Combination Chemotherapy and Filgrastim Before Surgery in Treating Patients With HER2-Positive Breast Cancer That Can Be Removed By Surgery

Study Overview
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Brief Summary
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This phase II trial studies how well giving combination chemotherapy and filgrastim together before surgery works in treating patients with human epidermal growth receptor 2 (HER2)-positive breast cancer that can be removed by surgery. Drugs used in chemotherapy, such as doxorubicin hydrochloride, cyclophosphamide, 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 combination chemotherapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Colony-stimulating factors, such as filgrastim, may increase the number of immune cells found in bone marrow or peripheral blood and may help the immune system recover from the side effects of chemotherapy. Giving doxorubicin hydrochloride, cyclophosphamide, and filgrastim together followed by paclitaxel before surgery may be an effective treatment for breast cancer

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 weekly doxorubicin (doxorubicin hydrochloride) and daily oral cyclophosphamide given with G-CSF (filgrastim) support for 12 weeks followed weekly paclitaxel for 12 weeks. SECONDARY OBJECTIVES: I. To assess the clinical response rate in patients with surgically resectable breast cancer treated with weekly doxorubicin and daily oral cyclophosphamide given with G-CSF support for 12 weeks. II. To assess the clinical response rate in patients with surgically resectable breast cancer treated with weekly paclitaxel for 12 weeks. III. To assess the relapse rate, overall and disease-free survival in patients with operable breast cancer treated with neoadjuvant chemotherapy consisting of weekly doxorubicin and daily oral cyclophosphamide given with G-CSF support for 12 weeks followed weekly paclitaxel for 12 weeks and adjuvant chemotherapy with Xeloda (capecitabine), Methotrexate and Navelbine (vinorelbine tartrate) (XMN). IV. To assess the toxicity associated with these regimens. V. To assess whether the phenotype of breast cancer changes with treatment. VI. To assess whether phenotypic changes in breast tumors predict outcome. OUTLINE: PART I: Patients receive doxorubicin hydrochloride intravenously (IV) on day 1 of each week, cyclophosphamide orally (PO) once daily (QD), and filgrastim subcutaneously (SC) QD on days 2-7 of each week. Treatment continues for 12 weeks in the absence of disease progression or unacceptable toxicity. PART II: Patients* receive paclitaxel IV over 1 hour on day 1 of each week. Treatment continues for 12 weeks in the absence of disease progression or unacceptable toxicity. Patients then undergo definitive surgical resection by partial mastectomy (lumpectomy) or mastectomy after completion of neoadjuvant chemotherapy. PART III: Patients** unable to achieve complete pathologic response (pCR) or disease that has been down-staged to =< 1 cm with no positive nodes following surgery receive capecitabine PO twice daily (BID) on days 1-14, methotrexate IV on days 1, 8 and 15, and vinorelbine tartrate IV over 6-10 minutes on days 1, 8, and 15. Treatment repeats every 3 weeks for 4 courses in the absence of disease progression or unacceptable toxicity. NOTE: *Patients with HER2/neu-positive disease also receive trastuzumab IV over 30-90 minutes once weekly or every 3 weeks for 1 year beginning in Part II. NOTE: **Patients with hormone receptor-positive disease also receive tamoxifen PO QD for 5 years (premenopausal) OR letozole PO QD or tamoxifen PO QD for 5 years (postmenopausal) beginning in Part III. After completion of study treatment, patients are followed up every 3 months for 3 years, every 6 months for 2 years, and then annually thereafter.

Official Title
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A Study of Weekly Doxorubicin and Daily Oral Cyclophosphamide Plus G-CSF Followed by Weekly Paclitaxel as Neoadjuvant Therapy for Resectable, Hormone Receptor Negative or Hormone Receptor Positive, HER-2/Neu Positive Breast Cancer Followed by a Novel Regimen of Capecitabine, Methotrexate and Vinorelbine for Patients Who Do Not Have Either a Macroscopic or Microscopic Pathologic Complete Response, a Phase II Study

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

Intervention / Treatment
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* Drug: doxorubicin hydrochloride
* Drug: cyclophosphamide
* Drug: paclitaxel
* Biological: filgrastim
* Drug: capecitabine
* Drug: methotrexate
* Drug: vinorelbine tartrate
* Procedure: needle biopsy
* Procedure: therapeutic conventional surgery
* Other: immunohistochemistry staining method
* Biological: trastuzumab
* Drug: tamoxifen citrate
* Drug: letrozole
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have known tumor HER-2/neu expression; if determination is intermediate by immunohistochemistry, fluorescent in situ hybridization (FISH) must be performed; protocol therapy is determined by HER-2/neu result Have histologically confirmed, operable breast cancer that is either: Hormone receptor (estrogen receptor [ER] or progesterone receptor [PR]) positive and HER2/neu positive or ER/PR negative Have radiographically measurable breast cancer > 1cm (Operable lesions are T1c-T3 and N0-N2a; histologic confirmation should be by core needle biopsy only) Be chemotherapy naïve Eastern Cooperative Oncology Group (ECOG) performance status of =< 2 Absolute neutrophil count (ANC) >= 1,500 Platelet count >= 100,000 Serum creatinine =< 1.5 x international upper limit of normal (IULN) Bilirubin < 2.0 Serum glutamic oxaloacetic transaminase (SGOT)/serum glutamic pyruvate transaminase (SGPT) =< 2 x IULN Alkaline phosphatase =< 2 x IULN Have staging studies and tumor assessment prior to registration; staging studies include physical exam with bidimensional tumor measurements and mammography, ultrasound, or magnetic resonance imaging (MRI) to assess tumor volume; sentinel lymph node dissection or axillary needle biopsy must be completed prior to enrollment; MRI and positron emission tomography (PET) (fluorodeoxyglucose [FDG], methoxyisobutylisonitrile [MIBI] and fluoroestradiol [FES]) imaging will be done before enrollment if clinically indicated to assess tumor volume or may be done within the first month of study participation on another institutional protocol Patients with clinically apparent cardiac disease, or history of same, are not eligible; patients who are >= 60 years of age or who have a history of hypertension must have an echocardiogram or multi gated acquisition scan (MUGA) prior to enrollment; patients with breast cancer that is HER-2/neu positive who will receive herceptin (trastuzumab) must have an echocardiogram or MUGA scan; the left ventricular ejection fraction (LVEF) must be within the institutional normal range; if LVEF is > 75%, the investigator should consider having the LVEF reviewed or repeating the MUGA prior to registration Women of childbearing potential must have a negative pregnancy test within seven days prior to registration 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; woman of childbearing potential with either a positive or no pregnancy test at baseline are excluded; postmenopausal woman must have been amenorrheic for at least 12 months to be considered of non-childbearing potential; patients must agree to continue contraception for 30 days from the date of the last study drug administration; woman of childbearing potential not using a reliable and appropriate contraceptive method are excluded Evidence of distant metastatic disease Prior chemotherapy or hormonal therapy for breast cancer Except for the following no other malignancy is allowed: synchronous ipsilateral breast cancer of the same subtype (ER/PR, HER-2/neu), adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer or other stage I or II cancer from which the patient has been disease free for at least 5 years Prior unanticipated severe reaction to fluoropyrimidine therapy, or known sensitivity to 5-fluorouracil Previous enrollment in an investigational drug study within the past four weeks 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 Patients with cardiac disease that would preclude the use of Adriamycin, Taxol or Herceptin are not eligible Active cardiac disease: Angina pectoris that requires the use of antianginal medication Cardiac arrhythmia requiring medication Severe conduction abnormality Clinically significant valvular disease Cardiomegaly on chest x-ray Ventricular hypertrophy on electrocardiogram (EKG) Uncontrolled hypertension, (diastolic greater than 100 mm/Hg or systolic > 200 mm/hg) Current use of digitalis or beta blockers for congestive heart failure (CHF) Clinically significant pericardial effusion History of cardiac disease: Myocardial infarction documented as a clinical diagnosis or by EKG or any other test Documented congestive heart failure Documented cardiomyopathy Documented arrhythmia or cardiac valvular disease that requires medication or is medically significant Major surgery within 4 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 written 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 (neoadjuvant therapy, adjuvant therapy)<br>See Detailed Description. | Drug: doxorubicin hydrochloride<br>* Given IV<br>* Other names: Adriamycin RDF;Drug: cyclophosphamide<br>* Given PO<br>* Other names: Endoxana;Drug: paclitaxel<br>* Given IV<br>* Other names: Taxol;Biological: filgrastim<br>* Given SC<br>* Other names: Neupogen;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;Procedure: needle biopsy<br>* Correlative studies<br>* Other names: puncture biopsy;Procedure: therapeutic conventional surgery<br>* Undergo definitive breast surgery<br>Other: immunohistochemistry staining method<br>* Correlative studies<br>* Other names: immunohistochemistry;Biological: trastuzumab<br>* Given IV<br>* Other names: MOAB HER2;Drug: tamoxifen citrate<br>* Given PO<br>* Other names: TMX;Drug: letrozole<br>* Given PO<br>* Other names: LTZ;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 |
| --- | --- | --- |
| Combined Rate of Microscopic pCR and Macroscopic Pathologic Complete Response (mCR) | Microscopic pCR: No evidence of microscopic invasive tumor at the primary site or in the regional lymph nodes at the time of definitive surgical resection. mCR: The examining pathologist cannot identify gross residual tumor mass in the surgical specimen. This differs from a pCR where the specimen must also be negative for invasive tumor by microscopy. For this study, we are using a definition of mCR that will make the trial more translatable to other institutions. For this study, mCR will be defined as no focus of invasive cancer >= 1 cm. Count of participants with either a pCR or mCR. | Up to 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and Percent of Patients Reporting Grade 2, 3, 4, or Fatal Toxicities of These Regimens, Need for Dose Reduction, or Treatment Interruption or Discontinuation |  | From the initiation of study treatments to 30 days after the end of neoadjuvant treatment or adjuvant treatment if received | 
| Correlation of Molecular Markers With Response |  | After completion of neoadjuvant therapy | 
| Relapse Rate in Patients With Operable Breast Cancer Treated With Neoadjuvant Chemotherapy for 12 Weeks Followed by Weekly Paclitaxel for 12 Weeks and Adjuvant Chemotherapy | Count of patients that relapsed. | Up to 8 years | 
| Time to Progression | Median time to progression free survival. | Up to 5 years | 
| OS in Patients With Operable Breast Cancer Treated With Neoadjuvant Chemotherapy for 12 Weeks Followed Weekly Paclitaxel for 12 Weeks and Adjuvant Chemotherapy With XMN | Kaplan-Meier estimate of overall survival, assessed at 1, 2, and 5 years. | 1, 2, and 5 years | 
| Disease-free Survival | Kaplan-Meier estimate of disease-free survival, assessed at 1, 2, and 5 years. | 1, 2, and 5 years | 
| Clinical Response to Neoadjuvant Therapy |  | Up to 12 weeks | 
| Clinical Response to Paclitaxel |  | Up to 24 weeks |