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A Phase I Dose Escalation Study of 5-Day Intermittent Oral Lapatinib Therapy With Biomarker Analysis in Patients With HER2-Overexpressing Breast Cancer

Phase 1
18 Years
Open (Enrolling)
Breast Cancer, Metastatic Cancer

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Trial Information

A Phase I Dose Escalation Study of 5-Day Intermittent Oral Lapatinib Therapy With Biomarker Analysis in Patients With HER2-Overexpressing Breast Cancer



- 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.


- 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

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.

Inclusion Criteria


- 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


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

- 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 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

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose of Lapatinib

Outcome Description:

Dose Escalation of 5-Day Intermittent Oral Lapatinib Therapy With Biomarker Analysis in Patients With HER2-Overexpressing Breast Cancer

Outcome Time Frame:

estimated to be 12 months

Safety Issue:


Principal Investigator

Mark M. Moasser, MD

Investigator Role:

Study Chair

Investigator Affiliation:

University of California, San Francisco


United States: Food and Drug Administration

Study ID:




Start Date:

August 2007

Completion Date:

November 2014

Related Keywords:

  • Breast Cancer
  • Metastatic Cancer
  • recurrent breast cancer
  • stage IIIA breast cancer
  • stage IIIB breast cancer
  • stage IIIC breast cancer
  • stage IV breast cancer
  • bone metastases
  • Breast Neoplasms
  • Neoplasm Metastasis
  • Neoplasms
  • Neoplasms, Second Primary



UCSF Helen Diller Family Comprehensive Cancer Center San Francisco, California  94115