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Study of Denosumab in Subjects With Giant Cell Tumor of Bone

Primary Purpose

Cancer, Giant Cell Tumors, Giant Cell Tumor of Bone

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Denosumab
Sponsored by
Amgen
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Cancer focused on measuring Giant Cell Tumor of Bone

Eligibility Criteria

12 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion criteria:

  • Pathologically confirmed GCTB within 1 year before study enrollment
  • Measurable evidence of active disease within 1 year before study enrollment
  • Subjects with surgically unsalvageable disease (eg, sacral, spinal GCTB, or multiple lesions including pulmonary metastases) OR subjects whose planned surgery includes joint resection, limb amputation, hemipelvectomy or surgical procedure resulting in severe morbidity
  • Karnofsky performance status equal or greater than 50% (ie, Eastern Cooperative Oncology Group status 0, 1, or 2)
  • Adults or skeletally mature adolescents (ie, radiographic evidence of at least 1 mature long bone [eg, humerus with closed growth epiphyseal plate]) equal or greater than 12 years of age
  • Skeletally mature adolescents must weigh at least 45 kg
  • Before any study-specific procedure is performed, the appropriate written informed consent must be obtained

Exclusion criteria:

  • Currently receiving other GCTB specific treatment (eg, radiation, chemotherapy, or embolization)
  • Concurrent bisphosphonate treatment
  • Known or suspected current diagnosis of underlying malignancy including high grade sarcoma, osteosarcoma, fibrosarcoma, malignant giant cell sarcoma
  • Known or suspected current diagnosis of non GCTB giant cell-rich tumors
  • Known or suspected current diagnosis of brown cell tumor of bone or Paget's disease
  • Known diagnosis of second malignancy within the past 5 years (subjects with definitively treated basal cell carcinoma and cervical carcinoma in situ are permitted)
  • 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
  • Planned invasive dental procedure for the course of the study
  • Subject currently is enrolled in or has not yet completed at least 30 days since ending other investigational device or drug study(s), or subject is receiving other investigational agent(s)
  • Subject has known sensitivity to any of the products to be administered during dosing
  • Unstable systemic disease including active infection, uncontrolled hypertension, unstable angina, congestive heart failure, or myocardial infarction within 6 months before enrollment
  • Subject is pregnant or breast feeding, or planning to become pregnant within 5 months after the end of treatment
  • Female subject of child bearing potential is not willing to use two methods of highly effective contraception during treatment and for 5 months after the end of treatment
  • Subject has any kind of disorder that compromises the ability of the subject to give written informed consent and/or to comply with study procedures

Sites / Locations

  • Research Site
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Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Denosumab

Arm Description

120 mg administered subcutaneously (SC) every 4 weeks (Q4W) with a loading dose of 120 mg SC on study days 8 and 15.

Outcomes

Primary Outcome Measures

Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
AE defined as any untoward medical occurrence in a clinical trial participant. Serious AE defined as AE that is fatal, life threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or other significant medical hazard. Severity of AEs assessed according to Common Terminology Criteria for Adverse Events (CTCAE, v3.0) based on the general guideline: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening or disabling; Grade 5: Death related to AE. Investigator assessed AEs for relatedness to study drug. Results are presented for treatment-emergent events (TEAEs) and included all AEs occurring from first dose in initial treatment phase to end of initial treatment phase (or for participants entering retreatment, from first dose in initial treatment phase until end of retreatment phase).
Number of Participants Who Experienced the Maximum Toxicity Grade (CTCAE Grade ≥ 3) in the Indicated Clinical Chemistry Parameters
Serum samples for clinical chemistry were collected on study day 1 (baseline), day 15, week 5 and each study visit Q4W thereafter until last study visit for the on-study period (ie, until end of initial treatment phase). The parameters included albumin, calcium (albumin-adjusted), creatinine, magnesium and phosphate. Results are presented for number of participants who experienced the maximum toxicity grade for each of these clinical parameters. The maximum toxicity grade experienced by each participant was based on CTCAE, v3.0, and are summarized for Grade 3 and 4. Increases and decreases in relationship to the normal parameter ranges are indicated as 'Above' and 'Below' respectively.

Secondary Outcome Measures

Time to Disease Progression or Recurrence During the On-Study Period for Cohort 1, Presented as Kaplan-Meier Estimates of Probability
Time to disease progression or recurrence during the on-study period was defined as the time interval (in days) from the date of first dose of study drug to the date of earliest Progressive Disease (PD) during the initial treatment phase. PD was defined as the response of progressive disease, locally recurrent disease or relapse as captured in the Disease Status page of the Case Report Form. If a participant had not had PD by the end of the initial treatment phase date, time to disease progression or recurrence were censored at her/his end of initial treatment phase date. Since median time to disease progression or recurrence for participants in cohort 1 was not reached, Kaplan-Meier estimates for the probability (expressed as a percentage) of participants in cohort 1 to have disease progression or recurrence at months 6, 12, 24, 36 and 60 are presented.
Percentage of Participants Without Any On-Study Surgery at Month 6 for Cohort 2
The percentage of participants without any surgery at month 6 was equivalent to the number of participants without any surgery by month 6 divided by the number of cohort 2 participants who had an opportunity to complete 6 months of treatment, expressed as a percentage.
Mean Serum Denosumab Trough Concentrations
Blood samples for determination of serum denosumab concentration levels were obtained from participants included in the pharmacokinetic (PK) substudy at baseline (prior to administration of study drug on day 1) and at scheduled time points during the study up to week 25.

Full Information

First Posted
May 15, 2008
Last Updated
September 9, 2022
Sponsor
Amgen
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1. Study Identification

Unique Protocol Identification Number
NCT00680992
Brief Title
Study of Denosumab in Subjects With Giant Cell Tumor of Bone
Official Title
An Open-label, Multi-center, Phase 2 Study of Denosumab in Subjects With Giant Cell Tumor of Bone
Study Type
Interventional

2. Study Status

Record Verification Date
September 2022
Overall Recruitment Status
Completed
Study Start Date
September 9, 2008 (Actual)
Primary Completion Date
May 17, 2018 (Actual)
Study Completion Date
May 17, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Amgen

4. Oversight

5. Study Description

Brief Summary
To determine how safe denosumab is in treating subjects with giant cell tumor of bone (GCTB)
Detailed Description
To determine how safe denosumab is in treating subjects with GCTB

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cancer, Giant Cell Tumors, Giant Cell Tumor of Bone, Benign Giant Cell Tumors
Keywords
Giant Cell Tumor of Bone

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
535 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Denosumab
Arm Type
Experimental
Arm Description
120 mg administered subcutaneously (SC) every 4 weeks (Q4W) with a loading dose of 120 mg SC on study days 8 and 15.
Intervention Type
Drug
Intervention Name(s)
Denosumab
Other Intervention Name(s)
AMG 162, Immunoglobulin G2 human monoclonal antibody to RANK ligand
Intervention Description
120 mg administered subcutaneously (SC) every 4 weeks (Q4W) with a loading dose of 120 mg SC on study days 8 and 15.
Primary Outcome Measure Information:
Title
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
Description
AE defined as any untoward medical occurrence in a clinical trial participant. Serious AE defined as AE that is fatal, life threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or other significant medical hazard. Severity of AEs assessed according to Common Terminology Criteria for Adverse Events (CTCAE, v3.0) based on the general guideline: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening or disabling; Grade 5: Death related to AE. Investigator assessed AEs for relatedness to study drug. Results are presented for treatment-emergent events (TEAEs) and included all AEs occurring from first dose in initial treatment phase to end of initial treatment phase (or for participants entering retreatment, from first dose in initial treatment phase until end of retreatment phase).
Time Frame
From first dose of study drug up to last study visit for treatment-emergent period (a maximum of approximately 111 months).
Title
Number of Participants Who Experienced the Maximum Toxicity Grade (CTCAE Grade ≥ 3) in the Indicated Clinical Chemistry Parameters
Description
Serum samples for clinical chemistry were collected on study day 1 (baseline), day 15, week 5 and each study visit Q4W thereafter until last study visit for the on-study period (ie, until end of initial treatment phase). The parameters included albumin, calcium (albumin-adjusted), creatinine, magnesium and phosphate. Results are presented for number of participants who experienced the maximum toxicity grade for each of these clinical parameters. The maximum toxicity grade experienced by each participant was based on CTCAE, v3.0, and are summarized for Grade 3 and 4. Increases and decreases in relationship to the normal parameter ranges are indicated as 'Above' and 'Below' respectively.
Time Frame
Baseline (day 1) up to last study visit for initial treatment phase (median duration approximately 30 months up to a maximum of approximately 109 months).
Secondary Outcome Measure Information:
Title
Time to Disease Progression or Recurrence During the On-Study Period for Cohort 1, Presented as Kaplan-Meier Estimates of Probability
Description
Time to disease progression or recurrence during the on-study period was defined as the time interval (in days) from the date of first dose of study drug to the date of earliest Progressive Disease (PD) during the initial treatment phase. PD was defined as the response of progressive disease, locally recurrent disease or relapse as captured in the Disease Status page of the Case Report Form. If a participant had not had PD by the end of the initial treatment phase date, time to disease progression or recurrence were censored at her/his end of initial treatment phase date. Since median time to disease progression or recurrence for participants in cohort 1 was not reached, Kaplan-Meier estimates for the probability (expressed as a percentage) of participants in cohort 1 to have disease progression or recurrence at months 6, 12, 24, 36 and 60 are presented.
Time Frame
From first dose of study drug up to the end of the initial treatment phase (median duration approximately 30 months up to a maximum of approximately 109 months).
Title
Percentage of Participants Without Any On-Study Surgery at Month 6 for Cohort 2
Description
The percentage of participants without any surgery at month 6 was equivalent to the number of participants without any surgery by month 6 divided by the number of cohort 2 participants who had an opportunity to complete 6 months of treatment, expressed as a percentage.
Time Frame
At month 6.
Title
Mean Serum Denosumab Trough Concentrations
Description
Blood samples for determination of serum denosumab concentration levels were obtained from participants included in the pharmacokinetic (PK) substudy at baseline (prior to administration of study drug on day 1) and at scheduled time points during the study up to week 25.
Time Frame
Blood samples were collected at baseline (day 1), days 8 and 15 and weeks 5, 9, 13 and 25.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
12 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion criteria: Pathologically confirmed GCTB within 1 year before study enrollment Measurable evidence of active disease within 1 year before study enrollment Subjects with surgically unsalvageable disease (eg, sacral, spinal GCTB, or multiple lesions including pulmonary metastases) OR subjects whose planned surgery includes joint resection, limb amputation, hemipelvectomy or surgical procedure resulting in severe morbidity Karnofsky performance status equal or greater than 50% (ie, Eastern Cooperative Oncology Group status 0, 1, or 2) Adults or skeletally mature adolescents (ie, radiographic evidence of at least 1 mature long bone [eg, humerus with closed growth epiphyseal plate]) equal or greater than 12 years of age Skeletally mature adolescents must weigh at least 45 kg Before any study-specific procedure is performed, the appropriate written informed consent must be obtained Exclusion criteria: Currently receiving other GCTB specific treatment (eg, radiation, chemotherapy, or embolization) Concurrent bisphosphonate treatment Known or suspected current diagnosis of underlying malignancy including high grade sarcoma, osteosarcoma, fibrosarcoma, malignant giant cell sarcoma Known or suspected current diagnosis of non GCTB giant cell-rich tumors Known or suspected current diagnosis of brown cell tumor of bone or Paget's disease Known diagnosis of second malignancy within the past 5 years (subjects with definitively treated basal cell carcinoma and cervical carcinoma in situ are permitted) 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 Planned invasive dental procedure for the course of the study Subject currently is enrolled in or has not yet completed at least 30 days since ending other investigational device or drug study(s), or subject is receiving other investigational agent(s) Subject has known sensitivity to any of the products to be administered during dosing Unstable systemic disease including active infection, uncontrolled hypertension, unstable angina, congestive heart failure, or myocardial infarction within 6 months before enrollment Subject is pregnant or breast feeding, or planning to become pregnant within 5 months after the end of treatment Female subject of child bearing potential is not willing to use two methods of highly effective contraception during treatment and for 5 months after the end of treatment Subject has any kind of disorder that compromises the ability of the subject to give written informed consent and/or to comply with study procedures
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
MD
Organizational Affiliation
Amgen
Official's Role
Study Director
Facility Information:
Facility Name
Research Site
City
Santa Monica
State/Province
California
ZIP/Postal Code
90403
Country
United States
Facility Name
Research Site
City
Stanford
State/Province
California
ZIP/Postal Code
94305
Country
United States
Facility Name
Research Site
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20010
Country
United States
Facility Name
Research Site
City
Gainesville
State/Province
Florida
ZIP/Postal Code
32607
Country
United States
Facility Name
Research Site
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
Research Site
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
Research Site
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
Facility Name
Research Site
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55455
Country
United States
Facility Name
Research Site
City
New York
State/Province
New York
ZIP/Postal Code
10003
Country
United States
Facility Name
Research Site
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19106
Country
United States
Facility Name
Research Site
City
Greenville
State/Province
South Carolina
ZIP/Postal Code
29605
Country
United States
Facility Name
Research Site
City
Camperdown
State/Province
New South Wales
ZIP/Postal Code
2250
Country
Australia
Facility Name
Research Site
City
Woolloongabba
State/Province
Queensland
ZIP/Postal Code
4102
Country
Australia
Facility Name
Research Site
City
East Melbourne
State/Province
Victoria
ZIP/Postal Code
3002
Country
Australia
Facility Name
Research Site
City
Nedlands
State/Province
Western Australia
ZIP/Postal Code
6009
Country
Australia
Facility Name
Research Site
City
Wien
ZIP/Postal Code
1090
Country
Austria
Facility Name
Research Site
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 1X5
Country
Canada
Facility Name
Research Site
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H4A 3J1
Country
Canada
Facility Name
Research Site
City
Lyon cedex 8
ZIP/Postal Code
69373
Country
France
Facility Name
Research Site
City
Marseille cedex 05
ZIP/Postal Code
13385
Country
France
Facility Name
Research Site
City
Villejuif cedex
ZIP/Postal Code
94805
Country
France
Facility Name
Research Site
City
Bad Saarow
ZIP/Postal Code
15526
Country
Germany
Facility Name
Research Site
City
Stuttgart
ZIP/Postal Code
70174
Country
Germany
Facility Name
Research Site
City
Bologna
ZIP/Postal Code
40136
Country
Italy
Facility Name
Research Site
City
Milano
ZIP/Postal Code
20133
Country
Italy
Facility Name
Research Site
City
Leiden
ZIP/Postal Code
2333 ZA
Country
Netherlands
Facility Name
Research Site
City
Warszawa
ZIP/Postal Code
01-211
Country
Poland
Facility Name
Research Site
City
Warszawa
ZIP/Postal Code
02-781
Country
Poland
Facility Name
Research Site
City
Palma de Mallorca
State/Province
Baleares
ZIP/Postal Code
07010
Country
Spain
Facility Name
Research Site
City
Barcelona
State/Province
Cataluña
ZIP/Postal Code
08025
Country
Spain
Facility Name
Research Site
City
Valencia
State/Province
Comunidad Valenciana
ZIP/Postal Code
46026
Country
Spain
Facility Name
Research Site
City
Lund
ZIP/Postal Code
221 85
Country
Sweden
Facility Name
Research Site
City
Birmingham
ZIP/Postal Code
B31 2AP
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
23867211
Citation
Chawla S, Henshaw R, Seeger L, Choy E, Blay JY, Ferrari S, Kroep J, Grimer R, Reichardt P, Rutkowski P, Schuetze S, Skubitz K, Staddon A, Thomas D, Qian Y, Jacobs I. Safety and efficacy of denosumab for adults and skeletally mature adolescents with giant cell tumour of bone: interim analysis of an open-label, parallel-group, phase 2 study. Lancet Oncol. 2013 Aug;14(9):901-8. doi: 10.1016/S1470-2045(13)70277-8. Epub 2013 Jul 16.
Results Reference
background
PubMed Identifier
24834795
Citation
Martin-Broto J, Cleeland CS, Glare PA, Engellau J, Skubitz KM, Blum RH, Ganjoo KN, Staddon A, Dominkus M, Feng A, Qian Y, Braun A, Jacobs I, Chung K, Atchison C. Effects of denosumab on pain and analgesic use in giant cell tumor of bone: interim results from a phase II study. Acta Oncol. 2014 Sep;53(9):1173-9. doi: 10.3109/0284186X.2014.910313. Epub 2014 May 19.
Results Reference
background
PubMed Identifier
26033180
Citation
Rutkowski P, Ferrari S, Grimer RJ, Stalley PD, Dijkstra SP, Pienkowski A, Vaz G, Wunder JS, Seeger LL, Feng A, Roberts ZJ, Bach BA. Surgical downstaging in an open-label phase II trial of denosumab in patients with giant cell tumor of bone. Ann Surg Oncol. 2015 Sep;22(9):2860-8. doi: 10.1245/s10434-015-4634-9. Epub 2015 Jun 2.
Results Reference
background
PubMed Identifier
31704134
Citation
Chawla S, Blay JY, Rutkowski P, Le Cesne A, Reichardt P, Gelderblom H, Grimer RJ, Choy E, Skubitz K, Seeger L, Schuetze SM, Henshaw R, Dai T, Jandial D, Palmerini E. Denosumab in patients with giant-cell tumour of bone: a multicentre, open-label, phase 2 study. Lancet Oncol. 2019 Dec;20(12):1719-1729. doi: 10.1016/S1470-2045(19)30663-1. Epub 2019 Nov 6.
Results Reference
background
PubMed Identifier
30231890
Citation
Engellau J, Seeger L, Grimer R, Henshaw R, Gelderblom H, Choy E, Chawla S, Reichardt P, O'Neal M, Feng A, Jacobs I, Roberts ZJ, Braun A, Bach BA. Assessment of denosumab treatment effects and imaging response in patients with giant cell tumor of bone. World J Surg Oncol. 2018 Sep 19;16(1):191. doi: 10.1186/s12957-018-1478-3.
Results Reference
background
PubMed Identifier
33038190
Citation
Bukata SV, Blay JY, Rutkowski P, Skubitz K, Henshaw R, Seeger L, Dai T, Jandial D, Chawla S. Denosumab Treatment for Giant Cell Tumor of the Spine Including the Sacrum. Spine (Phila Pa 1976). 2021 Mar 1;46(5):277-284. doi: 10.1097/BRS.0000000000003728.
Results Reference
background
PubMed Identifier
33482769
Citation
Palmerini E, Seeger LL, Gambarotti M, Righi A, Reichardt P, Bukata S, Blay JY, Dai T, Jandial D, Picci P. Malignancy in giant cell tumor of bone: analysis of an open-label phase 2 study of denosumab. BMC Cancer. 2021 Jan 22;21(1):89. doi: 10.1186/s12885-020-07739-8.
Results Reference
derived
PubMed Identifier
29211870
Citation
Uday S, Gaston CL, Rogers L, Parry M, Joffe J, Pearson J, Sutton D, Grimer R, Hogler W. Osteonecrosis of the Jaw and Rebound Hypercalcemia in Young People Treated With Denosumab for Giant Cell Tumor of Bone. J Clin Endocrinol Metab. 2018 Feb 1;103(2):596-603. doi: 10.1210/jc.2017-02025.
Results Reference
derived
PubMed Identifier
25684041
Citation
van der Heijden L, van de Sande MA, Hogendoorn PC, Gelderblom H, Dijkstra PD. Neoadjuvant denosumab for extensive giant cell tumor in os ischium: a case report. Acta Orthop. 2015 Jun;86(3):393-5. doi: 10.3109/17453674.2014.1002345. Epub 2015 Feb 14. No abstract available.
Results Reference
derived
Links:
URL
http://www.amgentrials.com
Description
AmgenTrials clinical trials website

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Study of Denosumab in Subjects With Giant Cell Tumor of Bone

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