Therapy With Bevacizumab (BEV), Epirubicin, and Cyclophosphamide Followed by Docetaxel Plus Trastuzumab and BEV Given as Neoadjuvant or Adjuvant Therapy for Women With Locally Advanced HER2 Positive Invasive Breast Cancer
The main purpose is to learn if adding bevacizumab to standard chemotherapy and trastuzumab to treat HER2-positive breast cancer will affect heart function. This study will evaluate:
- How bevacizumab, given with chemotherapy, and then bevacizumab given with trastuzumab after surgery, will affect breast tumors
- Side effects from adding bevacizumab to chemotherapy and trastuzumab
- Whether adding bevacizumab to chemotherapy and trastuzumab for breast cancer will affect the heart
- If receiving bevacizumab will have any effect on how patients recover from surgery
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase II Clinical Trial of Epirubicin Plus Cyclophosphamide Followed by Docetaxel Plus Trastuzumab and Bevacizumab Given as Neoadjuvant Therapy for HER2-Positive Locally Advanced Breast Cancer or Given as Adjuvant Therapy for HER2-Positive Pathologic Stage III Breast Cancer|
- Number of Patients With Pathological Complete Response (pCR) in the Breast and Nodes for Patients With HER2-positive LABC Following Neoadjuvant Treatment (Cohort A) [ Time Frame: Assessed at time of surgery on average at 8 months ] [ Designated as safety issue: No ]The determination of pCR is performed by the local pathologist following examination of tissue (breast and nodes)removed at the time of surgery. The outcome measure is the number of participants with no histologic evidence of invasive tumor cells in the surgical breast specimen, axillary nodes, or SNs identified after neoadjuvant chemotherapy.
- Cardiac Event Rate as Determined by LVEF Assessment [ Time Frame: Cohort A: Baseline, post-treatment with EC, 2-4 weeks after surgery, and 9, 12, 15, and 18 months from study entry. Cohort B: Baseline, post-treatment with EC, 2-3 weeks after the last dose of docetaxel, and 6, 9, 12, 15, and 18 months from study entry. ] [ Designated as safety issue: Yes ]
- pCR in the Breast (Cohort A) [ Time Frame: Assessed at the time of surgery ] [ Designated as safety issue: No ]
- Clinical Complete Response (cCR) [ Time Frame: Determined at baseline, between EC and docetaxel, and following docetaxel (before surgery) ] [ Designated as safety issue: No ]
- Grade 3 and 4 Toxicities, Including Toxicities Associated With Radiation Therapy(RT) [ Time Frame: Before each cycle of pre-op Rx; 2-4 wks after the last docetaxel dose; 2-4 wks post surgery (Cohort A); every 6 wks during post-op Rx (Cohort A); every 6 wks during targeted therapy alone (Cohort B); RT complications assessed at 12 mos from study entry ] [ Designated as safety issue: Yes ]
- Recurrence-free Survival [ Time Frame: From the first dose of study therapy until the date of recurrence or for a maximum of five (5) years from study entry ] [ Designated as safety issue: No ]
- Overall Survival [ Time Frame: From the first dose of study therapy until the date of death or for a maximum of five (5) years from study entry ] [ Designated as safety issue: No ]
- Percentage of Surgical Complications (From Mastectomy, Lumpectomy, and Axillary Staging Procedures) (Cohort A) [ Time Frame: 2-4 weeks after surgery and at 9 and 12 months from study entry ] [ Designated as safety issue: Yes ]
|Study Start Date:||May 2007|
|Estimated Study Completion Date:||May 2014|
|Primary Completion Date:||December 2009 (Final data collection date for primary outcome measure)|
Both Cohorts: Epirubicin 90 mg/m2 IV every 21 days x 4 cycles
Other Name: EllenceDrug: Cyclophosphamide
Both Cohorts: Cyclophosphamide 600 mg/m2 IV every 21 days x 4 cyclesDrug: Docetaxel
Both Cohorts: Docetaxel 100 mg/m2 IV on Day 1 every 21 days x 4 cycles
Other Name: TaxotereDrug: Trastuzumab
Cohort A: Pre-op therapy - 4 mg/kg IV first dose, then subsequent doses at 2 mg/kg IV weekly (16+ weeks) until 1-7 days prior to surgery. Post-operative therapy (beginning no sooner than 28 days after surgery and continuing every 3 weeks x 13 doses) - 8 mg/kg IV first post-op dose, then subsequent doses at 6 mg/kg IV
Cohort B: 4 mg/kg IV first dose, then subsequent doses at 2 mg/kg IV weekly on days 1, 8, and 15. Three (3) weeks after last dose of docetaxel, 6 mg/kg IV and continuing every 3 weeks x 13 doses
Other Name: HerceptinDrug: Bevacizumab
Cohort A: Cycles 1-4, 15 mg/kg IV on day 1 of cycle 4 only; Cycles 5-7, 15 mg/kg IV on day 1 every 21 days x 3 cycles; post-operative therapy (beginning no sooner than 28 days after surgery), 15 mg/kg IV every 3 weeks x 13 doses
Cohort B: Cycles 5-8, 15 mg/kg IV on day 1 every 21 days x 4 cycles; beginning 3 weeks after last dose of docetaxel, 15 mg/kg IV every 3 weeks x 13 doses
Other Name: Avastin
NSABP FB-5 is a Phase II study for women with HER2-positive invasive breast cancer evaluating a regimen of epirubicin plus cyclophosphamide followed by docetaxel plus trastuzumab and bevacizumab in two patient cohorts:
- Cohort A: Women with unresected locally advanced breast cancer (clinical Stage IIIA, IIIB, and IIIC)
- Cohort B: Women with resected pN2 or pN3 (pathologic Stage III) breast cancer.
The primary aims of the study are to determine the rate of cardiac events for all patients and the pCR rate in the breast and axillary lymph nodes for Cohort A. Cardiac events will be defined as NYHA Class III/IV congestive heart failure and cardiac death. For Cohort A, secondary aims of the study include determining the rate of pCR in the breast and the cCR rate following the neoadjuvant therapy. The secondary aims also include determining the value of the regimen in improving 5-year RFS and 5-year OS and determining the non-cardiac toxicities of the regimen in all patients.
Patients in Cohort A will receive neoadjuvant therapy consisting of epirubicin plus cyclophosphamide (EC) every 21 days for 4 cycles plus bevacizumab given on Day 1 of Cycle 4 only, followed by docetaxel every 21 days for 4 cycles plus bevacizumab every 21 days for the initial 3 cycles. Patients will also receive weekly trastuzumab beginning with the first cycle of docetaxel and continuing until 1-7 days before surgery. Patients will then have breast surgery (lumpectomy or mastectomy) with axillary staging. Approximately 4-6 weeks following surgery, bevacizumab and trastuzumab will resume and continue every 3 weeks for 13 doses to complete one year of targeted therapy.
Patients in Cohort B will receive adjuvant therapy consisting of EC every 21 days for 4 cycles followed by docetaxel every 21 days for 4 cycles. Beginning with the first cycle of docetaxel, patients will also receive bevacizumab every 21 days for 4 cycles and weekly trastuzumab until 3 weeks after the last docetaxel dose. Beginning 3 weeks after the last dose of docetaxel, both bevacizumab and trastuzumab will then be given every 3 weeks for 13 doses to complete 1 year of targeted therapy.
Cardiac monitoring will be conducted for both cohorts. For Cohort A, LVEF assessments will be conducted at baseline, post-EC, 2-4 weeks following surgery (about 6 months from study entry), and 9, 12, 15, and 18 months from study entry. For Cohort B, LVEF assessments will be conducted at baseline, post-EC, and 6, 9, 12, 15, and 18 months from study entry. The preferred method for LVEF assessment is 2-D echocardiogram; however, LVEF assessment by MUGA scan is permitted.
Patient follow-up will continue for 5 years following study entry.
The FB-5 sample size is 105 patients.
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|Principal Investigator:||Norman Wolmark, MD||NSABP Foundation, Inc.|