Ketoconazole and Dexamethasone in Prostate Cancer (Keto/Dex)

University of California San Francisco (UCSF)

Status and phase: Completed; Phase 2

Conditions: Prostate Cancer

Treatments: Drug: Ketoconazole; Drug: Hydrocortisone; Drug: Dexamethasone

Study type: Interventional

Funder types: Other

Identifiers

NCT01036594

09553

NCI-2011-01263 (Registry Identifier)

Details and patient eligibility

About

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.

Enrollment: 32 patients

Sex: Male

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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32 participants in 2 patient groups

Ketoconazole + Hydrocortisone

Experimental group

Description:

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.

Treatment:

Drug: Hydrocortisone

Drug: Ketoconazole

Ketoconazole + Dexamethasone

Experimental group

Description:

* 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.

Treatment:

Drug: Dexamethasone

Drug: Ketoconazole