Lapatinib and Tamoxifen in Treating Patients With Locally Advanced or Metastatic Breast Cancer That Did Not Respond to Previous Tamoxifen

PRIMARY OBJECTIVES:

I. To determine the response rate (complete response and partial response) of tamoxifen
(tamoxifen citrate) and GW572016 (lapatinib ditosylate) in women with hormone refractory,
metastatic breast cancer.

II. To describe the changes in phosphorylation of epidermal growth factor receptor (EGFR),
human EGFR 2 (her2), protein B kinase (AKT) kinase, mitogen activated protein kinase (MAPK),
estrogen receptor (ER)-Serine (Ser) 118, and ER-Ser167 in tumor tissue after administration
of tamoxifen and GW572016.

OUTLINE:

Patients receive lapatinib ditosylate orally (PO) daily and tamoxifen citrate PO daily.
Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 1 month and then every 3
months thereafter.

Inclusion Criteria:

- Primary adenocarcinoma of the breast confirmed by histology or cytology

- Locally advanced or metastatic disease not amenable to surgery or radiation therapy
with curative intent

- Estrogen and/or progesterone receptor positive cancer

- Patients have failed hormonal manipulation with tamoxifen, either showing no response
(primary resistance) to initial therapy or relapse/progression after showing initial
response (secondary failure)

- At least 1 measurable (target) lesion (i.e. any malignant tumor mass that can be
accurately measured in at least 1 dimension, >= 20 mm with conventional radiographic
techniques or >= 10 mm with magnetic resonance imaging [MRI] or spiral computerized
tomography [CT] scans), in a previously un-irradiated area

- No more than 450 mg/m^2 of prior doxorubicin

- Life expectancy >= 3 months

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

- Absolute neutrophil count (ANC) >= 1500/mm^3

- Platelets >= 100,000/mm^3

- Hemoglobin >= 9.0 g/dL

- Creatinine (Cr) =< upper limit of normal (ULN) or Cr clearance > 60 mL/min/m^2

- Total bilirubin =< 1.5 x ULN

- Alanine aminotransferase (ALT) =< 1.5 x ULN or =< 3 x ULN with liver metastases

- Aspartate aminotransferase (AST) =< 5 x ULN or =< 3 x ULN with liver metastases

- Cardiac ejection fraction within the institutional range of normal as measured by
echocardiogram or multi gated acquisition scan (MUGA) scan; (note that baseline and
on-treatment scans should be performed using the same modality and preferably at the
same institution)

- Patients on oral anticoagulants (Coumadin, warfarin) should either be switched to low
molecular weight heparin or have a very close monitoring of international normalized
ratio (INR), if continued on Coumadin

- Negative serum pregnancy test within 7 days of enrollment for pre-menopausal women and
women within 6 months of menopause; should a woman become pregnant or suspect she is
pregnant while participating in this study, she should inform her treating physician
immediately; both men and women should be counseled in contraceptive use due to
unknown effects of the drug on the fetus and breast feeding should be avoided

- Ability to understand and the willingness to sign a written informed consent document

- Ability to swallow and retain oral medication

Exclusion Criteria:

- Patients who have had prior treatment with EGFR and or Her-2 targeting therapies
(prior trastuzumab combined with chemotherapy in the adjuvant setting only is allowed,
but the combination of trastuzumab with hormonal therapy is not allowed)

- Current treatment with any other anti-neoplastic agent, including trastuzumab;
patients may continue to receive zoledronic acid for bone metastases or hypercalcemia

- Radiation therapy within 2 weeks of enrollment or surgery within 4 weeks

- Rapidly progressive disease in major organs (i.e. lymphangitic spread, bulky liver
metastasis) or known brain/leptomeningeal metastatic disease requiring active therapy;
(patients with asymptomatic, stable previously treated metastases to the central
nervous system and surrounding tissues are eligible; however patients must not have a
requirement for corticosteroids due to central nervous system metastases at the time
of study entry)

- Any of the following conditions within 6 months of enrollment: myocardial infarction,
severe/unstable angina, symptomatic congestive heart failure, cerebrovascular accident
or transient ischemic attack, coronary/peripheral artery bypass grafting; patients who
have experienced a pulmonary embolus, deep venous thrombosis or other clinically
significant thromboembolic event within 6 months of enrollment are eligible if they
are clinically stable on anticoagulation therapy

- Pregnancy or breast feeding; breastfeeding should be discontinued if the mother is
treated with GW572016; female patients must agree to use effective contraception
during the study period, be surgically sterile, or be post-menopausal; in addition,
male patients will be required to use effective contraception during the study period
or be surgically sterile; the definition of effective contraception will be based on
the judgment of the investigator

- Human immunodeficiency virus (HIV)-positive patients receiving combination
anti-retroviral therapy are excluded from the study

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to GW572016

- Patients with gastrointestinal (GI) tract disease resulting in an inability to take
oral medication, malabsorption syndrome, a requirement for intravenous (IV)
alimentation, prior surgical procedures affecting absorption, or uncontrolled
inflammatory GI disease (e.g., Crohn's, ulcerative colitis)

- Treatment with any agents that interact with cytochrome P450 3A should be avoided and
used with caution, if necessary; when possible, patients should be switched to
alternative medications; patients requiring anticoagulation should either be switched
to a low molecular weight heparin injection or have a very close monitoring of INR, if
continued on Coumadin

- Previous (within 5 years of enrollment) or current malignancies at other sites, except
adequately treated basal cell or squamous cell skin cancers and carcinoma in situ of
the cervix

- Other severe acute or chronic medical or psychiatric conditions or laboratory
abnormality that may increase the risk associated with study participation or study
drug administration or may interfere with interpretation of study results and, in the
judgment of the investigator, would make the patient inappropriate for study entry