Risedronate to Prevent Skeletal Related Events in Patients With Metastatic Prostate Cancer Commencing Hormonal Therapy

A Phase III, Randomized, Double-Blind, Placebo-Controlled Trial Evaluating the Ability of Risedronate to Prevent Skeletal Related Events in Patients With Metastatic Prostate Cancer Commencing Hormonal Therapy: Hoosier Oncology Group GU02-41

Risedronate is an orally administered pyridinyl bisphosphonate that is 36 times more potent than pamidronate and 72 times more potent than clodronate. Four randomized, double-blind trials have been carried out in patients with postmenopausal osteoporosis. In 2 of these studies, vertebral fracture incidence was reduced by a daily dose of 5 mg risedronate by up to 65% and 49% relative to placebo after 1 and 3 years, respectively. In these trials, risedronate improved lumbar spine, femoral neck, and femoral trochanter bone mineral density (BMD) at 6 months. In addition, preclinical studies have shown that risedronate is more potent than pamidronate and clodronate in inhibiting adhesion of prostate cancer cells to bone and preventing tumor cell invasion. The incidence of osteoporosis in prostate cancer patients has been well established; therefore, it is advantageous to assess the efficacy of oral bisphosphonate therapy.

Study Overview

• Status: Terminated
• Conditions: Metastatic Prostate Cancer
• Intervention / Treatment: Drug: Risedronate; Drug: Placebo

Detailed Description

OUTLINE: This is a randomized, placebo-controlled, double-blind, multicenter, 2 arm study.

The study population will consist of prostate cancer patients with metastatic bone disease for whom androgen-deprivation therapy is planned. After stratification based on the patient's age, performance status, and severity of metastatic disease, the patients will be randomized at a 1:1 ratio to the following treatment arms:

• Daily oral risedronate combined with androgen deprivation
• Daily oral placebo combined with androgen deprivation

Initial clinical evaluation will be performed during the 2-week screening period. While patients receive per-protocol treatment, study assessments will be performed every 4 weeks during the first 3 months, and every 12 weeks thereafter.

Performance Status: Eastern Cooperative Oncology Group (ECOG) 0 to 2

Life Expectancy: At least 12 weeks

Hematopoietic:

• Absolute neutrophil count (ANC) > 1,000/mm3
• Platelet count > 100,000/mm3
• international normalized ratio (INR) < 1.5 x upper limit of normal unless on therapeutic anticoagulation
• Partial thromboplastin time (PTT) < 1.5 x upper limit of normal unless on therapeutic anticoagulation

Hepatic:

• Bilirubin < 1.5 mg/dL
• Alanine transaminase (ALT) < 2.5 x upper limit of normal

Renal:

• Creatinine clearance of > 30 mL/min (by Cockcroft-Gault)

Cardiovascular:

• No significant history of uncontrolled cardiac disease (i.e., uncontrolled hypertension, unstable angina, and congestive heart failure).

Pulmonary:

• Not specified

Calcium:

• Corrected serum calcium = (4.0 g/dL - actual albumin g/dL)x 0.8 + serum calcium

• Study Type: Interventional
• Enrollment (Actual): 63
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Kelowna, British Columbia, Canada, V1Y 2H4
      • Southern Interior Medical Research, Inc.
    • Surrey, British Columbia, Canada, V3W 1N1
      • Andreou Research
    • Victoria, British Columbia, Canada, V8V 3N1
      • Dr. G. Steinhoff Clinical Research
  • New Brunswick
    • Fredericton, New Brunswick, Canada, E3B 5B8
      • Dr. Allan Patrick Professional Corporation
  • Ontario
    • Barrie, Ontario, Canada, L4M 7G1
      • Male/Female Health and Research
    • Burlington, Ontario, Canada, L7S 1V2
      • Urology Resource Centre
    • Burlington, Ontario, Canada, L7N 3V2
      • Burlington Professional Centre
    • Hamilton, Ontario, Canada, L8N 4A6
      • Hamilton District Urology Research Center
    • Kingston, Ontario, Canada, K7L-2V7
      • Centre for Advanced Urological Research
    • London, Ontario, Canada, N6A 4L6
      • London Region Cancer Program
    • New Market, Ontario, Canada, L3X 1W1
      • Mor Urology, Inc.
    • Oakville, Ontario, Canada, L6H 3P1
      • Male Health Centres
    • Scarborough, Ontario, Canada, M1P 2T7
      • Scarborough General Hospital, Medical Mall
    • Toronto, Ontario, Canada, M5G 2M9
      • University Health Network - Princess Margaret Division
• United States
  • California
    • La Mesa, California, United States, 91942
      • Center for Urological Research
    • San Bernardino, California, United States, 92404
      • San Bernadino Urological Associates
  • Connecticut
    • New Britain, Connecticut, United States, 06052
      • Grove Hill Medical Center Urology
  • Florida
    • Tampa, Florida, United States, 33607
      • Innovative Surgical Resources
  • Illinois
    • Galesburg, Illinois, United States, 61401
      • Medical & Surgical Specialists, LLC
    • Peoria, Illinois, United States, 61614
      • Peoria Urological Associates
  • Indiana
    • Evansville, Indiana, United States, 47714
      • Oncology Hematology Associates of SW Indiana
    • Goshen, Indiana, United States, 46527
      • Center for Cancer Care at Goshen Health System
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Cancer Center
    • Indianapolis, Indiana, United States, 46202
      • Quality Cancer Center (MCGOP)
    • Indianapolis, Indiana, United States, 46202
      • Urology of Indiana, LLC
    • Muncie, Indiana, United States, 47303
      • Urology Associates
    • South Bend, Indiana, United States, 46601
      • Northern Indiana Cancer Research Consortium
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Urologic Surgery Associates
    • Greenbelt, Maryland, United States, 20770
      • Drs. Werner, Murdock and Francis PA Urology Associates
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Rochester
  • Missouri
    • Kansas City, Missouri, United States, 64131
      • Kansas City Urology Care
    • St. Louis, Missouri, United States, 63110
      • Siteman Cancer Center
  • Nevada
    • Reno, Nevada, United States, 89511
      • Nevada Urology
  • New Jersey
    • New Brunswick, New Jersey, United States, 08903
      • Cancer Institute of New Jersey
    • Trenton, New Jersey, United States, 08648
      • Lawrenceville Urology
  • New York
    • Garden City, New York, United States, 11530
      • AccuMed Research Associates
    • Staten Island, New York, United States, 10304
      • Staten Island Urological Research, P.C.
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation
  • Oregon
    • Springfield, Oregon, United States, 97477
      • Oregon Urology Specialists
  • Pennsylvania
    • Lancaster, Pennsylvania, United States, 17604
      • Urological Associates of Lancaster
    • Pittsburgh, Pennsylvania, United States, 15212
      • Triangle Urological Group
  • Utah
    • Salt Lake City, Utah, United States, 84124
      • Salt Lake Research
  • Washington
    • Seattle, Washington, United States, 98166
      • David Reed, M.D.
    • Tacoma, Washington, United States, 98431
      • Madigan Army Medical Center Urology Service
  • Wisconsin
    • LaCrosse, Wisconsin, United States, 54601
      • Gundersen Lutheran Medical Center

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:

• Histologically or cytologically confirmed adenocarcinoma of the prostate with metastatic bone disease (by CT, MRI or bone scan) with plans to start or be < 30 days from beginning androgen deprivation therapy. Patients with lymph node or visceral metastases only are not eligible
• Patients may receive palliative radiation therapy at the investigators discretion during the first 4 weeks of beginning protocol therapy.

Exclusion Criteria:

• No neuroendocrine, small cell or transitional cell cancer of the prostate No abnormal bone metabolism (i.e., Paget's disease, untreated hyperthyroidism, untreated hyperprolactinemia, untreated Cushing's disease).
• No use of calcitonin within 14 days before being registered for protocol therapy or any previous use of bisphosphonates.
• No major surgery within 4 weeks of registration to protocol therapy.
• No adjuvant chemotherapy within 6 months of registration to protocol therapy.
• No previous chemotherapy for metastatic disease.
• No hormonal therapy in the adjuvant setting within 12 months of registration to protocol therapy; previous hormonal therapy must not have exceeded 6 months.
• No prior history of malignancy in the past 5 years with the exception of basal cell and squamous cell carcinoma of the skin.
• No history of allergy or drug reactions to bisphosphonates.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental Arm; Daily oral risedronate combined with androgen deprivation	Drug: Risedronate; Daily oral risedronate combined with androgen deprivation
Placebo Comparator: Placebo Arm; daily oral placebo combined with androgen deprivation	Drug: Placebo; Daily oral placebo combined with androgen deprivation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Numbers of SRE or Death Occurred Cumulatively	Number of participants experiencing a SRE(skeletal-related event) or death occurred, cumulative from each arm ( a daily oral dose of 30 mg risedronate, or placebo)	36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of Patients Archiving a PSA (Prostate Specific Antigen) Nadir < 0.2 ng/mL		36 months
Time to Development of Hormone Refractory Disease		36 months
Bone Turnover Marker Changes -- Urine Total Deoxypyridinoline (DPD)	Urine total DPD median in response to treatment on both study arms at week 24. compare median from baseline and week 24. Deoxypyridinoline (DPD) is measured in hydrolyzed urine samples using high-performance liquid chromatography technique. After extraction of the cross-links and elimination of the urine impurities by a Bio-Rad SPE cartridge (Bio-Rad Laboratories, Hercules, CA), total DPD is eluted from reverse-phase high-performance liquid chromatography by ion pair chromatography with isocratic elution. The compounds are detected as a result of their natural fluorescence with a fluorescence detector	24 weeks
Three- Year Survival Rate		36 months
Bone Turnover Marker Changes-- Urine N-telopeptide (NTX) Median	Urine N-telopeptide (NTX) median changes between baseline and week 24. The assays are performed with the NTx Reagent Pack kit from Ortho-Clinical Diagnostics (Ortho-Clinical Diagnostics/Johnson & Johnson, Amersham, UK), which is a kit designed for the quantitative determination of N-terminal telopeptide (NTx) in human urine on the automated Vitros Immunodiagnostic System ECi (Ortho-Clinical Diagnostics/Johnson & Johnson, Amersham, UK). A competitive immunoassay technique is used. This depends on competition between NTx present in the sample and a synthetic NTx peptide coated on the wells for binding by a horseradish peroxidase (HRP)-labeled antibody conjugate (mouse monoclonal anti-NTx). The conjugate is captured by the peptide coated on the wells; unbound materials are removed by washing. The bound HRP conjugate is measured by a luminescent reaction.	24 week
Bone Turnover Marker Changes-- Serum BAP	Serum BAP median changes between baseline and week 24. The Ostase assays are performed with an access immunoassay system, which is an assay of serum samples that provides a quantitative measurement of bone alkaline phosphatase (BAP). A mouse monoclonal antibody specific to BAP is added to a re-action vessel with paramagnetic particles coated with goat antimouse polyclonalantibody.Calibrators,controls,andsamplescontainingBAP are added to the coated particles and bind to the anti-BAP monoclonal antibody. After the formation of a solid phase/capture antibody/BAP complex, separation in a magnetic field and washing remove materials not bound to the solid phase. A chemiluminescent substrate, LumiPhos 530, is added to the reaction vessel, and light generated by the reaction is measured with a luminometer. The light production is directly proportional to the concentration of BAP in the sample. The amount of analyte in thesample is determined from a stored multipoint calibration curve	24 week
Bone Turnover Marker Changes-- Serum Osteocalcin (OC)	Serum Osteocalcin (OC) medians between baseline and 24 weeks areperformed with the Elecsys 2010 automated analyzer, which uses an electrochemiluminescence immunoassay technique for the in vitro quantitative determination of serum total osteocalcin in humanserum. The assay uses a sandwich test principle in which afirst biotinylated monoclonal antibody recognizing N-MID osteocalcin and a second monoclonal antibody against N-MID osteocalcin labeled with ruthenium are incubated with 20mL of serum. After a first incubation, streptavidin-coated microparticles are added for a second incubation, and the complex becomes bound to the solid phase by interaction of biotin and streptavidin.These microparticles are then magnetically captured onto the surface of an electrode. Application of a voltage on this electrode induces chemiluminescent emission, which is measured by a photomultiplierand compared with a calibration curve that is generated in aninstrument-specific manner by 2-point calibration.	24 week

Collaborators and Investigators

• Sponsor: Christopher Sweeney, MBBS
• Collaborators: Sanofi; Hoosier Cancer Research Network; Walther Cancer Institute
• Investigators: Study Chair: Christopher Sweeney, M.B.B.S., Hoosier Oncology Group, LLC

Publications and helpful links

General Publications

• Jakob T, Tesfamariam YM, Macherey S, Kuhr K, Adams A, Monsef I, Heidenreich A, Skoetz N. Bisphosphonates or RANK-ligand-inhibitors for men with prostate cancer and bone metastases: a network meta-analysis. Cochrane Database Syst Rev. 2020 Dec 3;12(12):CD013020. doi: 10.1002/14651858.CD013020.pub2.
• C. Sweeney, W. M. Dugan II, R. Dreicer, F. Chu, G. Parks, K. Baker, D. Reed, K. Jansz, J. Zadra, C. T. Yiannoutsos. J Clin Oncol 28, 2010 (suppl; abstr e15000)
• Hahn NM, Yiannoutsos CT, Kirkpatrick K, Sharma J, Sweeney CJ. Failure to suppress markers of bone turnover on first-line hormone therapy for metastatic prostate cancer is associated with shorter time to skeletal-related event. Clin Genitourin Cancer. 2014 Feb;12(1):33-40.e4. doi: 10.1016/j.clgc.2013.07.002. Epub 2013 Oct 12.

Study record dates

Study Major Dates

• Study Start: October 1, 2003
• Primary Completion (Actual): February 1, 2008
• Study Completion (Actual): March 1, 2008

Study Registration Dates

• First Submitted: September 13, 2005
• First Submitted That Met QC Criteria: September 14, 2005
• First Posted (Estimate): September 22, 2005

Study Record Updates

• Last Update Posted (Estimate): May 26, 2016
• Last Update Submitted That Met QC Criteria: May 25, 2016
• Last Verified: May 1, 2016

More Information

Terms related to this study

• 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; Membrane Transport Modulators; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Risedronic Acid
• Other Study ID Numbers: HOG GU02-41

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO