Paclitaxel Followed by FEC Versus Paclitaxel and RAD001 Followed by FEC In Women With Breast Cancer
Condition: Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: Paclitaxel; 5-Fluorouracil; Epirubicin; Cyclophosphamide; RAD001
Intervention description: 80 mg/m^2 by vein once weekly over 1 hour on day 1(+/- 2 days) each week for 3 weeks and for 12 cycles.; 500 mg/m^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles.; 100 mg/m^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles.; 500 mg/m^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles.; 30 mg by mouth weekly on Days 1, 8, & 15 for 12 cycles.
Intervention MeSH terms: Paclitaxel; Cyclophosphamide; Fluorouracil; Epirubicin; Everolimus
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 62.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Breast Cancer; ER negative; PR negative; HER2neu negative; Tumor Triple Negative Receptors; Paclitaxel; Taxol; RAD001; FEC; 5-Fluorouracil; 5-FU; Adrucil; Efudex; Epirubicin; Cyclophosphamide

Summary:

      The goal of this clinical research is to learn if RAD001 given in combination with
      chemotherapy will turn off the signaling pathway (a chain of information that tells cancer
      cells to grow quickly) and make the chemotherapies given on this study more effective.

      Primary Objective

      · To determine if the addition of an mTOR inhibitor to standard neoadjuvant chemotherapy in
      patients with triple receptor-negative breast cancer causes molecular changes
      (inhibition/activation) of the PI3K/PTEN/AKT pathway.

      Secondary Objectives

        -  To evaluate pathologic complete response (pCR) rates for each treatment group.

        -  To evaluate the relationship between pCR and the molecular changes
           (inhibition/activation) of the PI13K/PTEN/AKT pathway in each treatment group.

        -  To evaluate overall response rates (ORR) for each treatment group.

        -  To assess the toxicity of both regimens and to evaluate the relationship of toxicities
           with PI3K/PTEN/AKT pathway status.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Patients with histologic confirmation of invasive ER/PR and HER2/neu-negative breast
             carcinoma. Immunohistochemistry (IHC) must be used for ER/PR evaluation and IHC or
             FISH for determination of HER2/neu. ER/PR will be considered negative if equal or
             lower than 5% IHC staining and HER2/neu will be considered negative if IHC of 0% or
             negative FISH.

          2. Patients must have intact primary tumors.

          3. Age equal or greater than 18 years

          4. Patients should have stage IIA (T1N1) to IIIC non inflammatory breast cancer.

          5. Patients with bilateral breast cancers are eligible.

          6. Patients should have a Karnofsky performance scale of =/> 70%.

          7. Patients must have clinically measurable disease to be treated in the neoadjuvant
             setting. This includes patients with a non-palpable primary tumor who have
             histologically proven lymph node involvement that is clinically palpable and
             measurable by ultrasound.

          8. Patients should have adequate bone marrow function, as defined by peripheral
             granulocyte count of >/= 1500/mm3, and a platelet count >/= 100000/ mm3.

          9. Patients must have adequate liver function with a bilirubin within normal laboratory
             values. Alkaline phosphatase and transaminases (ALT and AST) may be up to 1.5 x upper
             limit of normal (ULN) of the institution.

         10. Patients should have adequate renal function with creatinine levels 2.0 mg/dL or lower

         11. Patients should have a normal left ventricular ejection fraction of =/> 50%.

         12. Negative serum pregnancy test for a woman of childbearing potential.

         13. Women of childbearing potential (WOCBP) must use a reliable and appropriate
             contraceptive method during the study and 6 months after chemotherapy is completed.
             WOCBP are women who are not menopausal for 12 months or had no previous surgical
             sterilization.

         14. Patients must agree to have study biopsies.

         15. Patients must sign an informed consent indicating that they are aware of the
             investigational nature of the study, in keeping with institutional policy.

         16. Hemoglobin 9.0 gm/dL or higher

        Exclusion Criteria:

          1. Patients whose tumors express ER, PR or HER2/neu gene amplification.

          2. Patients with a history of other invasive malignancies diagnosed and treated within
             the previous 5 years, except non-melanoma skin cancer and non-invasive cervical cancer

          3. Patients with an organ allograft or other history of immune compromise

          4. Prior exposure to mTOR inhibitors

          5. Hypersensitivity to rapamycin or other similar compounds

          6. Prior treatment with any investigational drug within the preceding 4 weeks

          7. Chronic treatment with systemic steroids or another immunosuppressive agent

          8. A known history of HIV seropositivity

          9. Impairment of gastrointestinal function or gastrointestinal disease that may
             significantly alter the absorption of RAD001 (e.g., ulcerative disease, uncontrolled
             nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection)

         10. Patients with an active, bleeding diathesis or on oral anti-vitamin K medication
             (except low dose coumadin defined as 1 mg a day).

         11. Other concurrent severe and/or uncontrolled medical disease which could compromise
             participation in the study (i.e., uncontrolled diabetes, uncontrolled hypertension,
             severe infection, severe malnutrition, unstable angina, or congestive heart failure -
             New York Heart Association Class III or IV, ventricular arrhythmias, active ischemic
             heart disease, myocardial infarction within six months, chronic liver or renal
             disease, active upper GI tract ulceration)

         12. Patients with a pre-existing peripheral neuropathy > grade 1

         13. Patients taking medications metabolized by the CYP3A4 subfamily will not be included
             in this study.