Lapatinib and Tamoxifen in Treating Patients With Advanced or Metastatic Breast Cancer

OBJECTIVES:

Primary

• Determine the pharmacokinetics of lapatinib ditosylate and tamoxifen citrate in patients with advanced or metastatic breast cancer.

Secondary

• Assess the safety of this regimen in these patients.
• Determine any relationship between drug exposure and adverse events or biological modifications of this regimen in these patients.
• Assess the antitumor activity of this regimen in patients with measurable disease.

OUTLINE: This is an open-label, randomized, multicenter study. Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive oral tamoxifen citrate on days 1-28 of course 1. In all subsequent courses, patients receive oral tamoxifen citrate and oral lapatinib ditosylate on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
• Arm II: Patients receive oral lapatinib ditosylate on days 1-14 of course 1. In all subsequent courses, patients receive oral lapatinib ditosylate and oral tamoxifen citrate on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

In both treatment arms, blood is collected periodically during courses 1 and 2 for pharmacokinetic studies.

After completion of study treatment, patients are followed periodically.

PROJECTED ACCRUAL: A total of 20 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed advanced or metastatic breast cancer

• Progressive disease after aromatase inhibitor therapy
• Hormone receptor status:

• Estrogen receptor- and/or progesterone receptor-positive tumor
• Patients with stable brain metastases (i.e., no neurological symptoms and no corticosteroid treatment) are eligible

PATIENT CHARACTERISTICS:

• Male or female
• Menopausal status not specified
• ECOG performance status 0-2
• Life expectancy ≥ 12 weeks
• Neutrophil count > 1,500/mm³
• Platelet count > 100,000/mm³
• AST and/or ALT < 3 times upper limit of normal (ULN)
• Creatinine < 1.5 times ULN
• Bilirubin < 1.5 times ULN
• Clinically normal cardiac function (i.e., LVEF normal by MUGA or ECHO)
• No current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases, or stable chronic live disease)
• No ischemic heart disease within the past 6 months
• Normal 12-lead ECG
• No active or uncontrolled infections
• No serious illnesses or medical conditions, including any of the following:

• Hypercalcemia
• Malabsorption syndrome
• Chronic alcohol abuse
• Hepatitis
• HIV
• Cirrhosis
• Able to swallow and retain oral medication
• No psychological, familial, sociological, or geographical condition potentially hampering study compliance
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 3 months after completion of study treatment

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• At least 2 days since prior and no concurrent inducers or inhibitors of CYP3A4, including any of the following:

• Rifabutin
• Clarithromycin
• Cyclosporine
• Voriconazole
• Fluoxetine
• Paroxetine
• Midazolam
• Isoniazid
• Dihydralazine
• Digitoxin
• Coumadin
• Phenytoin
• Verapamil
• Diltiazem
• Herbal constituents (e.g., bergamottin and glabridin)
• At least 2 weeks since prior aromatase inhibitor

• Aromatase inhibitors in the adjuvant and/or metastatic setting allowed
• At least 1 year since prior tamoxifen citrate
• No other concurrent anticancer therapy or investigational agents