Hormone Therapy and Combination Chemotherapy Before and After Surgery in Treating Patients With Stage I-IIIA Breast Cancer

Study Overview
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Brief Summary
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This phase II trial is studying how well giving hormone therapy together with combination chemotherapy before and after surgery works in treating patients with stage I-IIIA breast cancer. Estrogen can cause the growth of breast cancer cells. Hormone therapy using exemestane and triptorelin pamoate may fight breast cancer by lowering the amount of estrogen the body makes. Drugs used in chemotherapy, such as capecitabine, methotrexate, vinorelbine ditartrate, and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving hormone therapy together with combination chemotherapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving these treatments after surgery may kill any tumor cells that remain after surgery

Detailed Description
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PRIMARY OBJECTIVES: I. To assess the pathologic response rate in patients with operable breast cancer treated with a two part, neoadjuvant regimen consisting of complete hormonal blockade (CHB) for 2 weeks followed by four three-week cycles of Xeloda, Methotrexate and Navelbine with continuation of complete hormonal blockade. SECONDARY OBJECTIVES: I. To assess the clinical response rate in patients with surgically resectable breast cancer treated with complete hormonal blockade and four three-week cycles of Xeloda, Methotrexate and Navelbine. II. To assess the toxicity associated with these regimens. III. To assess the relapse rate, overall and disease-free survival in patients with operable breast cancer when treated with neoadjuvant CHB and XMN + CHB followed by adjuvant treatment using XMN or Taxol. IV. To assess whether the phenotype of breast cancer changes with treatment. V. To assess whether phenotypic changes in breast tumors predict outcome. OUTLINE: NEOADJUVANT CHB: Patients receive exemestane orally (PO) daily for 14 weeks. Premenopausal patients also receive triptorelin pamoate intramuscularly (IM) once monthly for 4 months beginning 2 weeks before the initiation of exemestane. NEOADJUVANT CHEMOTHERAPY: Patients receive capecitabine PO twice daily (BID) on days 1-14 and methotrexate intravenously (IV) and vinorelbine ditartrate IV over 6-10 minutes on days 1, 8, and 15. Treatment repeats every 21 days for 4 courses. SURGERY: Patients then undergo definitive surgical resection with or without radiation therapy. ADJUVANT CHEMOTHERAPY: Patients with microscopic complete response (pCR) or disease that has been down-staged to =< 1 cm with no positive nodes receive capecitabine PO BID on days 1-14 and methotrexate IV and vinorelbine ditartrate IV over 6-10 minutes on days 1, 8, and 15. Treatment repeats every 21 days for 4 courses. Patients with down-staged T and 0 or 1 positive node receive paclitaxel IV over 1 hour once weekly for 12 weeks. ADJUVANT HORMONAL THERAPY: Patients receive hormonal therapy for 5 years. Treatment continues in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed every 3 months for 3 years, every 6 months for 2 years, and then annually thereafter.

Official Title
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Neoadjuvant Complete Hormonal Blockade Followed by Neoadjuvant Chemotherapy for Resectable Hormone Receptor Positive, HER-2/Neu Negative Breast Cancer, A Phase II Study

Conditions
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Estrogen Receptor-positive Breast Cancer, HER2-negative Breast Cancer, Progesterone Receptor-positive Breast Cancer, Stage I Breast Cancer, Stage II Breast Cancer, Stage IIIA Breast Cancer

Intervention / Treatment
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* Drug: exemestane
* Drug: triptorelin pamoate
* Drug: capecitabine
* Drug: methotrexate
* Drug: vinorelbine tartrate
* Drug: paclitaxel
* Procedure: therapeutic conventional surgery
* Radiation: radiation therapy
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have histologically confirmed, operable ER or PR +, HER2/neu negative, radiographically measurable breast cancer > 1cm (Operable lesions are T1c - T3 and N0 - N2a; histologic confirmation should be by core needle biopsy only) Be chemotherapy naive Have an ECOG performance status of =< 2 Be assessed for menopausal status (For study purposes, postmenopausal is defined as: a prior documented bilateral oophorectomy, or a history of at least 12 months without spontaneous menstrual bleeding, or age 60 or older with a prior hysterectomy without oophorectomy, or Age less than 60 with a prior hysterectomy without oophorectomy [or in whom the status of the ovaries is unknown], with a documented FSH level demonstrating confirmatory elevation in the postmenopausal range for the lab) All premenopausal patients must have a baseline FSH and LH ANC >= 1,500 Platelet count >= 100,000 Serum creatinine =< 1.5 x IULN Estimated creatinine clearance > 50 ml/min Have staging studies and tumor assessment prior to registration Bone density exam must be done within the first 3 months of complete hormonal blockade Have a negative pregnancy test within seven days prior to registration if of childbearing potential Be informed of the investigational nature of this study and provide written informed consent in accordance with institutional and federal guidelines prior to study specific screening procedures Exclusion Criteria: Primary tumor =< 1 cm, not measurable; inflammatory disease Pregnant or lactating; women of childbearing potential with either a positive or no pregnancy test at baseline are excluded (Women of childbearing potential who are not using a reliable and appropriate contraceptive method are excluded; patients must agree to continue contraception for 30 days from the last study drug administration) Prior unanticipated severe reaction to fluoropyrimidine therapy, or known sensitivity to 5-fluorouracil Previous enrollment in an investigational drug study within the last 4 weeks Evidence of distant metastatic disease Prior chemotherapy or hormonal therapy for breast cancer Prior malignancy other than adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, other stage I or II cancer from which the patient has been disease free for at least 5 years History of uncontrolled seizures, central nervous system disorders, or psychiatric disability judged by the investigator to be clinically significant, precluding informed consent, or interfering with compliance with oral drug intake Any other life-threatening illness (e.g. serious, uncontrolled concurrent infection or clinically significant cardiac disease - congestive heart failure, symptomatic coronary artery disease, cardiac arrhythmia not well controlled with medication or myocardial infarction Major surgery within four weeks of the start of study treatment without complete recovery Lack of physical integrity of the upper gastrointestinal tract or malabsorption syndrome Known, existing uncontrolled coagulopathy Unwillingness to give informed consent Unwillingness to participate or inability to comply with the protocol for the duration of the study

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (hormone therapy and chemotherapy)<br>See detailed description | Drug: exemestane<br>* Given PO<br>* Other names: PNU 155971;Drug: triptorelin pamoate<br>* Given IM<br>* Other names: Trelstar Depot;Drug: capecitabine<br>* Given PO<br>* Other names: Xeloda;Drug: methotrexate<br>* Given IV<br>* Other names: MTX;Drug: vinorelbine tartrate<br>* Given IV<br>* Other names: VNB;Drug: paclitaxel<br>* Given IV<br>* Other names: Taxol;Procedure: therapeutic conventional surgery<br>* Undergo lumpectomy or mastectomy<br>Radiation: radiation therapy<br>* Undergo radiation therapy<br>* Other names: therapy, radiation;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Clinical Response | Defined as a > 50% decrease in sum of the products of the perpendicular diameters of bidimensionally measurable disease. | 1 month | 
| Number of Participants With Microscopic Pathologic Complete Response and Macroscopic Pathologic Complete Response | Defined as no evidence of microscopic invasive tumor at the primary site or in the regional lymph nodes at the time of definitive surgical resection and the examining pathologist cannot identify gross residual tumor mass in the surgical specimen. | From date of treatment start to surgery | 
| Disease-free Survival | Kaplan-Meier estimate assessed at 5 years | Up to 5 years | 
| Overall Survival | From the start of protocol therapy until the date of death from any cause or the last date the patient was known to be alive. Kaplan-Meier estimate assessed at 5 years. | Up to 5 years | 
| Quantification of All Grade 2, 3, 4 Adverse Events or Fatal Toxicities | Count of all incidences of grade 2, 3, 4 adverse events and fatal toxicities | Monthly during neoadjuvant treatment and then 6 months following treatment (including surgery) | 
| Number of Participants With Dose Reduction, Treatment Interruption, or Treatment Discontinuation | Count of patients with dose reduction, treatment interruption, or treatment discontinuation. | During adjuvant and neoadjuvant chemotherapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlation of Molecular Markers With Response, Time to Progression, and Survival |  | Weekly during CHB and XMN and pacitaxel |