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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Breast Cancer With Bone Metastasis

Intervention / Treatment
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* Drug: Zoledronic acid


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Every 3 months<br>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<br>* 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.<br>* Other names: Zometa®;|
| Experimental: Every 4 weeks<br>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<br>* 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.<br>* Other names: Zometa®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annual Overall Skeletal Morbidity Rate (SMR) | 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. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Experiencing Skeletal Related Event(s) (SREs) | 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. | 12 month | 
| Annual Incidence of Any Skeletal Related Events (SREs) | 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. | 12 months | 
| Median Time to First Skeletal Related Event(s) (SRE) | 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. | 12 month | 
| Percentage of Participants Skeletal Related Event (SRE) Free | 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. | 12 months | 
| Composite Bone Pain Score According to the Brief Pain Inventory (BPI) Questionnaire | 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 | At Baseline, Month 3, Month 6, Month 9 and Month 12 | 
| Evaluation of Pain According to Verbal Rating Scale (VRS) Based on Median Score Value | 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. | At Baseline, Month 3, Month 6, Month 9 and Month 12 | 
| Use Of Analgesic Medications According to the Analgesic Score Scale | 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 = Minor analgesics (aspirin, NSAID, acetaminophen, propoxyphene, etc.) = Tranquilisers, antidepressants, muscle relaxants, and steroids = Mild narcotics (oxycodone, meperidine, codeine, etc.) = 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 | At Baseline, Month 3, Month 6, Month 9 and Month 12 | 
| Assessment of the Eastern Cooperative Oncology Group (ECOG) Performance Score | 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 | At Baseline, Month 3, Month 6, Month 9 and Month 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast cancer, Zoledronic acid, Skeletal related events (SRE)