Conditions: Hematopoietic Malignancies
Keywords: Hematopoietic Malignancies Nonmyeloablative Peripheral Blood Stem Cell Transplant Posttransplantation
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 6
Healthy volunteers: no

Brief summary:
This is an open label phase II single arm study of peripheral blood stem cell transplantation and posttransplantation cyclophosphamide, using HLA full match or haploidentical related donors, in hematological malignancies including those difficult to engraft. The objective of this study is to evaluate the safety and feasibility in nonmyeloablative, partially HLA-mismatched or HLA-matched PBSC transplant from haploidentical donors or fully matched donors with post-grafting immunosuppression that includes high-dose cyclophosphamide, tacrolimus, and Mycophenolate mofetil (MMF).

Detailed description:
Primary Objective Estimate event free survival (EFS) (relapse, progression, or death) rate one year after transplant.

Secondary Objectives:

1. Estimate the cumulative incidences of severe acute grade III or higher GVHD, chronic GVHD (overall and by extent)
2. Estimate the cumulative incidence of systemic steroid initiation,
3. Summarize the graft failure frequency,
4. Summarize the kinetics of neutrophil and platelet recovery, and kinetics of donor chimerism in unsorted and CD3+ sorted peripheral blood.
5. Summarize major toxicities and complications associated with the transplantation procedure selected toxicities.

Exploratory Objectives:

Explore the association between the amount of donor T cell chimerism at \~ Day 28 and patient/graft characteristics (e.g., prior therapies, graft cell dose) and transplantation outcomes (sustained engraftment, relapse or progression, GVHD).

Arms:
arm 1: None

Interventions: intervention 1: Cyclophosphamide
Intervention descriptions: intervention 1: Shortened duration immunosuppression following nonmyeloablative peripheral blood stem cell transplant with high dose post transplantation cyclophosphamide in malignancies to engraft.

Protocol document:
Prot_SAP_000.pdf: 
 
CONFIDENTIAL
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor
PHASE II STUDY OF NONMYELOABLATIVE PERIPHERAL BLOOD STEM CELL TRANSPLANT 
WITH HIGH-DOSE POSTTRANSPLANTATION CYCLOPHOSPHAMIDE IN HEMATOPOIETIC 
MALIGNANCIES INCLUDING THOSE THAT ARE CHALLENGING TO ENGRAFT
Principal Investigator:
Ahmad Samer Al-Homsi, MD
Blood and Marrow Transplantation
NYU Langone Health – Ambulatory Care Center - Perlmutter 
Cancer Center
240 E 38th Street, 19th floor
New York, NY 10016
Tel: 646-501-4848
Email: Samer.Al-Homsi@nyumc.org
Co-Investigators:
David Kaminetzky, MD
Mohammad Maher Abdul Hay, MD
Naamit Gerber, MD
Michael Grossbard, MD
Study Product:
Cyclophosphamide
Protocol Number:
S17-00042
Biostatistician:
Benjamin A. Levinson, Ph.D.
Other Agent(s):
    Cyclophosphamide, commercial
Mesna, commercial
Fludarabine, commercial
Mycophenolate, commercial
Tacrolimus, commercial
Sirolimus, commercial
Initial version:
1/12/2017
Amended:
10/10/2017
Amended:
06/19/2018
Amended:
[date]
Protocol
NCT03187756


High-dose Post-transplantation Cyclophosphamide 
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authorized in writing by the study sponsor
Table of Contents
SCHEMAA ..................................................................................................................................................10
1  INTRODUCTION ....................................................................................................................................11
1.1
BACKGROUND .............................................................................................................................11
1.2
INVESTIGATIONAL AGENT .............................................................................................................15
1.3
DOSE RATIONALE ........................................................................................................................15
1.4
RESEARCH RISKS & BENEFITS .....................................................................................................15
1.4.1
Risk of Study Drug ................................................................................................................15
1.4.2
Other Risks of Study Participation ........................................................................................15
1.4.3
Potential benefits...................................................................................................................16
2
STUDY OBJECTIVES .......................................................................................................................16
3
STUDY DESIGN ................................................................................................................................16
3.1
GENERAL DESIGN........................................................................................................................16
4
SUBJECT SELECTION AND WITHDRAWAL..................................................................................16
4.1
SELECTION OF PATIENTS AND DONORS.........................................................................................16
ELIGIBILITY FOR TRANSPLANTATION ...........................................................................................................16
DONOR ELIGIBILITY ...................................................................................................................................17
DONOR PRIORITIZATION ............................................................................................................................18
4.2
EXCLUSION CRITERIA...................................................................................................................18
4.3
INCLUSION OF WOMEN AND MINORITIES........................................................................................18
4.4
SUBJECT RECRUITMENT...............................................................................................................18
4.4.1
Informed Consent..................................................................................................................19
4.5
REGISTRATION PROCEDURES.......................................................................................................19
4.5.1
General Guidelines ...............................................................................................................19
4.6
EARLY WITHDRAWAL OF SUBJECTS ..............................................................................................20
4.6.1
When and How to Withdraw Subjects...................................................................................20
4.6.2
Data Collection and Follow-up for Withdrawn Subjects ........................................................20
5
STUDY DRUG ...................................................................................................................................20
5.1
DESCRIPTION ..............................................................................................................................20
5.2
TRIAL TREATMENT .......................................................................................................................21
5.3
TREATMENT REGIMEN..................................................................................................................21
5.3.1
Transplantation regimen .......................................................................................................21
5.3.2
Fludarabine ...........................................................................................................................21
5.3.3
Pretransplantation cyclophosphamide ..................................................................................22
5.3.4
Total body irradiation.............................................................................................................22
5.3.5
Day of rest.............................................................................................................................22
5.3.6
Peripheral blood stem cell transplantation ............................................................................22
5.3.7
Posttransplantation cyclophosphamide.................................................................................23
5.3.8
Mycophenolate mofetil ..........................................................................................................23
5.3.9
Tacrolimus (or other immunosuppression with sirolimus).....................................................23
5.3.10
Growth factors ..................................................................................................................24
5.4
PREPARATION AND ADMINISTRATION OF STUDY DRUG...................................................................24
5.4.1
Cyclophosphamide................................................................................................................24
5.4.2
Fludarabine, mesna, mycophenolate mofetil, Tacrolimus or Sirolimus.................................24
5.5
SUBJECT COMPLIANCE MONITORING ............................................................................................25
5.6
PRIOR AND CONCOMITANT THERAPY ............................................................................................25
5.7
SUPPORTIVE CARE.......................................................................................................................25
5.8
POSTTRANSPLANTATION THERAPIES .............................................................................................25
5.9
POSTTRANSPLANTATION FOLLOW-UP ............................................................................................26
5.10
PACKAGING.................................................................................................................................26


High-dose Post-transplantation Cyclophosphamide 
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5.11
RECEIVING, STORAGE, DISPENSING AND RETURN .........................................................................26
6
STUDY PROCEDURES.....................................................................................................................26
6.1
STANDARD PRE/POSTTRANSPLANT EVALUATIONS..........................................................................26
6.2
BASELINE PERIOD........................................................................................................................27
6.3
TREATMENT PERIOD.....................................................................................................................27
6.4
POST-TREATMENT VISITS-FOLLOW UP VISITS ................................................................................27
6.5
RESEARCH SPECIMEN PROCEDURES ............................................................................................27
7
STUDY PARAMETERS.....................................................................................................................27
8
MEASUREMENT OF EFFECT AND ENDPOINTS ...........................................................................27
8.1
HEMATOLOGIC PARAMETERS ........................................................................................................27
8.2
GRAFT-VERSUS-HOST DISEASE.....................................................................................................27
8.3
DISEASE AND SURVIVAL ENDPOINTS..............................................................................................28
9
STATISTICAL METHODS.................................................................................................................28
9.1
PRIMARY ENDPOINT AND DESIGN...................................................................................................28
9.2
SECONDARY ENDPOINTS ..............................................................................................................28
9.3
EXPLORATORY ENDPOINTS...........................................................................................................29
9.4
SAMPLE SIZE DETERMINATION......................................................................................................29
9.5
SUBJECT POPULATION(S) FOR ANALYSIS ......................................................................................29
10
EXPECTED TOXICITIES...................................................................................................................29
10.1
DRUG INFORMATION ....................................................................................................................29
10.1.3
Fludarabine (Fludara) .......................................................................................................30
10.2
TOXICITIY GRADING......................................................................................................................33
10.3
TOXICITY REPORTING...................................................................................................................33
11
SAFETY AND ADVERSE EVENTS ..................................................................................................34
11.1
DEFINITIONS................................................................................................................................34
11.2
RECORDING OF ADVERSE EVENTS................................................................................................35
11.3
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS .................................36
11.3.1
Investigator reporting: NYULMC IRB and Perlmutter Cancer Center Clinical Trials Office
36
11.3.2
Investigator reporting: notifying the IRB............................................................................37
11.3.3
Sponsor reporting: Notifying the FDA ...............................................................................38
11.3.4
Sponsor reporting: Notifying participating investigators....................................................38
11.4
UNBLINDING PROCEDURES...........................................................................................................38
11.5
STOPPING RULES ........................................................................................................................38
11.6
MEDICAL MONITORING.................................................................................................................38
11.6.1
Data and Safety Monitoring Plan ......................................................................................38
12
DATA HANDLING AND RECORD KEEPING...................................................................................39
12.1
CONFIDENTIALITY ........................................................................................................................39
12.2
CONFIDENTIALITY AND HIPAA......................................................................................................39
12.3
SOURCE DOCUMENTS..................................................................................................................39
12.4
DATA AND SOURCE DOCUMENTATION ...........................................................................................40
12.5
RECORDS RETENTION..................................................................................................................40
13
STUDY MONITORING, AUDITING, AND INSPECTING ..................................................................40
13.1
STUDY MONITORING PLAN ...........................................................................................................40
13.2
AUDITING AND INSPECTING...........................................................................................................41
14
ETHICAL CONSIDERATIONS..........................................................................................................41
15
STUDY FINANCES............................................................................................................................41
15.1
FUNDING SOURCE .......................................................................................................................41


High-dose Post-transplantation Cyclophosphamide 
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15.2
CONFLICT OF INTEREST................................................................................................................41
15.3
SUBJECT STIPENDS OR PAYMENTS...............................................................................................41
16
PUBLICATION PLAN........................................................................................................................42
17
REFERENCES...................................................................................................................................43
18
APPENDIX.........................................................................................................................................45


High-dose Post-transplantation Cyclophosphamide 
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List of Abbreviations
CLL
chronic lymphocytic leukemia
CMML
chronic myelomonocytic leukemia
CNI
calcineurin inhibitor
CrCl
creatinine clearance
Cy
cyclophosphamide
GVHD
Graft-versus-host-disease
GVT
grat-versus-tumor
HSCT
Hematopoietic Stem Cell Transplantation
IMWG
International Myeloma Working Group
IST
immunosuppressive therapy
MDS
myelodysplastic syndrome
MHC
major histocompatibility complex
MM
multiple myeloma
MMF
mycophenolate mofetil
MPD
myeloproliferative disease
NRM
nonrelapse mortality
OS
overall survival
PBSC
peripheral blood stem cell
PFS
Progressive free survival
PRES
Posterior Reversible Encephalopathy Syndrome
TBI
Total Body Irradiation


High-dose Posttransplantation Cyclophosphamide 
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Title
Phase II study of nonmyeloablative peripheral blood stem cell transplant with 
high-dose posttransplantation cyclophosphamide in hematopoietic 
malignancies including those that are challenging to engraft
Protocol Number
s17-00042
Phase
II
Methodology
Single arm open label Phase II clinical trial of peripheral blood stem cell 
transplantation and posttransplantation cyclophosphamide therapy from full 
and haploidentical related donors in hematological malignancies, including 
those difficult to engraft
Study Duration
2.5 years (1 year after enrollment of last patient)
Study Center(s)
Laura & Isaac Perlmutter Cancer Center at NYU Langone
Objectives
Overall Objective:  In nonmyeloablative, related or unrelated donor, partially 
HLA-mismatched or HLA-mismatched transplant with post-grafting 
immunosuppression that includes high-dose cyclophosphamide and MMF, and 
standard tacrolimus (Day 5 through Day 180) evaluate the safety and 
feasibility of peripheral stem cells as a source of stem cells in hematopoietic 
malignancies, including those challenging to engraft.  
Primary Objective: 
 
Estimate the one year event (relapse, progression, or death) free survival 
(EFS) rate.
Secondary Objectives:
1.
Estimate the cumulative incidences of severe acute grade III or higher 
GVHD, chronic GVHD (overall and by extent)
2.
Estimate the cumulative incidence of systemic steroid initiation
3.
Summarize the graft failure frequency
4.
Summarize the kinetics of neutrophil and platelet recovery, and 
kinetics of donor chimerism in unsorted and CD3+ sorted peripheral 
blood
5.
Summarize major toxicities and complications associated with the 
transplantation procedure selected toxicities
 
Exploratory Objectives:
Explore the association between the amount of donor T cell chimerism at ~ 
Day 28 and patient/graft characteristics (e.g., prior therapies, graft cell dose) 
and transplantation outcomes (sustained engraftment, relapse or progression, 
GVHD)
Number of Subjects
15 subjects  


High-dose Posttransplantation Cyclophosphamide 
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Diagnosis and Main 
Inclusion Criteria
Eligibility for transplantation
1.
Presence of a suitable related, HLA-haploidentical or HLA-
matched stem cell donor 
a.
The donor and recipient must be identical at least one 
allele of each of the following genetic loci: HLA-A, HLA-B, 
HLA-Cw, HLA-DRB1, and HLA-DQB1.  A minimum match 
of 5/10 is therefore required for related donors, and will be 
considered sufficient evidence that the donor and recipient 
share one HLA haplotype.  Unrelated donors will be 10/10.
2.
Eligible diagnoses: 
a.
 Myelodysplastic syndrome (MDS) including chronic 
myelomonocytic leukemia [CMML]
b.
SLL or CLL with 17p deletion, or with progression < 6 
months after second or greater treatment regimen.
c.
T-cell PLL in PR or better prior to transplantation
d.
Interferon- or tyrosine kinase-refractory CML in first 
chronic phase, TKI-intolerant CML in first chronic phase
e.
Philadelphia chromosome negative myeloproliferative 
disease (including myelofibrosis)
f.
Multiple myeloma or plasma cell leukemia with a PR
g.
Hematologic malignancy in complete or partial remission 
with minimal residual disease (MRD) detectable or non-
detectable by conventional cytogenetics, FISH, flow 
cytometry, molecular testing or PET/CT imaging.
3.
 No active extramedullary leukemia
Donor eligibility
1.
Donors must be either:
a.
HLA-haploidentical or HLA-identical relatives of the patient 
based on allele or allele group level typing as defined in 
Section 3.1.  
2.
Medically fit to and willing to donate
3.
Lack of recipient anti-donor HLA antibody
Note: In some instances, low level, non-cytotoxic HLA 
specific antibodies may be permissible if they are found to be 
at a level well below that detectable by flow cytometry.  This 
will be decided on a case-by-case basis by the PI and one of 
the immunogenetics directors. Pheresis to reduce anti-HLA 
antibodies is permissible; however eligibility to proceed with 
the transplant regimen would be contingent upon the 
success of the desensitization. 
4.
Has not donated blood products to patient
Study Product, Dose, 
Route, Regimen
cyclophosphamide


High-dose Posttransplantation Cyclophosphamide 
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Schemaa
Days –6, –5                           Fludarabine 30 mg/m2 IV daily (adjusted for renal function)
Cyclophosphamide 14.5 mg/kg IV daily  
           
Days –4, –3, –2                    Fludarabine 30 mg/m2 IV daily (adjusted for renal function)

Day –1
TBI 200 cGy       

Day 0
Infuse T-cell replete peripheral stem cells
Begin antibiotic prophylaxis

Days 3, 4
Cyclophosphamide 50 mg/kg IV QD
Mesna 40 mg/kg IV QD in divided doses
                             
Day 5   
Begin tacrolimus (2 mg PO BID for pts > 18 y), 
               
MMF 15 mg/kg PO TID (maximum 3 g/day)
(Immunosuppression must begin at least 24 hours after Cy completion)
 (Switching to sirolimus for clinical reasons [e.g. tacrolimus nephrotoxicity or PRES] is allowed)
Begin GCSF 5 mcg/kg/d SC or IV, continue until ANC > 1000/mm3 over 3 days
 

Day 28 (+/- 3 d)
Assess chimerism
  
Day 35
          Discontinue MMF (optional if GVHD has occurred)

Day 56 (+/- 3 d)
Assess chimerism, GVHD 
Day 56 (+/- 3 d)
Evaluate disease 

Day 84 (+/- 5 d)
Assess chimerism, GVHD

Day 112 (+/- 7 d) 
Assess chimerism, GVHD 

Day 180 (+/- 7 d)
Assess chimerism, GVHD 
Evaluate disease
                                 
Discontinue tacrolimus

Day 270 (+/- 21 d)
Assess chimerism, GVHD

1 yr (+/- 30 d)
Assess chimerism
1 yr (+/- 30 d) and beyond
Evaluate disease, GVHD 
a See Section 5.3 for complete dosing instructions, and Section 7.0 for required evaluations.


High-dose Posttransplantation Cyclophosphamide 
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1  Introduction
This document is a protocol for a human research study. This study is to be conducted in accordance with 
US government research regulations, and applicable international standards of Good Clinical Practice, and 
institutional research policies and procedures.
This protocol has been modified from a Johns Hopkins Protocol “PHASE II STUDY OF 
NONMYELOABLATIVE 
PERIPHERAL 
BLOOD 
STEM 
CELL 
TRANSPLANT 
WITH 
HIGH-DOSE 
POSTTRANSPLANTATION CYCLOPHOSPHAMIDE IN HEMATOPOIETIC MALIGNANCIES INCLUDING 
THOSE THAT ARE CHALLENGING TO ENGRAFT” approved by the Johns Hopkins IRB 10/20/15.  The 
Johns Hopkins Protocol has an arm in which they discontinue immunosuppression at Day 90 in some 
patients; this arm is not included in the current study.
Recent advances in allogeneic blood or marrow transplant (HSCT) platforms for hematologic malignancies 
have substantially lowered transplant-related morbidity both in the HLA-matched and partially HLA-
mismatched settings.  One of these major advances is the incorporation of high-dose posttransplantation 
cyclophosphamide (Cy) for prophylaxis of graft-versus-host-disease (GVHD) and graft rejection, as 
developed at Johns Hopkins.1  This approach has made the use of mismatched donors, including 
haploidentical donors, possible. Historically, this approach has been used for HSCTs which have used 
marrow as the graft source.  However, the HSCT field has been moving towards using peripheral blood stem 
cells (PBSC) as a graft source in nonmyeloablative allogeneic transplants based on data showing lower graft 
failure, progression free survival (PFS) and overall survival (OS) benefit.2  Although transplants using PBSCs 
have higher rates of GVHD than those from marrow sources, the GVHD may translate into better outcomes 
in terms of OS and PFS.3,4  This might be particularly important for those diseases that are more challenging 
to 
engraft, 
including 
myelodysplastic 
syndrome 
(MDS), 
chronic 
lymphocytic 
leukemia 
(CLL), 
myeloproliferative diseases (MPD) and multiple myeloma (MM).   
This study will therefore asses engraftment, GVHD, and overall survival in patients receiving PBSC from  
HLA haploidentical or matched donors  using a nonmyeloablative conditioning regimen with GVH prophylaxis 
using post-transplant high-dose cyclophosphamide, tacrolimus, and mycophenolate mofetil.  Our goal is to 
estimate one year EFS rate, and summarize the rates of GVHD in our population.  We will compare our 
findings to published data of matched and haploidentical transplants, which have included bone marrow as a 
graft source and a range of post-transplant immunosuppression.
1.1
Background
Stem cell source
There has been a great deal of discussion on the importance of stem cell source on the risk of chronic graft-
versus-host disease5-9. Several studies have addressed this issue in the related setting. Of the eight 
randomized trials published10-18 only one reported an statistically significant increase in grades II-IV acute 
graft-versus-host disease with the use of peripheral blood stem cells when compared to bone marrow (52 vs. 
39%)16. Regarding chronic graft-versus-host disease,  the results are as follows: 3 studies have shown an 
increase of chronic graft-versus-host disease with peripheral blood stem cells as opposed to bone 
marrow12,16,19. One study showed a trend towards increase in chronic graft-versus-host disease with the use 
of peripheral blood stem cells19. A meta-analysis by Cutler et al. confirmed that both, acute and chronic graft-
versus-host disease are more common after peripheral blood stem cells than bone marrow7. Registry data 
showed in pediatric patients that chronic graft-versus-host disease was more frequent (as well as higher 
mortality) after peripheral blood stem cells than after bone marrow8. In adults, chronic graft-versus-host 
disease is also more prevalent20. Umbilical-cord stem cells also have been a source of grafts in children and 
young adults. As children tolerate mismatches better than adults, interpretation of risk in this group is difficult 
but it seems that the rate of chronic graft-versus-host disease is low for this stem cell sources, especially 
considering that almost all grafts are 1-3 antigen mismatches21,22. In the unrelated setting, a clinical trial by 
the BMT CTN comparing bone marrow versus peripheral blood did not detect significant survival. Peripheral-
blood stem cells may reduce the risk of graft failure (the overall incidence of graft failure in the peripheral-
blood group was 3% [95% CI, 1 to 5], versus 9% [95% CI, 6 to 13] in the bone marrow group [P=0.002]), 
whereas bone marrow may reduce the risk of chronic GVHD at 2 years (peripheral-blood group was 53% 


High-dose Posttransplantation Cyclophosphamide 
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[95% CI, 45 to 61], as compared with 41% [95% CI, 34 to 48] in the bone marrow group [P=0.01].17  The 
proportion of patients with extensive chronic GVHD was higher in the peripheral-blood group than in the 
bone marrow group (48% [95% CI, 42 to 54] vs. 32% [95% CI, 26 to 38], P<0.001). Among patients who 
were alive at 2 years, 57% of the patients in the peripheral-blood group were receiving immunosuppressive 
therapy, as compared with 37% of those in the bone marrow group (P=0.03). There were no significant 
between-group differences in the incidence of acute GVHD or relapse17.
Rationale for tacrolimus and Mycophenolate mofetil as immunosuppression for 180 days
With the advent of posttransplantation high-dose Cy, nonmyeloablative allogeneic HSCT platforms have 
been associated with acceptable rates of acute GVHD, graft failure, and nonrelapse mortality (NRM) that are 
similar to those seen with HLA-matched transplants.23,24  However, relapse remains a major problem, and 
approaches that augment the anti-tumor efficacy of the transplant procedure are needed.  Transplantation 
platforms that minimize the amount of pharmacologic immunosuppression, but that carry acceptable rates of 
severe GVHD and graft failure, are desirable for a number of reasons.  
Extensive published data demonstrate that allogeneic HSCT can be associated with a clinically significant 
graft-versus-tumor (GVT) effect mediated by donor T cells specific for host histocompatibility antigens.  Yet, 
the T cells that mediate a GVT effect may also cause clinically significant GVHD.  Tacrolimus, a calcineurin 
inhibitor (CNI), blocks T cell activation and the production of interleukin-2, a critical growth factor for T cells 
including regulatory T cells that control autoimmunity.  CNI’s are used to prevent acute GVHD, but they are 
associated with an increased incidence of renal dysfunction, hypertension, opportunistic infection, and other 
complications. Sirolimus is similarly used and applied.   Importantly, CNI’s block T cell development in the 
thymus16,17 resulting in delayed immunologic reconstitution, and by suppressing T cell activation may block 
the GVT effect and increase the risk of disease relapse after allogeneic HSCT.18-20  
MMF plus a CNI (i.e. tacrolimus or cyclosporine or sirolimus) represents standard GVHD prophylaxis for 
nonmyeloablative 
conditioning. 
In 
nonmyeloablative, 
HLA-matched 
HSCT 
with 
postgrafting 
immunosuppression consisting solely of MMF + cyclosporine, investigators at the Fred Hutchinson 
retrospectively evaluated three durations of cyclosporine: taper from Days 35 to 56, Days 56 to 77, or Days 
56 to 180.36  Grafts were derived from peripheral blood stem cells.  There was no significant association 
between cyclosporine duration and the rates of acute grade II-IV GVHD (57%, 43%, and 49% respectively), 
extensive chronic GVHD, or NRM; however, longer duration of cyclosporine was associated with a lower risk 
of acute severe (grade III-IV) GVHD and lower incidence of discontinuation of all systemic 
immunosuppression by 24 months (an indirect marker of the prevention and successful treatment of GVHD).  
In an older randomized trial of myeloablative, HLA-identical or one-antigen mismatched HSCT, where 
postgrafting 
immunosuppression 
consisted 
of 
methotrexate 
and 
cyclosporine 
with 
or 
without 
methylprednisolone, results suggested that cyclosporine could be stopped earlier (by Day 60) in patients 
without prior acute GVHD, whereas those with prior acute GVHD appeared to benefit from a longer course 
37.  In another randomized trial of myeloablative, HLA-matched related or unrelated donor HSCT, the risk of 
clinically extensive chronic GVHD and transplant-related mortality did not significantly differ in patients 
assigned to 6 months versus 24 months of cyclosporine.38  Other nonrandomized studies of myeloablative, 
HLA-matched sibling transplant have suggested a benefit to longer duration cyclosporine in chronic GVHD 
prevention, however.39  Some studies also have found an increased risk of relapse associated with higher 
doses of cyclosporine.40,41 
It is important to note that these experiences with immunosuppression duration with other allogeneic HSCT 
platforms cannot be directly extrapolated to the high-dose posttransplantation Cy platform that this protocol 
studies.  Immunosuppression must be sufficient to prevent graft failure and to prevent excessive rates of 
GVHD including severe GVHD; yet extended-course immunosuppression may increase the risk of infection, 
drug toxicity, and relapse.  There are presently no published data on the minimum required duration of 
tacrolimus or other immunosuppression after nonmyeloablative HSCT that includes high-dose Cy as part of 
postgrafting immunosuppression.  
The effectiveness of high-dose posttransplantation Cy in GVHD 
prevention, however, permits the investigation of this question.
High-dose posttransplantation cyclophosphamide


High-dose Posttransplantation Cyclophosphamide 
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The immunologic rationale for administering high-dose Cy after transplantation is that recently activated, 
alloreactive T cells (the cells most responsible for GVHD) are selectively sensitive to the toxic effects of this 
drug.25  High-dose Cy, when administered in a narrow window after transplantation, depletes alloreactive T 
cells from the donor and host and can inhibit both GVHD and graft rejection.25-30  As a form of drug-induced 
immunologic tolerance,31 the strategy of giving high-dose Cy after transplantation takes advantage of the 
heightened cytotoxic sensitivity of proliferating, alloreactive T cells over non-alloreactive, resting T cells to 
being killed by a DNA-damaging agent.32 Pre-clinical studies demonstrated that engraftment of major 
histocompatibility complex (MHC)-mismatched bone marrow could be achieved by conditioning mice with 
pretransplantation fludarabine and low dose (200 cGy) total body irradiation (TBI), with posttransplantation 
Cy.27  Additional studies demonstrated that posttransplantation Cy reduced the incidence and severity of 
GVHD in the setting of MHC-mismatched allogeneic HSCT after myeloablative conditioning.26 
After allogeneic HSCT, standard regimens of GVHD prophylaxis consist of a CNI (cyclosporine or tacrolimus) 
in combination with either methotrexate, MMF, or sirolimus.  However, a nonmyeloablative, partially HLA-
mismatched (haploidentical), related donor HSCT platform with high-dose posttransplantation Cy, MMF, and 
tacrolimus for GVHD and graft rejection prophylaxis has produced encouraging results24.  This approach has 
been associated with rapid and stable engraftment in most patients.24  Most importantly, this approach has 
carried acceptable rates of GVHD and NRM that parallel those seen with nonmyeloablative HLA-matched 
transplants (Figure 1).23,24,33,34  Cy, when administered at high doses after myeloablative, HLA-matched, 
related or unrelated donor HSCT, notably has been found to be effective single-agent prophylaxis against 
GVHD, obviating the need for CNI’s in this setting (Figure 1).35  
Figure 1. Acute GVHD after HSCT incorporating high-dose posttransplantation Cy. A) 
nonmyeloablative HSCT.24  B) myeloablative, HLA-matched, related or unrelated donor HSCT, with Cy as 
single-agent prophylaxis.35
Nonmyeloablative HSCT with fludarabine, TBI, and posttransplantation cyclophosphamide
The same approach to nonmyeloablative HSCT using partially HLA-mismatched, related donors has been 
adopted at Johns Hopkins for HLA-identical donor HSCT.  In a phase I trial (J0169) of nonmyeloablative, 
matched sibling donor HSCT, Cy alone on Day 3, Cy alone on Days 3 and 4, or Cy on Days 3 and 4 with 
MMF was investigated with the latter being favored.  Although the optimal postgrafting immunosuppression 
after high-dose Cy is not defined, MMF plus a CNI is standard GVHD prophylaxis for nonmyeloablative 
conditioning (i.e. omission of a CNI is nonstandard).  
Independent clinical trials have evaluated or are evaluating a nonmyeloablative, partially HLA-mismatched 
(haploidentical), related donor marrow transplant platform with high-dose posttransplantation Cy, tacrolimus, 
and MMF for GVHD and graft rejection prophylaxis.  Conditioning in these studies has historically consisted 
of fludarabine, low-dose Cy, and 200 cGy TBI.  The postgrafting immunosuppression regimen that underlies 
recent and ongoing research efforts at Johns Hopkins has been published.24,34  A combined analysis of two 
independent clinical trials for poor-risk hematologic malignancies was originally reported in 2008 (40 patients 
at Johns Hopkins, 28 at Fred Hutchinson Cancer Research Center), evaluating the safety and efficacy of a 
high-dose posttransplantation Cy platform after outpatient nonmyeloablative conditioning and T-cell-replete 
A
B


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HSCT from partially HLA-mismatched, related donors (Figure 2).24  Following transplantation, high-dose (50 
mg/kg) Cy was administered on Day 3 (Seattle group), or on Days 3 and 4 (Hopkins).  Pharmacologic 
prophylaxis of GVHD was initiated on the day following completion of posttransplantation Cy with MMF until 
Day 35, and tacrolimus which was tapered to off by Day 180 (Seattle) or continued at full dose until Day 180 
(Hopkins).  Filgrastim 5 g/kg/day was administered until recovery of neutrophils to >1000/L:
Figure 2. Treatment Schema in Previous Studies
Median times to recovery of neutrophils and platelets were 15 and 24 days, respectively.  Graft failure 
occurred in 9 of 66 evaluable patients (12%); all but one patient with graft failure had recovery of autologous 
hematopoiesis with median times to neutrophil and platelet recovery of 15 days (range, 11-42) and 28 days 
(range, 0 – 395 days) respectively.  Engrafting patients achieved full donor chimerism rapidly; with few 
exceptions, donor chimerism in patients with sustained engraftment was virtually complete (>95%) by 2 
months after transplantation.  The cumulative incidences of acute grade II-IV GVHD and acute grade III-IV 
GVHD by Day 200 were <35% and <10%, respectively, on competing-risk analysis.  The groups did not differ 
significantly in the incidence of acute grade II-IV or III-IV GVHD, although the risk of chronic GVHD appeared 
to be lower with two doses of Cy. The cumulative incidence of extensive chronic GVHD by 1 year was only 
5% in the group with two doses of Cy. The cumulative incidences of relapse and NRM at 1 year were 51% 
and 15% respectively on competing-risk analysis; however the event-free survival (EFS) probability at 1 year 
was only 34%.  Similar outcomes were seen in a recent analysis of 185 patients treated on these trials 
including follow-up phase II trial (J0457) of this approach.34 Interestingly, although increasing degrees of HLA 
mismatch between donor and recipient have historically been associated with greater GVHD and inferior 
survival after allogeneic HSCT, that analysis retrospectively found no such adverse effect of HLA 
mismatching using this approach in the haploidentical setting.34  On an updated analysis of 212 patients with 
advanced hematologic malignancies, uniformly treated at Johns Hopkins with related donor, partially HLA-
mismatched HSCT with fludarabine/Cy/TBI conditioning and postgrafting immunosuppression with 2 doses 
of Cy, MMF on Days 5-35, and full-dose tacrolimus on Days 5-180, the 1-year EFS was 44%, and cumulative 
incidence of NRM by competing risk analysis was 8% by Day 100 and 14% at 1 year.  The cumulative 
incidence of acute grade II-IV GVHD was 28% by Day 200, cumulative incidence of severe GVHD was only 
4%, and the cumulative incidence of chronic GVHD was 14% by competing risk analysis (unpublished data).   
Summary
In summary, post-transplant Cy after non-myeloablative haploidentical or matched donors appears to be a  
generally well-tolerated procedure  The toxicity of the procedure compares favorably to the toxicity of non-
myeloablative transplantation using unrelated or even HLA-identical sibling donors.23 The post- transplant 
immunsupression, which may play a role in the rate of relapse (which can be up to 50% at one year) is likely 
due to GVH, which in turn is related to stem cell source and immunsupression.  We propose that a 
nonmyeloablative conditioned HLA identical or haploidentical PBSC graft using post-transplant high dose 
cyclophosphamide, tacrolimus, and MMF will lead to successful engraftment, tolerable acute and chronic 
graft versus, potential progression free and overall survival benefit, especially in those hematologic 
malignancies that have been a challenge to engraft.


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1.2
Investigational Agent
Cyclophosphamide (Cytoxan®)
Cyclophosphamide is an alkylating agent whose metabolites form cross-links with DNA resulting in 
cell cycle-nonspecific inhibition of DNA synthesis and function.  
1.3
Dose Rationale
The rationale for dosing of the preparative regimen and the post-transplant cyclophosphamide is based on 
the literature and described in detail in the background sections “High-dose posttransplantation 
cyclophosphamide”, 
“Nonmyeloablative 
HSCT 
with 
fludarabine, 
TBI, 
and 
posttransplantation 
cyclophosphamide”. The dose rationale for pos-transplant tacrolimus is also included in “Rationale for 
tacrolimus as immunosuppression for 180 days”.
1.4
Research Risks & Benefits
1.4.1
Risk of Study Drug
Cyclophosphamide 
 
Very Common (> 30%chance this will happen)

Neutropenia, Anemia and thrombocytopenia

Alopecia

Nausea and vomiting

Sterility
Likely ( 10% to 30% chance this will happen)

Diarrhea

Mouth sores

Hemorrhagic cystitis

Fluid weight/gain

SIADH

Transaminitis

Cardiomyopathy

Pericarditis

Rash

Mucositis
Rare (< 10% chance this will happen)

Secondary myelodysplastic syndrome

Anaphylaxis
1.4.2
Other Risks of Study Participation
Allogeneic HSCT carries risk for major morbidity and mortality.  Major toxicities and risks of the transplant 
procedure include acute and chronic GVHD, severe infection, immunosuppression which may be prolonged, 
graft failure, end-organ damage, and death.  High-dose posttransplantation Cy appears to significantly lower 
the risk of GVHD.  Shorter-duration immunosuppression may be associated with increased risk of GVHD, 
increased severity of GVHD, and graft failure.  Additional risks to study participation include breach of 
confidentiality and risks associated with blood draw.  Privacy procedures in place and good clinical practice 
guidelines are followed for this study to minimize risks associated with research procedures and 
participation.  The risks associated with blood draw include weaknesses, redness, pain, bruising, bleeding or 
infection at the needle site.


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1.4.3
Potential benefits
The potential benefits of this trial are palliation of disease-related symptoms and prolongation of overall or 
event-free survival, including the possibility of long-term disease-free survival and cure.  Potential benefits 
also include fewer infectious and other complications and lower risk of relapse because of the shorter 
duration of immunosuppression. 
1.4.4
Cyclophosphamide FDA IND Exemption
Cyclophosphamide is currently marketed in the United States.  The proposed investigation is not 
attended to support a new indication, significant change in the labeling, or in the advertising of this 
medication.   The use of cyclophosphamide is not being studied in a different route, dose level, or in 
a different patient population that has not been studied by other investigators and has been 
published.  The current investigation will be conducted in compliance with requirements of the IRB 
review as set for in 21 CFR Part 56 and with the requirements for informed consent as set forth in 
the 21 CFR part 50.  In addition, this investigation will be conducted in compliance with 21 CFR 
312.7 regarding the promotion and charging for investigational drugs.
2
Study Objectives
Overall objective 
Evaluate the safety and feasibility in nonmyeloablative, partially HLA-mismatched or HLA-matched PBSC 
transplant from haploidentical donors or fully matched donors with post-grafting immunosuppression that 
includes high-dose cyclophosphamide, tacrolimus, and MMF.
Primary Objective
Estimate event free survival (EFS) (relapse, progression, or death) rate one year after transplant.
Secondary Objectives: 
1. Estimate the cumulative incidences of severe acute grade III or higher GVHD, chronic GVHD (overall and 
by extent)
2. Estimate the cumulative incidence of systemic steroid initiation,
3. Summarize the graft failure frequency, 
4. Summarize the kinetics of neutrophil and platelet recovery, and kinetics of donor chimerism in unsorted 
and CD3+ sorted peripheral blood.
5. Summarize major toxicities and complications associated with the transplantation procedure selected 
toxicities.
Exploratory Objectives:
Explore the association between the amount of donor T cell chimerism at ~ Day 28 and patient/graft 
characteristics (e.g., prior therapies, graft cell dose) and transplantation outcomes (sustained engraftment, 
relapse or progression, GVHD).


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3
Study Design
3.1
General Design
This is an open label phase II single arm study of peripheral blood stem cell transplantation and 
posttransplantation cyclophosphamide, using HLA full match or haploidentical related donors, in 
hematological malignancies including those difficult to engraft.
4
Subject Selection and Withdrawal
4.1
Selection of Patients and Donors
Eligibility for transplantation
The following are eligibility for study entry and transplantation.  Eligibility criteria for protocol-driven, 
early cessation of immunosuppression are designated in Section 5.3.9.3.
1.
Presence of a suitable related, HLA-haploidentical or HLA-matched stem cell donor 
a.
The donor and recipient must be identical at least one allele of each of the following 
genetic loci: HLA-A, HLA-B, HLA-Cw, HLA-DRB1, and HLA-DQB1.  A minimum match of 
5/10 is therefore required for related donors, and will be considered sufficient evidence 
that the donor and recipient share one HLA haplotype. 
2.
Eligible diagnoses: 
a.
Myelodysplastic syndrome (MDS) including chronic myelomonocytic leukemia [CMML] 
with at least one of the following poor-risk features:
i. Poor-risk cytogenetics
ii. IPSS score of INT-2 of greater
iii. Treatment-related or secondary MDS
iv. MDS diagnosed before age 21
v. Progression on or lack of response to standard DNA-methyltransferase inhibitor 
therapy
vi. Life-threatening cytopenias, including those requiring frequent transfusions
b.
SLL or CLL with 17p deletion, or with progression < 6 months after second or greater 
treatment regimen. Must have the following to be an acceptable candidate as well:
i.
 < 20% of bone marrow cellularity involved by SLL/CLL (to lower risk of graft 
rejection)
ii.
No lymph nodes > 5 cm in any dimension
iii.
No massive splenomegaly, defined as > 6 cm below the left costal margin
c.
T-cell PLL in PR or better prior to transplantation. Must also have < 20% of bone marrow 
cellularity involved by PLL (to lower risk of graft rejection).
d. Interferon- or tyrosine kinase-refractory CML in first chronic phase, TKI-intolerant CML in 
first chronic phase, or CML in second or subsequent chronic phase
e.
Philadelphia chromosome negative myeloproliferative disease (including myelofibrosis)
i. Intermediate-2 or High risk score by DIPSS Plus is required for a diagnosis of 
myelofibrosis
f.
Multiple myeloma or plasma cell leukemia with a PR or better to the last treatment 
regimen, based on the International Myeloma Working Group (IMWG) criteria.49
g.
Hematologic malignancy in complete remission with minimal residual disease (MRD) 
non detectable OR detectable by conventional cytogenetics, FISH, flow cytometry, or 
molecular testing or hematologic malignancies in partial remission
3.
No active extramedullary leukemia or known active CNS involvement by malignancy.  Such 
disease treated into remission is permitted.
4.
Any previous autologous HSCT must have occurred at least 3 months prior to start of 
conditioning
5.
No previous allogeneic HSCT
6.
Adequate end-organ function as measured by:


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a.
Left ventricular ejection fraction  35% or shortening fraction > 25%
b.
Bilirubin ≤ 3.0 mg/dL (unless due to Gilbert’s syndrome or hemolysis), and ALT and AST 
< 5 x ULN
c.
FEV1 and FVC > 40% of predicted; or if unable to perform pulmonary function tests due 
to young age, oxygen saturation >92% on room air 
7.
ECOG performance status < 2 or Karnofsky or Lansky score > 60.
8.
Age > 18 years and older.
9.
Not pregnant or breast-feeding.
10. No uncontrolled infection. 
Note:  Infection is permitted if there is evidence of response to medication. Eligibility 
of HIV infected patients will be determined on a case-by-case basis.  
Donor eligibility
1.
Donors must be either:
a.
HLA-haploidentical or HLA-identical relatives of the patient based on allele or allele 
group level typing as defined in Section 4.1.  
2.
Medically fit to and willing to donate
3.
Lack of recipient anti-donor HLA antibody
Note: In some instances, low level, non-cytotoxic HLA specific antibodies may be 
permissible if they are found to be at a level well below that detectable by flow cytometry.  
This will be decided on a case-by-case basis by the PI and one of the immunogenetics 
directors. Pheresis to reduce anti-HLA antibodies is permissible; however eligibility to 
proceed with the transplant regimen would be contingent upon the success of the 
desensitization. 
4.
Has not donated blood products to patient
Donor prioritization 
Donors will be prioritized in the following order:  
1.
Fit to donate
2.
HLA-matched prioritized over HLA-mismatched 
3.
Lack of major ABO incompatibility 
In order of priority:
a.   Compatible
b.   Minor incompatibility
c.   Major incompatibility 
4.
CMV serostatus: CMV negative donor preferred, if the patient is CMV negative; CMV positive 
donor preferred, if the patient is CMV is positive.
5.
Avoidance of female donor for male recipient
Other factors such as donor age and health history will be integrated into the donor selection process 
per standard practice and may be prioritized over HLA, ABO and CMV status.  
4.2
Exclusion Criteria
Any individual that does not meet the eligibility criteria for transplantation or donor eligibility will not be a part 
of this trial.
4.3
Inclusion of Women and Minorities
Every effort will be made to recruit women of all races and ethnic groups to this study.


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4.4
Subject Recruitment 
The eligibility criteria in this trial should not have a negative effect on the enrollment of the desired 
populations.  Target enrollment for this trial is 15 patients within 18 months.  Patients will be recruited from 
physicians at the NYU Langone Perlmutter Cancer Center.  Consenting, screening, and treatment will take 
place at the NYULMC PCC under the supervision of the Principal Investigator.  Prospective subjects will 
receive detailed information regarding this trial; 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 are answered by the PI and/or qualified research personnel.
The Principal Investigator will:
1.
Obtain signed and dated informed consent from the potential subject before any study specific 
procedures are performed.
2.
Determine patient eligibility See Sections 4.1 and 4.2
3.
Submit registration to NYU Langone Perlmutter Cancer Center CTO
4.
Receive registration confirmation form the Research Coordinator at NYU Perlmutter Cancer Center 
CTO, including a unique study identification number assigned to the patient by the research 
coordinator, which will be distributed to the study team upon registration of the patient.
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 the established procedures of the 
NYULMC Perlmutter Cancer Center Clinical Trials Office.
4.4.1
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 patients and address any 
questions or concerns prior to obtaining written informed consent for participation and HIPAA authorization.
Patients will be given adequate time to read the consent form.  They will be given time to ask questions 
about the study in private exam rooms.  Questions will be answered by a participating physician, or qualified 
research study team member all of whom have completed requisite training for human subject research.  
Investigators will review the informed consent form with patients and address any questions or concerns 
prior to obtaining written informed consent for participation.  Investigators will stress that participation in the 
study is completely voluntary and will not affect the care patients receive or result in any loss of benefits to 
which patients are otherwise entitled.
The Investigator will explain to each subject the nature of the study, its purpose, the procedures involved, the 
expected duration, the potential risks and benefits involved, potential compensation and or costs incurred by 
the patient and any discomfort this trial may entail.  This informed consent should be given by means of 
standard written statement, written in non-technical language.  No patient can enter the study before his/her 
informed consent has been obtained.  All patients will be required to sign a written informed consent prior to 
being registered on this study.  Every effort will be made to answer questions raised by patients and their 
families or advocates regarding the protocol and alternative therapies prior to asking a patient to sign the 
consent form.
The informed consent form is considered to be part of the protocol, and must be submitted by the 
investigator with it for IRB approval.
If applicable
For non-English speaking patients, institutional translation services will be utilized. All procedures for 
consenting non-English speaking patients will be accordance with NYU Langone Health PCC CTO 
guidelines and policies.
For patients who cannot read. A witness, not related to the research study will be present. The consent will 
be read to the patient. The patient will also be allowed to ask any questions s/he may have. The investigator 
will ask the patient questions to ensure s/he understands the study. If the investigator determines the subject 


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understands the study, the patient will mark an X where his/her name would go and the witness will sign the 
consent form.
4.4.2 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 and informed consent checklists will be stored in the 
subject’s medical chart.  
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 NYULMC PCC Clinical Trials Office.  The following materials must 
be submitted to the Research Coordinator for subject registration:
1.
 Complete signed and dated informed consent form
2.
Complete signed and dated eligibility checklist
3.
All supporting documentation verifying each criterion has been met
Registration will occur within 24 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 on study.  Subjects must not start any protocol study specific procedures, unless part of 
standard of care prior to registration.
4.6
Early Withdrawal of Subjects
4.6.1
When and How to Withdraw Subjects
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 also has the right to discontinue a patient from study 
treatment or to 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

Intolerable toxicity 

Any medical condition that the investigator determines may jeopardize the patient’s safety if 
s/he continues in the study or continues treatment with study drug.

The investigator determines it is in the best interest of the patient.

Failure of the subject to adhere to protocol procedure requirements

Pregnancy 


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
Failure to initiate conditioning regimen
The reason for withdrawal and the date of participant withdrawal must be documented in the case report 
form (CRF).
4.6.2
Data Collection and Follow-up for Withdrawn Subjects
If subjects are withdrawn prematurely from the study all attempts will be made to continue to follow-up and 
collect survival data and other data as outlined in the outcomes section.   Patients will be called a minimum 
of three times a week for three weeks at all numbers available in the demographic section of their charts, 
then next of kin, and then certified letter will be sent.  
5
Study Drug 
5.1
Description
Cyclophosphamide is an alkylating agent whose metabolites from cross-links with DNA resulting in cell cycle-
nonspecific inhibition of DNA synthesis and function.  Dose adjustments for cyclophosphamide will not be 
made.
5.2
Trial Treatment
The treatment to be used in this trial is outlined below in Table 1
Table 1 Trial Treatment
Drug
Dose/Potency
Dose 
Frequency
Route 
of 
Administration
Regimen/Treatment 
Period
Fludarabine
30mg/m2
Daily
IV infusion
Day -6, -5
Cyclophosphamide
14.5 mg/kg
Daily
IV infusion
Day -6, -5
Cyclophosphamide
50 mg/kg
QD
IV infusion
Day 3, 4
Mesna
40 mg/kg
QD
IV infusion
Day 3, 4
Mycophenolate 
Mofetil
15mg/kg
TID
PO
Day 5
Tacrolimus
2 mg
BID
PO
Day 5
Sirolimusa
1mg
BID
PO
Day 5
aSirolimus will be administered for patients that must switch from Tacrolimus, due to clinical reasons( e.g. 
tacrolimus nephrotoxicity or PRES)
5.3
Treatment Regimen
5.3.1
Transplantation regimen
The preparative regimen in each case consists of fludarabine, Cy, and TBI, with posttransplantation 
high-dose Cy, MMF, and tacrolimus. Tacrolimus may be replaced by sirolimus for clinical reasons 
(e.g. nephrotoxicity or PRES).
5.3.2
Fludarabine
Fludarabine 30 mg/m2/day (adjusted for renal function) is administered over a 30-60 minute IV 
infusion on Days –6 through –2 (maximum cumulative dose, 150 mg/m2).
The body surface area (BSA) for fludarabine dosing is based on actual body weight.  


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For decreased creatinine clearance (CrCl), fludarabine dosage is reduced as follows or by 
institutional standard:
CrCl  40-69 mL/min, fludarabine = 24 mg/m2
CrCl 20-39 mL/min, fludarabine = 20 mg/m2
For patients > 18 years old, CrCl will be estimated by the Cockcroft Formula, based on ideal body 
weight (IBW): 
CrCl = (140 – age) x IBW (kg)   x   0.85 for females
                       PCr x 72
A measured CrCl or a glomerular filtration rate may be substituted to determine CrCl.
Fludarabine dosing is based on the last CrCl prior to the start of conditioning. The estimated CrCl on 
the day preceding start of conditioning may be used.  The fludarabine dose should be the same on 
Days -6 to -2, even if the creatinine changes.  However, adjustment in fludarabine dose due to 
creatinine changes during conditioning is permitted.
5.3.3
Pretransplantation cyclophosphamide 
Cy 14.5 mg/kg/day is administered as a 1-2 hour IV infusion on Days –6 and –5 after hydration.  
Mesna 11.6 mg/kg IV daily on Days –6 and –5 is not required, but may be given.  
Cy and mesna are dosed according to IBW, unless the patient weighs less than IBW, in which case 
dose drug according to actual weight.  
5.3.4
Total body irradiation 
200 cGy TBI is administered in a single fraction on Day –1.  Radiation sources, dose rates, and 
shielding follow institutional practice.  
5.3.5
Day of rest
A day of rest, i.e. after preparative regimen completion and prior to peripheral blood stem cell 
infusion, is not routinely scheduled.  Up to two days of rest may be added in this window based on 
logistical considerations or clinically as indicated.  For one day of rest, fludarabine would be 
administered on Days –7 through –3, pretransplantation Cy on Day –7 and Day –6, and TBI on Day 
–2.  
For two days of rest, fludarabine would be administered on Days –8 through –4, 
pretransplantation Cy on Day –8 and Day –7, and TBI on Day –3.
5.3.6
Peripheral blood stem cell transplantation
On Day 0, peripheral blood stem cells are infused. The target stem cell dose is between 2 x 106/kg 
and 10 x 106/kg (actual body weight) CD34+ cells.  Sample of the product to be infused will be sent 
for flow cytometry to determine the content of CD34+ and CD3+ cells.  Graft dose including total 
nucleated cells infused/kg, CD34+ cells infused/kg, and CD3+ cells infused/kg will be recorded. The 
maximum CD34+ cell dose is 10 x 106/kg. If more than 10 x 106/kg CD34+ stem cells are collected, 
the excess will be discarded and not administered to the patient. Up to two leukapheresis procedures 
may be performed to obtain the minimum CD34+ cell target. If, after two leukapheresis procedures, 
fewer than 2 x 106/kg CD34+ cells have been collected, a bone marrow harvest will be 
recommended and the patient will be taken off trial.
The graft will not be manipulated to deplete T cells.  Processing for ABO incompatibility follows 
institutional practices.  Guidelines for peripheral blood stem cell infusion are established and outlined 


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in the ABO compatible/minor mismatched allogeneic HSCT or the ABO incompatible allogeneic 
HSCT standing orders.  
5.3.7
Posttransplantation cyclophosphamide 
Hydration prior to and following Cy, management of volume status, and monitoring for hemorrhagic 
cystitis will follow institutional standards.  Mesna will be used with posttransplantation Cy as per 
institutional standards.  
Cy and mesna are dosed according to IBW, unless the actual body weight is less, in which case 
dose drugs according to actual body weight.  
Cy 50 mg/kg IV, over approximately 1-2 hours (depending on volume), is given on Day 3 
posttransplantation (ideally between 60 and 72 hours after marrow infusion) and on Day 4 
(approximately 24 hours after Day 3 Cy).  
It is crucial that no systemic immunosuppressive agents are given from Day 0 until at least 24 
hours after the completion of the posttransplantation Cy.  This includes corticosteroids as 
anti-emetics. 
5.3.8
Mycophenolate mofetil 
MMF begins on Day 5, at least 24 hours after completion of posttransplantation Cy.  The MMF dose 
is 15 mg/kg PO TID (actual body weight) with total daily dose not to exceed 3 grams (i.e. maximum 1 
g PO TID).  Doses are rounded to the nearest strength tablets.  Equivalent IV dosing (1:1 
conversion) may instead be given.  Guidelines for dose modification are provided in Section 8.15. 
MMF prophylaxis is discontinued after the last dose on Day 35, or may be continued if there is 
GVHD. 
5.3.9
Tacrolimus (or other immunosuppression with sirolimus)
5.3.9.1 Tacrolimus initiation and dosing
Tacrolimus begins on Day 5, at least 24 hours after completion of posttransplantation Cy.
Duration of tacrolimus is designated in Section 5.3.9.2.
For patients > 18 years old, the tacrolimus starting dose is 2 mg PO BID or as per institutional 
standard. Patients who cannot tolerate PO may be started IV and changed to PO as per institutional 
standard. Dose is adjusted to maintain a serum trough level of 10 – 15 ng/mL, with a minimum 
acceptable trough level of 5 ng/mL.
Tacrolimus can be changed to a PO BID dosing schedule once a stable therapeutic level is achieved 
and the patient can tolerate PO medications. Dose is adjusted to maintain a serum trough level of 10 
– 15 ng/mL, with a minimum acceptable trough level of 5 ng/mL.
In the case of prohibitive toxicities to calcineurin inhibitors (e.g., PRES), other immunosuppression 
may be given after case-by-case discussion with the PI or co-PI.  Sirolimus is discussed here as the 
alternative. There are known patients s/p BMT as well as solid organ transplant who are able to 
tolerate sirolimus better from the nephrotoxicity standpoint.  If there are patients who have creatinine 
rises that the primary clinicians are not comfortable with in the setting of tacrolimus, sirolimus is a 
reasonable alternative.  Additionally there are more reports of posterior reversible encephalopathy 
syndrome (PRES) with tacrolimus and this would necessitate a switch to sirolimus as well.
5.3.9.2 Duration of immunosuppression


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Immunosuppression is discontinued after the last dose on Day 180 without taper; however in these 
patients, immunosuppression may be continued beyond Day 180 if GVHD has occurred or may be 
discontinued earlier in the context of relapse, progression, graft failure, or prohibitive toxicity.  
Patients with suspected graft failure should remain on immunosuppression until at least the ~Day 56 
chimerism assessment, although earlier discontinuation is permissible after discussion with the PI or 
co-PI. 
5.9.3.3 Evaluability for the primary endpoint
For protocol-driven, early cessation of immunosuppression, stopping immunosuppression up to 5 
days after the scheduled stop date is permissible for logistical reasons.  Such patients will be 
considered evaluable for both the safety and feasibility of early immunosuppression cessation.
Patients who should stop immunosuppression within this time frame (per protocol-driven criteria), but 
do not for logistical reasons, are unevaluable for safety; whether they remain evaluable for feasibility 
depends on the cause.  If immunosuppression is not stopped in the allowable window because of 
pending evaluations, feasibility will be based on the results of those evaluations, provided they were 
done no later than 5 days past the pre-specified date of immunosuppression cessation. Cases in 
which eligible patients do not stop immunosuppression early because of physician discretion will 
count against feasibility.   
Patients who are not evaluable for the primary endpoint may, if needed, be replaced but will continue 
on study unless consent is withdrawn.
5.3.10
Growth factors
GCSF (filgrastim) begins on Day 5 at a dose of 5 mcg/kg/day (actual body weight) IV or 
subcutaneously (rounding to the nearest vial dose is allowed), until the absolute neutrophil count 
(ANC) is ≥ 1,000/mm3 over the course of three days.  Additional GCSF may be administered as 
warranted.  Pegfilgrastim (Neulasta®) and GM-CSF are not permitted.
5.4
Preparation and Administration of Study Drug
Although cyclophosphamide will be administered for a non-standard indication (post-transplant 
immunosuppression), this agent is one of the most widely used agents in hematological malignancies and in 
transplant specifically.  Cyclophosphamide will be prepared and supplied as per standard NYULMC policy. 
5.4.1
Cyclophosphamide
Cyclophosphamide 14.5 mg/kg/day will be administered on Days -6 and -5 after hydration.  It will be 
administered as a 1-2 hour IV infusion .  
Cyclophosphamide 50 mg/kg IV, over approximately 1-2 hours (depending on volume), will be given on Day 
3 posttransplantation (ideally between 60 and 72 hours after marrow infusion) and on Day 4 (approximately 
24 hours after Day 3 Cy).  
5.4.2
Fludarabine, mesna, mycophenolate mofetil, Tacrolimus or Sirolimus
Fludarabine (30 mg/m2/day) will be administered Days -6 through -2, with a maximum cumulative dose, 150 
mg/m2
Mesna (11.6 mg/kg) may be given on Days-6 and -5, after cyclophosphamide administration.
Mycophenolate mofetil (15 mg/kg) will be begin on Day 5, with total daily dose not exceeding 3 grams. 


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Tacrolimus (2mg) or Sirolimus (2mg) begins on Day 5, with a maintenance serum trough level of 10-15 
ng/ml.
Criteria for treatment and dose modifications for each of these drugs will occur as per institutional standards 
of care.
5.5
Subject Compliance Monitoring
Subjects who are significantly non-compliant with protocol required visits, assessments, and/or dosing 
instructions may be withdrawn from the study by the investigator.  The investigator has the right to 
discontinue a subject from study treatment or withdraw a subject from the study at any time.
Participants will be removed from the study when any of the following criteria apply:

Lost to follow-up

Withdrawal of consent for data submission

Death
The reason for taking a participant off study, and the date the participant was removed, must be documented 
in the cased report form (CRF).
5.6
Prior and Concomitant Therapy
Patients will be able to maintain prior medications, or be placed upon medications (including post-transplant 
maintenance therapy) according to institutional guidelines (e.g. vaccination) or upon the discretion of the 
Transplant Attending responsible for the patient’s care.
5.7
Supportive care
Patients will receive transfusions, nutritional support, infection prophylaxis and treatment, and other 
supportive care according to standard of care and institutional guidelines. 
5.7.1
Anti-ovulatory treatment
Menstruating females should begin an anti-ovulatory agent before starting the preparative regimen.
5.7.2
Intravenous access
A central venous catheter is required for administration of IV medications and blood products.
5.7.3
Infection prophylaxis 
Patients will receive infection prophylaxis and treatment according to NYULMC institutional 
guidelines.  Infection prophylaxis should include agents or strategies to prevent herpes simplex, 
CMV, Pneumocystis jirovecii, fungal infections, and infections from oral flora secondary to mucositis.  
Posttransplantation immunizations will be given per institutional standard.
5.7.4  
Antiemetics
Note that steroids should not be used as an antiemetic agent after the graft is infused, until at least 
24 hours after the completion of all posttransplantation Cy. The use of steroids as antiemetics after 
this time frame is discouraged in the absence of relapsed/progressive disease.
5.8
Posttransplantation therapies
5.8.1
Donor lymphocyte infusion (DLI)
Prophylactic posttransplantation DLI (e.g., for persistent detectable malignancy, prophylaxis in the 
absence of detectable malignancy, or mixed donor chimerism) is not permitted before Day 200, as 
this carries a high risk of GVHD.  The use of DLI will be recorded and such patients will be censored 


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for analysis of disease and graft failure outcomes, GVHD, and related transplant-related toxicity 
outcomes.  Analysis of outcomes without such censoring is also planned.
5.8.2
Posttransplantation systemic therapy
Preemptive systemic chemotherapy or biologic therapy (e.g., hypomethylating agent for MDS, 
tyrosine kinase inhibitor for Philadelphia chromosome-positive malignancy) is permitted after 
transplantation. Intrathecal chemotherapy is permitted.  
5.8.3
Posttransplantation radiation
Consolidative radiation therapy is permitted after transplantation.
The use of preemptive therapy will be recorded. Patients who receive such therapies will not be censored for 
analysis of disease outcomes at that time, except as stated in Section 5.8.1. 
5.9
Posttransplantation follow-up
Required evaluations are designated in Section 7.0.
More frequent monitoring of disease status, vital status, and toxicities may be performed for study purposes 
including through collection of outside records and patient and physician contact.  Patients who relapse or 
progress will continue to be followed on study unless consent is withdrawn.  
Patients will be followed primarily at NYULMC at least until the ~ Day 56 evaluations, then periodically 
thereafter as designated in Section 7.0.  In the event that it is not possible or practical for a patient to come 
back to NYULMC for required evaluations, clinical and laboratory evaluations performed though a local 
oncologist may fulfill study requirements. This will be decided on a case-by-case basis by the PI or co-PI. 
5.10
Packaging
Although cyclophosphamide will be administered for a non-standard indication (post-transplant 
immunosuppression), this agent is one of the most widely used agents in hematological malignancies and in 
transplant specifically.  Cyclophosphamide will be supplied by the oncology pharmacy in standard packaging. 
and supplied as per standard NYULMC policy. 
5.11
Receiving, Storage, Dispensing and Return
Although cyclophosphamide will be administered for a non-standard indication (post-transplant 
immunosuppression), this agent is one of the most widely used agents in hematological malignancies and in 
transplant specifically.  Cyclophosphamide will be received, stored, dispensed and/or destroyed by the 
oncology pharmacy as per standard NYULMC policy. 
6
Study Procedures
The Study Parameter-Section 7 summarizes the trial procedures to be performed at each visit.  Individual 
trial procedures are described in detail below.  It may be necessary to perform these procedures at 
unscheduled time points if deemed clinically necessary by the investigator.
6.1
Standard Pre/Posttransplant evaluations
Demographics and baseline characteristics will be captured.  Characteristics to be recorded include: 
age, gender, race/ethnicity, performance status, disease type, remission status, prior treatments 
including prior transplantation and type, donor age, donor relationship to patient, donor gender, type of 
transplant (HLA-matched or mismatched), CMV sero status of patient and donor, ABO compatibility. 


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Other data captured, according to NYULMC Standard Operating Procedures include those that are 
reported to the Center for International Blood and Marrow Transplant program.
6.2
Baseline Period
The baseline period occurs < 1 month before initiation of conditioning therapy.  Results of evaluations 
performed before study entry as standard of care may be used for research purposes and to fulfill 
study requirements.
6.3
Treatment period
The treatment period includes D-6, when patients begin their preparative regimen, to Day 180 when 
immunosuppression is discontinued.
6.4
Post-treatment visits-Follow up Visits
All follow-up visits after 180 day will be up to the discretion of the Transplant Attending.
6.5
Research Specimen Procedures
All specimens obtained in this study, comprised of peripheral blood for chimerism studies and 
potentially skin and other biopsies to evaluate for GVH, are to be done as part of standard practice as 
part of the Transplant Procedure.  Thus their procurement and analysis and storage will be performed 
by a clinical NYULMC laboratory, or a laboratory contracted by NYULMC, according to their standard 
protocols.   
7
Study Parameters
The following table summarizes the minimum testing and clinical assessments required for study purposes.  
This is in addition to other testing and assessments indicated as standard of care, which may be collected for 
study purposes.  


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Table 2: Study Parameters
Baseline 
D28      
+/- 3 
d
D56
 +/- 3 d
D84  
+/- 5 d   
D112 
+/- 5 d  
D180       
+/- 7 d
D270       
+/- 21 d
D365   +/- 
30 d c
Standard pre/posttransplant 
evaluations a, b
History and physical exam 
X
 
X
X l
X l
X l
X l
X
Performance status
X
CBC / differential d
X
X
X
X k,l
X k,l
X k,l
X k,l
X k,l
Comprehensive 
metabolic 
panel (CMP) e
X
 
X
X k
X k
X k
X k
X k
Infectious disease evaluations 
f
X
Serum HCG (if applicable)
X
LV ejection fraction 
X
Pulmonary function tests 
X
Bone 
marrow 
biopsy 
and 
aspirate with flow cytometry 
and relevant cytogenetic and 
molecular studies g 
X
X,with 
chimeris
m 
analysis h
 
X, with 
chimeris
m 
analysis h
X, with 
chimeris
m 
analysis h
CT, PET/CT, or MRI of chest, 
abdomen, and pelvis (CLL 
only)
X
X
X l
X l
Response assessment to last 
therapy  i
X
HLA typing
X
Lymphocytotoxic 
antibody 
screen
X
Donor marrow or blood for 
VNTR or RFLP analysis 
X
Patient 
blood 
for 
baseline 
VNTR or RFLP analysis 
X
Peripheral blood chimerism, 
both total leukocyte (unsorted) 
and T-cell sorted  
 
X
X
X k
X k
X k
X k
X k
GVHD and other morbidity 
assessments j
  
X
X k
X k
X k
X k
X k
a Baseline evaluations studies should occur < 1 month before initiation of conditioning therapy but can be performed within 
the time interval outlined in the most recent version of the NYU BMT service standard operating proceedings.  HLA typing 
and baseline studies for chimerism determinations may occur at any point prior. Results of evaluations performed before 
study entry as standard of care may be used for research purposes and to fulfill study requirements.
b Demographics and baseline characteristics will be captured.  Characteristics to be recorded include: age, gender, 
race/ethnicity, performance status, disease type, remission status, prior treatments including prior transplantation and 
type, donor age, donor relationship to patient, donor gender, type of transplant (HLA-matched or mismatched), CMV 
serostatus of patient and donor, ABO compatibility.  
c Patients should continue to follow-up at NYULMC at least yearly on study, per institutional standard of care.  Follow-up 
data may be captured more frequently for study purposes.  Data that will continue to be recorded beyond 1 year include disease 
status 
until first relapse/progression, vital status, major transplant-related toxicities, and GVHD.  
d At minimum, CBC/differential should also be performed twice a week from start of preparative regimen, until ANC is 
>1000/uL over course of 3 days, then weekly until 12 weeks posttransplantation, and then periodically thereafterat the 
Transplant Attending’s discretion.  All data will be captured for the duration of the trial.
e CMP includes: BUN, creatinine, sodium, potassium, chloride, AST, ALT, total bilirubin, alkaline phosphatase. At minimum, these 
should be performed weekly until 12 weeks posttransplantation, then periodically until off immunosuppression; those need not be 
captured in the CRF.


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f Infectious disease evaluations follow institutional standard of care.  Minimum evaluations are CMV IgG, HSV IgG, VZV IgG, 
hepatitis 
panel (Hep B surface antigen, Hep B core antibody, Hep C antibody), HIV antibody (unless known to be HIV positive).  
g Follow-up studies should include relevant cytogenetics and molecular markers to detect residual disease, i.e. repeat of studies 
found to be positive at baseline. At the discretion of the PI, in certain circumstances a pre-transplant bone marrow biopsy maybe 
deferred.
h May be omitted if there is documented disease persistence, progression or relapse before scheduled assessment.
i Include comparison of pre- and post-treatment scans with bidimensional measurements where relevant. 
j GVHD and other morbidity assessments are also standardly performed weekly at NYULMC until at least ~Day 60.  Results of 
these and subsequent assessments may be collected for research purposes.  Patients may be asked to complete GVHD 
questionnaires.
k Day 84 and later CMP, chimerism, and GVHD evaluations may be omitted in patients with documented graft failure. 
CBC/differential, CMP, H & P, and morbidity assessment at these time points will be obtained.
l May be omitted in patients who receive treatment for disease persistence, progression, relapse. The dates of treatment initiation 
and DLI will be recorded. 
8
Measurement of Effect and Endpoints
8.1
Hematologic parameters
8.1.1
Neutrophil recovery: Post-nadir ANC > 500/mm3 for three consecutive measurements on different 
days.  The first of the three days will be designated as the day of neutrophil recovery.  
8.1.2
Platelet recovery:  Sustained platelet count > 20,000/mm3 or > 50,000/mm3 with no platelet transfusions in the 
preceding seven days.  The first of three consecutive measurements on different days will be designated as the 
day of initial platelet recovery. 
8.1.3
Donor chimerism: Mixed donor chimerism is defined as > 5%, but < 95%, donor.  Full donor 
chimerism is defined as > 95% donor. 
Prior to transplantation, a sample of peripheral blood from the patient, and either harvested peripheral blood stem 
cells or blood from the donor, are collected for genetic studies to establish a baseline for subsequent chimerism 
assays.  
Chimerism determinations from T cells (CD3+ sorted) and whole blood (total nucleated cells) will be made from 
peripheral blood per Section 7.0, and more frequently as indicated.  Methods may include (i) PCR analysis of 
variable number of tandem repeats (VNTR) in PBMC if informative, (ii) restriction fragment length polymorphism 
(RFLP) if the donor and recipient RFLPs are informative, (iii) fluorescence in-situ hybridization (FISH) for Y-
chromosome markers on PBMC if the donor is male and patient is female, (iv) cytogenetic analysis, (v) flow 
cytometric analysis of HLA-A, B or DR on lymphocytes in the peripheral blood if haploidentical and suitable 
reagents exist.  Chimerism may also be determined from the bone marrow.
8.1.4
Graft failure: < 5% donor chimerism in blood and/or bone marrow on ~Day 28 or after and on all 
subsequent measurements.  

Primary graft failure: < 5% donor chimerism in blood and/or bone marrow by ~ Day 56 

Secondary graft failure: achievement of > 5% donor chimerism, followed by sustained <5% 
donor chimerism in blood and/or bone marrow.
< 5% donor T cell chimerism, but with > 5 % donor chimerism in total leukocytes, is not considered 
graft failure.
8.2
Graft-versus-host disease
8.2.1
Acute GVHD:  Acute GVHD is graded by standard criteria (Appendix).42 All suspected cases of acute 
GVHD must be confirmed histologically by biopsy of an affected organ (e.g., skin, liver, or gastrointestinal tract).  
Date of symptom onset, date of biopsy confirmation of GVHD, maximum clinical grade, sites affected, and dates 


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and types of treatment will be recorded.  Dates of symptom onset of initial diagnosis of GVHD (even if non-
severe) and grade III-IV GVHD will be recorded.  
8.2.2 Chronic GVHD:  Chronic GVHD is graded by both NIH consensus criteria43 and Seattle criteria.44  Date of onset, 
date of biopsy confirmation (if any), dates and types of treatment, and extent will be recorded. The cumulative 
incidence of chronic GVHD (overall and according to extent) will be determined through competing risk analysis.  
8.3
Disease and survival endpoints
   8.3.1 Event free Survival (EFS): Interval from Day 0 to date of first objective disease progression or relapse, or death 
from any cause.  Patients without these failures will be censored at the last date they were assessed and deemed 
failure-free.  
   8.3.2 Relapse or progression: 
Defined per the following response criteria: 
a.
CLL: 2008 International Workshop criteria 45
b.
MDS: 2006 IWG criteria 46
Designation of disease status in other histologies will also follow standard criteria.  
9
Statistical Methods
9.1
Primary endpoint and design
Estimate the one year after transplantation event free survival () (EFS) rate  using a Kaplan-Meier curve with a 
90% confidence interval. An event for EFS is defined as the first of any of the following failures: relapse or 
disease progression or death from any cause.
9.2
Secondary endpoints
a.
Estimate the cumulative incidences of severe acute grade III or higher GVHD, chronic GVHD (overall and 
by extent)by one year
b.
Estimate the cumulative incidence of systemic steroid initiation, by 1 year after HSCT 
c.
The above cumulative incidences (a. & b.) will be similarly estimated using competing-risk analyses, 
wherein graft failure and death, or graft failure, death and treatment of relapse/progression, are 
considered competing risks.  The number and types of systemic immunosuppression used for GVHD 
treatment will be reported.  
d.
Summarize graft failure frequency. The graft failure frequency in evaluable patients (those having 
chimerism results at least at ~Day 28) will be estimated with 90% confidence intervals.  
e.
Summarize kinetics of neutrophil and platelet recovery, and kinetics of donor chimerism in unsorted and 
CD3+ sorted peripheral blood. Times to neutrophil and platelet recovery will be summarized using 
medians and ranges, and with cumulative incidence functions with death before count recovery as a 
competing risk.  The degree of donor chimerism in unsorted and CD3+ sorted peripheral blood at 
predefined time points (per Section 7.0) will be summarized using medians and ranges, and the 
proportion reaching full donor chimerism (total leukocyte, T cell)  by ~ Day 28 and ~ Day 56 will be 
estimated with 90% confidence intervals.  The proportion achieving >50% T cell donor chimerism at ~ 
Day 28 and ~ Day 56 will similarly be estimated.
f.
Summarize major toxicities and complications associated with the transplantation procedure selected 
toxicities.
  


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9.3
Exploratory endpoints
Explore the association between the amount of donor T cell chimerism at ~ Day 28 and patient/graft 
characteristics (e.g., prior therapies, graft cell dose) and transplantation outcomes (sustained 
engraftment, relapse or progression, GVHD).  Because of the limited sample size these investigations will 
be exploratory.  
9.4
Sample Size Determination
The primary goal of this study is to estimate the one year event free survival (EFS) rate after transplantation in both 
HLA haploidentical and identical related donors with post-transplant cyclophosphamide and the MF and tacrolimus 
regimen as described. In addition, we will estimate the Grade III/IV GVHD- and grade III/IV chronic GVHD-free 
incidence after transplantation.
Our predicted outcomes are based on published data from other studies using either bone marrow or peripheral 
blood as a source for stem cells and other immunosuppression regimens.    These data indicate that the cumulative 
incidences of acute grade II-IV GVHD and acute grade III-IV GVHD by Day 200 were ~35% and ~10%, respectively 
The cumulative incidence of extensive chronic GVHD by 1 year was only 5% in the group with two doses of Cy.  
The event-free survival (EFS) (relapse, progression or death) probability at 1 year was only 34%.  Similar outcomes 
were seen in a recent analysis of 185 patients treated on these trials including follow-up phase II trial  of this 
approach.34 On an updated analysis of 212 patients with advanced hematologic malignancies, uniformly treated at 
Johns Hopkins with related donor, partially HLA-mismatched HSCT with fludarabine/Cy/TBI conditioning and 
postgrafting immunosuppression with 2 doses of Cy, MMF on Days 5-35, and full-dose tacrolimus on Days 5-180, 
the 1-year EFS (relapse, progression or death) was 44%, The cumulative incidence of acute grade II-IV GVHD was 
28% by Day 200, cumulative incidence of severe GVHD was only 4%, and the cumulative incidence of chronic 
GVHD was 14% by competing risk analysis (unpublished data).  
Based on these data we will compare our findings to the published haploidentical transplant literature (including 
bone marrow as a source and a range of post-transplant immunosuppression) which demonstrate a 1 year EFS- 
defined as relapse, progression, or death of 45%. 
 
Assuming a historical one-year EFS rate of 45%, accrual time of 1.5 years, and follow up of 1 years from the last 
patient accrued, a two-sided, one-sample log-rank test based on a sample of 15 patients achieves 80% power at a 
10% significance level to detect an increase of 28% in one-year EFS rate (to a total of one-year EFS rate of 73%) 
under the new regimen. 
9.5
Subject Population(s) for Analysis
All patients enrolled onto this study will be analyzed for the primary and secondary endpoints. 
10
Expected Toxicities
10.1
Drug Information


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10.1.1 Cyclophosphamide (Cytoxan®)
Cyclophosphamide is an alkylating agent whose metabolites form cross-links with DNA resulting in cell cycle-
nonspecific inhibition of DNA synthesis and function.  Cyclophosphamide side effects include: nausea, vomiting, 
diarrhea, headache, dizziness, hemorrhagic cystitis, fluid weight gain/edema, SIADH, transaminitis, 
cardiomyopathy, 
pericarditis, 
rash, 
mucositis, 
alopecia, 
cytopenias, 
sterility, 
and 
rarely, 
secondary 
myelodysplastic syndrome and anaphylaxis.
Dose adjustments for cyclophosphamide will not be made.
10.1.2 Mesna (sodium-2-mercapto ethane sulphonate)
Mesna is a prophylactic agent used to prevent hemorrhagic cystitis induced by the oxasophosphorines 
(cyclophosphamide and ifosphamide).  
It has no intrinsic cytotoxicity and no antagonistic effects on 
chemotherapy.  Mesna binds with acrolein, the urotoxic metabolite produced by the oxasophosphorines, to 
produce a non-toxic thioether and slows the rate of acrolein formation by combining with 4-hydroxy metabolites of 
oxasophosphorines.
The total daily dose of mesna is equal to 80% of the total daily dose of cyclophosphamide.
At the doses used for uroprotection, mesna is virtually non-toxic.  However, potential adverse effects include 
nausea and vomiting, diarrhea, abdominal pain, altered taste, rash, urticaria, headache, joint or limb pain, 
hypotension, and fatigue.
10.1.3
Fludarabine (Fludara)
Fludarabine is a purine analog antimetabolite.  Side effects of fludarabine include:
a.
Neurotoxicity: Agitation or confusion, blurred vision, loss of hearing, peripheral neuropathy or weakness have 
been reported.  Severe neurologic effects, including blindness, coma, and death may occur; severe CNS 
toxicity is rarely seen with doses in the recommended range for nontransplant therapy. The dose used in this 
study is approximately 1.5 times the usual one-course dose given in non-transplant settings.  Doses and 
schedules similar to those used in this study have been used in adult and pediatric patients without observed 
increase in neurotoxicity.
b.
Anemia: Life-threatening and sometimes fatal autoimmune hemolytic anemia has been reported after one or 
more cycles of therapy in patients with or without a previous history of autoimmune hemolytic anemia or a 
positive Coombs’ test and who may or may not be in remission.  Corticosteroids may or may not be effective 
in controlling these episodes.  The majority of patients re-challenged developed a recurrence of the hemolytic 
process. 
c.
Cardiovascular: Deep venous thrombosis, phlebitis, transient ischemic attack, and aneurysm (1%) are 
reported.   
d.
Fever: 60% develop fever.
e.
Rash: 15% develop a rash, which may be pruritic. 
f.
Digestive: Gastrointestinal side effects include: nausea/vomiting (36%), diarrhea (15%), stomatitis (9%), 
anorexia (7%), GI bleeding and esophagitis (3%), mucositis (2%), liver failure, abnormal liver function test, 
constipation, dysphagia (1%) and mouth sores. 
g.
Some other effects include: Chills (11%), peripheral edema (8%), myalgias (4%), osteoporosis (2%), 
pancytopenia, arthralgias (1%), dysuria (4%), urinary tract infection and hematuria (2%); renal failure, 
abnormal renal function test, and proteinuria (1%); and, very rarely, hemorrhagic cystitis and pulmonary 
toxicity. 
Dose adjustments of fludarabine are required for renal insufficiency (see Section 5.21).
10.1.4
Total Body Irradiation (TBI)
TBI can cause: nausea and vomiting, diarrhea, parotitis (rapid onset within 24-48 hours, usually self-limited), 


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study sponsor
generalized mild erythema (usually within 24 hours, resolving in 48-72 hours) , hyperpigmentation, fever, 
mucositis, alopecia, and pancytopenia. Late effects include: cataracts (10-20%), hypothyroidism, nephropathy, 
interstitial pneumonitis, veno-occlusive disease, carcinogenesis, and sterility. 
10.1.5
Mycophenolate Mofetil (MMF, Cellcept®)
MMF is an ester prodrug of the active immunosuppressant mycophenolic acid (MPA). 
Side effects include: pancytopenia, infection (including sepsis, CMV, HSV, VZV, and Candida), nausea, vomiting, 
diarrhea, allergic reactions, hypertension, headache, dizziness, insomnia, hyperglycemia, electrolyte imbalances, 
rash, and leg cramps/bone pain. 
Drug interactions: MMF activity is decreased with oral antacids and cholestyramine. There are no 
pharmacokinetic interactions with cotrimoxazole, oral contraceptives, or cyclosporine.  Acyclovir or ganciclovir 
blood levels may increase due to competition for tubular secretion. High doses of salicylates or other highly 
protein-bound drugs may increase the free fraction of MPA and exaggerate the potential for myelosuppression.
Dose adjustments: No dose adjustments are required for liver dysfunction.  For renal insufficiency, MMF dosing 
should not be modified unless dialysis is needed, in which case MMF can be reduced to 25-50% of the starting 
dose.
10.1.6
Tacrolimus (FK-506, Prograf®)
Tacrolimus is a macrolide immunosuppressant that inhibits lymphocytes through calcineurin inhibition.  
Toxicities: There is a spectrum of well-described toxicities of tacrolimus. Toxicities include renal insufficiency, 
hypertension, hyperglycemia, hypomagnesemia, hypokalemia, nausea, diarrhea, headache, neurologic toxicity 
including tremor and leukoencephalopathy, infection, and rarely thrombotic thrombocytopenic purpura (TTP).
Drug interactions: Tacrolimus is well absorbed orally.  Tacrolimus is extensively metabolized by the cytochrome 
P-450 (CYP3A4) system and metabolized products are excreted in the urine.  Drugs that may increase tacrolimus 
levels include tri-azole drugs (especially voriconazole and posaconazole), nephrotoxic drugs, calcium channel 
blockers, cimetidine and omeprazole, metoclopramide, macrolide antibiotics, quinupristin/dalfopristin, danazol, 
ethinyl estradiol, methylprednisolone, and HIV protease inhibitors.  Drugs that may decrease tacrolimus levels 
include some anticonvulsants (phenobarbital, phenytoin, carbamazepine), caspofungin, rifamycins, and St. John’s 
wort.  
Dose adjustments: The tacrolimus dose is adjusted to maintain a serum trough level of 5-15 ng/mL, with a target 
of 10-15 ng/mL.  Patients with hepatic or renal insufficiency should receive doses at the lower end of therapeutic 
concentrations.  No dose adjustments are required in patients undergoing hemodialysis.
Due to extreme interactions with voriconazole and posaconazole, the tacrolimus dose should be 
empirically lowered when these azoles are initiated at steady state levels of tacrolimus.  Guidelines are 
provided in the table below section 8.17.  Dose adjustments for therapy with other azoles may be indicated.  
However, the initial tacrolimus dose (on Day 5) remains fixed. 
10.1.7  Sirolimus
Sirolimus is an immunosuppressant that inhibits cytokine-stimulated T-cell activation and proliferation, and also 
inhibits antibody formation.  
Drug formulations: The mean bioavailability of sirolimus after administration of the tablet is ~27% higher than the 
oral solution. Sirolimus oral tablets are not bioequivalent to the oral solution. Clinical equivalence has been 
demonstrated at the 2-mg dose level; however, it is not known if higher doses are clinically equivalent on a mg to 
mg basis.
a) Sirolimus oral solution: Sirolimus oral solution (1 mg/mL) should be stored protected from light and 
refrigerated at 2°C to 8°C (36°F to 46°F). For dilution, the appropriate dose should be measured using an 
amber oral syringe, then added to a glass or plastic container that holds at least 60 mL.  Before taking the 
dose, it should be diluted with water or orange juice then taken immediately; it should not be diluted with 
grapefruit juice.  The syringe should be discarded after one use.  Sirolimus oral solution provided in 
bottles may develop a slight haze when refrigerated, which does not affect product quality; allow the 
product to stand at room temperature and shake gently until the haze disappears. 


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b) Sirolimus tablets: Sirolimus tablets are available in 1 mg and 2 mg tablets that cannot be crushed or 
broken. Sirolimus tablets should be stored at 20° to 25° C (68°–77°F), protected from light.
Toxicities: The most common adverse reactions of sirolimus are: peripheral edema, hypertriglyceridemia, 
hypercholesterolemia, hypertension, increased creatinine, constipation, abdominal pain, nausea, diarrhea, 
headache, fever, urinary tract infection, anemia, thrombocytopenia, arthralgia, pain. Adverse reactions that have 
resulted in rates of sirolimus discontinuation >5% were increased creatinine, hypertriglyceridemia, and thrombotic 
thrombocytopenic purpura (TTP) / thrombotic microangiopathy (TMA).  Sirolimus toxicities are summarized in the 
table below:
Table3: Sirolimus toxicities
Common (>20%)
Occasional (5-20%)
Rare (<5%)
Immediate (within 1-2 
days)
Headache 
(L), 
hypertension 
(L), 
immunosuppression (L), 
fever, nausea, diarrhea, 
constipation
Chest 
pain, 
insomnia, 
dyspepsia, 
vomiting, 
dyspnea
Hypotension, 
asthma, 
cough, flu-like syndrome, 
tachycardia, 
anorexia, 
hypersensitivity 
reactions
Prompt 
(within 
2-3 
weeks)
Tremor 
(L), 
renal 
dysfunction, 
pain 
(abdominal, 
back, 
arthralgias), 
hyperlipidemia 
c 
(hypercholesterolemia, 
hypertriglyceridemia), 
hyperglycemia, 
edema 
including 
peripheral 
edema, anemia
Elevated 
LFT’s 
(with 
elevated sirolimus levels) 
a, stomatitis, infections 
(including UTI, URI), mild 
thrombocytopenia, 
leukopenia, 
electrolyte 
disturbances 
(hyper/hypokalemia 
[L], 
hypophosphatemia, 
hypomagnesemia 
[L]), 
rash, 
hives, 
pruritus, 
delayed wound healing 
or 
dehiscence 
(L), 
proteinuria, 
TTP/HUS/TMA 
b 
especially 
with 
concurrent CNI
Pleural and pericardial 
effusions, 
pulmonary 
toxicity 
(non-infectious 
pneumonitis, 
BOOP, 
pulmonary 
fibrosis),  
thombosis, myalgias
Delayed (any time later 
during therapy, excluding 
above conditions)
Acne
Kidney disease, CHF, 
ascites, arthrosis, bone 
necrosis, osteoporosis
Late 
(any 
time 
after 
completion of treatment)
Lymphoproliferative 
disorders, 
skin 
malignancies
Unknown frequency and 
timing
Embryo/fetotoxic; unknown whether excreted in human milk
(L): Toxicity may also occur later.
a Significant transaminitis, generally without sequelae, may occur. Sirolimus has been associated with higher 
rates of venoocclusive disease after myeloablative conditioning.
b Incidence 3% to < 20% in a trial of kidney transplantation.  In allogeneic BMT, increase in TMA from 4.2% with 
tacrolimus or cyclosporine alone, versus 10.8% with tacrolimus/sirolimus combination was noted.68 
c Lipid-lowering agent may be required; consider if fasting serum triglycerides are > 2.5 x ULN, and recommend 
starting if > 800 mg/dL.
Drug interactions: Sirolimus is known to be a substrate for both cytochrome CYP3A4 and P-glycoprotein.  Agents 
that may increase sirolimus levels include tri-azole drugs (especially voriconazole and posaconazole*), 
amiodarone, calcium channel blockers, macrolide antibiotics (but not azithromycin), micafungin, gastrointestinal 
prokinetic agents (cisapride, metoclopramide), cimetidine, cyclosporine, grapefruit juice, and HIV protease 
inhibitors. Agents that may decrease sirolimus levels include anticonvulsants (carbamezepine, phenobarbital, 
phenytoin), rifamycins, St. John’s Wort. 


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Dose adjustments: The sirolimus dose is adjusted to maintain a serum trough level of 5-12 ng/mL.  Changes in 
levels due to altered bioavailability should be apparent within 24-48 hours.  For sirolimus without CNI as in this 
study, a 20-25% reduction of sirolimus dose is recommended for trough levels >12 – 18 ng/mL, and a 20-25% 
increase is recommended for trough levels < 5 ng/mL.
Renal failure does not affect the excretion of sirolimus. Excretion is reduced in liver failure; impaired 
hepatic function should prompt consideration of reduction in sirolimus maintenance doses but no dose adjustment 
of the loading dose is necessary.
Due to extreme interactions with voriconazole and posaconazole, these drugs are relatively 
contraindicated during sirolimus therapy. Sirolimus dose is to be reduced by 90% when voriconazole is 
initiated and should also be significantly reduced with posaconazole. Dosing guidelines are provided in the 
table below.
Dosing considerations with concurrent azole therapy: Triazole antifungal medications are expected to increase 
serum CNI levels; therefore dosages of CNI’s should be adjusted accordingly. Guidelines are provided in the table 
below.  Of note, reversal of azole-mediated inhibition of CYP3A4 (and others) and P-glycoprotein is gradual when 
azoles are stopped.  Therefore, immediate significant dose increases in tacrolimus and sirolimus are not advised 
when azoles are stopped. Rather, dose increases should be cautious and based on more frequent monitoring of 
levels as appropriate.
Table : Suggested preemptive dose reduction of tacrolimus when azoles are initiated at steady state 
levels of tacrolimus or sirolimus
Antifungal
Tacrolimus
Dose ↓
Comment
Voriconazole 
67%
Strongly advised
Posaconazole
67%
Advised
Itraconazole
50%
Advised
Fluconazole
25% 
Consider
10.2
Toxicitiy grading
Toxicities are graded using the NCI’s Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm)
10.3
Toxicity reporting
The agents being used in the study are used extensively in the HSCT setting and have well-defined toxicity 
profiles.  In addition, there are many expected toxicities of allogeneic HSCT.  The following are examples of 
toxicities that are serious but not unexpected: Grade 4 cytopenias; neutropenic fever and sepsis; bacterial, fungal, 
or viral (including CMV, BK virus) infection; severe mucositis; severe GVHD; hepatic veno-occlusive disease; 
pulmonary toxicities; hemorrhagic cystitis; bleeding without hemodynamic compromise.
For study purposes, the following will be recorded and reported in accordance with IRB requirements:
a.
Any hospitalization and its reason in the first year of transplant, with the exception of hospitalizations 
related to relapsed disease or second HSCTs.
b.
Neutropenic fever is an expected, common complication; as such, hospitalizations for grade 4 
neutropenic fever will be reported in real-time to the IRB with hospitalizations for lesser grade neutropenic 
fever routinely reported on a yearly basis.
c.
Any death before Day 200, and any later death which is potentially transplant-related.
d.
Any unexpected, serious events deemed significant by the PI.
In addition, the following toxicities will be tracked for study purposes and reported on a yearly basis to the IRB, or 
earlier if warranted: 
a.
Clinically significant infections during the first year of transplant, with the exception of uncomplicated, 
culture-negative neutropenic fever. This includes CMV disease, other clinically significant documented 
viral infections, bacterial infections, and proven or probable invasive fungal infections.


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b.
CMV reactivation (including asymptomatic reactivation)
c.
Hepatic veno-occlusive disease
d.
Grade 3 or greater pulmonary toxicity during the first year of transplant that is potentially transplant-
related
Additional complications and toxicities may be tracked. This is in addition to evaluating hematologic parameters, 
GVHD, and disease and survival endpoints outlined in Section 8.0. 
11
Safety and Adverse Events
11.1
Definitions
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).
Adverse Event
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity during the course 
of the study.  Intercurrent illnesses or injuries should be regarded as adverse events.  Abnormal results of diagnostic 
procedures are considered to be adverse events if the abnormality:

results in study withdrawal

is associated with a serious adverse event

is associated with clinical signs or symptoms

leads to additional treatment or to further diagnostic tests

is considered by the investigator to be of clinical significance
Serious Adverse Event
Adverse 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. 
Adverse Event Reporting Period
The study period during which adverse events must be reported is normally defined as the period from the initiation of any 
study procedures to the end of the study treatment follow-up.  For this study, the study treatment follow-up is defined as 
30 days following the last administration of study treatment. 


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Preexisting Condition
A preexisting condition is one that is present at the start of the study.  A preexisting condition should be recorded as an 
adverse event if the frequency, intensity, or the character of the condition worsens during the study period.
General Physical Examination Findings
At screening, any clinically significant abnormality should be recorded as a preexisting condition.  At the end of the study, 
any new clinically significant findings/abnormalities that meet the definition of an adverse event must also be recorded and 
documented as an adverse event. 
Post-study Adverse Event
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.  The investigator should notify the study sponsor of any death or adverse event 
occurring at any time after a subject has discontinued or terminated study participation that may reasonably be related to 
this study.  The sponsor should also be notified if the investigator should become aware of the development of cancer or 
of a congenital anomaly in a subsequently conceived offspring of a subject that has participated in this study. 
Abnormal Laboratory Values
A clinical laboratory abnormality should be documented as an adverse event if any one of the following conditions is met: 

The laboratory abnormality is not otherwise refuted by a repeat test to confirm the abnormality

The abnormality suggests a disease and/or organ toxicity

The abnormality is of a degree that requires active management; e.g. change of dose, discontinuation of the drug, 
more frequent follow-up assessments, further diagnostic investigation, etc.
Hospitalization, Prolonged Hospitalization or Surgery
Any adverse event that results in hospitalization or prolonged hospitalization should be documented and reported as a 
serious adverse event unless specifically instructed otherwise in this protocol.  Any condition responsible for surgery 
should be documented as an adverse event if the condition meets the criteria for and adverse event. 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an adverse event in the 
following circumstances:

Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for a preexisting 
condition.  Surgery should not be reported as an outcome of an adverse event if the purpose of the surgery was 
elective or diagnostic and the outcome was uneventful.

Hospitalization or prolonged hospitalization required to allow efficacy measurement for the study.

Hospitalization or prolonged hospitalization for therapy of the target disease of the study, unless it is a worsening 
or increase in frequency of hospital admissions as judged by the clinical investigator.
11.2
Recording of Adverse Events
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.
All adverse events occurring during the study period must be recorded.  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.  Serious adverse events 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.


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Pregnancy
Although pregnancy is not considered an AE, it is the responsibility of the investigator to report any pregnancy occurring in 
a female subject or female partner of a male subject, during the study.  It must be reported immediately to the regulatory 
specialist, research coordinator, IRB, and NYUPCCsafetyreport@nyumc.org in accordance with the procedures 
described.  Any complication of pregnancy affecting a female study subject or female partner of a male study subject, 
and/or fetus and/or newborn must be reported as an SAE.  Every effort will be made to obtain permission to follow the 
outcome of the pregnancy and report the condition of the fetus and/or newborn to NYULMC.   
11.3
Reporting of Serious Adverse Events and Unanticipated Problems
Investigators and the protocol sponsor must conform to the adverse event reporting timelines, formats and requirements 
of the various entities to which they are responsible, but at a minimum those events that must be reported are those that 
are:

related to study participation,

unexpected, and 

serious or involve risks to subjects or others 
(see definitions, section 11.1).  
For Narrative Reports of Safety Events
If the report is supplied as a narrative, the minimum necessary information to be provided at the time of the initial report 
includes:

Study identifier

Study Center

Subject number

A description of the event

Date of onset

Current status

Whether study treatment was discontinued

The reason why the event is classified as serious

Investigator assessment of the association 
between the event and study treatment
11.3.1
Investigator reporting: NYULMC IRB and Perlmutter Cancer Center Clinical Trials Office
.  
The following describes events that must be reported to the study sponsor in an expedited fashion.
Initial Report: within 24 hours:
The following events must be reported to the study sponsor by telephone within 24 hours of awareness of the event: 

Unanticipated problems related to study participation, 

Serious adverse events, regardless of whether they are unexpected. 
Additionally, an FDA Form 3500A (MEDWATCH Form) must be completed by the investigator and faxed to the study 
sponsor within 24 hours.  The investigator shall maintain a copy of the MEDWATCH Form on file at the study site. 
  
NYUPCCsafetyreports@nyumc.org
AND
Ahmad Samer Al-Homsi, MD
Blood and Marrow Transplantation
NYU Langone Health – Perlmutter Cancer Center
240 E 38th Street, 19th floor
New York, NY 10016
Tel: 646-501-4848
Email: Samer.Al-Homsi@nyumc.org


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Follow-up report: within 48 hours:
As a follow-up to the initial report, within the following 48 hours of awareness of the event, the investigator shall provide 
further information, as applicable, on the unanticipated device event or the unanticipated problem in the form of a written 
narrative.  This should include a copy of the completed Unanticipated Problem form, and any other diagnostic information 
that will assist the understanding of the event.  Significant new information on ongoing unanticipated adverse device 
effects shall be provided promptly to the study sponsor.
Other Reportable events:

Deviations from the study protocol
Deviations from the protocol must receive both Sponsor and the investigator’s IRB approval before they are 
initiated. Any protocol deviations initiated without Sponsor and 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 
Sponsor and to the investigator’s IRB as soon as a possible, but no later than 5 working days of the protocol 
deviation.

Withdrawal of IRB approval
An investigator shall report to the sponsor a withdrawal of approval by the investigator’s reviewing IRB as soon as 
a possible, but no later than 5 working days of the IRB notification of withdrawal of approval.
11.3.2
Investigator reporting: 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 NYULMC IRB reporting requirements, though Investigators at participating 
sites are responsible for meeting the specific requirements of their IRB of record. 
The NYU IRB address is:
NYU IRB
1 Park Avenue, 6th Floor
New York, NY 10016
Report Promptly, but no later than 5 working days:
Researchers are required to submit reports of the following problems promptly but no later than 5 working days from the 
time the investigator becomes aware of the event:

Unanticipated problems including adverse events that are unexpected and related
– Unexpected: An event is “unexpected” when its specificity and 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 or sponsor, the event was more likely than not to be caused by the research procedures. 
– Harmful: either caused harm to subjects or others, or placed them at increased risk
Other Reportable events:
The following events also require prompt reporting to the IRB, though no later than 5 working days:

Complaint of a research subject when the complaint indicates unexpected risks or the complaint cannot be 
resolved by the research team.

Protocol deviations or violations (includes intentional and accidental/unintentional deviations from the IRB 
approved protocol) for any of the following situations: 
– one or more participants were placed at increased risk of harm 
– the event has the potential to occur again
– the deviation was necessary to protect a subject from immediate harm


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
Breach of confidentiality

Incarceration of a participant when the research was not previously approved under Subpart C and the 
investigator believes it is in the best interest of the subject to remain on the study.

New Information indicating a change to the risks or potential benefits of the research, in terms of severity or 
frequency. (e.g. analysis indicates lower-than-expected response rate or a more severe or frequent side effect; 
Other research finds arm of study has no therapeutic value; FDA labeling change or withdrawal from market)
Reporting Process
The reportable events noted above will be reported to the IRB using the form: “Reportable Event Form” or as a written 
report of the event (including a description of the event with information regarding its fulfillment of the above criteria, 
follow-up/resolution and need for revision to consent form and/or other study documentation).
Copies of each report and documentation of IRB notification and receipt will be kept in the Clinical Investigator’s study file.
11.3.3
Sponsor reporting: Notifying the FDA
11.3.4
Sponsor reporting: Notifying participating investigators
N/A
11.4
Unblinding Procedures
N/A
11.5
Stopping Rules 
N/A
.
11.6
Medical Monitoring
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 reviews these adverse events monthly.  The 
Data Safety and Monitoring Committee (DSMC) will review the study at least annually.  Medical monitoring will include a 
regular assessment of the number and type of serious adverse events.
11.6.1
Data and Safety Monitoring Plan
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 2014 National Cancer Institute 
approved Charter.  It is an existing and multidisciplinary committee (consisting of clinical investigators/oncologists, 
biostatisticians, nurses, and research administration staff knowledgeable of research methodology and design and in 
proper conduct of clinical trials) that is responsible for monitoring safety, conduct and compliance in accordance with 
protocol data monitoring plans for clinical trials conducted in the NYULMC Perlmutter Cancer Center that are not 
monitored by another institution or agency. The DSMC reports to the Director of the NYULMC PCC.  
Per the NYU PCC Institutional Data Safety and Monitoring Plan, this phase II trial will be monitored by DSMC annually 
(from the date the first patient is enrolled) 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 annually.


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12
Data Handling and Record Keeping
12.1
Confidentiality
The research team will maintain clinical and laboratory data in a manner that ensures patient confidentiality.  All study 
personnel have passed human subject protection courses and GCP.  Tissue samples sent to collaborators outside of 
NYU PCC will only be labeled with an assigned protocol subject identification number without patient identifiers.  Systems 
used for electronic data capture are compliant with HIPAA and applicable local regulatory agency guidelines.  All 
documents are kept in strictly confidential files and are only made accessible for specific study personnel, CTO quality 
assurance specialists, and authorized representatives of regulatory agencies as described in the informed consent 
document.  Samples sent to commercial labs or collaborating labs as per study protocol will be coded.  Samples 
remaining after completion of the study will be destroyed once this study is completed.  
12.2
Confidentiality and HIPAA
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.
12.3
Source 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. Source 
documentation refers to original records of observation, clinical findings, and evaluations that are subsequently recorded 
as data.  Source documentation should be consistent with data entered into Velos.  Relevant source documentation to be 
reviewed by the DSMC throughout the study includes:
1.
 Baseline measures to assess pre-protocol disease status
2.
Treatment records
3.
Concomitant medications
4.
Adverse events
12.4
Data and Source Documentation
Velos, 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 research 
coordinator, and CTO quality assurance specialists will have access to the database.  Velos is the primary data collection 
instrument for the study.  All data requested in Velos must be reported.  All missing data must be explained.  The quality 
assurance specialists will begin Interim monitoring visits within the first 6-8 weeks of first subject enrollment and then 
monitor this trial every 6-8 weeks thereafter for data entry and accuracy.
12.5
Records Retention
All patient records will be maintained for at least 10 years according to NYULMC policy.  Of note, all data collected in this 
study is part of the patient’s standard medical care and will be maintained in his/her medical record. 


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study sponsor
13
Study Monitoring, Auditing, and Inspecting
13.1
Study Monitoring Plan
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.), and has adequate space to conduct the monitoring 
visit. 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 
make regularly scheduled trips to the investigational site to 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 meet with the 
quality assurance specialist in order 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. In addition to 
on-site monitoring visits, the Sponsor and/or representatives will also be routinely reviewing data. 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..
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. 
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, annually
(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.
(4) In addition, the quality assurance unit will monitor this trial by quarterly interim monitoring visits, to verify 
adherence to the protocol; the completeness, accuracy and consistency of the data; and adherence to ICH Good 
Clinical Practice guidelines.
13.2
Auditing and Inspecting
The investigator will permit study-related monitoring, audits, and inspections by the IRB/EC, the sponsor, government 
regulatory bodies, and University compliance and quality assurance groups of all study related documents (e.g. source 
documents, regulatory documents, data collection instruments, study data etc.).  The investigator will ensure the capability 
for inspections of applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.).


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CONFIDENTIAL
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as authorized in writing by the 
study sponsor
Participation as an investigator in this study implies acceptance of potential inspection by government regulatory 
authorities and applicable University compliance and quality assurance offices.  The investigator will contact the PCC 
CTO immediately if contacted by a regulatory agency about an inspection at the center.
14
Ethical Considerations
This study is to be conducted accordance with applicable US government regulations and international standards of Good 
Clinical Practice, and applicable institutional research policies and procedures.
This protocol and any amendments will be submitted to the NYU Institutional Review Board (IRB) in agreement with local 
legal prescriptions, for formal approval of the study conduct.  The decision of the IRB concerning the conduct of the study 
will be made in writing to the investigator and a copy of this decision will be provided to the sponsor before 
commencement of this study.  The investigator should provide a list of IRB members and their affiliate to the sponsor.
All subjects for this study will be provided a consent form describing this study and providing sufficient information for 
subjects to make an informed decision about their participation in this study.  This consent form will be submitted with the 
protocol for review and approval by the IRB for the study.  The formal consent of a subject, using the IRB-approved 
consent form, must be obtained before that subject undergoes any study procedure.  The consent form must be signed by 
the subject or legally acceptable surrogate, and the investigator-designated research professional obtaining the consent. 
The consenting process and documentation will follow Standard Operating Procedures (Obtaining Informed Consent for 
Clinical Trials) of the NYULMC PCC CTO.
15
Study Finances
15.1
Funding Source
All drugs, nursing, and physician visits are considered part of standard care and will be covered by the patient and/or 
his/her insurance.  Data collection and analysis for this study will be funded by NYULMC and Perlmutter Cancer Center 
sources.
15.2
Conflict of Interest
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 that has been reviewed and approved by the study 
sponsor prior to participation in this study.  All NYULMC investigators will follow the applicable University conflict of 
interest policies.
15.3
Subject Stipends or Payments
No patient or subject will receive payments or stipends for participation in this research study.
16
Publication Plan
Neither the complete nor any part of the results of the study carried out under this protocol, nor any of the information 
provided for the purposes of performing the study, will be published or passed on to any third party without the consent of 
the study sponsor.  Any investigator involved with this study is obligated to provide the sponsor with complete test results 
and all data derived from the study.


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study sponsor
17
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18
Appendix
Appendix A:  Acute GVHD Grading
From Przepiorka D et al. 1994 Consensus Conference on Acute GVHD Grading. HSCT 1995; 15: 825-828.