Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

Lapatinib in Treating Women With Ductal Carcinoma In Situ of the Breast

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase II, Phase I	Biomarker/Laboratory analysis, Treatment	Active	21 and over	NCI	BCM-H-19895 H-19895, BCM-P50-CA-58183, NCT00555152

Special Category: SPORE trial

Objectives

Primary

1. 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.
2. 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

1. Determine whether lapatinib ditosylate treatment affects the incidence of DCIS seen at the time of surgical excision.
2. 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.

Entry 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

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

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

Expected Enrollment

Outcomes

Proliferation, as measured by Ki67 in malignant breast cells
Toxicity profile at each dose level

Incidence of ductal carcinoma in situ seen at resection
Biomarker analysis of proliferation markers in normal breast cells and cancerous breast cells

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.

Trial Contact Information

Trial Lead Organizations

Dan L. Duncan Cancer Center at Baylor College of Medicine

Powel Brown, MD, PhD, Principal investigator		Ph: 713-798-1609 Email: pbrown@breastcenter.tmc.edu

U.S.A.
District of Columbia
	Washington
	Georgetown University Medical Center
		Shawna Willey, MD	Ph:  202-444-0241
			Email: scw9@georgetown.edu
	Walter Reed Army Medical Center
		Clinical Trials Office - Walter Reed Army Medical Center	Ph:  202-782-7840
Massachusetts
	Boston
	Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
		Judy Garber, MD	Ph:  617-632-2282 866-790-4500
			Email: judy_garber@dfci.harvard.edu
Minnesota
	Rochester
	Mayo Clinic Cancer Center
		Clinical Trials Office - All Mayo Clinic Locations	Ph:  507-538-7623
Texas
	Houston
	Dan L. Duncan Cancer Center at Baylor College of Medicine
		Clinical Trials Office - Dan L. Duncan Cancer Center at Baylor College of Medicine	Ph:  713-798-1297
	M. D. Anderson Cancer Center at University of Texas
		Clinical Trials Office - M. D. Anderson Cancer Center at the University of Texas	Ph:  713-792-3245

Registry Information
Official Title		Neoadjuvant Trial of Lapatinib for the Treatment of Women with DCIS Breast Cancer
Trial Start Date		2007-09-01
Registered in ClinicalTrials.gov		NCT00555152
Date Submitted to PDQ		2007-10-15
Information Last Verified		2007-12-09
NCI Grant/Contract Number		CA58183