Lapatinib in Treating Patients With Advanced or Metastatic Breast Cancer That Overexpresses HER2

University of California San Francisco (UCSF)

Status and phase

Completed

Phase 1

Conditions

Metastatic Cancer

Breast Cancer

Treatments

Genetic: gene expression analysis

Drug: lapatinib ditosylate

Other: diagnostic laboratory biomarker analysis

Study type

Interventional

Funder types

Other

NIH

Identifiers

NCT00544804

UCSF-077518

Details and patient eligibility

About

RATIONALE: Lapatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PURPOSE: This phase I trial is studying the side effects and best dose of lapatinib in treating patients with advanced or metastatic breast cancer that overexpresses HER2.

Full description

OBJECTIVES:

Primary

To determine the maximum tolerated dose (MTD) of high-dose lapatinib ditosylate in patients with HER2-overexpressing advanced or metastatic breast cancer.
To determine the dose-limiting toxicity of this drug in these patients.

Secondary

To determine whether tumor HER2 can be completely inactivated by lapatinib ditosylate at its MTD in the 5-day schedule.
To determine whether the total inactivation of HER2 decreases cardiac ejection fraction.

OUTLINE: Patients are stratified according to dose level.

Patients receive escalating doses of oral lapatinib ditosylate twice daily on days 1-5 until the maximum tolerated dose is determined. Courses repeat every 2 weeks in the absence of disease progression or unacceptable toxicity.

Some patients undergo tumor tissue and blood sample collection periodically for biological and correlative studies. Samples are analyzed for evidence of cardiac injury, tumor target lysis effects, and to determine if the lapatinib serum levels result in the inactivation of tumor HER2 and HER3 kinase and oncogenic signaling.

After completion of study treatment, patients are followed every 2 months.

Enrollment

41 patients

Sex

Female

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

DISEASE CHARACTERISTICS:

Histologically confirmed breast cancer
- Advanced or metastatic disease
- No effective curative therapy available
Bone-only disease allowed
Tumor HER2 overexpression
- HER2 3+ expression by immunohistochemistry OR > 2-fold (HER2 2+) gene amplification by fluorescence in situ hybridization
Evaluable disease
- Measurable disease is not required
No progressive brain metastases
Hormone receptor status not specified

PATIENT CHARACTERISTICS:

Inclusion criteria:

ECOG performance status 0-2
Life expectancy > 3 months
Female
Menopausal status not specified
Absolute neutrophil count ≥ 1,000 cells/mm^3
Hemoglobin ≥ 9 g/dL
Platelet count ≥ 75,000 cells/mm^3
Total bilirubin normal
AST and ALT ≤ 3 x upper limits of normal (ULN) (≤ 5 x ULN with liver metastases)
Creatinine normal OR creatinine clearance ≥ 40 mL/min
INR ≤ 1.5
Potassium normal
Magnesium normal
Not pregnant
Negative pregnancy test
Fertile patients must use effective contraception prior to and during study therapy
Cardiac ejection fraction ≥ 50%
Consents to 2 tumor fine needle aspiration biopsies for biomarker analysis
- Lung-only disease or sites otherwise deemed high-risk for biopsy, the requirement for biopsy will be waived

Exclusion criteria:

History of significant cardiac disease including any of the following:
- Congestive heart failure
- Symptomatic cardiac arrhythmias
- Unstable angina
Uncontrolled prior lapatinib ditosylate therapy toxicity ≥ grade 2
Allergic reactions to IV contrast dye despite standard prophylaxis
History of malabsorption syndrome or disease significantly affecting gastrointestinal function or major resection of the stomach or small bowel that could affect absorption, distribution, metabolism, or excretion of study drug
Conditions that would impair the patient's ability to swallow and retain oral medication
Concurrent disease or condition that would make the patient inappropriate for study participation or would interfere with the patient's safety
Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol

PRIOR CONCURRENT THERAPY:

Prior lapatinib ditosylate or trastuzumab allowed
At least 4 weeks since prior and no concurrent chemotherapy or investigational anticancer agents
At least 2 weeks since prior and no concurrent hormonal therapy
At least 2 weeks since prior and no concurrent lapatinib ditosylate prohibited medications, including CYP3A4 inhibitors or inducers, all herbal supplements, and gastric pH modifiers
More than 4 weeks since prior radiotherapy
No aspirin or plavix therapy within 7 days prior to tumor biopsy
No concurrent coumadin
- Low molecular weight heparin allowed provided it can be held at least 24 hours prior to tumor biopsy
Concurrent gonadal suppression agents (i.e., Zoladex or Lupron) or palliative bisphosphonates (i.e., Zometa) allowed