Lapatinib and Radiation Therapy in Treating Patients With Locally Recurrent or Chemotherapy-Refractory Locally Advanced or Metastatic Breast Cancer
Condition: Breast Cancer
MeSH terms: Breast Neoplasms
Study type: Interventional
Phase: Phase 1

Summary: 
      RATIONALE: Lapatinib may stop the growth of tumor cells by blocking some of the enzymes
      needed for cell growth. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving
      lapatinib together with radiation therapy may kill more tumor cells.

      PURPOSE: This phase I trial is studying the side effects and best dose of lapatinib when
      given together with radiation therapy in treating patients with locally recurrent or
      chemotherapy-refractory locally advanced or metastatic breast cancer.
    

Detailed description: 
      OBJECTIVES:

      Primary

        -  Determine the toxicity of lapatinib ditosylate and radiotherapy in patients with locally
           recurrent breast cancer or chemotherapy-refractory, locally advanced or metastatic
           breast cancer.

        -  Determine the impact of this drug on inhibition of receptor and downstream signal
           transduction pathway activation in tumor tissue, in the context of inhibitor dose
           escalation with or without radiotherapy.

      Secondary

        -  Determine, preliminarily, the efficacy of lapatinib ditosylate and radiotherapy in these
           patients.

        -  Correlate response in these patients with inhibition of downstream signaling.

        -  Assess gene expression changes in tumor biopsy samples from patients treated with
           lapatinib ditosylate alone or in combination with radiotherapy.

      OUTLINE: This is a multicenter, parallel group, dose-escalation study of lapatinib
      ditosylate. Patients are stratified according to prior radiotherapy (yes vs no).

        -  Group I (prior radiotherapy): Patients receive oral lapatinib ditosylate once daily in
           the absence of disease progression or unacceptable toxicity. Beginning on day 8 of
           lapatinib ditosylate therapy, patients undergo concurrent radiotherapy 5 days a week for
           up to 5 weeks.

        -  Group II (no prior radiotherapy): Patients receive oral lapatinib ditosylate as in group
           I. Beginning on day 8, patients undergo concurrent radiotherapy 5 days a week for up to
           7 weeks.

      In each group, cohorts of 3-6 patients receive escalating doses of lapatinib ditosylate until
      the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that
      at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity during the first course.

      Patients undergo skin punch or core biopsy at baseline* and on day 8 and day 15. Tumor biopsy
      samples are examined by IHC for evaluation of EGFR, phospho-EGFR, HER2, phospho-HER2,
      phospho-Akt, and phospho-MAPK. Samples are also examined for cell proliferation by Ki-67,
      apoptosis by TUNEL, and angiogenesis by microvessel density. Additionally, mRNA is extracted
      from fresh frozen samples and examined by microarray analysis.

      NOTE: *Archival tissue acceptable for baseline sample, if available
    

Intervention name(s): lapatinib ditosylate; TdT-mediated dUTP nick end labeling assay; gene expression analysis; microarray analysis; immunohistochemistry staining method; biopsy; radiation therapy
Intervention type(s): Drug; Genetic; Genetic; Genetic; Other; Procedure; Radiation
Intervention description(s): Patients will be assigned in cohorts of 3. Dose levels of GW572106 will include 500mg, 1000mg,1500 mg (additional levels at 750 mg and 1250 mg will be added if needed). Lapatinib is an oral drug. It is taken every day.; Genetic analysis of tumor tissue; Genetic analysis of tumor tissue.; Genetic analysis of tumor tissue.; Laboratory analysis of tumor tissue.; Serial biopsies by skin punch or core biopsy or fine needle aspiration.; Radiotherapy will be delivered at standard dose and fractionation. For patients who have not received previous locoregional radiotherapy, 50-56 Gy will be delivered to the regional lymph nodes and/or chest wall at a dose of 2 Gy per fraction, 5 days per week followed by a boost to the sites of gross involvement to a total dose of 60-70 Gy over a course of 6-7 weeks. For patients who have received adjuvant radiotherapy, a dose of 35-45 Gy will be delivered to sites of chest wall involvement at a dose of 1.8 Gy per fraction over 4-5 weeks. In either de novo or reirradiated settings, the total dose to the brachial plexus will not exceed 60 Gy.
Intervention MeSH terms: Lapatinib
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: recurrent breast cancer; stage IIIA breast cancer; stage IIIB breast cancer; stage IIIC breast cancer; stage IV breast cancer; male breast cancer