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

• Sponsor: M.D. Anderson Cancer Center (Other)
• Overall Status: Unknown status
• CT.gov ID: NCT00499603
• Collaborator: Novartis (Industry), National Cancer Institute (NCI) (NIH)
• Enrollment: 62
• Location: 1
• Arms: 2
• Duration (Months): 117
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: Paclitaxel; Drug: 5-Fluorouracil; Drug: Epirubicin; Drug: Cyclophosphamide; Drug: RAD001	Phase 2

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 62 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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)
• Study Start Date: Jul 1, 2007
• Actual Primary Completion Date: Apr 1, 2012
• Anticipated Study Completion Date: Apr 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Paclitaxel + FEC 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; 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.; Other Names: Taxol ; Drug: 5-Fluorouracil; 500 mg/m^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles.; Other Names: 5-FU Adrucil Efudex ; Drug: Epirubicin; 100 mg/m^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles.; Drug: Cyclophosphamide; 500 mg/m^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles.; Other Names: Cytoxan® Neosar®
Experimental: Paclitaxel + RAD001 + FEC Paclitaxel + RAD001 Followed by FEC (5-Fluorouracil + Epirubicin + Cyclophosphamide)	Drug: Paclitaxel; 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.; Other Names: Taxol ; Drug: 5-Fluorouracil; 500 mg/m^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles.; Other Names: 5-FU Adrucil Efudex ; Drug: Epirubicin; 100 mg/m^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles.; Drug: Cyclophosphamide; 500 mg/m^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles.; Other Names: Cytoxan® Neosar® ; Drug: RAD001; 30 mg by mouth weekly on Days 1, 8, & 15 for 12 cycles.

Outcome Measures

Primary Outcome Measures

1. Number Participants With Inhibition of PI3K/PTEN/AKT Pathway at 48 Hours [48 hours after start of treatment]

   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.

Secondary Outcome Measures

1. Participant Responses Per Treatment Arm at 12 Weeks [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.

2. Participant Responses Per Treatment Arm at 24 Weeks [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030

Sponsors and Collaborators

• M.D. Anderson Cancer Center
• Novartis
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Stacy Moulder, M.D., M.D. Anderson Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• University of Texas MD Anderson Cancer Center Website

Publications

None provided.

• Responsible Party: M.D. Anderson Cancer Center
• ClinicalTrials.gov Identifier: NCT00499603
• Other Study ID Numbers: 2006-0790; NCI-2012-01514; 1K23CA121994-1; 1K23CA121994
• First Posted: Jul 11, 2007
• Last Update Posted: Nov 1, 2016
• Last Verified: Sep 1, 2016

• Keywords provided by M.D. Anderson Cancer Center: Breast Cancer; ER negative; PR negative; HER2neu negative; Tumor Triple Negative Receptors; Paclitaxel; Taxol; RAD001; FEC; 5-Fluorouracil; 5-FU; Adrucil; Efudex; Epirubicin; Cyclophosphamide
• Additional relevant MeSH terms: Breast Neoplasms; Paclitaxel; Cyclophosphamide; Fluorouracil; Epirubicin; Everolimus

Study Results

Participant Flow

Recruitment Details	Participants with triple negative breast cancer who were seen in the Breast Medical Oncology clinic of the MD Anderson Cancer Center were enrolled in the study prior to surgery from August 16, 2007 to September 14, 2010.
Pre-assignment Detail	Sixty-two (62) participants were registered but only fifty (50) were randomized. Nine patients failed the screening process, two patients withdrew consent, and one patient was discontinued due to therapy interruption for greater than 21 days.

Arm/Group Title	Paclitaxel + FEC	Paclitaxel + RAD001 + FEC
Arm/Group Description	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). 5-Fluorouracil : 500 mg/m^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Paclitaxel : 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. Cyclophosphamide: 500 mg/m^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Epirubicin : 100 mg/m^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles.	Paclitaxel + RAD001 Followed by FEC (5-Fluorouracil + Epirubicin + Cyclophosphamide) 5-Fluorouracil : 500 mg/m^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Paclitaxel : 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. RAD001 : 30 mg by mouth weekly on Days 1, 8, & 15 for 12 cycles. Cyclophosphamide: 500 mg/m^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Epirubicin : 100 mg/m^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles.
Period Title: Overall Study
STARTED	27	23
COMPLETED	27	22
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Paclitaxel + FEC	Paclitaxel + RAD001 + FEC	Total
Arm/Group Description	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). 5-Fluorouracil : 500 mg/m^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Paclitaxel : 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. Cyclophosphamide : 500 mg/m^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Epirubicin : 100 mg/m^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles.	Paclitaxel + RAD001 Followed by FEC (5-Fluorouracil + Epirubicin + Cyclophosphamide) 5-Fluorouracil : 500 mg/m^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Paclitaxel : 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. RAD001 : 30 mg by mouth weekly on Days 1, 8, & 15 for 12 cycles. Cyclophosphamide : 500 mg/m^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Epirubicin : 100 mg/m^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles.	Total of all reporting groups
Overall Participants	27	23	50
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	52	46	48
Sex: Female, Male (Count of Participants)
Female	27 100%	23 100%	50 100%
Male	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 7.4%	0 0%	2 4%
Not Hispanic or Latino	25 92.6%	23 100%	48 96%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	2 7.4%	0 0%	2 4%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	5 18.5%	6 26.1%	11 22%
White	18 66.7%	17 73.9%	35 70%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	2 7.4%	0 0%	2 4%
Region of Enrollment (participants) [Number]
United States	27 100%	23 100%	50 100%
Cancer Clinical Stage (participants) [Number]
T1	4 14.8%	3 13%	7 14%
T2	18 66.7%	17 73.9%	35 70%
T3	4 14.8%	1 4.3%	5 10%
T4	1 3.7%	1 4.3%	2 4%
Unknown or Not Reported	0 0%	1 4.3%	1 2%
Regional Lymph Node Stage (Number) [Number]
N0	8 29.6%	6 26.1%	14 28%
N1	10 37%	7 30.4%	17 34%
N2	4 14.8%	2 8.7%	6 12%
Nx	5 18.5%	7 30.4%	12 24%
Unknown or Not Reported	0 0%	1 4.3%	1 2%
Breast Cancer Stage (Number) [Number]
IIA	8 29.6%	8 34.8%	16 32%
IIB	8 29.6%	6 26.1%	14 28%
IIIA	4 14.8%	2 8.7%	6 12%
IIIB	2 7.4%	0 0%	2 4%
IIIC	5 18.5%	7 30.4%	12 24%

Outcome Measures

1. Primary Outcome

Title	Number Participants With Inhibition of PI3K/PTEN/AKT Pathway at 48 Hours
Description	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.
Time Frame	48 hours after start of treatment

Outcome Measure Data

Analysis Population Description

Participants were randomly assigned 1:1 to receive T-FEC or TR-FEC using a balanced block design stratified by disease stage and menopausal status. One participant in Arm 2 started treatment but had untolerable side effects and was taken off the study and thus was considered inevaluable.

Arm/Group Title	Paclitaxel + FEC	Paclitaxel + RAD001 + FEC
Arm/Group Description	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). 5-Fluorouracil : 500 mg/m^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Paclitaxel : 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. Cyclophosphamide : 500 mg/m^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Epirubicin : 100 mg/m^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles.	Paclitaxel + RAD001 Followed by FEC (5-Fluorouracil + Epirubicin + Cyclophosphamide) 5-Fluorouracil : 500 mg/m^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Paclitaxel : 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. RAD001 : 30 mg by mouth weekly on Days 1, 8, & 15 for 12 cycles. Cyclophosphamide : 500 mg/m^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Epirubicin : 100 mg/m^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles.
Measure Participants	27	22
Number [participants]	27 100%	22 95.7%

2. Secondary Outcome

Title	Participant Responses Per Treatment Arm at 12 Weeks
Description	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.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Participants who did not complete the entire 12 week of paclitaxel +/- RAD001 or the entire 4 cycles of FEC are evaluable for response.

Arm/Group Title	Paclitaxel + FEC	Paclitaxel + RAD001 + FEC
Arm/Group Description	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). 5-Fluorouracil : 500 mg/m^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Paclitaxel : 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. Cyclophosphamide: 500 mg/m^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Epirubicin : 100 mg/m^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles.	Paclitaxel + RAD001 Followed by FEC (5-Fluorouracil + Epirubicin + Cyclophosphamide) 5-Fluorouracil : 500 mg/m^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Paclitaxel : 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. RAD001 : 30 mg by mouth weekly on Days 1, 8, & 15 for 12 cycles. Cyclophosphamide: 500 mg/m^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Epirubicin : 100 mg/m^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles.
Measure Participants	27	23
CR	3 11.1%	0 0%
PR	5 18.5%	11 47.8%
SD	16 59.3%	11 47.8%
PD	3 11.1%	1 4.3%

3. Secondary Outcome

Title	Participant Responses Per Treatment Arm at 24 Weeks
Description	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.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

Participants who did not complete the entire 12 week of paclitaxel +/- RAD001 or the entire 4 cycles of FEC are evaluable for response.

Arm/Group Title	Paclitaxel + FEC	Paclitaxel + RAD001 + FEC
Arm/Group Description	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). 5-Fluorouracil : 500 mg/m^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Paclitaxel : 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. Cyclophosphamide: 500 mg/m^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Epirubicin : 100 mg/m^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles.	Paclitaxel + RAD001 Followed by FEC (5-Fluorouracil + Epirubicin + Cyclophosphamide) 5-Fluorouracil : 500 mg/m^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Paclitaxel : 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. RAD001 : 30 mg by mouth weekly on Days 1, 8, & 15 for 12 cycles. Cyclophosphamide: 500 mg/m^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Epirubicin : 100 mg/m^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles.
Measure Participants	27	23
CR	4 14.8%	2 8.7%
PR	16 59.3%	11 47.8%
SD	7 25.9%	7 30.4%
PD	0 0%	3 13%

Adverse Events

Time Frame	3 years and 9 months
Adverse Event Reporting Description	Serious Adverse Events reported include Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 and Grade 4 combined within each arm. Other Adverse Events were not assessed.
Arm/Group Title	Paclitaxel + FEC		Paclitaxel + RAD001 + FEC
Arm/Group Description	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). 5-Fluorouracil : 500 mg/m^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Paclitaxel : 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. Cyclophosphamide : 500 mg/m^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Epirubicin : 100 mg/m^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles.		Paclitaxel + RAD001 Followed by FEC (5-Fluorouracil + Epirubicin + Cyclophosphamide) 5-Fluorouracil : 500 mg/m^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Paclitaxel : 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. RAD001 : 30 mg by mouth weekly on Days 1, 8, & 15 for 12 cycles. Cyclophosphamide : 500 mg/m^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles. Epirubicin : 100 mg/m^2 by vein on day 1 every 3 weeks (+/- 7 days) for 4 cycles.
All Cause Mortality
	Paclitaxel + FEC		Paclitaxel + RAD001 + FEC
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Paclitaxel + FEC		Paclitaxel + RAD001 + FEC
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	27/27 (100%)		23/23 (100%)
Blood and lymphatic system disorders
Fatigue	2/27 (7.4%)	2	4/23 (17.4%)	4
Neutropenia	11/27 (40.7%)	11	12/23 (52.2%)	12
Increased leukocytes	3/27 (11.1%)	3	4/23 (17.4%)	4
Anemia	1/27 (3.7%)	1	4/23 (17.4%)	4
Lymphopenia	1/27 (3.7%)	1	0/23 (0%)	0
Thrombocytopenia	2/27 (7.4%)	2	1/23 (4.3%)	1
Gastrointestinal disorders
GI Disturbaces	5/27 (18.5%)	5	6/23 (26.1%)	6
Small bowel obstruction	1/27 (3.7%)	1	0/23 (0%)	0
General disorders
Nail changes	0/27 (0%)	0	1/23 (4.3%)	1
Edema of extremities	1/27 (3.7%)	1	0/23 (0%)	0
Syncope	1/27 (3.7%)	1	0/23 (0%)	0
Infections and infestations
Infection	0/27 (0%)	0	3/23 (13%)	3
Investigations
Hyperglycemia	1/27 (3.7%)	1	0/23 (0%)	0
Hypokalemia	0/27 (0%)	0	1/23 (4.3%)	1
Musculoskeletal and connective tissue disorders
Pain	2/27 (7.4%)	2	3/23 (13%)	3
Respiratory, thoracic and mediastinal disorders
Pulmonary embolus	0/27 (0%)	0	1/23 (4.3%)	1
Skin and subcutaneous tissue disorders
Rash	1/27 (3.7%)	1	2/23 (8.7%)	2
Vascular disorders
Neuropathy	1/27 (3.7%)	1	1/23 (4.3%)	1
Other (Not Including Serious) Adverse Events
	Paclitaxel + FEC		Paclitaxel + RAD001 + FEC
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.