Neoadjuvant Chemotherapy With Myocet/Taxotere/Herceptin for HER2 Positive Breast Cancer Patients

Study Overview
=================
Brief Summary
-----------------
This is an open-label study to assess the efficacy and tolerability of the combination Myocet®/Taxotere®/Herceptin® as primary treatment for HER2 positive breast cancer patients. HER2 status will be confirmed centrally by fluorescence in situ hybridization (FISH). Phase I: Initial doses will be: Myocet: 50-60 mg/m² day 1 every 3 weeks; Taxotere 60-75 mg/m² day 1 every 3 weeks; and Herceptin (4) 2 mg/kg weekly. Sample size will depend on the number of patients recruited during dose escalation. Three patients must be recruited in each dose level. If one out of three experiences a dose-limiting toxicity (DLT), 3 more patients must be recruited in the same dose level. Considering that there are 4 dose levels to be tested, the estimated number of patients is 9 to 24. Patients receiving the recommended dose (RD) will be incorporated into phase II of the study.

Detailed Description
-----------------
Phase II: The average pathological complete response rate reported in other trials is around 11%. The investigators expect to achieve an increase of 14% on this rate; that is, they expect a pathological response rate of 25%. With a= 0.05 and β=0.2, 18 patients are initially needed. If at least 3 pathological complete responses are achieved, recruitment will continue to up to 53 patients. At least 10 pathological complete responses are needed to probe the hypothesis. Considering a 10% post-randomization drop-out rate, a total of 59 patients must be recruited for the trial.

Official Title
-----------------
Open-label Phase I-II Clinical Trial to Evaluate Treatment With Myocet/Taxotere/Herceptin as Primary Chemotherapy Treatment for HER2neu Positive Breast Cancer Patients

Conditions
-----------------
Breast Cancer

Intervention / Treatment
-----------------
* Drug: Myocet
* Drug: Taxotere
* Drug: Herceptin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Written informed consent. Breast cancer stages II and IIIA with histological diagnoses by true-cut. Breast cancer tumours overexpressing HER2neu, centrally confirmed by FISH. No evidence of metastasis: bilateral mammography, thorax x-ray, computed tomography (CT)-scan or abdominal echography and bone scintigraphy. Estrogen and progesterone hormone receptor status, determined before study registration. Age >= 18 years old. Performance status (Karnofsky index) >= 80. Adequate cardiac function by LVEF in the previous 14 days. Hematology: neutrophils >= 2.0 x10^9/l; platelets >= 100 x10^9/l; hemoglobin >= 10 g/dl. Adequate hepatic function: total bilirubin <= 1x upper normal limit (UNL); SGOT and SGPT <= 2.5xUNL; alkaline phosphatase <= 2.5xUNL. Adequate renal function: creatinine <= 1xUNL; creatinine clearance >= 60 ml/min. Patients able to comply with study treatment and follow-up. Negative pregnancy test in the previous 14 days. Adequate contraceptive method during the study and up to 3 months after definitive surgery. Exclusion Criteria: HER2neu negative tumours. Prior systemic therapy for breast cancer. Prior treatment with anthracyclines or taxanes (paclitaxel, docetaxel) for any previous malignancy. Prior radiotherapy for breast cancer. Bilateral invasive breast cancer. Pregnant or lactating women. Previous grade >= 2 motor or sensorial neurotoxicity (National Cancer Institute Common Toxicity Criteria [NCI CTC]). Other serious comorbidities: congestive heart failure or unstable angina; prior history of myocardial infarction in previous year; uncontrolled hypertension (HT); high risk arrhythmias; history of significant neurological or psychiatric disorders; uncontrolled active infection; active peptic ulcer; unstable diabetes mellitus; dyspnea at rest; or chronic therapy with oxygen. Previous or current history of neoplasms different from breast cancer, except for skin carcinoma, cervical in situ carcinoma, or any other tumor curatively treated and without recurrence in the last 10 years; ductal in situ carcinoma in the same breast; lobular in situ carcinoma. Chronic treatment with corticosteroids. Contraindications for administration of corticosteroids, anthracyclines, docetaxel, trastuzumab or egg derivates. Concomitant treatment with other therapy for cancer. Males.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Myocet+Taxotere+Herceptin<br>Myocet 50 mg/m2; Taxotere 60 mg/m2; Herceptín 4 mg/Kg (first dose) and in the following cycles 2 mg/Kg | Drug: Myocet<br>* Myocet®: 60-75 mg/m² ASC (vía IV) día 1 / c3s for 6 cycles<br>* Other names: Lyposomal Doxorubicin;Drug: Taxotere<br>* Taxotere® 70-75 mg/m² ASC (vía IV) día 1 / c3s for 6 cycles<br>* Other names: Docetaxel;Drug: Herceptin<br>* Herceptin® (4) 2 mg/kg (vía IV) Semanal for 6 cycles<br>* Other names: Trastuzumab;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tolerability (Phase I): Recommended Doses of the combination treatment | Recommended Doses of the combination treatment | up to 24 months since last patient included in the Phase I | 
| Efficacy (Phase II): Percentage (%) pathological Complete Response achieved according to Miller and Payne Criteria | % pathological Complete Response achieved according to Miller and Payne Criteria | up to 24 months since last patient included in the Phase II | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical response rates | Clinical responses evaluated by radiological imaging | up to 6 months since last patient treatment | 
| Surgery type (conservative surgery versus mastectomy) | % conservative or mastectomy surgery | up to 7 months since last patient treatment | 
| Potential cardiac toxicity | Left ventricular ejection fraction [LVEF] by multiple-gated acquisition [MUGA]) | up to 12 months since last patient included | 
| Safety: Adverse Events evaluated according to NCI CTC v2.0 | Adverse Events evaluated according to NCI CTC v2.0 | 24 months since last patient included | 
| Post-surgery node status | according to Miller and Payne Criteria | up to 7 months since last patient treatment | 
| Molecular changes in blood and tissue exams | Different biomarkers evaluated | 24 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Her2neu positive breast cancer., Neoadjuvant treatment.