Comparative Study on Two Post-operative Adjuvant Chemotherapy Regimens for Treating Triple-negative Breast Cancer

Study Overview
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Brief Summary
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Recent clinical studies showed that triple-negative breast cancer patients (ER-/PR-/HER2-) may benefit more from Capecitabine chemotherapy. However, the optimum post-operative adjuvant Capecitabine chemotherapy regimen has not been determined for Chinese population with triple-negative breast cancer. Thus it's necessary to conduct a multi-center Phase III clinical trial to verify efficacy and safety of Capecitabine in the treatment of triple-negative breast cancer. In this study, a prospective, randomized, open, multi-center Phase III clinical study was conducted to compare efficacy and safety of sequential Docetaxel followed by Fluorouracil/Epirubicin/Cyclophosphamide (FEC) and sequential Docetaxel and Capecitabine followed by Capecitabine/Epirubicin/Cyclophosphamide (XEC) as post-operative adjuvant chemotherapy in the treatment of triple-negative breast cancer in Chinese population.

Detailed Description
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Post-operative adjuvant chemotherapy has been shown to improve overall survival, delay local relapse and reduce distant metastasis by multiple large-scale prospective clinical trial. In registry clinical trial for Capecitabine conducted by O Shaughnessy, it revealed that a combined chemotherapy of Capecitabine and Docetaxel achieved better outcomes compared with Docetaxel alone. And the significant effect of Capecitabine was also evidenced by CHAT trial in which Trastuzumab/Docetaxel/Capecitabine regimen was proved to perform greater than Trastuzumab/Docetaxel regimen. In addition to better outcomes, Capecitabine also showed good tolerance and safety profile. In 2009, Finnish Breast Cancer Group published their study results from FinXX clinical trial on Lancet Oncology, and in this trial, they compared the efficacy between sequential Docetaxel (3 cycles) followed by 3 cycles of Fluorouracil/Epirubicin/Cyclophosphamide (FEC) and sequential Docetaxel and Capecitabine (3 cycles) followed by 3 cycles of Capecitabine/Epirubicin/Cyclophosphamide (XEC) in lymph positive or high-risk lymph negative early-stage breast cancer patients. And their results showed a better outcome in TX-XEC regimen. 5-year follow-up analysis of this trial revealed that combined Capecitabine regimen can bring more significant clinical benefits to triple-negative breast cancer patients. Another clinical trial NO1062 released their preliminary results on comparison of AC-T and AC-XT regimens and it showed that combined Capecitabine regimen can significantly improve overall survival and this effect is more obvious in triple--negative breast cancer patients. Based on the results of FinXX and NO1062, it's of great value to optimize combined Capecitabine regimen and clarify involved questions, such as whether the efficacy of Capecitabine is related to its treatment course or not, whether Capecitabine should be combined into current standardized chemotherapy or a sequential therapy. Also, there are still no clear conclusions on the best post-operative adjuvant chemotherapy for triple--negative breast cancer patients. Especially in Chinese population, the efficacy and safety of Capecitabine in adjuvant chemotherapy has not been well established. So it's necessary to explore reasonable dosage, safety profile and efficacy of combined Capecitabine therapy. Based on this purpose, this study is hoped to compare efficacy and safety of sequential Docetaxel followed by Fluorouracil/Epirubicin/Cyclophosphamide (FEC) and sequential Docetaxel and Capecitabine followed by Capecitabine/Epirubicin/Cyclophosphamide (XEC) as post-operative adjuvant chemotherapy in the treatment of triple-negative breast cancer in Chinese population.

Official Title
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A Prospective, Randomized, Open, Multi-center Phase III Clinical Study Comparing Efficacy and Safety of Sequential T-FEC and TX-XEC as Post-operative Adjuvant Chemotherapy Options for the Treatment of Triple-negative Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: 5-Fu/epirubicin/CTX following Docetaxel
* Drug: Docetaxel/capecitabine followed by XEC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female aged 18 - 70 years old; Histological confirmed with unilateral invasive carcinoma (all pathological types are applicable); Newly diagnosed conditions allowing direct surgery without any absolute contraindication for surgery; No mass or microscopic tumor residue after surgery resection; Initiate adjuvant chemotherapy within 30 days after surgery; Axillary lymph node positive (including the sentinel lymph node positive and lymph node positive after axillary dissection), for example, axillary lymph node negative requires that primary tumor size must be greater than 1cm; Definite reports on ER/PR/Her2 receptor showing all ER/PR/Her2 negative (specific definitions: immunohistochemical detection of ER <10% tumor cells is defined as ER negative, PR <10% positive tumor cells is defined as PR-negative, Her2 is 0 1+ or 2+ but determined negative via FISH or CISH detected (no amplification) is defined as Her2 negative); No relevant clinical or imaging evidence of metastasis showing in the preoperative examination (M0); Without peripheral neuropathy; ECOG performance score is 0 or 1; Postoperative recovery was good and an interval of at least one week since the surgery is necessary; White blood cell count> 4 × 10^9/l, neutrophil count> 2 × 10^9/l, platelet count> 100 × 10^9/l and hemoglobin 9g/dl); ASAT and ALAT <1.5 folds of the upper limit of normal values, alkaline phosphatase <2.5 folds of the upper limit of normal values, total bilirubin <1.5 folds of the upper limit of normal values; Serum creatinine <1.5 folds of the upper limit of normal value; Women at childbearing age should take contraception measures during treatment; Cardiac function: echocardiographic examination showed LEVF> 50%; Informed consent form signed. - Exclusion Criteria: Bilateral breast cancer or carcinoma in situ (DCIS / LCIS); Metastasis at any location; Any tumor > T4a (UICC1987) (accompanied by skin involvement, lump adhesion and fixation, inflammatory breast cancer); Any of ER, PR or Her-2 is positive; Contralateral breast clinically or radiologically suspected to be malignant but not confirmed which needs a biopsy; Previous neoadjuvant therapy, including chemotherapy, radiotherapy and hormone therapy; Previously suffering from malignant tumors (except for basal cell carcinoma and cervical carcinoma in situ), including contralateral breast cancer; Already enrolled into other clinical trials; Severe systemic disease and/or uncontrollable infection, unable to be enrolled in this study LEVF <50% (echocardiography); Suffering from severe cardiovascular and cerebrovascular diseases within six months before the randomization (such as: unstable angina, chronic heart failure, uncontrollable high blood pressure > 150/90mmHg, myocardial infarction or brain vascular accident); Known allergic to taxane and anthracycline agents; Women at childbearing age refuse to take contraception measures during the treatment and 8 weeks after completion of treatment; Pregnant and breast-feeding women; Pregnancy test showed positive results before drug administration after enrolling in to the study; With mental illness and cognitive impairment, unable to understand trial protocol and side effects and complete trial protocol and follow-ups (systematic evaluation is required before recruiting into this study); Without personal freedom and independent civil capacity.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 5-Fu/epirubicin/CTX following Docetaxel<br>Docetaxel for the first 3 cycles of chemotherapy followed by 3 cycles of FEC (Fluorouracil, epirubicin and cyclophosphamide) chemotherapy | Drug: 5-Fu/epirubicin/CTX following Docetaxel<br>* Cycle 1-3: Docetaxel i.v. 75mg/m2 (One cycle = 21 days); Cycle 4-6: Fluorouracil i.v. 500 mg/m2, Epirubicin i.v. 75 mg/m2, Cyclophosphamide i.v. 500 mg/m2 (One cycle = 21 days)<br>* Other names: Fluorouracil: 5-Fu;|
| Experimental: Docetaxel/capecitabine followed by XEC<br>Docetaxel/ capecitabine (TX) for the first 3 cycles of chemotherapy followed by 3 cycles of capecitabine/epirubicin/cyclophosphamide (XEC) chemotherapy | Drug: Docetaxel/capecitabine followed by XEC<br>* Cycle 1-3: Docetaxel i.v. 75 mg/m2, Capecitabine, p.o., 1000 mg/m2，b.i.d (take Capecitabine for 2 weeks and withdraw for 1 week) (One cycle = 21 days); Cycle 4-6: Capecitabine, i.v. 1000 mg/m2, b.i.d (take for 2 weeks and withdraw for 1 week),Epirubicin, i.v. 75 mg/m2, Cyclophosphamide, i.v. 500 mg/m2 (One cycle = 21 days)<br>* Other names: Capecitabine: Xeloda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 5-year disease free survival | Including local relapse, distant metastasis, contralateral breast cancer, second primary cancer or death from any cause | 5 year after the completion of chemotherapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Adverse Events as a Measure of Safety | Safety will be evaluated based on adverse events observed and the number of participants with adverse events. Blood biological tests shall also be conducted for further examination. | Within 5 years after the completion of chemotherapy | 
| FACT-B scale scores as a Measure of living quality | FACT-B scale scores of participants would be assessed to reflect their living quality. | Baseline, Week 0 | 
| 5-year relapse free survival, distant disease free survival and overall survival as measures of efficacy | Disease relapse shall be considered as the endpoint of relapse free survival and the period between surgery and disease relapse shall be recorded as a measure of efficacy. Also disease distant metastasis shall be considered as the endpoint of distant disease free survival and the period between surgery and Disease distant metastasis shall be recorded as a measure of efficacy. | Within 5 years after the completion of chemotherapy | 
| FACT-B scale scores as a Measure of living quality | FACT-B scale scores of participants would be assessed to reflect their living quality. | Week 9 | 
| FACT-B scale scores as a Measure of living quality | FACT-B scale scores of participants would be assessed to reflect their living quality. | Week 18 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Triple-negative Breast Cancer, Post-operative adjuvant Chemotherapy, Docetaxel, Capecitabine, Epirubicin, Cyclophosphamide, Fluorouracil