Study of Denosumab in Subjects With Giant Cell Tumor of Bone

• Sponsor: Amgen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00680992
• Collaborator: (none)
• Enrollment: 535
• Locations: 33
• Arm: 1
• Actual Duration (Months): 116.2
• Patients Per Site: 16.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Cancer; Giant Cell Tumors; Giant Cell Tumor of Bone; Benign Giant Cell Tumors	Drug: Denosumab	Phase 2

Detailed Description

To determine how safe denosumab is in treating subjects with GCTB

Study Design

• Study Type: Interventional
• Actual Enrollment: 535 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 Study of Denosumab in Subjects With Giant Cell Tumor of Bone
• Actual Study Start Date: Sep 9, 2008
• Actual Primary Completion Date: May 17, 2018
• Actual Study Completion Date: May 17, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Denosumab 120 mg administered subcutaneously (SC) every 4 weeks (Q4W) with a loading dose of 120 mg SC on study days 8 and 15.	Drug: Denosumab; 120 mg administered subcutaneously (SC) every 4 weeks (Q4W) with a loading dose of 120 mg SC on study days 8 and 15.; Other Names: AMG 162, Immunoglobulin G2 human monoclonal antibody to RANK ligand

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Treatment-Emergent Adverse Events (TEAEs) [From first dose of study drug up to last study visit for treatment-emergent period (a maximum of approximately 111 months).]

   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).

2. Number of Participants Who Experienced the Maximum Toxicity Grade (CTCAE Grade ≥ 3) in the Indicated Clinical Chemistry Parameters [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).]

   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

1. Time to Disease Progression or Recurrence During the On-Study Period for Cohort 1, Presented as Kaplan-Meier Estimates of Probability [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).]

   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.

2. Percentage of Participants Without Any On-Study Surgery at Month 6 for Cohort 2 [At month 6.]

   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.

3. Mean Serum Denosumab Trough Concentrations [Blood samples were collected at baseline (day 1), days 8 and 15 and weeks 5, 9, 13 and 25.]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Santa Monica	California	United States	90403
2	Research Site	Stanford	California	United States	94305
3	Research Site	Washington	District of Columbia	United States	20010
4	Research Site	Gainesville	Florida	United States	32607
5	Research Site	Boston	Massachusetts	United States	02114
6	Research Site	Boston	Massachusetts	United States	02215
7	Research Site	Ann Arbor	Michigan	United States	48109
8	Research Site	Minneapolis	Minnesota	United States	55455
9	Research Site	New York	New York	United States	10003
10	Research Site	Philadelphia	Pennsylvania	United States	19106
11	Research Site	Greenville	South Carolina	United States	29605
12	Research Site	Camperdown	New South Wales	Australia	2250
13	Research Site	Woolloongabba	Queensland	Australia	4102
14	Research Site	East Melbourne	Victoria	Australia	3002
15	Research Site	Nedlands	Western Australia	Australia	6009
16	Research Site	Wien		Austria	1090
17	Research Site	Toronto	Ontario	Canada	M5G 1X5
18	Research Site	Montreal	Quebec	Canada	H4A 3J1
19	Research Site	Lyon cedex 8		France	69373
20	Research Site	Marseille cedex 05		France	13385
21	Research Site	Villejuif cedex		France	94805
22	Research Site	Bad Saarow		Germany	15526
23	Research Site	Stuttgart		Germany	70174
24	Research Site	Bologna		Italy	40136
25	Research Site	Milano		Italy	20133
26	Research Site	Leiden		Netherlands	2333 ZA
27	Research Site	Warszawa		Poland	01-211
28	Research Site	Warszawa		Poland	02-781
29	Research Site	Palma de Mallorca	Baleares	Spain	07010
30	Research Site	Barcelona	Cataluña	Spain	08025
31	Research Site	Valencia	Comunidad Valenciana	Spain	46026
32	Research Site	Lund		Sweden	221 85
33	Research Site	Birmingham		United Kingdom	B31 2AP

Sponsors and Collaborators

• Amgen

Investigators

• Study Director: MD, Amgen

Study Documents (Full-Text)

• Study Protocol - Sep 15, 2015
• Statistical Analysis Plan - Jul 17, 2018

More Information

Additional Information:

• AmgenTrials clinical trials website

Publications

• 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.
• 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.
• 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.
• 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.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT00680992
• Other Study ID Numbers: 20062004
• First Posted: May 20, 2008
• Last Update Posted: Feb 19, 2019
• Last Verified: Feb 1, 2019

• Keywords provided by Amgen: Giant Cell Tumor of Bone
• Additional relevant MeSH terms: Neoplasms; Giant Cell Tumors; Bone Neoplasms; Giant Cell Tumor of Bone; Denosumab; Immunoglobulins; Immunoglobulin G

Study Results

Participant Flow

Recruitment Details	Adults and skeletally mature adolescents (≥12 years of age) were enrolled in this open-label single-arm study. The study was conducted at 30 centers in North America, Europe, and Australia from 09 Sep 2008 to study completion on 17 May 2018. The planned study duration for each participant was at least 60 months (following protocol amendment 7).
Pre-assignment Detail	3 participants from study 20040215 (NCT00396279) were enrolled directly into safety follow-up phase without retreatment. They were excluded from all defined analysis sets and results are reported for the 532 participants enrolled into the treatment phase. Non-completion reasons are summarized for the on-study period (ie, initial treatment phase).

Arm/Group Title	Cohort 1 (Denosumab 120 mg Q4W)	Cohort 2 (Denosumab 120 mg Q4W)	Cohort 3 (Denosumab 120 mg Q4W)
Arm/Group Description	Participants with surgically unsalvageable disease (eg, sacral, spinal giant cell tumor of bone (GCTB), or multiple lesions including pulmonary metastases) were enrolled into cohort 1 and received denosumab 120 milligrams (mg) subcutaneously (SC) once every 4 weeks (Q4W), starting on study day 1, plus loading doses of 120 mg SC on days 8 and 15 in the first month of treatment.	Participants with surgically salvageable disease whose planned initial on-study surgery was associated with severe morbidity (eg, joint resection, limb amputation, or hemipelvectomy) were enrolled into cohort 2 and received denosumab 120 mg SC Q4W, starting on study day 1, plus loading doses of 120 mg SC on days 8 and 15 in the first month of treatment.	Participants who participated in study 20040215 and were eligible to enroll in the current study (20062004) for continuation of treatment were enrolled into cohort 3 and received denosumab 120 mg SC Q4W, starting on study day 1. Participants in cohort 3 did not receive loading doses of denosumab on days 8 and 15 in the first month of treatment.
Period Title: Overall Study
STARTED	268	252	12
Safety Analysis Set	265	249	12
Efficacy Analysis Set	260	242	11
COMPLETED	0	0	0
NOT COMPLETED	268	252	12

Baseline Characteristics

Arm/Group Title	Cohort 1 (Denosumab 120 mg Q4W)	Cohort 2 (Denosumab 120 mg Q4W)	Cohort 3 (Denosumab 120 mg Q4W)	Total
Arm/Group Description	Participants with surgically unsalvageable disease (eg, sacral, spinal GCTB, or multiple lesions including pulmonary metastases) were enrolled into cohort 1 and received denosumab 120 mg SC once Q4W, starting on study day 1, plus loading doses of 120 mg SC on days 8 and 15 in the first month of treatment.	Participants with surgically salvageable disease whose planned initial on-study surgery was associated with severe morbidity (eg, joint resection, limb amputation, or hemipelvectomy) were enrolled into cohort 2 and received denosumab 120 mg SC Q4W, starting on study day 1, plus loading doses of 120 mg SC on days 8 and 15 in the first month of treatment.	Participants who participated in study 20040215 and were eligible to enroll in the current study (20062004) for continuation of treatment were enrolled into cohort 3 and received denosumab 120 mg SC Q4W, starting on study day 1. Participants in cohort 3 did not receive loading doses of denosumab on days 8 and 15 in the first month of treatment.	Total of all reporting groups
Overall Participants	268	252	12	532
Age (Count of Participants)
<=18 years	14 5.2%	14 5.6%	0 0%	28 5.3%
Between 18 and 65 years	238 88.8%	231 91.7%	12 100%	481 90.4%
>=65 years	16 6%	7 2.8%	0 0%	23 4.3%
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	36.4 (14.6)	35.1 (13.5)	36.1 (14.9)	35.8 (14.1)
Sex: Female, Male (Count of Participants)
Female	154 57.5%	142 56.3%	5 41.7%	301 56.6%
Male	114 42.5%	110 43.7%	7 58.3%	231 43.4%
Race/Ethnicity, Customized (Count of Participants)
White or Caucasian	221 82.5%	208 82.5%	11 91.7%	440 82.7%
Black or African American	18 6.7%	12 4.8%	0 0%	30 5.6%
Hispanic or Latino	13 4.9%	13 5.2%	1 8.3%	27 5.1%
Asian	11 4.1%	14 5.6%	0 0%	25 4.7%
Native Hawaiian or Other Pacific Islander	0 0%	1 0.4%	0 0%	1 0.2%
Other	5 1.9%	4 1.6%	0 0%	9 1.7%
GCTB Disease Type (Number) [Number]
Primary resectable	0 0%	167 66.3%	0 0%	167 31.4%
Primary unresectable	93 34.7%	0 0%	2 16.7%	95 17.9%
Recurrent resectable	0 0%	85 33.7%	0 0%	85 16%
Recurrent unresectable	175 65.3%	0 0%	10 83.3%	185 34.8%

Outcome Measures

1. Primary Outcome

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).

Outcome Measure Data

Analysis Population Description

The safety analysis set included all enrolled participants who received at least one dose of denosumab on the study.

Arm/Group Title	Cohort 1 (Denosumab 120 mg Q4W)	Cohort 2 (Denosumab 120 mg Q4W)	Cohort 3 (Denosumab 120 mg Q4W)
Arm/Group Description	Participants with surgically unsalvageable disease (eg, sacral, spinal GCTB, or multiple lesions including pulmonary metastases) were enrolled into cohort 1 and received denosumab 120 mg SC once Q4W, starting on study day 1, plus loading doses of 120 mg SC on days 8 and 15 in the first month of treatment.	Participants with surgically salvageable disease whose planned initial on-study surgery was associated with severe morbidity (eg, joint resection, limb amputation, or hemipelvectomy) were enrolled into cohort 2 and received denosumab 120 mg SC Q4W, starting on study day 1, plus loading doses of 120 mg SC on days 8 and 15 in the first month of treatment.	Participants who participated in study 20040215 and were eligible to enroll in the current study (20062004) for continuation of treatment were enrolled into cohort 3 and received denosumab 120 mg SC Q4W, starting on study day 1. Participants in cohort 3 did not receive loading doses of denosumab on days 8 and 15 in the first month of treatment.
Measure Participants	265	249	12
Any TEAE	260 97%	231 91.7%	12 100%
Serious TEAE	98 36.6%	39 15.5%	5 41.7%
Fatal TEAE	8 3%	3 1.2%	0 0%
TEAE leading to treatment phase discontinuation	27 10.1%	24 9.5%	1 8.3%
TEAE leading to study drug discontinuation	27 10.1%	23 9.1%	1 8.3%
CTCAE Grade 3, 4, or 5	121 45.1%	59 23.4%	6 50%
Any TEAE related to study drug	184 68.7%	136 54%	9 75%

2. Primary Outcome

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).

Outcome Measure Data

Analysis Population Description

The safety analysis set included all enrolled participants who received at least one dose of denosumab on the study.

Arm/Group Title	Cohort 1 (Denosumab 120 mg Q4W)	Cohort 2 (Denosumab 120 mg Q4W)	Cohort 3 (Denosumab 120 mg Q4W)
Arm/Group Description	Participants with surgically unsalvageable disease (eg, sacral, spinal GCTB, or multiple lesions including pulmonary metastases) were enrolled into cohort 1 and received denosumab 120 mg SC once Q4W, starting on study day 1, plus loading doses of 120 mg SC on days 8 and 15 in the first month of treatment.	Participants with surgically salvageable disease whose planned initial on-study surgery was associated with severe morbidity (eg, joint resection, limb amputation, or hemipelvectomy) were enrolled into cohort 2 and received denosumab 120 mg SC Q4W, starting on study day 1, plus loading doses of 120 mg SC on days 8 and 15 in the first month of treatment.	Participants who participated in study 20040215 and were eligible to enroll in the current study (20062004) for continuation of treatment were enrolled into cohort 3 and received denosumab 120 mg SC Q4W, starting on study day 1. Participants in cohort 3 did not receive loading doses of denosumab on days 8 and 15 in the first month of treatment.
Measure Participants	265	249	12
Calcium corrected Grade 3 (Above)	0 0%	1 0.4%	0 0%
Calcium corrected Grade 4 (Above)	1 0.4%	1 0.4%	0 0%
Calcium corrected Grade 3 (Below)	1 0.4%	0 0%	0 0%
Calcium corrected Grade 4 (Below)	2 0.7%	0 0%	0 0%
Phosphate Grade 3 (Below)	60 22.4%	41 16.3%	4 33.3%
Magnesium Grade 3 (Above)	4 1.5%	5 2%	2 16.7%
Magnesium Grade 3 (Below)	1 0.4%	0 0%	0 0%
Creatinine Grade 3 (Above)	0 0%	1 0.4%	0 0%
Albumin Grade 3 (Below)	1 0.4%	0 0%	0 0%

3. Secondary Outcome

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).

Outcome Measure Data

Analysis Population Description

The efficacy analysis set included all enrolled participants who were eligible for the study, and who received at least one dose of denosumab on the study. Analysis was performed on cohort 1 only.

Arm/Group Title	Cohort 1 (Denosumab 120 mg Q4W)
Arm/Group Description	Participants with surgically unsalvageable disease (eg, sacral, spinal GCTB, or multiple lesions including pulmonary metastases) were enrolled into cohort 1 and received denosumab 120 mg SC once Q4W, starting on study day 1, plus loading doses of 120 mg SC on days 8 and 15 in the first month of treatment.
Measure Participants	260
Month 6	1.9
Month 12	4.3
Month 24	6.1
Month 36	8.2
Month 60	11.7

4. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

The efficacy analysis set included all enrolled participants who were eligible for the study, and who received at least one dose of denosumab on the study. Analysis was performed on cohort 2 only for those who had the opportunity to be on-study for at least 6 months.

Arm/Group Title	Cohort 2 (Denosumab 120 mg Q4W)
Arm/Group Description	Participants with surgically salvageable disease whose planned initial on-study surgery was associated with severe morbidity (eg, joint resection, limb amputation, or hemipelvectomy) were enrolled into cohort 2 and received denosumab 120 mg SC Q4W, starting on study day 1, plus loading doses of 120 mg SC on days 8 and 15 in the first month of treatment.
Measure Participants	238
Number (95% Confidence Interval) [Percentage of participants]	92.0 34.3%

5. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

The PK analysis set included all participants who received at least 1 dose of denosumab with baseline PK measurement and at least 1 post-baseline PK measurement. Only participants with available data at each time point were included in the analysis.

Arm/Group Title	Adolescent PK Subset (Denosumab 120 mg Q4W)	Adult PK Subset (Denosumab 120 mg Q4W)
Arm/Group Description	Adolescent participants enrolled in the PK substudy who received at least 1 dose of denosumab with baseline PK measurement and at least 1 post-baseline PK measurement were included in the adolescent PK analysis set. Participants received denosumab 120 mg SC Q4W, starting on study day 1, with loading doses of 120 mg SC on days 8 and 15 in the first month of treatment for those enrolled in cohorts 1 or 2.	Adult participants enrolled in the PK substudy who received at least 1 dose of denosumab with baseline PK measurement and at least 1 post-baseline PK measurement were included in the adult PK analysis set. Participants received denosumab 120 mg SC Q4W, starting on study day 1, with loading doses of 120 mg SC on days 8 and 15 in the first month of treatment for those enrolled in cohorts 1 or 2.
Measure Participants	10	15
Day 1	0.0 (0.0)	0.0 (0.0)
Day 8	11800 (4130)	12000 (4300)
Day 15	21800 (5620)	24200 (9050)
Week 5	30400 (6150)	33500 (8970)
Week 9	25100 (6450)	30000 (10300)
Week 13	22300 (6840)	29100 (10000)
Week 17	23600 (4370)	28300 (11600)
Week 25	22400 (6690)	25400 (10800)

Adverse Events

Time Frame	From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7).
Adverse Event Reporting Description	Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
Arm/Group Title	Denosumab 120 mg Q4W (All Cohorts)
Arm/Group Description	All participants received denosumab 120 mg SC Q4W, starting on study day 1, with loading doses of 120 mg SC on days 8 and 15 in the first month of treatment for those enrolled in cohorts 1 or 2.
All Cause Mortality
	Denosumab 120 mg Q4W (All Cohorts)
	Affected / at Risk (%)	# Events
Total	26/526 (4.9%)
Serious Adverse Events
	Denosumab 120 mg Q4W (All Cohorts)
	Affected / at Risk (%)	# Events
Total	176/526 (33.5%)
Blood and lymphatic system disorders
Anaemia	8/526 (1.5%)
Febrile neutropenia	1/526 (0.2%)
Leukopenia	1/526 (0.2%)
Microcytic anaemia	1/526 (0.2%)
Thrombocytopenia	1/526 (0.2%)
Cardiac disorders
Bradycardia	1/526 (0.2%)
Cardiac failure	2/526 (0.4%)
Coronary artery disease	1/526 (0.2%)
Supraventricular tachycardia	1/526 (0.2%)
Congenital, familial and genetic disorders
Aplasia	1/526 (0.2%)
Endocrine disorders
Hyperparathyroidism	2/526 (0.4%)
Toxic nodular goitre	1/526 (0.2%)
Gastrointestinal disorders
Abdominal pain	2/526 (0.4%)
Abdominal pain upper	1/526 (0.2%)
Colitis	1/526 (0.2%)
Diarrhoea	1/526 (0.2%)
Enterocolitis	1/526 (0.2%)
Gastritis	2/526 (0.4%)
Large intestine perforation	1/526 (0.2%)
Melaena	1/526 (0.2%)
Nausea	3/526 (0.6%)
Pancreatic failure	1/526 (0.2%)
Peptic ulcer	1/526 (0.2%)
Small intestinal obstruction	1/526 (0.2%)
Vomiting	2/526 (0.4%)
General disorders
Asthenia	2/526 (0.4%)
Chest pain	1/526 (0.2%)
Death	4/526 (0.8%)
Disease recurrence	1/526 (0.2%)
Hernia	1/526 (0.2%)
Impaired healing	2/526 (0.4%)
Malaise	1/526 (0.2%)
Mucosal inflammation	1/526 (0.2%)
Non-cardiac chest pain	1/526 (0.2%)
Pyrexia	4/526 (0.8%)
Hepatobiliary disorders
Cholecystitis	2/526 (0.4%)
Cholelithiasis	2/526 (0.4%)
Infections and infestations
Abdominal abscess	1/526 (0.2%)
Abdominal wall infection	1/526 (0.2%)
Abscess	2/526 (0.4%)
Abscess jaw	1/526 (0.2%)
Abscess neck	1/526 (0.2%)
Abscess oral	1/526 (0.2%)
Appendicitis	4/526 (0.8%)
Arthritis infective	1/526 (0.2%)
Aspergillus infection	1/526 (0.2%)
Bacteraemia	1/526 (0.2%)
Bacteroides bacteraemia	1/526 (0.2%)
Bone abscess	1/526 (0.2%)
Catheter site infection	1/526 (0.2%)
Cellulitis	2/526 (0.4%)
Device related infection	4/526 (0.8%)
Gastroenteritis	3/526 (0.6%)
Infected cyst	1/526 (0.2%)
Infected skin ulcer	1/526 (0.2%)
Infection	1/526 (0.2%)
Infectious colitis	1/526 (0.2%)
Muscle abscess	1/526 (0.2%)
Orchitis	1/526 (0.2%)
Osteomyelitis	4/526 (0.8%)
Osteomyelitis bacterial	1/526 (0.2%)
Peritonsillar abscess	1/526 (0.2%)
Pharyngitis	1/526 (0.2%)
Pneumonia	4/526 (0.8%)
Postoperative wound infection	1/526 (0.2%)
Pyelonephritis	1/526 (0.2%)
Scrotal abscess	1/526 (0.2%)
Sepsis	3/526 (0.6%)
Staphylococcal infection	1/526 (0.2%)
Staphylococcal osteomyelitis	1/526 (0.2%)
Subcutaneous abscess	2/526 (0.4%)
Tooth infection	1/526 (0.2%)
Urinary tract infection	3/526 (0.6%)
Wound infection	2/526 (0.4%)
Wound infection staphylococcal	1/526 (0.2%)
Injury, poisoning and procedural complications
Ankle fracture	1/526 (0.2%)
Atypical femur fracture	1/526 (0.2%)
Cervical vertebral fracture	1/526 (0.2%)
Endotracheal intubation complication	1/526 (0.2%)
Femoral neck fracture	1/526 (0.2%)
Femur fracture	3/526 (0.6%)
Fracture displacement	1/526 (0.2%)
Gun shot wound	1/526 (0.2%)
Joint dislocation	1/526 (0.2%)
Lumbar vertebral fracture	1/526 (0.2%)
Meniscus injury	1/526 (0.2%)
Overdose	1/526 (0.2%)
Post procedural fistula	1/526 (0.2%)
Postoperative respiratory failure	1/526 (0.2%)
Procedural haemorrhage	1/526 (0.2%)
Pubis fracture	1/526 (0.2%)
Radiation myelopathy	1/526 (0.2%)
Spinal compression fracture	1/526 (0.2%)
Stress fracture	2/526 (0.4%)
Thoracic vertebral fracture	1/526 (0.2%)
Tibia fracture	2/526 (0.4%)
Upper limb fracture	1/526 (0.2%)
Vena cava injury	1/526 (0.2%)
Wound	1/526 (0.2%)
Wound dehiscence	2/526 (0.4%)
Wrist fracture	1/526 (0.2%)
Metabolism and nutrition disorders
Decreased appetite	1/526 (0.2%)
Hypercalcaemia	4/526 (0.8%)
Hypertriglyceridaemia	1/526 (0.2%)
Hypokalaemia	1/526 (0.2%)
Musculoskeletal and connective tissue disorders
Arthralgia	5/526 (1%)
Back pain	5/526 (1%)
Bone pain	1/526 (0.2%)
Exposed bone in jaw	1/526 (0.2%)
Intervertebral disc protrusion	1/526 (0.2%)
Lumbar spinal stenosis	1/526 (0.2%)
Muscular weakness	1/526 (0.2%)
Musculoskeletal pain	1/526 (0.2%)
Myositis	1/526 (0.2%)
Osteitis	3/526 (0.6%)
Osteonecrosis	4/526 (0.8%)
Osteonecrosis of jaw	25/526 (4.8%)
Pain in extremity	3/526 (0.6%)
Pain in jaw	1/526 (0.2%)
Pathological fracture	1/526 (0.2%)
Pseudarthrosis	1/526 (0.2%)
Tendonitis	1/526 (0.2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon	1/526 (0.2%)
Basal cell carcinoma	1/526 (0.2%)
Bone giant cell tumour	19/526 (3.6%)
Bone neoplasm	1/526 (0.2%)
Bone sarcoma	2/526 (0.4%)
Breast cancer	1/526 (0.2%)
Breast cancer stage I	1/526 (0.2%)
Ganglioneuroma	1/526 (0.2%)
Invasive ductal breast carcinoma	2/526 (0.4%)
Lung neoplasm malignant	1/526 (0.2%)
Metastases to lung	3/526 (0.6%)
Myeloproliferative neoplasm	1/526 (0.2%)
Neoplasm	1/526 (0.2%)
Neuroendocrine tumour	1/526 (0.2%)
Oesophageal adenocarcinoma	1/526 (0.2%)
Oncologic complication	1/526 (0.2%)
Osteosarcoma	3/526 (0.6%)
Pelvic neoplasm	1/526 (0.2%)
Renal cancer	1/526 (0.2%)
Rhabdomyosarcoma	1/526 (0.2%)
Sarcoma	5/526 (1%)
Second primary malignancy	1/526 (0.2%)
Spindle cell sarcoma	1/526 (0.2%)
Thyroid cancer	1/526 (0.2%)
Thyroid cancer metastatic	1/526 (0.2%)
Tumour haemorrhage	1/526 (0.2%)
Tumour pain	2/526 (0.4%)
Nervous system disorders
Cauda equina syndrome	1/526 (0.2%)
Central nervous system lesion	1/526 (0.2%)
Cerebrovascular accident	1/526 (0.2%)
Dizziness	1/526 (0.2%)
Facial neuralgia	1/526 (0.2%)
Headache	1/526 (0.2%)
Lethargy	1/526 (0.2%)
Nerve compression	1/526 (0.2%)
Peripheral sensory neuropathy	1/526 (0.2%)
Presyncope	1/526 (0.2%)
Seizure	2/526 (0.4%)
Spinal cord compression	1/526 (0.2%)
Syncope	1/526 (0.2%)
Transient ischaemic attack	1/526 (0.2%)
Product Issues
Device breakage	1/526 (0.2%)
Device failure	1/526 (0.2%)
Device loosening	1/526 (0.2%)
Device occlusion	1/526 (0.2%)
Psychiatric disorders
Completed suicide	1/526 (0.2%)
Suicide attempt	2/526 (0.4%)
Renal and urinary disorders
Acute kidney injury	3/526 (0.6%)
Bladder prolapse	1/526 (0.2%)
Dysuria	1/526 (0.2%)
Nephrolithiasis	2/526 (0.4%)
Renal colic	1/526 (0.2%)
Renal failure	2/526 (0.4%)
Urethral fistula	1/526 (0.2%)
Urge incontinence	1/526 (0.2%)
Reproductive system and breast disorders
Dysmenorrhoea	1/526 (0.2%)
Pelvic pain	1/526 (0.2%)
Respiratory, thoracic and mediastinal disorders
Bronchial haemorrhage	1/526 (0.2%)
Haemoptysis	1/526 (0.2%)
Lung disorder	1/526 (0.2%)
Pharyngeal fistula	1/526 (0.2%)
Pneumothorax	1/526 (0.2%)
Pulmonary embolism	2/526 (0.4%)
Respiratory failure	2/526 (0.4%)
Skin and subcutaneous tissue disorders
Dermatitis psoriasiform	1/526 (0.2%)
Surgical and medical procedures
Bone lesion excision	2/526 (0.4%)
Leg amputation	1/526 (0.2%)
Spinal operation	1/526 (0.2%)
Vascular disorders
Circulatory collapse	1/526 (0.2%)
Haematoma	1/526 (0.2%)
Hypertension	1/526 (0.2%)
Orthostatic hypotension	1/526 (0.2%)
Thrombophlebitis superficial	1/526 (0.2%)
Vasculitis	1/526 (0.2%)
Other (Not Including Serious) Adverse Events
	Denosumab 120 mg Q4W (All Cohorts)
	Affected / at Risk (%)	# Events
Total	480/526 (91.3%)
Blood and lymphatic system disorders
Anaemia	30/526 (5.7%)
Gastrointestinal disorders
Abdominal pain	49/526 (9.3%)
Constipation	60/526 (11.4%)
Dental caries	32/526 (6.1%)
Diarrhoea	60/526 (11.4%)
Nausea	122/526 (23.2%)
Toothache	68/526 (12.9%)
Vomiting	66/526 (12.5%)
General disorders
Asthenia	48/526 (9.1%)
Fatigue	142/526 (27%)
Influenza like illness	27/526 (5.1%)
Oedema peripheral	46/526 (8.7%)
Pyrexia	47/526 (8.9%)
Infections and infestations
Bronchitis	28/526 (5.3%)
Influenza	44/526 (8.4%)
Nasopharyngitis	76/526 (14.4%)
Upper respiratory tract infection	48/526 (9.1%)
Injury, poisoning and procedural complications
Procedural pain	39/526 (7.4%)
Investigations
Weight increased	30/526 (5.7%)
Metabolism and nutrition disorders
Hypercalcaemia	29/526 (5.5%)
Hypocalcaemia	36/526 (6.8%)
Hypophosphataemia	66/526 (12.5%)
Musculoskeletal and connective tissue disorders
Arthralgia	192/526 (36.5%)
Back pain	154/526 (29.3%)
Bone pain	41/526 (7.8%)
Joint swelling	28/526 (5.3%)
Muscle spasms	37/526 (7%)
Musculoskeletal pain	70/526 (13.3%)
Myalgia	42/526 (8%)
Neck pain	29/526 (5.5%)
Pain in extremity	146/526 (27.8%)
Pain in jaw	40/526 (7.6%)
Nervous system disorders
Dizziness	34/526 (6.5%)
Headache	134/526 (25.5%)
Hypoaesthesia	38/526 (7.2%)
Paraesthesia	48/526 (9.1%)
Psychiatric disorders
Anxiety	29/526 (5.5%)
Depression	31/526 (5.9%)
Insomnia	45/526 (8.6%)
Respiratory, thoracic and mediastinal disorders
Cough	54/526 (10.3%)
Oropharyngeal pain	36/526 (6.8%)
Skin and subcutaneous tissue disorders
Pruritus	33/526 (6.3%)
Rash	45/526 (8.6%)

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 after completion. 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.