Tolerability of the Combination of Lapatinib and Trastuzumab in Adults Age 60 or Older With HER2 Positive Locally Advanced or Metastatic Breast Cancer

PRIMARY OBJECTIVES: I. To estimate the safety and tolerability of the combination of
trastuzumab and lapatinib (lapatinib ditosylate) in adults age 60 or older with locally
advanced or metastatic breast cancer. SECONDARY OBJECTIVES: I. To describe the full toxicity
profile including all grades; to estimate the rate of all grades of cardiac toxicity; to
estimate the rate of all grades of diarrhea, nausea, and vomiting. II. To describe the
pharmacokinetic parameters of lapatinib in older adults. III. To estimate objective response
rate and clinical benefit rate as defined by modified Response Evaluation Criteria In Solid
Tumors (RECIST) criteria. IV. To estimate median progression-free and overall survival. V. To
explore factors other than chronological age that can affect toxicity rates as identified
using a cancer-specific geriatric assessment. VI. To estimate rates of adherence to lapatinib
in older adults.

OUTLINE: Patients receive lapatinib ditosylate orally (PO) once daily (QD) and trastuzumab
intravenously (IV) over 30-90 minutes once weekly OR once every 3 weeks. Courses repeat every
21 days in the absence of disease progression or unacceptable toxicity. After completion of
study treatment, patients are followed up for 30 days and then periodically thereafter.

Inclusion Criteria:

- Locally advanced or metastatic Her2/Neu positive breast cancer (defined as
immunohistochemistry [IHC] 3+ or a fluorescence in situ hybridization [FISH] ratio of
>= 2.0); this may be on either a primary tumor or a metastatic site, and there is no
time limit from the time the specimen was obtained; locally advanced breast cancer
(LABC) includes breast cancers with advanced primary tumors, i.e., large diameter (at
least 5 cm) or those with skin and/or chest wall involvement, and advanced regional
lymph node involvement; it also includes a rare subgroup, inflammatory breast cancer;
in the 2010 American Joint Committee on Cancer and the International Union for Cancer
Control (AJCC-UICC) TNM breast cancer staging system, locally advanced breast cancer
(LABC) includes patients with stage III disease; this comprises:

- Advanced primary tumors (tumors > 5 cm in greatest dimension [T3]; direct
extension to the chest wall and/or to the skin [T4]: ulceration, skin nodules,
and/or edema (including peau d'orange) confined to the same breast, inflammatory
breast cancer [IBC, T4d])

- Advanced regional lymph nodes (ipsilateral level I, II axillary lymph nodes that
are clinically fixed or matted or clinically detected internal mammary lymph
nodes in the absence of axillary lymph node metastases [N2], ipsilateral
infraclavicular [level III axillary] lymph nodes, ipsilateral internal mammary
lymph node[s] with axillary lymph nodes, or ipsilateral supraclavicular lymph
nodes [N3])

- Both measurable and non-measurable disease are allowed

- Life expectancy of greater than 12 weeks

- Women of child-bearing potential and sexually active men must agree to use adequate
contraception prior to study entry for six months following duration of study
participation

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky
performance status >= 60%)

- Hemoglobin >= 10 g/dL (after transfusion if necessary)

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Total bilirubin within normal institutional limits

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/aspartate aminotransferase (ALT) (serum glutamate pyruvate transaminase
[SGPT]) =< 2.5 X institutional upper limit of normal

- Creatinine clearance >= 30 mL/min as measured using either the Cockcroft-Gault method
or 24-hour creatinine clearance

- The above tests must be obtained within 14 days of study treatment

- Cardiac ejection fraction >= 50% as measured by echocardiogram or multiple gated
acquisition scan (MUGA) scan

- The ability to swallow and retain oral medication

- Prior treatment with lapatinib or trastuzumab are allowed, provided that the agents
have never been given in combination

- Any number of prior cancer treatments, including investigational agents, chemotherapy,
hormone therapy, or targeted therapy are allowed

- All patients must have the ability to understand and the willingness to sign a written
informed consent

Exclusion Criteria:

- Concurrent investigational treatment, chemotherapy, or targeted therapy; prior
chemotherapy, hormonal therapy, targeted therapy, and investigational agents are
allowed but all toxicities grade >= 2 must have resolved by the time of study
commencement (except alopecia)

- Unstable or symptomatic brain metastases (however, patients with stable or treated
brain metastases who do not require steroids at doses above those permitted for
control of symptoms may be enrolled)

- History of allergic reactions attributed to compounds of similar chemical or
biological composition to lapatinib or trastuzumab; however, patients with a history
of infusion reaction to trastuzumab which was controlled with premedication on
subsequent infusions without a recurring infusion reaction are eligible

- Concomitant medications listed are prohibited; inhibitors or inducers of cytochrome
P450 3A4 (CYP3A4) not listed can be used with caution

- Ongoing or active infection (including human immunodeficiency virus [HIV]) or
psychiatric illness/social situations that would limit compliance with study
requirements

- Inability to take oral medication

- Malabsorption syndrome, (prior surgical procedures affecting absorption), or
inflammatory gastrointestinal (GI) disease (e.g., Crohn's, ulcerative colitis) which
in the opinion of the study coordinator is likely to limit normal absorption of the
drug

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

- Active cardiac disease, defined as (but not limited to):

- History of documented congestive heart failure (CHF) or systolic dysfunction
(left ventricular ejection fraction [LVEF] < 50%)

- High-risk uncontrolled arrhythmias (ventricular tachycardia, high-grade
atrio-ventricular [AV]-block, supraventricular tachycardias which are not
adequately rate-controlled)

- Angina pectoris requiring antianginal medications

- Evidence of transmural infarction on electrocardiogram (ECG)

- Clinically significant valvular heart disease

- Poorly controlled hypertension (e.g. systolic > 180 mm HG or diastolic > 100 mm
Hg)

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

- Subjects who, in the opinion of the investigator, may not be able to comply with the
safety monitoring requirements of the study are not eligible