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

Study Overview
=================
Brief Summary
-----------------
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.

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

Official Title
-----------------
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

Conditions
-----------------
Metastatic Prostate Cancer

Intervention / Treatment
-----------------
* Drug: Risedronate
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental Arm<br>Daily oral risedronate combined with androgen deprivation | Drug: Risedronate<br>* Daily oral risedronate combined with androgen deprivation<br>|
| Placebo Comparator: Placebo Arm<br>daily oral placebo combined with androgen deprivation | Drug: Placebo<br>* Daily oral placebo combined with androgen deprivation<br>|

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 |