Lapatinib Ditosylate and Capecitabine in Treating Patients With Stage IV Breast Cancer and Brain Metastases

OBJECTIVES:

Primary

• To assess the objective response rate by volumetric analysis of brain metastasis as assessed by MRI in patients with HER2-positive stage IV breast cancer treated with lapatinib ditosylate and capecitabine.

Secondary

• To document any toxicity evaluated by NCI CTC v3.0.
• To assess the time to radiotherapy.
• To document the time to disease progression in the central nervous system (CNS) of these patients.
• To evaluate the overall response rate for extra-CNS disease.
• To assess the clinical benefit (complete response, partial response, and stable disease for ≥ 6 months) for both CNS and extra-CNS disease in these patients.

Tertiary

• To evaluate serum proteomics and metabonomics markers as predictors of response.
• To evaluate the predictive value of circulating tumor cells (CTC) on response.

OUTLINE: This is a multicenter study.

Patients receive oral lapatinib ditosylate once daily. Patients also receive oral capecitabine twice daily on days 1-14. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed periodically.

DISEASE CHARACTERISTICS:

• Histologically confirmed invasive breast cancer

• Stage IV disease
• At least 1 measurable CNS lesion ≥ 10 mm on T1-weighted gadolinium-enhanced MRI

• No single brain metastasis that could be treated by surgery
• HER-2 positive primary tumor as defined as IHC3+ or IHC2+ and FISH-positive
• Hormone receptor status: not specified

PATIENT CHARACTERISTICS:

• Menopausal status not specified
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Life expectancy ≥ 3 months
• Absolute Neutrophil Count (ANC) ≥ 1,000/mm^3
• Platelet count ≥ 100,000/mm^3
• Hemoglobin ≥ 10g/dL
• Creatinine ≥ 1.5 times upper limit of normal (ULN)
• Albumin ≥ 2.5 g/dL
• Serum bilirubin ≤ 1.5 times ULN (unless due to Gilbert's syndrome)
• ASAT and ALAT ≤ 3 times ULN (≤ 5 times ULN with documented liver metastasis)
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception 2 weeks before, during, and for 28 days after completion of study treatment (female) or for 1 week after completion of treatment (male)
• Able to swallow and retain oral medication
• Affiliated to a Social Security System
• No known contraindication to MRI
• No prior or active malignancy, unless disease free for ≥ 10 years
• No other concurrent severe and/or uncontrolled medical disease which could compromise study participation, including any of the following:

• Infection
• Cardiac disease (e.g., uncontrolled hypertension, congestive cardiac failure, ventricular arrhythmias, active ischemic heart disease, myocardial infarction within the past year, Left Ventricular EJection Fraction (LVEF) > grade 2)
• Current active hepatic or biliary disease (except for Gilbert syndrome, asymptomatic gallstones, liver metastasis or stable chronic liver disease per investigator assessment)
• Renal disease
• Active gastrointestinal (GI) tract ulceration, malabsorption syndrome, active uncontrolled ulcerative colitis, or disease significantly affecting GI function
• Severely impaired lung function (e.g., spirometry and diffusion capacity of lung for carbon monoxide (DLCO) ≤ 50% of normal, and O_2 saturation ≤ 88% at rest on room air)
• No known dihydropyrimidine dehydrogenase deficiency
• No significantly altered mental status prohibiting the understanding of the study, or with psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
• Not deprived of liberty or placed under the authority of a tutor

PRIOR CONCURRENT THERAPY:

• At least 2 weeks since prior breast cancer treatment (e.g., trastuzumab, chemotherapy, immunotherapy or biological response modifiers, endocrine therapy, or radiotherapy)
• More than 30 days since prior investigational drugs
• More than 14 days since prior and no concurrent strong inhibitors or inducers of the cytochrome P450 isoenzyme 3A4 (CYP3A4) (i.e., clarithromycin, ketoconazole, itraconazole, voriconazole, ritonavir)
• No prior whole brain radiotherapy (WBRT) or brain stereotactic radiotherapy
• No prior treatment with capecitabine and/or lapatinib ditosylate
• No prior resection of the stomach or small bowel
• No concurrent systemic treatment or radiation therapy for breast cancer (except corticosteroid, bisphosphonates, or mannitol)