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Phase I Radiosensitization Study of GW572016 With Biologic Correlates in Locoregionally Recurrent Breast Cancer

Phase 1
18 Years
Not Enrolling
Breast Cancer

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Trial Information

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
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

Inclusion Criteria


- 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

- 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


- 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


- See Disease Characteristics

- Recovered from prior therapy

- At least 3 weeks since prior and no other concurrent systemic therapy for breast

- 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)

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Toxicity as assessed by NCI CTCAE v3.0

Outcome Time Frame:

4-5 years

Safety Issue:


Principal Investigator

Elizabeth C. Dees, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

UNC Lineberger Comprehensive Cancer Center


United States: Federal Government

Study ID:

LCCC 0411



Start Date:

April 2006

Completion Date:

August 2012

Related Keywords:

  • Breast Cancer
  • recurrent breast cancer
  • stage IIIA breast cancer
  • stage IIIB breast cancer
  • stage IIIC breast cancer
  • stage IV breast cancer
  • male breast cancer
  • Breast Neoplasms



Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel HillChapel Hill, North Carolina  27599-7570