Calcitriol in Combination With Ketoconazole and Therapeutic Hydrocortisone in Treating Patients With Prostate Cancer

This phase I/II trial studies the side effects and best dose of calcitriol when given in combination with ketoconazole and therapeutic hydrocortisone and to see how well it works in treating patients with prostate cancer. Calcitriol may help prostate cancer cells become more like normal cells and grow and spread more slowly. Ketoconazole and therapeutic hydrocortisone may help calcitriol work better by making tumor cells more sensitive to the drug. Giving calcitriol together with ketoconazole and therapeutic hydrocortisone may be a better treatment for prostate cancer.

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of oral calcitriol daily x 3 consecutive days a week in combination with oral ketoconazole (400 mg thrice daily \[TID\]) + oral hydrocortisone (20 mg AM, 10 mg PM) in men with androgen independent prostate cancer (AIPC). (Phase I) II. To estimate the prostate-specific antigen (PSA) response rate. (Phase II)

SECONDARY OBJECTIVES:

I. To evaluate the pharmacokinetics of the phase II dose of oral calcitriol with and without ketoconazole (400 mg TID).

II. Describe any objective tumor responses to the combination of oral calcitriol and ketoconazole and hydrocortisone among patients with measurable disease using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria.

III. Determine toxicities and tolerability of oral calcitriol combination with daily oral ketoconazole and hydrocortisone.

OUTLINE: This is a phase I, dose-escalation study of calcitriol followed by a phase II study.

PHASE I: Patients receive calcitriol orally (PO) once daily (QD) on days 1-3, 8-10, 15-17, and 22-24. Patients also receive ketoconazole PO TID on days 1-24 and therapeutic hydrocortisone PO twice daily (BID) on days -1 to 24. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

PHASE II: Patients receive calcitriol and therapeutic hydrocortisone as in phase I. Patients also receive ketoconazole PO TID on days 4-24. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Eligibility Criteria:
Inclusion Criteria:

* Histologically or cytologically confirmed adenocarcinoma consistent clinically with androgen independent prostate cancer
* Measurable disease with elevated PSA or evaluable disease (PSA elevation will constitute evaluable disease)
* =\< 2 regimens of cytotoxic chemotherapy prior to study entry; retinoids, vitamin D analogues, peroxisome proliferator-activated receptor (PPAR) gamma agonists or antagonists, antiandrogens, progestational agents, estrogens, prostate cancer (PC)-SPES, luteinizing hormone-releasing hormone (LHRH)-analogues, vaccines, cytokines will not be considered "cytotoxics"; patients who have previously received ketoconazole + glucocorticoids will be eligible for this trial
* Patients who have received antiandrogens or progestational agents as therapy for prostate cancer must discontinue therapy and demonstrate a rising PSA \>= 28 days following discontinuation (antiandrogen withdrawal- AAW) (\>= 42 days for bicalutamide or nilutamide); patients who receive megestrol acetate as therapy for "hot flashes" at a dose of =\< 40 mg per day may continue this therapy during this trial; the dose of the megestrol acetate should not be changed during protocol treatment; patients undergoing androgen deprivation using LHRH analogues must continue such agents or undergo orchiectomy to maintain castrate levels of testosterone
* Patients must have prostate cancer that is advanced or recurrent and for which standard curative or reliable palliative therapies do not exist or are no longer effective
* Patients should not have received any chemotherapy or investigational agents for at least 4 weeks before entering the study (6 weeks for nitrosoureas or mitomycin C)
* Eastern Clinical Oncology Group performance status =\< 2 (Karnofsky \>= 60%)
* Life expectancy \> 3 months
* Leukocytes: \>= 3,000/ul
* Hemoglobin: \>= 8 g/dl
* Absolute neutrophil count (ANC): \>= 1,500/ul
* Platelets: \>= 75,000/ul
* Total bilirubin: within normal institutional limit
* Aspartate aminotransferase (AST)/alanine aminotransferase (ALT): =\< 2.5 x institutional upper limit of normal
* Creatine: =\< 2 mg/dL
* Calcium: not above normal institutional limit
* Patients should be able to receive oral medications
* Patients with brain metastases which are stable and have been treated with surgery or irradiation will be eligible for this trial
* Men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while her partner is participating in this study, she should inform the treating physician immediately
* Ability to understand and the willingness to sign a written informed consent document
* PHASE II - GROUP B: Progressive disease must have occurred on abiraterone within the prior 12 months and patient has not received treatment with enzalutamide
* Men of all ethnic groups are eligible for this trial; efforts will be made to include minority groups and all representative ethnicities and races in the community serviced by Roswell Park Cancer Institute (RPCI)

Exclusion Criteria:

* Known severe hypersensitivity to ketoconazole, calcitriol or any of the excipients of these products
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to calcitriol, ketoconazole, or other agents used in study
* Evidence of any other significant clinical disorder or laboratory finding that makes it undesirable for the patient to participate in the trial
* History of kidney, ureteral, or bladder stones within the last 5 years
* Heart failure or significant heart disease including significant arrhythmias, myocardial infarction within the last 3 months, unstable angina, documented ejection fraction \< 30%, or current digoxin therapy
* Thiazide therapy within 7 days from entering the study
* Requirement for concurrent systemic glucocorticoid therapy at greater than physiologic replacement doses
* Unwillingness to stop calcium supplementation
* As judged by the investigator, any evidence of severe or uncontrolled systemic disease (e.g., unstable or uncompensated respiratory, cardiac, hepatic, or renal disease) or intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would lit compliance with study requirements
* Human immunodeficiency virus-positive patients receiving combination anti-retroviral therapy are excluded from the study
* Concomitant use of phenytoin, carbamazepine, barbiturates, rifampicin, phenobarbital, or St John's wort, alfentanil, alfuzosin, almotriptan, alprazolam, amiodarone, amitriptyline, amprenavir, aprepitant, aripiprazole, bepridil, bortezomib, bosentan, budesonide, buprenorphine, buspirone, carbamazepine, cilostazol, cisapride, cyclosporine, delavirdine, didanosine, digoxin, disopyramide dofetilide, donepezil, eletriptan, eplerenone, fluticasone, fosamprenavir, galantamine, systemic griseofulvin, indinavir, levobupivacaine, lopinavir, midazolam, mifepristone, modafinil, nateglinide, nefazodone, nelfinavir, oxcarbazepine, pimozide, quetiapine, quinidine, repaglinide, rifabutin, rifampin, rifapentine, ritonavir, saquinavir, sildenafil, sirolimus, tacrolimus, tadalafil, tolterodine, theophyllines, tolterodine, triazolam, valdecoxib, vardenafil, ziprasidone, zonisamide, statins, with the exception of pravastatin (Pravachol) or other "statins" which are not metabolized by or induce cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4), calcium channel blockers, Coumadin and macrolides or other agents that will be significantly perturbed in a clinically important way by the P450 inhibitory properties of ketoconazole
* Concomitant use of proton pump inhibitors or histamine (H)2 blockers
* Treatment with a non-approved or investigational drug or agent within 30 days before day 1 of trial treatment
* Any unresolved chronic toxicity greater then Common Terminology Criteria (CTC) grade 2 from previous anticancer therapy
* Incomplete healing from previous oncologic treatments or other major surgery
* Inability to swallow oral capsules
* Patients on digoxin will be excluded from this study