Clinical trial NCT01816230
Conditions: Hematological Malignancies Acute Lymphoblastic Leukemia (ALL) Acute Myeloid Leukemia (AML) Myelodysplastic Syndrome (MDS)
Sponsor: Gamida Cell ltd
Start date: 2013-04-01; Completion date: 2018-06-01
Enrollment: 36 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
A Study Evaluating the Safety and Efficacy of Transplantation of a single cord blood unit (CBU) of NiCord®, umbilical cord blood-derived Ex Vivo Expanded Stem and Progenitor Cells in Patients with Hematological Malignancies.

Detailed description:
Umbilical cord blood (UCB) is an alternative stem cell source for hematopoietic stem cell transplantations (HSCT) and can be used for the treatment of various life-threatening diseases, such as hematological malignancies or genetic blood disorders, in such cases where a matched related stem cell donor is not available. However, the major drawback of using this valuable stem cells source is the limited cell dose in a single cord blood unit (CBU), which was shown to be associated with inadequate hematopoietic reconstitution and high risk of transplant-related mortality. To improve outcomes and extend applicability of UCB transplantation, one potential solution is ex vivo expansion of UCB-derived stem and progenitor cells. NiCord® is a stem/progenitor cell based product composed of ex vivo expanded allogeneic UCB cells. NiCord® is based on a novel technology for the ex vivo cell expansion of cord blood derived hematopoietic progenitor cells. By increasing the number of the short and long-term reconstitution progenitor cells transplanted, NiCord® has the potential to enable the broader application of UCB transplantation, and improve the clinical outcomes of UCB transplantation.

The study is designed as a multi center, single arm study, evaluating the safety and efficacy of the transplantation of NiCord® to patients with hematological malignancies following myeloablative therapy.

Total study duration is approximately 400 days from the signing of informed consent to the last visit one year following transplantation

The overall study objective is to evaluate the safety and efficacy of NiCord®: single ex-vivo expanded cord blood unit transplantation in patients with hematological malignancies following myeloablative therapy as follows:

The main study objectives are to assess the cumulative incidence of patients with NiCord®-derived neutrophil engraftment at 42 days following transplantation and to assess the incidence of secondary graft failure at 180 days following transplantation of NiCord® Ten evaluable patients recruited for the study should be 12-65 years of age, up to a maximum of 15 treated patients.

Arms: arm 1: NiCord® is a stem/progenitor cell based product composed of ex vivo expanded allogeneic UCB cells.
Interventions: intervention 1: NiCord®
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 
 
 
GC P#03.01.020 
 
Date: August 24, 2015 
 
NiCord® Single CBU Protocol 
 
Page 1 
 
 
Study Title 
 
 
Allogeneic Stem Cell Transplantation of NiCord®, Umbilical Cord Blood-derived Ex 
Vivo Expanded Stem and Progenitor Cells, in Adolescent and Adult Patients with 
Hematological Malignancies 
 
Study Chairs 
Mitchell Horwitz, MD 
 
 
Guillermo F. Sanz, MD PhD 
Duke University Medical Center 
 
Hospital Universitario y Politecnico La Fe 
 
 
Clinical Phase 
 
 
Phase I/II  
 
Product: 
 
 
 
NiCord® 
 
IND Number: 
 
 
14459 
 
EudraCT Number:  
 
2014-000074-19 
 
Sponsor 
 
Gamida Cell Ltd. 
PO Box 34670 
Jerusalem 91340 
Israel 
Tel: 972-2-6595666 
Fax:  972-2-6595616 
 
Director, Medical Affairs  
 
Einat Galamidi Cohen, M.D. 
Protocol No.  
 
 
GC P#03.01.020 
Amendment #  
 
 
V 
Dated                                               
August 24, 2015 
 
 
 
 
 
 
 
 
This clinical study will be conducted in accordance with the Sponsor's Standard 
Operating Procedures (SOPs), this protocol, current Good Clinical Practice (GCP), the 
Declaration of Helsinki, the provisions of International Conference on Harmonization 
(ICH) Guidelines and all local applicable laws and regulations. 
 
 
CONFIDENTIAL 
The information in this document is considered privileged and confidential, and may not 
be disclosed to others except to the extent necessary to obtain Institutional Review Board 
(IRB)/Ethics Committee (EC) approval, written informed consent and the approval of 
local regulatory authorities as required by local law. 
 


 
 
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Table of Contents 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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SPONSOR PROTOCOL APPROVAL PAGE 
 
Protocol Title:  Allogeneic Stem Cell Transplantation of NiCord®, Umbilical Cord 
Blood-derived Ex Vivo Expanded Stem and Progenitor Cells, in Adolescent and Adult 
Patients with Hematological Malignancies 
 
 
Clinical Phase 
 
 
Phase I/II  
 
 
Protocol Number:   
 
GC P#03.01.020 
 
 
 
Approved by: 
 
Director, Medical Affairs  
 
Einat Galamidi Cohen, M.D. 
 
 
 
___________________________________  
___________________________ 
Signature  
 
 
 
 
 
Date 
 


 
 
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Protocol Title:  Allogeneic Stem Cell Transplantation of NiCord®, Umbilical Cord 
Blood-derived Ex Vivo Expanded Stem and Progenitor Cells, in Adolescent and Adult 
Patients with Hematological Malignancies 
 
 
Clinical Phase 
 
 
Phase I/II  
 
 
Protocol Number:   
 
GC P#03.01.020 
 
1. 
INVESTIGATOR’S AGREEMENT 
I have carefully read the foregoing protocol including all appendices and agree that it 
contains all the necessary information for conducting the study safely. 
I will conduct this study in strict accordance with this protocol and according to the 
current GCP regulations and will attempt to complete the study within the time 
designated. 
 
I will provide copies of the protocol and all other information relating to pre-clinical and 
prior clinical experience submitted by the Sponsor to all personnel responsible to me who 
participate in the study. I will discuss this information with them to ensure that they are 
adequately informed regarding the drug and conduct of the study. 
 
I agree to keep records on all subject information (CRFs, shipment, and all other 
information collected during the study) in accordance with the current GCP and local 
regulations. 
 
 
 
Principal Investigator’s Name 
 
 
 
 
Signature 
 
 
 
 
Date 
 
 
 
 
Institution 
 
 
 
 
 


 
 
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2. 
STUDY SYNOPSIS 
Protocol Number 
GC P# 03.01.020 
 
Protocol Title  
Allogeneic Stem Cell Transplantation of NiCord®, Umbilical Cord Blood-derived Ex 
Vivo Expanded Stem and Progenitor Cells, in Adolescent and Adult Patients with 
Hematological Malignancies 
 
Number of Centers and Planned Geographical Distribution 
Multicenter, multinational 
 
Clinical Phase 
Phase I/II 
 
Investigational Product    
NiCord® is a cryopreserved stem/progenitor cell based product _____________________ 
________________________________________________________________________
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________________________________________________________________________
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__________________________________________________________kept frozen until 
they are infused on the day of transplantation. 
Study Duration 
Total study duration per patient is approximately 400 days from the signing of informed 
consent to the last visit one year following transplantation.  An accrual period of 28 
months is estimated to obtain 40 evaluable patients.  The trial ends when the last patient 
completes their last visit.  
Study Objectives  
The overall study objective is to evaluate the safety and efficacy of NiCord®: single ex-
vivo expanded cord blood unit transplantation in patients with hematological 
malignancies following myeloablative therapy as follows:  
Primary Objectives 
• Assess the cumulative incidence of patients with NiCord®-derived neutrophil 
engraftment at 42 days following transplantation.  
• Assess the incidence of secondary graft failure at 180 days following 
transplantation of NiCord® 
 
 


 
 
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Secondary Objectives 
• Time from infusion to neutrophil engraftment 
• Time from infusion to platelet engraftment 
• Incidence of platelet engraftment at 100 days  
• Proportion of non-relapse mortality at 100 days 
• Incidence of acute GvHD grade II-IV and III-IV at 100 days 
• Incidence of chronic GvHD (limited or extensive) at 180 days and 1 year 
• Incidence of secondary graft failure at 1 year following transplantation of 
NiCord® 
• Overall survival at 180 days and 1 year 
• Safety and tolerability of NiCord® transplantation 
 
Exploratory Objectives  
• Immune reconstitution at 70, 100, 180, and 365 days 
 
Study Hypothesis 
 
Transplantation of NiCord® following myeloablative conditioning in patients with 
hematological malignancies will provide sustained engraftment. 
Study Design  
This is an open-label, non-randomized, interventional, single group assignment study of 
NiCord® in adolescent and adult patients suffering from hematological malignancies. 
Once an optimally matched CBU has been identified and the patient (or legal guardian) 
signed the informed consent (IC), the patient will be screened for the study. 
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________________________________________________________________________
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Number of Patients  
40 evaluable patients, up to a maximum of 50 treated patients.  
Inclusion Criteria 
1. Patients must be 12-65 years of age  
2. Patients with one of the following hematologic malignancies: 
▪ ____________________________________________________ 
a. _________________________________________________________
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b. ____________________________ 
i. 
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▪ ______________________________________________________
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________________________________________________________________________
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Exclusion Criteria 
 
1. __________________________________ 
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11. __________________________________________________________________
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Statistical Considerations 
 
The sample size for the study was not determined by statistical power considerations. 
Descriptive statistics will be applied to the results of all data from primary and secondary 
assessment. 
Primary End-point and Principal Analysis:  
Neutrophil engraftment is defined as achieving an absolute neutrophil count (ANC) 
greater than or equal to 0.5 x 109/L on 3 consecutive measurements on different days with 
donor chimerism (< 10% host cells by peripheral blood chimerism) within 42 days of 
transplant. The day of neutrophil engraftment is designated as the first of the 3 
consecutive measurements. 
Secondary graft failure consists of documented neutrophil engraftment, followed by 
severe neutropenia (<0.5 x 109/L for three or more consecutive laboratory values on 
separate days) with marrow cellularity <5%, without subsequent improvement occurring 
either spontaneously or after growth factor treatment. 
Interim Analysis and Safety Assessment Guidelines:  
The data emerging from this study will be reviewed by an independent DMC. This 
committee will review the accumulated data after 3 patients have entered the study and 
have been assessed at day 100 following the transplant. A 4th patient may be transplanted 
prior to DMC review. At this initial review, the DMC will monitor in particular: any 
occurrence of primary or secondary graft failure, as well as any substantial decrease in 
donor chimerism (especially myeloid chimerism), or evidence of impending graft failure, 


 
 
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as well as all study data in general. A subsequent DMC review will occur after 3 patients 
receive the cryopreserved NiCord product and have been assessed at day 100 following 
transplant.  Recruitment may continue during the follow-up of the third cryopreserved 
NiCord recipient.  The committee will make recommendations to the Sponsor regarding 
early stopping or study modification.  
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In addition to monitoring the overall study events, the above stopping guidelines will also 
be applied to each of the individual conditioning regimens separately.  Therefore, if one 
of the guidelines is met with respect to patients transplanted following a specific 
conditioning regimen, but not with respect to the overall study enrollment, then further 
use of that conditioning regimen will be prohibited until the DMC reviews the data and 
provides recommendations to the Sponsor regarding further use or modification of the 
conditioning regimen.  
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i. 
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ii. 
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NiCord® Single CBU Protocol 
Figure 1:  Study Scheme 
 


 
 
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3. 
INTRODUCTION 
3.1. Overview 
Successful blood and marrow transplantation (BMT) requires the infusion of a sufficient 
number of hematopoietic stem/progenitor cells (HSPCs), capable of both homing to the 
bone marrow and regenerating a full array of hematopoietic cell lineages with early and 
late repopulating ability in a timely fashion(Cottler-Fox[1],. 
Despite the development of large international volunteer donor registries, less than 50% 
of unrelated donor searches result in identification and availability of a suitably matched 
donor graft. Donor searches for recipients of non-Northern-European descent result in 
even lower success. Umbilical cord blood (UCB) is an alternative stem cell source for 
hematopoietic stem cell transplantations (HSCT) and is clinically in use for the treatment 
of diverse life-threatening diseases, such as hematological malignancies or genetic blood 
disorders. UCB grafts have been used in over 20,000 stem cell transplant recipients and 
provide an alternative source of stem cells in cases where a matched related or unrelated 
stem cell donor are unavailable. There are numerous advantages to UCB as a 
transplantable graft source. These include the ease of procurement, the absence of risk to 
the donor, the reduced risk of transmissible infections, and the availability for immediate 
use, potentially reducing a long wait and risk of disease progression - particularly 
important for patients with acute leukemia[Wagner 2009[2]; Aljitawi 2012[3] ]. However, a major 
drawback of UCB is the low stem cell dose available for transplantation, compared to 
mobilized peripheral blood (PB) or bone marrow[Aljitaw 2012[3]]. This low stem cell dose can 
compromise the chances of engraftment and contributes to delayed kinetics of neutrophil 
and platelet recovery (Yamazaki, Kuwana et al. 2006[4]). The delay in graft function may negatively 
impact transplant outcome [Brunstein, Gutman et al. 2010 [5] ; Ramirez, Brunstein et al. 2010[6]] and prolong 
the duration of hospitalization and costly supportive care measures.  
The transplant community has been actively engaged in developing methods to address 
the cell dose issue in cord blood transplantation (CBT), which is most acute in adolescent 
and adult recipients. Several approaches were developed, including dual umbilical cord 
blood transplantation (DCBT) and ex vivo expansion of UCB stem cells. Although to date 
no prospective clinical trials on the efficacy of single cord versus double cord in adults 
have been published, the DCBT has become standard practice in CBT for recipients in 
whom a single CBU of adequate cell dose is unavailable.[ Cottler-Fox [1], MacMillan, Weisdorf et al. 
2009 [7]; Brunstein, Gutman et al. 2010[5]; Ramirez, Brunstein et al. 2010[6]; Stanevsky, Shimoni et al. 2010[8]] Ex vivo 
expansion is still an experimental approach.  Published data of clinical studies evaluating 
this approach are discussed in section 3.2.  
NiCord® is a stem/progenitor cell-based product composed of ex vivo expanded 
allogeneic cells from one entire unit of UCB. NiCord® was developed based on the 
finding that Nicotinamide (NAM), a form of vitamin B3, delays differentiation and 
increases functionality of ex vivo expanded hematopoietic progenitor cells. Pre-clinical in 


 
 
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vitro and in vivo studies performed by the Sponsor demonstrated that ex vivo expansion 
of CD34+ cells in a NAM-containing culture system increases the fraction of early  
stem/progenitor cells within the expanded cell graft, and augments bone marrow homing 
and engraftment. Based on these results the Sponsor believes that NiCord® has the 
potential to enable broader application and improvement of clinical outcomes of UCB 
transplantation.  
The chief aim of the proposed study is to evaluate the safety and efficacy of NiCord® 
transplantation in a single cord blood unit (CBU) study in patients with hematological 
malignancies. 
Currently, NiCord® is being investigated in two pilot studies in a DCBT configuration, as 
described in Section 3.5 (the first study has been completed). In these pilot studies, the 
DCBT platform serves as a model to evaluate both the safety of use of a manipulated 
graft and enables the simultaneous tracking of the contribution of NiCord® to short- and 
long-term hematopoietic recovery and its relative contribution to the myeloid and 
lymphoid hematopoietic lineages reconstitution. 
The study GC P#01.01.020 was launched in September 2010 and completed follow-up in 
February 2013. A total of eleven patients were enrolled and transplanted with NiCord®. 
The study GC P#02.01.020 was initiated in May 2012 and as of December 17, 2013, five 
patients have been transplanted with NiCord®.  Both of these studies are evaluating the 
safety and efficacy of NiCord® transplantation in combination with a second, 
unmanipulated CBU in patients with hematological malignancies or sickle cell disease, 
respectively.  
3.2. The Use of DCBT and Ex-Vivo Expansion to Overcome the Cell 
Dose Limitation in CBT 
The following section provides a review of literature describing the advantages and 
disadvantages of the DCBT modality and published data describing the expansion 
technologies evaluated in DCBT studies.  
The DCBT approach is now standard practice for adolescent and adult recipients for 
whom a single UCB of adequate size is unavailable. Phase II non-comparative studies, 
and retrospective comparisons, suggest that by adding a second CBU, successful 
engraftment can be achieved at a rate that is comparable to a UCB transplantation using a 
single adequately sized CBU[(Verneris, Brunstein et al. 2009[9]]. Transplant-Related Mortality 
(TRM) and overall survival appear to be comparable in single and double CBT 
modalities. The use of DCBT as a transplant modality has been shown to possibly reduce 
the risk of relapse in patients with less advanced leukemia[ Stanevsky, Shimoni et al. 2010[8]; Sideri, 
Neokleous et al. 2011[10]]; however this may be associated with a slight increase in the risk of 
graft-versus-host disease (GvHD)[ (Verneris, Brunstein et al. 2009[9]].  Viability of UCB stem cells 
is a prerequisite for successful engraftment. Adequate viability cannot be confirmed until 
the CBU is thawed on the day of transplantation. The DCBT approach increases the 
chance that a highly viable CBU is provided to the patient[ Scaradavou, Smith et al. 2009[11]].  
Importantly, despite the increased cell dose provided by DCBT, time-to-neutrophil and 


 
 
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platelet engraftment (engraftment kinetics) and engraftment rates appear to be 
comparable between single and double CBT[ Sideri, Neokleous et al. 2011[10]].  Thus the use of 
DCBT does not appear to improve the hematopoietic recovery following transplantation. 
Another confounding topic to consider is that in DCBT usually only one of the two CBUs 
engrafts. Early after transplantation (day 21) both CBUs contribute to hematopoiesis in 
40–50% of patients, but by day 100, one CBU predominates in the vast majority of 
patients.[ Ramirez, Wagner et al. 2012[12]] The mechanism of single donor dominance is likely to be 
multi-factorial, involving intrinsic features of the CBUs such as homing properties and 
proliferative potential of the stem cells, graft-graft interactions mediated by T-cell 
interactions, as well as host-graft interactions. No reproducible association has been 
found between CBU characteristics such as median infused total nucleated cells (TNC), 
CD34+, and CD3+ cell doses and unit dominance[ Majhail, Brunstein et al. 2006 [13]], therefore the 
dominant CBU cannot yet be predicted. It has been postulated that graft-versus-graft 
immune interactions are the principal mechanism promoting the engraftment of a single 
CBU in patients undergoing DCBT. Delaney et al[ Newell, Milano et al. 2012 [14]] have 
demonstrated that early CD3+ PB chimerism predicts the long-term engrafting CBU 
following myeloablative DCBT. The correlation of higher early post-transplant donor 
CD3+ PB chimerism with the dominant CBU suggests a rapid immune mediated response 
as a primary mechanism of action for long-term single donor dominance. In vivo[ Eldjerou, 
Chaudhury et al. 2010 [15]] and in vitro[ Moretta, Andriolo et al. 2012 [16]] studies also suggest that the 
predominant CBU in the setting of double CBT is the CBU able to develop a prevalent 
cytotoxic activity directed against activated lymphocytes and HSC graft of the other 
CBU. The time needed for the predominant CBU to overcome the other CBU in vivo 
could depend on the degree of reciprocal alloantigen-specific cytotoxic potency of the 
two CBUs. It is therefore possible that a discordant dominance between the two CBUs, in 
terms of stem cell potency and graft-versus-graft alloreactivity, could result in graft 
failure, i.e. when the dominant CBU with respect to alloreactive capacity eradicates the 
CBU able to support a more efficient and robust hematopoietic engraftment[ Moretta, Andriolo 
et al. 2012[16]].  
Ex vivo expansion was suggested as a modality to increase the numbers and/or potency of 
cells in a single CBU and to enhance the efficacy and applicability of CBT[(Kelly, Parmar et al. 
2010 [17]; Dahlberg[18], Delaney et al. 2011 [19]; Aljitawi 2012[3]] . This has prompted intensive research and 
development of novel and more potent expansion technologies.   
DCBT serves as a model to evaluate novel graft manipulations[Wagner 2009 [2]] not only 
adding a measure of safety (with an unmanipulated CBU) but by permitting to track the 
contribution of the manipulated CBU to short- and long-term hematopoietic 
recovery[Ramirez, Wagner et al. 2012[12]]. Two studies reported so far describe the transplantation 
of ex vivo expanded cells from one CBU in combination with a second non-manipulated 
CBU[De Lima, Robinson et al. 2010 [20]; De Lima et al. 2012 [21]; Delaney, Heimfeld et al. 2010 [19]]. In their 
publications they show that the expanded cells contributed mainly to initial myeloid 
engraftment that occurred at a median time of about 15-16 days and platelet engraftment 
at a median of about 40-42 days. The expanded cells have been observed as early as one 
week post transplantation but were lost before or after engraftment, while the 
unmanipulated CBU took over in all of the recipients. A lack of in vivo persistence of the 


 
 
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expanded graft could either be due to loss of stem cell self-renewal capacity during 
culture or to an immune-mediated rejection as described above. It was therefore 
suggested that combining an ex vivo expanded CBU for early hematologic recovery with 
an unmanipulated CBU for long-term sustained hematopoiesis could be an optimal 
strategy to shorten the neutropenic phase following CBT. 
3.3. Rationale for the administration of NiCord® as a single expanded 
CBU 
Ideally, a successful expansion technology would obviate the need for DCBT, and in 
most cases would enable the clinician to choose a single, best HLA-matched CBU for the 
patient. Most ex vivo expansion technologies are successful in expanding a subset of 
hematopoietic progenitor cells (HPCs), which are expected to improve short-term early 
hematopoietic reconstitution; while the main concern still remains for preservation of 
long-term repopulating cells in ex vivo conditions[ Srour, Abonour et al. 1999 [22]; Ando, Yahata et al. 2006 
[23]; Drake, Khoury et al. 2011 [24]] . The concern is not only related to the persistence of such 
unique cells in culture, but also to their potential to differentiate and reconstitute all blood 
cell lineages including myeloid, T, NK and B cells, as efficiently as the long-term 
repopulating cells before expansion[ Holmes, Yan et al. 2012 [25]].  
Until the advent of NiCord® expansion technology, ex vivo expansion studies have only 
been successful in demonstrating short-term early hematopoietic reconstitution. 
In light of the accumulated data from both the literature described in section 3.2 and the 
preliminary results from the ongoing study as summarized below and detailed in section 
3.5, the Sponsor aims to assess whether UCB transplantation of a single expanded CBU 
using the NiCord® technology is feasible and provides sustained donor-derived 
engraftment in adult patients with hematological malignancies following myeloablative 
therapy.  
The clinical outcomes of patients with hematological malignancies transplanted with 
NiCord®, delivered as part of a DCBT approach, demonstrate that eight out of eleven 
patients engrafted with a myeloid predominance of the expanded CBU (NiCord®) and 
those eight patients achieved neutrophil and platelet engraftment at a median of 10.5 and 
31.5 days post-transplantation, respectively (Table 2). Based on the last chimerism tests 
performed the expanded cells are shown to persist in all eight patients initially engrafted 
with NiCord® (Table 3). In five out of eight patients, both myeloid and lymphoid cells 
derived entirely from the NiCord® graft (Table 3). Immune reconstitution analysis of 
these patients last performed at days 100, 180 and 365 post-transplantation also 
demonstrated the recovery of all blood cell lineages including CD3, CD4 and CD8 (T 
cells), CD19 (B cells) and CD56 (NK cells) (Table 4). The pattern of immunologic 
reconstitution of all blood cell lineages appears to be comparable between patients who 
engrafted with NiCord® only and patients who engrafted with the unmanipulated unit 
only (Table 4). At a median follow-up of 364 days after transplantation (range 100-404), 
9 of 11 transplanted patients are alive with no reported secondary graft failure.  
The DCBT approach adds a measure of safety to the evaluation of novel approaches to ex 
vivo expansion. However, as previously described, the drawback of this strategy is that 


 
 
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graft-versus-graft immune interactions lead to the engraftment of one of the two CBUs 
transplanted and therefore potentially, the most potent CBU with respect to hematopoietic 
reconstitution may be eradicated by the immunologically dominant CBU. Furthermore, 
the use of DCBT has not demonstrated any improvement in the rates or kinetics of 
engraftment. The Sponsor believes that unrelated CBT with NiCord® may make it 
possible to choose the best CBU for the patient, expand it in culture and transplant it to 
the patient in a single CBT approach. As detailed in section 3.6, the study has been 
designed to assess the use of NiCord® in a single CBT configuration while maintaining a 
careful monitoring of patient safety. Thus, prohibitive cell dose requirements will be 
applied, both to the CBU selection, and to the NiCord® product when administered as a 
single CBT. The primary endpoints focus on the risk of graft failure, both in the short and 
long term. Moreover, strict stopping rules are applied with regard to graft failure.  
Demonstration of successful, rapid and sustained engraftment of a single expanded CBU 
would obviate the need for the use of a second CBU, providing both potentially less 
GvHD and significant cost savings. NiCord® could potentially provide an alternative graft 
for unrelated donor transplantation in patients who do not have a matched adult donor 
option, thereby addressing a critical unmet need in the treatment of hematologic 
malignancies. 
The manufacturing of the fresh and the cryopreserved NiCord® cultured fraction is 
exactly the same apart for the re-suspension on the last manufacturing day.  The 
cryopreservation of NiCord® allows flexibility in the planning and timing of 
transplantation, to accommodate the patient’s disease status and any changes required, as 
resulting from the patient’s medical condition. 
3.4. Gamida Cell Expansion Technology 
NiCord® is composed of CB-derived allogeneic stem and progenitor cells expanded ex 
vivo from an entire CBU with cytokines and nicotinamide, a form of the vitamin B3. 
________________________________________________________________________
________________________________________________________________________
____________________________________________ 
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
___________________________________________________  ___ . 
The expansion technology is based on the finding that nicotinamide epigenetically 
regulates in vitro expansion of functional hematopoietic progenitor cells that display 
increased bone marrow homing and engraftment efficacy. 
Engraftment is a multi-step process involving directed migration of the inoculated cells, 
homing to the BM, retention within the BM niche followed by self-renewal and 
differentiation.  Engraftment efficacy following expansion is known to be low due to 
poor homing to the bone marrow compared to fresh CD34+ cells (Szilvassy 1999[26]; Ahmed, Ings et 
al. 2004[27]; Foguenne 2005[28]) or reduced self-renewal owing to enhanced differentiation in 
culture. 


 
 
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Therefore, the goal of the ex vivo expansion of hematopoietic progenitor cells (HPC) is 
to increase their numbers while maintaining their self-renewal capacity and their ability 
to home to the bone marrow (BM) and efficiently reconstitute hematopoiesis. Exposure 
of HPC to different combinations of cytokines promotes their exit from the G0 phase of 
the cell cycle and enables extensive proliferation. Nonetheless, in vitro proliferation is 
tightly coupled with commitment to differentiation, and reduced self-renewal (Von Drygalski, 
Alespeiti et al. 2004[29]). Exposure to early-acting cytokines (SCF, TPO, FLT3 and IL6) induces 
robust in vitro expansion of CD34+ cells, but expansion of engraftable progenitors is 
modest (Xu and Reems 2001[30]). This discrepancy could be explained, at least in part, by an 
acquired defect in the BM homing capacity of HPC expanded ex vivo (Szilvassy 1999[26]; 
Szilvassy, Meyerrose et al. 2000[31]), which is primarily attributed to their active cycling (Takatoku, Sellers 
et al. 2001[32]) accompanied by alterations in adhesion and chemokine receptor expression or 
functionality (Ahmed, Ings et al. 2004 [27]). Strategies to augment the BM homing and 
engraftment efficacy are particularly important to increase clinical applicability of ex 
vivo expanded CD34+ cells (Hofmeister 2007[33]). 
Gamida Cell extensive studies discovered that NAM delays differentiation and increases 
the engraftment efficacy of cord-blood derived, purified CD133+ cells cultured with a 
combination of 4-cytokines (FLT3, SCF, TPO and IL6) for 19-23 days. In the presence of 
NAM the fraction of CD34+CD38- early progenitor cells increases and the fraction of 
differentiated myelomonocitic cells (CD14+, CD11b+, CD11c+) decreases over cytokines 
alone treated cultures. CD34+ cells cultured with NAM displayed increased migration 
towards SDF-1 and home to the bone marrow (24hr post infusion) with higher efficacy 
than cells cultured with cytokines only or non-cultured cells (Peled 2012[34]). 
________________________________________________________________________
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_________________________________________  
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
____________________________________________________ 
NAM serves as a precursor of nicotinamide adenine dinucleotide (NAD+) (Berger, Ramirez-
Hernandez et al. 2004[35]). On the other hand, NAM is a potent inhibitor of enzymes that require 
NAD+ for their activity(Banasik, Komura et al. 1992[36]; Corda and Di Girolamo 2003[37]), such as mono-
ADPribosyltransferases (mARTs), poly-ADP-ribose polymerases (PARPs) and CD38, 
cADPR/NADase (Krebs, Adriouch et al. 2005[38]). Having multiple effects on numerous cells, 
NAM is implicated in regulation of cell adhesion, polarity, migration, proliferation and 
differentiation (Glowacki, Braren et al. 2002[39]). NAM was shown to modulate the fate of 
embryonic stem cells (Papaccio, Ammendola et al. 1999[40]) and of primary non-hematopoietic cells 


 
 
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(Papaccio, Ammendola et al. 1999; Sato, Mitaka et al. 1999[41]; Miura and Kameda 2005[42]). On hematopoietic cell 
lines it has dual effects; on the one hand it inhibits HL-60 cell differentiation mediated by 
retinoic acid, (Munshi, Graeffet al. 2002[43]) and on the other hand it directly drives HL-60 cell 
differentiation (Iwata, Ogata et al. 2003[44]). 
NAM has also been demonstrated as a strong noncompetitive inhibitor of SIRT1, the 
NAD-dependent class III histone deacetylase (Denu 2005[45]). In lower eukaryotes, Sir2 (the 
mammalian SIRT1 homolog) has been strongly implicated in the modulation of 
replicative lifespan and promotion of longevity while NAM strongly inhibits silencing 
and shortens replicative life span (Bitterman, Anderson et al. 2002[46]). 
In contrast to its function in lower eukaryotes, SIRT1 function in higher eukaryotes is 
still debatable (Vaca, Berna et al. 2003[47]). A growing body of evidence suggests SIRT1 to inhibit 
proliferation and to promote differentiation of mammalian cells, and NAM, through 
inhibition of SIRT1, to inhibit their differentiation (Blander, Bhimavarapu et al. 2008[48]; Kim, Ahn et al. 
2009[49]). Our studies show that EX-527, a specific inhibitor of SIRT1 catalytic activity, 
inhibits differentiation of culture expanded CD34+ cells similar to NAM. NAM positional 
isomers, NAM-related molecules or NAM non-related PARP and mARTs inhibitors did 
not inhibit differentiation, suggesting SIRT1 as the primary target of NAM-modulating 
differentiation of cultured CD34+ cells (Peled 2012). 
________________________________________________________________________
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________________________________________________________________________
_______________________________________ 
3.5. Clinical Experience 
Currently NiCord® is being investigated in two pilot studies in a DCBT configuration, as 
summarized in Table 1 below. 
Table 1:  Overview of Ongoing Clinical Studies of NiCord® 
Protocol Number 
(ClinicalTrials.gov 
Number) 
Study Title 
Study 
Status 
Institution / Principal 
Investigator 
GC P#01.01.020 
(NCT01221857a) 
Allogeneic Stem Cell Transplantation of 
NiCord®, Umbilical Cord Blood-Derived Ex 
Vivo Expanded Stem and Progenitor Cells, in 
Combination With a Second, Unmanipulated 
Cord Blood Unit in Patients With 
Hematological Malignancies 
 
Complete 
Duke University Health 
System/ 
Dr. Joanne Kurtzberg and 
Dr. Mitchell Horwitz 
Cardinal Bernardin Cancer 
Center, Loyola University/ 
Dr. Patrick Stiff 


 
 
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Protocol Number 
(ClinicalTrials.gov 
Number) 
Study Title 
Study 
Status 
Institution / Principal 
Investigator 
GC P#02.01.020 
(NCT01590628b) 
Allogeneic Stem Cell Transplantation of 
NiCord®, Umbilical Cord Blood-Derived Ex 
Vivo Expanded Stem and Progenitor Cells, in 
Combination with a Second, Unmanipulated 
Cord Blood Unit in Patients with Sickle Cell 
Disease 
Ongoing 
Duke University Health 
System/ 
Dr. Joanne Kurtzberg 
Cohen Children’s Medical 
Center of New York/ 
Dr. Joel Brochstein 
 http://clinicaltrials.gov/ct2/show/NCT01221857?term=nicord&rank=1.  
 http://clinicaltrials.gov/ct2/show/NCT01590628?term=NCT01590628&rank=1.  
The subsequent sections describe the clinical studies mentioned above. The preliminary 
clinical data provided in Tables 2-5 are updated as of December 17, 2013. 
3.5.1. Study GC P#01.01.020 
A pilot study (GC P#01.01.020), entitled: “Allogeneic Stem Cell Transplantation of 
NiCord®, Umbilical Cord Blood-derived Ex Vivo Expanded Stem and Progenitor Cells, in 
Combination with a Second, Unmanipulated Cord Blood Unit in Patients with 
Hematological Malignancies” has been completed at Duke University Medical Center, 
NC, USA and Loyola University Cardinal Bernardin Cancer Center, IL, USA. The study 
evaluated the transplantation of NiCord® in combination with an unmanipulated CBU, for 
the hematopoietic support of subjects with hematological malignancies receiving high-
dose chemotherapy.  
As of December 17, 2013, eleven adult subjects with hematological malignancies have 
received myeloablative therapy followed by the transplantation of an unmanipulated 
CBU and NiCord®. The conditioning regimen consisted of total body irradiation (TBI) 
1350 cGy fractionated to nine doses and fludarabine 160 mg/m2. Two patients also 
received cyclophosphamide 120 mg/kg. 
Study results show a 16-186 fold enrichment in the numbers of CD34+ cells infused 
following expansion, compared to the CD34+ cell dose in the CBU post-thaw. Ten out of 
eleven patients transplanted with NiCord® have experienced donor hematopoietic 
engraftment. In all eleven patients (including the non-engrafting patient), day seven PB 
chimerism demonstrated predominance of the NiCord® expanded CBU. Eight patients 
have engrafted with a myeloid predominance of the expanded CBU (NiCord®). As of 
December 17, 2013, based on last chimerism follow-up of 42-365 days after 
transplantation, the expanded cells are shown to persist in all eight patients that were 
initially engrafted with the expanded CBU (Table 3). These eight patients achieved 
neutrophil engraftment at a median of 10.5 days after transplantation (range 7-18 days), 
and platelet engraftment at a median of 31.5 days after transplantation (range 26-41 days, 
one patient did not achieve platelet engraftment at time of death 47 days post transplant). 
Within the eight patients engrafted with a myeloid predominance of the expanded CBU; 
one patient engrafted with myeloid cells from both NiCord® and the unmanipulated CBU 
and CD3 cells from the unmanipulated CBU, two patients engrafted with myeloid cells 


 
 
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from NiCord® only and CD3 cells from both NiCord® and the unmanipulated CBU, five 
patients engrafted with NiCord® alone.  
Based on the last chimerism (total PB, myeloid-CD15 and lymphoid-CD3) follow-up at 
days 42 to 365 post-transplantation, the expanded cells persist in all patients that initially 
engrafted with NiCord® (Table 3). In addition to myeloid recovery, the patients who are 
fully engrafted with the expanded CBU also demonstrate robust recovery of lymphoid 
cell lineages: T cells (CD3, CD4 and CD8), B cells (CD19), and NK cells (CD56/16) 
from NiCord®, as shown in Table 4.  
Two patients engrafted with a predominance of the unmanipulated CBU (Table 3). These 
patients achieved neutrophil engraftment at 18-26 days after transplantation, and platelet 
engraftment at 36-49 days (Table 2). One patient failed to achieve engraftment 42 days 
after transplantation (Table 2), and received a second stem cell transplant from a 
haploidentical donor.   
As of December 17, 2013, 9 of 11 transplanted patients are alive at follow-up of 42 to 
404 days post transplant with no reported relapse or secondary graft failure.  One patient 
died of pneumonia at 47 days post transplant and one patient died of relapse at 196 days 
post transplant.  
Subjects were monitored closely prior to, during, and for 24 hours post-transplantation. 
As of December 17, 2013, two patients were reported to have experienced Grade 3 
hypertension events and one patient reported a Grade 3 hematuria on the day of 
transplantation. All three events were resolved with no residual effects. Acute GvHD 
grade II was observed in five subjects (Table 2).  
In addition to the eleven patients described above, one patient received only the 
unmanipulated CBU due to a positive Gram stain result obtained from the NiCord® CF 
during release testing. NiCord® CF and NF were not infused to the patient and were 
discarded. NiCord® CF was tested for complete sterility (14 and 21 days) and the results 
of all the sterility tests were negative. The patient achieved hematopoietic recovery 
following infusion of the unmanipulated unit and is alive at 386 days post-
transplantation. This case was reported to the FDA in the annual report. 
The patient data were reviewed twice by the DSMB as per protocol, after the first three 
and six patients completed 100 days follow-up, with a subsequent recommendation to 
continue study accrual and transplantations.  
3.5.2. Study GC P#02.01.020 
The study GC P#02.01.020 entitled: “Allogeneic Stem Cell Transplantation of NiCord®, 
Umbilical Cord Blood-derived Ex Vivo Expanded Stem and Progenitor Cells, in 
Combination with a Second, Unmanipulated Cord Blood Unit in Patients with Sickle Cell 
Disease” is ongoing at Duke University Medical Center, NC, USA and Cohen Children’s 
Medical Center of New York. The study is evaluating the transplantation of NiCord® in 
combination with an unmanipulated CBU, for hematopoietic support of subjects with 
Sickle Cell Disease (SCD). The study was launched in May 2012. The first patient was 


 
 
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transplanted on October 31, 2012 and as of December 17, 2013, five patients have been 
transplanted with NiCord® in a double cord blood configuration. 


 
 
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Table 2:  Data from NiCord® Study (GC P#01.01.020) - Patient Follow-up 
Patient 
Number 
Disease 
Stage/Age 
Myeloid Engrafted 
CBU 
WBC at Day 
7 (/mm3) 
 
Engraftment Day 
Acute GvHD 
Grade (II-IV) 
 
Last Study Follow Up 
Post Transplanta 
ANC 
>500 
Platelet 
>20,000 
1 
AML (CR1)/61 
NiCord® + 
Unmanipulated CBU 
200 
14 
33 
aGvHD-II 
(Day 60) 
376 
2 
MDS (Int-2)/43 
NiCord® 
300 
11 
30 
No  aGvHD 
372 
3 
MDS (Int-2)/59 
NiCord® 
500 
10 
30 
No  aGvHD 
348 
6 
AML (CR2)/45 
NiCord® 
400 
10 
30 
No  aGvHD 
393 
7 
HL/21 
NiCord® 
1100 
7 
26 
aGvHD-II 
(Day 60) 
355 
9 
AML (CR1)/45 
NiCord® 
100 
14 
41 
aGvHD-II 
(Day 80) 
196c 
10 
AML (PR)/59 
NiCord® 
500 
18 
- 
No  aGvHD 
47d 
11 
ALL (CR1)/45 
NiCord® 
900 
7 
33 
aGvHD-II 
(Day 60) 
333 
4 
AML (CR2)/41 
Unmanipulated CBU 
100 
18 
36 
No  aGvHD 
364 
5 
AML (CR1)/57 
Unmanipulated CBU 
100 
26 
49 
aGvHD-II 
(Day 35) 
404 
8 
NHL/46 
Engraftment failure 
900b 
- 
- 
- 
100 
a Last follow-up, as of 13 December, 2013 
b Total blood chimerism at day 7: NiCord® 95%, unmanipulated CBU 2% 
c Patient Died at 196 days post transplant 
d Patient Died at 47 days post transplant 
 


 
 
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Table 3:  Data from NiCord® Study (GC P#01.01.020) - Chimerism of NiCord® and Unmanipulated CBU 
Patient 
Number 
Disease 
Stage/Age 
Myeloid Engrafted CBU 
Chimerism of NiCord® and Unmanipulated CBU 
Total Blood Chimerism at 
Engraftment Day 
Last Follow-up Chimerism 
NiCord® 
(%) 
Unmanipulated  
CBU (%) 
At 
Day 
NiCord® 
(%) 
Unmanipulated  
CBU (%) 
1 
AML(CR1)/61 
NiCord® + Unmanipulated 
CBU 
79 
21 
365 
TBCa -  ND 
CD15 - 42  
CD3 - 2 
TBC -  ND 
CD15 - 58 
CD3 – 78 
2 
MDS (Int-2)/43 
NiCord® 
100 
0 
365 
TBC -  98 
CD15 - 98  
CD3 - 98 
TBC -  2 
CD15 -2 
CD3 -2 
3 
MDS (Int-2)/59 
NiCord® 
95 
5 
365b 
TBC -  92 
CD15 - 98  
CD3 - 97 
TBC -  2 
CD15 - 2 
CD3 – 2 
6 
AML (CR2)/45 
NiCord® 
98 
1 
365 
TBC -  98 
CD15 - 98 
CD3 - 81 
TBC -  2 
CD15 - 2 
CD3 – 2 
7 
HL/21 
NiCord®  
98 
2 
365 
TBC -  84 
CD15 - 98 
CD3 - 24 
TBC -  16 
CD15 - 2 
CD3 – 76 
9 
AML (CR1)/45 
NiCord®  
87 
7 
180 
TBC -  ND 
CD15 - 72 
CD3 - 40 
TBC -  ND 
CD15 - 2 
CD3 – 2 
10 
AML (PR)/59 
NiCord® 
100 
0 
42 
TBC -  100 
CD15 - ND 
CD3 - ND 
TBC -  0 
CD15 - ND 
CD3 – ND 
11 
ALL (CR1)/45 
NiCord® 
98 
2 
365 
TBC -  98 
CD15 - 98 
CD3 - 98 
TBC -  1 
CD15 - 1 
CD3 – 2 
4 
AML (CR2)/41 
Unmanipulated CBU 
2 
98 
365b 
TBC -  2 
CD15 - 2 
CD3 - 2 
TBC -  98 
CD15 - 98 
CD3 – 98 
5 
AML (CR1)/57 
Unmanipulated CBU 
2 
98 
365b 
TBC -  2 
CD15 – 2 
CD3 – 2 
TBC -  98 
CD15 – 98 
CD3 – 98 
a Total Blood Chimerism  b TBC is day 365, CD3/15 are day 180.    


 
 
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____________________________________________________________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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 ______________________________________ 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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3.6. Overall Risk Benefit 
NiCord® is an allogeneic graft for HSCT composed of CB-derived stem and progenitor 
cells expanded ex vivo from an entire CBU with cytokines and nicotinamide, as well as 
non-cultured CD133- cells. NiCord is intended for the treatment of patients who are 
medically indicated for allogeneic hematopoietic stem cell transplantation following 
preparative conditioning, including high risk hematological malignancies. Non-clinical 
studies have demonstrated that culturing CD133+ cells with NAM delays differentiation 
and increases engraftment efficacy. 
UCB is an easily procured stem cell source for allogeneic HSCT, with high availability 
for patients of different ethnic backgrounds. However, its use is limited by the low stem 
cell dose, compromising robust and timely hematopoietic recovery, leading to increased 
morbidity and mortality post transplantation. Several technologies are attempting to 
improve the kinetics of engraftment following UCBT, by using dual CBT, whereby one 
of the CBUs undergoes ex-vivo manipulation or expansion. Such technologies may 
shorten the time to neutrophil engraftment, however the long-term durable hematopoietic 
recovery is provided by the second, unmanipulated CBU. 
The first study of NiCord® (GC P#01.01.020) has demonstrated that infusion of NiCord® 
together with a second unmanipulated CBU was well tolerated. Engraftment of NiCord® 
cells in eight of eleven patients provided rapid short term neutrophil and platelet recovery 
as well as stable, long term multilineage hematopoiesis. No NiCord® recipients 
developed grade III or IV acute GvHD. Five of the eleven who received the NiCord® 
study product developed grade II acute GvHD. Two patients died during the study period 
(AML relapse and pneumonia). Neither death was considered related to NiCord®. 
As in all cases of allogeneic HSCT, the overall risks of cord blood administration 
following a cytotoxic preparative regimen can be serious and fatal. The potential risks 
associated with cord blood include early death, infusion reactions, GvHD and graft 
failure. The deaths and other adverse events experienced by NiCord® recipients in study 
GC P#01.01.020 are common effects of allogeneic stem cell transplantation following 
myeloablative therapy. 
The current study aims to evaluate the ability of NiCord® to safely and durably engraft, 
when given as a sole stem cell source. Thus the primary endpoints assess the safety of 
NiCord® infusion, NiCord®-derived neutrophil engraftment, and secondary graft failure. 
The secondary endpoints assess non-relapse mortality and overall survival up to one year 
post transplantation, as well as the time to engraftment, and the incidence of GvHD. 
3.7. Rationale For Study Design & Dosages 
3.7.1. Study Population 
As reviewed above, the study will include adult and adolescent patients with 
hematological malignancies for whom myeloablative SCT is currently a recommended 
and potentially lifesaving treatment. __________________ the study will _____ enroll 


 
 
GC P#03.01.020 
 
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NiCord® Single CBU Protocol 
 
Page 38 
patients who do not have an adequate suitably matched and readily available stem cell 
donor.  
3.7.2. CBU Cell Dose 
The CBU intended for expansion is required to contain a pre-cryopreserved (post-
processing), total CD34+ cell count of at least 8x106, as well as a pre-cryopreserved 
(post-processing) total nucleated cell count of at least 1.8x109, and a total nucleated cell 
dose of at least1.8x107 TNC/kg body weight, a dose predicted to be sufficient in size to 
provide robust and sustained engraftment, based on the current clinical experience with 
NiCord® (study GC P#01.01.020 - see Table 5). __                                                            _           
________________________________________________________________________
________________________________________________________________________
______________________________________________________    
________________________________________________________________________
____________________________________ 
________________________________________________________________________
_________________________________ 
As transplantation is considered a life saving intervention in the study population, the 
selection of the optimal CBUs is at the Investigator's discretion. 
3.7.3. Selection of CBUs 
Decisions on the selection of CBUs are never arbitrary, but rather are based on specific 
histocompatibility data, cell dose, availability, and in some cases the source of the CBU. 
However, there is no clear consensus or evidence-based algorithm as to the hierarchy of 
these factors. Thus, some physicians believe cell dose is of greatest importance, some 
examine CD34+ dose, and others prioritize HLA matching. For this reason, the protocol 
does not specify prioritization rules when more than one eligible CBU is identified. 
Also, with regards to the use of unit(s) that does not meet the local applicable regulations, 
note that all the patients included in the study may be considered of “urgent medical 
need” by the nature of their underlying malignancy, and have a high (>50%) likelihood of 
death without receiving a CBU transplantation. The usage of ineligible unit(s) or units 
with unusual findings (e.g. "incomplete”) will only be permitted when no comparable 
eligible CBU is found, and when this is the best CBU found for this patient. The 
Investigator will document the urgent medical need, the CBU search results and selection 
rationale in such cases.  
3.7.4. Study Endpoints 
In order to assess the safety of administration of NiCord® as a single expanded UCB unit, 
the primary endpoints were chosen to be the cumulative incidence of patients with 
NiCord®-derived neutrophil engraftment at 42 days following transplantation, and the 
incidence of secondary graft failure at 180 days following transplantation of NiCord®. 


 
 
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Page 39 
The two primary endpoints together provide the assessment of successful and sustained 
engraftment achieved by NiCord® transplantation. 
 


 
 
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4. 
STUDY OBJECTIVES, HYPOTHESIS & STUDY ENDPOINTS 
4.1. Objectives   
 
Primary Objectives 
• Assess the cumulative incidence of patients with NiCord®-derived neutrophil 
engraftment at 42 days following transplantation.  
• Assess the incidence of secondary graft failure at 180 days following 
transplantation of NiCord® 
Secondary Objectives 
• Time from infusion to neutrophil engraftment 
• Time from infusion to platelet engraftment 
• Incidence of platelet engraftment at 100 days  
• Proportion of non-relapse mortality at 100 days 
• Incidence of acute GvHD grade II-IV and III-IV at 100 days 
• Incidence of chronic GvHD (limited or extensive) at 180 days and 1 year 
• Incidence of secondary graft failure at 1 year following transplantation of 
NiCord® 
• Overall survival at 180 days and 1 year 
• Safety and tolerability of NiCord® transplantation 
Exploratory Objectives  
• Immune reconstitution at 70, 100, 180, and 365 days 
 
Study Hypothesis 
 
Transplantation of NiCord® following myeloablative conditioning in patients with 
hematological malignancies will provide sustained engraftment. 
4.2. Definition Of Study Endpoints  
 
4.2.1. Neutrophil Engraftment 
Neutrophil engraftment is defined as achieving an absolute neutrophil count (ANC) 
greater than or equal to 0.5 x 109/L on 3 consecutive measurements on different days with 
donor chimerism (< 10% host cells by peripheral blood chimerism using RFLP or 
microsatellite) by day 42 inclusive. The first day of the three measurements will be 
designated the day of neutrophil engraftment. 
Primary graft failure is defined as failure to achieve neutrophil engraftment by day 42 as 
described above. Infusion of a second stem cell product on or prior to Day 42 will be 
considered primary graft failure, with the following exceptions:  
• Backup CBU transplantation within 5 days of NiCord® transplantation due to 
NiCord® bioassays outside of the specification limits will not be sufficient 
evidence of graft failure.    


 
 
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• Infusion of an additional stem cell product after documented neutrophil 
engraftment will be considered secondary graft failure, even if it occurs on or 
prior to Day 42. 
Secondary graft failure consists of documented neutrophil engraftment, followed by 
severe neutropenia (<0.5 x 109/L for three or more consecutive laboratory values on 
separate days) with marrow cellularity <5%, without subsequent improvement occurring 
either spontaneously or after growth factor treatment.  Infusion of an additional stem cell 
product after documented neutrophil engraftment will be considered secondary graft 
failure.   
4.2.2. Platelet Engraftment  
Platelet engraftment is defined as the first day of a minimum of 3 consecutive 
measurements on different days such that the patient has achieved a platelet count 
>20x109/L and >50x109/L with no platelet transfusions in the preceding 7 days (count 
day of engraftment as one of the preceding 7 days). The first day of the three 
measurements will be designated the day of platelet engraftment.  
4.2.3. Non-Relapse Mortality 
Non-Relapse mortality is defined as any death not preceded by relapse. 
4.2.4. Acute and Chronic GvHD  
Incidence of acute GvHD grade II-IV and III-IV will be assessed based on the Consensus 
Conference on Acute GvHD grading (Appendix A) on day 100.   Chronic GvHD will be 
assessed on day 180 and year 1 and classified as limited or extensive according to 
Appendix A. 
4.2.5. Immune Reconstitution 
Immune reconstitution will be assessed on days 70, 100, 180, 365. The humoral system 
will be assessed based on levels of immunoglobulins (IgG, IgA, IgM). Cellular immune 
recovery will be assessed based on lymphocyte subset analysis to quantify the numbers 
and proportions of different lymphocyte subpopulations (CD3, CD4, CD8, CD19, 
CD16/56), as well as additional immunophenotyping as per site practice.  T-Cell 
Receptor Excision Circles (TREC) analysis will be performed on days 100, 180 and 365. 
4.2.6. Safety and Tolerability of NiCord® Transplantation 
The safety and tolerability of NiCord® transplantation will be evaluated by the nature, 
incidence and frequency of adverse experiences and an estimation of the relationship to 
NiCord®, as well as infections and laboratory data follow-up, with special emphasis on 
safety of cell therapy, including the detection of infusion reactions, transmission of 
infections, new malignancies and autoimmune diseases. 
 


 
 
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4.2.7. Other Definitions 
4.2.7.1. 
Response Criteria for Acute Leukemia 
• Bone Marrow Myeloblasts < 5% by morphologic assessment; 
• No circulating leukemic myeloblasts; 
• Neutrophil count ≥ 1,000/µL; 
• Absence of previous cytogenetic or molecular abnormality identified prior to 
transplantation in the bone marrow aspirate. 
4.2.7.2. 
Response Criteria for CML 
• Bone Marrow Myeloblasts < 5% by morphologic assessment; 
• No circulating leukemic myeloblasts; 
4.2.7.3. 
Response Criteria for Lymphoma  
Response criteria for lymphoma are described in Table 6 below 


 
 
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Table 4:  Response Definitions for Lymphoma 
Table 2. Response Definitions for Clinical Trials 
Response  
Definition 
Nodal Masses 
Spleen, Liver 
Bone Marrow 
CR 
Disappearance of all evidence of 
disease 
(a) FDG-avid or PET positive prior to 
therapy; mass of any size permitted if 
PET negative 
(b) Variably FDG-avid or PET negative; 
regression to normal size on CT 
 
 
Not palpable, nodules 
disappeared 
 
Infiltrate cleared on repeat biopsy: 
If indeterminate by morphology, 
immunohistochemistry should be 
negative 
PR 
Regression of measurable disease 
and no new sites 
≥50% decrease in SPD of up to 6 largest 
dominant masses; no increase in size of other 
nodes 
(a) FDG-avid or PET positive prior to 
therapy; one or more PET positive at 
previously involved site 
(b) Variably FDG-avid or PET negative; 
regression on CT 
 
≥50% decrease in 
SPD of nodules (for 
single nodule in 
greatest transverse 
diameter); no 
increase in size of 
liver or spleen 
 
Irrelevant if positive prior to 
therapy; cell type should be 
specified 
SD 
Failure to attain CR/PR or PD 
(a) FDG-avid or PET positive prior to 
therapy; PET positive at prior sites of 
disease and no new sites on CT or 
PET 
(b) Variably FDG-avid or PET negative; 
no change in size of previous lesions 
on CT 
 
 
 
Relapse disease or PD 
Any new lesion or increase by 
≥50% of previously involved sites 
from nadir 
Appearance of a new lesion(s) > 1.5 cm in any 
axis, ≥50% increase in SPD of more than one 
node or ≥50% increase in longest diameter of a 
previously identified node > 1 cm in short axis 
Lesions PET positive if FDG-avid lymphoma 
or PET positive prior to therapy 
 
 
>50% increase from 
nadir in the SPD of 
any previous lesions 
 
New or recurrent involvement 
Abbreviations:  CR, complete remission; FDG [18F]fluorodeoxyglucose; PET, positron emission tomography; CT, computed tomography; PR, partial remission; SPD, sum of the 
product of the diameters; SD, stable disease; PD, progressive disease. 
From Cheson, B.D. et al.  Revised response criteria for malignant lymphoma.  J Clin Oncol 5:579-586, 2007. 


 
 
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4.2.7.4  Relapse and Residual Disease 
Relapse of malignancy - testing for recurrent malignancy in the blood, marrow or other 
sites will be used to assess relapse after transplantation. For the purpose of this study, 
relapse is defined by either morphological or cytogenetic evidence of AML, ALL, CML, 
MDS consistent with pre-transplant features or radiologic evidence (including the 
recurrence of fluoro-deoxyglucose [FDG]-avid lesions on PET scan) of progressive 
lymphoma.  When in doubt, the diagnosis of recurrent or progressive lymphoma should 
be documented by tissue biopsy.  
Minimal residual disease - minimal residual disease is defined by the sole evidence of 
malignant cells by flow cytometry, or fluorescent in situ hybridization (FISH), or 
Southern blot or Western blot, or polymerase chain reaction (PCR), or other techniques, 
in the absence of morphological or cytogenetic evidence of disease in blood or marrow.   
Since the frequency of testing for minimal residual disease is highly variable among 
centers, and the sensitivity is highly variable among laboratory techniques, evidence of 
minimal residual disease alone will not be sufficient to meet the definition of relapse in 
the context of this trial.  However, minimal residual disease that progresses will be 
considered as relapse and the date of relapse will be the date of detection of minimal 
residual disease that prompted an intervention by the treating physician.    
Acute Leukemia - Relapse will be defined as any of the following:  
• 
> 5% blasts in the marrow, not attributed to other causes (e.g., bone marrow 
regeneration)  
• 
The appearance of new dysplastic changes within the bone marrow. 
• 
Reappearance of leukemic blasts in the peripheral blood. 
• 
Reappearance of previous cytogenetic or molecular marker of disease present prior 
to transplantation.  
• 
The development of extramedullary leukemia or leukemic cells in the cerebral 
spinal fluid. 
• 
Institution of any therapy to treat relapsed disease, including withdrawal of 
immunosuppressive therapy or DLI, will be considered evidence of relapse 
regardless of whether the criteria described above are met. 
 
Chronic Myelogenous Leukemia (CML) –  
Hematologic relapse will be diagnosed when: 
1. Immature hematopoietic cells are persistently documented in the peripheral 
blood; or,  
2. There is myeloid hyperplasia in the bone marrow in the presence of cytogenetic 
relapse. 


 
 
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Cytogenetic relapse will be diagnosed when:  
1. 50% of the metaphases exhibit the characteristic 9;22 translocation with at least 
ten metaphases analyzed; or, 
2. At least one metaphase exhibits the 9;22 translocation on each of two separate 
consecutive examinations at least one month apart, regardless of number of 
metaphases analyzed. 
MDS - Relapse will be defined as any of the following: 
• 
Satisfying above criteria for evolution into acute leukemia; or, 
• 
Reappearance of pre-transplant morphologic abnormalities, detected in two 
consecutive bone marrow specimens taken at least one month apart; or,  
• 
Reappearance of pre-transplant cytogenetic abnormality in at least one 
metaphase on each of two separate consecutive examinations at least one 
month apart, regardless of the number of metaphases analyzed. 
• 
Institution of any therapy to treat relapsed disease, including withdrawal of 
immunosuppressive therapy or DLI, will be considered evidence of relapse 
regardless of whether the criteria described above are met. 
 
Lymphoma - Relapse will be diagnosed when one or more of the following criteria apply: 
• Appearance of any new lesion more than 1.5 cm in any axis during or at the end 
of therapy, even if other lesions are decreasing in size.  Increased FDG uptake in a 
previously unaffected site should only be considered relapsed or progressive 
disease after confirmation with other modalities.  In patients with no prior history 
of pulmonary lymphoma, new lung nodules identified by CT are mostly benign.  
Thus, a therapeutic decision should not be made solely on the basis of the PET 
without histologic confirmation. 
 
• At least a 50% increase from nadir in the sum of the product diameters (SPD) of 
any previously involved nodes, or in a single involved node, or the size of other 
lesions (e.g., splenic or hepatic nodules).  To be considered progressive disease, a 
lymph node with a diameter of the short axis of less than 1.0 cm must increase by 
 50% and to a size of 1.5 x 1.5 cm or more than 1.5 cm in the long axis.  
 
Lesions should be PET positive if observed in a typical FDG-avid lymphoma or 
the lesion was PET positive before therapy unless the lesion is too small to be 
detected with current PET systems (<.1.5 cm in its long axis by CT). 
 
• Institution of any therapy to treat persistent, progressive or relapsed disease, 
including withdrawal of immunosuppressive therapy or DLI, will be considered 
evidence of relapse/progression regardless of whether the criteria described above 
are met. 


 
 
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4.2.7.5 CML Stages 
 
Chronic phase is defined as:  
• Stable, not hematologic remission: blasts present in marrow and/or peripheral 
blood, but disease does not qualify as accelerated or blast phase 
• Hematological remission: no blast cells or precursor cells in the blood or marrow 
• Partial cytogenetic remission: Ph+ metaphases >0% but < 35% 
• Complete cytogenetic remission: absence of Ph+ metaphases 
 
Accelerated phase is defined as: 
• WBC difficult to control (> 50 x 109/L despite therapy) 
• Rapid doubling of WBC (< 5 days) 
• Anemia or thrombocytopenia unresponsive to standard treatment 
• Persistent thrombocytosis (> 1000 x 109/L) 
• Cytogenetic abnormalities in addition to Ph+ 
• Increasing splenomegaly 
• Marrow fibrosis 
 
Blasts Crisis is defined as: 
• 
> 5% blasts in the marrow, not attributed to other causes (e.g., bone marrow 
regeneration) 


 
 
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5. 
STUDY POPULATION 
5.1. Number Of Patients  
 
The sample size is 40 evaluable patients, up to a maximum of 50 treated patients, who 
received NiCord® and who, in addition, met all of the following criteria: 
• Did not receive any stem cells up to day 28 except for NiCord®  
• Did not die prior to day 21 
• Received myeloablative conditioning therapy as specified in the protocol 
• Did not seriously contravene the eligibility criteria specified in Section 5.2 below 
• Did not receive a NiCord® transplant that was outside the final process quality 
control (FPQC) limits specified in section 8.3 
Enrolled patients who have received a transplant of CB cells but did not meet all of the 
above criteria will enter the main statistical analysis (ITT) but will be considered non-
evaluable for the per protocol analysis. For completing the per protocol analysis such 
patients can be replaced.  
Any patient can be removed from the study at any time if in the judgment of the 
Investigator further treatment is not in the best interests of the patient. Patients may also 
withdraw themselves from the study at any time and for any reason. 
Patients will be defined as screening failures when withdrawn from the study before 
receiving NiCord® or as early termination/discontinuation, if dropout occurs after 
transplantation of the NiCord®.  Screening failures can be replaced.  
For early termination/discontinuation patients, termination visit should be completed. In 
case such patients did not withdraw consent, study investigator will make all efforts to 
gather information on the clinical outcomes as assessed during the usual clinical 
management of their disease over the first 365 days following transplantation and to 
capture this information in the CRF.  


 
 
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5.2. Eligibility Criteria  
5.3. Inclusion Criteria 
1. Patients must be 12-65 years of age  
2. Patients with one of the following hematologic malignancies: 
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Exclusion Criteria 
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Graft Selection 
• If more than one unit meets the minimum cell dose and HLA match requirements, 
the best available unit per investigator discretion should be selected for expansion.  
• CBUs should be procured from public banks that meet local applicable regulations. 
If the chosen unit for the patient is determined ineligible or with unusual findings 
as per regulation, the unit may be used under the urgent medical need provision 
• The unit selected for expansion should be typed twice (i.e. initial typing and 
confirmatory typing). Confirmatory typing should be in a laboratory that is 
ASHI/EFI accredited and must come from an attached segment 
Backup Grafts 
• In case NiCord® fails to meet the required specifications, the backup CBU will be 
transplanted as detailed in section 8.3. The clinical site will notify the CBB and 
the backup CBU will be shipped and transplanted. 
 


 
 
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6. 
CONCOMITANT MEDICATIONS & SUPPORTIVE 
CARE 
6.1 
Previous Medications 
All medications taken by/given to the patient, as a treatment for the primary and 
concomitant diseases within 30 days prior to screening, will be recorded in the patient 
files. 
All chemotherapy and radiotherapy courses administered to the patient, as prior treatment 
for his/her hematological malignancy, will be recorded in the CRF (including treatment 
regimen, number of cycles, and dates).  Sites should obtain this information from the 
referring physician for source verification. 
6.2 
Disallowed Concomitant Medications  
The following medications should not be given post transplant: 
• Methotrexate (unless approved in advance by Sponsor)  
• Any cytokines except G-CSF or GM-CSF should not be used (including IL-2 or 
others, unless approved by Sponsor) 
• The use of Bactrim is discouraged on or after day -2 until the time of engraftment as 
it may delay engraftment, and is reserved only for cases where it is assessed to be 
essential and superior to all alternative medications 
• Investigational agents, unless previously approved by the sponsor 
6.3 
Conditioning Regimen 
All patients will receive one of the conditioning regimens shown in Table 7 below.  Each 
transplant center must commit to use the same conditioning regimen for all patients 
transplanted at their center.  In unique cases where the use of a different conditioning 
regimen is deemed to be in the patient’s best interest, approval from the study chairs must 
be obtained prior to use of the different regimen. 
 
Table 7:  Conditioning Regimens 
Regimen A: 


 
 
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     Study    
      Day 
-11 
-10 
-9 
-8 
-7 
-6 
-5 
-4 
-3 
-2 
-1 
0 
Treatment  
TBI 1350 cGy in 8 or 
9 fractions 
 
 
x2 
or  
x1 
or  
x0 
x2 
x2 
x2 
x0 
or  
x1 
or  
x2 
 
 
 
REST 
Infusion 
of 
NiCord® 
Fludarabine# 40 
mg/m2 IV  
 
 
 
 
 
 
x  
x  
x  
x  
Cyclophosphamide 
60mg/Kg# IV 
(optional*) 
 
 
 
 
 
 
 
 
x  
x  
Thiotepa 5mg/kg IV 
(optional*) 
x 
x 
 
 
 
 
 
 
 
 
 
 
#Adjusted ideal body weight for adult patients 
*Either Cyclophosphamide or Thiotepa (not both) may be added to the TBI/Flu preparative regimen at the 
discretion of the managing physician, with consideration given to nature of the underlying malignancy 
(cytogenetics and/or minimal residual disease), patient risk status (extent of prior therapies and/or 
comorbidities), and, increased risk of graft failure in chemotherapy naïve patients. Cyclophosphamide or 
Thiotepa addition is recommended for patients with CML. 
 
Regimen B: 
 
     Study   
      Day 
-7 
-6 -5 
-4 
-3 
-2 
-1 
0 
Treatment 
 
Thiotepa# 5mg/kg IV  
x 
x 
 
 
 
REST REST Infusion of 
NiCord® 
Busulfan# 3.2 mg/kg 
IV  
 
 
x  
x  
x  
Fludarabine# 50 
mg/m2 IV over 1 hour 
 
 
x 
x 
x  
#Adjusted ideal body weight for adult patients 
Regimen C*: 
 
              Study     
              Day 
-5 -4 
-3 
-2 
-1 
0 
Treatment 
 
Clofarabine 30mg/m2  
 
x 
x 
x 
x 
REST Infusion of 
NiCord® 
Fludarabine 10mg/m2  
 
x 
x 
x 
x 


 
 
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Busulfan: weight based 
dosing#$  
x 
x 
x 
x 
*Clofarabine infused for 1 hour followed by Fludarabine infused for 1 hour, followed by Busulfan infused 
for 3 hours. 
#Dosing according to Bartelink et al,50  
$Cumulative target AUC (Area Under the Curve) = 90mg*h/L. Bu levels after 1st dose will be measured at 
5min, 1h, 2h and 4h after end of Bu infusion 
 
6.3.1 Radiotherapy (Regimen A) 
Patients may be treated either in the AP/PA position and/or in the right and left lateral 
position. Compensators or blocks may be used to compensate for the thinner parts of the 
anatomy (head, neck, lower legs and feet).  
Total dose will be 1350 cGy in 8 or 9 fractions over 4 or 5 days. Two fractions on the 
same day will be given at a minimum of 6 hours apart from beam on to beam on.  
Risks and Toxicities:  
TBI can cause: nausea and vomiting, diarrhea, parotitis (rapid onset within 24-48 hours, 
usually self-limited), generalized mild erythema, hyperpigmentation, fever, mucositis and 
alopecia.  Late effects include: possible growth retardation, vertebral deformities, 
cataracts, probable increased risk of secondary malignant neoplasms, sterility, 
nephropathy, interstitial pneumonitis and veno-occlusive disease.  
6.3.2 Fludarabine Administration (Regimens A, B, and C) 
Regimen A: Fludarabine 40 mg/m2/day will be administered as a 60 minute IV infusion 
on days -5 through -2.  
Regimen B: Fludarabine 50 mg/m2/day will be administered as a 60 minute IV infusion 
on days -5 through -3.  
Regimen C: Fludarabine 10 mg/m2/day will be administered as a 60 minute IV infusion 
on days -5 through -2. Fludarabine will be given after 1h infusion of Clofarabine. 
Fludarabine will be dosed as per adjusted ideal body weight (see below for 
cyclophosphamide).  Refer to Appendix E, ‘Drug Labels’, for risks and toxicities of 
Fludarabine administration.  
6.3.3 Cyclophosphamide (CY) Administration (Regimen A) 
Cyclophosphamide will be added to the preparative regimen at the discretion of the 
managing physician.  Reasons for the addition of cyclophosphamide include high-risk 
features of underlying malignancy (cytogenetics and/or minimal residual disease), patient 
risk status (extent of prior therapies and/or comorbidities), and increased risk of graft 
failure in chemotherapy naïve patients.  Cyclophosphamide addition is recommended for 
patients with CML. 


 
 
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Refer to Appendix E, ‘Drug Labels’, for risks and toxicities of cyclophosphamide 
administration. 
Cyclophosphamide 60 mg/Kg/day as per adjusted ideal body weight will be administered 
as per institutional practice. 
Doses and schedule for uroprotective agents (i.e. Mesna) should follow local institutional 
guidelines. For patients weighing more than 125% of their IBW, cyclophosphamide will 
be dosed based on the adjusted ideal body weight (AIBW).    
The following are dose adjustment formulas: 
▪ 
Ideal Body Weight (IBW) formulas: 
- 
Males IBW = 50 kg+2.3 kg/inch over 5 feet (or 50 kg + 0.91kg/cm over 
152.4cm)  
- 
Females IBW = 45.5 kg+2.3 kg/inch over 5 feet (or 45.5 kg + 0.91kg/cm 
over 152.4cm)  
▪ 
Adjusted Ideal Body Weight (AIBW) formula: 
- 
AIBW = IBW+[(0.25)x(ABW-IBW)] 
6.3.4  Thiotepa Administration (Regimen A and B) 
Regimen A: Thiotepa 5 mg/kg/day will be administered as a 4 hour IV infusion on days -
11 and -10. Thiotepa will be dosed as per adjusted ideal body weight (as described in 
section 6.3.3 for cyclophosphamide). 
Regimen B: Thiotepa 5 mg/kg/day will be administered as a 4 hour IV infusion on days -
7 and -6. Thiotepa will be dosed as per adjusted ideal body weight (as described in 
section 6.3.3 for cyclophosphamide).   
Refer to Appendix E, ‘Drug Labels’, for risks and toxicities of Thiotepa administration. 
6.3.5 Busulfan Administration (Regimen B and C) 
Regimen B: Busulfan 3.2 mg/kg/day will be administered as a 3 hour IV infusion (or in 
four separate 2 hour IV infusions every six hours) on days -5 through -3. Busulfan will be 
dosed as per adjusted ideal body weight (as described in section 6.3.3 for 
cyclophosphamide).  Refer to Appendix E, ‘Drug Labels’, for risks and toxicities of 
Busulfan administration. 
Regimen C: Busulfan (weight-based dosing according to Bartelink et al 50) will be 
administered over 3 hours IV infusion (or in four separate 2 hour IV infusions every six 
hours) on days -5 through -3 (after clofarabine and fludarabine). Busulfan dose will be 
adjusted (if necessary) on the second day to achieve a cumulative Busulfan exposure 
(AUC) after 4 days of 90 mg*h/L (+5 mg*h/L). 
6.3.6 Clofarabine  Administration (Regimen C) 
Clofarabine 30mg/m2 will be administered as a 1 hour IV infusion on days -5 through -2. 
For patients receiving Regimen C, Clofarabine will be infused first, followed by 


 
 
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Fludarabine, in turn followed by Busulfan.  Refer to Appendix E, ‘Drug Labels’, for risks 
and toxicities of Clofarabine administration. 
6.4 
GvHD Prophylaxis Medications 
All patients will receive GvHD prophylaxis with two drugs as follows:  
 
Calcineurin inhibitor (Tacrolimus or Cyclosporine) 
Each transplant center must commit to use the same calcineurin inhibitor (Tacrolimus or 
Cyclosporine) for all patients transplanted at their center.  In unique cases where the use 
of a different calcineurin inhibitor is deemed to be in the patient’s best interest, approval 
from the study chairs must be obtained prior to use of the different calcineurin inhibitor. 
Tacrolimus or Cyclosporine from day -3 through day +150 Target tacrolimus trough 
blood levels of 5-15 ng/ml. If administering via continuous IV infusion, target 
cyclosporine trough levels of 200-400 ng/mL by TDX method (or 100-250 ng/mL by 
Tandem MS or equivalent level for other CSA testing methods).  For intermittent dosing 
target cyclosporine trough levels of 150-300 ng/mL by TDX method (or equivalent level 
for other CSA testing methods).  In the event of toxicity, dosing may be adjusted per 
institutional standard practice.  Calcineurin inhibitor taper may begin at day +150 at the 
discretion of the managing physician, with the goal for discontinuation at day 180-200.  
Refer to Appendix E, ‘Drug Labels’, for risks and toxicities of tacrolimus administration. 
Mycophenolate Mofetil (MMF)  
Mycophenolate Mofetil (MMF) 1 g TID IV or PO (15 mg/kg IV TID if patient weighs 
<50 kg) beginning day -3 to at least day +60. In the event of toxicity, dosing may be 
adjusted per institutional standard practice.  Refer to Appendix E, ‘Drug Labels’, for risks 
and toxicities of mycophenolate mofetil administration. 
6.5 
Acute & Chronic GvHD Treatment  
Management of acute and chronic GvHD will be at the Investigator's discretion and in 
accordance with the institution's guidelines.  
6.6 
Venous Access  
Recipients will have appropriate long-term central venous access placed, per institutional 
standard practice, prior to beginning the conditioning regimen. The placement of a triple 
lumen tunneled catheter is recommended. 
6.7 
Infusion Support 
All patients will receive the following medications 30-60 mins prior to NiCord infusion.   
• Diphenhydramine 50 mg IVP (or 0.5 mg/kg up to a maximum of 50 mg) 
• Hydrocortisone 50 mg IVP (or 0.5 mg/kg up to a maximum of 50 mg) 


 
 
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• Acetaminophen 650 mg PO (or 10 mg/kg up to a maximum of 650 mg) 
Methylprednisolone should not be used in conjunction with standard delivery of NiCord 
to the patient.  Management of infusion reactions during and post transplant is at the 
discretion of the managing physician. 
6.8 
Supportive Cytokine Therapy 
G-CSF (e.g. Filgrastim, Neupogen, Granix) therapy will be started on day +1 at a dose of 
5 µg/kg/day (rounded to nearest vial size) given IV or SC and continuing at least until the 
ANC is >1,000/µl x 2 consecutive days as per site practice.  
6.9 
Blood Products 
Thrombocytopenia: Platelet counts should be maintained at >10,000/uL after allogeneic 
transplant by transfusion of platelets. When available, single donor platelets will be used. 
Anemia: Transfusions of packed red blood cells (RBC) are indicated for the management 
of symptomatic anemia per institutional guidelines.  In the absence of symptoms, RBC 
transfusions should be considered to maintain hemoglobin > 7g/dL.   
All blood products (except NiCord® or any other stem cell grafts administered) must be 
irradiated to at least 2500 cGy before administration to transplant recipients to reduce the 
risk of developing third-party graft-versus-host disease.  
6.10 Engraftment Syndrome 
Engraftment syndrome is a clinical diagnosis. The most frequently reported 
manifestations are transient fever, rash, and respiratory symptoms not attributable to 
infection or GVHD. The pathophysiology is poorly understood, but is thought to be 
multifactorial mediated by cellular, complement and cytokine components. 
Diagnostic criteria include fever (temperature >38.5° C) without an identifiable infectious 
cause prior to or with neutrophil recovery with or without an erythematous rash or 
capillary leak (weight gain, edema, ascites, effusions) or respiratory symptoms not 
attributable to IPS. Mild symptoms may not require therapy due to the self-limiting 
nature of this syndrome. Methylprednisolone should not be given as prophylaxis for 
engraftment syndrome prevention.  For progressive symptoms, methylprednisolone at 2 
mg/kg/day is recommended with tapering once response is achieved.  If recurrent or 
prolonged, investigation for GVHD is recommended. 
6.11 Infection Prophylaxis and Surveillance 
Institution guidelines will be followed to provide prophylaxis for infections. Strict 
guidelines for hygiene and care will be applied. Before starting the pre-transplant 
conditioning there should be no uncontrolled mucosal or cutaneous infections.  Oral 
candida prevention should be vigorously pursued.  


 
 
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All patients must be nursed in a single room during neutropenia and should preferably be 
nursed in a single room during all admissions. All visitors must be free of active 
infections. Rigorous hand washing is crucial. 
6.11.1 Anti-viral Prophylaxis 
Acyclovir 400 mg (or 250mg/m2) PO BID is recommended for anti-viral prophylaxis 
with conditioning through the duration of neutropenia and then at 800 mg PO BID (or 
60–90 mg/kg/day PO divided in 2–3 doses for patients <40kg, up to a maximum of 
800mg BID) until 1 year post transplant or until 6 months after immunosupression is 
discontinued. If unable to tolerate PO medications, IV prophylaxis will be necessary.  
Other anti-viral prophylaxis regimens may be administered per institutional guidelines, 
however, prophylaxis with ganciclovir or valganciclovir is strongly discouraged on or 
after day -2 until engraftment is achieved.   
6.11.2 Anti-bacterial Prophylaxis 
Anti-bacterial prophylaxis is required.  Ciprofloxacin 500 mg PO BID day 0-100 is 
recommended.  Other anti-bacterial prophylaxis regimens may be administered per 
institutional guidelines. 
6.11.3 PCP Prophylaxis 
Trimethoprim-sulfamethoxazole or an equivalent drug should be administered after 
engraftment as per institutional guidelines.  The use of Bactrim is discouraged on or after 
day -2 and prior to engraftment as it may delay engraftment, and is reserved only for 
cases where it is assessed to be essential and superior to all alternative medications. 
6.11.4 Fungal Prophylaxis 
Anti-fungal prophylaxis is recommended with agents such as fluconazole, itraconazole, 
voriconazole, or posaconazole. 
6.11.5 CMV Surveillance  
All recipients must be tested weekly for CMV using the PCR method after the start of the 
conditioning regimen until Day 42±3 and then at day 70±5 and day 100±7 or more 
frequently as clinically indicated. Antiviral therapy for CMV reactivation should 
commence preemptively if CMV testing reveals a high or rising viral load. If CMV 
reactivation occurs at or before engraftment, foscarnet is recommended to prevent 
marrow suppression.  
6.11.6 HHV6 Surveillance  
Quantitative HHV6 DNA assessment by PCR must be tested weekly after transplantation 
until absolute neutrophil count >500 cells/microliter.  Treatment is recommended if 
symptomatic or following 2 weeks of rising viral load or an absolute count above 10k 
copies/ml.  Treatment for HHV6 should follow institutional practice. If HHV6 
reactivation occurs at or before engraftment, treatment with foscarnet is recommended. 


 
 
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6.11.7 EBV Surveillance  
Quantitative EBV viral load assessment by PCR must be tested at least monthly after the 
start of the conditioning regimen, or more frequently as clinically indicated, until day 100 
(or longer if on immunosuppression).  Patients with a positive result (>1000 copies) 
should be treated as per institutional guidelines.  Rituximab treatment is recommended. 
6.11.8 Adenovirus Intervention Guideline 
Testing for adenovirus infection in the blood by PCR method is recommended in the 
event of symptoms suspicious for infection such as diarrhea, hepatic dysfunction or 
respiratory symptoms. If an active systemic infection is diagnosed, therapy should be 
instituted per institutional guidelines. 
6.11.9 Intravenous Immune Globulin 
Intravenous immune globulin may be administered according to institutional practice 
guidelines.  
6.11.10 Identification of Infectious Agents - Recommendations 
6.11.10.1 Blood Cultures 
Blood cultures should be taken at the presentation of fever prior to initiating antibiotics.  
In the event of clinical deterioration, suspicion of line infection, or chills following 
initiation of broad-spectrum antibiotics, additional cultures should be taken.  Repeat 
cultures for subsequent episodes of fever or persistent fever unresponsive to antibiotics. 
6.11.10.2 Blood Culture Procedure 
Blood cultures should be sampled twice per procedure.  Each sample should be tested for 
both aerobic and anaerobic organisms.  One sample should come from the peripheral 
blood and one sample from the central line (or a second sample from the peripheral blood 
if the central line is no longer in use).    If a peripheral blood draw is not successful and 
the patient has a central line with multiple lumens, then draw two samples from different 
lumen. 
6.11.10.3 Additional Identification Procedures 
The following procedures are recommended in patients with suspected infection: 
• Chest X-ray  
• Sinus CT in patients with suspected sinusitis  
• Diarrhea: Clostridium difficile toxin PCR to be determined once in patients with 
clinical suspicion. Viral diagnostics (rotavirus, adenovirus, norovirus, astrovirus) 
in patients with clinical suspicion of infectious cause.  
• Urine culture in patients with suspected infection of indwelling catheter  
• CSF culture in patients with suspected meningitis  


 
 
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• Skin lesions: biopsy or aspirate, for culture, Gram stain, GMS and cytology. 
• Pulmonary source of infection: sputum culture in patients with productive cough. 
Consider viral diagnostics using viral throat swab, especially in season: Influenza 
A and B, RSV, Coronavirus, Rhinovirus, Bocavirus, Para-influenza, Human 
metapneumovirus and mycoplasm. BAL in patients with chest HRCT 
abnormalities.  
6.11.11 Treatment of Infections 
Patients undergoing the myeloablation treatment outlined in this study are expected to 
develop immunodeficiency. Therefore, the approach to the diagnosis and treatment of 
fever in such patients should be an aggressive one. If any infections occur, they will be 
treated per institutional practice and will be recorded in the source documents and in the 
e-CRF.  As standard treatment practices differ between institutions, will evolve over 
time, and vary by patient circumstances, we do not prescribe a specific approach to 
treatment.  Rather, it is the responsibility of the treating physician to manage infections 
according to their institutional best practices.    
6.11.12 Discharge Instructions and Follow-up 
Patients and their treating physicians should be provided clear instructions at discharge 
that emphasize the importance of continued follow-up as per study protocol, including 
early reporting of infectious symptoms, medical treatments received and any other 
medical events to their clinical center.  The transplant center should attempt weekly 
contact with patients through day 70 to ask about infectious symptoms and any other 
medical events or treatments.  Transplant centers will continue with monthly contact 
from day 70 to the completion of follow-up. 
6.12 Nutrition  
All patients will be candidates for total parenteral nutrition; length of use is at the 
attending physician's discretion.   
6.13 Guidelines for Infusing a Second Stem Cell Product  
A second transplant should not be considered unless the patient has impending or actual 
graft failure. In the event of impending or actual graft failure then the patient may be 
treated per institutional guidelines.  As standard treatment practices differ between 
institutions, will evolve over time, and vary by patient circumstances, we do not prescribe 
a specific approach to treatment.  Rather, it is the responsibility of the treating physician 
to manage graft failure according to their institutional best practices. 
6.14 Investigational Agents 
Unless approved by the Sponsor, investigational agents should be withheld. 


 
 
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6.15 Other Medications  
Patients should receive full supportive care according to institutions’ practice patterns 
and clinical guidance as described above, including transfusions of blood and platelets, 
antibiotics, anti-emetics, or any other supportive care according to clinical judgment.  
All concomitant medications and blood products administered, from time of signature on 
the IC and until the end of the study, will be recorded in the source documents and the 
reason for administration should be clearly stated in the indications and if needed also 
documented as AEs.  All concomitant medications from time of transplant through ANC 
engraftment (or 42 days post transplant for non-engrafters) will be reported on the e-CRF. 
Rescue equipment (oxygen) and drugs such as hydrocortisone, epinephrine (other 
inotropic agents), and antihistamines should be available at the transplantation unit and 
will be administered at the Investigator’s discretion.


 
 
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Page 62 
Table 8:  Evaluations & Examinations Flow Sheet 
     NiCord® Study for Single Fresh - Schedule of Assessments Summary 
Baseline 
Days Post-transplant 
Phase 1: 
Screening 
Phase4 
Phase 
2: 
Conditi
oning 
Phase1 
Phase 3: 
Transplantation and FU Phase 
Days 
-43 to      
-12/-10/ 
-8/-6 
-11/-9/ 
-7/-5 
 to -1 
0 1 
2-
6 
7 
14±3 
21±3 
28±3 
35±3 
42±3 
70
±3 
100 
±14 
180 
±21 
365 
±21 
Identify UCB matching unit for expansion and 
backup CBU/s 2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Written Informed Consent3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm Eligibility within one week prior to 
conditioning 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBU sent to  the production site to arrive no later 
than two days before the start of manufacturing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Infectious disease markers 5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anti-HLA antibodies 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiac: EKG,  Echocardiography or MUGA scan 
for LVEF 6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest X-ray 6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulmonary Function Tests with DLCO, FEV1, 
FVC6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirmatory HLA typing7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT scan chest, abdomen, pelvis (HD/NHL) 8 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
BM aspiration/biopsy8  (when clinically indicated) 
morphology  
In Leukemia/MDS: FACS; Cytogenetics; 
Molecular markers 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 


 
 
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Days 
 
-43 to     
-12/-10/ 
-8/-6 
-11/-9/ 
-7/-5  
to -1 
0 
1 
2-6 
7 
14±3 
21±3 
28±3 
35±3 
42±3 
70±
3 
100 
±14 
180 
±21 
365 
±21 
Vital Signs9 
X10 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory 11 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Historical and Concomitant 
medications13  
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Karnofsky/Lansky performance 
scale 
X 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
Physical Examination  
X 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
Complete urinalysis 
X12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunophenotyping 
Lymphocyte subsets14  
 
 
 
 
 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
MultiPlex Immuno Assays 
analyses14 
 
 
X X 
 
X 
X 
X 
 
 
X 
 
 
 
 
Immunoglobulins (IgG, IgA, 
IgM) 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
T-cell Receptor Excision Circles 
(TREC)  and T cell receptor 
(TCR) beta within CD4+ & 
CD8+14 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Peripheral blood baseline sample 
for Chimerism15  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Peripheral blood chimerism16  
 
 
 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Conditioning regimen as per 
protocol 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
NiCord® CF, NF, and infusion 
solutions shipped to transplant 
center prior to transplant 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
NiCord® CF  thawing and 
infusion 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
NiCord® NF thawing and infusion 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Toxicity assessment 24 hours post 
infusion17 
 
 
X X 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Page 64 
1   Start of conditioning varies by conditioning regimen chosen: Day -11/-9 for Regimen A, Day -7 for Regimen B, Day -5 for Regimen C 
2   Before signing informed consent and according to CBUs matching criteria as detailed in Section 5.2 of the protocol. 
3    Signed consent is required prior to performing any protocol specific tests or procedures that are not part of the standard site practice.  
4    All eligibility criteria must be met prior to ordering the CBU for expansion.  Unless otherwise indicated, screening and eligibility testing must be performed within three weeks prior to shipment 
of the CBU for expansion to the production facility.   
5 Infectious disease markers must include: CMV, Hepatitis panel (HepB sAg, HepB Core Ab, HepC Ab), herpes simplex virus, syphilis, HIV and HTLV I/II antibody, and varicella zoster. 
6   Tests from within 6 weeks of screening are acceptable. 
7 HLA -A,-B, -C, -DRB1 must be typed at high resolution and patient must also have ABO and Rh typing performed.   
8 Baseline disease assessment should be as close as possible to CBU shipment to the production facility to minimize findings of relapse during CBU expansion.  Specific requirements for the 
timing of this assessment are provided in section 7.2.2 
9    Weight, temperature, blood pressure, pulse, respiratory rate as per site practice. 
10  Including height, weight and BSA. 
11 CBC performed daily from Day 0 until neutrophil engraftment.  Differentials required if WBC >=0.2.  Daily CBC and ANC counts must be uploaded to the eCRF on a weekly basis through 
neutrophil engraftment or day 42 post transplant for non-engrafters.  Blood chemistries include (at a minimum): serum creatinine,  total bilirubin, alkaline phosphatase, AST, ALT, and 
magnesium (at screening, day -1, day 0 and then at least twice weekly until Day 28, and weekly after Day 28 until 10 weeks post-transplant, 100 days, 6 months and 1 year post-transplant). 
12   As per site practice. 
13 Including total number of RBC and platelet units transfused until platelet recovery >50k 
14  Samples batch-shipped to University Medical Center Utrecht for analysis.  At screening and on days 70, 100, 180, and 365 site will perform a basic T-cell subset analysis (CD3, CD4, CD8, CD19, 
CD56/16) locally in addition to collecting samples for batch shipment  to  University Medical Center Utrecht. 
15  Patient sample will be obtained prior to the initiation of the conditioning regimen; CBU sample will be shipped to the transplant center along with the NiCord product 
16 Measured by molecular methods, in whole blood and fractionated for lymphoid and myeloid components.  Bone marrow chimerism is an acceptable alternative. 
17 (fever, chills, allergic reaction/hypersensitivity, anaphylaxis, sinus bradycardia, sinus tachycardia, hypertension, hypotension, nausea, vomiting, diarrhea, dyspnea, hypoxia, 
hemoglobinuria,  infection, flank pain and any other skin, CNS, cardiac, pulmonary or other toxicity manifestations) 
18 GVHD and other morbidity assessments at every visit post- transplant. 
 
Days 
 
-43 to     
-12/-10/ 
-8/-6 
-11/-9/ 
-7/-5 
 to -1 
0 
1 
2-
6 
7 
14±3 
21±3 
28±3 
35±3 
42±3 
70±3 
100 
±14 
180 
±21 
365 
±21 
Assess Acute GvHD 18 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assess Chronic GvHD 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
CMV PCR  
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
EBV PCR 
 
X 
 
 
 
 
 
X 
 
 
 
X 
X 
 
 
HHV6 PCR weekly until 
ANC>500    
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Infections 
 
 
Infections collected post transplant until end of study 
Adverse events 
 
From initiation of conditioning regimen until end of study 


 
 
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7. 
DETAILED STUDY PLAN 
7.1. Pre-Screening Activities: Search For Matching CBUs 
 
Potential candidates for CBT for whom a search yielded a matched CBU will be 
identified as screen candidates for the study. Patients must have one partially HLA-
matched CBU. The unit must be HLA-matched at 4-6/6 HLA class I (HLA-A & HLA-B, 
low resolution) and II (HLA-DRB1, high resolution) loci with the patient.  There must be 
at least one allele match at DRB1. 
 
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
_________________________________________________________     
 
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
_______________________________________________________ 
 
All CBUs should be procured from public banks that meet local applicable regulations. 
Donors are screened and tested in accordance with the relevant regulatory requirements. 
The CBU should be tested for the applicable infectious diseases and be eligible. In case 
the CBU is ineligible or with unusual findings, the clinical site should fill out an urgent 
medical need document. 
 
Once matching CBUs have been found, the patient will be required to sign a written 
informed consent for cord blood access as per Institutional and National requirements. 
 
If more than one unit meets the minimum cell dose and HLA match requirements, all 
CBU documents for expansion eligible units should be sent to the Sponsor's study 
logistics manager (SLM) for eligibility review.  At the request of the investigator, the 
SLM will send the CBU documents to the study chairs for a recommendation on the best 
available unit.  Ultimately, the investigator chooses the best available units for expansion 
and backup from among all eligible units.      
 


 
 
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The unit selected for expansion must be typed twice (i.e. initial typing and confirmatory 
typing). Confirmatory typing should be in a lab that is ASHI/EFI accredited and must 
come from an attached segment.  
 
7.2. 
Screening Assessments: (Three weeks prior to CBU shipment to the 
production facility)Acceptable CBUs (meeting CBU acceptance criteria as 
defined above) must be identified and available prior to patient’s screening. 
7.2.1. Informed Consent and Registration 
A conference will be held with the patient and family to discuss this study and alternative 
treatments available for the treatment of the underlying disease.  The conference will be 
conducted by the principal investigator or other designated physician.  
Standard of care workup for transplant may be done prior to patient consent.  Prior to 
performing any study activities/evaluations that are not part of the site’s routine clinical 
practices, the patient must be thoroughly informed about all aspects of the study, 
including scheduled study visits and activities, and must sign the written informed 
consent. Informed consent from the patient and/or his/her legal guardian will be obtained 
using a form approved by the Institutional Review Board or Ethics Committee of the 
institution enrolling the patient.  A signed copy of the written informed consent should be 
given to the patient and/or his/her legal guardian. 
Patients will be registered -_______________________________________________ 
________________________________________________________________________
________________________________________________________________________
______________________________________________________________. 
7.2.2. Eligibility and Baseline Assessments 
Unless otherwise specified, eligibility and baseline assessments must be scheduled within 
three weeks prior to CBU shipment to the production facility. Tests performed during 
pre-screening period according to the Centers’ routine evaluation of candidates for stem 
cell transplantation need not be repeated, provided they were performed recently enough, 
as detailed below.  
Patient’s eligibility for the study will be assessed. The activities will be performed as 
detailed in Table 9 and will include:  
• Baseline evaluation: 
 
Medical history including primary and concomitant diseases. Concomitant 
medications will be recorded in the patient’s medical record. 
 
Patients’ performance score by Karnofsky/Lansky scale  
 
Physical examination and vital signs (including height, weight and BSA) 
 
Laboratory: CBC with WBC differential, blood chemistry (serum creatinine, 
total bilirubin, alkaline phosphatase, AST, ALT, and magnesium at a minimum), 
serum beta HCG (females) (tests from the last week prior to screening are 


 
 
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acceptable); urinalysis including microscopic examinationAnti-HLA antibody 
testing 
 
Immunoglobulin levels (IgG, IgA, IgM) 
 
Lymphocyte subsets: CD3, CD4, CD8, CD19, CD16/56 and additional 
immunophenotyping as per site practice 
 
Collect blood samples for T-cell Receptor Excision Circles (TREC) and T cell 
receptor (TCR) beta within CD4+ & CD8+ for batch shipment to University 
Medical Center Utrecht  
 
Chest X-ray (tests from within 6 weeks prior to screening are acceptable).   
 
Bone Marrow morphology (aspiration/biopsy, when clinically indicated).  To 
minimize findings of relapse during CBU expansion, bone marrow must be 
assessed within: 
▪ six weeks prior to CBU shipment to the production site for MDS patients 
who have never shown >20% blasts (leukemic transformation) in prior 
bone marrow biopsies and have <5% blasts in the most recent assessment, 
CML patients who have never experienced blast crisis, Lymphoma 
patients. 
▪ three weeks prior to CBU shipment to the production site for all other 
patients 
▪ 
For Leukemia or MDS: peripheral blood and BM morphology 
(aspiration/biopsy), FACS assay, cytogenetics and molecular markers 
▪ 
For NHL and HD: CT abdomen, pelvis & chest (tests from within 6 weeks 
prior to screening are acceptable)  
 
Serologic infectious disease markers for HIV 1/2 Ab, HTLV I/II Ab, HBsAg, 
HBcAb, HCV Ab, HSV Ab, VZV Ab, Syphilis (RPR), and CMV Screen (IgG or 
Total) 
 
Physiologic reserves assessment:  
− Pulmonary Function Tests including Carbon Monoxide Diffusing 
Capacity (DLCO), FEV1, FVC, and oxygen saturation (tests from within 6 
weeks prior to screening are acceptable). 
− 12 lead ECG (tests from within 6 weeks prior to screening are acceptable) 
− Echocardiography or MUGA with left ventricular ejection fraction 
(LVEF) (tests from within 6 weeks prior to screening are acceptable).  
• UCB match: 
 
Patient and CBU ABO and Rh typing 
 
Patient HLA class I (A, B, and C) & II (DRB1) high resolution confirmatory 
typing.  Note that although the matching requirement per protocol only requires 
low resolution A and B matching, high resolution, DNA-based confirmatory 
typing is required for loci A, B, and C, as well as DRB1. 


 
 
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 
If more than one unit meets the eligibility criteria, all CBU documents for 
expansion eligible units should be sent to the Sponsor's study logistics manager 
(SLM) for eligibility review.  At the request of the investigator, the SLM will send 
the CBU documents to the study chairs for a recommendation on the best available 
unit.   
 
Peripheral blood baseline sample for chimerism laboratory 
All above mentioned activities must be completed prior to sending the CBU to the 
production site for expansion. 
7.3. CBU Shipment & Receipt at the Production Site and Clinical Site  
Once the Investigator has confirmed that the patient meets ___________________ 
_____________________________________________________ Patients will retain the 
same study ID that was assigned during screening.  The Sponsor's study logistics 
manager (SLM) and the CBBs or NMDP will be notified of the planned timeline for 
transplantation. Following confirmation of shipment timelines by the production site, the 
CBB will send the selected CBU for NiCord® expansion to the production site, to arrive 
no later than two days before the start of production. Qualified personnel at the 
production site will ensure that this is the requested CBU to be manipulated for the 
patient according to communication with the SLM and based on the CBU accompanying 
documentation ______________________________  
7.4. Transplant Suitability Confirmation: (Prior to the start of 
conditioning) 
Confirm that the patient is still suitable for transplant according to standard site practice.  
The site investigator, or designee, must sign a statement within 24 hours prior to the start 
of conditioning indicating that the patient remains suitable for transplant.  Patients no 
longer suitable for transplant will be treated according to investigator’s discretion and 
will be considered screen failures for this protocol.   
Additional viral screening is suggested prior to administration of the conditioning 
regimen to confirm absence of infection.  At the investigator’s discretion, patients with 
fever or suspected minor infection should await resolution of symptoms before starting 
the conditioning regimen. If, as a result of delays in the transplant schedule, tests and 
evaluations are no longer within the acceptable timeframe for transplant suitability, these 
tests must be repeated prior to the start of conditioning.   
7.5. Myeloablative Conditioning Day (-11/-9/-7/-5) to (-1)  
The preparative & conditioning regimen will be administered as detailed in section 6.3.  
GvHD prophylaxis will be administered as detailed in Section 6.4.  Patient monitoring 
during the conditioning phase (including physical examination, vital signs, CBC and 
blood chemistry) will be evaluated. 


 
 
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7.6. 
Transplantation Day (Day 0) 
Safety Assessment  
Prior to the transplantation of NiCord®, the patient will be evaluated by the Investigator 
or designee including: 
• Physical Examination including weight 
• CBC, blood chemistry (serum creatinine, total bilirubin, alkaline phosphatase, AST, 
ALT and magnesium, at a minimum) 
• Vital Signs: temperature, blood pressure, pulse, and respiratory rate  
7.6.1. Preparation and Infusion of NiCord®  
7.6.1.1. 
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________


 
 
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Page 70 
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
__________________________________  
7.6.1.2. 
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
__________________  
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
____________ 
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
__________________________________________ 
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________            __________  
7.6.1.3. 
__________________  
________________________________________________________________________
________________________________________________________________________


 
 
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Page 71 
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
_____________ 
 Evaluation and Treatment of IPQC/FPQC Safety Tests Failure 
The following safety test results may not be available at the time the patient is 
transplanted: 
• Final results of day 14 sterility test performed on the CF 
• Results of day 21 sterility and mycoplasma tests performed on the 
CF_____________________________________________________________-
____________________________________________________________________
_________  
The transplant site will get a final CoA containing all test results 
7.6.2. Post Transplantation Follow-Up (Day 0 to 1)  
Safety assessment including: 
• Vital Signs 
• Assessment of acute toxicity 24 hours post transplant  
• AEs Reporting 
• Filgrastim will be administered beginning on day +1 
• Blood samples for MultiPlex Immuno Assays collected for batch-shipment to 
University Medical Center Utrecht (day 0) 
7.7 
Scheduled Treatment Visits (As Detailed In Table 8) 
7.7.1. Scheduled Visits on Day 1, 2, 3, 4, 5, 6 
The following assessments are mandatory: 
• AEs  and concomitant medications (including RBC and platelet transfusions) will be 
recorded 
• Vital Signs 
• CBC with WBC differential (differential not required if WBC<0.2), blood chemistry 
(serum creatinine, total bilirubin, alkaline phosphatase, AST, ALT and magnesium, 
at a minimum) 


 
 
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• GvHD prophylaxis as specified in Section 6.4 
• Infection prophylaxis as specified in Section 6.11 
• Blood samples for MultiPlex Immuno Assays collected for batch-shipment to 
University Medical Center Utrecht (day 1) 
7.7.2. Scheduled Visits on Day 7/ Days (±3) 14, 21, 28, 35, 42, 70/ Day (±14) 100/ Days 
(+21) 180, 365   
The following assessments are mandatory: 
• Information about AEs, hospitalizations, and concomitant medications (including 
RBC and platelet transfusions) will be recorded in the patient’s medical record 
• Vital Signs 
• Physical examination (days 28, 70, 100, 180, and 365) including routine cardiac and 
pulmonary monitoring 
• Karnofsky/Lansky performance status score (days 28, 70, 100, 180, and 365) 
• CBC with WBC differential (differential not required if WBC<0.2), blood chemistry 
(serum creatinine, total bilirubin, alkaline phosphatase, AST, ALT and magnesium, 
at a minimum) 
• CMV PCR weekly until day 100 
• EBV PCR (monthly, or more frequently as clinically indicated, until day 100, or 
longer if patient is on immunosuppression)   
• HHV6 DNA assessment by PCR weekly until ANC >500    
• Peripheral blood collection for donor/host chimerism (days 7, 14, 21, 28, 42, 70, 100, 
180, and 365 only). Bone marrow chimerism is an acceptable alternative to 
peripheral blood.  Whole blood chimerism and lineage specific (CD3 and either 
CD15 or CD33) chimerism must be performed. In cases where NiCord® was 
transplanted with an additional CBU, chimerism testing will also delineate the donor 
source (donor1/donor2/host) 
• Bone Marrow (aspirate/biopsy, when clinically indicated) for morphology (all) and 
for FACS, molecular markers and cytogenetics (if abnormal findings present at 
diagnosis for leukemia/MDS patients)-days 100 and 365 or other as per Investigator's 
discretion  
• CT abdomen, pelvis, chest (lymphoma only) (day 100, 180, and 365 or other 
schedule as per Investigator's discretion) 
• Blood samples for Immunophenotyping for batch shipment to University Medical 
Center Utrecht (days 7, 14, 21, 42, 70, 100, 180, and 365).   


 
 
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o On days 70, 100, 180, and 365 site will assess T-cell subsets (CD3, 
CD4, CD8, CD19, CD56/16) locally as well as collecting samples for 
batch shipment to  University Medical Center Utrecht 
• Blood samples for MultiPlex Immuno Assays analyses sent to University Medical 
Center Utrecht (days 7, 14, 21, 42) 
• Immunoglobulin levels (IgG, IgA, IgM) (days 70, 100, 180, and 365) 
• Blood samples for T-cell Receptor Excision Circles (TREC) and T cell receptor 
(TCR) beta  within CD4+ & CD8+ for batch shipment to University Medical Center 
Utrecht (days 100, 180, and 365)  
• GvHD assessment:  
 Acute: At every visit post transplant, or more frequently as clinically indicated, 
Acute GvHD will be assessed according to the Consensus Conference on Acute 
GvHD grading (Appendix A) 
 Chronic: days 100,180, and 365 or more frequently as clinically indicated. 
Chronic GvHD will be assessed and classified as limited or extensive, according 
to standard criteria (Appendix A) and also classified as mild, moderate, or severe, 
according to the National Institute of Health consensus grading criteria51. 
• GvHD prophylaxis as specified in Section 6.4 
• Infection prophylaxis as specified in Section 6.11 
7.7.3. Evaluation and Treatment of Graft Failure 
Evaluation of Graft Failure: should a patient suffer primary or secondary graft failure, an 
attempt will be made to determine the cause of failure. Evaluation will include: 
• Bone marrow aspiration/biopsy for morphologic analysis as well as 
cytogenetics, chimerism studies, viral/bacterial cultures including PCR 
analysis for Herpes viruses (including CMV and HHV6).  Assessment should 
be performed between day 21 and 42 for primary graft failure. 
Treatment of Graft Failure: If the patient has less than 100 PMN at day +28 and most 
recent BM shows decreased marrow cellularity and paucity of donor cells (less than 20%) 
by chimerism analysis, this may be considered impending primary graft failure (different 
from actual graft failure as defined in section 4.2.1). In a case of impending or actual 
graft failure, the patient will be treated at the discretion of the treating physician. 
Graft Rejection: Graft rejection will be defined by absence of evidence of donor 
hematopoiesis with evidence of host hematopoiesis on or before day 42.  
In patients experiencing delayed or failed engraftment, serologic assessment of HHV6 
and CMV will be performed. 


 
 
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7.7.4. Early Discontinuation of Follow-up  
Reasons for withdrawal of the patient prior to Day 365 must be stated in the CRF and in 
the site source documentation for all study patients who were enrolled in the study. This 
includes patients who were screened and assigned a screening number but did not start 
the treatment. Patients will be defined as screening failures when withdrawn from the 
study before receiving the NiCord® infusion.  
Patients who do not receive a NiCord® infusion but are given a backup CBU are part of 
the intent to treat analysis and should be followed for ANC engraftment, secondary graft 
failure, survival, and relapse.  
For early termination patients that withdraw/are withdrawn from the study post 
transplant, any assessments due at the time of withdrawal (according to Table 9) are 
requested. 
Patients who experience graft failure or relapse post transplant will continue to be 
followed for survival.  No other study related assessments are required for these subjects 
after the date of graft failure or relapse. 
 
7.7.5. Criteria for Early Termination/Discontinuation 
Patients who are prematurely discontinued from the study should be followed and treated 
by the Investigator according to institutional guidelines. Patients who join the study will 
be asked for permission that their clinical investigator be allowed to transmit information 
to the trial center on the clinical outcomes as assessed during the usual clinical 
management of their disease over the first 365 days following treatment. This will allow 
us to continue to gather clinical information on patients who subsequently withdraw from 
active participation and did not withdraw informed consent, and to include them in the 
analyses of all clinical endpoints.  
A patient may withdraw or be withdrawn from the study for the following reasons: 
• Patient withdrew consent 
• Sponsor requested patient to be withdrawn 
• Request of primary care physician or Investigator 
• Non-compliance (per investigator judgment) 
• Lost to follow-up 
• AE 
7.8. Data Reporting  
7.8.1. Criteria for Forms Submission 
Criteria for timeliness of submission for all study forms are detailed in the Data 
Management Handbook and User’s Guide. ______________________________ 


 
 
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________________________________________________________________________ 
________________________________________________________________________ 
________________________________________________________________________ 
________________________________________________________________________ 
________________________________________________________________________ 
Adverse Events will be reported as outlined in Section 9 of this protocol.


 
 
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Study Medication  
8.1. Description 
8.1.1. NiCord® 
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
____ 
8.2. CBU Supply  
All CBUs should be procured from public banks that meet local applicable regulations. If 
the optimal unit(s) for the patient was determined ineligible or with unusual findings as 
per local regulations, the unit may be used under the urgent medical need provision and 
in consultation with the sponsor. 
NiCord® CF and NF manufacturing will be performed by the Sponsor's central 
production site in Israel. 
Myeloablative, GvHD prophylaxis, immunotherapy support and other supportive care, as 
detailed in Section 6, will be supplied by the study site.  
8.3. Manufacturing  
NiCord® is manufactured in a production site, inside a laminar flow hood (class 100, ISO 
5) within a room that has been qualified as a Class 10,000 (ISO 7), in compliance with 
the production instructions and procedures as provided by the Sponsor. 
Quality control (QC) tests are performed throughout the course of the manufacturing and 
on the final product and their results are documented. The testing includes in-process 
quality controls (IPQC) and final process quality controls (FPQC) performed according 
to ___________________. The IPQC and FPQC tests are performed according to written 
analytical methods either by QC employees or by trained outsourcing testing labs.  
IPQC samples from NiCord® are taken at different identified stages during the process 
and include both Bioassays and Safety tests as detailed in the table below. 


 
 
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Table 9: 
____________________________________________________________
____________________________________________________________     
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
_______________________ 
 
 


 
 
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Table 10:-----------------------                       
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
________________________________________________________________________
_______________________________________________________________________
_______________________________________________________________ 
 
 
 


 
 
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Table 11:  
____________________________________________________________
____________________________________________________________
____________________________________________________________
__________________________  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________________________________________________________________________
____________________________________________________________________________________
____________________________________  
 
All the safety and some of the IPQC and FPQC bioassays tests have specifications and 
the results should be within the provided specifications. Some of the IPQC and FPQC 
bioassays do not have specifications and results are only collected and documented. 
_______________________________________________________________________ 
________________________________________________________________________
______________________________________________________________________ 
______________________________________________________________________ 
 
8.3.1. Safety OOS Results 
In the event that a safety test result failed to meet its specification, an immediate 
investigation is initiated. The resulting report will be attached to the deviation report and 
filed in the Batch Record. 
• __________________________________________________________________ 
__________________________________________________________________ 
• ____________________________________________________________________
____________________________________________________________________
__________ 
• ____________________________________________________________________
____________________________________________________________________
____________________________________________________________________ 
• ____________________________________________________________________
____________________________________________________________________
____________________________________________________________________
___________________________________  


 
 
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i. 
_______________________________ 
ii. __________________________________________________________________
___________ 
iii. __________________________________________________________________
_______________________________________________ 
8.3.2. _______________________________________ 
________________________________________________________________________
________________________________________________________ 
• ____________________________________________________________________
____________________________________________________________________
__________________________________________________________________  
• ____________________________________________________________________
____________________________________________________________________
____________________________________________________________________
__________________________________________________________________ 
• ____________________________________________________________________
____________________________________________________________________
____________________________________________________________________
___________________________________ 
________________________________________________________________________
__________________________________________________                                   
________________________________________________________________________
________                                                                                                ____ 
In the case of European clinical site, the product is shipped with a QP "release for 
shipment" certificate and the different CoAs are faxed/emailed to the clinical sites with 
the QP "release for infusion" certificate. 
8.4. Handling of NiCord®  
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
Shipment  
NiCord® __________________________________________ will be shipped under 
quarantine status with all available CBU segments to the clinical site in a cryoshipper 
equipped with a calibrated data logger prior to transplantation with all necessary 
documentations.  
________________________________________________________________________  
The shipment of NiCord® will be controlled by the sponsor in order to assure that 
shipment conditions were maintained as described in the Sponsors procedures. The 


 
 
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checks performed will be documented in a special form ___________________________ 
When a shipment is received, the Investigator/Coordinator will acknowledge receipt.  


 
 
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9. SAFETY MONITORING 
9.1. 
Definitions 
9.1.1. Adverse Event (AE) 
Adverse event means any untoward medical occurrence associated with the use of the 
investigational product, whether or not considered related to the investigational product.  
Treatment-emergent AEs are any AEs that occur or worsen (i.e. increase in grade) during 
or after the infusion of the study product. 
9.1.2. Infusion Reaction 
Any adverse event that occurs or worsens (i.e. increases in grade) between the start of the 
cord blood infusion and 24 hours after the end of the cord blood infusion.   
9.1.3. Serious Adverse Event (SAE) 
An adverse event or suspected adverse reaction (see section 9.1.4) is considered “serious” 
if, in the view of either the investigator or sponsor, it fulfils one or more of the following 
criteria:  
• Results in death  
• Is life-threatening  
NOTE: An event is considered "life-threatening" if, in the view of either the 
investigator or sponsor, its occurrence places the patient or subject at immediate 
risk of death. It does not include an adverse event or suspected adverse reaction 
that, had it occurred in a more severe form, might have caused death.  CTCAE 
grade four events are not automatically defined as life threatening for SAE 
determination.  For example, a grade four increase in ALT/SGPT may or may not 
be deemed as life threatening by the investigator and/or sponsor. 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
NOTE:  Complications that occur during hospitalization are AEs.  If a 
complication prolongs hospitalization or fulfills any other serious criteria, the 
event is serious.  Elective or previously scheduled hospitalizations for pre-existing 
conditions which have not worsened after initiation of treatment should not be 
classified as SAEs.  Any hospitalization regardless of duration will be considered 
serious unless the hospitalization was for social or convenience reasons during 
which no untoward medical occurrence occurred.  
• Results in persistent or significant disability or incapacity 
NOTE:  The term disability is defined as a substantial disruption of the ability to 
conduct normal life functions.   This definition is not intended to include 
experiences of relatively minor medical significance, such as uncomplicated 
headache, nausea, vomiting, diarrhea, influenza, or accidental trauma (i.e., 
sprained ankle) that may interfere or prevent everyday life functions but do not 
constitute a substantial disruption.  
• Is a congenital anomaly/birth defect.  


 
 
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Important medical events that do not meet any of the criteria above should be considered 
serious when, based upon appropriate medical judgment, they jeopardize the patient or 
subject or require medical or surgical intervention to prevent one of the outcomes listed 
in this definition. 
9.1.4. Suspected Adverse Reaction 
A suspected adverse reaction is considered as any adverse event for which there is a 
reasonable possibility that the study product caused the event.  “Reasonable possibility” 
means there is evidence to suggest a causal relationship between the study product and 
adverse event. 
The Investigator must make the determination of relationship to the study product for 
each AE/SAE.  Alternative causes, such as natural history of the underlying diseases, 
concomitant therapy, other risk factors, and the temporal relationship of the event to the 
study product, will be considered and investigated. The Investigator will also consult the 
Clinical Investigator’s Brochure and/or Product Information for marketed products in the 
determination of his/her assessment. 
9.1.5. Causality 
The Investigator will use the following question when assessing causality of an adverse 
event to study product:  Is there a reasonable possibility that the study product caused 
the event?   An affirmative answer designates the event as a suspected adverse reaction.   
9.1.6. Expectation 
Unexpected: An event is considered “unexpected” when it is not listed in the IB or it is 
not listed at the specificity and severity that has been observed. It also refers to adverse 
events or suspected adverse reactions that are mentioned in the investigator’s brochure 
but are not specifically mentioned as occurring with the particular study product under 
investigation. 
9.1.7. Toxicity Grading 
GvHD symptoms will be graded according to the Consensus Conference on Acute GvHD 
grading52 for acute GvHD and National Institute of Health consensus grading criteria51 
for chronic GvHD. 
Infections will be graded according to the infection grading scale provided in the Data 
Management Handbook. 
All other AEs will be graded using NCI’s Common Terminology Criteria for Adverse 
Events (CTCAE) Version 4.03.   
An AE that is assessed as CTCAE grade three (i.e. “severe”) should not be confused with 
an SAE.  Severity is a category used for rating the intensity of an event; both AEs and 
SAEs can be assessed as severe.  An event is described as ‘serious’ when it fulfils one or 
more of the criteria described in Section 9.1.3 


 
 
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9.1.8. Expedited Reporting 
The following events meet the criteria for expedited reporting and require submission of 
an Adverse Event Form _______________ within 24 hours of knowledge of the event 
(note that all SAEs require reporting within 24 hours of knowledge of the event, although 
not all SAEs will require expedited reporting to regulatory authorities).  
• Grade 3-5 infusion reactions  
• Non-engraftment at 42 days post NiCord® infusion   
• All serious, unexpected, suspected adverse reactions as defined in 21 CFR312.32 and 
Directive 2001/20/EC 
A detailed summary of the events above are required from the Investigator within 2 
working days of knowledge of the event.  The summary will include date of onset, peak 
grade, potential causes, resolution date (if applicable), past medical history, concomitant 
medications, an event narrative, and actions taken.  A discharge summary or hospital 
notes with supporting labs and radiologic reports should be attached as well.   
Other Adverse Events that do not meet the criteria for expedited reporting should be 
recorded in the database as outlined in Appendix B.  Clinical centers are expected to 
report AEs to their IRB/EC according to their own institutional guidelines. 
An expedited report will also be submitted if an aggregate analysis indicates that serious 
expected serious adverse reactions are occurring more frequently or at a higher severity 
than what was previously expected. 
9.2. Observation, Detection and Recording of AEs and SAEs 
The Investigator and/or study personnel will enquire about the occurrence of AEs at 
every visit, after the subject has had the opportunity to spontaneously mention any 
problems.  Because of their underlying disease and toxic preparative therapy, a wide 
range of adverse events are anticipated.   
All AEs will be recorded in the source documents with sufficient detail to allow for 
grading per CTCAE v4.03, and reported on the appropriate CRF page.  
▪ All infections post transplant will be reported on an infection form.   
▪ Graft versus Host Disease (GvHD) will be reported on GvHD forms.  
▪ __________________________________________________________________
__________________________________________________________________
__________________________________________________________________
________________________________________________________________   
▪ __________________________________________________________________
________________________________________________ 
▪ Serious Adverse Events post transplant will be reported on SAE summary forms 
 


 
 
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___________________________________  
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
_______________________________________________ 
____________________________________________________  
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
__________________________________  
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
____________________________________  
Serious Adverse Events 
At all times after the start of conditioning, SAEs, grade 3-5 infusion reactions and non-
engraftment at day 42 post transplant will be reported on SAE summary forms.  These 
events may require reporting on other forms as well (e.g. Death form when applicable), 
however they should not be reported on the Adverse Event Log form.  SAEs should be 
reported within 24hrs of the sites’ knowledge of the event. 
Where possible, a diagnosis rather than a list of symptoms should be recorded. The 
Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. In such cases, the diagnosis should be documented as 
the AE/SAE and not the individual signs/symptoms. If a diagnosis has not been made 
then each symptom should be listed individually. 
For every SAE that occurs between the time of patient consent and the participant’s final 
study visit, the Investigator is responsible for reviewing all documentation (e.g., hospital 
progress notes, laboratory test results, and diagnostic reports) relating to the event.  For 
events that occur after the start of conditioning, the Investigator or designee will then 
record all relevant information about an SAE onto the appropriate page of the CRF.  The 
Investigator must review, sign, and date an SAE summary report form to confirm the 
accuracy of the recorded information.  The signed report will be maintained in the site’s 
study files.  It is not acceptable for the Investigator to send photocopies of the subject’s 
medical records in lieu of completion of the appropriate CRF pages.  Unless otherwise 
requested, transfer of subjects’ medical records with the CRF should be restricted to 
hospital admission and progress notes, laboratory and radiology reports, discharge 


 
 
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summaries and autopsy reports, if available.  When sending medical records, all subject 
identifiers (i.e., name, medical record number) must be obliterated prior to faxing the 
documents to the designated project contact. 
9.3. Follow-up of AEs and SAEs 
All reported AEs and SAEs will be followed and recorded until resolution with or 
without sequelae (the patient’s health has returned to baseline status or all variables have 
returned to normal), until the condition stabilizes (the Investigator does not expect any 
further improvement or worsening of the event), until an outcome is reached or the event 
is otherwise explained, or until there is agreement between the Investigator and sponsor 
that additional follow-up is not warranted. The Investigator will ensure that follow-up 
includes any supplemental investigations as may be indicated to elucidate the nature 
and/or causality of the AE/SAE.  This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health care 
professionals. Where appropriate, medical tests and examinations will be performed to 
document resolution of the event(s).  Additional follow-up information, if required, or 
available, must be reported in the same timelines as initial information.  New or updated 
information will be recorded on the originally completed CRF, with all changes to SAEs 
signed and dated by the Investigator on the original source document and maintained in 
the site’s study files. 
9.4. Medical Monitor Review 
Both the ________ Medical Monitor (MM) and the sponsor will be alerted ___________ 
________________________________________________________________________
____ 
• Grade 3-5 infusion reactions  
• Non-engraftment at 42 days post NiCord® infusion   
• All serious adverse events   
The MM is responsible for initial review of these events within 1 business day of email 
notification.  The MM review will be documented _______________. If the MM requires 
additional information to make an assessment, the transplant center will have 2 calendar 
days to respond to the request.  As noted above, most information is due within 2 
calendar days of the sites’ knowledge of the event.   
9.5. Clinical Laboratory Evaluations 
All laboratory measurements will be evaluated for abnormalities.  An abnormal 
laboratory value should be primarily interpreted in the context of the disease or the 
condition leading to it. The latter (instead of the laboratory abnormality itself) should be 
reported as adverse event and graded, whenever possible. A laboratory adverse event i.e., 
a laboratory abnormality not associated with any particular clinical findings (e.g., 
symptoms, signs), will be reported when judged clinically significant by the investigator. 


 
 
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An abnormal laboratory finding is not by itself considered to be an AE or SAE unless the 
investigator considers the abnormal finding to be of clinical significance.  The abnormal 
laboratory finding does not have to be associated with the use of NiCord® to be 
considered clinically significant.  If a laboratory adverse event is reported, it will be 
graded using the CTCAE toxicity grading scale version 4.03. A laboratory adverse event 
with a value falling within the specified CTCAE grade 4 boundaries will only be 
considered life-threatening from a regulatory perspective if it results in an actual life-
threatening consequence i.e., its occurrence places the subject at immediate risk of death. 
Grade 4 laboratory adverse events that are not life-threatening should not be reported as 
serious adverse events unless they meet other seriousness regulatory criteria. 
9.6. Pregnancy 
Pregnancy will not be considered as an AE. Any report of pregnancy recorded for any 
female study participant or a female partner of a male study participant should be 
reported immediately within 24 hours to the sponsor 
The Investigator will follow the pregnant woman until completion of the pregnancy, and 
must notify the Sponsor of the outcome within 24 hours of the Investigator’s knowledge 
of the pregnancy outcome.  This notification includes pregnancies resulting in live, 
“normal” births. 
If the pregnant subject experiences an SAE during pregnancy, or the outcome of the 
pregnancy meets the criteria for classification as an SAE, the Investigator should follow 
the procedures for reporting SAEs (i.e., report the event to the Sponsor within 24 hours of 
the Investigator’s knowledge of the event). 
All neonatal deaths and congenital anomalies that occur within 30 days of birth 
(regardless of causality) should be reported as SAEs to the Sponsor.  In addition, any 
infant death or congenital anomaly occurring after 8 weeks that the Investigator suspects 
is related to the in utero exposure to the study drug should also be reported to the 
Sponsor. 
9.7. Patient Withdrawal from Study Procedures due to Adverse 
Events 
Any patient can be removed from the study at any time if in the judgment of the 
Investigator further treatment is not in the best interests of the patient. Patients may also 
withdraw themselves from the study at any time and for any reason.  
9.8. Sponsor Obligations 
Any concerns regarding the type or frequency of an event will be communicated to the 
DMC Chair by the sponsor.  The DMC Chair will review the adverse event materials, 
determine if the information is complete, determine if additional DMC review is required 
and make recommendations to the sponsor concerning continuation or modification of 
the study. 


 
 
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9.9. Regulatory Authorities and IRB/ECs 
The Sponsor shall notify the concerned Regulatory Authorities of Suspected Unexpected 
Serious Adverse Reactions (SUSARs) for the IMP, or other AEs as per local 
requirements. In accordance with Directive 2001/20/EC and Chapter II of Volume 10 of 
the Rules Governing Medicinal Products in the European Community, the Sponsor will 
also report SUSARs to the EudraVigilance Clinical Trial Module (EVCTM).  
The Sponsor is responsible for reporting all unexpected fatal or life-threatening suspected 
adverse reactions to regulatory authorities, as per the concerned authorities’ requirements 
no later than seven calendar days after knowledge of the event.  All grade 3-5 infusion 
reactions, non-engraftment at 42 days post NiCord® infusion, and all other serious, 
unexpected, suspected adverse reactions are reported to the regulatory authorities by the 
Sponsor within 15 calendar days of receipt of the information.   
The Sponsor or designee shall notify the Central Ethics Committees (CEC) of SUSARs 
or significant risks to subjects, per country requirements. 
The Sponsor or designee shall notify the Investigator of potential serious risks from 
clinical trials or any other sources, including the following: 
• 
Suspected adverse reaction that is both serious and unexpected. 
• 
Any findings from other studies that suggest a significant risk in humans exposed 
to the drug. 
• 
Any finding from animal or in vitro testing that suggest a significant risk to 
humans exposed to the drug, such as mutagenicity, teratogenicity, or carcinogenicity; or 
report of significant organ toxicity at or near the expected human exposure. 
It is the responsibility of the Principal Investigator (PI) to notify the IRB/EC of all SAEs 
that occur at his or her site. Each site is responsible for notifying their IRB/EC of these 
additional SAEs. The Investigator must keep copies of all AE information, including 
correspondence with the Sponsor or Local Ethics Committees on file. 
 


 
 
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10. 
STATISTICAL METHODOLOGY 
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
Patients & Analysis Cohorts  


 
 
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10.4. Statistical Analysis  
Primary Objectives 
• Assess the cumulative incidence of patients with NiCord®-derived neutrophil 
engraftment at 42 days following transplantation.  
• Assess the incidence of secondary graft failure at 180 days following transplantation 
of NiCord® 
Secondary Objectives 
• Time from infusion to neutrophil engraftment 
• Time from infusion to platelet engraftment 
• Incidence of platelet engraftment at 100 days 
• Proportion of non-relapse mortality at 100 days 
• Incidence of acute GvHD grade II-IV and III-IV at 100 days 
• Incidence of chronic GvHD (limited or extensive) at 180 days and 1 year 
• Incidence of secondary graft failure at 1 year following transplantation of NiCord® 
• Overall survival at 180 days and 1 year 
Exploratory Objectives  
• Immune reconstitution at 70, 100, 180, and 365 days 
10.4.1. Primary Endpoints 
10.4.1.1. Neutrophil Engraftment 
To assess the incidence of neutrophil engraftment post transplant a cumulative incidence 
curve will be computed along with a 95% confidence interval at 42 days post-transplant.  
Death prior to engraftment will be considered as a competing risk. 
10.4.1.2. Incidence of Secondary Graft Failure    
The cumulative incidence of secondary graft failure out of those who had initial 
engraftment will be described using the cumulative incidence estimator, treating death 
and disease relapse/progression prior to secondary graft failure as a competing event.  
10.4.2. Secondary Endpoints  
10.4.2.1. Time from Infusion to Neutrophil Engraftment  
The incidence of initial neutrophil engraftment will be estimated with a cumulative 
incidence curve with death as a competing risk.  Median time to neutrophil (>0.5x109/L) 
engraftment will be estimated among those in whom engraftment is achieved.   


 
 
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10.4.2.2. Time from Infusion to Platelet Engraftment  
The incidence of platelet engraftment (>20x109/L and >50 x109/L) will be estimated with 
a cumulative incidence curve with death as a competing risk.  Median time to platelet 
(>20x109/L and >50 x109/L) engraftment will be estimated among those in whom 
engraftment is achieved.  
10.4.2.3Incidence of Platelet Engraftment at 100 days   
The incidence of platelet engraftment (>20x109/L and >50 x109/L) will be estimated with 
a cumulative incidence curve with death as a competing risk.   
10.4.2.4. Non-Relapse Mortality  
To assess the incidence of non-relapse mortality, a cumulative incidence curve of death 
occurring in a subject not preceded by relapse will be computed along with a 95% 
confidence interval at 100 days post-transplant.  Relapse and progressive disease will be 
considered as a competing risk. 
10.4.2.5. Acute GvHD Grade II-IV and III-IV 
The cumulative incidence of patients who experience these events will be computed 
along with a 95% confidence interval at day 100. Death and second transplant will be 
considered as a competing risk in the estimation.  
10.4.2.6. Chronic GvHD  
The cumulative incidence of patients who experience chronic GvHD will be computed 
along with a 95% confidence interval at 180 days and 365 days post transplant. Death and 
second transplant will be considered as a competing risk in the estimation. 
10.4.2.7. Overall survival  
The proportion of patients alive at 180 days and 365 days post transplant will be 
estimated using the Kaplan-Meier method. 
10.4.2.8. Safety and Tolerability of NiCord® Transplantation  
The safety and tolerability of NiCord® transplantation will be evaluated by the nature, 
incidence and frequency of adverse experiences and an estimation of the relationship to 
NiCord®, as well as infections and laboratory data follow-up, with special emphasis on 
safety of cell therapy, including the detection of infusion reactions, transmission of 
infections, new malignancies and autoimmune diseases. 
10.4.3. Exploratory Endpoints  
10.4.3.1. Immune Reconstitution 
The distributions of total immunoglobulin levels at days 70, 100, 180, and 365 (mean, 
standard deviation, median, quartiles) will be estimated. The distributions of the numbers 


 
 
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and proportions of different lymphocyte subpopulations at days 70, 100, 180, and 365 
(mean, standard deviation, median, quartiles) will also be estimated.  The distributions of 
T-cell excision circles at days 100, 180, and 365 (mean, standard deviation, median, 
quartiles) will also be estimated.  Patients who have graft failure, who relapse, or who die 
before target day (70, 100, 180, or 365 respectively) will be excluded from this analysis.   
10.5. Missing Data  
Unless otherwise specified, patients with missing data will be excluded from the analysis 
in which their data is missing.  For descriptive analyses of multiple timepoints, patients 
with data missing at some timepoints but not others will be censored from the analysis of 
those timepoints in which their data is missing.  For survival and incidence curves 
patients with missing data will be included and censored at the time of missing data, 
unless otherwise specified as a competing risk.   
10.6. Analysis Plan Deviations  
Deviations from the original statistical analysis plan will be reported in the final study 
report. 
10.7. Statistical Software  
SAS® version 9.1 or higher software and R version 2.10.0 or higher will be used for 
statistical analysis and data presentation of the information collected in this study. 


 
 
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11. 
CLINICAL DATA MANAGEMENT  
11.1. Data Quality Assurance  
This study will be organized, performed, and reported in compliance with the 
Sponsor/CRO’s SOPs, protocols and working practice documents, and the requirements 
of the Declaration of Helsinki and ICH/GCP guidelines. Compliance will be achieved 
through a combination of study specific audits of investigative sites and audits at regular 
intervals of the Sponsor/CRO’s systems for data handling, analysis, and reporting. 
A quality assurance audit of this trial may be conducted by the sponsor or sponsor’s 
designees. The quality assurance auditor will have access to all medical records, the 
investigator’s trial-related files and correspondence, and the informed consent 
documentation that is relevant to this clinical trial. 
11.2. Data Collection  
Investigators or designees will enter the information required by the protocol onto the 
CRFs. Each investigative site will be visited as frequently as documented in the 
monitoring plan by the CRO on behalf of the Sponsor to review the CRFs for 
completeness and accuracy. The CRO representative will highlight any discrepancies 
found between source documents and the completed CRFs and ensure that appropriate 
site personnel address the discrepancies. When a discrepancy results in corrected CRF 
data, the correction will be reviewed again against the correct source documentation. 
Uniform procedures will be discussed at the Site Initiation Visit. 
11.3. Source Documents  
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. All clinical data entered onto the CRF must be supported 
by source documentation maintained at the clinical site.  Data entered in the CRFs that 
are transcribed from source documents must be consistent with the source documents or 
the discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the trial; also current medical records 
must be available.  
Direct access to source data - documents 
• 
The investigator / institution will permit trial-related monitoring, audits, IRB / 
IEC review and regulatory inspection, providing direct access to all related source data / 
documents. 
• 
CRFs and all source documents, including progress notes and copies of laboratory 
and medical test results must be available at all times for review by the sponsor’s clinical 
trial monitor and inspection by health authorities (e.g. MS CA/EMA). The Clinical 
Research Associate (CRA) / on site monitor may review all CRFs, and written informed 
consents. The accuracy of the data will be verified by reviewing the documents. 
 


 
 
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11.4. Staff Training  
Prior to enrollment, all clinical study personnel will be trained to ensure adherence to the 
protocol and assure the highest possible data quality.  Training will be led by CRO and 
the sponsor at a central location.  Training presentations will address informed consent 
procedures, study operations and protocol requirements, data collection procedures, 
maintenance of source documentation, CRF completion and review, routine reporting 
requirements, data entry and management, and policies and procedures. 
11.5. Data Monitoring  
CRAs will be responsible for monitoring CRFs and source documents for accuracy, 
protocol compliance, subject safety, and adherence to guidelines in the Site Operations 
Manuals. 
At each site visit, the CRA will review recruitment guidelines and study eligibility 
criteria.  As the study progresses, completed data forms may be reviewed during site 
visits and compared to source documentation (medical or site records) to confirm 
accuracy. 


 
 
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APPENDIX A. 
GVHD CLASSIFICATION 
 
Acute GvHD Definition 
Acute GvHD will be assessed at every visit from transplantation (day 0) until end of 
study or more frequently as clinically indicated. GvHD will be classified according to the 
Consensus Conference on Acute GvHD grading[52]: 
 
Overall Grade 
Skin 
Liver 
Gut 
I 
Stage 1-2 
None 
None 
II 
Stage 3 or 
Stage 1 or 
Stage 1 
III 
 
Stage 2-3 or 
Stage 2-4 
IV 
Stage 4 or 
Stage 4 
 
 
*See following table for individual organ staging. The overall grade of GvHD, however, 
reflects the actual extent of disease. For each overall grade, an assessment of skin disease 
plus liver and/or gut involvement is required. 
 
Acute GvHD may be documented after day 99 (“late acute”) if according to clinical 
judgment the investigator feels it should be classified as acute rather than chronic. 
 
Clinical Manifestations and Staging of Acute Graft-versus-Host Disease 
Organ 
Clinical Manifestations 
Staging 
Skin 
Erythematous, maculopapular rash 
involving palms and soles; may 
become confluent 
Severe disease: bullae. 
Stage 1: <25% rash 
Stage 2: 25-50% rash 
Stage 3: generalized erythroderma 
Stage 4: bullae 
Liver 
Painless jaundice with conjugated 
hyperbilirubinemia and increased 
alkaline phosphatase. 
Stage 1: bilirubin 2-3 mg/dL 
Stage 2: bilirubin 3.1-6 mg/dL 
Stage 3: bilirubin 6.1-15 mg/dL 
Stage 4: bilirubin >15 mg/dL 
Gastrointestinal tract 
Upper: nausea, vomiting, anorexia. 
Lower: diarrhea, abdominal cramps, 
distention, ileus, bleeding. 
Stage 1: diarrhea >500 ml/day or 
persistent nausea 
Stage 2: diarrhea >1000 ml/day 
Stage 3: diarrhea >1500 ml/day 
Stage 4: large volume diarrhea and 
severe abdominal pain +/- ileus 
 
 
 
 
Chronic GvHD Definition 


 
 
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Chronic GvHD will be assessed from day 100 until day 365 or more frequently as 
clinically indicated. Chronic GvHD will be classified as limited or extensive according to 
the following criteria. 
 
 
Criteria for Extent of Involvement in Chronic Graft-versus-Host Disease 
Involvement 
Clinical Criteria 
Limited 
Localized skin involvement, liver dysfunction, or both. 
Extensive 
Generalized skin involvement 
OR 
Localized skin involvement or liver dysfunction plus any one of the following: 
Chronic aggressive hepatitis, bridging necrosis, cirrhosis. 
Eye involvement (result on Schirmer test: <5 mm). 
Involvement of mucosalivary glands. 
Mucosal involvement (on lip biopsy). 
Involvement of other target organs. 
 Chronic GvHD will also be classified as mild, moderate, or severe, according to the 
National Institute of Health consensus grading criteria51. 


 
 
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APPENDIX B. 
SAFETY DATA REPORTING 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* See appendix C for a list of common adverse events 
# With the exception of infections and GvHD symptoms which are reported on the Infection form and GvHD forms respectively.   
During Conditioning 
up to Start of NiCord 
Infusion 
During NiCord Infusion 
through 24 hours Post NiCord 
Infusion 
 
> 24 hours Post NiCord 
Infusion through Day 42 
Day 43 through Day 365 
 
Complete a Toxicity 
form with the highest 
grade of all common* 
adverse events 
 
Complete a Toxicity form 
with the highest grade of all 
common* adverse events 
 
Grade 3-5 events also require 
completion of SAE summary 
forms (AD1-AD5) 
 
All grade 1-2 uncommon non-
serious adverse events must be 
listed individually on the 
Adverse Event Log form.# 
 
 
Complete a weekly Toxicity 
form with the highest grade 
of all common* adverse 
events during that week. 
 
Non-engraftment at day 42 
requires completion of SAE 
summary forms (AD1-AD5) 
 
All other uncommon non-
serious adverse events must 
be listed individually on the 
Adverse Event Log form.# 
 
 
All grade 3-4 non-
serious adverse events 
must be listed 
individually on the 
Adverse Event Log 
form. # 
 
Infection form is required when applicable 
Scheduled  GvHD data collection at every visit on either the GVH or the CGV form. 
Any event that also meets the definition of an SAE, requires submission of SAE summary forms (AD1-AD5).  If the 
SAE is unexpected and associated with NiCord®, then an expedited report must be submitted. 
A Hospitalization form (ADM) and/or Death form (DTH) required if applicable  


 
 
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APPENDIX C. 
COMMON ADVERSE EVENTS 
Cardiac 
Cardiac Arrhythmias 
 
Gastrointestinal 
Abdominal distension 
Nausea 
Vomiting 
Constipation 
Dyspepsia 
Dysphagia 
Mucositis 
 
General Disorders 
Allergic reaction 
Chills 
Edema 
Fatigue/Malaise/Lethargy 
Fever 
Pain  
 
Injury/Poisoning/Procedural Complications 
Bruising 
Hemorrhage 
Vascular access complications 
 
Investigations 
Elevated alkaline phosphatase  
Elevated creatinine 
Elevated liver transaminases (ALT, AST) 
Elevated triglycerides 
Weight loss 
 
Metabolism and Nutrition 
Abnormal sodium  
Anorexia 
Dehydration 
Hyperglycemia 
Hypokalemia 
Hypomagnesemia 
Hypophosphatemia 
Hypoalbuminemia 
 


 
 
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Musculoskeletal 
 Generalized muscle weakness 
 
Neurologic 
Dizziness 
Dysgeusia 
Somnolence 
Syncope  
Tremors  
 
Psychiatric 
Anxiety 
Depression 
Insomnia 
 
Renal 
Non-infectious cystitis 
 
Respiratory 
Cough 
Dyspnea  
Epistaxis 
Hypoxia 
 
Skin 
Alopecia 
Dry skin 
Pruritis 
Skin hyperpigmentation  
 
Vascular 
Hypertension  
Hypotension


 
 
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APPENDIX D. 
COMMON TERMINOLOGY CRITERA FOR ADVERSE 
EVENTS V4.03  
(CTCAE)53  


 
 
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APPENDIX E: DRUG LABELS 
 
See attached documents. 


 
 
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APPENDIX F: PROTOCOL AMENDMENT SUMMARY 
 
Protocol Version Approved Sites  
Main Reason(s) for 
Amendment 
Original 
• Duke University Medical 
Center 
N/A 
Amendment I 
• Duke University Medical 
Center 
Expand patient population 
and clarify eligibility criteria 
Amendment II 
▪ Cedars Sinai Medical Center 
▪ Cleveland Clinic 
▪ Steven and Alexandra Cohen 
Children's Medical Center of 
New York 
▪ Duke University Medical 
Center 
▪ Vanderbilt University Medical 
Center 
Change in manufacturing 
procedure to cryopreserved 
product.  Modify eligibility 
criteria.  Additional option 
for conditioning regimen 
Amendment II.1 
▪ Hospital Universitario y 
Politécnico La Fe Hospital 
Universitari Vall d´Hebrón 
▪ Istituto Giannina Gaslini of 
Genoa 
▪ AOU San Luigi Gonzaga of 
Turin 
Add safety objective.  Define 
childbearing potential and 
appropriate contraception. 
Amendment II.2 
• University Medical Center 
Utrecht 
Additional option for 
conditioning regimen. 
Amendment III 
▪ Cedars Sinai Medical Center 
▪ Cleveland Clinic 
▪ Steven and Alexandra Cohen 
Children's Medical Center of 
New York 
▪ Duke University Medical 
Center 
▪ Vanderbilt University Medical 
Center 
▪ Hospital Universitario y 
Politécnico La Fe  
▪ Hospital Universitari Vall 
d´Hebrón 
Modify eligibility criteria.  
Additional regimen specific 
stopping guidelines.  
Additional supportive and 
viral monitoring care 
guidelines.  Update AE 
reporting guidelines. 
Amendment IV 
▪ Cedars Sinai Medical Center 
▪ Cleveland Clinic 
▪ Steven and Alexandra Cohen 
Children's Medical Center of 
New York 
Increase number of patients 
for study enrollment, modify 
eligibility criteria, COA 
release criteria, GvHD 
prophylaxis medication 


 
 
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▪ Duke University Medical 
Center 
▪ Vanderbilt University Medical 
Center 
▪ Hospital Universitario y 
Politécnico La Fe  
▪ Hospital Universitari Vall 
d´Hebrón 
administration and 
assessment grading criteria, 
 


 
 
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