A Randomized Phase 2 Clinical Trial of IMC-A12, as a Single Agent or in Combination With Cetuximab, in Patients With Metastatic Colorectal Cancer With Disease Progression on Prior Anti-EGFR Therapy

Inclusion Criteria

Inclusion Criteria

- The patient has histologically or cytologically-confirmed colorectal cancer with
metastatic disease documented on diagnostic imaging studies

- The patient has measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded),
measuring ≥ 2 cm on conventional measurement techniques or ≥ 1 cm on spiral computed
tomography (CT) scan

- The patient has clinical documentation of disease progression during treatment or
within 6 weeks after receiving the last dose of a therapeutic regimen for metastatic
disease containing an anti-EGFR-component (cetuximab or panitumumab). Toxicity or
planned treatment break will not be regarded as adequate evidence of disease
progression and such patients will not be eligible for this trial

- The patient has received at least one prior standard and/or investigational regimen
for metastatic disease

- The patient is age ≥ 18 years

- The patient has an Eastern Cooperative Oncology Group performance status (ECOG PS) of
0-1 (Karnofsky ≥ 80%)

- The patient has adequate hematologic function as defined by an absolute neutrophil
count ≥ 1500/μL, hemoglobin ≥ 9 g/dL, and a platelet count ≥ 100,000/μL

- The patient has adequate hepatic function as defined by a total bilirubin ≤ 1.5 x the
upper limit of normal (ULN),* and aspartate transaminase (AST) and alanine
transaminase (ALT) ≤ 3 x the ULN (or ≤ 5 x the ULN in the presence of known liver
metastases)

- The patient has adequate coagulation function as defined by international normalized
ratio (INR) ≤ 1.5 and partial thromboplastin time (PTT) ≤ 1.5 x the ULN. Patients on
full-dose anticoagulation must be on a stable dose of oral anticoagulant or low
molecular weight heparin, and if on warfarin must have an INR between 2 and 3 and
have no active bleeding or pathological condition that carries a high risk of
bleeding (eg, tumor involving major vessels or invading the rectal lumen, or known
varices)

- The patient has adequate renal function as defined by serum creatinine ≤ 1.5 x the
institutional ULN or creatinine clearance ≥ 60 mL/min for patients with creatinine
levels above the ULN, as well as urine protein ≤ 1+ on urine dipstick or routine
urinalysis (if urine dipstick/routine UA indicates ≥ 2+ protein, a 24-hour urine
collection for protein must demonstrate < 1000 mg of protein in 24 hours to allow
participation in the study)

- The patient has fasting serum glucose < 120 mg/dL or below the ULN

- The patient has a life expectancy of > 3 months

- Because the teratogenicity of IMC-A12 (cixutumumab) is not known, women of
childbearing potential and men must agree to use adequate contraception (hormonal or
barrier method of birth control; abstinence) prior to study entry and for the
duration of study participation

- The patient has the ability to understand and the willingness to sign a written
informed consent document

- The patient has a tumor that is KRAS wild-type (absence of mutations at codon 12 or
13, as determined by the DxS K-RAS Mutation Kit [PCR-based analysis]).

- The patient experienced either a confirmed partial response or stable disease of ≥ 24
weeks duration during prior treatment with a cetuximab- or panitumumab-containing
regimen *Except for patients with UGT1A1 promoter polymorphism, ie, Gilbert syndrome,
confirmed by genotyping or Invader®UGT1A1 Molecular Assay prior to enrollment.
Patients enrolled with Gilbert Syndrome must have a total bilirubin ≤ 3 x ULN. If the
patient has liver metastases, total bilirubin must be ≤ 3 x ULN.

Exclusion Criteria

- The patient has received chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or has not recovered from
adverse events due to agents administered more than 4 weeks earlier. Neurotoxicity,
if present, must have recovered to NCI-CTCAE Version 3.0 grade ≤ 2.

- The patient is receiving any other investigational agent(s).

- The patient has a history of treatment with other agents targeting the IGFR.

- The patient has known brain or leptomeningeal metastases.

- The patient has a history of primary central nervous system tumors, seizures not well
controlled with standard medical therapy, or history of stroke within 6 months prior
to randomization.

- The patient has a history of allergic reactions attributed to compounds of chemical
or biologic composition similar to those of cetuximab or IMC-A12 (cixutumumab).

- The patient has poorly controlled diabetes mellitus. Patients with a history of
diabetes mellitus are allowed to participate, provided that their blood glucose is
within normal range (fasting glucose < 120 mg/dL or below ULN) and that they are on a
stable dietary or therapeutic regimen for this condition.

- The patient has an uncontrolled intercurrent illness including, but not limited to,
ongoing or active infection requiring parenteral antibiotics, symptomatic congestive
heart failure, uncontrolled hypertension, clinically significant cardiac arrhythmia,
or psychiatric illness/social situations that would limit compliance with study
requirements.

- The patient is pregnant or lactating.

- The patient is known to be positive for infection with the human immunodeficiency
virus.

- The patient is receiving therapy with immune modulators such as cyclosporine or
tacrolimus.

- The patient has a history of another primary cancer, with the exception of: a)
curatively resected nonmelanomatous skin cancer; b) curatively treated cervical
carcinoma in-situ; or c) other primary solid tumor curatively resected treated with
no known active disease present and no treatment administered for the last 3 years.