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A Phase I/II Study of Oral Calcitriol in Combination With Ketoconazole in Androgen Independent Prostate Cancer

Phase 1/Phase 2
18 Years
Open (Enrolling)
Prostate Cancer

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Trial Information

A Phase I/II Study of Oral Calcitriol in Combination With Ketoconazole in Androgen Independent Prostate Cancer



- 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)


- To evaluate the pharmacokinetics of the phase II dose of calcitriol with and without

- 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

- Determine toxicities and tolerability of this regimen.

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

- 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.

Inclusion Criteria


- Histologically or cytologically confirmed androgen-independent adenocarcinoma of the

- 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


- 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

- 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


- 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

- 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

- 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

- 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

- Valdecoxib

- Vardenafil

- Ziprasidone

- Statins

- Calcium channel blockers

- 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

Type of Study:


Study Design:

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose of calcitriol (phase I)

Outcome Time Frame:

In 4 week cycles

Safety Issue:


Principal Investigator

Donald L. Trump, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Roswell Park Cancer Institute


United States: Food and Drug Administration

Study ID:

I 68905



Start Date:

October 2006

Completion Date:

Related Keywords:

  • Prostate Cancer
  • adenocarcinoma of the prostate
  • recurrent prostate cancer
  • stage III prostate cancer
  • stage IV prostate cancer
  • Prostatic Neoplasms



Roswell Park Cancer Institute Buffalo, New York  14263