Conditions: GVHD
Keywords: Cyclophosphamide Bortezomib
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 23
Healthy volunteers: no

Brief summary:
This is a single arm open label phase II clinical trial. Adult patients with hematological malignancies undergoing allogeneic HSCT from matched-related or unrelated donor are eligible for the study if they meet the standard criteria defined in the investigator's institutional standard operation procedures (SOPs), meet all inclusion criteria, and do not satisfy any exclusion criteria. Patients will receive reduced-intensity or myeloablative conditioning regimen of fludarabine, busulfan, and rabbit anti-thymocyte globulin (rATG). Patients will receive PTCyBor as GvHD prophylaxis.

Detailed description:

Arms:
arm 1: None

Interventions: intervention 1: Bortezomib intervention 2: Cyclophosphamide
Intervention descriptions: intervention 1: 1.3 mg/m2 IV 6 hours after graft infusion and 72 hours thereafter. intervention 2: 50 mg/kg IV over 2 hours on Day +3 and +4

Protocol document:
Prot_SAP_000.pdf: 
 
 
Official Title: 
A Phase II Study of High-Dose Post-Transplant Cyclophosphamide and 
Bortezomib (CyBor) for the Prevention of Graft-versus-Host Disease 
Following Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) 
NCT Number: 
NCT03945591 
Study Number: 
18-01185 
Document Type:  
Study Protocol and Statistical Analysis Plan 
Date of the 
Document: 
• 
 October 29, 2019 
 


Study number: s18-01185 
 
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A 
PHASE 
II 
STUDY 
OF 
HIGH-DOSE 
POST-TRANSPLANT 
CYCLOPHOSPHAMIDE AND BORTEZOMIB (PTCYBOR) FOR THE 
PREVENTION 
OF 
GRAFT-VERSUS-HOST 
DISEASE 
(GVHD) 
FOLLOWING 
ALLOGENEIC 
HEMATOPOIETIC 
STEM 
CELL 
TRANSPLANTATION (HSCT) 
 
 
Initial version: [July 2018] 
Amended: 
April 10, 2019 
Amended (1.0):April 26, 2019 
Principal Investigator: 
 
A Samer Al-Homsi MD, MBA 
Perlmutter Cancer Center 
240 East 38th Street 
New York, NY 10016 
Samer.Al-Homsi@nyulangone.org 
Additional Investigators: 
Maher Abdul-Hay MD 
Doyun Park MD 
Biostatistician: 
Judith Goldberg, ScD 
Pharmacist: 
Frank Cirrone, PharmD 
NYULH Study Number: 
S18-01185  
Funding Sponsor:  
None 
IND Number:  
Not applicable 
Regulatory Sponsor:  
Perlmutter Cancer Center  
240 East 38th Street 
New York, NY 10016 
 
Study Product: 
cyclophosphamide and bortezomib 
Study Product Provider:  
; cyclophosphamide and bortezomib covered as standard of 
care. 
ClinicalTrials.gov 
Number                 
Pending 


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Amended (1.1): August 28, 2019 
Statement of Compliance 
 
This study will be conducted in accordance with the Code of Federal Regulations on the Protection 
of Human Subjects (45 CFR Part 46), 21 CFR Parts 50, 56, 312, and 812 as applicable, any other 
applicable US government research regulations, and institutional research policies and 
procedures. The International Conference on Harmonisation (“ICH”) Guideline for Good Clinical 
Practice (“GCP”) (sometimes referred to as “ICH-GCP” or “E6”) will be applied only to the extent 
that it is compatible with FDA and DHHS regulations. The Principal Investigator will assure that 
no deviation from, or changes to the protocol will take place without prior agreement from the 
Institutional Review Board (IRB), except where necessary to eliminate an immediate hazard(s) to 
the trial participants. All personnel involved in the conduct of this study have completed Human 
Subjects Protection Training. 


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PROTOCOL APPROVAL SIGNATURES 
 
Protocol 
Title: 
 
A 
PHASE 
II 
STUDY 
OF 
HIGH-DOSE 
POST-TRANSPLANT 
CYCLOPHOSPHAMIDE AND BORTEZOMIB (PTCYBOR) FOR THE PREVENTION OF 
GRAFT-VERSUS-HOST DISEASE (GVHD) FOLLOWING ALLOGENEIC HEMATOPOIETIC 
STEM CELL TRANSPLANTATION (HSCT) 
 
Protocol Number: s18-01185 
 
This study will be conducted in compliance with the clinical study protocol (and amendments), 
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use guidelines for current Good Clinical Practice, and applicable 
regulatory requirements. 
 
 
 
 
 
_______________________________________ 
Signature 
 
 
_______________________________________ 
Date 
 
 


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TABLE OF CONTENTS 
1. Protocol Summary ……………………………………………………………...………………....7 
2. Background and Rationale  ......................................................................................... 11-15 
2.1. Potential Risks & Benefits  ............................................................................................. 15 
3.  Objectives and Purposes  ............................................................................................ 15-17 
3.1. Study Hypothesis  ......................................................................................................... 15 
3.2. Study Overview  ............................................................................................................ 15 
3.3. Objectives  .................................................................................................................... 16 
3.4. Study Endpoints  ........................................................................................................... 16 
3.5.  Definitions  ............................................................................................................... 16-17 
4.  Study Enrollment and Withdrawal .............................................................................. 17-21 
4.1. Inclusion Criteria  ........................................................................................................... 17 
4.2. Exclusion Criteria  .................................................................................................... 17-18 
4.3. Inclusion of Women, Minorities and Vulnerable Subjects  ......................................... 18 
4.4.  Strategies for Recruitment and Retention  ................................................................ 18-19 
4.5. Registration Procedures  ............................................................................................... 19 
4.6. Duration of Study Participation  ..................................................................................... 19 
4.7. Total Number of Participants and Sites .......................................................................... 19 
4.8. Participants Withdrawal or Termination  ........................................................................ 20 
4.9.  Premature Termination or Suspension of Study  ........................................................... 20 
4.10. Stopping for Excess TRM ………………………………………………………………… 20-21 
5.  Study Agent  ................................................................................................................. 21-23 
5.1. Velcade® (bortezomib) ............................................................................................. 21-22 
5.2. Cytoxan® (cyclophosphamide) ................................................................................. 22-23 
5.3. Study Agent Accountability Procedures  ........................................................................ 23 
5.4. Product Complaints  ...................................................................................................... 23 
6.  Required Study Activities (Appendix A)  ......................................................................... 24 
7.  Treatment Plan  ............................................................................................................ 24-26 
8. Assessment of Safety .................................................................................................. 26-34 
9. Clinical Monitoring ............................................................................................................ 34 
10. Statistical Consideration ............................................................................................. 34-36 
11. Source Documents and Access to Source Data and Documents ............................. 36-37 
12. Administrative Requirements ……………….…….………………………………….…….37-39 
13. Data Handling and Record Keeping  ........................................................................... 40-41 
14. Study Finances  ................................................................................................................. 41 
15. Conflict of Interest Policy ............................................................................................ 41-42 
16. References  ................................................................................................................... 42-44 
17. Appendices ................................................................................................................... 44-49 
 
 
 
 


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List of Abbreviations 
 
ADR 
Adverse drug reaction 
AE 
Adverse Event or Adverse Experience 
ALP 
Alkaline phosphatase 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate Aminotransferase 
ATG 
Anti-thymocyte globulin 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
Cl 
Confidence Interval 
CNI 
Calcineurin inhibitors 
CrCl 
Creatinine Clearance 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CSOC 
Clinical Study Oversight Committee 
CTO 
Clinical Trials Office 
DC 
Dendritic cell 
DSMC 
Data Safety Monitoring Committee 
ECI 
Event of Clinical Interest 
GRFS 
GvHD and relapse-free survival 
GvHD 
Graft-versus-Host Disease 
GvT 
Graft-versus-tumor 
HSCT 
Hematopoietic stem cell transplantation 


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LFTs 
Liver function tests 
LPS 
Lipopolysaccharide  
MMF 
Mycophenolate mofetil 
MTX 
Methotrexate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cells 
PI 
Proteasome inhibitors 
PTCy 
Post-Transplant cyclophosphamide  
rATG 
Rabbit  anti-thymocyte globulin 
RR 
Relapse rate 
TRM 
Treatment-related mortality 
 
 


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Protocol Summary 
Title 
A Phase II Study of High-Dose Post-Transplant Cyclophosphamide and 
Bortezomib (PTCyBor) for the Prevention of Graft-versus-Host Disease 
(GvHD) Following Allogeneic Hematopoietic Stem Cell Transplantation 
(HSCT) 
Short Title 
Cyclophosphamide and bortezomib for GvHD Prevention  
Brief Summary 
This is a single arm open label phase II clinical trial. Adult patients with 
hematological malignancies undergoing allogeneic HSCT from matched-
related or unrelated donor are eligible for the study if they meet the 
standard criteria defined in our institutional standard operation 
procedures (SOPs), meet all inclusion criteria, and do not satisfy any 
exclusion 
criteria. 
Patients 
will 
receive 
reduced-intensity 
or 
myeloablative conditioning regimen of fludarabine, busulfan, and rabbit 
anti-thymocyte globulin (rATG).  Patients will receive PTCyBor as GvHD 
prophylaxis. 
Phase 
Phase  II 
Objectives 
Primary Objective: 
• 
Estimate the incidence of acute GvHD in patients receiving 
cyclophosphamide and bortezomib as GvHD prophylaxis. 
• 
Estimate the incidence of chronic GvHD in patients receiving 
cyclophosphamide and bortezomib as GvHD prophylaxis 
Secondary Objectives: 
• 
Estimate the incidence of the following: primary graft failure, poor 
graft function, and secondary graft failure, treatment-related 
mortality (TRM), relapse rate (RR), GvHD and relapse-free 
survival (GRFS), and overall survival (OS). 
• 
Assess immune reconstitution by quantifying CD3+, CD4+, 
CD8+, and CD19+ in comparison to established reference data 
Methodology 
Interventional, non-randomized open label. 
Endpoint 
Primary: Acute GvHD by day +120 and chronic GvHD by day +365. 
Secondary: TRM, RR, GRFS, and OS. 
Study Duration 
Study will complete 2 years after the final participant’s date of transplant. 
Anticipate 3 year to complete enrollment and thus a 5-year total duration. 
Participant Duration 
Up to 2 years  


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Enrollment Period 
Up to 3 years 
Duration 
of 
IP 
administration 
Up to 1 week 
Study Center and 
Site 
NYU Langone Health 
Number 
of 
participants 
47 participants enrolled 
Description of Study 
Agent/Procedure 
Bortezomib 1.3 mg/m2 IV 6 hours after graft infusion and 72 hours 
thereafter. 
Cyclophosphamide 50 mg/kg IV over 2 hours on Day +3 and +4 
Key Procedures 
Examinations to include toxicity and GvHD assessments and blood 
draws to assess immune reconstitution. 
Statistical Analysis 
Sample size considerations: The primary outcome variables for this 
study include the (1) incidence of acute GvHD by day +120 post-
transplant and (2) incidence of chronic GvHD by day +365.  If we assume 
that the rate of acute GvHD grades II-IV with standard of care is 50% as 
reported in the literature, we can detect a reduction in acute GvHD 
incidence to 30% for PTCyBor, with alpha = 0.05 (2 sided) and power of 
80% with 47 patients using a z test for the test of the observed 
percentage compared to an expected percentage of 50%. With 47 
patients, the observed 95% confidence interval will 35.1% to 64.9% if the 
observed rate is 50%; if the observed rate is 30%, the corresponding 
confidence interval will be 17.5% to 45.1%.   
The primary analyses will include all patients who are transplanted and 
receive treatment. All primary endpoints will be evaluated using 
cumulative incidence functions; exact 95% confidence intervals will be 
provided for the day +120 incidence for acute GvHD and the day +365 
incidence for chronic GvHD. Secondary analyses will estimate the 
occurrence of primary graft failure, poor graft function, secondary graft 
failure, TRM, RR, GRFS, and OS. 
 
 
 
 
 


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Schematic of Study Design 
 
 
 
 
 
 
 


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1. KEY ROLES 
 
A Samer Al-Homsi MD, MBA- Principal Investigator 
Perlmutter Cancer Center 
240 East 38th Street 
New York, NY 10016 
Samer.Al-Homsi@nyulangone.org 
 
Maher Abdul Hay, MD- Co-Investigator 
Perlmutter Cancer Center 
240 East 38th Street, 19th Floor 
New York, NY 10016 
Maher.Abdulhay@nyulangone.org 
 
Doyun Park, MD- Co-Investigator 
Perlmutter Cancer Center 
240 East 38th Street, 19th Floor 
New York, NY 10016 
Doyun.Park@nyulangone.org 
 
Frank Cirrone, PharmD- Pharmacist 
545 First Avenue 
New York, NY 10016 
Frank.Cirrone@nyulangone.org 
 
Judith D Goldberg, ScD-co-Investigator and Biostatistics 
Perlmutter Cancer Center 
NYU Langone Health 
190Madison Ave, 4th floor, 451 
New York, NY 10061 
Juduth.Goldberg@nyulangone.org 
 
Kelli Cole, FNP-BC-Study Coordinator 
Perlmutter Cancer Center 
240 East 38th Street 
New York, NY 10016 
Kelli.Cole@nyulangone.org 
 
Kelsey Stocker, RN- Research Nurse 
Perlmutter Cancer Center 
240 East 38th Street 
New York, NY 10016 
Kelsey.Stocker@nyulangone.org 
 
 
 
 


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2. BACKGROUND AND RATIONALE 
 
Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative therapy for a variety 
of benign and malignant hematological conditions.1 According to the Center for International Bone 
Marrow Transplant Research (CIBMTR), more than 13,000 allogeneic HSCTs are performed annually in 
the US alone (http://www.cibmtr.org). However, despite the routine use of prophylactic 
immunosuppression, graft-versus-host disease (GvHD) continues to represent a frequent cause of 
morbidity and mortality of allogeneic HSCT.2-4 Furthermore, GvHD impairs the quality of life of patients 
undergoing allogeneic HSCT and hampers the utility and wide applicability of this treatment strategy. 
Therefore, innovative approaches to the prevention of GvHD are warranted.  
 
 
Current GvHD prophylactic regimens are based on different combinations of methotrexate (MTX), 
mycophenolate mofetil (MMF), calcineurin inhibitors (CNI), mTOR inhibitors, and anti-thymocyte globulin 
(ATG). In addition to their partial efficacy, the indiscriminate activity of these drugs against T cells results 
in delayed immune reconstitution and impaired graft-versus-tumor (GvT) effect, thus increasing the 
incidence of disease relapse.5 Furthermore, these agents are toxic and burdensome due to their common 
pharmacological interactions and the need for blood level monitoring and strict patient adherence.  
Post-Transplant Cyclophosphamide (PTCy) for GvHD Prevention:  
PTCy has recently been introduced for the prevention of GvHD. Contrary to the previously listed agents, 
PTCy selectively destroys rapidly proliferating host-reactive T cells, fosters regulatory T cells (Treg) 
expansion, and induces long-lasting tolerance by deleting intra-thymic alloreactive T cells.6,7 Because of 
its selective activity, targeting proliferating rather than resting T cells, PTCy  has been claimed to nurture 
rapid immune reconstitution and preserve GvT effect.8 Originally introduced to circumvent ex vivo T cell 
depletion following haploidentical HSCT, PTCy has now been studied alone in the setting of matched-
related and unrelated donor transplants.9 A recent multi-institutional trial of myeloablative and bone 
marrow allogeneic HSCT reported an incidence of grades II-IV and grades III-IV acute GvHD of 50% and 
15%, respectively. These rates were similar to the rates achieved with CNI-based regimens. On the other 
hand the incidence of chronic GvHD was more favorable at 14%. Importantly, the prophylactic treatment 
was complete by day +4 and was well tolerated.9 These findings were corroborated by several similar 
studies (reviewed in 10). However, when Alousi et al. tested PTCy alone as GvHD prophylaxis following 
reduced-intensity peripheral blood (as opposed to bone marrow) allogeneic HSCT, the authors reported 
excessive incidence of acute GvHD and decreased overall survival (OS) in comparison to a 
contemporaneous institutional control group.11 This has led a number of investigators to examine the 
combination of PTCy with conventional agents.12-13 The Blood and Marrow Transplant Clinical Trial 
Network (BMT CTN) recently completed a phase II multicenter trial (PROGRESS I) that randomly 
assigned patients to 1 of 3 GvHD prophylactic regimens: MTX, tacrolimus, and maraviroc, MTX, 
tacrolimus, and bortezomib, or MMF, tacrolimus, and PTCy. All patients received reduced-intensity 
peripheral blood allogeneic HSCT. Each regimen was compared to a nonrandomized prospective 
contemporaneous control cohort receiving MTX and tacrolimus as GvHD prophylaxis. The cumulative 
incidence of grade II-IV acute GvHD was not different for each arm versus the control cohort. However, 
grade III-IV acute GvHD and chronic GHD requiring systemic immunosuppressive therapy were lower in 
the MMF, tacrolimus, and PTCy arm in comparison to the control cohort. GvHD-free survival was also 
superior.14 


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Proteasome Inhibitors for GvHD Prevention:  
Dendritic cells (DC) play a pivotal role in the pathophysiology of GvHD.15 While recipient DC are 
necessary and sufficient for the development of GvHD, donor DC are only important for maximal GvHD.16 
Boeck et al. studied the kinetics of DC engraftment after allogeneic HSCT and demonstrated that the 
majority of patients lose recipient DC and achieve full donor DC chimerism at engraftment.17 
Consequently, targeting DCs early after allogeneic HSCT seems to represent a sound strategy to prevent 
GvHD.  
 
Bortezomib, the first-in-class proteasome inhibitors (PI), suppresses DC maturation and function and 
possesses a variety of  immune-modulatory effects.18-20 Several investigators have shown that 
bortezomib decreases lipopolysaccharide (LPS)-induced expression of maturation and co-stimulatory 
markers on the surface of DC generated from the peripheral blood mononuclear cells (PBMNC) of 
volunteer donors in presence of GM-CSF and IL-4.18-20 These surface molecules include CD40 ligand, 
chemokine receptor CCR7, CD54, CD80, CD83, CD86, and DC-SIGN. We have shown similar effect on 
naïve DCs isolated from the peripheral blood of volunteer donors using a magnetic beads-based selection 
procedure.21 Bortezomib also reduces the production of IL-1β, IL-6, IL-23, Il-12p70, and TNF-α of 
unstimulated DCs.18-20 In vivo, we demonstrated that DCs isolated from the peripheral blood of patients 
receiving a combination of PTC and bortezomib exhibit impaired LPS-mediated maturation and that T 
cell proliferation in response to the recipient’s irradiated DCs is suppressed. Although the treatment was 
completed by day +4, the drug effects remained notable on day +21.22 
 
In animal studies, bortezomib has been shown to decrease the incidence and severity of GvHD in a major 
histocompatibility complex (MHC)-mismatched transplantation murine model. The effect was due, at least 
in part, to DC inhibition.18-20 Notably, despite this beneficial effect of bortezomib administered early post-
transplant, delayed administration of bortezomib was associated with paradoxical worsening of GvHD-
associated intestinal injury and sudden death of animals.23 This phenomenon was attributed to increased 
serum levels of IL-1β and downstream, TNF-α and INF-γ.23 Using bioluminescence imaging, we 
demonstrated that the sudden deterioration in mice condition after delayed proteasome inhibition was 
associated with rapid accumulation of donor T cells in target organs and suggested that the phenomenon 
can be prevented by the addition of a lymphocyte depleting agent such as cyclophosphamide (see 
below).24-26 
 
In humans, Koreth el al. conducted a phase I-II study in mismatched-unrelated donor allogenic HSCT. 
GvHD prophylaxis consisted of a short course of bortezomib (days +1, +4, +7) in addition to MTX and 
tacrolimus. The incidence of grade II-IV and III-IV acute GvHD in this high-risk group was 22% and 7%, 
respectively. The incidence of chronic GvHD was 29%. Immune reconstitution was prompt.27 The same 
group recently reported the results of a randomized phase II study comparing 3 GvHD prevention 
regimens (MTX and tacrolimus, MTX, tacrolimus, and bortezomib, and MTX, tacrolimus, and sirolimus) 
in matched and mismatched-unrelated donor allogeneic HSCT.  The incidence of acute and chronic 
GvHD was similar in the 3 groups. However, a potential benefit of bortezomib was noted in patients 
receiving matched grafts.28  
 
PTCy and proteasome inhibitors in GvHD prevention:  


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As stated above, calcineurin and mTOR inhibitors have an unfavorable toxicity profile and are 
burdensome. They are typically administered for 6-9 months following allogeneic HSCT. We adopted a 
different approach to prevent GvHD using a short course of PTCy and bortezomib. We hypothesized that 
such combination is safe and effective and omits the need for calcineurin and mTOR inhibitors including 
in peripheral blood allogeneic HSCT.  
 
Preclinical data.  To examine the in vivo effect on the combination of PTCy and proteasome inhibitors 
we performed a series of experiments in a GvHD mouse model. First, we established that ixazomib, a 
proteasome inhibitor,29 has similar in vitro effects to bortezomib in term of effects on DC maturation and 
cytokine production.26 Additionally, in a MHC-mismatch mouse model, ixazomib ameliorated GvHD in a 
schedule dependent fashion mirroring the effects of bortezomib. Second, we aimed to determine the 
effectiveness of PTC and ixazomib in mice. Ten-week old BALB/c mice were irradiated (10 grays in two 
fractions) on day -1 and transplanted with 5x106 BM cells from C57BL6 mice. GvH inocula consisted of 
5x106 splenocytes from C57BL6 (some post-CFSE labeling) or B6;FVB-Ptprca Tg(CAG-Luc,-
GFP)L2G85Chco Thy1a/J (ubiquitously transgenic for firefly luciferase for bioluminescence imaging 
(BLI). All mice were kept in a pathogen-free environment. Mice were untreated or received 
cyclophosphamide (1 mg intraperitoneally) on day +2, ixazomib (30μg, subcutaneously) on days -1, +2, 
and +5, or both according to the same schedule. Mice were monitored for weight, GvHD score, and 
survival or were sacrificed on day +6 for cytokine measurement and splenic cell counts. For BLI, mice 
receiving transgenic splenocytes were injected with 150mg/kg of D-Luciferin intraperitoneally and were 
imaged 25 minutes later. GvHD worsening and sudden death occurred in a fraction of mice receiving 
ixazomib following a day +5 injection. The phenomenon was completely prevented when 
cyclophosphamide was administered. Importantly, the group receiving both cyclophosphamide and 
ixazomib had significantly improved weight, GvHD score, and survival when compared to the mice left 
untreated or receiving either drug alone (figure 1). The addition of cyclophosphamide to ixazomib 
prevented IL-1β increase, was associated with suppression of tumor necrosis factor α (TNFα), and 
resulted in a profound depletion of splenic total and donor CD4+ cells. Furthermore, proliferating cells 
(CFSE low) were preferentially depleted as opposed to quiescent cells (CFSE high). BLI imaging showed 
an increase in signal intensity shortly after the administration of ixazomib on day +5. On the other hand, 
the mice receiving cyclophosphamide in addition to ixazomib exhibited significantly lower donor T cell 
proliferation when compared to the other groups (figure 2).25 
 
                  
 
  
Figure 1                                                                     Figure 2 
 
 
 
 


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In summary, our preclinical data suggests that the combination of cyclophosphamide and proteasome 
inhibition suppresses cytokine production in vivo and reduces splenic total and donor CD4+ cell 
expansion with preferential depletion of proliferating cells, as opposed to quiescent cells and prevents 
the phenomenon of GvHD acceleration associated with delayed and prolonged proteasome inhibition. 
We also demonstrated that the combination results in improved survival of mice subjected to GvHD when 
compared to the control group and the groups receiving either drug alone.  
Clinical data. We performed a phase I dose escalation study with an expansion cohort in patients 
undergoing matched-related or unrelated donor allogeneic HSCT with reduced-intensity conditioning and 
peripheral blood allogeneic HSCT.  Patients received a fixed dose of PTCy (days +3 and +4) and an 
increasing dose of bortezomib in 3 cohorts, from 0.7 to 1 and to 1.3 mg/m2 administered 6 hours after 
graft infusion and 72 hours thereafter during the phase I. The study was then extended at the higher 
dose. Overall, 28 patients were enrolled. Patients receiving grafts from unrelated donors also received 
rabbit ATG (rATG). No graft failure and no unexpected grade ≥3 non-hematological toxicities were 
encountered. The median times to neutrophil and platelet engraftment were 16 and 27 days, respectively. 
Day +100 treatment-related mortality (TRM) was 3.6% (95% CI 0.2%-15.7%). The cumulative incidences 
of grade II-IV and grade III-IV acute GvHD were 35.9% (95% CI 18.6%-53.6 %) and 11.7% (95% CI 
2.8%-27.5%), respectively. The incidence of chronic GvHD was 27% (95% CI 11.4%-45.3%). The 
progression-free survival (PFS), OS, and GvHD & relapse-free survival (GRFS) rates were 50% (95% CI 
30.6%-66.6%), 50.8% (95% CI 30.1%-68.2%), and 37.7% (95% CI 20.1%-55.3%), respectively. Immune 
reconstitution, measured by CD3, CD4, and CD8 recovery was prompt. Notably, there was no negative 
impact on renal function. Although three patients had decreased glomerular filtration rates (GFR) at 
enrollment, all patients had normal GFR at last follow-up. The study suggested that the combination of 
PTCy and bortezomib (PTCyBor) for the prevention of GvHD is feasible and safe and yields promising 
results warranting further examination.30,31 
rATG for GvHD Prevention: 
The use of rATG following allogeneic HSCT has been extensively studied in systematic reviews and in 
randomized clinical trials.30-33 The incidence of acute and chronic GvHD was reduced without a 
concomitant in the relapse rate, in all studies except for one retrospective study by the CIBMTR. In the 
latter study, rATG had a negative impact on both disease-free and OS in patients receiving reduced-
intensity conditioning from matched siblings or mismatched unrelated.34 However, the median dose of 
rATG was 7 mg/kg and the impact of timing of administration was not considered. More recently, a study 
by Devellier at al. analyzed patients receiving a reduced-intensity conditioning regimen with 2.5 or 5 
mg/kg rATG prior to matched sibling donor allogeneic HSCT. The study showed lower rates of acute and 
chronic GvHD in the group receiving 5 mg/kg, without a negative impact on relapse; thus suggesting that 
there is a dose-dependent balance between acute and chronic GvHD prevention and long-term anti-
tumor effects.35  
 
Based on the above, we propose a phase II study using PTC and bortezomib for the prevention of GvHD 
following allogeneic HSCT in patient with hematological malignancies. Patients will also receive rATG.  
 
2.1.  
Potential Risks & Benefits 
2.1.1. Known Potential Risks 
2.1.1.1. 
Cyclophosphamide  


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The most common side effects of cyclophosphamide (Cytoxan®): 
Hematopoietic system: Neutropenia occurs in patients treated with cyclophosphamide. The degree of 
neutropenia is particularly important because it correlates with a reduction in resistance to infections. 
Fever without documented infection has been reported in neutropenic patients. 
Gastrointestinal system: Nausea and vomiting occur with cyclophosphamide therapy. Anorexia and, 
less frequently, abdominal discomfort or pain and diarrhea may occur. There are isolated reports of 
hemorrhagic colitis, oral mucosal ulceration and jaundice occurring during therapy. 
Skin and its structures: Alopecia occurs in patients treated with cyclophosphamide. Skin rash occurs 
occasionally in patients receiving the drug. Pigmentation of the skin and changes in nails can occur.  
 
2.1.1.2. 
Bortezomib 
The most common side effects of bortezomib (Velcade®): 
 Most commonly reported (incidence ≥ 20%) in clinical studies include nausea, diarrhea, 
thrombocytopenia, neutropenia, peripheral neuropathy, fatigue, neuralgia, anemia, leukopenia, 
constipation, vomiting, lymphopenia, rash, pyrexia, and anorexia.  
2.1.2. Other risks of study participation  
Additional risks associated with participation in this study, include risks associated with phlebotomy 
and breach of 
confidentiality. Risks associated with phlebotomy include weaknesses, redness, 
pain, bruising, bleeding, or infection at the needle site.  Privacy protection procedures are in place 
and good clinical practice guidelines are followed to minimize the risks associated with research 
procedures and participation. 
 
2.1.3. Known Potential Benefits 
It is possible that some study subjects receiving therapies may experience an improvement during the 
study.  Also, some subjects may not get any benefit from being in this research study. The information 
learned in this study may benefit future individuals with acute and chronic GvHD. 
3. OBJECTIVES AND PURPOSE 
 
STUDY DESIGN: 
3.1. Study hypothesis: We hypothesize that the administration of cyclophosphamide and a short-course 
of bortezomib in the setting of matched-related or unrelated donor allogeneic HSCT peripheral blood 
transplantation is effective in the prevention of GvHD and allows prompt immune reconstitution.  
 
3.2. Study overview:  This is a phase II clinical trial. Adult patients with hematological malignancies 
undergoing allogeneic HSCT from matched-related or unrelated donor are eligible for the study if 
they meet the standard criteria defined in our standard operation procedures (SOPs), meet all 
inclusion criteria, and do not satisfy any exclusion criteria. Patients will receive a reduced-intensity 
or myeloablative conditioning regimen with fludarabine, busulfan, and rATG. Patients will receive 
PTCyBor as GvHD prophylaxis (Appendix B).    


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3.3. Objectives 
3.3.1. 
Primary objectives: 
• 
Estimate the incidence of acute GvHD in patients receiving cyclophosphamide and 
bortezomib as GvHD prophylaxis.  
• 
Estimate the incidence of chronic GvHD in patients receiving cyclophosphamide and 
bortezomib as GvHD prophylaxis 
 
3.3.2. 
Secondary objectives: 
• 
Estimate the incidence of the following: primary graft failure, poor graft function, 
and secondary graft failure, TRM, RR, GRFS, OS. 
• 
Assess immune reconstitution by quantifying CD3+, CD4+, CD8+, and CD19+ in 
comparison to established reference data. 
3.4. Study Endpoints 
3.4.1. 
Primary study endpoints 
Acute GvHD: The first day of acute GvHD of any grade will be used to calculate the 
cumulative incidence for that grade. This end point will be evaluated through day +120 
post-transplant.  
Chronic GvHD: The first day of chronic GvHD will be used to calculate the cumulative 
incidence of chronic GvHD. This end point will be evaluated through day +365 post-
transplant.   
3.4.2. 
Secondary study endpoints 
Primary graft failure is evaluated to day +45 and as defined below.  
Poor graft function is evaluated to day +30 and as defined below.  
Secondary graft failure is evaluated following engraftment through day +730, as defined 
below. 
TRM are participant deaths not attributable to disease relapse or progression and will be 
evaluated to day +730.  
RR is evaluated to day +730 and is considered the date in which the disease for which 
transplant is performed is evident by methods of disease detection.  
GRFS is evaluated to day +730 and considers the number of participants that are without 
reported grade III-IV acute GvHD, chronic GvHD requiring systemic therapy and have not 
experienced relapse or death.  
OS is evaluated to day +730 and considers all participants alive at the end of the study’s 
evaluation period. 
3.5. Definitions 
3.5.1. 
Engraftment of Neutrophils: Absolute neutrophil count (ANC) recovery is defined as an 
ANC of ≥ 0.5 x 109/L for three consecutive laboratory values obtained on different days. 
The day used as neutrophil engraftment is the date of the first of three laboratory values. 
3.5.2. 
Engraftment of Platelets: Platelet engraftment is defined as a platelet count ≥ 20 x 109/L 
for 3 consecutive measurements obtained on different days. The patient must not have 
received a platelet infusion for seven consecutive days prior to the first day being 
considered. The day used as platelet engraftment is the date of the first of three laboratory 
values.   


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3.5.3. 
Primary graft Failure: Graft failure is defined as failure to achieve neutrophil engraftment 
by day +28 or lack of donor chimerism > 50% by day 45 not due to the underlying 
malignancy.  
3.5.4. 
Poor graft function is defined by at least 2 of the following 3 criteria: Hemoglobin < 8 
g/dL, ANC < 0.5 109/L, and platelets < 20 109/L. The cytopenia must be unexplained (such 
as by disease relapse) and unresponsive to cytokines and must last at least 4 weeks.  
3.5.5. 
Secondary graft failure is defined as poor graft function associated with donor chimerism 
< 5%.  
3.5.6. 
Acute GvHD: The first day of acute GvHD of any grade will be used to calculate the 
cumulative incidence for that grade (e.g., onset of grade III 70 days post-transplant - time 
to grade III is 70 days). This end point will be evaluated through day +120 post-transplant. 
The diagnosis of acute GvHD is based on clinical and pathological evaluation by the 
principal investigator in collaboration with the treating physician. The acute GvHD grading 
system is described in appendix B. 
3.5.7. 
Chronic GvHD: The first day of chronic GvHD will be used to calculate the cumulative 
incidence of chronic GvHD. The diagnosis of chronic GvHD is based on clinical and 
pathological evaluation by the principal investigator in collaboration with the treating 
physician. The chronic GvHD grading system is described in appendix C. 
 
4. STUDY ENROLLMENT AND WITHDRAWAL 
 
ELIGIBILITY: Patients with hematological malignancies undergoing an allogeneic transplant with a 
fludarabine, busulfan, and rATG conditioning regimen, using an eligible or suitable ≥ 8 out of 8 match 
(high resolution match at loci A, B, C, and DRB1) related or unrelated donor are eligible to participate. 
Donors are excluded in case of donor-specific HLA antibodies or positive cross-matching. Patients must 
meet all of the following inclusion criteria and none of the exclusion criteria. 
4.1. Inclusion Criteria 
4.1.1. 
Age ≥ 18 years 
4.1.2. 
Karnofsky score ≥ 70%   
4.1.3. 
No evidence of progressive bacterial, viral, or fungal infection 
4.1.4. 
Creatinine clearance > 50 mL/min/1.72m2  
4.1.5. 
Total bilirubin, ALT and AST < 2 x the upper limit of normal (except for Gilbert’s syndrome) 
4.1.6. 
Alkaline phosphatase ≤ 250 IU/L 
4.1.7. 
Left Ventricular Ejection Fraction (LVEF) > 45%  
4.1.8. 
Adjusted Carbon Monoxide Diffusing Capacity (DLCO) > 60% 
4.1.9. 
Negative HIV serology 
4.1.10. Negative pregnancy test: confirmation per negative serum β-human chorionic 
gonadotropin (β-hCG) 
4.2. Exclusion Criteria:  
4.2.1. 
Pregnant or nursing females or women of reproductive capability who are unwilling to 
completely abstain from heterosexual sex or practice 2 effective methods of contraception 
from the first dose of bortezomib through 90 days after the last dose. A woman of 


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reproductive capability is one who has not undergone a hysterectomy (removal of the 
womb), has not had both ovaries removed, or has not been post-menopausal (stopped 
menstrual periods) for more than 24 months in a row.   
4.2.2. 
Male subjects who refuse to practice effective barrier contraception during the entire study 
treatment period and through a minimum of 90 days after the last dose of study drug, or 
completely abstain from heterosexual intercourse.  This must be done even if they are 
surgically sterilized (i.e., post-vasectomy). 
4.2.3. 
Inability to provide informed consent. 
4.2.4. 
Patient had myocardial infarction within 6 months prior to enrollment or has New York 
Heart Association (NYHA) Class III or IV heart failure (see Appendix E), uncontrolled 
angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of 
acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG 
abnormality at screening must be documented by the investigator as not medically 
relevant. 
4.2.5. 
Known allergies to any of the components of the investigational treatment regimen. 
4.2.6. 
Serious medical or psychiatric illness likely to interfere with participation in this clinical 
study. 
4.2.7. 
Diagnosed or treated for another malignancy within 3 years of enrollment, with the 
exception of complete resection of basal cell carcinoma or squamous cell carcinoma, an 
in-situ malignancy, or low-risk prostate cancer after curative therapy. 
4.2.8. 
Participation in clinical trials with other investigational agents not included in this trial, 
within 14 days of the start of this trial and throughout the duration of this trial. 
4.2.9. 
Prisoners 
4.3. Inclusion of Women, Minorities and Vulnerable Subjects 
Both men and women of all races and ethnic groups are eligible for this trial.  
Vulnerable subjects will not be eligible for enrollment into this study.  Pregnant women are not 
included in this study, due to the unknown safety effects to the developing fetus.  Prisoners are not 
eligible. 
4.4. Strategies for Recruitment and Retention 
4.4.1. 
The inclusion and exclusion criteria in this study should not have a negative effect on 
the enrollment of the desired populations.   
4.4.2. 
Patients will be recruited from physicians participating in this study. Consenting, 
screening, and treatment will take place at the NYU Langone Health PCC under the 
supervision of the principal investigator, Dr. Al Homsi.  Prospective subjects will receive 
detailed information regarding this study; its investigational nature, required study 
procedures, alternative treatments, risks and potential benefits of the study.  They will also 
receive the informed consent document to read.  All questions will be answered by the PI 
or qualified research personnel. 
4.4.3. 
The Principal Investigator will: 
1. Obtain signed and dated informed consent from the potential subject before any 
study specific procedures are performed. 
2. Determine patient eligibility; see Section 4.1 and 4.2 


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3. Submit registration to NYU Langone Health PCC CTO. 
4. Receive registration confirmation from the NYU Langone Health PCC CTO, 
including a unique study identification number assigned to the patient that will 
be distributed to the study team upon registration of the patient. 
4.4.4. 
Recruitment and consenting will take place in a private area such as an exam room to 
protect the patient’s privacy.  The informed consent process and documentation follows 
that established procedures of the NYU Langone Health PCC CTO. 
4.5. 
Registration Procedures 
4.5.1. 
General Guidelines 
Each patient must sign and date an informed consent form before undergoing 
any study specific procedure unless a procedure is being performed as part of the 
patient’s standard of care. 
Enrollment in the study requires that all inclusion and exclusion criteria have 
been met. Enrollment occurs upon confirmation of registration from the NYULH 
PCC CTO. The following 
materials must be submitted to the CTO for subject 
registration: 
1. Complete signed and dated informed consent form 
2. Complete signed and dated eligibility checklist 
3. All supporting documentation verifying each eligibility criterion has been met 
 
Registration will occur within 48 hours of research coordinator receipt of all of the 
above documents. A 
written confirmation of enrollment including a unique study 
identification number assigned by the research coordinator will be disbursed to the 
study team upon registration. 
Once eligibility is verified, a unique patient study number will be issued within 24 
hours of receiving all required registration material. The patient will not be identified 
by name. This is the point, at which, the patient is considered accrued on study. 
4.5.2. 
Data Reporting to the Center for International Blood and Transplant Research 
(CIBMTR) 
All transplant centers are required to register patients with the Center for International 
Blood and Marrow Transplant Research (CIBMTR) and complete pre-transplant essential 
data forms, day 100 report forms and follow-up forms. CIBMTR data is covered under 
NYULH IRB: S11-00861. 
4.6 Duration of Study Participation 
Subjects may remain on study for as long as 2 years, with treatment as detailed in the protocol. 
Withdrawal due to toxicity, withdrawal of consent, or at the discretion of the investigator may occur. 
4.7 Total Number of Participants and Sites 
There will be one site participating in the study, with a total of 47 patients enrolled, accrued over 3 
years. 


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4.8 Participants Withdrawal or Termination 
4.8.1. Reasons for Withdrawal or Termination 
A subject has the right to voluntarily discontinue study treatment or withdraw from the 
study at any time, for any reason, and without repercussion.  The investigator has the right 
to discontinue a patient from study treatment or withdraw a patient from the study at any 
time. 
 
Reasons for subject withdrawal from the study may include, but are not limited to: 
• 
Subject withdrawal of consent at any time. 
• 
Disease progression (if applicable) 
• 
Intolerable toxicity (If applicable) 
• 
Any medical condition that the investigator determines may jeopardize the patient’s 
safety if s/he continues in the study or continues treatment with study drug. 
• 
The investigator determines it is in the best interest of the patient. 
• 
Failure of the subject to adhere to protocol procedure requirements 
• 
Pregnancy (if applicable) 
 
4.8.2. Handling of Participant Withdrawals or Termination 
Withdrawal from the study can be made in writing to the Principal Investigator, Dr. A 
Samer Al-Homsi.  
4.9  Premature Termination or Suspension of Study 
This study may be temporarily suspended or prematurely terminated if there is sufficient, 
reasonable 
cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to Dr. A Samer Al-Homsi 
and any regulatory authorities. If the study is prematurely terminated or suspended, the PI will 
promptly inform the IRB and will provide the reason(s) for the termination or suspension. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping 
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete or evaluable 
• 
Determination of futility 
Study may resume once concerns about safety, protocol compliance, data quality are 
addressed and satisfy the IRB. 
 
4.10. Stopping for excess TRM 
With 47 patients planned, we will test the hypothesis that the TRM rate is ≤ 20% versus the 
alternative hypothesis that the TRM rate is ≥ 40% with one sided α=0.05 and power of 90%, 
using an O’Brien Fleming group sequential alpha stopping boundary with three (3) interim 
and one (1) final look as summarized in Table 1 below. 
 
Table 1: Exact Stopping Boundaries for Excess Transplant Related Mortality (TRM) (1 sided 
α=0.05, power=80%, Ho: TRM≤0.20, Ha: TRM≥0.40) [Calculations from EAST 6.4 Cytel, Inc.] 


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Interim 
Look 
Number of 
Patients 
Cumulative 
Alpha Spent 
Stopping Boundaries: 
Reject TRM≤0.20 
≥Number 
Events  
≥Proportion 
Observed 
1 
12 
0 
9 
0.75 
2 
24 
0.006 
11 
0.46 
3 
35 
0.023 
13 
0.37 
Final 
47 
0.05 
15 
0.32 
5. STUDY AGENTS 
5.1. 
Bortezomib (Velcade®) – Millennium Pharmaceuticals  
5.1.1. Therapeutic Class: Proteasome Inhibitor 
5.1.2. Description: An antineoplastic agent available for intravenous 6 injection (IV) use only. 
Each single dose vial contains 3.5 mg of bortezomib as a sterile lyophilized powder. Inactive 
ingredient: 35 mg mannitol, USP. Bortezomib is a modified dipeptidyl boronic acid. The 
product is provided as a mannitol boronic ester which, in reconstituted form, consists of the 
mannitol ester in equilibrium with its hydrolysis product, the monomeric boronic acid. The 
drug substance exists in its cyclic anhydride form as a trimeric boroxine. The chemical name 
for bortezomib, the monomeric boronic acid, is [(1R)-3-methyl-1-[[(2S)-1-15 oxo-3-phenyl-
2-[(pyrazinylcarbonyl) amino]propyl]amino]butyl] boronic acid. Bortezomib has the following 
chemical structure: 
 
 
 
The molecular weight is 384.24. The molecular formula is C19H25BN4O4. The solubility of 
bortezomib, as the monomeric boronic acid, in water is 3.3 to 3.8 mg/mL in a pH range of 2 
to 6.5. 
5.1.3. Indications: Treatment of multiple myeloma patients who have received at least 1 prior 
therapy. 
5.1.4. Mechanism of Action: Bortezomib is a reversible inhibitor of the chymotrypsin-like activity 
of the 26S proteasome in mammalian cells. The 26S proteasome is a large protein complex 
that degrades ubiquitinated proteins. The ubiquitin-proteasome pathway plays an essential 
role in regulating the intracellular concentration of specific proteins, thereby maintaining 
homeostasis within cells. Inhibition of the 26S proteasome prevents this targeted 
proteolysis, which can affect multiple signaling cascades within the cell. This disruption of 
normal homeostatic mechanisms can lead to cell death. Experiments have demonstrated 
that bortezomib is cytotoxic to a variety of cancer cell types in vitro. Bortezomib causes a 
delay in tumor growth in vivo in nonclinical tumor models, including multiple myeloma. 


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5.1.5. Pharmacokinetics: Following intravenous administration of a 1.3 mg/m2 dose, the median 
estimated maximum plasma concentration of bortezomib was 509 ng/mL (range=109 to 
1300 ng/mL) in 8 patients with multiple myeloma and creatinine clearance values ranging 
from 31 to 169 mL/min. The mean elimination half-life of bortezomib after first dose ranged 
from 9 to 15 hours at doses ranging from 1.45 to 2.00 mg/m2 in patients with advanced 
malignancies. The pharmacokinetics of bortezomib as a single agent have not been fully 
characterized at the recommended dose in multiple myeloma patients. 
5.1.5.1. 
Absorption and Distribution: The distribution volume of bortezomib as a single 
agent was not assessed at the recommended dose in patients with multiple 
myeloma. The binding of bortezomib to human plasma proteins averaged 83% over 
the concentration range of 100 to 1000 ng/mL. 
5.1.5.2. 
Metabolism and excretion: In vitro studies with human liver microsomes and 
human cDNA-expressed cytochrome P450 isozymes indicate that bortezomib is 
primarily oxidatively metabolized via cytochrome P450 enzymes 3A4, 2C19, and 
1A2. Bortezomib metabolism by CYP 2D6 and 2C9 enzymes is minor. The major 
metabolic pathway is deboronation to form 2 deboronated metabolites that 
subsequently undergo hydroxylation to several metabolites. Deboronated 
bortezomib metabolites are inactive as 26S proteasome inhibitors. Pooled plasma 
data from 8 patients at 10 min and 30 min after dosing indicate that the plasma 
levels of metabolites are low compared to the parent drug. The pathways of 
elimination of bortezomib have not been characterized in humans. 
5.1.6. Administration and Storage: Local skin irritation was reported in 5% of patients, but 
extravasation of was not associated with tissue damage. Prior to use, the contents of each 
vial must be reconstituted with 3.5 mL of normal (0.9%) saline, Sodium Chloride Injection, 
USP. The reconstituted product should be a clear and colorless solution. Parenteral drug 
products should be inspected visually for particulate matter and discoloration prior to 
administration whenever solution and container permit. If any discoloration or particulate 
matter is observed, the reconstituted product should not be used. Unopened vials are stable 
until the date indicated on the package when stored in the original package protected from 
light. Bortezomib contains no antimicrobial preservative. When reconstituted as directed, it 
may be stored at 25ºC (77ºF). After reconstitution bortezomib should be administered within 
8 hours of preparation. The reconstituted material may be stored in the original vial and/or 
the syringe prior to administration. The product may be stored for up to 8 hours in a syringe; 
however total storage time for the reconstituted material must not exceed 8 hours when 
exposed to normal indoor lighting. Unopened vials may be stored at controlled room 
temperature 25ºC (77ºF); excursions permitted from 15 to 30ºC (59 to 86ºF). Retain in 
original package to protect from light. 
5.2. 
Cytoxan® (cyclophosphamide) – Bristol-Myers Squibb 
5.2.1. Therapeutic Class: nitrogen mustard alkylating agent 
5.2.2. Description:  CYTOXAN® (cyclophosphamide for injection, USP) is a sterile white powder 
containing cyclophosphamide monohydrate. CYTOXAN Tablets (cyclophosphamide 
tablets, USP) are for oral use and contain 25 mg or 50 mg cyclophosphamide (anhydrous). 
Inactive ingredients in CYTOXAN Tablets are: acacia, FD&C Blue No. 1, D&C Yellow No. 
10 Aluminum Lake, lactose, magnesium stearate, starch, stearic acid and talc. 


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Cyclophosphamide is a synthetic antineoplastic drug chemically related to the nitrogen 
mustards. Cyclophosphamide is a white crystalline powder with the molecular formula 
C7H15Cl2N2O2P•H2O and a molecular weight of 279.1. The chemical name for 
cyclophosphamide is 2-[bis (2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-
oxide monohydrate. Cyclophosphamide is soluble in water, saline, or ethanol and has the 
following structural formula:  
 
 
 
 
 
5.2.3. Indications: Treatment of malignant lymphomas, Hodgkin's disease, lymphocytic 
lymphoma, mixed-cell type or histiocytic lymphoma, Burkitt's lymphoma, multiple myeloma, 
chronic lymphocytic leukemia, chronic granulocytic leukemia, acute myelogenous and 
monocytic leukemia, acute lymphoblastic leukemia in children, mycosis fungoides, 
neuroblastoma, ovary adenocarcinoma, retinoblastoma, breast carcinoma. Treatment of 
biopsy proven "minimal change" nephrotic syndrome in children, but not as primary therapy.  
5.2.4. Mechanism of Action: Nitrogen mustard alkylating agent; exerts action by cross linking of 
tumor cell DNA. 
5.2.5. Pharmacokinetics: 
5.2.5.1. 
Absorption: Well absorbed; bioavailability (≥75%).  
5.2.5.2. 
Distribution: Plasma protein binding (≥60% as metabolites). 
5.2.5.3. 
Metabolism: Liver; active metabolites.  
5.2.5.4. 
Elimination: Urine (5-25% unchanged); T1/2=3-12 hrs. 
5.2.6. How Supplied:  Inj (Lyophilized): 500mg, 1g, 2g; Tab: 25mg, 50mg  
5.2.7. Administration and Storage: 
5.2.7.1. 
Administration: Oral, IV, IM, intraperitoneal, intrapleural route. Inspect drug 
product visually for particulate matter and discoloration prior to parenteral 
administration.  
5.2.7.2. 
Storage: Vial: Below 25°C (77°F). Tab: Below 25°C (77°F); excursions permitted 
to 30°C (86°F); protect from temperatures above 30°C (86°F). 
5.3. 
Study Agent Accountability Procedures 
Cyclophosphamide and bortezomib will both be purchased per standard of practice from a 
commercial source and compounded according to the package insert by the main hospital 
pharmacy.  
5.4. 
Product Complaints: A product complaint is a verbal, written, or electronic expression which 
implies dissatisfaction regarding the identity, strength, purity, quality, or stability of a drug 
product. Individuals who identify a potential product complaint situation should immediately 
contact the PI and report the event.  Whenever possible, the associated product should be 
maintained in accordance with the label instructions.  


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6.  REQUIRED STUDY ACTIVITIES (APPENDIX A) 
 
6.1. 
Recipient Pre-Transplant Work-Up and Eligibility for Transplant: The patient will undergo 
pre-transplant work-up per standard of care and in timeframes defined by standard operating 
procedures (SOPs).  This will include but is not limited to: history and physical examination, ABO 
and Rh type, CBC, CMP, PT-INR, PTT, creatinine clearance, high resolution HLA typing 
(including KIR for patients with myeloid malignancies), infectious disease markers (IDMs), β-
HCG serum pregnancy test (females of reproductive capability only – refer to exclusion criteria), 
chest x-ray (CXR), ECG, pulmonary function tests (PFT) with DLCO, ECHO to measure left 
ventricular ejection fraction (LVEF), informed consent for transplant, and final medical clearance 
by their treating physician. 
 
6.2. Donor Work-Up: The donor will also undergo a pre-transplant donor evaluation and eligibility 
per institutional SOPs or by donor center. Study procedures will not impact the donor. The 
attending physician will review all donor eligibility prior to the initiation of the conditioning 
chemotherapy. 
6.3. 
Pre-Transplant 
6.3.1. Work up as outlined in 6.1. 
6.3.2. Daily, from Day -7 through day 0: CBC, CMP, liver function tests (LFTs), and a physical 
exam, including toxicity assessment. 
 
6.4. 
Post-Transplant 
6.4.1. CBC and CMP daily until neutrophil engraftment, then at least weekly until day +100 (+/- 3 
days), and at least monthly until day +180 (+/- 7 days). 
6.4.2. LFT twice weekly until engraftment, then at least weekly until day +100 (+/- 3 days), and at 
least monthly until day +180 (+/- 7 days). 
6.4.3. Physical examination including toxicity and GvHD assessments daily until discharge, then 
weekly un 
6.4.4. til day +100 (+/- 3 days), and at least monthly until day +180 (+/- 7 days). 
6.4.5. From day +180 until day +730: CBC, CMP, LFTs, and a physical exam including toxicity and 
GvHD assessments will be done at least every three months (+/- 7 days). 
6.4.6. Post-chimerism: at engraftment, then at least monthly until day +180, and every 3 months 
until day +730 (+/- 7 days). 
6.4.7. Immune reconstitution studies will be drawn on days +30, +100, +180, and +365 (+/- 7 
days), 10-20mL of blood for CD3, CD4, CD8 and CD19. 
7. TREATMENT PLAN 
 
7.1. 
Conditioning Regimen (Study Schema): Eligible patients will receive one of the following 
conditioning regimens, both of which are standard of care, on an inpatient basis. The choice of 
the conditioning regimen is determined by the treating physician based on host factors and 


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disease nature and status. As described by BMT standard operating policy (procedure) (SOP) 
CLNTX007: Selection of Conditioning Regimens for Blood and Marrow Transplantation – Adult.  
7.1.1. Myeloablative:  
7.1.1.1. 
Fludarabine 40 mg/m2 IV once daily on days -5, -4, -3, and -2. 
7.1.1.2. 
Busulfan IV, q6 hours, on days -5, -4, -3, and -2. The busulfan dose will be 
determined based on pharmacokinetic (PK) studies performed on a one time test 
dose administered 1-3 weeks before the beginning of conditioning regimen. The 
target systemic exposure will be 900-1500 micoMol/min. PK will be sent to 
(Pharmacokinetics Laboratory, Mayo Medical Laboratories, 3050 Superior Drive 
NW, Rochester, MN 55901). See appendix F: Busulfan Information: Mail-In 
Specimen Instructions. Once the PK samples are received by Mayo Medical 
Laboratory, a report is generated and returned to the institution detailing the 
recommended dose.  This recommended dose will be the dose used for 
conditioning. 
7.1.1.3. 
rATG (Thymoglobulin®) 1 mg/kg, 1.5 mg/kg, and 2.5 mg/kg IV, daily, on days -4, -
3 and -2, respectively.  
7.1.1.4. 
Filgrastim (Neupogen®) will begin on day +5. Filgrastim will be stopped when 
patients achieve an ANC > 1.5 x 109/L on two consecutive days.  
 
7.1.2. Reduced intensity 
7.1.2.1. 
Fludarabine 30 mg/m2 IV once daily on days -7, -6, -5, -4, -3 and -2. 
7.1.2.2. 
Busulfan 130 mg/m2 IV, once daily, on days -3, -2.  
7.1.2.3. 
rATG (Thymoglobulin®) 1 mg/kg, 1.5 mg/kg, and 2.5 mg/kg IV, daily, on days -4, -
3 and -2, respectively.  
7.1.2.4. 
Filgrastim (Neupogen®) will begin on day +7. Filgrastim will be stopped when 
patients achieve an ANC > 1.5 x 109/L on two consecutive days.  
 
7.2. 
Graft Infusion: At least 2 x 106/kg peripheral blood CD34+ cells (HPC-A) will be infused on day 
0 per institutional protocol. The goal is to infuse 4.9 - 9 x 106/kg CD34+ cells. Stem cells are 
collected by apheresis after mobilization with 10 µg/kg of filgrastim (G-CSF or Neupogen®) per 
the National Marrow Donor Program and institutional program practice. 
7.3. 
GvHD prophylaxis: All patients will investigational GvHD prophylaxis based on a combination 
of PTCy and bortezomib. No other prophylactic treatment will be given.  
7.3.1. Cyclophosphamide 50 mg/kg IV over 1 hour on days +3 and +4 with concomitant 
hydration. The hydration will be NS with or without 20 mEq/L KCl at 250 mL/hr starting 4 
hours before and continuing until 24 hours after the second dose is complete. Furosemide 
is also given on an as needed basis to maintain fluid balance. 
7.3.2. Bortezomib 1.3 mg/m2 IV 6 hours after graft infusion and 72 hours thereafter.  
7.4. 
Drug Preparation: The drugs will be prepared under the supervision of a pharmacist, or 
appropriately 
qualified 
and 
trained 
personnel. 
Fludarabine, 
busulfan, 
rATG, 
and 
cyclophosphamide doses will be based on adjusted body surface area if actual body weight is > 
125% the ideal body weight.  


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7.5. 
Supportive care: Steroids will not be allowed after graft infusion. All supportive care including 
anti-emetics, anti-seizure, sinusoidal obstruction syndrome (SOS) prophylaxis, transfusion 
support, and infection prophylaxis will be administered per established routine institutional SOPs.  
7.6. 
Management of acute and chronic GvHD: Patients who develop acute or chronic GvHD will 
be managed by the treating physician according to his or her standard practice and as defined 
by BMT SOP CLNAL005: Definition, Prevention, Diagnosis, Grading, and Management of Graft-
versus-Host-Disease (GvHD) – Adults. 
7.7. 
. Patients will remain on study for follow-up and data collection. 
7.8. 
Ancillary Therapy: Patients will continue to receive any other therapy that the treating physician 
feels necessary according to the routine program practices.  Management of shared toxicities 
and adverse events associated with cyclophosphamide and bortezomib such as nausea, 
vomiting, diarrhea, etc. will be routinely managed according to the routine practices. 
8. ASSESSMENT OF SAFETY 
 
8.1. 
Specification of Safety Parameters  
8.2. 
Adverse Events (AE) and Serious Adverse Events (SAE) are unexpected toxicities that occur in 
the transplant setting (i.e. hematologic, gastrointestinal toxicities are expected). The Common 
Terminology Criteria for Adverse Events, Version 5.0, will be used for assessing the severity of 
adverse events. 
8.2.1. The following will be reported and monitored: 
• 
Grade 3 non-hematologic toxicity directly related to study drugs (such as 
peripheral neuropathy).  
• 
Grade 2 or higher hepatic bilirubin. 
8.2.2. Time  Period and Frequency for Event Assessment and Follow-up 
The investigator or site staff will be responsible for detecting, documenting and reporting 
events that meet the definition of an adverse event (AE) or serious adverse event (SAE). 
AEs and SAEs will be followed from the start of conditioning regimen to 30 days after the 
last study drug administration and/or until treatment-related adverse events resolve or 
stabilize, whichever occurs first. 
8.3. 
Adverse Events (AE) 
8.3.1. Definitions of Adverse Events (AE) 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens 
in severity during the course of the study. Intercurrent illnesses or injuries should be 
regarded as adverse events.  Abnormal results of diagnostic procedures are considered to 
be adverse events if the abnormality: 
• 
results in study withdrawal 
• 
is associated with a serious adverse event 
• 
is associated with clinical signs or symptoms 
• 
leads to additional treatment or to further diagnostic tests 
• 
is considered by the investigator to be of clinical significance 
 


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8.3.2. Reporting an Adverse Event: All adverse events, whether observed by the investigator or 
reported by the patient, must be recorded with details.  Information to be collected includes 
event description, time of onset, clinician’s assessment of severity, relationship to study 
product (assessed only by those with the training and authority to make a diagnosis), 
duration of episode, intensity of episode, action taken with respect to the test drug, time of 
resolution/stabilization of the event and patient outcome. The investigator must evaluate 
each adverse event for its relationship to the test drug and for its seriousness. The clinical 
course of each event should be followed until resolution, stabilization, or until it has been 
determined that the study treatment or participation is not the cause.  All AEs including local 
and systemic reactions not meeting the criteria for SAEs will be captured on the appropriate 
report forms. All unexpected AEs occurring while on study must be documented 
appropriately regardless of relationship.  
 
8.4. 
Serious Adverse Events (SAE) 
8.4.1. Definition of SAE: events are classified as serious or non-serious.  A serious adverse event 
is any AE that is:  
• 
fatal 
• 
life-threatening 
• 
requires or prolongs hospital stay 
• 
results in persistent or significant disability or incapacity 
• 
a congenital anomaly or birth defect 
• 
an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are 
clearly of major clinical significance. They may jeopardize the subject, and may require 
intervention to prevent one of the other serious outcomes noted above. For example, drug 
overdose or abuse, a seizure that did not result in in-patient hospitalization, or intensive 
treatment of bronchospasm in an emergency department would typically be considered 
serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as 
non-serious adverse events.  
 
8.4.2. Reporting a Serious Adverse Event: The Principal Investigator (PI), Dr. A. Samer Al-
Homsi, (who may also sometimes be referred to as the sponsor-investigator), is conducting 
the study and acting as the sponsor. Therefore, the ethical and legal obligations of the 
principal investigator include both those of a sponsor and those of an investigator.  
 
All SAEs, regardless of expectedness or relationship with any study drug, must be reported 
to the sponsor-investigator, as soon as possible, but no later than 24 hours of the 
investigator’s observation or awareness of the event.  
The occurrence of an AE or SAE may come to the attention of study personnel during study 
visits and interviews of a study participant presenting for medical care, or upon review by a 
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SAEs that are still ongoing at the end of the study period must be followed up to determine 
the final outcome.  Any serious adverse event that occurs after the study period and is 
considered to be possibly related to the study treatment or study participation should be 
recorded and reported immediately. 
 
Any medical condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if the study participant’s 
condition deteriorates at any time during the study, it will be recorded as an AE. UPs will be 
recorded in the data collection system throughout the study. 
 
Changes in the severity of an AE will be documented to allow an assessment of the duration 
of the event at each level of severity to be performed. AEs characterized as intermittent 
require documentation of onset and duration of each episode. 
 
At each contact with the subject, the investigator must seek information on adverse events 
by specific questioning and, as appropriate, by examination.  Information on all adverse 
events should be recorded immediately in the source document, and also in the appropriate 
adverse event module of the case report form (CRF).  All clearly related signs, symptoms, 
and abnormal diagnostic procedures results should recorded in the source document, 
though should be grouped under one diagnosis. At each study visit, the investigator will 
inquire about the occurrence of AE/SAEs since the last visit. Events will be followed for 
outcome information until resolution or stabilization.   
 
All unresolved adverse events should be followed by the investigator until the events are 
resolved, the subject is lost to follow-up, or the adverse event is otherwise explained.  At the 
last scheduled visit, the investigator should instruct each subject to report any subsequent 
event(s) that the subject, or the subject’s personal physician, believes might reasonably be 
related to participation in this study.   
   
Events should be reported using the NYU CTO Medical Events Form. 
 
Adverse events that do not fit the above immediately reportable criteria must still be reported 
to the IRB at each annual review, either in a summary or tabular format. 
 
Incidents or events that meet the OHRP criteria for UPs require the creation and completion 
of an UP report form. It is the site investigator’s responsibility to report UPs to their IRB and 
to the overall principal investigator. The UP report will include the following information: 
• 
Protocol identifying information: protocol title and number, PI’s name, and 
the IRB project number; 
• 
A detailed description of the event, incident, experience, or outcome; 
• 
An explanation of the basis for determining that the event, incident, 
experience, or outcome represents an UP; 
• 
A description of any changes to the protocol or other corrective actions that 
have been taken or are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following 
timeline: 
• 
UPs that are SAEs will be reported to the IRB and to the DCC within 24 
hours of the investigator becoming aware of the event. 
• 
Any other UP will be reported to the IRB and to the DCC within 24 hours of 
the investigator becoming aware of the problem. 


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• 
All UPs should be reported to appropriate institutional officials (as required 
by an institution’s written reporting procedures), the supporting agency 
head (or designee), and OHRP within 5 days of the IR’s receipt of the report 
of the problem from the investigator. 
 
SAE reporting will begin in conjunction with the date of treatment administration. Any 
SAEs that the investigator believes may have been caused by a protocol procedure 
must be reported immediately to the principal investigator, with a notification email 
sent to NYUPCCsafetyreports@nyulangone.org and recorded on the case report form. 
 
All fatal or life-threatening adverse events must be immediately reported to the Principal 
Investigator, via appropriate reporting mechanism and the NYU Langone Health IRB 
by telephone or e-mail. Within 24 hours of the event, the Serious Adverse Event 
Form must be emailed to NYUPCCsafetyreports@nyulangone.org whether full 
information regarding the event is known or not.  
 
Additional follow-up by the investigator will be required if complete information is not 
known. De-identified 
source documentation of all examinations, diagnostic 
procedures, etc. which were completed with respect to the event should be included 
with the SAE form. For laboratory results, include the laboratory normal ranges. 
 
The Serious Adverse Event Form must also be emailed to the principal investigator 
and Clinical Trials Office within 24-hours (NYUPCCsafetyreports@nyulangone.org), 
this documentation will be forwarded to the DSMC’s appointed medical monitor 
within 24 hours of the event whether full information regarding the event is known or 
not. Additional follow-up by the investigator will be required if complete information is 
not known. 
 
Current contact information shall be maintained at the site within the regulatory binder. 
 
All SAEs will be evaluated by the DSMC.  The investigator is responsible for reporting 
all SAEs to the appropriate IRB and DSMC. 
 
8.5. 
Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose must 
be reported as an SAE. 
 
8.6. 
Other Safety Considerations 
Any 
significant 
worsening 
noted 
during 
interim 
or 
final 
physical 
examinations, 
electrocardiograms, X-rays, and any other potential safety assessments, whether or not these 
procedures are required by the protocol, should also be recorded as a non-serious or serious 
AE, as appropriate, and reported accordingly. 
 
8.7. 
Definition of Unanticipated Problems (UP) 
Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria:  
• Unexpected in nature, severity, or frequency  (i.e. not described in study-related 
documents such as the IRB-approved protocol or consent form, the investigators 
brochure, etc) 


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• Related or possibly related to participation in the research (i.e. 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 subjects or others at greater risk of harm 
(including physical, psychological, economic, or social harm). 
 
8.8. 
Classification of an Adverse Event 
8.8.1. Severity of Event 
As described, AEs will be graded by criteria established by CTCAE, version 5.0. For AEs 
not able to be defined by this grading system, the following guidelines will be used to 
describe severity. 
• Mild: Events require minimal or no treatment and do not interfere with the 
participant’s daily activities. 
• Moderate: Events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with 
functioning. 
• Severe: Events interrupt a participant’s usual daily activity and may require 
systemic drug therapy or other treatment. Severe events are usually potentially 
life-threatening or incapacitating. 
8.8.2. Relationship to Study Agent 
For all collected AEs, the clinician who examines and evaluates the participant will 
determine the AE’s causality based on temporal relationship and his/her clinical judgment. 
The degree of certainty about causality will be graded using the categories below. 
• Definitely Related: There is clear evidence to suggest a causal relationship, and 
other possible contributing factors can be ruled out. The clinical event, including 
an abnormal laboratory test result, occurs in a plausible time relationship to drug 
administration and cannot be explained by concurrent disease or other drugs or 
chemicals. The response to withdrawal of the drug (dechallenge) should be 
clinically plausible. The event must be pharmacologically or phenomenologically 
definitive, with use of a satisfactory rechallenge procedure if necessary. 
• Probably Related: There is evidence to suggest a causal relationship, and the 
influence of other factors is unlikely. The clinical event, including an abnormal 
laboratory test result, occurs within a reasonable time after administration of the 
drug, is unlikely to be attributed to concurrent disease or other drugs or chemicals, 
and follows a clinically reasonable response on withdrawal (dechallenge). 
Rechallenge information is not required to fulfill this definition. 
• Possibly Related: There is some evidence to suggest a causal relationship (e.g., 
the event occurred within a reasonable time after administration of the trial 
medication). However, other factors may have contributed to the event (e.g., the 
participant’s clinical condition, other concomitant events). Although an AE may rate 
only as “possibly related” soon after discovery, it can be flagged as requiring more 
information and later be upgraded to “probably related” or “definitely related,” as 
appropriate. 
• Unlikely to be related: A clinical event, including an abnormal laboratory test 
result, whose temporal relationship to drug administration makes a causal 
relationship improbable (e.g., the event did not occur within a reasonable time after 
administration of the trial medication) and in which other drugs or chemicals or 
underlying disease provides plausible explanations (e.g., the participant’s clinical 
condition, other concomitant treatments). 


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• Not Related: The AE is completely independent of study drug administration, 
and/or evidence exists that the event is definitely related to another etiology. There 
must be an alternative, definitive etiology documented by the clinician. 
 
8.9. 
Non-serious Adverse Event Collection Reporting  
The collection of non-serious AE information should begin from the start of conditioning 
regimen. All non-serious adverse events (not only those deemed to be treatment-related) should 
be collected continuously during the treatment period and for a minimum of 30 days following 
the last dose of study drug.  
 
Non-serious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious. Follow-up is also required for non-serious AEs that cause interruption or 
discontinuation of study drug and for those present at the end of study treatment as appropriate. 
 
8.10. 
Expectedness 
The Principal investigator and/or sub-investigator(s) will be responsible for determining whether 
an AE is expected or unexpected. An AE will be considered unexpected if the nature, severity, 
or frequency of the event is not consistent with the risk information previously described for the 
study agent. 
 
8.11. 
Reporting of Pregnancy 
Procedures for Reporting Drug Exposure during Pregnancy and Birth Events: If a woman 
becomes pregnant or suspects that she is pregnant while participating in this study, she must 
inform the investigator immediately and permanently discontinue study drug(s). The pregnancy 
must be followed for the final pregnancy outcome (i.e., delivery, still birth, miscarriage) and PI 
will request this information from the investigator. If a female partner of a male patient becomes 
pregnant during the male patient’s participation in this study, this must be reported to PI 
immediately.  Every effort should be made to follow the pregnancy for the final pregnancy 
outcome. 
The pregnancy must be reported immediately to the principal investigator, and the Clinical 
Trials Office, by emailing: NYUPCCsafetyreports@nyulangone.org.  Pregnancy in itself 
is not regarded as an adverse event unless there is a suspicion that the investigational 
product may have interfered with the effectiveness of a contraceptive medication. 
8.12. 
Reporting Procedures - Notifying the IRB 
Federal regulations require timely reporting by investigators to their local IRB of 
unanticipated problems 
posing risks to subjects or others. The following describes the 
NYULH IRB reporting requirements, 
though Investigators at participating sites are 
responsible for meeting the specific requirements of their IRB of record.   
 
Report promptly, but no later than 5 working days: 
Researchers are required to submit reports of the following problems promptly but no later 
than 5 working days from the time the investigator becomes aware of the event: 
• 
Unanticipated problems including adverse events that are unexpected and 
related 
– 
Unexpected: An event is “unexpected” when its specificity and 


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severity are not accurately 
reflected in the protocol-related 
documents, such as the IRB-approved research protocol, any 
applicable investigator brochure, and the current IRB-approved 
informed consent document 
and other relevant sources of 
information, such as product labeling and package inserts. 
– 
Related to the research procedures: An event is related to the 
research procedures if in the opinion of the principal investigator, 
the event was more likely than not to be caused by the research 
procedures. 
– 
Harmful: either caused harm to subjects or others, or placed them at 
increased risk 
 
Other Reportable events: 
The following events also require prompt reporting to the IRB, though no later than 5 working 
days: 
• 
Complaint of a research subject when the complaint indicates unexpected 
risks or the complaint cannot be resolved by the research team. 
• 
Protocol 
deviations 
or 
violations 
(includes 
intentional 
and 
accidental/unintentional deviations from the IRB approved protocol) for 
any of the following situations: 
– 
one or more participants were placed at increased risk of harm 
– 
the event has the potential to occur again 
– 
the deviation was necessary to protect a subject from immediate 
harm 
• 
Breach of confidentiality 
• Incarceration of a participant when the research was not previously 
approved under Subpart C and the investigator believes it is in the best 
interest of the subject to remain on the study. 
New Information indicating a change to the risks or potential benefits of the 
research, in terms of severity or frequency. (e.g. analysis indicates lower-than-
expected response rate or a 
more severe or frequent side effect; Other 
research finds arm of study has no therapeutic value; FDA labeling change or 
withdrawal from market) 
 
8.13. 
Reporting Process 
The reportable events noted above will be reported to the IRB using the form: “Reportable 
Event Form” or as a written report of the event (including a description of the event with 
information regarding its fulfillment of the above criteria, follow-up/resolution and need 
for revision to consent form and/or other study documentation). 
 
Copies of each report and documentation of IRB notification and receipt will be kept in the 
Clinical Investigator’s study file. 
 
8.14. Other Reportable events: 
• 
Exceptions to the study protocol 
Exceptions to the protocol must investigator’s IRB approval before they are 
initiated. Any protocol deviations initiated without the investigator’s 
IRB 
approval that may affect the scientific soundness of the study, or affect the 


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rights, safety, or 
welfare of study subjects, must be reported to the 
investigator’s IRB as soon as a possible, but no later than 5 working days of 
the protocol deviation. 
 
 8.15. 
Study Halting Rules 
8.15.1.  Removal of Subjects from Study 
8.15.1.1. 
The investigator will make every reasonable effort to keep each patient in 
the study until all planned treatments and assessments have been 
performed. Unplanned discontinuation may occur for any of the following 
reasons: 
• 
Patient develops allergy to either study drug. 
• 
Treating physician feels that continuation in study is not 
appropriate.  Such a determination may be made if the patient 
experiences adverse events related to the study protocol of ≥ 
grade 3 other than hematologic or infection-related toxicity that 
the physician or PI determines the study is no longer in the 
subject’s best interest. 
• 
Patient withdraws informed consent. 
• 
Patient is not meeting the follow up requirements. 
8.15.1.2. 
If patients fail to complete the study doses of cyclophosphamide and 
bortezomib, alternative GVHD prophylaxis will be instituted immediately at 
the discretion of the treating physician.  
8.15.1.3. 
The PI can decide to replace patients withdrawn from the study at his 
discretion. All patients who receive the study drugs will be evaluated.  The 
study will enroll patients for a total of 47 evaluable patients, expected to be 
accrued over three years. 
8.15.1.4. 
Premature Closure of Study: This study may be prematurely terminated, 
if in the opinion of the sponsor-investigator, there is sufficient reasonable 
cause. Written notification documenting the reason for study termination 
will be provided by the terminating party. Circumstances that may warrant 
termination include but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable 
risk to patients, 
• 
Failure to enter patients at an acceptable rate, 
• 
Failure Insufficient adherence to protocol requirements,  
• 
Insufficient complete or evaluable data,  
• 
 Plans to modify, suspend, or discontinue the development 
of the drug. 
 
8.16. 
Safety Oversight 
All Internal SAEs reported by the CTO, occurring to patients on clinical trials that are not 
monitored 
by 
any 
other 
institution 
or 
agency, 
are 
reported 
via 
email: 
NYUPCCsafetyreports@nyulangone.org and reviewed within 48 hours by the medical 
monitor. Based on the review, one of three determinations will be made: 
 
SAE report is considered to be adequate 
Queries for clarification to PI regarding treatment attribution and/or resolution of SAE or 
completeness of other information. The committee may request a cumulative review of all 
SAEs on the study to date. 


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Request for full DSMC committee review of protocol at the next scheduled meeting. 
 
The DSMC Coordinator will record the committee’s decision and incorporate it into the study 
summary for the next scheduled study review. 
9. CLINICAL MONITORING  
Clinical site monitoring is conducted to ensure that the rights and well-being of human subjects are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of the 
trial is in compliance with the currently approved protocol/amendment(s), with GCP, and with applicable 
regulatory requirement(s). 
 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her site.  This 
safety monitoring will include careful assessment and appropriate reporting of adverse events as noted 
above, as well as the construction and implementation of a site data and safety-monitoring plan detailed 
below.  Adverse events are evaluated regularly by the principal investigator in conjugation with the 
research team, the DSMC is notified of adverse events via email initially, and then reviewed at the next 
DSMC monthly meeting.  The Data Safety and Monitoring Committee (DSMC) will review the study at 
least quarterly.  Medical monitoring will include a regular assessment of the number and type of serious 
adverse events. 
9.1. 
Data Monitoring Committee 
This investigator-initiated study will be monitored by the Data Safety Monitoring Committee 
(DSMC) of the New York University (NYU) Perlmutter Cancer Center (PCC). The DSMC 
operates based on the 2017 National Cancer Institute approved Charter.  It is an existing and 
multidisciplinary committee (consisting of clinical investigators/oncologists, biostatisticians, 
nurses, and research administration staff knowledgeable of research methodology and design 
and in proper conduct of clinical trials) that is responsible for monitoring safety, conduct and 
compliance in accordance with protocol data monitoring plans for interventional clinical trials 
conducted in the NYULH Perlmutter Cancer Center that are not monitored by another institution 
or agency. The DSMC reports to the Director of the NYULH PCC.   
 
Per the NYU PCC Institutional Data Safety and Monitoring Plan, this Phase II trial will be 
monitored by DSMC quarterly (from the date the first patient is enrolled), at protocol-specified 
interim time points, and at the completion of the study prior to study closure.  This review 
includes accrual data, subject demographics and adverse events. Principal Investigators 
are required to attend the review of their studies. Additional reviews can be scheduled 
based on SAE reports, investigator identified issues, external information, etc.  DSMC 
summary reports are available to facilitate the review and monitoring of this study.    These 
reports include the following:  patient listings and summary reports that describe study 
enrollment and accrual, eligibility, demographic characteristics, dose modifications, 
adverse experiences, subject’s death and additional external published data if applicable 
to the study.  Cumulative toxicities, SAEs, and AEs are reviewed, to identify possible 
adverse events with elevated frequency that is unexpected.  Once a recommendation is 
made if further action is required, the Investigator’s must respond within the timeframe 
specified by the DSMC. 
 
10 STATISTICAL CONSIDERATIONS 
 


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10.1 
Sample size: The primary outcome variables for this study include the incidence of acute and 
chronic GvHD.  For sample size considerations, we focus on the rate of acute GvHD. If we 
assume that the rate of acute GvHD grades II-IV with standard of care is 50% as reported in the 
literature and 30% in the experimental group, we can detect a reduction in acute GvHD 
incidence to 30% for high-dose post-transplant cyclophosphamide and bortezomib (CyBor) , 
with alpha = 0.05 (2 sided) and power of 80% with 47 patients using a z test for the test of the 
observed percentage compared to an expected percentage of 50%. With 47 patients, the 
observed 95% confidence interval will 35.1% to 64.9% if the observed rate is 50%; if the 
observed rate is 30%, the corresponding confidence interval will be 17.5% to 45.1%. 
 
The corresponding 95% confidence interval for the rate of chronic GvHD, expected to be 20% 
is 9.8% to 34.2%. 
 
Calculations from PASS 2014, NCSS, J. Hintze,Kaysville, Ut. 
 
10.2 
Statistical Analysis:  
Baseline Descriptive Statistics: Patient characteristics will be summarized using descriptive 
statistics. For qualitative characteristics (such as gender, co-morbid conditions, donor source, 
CMV status amongst others) proportions and frequency distributions will be provided. For 
quantitative characteristics including hematologic parameters, summary and graphical displays 
will be provided.  
10.3 
Analysis of the Primary Efficacy Endpoint(s):  
10.3.1 Acute GvHD: The first day of acute GvHD of any grade will be recorded for that grade. 
This end point will be evaluated through day +120 post-transplant. The diagnosis of acute 
GvHD is based on clinical and pathological evaluation by the principal investigator in 
collaboration with the treating physician. The acute GvHD grading system is described in 
appendix B. All participants that received a transplant and received any prophylactic 
treatment will be included in the analysis. An additional analysis will be carried out for all 
patients that received a transplant and completed prophylactic treatment with evaluation 
from date of completion of prophylactic treatment.  Cumulative incidence curves will be 
provided along with 95% confidence intervals for the 120 day cumulative incidence.  
10.3.2 Chronic GvHD: The first day of chronic GvHD will be recorded. The diagnosis of chronic 
GvHD is based on clinical and pathological evaluation by the principal investigator in 
collaboration with the treating physician. The chronic GvHD system is described in 
appendix C. The analysis will be based on the maximum grade of chronic GvHD. All 
participants that completed transplant  and any prophylactic treatment will be included in 
the  analysis. An additional analysis will be carried out for all patients that received a 
transplant and completed prophylactic treatment with evalution from date of completion of 
prophylactic treatment.  Cumulative incidence curves will be provided along with 95% 
confidence intervals for the day 365 cumulative incidence.  
Additional descriptive analysis will be provided for any GvHD. 
10.4 
Analysis of the Secondary Endpoint(s): 
All analyses of secondary endpoints will be based on cumulative incidence curves of 
Kaplan Meier curves to estimate the rates of occurrence as defined for each endpoint. 


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10.4.1 Primary graft failure is evaluated to day +45 and incidence of graft failure will be 
calculated from date of transplant to failure for all patients who receive a transplant and 
any prophylactic treatment and from date of completion of prophylactic treatment for all 
participants that completed treatment.   
10.4.2 Poor graft function is evaluated to day +30 incidence of poor graft function will be 
calculated, from date of transplant to failure for all patients who receive a transplant and 
any prophylactic treatment and from date of completion of prophylactic treatment for all 
participants that completed treatment.   
10.4.3 Secondary graft failure is evaluated after engraftment is achieved will be calculated from 
date of engraftment for all patients with engraftment.   
10.4.4 TRM will be analyzed based on participants that who received a transplant with any 
prophylactic treatment and for all patients who received a transplant and completed 
prophylactic treatment.  
10.4.5 RR is evaluated to day +730 and will be analyzed for all patients who received a transplant 
and for all transplanted patients that completed treatment. 
10.4.6 GRFS is evaluated to day +730 and considers as successes  participants that are without 
reported GvHD III-IV acute GvHD, chronic GvHD requiring systemic therapy and have not 
experienced relapse or death after transplant.  
10.4.7 OS is evaluated to day +730 and considers all participants who received a transplant and 
for all transplanted patients who completed prophylactic treatment as described above. .  
10.5 
Missing data: Distribution of patients and disease characteristics will be summarized for patients 
with missing data regarding key endpoints or who are non-compliant.  Comparisons will be made 
to patients who complete the study to evaluate bias. 
10.6 
Safety Analyses: All adverse events (expected and unexpected) will be tracked and graded per 
CTCAE, version 5.0 over time.  In addition, the attributed relationship to study drug will be 
summarized. All adverse events will be reviewed by the primary investigator, in conjunction with 
the sub-investigators to determine safety. 
11 SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA AND DOCUMENTS 
 
Source data is all information, original records of clinical findings, observations, or other activities 
in a clinical trial necessary for the reconstruction and evaluation of the trial.  Source data are 
contained in source documents.  Examples of these original documents, and data records include: 
hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies or transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at 
the pharmacy, at the laboratories, and at medico-technical departments involved in the clinical 
trial. It is acceptable to use CRFs as source documents. If this is the case, it should be stated in 
this section what data will be collected on CRFs and what data will be collected from other 
sources. 


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TrialMaster, an electronic database capture system will be created to record the data 
for this trial. Research coordinators will input clinical trial data into the database. This 
database is password protected and only the PI, assigned study team members, and 
CTO staff will have access to the database. DataCore, a core resource of the institution, 
will provide the primary data collection instrument for the study. All data requested in the 
system must be reported. All missing data must be explained. The quality assurance 
(QA) specialists will monitor this trial every 4-6 weeks for data entry accuracy. 
 
Source documentation should be consistent with data entered into any electronic medical 
record or TrialMaster. Relevant source documentation to be reviewed by the QA specialists 
throughout the study includes but are not limited to: 
1. Baseline measures to assess pre-transplant  status 
2. Treatment records 
3. Adverse events 
12 ADMINISTRATIVE REQUIREMENTS 
 
12.1 
Good Clinical Practice: The study will be conducted in accordance with the International 
Conference on Harmonization (ICH) for Good Clinical Practice (GCP) and the appropriate 
regulatory requirement(s).85 The investigator will be thoroughly familiar with the appropriate use 
of the study drugs as described in the protocol and Investigator’s Brochures. Essential clinical 
documents will be maintained to demonstrate the validity of the study and the integrity of the data 
collected.  Master files should be established at the beginning of the study, maintained for the 
duration of the study, and retained according to the appropriate regulations. 
 
12.1.1 Ethical Considerations: The study will be conducted in accordance with ethical principles 
founded in the Declaration of Helsinki. The IRB will review all appropriate study 
documentation in order to safeguard the rights, safety and well-being of the patients. The 
study will only be conducted at sites where IRB approval has been obtained. The protocol, 
Investigator’s Brochure, informed consent, advertisements (if applicable), written 
information given to the patients, safety updates, annual progress reports, and any 
revisions to these documents will be provided to the IRB by the investigator. 
 
Protocol Compliance: The investigator will conduct the study in compliance with the 
protocol, and given approval by the IRB, and the appropriate regulatory authority(ies). Any 
departures from the protocol must be fully documented in the source documents 
 
12.2 
Patient Information and Informed Consent: After the study has been fully explained, 
written informed consent will be obtained from the patient.  The method of obtaining and 
documenting the informed consent and the contents of the consent will comply with ICH-GCP and 
all applicable regulatory requirement(s). 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate 
in the study 
and continues throughout the individual’s study participation. Extensive 
discussion of risks and possible benefits of participation will be provided to the participants 


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and their families. Consent forms will be IRB-approved and the participant will be asked to 
read and review the document. The investigator will explain 
the research study to the 
participant and answer any questions that may arise. All participants will receive a verbal 
explanation in terms suited to their comprehension of the purposes, procedures, and potential 
risks of the study and of their rights as research participants. Participants will have the 
opportunity to carefully review the written consent form and ask questions prior to signing. 
The participants should have the opportunity to discuss the study with their surrogates or 
think about it prior to agreeing to participate. The participant will sign the informed consent 
document prior to any procedures being done specifically for the study.  The participants may 
withdraw consent at any time throughout the course of the trial. A copy of the signed informed 
consent document will be given to the participants for their records. The rights and welfare 
of the participants will be protected by emphasizing to them that the quality of their medical 
care will not be adversely affected if they decline to participate in this study. 
A copy of the signed informed consent document will be stored in the subject’s research 
record. The consent process, including the name of the individual obtaining consent, will be 
thoroughly documented in 
the subject’s research record. Any alteration to the standard 
consent process (e.g. use of a translator, consent from a legally authorized representative, 
consent document presented orally, etc.) and the justification for such alteration will likewise 
be documented. 
The consenting process and documentation will follow Standard Operating Procedures 
(Obtaining Informed Consent for Clinical Trials) of the NYULH PCC CTO. 
12.2.1. Informed Consent 
Consent will be obtained only by a participating investigator who has completed 
requisite training for human subject research and has been instructed by the 
Principal Investigator about the research study and consent process. Investigators 
will review the informed consent form with patients and address any questions or 
concerns prior to obtaining written informed consent for participation and HIPAA 
authorization. 
For non-English speaking patients, institutional translation services will be utilized. 
All procedures for consenting non-English speaking patients will be in accordance 
with NYU Langone Health PCC CTO guidelines and policies. 
For patients who cannot read; a witness, not related to the research study will be 
present. The consent will be read to the patient. The patient will also be allowed 
to ask any questions s/he may have. The investigator will ask the patient questions 
to ensure s/he understands the study. If the investigator determines the subject 
understands the study, the patient will mark an X where his/her name would go and 
the witness will sign the consent form. 
12.2.2. Documentation of Consent 
The Principal Investigator or IRB approved sub-investigator will be responsible for 
documentation in the 
medical record that consent has been obtained from all 
participants. A signed copy of the consent form 
will be given to each participant. 
Original consent forms will be stored in the subject’s medical chart. 


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12.2.3. Patient and Data Confidentiality: In order to maintain patient privacy, all information 
obtained in connection with this study which identifies the patient will remain confidential 
in accordance with state and federal law.  
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
Those regulations require a signed subject authorization informing the subject of the 
following:  
• 
What protected health information (PHI) will be collected from subjects in this 
study 
• 
Who will have access to that information and why 
• 
Who will use or disclose that information  
• 
The rights of a research subject to revoke their authorization for use of their 
PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of 
subject authorization.  For subjects that have revoked authorization to collect or use PHI, 
attempts should be made to obtain permission to collect at least vital status (i.e. that the 
subject is alive) at the end of their scheduled study period. 
 
Participant confidentiality is strictly held in trust by the participating investigators and their 
staff. This confidentiality is extended to cover testing of biological samples and genetic 
tests in addition to the clinical information relating to participants. Therefore, the study 
protocol, documentation, data, and all other information generated will be held in strict 
confidence. 
 
Representatives of the IRB may inspect all documents and records required to be 
maintained by the investigator, including but not limited to, medical records (office, clinic, 
or hospital) and pharmacy records for the participants in this study. The clinical study site 
will permit access to such records. 
 
The study participant’s contact information will be securely stored at each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept 
in a secure location for as long a period as dictated by local IRB and Institutional 
regulations. 
 
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored at NYU Langone Health. This will not include 
the participant’s contact or identifying information. Rather, individual participants and their 
research data will be identified by a unique study identification number. The study data 
entry and study management systems used by clinical sites and by NYU Langone Health 
research staff will be secured and password protected. At the end of the study, all study 
databases will be de-identified and archived at the NYU Langone Health. 


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13 DATA HANDLING AND RECORD KEEPING 
13.1. 
Data Collection and Management Responsibilities 
Data collection is the responsibility of the clinical trial staff at the site under the 
supervision of the site PI. The investigator is responsible for ensuring the accuracy, 
completeness, legibility, and timeliness of the data reported. 
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data. Black ink is required to ensure clarity of reproduced copies. When 
making changes or corrections, cross out the original entry with a single line, and initial 
and date the change. DO NOT ERASE, OVERWRITE, OR USE CORRECTION FLUID 
OR TAPE ON THE ORIGINAL. 
Data reported in the eCRF derived from source documents should be consistent with 
the source documents or the discrepancies should be explained 
and captured in a 
progress note and maintained in the participant’s official electronic study record. 
Clinical data (including AEs, concomitant medications, and expected adverse reactions 
data) and clinical laboratory data will be entered into Trialmaster, a 21 CFR Part 11-
compliant 
data capture system provided by DataCore. The data system includes 
password protection and internal quality checks to identify data that appear inconsistent, 
incomplete, or inaccurate. Clinical data will be entered directly from the source 
documents. 
 
13.2. 
Study Records Retention 
The sponsor-investigator will maintain all study records according to ICH-GCP and applicable 
regulatory requirement(s).  
 
13.3. Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or Manual of 
Procedures (MOP) requirements. The noncompliance may be either on the part of the participant, 
the investigator, or 
the study site staff. As a result of deviations, corrective actions are to be 
developed by the site and implemented promptly. 
These practices are consistent with ICH E6: 
• 4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 
• 5.1 Quality Assurance and Quality Control, section 5.1.1 
• 5.20 Noncompliance, sections 5.20.1, and 5.20.2. 
 
Protocol deviations must be reported to the local IRB per their guidelines. The site PI and 
study staff is responsible for knowing and adhering to their IRB requirements.  All protocol 
deviations must be addressed in study source documents and reported to IRB Program 
Official at the time of annual continuing review.  If a protocol deviation is determined to be 
reportable new information, the IRB will be notified immediately. 
 
13.4. Publication and Data Sharing Policy 


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This study will comply with the NIH Public Access Policy, which ensures that the public has 
access to the published results of NIH funded research. It requires scientists to submit final 
peer-reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed 
Central upon acceptance for publication. 
The International Committee of Medical Journal Editors (ICMJE) member journals have 
adopted a clinical 
trials registration policy as a condition for publication. The ICMJE 
defines a clinical trial as any research project that prospectively assigns human subjects 
to intervention or concurrent comparison or control groups to study the cause-and-effect 
relationship between a medical intervention and a health outcome. Medical interventions 
include drugs, surgical procedures, devices, behavioral treatments, process-of-care 
changes, and the like. Health outcomes include any biomedical or health-related measures 
obtained in 
patients or participants, including pharmacokinetic measures and adverse 
events. The ICMJE policy, and the Section 801 of the Food and Drug Administration 
Amendments Act of 2007, requires that all clinical trials be registered in a public trials 
registry such as ClinicalTrials.gov, which is sponsored by the National Library of Medicine. 
Other biomedical journals are considering adopting similar policies. For interventional 
clinical trials performed under NIH IC grants and cooperative agreements, it is the grantee’s 
responsibility to register the trial in an acceptable registry, so the research results may be 
considered for publication in ICMJE member journals. The ICMJE does not review specific 
studies to determine whether registration is 
necessary; instead, the committee 
recommends that researchers who have questions about the need to register err on the 
side of registration or consult the editorial office of the journal in which they wish to publish. 
Study results may be published, and patients may access the results of this study via 
clinicaltrails.gov or any published media.  However, no results will be sent directly to subjects. 
The study will be available on clinicaltrials.gov. 
14 STUDY FINANCES 
 
14.1 
Funding Source 
All study elements are standard of care and will be billed to third parties. The data management 
cost will be covered by the Disease Management Group (DMG).  
 
14.2. Costs to the Participant 
All aspects of care, including conditioning regimen and GvHD prevention is considered standard 
of care and will be billed to the insurance company or patient. 
 
14.3 
Participant Reimbursements or Payments 
No subject will receive payments or stipends for participation in this research study.   
 
15 CONFLICT OF INTEREST POLICY 
 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial 
gain greater than the minimum allowable by their institution, etc.) must have the conflict reviewed by 


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a properly 
constituted Conflict of Interest Committee with a Committee-sanctioned conflict 
management plan prior to participation in this study. All NYULH 
investigators will follow the 
applicable University conflict of interest policies. 
16 REFERENCES 
1. Appelbaum FR. Hematopoietic cell transplantation at 50. N Engl J Med 2007;357:1472-1475. 
2. Welniak LA, Blazar BR, Murphy WJ. Immunobiology of allogeneic hematopoietic stem cell 
transplantation. Annu Rev Immunol 2007;25:139–170. 
3. Remberger M, Ackefors M, Berglund S, Blennow O, Dahlöf G, Dlugosz A, at al. Improved survival 
after allogeneic hematopoietic stem cell transplantation in recent years. A single-center study. BBMT 
2011; 17:1688-1697. 
4. Arai S, Arora M, Wang T, Spellman S, He W, Couriel D, et al. Increasing incidence of chronic graft-
versus-host disease in allogeneic transplantation- A report from CIBMTR. BBMT 2014; 21:266-274. 
5. Cutler C, Li S, Ho VT, Koreth J, Alyea E, Soiffer RJ, et al. Extended follow-up of methotrexate-free 
immunosuppression using sirolimus and tacrolimus in related and unrelated donor peripheral blood 
stem cell transplantation. Blood 2007; 109:3108–3114. 
6. Luznik L, O’Donnell PV, Fuchs EJ. Post-transplantation cyclophosphamide for tolerance induction in 
HLA-haploidentical BMT. Semin Oncol 2012; 39:683:693.  
 
7. Ross D, Jones M, Komanduri K, Levy RB. Antigen and lymphopenia-driven donor T cells are 
differentially diminished by post-transplantation administration of cyclophosphamide after 
hematopoietic cell transplantation. BBMT 2013; 19:1430-1438. 
8. Luznik L, Bolaños-Meade J, Zahurak M, et al. High-dose cyclophosphamide as single-agent, short-
course prophylaxis of graft-versus-host disease. Blood 2010; 115: 3224-3230. 
9. Kankary GK, O’Donnell PV, Furlong T, de Lima MJ, Wei W, Medeot M, et al. Multi-institutional study 
of post-transplant cyclophosphamide as single-agent graft-versus-host disease prophylaxis after 
allogeneic bone marrow transplantation using myeloablative busulfan and fludarabine conditioning. 
Journal Clin Oncol 2014; 32:3497-3505. 
10. Al-Homsi AS, Roy TS, Cole K, Feng Y, Duffner U. Post-transplant high-dose cyclophosphamide for 
the prevention of graft-versus-host disease. BBMT 2015; 21:604-611.  
11. Alousi AM, Brammer JE, Saliba RM, Andersson B, Popat Y, Hosing C, et al. Phase II trial of graft-
versus-host disease prophylaxis with post-transplant cyclophosphamide after reduced-intensity 
busulfan/fludarabine conditioning for hematological malignancies. BBMT; 2015: 21:906-912.  
12. Solomon SR, Sanacore M, Zhang X, Brown S, Holland K, Morris LE, Bashey A. Calcineurin inhibitor-
free graft –versus-host disease with post-transplantation cyclophosphamide and brief course 
sirolimus following reduced-intensity peripheral blood stem cell transplantation. BBMT 2014; 
20:1828-1834.  
13. Carnevale-Schiannca F, Caravelli D, Gallo S, Coha v, D’Ambrosio L, Vassallo E, Fizzotti M, Nesi F, 
Gioeni L, Berger M, Polo A, Gammaitoni L, Becco P, Giraudo L, Mangioni M, Sangiolo D, Grignani 
G, Rota-Scalabrini D, Aglietta M. Post-transplant cyclophosphamide and tacrolimus-mycophenolate 
mofetil combination prevents graft-versus-host disease in allogeneic peripheral blood hematopoietic 
cell transplantation from HLA-matched donors. BBMT 2017; 3:459-466. 
14. Bolaños-Meade J, Reshef R, Fraser R, Fei M, Abhyankar S, Al-Khadimi Z, Alousi AM, Antin JH, 
Bickett K, Damon LE, Efebera YA, Geller N, Giralt SA, hari P, Holtan SG, Horowitz MM, Jacobson 


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D, Jones RJ, Liesveld J, Logan BR, MacMilan ML, Mielcarek MB, Noel P, Pidala JA, Porter DL, 
Weisdorf DJ, Wu J, Pasquini MC, Koreth J. Novel approaches for graft-versus-host disease (GvHD) 
prophylaxis: primary results of Progress I multicenter trial of matched allogeneic hematopoietic cell 
transplantation (alloHCT) using reduced intensity conditioning (RIC) BMT CTN 1203. BBMT 2018 
Epub ahead of print. 
15. Markey KA, MacDonald KPA, Hill GR. The biology of graft-versus-host disease: experimental 
systems instructing clinical practice. Blood 2014; 124:345-362. 
16. Matte CC, Liu J, Cormier J, Anderson BE, Athannasiadis I, et al. Donor APCs are required and are 
sufficient for the development of GvHD but not GvL. Nature Medicine 2004; 10:978-992. 
17. Boeck S, Hamann M, Pihusch V, Heller T, Diem H, Rolf B, et al. Kinetics of dendritic cee chimerism 
and T cell chimerism in allogeneic hematopoietic stem cell recipients. Bone Marrow Transplantation 
2006; 37:57-64. 
18. Tao Y, Zhang W, Fang Y, Yang D, Wang L, Zhou H, Wang J. Bortezomib attenuates acute graft-vs.-
host disease through interfering with host immature dendritic cells. Exp Hematol 2011; 39:710-720. 
19. Sun K, Welniak LA, Panoskaltsis-Mortari A, O'Shaughnessy MJ, Liu H, Barao I, Riordan W, Sitcheran 
R, Wysocki C, Serody JS, Blazar BR, Sayers TJ, Murphy WJ. Inhibition of acute graft-versus-host 
disease with retention of graft-versus-tumor effects by the proteasome inhibitor bortezomib. Proc 
Natl Acad, Sci U S A 2004; 101:8120-8125. 
20. Nencioni A, Grünebach F, Patrone F, Ballestretro A, Brossart R. The proteasome and its inhibitors 
in immune regulation and immune disorders. Critical Reviews in Immunology 2006; 26:487-497. 
21. Al-Homsi AS, Lai Z, Roy T, Kouttab N. Effect of novel proteasome inhibitors on dendritic cell 
maturation, function, and expression of IκB and NF-κB. Transpl Immunol 2013, 29:1-6. 
22. Al-Homsi As, Lai Z, Roy TS, Al-Malki MM, Koutab N, Junghans RP. Post-transplant 
cyclophosphamide and bortezomib inhibit dendritic cell maturation and function and alter their IκB 
and NF-κB expression. Transpl Immunol 2014; 30:40-45.  
23. Sun K, Wilkins DEC, Anver MR, Sayers TJ, Panoskaltsis-Mortaari A, Blazar BR, Welniak LA, Murphy 
WJ. Differential effects of proteasome inhibition by bortezomib on murine acute graft-versus-host 
disease (GVHD): delayed administration of bortezomib results in increased GVHD-dependent 
gastrointestinal toxicity. Blood 2005, 106:3293-3299.  
24. Al-Homsi AS, Feng Y, Duffner U, Al-Malki MM, Goodyke A, Cole K, Muilenburg M, Mageed AA. 
Bortezomib for the prevention and treatment of graft-versus-host disease after allogeneic 
hematopoietic stem cell transplantation. Exp Hem 2016; 44: 771-777. 
25. Al-Homsi As, Goodyke A, McLane M, Abdel-Mageed S, Cole K, Muilenburg M, Feng Y. Post-
transplant cyclophosphamide and ixazomib combination rescues mice subjected to experimental 
graft-versus-host disease and is superior to either agent alone. BBMT 2016;23:255-261.  
26. Al-Homsi As, Goodyke A, Cole K, Muilenburg M, McLane M, Abdel-Mageed S, Feng Y. Ixazomib 
Suppresses human dendritic cell and modulates murine graft-versus-host disease in a schedule-
dependent fashion. Exp Hem 2106; 48:50-57. 
27. Koreth J, Stevenson KE, Kim HT, McDonough SM, Bindra B, Armand P, et al. Bortezomib-based 
graft-versus-host disease prophylaxis in HLA-mismatched unrelated donor transplantation. J Clin 
Oncol 2012; 30:3202-3208. 
28. Koreth J, Kim HT, Lange PB, Poryanda SJ, Reynolds CG, Rai SC, Armand P, Cutler CS, Ho VT, 
Glotzbecker B, Yusuf R, Nikiforow S, Chen YB, Dey B, McMasters M, Ritz J, Blazar BR, Soiffer RJ, 
Antin JH, Alyea EP. Bortezomib-based immunosuppression after reduced-intensity conditioning 


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hematopoietic stem cell transplantation: randomized phase II results. Haematologica 2018; 103:522-
530.  
29. Kupperman E, Lee EC, Cao Y, Bannerman B, Fitzgerald M, Berger A, et al. Evaluation of the 
Proteasome Inhibitor MLN9708 in Preclinical Models of Human Cancer. Cancer Research. 2010; 
70:1970-1980. 
30. Al-Homsi AS, Cole K, Bogema M, Duffner U, Williams S, and Mageed A. Short course of post-
transplant cyclophosphamide and bortezomib for graft-versus-host disease prevention after 
allogeneic peripheral blood stem cell transplantation is feasible and yields favorable results: a phase 
I study. BBMT 2015; 21:1315-1320. 
31. Al-Homsi AS, Cole K, Muilenberg M, Duffner U, Abidi M, Willaims S, Mageed A. Phase I-II study of 
calcineurin inhibitor- and mTOR inhibitor-free post-transplant cyclophosphamide and bortezomib 
(CyBor) for the prevention of graft-versus-host disease. BBMT 2017; 23: 1651-1657. 
32. Mohty M. A bit of antithymocyte globulins can take you a long way! BBMT 2012; 47:617-618. 
33. Finke J, Bethge WA, Schomoor C, Ottinger HD, Steljes M, Zander AR, Volin L, Ruutu T, Heim DA, 
Schwerdfeger R, Kolbe K, Mayer J, Maertens J, Linkesch W, Holler E, Koza V, Bornhäusser M, 
Einsele H, kolb HJ, Bertz H, Egger M, Socié G, . Standard graft-versus-host disease prophylaxis with 
or without anti-T cell globulin in haematopoietic cell transplantation from HLA-matched unrelated 
donors: a randomized, open-label, multicenter phase 3 trail. Lancet Oncol 2009; 10:855-864.  
34. Mohty M, Labopin M, Balere ML, Scoié G, Milpied N, Tabrizi R, Ifrah N, Hicheri Y, Dhedin N, Michallet 
M, Buzyn A, Cahn JY, Bourhis JH, Blaise D, Raffoux C, Espérou H, Yakoub-Agha I.  Antithymocyte 
globulins and chronic graft-vs-host disease after myeloablative allogeneic stem cell transplantation 
from HLA-matched unrelated donors: a report from the Societe Francaise de Greffe de Moelle et de 
Therapie Cellulaire. Leukemia 2010; 24: 1867-1874.  
35. Kumar A, Mhaskar AR, Reljic, Mhaskar RS, Hharfan-Dabaja MA, Anasetti C, Mohty M, Djulbegovic 
B. Antithymocyte globulin for acute graft-versus-host disease prophylaxis in patients undergoing 
allogeneic hematopoietic cell transplantation: a systematic review. Leukemia 2012; 26:582-588 
36. Soiffer RJ, Lerademacher J, Ho V, Kan F, Artz A, Champlin RE, Devine S, Isola L, Lazarus HM, 
Marks DI, Porter DL, Waller EK, Horowitz MM, Eapen M. Impact of immune modulation with anti-T 
cell antibodies on the outcome of reduced-intensity allogeneic hematopoietic stem cell 
transplantation for hematologic malignancies. Blood 2011; 117: 6963-6970. 
37. Devellier R, Crocchiolo R, Castagna, Fürst S, El Chiekh J, Faucher C, Prebet T, Etienne A, 
Chabannon C, Vey N, Estemi B, Blaise D. The increase from 2.5 to 5 mg/kg of rabbit anti-thymocyte 
globulin dose in reduced-intensity conditioning reduces acute and chronic GvHD for patients with 
myeloid malignancies undergoing all-SCT. BMT 2012; 47: 639-645. 
17 APPENDICES 
17.1 
Appendix A: Required Study Activities  
17.2 
Appendix B: Acute Graft-Versus-Host Disease Assessment (aGVHD) 
17.3 
Appendix C: Chronic Graft-Versus-Host Disease Assessment (cGVHD) 
17.4 
Appendix D: New York Heart Association (NYHA) Classification of Cardiac Disease 
17.5 
Appendix E: Busulfan Pharmacokinetics Requisition  
 
 
 


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17.1  APPENDIX A: REQUIRED STUDY ACTIVITIES 
 
 
1Pre-transplant: per standard of care 
2Pre-tranplant: collect CBC, CMP, liver function tests, and physical exam, including toxicity assessments 
3 Cyclophosphamide administered Day +3 and Day +4 
4 Bortezomib administered on Day 0 (6 hours after graft infusion) and 72 hours thereafter 
5rATG administered Days -4, -3, and -2 
6Post-chimerism: at neutrophil engraftment, then at least monthly (+/- 7 days) until day +180, and every 3 months (+/- 
7 days) until day +730.  
7Blood samples for immune reconstitution will be collected on days +30, +100, +180, and +365 (+/- 7 days) after 
transplant. 
 
 
 
 
 
 
 
 
Activity 
Pre-
Study1 
Day -7 
to Day -
12 
 
 
Day 0 
Day 
+3 
Day 
+4 
Daily until 
Neutrophil 
Engraftment  
 
Daily until 
discharge 
Twice a 
week 
until 
Engraft
ment 
Weekly 
until 
Day 
+100 (+/- 
3 days) 
Monthly 
until 
Day 
+180 (+/- 
7 days) 
Every 3 
months 
until 
Day+73
0 (2 
years) 
(+/-
7days) 
Study 
team 
procedures 
 
 
 
 
 
 
 
 
 
 
 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
X 
X 
 
 
X 
X 
 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
 
 
 
X 
X 
 
X 
X 
X 
Cychlophophamide3 
 
 
 
X 
X 
 
 
 
 
 
 
Bortezomib4 
 
 
X 
X 
 
 
 
 
 
 
 
rATG5 
 
X 
 
 
 
 
 
 
 
 
 
Toxicity Assessment 
 
X 
X 
 
 
X 
X 
 
X 
X 
X 
GVHD Assessment 
 
 
 
 
 
X 
X 
 
X 
X 
X 
Chimerism6 
 
 
 
 
 
X 
 
 
 
X 
X 
Immune 
Reconstitution 
Samples7 
 
 
 
 
 
 
 
 
 
 
 
Laboratory 
Assessments 
 
 
 
 
 
 
 
 
 
 
 
CBC,CMP 
X 
X 
X 
 
 
X 
 
 
X 
X 
X 
LFTs 
 
X 
X 
 
 
 
 
X 
X 
X 
X 


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17.2  APPENDIX B: ACUTE GRAFT VERSUS HOST DISEASE ASSESSMENT (aGvHD) 
 
Overall Grade aGvHD 
 
Skin 
Liver 
Gut 
0 none 
0 
0 
0 
1 mild 
1-2 
0 
0 
2 moderate 
1-3 
1 
1 
3 severe 
2-3 
2-3 
2-3 
4 life threatening 
2-4 
2-4 
2-4 
 
 
 
Clinical staging of aGVHD 
Stage 
Skin 
Liver (bilirubin) 
Gastro-intestinal tract 
0 
No rash 
< 2.0 mg/dL 
Diarrhea ≤ 500 ml/day 
1 
Maculopapular rash < 25% of body 
surface 
2.0-3.0 mg/dL 
Diarrhea 501-1000 ml/day or nausea 
with biopsy proof 
2 
Maculopapular rash 25-50% body 
surface 
3.1 – 6.0 mg/dL 
Diarrhea 1001-1500 ml/day 
3 
Generalized erythroderma 
6.1 – 15 mg/d 
Diarrhea > 1500 ml/day 
4 
Generalized erythro-derma with blister 
or 
bullous 
formation 
and 
desquamation 
>15 mg/dL  
Severe abdominal pain without or with 


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17.3  APPENDIX C: CHRONIC GRAFT VERSUS HOST DISEASE ASSESSMENT (cGVHD) 
The involved organs are scored as follows: 
KPS: Karnofsky’s performance status. BSA: body surface area. GI: gastrointestinal. LFT: liver function tests. AP: alkaline 
phosphatase. SOB: shortness of breath. LFS: lung function score (FEV1 and DLCO are converted into numeric scores and 
added to each other to get the LFS: > 80% = 1, 70-79% = 2, 60-69% = 3, 50-59% = 4, 40-49% 5, < 40% 6). ADL: activities 
of daily life. 
 
Score 
Organ 
0 
1 
2 
3 
KPS 
100% 
80-90% 
60-70% 
< 60% 
Skin 
No symptoms 
< 18% BSA  
19-50% 
BSA 
or 
sclerotic 
features but able to pinch 
> 50% BSA or sclerotic changes 
and unable to pinch or with 
impaired mobility 
Mouth 
No symptoms 
Not 
limiting 
oral 
intake 
significantly 
Limiting oral intake partially 
Limiting oral intake severely 
Eyes 
No symptoms 
Dryness, requiring eye-drops ≤ 
3/day 
or 
asymptomatic 
keratoconjunctivitis sicca (KCS) 
Dryness, requiring eye-drops > 
3/day without visual impairment 
Unable to work because of ocular 
symptoms or vision loss 
GI tract 
No symptoms 
< 5% weight loss 
5-15% weight loss 
> 15% weight loss requiring calorie 
supplements 
or 
esophageal 
dilation 
Liver 
Normal LFT 
Elevated bilirubin, AP, AST, or 
ALT < 2 X normal 
Elevated bilirubin, AP, AST, or 
ALT  2-5 X normal 
Elevated bilirubin, AP, AST, or ALT 
. 5 X normal 
Lungs 
No 
symptoms, 
FEV1 > 80% or 
LFS  2 
SOB after 1 flight of steps FEV1 
60-70% or LFS 3-6 
SOB walking flat, FEV1 40-59% 
or LFS 6-9 
SOB at rest or requiring O2, FEV1 
≤ 39% or LFS 10-12 
Joints and 
fascia 
No symptoms 
Mild decrease in range of motion 
not affection ADL 
Moderate decrease in range of 
motion 
with 
moderate 
impairment of ADL 
Significant de-crease in range of 
motion with significant impairment 
of ADL 
Genital 
tract 
No symptoms 
Symptoms and with mild signs 
on exam and no effect on coitus 
Symptoms and with moderate 
signs on exam with discomfort 
on coitus 
Symptoms and with advanced 
signs on exam such as strictures or 
ulcerations with severe pain on 
coitus 
 
The following is checked and scored  (0-3) as applicable: 
Esophageal stricture or web 
Pleural effusions 
Pericardial effusion 
Ascites 
Platelets < 100 109/L 
Eosinophils > 0.5 109/L 
Peripheral neuropathy 
Polymyositis 
Myasthenia gravis 
Coronary artery disease 
Cardiac conduction defects 
Cardiomyopathy 


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Based on the organ scoring the severity of cGVHD is defined as follows:  
Mild cGVHD: involvement of 1-2 organs with maximum scores of 1 in all affected organs or sites.  
Moderate cGVHD: 1. involvement of 1-2 organ involvement with a maximum score of 2 in any affected organ or site (except 
for lungs). 2. involvement of 3 or more organs with maximum score of 1 in all affected organs or sites.  
Severe cGVHD: a lung score of 2 or a score 3 in any organ or site. 
17.4  APPENDIX D: NEW YORK HEART ASSOCIATION CLASSIFICATION OF CARDIAC DISEASE 
The following table presents the NYHA classification of cardiac disease. 
Class 
Functional Capacity 
Objective Assessment 
I 
Patients with cardiac disease but without resulting limitations of 
physical activity.  Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain. 
No 
objective 
evidence 
of 
cardiovascular disease. 
II 
Patients with cardiac disease resulting in slight limitation of physical 
activity.  They are comfortable at rest.  Ordinary physical activity results 
in fatigue, palpitation, dyspnea, or anginal pain. 
Objective 
evidence 
of 
minimal 
cardiovascular disease. 
III 
Patients with cardiac disease resulting in marked limitation of physical 
activity.  They are comfortable at rest.  Less than ordinary activity 
causes fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of moderately 
severe cardiovascular disease. 
IV 
Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort.  Symptoms of heart failure or the 
anginal syndrome may be present even at rest.  If any physical activity 
is undertaken, discomfort is increased. 
Objective 
evidence 
of 
severe 
cardiovascular disease. 
Source:  The Criteria Committee of New York Heart Association.  Nomenclature and Criteria for Diagnosis of Diseases 
of the Heart and Great Vessels.  9th Ed. Boston, MA:  Little, Brown & Co; 1994:253-256. 
 
 
 


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17.5  APPENDIX E: BUSULFAN PHARMACOKINETICS REQUISITION  
 


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Summary of Changes: 
Summary of Changes from Version 1.0 dtd 2019 Apr 26 to Version 1.1 dtd 2019 Aug 27 
Section 7.1.1.2 
Busulfan can be given q6 added.