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

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

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.

Study Overview

• Status: Terminated
• Conditions: Prostate Cancer
• Intervention / Treatment: Drug: Doxorubicin hydrochloride; Drug: Estramustine phosphate sodium; Drug: Ketoconazole; Drug: Vinblastine; Drug: Docetaxel; Drug: Prednisone; Drug: Dexamethasone; Radiation: Strontium chloride Sr 89

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 265
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Georgia
    • Gainesville, Georgia, United States, 30501
      • Northeast Georgia Medical Center
    • Savannah, Georgia, United States, 31403-3089
      • Curtis and Elizabeth Anderson Cancer Institute at Memorial Health University Medical Center
  • Illinois
    • Hines, Illinois, United States, 60141
      • Veterans Affairs Medical Center - Hines
    • Rockford, Illinois, United States, 61104-2315
      • Swedish-American Regional Cancer Center
  • Iowa
    • Bettendorf, Iowa, United States, 52722
      • Hematology Oncology Associates of the Quad Cities
    • Davenport, Iowa, United States, 52803
      • Genesis Regional Cancer Center at Genesis Medical Center
    • Sioux City, Iowa, United States, 51101
      • Siouxland Hematology-Oncology Associates, LLP
    • Sioux City, Iowa, United States, 51104
      • St. Luke's Regional Medical Center
    • Sioux City, Iowa, United States, 51104
      • Mercy Medical Center - Sioux City
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Cancer Clinic
  • Montana
    • Billings, Montana, United States, 59101
      • CCOP - Montana Cancer Consortium
    • Billings, Montana, United States, 59101
      • Hematology-Oncology Centers of the Northern Rockies - Billings
    • Billings, Montana, United States, 59101
      • Northern Rockies Radiation Oncology Center
    • Billings, Montana, United States, 59101
      • St. Vincent Healthcare Cancer Care Services
    • Billings, Montana, United States, 59107-7000
      • Billings Clinic - Downtown
    • Bozeman, Montana, United States, 59715
      • Bozeman Deaconess Cancer Center
    • Butte, Montana, United States, 59701
      • St. James Healthcare Cancer Care
    • Great Falls, Montana, United States, 59405
      • Great Falls Clinic - Main Facility
    • Great Falls, Montana, United States, 59405
    • Great Falls, Montana, United States, 59405-5309
      • Big Sky Oncology
    • Great Falls, Montana, United States, 59405
      • Sletten Cancer Institute at Benefis Healthcare
    • Helena, Montana, United States, 59601
      • St. Peter's Hospital
    • Kalispell, Montana, United States, 59901
      • Kalispell Regional Medical Center
    • Kalispell, Montana, United States, 59901
      • Glacier Oncology, PLLC
    • Kalispell, Montana, United States, 59901
      • Kalispell Medical Oncology at KRMC
    • Missoula, Montana, United States, 59801
      • Community Medical Center
    • Missoula, Montana, United States, 59804
      • Guardian Oncology and Center for Wellness
    • Missoula, Montana, United States, 59807-7877
      • Montana Cancer Specialists at Montana Cancer Center
    • Missoula, Montana, United States, 59807
      • Montana Cancer Center at St. Patrick Hospital and Health Sciences Center
  • Nebraska
    • Kearney, Nebraska, United States, 68848-1990
      • Good Samaritan Cancer Center at Good Samaritan Hospital
  • North Carolina
    • Kinston, North Carolina, United States, 28501
      • Kinston Medical Specialists
  • Ohio
    • Akron, Ohio, United States, 44309-2090
      • Summa Center for Cancer Care at Akron City Hospital
    • Barberton, Ohio, United States, 44203
      • Barberton Citizens Hospital
    • Salem, Ohio, United States, 44460
      • Cancer Care Center, Incorporated
    • Wooster, Ohio, United States, 44691
      • Cancer Treatment Center
  • South Carolina
    • Florence, South Carolina, United States, 29501
      • McLeod Regional Medical Center
    • Greenville, South Carolina, United States, 29615
      • CCOP - Greenville
  • Texas
    • Dallas, Texas, United States, 75230
      • Medical City Dallas Hospital
    • Houston, Texas, United States, 77030-4009
      • University of Texas MD Anderson Cancer Center
  • Wyoming
    • Sheridan, Wyoming, United States, 82801
      • Welch Cancer Center at Sheridan Memorial Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

1. 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
2. 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
3. Osteoblastic metastases on bone scan or CT scan
4. Androgen-independent prostate adenocarcinoma
5. Castrate testosterone level </= 50 ng/ml; treatment to maintain castrate levels of testosterone must be continued
6. >/= 18 years of age
7. Life expectancy of greater than or equal to 12 weeks
8. Zubrod performance status </= 3
9. 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
10. The patient must have the ability to understand and the willingness to sign a written informed consent document
11. 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:

1. History of allergic reactions attributed to compounds of similar chemical or biologic composition to the agents used on this trial
2. 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
3. More than one prior cytotoxic treatment
4. Prior Sr-89 or Sm-153 treatment
5. 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
6. 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
7. Predominant visceral metastases in the liver, lungs, or brain
8. Symptomatic lymphadenopathy (scrotal or pedal edema) or significant local invasive disease (hematuria)
9. Small cell carcinoma
10. Recent history of transient ischemic attacks (TIA) or myocardial infarctions (MI) within 12 months, or active angina or claudication sufficient to limit activity
11. Active or likely to become active second malignancy (other than non-melanoma skin cancer)
12. 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

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

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: M.D. Anderson Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Shi-Ming Tu, MD, M.D. Anderson Cancer Center

Publications and helpful links

General Publications

• Tu SM, Kim J, Pagliaro LC, Vakar-Lopez F, Wong FC, Wen S, General R, Podoloff DA, Lin SH, Logothetis CJ. Therapy tolerance in selected patients with androgen-independent prostate cancer following strontium-89 combined with chemotherapy. J Clin Oncol. 2005 Nov 1;23(31):7904-10. doi: 10.1200/JCO.2005.01.2310.

Helpful Links

• University of Texas MD Anderson Cancer Center Website

Study record dates

Study Major Dates

• Study Start: April 1, 2002
• Primary Completion (Actual): September 1, 2014

Study Registration Dates

• First Submitted: September 13, 2001
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (Estimate): January 27, 2003

Study Record Updates

• Last Update Posted (Estimate): March 22, 2016
• Last Update Submitted That Met QC Criteria: February 19, 2016
• Last Verified: February 1, 2016

More Information

Terms related to this study

• Keywords: stage IV prostate cancer; recurrent prostate cancer; adenocarcinoma of the prostate; Strontium-89; Induction Chemotherapy; Androgen-Independent Prostate Cancer
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Prostatic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Alkylating; Alkylating Agents; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Antibiotics, Antineoplastic; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; 14-alpha Demethylase Inhibitors; Docetaxel; Dexamethasone; Prednisone; Doxorubicin; Liposomal doxorubicin; Ketoconazole; Estramustine; Vinblastine
• Other Study ID Numbers: ID00-156; P30CA016672 (U.S. NIH Grant/Contract); U10CA045809 (U.S. NIH Grant/Contract); MDA-ID-00156 (Other Identifier: UT MD Anderson Cancer Center); NCI-3410; CDR0000068897 (Registry Identifier: NCI PDQ); NCI-2009-00009 (Registry Identifier: NCI CTRP)