Prostate Cancer
Conditions
Keywords
Ketoconazole, Dexamethasone
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.
Interventions
DRUGKetoconazole
200mg during first week of study (run-in phase), then 400mg po tid
DRUGHydrocortisone
Hydrocortisone 20mg po qam and 10mg po qpm If participant has ≥30% PSA decline at 12 week evaluation, treatment continues until progressive disease (by RECIST criteria OR by PSAWG criteria) is documented. After that, drug will be discontinued. If participant has \<30% PSA decline, patient goes off study.
DRUGDexamethasone
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.
Sponsors
University of California, San Francisco
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 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. |
| 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. |
| 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 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. |
| 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 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. |
| 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. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited through the Urologic Oncology Program at University of California, San Francisco
Pre-assignment details
All participants were prescribed ketoconazole for a 7 day run-in phase, then hydrocortisone + ketoconazole treatment. Participants not achieving \>=30% PSA decline at 12 weeks were taken off study. Participants continued treatment until progression at which time, hydrocortisone was discontinued and ketoconazole + dexamethasone treatment began.
Participants by arm
| Arm | Count |
|---|---|
| All Patients Who Received Treatment 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 patient has ≥ 30% PSA decline at 12 week evaluation, treatment continues until progressive disease (by RECIST criteria OR by PSAWG criteria) is documented. After that, drug will be discontinued. If participant has \< 30% PSA decline at 12 week evaluation, participant goes off study.
Based on the results of evaluation at 12 weeks , participants were offered to either stay on this regimen or receive
-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 on Ketoconazole + Hydrocortisone (by RECIST criteria OR by PSAWG criteria) is documented. | 32 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Treatment Regimen | Withdrawal by Subject | 1 | 0 |
| Run-In: Ketoconazole Only (200 mg) | Adverse Event | 1 | 0 |
| Treatment Regiments Post Week 12 | Adverse Event | 0 | 1 |
| Treatment Regiments Post Week 12 | Lack of Efficacy | 0 | 1 |
| Treatment Regiments Post Week 12 | Non-Cancer Disease Complications | 0 | 1 |
| Treatment Regiments Post Week 12 | Physician Decision | 1 | 1 |
| Treatment Regiments Post Week 12 | Withdrawal by Subject | 1 | 0 |
| Week 12 Evaluation | Adverse Event | 5 | 0 |
| Week 12 Evaluation | Physician Decision | 1 | 0 |
Baseline characteristics
| Characteristic | All Patients Who Received Treatment |
|---|---|
| Age, Customized 50-59 years | 1 Participants |
| Age, Customized 50-59 years old | 7 Participants |
| Age, Customized 60-69 years | 6 Participants |
| Age, Customized 60-69 years old | 11 Participants |
| Age, Customized 70-79 years | 2 Participants |
| Age, Customized 70-79 years old | 10 Participants |
| Age, Customized 80-89 years old | 4 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 27 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 26 Participants |
| Region of Enrollment United States | 32 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 32 | 0 / 9 |
| other Total, other adverse events | 25 / 32 | 5 / 9 |
| serious Total, serious adverse events | 4 / 32 | 0 / 9 |
Outcome results
Primary
Number of Participants Who Achieved a Second Decline in Prostate Specific Antigen (PSA) Following Progression on First Regimen
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.
Time frame: Up to 5 years
Population: Progression data for patients not enrolled to Dexamethasone arm are not used in this analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ketoconazole + Dexamethasone | Number of Participants Who Achieved a Second Decline in Prostate Specific Antigen (PSA) Following Progression on First Regimen | 0 Participants |
Secondary
Change in Cortisol Levels Over Time for Participants on Dexamethasone Over Time
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.
Time frame: Up to 5 years
Population: Cortisol data not collected for this endpoint. Planned statistical analysis could not be performed
Secondary
Change in Dehydroepiandrosterone (DHEA) Levels Over Time for Participants on Dexamethasone Over Time
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.
Time frame: Up to 5 years
Population: DHEA data was not collected for this endpoint. Planned statistical analysis could not be performed.
Secondary
Change in Dehydroepiandrosterone Sulfate (DHEA-S) Levels Over Time for Participants on Dexamethasone Over Time
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.
Time frame: Up to 5 years
Population: DHEA-S data was not collected for this endpoint. Planned statistical analysis could not be performed.
Secondary
Change in Estrodiol Levels Over Time for Participants on Dexamethasone
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.
Time frame: Up to 5 years
Population: Estrodiol data for this endpoint not collected. Planned statistical analysis could not be performed.
Secondary
Change in Serum Adrenal Androgen (AA) Levels Over Time for Participants on Dexamethasone Over Time
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.
Time frame: Up to 5 years
Population: AA data not collected for this endpoint. Planned statistical analyses could not be performed.
Secondary
Change in Testosterone Levels Over Time for Participants on Dexamethasone
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.
Time frame: Up to 5 years
Population: Testosterone data for this endpoint not collected. Planned statistical analysis could not be performed.
Secondary
Median Change Over Time in Adrenocorticotrophic Hormone (ACTH) Levels for Participants Taking Ketoconazole/Hydrocortisone
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.
Time frame: Up to 5 years
Population: ACTH data not collected for this endpoint. Planned statistical analysis could not be performed.
Secondary
Relationship of ACTH to the Duration of Castration Prior to Treatment With Ketoconazole/Hydrocortisone and With Response
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
Time frame: Up to 2 years
Population: Data on duration of castration prior to treatment data not collected. Planned analysis could not be performed.