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
Overview[ - collapse ][ - ]
| Purpose | 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. |
|---|---|
| Condition | Invasive Breast Cancer |
| Intervention | Drug: doxorubicin Drug: cyclophosphamide Drug: paclitaxel Drug: trastuzumab Drug: lapatinib |
| Phase | Phase 3 |
| Sponsor | National Surgical Adjuvant Breast and Bowel Project (NSABP) |
| Responsible Party | National Surgical Adjuvant Breast and Bowel Project (NSABP) |
| ClinicalTrials.gov Identifier | NCT00486668 |
| First Received | June 13, 2007 |
| Last Updated | December 19, 2013 |
| Last verified | December 2013 |
Tracking Information[ + expand ][ + ]
| First Received Date | June 13, 2007 |
|---|---|
| Last Updated Date | December 19, 2013 |
| Start Date | July 2007 |
| Estimated Primary Completion Date | July 2015 |
| Current Primary Outcome Measures | Determination of pathologic complete response (pCR), defined by the absence of microscopic evidence of invasive tumor cells in the post chemotherapy surgical breast specimen. [Time Frame: surgery following chemotherapy] [Designated as safety issue: No] |
| Current Secondary Outcome Measures |
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Descriptive Information[ + expand ][ + ]
| Brief Title | 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 |
|---|---|
| Official Title | A Randomized Phase III Trial of Neoadjuvant Therapy for Patients With Palpable and Operable HER2-Positive Breast Cancer Comparing the Combination of Trastuzumab Plus Lapatinib to Trastuzumab and to Lapatinib Administered With Weekly Paclitaxel Following AC Accompanied by Correlative Science Studies to Identify Predictors of Pathologic Complete Response |
| 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. |
| Study Type | Interventional |
| Study Phase | Phase 3 |
| Study Design | Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment |
| Condition | Invasive Breast Cancer |
| Intervention | Drug: doxorubicin 60 mg/m2 IV every 21 days for cycles 1-4 Drug: cyclophosphamide 600 mg/m2 IV every 21 days for cycles 1-4 Drug: paclitaxel 80 mg/m2 IV on days 1, 8, and 15 every 28 days for cycles 5-8 Drug: trastuzumab First dose: 4 mg/kg IV, subsequent doses: 2 mg/kg IV weekly beginning on day 1 of the first paclitaxel cycle until 1-7 days before surgery Drug: lapatinib Group 2: 1250 mg PO daily beginning on day 1 of the first paclitaxel cycle until 1 day before surgery. Group 3: 750 mg PO daily beginning on day 1 of the first paclitaxel cycle until 1 day before surgery. |
| Study Arm (s) |
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Recruitment Information[ + expand ][ + ]
| Recruitment Status | Active, not recruiting |
|---|---|
| Estimated Enrollment | 529 |
| Estimated Completion Date | July 2015 |
| Estimated Primary Completion Date | June 2012 |
| Eligibility Criteria | Inclusion criteria: - Female - 18 years or older - ECOG performance status of 0 or 1 - Primary breast tumor palpable and measures greater than or equal to 2.0 cm by physical exam - Diagnosis of invasive adenocarcinoma made by core needle biopsy - Breast cancer determined to be HER2-positive - LVEF assessment by MUGA scan or ECG within 3 months prior to randomization - Blood counts must meet the following criteria: - ANC greater than or equal to 1200/mm3 - Platelet count greater than or equal to 100,000/mm3 - Hemoglobin greater than or equal to 10 g/dL - Serum creatinine less than or equal to ULN for the lab - Adequate hepatic function by these criteria: - Total bilirubin less than or equal to the ULN for the lab unless the patient has a bilirubin elevation greater than ULN to 1.5 x ULN resulting from Gilbert's disease or similar syndrome due to slow conjugation of bilirubin; and - Alkaline phosphatase less than or equal to 2.5 x ULN; and - AST less than or equal to 1.5 x ULN for the lab. - If skeletal pain present or alkaline phosphatase greater than ULN (but less than or equal to 2.5 x ULN), bone scan or PET scan must not demonstrate metastatic disease - If AST or alkaline phosphatase greater than ULN , liver imaging (CT, MRI or PET scan) must not demonstrate definitive metastatic disease and the requirements in criterion for hepatic function must be met - Able to swallow oral medications Exclusion criteria: - FNA alone to diagnose the primary tumor - Excisional biopsy or lumpectomy was performed prior to randomization - Surgical axillary staging procedure prior to randomization. Exceptions: 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. - Tumors clinically staged as T4 - Ipsilateral cN2b or cN3 disease (Patients with cN1 or cN2a disease are eligible) - Definitive clinical or radiologic evidence of metastatic disease - Synchronous bilateral invasive breast cancer - Requirement for chronic use of any of the medications or substances specified in the protocol - Treatment including RT, chemotherapy, and/or targeted therapy for the currently diagnosed breast cancer prior to randomization - Any sex hormonal therapy, e.g., birth control pills, ovarian hormone replacement therapy, etc. (These patients are eligible if therapy is discontinued prior to randomization) - Continued therapy with any hormonal agent such as raloxifene, tamoxifen, or other SERM. (Patients are eligible only if these medications are discontinued prior to randomization) - Prior history of breast cancer, including DCIS (Patients with a history of LCIS are eligible) - Prior therapy with anthracyclines, taxanes, trastuzumab, or lapatinib for any malignancy - Other malignancies unless the patient is considered to be disease-free for 5 or more years prior to randomization and is deemed by her physician to be at low risk for recurrence. Patients with the following cancers are eligible if diagnosed and treated within the past 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. - Cardiac disease that would preclude the use of the drugs included in the B-41 treatment regimens. This includes but is not confined to: - Active cardiac disease: - angina pectoris requiring the use of anti-anginal medication; - ventricular arrhythmias except for benign premature ventricular contractions controlled by medication; - conduction abnormality requiring a pacemaker; - supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication; and - clinically significant valvular disease. - History of cardiac disease: - myocardial infarction; - congestive heart failure; or - cardiomyopathy. - Uncontrolled hypertension, defined as blood pressure greater than 150/90 mm/Hg on antihypertensive therapy - History of or current symptomatic interstitial pneumonitis or pulmonary fibrosis or definitive evidence of interstitial pneumonitis or pulmonary fibrosis described on CT or chest x-ray in asymptomatic patients - Sensory/motor neuropathy greater than or equal to grade 2, as defined by the NCI's CTCAE v3.0 - Malabsorption syndrome, ulcerative colitis, resection of the stomach or small bowel, or other disease significantly affecting gastrointestinal function - Other non-malignant systemic disease that would preclude treatment with any of the treatment regimens or would prevent required follow-up - Conditions that would prohibit administration of corticosteroids - Administration of any investigational agents within 30 days before randomization - Pregnancy or lactation |
| Gender | Female |
| Ages | 18 Years |
| Accepts Healthy Volunteers | No |
| Contacts | Not Provided |
| Location Countries | United States, Canada, Puerto Rico |
Administrative Information[ + expand ][ + ]
| NCT Number | NCT00486668 |
|---|---|
| Other Study ID Numbers | NSABP B-41 |
| Has Data Monitoring Committee | Yes |
| Information Provided By | National Surgical Adjuvant Breast and Bowel Project (NSABP) |
| Study Sponsor | National Surgical Adjuvant Breast and Bowel Project (NSABP) |
| Collaborators | GlaxoSmithKline |
| Investigators | Principal Investigator: Norman Wolmark, MD NSABP Foundation, Inc. |
| Verification Date | December 2013 |
Locations[ + expand ][ + ]
| MBCCOP, Gulf Coast | Mobile, Alabama, United States, 36608 |
|---|---|
| Scripps Cancer Center-San Diego | La Jolla, California, United States, 92037 |
| Pacific Shores Medical Group | Long Beach, California, United States, 90813 |
| University of California, Irvine Medical Center | Long Beach, California, United States, 90801 |
| St. Joseph Hospital | Orange, California, United States, 92868 |
| Desert Regional Medical Center Comprehensive Cancer Center | Palm Springs, California, United States, 92262 |
| Stanford University Medical Center | Palo Alto, California, United States, 94304 |
| Sutter Medical Center | Sacramento, California, United States, 95816 |
| Kaiser Permanente-San Diego | San Diego, California, United States, 92120 |
| Santa Rosa Memorial Hospital | Santa Rosa, California, United States, 95403 |
| Kaiser Permanente-Vallejo | Vallejo, California, United States, 94589 |
| University of Colorado Cancer Center | Aurora, Colorado, United States, 80045 |
| Memorial Hospital | Colorado Springs, Colorado, United States, 80909 |
| CCOP-Colorado Cancer Research Prog. Inc.(Administrative Only) | Denver, Colorado, United States, 80224 |
| Kaiser Permanente-Franklin | Denver, Colorado, United States, 80205 |
| Kaiser Permanente Rock Creek | Lafayette, Colorado, United States, 80026 |
| Hartford Hospital | Hartford, Connecticut, United States, 06102 |
| Eastern Connecticut Hematology & Oncology Associates | Norwich, Connecticut, United States, 06360 |
| Sibley Memorial Hospital | Washington, District of Columbia, United States, 20016 |
| MD Anderson Cancer Center | Orlando, Florida, United States, 32806 |
| Phoebe Putney Memorial Hospital | Albany, Georgia, United States, 31701 |
| MBCCOP, Medical College of Georgia Research Institute | Augusta, Georgia, United States, 30912 |
| University of Hawaii | Honolulu, Hawaii, United States, 96813 |
| Kaiser Permanente Hawaii - Moanalua Med Center | Honolulu, Hawaii, United States, 96819 |
| Kootenai Cancer Center | Coeur D'Alene, Idaho, United States, 83814 |
| Rush University Medical Center | Chicago, Illinois, United States, 60612 |
| Decatur Memorial Hospital | Decatur, Illinois, United States, 62526 |
| Cancer Institute at Alexian Brothers Hospital Network | Elk Grove, Illinois, United States, 60007 |
| Edward Hospital | Naperville, Illinois, United States, 60566 |
| Edward Cancer Center Plainfield | Plainfield, Illinois, United States, 60585 |
| CCOP, Central Illinois | Springfield, Illinois, United States, 62526 |
| CCOP, Carle Cancer Center | Urbana, Illinois, United States, 61801 |
| St. Vincent Hospital and Health Care Center | Indianapolis, Indiana, United States, 46260 |
| CCOP, Northern Indiana Cancer Research Consortium | South Bend, Indiana, United States, 46601 |
| CCOP, Des Moines, IA | Des Moines, Iowa, United States, 52501 |
| University of Iowa | Iowa City, Iowa, United States, 52242 |
| CCOP, Sioux Community Cancer consortium | Sioux City, Iowa, United States, 51101 |
| CCOP, Wichita KS | Wichita, Kansas, United States, 67214 |
| University of Kentucky Medical Center | Lexington, Kentucky, United States, 40536 |
| NortonHealtcare Inc. | Louisville, Kentucky, United States, 40202 |
| CCOP, Ochsner Clinic Foundation | New Orleans, Louisiana, United States, 70121 |
| Franklin Square Hospital Center | Baltimore, Maryland, United States, 21237 |
| Greater Baltimore Medical Center | Baltimore, Maryland, United States, 21204 |
| Boston Medical Center | Boston, Massachusetts, United States, 02118 |
| CCOP, Michigan Cancer Research Consortium | Ann Arbor, Michigan, United States, 48106 |
| Henry Ford Hospital | Detroit, Michigan, United States, 48202 |
| Henry Ford Health System | Detroit, Michigan, United States, 48202 |
| CCOP, Grand Rapids Clnical Oncology Program | Grand Rapids, Michigan, United States, 49503 |
| CCOP, Kalamazoo, MI | Kalamazoo, Michigan, United States, 49007 |
| Michigan State University - Breslin Cancer Center | Lansing, Michigan, United States, 48910 |
| CCOP, William Beaumont Hospital | Royal Oak, Michigan, United States, 48073 |
| Providence Hospital - Southfield | Southfield, Michigan, United States, 48075-9975 |
| Hennepin County Medical Center | Minneapolis, Minnesota, United States, 55415 |
| CCOP, Metro-Minnesota | Minneapolis, Minnesota, United States, 55416 |
| University of Missouri-Ellis Fischel | Columbia, Missouri, United States, 65203 |
| CCOP, Kansas City (Administrative Only) | Kansas City, Missouri, United States, 64131 |
| CCOP, Ozark Health Ventures LLC | Springfield, Missouri, United States, 65804 |
| CCOP, Heartland Cancer Research | St. Louis, Missouri, United States, 63131 |
| Saint Louis UniversityHealth Sciences Center | St. Louis, Missouri, United States, 63110 |
| CCOP, Montana Cancer Consortium | Billings, Montana, United States, 59101 |
| CCOP, Missouri Valley Consortium | Omaha, Nebraska, United States, 74136 |
| Cancer Institute of New Jersey | New Brunswick, New Jersey, United States, 08901 |
| Newark Beth Israel Medical Center | Newark, New Jersey, United States, 07112 |
| New York Oncology Hematology PC-Albany | Albany, New York, United States, 12206 |
| Cancer Center at Glens Falls Hospital | Glens Falls, New York, United States, 12801 |
| CCOP, Hematology-Oncology Associates of CNY | Syracuse, New York, United States, 13057 |
| Alamance Regional Medical Center | Burlington, North Carolina, United States, 27215 |
| University of North Carolina at Chapel Hill | Chapel Hill, North Carolina, United States, 28302 |
| CCOP, Southeast Cancer Control Consortium | Charlotte, North Carolina, United States, 28203 |
| Alamance Regional Medical Center - Off site Clinic | Mebane, North Carolina, United States, 27302 |
| Wake Forest University School of Medicine | Winston-Salem, North Carolina, United States, 27157 |
| Akron City Hospital | Akron, Ohio, United States, 44304 |
| Aultman Hospital | Canton, Ohio, United States, 44710 |
| Case Western Reserve/University Hospitals-Ireland Cancer Cntr. | Cleveland, Ohio, United States, 44106 |
| CCOP, Columbus, OH | Columbus, Ohio, United States, 43215 |
| Ohio State University | Columbus, Ohio, United States, 43017 |
| CCOP, Dayton, OH | Dayton, Ohio, United States, 45429 |
| CCOP, Oklahoma | Tulsa, Oklahoma, United States, 74136 |
| Lehigh Valley Hospital | Allentown, Pennsylvania, United States, 18105 |
| Geisinger Clinic | Danville, Pennsylvania, United States, 17882-2170 |
| Hershey Medical Center | Hershey, Pennsylvania, United States, 17033 |
| Albert Einstein Healthcare Network | Philadelphia, Pennsylvania, United States, 19141-3098 |
| NSABP Foundation, Inc. | Pittsburgh, Pennsylvania, United States, 15212 |
| Allegheny General Hospital/Allegheny-Singer Research Institute | Pittsburgh, Pennsylvania, United States, 15212 |
| Western Pennsylvania Hospital | Pittsburgh, Pennsylvania, United States, 15224 |
| University of Pittsburgh | Pittsburgh, Pennsylvania, United States, 15213 |
| Mercy Hospital | Scranton, Pennsylvania, United States, 18501 |
| Reading Hospital & Medical Center | West Reading, Pennsylvania, United States, 19612 |
| CCOP, Main Line Health | Wynnewood, Pennsylvania, United States, 19096 |
| CCOP, Upstate Carolina | Spartanburg, South Carolina, United States, 29303 |
| Sanford Cancer Center | Souix Falls, South Dakota, United States, 57104 |
| Thompson Cancer Survival Center-Dowell Springs | Knoxville, Tennessee, United States, 37909 |
| Joe Arrington Cancer Research & Treatment Center | Lubbock, Texas, United States, 79410 |
| University of Texas Health Science Center at San Antonio | San Antonio, Texas, United States, 78229 |
| MBCCOP, Virginia Commonwealth University | Richmond, Virginia, United States, 23298 |
| CCOP, Virginia Mason | Seattle, Washington, United States, 99519 |
| Puget Sound Oncology Consortium | Seattle, Washington, United States, 98109 |
| CCOP, Northwest | Tacoma, Washington, United States, 83706 |
| West Virginia University Hospitals Inc. | Morgantown, West Virginia, United States, 26506-9162 |
| Camden-Clark Memorial Hospital | Parkersburg, West Virginia, United States, 26101 |
| Wheeling Hospital | Wheeling, West Virginia, United States, 26003 |
| CCOP, Marshfield Clinic | Marshfield, Wisconsin, United States, 54449 |
| Medical College of Wisconsin | Milwaukee, Wisconsin, United States, 53226 |
| Odette Cancer Centre | Toronto, Ontario, Canada, M4N 3M5 |
| Royal Victoria Hospital | Montreal, Quebec, Canada, H3A 1A1 |
| University of Montreal Hospital Group | Montreal, Quebec, Canada |
| Jewish General Hospital | Montreal, Quebec, Canada, H3T 1E2 |
| St. Mary's Hospital Center | Montreal, Quebec, Canada, H3T 1M5 |
| Centre Hospitalier Affilie Universitaire De Quebec, Hospital du St-Sacrement | Quebec City, Quebec, Canada, G1S 4L8 |
| MBCCOP, San Juan, Puerto Rico | San Juan, Puerto Rico, 00936 |