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

UNC Lineberger Comprehensive Cancer Center

Status and phase

Completed

Phase 1

Conditions

Breast Cancer

Treatments

Genetic: gene expression analysis

Genetic: TdT-mediated dUTP nick end labeling assay

Genetic: microarray analysis

Other: immunohistochemistry staining method

Procedure: biopsy

Radiation: radiation therapy

Drug: lapatinib ditosylate

Study type

Interventional

Funder types

Other

NIH

Identifiers

NCT00379509

LCCC 0411

P30CA016086 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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.

Full 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

Enrollment

20 patients

Sex

All

Ages

18 to 120 years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

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)