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Zoledronic Acid

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.

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.

zoledronic acid

Andrew L. Himelstein, MD

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.

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.

Zoledronic Acid in Treating Patients With Metastatic Breast Cancer, Metastatic Prostate Cancer, or Multiple Myeloma With Bone Involvement

A Randomized, Phase III Study of Standard Dosing Versus Longer Dosing Interval of Zoledronic Acid in Metastatic Cancer

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

National Cancer Institute (NCI)

Alliance for Clinical Trials in Oncology

Arm I (Zoledronic Acid Every 4 Weeks)

Arm II (Zoledronic Acid Every 12 Weeks)

Total

Age, Continuous

Sex: Female, Male

United States

Region of Enrollment

All baseline patients demographics were analyzed.

All patients that were eligible and completed treatment were analyzed.

Percentage of Participants With at Least One Skeletal-related Event (SRE) Within 2 Years After Randomization

1766 patients completed treatment and were analyzed.

Average Pain Intensity Score as Assessed by the Brief Pain Inventory (BPI) Questionnaire

Average ECOG Performance Status

Incidence of Osteonecrosis of the Jaw

1689 patients completed treatment and were analyzed.

Incidence of Renal Dysfunction

Skeletal Morbidity Rate

Low CTX (<0.415ng/ml)

High CTX (>0.415ng/ml)

Patients with Breast Cancer 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.

Breast Cancer 4 Weeks

Breast Cancer 12 Weeks

266 breast cancer patients who were treated and included in this portion of the substudy.

Bone Turnover Assessed by Serum C-telopeptide (CTX) Levels (Breast Cancer)

820 patients completed treatment and were analyzed.

Proportion of Patients Having at Least One SRE Within 24 Months After Randomization for the Subgroups of Patients With Breast Cancer

Patients with Prostate Cancer 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.

Prostate Cancer 4 Weeks

Patients with Prostate Cancer 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.

Prostate Cancer 12 Weeks

660 patients completed treatment and were analyzed.

Proportion of Patients Having at Least One SRE Within 24 Months After Randomization for the Subgroups of Patients With Prostate Cancer

Multiple Myeloma 4 Weeks

Patients with Breast Cancer 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.

Multiple Myeloma 12 Weeks

265 patient completed treatment and were analyzed.

Proportion of Patients Having at Least One SRE Within 24 Months After Randomization for the Subgroups of Patients With Multiple Myeloma

High CTX (>.0.415ng/ml)

207 prostate cancer patients who were treated and included in this portion of the substudy.

Bone Turnover Assessed by Serum C-telopeptide (CTX) Levels (Prostate Cancer)

74 multiple myeloma patients were treated and included in this portion of the substudy.

Bone Turnover Assessed by Serum C-telopeptide (CTX) Levels (Multiple Myeloma)

Overall Study

Leukemia

Lymphoma

Lymphosarcoma

This is a study administering questionnaire and interviews using mixed quantitative and qualitative methodology with the aim to describe and evaluate musculoskeletal health of adult haematological cancer survivors and its impact to survivors.

Not an intervention study

Salina Tsui, MSc

Claire Higham, PhD

Salina Tsui

Haematological cancer treatment often includes use of high dose glucocorticoids (steroids), chemotherapy and radiotherapy and current evidence suggests that these patients may have lower bone mineral density after treatment when compared to the general population which can predispose them to increased risk of fragility fractures. Evidence of the impact of these musculoskeletal burden to patients (e.g. quality of life) are not available.

This study aims to describe musculoskeletal complications experienced by long-term haematological cancer survivors and examine the impact of the burden from the patient perspective. The study will be conducted in 2 parts; a questionnaire study and an interview study to help understand the extent of musculoskeletal problems experienced by this group of patients and the impact of this on quality of life.

Musculoskeletal Health in Adult Haematological Cancer Survivors

Musculoskeletal Health in Adult Haematoloigcal Cancer Survivors - a Mixed Methods Study

Musculoskeletal conditions and related symptoms will be recorded by patients on the study specific questionnaire and the validated questionnaire Nordic musculoskeletal questionnaire (NMQ-E) and gait, arms, legs and spine (GALS) assessment

The 10-year probability of hip fracture and major osteoporotic fracture (clinical spine, forearm, hip or shoulder fracture) of adult lymphoma and leukaemia survivors will be calculated using the Fracture Risk Assessment Tool (FRAX) and Q-Fracture calculator.

Validated questionniares will be used to assess if patients have sarcopenia (SARC-F questionnaire) and frailty (FiND questionnaire).

This will be assessed using validated questionnaires - Short Form Survey (SF36) and Short Musculoskeletal Function Assessment (SMFA).

Semi-structured qualitative interviews will be conducted with a topic guide to ensure same broad topics are explored in the interviews on musculoskeletal health experience, care and information provision.

This will be assessed using regression analysis to determine risk factors that may be associated with poor musculoskeletal health

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Zoledronic Acid in Treating Patients With Metastatic Breast Cancer, Metastatic Prostate Cancer, or Multiple Myeloma With Bone Involvement	NCT00869206	Breast Adenocar... DS Stage I Plas... DS Stage II Pla... Metastatic Mali... Pain Musculoskeletal... Urinary Complic...	zoledronic acid	18 Years -	Alliance for Clinical Trials in Oncology
Zoledronic Acid in Treating Patients With Metastatic Breast Cancer, Metastatic Prostate Cancer, or Multiple Myeloma With Bone Involvement	NCT00869206	Breast Adenocar... DS Stage I Plas... DS Stage II Pla... Metastatic Mali... Pain Musculoskeletal... Urinary Complic...	zoledronic acid	18 Years -	Alliance for Clinical Trials in Oncology
Musculoskeletal Health in Adult Haematological Cancer Survivors	NCT05865678	Lymphoma Leukemia Cancer Survivor... Musculoskeletal...	Not an interven...	18 Years -	The Christie NHS Foundation Trust

Spots Global Cancer Trial Database for musculoskeletal complication