Taxotere and Adriamycin/Cytoxan (AC) Validation in Breast Cancer Patients

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to learn if the biomarker information obtained (learned or received) from the earlier studies can tell us whether or not Taxotere and/or Adriamycin/Cytoxan can cause tumors to become smaller.

Detailed Description
-----------------
Large clinical trials have confirmed the value of systemic adjuvant therapy in decreasing the risk of recurrence and death in patients with early breast cancer. However, the need to identify breast cancer patients who will benefit from adjuvant therapy, while sparing others from the side effects of futile treatment, is spurring research into predictive markers of chemotherapy sensitivity and resistance. In the adjuvant setting, extremely large trials and long follow-up would be required to prospectively validate the predictive value of biomarkers of chemotherapy sensitivity or resistance. In part this is because response is not directly observable. Preoperative chemotherapy for large tumors (>3cm) or inoperable breast cancer is well established and is the standard of care for locally advanced breast cancer. Data from large series of patients have demonstrated that preoperative (neoadjuvant) chemotherapy leads to significant reduction of tumor size (downstaging) and improves both the rate and the cosmetic results of breast- conserving surgery. The degree of response to neoadjuvant therapy has been shown to predict improved overall survival. This is therefore an attractive setting to study predictors of response because tissue is accessible from pre- therapeutic biopsies and tumor response is directly observable. In an early proof-of-principle pilot study of single agent neoadjuvant docetaxol, we identified a predictive gene expression pattern, and, using leave-one-cross validation, a method of internal validation, we demonstrated that the pattern was likely to accurately discriminate between responders and non-responders (Chang, J.C., et al., Gene expression profiling for the prediction of therapeutic response to docetaxel in patients with breast cancer. Lancet, 2003. 362(9381): p. 362-9). A similar pilot study of neoadjuvant AC undertaken by a collaborator in the UK suggests that different profiles will be predictive for AC response. In order to definitively determine predictive patterns for both regimens (T and AC) using improved technology for RNA preparation and a larger, more comprehensive gene expression array, we undertook a randomized Phase II trial of these two widely used regimens (Protocol H-11624 - A RANDOMIZED MULTICENTER TRIAL OF NEOADJUVANT TAXOTERE AND ADRIAMYCIN/CYTOXAN (AC): A BIOLOGIC CORRELATIVE STUDY). The trial is nearing completion, having recruited more than 90 patients out of an expected 120 patients. To date, the risks associated with this study have been modest, and there have been no unexpected adverse events. The laboratory work is well underway and gives every indication that clinically useful classifiers to predict treatment efficacy will result.

Official Title
-----------------
A Randomized Multicenter Trial of Neoadjuvant Taxotere (T) and Adriamycin/Cytoxan (Ac): A Validation

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

Intervention / Treatment
-----------------
* Drug: Taxotere/Docetaxel
* Drug: Adriamycin/Cytoxan
* Drug: doxorubicin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: All patients must be female. Signed informed consent. Primary breast cancers must be of clinical and/or radiologic size >3 cm, and deemed surgically operable. Negative serum pregnancy test (bHCG) within 7 days of starting study, if of child-bearing potential. Adequate bone marrow function: Hematocrit of greater than 30%, total neutrophil count must be >1.5 x 10^9/L and platelets of > 100 x 10^9/L prior to the start of any cycle. Renal function tests: creatinine within 1.5 times of the institution's upper limit of normal (ULN). Liver function tests: Total serum bilirubin within ULN, and liver transaminases within 2.5 times ULN, and alkaline phosphatase within 5 times ULN. Electrocardiogram showing no acute ischemic changes. Performance status (World Health Organization [WHO] scale) <2. Age > 18 years. Patients older than 70 years of age should have left ventricular ejection fraction within ULN by multigated acquisition scan (MUGA) or 2D echocardiogram. Exclusion Criteria: Patients with metastatic breast cancer. Pregnancy or unwillingness to use a reliable contraceptive method in women of child-bearing potential. Women who are lactating or breastfeeding. Severe underlying chronic illness or disease. Peripheral neuropathy - grade 2 or greater. Patients on other investigational drugs while on study will be excluded. Severe or uncontrolled hypertension, history of congestive heart failure, acute myocardial infarction, or severe coronary arterial disease. Prior taxane or anthracycline chemotherapy for malignancy. Patients with a history of severe hypersensitivity reaction to Taxotere or other drugs formulated with polysorbate 80. No previous or current malignancies at other sites within the last 5 years, with exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri and basal or squamous cell carcinoma of the skin.

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

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

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

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

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A: Taxotere/Docetaxel<br>Chemotherapy In Arm A, patients will receive single agent Taxotere (100 mg/m2) every 3 weeks for 4 cycles before surgery. Primary surgery will then be conducted, if operable, following completion of neoadjuvant treatment. This will be followed by standard adjuvant AC (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2, every 3 weeks) for 4 cycles. For patients whose BSA is greater than 2.0 m2, the Adriamycin dosage will be calculated using BSA = 2.0 m2. This is done in order to minimize Adriamycin-induced cardiotoxicity. | Drug: Taxotere/Docetaxel<br>* Taxotere<br>* Other names: docetaxel;Drug: doxorubicin<br>* AC (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2, every 3 weeks) for 4 cycles before surgery.<br>* Other names: AC, ADRIAMYCIN/CYTOXAN;|
| Experimental: B: AC Adriamycin/Cytoxan<br>In Arm B, patients will receive AC (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2, every 3 weeks) for 4 cycles before surgery. For patients whose BSA is greater than 2.0 m2, the Adriamycin dosage will be calculated using BSA = 2.0 m2. Primary surgery will then be conducted, if operable, following completion of neoadjuvant treatment. This will be followed by 4 cycles of single agent Taxotere (100 mg/m2) every 3 weeks. | Drug: Adriamycin/Cytoxan<br>* Adriamycin/Cytoxan<br>* Other names: doxorubicin;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological Tumor Response to Neoadjuvant Chemotherapy (Taxotere and AC) | The patients' pathological response were assessed using Chevalier's system which graded the responses into Chevalier 1, 2, 3A, 3B, 3C, 3D, and 4, defined as: Disappearance of all tumor either on macroscopic or microscopic assessment in both the breast and LN (pCR) Presence of in situ carcinoma in the breast. No invasive tumor in breast and no tumor in LN (pCR) Presence of invasive cancer with stromal alteration such as sclerosis or fibrosis (pPR) 3A: Subjectively > 75% therapeutic effect 3B: Subjectively between 50% - 75% therapeutic effect 3C: Subjectively between 25% - 50% therapeutic effect 3D: Subjectively < 25% therapeutic effect OR Grade 4 No or few modification of tumoral appearance (pNR). | 10 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Relapse | Data associated with relapse and progression will be obtained over the course of 10 years. Relapse/progression was defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. | 10 years | 
| Overall Survival |  | 10 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
AC, Breast, Cancer, Taxotere, Validation, Neoadjuvant