Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Trial Contact Information
Registry Information

Alternate Title

Zoledronate Plus Standard Therapy Compared With Placebo Plus Standard Therapy to Prevent Bone Metastases in Patients With Recurrent Prostate Cancer That Has No Symptoms

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase III Treatment Closed 18 and over NCI UCLA-9908030 NOVARTIS-CZOL4460704, NCI-G00-1722, NCT00005073

Objectives

I. Compare the bone metastases free and overall survival in patients with 
asymptomatic recurrent prostate cancer treated with zoledronate vs placebo at 
different time points. 

II. Compare the time to first skeletal related events (pathological fractures, 
surgery to prevent or treat pathological fractures, spinal cord compression, 
and radiotherapy to bone) and skeletal morbidity rate in patients treated with 
these 2 regimens.

III. Assess quality of life and pain in these patients treated with these 2 
regimens.

Entry Criteria

Disease Characteristics:

Histologically proven asymptomatic recurrent prostate cancer 

Prior local treatment status
 Curatively treated OR
 Locally advanced disease noncuratively treated with LHRH agonist therapy

Currently receiving 1 line of hormonal therapy (with LHRH agonists or surgical
castration) and failing treatment with rising PSA only
 Patients who received LHRH agonists instead of surgical castration continue
  to receive LHRH agonist during study

Biochemical progression documented by 3 consecutively rising PSA measurements,
each at least 2 weeks apart, with the last measurement being 50% or greater
than the nadir PSA achieved after the last therapeutic maneuver (first line
hormonal therapy as noted above)

PSA (50% increased values) greater than 4 ng/mL for patients with intact
prostates and greater than 0.8 ng/mL for post-prostatectomy patients

Rising PSA for less than 10 months

Castrate levels of testosterone (less than 30 ng/dL)
  
No bone or visceral metastases by bone scan and CT scan of abdomen and pelvis
(except localized abnormalities and pelvic lymph node and soft tissue disease)
 
No CNS or leptomeningeal involvement

Prior/Concurrent Therapy:

Biologic therapy:
 No prior systemic biologic anticancer therapy

Chemotherapy:
 No prior chemotherapy
 Concurrent chemotherapy such as estramustine containing regimens or
  mitoxantrone allowed at the discretion of the protocol investigator

Endocrine therapy:
 See Disease Characteristics
 No prior systemic hormonal anticancer therapy except LHRH antagonists and/or
  nonsteroidal antiandrogens (e.g., flutamide, bicalutamide, or nilutamide) 
 Concurrent aminoglutethimide, prednisone, or diethylstilbestrol or other
  estrogens allowed at the discretion of the protocol investigator 

Radiotherapy:
 At least 6 weeks since prior palliative radiotherapy

Surgery:
 See Disease Characteristics

Other:
 No other prior systemic anticancer therapy
 At least 4 weeks since other prior investigational drugs
 No other concurrent bisphosphonate agent

Patient Characteristics:

Age:
 18 and over

Performance status:
 Karnofsky 90-100%

Life expectancy:
 Greater than 6 months

Hematopoietic:
 WBC at least 3,000/mm3
 Absolute neutrophil count at least 1,500/mm3
 Hemoglobin at least 8.0 g/dL
 Platelet count at least 75,000/mm3

Hepatic:
 Liver function tests no greater than 2.5 times upper limit of normal (ULN)

Renal:
 Creatinine no greater than 1.5 times ULN

Cardiovascular:
 No New York Heart Association class III or IV heart disease with uncontrolled
  and/or unstable cardiac or coronary artery disease

Other:
 No other malignancy within the past 5 years that would confound the etiology
  of metastatic disease except curatively treated nonmelanomatous skin cancer
 No other nonmalignant disease that would confound evaluation or preclude
  compliance
 Fertile patients must use effective contraception

Expected Enrollment

A total of 500 patients (250 per arm) will be accrued for this study.

Outline

This is a randomized, double blind, placebo controlled, open label, 
multicenter study.  Patients are stratified by prior local treatment 
(noncurative vs curative) and time interval between surgical castration or 
initiation of LHRH agonists and trial entry (less than 1 year vs 1-2 years vs 
greater than 2 years).  

Patients are randomized to 1 of 2 treatment arms:

Arm I: Patients receive zoledronate IV over 15 minutes on day 1.

Arm II: Patients receive placebo IV over 15 minutes on day 1.

Both arms: Treatment repeats every 4 weeks in the absence of documented bone 
metastasis, disease progression, or unacceptable toxicity.

All patients with documented bone metastases receive zoledronate as in arm I 
through year 4.  All patients receive oral calcium and oral vitamin D daily.  
Patients who received LHRH agonists instead of surgical castration prior to 
study continue LHRH agonist therapy during study.  

Quality of life and pain are assessed before each treatment.

Patients are followed every 6 months.

Smith MR, Kabbinavar F, Saad F, et al.: Natural history of rising serum prostate-specific antigen in men with castrate nonmetastatic prostate cancer. J Clin Oncol 23 (13): 2918-25, 2005.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

Jonsson Comprehensive Cancer Center at UCLA

Fairooz Kabbinavar, MD, Protocol chair		Ph: 310-206-3921; 888-798-0719

Registry Information
Official Title		A Randomized Double-Blind Placebo Controlled Phase III Trial Evaluating Zoledronate Plus Standard Therapy Versus Placebo Plus Standard Therapy in Patients With Recurrent Carcinoma of the Prostate Who Are Asymptomatic With Castrate Levels of Testosterone and Have Rising PSA Levels Without Radiologically-Evident Metastatic Disease
Trial Start Date		1999-10-12
Registered in ClinicalTrials.gov		NCT00005073
Date Submitted to PDQ		2000-02-11
Information Last Verified		2007-11-12
NCI Grant/Contract Number		P30-CA16042