Cixutumumab and Temsirolimus in Treating Patients With Metastatic Prostate Cancer

PRIMARY OBJECTIVES:

I. To confirm the safety and tolerability of IMC-A12 (cixutumumab) and temsirolimus using the
recommended phase II dose level for advanced solid tumors in chemo-naive patients with
metastatic castration-resistant prostate cancer and a rising prostate-specific antigen (PSA).
(Phase I) II. To confirm the safety and tolerability of IMC-A12 and temsirolimus given on an
every three weeks dosing schedule. (Phase I Extension) II. To determine the tumor response
rate and/or composite time to progression (cTTP) for chemotherapy-naive patients with
castration-resistant prostate cancer (CRPC) receiving the combination of IMC-A12 and CCI-779
(temsirolimus). (Phase II)

SECONDARY OBJECTIVES:

I. To determine the maximal percent decrease in PSA from baseline. II. To determine the
change in PSA doubling time (PSADT). III. To determine the time to PSA progression and
6-month progression-free survival (PFS).

IV. To determine the rate of adverse events.

EXPLORATORY OBJECTIVES:

I. To evaluate changes in circulating tumor cell (CTC) numbers with time. II. To evaluate
IGF1R and androgen receptor (AR) in CTCs and correlate with response.

III. To evaluate profiling CTCs at the molecular level by polymerase chain reaction (PCR) for
prostate cancer-specific genes.

IV. To explore the association between clinical outcomes, administration of therapy, and
serial fludeoxyglucose F 18 (FDG)-positron emission tomography (PET) imaging.

V. To correlate fluorine F 18 FMDHT (18-FDHT)-PET imaging findings with outcome measures of
response.

VI. To perform tumor biopsies and evaluate biomarkers that may correlate with active feedback
and tumor response to therapy, including anti-insulin receptor substrate 1 (IRS-1),
anti-IRS-2, phosphorylated (p) protein kinase B (Akt)(S473), p-ribosomal protein S6 kinase
(70/S6K), anti-phospho-AKT1 substrate 1 (proline-rich) (PRAS 40), and phosphatase and tensin
homolog gene (PTEN) status.

OUTLINE: This is a multicenter study.

Patients receive cixutumumab intravenously (IV) over 60-70 minutes and 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.

After completion of study treatment, patients are followed up at 4 weeks.

Inclusion Criteria:

- Histologically or cytologically confirmed adenocarcinoma of the prostate

- Distant metastases evaluable by radionuclide bone scan, CT scan, or magnetic
resonance imaging (MRI) within the past 28 days

- Evidence of progressive disease during androgen-deprivation therapy (including a trial
of antiandrogen-withdrawal therapy), as defined by ≥ 1 of the following criteria:

- Progressive measurable disease using conventional solid tumor criteria

- Bone scan progression, defined as ≥ 2 new lesions on bone scan

- Increasing PSA, defined as ≥ 2 consecutive rising PSA values over a reference
value taken ≥ 1 week apart (the third PSA value must be greater than the second
PSA value, if not, a fourth PSA value must be greater than the second PSA value)

- Castrate levels of serum testosterone (i.e., ≤ 50 ng/dL)

- No known brain metastases

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1 OR Karnofsky PS
70-100%

- Life expectancy > 6 months

- Leukocytes ≥ 3,000/μL

- Absolute neutrophil count (ANC) ≥ 1,500/μL

- Platelet count ≥ 100,000/μL

- Hemoglobin ≥ 9 g/dL

- Total bilirubin ≤ 2 times upper limit of normal (ULN)

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 times ULN

- Serum creatinine ≤ 1.5 times ULN

- Creatinine clearance ≥ 50 mL/min

- Able to adhere to the study visit schedule and other study requirements

- Fertile patients must use effective contraception before, during, and for 3 months
after completion of study treatment

- Adequate lung function (pulmonary function test ≥ 70% for diffusion capacity of the
lung for carbon monoxide [DLco])

- No poorly controlled diabetes mellitus

- Patients with a history of diabetes are eligible provided their blood glucose is
normal (i.e., fasting blood glucose < 120 mg/dL or < ULN) and they are on a
stable dietary or therapeutic regimen

- No other malignancy within the past 3 years except for treated basal cell or squamous
cell carcinoma of the skin or superficial transitional cell carcinoma of the bladder

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

- Active infection, including human immunodeficiency virus (HIV) infection or viral
hepatitis

- Symptomatic congestive heart failure (class III or IV)

- Unstable angina pectoris

- Myocardial infarction or acute coronary syndrome within the past year

- Serious cardiac arrhythmia

- Significant lung disease

- Major psychiatric illness

- No other concurrent anticancer agents or treatments

- No prior chemotherapy, except for neoadjuvant chemotherapy

- No prior anti-insulin-like growth factor receptor (IGFR) agents or mammalian target of
rapamycin (mTOR) inhibitors

- No prior strontium-89, rhenium-186, rhenium-188, or samarium-153 radionucleotide
therapy

- Prior standard-dose radiotherapy to the pelvis for prostate cancer and/or additional
external-beam radiotherapy to metastatic sites allowed

- More than 4 weeks since prior surgery, radiotherapy, combined androgen blockade
(excluding single-agent gonadotropin releasing-hormone agonists/antagonists), or
investigational therapies

- No concurrent second-line hormonal agents, including ketoconazole, diethylstilbestrol,
other estrogen-like agents, or finasteride

- No concurrent corticosteroids unless patient is on a stable maintenance dose of
hydrocortisone (≤ 30 mg/day) for ≥ 3 months