Cixutumumab and Temsirolimus in Treating Patients With Locally Advanced or Metastatic Cancer

PRIMARY OBJECTIVES:

I. To evaluate the safety and tolerability; and to determine maximum tolerated dose (MTD) of
the combination of IMC-A12 (cixutumumab) with temsirolimus in patients with or without
biopsiable advanced cancers.

II. To evaluate the biologic effect of each individual drug and this drug combination on
expression/phosphorylation of potential markers of response in patients with biopsiable
disease.

III. To assess tumor metabolism by positron emission tomography (PET).

SECONDARY OBJECTIVES:

I. To report the clinical tumor response of this combination in a descriptive fashion.

OUTLINE:

DOSE ESCALATION PHASE: Patients receive temsirolimus intravenously (IV) over 30 minutes and
cixutumumab IV over 60 minutes on days 1, 8, 15, and 22. Courses repeat every 28 days in the
absence of disease progression or unacceptable toxicity. After the MTD is determined,
subsequent patients are enrolled into the MTD expansion cohort.

MTD EXPANSION COHORT: Patients are assigned to 1 of 3 treatment groups.

GROUP A: Patients receive temsirolimus IV over 30 minutes on days 15 and 22 for course 1 and
on days 1, 8, 15, and 22 for all subsequent courses. Patients also receive cixutumumab IV
over 60 minutes on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of
disease progression or unacceptable toxicity.

GROUP B: Patients receive cixutumumab IV over 60 minutes on days 15 and 22 for course 1 and
on days 1, 8, 15, and 22 for all subsequent courses. Patients also receive temsirolimus IV
over 30 minutes on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of
disease progression or unacceptable toxicity.

GROUP C: Patients receive temsirolimus IV over 30 minutes and cixutumumab IV over 60 minutes
on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression
or unacceptable toxicity.

After completion of study treatment, patients are followed up within 30 days.

Inclusion Criteria:

- Patients with advanced or metastatic cancer

- Patients enrolled in the expansion cohorts may be on antidiabetic treatment, but
baseline glucose should be =< 120

- All patients must sign an informed consent indicating that they are aware of the
investigational nature of this study; patients must also have signed an authorization
for the release of their protected health information

- Patients are allowed to have unlimited prior treatments

- Patients must be registered in the MD Anderson Cancer Center (MDACC) institutional
database (CORE) prior to treatment with study drug

- Estimated life expectancy of greater than 3 months

- Patients must be ≥ 4 weeks beyond treatment of any chemotherapy, other
investigational therapy, biological, targeted agents or radiotherapy, and must have
recovered to =< grade 1 toxicity or previous baseline for each toxicity; exceptions:
patients must be >= 6 weeks beyond treatment with monoclonal antibodies; patients may
have received palliative low dose radiotherapy to the limbs 1-4 weeks before this
therapy provided pelvis, sternum, scapulae, vertebrae, or skull were not included in
the radiotherapy field

- Patients must be >= 2 weeks beyond treatment of hormonal therapy

- Eastern Cooperative Oncology Group (ECOG) performance status =< 1

- Absolute neutrophil count >= 1500/mL

- Platelets >= 100,000/mL

- Creatinine =< 2 X upper limit of normal (ULN)

- Total (T.) bilirubin =< 1.5 X ULN

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])
and/or alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 5 X ULN

- Women of childbearing potential MUST have a negative serum or urine human chorionic
gonadotropin (HCG) test unless prior hysterectomy or menopause (defined as 12
consecutive months without menstrual activity); patients should not become pregnant
or breastfeed while on this study; sexually active patients must agree to use
contraception prior to study entry, for the duration of study participation, and for
3 months after the last dose

- Patients must be >= 16 years of age; patients with Ewing's Sarcoma must be >= 14
years of age

Exclusion Criteria:

- Patients may not be receiving any other investigational agents

- Patients who are pregnant or breastfeeding

- Patients with history of abdominal fistula, gastrointestinal perforation or
intra-abdominal abscess within 28 days

- Patients with uncontrolled intercurrent illness including, but not limited to, active
infection requiring hospitalization

- Patients with history of hypersensitivity to monoclonal antibody treatment or
immunosuppressant agents

- Patients with history of cerebrovascular accident (CVA), myocardial infarction or
unstable angina within the previous six months before starting therapy

- Patients with New York Heart Association class III or greater congestive heart
failure or uncontrolled hyperlipidemia (cholesterol > 300 mg/dl; triglyceride 2.5 X
ULN despite lipid lowering agent)

- Patients with fasting blood sugar > 120; patients who are on oral hypoglycemic agents
and insulin will be excluded; exception: patients in the expansion cohorts may be on
antidiabetic treatment (including hypoglycemic agents and/or insulin) if controlled

- Patients on drugs that are strong P450 cytochrome P450, family 3, subfamily A,
polypeptide 4 (CYP3A4) inhibitors or inducers; these drugs should be stopped 5
half-lives prior to starting investigational agents with temsirolimus; the strong
inducing or inhibiting agents should not restart until 1 week after the end of study
treatment; the principal investigator (PI) or his designee will go over/check the
list of medication for individual patients; NOTE: Physiologic replacement of steroids
(with either prednisone or hydrocortisone) in patients with adrenalectomy will be
allowed

- Patients with history of brain metastasis are eligible, however the brain metastases
should have been treated (treatment defined as surgery or radiation therapy [RT]) and
the patient should have been free from symptoms/signs and off steroids for at least 3
months before study entry

- Patients with highly aggressive lymphoma (i.e. Burkitt's)