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

21 Years
Open (Enrolling)
Breast Cancer, Ductal Breast Carcinoma in Situ

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Trial Information

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


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.


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

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

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),

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

- 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,

- 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

- Prior cumulative dose of anthracycline therapy greater than 500 mg/m^2

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Outcome Measure:

Proliferation, as measured by Ki67 in malignant breast cells

Outcome Time Frame:

Up to 6 weeks

Safety Issue:


Principal Investigator

Powell Brown

Investigator Role:

Principal Investigator

Investigator Affiliation:

M.D. Anderson Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

January 2008

Completion Date:

Related Keywords:

  • Breast Cancer
  • Ductal Breast Carcinoma in Situ
  • Breast Neoplasms
  • Carcinoma
  • Carcinoma in Situ
  • Carcinoma, Intraductal, Noninfiltrating
  • Carcinoma, Ductal, Breast
  • Carcinoma, Ductal



Baylor College of Medicine Houston, Texas  77030
Dana-Farber Cancer Institute Boston, Massachusetts  02115
Mayo Clinic in Arizona Scottsdale, Arizona  85259-5404
M D Anderson Cancer Center Houston, Texas  77030