Randomized Phase II Trial of Capecitabine and Lapatinib With or Without IMC-A12 in Patients With HER2 Positive Breast Cancer Previously Treated With Trastuzumab and an Anthracycline and/or a Taxane

Inclusion Criteria:

- Histologically confirmed breast cancer, meeting one of the following criteria:

- Locally advanced disease (i.e., stage IIIB or IIIC [T4 primary tumor] disease)

- Metastatic disease

- Disease progressed after treatment with regimens that included trastuzumab
(Herceptin®) in combination with an anthracycline and/or a taxane

- Must have received 1-2 prior chemotherapy regimens in the neoadjuvant, adjuvant,
or metastatic setting

- One regimen must have included treatment with an anthracyclineand/or a
taxane

- Prior treatment with trastuzumab required unless there is a contraindication for
trastuzumab treatment

- HER2-positive disease, defined by any of the following:

- Validated IHC assay score of 3+ (defined as uniform, intensestaining of > 30% of
invasive tumor cells)

- Average HER2 gene copy number > 6

- Gene amplified (HER2:D17Z1 ratio > 2.20)

- Measurable disease according to RECIST criteria

- No evidence of active brain metastases, including leptomeningeal involvement

- CNSmetastasis controlled* by prior surgery and/or radiotherapy is allowed

- Hormone receptor status not specified

- Menopausal status not specified

- ECOG performance status 0-2

- Life expectancy > 3 months

- WBC ≥ 3,000/mm³

- ANC ≥ 1,500/mm³

- Platelet count ≥ 75,000/mm³

- Hemoglobin > 9.0 g/dL

- Total bilirubin ≤ 1.5 times upper limit of normal (ULN)

- AST and ALT ≤ 2.5 times ULN (5 times ULN if elevations are due to liver metastases)

- Serum creatinine ≤ 1.5 times ULN

- Creatinine clearance ≥ 30 mL/min

- Fasting glucose < 120 mg/dL

- Diabetes allowed provided blood glucose level meets the above criterion

- INR ≤ 1.5 times ULN

- LVEF ≥ 50% by MUGA or ECHO

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- Willing to provide tissue and blood samples for research purposes

- Able to complete questionnaires by self or with assistance

- No other stage III or IV invasive cancer within the past 5 years

- No other malignancy requiring active treatment, except nonmelanoma skin canceror
carcinoma in situ of the cervix

- History of prior malignancy allowed providedpatient is not receiving other
specific treatment for their malignancy

- No current, active hepatic or biliary disease, except Gilbert syndrome's
orasymptomatic gallstones

- No New York Heart Association class III or IV cardiovascular disease

- No concurrent uncontrolled illness including, but not limited to, any of the
following:

- Poorly controlled diabetes

- Ongoing or active infection

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Cardiac arrhythmia

- Psychiatric illness/social situation that would preclude compliance with
studyrequirements

- No co-morbid systemic illness or other severe concurrent disease that, in the
judgment of the investigator, would make the patient inappropriate for entry into
this study or interfere significantly with the proper assessment of the safety of the
prescribed study regimens

- Not immunocompromised (other than that related to the use of corticosteroids),
including known HIV-positivity with an AIDS-defining illness

- HIV-positive patients with a CD4 count within normal range and who have no
history of an AIDS-defining illness are eligible

- No other concurrent chemotherapeutic agents, biologic agents, or radiotherapy

- Prior hormonal therapy in the neoadjuvant, adjuvant, or metastatic setting allowed

- More than 6 weeks since prior major surgery, chemotherapy, or immunologic therapy

- More than 4 weeks since prior radiotherapy, except a single dose of palliative
radiotherapy or radiotherapy to a non-target lesion

- Prior radiotherapy to a target lesion is allowed only if there has been clear
progression of the lesion since completion of radiotherapy

- Recovered from prior radiotherapy

- No more than 2 prior chemotherapy regimens for metastatic disease

- No prior treatment with any therapy targeting IGF-I, IGF-II, or its receptors
(eithermonoclonal antibody or tyrosine kinase inhibitor) including, but not limited
to, anyof the following:

- Cixutumumab

- CP-751871

- AMG-479

- INSM-18

- MK-0646 (h7C10)

- 19D12

- R1507

- OSI-906

- BMS-536924

- PPP

- NVP-AEW541

- No other prior therapy targeting HER1 (EGFR) and/or HER2 (either monoclonal antibody
or tyrosine kinase inhibitor) including, but not limited to, any of the following:

- Lapatinib ditosylate

- Gefitinib

- Erlotinib hydrochloride

- Cetuximab

- Panitumumab

- No concurrent agents that would contraindicate study treatment, including any of the
following:

- CYP3A4 inhibitors and inducers, including grapefruit and grapefruit juice

- Warfarin, cimetidine,allopurinol, sorivudine or brivudine,ketoconazole,
itraconazole, ritonavir,amprenavir, or indinavir

- No concurrent treatment in another clinical study in which investigational procedures
are performed or investigational therapies are administered