Capecitabine and Lapatinib Ditosylate With or Without Cixutumumab in Treating Patients With Previously Treated HER2-Positive Stage IIIB-IV Breast Cancer

Inclusion Criteria:

Histologically confirmed, locally advanced: (a T4 primary tumor and stage IIIB or IIIC disease) or metastatic breast cancer that has progressed after treatment with regimens that included trastuzumab and either an anthracycline or a taxane or both

NOTE: Agents need not have been given concurrently, nor in the same regimen
NOTE: Prior treatment with trastuzumab is required unless there is a contraindication for trastuzumab treatment

Pre-treatment requirements:

Prior treatment with trastuzumab in the neo-adjuvant, adjuvant or metastatic setting is required

NOTE: Prior treatment with trastuzumab is required unless there is a contraindication for trastuzumab treatment
NOTE: Concomitant use of trastuzumab is not allowed in this study
Prior chemotherapy allowed in the neo-adjuvant, adjuvant, or metastatic setting; unlimited prior chemotherapy is allowed
Prior hormonal therapy allowed in the neo-adjuvant, adjuvant, or metastatic setting; unlimited prior hormonal therapy is allowed

HER2 positive, defined as:

Validated immunohistochemistry (IHC) assay score of 3+ (defined as uniform, intense staining of > 30% of invasive tumor cells)
-OR- Average HER2 gene copy number of > 6
-OR- Gene amplified (HER2:D17Z1 ratio > 2.20)
Must have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria
Negative pregnancy test done =< 7 days prior to registration, for women of childbearing potential only
Hemoglobin > 9.0 g/dL (obtained =< 7 days prior to registration)
White blood cells (WBC) >= 3,000/mL (obtained =< 7 days prior to registration)
Absolute neutrophil count (ANC) >= 1500/mL (obtained =< 7 days prior to registration)
Platelet count >= 75,000/mL (obtained =< 7 days prior to registration)
Total bilirubin =< 1.5 x upper limit of normal (ULN) (obtained =< 7 days prior to registration)
Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 2.5 x ULN or SGOT (AST) and SGPT (ALT) =< 5 x ULN if elevations are due to liver metastases (obtained =< 7 days prior to registration)
Serum creatinine =< 1.5 x ULN (obtained =< 7 days prior to registration)

Creatinine clearance >= 30 mL/min (calculated according to Cockcroft and Gault) (obtained =< 7 days prior to registration)

NOTE: In patients with moderate renal impairment (calculated creatinine clearance 30-50 mL/min) at baseline, a dose reduction of the capecitabine starting dose is required

Fasting glucose < 120 mg/dL (obtained =< 7 days prior to registration)

NOTE: Patients with diabetes are allowed to participate, provided that their blood glucose is within the guidelines above upon enrollment
International normalization ratio (INR) =< 1.5 x ULN (obtained =< 7 days prior to registration)
Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1 or 2
Adequate cardiac function defined as an ejection fraction >= 50% as determined by multi gated acquisition scan (MUGA) or echocardiogram
Life expectancy > 3 months
Has written informed consent been obtained?
Willingness to return to a North Central Cancer Treatment Group (NCCTG) or other participating cooperative group institution for treatment and follow-up
Patient willing to provide tissue and blood samples for research purposes

Availability of diagnostic material (i.e., diagnostic slides confirming locally advanced/metastatic disease and HER2 stained slides) and operative and pathology reports from diagnosis of locally advanced or metastatic breast cancer

NOTE: Biopsy of recurrent disease and submission of these materials is not required if materials available from initial diagnosis of locally advanced/metastatic disease
Ability to complete questionnaire(s) by themselves or with assistance

Exclusion Criteria:

Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:

Pregnant women
Nursing women
Men or women of childbearing potential who are unwilling to employ adequate contraception (as determined by the treating physician)
Stage III or IV invasive cancer, other than breast cancer, in =< 5 years prior to registration
Actively being treated for other malignancy, excepting non-melanotic skin cancer or carcinoma-in-situ of the cervix; if there is a history of prior malignancy, patient must not be receiving other specific treatment for their cancer
New York Heart Association class III or IV cardiovascular disease
Current, active hepatic or biliary disease except Gilbert's syndrome or asymptomatic gallstones

Evidence of active brain metastasis including leptomeningeal involvement; central nervous system (CNS) metastasis controlled by prior surgery and/or radiotherapy is allowed

NOTE: To be considered controlled, there must be at least 2 months of no symptoms or evidence of progression prior to study entry and corticosteroid therapy must have been discontinued
Major surgery, chemotherapy, or immunologic therapy =< 4 weeks prior to registration
Radiotherapy =< 4 weeks prior to registration, except if to a non-target lesion only; prior radiation to a target lesion is permitted only if there has been clear progression of the lesion since radiation was completed; if patient receives single dose radiation for palliation or radiation to non-target lesion, they may immediately proceed to registration without waiting; acute adverse events from radiation must have resolved to =< Common Terminology Criteria for Adverse Events (CTCAE) version (v) 3.0 grade 1

Prior treatment with any therapy targeting IGF-I, IGF-II or its receptors (either monoclonal antibody or tyrosine kinase inhibitor), including but not limited to any of the following (which would have been received on a previous clinical trial):

IMC-A12 (cixutumumab)
CP-751,871 (figitumumab)
AMG-479
INSM-18
MK0646 (h7C10)
SCH717454 (19D12, robatumumab)
R1507
OSI-906
BMS-754807
PPP
NVP-AEW541
AVE-1642
MEDI-573

Prior therapy with any therapy targeting HER1 (EGFR) and/or HER2 (either monoclonal antibody or tyrosine kinase) other than trastuzumab, including but not limited to any of the following:

Lapatinib (Tykerb)
Gefitinib (Iressa)
Erlotinib (Tarceva)
Cetuximab (Erbitux)
Panitumumab (Vectibix)

Currently receiving treatment with any agents that are contraindicated by study therapies:

IMC-A12 - none identified to date
Lapatinib - CYP3A4 inhibitors and inducers, including grapefruit and grapefruit juice
Capecitabine - warfarin (Coumadin), cimetidine (Tagamet), allopurinol (Lopurin), sorivudine (Usevir) or brivudine (Brivex), ketoconazole (Nizoral), itraconazole (Sporanox), ritonavir (Norvir), amprenavir (Agenerase) or indinavir (Crixivan)

Uncontrolled intercurrent illness including, but not limited to:

Poorly controlled diabetes
Ongoing or active infection
Symptomatic congestive heart failure
Unstable angina pectoris
Cardiac arrhythmia
Psychiatric illness/social situations that would limit compliance with study requirements
Co-morbid systemic illnesses or other severe concurrent disease which, 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 regimens
Currently receiving treatment in a different clinical study in which investigational procedures are performed or investigational therapies are administered
Immunocompromised patients (other than that related to the use of corticosteroids) including patients known to be human immunodeficiency virus (HIV) positive with an acquired immune deficiency syndrome (AIDS)-defining illness; HIV positive patients with cluster of differentiation (CD) 4 count within institutional normal range and no history of an AIDS-defining illness are eligible; however, some antiviral/antiretroviral medications which have CYP3A4 interactions are prohibited on this study