Safety and Efficacy of Zoledronic Acid in Patients With Breast Cancer With Metastatic Bone Lesions

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT00375427
First received: September 12, 2006
Last updated: April 9, 2012
Last verified: July 2011
  Purpose

The objective of this study is to assess the clinical benefit of two different dosing schedules of zoledronic acid in patients with metastatic bone lesions from breast cancer who have already been treated with zoledronic acid for about one year.


Condition Intervention Phase
Breast Cancer With Bone Metastasis
Drug: Zoledronic acid
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Prospective, Randomized, Multi-center Comparative 2-arm Trial of Efficacy and Safety of Zoledronic Acid (Every 3-months vs. Every 4 Weeks) Beyond Approximately 1 Year of Treatment With Zoledronic Acid in Patients With Bone Lesions From Breast Cancer

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Annual Overall Skeletal Morbidity Rate (SMR) [ Time Frame: 12 months ] [ Designated as safety issue: No ]

    The SMR was computed by summing all Skeletal Related Event(s) (SREs)which occurred during the observation period and dividing it by the ratio "days of observation period / 365.25", for each participant. SRE was defined as: pathologic bone fracture, spinal cord compression, surgery to bone both curative and prophylactic, radiation therapy to bone, or hypercalcemia of malignancy.

    SMR (years) = 365.25 x SMR(days) where SMR (days) = total number of SREs / total SRE risk period (days). Risk period for SMR was computed as the days from randomization date to the date of last visit.



Secondary Outcome Measures:
  • Percentage of Participants Experiencing Skeletal Related Event(s) (SREs) [ Time Frame: 12 month ] [ Designated as safety issue: No ]

    Skeletal Related Events (SREs) are defined as a:

    • pathologic bone fracture such as non-vertebral and vertebral compression fractures
    • spinal cord compression identified by positive diagnosis documented by X-ray evidence
    • surgery to bone both curative and prophylactic
    • radiation therapy to bone including palliative, therapeutic or prophylactic
    • hypercalcemia of malignancy, defined as a corrected serum calcium > 12 mg/dl (3.00 mmol/l) or a lower level of hypercalcemia which is symptomatic and which requires active treatment other than rehydration.

  • Annual Incidence of Any Skeletal Related Events (SREs) [ Time Frame: 12 months ] [ Designated as safety issue: No ]

    Skeletal Related Events (SREs) are defined as a:

    • pathologic bone fracture such as non-vertebral and vertebral
    • spinal cord compression identified by X-rays evidence
    • surgery to bone both curative and prophylactic
    • radiation therapy to bone including palliative, therapeutic or prophylactic
    • hypercalcemia of malignancy, defined as a corrected serum calcium > 12 mg/dl (3.00 mmol/l) or a lower level of hypercalcemia which is symptomatic and which requires active treatment other than rehydration. Annual incidence for each SRE was computed in the same way as annual overall SMR.

  • Median Time to First Skeletal Related Event(s) (SRE) [ Time Frame: 12 month ] [ Designated as safety issue: No ]
    Median Time to first skeletal related event (SRE) is defined as the time from randomization to the date of first occurrence of any SRE which includes at least one of the following: radiation therapy to bone, pathologic bone fracture, spinal cord compression, surgery to bone, and hypercalcemia of malignancy (HCM). Due to the few numbers of SRE, Kaplan-Meier estimate never reaches a failure probability >=25%; so median time, 25th and 75th percentiles are not determined.For this reason only the estimated percentage of patient SRE free are reported at each time point.

  • Percentage of Participants Skeletal Related Event (SRE) Free [ Time Frame: 12 months ] [ Designated as safety issue: No ]

    Percentage of participants SRE free is defined as the Kaplan-Meier estimate of participants free of any Skeletal Related Events(SRE) at each time point.

    Skeletal Related Events (SREs) are:

    • pathologic bone fracture; non-vertebral and vertebral
    • spinal cord compression identified by X-rays
    • surgery to bone both curative and prophylactic
    • radiation therapy to bone (palliative, therapeutic or prophylactic)
    • hypercalcemia of malignancy, defined as a corrected serum calcium > 12 mg/dl (3.00 mmol/l) or a lower level which is symptomatic and requires treatment other than rehydration.

  • Composite Bone Pain Score According to the Brief Pain Inventory (BPI) Questionnaire [ Time Frame: At Baseline, Month 3, Month 6, Month 9 and Month 12 ] [ Designated as safety issue: No ]
    Bone pain was assessed by means of a pain score obtained using the Brief Pain Inventory (BPI) questionnaire. The BPI can produce three pain scores: worst pain, a composite pain score, and a pain interference score. The composite pain score, which is the average of questions 3, 4, 5 and 6 of the questionnaire was used in this study. Pain was rated on a scale of 0 (no pain) to 10 (pain as bad as you can imagine). The outcome is given as the median score for participants at baseline, and 3, 6, 9 and 12 months of treatment

  • Evaluation of Pain According to Verbal Rating Scale (VRS) Based on Median Score Value [ Time Frame: At Baseline, Month 3, Month 6, Month 9 and Month 12 ] [ Designated as safety issue: No ]
    Pain intensity at rest and on movement is rated by the patient by means of a validated 6-point Verbal Rating Scale (VRS) and refers to the pain which occurred during the last week before the assessment. Median score value is the median of all the observed scores (none=0, very mild=1, mild=2, moderate=3, severe=5 and very severe=6) at each time point.

  • Use Of Analgesic Medications According to the Analgesic Score Scale [ Time Frame: At Baseline, Month 3, Month 6, Month 9 and Month 12 ] [ Designated as safety issue: No ]

    The analgesic score used for this study is modified from the Radiation Therapy Oncology Group (RTOG) analgesic score scale. The scale represents type of medication administered from 0 to 4 where:

    0 = None

    1. = Minor analgesics (aspirin, NSAID, acetaminophen, propoxyphene, etc.)
    2. = Tranquilisers, antidepressants, muscle relaxants, and steroids
    3. = Mild narcotics (oxycodone, meperidine, codeine, etc.)
    4. = Strong narcotics (morphine, hydromorphone, etc.) The outcome is given a the median score for the participants at Baseline and 3, 6, 9 and 12 months of treatment

  • Assessment of the Eastern Cooperative Oncology Group (ECOG) Performance Score [ Time Frame: At Baseline, Month 3, Month 6, Month 9 and Month 12 ] [ Designated as safety issue: No ]
    ECOG Performance Score has 4 grades. 0 = Fully active, able to carry out all pre-disease activities; 1 = Restricted in strenuous activity but ambulatory and able to carry out work of light or sedentary nature; 2 = Ambulatory and capable of all self-care but unable to carry out work activities. Active about 50% of waking hours; 3 = Capable of limited self-care, confined to bed/chair more than 50% of waking hours; 4 = Completely disabled; cannot carry on self-care. Totally confined to bed/chair. Outcome is given as median score for participants at Baseline and 3, 6 , 9 and 12 months of treatment


Enrollment: 430
Study Start Date: February 2006
Primary Completion Date: February 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Every 3 months
Zoledronic acid as a 15-minute (at least) intravenous (i.v.) infusion every three months. The dose of study drug will be the same administered before the study entry, that is 4 mg or a reduced dose, i.e. 3.5 mg, or 3.3 mg or 3.0 mg. Randomized patients will receive a maximum of 4 infusions in this group.
Drug: Zoledronic acid
Zoledronic acid as a 15-minute (at least) intravenous (i.v.) infusion. The dose of study drug will be the same administered before the study entry, that is 4 mg or a reduced dose, i.e. 3.5 mg, or 3.3 mg or 3.0 mg.
Other Names:
  • ZOL446
  • Zometa®
Experimental: Every 4 weeks
Zoledronic acid as a 15-minute (at least) intravenous (i.v.) infusion every 4 weeks. The dose of study drug will be the same administered before the study entry, that is 4 mg or a reduced dose, i.e. 3.5 mg, or 3.3 mg or 3.0 mg. Patients randomized to this group will receive up to 12 infusions.
Drug: Zoledronic acid
Zoledronic acid as a 15-minute (at least) intravenous (i.v.) infusion. The dose of study drug will be the same administered before the study entry, that is 4 mg or a reduced dose, i.e. 3.5 mg, or 3.3 mg or 3.0 mg.
Other Names:
  • ZOL446
  • Zometa®

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

  • Female patients ≥ 18 years of age.
  • Written informed consent given.
  • Histologically confirmed Stage IV breast cancer with at least one bone metastasis radiologically confirmed.
  • Previous treatment with zoledronic acid every 3-4 weeks, for 9-12 infusions over no more than 15 months.
  • Eastern Cooperative Oncology Group (ECOG) performance status ≤2 .
  • Life expectancy ≥ 1 year.

Exclusion criteria:

  • More than 3 months since last infusion of Zoledronic Acid (Zometa®).
  • Treatments with other bisphosphonate than Zoledronic Acid (Zometa®) at any time prior to study entry.
  • Serum creatinine > 3 mg/dL (265 μmol/L) or calculated (Cockcroft-Gault formula) creatinine clearance (CLCr) < 30 mL/min CrCl = ({[140-age (years)] x weight(kg)}/ [72 x serum creatinine (mg/dL)])x 0.85
  • Corrected (adjusted for serum albumin) serum calcium < 8 mg/dl (2 mmol/L) or > 12 mg/dL ( 3.0 mmol/L).
  • Current active dental problem including infection of the teeth or jawbone (maxilla or mandibular); dental or fixture trauma, or a recurrent or prior diagnosis of osteonecrosis of the jaw (ONJ), of exposed bone in the mouth, or of slow healing after dental procedures.
  • Recent (within 6 weeks) or planned dental or jaw surgery (e.g. extraction, implants).
  • Pregnant patients (with a positive pregnancy test prior to study entry) or lactating patients. Women of childbearing potential not using effective methods of birth control (e.g. abstinence, oral contraceptives or implants, IUD, vaginal diaphragm or sponge, or condom with spermicide).
  • History of non-compliance to medical regimens or potential unreliable behavior.
  • Known sensitivity to study drug(s) or class of study drug(s).
  • Patients with severe medical condition(s) that in the view of the investigator prohibits participation in the study
  • Use of any other investigational agent in the last 30 days.
  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: NCT00375427

Locations
Italy
Novartis Investigative Site
Forlì, Italy
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

No publications provided

Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT00375427     History of Changes
Other Study ID Numbers: CZOL446EIT14
Study First Received: September 12, 2006
Results First Received: February 28, 2011
Last Updated: April 9, 2012
Health Authority: Italy: Ethics Committee

Keywords provided by Novartis:
Breast cancer
Zoledronic acid
Skeletal related events (SRE)

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasm Metastasis
Bone Neoplasms
Bone Marrow Diseases
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Neoplastic Processes
Pathologic Processes
Bone Diseases
Musculoskeletal Diseases
Hematologic Diseases
Zoledronic acid
Diphosphonates
Bone Density Conservation Agents
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on September 14, 2014