Treating Patients With Prostate Cancer That Did Not Respond to Hormone Therapy

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.

• ketoconazole (Drug), also known as held for toxicity, missed days of therapy are not made up.: 400 tid
• lenalidomide (Drug): Lenalidomide will be administered daily at a dose of 25mg po qd on days 1-21 of the cycle.
• therapeutic hydrocortisone (Drug): 20mg qam 10mg qhs

Primary outcomes

• Number of Patients With a Partial Response, Progressive Disease, or Stable Disease Based on Prostate-Specific Antigen (PSA) or Measurable Disease [28 days]: Patients will be evaluated for clinical benefit monthly with PSA values.Patients who are benefiting from treatment are eligible for additional cycles of treatment. Thereafter, therapy will continue until criteria for progressive disease are met. Response is based on the RECIST criteria from the National Cancer institute. Complete Response (CR) disappearance of all target lesions; Partial Response (PR) >= 30% decrease in the sum of the longest diameter of target lesions from baseline; Progressive Disease (PD) >= increase in the sum of the longest diameter of target lesions from baseline; Stable Disease (SD) neither sufficient for partial response nor sufficient increase for progressive disease.

Secondary outcomes

• Time to Progression [One year (12 months) after start of treatment]: Patients will be evaluated for clinical benefit monthly with PSA values.Patients who are benefiting from treatment are eligible for additional cycles of treatment. Thereafter, therapy will continue until criteria for progressive disease are met. Response is based on the RECIST criteria from the National Cancer institute. Complete Response (CR) disappearance of all target lesions; Partial Response (PR) >= 30% decrease in the sum of the longest diameter of target lesions from baseline; Progressive Disease (PD) >= increase in the sum of the longest diameter of target lesions from baseline; Stable Disease (SD) neither sufficient for partial response nor sufficient increase for progressive disease.
• Number of Patients With Grade 3 and 4 Toxicity as Assessed by NCI CTCAE v3.0 [Up to 30 days after discontinuation of treatment]: Patients will be evaluated for toxicity every 2 weeks during the first cycle. Thereafter, evaluations will be done every 28 days or more frequently if clinically indicated.
• Change in Immune Response From Baseline [Week 8]: The pattern of immune response by assessing T cell and dendritic cell markers, specifically by measuring the levels of CD4+ FoxP3+ Regulatory T cells
• Ratio of Change in Immune Response From Baseline [Week 8]: The pattern of immune response by assessing T cell and dendritic cell markers, specifically by measuring the ratio of BDCA-2 to BDCA-1 cells

Sex: Male, ages: 18 Years to any

PATIENTS WITH PROSTATE CANCER PROGRESSIVE AFTER ANDROGEN DEPRIVATION Inclusion Criteria Understand and voluntarily sign an informed consent form. Age 18 years at the time of signing the informed consent form. Histologically confirmed adenocarcinoma of the prostate. Testosterone less than 50 ng/dL. Patients must continue primary androgen deprivation with an LHRH analogue if they have not undergone orchiectomy. All previous cancer therapy, including radiation, and surgery, must have been discontinued at least 4 weeks prior to receive first dose of study drug.

Progressive disease after androgen deprivation.

Exclusion Criteria Prior systemic chemotherapy for hormone refractory prostate cancer. Prior neoadjuvant and adjuvant chemotherapy are allowed when completed at least 12 months prior to enrollment.

Prior ketoconazole, aminoglutethimide or corticosteroids for the treatment of progressive prostate cancer.

Prior immunotherapy including, but not limited to, vaccines, Thalidomide, and or Lenalidomide like agents.

Supplements or complementary medicines/botanicals are not permitted while on protocol therapy, except for any combination of the following:

conventional multivitamin supplements selenium lycopene soy supplements Patients should review the label with their doctor prior to enrollment, and discontinue disallowed agents prior to study enrollment Serious intercurrent infections or non-malignant medical illnesses including autoimmune disorders that are uncontrolled.

Psychiatric illnesses/social situations that would limit compliance with protocol requirements.

Evidence of CNS (brain or Leptomeningeal) metastases or large pleural/pericardial effusions.

Known contraindication to receive Ketoconazole or Lenalidomide Concurrent use of ketoconazole with statin compounds is absolutely contraindicated. Thus, patients receiving Statin drugs (fluvastatin, atorvastatin, and simvastatin) should discontinue them for at least 7 days before starting ketoconazole.

Patients taking astemizole, terfenadine, or cisapride, rifampin or isoniazid are not eligible, unless they agreed to completely discontinue those agents. In that case, any of these agents should be discontinued at least 7 days prior to start therapy with Ketoconazole.

Use of any other experimental drug or therapy within 28 days of baseline. Known hypersensitivity to thalidomide or its analogues. Any prior use of Lenalidomide. Known positive for HIV or infectious hepatitis, type A, B or C. Disease free of prior malignancies for 5 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma "insitu" of the breast.

Participant flow

Outcome results

• Number of Patients With a Partial Response, Progressive Disease, or Stable Disease Based on Prostate-Specific Antigen (PSA) or Measurable Disease (Primary), Number, participants: Ketoconazole Plus Lenalidomide 7
• Time to Progression (Secondary), Median, Months: Ketoconazole Plus Lenalidomide 3 (-1.52 to 7.52)
• Number of Patients With Grade 3 and 4 Toxicity as Assessed by NCI CTCAE v3.0 (Secondary), Number, participants: Ketoconazole Plus Lenalidomide 19
• Change in Immune Response From Baseline (Secondary), Mean, cells/ul: Ketoconazole Plus Lenalidomide 0.18 +/- 0.31
• Ratio of Change in Immune Response From Baseline (Secondary), Mean, ratio: Ketoconazole Plus Lenalidomide -0.39 +/- 1.44

Adverse events

Time frame: 30 Days

Serious adverse events by term

Other adverse events by term

21 more terms not shown.

• Results publication: Barata PC, Cooney M, Mendiratta P, Tyler A, Dreicer R, Garcia JA. Ketoconazole plus Lenalidomide in patients with Castration-Resistant Prostate Cancer (CRPC): results of an open-label phase II study. Invest New Drugs. 2018 Dec;36(6):1085-1092. doi: 10.1007/s10637-018-0660-3. Epub 2018 Sep 6. PMID 30191523

• Jorge Garcia, MD, Principal investigator, Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center
• Matthew M. Cooney, MD, Principal investigator, University Hospitals Cleveland Medical Center, Seidman Cancer Center, Case Comprehensive Cancer Center