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

PRIMARY OBJECTIVES:

I. To compare progression-free survival of HER2+ breast cancer patients randomized to receive
lapatinib (lapatinib ditosylate) and capecitabine +/- IMC-A12 (cixutumumab).

SECONDARY OBJECTIVES:

I. To assess the safety and tolerability of lapatinib and capecitabine +/- IMC-A12 in HER2+
breast cancer patients.

II. To compare the overall survival time, time to treatment failure, confirmed tumor response
rate, and duration of response of lapatinib and capecitabine +/- IMC-A12 in HER2+ breast
cancer patients.

III. To assess patient compliance per treatment arm and to compare overall quality of life
and treatment side effects via patient-reported outcomes between treatment arms.

TERTIARY OBJECTIVES:

I. To determine the role of expression patterns and/or activation of IGF- and ErbB family of
receptors and signaling molecules in formalin-fixed, paraffin-embedded breast tumor tissue in
predicting response to lapatinib and capecitabine +/- IMC-A12.

II. To determine the role of expression patterns and/or activation of IGF- and ErbB receptors
and signaling molecules in circulating tumor cells from breast cancer patients in predicting
response to lapatinib and capecitabine +/- IMC-A12.

III. To determine the role of changes in expression patterns and/or activation of IGF- and
ErbB receptors and signaling molecules following treatment with lapatinib and capecitabine
+/- IMC-A12 in circulating tumor cells from breast cancer patients in predicting response to
lapatinib and capecitabine +/- IMC-A12.

IV. To determine the role of expression patterns of IGF-1, IGF-II, insulin, growth hormone,
and the IGF binding proteins in the serum of breast cancer patients in predicting response to
lapatinib and capecitabine +/- IMC-A12.

V. To determine the role of changes in expression patterns of IGF-1, IGF-II, insulin, growth
hormone, and the IGF binding proteins in the serum of breast cancer patients in predicting
response to lapatinib and capecitabine +/- IMC-A12.

VI. Banking of paraffin-embedded tissue blocks/slides and blood products (i.e., serum,
plasma, and buffy coat) for future studies.

VII. To assess the proportion of patients whose pathologic specimens were correctly diagnosed
as HER2 positive (according to 2007 American Society of Clinical Oncology [ASCO] College of
American Pathologist [CAP] guidelines) metastatic breast cancer.

OUTLINE: The first 10 patients enrolled on this study are assigned to cohort I (safety
analysis). All other patients are assigned to cohort II (randomized treatment).

COHORT I (SAFETY ANALYSIS, closed to accrual): Patients receive cixutumumab intravenously
(IV) over 1 hour on days 1, 8, and 15. Patients also receive capecitabine orally (PO) twice
daily (BID) on days 1-14 and lapatinib ditosylate PO once daily (QD) on days 1-21. Courses
repeat every 21 days in the absence of disease progression or unacceptable toxicity.

COHORT II (RANDOMIZED TREATMENT): Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients receive capecitabine PO BID on days 1-14 and lapatinib ditosylate PO QD on
days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable
toxicity.

ARM B: Patients receive capecitabine and lapatinib ditosylate as in Arm A. Patients also
receive cixutumumab IV over 1 hour on days 1, 8, and 15. Courses repeat every 21 days in the
absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months until disease
progression and then every 6 months for up to 5 years.

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:

- 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