Protocol. This trial protocol has been provided by the authors to give readers additional information about their work.

Transcription

1 Protocol This trial protocol has been provided by the authors to give readers additional information about their work. Protocol for: Masuda N, Lee S-J, Ohtani S, et al. Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med 2017;376: DOI: /NEJMoa

2 Supplementary Supplement to: Masuda N, Lee SJ, Ohtani S, et al. Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy Table of Contents Final protocol (version 3.0) Amendments Amendments April 14th, 2014 Amendments January 23rd, 2012 Amendments September 1st, 2011 Amendments April 1st, 2010 Amendments July 20th, 2009 Amendments May 15th, 2009 Original protocol Final statistical analysis plan (version 1.2) Amendments Amendments January 19, 2017 Amendments June 16, 2016 Original statistical analysis plan

3 2014/04/14 CREATE-X Japan Breast Cancer Research Group (JBCRG) Korean Breast Cancer Study Group (KBCSG) Korean Cancer Study Group (KCSG) A phase III randomized study of capecitabine as adjuvant chemotherapy versus observation in breast cancer with pathologic residual tumors after preoperative chemotherapy STUDY PROTOCOL Version 0.1 preparation date: March 2, 2006 Version 0.2 preparation date: March 16, 2006 Version 0.3 preparation date: September 2, 2006 Version 1.0 preparation date: October 18, 2006 Version 1.1 preparation date: December 28, 2006 Version 1.2 preparation date: February 24, 2007 Version 2.0 preparation date: October 4, 2007 Version 2.1 preparation date: June 19, 2008 Version 2.2 preparation date: October 31, 2008 Version 2.3 preparation date: February 20, 2009 Version 2.4 preparation date: April 18, 2009 Version 2.5 preparation date: May 15,2009 Version 2.6 preparation date: July 20,2009 Version 2.7 preparation date: April 1,2010 Version 2.8 preparation date: September 1st, 2011 Version 2.9 preparation date: January 23rd, 2012 Version 3.0 preparation date: April 14th, 2014

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5 CREATE-X (Capecitabine for REsidual cancer as Adjuvant ThErapy X) <PRINCIPAL INVESTIGATOR> - Norikazu Masuda /Dept. of Surgery, Osaka National Hospital <STEERING COMMITTEE> JAPAN Japan Breast Cancer Research Group (JBCRG) - Masakazu Toi /Dept. of Surgery (Breast Surgery) Graduate School of Medicine, Kyoto University - Seigo Nakamura /Dept. of Breast Surgical Oncology, Showa University School of Medicine - Katsumasa Kuroi /Tokyo Metropolitan Komagome Hospital (Director-General of the Secretariat) - Hiroji Iwata /Breast Dept. Aichi Cancer Center Hospital - Shinji Ohno /Breast Dept., Kyushu Cancer Center - Kenjiro Aogi /Dept. of Breast Oncology, National Hospital Organization Shikoku Cancer Center... KOREA Korean Breast Cancer Study Group (KBCSG) - Soo-Jung Lee /Dept. of general surgery, Yeungnam University Hospital - Dong-Young Noh /Dept. of general surgery, Seoul National University Hospital - Joon Jeong /Dept. of general surgery, Yonsei University Hospital Korean Cancer Study Group (KCSG) - Jung-Sil Ro /Dept. of medical Oncology, National Cancer Institute - Young-hyuck Im /Dept. of medical Oncology, Samsung Seoul hospital - Sung-Bae Kim /Dept. of medical Oncology, Seoul Asan hospital - Norikazu Masuda /Dept. of Surgery, Osaka National Hospital - Yasuo Ohashi /Department of Integrated Science and Engineering for Sustainable Society, Chuo University 2

6 TABLE OF CONTENTS 1. STUDY PROTOCOL SUMMARY Aims Target Patients Style of Trial Protocol Treatments Target Number of Patients Endpoints Study Duration GUIDELINES, ETC AIMS OF STUDY BACKGROUND Capecitabine Goserelin Leuprorelin Tamoxifen Toremifene Letrozole Anastrozole Exemestane Preoperative Chemotherapy Postoperative Adjuvant Chemotherapy Reasons for Preparation of this Protocol TARGET PATIENTS Inclusion Criteria Exclusion Criteria EXPLANATION AND INFORMED CONSENT Contents of Explanation STUDY DRUGS Capecitabine Goserelin Leuprorelin Tamoxifen Toremifene Letrozole

7 7.7 Anastrozole Exemestane STUDY METHODS Study Design Central Pathological Assessment Patient Enrolment (To be determined) Doses and Administration Method Criteria for Transfer to Next Course, etc Discontinuation Criteria Administration of Concomitant Treatment During the Study Period Radiotherapy Post Protocol Treatment Drug Interactions TEST AND ASSESSMENT METHODS AND SCHEDULE Test and Assessment Summary Methods and Schedule EVALUATION METHODS AND CRITERIA Handling of Patients Endpoints and Criteria DATA COLLECTION Submission of Data Data Management Data Keeping PREDICTED OBJECTIVE AND/OR SUBJECTIVE ADVERSE DRUG REACTIONS AND ABNORMAL CHANGES IN CLINICAL LABORATORY TEST RESULTS, AND TREATMENT OF THESE Due to Capecitabine Due to Goserelin Due to Leuprorelin Due to Tamoxifen Due to Toremifene Due to Letrozole Due to Anastrozole Due to Exemestane EMERGENCY CONTACTS AND TREATMENT FINAL EVALUATION

8 15. DATA-HANDLING AND EVALUATION METHODS STUDY PROTOCOL MODIFICATIONS, AND STUDY COMPLETION OR DISCONTINUATION Study Protocol Modifications Study Discontinuation Study Completion Study Protocol Preparation Records MONITORING CENTRAL MONITORING AUDITS Audit Committee Activities of the Audit Committee Protection of Personal Information Extramural Review by Audit Committee NUMBER OF TARGET PATIENTS, ETC Number of Target Patients Justification for Setting the Number of Target Patients INTERIM ANALYSIS Efficacy Safety STUDY DURATION HANDLING OF STUDY DRUGS SUMMARY OF PREDICTED RISKS AND BENEFITS OF PARTICIPATION IN THE STUDY Predicted Benefits Predicted Disadvantages Indemnity PUBLICATION OF DATA MAINTENANCE OF SECRECY OF PATIENTS INFORMATION ORGANIZATION Research Organization Research Support Organization Protocol Committee Members IDMC Medical Institutions, and Principal Investigators or subinvestigators Outlined in exhibit

9 26.6 Person Responsible for Statistical Analysis CSPOR Data Center Administrative Office REFERENCES

10 1. STUDY PROTOCOL SUMMARY 1.1 Aims This study is designed to investigate the efficacy and safety of capecitabine, as a postoperative adjuvant chemotherapy, for breast cancer patients who have pathologic residual cancer cells after the preoperative chemotherapy. In addition, the cost-effectiveness of capecitabine is to be investigated. 1.2 Target Patients The target patients for this study are breast cancer patients who have been pathologically confirmed to have residual cancer cells after the administration of preoperative chemotherapy involving anthracycline agents. These are termed non-pathological-complete-response (non-pcr) patients. 1.3 Style of Trial The study is to be a multi-center, collaborative, randomized controlled trial with centralized enrolment Randomization The efficacy with the standard postoperative treatment, which is hormone therapy in the case of hormone-sensitive patients and no treatment in the case of hormone-insensitive patients, is to be compared, by randomization, with the efficacy when capecitabine is administered in addition to the standard treatment. The capecitabine group is administered at least six courses of capecitabine. For patients in the capecitabine group, capecitabine is initiated after the completion of radiotherapy when indicated. The following dynamic balancing factors are to be used for stratification: 1. Hormone-receptor (ER) status (before receiving chemotherapy): ER-positive* versus ER-negative 2. Age (before receiving chemotherapy): 50 years old and less versus 51 years old and more 3. Use of taxane drugs: Yes(Anthracycline + Taxane) vs. No (Anthracycline only) vs TC only over 4 courses 4. Histological axillary lymph node metastasis (result at surgery): n0 versus n1-3 versus n>=4 versus unknown** 5. Use of 5-fluorouracil (5-FU) agents: Yes versus No 6. Institution * ER-positive: 10% and more by immunohistochemistry or positive in Allred score (including weak positive). Hormone therapy is allowed when over 1% of cells are stained though over 10% is a definition of ER(+) as a dynamic balancing factor (see and on Hormone Therapy in Postoperative Standard Therapy for details). ** Patients with axillary lymph node micrometastases, isolated tumor cells, pn0(i), and/or pn0(mol) are classed as n0. Classification of n0, n1-3, n>=4 based on sentinel lymph node (SLN) biopsy should comply with Appendix Protocol Treatments Capecitabine Study Arm: Capecitabine arm (capecitabine added onto the standard postoperative treatment) 7

11 Capecitabine: 1,250 mg/m 2, peroral,b.i.d., days 1 to 14 The treatment consists of at least six courses, each 3 weeks long. However, Independent Data Monitoring Committee (IDMC) will investigate tolerability and provide suggestions when first 50 patients in capecitabine arm completed 6 courses. Protocol Committee will decide whether to extend the treatment duration up to 8 courses based on the suggestions and announce the decision to participating institutions. Until obtaining the conclusion, 6 courses will be repeated. Patient enrollment continues during the interim analysis where tolerability in 6 courses of treatment will be investigated. [Extension of treatment period for up to eight courses] After investigating the tolerability, IDMC determined that the treatment duration could be extended for up to 8 courses. The Protocol Committee examined this conclusion and decided to approve the extended treatment duration. However, as a means of maintaining a completion rate of 80% or more, after disseminating the appropriate measures to manage HFS (hand-and-foot syndrome), conduct a follow up on the adverse drug reactions and completion rates of the first 20 patients who will undergo eight courses of planned treatment. As for details, refer to Investigation over Tolerable Course. Comparative arm: Non-capecitabine arm (the standard postoperative treatment) Hormone Therapy in the standard adjuvant therapy The following hormone therapies are administered in the hormone-sensitive patients, in accordance with menstrual status (i.e., whether or not the patients have passed menopause). Hormone therapy is allowed when over 1% of cells are stained based on decision in an institution though over 10% is a definition of ER(+) as a dynamic balancing factor. Data of ER positive rate and hormone therapy should be collected Premenopausal patients Tamoxifen at 20 mg/day or toremifene at 40 mg/day are administered perorally for 5 years. If necessary, in combination with a luteinizing-hormone-releasing hormone (LHRH) analog, selected from the two below alternatives, which is administered for 2 years, Goserelin: Leuprorelin: 3.6 mg/day, isc, at 4-week intervals 3.75 mg/day, isc, at 4-week intervals, or mg/day, isc, at 12-week intervals When a patient is confirmed to be postmenopausal, the tamoxifen or toremifene can be replaced with an aromatase-inhibitor. Furthermore, patients who are about 50 years old and have irregular menstruation are sometimes judged by the responsible physician to be perimenopausal, in which case it is acceptable for the LHRH analog to be omitted Postmenopausal patients One of the following aromatase-inhibitors is administered for 5 years. Letrozole: 2.5 mg/day, peroral Anastrozole: 1 mg/day, peroral Exemestane: 25 mg/day, peroral If aromatase-inhibitors are judged to be inappropriate, tamoxifen can be administered instead, perorally for 5 years, at either 20 mg/day of tamoxifen or 40 mg/day of toremifene. 8

12 1.4.3 Radiotherapy Radiotherapy after the surgical treatment for the primary cancer is optional at all medical institutions. For patients with whom the intention is to carry out postoperative radiotherapy on the conserved breast, thoracic wall, and/or supraclavicular lymph nodes, enrollment of this study is to be initiated after the completion of radiotherapy. Though radiotherapy is acceptable for both before and after administration of capecitabine, it is recommended to complete radiotherapy within 120 days from the surgical treatment if it is before capecitabine administration and to complete radiotherapy within 120 days after completion of capecitabine treatment if it is after capecitabine adminstration. The timing of radiotherapy (before or after capecitabine administration) should be determined for each patient based on status of margin Start of protocol treatment In this trial, the treatments, which are added to a standard adjuvant treatment (test arm and control arm), are defined as a protocol treatment. Starting a protocol treatment within 2 weeks after registration is a must. 1.5 Target Number of Patients Total number: 900 Number per group: 450 per group 1.6 Endpoints Primary Endpoint Disease-free survival (DFS) Secondary Endpoints Overall survival Period from the first day of preoperative chemotherapy to recurrence or death (time to recurrence, time to death) Safety Cost-effectiveness 1.7 Study Duration Study duration: Feb 2007 to Jun 2017 (It does not apply to Korea.) Patient enrolment duration: Feb 2007 to Jun 2012 Follow-up study duration: Max 5 years (until the specified number of recurrence events has been reached) 2. GUIDELINES, ETC. This study is to be carried out in accordance with the following: Ethical stipulations based on the Helsinki Agreement Guidelines for clinical evaluation methods for anti-tumor agents Full respect for Rules for performance of clinical studies on pharmaceutical products 9

13 3. AIMS OF STUDY The principal aim is to investigate the efficacy and safety of capecitabine as a postoperative adjuvant therapy for breast cancer patients confirmed histologically to have residual cancer cells after preoperative chemotherapy. A secondary aim is to evaluate the cost-effectiveness of capecitabine for these patients. 4. BACKGROUND From a relatively early stage in the progression of breast cancer, micrometastases that cannot be clinically detected throughout the whole body, and it is extremely difficult to control these surgically, however broadly the range of surgery is extended. Because these micrometastases cannot be controlled satisfactorily by such local treatments as surgery and radiotherapy, the importance of multi-modal therapy involving systemic treatments such as preoperative/ perioperative chemotherapy and hormone therapy has increased. Early-stage micrometastasis is a factor affecting the prognosis of breast cancer. There have been several clinical studies on preoperative chemotherapy methods that suppress such micrometastasis at an early stage, thereby possibly improving patients prognoses. The suggested advantages of preoperative chemotherapy are as follows: (i) The progression stage is lowered by decreasing the tumor size, which can result in a decreased excision size and thus improved breast conservation. (ii) Systemic treatment of micrometastases is made feasible at an early stage. (iii) Drug sensitivity can be assessed at an early stage. (iv) Chemotherapy is administered before surgical disruption of the tumor vascular system. It is hoped that DFS, overall survival, and response rate can thus be improved by preoperative chemotherapy. Therefore, numerous studies have been carried out in attempts to confirm the usefulness of preoperative chemotherapy, and high clinical response rates of 70% to 80% have been reported. Nevertheless, the pcr rate has not been found to exceed 15% to 25%. Furthermore, in clinical studies to date, the survival-affecting efficacy of preoperative chemotherapy has not usually been found to differ much from that of postoperative chemotherapy [1-3]. In the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 study, preoperative and postoperative administration were compared for doxorubicin + cyclophosphamide therapy (AC therapy), which is accepted as a standard treatment for breast cancer. Although, as stated above, no differences affecting survival were found between preoperative and postoperative AC therapy, those patients who showed pcr by preoperative AC therapy also showed clear improvements in DFS time, overall survival time, and general prognosis [4]. These findings were repeated in NSABP B-27 study [5]. Except with HER2-positive patients, the principal chemotherapy yielding, thus far, the highest pcr rates is involving anthracycline and taxane containing agents. After the preoperative treatments, however, it has not been clarified whether further systemic chemotherapy is necessary in patients who do not achieve pcr. The standard regimens for postoperative chemotherapy with breast cancer patients are those involving anthracycline agents, such as AC therapy, cyclophosphamide + epirubicine + 5-fluorouracil (5-FU) combination therapy (CEF), and 5-FU + epirubicine + cyclophosphamide combination therapy (FEC); and the standard treatments with breast cancer patients involve an 10

14 anthracycline agent regimen followed by a taxane agent regimen. Furthermore, with hormone-sensitive patients, the standard postoperative regimens involve hormone therapy following these chemotherapy regimens. In premenopausal patients, the hormone therapy of choice is an anti-estrogen (tamoxifen) with or without ovarian ablation (LHRH agonist), whereas in postmenopausal patients it is either an aromatase-inhibitor (e.g., letrozole, anastrozole, exemestane) or an anti-estrogen (e.g., tamoxifen, toremifene). There is as yet no proof for the systemic efficacy of preoperative chemotherapy, but, taking the above points into consideration, a common approach is currently to administer hormone therapy to hormone-sensitive patients following systemic chemotherapy, whereas with hormone-insensitive patients each patient s progress is observed without any further treatment. Patients in whom residual cancer cells were found after preoperative chemotherapy involving anthracycline agents were judged to show non-response to anthracycline. In recent years, favorable results have been reported with capecitabine even for advanced and/or recurrent breast cancer patients who showed resistance to anthracycline and taxane chemotherapy [6-10]. Furthermore, in Japan, with respect to health insurance coverage, capecitabine has been approved for advanced and/or recurrent breast cancer patients who have previously been treated with a regimen involving anthracycline agents. Capecitabine is a 5-FU derivative. It is transformed to 5 -deoxy-5-fluorouridine (doxifluridine or 5 -DFUR) in vivo, and the 5 -DFUR is transformed to 5-FU in tumor tissue, by thymidine phosphorylase. It is the 5-FU that shows anti-tumor efficacy, but the use of a derivative increases the tumor selectivity of 5 -DFUR [11]. Several clinical studies on metastatic breast cancer patients who showed disease progression during or after treatment with anthracycline and taxane agents have demonstrated that capecitabine mono-therapy is both effective and tolerated [6-10,12], also the same in older patients [13]. Futhermore, capecitabine is reported to be comparable to paclitaxel in patients with metastatic breast cancer pretreated with anthracycline [14] and also comparable to cyclopohsphamide, methotrexete and 5-FU (CMF) as first line therapy in patients with metastatic breast cancer [15], even though both of these two studies had small number of patients and we need further investigations. The current clinical study has been planned on the basis of the above background information, with the target patients being non-pcr patients (patients for whom no elimination of cancer cells was found with the preoperative therapy), and the study aim being assessment as to whether the administration of capecitabine in combination with the current standard treatment can be expected to improve patients prognoses. On the basis of the study results, it is expected to be possible to make progress in the analysis of such research questions as whether or not it will be necessary to administer supplementary chemotherapy to patients who are non-pcr with respect to preoperative chemotherapy, and, if this is necessary, whether capecitabine will be effective as a such chemotherapy regimen. 4.1 Capecitabine Details of Capecitabine Development Capecitabine is a new, orally administered fluorocytidine derivative that can be administered at a high dose. It was initially created in Nippon Roche s laboratories (now part of Chugai Pharmaceutical Co., Ltd.). After oral administration, the unmetabolized compound is absorbed in the gastrointestinal tract, and converted by carboxyl esterase in the liver to 5 -deoxy-5-fluorocytidine, which is then converted to 5 -DFUR by cytidine deaminase, which has especially high activity in the liver and in tumor tissue. The 5 -DFUR is then converted to 11

15 5-FU by thymidine phosphorylase, which has been reported to be the same as platelet-derived endothelial cell growth factor [16]. Thymidine phosphorylase is reportedly expressed at high levels in tumor tissues [11], and capecitabine was therefore designed to be transformed selectively at the tumor loci Recommended Clinical Dose for Capecitabine Mono-Therapy in Japan: Phase-I Results [17] This Phase-I study on capecitabine mono-therapy was carried out for patients with solid tumors, of whom 16 were enrolled. Capecitabine was administered twice daily, at doses of 502 to 2,510 mg/m 2 /day. The MTD was judged to be 2,510 mg/m 2 /day, and the DLTs were dermal symptoms and hemorrhagic gastric tumors. On the basis of these findings, the recommended clinical dose for daily capecitabine administration was set at 1,657 mg/m 2 /day Results of Japanese Phase-II Capecitabine Studies in Breast Cancer Patients [10, 12, 18] One Japanese Phase-II study was carried out with advanced and/or recurrent breast cancer patients who had been administered no more than one previous regimen [18]. Capecitabine was administered for 3 weeks at a dose of 1,657 mg/m 2 /day, followed by a 1-week recovery period. Fifty patients were enrolled, and 46 of these were included in the efficacy analysis. The response rate was found to be 28.3% (95% confidence interval: 16.0% to 43.5%). The safety evaluation, on the other hand, was carried out for all 50 patients who were administered capecitabine, and adverse drug reactions were seen in all of them. Grade-3 adverse drug reactions occurred in 23 patients, and those reactions that occurred at frequencies of 10% or higher were decreased lymphocyte count in 22.0%, hand-and-foot syndrome in 18.0%, and increased bilirubin in 10.0%. The administration was discontinued for three patients due to adverse events. Another Japanese Phase-II study was carried out in advanced and/or recurrent breast cancer patients refractory to docetaxel [10]. Capecitabine was administered for 3 weeks at 1,657 mg/m 2 /day, followed by a 1-week rest. Sixty patients were enrolled, and among the 55 who were included in the efficacy analysis, the response rate was 20.0% (95% confidence interval: 10.4% to 33.0%), and the time to progression was 84 days. The proportion of patients who showed partial responses, including against liver metastasis, was 33.3% (6 of 18). All 60 patients administered capecitabine were included in the safety analysis, and the adverse drug reaction frequency was 96.7% (58 of 60). Grade-3 or higher adverse drug reactions occurred in 33 patients, and those reactions with frequencies of 15% or higher were decreased lymphocyte count in 28.3%, and hand-and-foot syndrome in 13.3%. Recently, the Japanese phase II study for patients with metastatic breast cancer refractory to docetaxel was also reported [12]. Capecitabine was administered for 2 weeks at 2,500 mg/m 2 /day, followed by a 1-week rest. Thirty-five patients were enrolled, and among the 32 who were included in the efficacy analysis, the response rate was 21.9%, and the median time to progression was 103 days. Main adverse drug reactions were hand-and-foot syndrome, nausea, anorexia, stomatitis and diarrhea. 4.2 Goserelin Details of Goserelin Development Goserelin acetate is an LHRH analog, whose development was started by the UK company Imperial Chemical Industries PLC (ICI; now AstraZeneca) in In comparison with naturally occurring LHRH, the amino acids at positions 6 and 10 are replaced in goserelin, resulting in higher stability than the naturally occurring LHRH. 12

16 When goserelin is administered daily, the secretion of luteinizing hormone and follicle-stimulating hormone by the pituitary gland is initially stimulated, but this effect is later reversed, as the responsivity of the pituitary gland later decreases, and the secretion of these hormones is inhibited. The outcome, therefore, is that goserelin inhibits secretion of testosterone by the testes and estradiol by the ovaries. When this effect was identified, the research team started to investigate the clinical application of goserelin for treating prostate cancer, which is considered to be male-hormone-dependent. In the early stages of development, the formulation used was an aqueous solution for injection, which was administered once daily. Since then, progress was made with research of a slow-release formulation to reduce the burden on patients. Success was thus achieved by using a carrier (a base) that undergoes in vivo degradation, resulting in the development of a slow-release formulation that maintains efficacy for 4 weeks after each dose. This development was carried out in the UK, and the indication of prostate cancer was approved there in In Japan, Phase-I development was initiated in 1983, followed by confirmation, provided by Phase-II and Phase-III studies, of the usefulness of goserelin for treating prostate cancer. Subsequently, in 1991, importation of the 3.6-mg depot Zoladex formulation for that indication was approved. Finally, the use of goserelin for treating premenopausal breast cancer was investigated, with the efficacy based on the inhibition of estrogen secretion by the ovaries. This additional indication was approved in Results for Goserelin Treatment of Breast Cancer in Japan [19-21] In accordance with the criteria for judging therapeutic efficacy in advanced and/or recurrent breast cancer patients, the response rates in the Japanese clinical studies [18-20] were 30.5% (18 of 59 patients) for eligible patients (patients who met the criteria for participation in the study), and 32.1% (18 of 56) for patients that completed the treatment. Furthermore, when the response rates against metastatic foci were classified by tissue type, they were found to be 31.3% (10 of 32), 37.0% (10 of 27), and 29.4% (5 of 17), in the soft tissues, bone, and internal organs, respectively. 4.3 Leuprorelin Details of Leuprorelin Development The structure of LHRH was demonstrated in Since that date, research has been undertaken on the synthesis and therapeutic applications of agonists with higher activity. The first of such agents was leuprorelin acetate, which was synthesized in the laboratories of Takeda Pharmaceutical Co., Ltd., in It was an agonist with activity almost 100 times higher than LHRH. Contrary to expectation, however, continued administration of this high-activity agonist was found to suppress sex gland function and decrease sex hormone secretion. This paradoxical effect raised hopes that leuprorelin could be used for the treatment of highly sex-hormone-dependent diseases, such as prostate cancer, endometriosis, uterine leiomyoma, breast cancer, and central precocious puberty Results for Leuprorelin Treatment of Breast Cancer in Japan [22, 23] In a clinical study of premenopausal breast cancer patients, three doses of 3.75 mg of leuprorelin acetate were administered at the rate of one dose every 4 weeks, The response rates at week 12 for patients who had completed the administration and for all eligible patients were 30.4% (14 of 46) and 28.6% (14 of 49), respectively. Furthermore, with some patients, the administration of leuprorelin mono-therapy was continued for more than 12 weeks. The response rate for patients 13

17 who received the extended administration together with the rate for patients evaluated at 12 weeks was 37.0% (17 of 46), whereas the response for all eligible patients was 34.7%. 4.4 Tamoxifen Details of Tamoxifen Development Tamoxifen citrate, the active component of Nolvadex and Nolvadex D, is a nonsteroidal anti-estrogen that was developed by ICI (now AstraZeneca) in It is useful as an oral agent for treating breast cancer, and has elicited few adverse drug reactions. A 10-mg Nolvadex tablet was launched in the UK in As Nolvadex is administered over a long-term, there were demands for easier and more practical regimens. It was confirmed that, owing to the intestinal, hepatic, and circulatory characteristics of Nolvadex, it had a long elimination half-life, and a stable serum concentration could therefore be maintained even with only one dose per day. Therefore, a 20-mg tablet, Nolvadex D, which could be administered once daily, was developed, and was approved in the UK in Japanese Clinical Results with Tamoxifen [24, 25] The response rates according to the judgment criteria of the Union International Contre le Cancer (UICC) in two Japanese clinical studies on patients with advanced primary or recurrent breast cancer, one a double-blind, comparative study [33] and the other a general clinical study [34], were 9.0% (24 of 268) for complete response, and 21.3% (57 of 268) for partial response, the total being 30.2% (81 of 268). 4.5 Toremifene Details of Toremifene Development In 1979, a Finnish company, the Farmos Group (now Orion Corp.), initiated research with the aim of developing nonsteroidal anti-estrogen agents. To this end, it synthesized approximately 350 novel compounds containing triphenylethylene in the basic molecular structure, and screened these, with ER affinity, anti-estrogen activity, and in vitro and in vivo anti-tumor efficacy as the indices. The screening identified toremifene citrate as a compound with high ER affinity and high anti-tumor activity. Clinical studies on toremifene were initiated in February 1982, and in December 1988, the Finnish regulatory authorities approved it as an agent for treating breast cancer. In Japan, Nippon Kayaku Co., Ltd., entered into an agreement with the Farmos Group in 1986, and initiated the nonclinical and clinical development of toremifene, with NK-622 as the development code. As a result, toremifene citrate was shown to be useful for treating breast cancer, and was approved in Japan in March Japanese Clinical Results with Toremifene [26-28] The response rates when 40 mg of toremifene was administered to patients with recurrent or advanced primary breast cancer who had been treated with neither drug therapy nor radiotherapy, or had shown recurrence after completion of postoperative adjuvant therapy were 29.2% (7 of 24) in the Phase-II study, and 28.3% (15 of 53) in the late-phase-ii comparative study. The response rates with a dose of 120 mg in the same patient set were 13.8% (4 of 29) in the Phase-II study and 11.4% (5 of 44) in the late-phase-ii comparative study. With a dose of 40 mg, the results were approximately the same, whether or not treatment had been administered previously, whereas with a dose of 120 mg, efficacy was seen with both tamoxifen-resistant 14

18 patients and patients who had previously been administered tamoxifen, medroxy progesteron acetate, and/or chemotherapeutic agents. 4.6 Letrozole Details of Letrozole Development In terms of hormone therapy for postmenopausal breast cancer, in addition to ER-blocking anti-estrogen agents, aromatase-inhibitors are known to selectively inhibit aromatase, which is the rate-limiting enzyme in the estrogen synthesis pathway. This led to decreased estrogen concentrations in plasma and tumor tissue, resulting in decreased tumor size. In Japan, clinical studies on aromatase-inhibitors were initiated in May One daily dose of 1 mg was confirmed to be clinically useful, and the oral administration of one dose of 1 mg per day was approved for the indication of postmenopausal breast cancer in July Following that, however, the results of large-scale overseas clinical studies in which letrozole was compared with the standard overseas hormone therapy for breast cancer showed that the efficacy with 2.5 mg was superior to that with other doses, and the global standard dose, 2.5 mg, was therefore investigated in Japan. The efficacy and safety of the 2.5 mg letrozole dosage were then evaluated in Japanese patients. Data similar to those obtained from overseas were confirmed, resulting in the letrozole dose for postmenopausal breast cancer being set in Japan at 2.5 mg, administered once daily, and approval for importation on this basis was achieved in January Japanese Clinical Results with Letrozole [29] In a general clinical study of letrozole in postmenopausal patients with advanced and/or recurrent breast cancer who had previously been treated with anti-estrogen agents, the response rate with administration of 2.5 mg once per day was 29.0% (9 of 31), and the proportion of patients who either responded or showed stable disease for at least 24 weeks was 54.8% (17 of 31). Furthermore, in the late Phase II study, which was carried out in postmenopausal patients with advanced and/or recurrent breast cancer for whom anti-estrogen agents had previously been found to be ineffective, the response rate with administration of 2.5 mg of letrozole once per day was 21.1% (12 of 57). 4.7 Anastrozole Details of Anastrozole Development On the basis of a number of European and US clinical studies of aminoglutetimide, a non-selective aromatase-inhibitor, it was considered that a selective aromatase inhibitor would have no effect on the adrenal glands and would not result in serious adverse drug reactions. Thus, such a compound would be expected to be a useful hormone therapy agent for treating postmenopausal breast cancer. Then, in 1985, a UK company, Zeneca (now AstraZeneca), initiated exploratory research to find one or more compounds with stronger selective aromatase-inhibitory activities than aminoglutetimide and the possibility of once daily administration, by synthesizing and evaluating more than 3,000 candidate compounds. This research identified anastrazole as a compound with both strong and highly selective inhibitory activity on aromatase. Several 1-month repeated-dose toxicity studies on anastrazole in rats and dogs were carried out in 1990 and 1991, after which clinical studies were initiated. As a result of these studies, as of August 11, 2004, anastrazole had been approved as a therapeutic drug for postmenopausal 15

19 advanced and/or recurrent breast cancer in 102 countries, including the UK and USA. In addition, it has been approved as a postoperative adjuvant therapy for postmenopausal breast cancer in 77 countries. Japanese clinical development was initiated in 1993, with a Phase-I study, with reference to the overseas clinical study results. Development up to the early Phase II study was carried out in accordance with the Clinical evaluation method guidelines for anti-tumor drugs (February 4, 1991). The clinical data obtained in these early stages of development were similar in Japan, Europe, and the USA, and so it was confirmed by means of a Japanese small-scale clinical bridging study that data obtained from Europeans and Americans could also be applied to Japanese patients. The data from this bridging study and the overseas comparative studies were then pooled and analyzed, and the results were used as the late Phase II data. On the basis of the above clinical results, it was confirmed that anastrazole is highly useful for treating postmenopausal breast cancer, and it was thus approved for importation in December Japanese Clinical Results with Anastrozole [30-32] In the Phase-I and early Phase II studies, the safety and efficacy of anastrozole at doses of 0.5 to 10 mg/day were investigated with 90 postmenopausal breast cancer patients. In addition, pharmacodynamic activity (i.e., reduction in serum estrogen concentration) was investigated at doses of 0.5 and 1 mg/day in a clinical pharmacology study with healthy, postmenopausal, female volunteers; 12 volunteers were given single doses and 12 repeated administration. In Phase I [30], three anastrozole doses, 1, 5, and 10 mg/day, were each administered for at least 8 weeks to 20 postmenopausal patients with advanced and/or recurrent breast cancer, and, although mild adverse drug reactions (vomiting, vertigo, and headache) occurred in one patient, there were considered to be no problems from the point of view of safety. Clinical efficacy was demonstrated, and plasma estradiol concentrations decreased significantly at all doses. No clinically problematic abnormal clinical laboratory test results were found. In the early Phase II study [31], 70 postmenopausal patients with advanced and/or recurrent breast cancer were allocated randomly to groups administered 0.5 and 1 mg/day anastrozole for at least 12 weeks, and the response rate was found to be higher in the 1-mg/day group, with the safety being approximately the same in the two dose groups. On the basis of these results, the recommended clinical dose was judged to be one dose per day at 1 mg. With the aim of confirming the efficacy of anastrozole in Japanese patients, a pharmacology bridging study of the same design as that carried out Europe was carried out for 31 Japanese postmenopausal patients with advanced and/or recurrent breast cancer [32], and the safety and efficacy of anastrozole were confirmed to be approximately the same for both Japanese and Caucasian patients. The anti-tumor efficacy response rates with the above 31 evaluated patients, on the basis of the UICC judgment criteria, were 35.0% (7 of 20) in the tamoxifen group, and 45.5% (5 of 11) in the anastrozole group. 4.8 Exemestane Details of Exemestane Development Aromatase is the rate-limiting enzyme for the final step in the formation of estrogen from cholesterol. It is mainly present in the ovaries in premenopasual women and in adipose tissues in postmenopausal women. In postmenopausal breast cancer patients, aromatase activity is known to be elevated in the actual cancer tissue and/or in the surrounding tissues, and it is considered 16

20 that inhibition of aromatase would be useful for treating estrogen-dependent diseases such as breast cancer. In 1982, two Italian companies, Pharmacia and Carlo Erba (now Pfizer), initiated the development of highly selective aromatase-inhibitors, and created a novel irreversible aromatase-inhibitor, Aromasin, the nonproprietary name of which is exemestane. Overseas clinical studies were initiated in 1989, and the application for approval was submitted on the basis of a double-blind study involving a comparison with megestrol acetate (a corpus luteum hormone agent), carried out in postmenopausal patients with advanced breast cancer for whom tamoxifen and/or other anti-estrogen agents had been found to be ineffective. As of February 2002, regulatory approval had thus been achieved in 49 countries, including the EU and the USA. In Japan, an application for approval for importation was submitted in December 2000, on the basis of the overseas clinical studies, and also the Japanese Phase-I study, early-phase-ii study, and late Phase II study (pharmacology bridging study). Approval for the indication of postmenopausal breast cancer was then achieved in July Japanese Clinical Results with Exemestane [33-35] The Phase I study involved investigation of the safety and pharmacodynamic activity (i.e. reduction of serum estrogen concentration) of 0.5 to 50 mg/day exemestane in postmenopausal, healthy, female volunteers, with 14 being given single doses, and 25 repeated administrations [33]. As a result, the serum estrogen concentration decreased in a dose-dependent manner. The early-phase-ii study [34], carried out with postmenopausal breast cancer patients, involved investigation of the safety and efficacy of 10 and 25 mg exemestane (36 patients per dose group), and also attempted to set the clinical recommended dose. With respect to response rate, although the difference between the dose groups was not significant, the rate with 25 mg was somewhat higher than that with 10 mg, and 25 mg/day was therefore chosen as the recommended clinical dose. The response rate with 25 mg in patients who were resistant to hormone therapy was 26.1% (6 of 23). Furthermore, as clinical studies had already been carried out overseas, a late Phase II study (study No. 042) was carried out as a bridging study, in order to confirm the appropriateness of applying overseas data to Japanese patients [35]. In this late Phase II study, the safety and efficacy of exemestane treatment for 33 postmenopausal patients with anti-estrogen-resistant breast cancer were confirmed. An additional aim of this study was to confirm the reproducibility of the overseas clinical studies (study Nos and 010) that were designed similarly to this study. The response rate was found to be 24.2% (8 of 33), and the efficacy rate, including a long period without change, was 39.4% (13 of 33). 4.9 Preoperative Chemotherapy The currently available treatment regimens with the highest pcr rates involve the administration of anthracycline agents followed by taxane agents. In NSABP B-27 study, patients administered four courses of AC therapy (60 mg/m 2 doxorubicin mg/m 2 cyclophosphamide) at 3-week intervals were compared with patients administered the same four courses of AC therapy followed by four courses of 100 mg/m 2 docetaxel at 3-week intervals. The response rate, complete response rate, and pcr rate of the AC + docetaxel group were found to be 91%, 65%, and 26%, respectively, which were higher than the equivalent rates in the group administered only AC therapy; 85%, 40%, and 14% [5]. 17

21 4.10 Postoperative Adjuvant Chemotherapy Postoperative adjuvant chemotherapy involving taxanes has been investigated in a number of studies, including the following: (i) CALGB 9344: This study, carried out by Cancer and Leukemia Group B (CALGB), was a Phase III comparative study in which one group was administered four courses of AC therapy at 3-week intervals, followed by four courses of paclitaxel, and the other group was administered only the four courses of AC therapy at 3-week intervals [36]. (ii) NSABP B-28: This study, carried out by the NSABP, was a Phase III comparative study in which one group was administered four courses of AC therapy at 3-week intervals, followed by four courses of paclitaxel, and the other was administered only the four courses of AC therapy at 3-week intervals [37]. (iii) BCIRG 001: This study, carried out by the Breast Cancer International Research Group (BCIRG), was a Phase III comparative study in which one group was administered six courses of FAC therapy (5-FU + doxorubicin + cyclophosphamide) at 3-week intervals, and the other was administered six courses, at 3-week intervals, of TAC therapy, which was FAC therapy with 5-FU replaced with docetaxel (docetaxel + doxorubicin + cyclophosphamide) [38]. With respect to the assessment of postoperative adjuvant chemotherapy using 5-FU agents, the investigation was carried out by using 5 -DFUR, in a comparative study with 5 -DFUR monotherapy and observation [39] or with one group administered 5 -DFUR mono-therapy and the other administered 5 -DFUR in combination with cyclophosphamide. The results confirmed the safety and efficacy of the 5 -DFUR + cyclophosphamide combination therapy [40]. Furthermore, in a pooled analysis of six comparative studies in which uracil + tegafur (UFT therapy) was administered, the groups compared were those treated with surgery only, UFT therapy only, TAM therapy only, and UFT + TAM combination therapy [41]. The results of this analysis demonstrated the usefulness of UFT + TAM combination therapy. For this reason, and also because there are no reciprocal effects with concomitant administration of 5-FU agents and hormone therapy, there were judged to be no ethical difficulties with respect to the administration of capecitabine in combination with hormone therapy in the current study. Combination therapy of capecitabine and TAM was confirmed to be not antagonistic but effective based on the investigation in a preclinical study [42]. Furthermore, a 43 to 50% response rate was reported for the combination therapy of aromatase inhibitor and capecitabine in a pilot study of patients who received hormone therapy after recurrence [43]. Therefore, there is no ethical problem with the simultaneous administration of capecitabine and hormone therapy planned for this study. In the 5 -DFUR study, 5-FU agents are administered for 6 months [39, 40], and 2 years in the UFT study [41]. However, capecitabine is administered for 6 months in an overseas study. In an investigational study for postoperative adjuvant therapy targeting stage III rectum cancer patients, a 6-month administration of capecitabine was compared with that of 5-FU/LV. It was confirmed that the results of capecitabine monotherapy were equivalent to those with 5-FU/LV therapy [44]. For postoperative adjuvant therapy in breast cancer patients, the US oncology group is currently conducting a comparative clinical study in which 1 group is administered AC therapy (4 cycles) followed by paclitaxel (4 cycles) and another group is administered paclitaxel (4 cycles) in combination with capecitabine Reasons for Preparation of this Protocol The pcr rate with the preoperative chemotherapy regimen currently understood to be the most effective, that is, with anthracycline agents followed by taxane agents, is at most 30%, so pcr 18

22 does not occur with 70% of patients. The prognoses of the non-pcr patients were reported to be poorer than those of the pcr patients [5]. Capecitabine has been found to be safe and effective in patients for whom anthracycline and taxane agents are ineffective.it is hoped that it will also be effective in patients who achieved non-pcr by the standard preoperative chemotherapy. For the above reasons, the current study has been scheduled with the aim of confirming the efficacy and safety of capecitabine as a postoperative adjuvant chemotherapy regimen for patients who do not show pcr with preoperative chemotherapy. 19

23 5. TARGET PATIENTS The target patients are to be breast cancer patients who are non-pcr with respect to preoperative chemotherapy; that is, those who have been pathologically confirmed to have residual cancer cells. 5.1 Inclusion Criteria Each patient must meet all the following criteria: The patient is female, and primary, infiltrative breast cancer has been histological diagnosed (fine needle aspiration of primary tumor is not sufficient to diagnose invasive disease) The patient is diagnosed stage I IIIB at the first diagnosis and underwent curative resection The patient was non-pcr* after preoperative chemotherapy including anthracycline agents**; that is, she had undergone primary tumor resection and pathologically confirmed to have residual cancer cells. The previously administered preoperative chemotherapy must have involved at least four cycles of anthracycline agents. However, even if Anthracycline regimen is shorter than 4 courses, the following regimen can be registered. Patients who could not complete scheduled courses because of serious adverse drug reaction or disease progression can be registered if they completed at least 2 courses. FEC 3 courses (EPI>=100mg/m2)+Docetaxel 3 courses FEC 3 courses+tc (Docetaxel 75 mg/m2 + cyclophosphamide 600 mg/m2) 3 courses TC 3 courses+fec 3 courses TC only over 4 courses * Preoperative chemotherapy with anthracycline agents Node positive or sentinel lymph nodes (SLN) positive patients should be treated with either of the following treatments:. Anthracycline including regimen 1) followed by taxanes 2) Taxanes 2) followed by anthracycline including regimen 1) AT/ET 3) (It does not apply to Japan) Node negative or SLN negative patients should be treated with either of the following treatments: Anthracycline including regimen 1) TC only over 4 courses Anthracycline including regimen 1) followed by taxanes 2) Taxanes 2) followed by anthracycline including regimen 1) 1) Anthracycline containing regimen, initial dose: ADR>= 50 mg/m 2, EPI>= mg/m 2 2) Taxane, initial dose: DOC>=70 mg/m 2, q3w, PAC>>=80 mg/m 2, weekly 20

24 3) AT/ET: ADR>= 50 mg/m 2, EPI>=75 mg/m 2, DOC>=60 mg/m 2, PAC>=175 mg/m 2 <Notes> Treatments based on the above regimen are in principle. Dose reductions caused by adverse events are acceptable. * The applied criteria for pcr are the NSABP s global criteria, so patients are judged to show pcr even if they have residual ductal carcinoma in situ components (but no other cancer components). In addition, the pcr applies only to the breasts, so patients can show pcr even with residual lymph node metastatic foci. Notes: N represents lymph node based on clinical efficacy evaluation. should comply with TNM Classification of UICC (ver. 6). The evaluation The patient has been confirmed to be HER2-negative, with a score of 0 or 1 in an immunohistochemistry test and/or a negative result by the fluorescence in situ hybridization (FISH) method The patient is aged 20 to The patient s general performance status is 0 to The patient must have no carry-over of efficacy from any previous treatment. Therefore, the following recovery periods must have wash-out period before initiation of administration in this study: Chemotherapy, including capecitabine: 4 weeks Radiotherapy and/or surgery: 2 weeks The patient has maintained sufficient organ function to permit valid evaluation, with respect to physiology, of the safety of capecitabine and hormone therapy (LHRH agonists, anti-estrogen agents, and aromatase-inhibitors), as shown by meeting the following criteria, and she must not have been administered a blood transfusion and/or hematopoietic factors within 2 weeks before the tests for these criteria: Either Leukocyte count: 3,000 to 12,000 /mm 3 or neutrophil count: 1,500 /mm 3 Platelet count: 100,000 /mm 3 Hemoglobin concentration: 9.0g/dL AST (GOT), ALT (GPT): 2.5 times the upper limit of the medical institution s criteria (upper limit of normal) Alkaline phosphatase (Al-p): 2.5 times upper limit of normal Total bilirubin: 1.25 times upper limit of normal Serum creatinine: < 1.5 times upper limit of normal Electrocardiography Normal electrocardiographic parameters The patient must have no adverse drug reactions of grade 2 or higher carried over from previous treatment. However, test results in 7 and effects on general conditions, 21