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

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

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.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: lapatinib ditosylate; Drug: Doxil

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.

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60611-3013
      • Robert H. Lurie Comprehensive Cancer Center at Northwestern University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Northwestern University
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: William J Gradishar, M.D., Robert H. Lurie Cancer Center

Study record dates

Study Major Dates

• Study Start: May 1, 2006
• Primary Completion (Actual): August 1, 2011
• Study Completion (Actual): August 1, 2011

Study Registration Dates

• First Submitted: April 19, 2006
• First Submitted That Met QC Criteria: April 19, 2006
• First Posted (Estimate): April 21, 2006

Study Record Updates

• Last Update Posted (Estimate): November 8, 2013
• Last Update Submitted That Met QC Criteria: November 6, 2013
• Last Verified: November 1, 2013

More Information

Terms related to this study

• Keywords: stage IV breast cancer; recurrent breast cancer; male breast cancer
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Protein Kinase Inhibitors; Antibiotics, Antineoplastic; Doxorubicin; Lapatinib
• Other Study ID Numbers: NU 05B5; P30CA060553 (U.S. NIH Grant/Contract); NU-05B5; NU-1838-001; NCI-2011-00325 (Other Identifier: NCI CTRP#)