Breast Adenocarcinoma, DS Stage II Plasma Cell Myeloma, DS Stage I Plasma Cell Myeloma, Metastatic Malignant Neoplasm to the Bone, Musculoskeletal Complication, Pain, Urinary Complications
Conditions
Keywords
pain, Prostate Adenocarcinoma, urinary complications, stage IV breast cancer, Recurrent Breast Carcinoma, stage IV prostate cancer, recurrent prostate cancer, Recurrent Prostate Carcinoma, stage I multiple myeloma, stage II multiple myeloma, Refractory Plasma Cell Myeloma, bone metastases
Brief summary
This randomized phase III trial studies two different schedules of zoledronic acid to compare how well they work in reducing bone-related complications in patients with breast cancer, prostate cancer, or multiple myeloma that has spread to other places in the body and have bone involvement. Bone-related complications are a major cause of morbidity in patients with metastatic prostate cancer, breast cancer, and multiple myeloma. Zoledronic acid may stop the growth of cancer cells in the bone and may help relieve some of the symptoms caused by bone metastases. It is not yet known whether giving zoledronic acid more or less frequently is more effective in treating patients with metastatic cancer that has spread to the bone.
Detailed description
PRIMARY OBJECTIVES: I. To determine whether every-12-week therapy with zoledronic acid is not inferior to every-4-week therapy for patients with metastatic breast cancer, metastatic prostate cancer, or multiple myeloma involving bone, as measured by the proportion who experience at least one skeletal related event within 24 months after randomization. SECONDARY OBJECTIVES: I. To compare pain scores (Brief Pain Inventory) of patients with metastatic breast cancer, metastatic prostate cancer, or myeloma involving bone receiving every 12 week dosing of zoledronic acid to those receiving every 4 week dosing. II. To compare the functional status (Eastern Cooperative Oncology Group \[ECOG\] performance status) of patients with metastatic breast cancer, metastatic prostate cancer, or myeloma involving bone receiving every 12 week dosing of zoledronic acid to those receiving every 4 week dosing. III. To compare the incidence of osteonecrosis of the jaw in patients with metastatic breast cancer, metastatic prostate cancer, or myeloma involving bone receiving every 12 week dosing of zoledronic acid to those receiving every 4 week dosing. IV. To compare the incidence of renal dysfunction in patients with metastatic breast cancer, metastatic prostate cancer, or myeloma involving bone receiving every 12 week dosing of zoledronic acid to those receiving every 4 week dosing. V. To compare the skeletal morbidity rate of these patients, defined as the number of skeletal-related events per year, of patients receiving every 12 week dosing to those receiving every 4 week dosing. VI. To compare the suppression of serum markers of bone resorption of patients with metastatic breast cancer, metastatic prostate cancer, or myeloma involving bone receiving every 12 week dosing of zoledronic acid to those receiving every 4 week dosing. VII. To determine whether every 12 week therapy with zoledronic acid is not inferior to every-4-week therapy for each subgroup of patients with either breast cancer, prostate cancer, or multiple myeloma, as measured by the proportion who experience at least one skeletal related event within 24 months after randomization. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive zoledronic acid intravenously (IV) over at least 15 minutes every 4 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive zoledronic acid IV over at least 15 minutes every 12 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 4 weeks for 2 years from registration.
Interventions
DRUGzoledronic acid
Given IV
Sponsors
National Cancer Institute (NCI)
Alliance for Clinical Trials in Oncology
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Eligibility Criteria: * Histologic documentation of one of the following: breast adenocarcinoma, prostate adenocarcinoma or multiple myeloma * At least one site of bone metastasis or bone involvement by radiologic imaging including plain radiograph, computed tomography (CT), positron emission tomography (PET) scan, PET/CT scan, magnetic resonance imaging, bone scan, or skeletal survey; indeterminate lesions should be confirmed by a second imaging method * No prior treatment with IV bisphosphonates is allowed; prior treatment with oral bisphosphonates is allowed, but they must be discontinued prior to the initiation of protocol therapy * No prior treatment with denosumab * No prior treatment with radiopharmaceuticals; prior treatment with radioactive iodine is allowed; prostate cancer patients treated with brachytherapy are eligible * Prior radiation therapy to bone is allowed, provided that at least one site of bone metastasis has not been irradiated and radiation is completed prior to registration; there should be no plan for radiation therapy to non-irradiated sites of bone metastases * Prior adjuvant and metastatic chemotherapy, biologic therapy, and endocrine therapy is allowed * No current treatment with investigational agent(s) * Patients with known brain metastases are not eligible; patients who develop brain metastases during the study will be allowed to continue treatment as assigned * Not pregnant and not nursing * ECOG performance status 0-2 * 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) \* Corrected serum calcium should be calculated using standard institutional practices
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With at Least One Skeletal-related Event (SRE) Within 2 Years After Randomization | 2 years | To determine whether every-12-week therapy with zoledronic acid is not inferior to every-4-week therapy for patients with metastatic breast cancer, metastatic prostate cancer, or multiple myeloma involving bone, as measured by the proportion of patients who would have experienced at least one skeletal related event within 24 months after randomization. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Average ECOG Performance Status | from baseline up to 2 years | To compare functional status (ECOG performance status) of patients with metastatic breast cancer, metastatic prostate cancer, or myeloma involving bone receiving every 12 week dosing of zoledronic acid to those receiving every 4 week dosing. The change scores were evaluated in a general linear model with repeated measures for treatment effect and the time trend with patient-specific characteristics being adjusted. Specifically the difference in score change per 4 weeks for Arm I using Arm II as the reference is reported. ECOG performance status is a measurement of a patients disability ranging from 0, fully active and able to carry out all pre disease performance without restriction, to 5, dead. The average performance status is reported below by arm. |
| Incidence of Osteonecrosis of the Jaw | from baseline up to 2 years | To compare the incidence of osteonecrosis of the jaw in patients with metastatic breast cancer, metastatic prostate cancer, or myeloma involving bone receiving every 12 week dosing of zoledronic acid to those receiving every 4 week dosing. The percentage of participants with osteonecrosis is reported here. |
| Incidence of Renal Dysfunction | from baseline up to 2 years | To compare the incidence of renal dysfunction of patients with metastatic breast cancer, metastatic prostate cancer, or myeloma involving bone receiving every 12 week dosing of zoledronic acid to those receiving every 4 week dosing. The percentage of patients with renal dysfunction, defined as grade 3 or grade 4 increased creatinine (Common Terminology Criteria for Adverse Events version 3.0), will be reported here. |
| Skeletal Morbidity Rate | from baseline up to 2 years | To compare the skeletal morbidity rate, defined as the number of skeletal-related events per year, of patients receiving every 12 week dosing to those receiving every 4 week dosing. |
| Bone Turnover Assessed by Serum C-telopeptide (CTX) Levels (Breast Cancer) | from baseline up to 2 years | To compare the suppression of serum markers of bone resorption of patients with metastatic breast cancer, metastatic prostate cancer, or myeloma involving bone receiving every 12 week dosing of zoledronic acid to those receiving every 4 week dosing. The number of patients with high & low CTX values by arm will be reported here. |
| Average Pain Intensity Score as Assessed by the Brief Pain Inventory (BPI) Questionnaire | from baseline up to 2 years | To compare pain scores (Brief Pain Inventory) of patients with metastatic breast cancer, metastatic prostate cancer, or myeloma involving bone receiving every 12 week dosing of zoledronic acid to those receiving every 4 week dosing. The change scores were evaluated in a general linear model with repeated measures for treatment effect and the time trend with patient-specific characteristics being adjusted for the mean interference score. Specifically the difference in score change per 4 weeks for Arm I using Arm II as the reference is reported. The score of the BPI questionnaire ranges from 0 being no pain to 10 being the most pain. The average score is reported for each arm below. |
| Proportion of Patients Having at Least One SRE Within 24 Months After Randomization for the Subgroups of Patients With Prostate Cancer | from baseline up to 24 months | To determine whether every 12 week therapy with zoledronic acid is not inferior to every-4-week therapy for patients with prostate cancer, as measured by the proportion who experience at least one skeletal related event within 24 months after randomization. |
| Proportion of Patients Having at Least One SRE Within 24 Months After Randomization for the Subgroups of Patients With Multiple Myeloma | from baseline up to 24 months | To determine whether every 12 week therapy with zoledronic acid is not inferior to every-4-week therapy for patients with multiple myeloma, as measured by the proportion who experience at least one skeletal related event within 24 months after randomization. |
| Bone Turnover Assessed by Serum C-telopeptide (CTX) Levels (Prostate Cancer) | from baseline up to 24 months | To compare the suppression of serum markers of bone resorption of patients with metastatic breast cancer, metastatic prostate cancer, or myeloma involving bone receiving every 12 week dosing of zoledronic acid to those receiving every 4 week dosing. The number of patients with high & low CTX values by arm will be reported here. |
| Bone Turnover Assessed by Serum C-telopeptide (CTX) Levels (Multiple Myeloma) | from baseline up to 24 months | To compare the suppression of serum markers of bone resorption of patients with metastatic breast cancer, metastatic prostate cancer, or myeloma involving bone receiving every 12 week dosing of zoledronic acid to those receiving every 4 week dosing. The number of patients with high & low CTX values by arm will be reported here. |
| Proportion of Patients Having at Least One SRE Within 24 Months After Randomization for the Subgroups of Patients With Breast Cancer | from baseline up to 24 months | To determine whether every 12 week therapy with zoledronic acid is not inferior to every-4-week therapy for patients with breast cancer, as measured by the proportion who experience at least one skeletal related event within 24 months after randomization. |
Countries
Puerto Rico, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm I (Zoledronic Acid Every 4 Weeks) Patients receive zoledronic acid IV over at least 15 minutes every 4 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity. | 911 |
| Arm II (Zoledronic Acid Every 12 Weeks) Patients receive zoledronic acid IV over at least 15 minutes every 12 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity. | 911 |
| Total | 1,822 |
Baseline characteristics
| Characteristic | Arm I (Zoledronic Acid Every 4 Weeks) | Arm II (Zoledronic Acid Every 12 Weeks) | Total |
|---|---|---|---|
| Age, Continuous | 65.3 years STANDARD_DEVIATION 12.1 | 65.3 years STANDARD_DEVIATION 11.7 | 65.3 years STANDARD_DEVIATION 11.9 |
| Region of Enrollment United States | 911 participants | 911 participants | 1822 participants |
| Sex: Female, Male Female | 414 Participants | 428 Participants | 842 Participants |
| Sex: Female, Male Male | 497 Participants | 483 Participants | 980 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 41 / 879 | 42 / 868 |
| other Total, other adverse events | 779 / 879 | 750 / 868 |
| serious Total, serious adverse events | 96 / 879 | 103 / 868 |
Outcome results
Primary
Percentage of Participants With at Least One Skeletal-related Event (SRE) Within 2 Years After Randomization
To determine whether every-12-week therapy with zoledronic acid is not inferior to every-4-week therapy for patients with metastatic breast cancer, metastatic prostate cancer, or multiple myeloma involving bone, as measured by the proportion of patients who would have experienced at least one skeletal related event within 24 months after randomization.
Time frame: 2 years
Population: All patients that were eligible and completed treatment were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Zoledronic Acid Every 4 Weeks) | Percentage of Participants With at Least One Skeletal-related Event (SRE) Within 2 Years After Randomization | 67.6 percentage of participants |
| Arm II (Zoledronic Acid Every 12 Weeks) | Percentage of Participants With at Least One Skeletal-related Event (SRE) Within 2 Years After Randomization | 67.9 percentage of participants |
p-value: <=0.05Cochran-Mantel-Haenszel
Secondary
Average ECOG Performance Status
To compare functional status (ECOG performance status) of patients with metastatic breast cancer, metastatic prostate cancer, or myeloma involving bone receiving every 12 week dosing of zoledronic acid to those receiving every 4 week dosing. The change scores were evaluated in a general linear model with repeated measures for treatment effect and the time trend with patient-specific characteristics being adjusted. Specifically the difference in score change per 4 weeks for Arm I using Arm II as the reference is reported. ECOG performance status is a measurement of a patients disability ranging from 0, fully active and able to carry out all pre disease performance without restriction, to 5, dead. The average performance status is reported below by arm.
Time frame: from baseline up to 2 years
Population: 1766 patients completed treatment and were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (Zoledronic Acid Every 4 Weeks) | Average ECOG Performance Status | 0.82 score on a scale | Standard Error 0.042 |
| Arm II (Zoledronic Acid Every 12 Weeks) | Average ECOG Performance Status | 0.84 score on a scale | Standard Error 0.042 |
p-value: 0.64Mixed Models Analysis
Secondary
Average Pain Intensity Score as Assessed by the Brief Pain Inventory (BPI) Questionnaire
To compare pain scores (Brief Pain Inventory) of patients with metastatic breast cancer, metastatic prostate cancer, or myeloma involving bone receiving every 12 week dosing of zoledronic acid to those receiving every 4 week dosing. The change scores were evaluated in a general linear model with repeated measures for treatment effect and the time trend with patient-specific characteristics being adjusted for the mean interference score. Specifically the difference in score change per 4 weeks for Arm I using Arm II as the reference is reported. The score of the BPI questionnaire ranges from 0 being no pain to 10 being the most pain. The average score is reported for each arm below.
Time frame: from baseline up to 2 years
Population: 1766 patients completed treatment and were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (Zoledronic Acid Every 4 Weeks) | Average Pain Intensity Score as Assessed by the Brief Pain Inventory (BPI) Questionnaire | 2.06 score on a scale | Standard Error 0.14 |
| Arm II (Zoledronic Acid Every 12 Weeks) | Average Pain Intensity Score as Assessed by the Brief Pain Inventory (BPI) Questionnaire | 2.09 score on a scale | Standard Error 0.14 |
p-value: 0.68Mixed Models Analysis
Secondary
Bone Turnover Assessed by Serum C-telopeptide (CTX) Levels (Breast Cancer)
To compare the suppression of serum markers of bone resorption of patients with metastatic breast cancer, metastatic prostate cancer, or myeloma involving bone receiving every 12 week dosing of zoledronic acid to those receiving every 4 week dosing. The number of patients with high & low CTX values by arm will be reported here.
Time frame: from baseline up to 2 years
Population: 266 breast cancer patients who were treated and included in this portion of the substudy.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm I (Zoledronic Acid Every 4 Weeks) | Bone Turnover Assessed by Serum C-telopeptide (CTX) Levels (Breast Cancer) | Low CTX (<0.415ng/ml) | 83 Participants |
| Arm I (Zoledronic Acid Every 4 Weeks) | Bone Turnover Assessed by Serum C-telopeptide (CTX) Levels (Breast Cancer) | High CTX (>0.415ng/ml) | 54 Participants |
| Arm II (Zoledronic Acid Every 12 Weeks) | Bone Turnover Assessed by Serum C-telopeptide (CTX) Levels (Breast Cancer) | High CTX (>0.415ng/ml) | 54 Participants |
| Arm II (Zoledronic Acid Every 12 Weeks) | Bone Turnover Assessed by Serum C-telopeptide (CTX) Levels (Breast Cancer) | Low CTX (<0.415ng/ml) | 75 Participants |
Secondary
Bone Turnover Assessed by Serum C-telopeptide (CTX) Levels (Multiple Myeloma)
To compare the suppression of serum markers of bone resorption of patients with metastatic breast cancer, metastatic prostate cancer, or myeloma involving bone receiving every 12 week dosing of zoledronic acid to those receiving every 4 week dosing. The number of patients with high & low CTX values by arm will be reported here.
Time frame: from baseline up to 24 months
Population: 74 multiple myeloma patients were treated and included in this portion of the substudy.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm I (Zoledronic Acid Every 4 Weeks) | Bone Turnover Assessed by Serum C-telopeptide (CTX) Levels (Multiple Myeloma) | Low CTX (<0.415ng/ml) | 15 Participants |
| Arm I (Zoledronic Acid Every 4 Weeks) | Bone Turnover Assessed by Serum C-telopeptide (CTX) Levels (Multiple Myeloma) | High CTX (>.0.415ng/ml) | 23 Participants |
| Arm II (Zoledronic Acid Every 12 Weeks) | Bone Turnover Assessed by Serum C-telopeptide (CTX) Levels (Multiple Myeloma) | Low CTX (<0.415ng/ml) | 19 Participants |
| Arm II (Zoledronic Acid Every 12 Weeks) | Bone Turnover Assessed by Serum C-telopeptide (CTX) Levels (Multiple Myeloma) | High CTX (>.0.415ng/ml) | 17 Participants |
Secondary
Bone Turnover Assessed by Serum C-telopeptide (CTX) Levels (Prostate Cancer)
To compare the suppression of serum markers of bone resorption of patients with metastatic breast cancer, metastatic prostate cancer, or myeloma involving bone receiving every 12 week dosing of zoledronic acid to those receiving every 4 week dosing. The number of patients with high & low CTX values by arm will be reported here.
Time frame: from baseline up to 24 months
Population: 207 prostate cancer patients who were treated and included in this portion of the substudy.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm I (Zoledronic Acid Every 4 Weeks) | Bone Turnover Assessed by Serum C-telopeptide (CTX) Levels (Prostate Cancer) | Low CTX (<0.415ng/ml) | 34 Participants |
| Arm I (Zoledronic Acid Every 4 Weeks) | Bone Turnover Assessed by Serum C-telopeptide (CTX) Levels (Prostate Cancer) | High CTX (>.0.415ng/ml) | 70 Participants |
| Arm II (Zoledronic Acid Every 12 Weeks) | Bone Turnover Assessed by Serum C-telopeptide (CTX) Levels (Prostate Cancer) | Low CTX (<0.415ng/ml) | 49 Participants |
| Arm II (Zoledronic Acid Every 12 Weeks) | Bone Turnover Assessed by Serum C-telopeptide (CTX) Levels (Prostate Cancer) | High CTX (>.0.415ng/ml) | 54 Participants |
Secondary
Incidence of Osteonecrosis of the Jaw
To compare the incidence of osteonecrosis of the jaw in patients with metastatic breast cancer, metastatic prostate cancer, or myeloma involving bone receiving every 12 week dosing of zoledronic acid to those receiving every 4 week dosing. The percentage of participants with osteonecrosis is reported here.
Time frame: from baseline up to 2 years
Population: 1766 patients completed treatment and were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Zoledronic Acid Every 4 Weeks) | Incidence of Osteonecrosis of the Jaw | 2.0 percentage of participants |
| Arm II (Zoledronic Acid Every 12 Weeks) | Incidence of Osteonecrosis of the Jaw | 1.0 percentage of participants |
Secondary
Incidence of Renal Dysfunction
To compare the incidence of renal dysfunction of patients with metastatic breast cancer, metastatic prostate cancer, or myeloma involving bone receiving every 12 week dosing of zoledronic acid to those receiving every 4 week dosing. The percentage of patients with renal dysfunction, defined as grade 3 or grade 4 increased creatinine (Common Terminology Criteria for Adverse Events version 3.0), will be reported here.
Time frame: from baseline up to 2 years
Population: 1689 patients completed treatment and were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Zoledronic Acid Every 4 Weeks) | Incidence of Renal Dysfunction | 1.2 percentage of participants |
| Arm II (Zoledronic Acid Every 12 Weeks) | Incidence of Renal Dysfunction | .5 percentage of participants |
p-value: 0.195% CI: [-0.3, 1.7]Cochran-Mantel-Haenszel
Secondary
Proportion of Patients Having at Least One SRE Within 24 Months After Randomization for the Subgroups of Patients With Breast Cancer
To determine whether every 12 week therapy with zoledronic acid is not inferior to every-4-week therapy for patients with breast cancer, as measured by the proportion who experience at least one skeletal related event within 24 months after randomization.
Time frame: from baseline up to 24 months
Population: 820 patients completed treatment and were analyzed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I (Zoledronic Acid Every 4 Weeks) | Proportion of Patients Having at Least One SRE Within 24 Months After Randomization for the Subgroups of Patients With Breast Cancer | 113 Participants |
| Arm II (Zoledronic Acid Every 12 Weeks) | Proportion of Patients Having at Least One SRE Within 24 Months After Randomization for the Subgroups of Patients With Breast Cancer | 119 Participants |
Secondary
Proportion of Patients Having at Least One SRE Within 24 Months After Randomization for the Subgroups of Patients With Multiple Myeloma
To determine whether every 12 week therapy with zoledronic acid is not inferior to every-4-week therapy for patients with multiple myeloma, as measured by the proportion who experience at least one skeletal related event within 24 months after randomization.
Time frame: from baseline up to 24 months
Population: 265 patient completed treatment and were analyzed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I (Zoledronic Acid Every 4 Weeks) | Proportion of Patients Having at Least One SRE Within 24 Months After Randomization for the Subgroups of Patients With Multiple Myeloma | 35 Participants |
| Arm II (Zoledronic Acid Every 12 Weeks) | Proportion of Patients Having at Least One SRE Within 24 Months After Randomization for the Subgroups of Patients With Multiple Myeloma | 30 Participants |
Secondary
Proportion of Patients Having at Least One SRE Within 24 Months After Randomization for the Subgroups of Patients With Prostate Cancer
To determine whether every 12 week therapy with zoledronic acid is not inferior to every-4-week therapy for patients with prostate cancer, as measured by the proportion who experience at least one skeletal related event within 24 months after randomization.
Time frame: from baseline up to 24 months
Population: 660 patients completed treatment and were analyzed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I (Zoledronic Acid Every 4 Weeks) | Proportion of Patients Having at Least One SRE Within 24 Months After Randomization for the Subgroups of Patients With Prostate Cancer | 107 Participants |
| Arm II (Zoledronic Acid Every 12 Weeks) | Proportion of Patients Having at Least One SRE Within 24 Months After Randomization for the Subgroups of Patients With Prostate Cancer | 101 Participants |
Secondary
Skeletal Morbidity Rate
To compare the skeletal morbidity rate, defined as the number of skeletal-related events per year, of patients receiving every 12 week dosing to those receiving every 4 week dosing.
Time frame: from baseline up to 2 years
Population: 1766 patients were treated and analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (Zoledronic Acid Every 4 Weeks) | Skeletal Morbidity Rate | .4 SRE's per year | Standard Deviation 1 |
| Arm II (Zoledronic Acid Every 12 Weeks) | Skeletal Morbidity Rate | .4 SRE's per year | Standard Deviation 1.1 |