Clinical trial NCT04503616
Conditions: Graft-versus-host Disease
Sponsor: NYU Langone Health
Start date: 2020-09-16; Completion date: 2024-08-15
Enrollment: 46 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a single arm, open label, optimal 2-stage Simon design phase Ib-II clinical trial. Adult patients with hematological malignancies undergoing allogeneic HSCT from first- or second-degree haploidentical 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 non-myeloablative, reduced-intensity or myeloablative conditioning regimen followed by peripheral blood hematopoietic stem cells. Patients will receive cyclophosphamide, abatacept, and short-duration tacrolimus for GvHD prophylaxis.

Detailed description:

Arms: arm 1: Adult patients with hematological malignancies undergoing HLA-haploidentical HSCT from first-or second-degree family donors.
Interventions: intervention 1: Cyclophosphamide, Abatacept, and Tacrolimus for GvHD Prevention
Intervention descriptions: intervention 1: Cyclophosphamide 50 mg/kg IV over 2 hours on Day +3 and +4 Abatacept 10 mg/kg IV on days +5, +14, and +28 Tacrolimus 0.02 mg/kg IV by continuous infusion, starting on day +5. May switch to oral when tolerated, adjusted to maintain a drug level between 5-12ng/mL. Treatment is discontinued on day +60 after a 4 week-taper

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Official Title: 
A Phase IB-II Study Of High-Dose Post-Transplant Cyclophosphamide, 
Abatacept, and Short-Duration Tacrolimus for the Prevention of Graft-
Versus-Host Disease (GvHD) Following Haploidentical Hematopoietic 
Stem Cell Transplantation (HSCT)   
NCT Number: 
NCT04503616 
Study Number: 
20-00136 
Document Type:  
Study Protocol and Statistical Analysis Plan 
Date of the 
Document: 
• 
July 5, 2022 
 
 


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A 
PHASE 
IB-II 
STUDY 
OF 
HIGH-DOSE 
POST-TRANSPLANT 
CYCLOPHOSPHAMIDE, ABATACEPT, AND SHORT-DURATION TACROLIMUS FOR 
THE PREVENTION OF GRAFT-VERSUS-HOST DISEASE (GVHD) FOLLOWING 
HAPLOIDENTICAL HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT) 
 
Initial version: [May 2020] 
Amended: [February 2020] 
Amended v3: April 2021 
 
Amended v4: June 2021 
Amended v5: Dec 2021 
Administrative Amendment v5.1: 2022 Jun 07 
 
 
Principal Investigator: 
 
A Samer Al-Homsi MD, MBA 
Perlmutter Cancer Center 
240 East 38th Street 
New York, NY 10016 
Samer.Al-Homsi@nyulangone.org 
Biostatistician: 
Judith D. Goldberg, ScD 
Pharmacist: 
Frank Cirrone, PharmD 
NYULH Study Number: 
s20-00136 
Funding Sponsor:  
Perlmutter Cancer Center 
240 East 38th Street 
New York, NY 10016 
IND Number:  
IND 149936 
Regulatory Sponsor:  
Perlmutter Cancer Center  
240 East 38th Street 
New York, NY 10016 
NYULH Medical Monitor: 
David L. Green, MD 
Study Product: 
Cyclophosphamide, abatacept, and tacrolimus 
Study Product Provider:  
Cyclophosphamide, abatacept, and tacrolimus are covered as 
standard of care. 
ClinicalTrials.gov 
Number: 
NCT04503616 


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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 Harmonization (“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 
IB-II 
STUDY 
OF 
HIGH-DOSE 
POST-TRANSPLANT 
CYCLOPHOSPHAMIDE, ABATACEPT, AND SHORT-DURATION TACROLIMUS FOR THE 
PREVENTION 
OF 
GRAFT-VERSUS-HOST 
DISEASE 
(GVHD) 
FOLLOWING 
HAPLOIDENTICAL HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT) 
 
 
Protocol Number: s20-00136 
 
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  
 
STATEMENT OF COMPLIANCE ................................................................................................................. II 
LIST OF ABBREVIATIONS........................................................................................................................ VII 
PROTOCOL SUMMARY .............................................................................................................................. 1 
SCHEMATIC OF STUDY DESIGN ............................................................................................................... 3 
1 
KEY ROLES ......................................................................................................................................... 4 
2 
BACKGROUND RATIONALE ............................................................................................................. 5 
2.1 
POTENTIAL RISKS AND BENEFITS .................................................................................................... 7 
2.1.1 
Known Potential Risks ............................................................................................................. 7 
2.1.2 
Other Risks of Study Participation........................................................................................... 8 
2.1.3 
Known Potential Benefits ........................................................................................................ 8 
3 
OBJECTIVES AND PURPOSE ........................................................................................................... 9 
3.1 
STUDY HYPOTHESIS ....................................................................................................................... 9 
3.2 
STUDY OVERVIEW .......................................................................................................................... 9 
3.3 
OBJECTIVES .................................................................................................................................. 9 
3.3.1 
Primary Objectives .................................................................................................................. 9 
3.3.2 
Secondary Objectives ............................................................................................................. 9 
3.4 
STUDY ENDPOINTS......................................................................................................................... 9 
3.4.1 
Primary Study Endpoints ......................................................................................................... 9 
3.4.2 
Secondary Study Endpoints .................................................................................................... 9 
3.5 
DEFINITIONS ................................................................................................................................ 10 
4 
STUDY ENROLLMENT AND WITHDRAWAL .................................................................................. 10 
4.1 
INCLUSION CRITERIA .................................................................................................................... 10 
4.2 
EXCLUSION CRITERIA ................................................................................................................... 11 
4.3 
INCLUSION OF WOMEN, MINORITIES, AND VULNERABLE POPULATIONS ............................................ 11 
4.4 
STRATEGIES FOR RECRUITMENT AND RETENTION .......................................................................... 11 
4.5 
REGISTRATION PROCEDURES ....................................................................................................... 12 
4.6 
DURATION OF STUDY PARTICIPATION ............................................................................................ 13 
4.7 
TOTAL NUMBER OF PARTICIPANTS AND SITES ................................................................................ 13 
4.8 
PARTICIPANT WITHDRAWAL OR TERMINATION ................................................................................ 13 
4.8.1 
Reasons for Withdrawal or Termination ................................................................................ 13 
4.8.2 
Handling of Participant Withdrawals or Termination ............................................................. 13 
4.9 
PREMATURE TERMINATION OR SUSPENSION OF STUDY .................................................................. 13 
4.10 
STOPPING RULES ......................................................................................................................... 14 
5 
STUDY AGENTS ............................................................................................................................... 15 
5.1 
CYTOXAN® (CYCLOPHOSPHAMIDE) ............................................................................................... 15 
5.2 
PROGRAF® (TACROLIMUS) ........................................................................................................... 16 
5.3 
ORENCIA® (ABATACEPT) .............................................................................................................. 19 
5.4 
STUDY AGENT ACCOUNTABILITY PROCEDURES ............................................................................. 22 
5.5 
PRODUCT COMPLAINTS ................................................................................................................ 22 
6 
REQUIRED STUDY ACTIVITIES (APPENDIX A) ............................................................................. 22 
6.1 
RECIPIENT PRE-TRANSPLANT WORK-UP AND ELIGIBILITY FOR TRANSPLANT ................................... 22 
6.2 
DONOR WORK-UP ....................................................................................................................... 22 
6.3 
PRE-TRANSPLANT ........................................................................................................................ 23 
6.4 
POST-TRANSPLANT ...................................................................................................................... 23 
7 
TREATMENT PLAN........................................................................................................................... 23 


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7.1 
CONDITIONING REGIMEN (STUDY SCHEMA) ................................................................................... 23 
7.1.1 
Non-myeloablative conditioning ............................................................................................ 23 
7.1.2 
Reduced-intensity conditioning ............................................................................................. 23 
7.1.3 
TBI-based myeloablative conditioning .................................................................................. 23 
7.1.4 
Non TBI-based myeloablative conditioning ........................................................................... 23 
7.2 
GRAFT INFUSION .......................................................................................................................... 24 
7.3 
GVHD PROPHYLAXIS ................................................................................................................... 24 
7.4 
DRUG PREPARATION .................................................................................................................... 24 
7.5 
SUPPORTIVE CARE ...................................................................................................................... 24 
7.6 
MANAGEMENT OF ACUTE AND CHRONIC GVHD ............................................................................. 24 
7.7 
FOLLOW-UP AND DATA COLLECTION ............................................................................................. 24 
7.8 
ANCILLARY THERAPY.................................................................................................................... 24 
7.9 
DOSE ADJUSTMENTS .................................................................................................................... 24 
8 
ASSESSMENT OF SAFETY ............................................................................................................. 25 
8.1 
SPECIFICATION OF SAFETY PARAMETERS ...................................................................................... 25 
8.2 
ADVERSE EVENTS (AE) ................................................................................................................ 25 
8.2.1 
Definitions of Adverse Events ............................................................................................... 25 
8.2.2 
Reporting an Adverse Event ................................................................................................. 25 
8.3 
SERIOUS ADVERSE EVENTS (SAE) ............................................................................................... 26 
8.3.1 
Definition of Serious Adverse Events .................................................................................... 26 
8.3.2 
Reporting a Serious Adverse Event ...................................................................................... 26 
8.4 
OVERDOSE .................................................................................................................................. 28 
8.5 
OTHER SAFETY CONSIDERATIONS ................................................................................................. 28 
8.6 
DEFINITION OF UNANTICIPATED PROBLEMS (UP) ........................................................................... 28 
8.7 
CLASSIFICATION OF AN ADVERSE EVENT ....................................................................................... 29 
8.8 
NON-SERIOUS ADVERSE EVENT COLLECTION REPORTING ............................................................. 30 
8.9 
EXPECTEDNESS ........................................................................................................................... 30 
8.10 
REPORTING OF PREGNANCY ......................................................................................................... 30 
8.11 
REPORTING PROCEDURES - NOTIFYING THE IRB ........................................................................... 30 
8.12 
REPORTING PROCESS .................................................................................................................. 31 
8.13 
OTHER REPORTABLE EVENTS ....................................................................................................... 32 
8.14 
STUDY HALTING RULES ................................................................................................................ 32 
8.15 
SAFETY OVERSIGHT ..................................................................................................................... 33 
9 
CLINICAL MONITORING .................................................................................................................. 33 
9.1 
DATA MONITORING COMMITTEE .................................................................................................... 33 
10 
STATISTICAL CONSIDERATIONS .................................................................................................. 34 
10.1 
SAMPLE SIZE ................................................................................................................................ 34 
10.2 
STATISTICAL ANALYSIS ................................................................................................................. 34 
10.3 
ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) ...................................................................... 34 
10.4 
ANALYSIS OF THE SECONDARY ENDPOINT(S) ................................................................................. 35 
10.5 
MISSING DATA ............................................................................................................................. 35 
10.6 
SAFETY ANALYSES ....................................................................................................................... 35 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ................................. 36 
12 
QUALITY ASSURANCE AND QUALITY CONTROL ....................................................................... 37 
13 
ADMINISTRATIVE REQUIREMENTS ............................................................................................... 38 
13.1 
GOOD CLINICAL PRACTICE ........................................................................................................... 38 
13.1.1 Ethical Considerations ........................................................................................................... 38 
13.2 
PATIENT INFORMATION AND INFORMED CONSENT .......................................................................... 38 
13.2.1 Informed Consent .................................................................................................................. 39 
13.2.2 Documentation of Consent .................................................................................................... 39 
13.2.3 Posting of Clinical Trial Consent ........................................................................................... 39 


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13.2.4 Participant and Data Confidentiality ...................................................................................... 39 
14 
DATA HANDLING AND RECORD KEEPING ................................................................................... 40 
14.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES .............................................................. 40 
14.2 
STUDY RECORDS RETENTION ....................................................................................................... 41 
14.3 
PROTOCOL DEVIATIONS ............................................................................................................... 41 
14.4 
PUBLICATION AND DATA SHARING POLICY ..................................................................................... 41 
15 
STUDY FINANCES ............................................................................................................................ 42 
15.1 
FUNDING SOURCE ........................................................................................................................ 42 
15.2 
COSTS TO THE PARTICIPANT ......................................................................................................... 42 
15.3 
PARTICIPANT REIMBURSEMENTS OR PAYMENTS ............................................................................ 42 
16 
CONFLICT OF INTEREST POLICY .................................................................................................. 42 
17 
REFERENCES ................................................................................................................................... 43 
18 
APPENDICES .................................................................................................................................... 44 
18.1 
APPENDIX A: REQUIRED STUDY ACTIVITIES ................................................................................... 45 
18.2 
APPENDIX B: ACUTE GRAFT-VERSUS-HOST DISEASE ASSESSMENT (AGVHD) ............................... 46 
18.3 
APPENDIX C: CHRONIC GRAFT-VERSUS-HOST DISEASE ASSESSMENT (CGVHD) ........................... 47 
18.4 
APPENDIX D: NEW YORK HEART ASSOCIATION (NYHA) CLASSIFICATION OF CARDIAC DISEASE ...... 48 
 
 


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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 
ECRF 
EMR 
Event of Clinical Interest 
Electronic Case Report Form 
Electronic Medical Record 
GRFS 
GvHD and relapse-free survival 
GvHD 
Graft-versus-Host Disease 
GvT 
Graft-versus-tumor 
HSCT 
Hematopoietic stem cell transplantation 
LFTs 
Liver function tests 
LPS 
Lipopolysaccharide  
MMF 
Mycophenolate mofetil 
MTX 
Methotrexate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cells 
PI 
Proteasome inhibitors 
PTC 
Post-Transplant cyclophosphamide  
rATG 
Rabbit anti-thymocyte globulin 


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RR 
Relapse rate 
TRM 
Treatment-related mortality 
UP 
Unanticipated Problems 


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1 
Protocol Summary 
Title 
A PHASE IB-II STUDY OF HIGH-DOSE POST-TRANSPLANT CYCLOPHOSPHAMIDE, 
ABATACEPT, AND SHORT-DURATION TACROLIMUS FOR THE PREVENTION OF 
GRAFT-VERSUS-HOST 
DISEASE 
(GVHD) 
FOLLOWING 
HAPLOIDENTICAL 
HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT) 
Short Title 
Cyclophosphamide, abatacept, and tacrolimus for GvHD prevention  
Brief Summary 
This is a single arm, open label, optimal 2-stage Simon design phase Ib-II clinical trial. Adult 
patients with hematological malignancies undergoing allogeneic HSCT from first- or second-
degree haploidentical 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 non-myeloablative, reduced-
intensity or myeloablative conditioning regimen followed by peripheral blood hematopoietic 
stem cells.  Patients will receive cyclophosphamide, abatacept, and short-duration 
tacrolimus for GvHD prophylaxis.  
Phase 
Phase Ib-II 
Objectives 
Primary Objective: 
• 
Estimate the incidence of grade II-IV acute GvHD in patients receiving 
cyclophosphamide, abatacept, and tacrolimus as GvHD prophylaxis. 
Secondary Objectives: 
• 
Estimate the incidence of chronic GvHD in patients receiving cyclophosphamide 
abatacept, and tacrolimus as GvHD prophylaxis 
• 
Estimate the incidence of the following: primary graft failure, poor graft function, and 
secondary graft failure, treatment-related mortality (TRM), relapse rate (RR), 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, 2- stage optimal Simon design with interim futility 
analysis. 
Endpoint 
Primary: Grade II-IV acute GvHD by day +120. 
Secondary: Chronic GvHD, TRM, RR, GRFS, and OS. 
Study Duration 
Study will complete 2 years after the final participant’s date of transplant. Anticipate 4 years 
to complete enrollment and thus a 6-year total duration. 
Participant 
Duration 
Up to 2 years  
Enrollment Period Up to 4 years 
Duration 
of 
IP 
administration 
Up to 4 weeks 
Number 
of 
participants 
46 participants enrolled 


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2 
Description 
of 
Study Procedure 
Cyclophosphamide 50 mg/kg IV over 1 hour on Day +3 and +4 
Abatacept 10 mg/kg IV on days +5, +14, and +28 
Tacrolimus 0.02 mg/kg IV by continuous infusion, starting on day +5. May switch to oral 
when tolerated, adjusted to maintain a drug level between 5-12ng/mL. Treatment is 
discontinued on day +60 after a 4 week-taper 
Key Procedures 
 
Examinations to include toxicity and GvHD assessments and blood draws to assess immune 
reconstitution. 
Statistical 
Analysis 
Sample size: The primary outcome variable for this study is the incidence of grades II-IV 
acute GvHD.  We assume that the rate of grade II-IV acute GvHD, with the standard of care 
is 50%, as reported in the literature and 30% in the experimental group. Based on a 2-stage 
optimal Simon design, we can detect a reduction in the grade II–IV acute GvHD incidence 
to 30% for high-dose post-transplant cyclophosphamide abatacept, and tacrolimus, with 
alpha = 0.05 and power of 82% at the conclusion of the 2-stage design with 46 patients. The 
trial would stop for futility at the end of the first stage if 9 or more patients have grade II-IV 
acute GVHD, of the 22 patients enrolled. Otherwise, the trial will continue to the second 
stage with the total 46 patients enrolled. If the total number of patients with grade II-IV acute 
GVHD is 19 or greater at the end of stage II, the regimen will not be considered for further 
study. The rate of grade II-IV acute GVHD will be estimated at the end of the trial with exact 
95% Clopper Pearson confidence intervals. If the observed rate is 30%, this exact 
confidence interval with 46 patients, the corresponding confidence interval will be 17.4% to 
45.3%. Calculations from PASS 2019, NCSS, J. Hintze, Kaysville, Ut.  
 
The primary analyses will include all patients who are transplanted and receive treatment. 
All endpoints will be evaluated using cumulative incidence functions; exact 95% confidence 
intervals will be provided for the day +120 incidence for acute GvHD. Secondary analyses 
will estimate the occurrence of chronic GvHD, primary graft failure, poor graft function, 
secondary graft failure, TRM, RR, GRFS, and OS. 
 
 
 


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3 
Schematic of Study Design 
 
 
 
 
 


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4 
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 
 
 
Frank Cirrone, PharmD- Pharmacist 
545 First Avenue 
New York, NY 10016 
Frank.Cirrone@nyulangone.org 
 
Judith D Goldberg, ScD-co-Investigator and Biostatistics 
Division of Biostatistics, Dept. of Population Health and  
Perlmutter Cancer Center 
NYU Langone Health 
190 Madison Ave, 4th floor, 451 
New York, NY 10016 
JD.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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5 
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).  
 
The stem cell source for allogeneic HSCT has historically been from an HLA-matched related 
donor (MRD) or matched unrelated donor (MUD). However, such donor can be identified or 
mobilized in less than 50% of cases [2]. In particular, the availability of a MUD can be lower for 
members of certain ethnic groups who are underrepresented in the donor registries, including 
African Americans, Hispanics, and Asians [2]. In contrast, an HLA-haploidentical first- or second-
degree relative can be identified and mobilized rapidly for nearly any patient [3]. At Johns Hopkins 
University, More than 95% of patients were found to have at least 1 HLA-haploidentical first-
degree donor with an average number of donors per patient of 2.7 [3].  
 
The Outcomes of HLA-haploidentical transplantation have improved substantially over the past 
decade [4]. Multiple studies have now demonstrated that the outcomes of HLA-haploidentical 
transplantation and MUD are comparable (Table 1) [4]. Furthermore, the Blood and Marrow 
Transplant Clinical Trial Network (BMT CTN) has completed a two parallel phase II studies of 
either HLA-haploidentical related donor bone marrow transplants or double-unrelated donor cord 
blood transplantation in patients with hematological malignancies. The outcomes of the two 
cohorts were comparable. The 100-day incidence of grade II-IV acute GvHD was 32% in HLA-
haploidentical transplantation and 40% in cord blood transplantation. The 1-year cumulative 
incidence of treatment-related mortality (TRM) and relapse rate (RR) were 7% and 45% for HLA-
haploidentical transplantation and 24% and 31% for cord blood transplantation. The 1-year 
probability of overall survival (OS) was 62% and 54%, respectively [5]. Nowadays, HLA-
haploidentical transplantation represents an acceptable alternative in patients who lack a MRD 
[4]. According to the CIBMTR, the use of MUD and cord blood transplantation has declined in 
recent years in favor of HLA-haploidentical donor transplantation (Figure 1).  
 
 
Table 1 


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6 
The major drawback of HLA-haploidentical transplantation is the intense bidirectional 
alloreactivity [2]. The early studies of HLA-haploidentical transplantation have demonstrated the 
fundamental challenge inherent in crossing HLA barriers. Without T-cell depletion, the incidence 
of GvHD is high with TRM in excess of 50%. On the other hand, if T-cells are depleted from the 
graft, there is an unacceptable risk of graft failure, opportunistic infections and disease relapse. 
To overcome these challenges, selective T-cell depletion and add on strategies are being 
explored [6-8]. Alternatively, post-transplantation cyclophosphamide (PTC) can circumvent the 
need to graft manipulation and has emerged as an alternative approach to graft manipulation [9].   
 
Figure 1 
 
PTC for GvHD prevention:  
Since introduced by the Johns Hopkins University group, PTC has been extensively studied in 
HLA-haploidentical transplantation, following non-myeloablative and myeloablative conditioning 
regimens. Contrary to calcineurin inhibitors (CNI), methotrexate (MTX), and mycophenolate 
mofetil (MMF), PTC 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 [9]. Because of its selective activity, targeting proliferating rather than resting 
T cells, PTC has been claimed to nurture rapid immune reconstitution and preserve GvT effect 
[10]. Several studies, using non-myeloablative and myeloablative conditioning regimens and 
HLA-haploidentical related-donor transplantation have now validated this approach with PTC, 
tacrolimus and MMF used as GvHD prevention. Although the original studies focused on the use 
of bone marrow as the source of grafts, recent studies using peripheral blood grafts have reported 
comparable outcomes [11-16].  
 
Abatacept for GvHD prevention:  
Abatacept is a recombinant soluble fusion protein composed of the extracellular domain of 
cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) fused to the Fc region of IgG1. Abatacept 
blocks CD28-CD80I86 axis T-cell co-stimulation thus preventing T-cell activation [17]. Abatacept 
is FDA approved for adult rheumatoid arthritis, juvenile idiopathic arthritis and adult psoriatic 
arthritis.  
 
A phase I feasibility study using a short-course of abatacept in unrelated-donor allogeneic HSCT 
suggested the safety and potential efficacy of abatacept in the prevention of severe acute GvHD. 


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7 
In a recent larger study the role of abatacept in the prevention of aGvHD was examined in two 
cohorts of patients. The first cohort received a one locus-HLA mismatched unrelated-donor 
transplant. Patients received a combination of tacrolimus and methotrexate and in addition, 
abatacept, given at 10mg/kg on day -1, +5, +14, and +28. The cohort was compared to a registry-
matched cohort receiving tacrolimus and methotrexate with or without rabbit anti-thymocyte 
globulin (rATG). The outcomes were improved in the group that received abatacept with a 
reduced rate of grade III-IV acute GvHD (3% v 32%, p=0.0003 in comparison to the group that 
did not receive rATG and 3% v 22%, p=0.0054 in comparison to the group that received rATG). 
GvHD and relapse-free survival was also improved, as was disease-free survival. The rates of 
relapse were 8%, 21%, and 18% respectively (p=0.099 and 0.23). The second cohort included 
140 patients receiving HLA-matched donor transplant, randomized in a double-blinded fashion to 
receive tacrolimus and methotrexate with either placebo or abatacept. Grade III-IV acute GvHD 
was reduced in the group that received abatacept in comparison to placebo (7% v 15%, p=0.66). 
GRFS was also reduced (89% v 77%, p=0.05). There was no difference in TRM or relapse rate 
between the two groups. The authors concluded that a short-course of abatacept was safe and 
effective in the prevention of aGvHD without increasing relapse-rate [18]. In a smaller study, 
abatacept was combined with PTC and tacrolimus in patients receiving MRD or MUD transplants. 
Abatacept was given at 10mg/kg on day +5, +14, and +28. The treatment was deemed safe and 
no patients developed acute GvHD [19].  
 
Abatacept has now been granted a breakthrough therapy designation for the prevention of 
moderate to severe acute GvHD.  
 
Duration of tacrolimus for GvHD prevention:  
Tacrolimus targets T-cells indiscriminately. Its use following allogeneic HSCT is therefore 
associated with delayed immune reconstitution and impairment of graft-versus-tumor effect. 
Tacrolimus is also burdensome to use due to narrow therapeutic index that requires close drug 
level monitoring with multiple drug interactions and side effects including renal impairment and 
electrolyte wasting. Lastly, prolonged administration of tacrolimus delays the introduction of 
immune maneuvers and small molecules aimed to reduce the risk of relapse following allogeneic 
HSCT. 
There is paucity of prospective data on the optimal duration of CNI following allogeneic HSCT. 
The Johns Hopkins group recently reported the results of a single arm trial. Tacrolimus was pre-
specified to stop on day +60, +90, or +120 without pre-taper following HLA-haploidentical 
transplant with bone marrow grafts and PTC, tacrolimus and MMF for GvHD prevention. Safety 
stopping rules were not met. The incidence of grade II-IV and grades III-IV acute GvHD were 
<40% and <8% in both day +60 and day +90 arms. The GRFS rate was higher in the +60 arm. 
The authors concluded that stopping tacrolimus at day +60 was feasible and safe [20].  
 
Based on the above, we propose a phase Ib-II study using PTC, abatacept and short-duration 
tacrolimus for GvHD prevention following HLA-haploidentical allogeneic HSCT in patients with 
hematological malignancies.  
 
2.1. Potential Risks & Benefits 
2.1.1. Known Potential Risks 
 


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2.1.1.1. Cyclophosphamide  
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.  
 
Full 
prescribing 
information 
available 
at: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/012141s090,012142s1
12lbl.pdf 
 
2.1.1.2. Abatacept 
The most common side effects of abatacept (Orencia®):  
The most common adverse reactions events (≥ 10%) are headache, upper respiratory 
tract infection, nasopharyngitis, and nausea. 
 
2.1.1.3. Tacrolimus 
The most common side effects of tacrolimus (Prograf®):  
The most common adverse reactions (≥ 15%) are abnormal renal function, 
hypertension, diabetes mellitus, fever, CMV infection, tremor, hyperglycemia, 
leukopenia, infection, anemia, bronchitis, pericardial effusion, urinary tract infection, 
constipation, diarrhea, headache, abdominal pain, insomnia, paresthesia, peripheral 
edema, nausea, hyperkalemia, hypomagnesemia, and hyperlipidemia. 
 
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. 
 


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3. OBJECTIVES AND PURPOSE 
 
STUDY DESIGN: 
3.1. Study hypothesis: We hypothesize that the administration of cyclophosphamide, abatacept, 
and a short-course of tacrolimus in the setting of HLA-haploidentical HSCT peripheral blood 
transplantation is effective in the prevention of GvHD and allows prompt immune reconstitution.  
 
3.2. Study overview:  This is a phase Ib-II clinical trial. Adult patients with hematological 
malignancies undergoing HLA-haploidentical HSCT from first- or second-degree family donors 
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 non-myeloablative, reduced-intensity, or myeloablative conditioning regimen at the 
discretion of the transplant physician.  
 
3.3. Objectives 
3.3.1. Primary objectives: 
• 
Estimate the incidence of grades II-IV acute GvHD in patients receiving 
cyclophosphamide, abatacept, and tacrolimus as GvHD prophylaxis.  
3.3.2. Secondary objectives: 
• 
Estimate the incidence of the following: chronic GvHD, 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 endpoint will be evaluated through day +120 
post-transplant.  
3.4.2. Secondary study endpoints 
Chronic GvHD: The first day of chronic GvHD will be used to calculate the cumulative 
incidence of chronic GvHD. This endpoint will be evaluated through day +365 post-
transplant.   
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.  


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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.   
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 x 109/L, and platelets < 20 x 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 
conditioning regimen, as described in Appendix B, using an eligible HLA-haploidentical related donor. 
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. All testing performed 
per BMT SOP: CLNAL002: Related (MRD, Haplo) Allogeneic RECIPIENT Evaluation and 
Management – Adult and Pediatric and CLNAL003: Related (MRD, Haplo) DONOR Evaluation and 
Management – Adult and Pediatric. 
 
4.1. Inclusion Criteria: 
4.1.1. Age ≥ 18 years 


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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 diagnosed 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) for women of childbearing age and potential. 
 
4.2. Exclusion Criteria: 
4.2.1. Donors are excluded in case of donor-specific HLA antibodies or positive cross-match. 
4.2.2. Pregnant or nursing females or women of child bearing age or potential,  who are unwilling 
to completely abstain from heterosexual sex or practice 2 effective methods of 
contraception from the first dose of conditioning regimen through day +180. A woman of 
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. 
4.2.3. 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). 
4.2.4. Inability to provide informed consent. 
4.2.5. 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. 
4.2.6. Known allergies to any of the components of the investigational treatment regimen. 
4.2.7. Serious medical or psychiatric illness likely to interfere with participation in this clinical 
study. 
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.  
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.   


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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. AS 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. Consent may be delegated to a 
trained and qualified licensed professional, as delegated by the principal 
investigator. 
2. Determine patient eligibility; see Section 4.1 and 4.2 
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. Confirmation 
of subject registration must be obtained before any treatment is administered or 
study procedures are performed. 
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 NYULH Human Subject Research Standard Operating 
Procedures (HSR 301 Informed Consent Process and Documentation).  . 
 
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. 
Confirmation of subject registration is required before any treatment is administered or 


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13 
study procedures are performed (unless a procedure is being performed as part of the 
patient’s standard of care. 
 
 
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 46 participants enrolled, accrued 
over up to 4 years. 
 
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 the patient 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. 
AS 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, 


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14 
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 Rules  
4.10.1. Excess TRM 
With 46 patients planned, we will test the hypothesis that the TRM rate is ≤8.2% 
versus the alternative hypothesis that the TRM rate is ≥20% with one sided α=0.05 
and power of 80%, 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: Stopping Boundaries for Excess Transplant Related Mortality (TRM) (1 sided 
α=0.05, power=80%, Ho: TRM≤0.082, Ha: TRM≥0.20) [Calculations from EAST 6.5 Cytel, 
Inc.]. 
 
Interim 
Look 
Number 
of 
Patients 
Cumulative 
Alpha Spent 
Stopping Boundaries: 
Reject TRM≤0.082 
≥Number 
Events  
≥Proportion 
Observed 
1 
12 
0 
5 
0.39 
2 
23 
0.006 
6 
0.23 
3 
35 
0.025 
7 
0.18 
Final 
46 
0.05 
7 
0.15 
 
 
4.10.2. Stopping for excess day-30 grade 4 non-hematologic or any grade 5 regimen-
related toxicity 
With 46 patients planned, we will test the hypothesis that the day-30 grade 4 non-
hematologic or any grade 5 regimen-related rate is ≤8.2% versus the alternative 
hypothesis that the day-30 grade 4 non-hematologic or any grade 5 regimen-
related rate is ≥20% with one sided α=0.05 and power of 80%, using an O’Brien 
Fleming group sequential alpha stopping boundary with three (3) interim and one (1) 
final look as summarized in Table 2 below.   
 
Table 2: Stopping Boundaries for Proportion of Patients with Excess Day-30 Grade 4 
non-hematologic or any grade 5 regimen-related Toxicity at Least Possibly Related to 
Study Drugs at day 30 (1 sided α=0.05, power=80%, Ho: 30 day proportion ≤0.082, Ha: 
30 day proportion ≥0.2) [Calculations from EAST 6.5 Cytel, Inc.]   


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Interim 
Look 
Number 
of 
Patients 
Cumulative 
Alpha Spent 
Stopping Boundaries: 
Reject grade 4 non-hematologic 
or any grade 5 regimen-related 
toxicity ≤0.082 
≥Number 
Events  
≥Proportion 
Observed 
1 
12 
0 
5 
0.39 
2 
23 
0.006 
6 
0.23 
3 
35 
0.025 
7 
0.18 
Final 
46 
0.05 
7 
0.15 
 
4.10.3 Stopping for excess primary graft failure 
With 46 patients planned, we will test the hypothesis that the primary graft failure 
rate is ≤5% versus the alternative hypothesis that the graft failure rate is ≥15% with 
one sided α=0.05 and power of 83%, using an O’Brien Fleming group sequential 
alpha stopping boundary with three (3) interim and one (1) final look as summarized 
in Table 3 below. 
 
Table 3: Stopping Boundaries for Proportion of Patients with Graft Failure Rate  (1 sided 
α=0.05, power=83%, Ho: 30 day proportion ≤0.05, Ha: 30 day proportion ≥0.15) 
[Calculations from EAST 6.5 Cytel, Inc.] 
 
 
Interim 
Look 
Number 
of 
Patients 
Cumulative 
Alpha Spent 
Stopping Boundaries: 
Reject graft failure ≤0.05 
≥Number 
Events  
≥Proportion 
Observed 
1 
12 
0 
4 
0.29 
2 
23 
0.006 
4 
0.17 
3 
35 
0.025 
5 
0.13 
Final 
46 
0.05 
5 
0.11 
 
 
5. STUDY AGENTS 
 
All study agents are FDA-approved for other indications and are commercially available for purchase. 
Cyclophosphamide and abatacept will be supplied by NYULH pharmacy. Tacrolimus is commercially 
available and prescribed to subjects  to pick up from their pharmacy. 
 
5.1. Cytoxan® (cyclophosphamide) – Bristol-Myers Squibb 
5.1.1. Therapeutic Class: nitrogen mustard alkylating agent 
5.1.2. 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 


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Aluminum Lake, lactose, magnesium stearate, starch, stearic acid and talc. 
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: 
 
5.1.3. 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. 
5.1.4. Mechanism of Action: Nitrogen mustard alkylating agent; exerts action by cross linking 
of tumor cell DNA. 
5.1.5. Pharmacokinetics: 
5.1.5.1. 
Absorption: Well absorbed; bioavailability (≥75%). 
5.1.5.2. 
Distribution: Plasma protein binding (≥60% as metabolites). 
5.1.5.3. 
Metabolism: Liver; active metabolites.  
5.1.5.4. 
Elimination: Urine (5-25% unchanged); T1/2=3-12 hrs. 
5.1.6. How Supplied:  Inj (Lyophilized): 500mg, 1g, 2g; Tab: 25mg, 50mg 
5.1.7. Administration and Storage: 
5.1.7.1. 
Administration: Oral, IV, IM, intraperitoneal, intrapleural route. Inspect drug 
product visually for particulate matter and discoloration prior to parenteral 
administration. 
5.1.7.2. 
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). 
 
5.2. Prograf® (tacrolimus) – Astellas 
5.2.1. Therapeutic Class: calcineurin-inhibitor 
5.2.2. Description: Tacrolimus, previously known as FK506, is the active ingredient in Prograf. 
Tacrolimus is a calcineurin-inhibitor immunosuppressant produced by Streptomyces 
tsukubaensis.  
 
The chemical structure of tacrolimus is: 


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Tacrolimus has an empirical formula of C44H69NO12•H2O and a formula weight of 822.03. 
Tacrolimus appears as white crystals or crystalline powder. It is practically insoluble in 
water, freely soluble in ethanol, and very soluble in methanol and chloroform.  
 
Prograf is available for oral administration as capsules (tacrolimus capsules USP) 
containing the equivalent of 0.5 mg, 1 mg or 5 mg of anhydrous tacrolimus USP. Inactive 
ingredients include croscarmellose sodium NF, hypromellose USP, lactose monohydrate 
NF, and magnesium stearate NF. The 0.5 mg capsule shell contains ferric oxide NF, 
gelatin NF and titanium dioxide USP, the 1 mg capsule shell contains gelatin NF and 
titanium dioxide USP, and the 5 mg capsule shell contains ferric oxide NF, gelatin NF, and 
titanium dioxide USP. Prograf is also available as a sterile solution (tacrolimus injection) 
containing the equivalent of 5 mg anhydrous tacrolimus USP in 1 mL for administration by 
intravenous infusion only. Each mL contains the following inactive ingredients: dehydrated 
alcohol USP, 80.0% v/v and polyoxyl 60 hydrogenated castor oil (HCO-60), 200 mg. 
Prograf injection must be diluted with 0.9% Sodium Chloride Injection or 5% Dextrose 
Injection before use. Prograf Granules is available for oral administration as a suspension 
containing the equivalent of 0.2 mg or 1 mg of anhydrous tacrolimus USP. Inactive 
ingredients include croscarmellose sodium NF, hypromellose USP, and lactose 
monohydrate NF. 
5.2.3. Indications: Prograf is a calcineurin-inhibitor immunosuppressant indicated for the 
prophylaxis of organ rejection in adult and pediatric patients receiving allogeneic liver, 
kidney or heart transplants, in combination with other immunosuppressants. 
5.2.4. Mechanism of Action: Tacrolimus binds to an intracellular protein, FKBP-12. A complex 
of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin (a ubiquitous mammalian 
intracellular enzyme) is then formed, after which the phosphatase activity of calcineurin is 
inhibited. Such inhibition prevents the dephosphorylation and translocation of various 
factors such as the nuclear factor of activated T-cells (NF-AT), and nuclear factor kappa-
light-chain enhancer of activated B-cells (NF-κB). Tacrolimus inhibits the expression 
and/or production of several cytokines that include interleukin (IL)-1 beta, IL-2, IL-3, IL-4, 
IL-5, IL-6, IL-8, IL-10, gamma interferon, tumor necrosis factor-alpha, and granulocyte 
macrophage colony-stimulating factor. Tacrolimus also inhibits IL-2 receptor expression 
and nitric oxide release, induces apoptosis and production of transforming growth factor 
beta that can lead to immunosuppressive activity. The net result is the inhibition of T-
lymphocyte activation and proliferation, as well as T-helper-cell-dependent B-cell 
response (i.e., immunosuppression). 
5.2.5. Pharmacokinetics: 


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5.2.5.1. Absorption: Absorption of tacrolimus from the gastrointestinal tract after oral 
administration is incomplete and variable. The absolute bioavailability of tacrolimus 
was 17 ± 10% in adult kidney transplant patients (N = 26), 22 ± 6% in adult liver 
transplant patients (N = 17), 23 ± 9% in adult heart transplant patients (N = 11) and 
18 ± 5% in healthy volunteers (N = 16). A single dose trial conducted in 32 healthy 
volunteers established the bioequivalence of the 1 mg and 5 mg capsules. Another 
single dose trial in 32 healthy volunteers established the bioequivalence of the 0.5 
mg and 1 mg capsules. Tacrolimus maximum blood concentrations (Cmax) and area 
under the curve (AUC) appeared to increase in a dose-proportional fashion in 18 
fasted healthy volunteers receiving a single oral dose of 3, 7, and 10 mg. In 18 kidney 
transplant patients, tacrolimus trough concentrations from 3 to 30 ng/mL measured 
at 10-12 hours post-dose (Cmin) correlated well with the AUC (correlation coefficient 
0.93). In 24 liver transplant patients over a concentration range of 10 to 60 ng/mL, 
the correlation coefficient was 0.94. In 25 heart transplant patients over a 
concentration range of 2 to 24 ng/mL, the correlation coefficient was 0.89 after an 
oral dose of 0.075 or 0.15 mg/kg/day at steady-state. In a healthy volunteer adult 
study, the systemic exposure to tacrolimus (AUC) for Prograf Granules was 
approximately 16% higher than that for Prograf capsules when administered as 
single doses. If pediatric patients are converted between formulations, therapeutic 
drug monitoring must be performed and dose adjustments made to ensure that 
systemic exposure to tacrolimus is maintained. 
Food Effects: The rate and extent of tacrolimus absorption were greatest under 
fasted conditions. The presence and composition of food decreased both the rate 
and extent of tacrolimus absorption when administered to 15 healthy volunteers. The 
effect was most pronounced with a high-fat meal (848 kcal, 46% fat): mean AUC and 
Cmax were decreased 37% and 77%, respectively; Tmax was lengthened 5-fold. A 
high-carbohydrate meal (668 kcal, 85% carbohydrate) decreased mean AUC and 
mean Cmax by 28% and 65%, respectively. In healthy volunteers (N = 16), the time 
of the meal also affected tacrolimus bioavailability. When given immediately 
following the meal, mean Cmax was reduced 71%, and mean AUC was reduced 39%, 
relative to the fasted condition. When administered 1.5 hours following the meal, 
mean Cmax was reduced 63%, and mean AUC was reduced 39%, relative to the 
fasted condition. In 11 liver transplant patients, Prograf administered 15 minutes 
after a high fat (400 kcal, 34% fat) breakfast, resulted in decreased AUC (27 ± 18%) 
and Cmax (50 ± 19%), as compared to a fasted state. Prograf capsules should be 
taken consistently every day either with or without food because the presence and 
composition of food decreases the bioavailability of Prograf. 
5.2.5.2. Distribution: The plasma protein binding of tacrolimus is approximately 99% and is 
independent of concentration over a range of 5-50 ng/mL. Tacrolimus is bound 
mainly to albumin and alpha-1-acid glycoprotein, and has a high level of association 
with erythrocytes. The distribution of tacrolimus between whole blood and plasma 
depends on several factors, such as hematocrit, temperature at the time of plasma 
separation, drug concentration, and plasma protein concentration. In a U.S. trial, the 
ratio of whole blood concentration to plasma concentration averaged 35 (range 12 
to 67). 


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5.2.5.3. Metabolism: Tacrolimus is extensively metabolized by the mixed-function oxidase 
system, primarily the cytochrome P-450 system (CYP3A). A metabolic pathway 
leading to the formation of 8 possible metabolites has been proposed. Demethylation 
and hydroxylation were identified as the primary mechanisms of biotransformation 
in vitro. The major metabolite identified in incubations with human liver microsomes 
is 13-demethyl tacrolimus. In in vitro studies, a 31-demethyl metabolite has been 
reported to have the same activity as tacrolimus. 
5.2.5.4. Elimination: The mean clearance following IV administration of tacrolimus is 0.040, 
0.083, 0.053, and 0.051 L/hr/kg in healthy volunteers, adult kidney transplant 
patients, adult liver transplant patients, and adult heart transplant patients, 
respectively. In man, less than 1% of the dose administered is excreted unchanged 
in urine. 
5.2.6. How Supplied:  Intravenous Infusion (Injection): 5 mg/mL (equivalent of 5 mg of anhydrous 
tacrolimus USP per mL) supplied as a sterile solution in a 1 mL ampule, in boxes of 10 
ampules   Capsule: 0.5 mg, 1 mg and 5 mg. 
5.2.7. Administration and Storage: 
5.2.7.1. Administration: Tacrolimus can cause fetal harm. Prograf injection must be diluted 
with 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a concentration 
between 0.004 mg/mL and 0.02 mg/mL prior to use. Diluted infusion solution should 
be stored in glass or polyethylene containers and should be discarded after 24 hours. 
The diluted infusion solution should not be stored in a polyvinyl chloride (PVC) 
container due to decreased stability and the potential for extraction of phthalates. In 
situations where more dilute solutions are utilized (e.g., pediatric dosing, etc.), PVC-
free tubing should likewise be used to minimize the potential for significant drug 
adsorption onto the tubing. Parenteral drug products should be inspected visually for 
particulate matter and discoloration prior to administration, whenever solution and 
container permit. Due to the chemical instability of tacrolimus in alkaline media, 
Prograf injection should not be mixed or co-infused with solutions of pH 9 or greater 
(e.g., ganciclovir or acyclovir). Storage: Injection: Store between 5°C and 25°C 
(41°F and 77°F). Capsule: Store at 20°C to 25 C (68°F to 77°F); excursions 
permitted to 15°C to 30°C (59°F to 86°F). 
 
5.3. Orencia® (abatacept) – Bristol-Myers Squibb 
5.3.1. Therapeutic Class: selective T cell co-stimulation modulator 
5.3.2. Description:  is  a  soluble  fusion  protein  that  consists  of  the  extracellular  domain  of  
human  cytotoxic  T-lymphocyte­associated  antigen  4  (CTLA-4)  linked  to  the  modified  
Fc  (hinge,  CH2,  and  CH3  domains)  portion  of  human  immunoglobulin  G1  (IgG1). 
Abatacept is produced by recombinant DNA technology in a mammalian cell expression 
system. The apparent molecular weight of abatacept is 92 kilodaltons. 
5.3.3. Indications: Treatment of adult rheumatoid arthritis (RA), moderately to severely active 
RA in adults and may be used as monotherapy or concomitantly with DMARDs other than 
TNF antagonists.  Juvenile idiopathic arthritis, moderately to severely active polyarticular 
juvenile idiopathic arthritis in patients 2 years of age and older (may be used as 
monotherapy or concomitantly with methotrexate). Adult psoriatic arthritis (PsA active PsA 
in adults. Should not be given concomitantly with TNF antagonists. 


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5.3.4. Mechanism of Action: Abatacept,  a  selective  co-stimulation  modulator,  inhibits  T  cell  
(T  lymphocyte)  activation  by  binding to CD80 and CD86, thereby blocking interaction 
with CD28. This interaction provides a costimulatory signal necessary for full activation of 
T lymphocytes. Activated T lymphocytes are implicated  in  the  pathogenesis  of  RA  and  
PsA  and  are  found  in  the  synovium  of  patients  with  RA and PsA. In vitro, abatacept 
decreases T cell proliferation and inhibits the production of the cytokines TNF alpha 
(TNFα), interferon-γ, and interleukin-2. In a rat collagen-induced arthritis model, abatacept 
suppresses  inflammation,  decreases  anti-collagen  antibody  production,  and  reduces  
antigen specific  production  of  interferon-γ. The relationship of these biological response 
markers to the mechanisms by which ORENCIA exerts its clinical effects is unknown. 
5.3.5. Pharmacokinetics 
Healthy Adults and Adult RA: Intravenous Administration: The pharmacokinetics of 
abatacept were studied in healthy adult subjects after a single 10 mg/kg intravenous  
infusion  and  in  RA  patients  after  multiple  10  mg/kg  intravenous  infusions  (table 
below):  
The pharmacokinetics of abatacept in RA patients and healthy subjects appeared to be 
comparable. In RA patients, after multiple  intravenous  infusions,  the  pharmacokinetics  
of  abatacept  showed  proportional  increases of  Cmax and  AUC  over  the  dose  range  
of  2  mg/kg to 10 mg/kg.  At 10 mg/kg, serum  concentration  appeared  to  reach  a  
steady  state  by  day  60  with  a  mean (range) trough concentration of 24 mcg/mL (1 to 
66 mcg/mL). No systemic accumulation of abatacept occurred upon continued repeated 
treatment with 10 mg/kg at monthly intervals in RA patients. Population  pharmacokinetic  
analyses  in  RA  patients  revealed  that  there  was  a  trend  toward  higher clearance of 
abatacept with increasing body weight. Age and gender (when corrected for body weight) 
did not affect clearance. Concomitant methotrexate, NSAIDs, corticosteroids, and TNF 
blocking agents did not influence abatacept clearance. No formal studies were conducted 
to examine the effects of either renal or hepatic impairment on the pharmacokinetics of 
abatacept. 
Adult RA - Subcutaneous Administration: Abatacept exhibited linear pharmacokinetics 
following subcutaneous administration. The mean (range) for Cmin and Cmax at steady state 
observed after 85 days of treatment was 32.5 mcg/mL (6.6   to   113.8   mcg/mL)   and   
48.1   mcg/mL (9.8   to   132.4   mcg/mL), respectively. The bioavailability   of   abatacept   
following   subcutaneous administration relative to intravenous administration is 78.6%. 
Mean estimates for systemic clearance (0.28 mL/h/kg) volume of distribution (0.11 L/kg), 
and   terminal   half-life   (14.3   days)   were   comparable between subcutaneous and 
intravenous administration. Study  SC-2 was  conducted  to  determine  the  effect  of  


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monotherapy  use  of  ORENCIA  on immunogenicity following  subcutaneous  
administration  without  an  intravenous load.  When the intravenous loading  dose  was  
not  administered,  a  mean  trough  concentration  of  12.6  mcg/mL was achieved after 2 
weeks of dosing. Consistent with the intravenous data, population  pharmacokinetic 
analyses for subcutaneous abatacept  in  RA  patients  revealed  that  there  was  a  trend  
toward  higher  clearance  of  abatacept with  increasing  body  weight.  Age  and  gender  
(when  corrected  for  body  weight)  did  not  affect apparent clearance. Concomitant 
medication, such as methotrexate, corticosteroids, and NSAIDs, did not influence 
abatacept apparent clearance. Juvenile Idiopathic Arthritis - Intravenous Administration: 
In Study JIA-1 among patients 6 to 17 years of age, the mean (range) steady state serum 
peak and trough concentrations of abatacept were 217 mcg/mL (57 to 700 mcg/mL) and 
11.9 mcg/mL (0.15 to 44.6 mcg/mL). Population pharmacokinetic analyses of the serum 
concentration data showed that clearance of abatacept increased with baseline body 
weight.  The estimated mean (range) clearance of abatacept in the juvenile idiopathic 
arthritis patients was 0.4 mL/h/kg (0.20 to 1.12 mL/h/kg). After accounting for the effect of 
body weight, the clearance of abatacept was not related to age and gender. Concomitant 
methotrexate, corticosteroids, and NSAIDs were also shown not to influence abatacept 
clearance. Juvenile Idiopathic Arthritis - Subcutaneous Administration: In Study JIA-2 
among patients 2  to 17  years of age, steady  state  of  abatacept  was  achieved  by Day  
85  following  the  weekly  body-weight–tiered  subcutaneous  abatacept  dosing.  
Comparable trough  concentrations  across  weight  tiers  and  age  groups  were  achieved  
by  the  body-weight– tiered  subcutaneous  dosing  regimen. The mean (range) trough 
concentration  of  abatacept  at Day 113  was  44.4  mcg/mL  (13.4  to  88.1  mcg/mL),  
46.6  mcg/mL  (22.4  to  97.0  mcg/mL),  and 38.5  mcg/mL  (9.3  to  73.2  mcg/mL)  in  
pediatric  JIA  patients  weighing  10  to  <25  kg,  25  to <50 kg, and ≥50 kg, respectively. 
Consistent with the  intravenous  data,  population  pharmacokinetic analyses  for  
subcutaneous abatacept  in  JIA  patients  revealed  that  there  was  a  trend  toward  
higher  clearance  of  abatacept  with  increasing  body  weight. Age  and  gender  (when  
corrected  for  body  weight)  did  not  affect  apparent clearance. Concomitant medication, 
such as methotrexate, corticosteroids, and NSAIDs, did not influence abatacept apparent 
clearance. Adult Psoriatic Arthritis - Intravenous and Subcutaneous Administration: In 
Study, PsA-I, a dose ranging study, IV abatacept was administered at 3 mg/kg, 10 mg/kg 
(weight range-based dosing: 500 mg for patients weighing less than 60 kg, 750 mg for 
patients weighing 60 to 100 kg, and 1000 mg for patients weighing greater than 100 kg), 
or two doses of 30 mg/kg followed by weight   range-based dose of 10 mg/kg. Following 
monthly IV administration, abatacept showed  linear  PK  over  the  dose  range  of  3  
mg/kg  to  10  mg/kg.  At 10 mg/kg, the steady state of abatacept was reached by Day 57 
and the geometric mean (CV%) trough  concentration  (Cmin)  was  24.3  mcg/mL  (40.8%)  
at  Day  169.  In Study, PsA-II following weekly  SC  administration  of  abatacept  at  125  
mg,  the  steady state  of  abatacept  was  reached  at   
Day 57 and the geometric mean (CV%) Cmin was 25.6 mcg/mL (47.7%) at Day 169. 
Consistent  with  the  RA  results,  population  pharmacokinetic  analyses  for  abatacept  
in  psoriatic arthritis patients revealed that there was a trend toward higher clearance (L/h) 
of abatacept with increasing  body  weight.  In  addition,  relative  to  the  RA  patients  with  
the  same  body  weight,  abatacept  clearance  in  psoriatic  arthritis  patients  was  


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approximately  8%  lower,  resulting  in  higher abatacept exposures in patients with PsA. 
This slight difference in exposures, however, is not considered to be clinically meaningful. 
5.3.6. How Supplied:  Intravenous Infusion (Injection): 250   mg lyophilized   powder   in   a single 
use vial   for reconstitution and dilution prior to intravenous infusion. Subcutaneous 
Injection: 50 mg/0.4 mL, 87.5 mg/0.7 mL, 125 mg/mL solution in single-dose prefilled 
syringes for subcutaneous use or 125 mg/mL solution in a single-dose prefilled   ClickJect 
autoinjector for subcutaneous use. 
5.3.7. Administration and Storage: 
5.3.7.1. Administration: ORENCIA for Injection is a lyophilized powder for intravenous 
infusion. ORENCIA for Injection is  supplied  as  a  sterile,  white,  preservative-free,  
lyophilized  powder  for  reconstitution and  dilution  prior  to  intravenous 
administration.  Following  reconstitution  of  the  lyophilized  powder with  10  mL  of  
Sterile  Water  for  Injection,  USP,  the  solution  of  ORENCIA  is  clear,  colorless  
to  pale  yellow,  with  a  pH  range  of  7.2  to  7.8.  Each single-use vial of ORENCIA 
for Injection provides 250 mg abatacept, maltose (500 mg), monobasic sodium 
phosphate (17.2 mg), and sodium chloride (14.6 mg) for administration. ORENCIA 
Injection is  a sterile, preservative-free, clear to slightly opalescent, colorless to pale-
yellow  solution  with  a  pH  range of  6.8  to  7.4  for  subcutaneous  administration.  
ORENCIA Injection is supplied as a single-dose prefilled syringe or as a single-dose 
ClickJect autoinjector. 
5.3.7.2. Storage: ORENCIA lyophilized  powder supplied  in  a  vial  should  be refrigerated  
at  2°C  to  8°C  (36°F  to  46°F). Do not use beyond the expiration date on the vial. 
Protect the vials from light by storing in the original package until time of use. 
ORENCIA solution supplied   in   a   prefilled   syringe or   ClickJect autoinjector 
should be refrigerated at 2°C to 8°C (36°F to 46°F). Do not use beyond the expiration 
date on the prefilled syringe or autoinjector. Protect from light by storing in the original 
package until time of use. Do not allow the prefilled syringe or autoinjector to freeze. 
 
5.4. Study Agent Accountability Procedures: 
Cyclophosphamide, abatacept, will be purchased per standard of practice from a commercial 
source and compounded according to the package insert by the main hospital pharmacy. If any 
portion of the study drug is not administered, the amount infused will be recorded, the principal 
investigator notified and unused medications will be returned to the main hospital pharmacy for 
disposal. Tacrolimus is commercially available and is prescribed to subjects  to pick up from their 
pharmacy. During each visit, the dose used of tacrolimus and any adjustments in dosing are 
reviewed with the subject  and documented in the subject’s EMR. 
 
5.5. 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. 
 
 
6. REQUIRED STUDY ACTIVITIES (APPENDIX A) 


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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 BMT SOPs (SOP CLNAL003: Related (MRD, Haplo) DONOR Evaluation and 
Management – Adult and Pediatric). 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 until day +100 (+/- 3 days), and at least monthly until day +180 (+/- 7 days). 
6.4.4. 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). 
6.4.5. Post-chimerism: at engraftment, then at least monthly until day +180, and every 3 months 
until day +730 (+/- 7 days). 
6.4.6. Immune reconstitution studies will be drawn on day +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, all 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 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. Non-myeloablative conditioning: 
7.1.1.1. Fludarabine 30mg/m2 IV once daily on day -6, -5, -4, -3, and -2. 
7.1.1.2. Cyclophosphamide 14.5mg/kg IV once daily on day -6 and -5 
7.1.1.3. Total-body irradiation (TBI), 2 grays on day -1.  


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7.1.1.4. 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. 
7.1.2. Reduced-intensity conditioning: 
7.1.2.1. Fludarabine 25 mg/m2 IV once daily on day  -6, -5, -4, -3 and -2. 
7.1.2.2. Cyclophosphamide 14.5mg/kg IV once daily on day -3 and -2 
7.1.2.3. Busulfan 130 mg/m2 IV, once daily, on day  -6 and -5  
7.1.2.4. TBI, 2 grays on day -1. 
7.1.2.5. 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. 
7.1.3. TBI-based myeloablative conditioning: 
7.1.3.1. Fludarabine 25 mg/m2 IV once daily on day  -7, -6 and -5 
7.1.3.2. TBI 150 cGrays bid on day –4, -3, 2 and -1.  
7.1.3.3. 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. 
7.1.4. Non TBI-based myeloablative conditioning: 
7.1.4.1. Fludarabine 25 mg/m2 IV once daily on day  -6, -5, -4, -3 and -2. 
7.1.4.2. Cyclophosphamide 14.5mg/kg IV once daily on day -3 and -2 
7.1.4.3. Busulfan 110 mg/m2 IV, once daily, on day  -7, -6 , -5, and -4 
7.1.4.4. 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. 
 
7.2. 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 donor 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, abatacept and tacrolimus. No other prophylactic treatment will be given. 
7.3.1. Cyclophosphamide 50 mg/kg IV over 1 hour on day +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. Abatacept 10mg/kg IV over 30 minutes on day +5, +14, and +28.  
7.3.3. Tacrolimus 0.02 mg/kg IV by continuous infusion starting on day +5. The drug can be 
changed to oral route when the patient has adequate oral intake. The target trough level 
is 5-12 ng/mL. Treatment is continued until day +60 (+/-3) and then tapered over a period 
of 4 weeks in the absence of GvHD. 
 
7.4. Drug Preparation: The drugs will be prepared under the supervision of a pharmacist, or 
appropriately qualified and trained personnel. All doses will be based on adjusted body surface 
area if actual body weight is >125% the ideal body weight. 
 
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. 
All deviations must be documented by the principal investigator prior to occurrence.   


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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, abatacept and tacrolimus such as 
nausea, vomiting, diarrhea, etc. will be routinely managed according to the routine practices. 
 
7.9. Dose adjustments: No dose adjustments are allowed for cyclophosphamide. Abatacept must 
be discontinued in case of severe life threatening allergic reaction and in case of uncontrolled 
infection. Abatacept therapy can be resumed once the infection is controlled. Tacrolimus dose 
will be adjusted to maintain drug level as specified above in 7.3.3. The subject will be withdrawn 
from the study if, at the discretion of the treating physician: 
1. The subject  cannot receive the planned treatment with cyclophosphamide. 
2. The subject  cannot receive at least 1 dose of abatacept.  
3. The subject  cannot receive at least 4 weeks of tacrolimus. 
 
8. ASSESSMENT OF SAFETY 
 
8.1. Specification of Safety Parameters  
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. 
8.1.1. The following will be reported and monitored: 
• 
Grade 3 or higher, non-hematologic toxicity directly related to study drugs (such 
as peripheral neuropathy).  
• 
Grade 2 or higher hepatic bilirubin. 
 
8.1.2. 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 day +60 or until 
treatment-related adverse events, occurring before day +60 resolve or stabilize. 
 
8.2. Adverse Events (AE): 
8.2.1. Definition 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, which is unexpected. Intercurrent 
illnesses or injuries should be regarded as adverse events.  Abnormal results of diagnostic 
procedures are considered to be adverse events if the abnormality: 


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• 
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 
 
8.2.2. 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 stabilization and resolution 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. 
 
8.3. Serious Adverse Events (SAE): 
8.3.1. Definition of Serious Adverse Events (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. 
 
8.3.2. 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.  
 


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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 study monitor.  
 
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. 
Unanticipated Problems (UP) 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; 


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• 
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 within 10 working days and to the 
DSMC/Principal Investigator/Medical Monitor for all fatal or life threatening adverse 
events 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 10 working days of the 
investigator becoming aware of the problem. 
• 
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 10 working 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, assigned medical 
monitor, and 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 the principal investigator, assigned medical monitor, 
and 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, 
assigned medical monitor and DSMC, and NYUPCCsafetyreports@nyulangone.org    
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. 


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8.4. 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. 
 
8.5. 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. 
 
8.6. 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.) 
• 
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). 
 
8.7. Classification of an Adverse Event: 
8.7.1. 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. 
8.7.2. 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 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 


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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). 
• 
Not Related: The AE is completely independent of study drug administration, or 
evidence exists that the event is definitely related to another etiology. There must be 
an alternative, definitive etiology documented by the clinician. 
 
8.8. 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 to a minimum of day +60 post-transplant.  
 
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. 
 
8.9. 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. 
 
8.10. 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 


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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 DSMC 
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. 
 
8.11. 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 10 working days: 
 
Researchers are required to submit reports of the following problems promptly but no later 
than 10 working days from the time the investigator becomes aware of the event: 
• 
Unanticipated problems including adverse events that are unexpected and related and 
harmful.  
– 
Unexpected: An event is “unexpected” when its specificity and 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 10  
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 


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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) 
 
8.12. 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 and 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. 
 
 
 
8.13. Other Reportable events: 
Exceptions to the study protocol 
Exceptions to the protocol must obtain 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 rights, safety, or welfare of study subjects, 
must be reported to the investigator’s IRB as soon as a possible, but no later than 10 
working days of the protocol deviation. 
 
8.14. Study Halting Rules 
 
8.14.1. Removal of Subjects from Study 
8.14.1.1. The investigator will make every reasonable effort to keep each subject  in the study 
until all planned treatments and assessments have been performed. Unplanned 
discontinuation may occur for any of the following reasons: 
• 
Subject  develops allergy to either study drug. 
• 
Treating physician feels that continuation in study is not appropriate.  Such a 
determination may be made if the subject  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. See also 7.9. 
• 
Subject  withdraws informed consent. 
• 
Subject  is not meeting the follow up requirements 
8.14.1.2. If subjects  fail to complete the study treatment, alternative GVHD prophylaxis will 
be instituted immediately at the discretion of the treating physician. 
8.14.1.3. The PI can decide to replace subjects  withdrawn from the study at his discretion. All 
subjects  who receive cyclophosphamide, at least 1 dose of abatacept and 1 month 
of tacrolimus, will be evaluated (see 7.9).  The study will enroll subjects  for a total 
of 46 evaluable subjects, expected to be accrued over up to four years. 
8.14.1.4. 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 


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terminating party. Circumstances that may warrant termination include but are not 
limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to subjects, 
• 
Failure to enter subjects  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. 
 
8.15. 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 to the principal investigator, the medical 
monitor and the DSMC 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. 
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 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, 


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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.  The 
DSMC will review safety data every 3 months. 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 
 
10.1. Sample Size:  
The primary outcome variable for this study is the incidence of grades II-IV acute GvHD.  We 
assume that the rate of grade II-IV acute GvHD, with the standard of care is 50% [21-23], as 
reported in the literature and 30% in the experimental group. Based on a 2-stage optimal Simon 
design, we can detect a reduction in the grade II–IV acute GvHD incidence to 30% for high-
dose post-transplant cyclophosphamide, abatacept and tacrolimus with alpha = 0.05 and power 
of 82% at the conclusion of the 2-stage design with 46 patients. The trial would stop for futility 
at the end of the first stage if 9 or more patients have grade II-IV acute GVHD, of the 22 patients 
enrolled. Otherwise, the trial will continue to the second stage with the total 46 patients enrolled. 
If the total number of patients with grade II-IV acute GVHD is 19 or greater at the end of stage 
II, the regimen will not be considered for further study. The rate of grade II-IV acute GVHD will 
be estimated at the end of the trial with exact 95% Clopper Pearson confidence intervals. If the 
observed rate is 30%, this exact confidence interval with 46 patients, the corresponding 
confidence interval will be 17.4% to 45.3%. Calculations from PASS 2019, NCSS, J. Hintze, 
Kaysville, Ut.  
 
Additional monitoring rules are provided above for excess transplant related mortality and for 
excess drug related toxicity or graft failure. Each of these two rules incorporate 3 interim safety 
evaluations and one final safety evaluation at the completion of the trial.  
 
The study will be stopped for safety at any one of these interim safety evaluations should the 
criteria for either endpoint be reached without adjustment for the two parallel analyses. 


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All participants that receive post-transplant cyclophosphamide and at least 1 dose of abatacept 
and 1 month of tacrolimus will be included in interim safety evaluations.  
 
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. Grades II-IV Acute GvHD: The first day of grades II-IV acute GvHD 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 cyclophosphamide, and 
at least 1 dose of abatacept and a month of tacrolimus will be included in the analysis. 
Cumulative incidence curves will be provided along with 95% confidence intervals for the 
120 day cumulative incidence. 
 
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. 
10.4.1. 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.  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 evaluation 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 analyses will be provided for any GvHD TRM 
10.4.2. 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.   
10.4.3. 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.   
10.4.4. Secondary graft failure is evaluated after engraftment is achieved will be calculated from 
date of engraftment for all patients with engraftment.   


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10.4.5. 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.  
10.4.6. 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. 
10.4.7. 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.  
10.4.8. 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. 
 
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 
provide extensive monitoring including real-time review of all eCRFs to ensure completeness and 
compliance with the protocol.  A first subject audit is to be conducted within four weeks of enrollment.  
 


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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. QUALITY ASSURANCE AND QUALITY CONTROL 
 
This study will be monitored according to the monitoring plan detailed below.  The Investigator will 
also ensure that the monitor or other compliance or quality assurance reviewer is given access to 
all the above noted study-related documents and study related facilities (e.g. pharmacy, diagnostic 
laboratory, etc.) as necessary. A risk-based, data-driven monitoring approach will be used to verify 
data for this trial, which will also include a centralized review of data for quality, trends, consistency 
and general safety review.  A quality assurance specialist will regularly review the progress of the 
trial, study data and site processes.  At each visit, the monitor will review various aspects of the trial 
including, but not limited to:  screening and enrollment logs; compliance with the protocol and study 
manual and with the principles of Good Clinical Practice; completion of case report forms; source 
data verification; study drug accountability and storage; facilities and staff. 
 
During scheduled monitoring visits, the investigator and the investigational site staff must be 
available to discuss the progress of the trial, make necessary corrections to case report form 
entries, respond to data clarification requests and respond to any other trial-related inquiries of the 
monitor. Any queries identified through this review will be managed within the systems established 
for query resolution and tracking. Inquiries related to study conduct, which require further 
information or action will be discussed within the study team for appropriate and documented 
escalation plans. It is expected that response to data clarification requests and other trial-related 
inquiries will occur throughout the course of the study through regular communication with the site 
monitor, the Sponsor or representatives, and review/entry of data into the electronic study database. 
At any time during the course of the study, representatives of the FDA and/or local regulatory 
agencies 
may review the conduct or results of the study at the investigational site. The 
investigator must promptly inform NYU PCC CTO of any audit requests by health authorities, 
and will provide the results of any such audits and with copies of any regulatory documents 
related to such audits. 
 
In accordance with HIPAA and associated privacy regulations, a patient’s authorization to use 
personal 
identifiable health information may be required from each patient before 
commencement of research activities. This authorization document must clearly specify what 
parties will have access to a patient’s personal health information, for what purpose and for 
what duration. 
 
At the NYU Perlmutter Cancer Center, all investigator-initiated protocols are subject to a 
standardized data and safety monitoring, which includes scientific peer review, IRB review and 
DSMC review as well as internal auditing. 
 


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The review of AEs and trial conduct for this trial occurs at several levels: 
 
(1) Principal Investigator: Adverse events are evaluated monthly by the principal 
investigator in 
conjunction with the research nurses, data manager and 
research team. 
 
(2) DSMC, quarterly 
 
(3) Institutional Review Board (IRB): An annual report to the IRB is submitted by 
the trial PI for continuation of the protocol. It includes a summary of all AEs, 
total enrollment with demographics, protocol violations, and current status of 
subjects as well as available research data. 
 
In addition, the quality assurance unit will conduct monitoring of this trial every 4-6 weeks; this 
includes real-time review of all eCRFs to ensure completeness and to verify adherence to the 
protocol; the completeness, accuracy and consistency of the data; and adherence to ICH Good 
Clinical Practice guidelines.  Additionally, a first subject audit is to be conducted within four weeks 
of enrollment. 
 
13. ADMINISTRATIVE REQUIREMENTS 
 
13.1. 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. 
 
13.1.1. 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. 
 
13.1.2. Protocol Compliance: The investigator will conduct the study in compliance with the 
protocol, and given approval by the IRB, and the appropriate regulatory authorities. Any 
departures from the protocol must be fully documented in the source documents. 
 
13.2. 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 


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39 
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 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. 
 
13.2.1. 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 the patient may have. The investigator will ask the patient 
questions to ensure that the patient understands the study. If the investigator 
determines the subject understands the study, the patient will mark an X where the 
patient name would go and the witness will sign the consent form. 
 


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13.2.2. 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. 
 
13.2.3. Posting of Clinical Trial Consent: The informed consent form will be posted on the 
Federal website after the clinical trial is closed to recruitment and no later than 60 days 
after the last study visit by any subject, as required by the protocol.  Per Institutional 
guidelines, SOP#: HSR-601, instructs the principal investigator on registration and results 
reporting on clinicaltrials.gov. 
 
13.2.4. Participant and Data Confidentiality: In order to maintain participant privacy, all 
information obtained in connection with this study which identifies the participant 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. 


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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. 
 
14. 
DATA HANDLING AND RECORD KEEPING 
 
14.1. 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. 
 
Investigational product records are maintained by the NYU Langone Health Pharmacy. 
Cyclophosphamide and abatacept are provided by the NYU Langone Health pharmacy, 
however, Tacrolimus is commercially available and is prescribed to subjects to pick up from 
their pharmacy. All prescription records are maintained in subject’s EMR. 
 
14.2. Study Records Retention: 
The sponsor-investigator will maintain all study records according to ICH-GCP and applicable 
regulatory requirement(s). 
 
14.3. 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 


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42 
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. 
 
14.4. Publication and Data Sharing Policy: 
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 participants 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. 
 
15. STUDY FINANCES 


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43 
 
15.1. 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). 
 
15.2. 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 participant. 
 
15.3. Participant Reimbursements or Payments:  
No subject will receive payments or stipends for participation in this research study. 
 
16. 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 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. 
 
 
 


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17. REFERENCES 
 
1. 
Appelbaum FR. Hematopoietic cell transplantation at 50. N Engl J Med 2007; 357:1472-1475. 
2. 
Fuchs EJ. Haploidentical transplantation for hematologic malignancies: where do we stand. 
Hematology Am Soc Hematol Educ Program 2012; 230-236. 
3. 
Gladstone DE, Zachary A, Fuchs EJ, et al. Desensitization for mismatched hematopoietic stem 
cell transplantation (HSCT). Blood 2011; 1955 (abstract). 
4. 
Fuchs ET, et al. Related haploidentical donors are a better choice than matched unrelated 
donors: point. Blood Advances 2017; 6:397-400.  
5. 
Brunstein CG, Fuchs EJ, Carter SL, et al. Alternative donor transplantation after reduced intensity 
conditioning: results of parallel phase 2 trials using partially HLA-mismatched related bone 
marrow or unrelated double umbilical cord blood grafts. Blood 2011; 2:382-288.  
6. 
Bertaina A; Merli P; Rutella S; Pagliara D; Bernardo ME; Masetti R, et al. HLA-haploidentical 
stem cell transplantation after removal of alphabeta+ T and B cells in children with nonmalignant 
disorders. Blood 2014; 124:822-826. 
7. 
Balashov D; Shcherbina A; Maschan M; Trakhtman P; Skvortsova Y; Shelikhova L, et al. Single-
Center Experience of Unrelated and Haploidentical Stem Cell Transplantation with 
TCRalphabeta and CD19 Depletion in Children with Primary Immunodeficiency Syndromes. Biol 
Blood Marrow Transplant 2015; 21:1955-1962. 
8. 
Bertaina A; Zecca M; Buldini B; Sacchi N; Algeri M; Saglio F, et al. Unrelated donor vs HLA-
haploidentical alpha/beta T-cell- and B-cell-depleted HSCT in children with acute leukemia. 
Blood 2018; 132:2594-2607. 
9. 
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. 
10. Fuchs EJ, Selective allodepletion: have we finally found the holly grail? Biol Blood Marrow 
Transplant 2013; 19:1413-1414. 
11. 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. 
12. Kanate AS; Mussetti A; Kharfan-Dabaja MA; Ahn KW; DiGilio A; Beitinjaneh A, et al. Reduced-
intensity transplantation for lymphomas using haploidentical related donors vs HLA-matched 
unrelated donors. Blood 2016; 127:938-947. 
13. McCurdy SR; Kanakry JA; Showel MM; Tsai HL; Bolanos-Meade J; Rosner GL, et al. Risk-
stratified 
outcomes 
of 
nonmyeloablative 
HLA-haploidentical 
BMT 
with 
high-dose 
posttransplantation cyclophosphamide. Blood 2015; 125:3024-3031. 
14. Ghosh N; Karmali R; Rocha V; Ahn KW; DiGilio A; Hari PN, et al. Reduced-intensity 
transplantation for lymphomas using haploidentical related donors versus HLA-matched sibling 
donors: a center for international blood and marrow transplant research analysis. J Clin Oncol 
2016; 34:3141-3149. 
15. Bashey A; Zhang X; Sizemore CA; Manion K; Brown S; Holland HK, et al. T-cell replete HLA-
haploidentical hematopoietic transplantation for hematologic malignancies using post-
transplantation cyclophosphamide results in outcomes equivalent to those of contemporaneous 
HLA-matched related and unrelated donot transplantation. J Clin Oncol 2013; 31:130-1316.  


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45 
16. Raiola AM; Dominietto A; di Garzia C; Lamparelli T; Gualandi F; Ibatici A, et al. Unmanipulated 
haploidentical transplants comapred to with other alternative donors and matched sibling grafts. 
Biol Blood Marrow transplant 2014; 20:1573-1579. 
17. Herrero-Beaumont G, Martinez Calatrava MJ, Castaneda S. Abatacept mechanism of actions: 
concordance with its clinical profile. Rheumatol Clin 2012; 2:78-83. 
18. Watkins BK, Qayed M, Bratrude B, et al. T cell blockade with CTLA4-Ig (Abatacept) for acute 
GvHD prevention in HLA matched and mismatched unrelated donor transplantation: results of 
the first phase 2 trial. Biol Blood Marrow Transplant 2019; 65 (abstract).  
19. Patel A, Yong J. Elimination of acute GvHD with three doses of abatacpet prophylaxis combined 
with post-transplant cyclophosphamide after myeloablative treosulfan-based conditioning in the 
HLA identical sibling and unrelated (10-12/12) peripheral blood stem cell donor setting: improved 
safety and efficacy compared to alemtuzumab prophylaxis. Blood 2019; 4540 (abstract).  
20. Kasamon YL, Fuchs EJ, Zahurak M, et al. Shortened-duration aftet non-myeloablative, HLA-
haploidentical bone marrow transplantation. Biol Blood Marrow Transplant 2018; 5:1022-1028.  
21. Solomon SR, Sizemore CA, Sanacore M et al. Total body irradiation-based myeloablative 
haploidentical stem cell transplantation is a safe and effective alternative to unrelated donor 
transplantation in patients without matched sibling. Biol Blood Marrow Transplant 2015; 21:1299-
1307.  
22. Baker M, Wang H, Rowley SD, et al. Comaprative outcomes after haploidentical or unrelated 
donor bone marrow or blood stem cell transplantation in adult patients with hematological 
malignancies. Biol Blood Marrow Transplant 2016; 22:2047-2055. 
23. Kanate AS, Mussetti A, Kharfan_Dabaja MA, et al. Reduced-intensity transplantation for 
lymphoma using haploidentical related donors vs HLA-matched donors. Blood 2016; 127: 938-
947. 
 
18. APPENDICES 
18.1. Appendix A: Required Study Activities  
18.2. Appendix B: Acute Graft-Versus-Host Disease Assessment (aGVHD) 
18.3. Appendix C: Chronic Graft-Versus-Host Disease Assessment (cGVHD) 
18.4. Appendix D: New York Heart Association (NYHA) Classification of Cardiac Disease 
 
 
 
 
 
 
 
 
 


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18.1 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 Tacrolimus initiated on Day +5 
5 Abatacept given on Day +5, +14, +28 
6 Post-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 day +30, +100, +180, and +365 (+/- 7 days) after 
transplant. 
 
 
 
 
 
 
18.2 APPENDIX B: ACUTE GRAFT VERSUS HOST DISEASE ASSESSMENT (aGvHD) 
 
 
Activity 
Pre-
Stud
y1 
Day 
-7 
to 
Day 
-12 
Day 0 
Day 
+3 
Day 
+4 
 
 
 
 
Day 
+5 
 
 
 
 
Day 
+14 
 
 
 
 
Day 
+28 
Daily 
until 
Neutr
ophil 
Engr
aftme
nt  
 
Daily 
until 
disch
arge 
Twic
e a 
week 
until 
Engr
aftme
nt 
Week
ly 
until 
Day 
+100 
(+/- 3 
days) 
Mont
hly 
until 
Day 
+180 
(+/- 7 
days) 
Every 3 
months 
until 
Day+730 (2 
years) (+/-
7days) 
Study team 
procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
X 
X 
 
 
 
 
 
X 
X 
 
X 
X 
X 
KPS 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
 
 
 
 
 
 
X 
X 
 
X 
X 
X 
Cychlophophamide
3 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
Tacrolius4 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Abatacept5 
 
 
 
 
 
X 
X 
X 
 
 
 
 
 
 
Toxicity 
Assessment 
 
X 
X 
 
 
 
 
 
X 
X 
 
X 
X 
X 
GVHD Assessment 
 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
X 
Chimerism6 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
Immune 
Reconstitution 
Samples7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory 
Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC,CMP 
X 
X 
X 
 
 
 
 
 
X 
 
 
X 
X 
X 
LFTs 
 
X 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 


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47 
 
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 
No persistent nausea, vomiting or 
anorexia. Diarrhea ≤ 500 ml/day 
1 
Maculopapular rash < 25% of body 
surface 
2.0-3.0 mg/dL 
Persistent nausea, vomiting or anorexia. 
Diarrhea 501-1000 ml/day 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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18.3 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 
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. 
 
 
 


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49 
18.4 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.