Whole-Brain Radiation Therapy or Stereotactic Radiosurgery With or Without Lapatinib Ditosylate in Treating Patients With Brain Metastasis From HER2-Positive Breast Cancer

PRIMARY OBJECTIVES:

I. To determine if there is a signal for an increase in complete response (CR) rate in the
measurable brain metastases at 12 weeks post radiation therapy (RT) (whole brain or
stereotactic radiosurgery [SRS]) as determined by magnetic-resonance imaging (MRI) scan of
the brain, with the addition of lapatinib (lapatinib ditosylate) to whole-brain radiation
therapy (WBRT)/SRS compared to WBRT/SRS alone.

SECONDARY OBJECTIVES:

I. To evaluate CR rate of the measurable brain metastases at 4 weeks post RT (WBRT/SRS) as
determined by MRI scan of the brain, with the addition of lapatinib to WBRT/SRS compared to
WBRT/SRS alone.

II. To evaluate objective response rate of measurable brain metastases at 4 and 12 weeks post
RT (WBRT/SRS) as determined by MRI scan of the brain, with the addition of lapatinib to
WBRT/SRS compared to WBRT/SRS alone.

III. To evaluate targeted lesion-specific objective response rate (CR + partial response
[PR]) at 4 and 12 weeks post WBRT/SRS.

IV. To evaluate central nervous system (CNS) progressive disease outside the targeted
measurable disease with addition of lapatinib to WBRT/SRS compared to WBRT/SRS alone.

V. To evaluate targeted lesion-specific progression at 4 and 12 weeks post WBRT/SRS.

VI. To evaluate treatment related adverse events when adding lapatinib to WBRT/SRS compared
to WBRT/SRS alone.

VII. To evaluate overall CNS complete response: disappearance of all CNS target lesions
sustained for at least 4 weeks; with no new lesions, no use of corticosteroids, and patient
is stable or improved clinically, when adding lapatinib to WBRT/SRS compared to WBRT/SRS
alone.

VIII. To evaluate overall CNS progressive disease (within or outside targeted measurable
disease) with addition of lapatinib to WBRT/SRS compared to WBRT/SRS alone.

IX. To evaluate overall survival when adding lapatinib to WBRT/SRS compared to WBRT/SRS
alone.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients undergo WBRT 5 days a week for 3 weeks for a total of 15 treatments or SRS
for 1 treatment.

ARM B: Patients undergo WBRT or SRS as in Arm A. Patients also receive lapatinib ditosylate
orally (PO) once daily (QD) for 6 weeks.

After completion of study treatment, patients are followed up at 4 and 12 weeks and then
every 12 weeks thereafter.

Inclusion Criteria:

- Pathologically (histologically or cytologically) proven diagnosis of invasive breast
cancer

- HER2-overexpressing breast cancer (3+ staining by immunohistochemistry or HER2 gene
amplification by fluorescent in situ hybridization [FISH] or silver in situ
hybridization [SISH] >= 2.0)

- At least 1 measurable unirradiated parenchymal brain metastasis within 21 days prior
to study entry; patients who are to undergo SRS must have no more than 10 brain
metastases; there is no limit on number of brain metastases for WBRT; the minimum size
as measured on T1-weighted gadolinium-enhanced MRI must be as follows according to the
number of brain metastases:

- For a single solitary lesion the size must be >= 10 mm

- For 2 or more lesions, the size of at least 2 of the lesions must be >= 5 mm

- Patients may also have the following provided the size requirements above are
met:

- Progressive parenchymal brain metastasis following stereotactic radiosurgery
for 1-3 brain metastases, with at least 1 new measurable brain lesion

- Progressive parenchymal brain metastasis following surgical resection of 1-3
brain metastases, with at least 1 measurable brain lesion

- History/physical examination within 21 days prior to study entry

- Karnofsky performance status >= 60 within 21 days prior to study entry

- Able to swallow and retain oral medication (note: for patients unable to swallow
tablets, an oral suspension preparation is acceptable)

- Absolute neutrophil count (ANC) >= 1,200 cells/mm^3, within 21 days prior to study
entry

- Platelets >= 70,000 cells/mm^3, within 21 days prior to study entry

- Hemoglobin >= 8.0 g/dL (note: the use of transfusion or other intervention to achieve
hemoglobin [Hgb] >= 8.0 g/dL is acceptable), within 21 days prior to study entry

- Creatinine < 1.5 times institutional upper limit of normal, within 21 days prior to
study entry

- Bilirubin < 1.5 times institutional upper limit of normal, within 21 days prior to
study entry

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3.0 times
institutional upper limit of normal with or without liver metastasis, within 21 days
prior to study entry

- Patient must provide study specific informed consent prior to study entry

- Women of childbearing potential must have a negative serum pregnancy test within 21
days prior to study entry

- Sexually active women of childbearing potential and sexually active men must practice
adequate contraception during therapy and for 12 months after protocol treatment
completion

- Prior lapatinib is allowed as long as the last dose received was > 21 days prior to
study entry and provided the patient has not received it at any time after the
diagnosis of brain metastasis

Exclusion Criteria:

- Prior WBRT

- Prior radiation therapy (RT) (any site) with concurrent lapatinib defined as 1 or more
days on which the patient received both radiation therapy and lapatinib on the same
day

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Prior invasive malignancy (except non-melanomatous skin cancer, curatively resected
thyroid papillary carcinoma, and invasive and non-invasive cancers related to the
breast cancer) unless disease free for a minimum of 3 years

- Leptomeningeal disease

- Prior radiotherapy to the region of the study cancer that would result in overlap of
radiation therapy fields except patients who have progressed following stereotactic
radiosurgery for 1-3 brain metastases, with at least one new lesion

- Severe, active co-morbidity, defined as follows:

- Unstable angina and/or congestive heart failure requiring hospitalization within
the last 6 months

- Transmural myocardial infarction within the last 6 months

- Acute bacterial or fungal infection requiring intravenous antibiotics at the time
of study entry

- Chronic obstructive pulmonary disease exacerbation or other respiratory illness
requiring hospitalization or precluding study therapy at the time of study entry

- Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects;
hepatic or biliary disease that is acute or currently active or that requires
antiviral therapy (with the exception of patients with Gilbert's syndrome,
asymptomatic gallstones, liver metastases, or stable chronic liver disease per
investigator assessment)

- History of left ventricular ejection fraction (LVEF) below institutional normal
unless repeated and within institutional normal range within 90 days of study
entry

- Grade 2 or greater rash of any cause at time of study entry

- Grade 2 or greater diarrhea of any cause at time of study entry