Efficacy of Tamoxifen Versus Toremifene in CYP2D6 IM/PM of Premenopausal Patients With ER-positive Early Breast Cancer

NCT ID: NCT03351062

Last Updated: 2017-11-22

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Clinical Phase

PHASE3

Total Enrollment

844 participants

Study Classification

INTERVENTIONAL

Study Start Date

2017-11-30

Study Completion Date

2025-12-31

Brief Summary

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This clinical trial is designed to be a multi-center prospective, parallel-controlled Phase III clinical study. In this study, the efficacy of tamoxifen versus toremifene shall be compared in CYP2D6 intermediate/poor metabolizers of premenopausal patients with estrogen receptor-positive early breast cancer.

Detailed Description

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STUDY BACKGROUND Breast cancer is a serious disease that threatens human health and life. Especially in China, the incidence rate is increasing year by year. According to WHO data, the incidence of breast cancer in China in 2020 will reach 214,000. Selective estrogen receptor modulators (SERMs) are a classic form of endocrine therapy for early breast cancers, but not all hormone receptor positive breast cancers benefit from specific SERMs. Numerous studies have shown that CYP2D6 variant carriers (around 50% CYP2D6 variant carriers in Chinese population) will not benefit a lot from tamoxifen, and combined use of CYP2D6 inhibitors will further affect the efficacy of tamoxifen. However, studies on another SERM drug - toremifene have shown that its metabolism and pharmacological effects are not influenced by CYP2D6 genotype or enzyme activity. Therefore, in the principle of individualized medicine, it is necessary to compare the efficacy of using tamoxifen and toremifene in CYP2D6 variant carriers in China so as to provide more guidance for clinical use.

OBJECTIVES:

1. The main purpose of this study is to compare 5-year disease-free survival rate of adjuvant endocrine therapy with tamoxifen and toremifene in premenopausal women with estrogen receptor-positive early breast cancer who are CYP2D6 intermediate/poor metabolizers.
2. The secondary purpose of this study includes:

1. To compare 5-year overall survival (OS) and safety of adjuvant endocrine therapy with tamoxifen and toremifene in premenopausal patients with estrogen receptor-positive early breast cancer who are CYP2D6 intermediate/poor metabolizers.
2. To compare the changes of plasma concentration of the parent drugs and metabolites of tamoxifen and toremifene in premenopausal patients with estrogen receptor-positive early breast cancer who are CYP2D6 intermediate/poor metabolizers.
3. To assess the pharmacokinetics of tamoxifen and toremifene in premenopausal patients with estrogen receptor-positive early breast cancer who are CYP2D6 intermediate/poor metabolizers.

OUTLINE:

First, CYP2D6 genotype screening shall be conducted in premenopausal patients with estrogen receptor-positive early breast cancer in order to determine the frequency of different alleles. Then, patients who are CYP2D6 intermediate/poor metabolizers (with \*4, \*5, \*10, \*14, \*17, \*41 alleles) shall be stratified and randomized at the ratio of 1:1 ratio: allele status of CYP2D6 CYP2D6 intermediate/poor metabolizer (Heterozygous or homozygous), lymph node metastasis (with vs. without), prior chemotherapy (with vs. without), and HER2 status (positive vs. negative). Included patients shall be divided into two groups. One group will be given Tamoxifen (10mg Bid) for 5 years and the other group will be given toremifene (60mg qd) for 5 years. Then 5-year disease-free rate and overall survival and safety will be compared between these two groups. At Month 6, pharmacokinetic study on tamoxifen, toremifene and their metabolites will be conducted on patients.

Conditions

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Breast Cancer Female

Keywords

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premenopausal early breast cancer estrogen receptor positive

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Tamoxifen treatment group

Patients in this group will receive tamoxifen treatment.

Group Type ACTIVE_COMPARATOR

Tamoxifen

Intervention Type DRUG

Patients will be given 10mg Tamoxifen twice a day.

Toremifene treatment group

Patients in this group will receive Toremifene treatment.

Group Type ACTIVE_COMPARATOR

Toremifene

Intervention Type DRUG

Patients will be given 60mg Toremifene once a day.

Interventions

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Tamoxifen

Patients will be given 10mg Tamoxifen twice a day.

Intervention Type DRUG

Toremifene

Patients will be given 60mg Toremifene once a day.

Intervention Type DRUG

Other Intervention Names

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Tamoxifen citrate fareston

Eligibility Criteria

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Inclusion Criteria

1. Premenopausal women aged 18-50 years;
2. ECOG PS: 0-2 points;
3. Invasive breast cancer confirmed by histology with ER ≥ 10% (all test results should be reviewed and confirmed by Department of Pathology of the participant institution);
4. Participants have completed the standard local radical treatment (modified or conservative radical mastectomy) with or without neo-adjuvant/adjuvant chemotherapy or radiotherapy;
5. Participants must be able to understand this study and are willing to participate, agree to genotype screening and sign informed consent form with good compliance and cooperation in follow-ups;
6. Polymorphism analysis showed that patients are CYP2D6 \* 4, \* 5, \* 10, \* 14, \* 17, \* 41 allele carriers;
7. Hemoglobin ≥ 90g/L, neutrophils ≥ 1.5 × 109/L, platelets ≥ 75 × 109/L, AST and ALT ≤ 2.5 times the upper limit of normal (ULN), serum creatinine and urea nitrogen ≤ ULN.

Exclusion Criteria

1. Patients have previously received neoadjuvant endocrine therapy or have started adjuvant endocrine therapy;
2. There are any comorbidities that may increase the level of sex hormones: such as pituitary adenomas, ovarian tumors, thymic carcinomas, etc.;
3. There are any comorbidities that may reduce the level of sex hormones such as hyperthyroidism, hypothyroidism, cirrhosis, severe malnutrition, Turner syndrome, lack of sex hormone synthetase, intracranial tumors, pituitary atrophy etc.;
4. Patients have undergone or planned to conduct ovariectomy or ovarian function inhibition;
5. Patients needs to take other medicines which can influence the activity of CYP2D6 (such as fluoxetine, paroxetine, quinidine, bupropion), CYP3A4 (such as erythromycin, acetylspiramycin, ritonavir, ketoconazole, nicardipine);
6. Patients have been treated with other trial medications in the past 2 weeks;
7. Pregnant or lactating women (women of childbearing age must have a negative pregnancy test within 14 days of the first dosing, and if pregnant, Patients are required for ultrasound examination to exclude pregnancy);
8. Women of childbearing age who are not willing to take effective contraception during treatment;
9. There are serious non-malignant tumor comorbidities that may affect long-term follow-up;
10. Patients have family history of endometrial, ovarian or other gynecologic malignancies;
11. Transvaginal ultrasound suggested more serious ovarian abnormalities or endometrial thickening;
12. Patients have had thrombotic events such as cerebrovascular accident (including transient ischemic attack), deep venous thrombosis, and pulmonary embolism within 6 months prior to study initiation;
13. Serious liver insufficiency with Child-Pugh C grade;
14. Serious cardiac insufficiency with New York Heart Association (NYHA) grade ≥III;
15. Patients are known severely allergic to study drug;
16. Patients have history of other malignancies in the past five years, except for cutaneous basal cell carcinoma and cervical carcinoma in situ which have been cured;
17. In other cases, the researchers don't think the subjects are suitable for participate in the study.
Minimum Eligible Age

18 Years

Maximum Eligible Age

50 Years

Eligible Sex

FEMALE

Accepts Healthy Volunteers

No

Sponsors

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Fudan University

OTHER

Sponsor Role collaborator

Henan Cancer Hospital

OTHER_GOV

Sponsor Role collaborator

The First Hospital of Jilin University

OTHER

Sponsor Role collaborator

Southwest Hospital, China

OTHER

Sponsor Role collaborator

First Hospital of China Medical University

OTHER

Sponsor Role collaborator

Guangdong Provincial People's Hospital

OTHER

Sponsor Role collaborator

Harbin Medical University

OTHER

Sponsor Role collaborator

First Affiliated Hospital of Chongqing Medical University

OTHER

Sponsor Role collaborator

Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University

OTHER

Sponsor Role collaborator

Jiangsu Provincial People's Hospital

OTHER

Sponsor Role collaborator

Cancer Institute and Hospital, Chinese Academy of Medical Sciences

OTHER

Sponsor Role collaborator

Zhejiang Cancer Hospital

OTHER

Sponsor Role collaborator

Tianjin Medical University Cancer Institute and Hospital

OTHER

Sponsor Role collaborator

Union hospital of Fujian Medical University

OTHER

Sponsor Role collaborator

Hebei Tumor Hospital

OTHER

Sponsor Role collaborator

Hunan Cancer Hospital

OTHER

Sponsor Role collaborator

Affiliated Hospital of Qinghai University

OTHER

Sponsor Role collaborator

Wuhan TongJi Hospital

OTHER

Sponsor Role collaborator

Hainan People's Hospital

OTHER

Sponsor Role collaborator

The Third Affiliated Hospital of Kunming Medical College.

OTHER

Sponsor Role collaborator

The Third Affiliated Hospital of Nanchang University

OTHER

Sponsor Role collaborator

Chinese Anti-Cancer Association

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Zhimin Shao, Master

Role: PRINCIPAL_INVESTIGATOR

Fudan University

Locations

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Cancer Institute and Hospital, Chinese Academy of Medical Sciences

Beijing, Beijing Municipality, China

Site Status RECRUITING

First Affiliated Hospital of Chongqing Medical University

Chongqing, Chongqing Municipality, China

Site Status RECRUITING

Southwest Hospital, China

Chongqing, Chongqing Municipality, China

Site Status RECRUITING

Union hospital of Fujian Medical University

Fuzhou, Fujian, China

Site Status RECRUITING

Guangdong Provincial People's Hospital

Guangzhou, Guangdong, China

Site Status RECRUITING

Sun Yat-sen Memorial Hospital

Guangzhou, Guangdong, China

Site Status RECRUITING

Hainan People's Hospital

Haikou, Hainan, China

Site Status RECRUITING

Hebei Tumor Hospital

Shijiazhuang, Hebei, China

Site Status RECRUITING

Harbin Medical University Cancer Hospital

Harbin, Heilongjiang, China

Site Status RECRUITING

Henan Cancer Hospital

Zhengzhou, Henan, China

Site Status RECRUITING

Wuhan Tongji Hospital

Wuhan, Hubei, China

Site Status RECRUITING

Hunan Cancer Hospital

Changsha, Hunan, China

Site Status RECRUITING

Jiangsu Provincial People's Hospital

Nanjing, Jiangsu, China

Site Status RECRUITING

The Third Affiliated Hospital of Nanchang University

Nanchang, Jiangxi, China

Site Status RECRUITING

First Hospital of Jilin University

Changchun, Jilin, China

Site Status RECRUITING

First Hospital of China Medical University

Shenyang, Lining, China

Site Status RECRUITING

First Affiliated Hospital of Qingdao University

Qingdao, Shandong, China

Site Status RECRUITING

Fudan University Shanghai Cancer Center

Shanghai, Shanghai Municipality, China

Site Status RECRUITING

Tianjin Medical University Cancer Institute and Hospital

Tianjin, Tianjin Municipality, China

Site Status RECRUITING

The Third Affiliated Hospital of Kunming Medical College

Kunming, Yunnan, China

Site Status RECRUITING

Zhejiang Cancer Hospital

Hangzhou, Zhejiang, China

Site Status RECRUITING

Countries

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China

Central Contacts

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Zhimin Shao, M. D.

Role: CONTACT

Phone: 13611709888

Email: [email protected]

Ayong Cao, M. D.

Role: CONTACT

Phone: 18017317218

Email: [email protected]

Facility Contacts

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Xiang Wang, M. D.

Role: primary

Guosheng Ren, M. D.

Role: primary

Jun Jiang, M. D.

Role: primary

Chuangui Song, M. D.

Role: primary

Ning Liao, M. D.

Role: primary

Erwei Song, M. D.

Role: primary

Xiaojie Zhong, M. D.

Role: primary

Cuizhi Geng, M. D.

Role: primary

Da Pang, M. D.

Role: primary

Shude Cui, M. D.

Role: primary

Xingrui Li, M. D.

Role: primary

Lizhi Ouyang, M. D.

Role: primary

Shui Wang, M. D.

Role: primary

Yali Cao, M. D.

Role: primary

Zhimin Fan, M. D.

Role: primary

Feng Jin, M. D.

Role: primary

Haibo Wang, M. D.

Role: primary

Zhimin Shao, M. D.

Role: primary

Ayong Cao, M. D.

Role: backup

Jin Zhang, M. D.

Role: primary

Dedian Chen, M. D.

Role: primary

Hongjian Yang, M. D.

Role: primary

Other Identifiers

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CYP2D6-1.1

Identifier Type: -

Identifier Source: org_study_id