Lapatinib in Treating Women With Ductal Carcinoma In Situ of the Breast - Full Text View

Sponsor:	M.D. Anderson Cancer Center
Collaborator:	National Cancer Institute (NCI)
Information provided by:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00555152

Purpose

RATIONALE: Lapatinib may stop the growth of ductal carcinoma in situ cells by blocking some of the enzymes needed for cell growth.

PURPOSE: This randomized phase I/II trial is studying the side effects and best dose of lapatinib and to see how well it works in treating women with ductal carcinoma in situ of the breast.

Condition	Intervention	Phase
Breast Cancer	Drug: lapatinib ditosylate Other: placebo	Phase I Phase II

Study Type:	Interventional
Study Design:	Treatment, Randomized, Double-Blind, Placebo Control
Official Title:	Neoadjuvant Trial of Lapatinib for the Treatment of Women With DCIS Breast Cancer

Resource links provided by NLM:

Genetics Home Reference related topics: breast cancer

MedlinePlus related topics: Breast Cancer Cancer

Drug Information available for: Lapatinib Lapatinib Ditosylate

U.S. FDA Resources

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:

Proliferation, as measured by Ki67 in malignant breast cells [ Designated as safety issue: No ]
Toxicity profile at each dose level [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

Incidence of ductal carcinoma in situ seen at resection [ Designated as safety issue: No ]
Biomarker analysis of proliferation markers in normal breast cells and cancerous breast cells [ Designated as safety issue: No ]

Estimated Enrollment:	120
Study Start Date:	September 2007

Arms	Assigned Interventions
Arm I: Experimental Patients receive 1,500 mg of oral lapatinib ditosylate once daily for 2-6 weeks in the absence of disease progression or unacceptable toxicity.	Drug: lapatinib ditosylate Patients receive 750mg, 1,000 mg, or 1,500 mg of oral lapatinib ditosylate once daily for 2-6 weeks in the absence of disease progression or unacceptable toxicity.
Arm II: Experimental Patients receive 1,000 mg of oral lapatinib ditosylate once daily for 2-6 weeks in the absence of disease progression or unacceptable toxicity.	Drug: lapatinib ditosylate Patients receive 750mg, 1,000 mg, or 1,500 mg of oral lapatinib ditosylate once daily for 2-6 weeks in the absence of disease progression or unacceptable toxicity.
Arm III: Experimental Patients receive 750 mg of oral lapatinib ditosylate once daily for 2-6 weeks in the absence of disease progression or unacceptable toxicity.	Drug: lapatinib ditosylate Patients receive 750mg, 1,000 mg, or 1,500 mg of oral lapatinib ditosylate once daily for 2-6 weeks in the absence of disease progression or unacceptable toxicity.
Arm IV: Placebo Comparator Patients receive oral placebo once daily for 2-6 weeks in the absence of disease progression or unacceptable toxicity.	Other: placebo Patients receive oral placebo once daily for 2-6 weeks in the absence of disease progression or unacceptable toxicity.

Detailed Description:

OBJECTIVES:

Primary

Determine the minimal biologic dose of lapatinib ditosylate, defined as the smallest dose, when compared with placebo, that results in a statistically significant lower rate of proliferation in ductal carcinoma in situ (DCIS) breast cancer cells as measured by Ki67.
Determine the toxicity profile and frequency of adverse events in women with DCIS breast cancer taking lapatinib ditosylate at three doses (750 mg, 1,000 mg, and 1,500 mg) as compared with women taking placebo.

Secondary

Determine whether lapatinib ditosylate treatment affects the incidence of DCIS seen at the time of surgical excision.
Determine whether treatment with lapatinib ditosylate will modulate breast tissue histology or the expression of specific biomarkers in normal and DCIS breast cancer cells, including proliferation markers (Ki67 in normal cells), apoptosis marker (cleaved caspase 3), growth factor receptors (EGFR, ErbB2, ErbB3, ErbB4), signal transduction markers (MAPK, phospho-MAPK), hormone receptors (estrogen receptor, progesterone receptor), and p27.

OUTLINE: This is a multicenter study. Patients are stratified according to participating center. Patients are randomized to 1 of 4 treatment arms.

Arm I: Patients receive 1,500 mg of oral lapatinib ditosylate once daily for 2-6 weeks in the absence of disease progression or unacceptable toxicity.
Arm II: Patients receive 1,000 mg of oral lapatinib ditosylate once daily for 2-6 weeks in the absence of disease progression or unacceptable toxicity.
Arm III: Patients receive 750 mg of oral lapatinib ditosylate once daily for 2-6 weeks in the absence of disease progression or unacceptable toxicity.
Arm IV: Patients receive oral placebo once daily for 2-6 weeks in the absence of disease progression or unacceptable toxicity.

All patients then undergo surgery. Tissue samples from initial breast biopsy and subsequent excisional biopsy are collected for the following biomarker studies: proliferation by measuring Ki67 staining in ductal carcinoma in situ (DCIS) breast cancer cells; proliferation in normal cells; apoptosis marker (cleaved caspase 3) expression and activation; phospho-MAPK activation by immunohistochemistry (IHC); total MAPK expression; peptide growth factor receptors (ErbB1 [EGFR], ErbB2 [HER-2/neu], ErbB3, ErbB4) expression; estrogen receptor and progesterone receptor proliferation and differentiation; and p27 activation.

After completion of study treatment, patients are followed for 4-5 weeks.

Eligibility

Ages Eligible for Study:	21 Years and older
Genders Eligible for Study:	Female
Accepts Healthy Volunteers:	No

Criteria

DISEASE CHARACTERISTICS:

Diagnosis of ductal carcinoma in situ (DCIS) made by core needle biopsy
- DCIS cells must have high expression of erbB2 (3+ by IHC staining or amplification by FISH), and/or detectable expression of EGFR (1+ or more by IHC staining)
Hormone receptor status not specified

PATIENT CHARACTERISTICS:

Inclusion criteria:

Female
Pre- or postmenopausal
ECOG performance status 0-2
WBC > 4,000/mm³
Platelet count > 100,000/mm³
Hematocrit > 30%
BUN or serum creatinine ≤ 1.5 times upper limit of normal (ULN)
Total bilirubin ≤ 1.5 times ULN
ALT and AST ≤ 1.5 times ULN
Alkaline phosphatase ≤ 1.5 times ULN
Albumin ≤ 1.5 times ULN
LVEF normal by MUGA scan or cardiac ultrasound
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception during and for 1 month after completion of study treatment
Willing to refrain from donating blood to others during the study

Exclusion criteria:

Other active cancer or a prior history of malignancies other than 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
Severe underlying chronic illness or disease, such as uncontrolled diabetes
Known congestive heart disease or previous myocardial infarction
Hypokalemia or hypomagnesemia unless these conditions are corrected to within normal limits before starting study drug
Congenital long QT syndrome or baseline QTcF intervals > 480 msec on EKG

PRIOR CONCURRENT THERAPY:

Inclusion criteria:

See Disease Characteristics
At least 7 days since prior and no concurrent inhibitors of CYP3A4:
- Antibiotics: clarithromycin, erythromycin, troleandomycin
- HIV drugs: antiretrovirals (delavirdine), protease inhibitors (ritonavir, indinavir, saquinavir, nelfinavir, amprenavir, lopinavir)
- Antifungals: itraconazole, ketoconazole, voriconazole, fluconazole (doses up to 150 mg/day are permitted)
- Antidepressants: nefazodone, fluvoxamine
- Calcium channel blockers: verapamil, diltiazem
- Gastrointestinal : cimetidine, aprepitant, ranitidine, nizatidine, famotidine, proton pump inhibitors (omeprazole, esomeprazole, rabeprazole, pantoprazole, lansoprazole)
- Grapefruit or its juice
At least 7 days since prior and no concurrent gastric pH modifiers (antacids [prohibited within 1 hour before and after dosing])
At least 14 days since prior and no concurrent inducers of CYP3A4:
- Glucocorticoids: dexamethasone or dexamethasone equivalent dose > 1.5 mg/day
- Anticonvulsants: phenytoin, carbamazepine, phenobarbital
- HIV drugs: efavirenz, nevirapine
- Antibiotics: rifampin (rifampicin), rifabutin, rifapentine
- Miscellaneous: Hypericum perforatum (St. John's wort), modafinil
At least 6 months since prior and no concurrent amiodarone

Exclusion criteria:

Tamoxifen, raloxifene, letrozole, anastrozole, or exemestane in the past 3 months
Chemotherapy, biologic therapy (e.g., trastuzumab [Herceptin®]), or breast radiotherapy to the breast currently affected by DCIS within the past year for patients with breast cancer, nonmelanoma skin cancer, carcinoma in situ of the cervix, or early bladder cancer
Concurrent tamoxifen, raloxifene, or aromatase inhibitors (letrozole, anastrozole, exemestane)
Concurrent anticoagulation therapy (e.g., warfarin)
Concurrent participation in another study of an investigational drug
Concurrent anti-arrhythmics, beta blockers, or other medications that may lead to QT prolongation
Prior cumulative dose of anthracycline therapy greater than 500 mg/m²

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00555152

Locations

United States, District of Columbia
Georgetown University Medical Center	Recruiting
Washington, District of Columbia, United States, 20007
Contact: Shawna C. Willey, MD 202-444-0241 scw9@georgetown.edu
Walter Reed Army Medical Center	Recruiting
Washington, District of Columbia, United States, 20307-5001
Contact: Clinical Trials Office - Walter Reed Army Medical Center 202-782-7840
United States, Massachusetts
Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute	Recruiting
Boston, Massachusetts, United States, 02115-6084
Contact: Judy Garber, MD 617-632-2282 judy_garber@dfci.harvard.edu
United States, Minnesota
Mayo Clinic Cancer Center	Recruiting
Rochester, Minnesota, United States, 55905
Contact: Clinical Trials Office - All Mayo Clinic Locations 507-538-7623
United States, Texas
Dan L. Duncan Cancer Center at Baylor College of Medicine	Recruiting
Houston, Texas, United States, 77030
Contact: Clinical Trials Office - Dan L. Duncan Cancer Center at Baylor 713-798-1297
M. D. Anderson Cancer Center at University of Texas	Recruiting
Houston, Texas, United States, 77030-4009
Contact: Clinical Trials Office - M. D. Anderson Cancer Center at the U 713-792-3245

Sponsors and Collaborators

M.D. Anderson Cancer Center

National Cancer Institute (NCI)

Investigators

Principal Investigator:

Powel H. Brown, MD, PhD

M.D. Anderson Cancer Center

More Information

Additional Information:

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party:	Dan L. Duncan Cancer Center at Baylor College of Medicine ( Powel H. Brown )
Study ID Numbers:	CDR0000573719, MDA-P50-CA-58183, BCM-H-19895
Study First Received:	November 6, 2007
Last Updated:	October 20, 2009
ClinicalTrials.gov Identifier:	NCT00555152 History of Changes
Health Authority:	Unspecified

Keywords provided by National Cancer Institute (NCI):

ductal breast carcinoma in situ

Additional relevant MeSH terms:

Neoplasms by Histologic Type
Molecular Mechanisms of Pharmacological Action
Skin Diseases
Antineoplastic Agents
Breast Neoplasms
Enzyme Inhibitors
Lapatinib
Protein Kinase Inhibitors
Pharmacologic Actions
Carcinoma

Neoplasms
Neoplasms by Site
Therapeutic Uses
Carcinoma in Situ
Carcinoma, Intraductal, Noninfiltrating
Neoplasms, Ductal, Lobular, and Medullary
Adenocarcinoma
Breast Diseases
Neoplasms, Glandular and Epithelial

ClinicalTrials.gov processed this record on February 08, 2010