A Phase I Dose Escalation Study of the Safety and Tolerability of Lapatinib in Combination With Carboplatin, Paclitaxel, and Herceptin in Patients With Metastatic Breast Cancer

Inclusion Criteria

Inclusion criteria:

- Subjects must have histologically- or cytologically-confirmed invasive breast cancer
with Stage IV disease.

- Treatment Group A: Documentation of ErbB2 status (IHC 3+ or FISH+) in breast tumor
specimens must be demonstrated before study enrollment. It is requested that
archived breast tumor tissue be sent to a central laboratory for independent
confirmation of ErbB2 status by FISH analysis.

- Treatment Group B: Documentation of ErbB2 status (IHC or FISH) in breast tumor
specimen must be demonstrated before study enrollment. It is requested that
archived breast tumor tissue be sent to a central laboratory for independent
confirmation of ErbB2 status (FISH analysis).

- Subjects must be ≥18 years of age.

- Male or female

- Criteria for female subjects:

- Non-child-bearing potential (i.e., women with functioning ovaries who have a
current documented tubal ligation or hysterectomy, or women who are
post-menopausal defined as no menstruation for more than 12 months);

- Child-bearing 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. These subjects
must have a negative serum pregnancy test at screening and agree to one of the
following:

- Complete abstinence from intercourse from two weeks prior to administration of the
first dose of study medication until 28 days after the final dose of study
medication; or

- Consistent and correct use of one of the following acceptable methods of birth
control:

- 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); or

- barrier methods, including diaphragm or condom with a spermicide.

- Able to swallow and retain oral medication.

- Subjects must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of
0 to 1.

- Subjects may have measurable lesion(s) according to RECIST criteria as per protocol.
Patients with metastases only to bone are also eligible for study enrollment.

- Subjects with stable CNS metastases or leptomeningeal involvement are eligible only
if they are not taking oral steroids or enzyme-inducing anticonvulsants.

- Subjects that received prior radiotherapy must have completed radiotherapy treatment
at least four weeks before enrollment and recovered from all treatment-related
toxicities.

- Subjects must have a left ventricular ejection fraction (LVEF) ≥ 50% or ≥ lower limit
of normal for the institution based on Multiple-gated Acquisition (MUGA) scan or
echocardiogram (ECHO).

- Subjects must have adequate hematological, hepatic, and renal function.

- Hemoglobin of at least 9 gm/dL

- Absolute granulocyte count of at least 1,500/mm3 (1.5 x 109/L)

- Platelets of at least 100,000/mm3 (100 x 109/L)

- Total bilirubin not more than 2.5mg/dL

- ALT and/or AST not more than 1.5 times the upper limit of the normal range (ULN) and
alkaline phosphatase not more than 2.5 times the ULN. For subjects with liver
metastases, AST or ALT not more than 5 times the ULN may be enrolled if the total
bilirubin is less than 1.5 times the ULN and if the ALT and AST is checked twice with
an interval of at least 2 weeks prior to treatment to determine that liver function
is stable.

- Calculated creatinine clearance (ClCr) of at least 50mL/min according to the formula
of Cockcroft and Gault as per protocol.

- Subjects who received a taxane as part of adjuvant or neoadjuvant therapy are
eligible if they had recurrence of their disease more than six months after
completion of treatment. Subjects that received trastuzumab as part of adjuvant
therapy are eligible if they had recurrence of their disease more than six months
after completion of treatment.

- Subjects must provide signed written informed consent.

Exclusion criteria:

- Subject has peripheral neuropathy of Grade 2 or higher;

- Subject has had prior systemic cytotoxic chemotherapy for metastatic or locally
recurrent disease. Also, any subjects with prior chemotherapy in the adjuvant or
neoadjuvant setting with anthracycline or anthracenedione-containing regimens with
cumulative doses of ≥ 360mg/m2 of doxorubicin, ≥ 720mg/m2 of epirubicin, or ≥ 72
mg/m2 of mitoxantrone. Patients with prior hormonal therapy(ies) are eligible.

- Subjects with prior systemic investigational drugs within the past 30 days or topical
investigational drugs within the past seven days;

- Subjects with uncontrolled or symptomatic angina, arrhythmias.

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

- Subjects with a known immediate or delayed hypersensitivity or untoward reaction to
paclitaxel, trastuzumab, carboplatin, or other related compounds, or to drugs
chemically related to lapatinib. These include other anilinoquinazolines, such as
gefitinib (Iressa), erlotinib (Tarceva), or other chemically-related compounds.

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

- Subjects taking any prohibited medications as per protocol.