Protocol Number: 02-C-0149

Title:

A Phase I Trial of High Dose Ketoconazole Plus Weekly Docetaxel in Metastatic Androgen Independent Prostate Cancer

Number:

02-C-0149

Summary:

This study will determine the maximum dose of docetaxel that can be given safely in combination with ketoconazole for treating advanced prostate cancer. Docetaxel is approved for the treatment of several other types of cancers; ketoconazole is an approved antifungal medication that is also commonly used in high doses to treat prostate cancer.

Patients 18 years of age and older with advanced prostate cancer that does not respond to hormone therapy may be eligible for this study. Candidates will be screened with blood tests to evaluate liver, kidney and other organ function and with x-rays, scans, or other imaging tests to determine the extent of disease.

Participants will take the following medications:

- Docetaxel daily, infused through a vein over 30 minutes, in 4-week cycles-3 consecutive weeks of drug followed by one week of rest

- Dexamethasone, 12 hours and 1 hour before and 12 hours after docetaxel infusions to help prevent fluid retention caused by the docetaxel

- Ketoconazole, 3 times a day

- Hydrocortisone, twice a day to replace a loss of natural steroids caused by the ketoconazole

Patients will be hospitalized 1 to 2 days each for the first and second doses of docetaxel to allow for frequent blood draws to measure blood levels of the drug. Ketoconazole will be started about 2 weeks after the first dose of docetaxel and the second dose of docetaxel will be given 2 days after that. In order to determine the maximum tolerated dose of docetaxel, the first few patients in the study will be given a low dose of the drug, and subsequent patients will get increasingly higher doses until unacceptable side effects occur. Because prostate cancer cells may grow if exposed to testosterone, patients may have to have their testosterone production suppressed either surgically (removal of the testicles) or medically with an injection of leuprolide or goserelin, which are luteinizing hormone-release hormone agonists that reduce the amount of testosterone.

Imaging studies, such as x-rays, bone scans or computed tomography (CT) scans, will be done about every 3 months to examine how the tumor is responding to therapy. After six treatment cycles, patients will have monthly chest x-rays to check for fluid around the lining of the lungs, which may occur as a result of docetaxel therapy.

Treatment is expected to continue for at least 3 to 6 months, although this time could be shortened or extended depending on the tumor response to therapy or side effects of the drugs. Patients who do not experience bad side effects and whose tumor does not grow during the first 3 treatment cycles will continue treatment; those who experience unacceptable side effects will be taken off the study.

Sponsoring Institute:

National Cancer Institute (NCI)

Recruitment Detail

Type: Participants currently recruited/enrolled

Gender: Male

Referral Letter Required: No

Population Exclusion(s): Female

Children

Eligibility Criteria:

INCLUSION CRITERIA:

Patients must have histopathological documentation of prostate cancer confirmed in the Pathology Department of the Clinical Center at the National Institutes of Health or the National Naval Medical Center prior to starting this study. Patients whose pathology specimens are no longer available may be enrolled in the trial, if the patient has a clinical course consistent with prostate cancer and pathologic documentation of the diagnosis.

Patients must have metastatic progressive androgen-independent prostate cancer (progressive prostate cancer while continuing to receive hormonal ablation, such as that of an LHRH agonist) documented prior to entry. Progression must be documented by at least one of the following parameters:

1. Two consecutively rising PSA levels, separated by at least one week, with at least one measurement that is 50% above the nadir reached after the last therapeutic maneuver (as long as the measurement is 5 ng/ml or greater); and/or,

2. At least one new metastatic deposit on Tc-99 bone scintigraphy; and/or,

Progression of soft tissue metastases as measured by appropriate modalities (i.e., imaging, palpation):

1. Development of new area of malignant disease (measurable or non-measurable);

2. Measurable disease progression by RECIST criteria;

3. At least 4 weeks off of flutamide and 6 weeks off of bicultamide and nilutamide.

Patients who have not undergone surgical castration must continue treatment with an LHRH agonist. If for some reason the LHRH agonist has been discontinued prior to entry on the study, then it should be reinstituted and disease progression must be documented.

Patients must have a life expectancy of more than 3 months.

Patients must have a performance status of 0 to 2 according to the ECOG criteria.

Patients must have recovered from any acute toxicity related to prior therapy, including surgery.

Hematological eligibility parameters (within 2 weeks before starting therapy):

1. Granulocyte count greater than or equal to 1,500/mm(3)

2. Platelet count greater than or equal to 100,000/mm(3)

Biochemical eligibility parameters (within 2 weeks before starting therapy):

1. If the creatinine is greater than 1.5 mg/dl, a 24 hour urine collection must be obtained, and measured creatinine clearance must be at least 40 mL/min.

2. Hepatic function: Hepatic: Bilirubin less than 1.0 mg/dl, AST and ALT less than 2.5 times upper limit of normal. If the alkaline phosphatase is greater than 2.5 times the upper limit of normal, it must be fractionated and the hepatic alkaline phosphatase should be less than 2.5 times the upper limit of normal.

Hormonal profile for patients with prostate cancer

1. All patients who have not undergone surgical castration must have a serum testosterone under 50 ng/ml and continue on their GnRh agonist.

Patients must not have other active malignancies (within the past two years with the exception of non-melanoma skin cancers or carcinoma in situ of the bladder).

Patients with a history of unstable or newly diagnosed angina pectoris, recent myocardial infarction (within 6 months of enrollment), New York Heart Assoc. class II-IV congestive heart failure are not eligible.

Patients must be able to understand and sign an informed consent form.

Patients must be willing to travel from their home to the NIH for follow-up visits.

Patients must be greater than or equal to 18 years of age.

Must be able to ingest oral medications to be eligible.

EXCLUSION CRITERIA:

Patients with brain metastases will not be eligible.

Patients who have received strontium or samarium will not be eligible.

HIV-positive patients receiving combination anti-retroviral therapy will be excluded because of possible pharmacokinetic interactions with ketoconazole, docetaxel or other agents administered during the study. In fact, ketoconazole has been found to increase the toxic effects of several protease inhibitors by affecting CYP3A4 activity.

Patients on theophylline will be excluded.

Patients who are receiving cisapride will be excluded.

Patients who are receiving HMG-CoA inhibitors (lovastatin, atorvastatin, simvastatin, pravastatin and cerivastatin)

Patients currently taking known inhibitors and/or inducers of CYP3A4; patients taking known substrates of CYP3A4 will be evaluated by the primary investigator.

Patients who are receiving terfenadine, midazolam, triazolam, alprazolam, astemizole, loratadine, rifampin, isoniazid, dofetilide, pimozide, sirolimus or erythromycin will be excluded.

Because gastric acidity is necessary for the dissolution and absorption of ketoconazole, concomitant administration of drugs which decrease gastric acid output or increase gastric pH (e.g., antacids, cimetidine, ranitidine, antimuscarinics, omeprazole, and lansoprazole) may decrease absorption and thus will be prohibited.

Patients requiring warfarin will be excluded.

Special Instructions:

Currently Not Provided

Keywords:

Combination

Microtubule

Hormonal

Chemotherapy

Pharmacokinetics

Recruitment Keyword(s):

Prostate Cancer

Prostate

Condition(s):

Prostatic Neoplasms

Investigational Drug(s):

None

Investigational Device(s):

None

Intervention(s):

Drug: Ketaconazole

Drug: Docetaxel

Supporting Site:

National Cancer Institute

Contact(s):

NCI Referral Office
National Institute of Health Clinical Center (CC), 9000 Rockville Pike, Bethesda, Maryland 20892, United States: NCI Clinical Trials Referral Office
Phone: 1-888-NCI-1937
Fax: Not Listed
Electronic Address: ncicssc@mail.nih.gov

Citation(s):

Bissery MC, Guenard D, Gueritte-Voegelein F, Lavelle F Experimental antitumor activity of taxotere (RP 56976, NSC 628503), a taxolanalogue Cancer Res 1991 Sep 15;51(18):4845-52

Crawford ED, Eisenberger MA, McLeod DG, Spaulding JT, Benson R, Dorr FA,Blumenstein BA, Davis MA, Goodman PJ A controlled trial of leuprolide with and without flutamide in prostaticcarcinomaN Engl J Med 1989 Aug 17;321(7):419-24

Bubley GJ, et al Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-Specific Antigen Working Group J Clin Oncol 1999 Nov;17(11):3461-7

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