Paclitaxel Followed by FEC Versus Paclitaxel and RAD001 Followed by FEC In Women With Breast Cancer

Study Overview
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Brief Summary
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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.

Detailed Description
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RAD001 is a new drug that was designed to block proteins that are important in the development and growth of cancer. It may also stop the growth of new blood vessels that help tumor growth, resulting in cell death. Before you can start treatment on this study, you will have screening tests. These tests will help the doctor decide if you are eligible to take part in this study. You will have a complete physical exam. Blood (about 6 tablespoons) will be drawn for routine tests and to test for the amount of fat in the blood. You will have a chest x-ray, bone scan and a 2-D echocardiogram (a test to evaluate the pumping function of the heart). You will have a computed tomography (CT) scan of the chest and abdomen (stomach area). Women who are able to have children must have a negative blood (about 1 tablespoon) pregnancy test. You will have a mammogram and an ultrasound of the breast and armpit to record tumor size. As part of this study, you will have a fine needle biopsy of the breast tumor to test for the signaling pathway. You will receive a separate consent form for the mammogram, ultrasound, and biopsy and these procedures will be discussed with you in more detail. The fine needle biopsy is a procedure that would not be performed if you were not on this study. If you are found to be eligible to take part in this study, you will be randomly assigned (as in the toss of a coin) to one of two treatment groups. You will have an equal chance of being assigned to either group. If you are assigned to Group 1, you will receive paclitaxel once a week through a needle in your vein over 1 hour. You will have a total of 12 treatments. Before each treatment, you may also receive drugs to help prevent or reduce your risk of side effects from paclitaxel. If you are assigned to Group 2, you will receive paclitaxel and RAD001. You will receive paclitaxel once a week through a needle in your vein over 1 hour. You will have a total of 12 treatments. Before each treatment, you may also receive drugs to help prevent or reduce your risk of side effects from paclitaxel. You will take RAD001, by mouth, on each day you receive paclitaxel. You should take RAD001 on an empty stomach or after a light meal. Pills will not be taken out of their package until the staff is ready for you to take them, since they can be damaged by light or humidity. Participants in both groups will have blood (about 2 tablespoons) drawn for routine tests before each weekly dose of chemotherapy. You will have a second fine needle biopsy 2 days after starting treatment. This will be done to check to see if the signaling pathway has been affected. After your 12 weeks of treatment with paclitaxel or paclitaxel and RAD001, you will have an ultrasound and if tumor is visible, a fine needle biopsy to check to see if the signaling pathway has been affected. After the 12 week treatment with either paclitaxel or paclitaxel and RAD001, you will begin treatment with 5-fluorouracil, epirubicin, and cyclophosphamide. This drug combination is called FEC. You will receive FEC through needle in your vein (over 1 hour) once every 3 weeks. You will have 4 treatments (12 weeks total). Before each treatment, you may also receive drugs to help prevent or reduce your risk of side effects from FEC. Once you have finished treatment with FEC, you will have a mammogram and ultrasound to check the status of the disease. This mammogram and ultrasound will also be used by the doctor to decide whether to remove all or part of the breast and/or nearby lymph nodes during surgery. You will then have surgery to remove all or part of the breast that has the tumor. If there are signs that the lymph nodes in the armpit contain cancer, these lymph nodes will also be removed. You will receive a separate consent form for these procedures and your doctor will discuss them in more detail. If available, a portion of left over tumor tissue will be collected to check to see if the signaling pathway has been affected. You will be considered off study once you have had surgery. You will be taken off study early if the disease gets worse or intolerable side effects occur. This is an investigational study. Paclitaxel, 5-fluorouracil, cyclophosphamide, and epirubicin are all FDA approved and commercially available. RAD001 is not FDA approved or commercially available. It has been authorized for use in research only. Up to 50 patients will take part in this study. All will be enrolled at M. D. Anderson.

Official Title
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Open Label Randomized Clinical Trial of Standard Neoadjuvant Chemotherapy (Paclitaxel Followed by FEC) Versus the Combination of Paclitaxel and RAD001 Followed by FEC in Women With Triple Receptor-Negative Breast Cancer (CRAD001C24101)

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Paclitaxel
* Drug: 5-Fluorouracil
* Drug: Epirubicin
* Drug: Cyclophosphamide
* Drug: RAD001


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Patients must have intact primary tumors. Age equal or greater than 18 years Patients should have stage IIA (T1N1) to IIIC non inflammatory breast cancer. Patients with bilateral breast cancers are eligible. Patients should have a Karnofsky performance scale of =/> 70%. 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. Patients should have adequate bone marrow function, as defined by peripheral granulocyte count of >/= 1500/mm3, and a platelet count >/= 100000/ mm3. 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. Patients should have adequate renal function with creatinine levels 2.0 mg/dL or lower Patients should have a normal left ventricular ejection fraction of =/> 50%. Negative serum pregnancy test for a woman of childbearing potential. 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. Patients must agree to have study biopsies. Patients must sign an informed consent indicating that they are aware of the investigational nature of the study, in keeping with institutional policy. Hemoglobin 9.0 gm/dL or higher Exclusion Criteria: Patients whose tumors express ER, PR or HER2/neu gene amplification. 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 Patients with an organ allograft or other history of immune compromise Prior exposure to mTOR inhibitors Hypersensitivity to rapamycin or other similar compounds Prior treatment with any investigational drug within the preceding 4 weeks Chronic treatment with systemic steroids or another immunosuppressive agent A known history of HIV seropositivity 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) Patients with an active, bleeding diathesis or on oral anti-vitamin K medication (except low dose coumadin defined as 1 mg a day). 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) Patients with a pre-existing peripheral neuropathy > grade 1 Patients taking medications metabolized by the CYP3A4 subfamily will not be included in this study.

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 |
| --- | --- |
| Experimental: Paclitaxel + FEC<br>Paclitaxel 80 mg/m^2 intravenously (IV) on day 1(+/- 2 days) of each week, followed by four cycles of combination 5-Fluorouracil at 500 mg/m^2, Epirubicin at 100 mg/m^2 and Cyclophosphamide at 500 mg/m^2 (FEC) on day 1 every 3 weeks (+/- 7 days). | Drug: Paclitaxel<br>* 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.<br>* Other names: Taxol;Drug: 5-Fluorouracil<br>* 500 mg/m^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles.<br>* Other names: Efudex;Drug: Epirubicin<br>* 100 mg/m^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles.<br>Drug: Cyclophosphamide<br>* 500 mg/m^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles.<br>* Other names: Neosar®;|
| Experimental: Paclitaxel + RAD001 + FEC<br>Paclitaxel + RAD001 Followed by FEC (5-Fluorouracil + Epirubicin + Cyclophosphamide) | Drug: Paclitaxel<br>* 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.<br>* Other names: Taxol;Drug: 5-Fluorouracil<br>* 500 mg/m^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles.<br>* Other names: Efudex;Drug: Epirubicin<br>* 100 mg/m^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles.<br>Drug: Cyclophosphamide<br>* 500 mg/m^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles.<br>* Other names: Neosar®;Drug: RAD001<br>* 30 mg by mouth weekly on Days 1, 8, & 15 for 12 cycles.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number Participants With Inhibition of PI3K/PTEN/AKT Pathway at 48 Hours | Number of participants with inhibition of the PI3K/PTEN/AKT pathway at 48 hours after the start of treatment, regardless of the status of the pathway at the time of randomization. Molecular changes (inhibition/activation) of the PI3K/PTEN/AKT pathway evaluated using reverse phase protein arrays (RPPA) where fine-needle aspirations (FNAs) from the primary breast cancer obtained pretreatment, and at 48 hours. Bioinformatics cluster analysis of arrays used to define molecular changes as inhibition or activation where pathways called 'active' with presence of 2 or more phosphorilated pathway proteins (pAKT, pmTOR, pGSK3, pS6K1, pS6), and 'inhibited' with one or none phosphorilated pathway proteins present. | 48 hours after start of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participant Responses Per Treatment Arm at 12 Weeks | Radiographic criteria of response based on regional ultrasound examination (decrease in size of the primary tumor and/or fatty replacement in regional lymph nodes), and includes partial response and complete response. A decrease in size of the product of the two largest dimensions =/> 50% considered a partial response (PR), and a complete disappearance of the primary tumor by physical exam and or ultrasound and normalization of the lymph nodes by ultrasound will be considered a complete clinical response (CR). Stable Disease (SD) is carcinoma neither decreasing nor increasing in extent or severity, and Progression of disease (PD) defined as 30% increase in size primary tumor and/or lymph nodes on physical exam and/or ultrasound. | 12 weeks | 
| Participant Responses Per Treatment Arm at 24 Weeks | Radiographic criteria of response based on regional ultrasound examination (decrease in size of the primary tumor and/or fatty replacement in regional lymph nodes), and includes partial response and complete response. A decrease in size of the product of the two largest dimensions =/> 50% considered a partial response (PR), and a complete disappearance of the primary tumor by physical exam and or ultrasound and normalization of the lymph nodes by ultrasound will be considered a complete clinical response (CR). Stable Disease (SD) is carcinoma neither decreasing nor increasing in extent or severity, and Progression of disease (PD) defined as 30% increase in size primary tumor and/or lymph nodes on physical exam and/or ultrasound. | 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ER negative, Breast Cancer, PR negative, HER2neu negative, Tumor Triple Negative Receptors, Paclitaxel, Taxol, RAD001, FEC, 5-Fluorouracil, 5-FU, Adrucil, Efudex, Epirubicin, Cyclophosphamide