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

• Proliferation, as measured by Ki67 in malignant breast cells [ Time Frame: Up to 6 weeks ] [ Designated as safety issue: No ]
• Toxicity profile at each dose level [ Time Frame: Up to 5 weeks ] [ Designated as safety issue: Yes ]

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

• Incidence of ductal carcinoma in situ seen at resection [ Time Frame: Up to 6 weeks ] [ Designated as safety issue: No ]
• Biomarker analysis of proliferation markers in normal breast cells and cancerous breast cells [ Time Frame: Up to 6 weeks ] [ Designated as safety issue: No ]

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

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

PRIMARY OBJECTIVES:

I. To 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.

II. To 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 OBJECTIVES:

I. To determine whether lapatinib ditosylate treatment affects the incidence of DCIS seen at the time of surgical excision.

II. To 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.

• Breast Cancer
• Ductal Breast Carcinoma in Situ

• Drug: lapatinib ditosylate
  Given orally
  Other Names:

  • GSK572016
  • GW-572016
  • GW2016
  • Lapatinib
  • Tykerb
• Other: placebo
  Given orally
  Other Name: PLCB
• Other: laboratory biomarker analysis
  Correlative studies

• Experimental: Arm I (1,500 mg)
  Patients receive 1,500 mg of oral lapatinib ditosylate once daily for 2-6 weeks
  Interventions:

  • Drug: lapatinib ditosylate
  • Other: laboratory biomarker analysis
• Experimental: Arm II (1,000 mg)
  Patients receive 1,000 mg of oral lapatinib ditosylate once daily for 2-6 weeks
  Interventions:

  • Drug: lapatinib ditosylate
  • Other: laboratory biomarker analysis
• Experimental: Arm III (750 mg)
  Patients receive 750 mg of oral lapatinib ditosylate once daily for 2-6 weeks
  Interventions:

  • Drug: lapatinib ditosylate
  • Other: laboratory biomarker analysis
• Placebo Comparator: Arm IV (placebo)
  Patients receive oral placebo once daily for 2-6 weeks
  Interventions:

  • Other: placebo
  • Other: laboratory biomarker analysis

Inclusion Criteria:

• Pre- or postmenopausal
• ECOG performance status 0-2
• WBC > 4,000/mm^3
• Platelet count > 100,000/mm^3
• Hematocrit > 30%
• BUN or serum creatinine =< 1.5 times upper limit of normal (ULN)
• Total bilirubin =< 1.5 times ULN
• Albumin =< 1.5 times ULN
• ALT and AST =< 1.5 times ULN
• Alkaline phosphatase =< 1.5 times ULN
• LVEF normal by MUGA scan or cardiac ultrasound
• Not pregnant or nursing
• Fertile patients must use effective contraception during and for 1 month after completion of study treatment
• Negative pregnancy test
• At least 7 days since prior and no concurrent inhibitors of CYP3A4
• No antibiotics: clarithromycin, erythromycin, troleandomycin
• No HIV drugs: antiretrovirals (delavirdine), protease inhibitors (ritonavir, indinavir, saquinavir, nelfinavir, amprenavir, lopinavir)
• No antifungals: itraconazole, ketoconazole, voriconazole, fluconazole (doses up to 150 mg/day are permitted)
• No antidepressants: nefazodone, fluvoxamine
• No calcium channel blockers: verapamil, diltiazem
• No gastrointestinal inhibitors of CYP3A4: cimetidine, aprepitant, ranitidine, nizatidine, famotidine, proton pump inhibitors (omeprazole, esomeprazole, rabeprazole, pantoprazole, lansoprazole)
• No 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
• No glucocorticoids: dexamethasone or dexamethasone equivalent dose > 1.5 mg/day
• No anticonvulsants: phenytoin, carbamazepine, phenobarbital
• No HIV drugs: efavirenz, nevirapine
• No antibiotics: rifampin (rifampicin), rifabutin, rifapentine
• At least 6 months since prior and no concurrent amiodarone
• No miscellaneous inducers of CYP3A4: Hypericum perforatum (St. John's wort), modafinil

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
• Tamoxifen, raloxifene, letrozole, anastrozole, or exemestane in the past 3 months
• Concurrent tamoxifen, raloxifene, or aromatase inhibitors (letrozole, anastrozole, exemestane)
• Concurrent anticoagulation therapy (e.g., warfarin)
• Concurrent participation in another study of an investigational drug
• 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 anti-arrhythmics, beta blockers, or other medications that may lead to QT prolongation
• Prior cumulative dose of anthracycline therapy greater than 500 mg/m^2