Use of Low Dose Ketoconazole in Prostate Cancer That Does Not Respond to Hormone Therapy and Prior Chemotherapy

Study Overview
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Brief Summary
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The purpose of this study is to test the safety of ketoconazole and how well it works after chemotherapy has been used. Ketoconazole at lower doses has been used for fungal infections however has not yet been approved by the Food and Drug Administration for use in prostate cancer. Ketoconazole has been used for many years at high doses for prostate cancer, and this study will be to look at use of lower dose ketoconazole after someone has received chemotherapy. Ketoconazole works by halting the production of steroids in your body, including testosterone, and is thought to work directly on prostate cancer cells in published lab studies.

Detailed Description
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The aim of the study is to research the response of low dose ketoconazole in hormone refractory prostate cancer (HRPC) patients who have already undergone chemotherapy as part of their prostate cancer treatment. The hypothesis of the study is that HRPC patients who have been previously treated with chemotherapy will demonstrate objective PSA response rates to low dose ketoconazole, comparable to historical response rates reported in chemotherapy-naïve patients. This is a single arm trial, with all participants given ketoconazole 200mg TID, along with hydrocortisone given at 20mg in the morning, 10mg at night daily. Each cycle will consist of 28 days. The subject's study participation will continue until subject experiences disease progression, unacceptable toxicities, withdraws consent from the study or dies.

Official Title
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Assessing PSA Response in Low Dose Ketoconazole in Hormone Refractory Prostate Cancer Patients Who Have Failed at Least One Prior Systemic Chemotherapy Regimen

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: Ketoconazole
* Drug: Hydrocortisone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically or cytologically proven prostate cancer with a Gleason score available or interpretable. Patients must have prostate cancer deemed to be hormone refractory, by progression of measurable or evaluable disease or rising PSA. Patients must be >18 years old Patients must have received at least one prior chemotherapy regimen >3 weeks prior to initiation of study and patients must have recovered from the side effects of the therapy Patients must have an ECOG status of 0-3 Patients must have normal organ and marrow function, determined within 14 days of registration. Patients must have been surgically or medically castrated. If the method of castration was LHRH agonists (leuprolide or goserelin), then the patient must be willing to continue the use of LHRH agonists. Patients must have a serum total testosterone level <50 ng/dl If the patient has been treated with non-steroidal anti-androgens (flutamide, bicalutamide or nilutamide) or other hormonal treatment (megace or steroids), the patient must have stopped these agents at least 28 days prior to enrollment for flutamide, megace or steroids and at least 42 days prior to enrollment for bicalutamide or nilutamide; and the patients must have demonstrated progression of disease since the agents were suspended. Exclusion Criteria: Patients with any condition that impairs the ability to swallow medications orally Patients who are unable to give informed consent Patients who have received ketoconazole treatment for prostate cancer in the past Patients with other active malignancies in the past 3 years except nonmelanoma skin cancer Patients may not be receiving any other investigational agents Patients with known hypersensitivity to ketoconazole Patients may not be taking certain medications, including terbinafine, astemizole, triazolam, statins (except pravastatin and fluvastatin) and acid suppressive agents (antacids, H2 blockers, PPI) while on ketoconazole, and patients on these medications must agree to discontinue these medications and consider alternative therapies.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ketoconazole and Hydrocortisone<br>Ketoconazole 200mg PO TID + Hydrocortisone 20mg PO Qam, 10mg PO Qpm | Drug: Ketoconazole<br>* Ketoconazole is taken three times a day by mouth.<br>* Other names: Nizoral;Drug: Hydrocortisone<br>* Hydrocortisone is taken by mouth 20 mg every morning and 10 mg every evening.<br>* Other names: Cortef;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prostate Specific Antigen (PSA) Response (>50% Reduction From Baseline) | Percentage of patients who achieved a clinically significant decline in Prostate Specific Antigen (PSA) after initiation of ketoconazole therapy, defined as a >=50% decrease in PSA. | From date of enrollment, every Cycle (4 weeks), until disease progression, unacceptable toxicities, study withdrawal, or death from any cause, whichever came first, assessed up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PSA Response (>30% From Baseline) |  | From date of enrollment, every Cycle (4 weeks), until disease progression, unacceptable toxicities, study withdrawal, or death from any cause, whichever came first, assessed up to 2 years | 
| Progression Free Survival | Response Evaluation Criteria In Solid Tumors (RECIST) radiographic criteria for progression | From date of enrollment, every Cycle (4 weeks), until disease progression, unacceptable toxicities, study withdrawal, or death from any cause, whichever came first, assessed up to 2 years | 
| Duration of Stable Disease |  | From date of enrollment, every Cycle (4 weeks), until disease progression, unacceptable toxicities, study withdrawal, or death from any cause, whichever came first, assessed up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PSA, Ketoconazole, Prostate Cancer, Hormone Refractory, Chemotherapy Regimen