Hormonal Therapy and Chemotherapy Followed by Prostatectomy in Patients With Prostate Cancer

Study Overview
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Brief Summary
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This is a study for men who have locally-advanced prostate cancer and are eligible to undergo prostatectomy. Standard treatment is prostatectomy alone, but there is a chance that cancer may spread to other organs in the future, even after the prostate is removed. If this were to occur, standard treatment would be androgen deprivation therapy (ADT; hormone therapy that blocks testosterone) plus chemotherapy. Clinical trials suggest that neoadjuvant treatment (treatment given before primary therapy) may prevent a recurrence. The purpose of this research study is to assess the safety and benefit of ADT plus chemotherapy given before prostate removal.

Detailed Description
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This is an open-label, single-arm study of neoadjuvant ADT and chemotherapy in subjects with non-metastatic, locally-advanced prostate cancer who are eligible for radical prostatectomy. Patients will be treated with 4 monthly injections of degarelix along with two 8-week cycles of chemotherapy. Each cycle of chemotherapy will consist of 6 weeks of chemotherapy and 2 weeks of rest. In the absence of toxicity or disease progression, patients will receive 2 cycles of treatment prior to radical prostatectomy. The primary endpoint will be complete or near-complete pathologic response. Safety will be assessed on any patient receiving at least one dose of study drug by the reporting of adverse events, vital signs and by the assessment of findings on physical exam and routine safety laboratory determinations. The severity of adverse events and certain abnormal laboratory findings will be assessed according to the NCI CTCAE V4.03. Laboratory-based studies will evaluate the following: Complete metabolic profile o BUN, creatinine, alkaline phosphatase, ALT/AST, total bilirubin, LDH, calcium, albumin, glucose, magnesium, uric acid, phosphorous Electrolytes o Sodium, potassium, chloride, CO2 content Hematology CBC with differential, platelet count PT, INR, PTT Testosterone Biomarkers PSA CTCs

Official Title
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Neoadjuvant Androgen Deprivation Therapy and Chemotherapy Followed by Radical Prostatectomy in Patients With Prostate Cancer

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: Degarelix
* Drug: Doxorubicin
* Drug: Ketoconazole
* Drug: Docetaxel
* Drug: Estramustine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologic proof of prostatic adenocarcinoma without evidence of regional and/or distant metastasis, clinical stage T1c or T2a with high grade disease (Gleason 8-10) on initial biopsy, clinical stage T2b-T2c with Gleason grade 7 (4+3), or clinical stage T3. No neuroendocrine differentiation or small cell features. Recent (<6 weeks prior to study entry) negative bone scan and CT of the chest and abdomen. Appropriate surgical candidate for radical prostatectomy and a performance status of <2 (ECOG scale). Adequate bone marrow function as defined as an absolute peripheral granulocyte count >1500 and platelet count >100,000. Adequate hepatic function per the following criteria: Albumin ≥2.8 g/dL AST and ALT ≤5 x ULN Total bilirubin <2 mg/dL Adequate renal function per the following criteria: o Serum creatinine ≤1.5 x ULN Normal coagulation profile (INR ≤ 1.5, aPTT ≤ 1.5 x ULN for the lab) and no history of substantial non-iatrogenic bleeding diatheses. Use of anticoagulants is limited to local use only (for control of central line patency). Age ≥ 18 years Written informed consent to participate in this study. Exclusion Criteria: Prostatic adenocarcinoma with neuroendocrine differentiation or small cell features Surgical resection or major surgery within 4 weeks or stereotactic biopsy within 1 week of first ADT and chemotherapy treatment Previous or current hormonal treatment, chemotherapy, radiation therapy, immunotherapy, or investigational study drug. Unable to tolerate multiparametric MRI or is contraindicated. Patients not appropriate surgical candidates for radical prostatectomy based on the evaluation of coexistent medical diseases and competing causes of death. Patients with uncontrolled cardiac, hepatic, renal, or neurologic/psychiatric disorder. Severe gastrointestinal bleeding within 12 weeks of treatment with ADT and chemotherapy Patients who are HIV positive or have chronic hepatitis B or C infections. Congestive heart failure New York Heart Association (NYHA) class 3 or 4, or history of congestive heart failure New York Heart Association (NYHA) class 3 or 4, unless a 2D echocardiogram or multi-gated acquisition scan (MUGA) performed within 3 months of enrollment demonstrates a left ventricular ejection fraction >45%. Sensory neuropathy grade >1. History of another malignancy within the previous 5 years other than curatively treated non-melanoma skin cancer. Use of herbal products that may decrease PSA levels (e.g., saw palmetto) or systemic corticosteroids greater than the equivalent of 10 mg of prednisone per day within 4 weeks of enrollment. Any other condition, including concurrent medical condition, social circumstance or drug dependency, which in the opinion of the investigator could compromise patient safety and/or compliance with study requirements

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 |
| --- | --- |
| Other: ADT + chemotherapy<br>Patients will be treated with 4 monthly injections of degarelix along with two 8-week cycles of chemotherapy (doxorubicin and ketoconazole, weeks 1, 3, 5 and docetaxel and estramustine, weeks 2, 4, 6). Each cycle of chemotherapy will consist of 6 weeks of chemotherapy and 2 weeks of rest. In the absence of toxicity or disease progression, patients will receive 2 cycles of treatment prior to radical prostatectomy. | Drug: Degarelix<br>* Subcutaneous injection, once/month for 4 months<br>* Other names: degarelix acetate;Drug: Doxorubicin<br>* 20 mg/m2 as a 24-hour intravenous infusion on day 1 each week, weeks 1, 3, and 5<br>* Other names: Adriamycin;Drug: Ketoconazole<br>* 400 mg orally 3 times daily for 7 days, in weeks 1, 3, and 5<br>* Other names: Nizoral;Drug: Docetaxel<br>* 35 mg/m2 intravenously on day 1 of each week, weeks 2, 4, and 6<br>* Other names: Taxotere;Drug: Estramustine<br>* 280 mg orally 3 times daily for 7 days, in weeks 2, 4, and 6<br>* Other names: Emcyt;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy as Measured by Pathologic Response | Pathologic response is defined by percentage of tumor burden remaining at time of prostate removal. Percentage of tumor burden is measured based on a pathologist's assessment of the prostate tissue removed and visual estimate of how much tumor there is in the prostate. | Day of prostate removal, which is about 5 months following the day participant signed consent. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy as Measured by Prostate-specific Antigen (PSA) Levels | Prostate-specific antigen, or PSA, is a protein produced by normal, as well as malignant, cells of the prostate gland. The PSA test measures the level of PSA in a man's blood. For this test, a blood sample is sent to a laboratory for analysis. The results are reported as nanograms of PSA per milliliter (ng/mL) of blood. | baseline | 
| Efficacy as Measured by Prostate-specific Antigen (PSA) Levels | Prostate-specific antigen, or PSA, is a protein produced by normal, as well as malignant, cells of the prostate gland. The PSA test measures the level of PSA in a man's blood. For this test, a blood sample is sent to a laboratory for analysis. The results are reported as nanograms of PSA per milliliter (ng/mL) of blood. | Cycle 2 Day 1, about 8 weeks after treatment initiation (but before prostatectomy) | 
| Efficacy as Measured by Prostate-specific Antigen (PSA) Levels | Prostate-specific antigen, or PSA, is a protein produced by normal, as well as malignant, cells of the prostate gland. The PSA test measures the level of PSA in a man's blood. For this test, a blood sample is sent to a laboratory for analysis. The results are reported as nanograms of PSA per milliliter (ng/mL) of blood. | Cycle 2 Day 57, about 16 weeks after treatment initiation (but before prostatectomy) | 
| Efficacy as Measured by Prostate-specific Antigen (PSA) Levels | Prostate-specific antigen, or PSA, is a protein produced by normal, as well as malignant, cells of the prostate gland. The PSA test measures the level of PSA in a man's blood. For this test, a blood sample is sent to a laboratory for analysis. The results are reported as nanograms of PSA per milliliter (ng/mL) of blood. | Day 133, about 19 weeks after treatment initiation (but before prostatectomy) | 
| Efficacy as Measured by Prostate-specific Antigen (PSA) Levels | Prostate-specific antigen, or PSA, is a protein produced by normal, as well as malignant, cells of the prostate gland. The PSA test measures the level of PSA in a man's blood. For this test, a blood sample is sent to a laboratory for analysis. The results are reported as nanograms of PSA per milliliter (ng/mL) of blood. | about 20 weeks after treatment initiation (day of prostatectomy) | 
| Efficacy as Measured by Prostate-specific Antigen (PSA) Levels | Prostate-specific antigen, or PSA, is a protein produced by normal, as well as malignant, cells of the prostate gland. The PSA test measures the level of PSA in a man's blood. For this test, a blood sample is sent to a laboratory for analysis. The results are reported as nanograms of PSA per milliliter (ng/mL) of blood. | about 32 weeks after treatment initiation (about 12 weeks after prostatectomy) | 
| Efficacy as Measured by Prostate-specific Antigen (PSA) Levels | Prostate-specific antigen, or PSA, is a protein produced by normal, as well as malignant, cells of the prostate gland. The PSA test measures the level of PSA in a man's blood. For this test, a blood sample is sent to a laboratory for analysis. The results are reported as nanograms of PSA per milliliter (ng/mL) of blood. | about 44 weeks after treatment initiation (about 24 weeks after prostatectomy) | 
| Efficacy as Measured by Prostate-specific Antigen (PSA) Levels | Prostate-specific antigen, or PSA, is a protein produced by normal, as well as malignant, cells of the prostate gland. The PSA test measures the level of PSA in a man's blood. For this test, a blood sample is sent to a laboratory for analysis. The results are reported as nanograms of PSA per milliliter (ng/mL) of blood. | about 68 weeks after treatment initiation (about 48 weeks after prostatectomy) | 
| Efficacy as Measured by Circulating Tumor Cell (CTC) Numbers |  | From the time the participant signs the informed consent until prostatectomy, an average of 5 months. | 
| Efficacy as Measured by Volume of the Prostate Tumor as Assessed by Multiparametric Prostate Magnetic Resonance Imaging (mpMRI) | The volume of the prostate tumor was measured by a radiologist's assessment of multiparametric prostate magnetic resonance imaging. | baseline | 
| Efficacy as Measured by Volume of the Prostate Tumor as Assessed by Multiparametric Prostate Magnetic Resonance Imaging (mpMRI) | The volume of the prostate tumor was measured by a radiologist's assessment of multiparametric prostate magnetic resonance imaging. | post treatment but prior to prostatectomy (about 25 days after the end of treatment) | 
| Safety of Drug Regimen as Measured by Number of Adverse Events | Number of adverse events was measured as a count of all participant adverse events that occurred from the time participant first initiates ADT plus chemotherapy until participant's completion of neoadjuvant ADT plus chemotherapy. | From the time participant first initiates ADT plus chemotherapy until participant's completion of neoadjuvant ADT plus chemotherapy. | 
| Surgical Morbidity as Measured by Number of Adverse Events | Number of adverse events was measured as a count of all participant adverse events that occurred from the time participant first initiates ADT plus chemotherapy until the participant was taken off-study or the study was stopped, an average of 20 months | From the time the participant signs the informed consent until the participant was taken off-study or the study was stopped, an average of 20 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ADT, Advanced Prostate Cancer, Neoadjuvant, Hormone therapy, Androgen Deprivation Therapy, Chemotherapy, Radical Prostatectomy