Lapatinib Ditosylate in Treating Patients With Ductal Breast Carcinoma In Situ

Not Applicable

Completed

Conditions: HER2/Neu Positive
Ductal Breast Carcinoma In Situ

Interventions: Other: Laboratory Biomarker Analysis
Drug: Lapatinib Ditosylate
Other: Placebo

Registration Number: NCT00555152

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 22

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm II (placebo)	Laboratory Biomarker Analysis	Patients receive placebo PO QD for 2-6 weeks until the time of surgery.
Arm I (lapatinib ditosylate)	Lapatinib Ditosylate	Patients receive lapatinib ditosylate PO once QD for 2-6 weeks until the time of surgery.
Arm I (lapatinib ditosylate)	Laboratory Biomarker Analysis	Patients receive lapatinib ditosylate PO once QD for 2-6 weeks until the time of surgery.
Arm II (placebo)	Placebo	Patients receive placebo PO QD for 2-6 weeks until the time of surgery.

Primary Outcome Measures

Name	Time	Method
Incidence of Adverse Events Graded According to the National Cancer Institute (NCI) Common Terminology Criteria (CTCAE) Version 3.0	From baseline to 4-5 weeks after surgery	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.
Proliferation (Ki67 IHC) in Ductal Breast Carcinoma In Situ (DCIS)	2-6 weeks from baseline to surgery, up to 6 weeks	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.

Secondary Outcome Measures

Name	Time	Method
Biomarker Analysis of Proliferation Markers	2-6 weeks from baseline to surgery, Up to 6 weeks	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.
Incidence of Ductal Carcinoma in Situ Remaining at Resection	2-6 weeks from baseline to surgery, up to 6 weeks	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.

Trial Locations

Locations (2): M D Anderson Cancer Center
🇺🇸
Houston, Texas, United States
University of Alabama at Birmingham Cancer Center
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Birmingham, Alabama, United States