Clinical Trials /

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

NCT03351062

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Efficacy of Tamoxifen Versus Toremifene in CYP2D6 IM/PM of Premenopausal Patients With ER-positive Early Breast Cancer
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: CYP2D6-1.1
  • NCT ID: NCT03351062

Conditions

  • Breast Cancer Female

Interventions

DrugSynonymsArms
TamoxifenTamoxifen citrateTamoxifen treatment group
ToremifenefarestonToremifene treatment group

Purpose

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

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Tamoxifen treatment groupActive ComparatorPatients in this group will receive tamoxifen treatment.
  • Tamoxifen
Toremifene treatment groupActive ComparatorPatients in this group will receive Toremifene treatment.
  • Toremifene

Eligibility Criteria

        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.
      
Maximum Eligible Age:50 Years
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Disease-Free Survival
Time Frame:Within 5 years after randomization
Safety Issue:
Description: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

Secondary Outcome Measures

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

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Chinese Anti-Cancer Association

Trial Keywords

  • premenopausal
  • early breast cancer
  • estrogen receptor positive

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