Lapatinib and Doxorubicin Hydrochloride Liposome in Treating Patients With Metastatic Breast Cancer

OBJECTIVES:

Primary

• Evaluate the safety, tolerability, and feasibility of pegylated doxorubicin HCl liposome (PLD) when administered with lapatinib, particularly in terms of cardiac safety, in patients with metastatic breast cancer.
• Determine the optimally tolerated regimen (OTR) of PLD when administered with lapatinib in these patients.

Secondary

• Determine the pharmacokinetic profiles of lapatinib and PLD when given in combination at the OTR.
• Describe any preliminary evidence of efficacy of lapatinib and PLD in these patients.

OUTLINE: This is an open-label, dose-escalation study of pegylated doxorubicin HCl liposome (PLD).

Patients receive oral lapatinib once daily on days 1-28 and PLD IV over at least 30 minutes on day 1. Treatment repeats every 28 days for up to 8 courses in the absence of disease progression or unacceptable toxicity. Lapatinib may be continued alone in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of PLD until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 3 of 6 patients experience dose-limiting toxicity.

After completing study treatment, patients are followed for 30 days.

PROJECTED ACCRUAL: A total of 25 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Histologically confirmed adenocarcinoma of the breast with evidence of metastatic disease

• Epidermal growth factor receptor (EGFR) and/or erbB2 positivity not required
• Measurable disease, defined as ≥ 1 lesion that can be accurately measured in ≥ 1 dimension as ≥ 20 mm by conventional techniques OR as ≥ 10 mm by spiral CT scan
• No known brain metastases or leptomeningeal disease
• Hormone receptor status not specified

PATIENT CHARACTERISTICS:

• Male or female patients
• Menopausal status not specified
• Life expectancy ≥ 12 weeks
• ECOG performance status 0-1
• WBC ≥ 3,000/mm^3
• Absolute neutrophil count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3
• Bilirubin normal
• AST/ALT ≤ 2.5 times upper limit of normal
• Creatinine normal OR creatinine clearance ≥ 60 mL/min
• LVEF ≥ 50%
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Able to swallow and retain oral medication
• No history of allergic reactions attributed to compounds of similar chemical or biologic composition to lapatinib
• No gastrointestinal (GI) tract disease resulting in inability to take oral medication
• No malabsorption syndrome or requirement for IV alimentation
• No uncontrolled inflammatory GI disease (e.g., Crohn's disease, ulcerative colitis)

PRIOR CONCURRENT THERAPY:

• Prior trastuzumab (Herceptin ®) allowed
• Prior anthracyclines allowed provided total dose of doxorubicin hydrochloride ≤ 240 mg/m² or epirubicin ≤ 600 mg/m²
• More than 4 weeks since prior major surgery, hormonal therapy (other than replacement therapy), chemotherapy (6 weeks for nitrosoureas or mitomycin C), or radiotherapy and recovered
• No prior surgical procedures affecting absorption
• No prior EGFR-targeting therapies
• At least 7 days since prior and no concurrent CYP3A4 inhibitors
• At least 7 days since prior and no concurrent gastric pH modifiers

• Antacids allowed within 1 hour before and after lapatinib dosing
• At least 14 days since prior and no concurrent CYP3A4 inducers, including dexamethasone or dexamethasone equivalent dose > 1.5 mg/day
• At least 6 months since prior and no concurrent amiodarone
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No concurrent prophylactic growth factor support
• No concurrent herbal medications
• No other concurrent investigational agents or anticancer therapy