Conditions: Cancer Giant Cell Tumors Giant Cell Tumor of Bone Benign Giant Cell Tumors
Keywords: Giant Cell Tumor of Bone
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 535
Healthy volunteers: no

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

Arms:
arm 1: 120 mg administered subcutaneously (SC) every 4 weeks (Q4W) with a loading dose of 120 mg SC on study days 8 and 15.

Interventions: intervention 1: Denosumab
Intervention descriptions: intervention 1: 120 mg administered subcutaneously (SC) every 4 weeks (Q4W) with a loading dose of 120 mg SC on study days 8 and 15.

Protocol document:
Prot_000.pdf: 
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Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 
Date:  15 September 2015 
Page 2 of 69 
CONFIDENTIAL 
Investigator’s Agreement 
I have read the attached protocol entitled “An Open-label, Multi-center, Phase 2 Study of 
Denosumab in Subjects with Giant Cell Tumor of Bone”, dated 15 September 2015, and 
agree to abide by all provisions set forth therein. 
I agree to comply with the International Conference on Harmonisation Tripartite 
Guideline on Good Clinical Practice and applicable FDA regulations/guidelines set forth 
in 21 CFR Parts 11, 50, 54, 56, and 312. 
I agree to ensure that Financial Disclosure Statements will be completed by: 
•
me (including, if applicable, my spouse [or legal partner] and dependent children)
•
my subinvestigators (including, if applicable, their spouses [or legal partners] and
dependent children)
at the start of the study and for up to 1 year after the study is completed, if there are 
changes that affect my financial disclosure status. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Amgen Inc.  
Signature 
Name of Principal Investigator 
Date (DD Month YYYY) 


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Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 
Date:  15 September 2015 
Page 4 of 69 
CONFIDENTIAL 
 
 
Subjects who are currently receiving denosumab in study 20040215 will receive denosumab at a 
dose of 120 mg dosing according to their current Q4W schedule and will not receive any loading 
doses (ie, study day 8 and 15). 
For subjects with a complete tumor resection, denosumab treatment continues for 6 doses after 
pathological confirmation of partial response or complete response.  In all other cases, 
denosumab treatment continues until confirmation of disease progression, investigator’s 
recommendation of discontinuation, Amgen’s recommendation of discontinuation, the subject’s 
decision to discontinue for any reason, or administration of any of the proscribed therapies. 
During the time the study is still open, re-treatment may be allowed for subjects who 
demonstrated a response to denosumab and are currently not receiving denosumab treatment 
(eg, in the case of recurrent disease while subject is in the safety follow up phase or subjects that 
have completed the study and have later experienced disease progression).  The re-treatment 
decision including the use of the loading dose and discontinuation of therapy will be handled on a 
case-by-case basis; prior authorization from Amgen is required.  Subjects must meet all 
inclusion/exclusion criteria prior to being considered for re-treatment. 
To evaluate the long-term safety profile of denosumab, data (treatment plus follow-up) will be 
collected for all subjects enrolled through November 2012 for a minimum of 60 months, or until 
death or lost to follow-up, whichever comes first (Section 3.4.2).  For subjects enrolled after 
November 2012 (PK substudy), data (treatment plus follow-up) will be collected until the end of 
the clinical study (Section 3.4.2).  
Subjects who discontinue(d) investigational product will have an End of Treatment visit 
approximately 4 weeks after the last dose of investigational product.  Thereafter, they will 
complete safety follow-up visits approximately every 6 months (± 1 month) for the first year and 
every 12 months (± 1 month) thereafter until the end of the clinical study (Section 3.4.2).  During 
the safety follow-up phase, subjects will be asked about serious adverse events, adverse 
events of interest, and disease treatments and outcomes (Section 9.2). 
Prior to Amendment 7 IRB/IEC approval, subjects currently in the safety follow-up in study 
20040215 will continue on the safety follow-up in this study for up to 2 years after their end of 
study visit on study 20040215.  The total length of safety follow-up on this study for patients 
enrolling from the safety follow-up phase of Amgen study 20040215 will be 2 years less the time 
spent in safety follow-up on study 20040215.  Upon the approval of Amendment 7, subjects who 
enrolled in 20062004 from the 20040215 study will also follow the 20062004 schedule, and 
complete the assessments as described in Appendix A. 
Approximately 50 sites will participate. 
Primary and Secondary Endpoints:   
Safety profile of denosumab characterized in terms of the type, frequency, and severity of 
adverse events and laboratory abnormalities for each cohort.  
Primary study endpoints: 
Secondary study endpoints
• 
time to disease progression for cohort 1 
: 
• 
proportion of subjects without any surgery at month 6 for cohort 2 
• 
serum denosumab (trough) concentrations (PK subset) 
Sample Size:   
The number of subjects in this study is determined by the number of GCTB subjects who qualify 
for the study.  It is anticipated that approximately 530 subjects will participate.  Prior to 
Amendment 7, 510 subjects were enrolled.  Following Amendment 7, an additional approximately 
20 subjects (approximately 10 adolescents and approximately 10 adults) will be enrolled to the 
PK substudy.   


Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 
Date:  15 September 2015 
Page 5 of 69 
CONFIDENTIAL 
 
 
No more than 30 subjects will enroll from the Amgen study 20040215.  No adolescents will enroll 
into cohort 3, since all subjects participating in study 20040215 are adults (≥ 18 years of age). 
Summary of Subject Eligibility Criteria:   
• 
Pathologically confirmed giant cell tumor of bone within 1 year before study enrollment   
Inclusion criteria: 
• 
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 ≥ 50% (ie, ECOG 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]) ≥ 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 
Inclusion criteria for 20040215 subjects: 
• 
Subjects currently enrolled in study 20040215  
• 
Before any study-specific procedure is performed, the appropriate written informed consent 
must be obtained  
• 
Currently receiving other GCTB specific treatment (eg, radiation, chemotherapy, or 
embolization) 
Exclusion criteria: 
• 
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 a highly effective method of 
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 


Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 
Date:  15 September 2015 
Page 6 of 69 
CONFIDENTIAL 
 
 
• 
Developed sensitivity to mammalian cell derived drug products during the 20040215 study 
Exclusion criteria for 20040215 subjects: 
• 
Currently receiving any unapproved investigational product other than denosumab 
• 
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 a highly effective method of 
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 
Investigational Product Dosage and Administration:   
Denosumab will be supplied in a single use 3.0-mL vial containing 1.7 mL of 70 mg/mL.  Each vial 
contains a sterile, clear, colorless to slightly yellow, practically free from particles, preservative 
free liquid in open label glass.  Denosumab will be administered as a SC injection.  
All subjects should be adequately supplemented with calcium and vitamin D (at least 
500 mg of calcium and 400 IU of vitamin D), except in the case of pre-existing hypercalcemia. 
Control Group:   
None 
Procedures:   
Study procedures will only be performed after written independent ethics committee / institutional 
review board (IEC/IRB) approved informed consent is obtained from each subject.   
The site will complete an Inclusion/Exclusion Criteria Worksheet for each subject to be enrolled to 
this study.  Once this worksheet is submitted to Amgen and signed as approved, the site will 
receive a written enrollment confirmation from Amgen allowing the specific subject to enroll in the 
study.  The approval process is required for new enrolling subjects and subjects considered for 
retreatment.  Subjects enrolling from Amgen study 20040215 must complete the 
Inclusion/Exclusion Criteria Worksheet, but do not need to complete the approval process.  The 
site must receive the signed enrollment confirmation form back from Amgen before dosing may 
begin.  
The following procedures will be performed at screening for all subjects (except 20040215 safety 
follow-up subjects) enrolled to the study: medical history; Karnofsky performance status; physical 
exam; disease status; pregnancy test for women of childbearing potential; serum collection for 
anti-denosumab antibody assay (baseline); patient reported outcomes (baseline).  Local 
laboratory values, adverse events, concomitant medications, and treatment procedures will be 
collected.  Subjects enrolled to the PK substudy will also have serum and urine collection for PK 
and biomarker assessments.  A copy of the standard of care imaging reports obtained within 
1 year before enrollment, demonstrating active GCTB must be attached to the subject’s 
medical record.  Histopathology reports dated within 1 year before enrollment will also be 
collected.  Subjects from the 20040215 study will not be required to submit screening imaging 
and histopathology reports upon enrollment into this study.  Similar data from procedures 
performed as standard of care will be attached to the subject’s medical record.  Select 
historical and select on-study imaging performed as standard of care will be required to be sent to 
a central imaging vendor for evaluation of disease response. 
Statistical Considerations:   
The sample size for this study is determined by the number of subjects who qualify for the study.  
It is anticipated that approximately 530 subjects will participate. 
The first and second interim analyses were conducted after 50 and 100 subjects, respectively, 
had the opportunity to complete 6 months of treatment.  The third interim analysis was conducted 


Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 
Date:  15 September 2015 
Page 7 of 69 
CONFIDENTIAL 
 
 
with a data cut-off date of 25 March 2011 and included approximately 286 subjects enrolled.   An 
unplanned interim analysis was performed in August 2013 in response to a request from 
the European Medicines Agency that included approximately 507 subjects and a median 
follow up time of 20.8 months. 
Additional interim analyses may be conducted to monitor the ongoing safety of denosumab or to 
make decisions regarding the use of denosumab in the treatment of giant cell tumor of bone 
(GCTB). 
Treatment-emergent adverse events, treatment procedures, and anti-denosumab antibodies will 
be summarized for all subjects who receive at least 1 dose of denosumab. 
Sponsor:  Amgen Inc.


Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 
Date:  15 September 2013 
Page 8 of 69 
CONFIDENTIAL 
Study Design and Treatment Schema 
E
N
R 
O 
L 
L 
M 
E 
N 
T 
E
N
D 
O 
F 
T 
R
E 
A 
T
M
E
N
T
Surgery 
(1)
Cohort 3 
Current 20040215 Subjects (3) 
Denosumab 120 mg SC Q4W if 
receiving Denosumab in Amgen 
study 20040215  
Complete resection - If 
pathological CR/PR then 
denosumab 120 mg SC 
Q4W for 6 doses (2)
Cohort 1 
Unsalvageable  
Denosumab 120 mg SC Q4W 
with a loading dose of 120 mg SC 
on study days 8 and 15 
Continue denosumab 
120 mg SC Q4W if 
clinical benefit  
1.
Surgical resection may occur at any time during the study based on the clinical judgment of the investigator
2.
Subjects not achieving a complete resection post surgery may continue to receive denosumab at a dose of 120 mg SC Q4W if clinical benefit is determined
3.
Subjects participating in the 20040215 study will enroll and receive denosumab at a dose of 120 mg Q4W (subjects will not receive the day 8 and 15 dose).
4.
For all subjects, including the PK substudy, data (treatment plus follow-up) will be collected until the end of the clinical study (Section 3.4.2) which is when
subjects enrolled before Amendment 7 will complete a minimum of 60 months on study or otherwise have discontinued.  For subjects who discontinue(d)
investigational product, safety follow-up visits will be conducted approximately every 6 months (± 1 month) after the End of Treatment visit (approximately
4 weeks after the last dose of investigational product) for the first year, then every 12 months (± 1 month).  The final safety follow-up visit will be conducted at
the time of the end of the clinical study (Section 3.4.2) (even if this is not approximately 6 or12 months since the previous follow-up visit).
F 
O 
L 
L 
O 
W 
U 
P 
(4) 
S
C
R 
E 
E 
N 
I 
N 
G 
Study 
Day 1 
Study 
Day 8 
Study 
Day 15 
Week 
5 
Week 
9 
Week 
13 
Week 
17 
+ 
Q4W 
Informed 
Consent 
Signed 
Enroll 
End of 
Treatment 
Safety 
Follow up 
End of 
Study 
Q4W 
Q4W 
Q4W 
Cohort 2 
Salvageable 
Denosumab 120 mg SC Q4W 
with a loading dose of 120 mg SC 
on study days 8 and 15 
Continue denosumab 
120 mg SC Q4W if 
clinical benefit  


Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 
Date:  15 September 2015 
Page 9 of 69 
CONFIDENTIAL 
Study Glossary 
Abbreviation/Acronym 
Definition 
BPI-SF 
Brief Pain Inventory – Short Form 
CR 
Complete response  
CTCAE 
Common Terminology Criteria for Adverse Events (version 3) 
CT 
Computed tomography 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
GCTB 
Giant cell tumor of bone 
IEC/IRB 
Independent ethics committee/Institutional review board 
IHC 
Immunohistochemistry 
IPIM 
Investigational Product Instruction Manual 
IVRS 
Interactive Voice Response System 
MRI 
Magnetic resonance imaging 
ONJ 
Osteonecrosis of the jaw 
OPG 
Osteoprotegerin 
PET 
Positron emission tomography 
PET/CT 
Positron emission tomography/ Computed tomography 
PK 
Pharmacokinetic(s) 
POR 
Proof of Receipt 
PR 
Partial response 
sCTx 
Serum C- telopeptide 
SC 
Subcutaneous 
uNTx 
Urinary N-telopeptide 


Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 
Date:  15 September 2015 
Page 10 of 69 
CONFIDENTIAL 
 
 
Study Term 
Definition 
Baseline 
Closest recorded measurement prior to the administration of 
denosumab on study day 1 
Disease Status (ie, physician’s 
assessment status) 
Investigator’s subjective opinion of the subject’s health status 
which determines whether subject will enroll, continue 
treatment, or discontinue the study 
Enrollment 
Subject is considered enrolled once the screening procedures 
have been completed and the eligibility criteria worksheet is 
completed and signed by Amgen. 
EOS 
End of Study:  The end of the clinical study for all subjects will 
occur when all subjects enrolled through November 2012 
(before Amendment 7) have completed at least 60 months on 
study, or until death or lost to follow-up, whichever comes first.   
Study enrollment (prior to Amendment 7) concluded in 
November 2012; therefore the final study visits will be 
conducted and the study is anticipated to end by approximately 
November 2017. 
EOT  
End of Treatment visit:  the End of Treatment visit will occur 
approximately 4 weeks after the last dose of investigational 
product  
Screening period 
Begins once written informed consent is signed and ends 
before administration of investigational product on study day 1, 
Week 1 
Safety Follow-up 
Safety Follow Up:  
Subjects who discontinue(d) investigational product will have an 
End of Treatment visit approximately 4 weeks after the last 
dose of investigational product.  Thereafter, they will complete 
safety follow-up visits approximately every 6 months (± 1 
month) for the first year and then every 12 months (± 1 month) 
thereafter until the end of the clinical study (Section 3.4.2). 
Upon the approval of Amendment 7, subjects who enrolled in 
20062004 from the 20040215 study will also follow the 
20062004 schedule, and complete the assessments as 
described in Appendix A. 
Prior to Amendment 7 IRB/IEC approval, for subjects enrolling 
from the safety follow-up from study 20040215, subjects will 
continue on the safety follow-up in this study for up to 2 years 
after their end of study visit on study 20040215.  The total 
length of safety follow-up on this study for patients enrolling 
from the safety follow-up phase of Amgen study 20040215 will 
be 2 years less the time spent in safety follow-up on study 
20040215. 
Study day 1 
Defined as the first day investigational product is administered 
to the subject 
 


Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 
Date:  15 September 2015 
Page 11 of 69 
CONFIDENTIAL 
TABLE OF CONTENTS 
Protocol Synopsis ............................................................................................................. 3 
Study Design and Treatment Schema .............................................................................. 8 
Study Glossary .................................................................................................................. 9 
1.
OBJECTIVES ......................................................................................................... 14
1.1 
Primary ....................................................................................................... 14 
1.2 
Secondary .................................................................................................. 14 
1.3 
Exploratory ................................................................................................. 14 
2.
BACKGROUND AND RATIONALE ........................................................................ 14
2.1 
Disease ....................................................................................................... 14 
2.1.1 
Clinical Presentation of Giant Cell Tumor of Bone ..................... 14 
2.1.2 
Staging and Grading of Giant Cell Tumor of Bone ..................... 16 
2.1.3 
Pathophysiology of Giant Cell Tumor of Bone (GCTB) .............. 16 
2.2 
Denosumab Background ............................................................................ 17 
2.2.1 
Clinical Experience With Denosumab in Giant Cell 
Tumor of Bone (GCTB) .............................................................. 17 
2.2.2 
Summary of Effects of OPG-Fc Treatment on Tooth 
Eruption and Long Bone Geometry in Neonate Rats ................. 18 
2.3 
Rationale .................................................................................................... 18 
2.3.1 
Selection of Dose ....................................................................... 19 
2.4 
Hypotheses ................................................................................................. 21 
3.
EXPERIMENTAL PLAN ......................................................................................... 21
3.1 
Study Design .............................................................................................. 21 
3.2 
Number of Centers ..................................................................................... 22 
3.3 
Number of Subjects .................................................................................... 22 
3.4 
Estimated Study Duration ........................................................................... 23 
3.4.1 
Study Duration for Participants ................................................... 23 
3.4.2 
End of Study (EOS) .................................................................... 23 
4.
SUBJECT ELIGIBILITY .......................................................................................... 23
4.1 
Inclusion Criteria ......................................................................................... 24 
4.2 
Exclusion Criteria ........................................................................................ 24 
5.
SUBJECT ENROLLMENT ..................................................................................... 25
5.1 
Treatment Assignment ............................................................................... 26 
6.
TREATMENT PROCEDURES ............................................................................... 26
6.1 
Investigational Product Dosage, Administration, and Schedule ................. 27 
6.2 
Dose Escalation and Stopping Rules ......................................................... 27 
6.3 
Dosage Adjustments .................................................................................. 28 
6.4 
Concomitant Therapy (Calcium and Vitamin D Supplements) ................... 28 


Product:  Denosumab (AMG 162) 
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6.5 
Proscribed Therapy During Study Period ................................................... 28 
7. 
STUDY PROCEDURES ......................................................................................... 28 
7.1 
Screening/Baseline ..................................................................................... 29 
7.2 
Medical History ........................................................................................... 30 
7.3 
Treatment History ....................................................................................... 30 
7.4 
Physical Examination ................................................................................. 30 
7.4.1 
Oral Examination ........................................................................ 30 
7.5 
Imaging ....................................................................................................... 31 
7.6 
Histopathology ............................................................................................ 31 
7.7 
Laboratory Assessments ............................................................................ 31 
7.7.1 
Serum Chemistry ........................................................................ 31 
7.7.2 
Pregnancy Test .......................................................................... 31 
7.7.3 
Pharmacokinetic and Serum C-telopeptide (sCTx) 
Assessments (Pharmacokinetic Substudy) ................................ 31 
7.7.4 
Urine Assessments (Pharmacokinetic Substudy) ....................... 31 
7.7.5 
Anti-denosumab Antibody Assay ................................................ 32 
7.8 
Sample Storage and Destruction ................................................................ 32 
7.9 
Patient Reported Outcomes - Brief Pain Inventory - Short Form 
(BPI-SF) ...................................................................................................... 34 
7.10 
End of Treatment (EOT) Visit ..................................................................... 34 
7.11 
Safety Follow-up Phase .............................................................................. 34 
8. 
REMOVAL AND REPLACEMENT OF SUBJECTS ............................................... 35 
8.1 
Removal of Subjects ................................................................................... 35 
8.2 
Replacement of Subjects ............................................................................ 36 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ....................... 36 
9.1 
Definitions ................................................................................................... 36 
9.1.1 
Adverse Events .......................................................................... 36 
9.1.2 
Serious Adverse Events ............................................................. 37 
9.2 
Reporting Procedures for All Adverse Events ............................................ 38 
9.3 
Serious Adverse Event Reporting Procedures ........................................... 39 
9.4 
Pregnancy and Lactation Reporting ........................................................... 39 
9.4.1 
Adjudication Process for Suspected Osteonecrosis of 
the Jaw and Suspected Atypical Femoral Fracture 
Adverse Events .......................................................................... 40 
10. 
STATISTICAL CONSIDERATIONS ....................................................................... 41 
10.1 
Study Design .............................................................................................. 41 
10.2 
Study Endpoints, Subsets, and Covariates ................................................ 41 
10.2.1 
Primary Endpoint ........................................................................ 41 
10.2.2 
Secondary Endpoint ................................................................... 41 
10.2.3 
Exploratory ................................................................................. 41 
10.2.4 
Subsets ....................................................................................... 42 


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10.3 
Sample Size Considerations ...................................................................... 42 
10.4 
Access to Individual Subject Treatment Assignments ................................ 43 
10.5 
Interim Analysis and Early Stopping Guidelines ......................................... 43 
10.6 
Planned Methods of Analysis ..................................................................... 43 
10.6.1 
General Approach/Considerations ............................................. 43 
10.6.2 
Analysis of Key Study Endpoints ................................................ 43 
10.6.3 
Planned Methods of Analysis for the Safety Follow-up 
Phase ......................................................................................... 45 
11.
INVESTIGATIONAL PRODUCT ............................................................................ 45
11.1 
Denosumab ................................................................................................ 45 
11.2 
Compliance in Investigational Product Administration ................................ 46 
12.
REGULATORY OBLIGATIONS ............................................................................. 46
12.1 
Informed Consent ....................................................................................... 46 
12.2 
Independent Ethics Committee/Institutional Review Board ........................ 47 
12.3 
Prestudy Documentation Requirements ..................................................... 48 
12.4 
Subject Confidentiality ................................................................................ 48 
12.5 
Investigator Signatory Obligations .............................................................. 49 
13.
ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................... 49
13.1 
Protocol Amendments and Study Termination ........................................... 49 
13.2 
Study Documentation and Archive ............................................................. 49 
13.3 
Study Monitoring and Data Collection ........................................................ 50 
13.4 
Language.................................................................................................... 52 
13.5 
Publication Policy ....................................................................................... 52 
13.6 
Compensation ............................................................................................ 53 
14.
REFERENCES ....................................................................................................... 54
15.
APPENDICES ........................................................................................................ 55
List of Tables 
Table 1.  Estimated 95% Confidence Interval for Example Adverse Event 
Incidence Rates
 
 ....................................................................................... 42
List of Appendices 
Appendix A.  Schedule of Assessments
 
 ......................................................................... 56
Appendix B.  Adverse Event Severity Scoring System
 
 ................................................... 60
Appendix C.  Pregnancy Notification Worksheet
 
 ............................................................ 61
Appendix D.  Sample SAE Report Form
 
 ......................................................................... 62
Appendix E.  Karnofsky Performance Status and Eastern Cooperative 
Oncology Group (ECOG) Performance Status
 
 ........................................ 66
Appendix F.  Sample Brief Pain Inventory - Short Form (BPI-SF)
 
 .................................. 67
Appendix G.  Lactation Notification Worksheet
 
 ............................................................... 69


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Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 
Date:  15 September 2015 
Page 15 of 69 
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(Szendroi et al, 2003; Szendroi, 2004).  Giant cell tumor of bone (GCTB) develops after 
the epiphyseal plates have closed and is most commonly diagnosed during the third 
decade of life.  However, cases occur rarely in skeletally mature adolescents (ie, 
adolescents who have closed epiphyseal plates). 
Symptoms that accompany primary GCTB include localized pain, tenderness, and 
swelling and the osteolysis may lead to pathologic fractures, decreased joint motion and 
impaired function.  Lesions that originate in the spine may also result in neurological 
deficits.  
Surgery is the definitive therapy for GCTB and about 80% of primary GCTB patients 
have lesions amenable to surgical resection.  Although en bloc excisions of the tumor 
may be curative, they also carry significant morbidity (eg, amputation of a limb, joint 
resection) and greatly influence quality of life.  Curettage procedures with and without 
bone graft may allow for complete resection of the tumor and preservation of the limb or 
joint, but the risk for recurrence is greater.  Larger GCTB lesions may not be amenable 
to curettage resections and may result in severe morbid procedures.  In addition, lesions 
in bones of the hand and distal radius have the highest rate of metastasis even with 
en bloc excision.  Overall, the risk for recurrence is estimated at 10 to 20 percent after 
en bloc excision and at 40% to 75% (Malawer et al, 2005) after curettage, albeit a less 
debilitating procedure. 
The GCTB lesion has a wide transition zone and poorly defined borders.  In order to 
decrease the risk for recurrence with curettage resections, aggressive adjuvant surgical 
procedures are usually necessary.  These procedures are used to remove normal bone 
and ensure a wider surgical margin beyond the transition zone.  Adjuvant procedures 
such as cryosurgery, phenol instillation, high-speed burr, reconstitution with cement, 
and/or radiation therapy have been described.  Side effects may include localized bone 
necrosis, increased risk for fracture, and delayed union of bone.  Radiation therapy may 
be used and carries the risk of malignant induction to the bone. 
Prognosis for GCTB is excellent if it does not recur.  Recurrent GCTB commonly 
manifests as localized recurrence, however distant recurrence/metastasis may also 
occur.  The definitive therapy for local recurrences is also surgery.  More aggressive 
surgery for local recurrences carries significant morbidity and patients with local 
recurrences are at increased risk for subsequent localized and distant recurrences.   


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Protocol Number:  20062004 
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Eventually, patients become surgically unsalvageable.  For some patients with primary 
spinal or sacral lesions, there may be no definitive surgical option.  In these cases, 
treatment options are limited.  Radiation therapy may control local tumor growth; 
however, there is a risk for malignant transformation.  Systemic therapy with 
chemotherapy is of limited value and serial embolization of larger lesions may provide 
symptomatic relief. 
2.1.2 
Staging and Grading of Giant Cell Tumor of Bone 
In general, grades and histologic pattern do not correlate well with prognosis for 
recurrence or metastasis.  The presence of osteoid product in GCTB is not prognostic 
for recurrence or metastasis.  Giant-cell rich osteosarcoma may be difficult to 
differentiate from benign GCTB.  Likewise, the presence of giant cells in osteosarcoma 
is not prognostic for better outcomes.  A grading scale was described; grade I 
(completely benign), grade II (borderline), and grade III (frankly sarcomatous).  
Grade I and II have not been correlated with decreased risk for recurrence or metastasis 
(Malawer et al, 2005). 
2.1.3 
Pathophysiology of Giant Cell Tumor of Bone (GCTB) 
Giant Cell Tumors of bone (GCTB) are highly vascularized, expansile osteolytic lesions 
with indistinct borders and wide transitional zones.  The histological appearance of giant 
cell tumors includes three distinct cell types; multinucleated osteoclast-like giant cells, 
spindle-shaped osteoblast-like stromal cells and monocytes (likely precursors of the 
giant cells).  Although the name GCTB implies that the “giant cells” are the neoplastic 
component, the true neoplastic component remains unknown and controversial.  The 
similarity in appearance of giant cells to normal osteoclasts suggests that the stromal 
component (spindle-shaped cells) may be the true neoplastic component and that the 
giant cells are the reactive component (Morgan et al, 2005; Zheng et al, 2001).   
In archival samples (n = 33) of primary and recurrent GCTB, RANKL was expressed and 
detected by immunohistochemistry (IHC) and in situ hybridization.  RANKL expression 
was observed in the stromal component and osteoprotegerin and RANK were expressed 
on the giant cells.  In addition, soluble factors, presumably RANKL, secreted from 
stromal cells of GCTBs are able to induce osteoclastogenesis from peripheral blood 
monocytes (Nishimura et al, 2005).  Although TGF-b1, MCP-1, TNF IL-1, 6, 11, 17, 18, 
MCS-F and PTHrP are expressed in the tumor, none of these factors are known to 
induce osteoclast differentiation.  Endothelial cells of normal vessel did not express 
RANK or RANKL (Roudier et al, CTOS 2006).  


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2.2 
Denosumab Background 
Perturbations in the balance between bone formation and resorption can lead to 
generalized osteoporosis (resulting from estrogen deficiency and aging) or local bone 
lysis (resulting from rheumatoid arthritis and bone metastases).  RANK-RANK ligand 
(RANKL) system has been identified as an essential mediator of osteoclast formation, 
function, and survival (Teitelbaum et al, 2003).  RANKL binds RANK on osteoclasts or 
osteoclast precursors to stimulate or promote differentiation into osteoclasts and activate 
mature osteoclasts to resorb bone.  Therefore, RANKL is a therapeutic target for 
diseases associated with increased bone resorption. 
Denosumab is a fully human monoclonal IgG2 antibody to RANKL that binds with high 
affinity (Kd 3 x 10-12 M) and specificity to the soluble and cell membrane-bound forms of 
human RANKL.  Denosumab is highly specific because it binds only to RANKL and not 
to other members of the tumor necrosis factor (TNF) family, including TNFα, TNFβ, 
TNF-related apoptosis-inducing ligand, or CD40 ligand (Elliott et al, 2006).  Denosumab 
binding prevents the activation of RANK and inhibits the formation, activation, and 
survival of osteoclasts.  As a consequence, bone resorption and cancer-induced bone 
destruction are reduced.   
Refer to the latest version of the investigator brochure for additional and updated 
information on denosumab background, clinical experience, and safety information. 
2.2.1 
Clinical Experience With Denosumab in Giant Cell Tumor of Bone 
(GCTB) 
The Phase 2 study, Study 20040215, investigated the potential role for denosumab in 
the treatment of GCTB.  The study tested the hypothesis that denosumab, a RANKL 
inhibitor, can inhibit the growth and survival of tumor cells in patients with GCTB.   
Patients with unresectable or recurrent GCTB were treated with denosumab 120 mg 
administered SC every four weeks, with additional loading doses on days 8 and 15.  This 
dosing frequency was predicted to attain target serum concentrations of denosumab 
within the first month of treatment.   
The primary endpoint was tumor response, defined as complete or near complete 
elimination of giant cells or in the absence of histology data, a lack of radiologic 
progression (single largest dimension < 20% increase by computed tomography [CT] or 
magnetic resonance imaging [MRI]). 


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The primary analysis was conducted of 37 subjects (20 female) with a data cut off date 
of 07 April 2008.  Of these 37 subjects, 35 were evaluable for response to treatment.  
Eighty-six percent (30/35) of subjects had a tumor response:  20 of 20 by histology, and 
10 of 15 by radiology.  Adverse events (AEs) were reported in 33 of the 37 subjects 
included in the primary analysis.  One death was reported in a subject diagnosed with 
giant cell sarcoma who developed disease progression (not treatment-related) during the 
off treatment follow-up period.  No treatment-related serious AEs were reported. 
2.2.2 
Summary of Effects of OPG-Fc Treatment on Tooth Eruption and 
Long Bone Geometry in Neonate Rats 
Genetic ablation of RANKL in knockout mice, and lifelong inhibition of RANKL by OPG in 
transgenic rats, was associated with deleterious changes in long bone growth, geometry 
and/or strength (Ominsky et al, 2009; Li et al, 2000; Kong et al, 1999). RANKL knockout 
mice, but not OPG transgenic rats, also exhibited failure of tooth eruption 
(Kong et al, 1999). The pharmacologic effects of RANKL inhibition on tooth eruption and 
on long bone growth, geometry, and strength were therefore evaluated in several 
nonclinical studies in neonatal rats. RANKL inhibition in neonatal rats via administration 
of OPG-Fc or RANK-Fc resulted in reduced weight gain, growth plate abnormalities, 
reduced bone length, increased bone mass and increased structural bone strength 
parameters. Although material bone strength parameters were on average unchanged, 
femoral toughness was consistently reduced. Inhibited tooth eruption and impaired root 
development were also observed with doses of OPG-Fc that effected a dramatic 
reduction in bone resorption. These effects were partially reversible upon discontinuation 
of OPG-Fc, however, extrinsic long bone strength was reduced and reduced bone 
length, femur toughness, and abnormal tooth root development persisted.  
Overexpression of OPG in OPG-transgenic (OPG-Tg) rats prenatally through to skeletal 
maturity resulted in a suboptimal long bone phenotype. These data suggest that the use 
of denosumab in the rapidly growing skeleton carries potential risks from widened 
growth plates, decreased bone growth, decreased bone toughness, and impaired 
dentition. 
2.3 
Rationale 
GCTB is a rare disease characterized clinically by expansile osteolytic lesions and 
histologically by multi-nucleated giant cells that are similar to osteoclasts, the cells that 
mediate bone destruction.  The tumor cells express RANKL and its receptor, RANK.  
The RANK/RANKL pathway is an essential mediator of osteoclast function, formation 
and survival.  Denosumab, a fully human monoclonal antibody of RANKL, inhibits 


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osteoclast-mediated bone destruction and may provide therapeutic benefit for patients 
with giant cell tumor.   
For subjects with surgically unsalvageable GCTB, current treatment options are limited 
and may include treatments (radiation, embolization, chemotherapy) that lead to 
significant disability, poor quality of life and possibly death.  Bisphosphonates are 
currently under investigation in this subject population; however, only limited preclinical 
and clinical data are currently available (Cheng et al, 2004). 
Study 20040215 was an open-label, phase 2 safety and efficacy study of denosumab in 
subjects (n = 37) with recurrent or unresectable GCTB.  The primary analysis, 
demonstrated that denosumab has significant biological activity in GCTB based on 
assessment of histologic or radiologic response.  The safety profile of denosumab in this 
study appeared to be consistent with that observed in other settings. 
The potential elimination of osteoclasts by denosumab in subjects with GCTB is 
expected to inhibit osteolysis and in turn, inhibit the progression of GCTB and potentially 
improve clinical outcomes for these subjects. 
In addition, for patients with surgically salvageable GCTB that require severe morbid 
procedures, treatment with denosumab may reduce the size of the lesion and improve 
surgical options to allow limb and joint-sparing procedures. 
There have been rare reported cases of GCTB in adolescents.  Giant Cell Tumor of 
Bone (GCTB) usually occurs in skeletally mature adolescents after the epiphyseal plates 
have closed, and all adolescent subjects enrolled into this study will have radiological 
confirmation of skeletal maturity.  No further long bone growth is anticipated after 
epiphyseal plates are closed.  In the adolescent subset, eruption of adult dentition may 
not be complete, but in the majority of cases the non-erupted teeth are likely to be 
limited to non-essential wisdom teeth, which are absent from many adults.  There are 
few treatment options for adolescents with mature skeletons and GCTB.  Based on the 
seriousness of GCTB and the limited treatment options, Amgen believes that this 
protocol, which includes adolescents with mature skeletons and GCTB, presents greater 
than minimal risk, but also presents the prospect of direct benefit to the subject.  
2.3.1 
Selection of Dose 
The dose and schedule selected for this study consists of a loading dose regimen of 
three subcutaneous injections of denosumab 120 mg SC Q4W with a loading dose of 
120 mg SC on study days 8 and 15.  This dosing regimen is currently being used in the 


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Amgen study 20040215.  Subjects enrolling from study 20040215 will receive 
denosumab at a dose of 120 mg dosing according to their current Q4W schedule and 
will not receive any loading doses (ie, study day 8 and 15). 
The selection of the dose and schedule of denosumab was based on safety, 
pharmacokinetic and pharmacodynamic data obtained from the phase 1 and 2 studies 
described above.  Specifically, study 20040113 provided a comprehensive dataset 
guiding the dose selection for subjects with bone metastases.  All the denosumab arms 
showed biological activity in reducing bone resorption, which was comparable to that 
seen with the IV bisphosphonate arm.  The rate of skeletal-related events in the 
denosumab arms was similar to that observed in the bisphosphonate arm.  Among the 
denosumab doses and schedules evaluated, the regimen of 120 mg every 4 weeks was 
associated with maximum reduction of the bone turnover marker uNTX by week 13, the 
primary endpoint in the study.  
Unlike the 30 mg every 4-week dosing, the 120 mg every 4-week schedule avoided low 
exposures of denosumab (eg, serum levels below 4000 ng/mL) that could potentially 
translate into reduced efficacy in some subjects based on preliminary population PK/PD 
modeling of the phase 2 data.  Denosumab was found to be safe and well tolerated in all 
study arms.  While no symptomatic hypocalcemia was reported in study 20040113, the 
120 mg every 4-week schedule (n = 41) appeared preferable as no grade 2 or higher 
hypocalcemia was recorded as opposed to 5, grade 2 and one, grade 3 hypocalcemia in 
the denosumab 180 mg every 4-week treatment group (n = 43). 
The subjects on this study have active GCTB with surgically unsalvageable or large 
GCTB lesions.  The goal of denosumab treatment is to reduce or halt the growth of the 
GCTB lesion and prevent further osteolysis.  The pharmacodynamic goal is to quickly 
attain target serum concentrations of denosumab and maintain a constant level of 
maximal suppression of osteoclast activity and bone resorption. 
Based on the PK model, denosumab 120 mg given subcutaneously every 4 weeks 
would require 6 to 9 months to achieve steady-state.  With the loading doses on 
day 8 and 15, subjects are expected to achieve steady-state within the first month 
resulting in exposure levels that were previously tested in phase 2 studies. 
In clinical trials denosumab has been administered to adults with a weight as low as 
38 kg.  Adults weighing as low as 38 kg had a similar adverse event profile as compared 
to subjects in higher weight ranges.  It is anticipated that skeletally mature adolescents 


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Protocol Number:  20062004 
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weighing at least 38 kg will have a similar adverse event profile as adults in this lower 
weight range.   
2.4 
Hypotheses 
It is anticipated that denosumab, an inhibitor of RANKL, will be a well-tolerated treatment 
for patients with surgically unsalvageable GCTB disease, and patients with surgically 
salvageable disease whose planned on-study surgery is associated with severe 
morbidity.  
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a phase 2, international, multi-center, open-label study in subjects with GCTB, 
receiving denosumab at a dose of 120 mg SC Q4W with a loading dose of 120 mg SC 
on study days 8 and 15.   
There are 3 cohorts in this study: 
•
Cohort #1:  Subjects with surgically unsalvageable disease (eg, sacral, spinal GCTB,
or multiple lesions including pulmonary metastases)
•
Cohort #2: Subjects with surgically salvageable disease whose planned on-study
surgery is associated with severe morbidity (eg, joint resection, limb amputation, or
hemipelvectomy)
•
Cohort #3:  Subjects who are currently participating in Amgen study 20040215 giant
cell tumor study who are eligible to enroll
Subjects who are currently receiving denosumab in study 20040215 will receive 
denosumab at a dose of 120 mg dosing according to their current Q4W schedule and 
will not receive any loading doses (ie, study day 8 and 15). 
For subjects with a complete tumor resection, denosumab treatment continues for 
6 doses after pathological confirmation of partial response (PR) or complete response 
(CR).  In all other cases, denosumab treatment continues until confirmation of disease 
progression, investigator’s recommendation of discontinuation, Amgen’s 
recommendation of discontinuation, the subject’s decision to discontinue for any reason, 
or administration of any of the proscribed therapies. 
During the time the study is still open, re-treatment may be allowed for subjects who 
demonstrated a response to denosumab and are currently not receiving denosumab 
treatment (eg, in the case of recurrent disease while subject is in the safety follow up 
phase or subjects that have completed the study and have later experienced disease 
progression).  The re-treatment decision including the use of the loading dose and 


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Protocol Number:  20062004 
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discontinuation of therapy will be handled on a case-by-case basis; prior authorization 
from Amgen is required.  Subjects must meet all inclusion/exclusion criteria prior to 
being considered for re-treatment.   
To evaluate the long-term safety profile of denosumab, data (treatment plus follow-up) 
will be collected for all subjects enrolled through November 2012 for a minimum of 
60 months, or until death or lost to follow-up, whichever comes first (Section 3.4.2).  For 
subjects enrolled after November 2012 (PK substudy), data (treatment plus follow-up) 
will be collected until the end of the clinical study (Section 3.4.2).   
Subjects who discontinue(d) investigational product will have an End of Treatment visit 
approximately 4 weeks after the last dose of investigational product.  Thereafter, they 
will complete safety follow-up visits approximately every 6 months (± 1 month) for the 
first year and every 12 months (± 1 month) thereafter until the end of the clinical study 
(Section 3.4.2). 
Prior to Amendment 7 IRB/IEC approval, subjects currently in the safety follow-up in 
study 20040215 will continue on the safety follow-up in this study for up to 2 years after 
their end of study visit on study 20040215.  The total length of safety follow-up on this 
study for patients enrolling from the safety follow-up phase of Amgen study 20040215 
will be 2 years less the time spent in safety follow-up on study 20040215.  Upon the 
approval of Amendment 7, subjects who enrolled in 20062004 from the 20040215 study 
will also follow the 20062004 schedule, and complete the assessments as described in 
Appendix A. 
The overall study design is described by a study schema at the end of the protocol 
synopsis section. 
The study endpoints are defined in Section 10.2. 
3.2 
Number of Centers 
Approximately 50 sites will participate.  Sites that do not enroll at least one subject within 
6 months of site initiation may be terminated.  
3.3 
Number of Subjects 
Participants in this clinical investigation shall be referred to as “subjects”. 
The sample size for this study is governed by the number of subjects who qualify for the 
study.  It is anticipated that approximately 530 subjects will participate.  Prior to 
Amendment 7, 510 subjects were enrolled.  Following Amendment 7, an additional 


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Protocol Number:  20062004 
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CONFIDENTIAL 
approximately 20 subjects (approximately 10 adolescents and approximately 10 adults) 
will be enrolled to the PK substudy.  
No more than 30 subjects will enroll from the Amgen study 20040215.  No adolescents 
will enroll into cohort 3, since all subjects participating in study 20040215 are adults 
(≥ 18 years of age). 
3.4 
Estimated Study Duration 
3.4.1 
Study Duration for Participants 
For each subject enrolled through November 2012 (before Amendment 7), the total 
duration of a subject’s participation will be at least 60 months including treatment and 
follow-up, or until death or lost to follow-up, whichever comes first.  For subjects enrolled 
after November 2012 (PK substudy), data (treatment plus follow-up) will be collected 
until the end of the clinical study (Section 3.4.2).    
The total duration of this study from start of enrollment to end of follow-up for the last 
subject is expected to be approximately 9 years (approximately 4 years of enrollment 
prior to Amendment 7, and approximately 5 years of treatment and follow-up).  
3.4.2 
End of Study (EOS) 
The end of the clinical study for all subjects will occur when all subjects enrolled through 
November 2012 (before Amendment 7) have completed at least 60 months on study, or 
until death or lost to follow-up, whichever comes first.  Study enrollment (prior to 
Amendment 7) concluded in November 2012; therefore the final study visits will be 
conducted and the study is anticipated to end by approximately November 2017.  
Subjects enrolled in the PK substudy will complete treatment and/or follow-up at the 
same time as subjects included prior to Amendment 7. 
4. 
SUBJECT ELIGIBILITY 
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (ie, age, sex, 
and race), date, and outcome of the screening process (eg, enrolled into study, reason 
for ineligibility, or refused to participate). 
Before any study-specific procedure, the appropriate written informed consent must be 
obtained (see Section 12.1).  For adolescents, in addition to written informed consent, 
the assent of the adolescent also must be obtained if requested by the institutional 
review board/independent ethics committee. 


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4.1 
Inclusion Criteria 
Subjects meeting the following criteria are considered eligible for this study. 
4.1.1 Pathologically confirmed giant cell tumor of bone within 1 year before study 
enrollment 
4.1.2 Measurable evidence of active disease within 1 year before study enrollment 
4.1.3 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 
4.1.4 Karnofsky performance status ≥ 50% (ie, ECOG status 0, 1, or 2) 
4.1.5 Adults or skeletally mature adolescents (ie, radiographic evidence of at least 
1 mature long bone [eg, humerus with closed growth epiphyseal plate]) 
≥ 12 years of age 
4.1.6 Skeletally mature adolescents must weigh at least 45 kg 
4.1.7 Before any study-specific procedure is performed, the appropriate written 
informed consent must be obtained 
Inclusion Criteria for 20040215 subjects: 
4.1.8 Subjects currently enrolled in study 20040215 
4.1.9 Before any study-specific procedure is performed, the appropriate written 
informed consent must be obtained 
4.2 
Exclusion Criteria 
4.2.1 Currently receiving other GCTB specific treatment (eg, radiation, chemotherapy, 
or embolization) 
4.2.2 Concurrent bisphosphonate treatment 
4.2.3 Known or suspected current diagnosis of underlying malignancy including 
high-grade sarcoma, osteosarcoma, fibrosarcoma, malignant giant cell sarcoma 
4.2.4 Known or suspected current diagnosis of non GCTB giant cell-rich tumors 
4.2.5 Known or suspected current diagnosis of brown cell tumor of bone or Paget’s 
disease 
4.2.6 Known diagnosis of second malignancy within the past 5 years (subjects with 
definitively treated basal cell carcinoma and cervical carcinoma in situ are 
permitted) 
4.2.7 Prior history or current evidence of osteonecrosis/osteomyelitis of the jaw 
4.2.8 Active dental or jaw condition which requires oral surgery, including tooth 
extraction 
4.2.9 Non-healed dental/oral surgery 
4.2.10 Planned invasive dental procedure for the course of the study 
4.2.11 Subject currently is enrolled in or has not yet completed at least 30 days since 
ending other investigational device or drug study(ies), or subject is receiving 
other investigational agent(s) 


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4.2.12 Subject has known sensitivity to any of the products to be administered during 
dosing 
4.2.13 Unstable systemic disease including active infection, uncontrolled hypertension, 
unstable angina, congestive heart failure, or myocardial infarction within 
6 months before enrollment  
4.2.14 Subject is pregnant or breast feeding, or planning to become pregnant within 
5 months after the end of treatment 
4.2.15 Female subject of child bearing potential is not willing to use a highly effective 
method of contraception during treatment and for 5 months after the end of 
treatment 
4.2.16 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 
Exclusion Criteria for 20040215 subjects: 
4.2.17 Developed sensitivity to mammalian cell derived drug products during the 
20040215 study 
4.2.18 Currently receiving any unapproved investigational product other than 
denosumab 
4.2.19 Subject is pregnant or breast feeding, or planning to become pregnant within 
5 months after the end of treatment 
4.2.20 Female subject of child bearing potential is not willing to use a highly effective 
method of contraception during treatment and for 5 months after the end of 
treatment 
4.2.21 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 
5. 
SUBJECT ENROLLMENT 
Before subjects may be entered into the study, Amgen requires a copy of the site’s 
written independent ethics committee/institutional review board (IEC/IRB) approval of the 
protocol, informed consent form, and all other subject information and/or recruitment 
material, if applicable (see Section 12.3). 
All subjects who enter into the screening period for the study (defined as the point at 
which the subject signs the informed consent) will receive a unique subject identification 
number before any study procedures are performed.  This number will be used to 
identify the subject throughout the clinical study and must be used on all study 
documentation related to that subject.  The subject identification number must remain 
constant throughout the entire clinical study; it must not be changed at the time of 
rescreening or enrollment.  Subjects enrolling from the 20040215 study will receive a 
new subject identification number for this study. 


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The subject identification number will consist of 9 digits.  The first 3 digits will represent a 
protocol identifier (ie, 204) and will be identical for all sites.  The next 3 digits will 
represent the site number (ie, 101, 102, 103, etc.) and will be identical for all subjects at 
a particular site.  The last 3 digits will represent the subject identification and will be 
assigned in sequential order, per site, as subjects are screened (ie, 001, 002, 003, etc.).  
Therefore, the first subject to enter screening at site 101 will receive the number 
204101001; the second subject at this site will receive the number 204101002, etc. 
Once the site deems the subject is eligible for enrollment to the study and all screening 
procedures have been completed, the Eligibility Criteria Worksheet (found in the 
Regulatory Binder) and a case history of the subject’s disease must be completed and 
faxed to the US or European Sponsor Contact (see cover page for contact information) 
as appropriate, for approval before the first dose of investigational product can be 
administered to any subject.  The approval process is required for new enrolling subjects 
and subjects considered for retreatment.  Subjects enrolling from Amgen study 
20040215 must complete the Inclusion/Exclusion Criteria Worksheet, but do not need to 
complete the approval process.  The case history must include the treatment history, 
including original and translated imaging reports and histopathology reports (specimen 
source must be clearly identified in the report).  
Those subjects who meet the inclusion/exclusion criteria at the Screening visit and who 
receive an enrollment confirmation from Amgen may be enrolled into the study and 
begin the treatment period.  A subject is considered enrolled into the study once the 
eligibility criteria worksheet is signed by Amgen.  
5.1 
Treatment Assignment 
As this is an open-label study, all subjects will receive denosumab.  Investigational 
product management will be automatically resupplied to the sites through an interactive 
voice response system (IVRS).  
6. 
TREATMENT PROCEDURES 
Denosumab is considered to be the investigational product in this study; therefore, drug 
accountability must be obtained on all used and unused denosumab vials.  For further 
details regarding preparation and administration of the investigational product, refer to 
the Investigational Product Instruction Manual (IPIM), which is a document 
external to this protocol. 


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6.1 
Investigational Product Dosage, Administration, and Schedule 
Denosumab is to be administered by a licensed healthcare professional at a dose of 
120 mg SC Q4W with a loading dose of 120 mg SC on study days 8 and 15.  Subjects 
enrolling from study 20040215 will receive denosumab at a dose of 120 mg dosing 
according to their current Q4W schedule and will not receive any loading doses 
(ie, study day 8 and 15). 
6.2 
Dose Escalation and Stopping Rules 
For loading doses, if the study days 8 and 15 doses are delayed more than 8 calendar 
days, it will be considered a missed dose and recorded as such on the electronic case 
report form (eCRF).  The next dose is to be given at the next scheduled visit date (based 
on study day 1).  There must be at least 4 days (ie, 96 hours) between the study days 1, 
8, and 15 doses (ie, ± 3 days from the scheduled visit date). 
For Q4W doses, the planned dose may be given up to 7 days before the scheduled 
visit, as long as there are at least 21 days between doses.  If a planned dose 
(eg, week 5, week 9, etc.) is delayed more than 7 calendar days, it will be considered a 
missed dose and recorded as such on the eCRF.  The next dose is to be given at the 
next scheduled visit date (based on study day 1).  
For subjects with a complete tumor resection, denosumab treatment continues for 
6 doses after pathological confirmation of partial response or complete response.  In all 
other cases, denosumab treatment continues until confirmation of disease progression, 
investigator’s recommendation of discontinuation, Amgen’s recommendation of 
discontinuation, the subject’s decision to discontinue for any reason, or administration of 
any of the proscribed therapies.  See Section 3.1 for potential re-treatment with 
denosumab following discontinuation.  
Administration of investigational product is recommended to be withheld 30 days prior to 
any elective invasive oral/ dental procedure.  Investigational product administration is 
recommended to be withheld until documented evidence of complete mucosal healing 
following any invasive oral/ dental procedure.  
Subjects with osteonecrosis of the jaw (ONJ) on study may temporarily or permanently 
discontinue investigational product at investigator discretion.  Re-exposure to 
investigational product may occur if the investigator and sponsor agree subject safety 
will not be compromised. 
The dosing schedule is described by a schema in the protocol synopsis. 


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6.3 
Dosage Adjustments 
There will be no dose adjustments allowed in this study.  
6.4 
Concomitant Therapy (Calcium and Vitamin D Supplements) 
All subjects should be adequately supplemented with calcium and Vitamin D (at 
least 500 mg of calcium and 400 IU of Vitamin D), except in the case of pre-existing 
hypercalcemia.  Due to differences in regional availability, a dosage form of vitamin D 
that gives an equivalent of at least 400 IU daily may be given. 
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 6.5.  
6.5 
Proscribed Therapy During Study Period 
Concurrent treatment with bisphosphonates is not allowed while the subject is on study.  
Other active therapy for GCTB including chemotherapy, embolization and radiation 
therapy are not allowed while the subject is on study (embolization immediately prior to 
planned definitive surgery [e.g. to improve operative hemostasis] is allowed in 
accordance with local guidelines).  Use of any unapproved (ie, no marketing 
authorization has been granted) investigational product (other than denosumab) or 
device is not allowed until after all study assessments are completed. 
Invasive dental procedures should be avoided.  If a subject undergoes an invasive 
dental procedure while on study, a clinical decision to continue the subject on 
investigational product must be documented in the medical chart. 
7. 
STUDY PROCEDURES 
It is the responsibility of the investigator to obtain an IEC/IRB-approved, signed, 
informed consent from all subjects before any protocol-related procedures are 
performed.  
Study visits during the treatment period will occur every 4 weeks until the end of 
treatment with an additional visit at study days 8 and 15.  For those subjects enrolling 
from the 20040215 study, study visits will continue at every 4 week intervals until the end 
of treatment.  When possible, all assessments/procedures during the treatment phase of 
study should be obtained within 7 calendar days or less of the specified study visit 
(except during the loading dose period), relative to study day 1.  Every effort should be 
made to keep subjects on the study schedule as planned from study day 1.   


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To evaluate the long-term safety profile of denosumab, data (treatment plus follow-up) 
will be collected for all subjects enrolled through November 2012 for a minimum of 
60 months, or until death or lost to follow-up, whichever comes first (Section 3.4.2).  For 
subjects enrolled after November 2012 (PK substudy), data (treatment plus follow-up) 
will be collected until the end of the clinical study (Section 3.4.2).  
Subjects who discontinue(d) investigational product will have an End of Treatment visit 
approximately 4 weeks after the last dose of investigational product.  Thereafter, they 
will complete safety follow-up visits approximately every 6 months (± 1 month) for the 
first year and every 12 months (± 1 month) thereafter until the end of the clinical study 
(Section 3.4.2). 
Prior to Amendment 7 IRB/IEC approval, subjects currently in the safety follow-up in 
study 20040215 will continue on the safety follow-up in this study for up to 2 years after 
their end of study visit on study 20040215.  The total length of safety follow-up on this 
study for patients enrolling from the safety follow-up phase of Amgen study 20040215 
will be 2 years less the time spent in safety follow-up on study 20040215.  Upon the 
approval of Amendment 7, subjects who enrolled in 20062004 from the 20040215 study 
will also follow the 20062004 schedule, and complete the assessments as described in 
Appendix A. 
All study assessments must be completed before
Missed visits, procedures that are not performed, and examinations that are not 
conducted must be reported as such on the eCRFs.  
 investigational product administration. 
All imaging, histopathology samples and chemistry laboratory samples will be analyzed 
by the site's local laboratory/institution with the exception of antibody samples.  
The schedule of assessments is provided in Appendix A.  
7.1 
Screening/Baseline 
Screening assessments conducted as standard of care may be used as screening data 
prior to signing of informed consent if conducted within the required screening period.  
Subjects in Cohort 3 will not be required to submit this screening data upon enrollment 
into this study.  All screening procedures must be completed no more than 28 days 
before Study Day 1 (day of first dose of investigational product) with the following 
exceptions:    
•
Histopathology (reports only):  A copy of all standard of care reports obtained within
1 year before enrollment, confirming GCTB of bone must be provided to Amgen.


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•
Imaging (eg, PET, CT, PET/CT, MRI or X-ray): A copy of the standard of care reports
obtained within 1 year before enrollment, demonstrating active GCTB must be
provided to Amgen.  Select historical imaging performed as standard of care will be
required to be sent to a central imaging vendor for evaluation of disease response.
•
A negative pregnancy test, for women with reproductive potential, must be
documented no more than 7 days before first dose of denosumab (Study Day 1).  If a
pregnancy test result will be more than 7 days old before first dose of investigational
product, the test must be repeated and documented in the eCRF.
•
Informed consent may be obtained more than 28 days before Study Day 1.
7.2 
Medical History 
The subject’s medical history will be obtained ≤ 28 days before day 1 of the study and 
recorded on the eCRF.  A detailed history of all pre-existing conditions must be 
documented on the eCRF (and in the source documents).  Any illness or medical 
condition that is ongoing at the time of the subject’s first dose of study drug 
should be noted.  Worsening of a pre-existing condition should be reported as an 
adverse event.   
7.3 
Treatment History 
Anti-neoplastic treatment, including chemotherapy, radiotherapy, and surgery specifically 
used to treat the subject’s primary and metastatic giant cell tumor of bone will be 
collected.  
7.4 
Physical Examination 
Each physical examination visit will include assessment of Karnofsky performance 
status, disease status, vital signs (screening only), height (screening only), and weight 
(screening only).  Refer to Appendix E for Karnofsky performance status criteria. 
7.4.1 
Oral Examination 
A visual examination of the oral cavity (oral examination), including teeth, mucosa, and 
jaws, will be conducted by the investigator, or designated licensed healthcare 
professional, at screening (for newly enrolled subjects), to establish baseline oral health 
conditions, and approximately at least 24 weeks thereafter (approximately every 
6 months) to identify and document any new abnormalities or changes in pre-existing 
conditions.  Routine oral examinations should be conducted as part of standard subject 
management. 
Appropriate preventive dentistry should be considered prior to treatment with 
denosumab. 


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If any new abnormalities or changes in pre-existing conditions are identified, additional 
information may be requested. 
7.5 
Imaging 
A copy of imaging reports (eg, PET, CT, PET/CT, MRI, or X-ray) performed as standard 
of care must be attached to the subject’s medical record.  Select on-study imaging 
performed as standard of care will be required to be sent to a central imaging vendor for 
evaluation of disease response.     
7.6 
Histopathology 
A copy of all available pathology reports obtained as standard of care must be attached 
to the subject’s medical record, including the surgical report of the GCTB target lesion 
resection.  The histopathology samples and reports may be requested either during the 
study or at end of study for evaluation of histopathological response to treatment. 
7.7 
Laboratory Assessments 
7.7.1 
Serum Chemistry 
At a minimum, calcium, albumin, magnesium, phosphorus, and creatinine will be 
collected and analyzed at the site’s local laboratory.  No lab supplies will be provided to 
sites for these tests. 
7.7.2 
Pregnancy Test 
Urine/serum pregnancy labs will be collected and analyzed at the site’s local laboratory.  
No lab supplies will be provided to sites for these tests. 
7.7.3 
Pharmacokinetic and Serum C-telopeptide (sCTx) Assessments 
(Pharmacokinetic Substudy)  
Serum samples for serum denosumab concentration levels and sCTx will be obtained on 
a subset of approximately 20 subjects
Appendix A
 (approximately 10 adolescent and 10 adult 
subjects) at baseline (prior to administration of investigational product on study day 1) 
and on study as outlined in the schedule of assessments (
).  Amgen Inc or its 
designee will be responsible for analyzing these samples. 
7.7.4 
Urine Assessments (Pharmacokinetic Substudy) 
All urine samples will be collected prior to investigational product administration. Urine 
samples will be collected for urinary N-telopeptide (uNTx).  Urine analytes will include 
creatinine and raw N-telopeptide (NTx).  Amgen Inc or its designee will perform these 
assays and will measure urine creatinine. 


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The uNTx will be corrected for urine creatinine by generating a ratio.  Using the uNTx as 
reported in units of nM and urine creatinine in units of mg/dL, the creatinine 
measurement will be multiplied by 0.0884, and used to generate the corrected ratio.  The 
resulting equation will be:  uNTx/Cr (nM BCE/mM) = uNTx/(Cr*0.0884). 
Urine will be obtained on a subset of approximately 20 subjects (approximately 
10 adolescent and 10 adult subjects) at baseline (prior to administration of 
investigational product on study day 1) and on study as outlined in the schedule of 
assessments (Appendix A).  
Urine collection instructions 
A urine sample will be collected from subjects after the first void and preferably in the 
morning.  It is recommended that urine samples be collected in the clinic, if feasible.  If 
the subject is to collect the urine sample at home, he/she will need to be provided with 
containers for sample collection and for transporting the sample to the site on the day of 
collection.  Subject instructions will be provided on how and when to collect the sample, 
recording the time of collection, and storing the sample (refrigerated) until it is brought to 
the study site for processing. 
7.7.5 
Anti-denosumab Antibody Assay 
Serum for anti-denosumab antibody assay will be collected at baseline and as outlined 
on the schedule of assessments (Appendix A).  
Prior to Amendment 7 IRB/IEC approval, for subjects who were in the safety follow-up of 
study 20040215 and are enrolling in this study, serum samples for anti-denosumab 
antibody assay will be collected approximately every 6 months for up to 24 months after 
the end of study visit in the 20040215 study.  Upon the approval of Amendment 7, 
subjects who enrolled in 20062004 from the 20040215 study will also follow the 
20062004 schedule, and complete the assessments as described in Appendix A. 
Amgen Inc., or its designee, will be responsible for analyzing serum samples for the 
assessment of anti-denosumab antibodies.  Amgen Biological Sample Management 
(BSM) will provide a study manual that outlines handling, labeling, and shipping 
procedures for serum samples.  These samples may also be used for future biomarker 
development testing. 
7.8 
Sample Storage and Destruction 
Any serum or urine samples collected according to the schedule of assessments 
(Appendix A) can be analyzed for any of the tests outlined in the protocol and for any 


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tests necessary to minimize risks to study subjects.  This includes testing to ensure 
analytical methods produce reliable and valid data throughout the course of the study.  
This can also include, but is not limited to, investigation of unexpected results, incurred 
sample reanalysis, and analyses for method transfer and comparability.  
All samples and associated results will be no less than single coded prior to being 
shipped from the site for analysis, or storage.  Tracking of samples will be independent 
of the subject’s identification number for the study.  Results are stored in a secure 
database to ensure confidentiality.   
If informed consent is provided by the subject, Amgen can do additional testing on 
remaining samples (ie, residual and back-up) to investigate and better understand Giant 
Cell Tumor of Bone, the dose response and/or prediction of response to denosumab, 
characterize antibody response, and characterize aspects of the molecule (eg, 
mechanism of action/target, metabolites).  Results from this analysis are to be 
documented and maintained, but are not necessarily reported as part of this study.  
Samples can be retained for up to 20 years.   
Since the evaluations are not expected to benefit the subject directly or to alter the 
treatment course, the results of the pharmacokinetic study, biomarker studies, or other 
exploratory studies are not placed in the subject’s medical record and are not to be 
made available to the subject, members of the family, the personal physician, or other 
third parties, except as specified in the informed consent. 
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the investigator is to 
provide the sponsor with the required study and subject number so that any remaining 
serum or urine samples and any other components from the cells can be located and 
destroyed.  Samples will be destroyed once all protocol-defined procedures are 
completed.  However, information collected from samples prior to the request for 
destruction, will be retained by Amgen. 
The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the Investigator, at the end of the storage period, or as 
appropriate (eg, the scientific rationale for experimentation with a certain sample type no 
longer justifies keeping the sample).  If a commercial product is developed from this 
research project, the sponsor owns the commercial product.  The subject has no 


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commercial rights to such product and has no commercial rights to the data, information, 
discoveries, or derivative materials gained or produced from the sample. 
7.9 
Patient Reported Outcomes - Brief Pain Inventory - Short Form 
(BPI-SF) 
The BPI-SF is a patient completed questionnaire that has been shown to be a valid 
measure of pain in cancer (Cleeland CS, 1991).  It captures information on the intensity 
of pain (pain severity) as well as the degree to which pain interferes with function (pain 
interference).  The BPI-SF will be collected prior to each administration of investigational 
product.  
7.10 
End of Treatment (EOT) Visit 
Each subject will have an End of Treatment visit approximately 4 weeks after their last 
dose of investigational product.  Study procedures are listed in Appendix A. 
7.11 
Safety Follow-up Phase 
Subjects who discontinue(d) investigational product will have an End of Treatment visit 
approximately 4 weeks after the last dose of investigational product.  Thereafter, they 
will complete safety follow-up visits approximately every 6 months (± 1 month) for the 
first year and then every 12 months (± 1 month) thereafter until the end of the clinical 
study (Section 3.4.2).  During the safety follow-up phase, subjects will be asked 
about serious adverse events, adverse events of interest, and disease treatments 
and outcomes (Section 9.2). 
Upon the approval of Amendment 7, subjects who enrolled in 20062004 from the 
20040215 study will also follow the 20062004 schedule, and complete the assessments 
as described in Appendix A. 
Prior to Amendment 7 IRB/IEC approval, for subjects who were in the safety follow-up 
on study 20040215 and are enrolling in this study, safety data including SAEs, AEs, 
concomitant medications, and serum samples for anti-denosumab antibody testing will 
be collected approximately every 6 months for up to 24 months after the end of study 
visit in the 20040215 study.  Thus, the total length of safety follow-up on this study will 
be 2 years less the time spent in safety follow-up on Amgen study 20040215. 
The safety follow-up visits at 6 and 12 months after the End of Treatment visit must be 
conducted in the clinic.  Thereafter, subjects may be contacted by other methods (eg, 
telephone) to complete the assessments.  


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Subjects will be asked to provide information regarding their GCTB status and 
current treatments.  Additionally, subjects will be asked if they have experienced 
any of the following adverse events of interest: 
•
ONJ
•
Malignancy, including malignancy in GCTB
•
Atypical femoral fracture
If the subject has experienced any of the adverse events of interest, specific 
additional information will be requested/collected as necessary according to each 
type of event.  The additional information will include, but is not limited to: 
•
ONJ:  dental records; information will be sent for adjudication by
independent reviewers (see Section 9.4.1)
•
Malignancy (including malignancy in GCTB):  pathology reports
•
Atypical femoral fracture:  x-ray or other imaging; medical/surgical
records.  Information will be sent for adjudication by independent
reviewers (see Section 9.4.1).
If the subject has experienced any serious adverse event (Section 9.1.2), 
information is to be collected and reported (see Section 9.3). 
If the subject has been receiving treatment with commercial denosumab (XGEVA), 
or any other Amgen product as standard of care for GCTB or any other condition, 
Adverse Drug Reactions related to that product will be collected. 
8. 
REMOVAL AND REPLACEMENT OF SUBJECTS 
8.1 
Removal of Subjects 
Subjects have the right to withdraw fully or partially from the study at any time and for 
any reason without prejudice to his or her future medical care by the physician or at the 
institution. 
Withdrawal of full consent for a study means that the subject does not wish to receive 
further investigational treatment and does not wish to or is unable to continue further 
study participation.  Any subject may withdraw full consent to participate in the study at 
any time during the study.  The investigator will discuss with the subject the most 
appropriate way to withdraw to ensure the subject’s health.   
Withdrawal of partial consent means that the subject does not wish to take 
investigational product any longer but is still willing to collaborate in providing further 
data by continuing on study (eg, participate in all subsequent study visits or procedures).  


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Subjects may decline to continue receiving investigational product at any time during the 
study.  These subjects, as well as those who have stopped receiving investigational 
product for other reasons (eg, investigator or sponsor concern) should continue the 
schedule of study observations.   
Reasons for removal from investigational product or observation might include: 
•
withdrawal of consent
•
administrative decision by the investigator or Amgen
•
pregnancy (report on Pregnancy Notification Worksheet, see Appendix C)
•
ineligibility
•
significant protocol deviation
•
subject noncompliance
•
adverse event
•
disease progression
•
administration of bisphosphonates or other proscribed therapies
8.2 
Replacement of Subjects 
No subjects will be replaced. 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING 
9.1 
Definitions 
9.1.1 
Adverse Events 
An adverse event is defined in the International Conference on Harmonisation (ICH) 
Guideline for Good Clinical Practice as “any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product and that does not 
necessarily have a causal relationship with this treatment.” (ICH E6:1.2) 
This definition of adverse events is broadened in this study to include any such 
occurrence (eg, sign, symptom, or diagnosis) or worsening of a pre-existing medical 
condition from the time that a subject has signed informed consent to the time of 
enrollment to or initiation of investigational product. 
This definition of adverse events also includes worsening of a pre-existing medical 
condition.  Worsening indicates that the pre-existing medical condition (eg, cancer, 
diabetes, migraine headaches, gout) has increased in severity, frequency, or duration of 
the condition or an association with significantly worse outcomes. 


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Interventions for pretreatment conditions (eg, elective cosmetic surgery) or medical 
procedures that were planned before study enrollment are not considered adverse 
events. 
Pregnancy is not considered an adverse event (see Appendix C for reporting any 
pregnancy). 
The investigator is responsible for reviewing laboratory test results and determining 
whether an abnormal value in an individual study subject represents a change from 
values before the study.  In general, abnormal laboratory findings without clinical 
significance (based on the investigator's judgment) should not be recorded as adverse 
events; however, laboratory value changes requiring therapy or adjustment in prior 
therapy are considered adverse events. 
9.1.2 
Serious Adverse Events 
A serious adverse event (SAE) is defined as an adverse event that meets at least 1 of 
the following serious criteria: 
•
is fatal
•
is life threatening (places the subject 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
A hospitalization meeting the regulatory definition for “serious” is any inpatient hospital 
admission that includes a minimum of an overnight stay in a health care facility excluding 
hospitalizations for anticipated protocol-specified procedures (eg, to perform resection 
on affected limb/region with giant cell tumor) or blood product transfusions, if being 
administered for cancer-related treatment.  However, prolongation of hospitalization or 
re-admission after the subject has been discharged would be considered a Serious 
Adverse Event.  Elective hospitalizations or routine hospitalizations for standard of care 
administration are not considered to be serious adverse events. 
Any adverse event that does not meet one of the definitions of serious (eg, emergency 
room visit, outpatient surgery, or requires urgent investigation) may be considered by the 
investigator to meet the “other significant medical hazard” criterion for classification as a 
serious adverse event.  Examples include allergic bronchospasm, convulsions, and 
blood dyscrasias. 


Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 
Date:  15 September 2015 
Page 38 of 69 
CONFIDENTIAL 
9.2 
Reporting Procedures for All Adverse Events 
The investigator is responsible for ensuring that all adverse events (as defined in 
Section 9.1 and as further specified below) and adverse events of interest 
(Section 7.11) observed by the investigator or reported by subjects during screening 
(excluding cohort 3 subjects), treatment, through the first 6-month safety follow up visit 
as well as through the end of safety follow-up phase for adverse events of interest 
(Section 3.4.2) are collected and recorded in the subjects’ medical records and in 
designated study documents (ie, eCRF, and, on the serious adverse event report 
(SAER) form for serious adverse events).  These adverse events will include all serious 
and non serious adverse events (as defined in Sections 9.1.1 and 9.1.2) that occur after 
the subject has signed the informed consent form.   
The following adverse event attributes must be assigned by the investigator:  adverse 
event diagnosis or syndrome(s) (if known, signs or symptoms if not known); event 
description (with detail appropriate to the event); dates of onset and resolution; severity; 
assessment of relatedness to investigational product and action taken.  Diagnoses or 
syndromes-rather than signs or symptoms-should be recorded.  The investigator may be 
asked to provide follow-up information, discharge summaries, and extracts from medical 
records or eCRFs. 
If applicable, the relationship of the adverse event to the investigational product will be 
assessed by means of the question:  “Is there a reasonable possibility that the event 
may have been caused by the investigational product?”  The investigator should respond 
to this question with either Yes or No. 
The severity grading scale used in this study is described in Appendix B. 
Medically significant adverse events considered related to the investigational product by 
the investigator or the sponsor will be followed until resolved or considered stable. 
It will be left to the investigator’s clinical judgment to determine whether an adverse 
event is related and of sufficient severity to require the subject’s removal from treatment 
or from the study.  A subject may also voluntarily withdraw from treatment due to what 
he or she perceives as an intolerable adverse event.  If either of these situations arises, 
the subject should be strongly encouraged to undergo an end-of-study assessment and 
be under medical supervision until symptoms cease or the condition becomes stable. 


Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 
Date:  15 September 2015 
Page 39 of 69 
CONFIDENTIAL 
9.3 
Serious Adverse Event Reporting Procedures 
Serious adverse events will be collected and recorded beginning with the signing of the 
informed consent through the end of the safety follow up phase.   
All serious adverse events must be reported to Amgen within 24 hours of discovery or 
notification of the event.  Initial serious adverse event information and all amendments or 
additions must be recorded on a Serious Adverse Event Report Form (Appendix D) and 
faxed to Amgen Global Safety.  Relevant medical records should be faxed to Amgen 
Global Safety as soon as they become available; autopsy reports should be provided for 
deaths if available.   
For all deaths, available autopsy reports and relevant medical reports should be faxed to 
Amgen Global Safety.   
If a subject is permanently withdrawn from the study or safety follow-up because of a 
serious adverse event, this information must be included in the initial or follow-up 
Serious Adverse Event Report Form as well as the End of Study or End of Safety 
Follow-up eCRF. 
Amgen will report serious adverse events (SAEs) and suspected unexpected serious 
adverse reactions (SUSARS) as required to regulatory authorities, 
investigators/institutions and ethics committees in compliance with all applicable 
regulatory requirements and ICH GCP Guidelines. 
The investigator should notify the appropriate IRB or ethics committee of serious 
adverse events occurring at the site and other adverse event reports received from 
Amgen, in accordance with local procedures and statutes. 
9.4 
Pregnancy and Lactation Reporting 
Throughout denosumab treatment and through 5 months after the last dose of IP, the 
investigator should counsel subjects who are women of childbearing potential on the 
risks of pregnancy while receiving denosumab, and discuss methods to decrease the 
risk of becoming pregnant.  It is recommended to document these discussions in the 
medical records. 
If a pregnancy occurs in a female subject, or female partner of a male subject, while the 
subject is taking protocol-required therapies report the pregnancy to Amgen as specified 
below. 


Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 
Date:  15 September 2015 
Page 40 of 69 
CONFIDENTIAL 
In addition to reporting any pregnancies occurring during the study, investigators should 
report pregnancies that occur after the last dose of protocol-required therapies through 
5 months after the last dose with the exception of subjects who are receiving a 
commercial Xgeva in the safety follow-up phase.  For those subjects investigators 
should report pregnancies until the end of the safety follow-up phase.  
For both situation/ scenarios the pregnancy should be reported to Amgen Global 
Patient Safety within 24 hours of the investigator’s knowledge of the event of a 
pregnancy.  Report a pregnancy on the Pregnancy Notification Worksheet (Appendix C).  
Amgen will seek to follow the pregnant woman throughout her pregnancy and her baby 
up to 12 months after birth. 
If a lactation case occurs while the female subject is taking protocol-required therapies, 
report the lactation case to Amgen as specified below.  
In addition to reporting a lactation case during the study, investigators should report 
lactation cases that occur after the last dose of protocol-required therapies through 
5 months after the last dose.  For those subjects receiving a commercial Xgeva in 
the safety follow-up phase investigators should report lactation cases until the 
end of the safety follow-up phase.  
Any lactation case should be reported to Amgen Global Patient Safety within 24 hours 
of the investigator’s knowledge of event.  Report a lactation case on the Lactation 
Notification Worksheet (Appendix G). 
9.4.1 
Adjudication Process for Suspected Osteonecrosis of the Jaw and 
Suspected Atypical Femoral Fracture Adverse Events 
All subjects with an oral adverse event suspicious of ONJ should be examined by 
a dentist or other qualified oral specialist (eg, oral surgeon).  All subjects 
presenting with new or unusual thigh, hip, or groin pain should be evaluated for a 
suspected adverse event of atypical femoral fracture. 
Adverse events reported as ONJ or atypical femoral fracture as well as adverse 
events identified by Amgen as potentially representing ONJ or atypical femoral 
fracture will be reviewed by an independent adjudication panel of experts to 
determine whether the pre-defined criteria for ONJ or atypical femoral fracture are 
met.  Amgen will request the investigating site to provide all available source 
documents surrounding that event to be reviewed by the blinded adjudication 


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Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 
Date:  15 September 2015 
Page 43 of 69 
CONFIDENTIAL 
10.4 
Access to Individual Subject Treatment Assignments 
All subjects will receive denosumab in this open label study. 
10.5 
Interim Analysis and Early Stopping Guidelines 
The first and second interim analyses were conducted after 50 and 100 subjects, 
respectively, had the opportunity to complete 6 months of treatment.  The third interim 
analysis was conducted with a data cut-off date of 25 March 2011 and included 
approximately 286 subjects enrolled.  An unplanned interim analysis was performed 
in August 2013 in response to a request from the European Medicines Agency that 
included approximately 507 subjects and a median follow up time of 20.8 months. 
Additional interim analyses may be conducted to monitor the ongoing safety of 
denosumab or to make decisions regarding the use of denosumab in the treatment of 
giant cell tumor of bone (GCTB). 
10.6 
Planned Methods of Analysis 
10.6.1 
General Approach/Considerations 
The statistical analysis in this open-label study will be descriptive in nature and no 
hypothesis testing will be performed.  All the efficacy analyses will be conducted 
separately in each cohort and for cohorts 1 and 2 combined unless specified otherwise; 
and the safety analyses will be conducted for all cohorts combined.  The analyses will be 
repeated for the adolescent population as applicable.  Categorical data will be presented 
in the form of number and percentage.  Continuous data will be provided with the 
descriptive statistics (n, mean, standard deviation, median, 25th percentile, 
75th percentile, minimum, and maximum).  The primary analysis will be conducted after 
all subjects have an opportunity to complete 12 months of treatment. 
10.6.2 
Analysis of Key Study Endpoints 
Adverse Events  
The analysis will be based on the combined sets of subjects receiving at least one dose 
of denosumab.  The incidence of adverse events will be summarized by system organ 
class and by preferred term according to the current MedDRA dictionary.  This summary 
includes all treatment-emergent adverse events recorded from the start of investigational 
product on this study, or any worsening of adverse events initially experienced before 
initiation of this study.  This summary for adverse events will be performed for the 
following categories: 
•
All adverse events
•
Investigational product (IP) related adverse events


Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 
Date:  15 September 2015 
Page 44 of 69 
CONFIDENTIAL 
 
 
• 
CTCAE grade 3, 4, or 5 adverse events  
• 
IP related CTCAE grade 3, 4, or 5 adverse events 
• 
Serious adverse events 
• 
IP related serious adverse events 
• 
Adverse events leading to study discontinuation 
• 
IP related adverse events leading to study discontinuation 
• 
Adverse events leading to investigational product discontinuation 
• 
Fatal events 
Pharmacokinetic/ Pharmacodynamic Analyses 
Summary statistics for serum concentrations of denosumab will be provided for each 
timepoint (scheduled visit).  Summary statistics for the bone turnover markers, uNTx/Cr 
and sCTx, and their changes from baseline (absolute and % change) will be provided at 
scheduled visits. The analysis will be based on adolescent and adult subjects enrolled in 
the PK substudy receiving at least one dose of denosumab.   
Laboratory Parameters 
The analysis will be based on the combined sets of subjects receiving at least one dose 
of denosumab.  Summary statistics for lab values and their changes from baseline will 
be provided at scheduled visits.  Laboratory shift tables summarizing the worst changes 
in Common Terminology Criteria for adverse event (v3.0 or higher) grades between 
baseline and any study visits during the treatment period will be provided. 
Time to Disease Progression, Time to Disease Recurrence, Progression Free 
Survival, and Time to Surgery 
Kaplan-Meier estimates will be graphically displayed.  Kaplan-Meier event rates at 
various time points (eg, month 3, month 6, etc) with 2-sided confidence intervals will be 
summarized.  In addition, Kaplan-Meier estimates of quartiles (median, 25th and 
75th percentiles) with 2-sided 95% confidence intervals will be calculated if applicable.  
Time to disease progression, time to disease recurrence, and progression free survival 
will be analyzed by cohort and for cohorts 1 and 2 combined.  Time to surgery will be 
analyzed for cohort 2 only. 
Proportion of Subjects Without Any Surgery, Proportion of Subjects with 
Pathologic Response, Proportion of Subjects Without Tumor Post-baseline, 
Proportion of Subjects Able to Undergo a Less Morbid Surgical Procedure 
Compared With the Planned Surgical Procedure  


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Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 
Date:  15 September 2015 
Page 46 of 69 
CONFIDENTIAL 
The fill lot number of investigational product is to be recorded on each subject’s eCRF. 
11.2 
Compliance in Investigational Product Administration 
When investigational product is dispensed for administration to the subject during a 
study, the investigator or responsible person will determine the level of compliance with 
the administration of the investigational product.  The subject’s investigational product 
compliance (eg, amount administered) will be recorded on the subject’s eCRF.     
12. 
REGULATORY OBLIGATIONS 
12.1 
Informed Consent 
An initial generic informed consent and a Pediatric Assent Informed Consent form has 
been provided to the investigator for preparation of the informed consent document to be 
used at his or her site.  Updates to the template will be communicated by letter from the 
clinical study manager to the investigator.  The written informed consent document 
should be prepared in the language(s) of the potential patient population. 
Before a subject’s participation in the clinical study, the investigator is responsible for 
obtaining written informed consent from the subject / subject’s parent or legally 
acceptable representative after adequate explanation of the aims, methods, anticipated 
benefits, and potential hazards of the study and before any protocol-specific screening 
procedures (with the exception of procedures performed as standard of care) or any 
investigational product is administered.   
A legally acceptable representative is an individual or other body authorized under 
applicable law to consent, on behalf of a prospective subject, to the subject’s 
participation in the clinical study.   
If applicable, the investigator is also responsible for asking the subject / subject’s parent 
or legally acceptable representative if the subject agrees to have his/her primary care 
physician informed of the subject’s participation in the clinical study and recording the 
subject’s preference in the medical chart.  If the subject / subject’s parent or legally 
acceptable representative agrees to such notification, the investigator shall inform the 
subject’s primary care physician of the subject’s participation in the clinical study.  If the 
subject does not agree to such notification, the investigator shall not inform the subject’s 
primary care physician. 
The acquisition of informed consent if applicable, the subject’s / subject parent’s or 
legally acceptable representative agreement or refusal of his/her notification of the 
primary care physician, should be documented in the subject’s medical records, and the 


Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 
Date:  15 September 2015 
Page 47 of 69 
CONFIDENTIAL 
 
 
informed consent form should be signed and personally dated by the subject and by the 
person who conducted the informed consent discussion (not necessarily an 
investigator).  The original signed informed consent form should be retained in 
accordance with institutional policy, and a copy of the signed consent form should be 
provided to the subject / subject parent’s or legally acceptable representative. 
If a potential subject is illiterate or visually impaired and does not have a legally 
acceptable representative, the investigator must provide an impartial witness to read the 
informed consent form to the subject and must allow for questions.  Thereafter, both the 
subject and the witness must sign the informed consent form to attest that informed 
consent was freely given and understood.  
In this study, obtaining assent from the adolescent and consent from the parents or 
legally authorized representative, as defined by local law, will apply.  An adolescent is 
defined as a person who has not attained the legal age for consent for treatments or 
procedures involved in clinical investigations, under the applicable law of the jurisdiction 
in which the clinical investigation will take place.  The local IEC/IRB will determine the 
process for obtaining and documenting the assent process for pediatric subjects, but 
should follow the guidelines established by the Department of Health and Human 
Services (DHHS) Office of Human Research Protections guidelines, which state an 
explanation of the procedures involved in the study should be made in a language 
appropriate to the adolescent’s age, experience, maturity and condition. 
12.2 
Independent Ethics Committee/Institutional Review Board 
A copy of the protocol, proposed informed consent form, Pediatric Assent form (if 
appropriate), other written subject information, and any proposed advertising material 
must be submitted to the IEC/IRB for written approval.  A copy of the written approval of 
the protocol and informed consent form must be received by Amgen before recruitment 
of subjects into the study and shipment of investigational product. 
The investigator must submit and, where necessary, obtain approval from the IEC/IRB 
for all subsequent protocol amendments and changes to the informed consent and 
Pediatric Assent form (if appropriate) documents.  The investigator should notify the 
IEC/IRB of deviations from the protocol or serious adverse events occurring at the site 
and other adverse event reports received from Amgen Global Safety, in accordance with 
local procedures.  


Product:  Denosumab (AMG 162) 
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Page 48 of 69 
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The investigator will be responsible for obtaining annual IEC/IRB approval/renewal 
throughout the duration of the study.  Copies of the investigator’s reports and the 
IEC/IRB’s continuance of approval must be sent to Amgen. 
12.3 
Prestudy Documentation Requirements 
The investigator is responsible for forwarding the following documents to Amgen for 
review before study initiation from Amgen or its designee can occur: 
•
Signed and dated protocol signature page (Investigator’s Agreement)
•
Copy of approved informed consent form and Pediatric Assent Form (if appropriate)
•
Copy of the IEC/IRB approval of the denosumab IB, protocol, consent form, and
subject information sheet, if applicable
•
Up-to-date curricula vitae of principal investigator and all subinvestigators
•
IEC/IRB composition and/or written statement that IEC/IRB is in compliance with
regulations
•
Laboratory normal ranges and documentation of laboratory certification (or
equivalent, if applicable)
•
Current subject/investigator indemnity insurance, if applicable
•
Signed study contract
•
Completed FDA form 1572 (or equivalent)
•
Completed Financial Disclosure statements for the principal investigator, all
subinvestigators, and their spouses (legal partners) and dependent children
12.4 
Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained.  On the 
eCRFs or other documents submitted to Amgen subjects should be identified by study 
subject number only.  Documents that are not for submission to Amgen (eg, signed 
informed consent forms, Pediatric Assent form [if appropriate]) should be kept in strict 
confidence by the investigator. 
In compliance with Federal regulations/ICH GCP Guidelines, it is required that the 
investigator and institution permit authorized representatives of the company, of the 
regulatory agency(s), and the IEC/IRB direct access to review the subject’s original 
medical records for verification of study-related procedures and data.  Direct access 
includes examining, analyzing, verifying, and reproducing any records and reports that 
are important to the evaluation of the study.  The investigator is obligated to inform and 
obtain the consent of the subject to permit named representatives to have access to 
his/her study-related records without violating the confidentiality of the subject. 


Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 
Date:  15 September 2015 
Page 49 of 69 
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12.5 
Investigator Signatory Obligations 
Each clinical study report should be signed by the investigator or, in the case of 
multicenter studies, the coordinating investigator. 
The coordinating investigator, identified by Amgen, will either be: 
•
a recognized expert in the therapeutic area
•
an investigator who provided significant contributions to either the design or
interpretation of the study
•
an investigator contributing a high number of eligible subjects
13. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
13.1 
Protocol Amendments and Study Termination 
Protocol amendments, except where necessary to eliminate an immediate hazard to 
subjects, must be made only with the prior approval of Amgen.  Agreement from the 
investigator must be obtained for all protocol amendments and amendments to the 
informed consent and Pediatric Assent form (if appropriate) documents.  The IEC/IRB 
must be informed of all amendments and give approval.  The investigator must send a 
copy of the approval letter from the IEC/IRB to Amgen. 
Both Amgen and the investigator reserve the right to terminate the study according to 
the study contract.  The investigator should notify the IEC/IRB in writing of the study’s 
completion or early termination and send a copy of the notification to Amgen. 
Subjects may be eligible for continued treatment with investigational product by 
extension protocol or as provided for by the local country’s regulatory mechanism.  
However, Amgen reserves the unilateral right, at its sole discretion, to determine 
whether to supply the investigational product, and by what mechanism, after termination 
of the trial and before it is available commercially. 
13.2 
Study Documentation and Archive 
The investigator should maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties.  All persons authorized to make entries and/or corrections 
on eCRFs will be included on the Amgen Delegation of Authority Form. 
Source documents are original documents, data, and records from which the subject’s 
eCRF data are obtained.  These include but are not limited to hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, 
pathology reports, and correspondence.   


Product:  Denosumab (AMG 162) 
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The investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities.  Elements should include: 
•
Subject files containing completed eCRFs (data disc is provided at study closure)
and informed consent forms and Pediatric Assent form (if appropriate)
•
Study files containing the subject identification list, protocol with all amendments,
investigator’s brochure, copies of prestudy documentation (see Section 12.3), and all
correspondence to and from the IEC/IRB and Amgen.
•
Proof of receipt, Investigational Product Accountability Record, Return of
Investigational Product for Destruction, Final Investigational Product Reconciliation
Statement, and all drug-related correspondence
In addition, all original source documents supporting entries in the eCRFs must be 
maintained and be readily available. 
No study document should be destroyed without prior written agreement between 
Amgen and the investigator.  Should the investigator wish to assign the study records to 
another party or move them to another location, he/she must notify Amgen in writing of 
the new responsible person and/or the new location. 
13.3 
Study Monitoring and Data Collection 
The Amgen representative and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various subject confidentiality is respected. 
The Amgen monitor is responsible for verifying the eCRFs at regular intervals throughout 
the study to verify adherence to the protocol; completeness, accuracy, and consistency 
of the data; and adherence to local regulations on the conduct of clinical research.  The 
monitor should have access to subject medical records and other study-related records 
needed to verify the entries on the eCRFs. 
The investigator agrees to cooperate with the monitor to ensure that any problems 
detected in the course of these monitoring visits, including delays in completing eCRFs, 
are resolved. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Clinical Quality Assurance Department (or 
designees).  Inspection of site facilities (eg, pharmacy, drug storage areas, laboratories) 


Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 
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Page 51 of 69 
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and review of study-related records will occur to evaluate the study conduct and 
compliance with the protocol, ICH GCP, and applicable regulatory requirements. 
All data capture for this study is planned to be electronic, however if necessary data 
capture may be performed utilizing paper CRFs: 
• 
Corrections to paper forms will be made by a single line stroke through the error and 
insertion of the correction above or beside the error.  The change must be initialed 
and dated by the investigator or a member of the study staff authorized by the 
investigator on the Amgen Delegation of Authority Form.  No erasures, correction 
fluid, or tape may be used.   
• 
Corrections to electronic forms will be automatically documented through the 
software’s “audit trail”. 
• 
To ensure the quality of clinical data across all subjects and sites, a clinical data 
management review will be performed on subject data received at Amgen.  During 
this review, subject data will be checked for consistency, omissions, and any 
apparent discrepancies.  In addition, the data will be reviewed for adherence to the 
protocol and GCP.  To resolve any questions arising from the clinical data 
management review process, data queries and/or site notifications will be raised in 
the EDC system for site completion. 
• 
EDC only:  The principal investigator signs only the Investigator Verification Form for 
all EDC studies.  The principal investigator will sign and date the indicated places on 
the CRF.  These signatures will indicate that the principal investigator inspected or 
reviewed the data on the eCRFs, the data queries, and the site notifications, and 
agrees with the content.  Paper output of the eCRF is available should the 
Investigator or the IEC/IRB require hard copy output for review, signature, and 
storage at the study site. 
• 
Amgen’s clinical data management department or designees will correct the 
database for the following eCRF issues without notification to site staff: 
− 
misspellings that do not change the meaning of the word (excluding adverse 
events and medications) 
− 
location of data recorded on an incorrect eCRF (eg, moving lab data from 
general comments to the appropriate lab table) 
− 
date errors that occur into the new year 
− 
standard time to 24-hour clock 
− 
temperature unit errors (Fahrenheit vs Centigrade) 
− 
weight unit errors (pounds vs kilograms) if a baseline weight has been 
established 
− 
height unit errors (in. vs cm) 
− 
administrative data (eg, event names for unscheduled visits or retests) 
− 
clarifying “other, specify” if data are provided (eg, race, physical exam) 
− 
if both the end date and a status of continuing is indicated (eg, for adverse 
events, concomitant medication, hospitalization), the end date will supersede 
− 
deletion of obvious duplicate data (eg, same results sent twice with the same 
date but different clinical planned events—week 4 and early termination) 


Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 
Date:  15 September 2015 
Page 52 of 69 
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− 
for adverse events that record action taken code = 01 (none) and any other 
action code, 01 (none) may be deleted as it is superseded by other existing data 
− 
if equivalent units or terms are recorded instead of the acceptable Amgen 
standard (eg, cc for mL, SQ for SC route, Not Examined for Not Done), the 
Amgen units or terms will be used 
− 
if the answer to a YES or NO question is blank or obviously incorrect (eg, 
Answers to the following questions do not reflect the data that are recorded or 
missing:  Were there any adverse events?  Concomitant medications?  
Hospitalizations?) 
− 
correct eCRF page numbers 
13.4 
Language 
Electronic case report forms (eCRFs) must be completed in English.  
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood.  Consult the 
country-specific requirements for language requirements. 
13.5 
Publication Policy 
To coordinate dissemination of data from this study, Amgen encourages the formation of 
a publication committee consisting of several principal investigators and appropriate 
Amgen staff.  The committee is expected to solicit input and assistance from other 
investigators and Amgen staff as appropriate.  Membership on the committee (both for 
investigators and Amgen staff) does not guarantee authorship-the criteria described 
below should be met for every publication. 
Authorship of any publications resulting from this study will be determined on the basis 
of the Uniform Requirement for Manuscripts Submitted to Biomedical Journals 
(International Committee of Medical Journal Editors, 2005), which states: 
•
Authorship credit should be based on (1) substantial contributions to conception and
design, acquisition of data, or analysis and interpretation of data; (2) drafting the
article or revising it critically for important intellectual content; (3) final approval of the
version to be published.  Authors should meet conditions 1, 2, and 3.
•
When a large, multicenter group has conducted the work, the group should identify
the individuals who accept direct responsibility for the manuscript.  These individuals
should fully meet the criteria for authorship defined above.
•
Acquisition of funding, collection of data, or general supervision of the research
group, alone, does not justify authorship.
•
All persons designated as authors should qualify for authorship, and all those who
qualify should be listed.
•
Each author should have participated sufficiently in the work to take public
responsibility for appropriate portions of the content.


Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 
Date:  15 September 2015 
Page 53 of 69 
CONFIDENTIAL 
All publications (eg, manuscripts, abstracts, oral/slide presentations, book chapters) 
based on this study must be submitted to Amgen for corporate review.  The Clinical 
Study Agreement among the institution, principal investigator, and Amgen Inc. will detail 
the procedures for, and timing of, Amgen Inc.’s review of publications. 
13.6 
Compensation 
If personal injury occurs as a result of participating in this research study, the subject 
and/or their insurance provider will be responsible for paying for the treatment.  No 
compensation is available from Amgen, other than that provided by law. 


Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 
Date:  15 September 2015 
Page 54 of 69 
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14. 
REFERENCES 
Amgen.  Denosumab Investigator’s Brochure 
Cheng, YY, Huang, L, Lee, M, Xu, K, Zheng, MH, Kumta, SM.  Bisphosphonates induce 
apoptosis of stromal tumor cells in giant cell tumor of bone.  Calcif Tissue Int.  
2004;75:71-77. 
Cleeland CS.  Pain assessment in Cancer.  In: Osaba D (ed).  Effect of Cancer on 
Quality of Life, Chapter 21.  CRC Press, Boca Raton FL, 1991. 
Elliott R, Kostenuik P, Chen C, et al.  Denosumab is a selective inhibitor of human 
receptor activator of NF-κβ ligand that blocks osteoclast formation in vitro and in vivo.  
Eur J Ca Suppl.  2006; 4:62. 
Kong Y-Y, Yoshida H, Sarosi I, et al. OPGL is a key regulator of osteoclastogenesis, 
lymphocyte development and lymph node organogenesis. Nature. 1999;315-323. 
Li J, Sarosi I, Yan XQ, et al. RANK is the intrinsic hematopoietic cell surface receptor 
that controls osteoclastogenesis, and regulation of bone mass and calcium metabolism. 
Proc Natl Acad Sci USA. 2000;97:1566-1571. 
Malawer M, Helman L, and Brian O’ Sullivan.  In: Cancer: Principles & Practice of 
Oncology, 7th Edition.  Sarcomas of the Soft Tissues and Bone - Chapter 35.  Lippincott 
Williams & Wilkins. 2005  
Morgan T, Atkins GJ, Trivett MK, et al.  Molecular profiling of giant cell tumor of bone 
and the osteoclastic localization of ligand for receptor activator of nuclear factor kappaB.  
Am J Pathol.  2005;167(1):117-128.  
Nishimura M, Yuasa K, Mori K, et al.  Cytological properties of stromal cells derived from 
giant cell tumor of bone (GCTSC) which can induce osteoclast formation of human blood 
monocytes without cell to cell contact.  J Orthop Res.  2005;23(5):979-987. 
Oken et al.  Toxicity and Response Criteria of the Eastern Cooperative Oncology Group.  
Am J Clin Onc.  5: 649 – 655, 1982. 
Ominsky MS, Stolina M, Li X, Corbin TJ, Asuncion FJ, Barrero M, Niu Q-T, Dwyer D, 
Adamu S, Warmington KS, Grisanti M, Tan HL, Ke HZ, Simonat WS, Kostenuil PJ. One 
year of transgenic overexpression of osteoprotegerin in rats suppressed bone resorption 
and increased vertebral bone volume, density and strength. J Bone Miner Res. 
2009;23:1234-1246. 
Roudier M, Kellar-Graney L, Huang LY, et al.  RANKL and RANK expression in giant cell 
tumors of the bone: an immunohistochemical study.  Connective Tissue Oncology 
Society; 11th Annual CTOS Meeting. 2006; poster 
Szendroi, M.  Giant-cell tumour of bone.  Br Editorial Society Bone Joint Surg.  
2004;86-B:5-12. 
Szendroi, M, Kiss, J., Antal, I.  Surgical treatment and prognostic factors in giant cell 
tumor of bone.  Acta Chir Orthop Traumatol Cech.  2003;70(3):142-150. 
Teitelbaum SL, Ross FP. Genetic regulation of osteoclast development and function.  
Nat Rev Genet. 2003;4:638-649. 
Zheng, MH, Robbins, P, Xu, J, Juang, L, Wood, DJ, Papadimitriou, JM.  The 
histogenesis of giant cell tumour of bone:  a model of interaction between neoplastic 
cells and osteoclasts.  Histol Histopathol.  2001;16:297-307. 


Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 
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15. 
APPENDICES


Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 
Date:  17 July 2015 
Page 56 of 69 
CONFIDENTIAL 
Appendix A.  Schedule of Assessments 
Protocol Activities 
Prior To 
 Day 1 Wk 1 
First 4-wk period 
(days 1 to 28) 
Treatment Period:  (Weeks) 
≤ 28 
days 
≤ 7 
days 
Day 
1 
Day 8 
Day 
15 
Day 29 
W5 
W9 
W13 
W17 
W21 
W25 
W29 
W33 
W37 
W41 
W45 
End of 
Treatment 
Informed Consent
12 
X 
Medical history 
X 
Pathology sample
4 
←←←←←May be requested either during the study or at end of study for evaluation of histopathological response to 
treatment →→→→→→→ 
X 
Pathology reports
3 
X 
←←←←←Must be attached to the subject’s medical record if performed as standard of care→→→→→→→ 
X 
Imaging reports
5 
X 
←←←←←←Must be attached to the subject’s medical record if performed as standard of care→→→→→→→ 
Serum 
chemistries
6,14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PE, Karnofsky
7, 14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Disease Status
7,14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Oral Exam 
X 
X 
X 
Pregnancy test
8, 14 
X 
X 
X 
X 
X 
X 
Antibody assay
10 
X 
X 
Pharmacokinetics
15 
X 
X 
X 
X 
X 
X 
X 
X 
sCTx
15 
X 
X 
X 
X 
X 
X 
X 
X 
uNTx
15 
X 
X 
X 
X 
X 
X 
X 
X 
Denosumab 
Administration
1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient Reported 
Outcomes
9,13 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Calcium / Vitamin D 
←←←←←←←←←←  All subjects should be adequately supplemented with calcium and Vitamin D →→→→→→→ 
AE Assessment
11 
X 
X 
←←←←←←←←←←←Documented throughout the study→→→→→→→→→→→ 
X 
Adverse Events of 
Interest 
←←←←←←←←←←←Documented throughout the study→→→→→→→→→→→ 
X 
Con Med Review 
X 
X 
←←←←←←←←←←←Documented throughout the study→→→→→→→→→→→ 
X 
Page 1 of 2 
Footnote displayed on the last page of the table 


Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 
Date:  17 July 2015 
Page 57 of 69 
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Protocol Activities 
W49 
W53 
W57 
W61 
W65 
W69 
W73 
W77 
W81 
W85 
W89 
W93 
and 
Q4W 
Additional Tests 
at W97 and 
Q12W 
End of  
Treatment 
SFU
2 
6 mo 
SFU
2 
12 mo 
SFU
2 
Every 
12 mo 
Pathology sample
4 
←←←←← May be requested either during the study or at end of study for evaluation of histopathological 
response to treatment →→→→→→→ 
X 
 
 
 
Pathology reports
3 
←←←←← Must be attached to the subject’s medical record if performed as standard of care →→→→→→→ 
X 
 
 
 
Imaging reports
5 
←←←←←←Must be attached to the subject’s medical record if performed as standard of care→→→→→→→ 
 
 
 
Serum 
chemistries
6,14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
PE, Karnofsky
7, 14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Disease Status
7,14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Oral Exam 
X 
 
 
 
 
 
X 
 
 
 
 
 
Q24W 
X 
X 
 
 
Pregnancy test
8, 14  
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
 
Antibody assay
10 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
Denosumab 
Administration
1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Patient Reported 
Outcomes
9,13 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
 
 
Calcium / Vitamin D 
←←←←← Subjects should be adequately supplemented with calcium and Vitamin D →→→→→→→ 
 
 
 
 
AE Assessment
11 
←←←←←Documented throughout treatment→→→→→→→ 
X 
X 
 
 
Adverse events of 
interest 
←←←←←Documented throughout the study→→→→→→→ 
X 
X 
X 
X 
Con Med Review 
←←←←←Documented throughout treatment→→→→→→→ 
X 
 
 
 
Page 2 of 2  
Footnote displayed on the next page of the table 


Product:  Denosumab (AMG 162) 
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1. 
Subjects will continue to receive denosumab until complete tumor resection (if applicable), disease progression physician’s or subject’s decision, or Amgen’s 
decision to discontinue for any reason, or administration of any of the proscribed therapies listed in Section 
Footnotes: 
6.5.  Denosumab 120 mg is given by SC injection as a 
1.7 mL injection of denosumab 70 mg/mL.  
2.  Safety Follow-Up:  For all subjects, including the PK substudy, data (treatment plus follow-up) will be collected until the end of the clinical study (Section 3.4.2) 
which is when subjects enrolled before Amendment 7 will complete a minimum of 60 months on study or otherwise have discontinued.  For subjects who 
discontinue(d) investigational product, safety follow-up visits will be conducted approximately every 6 months (± 1 month) after the End of Treatment visit 
(approximately 4 weeks after the last dose of investigational product) for the first year, then every 12 months (± 1 month).  The final safety follow-up visit will be 
conducted at the time of the end of the clinical study (Section 3.4.2) (even if this in not approximately 6 or 12 months since the previous follow-up visit).  Prior to 
Amendment 7, for subjects who were in the safety follow-up of study 20040215 and were enrolling in this study, safety data will be collected approximately every 
6 months for up to 24 months after the end of study visit in the 20040215 study.  Upon the approval of Amendment 7, subjects that enrolled from the 20040215 
study will also follow the 20062004 schedule, and complete the assessments as described in Appendix A.  The safety follow-up visits at 6 and 12 months after the 
End of Treatment visit must be conducted in the clinic.  Thereafter, subjects may be contacted by other methods (eg telephone) to complete the assessments. 
3.  Histopathology reports confirming the diagnosis of GCT of bone and demonstrating active disease are to be obtained to determine eligibility at screening (not 
required for 20040215 subjects).  All on-study reports are to be attached to the subject’s medical record if performed as standard of care except at end of study 
where this may be requested.  
4.  Histopathology samples may be requested during or at end of study. 
5.  Imaging report will be required at screening to confirm eligibility (not required for 20040215 subjects).  All on-study imaging reports  must be attached to the 
subject’s medical record if performed as standard of care.  Select historical and select on-study imaging performed as standard of care will be required to be 
sent to a central imaging vendor for evaluation of disease response. 
6.  Serum chemistries performed by local lab must include serum creatinine, calcium, albumin, magnesium and phosphorus.  
7.  Physical exam: The screening PE includes medical history, Karnofsky performance status, disease status, blood pressure, respiratory rate, temperature, weight 
and height. (After the subject has signed the informed consent and the medical history is recorded on the Medical and Surgical History eCRF, any new or 
worsening conditions should be reported on the Adverse Event eCRF, including any reported during the screening period.) Thereafter, only a disease status and 
Karnofsky performance status will be collected during the treatment phase of the study and at 6 and 12 months of safety follow up.   
8.  Pregnancy test for women of childbearing potential is to be conducted at screening, on study (approximately every 12 weeks while receiving denosumab 
treatment) and during safety follow up (only at 6 months after EoT).  A urine/serum pregnancy test must be done at baseline prior to first dose of denosumab if 
study day 1 is greater than 7 days from the pregnancy confirmation done at screening. 
9. Patient Reported Outcomes (PRO): Consist of BPI-SF. The BPI-SF will be administered prior to each administration of investigational product at baseline, study 
days 8 and 15, then every 4 weeks (Q4W) from weeks 5 – 25, then every 12 weeks (Q12W) to end of study. 
10. Serum for anti- denosumab antibody assay will be collected at baseline and as outlined on the schedule of assessments, including 2 samples during follow up 
(approximately 6 and 12 months after the end of study visit).  Prior to Amendment 7, for subjects who were in the safety follow-up of study 20040215 and are 
enrolling in this study, serum samples for anti-denosumab antibody assay will be collected approximately every 6 months for up to 24 months after the end of study 
visit in the 20040215 study.  Upon approval of Amendment 7, subjects that enrolled in 20062004 from 20040215 study will also follow the 20062004 schedule, and 
complete the assessments as described in Appendix A.  These samples may also be used for future biomarker development testing  


Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 
Date:  17 July 2015 
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11. Adverse event assessment should be documented and recorded at each visit upon signing informed consent through the first 6 month safety follow-up visit.  
Adverse events of interest will be followed through the last safety follow-up visit.  Subjects must be followed for adverse events until all denosumab 
treatment-related toxicities have resolved. 
12. Informed consent may be obtained more than 28 days before Day 1 week 1. 
13. Cohort 3 subjects will enroll at their next Q4W visit (based on their 20040215 schedule).  Informed consent will be obtained prior to any protocol specific 
procedures; PROs will be collected at their next Q12W assessment visit. 
14. Prior to Amendment 7, for subjects who were in the safety follow-up of study 20040215 and are enrolling in this study, serum chemistries, physical examination, 
disease status, Karnofsky performance status,and pregnancy testing are not required during the safety follow-up.  Upon the approval of Amendment 7, subjects 
that enrolled in 20062004 from the 20040215 study will also follow the 20062004 schedule, and complete the assessments as directed in Appendix A. 
15. Pharmacokinetic Substudy – Approximately 10 adolescent and approximately 10 adult subjects will contribute to the PK substudy.  Samples for pharmacokinetic, 
uNTx, and sCTx analysis on Study Day 1 will be obtained prior to IP administration.  Subjects enrolled in the PK substudy will be followed (treatment plus 
follow-up) until all subjects enrolled before Amendment 7 complete a minimum of 60 months. 


Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 
Date:  15 September 2015 
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CONFIDENTIAL 
Appendix B.  Adverse Event Severity Scoring System  
The Common Terminology Criteria for Adverse Events (CTCAE, version 3.0) are 
available at the following link:   
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.
pdf 


Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 
Date:  15 September 2015 
Page 61 of 69 
CONFIDENTIAL 
Appendix C.  Pregnancy Notification Worksheet 


Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 
Date:  15 September 2015 
Page 62 of 69 
CONFIDENTIAL 
Appendix D.  Sample SAE Report Form 


Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 
Date: 15 September 2015 
Page 63 of 69 
CONFIDENTIAL 
 
 
A 
20062004 
Clinical Trial Serious Adverse Event Report – Phase 1–4 
Notify Amgen Within 24 Hours of knowledge of the event 
New 
Follow-up 
 
1. SITE INFORMATION 
Site Number 
Investigator 
 
Country 
Date of Report 
Day          Month           Year 
 
 
 
 
 
 
 
Reporter 
 
 
Phone Number 
(              ) 
Fax Number 
(              ) 
2. SUBJECT INFORMATION 
Subject ID Number 
Date of Birth 
Day          Month           Year 
 
Sex 
□F  □M 
 
Race 
 
 
 
 
 
 
 
 
 
 
 
 
 
3. SERIOUS ADVERSE EVENT - Information in this section must also be entered on the Serious Adverse Event Summary CRF 
Provide the date the Investigator became aware of this Serious Adverse Event Information:   Day_____Month____Year______ 
Serious Adverse Event Diagnosis or 
Syndrome 
If diagnosis is unknown, enter Signs / 
Symptoms 
When Final Diagnosis is known, enter as 
Adverse Event 
 
List one event per line.  If event is fatal, 
enter the Cause of Death.  Entry of 
“Death” is not acceptable, as this is an 
outcome. 
Date Started 
Date Ended 
Check 
only if 
event    
occurred 
before 
first dose 
of IP 
Enter 
Serious 
Criteria 
code 
 
(see 
codes 
below) 
Relationship 
Is there a 
reasonable 
possibility that the 
event 
may have been 
caused by 
IP? If yes see 
section 10 
Relationship 
Is there a reasonable 
possibility that the 
event 
may have been caused 
by 
an Amgen device? 
Outcome 
of Event 
 
01 Resolved 
02 Resolving 
03 Not  resolved 
04 Fatal 
Check only if event is 
related to  
study 
procedure  
eg, biopsy 
Day     Month     Year 
Day     Month     Year 
No 
Yes 
 
No
 
Yes
 
If Yes, 
what 
device? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serious 
Criteria: 
01 Fatal 
02 Immediately life-threatening 
03 Required hospitalization 
04 Prolonged hospitalization 
05 Persistent or significant disability /incapacity 
06 Congenital anomaly / birth defect 
07 Other significant medical 
hazard 
4. HOSPITALIZATION 
 
Date Admitted 
Date Discharged 
Day       Month       Year 
Day       Month       Year 


Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 
Date: 15 September 2015 
Page 64 of 69 
CONFIDENTIAL 
 
 
Was subject hospitalized? □No  □Yes, If yes, please complete date(s):  
 
 
5. INVESTIGATIONAL PRODUCT (IP) 
 
Initial Start Date 
Prior to, or at time of Event 
Action Taken with Product 
01 Still being Administered 
02 Permanently discontinued 
03 Withheld 
Day       Month       Year 
Date of Dose 
Dose 
Route 
Frequency 
Day       Month       Year 
<<IMP>> 
□Blinded □Open Label 
 
 
 
 
 
 
6. CONCOMITANT MEDICATIONS (eg, chemotherapy)        Any Concomitant Medications?   No  Yes,  If yes, please complete: 
Medication Name(s) 
Start Date 
Stop Date 
Co-suspect 
Continuing 
Dose 
Route 
Freq. 
Treatment Med 
Day        Month        Year 
Day        Month        Year 
No 
Yes 
No 
Yes 
No 
Yes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Site Number 
Subject ID Number 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.  RELEVANT MEDICAL HISTORY (include dates, allergies and any relevant prior therapy) 
 
 
 
 
 
 
 
 
8.  RELEVANT LABORATORY VALUES (include baseline values)  Any Relevant Laboratory values? □ No □ Yes, If yes, please complete: 
Date 
Test 
 
 
 
 
 
 
 
 
 
 
Unit 
 
 
 
 
 
 
 
 
 
 
Day            Month            Year 
 
 
 
 
 
 
 
 
 
 
 
 


Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 
Date: 15 September 2015 
Page 65 of 69 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.  OTHER RELEVANT TESTS (diagnostics and procedures)                Any Other Relevant tests?   □ No   □ Yes,  If yes, please complete: 
Date 
Additional Tests 
Results 
Units 
Day        Month        Year 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.  CASE DESCRIPTION (Provide narrative details of events listed in section 3) For each event in section 3, where relationship=Yes, 
please provide rationale. 
 
 
 
 
 
 
 
Signature of Investigator or Designee 
Title 
Date 
 
 
 
 


Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 
Date:  15 September 2015 
Page 66 of 69 
CONFIDENTIAL 
Appendix E.  Karnofsky Performance Status and Eastern Cooperative Oncology 
Group (ECOG) Performance Status 
Karnofsky Performance Status 
100% - 
Normal; no complaints; no evidence of disease. 
90% 
- 
Able to carry on normal activity; minor signs or symptoms of disease. 
80% 
- 
Normal activity with effort; some signs or symptoms of disease. 
70% 
- 
Cares for self, unable to carry on normal activity or do active work. 
60% 
- 
Requires occasional assistance, but is able to care for most personal needs. 
50% 
- 
Requires considerable assistance and frequent medical care. 
40% 
- 
Severely disabled; hospitalization indicated, although death not imminent. 
30% 
- 
Severely disabled; hospitalization necessary; active support treatment is 
  necessary. 
20% 
- 
Very sick; hospitalization necessary; active support treatment is necessary. 
10% 
- 
Moribund; fatal processes progressing rapidly. 
0% 
- 
Dead. 
ECOG Scale Performance Status 
0 
- 
Fully active, able to carry out all pre-disease performance without restriction. 
1 
- 
Restricted in physically strenuous activity, but ambulatory and able to carry out 
work of a light or sedentary nature, (e.g. light housework, office work). 
2 
- 
Ambulatory and capable of all self care, but unable to carry out any work 
 activities.  Up and about more than 50% of waking hours. 
3 
- 
Capable of only limited self-care, confined to bed or chair more than 50% of 
  waking hours. 
4 
- 
Completely disabled.  Cannot carry out any self-care.  Totally confined to bed or 
  chair. 
5 
- 
Dead. 
Karnofsky Score of 100 - 90% corresponds to ECOG 0 
Karnofsky Score of   80 - 70% corresponds to ECOG 1 
Karnofsky Score of   60 - 50% corresponds to ECOG 2 
Karnofsky Score of   40 - 30% corresponds to ECOG 3 
Karnofsky Score of   20 - 10% corresponds to ECOG 4 
Karnofsky Score of            0% corresponds to ECOG 5 
Oken et al.  Toxicity and Response Criteria of the Eastern Cooperative Oncology Group.  
Am J Clin Onc.  5: 649 – 655, 1982. 


Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 
Date:  15 September 2015 
Page 67 of 69 
CONFIDENTIAL 
Appendix F.  Sample Brief Pain Inventory - Short Form (BPI-SF) 


Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 
Date:  15 September 2015 
Page 68 of 69 
CONFIDENTIAL 
 
 
 


Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 
Date:  15 September 2015 
Page 69 of 69 
CONFIDENTIAL 
Appendix G.  Lactation Notification Worksheet 


Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 
Date:  15 September 2015 
Page 1 of 13 
CONFIDENTIAL 
Amendment 8 
Protocol Title:  An Open-label, Multi-center, Phase 2 Study of Denosumab in 
Subjects with Giant Cell Tumor of Bone 
Amgen Protocol Number 20062004 
EudraCT# 2008-001606-16 
Date: 
Amendment 1: 
Amendment 2: 
Amendment 2 (Superseding) 
Amendment 3: 
Amendment 4: 
Amendment 5: 
Amendment 6: 
Amendment 7: 
Amendment 8: 
Amendment 8 (Superseding): 
22 April 2008 
12 December 2008 
22 October 2009 
11 January 2010 
14 May 2010 
15 November 2010 
05 May 2011 
30 August 2011 
15 May 2013 
17 July 2015 
15 September 2015 
Rationale: 
•
Safety follow-up period information was updated and adverse events of interest
were listed to align the protocol language with post marketing data collection
requirements and to increase compliance with long-term follow-up data
requirements.
•
Interim analysis 4 was removed as it is not a regulatory requirement and no study
report is expected from this interim analysis per regulatory requirements.
•
Pharmacy guide is obsolete and has been replaced by IPIM in Amgen protocols.
•
Medical history section was updated for clarification and to align with other
sections of the protocol.
•
The dose escalation and stopping rules section was modified to clarify that the
planned dose may be given up to 7 days before the scheduled visit, as long as
there are at least 21 days between doses.
•
Calcium and Vitamin D information was updated to match Xgeva product
information.
•
The number of birth control methods and amount of washout time required
between the end of treatment and pregnancy or breastfeeding was updated to
align with the informed consent and current safety information.
•
Pregnancy reporting was changed from the Pregnancy Surveillance Program to
Amgen Global Patient Safety as per current Amgen standard.
•
Administration, typographical and formatting changes were made throughout the
protocol.


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Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 
Date:  15 September 2015 
Page 3 of 13 
CONFIDENTIAL 
 
 
With: 
• 
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 a highly 
effective method of contraception during treatment and for 5 months 
after the end of treatment 
 
 
Section: 
Protocol Synopsis, Exclusion criteria for 20040215 subjects 
Replace: 
• 
Subject is pregnant or breast feeding, or planning to become 
pregnant within 7 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 
7 months after the end of treatment 
With: 
• 
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 a highly 
effective method of contraception during treatment and for 5 months 
after the end of treatment 
 
 
Section: 
Protocol Synopsis, Investigational Product Dosage and Administration 
Replace: 
It is strongly recommended that subjects take daily supplementation of 
at least 500 mg of calcium and 400 IU of vitamin D, except in the case of 
pre-existing hypercalcemia. 
With: 
All subjects should be adequately supplemented with calcium and 
vitamin D (at least 500 mg of calcium and 400 IU of vitamin D), 
except in the case of pre-existing hypercalcemia. 
 
 
Section: 
Protocol Synopsis, Procedures, paragraph 2 
Add: 
The approval process is required for new enrolling subjects and 
subjects considered for retreatment. 
 
 
Section: 
Protocol Synopsis, Procedures, paragraph 3 
Add: 
A copy of the standard of care imaging reports obtained within 
1 year before enrollment, demonstrating active GCTB must be 
attached to the subject’s medical record. 
Delete: 
Imaging and 
Delete: 
collected throughout the study 
Add: 
Similar data from procedures performed as standard of care will be 
attached to the subject’s medical record 
 
 


Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 
Date:  15 September 2015 
Page 4 of 13 
CONFIDENTIAL 
 
 
Section: 
Protocol Synopsis, Statistical Considerations, paragraph 2 
Delete: 
An interim analysis will occur when at least 200 subjects have had the 
opportunity to complete 5 years on study. 
Add: 
An unplanned interim analysis was performed in August 2013 in 
response to a request from the European Medicines Agency that 
included approximately 507 subjects and a median follow up time 
of 20.8 months. 
 
 
Section: 
Study Glossary 
Add: 
IPIM    Investigational Product Instruction Manual 
ONJ    Osteonecrosis of the jaw 
 
 
Section: 
Study Term EOS 
Delete: 
trial 
Add: 
study 
 
 
Section: 
Study Term EOT 
Replace: 
end of treatment visit 
With: 
End of Treatment visit 
 
 
Section: 
Table of Contents, List of Appendices 
Delete: 
Appendix C   Pharmacy Guide 
Move subsequent appendices up one letter 
 
 
Section: 
2.2.1  Clinical Experience With Denosumab in Giant Cell Tumor of Bone 
(GCTB) 
Replace: 
Study 20040215 is an ongoing Phase 2 proof of concept study 
investigating the potential role for denosumab in the treatment of GCTB.  
The study tests the hypothesis that denosumab, a RANKL inhibitor, can 
inhibit the growth and survival of tumor cells in patients with GCTB.   
With: 
The Phase 2 study, Study 20040215, investigated the potential role for 
denosumab in the treatment of GCTB.  The study tested the hypothesis 
that denosumab, a RANKL inhibitor, can inhibit the growth and survival 
of tumor cells in patients with GCTB.   
 
 
Section: 
3.3  Number of Subjects, paragraph 2 
Delete: 
and a minimum of 5 subjects will be adolescents   
 
 


Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 
Date:  15 September 2015 
Page 5 of 13 
CONFIDENTIAL 
 
 
Section: 
3.4.2   End of Study (EOS), paragraph 1 
Replace: 
trial 
With: 
study 
 
 
Section: 
4.2 Exclusion Criteria, 4.2.14 and 4.2.15 
Replace: 
• 
Subject is pregnant or breast feeding, or planning to become 
pregnant within 7 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 
7 months after the end of treatment 
With: 
• 
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 a highly 
effective method of contraception during treatment and for 5 months 
after the end of treatment 
 
 
Section: 
4.2 Exclusion Criteria for 20040215 subjects, 4.2.19 and 4.2.20 
Replace: 
• 
Subject is pregnant or breast feeding, or planning to become 
pregnant within 7 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 
7 months after the end of treatment 
With: 
• 
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 a highly 
effective method of contraception during treatment and for 5 months 
after the end of treatment 
 
 
Section: 
5.   SUBJECT ENROLLMENT, Paragraph 4 
Add: 
The approval process is required for new enrolling subjects and 
subjects considered for retreatment. 
 
 
Section: 
6.  TREATMENT PROCEDURES 
Replace: 
For further details regarding preparation and administration of the 
investigational product, refer to Appendix C (Pharmacy Guide). 
With: 
For further details regarding preparation and administration of the 
investigational product, refer to the Investigational Product 
Instruction Manual (IPIM), which is a document external to this 
protocol. 
 
 


Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 
Date:  15 September 2015 
Page 6 of 13 
CONFIDENTIAL 
 
 
Section: 
6.2   Dose Escalation and Stopping Rules, paragraph 2 
Replace: 
For Q4W doses, if a planned dose (eg, week 5, week 9, etc.) is delayed 
more than 7 calendar days, it will be considered a missed dose and 
recorded as such on the eCRF. 
With: 
For Q4W doses, the planned dose may be given up to 7 days before 
the scheduled visit, as long as there are at least 21 days between 
doses.  If a planned dose (eg, week 5, week 9, etc.) is delayed more 
than 7 calendar days, it will be considered a missed dose and recorded 
as such on the eCRF. 
 
Paragraph 5 
Add: 
(ONJ) 
 
 
Section: 
6.4  Concomitant Therapy (Calcium and Vitamin D Supplements) 
Replace: 
It is strongly recommended that subjects take daily supplementation of 
at least 500 mg of calcium and 400 IU of Vitamin D, except in the case 
of pre-existing hypercalcemia.   
With: 
All subjects should be adequately supplemented with calcium and 
Vitamin D (at least 500 mg of calcium and 400 IU of Vitamin D), except 
in the case of pre-existing hypercalcemia. 
 
 
Section: 
7.2 Medical History 
Replace: 
The subject’s medical history will be obtained prior to enrollment and 
recorded on the eCRF.  Detailed history of all pre-existing conditions 
must be documented on the eCRF (and in the source documents).  All 
major and minor significant illnesses, surgeries, and conditions that are 
both historical and present/ongoing at the time of first dose of 
investigational product will be obtained.   
With: 
The subject’s medical history will be obtained ≤ 28 days before day 1 of 
the study and recorded on the eCRF.  A detailed history of all 
pre existing conditions must be documented on the eCRF (and in the 
source documents).  Any illness or medical condition that is ongoing 
at the time of the subject’s first dose of study drug should be 
noted.  Worsening of a pre-existing condition should be reported 
as an adverse event.   
 
 
Section: 
7.4  Physical Examination  
Replace: 
Refer to Appendix F for Karnofsky performance status criteria. 
With: 
Refer to Appendix E for Karnofsky performance status criteria. 
 
 
Section: 
7.5  Imaging 
Replace: 
A copy of imaging reports (eg, PET, CT, PET/CT, MRI, or X-ray) 
performed as standard of care must be provided to Amgen.   


Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 
Date:  15 September 2015 
Page 7 of 13 
CONFIDENTIAL 
 
 
With: 
A copy of imaging reports (eg, PET, CT, PET/CT, MRI, or X-ray) 
performed as standard of care must be attached to the subject’s 
medical record.   
 
 
Section: 
7.6  Histopathology 
Replace: 
A copy of all available pathology reports obtained as standard of care 
must be provided to Amgen including the surgical report of the GCTB 
target lesion resection.  Histopathology samples and reports may be 
requested at end of study. 
With: 
A copy of all available pathology reports obtained as standard of care 
must be attached to the subject’s medical record, including the 
surgical report of the GCTB target lesion resection.  The histopathology 
samples and reports may be requested either during the study or at 
end of study for evaluation of histopathological response to 
treatment. 
 
 
Section: 
7.10  End of Treatment (EOT) Visit 
Replace: 
Each subject will have an end of treatment visit approximately 4 weeks 
after their last dose of investigational product. 
With: 
Each subject will have an End of Treatment visit approximately 4 weeks 
after their last dose of investigational product. 
 
 
Section: 
7.11  Safety Follow-up Phase 
 
Paragraph 1 
Add: 
During the safety follow-up phase, subjects will be asked about 
serious adverse events, adverse events of interest, and disease 
treatments and outcomes (Section 9.2). 
 
Paragraph 5 
Add: 
Subjects will be asked to provide information regarding their GCTB 
status and current treatments.  Additionally, subjects will be asked 
if they have experienced any of the following adverse events of 
interest: 
• 
ONJ 
• 
Malignancy, including malignancy in GCTB 
• 
Atypical femoral fracture 
If the subject has experienced any of the adverse events of interest, 
specific additional information will be requested/collected as 
necessary according to each type of event.  The additional 
information will include, but is not limited to:   
• 
ONJ:  dental records; information will be sent for 
adjudication by independent reviewers (see Section 9.4.1) 
• 
Malignancy (including malignancy in GCTB):  pathology 
reports 
• 
Atypical femoral fracture:  x-ray or other imaging; 
medical/surgical records.  Information will be sent for 
adjudication by independent reviewers (see Section9.4.1). 


Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 
Date:  15 September 2015 
Page 8 of 13 
CONFIDENTIAL 
 
 
If the subject has experienced any serious adverse event 
(Section 9.1.2), information is to be collected and reported (see 
Section 9.3). 
If the subject has been receiving treatment with commercial 
denosumab (XGEVA), or any other Amgen product as standard of 
care for GCTB or any other condition, Adverse Drug Reactions 
related to that product will be collected. 
 
 
Section: 
8.1  Removal of Subjects, paragraph 4 
Replace: 
• 
pregnancy (report on Pregnancy Notification Worksheet, see 
Appendix D)  
With 
• 
pregnancy (report on Pregnancy Notification Worksheet, see 
Appendix C)  
 
 
Section: 
9.1.1 Adverse Events, paragraph 5 
Replace: 
Pregnancy is not considered an adverse event (see Appendix D for 
reporting any pregnancy).  
With: 
Pregnancy is not considered an adverse event (see Appendix C for 
reporting any pregnancy). 
 
 
Section: 
9.2  Reporting Procedure for All Adverse Events, paragraph 1 
Replace: 
The investigator is responsible for ensuring that all adverse events (as 
defined in Section 9.1 and as further specified below) observed by the 
investigator or reported by subjects during the screening (excluding 
cohort 3 subjects), treatment and through the first 6 month safety follow 
up visit of the study are collected and recorded in the subjects’ medical 
records and in designated study documents (ie, eCRF, and, on the 
serious adverse event report (SAER) form for serious adverse events). 
With: 
The investigator is responsible for ensuring that all adverse events (as 
defined in Section 9.1 and as further specified below) and adverse 
events of interest (Section 7.11) observed by the investigator or 
reported by subjects during screening (excluding cohort 3 subjects), 
treatment, through the first 6-month safety follow up visit as well as 
through the end of safety follow-up phase for adverse events of 
interest (Section 3.4.2) are collected and recorded in the subjects’ 
medical records and in designated study documents (ie, eCRF, and, on 
the serious adverse event report (SAER) form for serious adverse 
events). 
 
 
Section: 
9.3  Serious Adverse Event Reporting Procedures, paragraph 2 
Replace: 
Initial serious adverse event information and all amendments or 
additions must be recorded on a Serious Adverse Event Report Form 
(Appendix E) and faxed to Amgen Global Safety. 


Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 
Date:  15 September 2015 
Page 9 of 13 
CONFIDENTIAL 
 
 
With: 
Initial serious adverse event information and all amendments or 
additions must be recorded on a Serious Adverse Event Report Form 
(Appendix D) and faxed to Amgen Global Safety. 
 
 
Section: 
9.4  Pregnancy and Lactation Reporting, Paragraph 1 
Replace: 
Throughout denosumab treatment and through 7 months after the last 
dose of IP, the investigator should counsel subjects who are women of 
childbearing potential on the risks of pregnancy while receiving 
denosumab, and discuss methods to decrease the risk of becoming 
pregnant. 
With: 
Throughout denosumab treatment and through 5 months after the last 
dose of IP, the investigator should counsel subjects who are women of 
childbearing potential on the risks of pregnancy while receiving 
denosumab, and discuss methods to decrease the risk of becoming 
pregnant. 
 
Paragraphs 3 and 4 
Replace: 
In addition to reporting any pregnancies occurring during the study, 
investigators should monitor for pregnancies that occur after the last 
dose of protocol-required therapies through 7 months after the last dose. 
The pregnancy should be reported to Amgen’s global Pregnancy 
Surveillance Program within 24 hours of the investigator’s knowledge of 
the event of a pregnancy.  Report a pregnancy on the Pregnancy 
Notification Worksheet (Appendix D).  The Pregnancy Surveillance 
Program (PSP) will seek to follow the pregnant woman throughout her 
pregnancy and her baby up to 12 months after birth. 
With: 
In addition to reporting any pregnancies occurring during the study, 
investigators should report pregnancies that occur after the last dose of 
protocol-required therapies through 5 months after the last dose with 
the exception of subjects who are receiving a commercial Xgeva in 
the safety follow-up phase.  For those subjects investigators 
should report pregnancies until the end of the safety follow-up 
phase. 
For both situation/ scenarios the pregnancy should be reported to 
Amgen Global Patient Safety within 24 hours of the investigator’s 
knowledge of the event of a pregnancy.  Report a pregnancy on the 
Pregnancy Notification Worksheet (Appendix C).  Amgen will seek to 
follow the pregnant woman throughout her pregnancy and her baby up 
to 12 months after birth. 
 
Paragraphs 6 and 7 
Replace: 
In addition to reporting a lactation case during the study, investigators 
should monitor for lactation cases that occur after the last dose of 
protocol-required therapies through 7 months after the last dose. 
Any lactation case should be reported to Amgen’s global Lactation 
Surveillance Program (LSP) within 24 hours of the investigator’s 
knowledge of event.  Report a lactation case on the Lactation 
Notification Worksheet (Appendix H).   


Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 
Date:  15 September 2015 
Page 10 of 13 
CONFIDENTIAL 
 
 
With: 
In addition to reporting a lactation case during the study, investigators 
should report lactation cases that occur after the last dose of 
protocol-required therapies through 5 months after the last dose.  For 
those subjects receiving a commercial Xgeva in the safety 
follow-up phase, investigators should report lactation cases until 
the end of the safety follow-up phase. 
Any lactation case should be reported to Amgen Global Patient Safety 
within 24 hours of the investigator’s knowledge of event.  Report a 
lactation case on the Lactation Notification Worksheet (Appendix G).   
 
 
Section: 
9.4.1  Adjudication Process for Suspected Osteonecrosis of the Jaw and 
Suspected Atypical Femoral Fracture Adverse Events, paragraphs 1 and 
2 
Add: 
All subjects with an oral adverse event suspicious of ONJ should 
be examined by a dentist or other qualified oral specialist (eg, oral 
surgeon).  All subjects presenting with new or unusual thigh, hip, 
or groin pain should be evaluated for a suspected adverse event of 
atypical femoral fracture. 
Adverse events reported as ONJ or atypical femoral fracture as well 
as adverse events identified by Amgen as potentially representing 
ONJ or atypical femoral fracture will be reviewed by an 
independent adjudication panel of experts to determine whether 
the pre-defined criteria for ONJ or atypical femoral fracture are met.  
Amgen will request the investigating site to provide all available 
source documents surrounding that event to be reviewed by the 
blinded adjudication committee.  If an event is adjudicated positive 
for ONJ, the investigator will be notified of the adjudication 
decision. 
 
 
Section: 
10.5  Interim Analysis and Early Stopping Guidelines 
Replace: 
An interim analysis will occur when at least 200 subjects have had the 
opportunity to complete 5 years on study. 
With: 
An unplanned interim analysis was performed in August 2013 in 
response to a request from the European Medicines Agency that 
included approximately 507 subjects and a median follow up time 
of 20.8 months. 
 
 
Section: 
10.6.2  Analysis of Key Study Endpoints 
Delete: 
The analysis of BPI-SF outcomes will employ a piecewise growth curve 
model (Fairclough et al, 2004).  If analgesic use increases over time, the 
on-study analgesic score will be included as an additional covariate in 
the analysis. 
Replace: 
Change in pain score from baseline  
Kaplan-Meier curves reflecting 1) ≥ 2-point decrease in ‘pain at its worst’ 
question from baseline, 2) ≥ 2-point increase in ‘pain at its worst’ 
question from baseline, and 3) > 4-point in ‘pain at its worst’ question (in 


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Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 
Date:  15 September 2015 
Page 12 of 13 
CONFIDENTIAL 
 
 
Section: 
Appendix A, Schedule of Assessments, Imaging reports and pathology 
reports 
Replace: 
To be submitted if performed as standard of care 
With: 
Must be attached to the subject’s medical record if performed as 
standard of care 
Add: 
Adverse events of interest 
←←←←←←←←←←←Documented throughout the 
study→→→→→→→→→→→ 
X  in end of treatment box; X in SFU 6 mo, SFU 12 mo, and SFU Every 
12 mo boxes 
 
 
Replace: 
Calcium / Vitamin D:  Strongly recommended to be taken daily 
With: 
←←←←←←←←←←  All subjects should be adequately 
supplemented with calcium and Vitamin D →→→→→→→ 
 
 
Section: 
Appendix A, PE, Karnofsky 
Add: 
X at 6 and12 month SFU 
 
 
Section: 
Appendix A, footnote 3 
Replace: 
All on-study reports will be collected if performed as standard of care 
except at end of study where this may be requested. 
With: 
All on-study reports are to be attached to the subject’s medical 
record if performed as standard of care except at end of study where 
this may be requested. 
 
 
Section: 
Appendix A, footnote 4 
Add: 
Histopathology samples may be requested during or at end of study. 
 
 
Section: 
Appendix A, footnote 5 
Replace: 
All on-study imaging reports will be collected if performed as standard of 
care. 
With: 
All on-study imaging reports must be attached to the subject’s 
medical record if performed as standard of care. 
 
 
Section: 
Appendix A, footnote 7 
Add: 
Thereafter, only a disease status and Karnofsky performance status will 
be collected during the treatment phase of the study and at 6 and 
12 months of safety follow up. 
 
 


Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 
Date:  15 September 2015 
Page 13 of 13 
CONFIDENTIAL 
 
 
Section: 
Appendix A, footnote 8 
Replace: 
EoS 
With: 
EoT 
 
 
Section: 
Appendix A, footnote 11 
Add: 
Adverse events of interest will be followed through the last safety 
follow-up visit. 
 
 
Section: 
Appendix C 
Replace: 
Appendix D.  Pregnancy Notification Worksheet 
With: 
Appendix C. Pregnancy Notification Worksheet 
 
 
Section: 
Appendix D 
Replace: 
Appendix E.  Sample SAE Report Form 
With: 
Appendix D. Sample SAE Report Form 
New Form 
 
 
Section: 
Appendices E, F, G 
Replace: 
Appendix F, G, H in title 
With: 
Appendix E, F, G, respectively 
 


Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 
Date:  17 July 2015 
Page 1 of 13 
CONFIDENTIAL 
 
 
Amendment 8 
Protocol Title:  An Open-label, Multi-center, Phase 2 Study of Denosumab in 
Subjects with Giant Cell Tumor of Bone 
 
Amgen Protocol Number 20062004 
EudraCT# 2008-001606-16 
 
Date: 
Amendment 1: 
Amendment 2: 
Amendment 2 (Superseding) 
Amendment 3: 
Amendment 4: 
Amendment 5: 
Amendment 6: 
Amendment 7: 
Amendment 8: 
22 April 2008 
12 December 2008 
22 October 2009 
11 January 2010 
14 May 2010 
15 November 2010 
05 May 2011 
30 August 2011 
15 May 2013 
17 July 2015 
 
Rationale: 
• 
Safety follow-up period information was updated and adverse events of interest 
were listed to align the protocol language with post marketing data collection 
requirements and to increase compliance with long-term follow-up data 
requirements. 
• 
Interim analysis 4 was removed as it is not a regulatory requirement and no study 
report is expected from this interim analysis per regulatory requirements. 
• 
Pharmacy guide is obsolete and has been replaced by IPIM in Amgen protocols. 
• 
Medical history section was updated for clarification and to align with other 
sections of the protocol. 
• 
The dose escalation and stopping rules section was modified to clarify that the 
planned dose may be given up to 7 days before the scheduled visit, as long as 
there are at least 21 days between doses. 
• 
Calcium and Vitamin D information was updated to match Xgeva product 
information. 
• 
The number of birth control methods and amount of washout time required 
between the end of treatment and pregnancy or breastfeeding was updated to 
align with the informed consent and current safety information. 
• 
Pregnancy reporting was changed from the Pregnancy Surveillance Program to 
Amgen Global Patient Safety as per current Amgen standard. 
• 
Administration, typographical and formatting changes were made throughout the 
protocol. 


Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 
Date:  15 May 2013 
Page 72 of 99 
 
Amendment 7:  Rationale and Summary of Amendment Changes 
An Open-label, Multi-center, Phase 2 Study of Denosumab in Subjects with Giant 
Cell Tumor of Bone 
Amgen Protocol Number 20062004 
EudraCT 2008-001606-16 
 
15 May 2013 
Summary of Changes:  
The primary reason for the amendment is to include pharmacokinetic analyses for an 
additional approximately 20 subjects, approximately 10 adolescents and 10 adults.  
Additionally, the end of the clinical trial is defined as when subjects enrolled through 
November 2012 (before Amendment 7) complete a minimum of 60 months on study, or 
until death or lost to follow-up, whichever comes first.  Safety follow-up visits are 
described. 
Additional changes include the following: 
• 
Added objectives, endpoints, sample collection, and analyses consistent with the 
pharmacokinetic subset  
• 
Clarified that subjects who rolled over from 20040215 will follow the 20062004 
schedule under Amendment 7 
• 
Clarified the End of Treatment visit and Safety Follow-up visits 
• 
Added oral examinations for all subjects, and provided additional guidance regarding 
IP dosing and oral/dental procedures 
• 
Clarified safety reporting timelines 
• 
Added updated pregnancy and lactation reporting section, with additional instructions 
regarding counseling women of childbearing potential on the risks of pregnancy while 
receiving denosumab and discussing methods to decrease the risk 
• 
Removed references to and sections pertaining to Daiichi Sankyo Co Ltd and 
Japanese sites, as there are no Japanese sites in this trial. 
• 
Typographic and formatting errors, redundancies, and inconsistencies were 
corrected 


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Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 – Amendment 5 
Date:  05 May 2011 
Page 68 of 74 
 
Amendment 5:  Rationale and Summary of Amendment Changes 
An Open-label, Multi-center, Phase 2 Study of Denosumab in Subjects with Giant 
Cell Tumor of Bone 
Amgen Protocol Number 20062004 
EudraCT 2008-001606-16 
IND # BB-9838 
 
 
05 May 2011 
 
Rationale:  
The primary reason for this amendment is to modify the exclusion criteria for 
contraception to include two methods of highly effective contraception during treatment 
and for 7 months after the end of treatment. 
Additionally, historical and on-study imaging performed as standard of care will be 
requested to be sent to a central imaging vendor for evaluation of disease response.  
Additional changes include the following: 
• 
The criteria for a subject to receive re-treatment has been clarified  
• 
The frequency of interim analyses has been modified 
• 
Typographic and formatting errors, redundancies, and inconsistencies were 
corrected 
 
Description of Changes (all changes to the protocol are indicated in bolded text): 
Section:  Global 
Change:  Add “Protocol Amendment 5 – 05 May 2011” 
 


Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 – Amendment 4 
Date:  15 November 2010 
Page 68 of 72 
 
Amendment 4:  Rationale and Summary of Amendment Changes 
An Open-label, Multi-center, Phase 2 Study of Denosumab in Subjects with Giant 
Cell Tumor of Bone 
Amgen Protocol Number 20062004 
EudraCT 2008-001606-16 
IND # BB-9838 
 
 
15 November 2010 
 
Rationale:
The primary reason for this amendment is to increase the sample size from 250 subjects 
to 375 subjects.  This sample size will allow additional subject to be enrolled onto this 
study allowing greater safety data to be collected in this subject population. 
  
Additional changes include the following: 
• 
The secondary Objectives have been clarified 
• 
The analysis of safety data from the safety follow-up has been clarified in section 
10.6.3  
• 
Typographic and formatting errors, redundancies, and inconsistencies were 
corrected 
 
 
Description of Changes
Section:  Global 
 (all changes to the protocol are indicated in bolded text): 
Change:  Add “Protocol Amendment 4 – 15 November 2010 
 
Section:  Global 
Change:  change references to “long-term” follow-up to “safety” follow-up 
 
 
Section:  Synopsis; Secondary Objectives: 
Replace:   
• 
evaluation of the proportion of subjects who do not require surgery in denosumab 
treated subjects with salvageable GCTB who would have otherwise required en bloc 
excision (cohort 2)   
With: 
• 
evaluation of the proportion of subjects who do not require surgery in denosumab 
treated subjects with salvageable GCTB (cohort 2) 
 
 
 


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Product:  Denosumab (AMG 162) 
Protocol Number:  20062004 – Amendment 2 - Superseding 
Date:  11 January 2010 
Page 68 of 91 
Amendment 2:  Rationale and Summary of Amendment Changes 
An Open-label, Multi-center, Phase 2 Study of Denosumab in Subjects with Giant 
Cell Tumor of Bone 
Amgen Protocol Number 20062004 
EudraCT 2008-001606-16 
IND # BB-9838 
 
 
 
11 January 2010 
 
Rationale:  
The primary reason for this amendment is to increase the sample size from 
approximately 100 subjects enrolled to approximately 250 subjects enrolled.  This 
sample size will allow additional subject to be enrolled onto this study allowing greater 
safety data to be collected in this subject population. 
Additional changes include the following: 
• 
Clarification of secondary objective and endpoint to include subjects who do not 
require any surgery 
• 
Addition of exploratory endpoints 
• 
An eligibility criteria excluding women of child-bearing potential who are evidently 
pregnant or breast feeding has been added 
• 
Addition of interim analyses corresponding with the increased sample size 
• 
The schema, glossary, and schedule of assessments have been updated to 
reflect changes in the protocol   
• 
Other minor changes and typographical errors have been corrected throughout 
and highlighted in bold text 
 
 
Description of Changes (all changes to the protocol are indicated in bolded text): 
Pages:  Global 
Change:  Add “Protocol Amendment 2 – Superseding  Date:  11 January 2010 to each 
header 
 
Pages:  Global 
Change:  Case report form or CRF to eCRF 
 
Pages:  Global 
Change:  IRB to IEC/IRB 
 
 


 
Printed copy is not official record. 
                                         
 
Product:  Denosumab 
Protocol Number:  20062004 
Date:  12 December 2008 
 
Page 1 of 18 
Amendment 1 
Protocol Title: 
 An Open-label, Multi-center, Phase 2 Study of Denosumab in Subjects with Giant 
Cell Tumor of Bone 
Amgen Protocol Number 20062004 
EudraCT 2008-001606-16 
IND # BB-9838 
 
 
 
Amendment 1 Date: 
12 December 2008 
 
Rationale:  
The primary reason for this amendment is to include skeletally mature adolescents (ie, 
adolescents who have closed epiphyseal plates) into this study.  There have been rare 
reported cases of GCT of bone in adolescents.  Giant Cell Tumor of bone usually occurs 
in skeletally mature adolescents after the epiphyseal plates have closed, and all 
adolescent subjects enrolled into this study will have radiological confirmation of skeletal 
maturity.  No further long bone growth is anticipated after epiphyseal plates are closed. 
 There are few treatment options for adolescents with mature skeletons and GCT of 
bone.  Based on the seriousness of GCT and the limited treatment options, Amgen 
believes that this protocol, which includes adolescents with mature skeletons and GCT 
of bone, presents greater than minimal risk, but also presents the prospect of direct 
benefit to the subject 
Additional changes include the following: 
• 
The sample size has been clarified to include approximately 100 subjects 
enrolled and the supporting sample size calculations  
• 
An eligibility criteria excluding women of child-bearing potential who are evidently 
pregnant or breast feeding has been added 
• 
Extension of follow-up visit to up to 12 months from 6 months 
• 
Other minor changes and typographical errors have been corrected throughout 
 
 
 
Confidential 
 
 

SAP_001.pdf: 
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Product:  Denosumab (AMG 162) 
Statistical Analysis Plan 20062004 
Dated:  17 July 2018 
Page 2 
Table of Contents 
Table of Abbreviations ..................................................................................................... 4 
1.
Introduction ............................................................................................................. 5
2.
Objectives ............................................................................................................... 5
2.1 
Primary ....................................................................................................... 5 
2.2 
Secondary ................................................................................................... 5 
2.3 
Exploratory .................................................................................................. 5 
3.
Study Overview ...................................................................................................... 6
3.1 
Study Design ............................................................................................... 6 
3.2 
Sample Size ................................................................................................ 6 
4.
Study Endpoints ..................................................................................................... 7
4.1 
Primary Endpoint ......................................................................................... 7 
4.2 
Secondary Endpoints .................................................................................. 7 
4.3 
Exploratory Endpoints ................................................................................. 7 
5.
Hypothesis .............................................................................................................. 8
6.
Definitions ............................................................................................................... 8
6.1 
Basic Definition ........................................................................................... 8 
6.2 
Study Points of Reference ........................................................................... 8 
6.3 
Study Dates ................................................................................................ 9 
6.4 
Study Time Intervals ................................................................................... 9 
6.5 
Subject Dispositions .................................................................................. 10 
6.6 
Derived Variables ...................................................................................... 11 
6.7 
Study Specific Definitions .......................................................................... 12 
7.
Analysis Subsets .................................................................................................. 16
7.1 
Safety Analysis Set ................................................................................... 16 
7.2 
Efficacy Analysis Set ................................................................................. 16 
7.3 
Patient Reported Outcome (PRO) Analysis Set......................................... 16 
7.4 
PK Analysis Set......................................................................................... 17 
7.5 
Interim Analyses Set ................................................................................. 17 
8.
Interim Analysis and Early Stopping Guidelines .................................................... 17
9.
Data Screening and Acceptance ........................................................................... 17
9.1 
Data Handling and Electronic Transfer of Data ......................................... 17 
9.2 
Handling of Missing and Incomplete Data ................................................. 17 
9.2.1 
Missing Dates ............................................................................ 18 
9.2.2 
Missing PRO Data ..................................................................... 19 
9.3 
Validation and Configuration Management ................................................ 19 
10.
Statistical Methods of Analysis.............................................................................. 19


Product:  Denosumab (AMG 162) 
Statistical Analysis Plan 20062004 
Dated:  17 July 2018 
Page 3 
10.1 
General Principles ..................................................................................... 19 
10.2 
Subject Accountability ............................................................................... 20 
10.3 
Important Protocol Deviations ................................................................... 20 
10.4 
Demographic and Baseline Characteristics ............................................... 20 
10.5 
Efficacy Analyses ...................................................................................... 21 
10.5.1 
Analyses of Key Efficacy Endpoints ........................................... 21 
10.5.2 
Analyses of Exploratory Efficacy Endpoints ............................... 22 
10.6 
Safety Analyses ........................................................................................ 24 
10.6.1 
Adverse Events ......................................................................... 24 
10.6.2 
Adverse Events of Interest ......................................................... 25 
10.6.3 
Adverse Events Occurred After Treatment-emergent 
Period ....................................................................................... 26 
10.6.4 
Adverse Events for Adolescent Subjects ................................... 26 
10.6.5 
Adverse Events for Adult Subjects ............................................. 27 
10.6.6 
Laboratory Test Results ............................................................ 27 
10.6.7 
Immunogenic Response ............................................................ 27 
10.6.8 
Exposure to Investigational Product .......................................... 28 
10.6.9 
Concomitant Medications and Safety Follow Up 
Intervention ............................................................................... 28 
11.
Changes from Protocol-specified Analyses ........................................................... 28
12.
Literature Citations / References ........................................................................... 29
13.
Appendices ........................................................................................................... 30
List of Tables 
Table 1.  Imputation Rules for Incomplete Dates ........................................................... 18 
List of Appendices 
Appendix A.  Reference Values / Toxicity Grades ......................................................... 31 
Appendix B.  BPI-SF ...................................................................................................... 32 


Product:  Denosumab (AMG 162) 
Statistical Analysis Plan 20062004 
Dated:  17 July 2018 
Page 4 
Table of Abbreviations 
Abbreviation/Acronym 
Definition 
BPI-SF 
Brief Pain Inventory – Short Form 
CR 
Complete response 
CSE 
Clinical Summary of Efficacy 
CTCAE 
Common Terminology Criteria for Adverse Events (version 3) 
CT 
Computed tomography 
DR 
Disease recurrence or recurrent disease  
GCTB 
Giant cell tumor of bone 
IP 
Investigational product  
MRI 
Magnetic resonance imaging 
PD 
PK 
Progressive disease  
Pharmacokinetics 
PET 
Positron emission tomography 
PET/CT 
Positron emission tomography/ Computed tomography 
PR 
Partial response 
SC 
Subcutaneous 
SD 
Stable disease 


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Product:  Denosumab (AMG 162) 
Statistical Analysis Plan 20062004 
Dated:  17 July 2018 
Page 6 
3. 
Study Overview 
3.1 
Study Design 
This is a phase 2, international, multi-center, open-label study in subjects with GCTB, 
receiving denosumab at a dose of 120 mg SC Q4W with a loading dose of 120 mg SC 
on study days 8 and 15. 
There are 3 cohorts in this study: 
•
Cohort #1:  Subjects with surgically unsalvageable disease (eg, sacral, spinal GCTB,
or multiple lesions including pulmonary metastases)
•
Cohort #2: Subjects with surgically salvageable disease whose planned initial
on-study surgery is associated with severe morbidity (eg, joint resection, limb
amputation, or hemipelvectomy)
•
Cohort #3: Subjects who are currently participating in Amgen study 20040215 giant
cell tumor study who are eligible to enroll
3.2 
Sample Size 
The number of subjects in this study is governed by the number of GCTB subjects who 
qualify for the study.  It is anticipated that approximately 530 subjects will participate, 
and a minimum of 20 subjects will be skeletal mature adolescents.  Prior to 
Amendment 7, 510 subjects were enrolled.  Following Amendment 7, an additional 
approximately 20 subjects (approximately 10 adolescents and approximately 10 adults) 
will be enrolled to the PK substudy. 
No more than 30 subjects will enroll from the Amgen study 20040215.  No adolescents 
will enroll into cohort 3, since all subjects participating in study 20040215 are adults 
(≥ 18 years of age). 
Subjects will continue to receive denosumab Q4W until one of the following occurs: 
•
For subjects with a complete tumor resection, denosumab treatment continues for
6 doses after pathological confirmation of partial response or complete response.
•
In all other cases, denosumab treatment continues until confirmation of disease
progression, investigator’s recommendation of discontinuation, Amgen’s and Daiichi
Sankyo Co., Ltd’s. (for Japanese sites only) recommendation of discontinuation, the
subject’s decision to discontinue for any reason, or administration of any of the
proscribed therapies.
In the protocol dated 15 Dec 2017, data (treatment plus follow up) will be collected 
for all subjects enrolled until the end of the clinical study.  This is anticipated to 
be when subjects enrolled prior to a minimum of 60 months or until death or lost 
to follow-up, whichever comes first.  


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Product:  Denosumab (AMG 162) 
Statistical Analysis Plan 20062004 
Dated:  17 July 2018 
Page 9 
6.3 
Study Dates 
Informed Consent Date 
The informed consent date is the date on which a subject signs the informed consent for 
this study. 
Enrollment Date 
The enrollment date is the date on which a subject is registered as enrolled to this study.  
First Dose Date 
The first dose date is the date on which a subject is administered the first dose of IP on 
20062004 study. 
Last Dose Date (of a treatment phase) 
The last dose date is the date on which a subject is administered the final dose of IP 
(during a treatment phase).   
End of Initial Treatment Phase Date 
The end of initial treatment phase date is the date recorded on the End of Study page of 
the Case Report Form (CRF) for an enrolled subject (approximately 4 weeks after last 
dose date in the initial treatment phase). 
End of Retreatment Phase Date  
The end of retreatment phase date for an enrolled subject is the date recorded on 
the End of Study page of the CRF in the retreatment folder for an enrolled subject 
(approximately 4 weeks after last dose date of retreatment phase). 
End of Safety Follow-up Phase 
The end of safety follow-up phase date for an enrolled subject is the date recorded 
on the End of Follow-up Phase page of CRF for an enrolled subject. 
6.4 
Study Time Intervals 
Screening Period  
The screening period for a subject is defined as the time from the informed consent date 
to the day of enrollment. 
On-Study Period  
The on-study period for an enrolled subject is defined as the time from study day 1 to 
the end of the initial treatment phase date.  


Product:  Denosumab (AMG 162) 
Statistical Analysis Plan 20062004 
Dated:  17 July 2018 
Page 10 
Retreatment Phase 
Subjects are considered in the retreatment phase when they enroll in retreatment 
phase after initial treatment phase. 
Safety Follow-up Phase (after a treatment phase) 
Subjects are considered in the safety follow-up phase after ending the initial treatment 
phase (or retreatment phase) when they have an end of initial treatment phase date 
(or end of retreatment phase date) which is captured in the End of Study page of the 
CRF, and the end of study reason is not due to death, full consent withdrawn or lost to 
follow-up. 
Treatment-Emergent Period 
The treatment-emergent period for an enrolled subject is defined as the time from 
the first dose in the initial treatment phase to the end of the initial treatment phase 
(or for subjects who entered retreatment, from the first dose date in the initial 
treatment phase through any follow-up prior to a retreatment, until the end of 
retreatment phase). 
6.5 
Subject Dispositions 
Enrolled 
Subjects are considered enrolled once all required screening assessments have been 
successfully completed and the eligibility criteria worksheets are signed by Amgen or 
Daiichi Sankyo Co., Ltd. (for Japanese sites only).  Three subjects from 
study 20040215 rolled over to the safety follow up phase in study 20062004 


Product:  Denosumab (AMG 162) 
Statistical Analysis Plan 20062004 
Dated:  17 July 2018 
Page 11 
without retreatment were excluded from all analysis sets (including the enrolled 
subjects set). 
Exposed to Investigational Product 
Subjects are defined as exposed to IP if they have received one or more doses of IP. 
6.6 
Derived Variables 
Baseline Measurements  
Baseline measurements are the closest recorded measurements prior to the first dose of 
denosumab.  If there are multiple valid records on an individual at the same date and 
time, then the average of these records will be used.  If the measurement is taken on the 
same day as the first dose and the exact measurement time relative to the first dose is 
unknown, it will be assumed to have been taken prior to the first dose of investigational 
product. 
Change from Baseline Values 
The arithmetic difference between a value of interest and a baseline value: Change from 
Baseline Value = (Value of Interest - Baseline Value) 
Percent Change from Baseline Value 
The ratio of the arithmetic difference between a value of interest and the baseline value 
to the baseline value multiplied by 100: Percent Change from Baseline Value = 100* 
[(Value of Interest - Baseline Value) / Baseline Value] 
Subject Incidence Rate 
The subject incidence rate for a given event is defined as the number of subjects with 
one or more reported occurrence of the event divided by the number of subjects who 
had the opportunity to experience the event.   
Subject Age at Study Entry 
The number of whole years from a subject’s birth date to the enrollment date. 
Analgesic Score 
Analgesic use will be summarized using analgesic score based on clinical’s review 
defined as follows. 
0 = No analgesic 
1 = Non-opioid analgesics  
2 = Weak opioids (eg, meperidine and codeine) 
3 = Strong opioids ≤ 75 mg oral morphine equivalent (OME) per day 


Product:  Denosumab (AMG 162) 
Statistical Analysis Plan 20062004 
Dated:  17 July 2018 
Page 12 
4 = Strong opioids with > 75-<= 150 mg OME per day  
5 = Strong opioids with > 150-<= 300 mg OME per day 
6 = Strong opioids with > 300-<= 600 mg OME per day 
7 = Strong opioids with > 600 mg OME per day  
Analgesic score will be used as numerical value.  For guidance on OME calculation and 
analgesic scoring derivation process and analgesic assumptions, please refer to User 
Manual, Opioid Analgesic Quantification for Denosumab Oncology Skeletal Related 
Event Clinical Studies, and Process guide for Opioid Analgesic Quantification Algorithm 
for Study 20090482.  The User Manual will be updated before the analysis, and kept on 
file at Amgen. 
6.7 
Study Specific Definitions 
Progressive Disease (PD)  
It is defined as the response of progressive disease, locally recurrent disease or 
relapse as captured in the Disease Status page of the CRF. 
Last Contact Date  
The last contact date for a subject is defined as the end of initial treatment phase 
date, the end of retreatment phase date, the end of safety follow-up phase date, 
the last date on the Disease Status page of the CRF, or the last contact date or 
death date on the Safety Follow-Up Phase page of the CRF, whichever comes 
later. 
Disease Progression or Recurrence during On-Study Period 
It is defined as the best response of PD during on-study period for subjects without 
any on-study CR/PR/SD (the response of complete response/partial 
response/stable disease) or a response of PD during on-study period following an 
on-study CR/PR/SD.  
Time to Disease Progression or Recurrence during On-Study Period 
It is defined as the time interval (in days) from the first dose date to the date of earliest 
PD.  If a subject has not had PD by the end of initial treatment phase date, time to 
disease progression or recurrence will be censored at her/his end of initial treatment 
phase date. 


Product:  Denosumab (AMG 162) 
Statistical Analysis Plan 20062004 
Dated:  17 July 2018 
Page 13 
 
Disease Recurrence (DR) after On-Study Complete Response (CR) 
It is defined as a response of PD during the full course of clinical trial after first 
on-study CR.  Subjects who do not have on-study CR will not be included in the 
analysis. 
Time to Disease Recurrence (DR) after On-Study Complete Response (CR) 
It is defined as the time interval (in days) from the first date of CR during on-study period 
to the first date of DR at any time during the full course of clinical trial following 
CR.  If a subject has not had DR following CR by final database lock, time to DR will be 
censored at her/his last contact date. 
Disease Progression after Best Post-Baseline On-Study Response of Partial 
Response (PR) 
It is defined as a response of disease progression during the full course of clinical 
trial after first best post-baseline on-study response of PR.  Subjects who do not 
have on-study PR will not be included in the analysis. 
Time to Disease Progression after Best Post-Baseline On-Study Response of 
Partial Response (PR) 
It is defined as the time interval (in days) from the first date of PR during on-study 
period to the first date of disease progression during the full course of clinical 
trial following PR.  If a subject has not had disease progression following PR by 
final database lock, time to disease progression will be censored at his/her last 
contact date. 
Disease Progression after Best Post-Baseline On-Study Response of Stable 
Disease (SD) 
It is defined as a response of disease progression during the full course of clinical 
trial after first best post-baseline on-study response of SD.  Subjects who do not 
have on-study SD will not be included in the analysis. 
Time to Disease Progression after Best Post-Baseline On-Study Response of 
Stable Disease (SD) 
It is defined as the time interval (in days) from the first date of SD during on-study 
period to the first date of disease progression during the full course of clinical 
trial following SD.  If a subject has not had disease progression following SD by 
final database lock, time to disease progression will be censored at his/her last 
contact date. 


Product:  Denosumab (AMG 162) 
Statistical Analysis Plan 20062004 
Dated:  17 July 2018 
Page 14 
 
Duration of Response 
It is defined as the time interval (in days) from the first date of complete response 
(CR) or partial response (PR) during on-study period to the first date of 
progressive disease (PD) at any time during the full course of clinical trial 
following CR or PR.  If a subject has not had PD following on-study CR or PR by 
final database lock, time to PD will be censored at her/his last contact date. 
Subjects who do not have on-study CR or PR will not be included in the analysis. 
Disease Progression or Recurrence after On-study GCTB Surgery 
It is defined as a response of PD during the full course of clinical trial after first 
on-study GCTB surgery.  Subjects who do not have on-study surgery will not be 
included in the analysis.  The analysis of this endpoint will be conducted by 
cohort. 
Time to Disease Progression or Recurrence After On-study GCTB Surgery 
It is defined as the time interval (in days) from date of first on-study GCTB surgery to the 
date of first PD during the full course of clinical trial after on-study GCTB surgery.  If 
a subject has not had any PD after on-study GCTB surgery by final database lock, time 
to disease progression or recurrence will be censored at her/his last contact date  
Disease Progression or Recurrence after Discontinuation of IP 
It is defined as a response of PD during the full course of clinical trial after 
discontinuation of IP (ending the initial treatment phase).  Subjects who had PD 
during the initial treatment phase or who discontinued IP and discontinuation reason 
was due to consent withdrawn, lost to follow up, death, or disease progression will not 
be included in the analysis. 
Time to Disease Progression or Recurrence after Discontinuation of IP 
It is defined as the time interval (in days) from last dose date in initial treatment phase 
to the date of first PD after discontinuation of IP.  If a subject has not had any PD after 
discontinuation of IP by the final database lock, time to disease progression or 
recurrence will be censored at her/his last contact date. 
Time to On-study GCTB Surgery 
It is defined as the time interval (in days) from the first dose date to the date of first 
on-study GCTB surgery.  If a subject has not had any on-study GCTB surgery by the 
end of initial treatment phase date, time to on-study GCTB surgery will be censored at 


Product:  Denosumab (AMG 162) 
Statistical Analysis Plan 20062004 
Dated:  17 July 2018 
Page 15 
 
her/his end of initial treatment phase date.  The analysis for this endpoint will be for 
subjects in cohort 2 only. 
Time to Second GCTB Surgery after First On-study GCTB Surgery 
It is defined as the time interval (in days) from the first on-study GCTB surgery date to 
the date of the second GCTB surgery including surgery captured during the full course 
of clinical trial.  If a subject only had one GCTB surgery by final database lock, time to 
second GCTB surgery will be censored at her/his last contact date.  Subjects who do 
not have any on-study surgery will not be included in the analysis. 
Progression-Free Survival Time 
It is defined as the time interval (in days) from the first dose date to the date of PD 
or death from any cause during on-study period, whichever comes first.  If a 
subject has not had any PD and been known to be alive by the end of initial 
treatment phase date, he/she will be censored at the end of initial treatment phase 
date. 
Proportion of Subjects without Any Surgery at Month 6  
It is defined as the number of subjects without any surgery by month 6 divided by the 
number of cohort 2 subjects who have an opportunity to complete 6 months of treatment 
in the efficacy analysis set.  
Proportion of Subjects Able to Undergo a Less Morbid Surgical Procedure  
It is defined as the number of subjects who underwent a less morbid surgical procedure 
based on clinical review of the planned versus actual surgery performed divided by 
the number of subjects who had planned surgical procedures at baseline in the efficacy 
analysis set. 
Proportion of Subjects with Pathologic Response  
It is defined as the number of subjects with pathologic response divided by the number 
of subjects with at least one evaluable post-baseline pathologic sample included in the 
efficacy analysis set.  
Proportion of Subjects without Tumor Post-baseline  
It is defined as the number of subjects without tumor post-baseline divided by the 
number of subjects with at least one evaluable post-baseline pathologic sample 
included in the efficacy analysis set. 


Product:  Denosumab (AMG 162) 
Statistical Analysis Plan 20062004 
Dated:  17 July 2018 
Page 16 
Radiographic Changes Over Time  
It is categorized as improved, stable and worsened by the investigator’s qualitative 
judgment.  For an individual, if multiple imaging studies are present, the best 
response prior to on-study GCTB surgery (for subjects undergoing surgery) or 
prior to the end of initial treatment phase (for subjects without on-study surgery) 
will be used. 
Disease Status Changes 
It is categorized as complete response, partial response, stable disease and disease 
progression by the physician’s assessment. 
Time to Pain Score Change 
It is defined as the time interval (in days) from the first dose date to the date of clinical 
meaningful pain score change (2-point decrease).  If a subject has a GCTB surgery, pain 
score after GCTB surgery will be censored.  If a subject has not had clinical meaningful 
pain score change by on-study GCTB surgery date or final database lock, time to pain 
score change will be censored at her/his end of initial treatment phase date or on-
study GCTB surgery date. 
7. 
Analysis Subsets 
7.1 
Safety Analysis Set 
The safety analysis set, for adverse events and lab parameters, includes all enrolled 
subjects who received at least one dose of IP on 20062004 study. 
7.2 
Efficacy Analysis Set 
The efficacy analysis set included all enrolled subjects who were eligible for the study, 
and received at least one dose of IP on 20062004 study.  Subjects with key 
inclusion/exclusion deviations of the eligibility criteria ‘pathologically confirmed 
giant cell tumor’ and/or ‘known or suspected diagnosis of underlying malignancy’ 
were excluded from the efficacy analysis set.  Subjects who rolled over from 
Study 20040215 to the safety follow-up phase in Study 20062004 and later 
received retreatment were also excluded from the efficacy analysis set.   
7.3 
Patient Reported Outcome (PRO) Analysis Set 
Includes all subjects in the efficacy analysis set who had at least one PRO assessment 
and used consistent recall periods throughout the study.   


Product:  Denosumab (AMG 162) 
Statistical Analysis Plan 20062004 
Dated:  17 July 2018 
Page 17 
7.4 
PK Analysis Set 
 Includes all subjects who received at least one dose of IP with baseline PK 
measurement and at least one post-baseline PK measurement. 
7.5 
Interim Analyses Set 
The Safety/Efficacy/PRO Analysis Sets are the respective analysis sets of all enrolled 
subjects up to the time of the interim analyses.  The safety analysis set includes all 
enrolled subjects who received at least one dose of IP by the interim analysis cut-off 
date.  The efficacy analysis set includes all enrolled subjects who were eligible for the 
study and received at least one dose of IP by the interim analysis cut-off date.  The PRO 
analysis set includes all subjects in the efficacy analysis set who had at least one PRO 
assessment by the interim analysis cut-off date.   
8. 
Interim Analysis and Early Stopping Guidelines  
The first and second interim analyses were conducted after 50 and 100 subjects, 
respectively, had the opportunity to complete 6 months of treatment.  The third interim 
analysis was conducted with a data cut-off date of 25 March 2011 and included 
approximately 286 subjects enrolled.  An independent analysis of the radiographic 
images retrospectively collected for the study up to March 25, 2011, the data cutoff date 
for the CSR to be included in the GCTB filing, was performed.  An external radiology 
vendor was selected for this retrospective radiographic image review.  For analysis 
details and results, please see GCTB CSE SAP and the report on the integrated 
radiology assessments.  An unplanned analysis based on agency’s requested was 
performed based on the data cutoff date of August 30, 2013.  In addition, a planned 
primary analysis was conducted after subjects enrolled to the Pharmacokinetic 
Sub Study had an opportunity to complete 12 months of treatment (data cut-off on 
24 Feb 2017). 
9. 
Data Screening and Acceptance 
9.1 
Data Handling and Electronic Transfer of Data 
All data for this study will be received from Amgen’s data management department.  For 
studies in RAVE, since RAVE has no snapshot function, the study team will specify 
criteria to subset data for interim analysis.   
9.2 
Handling of Missing and Incomplete Data 
Subjects may have missing data points for a variety of reasons.  In general, data may be 
missing due to subject’s early withdrawal from study, a missed visit, or non-evaluability 
of an endpoint at a particular point in time.  For the primary outcome, no imputation will 


Product:  Denosumab (AMG 162) 
Statistical Analysis Plan 20062004 
Dated:  17 July 2018 
Page 18 
be used.  For lab results, no imputation will be used.  For the PRO data outcome, 
primary imputation will be used. 
Adverse events (AE) for which the start date is entirely missing despite Amgen’s 
attempts to obtain the missing dates will be counted as on-treatment adverse events.  
Adverse events with a partially missing start date that occur prior to study day 1 will be 
considered pre-treatment adverse events and excluded from safety analyses.  
Otherwise, they will be considered as after study day 1 and included in the safety 
summary.   
9.2.1 
Missing Dates 
Incomplete event start dates and concomitant medications start or stop dates will be 
imputed as described in the table below.  If the start date is missing, assume the event 
or medication started before enrollment; if the stop date and the flag for medication 
continuing are both missing for an on-study event or medication, assume the event or 
medication stopped after the end of study date.  Partial dates will be listed as is on the 
listings. 
Table 1.  Imputation Rules for Incomplete Dates 
Missing 
Imputation 
Exception 
Start date 
(AE, concomitant 
medication) 
Day 
01 
Default to study day 1 if an event starts 
the same year and month as study day 1 
Day / Month 
01JAN 
Default to study day 1 if an event started 
the same year as study day 1 
Stop date 
(concomitant 
medication only) 
Day 
Last day of 
the month 
Default to the End of Study (EOS) date or 
the analysis cut-off date (for ongoing 
subjects) if the concomitant medication 
stopped the same year and month as the 
EOS date or the analysis cut-off date for 
ongoing subjects respectively  
Default to the EOS date or the analysis 
cut-off date (for ongoing subjects) if the 
concomitant medication stopped the 
same year as the EOS date or analysis 
cut-off date for ongoing subjects 
respectively 
Day / Month 
31DEC 


Product:  Denosumab (AMG 162) 
Statistical Analysis Plan 20062004 
Dated:  17 July 2018 
Page 19 
9.2.2 
Missing PRO Data 
The primary imputation method is: 
•
If there are observations before and after the missing response, take the average of
the two neighboring responses to obtain the imputed value.
•
If there is no observation before the missing response, apply last observation carried
backward.  Missing baseline will not be imputed.
•
If there is no observation after the missing response, apply the worst case scenario
on the subject level (eg. for ‘Worst’ pain, if responder criteria is ≥ 2-pt increase, then
assume subject had a ≥ 2-pt increase; if responder criteria is ≥ 2-pt decrease, then
assume subject did not have a ≥ 2-pt decrease).
•
Baseline will not be used to impute missing post-baseline response.
9.3 
Validation and Configuration Management 
Programs will be developed and maintained and output will be verified according to 
processes described in applicable departmental and product-level procedures, including 
but not limited to the SOP on Configuration Management of Statistical Analysis 
Reporting Systems and Statistical Analysis and Reporting System Development and 
Validation. 
Tables, listings, and graphs will be produced with standard macro programs where such 
macros can produce the specified outputs.   
The production environment consists of Amgen-supported versions of the SAS System 
and S-Plus running on the Sun Solaris operating system.  The SAS version used to 
generate datasets and produce analyses will be documented in the clinical study report.  
10. 
Statistical Methods of Analysis 
10.1 
General Principles 
The statistical analysis in this open-label study will be descriptive in nature and no 
hypothesis testing will be performed.  All the efficacy analyses will be conducted 
separately in each cohort and for cohorts 1 and 2 combined for all subjects in the 
efficacy analysis set, unless specified otherwise.  Safety analysis of adverse events 
will be performed by cohort and for all subjects in safety analysis set.  Safety 
analysis of lab results will be performed by cohort and for all subjects in safety 
analysis set.  Some efficacy and safety analyses will be repeated for the adolescent 
population and adult population as applicable.  PK related analysis will be conducted 
separately by adolescent subjects and adult subjects. 
Categorical data will be presented in the form of frequency and percentage.  Continuous 
data will be provided with the descriptive statistics, which includes n (number of 


Product:  Denosumab (AMG 162) 
Statistical Analysis Plan 20062004 
Dated:  17 July 2018 
Page 20 
non-missing observations), mean, standard deviation, median, 25th percentile, 
75th percentile, minimum, and maximum).  
10.2 
Subject Accountability 
For all enrolled subjects, enrolled adolescent subjects, enrolled adult subjects and 
enrolled subjects in PK analysis subset, the numbers and percentages achieving the 
planned assessments listed below will be tabulated by cohort: 
•
Subjects who received IP, who discontinued IP from initial treatment phase, and their
reasons for IP discontinuation
•
Subjects who enrolled in treatment phase, who discontinued the initial treatment
phase, and their reason for initial treatment phase discontinuation.
For all enrolled subjects, the numbers and percentages achieving the planned 
assessments listed below will be tabulated by cohort: 
•
Subject enrollment by country and investigator
•
Subjects in each key analysis set
In addition, listings will be provided for unique manufacturing lot numbers and 
manufacturing lot numbers for all subjects in safety analysis sets. 
10.3 
Important Protocol Deviations 
Important Protocol Deviations (IPDs) categories are defined by the study team before 
the first patient visit and updated during the IPD reviews throughout the study prior to 
database lock.  These definitions of IPD categories, sub-category codes and 
descriptions will be used during the course of the study. 
Listings for important protocol deviation and all protocol inclusion/exclusion deviations 
will be provided for all enrolled subjects. 
10.4 
Demographic and Baseline Characteristics 
A summary of baseline demographics for all enrolled subjects, enrolled adolescent 
subjects, enrolled adult subjects and enrolled subjects in PK analysis subset will 
include: age, sex, race, and geriatric age group (if applicable).   
A summary of baseline physical characteristics for all enrolled subjects, enrolled 
adolescent subjects, enrolled adult subjects will include: weight, height, and body 
mass index.   
A summary of baseline laboratory parameters for all enrolled subjects will include: 
Albumin-adjusted calcium, albumin, magnesium, phosphorus, and creatinine.  


Product:  Denosumab (AMG 162) 
Statistical Analysis Plan 20062004 
Dated:  17 July 2018 
Page 21 
A summary of baseline disease characteristics for all enrolled subjects, enrolled 
adolescent subjects, enrolled adult subjects and enrolled subjects in PK analysis 
subset will include: Karnofsky performance status score, GCTB disease type (primary 
resectable, primary unresectable, recurrent resectable, or recurrent unresectable), the 
longest dimension and location of the target lesion, and planned surgery.  
A summary of prior treatments for all enrolled subjects will include the use of following 
for the initial GCTB, bisphosphonate therapy, radiation therapy, chemotherapy, and 
surgeries for GCTB. 
A summary of prior GCTB history for all enrolled subjects will include time from initial 
GCTB to enrollment, initial GCTB lesion location and prior GCTB surgery location. 
A summary of baseline BPI-SF outcome scores for all enrolled subjects will include: 
‘‘pain at its worst’ score, pain severity score, and pain interference score.  
Baseline analgesic use will also be summarized. 
All analyses mentioned in this section will be conducted by cohort and for all 
subjects unless otherwise specified.  The analyses for PK subset will be provided 
by adolescent and adult subjects and for all subjects in the PK analysis set. 
10.5 
Efficacy Analyses 
10.5.1 
Analyses of Key Efficacy Endpoints 
Time to Disease Progression for Cohort 1  
Kaplan-Meier estimates will be graphically displayed.  Kaplan-Meier event rates at 
various time points (eg, month 6, month 12, etc) with 2-sided confidence intervals will be 
summarized.  In addition, Kaplan-Meier estimates of quartiles (median, 25th and 
75th percentiles) with 2-sided 95% confidence intervals will be calculated if applicable.  
This analysis will be conducted for adolescent subjects, adult subjects and all subjects in 
the efficacy analysis set. 
Proportion of Subjects Without Any Surgery at Month 6 for Cohort 2 
Crude estimates with 2-sided exact 95% confidence intervals will be summarized for 
cohort 2 subjects who have an opportunity to complete 6 months of treatment in the 
efficacy analysis set.  This analysis will be conducted for adolescent subjects, adult 
subjects and all subjects from cohort 2 in the efficacy analysis set. 


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Product:  Denosumab (AMG 162) 
Statistical Analysis Plan 20062004 
Dated:  17 July 2018 
Page 25 
The summary of treatment-emergent adverse events will be provided for the following 
categories by system organ class, high level term and preferred term in descending 
order of frequency, and by preferred term in descending order of frequency.  
•
All treatment-emergent adverse events
•
IP related treatment-emergent adverse events
•
CTCAE grade 3, 4, or 5 treatment-emergent adverse events
•
IP related CTCAE grade 3, 4, or 5 treatment-emergent adverse events
•
Treatment-emergent serious adverse events
•
IP related treatment-emergent serious adverse events
•
Treatment-emergent adverse events leading to treatment phase discontinuation
•
IP related treatment-emergent adverse events leading to treatment phase
discontinuation
•
Treatment-emergent adverse events leading to IP discontinuation
•
Treatment-emergent fatal events
The analysis will be provided by cohort and for all subjects in the safety analysis 
set. 
10.6.2 
Adverse Events of Interest 
Protocol-specified adverse events of interest namely, positively adjudicated 
atypical femoral fracture (AFF), positively adjudicated osteonecrosis of the jaw 
(ONJ) and new malignancy events were evaluated during and after the 
treatment-emergent period of the study.   
Other adverse events of interest namely musculoskeletal pain, osteonecrosis 
outside the jaw, hypocalcaemia, adverse events potentially associated with 
hypersensitivity, infection, cardiac disorders and vascular disorders were 
evaluated during the treatment-emergent period of the study.  Hypercalcaemia 
events that occurred after 30 days following the last dose of IP in the initial 
treatment phase were also evaluated as an event of interest.   
Malignancy type (ie, new malignancies, and new malignancy in GCTB) will be 
determined by medical review.  
The incidences of all adverse events of interest by cohort and for all subjects in 
safety analysis set will be summarized, and discussed in the clinical study report. 
Subject-year adjusted rate of adjudicated positive ONJ will be summarized by 
cohort and for all subjects in the safety analysis set by time period. 


Product:  Denosumab (AMG 162) 
Statistical Analysis Plan 20062004 
Dated:  17 July 2018 
Page 26 
10.6.3 
Adverse Events Occurred After Treatment-emergent Period  
Subject incidence of adverse events and adverse events related to investigational 
product which occurred after the treatment-emergent period will be provided for all 
adverse events, serious adverse events, fatal adverse events, grade ≥ 3 (ie, CTCAE 
grade 3, 4, or 5) adverse events, adverse events leading to treatment phase 
discontinuation, and adverse events leading to investigational product discontinuation. 
The summary of all adverse events and serious adverse events after the 
treatment-emergent period will be provided by system organ class, high level term and 
preferred term in descending order of frequency, and by preferred term in descending 
order of frequency. 
The summary of adverse events leading to treatment phase discontinuation and fatal 
adverse events after the treatment-emergent period will be provided by preferred term in 
descending order of frequency. 
All analyses in this section will be conducted by cohort and for all subjects in the 
safety analysis set and at risk for this analysis. 
Subjects who rolled over to study 20062004 safety follow-up phase and does not 
receive IP on 20062004 study are excluded from safety analysis set.  Their safety 
data will be reported in a separate listing.  
10.6.4 
Adverse Events for Adolescent Subjects 
Subject incidence of treatment-emergent adverse events and treatment-emergent 
adverse events related to investigational product will be provided for all adverse events, 
serious adverse events, fatal adverse events, grade ≥ 3 (ie, CTCAE grade 3, 4, or 5) 
adverse events, adverse events leading to treatment phase discontinuation, and adverse 
events leading to investigational product discontinuation. 
The summary of all treatment-emergent adverse events and treatment-emergent serious 
adverse events will be provided by system organ class, high level term and preferred 
term in descending order of frequency, and by preferred term in descending order of 
frequency. 
Subject incidence of adverse events and adverse events related to investigational 
product which occurred after the treatment-emergent period will be provided for all 
adverse events, serious adverse events, fatal adverse events, grade ≥ 3 (ie, CTCAE 
grade 3, 4, or 5) adverse events, adverse events leading to treatment phase 
discontinuation, and adverse events leading to investigational product discontinuation. 


Product:  Denosumab (AMG 162) 
Statistical Analysis Plan 20062004 
Dated:  17 July 2018 
Page 27 
The summary of all adverse events after treatment-emergent period and serious adverse 
events after treatment-emergent period will be provided by system organ class, high 
level term and preferred term in descending order of frequency, and by preferred term in 
descending order of frequency. 
Subject incidence of adverse events of interest and new malignancy in GCTB will be 
tabulated.  
All analyses in this section will be conducted by cohort and for all adolescent subjects in 
the safety analysis set. 
10.6.5 
Adverse Events for Adult Subjects 
Subject incidence of treatment-emergent adverse events and treatment-emergent 
adverse events related to investigational product will be provided for all adverse events, 
serious adverse events, fatal adverse events, grade ≥ 3 (ie, CTCAE grade 3, 4, or 5) 
adverse events, adverse events leading to treatment phase discontinuation, and adverse 
events leading to investigational product discontinuation. 
Subject incidence of adverse events and adverse events related to investigational 
product which occurred after the treatment-emergent period will be provided for all 
adverse events, serious adverse events, fatal adverse events, grade ≥ 3 (ie, CTCAE 
grade 3, 4, or 5) adverse events, adverse events leading to treatment phase 
discontinuation, and adverse events leading to investigational product discontinuation. 
Subject incidence of adverse events of interest and new malignancy in GCTB will be 
tabulated.  
All analyses in this section will be conducted by cohort and for all adult subjects in the 
safety analysis set. 
10.6.6 
Laboratory Test Results 
Laboratory parameters will be summarized over time using descriptive statistics for 
recorded values and change from baseline.  In addition, CTCAE grade shift tables, in 
which the incidence of shift of toxicity grades in recorded values from baseline to “worst” 
on-study value is displayed, will also be provided.  All analyses in this section will be 
conducted by cohort and for all subjects in the safety analysis set 
10.6.7 
Immunogenic Response 
Immunogenic response will be described by tabulating the numbers of subjects who 
tested positive (binding, neutralizing) for anti-denosumab antibodies in the subjects 


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Product:  Denosumab (AMG 162) 
Statistical Analysis Plan 20062004 
Dated:  17 July 2018 
Page 29 
12. 
Literature Citations / References 
Fairclough D.L, Gagnon D, and Papadopoulos G. Planning Analyses of Quality-of-Life 
Studies: A Case Example with Migraine Prophylaxis. J. Biopharm Stat 2004;14:31–51 


Product:  Denosumab (AMG 162) 
Statistical Analysis Plan 20062004 
Dated:  17 July 2018 
Page 30 
13. 
Appendices 


Product:  Denosumab (AMG 162) 
Statistical Analysis Plan 20062004 
Dated:  17 July 2018 
Page 31 
Appendix A.  Reference Values / Toxicity Grades 
The Common Terminology Criteria for Adverse Events (CTCAE) are available at the 
following link: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf. 


Product:  Denosumab (AMG 162) 
Statistical Analysis Plan 20062004 
Dated:  17 July 2018 
Page 32 
Appendix B.  BPI-SF 
Question Mapping 
MEASURES (scale) 
QUESTIONS 
Pain Interference 
8a-8g 
Pain Severity 
3-6 
Scoring Algorithm  
The scoring algorithm of the BPI-SF questionnaire generates two measures based upon 
the subdomains of pain severity and pain interference.  Measures of severity are scored 
by reports of experiencing the "worst pain" or computing the arithmetic mean of the 
4 severity items.  Measures of interference are scored by the arithmetic mean of the 
7 interference items. 
When calculating subscale scores by taking the arithmetic mean, ie, the pain severity 
and pain interference scores, make sure that the majority of the items are responded to.  
For example, 3 out of 4 pain severity and 4 out of the 7 pain interference would 
represent the majority of the items for the subscale.  If there are less than the indicated 
items, we consider the subscale 'missing'.