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
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- 入组人数
- 844
- 试验地点
- 21
- 主要终点
- Disease-Free Survival
研究概览
简要总结
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.
详细描述
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:
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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.
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The secondary purpose of this study includes:
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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.
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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.
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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:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 50 Years（Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Premenopausal women aged 18-50 years;
- •ECOG PS: 0-2 points;
- •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);
- •Participants have completed the standard local radical treatment (modified or conservative radical mastectomy) with or without neo-adjuvant/adjuvant chemotherapy or radiotherapy;
- •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;
- •Polymorphism analysis showed that patients are CYP2D6 * 4, * 5, * 10, * 14, * 17, * 41 allele carriers;
- •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.
排除标准
- •Patients have previously received neoadjuvant endocrine therapy or have started adjuvant endocrine therapy;
- •There are any comorbidities that may increase the level of sex hormones: such as pituitary adenomas, ovarian tumors, thymic carcinomas, etc.;
- •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.;
- •Patients have undergone or planned to conduct ovariectomy or ovarian function inhibition;
- •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);
- •Patients have been treated with other trial medications in the past 2 weeks;
- •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);
- •Women of childbearing age who are not willing to take effective contraception during treatment;
- •There are serious non-malignant tumor comorbidities that may affect long-term follow-up;
- •Patients have family history of endometrial, ovarian or other gynecologic malignancies;
- •Transvaginal ultrasound suggested more serious ovarian abnormalities or endometrial thickening;
- •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;
- •Serious liver insufficiency with Child-Pugh C grade;
- •Serious cardiac insufficiency with New York Heart Association (NYHA) grade ≥III;
- •Patients are known severely allergic to study drug;
- •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;
- •In other cases, the researchers don't think the subjects are suitable for participate in the study.
研究组 & 干预措施
Tamoxifen treatment group
Patients in this group will receive tamoxifen treatment.
干预措施: Tamoxifen (Drug)
Toremifene treatment group
Patients in this group will receive Toremifene treatment.
干预措施: Toremifene (Drug)
结局指标
主要结局
Disease-Free Survival
时间窗: 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
次要结局
- Overall Survival(Within 5 years after randomization)
- Adverse drug reaction(Within 5 years after administration)
- Serum drug concentration(Within 6 months after administration)