Phase 2 Study of Denosumab (NSC# 744010), a RANK Ligand Antibody, for Recurrent or Refractory Osteosarcoma
Phase: PHASE2
Conditions: Metastatic Osteosarcoma, Recurrent Osteosarcoma, Refractory Osteosarcoma, Stage IV Osteosarcoma AJCC v7, Stage IVA Osteosarcoma AJCC v7, Stage IVB Osteosarcoma AJCC v7
Sponsor: Children's Oncology Group

 
 
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CHILDREN’S ONCOLOGY GROUP 
 
 
AOST1321 
 
 
Phase 2 Study of Denosumab (IND# 127430, NSC# 744010), a RANK Ligand Antibody, for Recurrent or 
Refractory Osteosarcoma 
 
 
An Intergroup NCTN Phase 2 Study 
 
IND sponsor for Denosumab: COG 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, AND SHOULD NOT BE COPIED, REDISTRIBUTED OR USED FOR 
ANY OTHER PURPOSE. MEDICAL AND SCIENTIFIC INFORMATION CONTAINED WITHIN THIS PROTOCOL IS NOT 
INCLUDED TO AUTHORIZE OR FACILITATE THE PRACTICE OF MEDICINE BY ANY PERSON OR ENTITY. RESEARCH 
MEANS A SYSTEMATIC INVESTIGATION, INCLUDING RESEARCH DEVELOPMENT, TESTING AND EVALUATION, 
DESIGNED TO DEVELOP OR CONTRIBUTE TO GENERALIZABLE KNOWLEDGE. THIS PROTOCOL IS THE RESEARCH 
PLAN DEVELOPED BY THE CHILDREN’S ONCOLOGY GROUP TO INVESTIGATE A PARTICULAR STUDY QUESTION OR 
SET OF STUDY QUESTIONS AND SHOULD NOT BE USED TO DIRECT THE PRACTICE OF MEDICINE BY ANY PERSON OR 
TO PROVIDE INDIVIDUALIZED MEDICAL CARE, TREATMENT, OR ADVICE TO ANY PATIENT OR STUDY SUBJECT. THE 
PROCEDURES IN THIS PROTOCOL ARE INTENDED ONLY FOR USE BY CLINICAL ONCOLOGISTS IN CAREFULLY 
STRUCTURED SETTINGS, AND MAY NOT PROVE TO BE MORE EFFECTIVE THAN STANDARD TREATMENT. ANY PERSON 
WHO REQUIRES MEDICAL CARE IS URGED TO CONSULT WITH HIS OR HER PERSONAL PHYSICIAN OR TREATING PHYSICIAN 
OR VISIT THE NEAREST LOCAL HOSPITAL OR HEALTHCARE INSTITUTION. 
 
 
 
STUDY CHAIR 
 
 
 
 
 
 
 
 
 
 
 
 
 
Activated: 
11/09/15      
Version Date: 
10/22/18 
Closed: 
07/20/18 
Amendment: 
#3 

 
 
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Participating Organizations 
 
COG / Children's Oncology Group 
 
ALLIANCE / Alliance for Clinical Trials in Oncology 
 
ECOG-ACRIN / ECOG-ACRIN Cancer Research Group 
 
NRG / NRG Oncology  
 
SWOG / SWOG 
 
 
 
CONTACT INFORMATION 
 
To submit site registration 
documents: 
For patient enrollments: 
Submit study data 
Regulatory documentation must 
be submitted to the CTSU via the 
Regulatory Submission Portal. 
Regulatory Submission Portal: 
(Sign in at www.ctsu.org,            
and select the Regulatory 
Submission sub-tab under the 
Regulatory tab.)  
 
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU Regulatory 
Office immediately at 1-866-651-
2878 to receive further instruction 
and support. 
 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-2878 for 
regulatory assistance. 
Please refer to the patient enrollment 
section of the protocol for instructions 
on using the Oncology Patient 
Enrollment Network (OPEN) which 
can be accessed at 
https://www.ctsu.org/OPEN_SYSTEM/ 
or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk with any 
OPEN-related questions at 
ctsucontact@westat.com. 
Data collection for this study 
will be done exclusively through 
Medidata Rave. Please see the 
Data Submission Schedule in the 
CRF packet for further 
instructions.  
 
 
The most current version of the study protocol and all supporting documents must be downloaded from the 
protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org. Access to the 
CTSU members’ website is managed through the Cancer Therapy and Evaluation Program - Identity and Access 
Management (CTEP-IAM) registration system and requires user log on with CTEP-IAM username and 
password. Permission to view and download this protocol and its supporting documents is restricted and is 
based on person and site roster assignment housed in the CTSU RSS.  
For clinical questions (i.e. patient eligibility or treatment-related) contact the Study PI of the Lead Protocol 
Organization. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data submission) 
contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and correspondence 
will be triaged to the appropriate CTSU representative.  
The CTSU Website is located at https://www.ctsu.org. 
 
 

 
 
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TABLE OF CONTENTS 
 
SECTION 
PAGE 
STUDY COMMITTEE 
5 
ABSTRACT 
7 
EXPERIMENTAL DESIGN SCHEMA 
8 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
9 
1.1 
Primary Aims 
9 
1.2 
Secondary Aims 
9 
2.0 
BACKGROUND 
9 
2.1 
Introduction/Rationale for Development 
9 
2.2 
Preclinical Studies 
14 
3.0 
STUDY ENROLLMENT PROCEDURES AND PATIENT ELIGIBILITY 
16 
3.1 
Study Enrollment 
16 
3.2 
Patient Eligibility Criteria 
19 
4.0 
TREATMENT PLAN 
23 
4.1 
Overview of Treatment Plan 
23 
4.2 
Therapy Delivery Map for Cycle 1 
24 
4.3 
Therapy Delivery Map for Cycles 2-26 
27 
5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
30 
5.1 
Denosumab Dose Delay 
30 
6.0 
DRUG INFORMATION 
30 
6.1 
DENOSUMAB 
30 
7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
34 
7.1 
End of Therapy & Follow-up 
34 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
35 
8.1 
Criteria for Removal from Protocol Therapy 
35 
8.2 
Off Study Criteria 
35 
9.0 
STATISTICAL CONSIDERATIONS 
35 
9.1 
Statistical Design 
35 
9.2 
Patient Accrual and Expected Duration of Trial 
37 
9.3 
Statistical Analysis Methods 
38 
9.4 
Gender and Minority Accrual Estimates 
40 
10.0 
EVALUATION CRITERIA 
40 
10.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
40 
10.2 
Response Criteria for Patients with Solid Tumors 
40 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
46 
11.1 
Purpose 
46 
11.2 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
46 

 
 
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11.3 
Specific Examples for Expedited Reporting 
47 
11.4 
Reporting Requirements for Specialized AEs 
49 
11.5 
Exceptions to Expedited Reporting 
49 
11.6 
Reporting Requirements - Investigator Responsibility 
49 
11.7 
General Instructions for Expedited Reporting via CTEP-AERS 
50 
11.8 
Reporting Table for Late Phase 2 and Phase 3 Studies – Table A 
52 
11.9 
Routine Reporting of Adverse Events 
53 
12.0 
RECORDS AND REPORTING 
53 
12.1 
CDUS 
53 
12.2 
Data and Safety Monitoring Committee 
53 
13.0 
SURGICAL GUIDELINES 
53 
14.0 
PATHOLOGY GUIDELINES AND SPECIMEN REQUIREMENTS 
54 
15.0 
SPECIAL STUDIES SPECIMEN REQUIREMENTS 
54 
15.1 
Denosumab Pharmacokinetics 
54 
15.2 
Denosumab Pharmacodynamics 
56 
15.3 
Evaluation of RANK / RANKL Expression in Pre-Treatment Tumor Specimens 
57 
16.0 
IMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING 
58 
16.1 
Required and Recommended Osteosarcoma Imaging 
59 
APPENDIX I:  CTEP AND CTSU REGISTRATION PROCEDURES 
62 
APPENDIX II:  YOUTH INFORMATION SHEETS 
64 
REFERENCES 
65 
 
 

  
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Email: rlrandall@ucdavis.edu 
 
 
AGENT  
 
NSC# 
 
IND# 
 
Denosumab 
 
744010  
127430 
 
 
 
IND sponsor for denosumab: COG 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SEE SECTION 15.0 FOR SPECIMEN SHIPPING ADDRESSES.

  
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The Children's Oncology Group has received a Certificate of Confidentiality from the federal government, 
which will help us protect the privacy of our research subjects. The Certificate protects against the 
involuntary release of information about your subjects collected during the course of our covered studies. 
The researchers involved in the studies cannot be forced to disclose the identity or any information collected 
in the study in any legal proceedings at the federal, state, or local level, regardless of whether they are 
criminal, administrative, or legislative proceedings. However, the subject or the researcher may choose to 
voluntarily disclose the protected information under certain circumstances. For example, if the subject or 
his/her guardian requests the release of information in writing, the Certificate does not protect against that 
voluntary disclosure. Furthermore, federal agencies may review our records under limited circumstances, 
such as a DHHS request for information for an audit or program evaluation or an FDA request under the 
Food, Drug and Cosmetics Act.  
The Certificate of Confidentiality will not protect against mandatory disclosure by the researchers of 
information on suspected child abuse, reportable communicable diseases, and/or possible threat of harm to 
self or others. 
 
 
ABSTRACT 
Patients with recurrent osteosarcoma have a very poor prognosis and limited treatment options. It is a 
priority to identify novel agents with evidence of clinical activity in osteosarcoma. This is a prospective 
single arm, open-label, phase 2 trial of RANKL antibody, denosumab, in recurrent osteosarcoma with 
osteosarcoma-specific cohorts and osteosarcoma-specific endpoints. Patients will enroll on either the 
measurable disease cohort or the completely resected disease cohort. All patients will receive subcutaneous 
denosumab every 4 weeks with a loading dose on Days 8 and 15 of Cycle 1. Endpoints for the cohort with 
measurable disease (Cohort 1) are the disease control rate at 4 months as compared to historical COG 
experience or objective response rate. The endpoint for the fully resected cohort (Cohort 2) is the disease 
control rate at 12 months as compared to historical COG experience. Secondary objectives include 
pharmacokinetics, pharmacodynamics and tolerability of denosumab in patients with recurrent 
osteosarcoma. Biological markers, particularly RANK and RANKL expression will be explored. 
 
 
 
 
 
 

  
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EXPERIMENTAL DESIGN SCHEMA 
 
 
 
 
 
 
 
Study Entry 
Off Protocol 
Therapy 
Recurrent Measurable 
Osteosarcoma 
(Cohort 1) 
End Protocol 
Therapy 
Cycle 1 Denosumab 
Days 1, 8 and 15 
Cycle 2 Denosumab  
Day 1 only 
Evaluation 
Cycle 3-26* Denosumab 
Day 1 only 
Evaluation prior 
to every odd 
cycle 
Progressive Disease or 
Unacceptable Toxicity 
*Continue Denosumab for up to 24 months or 26 cycles, whichever occurs first 
 
 
Recurrent Resected 
Osteosarcoma 
(Cohort 2) 

  
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1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
 
 
 
 
 
 
2.0 
BACKGROUND 
 
The 5-year and 10-year overall survival for patients with localized osteosarcoma is 
approximately 70% and 65% respectively.1-3 Outcomes have not changed for the past 
2 decades.4 This reflects the fact that medical therapy has remained essentially unchanged 
during this period with no new therapies identified to complement the activity of standard 
therapy with high-dose methotrexate, adriamycin and cisplatin. The Children’s Oncology 
Group (COG) Bone Tumor Committee plans to continue to investigate the impact of the 
addition of targeted agents to standard osteosarcoma chemotherapy in patients with 
localized osteosarcoma. The primary challenge is a paucity of pre-clinical and clinical data 
for targeted agents with demonstrated activity against osteosarcoma. The COG phase 2 
studies that included osteosarcoma strata that have been completed over the past decade 
include ADVL0122 (imatinib), ADVL0421 (oxaliplatin), ADVL0524 (ixabepilone) and 
ADVL0525 (pemetrexed). Unfortunately, there was no evidence of objective drug activity 
in the osteosarcoma stratum for any of these trials. That being said, objective radiographic 
responses are rare in osteosarcoma for agents with known activity against osteosarcoma in 
the neoadjuvant setting. The lack of objective anti-tumor activity is likely due to the nature 
of the intratumoral stromal tissue that contains calcified bone matrix. Consequently, in this 
phase 2 trial of denosumab, an additional end point, believed to be more appropriate for 
assessment of activity in osteosarcoma will be utilized. 
 
Prognosis for patients with recurrent osteosarcoma is poor. Subjects enrolled on 
INT-0133 who experienced recurrence had an overall survival rate of 20% at 

  
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10 years, similar outcomes are reported by other groups.5-10 There are no standard 
chemotherapy agents or targeted therapies proven to improve overall survival in 
patients with recurrent osteosarcoma and chemotherapeutic treatment options for 
patients with recurrent osteosarcoma are limited. Aggressive thoracotomies are 
generally accepted to be standard treatment for resectable osteosarcoma 
recurrences limited to the lung.11,12 Experts recommend open thoracotomy as the 
standard surgical approach to resection given that in 50% of cases more nodules 
are discovered on surgical exploration than were present on radiographic imaging. 
However, the rarity of this disease process, coupled with differing institutional 
biases and retrospective reviews on thoracic surgical management have 
contributed to a lack of unity in surgical approach. There are no prospectively 
collected data regarding management of pulmonary metastases in recurrent 
osteosarcoma.   
 
In order to determine the historical disease control rate in patients with recurrent 
osteosarcoma enrolled on COG phase 2 trials a retrospective analysis of data for 
all eligible patients with relapsed or refractory osteosarcoma enrolled on A09713, 
ADVL0122, ADVL0421, ADVL0524, ADVL0525, CCG-0962, P9761 and P9963 
was performed. For each patient identified, event-free survival (EFS), defined as 
time from study enrollment until date of last contact, date of disease progression 
or detection of disease at a previously uninvolved site, or date of death was 
calculated. Patients who died or experienced disease progression were considered 
to have experienced an EFS event; otherwise, the patient was considered censored 
at the date of last follow-up. EFS as a function of time since study enrollment was 
estimated according to the method of Kaplan and Meier. The equality of the hazard 
rate for EFS-event across studies was tested using the log-rank test. The potential 
prognostic factors for risk of EFS-event that were examined included: (1) study; 
(2) age; (3) number of prior chemotherapy regimens; (4) sex; and (5) race.  
 
Ninety-six (96) patients were identified for inclusion in this dataset, 95 of whom 
with some follow-up for EFS, and 93 with an EFS event. Two (2) patients were 
reported as alive and without EFS-event at 8 and 46 months after enrollment. Both 
were enrolled on ADVL0421. The EFS for patients with recurrent osteosarcoma 
enrolled on these seven closed phase 2 studies from the COG or its predecessor 
groups was 12% at 4 months with a 95% C.I. of 6-19%. There was no significant 
difference in the EFS across the different studies. The characteristics such as age, 
gender, race, and the number of prior chemotherapy regimens did not have any 
effect on EFS.  
 
In addition, in an attempt to gain some insight into how our analysis of COG data 
might compare to data for relapsed osteosarcoma outside of COG we have 
evaluated a report from the Cooperative Osteosarcoma Study Group (COSS). In a 
2005 analysis, Bielack et al presented data for patients with relapsed 
osteosarcoma.6 Although the overall survival was very poor for patients with 
unresectable disease, overall survival at 2 years of 4%, it is not possible to make a 
valid comparison of this data to the COG data due to the differences in the data 
including a different start time (time of recurrence vs. time of enrollment on a 
phase 2 trial) and different reported outcome (overall vs. event-free survival). The 
COG data are more relevant to the patient population to be enrolled to Cohort 1 of 
this study (measurable disease).   

  
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For patients with fully resected disease (Cohort 2 of this study), the EFS data of 
patients enrolled on AOST0221, a phase 2 study of inhaled GMCSF in patients 
with first pulmonary recurrence of osteosarcoma were used to determine the 
historical disease control rate.13 Osteosarcoma patients enrolled on this trial had a 
first recurrence restricted to resectable nodules in the lung that was completely 
resected. Consequently the population enrolled on AOST0221 represents the group 
of patients with completely resected osteosarcoma with the best possible outcome. 
The intervention in AOST0221 (inhaled GMCSF) was determined to lack activity 
on the basis of the primary outcome measure. An improvement in outcome above 
the baseline determined by AOST0221 would likely represent denosumab activity. 
Forty-two patients were enrolled on AOST0221. The 12 month EFS was 20% with 
a 95% confidence interval of 10-34%. In an attempt to gain some insight into how 
our analysis of COG data might compare to data for relapsed osteosarcoma outside 
of COG we have evaluated the 2005 report from the COSS. Two-year EFS in 
patients who achieved a second complete resection was 33%. Again it is not 
possible to make a valid comparison of this data to the COG data due to the 
difference in start time (time of recurrence vs. time of enrollment on a phase 2 
trial). The COG data are more relevant to the patient population to be enrolled to 
Cohort 2 of this study.   
 
Denosumab is a fully human monoclonal antibody to the receptor activator of 
nuclearfactor-κB ligand (RANKL). It is approved by the FDA for prevention of 
skeletal-related events in adults with solid tumor bone metastases (Xgeva) and for 
adults and skeletally mature adolescents with giant cell tumor of bone that is 
unresectable or where surgical resection is likely to result in severe morbidity and 
treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy. 
 
2.1.3.1 
Denosumab PK/PD 
Denosumab is administered subcutaneously and has a long half-life. The 
bioavailability following subcutaneous administration is 62%. The FDA 
approved dose for skeletal related events in patients with bone metastasis 
is 120 mg every 4 weeks. In phase 1 studies of denosumab in adults 
weight based doses up to 3 mg/kg were well tolerated. Subsequent 
studies utilized a fixed dose as high as 180 mg every 4 weeks.14,15 Fixed 
doses have been administered to adults weighing as little as 45 kg. 
 
Denosumab clearance and volume of distribution are proportional to 
body weight. At 120 mg every 4 week dosing, serum denosumab 
concentrations reach steady state at 6 months. In order to achieve steady 
state more rapidly, in the giant cell tumor study loading doses were 
administered on days 8 and 15. At steady state the mean elimination half-
life of denosumab is 28 days. 
 
All data on denosumab PK are from samples obtained from adult 
subjects. Therefore, data obtained from patients enrolled on this protocol 
will be used to characterize PK parameters for patients less than 18 years 
of age. To accomplish this, all patients enrolled onto the first stage of 
Cohort 1 (Stratum 1) will be required to be less than 18 years of age at 
enrollment. As discussed in Section 2.1.2, analyses of a group of patients 

  
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with RECIST measurable disease enrolled on previous COG single-
agent phase 2 studies has demonstrated that advancing age was unrelated 
to increased risk of EFS-event. There were an insufficient number of 
RECIST responders to assess the influence of age at the start of 
treatment on the likelihood of response. Restricting enrollment of 
Stratum 1 patients to those less than 18 years of age will not result in an 
underestimate of the rate of disease control in this group of patients. 
 
Denosumab rapidly inhibits bone turnover. In patients with breast cancer 
and bone metastases, the median reduction in urinary N-
telopeptides/creatinine (uNTx/Cr) was 82% within 1 week of the first 
dose. Rapid decline in serum c-telopeptide is also observed.16 In a group 
of patients with breast cancer receiving concurrent chemotherapy, the 
median duration of time to achieve > 65% reduction in uNTx/Cr was 9-
13 days depending on the denosumab dose.15  
 
2.1.3.2 
Denosumab Toxicity 
Denosumab-associated toxicity is limited. At the 120 mg every 4 week 
dose, the most common adverse effects are hypocalcemia and 
hypophosphatemia with incidences of 18% and 32%, respectively. 
Serum calcium concentrations of < 7 mg/dL occurs in 3.1% of adults. 
Hypocalcemia is observed particularly during the first 6 weeks of 
therapy.17,18 In the post marketing setting, severe symptomatic 
hypocalcemia has been reported, including fatal cases. In clinical studies 
of subjects without advanced cancer with varying degrees of renal 
function (including patients with severe renal impairment [creatinine 
clearance < 30 mL/min] or receiving dialysis), there was a greater risk 
of developing hypocalcemia with increasing degree of renal impairment, 
and in the absence of calcium supplementation. Therefore, pre-existing 
hypocalcemia must be corrected prior to initiating therapy with 
denosumab 120 mg. Supplementation of calcium and vitamin D is 
required in all patients, unless hypercalcemia is present. Monitoring of 
calcium levels is recommended during treatment, especially in the first 
weeks of initiating therapy. In addition, a transient increase in bone 
remodeling associated with significant hypercalcemia following 
discontinuation of denosumab has been reported to occur. This off-
treatment hypercalcemia has been observed up to 8 months after 
stopping Denosumab.19,20 
 
Osteonecrosis of the jaw has been observed at a rate similar to that seen 
with bisphosphonates (2.2%). ln three phase 1 active-controlled clinical 
trials in patients with advanced malignancies involving bone, ONJ was 
confirmed in 1.8% of subjects in the denosumab 120 mg group (median 
exposure of 12.0 months; range 0.1 -40.5) and 1.3% of subjects in the 
zoledronic acid group. The trials in subjects with breast or prostate 
cancer included a denosumab 120 mg extension treatment phase (median 
overall exposure of 14.9 months; range 0.1-67.2). The subject-year 
adjusted incidence of confirmed ONJ was 1.1% during the first year of 
treatment and 4.1% thereafter. The median time to ONJ was 20.6 months 
(range: 4 - 53). In clinical trials, the incidence of ONJ was higher with 
longer duration of exposure. Poor oral hygiene, invasive dental 

  
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procedures, treatment with anti-angiogenic medication, local gum or oral 
infection were risk factors for ONJ in patients receiving denosumab 
120 mg in clinical trials. Examples of invasive dental procedures that 
result in major disruption of the mucosal integrity and may increase the 
risk of ONJ include dental implants, dental or periodontal infection, 
dentures, tooth extraction, endodontic surgery and periodontal surgery. 
Osteonecrosis of the jaw may be less common in children and young 
adults. There are no reports of osteonecrosis of the jaw as a result of 
braces. There are animal models of bisphosphonates and orthodontics. 
These show decreased tooth movement in response to braces. In 2 papers 
of orthodontics in adults receiving bisphosphonates patients experienced 
longer treatment times and increased risk of poor parallelism but no cases 
of osteonecrosis of the jaw.17,18,21,22  
 
Atypical femoral fracture has been reported with denosumab. Atypical 
femoral fractures may occur with little or no trauma in the 
subtrochanteric and diaphyseal regions of the femur and may be bilateral. 
Specific radiographic findings characterize these events. Atypical 
femoral fractures have also been reported in patients with certain 
comorbid conditions (e.g. vitamin D deficiency, rheumatoid arthritis, 
hypophosphatasia) and with use of certain pharmaceutical agents (e.g. 
bisphosphonates, glucocorticoids, proton pump inhibitors). These events 
have also occurred without antiresorptive therapy.  
 
Hypersensitivity, including anaphylactic reactions, has been identified as 
an adverse drug reaction. Musculoskeletal pain, including severe cases, 
has been identified as an adverse drug reaction based on data from the 
postmarketing setting. 
 
2.1.3.3 
Clinical Data Regarding Long-term Denosumab 
Studies of longer-term denosumab administration are just reaching 
maturity. Safety data are now available for a phase 3 study (vs. 
zolendronic acid) of prevention of skeletal-related events. In contrast to 
zoledronic acid, denosumab did not require monitoring or dose 
modification/withholding based on renal status, and was not associated 
with acute-phase reactions. Hypocalcaemia was more common for 
denosumab. Osteonecrosis of the jaw occurred at a similar rate 
(P = 0.13). The median number of denosumab doses received by 
participants in this study were 13, equal to 52 weeks of treatment. Rates 
of adverse events were not increased in the denosumab group.23  
 
2.1.3.4 
Clinical Data Regarding Denosumab in children and adolescents 
Denosumab (120 mg) has been administered to 10 skeletally mature 
adolescents with giant cell tumor of bone in a prospective open-lable 
phase 2 study and in children.24 In this open label phase 2 study, in Giant 
Cell Tumor of Bone, including 10 adolescents, adverse events were 
consistent with the known safety profile of denosumab. In addition there 
are case reports of 2 children who received denosumab: one with 
metastatic giant cell tumor of bone and one with McCune-Albright 
syndrome.19,20  
 

  
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RANKL and its receptor RANK have the physiologic function of regulating bone 
turnover. In response to RANKL-RANK binding, osteoclast precursors 
differentiate and become activated resulting in bone resorption.25  
 
Osteosarcoma expresses both RANK and RANKL. In one set of studies, RANK 
was expressed in 57% of human osteosarcomas, most human osteosarcoma cell 
lines and 70% of canine osteosarcomas including 2 of 2 canine osteosarcoma skin 
metastases.26,27 In contrast, results from another study presented in abstract form 
showed little to no RANK expression in human osteosarcoma tumor cells, though 
> 50% of tumor associated osteoclasts or osteoclast precursors expressed RANK.28 
This same study identified osteosarcoma tumor cell RANKL expression in 65-75% 
of human osteosarcoma samples. Expression was generally less intense compared 
with positive control samples from giant cell tumors of bone. Another study 
reported that RANKL is expressed in 75% of human osteosarcoma tumor 
specimens and the strength of expression is associated with prognosis.29 In 
osteosarcoma, RANKL activates downstream signaling and modulates gene 
expression.27,30  
 
In an orthotopic model of metastatic osteosarcoma utilizing the human cell lines 
HOS and SAOS2, Smad7 inhibition of TGF beta signaling reduces the 
development of lung metastasis and enhances tumor-associated bone formation. 
Smad7 inhibition of TGF beta signaling markedly reduced RANKL expression.31 
In a murine model of osteosarcoma established by p53 and Rb deletion, PTHR1 
knockdown decreased invasion in vitro, and in vivo, decreased size of primary 
tumor and increased mineralization. When bone markers expression was 
evaluated, RANKL expression decreased and OPG, decoy receptor for RANKL, 
increased. These two studies provide inferential evidence that decreased RANK-
RANKL signaling may be related to decreased invasion, reduced proliferation and 
increased differentiation.32 
 
Further evidence supporting activity of the RANK-RANKL pathway in 
osteosarcoma is provided by a transgenic mouse model of osteosarcoma. In this 
mouse model, expression of the SV40 T/t antigen from the osteocalcin promoter 
results in highly penetrant osteosarcoma. In this model, heterozygous deletion of 
Prkar1a accelerates development of osteosarcoma via increased RANKL gene 
expression. A subset of human osteosarcomas have low Prkar1a expression and 
high RANKL expression.33 
 
In vivo studies of denosumab are limited because the antibody does not recognize 
murine or canine RANKL. To circumvent these limitations, in vivo studies have 
utilized other approaches to inhibit RANKL activity including osteoprotegerin 
(OPG), a decoy receptor for RANKL, RANK-Fc, a chimeric protein that 
efficiently binds RANKL, or SiRNA directed against RANKL. In a murine 
orthotopic osteosarcoma model, OPG gene therapy decreased primary and 
metastatic tumor burden: Mice receiving OPG gene transfer did not develop 
osteosarcoma lung metastases while 80% of control mice developed lung 
metastases.34 A study by the same group using RANK-Fc confirmed these original 
findings.35  
 

  
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Studies assessing the utility of RANKL directed strategies against osteosarcoma 
that has metastasized outside of the bone environment have contradictory results. 
In one experiment, gene therapy with RANK-Fc did not seem to improve survival 
from lung metastases in mice following retro-orbital injection of osteosarcoma 
cells.35 However, experiments by another group demonstrate that RANK-Fc 
decreases migration and invasion in vitro and leads to a decreased metastatic tumor 
burden in vivo.36 In addition, in transgenic mice that developed osteosarcoma 
following deletion of Rb, p53 and Prkar1a administration of RANK-Fc resulted in 
improved survival (R. Khokha, unpublished data). In these two in vivo models, 
there is evidence of activity of RANKL-directed therapy in osteosarcoma that has 
metastasized to extra-skeletal locations. It is not clear which tumor model or which 
method of interfering with RANKL will be representative of denosumab activity 
in osteosarcoma metastatic to extra-skeletal locations in humans. Because of the 
limitations mentioned above, additional in vivo testing of denosumab by the 
Pediatric Preclinical Testing Program (PPTP) or other investigators is unlikely to 
proceed. Consequently, the Bone Tumor Committee feels the existing pre-clinical 
data are sufficient to support a phase 2 study of denosumab in patients with 
recurrent osteosarcoma with extra-skeletal metastases.  
 
In summary, a breadth of pre-clinical data demonstrates a role for RANK-RANKL 
signaling in osteosarcoma and supports a potential benefit of denosumab for 
patients with relapsed or refractory osteosarcoma. The pre-clinical studies in 
murine models are summarized in the table below: 
 
Reference (first 
author, year of 
publication, 
PMID) 
Model 
Method of 
inhibiting 
RANKL* 
Osteosarcoma 
response (bone 
site) 
Osteosarcoma 
response (lung 
metastasis site) 
Lamora A, 2014, 
25107916 
Xenograft 
(orthotopic 
injection) 
Smad7 
overexpression 
Statistically 
significant 
decrease in tumor 
volume 
Statistically 
significant decrease 
in number of 
nodules 
Ho PW, 2014,  
25043296 
 
Xenograft 
Pthr1 knockdown 
Statistically 
Significant 
decrease in tumor 
weight 
Not applicable 
Khokha, R, 
personal 
communication, 
2013 
Genetically 
engineered 
mouse model 
RANK-FC 
Improved survival 
Improved survival 
Akiyama T, 
2010,  20383567 
Xenograft 
(orthotopic) 
RANK-FC 
No change in 
tumor volume 
Statistically 
significant decrease 
in number of 
nodules 
Lamoureux F, 
2008, 18852142 
Xenograft 
(orthotopic 
injection OR 
retro-orbital 
injection) 
RANK-FC 
Statistically 
Significant 
decrease in tumor 
volume and in the 
% of mice with 
tumors 
Decreased number 
of metastases in 
orthotopically 
injected mice 
 
No impact on 
metastases with 
retro-orbital 
injection. 

  
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*Denosumab is an antibody that does not recognize murine or canine RANKL. To 
circumvent this limitation in pre-clinical studies, alternate approaches to inhibit 
RANKL are utilized. 
 
Unpublished pre-clinical Amgen data suggest that administration of denosumab to 
skeletally immature children may result in risks to developing bone. Neonatal rats 
receiving OPG-Fc had decreased bone growth and tooth eruption. This effect was 
partially reversible upon discontinuation of OPG-Fc. Adolescent monkeys 
receiving 5-10 times the recommended denosumab dose had abnormal growth 
plates. However, in published data, inhibiting RANKL activity seems to have 
minimal impact on bone growth and development.37 Denosumab therapy in 
skeletally immature patients may result in a risk of skeletal toxicity, but the poor 
prognosis of patients with recurrent osteosarcoma support the use of novel agents 
in this disease and the risk profile of denosumab compares favorably with other 
agents used in this clinical setting. Long-term follow up data regarding skeletal 
growth is not likely to be available from the patients enrolled on this study related 
to the overall prognosis of this patient population. 
 
 
3.0 
STUDY ENROLLMENT PROCEDURES AND PATIENT ELIGIBILITY 
Prior to enrollment on this study, patients must be assigned a COG patient ID 
number. This number is obtained via the Patient Registry module in OPEN once 
authorization for the release of protected health information (PHI) has been 
obtained. The COG patient ID number is used to identify the patient in all future 
interactions with COG. If you have problems with the registration, please refer to 
the online help. For additional help or information, please contact the CTSU Help 
Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
A Biopathology Center (BPC) number will be assigned as part of the registration 
process. Each patient will be assigned only one BPC number per COG Patient ID. 
For additional information about the labeling of specimens please refer to the 
Pathology and/or Biology Guidelines in this protocol. 
 
Please see Appendix I for detailed CTEP Registration Procedures for Investigators 
and Associates, and Cancer Trials Support Unit (CTSU) Registration Procedures 
including: how to download site registration documents; requirements for site, 
submission of regulatory documents and how to check your site’s registration 
status. 
 
NOTE: In order for an institution to maintain COG membership requirements, 
every newly diagnosed patient needs to be offered participation in ACCRN07, 
Protocol for the Enrollment on the Official COG Registry, The Childhood Cancer 
Lamoureux F, 
2007, 17671200 
Xenograft 
(orthotopic 
injection) 
Osteoprotegerin 
(OPG) transgene 
expression 
Statistically 
Significant 
decrease in tumor 
volume and in the 
% of mice with 
tumors 
Decrease in 
proportion of mice 
with metastases (0% 
vs. 80%) 

  
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Research Network (CCRN) or APEC14B1, Project:EveryChild A Registry, 
Eligibility Screening, Biology and Outcome Study. 
 
Sites must obtain IRB/REB approval for this protocol and submit IRB/REB 
approval and supporting documentation to the CTSU Regulatory Office before 
they can be approved to enroll patients. Allow 3 business days for processing. The 
submission must include a fax coversheet (or optional CTSU IRB Transmittal 
Sheet) and the IRB approval document(s). The CTSU IRB Certification Form may 
be submitted in lieu of the signed IRB approval letter. All CTSU forms can be 
located on the CTSU web page (https://www.ctsu.org). Any other regulatory 
documents needed for access to the study enrollment screens will be listed for the 
study on the CTSU Member’s Website under the RSS Tab. 
 
IRB/REB approval documents may be submitted to the CTSU Regulatory Office 
via the Regulatory Submission Portal, where they will be entered and tracked in 
the CTSU RSS.  
 
Regulatory Submission Portal: www.ctsu.org  (members’ area)  Regulatory Tab 
Regulatory Submission  
 
Institutions with patients waiting that are unable to use the Portal should alert the 
CTSU Regulatory Office immediately at 1-866-651-2878 in order to receive 
further instruction and support. For general (non-regulatory) questions call the 
CTSU General Helpdesk at: 1-888-823-5923. 
 
Study centers can check the status of their registration packets by querying the 
Regulatory Support System (RSS) site registration status page of the CTSU 
members’ web site by entering credentials at https://www.ctsu.org. For sites under 
the CIRB initiative, IRB data will automatically load to RSS. 
 
Note: Sites participating on the NCI CIRB initiative and accepting CIRB 
approval for the study are not required to submit separate IRB approval 
documentation to the CTSU Regulatory Office for initial, continuing or 
amendment review. This information will be provided to the CTSU Regulatory 
Office from the CIRB at the time the site’s Signatory Institution accepts the CIRB 
approval. The Signatory site may be contacted by the CTSU Regulatory Office or 
asked to complete information verifying the participating institutions on the study. 
Other site registration requirements (i.e., laboratory certifications, protocol-
specific training certifications, or modality credentialing) must be submitted to the 
CTSU Regulatory Office or compliance communicated per protocol instructions. 
 
Prior to obtaining informed consent and enrolling a patient, a reservation must be 
made following the steps below. Reservations may be obtained 24 hours a day 
through the Oncology Patient Enrollment Network (OPEN) system.  
 
Patient enrollment for this study will be facilitated using the Slot-Reservation 
System in conjunction with the Registration system in OPEN. Prior to discussing 
protocol entry with the patient, site staff must use the CTSU OPEN Slot 
Reservation System to ensure that a slot on the protocol is available for the patient. 

  
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Once a slot-reservation confirmation is obtained, site staff may then proceed to 
enroll the patient to this study.  
 
If the study is active, a reservation can be made by following the steps below: 
 
1) 
Log in to https://open.ctsu.org/open/ using your CTEP IAM user name and 
password.  
2) 
In order to make a reservation, the patient must have an OPEN patient 
number. Click on the ‘Slot Reservation’ tab to create an OPEN patient 
number, under ‘Patients’. 
3) 
Using the OPEN patient number ‘RESERVE’ a slot for that patient.  
4) 
On the ‘Create Slot Reservation’ page, select the Protocol Number, enter the 
COG Patient ID, and choose the required stratum (if applicable) in order to 
obtain a reservation. 
 
Refer to the ‘SITE – Slot Reservation Quick Reference’ guide posted under the 
‘Help’ tab in OPEN for detailed instructions:  
https://www.ctsu.org/readfile.aspx?fname=OPEN/OPEN_SlotReservation_Quick
Reference_SiteUserGuide_102612.pdf&ftype=PDF 
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment 
Network (OPEN). OPEN is a web-based registration system available on a 
24/7 basis. To access OPEN, the site user must have an active CTEP-IAM account 
(check at < https://eapps-ctep.nci.nih.gov/iam/index.jsp >) and a 'Registrar' role on 
either the lead protocol organization (LPO) or participating organization roster. 
 
All site staff will use OPEN to enroll patients to this study. It is integrated with the 
CTSU Enterprise System for regulatory and roster data and, upon enrollment, 
initializes the patient position in the Rave database. OPEN can be accessed at 
https://open.ctsu.org or from the OPEN tab on the CTSU members’ side of the 
website at https://www.ctsu.org.  
 
Prior to accessing OPEN, site staff should verify the following: 
 

All eligibility criteria have been met within the protocol stated timeframes. 

All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable). 
 
Note: The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. Please print this confirmation for your 
records. 
 
Further instructional information is provided on the CTSU members' web site 
OPEN tab or within the OPEN URL (https://open.ctsu.org). For any additional 
questions 
contact 
the 
CTSU 
Help 
Desk 
at 
1-888-823-5923 
or 
ctsucontact@westat.com. 
 

  
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Patients must be enrolled before treatment begins. The date protocol therapy is 
projected to start must be no later than five (5) calendar days after the date of study 
enrollment. 
 
All clinical and laboratory studies to determine eligibility must be performed 
within 7 days prior to enrollment unless otherwise indicated in the eligibility 
section below. 
 
In order to minimize the potential for non-compliance once enrolled, 
patients/guardians must be made aware that a number of the biology research 
studies are mandatory and understand that a number of non-standard blood samples 
will be required. 
 
Both men and women of all races and ethnic groups are eligible for this study.  
 
 
Important note: The eligibility criteria listed below are interpreted literally and cannot 
be waived. All clinical and laboratory data required for determining eligibility of a 
patient enrolled on this trial must be available in the patient's medical/research record 
which will serve as the source document for verification at the time of audit.  
 
All clinical and laboratory studies to determine eligibility must be performed within 
7 days prior to enrollment unless otherwise indicated. Laboratory values used to 
assess eligibility must be no older than seven (7) days at the start of therapy. 
Laboratory tests need not be repeated if therapy starts within seven (7) days of 
obtaining labs to assess eligibility. If a post-enrollment lab value is outside the limits 
of eligibility, or laboratory values are > 7 days old, then the following laboratory 
evaluations must be re-checked within 48 hours prior to initiating therapy: CBC with 
differential, bilirubin, ALT (SGPT), serum creatinine, calcium, magnesium and 
phosphorous. If the recheck is outside the limits of eligibility, the patient may not 
receive protocol therapy and will be considered off protocol therapy. Imaging studies, 
if applicable, must be obtained within 2 weeks prior to planned start of protocol 
therapy (repeat the tumor imaging if necessary). 
 
See Section 4.2.1 for required studies to be obtained prior to starting protocol therapy. 
 
Patients must be equal to or greater than 11 years of age but less than 50 years of 
age at the time of enrollment.  

Female patients must have a bone age of equal to or greater than 12 years 
of age as determined by local read of appropriate radiographic imaging 
(see Section 16.0).  
 
Male patients must have a bone age of equal to or greater than 14 years of 
age as determined by local read of appropriate radiographic imaging (see 

  
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Page 20  
Section 16.0). 
  
3.2.2.1 
Patients must have relapsed or become refractory to conventional 
therapy, with a regimen including some combination of high dose 
methotrexate, doxorubicin, cisplatin, ifosfamide and etoposide; and have 
had histologic verification of osteosarcoma at original diagnosis or at the 
time of recurrence. 
 
3.2.2.2 
Cohort 1 patients must have measurable disease according to RECIST 
1.1 (see Section 10.2). 
Note: Patients in Cohort 1 will be stratified as follows: 
 
Stratum 1: Patients ≥ 11 years of age but < 18 years 
 
Stratum 2: Patients ≥ 11 years of age but < 50 years 
 
3.2.2.3 
Cohort 2 patients must have had a complete resection of all sites of 
metastatic disease within 30 days prior to enrollment. 
 
3.2.2.3.1 Patients will only be eligible after they have undergone 
complete surgical resection of suspected metastatic disease 
that is histopathologically confirmed to be osteosarcoma 
prior to enrollment. 
 
Note: The definition of complete resections is: gross resection of all 
disease as per the operating surgeon. (For further details see 
https://www.cogmembers.org/_files/Disc/surgery/handbooks/O
steoBoneHandbook.pdf.) Post-operative imaging is not required 
for confirmation of complete resection. 
 
3.2.2.3.2 Patients must undergo resection of any lung lesion meeting 
criteria for likely metastatic disease, defined as:  
 
3 or more lesions > 5 mm in diameter OR a single 
lesion > 1 cm. 
 
3.2.2.3.3 Patients with lung as the only site of resected metastatic 
disease must have refused participation in protocol 
AOST1421.  
Note: This applies if AOST1421 is open to enrollment at the 
enrolling institution on the day the patient consents.  
 
Patient must have adequate tumor specimen available for submission (see 
Section 15.3). 
 

  
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Patients must have a performance status corresponding to ECOG scores of 0, 1 or 
2. Use Karnofsky for patients > 16 years of age and Lansky for patients  16 years 
of age. 
See https://www.cogmembers.org/_files/protocol/Standard/PerformanceStatusSc
alesScoring.pdf. 
 
3.2.5.1 
Adequate renal function defined as: 
- 
Creatinine clearance or radioisotope GFR  70 mL/min/1.73 m2 or 
- 
A serum creatinine based on age/gender as follows: 
 
Age 
Maximum Serum 
Creatinine (mg/dL) 
 
Male 
Female 
11 to < 13 years 
1.2 
1.2 
13 to < 16 years 
1.5 
1.4 
≥ 16 years 
1.7 
1.4 
The threshold creatinine values in this Table were derived from the Schwartz 
formula for estimating GFR38 utilizing child length and stature data 
published by the CDC. 
 
3.2.5.2 
Adequate liver function defined as: 
- Total bilirubin  1.5 x upper limit of normal (ULN) for age, and 
- SGOT (AST) or SGPT (ALT) < 2.5 x ULN for age. 
- Serum 
calcium 
or 
albumin-adjusted 
serum 
calcium 
≥ 2.0 mmol/L (8.0 mg/dL) and ≤ 2.9 mmol/L (11.5 mg/dL). 
 
3.2.6.1 
Patients with known sensitivity to any of the products to be administered 
during the study (eg, mammalian derived products, calcium or 
Vitamin D). 
 
3.2.6.2 
Patients who are receiving other cancer directed therapy at the time of 
enrollment. 
 
3.2.6.3 
Patients who have previously received denosumab 
 
3.2.6.4 
Patients who have previously received mithramycin, strontium-89, 
samarium-153 or rhenium. 
 
3.2.6.5 
Patients receiving bisphosphonates. 
 
3.2.6.6 
Pre-existing conditions 
3.2.6.6.1 Disorders associated with abnormal bone metabolism. 
 
3.2.6.6.2 Hypocalcemia that is not corrected with oral calcium 
supplementation. 
 
3.2.6.6.3 Vitamin D < 20 ng/mL 
 
3.2.6.6.4 Paget’s disease. 

  
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Page 22  
 
3.2.6.6.5 Prior history or current evidence of osteonecrosis of the jaw. 
 
3.2.6.6.6 Any dental or oral condition likely to result in disruption of 
mucosal integrity during denosumab therapy including: 
active dental or jaw condition requiring oral surgery or tooth 
extraction; non-healed dental or oral surgery or planned 
invasive dental procedures during the anticipated course of 
study therapy. 
 
3.2.6.6.7 Unstable systemic disease, excluding osteosarcoma, such as 
unstable proximal renal tubule dysfunction (Fanconi 
Syndrome) or congestive heart failure. 
 
3.2.6.7 
Pregnancy and Breast Feeding 
3.2.6.7.1 Female patients who are pregnant, since fetal toxicities and 
teratogenic effects have been noted for the study drug. A 
pregnancy test is required for female patients of childbearing 
potential. 
 
3.2.6.7.2 Lactating females who plan to breastfeed their infants while 
on study therapy and through 5 months after completion of 
study therapy. 
 
3.2.6.7.3 Sexually active patients of reproductive potential who have 
not agreed to use a highly effective contraceptive method for 
the duration of their study participation and for 5 months 
after the end of study treatment. 
 
3.2.7.1 
All patients and/or their parents or legal guardians must sign a written 
informed consent. 
 
3.2.7.2 
All institutional, FDA, and NCI requirements for human studies must be 
met. 
 
 
 

  
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4.0 
TREATMENT PLAN 
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on established 
standards of care. Minor unavoidable departures (up to 72 hours) from protocol directed therapy 
and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and family 
logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable (except 
where explicitly prohibited within the protocol). 
 
All subjects will receive denosumab 120 mg subcutaneously every 4 weeks. Two additional 
loading doses will be given on Days 8 and 15 of Cycle 1 (Weeks 2 and 3) only. In the 
absence of progressive disease or unacceptable toxicity denosumab may be continued for 
up to 24 months in total or 26 cycles, whichever occurs first. 
 
Other therapy: Although not encouraged, subjects in Cohort 1 who achieve a complete or 
partial response following the pre-Cycle 5 evaluation time point that is confirmed with 
imaging performed 4 weeks later will be allowed to undergo resection of sites of disease 
or radiation and remain on protocol therapy. Therapy will be held during surgery and 
resumed upon recovery from surgery, but at least 2 weeks after surgery. Denosumab 
therapy will be held during radiation and may be resumed upon completion of the radiation 
treatment course. If the patient has not recovered from surgery within 6 weeks the patient 
will go off protocol therapy. Surgery or radiation performed in a patient who does not 
achieve a confirmed complete or partial response will render the patient inevaluable for 
disease control assessment and the patient will go off protocol therapy. 
 
Please note: Avoid invasive dental procedures during treatment with denosumab 120 mg. 
For patients in whom invasive dental procedures cannot be avoided, the clinical judgment 
of the treating physician should guide the management plan based on individual 
benefit/risk assessment. In addition, administration of denosumab will be withheld 30 days 
prior to any elective invasive oral/dental procedure and until documentation of complete 
mucosal healing following any invasive oral/dental procedure. 
 
For COG Supportive Care Guidelines see:  
https://childrensoncologygroup.org/index.php/cog-supportive-care-guidelines. 
 
 

  
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Page 24  
Cycle 1 
 
Each cycle lasts 4 weeks (28 days). Treatment may continue for up to 24 months or 26 cycles, whichever 
occurs first. Only Cycle 1 of this study is described in this TDM. This TDM is on one page.  
 
____________________________ 
Patient COG ID number 
________________________ 
DOB  
 
Begin denosumab therapy only when: Cr clearance or radioisotope GFR  70 mL/min/1.73 m2 or a serum creatinine based on age/gender as per Section 4.2.1; Total bilirubin 
≤ 1.5 x upper limit of normal (ULN) for age, and SGOT (AST) or SGPT (ALT) < 2.5 x ULN for age and serum calcium or albumin-adjusted serum calcium ≥ 2.0 mmol/L 
(8.0 mg/dL) and ≤ 2.9 mmol/L (11.5 mg/dL). A negative pregnancy test is required for all female patients with childbearing potential. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Denosumab 
IND #127430  
Subcutaneous injection 
120 mg 
1, 8 & 15 
Calcium and Vitamin D supplementation according to Section 
4.2.2 is required to begin with the first dose of denosumab. 
Denosumab can be administered at a single site with a maximum 
volume of 2 mL. 
 
 
 
Ht _________cm 
 
Wt _________kg 
 
BSA _________m2 
 
 
Date Due 
Date 
Given 
Day 
Denosumab 
120 mg 
Studies  
(See details on next page) 
Record Calcium and 
Vitamin D supplementation 
 
Enter actual dose administered below 
 
 
 
 
 
1 
 
______mg 
 
a - r 
 
 
 
 
8 
 
______mg 
 
f, m, n 
 
 
 
 
15 
 
______mg 
 
f, m, n 
 
 
 
 
22 
 
 
f, m, n 
Start Cycle 2 on Day 29 or as soon as starting criteria are met, whichever occurs later. Treatment should continue up to 24 months or 26 cycles, whichever 
occurs first, in the absence of disease progression or unacceptable toxicity. If disease progression or unacceptable toxicity occurs, the patient will be taken off 
protocol therapy. 
 
See Section 5.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines. 
 
Page 1 of 1 

  
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Cycle 1 
 
All baseline studies must be performed prior to starting protocol therapy 
unless otherwise indicated below.  
 
a. 
History/PE/Wt /Ht  
b. CBC/diff/platelets  
c. 
Total bilirubin  
d. Performance status  
e. 
Electrolytes, Bun  
f. 
Ca++, PO4, Mg++ 
g. Vitamin D 
h. AST, ALT, Albumin. For patients with low albumin, albumin or ionized calcium 
along with serum calcium should be ordered every week until normal. 
i. 
Serum creatinine or GFR or creatinine clearance  
j. 
Bone scan 
k. CT chest 
l. 
CT or MRI of any sites of active disease in bone or soft tissue. Bone or soft tissue 
sites of disease, if present, should be imaged with CT or MRI prior to the start of 
therapy. The same imaging modality as was used prior to the start of therapy should 
be used for follow-up imaging. 
m. Pharmacokinetics are required for patients enrolled in Cohort 1, Stratum 1. 
Pharmacokinetics are optional for all other patients. Blood will be drawn prior to 
denosumab dosing on Day 1, 8, 15 and 22 (no denosumab is given on Day 22). See 
Section 15.1 for details. 
n. Pharmacodynamics (required). Urine N-telopeptides (uNTx/Cr) from the second 
morning urine and serum c-telopeptides (sCTx). uNTx/Cr and sCTx will be obtained 
prior to denosumab dosing on Day 1, 8, 15 and 22 (no denosumab is given on Day 
22). See Section 15.2 for details. 
o. Dental exam with appropriate preventive dentistry prior to treatment with denosumab. 
p. Bone age (Patients ≤ 18 years of age only). 
q. Pregnancy test. Female patients of childbearing potential require a negative pregnancy 
test prior to starting treatment. 
r. 
Pathology and surgical report submission is required for patients enrolled on Cohort 2 
within 4 weeks of enrollment. See Sections 13.0.and 14.0. 
 
This listing only includes evaluations necessary to answer the primary and 
secondary aims. OBTAIN OTHER STUDIES AS REQUIRED FOR GOOD 
CLINICAL CARE.  
 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
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Cycle 1 
 
Cycle 1 of denosumab treatment is described below. During Cycle 1 only, 
denosumab is given on Days 1, 8, and 15 in order to reach steady state 
concentrations.  
 
Denosumab: Subcutaneous 
Days: 1, 8, and 15  
Dose: 120 mg 
 
Calcium and Vitamin D supplements 
Supplementation with at least 500 mg of calcium daily and 400 IU of Vitamin D 
daily is required unless the patient has or develops hypercalcemia.  
 
Criteria to start Cycle 1: 
 
Adequate renal function defined as: 
- Creatinine clearance or radioisotope GFR  70 mL/min/1.73 m2 or 
- A serum creatinine based on age/gender as follows: 
 
Age 
Maximum Serum 
Creatinine (mg/dL) 
 
Male 
Female 
11 to < 13 years 
1.2 
1.2 
13 to < 16 years 
1.5 
1.4 
≥ 16 years 
1.7 
1.4 
The threshold creatinine values in this Table were derived from the Schwartz 
formula for estimating GFR38 utilizing child length and stature data 
published by the CDC. 
 
 
Adequate liver function defined as: 
- Total bilirubin  1.5 x upper limit of normal (ULN) for age, and 
- SGOT (AST) or SGPT (ALT) < 2.5 x ULN for age. 
 
 
Serum calcium or albumin-adjusted serum calcium ≥ 2.0 mmol/L 
(8.0 mg/dL) and ≤ 2.9 mmol/L (11.5 mg/dL) 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
Start the next cycle on Day 29 (Day 1 of Cycle 2) or as soon as starting criteria are 
met, whichever occurs later. Treatment should continue up to 24 months or 
26 cycles, whichever occurs first. See Section 4.3 for details of Cycles 2-26. 
 

  
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Cycle 2-26 
 
Each cycle lasts 4 weeks (28 days). Treatment may continue for up to 24 months or 26 cycles, whichever 
occurs first. One cycle of treatment is described in this TDM. This TDM is on one page. 
Use a copy of this page once for each cycle (please note cycle number below). 
 
____________________________ 
Patient COG ID number 
________________________ 
DOB  
 
Begin denosumab therapy only when: Cr clearance or radioisotope GFR ≥ 70 mL/min/1.73 m2 or a serum creatinine based on age/gender as per Section 4.3.1; Total 
bilirubin ≤ 1.5 x upper limit of normal (ULN) for age, and SGOT (AST) or SGPT (ALT) < 2.5 x ULN for age and Serum calcium or albumin-adjusted serum calcium 
≥ 2.0 mmol/L (8.0 mg/dL) and ≤ 2.9 mmol/L (11.5 mg/dL). 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Denosumab 
IND #127430 
Subcutaneous injection 
120 mg 
1 
Calcium and Vitamin D supplementation according to Section 
4.3.2 required to begin with the first dose of denosumab. 
Denosumab can be administered at a single site with a maximum 
volume of 2 mL. 
 
 
Enter Cycle #: _____  
 
Ht _________cm 
 
Wt _________kg 
 
BSA _________m2 
 
 
Date Due 
Date 
Given 
Day 
Denosumab 
120 mg 
Studies  
(See details on next page) 
Record Calcium and 
Vitamin D supplementation 
 
Enter actual dose administered below 
 
 
 
 
 
1 
 
______mg 
 
a-n  
 
 
 
8 
 
 
d 
 
 
 
 
15 
 
 
d, j 
 
 
 
 
22 
 
 
d 
Start the next cycle on Day 29 or as soon as starting criteria are met, whichever occurs later. Treatment should continue up to 24 months or 26 cycles, whichever occurs first, 
in the absence of disease progression or unacceptable toxicity. If disease progression or unacceptable toxicity occurs, the patient will be taken off protocol therapy. 
 
See Section 5.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines. 
 
 
Page 1 of 1 

  
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Cycle 2-26 
 
 
All baseline studies must be performed prior to starting protocol therapy 
unless otherwise indicated below.  
 
a. 
History/PE/Wt/Ht.  
b. Total bilirubin 
c. 
Electrolytes, Bun 
d. Ca++, PO4, Mg++ weekly for the first 8 weeks only and then prior to the start of every 
cycle. It is strongly recommended that Ca++ continue to be monitored weekly for any 
patient with hypocalcemia on any prior blood draw or in patients with evidence of 
rapid bone turnover as assessed by Urine N-telopeptides or serum c-telopeptides.  
e. 
AST, ALT, Albumin. For patients with low albumin, albumin or ionized calcium 
along with serum calcium should be ordered every week until normal. 
f. 
Serum creatinine or GFR or creatinine clearance  
g. Bone Scan every 6 months. 
h. CT Chest prior to the start of every odd numbered cycle only. 
i. 
CT or MRI of any sites of active disease in bone or soft tissue prior to the start of 
every odd numbered cycle only. The same imaging modality as was used prior to the 
start of therapy should be used for follow-up imaging.  
 
For patients who undergo a surgical resection following Cycle 4, either a CT scan 
or MRI post-surgery to establish a new baseline is strongly recommended before 
re-initiating denosumab therapy.  
 
Patients who have a RECIST response (CR or PR) on any evaluation following 
Cycle 4 will have confirmatory imaging 4 weeks after the evaluation upon which 
the RECIST response was detected (additional imaging time point). 
j. 
Pharmacokinetics are required for patients enrolled in Cohort 1, Stratum 1. 
Pharmacokinetics are optional for other patients. Blood will be drawn prior to 
denosumab dosing on Day 1 of Cycles 2, 3, 4 and 7 only and on Day 1 and 15 of Cycle 
6 only (no denosumab is given on Day 15). Even when PK is required, the Cycle 6 
Day 15 time point is only for patients who have provided consent. See Section 15.1 
for details. 
k. Pharmacodynamics (required). Blood and urine collection for Urine N-telopeptides 
(uNTx/Cr) from the second morning urine and serum c-telopeptides (sCTx). uNTx/Cr 
and sCTx will be obtained prior to denosumab dosing on Day 1 of Cycle 2, 3, 4 and 
7. See Section 15.2 for details. 
l. 
Dental exam every 6 months.  
m. Bone age every 6 months only in patients without epiphyseal closure at the time of 
enrollment.  
n. Pregnancy test. Female patients of childbearing potential require a negative pregnancy 
test prior to each cycle of treatment. 
 
This listing only includes evaluations necessary to answer the primary and 
secondary aims. OBTAIN OTHER STUDIES AS REQUIRED FOR GOOD 
CLINICAL CARE.  
 
Comments 
 
 
 
 
 
 
 
 

  
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Cycle 2-26 
 
 
One cycle of denosumab treatment is described below. A cycle may be repeated 
every 28 days if the patient has at least stable disease and has again met laboratory 
parameters as defined below. 
 
Denosumab: Subcutaneous 
Day: 1 of each 28 day cycle 
Dose: 120 mg 
 
Calcium and Vitamin D supplements 
Supplementation with at least 500 mg of calcium daily and 400 IU of Vitamin D 
daily is required unless the patient has or develops hypercalcemia.  
 
Criteria to start each cycle: 
 
Adequate renal function defined as: 
- Creatinine clearance or radioisotope GFR  70 mL/min/1.73 m2 or 
- A serum creatinine based on age/gender as follows: 
 
Age 
Maximum Serum 
Creatinine (mg/dL) 
 
Male 
Female 
11 to < 13 years 
1.2 
1.2 
13 to < 16 years 
1.5 
1.4 
≥ 16 years 
1.7 
1.4 
The threshold creatinine values in this Table were derived from the Schwartz 
formula for estimating GFR38 utilizing child length and stature data 
published by the CDC. 
 
 
Adequate liver function defined as: 
- Total bilirubin  1.5 x upper limit of normal (ULN) for age, and 
- SGOT (AST) or SGPT (ALT) < 2.5 x ULN for age. 
 
 
Serum calcium or albumin-adjusted serum calcium ≥ 2.0 mmol/L (8.0 mg/dL) 
and ≤ 2.9 mmol/L (11.5 mg/dL) 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
 
 

  
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5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
Patients who have Grade 3 or 4 allergic reaction or anaphylaxis or recurrence of 
Grade 2 allergic reaction with appropriate pre-medication (anti-histamine such as 
diphenhydramine and steroid such as dexamethasone) must be removed from protocol 
therapy. 
 
Hold denosumab until starting criteria to begin the cycle are met. Specifically, 
Denosumab should not be given on Day 1 of any cycle or on Days 8 and 15 of Cycle 1 
if serum calcium is less than 2.0 mmol/L (8.0 mg/dL). Denosumab will be held for 
Grade 3 or 4 adverse events per CTCAE reported by investigator as related to 
denosumab. Denosumab may be resumed when the event resolves to Grade 1 or 
returns to baseline. The start of a cycle may be held for a maximum of 2 weeks. If 
toxicity prevents the start of a cycle following a 2 week delay, the patient will be 
removed from protocol therapy.  
 
 
6.0 
DRUG INFORMATION  
(AMG 162, Xgeva®, NSC# 744010, IND# 127430) 
 
 
(09/18/18) 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
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. 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
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7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on established 
standards of care. Minor unavoidable departures (up to 72 hours) from protocol directed therapy 
and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and family 
logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable (except where 
explicitly prohibited within the protocol). 
 
Subjects who discontinue investigational product will have an End of Treatment visit 
approximately 4 weeks after the last dose of investigational product (see below). 
Thereafter, they will complete safety follow-up visits approximately every month for the 
first year off protocol therapy. Serum calcium should be checked at each safety follow-up 
visit due to possible occurrence post-treatment hypercalcemia. Reporting of adverse events 
observed at safety follow-up visits is as per Section 11.0. 
 
 
STUDIES TO BE OBTAINED 
End of Therapy 
History 
X 
Physical exam with VS 
X 
Ht, Wt, BSA 
X 
Performance status 
X 
Pregnancy test 
X 
CBC, differential, platelets 
X 
Electrolytes including Ca++, PO4, Mg++ 
X 
Creatinine, SGPT, total bilirubin 
X 
Tumor disease evaluation 
X 
 

  
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See COG Late Effects Guidelines for recommended post treatment follow-up:  
http://www.survivorshipguidelines.org/ 
 
Note: Follow-up data must be submitted in accordance with the Case Report Forms (CRFs) 
schedule. 
 
 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
a) Progressive disease. 
b) Osteonecrosis of the jaw. 
c) Fracture excluding pathological fracture at the site of osteosarcoma bone metastasis or 
fracture at the site of prior orthopedic surgery. 
d) Refusal of further protocol therapy by patient/parent/guardian. 
e) Completion of planned therapy. 
f) Physician determines it is in patient’s best interest. 
g) Development of a second malignancy. 
h) Pregnancy. 
i) 
Surgery or radiation performed in a patient who has not achieved a confirmed complete 
or partial response. 
j) 
Repeat eligibility studies (if required) prior to the initiation of protocol therapy are outside 
the parameters required for eligibility (see Section 3.2). 
k) Unacceptable toxicity due to protocol therapy (see Section 5.0). 
 
Patients who are off protocol therapy are to be followed until they meet the criteria for Off 
Study (see below). Follow-up data will be required unless patient is taken off study.  
 
a) Death. 
b) Lost to follow-up. 
c) Patient enrollment onto another COG study with tumor therapeutic intent (eg, at 
recurrence). 
d) Withdrawal of consent for any further data submission. 
e) Fifth anniversary of the date the patient was enrolled on this study. 
 
 
9.0 
STATISTICAL CONSIDERATIONS 
Cohort 1 (Evaluation of Aim 1.1.1): A maximum of 41 evaluable patients will be enrolled 
in two stages. In the first stage, 15 disease control and RECIST response evaluable patients 
will be enrolled. Only those patients enrolled in Stratum 1 will be considered eligible for 
Stage 1 of Cohort 1. 
 

  
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Each patient will be evaluated for both outcome measures: (1) disease control success; and 
(2) RECIST response (CR or PR v. not CR or PR). If 2 or fewer disease control successes 
and no RECIST responses are observed, enrollment to this cohort will be terminated with 
the conclusion that denosumab is not associated with sufficient activity for further single-
agent investigation. Otherwise, an additional 26 response evaluable patients will be 
enrolled at which point cohort enrollment will be terminated. If, cumulatively, 12 or fewer 
disease control successes and 4 or fewer RECIST responses are observed, we will conclude 
denosumab is not associated with sufficient activity for further single-agent investigation. 
Otherwise, we will conclude denosumab is associated with sufficient activity for further 
single-agent investigation.   
 
Each patient enrolled will be evaluated for: (1) complete or partial response as defined by 
the RECIST criteria where the first evaluation of CR or PR is made at or before the end of 
the fifth cycle of study therapy (denoted as R below); or (2) stable disease four months 
after study enrollment (denoted as S below). We will not be interested in promoting the 
agent for further investigation if the probability of response in any particular individual is 
less than or equal to 0.05 (P(R)≤0.05) and the probability of remaining analytic event free 
in any particular individual is less than or equal to 0.20 (P(S)≤0.20). We will be interested 
in promoting the agent for further investigation if the probability of response in any 
particular individual is at least 0.20 (P(R)≥0.20) or the probability of remaining analytic 
event free in any particular individual is at least 0.40 (P(S)≥0.40). 
 
For the calculations below, it is assumed 


Pr
|
0.90.
S R 
 
 
The statistical characteristics of this design are: 
 
Probability 
of four 
month 
disease 
control 
Probability of 
RECIST 
response 
Probability of 
Stopping After 
Stage 1 (and 
concluding the 
drug is 
ineffective) 
Probability of 
Concluding the 
Drug is 
Ineffective at 
the Conclusion 
of the Trial 
Probability of 
Concluding the 
Drug is 
Effective at the 
Conclusion of 
the Trial 
0.20 
0.05 
0.25 
0.91 
0.09 
0.40 
0.20 
0.0062 
0.029 
0.971 
0.40 
0.05 
0.020 
0.11 
0.89 
0.20 
0.20 
0.035 
0.088 
0.912 
 
Cohort 2 (Evaluation of Aim 1.1.2): The primary outcome measure is disease control 
during the first 12 months after enrollment. Patients considered evaluable for the primary 
outcome of disease control will be assessed during the first 12 months of protocol therapy 
or during the first 12 months of enrollment, if the patient’s protocol therapy is terminated 
for reasons other than death or disease progression prior to the completion of 12 months of 
therapy (‘evaluation period’).  
 
Each patient enrolled will be evaluated for stable disease after 12 cycles of study therapy. 
We are not interested in promoting the agent for further investigation if the probability of 
remaining analytic event free in any particular individual is less than or equal to 30%. We 
will be interested in promoting the agent for further investigation if the probability of 
remaining analytic event free in any particular individual is at least 50%. The statistical 

  
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analysis of prior phase 2 COG studies demonstrates that the current point estimate of the 
12 month EFS is 0.2 with an upper 95% confidence bound of approximately 30%, so the 
target 12 month EFS probability is associated with an odds ratio of 2.3 compared with the 
largest plausible value for 12 month EFS supported by the historical data. One group of 
39 patients will be enrolled in Cohort 2. The maximum time by which the final assessment 
for this stratum will be made is until all patients have experienced an analytic event or the 
last patient enrolled is followed for 12 months, whichever occurs first. If 15 or fewer of the 
planned 39 patients in this cohort demonstrate disease control at 12 months, denosumab 
will not be considered for further development in this cohort, otherwise, denosumab will 
be considered of sufficient activity to warrant further study. If all 39 patients are enrolled 
and the true 12 month disease control probability is 30%, the therapy will not be considered 
for further development with probability 0.91. If all 39 patients are enrolled and the true 
12 month disease control probability is 50%, the therapy will be considered for further 
development with probability 0.90. Enrollment will be terminated in this cohort with the 
conclusion that denosumab will not be considered for further development if, at any time, 
more than 23 patients demonstrate disease progression or die prior to 12 months after study 
enrollment. 
 
Potential factors that could be related to risk for EFS-event included are age group at 
enrollment, patient sex, race, ethnicity, time from diagnosis to first recurrence, initial 
diagnosis of metastatic disease and site of initial recurrence (lung only, bone only, lung 
and bone, other). For categorical characteristics, we will estimate the relative hazard rate 
and 95% confidence interval associated with the various categories using the proportional 
hazards regression model with the characteristic of interest as the only variable in the 
model. The logrank statistic will be used to quantify statistical significance. Age at 
enrollment will be treated as a continuous variable and we will also survey the peer-
reviewed literature and test age cutoffs reported in reliable publications. 
 
Cohort 1: A review of enrollment on COG single-agent phase 2 studies demonstrates that 
approximately 2 patients per month without regard for patient sex or age can be expected 
for enrollment. An assessment of enrollment to ADVL0421, ADVL0524 and ADVL0525 
indicates more than 65% of enrollments conformed to the age and sex requirements for 
AOST1321. More recently, enrollment on AOST1322 was 4.75 patients per month. 58% 
or 2.75 patients per month were under age 18. We assume that as in the predecessor studies, 
only 65% of the enrollees on AOST1321 would meet the developmental age requirements 
of AOST1321. Thus, we expect at least 1.5 patients per month to be enrolled. A maximum 
of 41 outcome evaluable patients will be required in this cohort. Providing for possible 
ineligible and inevaluable patients, the maximum enrollment will be 46 patients. 
 
With these entry rates, the probability we will accrue 46 patients in 36 months is in excess 
of 93%. The study will likely require at most 3 years to enroll sufficient patients. A 
maximum of 46 patients is anticipated for this cohort. 
 
Cohort 2: A maximum of 39 evaluable patients are required for this study. Providing for 
possible ineligible and disease control inevaluable patients, the maximum enrollment is 
expected to be 44 patients. We expect 1.6 patients per month to be enrolled on study, thus 
enrollment to this cohort is expected to be completed within 2.5 years of opening the study. 
 

  
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Evaluability 
Response (Cohort 1 Patients Only): Any eligible patient who receives at least one dose of 
denosumab will be considered evaluable for response with the following exception: if a 
patient receives non-protocol anti-cancer therapy during the response evaluation period 
after the patient is considered as having a partial or complete response but prior to 
confirmation of this status by tumor imaging and before progressive disease is noted, the 
individual will be considered inevaluable for the response endpoint. The exception to this 
exception is patients who stop denosumab after the 1st evaluation due to toxicities or death, 
and these patients will be considered evaluable for the response evaluation.  
 
Disease Control (Cohort 1 and Cohort 2 Patients): Any eligible patient who receives at 
least one dose of denosumab will be considered evaluable for disease control, with the 
exception noted above for “Response Evaluation”. Only patients who are inevaluable for 
the response endpoint may be replaced for the purpose of the statistical rule.  
 
Aim 1.2.1: To investigate the pharmacokinetics (PK) and pharmacodynamics (PD) of 
denosumab in subjects with recurrent osteosarcoma. 
All eligible patients who receive at least one dose of denosumab and for whom at least one 
PK or PD sample is submitted will be considered evaluable for PK or PD, respectively. 
The presentation of PK values will be segregated according to time point at which the 
denosumab was administered. Sample means, medians and variances will be calculated. 
Clearance and volume of distribution will be determined. PD will be characterized by 
uNTx/Cr ratio and c-telopeptide levels. Both of these characteristics will be modeled 
according to a repeated measures linear regression model. Depending on the fit of the 
quadratic model, additional terms in powers of time since enrollment may be added to 
explore how the PD parameters vary with time. 
 
Aim 1.2.2: Evaluating the Tolerability of Denosumab 
Tolerability of Denosumab - An eligible patient will be considered for toxicity monitoring 
if one of the following occurs: (1) complete one cycle of denosumab prior to receiving non-
protocol anticancer therapy; (2) die on protocol therapy for a reason considered possibly, 
probably or likely related to denosumab; or (3) are removed from protocol therapy because 
of an adverse experience possibly, probably or likely related to denosumab. A toxicity-
evaluable patient will be considered in the analysis during the interval from study 
enrollment until the termination of protocol therapy. A toxicity-evaluable patient will be 
considered to have experienced an excessive toxicity event if: (1) the patient dies on 
protocol therapy for a reason considered possibly, probably or likely related to denosumab; 
or (2) experiences a dose-limiting toxicity. DLTs will be: any ≥ Grade 3 event not 
considered attributable to osteosarcoma except hypocalcemia ≥ Grade 3 corrected with 
medical therapy, hypophosphatemia ≥ Grade 3 corrected with medical therapy, 
≥ Grade 3 cardiac toxicity in a subject who previously received Adriamycin and ≥ Grade 3 
ototoxicity in a subject who previously received cisplatin. Osteonecrosis of the jaw (ONJ) 
and fractures (excluding pathologic fracture at the site of an osteosarcoma bony metastasis) 
will be considered DLTs and will require cessation of therapy. Serum calcium, magnesium 
and phosphate will be monitored at the start of every cycle and weekly during the first 8 
weeks. Bone age and assessment for epiphyseal closure will be performed every 6 months 
in those patients without epiphyseal closure at the time of enrollment. Patients will be 
subject to routine AE reporting while on protocol therapy and for up to 30 days off protocol 
therapy. Expedited reporting of serious adverse events according to Section 11 of the 

  
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Page 39  
protocol will continue as long as a patient is considered on study according to Section 8 of 
the protocol. 
 
The analytic unit for monitoring for excessive toxicity will be the patient-cycle: Each cycle 
where the patient receives denosumab and does not receive non-protocol anticancer therapy 
will be considered in the analysis. We will use a Bayesian rule to monitor for excessive 
toxicity. We will assume a beta prior distribution with α=0.6 and =1.4. If this posterior 
probability of the chance of DLT is at least 30% exceeds 80%, we will identify the regimen 
to the COG DSMC, Bone Tumor leadership and CTEP as associated with a toxicity profile 
that may require modification of the regimen. Descriptive analyses of this safety 
information will be performed and will include the incidence of adverse events, severe 
adverse events, serious adverse events, and fatal adverse events. Type, frequency, and 
severity of laboratory abnormalities will also be analyzed. Safety analyses will be 
performed in aggregate, by cohort, and by age group (≤ 18 years and in patients > 18 years 
of age). The safety of denosumab in adults and adolescents will be compared. In addition 
a subset analysis of the safety of denosumab in patients ≤ 15 years and in patients > 15 years 
of age will be performed. 
 
Aim 1.2.3: Estimation of the Response and Disease Control Rates 
Cohort 1: P(R) and P(S) will be estimated using the maximum likelihood estimates, viz., 
 


ˆ
;
ˆ
1
4
ˆ
ˆ
1
R
S
Number of Patients Considered as PR or CR
P R
p
Number of Evaluable Patients in Cohort
Number of Patients With DiseaseControl at
Months
P S
p
Number of Evaluable Patients in Cohort




  
 
Confidence intervals will be constructed using the approximate normal distribution of 
each of the estimates and their asymptotic variances: 
 
 








ˆ
ˆ
1
ˆ
;
ˆ
1
ˆ
ˆ
1
ˆ
ˆ
1
R
R
R
S
S
S
p
p
V p
Number of Evaluable Patients in Cohort
p
p
V p
Number of Evaluable Patients in Cohort




  
Cohort 2: The proportion of patients who experience 12 month disease control will be 
estimated by the method of Kaplan and Meier.39 The complementary log-log 
transformation of the Kaplan-Meier estimate of the 12 month disease control probability 
will be used to construct confidence intervals of that probability.40  
 
 

  
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The gender and minority distribution of the study population is expected to be: 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
American Indian/ Alaska 
Native 
0 
0 
0 
0 
0 
Asian 
1 
1 
0 
0 
2 
Native Hawaiian or Other 
Pacific Islander 
0 
0 
0 
0 
0 
Black or African American 
4 
13 
0 
0 
17 
White 
21 
40 
3 
7 
71 
More Than One Race 
0 
0 
0 
0 
0 
Total 
26 
54 
3 
7 
90 
This distribution was derived from ADVL0821, ADVL0921, ADVL1221, AOST0221. 
 
10.0 
EVALUATION CRITERIA 
 
This study will utilize version 4.0 of the CTCAE of the National Cancer Institute (NCI) for 
toxicity and performance reporting. A copy of the CTCAE version 4.0 can be downloaded 
from the CTEP website  
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
Additionally, toxicities are to be reported on the appropriate case report forms. 
 
Please note: ‘CTCAE v4.0’ is understood to represent the most current version of CTCAE 
v4.0 as referenced on the CTEP website (ie, v4.02 and all subsequent iterations prior to 
version 5.0). 
 
For the purposes of this study, patients should be evaluated for response prior to Cycle 3, 
Cycle 5 and every odd cycle thereafter.  
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) 
guideline (version 1.1).41 Changes in the largest diameter (unidimensional measurement) 
of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are 
used in the RECIST criteria. 
 
10.2.1.1 Evaluable for objective response: See Section 9.3 
 

  
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10.2.2.1 Measurable disease: Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be 
recorded) as ≥ 20 mm by chest x-ray, as ≥ 10 mm with CT scan, or 
≥ 10 mm with calipers by clinical exam. All tumor measurements must 
be recorded in millimeters (or decimal fractions of centimeters). 
 
10.2.2.2 Malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be ≥ 15 mm in short axis when assessed 
by CT scan (CT scan slice thickness recommended to be no greater than 
5 mm). At baseline and in follow-up, only the short axis will be measured 
and followed. 
 
10.2.2.3 Non-measurable disease: All other lesions (or sites of disease), including 
small lesions (longest diameter < 10 mm or pathological lymph nodes 
with ≥ 10 to < 15 mm short axis), are considered non-measurable disease. 
Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as 
non-measurable. 
 
Note: Cystic lesions that meet the criteria for radiographically defined 
simple cysts should not be considered as malignant lesions (neither 
measurable nor non-measurable) since they are, by definition, simple 
cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered 
as measurable lesions, if they meet the definition of measurability 
described above. However, if non-cystic lesions are present in the same 
patient, these are preferred for selection as target lesions. 
 
10.2.2.4 Target lesions: All measurable lesions up to a maximum of 2 lesions per 
organ and 5 lesions in total, representative of all involved organs, should 
be identified as target lesions and recorded and measured at baseline. 
Target lesions should be selected on the basis of their size (lesions with 
the longest diameter), be representative of all involved organs, but in 
addition should be those that lend themselves to reproducible repeated 
measurements. It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement in which circumstance 
the next largest lesion which can be measured reproducibly should be 
selected. A sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters. If lymph nodes are to be included 
in the sum, then only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any 
objective tumor regression in the measurable dimension of the disease. 
 
10.2.2.5 Non-target lesions: All other lesions (or sites of disease) including any 
measurable lesions over and above the 5 target lesions should be 
identified as non-target lesions and should also be recorded at baseline. 

  
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Measurements of these lesions are not required, but the presence, 
absence, or in rare cases unequivocal progression of each should be 
noted throughout follow-up.  
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination unless 
the lesion(s) being followed cannot be imaged but are assessable by clinical exam. 
 
10.2.3.1 Clinical lesions: Clinical lesions will only be considered measurable 
when they are superficial (eg, skin nodules and palpable lymph nodes) 
and  10 mm diameter as assessed using calipers (eg, skin nodules). In 
the case of skin lesions, documentation by color photography, including 
a ruler to estimate the size of the lesion, is recommended.  
 
10.2.3.2 Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions 
when they are clearly defined and surrounded by aerated lung. However, 
CT is preferable.  
 
10.2.3.3 Conventional CT and MRI: This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 
5 mm or less. If CT scans have slice thickness greater than 5 mm, the 
minimum size for a measurable lesion should be twice the slice 
thickness. MRI is also acceptable in certain situations (eg, for body 
scans). 
 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, 
and temporal resolution; however, there are many image acquisition 
variables involved in MRI, which greatly impact image quality, lesion 
conspicuity, and measurement. Furthermore, the availability of MRI is 
variable globally. As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for 
the evaluation of the type and site of disease. Furthermore, as with CT, 
the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse 
sequence. It is beyond the scope of the RECIST guidelines to prescribe 
specific MRI pulse sequence parameters for all scanners, body parts, and 
diseases. Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior 
scans. Body scans should be performed with breath-hold scanning 
techniques, if possible. 
 
10.2.3.4 Ultrasound: Ultrasound is not useful in assessment of lesion size and 
should not be used as a method of measurement. Ultrasound 

  
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examinations cannot be reproduced in their entirety for independent 
review at a later date and, because they are operator dependent, it cannot 
be guaranteed that the same technique and measurements will be taken 
from one assessment to the next. If new lesions are identified by 
ultrasound in the course of the study, confirmation by CT or MRI is 
advised. If there is concern about radiation exposure at CT, MRI may be 
used instead of CT in selected instances. 
 
10.2.3.5 Endoscopy, Laparoscopy: The utilization of these techniques for 
objective tumor evaluation is not advised. However, such techniques 
may be useful to confirm complete pathological response when biopsies 
are obtained or to determine relapse in trials where recurrence following 
complete response (CR) or surgical resection is an endpoint. 
 
10.2.3.6 Cytology, Histology: These techniques can be used to differentiate 
between partial responses (PR) and complete responses (CR) in rare 
cases (eg, residual lesions in tumor types, such as germ cell tumors, 
where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that 
appears or worsens during treatment when the measurable tumor has met 
criteria for response or stable disease is mandatory to differentiate 
between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
 
10.2.4.1 Evaluation of Target Lesions 
 
Complete Response (CR): 
Disappearance of all target lesions. Any pathological 
lymph nodes (whether target or non-target) must have 
reduction in short axis to < 10 mm. 
 
Partial Response (PR):  
At least a 30% decrease in the sum of the diameters 
of target lesions, taking as reference the baseline sum 
diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on 
study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase 
of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. (Note: the appearance of 
one or more new lesions is also considered 
progression). 
 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as 
reference the smallest sum diameters while on study. 
 

  
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10.2.4.2 Evaluation of Non-Target Lesions 
 
Complete Response (CR): 
Disappearance of all non-target lesions and 
normalization of tumor marker level. All lymph 
nodes must be non-pathological in size (< 10 mm 
short axis). 
 
Non-CR/Non-PD: 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal 
limits. 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target 
lesions. 
Unequivocal 
progression 
should 
not 
normally trump target lesion status. It must be 
representative of overall disease status change, not a 
single lesion increase. 
 
Although a clear progression of “non-target” lesions 
only is exceptional, the opinion of the treating 
physician should prevail in such circumstances, and 
the progression status should be confirmed at a later 
time by the review panel (or Principal Investigator). 
 
10.2.4.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of 
the treatment until disease progression/recurrence (taking as reference 
for progressive disease the smallest measurements recorded since the 
treatment started). The patient's best response assignment will depend on 
the achievement of both measurement and confirmation criteria. 

  
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For Patients with Measurable Disease (ie, Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall 
Response when 
Confirmation is 
Required* 
CR 
CR 
No 
CR 
≥ 4 wks. 
Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
 
≥ 4 wks. 
Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
documented at least 
once ≥ 4 wks. from 
baseline** 
PD 
Any 
Yes 
or 
No 
PD 
 
no prior SD, PR or 
CR 
Any 
PD*** 
Yes 
or 
No 
PD 
Any 
Any 
Yes 
PD 
*See RECIST 1.1 manuscript for further details on what is evidence of a 
new lesion. 
**Only for non-randomized trials with response as primary endpoint. 
***In exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression. 
 
Note: Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease 
progression at that time should be reported as “symptomatic 
deterioration.” Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (ie, Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target 
disease since SD is increasingly used as an endpoint for assessment of 
efficacy in some trials so to assign this category when no lesions can be 
measured is not advised 
 

  
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10.2.5.1 Duration of overall response: The duration of overall response is 
measured from the time measurement criteria are met for CR or PR 
(whichever is first recorded) until the first date that recurrent or 
progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the 
treatment started). 
 
The duration of overall CR is measured from the time measurement 
criteria are first met for CR until the first date that progressive disease is 
objectively documented. 
 
10.2.5.2 Duration of stable disease: Stable disease is measured from the start of 
the treatment until the criteria for progression are met, taking as reference 
the smallest measurements recorded since the treatment started, 
including the baseline measurements.  
 
 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of patients enrolled in the studies as well as those who 
will enroll in future studies using similar agents. Certain adverse events must be reported 
in an expedited manner to allow for timelier monitoring of patient safety and care. The 
following sections provide information about expedited reporting. 
 
To ensure compliance with these regulations/this guidance, NCI requires that AEs be 
submitted according to the timeframes in the AE reporting tables assigned to the protocol, 
using the CTEP Adverse Event Reporting System (CTEP-AERS). 
 
Any AE that is serious qualifies for expedited reporting. An AE is defined as any 
untoward medical occurrence associated with the use of a drug in humans, whether or not 
considered drug related. A Serious Adverse Event (SAE) is any adverse drug event 
(experience) occurring at any dose that results in ANY of the following outcomes: 
 
1) Death. 
2) A life-threatening adverse drug experience. 
3) An adverse event resulting in inpatient hospitalization or prolongation of existing 
hospitalization (for ≥ 24 hours). This does not include hospitalizations that are part 
of routine medical practice. 
4) A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
5) A congenital anomaly/birth defect. 
6) Important Medical Events (IME) that may not result in death, be life threatening, 
or require hospitalization may be considered a serious adverse drug experience 
when, based upon medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. 

  
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Any Serious Adverse Event that occurs more than 30 days after the last 
administration of the investigational agent/intervention and has an attribution of a 
possible, probable, or definite relationship to the study therapy must be reported 
according to the CTEP-AERS reporting tables in this protocol.  
 
Any AE that results in persistent or significant incapacity or substantial disruption 
of the ability to conduct normal life functions (formerly referred to as disabilities), 
congenital anomalies or birth defects, must be reported via CTEP-AERS if it 
occurs at any time following treatment with an agent under a NCI, COG, or 
industry sponsor IND/IDE since these are considered to be serious AEs. 
 
Reportable Categories of Death  
o Death attributable to a CTCAE term.  
o Death Neonatal: A disorder characterized by cessation of life during the first 
28 days of life.  
o Sudden Death NOS: A sudden (defined as instant or within one hour of the 
onset of symptoms) or an unobserved cessation of life that cannot be attributed 
to a CTCAE term associated with Grade 5.  
o Death NOS: A cessation of life that cannot be attributed to a CTCAE term 
associated with Grade 5.  
o Death due to progressive disease should be reported as Grade 5 “Disease 
progression” in the system organ class (SOC) “General disorders and 
administration site conditions.” Evidence that the death was a manifestation 
of underlying disease (e.g., radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a disease process) should be 
submitted.  
 
Any death occurring within 30 days of the last dose, regardless of attribution to 
the investigational agent/intervention requires expedited reporting within 24 hours.  
Any death occurring greater than 30 days after the last dose of the investigational 
agent/intervention requires expedited reporting within 24 hours only if it is 
possibly, probably, or definitely related to the investigational agent/intervention. 
 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (eg, treatment with investigational agent/intervention, radiation or 
chemotherapy). A metastasis of the initial neoplasm is not considered a secondary 
malignancy.  
 
All secondary malignancies that occur following treatment need to be reported via 
CTEP-AERS. Three options are available to describe the event:  

Leukemia secondary to oncology chemotherapy  

Myelodysplastic syndrome  

Treatment related secondary malignancy  

  
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Any malignancy possibly related to cancer treatment (including AML/MDS) must 
also be reported via the routine reporting mechanisms outlined in this protocol. 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and 
is NOT a metastasis from the initial malignancy). Second malignancies require 
ONLY routine reporting via CDUS unless otherwise specified. 
 
NOTE: When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy loss”, 
or “Neonatal loss”, the Pregnancy Information Form, available at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/Pregna
ncyReportForm.pdf, needs to be completed and faxed along with any additional 
medical information to (310) 640-9193. The potential risk of exposure of the fetus 
to the investigational agent(s) or chemotherapy agent(s) should be documented in 
the “Description of Event” section of the CTEP-AERS report. 
 
11.3.6.1 Pregnancy 
Patients who become pregnant on study risk intrauterine exposure of the 
fetus to agents that may be teratogenic. For this reason, pregnancy needs 
to be reported in an expedited manner via CTEP-AERS as Grade 3 
“Pregnancy, 
puerperium 
and 
perinatal 
conditions 
- 
Other 
(pregnancy)” under the “Pregnancy, puerperium and perinatal 
conditions” SOC. 
 
Pregnancy needs to be followed until the outcome is known. If the baby 
is born with a birth defect or anomaly, then a second CTEP-AERS report 
is required. 
 
11.3.6.2 Pregnancy Loss (Fetal Death) 
Pregnancy loss is defined in CTCAE as “Death in utero.” Any pregnancy 
loss should be reported expeditiously, as Grade 4 “Pregnancy loss” 
under the “Pregnancy, puerperium and perinatal conditions” SOC. 
Do NOT report a pregnancy loss as a Grade 5 event since CTEP-AERS 
recognizes any Grade 5 event as a patient death. 
 
11.3.6.3 Death Neonatal  
Neonatal death, defined in CTCAE as “Newborn death occurring during 
the first 28 days after birth” should be reported expeditiously as Grade 
4 “Death neonatal” under the “General disorders and administration” 
SOC when the death is the result of a patient pregnancy or 
pregnancy in partners of men on study. Do NOT report a neonatal 
death resulting from a patient pregnancy or pregnancy in partners of men 
on study as a Grade 5 event since CTEP-AERS recognizes any Grade 5 
event as a patient death.  
 

  
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Although a pertinent positive finding identified on baseline assessment is not an 
AE, when possible it is to be documented as “Course Zero” using CTCAE 
terminology and grade. An expedited AE report is not required if a patient is 
entered on a protocol with a pre-existing condition (eg, elevated laboratory value, 
diarrhea). The baseline AE must be re-assessed throughout the study and reported 
if it fulfills expedited AE reporting guidelines. 
 
a. If the pre-existing condition worsens in severity, the investigator must 
reassess the event to determine if an expedited report is required. 
b. If the AE resolves and then recurs, the investigator must re-assess the event 
to determine if an expedited report is required. 
c. No modification in grading is to be made to account for abnormalities 
existing at baseline. 
 
A persistent AE is one that extends continuously, without resolution between 
treatment cycles/courses.  
ROUTINE reporting: The AE must be reported only once unless the grade 
becomes more severe in a subsequent course. If the grade becomes more severe 
the AE must be reported again with the new grade. 
EXPEDITED reporting: The AE must be reported only once unless the grade 
becomes more severe in the same or a subsequent course. 
 
A recurrent AE is one that occurs and resolves during a cycle/course of therapy 
and then reoccurs in a later cycle/course. 
ROUTINE reporting: An AE that resolves and then recurs during a subsequent 
cycle/course must be reported by the routine procedures. 
EXPEDITED reporting: An AE that resolves and then recurs during a subsequent 
cycle/course does not require CTEP-AERS reporting unless: 
1) The grade increases OR 
2) Hospitalization is associated with the recurring AE. 
 
An expedited report may not be required for a specific protocol where an AE is 
listed as expected. The exception or acceptable reporting procedures will be 
specified in the protocol. The protocol specific guidelines supersede the NCI 
Adverse Event Reporting Guidelines. These special situations are listed under the 
CTEP-AERS reporting Table A for this protocol. 
 
Clinical investigators in the treating institutions and ultimately the Study Chair have the 
primary responsibility for AE identification, documentation, grading, and assignment of 
attribution to the investigational agent/intervention. It is the responsibility of the treating 
physician to supply the medical documentation needed to support the expedited AE reports 
in a timely manner.  

  
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Note: All expedited AEs (reported via CTEP-AERS) must also be reported via routine 
reporting. Routine reporting is accomplished via the Adverse Event (AE) Case Report 
Form (CRF) within the study database.   
 
 
The reporting methods described below are specific for clinical trials evaluating 
agents for which the IND is held by COG, an investigator, or a pharmaceutical 
company. It is important to note that these procedures differ slightly from those used 
for reporting AEs for clinical trials for which CTEP holds the IND. 
 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting. All 
appropriate treatment areas should have access to a copy of the CTCAE version 5.0. A 
copy of the CTCAE version 5.0 can be downloaded from the CTEP website at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
An expedited AE report must be submitted electronically via CTEP-AERS at:  
https://eapps-ctep.nci.nih.gov/ctepaers 
 

Expedited AE reporting timelines are defined as: 
o 24-Hour; 5 Calendar Days - The AE must initially be reported via CTEP-
AERS within 24 hours of learning of the event, followed by a complete 
expedited report within 5 calendar days of the initial 24-hour report. 
o 7 Calendar Days - A complete expedited report on the AE must be submitted 
within 7 calendar days of the investigator learning of the event.  
 

Any event that results in a persistent or significant incapacity/substantial disruption of 
the ability to conduct normal life functions, or a congenital anomaly/birth defect, or is 
an IME, which based upon the medical judgment of the investigator may jeopardize 
the patient and require intervention to prevent a serious AE, must be reported via 
CTEP-AERS if the event occurs following investigational agent administration.  
 

Any death occurring within 30 days of the last dose, regardless of attribution to an 
agent/intervention requires expedited reporting within 24 hours via e-mail to the COG 
CTEP-AERS Coordinator and Study Chair.   
 

Any death occurring greater than 30 days of the last dose with an attribution of 
possible, probable, or definite to an agent/intervention requires expedited reporting 
within 24 hours via e-mail to the COG CTEP-AERS Coordinator and Study Chair. 
 
CTEP-AERS Medical Reporting includes the following requirements as part of the report: 
1) whether the patient has received at least one dose of an investigational agent on this 
study; 2) the characteristics of the adverse event including the grade (severity), the 
relationship to the study therapy (attribution), and the prior experience (expectedness) of 
the adverse event; 3) the phase (1, 2, or 3) of the trial; and 4) whether or not hospitalization 
or prolongation of hospitalization was associated with the event.  
 
Fax or email supporting documentation for AEs related to investigational agents to 
COG: 
Fax # 310-640-9193; email: COGAERS@childrensoncologygroup.org; Attention: COG 
AERS Coordinator.  
 

  
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
ALWAYS include the ticket number on all faxed documents. 
 

Use the NCI protocol number and the protocol-specific patient ID provided 
during trial registration on all reports. 
 
 

  
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Expedited Reporting Requirements for Adverse Events that Occur on Studies under an 
IND/IDE within 30 Days of the Last Administration of the Investigational 
Agent/Intervention 1 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 
312)  
NOTE: Investigators MUST immediately report to the sponsor (COG) ANY Serious Adverse Events, 
whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 
312.64)  
An adverse event is considered serious if it results in ANY of the following outcomes:  
1) Death.  
2) A life-threatening adverse event.  
3) Any AE that results in inpatient hospitalization or prolongation of existing hospitalization for 
 
≥ 24 hours. This  
does not include hospitalizations that are part of routine medical 
 
practice. 
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
 
life functions.  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
 
hospitalization may be considered serious when, based upon medical judgment, they may 
 
jeopardize the patient or subject and may require medical or surgical intervention to prevent one 
 
of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6.)  
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the 
NCI via CTEP-AERS within the timeframes detailed in the table below.   
 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization 
≥ 24 hrs 
 
7 Calendar Days 
 
 
24-Hour Notification 
5 Calendar Days 
Not resulting in 
Hospitalization 
≥ 24 hrs 
 
Not Required 
 
7 Calendar 
Days 
NOTE: Protocol specific exceptions to expedited reporting of serious adverse events are found in the 
Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. Additional 
Special Situations as Exceptions to Expedited Reporting are listed below.  
 
Expedited AE reporting timelines are defined as:  
“24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-
hour notification. 
“7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar days 
of learning of the AE.  
 
1SAEs that occur more than 30 days after the last administration of investigational agent/intervention 
and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for:  

All Grade 4, and Grade 5 AEs  
Expedited 7 calendar day reports for:  

Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  

Grade 3 adverse events  

  
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Note: The guidelines below are for routine reporting of study specific adverse events on 
the COG case report forms and do not affect the requirements for CTEP-AERS reporting. 
 
Routine reporting is accomplished via the Adverse Event (AE) Case Report Form (CRF) 
within the study database. For this study, routine reporting will include all CTEP-AERS 
reportable events and Grade 3 and higher Adverse Events. 
 
 
12.0 
RECORDS AND REPORTING 
See the Case Report Forms posted on the COG web site with each protocol under “Data 
Collection/Specimens”. A submission schedule is included. 
 
This study will be monitored by the Clinical Data Update System (CDUS). Cumulative 
CDUS data will be submitted quarterly to CTEP by electronic means. Reports are due 
January 31, April 30, July 31 and October 31. This is not a responsibility of institutions 
participating in this trial. 
 
To protect the interests of patients and the scientific integrity for all clinical trial research 
by the Children’s Oncology Group, the COG Data and Safety Monitoring Committee 
(DSMC) reviews reports of interim analyses of study toxicity and outcomes prepared by 
the study statistician, in conjunction with the study chair’s report. The DSMC may 
recommend the study be modified or terminated based on these analyses.  
 
Toxicity monitoring is also the responsibility of the study committee and any unexpected 
frequency of serious events on the trial are to be brought to the attention of the DSMC. The 
study statistician is responsible for the monitoring of the interim results and is expected to 
request DSMC review of any protocol issues s/he feels require special review. Any COG 
member may bring specific study concerns to the attention of the DSMC.  
 
The DSMC approves major study modifications proposed by the study committee prior to 
implementation (eg, termination, dropping an arm based on toxicity results or other trials 
reported, increasing target sample size, etc.). The DSMC determines whether and to whom 
outcome results may be released prior to the release of study results at the time specified 
in the protocol document. 
 
 
13.0 
SURGICAL GUIDELINES 
Patients who have had a complete resection of all sites of metastatic disease within 30 days 
prior to enrollment (Cohort 2) must upload the surgical report into RAVE within 4 weeks 
of enrollment. 
 
See COG Surgical Guidelines for osteosarcoma at: 
https://www.cogmembers.org/_files/Disc/surgery/handbooks/OsteoBoneHandbook.pdf. 
 
 

  
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14.0 
PATHOLOGY GUIDELINES AND SPECIMEN REQUIREMENTS 
Patients who have had a complete resection of all sites of metastatic disease within 30 days 
prior to enrollment (Cohort 2) must upload the pathology report into RAVE within 4 weeks 
of enrollment. 
 
All patients enrolling on this protocol require institutional histological confirmation of osteosarcoma 
at the time of original diagnosis or at the time of recurrence. For enrollment on Cohort 1, histologic 
confirmation of recurrence/relapse is strongly encouraged but NOT required. For enrollment on 
Cohort 2 histologic confirmation of recurrence is required as detailed in Section 3.2.2.3. 
 
Please note: all patients must have adequate tumor specimen available for submission as detailed in 
Section 15.3. 
 
COG sites: For patients enrolled on AOST06B1 or APEC14B1 who have a biopsy or who undergo 
surgical resection, tissue submission is encouraged. (See AOST06B1 protocol or APEC14B1 Manual 
of Procedures.) 
 
Autopsy  
In the event of patient death on AOST1321, a complete unrestricted postmortem examination is 
strongly encouraged. For patients enrolled on AOST06B1 or APEC14B1 at COG sites, tissue 
submission is requested. (See AOST06B1 protocol or APEC14B1 Manual of Procedures.)  
 
 
15.0 
SPECIAL STUDIES SPECIMEN REQUIREMENTS 
The first 15 evaluable patients < 18 years of age enrolled on Cohort 1 (ie, Stratum 1) are 
required to have serial blood samples for the assessment of denosumab serum 
concentrations. Pharmacokinetic sampling will be optional for all other patients.  
 
 

  
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Serum will be drawn prior to denosumab dosing at 
the following time points. 
Cycle 1 

Day 1 

Day 8 

Day 15 

Day 22 
Cycle 2 

Day 1 
 
Cycle 3 
Cycle 4 
Cycle 6 

Day 1  

Day 15* 
Cycle 7 

Day 1 
*Cycle 6 Day 15 sampling time point requires patient consent from all patients, including 
those enrolled on Stratum 1. Collection at this time point will permit measurement of 
denosumab clearance and volume of distribution. 
 
At each protocol specified time point, fill one appropriately labeled (waterproof 
ink) 5.0 mL Serum Separator drawing tube (SST), containing no anti-coagulant 
until the vacuum is exhausted and blood flow ceases. Gently invert the filled tube 
5 times and allow to clot for 30 to 60 minutes (maximum clotting time 1 hour) at 
room temperature. 
 
Centrifuge at 1500 x g for 15 minutes at room temperature (if you have a 
temperature controlled centrifuge set to 20⁰C).  
 
Prepare two 4-mL polypropylene storage tubes per subject per time point. Each 
tube should have a freezer-safe label with:  
 
• AOST1321  
• COG patient ID number  
• Study Day  
• Sampling Date  
• One tube will be labeled “A” and the other “B” 
 
Using a pipette, remove serum from the top of the tube without disturbing the blood 
cells and transfer an equal volume (ideally 2 mL each) into each of the two labeled 
4 mL cryovials.   
 

  
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Note: If there is an inadequate amount of serum for 2 mL per cryovial then split 
the available serum volume equally into all cryovials.  
 
Immediately place the 4 mL cryovials containing the serum sample in a -70 ± 10⁰C 
freezer. All tubes should be stored in an upright position.  
 
The serum sample must be frozen within 2 hours of blood collection. 
 
Following the plasma harvest, the remaining buffy coat and red blood cell layers 
should be discarded as biological specimen. 
 
Each tube should have a freezer-safe label with the details listed in Section 15.1.1.  
 
When possible, primary “A” tubes and backup “B” tubes should be shipped on 
different days. All “A” tubes will be shipped frozen in appropriately insulated 
containers with enough dry ice to last 3 days. The tubes should be shipped on the 
first Monday, Tuesday, or Wednesday following the last scheduled sample 
collection by overnight delivery such that they reach PPD before or by Thursday 
of that week. A study-specific paper PK transmittal form should be completed in 
RAVE, printed and sent with the specimen to the following address:  
 
PPD Sample Management, Attention James Rhyne 
2246 Dabney Road 
Richmond, VA 23230 
Tel: (804) 977-8430 
E-mail: RichmondSMOpeners@ppdi.com 
 
If feasible, specimens should be collected at the clinical site and shipped in a batch 
to PPD. Specimens must be shipped in accordance with rules and laws governing 
the shipment of human diagnostic specimens 
  
PPD should be notified by e-mail that a shipment is on its way. The courier and 
tracking number should be provided.  
 
No shipments should be made within 3 days of a holiday.  
 
Pharmacodynamic sampling will be required of all patients and will be analyzed by the 
institution’s laboratory as would be performed for clinical testing. A serum sample and a 
urine sample will be required at each time point. 
 
 

  
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uNTx/Cr and sCTx will be obtained prior to 
denosumab dosing at the following time points. 
Cycle 1 

Day 1 

Day 8 

Day 15 

Day 22 
Cycle 2 

Day 1 
Cycle 3 
Cycle 4 
Cycle 7 
 
A urine N-telopeptide (uNTx/Cr) from the second morning urine and serum 
c-telopeptide (sCTx) will be analyzed by the institution’s laboratory as would 
be performed for clinical testing. 
 
Changes in urine N –telopeptide (uNTx/Cr) and serum c-telopeptide (sCTx) will 
be used to evaluate the impact of denosumab on bone turnover 
(pharmacodynamics).  
 
Immunohistochemical analyses (IHC) of RANK and RANKL expression will be 
performed by Clarient Diagnostic Services Inc., Aliso Viejo, CA using prototype assays, 
which have been developed and optimized by Dako on their automated staining platform. 
A total of 7 slides will be required for the RANK IHC [H&E stain (one slide), RANK IHC 
plus negative control (2 slides), RANKL IHC plus negative control (2 slides), slides to 
potentially repeat a failed RANK/RANKL IHC (2 slides)].  
 
Submission of a formalin fixed paraffin embedded (FFPE) sample of tumor is 
required. A block is preferred. If a block is not available, 7 unstained slides must 
be provided from the most recent recurrence (preferred), a more distant recurrence 
(second choice) or original diagnosis (third choice). The handling and age of tumor 
tissue slides will adversely affect the results of the RANK and RANKL IHC due 
to epitope instability. The tumor material must be sent within 4 weeks of patient 
enrollment. 
 
If slides are being sent in place of a block, section from FFPE blocks at 5 µm the 
day before shipment to the Biopathology Center (BPC) and mount on superfrost 

  
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plus coated slides. Slides are to be air dried overnight and placed in a rigid slide 
box and shipped ambient temperature on the next business day. 
 
All tumor material must be labeled with the patient’s COG patient ID number, 
specimen type, surgical pathology ID, block number and collection date.  
 
All tumor material and associated pathology report(s) for that sample should be 
sent to the BPC at room temperature by regular mail or by the submitting 
institution’s courier account. A study specific specimen transmittal form should be 
completed in RAVE, printed and sent with the specimen to the following address: 
 
Biopathology Center (BPC) 
Nationwide Children’s Hospital 
Protocol AOST1321 
700 Children’s Drive, WA1340* 
Columbus, OH 43205 
Phone: 
(614) 722-2865 
Fax: 
(614) 722-2897 
  
For questions about this correlative study, please contact the study chair, Dr. 
Janeway. For questions about shipping the slides, please contact the BPC directly.  
 
RANK / RANKL expression in pre-treatment specimens with an emphasis on 
metastatic lesions (when available) will be performed by immunohistochemistry. 
Utilizing pre-treatment specimens (when available), gene profiling will be 
performed and genomic data will be analyzed to determine patterns associated with 
a favorable response to denosumab. If there is variable expression of RANK / 
RANKL between tumors, expression array data will be analyzed for genes 
associated with RANK / RANKL expression. 
 
 
16.0 
IMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING 
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on established 
standards of care. Minor unavoidable departures (up to 72 hours) from protocol directed therapy 
and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and family 
logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable (except where 
explicitly prohibited within the protocol). 

  
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Site 
Anatomic Imaging 
Functional 
Imaging 
Timing 
Bone or soft 
tissue sites of 
disease 
CT or MRI with 
gadolinium 
 
 
Prior to starting protocol 
therapy and prior to 
every odd cycle*  
Bone age 
(patients ≤ 18 
years of age) 
AP radiograph of the 
left hand 
 
 
Prior to starting protocol 
therapy and every 
6 months only in 
patients without 
epiphyseal closure at the 
time of enrollment. 
Chest 
CT 
 
Prior to starting protocol 
therapy and prior to 
every odd cycle 
Whole body 
 
MDP bone 
scintigraphy  
Prior to starting protocol 
therapy and every 6 
months 
*For patients who undergo a surgical resection following Cycle 4, either a CT scan 
or MRI post-surgery to establish a new baseline is strongly recommended before 
re-initiating denosumab therapy.   
 
NOTE: patients who have a RECIST response (CR or PR) on any evaluation 
following Cycle 4 will have confirmatory imaging 4 weeks after the initial 
evaluation demonstrating a RECIST response (additional imaging time 
point). 
 
CT and MRI guidelines are available on the COG Member site at: 
https://www.cogmembers.org/_files/reference/RefMaterial/DiagnosticImagingGu
idelines_MRICT.pdf. 
 
Bone age will be determined based on an AP radiograph of the left hand and with 
reference to the atlas of Greulich & Pyle (GP). Bone age is calculated by 
comparing the left wrist radiographs of the subject with the nearest matching 
reference radiographs provided in the atlas, which are standard for different ages 
provided in the atlas.  
 
The hand radiographs are quite safe to obtain as the effective dose of radiation 
received during each exposure is between 0.0001-0.1 mSV. This dose is less than 
20 minutes of natural background radiation or the amount of radiation received by 
an individual on a 2 minute transatlantic flight. 
 
The pattern of ossification in the hand and wrist bones is in a fairly predictable 
manner and age specific until end of adolescence when the elongation of bone is 
complete. Thus, the standards of bone age have been derived by comparing the 
level of maturation of hand and wrist bones with normal age levels. The method 

  
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based on “The Radiographic Atlas of Skeletal Development of the Hand and 
Wrist”, by Dr. William Walter Greulich and Dr. Sarah Idell Pyle, its last edition 
published in 1959, is still one of the most commonly used atlas for bone age 
measurement. It contains reference images of male and female standards of the left 
wrist and hand from birth till 18 years for females and 19 years for males. Also, 
explanation regarding the gradual age related changes observed in the bone 
structure is provided with each standard image.  
 
MDP bone scintigraphy  

Whole body bone scintigraphy should be performed and include 
planar images of the skeleton, including anterior and posterior views 
of the axial skeleton. Anterior and/or posterior views should be 
obtained of the appendicular skeleton. 

Delayed (skeletal phase) images should be performed in all cases with 
flow and blood pool images as per local custom and clinical need. 

Dose Administration: Dose administered should be according to 
standard weight-based protocols. Injection site should be away from 
lesion extremity or contralateral extremity if flow imaging is to be 
performed. Three-phase imaging is not required unless warranted by 
symptoms for a focal lesion to assess hyperemia. 

Imaging Parameters: Whole body delayed imaging is acquired 2-
3 hours after injection of the radiopharmaceutical. Spot views should 
be acquired of specific sites of symptoms or of any sites of 
abnormality as warranted by the whole body views. 

Single-photon 
emission 
computed 
tomography 
(SPECT) 
is 
recommended, but not required, particularly in cases with suspicion of 
lung metastases. 

SPECT Imaging: SPECT should be performed of the lesion site. 
SPECT imaging should be performed as recommended by the camera 
manufacturer. Typical acquisition and processing parameters are 360° 
circular orbit, 60–120 stops, 64 ´ 64 ´ 16 or greater matrix, and 10–
40 s/stop. An equivalent total number of counts should be acquired if 
continuous acquisition is used. 

Special Consideration: Imaging of pelvis can be difficult due to 
overlying bladder activity. To lessen this problem, repeat imaging can 
be 
performed 
immediately 
after 
patient 
voiding. 
Bladder 
catheterization may be used, but should be reserved for patients in 
whom visualization of the pelvis is essential. For SPECT acquisition 
of the pelvis: “Single or multiple rapid (5-10 min/acquisition) SPECT 
acquisition(s) are preferred to avoid artifacts caused by changing 
activity in the bladder. Bladder artifacts are exaggerated in the plane 
in which the SPECT acquisition begins and ends. Beginning SPECT 
acquisition with the camera heads in the left and right lateral positions 
(for dual-head camera) or posterior position (for single-head camera) 
will help reduce bladder filling artifact.  
 
 
 
 

  
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RELATIONSHIP BETWEEN CHANGE IN SINGLE DIAMETER (RECIST), PRODUCT OF TWO 
DIAMETERS (WHO), AND THREE PERPENDICULAR DIAMETERS (“VOLUME”) 
 
Target lesions at baseline must measure greater than 1 cm; if these target lesions decrease in size to 
below 1 cm, care should be taken in measuring and inadvertently progressing a patient due to minimal 
changes in measurement from a nadir value below 1 cm, which may be within measurement error. 
When multiple primary or metastatic masses are present, all masses will be described. However, up to 
5 target masses should be measured, using the same method in subsequent follow ups.  
 
 
 
 
 
 
 
Diameter, 2R 
Product, (2R)2 
Volume, 4/3R3 
 
Response 
 
Decrease 
Decrease 
Decrease 
 
 
 
30% 
 
    50%   
65% 
 
 
 
50% 
 
   75%  
87% 
 
Disease Progression 
Increase 
Increase 
Increase 
 
 
 
12% 
 
    25%  
 40% 
 
 
 
20% 
                   44%                  73% 
 
 
 
25% 
                   56%                  95% 
 
 
 
30% 
                   69%                120% 
 
Z
AXIS
W
T
A
B
C
D
E
COG GUIDELINE: TUMOR SIZE 
MEASUREMENT BASED ON CROSS-
SECTIONAL IMAGING
A, B, C, D, & E are contiguous parallel slices     
in the X-Y plane (usually axial) showing the 
tumor
W and T are the maximal perpendicular 
diameters on the slice (C in this example) 
showing the largest surface area
Tumor length in the Z-axis (L) (perpendicular 
to X-Y plane) can be obtained either by the [a] 
(difference in table position of the first and last 
slices showing the tumor plus one slice
thickness), or [b] the product of ([slice 
thickness + gap] and the number of slices 
showing the tumor) minus one gap distance
• WHO criteria: TxW is used
• RECIST: the larger of the two (T & W) is      
used (W in this example)
• Elliptical model volume=0.5 LxWxT
• The same modality and measurement method 
used in the initial imaging should be used in 
follow ups
X-Y
PLANE
L

  
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APPENDIX I:  CTEP AND CTSU REGISTRATION PROCEDURES 
 
CTEP INVESTIGATOR REGISTRATION PROCEDURES 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy require all 
investigators participating in any NCI-sponsored clinical trial to register and to renew their registration 
annually. 
 
Registration requires the submission of: 
 

a completed Statement of Investigator Form (FDA Form 1572) with an original signature 

a current Curriculum Vitae (CV) 

a completed and signed Supplemental Investigator Data Form (IDF) 

a completed Financial Disclosure Form (FDF) with an original signature 
 
Fillable PDF forms and additional information can be found on the CTEP website at 
<http://ctep.cancer.gov/investigatorResources/investigator_registration.htm>. For questions, please contact 
the CTEP Investigator Registration Help Desk by email at <pmbregpend@ctep.nci.nih.gov>. 
 
CTEP Associate Registration Procedures / CTEP-IAM Account 
 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management (IAM) application is a 
web-based application intended for use by both Investigators (i.e., all physicians involved in the conduct of 
NCI-sponsored clinical trials) and Associates (i.e., all staff involved in the conduct of NCI-sponsored 
clinical trials). 
 
Associates will use the CTEP-IAM application to register (both initial registration and annual re-
registration) with CTEP and to obtain a user account. 
 
Investigators will use the CTEP-IAM application to obtain a user account only. (See CTEP Investigator 
Registration Procedures above for information on registering with CTEP as an Investigator, which must be 
completed before a CTEP-IAM account can be requested.) 
 
An active CTEP-IAM user account will be needed to access all CTEP and CTSU (Cancer Trials Support 
Unit) websites and applications, including the CTSU members’ website. 
 
Additional 
information 
can 
be 
found 
on 
the 
CTEP 
website 
at 
<http://ctep.cancer.gov/branches/pmb/associate_registration.htm>. For questions, please contact the CTEP 
Associate Registration Help Desk by email at <ctepreghelp@ctep.nci.nih.gov>. 
 
 

  
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CTSU REGISTRATION PROCEDURES 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU).  
 
Downloading Site Registration Documents: 
 
Site registration forms may be downloaded from the AOST1321 protocol page located on the CTSU 
members’ website. Permission to view and download this protocol and its supporting documents is 
restricted and is based on person and site roster assignment housed in the CTSU RSS. 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM username and 
password 
Click on the Protocols tab in the upper left of your screen 
Click on the COG link to expand, then select trial protocol AOST1321 
Click on the Site Registration Documents link 
 
Requirements for AOST1321 Site Registration: 
 
• 
CTSU IRB Certification (for sites not participating via the CIRB) 
• 
CTSU IRB/Regulatory Approval Transmittal Sheet (for sites not participating via the NCI CIRB)  
 
Submitting Regulatory Documents: 
 
Submit required forms and documents to the CTSU Regulatory Office, where they will be entered and 
tracked in the CTSU RSS.  
 
Regulatory Submission Portal: www.ctsu.org  (members’ area)  Regulatory Tab Regulatory 
Submission  
 
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU Regulatory 
Office immediately at 1-866-651-2878 in order to receive further instruction and support. 
 
Checking Your Site’s Registration Status: 
 
Check the status of your site’s registration packets by querying the RSS site registration status page of the 
members’ section of the CTSU website. (Note: Sites will not receive formal notification of regulatory 
approval from the CTSU Regulatory Office.) 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM username and 
password 
Click on the Regulatory tab at the top of your screen 
Click on the Site Registration tab 
Enter your 5-character CTEP Institution Code and click on Go 
 
 
 

  
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APPENDIX II:  YOUTH INFORMATION SHEETS 
 
INFORMATION SHEET REGARDING RESEARCH STUDY AOST1321 
(for subjects from 11 to 17 years of age) 
 
A trial using denosumab to treat osteosarcoma that has not responded to treatment or that has come back 
 
 
1. We have been talking with you about your illness, osteosarcoma. Osteosarcoma is a type of cancer that 
grows in the cells that produce bones. Recurrent means that the cancer has come back after treatment. 
After doing tests, we have found that you have this type of cancer.  
 
2. We are asking you to take part in a research study because you have recurrent osteosarcoma. A research 
study is when doctors work together to try out new ways to help people who are sick. In this study we 
are trying to learn more about how to treat osteosarcoma that has come back. We will do this by giving 
a new drug to treat recurrent osteosarcoma. We do not know how well the new drug will work in 
children, teens and young adults. That is why we are doing this study.  
 
3. Children and teens and young adults who are part of this study will be given a new drug. You will also 
have imaging tests to see if the cancer is getting worse, staying the same or getting better. There is a 
possibility that you will also have surgery or radiation therapy (high energy X-rays) while you are part 
of this study. Surgery and radiation therapy are often used to treat osteosarcoma and they are not 
experimental. 
 
4. Sometimes good things can happen to people when they are in a research study. These good things are 
called “benefits.” We hope that a benefit to you of being part of this study is that you are able to get rid 
of the cancer. But we don’t know for sure if there is any benefit of being part of this study. 
 
5. Sometimes bad things can happen to people when they are in a research study. These bad things are 
called “risks.” Being in this study may involve special risks, which your doctor will discuss with you. 
Other things may happen to you that we don’t yet know about. 
 
6. You or your family can choose to be part of this study or not. Your family can also decide to stop being 
in this study at any time once you start. Please talk this over with your parents. Together you can decide 
if you want to take part in the study or not. There may be other treatments for your illness that your 
doctor can tell you about. Make sure to ask your doctors any questions that you have.  
 
7. We are trying to learn how child and teenage bodies handle the new drug denosumab. We also want to 
see if there are ways to tell how the cancer will respond to treatment. To do this, we will collect extra 
blood, urine and tumor samples from you for research tests. Most of these samples will be taken when 
other standard blood draws, urine collection or tumor surgery are being performed but there may be 
extra blood draws. These additional blood tests may help children, teens and adults who receive this 
drug in the future. 
 
 

  
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