Ipilimumab and Sargramostim in Treating Patients With Metastatic Prostate Cancer

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose of anti-cytotoxic T-lymphocyte-associated antigen-4
monoclonal antibody (MDX-010) (ipilimumab) administered with sargramostim (GM-CSF) in
patients with metastatic androgen-independent prostate cancer. (Phase I) II. Determine the
safety of this regimen in these patients. (Phase I) III. Evaluate the efficacy as measured by
reduction in PSA associated with combining GM-CSF with CTLA-4 blockade with ipilimumab at a
dosage of 3 mg/kg given monthly x 6 doses (d1 of courses 1-6). (Cohort Expansion)

SECONDARY OBJECTIVES:

I. Determine the T-cell immunity and T-cell response in patients treated with this regimen.
(Phase I) II. Determine the pharmacokinetics of MDX-010 in these patients. (Phase I) III.
Determine the prostate-specific antigen and/or objective responses in patients treated with
this regimen. (Phase I) IV. Determine the percentages of activated, naive, and memory
T-cells. (Cohort Expansion) V. Determine the measurement of T-cell response to describe
epitopes from prostate antigens including PSA, PSMA, and PAP. (Cohort Expansion) VI.
Quantitate T-cell response to antigens in patients with relevant HLA allele using HLA*0201
tetramers. (Cohort Expansion) VII. Evaluate the toxicity of this regimen in these patients.
(Cohort Expansion) VIII. Determine the initial efficacy as measured by reduction in PSA
associated with combining GM-CSF with CTLA-4 blockade with ipilimumab at a dosage of 3 mg/kg
given monthly x 6 doses (d1 of courses 1-6). (Cohort Expansion) IX. Determine objective
response by post-therapy measurable disease changes using RECIST criteria. (Cohort Expansion)

OUTLINE: This is a multicenter, dose-escalation study of ipilimumab.

Patients receive ipilimumab intravenously (IV) over 90 minutes on day 1 and sargramostim
(GM-CSF) subcutaneously (SC) on days 1-14. Treatment repeats every 28 days for 4-6 courses.
GM-CSF continues beyond 4 courses in the absence of disease progression or unacceptable
toxicity. Cohorts of 3-6 patients receive escalating doses of ipilimumab until the maximum
tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2
of 3 or 2 of 6 patients experience dose-limiting toxicity. Some patients undergo blood sample
collection periodically for laboratory and pharmacokinetic studies. Samples are analyzed for
human anti-human antibodies, IgG antibodies to ipilimumab semi-quantitative ELISA assay, and
plasma concentrations of ipilimumab via quantitative ELISA assay.

Patients are followed at 30 days.

Inclusion Criteria:

- Histologically confirmed prostate cancer

- Metastatic disease

- Progressive disease after prior androgen deprivation as defined by at least 1 of the
following criteria:

- Patients with measurable disease must have an increase of at least 20% in the sum
of the longest diameter of target lesions OR the appearance of 1 or more new
lesions

- Patients with nonmeasurable disease must have a positive bone scan and a
prostate-specific antigen (PSA) level of at least 5 ng/mL, which has risen on at
least 2 successive occasions at least 2 weeks apart*

- At least 1 PSA level must be obtained at least 4 weeks after flutamide (6
weeks after bicalutamide or nilutamide)

- Testosterone no greater than 50 ng/dL

- Patients with no prior orchiectomy must continue luteinizing hormone-releasing
hormone agonist therapy

- No history or radiologic evidence of CNS metastases

- Performance status - ECOG 0-2

- At least 12 weeks

- Absolute neutrophil count greater than 1,500/mm^3

- Platelet count at least 100,000/mm^3

- Hemoglobin at least 8 g/dL

- Bilirubin less than 1.5 times upper limit of normal (ULN)

- SGOT and SGPT no greater than 2.5 times ULN

- Creatinine no greater than 1.5 times ULN

- No significant cardiovascular disease

- No New York Heart Association class III or IV congestive heart failure

- No active angina pectoris

- No myocardial infarction within the past 6 months

- Not pregnant or nursing

- Fertile patients must use effective contraception prior to, during, and for 3 months
after study participation

- No history of autoimmune disease including, but not limited to, any of the following:

- Autoimmune hemolytic anemia

- Ulcerative and hemorrhagic colitis

- Endocrine disorders (e.g., thyroiditis, hyperthyroidism, hypothyroidism of immune
etiology, autoimmune hypophysitis/hypopituitarism, or adrenal insufficiency)

- Sarcoid granuloma

- Myasthenia gravis

- Polymyositis

- Guillain-Barre syndrome

- Systemic lupus erythematosus

- Rheumatoid arthritis

- Inflammatory bowel disease

- No other medical or psychiatric illness that would preclude study participation or
giving informed consent

- 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

- No prior immunotherapy (e.g., vaccines or investigational)

- No other concurrent colony-stimulating factors

- No prior chemotherapy

- No concurrent chemotherapy

- See Disease Characteristics

- At least 4 weeks since prior systemic corticosteroids

- At least 4 weeks since other prior hormonal therapy, including megestrol and
finasteride

- No concurrent systemic steroid therapy except inhaled or topical steroids

- No other concurrent hormonal therapy

- Hormones administered for nondisease-related conditions (e.g., insulin for
diabetes) allowed

- At least 4 weeks since prior radiotherapy and recovered

- More than 8 weeks since prior radiopharmaceuticals (e.g., strontium chloride Sr 89 and
samarium Sm 153 lexidronam pentasodium)

- Prior irradiation of a symptomatic lesion or one that may produce disability (e.g.,
unstable femur) allowed

- No concurrent palliative radiotherapy

- See Disease Characteristics

- At least 4 weeks since prior herbal products known to decrease PSA levels (e.g.,
PC-SPES or saw palmetto)