Neoplasms

Symptoms and General Pathology

All Conditions

Skin and Connective Tissue Diseases

Nutritional and Metabolic Diseases

Neoplasm Metastasis

Breast Neoplasms

Recurrence

Pain

Hypercalcemia

Breast Diseases

Skin Diseases

Metabolic Diseases

Calcium Metabolism Disorders

Water-Electrolyte Imbalance

Bone Density Conservation Agents

All Drugs and Chemicals

Zoledronic Acid

Ibandronic Acid

ibandronate

zoledronate

quality-of-life assessment

Saul E. Rivkin, MD

Kathy S. Albain, MD

Dawn Hershman, MD

RATIONALE: Zoledronate and ibandronate may prevent or help relieve bone pain and other symptoms caused by bone metastases. It is not yet known whether zoledronate is more effective than ibandronate in preventing bone problems caused by bone metastases due to breast cancer.

PURPOSE: This randomized phase III trial is studying zoledronate to see how well it works compared to ibandronate in preventing bone problems in women with stage IV breast cancer that has spread to the bone.

OBJECTIVES:

Primary

* Compare the efficacy of zoledronate vs ibandronate, in terms of preventing the occurrence of skeletal-related events (SRE) (e.g., fracture, spinal cord compression, radiotherapy or surgery for bone symptoms or events, or hypercalcemia ≥ grade 3), in women with stage IV breast cancer and bone metastases.

Secondary

* Compare the change in patient-reported measures of pain and use of analgesics in patients treated with these drugs.
* Compare the time to first clinically apparent SRE in patients treated with these drugs.
* Compare the toxicity of these drugs.
* Compare the changes in performance status and overall survival of patients treated with these drugs.

OUTLINE: This is a multicenter, randomized study. Patients are stratified according to hormone receptor status (estrogen receptor \[ER\] and progesterone receptor \[PR\] negative vs ER and/or PR positive) and current evidence of fracture (vertebral or nonvertebral) or spinal compression (yes vs no). Patients are randomized to 1 of 2 treatment arms.

* Arm I: Patients receive oral ibandronate once daily on days 1-28.
* Arm II: Patients receive zoledronate IV over 15 minutes on day 1. In both arms, treatment repeats every 28 days for up to 18 courses in the absence of unacceptable toxicity.

Quality of life and pain are assessed at baseline, every 3 courses during study treatment, and at the end of study treatment.

After completion of study treatment, patients are followed periodically for up to 3 years.

PROJECTED ACCRUAL: A total of 488 patients will be accrued for this study.

S0308 Zoledronate or Ibandronate in Preventing Bone Problems in Women With Stage IV Breast Cancer That Has Spread to the Bone

A Phase III Randomized, Multicenter Non-Inferiority Trial Evaluating the Efficacy of Oral Ibandronate Versus Intravenous Zoledronate in the Reduction of Skeletal-Related Events in Patients With Metastatic Breast Cancer

National Cancer Institute (NCI)

SWOG Cancer Research Network

Blood and Lymph Conditions

Musculoskeletal Diseases

Hematologic Neoplasms

Bone Diseases

Bone Neoplasms

Neoplastic Processes

Participants will receive ibandronate, 6 mg via IV infusion, every 3 to 4 weeks for 4 months.

Participants will receive ibandronate, 50 mg PO daily, for 4 months.

Participants will receive ibandronate, either as a 6-mg IV infusion every 3 to 4 weeks or a 50-mg tablet PO daily, for 4 months.

Ibandronate

Clinical Trials

This study will assess the efficacy and safety of ibandronate (Bondronat), administered intravenously (IV) or orally (PO), in participants with malignant bone disease and moderate to severe pain. Participants will be randomized to receive ibandronate either as a 6-mg IV infusion every 3 to 4 weeks or a 50-mg tablet PO daily. Pain response and Karnofsky Performance Index (KPI) will be measured at intervals throughout the study. The anticipated time on study treatment is 4 months and the target sample size is 150 individuals.

A Study of Ibandronate (Bondronat) in Participants With Malignant Bone Disease

Randomized, Open Label Study to Assess the Efficacy and Safety of the Intravenous and Oral Ibandronic Acid for Improving the Performance Status of Patients With Malignant Bone Disease Secondary to Solid Tumors and Hematological Malignancies

Hoffmann-La Roche

Participants will receive ibandronate IV infusions over a 15-minute interval.

Participants will receive ibandronate IV infusions over a 60-minute interval.

Participants will receive ibandronate, 6 mg via IV infusion, every 3 weeks for up to 9 cycles. The infusion interval will be either 15 or 60 minutes depending upon treatment group assignment every 3 weeks (9 treatment cycles in total).

This study will evaluate renal function in participants with metastatic bone disease due to breast cancer receiving intravenous (IV) infusions of ibandronate (Bondronat) 6 milligrams (mg), over either 15 minutes or 60 minutes, every 3 weeks. Efficacy and safety of ibandronate in the 2 groups of participants will also be compared. The anticipated time on study treatment is 7 months, and the target sample size is 318 individuals.

A Study to Evaluate Renal Safety of Intravenous Ibandronate (Bondronat) in Participants With Metastatic Bone Disease Due to Breast Cancer

Randomized, Open Label Study to Evaluate Renal Safety of Intravenous Bondronat 6 mg Infusions Over 15 Minutes Versus 60 Minutes in Patients With Metastatic Bone Disease Due to Breast Cancer

Digestive System Diseases

Rare Diseases

Esophageal Neoplasms

Carcinoma

Adenocarcinoma

Osteoporosis

Carcinoma, Squamous Cell

Bone Diseases, Metabolic

Gastrointestinal Neoplasms

Digestive System Neoplasms

Head and Neck Neoplasms

Gastrointestinal Diseases

Esophageal Diseases

Esophageal Cancer

Channel Blockers

Etidronic Acid

Alendronate

Raloxifene Hydrochloride

Risedronic Acid

Calcium

Calcium Channel Blockers

Calcium, Dietary

Hormones

Estrogens

Estrogen Antagonists

Estrogen Receptor Antagonists

Hormone Antagonists

Selective Estrogen Receptor Modulators

Estrogen Receptor Modulators

Participants with any United Kingdom General Practice Research Database (GPRD) Medical code for esophageal cancer (cases). Cases were confirmed and case onset dates determined by electronic algorithm (based on electronic medical record data) or by medical record review.

Participants who were matched to cases by age and membership in the GPRD on the case's onset date, and had not experienced any form of esophageal cancer or Paget's Disease and had not received oral or intravenous steroids or chemotherapy or radiotherapy, as indicated by GPRD codes.

Participants who did not initiate treatment of osteoporosis with a study drug

Participants initiating treatment for osteoporosis with alendronate

Participants initiating treatment for osteoporosis with etidronate

Participants initiating treatment for osteoporosis with ibandronate

Participants initiating treatment for osteoporosis with risedronate

Participants initiating treatment for osteoporosis with raloxifene

Etidronate

Risedronate

Raloxifene

Alec Walker, MD, DrPH

This is a 2-phase retrospective database study, using both case-cohort and inception (intention-to-treat) cohort analyses to evaluate any association between oral treatments for osteoporosis and the risk of esophageal cancer in women.

Observational Study of Incidence Rates of Esophageal Cancer in Women Taking Medications for the Prevention or Treatment of Osteoporosis (MK-0217A-352)

The Risk of Esophageal Cancer in Relation to the Treatment and Prevention of Osteoporosis in Women

To determine the use of study drugs (alendronate, etidronate, ibandronate, risedronate, and raloxifene) among female participants with esophageal cancer (cases) and a comparison subcohort, a case-cohort analysis was performed using women meeting criteria from the General Practice Research Database (GPRD, United Kingdom). Exposure to osteoporosis drugs administered 720 days before cancer onset was determined in cases and compared to contemporaneous assessments in a comparison subcohort matched by year of birth and membership in the GPRD on the case's onset date. Cases were confirmed and case onset dates determined by electronic algorithm (based on electronic medical record data) or by medical record review.

To assess the relative risk of esophageal cancer associated with osteoporosis study drugs (alendronate, etidronate, ibandronate, risedronate, and raloxifene), initiators of osteoporosis drugs and non-initiators (comparators, women sharing match criteria with the initiator) entered an inception cohort for every three-month period, beginning in the first quarter of 1996. Assignment to study drug exposure group remained fixed from the start of follow-up, analogous to an intent-to-treat analysis. The risk of esophageal cancer among initiators of study drug compared to non-initiators of study drug was estimated through calculation of a hazard ratio. For calculation of 721+ day hazard ratios, only esophageal cancer cases occurring at least 721 days from initiation of study drug were used. For calculation of 1441+ day hazard ratios, only esophageal cancer cases occurring at least 1441 days from initiation of study drug were used.

World Health Information Science Consultants, LLC

Organon and Co

Adverse events were not collected during this study.

Overall Study Population

≥55

Age, Customized

Sex: Female, Male

Senior Vice President, Global Clinical Development

A hazard ratio estimate was calculated from the case-control matched set to measure the risk association between exposure to alendronate treatment and incidence of esophageal cancer.

A hazard ratio estimate was calculated from the case-control matched set to measure the risk association between exposure to etidronate treatment and incidence of esophageal cancer.

A hazard ratio estimate was calculated from the case-control matched set to measure the risk association between exposure to ibandronate treatment and incidence of esophageal cancer.

A hazard ratio estimate was calculated from the case-control matched set to measure the risk association between exposure to risedronate treatment and incidence of esophageal cancer.

A hazard ratio estimate was calculated from the case-control matched set to measure the risk association between exposure to raloxifene treatment and incidence of esophageal cancer.

Participants with any GPRD Medical Code for esophageal cancer (cases).

Esophageal Cancer Cohort

Comparison Sample (Case Cohort)

Case-Cohort analysis population came from the Overall Study Population and comprised 929 women with esophageal cancer (cases) and a Comparison Sample of 338,911 matched control women. Participants may have been exposed to more than one study drug. Also, one comparator may have been used for multiple study drugs.

Percentage of Participants With Exposure to Study Drugs (Case-Cohort Analysis)

A hazard ratio was calculated to estimate the risk of esophageal cancer among initiators of alendronate

compared to non-initiators of alendronate. For calculation of this hazard ratio, esophageal cancer cases occurring during the entire follow-up period were used.

A hazard ratio was calculated to estimate the risk of esophageal cancer among initiators of etidronate

compared to non-initiators of etidronate. For calculation of this hazard ratio, esophageal cancer cases occurring during the entire follow-up period were used.

A hazard ratio was calculated to estimate the risk of esophageal cancer among initiators of ibandronate

compared to non-initiators of ibandronate. For calculation of this hazard ratio, esophageal cancer cases occurring during the entire follow-up period were used.

A hazard ratio was calculated to estimate the risk of esophageal cancer among initiators of risendronate

compared to non-initiators of risendronate. For calculation of this hazard ratio, esophageal cancer cases occurring during the entire follow-up period were used.

A hazard ratio was calculated to estimate the risk of esophageal cancer among initiators of raloxifene

compared to non-initiators of raloxifene. For calculation of this hazard ratio, esophageal cancer cases occurring during the entire follow-up period were used.

A hazard ratio was calculated to estimate the risk of esophageal cancer among initiators of

alendronate compared to non-initiators of alendronate. For calculation of 721+ day hazard ratios, only esophageal cancer cases occurring at least 721 days from initiation of study drug (data not shown) were used.

A hazard ratio was calculated to estimate the risk of esophageal cancer among initiators of

etidronate compared to non-initiators of etidronate. For calculation of 721+ day hazard ratios, only

esophageal cancer cases occurring at least 721 days from initiation of study drug (data not shown) were used.

A hazard ratio was calculated to estimate the risk of esophageal cancer among initiators of

ibandronate compared to non-initiators of ibandronate. For calculation of 721+ day hazard ratios,

only esophageal cancer cases occurring at least 721 days from initiation of study drug (data not shown) were used.

A hazard ratio was calculated to estimate the risk of esophageal cancer among initiators of

risedronate compared to non-initiators of risedronate. For calculation of 721+ day hazard ratios,

only esophageal cancer cases occurring at least 721 days from initiation of study drug (data not shown) were used.

A hazard ratio was calculated to estimate the risk of esophageal cancer among initiators of

raloxifene compared to non-initiators of raloxifene. For calculation of 721+ day hazard ratios, only

esophageal cancer cases occurring at least 721 days from initiation of study drug (data not shown) were used.

A hazard ratio was calculated to estimate the risk of esophageal cancer among initiators of alendronate

compared to non-initiators of alendronate. For calculation of 1441+ day hazard ratios, only esophageal cancer cases occurring at least 1441 days from initiation of study drug (data not shown) were used.

A hazard ratio was calculated to estimate the risk of esophageal cancer among initiators of etidronate

compared to non-initiators of etidronate. For calculation of 1441+ day hazard ratios, only esophageal cancer cases occurring at least 1441 days from initiation of study drug (data not shown) were used.

A hazard ratio was calculated to estimate the risk of esophageal cancer among initiators of risedronate

compared to non-initiators of risedronate. For calculation of 1441+ day hazard ratios, only esophageal cancer cases occurring at least 1441 days from initiation of study drug (data not shown) were used.

A hazard ratio was calculated to estimate the risk of esophageal cancer among initiators of raloxifene

compared to non-initiators of raloxifene. For calculation of 1441+ day hazard ratios, only esophageal cancer cases occurring at least 1441 days from initiation of study drug (data not shown) were used.

Participants who did not initiate osteoporosis treatment with a study drug

Comparators

Participants who initiated osteoporosis treatment with alendronate

Participants who initiated osteoporosis treatment with etidronate

Participants who initiated osteoporosis treatment with ibandronate

Participants who initiated osteoporosis treatment with risedronate

Risendronate

Participants who initiated osteoporosis treatment with raloxifene

Inception Cohort came from the Overall Study Population beginning treatment with an osteoporosis study drug (initiators, 78,630 women) and 300,610 matched control women, who did not receive study drug (noninitiators). Participants may have been exposed to more than one study drug. Also, one comparator may have been used for multiple study drugs.

Number of Cases of Esophageal Cancer Per 100,000 Woman-Years (Intent-to-Treat Analysis)

Overall Study

Heart and Blood Diseases

Immune System Diseases

Multiple Myeloma

Neoplasms, Plasma Cell

Neoplasms by Histologic Type

Hemostatic Disorders

Blood Coagulation Disorders

Vascular Diseases

Paraproteinemias

Blood Protein Disorders

Hematologic Diseases

Hemorrhagic Disorders

Lymphoproliferative Disorders

Immunoproliferative Disorders

Participants with multiple myeloma will be randomized to receive ibandronate every 4 weeks for a planned duration of 92 weeks.

Participants with multiple myeloma will be randomized to receive zoledronate every 4 weeks for a planned duration of 92 weeks.

Ibandronate will be administered via 15-minute intravenous (IV) infusion as 6 milligrams (mg) every 4 weeks for 92 weeks.

Zoledronate will be administered via 15-minute IV infusion as 4 mg every 4 weeks for 92 weeks.

Zoledronate

This multicenter, open-label trial will randomize participants with multiple myeloma to a regimen of ibandronate or zoledronate in order to compare the incidence of nephrotoxicity, measured as creatinine clearance (CrCl) reduction greater than (\>) 30 percent (%) or an absolute value of 30 milliliters per minute (mL/min) or lower.

Comparison of Ibandronate - Zoledronate Regarding Nephrotoxicity in Multiple Myeloma

COMPARE: Comparison of Ibandronate - Zoledronate Regarding Nephrotoxicity in Patients With Multiple Myeloma

CrCl was calculated from blood samples using the Cockcroft-Gault formula. Relevant deterioration in renal function was defined as CrCl reduction of 30 percent (%) from Baseline or an absolute value less than or equal to (≤) 30 milliliters per minute (mL/min) at Week 44. The last available value on/before Week 44 was used in the calculation. The percentage of participants with deterioration in renal function at Week 44 was reported.

CrCl was calculated from blood samples using the Cockcroft-Gault formula. Relevant deterioration in renal function was defined as CrCl reduction of 30% from Baseline or an absolute value ≤30 mL/min at Week 92. The last available value on/before Week 92 was used in the calculation. The percentage of participants with deterioration in renal function at Week 92 was reported.

SREs were defined according to the Bondronat Summary of Product Characteristics (SmPC) to include radiotherapy to bone for treatment of fractures/impending fractures, surgery to bone for treatment of fractures, vertebral fractures, and non-vertebral fractures. The percentage of participants with at least 1 SRE during the study was reported.

SREs were defined according to the Bondronat SmPC to include radiotherapy to bone for treatment of fractures/impending fractures, surgery to bone for treatment of fractures, vertebral fractures, and non-vertebral fractures. Time to first SRE was defined as the time from first dose of study drug to the time of SRE during the study. The median time to first SRE was estimated by Kaplan-Meier analysis and expressed in days.

SREs were defined according to the Bondronat SmPC to include radiotherapy to bone for treatment of fractures/impending fractures, surgery to bone for treatment of fractures, vertebral fractures, and non-vertebral fractures. The number of SREs was averaged across all participants, including those participants who did not experience SREs during the study.

The percentage of participants with at least 1 event of osteonecrosis of jaw during the study was reported.

The number of events of osteonecrosis of jaw was averaged across all participants, including those participants who did not experience the event during the study.

The percentage of participants with at least 1 zoledronate dose reduction during the study was reported.

The number of zoledronate dose reductions was averaged across all participants, including those participants who did not have any dose reductions during the study.

The percent change in B-NAG was calculated as \[Week 44 or 92 B-NAG minus Baseline B-NAG\] divided by Baseline B-NAG, multiplied by 100. For the Week 44 analysis, the last available value on/before Week 44 was used in the calculation. For the Week 92 analysis, the last available value on/before Week 92 was used in the calculation.

The percent change in A1-microglobulin was calculated as \[Week 44 or 92 A1-microglobulin minus Baseline A1-microglobulin\] divided by Baseline A1-microglobulin, multiplied by 100. For the Week 44 analysis, the last available value on/before Week 44 was used in the calculation. For the Week 92 analysis, the last available value on/before Week 92 was used in the calculation.

The percent change in GGT was calculated as \[Week 44 or 92 GGT minus Baseline GGT\] divided by Baseline GGT, multiplied by 100. For the Week 44 analysis, the last available value on/before Week 44 was used in the calculation. For the Week 92 analysis, the last available value on/before Week 92 was used in the calculation.

Elevation in SCr was defined as an increase greater than (\>) 0.5 milligrams per deciliter (mg/dL) for participants with Baseline SCr less than (\<) 1.4 mg/dL, or an increase \>1.0 mg/dL for participants with Baseline SCr greater than or equal to (≥) 1.4 mg/dL. For the Week 44 analysis, the last available value on/before Week 44 was used. For the Week 92 analysis, the last available value on/before Week 92 was used. The percentage of participants with elevation of SCr at Weeks 44 and 92 was reported.

CrCl was calculated from blood samples using the Cockcroft-Gault formula, and was also measured by urinalysis. The percent change in CrCl was calculated as \[Week 44 or 92 CrCl minus Baseline CrCl\] divided by Baseline CrCl, multiplied by 100. For the Week 44 analysis, the last available value on/before Week 44 was used in the calculation. For the Week 92 analysis, the last available value on/before Week 92 was used in the calculation.

Roche Pharma AG

Safety Population: All participants who received at least one dose of study medication and completed at least one follow-up assessment visit.

Participants with multiple myeloma received ibandronate via 15-minute IV infusion as 6 mg every 4 weeks for up to 92 weeks. As a result of slow recruitment, the treatment duration was shortened to 40 weeks for participants who had not yet received 48 weeks of treatment. All participants returned for an additional follow-up observation 4 weeks after the end of treatment.

Participants with multiple myeloma received zoledronate via 15-minute IV infusion as 4 mg every 4 weeks for up to 92 weeks. As a result of slow recruitment, the treatment duration was shortened to 40 weeks for participants who had not yet received 48 weeks of treatment. All participants returned for an additional follow-up observation 4 weeks after the end of treatment.

Total

Age, Continuous

Intent-to-Treat (ITT) Population: All participants who were randomized and received at least one dose of study medication and for whom at least one measurement of creatinine clearance (CrCl) was obtained.

The Study was terminated as a result of slow recruitment. At the time of the decision to halt recruitment, the treatment duration was shortened to 40 weeks (instead of 92 weeks) for those participants who had not yet reached Week 48.

Medical Communications

Percentage of Participants With Deterioration in Renal Function According to Reduction in Creatinine Clearance (CrCl) From Baseline to Week 44

Percentage of Participants With Deterioration in Renal Function According to Reduction in CrCl From Baseline to Week 92

Percentage of Participants With Skeletal-Related Events (SREs)

Time to First SRE

Number of SREs for Each Participant

Percentage of Participants With Osteonecrosis of Jaw

Number of Events of Osteonecrosis of Jaw for Each Participant

ITT Population; only the Zoledronate arm was included.

Percentage of Participants With Zoledronate Dose Reduction

Number of Zoledronate Dose Reductions for Each Participant

Week 44

Week 92

ITT Population. The "Number of Participants Analyzed" reflects the total number of participants who provided evaluable data for the endpoint.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
S0308 Zoledronate or Ibandronate in Preventing Bone Problems in Women With Stage IV Breast Cancer That Has Spread to the Bone	NCT00301886	Breast Cancer Hypercalcemia o... Metastatic Canc... Pain	ibandronate zoledronate quality-of-life...	18 Years -	SWOG Cancer Research Network
A Study of Ibandronate (Bondronat) in Participants With Malignant Bone Disease	NCT02561039	Pain; Bone Neop...	Ibandronate	18 Years -	Hoffmann-La Roche
A Study to Evaluate Renal Safety of Intravenous Ibandronate (Bondronat) in Participants With Metastatic Bone Disease Due to Breast Cancer	NCT02716792	Pain; Bone Neop...	Ibandronate	18 Years -	Hoffmann-La Roche
Observational Study of Incidence Rates of Esophageal Cancer in Women Taking Medications for the Prevention or Treatment of Osteoporosis (MK-0217A-352)	NCT01077817	Esophageal Canc... Squamous Cell C... Adenocarcinoma	Alendronate Etidronate Ibandronate Risedronate Raloxifene	55 Years -	Organon and Co
Comparison of Ibandronate - Zoledronate Regarding Nephrotoxicity in Multiple Myeloma	NCT02739594	Multiple Myelom...	Ibandronate Zoledronate	18 Years -	Hoffmann-La Roche
A Study of Ibandronate (Bondronat) in Participants With Metastatic Bone Disease	NCT02564107	Pain; Bone Neop...	Ibandronate	18 Years -	Hoffmann-La Roche
S0308 Zoledronate or Ibandronate in Preventing Bone Problems in Women With Stage IV Breast Cancer That Has Spread to the Bone	NCT00301886	Breast Cancer Hypercalcemia o... Metastatic Canc... Pain	ibandronate zoledronate quality-of-life...	18 Years -	SWOG Cancer Research Network
A Study to Assess the Short Term Efficacy of Intravenous Ibandronate (Bondronat) in Participants With Metastatic Bone Pain Due to Breast Cancer	NCT02553707	Pain; Bone Neop...	Ibandronate	18 Years -	Hoffmann-La Roche
Observational Study of Incidence Rates of Esophageal Cancer in Women Taking Medications for the Prevention or Treatment of Osteoporosis (MK-0217A-352)	NCT01077817	Esophageal Canc... Squamous Cell C... Adenocarcinoma	Alendronate Etidronate Ibandronate Risedronate Raloxifene	55 Years -	Organon and Co
Prevention of Osteoporosis in Bone Marrow Transplantation (BMT) Patients	NCT00824993	Hematological M...	Ibandronate Vitamin Supplem...	18 Years -	M.D. Anderson Cancer Center

Spots Global Cancer Trial Database for ibandronate

Every month we try and update this database with for ibandronate cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for ibandronate

Every month we try and update this database with for ibandronate cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for ibandronate cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.