Lapatinib in Women With Metastatic Breast Cancer Who Have Failed Prior Antihormone Therapy

Endocrine therapy forms the backbone of treatment for both early stage and advanced stage
hormone receptor positive breast cancer. Although most patients with advanced estrogen
receptor positive metastatic disease respond initially to endocrine therapies, this response
is short lived. New therapies able to provide additional benefit to patients with hormone
receptor positive, endocrine-resistant, advanced metastatic breast cancer are required. This
study proposes to add lapatinib to endocrine therapy to treat hormone receptor positive
HER-2 negative metastatic breast cancer patients.

Inclusion Criteria

- Histologically or cytologically confirmed invasive breast cancer, which at time of
study entry is either stage III (locally advanced) disease not amenable to curative
therapy or stage IV disease. Histological confirmation of recurrent/metastatic
disease is encouraged but not required if clinical evidence of stage IV disease
recurrence is available.

- ER and/or Progesterone Receptor (PgR )positive breast cancer (10% or more of
infiltrating cancer cells exhibit nuclear staining for ER and/or PgR)

- Have had progressive disease or development of new metastatic disease while on
treatment or within 12 months of treatment with an aromatase inhibitor and/or
Fulvestrant in adjuvant or metastatic setting

- Have measurable (defined as at least 1 lesion that can be accurately measured in at
least 1 dimension [longest diameter to be recorded], with minimum lesion size ≥ 2cm
on conventional measurement techniques or ≥ 1cm on spiral computed tomography [CT]
scan), or evaluable disease. Patients with lytic or blastic bone disease as only site
of disease will be eligible for the study. These patients will be evaluable for
progression but not for response.

- Primary tumor was HER-2 negative (IHC 0 or IHC 1+/2+ and FISH negative)

- Patients could have received prior Tamoxifen either as adjuvant therapy or for stage
IV disease

- Performance status of 2 or better per Eastern Cooperative Oncology Group (ECOG)
criteria

- Adequate cardiac function (cardiac ejection fraction ≥ 50% as measured by
echocardiogram or multigated acquisition (MUGA) scan).

- IV bisphosphonate and denosumab for bony metastatic disease will be allowed

- Palliative radiation therapy to bony metastases will be allowed

- Adequate bone marrow function per good medical practice. Results of these tests do
not determine eligibility. Minor deviations are acceptable if they do not impact
safety in the judgment of the treating physician. Absolute neutrophil count (ANC) ≥
1500/mm3, platelet count ≥ 100,000/mm3, and hemoglobin ≥ 10 g/dL

- Adequate kidney function: serum creatinine of ≤ 1.5mg/dl and/or creatinine clearance
of ≥ 60 mL/min

- Adequate hepatic function: transaminases < 2 x upper limit of normal and total
bilirubin ≤ 1.5 mg/dL.

- Must have a serum albumin ≥ 3.0 g/dL.

- Must be informed of investigational nature of study and must sign informed consent in
accordance with institutional rules.

- Pretreatment lab values must be performed within 14 days of patient registration and
other baseline studies within 30 days.

- Patients will have a baseline, bone scan, CT chest,abdomen and pelvis or PET/CT.

- If previously treated brain metastasis and free of central nervous system (CNS)
symptoms and > 3 months from treatment of brain metastasis are eligible

Exclusion Criteria

- Prior HER-2 targeted therapy for metastatic disease

- Has uncontrolled brain metastasis or leptomeningeal disease

- Has rapidly progressing and/or bulky disease which in the opinion of the investigator
may be more appropriately treated with a chemotherapy-based strategy.

- Has an uncontrolled intercurrent illness including, but not limited to ongoing or
active infection requiring parenteral antibiotics or psychiatric illness/social
situations that would limit compliance with study requirements.

- Concomitant requirement for medication classified as CYP3A4 inducers or inhibitors

- Patients with GI tract disease resulting in an inability to take oral medication,
malabsorption syndrome, a requirement for IV alimentation, prior surgical procedures
affecting absorption, uncontrolled inflammatory GI disease (eg, Crohn's, ulcerative
colitis).

- Current active hepatic or biliary disease (exception of patients with Gilbert's
syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease
per investigator assessment)

- Renal function as measured by creatinine clearance <3 0ml/min (ratio to norm < 0.1)

- HIV-positive patients receiving combination antiretroviral therapy

- Pregnant women

- Active cardiac disease defined as:

- History of uncontrolled or symptomatic angina

- History of arrhythmias requiring medications, or clinically significant, with
the exception of asymptomatic atrial fibrillation requiring anticoagulation

- Myocardial infarction < 6 months from study entry

- Uncontrolled or symptomatic congestive heart failure

- Ejection fraction below institutional normal limit

- Any other cardiac condition, which in the opinion of treating physician, would
make this protocol unreasonably hazardous for the patient

- History of another primary cancer, with exception of:

- curatively resected nonmelanomatous skin cancer

- curatively treated cervical carcinoma in-situ

- other primary solid tumor curatively resected treated with no known active
disease present and no treatment administered for the last 3 years.

- Life expectancy of < 2 months