A Phase 1/2 Trial of Uproleselan Combined With High Dose Busulfan Pre-Transplant Conditioning in Hematopoietic Stem Cell Transplantation for Patients With Chemotherapy Resistant Acute Myeloid Leukemia
Phase: PHASE1
Conditions: Acute Myeloid Leukemia, Pediatric Cancer
Sponsor: Malika Kapadia

NCT05569512 
Title: A Phase 1/2 Trial of Uproleselan Combined with High Dose Busulfan Pre‐Transplant CondiƟoning in 
HematopoieƟc Stem Cell TransplantaƟon for PaƟents with Chemotherapy Resistant Acute Myeloid 
Leukemia 
Protocol Version: 2023NOV27 

 
1
DF/HCC Protocol #: 22-063  
TITLE:  A Phase 1/2 Trial of Uproleselan Combined with High Dose Busulfan Pre-Transplant 
Conditioning in Hematopoietic Stem Cell Transplantation for Patients with Chemotherapy 
Resistant Acute Myeloid Leukemia
Sponsor-Investigator:
John Horan, MD, MPH
Boston Children’s Hospital
Dana Farber Cancer Institute
john_horan@dfci.harvard.edu 
Study Co-Chairs:
John Horan, MD, MPH
Boston Children’s Hospital
Dana Farber Cancer Institute
john_horan@dfci.harvard.edu
Joseph Chewning, MD
University of Alabama Birmingham
Children’s of Alabama
jchewning@peds.uab.edu
Malika Kapadia, MD
Boston Children’s Hospital
Dana-Farber Cancer Institute
Malika_Kapadia@dfci.harvard.edu 
Study Committee Members:
Edward Anders Kolb, MD
Alfred I du Pont Hospital for Children
eakolb@nemours.org
Amy Keating, MD
Troy C. Quigg. DO
Co-chair, Oncology Strategy Group
Co-chair, Oncology Strategy Group
Pediatric Transplant and Cellular 
Pediatric Transplant and Cellular 
Therapy Consortium (PTCTC)
Therapy Consortium (PTCTC)
Dana Farber Cancer Institute
Helen DeVos Children’s Hospital
amy_keating@dfci.harvard.edu 
Troy.Quigg@spectrumhealth.org
Maria Luisa Sulis, MD
William G. Woods, MD
Memorial Sloan Kettering Cancer Center
Children’s Healthcare of Atlanta
sulism@mskcc.org
Emory University
William.Woods@choa.org

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Muna Qayed, MD, MSCR
Matthew A. Kutny, MD
Children’s Healthcare of Atlanta
University of Alabama Birmingham
Emory University
Children’s of Alabama
Muna.Qayed@choa.org
mkutny@peds.uab.edu
Jaap Jan Boelens, MD, PhD
Memorial Sloan Kettering Cancer Center
boelensj@mskcc.org 
 
Melinda Pauly, MD
Michael R. Verneris, MD
Children’s Healthcare of Atlanta
Children’s Hospital Colorado
Emory University
michael.verneris@ucdenver.edu
Melinda.Pauly@choa.org
Malika Kapadia, MD
Jessica Pollard, MD
Boston Children’s Hospital
Boston Children’s Hospital
Dana-Farber Cancer Institute
Dana-Farber Cancer Institute
Malika_Kapadia@dfci.harvard.edu
Jessica_Pollard@dfci.harvard.edu 
Franziska Wachter, MD
Boston Children’s Hospital
Dana-Farber Cancer Institute 
Franziska_Wachter@dfci.harvard.edu 
Pediatric Pharmacologist:
Pharmacometrician:
Janel Long-Boyle, PharmD, PhD
Joga Gobburu, PhD, MBA
University of California San Francisco
University of Maryland
janel.long-boyle@ucsf.edu
jgobburu@rx.umaryland.edu 
Statistician:
SOS Adjudication:
Wendy B. London, PhD
Christine Duncan, MD
Boston Children’s Hospital
Boston Children’s Hospital
Dana Farber Cancer Institute
Dana Farber Cancer Institute
wendy.london@childrens.harvard.edu 
Christine_Duncan@dfci.harvard.edu 
Biomarkers:
E-selectin Ligand Related 
Flow cytometric measurement of 
Gene Expression:
E-selectin Ligand Expression:
Soheil Meshinchi, MD, PhD
Michael R. Loken, PhD
Seattle Children's Hospital
Hematologics, Inc. Fred Hutchinson
smeshinc@fhcrc.org
Cancer Research Center
mrloken@hematologics.com 
Agent Supply:  
GlycoMimetics, Inc.: Uproleselan (investigational supply)

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Commercial supply: busulfan, clofarabine, tacrolimus, methotrexate, mycophenolate mofetil
IND #:  155923
IND Sponsor:  John Horan, MD, MPH
PTCTC Study #: ONC 2201

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SCHEMA
Dosing schedule for uproleselan and standard conditioning

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TABLE OF CONTENTS
SCHEMA.........................................................................................................................................4
OBJECTIVES..................................................................................................................................8
1.1
Hypothesis................................................................................................................8
1.2
Study Design............................................................................................................8
1.3
Primary Objectives...................................................................................................8
1.4
Secondary Objectives...............................................................................................8
1.5
Exploratory Objectives ............................................................................................8
2.
BACKGROUND .................................................................................................................9
2.1
IND Agent: Uproleselan ..........................................................................................9
2.2
Relapse after HSCT for AML................................................................................12
2.3
Incorporating Uproleselan into Busulfan Conditioning to Enhance its Anti-
leukemic Effect......................................................................................................12
2.4
Rationale ................................................................................................................13
2.5
Correlative Studies Background ............................................................................14
3.
PARTICIPANT SELECTION...........................................................................................15
3.1
Eligibility Criteria..................................................................................................15
3.2
Exclusion Criteria ..................................................................................................16
3.3
Definitions of CNS Disease...................................................................................18
3.4
Inclusion of Children and Minorities.....................................................................19
3.5
Co-Enrollment on Other Studies............................................................................19
4.
REGISTRATION PROCEDURES ...................................................................................19
4.1
General Guidelines for Dana-Farber/Boston Children’s Cancer and Blood 
Disorders Center ....................................................................................................19
4.2
Registration Process for DF/HCC Institution ........................................................20
4.3
General Guidelines for Other Investigative Sites ..................................................20
4.4
Registration Process for Other Investigative Sites.................................................20
5.
TREATMENT PLAN........................................................................................................21
5.1
Treatment Regimen................................................................................................21
5.2
Agent Administration.............................................................................................22
5.3
Definition of Dose-Limiting Toxicity (DLT) ........................................................26
5.4
Supportive Care Guidelines...................................................................................27
5.5
Criteria for Taking a Participant Off Protocol Therapy.........................................27
5.6
Duration of Follow Up...........................................................................................28
5.7
Criteria for Taking a Participant Off Study ...........................................................28
6.
DOSE MODIFICATIONS ................................................................................................28
6.1
Dosing Modifications for Tacrolimus....................................................................29
6.2
Dosing Modifications for Methotrexate.................................................................29
6.3
Dosing Modifications for Obesity .........................................................................29

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7.
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................29
7.1
Expected Toxicities................................................................................................30
7.2
Adverse Event Characteristics...............................................................................37
7.3
Adverse Event Collection ......................................................................................37
7.4
Serious Adverse Events .........................................................................................38
7.5
Expedited Reporting ..............................................................................................39
7.6
Reporting to the Food and Drug Administration (FDA) .......................................40
7.7
Reporting to GlycoMimetics, Inc. .........................................................................40
7.8
Reporting to Hospital Risk Management...............................................................41
8.
PHARMACEUTICAL INFORMATION..........................................................................41
8.1
Uproleselan Injection.............................................................................................41
8.2
Busulfan.................................................................................................................43
8.3
Clofarabine.............................................................................................................45
8.4
Fludarabine ............................................................................................................47
8.5
Tacrolimus .............................................................................................................50
8.6
Methotrexate ..........................................................................................................53
8.7
Mycophenolate Mofetil..........................................................................................54
9.
PHARMACOKINETIC AND BIOMARKER STUDIES (REQUIRED).........................56
9.1
Pharmacokinetic Assessment.................................................................................59
9.2
Biomarker Assessments.........................................................................................60
10.
STUDY CALENDAR AND REQUIRED ROUTINE TESTING/CLINICAL 
EVALUATIONS ...............................................................................................................62
10.1
Pre-Transplant........................................................................................................64
10.2
Post-Transplant Laboratory Testing ......................................................................64
10.3
Other Post-Transplant Evaluations ........................................................................64
11.
MEASUREMENT OF EFFECT .......................................................................................65
11.1
Refractory Disease.................................................................................................65
11.2
Leukemic Relapse..................................................................................................65
11.3
Extramedullary Relapse.........................................................................................66
12.
DATA REPORTING / REGULATORY REQUIREMENTS...........................................67
12.1
Data Reporting.......................................................................................................67
12.2
Data Safety Monitoring..........................................................................................67
12.3
Multicenter Guidelines...........................................................................................68
13.
STATISTICAL CONSIDERATIONS...............................................................................68
13.1
Definition of Evaluability ......................................................................................68
13.2
Study Design/Endpoints ........................................................................................69
13.3
Sample Size, Accrual Rate and Study Duration ....................................................71
13.4
Stratification Factors..............................................................................................71
13.5
Interim Monitoring Plan ........................................................................................71
13.6
Analysis of Primary Endpoints..............................................................................72
13.7
Analysis of Secondary Endpoints..........................................................................73

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13.8
Analysis of Exploratory Endpoints........................................................................73
14.
REFERENCES ..................................................................................................................74
APPENDIX A
PERFORMANCE STATUS SCALES/SCORES......................................77
APPENDIX B 
DANA-FARBER/HARVARD CANCER CENTER MULTI-CENTER 
DATA AND SAFETY MONITORING PLAN ................................................................78
APPENDIX C
HEPATIC SOS/VOD DIAGNOSTIC AND GRADING CRITERIA.......88
APPENDIX D
BEARMAN SCALE..................................................................................92

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OBJECTIVES
1.1
Hypothesis
The long range hypothesis of this project is that incorporating uproleselan into pre-transplant 
conditioning for acute myeloid leukemia will decrease post-transplant relapse and improve 
leukemia free survival.
1.2
Study Design
Single arm, multi-center, phase 1/2 trial.
1.3
Primary Objectives
Phase 1. To assess the safety and tolerability and identify the recommended phase 2 dose (RP2D) 
of uproleselan when combined with myeloablative, busulfan-based, pre-transplant conditioning 
regimens for treatment of acute myeloid leukemia.  
Phase 2. To describe the safety of uproleselan at the RP2D when combined with myeloablative, 
busulfan-based, pre-transplant conditioning regimens for treatment of acute myeloid leukemia.
1.4
Secondary Objectives
1) To describe the pharmacokinetics of uproleselan in pediatric patients receiving 
myeloablative, busulfan based pre-transplant conditioning (this will encompass both 
phase 1 and phase 2).  
2) To describe the preliminary efficacy of uproleselan by estimating the 12-month 
leukemia-free survival (LFS), overall survival (OS), and relapse in patients receiving 
uproleselan at the RP2D
3) To describe the maximal severity of oral and gastrointestinal mucositis in patients 
receiving uproleselan at the RP2D.
1.5
Exploratory Objectives
These preliminary assessments will be performed to prepare for more definitive 
assessments in a full scale clinical trial. 
1) To obtain preliminary data on AML blast E-selectin ligand (EsL) expression by multi-
dimensional flow cytometry as predictor of uproleselan response. 
2) To obtain preliminary data on AML transcript expression of the EsL related glycan 
synthesis genes ST3GAL4 and FUT7. 

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2. BACKGROUND
2.1
IND Agent: Uproleselan
E-selectin is constitutively expressed on the sinusoidal endothelial cells of the marrow’s vascular 
niche and plays a critical role in the regulation of hematopoietic stem cell quiescence, self-
renewal, activation and homing.  AML cells hijack the vascular niche through secretion of TNFα 
and other inflammatory mediators, increasing endothelial expression of E-selection, and through 
alterations in the E-selectin ligand, augmenting their E-selectin binding potential. E-selectin 
activates pro-survival signaling in AML cells through AKT/NF-kB pathways. This protects 
AML leukemia regenerating cells from cytotoxic chemotherapy. Uproleselan, a small molecule 
E-selectin mimetic, blocks this interaction, abrogating pro-survival signaling and, thereby, 
sensitizing AML cells to chemotherapy.1
A phase I/II trial combining uproleselan with conventional chemotherapy for treatment of adults 
with AML has been completed (ClinicalTrials.gov identifier: NCT02306291).2  In the phase I 
portion, patients ≥18 years with relapsed or refractory disease were enrolled and received 
uproleselan combined with mitoxantrone, etoposide and cytarabine (MEC) as induction therapy. 
Three dose levels (5 mg/kg, 10 mg/kg, and 20 mg/kg bid IV) were assessed, and no dose limiting 
toxicities were identified. 10 mg/kg was selected as the dose for phase II assessment based on the 
pharmacokinetic and pharmacodynamic assessments. The phase II portion involved two strata: 
one for patients ≥18 years with relapsed or refractory disease who received uproleselan 
combined with MEC for induction (patients achieving remission could receive a second course 
as consolidation) ); and a second stratum for patients ≥60 years with newly diagnosed AML who 
received uproleselan combined with daunomycin and cytarabine (“7+3”) as induction (patients 
achieving remission could receive a course of consolidation with uproleselan combined with 
idarubicin and cytarabine).
Severe (≥ grade 3) non-hematologic adverse events were uncommon; the incidences of oral 
mucositis, intestinal mucositis and blood stream infections were low and consistent with what 
would be expected for adult AML patients receiving intensive chemotherapy. The induction 
mortality rate was low for both the relapsed refractory and the newly diagnosed cohort. There 
were no DLT’s attributed to uproleselan. For subjects who received uproleselan (any dose level) 
plus MEC, 23/66 (35%) experienced at least 1 CTCAE Grade 3 or 4 treatment emergent adverse 
event (TEAE) assessed to be related to uproleselan. A total of 8/25 subjects (32%) who received 
uproleselan 10 mg/kg plus 7+3 experienced at least 1 related CTCAE Grade 3 or 4 TEAE 
assessed to be related to uproleselan. The most frequently reported CTCAE Grade 3 or 4 TEAEs 
assessed to be related to uproleselan for subjects who received uproleselan (any dose level) plus 
MEC were febrile neutropenia (11/66 subjects; 17%), thrombocytopenia (7/66; 11%), anemia 
(5/66; 8%), neutropenia (3/66; 5%), sepsis (3/66; 5%), and platelet count decreased (4/66 
subjects; 6%).  The most frequently reported CTCAE Grade 3 or 4 TEAEs assessed to be related 
to uproleselan for subjects who received uproleselan 10 mg/kg plus 7+3 were febrile neutropenia 
(3/25 subjects; 12%), thrombocytopenia (3/25; 12%), anemia (2/25; 8%), and pneumonia (2/25 
subjects; 8%). Durable high remission rates were achieved in both groups. The complete 

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remission/complete remission with incomplete hematologic recovery (CR/CRi) rate was 41% 
(27/66 subjects) for subjects who received uproleselan (any dose level) plus MEC and 43% 
(23/54 subjects) for subjects who received the RP2D uproleselan 10 mg/kg plus MEC.  For 
patients receiving “7+3” the CR/CRi was 68% (17/25). Overall survival was also encouraging in 
both groups.  The median OS was 8.8 months (range 0.9 – 28.8 months) for participants who 
received RP2D of uproleselan plus MEC and 8.8 months (range 0.9 – 28.8 months) for subjects 
who received the RP2D uproleselan 10 mg/kg plus MEC.  The median OS was 12.6 months 
(range 0.1 – 22.0 months) for participants who received uproleselan 10 mg/kg plus 7+3.  
Correlative studies yielded two important findings: one, that E-selectin ligand is detectable on 
blasts of all patients; two, that the proportion of functional E-selectin binding by circulating 
blasts is associated with the achievement of remission and survival. 
This trial’s encouraging results paved the way for two full scale clinical trials: a phase II/III RCT 
of daunomycin and cytarabine induction +/- uproleselan in older adults with newly diagnosed 
AML being conducted by the NCI and led by the Alliance (ClinicalTrials.gov identifier: 
NCT03701308); and a phase III RCT of MEC or fludarabine, cytarabine and idarubicin (FAI) +/- 
uproleselan in adults with relapsed or refractory AML being conducted by GlycoMimetics, Inc. 
(ClinicalTrials.gov identifier: NCT03616470). In these trials, a fixed dose of 800 mg of 
uproleselan is being used to provide an exposure approximating the weight-based dose of 10 
mg/kg. In the Phase I/II study, the RP2D dose was 10 mg/kg, and subjects had a median weight 
of 81.3 kg. The results of the population PK analysis suggest that clearance does not vary with 
body size. As a result, a fixed dose, rather than a weight-adjusted dose is likely to minimize 
between-subject variability. Combining the RP2D and median weight with the lack of body size 
as a covariate, suggests that a fixed dose of 800 mg would provide equivalent exposure as the 
RP2D (10 mg/kg) (Helen Thackray, GlycoMimetics, Inc.-personal communication, January, 
2020).
2.1.1
Uproleselan’s potential to decrease transplant-related mortality and morbidity by 
reducing mucositis.

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As noted above, in the phase 1/2 trial of uproleselan combined with intensive AML 
chemotherapy, the incidences of severe oral and intestinal mucositis were low. 
Uproleselan has been shown to diminish oral and intestinal mucosal barrier injury 
following high dose chemotherapy or total body irradiation in mice. Mechanistic studies 
indicate that this is due to inhibition of E-selectin mediated migration of macrophages to 
sites of cytotoxic mucosal injury, thereby, abrogating mucosal inflammation.3,4 Protection 
against mucosal barrier injury could yield two additional benefits in the setting of 
allogeneic HSCT.  First, it could mitigate bacterial translocation, decreasing the risk for 
blood stream infections.5 Notably, the incidence of bacteremia in the phase 1/2 trial was 
low. Second, protection against mucosal barrier injury could lessen the risk for acute 
graft-versus-host disease (GVHD), since gastrointestinal mucosal injury plays a central 
role in the pathogenesis of acute GVHD.6
 
2.1.2
Protection of normal hematopoietic stem cells from the cytotoxic effects of chemotherapy 
by uproleselan
 
In murine models, the effects of uproleselan on normal hematopoietic stem cells and 
leukemia cells are divergent. Rather than sensitizing normal hematopoietic stem cells to 
the cytotoxic effects of chemotherapy, it protects them. With conventional chemotherapy 
treatment, uproleselan accelerates neutrophil recovery, providing another mechanism by 
which uproleselan could prevent mucositis and blood stream infections.4 In the setting of 
allogeneic HSCT, uproleselan’s protection of normal hematopoietic stem cells could be 
disadvantageous.  By protecting host hematopoietic stem cells from the effects of 
conditioning, uproleselan could hinder donor hematopoietic stem cell engraftment. 
However. according to recent experiments conducted by GlycoMimetics, Inc. the 
protective effect of uproleselan on normal hematopoietic stem cells may not be sufficient 
to impede donor engraftment. In a murine congenic transplant model, uproleselan 
administered prior to myeloablative total body irradiation did not alter engraftment.7
2.1.3
Justification for dose levels and pharmacokinetic assessment

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Previous trials in adult patients have provided a robust pharmacokinetic (PK) dataset for 
use in population PK modeling, which allows simulation of dose levels and subsequent 
exposure across different weight and age groups.  Doses from 2 to 40 mg/kg were 
assessed in adults, in both healthy volunteer and patient trials. Minimal accumulation of 
uproleselan at any dose level was observed, as expected from its short half-life.  The PK 
optimal model was a three-compartment model that included a time-lagged input and the 
effect of renal function (as estimated by creatinine clearance, using the Cockcroft-Gault 
equation) on clearance.  Clearance of uproleselan varies with renal function and does not 
vary with body size or any other covariate evaluated in the adult population (50-150kg).   
Since this trial is the first in children and the first in hematopoietic stem cell 
transplantation (HSCT), dosing will start at 10 mg/kg/dose q12H and will not be 
escalated.  It includes a provision for de-escalation to 5 mg/kg/dose q 12 H, if the starting 
dose is not well tolerated. PK data obtained from this trial will be assessed using a 
population PK model. to determine actual exposure and coefficient of variation in 
children and adolescents  . These results will inform uproleselan in future pediatric trials. 
2.2
Relapse after HSCT for AML
Recurrence of disease represents the most important cause of treatment failure after allogeneic 
hematopoietic stem cell transplantation (HSCT) for patients with acute myeloid leukemia 
(AML).8-12 Most relapses occur in the first year after transplant and durable remissions after 
relapse are rare.13  Hence, prevention of relapse represents a major focus of research. In the 
Second Annual International Cancer Institute’s Workshop on the Biology, Prevention and 
Treatment of Relapse after HSCT, the incorporation of novel agents into pre-transplant 
conditioning regimens to enhance their anti-leukemic effect was proposed as one of the key 
strategies to be explored for relapse prevention.14
2.3
Incorporating Uproleselan into Busulfan Conditioning to Enhance its Anti-leukemic 
Effect
In this trial, uproleselan will be combined with the busulfan, fludarabine and clofarabine 
regimen, a regimen developed from the standard busulfan and fludarabine regimen commonly 
employed for both adults and children with AML.15-19 Building on pre-clinical research 
demonstrating that the newer purine analogue clofarabine possesses greater activity against AML 
than fludarabine, and that clofarabine’s activity can be enhanced by low doses of fludarabine, 
investigators at MD Anderson have conducted two randomized controlled trials to assess the 
effects of combining fludarabine and clofarabine with busulfan. In the first, an early phase trial 
in adults with AML or MDS, they examined varying dose combinations of the two purine 
analogues and identified 10 mg/m2/dose of fludarabine and 30 mg/m2/dose of clofarabine as the 
optimal combination.20,21 In the second, a recently completed phase 3 trial, 250 (median age =51 
years, range =3 to 70 years) patients with AML (n=181) or MDS (n=69) receiving HLA matched 
related or unrelated donor transplants were randomized to receive busulfan with fludarabine (40 
mg/m2/dose) or busulfan with fludarabine (10 mg/m2/dose) and clofarabine (30 mg/m2/dose). 
Preliminary trial results indicate that busulfan-fludarabine-clofarabine’s (BFC) is associated with 
a lower risk of relapse, especially in patients whose disease is not in remission at the time of 

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admission, but is also associated with a higher risk of non-relapse mortality, especially in 
patients with multiple pre-existing co-morbidities. As a result for the group as a whole, there 
were no differences in progression-free or overall survival.  In a sub-group analysis of the 
patients without significant co-morbidity (co-comorbidity index=0-2) and not remission, 
however, overall survival was significantly higher patients receiving BFC22.  
Importantly, BFC has been extended to a large group of children and adolescents at the Leiden 
University Medical Center and University Medical Center Utrecht transplant centers in the 
Netherlands. 155 children (median age 9.7 years) with hematologic malignancies were enrolled, 
including 69 with AML (28 in CR1, 40 in CR2, 1 with active disease). 119 patients received 
transplants from unrelated donor. Most patient received either bone marrow (n=79) or cord blood 
(n=66) grafts. There were only 2 cases of non-engraftment.  Non-relapse mortality at 3 years was 
10.3%. No veno-occlusive disease of the liver was observed. The cumulative incidence of 
relapse in AML was 22.5% and event free survival for patients transplanted in AML in 1st CR 
and 2nd CR was 64% and 65%, respectively. These results demonstrate that in pediatric patients 
BFC is safe, well suited for cord blood transplantation and effective for AML23.
BFC was chosen for use as the conditioning backbone in this trial because it may be more 
effective in patients with chemotherapy-resistant AML, because it is safe in pediatric patients 
and because it is immunosuppressive enough to produce robust engraftment in cord blood 
transplantation.  
The current trial builds on other recent attempts to add novel chemotherapy agents to BF or BFC 
conditioning in adults with AML. The list of agents that have been tested or are currently being 
tested in early phase trials includes plerixafor24, CPX-35121 and vorinostat25 (NCT02083250). 
 
2.4
Rationale
This phase 1/2 trial will allow us to prepare for a full-scale clinical trial, open to patients with 
chemo-sensitive as well as chemo-resistant AML and to patients receiving a wider variety of 
donor/graft types and forms of conditioning and GVHD prophylaxis. We anticipate that in the 
full-scale clinical trial, patients with chemo-sensitive disease will be assigned to a randomized 
stratum (uproleselan vs. placebo), while patients with chemo-resistant disease will be non-
randomly assigned to treatment with uproleselan.
Eligibility: Eligibility for the trial will be limited to those patients at highest risk for relapse: 
those transplanted with refractory disease (not in remission) or transplanted in a complete 
remission, but with measurable residual disease on marrow testing by multidimensional flow 
cytometry (MRD positive). The risk of relapse associated with pre-transplant MRD approaches 
that associated with refractory disease. A large analysis of children and adults transplanted for 
AML in first or second complete remission (CR1 or CR2) showed that patients with any level of 
MRD pre-transplant had a nearly five-fold higher risk of relapse at 3 years compared to those 
who were MRD negative.  Importantly, pre-transplant MRD obviated the significance of 
traditional risk factors, including cytogenetic risk and remission number.26 Similar results were 
shown in a pediatric only cohort in the Pediatric Blood and Marrow Transplant Consortium study 
ONC001 for patients receiving allo-HSCT in CR1 or CR2. The 2-year cumulative incidence of 

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relapse was 32% for the 113 patients who were MRD negative prior to HSCT as compared to 
70% for the 10 patients who were MRD pos. (p=0.01).27 In both of these studies, most of the 
relapses in patients who had pre-HSCT MRD occurred by 6 months.  In both studies, relapse-
free survival for MRD positive patients was approximately 40% at 6 months.
2.5
Correlative Studies Background
In this trial, we will explore   E-selectin related biomarkers.  We will assess the proportion of 
baseline bone marrow blasts with detectable E-selectin ligand (EsL), which could be an 
important determinant of benefit from uproleselan. The proportion of blast cells expressing EsL 
could thereby inform eligibility for future trials of uproleselan in HSCT. 
 
In patients not receiving uproleselan, EsL expression has been shown to be associated with 
poorer prognosis. Investigators from the Children’s Oncology Group (COG) examined the 
prognostic importance of EsL expression in 1074 children, adolescents and young adults with 
newly diagnosed AML enrolled on the phase 3 AAML1031 trial. They assessed expression with 
transcriptome analysis of 24 genes involved in glycosylation of EsL. In their transcriptome 
analysis, they identified 7 genes where expression was associated with increased risk of 
treatment failure. Of these, they selected two for further analysis, ST3GAL4 and FUT7, as they 
directly synthesize sLex. Overall survival ranged from 45.8% in patients with high expression 
(highest quartile) of both genes (SFhigh), to 55.5% in patients with high expression of one gene 
(SFinter), to 71.0% in patients without high expression of either (SFlow, p<0.0001). These 
investigators also observed variation in expression of these genes across patient sub-groups. 
71.5% of infants <1 year were SFlow, and only 4.66% SFhigh. 97% of patients with core 
binding factor AML were SFlow and 0% SFhigh. These investigators also performed 
multidimensional flow cytometry (MDF) to detect cell surface EsL expression and demonstrated 
that SF gene expression was strongly correlated with EsL surface expression7. 
 
A cross-sectional study in adults with AML demonstrated much higher EsL expression by MDF 
in patients with relapsed/refractory AML than in patients with newly diagnosed AML. Similarly, 
EsL expression was much higher in patients with unfavorable cytogenetic/molecular 
abnormalities than those with favorable/intermediate risk markers.28  
 
The adverse impact of EsL on prognosis may be negated by uproleselan. In fact, preliminary data 
from the phase 1/2 trial in adults discussed above suggests that degree of EsL expression may 
influence response to uproleselan. Data on EsL expression measured by MDF was available at 
study entry in 36 of 66 patients enrolled.  Though EsL was detectable on blasts in all patients, 
there was great variation. Degree of expression on leukemia stem cells was dichotomized. In 22 
patients (61%), the level was ≥ 10%.  In the remaining 14 patients it was < 10 %. In the high 
expression group, the CR/Cri rate was 45% and median overall survival was 12.7 months.  In the 
low expression group, the response rate was 29% and median survival 5.4 months28.  More data 
is needed to determine if EsL expression can be used to identify patients likely to benefit from 
uproleselan.  In the current trial, pre-transplant marrow samples will be evaluated for EsL 
expression by gene expression and MDF. 
 

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3. PARTICIPANT SELECTION
Once informed consent has been obtained, the investigator may begin screening studies to 
confirm eligibility. Once all eligibility criteria have been satisfied, the investigator may enroll the 
participant according to Section 4. All clinical and laboratory studies to determine eligibility 
must be performed within 28 days prior to enrollment.  
Exceptions: 

Disease staging bone marrow testing, CSF assessment and assessment of other 
extramedullary disease must be performed within 14 days prior to enrollment. 
Start of conditioning must be within 7 days of enrollment. 
3.1
Eligibility Criteria 
3.1.1
Age ≥12 months and ≤ 39 years
The minimum and maximum number of subjects enrolled on the study are 20 and 28, 
respectively. In order to ensure at least 70% of the population are under the age of 18 years of 
age, the number of subjects >=18 years old will be limited as follows: 

At least 7 of the first 10 subjects must be under 18 years old

At least 7 of the second 10 subjects must be under 18 years old 

At least 6 of the last 8 subjects enrolled must be under 18 years old
3.1.2
Lansky/Karnofsky performance status  ≥70% (see Appendix A)
3.1.3
Weight ≥10 kg
3.1.4
Acute myeloid leukemia that arises de novo or is secondary to:

cytotoxic chemoradiotherapy

myelodysplastic syndrome

a leukemia predisposition syndrome or inherited marrow failure syndrome other 
than ones associated with transplant-related morbidity and mortality.  A 
predisposition resulting from a germline RUNX1 mutation is example of an 
eligible disorder. Fanconi Anemia and Dyskeratosis Congenita are examples of 
ineligible disorders.
3.1.5
Disease status: 
Multidimensional flow cytometry (MDF) to assess disease status for eligibility will be 
performed centrally by Hematologics. 

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
In a first or second complete remission (defined as marrow with ≤1% leukemic 
blasts by MDF and no evidence of extramedullary disease) with minimal residual 
disease (MRD, defined as marrow with ≥0.05% leukemic blasts by MDF)  after at 
least 2 cycles of induction/re-induction chemotherapy.

Have newly diagnosed disease or disease in first relapse that is refractory (defined 
as marrow with >1% leukemic blasts by MDF or persistence of extramedullary 
disease) to at least 2 cycles of induction/re-induction chemotherapy. 
This sample will be used for eligbility as well as correlative biomarkers.  Please see 
section 9.2 for details regarding collection, processing, and shipping of the sample. 
3.1.6
Graft and Donor Types: 
Patients must be receiving bone marrow or peripheral blood stem cells from a HLA 
identical related or HLA matched unrelated (allele level matched at A, B, C and DRB1 
loci) donor.
Eligibility of prospective donors should be determined in compliance with requirements 
of 21 CFR Part 1271.  This should include donor screening for COVID-19 exposure or 
infection.  https://www.fda.gov/vaccines-blood-biologics/safety-availability-
biologics/updated-information-human-cell-tissue-or-cellular-or-tissue-based-product-
hctp-establishments
3.1.7
Ability to understand and/or the willingness of their parent or legally authorized 
representative to sign a written informed consent document.
3.2
Exclusion Criteria
3.2.1
Participants who have had a previous hematopoietic stem cell transplantation 
3.2.2
Participants who have had prior treatment with uproleselan
3.2.3
CNS 3 disease at time of admission for HSCT.  Patients previously diagnosed CNS 3 
disease that has improved (CNS1 or CNS2) will be eligible. (See Section 3.3 for 
definitions).
3.2.4
Down Syndrome
3.2.5
Fanconi Anemia, Dyskeratosis Congenita and other disorders associated with excess risk 
for transplant related toxicities
3.2.6
Acute Promyelocytic Leukemia

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3.2.7
Multiply relapsed (≥2) disease
3.2.8
Pregnancy (positive serum beta-HCG) or breastfeeding
Because there is an unknown but potential risk for adverse events in nursing infants 
secondary to treatment of the mother with uproleselan, breastfeeding should be 
discontinued if the mother is treated with uproleselan. These potential risks also apply to 
other agents used in this study.
3.2.9
Absolute neutrophil count <300/µL due to treatment (chemotherapy or immunotherapy).
Patients with neutropenia due to disease related marrow dysfunction (refractory disease, 
underlying myelodysplasia or an underlying marrow failure disorder) will be eligible 
regardless of the absolute neutrophil count. However, enrolling centers must provide 
clear evidence that the neutrophil count is not rising, that the patient does not have an 
inadequately controlled infection (see section 3.2.15), and that the patient is on broad 
anti-fungal prophylaxis. 
Given the serious risk associated with starting conditioning in patients with severe 
neutropenia, centers are encouraged to delay transplant if they have any reason to believe 
that the absolute neutrophil count may improve. 
3.2.10 Estimated GFR of <60 mL/min/1.73 m2. Estimated GFR may be calculated using the 
CKD-EPI Creatinine Equation (2009) for patients ≥19 years or creatinine-based Bedside 
Schwartz equation (2009) for patients <19 years.  It is recommended that estimates be 
determined using the calculators found on the National Kidney Foundation website. the   
(https://www.kidney.org/professionals/KDOQI/gfr_calculator). Any patient for whom 
these equations yields a GFR less than 90 mL/min/1.73 m2 should have radionucleotide 
testing. Measurement of 24-hour urine creatinine clearance is not an acceptable substitute 
for radionucleotide testing.
3.2.11 Cardiac ejection fraction <50% or shortening fraction <27%
3.2.12 Total bilirubin (with elevated direct bilirubin) or ALT >2 X ULN.
3.2.13 Pulmonary disease with FVC, FEV1 or DLCO (corrected for hemoglobin) <50 % 
predicted or requiring supplemental oxygen. Children who are developmentally unable to 
perform pulmonary function testing will be assessed solely on their need for 
supplemental oxygen
3.2.14 Active hepatitis B or C infection

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3.2.15 Active, poorly controlled infections. In patients being treated for infection at the time of 
enrollment, source documentation of the results of all microbiologic, radiographic and 
pathology assessments performed for diagnosis and for evaluation of response to 
treatment will be required. 
3.2.16 Patients with a known history of HIV are excluded, unless they meet all of the following 
conditions:

No history of HIV complications with the exception of CD4 count <200 
cells/mm3

No antiretroviral therapy with overlapping toxicity such as myelosuppression

CD4 count >500 cells/mm3 prior to the diagnosis of relapsed AML

HIV viral loads below the limit of detection

No history of highly active antiretroviral therapy (HAART)-resistant HIV
3.2.17 Patients who have received another investigational drug within 28 days or 5 half-lives 
(whichever is longer). 
3.3
Definitions of CNS Disease
CNS 1: In cerebral spinal fluid (CSF), absence of blasts on cytospin preparation, 
regardless of the number of white blood cells (WBCs).
CNS 2: CNS2 is defined as any one of the following:
CNS 2a: Blasts present in cytospin CSF with CSF WBC <5/μL and CSF RBC < 
10/μL (atraumatic tap)
CNS 2b: Blasts present in cytospin CSF with CSF WBC <5/μL and CSF RBC ≥ 
10/μL (traumatic tap)
CNS 2c: Blasts present in cytospin CSF with CSF WBC ≥5/μL and CSF RBC ≥ 
10/μL (traumatic tap) in which the WBC/RBC ratio in the CSF is less than twice that 
in the peripheral blood (see Steinherz/Bleyer calculation method below)
CNS3: CNS3 is defined as any one of the following:
CNS3a: Blasts present in cytospin CSF with CSF WBC ≥5/uL and CSF RBC <10/uL 
(atraumatic tap)
CNS3b: Blasts present in cytospin CSF with CSF WBC ≥5/uL in a traumatic tap 
(CSF RBC ≥10/uL) in which the WBC/RBC ratio in the CSF is twice or greater that 
in the peripheral blood (see Steinherz/Bleyer calculation method below)
CNS3c: Clinical signs of CNS leukemia (such as facial nerve palsy, brain/eye 
involvement or hypothalamic syndrome) OR radiographic evidence of an intracranial 
or intradural mass consistent with a chloroma. Retinal hemorrhage and extra-ocular 
orbital masses are not considered CNS leukemia.
STEINHERZ/BLEYER ALGORITHM FOR EVALUATING TRAUMATIC LUMBAR 
PUNCTURES:
If the patient has leukemic cells in the peripheral blood and the lumbar puncture is 

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traumatic (CSF RBC ≥10/uL) and the cytospin contains ≥ 5 WBC/μL with blasts, the 
following equation should be used to distinguish between CNS2 and CNS3 disease:
CNS2c: (CSF WBC ÷ CSF RBC) < 2 x (Blood WBC ÷ Blood RBC)
CNS3b: (CSF WBC ÷ CSF RBC) ≥ 2 x (Blood WBC ÷ Blood RBC)
For example, the following patient would be classified as CNS3: 
CSF WBC = 60/μL; CSF RBC = 1500/μL; 
blood WBC = 46000/μL; 
blood RBC = 3.0 X 106/μL:
  60    = 0.04  > 2X     46000
= 0.015
1500
    3.0 X 106
3.4
Inclusion of Children and Minorities
Both male and female children of all races and ethnic groups are eligible for this trial.
3.5
Co-Enrollment on Other Studies
If seeking to enroll patients on this uproleselan trial who are currently enrolled on another study , 
centers must indicate any and all studies that the patients are currently enrolled on and the 
Sponsor-Investigator or their designee will review this information and determine whether the 
patient can be approved for enrollment. Patients who are not currently enrolled on another study 
but who seek to enroll in another trial (either while they enroll on the uproleselan trial or after 
they enroll on the uproleselan trial) must be granted permission by the Sponsor-Investigator or 
their designee. Patients will be taken off uproleselan if they need to be treated with another 
investigational product.
4. REGISTRATION PROCEDURES 
4.1
General Guidelines for Dana-Farber/Boston Children’s Cancer and Blood 
Disorders Center
Dana-Farber/Boston Children’s study staff will register eligible participants in the Clinical Trials
Management System (CTMS) OnCore. The participant will first be registered in OnCore after 
the screening consent is signed and reviewed by the lead site study staff. The participant will 
then be fully enrolled on study after the main consent is signed and eligibility criteria is reviewed 
by the lead site study staff. Registration and enrollment  must occur prior to the initiation of 
protocol therapy. Any participant not registered to the protocol before protocol-specific therapy 
or intervention begins will be considered ineligible and registration will be denied.
An investigator will confirm eligibility criteria (including confirmed marrow testing eligibility 
from Hematologics) and will complete and sign the protocol-specific eligibility checklist.
If the subject fails eligibility review, the subject may re-screen at the discretion of the Sponsor-

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Investigator. 
Following enrollment, participants must begin conditioning within 7 days. Issues that would 
cause treatment delays should be discussed with the Sponsor-Investigator or designee. If the 
subject does not receive protocol therapy following registration, the subject must be taken off 
study in the CTMS (OnCore) with an appropriate date and reason entered.  
4.2
Registration Process for DF/HCC Institution
Institutions will register eligible participants in the Clinical Trials Management Systems (CTMS) 
OnCore as required by DF/HCC Policy REGIST-101. 
4.3
General Guidelines for Other Investigative Sites
The participant will first be registered in OnCore after the screening consent is signed and 
reviewed by the lead site study staff. The participant will then be fully enrolled on study after the 
main consent is signed and eligibility criteria is reviewed by the lead site study staff. Registration 
and enrollment  must occur prior to the initiation of protocol therapy. 
Eligible participants will be entered on study centrally at the coordinating center by the study 
coordinator (or designee).  All sites should contact the study coordinator to verify dose level 
availabilities.The coordinating center requires 48 hours to review eligibility and register a 
participant, and is available business days from 9:00AM- 5:00PM EST.
Following full study enrollment, participants must begin conditioning within 7 days. Issues that 
would cause treatment delays should be discussed with the Sponsor-Investigator or designee.  If 
a participant does not receive protocol therapy following registration, the subject must be taken 
off study in the CTMS (OnCore) with an appropriate date and reason entered.  
4.4
Registration Process for Other Investigative Sites
To register a participant, the following documents should be completed by the participating 
institution and faxed or e-mailed to the coordinating center: [Email: lead study coordinator or 
study team at UproTrial@DFCI.Harvard.edu or Fax: 617-632-3977]

Completed copy of Registration Request and Email/Fax Cover Sheet

Copy of all screening and eligibility source documents

Signed informed consent documents (and assents, if applicable) with patient initials and 
date of birth on every page of the consent

HIPAA authorization form (if separate from the informed consent document)

Completed eligibility checklist

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The research team at the participating site will then e-mail [UproTrial@DFCI.Harvard.edu] the 
Coordinating Center Lead Study Coordinator to verify eligibility.  To complete the registration 
process, the coordinator will follow DF/HCC Policy REGIST-101 and register the participant on 
the protocol.  The coordinator will fax or e-mail the participant study number, and if applicable 
the dose treatment level, to the participating site.  The coordinator will also call the research team 
at the participating site and verbally confirm registration
Treatment may not begin without confirmation from the coordinating center that the
participant has been registered and enrolled on study.
5. TREATMENT PLAN
5.1
Treatment Regimen
This is a phase 1/2 trial comprised of a dose-finding phase (phase 1) to determine the RP2D of 
uproleselan followed by a dose expansion phase (phase 2) to further assess safety and to make a 
preliminary assessment of efficacy of the RP2D. In both phases, uproleselan will be combined 
with a high dose busulfan-based myeloablative conditioning regimen (busulfan, fludarabine, and 
clofarabine) starting with a single dose on day -8, followed by doses q12 hours (H) on 
conditioning day -7 and ending on day -2 (Table 1). 
Table 1. Pre-transplant Conditioning 
Uproleselan with Busulfan, Fludarabine, Clofarabine 
Days -8 to day -2
Uproleselan will be administered IV over 20 minutes (+/- 2 minutes) per 
assigned dose level in the phase 1 portion or at the RP2D in the phase 2 
portion. The maximum dose of uproleselan is 800mg BID. The 20 
minute infusion time should include the line flush to ensure the full dose 
has been infused.

A single primer dose will be administered on day -8

Beginning on day -7 (with start of fludarabine, clofarabine and 
busulfan) 12 doses of uproleselan will be administered q 12 H. 

The 1st, 3rd, 5th, and 7th of theses 12 doses (not including initial 
day -8 dose) should be administered sequentially, after 
clofarabine and just prior to busulfan. Delay of doses should be 
avoided. 

The last dose of uproleselan will be administered 12 hours (+/- 60 
minutes) after dose 11. 
Fludarabine 10 mg/m2/dose daily IV administered as a 30 minute* 
infusion immediately prior to clofarabine
Clofarabine 30 mg/m2/dose daily IV administered as a 120 minute* 
infusion immediately after fludarabine and just prior to uproleselan
Days –7 to –4
Busulfan IV daily IV over 3 hours administered immediately after 
uproleselan. 

See section 5.2.1 for details

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
Busulfan exposure targeted to 80-100 mg x h/L
Day -1 
Rest
Day 0
Hematopoietic Stem Cell Infusion
*Duration of infusion may be adjusted per institutional standards
Phase 1 Design
Patients will be assigned a uproleselan dose level at the time of enrollment (Table 2). The 
starting dose will be 10 mg/kg/dose (DL1). Dose finding decisions are governed by the standard 
3+3 design (see section 13.2.3). 
Table 2. Uproleselan Dosing
Dose Level
Uproleselan Dose
Level 0
5 mg/kg/dose*
Level 1 – Starting Dose
10 mg/kg/dose*
*The maximum dose of uproleselan is 800mg BID.
Phase 2 Design
After completion of the phase 1 portion of the trial, enrollment at the recommended phase 2 dose 
will be expanded to bring total enrollment at this dose to 20 evaluable patients. Information 
about patients treated at the RP2D will be used to obtain preliminary estimates of drug exposure 
and efficacy, and to confirm safety. A one-stage stopping rule will monitor transplant-related 
mortality (TRM) for the 20 patients treated at the RP2D (see section 13.5).
Once the RP2D has been identified, an additional 14 to 17 evaluable patients will be enrolled at 
the RP2D. Interim monitoring of treatment related mortality (TRM) of the 20 patients treated at 
the RP2D (3 to 6 from Phase 1 and 14 to 17 from Phase 2) is described in section 13.5.
Treatment will be administered on an inpatient basis.  Reported adverse events and potential 
risks are described in Section 7.  Appropriate dose modifications are described in Section 6.  No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the participant's malignancy.
5.2
Agent Administration
Uproleselan will be administered as a 20 minute (+/- 2 minutes) IV infusion (including flush) 
with dose per assigned level. The maximum dose of uproleselan is 800mg BID. A single priming 
dose will be administered on Day -8.  12 additional doses will then be administered q 12 H 
beginning immediately after clofarabine and just before busulfan on Day -7. The dose of 
uproleselan can be rounded to the nearest whole unit to avoid decimal dosing. Dosing will be 
based on actual weight. Weight can be collected up to 7 days prior to first dose administration, if 
weight changes by >10% prior to first dose, dose will be adjusted to current weight. Doses of 
Uproleselan should not be adjusted once conditioning has started.

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Reactions to uproleselan infusions have not been observed to date.  Patients should have vital 
signs just prior to infusion and repeated with the start of the infusion three times at 10-minute 
(+/- 2 minutes) intervals. Frequent vitals can be discontinued if the patient has not manifested 
any signs of anaphylaxis or other serious infusion-related reaction. The infusion should be 
discontinued for any signs of anaphylaxis and the event should be reported immediately to the 
study team.
5.2.1
Administration of other Conditioning Agents
Fludarabine Administration
Fludarabine will be administered 10 mg/m2 IV daily as a 30 minute infusion for four days (-7 to -
4). Patients with an estimated of GFR < 70 ml/min/1.73 m2 shall receive 8 mg/m2 IV daily. 
Dosing will be based on AIBW in patients whose actual weight exceeds 125% of their IBW (see 
formula in section 6.3). Duration of fludarabine infusion may be adjusted per institutional 
standards.
Clofarabine Administration
Clofarabine will be administered 30 mg/m2 IV daily as a 120 minute infusion for four days (-7 to 
-4). Dosing will be based on AIBW in patients whose actual weight exceeds 125% of their IBW 
(see formula in section 6.3). Doses will be administered immediately after completion of 
fludarabine infusion and just prior to start of uproleselan infusion. Duration of clofarabine 
infusion may be adjusted per institutional standards
Hydrocortisone 100 mg/m2/dose IV may be administered 30 minutes prior to each clofarabine 
dose for prevention of capillary leak syndrome.
Busulfan Administration 
Busulfan will be administered once daily (q24) IV for four days (-7 to -4) over 3 hours. 
Pharmacy will provide busulfan at final concentration of 0.5mg/ml.  Recommended weight-
based initial doses are listed in (Table 3) and based on actual body weight of the patient in kg.
Table 3-  Estimated initial busulfan dosing in mg/kg by subject weight aimed 
to target a goal cAUC exposure of 90mg*hr/L (range 80-100mg*hr/L) for 
patients receiving a regimen containing busulfan/fludarabine/clofarabine.
Actual Body Weight1
Initial Busulfan Dose 
>10 - 15kg
4.3 mg/kg/dose
>15 - 20kg
4.2 mg/kg/dose
>20 - 25kg
3.9 mg/kg/dose
>25 - 30kg
3.7 mg/kg/dose
>30 - 35kg
3.5 mg/kg/dose
>35 - 40kg
3.3 mg/kg/dose
>40 - 45kg
3.3 mg/kg/dose
>45 - 50kg
3.2 mg/kg/dose

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>50 - 55kg
3.2 mg/kg/dose
>55 - 60kg
3.1 mg/kg/dose
>60 - 65kg
3.0 mg/kg/dose
>65 - 70kg
2.9 mg/kg/dose
>70 - 75kg
2.8 mg/kg/dose
>75 - 80kg
2.7 mg/kg/dose
>80 - 85kg
2.6 mg/kg/dose
>85 - 90kg
2.5 mg/kg/dose
>90 - 95kg
2.4 mg/kg/dose
>95 - 100kg
2.3 mg/kg/dose
>100 - 110kg
2.2 mg/kg/dose
These doses are a simplification of the nomogram published by Shukla et al29.
1Actual body weight should be applied in all subjects.
Busulfan Pharmacokinetic (PK) Assessments
Busulfan will be infused at a continuous rate over 3 hours. Blood Sample collections for PK 
sampling assessment whole blood will be performed with Dose 1 and used to determine dose 
modifications for subsequent doses, if needed. Recommended times for blood sample collections 
are based on an individualized optimal validated sampling strategy with for a 3 hour infusion and 
blood collection times at 15 minutes, 1 hour, 3 hours, and 5 hours post the end of the busulfan 
infusion. These Dose 1 PK data will be used to calculate cumulative busulfan exposure (cAUC) 
to guide dose adjustment. The cAUC will be estimated using standard compartmental PK 
methods in Pumas 2.0 (Pumas-AI, Baltimore) and verified by the study pharmacologist and 
pharmacometrician.
Irrespective of if a dose modification is needed guided by Dose 1 data, PK sampling will be 
repeated with a subsequent dose (Doses 2, 3 or 4) for a minimum of two complete PK sets 
(including Dose 1) per subject. Recommended times for sample collections for a 3 hour infusion 
are 15 minutes, 1 hour, 3 hours and 5 hours post the end of the busulfan infusion. 
Estimation of cAUC and dose modifications
After busulfan PK results are provided by the institution’s respective lab, individual AUC will be 
estimated by the standard equation:
AUC(0-infinity) = Dose(mg) / CL(individual)
(Equation 1)
Updated individualized doses for Doses 2-4 will be calculated by scaling the previous dose with 
the ratio of obtained AUC(0-infinity)  and predefined AUCtarget using the equation and solving for 
new dose as follows:  
Dose(mg) / AUC(0-infinity) = New dose (mg) / Desired AUCtarget  
(Equation 2)

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Busulfan Exposure and Therapeutic Drug Monitoring:  Initial doses for busulfan will be 
individualized for each subject and aimed to achieve a cumulative area-under-the-curve (cAUC) 
of 80-100 mg x h/L.  Individualized doses will be derived using a validated dose algorithm for 
busulfan in children.29  To ensure the cAUC goal is achieved, therapeutic drug monitoring will 
be performed as standard of care in all patients.  Busulfan will be administered once daily 
infused at a continuous rate over 3 hours. Blood collections for pharmacokinetic (PK) sampling 
will be performed with dose 1 and used to determine dose modifications for subsequent doses, if 
needed. Recommended times for blood collections are as followed:  15 minutes, 1 hour, 3 hours, 
and 5 hours post the end of the busulfan infusion. Irrespective of whether modification of the 
first dose is needed, PK sampling will be repeated following dose 2, 3 or dose 4 in all patients to 
ensure accurate estimation of cumulative overall exposure.  The cAUC will be estimated using 
standard compartmental PK methods in Pumas 2.0 (Pumas-AI, Baltimore) and verified by the 
study pharmacologist and pharmacometrician. 
Timing of Combination Chemotherapy Administration 
The timing of the administration of busulfan, fludarabine and clofarabine may be altered to 
accommodate busulfan pharmacokinetic testing. The last dose of uproleselan, then, will be 
administered in the evening of Day -2 or the morning on Day -1, depending on the timing of 
combination chemotherapy administration.
5.2.2
Graft Versus Host Disease Prophylaxis and Treatment
Tacrolimus will be combined with methotrexate for Graft Versus Host Disease 
Prophylaxis. Mycophenolate will also be substituted for patients not tolerating 
methotrexate.  
Tacrolimus: Administration will commence on  day –2 (at least 36 hours before the stem 
cell infusion); tacrolimus route and dosing will be adjusted according to institutional 
preference to maintain a level of 5-15 ng/ml. The timing and the schedule for tapering 
will be determined by the treating center.  
For dosing modifications, see Section 6.1.
Methotrexate: Methotrexate will be given at a dose of 5 mg/m2 IV on Days +1, +3, +6 
and +11. Dosing shall be based on actual weight. The Day +1 dose shall not be 
administered until 24 hours following completion of the stem cell infusion
For dosing modifications, see Section 6.2.

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Mycophenolate mofetil: For patients where methotrexate needs to be discontinued 
before the 3rd dose (see section 6.2),  mycophenolate mofetil should be started. It will be 
dosed at 15 mg/kg/dose IV or PO (maximum of 1000 mg/dose) q 8H and administered 
through at least Day +30.  It may be continued longer at the discretion of the treating 
physician. It should be discontinued without tapering. 
Treatment of acute and chronic GVHD: Treatment of patients who develop GVHD 
either acute or chronic, will be prescribed by the treating physician.
5.2.3
Hematopoietic stem cell infusion
The donor graft will be infused on Day 0. Institutional guidelines should be followed for 
preparation and infusion of grafts.
5.3
Definition of Dose-Limiting Toxicity (DLT) 
As mentioned, uproleselan has been well tolerated when combined with AML chemotherapy in 
the phase 1/2 trial in adults. No toxicities have been identified to date. In the present trial, DLT 
will be defined to encompass two forms of transplant related adverse events:  Regimen related 
toxicity (RRT) and failure of engraftment.  
RRT is defined using a modification of the Seattle Toxicity Criteria (AKA Bearman Criteria).30 
We have modified the system by adding skin to the list of assessed organs, since both busulfan 
and clofarabine can cause erythroderma, assessed according to the NCI CTCAE v.5.0 (Table 4). 
(Appendix C). Thresholds for DLT are included.  Organ toxicity attributable to serious 
infection, will not be considered RRT. Patients will be evaluated for RRT from transplant day 
0 through post-transplant Day +30. 
Failure of engraftment is defined as failure of recovery of an absolute neutrophil count to 500 
cells/mm3 by Day +30 or a peripheral blood donor myeloid chimerism (obtained no later than 
Day +35) of at least 90%.
Table 4.  Regimen-Related Toxicities
Organ
Seattle Toxicity Criteria-
threshold for DLT
CTCAE 
Term
CTCAE-threshold 
for DLT
Renal
≥3
Bladder
≥3
Gastrointestinal
≥3
Hepatic
≥3
Oral 
≥3

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Cardiovascular
≥3
Nervous 
System
≥2
Pulmonary
≥3
Skin
N/A
Erythroderma
≥4
5.4
Supportive Care Guidelines
Growth factor: The use of filgrastim (G-CSF) or biosimilar may be used at the treating 
physician’s discretion. It is recommended that GCSF be avoided when possible in forms of AML 
where it may stimulate leukemia (e.g. AML with monosomy 7 or CSF3R mutations).  
Blood Products: The transfusion of blood products (erythrocytes and platelets) will be 
administered according to local institutional guidelines. Granulocyte infusions may be used at 
the discretion of the treating physician for treating serious infection.
Prophylaxis and Management of Infections: Strategies to prevent and treat infections (viral, 
fungal, bacterial, PJP) should be administered according to institution guidelines. 
Busulfan precautions: Lorazepam (or other suitable benzodiazepine) or levetiracetam should be 
administered according to institutional guidelines to prevent seizures.  If feasible, administration 
of acetaminophen should be held beginning 72 hours prior to administration of first dose of 
busulfan through 24 hours after last dose administered.   
5.5
Criteria for Taking a Participant Off Protocol Therapy
Adherence to protocol therapy is required through Day +30, the time point at which dose limiting 
toxicity will be assessed, unless one of the following criteria are met.

Disease progression

Intercurrent illness that prevents further administration of treatment

Unacceptable adverse event(s)

Participant demonstrates an inability or unwillingness to comply with the medication 
regimen and/or documentation requirements

Participant decides to withdraw from the protocol therapy

General or specific changes in the participant's condition render the participant 

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unacceptable for further treatment in the judgment of the treating investigator
Participants will be removed from the protocol therapy when any of these criteria apply. The
reason for removal from protocol therapy, and the date the participant was removed, must be
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant.
When a participant is removed from protocol therapy, the participant’s status must be updated in 
OnCore by the study team at the coordinating center in accordance with REGIST-OP-1. Patients 
coming off protocol therapy will stay on study. 
In the event of unusual or life-threatening complications, treating investigators must immediately
notify the Sponsor-Investigator or designee.
5.6
Duration of Follow Up
Participants will be followed for adverse event reporting from the time of enrollment through 
when the participant is taken off study (see section 5.7). Participants who experience adverse 
events associated with study therapy will be followed until resolution or stabilization (new 
baseline) of the adverse event.
In addition, we are interested in the long-term outcome of patients who participated in the study. 
Therefore, we plan to follow patients for 2 years (Day +730) from day of transplantation (Day 0) 
or until death, if the patient dies prior to 2 years post-transplant. Participants will be taken off 
study at the end of follow-up. We will obtain information regarding participant status via phone 
call or electronic mailing if no longer followed locally.
5.7
Criteria for Taking a Participant Off Study
Participants will be removed from study when any of the following criteria apply:

Completion of planned follow-up

Lost to follow-up

Withdrawal of consent for data submission

Death
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). In addition, the study team at the coordinating center 
will ensure the participant’s status is updated in OnCore in accordance with REGIST-OP-1. 
 
6. DOSE MODIFICATIONS
Dose modifications will be made as indicated below. 
There will be no dosing modifications or delays for uproleselan.

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6.1
Dosing Modifications for Tacrolimus
Tacrolimus dosing should be modified for for significant renal toxicity, poorly controlled 
hypertension, neurotoxicity, and other serious toxicities.
6.2
Dosing Modifications for Methotrexate
The methotrexate dose should be reduced by 50% in the following situations:

Serum creatinine 2-3 times baseline.

Serum ALT 5-10 times the upper limit of normal or direct bilirubin 2.1-4.0 mg/dL.

Oropharyngeal mucositis that is causing symptomatic, but non-life threatening airway 
obstruction
The methotrexate dose should be held in the following situations:

Serum creatinine >3 times baseline.

Serum ALT >10 times the upper limit of normal or direct bilirubin >4.0 mg/dL.

Oropharyngeal mucositis that is causing life threatening airway obstruction.

Significant third-spacing of fluid (i.e. pleural effusion, pericardial effusion, or ascites).
If methotrexate is discontinued before the 3rd dose is administered, mycophenolate should be 
started in its place.
6.3
Dosing Modifications for Obesity
For patients weighing more than 125% of their ideal body weight, dosing for fludarabine, and 
clofarabine (but not busulfan,uproleselan, or medications used for graft versus host disease 
prophylaxis) will be based on adjusted ideal body weight as outlined below.
IDEAL AND ADJUSTED IDEAL BODY WEIGHT (IBW AND AIBW) FORMULAS:
Pts ≤60 inches: IBW = [(height) ² x 1.65] / 1000, where ht=cm, IBW=kg
Patients >60 inches:
Males IBW=39.0+[2.27*(ht-60)] where ht=inches, IBW=kg 
Females IBW=42.2+[2.27*(ht-60)] where ht=inches, IBW=kg
AIBW = IBW + [(0.25) x (Actual BW - IBW)]
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. This is done 
to ensure the safety of patients enrolled in the studies as well as those who will enroll in future 
studies using similar agents. The following lists of expected toxicities (Section 7.1) and the event 
characteristics of an observed AE (Section 7.2) will determine whether the event requires 
expedited reporting in addition to routine reporting.

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7.1
Expected Toxicities
7.1.1
Adverse Event List for Uproleselan
The adverse events observed with uproleselan in the phase 1/2 clinical trial of uproleselan 
combined with induction chemotherapy did not differ in type or frequency from those 
associated with AML induction chemotherapy alone. Likewise, no toxicities have been 
observed in animal studies. As mentioned, because the drug has been shown to protect 
normal hematopoietic stem cells from the cytotoxicity of chemotherapy, there is a 
concern that it could impede engraftment of donor hematopoietic stem cells. 
In A Phase I/II, open-label, multicenter trial (GMI-1271-201) as an adjunct to standard 
chemotherapy in 91 subjects with AML patients were enrolled in both the 
relapsed/refractory and newly diagnosed populations and added uproleselan to standard 
induction chemotherapy (MEC or cytarabine + idarubicin ‘7+3’), with the option in 
Phase II for consolidation (uproleselan plus chemotherapy) in patients who responded to 
treatment.  In the relapsed/refractory patient population, no additive toxicity was detected 
and the adverse event (AE) profile was consistent with that normally observed with 
cytarabine-based chemotherapy.  The safety profile observed in the elderly newly 
diagnosed patient population suggested no additive toxicity in this more vulnerable group 
(refer to the uproleselan IB).  Collectively, the treatment of AML in adult patients up to 
75 years of age was not found to raise any concerns for the safety profile of uproleselan 
when combined with 2 different cytarabine-based induction regimens. Further, while 
more limited, the patient experience with cytarabine-based consolidation and uproleselan 
appears to be consistent with this profile.
7.1.2
Adverse Event List for Allogeneic HSCT with Busulfan, Fludarabine, Clofarabine 
Conditioning with Tacrolimus and Methotrexate or Myecophenolate Mofetil GVHD 
Prophylaxis. 
There are many expected AEs of the treatment that uproleselan is being incorporated into.  
These include, but are not limited to, serious bacterial, viral and fungal infections, veno-
occlusive disease of the liver, acute kidney injury, thrombotic microangiopathy, oral and 
gastrointestinal mucositis, idiopathic pneumonia syndrome, encephalopathy, bleeding, 
dermatitis, and GVHD. These and other toxicities known to occur in HSCT using these 
forms of conditioning and GVHD prophylaxis are considered expected.
7.1.3
Adverse Event List for Busulfan
Common
Happens to 21-100 children 
out of every 100
Occasional
Happens to 5-20 
children out of every 
100
Rare
Happens to < 5 children 
out of every 100

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Immediate: Within 1-2 
days of receiving drug
Nausea, vomiting, fever, 
electrolyte changes 
(hypokalemia, 
hypomagnesemia, 
hypocalcemia, 
hypophosphatemia, and 
hyponatremia), hyperglycemia, 
dizziness, rash, pruritus, 
urticaria, injection site pain 
and inflammation, back pain, 
tachycardia, chest pain, edema, 
insomnia, anxiety, depression, 
headache, abdominal pain, 
diarrhea
(L) or constipation, anorexia, 
rectal discomfort, dyspnea, 
epistaxis
Weight gain, confusion
Seizures (rare with 
phenytoin prophylaxis), 
hematemesis, 
hyperuricemia, 
arrhythmias other than 
tachycardia, pleural 
effusion, alveolar 
hemorrhage
Prompt: Within 2-3 
weeks
Myelosuppression, asthenia, 
immunosuppression (L), 
mucositis, 
hyperbilirubinemia
Hepatotoxicity, 
sinusoidal obstruction 
syndrome (SOS, 
formerly VOD) (L), mild 
alopecia (L), arthralgia, 
myalgia, hemorrhagic 
cystitis,
hyperpigmentation (L), 
elevated creatinine and 
BUN
Reduced adrenal function 
(L), esophagitis, radiation 
recall reactions
Late:
Any time after completion 
of treatment
Infertility, testicular atrophy 
and azoospermia, 
amenorrhea, ovarian failure
Secondary malignancy, 
breast enlargement, 
cataracts, idiopathic 
pulmonary syndrome 
(cough, dyspnea, pleural 
effusion, infiltrates, and 
hypoxemia), 
bronchopulmonary 
dysplasia with interstitial 
pulmonary fibrosis and 
pneumonitis, myocardial 
fibrosis,
Osteonecrosis
Unknown
Frequency and Timing:
Fetal toxicities and teratogenic effects of busulfan and its solvent have been noted in 
animals.
Toxicities include: multiple anomalies and low birth weight. It is unknown whether 
the drug or its solvent is excreted in breast milk.
7.1.4
Adverse Event List for Clofarabine
Incidence
Toxicities

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Common
(> 20% of patients)

Tachycardia

Hypotension

Headache

Fever, chills

Fatigue

Anxiety

Skin rash, pruritus

Nausea, vomiting, diarrhea, abdominal pain

Anorexia

Leukopenia

Anemia

Thrombocytopenia

Lymphopenia

Febrile neutropenia

Infection

Epistaxis, petechiae

Aspartate aminotransferase increased

Alanine aminotransferase increased

Bilirubin increased

Serum creatinine increased

Pain
Occasional
(4-20% of patients)

Capillary leak syndrome

Pericardia effusion

Pleural effusion

Mucositis, gingival or mouth bleeding

Hematuria

Drowsiness, irritability, lethargy, agitation

Tumor lysis syndrome

Respiratory distress, tachypnea, dyspnea

Flushing

Hypertension

Edema

Palmar-plantar erythrodysesthesia, erythema

Sepsis
Rare
(≤ 3% of patients)

Sinusoidal obstruction syndrome

Typhlitis

Pancreatitis

Acute renal failure

Hypersensitivity

Gastrointestinal hemorrhage

Hepatitis, hepatic failure

Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN)
Pregnancy & Lactation
Adverse events were observed in animal reproduction studies. May cause 
fetal harm if administered to a pregnant woman. Women of childbearing 
potential should avoid becoming pregnant during therapy. Patients should 

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use effective contraception to prevent pregnancy during treatment. It is not 
known clofarabine is excreted in breast milk. Due to the potential for 
serious adverse reactions in the nursing infant, breast-feeding is not 
recommended by the manufacturer. 
7.1.5
Adverse Event List for Fludarabine
Common
Happens to 21-
100 subjects out 
of every 100
Occasional
Happens to 5-20 
subjects out of every 
100
Rare
Happens to < 5 subjects out of every 100
Immediate: Within 
1-2 days of 
receiving drug
Fever, fatigue, 
weakness, pain, 
nausea, 
vomiting, 
anorexia, cough, 
dyspnea
Edema including 
peripheral edema, 
chills, rash, 
diarrhea, rhinitis, 
diaphoresis, 
malaise, abdominal 
pain, headache, 
back pain, myalgia, 
stomatitis,
flu-like syndrome
Anaphylaxis, tumor lysis syndrome, 
dehydration*
Prompt: Within 
2-3 weeks, prior 
to next course
Myelosuppressio
n (anemia, 
neutropenia, 
thrombocytopeni
a), infection 
(urinary tract 
infection, herpes 
simplex 
infection, 
pneumonia, 
upper 
respiratory)
Weight loss, 
gastrointestinal 
bleeding, 
hemoptysis, 
paresthesia, allergic 
pneumonitis, 
bronchitis, 
pharyngitis, visual 
disturbance, 
hearing loss, 
hyperglycemia
Sinusitis, dysuria, opportunistic infections and 
reactivation of latent viral infections like Epstein-
Barr virus (EBV), herpes zoster and John 
Cunningham (JC) virus (progressive multifocal 
leukoencephalopathy [PML])L, EBV associated 
lymphoproliferative disorder, panycytopenia (can 
be prolonged), pulmonary hypersensitivitya 
(dyspnea, cough, hypoxia, interstitial pulmonary 
infiltrate), pulmonary toxicity (acute respiratory 
distress syndrome [ARDS], pulmonary fibrosis, 
pulmonary hemorrhage, respiratory distress, 
respiratory failure), pericardial effusion, skin 
toxicity (erythema multiforme, Stevens-Johnson 
syndrome, toxic epidermal necrolysis, pemphigus), 
liver failure, renal failure, hemorrhage, transfusion-
associated graft-versus-host disease has occurred 
following transfusion of nonirradiated blood 
products, phlebitis*, sleep disorder*, cerebellar 
syndrome*, depression*, mentation impaired*, 
alopecia*, pruritus*, seborrhea*, esophagitis*, 
constipation*, mucositis*, dysphagia*, hesitancy*, 
cholelithiasis*, abnormal liver function tests*, 
osteoporosis*, arthralgia*, abnormal renal function 
test*, proteinuria*,
epistaxis*, hemorrhagic cystitis*, 
eosinophilia*

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Delayed:
Any time later 
during therapy, 
excluding the 
above conditions
Neurotoxicity (increased with high doses): seizures, 
agitation, confusion, weakness, visual disturbances, 
optic neuritis, optic neuropathy, photophobia, 
blindness, paralysis, coma, death, peripheral 
neuropathya; autoimmune phenomena: 
thrombocytopenia/thrombocytopenic purpura (ITP), 
Evans syndrome, hemolytic anemia,
acquired hemophilia
Late:
Any time after 
completion of 
treatment
Myelodysplastic syndrome/acute myeloid
leukemia (mainly associated with prior or 
concomitant or subsequent treatment with
other anticancer treatments), skin cancer (new onset 
or exacerbation)
Unknown 
Frequency and 
Timing:
Pregnancy Category D
Based on its mechanism of action, fludarabine phosphate can cause fetal harm when 
administered to a pregnant woman. Fludarabine phosphate was embryolethal and teratogenic 
in both rats and rabbits.
(L) Toxicity may also occur later. 
* Reported in ≤ 3% of subjects. Since these are not considered life threatening they are not included in the consent. 
a These effects were not reported in children.
7.1.6
Adverse Event List for Tacrolimus
Common
Happens to 21-100 
subjects out of every 
100
Occasional
Happens to 5-20 
subjects out of every 
100
Rare
Happens to < 5 subjects out of every 
100
Immediate: Within 1-2 
days of receiving drug
Nausea, vomiting, 
diarrhea, abdominal 
pain, rash, pruritus.
Anaphylaxis, allergic reaction, dyspnea, 
bloating, dyspepsia, taste perversion, QT
prolongation, torsade de pointes, 
headache, dizziness, seizure.
Prompt: Within 2-3 
weeks, prior to next 
course
Elevated ALT/AST
Stevens-Johnson syndrome and toxic 
epidermal necrolysis, hypokalemia, 
hypercholesterolemia, 
hypertriglyceridemia, leucopenia 
including neutropenia and 
agranulocytosis,
eosinophilia, thrombocytopeniaL, 
hepatitis, cholestasis, fulminant liver 
failure
Delayed:
Any time later during 
therapy, excluding the
above conditions
Alopecia with prolonged used
Unknown Frequency 
and Timing:
Pregnancy Category C. There are no adequate and well controlled studies in pregnant 
women. There have been reports of multiple congenital abnormalities in infants 
whose mothers were being treated for 3 or more months with high dose (400-800 
mg/day) of fluconazole. The
relationship between fluconazole use and these events is unclear. Fluconazole should 
be used in pregnancy only if the potential benefit justifies the possible risk to the 

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fetus.
(L) Toxicity may also occur later.
7.1.7
Adverse Event List for Methotrexate (IV Only)
Common
Happens to 21-100 
children out of every 
100
Occasional
Happens to 5-20 
children out of every 
100
Rare
Happens to <5 children out of 
every 100
Immediate: Within 1-2 
days of receiving drug
Transaminase 
elevations
Nausea, 
vomiting, 
anorexia
Anaphylaxis, chills, fever, 
dizziness, malaise, drowsiness, 
blurred vision, acral erythema, 
urticaria, pruritus, toxic 
epidermal necrolysis, Stevens-
Johnson
Syndrome, tumor lysis 
syndrome, seizures1, 
photosensitivity
Prompt:
Within 2-3 weeks, prior to the 
next course
Myelosuppression, 
stomatitis, 
gingivitis, 
photosensitivity, 
fatigue
Alopecia, folliculitis, acne, renal 
toxicity (ATN, increased 
creatinine/BUN, hematuria), 
enteritis, GI ulceration and 
bleeding, acute neurotoxicity1 
(headache, drowsiness, aphasia, 
paresis, blurred vision, transient 
blindness, dysarthria, 
hemiparesis,
decreased reflexes) diarrhea, 
conjunctivitis
Delayed:
Any time later during therapy, 
excluding the above 
conditions
Learning disability1 
(L)
Pneumonitis, pulmonary fibrosis 
(L), hepatic fibrosis (L), 
osteonecrosis (L), 
leukoencephalopathy1 (L),
pericarditis, pericardial 
effusions, hyperpigmentation of 
the nails
Late:
Any time after the completion 
of therapy
Progressive CNS deterioration1
Unknown Frequency and 
Timing:
Methotrexate crosses the placenta. Fetal toxicities and teratogenic effects of 
methotrexate have been noted in humans. The toxicities include: congenital 
defects, chromosomal
abnormalities, severe newborn myelosuppression, low birth weight, abortion, 
and fetal death. Methotrexate is excreted into breast milk in low 
concentrations.

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1 May be enhanced by HDMTX and/or cranial irradiation.
(L) Toxicity may also occur later.
7.1.8
Adverse Event List for Myecophenolate Mofetil
Incidence
Toxicities
Common
(>20% of patients)
Hypertension, edema (face, limbs, trunk), rash maculo-papular, cholesterol 
high, hyperglycemia, hyperkalemia, hypocalcemia, hypokalemia, 
hypomagnesemia, abdominal pain, constipation, diarrhea, nausea, vomiting, 
anorexia, dyspepsia, anemia, white blood cell decreased, platelet count 
decreased, back pain, anxiety, generalized muscle weakness, dizziness, 
headache, insomnia, tremor, creatinine increased, dyspnea, cough, fever, 
pleural effusion, alanine aminotransferase increased, alkaline phosphatase 
increased, aspartate aminotransferase increased, blood bilirubin increased, 
GGT increased, pain, paresthesia, infection1
Occasional
(4-20% of patients)
Sepsis, urinary tract pain, urinary frequency, phlebitis (IV only), thrombosis 
(IV only)
Rare
(<3% of patients)
Neoplasms benign, malignant and unspecified (including cysts and polyps) - 
Other, [Malignant epithelial neoplasm of skin, non-melanoma; 
lymphoproliferative disease or lymphoma], gastric ulcer, gastrointestinal 
hemorrhage, gastric perforation, mucositis oral, thromboembolic event, 
infective
endocarditis, renal calculi, pulmonary fibrosis, pneumonitis, neutrophil 
count decreased, leukoencephalopathy, colitis, pancreatitis, pure red cell 
aplasia
Pregnancy & Lactation
Pregnancy Category D
Mycophenolate is associated with an increased risk of congenital 
malformations and spontaneous abortions when used during pregnancy. 
Adverse events have been reported in animal studies at doses less than the 
equivalent recommended human dose. Data from the National Transplantation 
Pregnancy Registry (NTPR) have observed an increase in structural 
malformations (including ear malformations) in infants born to mothers taking 
mycophenolate during pregnancy. Spontaneous abortions have also been 
noted. Females of childbearing potential should have a negative pregnancy test 
within 1 week prior to beginning therapy. Two reliable forms of contraception 
should be used beginning 4 weeks prior to, during, and for 6 weeks after 
therapy. The effectiveness of hormonal contraceptive agents may be affected 
by mycophenolate.
It is unknown if mycophenolate is excreted in human milk. Due to potentially 
serious adverse reactions, the decision to discontinue the drug or discontinue 
breast-feeding should be considered. Breast-feeding is not recommended 
during
therapy or for 6 weeks after treatment is complete.
1Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC.

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7.2
Adverse Event Characteristics
Investigators are to provide the following adverse event characteristics for all adverse events
experienced from the time of enrollment through when the participant is taken off study (see 
section 5.7).
In this trial, in which uproleselan, an investigational agent is being administered in combination 
with commercial agents (fludarabine, clofarabine, and busulfan), the combination is considered 
investigational and expedited reporting of adverse events will follow the guidelines for 
investigational agents. Attribution and expectedness for adverse events will not be evaluated 
with respect to uproleselan alone; these evaluations will be done based on the combination of 
uproleselan and the above commercial agents as a single study treatment. 
CTCAE term (AE description) and grade: The descriptions and grading scales found in the
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be
utilized for AE reporting. All appropriate treatment areas should have access to a copy of the 
CTCAE version 5.0.  A copy of the CTCAE version 5.0 can be downloaded from the CTEP web 
site http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
Expectedness of the AE: In addition to term, grade, attribution, and seriousness, are to be 
designated as “expected” or “unexpected.”  For the purposes of determining expectedness, all the 
adverse events listed in Sections 7.1.1-7.1.8 or in the consent documents  are to be considered 
expected.  Any adverse events not listed in sections Sections 7.1.1-7.1.8  or in the consent 
documents are to be considered unexpected. 
Attribution of the AE:

Definite – The AE is clearly related to the study treatment.

Probable – The AE is likely related to the study treatment.

Possible – The AE may be related to the study treatment.

Unlikely – The AE is doubtfully related to the study treatment.

Unrelated – The AE is clearly NOT related to the study treatment.
As stated above, attribution and expectedness for adverse events will not be evaluated with 
respect to uproleselan alone; these evaluations will be done based on the combination of 
uproleselan and the above commercial agents as a single study treatment. 
7.3
Adverse Event Collection
All Grade 3 and higher non-hematologic adverse events occurring through transplant day +30 
(regardless of attribution or expectedness) will be routinely reported. Routine reporting is 
accomplished via the Adverse Event (AE) Case Report Form (CRF) within the study database. 
Adverse events that require collection are defined in Tables 5 and Table 6 and must be reported 
in routine study data submissions on the toxicity case report forms. This includes adverse events 
previously reported in an expedited manner (see section 7.5).

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Table 5. Hematologic Adverse Event Routine Collection Requirements
Grade 1-4
Short-term, reversible grades 1-4 hematologic laboratory abnormalities are 
expected during transplant and do not require collection or reporting.
Grade 5
All grade 5 AEs should be collected and reported.
Table 6. Non-Hematologic Adverse Event Routine Collection Requirements
Grade 1
Grade 1 AEs do not need to be collected unless they otherwise meet criteria 
for a serious adverse events (SAE) as described in Section 7.4.
Grade 2
Unexpected grade 2 AEs will be collected with the following exceptions:

Abnormal laboratory values or test results that are not associated with 
clinical signs or symptoms and are not considered clinically significant 
(i.e., require no treatment or further diagnostic testing)
Grade 3
All grade 3 non-hematologic AEs should be collected and reported.
Grade 4
All grade 4 non-hematologic AEs should be collected and reported.
Grade 5
All grade 5 non-hematologic AEs should be collected and reported.
Between Day +30 – Day +100 the following adverse events should be collected and reported to 
the Sponsor:

Events that are deemed to be Serious and Unexpected

The following adverse events of special interest would be deemed SAEs: VOD/SOS; 
graft failure; graft rejection; and > or = grade 3 pulmonary toxicity per CTCAE criteria.
These events should be reported to the Sponsor Investigator within 5 business days of discovery.
7.4
Serious Adverse Events
A serious adverse event (SAE) is any adverse event, regardless of causality that:

Results in death (Grade 5).

Is life-threatening. Life-threatening means that the person was at immediate risk of death 
from the reaction as it occurred, i.e., it does not include a reaction which hypothetically 
might have caused death had it occurred in a more severe form.

Requires inpatient hospitalization or prolongation of existing hospitalization ≥ 24 hours. 
Hospitalizations for routine treatment or monitoring not associated with deterioration in 
condition, elective or pre-planned treatment for a pre-existing condition unrelated to 
indication under study, and social reasons and respite care in absence of patient’s general 
condition should not be reported as serious adverse events.

Requires intensive inpatient medical interventions, including mechanical ventilation, pressor 
support, and/or fluid resuscitation, or emergent surgical operations.

Results in persistent or significant disability/incapacity. Disability is defined as a substantial 
disruption of a person’s ability to conduct normal life functions.

Is a congenital anomaly or birth defect.

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
Is an important medical event (IME) when, based upon appropriate medical judgment, it may 
jeopardize the participant and require medical or surgical intervention to prevent one of the 
outcomes listed above. An example of such a medical event is allergic bronchospasm 
requiring intensive treatment in an emergency room or in the hospital.

Any event that is unexpected and related to study drug.
7.5
Expedited Reporting
All SAEs must be reported to the Sponsor Investigator immediately, no later than 24 hours of 
first becoming aware of the event. All SAEs must be reported despite grade or whether or not 
considered drug related, including those listed in the protocol or investigator brochure and must 
include an assessment of whether there is a reasonable possibility that the drug caused the event.
The Sponsor Investigator (Dr. John Horan) and DFCI study team 
(UproTrial@DFCI.Harvard.edu) should be informed by email within 24 hours of all SAEs that 
occur after the patient has provided informed consent, during treatment, or until the participant is 
taken off study. In the event that the participating investigator does not become aware of the 
SAE immediately, the participating investigator is to report the event within 24 hours of learning 
of it and document the time of his or her first awareness of the event.
The study site will have 5 business days from the discovery of the SAE to send a complete 
expedited report to the Sponsor Investigator. 
In addition to SAEs, per DFCI’s Expedited Reporting requirements, the following events also 
require expedited  reporting unless they are specifically excluded in Section 7.3:
o
Unexpected grade 2 or 3 with a possible, probable, or definite attribution
o
Unexpected grade 4 toxicities regardless of attribution
o
Dose limiting toxicities that are described in section 5.3
Pregnancies: To ensure patient safety, each pregnancy in a patient on study treatment must be 
reported  to  the  Sponsor Investigator.  Pregnancy  follow-up  should  include  an  assessment  of  
thepossible relationship  to  the  study  treatment  any  pregnancy  outcome.  Any  SAE  
experienced  during pregnancy  must  be  reported.  Additionally,  pregnancy  outcomes  should  
be  collected  for  the female  partners  of  any  male  study  participants.  Consent  to  report  
information  
regarding  these pregnancy outcomes should be obtained from the pregnant partner. Sites should 
follow their institutional policies regarding consenting pregnant partners. 
Unanticipated problems or life-threatening complications: In the event of an unanticipated 
problem or life-threatening complications that places subjects or other persons at greater risk of 
harm than previously recognized occurs, treating investigators must immediately notify the 
Sponsor-Investigator.
Sponsor-Investigator contact information:

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
Dr. John Horan

Email: john_horan@dfci.harvard.edu 

Telephone: (617) 582-7742 

DFCI lead study coordinator or study team: UproTrial@DFCI.Harvard.edu
Outside institutions will report expedited AEs to their respective IRB according to the local 
IRB’s policies and procedures in reporting adverse events. These sites will also complete a 
DF/HCC AE Reporting form and submit to the Sponsor-Investigator and DFCI study team. The 
Sponsor-Investigator and DFCI study team will then submit the DF/HCC AE Reporting form 
from outside institutions to the DFCI OHRS according to DFCI IRB policies and procedures in 
reporting adverse events.
7.6
Reporting to the Food and Drug Administration (FDA)
The Sponsor-Investigator will be responsible for all communications with the FDA. The 
Sponsor-Investigator will report to the FDA, regardless of the site of occurrence, any serious 
adverse event that meets the FDA’s criteria for expedited reporting following the reporting 
requirements and timelines set by the FDA. All adverse events reported to the FDA will 
simultaneously be forwarded to GlycoMimetics, Inc.
Unexpected fatal or life-threatening events associated with the use of the investigational 
treatment will be reported to the FDA as soon as possible but no later than 7 calendar days after 
initial receipt of the information.
All other serious unexpected events associated with the use of the investigational treatment will 
be reported to the FDA as soon as possible but no later than 15 calendar days after initial receipt 
of the information.
Findings from other clinical, animal, or in-vitro studies that suggest significant human risk will
be reported to the FDA as soon as possible but no later than 15 calendar days after initial receipt 
of the information.
7.7
Reporting to GlycoMimetics, Inc.
As the holder of the IND for the Study, DF/HCC Sponsor, John Horan, MD, MPH, will be 
responsible for all required regulatory reporting obligations and will submit Adverse Event 
reports to the FDA in accordance with applicable laws and regulations. 
Reports will be submitted to GlycoMimetics, Inc. by the following guidelines:
-
Sponsor will send a final copy of all Suspected Unexpected Serious Adverse Reaction 
(SUSAR) reports to GlycoMimetics, Inc. in parallel to submission to FDA
-
Sponsor will send a final copy of all Serious Adverse Event reports to GlycoMimetics, 
Inc. within 15 days of Sponsor awareness of the event 
-
All SAE and SUSAR reports should be e-mailed to IQVIA Biotech: Safety-
inbox.biotech@iqvia.com.

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Any additional information pertaining to the SAE and SUSAR, including complications, 
progression of the initial event, and recurrent episodes, will be reported as follow up to the 
original episode.
7.8
Reporting to Hospital Risk Management
Participating investigators will report to their local Risk Management office any participant 
safety reports or sentinel events or unanticipated problems that require reporting according to 
institutional policy. 
8. PHARMACEUTICAL INFORMATION
A list of the adverse events and potential risks associated with the investigational or other agents 
administered in this study can be found in Section 7.1.
8.1
Uproleselan Injection 
(50 mg/mL)
8.1.1
Description
Uproleselan is a synthetic, glycomimetic molecule and E-selectin (CD62E) antagonist, 
with potential anti-thrombotic, antineoplastic and chemo-potentiating activities. Upon 
administration, uproleselan binds to E-selectin expressed on endothelial cells and 
prevents their interaction with selectin-E ligand-expressing cancer cells. It has a terminal 
half-life of approximately 3 hours, and is excreted unchanged in the urine. 
Its chemical name is sodium (1R, 3R, 4R, 5S)-3-({2-N-acetylamino-2-deoxy-3-O-[(1S)-
1-carboxylato-2-cyclohexylethyl]-β-D-galactopyranosyl}
oxy)-4-({6-deoxy-α-L-galactopyranosyl}oxy)-5-ethyl-cyclohexan-1-yl-(38-oxo-
2,5,8,11,14,17,20,23,26,29, 32,35-dodecaoxa-39-azahentetracontan-41-yl) carboxamide.
Uproleselan is also known as GMI-1271.The molecular formula is C60H108N3NaO27 
and the molecular weight is 1326.5.
8.1.2
Form
Uproleselan will be supplied by GlycoMimetics, Inc. as a ready to use vial (800 mg 
Uproleselan in 16 ml).
8.1.3
Storage and Stability
Uproleselan injection 50 mg/mL is stored per the specified conditions on the label, 
refrigerated (2°C to 8 °C), prior to administration.  Vials of uproleselan will be 
refrigerated and should be brought to room temperature and gently inverted 4 to 5 times 
before dose preparation. 

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Uproleselan is to be kept in a locked and secured storage facility, accessible only to those 
individuals authorized by the principal investigator (PI).
8.1.4
Compatibility
Uproleselan has not been studied for compatibility with other medications, and should be 
administered in a separate line.
8.1.5
Handling
Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and safe 
disposal of uproleselan in a self-contained and protective environment. 
8.1.6
Availability
Uproleselan will be provided directly to participating centers by GlycoMimetics, Inc. 
8.1.7
Preparation
Uproleselan must be prepared in one of two ways to maintain stability requirements. Sites 
should use the practice that best fits within their specific institutional preparation 
protocol. 
1.   Uproleselan may be prepared at the time of administration in syringes or IV 
bags. Only one dose of uproleselan can be prepared when using this method. 
 Allow prepared dose to reach room temperature, and then administer to 
subject. Storage expiration at controlled room temperature (CRT) is a 
maximum of 24 hours.
OR
2.    Uproleselan may be prepared up to 72 hours before administration in syringes 
or IV bags. Up to two doses of uproleselan may be prepared in advance for 
each subject (e.g. morning and evening doses). Store prepared doses in 
refrigerated conditions (+2°C to +8°C). Allow prepared doses to reach room 
temperature, and then administer to subject.  
Dilutions are acceptable for ease of administration, but are not required. Uproleselan may 
be administered undiluted at a concentration of 50mg/mL or may be further diluted with 
Sodium Chloride, 0.9% to a final concentration in the range of 5 to 10mg/mL.   
Example: If diluting with a 100 mL normal saline (NS) IV bag, remove 36 mL NS from 
the IV bag. Add the entire contents of uproleselan vial (16 mL) to the remaining 64 ml to 
reach the final volume of 80 mL/10 mg/mL (concentration). If dilution is performed, the 

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amount of dilution should be recorded.
Intravenous lines consisting of PVC with DEHP should be avoided when possible.  If 
PVC with DEHP administration sets must be used they should be primed with 
uproleselan solution no more than 2 hours before dosing.  It is highly recommended that 
uproleselan prepared prior to administration be refrigerated until 1 hour prior to dosing.   
8.1.8
Administration
Uproleselan injection should be administered IV into a peripheral line, a central catheter, 
or a peripherally inserted central line catheter (PICC).  
Infusion should take place at a steady rate over a period of 20 minutes (including flush if 
used) using a syringe pump or IV pump.  Microbore tubing is preferred.  In-line filtration 
(0.2 micron) is highly recommended.
Compatibility with other therapeutic agents has not been determined; therefore, 
uproleselan injection should be administered via a separate IV line and should not be 
administered concurrently with anything other than saline.  If a flush is used, saline flush 
is preferred. The flush should be included in the 20 minute infusion. 
8.1.9
Ordering
Individual sites will order uproleselan directly from GlycoMimetics, Inc.
8.1.10 Accountability
The investigator, or a responsible party designated by the investigator, should maintain a 
careful record of the inventory and disposition of the agent using the NCI Drug 
Accountability Record Form (DARF) or another comparable drug accountability form.  
(See the NCI Investigator’s Handbook for Procedures for Drug Accountability and 
Storage.)
8.1.11 Destruction and Return
All participating centers will return unused uproleselan to GlycoMimetics, Inc. after the 
last participant enrolled has completed uproleselan.
8.2
Busulfan
Injection (Busulfex®) NSC #750
8.2.1
Description
Busulfan is a non-cell course specific bifunctional alkylating agent. In aqueous media, 
busulfan hydrolyzes to release methanesulfonate groups. This produces reactive 
carbonium ions that interact with cellular thiol groups and nucleic acids to form DNA 

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cross-links. Busulfan injection is 100% bioavailable by definition of intravenous 
administration. The elimination of busulfan appears to be independent of renal function, 
presumably reflecting the extensive metabolism of the drug in the liver, since less than 
2% of the administered dose is excreted in the urine unchanged within 24 hours. The drug 
is metabolized by enzymatic activity to at least 12 metabolites, among which 
tetrahydrothiophene, tetrahydrothiophene 12 oxide, sulfolane, and 3-hydroxysulfolane 
were identified. These metabolites do not have cytotoxic activity. Irreversible binding to 
plasma proteins (primarily albumin) is approximately 32.4%. Busulfan has a plasma 
terminal elimination half-life (t1/2) of about 2.6 hours and demonstrates linear kinetics. It 
is rapidly distributed into tissue and crosses the blood-brain and the placental barriers. 
CSF concentrations are approximately equal to those in plasma. Itraconazole reduced 
busulfan clearance by up to 25% in patients receiving itraconazole compared to patients 
who did not receive itraconazole. Higher busulfan exposure due to concomitant 
itraconazole could lead to toxic plasma levels in some patients. Fluconazole had no effect 
on the clearance of busulfan.
8.2.2
Form
Each ampoule or vial of busulfan injection contains 60 mg (6 mg/mL) of busulfan, N,N 
dimethylacetamide (DMA) 33% vol/vol and polyethylene glycol 400, 67% vol/vol.
8.2.3
Storage and Stability
Store refrigerated at 2°- 8°C, (36°- 46°F).
8.2.4
Compatibility
Busulfan injection contains N,N-dimethylacetamide, which is incompatible with many 
closed-system transfer devices (CSTDs); the plastic components of CSTDs may dissolve 
and result in subsequent leakage and potential infusion of dissolved plastic into the 
patient.
8.2.5
Handling
Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and safe 
disposal of busulfan in a self-contained and protective environment.
8.2.6
Availability
Commercially available from various manufacturers. See package insert for further 
information.
8.2.7
Preparation
Dilute busulfan injection to a final concentration of approximately 0.5 mg/mL with NS or 

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D5W (the diluent quantity should be 10 times the volume of busulfan). The drug should 
not be infused with any other drug or IV solution other than NS or D5W. Always add the 
busulfan to the diluent, not the diluent to the busulfan injection. Mix thoroughly by 
inverting several times. Do not use polycarbonate syringes or filter needles with busulfan 
injection. Busulfan injection diluted in NS or D5W is stable at room temperature (25°C) 
for up to 8 hours but the infusion must be completed within that time. Busulfan injection 
diluted in NS is stable at refrigerated conditions 2°- 8°C (36°-46°F) for up to 12 hours but 
the infusion must be completed within that time. Busulfan 0.54 mg/mL solution in 0.9% 
sodium chloride injection was physically and chemically stable for 30 hours when stored 
in 50 mL polypropylene syringes at 2–8°C (36°-46°F) and protected from light. 
(Guichard N, et al. Am J Health-Syst Pharm. 2017; 74:1887-94)
8.2.8
Administration
Busulfan injection should be administered by IV infusion through a central venous 
catheter. Patients receiving busulfan in a conditioning regimen for bone marrow 
transplant must receive seizure prophylaxis with anticonvulsants (e.g., benzodiazepines, 
phenytoin, valproic acid or levetiracetam) to prevent seizures reported with the use of 
high dose busulfan. Administer anticonvulsants 12 hours prior to busulfan to 24 hours 
after the last dose of busulfan.
In dose-finding studies of busulfan where patients received concomitant busulfan and 
phenytoin, phenytoin reduced busulfan plasma AUC by approximately 15%. After an 
initial dose of busulfan injection, blood levels are monitored with bone marrow transplant 
patients in order to achieve a target area-under-the-curve (AUC) plasma concentration.
8.3
Clofarabine
(Cl-F-Ara-A, CAFdA, Clolar™, Evoltra) NSC# 606869
8.3.1
Description
Clofarabine (2-chloro-9-[2′-deoxy-2′-fluoro-β-D-arabinofuranosyl]-9H-purine-6-amine) 
is a second-generation purine nucleoside analog designed as a hybrid molecule to 
overcome the limitations and incorporate the best qualities of fludarabine and cladribine. 
Clofarabine has several advantages over other nucleoside analogues: (1) increased 
resistance to deamination and phosphorolysis, hence better stability; (2) higher affinity to 
deoxycytidine kinase; (3) prolonged retention of the triphosphate compound in leukemic 
blasts; and (4) potent inhibition of DNA synthesis and of ribonucleotide reductase 
(RNR). Clofarabine is S-phase specific and cell cycle phase non-specific. Like other 
nucleoside analogs, clofarabine must be serially phosphorylated, first by deoxycytidine 
kinase and then by other kinases, to be active within cells. The primary cytotoxic effect 
of clofarabine is likely due to its inhibition of DNA synthesis. The triphosphate form of 
clofarabine is an inhibitor of both DNA polymerase and ribonucleotide reductase. These 
effects lead to depletion of intracellular deoxynucleotide triphosphate pools, and 
inhibition of elongation of DNA strands during synthesis. Clofarabine has been shown to 
disrupt the integrity of the mitochondrial membrane leading to the release of pro-

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apoptotic mitochondrial factors and to programmed cell death. In addition to its anti-
leukemic activity as a single agent, in vitro studies supported a role for clofarabine in 
biochemical modulation strategies to enhance the efficacy of other nucleoside analogs 
such as cytarabine. Clofarabine has been approved by the FDA for the treatment of 
pediatric patients with relapsed or refractory acute lymphoblastic leukemia (ALL) after at 
least two prior regimens. 
The population pharmacokinetics of clofarabine were studied in 40 pediatric patients 
aged 2 to 19 years (21 males/19 females) with relapsed or refractory ALL or acute 
myelogenous leukemia (AML). At the given 52 mg/m2 dose, similar concentrations were 
obtained over a wide range of BSAs. Clofarabine was 47% bound to plasma proteins, 
predominantly to albumin. Based on non-compartmental analysis, systemic clearance and 
volume of distribution at steady-state were estimated to be 28.8 L/h/m2 and 172 L/m2, 
respectively. The terminal half-life was estimated to be 5.2 hours. No apparent difference 
in pharmacokinetics was observed between patients with ALL and AML or between 
males and females. Based on 24-hour urine collections in the pediatric studies, 49-60% of 
the dose is excreted in the urine unchanged. 
In vitro studies using isolated human hepatocytes indicate very limited metabolism 
(0.2%), therefore the pathways of non-renal elimination remain unknown. The 
pharmacokinetics of clofarabine have not been evaluated in patients with hepatic 
dysfunction. Reduce clofarabine starting dose by 50% in patients with CrCl of 30 to 60 
mL/min. There is insufficient information to make a dosage recommendation in patients 
with CrCl less than 30 mL/min or in patients on dialysis. 
8.3.2
Form
Clofarabine (1 mg/mL) is supplied in a 20 mL, single-use flint vial. Each vial contains 20 
mg clofarabine in 20 mL of solution.
8.3.3
Storage and Stability
The pH range of the solution is 4.5 to 7.5. Store at 25°C (77°F); excursions permitted to 
15-30°C (59-86°F).
8.3.4
Compatibility
In vitro studies suggested that clofarabine undergoes limited metabolism and does not 
inhibit or induce major CYP enzymes. CYP inhibitors and inducers are unlikely to affect 
the metabolism of clofarabine. Clofarabine is unlikely to affect the metabolism of CYP 
substrates. However, no in vivo drug interaction studies have been conducted.
An in vitro transporter study suggested that clofarabine is a substrate of human 
transporters OAT1, OAT3, and OCT1. A preclinical study using perfused rat kidney 
demonstrated that the renal excretion of clofarabine was decreased by cimetidine, an 
inhibitor of the hOCT2. Although the clinical implications of this finding have not been 

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determined, signs of clofarabine toxicity should be monitored when administered with 
other hOAT1, hOAT3, hOCT1 and hOCT2 substrates or inhibitors.
8.3.5
Handling
Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and safe 
disposal of clofarabine in a self-contained and protective environment.
8.3.6
Availability
Commercially available. See package insert for further information.
8.3.7
Preparation
Filter clofarabine through 0.2 micron syringe filter prior to dilution. Dilute clofarabine 
with 5% dextrose injection or 0.9% sodium chloride injection to a final concentration of 
between 0.15 mg/mL and 0.4 mg/mL. The resulting admixture may be stored at room 
temperature but must be used within 24 hours of preparation.
8.3.8
Administration
Infuse over 2 hours. May be infused over 1 hour or per institutional guidelines in some 
protocols, especially when lower doses are used. Continuous IV fluids are encouraged to 
decrease adverse events and tumor lysis effects. Consider prophylactic corticosteroids 
(see Treatment section) to prevent signs/symptoms of capillary leak syndrome or 
systemic inflammatory response syndrome (SIRS). Hypotension may be a sign of 
capillary leak syndrome or systemic inflammatory response syndrome (SIRS). 
Discontinue if the patient becomes hypotensive during administration; may consider 
therapy re-initiation with 25% dose reduction after return to baseline. An inline filter is 
not needed for administration. Do not administer any other medications through the same 
IV line.
Since clofarabine is primarily excreted through the kidneys, drugs with known renal 
toxicity should be avoided during clofarabine administration. In addition, since the liver 
is a known target organ for clofarabine toxicity, concomitant use of medications known 
to induce hepatic toxicity should be avoided.
8.4
Fludarabine
(Fludara®, fludarabine phosphate, 2-fluoro-ara-AMP) NSC# 312887
8.4.1
Description
Fludarabine phosphate is a synthetic purine nucleoside. It differs from the physiologic 
nucleosides, adenosine, in that the sugar moiety is arabinose instead of ribose, and by the 
addition of a fluorine atom to the purine base adenine. Fludarabine is also a fluorinated 

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nucleotide analog the antiviral agent vidarabine, (ara-A). The addition of fluorine results 
in increased aqueous solubility and resistance to enzymatic degradation by adenosine 
deaminase. Fludarabine (2-fluoro-ara-A) is commercially available as the monophosphate 
salt (2-fluoro-ara-AMP). The monophosphorylation increases the drug's aqueous 
solubility while maintaining pharmacologic activity. The chemical name for fludarabine 
phosphate is 9H-Purin-6-amine, 2-fluoro-9-(5-0-phosphono β-D-arabino-furanosyl) (2-
fluoro-ara-AMP) and the molecular weight is 365.2.
Fludarabine is a purine antagonist antimetabolite. In vivo, fludarabine phosphate is 
rapidly dephosphorylated to 2-fluoro-ara-A and then it is phosphorylated intracellularly 
by deoxycytidine kinase to the active triphosphate, 2-fluoro-ara-ATP. This metabolite 
appears to act by inhibiting DNA polymerase alpha, ribonucleotide reductase and DNA 
primase, thus inhibiting DNA synthesis. The mechanism of action of this antimetabolite 
is not completely characterized and may be multi-faceted.
Phase 1 studies in humans have demonstrated that within several minutes after 
intravenous infusion, fludarabine phosphate is converted to the active metabolite, 2-
fluoro-ara-A and becomes undetectable. Therefore, pharmacokinetics studies have 
focused on 2-fluoro-ara-A. Fludarabine phosphate 25 mg/m2 infused intravenously over 
30 minutes to adult cancer patients, showed a moderate accumulation of 2-fluoro-ara-A. 
During a 5-day treatment schedule, 2-fluoro-ara-A plasma trough levels increased by a 
factor of about 2.
Fludarabine is widely distributed. The volume of distribution at steady state (Vss) 
reported after daily administration of 25 mg/m2 for 5 days to adults averaged at 96-
98 L/m2. Tissue distribution studies in animals indicate that the highest concentrations of 
the drug are in liver, kidney, and spleen. Although the extent to which fludarabine and/or 
its metabolites distribute into the CNS in humans has not been determined to date, severe 
neurologic toxicity (e.g., blindness, coma) has been reported in patients receiving the 
drug, particularly in high dosages. There is evidence from animal studies that fludarabine 
distributes into the CNS and that a toxic metabolite (2-fluoroadenine, possibly formed by 
bacteria in the GI tract), can be absorbed systematically via enterohepatic circulation and 
distributed into CSF. According to in vitro data, about 19-29% of fludarabine is bound to 
plasma proteins.
Following IV administration, fludarabine phosphate is dephosphorylated rapidly to 
fludarabine. Plasma concentrations of fludarabine decline in a linear, dose-independent 
manner. The elimination profile of fludarabine also has been reported to be either 
biphasic or triphasic; however, reported terminal elimination half-lives have been similar. 
In adult cancer patients receiving fludarabine 25 mg/m2 as a 30-minute IV infusion daily 
for 5 days, a terminal half-life of about 20 hours was reported. In a limited number of 
pediatric patients, the plasma concentration profile of fludarabine exhibited both 
monoexponential and biexponential decay, with a mean t1/2 of 10.5 hours in patients with 
monoexponential elimination and a t1/2 of 1.2-1.4 and 12.4-19 hours, respectively, in 
patients with biexponential elimination.

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Renal clearance accounts for about 40% of the total body clearance of fludarabine. Renal 
elimination appears to become more important at high dosages of the drug. The dose of 
fludarabine needs to be adjusted in patients with moderate renal impairment.
8.4.2
Form
Fludarabine phosphate injection is available as sterile lyophilized powder and in solution. 
Each single dose vial of powder contains 50 mg of the active ingredient fludarabine 
phosphate, 50 mg of mannitol, and sodium hydroxide to adjust the pH to 7.7. After 
reconstitution, the pH range for the final product is 7.2-8.2. The single-dose solution vial 
contains 25 mg/mL, 2 mL of fludarabine phosphate. It may contain mannitol and is 
preservative-free.
8.4.3
Storage and Stability
Fludarabine phosphate vials should be stored refrigerated at 2-8ºC (36-46ºF).
8.4.4
Compatibility
The use of fludarabine in combination with pentostatin is not recommended due to the 
risk of severe pulmonary toxicity.
8.4.5
Handling
Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and safe 
disposal of fludarabine in a self-contained and protective environment.
8.4.6
Availability
Commercially available from various manufacturers. See package insert for further 
information.
8.4.7
Preparation
Fludarabine phosphate powder should be reconstituted with 2 mL of Sterile Water for 
Injection. The solid cake should fully dissolve in 15 seconds or less. The resulting 
concentration is 25 mg/mL. When reconstituted to a final concentration of 25 mg/mL, the 
drug is stable for at least 16 days at room temperature and normal light conditions. The 
manufacturer recommends that the solution be used within 8 hours after reconstitution.
8.4.8
Administration
Prior to administration, fludarabine 25 mg/mL solution or the reconstituted 25 mg/mL 
solution should be further diluted in 100 mL or 125 mL of D5W or NS. Concentrations of 
0.25 to 1 mg/mL have been used in clinical trials. When diluted to a final concentration 

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of 1 mg/mL, fludarabine is stable for at least 16 days at room temperature and normal 
light conditions. The manufacturer recommends that the diluted solution be used within 8 
hours after preparation. Parenteral drug products should be inspected visually for 
particulate matter and discoloration prior to administration.
8.5
Tacrolimus
(FK-506, Prograf®) NSC #717865  
8.5.1
Description
Tacrolimus is a macrolide immunosuppressant produced by Streptomyces tsukubaensis. 
Tacrolimus is a potent immunosuppressive agent which prolongs the survival of the host and 
transplanted grafts in animal transplant models of liver, kidney, heart, bone marrow, small bowel 
and pancreas, lung and trachea, skin, cornea, and limb. Tacrolimus inhibits T-lymphocyte 
activation, although the exact mechanism of action is not known. Experimental evidence 
suggests that tacrolimus binds to an intracellular protein, FKBP-12. A complex of tacrolimus-
FKBP-12, calcium, calmodulin, and calcineurin is then formed and the phosphatase activity of 
calcineurin inhibited. This effect may prevent the dephosphorylation and translocation of nuclear 
factor of activated T-cells (NF-AT), a nuclear component thought to initiate gene transcription 
for the formation of lymphokines (such as interleukin-2, gamma interferon). The net result is the 
inhibition of T-lymphocyte activation (immunosuppression). 

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Additionally, tacrolimus may inhibit cellular activities such as nitric oxide synthetase 
activation and apoptosis, and may potentiate the action of corticosteroids in these 
processes. Tacrolimus activity is primarily due to the parent drug. The plasma protein 
binding of tacrolimus is approximately 99% and is independent of concentration over a 
range of 5-50 ng/mL. Tacrolimus is bound mainly to albumin and alpha-1-acid 
glycoprotein, and has a high level of association with erythrocytes. The t½ in adult 
patients ranges from 11-19 hours. The pharmacokinetics of tacrolimus have been studied 
in pediatric liver transplant patients (0.7 to 13.2 years of age). Following the IV 
administration of a 0.037 mg/kg/day dose to 12 pediatric patients, mean terminal half-
life, volume of distribution and clearance were 11.5 ± 3.8 hours, 2.6 ± 2.1 L/kg and 0.138 
± 0.071 L/hr/kg, respectively. Following oral administration to 9 pediatric patients, the 
absolute bioavailability was 31 ± 21%. Whole blood trough concentrations from 31 
patients less than 12 years old showed that pediatric patients needed higher doses than 
adults to achieve similar tacrolimus trough concentrations. Tacrolimus is extensively 
metabolized by the mixed-function oxidase system, primarily the cytochrome P-450 
system (CYP3A) in the liver and to a lesser extent in the intestinal mucosa. The major 
metabolite identified in incubations with human liver microsomes is 13-demethyl 
tacrolimus. The main route of elimination is via the biliary tract and excretion in feces. 
The mean clearance in renal dysfunction and mild hepatic dysfunction is the same as 
normal volunteers. Severe hepatic dysfunction (Pugh score > 10) led to a substantially 
decreased clearance. A retrospective comparison of Black and Caucasian kidney 
transplant patients indicated that Black patients required higher tacrolimus doses to attain 
similar trough concentrations; there were no gender-based differences. The absorption of 
tacrolimus from the gastrointestinal tract is incomplete and variable exhibiting large 
intra- and inter-patient variability. Administration with food significantly decreases the 
rate and extent of absorption Drugs that stimulate or inhibit hepatic p-450 enzymes will 
alter clearance of tacrolimus and close attention to potential drug interactions is crucial.
8.5.2
Form
Injection: Tacrolimus is available as a sterile solution (tacrolimus injection) containing 
the equivalent of 5 mg anhydrous tacrolimus per 1 mL. Each mL also contains polyoxyl 
60 hydrogenated castor oil (HCO-60), 200 mg, and dehydrated alcohol, USP, 80% v/v.
Oral: Tacrolimus is available for oral administration as capsules containing the 
equivalent of 0.5 mg, 1 mg, or 5 mg of anhydrous tacrolimus. Inactive ingredients include 
lactose, hydroxypropyl methylcellulose, croscarmellose sodium, and magnesium stearate. 
The 0.5 mg capsule shell contains gelatin, titanium dioxide and ferric oxide, the 1 mg 
capsule shell contains gelatin and titanium dioxide, and the 5 mg capsule shell contains 
gelatin, titanium dioxide and ferric oxide.
8.5.3
Storage and Stability
Injection: Store between 5°C and 25°C (41°F and 77°F).
Oral: Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F).

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8.5.4
Compatibility
Drugs that stimulate or inhibit hepatic p-450 enzymes will alter clearance of tacrolimus 
and close attention to potential drug interactions is crucial.
8.5.5
Handling
Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and safe 
disposal of tacrolimus in a self-contained and protective environment.
8.5.6
Availability
Commercially available from various manufacturers. See package insert for further 
information.
8.5.7
Preparation
See Treatment (section 5) and Dose Modifications (section 6.1) sections of the protocol.
Injection: 
Tacrolimus injection must be diluted with NS or D5W before use to a concentration 
between 0.004 mg/mL and 0.02 mg/mL. Diluted infusion solution should be stored in 
glass or polyethylene containers and should be discarded after 24 hours. The 
polyoxyethylated castor oil contained in the concentrate for intravenous infusion can 
cause phthalate stripping from PVC. It is strongly recommended that non-PVC tubing be 
used to minimize patient exposure to DEHP. Due to the chemical instability of tacrolimus 
in alkaline media, tacrolimus injection should not be mixed or co-infused with solutions 
of pH 9 or greater (e.g., ganciclovir or acyclovir). 
Tacrolimus 0.001 mg/mL solution stored in polyolefin bags at room temperature (20–
25°C) was stable for 24 hours when prepared in NS and for at least 48 hours when 
prepared in D5W. Solutions of 0.01 and 0.1 mg/mL prepared in either NS or D5W were 
stable for at least 48 hours at room temperature in polyolefin bags (Lee JH, et al. Am J 
Health-Syst Pharm. 2016;73:137-42).
8.5.8
Administration
Injection: Monitor closely for an acute allergic reaction for the first 30 minutes and at 
frequent intervals thereafter. 
Oral: Administer at a consistent time of day and at consistent intervals with regard to 
meals. Tacrolimus may be given with food as long as it is given the same way each time, 
however, administration with food significantly decreases the rate and extent of 

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absorption. Grapefruit or grapefruit juice should be avoided during the entire course of 
tacrolimus administration.
8.6
Methotrexate
IV Only (MTX, amethopterin) NSC #000740
8.6.1
Description
A folate analogue which reversibly inhibits dihydrofolate reductase, the enzyme that 
reduces folic acid to tetrahydrofolic acid. Inhibition of tetrahydrofolate formation limits 
the availability of one carbon fragments necessary for the synthesis of purines and the 
conversion of deoxyuridylate to thymidylate in the synthesis of DNA and cell 
reproduction. The polyglutamated metabolites of MTX also contribute to the cytotoxic 
effect of MTX on DNA repair and/or strand breaks. MTX cytotoxicity is highly 
dependent on the absolute drug concentration and the duration of drug exposure. MTX is 
actively transported across cell membranes. At serum methotrexate concentrations 
exceeding 0.1 μmol/mL, passive diffusion becomes a major means of intracellular 
transport of MTX. The drug is widely distributed throughout the body with the highest 
concentration in the kidney, liver, spleen, gallbladder, and skin. Plasma concentrations 
following high dose IV MTX decline in a biphasic manner with an initial half-life of 1.5-
3.5 hours, and a terminal half-life of 8-15 hours. About 50% is bound to protein. MTX is 
excreted primarily by the kidneys via glomerular filtration and active secretion into the 
proximal tubules. Renal clearance usually equals or exceeds creatinine clearance. Small 
amounts are excreted in the feces. There is significant entero-hepatic circulation of MTX. 
The distribution of MTX into third-space fluid collections, such as pleural effusions and 
ascitic fluid, can substantially alter MTX pharmacokinetics. The slow release of 
accumulated MTX from these third spaces over time prolongs the terminal half-life of the 
drug, leading to potentially increased clinical toxicity.
8.6.2
Form
Methotrexate for injection is available as a lyophilized powder for injection in 1000 mg 
vials. The powder for injection contains approximately 7 mEq sodium in the 1000 mg 
vial. Methotrexate for Injection is also available as a 25 mg/mL solution in 2, 4, 8, 10, 
and 40 mL preservative free vials and 2 and 10 mL vials with preservative. The 2, 4, 8, 
10, and 40 mL solutions contain approximately 0.43 0.86, 1.72, 2.15, and 8.6 mEq 
sodium per vial, respectively. The preserved vials contain 0.9% benzyl alcohol as a 
preservative.
8.6.3
Storage and Stability
Sterile methotrexate powder or solution is stable at 20º-25ºC (68º-77ºF); excursions 
permitted to 15º-30ºC (59º- 86 Fº). Protect from light.
8.6.4
Compatibility

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Avoid sulfamethoxazole/trimethoprim, probenecid, penicillins, cephalosporins, aspirin, 
proton pump inhibitors, and NSAIDS as renal excretion of MTX is inhibited by these 
agents.
8.6.5
Handling
Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and safe 
disposal of methotrexate in a self-contained and protective environment.
8.6.6
Availability
Commercially available from various manufacturers. See package insert for further 
information.
8.6.7
Preparation
For IV use: Powder for injection: Dilute 1000 mg vial with 19.4 mL of preservative free 
SWFI, D5W or NS to a 50 mg/mL concentration. The powder for injection may be 
further diluted in NS or dextrose containing solutions to a concentration of ≤ 25 mg/mL 
for IV use. 
Do not use the preserved solution for high dose methotrexate administration due to risk of 
benzyl alcohol toxicity. Methotrexate dilutions are chemically stable for at least 7 days at 
room temperature but contain no preservative and should be used within 24 hours. 
Diluted solutions especially those containing bicarbonate exposed to direct sunlight for 
periods exceeding 4 hours should be protected from light.
8.6.8
Administration
See Treatment (section 5) and Dose Modifications (section 6.2) sections of protocol. 
8.7
Mycophenolate Mofetil
(Cellcept®, MMF, RS-61443) NSC# 724229
8.7.1
Description
Mycophenolate mofetil is the 2-morpholinoethyl ester of mycophenolic acid (MPA), an 
immunosuppressive agent. Side effects include diarrhea, leukopenia, sepsis, and 
vomiting, as well as a higher risk of certain infections.
MMF has been used in a variety of solid organ and hematopoietic stem cell transplant 
settings for the prevention of acute rejection. MMF is a prodrug which, after oral 
administration, is rapidly and primarily hydrolyzed by the liver to the biologically 
active metabolite mycophenolic acid. MPA is metabolized principally by glucuronyl 

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transferase to form the pharmacologically inactive phenolic glucuronide of MPA 
(MPAG). In vivo, MPAG is converted to MPA via enterohepatic recirculation. 
Mycophenolic acid inhibits nucleic acid synthesis and produces a potent, 
noncompetitive, and reversible inhibition of inosine monophosphate dehydrogenase 
(IMPDH), blocking the de novo synthesis of guanosine nucleotides without being 
incorporated into DNA. Both T and B lymphocytes rely on this de novo pathway for 
purine synthesis. As a result, the proliferative responses of T and B lymphocytes to 
both mitogenic and allospecific stimulation are inhibited. Other rapidly dividing cell 
lines are capable of recycling purine nucleotides via the "salvage" pathway, which is 
not blocked by mycophenolic acid.
In vitro and in vivo studies have demonstrated the ability of mycophenolic acid to 
block proliferative responses of T and B lymphocytes, inhibit antibody formation and 
the generation of cytotoxic T-cells, and suppress antibody formation by B 
lymphocytes. Mycophenolic acid prevents the glycosylation of lymphocyte and 
monocyte glycoproteins that are involved in intercellular adhesion of these cells to 
endothelial cells, and may inhibit recruitment of leukocytes into sites of inflammation 
and graft rejection. Antirejection effects have been attributed to decreased 
recruitment of activated lymphocytes to the graft site.
8.7.2
Form
Commercially available for oral administration as capsules containing 250 mg of 
mycophenolate mofetil, tablets containing 500 mg of mycophenolate mofetil, and as a 
powder for oral suspension, which when constituted contains 200 mg/l. It is also 
available in an intravenous formulation as a hydrochloride salt in vials containing 500 mg 
of mycophenolate mofetil.
8.7.3
Storage and Stability
Oral formulations should be stored at 25°C (77°F); excursions are permitted to 15°C to 
30°C (59°F to 86°F). Protect from moisture and light. Once reconstituted, the oral 
solution may be stored at room temperature or under refrigeration. Do not freeze. The 
mixed suspension is stable for 60 days.
Store intact vials and diluted solutions at 25°C (77°F); excursions permitted to 15°C to 
30°C (59°F to 86°F). Do not freeze. Begin infusion within 4 hours of reconstitution.
8.7.4
Compatibility
The mean absolute bioavailability of oral mycophenolate mofetil relative to intravenous 
mycophenolate mofetil (based on MPA AUC) was 94% in a small sample of healthy, 
adult volunteers. In this group the mean (±SD) apparent volume of distribution of MPA 
was approximately 3.6 (±1.5) and 4.0 (±1.2) L/kg following intravenous and oral 
administration, respectively. At clinically relevant concentrations, MPA is 97% bound to 

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plasma albumin. MPAG is 82% bound to plasma albumin at MPAG concentration ranges 
that are normally seen in stable renal transplant patients; however, at higher MPAG 
concentrations (eg, patients with renal impairment), the binding of MPA may be reduced 
as a result of competition between MPAG and MPA for protein binding. A negligible 
amount of the agent (< 1% of dose) is excreted as MPA in the urine. Most of the 
administered dose (~87%) is excreted in the urine as MPAG. Bile acid sequestrants (e.g., 
cholestyramine) reduce the AUC of MPA by interfering with the enterohepatic 
circulation of the drug.
8.7.5
Handling
Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and safe 
disposal of mycophenolate mofetil in a self-contained and protective environment.
8.7.6
Availability
Commercially available from various manufacturers. See package insert for further 
information.
8.7.7
Preparation
To  prepare the oral suspension, add 47 mL of water to  the bottle and  shake well for 
approximately        1 minute. Add another 47 mL of water to the bottle and shake well for 
an additional minute. The final concentration is 200 mg/mL of mycophenolate mofetil. 
Avoid inhalation or direct contact with skin or mucous membranes of the dry powder or 
the constituted suspension. If such contact occurs, wash thoroughly with soap and water; 
rinse eyes with water.
To prepare the intravenous injection, reconstitute the contents of each vial with 14 mL of 
D5W. Dilute the contents of a vial with D5W to a final concentration of 6 mg/mL. Each 
vial is vacuum-sealed; if a lack of vacuum is noted during preparation, the vial should not 
be used.
8.7.8
Administration
Oral formulations of MMF should be administered on an empty stomach to avoid 
variability in MPA absorption. The oral solution may be administered via a nasogastric 
tube (minimum 8 French, 1.7 mm interior diameter). Do not mix the oral suspension with 
other medications. Some products may contain phenylalanine; refer to the package 
labeling for additional details.
9. PHARMACOKINETIC AND BIOMARKER STUDIES (REQUIRED)
The pharmacokinetic (PK) and Pre-transplant bone marrow AML blast E-selectin ligand 
expression will be performed on all patients across the study. Patient samples will be collected as 

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indicated below (Table 7). 
For all samples discussed below, all aliquots will be disposed of either at the conclusion of 
testing or the end of the study, whichever is later. Samples from this study will not be banked for 
future use.
Specimen collection and shipment will be supported by GlycoMimetics, Inc.

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Table 7.
Research Sample Collection Plan 
PK 
Subjects 
≥6 years
PK
Subjects 
<6 years
E-selectin 
Ligand
2 
mL/sample
1 
mL/sample 2-3 mL/sample
Na Citrate Na Citrate
Na Heparin
PB
PB
Bone Marrow 
Aspirate
Day
Time point
Pre-
Conditioning
At time of clinical 
bone marrow, after 
screening consent
X
Day -8
(1st dose of 
uproleselan)
Immediately Predose
X
X
30 minutes 
(±5 minutes)a
X
X
1 hours 
(±20 minutes)a
X
X
2 hours 
(±20 minutes)a
X
4 hours 
(±60 minutes)a
X
X
Day -4
Immediately Pre-
dose
X
X
30 minutes 
(±5 minutes)a
X
X
1 hours 
(±20 minutes)a
X
X
(1st dose of 
day)
2 hours 
(±20 minutes)a
X
4 hours 
(±20 minutes)a
X
X
PK = pharmacokinetic
a After start of the infusion

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9.1
Pharmacokinetic Assessment
Pharmacokinetic testing for uproleselan will be done on plasma samples collected on a sparse-
sampling basis across all subjects in the trial.  Both the start and end times of investigational 
drug administration and sample collection times must be accurately recorded in the subject’s 
records.  Sample times for PK collection are in relation to the start of investigational drug 
infusion.  Actual date and time of collection is to be recorded for every sample for an accurate 
PK assessment.  See Table 7 for sparse-sampling times and volumes.
On days of PK testing, a dedicated CVL lumen should be used for uproleselan infusion and 
a separate dedicated CVL lumen should be used PK sampling. Uproleselan will not stick to 
the inside of the catheter lumens so the lumens dedicated for infusion and PK testing on 
day -8 and day -4 may differ. 
9.1.1
PK Sampling and Processing 
Blood will be drawn into sodium citrate tubes, inverted 3-4 times and stored in an ice 
bath until centrifugation. Samples will be centrifuged at 2000-2500 rpm at 4°C for 10 
minutes. Ideally, samples should be immediately centrifuged following collection. If 
institutional staffing and/or logistics do not allow for this, samples may be stored (at 
approximately 4°C) for 48-72 hours before centrifugation.
After centrifugation, pipette half of plasma into an appropriately labelled (participant ID, 
day/time of collection and primary vs back-up) cryovial (primary aliquot).  Pipette the 
remaining plasma into an additional appropriately labelled cryovials (back-up aliquot).
 
The aliquots will be stored in a freezer set at -70 to -80°C until shipped for analysis.
9.1.2
PK Sample Shipments
Samples will be shipped after each subject collection is complete. The primary and back-
up aliquots will be shipped on separate days to mitigate loss (Monday - Wednesday 
only), via overnight carrier with the appropriate amount of dry ice.
Pyxant Labs
4720 Forge Road
Colorado Springs, Colorado 80907
Contact: Emily Munk
E-mail: emunk@pyxant.com and SampleReceipt@pyxant.com
Tel.: +1 (719) 593-1165 X50
Upon shipment of the samples, an e-mail will be sent containing a sample manifest, the 
name of the courier, the airway bill number, and a confirmation of the number of samples 
in the shipment. 

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9.1.3
PK Interim Analysis 
An interim analysis will be performed at the completion of phase 1, as phase 2 enrollment 
commences. Data to be included in the interim analysis include, but is not limited to, 
subject ID, demogrpahics, vital signs, baseline laboratory values (hematology, full and 
basic chemistry, coagulation, urinalysis), uproleselan administration (dose level, volume 
administered, actual dates/times of collection and dilution of amount if used), PK 
collection dates/times. 
Depending on the results of the analysis, the phase 2 dosing may be adjusted and the 
protocol amended. 
9.2
Biomarker Assessments
Pre-transplant bone marrow AML blast E-selectin ligand expression will be assessed by 
multidimensional flow cytometry and by gene expression profiling via RNA analysis. 
Residual disease will also be measured as part of the flow cytometry assessment.  
9.2.1
Multidimensional flow cytometry (eligibility), E-selectin ligand expression, and gene 
expression profiling sampling and processing
1. Perform pre-transplant bone marrow procedure, as per institutional procedure
2. Collect 2-3 ml bone marrow aspirate in a 5 ml Sodium Heparin tube 
a) If aspirate is unable to be obtained (i.e., dry tap), a fresh bone marrow biopsy can 
be provided.  Biopsy samples can be collected in either: 15mL conical tube, 
adding enough RPMI to ensure the sample is submerged at all times during transit 
or NaHep 4.5mL hemoguard tube, adding enough RPMI to ensure the sample is 
submerged at all times during transit, and adding parafilm on the top of the tube 
for safety. Biopsy samples will be shipped at ambient temperature.
3. Immediately after sample is drawn, gently invert the tube 180° and back, 8-10 
times.
a) Keep sample at AMBIENT TEMPERATURE and ship immediately.
No additional specimen will be required for RNA testing.  The sample collected for 
multidimensional flow cytometry will provide sufficient material for RNA aliquoting.  
*Note: If the subject’s pre-transplant disease evaluation is coordinated at another center, 
the study site should attempt to conduct a screening consent prior to the bone marrow. If 
the subject consents to the bone marrow samples, the study site should coordinate 
collection and shipment with procedure center for sample receipt at Hematologics, Inc.
9.2.2
Multidimensional flow cytometry (eligibility), E-selectin ligand expression, and gene 
expression profiling shipments

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Samples should be shipped ambient on the day of collection. Samples can be accepted 
Monday through Saturday. 
Hematologics, Inc.
3161 Elliott Ave., Suite 200
Seattle, Washington 98121
Contact: Wayne Fritschle
E-mail: wayne@hematologics.com
Tel.: +1 8008600934 or +1 206 223 2700
Prior to shipping samples an email notification should be sent to 
laboratory@hematologics.com, including the protocol number, subject ID number 
and carrier tracking number.
Each sample should be labeled with collection date and time obtained (for fresh 
samples), protocol number, subject ID number, and site code. Corresponding 
information must be placed on the Hematologics Laboratory Test Requistion Form. 
This form must be scanned and emailed to laboratory@hematologics.com and study 
coordinator, the original retained at the site, and a copy included in the packaging. 

 
62
10. STUDY CALENDAR AND REQUIRED ROUTINE TESTING/CLINICAL EVALUATIONS
Table 8. Study Calendar
Day Relative to Transplant
+30
+50
+100
+180
+365
+730
Routine Testing and Clinical Evaluations
Baselinea
-8
-4
0
+14
+/- 5 
days
+/-7 
days
+/- 7 
days
+/- 14 
days
+/- 30 
days
+/- 90 
days
InForm Timepoints
Informed consent/assent
X
Baseline
Demographics
X
Baseline
Medical history
X
X
Baseline, Day -8
Physical exam
Xb
X
X
X
X
X
X
Baseline, Days -8, 0, +30, 
+100, +365, and +730
Performance status
X
X
X
X
X
X
X
Baseline, Days -8, 0, +30, 
+100, +365, and +730
Serum Pregnancy Test
X
Baseline
Estimated GFR
X
Baseline
Echocardiography
X
Baseline
Pulmonary Functionc 
X
Baseline
Testing Hep B and Hep C infection
X
Baseline
PK collectiond
X
X
Day +30
E-selectin ligand BM collectiond
X
Baseline
Disease re-evaluatione
X
X
Baseline, Day +30
Blood chemistriesf
X
Twice weekly through Day +50
Per institutional guidelines
Baseline, Day +30, Day +100
CBC
X
Per institutional guidelines
Baseline, Day +30, Day +100
Coagulation studies
X
Baseline
Urinalysis
X
Baseline
TNC dose, CD3+ and CD34+ counts on infused product
X
Day 0
Peripheral blood chimerismg
X
Day +30
RRT evaluation
 D0 - D+30 Daily 
while inpatient, or 3x 
weekly if outpatient
Day +30
MBI-LCBI
 D0 - D+30  Daily 
while inpatient, or 3x 
weekly if outpatient
Day +30
VOD/SOS evaluation
 D0 - D+30  Daily 
while inpatient, or 3x 
weekly if outpatient
Day +30
Oral and Intestinal Mucositis Evaluation
Daily D0 -
D+14
Day +30
Acute and Chronic GVHD Evaluation
Per institutional guidelines through Day +365
All
Relapse and Survival
Per institutional guidelines through Day +730
All
a.
All clinical and laboratory studies to determine eligibility must be performed within 28 days prior to enrollment unless otherwise indicated in Section 3
b.
Baseline includes height and weight
c.
For patients developmentally unable to perform pulmonary function tests, documentation of oxygen saturation on room air will suffice
d.
Refer to Table 7 for timing and other instructions for collection
e.
Includes marrow testing and re-assessment of any extramedullary disease, including imaging and/or CSF, as indicated, +/- 5 days from Day +30 assessment

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f.
Creatinine, bilirubin, alkaline phosphatase, ALT, AST, and other blood chemistries, after Day +50 obtained per institutional practice
g.
Sorted for T cells (CD3+) and myeloid cells (CD33+ or CD15+), +/- 5 days

 
64
10.1
Pre-Transplant
10.1.1 As per eligibility criteria. See section 3.
10.1.2 Medical history, physical exam, performance status on Day -8.
10.1.3 PK collection and E-selectin ligand BM collection as per Table 7.
10.2
Post-Transplant Laboratory Testing
10.2.1 Total nucleated cell count, CD3+, and CD34+ counts on the infused product on Day 0.
10.2.2 Physical exam and performance status on Day 0.
10.2.3 Peripheral blood chimerism analysis to assess donor engraftment at Day +30 +/- 5 days 
Samples shall be sorted for T cells (CD3+) and myeloid cells (CD33+ or CD15+). 
10.2.4 Disease re-evaluation will be performed at Day +30 +/- 5 days.  It should include marrow 
testing and re-assessment of any extramedullary disease, including imaging and/or CSF, 
as indicated.  
10.2.5 Complete blood counts with a differential shall be obtained according to institutional 
practice to monitor myeloid recovery and to determine transfusion needs.
10.2.6 Creatinine, bilirubin, alkaline phosphatase, ALT, AST, and other blood chemistries shall 
be performed at least twice weekly through Day +50 and otherwise obtained according to 
institutional practice.
10.2.7 Routine clinical monitoring for CMV and other infections shall be performed according 
to institutional practice. 
10.2.8 Immune reconstitution testing shall be performed according to institutional practice.
10.3
Other Post-Transplant Evaluations 
10.3.1 Mucosal barrier injury-associated laboratory-confirmed bloodstream infection (MBI-
LCBI)  
MBI-LCBI will be assessed from day 0 through Day +30 and defined according to CDC 
criteria: https://www.cdc.gov/nhsn/pdfs/pscmanual/4psc_clabscurrent.pdf*-
Oral mucositis severity will be assessed daily from Day 0 through Day +14, using 
CTCAE v5 criteria.
Intestinal mucositis severity will be assessed daily from Day 0 through Day +14, using 

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CTCAE v5 criteria for enterocolitis.
10.3.2 Hepatic veno-occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS) will be 
will be diagnosed and graded according to the pediatric (<18 years) and adult (≥18 years) 
European Society for Blood and Marrow Transplantation (EBMT) criteria (Appendix 
C)31,32.
All reported cases of sinusoidal obstruction syndrome will be adjudicated (diagnosis and 
grading) by a physician with expertise in this area. 
10.3.3 Acute GVHD will be assessed through 1 year according to the Blood and Marrow 
Transplant Clinical Trials Network Manual of Procedures. 
https://web.emmes.com/study/bmt2/public/MOP/BMTCTNTechnicalMOPv3.pdf 
10.3.4 Physical exam and performance status collected at least on Day 0, +30, +100, +365, and 
+730. May be collected more often as per institutional guidelines.
10.3.5 Chronic GVHD will be assessed through 1 year using the NIH consensus criteria.33 
10.3.6 Relapse will be assessed per institutional guidelines through 2 years post transplant. 
11. MEASUREMENT OF EFFECT
11.1
Refractory Disease
Applies to patients who were not in remission at the time of transplant. 
At Day +30 (+/-5 days) post-transplant disease evaluation, there is persistence of >1% leukemic 
blasts by multidimensional flow cytometry (MDF) or there is persistence of EMD.
11.2
Leukemic Relapse
Applies to patients who were in remission at the time of transplant and pateints not in remission 
at the time of transplant who achieve remission post-transplant (based on day +30 assessment)
11.2.1 Bone Marrow Relapse
Defined in accordance with the Children’s Oncology Group’s AAML1831 trial protocol 
criteria:
A single bone marrow sample (aspirate or biopsy) showing ≥5% leukemic blasts 
confirmed by flow cytometry, FISH testing, ICH, or other molecular method. 
OR
A single bone marrow sample with at least two tests showing ≥1% leukemic blasts. 

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Examples of tests include:
o
Flow cytometry showing leukemia ≥1% by multidimensional flow cytometry 
(MDF) in a CLIA-approved laboratory. 
o
Karyotypic abnormality (must display at least 1 metaphase similar/identical to 
diagnosis; central cytogenetic review by COG required).
o
FISH abnormality identical to one present at diagnosis (must be above level of 
sensitivity of specific FISH probe; central cytogenetic review by COG required).
o
PCR or NGS-based demonstration of validated pathogenic leukemogenic lesion 
(e.g., fusion, mutation) in a CLIA-approved laboratory that matches initial 
diagnosis and is quantifiable as ≥1%.
OR 
Two serial marrows with at least two tests showing a one log increase of leukemic 
involvement with the second tests quantified as ≥0.1%. Examples of tests include: 
o
MDF in CLIA-approved laboratory
o
PCR or NGS-based demonstration of validated leukemogenic lesion (e.g., fusion, 
mutation) that matches diagnosis and is quantifiable where the positive result is at 
or above the assay sensitivity and meets the criteria above (one log increase and 
second test quantified as ≥0.1%)
11.3
Extramedullary Relapse
Defined as radiographic or biopsy proven extramedullary disease after documented CR or 
evidence of CSF recurrence.
11.3.1 CNS Relapse
A single CSF sample with CNS3 status (Rel-CNS3a/b).
OR
Clinical signs of CNS leukemia such as facial nerve palsy, brain/eye involvement, or 
hypothalamic syndrome (Rel-CNS3c). Competing explanations for clinical symptoms 
should be ruled out.
OR
Radiographic evidence of an intracranial, intradural mass consistent with a chloroma 
(Rel-CNS3c).

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Equivocal CNS Relapse (Eq-CNS)
A single CSF sample with CNS2 status 
In the case of equivocal relapse, CSF evaluation should be repeated at least 1 week and at 
most 4 weeks later. For repeat CSF assessment, flow cytometric testing is strongly 
recommended and FISH (if a diagnostic FISH marker is available) should be sent 
To convert to definitive relapse, the repeat CSF or clinical status must:
o
Meet criteria for definitive relapse (Rel-CNS3a/b/c)
o
Re-demonstrate CNS2 status, but with myeloblasts confirmed by flow cytometry 
and/or FISH (Rel-CNS2)
o
For Rel-CNS2, the two CSF samples MUST BE CONSECUTIVE
12. DATA REPORTING / REGULATORY REQUIREMENTS
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7 
(Adverse Events: List and Reporting Requirements).
12.1
Data Reporting
12.1.1 Method
The DF/HCC Office of Data Quality (ODQ) will collect, manage, and perform quality 
checks on the data for this study.
12.1.2 Responsibility for Data Submission
Investigative sites are responsible for submitting data and/or data forms to the Office of 
Data Quality (ODQ). All data will be entered within two weeks of the indicated time 
point. 
12.2
Data Safety Monitoring
This study will be centrally reviewed by the Data Safety and Monitoring Committee (DSMC) of 
the Pediatric Transplant and Cellular Therapy Consortium (PTCTC). This DSMC is chartered to 
monitor trials enrolling both children and adult patients. The DSMC is a standing committee, 
composed of a chair, patient advocate, biostatistician, nurse representative and 2 bone marrow 
transplant physicians with procedures and processes as defined in the PTCTC DSMC Charter. 
The DSMC will review the study protocol prior to study activation and IRB review, and will 
continue to review the study on a regular basis according to the committee rules.  The DSMC 
will meet at regular intervals to review all adverse events and deaths and determine whether any 
patient safety problems necessitate protocol modifications or discontinuation of the trial. The 
DSMC will also meet on an ad hoc basis to review the results of interim analyses or if 
unexpected safety events occur that may necessitate study suspension or closure. The DSMC will 
discontinue the review of outcomes when administration of the study product has ended for all 

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subjects. The DSMC has the authority to unblind study personnel prior to study closure if, in 
their opinion, doing so will be critical to patient safety.
Before each regularly scheduled DSMC meeting, the study coordinator will submit a report 
including tabular summaries of all reported SAEs, AEs and deaths on study to date. The report 
will also include a brief summary of each previously unreported SAE and death, including an 
assessment of whether the event was unexpected or related to the study.  If the DSMC 
recommends protocol or informed consent changes during the study, the recommendations will 
be reviewed by the Protocol Chair and incorporated into the protocol as deemed appropriate. The 
protocol with incorporated changes will be distributed to the participating PIs after approval by 
the Dana Farber Cancer Institute IRB. It is the responsibility of each Transplant Center PI to 
forward the distributed communications from the DSMC to their local IRB.
12.3
Multicenter Guidelines
This protocol will adhere to DF/HCC Policy MULTI-100 and the requirements of the DF/HCC 
Multi-Center Data and Safety Monitoring Plan.  The specific responsibilities of the Sponsor-
Investigator, Coordinating Center, and External Sites and the procedures for auditing are 
presented in Appendix B.
13. STATISTICAL CONSIDERATIONS
This is a prospective, multicenter, single treatment arm phase 1/2 clinical trial. Phase 1 will 
proceed according to a standard 3+3 design. Phase 2 will expand enrollment to N=20 patients at 
the RP2D identified in Phase 1 to confirm safety and estimate preliminary efficacy.  In phase 2, 
interim monitoring will be performed for transplant-related mortality within 100 days of 
transplant (see section 13.5).
13.1
Definition of Evaluability
13.1.1 Definition of Evaluability for Dose Escalation Evaluation (Phase 1)
Eligible patients who are evaluable for the dose-determining analysis are those who either:
A) meet the following minimum exposure criterion and complete the DLT observation period 
without experiencing a DLT;
or
B) receive at least 1 dose of uproleselan and experience a DLT during the DLT observation 
period.
A patient is considered to have met the minimum exposure criterion if he/she received
at least 10 of the 12 of planned doses of uproleselan in the first cycle of dosing.  Patients who do 
not meet criteria for inclusion in the dose-determining analysis population will be replaced in the 
study accrual.

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13.1.2 Definition of Evaluability for estimation of efficacy (Phase 2)
Eligible patients will be evaluable for estimation of efficacy if they have received at 
least one dose of uproleselan at the RP2D. Patients who do not receive any 
uproleselan will be replaced in the trial accrual.
13.1.3 Patients to be included in safety analysis (Phase 1 and 2)
Eligible patients will be included in reporting toxicities if they have received at least one 
dose of uproleselan.
13.2
Study Design/Endpoints
13.2.1 Primary Endpoints
Phase 1. The occurrence of a DLT as defined in section 5.3.
Phase 2. The occurrence of a DLT as defined in section 5.3. 
13.2.2 Secondary Endpoints
Leukemia-free survival: The time from transplant to the first occurrence of an event 
(leukemic relapse [section 11.2] or death from any cause), or censored on date of last 
contact, if no event occurs.
Overall survival: The time from transplant to death from any cause, or censored on date 
of last contact, if no death occurs. Cause of death will be classified according to 
CIBMTR consensus criteria.34 
Non-relapse mortality: The time from transplant to death while in continuous complete 
remission, or censored on date of last contact, if no death occurs.  
Relapse: The time to leukemic relapse. 
Oral and gastrointestinal mucositis endpoint. The occurrence and severity of oral or 
gastrointestinal mucositis (between day 0 and post-transplant day 14) as graded by 
CTCAEv5.0.
Neutrophil engraftment: time to the first of 3 consecutive days following the nadir that 
the absolute neutrophil count is at least 500/µl.
Platelet engraftment:  time to the first day following the nadir that the platelet count is at 
least 20,000/µl without a transfusion in the preceding 7 days.
Mucosal barrier injury-associated laboratory-confirmed bloodstream infection (MBI-
LCBI) : cumulative incidence of MBI-LCBI by Day +30.

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13.2.3 Phase 1 Design
Dose escalation will proceed according to the standard 3+3 design (Table 9). Dose 
limiting toxicities (DLT) are defined in section 5.3. The DLT observation window is 
from transplant Day 0 through post-transplant Day +30. Cohorts of three patients will be 
enrolled on the current dose level. If 0 out of 3 patients experience a DLT,  the RP2D has 
been identified. If ≥2 out of 3 patients experience a DLT, assessment of this dose 
levelwill stop. If this occurs at dose level 1, the dose will be de-escalated to level 0. If this 
occurs at dose level 0, the trial will be terminated. If 1 out of 3 patients experience a 
DLT, 3 additional patients will be enrolled at the current dose level. If 0 out of these 3 
additional patients experience a DLT, the RP2D has been identified. If ≥ 1 out of these 3 
additional patients experience a DLT, assessment of this dose level will stop. If this 
occurs at dose level 1, the dose will be de-escalated to level 0.If this occurs at dose level 
0, the trial will be terminated. 
The maximum tolerated dose (MTD) is declared as the highest dose level at or below the 
maximally administered dose where ≤1 out of 6 patients experienced a DLT.
The RP2D is the dose recommended by the study team after the declaration of the MTD 
and review of the study data.
Table 9. Dose Escalation Schema
Number of Participants with DLT 
at a Given Dose Level 
Escalation Decision Rule
0 out of 3
This is the RP2D
>2 out of 3
If occurs at dose level 1, then de-escalate to dose level 
0. If occurs at dose level 0, trial will be terminated. 
1 out of 3
Enter 3 more participants at this dose level.

If 0 of these 3 participants experience DLT, this is 
the RP2D. 

If 1 or more of this group suffer DLT, then 
assessment at this level  is stoppedIf this occurs at 
dose level 1, then de-escalate to dose level 0.  If this 
occurs at dose level 0, the trial will be terminated. 
≤1 out of 6 at highest dose level at or 
below the maximally administered 
dose
This will be the RP2D. 
13.2.4 Phase 2 Design
Once the RP2D has been identified, an additional 14 to 17 evaluable patients will be 
enrolled at the RP2D. Interim monitoring of treatment related mortality (TRM) of the 20 
patients treated at the RP2D is described in section 13.5 below.

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13.3
Sample Size, Accrual Rate and Study Duration
During Phase 1, a minimum of 3 evaluable patients will be required (if 0 out of 3 patients at dose 
level 1 experience a DLT, the RP2D has been identified). A maximum of 12 evaluable patients 
will be required (6 patients at dose level 1 followed by 6 patients at dose level 0).
During Phase 2, an additional 14 to 17 evaluable patients will be required to reach a total of 20 
evaluable patients treated at the RP2D. A sample size of 20 evaluable patients achieves an exact 
95% confidence interval width equal to 0.379 assuming that the observed proportion of patients 
experiencing a DLT is 0.20.
Total Sample Size. A minimum of 3 and a maximum of 26 evaluable patients will be required. 
To account for up to 2 potentially unevaluable patients, a maximum sample size of up to 28 
patients is anticipated.
Study Duration. Assuming an accrual rate of 1 patient per month, accrual of the up to 28 patients 
will take about 2 years and 4 months, plus 2 years of follow-up on the last patient, for a total 
study duration of about 4 years 4 months.
13.4
Stratification Factors
There are no stratification factors in this trial.
13.5
Interim Monitoring Plan
13.51 Monitoring rule for TRM
A one-stage stopping rule will monitor transplant-related mortality (TRM) for the N=20 patients 
treated at the RP2D. TRM is defined as the occurrence of death from any cause from Day -7 pre-
transplant to post-transplant Day +100.
The one-stage interim monitoring rule for TRM is presented in Table 10. If there are 3 or more 
transplant-related deaths in the 20 patients treated at the RP2D, enrollment to the trial will be 
suspended so that DSMC can consider terminating the trial. If there are 2 or fewer transplant-
related deaths in the 20 patients treated at the RP2D, uproleselan will be declared as safe for 
further investigation in pediatric patients.
Table 10. One-stage stopping rule for treatment-related mortality for patients treated at 
the RP2D 
Decision Rule
Action
≥3 transplant-related deaths out of 20 patients
Trial termination recommended. 
≤2 transplant-related deaths out of 20 patients
Uproleselan is safe for further investigation 
in pediatric patients
This one-stage rule has 92.5% power with an 9.1% type 1 error rate to test the null hypothesis 
that P>0.25 versus the alternative that P<0.05, where P is the probability of a transplant-related 

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death.  The choice of the null and alternative hypothesis is based on an observed non-relapse 
mortality of 10.3% at 3 years for the BFC trial of pediatric patients in the Netherlands23.
13.52 Monitoring rule for RRT
A one-stage stopping rule will monitor regimen-related toxicity (RRT) for the N=20 patients 
treated at the RP2D. RRT is defined as the occurrence of dose limiting toxicities as outlined in 
Table 4, from Day -7 pre-transplant to post-transplant Day +30.
The one-stage interim monitoring rule RRT is presented in Table 11. If there are 3 or more 
patients with dose limiting RRT in the 20 patients treated at the RP2D, enrollment to the trial 
will be suspended so that DSMC can consider terminating the trial. If there are 2 or fewer 
patients with RRT in the 20 patients treated at the RP2D, this is evidence in support of safe use 
of uproleselan for further investigation in pediatric patients.
The choice of the null and alternative hypothesis is derived from two early phase clinical trials of 
conditioning with busulfan and a purine analogue.  In a trial of fludarabine and busulfan in 
adolescents and adults transplanted for hematologic malignancies, where busulfan exposure was 
escalated, 5 of 40 patients (12.5%) receiving busulfan targeted to an average AUC 6, 000 Mol-
min  developed grade 4 regimen related toxicity (based on CTCAE criteria, mucositis and/or 
transaminitis){Perkins, 2012 #76}.  In a phase 1/2 trial in children and adults transplanted for 
hematologic malignancies, 1 of 22 patients (4.5%) receiving fludarabine 10 mg/m2, clofarabine 
30 mg/m2 and busulfan targeted to an average AUC 6, 000 Mol-min developed grade 4 
regimen related toxicity (based on CTCAE criteria){Andersson, 2011 #59}.
Table 11. One-stage stopping rule for RRT for patients treated at the RP2D 
Decision Rule
Action
≥3 RRTs out of 20 patients
Trial termination recommended. 
≤2 RRT out of 20 patients 
Evidence supports safety of uproleselan for 
further investigation in pediatric patients
This one-stage rule has 94% power with an 9.3% type 1 error rate to test the null hypothesis that 
P>0.185 versus the alternative that P<0.020, where P is the probability of a transplant-related 
death.  The choice of the null and alternative hypothesis is based on sinusoidal obstruction 
syndrome accounting for the majority of severe RRT in HSCT and an expected incidence of 
severe VOD of approximately 10%35
13.6
Analysis of Primary Endpoints
To address primary objective in section 1.3 Phase 1, the RP2D will be identified through the 
application of the 3+3 design.  Accrual will be temporarily suspended after the enrollment of 
each cohort of 3 patients on a dose level, until all 3 patients have either completed the DLT 
observation period (30 days) or experienced a DLT.
To address primary objective in section 1.3 Phase 2, all observed toxicities will be summarized 

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using frequencies, proportions, and 95% confidence intervals by type (organ affected or 
laboratory determination), severity (by CTCAEv5.0), attribution, and expectedness. Only the 
maximum grade for each type of toxicity will be tabulated for each patient.
13.7
Analysis of Secondary Endpoints
To address secondary objective 1.3.2.1, additional pharmacokinetic parameters, including 
clearance, Cmax, and terminal half-life, for uproleselan will be calculated using standard 
methods and reported descriptively, in aggregate and by assigned dose level.
To address secondary objective 1.3.2.2, Kaplan-Meier curves of leukemia-free survival (LFS), 
overall survival (OS), and non-relapse mortality (NRM) will be generated for the cohort treated 
at the RP2D, and the point estimates of 1-year LFS, OS, and NRM will be calculated, with 
standard error according to Greenwood.
To address secondary objective 1.3.2.3, the proportion (and corresponding 95% exact confidence 
interval [CI]) of patients who experience oral and/or gastrointestinal mucositis will be 
summarized by severity.
13.8
Analysis of Exploratory Endpoints
To address exploratory objective 1.3.3.1, the median proportion (and corresponding 95% exact 
confidence interval [CI]) of pre-transplant marrow blasts with detectable E-selectin ligand (EsL) 
for the cohort treated at the RP2D will be summarized by leukemia-free survival (LFS) status 
(yes/no) 1-year post-transplant. 
To address exploratory objective 1.3.3.2, LFS status at 1 year (yes/no) for the cohort treated at 
the RP2D, will be described by level of expression (low, high, intermediate) of the EsL related 
glycan synthesis genes ST3GAL4 and FUT7 (as defined in section 2.8). 

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Shukla P, Goswami S, Keizer RJ, et al. Assessment of a Model-Informed Precision 
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Bearman SI, Appelbaum FR, Buckner CD, et al. Regimen-related toxicity in patients 
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Corbacioglu S, Carreras E, Ansari M, et al. Diagnosis and severity criteria for 
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Mohty M, Malard F, Abecassis M, et al. Revised diagnosis and severity criteria for 
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Hahn T, Sucheston-Campbell LE, Preus L, et al. Establishment of Definitions and 
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35.
Corbacioglu S, Cesaro S, Faraci M, et al. Defibrotide for prophylaxis of hepatic veno-
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6736(11)61938-7

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APPENDIX A
PERFORMANCE STATUS SCALES/SCORES
Performance Status Criteria 
Karnofsky and Lansky performance scores are intended to be multiples of 10 
ECOG (Zubrod) 
Karnofsky 
Lansky* 
Score 
Description 
Score 
Description 
Score 
Description 
100 
Normal, no complaints, no 
evidence of disease 
100 
Fully active, normal. 
0 
Fully active, able to carry on all 
pre-disease performance 
without restriction. 
90 
Able to carry on normal 
activity, minor signs or 
symptoms of disease. 
90 
Minor restrictions in physically 
strenuous activity. 
80 
Normal activity with effort; 
some signs or symptoms of 
disease. 
80 
Active, but tires more quickly 
1 
Restricted in physically 
strenuous activity but 
ambulatory and able to carry 
out work of a light or sedentary 
nature, e.g., light housework, 
office work. 
70 
Cares for self, unable to carry 
on normal activity or do active 
work. 
70 
Both greater restriction of and less 
time spent in play activity. 
60 
Required occasional assistance, 
but is able to care for most of 
his/her needs. 
60 
Up and around, but minimal 
active play; keeps busy with 
quieter activities. 
2 
Ambulatory and capable of all 
self-care but unable to carry out 
any work activities. Up and 
about more than 50% of waking 
hours 
50 
Requires considerable 
assistance and frequent 
medical care. 
50 
Gets dressed, but lies around 
much of the day; no active play, 
able to participate in all quiet play 
and activities. 
40 
Disabled, requires special care 
and assistance. 
40 
Mostly in bed; participates in 
quiet activities. 
3 
Capable of only limited self-
care, confined to bed or chair 
more than 50% of waking 
hours. 
30 
Severely disabled, 
hospitalization indicated. 
Death not imminent. 
30 
In bed; needs assistance even for 
quiet play. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
20 
Often sleeping; play entirely 
limited to very passive activities. 
4 
Completely disabled. Cannot 
carry on any self-care. Totally 
confined to bed or chair. 
10 
Moribund, fatal processes 
progressing rapidly. 
10 
No play; does not get out of bed. 
*The conversion of the Lansky to ECOG scales is intended for NCI reporting purposes only.

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APPENDIX B 
DANA-FARBER/HARVARD CANCER CENTER MULTI-CENTER DATA AND 
SAFETY MONITORING PLAN
INTRODUCTION
The Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan 
(DF/HCC DSMP) outlines the procedures for conducting a DF/HCC Multi-Center research 
protocol. The DF/HCC DSMP serves as a reference for any sites external to DF/HCC that are 
participating in the research protocol.
Purpose
To establish standards that will ensure that a Dana-Farber/Harvard Cancer Center Multi-Center 
protocol will comply with Federal Regulations, Health Insurance Portability and Accountability 
Act (HIPAA) requirements and applicable DF/HCC Policies and Operations. 
GENERAL ROLES AND RESPONSIBILITIES
For DF/HCC Multi-Center Protocols, the following general responsibilities apply, in addition to 
those outlined in DF/HCC Policies for Sponsor-Investigators: 
DF/HCC Sponsor
The DF/HCC Sponsor, John Horan, MD, MPH, will accept responsibility for all aspects of 
conducting a DF/HCC Multi-Center protocol which includes but is not limited to: 

Oversee the coordination, development, submission, and approval of the protocol as well 
as subsequent amendments. 

Ensure that the investigators, study team members, and Participating Institutions are 
qualified and appropriately resourced to conduct the protocol.  

Include the Multi-Center Data and Safety Monitoring Plan as an appendix to the protocol.

Ensure all Participating Institutions are using the correct version of the protocol.

Ensure that each participating investigator and study team member receives adequate 
protocol training (and/or a Site Initiation Visit prior to enrolling participants) and 
throughout trial’s conduct as needed.

Ensure the protocol will be provided to each participating site in a language 
understandable to all applicable site personnel when English is not the primary language. 

Monitor progress and overall conduct of the study at all Participating Institutions. 

Ensure all DFCI Institutional Review Board (IRB), DF/HCC and other applicable (FDA) 
reporting requirements are met. 

Review data and maintain timely submission of data for study analysis. 

Act as the single liaison with the FDA (investigator-held IND trials) as applicable.

Ensure compliance with all requirements as set forth in the Code of Federal Regulations, 
applicable DF/HCC requirements, HIPAA requirements, and the approved protocol.

Commit to the provision that the protocol will not be rewritten or modified by anyone 

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other than the DF/HCC Sponsor.

Identify and qualify Participating Institutions and obtain accrual commitments prior to 
extending the protocol to that site.

Monitor accrual and address Participating Institutions that are not meeting their accrual 
requirements. 
Coordinating Center (Dana-Farber Cancer Institute)
The general responsibilities of the Coordinating Center may include but are not limited to:

Assist in protocol development. 

Maintain CTEP, FDA or OBA correspondence, as applicable.

Review registration materials for eligibility and register participants from Participating 
Institutions in the DF/HCC clinical trial management system (CTMS).

Distribute protocol and informed consent document updates to External Sites as needed.

Oversee the data collection process from External Sites.

Maintain documentation of Serious Adverse Event (SAE) reports and 
deviations/violation submitted by External Sites and provide to the DF/HCC Sponsor for 
timely review and submission to the IRB of record, as necessary. 

Distribute serious adverse events reported to the DF/HCC Sponsor that fall under the 
reporting requirements for the IRB of record to all External Sites.

Provide External Sites with information regarding DF/HCC requirements that they will 
be expected to comply with.

Carry out plan to monitor External Sites either by on-site or remote monitoring. 

Maintain Regulatory documents of all External Sites which includes but is not limited to 
the following: local IRB approvals/notifications from all External Sites, confirmation of 
Federalwide Assurances (FWAs) for all sites, all SAE submissions, Screening Logs for 
all sites, IRB approved consents for all sites

Conduct regular communications with all External Sites (conference calls, emails, etc) 
and maintain documentation all relevant communications.
External Site
An External Site is an institution that is outside the DF/HCC and DF/PCC consortium that is 
collaborating with DF/HCC on a protocol where the sponsor is a DF/HCC investigator.  The 
External Site acknowledges the DF/HCC Sponsor as having the ultimate authority and 
responsibility for the overall conduct of the study. 
Each External Site is expected to comply with all applicable DF/HCC requirements stated within 
this Data and Safety Monitoring Plan and/or the protocol document. 
The general responsibilities for each External Site may include but are not limited to:

Document the delegation of research specific activities to study personnel.

Commit to the accrual of participants to the protocol.

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
Submit protocol and/or amendments to their IRB of record. For studies under a single 
IRB, the Coordinating Center will facilitate any study-wide submissions.

Maintain regulatory files as per ICH GCP and federal requirements.

Provide the Coordinating Center with regulatory documents or source documents as 
requested.

Participate in protocol training prior to enrolling participants and throughout the trial as 
required.

Update Coordinating Center with research staff changes on a timely basis.

Register participants through the Coordinating Center prior to beginning research related 
activities when required by the sponsor. 

Submit Serious Adverse Event (SAE) reports to sponsor, Coordinating Center, and IRB 
of record as applicable, in accordance with DF/HCC requirements. 

Submit protocol deviations and violations to the Sponsor, Coordinating Center, and IRB 
of record as applicable.

Order, store and dispense investigational agents and/or other protocol mandated drugs per 
federal guidelines and protocol requirements.

Participate in any quality assurance activities and meet with monitors or auditors at the 
conclusion of a visit to review findings.

Promptly provide follow-up and/or corrective action plans for any monitoring queries or 
audit findings.

Notify the sponsor immediately of any regulatory authority inspection of this protocol at 
the External Site.
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS
Certain DF/HCC Policy requirements apply to External Sites participating in DF/HCC research. 
The following section will clarify DF/HCC requirements and further detail the expectations for 
participating in a DF/HCC Multi-Center protocol. 
Protocol Revisions and Closures
The External Sites will receive notification of protocol revisions and closures from the 
Coordinating Center.  When under a separate IRB, it is the individual External Site’s 
responsibility to notify its IRB of these revisions.
Protocol revisions: External Sites will receive written notification of protocol revisions from the 
Coordinating Center. All protocol revisions should be IRB approved and implemented within a 
timely manner from receipt of the notification.
Non-life-threatening revisions: Participating Institutions will receive written notification of 
protocol revisions regarding non-life-threatening events from the Coordinating Center. Non-life-
threatening protocol revisions must be IRB approved and implemented within 90 days from 
receipt of the notification.
Revisions for life-threatening causes: Participating Institutions will receive immediate 
notification from the Coordinating Center concerning protocol revisions required to protect lives 

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with follow-up by fax, mail, e-mail, etc.  Life-threatening protocol revisions will be implemented 
immediately followed by IRB request for approval.
Protocol closures and temporary holds: External Sites will receive notification of protocol 
closures and temporary holds from the Coordinating Center. Closures and holds will be effective 
immediately.  In addition, the Coordinating Center, will update the External Sites on an ongoing 
basis about protocol accrual data so that they will be aware of imminent protocol closures.
The following (but not limited to) must be on file with the Coordinating Center:

Initial approval letter of the Participating Institution's IRB. 

Copy of the Informed Consent Form(s) approved by the Participating Institution’s IRB. 

Participating Institution’s IRB approval for all amendments.

Annual approval letters by the Participating Institution's IRB.
Informed Consent Requirements
The DF/HCC approved informed consent document will serve as a template for the informed 
consent for External Sites. The External Site consent form must follow the consent template as 
closely as possible and should adhere to specifications outlined in the DF/HCC Guidance 
Document on Model Consent Language for Investigator-Sponsored Multi-Center Trials.  This 
document will be provided separately to each External Site upon request.
External Sites must send their version of the informed consent document to the Coordinating 
Center for sponsor review and approval. If the HIPAA authorization is a separate document, 
please submit to the sponsor for the study record. Once sponsor approval is obtained, the 
External site may submit to their IRB of record, as applicable. In these cases, the approved 
consent form must also be submitted to the Coordinating Center after approval by the local IRB 
for all consent versions.
The Principal Investigator (PI) at each External Site will identify the appropriate members of the 
study team who will be obtaining consent and signing the consent form for protocols. External 
Sites must follow the DF/HCC requirement that for all interventional drug, biologic, or device 
research, only attending physicians may obtain initial informed consent and any re-consent that 
requires a full revised consent form.  
IRB Re-Approval
Verification of IRB re-approval for the External Sites is required in order to continue research 
activities.  There is no grace period for continuing approvals.
The Coordinating Center will not register participants if a re-approval letter is not received for 
the External Site on or before the anniversary of the previous approval date.  
DF/HCC Multi-Center Protocol Confidentiality

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All documents, investigative reports, or information relating to the participant are strictly 
confidential. Whenever reasonably feasible, any participant specific reports (i.e. Pathology 
Reports, MRI Reports, Operative Reports, etc.) submitted to the Coordinating Center should be 
de-identified. It is recommended that the assigned protocol case number be used for all 
participant specific documents. Participant initials may be included or retained for cross 
verification of identification. 
Participant Registration and Randomization 
See detailed registration instructions in protocol Section 4.4.
Initiation of Therapy
Participants must be registered with the DF/HCC CTMS before the initiation of treatment or 
other protocol-specific interventions. Treatment and other protocol-specific interventions may 
not be initiated until the External Site receives confirmation of the participant’s registration from 
the Coordinating Center. The DF/HCC Sponsor and IRB of record must be notified of any 
violations to this policy.
Eligibility Exceptions
No exceptions to the eligibility requirements for a protocol without IRB approval will be 
permitted. All External Sites are required to fully comply with this requirement. The process for 
requesting an eligibility exception is defined below.
Data Management
DF/HCC Inform develops case report forms (CRF/eCRFs), for use with the protocol. These 
forms are designed to collect data for each study. DF/HCC  provides a web-based training for all 
eCRF users.
  
Data Forms Review
Data submissions are monitored for timeliness and completeness of submission. If study forms 
are received with missing or questionable data, the submitting institution will receive a written or 
electronic query from the DF/HCC Office of Data Quality, Coordinating Center, or designee. 
Responses to all queries should be completed and submitted in a timely manner..  
If study forms are not submitted on schedule, the External Sites will periodically receive a 
Missing Form Report from the Coordinating Center noting the missing forms. 
Protocol Reporting Requirements
Protocol Deviations, Exceptions and Violations

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Federal Regulations require an IRB to review proposed changes in a research activity to ensure 
that researchers do not initiate changes in approved research without IRB review and approval, 
except when necessary to eliminate apparent immediate hazards to the participant. DF/HCC 
requires all departures from the defined procedures set forth in the IRB approved protocol to be 
reported to the DF/HCC Sponsor and to the IRB of record.
For reporting purposes, DF/HCC uses the terms “violation”, “deviation” and “exception” to 
describe departures from a protocol. All Participating Institutions must adhere to requirements 
for reporting to the DF/HCC Sponsor and will follow their institutional policy for reporting to 
their local IRB.
Definitions
Protocol Deviation: Any departure from the defined procedures set forth in the IRB-approved 
protocol which is prospectively approved prior to its implementation.
Protocol Exception:  Any protocol deviation that relates to the eligibility criteria, e.g. enrollment 
of a participant who does not meet all inclusion/exclusion criteria.
Protocol Violation: Any protocol departure that was not prospectively approved by the IRB prior 
to its initiation or implementation.
Reporting Procedures
DF/HCC Sponsor: is responsible for ensuring that clear documentation is available in the 
medical record and/or regulatory documents to describe all protocol exceptions, deviations and 
violations. The DF/HCC Sponsor will also be responsible for ensuring that all protocol 
violations/deviations are promptly reported per DFCI IRB guidelines. 
Participating Institutions: Protocol deviations require prospective approval from the DFCI IRB. 
The Participating Institution must submit the deviation request to the Coordinating Center who 
will then submit the deviation request to the DFCI IRB. Upon DFCI IRB approval the deviation 
is submitted to the Participating Institution IRB, per institutional policy. A copy of the 
Participating Institution’s IRB report and determination will be forwarded to the Coordinating 
Center within 10 business days after the original submission.  The deviation may not be 
implemented without all required approvals.
All protocol violations must be sent to the Coordinating Center in a timely manner. The 
Coordinating Center will provide training for the requirements for the reporting of violations. 
Coordinating Center:  Upon receipt of the violation/deviation report from the Participating 
Institution, the Coordinating Center will submit the report to the DF/HCC Sponsor for review. 
Subsequently, the Participating Institution’s IRB violation/deviation report will be submitted to 
the DFCI IRB for review per DFCI IRB reporting guidelines. 
Reporting Procedures

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Requests to deviate from the protocol require approval from the IRB of record and the sponsor. 
All protocol violations must be sent to the Coordinating Center in a timely manner. The 
Coordinating Center will provide training for the requirements for the reporting of violations. 
Guidelines for Processing IND Safety Reports 
The DF/HCC Sponsor will review all IND Safety Reports per DF/HCC requirements, and ensure 
that all IND Safety Reports are distributed to the External Sites as required by DF/HCC Policy. 
External Sites will review/submit to the IRB according to their institutional policies and 
procedures.
MONITORING: QUALITY CONTROL
The Coordinating Center, with the aid of the DF/HCC Office of Data Quality, provides quality 
control oversight for the protocol.
Ongoing Monitoring of Protocol Compliance
 
The Participating Institutions may be required to submit participant source documents to the 
Coordinating Center for monitoring. Participating Institution may also be subject to on-site 
monitoring conducted by the Coordinating Center. 
The Coordinating Center will implement ongoing monitoring activities to ensure that 
Participating Institutions are complying with regulatory and protocol requirements, data quality, 
and participant safety. Monitoring practices may include but are not limited to source data 
verification, and review and analysis of eligibility requirements, informed consent procedures, 
adverse events and all associated documentation, review of study drug administration/treatment, 
regulatory files, protocol departures reporting, pharmacy records, response assessments, and data 
management. 
Site Qualification
Sites are invited to participate in this protocol if they are familiar with and have participated in 
prior Phase I studies, have an appropriate volume of patients to be able to contribute to study 
enrollment goals, and have appropriate resources, including IRB support, investigational 
pharmacists, clinical research coordinators, research nurses, and experienced physician 
investigators to conduct Phase I research.  DF/HCC Site/Protocol Feasibility Questionnaires 
must be completed by each site.  The Sponsor will assess that the investigators, study team 
members, and Participating Institutions are qualified and appropriately resourced to conduct the 
protocol.  The DF/HCC Sponsor will have final approval of any participating sites on this trial.
Regulatory Documents: 
DFCI will collect all required regulatory documentation prior to study activation. The study team 
will work with all participating sites to ensure all updated / revised regulatory documentation is 
maintained at each site and forwarded to DFCI and maintained in the Trials Master File.

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Once a proposed Participating Institution receives institutional IRB approval, all approval 
documentation and IRB-approved related documents will be emailed to the Coordinating Center 
study staff and an amendment to add a site will be submitted to the DF/HCC IRB.  Once 
approval is received to add the Participating Institution study materials will be sent to the 
Participating Institution.  Study materials will include, but are not limited to, regulatory 
documents and participant tracking forms. 
All Participating Institutions must maintain and update all essential regulatory documents in a 
regulatory binder.  A designated member of the DF/HCC Lead Institution will be responsible for 
maintaining the Trial Master File which will include copies of all regulatory documentation for 
the Lead Site and all Participating Institutions.  
All Participating Institutions are required to submit all institutional IRB correspondences and 
approvals to be retained in the Trial Master File at the Lead Institution.  The Lead Institution will 
review all working study documents and ensure that the most current IRB-approved protocol and 
study documents are being used by the Participating Institutions. 
Delegation of Authority/Responsibility: 
Participating Institutions will be instructed to complete a Delegation of Responsibility/ Authority 
Log which will be reviewed/approved by the DF/HCC Sponsor.  A copy of this document will be 
retained in the Trial Master File.  Participating Institutions will be instructed to inform the 
Coordinating Center immediately should there be a change in personnel.  An updated training 
and Delegation of Authority/Responsibility log will need to be completed as soon as possible. 
Site Initiation Visit: 
A Site Initiation Visit (SIV) will be conducted with all participating sites prior to enrolling 
participants.  The SIV will cover study objectives and rationale, study design, eligibility, 
registration, required data, treatment schedule, side effects/AEs, SAE reporting, and dose 
modification.  It will be led by the DFCI Overall Principal Investigator, John Horan, MD, MPH.  
It is expected that the Participating Institution Site PI and all study staff will attend.
Ongoing Communication and Training: 
Regularly scheduled teleconferences will occur between the Coordinating Center and 
Participating Institutions. This will be a forum to discuss and study related issues not limited to 
the following: protocol amendments, study accrual, SAE’s/AE’s experienced, clinical response 
and deviations/violations. An agenda will be sent to all sites at the time the teleconference is 
scheduled.  Minutes will be taken and distributed to the participating institutions after each 
teleconference.
Virtual Monitoring
The Coordinating Center will request source documentation from Participating Institutions as 
needed to complete virtual monitoring activities.  Participating Institutions will be asked to 

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forward de-identified copies of participants’ medical record and source documents to the 
Coordinating Center to aid in source data verification.
On-Site Monitoring
On-Site monitoring may occur on an as needed basis. On-site source documentation verification 
(SDV) will be conducted by having access to participants’ complete medical record and source 
documents. In addition, upon request from a monitor or auditor, Participating Institutions should 
provide access to regulatory documents, pharmacy records, local policies related to the conduct 
of research, and any other trial-related documentation maintained by the participating site. If 
there are concerns for protocol compliance, issues that impact subject safety or the integrity of 
the study are found, or trends identified based on areas of need, additional monitoring visits may 
be scheduled.
Adverse Event Reporting:
Documentation of all adverse events must be included as part of source documentation.  
Documentation that a physician determined attribution of each event must also be included.  AEs 
and SAEs must be reported as instructed in the protocol with the log serving as record for all 
events at each Participating Institution.  The DF/HCC Sponsor, John Horan, MD, MPH, will be 
notified/report all AEs SAEs as per protocol. 
Drug Accountability: 
Participating pharmacies will be required to submit Drug Accountability Logs at the time of 
monitoring documenting receipt and shipment of drug supply, dispensing/ordering of supply, and 
destruction of unused study medication and/or damaged or expired drug.  
Monitoring Reports
The DF/HCC Sponsor will review all monitoring reports to ensure protocol compliance. The 
DF/HCC Sponsor may increase the monitoring activities at External Sites that are unable to 
comply with the protocol, DF/HCC Sponsor requirements or federal and local regulations. 
Accrual Monitoring
Prior to extending a protocol to an external site, the DF/HCC Sponsor will establish accrual 
requirements for each External Site. Accrual will be monitored for each External Site by the 
DF/HCC Sponsor or designee. Sites that are not meeting their accrual expectations may be 
subject to termination.
It is expected that each External Site will accrue 2 - 5 patients over the duration of the trial.
AUDITING: QUALITY ASSURANCE

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DF/HCC Internal Audits
 
All External Sites are subject to audit by the DF/HCC Office of Data Quality (ODQ). Typically, 
approximately 3-4 participants would be audited at the site over a 2-day period. If violations 
which impact participant safety or the integrity of the study are found, more participant records 
may be audited. 
Audit Notifications
It is the External Site’s responsibility to notify the Coordinating Center of all external audits or 
inspections (e.g., FDA, EMA, NCI) that involve this protocol. All institutions will forward a 
copy of final audit and/or re-audit reports and corrective action plans (if applicable) to the 
Coordinating Center, within 12 weeks after the audit date. 
Audit Reports 
The DF/HCC Sponsor will review all final audit reports and corrective action plans, if 
applicable. The Coordinating Center must forward any reports to the DF/HCC ODQ per 
DF/HCC policy for review by the DF/HCC Audit Committee. For unacceptable audits, the 
DF/HCC Audit Committee would forward the final audit report and corrective action plan to the 
IRB as applicable.
External Site Performance
The DF/HCC Sponsor and the IRB of record are charged with considering the totality of an 
institution’s performance in considering institutional participation in the protocol.
External Sites that fail to meet the performance goals of accrual, submission of timely and 
accurate data, adherence to protocol requirements, and compliance with state and federal 
regulations, may be put on hold or closed. 

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APPENDIX C
HEPATIC SOS/VOD DIAGNOSTIC AND GRADING CRITERIA
Pediatric EBMT diagnostic criteria for hepatic SOS/VOD
The presence of two or more of the following:
Criterion
Comments
Unexplained consumptive and transfusion-
refractory thrombocytopenia
⩾one platelet transfusion/day.
Otherwise unexplained weight gain on three 
consecutive days despite the use of diuretics or 
a weight gain >5% above baseline value
Hepatomegaly 
Best if confirmed by imaging above baseline value*
Ascites 
Best if confirmed by imaging above baseline value*
Rising bilirubin from a baseline value on 3 
consecutive days or bilirubin ⩾2 mg/dL within 
72 h
*Suggested: imaging (US, CT or MRI) immediately before HCT to determine baseline value for both 
hepatomegaly and ascites.

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EBMT criteria for grading the severity of suspected hepatic SOS/VOD in childrena
CTCAE
Mild
Moderate
Severe
Very severe MOD/MOF
 
1
2
3
4
LFTb (ALT, AST, 
GLDH)
⩽2 × 
normal
>2 and ⩽5 × 
normal
>5
Persistent RTb
<3 days
3–7 days
>7 days
Bilirubin (mg/dL)b, c
<2
⩾2
Bilirubin (μmol/L)
<34
⩾34
Ascitesb
Minimal
Moderate
Necessity for 
paracentesis (external 
drainage)
Bilirubin kinetics
Doubling within 48 h
Coagulation
Normal
Normal
Impaired coagulation
Impaired coagulation with need 
for replacement of coagulation 
factors
Renal function GFR 
(mL/min)
89–60
59–30
29–15
<15 (renal failure)
Pulmonary function 
(oxygen requirement)
<2 L/min
>2 L/min
Invasive pulmonary 
ventilation (including 
CPAP)
CNS
Normal
Normal
Normal
New onset cognitive 
impairment
Abbreviations: ALT=alanine transaminase; AST=aspartate transaminase; CNS=central nervous 
system; CPAP=continuous positive airway pressure; CTCAE=Common Terminology Criteria 
for Adverse Events; GFR=glomerular filtration rate; GLDH=glutamate dehydrogenase; 
LFT=liver function test; MOD/MOF=multi-organ dysfunction/multi-organ failure; 
RT=refractory thrombocytopenia; SOS/VOD, sinusoidal obstruction syndrome/veno-occlusive 
disease.
aIf patient fulfills criteria in different categories they must be classified in the most severe 
category. In addition, the kinetics of the evolution of cumulative symptoms within 48 h predicts 
severe disease.
bPresence of ⩾2 of these criteria qualifies for an upgrade to CTCAE level 4 (very severe 
SOS/VOD).
cExcluding pre-existent hyperbilirubinemia due to primary disease.

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APPENDIX D
BEARMAN SCALE