A Study to Evaluate Exemestane Tablets Combined With Ovarian Function Suppression/Ablation in Treatment of Premenopausal Breast Cancer Patients With CYP2D6*10 Mutations （STEP） (STEP)

A Study to Evaluate Exemestane Tablets Combined With Ovarian Function Suppression/Ablation in Treatment of Premenopausal Breast Cancer Patients With CYP2D6*10 Mutations （STEP）

A Randomized Controlled Study to Evaluate Exemestane Tablets Combined With Ovarian Function Suppression/Ablation in Treatment of Premenopausal Breast Cancer Patients With CYP2D6*10 Mutations （STEP）

This is a multicenter, randomized, open-label, parallel, active-controlled superiority clinical study conducted in early premenopausal estrogen-receptor positive breast cancer patients with CYP2D6*10 mutations. The efficacy and safety of Exemestane Tablets combined with ovarian function suppression/ablation and Tamoxifen Tablets combined with ovarian function suppression/ablation in the treatment of early premenopausal estrogen-receptor positive breast cancer patients with CYP2D6*10 mutations are compared.

The target population for this study is early stage premenopausal estrogen-receptor positive breast cancer patients with CYP2D6*10 mutations. All the potential subjects must provide the informed consent. The subjects who provide the informed consent form (ICF) will enter the screening period, and will be evaluated for the eligibility. This study expects to enroll 300 subjects, eligible subjects will be randomized at a ratio of 1:1 into treatment group (Exemestane Tablets combined with ovarian function suppression/ablation) or control group (Tamoxifen Tablets combined with ovarian function suppression/ablation). The subjects who are assigned to treatment group will receive Exemestane Tablet combined with ovarian function suppression/ablation, Exemestane Tablets orally, once a day, one tablet each time (25 mg) and to be taken within 8 weeks from receiving ovarian function suppression treatment or after bilateral ovariectomy, and continue for 5 years or until endpoint event occurs. If the patients are not treated for 5 years because of adverse events (AE) or other reasons, the patient should be followed up until 5 years. The subjects who are assigned to the control group will receive Tamoxifen Tablets combined with ovarian function suppression/ablation, Tamoxifen Tablets orally, twice a day, one tablet each time (10mg) and to be taken within 8 weeks from receiving ovarian function suppression treatment or after bilateral ovariectomy, and continue for 5 years or until endpoint event occurs. If the patients are not treated for 5 years because of adverse events (AE) or other reasons, the patient should be followed up until 5 years. The treatment regimen of ovarian function suppression/ablation is as follows: Gonadotropin-releasing hormone analogue Goserelin Injection 3.6mg or Leuprorelin Injection 3.75 mg, a subcutaneous injection will be done every 28±2 days, or bilateral ovariectomy. According to clinical practice of adjuvant endocrine therapy for Chinese patients with breast cancer, safety and effectiveness of all patients will be evaluated once every 3 months within 2 years after receiving the study treatment, every 6 months in 3 and 4 years, every 12 months in 5 years and 30 days after treatment discontinuation. After randomization, all patients should be regularly checked for signs, symptoms, and evidence of disease recurrence by collecting their medical history, physical examination, and local examination of the breast (specialized physical examination and/or imaging examination). Patients are advised to take a bone mineral density test once a year within five years from 6 months after randomization, and receive calcium or phosphate correspondingly based on the condition. Throughout the study, the adverse events need to be closely monitored, and the frequency and severity of adverse events are recorded as well. The study results will be statistically analyzed after the study to compare the efficacy and safety variables between the two groups, thus, the superiority of Exemestane Tablets combined with ovarian function suppression/ablation to Tamoxifen Tablets combined with ovarian function suppression/ablation in disease-free survival (DFS) will be demonstrated. Stratified analyses according to lymph-node status and age.

Gonadotropin-releasing hormone analogue Goserelin Injection 3.6mg or Leuprorelin Injection 3.75 mg, a subcutaneous injection should be done every 28±2 days; or Bilateral ovariectomy.

It is defined as the time from randomization to the first breast cancer local/distant recurrence, the new breast cancer of the contralateral breast, second primary cancer and the death caused by any reason

the first breast cancer local/distant recurrence, the new breast cancer of the contralateral breast, second primary cancer and the death caused by any reason in 5 years

Recurrence rate (local or distant) is defined as breast cancer local or distant recurrence rate in patients from two groups

It will be conducted once every 3 months in the first 2 years during the treatment period, every 6 months in 3 and 4 years, every 12 months in 5 years

It will be conducted once every 3 months in the first 2 years during the treatment period, every 6 months in 3 and 4 years, every 12 months in 5 years

Results of AE/serious adverse event (SAE), clinical lab tests, 12 lead ECG, vital signs and physical examination will be evaluated throughout the study to monitor the safety of subjects

It will be conducted once every 3 months in the first 2 years during the treatment period, every 6 months in 3 and 4 years, every 12 months in 5 years

Breast cancer free survival is defined as the time from randomization to the first observation of breast cancer local/distant recurrence or occurrence of contralateral breast cancer

It will be conducted once every 3 months in the first 2 years during the treatment period, every 6 months in 3 and 4 years, every 12 months in 5 years

Distant relapse free survival is defined as the time from randomization to the first observation of breast cancer distant recurrence

It will be conducted once every 3 months in the first 2 years during the treatment period, every 6 months in 3 and 4 years, every 12 months in 5 years

The occurrence rate of the contralateral breast cancer is defined as contralateral breast cancer occurrence rate in patients from two groups after randomization

It will be conducted once every 3 months in the first 2 years during the treatment period, every 6 months in 3 and 4 years, every 12 months in 5 years

It will be conducted once every 3 months in the first 2 years during the treatment period, every 6 months in 3 and 4 years, every 12 months in 5 years

Inclusion Criteria: Providing informed consent forms voluntarily before screening evaluation; For Chinese premenopausal women, her estradiol level must be within the premenopausal level, or the patient meet the following 4 criteria in the prior 6 months: No chemotherapy, Regular menstruation, No use of hormonal, contraceptives, No use of hormone for treatment or for temporary amenorrhea caused by chemotherapy, the estradiol level tested within 8 months after the last dose of chemotherapeutics is within the premenopausal level; Patients with invasive breast cancer which has been confirmed by histological examination; Complete removal of tumor by surgery without local residual; Neoadjuvant chemotherapy before surgery is permitted if the surgery for primary breast cancer is performed within 12 weeks without any further adjuvant chemotherapy, or adjuvant chemotherapy is completed within 8 months; Estrogen receptor (ER) and/or progesterone receptor (PR) positive: If the patient has more than one breast tumor lesions, each tumor lesion should be ER and/or PR positive. Her-2 negative; Genotyping test performed by the central laboratory designated by sponsor with the results confirmed as CYP2D6*10T/T gene mutation. Women of childbearing age with negative serum pregnancy test result, and agreeing to adopt highly efficient non-hormonal contraception measure throughout the study; Subject without major organ dysfunction, and with normal heart, liver, kidney, lung and other major organ function. Exclusion Criteria: Inflammatory breast cancer; Breast cancer patients with supraclavicular lymph nodes metastasis; Patients with enlarged internal mammary lymph nodes (except for patients with negative pathologic findings); Ovariectomy which is not specified in the study; Patients with ovary protection during the chemotherapy; Concomitant use of other aromatase inhibitors (not Exemestane); Received major surgery which was unrelated to breast cancer within four weeks before randomization, or the patients had not yet fully recovered from such surgery; Pregnant or lactating women; Known active hepatitis B or hepatitis C or HIV; Having difficulty in swallowing oral preparations and gastrointestinal dysfunction; Recently had severe and uncontrolled systemic diseases (e.g.: cardiovascular disease, lung disease, or metabolic disease, venous thrombosis with clinical significance); Currently or previously suffering from other malignant tumors (except for skin basal cell carcinoma or squamous cell carcinoma, carcinoma in situ of cervix which had been fully treated), unless a radical treatment had been done with the evidence of no-recurrence or metastasis in nearly five years; Allergic to any study drug or any ingredients of drug; Patient with poor compliance or other conditions which makes the patient unsuitable to participate in this study judged by the investigator.

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