A Phase I Study of Repetitive Dosing of Anti-CTLA-4 Antibody (Ipilimumab) in Combination With GM-CSF in Patients With Metastatic, Androgen-Independent Prostate Cancer
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)
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
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.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
MTD of the combination of ipilimumab with GM-CSF that results in < 33% DLT
Graded according to the National Cancer Institute (NCI) common toxicity criteria, version 3.0. Results will be tabulated by dose cohort and overall for this trial. DLT is defined by any of the following that are attributable to therapy: any >= grade 4 toxicity, any ocular toxicity considered immune mediated and requiring systemic steroids, any grade 3 toxicity considered immune mediated that cannot be controlled with systemic steroids.
University of California San Francisco Medical Center-Mount Zion
United States: Food and Drug Administration
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