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

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Lapatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as doxorubicin hydrochloride liposome work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving lapatinib together with doxorubicin hydrochloride liposome may kill more tumor cells. PURPOSE: This phase I trial is studying the side effects and best dose of doxorubicin hydrochloride liposome when given together with lapatinib in treating patients with metastatic breast cancer.

Detailed Description
-----------------
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.

Official Title
-----------------
A Phase I, Open-Label Study of the Safety, Tolerability and Pharmacokinetics of Lapatinib in Combination With Liposomal Doxorubicin in Patients With Metastatic Breast Cancer

Conditions
-----------------
Breast Cancer

Intervention / Treatment
-----------------
* Drug: lapatinib ditosylate
* Drug: Doxil


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lapatinib Ditosylate and Doxil<br> | Drug: lapatinib ditosylate<br>* 1500 mg orally daily for as long as patients remain on trial (up to 8 cycles).<br>Drug: Doxil<br>* Administered intravenously (IV) every 4 weeks in a dose-escalating fashion according to a set schedule<br>* Other names: Dox-SL;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cardiac safety |  | Throughout treatment and up to 30 days post-treatment | 
| Maximum tolerated dose |  | After the first cycle of therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic profiles |  | After treatment completion for 12 patients treated at the maximum tolerated dose | 
| Efficacy |  | At time of disease progression | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
stage IV breast cancer, recurrent breast cancer, male breast cancer