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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

Phase 3
18 Years
Open (Enrolling)
Metastatic Cancer, Prostate Cancer

Thank you

Trial Information

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



- Compare the time to first skeletal-related events in patients with prostate cancer and
bone metastases undergoing androgen deprivation therapy when treated with zoledronate
vs placebo.


- Compare the overall and progression-free survival of patients treated with these

- Compare the toxic effects in patients treated with these regimens.

OUTLINE: 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). 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. In both arms, courses
repeat every 4 weeks in the absence of disease progression or a skeletal-related event.
All patients receive concurrent androgen deprivation therapy. Patients also receive
oral calcium and cholecalciferol (vitamin D) supplements daily.

Patients progressing to androgen-independent prostate cancer proceed to open-label therapy
comprising zoledronate IV over 15 minutes on day 1. Courses repeat every 3 weeks in the
absence of disease progression or a skeletal-related event.

Patients are followed periodically for approximately 10 years after randomization.

PROJECTED ACCRUAL: A total of 680 patients (340 per treatment arm) will be accrued for this
study within 4 years.

Inclusion Criteria


- Histologically confirmed adenocarcinoma of the prostate

- No small cell, neuroendocrine, or transitional cell carcinomas

- At least 1 bone metastasis by bone scan, MRI, CT scan, or plain radiographs

- Indeterminate lesions should be confirmed by a second imaging method

- At least 1 bone metastasis with no prior irradiation

- Concurrent androgen deprivation therapy required, defined as any of the following:

- Bilateral orchiectomy

- Gonadotropin-releasing hormone (GnRH) agonist with or without an antiandrogen



- 18 and over

Performance status

- ECOG 0-2

Life expectancy

- Not specified


- Not specified


- Not specified


- Creatinine clearance ≥ 30 mL/min

- Corrected calcium ≥ 8.0 mg/dL and < 11.6 mg/dL


- Fertile patients must use effective contraception


Biologic therapy

- Concurrent standard biologic response modifiers allowed during open-label therapy


- Concurrent standard cytotoxic chemotherapy allowed during open-label therapy only

Endocrine therapy

- See Disease Characteristics

- Prior neoadjuvant and/or adjuvant hormonal therapy allowed provided duration of
therapy was no more than 6 months AND therapy was discontinued more than 6 months
before study entry

- No more than 6 months since initiation of any of the following hormonal therapies:

- Orchiectomy

- GnRH agonist (e.g., leuprolide, goserelin, or triptorelin)

- Estrogen therapy

- Antiandrogens (e.g., bicalutamide, flutamide, or nilutamide)

- Any other therapy known to lower testosterone levels or inhibit testosterone

- No intermittent androgen deprivation therapy except for patients concurrently
enrolled on SWOG-9346

- Concurrent palliative corticosteroids allowed during open-label therapy only

- Concurrent standard hormonal agents allowed during open-label therapy only


- See Disease Characteristics

- No prior radiopharmaceuticals

- At least 4 weeks since prior radiotherapy

- Concurrent standard radiotherapy to extraskeletal tumor sites allowed during
open-label therapy only


- See Disease Characteristics


- No prior bisphosphonates

- No prior denosumab

- No other concurrent agents expected to alter osteoclast activity (e.g., denosumab,
calcitonin, mithramycin, gallium nitrate, or any other bisphosphonate)

- Concurrent daily supplemental elemental calcium (500 mg) and a multivitamin
containing cholecalciferol (Vitamin D) (400 IU) OR a combination tablet containing
both recommended

- Concurrent standard marketed antineoplastic therapies allowed during open-label
therapy only

Type of Study:


Study Design:

Allocation: Randomized, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Time to first skeletal related event

Safety Issue:


Principal Investigator

Matthew R. Smith, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Massachusetts General Hospital


United States: Food and Drug Administration

Study ID:




Start Date:

January 2004

Completion Date:

Related Keywords:

  • Metastatic Cancer
  • Prostate Cancer
  • adenocarcinoma of the prostate
  • recurrent prostate cancer
  • stage IV prostate cancer
  • bone metastases
  • Neoplasm Metastasis
  • Neoplasms
  • Neoplasms, Second Primary
  • Prostatic Neoplasms



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