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

Inclusion Criteria

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