A Phase II Multicenter, Single Arm, Open-Label Trial to Evaluate the Efficacy and Safety of Denosumab in Treatment of Post-Allogenic Hematopoietic Stem Cell Transplant Bone Loss
Phase: PHASE2
Conditions: Allogeneic Hematopoietic Stem Cell Transplantation Recipient, Osteopenia, Osteoporosis
Sponsor: Roswell Park Cancer Institute

Document Coversheet 
 
 Study Title:     A Phase II Multicenter, Single Arm, Open-Label Trial to Evaluate the Efficacy and 
Safety of Denosumab in Treatment of Post-Allogenic Hematopoietic Stem Cell Transplant Bone 
Loss 
 
 
 
Institution/Site:  
Roswell Park Comprehensive Cancer Center 
Document (Approval/Update) Date: 
09/09/2021 
NCT Number: 
NCT03925532 
IRB Number 
I 78618 
 

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PROTOCOL TITLE: 
A Phase II Multicenter, Single Arm, Open-Label Trial to Evaluate the Efficacy and Safety 
of Denosumab in Treatment of Post-Allogenic Hematopoietic Stem Cell Transplant Bone 
Loss 
PROTOCOL NUMBER: 
I 78618 
PRINCIPAL INVESTIGATOR: 
Philip L. McCarthy 
Roswell Park Comprehensive Cancer Center 
Elm and Carlton Street 
Buffalo, New York 14263 
716-845-8412 
philip.mccarthy@roswellpark.org 
VERSION NUMBER: 
5 
DATE: 
20 July 2021 
Confidentiality Statement 
Any and all information presented in this document shall be treated as confidential and shall 
remain the exclusive property of the party (ies) mentioned above (Roswell Park Cancer Institute 
Corporation d/b/a Roswell Park Comprehensive Cancer Institute). The use of such confidential 
information must be restricted to the recipient for the agreed purpose and must not be disclosed, 
published, or otherwise communicated to any unauthorized persons, for any reason, in any form 
whatsoever without the prior written consent of the party(ies) above.
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Table of Contents 
1. 
Objectives........................................................................................................................ 5 
1.1 
Primary Objective ......................................................................................................... 5 
2 
Background ..................................................................................................................... 5 
2.1 
Bone Health in Hematopoietic Stem Cell Transplant ...................................................... 5 
2.2 
Denosumab ................................................................................................................... 5 
2.2.1 
Mechanism of Action................................................................................................. 6 
2.2.2 
Preclinical Pharmacology and Pharmacokinetics ......................................................... 6 
2.2.3 
Toxicology/ Interactions ............................................................................................ 6 
2.3 
Clinical Studies with Denosumab................................................................................... 7 
2.3.1 
Osteoporosis in Postmenopausal Women at High Risk for Fracture ............................. 7 
2.3.2 
Osteoporosis in Men at High Risk for Fracture ........................................................... 7 
2.3.3 
Treatment of Bone Loss in Men with Prostate Cancer ................................................. 7 
2.3.4 
Treatment of Bone Loss in Women with Breast Cancer............................................... 7 
2.4 
Rationale....................................................................................................................... 8 
3 
Inclusion and Exclusion Criteria ....................................................................................... 8 
3.1 
Inclusion Criteria........................................................................................................... 8 
3.2 
Exclusion Criteria ......................................................................................................... 8 
3.3 
Special Populations ....................................................................................................... 9 
3.4 
Inclusion of Women and Minorities ............................................................................... 9 
4 
Local and Study-Wide Number of Subjects....................................................................... 9 
5 
Local and Study-Wide Recruitment Methods .................................................................... 9 
6 
Multi-Site Research.......................................................................................................... 9 
7 
Study Timelines ............................................................................................................. 10 
8 
Study Endpoints............................................................................................................. 10 
8.1 
Primary Endpoint(s) .................................................................................................... 10 
8.2 
Secondary Endpoints ................................................................................................... 11 
9 
Design ........................................................................................................................... 11 
10 Treatment ...................................................................................................................... 11 
10.1 Dosing and Administration .......................................................................................... 11 
10.2 Dose Modifications and Treatment Delays ................................................................... 12 
10.3 General Concomitant Medication and Supportive Care ................................................. 12 
10.4 Duration of Treatment ................................................................................................. 12 
10.5 Off-Study Treatment ................................................................................................... 12 
11 Procedures Involved....................................................................................................... 12 
11.1 Participant Registration ............................................................................................... 13 
11.2 Correlative Studies ...................................................................................................... 13 
12 Withdrawal of Subjects .................................................................................................. 13 
12.1 Treatment Discontinuation........................................................................................... 13 
13 Risks to Subjects ............................................................................................................ 14 
14 Potential Benefits to Subjects ......................................................................................... 14 
15 Data and Specimen Banking ........................................................................................... 14 
16 Measurement of Effect ................................................................................................... 14 
16.1 Bone Density Status .................................................................................................... 14 
16.2 Other Response Parameters ......................................................................................... 14 
17 Safety Evaluation ........................................................................................................... 14 
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17.1 Adverse Events ........................................................................................................... 14 
17.1.1 Diagnosis Versus Signs and Symptoms .................................................................... 15 
17.1.2 Adverse Events Occurring Secondary to Other Events .............................................. 15 
17.1.3 Abnormal Laboratory Values ................................................................................... 15 
17.1.4 Preexisting Medical Conditions (Baseline Conditions) .............................................. 15 
17.2 Grading and Reporting Adverse Events........................................................................ 16 
17.2.1 Grading and Relationship to Drug ............................................................................ 16 
17.3 Reporting Adverse Events ........................................................................................... 16 
17.4 Serious Adverse Events ............................................................................................... 16 
17.4.1 Reporting Serious Adverse Events............................................................................ 17 
17.5 Investigator Reporting: Notifying the Study Sponsor .................................................... 17 
17.6 Follow-Up for Serious Adverse Events ........................................................................ 17 
17.7 Unanticipated Problems............................................................................................... 17 
17.7.1 Reporting Unanticipated Problems: .......................................................................... 18 
17.8 Amgen Safety Reporting ............................................................................................. 18 
17.9 FDA Reporting ........................................................................................................... 18 
18 Data Management and Confidentiality ............................................................................ 19 
18.1 Data Collection ........................................................................................................... 19 
18.2 Maintenance of Study Documents................................................................................ 19 
18.3 Revisions to the Protocol ............................................................................................. 19 
18.4 Termination of the Study ............................................................................................. 19 
18.5 Confidentiality ............................................................................................................ 19 
19 Statistical Plan ............................................................................................................... 19 
19.1 Sample Size Determination.......................................................................................... 20 
19.2 Demographics and Baseline Characteristics.................................................................. 20 
19.3 Efficacy Analysis ........................................................................................................ 20 
19.4 Adverse Events ........................................................................................................... 20 
19.5 Interim Analysis and Criteria for Early Termination of the Study .................................. 20 
19.6 Correlative Data Analysis ............................................................................................ 21 
20 Provisions to Monitor the Data to Ensure the Safety of Subjects ...................................... 21 
21 Vulnerable Populations .................................................................................................. 21 
22 Community-Based Participatory Research ...................................................................... 21 
23 Sharing of Results with Subjects..................................................................................... 21 
24 Setting ........................................................................................................................... 21 
25 Provisions to Protect the Privacy Interests of Subjects ..................................................... 21 
26 Resources Available....................................................................................................... 21 
27 Prior Approvals.............................................................................................................. 21 
28 Compensation for Research-Related Injury ..................................................................... 21 
29 Economic Burden to Subjects ......................................................................................... 22 
30 Consent Process ............................................................................................................. 22 
31 Process to Document Consent in Writing ........................................................................ 22 
32 Drugs or Devices ........................................................................................................... 23 
32.1 Denosumab (Prolia®).................................................................................................. 23 
32.2 Active Substance and Source ....................................................................................... 23 
32.3 Drug Shipment ............................................................................................................ 23 
32.4 Preparation for Administration..................................................................................... 23 
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32.5 Storage and Stability ................................................................................................... 23 
33 References ..................................................................................................................... 24 
34 Appendices .................................................................................................................... 25 
 
 
 
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1. OBJECTIVES 
1.1 
Primary Objective 
• To evaluate the efficacy and safety of denosumab therapy for the treatment of bone loss in 
patients who have received an allogeneic hematopoietic stem cell transplant. 
2 
BACKGROUND 
2.1 
Bone Health in Hematopoietic Stem Cell Transplant 
Allogeneic Hematopoietic Stem Cell Transplant (HSCT) is a curative treatment of hematologic 
malignancies but can have varying effects on quality of life due to complications. 1Amongst 
survivorship monitoring in these patients bone mineral density (BMD) by dual-energy x-ray 
absorptiometry (DXA) scan is commonly monitored due to accelerated bone loss from the effects 
of previous chemotherapy, the HSCT, and/or administration of steroids. Previous research has 
shown on average a patient undergoing HSCT can expect to have a decrease in BMD by 3.5% to 
8.5% correlating with 7 to 17 years of bone loss with in a 4-month time frame after HSCT. 
2Furthermore, accelerated bone loss exponentially increases the risk of a fracture with 10% to 15% 
of bone loss correlated to a doubling of the fracture risk regardless of osteopenia/osteoporosis 
status. This is leading to direct and indirect increases in treatment costs as well as a hindrance to 
the quality of life of post-HSCT patients. 3 
Currently, bisphosphonate therapy including zoledronic acid infusions have shown benefit in 
slowing and even reversing the effects of bone loss in HSCT patients but can be associated with 
adverse effects, including infusion reactions associated with fevers and flu-like symptoms, which 
can lead to unsubstantiated evaluation and treatment of infection, decreased compliance, and 
even discontinuation. 4Denosumab is a receptor activator of nuclear factor kappa-B ligand 
(RANKL) inhibitor which is also currently approved for treatment of osteoporosis and is less 
likely to be associated with the same injection reactions as zoledronic acid 
(http://www.pi.amgen.com/~/media/amgen/repositorysites/pi-amgen-com/prolia/prolia_pi.ashx). 
Currently, there has been minimal data produced on the efficacy and safety of denosumab in 
HSCT patients. To address this lack of published data, Roswell Park and Cleveland Clinic are 
proposing a joint phase 2 study to evaluate the utility of denosumab in post-allogeneic HSCT 
patients. 
2.2 
Denosumab  
Denosumab is a fully human monoclonal antibody with high affinity and specificity to RANK 
Ligand (RANKL) leading to decreased activation. Denosumab has high specificity to RANKL 
while being devoid of activity towards other members of the tumor necrosis factor (TNF) family 
including TNFα, TNFβ, TNF-related apoptosis-inducing ligand (TRAIL), or CD40 ligand. Down 
regulation of RANKL caused by denosumab decreases bone resorption by indirect inhibition of 
osteoclast formation, leading to an increase in bone mass and strength. 
Currently, denosumab is approved in the United States (US) for treatment of osteoporosis in 
postmenopausal women as well as men at increased or high risk for fracture, bone loss due to 
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hormone-ablation therapy in men with prostate cancer as well as women with breast cancer at 
high risk for fracture. 
A detailed discussion of the preclinical pharmacology, pharmacokinetics, and toxicology of 
denosumab can be found in the Investigator’s Brochure. 
2.2.1 Mechanism of Action 
Denosumab Binds to RANKL, a transmembrane or soluble protein essential for the formation, 
function, and survival of osteoclasts, the cells responsible for bone resorption. Prolia prevents 
RANKL from activating its receptor, RANK, on the surface of osteoclasts and their precursors.  
Prevention of the RANKL/ RANK interaction inhibits osteoclast formation, function, and survival, 
thereby decreasing bone resorption and increasing bone mass and strength in both cortical and 
trabecular bone.  
2.2.2 Preclinical Pharmacology and Pharmacokinetics 
Onset of action: Decreases markers of bone resorption by ~85% within 3 days; maximal reduction 
observed within 1 month. 
Duration: Markers of bone resorption return to baseline within 12 months of discontinuing therapy2 
Bioavailability: SubQ: 62% 
Half-life elimination: ~25 to 28 days 
Time to peak: 10 days (range 3 to 21) 
Elimination: Clearance may occur via reticuloendothelial system; renal excretion not expected 
2.2.3 Toxicology/ Interactions 
No preclinical drug-drug interactions were studied using Denosumab. 
In ovariectomized monkeys, once-monthly treatment with Denosumab suppressed bone turnover 
and increased bone mineral density and strength of cancellous and cortical bone at doses 50-fold 
higher than the recommended human dose of 60 mg administered once every 6 months, based on 
body weight. Bone tissue was normal with no evidence of mineralization defects, accumulation of 
osteoid or woven bone. 
Adolescent primates treated with Denosumab at doses >10 times higher than the recommended 
human dose of 60 mg administered once every 6 months, based on mg/ kg, had abnormal growth 
plates, considered to be consistent with the pharmacological activity of Denosumab. 
RANK/ RANKL knockout mice exhibited absence of lymph node formation, as well as an absence 
of lactation due to inhibition of mammary gland maturation. Neonatal RANK/ RANKL knockout 
mice exhibited reduced bone growth and lack of tooth eruption. A corroborative study in 2-week-
old rats given the RANKL inhibitor also showed reduced bone growth, altered growth plates, and 
impaired tooth eruption. 
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2.3 
Clinical Studies with Denosumab 
2.3.1 Osteoporosis in Postmenopausal Women at High Risk for Fracture 
A 3-year, randomized, double-blind, placebo-controlled trial enrolled postmenopausal women 
with baseline BMD T-scores between -2.5 and -4.0 at either the lumbar spine or total hip: 
A total of 7808 woman were enrolled with a mean age of 72 years and either received denosumab 
60 mg (n=3902) or placebo (n=3906) every 6 months along with 1000 mg calcium and 400 IU 
vitamin D daily. The primary efficacy variable was incidence of vertebral fracture after 3 years. 
The incidence of new vertebral fractures was clinically significant (P < 0.0001) between the 
placebo group (7.2%) compared to the denosumab group (2.3%) over the 3-year period. This 
produced an absolute risk reduction of 4.8% and a relative risk reduction of 68%. A secondary 
outcome of the study was incidence of hip fractures which was clinically significant (P=0.04) as 
well between the placebo group (1.2%) compared to the denosumab group (0.7%) after 3 years. 
This produced an absolute risk reduction of 0.3% and a relative risk reduction of 40%.  
2.3.2 Osteoporosis in Men at High Risk for Fracture 
A 1-year, randomized, double-blind, placebo-controlled trial enrolled men with baseline BMD T-
scores between -2.0 and -3.5 as well as men with previous fractures with BMD T-scores between 
-1.0 and -3.5 at the lumbar spine or femoral neck: 
A total of 242 men were enrolled with a mean age of 65 years and either received denosumab 60 
mg (n=121) or placebo (n=121) every 6 months along with 1000 mg calcium and 400 IU vitamin 
D daily. The primary efficacy variable was percentage change in the BMD of the lumbar spine, 
total hip, and femora neck from baseline to 1 year. The treatment differences were 4.8% [(+0.9% 
placebo, +5.7% denosumab (95% CI 4.0, 5.6), p< 0.0001)] at lumbar spine, 2% (+0.3% placebo, 
+2.4% denosumab) at the hip, and 2.2% (0.0% placebo, +2.1% denosumab) at femoral neck.  
2.3.3 Treatment of Bone Loss in Men with Prostate Cancer 
A 3-year, randomized, double-blind, placebo-controlled, multinational study: 
The trial enrolled men < 70 years of age with baseline BMD T-scores between -1.0 and -4.0 at the 
lumbar spine, total hip or femoral neck, or had a history of osteoporotic fracture. A total of 1468 
men were enrolled with a median age of 76 years (Range: 48 to 97 years) and either received 
denosumab 60 mg (n=734) or placebo (n=734) every 6 months for a total of 6 doses along with 
1000 mg calcium and 400 IU vitamin D daily. The primary efficacy variable was percentage 
change in the BMD of the lumbar spine from baseline to 2 years. The treatment differences were 
6.7% (-1.0% placebo, +5.6% denosumab; (95% CI 6.2, 7.1); p< 0.0001) 
2.3.4 Treatment of Bone Loss in Women with Breast Cancer 
A 2-year, randomized, double-blind, placebo-controlled, multinational study: 
The trial enrolled women with baseline BMD T-scores between -1.0 and -2.5 at the lumbar spine, 
total hip or femoral neck, and had not experienced a fracture after age 25. A total of 252 women 
were enrolled with a median age of 59 years (Range: 35 to 84 years) and either received denosumab 
60 mg (n=127) or placebo (n=125) every 6 months for a total of 4 doses along with 1000 mg 
calcium and 400 IU vitamin D daily. The primary efficacy variable was percentage change in the 
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BMD of the lumbar spine from baseline to 1 year. The treatment differences were 5.5% [(-0.7% 
placebo, +5.5% denosumab, (95% CI 4.8, 6.3); p< 0.0001)].  
2.4 
Rationale 
Fractures due to bone loss in HSCT patients have been shown to have an enormous effect on 
patient satisfaction and quality of life. Denosumab has been proven to not only decrease the rate 
of bone loss but also reverse the effects in both cancer patients as well as the general public. This 
study intends to prove that denosumab is a viable option to prevent HSCT-associated bone loss 
thus decreasing the risk of fractures in this patient population. This study is intended to evaluate 
these effects in all patients with any statistically bone loss from the pre-transplant DXA to the post-
transplant DXA and/or osteopenia/osteoporosis at any DXA (pre or post-transplant). 
3 
INCLUSION AND EXCLUSION CRITERIA 
3.1 
Inclusion Criteria 
To be included in this study, participants must meet the following criteria: 
1. The patient is ≥ 18 years. 
2. The patient has undergone an Allogeneic Hematopoietic Stem Cell Transplant. 
3. The patient has completed a base line DXA scan ≤ 6 months prior to transplantation. 
4. The patient has completed a post-transplant DXA scan at Day 100 (±30 days) or up to 6 
months post transplantation. 
5. The patient has completed and passed a dental clearance exam up to 6 months prior to 
transplant or 6 months after transplant. 
6. Participants of child-bearing potential must agree to use adequate contraceptive methods 
(e.g., hormonal or barrier method of birth control; abstinence) prior to study entry. Should 
a woman become pregnant or suspect she is pregnant while she or her partner is 
participating in this study, she should inform her treating physician immediately. 
7. Participant must understand the investigational nature of this study and sign an Independent 
Ethics Committee/Institutional Review Board approved written informed consent form 
prior to receiving any study related procedure. 
Refer to Appendix A for the ELIGIBILITY VERIFICATION FORM: INCLUSION CRITERIA 
checklist. 
3.2 
Exclusion Criteria 
Participants will be excluded from this study for the following: 
1. The patient has a history of a hypersensitivity reaction to denosumab. 
2. The patient has a history of osteonecrosis of the jaw. 
3. The patient has predisposing risk factors for hypocalcemia including the following: 
a. Hypoparathyroidism 
b. CrCl < 30 mL/min 
c. Dialysis 
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d. Malabsorption Syndrome 
4. The patient has history of any bone fracture ≤ 30 days prior to denosumab therapy. 
5. Pregnant or nursing female patients. 
6. The patient has clinically significant GVHD leading to hospitalization at the time of 
denosumab dose per prescriber discretion. 
7. The patient has clinically significant infection leading to hospitalization at the time of 
denosumab dose (excluding hospitalization due to complexity of treatment leading to 
inability to treat outpatient, i.e., Foscarnet) per prescriber discretion. 
8. The patient is unwilling or unable to follow protocol requirements. 
9. The patient has any condition which in the Investigator’s opinion deems the participant an 
unsuitable candidate to receive study drug including relapsed malignancy. 
Refer to Appendix B for the ELIGIBILITY VERIFICATION FORM: EXCLUSION 
CRITERIA checklist. 
3.3 
Special Populations 
The following special populations are excluded from this study: 
• Cognitively impaired adults/adults with impaired decision-making capacity 
• Individuals who are not yet adults (infants, children, teenagers) 
• Prisoners 
• Pregnant women 
3.4 
Inclusion of Women and Minorities 
Both men and women and members of all races and ethnic groups are eligible for this study. 
4 
LOCAL AND STUDY-WIDE NUMBER OF SUBJECTS 
A target of 114 participants (a maximum of 150 participants and a minimum of 100 evaluable 
participants) at multiple sites, including Roswell Park, will be enrolled over a 3.6-year period with 
enrollment to conclude by August 2022. 
5 
LOCAL AND STUDY-WIDE RECRUITMENT METHODS 
Participants will be identified/recruited/screened from patients at the BMT clinic at Roswell Park 
and participating sites and from multi-disciplinary conference discussion. 
6 
MULTI-SITE RESEARCH 
Two centers will be enrolling in this study in parallel single-center studies. The data will be jointly 
analyzed from Roswell Park Cancer Institute and the Cleveland Clinic. 
This is a multi-site study. It is the responsibility of the lead investigator to ensure that: 
• All sites have the most current version of the protocol, consent document, and HIPAA 
authorization. 
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• All required approvals (initial, continuing review and modifications) have been obtained 
at each site (including approval by the site’s IRB of record). 
• All modifications have been communicated to sites and approved (including approval by 
the site’s IRB of record) before the modification is implemented. 
• All engaged participating sites will safeguard data, including secure transmission of data, 
as required by local information security policies. 
• All local site investigators will conduct the study in accordance with applicable federal 
regulations and local laws. 
• All non-compliance with the study protocol or applicable requirements will be reported in 
accordance with local policy. 
Refer to: Instructions for Multi-Site Studies (Appendix F) for additional details. 
7 
STUDY TIMELINES 
A maximum of 150 participants, at multiple sites including Roswell Park, will be enrolled. Accrual 
is expected to take up to 3.6 years with enrollment to conclude by August 2022, with follow-up 
for 12 months from the start of investigational treatment. We will attempt to enroll 75 patients at 
Roswell Park and 75 patients at the Cleveland Clinic with a goal of 57 evaluable patients at each 
site for a total of 114 evaluable patients. In the event that one site reaches that site’s expected 
accrual number goal before the other site’s goal is met, the site that has reached the site expected 
accrual may continue to enroll patients in order to contribute to the overall accrual goal. 
Patient’s participation in the study will be initiated with enrollment and last for approximately 365 
days with completion of “Day 465” DXA Scan. 
Patients will be given a maximum of two (2) subcutaneous doses of denosumab 60 mg during the 
study time frame.  
The time frame to enroll all patients will take up to 3.6 calendar years from the initiation of the 
study with enrollment to conclude by August 2022, and completion of data collection will take 
365 days from the final patient enrolled. We estimate preliminary analyses will be completed 2 
years after the completion of the study accrual. 
8 
STUDY ENDPOINTS 
8.1 
Primary Endpoint(s) 
• The primary endpoint will be BMD on “Day 465” DXA Scans (Appendix E) in 
comparison to “Day 100” DXA scans based on the percent change in BMD (g/cm 2) in the 
Total hip and/or lumbar spine between the two time points. Stabilization of BMD will be 
defined as a Least Significant Change (LSC) in BMD from “Day 100” DXA to “Day 465” 
DXA while improvement will be defined as any increase in BMD from “Day 100” DXA 
to “Day 465” DXA. 
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8.2 
Secondary Endpoints 
Secondary endpoints include: 
• Percent change in BMD between the pre-HSCT and the Day 465 DXA scans for Total hip 
and/or lumbar spine (L1-L4) 
• Frequency of bone fractures  
• Frequency of adverse effects of denosumab (see section 17) including but not limited to 
the following: 
o Injection/Hypersensitivity related reactions 
o Osteonecrosis of the jaw 
o Graft Versus Host Disease 
9 
DESIGN 
This is a Phase II, multicenter, single-arm, open-label study designed to evaluate the efficacy and 
safety of denosumab therapy for the treatment of BMD loss in allogeneic HSCT patients. Eligible 
patients must have been treated with an allogeneic HSCT and at the “Day +100” DXA scan must 
have decrease in BMD compared to the pre-transplant DXA scan, or have osteopenia, and/or 
osteoporosis on either the pre-HSCT or Day +100 (up to 6 months) post-HSCT DXA scan. 
This is a Phase II multicenter, single-arm, open-label study where all patients who meet inclusion 
criteria will receive the study drug (denosumab). All patients will be followed for about 1 year 
after the first dose of denosumab and/or a minimum of 15 months post HSC infusion (Day 0). A 
total of 150 patients will be accrued. Assuming 80% complete the follow-up period, 114 patients 
should be evaluable for the primary endpoint. Patients with a Day +100 and Day +465 DXA scans, 
and who received at least one dose of denosumab, will be considered evaluable for 
response/efficacy. Response/Efficacy will be based on stabilization and/or improvement of BMD 
(defined in Section 8.1). Patients who received at least one dose of denosumab will be evaluable 
for safety. 
10 TREATMENT 
Reported adverse events (AEs) and potential risks are described in Section 13. Appropriate dose 
modifications are described in Section 10.2. 
Treatment is intended for an outpatient setting. However, at the investigator’s/physician’s 
discretion, the participant may receive treatment as an inpatient, if deemed necessary. 
10.1 Dosing and Administration 
Denosumab 
• Dose: 60 mg prefilled syringe 
• Administration Route: Subcutaneous Injection (See Appendix D) 
o All subjects will receive one subcutaneous (SC) injection administered in the 
subject’s upper arm, upper thigh, or abdomen by an experienced and qualified staff 
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member. It is recommended that all subjects be closely observed for approximately 
30 minutes after 1st dosing with IP. 
o Patients are to be evaluated for hypocalcemia (corrected calcium < 8.4 mg/dL 
and/or ionized calcium < 1.19 mmol/L) prior to administration(See Appendix C)  
and this should be corrected prior to administration of denosumab. 
• Frequency: Every 6 months for a maximum of 2 doses  
o Dose #1: Receive between Day 70 and Day 130 
o Patients should be monitored for a minimum of 30 minutes after their 1 st dose due 
to risk of hypersensitivity reactions 
o Dose #2: Receive between Day 250 and Day 310 
10.2 Dose Modifications and Treatment Delays 
This medication is commercially available, and all treatment delays should be determined as 
specified from the treating clinician. There will be no dose modifications based on the product 
being only commercially available as a prefilled syringe.  
(https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125320s181lbl.pdf ) 
10.3 General Concomitant Medication and Supportive Care 
Participants should not be given any concomitant bone strengthening agents including 
bisphosphonates. 
Administration of calcium and vitamin D as necessary to treat or prevent hypocalcemia will be per 
the physician’s discretion. 
10.4 Duration of Treatment 
Participants may remain on study and receive the two (2) doses of denosumab in the absence of 
disease progression, unacceptable toxicity or withdrawal from study, inter-current illness that 
prevents further administration of treatment, participant demonstrates an inability/refusal to 
comply with medication regime and, participant withdraws from study or as per discretion of the 
providing clinician.   
10.5 Off-Study Treatment 
At the discretion of the treating physician, patients may continue to be treated with any available 
agent once they are off study treatment. 
11 PROCEDURES INVOLVED 
The study-specific assessments are detailed in this section and outlined in Appendix C: Schedule 
of Procedures and Observations. 
Baseline and/or Screening assessments must be performed within 14 days prior to the first dose of 
investigational product, unless otherwise indicated. Any results falling outside of the reference 
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ranges may be repeated at the discretion of the investigator. All on-study visit procedures are 
allowed a window of ± 30 days unless otherwise noted. 
11.1 Participant Registration 
Eligibility of each participant will be established prior to study enrollment. 
Informed consent MUST be completed prior to receiving any study related procedures. 
11.2 Correlative Studies 
BMD studies by DXA scan will be performed on patients prior to HSCT as well as Day 100 
± 30 days (up to 6 months) (both as part of BMT standard of care) and Day 465(± 60 days) post 
HSCT. These studies will include BMD (g/cm2), T-score (standard deviations), and change from 
baseline (%). 
12 WITHDRAWAL OF SUBJECTS 
12.1 Treatment Discontinuation 
Upon treatment discontinuation all end of treatment evaluations and tests will be conducted. All 
participants who discontinue due to an AE must be followed until the event resolves or stabilizes. 
Appropriate medical care should be provided until signs and symptoms have abated, stabilized, or 
until abnormal laboratory findings have returned to acceptable or pre-study limits. The final status 
of the AE will be reported in the participant’s medical records and the appropriate eCRF. 
Reasons for treatment discontinuation should be classified as follows: 
• Death 
• Progressive disease (Per Physician Discretion) 
• Toxicity: treatment related or unrelated 
• Hypersensitivity Reaction 
• Osteonecrosis of the Jaw 
• Any bone fracture 
• Investigator judgment 
o The Investigator may discontinue a participant if, in his/her judgment, it is in the 
best interest of the participant to do so. 
• Noncompliance 
• Participant voluntary withdrawal 
o A participant may withdraw from the study at any time, for any reason. If a 
participant discontinues treatment, an attempt should be made to obtain information 
regarding the reason for withdrawal. 
• Sponsor decision. 
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13 RISKS TO SUBJECTS 
Most common adverse reactions reported for denosumab for the following indications: 
• Postmenopausal osteoporosis: Most common adverse reactions (> 5% and more common 
than placebo) were: back pain, pain in extremity, hypercholesterolemia, musculoskeletal 
pain, and cystitis. Pancreatitis has been reported in clinical trials. 
• Male osteoporosis: Most common adverse reactions (> 5% and more common than 
placebo) were: back pain, arthralgia, and nasopharyngitis. 
• Bone loss due to hormone ablation for cancer: Most common adverse reactions (≥ 10% 
and more common than placebo) were: arthralgia and back pain. Pain in extremity and 
musculoskeletal pain have also been reported in clinical trials. 
14 POTENTIAL BENEFITS TO SUBJECTS 
Patients may have stabilization and/or improvement of bone mineral density after administration 
of denosumab. This may decrease the risk of future adverse events associated with bone loss after 
transplantation including fractures. 
15 DATA AND SPECIMEN BANKING 
Not Applicable. 
16 MEASUREMENT OF EFFECT 
16.1 Bone Density Status 
Bone Density Status: “Day 465” DXA scans [(465 days ± 60 days from transplantation (Day 0)] 
obtained in comparison to Day +100 ± 30 days (up to 6 months from transplantation) DXA scans 
based on percent change in Bone Mineral Density in both the Total Hip and lumbar spine (L1-L4). 
16.2 Other Response Parameters 
Patients will also be evaluated based on percentage change in BMD (g/cm2) from pre-HSCT to 
Day 465 post-HSCT. 
17 SAFETY EVALUATION 
17.1 Adverse Events 
Only grade 3 or greater adverse events will be captured, with an exception for events of special 
interest. All grades of events of special interest will be captured and reported to Amgen. Events of 
special interest include:  pregnancy, lactation, fractures, and osteonecrosis of the jaw and infusion 
reactions (study drug only). 
An AE is considered “unexpected” if it is not listed in the investigator brochure or is not listed at 
the specificity or severity that has been observed. 
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17.1.1 Diagnosis Versus Signs and Symptoms 
If known, a diagnosis should be recorded on the CRF rather than individual signs and symptoms 
(e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases). However, if a constellation of signs and/or symptoms cannot be clinically 
characterized as a single diagnosis or syndrome at the time of reporting, each individual event 
should be recorded as an AE or SAE on the CRF. If a diagnosis is subsequently established, it 
should be reported as follow-up information. 
17.1.2 Adverse Events Occurring Secondary to Other Events 
In general, AEs occurring secondary to other events (e.g., cascade events or clinical sequelae) 
should be identified by their primary cause. For example, if severe diarrhea is known to have 
resulted in dehydration, it is sufficient to record only diarrhea as an AE or SAE on the CRF.  
However, clinically significant AEs occurring secondary to an initiating event that are separated 
in time should be recorded as independent events on the CRF. For example, if a severe 
gastrointestinal hemorrhage leads to renal failure, both events should be recorded separately on 
the CRF. 
17.1.3 Abnormal Laboratory Values 
Only clinically significant (Grade 3-5)  laboratory abnormalities that do not predate the 1st infusion 
of the investigational agent,  that require active management will be recorded as AEs or SAEs on 
the CRF (e.g., abnormalities that require study drug dose modification, discontinuation of study 
treatment, more frequent follow-up assessments, further diagnostic investigation, etc.). 
If the clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., alkaline 
phosphatase and bilirubin 5 x the upper limit of normal associated with cholecystitis), only the 
diagnosis (e.g., cholecystitis) needs to be recorded on the Adverse Event CRF. 
If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded as an AE or SAE on the CRF. If the laboratory abnormality 
can be characterized by a precise clinical term, the clinical term should be recorded as the AE or 
SAE. For example, an elevated blood potassium level of 7 mEq/L should be recorded as 
“hyperkalemia”. 
Observations of the same clinically significant laboratory abnormality from visit to visit should 
not be repeatedly recorded as AEs or SAEs on the CRF, unless their severity, seriousness, or 
etiology changes. 
17.1.4 Preexisting Medical Conditions (Baseline Conditions) 
A preexisting medical condition should be recorded as an AE or SAE only if the frequency, 
severity, or character of the condition worsens during the study. When recording such events on 
an Adverse Event CRF, it is important to convey the concept that the preexisting condition has 
changed by including applicable descriptors (e.g., “more frequent headaches”). 
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17.2  Grading and Reporting Adverse Events 
17.2.1 Grading and Relationship to Drug 
The descriptions and grading scales found in the CTEP Version 5 of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) will be utilized for AE reporting. CTEP 
Version 5 of the CTCAE is identified and located at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
AEs not covered by specific terminology listed should be reported with common medical 
terminology and documented according to the grading scales provided in the CTCAE Version 5. 
The relationship of event to study drug will be documented by the Investigator as follows: 
• Unrelated: The event is clearly related to other factors such as the participant’s clinical 
state, other therapeutic interventions or concomitant drugs administered to the participant. 
• Unlikely: The event is doubtfully related to investigational agent(s). The event was most 
likely related to other factors such as the participant’s clinical state, other therapeutic 
interventions, or concomitant drugs. 
• Probable: The event follows a reasonable temporal sequence from the time of drug 
administration and follows a known response pattern to the study drug. The event cannot 
be reasonably explained by other factors such as the participant’s clinical state, therapeutic 
interventions or concomitant drugs. 
• Definite: The event follows a reasonable temporal sequence from the time of drug 
administration, follows a known response pattern to the study drug, cannot be reasonably 
explained by other factors such as the participant’s condition, therapeutic interventions or 
concomitant drugs; AND occurs immediately following study drug administration, 
improves upon stopping the drug, or reappears on re-exposure. 
17.3 Reporting Adverse Events 
Significant AEs (grade 3-5) which are new and considered probable or definite in relation to the 
investigational agent that are occurring between the start date of intervention until 30 days after 
the last intervention, or until the event has resolved, the study participant is lost to follow-up, the 
start of a new treatment, or until the study investigator assesses the event(s) as stable or irreversible, 
will be reported. New information will be reported after it is received. 
17.4 Serious Adverse Events 
A serious adverse event (SAE) is any adverse event (experience) that in the opinion of either the 
investigator or sponsor is probable or definite in relation to the investigational agent and results in 
ANY of the following: 
• Death. 
• A life-threatening adverse event (experience). Any AE that places a participant or 
participants, in the view of the Investigator or sponsor, at immediate risk of death from the 
reaction as it occurred. It does NOT include an AE that, had it occurred in a more severe 
form, might have caused death. 
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• Inpatient hospitalization or prolongation of existing hospitalization (for > 24 hours). 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
• A congenital anomaly or birth defect. 
• Important Medical Event (IME) that, based upon medical judgment, may jeopardize the 
participant and may require medical or surgical intervention to prevent one of the outcomes 
listed above. 
17.4.1 Reporting Serious Adverse Events 
All new SAEs meeting the above definition occurring from the date the participant signs consent 
for the investigational study until 30 days after the last intervention or a new treatment is started, 
whichever comes first, will be reported. The Roswell Park SAE Source Form is to be completed 
with all available information, including a brief narrative describing the SAE and any other 
relevant information.  
SAEs occurring after the 30-day follow-up period that the investigator determines to be possibly, 
probably or definitely related to the study intervention should be reported. 
SAEs as unexpected and possibly, probably, or definitely related must be reported as an 
Unanticipated Problem. Please refer to Section 17.7.1 for details on reporting Unanticipated 
Problems. 
17.5 Investigator Reporting: Notifying the Study Sponsor 
Investigators MUST report (within 1 business day upon becoming aware), to the sponsor ANY 
Serious Adverse Events that are considered probable or definite in relation to the investigational 
agent(s)/intervention. 
17.6 Follow-Up for Serious Adverse Events 
All related SAEs should be followed to their resolution, until the study participant is lost to 
follow-up, the start of a new treatment, or until the study investigator assesses the event(s) as stable 
or irreversible. New information will be reported when it is received. 
17.7 Unanticipated Problems 
An Unanticipated Problem (UP) is any incident, experience, or outcome that meets all of the 
following criteria: 
• Unexpected (in terms of nature, severity, or frequency) given: 
o The research procedures that are described in the study-related documents, including 
study deviations, as well as issues related to compromise of participant privacy or 
confidentiality of data. 
o The characteristics of the participant population being studied. 
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• Related or possibly related to participation in the research (possibly related means there is 
a reasonable possibility that the incident, experience, or outcome may have been caused by 
the procedures involved in the research). 
• Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized or if in relation to an AE is deemed Serious per Section 17.3. 
17.7.1 Reporting Unanticipated Problems: 
The Reportable New Information (RNI) Form will be submitted to the CRS Quality Assurance 
(QA) Office within 1 business day of becoming aware of the Unanticipated Problem. After review, 
CRS QA Office will submit the RNI to the IRB. 
When becoming aware of new information about an Unanticipated Problem, submit the updated 
information to CRS QA Office with an updated Reportable New Information Form. The site 
Investigator or designated research personnel will report all unanticipated problems to the IRB in 
accordance with their local institutional guidelines. 
17.8 Amgen Safety Reporting 
Amgen Adverse Event Reporting Process: 
Safety Data 
Timeframe for submission to Amgen 
Suspected Unexpected Serious Adverse 
Reactions (SUSARs) 
Sent to Amgen at time of regulatory 
submission 
Pregnancy/Lactation 
Within 10 calendar days of Sponsor 
awareness 
Annual Safety Report 
(e.g., EU Clinical Trial Directive [CTD] 
DSUR, and US IND Annual Report) 
 
Annually 
Other Aggregate Analyses 
(any report containing safety data generated 
during the course of a study) 
 
Sent to Amgen at time of regulatory 
submission (e.g., FDA, IRB) 
Final (End of Study Report, including): 
• 
Reports of unauthorized use of a 
marketed product 
 
Sent to Amgen at time of regulatory 
submission (e.g., FDA, IRB) but not later 
than 1 calendar year of study completion 
17.9 FDA Reporting 
Roswell Park is not the IND holder and therefore this section is not applicable.  
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18 DATA MANAGEMENT AND CONFIDENTIALITY 
18.1 Data Collection 
Full build studies are managed by Roswell Park CRS Data Management for analysis by Roswell 
Park Biostatisticians. All electronic case report form (eCRF) data are captured for these studies. 
Data management activities are performed using a CTMS system that enables the collection, 
cleaning and viewing of clinical trial data. CRS Data Management designs the study-specific 
database and facilitates development by the Information Technology team. Once the database 
design is approved by the Investigator, Statistician, and Clinical Research Coordinator, the 
database is put into production and data entry can begin. Data can be entered and changed only by 
those with the rights to do so into the eCRFs. 
18.2 Maintenance of Study Documents 
Essential documents will be retained per Roswell Park’s policy for 6 years from the study 
termination date. These documents could be retained for a longer period, however, if required by 
the applicable local regulatory requirements or by an agreement with Roswell Park. 
18.3 Revisions to the Protocol 
Roswell Park may make such changes to the protocol as it deems necessary for safety reasons or 
as may be required by the U.S. FDA or other regulatory agencies. Revisions will be submitted to 
the IRB/ERC for written approval before implementation. 
18.4 Termination of the Study 
It is agreed that, for reasonable cause, either the Roswell Park Investigators or the Sponsor, may 
terminate this study, provided a written notice is submitted within the time period provided for in 
the Clinical Trial Agreement. In addition, Roswell Park may terminate the study at any time upon 
immediate notice if it believes termination is necessary for the safety of participants enrolled in 
the study. 
18.5 Confidentiality 
Any data, specimens, forms, reports, video recordings, and other records that leave the site will be 
identified only by a participant identification number (Participant ID, PID) to maintain 
confidentiality. All records will be kept in a limited access environment. All computer entry and 
networking programs will be done using PIDs only. Information will not be released without 
written authorization of the participant. 
19 STATISTICAL PLAN 
The primary objective is to show the effectiveness of denosumab on stabilization and/or 
improvement of BMD (defined in Section 8.1) in allogeneic HSCT patients who have experienced 
either BMD loss between baseline (pre-HSCT) and Day +100 (up to 6 months) post-HSCT, or 
who have osteopenia or osteoporosis at either the pre-BMT or Day+100 (up to 6 months) post-
HSCT DXA scan. DXA scans will be obtained at baseline (pre- HSCT), at time of enrollment (Day 
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+100, (up to 6 months) post- HSCT) and at Day +465 post- HSCT. The primary endpoint will be 
the slope in bone mineral density (g/cm2) regressed on time from the time of enrollment to Day 
465 post HSCT in both Total Hip and lumbar spine (average of L1-L4). 
The primary analysis for both the Total Hip and lumbar spine will consist of a regression model 
of the percent change from enrollment to Day 465 post HSCT regressed on the enrollment BMD 
levels, which is a more stable approach to modeling percent change type outcomes in terms of 
model assumptions. The analysis model will be fit using Ordinary Least Square (OLS) methods. 
A secondary model will include and expand upon a list of covariates to explore the effects of 
demographic, disease and treatment characteristics on BMD loss and effectiveness of denosumab 
using an analysis-of-covariance (ANCOVA) model. Examples of covariates to be tested are age, 
sex, corticosteroid exposure, and graft-versus-host disease. Given the assumed high degree of 
correlation between the Total Hip and lumbar spine percent change values, both models will be 
tested at alpha=0.05 (two-sided). Residual plots and other diagnostic methods will be used to 
evaluate compliance with model assumptions and goodness of fit. 
It is assumed under the null that the historical percent change in BMD from enrollment in the Total 
Hip is -6.3% and for the lumbar spine is -2.3%, which translates to testing in our regression model 
about the hypotheses 𝐻0: 𝛽1 = −0.063 vs 𝐻𝑎: 𝛽1 ≠−0.063 and 𝐻0: 𝛽1 = −0.023 vs 𝐻𝑎: 𝛽1 ≠
−0.023 for the Total Hip and lumbar spine, respectively. 
19.1 Sample Size Determination 
BMD will be reported in g/cm2. We are setting the sample size target to n=114 evaluable subjects 
assuming a 20% drop-out rate between enrollment and Day 465 post BMT. Setting power to 0.80 
we will be able to detect a regression coefficient for the Total Hip different from 𝛽1 = −0.063  of 
-0.050 or larger and we will be able to detect a regression coefficient for the lumber different from 
𝛽1 = −0.023 of -0.016 or larger, respectively, assuming a standard deviation for the Total Hip 
BMD percent change of 5% and a standard deviation for the lumber BMD percent change of 2.5%. 
19.2 Demographics and Baseline Characteristics 
Descriptive statistics (as appropriate: n, percent, mean, median, min and max) will be used to 
summarize demographic and baseline characteristics. 
19.3 Efficacy Analysis 
Objective BMD response will be tabulated overall. Only participants who have completed at least 
one dose of denosumab and both study DXA scans will be evaluable for response. 
19.4 Adverse Events 
The frequency of toxicities will be tabulated by grade. The frequency of toxicities will also be 
tabulated. All participants who receive at least one dose of denosumab will be evaluable for 
toxicity. 
19.5 Interim Analysis and Criteria for Early Termination of the Study 
No explicit interim analyses are planned for this study. 
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19.6 Correlative Data Analysis 
20 PROVISIONS TO MONITOR THE DATA TO ENSURE THE SAFETY OF 
SUBJECTS 
The Roswell Park Data and Safety Monitoring Committee will assess the progress of the study, 
the safety data, and critical efficacy endpoints. The DSMC will review the study and will make 
recommendations that include but not limited to: (a) continuation of the study, (b) modifications 
to the design, (c) suspension of, or (d) termination of the study. 
21 VULNERABLE POPULATIONS 
Not Applicable. 
22 COMMUNITY-BASED PARTICIPATORY RESEARCH 
Not Applicable. 
23 SHARING OF RESULTS WITH SUBJECTS 
Individual response data is shared with the participant as a part of their clinical care. 
24 SETTING 
All treatment will be conducted on an outpatient basis at BMT clinic at Roswell Park and the 
Cleveland Clinic. Potential study participants will be identified and recruited from current BMT 
clinic patients and from community referral. 
25 PROVISIONS TO PROTECT THE PRIVACY INTERESTS OF SUBJECTS 
Any data, specimens, forms, reports, video recordings, and other records that leave the site will be 
identified only by a participant identification number (Participant ID, PID) to maintain 
confidentiality. All records will be kept in a limited access environment. All computer entry and 
networking programs will be done using PIDs only. Information will not be released without 
written authorization of the participant. 
26 RESOURCES AVAILABLE 
Not Applicable. 
27 PRIOR APPROVALS 
Not Applicable. 
28 COMPENSATION FOR RESEARCH-RELATED INJURY 
If the subject believes they have been injured as a direct result of their participation in this research 
study, they will be advised to notify the Roswell Park Patient Advocate at (716) 845-1365 or the 
Study Doctor at (716) 845-8412. 
Medical diagnosis and treatment for the injury will be offered, and a determination will be made 
regarding appropriate billing for the diagnosis and treatment of the injury. A financial counselor 
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(716-845-3161) will be able to provide an explanation of coverage and to answer questions the 
subject may have regarding study related billing. 
The subject is not prevented from seeking to collect compensation for injury related to malpractice, 
fault, or blame on the part of those involved in the research. 
29 ECONOMIC BURDEN TO SUBJECTS 
The participants will not be subject to any economic burden. 
30 CONSENT PROCESS 
This study will not be initiated until the protocol and informed consent document(s) have been 
reviewed and approved by a properly constituted Institutional Review Board (IRB) or Independent 
Ethics Committee (IEC). Each participant (or legal guardian) shall read, understand, and sign an 
instrument of informed consent prior to performance of any study-specific procedure. It is the 
responsibility of the investigator to ensure that the participant is made aware of the investigational 
nature of the treatment and that informed consent is given. Consent and enrollment will occur after 
“Day 100” DXA is completed as this will be the main determination of eligibility of patients. 
The Investigator is responsible for the retention of the participant log and participant records; 
although personal information may be reviewed by authorized persons, that information will be 
treated as strictly confidential and will not be made publicly available. The investigator is also 
responsible for obtaining participant authorization to access medical records and other applicable 
study specific information according to Health Insurance Portability and Accountability Act 
(HIPAA) regulations (where applicable). 
This study will be conducted in compliance with all applicable laws and regulations of the state 
and/or country and institution where the participant is treated. The clinical trial should be 
conducted in accordance with the ethical principles embodied in the Belmont Report: Ethical 
Principles and Guidelines for the Protection of Human Subjects of Research, consistent with good 
clinical practice and the applicable regulatory requirements and according to the guidelines in this 
protocol, including attached appendices. 
31 PROCESS TO DOCUMENT CONSENT IN WRITING 
The Investigator (or IRB specified designee) is responsible for obtaining written consent from each 
participant in accordance with GCP guidelines using the approved informed consent form, before 
any study specific procedures (including screening procedures) are performed. The informed 
consent form acknowledges all information that must be given to the participant according to 
applicable GCP guidelines, including the purpose and nature of the study, the expected efficacy 
and possible side effects of the treatment(s), and specifying that refusal to participate will not 
influence further options for therapy. Any additional information that is applicable to the study 
must also be included. Additional national or institutionally mandated requirements for informed 
consent must also be adhered to. The participant should also be made aware that by signing the 
consent form, processing of sensitive clinical trial data and transfer to other countries for further 
processing is allowed. 
The Investigator or designee shall provide a copy of the signed consent form to the participant and 
the signed original shall be maintained in the Investigator File. A copy of the signed consent form 
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must be filed in the participant file. At any stage, the participant may withdraw from the study and 
such a decision will not affect any further treatment options. 
32 DRUGS OR DEVICES 
32.1 Denosumab (Prolia®) 
32.2 Active Substance and Source 
Denosumab is supplied in a single-use prefilled syringe (PFS) containing 60 mg in a 1 mL solution. 
Each PFS is intended for single use only. 
32.3 Drug Shipment 
Denosumab will be provided by Amgen and will be shipped by Amgen to each participating site. 
32.4 Preparation for Administration 
Denosumab needs to be visually inspected for discoloration or particulate matter as it should be a 
clear, colorless to pale yellow solution that may contain trace amounts of translucent to white 
particles. The solution should be discarded if discolored or cloudy or contains foreign particulates. 
Prior to administration denosumab may be removed from the refrigerator and brought to room 
temperature (up to 25°C/77°F) by standing in the original container for 15-30 minutes. Do not 
warm in any other way. 
Please refer to the Pharmacy Guide for additional details. 
32.5 Storage and Stability 
The Investigator or designate will be responsible for ensuring that the investigational product is 
securely maintained in a locked, limited-access facility and, in accordance with the applicable 
regulatory requirements. 
Store denosumab in a refrigerator at 2oC to 8oC in the original carton: Do not freeze. 
Prior to administration, denosumab may be allowed to reach room temperature (up to 25oC) in the 
original container. Once removed from the refrigerator, denosumab must not be exposed to 
temperatures above 25oC and must be used within24 hours, once at room temperature. If not used 
within 24 hours, denosumab should be discarded. Protect from direct light and heat. Avoid 
vigorous shaking of denosumab. 
Drug storage temperature will be maintained and recorded, as applicable. 
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33 REFERENCES 
1. 
Copelan EA. Hematopoietic stem-cell transplantation. N Engl J Med 2006;354:1813-26. 
2. 
Yao S, Smiley SL, West K, et al. Accelerated bone mineral density loss occurs with 
similar incidence and severity, but with different risk factors, after autologous versus allogeneic 
hematopoietic cell transplantation. Biology of blood and marrow transplantation : journal of the 
American Society for Blood and Marrow Transplantation 2010;16:1130-7. 
3. 
Faulkner KG. Bone matters: are density increases necessary to reduce fracture risk? 
Journal of bone and mineral research : the official journal of the American Society for Bone and 
Mineral Research 2000;15:183-7. 
4. 
Pundole X, Cheema HI, Petitto GS, Lopez-Olivo MA, Suarez-Almazor ME, Lu H. 
Prevention and treatment of bone loss and fractures in patients undergoing a hematopoietic stem 
cell transplant: a systematic review and meta-analysis. Bone marrow transplantation 
2017;52:663-70. 
 
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34 APPENDICES 
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Appendix A ELIGIBILITY VERIFICATION FORM: INCLUSION CRITERIA 
Participant Name: (Multi-site: use participant initials): ___________________________ 
Medical Record No.: (Multi-site: use participant IDs): _____________________________ 
Title: A Phase II, Open-Label, Multicenter Trial to Evaluate the Efficacy and Safety of 
Denosumab in Treatment of Post-Allogenic Hematopoietic Stem Cell Transplant Bone Loss 
INCLUSION CRITERIA 
Yes 
No 
N/A 
All answers must be “Yes” or “N/A” for participant enrollment. 
Date 
 
 
 
1. The patient is ≥ 18 years. 
 
 
 
 
2. The patient has undergone an Allogeneic Hematopoietic Stem Cell 
Transplant. 
 
 
 
 
3. The patient has completed a base line DXA scan ≤ 6 months prior 
to transplantation.  
 
 
 
 
4. The patient has completed a post-transplant DXA scan at Day 100 
(± 30 days) or up to 6 months post transplantation. 
 
 
 
 
5. The patient has completed and passed a dental clearance exam up 
to 6 months prior to transplant or 6 months after transplant. 
 
 
 
 
6. Participants of child-bearing potential must agree to use adequate 
contraceptive methods (e.g., hormonal or barrier method of birth 
control; abstinence) prior to study entry. Should a woman become 
pregnant or suspect she is pregnant while she or her partner is 
participating in this study, she should inform her treating physician 
immediately. 
 
 
 
 
7. Participant must understand the investigational nature of this study 
and sign an Independent Ethics Committee/Institutional Review 
Board approved written informed consent form prior to receiving 
any study related procedure. 
 
Investigator Signature: ________________________________Date: ___________ 
Printed Name of Investigator: __________________________________________ 
 
 
 
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Appendix B ELIGIBILITY VERIFICATION FORM: EXCLUSION CRITERIA 
Participant Name: (Multi-site: use participant initials): ___________________________ 
Medical Record No.: (Multi-site: use participant IDs): _____________________________ 
Title: A Phase II, Open-Label, Multicenter Trial to Evaluate the Efficacy and Safety of 
Denosumab in Treatment of Post-Allogenic Hematopoietic Stem Cell Transplant Bone Loss 
EXCLUSION CRITERIA 
Yes 
No 
N/A 
All answers must be “No” or “N/A” for participant enrollment. 
Date 
 
 
 
1. The patient has a history of a hypersensitivity reaction to 
denosumab. 
 
 
 
 
2. The patient has a history of osteonecrosis of the jaw. 
 
 
 
 
3. The patient has predisposing risk factors for hypocalcemia 
including the following: 
a. 
Hypoparathyroidism 
b. 
CrCl < 30 mL/min 
c. 
Dialysis 
d. 
Malabsorption Syndrome. 
 
 
 
 
4. The patient has history of any bone fracture ≤ 30 days prior to 
denosumab therapy. 
 
 
 
 
5. Pregnant or nursing female participants. 
 
 
 
 
6. The patient has clinically significant GVHD leading to 
hospitalization at the time of denosumab dose per prescriber 
discretion. 
 
 
 
 
7. The patient has clinically significant infection leading to 
hospitalization at the time of denosumab dose (excluding 
hospitalization due to complexity of treatment leading to inability 
to treat outpatient (i.e. Foscarnet)) per prescriber discretion. 
 
 
 
 
8. The patient is unwilling or unable to follow protocol requirements. 
 
 
 
 
9. The patient has any condition which in the Investigator’s opinion 
deems the participant an unsuitable candidate to receive study 
drug. 
 
Participant meets all entry criteria: 
 
  Yes 
  No 
If “NO”, do not enroll participant in study. 
Investigator Signature: ________________________________ Date: __________ 
Printed Name of Investigator: ___________________________________________ 
 
 
 
 
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Appendix C Schedule of Procedures and Observations 
Evaluation 
Baseline 
(Pre-Transplant 
Evaluation) 
Cycle 1- 
Day 100 
(± 30 days) 
Cycle 2- 
Day 280 
(± 30 days) 
End of 
Treatment: 
Day 
465(± 60 days) 
Follow-
Up2 
Patient Consent 
 
X 
 
 
 
Medical History 
X 
 
 
 
X 
Pre-Existing 
Conditions 
X 
 
 
 
 
Physical Examination 
(including vital signs3) 
X 
 
 
 
X 
Chemistry4 
X 
X1 
X1 
 
 
ECOG Performance 
Status 
X 
 
 
 
 
Dental Clearance5 
X 
X 
 
 
 
DXA Scan 
X 
X6 
 
X 
 
Denosumab 
 
X 
X 
 
 
Concomitant7 
Medications 
 
X 
X 
 
 
Adverse Events 
 
X 
X 
X 
 
Off-Study Treatment 
 
 
 
 
X8 
1. 
Performed day of treatment prior to denosumab administration to evaluate for hypocalcemia. 
2. 
Follow-up safety evaluations will occur 6 months after discontinuation of study medication for evaluation of 
vertebral/femoral fractures. 
3. 
Vital signs: temperature, heart rate, respiratory rate, blood pressure, body weight, and height. Height 
collected at baseline only. 
4. 
Chemistry (CMP): chloride, CO2, potassium, sodium, BUN, glucose, calcium, creatinine, total protein, 
albumin, total bilirubin, alkaline phosphatase, AST, ALT, A/G ratio, BUN/creatinine ratio, osmol (Calc), 
anion gap). 
5. 
The dental clearance exam is either up to 6 months prior to transplant or 6 months after transplant. 
6. 
The post-transplant DXA scan (Day 100) may be up to 6 months after transplant. 
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7. 
Only pertains to vitamin D, calcium (as necessary to treat or prevent hypocalcemia, per physician’s’ 
discretion), any other bone strengtheners (if so, which one(s)), or for the treatment of an adverse drug 
reaction.  See Section 10.3. 
8. 
 At the discretion of the treating physician, patient may continue to be treated with any available agent once 
they are off study treatment, when clinically necessary.  At the discretion of the treating physician, patient 
may continue to be treated with any available bone strengthening agent after the end of treatment DXA Scan, 
as clinically necessary. Subsequent bone strengtheners taken during the follow-up period will be captured as 
concomitant medications. 
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Appendix D Prefilled Syringe Instructions 
 
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Appendix E X-Ray Bone Densitometer 
 
Intended Use 
 
The X-ray Bone Densitometer (DPX-Bravo, DPX-Duo, DPX-NT, Prodigy, iDXA) supports the 
following intended uses: 
 
Provides an estimate of bone mineral density at various anatomical sites (Spine, Total Hip, Total 
Body, and Forearm). These values can then be compared to an Adult reference population at the 
sole discretion of the physician. 
 
Provides an assessment of relative fracture risk based on the patient’s T-score value using the 
categories of fracture risk defined by the World Health Organization (WHO). 
 
Provides a standardized bone density report using data from each densitometer and physician- 
generated assessments based on the patient’s demographics, which can assist the physician in 
communicating scan results to the patient and the patient’s referring physician 
 
Device Description 
 
Structure  
 
The X-Ray Bone Densitometer is made up of a scan arm, X-ray source assembly, and exam 
table.  
 
Product Model 
 
DPX Bravo and Duo 
 
The DPX Bravo and Duo models use pencil beam technology with a single-crystal detector and 
have a compact table design to provide space efficiency (see images below).  
The DPX Duo and the DPX Bravo come equipped with a scan arm that swings to the side of the 
table when not in use when not in use as a densitometer and to facilitate patient loading. X-ray 
scanning is not possible until the scan arm is locked into the scan position. A handle releases the 
scan arm interlock and allows operator to move the scan arm for patient loading. Once the 
patient is loaded on the table, the operator moves the scan arm back to scanning position and the 
arm locks into scan position. 
 
Measurement/Reporting 
 
Bone Mineral Density (BMD) is measured using Dual-Energy X-Ray Absorptiometry (DEXA). 
 
The bone mineral density of the lumbar spine, L1-L4, and the Total Hip total mean is measured 
in g/cm2 as well as standard deviations within the young adult population and within the age-
matched mean. These are also compared to baseline data as a percentage change. 
 
 
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Appendix F Instructions for Multi-Site Studies 
1. 
CONTACT INFORMATION 
All questions related to the protocol or study implementation should be directed to: 
Roswell Park Cancer Institute 
CRS Quality Assurance (QA) Network Office 
CRSNetworkCoordinators@RoswellPark.org  
Elm and Carlton Streets 
Buffalo, New York 14263 
Telephone: 
Monday - Friday; 8: 00 AM to 4: 30 PM EST 
716-845-8084 
After hours, weekends, and holidays request the Roswell Park Investigator 
716-845-2300 
2. 
INFORMED CONSENT 
• Informed consent must be obtained by the site Investigator/designee from any participants 
wishing to participate, prior to any procedures or treatment. 
• An informed consent template is provided by Roswell Park and can be amended to reflect 
institutional requirements. 
• All consent changes must be reviewed by Roswell Park CRS QA Network Office prior to 
submission to the site IRB. 
• The informed consent must be IRB approved. 
• Always check that the most up to date version of the IRB approved consent is being used. 
• Within 5 business days, notify the Roswell Park CRS QA Network Office of all participant 
withdrawals or consent to limited study participation and appropriately document the 
discontinuation and the reason(s) why. 
3. 
PARTICIPANT REGISTRATION 
The participant completes the Gender, Race, and Ethnicity Form and this is placed in the study 
binder. 
Roswell Park does not grant exceptions to eligibility criteria. 
Phase 2 Protocol Registration Instructions 
The 
Subject 
Screening 
and 
Enrollment 
Log 
must 
be 
emailed 
(CRSNetworkCoordinators@RoswellPark.org) to the Roswell Park CRS QA Network Office 
within 1 business day of the date the participant is consented. Once the Investigator has determined 
that eligibility has been met, complete the eligibility check list and email it to the Roswell Park 
Network QA Coordinator at CRSNetworkCoordinators@RoswellPark.org. 
4. 
STUDY DEVIATIONS 
• If a deviation has occurred to eliminate hazard, this must be reported to the Roswell Park 
Network, site IRB and any other regulatory authority involved in the study. 
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• ALL study deviations will be recorded on the Study Deviation Log. 
• Participants inadvertently enrolled with significant deviation(s) from the study-specified 
criteria will be removed from the study, at the discretion of the Principle Investigator. 
5. 
STUDY DOCUMENTATION 
• Study documents must be filled out completely and correctly. Ditto marks are not allowed. 
• If an entry has been documented in error put a single line through the entry and initial and 
date the change. The Roswell Park Network QA Coordinator must be able to read what has 
been deleted. 
• Do NOT use white-out, magic marker, scratch-outs. 
• Do NOT erase entries. 
• Use only black ink for documentation on the accountability form and any other study 
forms. 
• It is the responsibility of Roswell Park to inform the Investigator/ institution as to when 
these documents no longer need to be retained. If, for any reason, the Investigator desires 
to no longer maintain the study records, they may be transferred to another institution, 
another investigator, or to Roswell Park upon written agreement between the Investigator 
and Roswell Park. 
6. 
DRUG ACCOUNTABILITY 
Drug accountability must be strictly maintained. 
• Responsibility rests solely with the Investigator but can be delegated as appropriate (e.g., to 
pharmacy personnel). 
• A drug accountability record form (DARF) will record quantities of study drug received, 
dispensed to participants and wasted, lot number, date dispensed, participant ID number 
and initials, quantity returned, balance remaining, manufacturer, expiration date, and the 
initials of the person dispensing the medication. 
• Study drug supply will only be used in accordance with the IRB approved study. 
• Drug accountability forms are protocol and agent specific; they are study source documents 
and will be used to verify compliance with the study. 
• An inventory count must be performed with each transaction. Any discrepancies shall be 
documented and explained. 
• Drug accountability forms must be stored with study related documents. 
• Each medication provided for this study and each dosage form and strength must have its 
own DARF. 
• Dispensing the wrong study supply is considered a medication error. 
• NEVER replace investigational agents with commercial product. 
• Do NOT “transfer”, “borrow” or “replace” supplies between studies. 
7. 
SERIOUS ADVERSE EVENT REPORTING 
The site Investigator or designated research personnel will report all SAEs, whether related or 
unrelated to the investigational agent(s) to the IRB in accordance with their local institutional 
guidelines. The site will notify the Roswell Park Network QA Coordinator within 1 business day 
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of being made aware of the SAE. A preliminary written report must follow within 1 business day 
of the first notification using the following forms: 
• Roswell Park SAE Source form 
• MedWatch 3500A  
For instructions on notifying Amgen Please see Section 17.8. 
A complete follow-up report must be sent to the Roswell Park Network QA Coordinator when 
new information becomes available. 
8. 
UNANTICIPATED PROBLEM REPORTING 
An unanticipated problem (UP) is any incident, experience, or outcome that meets all of the criteria 
in Section 17.7. 
For all adverse events occurring that are unanticipated and related or possibly related to the 
research drug, biologic or intervention, the participating physician or delegated research staff from 
each site will notify their local IRB in accordance with their local institutional guidelines. The 
site must also notify the Roswell Park Network QA Coordinator within 1 business day of being 
made aware of the Unanticipated Problem by completing the Roswell Park Unanticipated 
Problem Report Form and emailing it to the Roswell Park Network QA Coordinator. 
 
 
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