A Phase II Study of GW572016 and Tamoxifen in Patients With Metastatic Breast Cancer Resistant to Single-Agent Tamoxifen
- At least 7 days since prior and no concurrent CYP3A4 inhibitors, including any of the
- Fluconazole (doses =< 150 mg/day allowed)
- 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
- Hypericum perforatum (St. John's wort)
- At least 6 months since prior and no concurrent amiodarone.
- No concurrent gastric pH modifiers within 1 hour before and after lapatinib
- 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
- 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
- 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
- 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
- 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
- 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
- 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.
- Estrogen receptor status unknown.
- History of myocardial infarction within 6 months.
- Performance status 3 or 4.
- Progesterone receptor status unknown.