of follow-up and. However, the loss in BMD was significantly more pronounced in women with osteopenia at baseline compared to women with normal baseline BMD (Perez, 2004). Lonning et al recently described the results of the first randomized study of an AI versus placebo in women with early breast cancer. Women with DCIS or early breast cancer (n=147) who were considered ineligible for standard adjuvant therapy due to their low-risk profile were randomized postoperatively to receive either exemestane or placebo for 2 years. There was no significant difference in mean annual BMD loss in the lumber spine (2.17% vs. 1.84% on placebo) but a significant loss was observed in the BMD of the femoral neck in the exemestane group (2.72% vs % on placebo). Similarly exemestane significantly increased markers of bone resorption, but unlike the MA.17 bone sub-study, it also increased markers of bone formation. There was no difference in the rate of fractures or the number of osteopenic patients developing osteoporosis (Lonning,, 2005). It is interesting to note that within 6 months of stopping exemestane, bone resorption biomarkers returned to baseline values and within 1 year of stopping exemestane, the LS BMD was almost back to baseline and the FN BMD was stable. In summary, the current data suggests that AI s may negatively affect bone metabolism to varying degrees. However, unlike anastrozole or letrozole, a significant increase in the incidence of osteoporosis and / or clinical fracture rates, arguably the most clinically meaningful bone endpoints, have not been observed for patients on exemestane. However, it should also be stressed that the Lonning study is the only trial, thus far, to provide information on an AI s effect on bone health without being confounded by previous tamoxifen exposure. CONFIDENTIAL 9 CONFIDENTIAL

14 2.4 Aromatase Inhibitors and Cardiovascular Health Amendment #4: 2006-JUL-20 According to a recent review by Chlebowski et al (Chlebowski,, 2006), aromatase inhibitors do not appear to have an adverse effect on lipid profile when compared to tamoxifen or placebo. Overall, aromatase inhibitors do not result in any substantial change in levels of total cholesterol or low density lipoproteins (LDL). There is a suggestive trend towards an increase in high density lipoproteins (HDLs) with AI use and a decrease in triglyceride levels. (Chlebowski,, 2006) It is too early to know if there are distinct differences on lipid profile associated with specific AIs. Conversely, the majority of studies that have measured lipids at baseline and while on study protocol have observed that tamoxifen consistently reduces LDL cholesterol and likely increases triglycerides. (Herrington and Klein,, 2001; Sawado and Sato, 2003; Atalay, 2004). The effects of tamoxifen on HDL cholesterol is mixed, with at least one study observing an increase in HDL levels (Banerjee, 2005). In one very large study comparing raloxifene to placebo (RUTH trial), raloxifene was associated with significant decreases in LDL and increases in HDL cholesterol. (Barrett-Connor, 2006) Despite the suggested favourable effect of tamoxifen on certain serum lipid profiles such as reduced LDL cholesterol, tamoxifen has been shown to consistently increase the risk of stroke in randomized controlled trials (Bushnell 2004; Geiger, 2004). However, while there is no definitive evidence on the effect of tamoxifen on coronary heart disease (MI or angina), the evidence is suggestive of a modest protective effect of tamoxifen for CHD death, especially in individuals at a higher baseline risk for CHD (Chlebowski,, 2006). The effect of raloxifene on coronary heart disease (and breast cancer prevention) was specifically studied in the Raloxifene Use for the Heart (RUTH) study, which was designed to assess the risks and benefits of treatment with raloxifene in women with or at increased risk of CHD (Barrett-Connor, 2006). As compared to placebo, raloxifene had no significant effect on the risk of primary coronary events (HR=0.95; 95% CI: ). However, raloxifene was associated with an increased incidence of fatal strokes (HR=1.49; 95% CI: ) and venous thromboembolism (HR=1.44; 95% CI: ). Therefore, despite promising suggestions from earlier clinical trials that raloxifene improved the lipidemic profile (i.e. reduced levels of LDL), this did not translate into cardioprotection in the RUTH study. Aromatase inhibitors now play a predominant role in the management of postmenopausal patients with receptor-positive cancers because they appear to be more effective than tamoxifen in decreasing breast cancer recurrence and are associated with fewer life-threatening adverse effects. However, there is concern that the very low estrogen levels associated with AI use might still have a negative impact on the risks of CHD and stroke (Chlebowski,, 2005). Preliminary evidence from the ATAC study suggests that there are no important differences between anastrozole and tamoxifen for CHD risk (MI incidence was similar in both groups), but fewer women on anastrozole experienced an ischemic cerebral vascular event or thromboembolic event as compared to women on tamoxifen (Howell, 2005). Similarly, letrozole had no influence on ischemic cardiovascular events in the MA.17 trial when compared to placebo. The incidence rates for MI, new or worsening angina, stroke/transient ischemic attack, or thromboembolic events were similar in both groups (Goss, 2005). In contrast, in a re-review of all severe adverse events, the BIG I-98 study observed more cerebrovascular events and cardiac events in the letrozole group compared to the tamoxifen group (Thurlimann, 2005). In a very recent update of the IES trial there were no significant differences in myocardial infarctions, angina, or cerebrovascular accidents between those women on exemestane or who continued on tamoxifen. However, there were more thromboembolic events observed in the tamoxifen group (Coombes, 2006). CONFIDENTIAL 10 CONFIDENTIAL

15 Amendment #2: 2004-MAY-25; #3: 2005-JAN-24; #4: 2006-JUL-20; Amendment #5: 2009-APR-07 Finally, Exemestane may also have a better acute toxicity profile and cause less menopausal symptomatology than other aromatase inhibitors eg. anastrozole. In the trials of the inhibitors against megestrol acetate, exemestane (1.7% versus 5%) (Kaufmann, 2000) but not letrozole (2.4% versus 4%) (Buzdar, 2001) showed a statistically lower rate of cessation of the aromatase inhibitor compared to megestrol acetate. Exemestane also resulted in grade 2 or 3 hot flashes in only 3.2% of patients compared with 13.5% for megace. Neither letrozole nor anastrozole showed improved rates of hot flashes over megestrol acetate (Buzdar, 2001; Buzdar, 1997). In summary, exemestane may have better efficacy and end-organ effects than non-steroidal aromatase inhibitors, thereby affording it a better therapeutic index and a superior choice, to a non-steroidal inhibitor in the prevention of breast cancer. Positive effects in bone and lipid metabolism could also make it a compound of interest in women s health in general, a feature distinct from the non-steroidal aromatase inhibitors 2.5 Study Rationale Our trial is a randomized double blind placebo controlled multicentre, multinational trial. Despite the fact that tamoxifen and raloxifene have been approved as a means to reduce breast cancer risk in women who would be eligible for this trial, we feel the use of a placebo control arm is justified for several reasons: 1. Although tamoxifen is approved for the indication of reducing the short-term incidence of breast cancer, many women whose level of risk would qualify them for the prescription of tamoxifen refuse the drug because of its toxicity profile (Port, 2001). Raloxifene is another option that women may consider for breast cancer risk reduction. However, while the risk profile for raloxifene may be better than tamoxifen, it is still associated with increased risk of thromboemoblic events and decreased sexual function. {Vogel, 2006} There is, therefore, a population of women eligible for this trial who have chosen or will choose even after appropriate counseling not to take tamoxifen or raloxifene. Such women might well wish to enter a placebo controlled trial where the agents under study may have more favorable toxicity profiles. 2. The Technology Assessment mentioned earlier (Chelbowski, 2002) concluded that placebo controls are appropriate for breast cancer risk reduction trials since no intervention has been demonstrated to favorably impact net health or survival. Although this trial is not expected to demonstrate an impact on survival, for the reasons discussed below, we think its results may well indicate a more favorable therapeutic ratio for exemestane than for tamoxifen or raloxifene in postmenopausal women. 3. The placebo arm will allow a true determination of efficacy in reducing invasive breast cancer, of adverse effects and of impact on overall and menopausal-specific quality of life. Preclinical data suggests that unlike tamoxifen or raloxifene that only block ER-mediated function, AIs reduce estradiol levels and consequently block ER-mediated function and effects of genotoxic estradiol metabolites (Yue 2005). In addition, recent clinical data from the ATAC trial demonstrated that anastrozole (AI) resulted in 42% greater reduction of invasive contralateral breast cancer at four years, compared to tamoxifen (Howell, 2005). Therefore, based on the known preclinical and clinical profile of the aromatase inhibitors it is reasonable to assume a greater reduction in breast cancer incidence with this class of agents than with tamoxifen or raloxifene. Our global intention is to demonstrate a reduction in the short-term incidence of invasive breast cancer using a steroidal aromatase inhibitor, exemestane. This indication would mimic the FDA approved indication for tamoxifen. The preclinical and clinical data suggest to us that exemestane will be more effective than tamoxifen in terms of efficacy. In addition, exemestane and 17- hydroexemestane, its principal metabolite, have mild androgenic/anabolic effects that we believe will afford it superior effects on quality of life and menopausal symptomatology. The preclinical data suggest positive effects on bone metabolism. CONFIDENTIAL 11 CONFIDENTIAL

16 Amendment #4: 2006-JUL-20 Quality of Life (QoL) and Menopause-Specific QoL (MENQOL) will be collected on all women. It is important that global QoL, general QoL and menopausal specific QoL are prospectively and systematically collected. Vasomotor, urogenital, gastrointestinal and symptoms of adverse sexual functioning are among the important quality of life symptoms which have been reported for this group of subjects and which may be improved on this trial. In the recently reported ATAC trial of adjuvant tamoxifen versus anastrozole alone or in combination with tamoxifen a detailed quality of life study was conducted by Fallowfield et al. A significant discrepancy was found in treatment related effects as reported by the clinical investigators versus the patients. In particular vasomotor symptoms and sexual function were discordantly reported (Fallowfield, 2002). For this reason three extra questions were added to the MENQOL to capture these data. In the STAR trial, quality of life was measured prospectively in a subgroup of 1983 participants. No significant differences existed between the tamoxifen and raloxifene groups for the primary QOL endpoints; namely physical health and mental health, measured with the SF-36 Physical and Mental Component Summaries, respectively. Patient reported symptoms were collected on all 19,747 participants, using a 36-item checklist. Self-reported symptoms varied slightly by treatment group. Based on the proportion of women in each treatment group who experienced an increase in symptom severity from baseline to 6 months, the tamoxifen group had more gynecological, vasomotor and bladder control problems. The raloxifene group experienced more musculoskeletal problems, pain during coitus and weight gain. Overall, the symptom profile slightly favoured raloxifene (Land, 2006).We hypothesize that exemestane, due to its pharmacologic profile, will have a positive effect on bone and lipid metabolism and on parameters of overall and menopausal-specific quality of life. Please see Section 13.0 (Central Review Procedures) for the rationale for the collection of plasma hormone and DNA samples and mammograms for breast density. CONFIDENTIAL 12 CONFIDENTIAL

17 3.0 BACKGROUND THERAPEUTIC INFORMATION 3.1 Exemestane Name and Chemical Information Aromasin tablets contain 25 mg of exemestane, an irreversible steroidal aromatase inactivator Chemical Structure Exemestane is chemically described as 6-methlyenandrostal, 4-diene 3, 17-dione. Its molecular formula is C 20 H 24 O Mechanism of Action Exemestane irreversibly inhibits aromatase activity (approximately 98%) and reduces plasma estrone, estradiol and estrone sulphate levels by 85-95%. Exemestane is 150-times more potent than aminoglutethimide in inhibiting aromatase. Maximal aromatase suppression occurs at exemestane doses of mg. In postmenopausal women, the principal source of circulating estrogens is from the conversion of adrenal and ovarian androgens (androstenedione and testosterone) to estrogens (estrone and estradiol) by aromatase in peripheral tissues. Exemestane is structurally related to androstenedione and functions as false substrate for aromatase. Exemestane is processed to an intermediate that binds irreversibly to the active site of aromatase causing its inactivation, also known as "suicide inhibition." Non-steroidal aromatase inhibitors (e.g., anastrozole and letrozole) competitively bind to a different part of the aromatase enzyme. Exemestane has no detectable effect on adrenal biosynthesis of corticosteroids or aldosterone. Exemestane has no effect on other enzymes involved in steroid synthesis up to a concentration of at least 600-times higher than that needed to inhibit aromatase. Exemestane has a slight affinity for the androgen receptor. The binding of the 17-dihydrometabolite is 100-times that of exemestane; however, significant increases in testosterone or androstenedione have only been seen at exemestane doses >200 mg/day. A dose-dependent decrease in sex hormone binding globulin (SHBG) has been observed with doses of exemestane > 2.5 mg/day. Slight, non dose-dependent increases in serum lutenizing hormone (LH) and follicle-stimulating hormone (FSH) levels have been observed as a consequence of feedback at the pituitary level {Pharmacia Corporation 1995}. CONFIDENTIAL 13 CONFIDENTIAL

18 3.1.4 Experimental Antitumour Activity Exemestane produced tumour regression in a rodent model of postmenopausal breast cancer. In ovariectomized testosterone-supplemented rats with DMBA induced mammary tumours, 4 weeks of treatment with oral exemestane at 10 mg and 100 mg/kg/day achieved regression in 76% and 88% of existing tumours. In comparison, 52% regression occurred in control rats (Pharmacia Corporation 1995) Phase I Trials A total of 182 subjects have been treated in five phase I studies conducted in Europe with exemestane at various daily doses (up to 600 mg/day). No maximum tolerated dose (MTD) was determined (Pharmacia Corporation 1995) Phase II and III Trials Phase II A total of 762 subjects were treated in six open, uncontrolled phase II studies in patients whose tumours had failed tamoxifen alone, tamoxifen and megestrol acetate, or tamoxifen and aminoglutethimide (AG). Failed Antiestrogen Therapy: A total of 265 women were treated with exemestane in two phase II studies (US study and European study 010) carried out at the standard daily dose of 25 mg daily. Subjects in these studies were refractory to tamoxifen. The objective response rate (CR + PR) was 31% and 28% in the European study and US study, respectively. The overall clinical benefit (CR, PR or disease stabilization > 24 weeks) was 59% and 47% in the European study and US study, respectively. The median TTP was around 24 weeks in both studies {Kvinnsland 2000}. Failed Multiple Hormonal Therapies: A total of 497 women have been treated with exemestane in four phase II studies. Three of the studies (US studies and 022, and a worldwide study 017 which included US centres) included 419 women who failed multiple hormonal therapies at the recommended dose of 25 mg/day. The fourth study was performed in 78 women from a similar population but at a higher dose (200 mg/day; study 009). In the worldwide study, 241 women had failed non-steroidal aromatase inhibitors as the last hormonal therapy. The objective response rate was 7%. The overall response rate (CR, PR or disease stabilization > 24 weeks) was 24%. The median duration of response was 58 weeks and median TTP was 15 weeks {Lonning 2000}. In two US studies, a total of 178 women who experienced failure to TAM and megestrol acetate were treated with exemestane. In these studies, the objective response rates ranged from 9-13% and approximately 30% had an overall response (CR, PR or disease stabilization > 24 weeks). The median duration of response ranged from weeks and median TTP was 9-16 weeks {Jones, 1999}. A total of 78 women were treated in a study assessing the efficacy of exemestane (200 mg daily dose) in subjects progressing on AG {Thurlimann 1997}. They include 33 subjects unresponsive to AG, 39 subjects who had progressed after an initial response to AG, and 6 subjects for whom response to prior therapy was either not available or not evaluable. Overall, the objective response rate was 26% (12% in subjects refractory to AG and 33% in the responsive ones). Disease stabilization (> 24 weeks) was achieved in an additional 13% of subjects (15% of those refractory to AG and 13% of CONFIDENTIAL 14 CONFIDENTIAL

19 those responsive). Thus, the percentage of subjects benefiting from therapy was 39% in this study. The median duration of objective response (CR+PR), overall response (CR+PR or disease stabilization > 24 weeks) and TTP were 59, 48, and 21 weeks, respectively. This study confirms other observations of lack of cross-resistance when steroidal aromatase inhibitors are sequenced with nonsteroidal aromatase inhibitors. Phase III Exemestane (25 mg daily) was evaluated in a phase III, randomized, double-blind, multicentre, multinational comparative study of postmenopausal women with advanced breast cancer who had disease progression after hormonal treatment with antiestrogens (primarily TAM) for metastatic disease or as adjuvant therapy {Kaufmann 2000}. Subjects were required to have measurable metastases or lytic bone disease due to breast cancer, reasonable performance status, ER/PgR tumor receptor status positive or unknown, and near-normal organ function. Subjects may also have received prior cytotoxic therapy, either as adjuvant treatment or for metastatic disease. In this study (94 OEXE 018), 769 subjects were randomized to receive exemestane 25 mg once daily (n = 366) or megestrol acetate 40 mg four times daily (n = 403). Intent-to-treat results for randomized subjects from the study are summarized in Table 2 Table 2. Efficacy Results from a Phase III Study of Postmenopausal Women with Advanced Breast Cancer Whose Disease Had Progressed after Antiestrogen Therapy {Kaufmann 2000} Response Characteristics Objective Response Rate = CR + PR (%) 95% Confidence Interval Overall Success = CR + PR + SD 24 Weeks (%) 95% Confidence Interval Exemestane (N=366) 15.0 ( ) 37.4 ( ) Megestrol acetate (N=403) 12.4 ( ) 34.6 ( ) P-value CR (%) PR (%) SD (%) SD 24 Weeks (%) PD (%) Other (%)* Median Duration of Response (weeks) Median Duration of Overall Success (weeks) Median Duration of SD 24 Weeks (weeks) Median TTP (weeks) Hazard Ratio (Exemestane-MA) Median TTF (weeks) Median Overall Survival (weeks) Not reached % Survival (weeks) 95% Confidence Interval 74.6 ( ) 55.0 ( ) * Includes subjects who were not treated or not evaluable 25 th percentile Abbreviations: CR = complete response, PD = progressive disease, PR = partial response, SD = stable disease (no change), TTP = time to tumour progression, TTF = time to treatment failure CONFIDENTIAL 15 CONFIDENTIAL

20 3.1.7 Safety General. Exemestane should not be administered to women with premenopausal endocrine status. Exemestane should not be co-administered with estrogen-containing agents as these could interfere with its pharmacologic action. Laboratory Tests. Approximately 20% of subjects receiving exemestane in clinical studies, particularly those with a pre-existing lower NCI CTC grade lymphocytopenia, experienced NCI CTC grade 3 or 4 lymphocytopenia. However, mean lymphocyte values in these subjects did not change significantly over time. Forty percent of subjects either recovered or improved to a lesser severity while on study. Subjects did not have a significant increase in viral infections, and no opportunistic infections were observed. Elevation of serum levels of AST, ALT, alkaline phosphatase and gamma glutamyl transferase > 5 times the upper value of the normal range have been rarely reported but appear mostly attributable to the underlying presence of liver and/or bone metastases. In the phase III study, elevation of the gamma glutamyl transferase (NCI CTC grade 3 or 4) without documented evidence of liver metastasis was reported in 2.7% of subjects treated with exemestane and in 1.8% of subjects treated with megestrol acetate. Drug Interactions. Coadministration of ketoconazole, a potent inhibitor of CYP 3A4, has no significant effects on exemestane pharmacokinetics. Significant pharmacokinetic interactions mediated by alterations in major CYP isoenzymes appear unlikely; however, a possible decrease of exemestane plasma levels by known inducers of CYP 3A4 cannot be excluded. Drug/Laboratory Tests Interactions. No clinically relevant changes in the results of clinical laboratory tests have been observed. A total of 1058 subjects were treated with exemestane 25 mg once daily in the overall clinical trials program which includes the phase III study. Exemestane was generally well tolerated, and adverse events were usually mild to moderate. Only one death was considered possibly related to treatment with exemestane; an 80-year-old woman with known coronary artery disease had a myocardial infarction with multiple organ failure after 9 weeks on study treatment. In the clinical studies program, only 2.8% of the subjects discontinued treatment with exemestane because of adverse events, mainly within the first 10 weeks of treatment; late discontinuations due to adverse events were uncommon (0.3%). Adverse events were assessed for 358 subjects treated with exemestane and 400 subjects treated with megestrol acetate in the phase III study. Fewer subjects receiving exemestane discontinued treatment because of adverse events than those treated with megestrol acetate (2% versus 5%). Table 3 shows the adverse events of all NCI CTC grades regardless of causality reported in 5% or greater of subjects in the phase III study treated either with exemestane or megestrol acetate. Adverse events of any cause reported in 5% or greater of subjects treated with exemestane 25 mg once daily in the overall clinical trials program but not in the phase III study included pain at tumour sites (8%), asthenia (6%) and fever (5%). Less frequent adverse events of any cause (2% to 5%) reported in all subjects receiving exemestane 25 mg once daily in the overall clinical trials program but not in the phase III study included chest pain, hypoesthesia, confusion, dyspepsia, arthralgia, back pain, skeletal pain, infection, upper respiratory tract infection, pharyngitis, rhinitis and alopecia. CONFIDENTIAL 16 CONFIDENTIAL