Clinical trial NCT02593123
Conditions: Hodgkin's Lymphoma Lymphoid Leukemia Lymphoma Leukemia Myeloma Acute Lymphocytic Leukemia Non Hodgkin Lymphoma Chronic Lymphocytic Leukemia Multiple Myeloma Chronic Myelogenous Leukemia Myelodysplastic Syndromes Recurrent Acute Myeloid Leukemia, Adult Recurrent Hodgkin Lymphoma Recurrent Non-Hodgkin Lymphoma Recurrent Plasma Cell Myeloma Recurrent Chronic Lymphocytic Leukemia Recurrent Chronic Myelogenous Leukemia Acute Myelogenous Leukemia
Keywords: Donor Type (Matched Related Donor or Matched Unrelated Donor)
Sponsor: Virginia Commonwealth University
Start date: 2015-11-04; Completion date: 2022-03-18
Enrollment: 31 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Determine the relapse-free, donor lymphocyte infusion (DLI)-free survival in patients receiving the investigational regimen.This is a randomized phase II clinical trial, comparing two different dosing schedules of mycophenolate mofetil for graft versus host disease (GVHD) prevention following allogeneic stem cell transplantation. Risk for relapse, GVHD and non-relapse mortality will be assessed. Adaptive randomization between two study arms will be performed based on T cell counts at day 60.

Detailed description:
In this study, the investigators will utilize a regimen combining low dose total body irradiation and rabbit ATG to facilitate stem cell transplantation (SCT) with human leukocyte antigen (HLA) matched related and unrelated donors. Based on the hypothesis that early treatment interventions have significant late effects in allogeneic SCT, a simple intervention, varying the duration of intense immunosuppression following SCT, will be investigated in this study. This may allow more robust recovery of donor immune system cells in the first two months following transplantation and eventually result in lower risk of cancer relapse, while maintaining effective graft versus host disease (GVHD) control. Patients will be randomly assigned to receive GVHD prevention therapy using one of two different immunosuppressive regimens with tacrolimus \& mycophenolate mofetil (MMF). Patients assigned to the investigational group will receive MMF for 15 days following SCT with growth factor support using granulocyte macrophage colony stimulating factor (GM-CSF) beginning on post-transplant day 4. Patients randomized to the standard treatment group will receive MMF for 30 days following SCT with cytokine support using granulocyte colony stimulating factor (G-CSF) beginning on post-transplant day 4. If one of these treatment groups demonstrates an improvement in donor immune cell recovery, there may be a slow increase in the likelihood of patients being assigned to that more successful treatment group. Eventually the two groups will be compared with respect to the likelihood of either relapse or GVHD developing.

Arms: arm 1: Patients receive mycophenolate mofetil (MMF) PO or IV twice daily (BID) on days 0-15 and sargramostim SC from post-transplant day 4 until neutrophil engraftment. arm 2: Patients receive mycophenolate mofetil PO or IV (twice daily) BID on days 0-30 and filgrastim G-CSF from post-transplant day 4 until neutrophil engraftment.
Interventions: intervention 1: mycophenolate mofetil intervention 2: Sargramostim intervention 3: Filgrastim
Intervention descriptions: intervention 1: Given PO, by mouth, orally or IV, intravenous medication administration. intervention 2: GM-CSF beginning post-transplant day 4 and continuing until hematopoietic reconstitution. Patients in the MMF-15 cohort will receive sargramostim (GM-CSF) 250 mcg/m2/day beginning on post-transplant day 4 and continuing until neutrophil engraftment.

Patients receiving GM-CSF will also receive inhaled corticosteroids, fluticasone (Flovent) 2 puffs twice daily, starting on post-transplant day 4 and stopping after cessation of GM-CSF, to diminish the risk of pneumonitis.

Note: At investigator discretion, patients in the MMF-15 cohort who have preexisting pulmonary risk factors, will be permitted to receive G-CSF. intervention 3: G-CSF beginning post-transplant day 4 and continuing until hematopoietic reconstitution. Patients in the MMF-30 cohort will receive filgrastim (G-CSF) 5 mcg/kg/day beginning on post-transplant day 4 and continuing until neutrophil engraftment.

Protocol documents:
Prot_SAP_000.pdf: 
MCC-14-10739
NCT02593123
Adoptive Immunotherapy in Patients with Relapsed Hematological Malignancy: Effect of 
Duration and Intensity of Early GVHD Prophylaxis on Long-Term Clinical Outcomes
IRB Version Date: 11/24/2021




Version #4 
Version Date 11/24/2021 
Cover Page (continued) 
Biostatistician 
Roy T. Sabo, PhD 
Virginia Commonwealth University 
Department of Biostatistics 
PO Box 980032 
Richmond, VA 23298-0032 
Phone: 804-828-3047 
Fax: 804-828-8900 
Email: rsabo@vcu.edu 
Study Coordinator 
Catherine H. Roberts, PhD 
VCU Massey Cancer Center 
Bone Marrow Transplant Program 
1300 East Marshall Street 
PO Box 980157 
Richmond, VA 23298-0157 
Phone: 804-828-1292 
Email: croberts2@vcu.edu 
IND-Exempt 


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TABLE OF CONTENTS 
REVISION HISTORY ..................................................................................................................6 
LIST OF ABBREVIATIONS ........................................................................................................8 
STUDY SCHEMA .......................................................................................................................9 
1 
BACKGROUND ......................................................................................................... 10 
1.1 
INTRODUCTION ....................................................................................................................................... 10 
1.2 
RATIONALE AND PREVIOUS WORK .................................................................................................... 10 
1.3 
PRELIMINARY DATA ............................................................................................................................... 12 
1.4 
PROPOSED STUDY ................................................................................................................................ 16 
1.5 
INVESTIGATIONAL REGIMEN ................................................................................................................ 17 
1.6 
POTENTIAL RISKS AND BENEFITS OF THE INVESTIGATIONAL REGIMEN ..................................... 18 
1.7 
CORRELATIVE STUDIES ........................................................................................................................ 18 
2 
OBJECTIVES ............................................................................................................. 19 
2.1 
PRIMARY OBJECTIVE ............................................................................................................................ 19 
2.2 
SECONDARY OBJECTIVES.................................................................................................................... 19 
2.3 
EXPLORATORY OBJECTIVES ............................................................................................................... 19 
3 
STUDY DESIGN ......................................................................................................... 20 
3.1 
GENERAL DESCRIPTION ....................................................................................................................... 20 
3.2 
PRIMARY ENDPOINT .............................................................................................................................. 20 
3.3 
SECONDARY ENDPOINTS ..................................................................................................................... 20 
4 
PATIENT SELECTION ............................................................................................... 21 
4.1 
INCLUSION CRITERIA............................................................................................................................. 21 
4.2 
EXCLUSION CRITERIA ........................................................................................................................... 22 
5 
STUDY ENTRY AND WITHDRAWAL PROCEDURES .............................................. 22 
5.1 
STUDY ENTRY PROCEDURES .............................................................................................................. 22 
5.2 
RANDOMIZATION PROCEDURES ......................................................................................................... 23 
5.3 
STUDY WITHDRAWAL ............................................................................................................................ 23 
6 
TREATMENT PLAN ................................................................................................... 23 
6.1 
TREATMENT RANDOMIZATION ............................................................................................................. 23 
6.2 
HLA TYPING ........................................................................................................................................... 24 
6.3 
PERIPHERAL BLOOD STEM CELL (PBSC) MOBILIZATION ............................................................. 24 
6.4 
PREPARATIVE REGIMEN ....................................................................................................................... 24 
6.5 
INFECTION PROPHYLAXIS .................................................................................................................... 25 
6.6 
TRANSPLANT .......................................................................................................................................... 25 
6.7 
GVHD PROPHYLAXIS ........................................................................................................................... 26 
6.8 
POST-TRANSPLANT CYTOKINE SUPPORT......................................................................................... 27 
6.9 
TREATMENT OF ACUTE GVHD ...................................................................................... 28 
6.10 POST-TREATMENT EVALUATION ........................................................................................................ 28 
6.11 MANAGEMENT OF MIXED CHIMERISM/RELAPSE ............................................................................. 28 
6.12 GRAFT FAILURE ..................................................................................................................................... 29 
6.13 ADDITIONAL TREATMENT MODALITIES .............................................................................................. 29 
6.14 GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES ......................... 29 


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6.15 FOLLOW-UP PERIOD ............................................................................................................................. 29 
7 
DOSING DELAYS/DOSE MODIFICATIONS .............................................................. 30 
8 
ADVERSE EVENTS: DEFINITIONS AND REPORTING REQUIREMENTS .............. 30 
8.1 
DEFINITIONS ........................................................................................................................................... 30 
8.2 
KNOWN AES RELATED TO MMF, GM-CSF, AND G-CSF ................................................. 32 
8.3 
RECORDING AES, SAES, AND UPS .................................................................................................. 32 
8.4 
TIME PERIOD AND GRADE OF AE CAPTURE .................................................................................... 32 
8.5 
AES REQUIRING EXPEDITED REPORTING ........................................................................................ 32 
8.6 
EXPEDITED REPORTING PROCEDURES FOR SAES, AND UPS .................................................... 33 
9 
PHARMACEUTICAL INFORMATION ........................................................................ 34 
10 
MEASUREMENT OF EFFECT ................................................................................... 34 
10.1 ENGRAFTMENT ....................................................................................................................................... 34 
10.2 COMPLETE REMISSION ......................................................................................................................... 34 
10.3 LENGTH OF RELAPSE-FREE/DLI-FREE SURVIVAL AND SURVIVAL .............................................. 34 
10.4 TREATMENT FAILURE ............................................................................................................................ 34 
10.5 RELAPSE FROM REMISSION ................................................................................................................ 35 
10.6 GVHD STAGING AND GRADING ......................................................................................................... 35 
11 
CORRELATIVE STUDIES ......................................................................................... 36 
11.1 PARTICIPATION IN CORRELATIVE STUDIES ...................................................................................... 36 
11.2 PROCESSING AND DISTRIBUTION OF BLOOD SAMPLES ................................................................ 36 
11.3 BLOOD SAMPLES FOR CORRELATIVE STUDIES ............................................................................... 36 
11.4 LABELING FOR ALL BLOOD SAMPLES ................................................................................................ 37 
11.5 PROCESSING OF BLOOD SAMPLES .................................................................................................... 37 
12 
STUDY CALENDAR .................................................................................................. 37 
12.1 PRIOR TO RANDOMIZATION ................................................................................................................. 37 
12.2 FOLLOWING RANDOMIZATION ............................................................................................................. 37 
12.3 STUDY CALENDAR ................................................................................................................................. 37 
13 
STATISTICAL CONSIDERATIONS ........................................................................... 40 
13.1 RANDOMIZATION SCHEME ................................................................................................................... 40 
13.2 STRATIFICATION FACTORS .................................................................................................................. 41 
13.3 STATISTICAL METHODS ........................................................................................................................ 41 
13.4 SAMPLE SIZE AND POWER DETERMINATION ................................................................................... 42 
13.5 STOPPING CRITERIA ............................................................................................................................. 42 
14 
DATA AND SAFETY MONITORING PLAN (DSMP) .................................................. 44 
14.1 STUDY TEAM .......................................................................................................................................... 44 
14.2 AUDIT COMMITTEE ................................................................................................................................ 44 
14.3 DATA AND SAFETY MONITORING COMMITTEE (DSMC) .................................................... 44 
15 
REGULATORY COMPLIANCE AND ETHICS ........................................................... 45 
15.1 ETHICAL STANDARD .............................................................................................................................. 45 
15.2 REGULATORY COMPLIANCE ................................................................................................................ 45 
15.3 INSTITUTIONAL REVIEW BOARD ......................................................................................................... 45 
15.4 INFORMED CONSENT PROCESS ......................................................................................................... 45 


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15.5 PATIENT CONFIDENTIALITY AND ACCESS TO SOURCE DOCUMENTS/DATA .............................. 46 
16 
DATA HANDLING AND RECORD KEEPING ............................................................ 46 
16.1 DATA MANAGEMENT RESPONSIBILITIES ........................................................................................... 46 
16.2 SOURCE DOCUMENTS .......................................................................................................................... 46 
16.3 CASE REPORT FORMS ......................................................................................................................... 46 
16.4 STUDY RECORD RETENTION ............................................................................................................... 47 
17 
REFERENCES ........................................................................................................... 48 
List of FIGURES 
Figure 1. Comparison of overall survival in ATG TBI conditioned patients 
randomized to 2 ATG doses (P=0.7) ........................................................................... 14 
Figure 2. (A) Absolute lymphocyte count (µL-1) recovery following ATG+TBI and 
either MRD or URD SCT; (B) Association of early monocyte recovery with 
late lymphocyte recovery ............................................................................................ 15 
Figure 3. Overview of the randomized temporal variation of GVHD prophylaxis and 
randomized agent for cytokine support ....................................................................... 27 
Figure 4. Event (Engraftment Failure, Day 100 TRM, and Severe Engraftment 
Syndrome) Frequency Threshold for Applying Stopping Criteria at Patient 
Accrual Milestones ..................................................................................................... 43 
Figure 5. Event (GVHD) Frequency Threshold for Applying Stopping Criteria at 
Patient Accrual Milestones .......................................................................................... 43 
 
 
List of TABLES 
Table 1. Expedited Reporting Requirements ............................................................................. 33 
Table 2. GVHD Staging ............................................................................................................. 35 
Table 3. GVHD Grading ............................................................................................................ 36 
Table 4. Study-Required Tests and Assessments ..................................................................... 38 
Table 5. Early Stopping Criteria ................................................................................................. 43 


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REVISION HISTORY 
Version 2, Version Date 06/23/2017 
•
The date and version number were updated on the cover page and throughout the
protocol.
•
Dr. Gary Simmons was added as a Co-Investigator on the cover page.
•
A Revision History page was added.
•
The List of Abbreviations was updated.
•
Clarifications were made in the Background in Section 1.1 and text regarding G-CSF and
GM-CSF was re-arranged in Section 1.2.
•
A study goal of comparing the survival rate of patients with multiple myeloma in either
study cohort with historical control patients was added to the study. Text was added in the
following sections to address this goal: Rationale (Section 1.2); Exploratory Objectives
(Section 2.3.5); and Statistical Considerations (Sections 13.3.3).
•
The secondary endpoints (Section 3.3.1) were rearranged to improve their organization.
•
Text describing the stratification factors based on diagnosis was revised in the Schema
and in Sections 1.4, 3.1, and 13.2 to include the malignancies added in eligibility (see
below).
•
The types of eligible hematologic malignancies were expanded to include patients with
acute lymphocytic leukemia, chronic myelogenous leukemia, and myelodysplastic
syndrome (Section 4.1.1).
•
The note regarding HLA-matched stem cells in unrelated donors was clarified
(Section 4.1.4).
•
The age of the eligible patient population was expanded to include patients with an age of
40-49 years (Section 4.1.5).
•
The note regarding substitutions for infection prophylaxis was expanded to allow
substitutions if toxicities develop (Section 6.5).
•
The instructions regarding tacrolimus were revised to allow adjustment in target tacrolimus
levels for drug toxicity (bullet 1, Section 6.7.1).
•
The instruction regarding the duration of MMF-15 and MMF-30 was clarified (Sections 6.8,
6.8.1, and 6.8.2).
•
The description regarding relapse prevention interventions was revised to allow relapse
prevention therapy to be given after day 60 in patients who are at high risk for relapse
(Section 6.11.1).
•
Exceptions to the requirement for recording AEs (AEs expected with stem cell transplant)
were added in Section 8.4.
•
The relapse criteria text in Section 10.5.3 was revised to include the malignancies added
in the inclusion criterion in Section 4.1.1 as noted above.


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• 
The study calendar was corrected by removing 2 time points for collection of flow 
cytometry samples from Table 4 (row 22, columns 2 and 3). 
• 
The permitted window of time for tests/assessments was revised in footnote C of Table 4 
to provide more flexibility after 6 months. 
• 
Text was added in footnote P of Table 4 to explain the purpose of pre-transplant 
genotyping for chimerism determination. 
 
Version 1, Version Date 07/23/2015 
 
Initial version of the protocol. 


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LIST OF ABBREVIATIONS 
 
AE 
adverse event 
ALL 
acute lymphocytic leukemia 
ALT 
alanine aminotransferase 
AML 
acute myelogenous leukemia 
AST 
aspartate aminotransferase 
ATG 
rabbit, anti-thymocyte globulin (Thymoglobulin; Sanofi-Aventis) 
AUC 
area under the curve 
BID 
twice per day 
BMT 
bone marrow transplant 
BP 
blood pressure 
CIBMTR 
Center for International Blood and Marrow Transplant Research 
CML 
chronic myelogenous leukemia 
CRF 
case report form 
CTCAE v4.0 
Common Terminology Criteria for Adverse Events Version 4.0 
cGVHD 
chronic graft versus host disease 
ddCD3 
donor-derived CD3+ (cell count) 
DLCO 
diffusing capacity of the lung for carbon monoxide 
DLI 
donor lymphocyte infusion 
DSMC 
Data Safety and Monitoring Committee 
FDA 
Food and Drug Administration 
FEV1 
forced expiratory volume in 1 second 
G-CSF 
granulocyte colony stimulating factor 
GM-CSF 
granulocyte macrophage colony stimulating factor 
GVHD 
graft versus host disease 
HCT 
hematopoietic cell transplant 
HL 
Hodgkin lymphoma 
HLA 
human leukocyte antigen 
IBW 
ideal body weight 
MCC-VCUHS 
Massey Cancer Center-Virginia Commonwealth University Health System 
MDS 
myelodysplastic syndrome 
MM 
multiple myeloma 
MMF-15 
mycophenolate mofetil – 15 day duration 
MMF-30 
mycophenolate mofetil – 30 day duration 
MRD 
matched related donor 
NHL 
Non-Hodgkin lymphoma 
OHRP 
Office for Human Research Protections 
PBSC 
peripheral blood stem cells 
PO 
by mouth 
RIC 
reduced intensity conditioning 
SAE 
serious adverse event 
SCT 
stem cell transplantation 
TBI 
total body irradiation 
TRM 
transplant-related mortality 
ULN 
upper limit of normal 
UP 
unanticipated problem 
URD 
unrelated donor 
VCU 
Virginia Commonwealth University 
WBC 
white blood cell 
WCBP 
woman of childbearing potential 




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1 BACKGROUND 
1.1 Introduction 
 
The last decade has seen allogeneic stem cell transplantation (SCT) evolve from a single 
intense therapeutic intervention in young healthy individuals, to a series of adoptive 
immunotherapy interventions resulting in disease control in older individuals with 
comorbidities (1-8). In this study, we will utilize a regimen combining low dose total body 
irradiation (TBI) and rabbit anti-thymocyte globulin (ATG; Thymoglobulin, Sanofi-Aventis) 
to facilitate SCT with human leukocyte antigen (HLA)-matched related and unrelated 
donors (9-13). Based on the hypothesis that early treatment interventions have significant 
late effects in allogeneic SCT, a simple intervention, varying the duration of intense 
immunosuppression following SCT, will be investigated in this study. Patients will receive 
graft versus host disease (GVHD) prophylaxis using 2 different immunosuppressive 
regimens with tacrolimus + mycophenolate mofetil (MMF). Patients randomized to the 
investigational cohort will receive MMF for 15 days following SCT with cytokine support 
using granulocyte macrophage colony stimulating factor (GM-CSF) beginning on post- 
transplant day 4. Patients randomized to the control cohort will receive MMF for 30 days 
following SCT with cytokine support using granulocyte colony stimulating factor (G-CSF) 
beginning on post-transplant day 4. 
 
Despite the advancements made in allogeneic SCT over the past few decades, patient 
survival following allogeneic SCT remains highly unpredictable. The ability to identify 
unique immunologic profiles for patients with next generation sequencing and recently 
discovered patterns in genetic variation relating to donors and recipients may be critical 
tools in the process of furthering the understanding of patient prognosis following 
allogeneic SCT. A dynamical modeling system approach will be utilized to explore the 
validity of predicting patient outcomes post-transplant based on analysis of individual 
immune reconstitution in a trial comparing temporal variation of GVHD prophylaxis. 
 
1.2 Rationale and Previous Work 
 
The rationale for this study is based on the recent findings that transplant outcomes are 
determined by the rate of T-cell reconstitution and lymphoid recovery in the first 2 months 
of SCT. 
 
Donor-derived T cells exert a powerful anti-malignancy effect in patients with acute and 
chronic myeloproliferative and lymphoproliferative disorders. However, these disorders 
largely affect an elderly population where patients are unable to tolerate complications of 
SCT resulting from alloreactivity between donors and recipients, specifically GVHD. 
Adoptive immunotherapy interventions, such as reduced intensity conditioning and SCT 
followed by DLI, have resulted in disease control in older individuals. While this has 
enabled clinicians to pursue SCT in large numbers of elderly patients with hematological 
malignancy, GVHD remains a major complication of transplantation and continues to take 
a heavy toll on these patients. 
 
Further complicating matters is the unpredictability in the likelihood of GVHD developing in 
HLA-matched individuals transplanted using identical preparative regimens. Ability to 
predict clinical outcomes in patients as they go through the transplant process would be a 


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major advance in the clinical management of these patients. Clinical medicine is replete 
with phenomenon where interventions produce predictable results in a majority of 
instances. Examples of this may be seen most readily in cardiovascular and pulmonary 
medicine, where administration of a beta-blocker may slow down a tachycardic rhythm or 
administration of a beta-agonist relieves bronchospasm. In both these instances, 
administration of a drug, which interrupts or facilitates passage of an ionic current across 
cell membranes, yields an outcome, which may be predicted with a fair measure of 
confidence in most patients. Indeed these systems may be considered analogous to 
dynamical systems often encountered in the physical sciences, where a measurable 
change of state is produced over time as the variables determining that state undergo 
change, for example, change in velocity as an object accelerates. Thus, by reducing the 
excitability of the cardiac conduction system, beta-antagonists can stabilize a chaotic 
cardiac rhythm and restore normal sinus rhythm. 
 
Unlike the clinical situations described above, survival likelihood following allogeneic SCT 
remains probabilistic despite decades of clinical refinement and advances. Attempts to 
predict outcomes in individuals undergoing this life-saving, albeit dangerous, procedure are 
limited to calculations of survival odds derived from population-based studies. Although 
generalities such as HLA matching, availability of a family donor, application of certain 
pharmacological interventions, or others do predict for better results when cohorts of 
patients are examined, foretelling the course of an individual transplant recipient remains 
impossible. This has led to stochastic modeling of transplant interventions, which though 
valuable in identifying factors contributing to improved population outcomes, fails to yield 
mechanistic insights into transplant immunobiology when examined in an ‘isolated’ donor- 
recipient pair. 
 
Recently, application of next generation sequencing has led to the unveiling of a 
remarkably complex immune repertoire in allogeneic transplant recipients following 
transplantation. While on the surface this complexity is chaotic and disorganized, it does 
offer an excellent opportunity to explore the unique patterns that may characterize each 
individual’s immunologic repertoire during reconstitution (14). Furthermore, the genetic 
variation demonstrated between individual transplant donors and recipients displays a 
corresponding degree of complexity to that of the post-transplant immune repertoire, 
making it entirely plausible that the latter is predicated upon the former (15, 16). If this is 
the case, then SCT may be considered to be a dynamical system; as such, SCT may be 
susceptible to the interpretation and analysis applicable to a dynamical system if all the 
variables determining the evolution of the system following SCT can be identified and 
quantified (17). 
 
Several lines of evidence suggest that early interventions during the course of SCT have a 
profound influence on long-term outcomes in transplant recipients. This is analogous to 
certain types of dynamical systems, where minor modifications in the state of the system at 
an early time point can produce large variation in later outcomes. Extrapolating this logic to 
SCT suggests that it is likely that interventions made early in the course of transplant may 
have profound effects on the later stages of immune reconstitution. The progression of 
immune reconstitution following SCT appears to follow the same dynamics that govern the 
growth of biological systems. These growth dynamics are described by the logistic 
equation describing sigmoidal growth (18), which models initial slow growth followed by 
exponential expansion, eventually culminating in a stable population. The parameters 


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describing the lymphocyte reconstitution curve in each individual are associated with 
clinical outcomes. 
 
The next generation sequencing work done by our group also reveals a previously 
undescribed magnitude of alloreactivity potential between SCT donors and recipients. This 
provides an explanation for drugs such as ATG that can ameliorate the risk of GVHD. In a 
recently concluded trial, our group demonstrated that it is feasible to combine ATG with low 
dose TBI. A lower dose of ATG results in reliable T-cell engraftment with low risk of GVHD. 
However, disease relapse remains a problem and is more prevalent when the rate of 
immune reconstitution is low. The dynamical system nature of immune reconstitution would 
imply that relatively minor changes in treatments earlier in the course of SCT will result in 
significant long-term therapeutic effects in patients. Therefore, a clinical trial comparing 2 
cohorts of patients treated uniformly with a background of ATG and TBI, except for small 
differences in early post-transplant immunosuppression, would be informative in this 
regard. Further, in addition to optimizing clinical outcomes, such a study may yield 
important mechanistic insights into the interaction between the kinetics of immune 
reconstitution and clinical outcomes. 
 
G-CSF (filgrastim) and GM-CSF (sargramostim) are regulatory glycoproteins that stimulate 
the proliferation, differentiation, and functional activity of neutrophils. While G-CSF is a 
late-acting hematopoietin restricted to the neutrophil lineage, GM-CSF is a multi-lineage 
hematopoietin essential for production of granulocytes, monocytes, and macrophages (19). 
We have recently shown that early monocyte recovery is associated with faster T-cell 
reconstitution in ATG-conditioned patients (20). Thus, we hypothesize that using GM-CSF 
following transplantation would enhance monocyte recovery and subsequent T-cell 
reconstitution. While experience with GM-CSF following allogeneic SCT is more limited 
than experience with G-CSF, several randomized, double-blind trials have shown 
significantly reduced time to achieve neutrophil recovery with the use of GM-CSF after 
bone marrow or peripheral blood stem cell (PBSC) transplantation (21-24). Additionally, a 
large meta-analysis identified no significant increase in the risk of acute or chronic GVHD 
following treatment with GM-CSF (25). 
 
A further goal of this study will be comparison of clinical outcomes achieved with 
allografting in patients with multiple myeloma. Allografting for myeloma is a therapeutic 
conundrum given the competing risks of disease relapse and non-relapse mortality from 
GVHD and immune compromise. Given the focus of this trial on ameliorating GVHD and 
consequently minimizing immunosuppression, it is logical that, compared to standard 
allografting approaches, myeloma patients will experience an improvement in survival 
because of the reduction in non-relapse mortality. In order to accomplish these 
comparisons, we will conduct an analysis comparing outcomes in myeloma patients 
transplanted on this trial with historical outcomes in patients matched for clinical 
characteristics, but who did not undergo allografting. 
 
1.3 Preliminary Data 
 
The clinical trial we propose is based on an allogeneic SCT regimen incorporating rabbit 
anti-thymocyte globulin (ATG) and low dose (450 cGy) TBI. This regimen is based on the 
preclinical model of using anti-T-cell antibodies prior to SCT to achieve a tolerant platform 
on which to perform adoptive immunotherapy with DLIs. 


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The rationale for the use of ATG in this regimen is to facilitate engraftment and deplete 
donor T cells capable of causing acute and chronic GVHD (26, 27). The combination of 
ATG and TBI has further been shown to reduce GVHD by altering residual host T-cell 
subsets to favor regulatory natural killer T cells (12, 28). These specific T cells may 
suppress GVHD by polarizing donor conventional T cells toward secretion of 
non-inflammatory cytokines such as IL-4 and promoting expansion of donor T regulatory 
cells. 
 
Given that reduced intensity conditioning (RIC) relies on the graft vs malignancy effect 
mediated primarily by donor T cells, there is concern the use of ATG may increase relapse 
in this setting. In 2011, a large retrospective registry analysis from the Center for 
International Blood and Marrow Transplant Research (CIBMTR) was published (29). This 
analysis examined outcomes of adult patients with hematologic malignancies who received 
RIC from 2000 to 2007 and included 879 patients who did not receive ATG and 584 
patients who received varying doses and preparations of ATG. In the multivariate analysis, 
relapse rates at 3 years were higher in the ATG group vs non-ATG group (49% vs. 38%, p 
<0.01), negatively impacting overall survival. While the results of this trial raise important 
questions regarding the use of ATG in RIC, we do not believe the findings of this analysis 
can be applied to our trial design. The median dose of rabbit ATG administered to patients 
included in the CIBMTR report was high at 7mg/kg and administered closer to the time of 
stem cell infusion based on the most common conditioning regimens reported (fludarabine 
and busulfan, fludarabine and melphalan, and fludarabine and cyclophosphamide). The 
ATG dose proposed in our trial is lower at 5.1 mg/kg and administered early (days -9 
through -7), limiting effects on donor T cells. In a similar study of total lymphoid irradiation 
and ATG conducted by Lowsky and colleagues, ATG was administered early prior to 
allogeneic SCT on days -11 through -7. Serum levels of active ATG (capable of binding 
CD3+ T cells) were measured and were nearly undetectable on the day of transplantation 
and absent beyond day +7 (30). Finally, the relapse results noted in the CIBMTR registry 
report are also limited by the lack of data on immune reconstitution and use of DLI. 
 
The ATG+TBI regimen is followed by tacrolimus and MMF for GVHD prophylaxis. In earlier 
versions of this regimen, a schedule of ATG (10 mg/kg) given from day -10 to day -7 prior 
to blood stem cell infusion was found to yield superior T-cell recovery when compared with 
ATG administered more proximal to SCT (31). 
 
In a follow-up trial to determine the optimal dose of ATG, a schedule of 5.1 mg/kg delivered 
on day -9 to -7 was found to accomplish superior T-cell engraftment when compared with a 
7.5 mg/kg dose in patients with hematological malignancies (32). In the cohorts treated to 
date using this regimen, classical onset of grade III-IV acute GVHD has not occurred, nor 
has day 100 treatment-related mortality. Higher rates of mixed chimerism and the need for 
DLI (4/19 and 10/22 in ATG5 and ATG7.5, respectively) were recorded in the higher dose 
ATG arm. Patients with higher donor-derived T-cell counts (ddCD3) at 8 weeks post- 
transplant were more likely to achieve full donor chimerism and have a lower relapse rate, 
but sustained a higher frequency of GVHD (33). With 41 patients enrolled in this 
randomized phase 2 trial stratified for donor type (matched related donor [MRD] [n=19] vs 
unrelated donor [URD] [n=22]), overall survival at 2 years in the 2 arms was similar 
(68±1% vs 63±1%, p=NS) (Figure 1). Relapse occurred in 32% (6/19) vs 46% (10/22) of 
the ATG5 and ATG7.5 patients, respectively (Chi-square P=0.364). 


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Figure 1. Comparison of overall survival in ATG TBI conditioned patients randomized to 2 
ATG doses (P=0.7) 
 
Given the importance of donor-derived T cells in terms of clinical outcomes, the T- 
cell receptor β repertoire was studied using high throughput sequencing of the T-cell 
receptor β. This revealed that rather than a random collection of T-cell clones, the 
immune repertoire in normal donors and SCT recipients had a fractal organization. 
Furthermore, when the genomic differences between donors and recipients of SCT 
were determined using whole exome sequencing, a very large amount of protein 
coding variation was observed. This variation across the exome, when translated to 
HLA-binding oligopeptides, demonstrated a HLA-binding affinity profile that mirrored 
the T-cell repertoire organization (34). This observation suggests that SCT 
represents an example of a dynamical system, albeit a very complex system, where 
T-cell clonal expansion mimics population growth and may be modeled using the 
logistic equation. 
 
Absolute lymphocyte count recovery was defined as an average representation of 
T-cell clonal recovery and plotted for each individual patient following SCT 
(Figure 2). Notably, several individuals demonstrated a biphasic logistic growth 
curve. The first phase of exponential lymphocyte growth was observed coincident 
with engraftment around day 15-20 post-transplant and a second exponential 
growth phase was observed after cessation of MMF around day 40-50. This is 
consistent with the observation that the day 60 ddCD3 count has prognostic 
significance. It also provides an important clue regarding the optimal timing of 
immunological intervention following SCT. 


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A. 
 
 
B. 
 
 
Figure 2. (A) Absolute lymphocyte count (µL-1) recovery following ATG+TBI and either MRD 
or URD SCT; (B) Association of early monocyte recovery with late lymphocyte recovery 
In (A) of Figure 2, two periods of logistic growth are seen: from day 0-30 when patients are 
on MMF (blue outline) and from day 20 to approximately day 120 (orange outline). Each of 
these periods demonstrates an initial phase of slow growth followed by exponential 
expansion before finally leveling out with relatively stable counts until tacrolimus is 
discontinued. In (B) of Figure 2, two different patterns of monocyte recovery are associated 
with different lymphocyte recovery kinetics (20). 


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1.4 Proposed Study 
 
In this trial we will attempt to optimize post-transplant immunosuppression in a cohort of 
patients conditioned using an ATG-based regimen, with the goal of improving long-term 
immune reconstitution. This will likely reduce the risk of opportunistic infections, graft loss, 
and relapse in patients undergoing reduced intensity conditioning with a regimen 
incorporating ATG. Abbreviating the course of MMF will allow faster T-cell reconstitution. 
Additionally, we have recently shown that early monocyte recovery is associated with 
faster T-cell reconstitution in ATG-conditioned patients. Using GM-CSF would enhance 
monocyte recovery in patients, potentially improving T-cell reconstitution. 
 
In a series of trials investigating ATG use with low dose TBI, the optimal dose and 
schedule of ATG has been determined (31, 33). In the first trial the optimal schedule for 
ATG dosing with low dose TBI was determined; in the follow-up trial the dose of ATG to be 
given was selected. In the proposed study we will utilize the regimen combining rabbit 
anti-thymocyte globulin (ATG; Thymoglobulin, Sanofi-Aventis) 1.7 mg/kg/day given on day 
-9 through day -7, and 450 cGy TBI delivered in 3 fractions of 150 cGy each on day -1 and 
day 0. SCT will be with blood stem cells or marrow from HLA-matched related and 
unrelated donors. 
 
Based on the hypothesis that early treatment interventions have significant late effects in 
allogeneic SCT, the main interventions to be investigated in this study are: 1) varying the 
duration of intense immunosuppression following SCT and 2) administering different 
cytokines for hematopoietic reconstitution. Patients will receive GVHD prophylaxis with 2 
different immunosuppressive regimens using tacrolimus + MMF. Patients in the control 
cohort will receive MMF for 30 days following SCT and, in the investigational cohort, MMF 
will be given for 15 days post SCT. The control arm patients will receive G-CSF 5 
mcg/kg/day (filgrastim) for hematopoietic reconstitution, while the patients in the 
investigational arm will receive 250 mcg/m2/day of GM-CSF (sargramostim) (35). 
 
An adaptive trial design will be used, with the study endpoint for adaptive allocation on the 
2 study cohorts being donor-derived T-cell recovery at post-transplant day 60. Patients will 
be stratified by diagnosis (Hodgkin lymphoma [HL], Non-Hodgkin lymphoma [NHL], acute 
lymphocytic leukemia [ALL], and chronic lymphocytic leukemia [CLL] or multiple myeloma 
[MM] or acute myelogenous leukemia [AML], chronic myelogenous leukemia [CML], and 
myelodysplastic syndrome [MDS]) and by donor type (matched related or matched 
unrelated). Following adaptive allocation, patients will be eligible to undergo disease- 
specific relapse prevention therapies according to MCC-VCUHS BMT Program standards. 
Subsequent to this, patients will be followed for survival, relapse, GVHD, and immune 
reconstitution endpoints. 
 
The impact of variation in the duration and intensity of early post-transplant GVHD 
prophylaxis in patients conditioned with ATG 5.1 mg/kg and low dose TBI will be studied. 
Lymphoid recovery following SCT appears to follow a bilogistic pattern with the current 
GVHD prophylaxis regimen. It appears that the one month long course of MMF following 
SCT delays T-cell reconstitution and may delay the establishment of full donor T-cell 
chimerism in ATG-based reduced intensity conditioning regimens. Because the first phase 
of exponential lymphoid expansion was observed around the time of engraftment and 


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because in the dynamical system model the very first phase of the T-cell clonal growth will 
be critical for the long-term outcome, the investigational arm will have MMF discontinued at 
day 15 to allow uninhibited growth of T-cell clonal populations. This will likely be reflected 
in ddCD3 recovery at 8 weeks post SCT. Hypothetically, the relapse rate and opportunistic 
infection incidence will be reduced in these patients as compared to the control cohort. 
 
Two post-transplant outcomes will be studied in this randomized phase 2 SCT trial: clinical 
outcomes and immune reconstitution in the background of genetic variation between 
donors and recipients. The ddCD3 cell count at 8 weeks post-transplant will be used to 
adaptively allocate patients to the 2 study arms, which will compare post-transplant GVHD 
prophylaxis with MMF given for either 15 days or 30 days. As noted above, in the previous 
trials a marked increase in lymphocyte counts following the cessation of MMF was 
frequently observed. This makes it plausible that discontinuation of MMF earlier will hasten 
lymphocyte recovery and lead to improved clinical outcomes. 
 
Patients with hematological malignancies will be conditioned using ATG 5.1 mg/kg given in 
divided doses from day -9 thru -7, followed by 450 cGY TBI in 3 fractions administered on 
day -1 and day 0. Blood stem cells from HLA-A, -B, -C, and -DRB1 8/8 matched related or 
unrelated donors will be provided and post-graft GVHD prophylaxis will be administered 
using tacrolimus (day -3 to day 120; tapered thereafter depending on donor-derived T-cell 
count) and MMF. 
 
The randomization of the stratified cohorts will be between MMF 15 mg/kg administered 
twice daily from day 0 to day 30 in the control cohort (MMF-30) and day 0 to day 15 in the 
investigational cohort (MMF-15). The MMF-30 arm is similar to the regimen used in 
MCC-11561 and will serve as the control arm, whereas the investigational arm will be 
MMF-15, where MMF will be discontinued closer to the time of myeloid engraftment. 
Patients in the investigational arm (MMF-15) will also receive sargramostim (GM-CSF) for 
hematopoietic reconstitution with the hypothesis that this will lead to more robust monocyte 
recovery and consequently rapid lymphocyte reconstitution. Patients randomized to the 
control cohort (MMF-30) will receive filgrastim (G-CSF). Presumably, this will result in 
faster and more robust eventual T-cell reconstitution, helping reduce relapse and infection 
risk without affecting GVHD risk. 
 
1.5 Investigational Regimen 
 
1.5.1 MMF 
 
MMF is a potent uncompetitive inhibitor of inosine monophosphate dehydrogenase 
and, therefore, inhibits the de novo pathway of guanosine nucleotide synthesis 
without incorporation into DNA. Because lymphocytes are critically dependent for 
their proliferation on de novo synthesis of purines, whereas, other cell types can 
utilize salvage pathways, the active component of MMF (mycophenolic acid [MPA]) 
has potent cytostatic effects on lymphocytes. MPA also inhibits proliferative 
responses of T and B cell mitogens, antibody formation by B cells, and prohibits 
glycosylation of glycoproteins that mediate adhesion. 
 
MMF is indicated for the prophylaxis of organ rejection in patients receiving 
allogeneic renal, cardiac, or hepatic transplants. In experimental animal models, 
MMF has been demonstrated to prolong the survival of allogeneic transplants 


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(e.g., kidney, heart, liver, intestine, limb, small bowel, pancreatic islets, and bone 
marrow). MMF has been extensively studied in clinical trials following bone marrow 
transplantation and has been included in GVHD prophylaxis following blood and 
bone marrow transplant for more than 15 years. 
 
Gastrointestinal adverse reactions including diarrhea, nausea/vomiting, and 
mucositis have been reported. Constitutional symptoms include pain, fever, 
headache, and asthenia. Hematological toxicities, such as anemia and leukopenia, 
occur in 25% of patients. Peripheral edema has also been reported. 
 
Previous clinical studies in patients after renal allografting suggested that the 
principal adverse reactions associated with the administration of MMF include 
diarrhea, leukopenia, sepsis, vomiting, and a higher incidence of certain viral 
infections, e.g., cytomegalovirus (CMV), varicella zoster virus, and herpes simplex 
virus. 
 
1.5.2 Cytokine Support following SCT 
 
The cytokine to be used for hematopoietic reconstitution will be specified as part of 
the randomized treatment regimen. The investigational cohort (MMF-15) will receive 
GM-CSF (sargramostim) to potentially provide more robust monocyte recovery and 
consequently rapid lymphocyte reconstitution. The control cohort (MMF-30) will 
receive granulocyte colony stimulating factor (G-CSF; filgrastim). Both colony 
stimulating factors have been used extensively in the treatment of patients receiving 
myelosuppressive therapies since initial approval by the Food and Drug 
Administration (FDA) in 1991. 
 
1.6 Potential Risks and Benefits of the Investigational Regimen 
 
1.6.1 Potential Risks 
 
The potential risks associated with the study design include a higher risk of acute 
and/or chronic GVHD and higher risk of engraftment syndrome in the investigational 
cohort. These potential risks are included in the stopping criteria described in 
Section 13.5. 
 
1.6.2 Potential Benefits 
 
As described previously, reducing the intensity of the GVHD prophylaxis by 
shortening the duration of MMF will potentially result in faster and more robust 
eventual T-cell reconstitution, helping reduce relapse and infection risk. 
 
1.7 Correlative Studies 
 
To allow for mathematical modeling changes over time, additional blood samples for flow 
cytometry to assess monocytes, T-cell subset, B cell, and natural killer (NK) cell recovery 
will be drawn (4 mL) at 2, 6, and 10 weeks (in addition to the standard time points of 4, 8, 
12, 24, and 52 weeks). Additional blood samples will be drawn (4 mL) pre-transplant, about 
30 days and 100 days post-transplant, and at the time of GVHD diagnosis. These will be 
processed and stored for future T-cell receptor (TCR) sequencing. Cryopreserved 


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peripheral blood mononuclear cells (PBMCs) will be obtained and stored through the VCU 
Tissue and Data Acquisition and Analysis Core (TDAAC). 
 
2 OBJECTIVES 
2.1 Primary Objective 
 
To determine the difference in the relapse-free/DLI-free survival rate between patients 
randomized to MMF-30 (control cohort) and MMF-15 (investigational cohort) 
 
2.2 Secondary Objectives 
 
2.2.1 To determine the difference between patients randomized to MMF-30 (control 
cohort) and MMF-15 (investigational cohort) in the following: 
 
2.2.1.1 Day 60 ddCD3 
 
2.2.1.2 Overall survival (OS) 
 
2.2.1.3 Rate of acute GVHD 
 
2.2.1.4 Rate of chronic GVHD 
 
2.2.1.5 Rate of opportunistic infection 
 
2.2.1.6 Rate of graft loss 
 
2.2.1.7 Rate of engraftment syndrome 
 
2.2.1.8 Rate of achieving donor chimerism 
 
2.2.1.9 T-cell recovery kinetics following SCT 
 
2.3 Exploratory Objectives 
 
2.3.1 To evaluate dynamic exposure to immunosuppressive therapies 
 
2.3.2 To determine HLA-specific alloreactivity potential between HLA-identical transplant 
recipients 
 
2.3.3 To determine T-cell receptor beta and alpha repertoire restoration kinetics following 
SCT 
 
2.3.4 To explore the association and relationship between T-cell recovery kinetics, 
dynamic exposure to immunosuppressive therapies, HLA-specific alloreactivity 
potential between HLA-identical transplant recipients, and T-cell receptor beta and 
alpha repertoire restoration kinetics 


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2.3.5 To determine the difference in survival rate between patients with multiple myeloma 
in either study cohort (MMF-15 or MMF-30) and historical control patients with 
multiple myeloma who have relapsed but have never received an allogeneic 
transplant 
 
3 STUDY DESIGN 
3.1 General Description 
 
This is a randomized phase 2 trial for patients with high risk or recurrent hematological 
malignancies who are candidates for reduced intensity allogeneic stem cell transplantation. 
All transplant-related treatment interventions are performed according to standard 
transplant procedures with the exception of the duration (15 days vs 30 days) of MMF, an 
agent routinely included in GVHD prophylaxis. The agent used for cytokine support for the 
investigational cohort (MMF-15) will be GM-CSF; G-CSF will be included in the treatment 
regimen for the control cohort (MMF-30). Both cytokines are routinely used following 
allogeneic SCT. 
 
Patients enrolled in the study will undergo randomization stratifying them according to 
diagnosis (HL/NHL/ALL/CLL or MM or AML/CML/MDS) and donor type (matched related 
donor or matched unrelated donor [MRD or URD]). A total of 60 patients will be accrued in 
the study over a period of 5 years. 
 
3.2 Primary Endpoint 
 
The proportion of patients with event-free survival in the investigational cohort compared to 
the proportion of patients with event-free survival in the control cohort where the 
conditional events are the occurrence of relapse or DLI. 
 
3.3 Secondary Endpoints 
 
3.3.1 Secondary endpoints for the objective to determine the differences between patients 
randomized to MMF-30 (control cohort) and MMF-15 (investigational cohort) 
3.3.1.1 ddCD3 counts measured on day 60 
3.3.1.2 Overall survival (days to event) 
3.3.1.3 Diagnosis of acute GVHD 
3.3.1.4 Diagnosis of chronic GVHD 
3.3.1.5 Diagnosis of an opportunistic infection 
3.3.1.6 Diagnosis of graft loss 
3.3.1.7 Diagnosis of engraftment syndrome 
3.3.1.8 Donor chimerism 
3.3.1.9 Number of T cells indicating recovery following SCT 


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4 PATIENT SELECTION 
4.1 Inclusion Criteria 
 
A patient must meet all of the following inclusion criteria to be eligible to participate in the 
study. 
 
4.1.1 Any of the following high risk or recurrent hematological malignancies: 
• 
Hodgkin lymphoma (HL) 
• 
Non-Hodgkin lymphoma (NHL) 
• 
Chronic lymphocytic leukemia (CLL) 
• 
Multiple myeloma (MM) 
• 
Acute myelogenous leukemia (AML) 
• 
Acute lymphocytic leukemia (ALL) 
• 
Chronic myelogenous leukemia (CML) 
• 
Myelodysplastic syndrome (MDS) 
Note: Determination that the malignancy is high risk will be made by the 
investigator. 
 
4.1.2 Investigator determination that the patient is an appropriate candidate for reduced 
intensity allogeneic SCT with the standard MCC-VCUHS BMT Program regimen 
employed in this trial 
 
4.1.3 Patients with or without previous myeloablative autologous transplant 
 
4.1.4 HLA-matched stem cell donor, either related (6/6 or 5/6 loci matched) or unrelated 
(8/8 or 7/8 loci matched) 
Note: Unrelated donors should be matched at HLA-A, -B, -C, and -DRB1 loci. 
However, a single locus mismatch will be acceptable in the event a more closely 
matched donor is not available. 
 
4.1.5 Age ≥ 40 to < 75 years; patients 18 to 39 years of age will be eligible only if the 
investigator has determined that the patient has comorbidity(ies) precluding 
conventional allogeneic transplantation with full intensity myeloablative conditioning 
 
4.1.6 Karnofsky Performance Status of 70-100% 
 
4.1.7 Negative serology for HIV 
 
4.1.8 Women who are not postmenopausal or have not undergone hysterectomy must 
have a documented negative serum pregnancy test per standard MCC-VCUHS 
BMT Program guidelines 
4.1.9 Ability to understand and the willingness to sign a written informed consent 
document 


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Note: The consent form must be signed and dated prior to initiation of SCT 
preparative treatments (see Section 6.4). 
 
4.2 Exclusion Criteria 
 
A patient who meets any of the following exclusion criteria is ineligible to participate in the 
study. 
 
4.2.1 Previous therapeutic radiation therapy (RT) that exceeds critical structure tolerance 
doses as determined by a radiation oncologist 
4.2.2 Uncontrolled viral, fungal, or bacterial infection 
 
4.2.3 Active meningeal or central nervous system disease 
 
4.2.4 Previous therapy with rabbit anti-thymocyte globulin (ATG); previous treatment with 
equine ATG is allowed if more than 3 months ago 
Note: Previous myeloablative autologous transplant is permitted but not required. 
 
4.2.5 Pregnancy or breastfeeding 
 
4.2.6 Medical, psychological, or social condition that, in the opinion of the investigator, 
may increase the patient’s risk or limit the patient’s adherence with study 
requirements 
 
5 STUDY ENTRY AND WITHDRAWAL PROCEDURES 
5.1 Study Entry Procedures 
 
5.1.1 Required Pre-Registration Screening Tests and Procedures 
 
Refer to the study calendar in Section 12 for the screening tests and procedures 
that are required prior to registration, and for the timing of these events relative to 
the start of the SCT preparative regimen. 


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5.1.2 Study Enrollment 
 
The following are needed for patient registration: 
 
• Completed, signed, and dated eligibility checklist 
• Signed and dated consent form 
 
The patient’s initial enrollment data (e.g., demographics, consent, eligibility, on 
study, treatment assignment) will be entered into the OnCore database within 24 
hours of registration and before treatment begins. 
 
5.2 Randomization Procedures 
Upon registration, patients will be randomized to either the investigational cohort 
(MMF-15 with GM-CSF) or to the control cohort (MMF-30 with G-CSF) according to a 
pre-specified randomization assignment provided by the statistician (see Section 13.1). 
 
5.3 Study Withdrawal 
 
A patient will be removed from the study for any of the following reasons: 
• 
Consent withdrawal for study treatment and study procedures 
• 
If, in the opinion of the investigator, it is in the best interest of the patient to do so 
• 
The study has been closed by the Principal Investigator 
• 
The study has been closed by the study sponsor 
 
The reason for withdrawal from the study and the date the patient was removed from the 
study must be documented in the case report form. 
 
6 TREATMENT PLAN 
6.1 Treatment Randomization 
 
Eligible patients who consent to participate in the study will undergo randomization 
between 2 GVHD prophylaxis cohorts. 
 
6.1.1 MMF-15 Cohort 
 
The investigational cohort will receive MMF orally at a dose of 15 mg/kg BID from 
day 0 to day 15. GM-CSF will be administered by subcutaneous injection to support 
hematopoietic reconstitution. 
 
6.1.2 MMF-30 Cohort 
 
The control cohort will receive MMF orally at a dose of 15 mg/kg BID from 
day 0 to day 30. G-CSF will be administered by subcutaneous injection to support 
hematopoietic reconstitution. 


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6.2 HLA Typing 
 
All HLA typing will be confirmed according to the standard procedures of the MCC-VCUHS 
BMT Program. 
 
6.3 Peripheral Blood Stem Cell (PBSC) Mobilization 
 
Donors should be mobilized using a standard stem cell mobilization protocol as follows: 
 
• 
Filgrastim (G-CSF) 10 mcg/kg/day administered by subcutaneous injection beginning 
on day 1 of the stem cell mobilization protocol and continuing through day 5 
 
• 
Apheresis performed on days 4 and 5; a CD34+ cell dose of at least 
5 x 106 CD34+ cells/kg recipient body weight will be obtained, if possible. 
 
For unrelated donors at National Marrow Donor Program (NMDP) centers, although PBSC 
will be the first choice, bone marrow will be acceptable based on donor choice if no other 
donors are available. 
 
6.4 Preparative Regimen 
 
6.4.1 ATG 
 
All patients will receive rabbit ATG (Thymoglobulin, Sanofi-Aventis) at a dose of 
1.7 mg/kg/day for 3 days (5.1 mg/kg total). ATG will be administered intravenously 
over 10-12 hours, starting on day -9 and continuing daily through day -7. 
 
Patients who weigh greater than 125% of their ideal body weight (IBW) will have 
their ATG dose calculated using adjusted weight according to MCC-VCUHS BMT 
Program practice: 
 
Adjusted Weight (KG) = [(Weight - IBW) × 0.4] + IBW 
 
6.4.2 Premedications for ATG 
 
ATG-related premedications should be administered as follows: 
• 
Benadryl 50 mg IV, acetaminophen 650 mg PO, and methylprednisolone 
2 mg/kg IV will be given on each day as a premedication for ATG. 
• 
Repeat the methylprednisolone at the same dose halfway through each ATG 
infusion. 
Patients will be monitored according to standard procedures of the MCC-VCUHS 
BMT Program for infusion-related side effects. 


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6.4.3 Total Body Irradiation (TBI) 
 
TBI will be administered twice on day -1 and once on the morning of day 0 with an 
AP-PA technique, prior to hematopoietic cell infusion. The total dose of radiation is 
450 cGy given in 3 fractions of 150 cGy/fraction and at a dose rate of 
10-15 cGy/minute prescribed at the midpoint (central axis). No lens or lung shielding 
will be used. 
 
6.5 Infection Prophylaxis 
 
A standard regimen for infection prophylaxis will be followed as described below 
beginning on day -9 (or earlier, if necessary per investigator’s discretion). 
Note: Investigators may substitute appropriate medications for patients who have an 
allergy history or if toxicities develop related to the medications listed. 
• 
All patients will receive: 
− 
Voriconazole 200 mg PO every 12 hours or 4 mg/kg IV every 12 hours; may be 
discontinued when tacrolimus is stopped. Patients intolerant of voriconazole may 
receive fluconazole 400 mg PO daily. 
− 
Levofloxacin 500 mg/day PO; continue until neutrophil engraftment. 
− 
Bactrim DS once daily on 3 days a week; continue for 6 months post-transplant 
• 
For CMV-seropositive donor or recipient: 
− 
Valacyclovir at 1000 mg TID for CMV prophylaxis; continue for 12 months 
post-transplant 
• 
For CMV-seronegative donor and recipient: 
− 
Acyclovir 400 mg PO BID for HSV prophylaxis 
 
Appropriate therapeutic substitution may be made in the event of drug intolerance or 
toxicity. 
 
6.6 Transplant 
 
• 
Peripheral blood stem cells/bone marrow will be infused intravenously according to 
standard procedures for the BMT Program at MCC-VCUHS on day 0, after the last TBI 
treatment. 
• 
ABO-incompatible marrow will be red-cell depleted. 
• 
Corticosteroids will NOT be routinely used to support cell infusion. 


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6.7 GVHD Prophylaxis 
 
Two agents, tacrolimus and MMF, will be used for GVHD prophylaxis in all patients as 
follows: 
 
6.7.1 Tacrolimus 
 
• 
Tacrolimus will be initiated orally at 0.04 mg/kg/day in divided doses beginning 
on day –2 and continuing until day 90 maintaining levels of approximately 
10-14 ng/µL in the first month after transplant and 8-12 ng/µL in the next 2 
months after transplant. Target tacrolimus levels may be adjusted for drug 
toxicity at the investigator’s discretion. 
 
• 
Tacrolimus taper will begin at day 90 over a 2-month period at the transplanter’s 
discretion. The tacrolimus taper schedule may be modified by the transplant 
attending physician according to clinical judgment based on relapse or GVHD 
risk or engraftment status. 
 
6.7.2 MMF 
 
• 
MMF will be taken orally at a dose of 15 mg/kg BID; the patient’s adjusted 
weight will be used for dose calculation (see Section 6.4.1 for the formula for 
calculating adjusted weight). 
• 
The dose may be rounded to the nearest capsule size (250 mg). 
• 
If the patient cannot tolerate oral MMF, MMF may be administered IV using an 
equivalent IV dose. 
• 
The duration of MMF will be per randomized cohort. 
 
− 
Patients randomized to the investigational cohort (MMF-15) will take MMF 
from day 0 to day 15. 
− 
Patients randomized to the control cohort (MMF-30) will take MMF from day 
0 to day 30. 
 
The randomized assignments for the duration of MMF and for the post-transplant 
cytokine support are illustrated in Figure 3. 




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6.9 Treatment of Acute GVHD 
• 
Treatment of > grade II acute GVHD (see Section 10.6) will be initiated promptly with 
methylprednisolone until control is obtained, which will be determined by the 
investigator. 
• 
Patients with steroid-refractory acute GVHD will be treated according to standard 
GVHD therapy protocols for the MCC-VCUHS BMT Program. 
 
6.10 Post-Treatment Evaluation 
• 
All patients will undergo standard blood tests for granulocyte and T-cell chimerism at 
approximately 2, 4, 6, 8, 12, 24, and 52 weeks following transplant. 
• 
Flow cytometry to assess monocytes, T-cell subset, B cell, and NK cell recovery will be 
performed at 4, 8, 12, 24, and 52 weeks post-transplant. These assessments will also 
be performed at weeks 2, 6, and 10 for the correlative studies (Section 1.7). 
• 
Relevant and disease-specific restaging studies will be performed per standard 
procedures of the MCC-VCUHS BMT Program following transplantation at 
approximately 3, 6, and 12 months post-transplant or earlier if clinically indicated. 
 
6.11 Management of Mixed Chimerism/Relapse 
 
6.11.1 Eligibility to Discontinue Immunosuppression and Administer DLI or Other 
Intervention 
 
Patients demonstrating ≤ 90% donor chimerism (mixed chimerism) at any time point 
beyond approximately 8 weeks post-transplant and patients with residual/relapsing 
disease on restaging studies in the absence of GVHD at any time following 
transplant, will be eligible to discontinue immunosuppression and receive DLI or 
other relapse prevention intervention such as azacitidine (AML patients), rituximab 
(CD20-positive NHL), brentuximab (CD30-positive HL or ALCL), or lenalidomide 
(MM) along with tapering of tacrolimus at investigator discretion. For patients at high 
risk for relapse, relapse prevention therapy may be given after day 60. 
 
Immunosuppression should be stopped or tapered before administration of DLI. DLI 
may be given the day following cessation of immunosuppression at the discretion of 
the investigator. 
 
Active (i.e., ongoing or unresolved) grade 3 acute GVHD or moderate chronic 
GVHD is a contraindication for DLI. Caution should be exercised in DLI 
administration to patients with a previous history of steroid-refractory GVHD and 
grade III-IV active GVHD as well as extensive chronic GVHD. 


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6.11.2 Donor Lymphocyte Infusion (DLI) 
• 
Donor lymphocytes will be collected with either G-CSF or without any 
stimulation, using standard apheresis techniques. 
• 
In the absence of disease relapse, the first infusion will generally consist of 
5 x106 CD3+ cells /kg recipient body weight. Dose escalation from 1 to 10 x107 
CD3+ cells /kg is allowed for subsequent infusions. Four to 8 weeks will be 
allowed between infusions. 
• 
Chimerism studies will be obtained at 4 weeks following DLI, and as clinically 
indicated thereafter. Disease restaging will be done as clinically indicated. 
 
6.12 Graft Failure 
 
Patients with failure to engraft the allogeneic stem cell graft beyond day 28 (or earlier at 
the discretion of the investigator) will be eligible to receive a hematopoietic stem cell (HSC) 
boost from the donor. 
 
6.13 Additional Treatment Modalities 
 
• 
Medications for the prevention of GVHD, other than those specified in this protocol, are 
not permitted. 
• 
Appropriate therapeutic substitution for other transplant-related interventions may be 
made in the event of drug intolerance or toxicity. 
 
6.14 General Concomitant Medication and Supportive Care Guidelines 
 
Standard transplant-related supportive medications, other than non-protocol medications 
for the prevention of GVHD and cytokine support, may be administered at the 
investigator’s discretion. 
 
6.15 Follow-Up Period 
 
The patient’s follow-up status will be recorded in the source documents and the CRFs. 
Study follow-up will be conducted as follows: 
 
6.15.1 Evaluation of Adverse Events (AEs) 
 
Patients will continue to be evaluated for AEs until 6 months post-transplant or until 
the time of relapse, whichever occurs first. 
 
6.15.2 Relapse-Free Survival 
 
Follow-up for relapse-free survival will continue for 5 years following transplantation 
per standard post-transplant procedures or until subsequent transplant or death. 
 
6.15.3 Survival 
 
Patients will be followed for survival for 5 years. 


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7 DOSING DELAYS/DOSE MODIFICATIONS 
There are no study-required dosing delays or dose modifications for any of the agents 
included in the SCT preparatory, GVHD prophylaxis, infection prophylaxis, or transplantation 
regimens. Dose modifications and delays, if needed for patient support and safety, will be 
per investigator discretion. 
8 ADVERSE EVENTS: DEFINITIONS AND REPORTING 
REQUIREMENTS 
8.1 Definitions 
8.1.1 Adverse Event (AE) 
AE means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
8.1.2 Serious AE (SAE) 
An AE is considered “serious” if, in the view of the investigator, it results in any of 
the following outcomes: 
•
death,
•
a life-threatening AE (An AE is consider “life-threatening” if, in the view of the
investigator, its occurrence places the patient at immediate risk of death. It does
not include an AE that, had it occurred in a more severe form, might have
caused death.),
•
inpatient hospitalization or prolongation of existing hospitalization,
Planned inpatient hospitalizations are exempt from SAE reporting. Events
that prolong hospitalization beyond the expected period of time and otherwise
meet reporting criteria are, however, subject to SAE reporting requirements.
•
a persistent or significant incapacity or substantial disruption of the ability to
conduct normal life functions, or
•
a congenital anomaly/birth defect.
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 


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8.1.3 Unanticipated Problem (UP) 
Unanticipated problems include any incident, experience, or outcome that meets all 
of the following criteria: 
•
unexpected (in terms of nature, severity, frequency) given (a) the research
procedures that are described in the protocol-related documents, such as the
IRB-approved research protocol and informed consent document; and (b) the
characteristics of the patient population being studied;
•
related or possibly related to participation in the research (possibly related
means there is a reasonable possibility that the incident, experience, or outcome
may have been caused by the procedures involved in the research); and
•
suggests that the research places patients or others at a greater risk of harm
(including physical, psychological, economic, or social harm) than was
previously known or recognized.
8.1.4 AE Description and Grade 
The descriptions and grading scales found in the revised Common Terminology 
Criteria for Adverse Events version 4.0 (CTCAE v4.0) will be utilized for AE 
reporting. 
8.1.5 AE Expectedness 
AEs can be ‘Unexpected’ or ‘Expected’. Refer to Section 8.2 regarding expected 
AEs. Unexpected AEs are those AEs occurring in one or more patients participating 
in the study, the nature, severity, or frequency of which is not consistent with either: 
•
The known or foreseeable risk of AEs associated with the procedures involved
in the research that are described in (a) the protocol-related documents, such as
the IRB-approved research protocol and the current IRB-approved informed
consent document, and (b) other relevant sources of information, such as
product labeling and package inserts; or
•
The expected natural progression of any underlying disease, disorder, or
condition of the patient(s) experiencing the AE and the patient’s predisposing
risk factor profile for the AE.
8.1.6 AE Attribution 
•
Definite – The AE is clearly related to the study intervention.
•
Probable – The AE is likely related to the study intervention.
•
Possible – The AE may be related to the study intervention.
•
Unlikely – The AE is doubtfully related to the study intervention.
•
Unrelated – The AE is clearly NOT related to the study intervention.


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8.2 Known AEs Related to MMF, GM-CSF, and G-CSF 
Patients randomized to the investigational cohort will receive MMF and GM-CSF. The 
control cohort will receive MMF and G-CSF. All 3 agents are routinely used in the clinical 
management of patients undergoing SCT. Refer to the current FDA-approved prescribing 
information for MMF, GM-CSF, and G-CSF. 
8.3 Recording AEs, SAEs, and UPs 
All AEs to be collected per protocol, all SAEs, and all UPs will be recorded per standard 
practice in the MCC-VCUHS BMT Program. In most cases, it is acceptable to record only 
the highest grade of a toxicity occurring during a particular study segment when an event 
has serial fluctuations in grade over time. 
SAE’s will be entered into the OnCore SAE domain. UPs will be entered into the OnCore 
Deviations domain. An SAE that is both an SAE and a UP will be entered in both domains. 
For all SAEs, a corresponding entry should be made in the routine AE record to match the 
event entries in the SAE domain. Additionally, events related to stopping criteria will be 
entered in OnCore as an event of special interest. 
8.4 Time Period and Grade of AE Capture 
AEs ≥ grade 3 including those expected with SCT (e.g., diarrhea, hematuria, hemorrhage, 
hypoxia, sepsis, mental status changers, pneumonitis, and veno-occlusive disease) will be 
recorded for study tabulation and analysis beginning on day 0 and continuing until day 180. 
Exception: Expected ≥ grade 3 cytopenias and changes in electrolytes (e.g., magnesium, 
potassium, phosphorus, and calcium) will not be recorded. 
Toxicity assessments will include a review of all toxicities experienced during each 
assessment period. The highest grade of each ≥ grade 3 toxicity will be recorded. 
8.5 AEs Requiring Expedited Reporting 
All patients in this study will be receiving potentially toxic preparative therapy, therefore, 
significant regimen-related toxicity is anticipated, i.e., expected AEs. 
8.5.1 Expedited Reporting Requirements 
All grade 3, 4, and 5 unexpected AEs regardless of attribution will be reported in an 
expedited manner from the first dose of MMF (on day 0) until post-transplant day 
180. (Refer to Section 8.5.2 for AEs that should NOT be considered unexpected.)




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9 PHARMACEUTICAL INFORMATION 
Refer to the current FDA-approved prescribing information for the pharmaceutical 
information for all of the agents, including MMF, GM-CSF, and G-CSF, used in the 
management of patients enrolled on the study. 
 
10 MEASUREMENT OF EFFECT 
10.1 Engraftment 
 
Hematopoietic engraftment is defined as all of the following: 
• 
Recovery from post-transplant cytopenia with an absolute neutrophil count 
of ≥ 0.5 x 109 /L for 3 consecutive measurements or ≥ 1.0 x 109 /L for 1 day; 
• 
Platelet count of ≥ 20 x 109 /L for 7 days without transfusion; and 
• 
Evidence by chimerism studies that hematopoiesis is of donor origin (≥ 95% donor 
DNA by short tandem repeat (STR) analysis in whole blood, myeloid, and lymphoid 
lineages). 
 
10.2 Complete Remission 
 
Complete remission is defined as engraftment along with attainment of a normocellular 
marrow with trilineage hematopoiesis and without evidence of residual disease by 
conventional, cytogenetic, or molecular criteria (i.e., flow cytometry, fluorescence in situ 
hybridization [FISH], and polymerase chain reaction [PCR] for relevant disease-specific 
markers). CT scans should demonstrate normalization with any residual masses being 
negative by PET scanning in patients with lymphoma. Patients with myeloma should have 
a negative immunofixation. 
 
10.3 Length of Relapse-Free/DLI-Free Survival and Survival 
 
All study patients including those removed from the treatment protocol will be followed for 
survival every 3 months. 
• 
Length of relapse-free/DLI-free survival is measured from transplant to relapse, DLI, 
death, or time of last contact, censoring for patients alive and 
relapse-free/DLI-free at the time of last contact. 
 
• 
Length of survival is measured from transplant to death or time of last contact, 
censoring for patients alive at time of last contact. 
 
10.4 Treatment Failure 
 
Treatment failure is defined as death from toxicities associated with transplant procedure, 
relapse or progression of malignancy, or autologous hematopoietic recovery with loss of 
donor chimerism. 






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11.4 Labeling for all Blood Samples 
Each collected blood sample should be labeled as follows: 
•
Study number
•
Patient study identification number
•
Date of sample collection
•
Time of sample collection
•
Study time point
11.5 Processing of Blood Samples 
Samples will be processed, stored, and cataloged by TDAAC until the appropriate time for 
T-cell sequencing, which will be performed by a commercial laboratory selected for the
study.
12 STUDY CALENDAR 
12.1 Prior to Randomization 
The hospital admission date and other treatments related to the transplant should be 
scheduled prior to randomization. 
12.2 Following Randomization 
Treatment should be initiated as soon as possible after randomization. 
12.3 Study Calendar 
Study-required assessments, tests, and collection of blood samples for correlative studies 
are outlined on Table 4. 




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Table 4 Footnotes: 
A.
In addition to the assessments/tests listed on Table 4, other tests and exams may be performed per standard guidelines for the MCC-VCUHS
BMT Program and per investigator discretion.
B.
Timing prior to randomization should be consistent with the usual MCC-VCUHS BMT Program practices to screen patients for SCT.
C.
Following hospital discharge, assessments/tests should be performed within +/- 1 week of the day indicated on the calendar until 6 months;
then +/- 3 weeks.
D.
For patients who are not able to return for evaluation during years 3-5, follow-up may be performed by telephone contact with the patient or
through the patient’s referring physician.
E.
Donor and recipient.
F.
Frequency per standard practice of the MCC-VCUHS BMT Program.
G. Blood chemistries include serum creatinine, total bilirubin, alkaline phosphatase, AST, ALT, and additional tests per investigator discretion.
H.
Blood chemistries performed twice weekly until hospital discharge; performed weekly after hospital discharge until weekly testing is no longer
indicated per investigator assessment.
I.
For WCBP: At baseline (prior to study enrollment), serum pregnancy test within 30 days prior to initiation of the preparatory regimen.
J.
Infectious disease markers include: CMV, EBV, Hepatitis panel (HepA Ab, HepB SAb, HepB SAg, HepB Core Ab, HepC Ab), herpes simplex
virus, syphilis, HIV-1 and -2 and HTLV-I and –II antibody, varicella zoster, and toxoplasmosis.
K.
Cardiac assessments include ECG and left ventricular ejection fraction or shortening fraction by echocardiogram or MUGA.
L.
Pulmonary function tests include DLCO (adjusted for hemoglobin), FEV1, and FVC.
M. Relevant and disease-specific staging according to the MCC-VCUHS BMT Program usual practice.
N.
Refer to Section 8 for AE reporting requirements and instructions.
O. Performed weekly until Day 63 post-transplant and as indicated on the calendar; assessment will include review of all abnormalities
experienced during entire assessment period; highest grade for each abnormality (whether attributed to GVHD or not) will be recorded on the
appropriate CRF.
P.
Granulocyte and T-cell chimerism. (Chimerism pre-transplant is donor/recipient genotyping to allow for chimerism determination after
transplant.)
Q. Blood samples for flow cytometry: T-cell subset, B cells, NK cells.
R.
Blood samples collected at weeks 2, 6, and 10 will be used for correlative studies (see Section 11).
S.
Blood samples collected for future T-cell receptor sequencing (see Section 11).
T.
Baseline sample: after study registration but before SCT; per investigator discretion, the specific timing for collection of the 30- and 100-day
samples can be adjusted based on the patient’s clinical status; if GVHD is diagnosed, the sample should be collected as soon as possible.


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13 STATISTICAL CONSIDERATIONS 
13.1 Randomization Scheme 
To allocate consented and enrolled patients between treatments, we propose an outcome- 
adaptive allocation scheme that would increase the probability that patients are allocated 
to the more effective treatment regimen. We propose the use of the doubly adaptive biased 
coin design (DBCD) (36) coupled with optimal allocation of continuous outcomes, which 
has been shown to more greatly reduce treatment failures than other adaptive strategies 
while simultaneously maintaining power (37). In this set-up, the allocation probability for 
treatment A (MMF-15) is the function 
𝑛𝑛𝑛𝑛 
𝑛𝑛𝑛𝑛𝐴𝐴𝐴𝐴೦ 
2 /𝜌𝜌𝜌𝜌
  𝐴𝐴𝐴𝐴 
೦ 
𝑛𝑛𝑛𝑛೦ 
 
𝑔𝑔𝑔𝑔 ೦ 
, 𝜌𝜌𝜌𝜌೦ = 
, 
𝑛𝑛𝑛𝑛 
𝑛𝑛𝑛𝑛𝐴𝐴𝐴𝐴೦ 
2/𝜌𝜌𝜌𝜌 + 
೦𝑛𝑛𝑛𝑛𝐵𝐵𝐵𝐵೦
2 /(1 − 𝜌𝜌𝜌𝜌) 
೦ 
𝑛𝑛𝑛𝑛೦ 
𝑛𝑛𝑛𝑛೦ 
where 𝑛𝑛𝑛𝑛𝐴𝐴𝐴𝐴 is the number of patients currently allocated to treatment “A”, n is the total 
number of currently accrued patients, ρ is the optimal allocation ratio defined as: 
 
𝑠𝑠𝑠𝑠𝐴𝐴𝐴𝐴೦𝑥𝑥𝑥𝑥̅𝐵𝐵𝐵𝐵 
𝜌𝜌𝜌𝜌 = ೦𝑠𝑠𝑠𝑠𝐴𝐴𝐴𝐴೦𝑥𝑥𝑥𝑥̅𝐵𝐵𝐵𝐵 +
𝑠𝑠𝑠𝑠𝐵𝐵𝐵𝐵೦𝑥𝑥𝑥𝑥𝐴𝐴̅ 
1/2, 𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜ℎ𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑠𝑠𝑠𝑠𝑒𝑒𝑒𝑒, 
𝑒𝑒𝑒𝑒𝑖𝑖𝑖𝑖 (𝑥𝑥𝑥𝑥𝐴𝐴 < 𝑥𝑥𝑥𝑥̅𝐵𝐵𝐵𝐵  𝑎𝑎𝑎𝑎𝑛𝑛𝑛𝑛𝑎𝑎𝑎𝑎 𝑒𝑒𝑒𝑒 > 1)𝑜𝑜𝑜𝑜𝑒𝑒𝑒𝑒 (𝑥𝑥𝑥𝑥𝐴𝐴 
> 𝑥𝑥𝑥𝑥𝐵𝐵𝐵𝐵 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑒𝑒𝑒𝑒 < 1) 
 
 
where 𝑒𝑒𝑒𝑒 = 
𝑠𝑠𝑠𝑠𝐴𝐴𝐴𝐴೦𝑥𝑥𝑥𝑥𝐴𝐴 
/𝑠𝑠𝑠𝑠𝐵𝐵𝐵𝐵೦𝑥𝑥𝑥𝑥̅𝐵𝐵𝐵𝐵, and 𝑠𝑠𝑠𝑠𝑗𝑗𝑗𝑗  and 
𝑥𝑥𝑥𝑥𝑗𝑗 
are the sample standard deviation and sample 
mean, respectively, in the jth treatment. 
Thus, the allocation probability for treatment B (MMF-30) is: 
𝑔𝑔𝑔𝑔 
𝑛𝑛𝑛𝑛𝐵𝐵𝐵𝐵೦   , 𝜌𝜌𝜌𝜌೦ = 1 − 𝑔𝑔𝑔𝑔  𝑛𝑛𝑛𝑛𝐴𝐴𝐴𝐴೦   , 𝜌𝜌𝜌𝜌೦.
೦ 
𝑛𝑛𝑛𝑛 
೦ 
𝑛𝑛𝑛𝑛 
The treatment-specific, day-60 ddCD3 count (33) will be the continuous measure used in 
the adaptive allocation algorithm listed above, with implications that, as the trial 
progresses, patients will be increasingly likely to be allocated to the treatment with larger 
mean ddCD3 count, provided a difference exists between the 2 groups. A two-patient 
lead-in will be used in both groups, where the allocation ratio is held constant (1:1) until at 
least 2 patients have provided their day-60 ddCD3 measurements in each group; this will 
ensure the mean and standard deviations for each group are estimable. As large treatment 
differences in mean ddCD3 counts between the 2 treatment groups could lead to 
imbalanced treatment groups, we will perform additional statistical analyses (described 
below) using patient information from the previous ATG TBI trial whose treatment regimen 
is identical to that in the MMF-30 group. Note that we anticipate patients allocated to 


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MMF-30 will have inferior ddCD3 counts compared to patients allocated to MMF-15, on 
account of the earlier cessation of MMF at day 15 in the MMF-15 group as opposed to day 
30 in the control cohort in this study (MMF-30) and as in the previous study (MCC-11561). 


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13.2 Stratification Factors 
Patients will be stratified at the time of randomization according to the following factors: 
•
Diagnosis (Hodgkin lymphoma, NHL, ALL, CLL or MM or AML, CML, MDS)
•
Donor type (MRD or URD)
Adaptive allocation rates will be determined separately within each level/combination of the 
stratification factors. 
13.3 Statistical Methods 
13.3.1 Primary Endpoint 
The primary outcome in this study is event-free survival, where the conditional 
events are the occurrence of relapse or DLI. 
13.3.2 Secondary Endpoints (with measurement type) 
•
Overall survival (days to event or survival: time-to-event; survival: categorical)
•
Acute and chronic GVHD (days to positive diagnosis: time-to-event; positive
diagnosis: categorical)
•
Engraftment loss (days to loss: time-to-event; graft loss: categorical)
•
Engraftment syndrome (categorical)
•
Immune reconstitution (numerical)
•
DLI administration (days to administration: time-to-event; administration:
categorical)
•
Rate of T-cell recovery following SCT
13.3.3 Statistical Analysis 
The difference in the survival rate between patients allocated to MMF-30 and 
MMF-15 will be tested using a log-rank test and will be graphically represented with 
a Kaplan-Meier step-function for each treatment group; all time-to-event outcomes 
will be similarly analyzed and will account for the competing hazard of fatality using 
Gray’s test (38). Odds ratios of successful treatment for categorical outcomes 
between the 2 treatment groups will be estimated using logistic regression with a 
two-group treatment indicator. Treatment-specific means of numerical 
measurements will be compared between treatment groups using a one-factor 
analysis of variance model with 2 levels. 
To account for patient demographics and other characteristics, a proportional 
hazards model will be used for time-to-event measurements, multiple logistic 
regression will be used for categorical outcomes, and analysis of covariance will be 
used for numerical outcomes. For repeated-measure numerical outcomes 
(e.g., immune reconstitution), mixed-effect repeated-measure analysis of variance 
will be used, where a patient-level random effect will be used to account for intra- 


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subject dependence, which will be modeled with an autoregressive correlation 
structure. All categorical measures will be summarized with frequencies, 
proportions, and 95% confidence intervals for each treatment group, and odds ratios 
will also be reported. All numerical measures will be summarized with means, and 
95% confidence intervals, and standard deviations for each treatment group. 
Summary measures (proportions, means) and analytic measures (odds ratios, 
differences in means, hazard ratios) will also be adjusted for patient demographics 
and characteristics. 
All analyses will be conducted in the manner described above in 2 different 
scenarios: (i) including only patients accrued within this study period, and 
(ii) including both patients accrued within this study period as well as those allocated
to the 5.1-dose group of the previous study (MCC-11561) (n=19). These additional
patients will be included in the MMF-30 treatment group, and all analyses will be
adjusted by a random cohort effect to account for any between-study differences.
These secondary analyses with additional patients will have greater power (see
below) than analyses featuring patients solely from the current study, and will help
protect against any imbalances caused by the outcome-adaptive allocation
mechanism.
Additionally, we will conduct a sub-set analysis consisting of the following: 
(1) patients diagnosed with multiple myeloma (MM) in both the MMF-15 and
MMF-30 groups who have relapsed; (2) a group of historical control patients with
MM who have relapsed but have never received an allogeneic transplant. We
assume that nearly 1/3 of the 60 patients in the current study (n ≈ 20) will be
diagnosed with MM. The historical control group will consist of 20 patients matched
for age, gender and race. The difference in the survival rate between patients who
received an allogeneic transplant (treated at either MMF-15 or MMF-30) and the
group of historical control patients will be tested using a log-rank test and will be
graphically represented using a Kaplan-Meier step function in each group.
13.4 Sample Size and Power Determination 
The following calculations assume that 12 patients will be accrued per year for 5 years (60 
total), that there will be twice the allocated patients (due to the outcome-adaptive allocation 
algorithm) in the MMF-15 group than in the MMF-30 group, and an event rate of 0.421 
(observed rate at 2 years in the MMF-30 group in the previous study [MCC-11561]). Then 
assuming a 15% reduction in the event rate in the MMF-15 group, we will have 80% power 
(at 10% significance) to detect a hazard ratio as small as 1.53. If we add the patient 
information from the previous study into the MMF-30 group (which would help balance the 
expected sample sizes between treatment groups), then we will have 80% power to detect 
a hazard ratio as small as 1.50. 
13.5 Stopping Criteria 
The early stopping criteria will be applied to each treatment group separately once 5 
patients within a group have been accrued. The study will be stopped early if the observed 
number of patients experiencing one of the 4 events listed on Table 5 exceeds the 
threshold number of events (see Figure 4 and Figure 5), where the threshold number of 




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The events comprising the stopping rule will be defined as: 
• 
Engraftment failure defined as loss of established donor chimerism or failure to 
establish stable mixed donor chimerism, with or without autologous reconstitution, 
despite withdrawal of immunosuppression and DLI beyond day 100. In the absence of 
progressive disease, an observation period of 8 weeks post DLI will be required prior to 
declaring engraftment failure. 
• 
Steroid-refractory GVHD defined as biopsy-proven ≥ grade III classic acute GVHD 
(developing before day 100) requiring therapy with systemic corticosteroids for 
> 1 week for control. 
• 
Treatment-related day 100 mortality, excluding relapse/progressive disease, 
i.e., GVHD, sepsis, VOD, pneumonitis, etc. 
• 
Severe engraftment syndrome, defined as fever, rash, hypoxia, pneumonitis, and 
diarrhea requiring therapy with corticosteroids (methylprednisolone > 2 mg/kg/day) or 
etanercept. 
 
Patients unable to receive protocol-specified conditioning and GVHD prophylaxis will be 
excluded from the analysis for early stopping criteria. For example, patients unable to 
receive either tacrolimus or MMF will not count towards engraftment failure and GVHD 
analysis. Likewise, the stopping rule for engraftment failure and treatment-related mortality 
requires that the patients included in the analyses be transplanted. 
 
14 DATA AND SAFETY MONITORING PLAN (DSMP) 
The DSMP for this study will consist of the following 3 elements: 
 
14.1 Study Team 
 
The study team minimally consists of the principal investigator, the co-investigators, the 
study coordinator, the clinical research associate, and the study biostatistician. While 
patients are on treatment, the principal investigator, the study coordinator, and the clinical 
research associate will meet at least monthly and will meet at least quarterly with the study 
biostatistician to review study status. This review will include, but not be limited to, 
reportable AEs and UPs, and an update of the ongoing study summary that describes 
study progress in terms of the study schema. The appropriateness of further patient 
enrollment is addressed. All meetings including attendance are documented. 
 
14.2 Audit Committee 
 
This trial will be audited by the MCC Audit Committee. 
 
14.3 Data and Safety Monitoring Committee (DSMC) 
 
The study will be monitored by the MCC DSMC. The frequency with which the protocol is 
reviewed will be determined by the Protocol Review and Monitoring Committee. 


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15 REGULATORY COMPLIANCE AND ETHICS 
15.1 Ethical Standard 
 
This study will be conducted in conformance with the principles set forth in The Belmont 
Report: Ethical Principles and Guidelines for the Protection of Human Subjects of 
Research (US National Commission for the Protection of Human Subjects of Biomedical 
and Behavioral Research, April 18, 1979). 
 
15.2 Regulatory Compliance 
 
This study will be conducted in compliance with: 
• 
The protocol 
• 
Federal regulations, as applicable, including: 21 CFR 50 (Protection of Human 
Subjects/Informed Consent); 21 CFR 56 (Institutional Review Boards); 21 CFR 312 
(IND Application); and 45 CFR 46 Subparts A (Common Rule), B (Pregnant Women, 
Human Fetuses and Neonates), C (Prisoners), and D (Children) 
 
15.3 Institutional Review Board 
 
The VCU IRB, which is registered with the Office for Human Research Protections 
(OHRP), will review and provide approval for the protocol, the associated informed consent 
document, material that will be provided to participating patients, and any recruitment 
material. Any amendments to the protocol, consent form, or other materials will also be 
approved by the IRB. 
 
15.4 Informed Consent Process 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to 
participate in the study and continues throughout the individual’s study participation. 
Extensive discussion of risks and possible benefits of this therapy will be provided to the 
patients and their families. Consent forms describing in detail the study interventions/ 
products, study procedures, and risks are given to the patient and written documentation of 
informed consent is required prior to starting intervention/administering study product. The 
consent form will be IRB-approved and the patient will be asked to read and review the 
document. Upon reviewing the document, the investigator will explain the research study to 
the patient and answer any questions that may arise. The patient will sign the informed 
consent document prior to any procedures being done specifically for the study. The 
patients should have the opportunity to discuss the study with their surrogates or think 
about it prior to agreeing to participate. Patients may withdraw consent at any time 
throughout the course of the trial. A copy of the informed consent document will be given to 
patients for their records. The rights and welfare of the patients will be protected by 
emphasizing to them that the quality of their medical care will not be adversely affected if 
they decline to participate in this study. 


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15.5 Patient Confidentiality and Access to Source Documents/Data 
 
Patient confidentiality is strictly held in trust by the participating investigators and their staff. 
This confidentiality includes the clinical information relating to participating patients, as well 
as any genetic or biological testing. 
 
The study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the principal investigator. 
 
The principal investigator will allow access to all source data and documents for the 
purposes of monitoring, audits, IRB review, and regulatory inspections. 
 
The study monitor or other authorized representatives of the principal investigator may 
inspect all documents and records required to be maintained by the investigator, including 
but not limited to, medical records (office, clinic, or hospital) and pharmacy records for the 
patients in this study. The clinical study site will permit access to such records. 
 
16 DATA HANDLING AND RECORD KEEPING 
16.1 Data Management Responsibilities 
 
The principal investigator is responsible for: (i) the overall conduct of the investigation; 
(ii) ongoing review of trial data including all safety reports; and (iii) apprising participating 
investigators of any UPs. Participating investigators are responsible for reporting SAEs and 
UPs as required in Section 8. 
 
Any laboratory conducting correlative studies must maintain the laboratory records and 
documentation (laboratory notebooks, laboratory protocols, print-outs, recordings, 
photographs, etc). 
 
16.2 Source Documents 
 
Source documents for clinical information (patient history, diagnosis, clinical and diagnostic 
test reports, etc) are maintained in the patient’s clinical file. Source documents for the 
correlative studies are maintained in the laboratory conducting the study. 
 
16.3 Case Report Forms 
 
Standard and study-specific case report forms (CRFs) will be used to capture all the 
information required by the protocol. The CRFs will be created and approved by the study 
team to ensure the most effective data acquisition. All information on the CRFs will be 
traceable to the source documents which are generally maintained in the patient’s file. All 
CRFs should be completed and available for collection within a timely manner, preferably 
no more than 7 days after the patient’s visit. 


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16.4 Study Record Retention 
 
As applicable, study records will be maintained a minimum of 5 years beyond: (i) the 
publication of any abstract or manuscript reporting the results of the protocol; (2) the 
submission of any sponsored research final report; or (iii) submission of a final report to 
clinicaltrials.gov. 


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Gyurkocza B, Sandmaier BM. Conditioning regimens for hematopoietic cell 
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Dey BR, McAfee S, Colby C, Cieply K, Caron M, Saidman S, Preffer F, Shaffer J, 
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Baron F, Maris MB, Sandmaier BM, Storer BE, Sorror M, Diaconescu R, Woolfrey AE, 
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Niederwieser D, Maris M, Shizuru JA, Petersdorf E, Hegenbart U, Sandmaier BM, 
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11. Portier DA, Sabo RT, Roberts CH, Fletcher DS, Meier J, Clark WB, Neale MC, Manjili 
MH, McCarty JM, Chung HM, Toor AA. Anti-thymocyte globulin for conditioning in 
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15. Sampson JK, Sheth NU, Koparde VN, Scalora AF, Serrano MG, Lee V, Roberts CH, 
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derivation of hla-specific alloreactivity potential from whole exome sequencing of stem 
cell transplant donor-recipient pairs. Biol Blood Marrow Transplant. 2014; 20:S269- 
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17. Toor AA, Kobulnicky JD, Salman S, Roberts CH, Jameson-Lee M, Meier J, Scalora A, 
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MH, Sabo RT, Neale MC. Stem cell transplantation as a dynamical system: Are clinical 
outcomes deterministic? Front Immunol. 2014; 5:613. PMCID:PMC4253954. 
18. Toor AA, Sabo R, Salman SR, Moore B, Scalora AF, Aziz M, Kobulnicky J, Meier JA, 
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transplantation (sct) conditioned with rabbit anti-thymocyte globulin. Biol Blood Marrow 
Transplant. 2015; 21:S169-S170. 
19. Grant SM, Heel RC. Recombinant granulocyte-macrophage colony-stimulating factor 
(rgm-csf). A review of its pharmacological properties and prospective role in the 
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20. Toor AA, Sabo RT, Roberts CH, Moore BL, Salman SR, Scalora AF, Aziz MT, Shubar 
Ali AS, Hall CE, Meier J, Thorn RM, Wang E, Song S, Miller K, Rizzo K, Clark WB, 
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reconstitution after allogeneic stem cell transplantation identifies patients at risk for 
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21. Greenberg P, Advani R, Keating A, Gulati SC, Nimer S, Champlin R, Karanes C, Gorin 
NC, Powles RL, Smith A, Lamborn K, Cuffie C. Gm-csf accelerates neutrophil recovery 
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1996; 18:1057-1064. 
22. Link H, Boogaerts MA, Carella AM, Ferrant A, Gadner H, Gorin NC, Harabacz I, 
Harousseau JL, Herve P, Holldack J, et al. A controlled trial of recombinant human 
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23. Nemunaitis J, Rosenfeld CS, Ash R, Freedman MH, Deeg HJ, Appelbaum F, Singer 
JW, Flomenberg N, Dalton W, Elfenbein GJ, et al. Phase iii randomized, double-blind 
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24. Trigg ME, Peters C, Zimmerman MB. Administration of recombinant human 
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25. Ho VT, Mirza NQ, Junco Dd D, Okamura T, Przepiorka D. The effect of hematopoietic 
growth factors on the risk of graft-vs-host disease after allogeneic hematopoietic stem 
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26. Bacigalupo A, Lamparelli T, Bruzzi P, Guidi S, Alessandrino PE, di Bartolomeo P, 
Oneto R, Bruno B, Barbanti M, Sacchi N, Van Lint MT, Bosi A. Antithymocyte globulin 
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ICF_001.pdf: 
MCC-14-10739
NCT02593123
Adoptive Immunotherapy in Patients with Relapsed Hematological Malignancy: Effect of
Duration and Intensity of Early GVHD Prophylaxis on Long-Term Clinical Outcomes
IRB Approval Date: 12/17/2021
Document Date 11/24/2021


RESEARCH PARTICIPANT INFORMED CONSENT FORM
TITLE:
Adoptive Immunotherapy in Patients with Relapsed Hematological Malignancy: 
Effect of Duration and Intensity of Early GVHD Prophylaxis on Long-Term 
Clinical Outcomes
PROTOCOL #:
MCC-14-10739
VCU IRB #:
HM20005586
SPONSOR:
Virginia Commonwealth University Massey Cancer Center
INVESTIGATOR: Amir A. Toor, MD
Virginia Commonwealth University
PO Box 980157
Richmond, VA 23298
804-828-4360
AN OVERVIEW OF THE STUDY AND KEY INFORMATION
This consent form will tell you about this research study, which is also called a clinical trial. Your 
study doctor or study team will explain the research study to you. Research studies only include 
people who choose to take part. You have the option to not participate. You may take home an 
unsigned copy of this consent form so that you can discuss the study with your family or friends 
before making your decision. You may also discuss it with your health care team. If you have any 
questions, ask your study doctor or study team for more explanation. Please take your time to 
make your decision about taking part in this study.
What is the usual approach to treating my cancer?
You are being asked to take part in this study because you and your study doctor have agreed 
that you will be undergoing a stem cell transplant for a type of cancer that affects your blood and 
bone marrow, for example, leukemia, lymphoma, or multiple myeloma.
You have already received standard treatments, if available, for your type of cancer, but your 
disease returned or is progressing. People who are not in a research study may be treated with 
stem cell transplant or with drugs, radiation, or a combination of drugs and radiation without a 
transplant, if available for their type of cancer.
Why is this study being done?
A common problem that may occur after a stem cell transplant is a condition known as graft 
versus host disease (GVHD). The word “graft” refers to the stem cells that are transplanted from 
a donor into you, the “host”. GVHD occurs when the donor graft attacks the tissues in the host. 
GVHD can cause skin rash, intestinal problems such as nausea, vomiting, or diarrhea. It may 
also damage the liver and cause hepatitis or jaundice. GVHD may increase your risk of infection 
and cause other health problems. Treatment with drugs that can decrease the chance of having 
GVHD or decrease the severity of GVHD is a standard part of patient care following stem cell 
transplant. One of these drugs is mycophenolate mofetil (MMF). MMF is approved by the Food
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and Drug Administration (FDA) as a treatment for preventing GVHD after organ and tissue 
transplant.
The purpose of this research study is to compare any good and bad effects of giving MMF for 
15 days following stem cell transplant instead of the usual 30 days. Researchers believe that 
giving MMF for a shorter period of time after transplant may help the transplanted stem cells 
become engrafted sooner, which could increase the chance of a successful transplant.
Another standard treatment after stem cell transplant is a drug that helps support bone marrow 
function until your bone marrow can produce enough white blood cells to fight infection. One of 
the drugs used for supporting bone marrow function is granulocyte-colony stimulating factor
(G-CSF). G-CSF will be given to patients who will be taking MMF for 30 days. A drug similar to 
G-CSF called granulocyte macrophage-colony stimulating factor (GM-CSF) will be given to
patients who will be taking MMF for 15 days. The researchers believe that GM-CSF will be more
helpful than G-CSF in supporting bone marrow recovery in patients who will be taking MMF for
15 days. Both drugs are FDA-approved for treating patients who have had stem cell transplant
or other cancer treatments that affect bone marrow function.
There will be about 60 people taking part in this study.
What will happen if I participate?
If you decide to take part in this study, most of the treatments and procedures you will have are 
the usual approach in treating patients with leukemia, lymphoma, or multiple myeloma who have 
a stem cell transplant. Your study doctor or study team will tell you about these.
After your stem cell transplant, you will take MMF pills for either 15 days or 30 days. You will 
also receive GM-CSF or G-CSF until about 2 to 3 weeks after your transplant procedure. A 
computer will decide which group you are in. We tell you more about this in the “Study 
Treatment” section of this consent form.
This study also includes research using blood samples to study the effects of giving MMF for 
fewer days on bone marrow recovery after transplant. Blood samples, each measuring about 1 
teaspoon, will be collected for research purposes before the transplant and at about 2, 4, 6, 10, 
and 14 weeks after your stem cell transplant. A blood sample will also be collected if you 
develop GVHD.
This study plans to use your blood samples to sequence all or part of your DNA. 
Deoxyribonucleic acid (DNA) is the “blueprint” or “recipe” that gives the body’s cells instructions 
on how to do their jobs. Scientists use sequencing to determine the order of the molecules that 
make up your DNA, like reading all the letters in a book. Sequencing is usually done to look for 
changes in the molecules of DNA that may cause health problems.
Individual results of the research using your samples will not be provided to you. The samples 
are collected only for the research study. There will be no benefit to you. If any inventions or 
discoveries result from the use of your samples, there are no plans to share any money or 
profits with you.
You will continue to receive care that is standard after stem cell transplant for about 1 year. 
Your doctor will continue to check you for side effects and follow your cancer response to the 
transplant until about 5 years after the transplant.
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What are my other choices if I do not take part in this study?
If you decide not to take part in this study, you have other choices. For example:

You may choose to have a stem cell transplant without being in the study or to have 
another type of treatment, if any are available for your type of cancer

You may choose to take part in a different study, if one is available

Or you may choose not to be treated for cancer but you may want to receive comfort 
care to relieve symptoms
What are the risks and benefits of participating?
There are both risks and benefits of participating in research studies. We want you to know 
about a few key risks right now. We will give you more information in the “Risks and 
Discomforts” section.
Risks

There may be possible risks of giving MMF for 15 days instead of the usual 30 days that 
researchers do not yet know about. For example, there may be a greater risk that GVHD 
will occur or will be more severe when MMF is given on fewer days. The risk of 
engraftment syndrome may also be increased. Engraftment syndrome includes fever 
that is not due to infection, skin rash, diarrhea, weight gain, and fluid in the lungs, which 
is called pulmonary edema.

You should not get pregnant, breastfeed, or father a baby while in this study. The 
treatment used in this study, which is part of the usual care following a stem cell 
transplant, could be damaging to an unborn baby and could cause a miscarriage.

You may feel brief pain or have some bleeding or bruising at the puncture site used to 
collect the blood sample. There is also a small risk of infection, light-headedness, and 
fainting.

Participation in research might involve some loss of privacy. There is a small risk that 
someone outside the research study could see and misuse information about you.
Benefits

It is not possible to know at this time if the study approach is better than the usual 
approach, so this study may or may not help you. This study may help people in the 
future.
Now that you have a general overview of the study, we want to provide the details about what 
your participation involves. Please read, or have someone read to you, the rest of this 
document. If there is anything you don’t understand, be sure to ask the study staff.
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STUDY TREATMENT
This study has two study groups.
Group 1 – Study Treatment
If you are in Group 1, you will take MMF pills by mouth twice each day for 15 days beginning on 
the day of the transplant. Also, you will be given GM-CSF intravenously, which means by vein 
(IV), or by a shot once each day beginning 4 days after your transplant and continuing until your 
bone marrow is able to make enough white blood cells to be able to fight infection. You will also 
be given all of the drugs and treatments that are usually included in the care of patients who 
have had a stem cell transplant.
Group 2 – Usual Treatment
If you are in Group 2, you will take MMF pills by mouth twice each day for 30 days beginning on 
the day of the transplant. Also, you will be given G-CSF intravenously, which means by vein 
(IV), or by a shot once each day beginning 4 days after your transplant and continuing until your 
bone marrow is able to make enough white blood cells to be able to fight infection. You will also 
be given all of the drugs and treatments that are usually included in the care of patients who 
have had a stem cell transplant.
A computer will assign you to one of the treatment groups in the study. When the study begins, 
participants will have a 50:50 chance of being assigned to Group 1 or Group 2. The computer 
will keep track of which treatment group might be doing better. As time goes on, a larger 
proportion of participants could be assigned to the group that seems to be doing better. The 
chart below shows the treatment groups at the very beginning of the study. Start reading at the 
left side and read across to the right.
RISKS AND DISCOMFORTS
You will be receiving many drugs and treatments as part of your care before and after the stem 
cell transplant. Your study doctor or study team will tell you about the side effects of those 
treatments, and you will be asked to sign a consent form that describes the risks of the stem cell 
transplant. MMF and G-CSF or GM-CSF are all drugs that will be included in your care even if 
you decide you do not want to participate in this study. Your study doctor or study team will talk 
with you about the side effects of these drugs and you will be given drug information sheets.
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The computer 
will put you in 
Group 1 or
Group 2
You agree 
to take part 
in the study
Group 2
MMF for 30 days 
and G-CSF
(Usual Approach)
Group 1
MMF for 15 days 
and GM-CSF
(Study Group)
Stem Cell 
Transplant
Standard 
Treatments 
Before and 
After the 
Transplant with 
Either Group 1
or Group 2 
Treatment
Approved by the VCU IRB on 12/17/2021


Here are important points about side effects:

Your study doctor does not know who will or will not have side effects.

Some side effects may go away soon, some may last a long time, or some may never go 
away.

Some side effects may be serious and may even result in death.
Here are important points about how you and your study doctor can make side effects less of a 
problem:

Tell your study doctor if you notice or feel anything different so they can see if you are 
having a side effect.

Your study doctor may be able to treat some side effects.

Your study doctor may adjust the study drugs to try to reduce side effects.
If important new side effects are found, your study doctor will discuss these with you.
Let your study doctor know of any questions you have about possible side effects. You can ask 
your study doctor questions about side effects at any time.
Reproductive Risks
The treatment used in this study, which is part of the usual care following a stem cell transplant, 
could be damaging to an unborn baby and could cause a miscarriage. If you are able to become 
pregnant, you will be asked to have a pregnancy test before you begin the stem cell transplant 
procedures. You will also be asked to use a reliable method to prevent pregnancy for at least 
one year following your transplant. Check with the study doctor about what methods of 
preventing pregnancy are acceptable for you.
CAN I STOP TAKING PART IN THIS STUDY?
Yes. You can decide to stop at any time. If you decide to stop for any reason, it is important to 
let the study doctor know as soon as possible so you can stop safely. If you stop, you can 
decide whether or not to let the study doctor continue to provide your medical information for the 
purposes of the study.
The study doctor will tell you about new information or changes in the study that may affect your 
health or your willingness to continue in the study. The study doctor may take you out of the 
study:

If your health changes and the study is no longer in your best interest

If new information becomes available

If you do not follow the study rules

If the study is stopped by the sponsor, the FDA, or the institutional review board (IRB), 
which is a group of people who review the research with the goal of protecting the 
people who take part in the study.
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WHAT ARE MY RIGHTS IN THIS STUDY?
Taking part in this study is your choice. No matter what decision you make, and even if your 
decision changes, there will be no penalty to you. You will not lose medical care or any legal 
rights.
WHAT ARE THE COSTS OF TAKING PART IN THIS STUDY?
You will not be charged for any costs related to the blood samples that are collected for 
research purposes. These samples are not used for testing that affects your care.
You and/or your health plan/insurance company will be billed for all standard costs of treating 
your cancer, including the cost of tests, procedures, or medicines to manage any side effects.
You will not be paid for taking part in this study.
WHAT HAPPENS IF I AM INJURED OR HURT BECAUSE I TOOK PART IN THIS STUDY?
If you are injured or hurt as a result of taking part in this study and need medical treatment, 
please tell your study doctor. Your study doctor or study team will talk with you about your 
options for medical treatment.
Fees for such treatment may be billed to you or to your health plan/insurance company. Your 
health insurance company may or may not pay for treatment of injuries or illness as a result of 
your participation in this study. The study will not pay for medical treatment.
To help decrease the risk of research-related injury or illness, it is very important to follow all 
study directions.
WHO WILL SEE MY MEDICAL INFORMATION?
Your privacy is very important to us. The researchers will make every effort to protect it, but your 
information may be given out if required by law. However, the researchers will do their best to 
make sure that any information that is released will not identify you.
Your research information and your personal identifying information will be kept private through 
the use of password-protected electronic files, locked research areas, and study identification 
numbers. The blood samples obtained for research purposes will be stored with the same 
safeguards. The results of this research may be presented at meetings or in publications, but 
you will not be identified by name.
There are organizations that may inspect your records. These organizations are required to 
make sure your information is kept private, unless required by law to provide information. Some 
of these organizations are:

Virginia Commonwealth University (VCU)

VCU IRB

FDA

National Cancer Institute (NCI)
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In the future, identifiers (like your name and birthday) might be removed from the information 
and samples you provide for this study. After that removal, your information and samples could 
be used for new studies without asking for your consent again. Those possible new studies 
could be done by this study team or other researchers and might involve sequencing all or part 
of your DNA.
WHERE CAN I GET MORE INFORMATION?
You may visit the NCI website at http://cancer.gov/ for more information about studies or 
general information about cancer. You may also call the NCI Cancer Information Service to get 
the same information at: 1-800-4-CANCER (1-800-422-6237).
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by
U.S. law. This website will not include information that can identify you. At most, the website will 
include a summary of the results. You can search this website at any time.
WHO CAN ANSWER MY QUESTIONS ABOUT THIS STUDY?
You can talk to your study doctor about any questions or concerns you have about this study or 
to report side effects or injuries. You can also contact a study team member at 804-828-1292.
The Office of Research can answer your general questions or concerns about your rights as a 
participant in this or any other research. Also, if you would like to speak to a person who does 
not work directly with your study doctor and the study team or if you cannot reach your study 
doctor or a member of the study team, you may contact the Office of Research.
Office of Research
Virginia Commonwealth University 
800 East Leigh Street, Suite 3000
Box 980568
Richmond, VA 23298
804-827-2157
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MY SIGNATURE AGREEING TO TAKE PART IN THIS STUDY
I have been given the opportunity to carefully read this consent form. All of the questions that I 
wish to raise concerning this study have been answered.
By signing this consent form, I have not given up any of my legal rights or benefits. My signature 
indicates that I freely consent to participate in this research study. I will receive a copy of the 
signed consent form.
Participant Name (Printed)
Participant Name (Signature)
Date
Person Conducting Informed Consent Discussion/Witness 
(Printed Name)
Person Conducting Informed Consent Discussion/Witness
Date 
(Signature)
Signature of Investigator (If different than above)
Date
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