Safety and Efficacy Study of Denosumab in Patients With Recurrent or Unresectable Giant Cell Tumor of Bone

• Sponsor: Amgen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00396279
• Collaborator: (none)
• Enrollment: 37
• Arm: 1
• Actual Duration (Months): 54.8

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
GCT; Giant Cell Tumor of Bone	Biological: Denosumab; Dietary Supplement: Calcium/Vitamin D	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 37 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label, Multi-Center, Phase 2 Safety and Efficacy Study of Denosumab (AMG 162) in Subjects With Recurrent or Unresectable Giant Cell Tumor (GCT) of Bone
• Actual Study Start Date: Jul 10, 2006
• Actual Primary Completion Date: Apr 7, 2008
• Actual Study Completion Date: Feb 1, 2011

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: Xgeva® ; Dietary Supplement: Calcium/Vitamin D

Outcome Measures

Primary Outcome Measures

1. 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

1. 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.

2. 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.

3. 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).

4. 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.

5. 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

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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:

• AmgenTrials clinical trials website

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.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT00396279
• Other Study ID Numbers: 20040215
• First Posted: Nov 6, 2006
• Last Update Posted: Feb 19, 2019
• Last Verified: Feb 1, 2019

• Keywords provided by Amgen: Giant Cell Tumor of Bone
• Additional relevant MeSH terms: Giant Cell Tumors; Bone Neoplasms; Giant Cell Tumor of Bone; Vitamin D; Denosumab; Calcium

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.

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

1. Primary Outcome

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%

2. Secondary Outcome

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

3. Secondary Outcome

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

4. Secondary Outcome

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)

5. Secondary Outcome

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%

6. Secondary Outcome

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

[Not Specified]

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.