Neoadjuvant Chemotherapy + Herceptin in HER2 Positive Stage II-III Breast Cancer Patients

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the effectiveness and tolerability of the combination of the following medications given every two weeks in HER2 positive breast cancer patients: trastuzumab (Herceptin) epirubicin (Ellence) cyclophosphamide (Cytoxan) docetaxel (Taxotere)

Detailed Description
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This is an investigator-initiated, Phase II, non-randomized, single-arm, prospective treatment study. The study will consist of neoadjuvant treatment period (weeks 1 to 20), surgical evaluation period (weeks 20 to 24), and a post-surgical/follow-up period (approximately 3 years). Subjects will be treated on an outpatient basis. Neoadjuvant therapy will consist of epirubicin + cyclophosphamide given every 2 weeks for four cycles followed by a three week break. Subjects will then receive docetaxel every two weeks for four cycles + trastuzumab (one loading dose) then maintenance dose every 2 weeks for 4 treatments.

Official Title
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Pilot Trial of Sequential Dose-Dense Neoadjuvant Chemotherapy Plus Herceptin in HER2 Positive Stage II-III Breast Cancer Patients

Conditions
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Breast Neoplasm

Intervention / Treatment
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* Drug: epirubicin
* Drug: cyclophosphamide
* Drug: docetaxel
* Drug: trastuzumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Non-pregnant females =/> 18 years of age Non-inflammatory breast cancer stage IIA - IIIC or high risk node negative Core biopsy of breast demonstrating invasive cancer and documented ER/PgR receptor status Normal cardiac function and adequate hematologic function Human epidermal growth factor receptor 2 protein (HER2) positive No evidence of metastatic disease ECOG Performance Status 0 - 1 Women of childbearing potential must agree to using effective contraception while on treatment and for at least 3 months post-treatment Exclusion Criteria: Treated with other investigational drugs within 30 days Uncontrolled intercurrent disease or active infection Known sensitivity to e. coli-derived proteins or polysorbate 80 Psychiatric illness or social situation that would limit study compliance Pre-existing peripheral neuropathy > Grade 1 Cancer within 5 years of screening with the exception of surgically cured nonmelanomatous skin cancer; in-situ carcinoma of the cervix; or in-situ carcinoma of the breast Bilateral synchronous breast cancer Inflammatory breast cancer Women who are pregnant or breast feeding

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Neoadjuvant therapy<br>Neoadjuvant therapy will consist of epirubicin (100 mg/m^2) + cyclophosphamide (600 mg/m^2) every 2 weeks for 4 cycles; followed by a 3-week break; followed by docetaxel (75 mg/m^2) every 2 weeks for 4 cycles + trastuzumab (6 mg/kg [loading dose] once then 4 mg/kg [maintenance dose]) every 2 weeks for 4 treatments. | Drug: epirubicin<br>* epirubicin (100 mg/m^2) every 2 weeks for 4 cycles<br>* Other names: Ellence®;Drug: cyclophosphamide<br>* cyclophosphamide (600 mg/m^2) every 2 weeks for 4 cycles<br>* Other names: Cytoxan;Drug: docetaxel<br>* docetaxel (75 mg/m^2) every 2 weeks for 4 cycles<br>* Other names: Taxotere®;Drug: trastuzumab<br>* trastuzumab (6 mg/kg [loading dose] once then 4 mg/kg [maintenance dose]) every 2 weeks for 4 treatments<br>* Other names: Herceptin®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects Able to Complete > 85% of the Planned Dose on Schedule | Feasibility will be determined by evaluating the percentage of subjects able to complete the neoadjuvant portion of the study on time with > 85% of the protocol-specified dose. | From the start of treatment through the neoadjuvant treatment period (approximately 20 weeks) | 
| Frequency of Grade 3 or 4 Hematologic and Nonhematologic Toxicities | Toxicities are evaluated according to the Common Terminology Criteria for Adverse Events, version 3.0. Grade refers to the severity of the adverse event (AE). Generally, grade 1 = mild AE; grade 2 = moderate AE; grade 3 = severe AE; grade 4 = life-threatening or disabling AE; grade 5 = death related to AE. | Toxicities are evaluated every 2 weeks during neoadjuvant treatment and assessed once during the post-treatment follow-up period, up to 25 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathologic Response | Pathologic response was assessed at time of definitive surgery, scheduled to occur 20-24 weeks after study treatment start. Pathologic complete response was defined as no invasive carcinoma in surgical specimen of breast, but residual ductal carcinoma in situ may be present. Pathologic partial response was defined as >= 50% decrease in sum of diameters in pathologic cancer size compared to pretreatment clinical size. Stable disease was defined as < 50% decrease in sum of diameters in pathologic cancer size compared to pretreatment clinical size, and < 25% increase in sum of diameters. | At completion of neoadjuvant treatment period, up to 24 weeks. | 
| Clinical Response Prior to Surgery | Clinical response was assessed via physical exam every 2 weeks during neoadjuvant treatment and via imaging prior to definitive surgery. Clinical complete response was defined as no evidence of cancer in breast by exam or imaging. Clinical partial response was defined as >= 50 % reduction in sum of diameters to measurement of primary lesion compared to pretreatment by exam or imaging. Clinical stable disease was defined as < 50% reduction in sum of diameters to measurement of primary lesion compared to pretreatment by exam or imaging, and < 25% increase in sum of diameters. | Assessed every 2 weeks during neoadjuvant treatment and prior to definitive surgery, up to 23 weeks. | 
| Left Ventricular Ejection Fraction (LVEF) | LVEF was assessed by echocardiogram (ECHO) or multigated angiogram (MUGA) during neoadjuvant treatment and during follow-up. | At screening, prior to cycle 5, prior to surgery, and then during follow-up at Month 6, 12, 24, and 36 | 
| Progression-free Survival (PFS) | PFS is defined as the duration of time from start of treatment to time of progression or death, whichever comes first. | PFS was measured from day 1 of treatment until time of progression or death, whichever comes first, assessed up to 48 months. | 
| Overall Survival (OS) | Overall survival is defined as the time from treatment start until death from any cause. The median overall survival time is used to measure OS. | Measured from day 1 of treatment until time of death, assessed up to 48 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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neoadjuvant chemotherapy, HER2 positive breast cancer, stage II - III breast cancer