Lapatinib and Radiation Therapy in Treating Patients With Locally Recurrent or Chemotherapy-Refractory Locally Advanced or Metastatic Breast Cancer

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

DISEASE CHARACTERISTICS:

• Diagnosis of breast cancer meeting 1 of the following criteria:

• Locally recurrent disease
• Locally advanced disease AND meets the following criterion:

• Chemotherapy-refractory disease (achieved < partial response to ≥ 3 courses of neoadjuvant chemotherapy)
• Metastatic disease
• Evaluable disease by exam and/or imaging studies

• Amenable to serial biopsies by skin punch, core biopsy, or fine-needle aspiration
• Unresectable disease after standard neoadjuvant chemotherapy

• Resectability must be determined by a surgical oncologist prior to treatment
• Stable CNS metastases allowed
• Hormone receptor status not specified

PATIENT CHARACTERISTICS:

• Male or female
• Menopausal status not specified
• Life expectancy > 12 weeks
• ECOG performance status 0-2
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Able to swallow and retain oral medication
• WBC ≥ 3,000/mm³
• ANC ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Total bilirubin normal
• AST and ALT ≤ 2.5 times upper limit of normal
• Creatinine normal OR creatinine clearance ≥ 60 mL/min
• Cardiac ejection fraction normal by ECHO or MUGA
• No other malignancy within the past 5 years
• No concurrent disease or condition that would preclude study participation
• No ongoing coagulopathy
• No active severe infection

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• Recovered from prior therapy
• At least 3 weeks since prior and no other concurrent systemic therapy for breast cancer
• At least 14 days since prior and no concurrent herbal or alternative medicine
• At least 14 days since prior and no concurrent dietary supplement
• At least 14 days since prior CYP3A4 inducers
• At least 7 days since prior CYP3A4 inhibitors
• No antacid within 1 hour before or after study drug administration
• Concurrent bisphosphonate allowed
• No concurrent oral glucocorticosteroid > 1.5 mg of dexamethasone (or equivalent)