Primary Outcome Measures:
- Maximum tolerated dose of calcitriol (phase I) [ Designated as safety issue: Yes ]
- Prostate-specific antigen response rate (complete and partial) (phase II) [ Designated as safety issue: No ]
Secondary Outcome Measures:
- Toxicity as measured by NCI CTC version 3.0 [ Designated as safety issue: Yes ]
- Objective tumor response as measured by monthly physical exam and radiographic evaluation every 12 weeks [ Designated as safety issue: No ]
OBJECTIVES:
Primary
- To determine the maximum tolerated dose (MTD) of oral calcitriol when given together with ketoconazole and hydrocortisone in patients with advanced or recurrent androgen-independent prostate cancer. (Phase I)
- To estimate the prostate-specific antigen response rate. (Phase II)
Secondary
- To evaluate the pharmacokinetics of the phase II dose of calcitriol with and without ketoconazole.
- Describe any objective tumor responses to the combination of calcitriol, ketoconazole, and hydrocortisone among patients with measurable disease using RECIST criteria.
- Explore the pharmacodynamic effects of this combination in peripheral blood mononuclear cells.
- Determine toxicities and tolerability of this regimen.
OUTLINE: This is a phase I, dose-escalation study of calcitriol followed by a phase II study.
- Phase I: Patients receive oral calcitriol once daily on days 1-3, 8-10, 15-17, and 22-24, oral ketoconazole three times daily on days 1-28, and oral hydrocortisone twice daily on days 0-28 of course 1 and days 1-28 of all subsequent courses. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
Cohorts of 3-6 patients receive escalating doses of calcitriol 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.
- Phase II: Patients receive oral calcitriol at the MTD determined in phase I on days 1-3, 8-10, 15-17, and 22-24, oral ketoconazole three times daily on days 4-28, and oral hydrocortisone as in phase I. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
Peripheral blood mononuclear cells are collected periodically to evaluate the pharmacodynamics of calcitriol, hydrocortisone, and ketoconazole. Some patients undergo blood collection on days 1 and 15 for calcitriol pharmacokinetic studies.