Primary Chemotherapy With Docetaxel-Capecitabine and Doxorubicin-Cyclophosphamide in Breast Cancer

Study Overview
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Brief Summary
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This study will assess the usefulness of a technique called complementary deoxyribonucleic acid (cDNA) microarray-an examination of a wide array of genes to identify disease-associated patterns-for measuring tumor response to chemotherapy in breast cancer patients. The study will look for markers that can help select the most effective type of chemotherapy. It will also evaluate the safety and effectiveness of a new drug combination of capecitabine and docetaxel. Patients age 18 years and older with stage II or III breast cancer whose tumor is 2 centimeters or larger may be eligible for this study. Those enrolled will be treated with surgery, standard chemotherapy using doxorubicin (Adriamycin) and cyclophosphamide (Cytoxan), and the capecitabine and docetaxel combination. Patients will have a physical examination, mammogram and magnetic resonance imaging to evaluate their tumor before beginning treatment. They will then have four 21-day treatment cycles of docetaxel and capecitabine, as follows: docetaxel intravenously (through a vein) on day 1 and capecitabine pills (by mouth) twice a day from days 2 through 15. No drugs will be given from days 16 through 21. This regimen will be repeated four times, after which the tumor will be re-evaluated by physical examination, mammogram, and magnetic resonance imaging. Patients will then have surgery to remove the cancer-either lumpectomy with removal of the underarm lymph nodes; mastectomy and removal of the underarm lymph nodes; or modified radical mastectomy. After recovery, they will have four more cycles of chemotherapy, this time with a doxorubicin and cyclophosphamide. Both drugs will be given intravenously on day 1 of four 21-day cycles. Some patients who had a mastectomy (depending on their tumor characteristics and whether tumor cells were found in their lymph nodes) and all those who had a lumpectomy will also have radiation therapy. Patients with hormone receptor-positive tumors will also receive tamoxifen treatment for 5 years. In addition to the above procedures, all patients will have tumor biopsies (removal of a small piece of tumor tissue) before beginning treatment, on day 1 of cycle 1, before cycle 2, and at the time of surgery, and physical examinations, chest X-rays, bone scans, computerized tomography (CT) scans, electrocardiograms, multi-gated acquisition scan-MUGA (nuclear medicine test of cardiac function) or echocardiograms of heart function, mammograms and blood tests at various times during the study. Patients will be followed at National Institutes of Health (NIH) for 3 years after diagnosis with physical examinations, blood tests, X-rays, and computed tomography (CT) scans. Although it is not known whether this treatment will help an individual patient's cancer, possible benefits are tumor shrinkage and decreased risk of disease recurrence. In addition, the information gained about genetic changes after chemotherapy will help determine if additional studies on the use of cDNA microarray to measure tumor response are warranted.

Detailed Description
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This phase II trial in patients with stage II and stage III breast cancer will test the feasibility of using cDNA microarray as a measure of a tumor's biological response to chemotherapeutic agents by characterizing the cDNA expression patterns in breast cancer before and after primary chemotherapy. Thirty-six patients receive docetaxel/capecitabine induction chemotherapy followed by surgery and doxorubicin/cyclophosphamide adjuvant therapy (TX/AC). We will determine the response rate of TX induction therapy and the toxicities of the sequential combinations (TX/AC). We will also obtain tumor tissue for correlative biological determinations.

Official Title
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A Pilot Trial of Sequential Primary (Neoadjuvant) Combination Chemotherapy With Docetaxel/Capecitabine (TX) and Doxorubicin/Cyclophosphamide (AC) in Primary Breast Cancer With Evaluation of Chemotherapy Effects on Gene Expression

Conditions
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Breast Cancer, Breast Neoplasm

Intervention / Treatment
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* Drug: Docetaxel - Dose A
* Drug: Anastrozole
* Drug: cyclophosphamide
* Drug: Docetaxel - Dose B
* Drug: Doxorubicin hydrochloride
* Drug: Tamoxifen Citrate
* Drug: Capecitabine - Dose B
* Drug: Capecitabine - Dose A


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Stage II or III breast cancer with a tumor size of greater than 2 cm. Patients with a previous biopsy are eligible provided adequate tumor tissue remains for biopsy in this study. At least 18 years of age. Adequate hematopoietic function as defined by absolute neutrophil count greater than 1200/mm^3 and platelet count greater than 100,000/mm^3. Adequate renal function as defined by creatinine less than 1.6 mg/dL. Adequate hepatic function as defined by total (T.) bilirubin less than 1.4 mg/dL and serum glutamic oxaloacetic transaminase (SGOT)/serum glutamic pyruvic transaminase (SGPT) less than 1.5 times the upper limit of normal and alkaline phosphatase less than 2.5 times upper limit of normal Zubrod Performance status 0-2. EXCLUSION CRITERIA: Medical or psychiatric condition that, in the opinion of the Principal Investigator, would preclude chemotherapy administration. Patients may be evaluated by psychiatry or medical subspecialties as appropriate. Pregnant or lactating women Known bleeding disorders Hypersensitivity to Tween 80 (Polysorbate) Cardiac ejection fraction below normal limits, myocardial infarction within the past 12 months, or symptomatic arrhythmia requiring medical intervention. Prior chemotherapy or hormonal therapy for breast cancer. Patients treated with hormonal chemoprevention (tamoxifen or raloxifene) will be eligible. Active malignancy diagnosed within the last 5 years. (Cervical cancer or non-melanomatous skin cancer that has been treated with curative intent will be eligible).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose A-Cohort 1-Arm 1-Docetaxel & Capecitabine<br>Docetaxel 75 mg/m^2 intravenous day 1, capecitabine 1000 mg/m^2 orally twice daily day 2-15 for 4 cycles | Drug: Docetaxel - Dose A<br>* Dose A-Cohort 1 Docetaxel 75 mg/m^2 intravenous day 1<br>* Other names: Taxotere/Xeloda;Drug: Anastrozole<br>* 1 mg orally daily for five years<br>* Other names: Arimidex;Drug: cyclophosphamide<br>* 600 mg/m^2 will be diluted in 100 mL 0.9% normal saline (NS) and administered intravenously over 30 minutes on day 1<br>* Other names: Cytoxan;Drug: Doxorubicin hydrochloride<br>* 60 mg/m^2 will be administered as a slow intravenous push on day 1<br>* Other names: Adriamycin;Drug: Tamoxifen Citrate<br>* 20 mg/day orally for five years<br>* Other names: Nolvadex;Drug: Capecitabine - Dose A<br>* capecitabine 1000 mg/m^2 orally twice daily day 2-15 for 4 cycles<br>|
| Experimental: Dose B-Cohort 2-Arm 2 Reduced dose-Docetaxel & Capecitabine<br>Docetaxel 60 mg/m^2 intravenous day 1, capecitabine 937.5 mg/m^2 orally twice daily day 2-15 for 4 cycles | Drug: Anastrozole<br>* 1 mg orally daily for five years<br>* Other names: Arimidex;Drug: cyclophosphamide<br>* 600 mg/m^2 will be diluted in 100 mL 0.9% normal saline (NS) and administered intravenously over 30 minutes on day 1<br>* Other names: Cytoxan;Drug: Docetaxel - Dose B<br>* Dose B - Cohort 2 Docetaxel 60 mg/m^2 intravenous day 1<br>* Other names: Taxotere;Drug: Doxorubicin hydrochloride<br>* 60 mg/m^2 will be administered as a slow intravenous push on day 1<br>* Other names: Adriamycin;Drug: Tamoxifen Citrate<br>* 20 mg/day orally for five years<br>* Other names: Nolvadex;Drug: Capecitabine - Dose B<br>* Dose B - Cohort 2 capecitabine 937.5 mg/m^2 orally twice daily day 2-15<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events | Here is the number of participants with adverse events. For the detailed list of adverse events see the adverse event module. | 6 years | 
| Overall Clinical Response Rate | Overall response rate is defined as the percentage of participants with a CR (complete disappearance of all target lesions), PR (a 30% decrease in the sum of the longest diameter of target lesions) determined by clinical measurements per the Response Evaluation Criteria in Solid Tumors (RECIST) and/or a complete pathologic response (disappearance of all invasive tumor pathologically or presence of ductal carcinoma in situ) per the Chevallier criteria. For details about the RECIST or Chevallier criteria see the protocol link module. | 6 years | 
| Complementary Deoxyribonucleic Acid (cDNA) Expression | Patients were classified as responders or non-responders based on change in tumor size by clinical exam and pathologic response.For instance, patients with a pathological complete response, micro-invasive disease at surgery, or clinical complete response after four cycles of treatment were considered responders. Changes in gene expression associated with treatment was assessed before/after chemotherapy. All gene expression summary intensities below 50 were thresholded to the value of 50 and genes showing variability significantly smaller than the median gene variability were screened out. | 6 years | 
| Number of Participants, e.g. Responders and Non-responders With a Percent Change in Expression Patterns After Chemotherapy With Changes in Expression Patterns After Chemotherapy in Preclinical Models | Patients were classified as responders or non-responders based on change in tumor size by clinical exam and pathologic response.For instance, patients with a pathological complete response, micro-invasive disease at surgery, or clinical complete response after four cycles of treatment were considered responders. Changes in gene expression associated with treatment was assessed before/after chemotherapy. All gene expression summary intensities below 50 were thresholded to the value of 50 and genes showing variability significantly smaller than the median gene variability were screened out. | 6 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cDNA Microarray, Stage II and Stage III Breast Cancer, Biological Response, Molecular Profiling, Fine Needle Aspirate, Breast Cancer