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

November 20, 2017 updated by: Chinese Anti-Cancer Association

Multicenter Prospective, Parallel-controlled Phase III Clinical Study on Comparing Efficacy of Tamoxifen Versus Toremifene in CYP2D6 Intermediate/Poor Metabolizers of Premenopausal Patients With ER-positive Early Breast Cancer

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Anticipated)

844

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • China
    • Beijing
      • Beijing, Beijing, China
        • Recruiting
        • Cancer Institute and Hospital, Chinese Academy of Medical Sciences
        • Contact:
        • Principal Investigator:
          • Xiang Wang, M. D.
    • Chongqing
      • Chongqing, Chongqing, China
        • Recruiting
        • First Affiliated Hospital of Chongqing Medical University
        • Contact:
        • Principal Investigator:
          • Guosheng Ren, M. D.
      • Chongqing, Chongqing, China
        • Recruiting
        • Southwest Hospital, China
        • Contact:
        • Principal Investigator:
          • Jun Jiang, M. D.
    • Fujian
      • Fuzhou, Fujian, China
        • Recruiting
        • Union Hospital of Fujian Medical University
        • Contact:
        • Principal Investigator:
          • Chuangui Song, M. D.
    • Guangdong
      • Guangzhou, Guangdong, China
        • Recruiting
        • Guangdong Provincial People's Hospital
        • Contact:
        • Principal Investigator:
          • Ning Liao, M. D.
      • Guangzhou, Guangdong, China
        • Recruiting
        • Sun Yat-sen Memorial Hospital
        • Contact:
        • Principal Investigator:
          • Erwei Song, M. D.
    • Hainan
      • Haikou, Hainan, China
        • Recruiting
        • Hainan People's Hospital
        • Contact:
        • Principal Investigator:
          • Xiaojie Zhong, M. D.
    • Hebei
      • Shijiazhuang, Hebei, China
        • Recruiting
        • Hebei Tumor Hospital
        • Contact:
        • Principal Investigator:
          • Cuizhi Geng, M. D.
    • Heilongjiang
      • Harbin, Heilongjiang, China
        • Recruiting
        • Harbin Medical University Cancer Hospital
        • Contact:
        • Principal Investigator:
          • Da Pang, M. D.
    • Henan
      • Zhengzhou, Henan, China
        • Recruiting
        • Henan Cancer Hospital
        • Contact:
        • Principal Investigator:
          • Shude Cui, M. D.
    • Hubei
      • Wuhan, Hubei, China
        • Recruiting
        • Wuhan Tongji Hospital
        • Contact:
        • Principal Investigator:
          • Xingrui Li, M. D.
    • Hunan
      • Changsha, Hunan, China
        • Recruiting
        • Hunan Cancer Hospital
        • Contact:
        • Principal Investigator:
          • Lizhi Ouyang, M. D.
    • Jiangsu
      • Nanjing, Jiangsu, China
        • Recruiting
        • Jiangsu Provincial People's Hospital
        • Contact:
        • Principal Investigator:
          • Shui Wang, M. D.
    • Jiangxi
      • Nanchang, Jiangxi, China
        • Recruiting
        • The Third Affiliated Hospital of Nanchang University
        • Contact:
        • Principal Investigator:
          • Yali Cao, M. D.
    • Jilin
      • Changchun, Jilin, China
        • Recruiting
        • First Hospital of Jilin University
        • Contact:
        • Principal Investigator:
          • Zhimin Fan, M. D.
    • Lining
      • Shenyang, Lining, China
        • Recruiting
        • First Hospital of China Medical University
        • Contact:
        • Principal Investigator:
          • Feng Jin, M. D.
    • Shandong
      • Qingdao, Shandong, China
        • Recruiting
        • First Affiliated Hospital of Qingdao University
        • Contact:
        • Principal Investigator:
          • Haibo Wang, M. D.
    • Shanghai
      • Shanghai, Shanghai, China
        • Recruiting
        • Fudan University Shanghai Cancer Center
        • Contact:
        • Contact:
    • Tianjin
      • Tianjin, Tianjin, China
        • Recruiting
        • Tianjin Medical University Cancer Institute and Hospital
        • Contact:
        • Principal Investigator:
          • Jin Zhang, M. D.
    • Yunnan
      • Kunming, Yunnan, China
        • Recruiting
        • The Third Affiliated Hospital of Kunming Medical College
        • Contact:
        • Principal Investigator:
          • Dedian Chen, M. D.
    • Zhejiang
      • Hangzhou, Zhejiang, China
        • Recruiting
        • Zhejiang Cancer Hospital
        • Contact:
        • Principal Investigator:
          • Hongjian Yang, M. D.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years to 48 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Tamoxifen treatment group
Patients in this group will receive tamoxifen treatment.
Drug: Tamoxifen
Patients will be given 10mg Tamoxifen twice a day.
Other Names:
  • Tamoxifen citrate
Active Comparator: Toremifene treatment group
Patients in this group will receive Toremifene treatment.
Drug: Toremifene
Patients will be given 60mg Toremifene once a day.
Other Names:
  • fareston

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Disease-Free Survival
Time Frame: Within 5 years after randomization
The time period from randomization to local or distant invasive cancer recurrence, contralateral invasive breast cancer, second (non-breast) primary invasive cancer and all-cause death
Within 5 years after randomization

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall Survival
Time Frame: Within 5 years after randomization
The time period from randomization to all-cause death
Within 5 years after randomization
Adverse drug reaction
Time Frame: Within 5 years after administration
The time period from administration to adverse events (dyslipidemia, endometrial hyperplasia) with confirmed, probably and possibly relevant relationship to trial medicine.
Within 5 years after administration
Serum drug concentration
Time Frame: Within 6 months after administration
Blood level of trial medicines and their metabolites
Within 6 months after administration

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Chinese Anti-Cancer Association

Collaborators

Zhejiang Cancer Hospital
Fudan University
Cancer Institute and Hospital, Chinese Academy of Medical Sciences
Henan Cancer Hospital
Southwest Hospital, China
Hunan Cancer Hospital
Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
Tianjin Medical University Cancer Institute and Hospital
Guangdong Provincial People's Hospital
The First Hospital of Jilin University
First Hospital of China Medical University
Harbin Medical University
First Affiliated Hospital of Chongqing Medical University
Wuhan TongJi Hospital
Affiliated Hospital of Qinghai University
The Third Affiliated Hospital of Nanchang University
Hainan People's Hospital
Jiangsu Provincial People's Hospital
Union hospital of Fujian Medical University
The Third Affiliated Hospital of Kunming Medical College.
Hebei Tumor Hospital

Investigators

  • Principal Investigator: Zhimin Shao, Master, Fudan University

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Anticipated)

November 1, 2017

Primary Completion (Anticipated)

December 1, 2025

Study Completion (Anticipated)

December 1, 2025

Study Registration Dates

First Submitted

November 20, 2017

First Submitted That Met QC Criteria

November 20, 2017

First Posted (Actual)

November 22, 2017

Study Record Updates

Last Update Posted (Actual)

November 22, 2017

Last Update Submitted That Met QC Criteria

November 20, 2017

Last Verified

November 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CYP2D6-1.1

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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