Doxorubicin and Cyclophosphamide Followed By Trastuzumab, Paclitaxel, and Lapatinib in Treating Patients With Early-Stage HER2-Positive Breast Cancer That Has Been Removed By Surgery
Condition: Breast Cancer; Cardiac Toxicity
MeSH terms: Breast Neoplasms; Cardiotoxicity
Study type: Interventional
Phase: Phase 2

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.
    

Intervention name(s): trastuzumab; cyclophosphamide; doxorubicin hydrochloride; lapatinib ditosylate; paclitaxel; gene expression analysis; reverse transcriptase-polymerase chain reaction; fluorophotometry; laboratory biomarker analysis; mass spectrometry; adjuvant therapy; quality-of-life assessment
Intervention type(s): Biological; Drug; Drug; Drug; Drug; Genetic; Genetic; Other; Other; Other; Procedure; Procedure
Intervention MeSH terms: Paclitaxel; Cyclophosphamide; Doxorubicin; Liposomal doxorubicin; Trastuzumab; Lapatinib
Allocation: Randomized
Intervention model: Single Group Assignment
Primary purpose: Treatment
Keywords: cardiac toxicity; male breast cancer; stage I breast cancer; stage II breast cancer; stage IIIA breast cancer