Ketoconazole Plus Docetaxel to Treat Prostate Cancer

High dose ketoconazole and weekly docetaxel have both been shown to have activity against
androgen independent prostate cancer (AIPC). We have demonstrated synergy in prostate cancer
in an in vitro model. This is an open label phase I study of high-dose ketoconazole plus
weekly docetaxel in patients with metastatic AIPC. The primary objective of this study will
be to determine the side effect profile of ketoconazole when combined with weekly docetaxel
therapy and determine the maximum tolerated dose (MTD) and a recommended phase II dose
(RPIID) of docetaxel when combined with high dose ketoconazole. Since ketoconazole may alter
the metabolism of docetaxel, this study will evaluate potential drug interactions and adverse
events between these two agents. Ketoconazole dose will be 600mg per day (given 200 mg, three
times a day), plus 30mg of hydrocortisone (20mg in the morning and 10mg in the evening), plus
docetaxel 10-43 mg/m(2) in a dose escalation, repeated in 28-day cycles, comprising weekly
treatments for three consecutive weeks followed by one week off. Each patient will be
evaluated every four weeks for the duration of the study.

- 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.