Clinical trial NCT03351062: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Breast Cancer Female
Keywords: premenopausal
early breast cancer
estrogen receptor positive
Lead sponsor: Chinese Anti-Cancer Association
Sponsor class: OTHER
Collaborators: name: Fudan University
name: Henan Cancer Hospital
name: The First Hospital of Jilin University
name: Southwest Hospital, China
name: First Hospital of China Medical University
name: Guangdong Provincial People's Hospital
name: Harbin Medical University
name: First Affiliated Hospital of Chongqing Medical University
name: Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
name: Jiangsu Provincial People's Hospital
name: Cancer Institute and Hospital, Chinese Academy of Medical Sciences
name: Zhejiang Cancer Hospital
name: Tianjin Medical University Cancer Institute and Hospital
name: Union hospital of Fujian Medical University
name: Hebei Tumor Hospital
name: Hunan Cancer Hospital
name: Affiliated Hospital of Qinghai University
name: Wuhan TongJi Hospital
name: Hainan People's Hospital
name: The Third Affiliated Hospital of Kunming Medical College.
name: The Third Affiliated Hospital of Nanchang University
First posted: 2017-11-22
Enrollment: 844
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Primary outcomes:
measure: Disease-Free Survival
timeFrame: Within 5 years after randomization
Secondary outcomes:
measure: Overall Survival
timeFrame: Within 5 years after randomization
measure: Adverse drug reaction
timeFrame: Within 5 years after administration
measure: Serum drug concentration
timeFrame: Within 6 months after administration
Other outcomes:
Locations:
city: Beijing
country: China
facility: Cancer Institute and Hospital, Chinese Academy of Medical Sciences
state: Beijing
city: Chongqing
country: China
facility: First Affiliated Hospital of Chongqing Medical University
state: Chongqing
city: Chongqing
country: China
facility: Southwest Hospital, China
state: Chongqing
city: Fuzhou
country: China
facility: Union hospital of Fujian Medical University
state: Fujian
city: Guangzhou
country: China
facility: Guangdong Provincial People's Hospital
state: Guangdong
city: Guangzhou
country: China
facility: Sun Yat-sen Memorial Hospital
state: Guangdong
city: Haikou
country: China
facility: Hainan People's Hospital
state: Hainan
city: Shijiazhuang
country: China
facility: Hebei Tumor Hospital
state: Hebei
city: Harbin
country: China
facility: Harbin Medical University Cancer Hospital
state: Heilongjiang
city: Zhengzhou
country: China
facility: Henan Cancer Hospital
state: Henan
city: Wuhan
country: China
facility: Wuhan Tongji Hospital
state: Hubei
city: Changsha
country: China
facility: Hunan Cancer Hospital
state: Hunan
city: Nanjing
country: China
facility: Jiangsu Provincial People's Hospital
state: Jiangsu
city: Nanchang
country: China
facility: The Third Affiliated Hospital of Nanchang University
state: Jiangxi
city: Changchun
country: China
facility: First Hospital of Jilin University
state: Jilin
city: Shenyang
country: China
facility: First Hospital of China Medical University
state: Lining
city: Qingdao
country: China
facility: First Affiliated Hospital of Qingdao University
state: Shandong
city: Shanghai
country: China
facility: Fudan University Shanghai Cancer Center
state: Shanghai
city: Tianjin
country: China
facility: Tianjin Medical University Cancer Institute and Hospital
state: Tianjin
city: Kunming
country: China
facility: The Third Affiliated Hospital of Kunming Medical College
state: Yunnan
city: Hangzhou
country: China
facility: Zhejiang Cancer Hospital
state: Zhejiang
Study officials:
affiliation: Fudan University
name: Zhimin Shao, Master
role: PRINCIPAL_INVESTIGATOR
References: