A Phase II Study to Evaluate the Efficacy, Safety and Pharmacodynamics of Lapatinib in Patients With Relapsed or Refractory Inflammatory Breast Cancer

Inclusion Criteria

Inclusion criteria:

- Must have a life expectancy of at least 12 weeks.

- Has a left ventricular ejection fraction (LVEF) ≥ 50%, or ≥ lower limit of normal for
the institution, based on ECHO or MUGA.

- Aspartate and alanine transaminase (AST or ALT) ≤ 3 times the upper limit of the
reference range (patients with liver metastases may have AST and ALT ≤ 5 times the
upper limit of the reference range and may be enrolled).

- Total bilirubin ≤ 3.0 mg/dL.

- Serum creatinine ≤ 2.0 mg/dL or calculated creatinine clearance (CrCl) ≥ 30 mL/min

- Adequate bone marrow function. Hemoglobin ≥ 9 gm/dL. Absolute granulocyte count ≥
1,500/mm³ (1.5 x 10^9/L). Platelets ≥ 75,000/mm³ (100 x 10^9/L).

- Recovered or stabilized sufficiently from side effects associated with previous
chemotherapy, surgery or radiotherapy.

- Provided written informed consent.

- ECOG (Eastern Cooperative Oncology Group) performance status 0 to 2.

- Able to swallow and retain oral medication.

- Male or female, if female:

A female is eligible to enter and participate in the study if she is of:

1. Non-childbearing potential (i.e., women with functioning ovaries who have a current
documented tubal ligation or hysterectomy, or women who are postmenopausal); or

2. Childbearing potential (i.e., women with functioning ovaries and no documented
impairment of oviductal or uterine function that would cause sterility. This category
includes women with oligomenorrhoea (severe), women who are perimenopausal, and young
women who have begun to menstruate), has a negative serum pregnancy test at
screening, and agrees to one of the following where considered acceptable to the
local IRB/IEC: Double-barrier contraception (condom with spermicidal jelly, foam
suppository, or film; diaphragm with spermicide; or male condom and diaphragm).

Abstinence from sexual intercourse from 2 weeks prior to administration of the
investigational product, throughout the active study treatment period, and through the
post-treatment follow-up visit (to occur 28 days after last dose of investigational
product).

Male partner who is sterile prior to the female subject's entry into the study and is the
sole sexual partner for that female subject.

Implants of levonorgestrel. Injectable progestogen. Any intrauterine device (IUD) with a
documented failure rate of less than 1% per year.

Oral contraceptives (either combined or progestogen only). Barrier methods including
diaphragm or condom with a spermicide.

- At least 18 years of age.

- Has either measurable disease by Response Evaluation Criteria in Solid Tumors
(RESIST) or clinically evaluable skin disease. Measurable lesions may be in the
field of prior adjuvant irradiation; however, there must be at least an 8 week period
between the last radiation treatment and the baseline scan documenting disease status
for the lesion to be measurable.

- Tumor that is accessible for biopsy.

- Tumor that overexpresses ErbB2 defined as 3+ by IHC or FISH +. The ErbB 2
overexpression must be documented prior to dosing.

- Documented disease progression or relapse following treatment, which must have
contained a taxane and anthracycline-containing regimen in the adjuvant or metastatic
setting (30 patients) plus trastuzumab (90 patients)

- Histological diagnosis of breast carcinoma with a clinical diagnosis of IBC based on
the presence of inflammatory changes in the involved breast, including diffuse
erythema and edema (peau d'orange), with or without an underlying palpable mass
involving the majority of the skin of the breast. Pathologic evidence of dermal
lymphatic invasion should be noted but is not required for diagnosis.

Exclusion criteria:

- Is clinically assessed to have inadequate venous access for protocol-related blood
draws.

- Has a clinically significant electrocardiogram (ECG) abnormality.

- Has Class II to IV heart failure as defined by the New York Heart Association (NYHA)
functional classification system.

- Has physiological, familial, sociological, or geographical conditions that do not
permit compliance with the protocol.

- Is currently receiving oral steroid treatment (inhaled steroids are permitted), or
any other medication on the prohibited medications list

- Is currently receiving amiodarone or has received amiodarone in the 6 months prior to
screening.

- Has received chemotherapy, immunotherapy, biologic therapy or hormonal therapy within
the past 14 days, with the exception of mitomycin C within the past 6 weeks.

- Has received treatment with any investigational drug in the previous 4 weeks.

- Has a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
chemically related to the investigational product. These include other
anilinoquinazolines, such as gefitinib [Iressa], erlotinib [Tarceva], or other
chemically related compounds.

- Is considered medically unfit for the study by the investigator as a result of the
medical interview, physical exam, or screening investigations.

- Has evidence of symptomatic or uncontrolled brain metastases or leptomeningeal
disease. Patients with brain metastases treated by surgery and/or radiotherapy are
eligible if neurologically stable and do not require steroids or anticonvulsants.

- Has malabsorption syndrome, a disease affecting gastrointestinal function, or
resection of the stomach or small bowel.

- Is a pregnant or lactating female.