Safety and Efficacy Study of Denosumab in Patients With Recurrent or Unresectable Giant Cell Tumor of Bone
Study Details
Study Description
Brief Summary
To determine how safe and effective denosumab is in treating patients with giant cell tumor of bone.
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
|
Phase 2 |
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Experimental: Denosumab Participants received denosumab 120 mg once every 4 weeks (Q4W), with an additional 120 mg doses on Days 8 and 15 of the first month of treatment. All participants were instructed to take daily supplements of at least 500 mg of calcium and 400 IU of vitamin D. Participants were to continue to receive denosumab until one of the following occurred: complete tumor resection, disease progression without clinical benefit, or decision by the participant to discontinue for any reason. |
Biological: Denosumab
Administered by subcutaneous injection
Other Names:
Dietary Supplement: Calcium/Vitamin D
|
Outcome Measures
Primary Outcome Measures
- Percentage of Participants With Giant Cell Tumor Response [From enrollment until 25 weeks]
A treatment response was defined for participants with tissue samples obtained and measured by histopathology as: • at least 90% elimination of giant cells relative to Baseline, or • complete elimination of giant cells in cases where giant cells represent < 5% of tumor cells. A response was defined for participants who have only radiographs (histopathology not available) as lack of progression of the target lesion at week 25 by radiographic measurements compared with Baseline. For participants with both a core biopsy and resected tissue obtained, the sample closest to week 25 was used in the analysis.
Secondary Outcome Measures
- Percent Change From Baseline in Urinary N-telopeptide Corrected for Urine Creatinine [Baseline and Weeks 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, and 81]
Urinary N-telopeptide (of type 1 collagen) corrected for urine creatinine (uNTX/Cr) is a bone turnover marker used to measure the activity of denosumab. Percent change from Baseline in uNTX/Cr was measured over time.
- Percent Change From Baseline in Serum C-terminus Peptide (of Type 1 Collagen) [Baseline and Weeks 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, and 81]
Serum C-terminus peptide (of type 1 collagen; CTX1) is a bone turnover marker used to measure the activity of denosumab. Percent change from Baseline in CTX was measured over time.
- Serum Denosumab Trough Concentrations [Blood samples were collected on Days 1 (baseline), 8, 15 and Weeks 5 (Day 29), 9, 13, 25, and 49.]
Serum concentrations of denosumab were measured by a validated conventional sandwich enzyme-linked immunosorbent assay (ELISA).
- Number of Participants With Adverse Events (AEs) [From the first dose of study drug until the data cut-off date of April 7 2008; a maximum of 18 months]
An adverse event is defined as an undesirable medical occurrence (e.g., sign, symptom, or diagnosis) or worsening of a pre-existing medical condition. A serious adverse event (SAE) is defined by regulatory authorities as one that • is fatal • is life threatening (places the participant at immediate risk of death) • requires in-patient hospitalization or prolongation of existing hospitalization • results in persistent or significant disability/incapacity • is a congenital anomaly/birth defect • other significant medical hazard. The severity of adverse events was assessed according to the Common Terminology Criteria for Adverse Events (CTCAE, version 3.0) based on the following general guideline: Grade 1: Mild AE Grade 2: Moderate AE Grade 3: Severe AE Grade 4: Life-threatening or disabling AE Grade 5: Death related to AE. AEs were assessed by the Investigator for relatedness to study drug.
- Number of Participants With Anti-Denosumab Antibodies [From enrollment until the data cut-off date of April 7 2008; a maximum time of 18 months.]
Validated immunoassays were used to test for the presence of anti-denosumab antibodies throughout the study.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Adults, 18 years and older
-
Histologically confirmed and measurable giant cell tumor (GCT)
-
Recurrent GCT confirmed by radiology or unresectable GCT
-
Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
Exclusion Criteria:
-
Pateints for whom surgery to the affected limb/area is planned within 27 days after receiving 1st dose of denosumab
-
Radiation to affected region within 28 days before enrollment to study
-
Known diagnosis of osteosarcoma or brown tumor of bone
-
Known history of second malignancy within the past 5 years, except for basal cell carcinoma or cervical carcinoma in situ
-
Concurrent treatment with bisphosphonates, calcitonin, or interferon.
Other criteria also apply.
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- Amgen
Investigators
- Study Director: MD, Amgen
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
- Branstetter DG, Nelson SD, Manivel JC, Blay JY, Chawla S, Thomas DM, Jun S, Jacobs I. Denosumab induces tumor reduction and bone formation in patients with giant-cell tumor of bone. Clin Cancer Res. 2012 Aug 15;18(16):4415-24. doi: 10.1158/1078-0432.CCR-12-0578. Epub 2012 Jun 18.
- Thomas D, Henshaw R, Skubitz K, Chawla S, Staddon A, Blay JY, Roudier M, Smith J, Ye Z, Sohn W, Dansey R, Jun S. Denosumab in patients with giant-cell tumour of bone: an open-label, phase 2 study. Lancet Oncol. 2010 Mar;11(3):275-80. doi: 10.1016/S1470-2045(10)70010-3. Epub 2010 Feb 10.
- 20040215
Study Results
Participant Flow
Recruitment Details | First patient enrolled 10 July 2006; Last patient enrolled 25 January 2008. Results data are reported as of the data cut-off date of 07 April 2008. |
---|---|
Pre-assignment Detail |
Arm/Group Title | Denosumab |
---|---|
Arm/Group Description | Participants received denosumab 120 mg once every 4 weeks (Q4W), with an additional 120 mg dose on Days 8 and 15 of the first month of treatment. All participants were instructed to take daily supplements of at least 500 mg of calcium and 400 IU of vitamin D. Participants were to continue to receive denosumab until one of the following occurred: complete tumor resection, disease progression without clinical benefit, or decision by the participant to discontinue for any reason. |
Period Title: Overall Study | |
STARTED | 37 |
COMPLETED | 7 |
NOT COMPLETED | 30 |
Baseline Characteristics
Arm/Group Title | Denosumab |
---|---|
Arm/Group Description | Participants received denosumab 120 mg once every 4 weeks (Q4W), with an additional 120 mg dose on Days 8 and 15 of the first month of treatment. All participants were instructed to take daily supplements of at least 500 mg of calcium and 400 IU of vitamin D. Participants were to continue to receive denosumab until one of the following occurred: complete tumor resection, disease progression without clinical benefit, or decision by the participant to discontinue for any reason. |
Overall Participants | 37 |
Age (years) [Mean (Standard Deviation) ] | |
Mean (Standard Deviation) [years] |
33.9
(12.3)
|
Sex: Female, Male (Count of Participants) | |
Female |
20
54.1%
|
Male |
17
45.9%
|
Race/Ethnicity, Customized (participants) [Number] | |
White or Caucasian |
27
73%
|
Black or African American |
2
5.4%
|
Hispanic or Latino |
5
13.5%
|
Asian |
3
8.1%
|
Giant Cell Tumor Disease Type (participants) [Number] | |
Primary unresectable |
13
35.1%
|
Recurrent unresectable |
18
48.6%
|
Recurrent resectable |
6
16.2%
|
Eastern Cooperative Oncology Group (ECOG) Performance Status (participants) [Number] | |
0 - Fully Active |
13
35.1%
|
1 - Restricted but ambulatory |
21
56.8%
|
2 - Ambulatory but unable to work |
1
2.7%
|
3 - Limited selfcare, confined to bed >50% daytime |
0
0%
|
4 - Completely disabled |
0
0%
|
Missing |
2
5.4%
|
Percent of giant cells in tumor on pre-treatment biopsy (percentage of giant cells in tumor) [Mean (Standard Deviation) ] | |
Mean (Standard Deviation) [percentage of giant cells in tumor] |
28.7
(16.1)
|
Location of target lesion (participants) [Number] | |
Lower extremities |
8
21.6%
|
Upper extremities |
5
13.5%
|
Pelvis |
9
24.3%
|
Spine |
3
8.1%
|
Pulmonary disease |
9
24.3%
|
Dorsal vertebrae |
1
2.7%
|
Pelvic region |
1
2.7%
|
Missing |
1
2.7%
|
Outcome Measures
Title | Percentage of Participants With Giant Cell Tumor Response |
---|---|
Description | A treatment response was defined for participants with tissue samples obtained and measured by histopathology as: • at least 90% elimination of giant cells relative to Baseline, or • complete elimination of giant cells in cases where giant cells represent < 5% of tumor cells. A response was defined for participants who have only radiographs (histopathology not available) as lack of progression of the target lesion at week 25 by radiographic measurements compared with Baseline. For participants with both a core biopsy and resected tissue obtained, the sample closest to week 25 was used in the analysis. |
Time Frame | From enrollment until 25 weeks |
Outcome Measure Data
Analysis Population Description |
---|
The efficacy analysis set included participants with a Baseline histology assessment and at least 1 postdose histology assessment from weeks 5-25; or a Baseline radiology assessment and at least 1 postdose radiology assessment from weeks 5-25. Evaluable participants had to be on study for at least 28 days after administration of the first dose. |
Arm/Group Title | Denosumab |
---|---|
Arm/Group Description | Participants received denosumab 120 mg once every 4 weeks (Q4W), with an additional 120 mg dose on Days 8 and 15 of the first month of treatment. All participants were instructed to take daily supplements of at least 500 mg of calcium and 400 IU of vitamin D. Participants were to continue to receive denosumab until one of the following occurred: complete tumor resection, disease progression without clinical benefit, or decision by the participant to discontinue for any reason. |
Measure Participants | 35 |
Number (95% Confidence Interval) [percentage of participants] |
85.7
231.6%
|
Title | Percent Change From Baseline in Urinary N-telopeptide Corrected for Urine Creatinine |
---|---|
Description | Urinary N-telopeptide (of type 1 collagen) corrected for urine creatinine (uNTX/Cr) is a bone turnover marker used to measure the activity of denosumab. Percent change from Baseline in uNTX/Cr was measured over time. |
Time Frame | Baseline and Weeks 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, and 81 |
Outcome Measure Data
Analysis Population Description |
---|
Efficacy Analysis Set with available data at each time point (n). |
Arm/Group Title | Denosumab |
---|---|
Arm/Group Description | Participants received denosumab 120 mg once every 4 weeks (Q4W), with an additional 120 mg dose on Days 8 and 15 of the first month of treatment. All participants were instructed to take daily supplements of at least 500 mg of calcium and 400 IU of vitamin D. Participants were to continue to receive denosumab until one of the following occurred: complete tumor resection, disease progression without clinical benefit, or decision by the participant to discontinue for any reason. |
Measure Participants | 35 |
Week 5 (n=30) |
-70.9
|
Week 9 (n=29) |
-77.0
|
Week 13 (n=27) |
-60.0
|
Week 17 (n=26) |
-59.5
|
Week 21 (n=24) |
-64.5
|
Week 25 (n=20) |
-56.4
|
Week 29 (n=21) |
-52.8
|
Week 33 (n=15) |
-35.0
|
Week 37 (n=13) |
-71.1
|
Week 41 (n=11) |
-57.3
|
Week 45 (n=8) |
-59.1
|
Week 49 (n=7) |
-59.0
|
Week 53 (N=8) |
-49.0
|
Week 57 (n=6) |
-65.1
|
Week 61 (n=3) |
-59.2
|
Week 65 (n=3) |
-69.2
|
Week 69 (n=4) |
-64.2
|
Week 73 (n=1) |
-47.5
|
Week 77 (n=2) |
-76.8
|
Week 81 (n=2) |
-13.3
|
Title | Percent Change From Baseline in Serum C-terminus Peptide (of Type 1 Collagen) |
---|---|
Description | Serum C-terminus peptide (of type 1 collagen; CTX1) is a bone turnover marker used to measure the activity of denosumab. Percent change from Baseline in CTX was measured over time. |
Time Frame | Baseline and Weeks 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, and 81 |
Outcome Measure Data
Analysis Population Description |
---|
Efficacy Analysis Set with available data at each time point (n). |
Arm/Group Title | Denosumab |
---|---|
Arm/Group Description | Participants received denosumab 120 mg once every 4 weeks (Q4W), with an additional 120 mg dose on Days 8 and 15 of the first month of treatment. All participants were instructed to take daily supplements of at least 500 mg of calcium and 400 IU of vitamin D. Participants were to continue to receive denosumab until one of the following occurred: complete tumor resection, disease progression without clinical benefit, or decision by the participant to discontinue for any reason. |
Measure Participants | 35 |
Week 5 (n=33) |
-78.9
|
Week 9 (n=33) |
-79.8
|
Week 13 (n=31) |
-80.4
|
Week 17 (n=28) |
-82.6
|
Week 21 (n=26) |
-82.0
|
Week 25 (n=24) |
-79.5
|
Week 29 (n=21) |
-82.8
|
Week 33 (n=16) |
-74.8
|
Week 37 (n=14) |
-82.4
|
Week 41 (n=10) |
-86.1
|
Week 45 (n=8) |
-79.6
|
Week 49 (n=7) |
-82.0
|
Week 53 (N=8) |
-87.3
|
Week 57 (n=6) |
-86.2
|
Week 61 (n=4) |
-84.9
|
Week 65 (n=3) |
-83.5
|
Week 69 (n=4) |
-84.2
|
Week 73 (n=2) |
-81.9
|
Week 77 (n=2) |
-84.2
|
Week 81 (n=2) |
-84.9
|
Title | Serum Denosumab Trough Concentrations |
---|---|
Description | Serum concentrations of denosumab were measured by a validated conventional sandwich enzyme-linked immunosorbent assay (ELISA). |
Time Frame | Blood samples were collected on Days 1 (baseline), 8, 15 and Weeks 5 (Day 29), 9, 13, 25, and 49. |
Outcome Measure Data
Analysis Population Description |
---|
The pharmacokinetics analysis set included participants who received at least 1 dose of denosumab and for whom at least 1 serum denosumab trough concentration was available. 'n' indicates the number of participants with available data at each time point. |
Arm/Group Title | Denosumab |
---|---|
Arm/Group Description | Participants received denosumab 120 mg once every 4 weeks (Q4W), with an additional 120 mg dose on Days 8 and 15 of the first month of treatment. All participants were instructed to take daily supplements of at least 500 mg of calcium and 400 IU of vitamin D. Participants were to continue to receive denosumab until one of the following occurred: complete tumor resection, disease progression without clinical benefit, or decision by the participant to discontinue for any reason. |
Measure Participants | 37 |
Day 1 (n=32) |
NA
(NA)
|
Day 8 (n=32) |
19000
(24100)
|
Day 15 (n=28) |
31600
(27300)
|
Day 29 (n=33) |
36400
(20600)
|
Week 9 (n=32) |
27500
(17300)
|
Week 13 (n=25) |
23300
(12400)
|
Week 25 (n=23) |
19900
(9700)
|
Week 49 (n=9) |
21400
(8900)
|
Title | Number of Participants With Adverse Events (AEs) |
---|---|
Description | An adverse event is defined as an undesirable medical occurrence (e.g., sign, symptom, or diagnosis) or worsening of a pre-existing medical condition. A serious adverse event (SAE) is defined by regulatory authorities as one that • is fatal • is life threatening (places the participant at immediate risk of death) • requires in-patient hospitalization or prolongation of existing hospitalization • results in persistent or significant disability/incapacity • is a congenital anomaly/birth defect • other significant medical hazard. The severity of adverse events was assessed according to the Common Terminology Criteria for Adverse Events (CTCAE, version 3.0) based on the following general guideline: Grade 1: Mild AE Grade 2: Moderate AE Grade 3: Severe AE Grade 4: Life-threatening or disabling AE Grade 5: Death related to AE. AEs were assessed by the Investigator for relatedness to study drug. |
Time Frame | From the first dose of study drug until the data cut-off date of April 7 2008; a maximum of 18 months |
Outcome Measure Data
Analysis Population Description |
---|
All participants who received at least 1 dose of denosumab. |
Arm/Group Title | Denosumab |
---|---|
Arm/Group Description | Participants received denosumab 120 mg once every 4 weeks (Q4W), with an additional 120 mg dose on Days 8 and 15 of the first month of treatment. All participants were instructed to take daily supplements of at least 500 mg of calcium and 400 IU of vitamin D. Participants were to continue to receive denosumab until one of the following occurred: complete tumor resection, disease progression without clinical benefit, or decision by the participant to discontinue for any reason. |
Measure Participants | 37 |
Any AE |
33
89.2%
|
Serious AE |
5
13.5%
|
Fatal AE |
1
2.7%
|
AE leading to study discontinuation |
2
5.4%
|
AE leading to study drug discontinuation |
3
8.1%
|
CTCAE Grade 3, 4, or 5 |
5
13.5%
|
Any AE related to study drug |
10
27%
|
Title | Number of Participants With Anti-Denosumab Antibodies |
---|---|
Description | Validated immunoassays were used to test for the presence of anti-denosumab antibodies throughout the study. |
Time Frame | From enrollment until the data cut-off date of April 7 2008; a maximum time of 18 months. |
Outcome Measure Data
Analysis Population Description |
---|
Participants who received at least 1 dose of denosumab and had at least 1 anti-denosumab antibody sample. |
Arm/Group Title | Denosumab |
---|---|
Arm/Group Description | Participants received denosumab 120 mg once every 4 weeks (Q4W), with an additional 120 mg dose on Days 8 and 15 of the first month of treatment. All participants were instructed to take daily supplements of at least 500 mg of calcium and 400 IU of vitamin D. Participants were to continue to receive denosumab until one of the following occurred: complete tumor resection, disease progression without clinical benefit, or decision by the participant to discontinue for any reason. |
Measure Participants | 31 |
Number [participants] |
0
0%
|
Adverse Events
Time Frame | up to 1 year 6 months | |
---|---|---|
Adverse Event Reporting Description | The table of Other Adverse Events summarizes non-serious occurrences of adverse events that exceeded a 5% frequency. | |
Arm/Group Title | Denosumab 120 mg Q4W | |
Arm/Group Description | Participants received a dose loading regimen of 3 subcutaneous injections of denosumab 120 mg every week for 3 weeks (study Days 1, 8, and 15), followed by a week of rest, and then 120 mg denosumab once every 4 weeks (Q4W) from Day 29. | |
All Cause Mortality |
||
Denosumab 120 mg Q4W | ||
Affected / at Risk (%) | # Events | |
Total | / (NaN) | |
Serious Adverse Events |
||
Denosumab 120 mg Q4W | ||
Affected / at Risk (%) | # Events | |
Total | 5/37 (13.5%) | |
Gastrointestinal disorders | ||
Nausea | 1/37 (2.7%) | |
Infections and infestations | ||
Lower respiratory tract infection | 1/37 (2.7%) | |
Pneumonia | 1/37 (2.7%) | |
Injury, poisoning and procedural complications | ||
Ankle fracture | 1/37 (2.7%) | |
Musculoskeletal and connective tissue disorders | ||
Back pain | 1/37 (2.7%) | |
Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||
Metastases to lung | 1/37 (2.7%) | |
Psychiatric disorders | ||
Depression | 1/37 (2.7%) | |
Respiratory, thoracic and mediastinal disorders | ||
Acute respiratory distress syndrome | 1/37 (2.7%) | |
Dyspnoea | 2/37 (5.4%) | |
Other (Not Including Serious) Adverse Events |
||
Denosumab 120 mg Q4W | ||
Affected / at Risk (%) | # Events | |
Total | 25/37 (67.6%) | |
Gastrointestinal disorders | ||
Constipation | 2/37 (5.4%) | |
Diarrhoea | 3/37 (8.1%) | |
Nausea | 2/37 (5.4%) | |
General disorders | ||
Asthenia | 2/37 (5.4%) | |
Fatigue | 3/37 (8.1%) | |
Infections and infestations | ||
Bronchitis | 2/37 (5.4%) | |
Influenza | 2/37 (5.4%) | |
Nasopharyngitis | 3/37 (8.1%) | |
Upper respiratory tract infection | 2/37 (5.4%) | |
Metabolism and nutrition disorders | ||
Anorexia | 2/37 (5.4%) | |
Hypocalcaemia | 2/37 (5.4%) | |
Hypophosphataemia | 2/37 (5.4%) | |
Musculoskeletal and connective tissue disorders | ||
Arthralgia | 3/37 (8.1%) | |
Back pain | 4/37 (10.8%) | |
Muscle spasms | 2/37 (5.4%) | |
Musculoskeletal pain | 2/37 (5.4%) | |
Pain in extremity | 7/37 (18.9%) | |
Nervous system disorders | ||
Dizziness | 2/37 (5.4%) | |
Headache | 4/37 (10.8%) | |
Respiratory, thoracic and mediastinal disorders | ||
Cough | 2/37 (5.4%) |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results aftercompletion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.
Results Point of Contact
Name/Title | Study Director |
---|---|
Organization | Amgen Inc. |
Phone | 866-572-6436 |
- 20040215