Lapatinib in Treating Patients With Advanced or Metastatic Breast Cancer That Overexpresses HER2

Study Overview
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Brief Summary
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RATIONALE: Lapatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. PURPOSE: This phase I trial is studying the side effects and best dose of lapatinib in treating patients with advanced or metastatic breast cancer that overexpresses HER2.

Detailed Description
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OBJECTIVES: Primary To determine the maximum tolerated dose (MTD) of high-dose lapatinib ditosylate in patients with HER2-overexpressing advanced or metastatic breast cancer. To determine the dose-limiting toxicity of this drug in these patients. Secondary To determine whether tumor HER2 can be completely inactivated by lapatinib ditosylate at its MTD in the 5-day schedule. To determine whether the total inactivation of HER2 decreases cardiac ejection fraction. OUTLINE: Patients are stratified according to dose level. Patients receive escalating doses of oral lapatinib ditosylate twice daily on days 1-5 until the maximum tolerated dose is determined. Courses repeat every 2 weeks in the absence of disease progression or unacceptable toxicity. Some patients undergo tumor tissue and blood sample collection periodically for biological and correlative studies. Samples are analyzed for evidence of cardiac injury, tumor target lysis effects, and to determine if the lapatinib serum levels result in the inactivation of tumor HER2 and HER3 kinase and oncogenic signaling. After completion of study treatment, patients are followed every 2 months.

Official Title
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A Phase I Dose Escalation Study of 5-Day Intermittent Oral Lapatinib Therapy With Biomarker Analysis in Patients With HER2-Overexpressing Breast Cancer

Conditions
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Breast Cancer, Metastatic Cancer

Intervention / Treatment
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* Drug: lapatinib ditosylate
* Genetic: gene expression analysis
* Other: diagnostic laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed breast cancer Advanced or metastatic disease No effective curative therapy available Bone-only disease allowed Tumor HER2 overexpression HER2 3+ expression by immunohistochemistry OR > 2-fold (HER2 2+) gene amplification by fluorescence in situ hybridization Evaluable disease Measurable disease is not required No progressive brain metastases Hormone receptor status not specified PATIENT CHARACTERISTICS: Inclusion criteria: ECOG performance status 0-2 Life expectancy > 3 months Female Menopausal status not specified Absolute neutrophil count ≥ 1,000 cells/mm^3 Hemoglobin ≥ 9 g/dL Platelet count ≥ 75,000 cells/mm^3 Total bilirubin normal AST and ALT ≤ 3 x upper limits of normal (ULN) (≤ 5 x ULN with liver metastases) Creatinine normal OR creatinine clearance ≥ 40 mL/min INR ≤ 1.5 Potassium normal Magnesium normal Not pregnant Negative pregnancy test Fertile patients must use effective contraception prior to and during study therapy Cardiac ejection fraction ≥ 50% Consents to 2 tumor fine needle aspiration biopsies for biomarker analysis Lung-only disease or sites otherwise deemed high-risk for biopsy, the requirement for biopsy will be waived Exclusion criteria: History of significant cardiac disease including any of the following: Congestive heart failure Symptomatic cardiac arrhythmias Unstable angina Uncontrolled prior lapatinib ditosylate therapy toxicity ≥ grade 2 Allergic reactions to IV contrast dye despite standard prophylaxis History of malabsorption syndrome or disease significantly affecting gastrointestinal function or major resection of the stomach or small bowel that could affect absorption, distribution, metabolism, or excretion of study drug Conditions that would impair the patient's ability to swallow and retain oral medication Concurrent disease or condition that would make the patient inappropriate for study participation or would interfere with the patient's safety Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol PRIOR CONCURRENT THERAPY: Prior lapatinib ditosylate or trastuzumab allowed At least 4 weeks since prior and no concurrent chemotherapy or investigational anticancer agents At least 2 weeks since prior and no concurrent hormonal therapy At least 2 weeks since prior and no concurrent lapatinib ditosylate prohibited medications, including CYP3A4 inhibitors or inducers, all herbal supplements, and gastric pH modifiers More than 4 weeks since prior radiotherapy No aspirin or plavix therapy within 7 days prior to tumor biopsy No concurrent coumadin Low molecular weight heparin allowed provided it can be held at least 24 hours prior to tumor biopsy Concurrent gonadal suppression agents (i.e., Zoladex or Lupron) or palliative bisphosphonates (i.e., Zometa) allowed

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lapatinib<br>Dose Escalation Study of 5-Day Intermittent Oral Lapatinib Therapy With Biomarker Analysis in Patients With HER2-Overexpressing Breast Cancer | Drug: lapatinib ditosylate<br> <br> Genetic: gene expression analysis<br> <br> Other: diagnostic laboratory biomarker analysis<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose of Lapatinib | Dose Escalation of 5-Day Intermittent Oral Lapatinib Therapy With Biomarker Analysis in Patients With HER2-Overexpressing Breast Cancer | estimated to be 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent breast cancer, stage IIIA breast cancer, stage IIIB breast cancer, stage IIIC breast cancer, stage IV breast cancer, bone metastases