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

Sponsor

UNC Lineberger Comprehensive Cancer Center (Other)

Overall Status

Completed

CT.gov ID

NCT00379509

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Location

Arm

Duration (Months)

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: lapatinib ditosylate Genetic: TdT-mediated dUTP nick end labeling assay Genetic: gene expression analysis Genetic: microarray analysis Other: immunohistochemistry staining method Procedure: biopsy Radiation: radiation therapy	Phase 1

Detailed 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

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

Study Design

Study Type:

Interventional

Actual Enrollment :

20 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Apr 1, 2006

Actual Primary Completion Date :

Jun 1, 2010

Actual Study Completion Date :

Aug 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: GW572016	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 tissue Genetic: 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.

Arm

Intervention/Treatment

Experimental: GW572016

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 tissue

Genetic: 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.

Outcome Measures

Primary Outcome Measures

Toxicity as assessed by NCI CTCAE v3.0 [4-5 years]
Inhibition of receptor and downstream signal transduction pathway activation in tumor tissue as assessed by IHC [4-5 years]

Secondary Outcome Measures

Efficacy [4-5 years]
Correlation of response with inhibition of downstream signaling [4-5 years]
Gene expression [4-5 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 120 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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)