Official Title: “Phase II Trial to Assess the Activity of Ketoconazole Plus Lenalidomide in Patients With Prostate Cancer Progressive After Androgen Deprivation”

RATIONALE: Androgens can cause the growth of prostate cancer cells. Drugs, such as ketoconazole, may stop the adrenal glands from making androgens. Lenalidomide may stop the growth of prostate cancer by blocking blood flow to the tumor. Giving ketoconazole and hydrocortisone together with lenalidomide may be an effective treatment for prostate cancer.

PURPOSE: This phase II trial is studying how well giving ketoconazole and hydrocortisone together with lenalidomide works in treating patients with prostate cancer that did not respond to hormone therapy.

Study Type: Interventional

Study Design: Treatment, Non-Randomized, Open Label

OBJECTIVES:

Primary - Determine the objective response frequency in patients with hormone-refractory progressive prostate cancer treated with ketoconazole, hydrocortisone, and lenalidomide.

Secondary - Determine the effect of this regimen on time to clinical progression in these patients. - Determine the safety of this regimen in these patients. - Determine the effects of this regimen on serum cytokines, including tumor necrosis factor-alpha, basic fibroblast growth factor, plasma soluble interleukin (IL)-2 receptor, IL-8, and IL-12, as well as serum vascular endothelial growth factor levels in these patients. - Determine the co-stimulatory effects of this regimen on dendritic cells and CD4-positive, CD25-positive, T-regulatory cells in these patients.

OUTLINE: This is a nonrandomized, open-label study.

Patients receive oral ketoconazole 3 times daily and oral hydrocortisone twice daily on days 1-28 and oral lenalidomide once daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients undergo blood collection periodically during study for evaluation of prostate cancer-specific immune response. Blood samples are assessed by serum analysis, flow cytometry, real-time PCR, and enzyme-linked immunosorbent assay techniques to detect and quantify different cytokines, antiangiogenic markers, dendritic cells, and specific T-regulatory cells.

After completion of study therapy, patients are followed at 30 days.

PROJECTED ACCRUAL: A total of 34 patients will be accrued for this study.

Primary:

• Objective response (complete and partial response) based on PSA or measurable disease No

Secondary:

• Time to progression No
• Toxicity as assessed by NCI CTCAE v3.0 Yes
• Pattern of immune response, in terms of T-cell and dendritic-cell markers and serum levels of tumor necrosis factor-alpha, basic fibroblast growth factor, plasma soluble interleukin (IL)-2 receptor, IL-8, IL-12, and vascular endothelial growth factor No
• Change in mean T-cell immunohistochemical markers and dendritic cells over time No

DISEASE CHARACTERISTICS:

• Histologically confirmed adenocarcinoma of the prostate
• Progressive disease after androgen deprivation therapy, defined by 1 of the following:
• Measurable progressive disease
• No measurable disease AND meets 1 of the following criteria:
• Elevated PSA with PSA level ≥ 2 ng/mL, rising on ≥ 2 consecutive occasions measured ≥ 2 weeks apart (if the third confirmatory PSA value is < the second value, then a fourth PSA value is required to document progression)
• Positive bone scan with or without elevated PSA
• Demonstrates disease progression after antiandrogen withdrawal, as defined by 1 of the following:
• Documented osseous or soft tissue progression
• Two consecutive rising PSA values (obtained ≥ 2 weeks apart)
• Testosterone < 50 ng/dL
• Must continue concurrent primary androgen deprivation with a luteinizing hormone releasing hormone analogue if no prior orchiectomy
• No large pleural or pericardial effusions
• No CNS (brain or leptomeningeal) metastases

PATIENT CHARACTERISTICS:

• Karnofsky performance status 70-100%
• Fertile patients must use effective contraception during and for 4 weeks after completion of study therapy (even if patient has undergone a prior successful vasectomy)
• ANC ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Hemoglobin ≥ 8 g/dL
• ALT and AST normal
• Creatinine ≤ 1.5 times upper limit of normal
• Bilirubin normal
• PT/INR and PTT normal (unless on anticoagulants)
• Calcium normal
• No other malignancies within the past 5 years except curatively treated basal cell or squamous cell skin cancer, stage Ta transitional cell carcinoma of the bladder, or carcinoma in situ of the breast
• No serious, concurrent infection or nonmalignant medical illness, including uncontrolled autoimmune disorders
• No known contraindication to ketoconazole or lenalidomide
• No known hypersensitivity to thalidomide or its analogues
• No known positivity for HIV or infectious hepatitis type A, B, or C
• No psychiatric illness or social situation that would preclude study compliance

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• At least 4 weeks since prior cancer therapy, including radiotherapy and surgery
• At least 4 weeks since prior megestrol acetate, finasteride, any herbal product known to decrease PSA levels (e.g., saw palmetto or PC-SPES), or any systemic corticosteroids
• At least 8 weeks since prior radiopharmaceuticals (e.g., strontium chloride Sr 89 or samarium Sm 153 lexidronam pentasodium) and recovered
• At least 6 weeks since prior bicalutamide or nilutamide
• At least 4 weeks since prior flutamide
• No prior systemic chemotherapy for prostate cancer
• All other systemic chemotherapy must have been completed ≥ 5 years prior to study entry
• No prior ketoconazole, aminoglutethimide, or corticosteroids for treatment of progressive prostate cancer
• No prior immunotherapy including, but not limited to, vaccines, sargramostim (GM-CSF), thalidomide, and/or lenalidomide-like agents
• No prior lenalidomide
• At least 7 days since prior and no concurrent statin drugs (e.g., fluvastatin, atorvastatin, lovastatin, and simvastatin)
• At least 7 days since prior and no concurrent astemizole, terfenadine, cisapride, rifampin, or isoniazid
• More than 28 days since prior experimental drug or therapy
• No concurrent supplements or complementary medicines/botanicals, except for any combination of the following:
• Conventional multivitamin supplements
• Selenium
• Lycopene
• Soy supplements
• Concurrent bisphosphonates allowed provided the following criteria are met:
• Patient is on a stable dose that shows tumor progression
• No bisphosphonate therapy is initiated within 4 weeks of study entry
• Concurrent acetylsalicylic acid or warfarin allowed for deep vein thrombosis (DVT) prophylaxis provided the following criteria are met:
• Daily acetylsalicylic acid is initiated on day 1 of study therapy
• Patients with a history of DVT are on a stable-dose of warfarin
• No concurrent GM-CSF or other anticancer therapies, including radiotherapy, thalidomide, chemotherapy, immunotherapy, or other investigational agents
• No concurrent use of the following drugs:
• Alprazolam
• Diazepam
• Temazepam
• Triazolam
• Midazolam
• Ergot alkaloids
• Pimozide

Lead Sponsor: Case Comprehensive Cancer Center

Case Comprehensive Cancer Center

Cleveland Ohio 44106-5065 United States

Cleveland Clinic Taussig Cancer Center

Cleveland Ohio 44195 United States

Geauga Regional Hospital

Chardonr Ohio 44024 United States

Lake/University Ireland Cancer Center

Mentor Ohio 44060 United States

Mercy Cancer Center at Mercy Medical Center

Canton Ohio 44708 United States

Southwest General Health Center

Middleburgh Heights Ohio 44130 United States

UHHS Chagrin Highlands Medical Center

Orange Villager Ohio 44122 United States

UHHS Westlake Medical Center

Westlaker Ohio 44145 United States

University Suburban Health Center

South Euclid Ohio 44121 United States

Overall Clinical Trial Officials and Contacts

Matthew M. Cooney, MD Principal Investigator Case Comprehensive Cancer Center  

Information obtained from ClinicalTrials.gov on July 18, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00460031

Study ID Number: CDR0000540496

ClinicalTrials.gov Identifier: NCT00460031

Health Authority: Unspecified

Clinical trial summary from the National Cancer Institute's PDQ® database