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
Overview
- Phase
- Phase 2
- Intervention
- Epirubicin
- Conditions
- Breast Cancer
- Sponsor
- NSABP Foundation Inc
- Enrollment
- 105
- Locations
- 36
- Primary Endpoint
- Number of Participants With Cardiac Events
- Status
- Completed
- Last Updated
- 4 years ago
Overview
Brief Summary
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
Detailed Description
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Conditions for eligibility for patients with LABC (Cohort A):
- •The diagnosis of invasive adenocarcinoma of the breast must have been made by core needle biopsy or limited incisional biopsy.
- •Patients must have clinical Stage IIIA, IIIB, or IIIC disease with a mass in the breast or axilla that is greater than or equal to 2.0 cm measured by clinical exam, unless the patient has inflammatory breast carcinoma, in which case measurable disease is not required.
- •Conditions for eligibility for patients with resected Stage III breast cancer (Cohort B)
- •Patients must have undergone either a total mastectomy or a lumpectomy.
- •Patients must have completed one of the following procedures for evaluation of pathologic nodal status.
- •Sentinel lymphadenectomy followed by removal of additional non-sentinel lymph nodes, or
- •Axillary lymphadenectomy without SN isolation procedure.
- •The interval between the last surgery (for breast cancer treatment or staging) and study entry must be no more than 84 days.
- •By pathologic evaluation, ipsilateral nodes must be pN2 or pN
Exclusion Criteria
- •Conditions for patient ineligibility (Cohort A)
- •FNA alone to diagnose the primary tumor.
- •Surgical axillary staging procedure prior to study entry. (Procedures that are permitted include: 1) FNA or core biopsy of an axillary node for any patient, and 2) although not recommended, a pre-neoadjuvant therapy SN biopsy for patients with clinically negative axillary nodes.
- •Condition for patient ineligibility (Cohort B)
- •Breast reconstruction using tissue expanders or implants at the time of mastectomy.
- •Conditions for patient ineligibility (ALL patients)
- •Definitive clinical or radiologic evidence of metastatic disease.
- •Synchronous bilateral invasive breast cancer.
- •History of ipsilateral or contralateral invasive breast cancer regardless of treatment or ipsilateral DCIS treated with RT.
- •History of non-breast malignancies within the 5 years prior to study entry. Patients with the following cancers are eligible if diagnosed and treated within the previous 5 years: carcinoma in situ of the cervix, carcinoma in situ of the colon, melanoma in situ, and basal cell and squamous cell carcinoma of the skin.
Arms & Interventions
1
* 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
Intervention: Epirubicin
1
* 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
Intervention: Cyclophosphamide
1
* 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
Intervention: Docetaxel
1
* 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
Intervention: Trastuzumab
1
* 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
Intervention: Bevacizumab
Outcomes
Primary Outcomes
Number of Participants With Cardiac Events
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.
The number of cardiac events defined as NYHA Class III/IV CHF and cardiac death.To determine the rate of cardiac events (NYHA Class III/IV CHF and cardiac death) of a regimen of EC followed by THA when administered to: Cohort A as neoadjuvant therapy for HER-2 positive locally advanced (clinical stage IIIA, IIIB or IIIC breast cancer or Cohort B as adjuvant therapy for resected HER2-positive pN2 or pN3 (pathologic stage III) breast cancer. The number of participants with one or more cardiac events are being reported.
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
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.
Secondary Outcomes
- Percentage of Participants With Surgical Complications (From Mastectomy, Lumpectomy, and Axillary Staging Procedures) (Cohort A)(2-4 weeks after surgery and at 9 and 12 months from study entry)
- Clinical Complete Response (cCR)(Determined at baseline, 2-3 weeks after the last EC dose, 2-4 weeks after last Docetaxel dose-before surgery.)
- Grade 3 and 4 Toxicities, Including Toxicities Associated With Radiation Therapy(RT)(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)
- Overall Survival(From the first dose of study therapy until the date of death or for a maximum of five (5) years from study entry)
- Number of Participants With no Histologic Evidence of Invasive Tumor Cells in the Surgical Breast Specimen.(Assessed at the time of surgery)
- Recurrence-free Survival(From the first dose of study therapy until the date of recurrence or for a maximum of five (5) years from study entry)