Bicalutamide and Goserelin or Leuprolide Acetate With or Without Cixutumumab in Treating Patients With Newly Diagnosed Metastatic Prostate Cancer

OBJECTIVES:

Primary

- To compare the undetectable PSA rate (< 0.2 ng/mL) in patients with newly diagnosed
hormone-sensitive metastatic prostate cancer treated with combined androgen deprivation
comprising bicalutamide and goserelin or leuprolide acetate with versus without
cixutumumab.

Secondary

- To assess the safety and tolerability of these regimens in these patients.

- To compare the proportion of patients who do not achieve a PSA < 4 ng/mL.

- To assess the accuracy of the prognostic model of undetectable PSA (that was developed
from SWOG-9346) using current trial data from each treatment arm.

- To assess serum samples and peripheral blood mononuclear cells for pharmacodynamic
activity with potential biomarkers for cixutumumab, including IGF-1, free IGF-1,
IGF-II, IGFBP-2, IGFBP-3, growth hormone, insulin, and C-peptide. (Exploratory)

- To determine circulating tumor cell (CTC) quantities at baseline and response to
therapy (for those patients with detectable CTC levels ≥ 1) after 12 weeks of combined
therapy. (Exploratory)

- To determine serum levels of microRNA, including mi-141, at baseline and after 12 weeks
of combined therapy. (Exploratory)

OUTLINE: This is a multicenter study. Patients are stratified according to Zubrod
performance status (0-1 vs 2-3), and pre-LHRH agonist, baseline PSA (< 20 ng/mL vs ≥ 20
ng/mL). Patients are randomized to 1 of 2 treatment arms.

- Arm I: Patients receive androgen deprivation therapy comprising oral bicalutamide once
daily on days 1-28 and either goserelin subcutaneously or leuprolide acetate
intramuscularly every 1, 3, 4, 6, or 12 months. Patients also receive cixutumumab IV
over 1 hour on days 1 and 15. Treatment repeats every 28 days for 7 courses in the
absence of disease progression or unacceptable toxicity.

- Arm II: Patients receive androgen deprivation therapy comprising bicalutamide and
either goserelin or leuprolide acetate as in arm I.

Some patients undergo blood sample collections at baseline and after 12 weeks of treatment
for measurement of circulating tumor cells and microRNA levels, pharmacodynamic studies, and
other correlative studies.

After completion of study therapy, patients are followed up every 6 months for 2 years and
then annually for 3 years.

DISEASE CHARACTERISTICS:

- Histologically or cytologically confirmed adenocarcinoma of the prostate

- Metastatic disease as evidenced by soft tissue and/or bony metastases, including
≥ 1 of the following:

- Visceral disease (liver, lung, or other viscera)

- Bone metastases to sites in either the axial (spine, pelvis, ribs, or
skull) and/or the appendicular (clavicle, humerus, or femur) skeleton

- Lymph node disease not considered to be encompassed within a single
radiotherapy port (e.g., above the aortic bifurcation)

- Patients with measurable disease must have radiographic assessment (at least an
abdominal/pelvic CT scan) within the past 28 days

- Patients with non-measurable disease must be assessed (e.g., bone scan) within
the past 42 days

- PSA ≥ 5 ng/mL within 90 days before initiation of androgen-deprivation therapy

- No known brain metastases

- Brain imaging studies not required for patients with no neurologic signs or
symptoms

PATIENT CHARACTERISTICS:

- Zubrod performance status (PS) 0-2

- Zubrod PS 3 allowed if due to bone pain

- WBC ≥ 3,000/mm^3

- ANC ≥ 1,500/mm^3

- Platelet count ≥ 100,000/mm^3

- Hemoglobin ≥ 9 g/dL

- Bilirubin ≤ 1.5 times upper limit of normal (ULN)

- AST and ALT ≤ 3 times ULN (≤ 5 times ULN for liver metastases)

- Creatinine ≤ 2.0 times ULN OR creatinine clearance ≥ 40 mL/min

- INR ≤ 1.5

- PTT ≤ 5 seconds above the ULN

- HgA1C ≤ 7 AND fasting glucose < 160 mg/dL or below ULN

- Patients with diabetes mellitus who meet this criterion are eligible provided
they are on a stable dietary or therapeutic regimen

- Fertile patients must use effective contraception during and for ≥ 3 months after
completion of study therapy

- No known LVEF ≥ 10% below the lower limit of normal

- Patients with suspected LV dysfunction not confirmed by review of medical
history must undergo MUGA or ECHO within 90 days before study entry

- No history of symptomatic congestive heart failure

- No history of allergic reaction attributed to compounds of similar chemical or
biological composition to cixutumumab

- No other malignancy within the past 5 years except adequately treated basal cell or
squamous cell skin cancer or stage I or II cancer currently in complete remission

PRIOR CONCURRENT THERAPY:

- Prior medical castration allowed provided it was initiated within the past 30 days

- Patients on a luteinizing hormone-releasing hormone (LHRH) agonist (e.g.,
leuprolide acetate or goserelin) must be willing to continue the LHRH agonist in
addition to bicalutamide during study treatment

- Patients on a different anti-androgen (e.g., flutamide) must be willing change
to bicalutamide during study treatment

- Prior bilateral orchiectomy allowed provided it was performed within the past 30 days

- At least 28 days since prior non-orchiectomy surgery and recovered

- More than 28 days since prior strontium-89, rhenium-186, rhenium-188, or samarium-153
radionuclide therapy

- At least 28 days since prior radiotherapy or biologic therapy (e.g., vaccines,
immunotherapy, anti-sense agents, small molecules, or monoclonal antibodies) and
recovered

- No prior cytotoxic chemotherapy for metastatic prostate cancer

- No prior treatment with agents that directly inhibit IGF or IGFR

- No prior chimerized or murine monoclonal antibody therapy

- No concurrent antiretroviral therapy for HIV-positive patients

- No concurrent treatment with any of the following:

- Chemotherapy

- Hormonal therapy (other than the LHRH agonist and oral anti-androgen)

- Radiotherapy

- Immunotherapy

- Any other anticancer therapy

- 5-alpha reductase inhibitors (e.g., finasteride or dutasteride)

- Ketoconazole

- Diethylstilbestrol/DES

- Other estrogen-based therapy

- Concurrent prophylactic low-dose coumadin or low-molecular weight heparin allowed
provided coagulation criteria are met

- Patients requiring full-dose (therapeutic) anticoagulation are eligible provided
they are on a stable dose of anticoagulation AND the coagulation parameters are
stable within the therapeutic range (e.g., INR 2-3 for patients on therapeutic
warfarin)