Studying the Benefits of Adjuvant Sequential vs. Combined Taxane Based Chemotherapy, Followed by Different Biological Treatment Strategies in Early, HER2-positive Breast Cancer

Study Overview
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Brief Summary
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This is an open-label, multicenter randomized controlled, Phase III study comparing the disease free survival after randomisation in patients treated with 3 cycles of Epirubicin-Fluorouracil-Cyclophosphamide (FEC)-chemotherapy, followed by 3 cycles of Docetaxel (D)-chemotherapy versus 3 cycles of Epirubicin-Fluorouracil- Cyclophosphamide (FEC), followed by 3 cycles of Gemcitabine-Docetaxel(DG)- chemotherapy. Patients will be required to have HER2-neu positive disease and histopathological proof of axillary lymph node metastases (pN1-3) or high risk node negative, defined as: pT>=2 or histopathological grade 3, or age <= 35 or negative hormone receptor', but are not allowed to have evidence of distant disease. Patients will have to be entered into the study no later than 6 weeks after complete resection of the primary tumor. No other antineoplastic treatment other than surgical treatment, the defined cytotoxic and endocrine treatment and radiotherapy will be allowed prior to study entry and during the course of the study.

Official Title
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Prospectively Randomized Phase III Trial, Studying the Benefits of Adjuvant Sequential vs. Combined Taxane Based Chemotherapy, Followed by Different Biological Treatment Strategies in Early, HER2-positive Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: 3 x FEC 3 x DOC / Gemcitabine
* Drug: 3 x FEC 3 x DOC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Primary epithelial invasive carcinoma of the breast pT1-4, pN0-3, M0 Evidence of HER2-neu overexpressing (IHC +++) or amplifying (FISH +) tumor Histopathological proof of axillary lymph node metastases (pN1-3) or high risk node negative, defined as at least two criteria of the following: 'pT³2, histopathological grade 3, age £ 35, negative hormone receptor' Complete resection of the primary tumor with margins of resection free of invasive carcinoma not more than 6 weeks ago Females >= 18 years of age Performance Status <2 on ECOG-Scale Adequate bone marrow reserve: leucocytes ³ 3.0 x 109/l and platelets ³ 100 x 109/l Bilirubin within one fold of the reference laboratory's normal range, ASAT (SGOT), ALAT (SGPT) and AP within 1,5 fold of the reference laboratory's normal range for patients Intention of regular follow up visits for the duration of the study Ability to understand the nature of the study and to give written informed consent Women of childbearing potential must agree to use an effective method of contraception (Pearl-Index < 1, e.g. , intrauterine devices or sterilization) during treatment and for at least 6 months thereafter. Exclusion Criteria: Inflammatory breast cancer Previous or concomitant cytotoxic or other systemic antineoplastic treatment which is not part of this study A second primary malignancy (except in situ carcinoma of the cervix or adequately treated basal cell carcinoma of the skin) Cardiomyopathy with impaired ventricular function (NYHA > II), cardiac arrhythmias influencing LVEF and requiring medication, history of myocardial infarction or angina pectoris within the last 6 months, or arterial hypertension not being controlled by medication Any known hypersensitivity reaction against docetaxel, epirubicin, cyclophosphamide, gemcitabine or any other medication included in the study protocol. The contraindication, warning notices and measures of precaution of the products, as notified in the product information, have to be respected Instable diabetes mellitus, out of sufficient medical control Use of any investigational agent within 3 weeks prior to inclusion Patients in pregnancy or breast feeding (in premenopausal women contraception has to be assured)

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: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br> | Drug: 3 x FEC 3 x DOC / Gemcitabine<br>* 3 cycles of 5-Fluorouracil 500 mg/m² i.v. body surface area and Epirubicin 100 mg/m² i.v. and Cyclophosphamide 500 mg/m² i.v., (FEC100), each administered on day 1, repeated on day 22, subsequently followed by 3 cycles of Docetaxel 75 mg/m² body surface area i.v. (D), and Gemcitabine 1000 mg/m² i.v. (30 min infusion) (G), administered on day 1, followed by Gemcitabine 1000 mg/m² i.v. (30 min infusion) on day 8, repeated on day 22<br>|
| Active Comparator: B<br> | Drug: 3 x FEC 3 x DOC<br>* 3 cycles of 5-Fluorouracil 500 mg/m² i.v. body surface area and Epirubicin 100 mg/m² i.v. and Cyclophosphamide 500 mg/m² i.v., (FEC100), each administered on day 1, repeated on day 22, subsequently followed by 3 cycles of Docetaxel 100 mg/m² body surface area i.v. (D), administered on day 1, repeated on day 22<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease free survival |  | 5 y | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival time after randomization |  | 5 Y | 
| Distant disease free survival |  | 5 Y | 
| Toxicity |  | 5 Y | 
| Changes in quality of life over time as defined by EORTC QLQ-C30 and QLQBR23 questionnaire |  | 5 Y | 
| Skeletal related events |  | 5 Y | 
| Incidence of secondary primaries |  | 5 Y | 
| Endpoints of adjunct translational research program |  | 5 Y |