S9916, Combination Therapy in Treating Patients With Advanced Prostate Cancer That Has Not Responded to Hormone Therapy

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy and hormone therapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug and giving drugs in different ways may kill more tumor cells. It is not yet known whether estramustine plus docetaxel is more effective than mitoxantrone plus prednisone for prostate cancer. PURPOSE: Randomized phase III trial to compare the effectiveness of estramustine plus docetaxel with that of mitoxantrone plus prednisone in treating patients who have stage IV prostate cancer that has not responded to hormone therapy.

Detailed Description
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OBJECTIVES: Compare the overall survival and progression-free survival in patients with hormone-refractory, metastatic adenocarcinoma of the prostate treated with docetaxel and estramustine vs mitoxantrone and prednisone. Compare the qualitative and quantitative toxic effects of these regimens in this patient population. Compare the quality of life, including palliation of metastatic bone pain and global quality of life, of patients treated with these regimens. Record prostate-specific antigen values for future correlations with response and survival in patients treated with these regimens. Compare the responses in patients with bidimensionally measurable disease treated with these regimens. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to disease status (measurable or evaluable disease progression vs rising PSA only), NCI Common Toxicity Criteria version 2.X pain scale (grade 2 or greater vs less than 2), and SWOG performance status (0-1 vs 2-3). Patients are randomized to one of two treatment arms. Arm I: Patients receive oral estramustine 3 times daily on days 1-5 and docetaxel IV over 1 hour on day 2. Arm II: Patients receive mitoxantrone IV over 30 minutes on day 1 and oral prednisone twice daily on days 1-21. Treatment in both arms repeats every 3 weeks for a maximum of 12 courses in the absence of unacceptable toxicity or disease progression. Quality of life is assessed at baseline, after courses 4 and 8, and then at 1 year after randomization. Patients are followed every 6 months for 2 years and then annually for 1 year. PROJECTED ACCRUAL: A total of 620 patients (310 per arm) will be accrued for this study within 3.5 years.

Official Title
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Docetaxel and Estramustine Versus Mitoxantrone and Prednisone for Advanced, Hormone Refractory Prostate Cancer

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: docetaxel
* Drug: estramustine
* Drug: mitoxantrone
* Drug: prednisone


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed metastatic adenocarcinoma of the prostate Unresponsive or refractory to hormonal therapy, as defined by at least 1 of the following criteria: Progression of bidimensionally measurable disease Progression of evaluable but not measurable disease (bone scan) At least 2 consecutive rises in PSA and a PSA level of at least 5 ng/mL No minimum PSA required for measurable disease or non-PSA evaluable disease Soft tissue disease that has been irradiated within the past 2 months is not considered measurable disease Prior orchiectomy OR Medical castration using leuprolide or goserelin Luteinizing hormone-releasing hormone (LHRH) agonist therapy must continue during study Prior nonsteroidal antiandrogens (flutamide, ketoconazole, bicalutamide, or nilutamide) allowed if disease progression occurred No third-space fluid accumulation such as ascites or symptomatic pleural effusion No brain metastases PATIENT CHARACTERISTICS: Age: 18 and over Performance status: SWOG 0-3 Performance status 3 must be due to pain secondary to bone metastases Life expectancy: Not specified Hematopoietic: No hypercoagulability Hepatic: Not specified Renal: Creatinine no greater than 2.0 mg/dL Cardiovascular: No history of myocardial infarction No history of congestive heart failure unless well controlled No history of cerebrovascular accident or atrial fibrillation No active thrombophlebitis Left ventricular ejection fraction (LVEF) at least 50% by Multi Gated Acquisition Scan (MUGA) scan or 2-D echocardiogram Pulmonary: No history of pulmonary embolus Other: Recovered from major infections No other significant active medical illness No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer or stage I or II cancer currently in complete remission PRIOR CONCURRENT THERAPY: Biologic therapy: At least 4 weeks since prior biologic therapy and recovered No more than 1 prior biologic therapy regimen No concurrent biological response modifiers Chemotherapy: At least 4 weeks since prior chemotherapy and recovered No more than 1 prior chemotherapy regimen No prior estramustine, taxanes, anthracyclines, or mitoxantrone No other concurrent chemotherapy Endocrine therapy: See Disease Characteristics At least 4 weeks since prior flutamide or ketoconazole (6 weeks for bicalutamide or nilutamide) No concurrent corticosteroids or hormonal therapy (except megestrol for hot flashes or continuing LHRH treatment) Radiotherapy: See Disease Characteristics Prior samarium Sm 153 lexidronam pentasodium allowed At least 4 weeks since prior radiotherapy and recovered No prior radiotherapy to 30% or more of bone marrow No prior strontium chloride Sr 89 No concurrent radiotherapy Surgery: See Disease Characteristics At least 3 weeks since prior surgery and recovered Other: At least 4 weeks since prior bisphosphonates No prior anticoagulation therapy (i.e., warfarin), except aspirin No concurrent bisphosphonates

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Docetaxel and Estramustine<br>Estramustine, 280 mg, PO, TID, Days 1-5; q 21 days Docetaxel, 60mg/m2, IV, Day 2; q 21 days | Drug: docetaxel<br> <br> Drug: estramustine<br> <br> |
| Active Comparator: Mitoxantrone and Prednisone<br>Mitoxantrone, 12 mg/m2, IV, Day 1; q 21 days Prednisone, 5 mg, PO, BID, Days 1-21; q 21 days | Drug: mitoxantrone<br> <br> Drug: prednisone<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compare overall survival in the two study arms | Measured from date of registration to date of death due to any cause | up to 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compare progression-free survival between two study arms | Measured from date of registration to date of first observation of progression disease, or death due to any cause | up to 4 years | 
| Compare Prostate-Specific Antigen (PSA) response between two study arms | A confirmed partial response of non-measurable disease was defined as a reduction by more than 50% over baseline in two or more Prostate-Specific Antigen (PSA) measurements obtained at least four weeks apart, with no evidence of disease progression on imaging. Progressive disease was defined as a 25% increase in the serum PSA level - to at least 5 ng per milliliter - over the last preregistration measurement, with confirmation of the increase at least four weeks later. For patients with a decrease in serum PSA levels during the trial, progressive disease was defined as a confirmed increase of 25%, to at least 5 ng per milliliter over the nadir. | up to 4 years or time of disease progression | 
| Compare objective responses between two study arms | Objective responses were defined on the basis of the sum of bi-dimensional measurements of metastatic lesions. Confirmed objective responses required a follow-up scan (a minimum of four weeks later) that demonstrated a continued response. Progression was defined by one of the following: a 50 percent increase or an increase of 10 cm^2, whichever was smaller, in the sum of measurements of metastatic lesions over the sum at baseline; a clear worsening of nonmeasurable disease; reappearance of any lesion that had disappeared; appearance of any new lesion; or death. | up to 12 cycles of treatment ( 1cycle = 21 days) | 
| Compare toxicities between the two study arms |  | up to 12 cycles of treatment (1 cycle = 21 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adenocarcinoma of the prostate, stage IV prostate cancer, recurrent prostate cancer