Ketoconazole and Dexamethasone in Prostate Cancer

Phase 2

Completed

Conditions: Prostate Cancer

Interventions: Drug: Ketoconazole
Drug: Hydrocortisone
Drug: Dexamethasone

Registration Number: NCT01036594

Lead Sponsor: University of California, San Francisco

Brief Summary: This is an open label, phase II, single center trial of ketoconazole/dexamethasone to determine if the administration of ketoconazole/dexamethasone, after disease progression with ketoconazole/hydrocortisone slows or reverses disease progression in men with progressive prostate cancer.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 32

Inclusion Criteria

Histologically confirmed adenocarcinoma of the prostate.
Testosterone < 50 ng/dL. Participants must continue primary androgen deprivation with an luteinizing hormone-releasing hormone (LHRH) analogue if they have not undergone orchiectomy.
Progressive non-metastatic or metastatic disease after androgen deprivation. Participants must have EITHER:
1. Progression as defined by RECIST criteria. OR
2. Progressive PSA documented within 4 weeks of enrollment. PSA evidence for progressive prostate cancer consists of a PSA level of at least 5 ng/ml which has risen on at least 2 successive occasions, at least 2 weeks apart. If the confirmatory PSA value is less than the first documented rising PSA value, then an additional test for rising PSA will be required to document progression.
Participants who are receiving an antiandrogen as part of primary androgen ablation must demonstrate disease progression following discontinuation of antiandrogen.
1. Disease progression after antiandrogen withdrawal is defined as 2 consecutive rising PSA values, obtained at least 2 weeks apart, or documented osseous or soft tissue progression.
2. For participants receiving flutamide, at least one of the PSA values must be obtained 4 weeks or more after flutamide discontinuation.
3. For participants receiving bicalutamide (Casodex) or nilutamide, at least one of the PSA values must be obtained 6 weeks or more after antiandrogen discontinuation.
Karnofsky Performance Status ≥ 60%.
Participants receiving any other hormonal therapy, including any dose of megestrol acetate (Megace), Proscar (finasteride), any herbal product known to decrease PSA levels (e.g., Saw Palmetto and PC-SPES), or any systemic corticosteroid must discontinue the agent for at least 4 weeks prior to enrollment.
Participants on stable doses of bisphosphonates may continue on this medication; further, patients may initiate bisphosphonate therapy at the time of ketoconazole initiation.
Prior radiation therapy completed ≥ 4 weeks prior to enrollment.
Liver function tests (alanine aminotransferase (ALT), aspartate aminotransferase (AST), and Bilirubin) must be within normal limits.
Absolute Neutrophil Count (ANC) >1500/µl, Platelet count > 100,00/µl, Creatinine <1.5 x upper limit of normal (ULN), Hemoglobin > 8 mg/dl.

Exclusion Criteria

Prior chemotherapy for prostate cancer is not allowed with the exception of cases in which chemotherapy has been administered in a neoadjuvant or adjuvant fashion AND >1 year has elapsed since the administration of this therapy.
No prior ketoconazole, abiraterone, aminoglutethimide or corticosteroids for treatment of progressive prostate cancer.
No supplements or complementary medicines/botanicals are permitted while on protocol therapy, except for any combination of the following: (conventional multivitamin supplements, selenium, lycopene, soy supplements) No prior radiopharmaceuticals (strontium, samarium) within 8 weeks prior to enrollment.
No "currently active" second malignancy, other than non-melanoma skin cancer.
No serious intercurrent infections or nonmalignant medical illnesses that are uncontrolled.
No psychiatric illnesses/social situations that would limit compliance
No active or uncontrolled autoimmune disease.
No adrenal insufficiency as demonstrated by a baseline adrenocorticotropic hormone (ACTH) stimulation test demonstrating a peak cortisol >18 µg/dL.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Ketoconazole + Hydrocortisone	Ketoconazole	po = oral tid = 3 times per day qam = every morning qom = every evening bid = twice daily 1 cycle = 28 days * Ketoconazole: 200mg during first week of study (run-in phase), then 400mg po tid * Hydrocortisone 20mg po qam and 10mg po qpm: If participant has ≥ 30% Prostate-specific antigen (PSA) decline at 12 week evaluation, treatment continues until progressive disease (by RECIST criteria OR by Prostate Specific Antigen Working Group (PSAWG) criteria) is documented. After that, drug will be discontinued. If participant has \< 30% PSA decline at 12 week evaluation, participant goes off study.
Ketoconazole + Dexamethasone	Ketoconazole	* Ketoconazole: 400mg po tid * Dexamethasone 0.5mg po bid: If ≥ 30% PSA decline (Prostate-specific antigen) at 12 week evaluation, administration starts when disease progression (by RECIST criteria OR by PSAWG criteria) is documented.
Ketoconazole + Hydrocortisone	Hydrocortisone	po = oral tid = 3 times per day qam = every morning qom = every evening bid = twice daily 1 cycle = 28 days * Ketoconazole: 200mg during first week of study (run-in phase), then 400mg po tid * Hydrocortisone 20mg po qam and 10mg po qpm: If participant has ≥ 30% Prostate-specific antigen (PSA) decline at 12 week evaluation, treatment continues until progressive disease (by RECIST criteria OR by Prostate Specific Antigen Working Group (PSAWG) criteria) is documented. After that, drug will be discontinued. If participant has \< 30% PSA decline at 12 week evaluation, participant goes off study.
Ketoconazole + Dexamethasone	Dexamethasone	* Ketoconazole: 400mg po tid * Dexamethasone 0.5mg po bid: If ≥ 30% PSA decline (Prostate-specific antigen) at 12 week evaluation, administration starts when disease progression (by RECIST criteria OR by PSAWG criteria) is documented.

Primary Outcome Measures

Name	Time	Method
Number of Participants Who Achieved a Second Decline in Prostate Specific Antigen (PSA) Following Progression on First Regimen	Up to 5 years	The number of participants who experience a ≥30% decline in PSA between the time of first progression on ketoconazole and hydrocortisone and eight weeks after dexamethasone therapy was initiated.

Secondary Outcome Measures

Name	Time	Method
Change in Serum Adrenal Androgen (AA) Levels Over Time for Participants on Dexamethasone Over Time	Up to 5 years	For PSA responders to ketoconazole/ hydrocortisone continuing with dexamethasone treatment after initial disease progression, the overall pattern of AA levels will be investigated with nonparametric methods for statistical analyses. This will include Friedman's analysis of variance method using ranks for repeated measures. A key comparison using the Wilcoxon test for matched pairs will investigate the change in AA levels from progression #1 to progression #2.
Change in Cortisol Levels Over Time for Participants on Dexamethasone Over Time	Up to 5 years	For PSA responders to ketoconazole/ hydrocortisone continuing with dexamethasone treatment after initial disease progression, the overall pattern of cortisol levels will be investigated with nonparametric methods for statistical analyses. This will include Friedman's analysis of variance method using ranks for repeated measures. A key comparison using the Wilcoxon test for matched pairs will investigate the change in cortisol levels from progression #1 to progression #2.
Relationship of ACTH to the Duration of Castration Prior to Treatment With Ketoconazole/Hydrocortisone and With Response	Up to 2 years	The Spearman rank correlation will be calculated to explore the relationship between the baseline ACTH level and the duration of castration prior to the start of any ketoconazole therapy
Change in Dehydroepiandrosterone (DHEA) Levels Over Time for Participants on Dexamethasone Over Time	Up to 5 years	For PSA responders to ketoconazole/ hydrocortisone continuing with dexamethasone treatment after initial disease progression, the overall pattern of DHEA levels will be investigated with nonparametric methods for statistical analyses. This will include Friedman's analysis of variance method using ranks for repeated measures. A key comparison using the Wilcoxon test for matched pairs will investigate the change in DHEA levels from progression #1 to progression #2.
Change in Estrodiol Levels Over Time for Participants on Dexamethasone	Up to 5 years	For PSA responders to ketoconazole/ hydrocortisone continuing with dexamethasone treatment after initial disease progression, the overall pattern of estrodiol levels will be investigated with nonparametric methods for statistical analyses. This will include Friedman's analysis of variance method using ranks for repeated measures. A key comparison using the Wilcoxon test for matched pairs will investigate the change in estrodiol from progression #1 to progression #2.
Change in Dehydroepiandrosterone Sulfate (DHEA-S) Levels Over Time for Participants on Dexamethasone Over Time	Up to 5 years	For PSA responders to ketoconazole/ hydrocortisone continuing with dexamethasone treatment after initial disease progression, the overall pattern of DHEA-S levels will be investigated with nonparametric methods for statistical analyses. This will include Friedman's analysis of variance method using ranks for repeated measures. A key comparison using the Wilcoxon test for matched pairs will investigate the change in DHEA-S levels from progression #1 to progression #2.
Median Change Over Time in Adrenocorticotrophic Hormone (ACTH) Levels for Participants Taking Ketoconazole/Hydrocortisone	Up to 5 years	Nonparametric Wilcoxon test for matched pairs will be used to test the difference in ACTH levels from baseline until the time of disease progression for participants taking ketoconazole/hydrocortisone for participants with evaluable laboratory values.
Change in Testosterone Levels Over Time for Participants on Dexamethasone	Up to 5 years	For PSA responders to ketoconazole/ hydrocortisone continuing with dexamethasone treatment after initial disease progression, the overall pattern of testosterone levels will be investigated with nonparametric methods for statistical analyses. This will include Friedman's analysis of variance method using ranks for repeated measures. A key comparison using the Wilcoxon test for matched pairs will investigate the change in testosterone from progression #1 to progression #2.