Lapatinib Ditosylate in Treating Patients With Ductal Breast Carcinoma In Situ

Study Overview
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Brief Summary
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This randomized phase I/II trial studies the side effects and best dose of lapatinib ditosylate and to see how well it works in treating patients with ductal breast carcinoma in situ. Lapatinib ditosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine whether lapatinib (lapatinib ditosylate) therapy at the dose of 1000 mg results in a statistically significantly lower rate of proliferation in ductal carcinoma in situ (DCIS) breast cancer cells as measured by Ki67 when compared to placebo. II. Determine the toxicity profile and frequency of adverse events in women with DCIS breast cancer taking lapatinib at 1000 mg as compared to women taking placebo. SECONDARY OBJECTIVES: I. Determine whether lapatinib treatment affects the incidence of DCIS seen at the time of surgical excision. II. Determine whether treatment with lapatinib will modulate breast tissue histology or the expression of specific biomarkers in normal and DCIS breast cancer cells. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive lapatinib ditosylate orally (PO) once daily (QD) for 2-6 weeks until the time of surgery. ARM II: Patients receive placebo PO QD for 2-6 weeks until the time of surgery. After completion of study treatment, patients are followed for 4-5 weeks.

Official Title
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Neoadjuvant Trial of Lapatinib for the Treatment of Women With DCIS Breast Cancer

Conditions
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Ductal Breast Carcinoma In Situ, HER2/Neu Positive

Intervention / Treatment
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* Other: Laboratory Biomarker Analysis
* Drug: Lapatinib Ditosylate
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must be premenopausal or postmenopausal Participants must have a diagnosis of ductal carcinoma in situ made by core needle biopsy The DCIS cells must have high expression of human epidermal growth factor receptor 2 (erbB2) (3+ by immunohistochemical staining or amplification by fluorescence in situ hybridization [FISH]), and/or have detectable expression of epidermal growth factor receptor (EGFR) (1+ or more by immunohistochemical staining) All participants must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines Individuals with a diagnosis of breast cancer, non-melanoma skin cancer, cervical cancer in situ, or early bladder cancer are eligible if they have not been treated with chemotherapy, biological therapy, or breast radiotherapy to the breast currently affected by DCIS within one year; in addition, individuals with a diagnosis of breast cancer may not have used tamoxifen, raloxifene, or other antiestrogen compounds within three months of study day 1 If subjects are of reproductive potential, they must agree to use a reliable contraceptive method or be sexually abstinent; subjects must fulfill these conditions beginning at the time of starting study medications and ending one month after study termination Negative serum pregnancy test (beta-human chorionic gonadotropin [HCG]) at baseline (within 30 days of day 0) for women of child bearing potential Serum creatinine =< 1.5 times the institution?s upper limit of normal Total bilirubin =< 1.5 times the institution's upper limits of normal Serum glutamic oxaloacetic transaminase (SGOT) =< 1.5 times the institution's upper limits of normal Alkaline phosphatase =< 1.5 times the institution's upper limits of normal Albumin =< 1.5 times the institution's upper limits of normal White blood cells (WBC) > 4.0 k/uL Platelet count > 100,000/uL Hematocrit of > 30% Cardiac ejection fraction within normal limits for the institution by multi gated acquisition scan (MUGA) scan or normal cardiac ultrasound (defined as within the upper limit of normal [ULN] for the institution) Eastern Cooperative Oncology Group (ECOG) performance status =< 2 Willingness to refrain from donating blood to others during the study Exclusion Criteria: Individuals are ineligible if they have either active cancer or a prior history of malignancies other than (e.g., breast cancer, skin cancer [basal or squamous cell carcinoma], cervical cancer in situ, or early bladder cancer [preinvasive transitional cell carcinoma of the bladder]) within the past five years Participants are ineligible if they are currently being treated with tamoxifen, raloxifene, or with aromatase inhibitors (letrozole, anastrozole, exemestane) Individuals are ineligible if they have received chemotherapy, biological therapy (e.g., Herceptin), or radiotherapy for the treatment of any cancer within 1 year or if they have received tamoxifen, raloxifene, letrozole, anastrozole, or exemestane therapy within 3 months of study day 1 Individuals currently receiving anticoagulation therapy (e.g., Coumadin) are ineligible Blood urea nitrogen [BUN] > 1.5 x ULN or Creatinine [Cr] > 1.5 x ULN SGOT > 1.5 x ULN Serum glutamate pyruvate transaminase (SGPT) > 1.5 x ULN Alkaline phosphatase > 1.5 x ULN Bilirubin > 1.5x ULN Individuals who are currently participating in a study of an investigational drug Pregnancy, lactation or unwillingness to use a reliable contraceptive method in women of childbearing potential Severe underlying chronic illness or disease, such as uncontrolled diabetes Individuals with known congestive heart disease or previous myocardial infarction are ineligible Patients taking any prohibited medications Individuals with hypokalemia or hypomagnesemia are ineligible unless these conditions are corrected to within normal limits before starting drug Individuals with congenital long QT syndrome or baseline QTcF intervals > 480 msec on electrocardiogram (EKG) Individuals taking anti-arrhythmics, beta blockers, or other medications that may lead to QT prolongation Individuals who have received a cumulative dose of anthracycline therapy greater than 500 mg/m^2 are ineligible

Ages Eligible for Study
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Minimum Age: 21 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (lapatinib ditosylate)<br>Patients receive lapatinib ditosylate PO once QD for 2-6 weeks until the time of surgery. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Lapatinib Ditosylate<br>* Given PO<br>* Other names: Tykerb;|
| Placebo Comparator: Arm II (placebo)<br>Patients receive placebo PO QD for 2-6 weeks until the time of surgery. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Placebo<br>* Given PO<br>* Other names: sham therapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proliferation (Ki67 IHC) in Ductal Breast Carcinoma In Situ (DCIS) | Reduction in percent of Ki67 positive cells at surgery compared to baseline as a function of treatment. Analysis of the primary treatment comparison will be based on a two sample t-test comparing change in log-transformed Ki67% for placebo and treated subjects. P-values of 0.05 will be considered significant. Proliferation will be assessed by immunohistochemical (IHC) staining for Ki67, and the change in percentage of Ki67 positive cells will be compared in lapatinib-treated samples versus placebo. | 2-6 weeks from baseline to surgery, up to 6 weeks | 
| Incidence of Adverse Events Graded According to the National Cancer Institute (NCI) Common Terminology Criteria (CTCAE) Version 3.0 | Toxicity profile summarized reflects incidence by number of participants affected with adverse events by Maximum Grade 1 to 3, additional adverse event according to the NCI CTCAE version 3.0 reported in Adverse Event section results. | From baseline to 4-5 weeks after surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Ductal Carcinoma in Situ Remaining at Resection | Number of participants with DCIS incidence on surgical excision. Differences in histologic response (disappearance of DCIS) will be evaluated using Fisher's exact test. Correlation analysis and linear models will be used to evaluate associations among marker values at baseline and among changes in marker values and treatment. All statistical tests will be two-sided. | 2-6 weeks from baseline to surgery, up to 6 weeks | 
| Biomarker Analysis of Proliferation Markers | Correlation analysis and linear models will be used to evaluate associations among marker values at baseline and among changes in marker values and treatment. All statistical tests will be two-sided. | 2-6 weeks from baseline to surgery, Up to 6 weeks |