Clinical trial NCT00436566
Conditions: Breast Cancer Cardiac Toxicity
Keywords: cardiac toxicity male breast cancer stage I breast cancer stage II breast cancer stage IIIA breast cancer
Sponsor: Mayo Clinic
Start date: 2007-03-16; Completion date: 2019-07-22
Enrollment: 122 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
RATIONALE: Drugs used in chemotherapy, such as doxorubicin, cyclophosphamide, and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as trastuzumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Lapatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving combination chemotherapy together with trastuzumab and lapatinib after surgery may kill any tumor cells that remain after surgery.

PURPOSE: This randomized phase II trial is studying the side effects and how well giving doxorubicin together with cyclophosphamide followed by trastuzumab, paclitaxel, and lapatinib works in treating patients with early-stage HER2-positive breast cancer that has been removed by surgery.

Detailed description:
OBJECTIVES:

Primary

* Determine the cardiac safety of adjuvant therapy comprising doxorubicin hydrochloride and cyclophosphamide followed by paclitaxel, trastuzumab (Herceptin®), and lapatinib ditosylate in patients with resected early-stage HER2-positive breast cancer.

Secondary

* Determine the adverse event profile of this regimen in these patients.
* Determine the cumulative incidence of cardiac events in patients treated with this regimen.
* Determine the LVEF in patients treated with this regimen.
* Determine the disease-free and overall survival of patients treated with this regimen.
* Compare selected quality-of-life (QOL) questionnaires in these patients.
* Evaluate QOL of patients treated with this regimen.
* Determine the cumulative incidence of pulmonary events in patients treated with this regimen.

Tertiary

* Compare Veridex CellSearch system vs quantitative reverse transcriptase polymerase chain reaction for detecting circulating tumor cells.
* Determine the relationship between serum levels of HER1 and HER2 and response to treatment.
* Evaluate cardiac markers (i.e., troponin-T, troponin-I, brain natriuretic peptide, and creatine kinase MB isoenzyme) at baseline.
* Determine the association between abnormal levels of cardiac markers and incidence of cardiac adverse events.
* Evaluate patterns of 500 metabolites in plasma in patients treated with this regimen and determine the association between metabolite patterns/molecular signatures and cardiotoxicity.
* Determine the time course of these molecular signatures and evaluate whether they are accurate predictors of cardiotoxicity that precede other evidence of cardiotoxicity (e.g., changes in left ventricular function seen by echocardiogram or MUGA scan).
* Compare metabolic signatures of cardiotoxicity with known laboratory evidence of cardiac damage (e.g., troponins or brain natriuretic peptide) in terms of sensitivity and specificity.

OUTLINE: This is a randomized, pilot, multicenter study. Patients are stratified according to educational level (less than high school vs high school or GED vs formal education beyond high school).

Patients receive doxorubicin hydrochloride IV and cyclophosphamide IV on day 1. Treatment repeats every 2-3 weeks for 4 courses. Patients then receive paclitaxel IV over 60 minutes and trastuzumab (Herceptin®) IV over 90 minutes on days 1, 8, and 15 and oral lapatinib ditosylate on days 1-21. Treatment with paclitaxel, trastuzumab, and lapatinib repeats every 3 weeks for up to 4 courses. Patients then receive trastuzumab IV over 30-90 minutes on day 1 and oral lapatinib ditosylate on days 1-21. Treatment with trastuzumab and lapatinib ditosylate repeats every 3 weeks for up to 12 courses.

Patients complete Linear Anologue Self Assessment (LASA) and Symptoms Distress Scale (SDS) questionnaires, including fatigue, diarrhea, and rash assessment, at baseline, after 2-3, 5-6, and 18 months of treatment, and 5 years after completion of treatment. Patients are also randomized to 1 of 2 arms to complete additional quality of life questionnaires at these same time points.

* Arm I: Patients complete EORTC QLQ-C30 and EORTC QLQ-BR23 questionnaires.
* Arm II: Patients complete FACT-B questionnaire. Blood samples are acquired periodically throughout and at the completion of study treatment. Samples are analyzed for circulating tumor cells by Veridex CellSearch system, quantitative reverse transcriptase polymerase chain reaction, and liquid chromatography with tandem mass spectrometry, soluble HER1- and HER2-receptor concentrations, circulating cardiac markers, and metabolic markers for possible correlation with cardiac events.

After completion of study treatment, patients are followed periodically for up to 10 years.

PROJECTED ACCRUAL: A total of 109 patients will be accrued for this study.

Interventions: intervention 1: trastuzumab intervention 2: cyclophosphamide intervention 3: doxorubicin hydrochloride intervention 4: lapatinib ditosylate intervention 5: paclitaxel intervention 6: gene expression analysis intervention 7: reverse transcriptase-polymerase chain reaction intervention 8: fluorophotometry intervention 9: laboratory biomarker analysis intervention 10: mass spectrometry intervention 11: adjuvant therapy intervention 12: quality-of-life assessment
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None intervention 5: None intervention 6: None intervention 7: None intervention 8: None intervention 9: None intervention 10: None intervention 11: None intervention 12: None

Protocol documents: