Lapatinib and Radiation Therapy in Treating Patients With Locally Recurrent or Chemotherapy-Refractory Locally Advanced or Metastatic Breast Cancer
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.
Drug: lapatinib ditosylate
Genetic: TdT-mediated dUTP nick end labeling assay
Genetic: gene expression analysis
Genetic: microarray analysis
Other: immunohistochemistry staining method
Radiation: radiation therapy
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase I Radiosensitization Study of GW572016 With Biologic Correlates in Locoregionally Recurrent Breast Cancer|
- Toxicity as assessed by NCI CTCAE v3.0 [ Time Frame: 4-5 years ] [ Designated as safety issue: Yes ]
- Inhibition of receptor and downstream signal transduction pathway activation in tumor tissue as assessed by IHC [ Time Frame: 4-5 years ] [ Designated as safety issue: No ]
- Efficacy [ Time Frame: 4-5 years ] [ Designated as safety issue: No ]
- Correlation of response with inhibition of downstream signaling [ Time Frame: 4-5 years ] [ Designated as safety issue: No ]
- Gene expression [ Time Frame: 4-5 years ] [ Designated as safety issue: No ]
|Study Start Date:||April 2006|
|Study Completion Date:||August 2012|
|Primary Completion Date:||June 2010 (Final data collection date for primary outcome measure)|
Drug: lapatinib ditosylate
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: TdT-mediated dUTP nick end labeling assay
Genetic analysis of tumor tissueGenetic: gene expression analysis
Genetic analysis of tumor tissue.Genetic: microarray analysis
Genetic analysis of tumor tissue.Other: immunohistochemistry staining method
Laboratory analysis of tumor tissue.Procedure: biopsy
Serial biopsies by skin punch or core biopsy or fine needle aspiration.Radiation: radiation therapy
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.
- 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.
- 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
Please refer to this study by its ClinicalTrials.gov identifier: NCT00379509
|United States, North Carolina|
|Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill|
|Chapel Hill, North Carolina, United States, 27599-7295|
|Principal Investigator:||Elizabeth C. Dees, MD||UNC Lineberger Comprehensive Cancer Center|