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

Sponsor

Chinese Anti-Cancer Association (Other)

Overall Status

Recruiting

CT.gov ID

NCT03351062

Collaborator

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

844

Enrollment

Locations

Arms

Anticipated Duration (Months)

40.2

Patients Per Site

0.4

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer Female	Drug: Tamoxifen Drug: Toremifene	Phase 3

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:

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.
The secondary purpose of this study includes:
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.
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.
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 Design

Study Type:

Interventional

Anticipated Enrollment :

844 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Anticipated Study Start Date :

Nov 1, 2017

Anticipated Primary Completion Date :

Dec 1, 2025

Anticipated Study Completion Date :

Dec 1, 2025

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Disease-Free Survival [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

Secondary Outcome Measures

Overall Survival [Within 5 years after randomization]
The time period from randomization to all-cause death
Adverse drug reaction [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.
Serum drug concentration [Within 6 months after administration]
Blood level of trial medicines and their metabolites

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 50 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

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.

Exclusion Criteria:

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.

Contacts and Locations

Locations

	Site	City	State	Country
1	Cancer Institute and Hospital, Chinese Academy of Medical Sciences	Beijing	Beijing	China
2	First Affiliated Hospital of Chongqing Medical University	Chongqing	Chongqing	China
3	Southwest Hospital, China	Chongqing	Chongqing	China
4	Union hospital of Fujian Medical University	Fuzhou	Fujian	China
5	Guangdong Provincial People's Hospital	Guangzhou	Guangdong	China
6	Sun Yat-sen Memorial Hospital	Guangzhou	Guangdong	China
7	Hainan People's Hospital	Haikou	Hainan	China
8	Hebei Tumor Hospital	Shijiazhuang	Hebei	China
9	Harbin Medical University Cancer Hospital	Harbin	Heilongjiang	China
10	Henan Cancer Hospital	Zhengzhou	Henan	China
11	Wuhan Tongji Hospital	Wuhan	Hubei	China
12	Hunan Cancer Hospital	Changsha	Hunan	China
13	Jiangsu Provincial People's Hospital	Nanjing	Jiangsu	China
14	The Third Affiliated Hospital of Nanchang University	Nanchang	Jiangxi	China
15	First Hospital of Jilin University	Changchun	Jilin	China
16	First Hospital of China Medical University	Shenyang	Lining	China
17	First Affiliated Hospital of Qingdao University	Qingdao	Shandong	China
18	Fudan University Shanghai Cancer Center	Shanghai	Shanghai	China
19	Tianjin Medical University Cancer Institute and Hospital	Tianjin	Tianjin	China
20	The Third Affiliated Hospital of Kunming Medical College	Kunming	Yunnan	China
21	Zhejiang Cancer Hospital	Hangzhou	Zhejiang	China