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

Study Description

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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.

Condition or disease	Intervention/treatment	Phase
Breast Adenocarcinoma; DS Stage I Plasma Cell Myeloma; DS Stage II Plasma Cell Myeloma; Metastatic Malignant Neoplasm to the Bone; Pain; Musculoskeletal Complication; Urinary Complications	Drug: zoledronic acid	Phase 3

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	1758 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Supportive Care
Official Title:	A Randomized, Phase III Study of Standard Dosing Versus Longer Dosing Interval of Zoledronic Acid in Metastatic Cancer
Study Start Date :	March 2009
Actual Primary Completion Date :	June 2014

Arms and Interventions

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Arm	Intervention/treatment
Experimental: 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.	Drug: zoledronic acid; Given IV
Experimental: 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.	Drug: zoledronic acid; Given IV

Outcome Measures

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Primary Outcome Measures :

1. Proportion of patients with at least one skeletal-related event (SRE) within 2 years after randomization [ Time Frame: 2 years ]

Secondary Outcome Measures :

1. Pain intensity score as assessed by the Brief Pain Inventory (BPI) questionnaire [ Time Frame: Up to 2 years ]
2. ECOG performance status [ Time Frame: Up to 2 years ]
3. Incidence of osteonecrosis of the jaw [ Time Frame: Up to 2 years ]
4. Incidence of renal dysfunction [ Time Frame: Up to 2 years ]
5. Skeletal morbidity rate [ Time Frame: 2 years ]
6. Bone turnover assessed by serum N-telopeptide (NTX) levels [ Time Frame: Up to 2 years ]
7. Proportion of patients having at least one SRE within 24 months after randomization for the subgroups of patients with breast cancer, prostate cancer, and multiple myeloma [ Time Frame: 24 months ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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

Contacts and Locations

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  Show 504 Study Locations

Sponsors and Collaborators

Alliance for Clinical Trials in Oncology

National Cancer Institute (NCI)

Investigators

Study Chair:	Andrew L. Himelstein, MD	Helen F. Graham Cancer Center at Christiana Hospital

More Information

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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Himelstein AL, Foster JC, Khatcheressian JL, Roberts JD, Seisler DK, Novotny PJ, Qin R, Go RS, Grubbs SS, O'Connor T, Velasco MR Jr, Weckstein D, O'Mara A, Loprinzi CL, Shapiro CL. Effect of Longer-Interval vs Standard Dosing of Zoledronic Acid on Skeletal Events in Patients With Bone Metastases: A Randomized Clinical Trial. JAMA. 2017 Jan 3;317(1):48-58. doi: 10.1001/jama.2016.19425.

Responsible Party:	Alliance for Clinical Trials in Oncology
ClinicalTrials.gov Identifier:	NCT00869206 History of Changes
Other Study ID Numbers:	CALGB-70604; CDR0000637947 ( Registry Identifier: NCI Physician Data Query ); NCI-2009-01102 ( Registry Identifier: NCI Clinical Trial Reporting Program ); U10CA037447 ( U.S. NIH Grant/Contract )
First Posted:	March 25, 2009
Last Update Posted:	October 5, 2016
Last Verified:	October 2016

Keywords provided by Alliance for Clinical Trials in Oncology:

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

Additional relevant MeSH terms:

Multiple Myeloma; Neoplasms, Plasma Cell; Adenocarcinoma; Neoplasms; Neoplasms, Second Primary; Bone Neoplasms; Bone Marrow Diseases; Neoplasm Metastasis; Neoplasms by Histologic Type; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases	Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Site; Bone Diseases; Musculoskeletal Diseases; Neoplastic Processes; Pathologic Processes; Zoledronic acid; Diphosphonates; Bone Density Conservation Agents; Physiological Effects of Drugs