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Denosumab Compared to Zoledronic Acid in the Treatment of Bone Disease in Patients With Multiple Myeloma

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ClinicalTrials.gov Identifier: NCT01345019
Recruitment Status : Completed
First Posted : April 29, 2011
Results First Posted : March 7, 2018
Last Update Posted : March 31, 2020
Sponsor:
Collaborator:
Daiichi Sankyo, Inc.
Information provided by (Responsible Party):
Amgen

Study Description
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Brief Summary:
The purpose of this study is to determine if denosumab is non-inferior to zoledronic acid in the treatment of bone disease from multiple myeloma.

Condition or disease Intervention/treatment Phase
Cancer Hematologic Malignancies Multiple Myeloma Oncology Bone Metastases Multiple Myeloma Bone Lesions Drug: Denosumab Drug: Zoledronic acid Drug: Placebo to Denosumab Drug: Placebo to zoledronic acid Drug: Denosumab (for the open-label treatment phase) Phase 3

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 1718 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Supportive Care
Official Title: A Randomized, Double-Blind, Multicenter Study of Denosumab Compared With Zoledronic Acid in the Treatment of Bone Disease in Subjects With Newly Diagnosed Multiple Myeloma
Actual Study Start Date : May 17, 2012
Actual Primary Completion Date : July 19, 2016
Actual Study Completion Date : March 29, 2019

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Arms and Interventions
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Arm Intervention/treatment
Active Comparator: Zoledronic acid
Zoledronic acid 4 mg intravenously plus placebo to denosumab subcutaniously (SC) once every 4 weeks (Q4W) in the double-blind treatment period (Since denosumab was determined to have a positive benefit:risk profile in the primary analysis of the study, per protocol, participants who were still undergoing Q4W scheduled assessments were offered open-label denosumab 120 mg SC Q4W for up to 2 years)
 Drug: Zoledronic acid
Administered by intravenous infusion over 15 minutes once every 4 weeks
Other Name: Zometa®

Drug: Placebo to Denosumab
Administered by subcutaneous injection once every 4 weeks.

Drug: Denosumab (for the open-label treatment phase)
Administered by subcutaneous injection once every 4 weeks.
Other Names:
  • XGEVA®
  • AMG 162
Experimental: Denosumab
Denosumab 120 mg subcutaniously (SC) plus placebo to zoledronic acid intravenously once every 4 weeks (Q4W) in the double-blind treatment period (Since denosumab was determined to have a positive benefit:risk profile in the primary analysis of the study, per protocol, participants who were still undergoing Q4W scheduled assessments were offered open-label denosumab 120 mg SC Q4W for up to 2 years)
 Drug: Denosumab
Administered by subcutaneous injection once every 4 weeks.
Other Names:
  • XGEVA®
  • AMG 162

Drug: Placebo to zoledronic acid
Administered by intravenous infusion over 15 minutes once every 4 weeks

Drug: Denosumab (for the open-label treatment phase)
Administered by subcutaneous injection once every 4 weeks.
Other Names:
  • XGEVA®
  • AMG 162


Outcome Measures
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Primary Outcome Measures :
  1. Time to First On-study Skeletal Related Event [ Time Frame: From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively. ]
    A skeletal-related event (SRE) is defined as one of the following: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression. Time to first on-study SRE is defined as the time interval (in days) from the randomization date to the date of first occurrence of on-study SRE. If there was no known event, and the participant was monitored for any one of the four SRE components, time to first on-study SRE was censored at the end of the treatment phase date or the primary analysis data cut-off date, whichever came first.

  2. Percentage of Participants With an On-study Skeletal Related Event [ Time Frame: From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively. ]
    A skeletal-related event (SRE) is defined as one of the following: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression.

  3. Kaplan-Meier Estimate of Percentage of Participants With an On-study Skeletal Related Event [ Time Frame: From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively. The Kaplan-Meier estimate at weeks 25, 49 and 109 is reported. ]
    A skeletal-related event (SRE) is defined as one of the following: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression.


Secondary Outcome Measures :
  1. Time to First On-study Skeletal Related Event - Superiority Analysis [ Time Frame: From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively. ]
    A skeletal-related event (SRE) is defined as one of the following: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression. Time to first on-study SRE is defined as the time interval (in days) from the randomization date to the date of first occurrence of on-study SRE. If there was no known event, and the participant was monitored for any one of the four SRE components, time to first on-study SRE was censored at the end of the treatment phase date or the primary analysis data cut-off date, whichever came first.

  2. Time to First and Subsequent On-Study Skeletal Related Event - Number of Events Per Patient [ Time Frame: From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively. ]

    A skeletal-related event (SRE) is defined as one of the following: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression. Time to first on-study SRE is defined as the time interval (in days) from the randomization date to the date of first occurrence of on-study SRE. Time to a subsequent SRE is defined, similarly to the time to first on-study SRE, as the time interval from the randomization date to the date of a subsequent occurrence of on-study SRE, which had to be at least 21 days after the previous SRE.

    A multiple event analysis was used, which accounts for both the absolute number of SREs and for the time between two consecutive events, and therefore, provides a more sensitive assessment of the risk of experiencing an SRE. The average number of events per patient is reported.


  3. Time to First and Subsequent On-Study Skeletal Related Event - Number of Events [ Time Frame: From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively. ]

    A skeletal-related event (SRE) is defined as one of the following: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression. Time to first on-study SRE is defined as the time interval (in days) from the randomization date to the date of first occurrence of on-study SRE. Time to a subsequent SRE is defined, similarly to the time to first on-study SRE, as the time interval from the randomization date to the date of a subsequent occurrence of on-study SRE, which had to be at least 21 days after the previous SRE.

    A multiple event analysis was used, which accounts for both the absolute number of SREs and for the time between two consecutive events, and therefore, provides a more sensitive assessment of the risk of experiencing an SRE. The total number of events is reported.


  4. Overall Survival [ Time Frame: From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively. ]
    Overall survival was defined as the time interval (in days) from the randomization date to the date of death. If a participant was still alive at the primary analysis data cut-off date or was lost to follow-up by the primary analysis data cut-off date, survival time was censored at their last contact date or the primary analysis data cut-off date, whichever was first.

  5. Percentage of Participants Who Died [ Time Frame: From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively. ]

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

Inclusion Criteria:

  • Documented evidence of multiple myeloma (per local assessment):
  • Monoclonal plasma cells in the bone marrow greater than or equal to 10% and/or presence of a biopsy-proven plasmacytoma, and
  • Monoclonal protein present in the serum and/or urine
  • Radiographic (X-ray, or computer tomography [CT]) evidence of at least 1 lytic bone lesion (or at least 1 focal lesion per magnetic resonance imaging [MRI])
  • Plan to receive or is receiving primary frontline anti-myeloma therapies
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
  • Age ≥ 18 years

  • Adequate organ function, as defined by the following criteria (per central or local laboratory values):

    • Serum aspartate aminotransferase (AST) ≤ 2.0 x upper limit of normal (ULN)
    • Serum alanine aminotransferase ≤ (ALT) 2.0 x ULN
    • Serum total bilirubin ≤ 2.0 x ULN
    • Creatinine clearance ≥ 30 mL/min
    • Serum calcium or albumin-adjusted serum calcium 2.0 mmol/L (8.0 mg/dL) and 2.9 mmol/L (11.5 mg/dL)
  • Written informed consent before any study-specific procedure is performed

Exclusion Criteria:

  • Nonsecretory multiple myeloma based upon standard M-component criteria (ie, measurable serum/urine M-component) unless the baseline serum free light chain level is elevated
  • POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
  • Plasma cell leukemia
  • More than 30 days of previous treatment (before screening) with anti-myeloma therapy (does not include radiotherapy or a single short course of steroid [ie, less than or equal to the equivalent of dexamethasone 60 mg/day for 4 days]).
  • Planned radiation therapy or surgery to the bone (does not include procedures performed before randomization)
  • Prior administration of denosumab
  • Use of oral bisphosphonates with a cumulative exposure of more than 1 year
  • More than 1 previous dose of IV bisphosphonate administration
  • Prior history or current evidence of osteonecrosis/osteomyelitis of the jaw
  • Active dental or jaw condition which requires oral surgery, including tooth extraction
  • Non-healed dental/oral surgery, including tooth extraction
  • Planned invasive dental procedures

  • Evidence of any of the following conditions per subject self-report or medical chart review:

    • Any prior invasive malignancy within 5 years before randomization
    • Any non-invasive malignancy not treated with curative intent or with knownactive disease within 5 years before randomization
    • Major surgery or significant traumatic injury occurring within 4 weeks before randomization
    • Active infection with Hepatitis B virus or Hepatitis C virus
    • Known infection with human immunodeficiency virus (HIV)
    • Active infection requiring IV anti-infective therapy
  • Subject is pregnant or breast feeding, or planning to become pregnant within 5 months after end of treatment
  • Female subject of child bearing potential is not willing to use highly effective contraception during treatment and for 5 months after the end of treatment (see section 6.3)
  • Known sensitivity to any of the products to be administered during the study (eg, mammalian derived products, calcium or vitamin D)
  • Subject is receiving or is less than 30 days since ending other experimental device or drug (no marketing authorization for any indication)
  • Subject will not be available for follow-up assessment
  • Any major medical or psychiatric disorder that in the opinion of the investigator, might prevent the subject from completing the study or interfere with the interpretation of the study results
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01345019


Locations
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Sponsors and Collaborators
Amgen
Daiichi Sankyo, Inc.
Investigators
Layout table for investigator information
Study Director: MD Amgen
More Information
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Additional Information:

Publications:

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

Layout table for additonal information
Responsible Party: Amgen
ClinicalTrials.gov Identifier: NCT01345019    
Other Study ID Numbers: 20090482
2010-020454-34 ( EudraCT Number )
First Posted: April 29, 2011    Key Record Dates
Results First Posted: March 7, 2018
Last Update Posted: March 31, 2020
Last Verified: March 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Time Frame: Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication (or other new use) have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.
Access Criteria: Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors, and if not approved, may be further arbitrated by a Data Sharing Independent Review Panel. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the link below.
URL: https://www.amgen.com/datasharing
Keywords provided by Amgen:
zoledronic acid
hematologic malignancies
SRE
skeletal-related event
blood cancer
lytic bone lesions
bone metastases
myeloma
fractures
spinal cord compression
radiation to bone
surgery to bone
bisphosphonates
Neoplasms, Plasma Cell
 Paraproteinemias
Neoplasms
Neoplasm Metastasis
Bone Neoplasms
Bone Marrow Diseases
Blood Protein Disorders
Hematologic Diseases
multiple myeloma
denosumab
Neoplastic Processes
Bone Diseases
Diphosphonates
Bone Density Conservation Agents
Additional relevant MeSH terms:
Layout table for MeSH terms
Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasm Metastasis
Neoplasms
Hematologic Neoplasms
Bone Diseases
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
Neoplastic Processes
Pathologic Processes
Neoplasms by Site
Musculoskeletal Diseases
Zoledronic Acid
Denosumab
Bone Density Conservation Agents
Physiological Effects of Drugs