Lapatinib and Vinorelbine in Treating Women With HER2-Overexpressing Locally Advanced or Metastatic Breast Cancer

OBJECTIVES:

Primary

• Evaluate the tolerability and feasibility of the lapatinib ditosylate and vinorelbine ditartrate combination by determining the maximum tolerated dose of vinorelbine ditartrate in combination with a biologically active dose of lapatinib ditosylate.

Secondary

• Determine the maximum administered dose.
• Investigate the pharmacokinetic interactions related to the combination of vinorelbine ditartrate and lapatinib ditosylate.
• Determine the toxicity of vinorelbine ditartrate and lapatinib ditosylate.
• Determine the objective response rate in patients with measurable lesions.
• Validate the safety and efficacy of the oral vinorelbine ditartrate and lapatinib ditosylate combination, according to the vinorelbine ditartrate oral/IV dose equivalence.

OUTLINE: This is a multicenter, dose-escalation study.

Patients receive oral lapatinib ditosylate on days -7 to 21 for course 1 and on days 1-21 for all other courses. Patients also receive vinorelbine ditartrate IV over 15 minutes on days 1 and 8. Courses repeat every 21 days for up to 12 months in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-9 patients receive escalating doses of lapatinib ditosylate and vinorelbine ditartrate until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 9 patients experience dose-limiting toxicity during course 1.

Once the MTD is determined for oral lapatinib ditosylate and IV vinorelbine ditartrate, an additional cohort of 9 patients receive oral vinorelbine ditartrate with oral lapatinib ditosylate as above.

DISEASE CHARACTERISTICS:

• Histologically confirmed advanced breast cancer (metastatic or locally advanced)
• Tumor overexpressing HER2 (HER2 3+ by IHC OR HER2 2+ by IHC and FISH positive) in samples from the primary and/or secondary tumor
• Measurable or evaluable disease
• Cancer is progressive after treatment with at least 1 line or, at most, 2 lines, of chemotherapy that included trastuzumab (Herceptin®)
• Patients presenting with treated asymptomatic cerebral metastases or leptomeningeal metastases may be included if they are neurologically stable and have not received steroids or anticonvulsant treatment for at least 4 weeks before study entry

PATIENT CHARACTERISTICS:

Inclusion criteria

• Female
• Menopausal status not specified
• Patients must have an estimated survival of at least 3 months
• WHO performance status (ECOG) 0-2
• Hemoglobin ≥ 9 g/dL
• ANC ≥ 1,500/mm³
• Platelets ≥ 100,000/mm³
• Total bilirubin ≤ 2.5 mg/dL
• ALT and AST ≤ 3 times upper limit of normal
• Serum creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 40 mL/min
• LVEF ≥ 50% (echographic or isotopic method)
• Potentially reproductive patients must agree to use an effective contraceptive method while on study treatment
• Patients must be affiliated with a Social Security system

Exclusion criteria

• Uncontrolled cardiac pathology
• Dysphagia or inability to swallow the vinorelbine ditartrate soft capsules
• Malabsorption syndrome or disease significantly affecting gastrointestinal function
• Preexisting neuropathy (grade ≥ 2)
• Pregnant women, women who are likely to become pregnant, or women who are breastfeeding
• Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
• Individuals deprived of liberty

Exclusion criteria

• Prior major resection of stomach or proximal bowel that could affect absorption of oral drugs
• Prior vinorelbine