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Zoledronate in Preventing Skeletal (Bone)-Related Events in Men Who Are Receiving Androgen Deprivation Therapy For Prostate Cancer and Bone Metastases

This study has been completed.
Sponsor:
Collaborators:
Southwest Oncology Group
Eastern Cooperative Oncology Group
NCIC Clinical Trials Group
Novartis Pharmaceuticals
Information provided by (Responsible Party):
Alliance for Clinical Trials in Oncology
ClinicalTrials.gov Identifier:
NCT00079001
First received: March 8, 2004
Last updated: October 27, 2014
Last verified: October 2014
  Purpose

RATIONALE: Zoledronate may prevent or decrease skeletal (bone)-related events (such as pain or fractures) caused by bone metastases and androgen deprivation therapy. It is not yet known whether treatment with zoledronate is effective in preventing bone-related events in patients who have prostate cancer and bone metastases.

PURPOSE: This randomized phase III trial is studying how well zoledronate works in preventing bone-related events in patients who are receiving androgen deprivation therapy for prostate cancer and bone metastases.


Condition Intervention Phase
Metastatic Cancer
Prostate Cancer
Drug: zoledronic acid
Other: placebo
Drug: androgen deprivation therapy
Drug: GnRH agonist
Dietary Supplement: Calcium supplement
Dietary Supplement: Vitamin D
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized Double-Blind, Placebo-Controlled Phase III Study of Early Versus Standard Zoledronic Acid to Prevent Skeletal Related Events in Men With Prostate Cancer Metastatic to Bone

Resource links provided by NLM:


Further study details as provided by Alliance for Clinical Trials in Oncology:

Primary Outcome Measures:
  • Time to First Skeletal Related Event [ Time Frame: Up to 10 years ] [ Designated as safety issue: Yes ]
    Time to first skeletal related event (SRE) was defined as the time from randomization to first skeletal event. Skeletal events are defined as radiation to bone, clinical fracture, surgery to bone and spinal cord compression and death due to prostate cancer. The median with 95% CI was estimated using the Kaplan Meier method.


Secondary Outcome Measures:
  • Overall Survival [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
    Overall survival (OS) was defined as the time from randomization to death of any cause. Surviving patients were censored at the date of last follow-up. The median OS with 95% CI was estimated using the Kaplan Meier method.

  • Progression-free Survival [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]

    Progression Free Survival (PFS) was defined as the time from registration until disease progression or death, whichever occurs first. The median PFS with 95% CI was estimated using the Kaplan-Meier method.

    Progression is defined as one or more of the following: new bone metastases, biochemical progression of PSA, treatment with radiation therapy while on treatment.



Enrollment: 645
Study Start Date: January 2004
Study Completion Date: July 2012
Primary Completion Date: July 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Zoledronic acid + androgen deprivation therapy
4mg by IV over 15 minutes every 4 weeks in the absence of disease progression or the first skeletal-related event. Participants who progression on blinded treatment before having a skeletal event may continue on open label Zoledronic acid (4 mg by IV over 15 minutes every 3 weeks).
Drug: zoledronic acid
Given IV
Drug: androgen deprivation therapy
Patients concurrently enrolled on the Phase III study of intermittent androgen deprivation in patients with stage D2 prostate cancer will receive androgen deprivation therapy per SWOG-9346. All other patients will receive androgen deprivation therapy at a standard dose and schedule throughout the study.
Drug: GnRH agonist
Patients concurrently enrolled on the Phase III study of intermittent androgen deprivation in patients with stage D2 prostate cancer will receive the GnRH agonist per SWOG-9346. All other patients will receive GnRH agonist at a standard dose and schedule throughout the study.
Dietary Supplement: Calcium supplement
Patients will receive 500 mg by mouth daily of a calcium supplement or a combination tablet containing approximately 500 mg elemental calcium and 400-500 IU vitamin D by mouth daily.
Dietary Supplement: Vitamin D
Patients will receive a multivitamin tablet containing 400-500 IU vitamin D by mouth daily or a combination tablet containing approximately 500 mg elemental calcium and 400-500 IU vitamin D by mouth daily.
Active Comparator: Placebo + androgen deprivation therapy
Placebo bu IV over 15 minutes for 4 weeks in the absence of disease progression or the first skeletal-related event. Participants who progress on blinded treatment before having a skeletal event may continue on open label Zoledronic acid.
Other: placebo
Given IV
Drug: androgen deprivation therapy
Patients concurrently enrolled on the Phase III study of intermittent androgen deprivation in patients with stage D2 prostate cancer will receive androgen deprivation therapy per SWOG-9346. All other patients will receive androgen deprivation therapy at a standard dose and schedule throughout the study.
Drug: GnRH agonist
Patients concurrently enrolled on the Phase III study of intermittent androgen deprivation in patients with stage D2 prostate cancer will receive the GnRH agonist per SWOG-9346. All other patients will receive GnRH agonist at a standard dose and schedule throughout the study.
Dietary Supplement: Calcium supplement
Patients will receive 500 mg by mouth daily of a calcium supplement or a combination tablet containing approximately 500 mg elemental calcium and 400-500 IU vitamin D by mouth daily.
Dietary Supplement: Vitamin D
Patients will receive a multivitamin tablet containing 400-500 IU vitamin D by mouth daily or a combination tablet containing approximately 500 mg elemental calcium and 400-500 IU vitamin D by mouth daily.

Detailed Description:

Zoledronic acid decreases the risk of skeletal related events in men with prostate cancer metastatic to bone and disease progression after primary hormonal therapy.

This study is designed to evaluate whether earlier treatment with zoledronic acid will further decrease the risk of skeletal related events. This is a randomized, double-blind, placebo-controlled, multicenter study followed by an open-label study. Patients are stratified according to ECOG performance status (0-1 vs 2), prior skeletal-related event (no vs yes), and serum alkaline phosphatase (< upper limit of normal [ULN] vs ≥ ULN).

The primary objective of the study is to determine whether treatment with zoledronic acid at the time of initiation of androgen deprivation therapy for metastatic prostate cancer will delay the time to first skeletal related event. The secondary objective of the study is to compare the effect of treatment with zoledronic acid to placebo on overall survival (OS), progression-free survival (PFS) and toxicity in men receiving androgen deprivation therapy for metastatic prostate cancer.

Patients are randomized to 1 of 2 treatment arms. Treatment continues in the absence of disease progression or a skeletal-related event. All patients receive concurrent androgen deprivation therapy with a GnRH agonist. Patients also receive oral calcium and (vitamin D) supplements daily. Patients progressing to androgen-independent prostate cancer proceed to the open-label therapy with zoledronic acid IV. Treatment continues for 3 weeks in the absence of disease progression or the first skeletal-related event.

Patients are followed periodically for approximately 10 years after entry on the study.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria
  1. Histologic Documentation: Histologic documentation of prostate adenocarcinoma. Patients with small cell, neuroendocrine, or transitional cell carcinomas are not eligible.
  2. Staging: At least one bone metastasis by radiographic imaging (bone scan, magnetic resonance imaging, computed tomography, or plain radiographs). Indeterminate lesions should be confirmed by a second imaging method. Imaging to document bone metastases is to be completed either within 12 weeks before registration or within 12 weeks before initiating androgen deprivation therapy for bone metastases.
  3. Hormone Therapy

    • While on this study, patients must receive androgen deprivation therapy (ADT) for treatment of prostate cancer. Androgen deprivation therapy may have begun prior to enrollment on this study; however patients must have initiated ADT ≤ 6 months prior to enrollment.
    • Androgen deprivation therapy is defined as bilateral orchiectomy or gonadotropin- releasing hormone (GnRH) agonist with or without an antiandrogen.
    • Patients treated with intermittent androgen deprivation therapy are not eligible except for patients concurrently enrolled in SWOG-9346/INT-0162/CALGB 9594, Phase III Study of Intermittent Androgen Deprivation in Patients with Stage D2 Prostate Cancer.
  4. Prior Treatment:

    • Hormone therapy at any point prior to 6 months before enrollment is prohibited. This includes any of the following treatments:

      • orchiectomy,
      • GnRH agonist (e. g., leuprolide, goserelin, triptorelin),
      • estrogen therapy,
      • antiandrogen (e. g., bicalutamide, flutamide, nilutamide), or
      • any other therapy known to lower testosterone level or inhibit testosterone effect.
    • Prior neoadjuvant and/or adjuvant hormone therapy is allowed provided that the duration of hormone therapy was six months or less and the hormone therapy was discontinued more than 6 months prior to study entry.
    • No prior treatment with a bisphosphonate
    • No prior treatment with denosumab
    • No prior treatment with radiopharmaceuticals
    • ≥ 4 weeks since completion of prior radiation therapy with at least one bone metastasis present that has NOT been radiated.
  5. ECOG (CTC) performance status 0-2
  6. Age: ≥ 18 years
  7. Required Initial Laboratory Data:

    • Calculated Creatinine Clearance ≥ 30 mL/min
    • Corrected serum calcium ≥ 8.0 mg/dL (2.00 mmol/L) and <11.6 mg/dL (2.90 mmol/L)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00079001

  Show 241 Study Locations
Sponsors and Collaborators
Alliance for Clinical Trials in Oncology
Southwest Oncology Group
Eastern Cooperative Oncology Group
NCIC Clinical Trials Group
Novartis Pharmaceuticals
Investigators
Study Chair: Matthew R. Smith, MD, PhD Massachusetts General Hospital
  More Information

Additional Information:
Publications:
Responsible Party: Alliance for Clinical Trials in Oncology
ClinicalTrials.gov Identifier: NCT00079001     History of Changes
Obsolete Identifiers: NCT00698308
Other Study ID Numbers: CDR0000353209, U10CA031946, CALGB-90202, CAN-NCIC-PRC2
Study First Received: March 8, 2004
Results First Received: October 27, 2014
Last Updated: October 27, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Alliance for Clinical Trials in Oncology:
adenocarcinoma of the prostate
recurrent prostate cancer
stage IV prostate cancer
bone metastases

Additional relevant MeSH terms:
Neoplasm Metastasis
Prostatic Neoplasms
Genital Diseases, Male
Genital Neoplasms, Male
Neoplasms
Neoplasms by Site
Neoplastic Processes
Pathologic Processes
Prostatic Diseases
Urogenital Neoplasms
Androgens
Deslorelin
Diphosphonates
Ergocalciferols
Vitamin D
Vitamins
Zoledronic acid
Bone Density Conservation Agents
Enzyme Inhibitors
Growth Substances
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Micronutrients
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on November 27, 2014