Epirubicin and Paclitaxel, Alone or Together With Capecitabine as First Line Treatment in Metastatic Breast Cancer

Study Overview
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Brief Summary
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Anthracycline-taxane regimens are effective means of postponing progression in metastatic breast cancer. It is yet unclear whether addition of capecitabine to this combination improves the treatment outcome. Patients with advanced breast cancer are randomized to first-line chemotherapy with a combination of epirubicin (Farmorubicin®) and paclitaxel (Taxol®) alone (ET) or in combination with capecitabine (Xeloda®, TEX). Starting doses for ET are epirubicin 75 mg/m2 plus paclitaxel 175 mg/m2, and for TEX epirubicin 75mg/m2, paclitaxel 155 mg/m2, and capecitabine 825 mg/m2 BID for 14 days. Subsequently, doses are tailored related to side effects. Primary endpoint is progression-free survival (PFS); secondary endpoints are overall survival (OS), time to treatment failure (TTF), objective response (OR), safety and quality of life (QoL).

Official Title
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Treatment With the Combination of Epirubicin and Paclitaxel Alone or Together With Capecitabine as First Line Treatment in Metastatic Breast Cancer. A Multicenter, Randomized Phase III Study

Conditions
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Metastatic Breast Cancer

Intervention / Treatment
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* Drug: Epirubicin
* Drug: Paclitaxel
* Drug: Capecitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Morphologically proven breast carcinoma Written patient consent must be obtained Measurable disease (i.e. at least one lesion that can be accurately measured in at least one dimension as ≥20 mm by conventional techniques, or as ≥10 mm by spiral CT scan) as defined in section 8. Lytic and blastic bone metastases as only site of recurrence are allowed Age 18 years or older ECOG performance status 0-2 Life expectancy of at least three months Adequate cardiac functions Adequate hematological, renal and hepatic functions Patient must be accessible for treatment and follow-up. Exclusion Criteria: Treatment-free interval less than one year, if previous adjuvant, neoadjuvant or after radically treated locoregional recurrence given regimen contained anthracycline, taxane or capecitabine. This limitation does not apply for regimens containing other than the drugs mentioned During adjuvant treatment obtained cumulative doses exceeding 375 mg/m2 for doxorubicin, or 550 mg/m2 for epirubicin, abnormal ECG or reduced cardiac function measured by left ventricular ejection fraction (LVEF). Indication for the use of trastuzumab (Herceptin) as first-line treatment in patients with tumor overexpressing c-erbB2. Any previous chemotherapy for metastatic disease, except for radically treated locoregional relapse Neoplasm other than breast carcinoma, except for non-melanoma skin cancer or curatively treated carcinoma in situ of the cervix, diagnosed during the past five years Pregnancy or lactation Known brain metastases History of atrial or ventricular arrhythmias and/or congestive heart failure, even if medically controlled. History of clinical and electrocardiographically documented myocardial infarction Preexisting motor or sensory neuropathy ≥ grade 2 according to NCI CTC 2.0 criteria (severe paresthesia and/or mild weakness, or worse) Severe hepatic or renal impairment (for capecitabine: calculated creatinine clearance below 30 ml/min; for calculation, see p. 5.1.4) not allowing for adequate use of the proposed regimens History of known dihydropyrimidine dehydrogenase (DPD) deficiency (severe reaction on previous treatment with fluorouracil, e.g experience of mucositis, hand-foot syndrome, or diarrhea) Active infection or other serious underlying medical condition which would impair the ability of the patient to receive protocol treatment, including prior allergic reactions to drugs containing cremophor, such as teniposide, cyclosporin or vitamin K Dementia or significantly altered mental status that would prohibit the understanding and giving of informed consent.

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: Epirubicin + paclitaxel (Taxol)<br>Epirubicin 75mg/m2 i.v., paclitaxel 175 mg/m2 i.v. on day 1 every 21 days. | Drug: Epirubicin<br>* 75 mg/m2 i.v. every 3 weeks, both study arms<br>Drug: Paclitaxel<br>* 175 mg/m2 i.v., every 3 weeks study arm A 155 mg/m2 i.v., every 3 weeks study arm B<br>* Other names: Taxol;|
| Active Comparator: Paclitaxel + epirubicin + capecitabine<br>Paclitaxel 155 mg/m2 i.v., epirubicin 75 mg/m2 i.v day 1, capecitabine 1650 mg/m2 p.o. on days 1-14 every 21 days. | Drug: Epirubicin<br>* 75 mg/m2 i.v. every 3 weeks, both study arms<br>Drug: Paclitaxel<br>* 175 mg/m2 i.v., every 3 weeks study arm A 155 mg/m2 i.v., every 3 weeks study arm B<br>* Other names: Taxol;Drug: Capecitabine<br>* 1650 mg/m2 p.o. days 1-14 every 3 weeks study arm B<br>* Other names: Xeloda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to progression | Time to progression comparing treatment with ET vs. TEX in patients with advanced breast cancer. Evaluation every 9 weeks during treatment until progression as long as study treatment was given, and every 12 weeks until date of progression, if treatment was disrupted for any other reason. Patients in the state of persistent complete response after primary completion date were reported only upon date of progression or death up to 78 months | From date of randomisation until date of first radiolocically documented progression or death from any cause, whichever comes first up to 78 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to treatment failure | Time on treatment irrespective of reason for disruption (toxicity, patients wish) | From date of randomization until date of treatment disruption for any reason up to 78 months | 
| Response rate |  | Every 9 weeks during treatment | 
| Overall survival | Date and cause of death reported yearly during the ongoing trial, up to 78 months after primary completion date only on the occasion of death | Time from randomisation until date of death up to 78 months | 
| Number of participants with adverse events | All side effects which appear during treatment are reported and graded according CTC v.2. | Continuously during treatment and until 2 months after termination | 
| Quality of life | Measured at five points during nine months from randomization. | Baseline, 2, 4, 6 and 9 months | 
| Tumor biological data related to treatment | Fine needle aspirates from metastases | Within two weeks before start of treatment |