Chemotherapy With or Without Strontium-89 in Treating Patients With Prostate Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Radioactive substances such as strontium-89 may relieve bone pain associated with prostate cancer. It is not yet known whether chemotherapy is more effective with or without strontium-89 in treating bone metastases. PURPOSE: This randomized phase III trial is studying giving chemotherapy together with strontium-89 to see how well it works compared to chemotherapy alone in treating patients with prostate cancer that has spread to the bone.

Detailed Description
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OBJECTIVES: Compare the effectiveness, in terms of overall survival, of consolidation therapy with or without strontium chloride Sr 89 after induction chemotherapy in patients with androgen-independent prostate cancer. OUTLINE: This is a randomized study. Patients are stratified according to type of induction chemotherapy (KAVE vs prednisone and docetaxel), number of bony metastases (no more than 20 vs more than 20), Eastern Cooperative Oncology (ECOG) performance status (0-1 vs 2-3), and use of zoledronate (yes vs no). Induction therapy: Patients receive 1 of 2 induction therapy regimens. Regimen A (KAVE): Patients receive doxorubicin IV over 24 hours on day 1 and oral ketoconazole three times daily on days 1-7 of weeks 1, 3, and 5. Patients receive vinblastine IV over 30 minutes on day 1 and oral estramustine three times daily on days 1-7 of weeks 2, 4, and 6. Patients receive no treatment on weeks 7 and 8. Treatment repeats every 8 weeks for at least 2 courses* in the absence of disease progression or unacceptable toxicity. NOTE: *Patients continue to receive oral ketoconazole three times daily until disease progression. Regimen B (prednisone and docetaxel): Patients receive oral prednisone twice daily on days 1-21 (days 1-14 of course 5 only) and docetaxel IV over 1 hour on day 1. Treatment repeats every 21 days for at least 5 courses in the absence of disease progression or unacceptable toxicity. Consolidation therapy: Patients with a prostate-specific antigen (PSA) response (at least 50% decline in PSA level from baseline at week 16 OR at least 2 PSA levels decreased at least 50% from baseline) are randomized to 1 of 2 consolidation treatment arms. Arm I: Patients receive doxorubicin IV over 24 hours once weekly for 6 weeks plus strontium chloride Sr 89 IV once at the beginning of chemotherapy. Arm II: Patients receive doxorubicin as in arm I. Patients are followed every 4 weeks until PSA progression and then every 3 months thereafter. PROJECTED ACCRUAL: Approximately 480 patients (240 randomized) will be accrued for this study within 48 months.

Official Title
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A Prospective Randomized Phase III, Trial Comparing Consolidation Therapy With or Without Strontium-89 Following Induction Chemotherapy in Androgen-Independent Prostate Cancer

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: Docetaxel
* Drug: Doxorubicin hydrochloride
* Drug: Estramustine phosphate sodium
* Drug: Ketoconazole
* Drug: Prednisone
* Drug: Vinblastine
* Radiation: Strontium chloride Sr 89
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Rising PSA on at least 2 occasions >1 week apart (minimum value of 5 ng/ml), accompanied either by bone pain or, if the patient is asymptomatic, by a worsening bone scan with new lesions over a period of <6 months Patients on antiandrogens should be discontinued from flutamide or nilutamide for at least 4 weeks and bicalutamide for 6 weeks; If progression is documented during this time interval as in inclusion criterion # 1, patients are eligible Osteoblastic metastases on bone scan or CT scan Androgen-independent prostate adenocarcinoma Castrate testosterone level </= 50 ng/ml; treatment to maintain castrate levels of testosterone must be continued >/= 18 years of age Life expectancy of greater than or equal to 12 weeks Zubrod performance status </= 3 Patients must have normal organ and marrow function as defined below: Leukocytes greater than 3,000/mcL Absolute neutrophil count greater than 1,500/mcL Platelets greater than 100,000/mcL Total bilirubin less than or equal to 2X institutional upper limit of normal AST(SGOT)/ALT(SGPT) less than or equal to 2X institutional upper limit of normal The patient must have the ability to understand and the willingness to sign a written informed consent document Participating subjects and their female partners agree to the use of adequate contraception (hormonal or barrier method of birth control) prior to study entry and for the duration of study participation Exclusion Criteria: History of allergic reactions attributed to compounds of similar chemical or biologic composition to the agents used on this trial Prior doxorubicin, or vinblastine in the KAVE arm and prior docetaxel in the prednisone plus docetaxel arm. However, previous treatment using other secondary hormonal agents (aminoglutethimide, diethylstilbesterol, estramustine), steroids (dexamethasone, prednisone, hydrocortisone), angiogenesis inhibitors, gene therapy, or immunotherapy are allowed More than one prior cytotoxic treatment Prior Sr-89 or Sm-153 treatment Patients who have had chemotherapy, immunotherapy, or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier Previous vagotomy or other conditions (such as pernicious anemia) associated with achlorhydria. Patients with active peptic ulcer disease who still require regular use of H2 blockers (such as cimetidine [Tagamet], ranitidine [Zantac], famotidine [Pepcid], etc), proton pump inhibitors (omeprazole [Prilosec]), or antacids (Mylanta, Maalox, Tums, etc) at week 16 of induction chemotherapy (option 1 only) might not be suitable for randomization Predominant visceral metastases in the liver, lungs, or brain Symptomatic lymphadenopathy (scrotal or pedal edema) or significant local invasive disease (hematuria) Small cell carcinoma Recent history of transient ischemic attacks (TIA) or myocardial infarctions (MI) within 12 months, or active angina or claudication sufficient to limit activity Active or likely to become active second malignancy (other than non-melanoma skin cancer) Uncontrolled inter-current illness: including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Induction regimen A<br>Doxorubicin IV over 24 hours day 1; Oral ketoconazole 3 x daily on days 1-7 of weeks 1, 3, and 5; Vinblastine IV over 30 minutes Day 1, oral Estramustine 3 x daily on Days 1-7 of weeks 2, 4, and 6. | Drug: Doxorubicin hydrochloride<br>* 20 mg/m2 IV, day 1 on Weeks 1, 3, 5<br>* Other names: Doxorubicin;Drug: Estramustine phosphate sodium<br>* 140 mg orally 3 x day, Days 1 through 7 on Weeks 2, 4, 6<br>* Other names: Estramustine;Drug: Ketoconazole<br>* 400 mg orally (po) 3 x day, Days 1 through 7<br>* Other names: Nizoral;Drug: Vinblastine<br>* 4 mg/m2 IVPB, Day 1 on Weeks 2, 4, 6<br>* Other names: Velban;|
| Experimental: Induction regimen B<br>Oral Prednisone 2 x daily on days 1-21 (days 1-14 of course 5 only) and Docetaxel IV over 1 hour Day 1. | Drug: Docetaxel<br>* 75 mg/m2 intravenous piggyback (IVPB) over 1 hour, Day 1, every 3 weeks.<br>* Other names: Taxotere;Drug: Prednisone<br>* 5 mg orally 2 x daily, weeks 1-14<br>Drug: Dexamethasone<br>* 4 mg is given orally at 12 and 1 hours before and 12 hours after docetaxel.<br>* Other names: Decadron;|
| Experimental: Consolidation arm I<br>Doxorubicin IV over 24 hours once weekly for 6 weeks + Strontium-89 IV once at beginning of chemotherapy. | Drug: Doxorubicin hydrochloride<br>* 20 mg/m2 IV, day 1 on Weeks 1, 3, 5<br>* Other names: Doxorubicin;Radiation: Strontium chloride Sr 89<br>* One dose (4 mCi total dose) IV<br>* Other names: Metastron;|
| Experimental: Consolidation arm II<br>Doxorubicin as in Consolidation arm I. | Drug: Doxorubicin hydrochloride<br>* 20 mg/m2 IV, day 1 on Weeks 1, 3, 5<br>* Other names: Doxorubicin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival From Randomization | Overall survival (OS) was computed using the number of months from the date of randomization to the date of death. Participants still alive were censored at the last follow-up date. Kaplan-Meier methodology was used to evaluate OS. | Followed every 4 weeks from randomization until death, up to 7 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival From Registration | Overall survival (OS) was computed using the number of months from the date of registration to the date of death. Participants still alive were censored at the last follow-up date. Kaplan-Meier methodology was used to evaluate OS. | Followed every 4 weeks from registration until death, up to 7 years. | 

 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, Strontium-89, Induction Chemotherapy, Androgen-Independent Prostate Cancer