A Study of AC Followed by a Combination of Paclitaxel Plus Trastuzumab or Lapatinib or Both Given Before Surgery to Patients With Operable HER2 Positive Invasive Breast Cancer
- Conditions
- Invasive Breast Cancer
- Interventions
- Registration Number
- NCT00486668
- Lead Sponsor
- NSABP Foundation Inc
- Brief Summary
The primary purpose of this study is to determine whether breast cancer tumors respond (as measured by pathologic complete response: the absence of microscopic evidence of invasive tumor cells in the breast) to combined chemotherapy of AC(doxorubicin and cyclophosphamide) followed by paclitaxel plus trastuzumab or lapatinib or both given before surgery to patients with HER2-positive breast cancer. Trastuzumab will also be given to all patients after surgery. The study will also evaluate the toxic effects of the chemotherapy combination, including effects on the heart, and will determine survival and progression-free survival 5 years after treatment. Also, the study will look at whether there are gene expression profiles in the tumor tissue that can predict pathologic complete response.
- Detailed Description
Women with breast cancers that overexpress HER2 are at greater risk for disease progression and death than women whose tumors do not overexpress HER2. Trastuzumab, a recombinant humanized monoclonal antibody against the extracellular domain of the HER2 protein blocks downstream signaling of HER2 and substantially improves the efficacy of chemotherapy in women with metastatic and early-stage HER2-positive breast cancers. Because resistance to trastuzumab eventually results in progressive disease in the metastatic setting and contributes to recurrence following adjuvant trastuzumab-based therapy, it is important to develop agents other than trastuzumab that target HER2 signaling through different mechanisms of action. Lapatinib is an oral, small molecule, dual tyrosine kinase inhibitor of HER2 and EGFR. Lapatinib has shown a lack of cross-resistance with trastuzumab in preclinical studies and activity in women with HER2-positive, metastatic breast cancer that has progressed during trastuzumab treatment. Trastuzumab blocks the downstream signaling of HER2 by binding to the extracellular domain of the receptor. Lapatinib binds to the intracellular domains of HER2 and EGFR and prevents activation of downstream signaling pathways. Because of this different mechanism of action, lapatinib may be effective in trastuzumab-resistant disease. The study will also provide important safety information on trastuzumab and lapatinib combinations immediately following anthracycline exposure, and also provide an initial direct comparison of cardiac effects of trastuzumab and lapatinib when incorporated into a standard sequential AC followed by weekly paclitaxel (neo)adjuvant regimen.
Availability of a second agent that can interrupt HER2-signaling pathways through completely different mechanisms than those of trastuzumab offers the potential for further improvement in the management of patients with HER2-overexpressing breast cancer in both the adjuvant and metastatic setting. Co-administration of both trastuzumab and lapatinib with chemotherapy may be important in improving outcomes in subsets of HER2-positive breast cancers. However, use of two inhibitors of the HER2 pathway will increase costs and may increase toxicity, so it will be important to identify the subsets of patients who would benefit from the dual therapy. Inhibition of HER2 with a single agent clearly is sufficient for many patients as evidenced by the results of the trastuzumab trials. Therefore, co-administration to unselected populations of women with HER2-positive breast cancers would not represent an optimal approach. Given the activity of lapatinib, it is likely that it will also be sufficiently active in inhibiting HER2-pathway activation in some patients to allow for its use as the sole inhibitor of the HER2 pathway. Different populations may also derive greater benefit from one of the HER2-blocking agents relative to the other. Identification of potential predictive factors for pathologic complete response to the combination or to either agent administered alone in neoadjuvant trials would provide important information for adjuvant trials designed to definitively address these important issues.
This study will compare 3 combined chemotherapy regimens: AC followed by paclitaxel plus trastuzumab and lapatinib, AC followed by paclitaxel plus lapatinib, and AC followed by paclitaxel plus trastuzumab given before surgery to patients with HER2-positive breast cancer.
Recruitment & Eligibility
- Status
- UNKNOWN
- Sex
- Female
- Target Recruitment
- 529
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Group 1: AC then paclitaxel + trastuzumab doxorubicin AC followed by paclitaxel plus trastuzumab Group 1: AC then paclitaxel + trastuzumab cyclophosphamide AC followed by paclitaxel plus trastuzumab Group 1: AC then paclitaxel + trastuzumab paclitaxel AC followed by paclitaxel plus trastuzumab Group 1: AC then paclitaxel + trastuzumab trastuzumab AC followed by paclitaxel plus trastuzumab Group 2: AC then paclitaxel + lapatinib doxorubicin AC followed by paclitaxel plus lapatinib Group 2: AC then paclitaxel + lapatinib cyclophosphamide AC followed by paclitaxel plus lapatinib Group 2: AC then paclitaxel + lapatinib paclitaxel AC followed by paclitaxel plus lapatinib Group 2: AC then paclitaxel + lapatinib lapatinib AC followed by paclitaxel plus lapatinib Group 3: AC then paclitaxel + trastuzumab + lapatinib doxorubicin AC followed by paclitaxel plus trastuzumab plus lapatinib Group 3: AC then paclitaxel + trastuzumab + lapatinib trastuzumab AC followed by paclitaxel plus trastuzumab plus lapatinib Group 3: AC then paclitaxel + trastuzumab + lapatinib cyclophosphamide AC followed by paclitaxel plus trastuzumab plus lapatinib Group 3: AC then paclitaxel + trastuzumab + lapatinib paclitaxel AC followed by paclitaxel plus trastuzumab plus lapatinib Group 3: AC then paclitaxel + trastuzumab + lapatinib lapatinib AC followed by paclitaxel plus trastuzumab plus lapatinib
- Primary Outcome Measures
Name Time Method Determination of pathologic complete response (pCR), defined by the absence of microscopic evidence of invasive tumor cells in the post chemotherapy surgical breast specimen. surgery following chemotherapy
- Secondary Outcome Measures
Name Time Method The determination of pCR in the surgical breast and lymph node specimens following chemotherapy. surgery following chemotherapy Clinical tumor measurement as assessed by physical exam of the breast and lymph nodes baseline (prior to starting protocol therapy), at the completion of AC (before starting paclitaxel and trastuzumab and/or lapatinib), and at the conclusion of the sequential regimens (prior to surgery). Determination of cardiac toxicity as measured by the incidence of cardiac events defined as definite or probable cardiac death two year cumulative incidence Determination of non-cardiac toxicities as measured by frequencies of adverse events categorized using CTCAE v3.0. through 5 years after entry Overall survival as measured by time from randomization until death from any cause. through 5 years after entry Recurrence-free interval as measured by occurrence of inoperable progressive disease, or from time of surgery to occurrence of local, regional, or distant recurrence in patients with operable disease. through 5 years after entry In tumor tissue, a comparison of array comparative genomic hybridization (CGH) data with gene expression profile data to examine coordinated overexpression of amplified genes, especially in HER2 and cMYC loci. Tissue sample collected at surgery following chemotherapy
Trial Locations
- Locations (110)
MBCCOP, Gulf Coast
🇺🇸Mobile, Alabama, United States
Scripps Cancer Center-San Diego
🇺🇸La Jolla, California, United States
University of California, Irvine Medical Center
🇺🇸Long Beach, California, United States
Pacific Shores Medical Group
🇺🇸Long Beach, California, United States
St. Joseph Hospital
🇺🇸Orange, California, United States
Desert Regional Medical Center Comprehensive Cancer Center
🇺🇸Palm Springs, California, United States
Stanford University Medical Center
🇺🇸Palo Alto, California, United States
Sutter Medical Center
🇺🇸Sacramento, California, United States
Kaiser Permanente-San Diego
🇺🇸San Diego, California, United States
Santa Rosa Memorial Hospital
🇺🇸Santa Rosa, California, United States
Scroll for more (100 remaining)MBCCOP, Gulf Coast🇺🇸Mobile, Alabama, United States