Combination Chemotherapy and Paclitaxel Plus Trastuzumab in Treating Women With Palpable Breast Cancer That Can Be Removed by Surgery

Study Overview
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Brief Summary
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This randomized phase III trial is studying giving fluorouracil together with epirubicin and cyclophosphamide followed by paclitaxel and trastuzumab to see how well it works compared with giving paclitaxel together with trastuzumab followed by fluorouracil, epirubicin, cyclophosphamide, and trastuzumab in treating women with palpable breast cancer that can be removed by surgery. Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as trastuzumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. It is not yet known whether it is more effective to give combination chemotherapy before or after treatment with paclitaxel plus trastuzumab.

Detailed Description
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PRIMARY OBJECTIVES: I. The primary objective of this study is to compare the pathologic complete response rate (pCR) within the breast of a sequential regimen of concurrent weekly paclitaxel and trastuzumab, followed by continued weekly trastuzumab administered concurrently with FEC-75 (Arm 2), to the pCR rate of a sequential regimen of FEC-75 alone followed by concurrent weekly paclitaxel and trastuzumab (Arm 1). SECONDARY OBJECTIVES: I. To estimate the cardiotoxicity of a sequential regimen of concurrent weekly paclitaxel and trastuzumab, followed by continued weekly trastuzumab administered concurrently with FEC-75, followed postoperatively by q 3 week trastuzumab for a total duration of trastuzumab therapy through 52 weeks from the first dose (Arm 2), and compare the cardiotoxicity to that of a sequential regimen of FEC-75 alone followed by concurrent weekly paclitaxel and trastuzumab, followed by q 3 week trastuzumab for a total duration of trastuzumab therapy through 52 weeks from the first dose (Arm 1). II. To compare the combined pCR rate in the breast and ipsilateral axilla obtained with the two regimens evaluated in this study. III. To compare the clinical response rates (cRR) of the two regimens evaluated in this study. IV. To compare the non-cardiac toxicity of the two regimens evaluated in this study. V. To compare breast conservation rates achieved with the two regimens evaluated in this study. VI. To evaluate disease-free survival and overall survival at 5 years post-randomization. VII. To correlate pCR rate with potential molecular markers of response. OUTLINE: Patients are stratified by clinical tumor size (breast tumor size < 2 cm and nodal metastases < 2 cm vs breast tumor size < 2 cm and nodal metastases ≥ 2 cm vs breast tumor size 2-4 cm [any nodal status] vs breast tumor size ≥ 4 cm [any nodal status]), age (< 50 vs ≥ 50) and hormone receptor status (estrogen receptor [ER]- and progesterone receptor [PgR]-negative vs ER- and/or PgR-positive). Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive FEC comprising fluoroucacil intravenously (IV), epirubicin hydrochloride IV, and cyclophosphamide IV on day 1. Treatment repeats every 21 days for 4 courses. Beginning 21 days after completion of FEC, patients receive paclitaxel IV once weekly and trastuzumab (Herceptin) IV once weekly for 12 weeks. Within 6 weeks after completion of paclitaxel and trastuzumab, patients undergo surgery. Beginning 3-4 weeks after surgery, patients receive trastuzumab IV once every 3 weeks for up to 52 weeks. ARM II: Patients receive paclitaxel IV once weekly and trastuzumab IV once weekly for 12 weeks. Beginning 7 days after completion of paclitaxel and trastuzumab, patients receive FEC comprising fluoroucacil IV, epirubicin IV, and cyclophosphamide IV on day 1. Treatment repeats every 21 days for 4 courses. Patients also receive trastuzumab IV once weekly for an additional 12 weeks. Within 6 weeks after completion of FEC and trastuzumab, patients undergo surgery. Beginning 3-4 weeks after surgery, patients receive trastuzumab as in arm I. After completion of study therapy, patients are followed every 3 months for 1 year and then every 6 months for 4 years.

Official Title
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A Randomized Phase III Trial Comparing a Neoadjuvant Regimen of FEC-75 Followed by Paclitaxel Plus Trastuzumab With a Neoadjuvant Regimen of Paclitaxel Plus Trastuzumab Followed by FEC-75 Plus Trastuzumab in Patients With HER-2 Positive Operable Breast Cancer

Conditions
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HER2/Neu Positive, Stage IA Breast Cancer, Stage IB Breast Cancer, Stage II Breast Cancer, Stage IIIA Breast Cancer

Intervention / Treatment
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* Drug: Cyclophosphamide
* Drug: Epirubicin Hydrochloride
* Other: Laboratory Biomarker Analysis
* Drug: Paclitaxel
* Procedure: Therapeutic Conventional Surgery
* Biological: Trastuzumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of invasive adenocarcinoma by core needle biopsy Fine needle aspiration allowed provided primary tumor size < 2 cm and lymph node metastases are present Excisional biopsy of the primary tumor allowed provided biopsy-positive lymph nodes are present Primary tumor ≥ 2 cm and/or ≥ 1 biopsy-positive lymph node HER2-positive disease Confirmation by fluorescent in situ hybridization (FISH) requires gene amplification Confirmation by immunohistochemistry (IHC) requires a strongly positive (3+) staining intensity score Ductal carcinoma in situ (DCIS) or synchronous DCIS of the contralateral breast regardless of prior therapy allowed Synchronous invasive breast cancer not allowed Ipsilateral DCIS treated by local excision with or without hormonal therapy allowed Those treated with radiation therapy are not allowed No definitive clinical or radiologic evidence of metastatic disease No history of invasive breast cancer Hormone receptor status known Menopausal status not specified ECOG performance status of 0 -1 Absolute neutrophil count ≥ 1,200/mm³ Platelet count ≥ 100,000/mm³ Total bilirubin normal unless the patient has a grade 1 bilirubin elevation (normal to 1.5 times upper limit of normal [ULN]) resulting from Gilbert disease or similar syndrome due to slow conjugation of bilirubin Alkaline phosphatase ≤ 2.5 times ULN AST ≤ 1.5 times ULN Creatinine normal Left ventricular ejection fraction (LVEF) ≥ 55 by multi gated acquisition scan (MUGA) or echocardiogram (ECHO) within the past 3 months Patients with either skeletal pain or alkaline phosphatase that is > ULN but ≤ 2.5 times ULN allowed if bone scans fail to demonstrate metastatic disease Suspicious findings on bone scan must be confirmed as benign by x-ray, MRI, or biopsy Prior non-breast malignancies allowed if disease-free for 5 years since completion of initial treatment regimen and deemed by their physician to be at low risk for recurrence Patients who had the following cancers are eligible if diagnosed and treated within the past 5 years: Carcinoma in situ of the cervix Colon carcinoma in situ Melanoma in situ Basal cell and squamous cell carcinoma of the skin No cardiac disease that would preclude the use of epirubicin hydrochloride or trastuzumab (Herceptin®) including any of the following: 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 EKG Patient's with poorly controlled hypertension ( i.e., diastolic greater than 100 mm/Hg) Patients with hypertension that is well controlled on medication are eligible History of cardiac disease Myocardial infarction documented as a clinical diagnosis or by EKG or any other tests Documented congestive heart failure Documented cardiomyopathy No sensory or motor neuropathy ≥ grade 2, as defined by the NCI's CTCAE v3.0 Women of reproductive potential must agree to use an effective non-hormonal method of contraception during therapy Women of child bearing potential must have a negative urine or serum pregnancy test within 2 weeks of registration Not pregnant or nursing No psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements No non-malignant systemic disease (e.g., cardiovascular, renal, hepatic) that would preclude treatment with either of the treatment regimens No prior surgical axillary staging procedure Prior non-excisional biopsy of an axillary node allowed No prior treatment for this breast cancer Hormonal therapy allowed if had been given for up to a total of 28 days anytime after diagnosis and before study entry Hormonal therapy must stop at or before study entry and be re-started, if indicated, following surgery No prior therapy with anthracyclines or taxanes for any malignancy No other investigational agents within the past 30 days No concurrent sex hormonal therapy (e.g., birth control pills, ovarian hormonal replacement therapy) No concurrent therapy with any hormonal agent such as raloxifene, tamoxifen, or other selective estrogen receptor modulator (SERM), either for osteoporosis or breast cancer prevention

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: FEC-75 then Paclitaxel/trastuzumab<br>Patients receive FEC comprising fluoroucacil IV, epirubicin hydrochloride IV, and cyclophosphamide IV on day 1. Treatment repeats every 21 days for 4 courses. Beginning 21 days after completion of FEC, patients receive paclitaxel IV once weekly and trastuzumab (Herceptin) IV once weekly for 12 weeks. Within 6 weeks after completion of paclitaxel and trastuzumab, patients undergo surgery. Beginning 3-4 weeks after surgery, patients receive trastuzumab IV once every 3 weeks for up to 52 weeks. | Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Drug: Epirubicin Hydrochloride<br>* Given IV<br>* Other names: Pharmorubicin PFS;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Paclitaxel<br>* Given IV<br>* Other names: Taxol Konzentrat;Procedure: Therapeutic Conventional Surgery<br>* Undergo surgery<br>Biological: Trastuzumab<br>* Given IV<br>* Other names: Trastuzumab Biosimilar PF-05280014;|
| Experimental: Paclitaxel/trastuzumab then trastuzumab/FEC-75<br>Patients receive paclitaxel IV once weekly and trastuzumab IV once weekly for 12 weeks. Beginning 7 days after the completion of paclitaxel and trastuzumab, patients receive FEC comprising fluoroucacil IV, epirubicin IV, and cyclophosphamide IV on day 1. Treatment repeats every 21 days for 4 courses. Patients also receive trastuzumab IV once weekly for an additional 12 weeks. Within 6 weeks after completion of FEC and trastuzumab, patients undergo surgery. Beginning 3-4 weeks after surgery, patients receive trastuzumab as in arm I. | Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Drug: Epirubicin Hydrochloride<br>* Given IV<br>* Other names: Pharmorubicin PFS;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Paclitaxel<br>* Given IV<br>* Other names: Taxol Konzentrat;Procedure: Therapeutic Conventional Surgery<br>* Undergo surgery<br>Biological: Trastuzumab<br>* Given IV<br>* Other names: Trastuzumab Biosimilar PF-05280014;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| pCR Within the Breast, Defined as no Evidence of Invasive Tumor Remaining in the Breast at Surgery Following Completion of Chemotherapy | Pathological complete response (pCR) rates will be based on institutional pathology reports. In the final analysis for publication, rates will be based on blinded central review of these institutional pathology reports. The Chi-squared test will be conducted at the two-sided 0.05 level. A 95% confidence interval will be computed for the difference in pCR rates. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Combined pCR Rate in the Breast and Axillary Lymph Nodes Defined as no Evidence of Invasive Tumor Remaining in Either the Breast or Axillary Nodes at Surgery Following Completion of Chemotherapy | pCR Rate in the Breast and Axillary Lymph Nodes Defined as no Evidence of Invasive Tumor Remaining in Either the Breast or Axillary Nodes at Surgery Following Completion of Chemotherapy (among those with Metastasis to movable ipsilateral axillary lymph node(s) (cN1-3) disease). | Up to 5 years | 
| Asymptomatic Decreases From Baseline in Left Ventricular Ejection Fraction (LVEF) at Week 12 | The summary of asymptomatic decrease in LVEF. | Baseline, at 12 week | 
| Asymptomatic Decreases From Baseline in LVEF at Week 24 | The summary of asymptomatic changed in LVEF. | Baseline, at 24 week | 
| LVEFs From Regularly Scheduled Multi Gated Acquisition Scan (MUGA)/Echo Scans as Reported at 12 Week | All patients who had a MUGA or ECHO performed at week 12 are included in the summary of asymptomatic changed in LVEF at week 12. Difference from pretreatment LVEF (%) at 12 weeks [median change from baseline Inter Quartile Range (IQR)]. | At 12 week | 
| Change in LVEFs (From Regularly Scheduled Multi Gated Acquisition Scan (MUGA)/Echo Scans) From Baseline and at 24 Week | Difference from pretreatment LVEF (%) at 24 weeks [median change from baseline Inter Quartile Range (IQR)]. | Baseline, at 24 week | 
| Breast Conservation | Surgery was categorized as breast conserving surgery (Partial Mastectomy) or non-conserving surgery (Total Mastectomy or Modified Radical Mastectomy). Reported below is the percentage of patients receiving Partial Mastectomy. This was calculated by dividing the number of patients receiving Partial Mastectomy by the total number of patients undergoing surgery multiplied by 100 (to obtain the percentage). | From time surgery to up to 5 years | 
| Disease-free Survival (DFS) | DFS defined as inoperable progressive disease, gross residual disease following definitive surgery, local, regional or distant recurrence, contralateral breast cancer, other second primary cancers, and death prior to recurrence or second primary cancer. DFS of Arm I and Arm II patients will be estimated using the Kaplan-Meier method. | From time to registration to time of event, assessed up to 5 years | 
| Overall Survival (OS) | OS of Arm I and Arm II patients will be estimated using the Kaplan-Meier method. | From time to registration to death, assessed up to 5 years |