Phase I Radiosensitization Study of GW572016 With Biologic Correlates in Locoregionally Recurrent Breast Cancer
- 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
- 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
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Toxicity as assessed by NCI CTCAE v3.0
Elizabeth C. Dees, MD
UNC Lineberger Comprehensive Cancer Center
United States: Federal Government
|Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill||Chapel Hill, North Carolina 27599-7570|