A Phase II Study of GW572016 and Tamoxifen in Patients With Metastatic Breast Cancer Resistant to Single-Agent Tamoxifen

Inclusion Criteria:

- At least 7 days since prior and no concurrent CYP3A4 inhibitors, including any of the
following:

- Clarithromycin

- Erythromycin

- Troleandomycin

- Itraconazole

- Ketoconazole

- Voriconazole

- Fluconazole (doses =< 150 mg/day allowed)

- Fluvoxamine

- Nefazodone

- Verapamil

- Diltiazem

- Cimetidine

- Aprepitant

- Proton pump inhibitors

- H2 blockers

- Grapefruit or grapefruit juice

- Bitter orange

- At least 14 days since prior and no concurrent CYP3A4 inducers, including any of the
following:

- Phenytoin

- Carbamazepine

- Phenobarbital

- Oxcarbazepine

- Efavirenz

- Nevirapine

- Rifampin

- Rifabutin

- Rifapentine

- Hypericum perforatum (St. John's wort)

- Modafinil

- At least 6 months since prior and no concurrent amiodarone.

- No concurrent gastric pH modifiers within 1 hour before and after lapatinib
administration.

- No concurrent combination antiretroviral therapy for HIV-positive patients.

- No other concurrent antineoplastic agents.

- Histologically or cytologically confirmed primary adenocarcinoma of the breast:
Locally advanced or metastatic disease not amenable to curative surgery or
radiotherapy

- Tamoxifen-resistant disease, defined as 1 of the following: No response to initial
therapy (primary resistance); disease relapse or progression after showing an initial
response to therapy (secondary resistance)

- Disease progression, as documented by 1 of the following: CT scan, MRI, or x-ray;
increase in the number of bone lesions; increased pain in an area of known bony
metastasis AND >= 2 serial tumor marker elevations.

- Measurable disease, defined as >= 1 unidimensionally measurable target lesion >= 20
mm by conventional techniques OR >= 10 mm by MRI or spiral CT scan and not in a
previously irradiated area.

- No other concurrent investigational agents.

- No known brain or leptomeningeal metastases requiring active therapy.

- No rapidly progressive disease in major organs (i.e., lymphangitic spread or bulky
liver metastasis).

- Estrogen and/or progesterone receptor positive disease.

- Concurrent zoledronate for bone metastases or hypercalcemia allowed.

- Concurrent oral anticoagulants (e.g., warfarin) allowed provided there is increased
vigilance in INR monitoring.

- ECOG 0-2 or Karnofsky 60-100%

- At least 3 months life expectancy

- Absolute neutrophil count ≥ 1,500/mm3

- Platelet count ≥ 100,000/mm3

- Hemoglobin ≥ 9.0 g/dL

- ALT and AST ≤ 1.5 times upper limit normal (ULN) (3 times ULN if liver metastases are
present)

- Bilirubin ≤ 1.5 times ULN

- Creatinine normal or creatinine clearance > 60 mL/min

- Ejection fraction normal by echocardiogram or MUGA

- None of the following cardiovascular conditions within the past 6 months: Myocardial
infarction, severe or unstable angina, symptomatic congestive heart failure,
cerebrovascular accident or transient ischemic attack.

- Deep venous thrombosis or other clinically significant thromboembolic event within
the past 6 months allowed provided patient is clinically stable on anticoagulation
therapy.

- Pulmonary embolus within the past 6 months allowed provided patient is clinically
stable on anticoagulation therapy

- No malabsorption syndrome

- No requirement for IV alimentation

- Able to swallow and retain oral medication

- Not pregnant or nursing

- No gastrointestinal (GI) tract disease that would preclude ability to take oral
medication.

- No other severe acute or chronic medical or psychiatric condition or laboratory
abnormality that would preclude study participation.

- No history of allergic reaction attributed to compounds of similar chemical or
biological composition to lapatinib.

- No uncontrolled inflammatory GI disease (e.g., Crohn's disease or ulcerative
colitis).

- Negative pregnancy test

- Fertile patients must use effective barrier contraception during and for >= 2 weeks
after completion of study treatment.

- No other malignancy within the past 5 years except adequately treated basal cell or
squamous cell skin cancer or carcinoma in situ of the cervix.

- Prior trastuzumab (Herceptin®) in combination with chemotherapy in the adjuvant
setting only is allowed.

- No prior trastuzumab in combination with hormonal therapy.

- No concurrent trastuzumab.

- Prior cumulative doxorubicin dose =< 450 mg/m2.

- At least 14 days since prior and no concurrent dexamethasone or dexamethasone
equivalent dose > 1.5 mg/day.

- More than 2 weeks since prior radiotherapy.

- More than 4 weeks since prior surgery

- More than 6 months since prior coronary or peripheral artery bypass grafting.

- No prior surgical procedure affecting absorption.

- No prior epidermal growth factor receptor- or HER2/neu-targeting therapies.

- Previously treated asymptomatic stable CNS metastases allowed provided patient does
not require corticosteroids for CNS metastases.

Exclusion Criteria:

- Estrogen receptor status unknown.

- History of myocardial infarction within 6 months.

- Performance status 3 or 4.

- Progesterone receptor status unknown.