Oral Calcitriol With Ketoconazole in CRPC

Inclusion Criteria For inclusion in the trial, a patient must fulfill all of the following criteria: 1. Greater than or equal to 18 years of age. The effects of ketoconazole and high-dose calcitriol have not been studied adequately in patients \<18 years of age and prostate cancer has not been described in children. 2. Histologically or cytologically confirmed adenocarcinoma consistent clinically with androgen Independent prostate cancer 3. Measurable disease with elevated PSA or evaluable disease (PSA elevation will constitute evaluable disease). 4. No cytotoxic chemotherapy for extensive disease prior to study entry will be allowed; given the recent data regarding the role of docetaxel + ADT in patients beginning ADT for advanced disease, such "adjuvant chemotherapy will be allowed (no more than 6 cycles) retinoids, vitamin D analogues, PPAR agonists or antagonists, antiandrogens, progestational agents, estrogens, PC-SPES, LHRH analogues, vaccines, cytokines will not be considered "cytotoxics." Patients who have previously received ketoconazole + glucocorticoids will NOT be eligible for this trial. 5. 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 \<40mg 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. 6. Patients must have prostate cancer that is advanced or recurrent. 7. Patients should not have received any chemotherapy or investigational agents for at least 28 days before entering the study. 8. Eastern Clinical Oncology Group performance status 0 or 1 9. Life expectancy \>3 months. 10. Patients must have normal organ and marrow function as defined below: leukocytes: \>3,000/μl hemoglobin: \> 8 g/dl absolute neutrophil count (ANC):\>1,500/μl platelets: \>75,000/μl total bilirubin: within normal institutional limit AST/ALT: \<2.5 X institutional upper limit of normal creatinine: \< 2mg/dL calcium: not above normal institutional limit 11. Patients should be able to receive oral medications. 12. Patients with brain metastases which are stable and have been treated with surgery and/or irradiation will be eligible for this trial. 13. The effects of high-dose calcitriol and ketoconazole on the developing human fetus are unknown. For this reason and because these agents as well are known to be teratogenic, 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. 14. Ability to understand and the willingness to sign a written informed consent document. 15. Progressive disease must have occurred on abiraterone within the prior 12 months and patient must not have 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. Exclusion Criteria Any of the following is a criterion for exclusion from the trial: 1. Known severe hypersensitivity to ketoconazole, calcitriol or any of the excipients of these products. 2. History of allergic reactions attributed to compounds of similar chemical or biologic composition to calcitriol, ketoconazole, or other agents used in study. 3. Evidence of any other significant clinical disorder or laboratory finding that makes it undesirable for the patient to participate in the trial. 4. History of kidney, ureteral, or bladder stones within the last 5 years 5. 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. 6. Thiazide therapy within 7 days from entering the study. 7. Requirement for concurrent systemic glucocorticoid therapy at greater than physiologic replacement doses 8. Unwillingness to stop calcium supplementation. 9. 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 limit compliance with study requirements. 10. Human immunodeficiency virus-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible PK interactions with ketoconazole or other agents administered during the study. Appropriate studies will be undertaken in patients receiving combination anti-retroviral therapy when indicated. 11. 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, disopyramidedofetilide, donepezil, eletriptan, eplerenone, fluticasone, fosamprenavir, galantamine, systemic griseofulvin, indinavir, levobupivacaine, lopinavir, midazolam, mifepristone, modafinil, nateglinide, nefazadone, 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 CYP3A4, calcium channel blockers, and macrolides or other agents that will be significantly perturbed in a clinically important way by the P450 inhibitory properties of ketoconazole 12. Concomitant use of proton pump inhibitors or H2 blockers 13. Treatment with a non-approved or investigational drug or agent within 28 days before day 1 of trial treatment. 14. Any unresolved chronic toxicity greater then CTC Grade 2 from previous anticancer therapy. 15. Incomplete healing from previous oncologic treatments or other major surgery. 16. Inability to swallow oral capsules. 17. Patients on digoxin will be excluded from this study. Products Dosage and Mode of Administration * Ketoconazole, 200 mg tablets, 2 tablets orally TID * Calcitriol (0.5 mcg caplets) given in escalating doses, orally QD X3 consecutive days every week * Hydrocortisone 20mg AM, 10mg PM orally starting in the evening before the first dose of Calcitriol.