Ipilimumab in Combination With Androgen Suppression Therapy in Treating Patients With Metastatic Hormone-Resistant Prostate Cancer

PRIMARY OBJECTIVES:

I. Proportion of patients who achieve an undetectable prostate-specific antigen (PSA) (=< 0.2
ng/ml) after initiation of ipilimumab therapy.

SECONDARY OBJECTIVES:

I. Time to PSA progression. II. Time to progression by any measure. III. Maximum percentage
of PSA reduction in each patient. IV. Number of patients with immune related adverse events
(IRAEs) and correlation of these with complete PSA response, time to progression, and T cell
measurements.

V. Measures of T cell response to therapy with flow cytometry. VI. Response in measurable
disease by modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria.

VII. Time to death from any cause. VIII. To examine correlative biomarkers and their
relationship to clinical outcomes. Potential biomarkers include, but are not limited to
C-reactive protein (CRP), insulin-like growth factor (IGF)-1 and -2, or follicle stimulating
hormone (FSH).

XV. Bank samples for future molecular correlative studies, biomarker, or other studies.

OUTLINE:

Patients receive ipilimumab intravenously (IV) over 90 minutes on day 1. Treatment repeats
every 21 days for up to 4 courses in the absence of disease progression or unacceptable
toxicity. Patients without progression then receive maintenance ipilimumab IV once every 3
months for 4 additional doses.

After completion of study treatment, patients are followed up every 6 months for up to 5
years.

Inclusion Criteria:

- Willing and able to give written informed consent

- Histologic diagnosis of adenocarcinoma of the prostate

- A PSA of > 0.2 ng/ml after 6-18 months of androgen suppression therapy, which may
consist of luteinizing hormone-releasing hormone (LHRH) agonist or antagonist alone or
the combination of an LHRH agonist or antagonist plus an antiandrogen, such as
bicalutamide; androgen suppression therapy will continue without interruption

- Radiographic evidence of regional or distant metastasis at the time of study
enrollment or at the time of diagnosis

- White blood cell (WBC) >= 2000/uL

- Absolute neutrophil count (ANC) >= 1000/uL

- Platelets >= 50 x 10^3/uL

- Hemoglobin >= 8 g/dL

- Creatinine =< 3.0 x upper limit of normal (ULN)

- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x ULN for
patients without liver metastasis

- Bilirubin =< 3.0 x ULN, (except patients with Gilbert's syndrome, who must have a
total bilirubin less than 3.0 mg/dL)

- No known active or chronic infection with human immunodeficiency virus (HIV),
hepatitis B, or hepatitis C; patients should be assessed for high risk behaviors that
may result in these infections, such as intravenous drug use or multiple sexual
partners; the assessment should be noted

- Eastern Cooperative Oncology Group (ECOG) =< 1

- Patients receiving any herbal product known to decrease PSA levels (i.e. saw palmetto
and prostate cancer [PC]-SPES), or any immunosuppressive dose of systemic or
absorbable topical corticosteroid (except prednisone up to 10 mg orally per [q] day,
or its equivalent), must discontinue the agent for at least 2 weeks prior to
screening; progressive disease must be documented after discontinuation of these
products

- Patients receiving bisphosphonate therapy must have been on stable doses for at least
4 weeks with stable symptoms prior to the first infusion with ipilimumab

- Total testosterone < 50 ng/ml, except in patients with prior orchiectomy, where
testosterone does not need to be measured; patients must continue their LHRH agonist
therapy throughout study duration

- Life expectancy >= 6 months; this must be documented

- Patients who are sexually active with a partner who could become pregnant are to use
an effective form of barrier contraception, such as condoms or a partner using oral
contraceptive pills; persons of reproductive potential must agree to use an adequate
method of contraception throughout treatment and for at least 8 weeks after ipilimumab
is stopped

- If a patient enters the trial on androgen suppression therapy (AST) that consists of
both an LHRH agonist and an oral antiandrogen, both agents should be continued
throughout the study; if an antiandrogen is stopped prior to study entry, it should be
stopped 4 weeks before for nilutamide and flutamide and 6 weeks before for
bicalutamide to ensure that a withdrawal phenomenon does not interfere with
interpretation of efficacy results

Exclusion Criteria:

- Radiation to any area of the body < 28 days prior to randomization

- Any other active malignancy with the exception of adequately treated basal or squamous
cell skin cancer or superficial bladder cancer

- Autoimmune disease: patients with a history of inflammatory bowel disease are excluded
from this study, as are patients with a history of symptomatic disease (eg, rheumatoid
arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus,
autoimmune vasculitis [eg, Wegener's granulomatosis]); motor neuropathy considered of
autoimmune origin (e.g. myasthenia gravis, Guillain-Barre syndrome); those with
immune-mediated skin toxicity (i.e. toxic epidermal necrolysis, Stevens-Johnson
syndrome) will also be excluded

- Any underlying medical or psychiatric condition, which in the opinion of the
investigator will make the administration of ipilimumab hazardous or obscure the
interpretation of adverse events (AEs), such as a condition associated with frequent
diarrhea

- Any non-oncology vaccine therapy used for prevention of infectious diseases (for up to
1 month before or after any dose of ipilimumab)

- A history of prior treatment with ipilimumab or prior cluster of differentiation
(CD)137 agonist or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor or
agonist

- Concomitant therapy with any of the following: interleukin (IL)-2, interferon, or
other non-study immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive
agents (over the counter [OTC]/herbal/prescribed); immunostimulant agents, other than
the study agent; other investigational therapies; or chronic use of systemic
corticosteroids (greater than prednisone 10 mg orally per day, or its equivalent)

- Prisoners or patients who are compulsorily detained (involuntarily incarcerated) for
treatment of either a psychiatric or physical (i.e., infectious) illness