Conditions: Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive Acute Biphenotypic Leukemia Acute Leukemia Acute Lymphoblastic Leukemia Acute Lymphoblastic Leukemia in Remission Acute Myeloid Leukemia Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome Chemotherapy-Related Leukemia Chronic Lymphocytic Leukemia Chronic Myelogenous Leukemia, BCR-ABL1 Positive Chronic Myelomonocytic Leukemia Hodgkin Lymphoma Langerhans Cell Histiocytosis Minimal Residual Disease Myelodysplastic Syndrome Myelodysplastic Syndrome With Excess Blasts Non-Hodgkin Lymphoma Recurrent Hodgkin Lymphoma Refractory Acute Lymphoblastic Leukemia Refractory Myelodysplastic Syndrome Small Lymphocytic Lymphoma Therapy-Related Myelodysplastic Syndrome
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 6
Healthy volunteers: no

Brief summary:
This phase II trial studies how well an umbilical cord blood transplant with added sugar works with chemotherapy and radiation therapy in treating patients with leukemia or lymphoma. Giving chemotherapy and total-body irradiation before a donor umbilical cord blood transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. The umbilical cord blood cells will be grown ("expanded") on a special layer of cells collected from the bone marrow of healthy volunteers in a laboratory. A type of sugar will also be added to the cells in the laboratory that may help the transplant to "take" faster.

Detailed description:
PRIMARY OBJECTIVES:

I. To evaluate the safety and feasibility of transplantation of cord blood which is expanded in mesenchymal precursor cell (MPC) co-cultures then fucosylated with fucosyltransferase (FT)-VI and guanosine diphosphate (GDP) fucose prior to infusion in patients with hematologic malignancies following high-dose therapy.

II. To evaluate the time to engraftment using expanded fucosylated cord blood.

SECONDARY OBJECTIVES:

I. To evaluate the rate and severity of graft versus host disease. II. To evaluate the rates of infectious complications. III. To evaluate the rates of disease-free and overall survival.

Summary: All patients receive Busulfan as per standard of care. Busulfan test dose can be administered either as an outpatient prior to admission or as an inpatient on Day -10.

Busulfan pharmacokinetics will be performed with the test dose and the first dose on Day -7 per standard of care. The doses of Days -6, -5, and -4 will be subsequently adjusted to target an AUC of 4,000 microMol.min-1. In the event that PK adjusting were not possible a dose of busulfan of 130 mg/m2 will be administered.

GVHD PROPHYLAXIS: All patients receive mycofenolate mofetil IV over 2 hours or orally (PO) twice daily (BID) on days -3 with a taper beginning on day 100 in the absence of GVHD, tacrolimus IV or PO starting on day -2 for 6 months in the absence of GVHD, and filgrastim-sndz subcutaneously (SC) once daily (QD) starting on day 0 until white blood count begins to recover.

After completion of study treatment, patients are followed up at months 1, 3, 6, and 12.

Arms:
arm 1: All patients received Busulfan as per standard of care. Busulfan test dose can be administered either as an outpatient prior to admission or as an inpatient on Day -10.

Busulfan pharmacokinetics will be performed with the test dose and the first dose on Day -7 per standard of care. The doses of Days -6, -5, and -4 will be subsequently adjusted to target an AUC of 4,000 microMol.min-1. In the event that PK adjusting were not possible a dose of busulfan of 130 mg/m2 will be administered.

GVHD PROPHYLAXIS: All patients also receive mycofenolate mofetil IV over 2 hours or PO BID on days -3 with a taper beginning on day 100 in the absence of GVHD, tacrolimus IV or PO starting on day -2 for 6 months in the absence of GVHD, and filgrastim-sndz SC QD starting on day 0 until white blood count begins to recover.

Interventions: intervention 1: Anti-Thymocyte Globulin intervention 2: Busulfan intervention 3: Clofarabine intervention 4: Cyclophosphamide intervention 5: Filgrastim-sndz intervention 6: Fludarabine intervention 7: Melphalan intervention 8: Mycophenolate Mofetil intervention 9: Rituximab intervention 10: Tacrolimus intervention 11: Total-Body Irradiation intervention 12: Umbilical Cord Blood Transplantation
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given IV intervention 4: Given IV intervention 5: Given SC intervention 6: Given IV intervention 7: Given IV intervention 8: Given IV or PO intervention 9: Given IV intervention 10: Given IV intervention 11: Undergo total body irradiation intervention 12: Undergo cord blood transplant

Protocol document:
Prot_SAP_000.pdf: 
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MD Anderson IND Sponsor Cover Sheet 
 
Protocol ID 
2016-0051 
Protocol Title 
Cord Blood ex-vivo MPC Expansion plus Fucosylation to 
Enhance Homing and Engraftment 
Protocol Phase 
Phase II 
Protocol Version 11.0 
Version Date 
11 March 2021 
 
Protocol PI 
Amanda L. Olson, M.D. 
Department 
Stem Cell Transplantation and Cellular Therapy 
 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
17378 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Cord Blood ex-vivo MPC Expansion plus Fucosylation to Enhance  
Homing and Engraftment 
 
 
 
 
 
 
 
 
1 The University of Texas MD Anderson Cancer Center, Stem Cell Transplantation and Cellular Therapy Department  
2 The University of Texas MD Anderson Cancer Center, Division of Pediatrics 
3 The University of Texas MD Anderson Cancer Center, Biostatistics Department 
Institution Study Number:  2016-0051 
Sponsor:   MD Anderson Cancer Center 
IND Holder:  The University of Texas MD Anderson Cancer Center  
 
IND Number:  17378 
Principal Investigator:  Amanda L. Olson, M.D. 
The University of Texas MD Anderson Cancer Center  
Stem Cell Transplantation and Cellular Therapy Department 
1515 Holcombe Blvd, Unit 0423 
Houston, TX 77030 
Telephone: 713-745-1505 
Fax: 713-794-4902 
alolson@mdanderson.org 
Co-Chair:  Elizabeth Shpall, MD1 
Collaborators:  Sajad J. Khazal2 
Kris M. Mahadeo2  
Demetrios Petropoulos2 
Katy Rezvani2 
Peter F. Thall3 
 
 
   


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Table of Contents 
 
 
1.0   Objectives ........................................................................................................................................... 4 
2.0   Background ........................................................................................................................................ 4 
3.0   Background Drug Information ........................................................................................................... 20 
4.0   Patient Eligibility ............................................................................................................................... 28 
5.0   Treatment Plan ................................................................................................................................. 30 
6.0   Pretreatment evaluation .................................................................................................................... 38 
7.0   Evaluation During Study ................................................................................................................... 39 
8.0   Statistical Considerations.................................................................................................................. 39 
9.0   Criteria for Response ........................................................................................................................ 41 
10.0 Criteria for Removal from the Study .................................................................................................. 42 
11.0   Adverse Events and Reporting Requirements .................................................................................. 42 
12.0 References ....................................................................................................................................... 48 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Protocol Body 
1.0 Objectives 
Primary objectives: 
a. To evaluate the safety and feasibility of transplantation in which one unit of 
cord blood is expanded in mesynchymal precursor cell (MPC) co-cultures and 
the other unit of cord blood is fucosylated with fucosyltransferase (FT)-VI and 
guanosine diphosphate (GDP) fucose prior to infusion in patients with 
hematologic malignancies following high-dose therapy 
b. To evaluate the time to engraftment using one expanded  and one 
fucosylated cord blood 
 
Secondary objectives: 
a. To evaluate the rate and severity of graft versus host disease 
b. To evaluate the rates of infectious complications 
c. To evaluate the rates of disease-free and overall survival 
2.0 Background 
For more than two decades, umbilical cord blood (CB) has been investigated clinically 
as an alternative source of hematopoietic progenitors for allogeneic transplantation of 
patients lacking an HLA-matched marrow donor. Fewer T-cells and/or less developed
1 
T-cells in CB compared to marrow allows for the possibility that CB grafts will produce 
less Graft vs. Host Disease (GVHD), the major cause of morbidity and mortality in the
2-4 
allogeneic transplant setting. Other potential advantages include the ability to markedly 
increase the number of allografts available and thus the number of patients who could 
be transplanted, given the availability and ease of collecting CB from placental veins 
prior to disposal of the placenta, compared to collecting bone marrow
5 or peripheral 
blood progenitor cells (PBPCs)
6 from living donors. This source of hematopoietic 
progenitors has allowed CB banks to target collection of units with human leukocyte 
antigen (HLA) types such as those of minority African American and Hispanic 
populations, which are under-represented in the National Marrow Donor Program 
Registry.
7
 
 
Since the first CB transplant performed by Gluckman’s group in 1988, more than 5,000 
patients world-wide have received related or unrelated CB transplants for a variety of 
malignant and non-malignant diseases.
8-23 The progression-free survival rates reported 
thus far are comparable to results achieved following allogeneic bone marrow 
transplantation. Moreover, there are many reports of what appears to be less GVHD 
than that associated with bone marrow transplants, despite the use of CB grafts with 
substantially more donor-recipient HLA disparity than that tolerated in recipients of 
marrow
11,12,16,17,23 or PBPC
24-26 allografts. The major disadvantage of CB is the low cell 
dose, which results in slower time to engraftment and higher rates of engraftment failure 
when compared to bone marrow transplantation.
27-31 In studies of CB transplantation 


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published by Kurtzberg
1, Gluckman
1, Rubinstein
1, Rizzieri
2, and Laughlin
2 the median 
times to an absolute neutrophil count (ANC) of > 0.5 x 10
9 /L ranged from 22 to 34 days. 
Median times to a transfusion-independent platelet count > 20 x 10
9 /L varied from 56 to 
over 100 days, with engraftment failure rates of 12-18%. However, as shown in Table 1, 
the engraftment failure rate for the adult patients (> 18 years old and/or >45 Kg) in 
those series was substantially higher, ranging from 10-62%. It is these larger, adult 
patients, who might benefit the most from the fucosylation of CB progenitor cells as 
discussed below. 
 
Table 1. Cord Blood Transplants: Engraftment Results 
 
Source 
N 
Days to 
ANC (500) 
Days to 
plats. (20K) 
Engraft. 
Failure 
Ref. 
NYBC-All 
560 
25 
71 
13% 
[17] 
NYBC-Adults 
97 
34 
128 
46% 
[17]* 
Duke-Peds 
25 
22 
82 
12% 
[12] 
Duke-Adults 
38 
26 
80 
21% 
[21] 
Gluckman-All 
143 
30 
56 
18% 
[16] 
Gluckman-Adults 
23>45 kg 
NR 
NR 
62% 
[16]* 
Laughlin-Adults 
68 
27 
58 
10% 
[22] 
>2.4 TNC/kg 
26 
0/5 
<2.4 TNC/kg 
32 
5/5 
 
* Data abstracted for adult patients from reference 
 
Rationale for Expanding Cord Blood Cells Ex vivo 
 
Single Umbilical Cord Transplantation 
 
Cord blood recipients receive approximately 1 log fewer mononuclear cells and 
substantially fewer myeloid progenitors, measured as colony-forming 
units-granulocyte/macrophage (CFU- GM), than do bone marrow recipients. In most of 
the cord blood transplant studies referenced above, there appeared to be a threshold 
effect in the total nucleated cell (TNC) dose of unmanipulated cord blood infused and 
time to engraftment, i.e., subjects who received doses above the median for a given 
study appeared to experience superior engraftment as compared with subjects who 
received TNC doses below the median. In the study by Gluckman,
16 engraftment and 
survival were superior in subjects who received  3.7 x 10
7 TNC/kg. This large a cell 
dose is not generally available for subjects weighing more than 45 kg. For adult 
subjects it appears that recipients of  1.0 x 10
7 TNC/kg had more favorable 
engraftment than recipients of lower cell doses.
16,22 In another study,
12 a linear 
correlation between the number of cord blood nucleated cells infused and time to 
neutrophil engraftment (p < 0.002) was reported in the unrelated cord blood transplant 
setting. 


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Double Umbilical Cord Transplantation 
 
Brunstein
32 recently analyzed the outcome of 536 subjects who underwent 
hematopoietic cell transplantation for hematologic malignancies at the Fred Hutchinson 
Cancer Research Center and the University of Minnesota (USA). In this study, the 128 
subjects who underwent double umbilical cord transplantation had a reduced risk of 
relapse compared to subjects who had the other graft types. In the double unrelated 
cord blood transplants, the median neutrophil recovery time was 26 days, more than a 
week longer than the median times for transplants from other donor sources, and 
median platelet recovery time was at least 4 weeks longer than that following other graft 
types and often not reached. An important finding of the study was for the 50% of 
recipients of double unrelated cord blood transplants who recovered neutrophils most 
rapidly (< 26 days), non-relapse mortality was only 16% compared to 41% in those who 
recovered later. The difference was primarily due to different rates of infectious 
complications. 
 
Collectively, these studies suggest giving more cord blood cells may result in faster 
neutrophil recovery. Expansion of cord blood progenitors ex vivo prior to infusion could 
potentially ameliorate inadequate hematopoietic recovery by generating higher numbers 
of the cells responsible for short-term reconstitution. 
 
Development of the Mesenchymal Precursor Cells (MPC)-Expanded Cord Blood 
Product 
 
To date, most studies of MPC-expanded cord blood for clinical use have been 
performed using CD34+ or CD133+ immunoselection of the cord blood followed by 
liquid suspension cultures with cytokine supplements.
33 A copper chelator 
tetraethylenepentamine (TEPA) has also been used to expand the more primitive 
CD34+ population.
34 A significant limitation of the immunoselection method is the low 
recovery of CD34+ and CD133+ cells following the positive selection process. In the 
MD Anderson Cancer Center cord blood expansion study involving CD34+ positive 
selection, the recovery of CD34+ cells from cord blood units was only 49% (range 4% to 
70%).
35 To avoid the unacceptable CD34+ cell losses associated with the positive 
selection procedure, new approaches were developed. 
 
Ex vivo liquid cord blood expansion removes the primitive hematopoietic progenitors 
from the hematopoietic microenvironment and relies on the addition of exogenous 
growth factors to prevent apoptosis and to stimulate proliferation, potentially driving 
differentiation at the expense of self-renewal. Thus, an alternative approach for ex vivo 
expansion is the co-culture of cord blood cells with MSC components of the 
hematopoietic microenvironment. Cord blood-MSC co-culture does not require the 
isolation of CD34+ or CD133+ cells prior to expansion minimizing manipulation and loss 
of hematopoietic progenitor cells. Starting with cord blood, McNiece
36 demonstrated a 
10- to 20-fold increase in TNC, a 7- to 18-fold increase in committed progenitor cells 
(colony-forming cells), a 2- to 5-fold increase in primitive progenitor cells (high 


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proliferative potential colony-forming cells), and a 16- to 37-fold increase in CD34+ cells, 
using an MSC co-culture expansion technique. 
 
As originally developed, it was necessary to generate primary MSCs from every subject 
or a family member, which severely limited the widespread use of this technology. Many 
subjects do not have an appropriate family member available who can serve as the 
MSC donor. Many other subjects, in particular those with acute leukemia, are in fragile 
remissions prior to transplant and at high risk of relapsing during the 4 weeks needed to 
generate the MSCs and then perform the co-cultures. An “off-the shelf” source offers 
major potential advantages over MSCs derived from a family member. First, the cells 
can be made available for immediate use without the need for lengthy processing or the 
possibility of contamination during culture. The development of master cell banks from 
young, healthy volunteers offers a way to bypass disease-related decline in stem cell 
function providing the optimal source of MSCs for the cord blood co-cultures. Finally, 
standardization of selection and isolation procedures provides a very reproducible 
product. 
 
Mesoblast International Sàrl (Mesoblast) has developed mesenchymal precursor cells, 
an off-the-shelf allogeneic source of mesenchymal cells and is the provider of MPCs to 
be used for the cord blood unit expansion in this study. Bone marrow cells are 
harvested from the posterior iliac crest of healthy human donors. The mononuclear cells 
are immunoselected for stromal enrichment using the STRO-3 monoclonal antibody, 
subsequently expanded, and cryopreserved to produce a cell bank. The expansion of 
immunoselected bone marrow mononuclear cells selected for mesenchymal precursors 
yields a product with defined purity, expression of mesenchymal-precursor-specific 
markers, and potent biological activity. Further research confirmed the immunological 
tolerance of the allogeneic MPCs in a variety of nonclinical and clinical allogeneic 
settings. The MPC product is produced in compliance with Good Manufacturing 
Practices (GMP). 
 
After process development work demonstrated MPCs were effective in the ex vivo 
expansion of unselected cord blood
37, researchers at MD Anderson Cancer Center 
treated a cohort of 24 subjects as part of a Phase 2 open-label, noncomparative study 
(study 2005-0781) using this technology. The results of ex vivo expansion of cord blood 
with MPCs indicate it is feasible to reproducibly generate large numbers of stem and 
progenitor cells in a cord blood unit. 
 
Name and Description of Investigational Product 
 
The expanded cord blood product is produced by the ex-vivo co-culture of cord blood 
with MPCs derived from adult bone marrow mononuclear cells. The cord blood unit to 
be expanded will be thawed and undergo ex vivo expansion by co-culture on MPCs. 
This process requires 14 days, after which the MPC-expanded cord blood is fucosylated 
with FT-VI and GDP-fucose, followed by a wash and then transported for direct infusion. 
Four to seven days prior to thawing and washing of the cord blood unit that will undergo 
expansion, a vial of MPCs is thawed and expanded into culture flasks for 14 days prior 


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to the fucosylation of the expanded cord unit. In total, the release of the final 
investigational product, the expanded cord blood unit, may take up to 21 days. Several 
clinical studies showing safety of both approaches are outlined below. 
 
Findings from Nonclinical and Clinical Studies 
Nonclinical Studies 
No formal animal safety or efficacy studies were required by the United States (US) 
Food and Drug Administration (FDA) prior to initiating clinical studies. 
 
Clinical Studies 
 
A Phase 2 study (study 2005-0781) of MPC-expanded cord blood was conducted by 
researchers at the MD Anderson Cancer Center. Results from this study of 24 subjects 
with hematologic malignancies indicated the majority of subjects had early recovery of 
neutrophils and platelets in comparison to historical data from subjects receiving 
unmanipulated double cord blood transplants, specifically a cohort of similar subjects 
from the Center for International Blood and Marrow Transplant Research (CIBMTR) 
database, according to its chief scientific director Mary M. Horowitz, MD, MS (personal 
communication, 2010). 
 
Ex vivo, MPC-expanded cord blood along with an unmanipulated cord blood unit was 
infused to 24 subjects who had undergone myeloablative conditioning for the treatment 
of hematologic malignancies following at least 1 relapse or those with high-risk disease. 
Each subject received 2 infusions. The first infusion (donor A) used an unmanipulated 
cord meeting the standard HLA and cell dose requirements (HLA matched 4 of 6 [4/6] or 
higher and cell dose 1.5 x 10
7 TNC/kg). The second infusion used a cord blood unit 
(donor B) that also met the standard cell dose and donor HLA matching requirements 
and additionally was expanded ex vivo in co-culture with MPCs. 
 
Patient Demographics and Disposition 
 
The mean subject age was 38.5 years and 58% of subjects were women (Table 2). 
Eighteen of 24 subjects who received transplants had relapsed or high-risk acute 
leukemia (4 with acute lymphoblastic leukemia [ALL], 13 with acute myelogenous 
leukemia [AML], and 1 with myelodysplastic syndrome [MDS]/ALL). 


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Mesenchymal Precursor Cells-Expanded Cord Blood Product Characteristics 
 
Subjects received a mean TNC dose of 8.9 x10
7 TNC/kg; the mean CD34+ cell dose 
was 2.1 x 10
6 CD34+/kg. The mean TNC and CD34+ doses in the MPC-expanded cord 
were 6.4x10
7 (standard deviation [SD] 4.0x10
7) cells/kg, and 2.0 x 10
6 (SD 2.3 x 10
6) 
cells/kg, respectively. By comparison, the mean TNC and CD34+ doses in the 
unmanipulated cord were 2.5 x 10
7 (SD 8.4x10
6) cells/kg, and 1.2 x 10
5 (SD 9.5x10
4) 
cells/kg, respectively. 
 
Overall, use of an ex-vivo MPC-expanded cord blood cell product resulted in a CD34+ 
cell dose approximately l log higher than the dose achievable from other cord products 
in this size population and within the range of CD34+ cells/kg achievable with other 
progenitor cell types (marrow and mobilized blood cells). 
 
Engraftment Results 
 
The TNC/kg dose of MPC-expanded cord blood strongly correlated with neutrophil 
recovery (p=0.007) (Figure 1). However, TNC/kg did not correlate with platelet recovery 
(p=0.792). For CD34+ cells/kg dose, there was a trend toward significance for both 
neutrophil and platelet recovery. These data strongly support TNC/kg as a relevant 


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marker for the potency of the MPC-expanded cord blood product for neutrophil 
recovery. There was also a trend indicating that CD34+ cells/kg dose correlated with 
both neutrophil and platelet recovery and may therefore also be an indicator of 
MPC-expanded cord blood product potency. 
 
Figure 1. Correlations of Total Nucleated Cells/kg and CD34+ Cells/kg with 
Neutrophil and Platelet Recovery 
 
Of the 24 subjects enrolled, complete or partial response was observed in 19 subjects 
(79%). Of the evaluable subjects, the median time to response was 56.5 days (range 
16-116 days); in the 5 subjects who progressed without responding, the median time to 
progression was 188 days. The range of follow-up was 31 to 426 days. At last follow-up, 
16 subjects had died. Causes of death were infection (n=7), GVHD (n=5), progressive 
disease (n=3), and multi-organ failure (n=1). 
 
Subjects who received ex vivo MPC-expanded cord blood cells in addition to an 
unmanipulated cord blood transplant achieved neutrophil recovery at a median of 15 
days (n=23, range 9-42 days) and platelet recovery at a median of 43 days (n=17, 
range 18-62 days). Notably, 21 of 23 evaluable subjects achieved neutrophil recovery 
by day 26. Furthermore, platelet recovery occurred in 17 of 21 evaluable subjects by 
day 100. Overall, 23 subjects had engraftment and there were no engraftment failures 
(Table 3). One subject was not evaluable for neutrophil engraftment due to death at day 
31. Engraftment of neutrophils by 42 days was achieved in all 23 evaluable subjects. 


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Table 3: Engraftment Results 
 
Considering the study population as a whole, the median time to neutrophil recovery 
was 15 days (95% confidence interval [CI] 13.0-23.0) (Figure 2). The median time to 
platelet recovery to  20 x 10
9/L was 54 days (95% CI 37-57) and the median time to 
platelet recovery to  50 x 10
9/L was 66 days (95% CI 50-no upper boundary). These 
estimates account for data on subjects who were censored prior to recovery; they differ 
from the estimates in Table 3, which are based on subjects who recovered. 


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Figure 2: Cumulative Time to Neutrophil and Platelet Recovery (N=24) 
 
Engraftment duration was monitored by cell counts and chimerism data. All subjects 
had donor recipient disparity allowing identification of the graft source as donor or 
recipient (and MPC-expanded or unmanipulated cord blood) by variable number of 
tandem repeats (VNTR) assay. Both myeloid and T cell chimerism were assessed. 
Donor T cells were predominantly ( 99%) derived from the unmanipulated cord donor 
in 78% (18 of 23) of the subjects by day 100. Donor myeloid cells were predominantly ( 
99%) derived from the unmanipulated cord donor in 65% (15 of 23) of the subjects by 
day 100. Several subjects demonstrated mixed chimerism prior to day 100 but 
transitioned to unmanipulated cord donor type by the day 100 assessment. These 
findings demonstrate that the long-term engraftment is predominantly derived from the 
unmanipulated cord blood, but engraftment rates and times are likely facilitated by the 
infusion of MPC-expanded cord blood. 
 
Transfusion Results 
 
Platelet and red blood cell (RBC) transfusions were measured to explore hematopoietic 
recovery times with transfusion requirements and duration of transfusion support. The 
time to last platelet transfusion (median 54.5 days) correlated with the time to platelet 
recovery  50 x 10
9/L (median 50.5 days) more than platelets recovery to  20 x 10
9/L 
(median 43 days) (Table 4). Subjects received a median of 146 units of random donor 


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platelets, which was converted to transfusion episodes by dividing by 6 (size of a 
platelet pool) to report the number of platelet transfusion episodes (median 24.3) and 
platelet transfusion episodes per day (until day 100, median 0.5 platelet transfusions per 
day). Similarly, the RBC transfusion requirements were 16.5 (median) units transfused 
per subject and the time to last RBC transfusion was 70 days (range 13-165 days). Red 
blood cell transfusion requirements were not closely associated with times to neutrophil 
or platelet recovery. 
 
Table 4: Transfusion Outcomes (N=24) 
 
 
Adverse Events 
 
Toxicity and adverse events were expected due to myelosuppression, chemotherapy 
intolerance, and underlying disease. Although many adverse events were deemed 
related to the study treatment (transplant), no adverse events or toxicities were 
considered likely or possibly due to the investigational agent, i.e., ex vivo 
MPC-expanded cord blood cell product or infusion (Table 5). The most common grade 
3/4 events post-transplant were dysphagia, elevated bilirubin, infection, hemoptysis, 
hyperglycemia, somnolence, reduced ejection fraction, and urinary creatinine. Seven 
subjects had post-transplant events of infection and died. 
 
Table 5: All Adverse Events (Pre- and Post-Transplant) 
 
 
Acute GVHD developed in 16 (67%) subjects. Of these, 3 developed grade 3 or higher 
GVHD. The time to GVHD onset for grade 3 or higher was 58 days (range 27-118 


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days). There were no cases of grade 4 GVHD. Chronic GVHD occurred in 10 (53%) of 
19 evaluable subjects. Acute and chronic GVHD were the primary cause of death in 1 
and 4 subjects, respectively. 
 
The frequencies and descriptions of toxicities related to neutropenia were reported from 
day 0 to end of follow-up (Table 6). All 23 evaluable subjects had at least 1 diagnosed 
infection. The time to first infection was 22 days (range 0-97 days). The median times to 
onset of fever or fever and neutropenia (in the absence of diagnosed infection) were 10 
days each (ranges 8-10 and 3-17 days, respectively). Fever with neutropenia was 
experienced by 11 (46%) of 24 subjects; however, unexplained fever in the absence of 
diagnosed infection and/or neutropenia was uncommon. Fever in the absence of 
diagnosed infection occurred more often before day 10. 
 
Table 6: Neutropenia-Related Toxicities Post-Transplant 
 
 
 
Survival Outcomes 
 
The median survival time for the 24 subjects at both 1 year and overall was 217 days 
(95% CI 119-272), indicating that 1-year survival is predictive of overall survival in this 
24-subject study. At 6 months the median survival time was not reached. 
 
 


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Summary of MD Anderson Cancer Center Study 
 
An analysis of the 24 subjects in the MD Anderson Phase 2 study found the median 
time to neutrophil recovery was 15 days (95% CI 14-24 days) with 88% (21 of 24) of 
subjects recovering within 26 days. The median time to platelet recovery was 54 days 
(95% CI 40-57 days) with 67% (16 of 24) of subjects recovering by day 60. 
The noted improvement in neutrophil and platelet recovering is compelling evidence that 
the graft content of TNC and CD34+ cells correlates with product potency and 
engraftment kinetics. The marked improvement in platelet recovery indicates an 
engraftment improvement that has not been consistently seen in cord blood 
transplantation. Notably, the expanded MPC cord is an engraftment facilitator and does 
not specifically engraft, as demonstrated by the absence of MPC-expanded cord donor 
cell types (at day 100) in chimerism studies. The results of the study can be put into 
context by comparison with historical registry data. 
 
The Center for International Blood and Marrow Transplant Research (CIBMTR) also 
identified a matched cohort of subjects receiving double unrelated cord blood 
transplants (N=80) who underwent similar myeloablative conditioning regimens as used 
in the MD Anderson study. They performed a number of analyses comparing the 
probabilities of neutrophil and platelet recovery. The analysis showed only 53% (42 of 
80) of subjects receiving 2 unmanipulated cord blood units recovered neutrophils within 
26 days (p<0.0001). Similarly, for platelets, only 30% (24 of 79) of the CIBMTR matched 
cohorts recovered platelets by day 60 (p-value=0.0008). In addition, the median time to 
neutrophil recovery was 25 days (95% CI 22-28 days) with 53% (42 of 80) of subjects 
recovering by day 26. The median time to platelet recovery was 77 days (95% CI 
65-over 100 days) with only 31% (24 of 79) of subjects recovering by day 60. 
 
In a separately conducted analysis of subjects by CIBMTR, survival at 6 months was 
improved for the engraftment composite success group (defined as neutrophil recovery 
by day 42 and platelet recovery by day 60) (n=24 of 80 subjects) compared to others 
(81% [95% CI 59%-96%] versus 13% [95% CI 0-42%]), and improved survival at 6 
months was predictive of improved survival at 1 year. 
 
Rationale for Fucosylating Cord Blood 
 
A critical part of engraftment is the recruitment of primitive hematopoietic progenitor 
cells (HPC) to the bone marrow (BM). This process is governed by a cascade of 
molecular interactions between members of the selectin, integrin and CD44 
superfamilies of adhesion molecules expressed by HPC and their receptors expressed 
by the hematopoietic microvasculature.
38-45 The initial step associated with homing is the 
rolling of HPC on the vascular endothelium of the hematopoietic microenvironment,
38-48 
an interaction mediated by P- and E-selectins constitutively expressed by the BM 
endothelium and counter-receptors expressed by the HPC.
49 While the delay in 
engraftment and elevated risk of graft failure observed for CB recipients are thought to 
be due, at least in part, to low total nucleated cell (TNC)
17,50 and CD34+ cell
51 dose, there 


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is evidence that CB CD34+ cells may also have a defect in homing to the bone  
marrow.
52,53 In vitro (rolling) and in vivo (homing) evidence suggest that CB CD34+ cells 
interact poorly with selectins when compared to CD34+ cells from PB or marrow. 
Appropriate carbohydrate modification (fucosylation) of selectin ligands appears to be 
critical for the rolling of primitive hematopoietic cells on P- and E-selectins expressed by 
the hematopoietic microvasculature.
47,52,53 An in vitro correlation has been demonstrated 
between the level of CB CD34+ fucosylation and binding to P- and E-selectins.52 More 
heavily fucosylated CD34+ cells exhibit a greater affinity for P- and E-selectins than less-
fucosylated CD34+ cells. The correlation between the level of fucosylation of engrafting 
hematopoietic cells and their interaction with selectins expressed by the hematopoietic 
microvasculature highlights an important role for fucosylation in the homing process. 
 
Levels of fucosylation can be markedly increased by ex vivo treatment of HPC with a 
1-3 fucosyltransferase (FT)-VI.
52,53 Increased levels of fucosylation have been shown to 
augment the level of P- and E-selectin binding of CD34+ cells as demonstrated by 
increased levels of rolling on surfaces coated with P- or E-selectin in vitro under flow 
conditions
52, and vascular rolling, through an intravital imaging technique.
53 However the 
ultimate impact of such ex vivo fucosylation on hematopoietic engraftment remains to 
be documented which is the subject of this clinical trial. 
 
Cord Blood Fucosylation - Results 
 
As discussed above cord blood progenitor cells appear to have a deficit in homing and 
engraftment. CB hematopoietic progenitor cells have low levels of surface fucosylation. 
Thus for our recently published phase II study,
54 we postulated that by increasing the 
level of surface fucosylation might improve interactions with selectins expressed by the 
microvasculature of the hematopoietic microenvironment, potentially improving homing 
and engraftment. We used the NOD-SCID IL-2Rgnull (NSG) mouse model
33 to explore 
the impact of fucosylation on the rate and magnitude of engraftment with the goal of 
improving engraftment following CB transplantation in the clinic. 
 
Development of fucosyltransferase (FT)-VI for clinical use. The laboratory 
conditions for use of FT-VI included incubation of CD34+ cells at 37°C, for 30 minutes 
with 10 mM manganese in HBSS containing 1% HSA. To refine the procedure for 
clinical use, we performed flow cytometry with HECA-452 antibody (BD Bioscience) to 
sialyl Lewis X (sLex)/cutaneous lymphocyte antigen (CLA), a fucosylated selectin 
ligand, to measure the levels of cell surface fucosylation.
4;83;86 Optimal conditions for the 
fucosylation of selected CB CD34+ cells required at least 30 minutes of incubation with 
FT-VI enzyme at *160 mU/ml, at room temperature in HBSS containing 1% HSA and 1 
mM GDP ꞏ-fucose and 1 mM MnCl2. (*1 mU FT-VI is defined by the manufacturer as 
the amount of FT-VI that transfers 1 nMol of GDP-Fuc to Gal1-•-4 GlcNAc-•-PNP in 1 
hour.) Fucosylated CB MNC remained stably fucosylated for up to 2 hours as assessed 
by HECA-452 staining (Figure 3). 
 
 


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Figure 3. 
 
 
 
Fucosylation of CB MNC. Since CB CD34+ cell selection is time-consuming, 
expensive, and results in significant CD34+ cell losses, experiments were performed to 
determine whether fucosylation of unmanipulated CB mononuclear cells (MNC) would 
be feasible. Near maximal fucosylation of the CD34+ cells in the CB MNC preparation 
was achieved over a significant range of CB MNC cellularities (from 8-64x106 cell/ml) ( 
Figure 4) suggesting that fucosylation of CD34+ cells in an MNC preparation containing 
108 cells/ml is feasible without a reduction in enzyme efficacy. 
 
Figure 4. 
 
 
 
Improved engraftment after fucosylation of minimally manipulated CB cells. To 
exploit the in vitro conditions in animal studies, we treated CB CD34+ and CB MNC with 
FT-VI, washed the cells after the fucosylation procedure to remove residual Mn2+ and 
infused them into sublethally irradiated (270 cGy), NSG mice (5 mice/group): (A) CB 
CD34+ ± FT-VI. Each mouse received ~4.5x104 CB CD34+ cells ± FT-VI treatment 
cells and was monitored longitudinally via retro-orbital bleeding for the presence of 
human cells in the peripheral blood by flow cytometry using the human CD45+ antibody. 
Human engraftment in mice receiving CB CD34+ cells treated with FT-VI was detected 
more rapidly (earlier) and at a significantly higher level (~4-fold) than in recipients of 
untreated CD34+ CB cells (Figure 5A). 
 
(B) CB MNC ± FT-VI. Since the processes associated with the selection of CB CD34+ 
cells result in significant cell losses and since CB recipients receive unmanipulated 
(non-selected products) at transplant, the efficacy of fucosylation on engraftment 
following unmanipulated CB MNC ± FT-VI treatment was investigated. 
Sublethally-irradiated NSG mice received 6x106 MNC containing ~2.5x104 CB CD34+ 
cells (5 mice/group). Consistent with results observed when selected CD34+ cells were 
fucosylated using FT-VI, human engraftment in mice receiving MNC treated with FT-VI 
was detected more rapidly (earlier) and at a significantly higher(>3-fold) level than in 


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recipients of untreated CB MNC160 (Figure 5B). 
 
 
 
 
These data suggest that fucosylation of minimally manipulated CB cells is an effective 
strategy to improve the speed and magnitude of engraftment. The persistence of 
engraftment over the longer term (>8 weeks, data not shown) suggests that fucosylation 
does not negatively impact the long-term repopulating capacity of the graft. 
 
In our Phase II study we found that the median time to neutrophil and platelet 
engraftment after 30 minutes of fucosylation prior to infusion with one CB unit was 17 
days (range 12-34 days) and 33 days (range 18-100 days).54 (Figure 6) 


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Figure 6 Neturophil and Platelet Engraftment 
 
 
 
MSC expanded cord blood has higher endogenous fucosylation than unmanipulated 
CB. These cells then can be fucosylated to maximally express CLA/sLEX. (Figure 7) 
Figure 7. Fucosylation status of Unmanipulated, Expanded and FT-VI Treated CB cells, 
MSC-expanded CB has higher endogenous fucosylation than unmanipulated CB can then be 
fucosylated to maximally express CLA/sLex. 
 
 
 
 
 
 
 
 


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Figure 8 demonstrates in NSG mice, engraftment at Day 7 with Expansion + 
Fucosylation may be possible. 
 
Double Cord Blood Transplants 
 
In an attempt to increase the number of CB cells infused following high-dose or 
nonmyeloablative therapy, investigators have combined two units of differing HLA types 
and infused them as allogeneic hematopoietic support. Barker et al.reported results of  
patients transplanted with two unmanipulated CB units.68 Eight adults, with a median 
age of 47 years (range 22-56) and median weight of 81kg (range 63-109), were enrolled 
on the study. Of 7 patients alive without relapse at day +28, all had 97-100% donor 
chimerism on day +21 marrow biopsy. ANC recovery of 0.5 x 10
9 /L occurred at a 
median of 25 days (range 21-28). The authors concluded that their data support the 
principle that transplantation of two immunologically distinct CB units is safe in terms of 
crossed immunological rejection. Graft failure was not observed, but the majority of 
patients did engraft with only a single CB unit. In the current trial we will use two CB 
units, one of which will be co-cultured with MPCs for expansion then fucosylated in 
attempt to reduce the time to engraftment in CB transplant recipients below the 20-30 
days typically reported in this setting. 
 
3.0 Background Drug Information 
1. 
Antithymocyte globulin (ATG) 
THERAPEUTIC CLASSIFICATION: Immunosuppressant. 
MECHANISM OF ACTION: ATG is a rabbit anti-thymocyte globulin. It is a purified, 
sterile, primarily monomeric IgG fraction of hyperimmune serum of selective 
immunosuppressant. It is believed to act by modifying the number and function of 
lymphocytes. 
PHARMACEUTICAL DATA: ATG is diluted in 0.9% NaCl. ATG is given intravenously 
as a 4-hour infusion into a central vein. It is a colorless to slightly opalescent protein 
solution. ATG should not be diluted in dextrose or low salt fluids, as this may cause 


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precipitation. Infusion with acidic solution may cause physical instabilities. Although no 
further incompatibilities or drug interactions are known, it is recommended to 
administer ATG alone. 
STORAGE AND STABILITY: Commercially available. Solution for infusion contains 1 
mg of ATG/2 ml. It should be stored in a refrigerator at 2°C to 8°C (do not freeze). 
Diluted ATG is stable for 24 hours. 
KNOWN SIDE EFFECTS: ATG may cause cytopenia of any cell line, chills, fever, or 
edema. A serum-sickness like syndrome may also develop. Adverse reactions 
including rash, pruritus, urticaria, wheal and flare reactions, bronchospasm bleeding 
and anaphylactic shock have been reported. Resuscitation equipment should be 
available during administration. After an anaphylactic reaction, infusion should not be 
resumed. 
2. 
Busulfan 
Therapeutic Classification: Antineoplastic Alkylating agent. 
 
Pharmaceutical data: Busulfan injection is a sterile, pyrogen-free solution provided 
in a mixture of dimethylacetamide (DMA) and polyethyleneglycol 400 (PEG400). It is 
supplied in 10 ml single use ampoules at a concentration of six (6) mg busulfan per 
ml. Each ampoule contains 60 mg of busulfan in 3.3 ml of DMA and 6.7 ml of 
PEG400. When diluted in normal saline or D5W to a concentration of 0.5 mg/ml, the  
resulting solution must be administered within eight 
 
(8) hours of preparation including the three (3) hour infusion of the drug. 
 
Stability and storage: Ampoules should be stored refrigerated at 2-8°C (35-46°F). 
Stable at 4°C for at least twelve (12) months. Additional stability studies are in 
progress. DO NOT use beyond the expiration date. DO NOT use if the solution is 
cloudy or if particulates are present. 
 
Solution Preparation: Prepare the busulfan solution as follows (the patient will 
receive their busulfan “test” dose at 32 mg/m2 either as an outpatient prior to 
admission or as an inpatient on Day -9. Busulfan pharmacokinetics will be 
performed with the test dose and the day -7 dose and doses for day -7 to day -4 are 
subsequently adjusted to target an AUC of 4,000 microMol.min-1 then mixed into 
normal saline to a final concentration of 0.5 mg/mL. 
 
In each bag 6.0 mg busulfan (1.0 ml at 6 mg/ml and 11 ml saline) should be added 
to compensate for drug lost in the tubing with each infusion (approximately 12 ml at 
0.5 mg/ml is lost in the tubing when using the controlled rate infusion pump). 
 
Route of Administration: It is to be noted, that a sufficient amount of diluted busulfan 
should be added to compensate for the amount needed to prime the IV tubing; 
when hanging the infusate, the tubing should be primed with the busulfan solution 
and connected as close to the patient as possible. After completed infusion, the 
tubing with remaining busulfan (approximately 12 mL) should be disconnected and 


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discarded. All busulfan infusions should be performed by programmable pump. 
 
The test dose of busulfan is given over 45 minutes and the high-dose busulfan will 
be given by slow intravenous infusion over three (3) hours into a central venous 
catheter. 
 
CAUTION: DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS. 
 
An infusion pump will be used with the busulfan solutions as prepared above. A new 
infusion set must be used for administration of each dose. Prior to and following 
each infusion, flush the catheter line with normal saline or (approximately 5 ml). 
Start the three-hour infusion at the calculated flow rate. DO NOT infuse 
concomitantly with another intravenous solution of unknown compatibility. 
 
If a delay in administration occurs after the infusion solution is prepared, the 
properly identified container should be kept at room temperature (20-25°C), but 
administration must be completed within eight (8) hours of preparation including the 
three (3) hour drug infusion. 
 
Adverse Events: Dose limiting toxicity is expected to be hematological when used 
without stem cell support. Other toxicities seen frequently following high-dose 
busulfan in preparative regimens for bone marrow transplantation include: VOD, 
nausea, vomiting, pulmonary fibrosis, seizures, rash, and an Addison’s-like 
syndrome. 
 
Mechanism of action: Interferes with DNA replication and transcription of RNA 
through DNA alkylation, and ultimately results in the disruption of nucleic acid 
function. 
 
Animal Tumor Data: Busulfan has been shown to be active against a variety of 
animal neoplasm in vivo, including mouse sarcoma 180 and Ehrlich’s mouse ascites 
tumor. 
 
Human Pharmacology: Limited pharmacology data are available for the parenteral 
formulation to be used in this study and is detailed in the evaluation of IV Bu in a Phase 
II Trial using IV Bu at 0.8 mg/kg BW given over 2 hr every 6 hr for a total of 16 doses 
(Andersson et al, 2002) and when administered once daily for 4 days at a dose of 130 
mg/m2 in combination with Flu (Madden et al, AHS 2003, de Lima et al, BLOOD 2004). 
The pharmacokinetic data suggests that the plasma decay of the formulation fits an 
open one-compartment model with linear pharmacokinetics in the dose range of 12 
mg-130 mg/m2. Based on studies of oral Bu, the drug is reported to be extensively 
metabolized; twelve (12) metabolites have been isolated, but most have not been 
identified. The drug is slowly excreted in the urine, chiefly as methanesulfonic acid. Ten 
to fifty percent (10-50%) of a dose is excreted as metabolites within twenty-four (24) 
hours (Nadkarni 1959). 
 


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3. 
Cyclophosphamide 
Therapeutic classification: Antineoplastic alkylating agent 
Mechanism of action: Interferes with deoxyribonucleic acid (DNA) replication and 
transcription of ribonucleic acid (RNA) and ultimately results in the disruption of nucleic 
acid function. 
Pharmaceutical data: Lyophilized cyclophosphamide for injection contains 75 mg of 
mannitol per 100 mg of cyclophosphamide (anhydrous) and is supplied in vials for 
single-dose use. Storage and stability: Storage at or below 77ºF (25ºC) is 
recommended; this product will withstand brief exposure to temperatures up to 86ºF 
(30ºC) but should be protected from temperatures above 86ºF. Reconstituted 
lyophilized cyclophosphamide for injection is chemically and physically stable for 24 
hours at room temperature or for 6 days in the refrigerator; it does not contain any 
antimicrobial preservative and thus care must be taken to assure the sterility of 
prepared solutions. 
Known side effects: Dose limiting toxicity is hematologic. Nausea and vomiting is 
common. Anorexia and, less frequently, abdominal discomfort or pain and diarrhea may 
occur. There are isolated reports of hemorrhagic colitis, oral mucosal ulceration and 
jaundice occurring during therapy. Azotemia has been reported. Alopecia and 
hypersensitivity reactions when high doses are utilized. Hemorrhagic cystitis may 
develop in patients treated with cyclophosphamide. Rarely, this condition can be severe  
and even fatal. Acute cardiac toxicity has been reported 
with doses as low as 2.4 g/m2 to as high as 26 g/m2, usually as a portion of an intensive 
antineoplastic multi-drug regimen or in conjunction with transplantation procedures. 
Interstitial pulmonary fibrosis has been reported in patients receiving high doses of 
cyclophosphamide over a prolonged period. 
Note: It is recommended that administration of azoles should be avoided before and 
during infusion of cyclophosphamide. 
 
4. 
Clofarabine 
Therapeutic Classification: Antimetabolite; Purine analog 
 
Mechanism of Action: Clofarabine, a purine (deoxyadenosine) nucleoside analog, is 
metabolized to clofarabine 5'-triphosphate. Clofarabine 5'-triphosphate decreases 
cell replication and repair as well as causing cell death. 
 
Solution Preparation: Clofarabine is formulated as a concentration of 1mg/mL in 
United States Pharamacopeia (USP) sodium chloride (9mg/mL), and USP water for 
injection (qs to 1mL). Clofarabine is supplied in 2 vial sizes: a 10mL flint vial and 
20mL flint vial. The 10 mL flint vials contain 5mL (5mg) of solution and the 20mL flint 
vials contain 20mL (20mg). For both vial types, the pH range of the solution is 4.0 to 
7.0. The solution is clear with color ranging from colorless to yellow and is free from 
visible particulate matter. 
 


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Clofarabine should be filtered through a sterile 0.2 micron syringe filter and then 
diluted with 5% Dextrose Injection, USP, or 0.9% Sodium Chloride Injection, USP, 
prior to intravenous (IV) infusion to a final concentration of 0.4 mg/mL. Use within 24 
hours of preparation. 
 
Clofarabine Formulation and Stability: 
 
Clofarabine vials containing undiluted clofarabine for injection should be stored at 
25°C or 77°F with temperature excursion permitted to 15 to 30°C or 59 to 86°F. 
Ongoing shelf-life stability indicate that clofarabine is stable for 36 months at 25°C 
(±2°C) and 60% (±5%) relative humidity and for 6 months at 40°C (±2°C) and 75% 
(±5%) relative humidity. 
 
Expected toxicities: 
 
Myelosuppression, nausea/vomiting, diarrhea, mucositis, skin rash (particularly 
hand-foot syndrome), fatigue, mental status changes/coma, allergic reactions 
(including fever, muscle aches, edema, dyspnea), congestive heart failure, 
conjunctivitis, anorexia, febrile neutropenia, pruritus, headache, flushing and pyrexia, 
hepatic enzyme elevations, liver failure. 
 
5. 
Filgrastim-sndz (Zarxio, G-CSF) 
THERAPEUTIC CLASSIFICATION: Recombinant growth factor 
MECHANISM OF ACTION: Filgrastim, filgrastim-sndz, and tbo-filgrastim are 
granulocyte colony stimulating factors (G-CSF) produced by recombinant DNA 
technology. G-CSFs stimulate the production, maturation, and activation of neutrophils 
to increase both their migration and cytotoxicity. 
PHARMACEUTICAL DATA: SC Injection-IV Infusion. Commercially available in 
single-dose, preservative-free vials containing 300 mcg (1 mL, 1.6 mL) and 480 mcg 
(0.8 mL) of Filgrastim-sndz. Used portions should be discarded. 
STORAGE AND STABILITY: Filgrastim-sndz should be stored at 2° to 8° C. Prior to 
injection, Filgrastim-sndz may be allowed to reach room temperature, however, any 
vials left at room temperature for greater than 24 hours should be discarded. Vials 
should not be shaken. Vials should be inspected for sedimentation or discoloration prior 
to administration. If sedimentation or discoloration is observed, the vials should not be 
used. 
KNOWN SIDE EFFECTS: Mild to moderate bone pain is possible in patients receiving 
myelosuppressive therapy. General skin rash, alopecia, fevers, thrombocytopenia, 
osteoporosis, nausea, vomiting, diarrhea, mucositis, anorexia, inflammation of the blood 
vessels, and/or cardiac dysrhythmia can occur. Splenomegaly may result at high doses 
of Filgrastim-sndz. 
6. 
Fludarabine 
THERAPEUTIC CLASSIFICATION: Antineoplastic fluorinated nucleoside analog 
 


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MECHANISM OF ACTION: After phosphorylation to fluoro-ara-ATP the drug appears 
toincorporate into DNA and inhibit DNA polymerase alpha, ribonucleotide reductase and 
DNA primase, thus inhibiting DNA synthesis.The half-life of the activated compound is 
approximately 10 hours, but the pharmacology is incompletely understood. Excretion is 
impaired in patients with impaired renal function. 
 
PHARMACEUTICAL DATA: Each vial contains 50 mg lyophilized drug, to be 
reconstituted with 2 ml sterile water to a solution that is 25 mg/ml for IV administration. 
Solution Preparation: mix each vial with 2 ml sterile pyrogen-free water to a clear 
solution, which is 25 mg/ml for IV administration only. 
 
STABILITY AND STORAGE: Reconstituted solution should be used within 8 hours. 
KNOWN SIDE EFFECTS: pancytopenia, immunosuppression, autoimmune hemolytic 
anemia has (rarely) been reported, and recurred when patients were retreated with the 
drug. Nausea, vomiting, anorexia, weakness. From the CNS: agitation, visual 
disturbances, confusion, coma, peripheral neuropathies have been reported. With high 
dose use confusion, blindness, coma and death have been reported. 
SPECIAL PRECAUTIONS: for other antineoplastic agents Fludarabine should be 
handled by trained personnel using procedures for proper handling. The use of gloves 
and protective glasses is recommended to avoid exposure upon accidental spillage. 
7. 
Melphalan 
THERAPEUTIC CLASSIFICATION: Antineoplastic alkylating agent 
MECHANISM OF ACTION: Interferes with DNA replication and transcription of RNA 
and ultimately results in the disruption of nucleic acid function. 
PHARMACEUTICAL DATA: Supplied as 50 mg vials, reconstitute in 10 ml of diluent 
STORAGE AND STABILITY: Reconstituted solution retains 90% potency for about 3 
hours at 30º C. Storage at 5º C results in precipitation. Intact packages can be stored at 
room temperature. 
 
KNOWN SIDE EFFECTS: Dose limiting toxicity is hematologic. GI toxicity is infrequent 
and mild including; nausea, vomiting, stomatitis, abdominal cramping and diarrhea. 
Azotemia has been reported. Alopecia and hypersensitivity reactions when high-doses 
are utilized. 
 
8. 
Mycophenalate Mofetil (MMF) 
THERAPEUTIC CLASSIFICATION: Immunosuppressant for GVHD prophylaxis 
MECHANISM 
OF ACTION: MPA inhibits T and B cell proliferation by blocking the 
production of guanosine nucleotides required for DNA synthesis. 
PHARMACEUTICAL DATA: Oral: 250-mg and 500-mg capsules, and as 200 mg/mL 
oral suspension. It may also be prepared extemporaneously as an oral suspension (100 
mg /mL; in cherry syrup; pH = 6.0 - 6.7; Injectable: 500 mg vial to be reconstituted in 14 
mL of D5W to yield about 15 mL containing 33.33 mg/mLof MMF. 


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STABILITY AND STORAGE: Oral: stable for at least four months at room temperature. 
Injectable: Each 500-mg vial should be reconstituted with 14 mL D5W to yield about 15 
mL of MMF solution (33.33 mg/mL) as above. The dose should be further diluted in 
D5W to a final concentration of about 6 mg/mL. The solution should not be refrigerated 
and should be administred within 4 hrs of preparation. The dose should be infused over 
at least two hrs. The manufacturer does not specify the type of container to use for 
parenteral MMF. 
KNOWN SIDE EFFECTS: constipation, diarrhea, nausea, vomiting, headache, 
confusion, tremor, gastrointestinal bleeding, hypertension, peripheral edema, cough 
exacerbation, infection, sepsis and bone marrow suppression including severe 
neutropenia. 
9. 
Rituximab 
THERAPEUTIC CLASSIFICATION: A genetically engineered chimeric/murine 
monocolonal antibody 
MECHANISM OF ACTION: The Fab domain of rituximab binds to the CD20 antigen on 
the B lymphocytes, and the Fc domain recruits immune effector functions to mediate B 
cell lysis in vitro. Possible mechanisms of cell lysis include complement-dependent  
cytotoxicity (CDC) and antibody-dependent cell mediated toxicity (ADCC). The antibody 
has been shown to induce apoptosis in the DHL-4 human B cell lymphoma line. 
PHARMACEUTICAL DATA: Rituximab is diluted in 5% Dextrose in Water or 0.9% NaCl 
to a final concentration of 1-4mg/ml and administered as an IV infusion (see section 5, 
treatment schedule). It should not be administered as a IV bolus. It s supplied as 100 
mg and 500 mg sterile, preservative free, single use vials. 
STORAGE AND STABILITY: Rituximab vials should be stored at 2-8 C. Vials should be 
protected from direct sunlight. Diluted rituximab solution is stable at 2-8 C for 24 hours 
and at room temperature for an additional 12 hours. 
KNOWN SIDE EFFECTS: Rituximab is associated with a infusion related symptom 
complex comprising of fever and chill/rigors. Other frequent infusion-related symptoms 
include nausea, urticaria, fatigue, headache, pruritis, bronchospasm, dyspnea, 
angioedema, rhinitis, vomiting, hypotension, flushing and pain at disease sites. 
10. 
Tacrolimus 
THERAPEUTIC CLASSIFICATION: A cyclic polypeptide immunosuppressive. 
 
MECHANISM OF ACTION: Macrolide antibiotic produced by Streptomyses 
tsukubaensis that inhibits T and B cell proliferation. 
 
PHARMACEUTICAL DATA: Available in 5mg/mL vials. Anhydrous is diluted in alcohol 
dehydrated 80% v/v and polyoxyl 60 hydrogenated castor oil 200 mg/mL. For IV 
infusion, solution is diluted with 0.9% sodium chloride or 5%dextrose to a concentration 
of 4-20 ug/mL. Also available in tablets; 0.5, 1, and 5 milligrams. Disposition is biphasic 
with a terminal half life of 10-30 hours. Elimination is mainly by hepatic metabolism and 
biliary excretion. 


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STORAGE AND STABILITY: The oral form is stable at room temperature protected 
from light for at least 2 months. The IV preparation is diluted in D5W or NS and is stable 
for 24 hours. 
KNOWN SIDE EFFECTS: renal failure, hepatic toxicity, hypertension, nausea, 
headache, confusion, tremor, seizures, peripheral edema, infection, sepsis and bone 
marrow suppression 
11. 
Total Body Irradiation (TBI) 
TBI may cause low blood cell counts (white blood cells, red blood cells, and platelets). 
During 
treatment there is an increased risk of infection, including pneumonia. Other side effects 
include anemia, abnormal bleeding, bruising, fatigue, and/or shortness of breath. A 
blood transfusion may be required. 
TBI may cause nausea, vomiting, mouth sores, diarrhea, esophageal pain, liver damage 
from veno-occlusive disease, and/or hair loss. It may cause cataracts, chronic injury to 
the lungs resulting from increased fibrosis, and/or destruction of lung tissue. It may 
cause an increased risk of developing other cancers. 
TBI may damage the heart and/or the lungs, which may result in shortness of breath. 
TBI may also cause swelling of and bleeding from the bladder, hepatitis, and/or 
abnormal levels of minerals in the blood. It may cause dry mouth and/or changes in 
taste. 
Fucosylation Reagents 
12. 
Alpha 1,3 fucosyltransferase-VI (FTVI) 
THERAPEUTIC CLASSIFICATION: Adhesion molecule (selectin ligand) modulator 
 
MECHANISM OF ACTION: FTVI is a glycosyltransferase that modifies terminal 
sugars known as “type 2 sialyllactosamine units”, thereby engendering expression of 
an oligosaccharide known as sialyl Lewis X (sLeX; CD15s). The sLeX motif is the 
principal E-selectin binding determinant, and is displayed on the CD44, PSGL-1, and 
CD43 glycoproteins of human CD34+ hematopoietic stem/progenitor cells (HSPCs). 
Expression of sLex 
mediates binding of human HSPCs to E-selectin-bearing 
bone marrow microvascular cells. This adhesive interaction results in homing of 
human HSPCs to bone marrow. 
 
PHARMACEUTICAL DATA: FTVI (supplied by Warrior Therapeutics) is provided as a 
frozen sterile solution in a vial containing 452 ug enzyme (at concentration of 1.19 
mg/mL) in 5% glycerol and 95% Hank’s Balanced Salt Solution without 
calcium/magnesium (i.e., HBSS without Ca/Mg). Each vial will contain requisite enzyme 
to achieve fucosylation of human umbilical cord blood cells suspended in a 50 ml 
reaction volume. Upon thawing, FTVI is a clear, colorless solution, visibly free of 
particulate material. FTVI is a reagent, used ex vivo as a critical component in the 
enzymatic fucosylation processing of human umbilical cord blood stem cells for infusion. 
 
STORAGE AND STABILITY: FTVI should be stored at -80°C (-70°C to -80°C). Once 
thawed, it should be used promptly in the fucosylation reaction. Fucosylated stem cells 


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are stable for up to 2 hours at room temperature. Unused or expired FTVI will be 
destroyed per institutional policy. 
 
KNOWN SIDE EFFECTS: None. 
 
13. Guanosine-5’diphospho--L-fucose (GDP-fucose) 
THERAPEUTIC CLASSIFICATION: Adhesion molecule (selectin ligand) modulator 
MECHANISM OF ACTION: GDP-fucose is the donor nucleotide sugar substrate utilized 
by FTVI in the aforementioned enzymatic reaction, thereby providing the needed 
missing fucose on the terminal type 2 sialyllactosamine unit(s) to create sLeX., 
 
PHARMACEUTICAL DATA: GDP-fucose (supplied by Warrior Therapeutics) is provided 
as a sterile powder of white appearance in vials packaged in amount of 31.7 mg, 
requisite to achieve a final concentration of 1 mM GDP-fucose in 50 ml reaction volume. 
For enzymatic reactions, it is reconstituted in sterile HBSS without Ca/Mg, with the 
appearance of clear, colorless solution, visibly free of particulate material. 
GDP-fucose is a reagent, used ex vivo as a critical component in the enzymatic 
fucosylation processing of human umbilical cord blood stem cells for infusion. 
 
STORAGE AND STABILITY: GDP-fucose powder is stable at room temperature and in 
the cold (i.e., it can be stored in frost-free freezers). Once reconstituted into solution, it 
should be used promptly in the fucosylation reaction. Fucosylated stem cells are stable 
for up to 2 hours at room temperature. Unused or expired GDP-fucose will be destroyed 
per institutional policy. 
 
KNOWN SIDE EFFECTS: None. 
 
4.0 Patient Eligibility 
Inclusion Criteria 
 
1. Patients must have one of the following hematologic malignancies: 
 
a. Acute Myelogenous Leukemia (AML), induction failure, high-risk for relapse first 
remission (with intermediate-risk or high-risk cytogenetics, flt3 mutation positive 
and/or evidence of minimal residual disease by flow cytometry), secondary 
leukemia from prior chemotherapy and/or arising from MDS, Langerhan's cell 
histiocytosis, any disease beyond first remission. 
 
b. Myelodysplastic Syndrome (MDS): MDS IPSS INT-1 will be enrolled only if the 
subjects have failed previous leukemia treatments and are 
transfusion-dependent. MDS may be primary or therapy related, including 
patients that will be considered for transplant. Including the following categories: 
1) revised IPSS intermediate and high risk groups, 2) MDS with transfusion 
dependency, 3) failure to respond or progression of disease on hypomethylating 


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agents, 4) refractory anemia with excess of blasts, 5) transformation to acute 
leukemia, 6) chronic myelomonocytic leukemia, 7) atypical 
MDS/myeloproliferative syndromes, 8) complex karyotype, abn(3g), -5/5g-, 
-7/7g-, abn(12p), abn(17p). 
 
c. Acute Lymphoblastic Leukemia (ALL) patients with the following will be 
considered: Induction failure, primary refractory to treatment (do not achieve 
complete remission after first course of therapy) or are beyond first remission 
including second or greater remission or active disease. Patients in first 
remission are eligible if they are considered high risk, defined as any of the 
following detected at any time: with translocations 9;22 or 4;11, hypodiploidy, 
complex karyotype, secondary leukemia developing after cytotoxic drug 
exposure, and/or evidence of minimal residual disease, or acute biphenotypic 
leukemia which includes > 7 chromosomal abnormalities, or double hit 
non-Hodgkin's lymphoma. 
 
d. Non-Hodgkin's Lymphoma (NHL) in second or third complete remission or 
relapse (including relapse post autologous hematopoietic stem cell transplant), or 
relapsed double hit lymphoma. 
 
e. Small Lymphocytic Lymphoma (SLL), or Chronic Lymphocytic Leukemia (CLL) 
with progressive disease with progression after standard of care therapy or have 
failed/been intolerant to ibrutinib. 
 
f. CML second chronic phase or accelerated phase. 
 
g. Hodgkin's Disease (HD): Induction failure after the first complete remission, or 
relapse (including relapse post autologous hematopoietic stem cell transplant), or 
those with active disease. 
 
2. The first 6 patients must be  18 and  65 years old. The subsequent patients may 
include pediatric patients  12 and  65 years old. Eligibility for pediatric patients will 
be determined in conjunction with an MDACC pediatrician. 
3. Performance score of at least 80% by Karnofsky or PS < 3 (ECOG) (age  12 
years). 
4. Adequate major organ system function as demonstrated by: 
a. Left ventricular ejection fraction of > 40% 
b. Pulmonary function test (PFT) demonstrating a diffusion capacity of least 50% 
predicted. 
c. Creatinine  1.5 mg/dL. 
d. SGPT/bilirubin  to 2.0 x normal. 
5. Negative Beta HCG test in a woman with child bearing potential defined as not 
post-menopausal for 12 months or no previous surgical sterilization and willing to 
use an effective contraceptive measure while on study. 
6. Patients must have two CB units available which are matched with the patient at 4, 
5, or 6/6 HLA class I (serological) and II (molecular) antigens. Each cord must 


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contain at least 1.5 x 10
7 total nucleated cells/Kg recipient body weight (pre-thaw). 
7. Patient must not have a 10/10 HLA matched family member or unrelated donor. 
8. Patients will have a back-up graft from any of the following: an available fraction of 
autologous marrow; or PBPCs harvested and cryopreserved; or family member 
donor; or a third cord blood unit. 
9. Prior to initiating chemotherapy in this study, twenty-one or more days must have 
elapsed since the patient's last radiation or chemotherapy administration (Hydrea, 
Gleevec and other TKI inhibitors as well as intra-thecal therapy are accepted 
exceptions). 
10. Patients enrolled in this study may be on other IND studies at the discretion of the 
PI. 
 
Patient Exclusion Criteria 
 
1. Patients with known history of HIV/AIDS. 
2. Patients with positive hepatitis serology that is definitive of active disease. 
3. Active CNS disease in patient with history of CNS malignancy. 
4. Patients with chronic active hepatitis or cirrhosis. If positive hepatitis serology, the Study 
Chair may deem the patient eligible based on the results of liver biopsy. 
5. Patients with uncontrolled serious medical condition such as persistent septicemia 
despite adequate antibiotic therapy, decompensated congestive heart failure despite 
cardiac medications or pulmonary insufficiency requiring intubation (excluding 
primary disease for which CB transplantation is proposed), or psychiatric condition 
that would limit informed consent. 
6. Pediatric patients with acute lymphoblastic leukemia (ALL) that is t (9,22) positive in 
first remission are not eligible unless there is evidence of minimal residual disease 
after initial induction and/or consolidation treatment or the pediatric Ph+ ALL is 
clinically refractory to available therapies with evidence of persistence in the bone 
marrow or peripheral blood. 
7. Patients with options for treatment that are known to be curative are not eligible. 
5.0 Treatment Plan 
The investigational component of the treatment plan of this study is the infusion of one 
MPC expanded and one fucosylated CB unit. 
 
Enrollment of the first 3 participants will be staggered by at least 30 days. The 
occurrence of two or more subjects with Grade 3 or 4 toxicities considered related or 
one death considered related within 30 days following stem cell infusion will stop further 
enrollment of study subjects and treatment with study agent pending investigation of the 
risk by the MDACC IRB and the FDA. 
 
Participant data will be collected in CORe and PDMS. A cohort summary must be 
completed and submitted to the IND Office Medical Monitor after the 3rd subject 
reaches 42 days post infusion, after the 4th subject reaches 42 days post infusion, and 
every 4 subjects thereafter. 


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Preparative regimens used in this study are commonly used for CB transplantation. The 
selection of these will depend on patient’s age, disease and co-morbid condition. 
Prior to initiating chemotherapy in this study, twenty-one or more days must have 
elapsed since the patient's last radiation or chemotherapy administration (Hydrea, 
Gleevec and other TKI inhibitors as well as intra-thecal therapy are accepted 
exceptions). Patients will have a back-up graft from any of the following: an available 
fraction of autologous marrow; or PBPCs harvested and cryopreserved; or family 
member donor; or a third cord blood unit. 
 
Study Design 
 
Once consented, the CB units will be shipped to MD Anderson. The CB unit which is the 
least well HLA-matched will be expanded with MPC while the better HLA-matched CB 
unit will be fucosylated. If both CB units have the same HLA-match, the smaller unit 
(lower total nucleated cell dose) will be expanded and larger fucosylated. 
 
Patients will be admitted to the hospital on day -11, -10, or -9 for hydration and will 
receive the designated preparative regimen as described in Preparative Regimens, 
below. 
 
The CB unit to be expanded will be thawed and undergo ex vivo expansion by 
co-culture on MPCs. Four to seven days prior to the thawing and washing of the CB 
unit that will undergo expansion, a container of MPCs is thawed and expanded into 
culture flasks. The CB unit to undergo expansion is evenly divided among 10 flasks of 
MPCs for the co-culture expansion. After 7 days of co-culture of the CB cells on the 
MPC adherent cells, the non- adherent CB cells are collected from the flasks containing 
the MPCs and transferred to cell culture bags. Culture of any residual CB cells 
remaining in the MPC flasks is also continued. Cells in both bags and flasks are 
cultured expanded for an additional 7 days. After a total of 14 days in culture, the 
non-adherent CB stem cells from both the bags and flasks are pooled together. The 
other CB unit will be incubated with GDP -fucose and the enzyme 
fucosyltransferase-VI (FT-VI) for up to 60 minutes. After incubation, the CB cells will be 
washed and immediately infused. 
 
Unmanipulated Cord Blood: The unmanipulated CB units are obtained from the 
National Marrow Donor Program, Netcord, and other suitable registries and are 
matched with the subject at 4, 5, or 6/6 HLA class I (intermediate resolution) and II (high 
resolution) loci. 
 
On day 0, the CB unit will be thawed, fucosylated, washed, and infused, followed by the 
infusion of the MPC-expanded CB unit. The infusions will be separated by a minimum of 
30 minutes. 
 
Both CB units will be administered with the use of a standard Y-type blood/solution set 
with large blood filter 170 to 260 micron filter by intravenous infusion (IV) via gravity. CB 


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units are not to be infused with the use of an infusion pump. The rate of administration 
of the CB units is not to exceed 250 mL/hour (maximum infusion rate). 
 
Unused or expired fucosylation agents will be used for validation experiments or 
destroyed per institutional policy. 
 
Figure 9 Study Design 
 
 
 
 
 
 
 
Preparative Regimens 
 
Chemotherapy agent doses and administration. 
 
Below are the regimens combination, doses and schedule.  
 
Patients with B cell malignancies will receive Rituximab (or a biosimilar of rituximab). 
 
ATG is dosed per actual body weight. 
 
Clofarabine and fludarabine are dose adjusted per body weight if patient is >20% 
expected weight. 
 
Rituximab is dosed per actual body weight. 
 
 
 
 
 


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Fludarabine/Clofarabine/Busulfan/TBI (Myeloablative Regimen) 
 
Recommended for patients who are <55 years old. Patients > 55 but < 65 years 
who have a Performance Status of 0 or 1 and no comorbidities may receive the 
myeloablative regimen at the discretion of the investigator(s). 
 
Flu-Clo-Bu-TBI 
Flu = Fludarabine 
Clo = Clofarabine 
Bu = Busulfan 
ATG = Rabbit Antithymocyte Globulin 
TBI = Total Body Irradiation (low dose) 
Patients will receive Busulfan as per standard of care. Busulfan test dose can be 
administered either as an outpatient prior to admission or as an inpatient on Day -10. 
Busulfan pharmacokinetics will be performed with the test dose and the first dose on 
Day -7 per standard of care. The doses of Days -6, -5, and -4 will be subsequently 
adjusted to target an AUC of 4,000 microMol.min-1. In the event that PK adjusting were 
not possible a dose of busulfan of 130 mg/m2 will be administered. 
 
All patients will receive echinocandins for fungal prophylaxis until patient engrafts 
neutrophils unless prior infectious history dictates an azole. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Inpatient Busulfan Test Dose Treatment Plan: 
 
 
Day 
Treatment 
-20 
(approximate) 
MPC start 
-14 
Cord culture 
-11 
Admit / IV Hydration / Rituximab 375 mg/m IV (B cell malignancy)* 
-10 
Test dose Bu 32 mg/m
2 (PK sampling) 
-9 
Rabbit ATG 1.25 mg/Kg IV 
-8 
Rabbit ATG 1.75 mg/Kg IV 
-7 
Flu 10 mg/m
2 / Clo 30 mg/m
2 / Bu AUC 4,000 (PK sampling) 
-6 
Flu 10 mg/m
2 / Clo 30 mg/m
2 / Bu AUC 4,000 
-5 
Flu 10 mg/m
2 / Clo 30 mg/m
2 / Bu AUC 4,000 
-4 
Flu 10 mg/m
2 / Clo 30 mg/m
2 / Bu AUC 4,000 
-3 
Low-Dose TBI 2 Gy in AM 
-2 
Rest 
-1 
Rest 
0 
Cord Blood Infusions 
 
 
* A biosimilar of rituximab may be used. 
 
 
 
 
 
 
 
 


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Outpatient Busulfan Test Dose Treatment Plan: 
 
 
Day 
Treatment 
Outpatient test dose BU 32 mg/m
2 (PK Sampling) 
-20 
(approximate) 
MPC start 
-14 
Cord culture 
-10 
Admit / IV Hydration / Rituximab 375 mg/m (B cell malignancy)* 
-9 
Rabbit ATG 1.25 mg/Kg IV 
-8 
Rabbit ATG 1.75 mg/Kg IV 
-7 
Flu 10 mg/m
2 / Clo 30 mg/m
2 / Bu AUC 4,000 (PK Sampling) 
-6 
Flu 10 mg/m
2 / Clo 30 mg/m
2 / Bu AUC 4,000 
-5 
Flu 10 mg/m
2 / Clo 30 mg/m
2 / Bu AUC 4,000 
-4 
Flu 10 mg/m
2 / Clo 30 mg/m
2 / Bu AUC 4,000 
-3 
Low-Dose TBI 2 Gy in AM 
-2 
Rest 
-1 
Rest 
0 
Cord Blood Infusions 
 
* A biosimilar of rituximab may be used. 
 
 
 
 
 
 
 
 
Fludarabine/Melphalan (Reduced Intensity) 


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Recommended for patients of any age that in the opinion of the investigator(s) would 
preclude myeloablative therapy. 
 
 
DAY 
TREATMENT 
-20 
(approximate) 
MPC start 
-14 
Cord culture 
-9 
Admit/Hydration 
-8 
Rabbit ATG 1.25 mg/Kg IV 
-7 
Rabbit ATG 1.75 mg/Kg IV 
-6 
Rest 
-5 
Fludarabine 40 mg/m
2 IV 
-4 
Fludarabine 40 mg/m
2 IV 
-3 
Fludarabine 40 mg/m
2 IV 
-2 
Fludarabine 40 mg/m
2 IV / Melphalan 140 mg/m IV 
-1 
Rest 
0 
Cord Blood infusions 


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Fludarabine/Cyclophosphamide/TBI 200 
 
Recommended for patients of any age that in the opinion of the investigator(s) would 
preclude myeloablative therapy. 
 
DAY 
TREATMENT 
-20 
(approximate) 
MPC start 
-14 
Cord culture 
-9 
Admit/Hydration 
-8 
ATG 1.25 mg/kg IV 
-7 
ATG 1.75 mg/kg IV 
-6 
Fludarabine 40mg/m
2 IV / Cyclophosphamide 50 mg/kg IV / 
Mesna 50 mg/kg IV 
-5 
Fludarabine 40mg/m
2 IV 
-4 
Fludarabine 40mg/m
2 IV 
-3 
Fludarabine 40mg/m
2 IV 
-2 
Rest 
-1 
TBI 200 cGy 
0 
Cord Blood infusions 
 
GVHD Prophylaxis and Supportive Care as per standard practice in patients 
receiving allogeneic transplant and SCTCT Guidelines 
 
Graft Versus Host Disease prophylaxis with Tacrolimus and MMF. Tacrolimus starting 
dose 0.03 mg/kg or 0.015 mg/kg (ideal body weight) IV starting on D -2 and will be 
tapered around D+180 if no GvHD is present. Mycophenolate (MMF) will be dosed at 
15mg/kg (actual body weight with a maximum dose of 1 gram twice daily) IV or PO 
administered from days D -3 to D +100 in the absence of GvHD. MMF can be adjusted 
based on renal function. 
 
Filgrastim-sndz dose 5 micrograms/kg/day SQ rounded to the nearest vial starting on 


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Day 0 until engraftment. For Pediatric dosing, 5 micrograms/kg/day, dose may be  
increased to 10mcg/kg/day starting on Day +21. Pediatric dosing should not be 
rounded to the nearest vial size, unless indicated by treating physician. 
 
Infectious disease prophylaxis, blood and platelet transfusion and other supportive 
treatment as clinically indicated. 
 
Birth Control 
 
All participants who are able to have children must practice effective birth control while 
on study. Acceptable forms of birth control for female patients include: hormonal birth 
control, intrauterine device, diaphragm with spermicide, condom with spermicide, or 
abstinence, for the length of the study. If the participant is a female and become 
pregnant or suspects pregnancy, she must immediately notify her doctor. If the 
participant becomes pregnant during this study, she will be taken off this study. Men 
who are able to have children must use effective birth control while on the study. If the 
male participant fathers a child or suspects that he has fathered a child while on the 
study, he must immediately notify his doctor. 
 
Concurrent Treatment 
 
Patients that develop life-threatening graft versus host disease, veno-occlusive disease, 
cytomegalovirus, adenovirus, Epstein Barr, or BK viral infections may be enrolled on an 
investigational treatment study with the approval of the principal investigator. 
6.0 Pretreatment evaluation 
The following evaluation includes standard tests performed to determine patient eligibility 
for transplant and are not required to be repeated prior to starting treatment unless 
treatment is delayed for more than 30 days after registration. 
 
1. History and physical examination. 
2. CBC, differential and platelet count. 
3. BUN, creatinine, bilirubin, alanine aminotransferase, aspartate aminotransferase. 
4. Infectious disease screening, which will include testing for HIV, Hepatitis B, Hepatitis 
C, West Nile Virus, HTLV, TPHA, and CMV. 
5. Chest X-Ray, mini sinus CT. 
6. EKG. 
7. Echocardiogram or MUGA scan. 
8. Pulmonary function tests with DLCO. 
9. Bone marrow aspirate with cytogenetics (not required if patient has circulating blasts 
and known cytogenetic results). 
10. HLA class I and II typing. 
11. Beta HCG for women of child bearing potential (not postmenopausal for 12 months; 
no prior surgical sterilization). 


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7.0 Evaluation During Study 
Post transplant Evaluations: 
 
To be performed at approximately 30 days, 3, 6, and 12 months post transplant. These 
evaluations follow our standard practice and are done to determine engraftment and 
disease status. If clinically indicated these studies may be done at other time points which 
can replace the nearest planned timepoint. 
 
1. Chimerism studies from peripheral blood performed on separated T-cells and 
myeloid cells. 
2. At each visit, a physical examination and adverse event documentation including 
GvHD assessment. 
3. The following lab tests are to be performed as frequently as clinically indicated: 
CBC, differential, platelets, SGPT, calcium, glucose, uric acid, magnesium, serum 
bilirubin, BUN and creatinine, serum protein, albumin, alkaline phosphatase, 
electrolytes, urinalysis, tacrolimus levels and CMV antigenemia. 
4. Disease specific assessment as per standard of care and the Stem Cell 
Transplantation and Cellular Therapy Department guidelines. 
 
Additional lab tests: 
 
Additional lab draws may be requested to monitor the cord blood units and patient 
disease status. The patient may be asked to sign a separate consent for protocol 
LAB00-099 for these additional samples. Analysis will be performed in Dr. Katy 
Rezvani's Lab free of charge for the patient. Analysis results from these samples 
performed under protocol LAB00-099 will be used in protocol 2016-0051. 
8.0 Statistical Considerations 
This is a phase 2 clinical trial in which patients with hematologic malignancies following 
high-dose therapy will receive one MPC expanded CB unit plus one fucosylated CB unit 
in the DUCBT setting. The CB unit which is the least well HLA-matched will be 
expanded with MPC co-culture while the better HLA-matched CB unit will be 
fucosylated. If both CB units have the same HLA-match, the smaller unit (lower total 
nucleated cell dose) will be expanded for 14 days while the larger will be fucosylated 
with FTVI and GDP-fucose both as previously described in the body of this protocol. CB 
infusion of the fucosylated unit is to take place on day 0 after infusion of the first, 
unmanipulated CB unit. 
 
We define feasibility as having a sterile expanded MPC product and/or fucosylation a 
>50% fucosylated unit in the majority of the patients enrolled. 
 
Enrollment of the first 3 participants will be staggered by at least 30 days. The 
occurrence of two or more subjects with Grade 3 or 4 toxicities considered related or 
one death considered related within 30 days following stem cell infusion will stop further 


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enrollment of study subjects and treatment with study agent pending investigation of the 
risk by the MDACC IRB and the FDA. 
 
Monitoring Time to Engraftment. The distribution of time to engraftment will be 
estimated using Kaplan-Meier plots and the relationship to covariates evaluated by 
piecewise exponential Bayesian regression. Time to engraftment will be monitored by 
the Bayesian statistical method of Thall et al., assuming an accrual rate of 10 patients 
per year with a maximum sample size of 25 patients. A mean time to engraftment 
(TTE) of 7 days will be considered desirable and a mean TTE of 21 days will be 
considered undesirable. The design is based on the assumptions that mS = standard 
(historical) mean time-to-engraftment follows an informative Inverse Gamma (51, 350) 
prior, with a mean of 7 days and variance of 1, and that mE follows a non-informative 
Inverse Gamma (2.49, 10.43) prior, which also has a mean of 7 days but a much larger 
variance of 100. The possibly right-censored times time-to-engraftment will be 
monitored continuously throughout the trial. Accrual will be terminated due to futility if 
at any time during the trial Prob(mE < mS | data) < .0985. This cut-off was chosen to 
ensure a small early stopping probability if the true mean time to engraftment = 7 days 
(median = 4.85 days). The operating characteristics of this monitoring rule were 
computed using the program TTEDesigner version 1.2.2, available from the MDACC 
Department of Biostatistics (Table 3). The trial will be conducted using the Clinical 
Trials Data Monitoring website maintained by the Department of Biostatistics at 
MDACC. 
 
Table 3. Operating characteristics of the design for monitoring time-to-engraftment, with 
maximum samples size 25. 
 
True Mean Time 
to Engraftment 
(days) 
True Median Time 
to Engraftment 
(days) 
True Prob of 
Engraftment 
within 7 days 
Pr (Stop Early) 
Mean Sample Size 
7 
4.85 
0.37 
0.14 
22.8 
21 
14.56 
0.05 
1.0 
4.0 
 
Infusion-related mortality (IRM) is defined as death within 24 hours that is definitely 
related to the stem cell infusion. Accrual will be terminated if any IRM is observed. 
 
Monitoring GVHD. GVHD4 = grade 4 graft-versus host disease within 42 days will be 
monitored using the Bayesian statistical method of Thall and Sung (1998), Denoting pE 
= Pr(GVHD4 with the experimental therapy), the historical value .20 will be considered 
acceptable and .40 unacceptable. Assuming that pE follows an uninformative 
beta(.20,.80) prior, and that the historical probability pS follows an informative 
beta(200,800) prior, accrual will be terminated early if Pr( pS < pE | data) > .95. 
Applying this rule after each cohort of 4 patients, the trial will be stopped if [# patients 
with GVHD4] / [# patients evaluated ] is greater than or equal to 3/4, 4/8, 6 /12, 7/16, 8 
/20 or 9/24. For (undesirably high) true p = .40, this rule has early stopping probability is 
.75, with sample size quartiles (8, 16, 25). For (acceptably low) true p = .20, the early 
stopping probability is .10 with sample size quartiles (25, 25, 25). 
 


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Secondary outcomes include disease-free survival, TRM, and OS.   
The distributions of disease-free survival and overall survival time will be estimated 
using Kaplan-Meier plots and their relationships to covariates evaluated by piecewise 
exponential Bayesian regression. TRM will be evaluated by tabulation, Kaplan-Meier 
plots, and piecewise exponential Bayesian regression. TRM will be evaluated by 
tabulation, Kaplan-Meier plots, and piecewise exponential Bayesian regression. 
9.0 Criteria for Response 
Disease Response Is defined according to disease specific criteria as per the CIBMTR. 
 
Engraftment is defined as the evidence of donor derived cells (more than 95%) by 
chimerism studies in the presence of neutrophil recovery by day 28 post cord blood 
infusion. 
 
Other definitions used to assess engraftment: 
 
Neutrophil recovery is defined as a sustained absolute neutrophil count (ANC) > 0.5 x 
10
9 /L for 3 consecutive days. 
 
Engraftment date is the first day of three (3) consecutive days that the ANC exceeds 
0.5 x10
9 /L. 
 
Delayed engraftment is defined as the evidence of engraftment beyond day 28 post 
blood unit infusion achieved after the administration of therapeutic (high dose) 
hematopoietic growth factors. 
 
Primary Graft failure is defined as failure to achieve an ANC > 0.5 x 10
9 /L for 3 
consecutive days by day 28 post cord blood infusion, with no evidence of donor derived 
cells by bone marrow chimerism studies and no evidence of persistent or relapsing 
disease. 
 
Secondary graft failure is defined as a sustained declined of ANC <0.5 x 10
9 /L for 7 
consecutive days unresponsive to hematopoietic growth factors in the absence of 
relapse after initial documented engraftment or loss of donor chimerism in the absence 
of leukemic relapse. 
 
Autologous reconstitution is defined by the presence of ANC > 0.5 x 10
9 /L without 
evidence of donor-derive cells by bone marrow chimerism studies. This can occur at 
initial engraftment or later after initial engraftment has been documented. 
 
Treatment of Engraftment Failure. Will be further defined according to patient's 
condition and type of graft available following the SCT&CT guidelines for treatment of 
graft failure. 


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10.0 Criteria for Removal from the Study 
Any patient can be removed from study for the following: 
 
- 
Patient withdrawal of the informed consent 
 
- 
Patient not being compliant 
 
- 
An increasing or unexpected pattern of toxicity is observed deemed unacceptable by 
the study chairman 
 
- 
Disease progression 
 
- 
Investigator judgment when the well being and best interest of the patient is 
compromised 
 
- 
Primary or Secondary Graft Failure 
 
- 
Death 
 
- 
One year from treatment completion 
 
11.0 Adverse Events and Reporting Requirements 
Assessment of the Adverse Events Severity 
 
The severity of the adverse events (AEs)  Grade 3 will be graded according to the 
Common Terminology Criteria v4.0 (CTCAE) from the start of preparative regimen up to 
D+100. Events not included in the CTCAE chart will be scored as follows: 
 
General grading: 
 
Grade 1: Mild: discomfort present with no disruption of daily activity, no treatment 
required beyond prophylaxis. 
 
Grade 2: Moderate: discomfort present with some disruption of daily activity, require 
treatment. 
 
Grade 3: Severe: discomfort that interrupts normal daily activity, not responding to first 
line treatment. 
 
Grade 4: Life Threatening: discomfort that represents immediate risk of death 
Grading for specific syndromes: Veno-occlusive disease (VOD): 
Grade 3: Bili >2mg/dl with at least two of the following: increased weight >4% from 


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baseline, ascites or hepatomegaly 
Grade 4: pulmonary and or renal failure 
Pulmonary events not caused by CHF (interstitial pneumonitis (IP), pulmonary 
hemorrhage (DAH): 
 
Grade 1: CXR showing mild infiltrates or interstitial changes Grade 2: mild SOB 
 
Grade 3: requires supplemental oxygen, or is a documented infection Grade 4: requires 
intubation 
 
Thrombotic thrombocytopenic purpura (TTP): Grade 1: No treatment required 
 
Grade 2: Requires steroids and/or plasma transfusions Grade 3: Requires plasma 
exchange 
 
Cytokine storm or engraftment syndrome: Grade 1: No treatment required Grade 2: 
Treatment required 
 
Grade 3: Organ dysfunction Grade 4: Total Bilirubin >5 
Hemorrhagic Cystitis: 
Grade 1: minimal or microscopic bleeding/pain Grade 2: gross bleeding/pain and 
spasms 
 
Grade 3: transfusion/irrigation required Grade 4: dialysis required 
 
Causality Assessment 
 
The investigational component of the treatment plan of this study is the infusion of an 
MPC-expanded, then fucosylated CB unit in conjunction with an unmanipulated CB unit. 
 
The infusion of an MPC-expanded then fucosylated CB unit has not been fully tested in 
humans and the side effects are not well understood. Therefore, for the purpose of this 
study when in the presence of an adverse event which a direct relationship to the 
fucosylated CB unit is supected, the casualty of the event will be attributed to the 
fucosylation plus MPC expansion. 
 
In this study the treatment plan (preparative regimen followed by infusion of both CB) is 
defined as the “transplant package”. Therefore, events known to be caused by 
components of the transplant package and its direct consequences as well as those 
events known to be related to drugs used for the treatment of GVHD, infections and 
supportive treatment will be scored as unrelated to the fucosylation. 


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The principal investigator will be the final arbiter in determining the casualty 
assessment. 
 
List of most common expected adverse events 
 
1. Infections in the presence or absence of neutropenia: fungal, bacterial and or viral 
infections. 
2. Fever: Non-neutropenic or neutropenic without infection 
3. Acute graft versus host disease (aGVHD): most commonly manifested by skin 
rash, diarrhea and abnormal liver function tests could also present with some 
degree of fever, upper gastrointestinal symptoms (nausea and vomiting) mucositis 
and eye dryness. 
4. Gastrointestinal (GI tract): the GI tract manifestations could be not only due to 
direct damage from the preparative regiment but also be a manifestation of GVHD 
or infections. Therefore, the time, course, and its presentation are crucial when 
assessing these as adverse events. Nausea/vomiting, mucositis, and diarrhea 
when presented within first 7 to 10 days most likely will be related to the 
preparative regimen. 
5. Skin rash: not related to GVHD could be caused by chemotherapy used for the 
preparative regimen or antibiotics used as supportive treatment. 
6. Transaminitis: liver function test elevation. 
7. Pulmonary events: not related to CHF most likely caused by drug injury or 
infection. These could present with a pneumonitis pattern manifested with 
shortness of breath, pulmonary infiltrates on chest radiograph, sometimes 
accompanied by fever and cough and progress to acute respiratory insufficiency 
and a diffuse bilateral alveolar pattern. 
8. Cytokine Storm/ engraftment syndrome: most likely caused by released cytokines. 
9. Hemorrhagic cystitis: not related to chemotherapy agents used in the proposed 
preparative regimen is most likely caused by viral infection. 
10. Thrombotic thrombocytopenic purpura (TTP). 
11. Veno-occlusive Disease of the Liver (VOD): known to have a higher incidence in 
patients undergoing high dose chemotherapy. Some antimicrobial agents have 
been also incriminated in its development. 
12. Fluid overload due to hydration required for conditioning regimen, blood product 
transfusions and or IV alimentation 
13. Graft failure. 
14. Chronic GVHD. 
15. For the purpose of this study the following events would not be considered adverse 
events and would not be recorded in the database: 
1. Flu-like symptoms not associated with infection 
3. Abnormal laboratory findings considered associated to the original disease 
4. Isolated changes in laboratory parameters such as electrolyte, magnesium 
and metabolic imbalances, uric acid changes, elevations of ALT, AST, LDH 
and alkaline phosphatase. 
 
 


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Adverse events considered serious 
 
1. 
Prolonged hospitalization due to infections and/or organ failure requiring extensive 
supportive care (i.e. dialysis, mechanical ventilation). 
2. 
Readmissions from any cause resulting in a prolonged hospitalization (>10 days). 
3. 
Graft Failure/ rejection. 
4. 
Any expected or unexpected event resulting in an irreversible condition and/or 
leading to death. 
 
Adverse events data collection 
 
Adverse events will be collected in PDMS/CORe as applicable. 
 
From the start of preparative regimen up to D+100 the collection of adverse events will 
reflect the onset and resolution date and maximum grade; beyond this point some 
events considered related to chronic GVHD or late complications post transplant might 
be recorded only with the first date of their awareness with no grade or resolution date. 
Intermittent events should be labeled as such and followed until resolution. 
 
If a patient is taken off study while an event is still ongoing, this will be followed until 
resolution unless another therapy is initiated. Pre-existing medical conditions will be 
recorded only if an exacerbation occurs during the active treatment period. Co-morbid 
events will not be scored separately. 
 
Adverse events will be documented based on progress notes, including the flowsheet, 
in the electronic patient medical record (EPIC). 
 
PDMS/CORe will be used as the electronic case report form for this protocol and all 
protocol specific data will be entered into PDMS/CORe. 
 
Concurrent medication 
 
As stated in the treatment plan, patients treated on this protocol will require supportive 
care treatment (concurrent medications). These medications are considered standard of 
care and have no scientific contributions to the protocol, therefore no data will be 
captured on the various medications needed or their side effects. 
 
Serious Adverse Events Reporting (SAE) 
 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of 
either the investigator or the sponsor, it results in any of the following outcomes: 
 
 
Death 
 
A life-threatening adverse drug experience – any adverse experience that places the 
patient, in the view of the initial reporter, at immediate risk of death from the adverse 
experience as it occurred. It does not include an adverse experience that, had it 


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occurred in a more severe form, might have caused death. 
 
Inpatient hospitalization or prolongation of existing hospitalization 
 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
 
A congenital anomaly/birth defect. 
 
Incidence of acute graft versus host disease (GVHD)  Grade 3 over 50%. 
 
CTCAE grade  3 reactions related to the study cell infusion. 
 
CTCAE grade  3 organ toxicity (cardiac, dermatologic, gastrointestinal, hepatic, 
pulmonary, renal/genitourinary, or neurologic) not preexisting or due to the 
underlying malignancy and occurring within 30 days of study product infusion. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based 
upon appropriate medical judgment, they may jeopardize the patient or subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse (21 CFR 312.32). 
 
 
Important medical events as defined above, may also be considered serious 
adverse events. Any important medical event can and should be reported as 
an SAE if deemed appropriate by the Principal Investigator or the IND 
Sponsor, IND Office. 
 
All events occurring during the conduct of a protocol and meeting the definition of a 
SAE must be reported to the IRB in accordance with the timeframes and procedures 
outlined in “The University of Texas M. D. Anderson Cancer Center Institutional 
Review Board Policy for Investigators on Reporting Unanticipated Adverse Events 
for Drugs and Devices”. Unless stated otherwise in the protocol, all SAEs, expected 
or unexpected, must be reported to the IND Office, regardless of attribution (within 5 
working days of knowledge of the event). 
 
All life-threatening or fatal events, that are unexpected, and related to the study 
drug, must have a written report submitted within 24 hours (next working day) of 
knowledge of the event to the Safety Project Manager in the IND Office. 
 
Unless otherwise noted, the electronic SAE application (eSAE) will be utilized 
for safety reporting to the IND Office and MDACC IRB. 
 
Serious adverse events will be captured from the time of the first 
protocol-specific intervention, until 30 days after the last dose of drug, unless 
the participant withdraws consent. Serious adverse events must be followed 
until clinical recovery is complete and laboratory tests have returned to 
baseline, progression of the event has stabilized, or there has been acceptable 
resolution of the event. 
 
Additionally, any serious adverse events that occur after the 30 day time 
period that are related to the study treatment must be reported to the IND 
Office. This may include the development of a secondary malignancy. 


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Reporting to FDA: 
 
 
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project 
Manager IND Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure serious adverse 
events are reported according to the Code of Federal Regulations, Good Clinical 
Practices, the protocol guidelines, the sponsor’s guidelines, and Institutional 
Review Board policy. 
 
 


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