Official Title: “A Phase I/II Study of Oral Calcitriol in Combination With Ketoconazole in Androgen Independent Prostate Cancer”

RATIONALE: Calcitriol may help prostate cancer cells become more like normal cells and grow and spread more slowly. Ketoconazole may help calcitriol work better by making tumor cells more sensitive to the drug. Giving calcitriol together with ketoconazole and hydrocortisone may be an effective treatment for prostate cancer.

PURPOSE: This phase I/II trial is studying the side effects and best dose of calcitriol when given together with ketoconazole and hydrocortisone and to see how well it works in treating patients with advanced or recurrent prostate cancer.

Study Type: Interventional

Study Design: Treatment

Study Primary Completion Date: July 2009

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.

Intervention(s) in this Clinical Trial

• Drug: calcitriol
• Drug: ketoconazole
• Drug: therapeutic hydrocortisone

Primary Measures

• Maximum tolerated dose of calcitriol (phase I)
  • Safety Issue?: Yes
• Prostate-specific antigen response rate (complete and partial) (phase II)
  • Safety Issue?: No

Secondary Measures

• Toxicity as measured by NCI CTC version 3.0
  • Safety Issue?: Yes
• Objective tumor response as measured by monthly physical exam and radiographic evaluation every 12 weeks
  • Safety Issue?: No

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed androgen-independent adenocarcinoma of the prostate
• Advanced or recurrent disease for which standard curative or reliable palliative therapy does not exist or is no longer effective
• Measurable disease with elevated prostate-specific antigen (PSA) or evaluable disease (PSA elevation will constitute evaluable disease)
• Patients who have received prior antiandrogens or progestational agents as therapy for prostate cancer must discontinue therapy and demonstrate a rising PSA ≥ 28 days* after discontinuation NOTE: *At least 42 days for bicalutamide or nilutamide
• Patients undergoing androgen deprivation using luteinizing hormone-releasing hormone (LHRH) analogues must continue therapy or undergo orchiectomy to maintain castrate levels of testosterone
• Patients with brain metastases which are stable and have been treated for surgery or irradiation are eligible

PATIENT CHARACTERISTICS:

• ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%
• Life expectancy > 3 months
• Leukocytes ≥ 3,000/mm^3
• Hemoglobin ≥ 8 g/dL
• Absolute neutrophil count ≥ 1,500/mm^3
• Platelet count ≥ 75,000/mm^3
• Total bilirubin normal
• AST/ALT ≤ 2.5 x upper limit of normal
• Creatinine ≤ 2 mg/dL
• Calcium normal
• Must be able to receive oral medications, including oral capsules
• Fertile patients must use effective contraception before and during study treatment
• No known severe hypersensitivity to ketoconazole, calcitriol, or any of the excipients of these products
• No history of allergic reaction attributed to compounds of similar chemical or biologic composition to calcitriol, ketoconazole, or other agents used in the study
• No evidence of any other significant clinical disorder or laboratory finding that would make it undesirable for the patient to participate in the trial
• No history of kidney, ureteral, or bladder stones within the past 5 years
• No incomplete healing from prior oncologic treatments or other major surgery
• No unresolved chronic toxicity > grade 2
• No heart failure or significant heart disease, including any of the following:
• Significant arrhythmias
• Myocardial infarction within the past 3 months
• Unstable angina pectoris
• Documented ejection fraction < 30%
• No other severe or uncontrolled systemic disease (e.g., unstable or compensated respiratory, cardiac, hepatic, or renal disease) or intercurrent illness including, but not limited to any of the following:
• Ongoing or active infection
• Symptomatic congestive heart failure
• Psychiatric illness/social situation that would limit compliance with study requirements

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• Recovered from prior anticancer therapy
• At least 7 days since prior thiazide therapy
• At least 30 days since prior treatment with a non-approved or investigational drug or agent
• At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C)
• At least 4 weeks since prior radiotherapy or cytotoxic therapy
• No more than 2 prior cytotoxic chemotherapy regimens
• Retinoids, vitamin D analogues, PPARγ agonists or antagonists, antiandrogens, progestational agents, estrogens, PC-SPES, LHRH analogues, vaccines, and cytokines are not considered cytotoxics
• Prior ketoconazole and glycocorticoids allowed
• Concurrent megestrol acetate for hot flashes at a dose of ≤ 40 mg/day allowed
• No concurrent digoxin therapy
• No concurrent systemic glucocorticoid therapy at greater than physiologic replacement doses
• No concurrent calcium supplementation
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No concurrent proton pump inhibitors or H2 blockers
• No concurrent use of any of the following:
• Phenytoin
• Carbamazepine
• Barbiturates
• Rifampicin
• Phenobarbital
• Hypericum perforatum (St. John wort)
• Alfentanil
• Alfuzosin
• Almotriptan
• Alprazolam
• Amiodarone
• Amitriptyline
• Aprepitant
• Amprenavir
• Aripiprazole
• Bepridil
• Bortezomib
• Bosentan
• Budesonide
• Buprenorphine
• Buspirone
• Cilostazol
• Cisapride
• Cyclosporine
• Delavirdine
• Didanosine
• 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
• Valdecoxib
• Vardenafil
• Ziprasidone
• Zonisamide
• Statins
• Calcium channel blockers
• Coumadin
• Macrolides
• Sildenafil
• Sirolimus
• Tacrolimus
• Tadalafil
• Tolterodine
• Theophyllines
• Triazolam
• Zonisamide
• Other agents that would be significantly perturbed in a clinically important way by the P450 inhibitory properties of ketoconazole

Gender Eligibility for this Clinical Trial: Male

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Roswell Park Cancer Institute

Overall Clinical Trial Officials and Contacts

Donald L. Trump, MD Principal Investigator Roswell Park Cancer Institute  

Information obtained from ClinicalTrials.gov on August 28, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00536991

Study ID Number: CDR0000565063

ClinicalTrials.gov Identifier: NCT00536991

Health Authority: Unspecified

Clinical trial summary from the National Cancer Institute's PDQ® database