Exogenous Testosterone Plus Dutasteride for the Treatment of Castrate Metastatic Prostate Cancer

Study Overview
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Brief Summary
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Usually, the male hormone testosterone makes prostate cancer cells grow. Lowering testosterone usually stops the growth of prostate cancer. However, after a period of time without testosterone, prostate cancer cells learn to grow again. You are able to join this trial because your prostate cancer is growing even though you have very low levels of testosterone. Studies have shown that high doses of testosterone, in this situation, can cause prostate cancer cells to stop growing. The investigators did a study several years ago in which the investigators gave high doses of testosterone to patients such as yourself. The investigators showed that giving testosterone in this situation was safe. The investigators also showed that the investigators could, in some cases, make the PSA go down using high-dose testosterone. The investigators believe that they can improve this type of treatment by combining testosterone with another drug called dutasteride. Dutasteride is another type of hormone. It should make testosterone levels rise. The investigators believe that combination of dutasteride and testosterone will be more a more powerful regimen against your cancer than testosterone alone.

Official Title
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Phase II Trial of Exogenous Testosterone Plus Dutasteride for the Treatment of Castrate Metastatic Prostate Cancer

Conditions
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Prostate Cancer, Castration-resistant, Metastatic

Intervention / Treatment
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* Other: testosterone (AndroGel®) with the 5α-reductase inhibitor dutasteride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients should have histologically confirmed castration-resistant metastatic prostate cancer with evidence of disease progression. Patients must have been in a castrate state either by orchiectomy or by GnRH analogues for a minimum of one year. In detail, they should meet all of the following criteria: Adult male > or = to 18 years of age Histologically confirmed prostate cancer, currently with progressive disease, defined as rising PSA (50% or more increase to a level of 2 ng/mL or more, based on at least 3 PSA determinations obtained at least 1 weeks apart), or 2 new osseous lesions by bone scan, soft tissue disease progression by RECIST 1.1 criteria , or the appearance of new sites of disease (by MRI/CT). Evidence of metastatic disease, documented within 4 weeks prior to dutasteride treatment initiation, based on a: CT or MRI of the abdomen and pelvis, and/or Radionuclide bone scan (in case of findings suspicious for spinal metastasis, MRI of the spine will be performed to rule out epidural disease) Serum PSA ≥ 2 ng/mL within 4 weeks prior to dutasteride treatment initiation in order to register to the protocol Normal organ function with acceptable initial laboratory values documented within 4 weeks prior to dutasteride treatment initiation: WBC > or = to 3000/µL Platelets > or = to 100,000/µL Creatinine < or = to 2 mg/dL Bilirubin < or = to 1.5 X ULN (institutional upper limits of normal) AST/ALT < or = to 2 X ULN Karnofsky performance status > or = to 70% Willingness to undergo serial blood draws for the purpose of measuring CTCs and other biomarkers. MSKCC patients will need to agree to participate in MSKCC protocol 90-040 Molecular studies and clinical correlations in human prostate cancer [PI: Scher]. Also, MSKCC patients will undergo serial imaging by FDHT and FDG PET scans, under protocol 00-095 [18f]-fluoro-2-deoxy-D-glucose and [18f]-dihydro-testosterone PET imaging in patients with progressive prostate cancer (PI: Morris), depending on tracer and scanner time availability. If the study is opened in other centers outside MSKCC, those centers will be exempt from procedures linked to the MSKCC Protocol # 00-095. ADT treatment for at least 12 months prior to study entry with serum testosterone < 50 ng/dL. Ability to understand and willingness to sign a written informed consent document Exclusion Criteria: Patients meeting any of the following criteria will not be eligible for study entry: Evidence of small-cell or neuroendocrine pathologic features Uncontrolled urinary obstruction Osseous metastatic disease with imminent risk (at the discretion of the treating physician) of pathologic fracture or cord compression (in patients with known spinal metastasis raising concern for cord compression, MRI of the spine should be performed to rule out epidural disease) Any situation where, at the discretion of the treating physician, a potential tumor flare would be life-threatening Sleep apnea (unless under good control with current treatment) Polycythemia vera History of allergic reactions attributed to compounds of similar chemical or biological composition to dutasteride Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness or social situation that would compromise compliance with study requirements Currently active secondary malignancy (as determined by the treating physician) other than non-melanoma skin cancer Use of the following medications will be prohibited during the study: Current and/or previous use of the following medications: Finasteride (Proscar, Propecia) or dutasteride (GI198745, Avodart) exposure within 6 months of study entry. Anabolic androgenic steroids, including but not limited to testosterone, 17β testosterone esters, methyltestosterone, stanozolol, and danazol (within 6 months of study entry). Corticosteroids, including hydrocortisone, dexamethasone and prednisone are acceptable. Additional hormonal therapy within 4 weeks of study entry: Including megestrol, medroxyprogesterone, cyproterone, and DES Drugs with antiandrogenic properties (eg, spironolactone if > 50mg/d, flutamide, bicalutamide, nilutamide, ketoconazole,* progestational agents) * Includes topical ketoconazole. Evidence of epidural disease by MRI

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: testosterone with the 5α-reductase inhibitor dutast<br>This trial is a multi-center, open-label, phase II trial of the combination of exogenous testosterone (AndroGel®) with the 5α-reductase inhibitor dutasteride in patients with castration-resistant metastatic prostate cancer. | Other: testosterone (AndroGel®) with the 5α-reductase inhibitor dutasteride<br>* Patients will be treated with dutasteride 3.5 mg once daily (oral administration). To avoid rapid conversion of testosterone to DHT in case 5α-reductase is not adequately inhibited during the first few days of concurrent treatment with dutasteride and testosterone, daily dutasteride treatment will be initiated 7 days prior to testosterone initiation. Patients will receive AndroGel® at the dose of 15 g (3 times the standard replacement dose for hypogonadism) once daily (topical administration), starting on Day 8 and continuing for 12 weeks (or until disease progression or withdrawal from the study).<br>* Other names: free testosterone, DHT, SHBG, LDH, lipid panel.;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| determine anti-tumor effects of the combination of testosterone + dutasteride in pts with castration-resistant prostate ca, as indicated by the proportion of pts remaining alive & progression free |  | 12 weeks from the start of testosterone treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To explore the association between AR expression in CRPC, as determined at baseline separately by AR FISH (performed on CTCs) and by 18F-FDHT uptake on PET scan, and progression free survival to the combination of testosterone plus dutasteride. |  | 12 weeks | 
| To correlate post-treatment changes in CTCs and FDG and FDHT PET scans with post-treatment alterations in PSA and standard CT (or MRI) and bone scans. |  | post treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prostate, DUTASTERIDE, TESTOSTERONE, 09-008, Consortium Protocol LOI# c09-028