Phase Ib/II Study of Uproleselan Added to Cladribine Plus Low Dose Cytarabine (LDAC) Induction Followed by Consolidation With Uproleselan Plus Cladribine Plus LDAC in Patients With Treated Secondary AML (TS-AML)
Phase: PHASE1
Conditions: Secondary Acute Myeloid Leukemia
Sponsor: M.D. Anderson Cancer Center

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PHASE Ib/II STUDY OF UPROLESELAN ADDED TO CLADRIBINE PLUS LOW 
DOSE CYTARABINE (LDAC) INDUCTION FOLLOWED BY CONSOLIDATION 
WITH UPROLESELAN PLUS CLADRIBINE PLUS LDAC IN PATIENTS WITH 
TREATED SECONDARY AML (TS-AML)  
 
1.0 
OBJECTIVES 
 
2.0 
BACKGROUND 
 
3.0 
PATIENT SELECTION 
 
4.0 
TREATMENT PLAN 
 
5.0 
PATIENT EVALUATION 
 
6.0 
DOSING DELAYS / DOSE MODIFICATIONS 
 
7.0 
AGENT FORMULATION AND PROCUREMENT 
 
8.0 
STATISTICAL CONSIDERATIONS 
 
9.0 
MEASUREMENT OF EFFECT 
 
10.0 
REGUALATORY AND REPORTING REQUIREMENTS 
 
11.0  
DATA SECURITY/CONFIDENTIALITY 
 
12.0 
STUDY OVERSIGHT 
 
13.0 
STATEMENT OF COMPLIANCE 
 
14.0 
REFERENCES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1.0 OBJECTIVES 
 
1. 
Primary objective: 
• To determine the safety, tolerability, and recommended phase II dose (RP2D) of 
uproleselan combined with cladribine + low dose cytarabine (LDAC) in patients 
with treated-secondary AML (ts-AML) 
 
2. 
Secondary objectives: 
 
• To assess the efficacy (overall response rate [ORR], complete response 
[CR], complete response without blood count recovery [CRi], CR with 
partial hematologic recovery [CRh], partial response [PR], or morphologic 
leukemia-free state (MLFS) of uproleselan combined with cladribine + 
LDAC in patients with ts-AML. 
• To assess the rate of minimal residual disease (MRD) negativity by flow 
cytometry at response.  
• To assess overall survival (OS), remission duration (CRd), and 
progression-free survival (PFS) in patients with ts-AML treated with 
uproleselan combined with cladribine + LDAC. 
• To assess the rate of complete cytogenetic response (CCyR) in patients with ts-
AML with abnormal baseline karyotype, treated with uproleselan combined with 
cladribine + LDAC. 
• To assess toxicity and induction mortality of patients with AML treated with 
uproleselan added to cladribine + LDAC.  
 
3. Exploratory objective: 
 
• To explore biomarkers of response and resistance in patients with ts-AML treated 
with uproleselan combined with cladribine + LDAC. 
• To examine the correlation of E-selectin ligand-forming glycosylation genes of 
leukemic blasts with clinical outcome. 
 
2.0 BACKGROUND 
 
2.1 Acute Myeloid Leukemia (AML) 
 
AML is the cause of approximately 1.2% of all cancer deaths in the US with an 
annual incidence rate of 2.2 per 100,000 and approximately 10,000 new cases per 
year. Age-adjusted incidence ranges from 1 per 100,000 in people < 20 years to > 
10 per 100,000 in the elderly. AML represents approximately 90% of all acute 
leukemias in adults, and accounts for about 25% of all cases of leukemia 
diagnosed in the Western hemisphere.1,2 AML is a clonal myelopoietic stem cell 
disorder characterized by the accumulation of neoplastic cells in the bone marrow 

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and in the peripheral circulation. Current induction chemotherapy protocols 
combining cytarabine and an anthracycline administered as first-line treatment 
induce complete remissions in a majority (55% to 75%) of patients. Standard 
consolidation therapy with high doses of cytarabine leads to improved survival in 
younger patients, but provides little benefit for patients who are older than 60 
years. Overall, up to 70% of patients can be expected to relapse, so that only 
about 20-30% attain long-term disease-free survival. 
 
A number of risk factors have been identified that predict the length of remission 
and the possibility of long-term survival. Age has emerged as a major factor that 
determines the prognosis of patients with untreated AML. For those patients, 
treatment has not improved significantly in recent years when compared with the 
progress that has been made in younger patients.3-5 AML occurring in patients > 
60 years of age thus continues to carry a poor prognosis. Using a standard 
induction combination such as the 3+7 regimen (cytarabine plus an 
anthracycline), complete remission rates decrease by about 10% per additional 
decade of life, induction mortality can be substantial, easily exceeding 20%, and 
remission durations are usually transient and rarely last more than 12 months. The 
median time from treatment to death is 5 to 10 months and less than 10% of 
patients stay in remission at 3 years.3 We recently reviewed our own experience in 
older patients treated between 1990 and 2009 with intensive chemotherapy.  In 
446 patients, the overall CR rate was 45%, with a 4-week mortality of 26%, an 8-
week mortality of 36%, a 1-year survival rate of 28%, and a median overall 
survival of 4.6 months.  The reasons for this difference in outcome when 
compared to younger patients are multiple. Differences in the biology of AML in 
older patients is reflected by a higher proportion of patients with an unfavorable 
karyotype, a higher rate of primary drug resistance associated with overexpression 
of P-glycoprotein (P-gp), and an increased frequency of disease evolution from a 
preexisting and at times probably unrecognized myelodysplasia. Poorer tolerance 
of combination chemotherapy regimens leads to the use of less intensive 
treatment protocols.6 Acknowledging the particular challenges posed by older 
patients with AML both based on patient and disease-related factors, considerable 
efforts are being invested in targeting this particular group of patients. Realizing 
the poor response with standard therapy, new agents and newer strategies are 
continuously being studied. The development of new and effective anti-AML 
approaches therefore remains a cornerstone of the continued efforts to improve 
the outcome of poor prognosis patients.7 Both cladribine and 5-azacytidine have 
been studied in myeloid disorders and are the main ingredients of the proposed 
study. 
 
2.12  Treated-secondary AML (ts-AML) 
 
Secondary AML refers to a subset of AML that arises from a prior or antecedent 
myeloid disorder such as myelodysplastic syndrome (MDS), myeloproliferative 
neoplasms (MPN), or aplastic anemia.  These are known to be clonal myeloid 
neoplasms with a high risk of transformation to AML as part of their natural 
history. Recently, the World Health Organization (WHO) has revised its 

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classification schema of AML to include a subset of “AML with MDS-related 
changes”, which includes (1) AML arising from prior MDS/MPN, (2) AML with 
MDS related cytogenetic abnormality, and (3) AML with morphologic evidence 
of multilineage dysplasia.  Compared to so-called ‘de novo’ AML, secondary 
AML has been associated with a poor overall prognosis, with lower response rates 
to standard therapy and an overall inferior survival outcome.   
 
With the introduction of hypomethylating agents (HMAs) such as 5-azacytidine 
(AZA) and decitabine, treatment of antecedent hematologic disorders such as 
MDS and MPN has improved, with improved OS and reduced transformation to 
AML.  However, the increased use of HMAs has led to a growing cohort of 
patients with AML who have had an antecedent myeloid malignancy (MDS or 
MPN) and have been treated for that malignancy with HMAs.  These patients, 
classified as having treated-secondary AML (ts-AML) have recently been shown 
to have a particularly adverse prognosis and should likely be considered a 
separate high-risk cohort that needs effective new approaches. 
 
We recently reviewed our experience of ts-AML treated over 15 years to define 
their overall prognosis and response to differential therapeutic approaches (Boddu 
P, et al 2017).  A total of 254 patients with ts-AML were examined and compared 
to patients without ts-AML, including those with s-AML and de novo AML.  
Overall, patients with ts-AML had a median OS of 4.2 months compared to 9.2 
months in patients with untreated s-AML (P< 0.001).  This poor survival was 
evident in patients < 60 years of age (median OS, 5 months) and those > 60 years 
of age (median OS, 4.7months).  Emphasizing its particularly adverse prognosis, 
patients with ts-AML had median OS that was inferior to other well established 
high-risk subgroups, including those with TP53 mutations, monosomy 5/7, 
chromosome 3q abnormalities, and those with therapy related AML.   
 
We also reviewed response rates and mortality rates by treatment intensity, 
divided into high intensity (> 1 gram/m2 of cytarabine), moderate intensity (100 – 
500 mg/m2 of cytarabine), or lower intensity (low dose cytarabine combinations 
or HMAs).  High intensity therapy produced CR/CRp rates of 26% and 32% 
among younger and older patients respectively, but were associated with 8-week 
mortality rates of 35% and 32%, respectively.  Moderate intensity approaches 
yielded CR/CRp rates of 43% and 27%, respectively, along with 8-week mortality 
rates of 14% and 36%, respectively.  When using lower intensity therapies, 
CR/CRp rates were 11% and 22%, respectively among younger and older 
patients, with associated 8-week mortality rates of 22% and 19%, respectively. 
 
These adverse outcomes across different therapy intensities, and without regard to 
age, highlights an important area of unmet need that requires focused research on 
newer therapies.  We have designed the current study to investigate a combination 
that may help improve outcomes in this difficult subset of patients. 
 
2.2 Cladribine in AML 
 

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Cladribine (2-chloro-2’-deoxyadenosine, 2-CDA) is a synthetic purine nucleoside 
analogue that is currently FDA approved for the treatment of symptomatic Hairy 
Cell leukemia.8  Based on the success of cytarabine (AraC) in leukemia, 2-CDA 
was rationally designed to be resistant to degradation by adenosine deaminase and 
thereby increase its cytotoxicity.  Cladribine’s cytotoxic effects have been 
attributed to its ability to interfere with DNA synthesis in replicating cells9 as well 
as inhibition of DNA repair and accumulation of DNA strand breaks in 
nonproliferating cells10,11.  Clinically, 2-CDA has been shown to have single-
agent activity in hairy cell leukemia, chronic lymphocytic leukemia, as well as 
acute myeloid leukemia.12,13  Building on a phase I study in pediatrics14 that 
confirmed safety and potential efficacy, Santana et. al.15 conducted a phase II 
study of 2-CDA in pediatric patients with relapsed AML and ALL.  Patients were 
given 2-CDA as a 5-day continuous infusion at a dose of 8.9 mg/m2/d.  Of 17 
patients with AML, 8 (47%) achieved a CR and 2 (12%) achieved a PR, for an 
overall response rate of 59%.  The drug was very well tolerated with the major 
toxicity being severe myelosuppression. 
 
These initial promising results in pediatric AML led to follow-up studies in 
adults.  In a phase I study of adults with relapsed or refractory AML, patients 
were given 2-CDA at doses ranging from 5 to 13 mg/m2/d by continuous infusion 
for 7 days.16  Of the 27 patients treated, 2 died before they could be evaluated and 
16/25 remaining patients cleared their bone marrow of leukemia with regrowth in 
9 patients after a median of 2 weeks.  There were no complete remissions in this 
population.  Toxicity was mild except for 3 cases of grade III or IV renal 
dysfunction.  The MTD was defined as 10.8 mg/m2/d x 7 days.  The authors 
concluded that 2-CDA was a potent cytoreductive agent in adult AML, but not 
sufficient as a single-agent to yield CRs in this relapsed population.  The 
importance of this study is that it served as a lead-in to a combination trial with 
AraC16,17 that utilized intracellular pharmacodynamic data and was based on 
preclinical models of synergy between the 2 compounds.18   
 
The cytotoxicity and clinical activity of AraC, the most active agent in AML, is 
directly related to the intracellular generation and retention of ara-CTP (the 
triphosphate form).  Strategies that increase intracellular ara-CTP are therefore 
desired to increase its activity.  2-CDA is a potent inhibitor of ribonucleotide 
reductase and therefore leads to a significant decrease in intracellular 
deoxynucleotide pools.  This has 2 major effects with respect to intracellular 
AraC.  First, it augments the activity of deoxycytidine kinase which rapidly 
generates intracellular ara-CTP from AraC.  Second, as a result of the depletion of 
normal intracellular deoxynucleotides, ara-CTP and Cd-ATP (the triphosphate 
form of 2-CDA) become more prominent as substrates for DNA polymerase in 
dividing cells.  They are more likely to get incorporated into DNA and exert their 
cytotoxic effects.  This hypothesis has been confirmed in preclinical studies.  In 
vitro incubation of AML blasts with 2-CDA followed by AraC produced a higher 
rate of ara-CTP accumulation than AraC alone.19   
 

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As an extension of the aforementioned phase I study of 2-CDA in adults with 
AML, a phase II study combining AraC 1 g/m2 with 2-CDA 12mg/m2/d x 5 days 
was conducted to test this hypothesis clinically.16,17  Of the 17 patients treated, 2 
patients achieved a CR (12%) and 69% cleared their bone marrow.  Correlative 
studies from this trial confirmed a median 40% increase in the rate of ara-CTP 
accumulation in the leukemia blasts of patients after pretreatment with 2-CDA.  In 
addition, the DNA synthetic capacity of the circulating blasts was inhibited to a 
greater extent by administration of 2-CDA and AraC in combination than by 
either one alone.  Both 2-CDA and AraC (CdAMP and ara-CMP, respectively) 
were found to be incorporated into DNA, with the tandem incorporation having 
the most potent chain-termination effect.17 This strategy of combining a potent 
ribonucleotide reductase inhibitor with AraC to increase its clinical activity has 
been successfully replicated using other nucleoside analogues such as 
fludarabine20-22 and clofarabine.23 
 
Based on this data, several groups have studied combinations of 2-CDA and 
different doses of AraC in the treatment of AML.  In a multicenter phase II 
study24 from the Polish Adult Leukemia Group (PALG) 58 patients with 
refractory AML (50 primarily resistant and 8 with short CR durations) were 
treated with 2-CDA (5 mg/m2/d IV over 2 hrs x 5 days) combined with AraC (2 
g/m2/d IV over 4 hrs - starting 2 hrs after CDA x 5 days) and G-CSF (300 µg 
subcutaneously daily x 6 days).  The CR rate was 50%.  Notably 5/6 (83%) of 
patients with MDS/AML achieved a remission.  Myelosuppression was the most 
prominent toxicity.  The 1-yr overall survival for the entire cohort and for those 
who achieved a CR was 42% and 65%, respectively and the disease free survival 
(DFS) at 1 year was 29%.  
 
Investigators from Sweden conducted a randomized phase II trial25 in de novo 
AML patients aged > 60 years, comparing the combination of 2-CDA + AraC + 
idarubicin (CCI) to AraC + idarubicin (CI).  A total of 63 patients with a median 
age of 70 years were randomized 2:1 to treatment with 2-CDA (5 mg/m2/d IV 
over 1 hr x 4 days) plus ara-C (1 g/m2/d IV over 2 hrs x 4 days) plus idarubicin 
(10 mg/m2/d IV over 1 hr x 2 days) versus the 2 drug combination.  The CR rate 
was 51% for CCI vs 35% for CI (p=0.014).  There were no differences in toxicity 
between the 2 arms.  The median overall survival was 14 months, with a 2-year 
survival over 30%.  There was no significant difference in survival between the 2 
arms. 
 
The PALG conducted a similar study combining 2-CDA, an anthracycline, and a 
lower dose of AraC in younger patients with untreated AML.  Among 50 patients 
treated with 2-CDA (5 mg/m2/d IV over 1 hr x 5 days) plus ara-C (200 mg/m2/d 
IV x 7 days) plus daunorubicin (60 mg/m2/d IV daily x 3 days), the CR rate was 
72%.  This led to the phase III multicenter study26 comparing this combination 
(DAC-7) with daunorubicin and ara-C without cladribine.  A total of 400 patients 
with a median age of 45 were randomized to the daunorubicin plus cytarabine 
(DA-7) or the 3-drug combination outlined above (DAC-7).  The CR rate after a 
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median hospitalization time was shorter for DAC-7 vs. DA-7 (33 vs. 40 day, 
p=0.002).  Toxicity was comparable between both groups and primarily consisted 
of myelosuppression and its sequelae.  Overall, the probability of leukemia free 
survival (LFS) was 43% and 34% between DAC-7 and DA-7, respectively 
(p=NS).  However, in patients aged > 40 years, there was a trend for higher LFS 
in those who received DAC-7 (44% vs. 28%, p=0.05).  These studies demonstrate 
tolerability and suggest enhanced antileukemia efficacy with the addition of 
cladribine to induction regimens, particularly in older patients and those with 
MDS/AML.   
 
2.3 Cladribine + Low Dose AraC (LDAC) in AML 
 
Based on the observation of synergy and clinical efficacy of the combination of 
cladribine and cytarabine as part of an intensive regimen in AML, we designed a 
lower intensity approach combining cladribine with lower doses of cytarabine for 
older and unfit patients with newly diagnosed AML.  The regimen combines 
cladribine 5 mg/m2 IV on D1-5 with low dose cytarabine (LDAC) at a dose of 
20mg SQ twice daily on D1-10 of a 28 day cycle.  The goal was to produce higher 
rates of response while maintaining excellent tolerability.  We recently published 
our experience with the cladribine/LDAC regimen with a median follow-up of 
30+ months, achieving these goals (Kadia 2018). 
 
The report included 118 patients with a median age of 69 years (range, 49-85) 
with 41% having an adverse karyotype.  The overall response rate was 68%, 
including a CR rate (with complete count recovery) of 58% and a CRi rate of 9%.  
The CR duration was 14.7 months and the median overall survival was 13.8 
months overall, one of the longest reported historically among older patients with 
AML.  Among patients with a diploid karyotype, the median OS was 19.9 
months. 
 
When we reviewed outcomes of patients with ts-AML treated with a 
cladribine/LDAC based regimen, we observed a CR rate of 39%, and CRp rate of 
8% for a CR/CRp rate of 47% (Boddu 2017).  The therapy was associated with a 
4-week mortality of 3% in this difficult population.  Based on our own historical 
experience with older AML and from published data, this backbone of 
Cladribine/LDAC alternating with HMA represented a significant improvement 
from the standard HMA-based lower intensity therapy in AML.  It represents a 
safe and effective backbone of chemotherapy that we can build on to continue and 
improve results. 
 
2.4 
Clinical Experience with Uproleselan in AML 
 
Binding of E-selectin within the microenvironment, to the leukemic cell surface, 
activates cell survival pathways and promotes chemotherapy resistance in AML.  
Expression of the E-selectin ligand is associated with increased risk of relapse 
and poor survival in AML.  Uproleselan is a novel E-selectin antagonist that 
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protects from toxicity with improved survival in in vivo models.  Uproleselan has 
been studied in combination with chemotherapy in patients with treatment naïve 
(TN) and R/R AML. 
 
Ninety-one patients, including 25 with TN AML were enrolled on a phase I/II 
trial to assess safety and efficacy of uproleselan combined with chemotherapy.  
Patients with R/R AML were treated with uproleselan combined with 
mitoxantrone, etoposide, and cytarabine (MEC).  Dose escalation established the 
recommended phase II dose (RP2D) uproleselan with chemotherapy to be 10 
mg/kg.  Among 66 patients with R/R AML with a median age of 59 years, the 
CR/CRi rate was 39% and 41% at the RP2D; 69% of patients evaluable for MRD 
were negative at the time of response. The median OS in this population was 8.8 
months at the RP2D.  Among patients treated with this uproleselan combination, 
intensity of the E-selectin ligand expression correlated with MRD negative 
response and the higher E-selectin ligand expression on leukemic stem cells 
(LSC) correlated positively with responders and overall survival. 
 
Patient with TN AML were treated with uproleselan combine with 7+3.  The 
median age of these 25 patients was 67 years (range, 60-79), with 48% having 
adverse karyotype and 52% with secondary AML.  The combination was well 
tolerated with a CR/CR rate of 72% overall and 69% among patients with 
secondary AML.  The median OS was 12.6 months.  The median LSC 
expression of E-selectin ligand among responders and non-responder was similar 
in this untreated population.  Phase III studies in patients with R/R AML and 
older AML are underway. 
 
2.4.2 
Rationale for studying cladribine, ara-C, and Uproleselan in patients with 
ts-AML 
 
 
 
Treated secondary AML (ts-AML) or patients often referred to as having 
“hypomethylating agent (HMA) failure” is a group defined as having had HMA 
treatment for a prior myeloid neoplasm prior to developing AML (≥ 20% blasts).  
These are most often patients with myelodysplastic syndrome (but also with 
myeloproliferative neoplasms) treated for months or years before transforming 
into AML.  With the widespread and growing use of HMA for these patients, and 
in the context of an aging population with higher incidence of MDS, this is a 
subset of patients that is steadily growing. 
As we and others have shown, the prognosis of patients with ts-AML is 
extremely poor, representing among the worse outcomes across AML subtypes – 
with a median OS of approximately 4.7 months (regardless of age), low response 
rates to chemotherapy, and high rates of early mortality.  In this setting, there are 
very limited options.  Using another HMA in a setting where the disease has just 
progressed on HMA therapy is not desirable nor effective.  New therapies with 
good safety profile and high efficacy are needed. 
 
In the early clinical studies of uproleselan in AML, E-selectin ligand expression 
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achieving CR/CRi among previously treated patients.  Furthermore, higher E-
selectin ligand expression among patients treated with uproleselan was 
associated with higher rates of MRD negativity and superior OS.   
 
Preclinical studies have demonstrated that exposure of AML cells to HMAs 
actually increases expression of E-selectin ligand on blasts, an effect that is 
quenched by the addition of uproleselan (Figure).  Among patients with ts-AML, 
who have presumably had prolonged prior exposure to HMA therapy, E-selectin 
expression is likely upregulated, serves as a mechanism of chemoresistance, and 
provides a rational target for combination therapy with uproleselan.   
 
         
 
 
 
We therefore propose the current study, combining the E-selectin antagonist 
uproleselan with an active, lower-intensity chemotherapy backbone, for patients 
with ts-AML. 
 
2.5 
Cladribine 
 
Cladribine is available commercially. 
 
Cladribine Injection (also commonly known as 2-chloro-2´-deoxy-ß-D-adenosine) 
is a synthetic antineoplastic agent for intravenous infusion. It is a clear, colorless, 
sterile, preservative-free, isotonic solution. Cladribine Injection is available in 
single-use vials containing 10 mg (1 mg/mL) of Cladribine, a chlorinated purine 
nucleoside analog. Each mL of Cladribine injection contains 1 mg of the active 
ingredient and 9 mg (0.15 mEq) of sodium chloride as an inactive ingredient. The 
solution has a pH range of 5.5 to 8.0. Phosphoric acid and/or dibasic sodium 
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The selective toxicity of 2-chloro-2´-deoxy-ß-D-adenosine towards certain normal 
and malignant leukocyte populations is based on the relative activities of 
deoxycytidine kinase and deoxynucleotidase. Cladribine passively crosses the cell 
membrane. In cells with a high ratio of deoxycytidine kinase to 
deoxynucleotidase, it is phosphorylated by deoxycytidine kinase to 2-chloro-2´-
deoxy-ß-D-adenosine monophosphate (2-CdAMP). Since 2-chloro-2´-deoxy-ß-D-
adenosine is resistant to deamination by adenosine deaminase, 2-CdAMP 
accumulates intracellularly and is subsequently converted into the active 
triphosphate deoxynucleotide, 2-chloro-2´-deoxy-ß-D-adenosine triphosphate (2-
CdATP). It is postulated that cells with high deoxycytidine kinase and low 
deoxynucleotidase activities will be selectively killed by 2-chloro-2´-deoxy-ß-D-
adenosine as toxic deoxynucleotides accumulate intracellularly. 
Cells containing high concentrations of deoxynucleotides are unable to properly 
repair single-strand DNA breaks. The broken ends of DNA activate the enzyme 
poly (ADP-ribose) polymerase resulting in NAD and ATP depletion and 
disruption of cellular metabolism. There is evidence, also, that 2-CdATP is 
incorporated into the DNA of dividing cells, resulting in impairment of DNA 
synthesis. Thus, 2-chloro-2´-deoxy-ß-D-adenosine is cytotoxic to both actively 
dividing and quiescent cells, inhibiting both DNA synthesis and repair. 
Cladribine plasma concentration after intravenous administration declines multi-
exponentially with an average half-life of 6.7 + 2.5 hours. In general, the apparent 
volume of distribution of Cladribine is approximately 9 L/kg, indicating an 
extensive distribution in body tissues. 
Cladribine penetrates into cerebrospinal fluid. One report indicates that 
concentrations are approximately 25% of those in plasma. 
Cladribine is bound approximately 20% to plasma proteins. 
 
2.6 
Cytarabine 
 
Cytarabine is available commercially. 
 
Cytarabine is a deoxycytidine analog that is metabolized to cytarabine 
triphosphate, a substance that inhibits DNA polymerase. It is S phase specific, and 
thus affects DNA synthesis. It has an initial plasma half-life of about 15 minutes, 
with a secondary phase of about 2 hours, and is rapidly catabolized by hepatic 
cytidine deaminases to Ara-U. 
 
Cytarabine injection, an antineoplastic is a sterile solution of cytarabine for 
intravenousadministration. Each mL contains 20 mg cytarabine in 100 mg (20 
mg/mL) single dose vials and 100 mg cytarabine in 2 g (100 mg/mL) single dose 
vial. 
 

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Cytarabine injection 100 mg/5 mL is a sterile solution for intravenous 
administration. Each mL contains 20 mg cytarabine USP, and the following 
inactive ingredients: sodium chloride 6.8 mg and Water for Injections qs. When 
necessary the pH is adjusted with hydrochloric acid and/or sodium hydroxide to a 
pH of 7.7. 
 
Chemical stability studies were performed by ultraviolet assay on cytarabine 
injection in infusion solutions. These studies showed that when cytarabine 
injection was added to Water for Injection, 5% Dextrose in Water or Sodium 
Chloride Injection, 94% to 96% of the cytarabine was present after 192 hours 
storage at room temperature. Parenteral drugs should be inspected visually for 
particulate matter and discoloration, prior to administration, whenever solution 
and container permit. 
 
2.7 
Uproleselan injection, 50 mg/mL 
 
The investigational product, uproleselan injection, 50 mg/mL, is a sterile, isotonic 
solution for IV administration.  The drug substance is present as the sodium salt; 
however, the solution concentration is based on the free-acid active moiety.  The 
formulation contains precedented compendial excipients.  The sodium content of 
the formulation is 3.3 mg/mL.  The clinical product formulation includes 10 mM 
Tris buffer to stabilize the pH at 7.4 (6.4 to 8.4).   
 
Uproleselan injection is supplied in single-dose vials at a concentration of 
50 mg/mL.  Uproleselan injection 50 mg/mL is stored per the specified conditions 
on the label, either frozen (10 °C to -25 °C) or refrigerated (2-8°C), prior to 
administration.  The frozen product can appear as a homogenous solid, a striated 
solid, or as a super-cooled liquid.  When using frozen supply, vials should be 
brought to room temperature before dose preparation.  Upon thawing, the product 
should be gently inverted 4 to 5 times to ensure homogeneity of the solution.  The 
thawed solution is clear, colorless to slightly yellow, and free from visible 
particulates.  Reconstitution and dilution are not necessary.  Dilution up to 10X 
may be performed with normal saline. 
 
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 using a 
syringe pump or IV pump.  Microbore tubing is preferred.  In-line filtration 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. 
 

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When prepared in syringes or intravenous (IV) bags without an administration set 
attached, uproleselan may be stored refrigerated up to 72 hours prior to 
administration or up to 24 hours at controlled room temperature prior to 
administration.  Administration sets manufactured from materials of construction 
other than polyvinyl chloride (PVC) with di(2-ethylhexyl)phthalate (DEHP) can 
be primed up to 72 hours before dosing if stored refrigerated or up to 24 hours 
before dosing if stored at controlled room temperature.  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.    
 
Uproleselan is to be kept in a locked and secured storage facility, accessible only 
to those individuals authorized by the principal investigator (PI). 
 
3.0 PATIENT SELECTION 
 
3.1 Inclusion Criteria:  
 
1. Patients with a diagnosis of treated secondary-AML (TS-AML) who have not 
received therapy for their AML will be eligible.  
2. TS-AML is defined as AML arising from a previously treated antecedent 
myeloid neoplasm (myelodysplastic syndrome or myeloproliferative neoplasm 
that has been previously treated with hypomethylating agents).   
3. Patients must be at least 7 days from their last therapy for the antecedent 
myeloid neoplasm  
4. Age >/= 18 years.   
5. Adequate organ function as defined below: 
• liver function (total bilirubin < 2mg/dL, AST and/or ALT <3 x ULN – or 
<5 x ULN if related to leukemic involvement) 
• kidney function (creatinine < 1.5 x ULN ). 
• known cardiac ejection fraction of > or = 45% within the past 6 months 
6. ECOG performance status of ≤ 2. 
7. A negative urine or serum pregnancy test is required within 1 week for all 
women of childbearing potential prior to enrolling on this trial. 
8. Patient must have the ability to understand the requirements of the study and 
informed consent.  A signed informed consent by the patient is required prior 
to their enrollment on the protocol. 
 
3.2 Exclusion Criteria 
 
1. Pregnant women are excluded from this study because the agents used in this 
study have the potential for teratogenic or abortifacient effects.  Because there 
is a potential risk for adverse events in nursing infants secondary to treatment 
of the mother with the chemotherapy agents, breastfeeding should also be 
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2. Uncontrolled intercurrent illness including, but not limited to active 
uncontrolled infection, symptomatic congestive heart failure (NYHA Class III 
or IV), unstable angina pectoris, clinically significant cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study 
requirements. 
3. Patients with documented hypersensitivity to any of the components of the 
chemotherapy program. 
4. Men and women of childbearing potential who do not practice contraception.  
Women of childbearing potential and men must agree to use contraception 
prior to study entry and for the duration of study participation. 
5. Prior treatment with uproleselan. 
6. Patients with a diagnosis of acute promyelocytic leukemia (AML-M3) will be 
excluded from this study. 
 
4.0 TREATMENT PLAN 
 
This is a single arm phase Ib/II study in which patients will be treated with uproleselan 
given intravenously, combined with cladribine, (2-CDA, given intravenously [IV]) in 
combination low dose cytarabine (LDAC, given subcutaneously [SQ]) as induction 
therapy, followed by up to 6 cycles of consolidation/maintenance therapy composed of 
2-CDA + LDAC (according to schema below) also in combination with uproleselan.  In 
patients who do not achieve  CR/CRi/MLFS after cycle 1, an additional course of re-
induction with 2-CDA+LDAC+uproleselan may be given.   
 
Treatment will be continued during the duration of the study unless patient exhibits 
evidence of clinically significant treatment failure, clinically significant disease 
progression, unacceptable toxicity, or if the investigator determines that discontinuation 
is in the best interest of the patient.  Patients who do not achieve at least MLFS after 
two cycles of therapy will be taken off study.  Relapsing patients may remain on the 
study if participation in the study is still providing disease control or clinical benefit 
and is considered in the best interest of the patient after discussion with the principal 
investigator.   
 
Patients will be treated with the study drugs per protocol, based on the calculation of 
the patient’s body surface area (BSA).  The BSA will be calculated before each cycle 
and will be based on the patient’s height and weight.   
 
Patients will be instructed to self-administer cytarabine at home unless hospitalized and 
return unused drug in accordance with institutional guidelines.  All induction and 
consolidation intravenous infusions will be administered at MD Anderson Cancer 
Center (MDACC) or at the MDACC Houston Area Locations (HALs). 
 
The primary objective is to determine the safety of this combination and also to 
determine efficacy in achieving CR, CRi; and prolonging RFS and OS.  All patients 
will be registered for the protocol via the Clinical Oncology Research (CORe) system 
at MDACC (single institution study).   
 

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The study will have 2 dose levels during lead-in, followed by an expansion cohort of 25 
patients at the safe and tolerable dose level.  All patients will be treated with the RP2D 
of uproleselan of 800 mg IV on D1 and then IV q12 hours on D2-12.   
 
During safety lead-in, we will use the BOIN design (see section 8.0) to identify the 
RP2D of the combination therapy. During phase II, 25 additional patients will be 
enrolled at the RP2D level to confirm safety and to assess preliminary efficacy. 
 
4.1 Treatment Schema (4-week cycles +/- 7 days) 
 
4.1.1 Induction therapy will consist of: 
 
A. Uproleselan 800 mg IV on D1 and then 800mg IV Q12 hours (+/- 2 hours) on 
D2-12 approximately 1 hour prior to cladribine (+/- 15 minutes).   
 
B. Cladribine at the assigned dose level IV over approximately 1 to 2 hours, daily 
on days 1-5 combined with cytarabine at the assigned dose level SQ twice 
daily on days 1-10.  The cytarabine should be administered approximately 3-6 
hours following the start of the cladribine infusion.   
 
4.1.1.1 Patients who do not achieve a CR or CRi after cycle 1 may proceed 
with a second induction cycle as noted in Table 2 below. 
4.1.1.2 Patients who do not achieve a CR or CRi after cycle 2 may continue 
on protocol (as shown in Table 2) as long as the patient is deriving 
clinical benefit in the opinion of the investigator. 
 
4.1.2 Consolidation/Maintenance therapy will consist of: 
 
(A) Uproleselan 800 mg IV on D1 and then 800mg IV Q12 hours (+/- 2 hours) 
on D2-12 approximately 1 hour prior to cladribine (+/- 15 minutes). In 
patients who have achieved at least CR/CRi or morphologic leukemia-free 
state, uproleselan will be given ONCE daily on D1-12. 
 
(B) Cladribine at the assigned dose level IV over 1 to 2 hours, daily on days 1-3 
combined with Cytarabine at the assigned dose level SQ twice daily on days 
1-10.  The cytarabine should be administered 3-6 hours following the start 
of the cladribine infusion.  
 
Table 1. 
Dose Escalation Table 
 
Dose level 
Cladribine 
(mg/m2 IV daily on days 1-5)* 
Cytarabine  
(mg SQ twice daily on days 1-10) 
1 
5 
20 
-1 
3.75 
15 
 
One cycle of therapy is considered 4 weeks.  Subsequent cycles may be 
started within 4-7 weeks after the start of the previous cycle depending on 
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treating physician.  Subsequent cycle delay beyond 7 weeks may be 
allowed after discussion with the principal investigator and documentation 
of the discussion.   
 
Patients with progressive or proliferating disease requiring initiation of a 
subsequent cycle of chemotherapy prior to day 28 of a previous cycle may 
start therapy no earlier than day 21 of a previous cycle after discussion 
with the principal investigator and documentation of the discussion. 
 
The flow of treatment schema is outlined in the table below: 
 
Table 2. 
Cycle 
Number 
Induction 
Consolidation 
1 
Cladribine IV daily on days 1-5 
 
Cytarabine SQ twice daily on days 1-10 
 
Uproleselan 800 mg IV on D1 and then 800mg 
IV Q12 hours on D2-12 
NOT APPLICABLE 
2 
<IF RE-INDUCTION IS INDICATED> 
 
 
Cladribine IV daily on days 1-5 
 
Cytarabine SQ twice daily on days 1-10 
 
Uproleselan 800 mg IV on D1 and then 800mg 
IV Q12 hours on D2-12 
<IF PT ACHIEVES CR or CRi or MLFS after 
CYCLE 1> 
 
Cladribine IV daily on days 1-3 
 
Cytarabine SQ twice daily on days 1-10 
 
Uproleselan 800 mg IV daily on D1-12 
3 - 6 
 
Cladribine IV daily on days 1-3 
 
Cytarabine SQ twice daily on days 1-10 
 
Uproleselan 800 mg IV daily on D1-12 
 
4.1.3 Definition of DLT 
 
Dose Limiting Toxicity (DLT) - DLT will be graded according to the NCI 
Common Terminology Criteria for Adverse Events (CTCAE, version 5) by 
organ system.  DLT will be defined as adverse events during cycle one. 
 
A) Grade 3 or greater, non-hematologic toxicities at least possibly related to 
study treatment will be considered DLTs.Any Grade 3 nausea, vomiting or 
diarrhea that requires hospitalization, tube feeding or TPN is a DLT unless 
definitely attributed to a different cause. As the following are common 
events in patients with leukemia (> 50%), they will not be used for the 
definition of DLT: prolonged myelosuppression (grade 3 - 4), neutropenic 
fever without infection (grade 3), non-neutropenic fever (grade 3), 
infections with grade 3 and 4 neutropenia [exception – see bullet E 
below], infections without neutropenia (grade 3) [exception – see bullet E 
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resulting in death, transfusions of platelets and packed RBCs (grade 3), 
low blood pressure due to dehydration requiring fluid replacement, 
abnormalities of LDH (lactate dehydrogenase) and alkaline phosphatase, 
tumor lysis syndrome related to disease bulk (grade 3-4), disturbances in 
electrolytes (magnesium, phosphorus, calcium), alopecia, nausea and 
vomiting (if manageable with supportive care measures). Grade >/= 4 non-
hematologic organ toxicities that are not definitely attributed to another 
reason will be considered DLTs. 
 
B) Grade 4 neutropenia or thrombocytopenia lasting beyond day 42 of the 
cycle in the absence of leukemia. Anemia will not be considered a 
hematologic DLT. 
 
C)  Any adverse reaction that leads to dose reduction or withdrawal should be 
considered a DLT.  For the following, if not definitively related to disease 
or concomitant drugs: Grade 3 transaminitis (AST/ALT) elevation that 
does not return to Grade 1 or lower within 72 hours is a DLT.  Grade 3 
electrolyte abnormalities (Na, K, Cl, CO2, Ca, Mg, phosphate) that do not 
return to Grade 1 or lower within 72 hours is a DLT. 
 
D)  Any grade 3 liver abnormality conforming to Hy’s Law will be considered 
a DLT unless it resolves within 72 hrs.  The criteria for Hy’s Law are as 
follows:  (1) 3-fold or greater elevations above the ULN of ALT or AST; 
(2) concomitant elevation of serum total bilirubin to >2x ULN, without 
findings of cholestasis (or elevated serum ALP), and (3) No other reason 
can be found to explain the combination of increased transaminases and 
bilirubin, such as viral hepatitis A, B, or C; preexisting or acute liver 
disease; or another drug capable of causing the observed injury 
 
E) Any grade 3 infection lasting for more than 7 days without improvement 
when leukemia is in remission is considered a DLT.  Any grade 3 bleeding 
with thrombocytopenia worsening and uncontrolled by appropriate 
measures when leukemia is in remission is considered a DLT. 
 
 
4.2 Supportive Care Measures during treatment 
 
Necessary supportive measures for optimal medical care can be given throughout 
the study as indicated by the treating physician's assessment of the patient's 
medical need and by the institutional guidelines. Administration of antiemetics 
during drug administration and throughout treatment course is permitted as 
clinically indicated and according to departmental guidelines.  Blood products 
should be transfused as indicated and in accordance with institutional guidelines. 
The use of other anti-leukemia therapy is not allowed during the course of therapy 
except for hydroxyurea which is allowed for the first 3 cycles of therapy only. 
Concomitant intrathecal chemotherapy and/or radiation therapy is permitted 
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4.2.1 Hematopoietic growth factors 
 
Hematopoietic growth factors such as filgrastim or pegfligrastim (GCSF) 
is permitted as clinically indicated at the discretion of the treating 
physician. 
 
4.2.2 Infection prophylaxis 
 
Antibacterial, antifungal, and antiviral agents may be used in patients 
being treated on this study in accordance with the standard of care.   
 
4.3 Duration of Therapy 
 
In the absence of treatment delays due to adverse events, the treatment will be 
administered approximately once every 4 weeks for up to 6 cycles. The patient 
will continue on the study unless one of the following criteria applies: 
 
• Clinically significant progressive disease as defined by Modified International 
Working Group Criteria (see section 9) without evidence of clinical benefit.  
(Patients who have not had at least 50% reduction in bone marrow blasts by 4-
6 cycles would be considered not to have clinical benefit and will come off 
study). 
• Possibility of undergoing allogeneic bone marrow transplant. 
• Intercurrent illness that prevents further administration of treatment. 
• Patient request. 
• Unacceptable toxicity. 
• Need for further, alternative treatment. 
• General or specific changes in the patient’s condition that render the patient 
unacceptable for further treatment in the judgment of the investigator or 
treating physician. 
 
5.0 PATIENT EVALUATION 
 
AML patients are typically admitted for the first month of therapy in the hospital and 
monitored daily for toxicities by oncologists.  Following the first cycle, they are seen 
frequently by mid-level providers or oncologists throughout their treatment course.  
Toxicities are assessed by history, physical, and review of laboratory and radiologic 
data.  These are reported to the research nurse coordinator, treating MD, and/or PI, 
given attribution and documented in the EMR on study interim notes.  Toxicity logs 
will be utilized to record adverse events. 
 
5.1 Pretreatment Evaluation. (To be completed within 14 days of study entry unless 
otherwise indicated) 
 
a. History and physical examination, including vital signs, height, weight and 
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b. Bone marrow aspirate and/or biopsy (Cytogenetics, flow cytometry and 
molecular studies performed as appropriate) within 7 +/- 3 days of treatment 
start. 
c. Biomarker testing for correlative studies will be collected as described in 
section 5.4. 
d. CBC with differential (within 3 days) (differential not required if WBC ≤0.5 
x109/L). 
e. Serum chemistry: BUN, creatinine, bilirubin, AST and/or ALT, Magnesium, 
glucose, uric acid, (within 3 days). 
f. Serum coagulation studies: PT/PTT/INR; (within 3 days) 
g. Urine or serum pregnancy test within one week for women of childbearing 
potential. 
h. Signed informed consent. 
 
5.1 During Treatment Evaluation (Cycle 1) 
 
a. Physical examination (including vital signs) 3 times per week. 
b. CBC with differential (differential not required if WBC ≤0.5 x109/L), 3 times 
per week (or as clinically indicated) until remission, then every 2 to 4 weeks 
during active treatment, and then every 4 to 8 weeks thereafter as long as they 
are on study. 
c. Serum chemistry profile (including uric acid) 3 times per week for the first 4 
weeks and then every 2 to 4 weeks during active treatment. 
d. Biomarker testing for correlative studies on D1, 5, 10, and 12 of cycle 1 as 
summarized in section 5.4. 
e. Evaluation of toxicity assessment prior to each cycle. 
 
5.2 During Treatment Evaluation (Cycle 2 and beyond). 
 
a. Physical examination (including vital signs, weight, performance status) prior 
to each cycle. 
b. CBC with differential (differential not required if WBC ≤0.5 x109/L), at least 
1-2 times per week (or as clinically indicated) until remission, then every 2 to 
4 weeks during active treatment, and then every 4 to 8 weeks thereafter as 
long as they are on study. 
c. Serum chemistry profile at least once weekly until remission and then every 2 
to 4 weeks during active treatment. 
d.  Evaluation of toxicity assessment prior to each cycle.  
 
5.3 Outcome assessments 
 
a. Bone marrow aspiration and/or biopsy starting on day 21 (+/- 7 days) of 
therapy and then every 2 weeks (+/- 7 days) as required by leukemia evolution 
until remission or non-response.  Bone marrow tests may be ordered more 
frequently as indicated by changes in peripheral blood counts.  No repeat bone 
marrow is necessary if non-response or progressive disease can be 
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WBC <0.4 x109/L, if the bone marrow is considered non-contributory by the 
investigator at any point.   
b. Patients will be followed for relapse and survival every 6 to 12 months after 
completion of active treatment and while still on study or be enrolled on the 
leukemia department long-term follow-up umbrella protocol.  This may be 
completed by phone call if the patient is not coming for routine visits. 
 
5.4 Correlative Studies  
The presence of the E-selectin ligand on AML blasts in the bone marrow will be 
assessed using flow cytometry.  Gene expression profiling via RNA analysis will 
be performed to include the quantification of gene products responsible for E-
selectin ligand expression.  Levels of soluble E-selectin will be assessed using 
ELISA.  Samples will be obtained as detailed in the Correlative Study Collection 
Table and sent to a central laboratory for testing.  Any missed collection of 
samples for correlative studies during the Pre-Treatment evaluation and/or during 
Treatment evaluation will not be considered a protocol deviation. 
 
Correlative Study Collection Table 3 
Procedures 
Pre 
Treatment 
Cycle 1 
≤ 14 d prior 
to Day 1 
Day 1 Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Day 8 
Day 9 Day 10 Day 11 Day 12 
Cladribine AdministrationA 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Cytarabine AdministrationA 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Uproleselan AdministrationB 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Bone Marrow Aspirate 
Collection (E-selectin Ligand 
Expression and RNA) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker Collection (sE-
selectin by ELISA) 
XC 
XC,D 
 
 
 
XE 
 
 
 
 
XF 
 
XG 
A Cladribine at the assigned dose level IV over approximately 1 to 2 hours, daily on days 1-5 combined with 
cytarabine at the assigned dose level SQ twice daily on days 1-10.  The cytarabine should be administered 
approximately 3-6 hours following the start of the cladribine infusion.   
B Uproleselan 800 mg IV on D1 and then IV Q12 hours on D2-12 
C Pre-dose samples prior to Day 1 dosing; 2 sample collections - Screening and Baseline prior to dosing  
D Day 1 sample – after uproleselan but prior to CLAD/cytarabine administration  
E Day 5 sample after CLAD regimen administration 
F Day 10 sample after cytarabine administration 
G Day 12 after final uproleselan administration; 1 hour post last dose 
 
E-selectin mediated interactions may play a role in AML and the expression of E-
selectin or its binding epitope (sialyl Lea/x) may predict the clinical course and 
patient outcomes in AML. Increased expression of E-selectin, as seen in 
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chemotherapy, is also associated with increased shedding of E-selectin from the 
cell surface resulting in higher levels of sE-selectin in the circulation. 
 
We will measure the levels of E-selectin ligand on pretreatment bone marrow 
blasts in patients treated with uproleselan to describe the cell-surface expression 
pattern of E-selectin ligand on AML blasts and to determine the effect on clinical 
outcomes. We will also examine plasma sE-selectin at baseline and after 
treatment with chemotherapy and uproleselan to determine if E-selectin inhibition 
affects sE-selectin levels and to correlate plasma levels with clinical outcomes. 
 
We will measure the expression of E-selectin ligand-forming glycosylation genes 
from pretreatment bone marrow blasts treated with or without uproleselan to 
describe the RNA expression levels of these genes on AML blasts and to 
determine the effect on clinical outcomes. 
 
E-selectin is a cell adhesion glycoprotein that is expressed on endothelial cells and 
has been implicated in therapeutic resistance. In most myeloid leukemias, 
leukemic blasts express E-selectin ligands, which contain the glycan epitope of 
the carbohydrate sialyl Lex (sLex). This sequestration in the bone marrow vascular 
niche, leading to cell adhesion-mediated drug resistance and resultant poor 
clinical outcome.  Uproleselan is an E-selectin antagonist which interrupts 
leukemic cell homing to the vascular niche, increases susceptibility to cytotoxic 
and targeted therapies and can be a potent adjunct to therapeutics. In deed data 
has demonstrated a correlation between leukemic cell surface levels of E-selectin 
ligands using multiparameter flow cytometry and response to uproleselan. 
 
Recently, transciptome profiling of E-selectin ligand-forming glycosylation genes 
have been explored from public data sets to identify elevated E-selectin ligand 
expression in patients with AML.  RNA-seq data from patients treated in COG 
AAML1031 (N = 1,074) was available for evaluation.  Of 24 genes examined, 
Fucosyltransferase 7 (FUT7) and ST3 beta-galactoside alpha-2,3-sialyltransferase 
4 (ST3GAL4) were significantly associated with adverse outcome (HR = 1.013, p 
< 0.0001, and HR = 1.023, p < 0.0001, respectively) and directly synthesize sLex.  
Patients highly expressing FUT7 (highest quartile of expression) had significantly 
worse outcome than lower expressors (lowest 3 quartiles of expression), with a 5-
year OS of 50.3% vs. 68.3% (p < 0.0001). Similarly, those with high ST3GAL4 
expression had a 5-year OS of 51.3%, compared to 68.1% for low expressors (p < 
0.0001).  High expression of these genes was shown to be associated with cell 
surface E-selectin ligand expression.  Taken together these data suggest a strong 
correlation between transcriptome measurements of E-selectin ligand-forming 
glycosylation genes and cell surface glycosylation levels of E-selectin ligands, 
and lend support for the use of E-selectin ligand glycosylation genes as predictive 
biomarkers.  
 
5.4.1 
Soluble E-selectin Sampling and Processing 

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Care should be taken that blood for sE-selectin assessment is drawn from a vein 
apart from the site of investigational drug infusion (e.g., from a different limb or 
central line).  
Blood (3-5 mL) 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 (via an ice bath or at approximately 4°C) 
for 48-72 hours before centrifugation.   
After centrifugation, pipette half of plasma into an appropriately labelled 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. 
 
5.4.2 
Soluble E-selectin 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. 
QPS, LLC 
ATTN Sample Coordinator 
1 Innovation Way, Suite 200 
Newark, Delaware 19711 
Contact: Susan ZONDLO 
E-mail: susan.zondlo@qps.com and tlmsmt@qps.com 
Tel.: + 1 302 453 5911 
 
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.  
 
5.4.3 
E-selectin ligand/RNA Sampling and Processing 
1. Perform bone marrow procedure, as per institutional procedure 
2. Collect 2 ml bone marrow aspirate in a Sodium Heparin tube  
3. Immediately after sample is drawn, gently invert the tube 180° and back, 8-
10 times. 
a. Keep sample at AMBIENT TEMPERATURE  
No additional specimen will be required for RNA testing.  The sample collected 
for E-selectin ligand testing will provide sufficient material for RNA aliquoting.   
 
5.4.5 
E-selectin ligand Shipments 
Samples should be shipped ambient on the day of collection.   
Hematologics, Inc. 

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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. 
 
5.5 Outside Physician Participation During Treatment  
Interim visits can be provided by physicians outside MDACC.  Additionally, in the event the 
patient cannot travel to MDACC for a new cycle visit, a telemedicine visit including 
laboratory review is acceptable and medications will be shipped directly to the patient.  Local 
care for the patient includes routine blood work monitoring in between treatment cycles. 
 
1.  A letter to the local physician outlining the patient's participation in a clinical trial will 
request local physician agreement to participate in the patient's care. 
2.  Protocol required evaluations outside MDACC will be obtained by ‘Care Everywhere’ in 
EMR, fax, or email. Records obtained via fax or email will be and scanned into the patient’s 
record.  
3.  Changes in drug dose and/or schedule must be discussed with and approved by the 
MDACC physician investigator or their representative prior to initiation and documented in 
the patient record. 
4.  MDACC investigators will perform all decisions regarding dose adjustments and 
treatment interruptions or re-initiation of treatment, grading and attribution of adverse events, 
and assessment of efficacy. The home physician will not make any decisions regarding dose 
adjustments and/or treatment interruptions or resumption of treatment, grading and/or 
attribution of adverse events, or assessing efficacy. These will all be done by the MDACC 
investigators.  
5.  Routine, standard-of-care laboratory assessments (and physical exam when/if needed) will 
be performed by the home physician.  
6.  A copy of the informed consent and treatment schema will be provided to the local 
physician. 
7.  Documentation to be provided by the local physician will include drug administration 
records, vital signs, ECOG, concomitant medications, and progress notes, reports of the 
protocol required laboratory and diagnostic studies, and documentation of any 
hospitalizations. 
8.  The home physician will be requested to report to the MDACC physician investigator all 
life-threatening events within 24 hours of documented occurrence. 
 

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6.0 DOSING DELAYS / DOSE MODIFICATIONS FOR SUBSEQUENT CYCLES 
 
6.1 Suggested dose levels for dose adjustments 
 
Table 4 
Dose 
level 
Cladribine 
(mg/m2 IV daily 
on days 1-5)* 
Cytarabine  
(mg SQ twice daily on 
days 1-10) 
1 
5 
20 
-1 
3.75 
15 
-2 
2.5 
10 
-3 
1.25 
5 
*3 days in consolidation 
 
6.1.2. Dose levels different than dose described above may be allowed after 
discussion with the PI and documentation of the discussion.  
 
6.1.3 Dose reductions for uproleselan are not planned.  If there is a clinically 
significant grade 3 toxicity deemed related to uproleselan, it will be 
discontinued and patients will continue with chemotherapy alone. 
 
Table 5 
Non-Hematologic Toxicity 
Drug-related Grade 2 Toxicity 
Initiation of a treatment cycle will be delayed if a > Grade 1 non-hematologic toxicity has occurred or 
worsened and not yet returned to < Grade 2 prior to the start of the next cycle. 
 
Uproleselan will be discontinued in patients who experience a grade 2 or higher hypersensitivity reaction to 
the uproleselan. 
Infection 
If a patient develops a clinically significant infection of any grade,1 initiation of treatment cycles may be 
delayed or withheld until the infection is clinically controlled (e.g., the patient is afebrile and with 
improving signs/symptoms). Treatment (i.e., subsequent cycles) may then resume at the full dose. At the 
discretion of the investigator, prophylactic therapy to prevent recurrence of infection can be instituted as 
clinically indicated. 
Description of Event: Non-Hematologic 
Dose Modifications 
Non-hematologic Grade 3 adverse event 
 
Drug-related grade 4 nausea, vomiting not 
optimally managed.   
 
Hold therapy until recovery to Grade ≤1, then re-
start and reduce one dose level. If toxicity recurs 
again, hold therapy until recovery to grade ≤1, then 
re-start and reduce one dose level.  Dose reductions 
below dose level -3 will be considered on an 
individual basis after discussion with the principal 
investigator. 
For other grade 4 non-hematologic toxicity 
Study drug should be discontinued 
Persistent grade 2 toxicity considered clinically 
significant or upon patient’s request 
Consider holding therapy until recovery to Grade 
≤1, then re-start and reduce one dose level. If 
toxicity recurs again, hold therapy until recovery to 
grade ≤1, then re-start and reduce one dose level.  
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considered on an individual basis after discussion 
with the principal investigator. 
Any occurrence of >/= drug related Grade 2 
neurologic Events 
The patient's study drug doses are to be re-evaluated 
in consultation with the Principal Investigator, and 
may be reduced according to the above parameters, 
or discontinued based on the event, and the time to 
resolution to <Grade 1.   
1 Includes, but is not limited to, bacteremia, systemic fungal infections, cytomegalovirus (CMV) infection, 
Pneumocystis carinii pneumonia (PCP), disseminated Varicella, etc. 
 
6.2 Patients in whom the toxicity occurs or persists beyond the planned completion of 
drug administration for the cycle will have the dose reductions implemented in 
subsequent cycles provided the toxicity has resolved as specified in the table 
above.  
 
6.3 Myelosuppression: Patients with leukemias usually present with abnormal 
peripheral blood counts at the time therapy is started and myelosuppression is an 
expected event during the course of therapy for acute leukemias and 
myelodysplastic syndromes. Thus, no dose adjustments or treatment interruptions 
for myelosuppression will be planned for the first 4 weeks of therapy. After this 
time, treatment interruptions and dose adjustments may be considered according 
to the following guidelines: 
 
6.3.1 Patients with neutropenia or thrombocytopenia as a consequence of the 
disease do not require treatment interruptions for myelosuppression. Dose-
reductions in these patients should be considered in an individual case and 
discussed with the PI. The following guidelines can be used for these 
patients: 
 
6.3.1.1 Patients with a response and pre-cycle counts of neutrophils >1 
x109/L and platelets >50 x109/L who have sustained low counts of 
neutrophils <0.5 x109/L or a platelet count <20 x x109/L for more 
than 2 consecutive weeks in the current cycle, may receive a 
subsequent course at 1 dose level reduction.  A reduction of 2 dose 
levels may be considered if the myelosuppression was deemed 
severe and life threatening by the treating physician, and if it is in 
the patient's best interest. 
 
6.3.1.2 If there are persistent peripheral blood blasts, or the bone marrow 
shows >5% blasts, continue treatment regardless of neutrophil and 
platelet count and give supportive care as needed.  
 
6.3.1.3 If no marrow evidence of leukemia, hold therapy until recovery of 
granulocytes to ≥1 x109/L and platelets ≥ 60 x109/L, then resume 
at same or 1 lower dose level according to guidelines mentioned 
above. 
 
7.0 AGENT FORMULATION AND PROCUREMENT 

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Cladribine, and cytarabine are FDA approved and commercially available.  
Commercial supply will be used. 
 
Uproleselan is an investigational agent and will be provided for the study by the 
manufacturer, GlycoMimetics.  Expired or unused drug will be destroyed per 
institutional policy. 
 
8.0 STATISTICAL CONSIDERATIONS 
 
For Phase Ib, we will employ the Bayesian optimal interval (BOIN) design (Liu and Yuan, 
2015; Yuan et al., 2016) to find the RP2D. The BOIN design is implemented in a simple way 
similar to the traditional 3+3 design, but is more flexible and possesses superior operating 
characteristics that are comparable to those of the more complex model-based designs, such 
as the continual reassessment method (CRM) (Zhou et al., 2018). 
 
The target toxicity rate is 𝜙𝜙= 0.3 and the maximum sample size is 12 for phase Ib. We will 
enroll and treat patients in cohorts of size 3. DLTs are defined in section 4.1.3, and only 
those DLTs that occur within cycle 1 will be used for dose finding. The BOIN design uses 
the following rule, optimized to minimize the probability of incorrect dose assignment, to 
guide dose escalation/de-escalation: 
• 
if the observed DLT rate at the current dose is ≤ 0.236, escalate the dose to the next 
higher dose level; 
• 
if the observed DLT rate at the current dose is ≥ 0.359, de-escalate the dose to the next 
lower dose level; 
• 
otherwise, stay at the current dose. 
For the purpose of overdose control, doses 𝑗𝑗 and higher levels will be eliminated from further 
examination if Pr(𝑝𝑝𝑗𝑗> 0.3 | data) > 0.95 and at least 3 patients have been treated at dose 
level 𝑗𝑗, where 𝑝𝑝𝑗𝑗 is the true DLT rate of dose level 𝑗𝑗, 𝑗𝑗= 1, 2. This posterior probability is 
evaluated based on the beta-binomial model 𝑦𝑦𝑗𝑗∣𝑝𝑝𝑗𝑗∼binomial(𝑝𝑝𝑗𝑗) with 𝑝𝑝𝑗𝑗∼
uniform(0,1), where 𝑦𝑦𝑗𝑗 is the number of patients experienced DLT at dose level 𝑗𝑗. When the 
lowest dose is eliminated, stop the trial for safety.  
 
The above dose escalation/de-escalation and elimination rule can be equivalently presented 
in Table 1, which will be used to conduct the trial. The steps to implement the BOIN design 
are described as follows: 
 
1. 
Patients in the first cohort are treated at dose level -1. 
2. 
To assign a dose to the next cohort of patients, conduct dose escalation/de-escalation 
according to the rule displayed in Table 1. When using Table 1, please note the 
following: 
a. 
“Eliminate” means eliminate the current and higher doses from the trial to 
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b. 
When we eliminate a dose, automatically de-escalate the dose to the next lower 
level. When the lowest dose is eliminated, stop the trial for safety. In this case, 
no dose should be selected as the RP2D. 
c. 
If none of the actions (i.e., escalation, de-escalation or elimination) is triggered, 
treat the new patients at the current dose. 
d. 
If the current dose is the lowest dose and the rule indicates dose de-escalation, 
treat the new patients at the lowest dose unless the number of DLTs reaches the 
elimination boundary, at which point terminate the trial for safety. 
e. 
If the current dose is the highest dose and the rule indicates dose escalation, treat 
the new patients at the highest dose. 
3. 
Repeat step 2 until the maximum sample size of 12 is reached, or the trial is stopped 
early due to the elimination of the lowest dose. 
 
Table 6. Dose escalation/de-escalation rule for the BOIN design 
Number of patients treated at current dose 
3 6 9 12 
Escalate if # of DLT <= 
0 1 2 2 
De-escalate if # of DLT >= 
2 3 4 5 
Eliminate if # of DLT >= 
3 4 5 7 
Note. # of DLT is the number of patients with at least 1 DLT. When none of the actions (i.e., 
escalate, de-escalate or eliminate) is triggered, stay at the current dose for treating the next 
cohort of 3 patients.  
 
When phase Ib is completed, select the RP2D based on isotonic regression as specified in Liu 
and Yuan (2015). This computation is implemented by the shiny app “BOIN” available at 
http://www.trialdesign.org. Specifically, select as the RP2D the dose for which the isotonic 
estimate of the toxicity rate is closest to the target toxicity rate of 30%.  In addition, in order 
for a dose to be declared as RP2D, at least 6 patients have been treated with at least 80% of 
the planned doses and the observed DLT rate at the RP2D level is < 30% (for example, <=1 
out of 6, or <=2 out of 7~9, etc.). 
 
Operation Characteristics 
Table 2 shows the operating characteristics of the trial design based on 1000 simulations of 
the trial using shiny app “BOIN” available at http://www.trialdesign.org.  
 
Table 7. Operating characteristics of the BOIN design 
 
1 
2 
Number of 
Patients 
% Early 
Stopping 
Scenario 1 
 
 
 
 
True DLT Rate 
0.3 
0.48 
 
 
Selection % 
58.9 
27.4 
 
13.7 
% Pts Treated 
70.2 
29.8 
11.2 
 
 
 
 
 
 
Scenario 2 
 
 
 
 

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True DLT Rate 
0.16 
0.3 
 
 
Selection % 
27.4 
71.3 
 
1.3 
% Pts Treated 
48.5 
51.5 
11.9 
 
 
 
 
 
 
Scenario 3 
 
 
 
 
True DLT Rate 
0.4 
0.55 
 
 
Selection % 
56.4 
12.6 
 
31 
% Pts Treated 
82.3 
17.7 
10.4 
 
 
For phase II portion, a maximum of 25 patients will be enrolled and treated at the RP2D 
level. The Bayesian approach of Thall, Simon, Estey (1995, 1996) will be used to monitor 
overall response (OR) and treatment-related toxicities. The OR is defined as either CR or 
CRi and the assessment window for OR will be 2 cycles. The toxicities to be monitored 
include those defined in section 4.1.2 which during cycle 1.  
 
Based on published data, an overall response rate (ORR) of 35% is expected for this 
population and we aim to improve the ORR by 25%, that is to say, the target response rate 
would be about 45%, while maintaining the toxicity rate at or below 30%. With a sample size 
of 25 patients, the 95% posterior credible interval for ORR will range between 0.27 and 0.63, 
assuming an ORR of 45% (i.e., 11 out of 25 patients having responses) and a non-
informative prior of beta (1, 1).  
 
Denoting the historical probabilities of ORR and toxicity rate by {p(ORR,H) , p(TOX,H)}, 
the following monitoring rules will be applied:  
 
1) Stop if Prob{p(ORR,H) + δORR > p(ORR,E) | data} > 0.99, where δORR = 0.1  
2) Stop if Prob{p(TOX,H) < p(TOX,E)| data} > 0.95 
 
where p(ORR, E) and p(TOX, E) are the true ORR and toxicity rates for the combination 
therapy. The priors of ORR and toxicities for the combination therapy are assumed to be Beta 
(1, 1) and Beta (0.6, 1.4), respectively. Patients will be monitored in cohort size of 5 
according to the following stopping boundaries for ORR and toxicities. 
 
Table 8: Stopping Boundaries for ORR and Toxicities, in cohort size of 5.  
# Patients  
treated 
Stop the trial if there are  
this many patients with CR/CRi:  
Stop the trial if there are  
this many patients with toxicities:  
 
5 
 never stop 
4-5 
10 
0 
6-10 
15 
0-2 
8-15 
20 
0-3 
10-20 
25 
Always stop with this many patients 
Always stop with this many patients 
 
The operating characteristics are summarized in the following table (based on simulations 
from 10,000 trials). 
 

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Table 9: Operating Characteristics for toxicity and futility monitoring.  
P(TOX) 
P(ORR) 
P(Stop Early) 
0.20 
0.25 
0.30 
 
0.35 
0.09 
 
0.45 
0.03 
 
 0.55 
0.02 
0.30 
0.25 
0.36 
 
0.35 
0.17 
 
0.45 
0.11 
 
 0.55 
0.10 
0.40 
0.25 
0.53 
 
0.35 
0.39 
 
0.45 
0.34 
 
 0.55 
0.34 
0.50 
0.25 
0.76 
 
0.35 
0.69 
 
0.45 
0.67 
 
 0.55 
0.66 
 
Multc Lean Desktop (version 2.1.0) was used to generate the toxicity and futility stopping 
boundaries and the operating characteristics table.  
 
ANALYSIS PLAN 
 
Summary statistics will be provided for continuous variables.  Frequency tables will be used 
to summarize categorical variables.  The overall response rate will be estimated along with 
the 95% credible interval. Similar analyses will be performed for other binary outcomes such 
as CR, CRi, etc. Overall survival (OS) is defined as the time interval between treatment start 
and the date of death or last follow-up, whichever occurred first. Remission duration (CRd) is 
defined, within patients who achieve CR/CRi, the time interval between the date of CR/CRi 
and the date of disease relapse, death or last follow-up, whichever occurred first. 
Progression-free survival (PFS) is defined as the time interval between treatment start and the 
date of death, relapse or last follow-up, whichever occurred first. Kaplan-Meier method will 
be used to assess OS, CRd and PFS probabilities. Data from all subjects who receive any 
study drug will be included in the safety analyses. Subjects who entered the study and did not 
take any of the study drugs and had this confirmed will not be evaluated for safety. The 
severity of the toxicities will be graded according to the NCI CTCAE v5.0 whenever 
possible. We will follow standard reporting guidelines for adverse events. Safety data will be 
summarized by category, severity and frequency.  
 
Cohort Summaries 
 
The Investigator is responsible for completing toxicity summary reports and submitting them 
to the IND office Medical Affairs and Safety Group, for review and approval.  These should 
be submitted as follows:  

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Phase 1B: 
After the first 3 evaluable patients, complete cycle 1 of study treatment, and every 3 
evaluable patients thereafter, prior to expanding/changing dose levels, or opening Phase II. 
  
Phase II: 
After the first 5 evaluable patients per cohort, complete cycle 2 of study treatment, and every 
5 patients thereafter, until enrollment is complete. 
 
A copy of the summary report should be placed in the Investigator’s Regulatory Binder under 
“sponsor correspondence”. 
 
 
9.0 MEASUREMENT OF EFFECT 
 
9.1 Criteria for Response 
 
9.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the 
time of their first treatment on study. 
 
Evaluable for response.  Patients who have received at least one cycle of 
therapy, and have had their disease re-evaluated will be considered 
evaluable for response.  These patients will have their response classified 
according to the definitions stated below.  (Note:  Patients who exhibit 
objective disease progression prior to the end of cycle 1 will also be 
considered evaluable.) 
 
9.1.2 Response Criteria 
 
Response Criteria are according to the Revised Recommendations of the 
International Working Group Response Criteria in Acute Myeloid 
Leukemia.  They are summarized below. 
 
 
 
9.1.3 Complete remission (CR) 
 
 
 
 
 
Disappearance of all clinical and/or radiologic evidence of disease, 
including extramedullary leukemia. Neutrophil count ≥ 1.0 x 109/L and 
platelet count ≥ 100 x 109/L, and bone marrow differential showing ≤ 5% 
blasts. 
 
 
 
9.1.4  Complete remission without count recovery (CRi) 
 
 
 
 
 
 
 
 
Have met all criteria for CR, except for either residual neutropenia (ANC 
< 1.0 x 109/L) or thrombocytopenia (platelet count < 100 x 109/L). 
 

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9.1.5 Complete remission with partial hematologic recovery (CRh) 
 
 
 
 
 
Having met all criteria for CR, but with only partial recovery of the 
peripheral blood count: ANC ≥ 0.5 x 109/L and platelets ≥ 50 x 109/L. (A 
subset of CRi) 
 
 
 
9.1.6 Partial remission (PR) 
 
 
 
 
 
Blood count recovery as for CR, but with a decrease in marrow blasts of at 
least 50% and not more than 6 to 25% abnormal cells in the bone marrow. 
 
 
 
9.1.7  
Morphologic Leukemia-Free State (MLFS) 
 
 
 
 
Bone marrow differential showing < 5% blasts, no evidence of peripheral 
blasts or extramedullary disease, but without peripheral blood count 
recovery to neutrophil count ≥ 1.0 x 109/L & platelet count ≥ 100 x 109/L. 
 
 
 
 
9.1.8 Relapse-free survival (RFS) 
 
 
 
 
 
Time from CR or CRi until the date of first objective documentation of 
disease-relapse or death. 
 
 
 
9.1.9 Overall survival (OS) 
 
 
 
 
 
 
 
 
 
Time from date of treatment start until date of death due to any cause. 
 
 
 
9.1.10 Disease progression 
 
 
 
 
 
Progression will be defined as recurrence of the disease necessitating 
change in therapy, or failure to respond to therapy requiring change in 
treatment. 
 
10. REGULATORY AND REPORTING REQUIREMENTS 
 
10.1 Regulatory and Reporting Requirements 
 
CTCAE term (AE description) and grade:  The descriptions and grading scales 
found in the CTEP Version 5of the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) will be utilized for AE reporting.  The CTEP Version 5 
of the CTCAE is identified and located on the CTEP website at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  All 
appropriate treatment areas should have access to a copy of the CTEP Version 5 
of CTCAE. 
 
Refer to Section 10.2 for Leukemia-Specific Adverse Event Recording 
Guidelines.    AE data will be collected in Prometheus 

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10.2 Leukemia-specific Adverse Event Recording and Reporting Guidelines 
 
         Adverse Event Definition 
 
An adverse event is the appearance or worsening of any undesirable sign, 
symptom, or medical condition occurring after starting the study drug even if the 
event is not considered to be related to study drug. Medical conditions/diseases 
present before starting study drug are only considered adverse events if they 
worsen after starting study drug. Abnormal laboratory values or test results 
constitute adverse events only if they induce clinical signs or symptoms, are 
considered clinically significant, or require therapy. 
 
Adverse Event Attribution 
 
Attribution is the determination of whether an adverse event is related to a 
medical treatment or procedure.  
 
Definite - the adverse event is clearly related to the investigational agent(s). 
Probable - the adverse event is likely related to the investigational agent(s). 
Possible - the adverse event may be related to the investigational agent(s). 
Unlikely - The adverse event is doubtfully related to the investigational agent(s). 
Unrelated - The adverse event is clearly NOT related to the investigational 
agent(s). 
 
                  Adverse Event Severity 
 
The severity of the adverse events (AEs) will be graded according to the U.S. 
Department of Health and Human Services, National Institutes of Health, 
National Cancer Institute, Common Terminology Criteria for Adverse Events 
(CTCAE), Version 5.  
  
Events not included in the NCI CTCAE will be scored as follows: 
• Grade 1: Mild: discomfort present with no disruption of daily activity, no 
treatment required beyond prophylaxis. 
• Grade 2: Moderate: discomfort present with some disruption of daily 
activity, require treatment. 
• Grade 3: Severe: discomfort that interrupts normal daily activity, not 
responding to first line treatment.  
• Grade 4: Life Threatening: discomfort that represents immediate risk of 
death 
 
                  Adverse Events Recording: 
 
These guidelines will be followed for the recording and reporting of adverse and 
serious adverse events. 

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1. Baseline events will be recorded in the medical history section of the case 
report form and will include the terminology event name, grade, and start date 
of the event. 
a. Baseline events are any medical condition, symptom, or clinically 
significant lab abnormality present before the informed consent is signed 
i. Hematologic laboratory abnormalities will not be recorded as baseline 
events for patients with acute leukemia, myelodysplastic syndrome, 
chronic lymphocytic leukemia, or chronic myeloid leukemia in blast 
phase. 
ii. If exact start date is unknown, month and year or year may be used as 
the start date of the baseline event. 
2. The maximum grade of the adverse event will be captured per course or 
protocol defined visit date. 
3. These adverse events will be recorded in the case report form: 
a. Any grade adverse event that is possibly, probably, or definitely related to 
the study drug(s). 
b. All serious adverse events regardless of attribution to the study drug(s). 
c. Any grade adverse event regardless of attribution to the study drug(s) that 
results in any dose modification. 
4. Hematologic adverse events will not be recorded or reported for studies in 
patients with acute leukemia,  myelodysplastic syndrome, chronic 
lymphocytic leukemia, or chronic myeloid leukemia in blast phase except for: 
a. Prolonged myelosuppression as defined by the NCI-CTCAE criteria 
specific for leukemia, e.g. marrow hypocellularity on day 42 or later (6 
weeks) from start of therapy without evidence of leukemia (< 5% blasts), 
or that results in dose modifications, interruptions or meets the protocol 
definition of DLT or SAE. 
5. Serious adverse events will be reported according to institutional policy. 
6. Protocol specific language regarding the recording and reporting of adverse 
and serious adverse events will be followed in the event of discordance 
between the protocol and Leukemia-specific adverse event recording and 
reporting guidelines. 
 
The investigator (or physician designee) is responsible for verifying and providing 
source documentation for all adverse events and assigning the attribution for all 
adverse events for subjects enrolled. 
 
 
Serious Adverse Event (SAE) Reporting Requirements 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either 
the investigator or the sponsor, it results in any of the following outcomes:  

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• 
Death 
• 
A life-threatening adverse event  
• 
Inpatient hospitalization or prolongation of existing hospitalization. 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions. 
• 
A congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse (21 CFR 
312.32). 
Important medical events as defined above may also be considered serious adverse events.  
Any important medical event can and should be reported as an SAE if deemed appropriate by 
the Principal Investigator or the IND Sponsor. 
• All events occurring during the conduct of a protocol and meeting the definition 
of a SAE must be reported to the applicable Institutional Review Board (IRB) of 
record in accordance with their timeframes and procedures. 
• Serious adverse events will be captured from the time of consent until 30 days 
after the last dose of drug or protocol specific timeline, unless the participant 
withdraws consent.   
• Serious adverse events must be followed until clinical recovery is complete and 
laboratory tests have returned to baseline, progression of the event has stabilized, 
or there has been acceptable resolution of the event. 
• All SAEs, including the development of new malignancies, must be reported to 
the IND/IDE Sponsor within 24 hours of knowledge of the event regardless of 
the attribution. 
• Additionally, any serious adverse events that occur after the 30-day time period 
that are related to the study treatment must be reported to the IND/IDE Sponsor. 
This may include the development of new malignancies. 
• All events reported to the supporting company must also be reported to the 
IND/IDE Sponsor. 
 
Reporting to FDA: 
Serious adverse events will be reported to the FDA by the IND/IDE Sponsor according to 
21 CFR 312.32. For SAEs determined by the IND Sponsor to meet the criteria for prompt 
reporting to the FDA, the principal investigator will be provided with a MedWatch form. 
The completed MedWatch form must be returned to the IND Sponsor by the due date 
specified by the IND Sponsor.  
It is the responsibility of the PI and the research team to ensure serious adverse events are 
reported according to the Code of Federal Regulations, Good Clinical Practices, the protocol 
guidelines, the IND/IDE sponsor’s guidelines, and Institutional Review Board policy. 
 

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Reporting of Serious Adverse Events to GlycoMimetics 
All SUSARs occurring during the Study should be reported to GlycoMimetics with a 
Completed Regulatory Form (Institution’s eSAE form) for initial and follow-up in parallel 
with submission to the FDA for patients exposed to GMI product by email to (Safety-
inbox.biotech@iqvia.com) .  All serious adverse events and follow-up occurring during the 
Study should also should be reported within 15 days post-Sponsor awareness date for 
patients exposed to GMI product by email to (Safety-inbox.biotech@iqvia.com).   
 
 
11.0 DATA SECURITY/CONFIDENTIALITY  
Participant confidentiality and privacy is strictly held in trust by the participating 
investigator, their staff, the safety and oversight monitor(s), and the sponsor(s) and funding 
agency. This confidentiality is extended to the data being collected as part of this study. Data 
that could be used to identify a specific study participant will be held in strict confidence 
within the research team. No personally identifiable information from the study will be 
released to any unauthorized third party without prior written approval of the 
sponsor/funding agency, as applicable. 
 
All research activities will be conducted in as private a setting as possible. 
 
Access to Study Records 
 
Study records may be accessed by IRB approved study personnel, or authorized inspectors. 
The study monitor, other authorized representatives of the sponsor or funding agency, 
representatives of the Institutional Review Board (IRB), regulatory agencies or 
representatives from companies or organizations supplying the product, may inspect all 
documents and records required to be maintained by the investigator, including but not 
limited to, medical records (office, clinic, or hospital) and pharmacy records for the 
participants in this study. The clinical study site will permit access to such records. 
 
Methods of Storage of Study Records 
 
All data collected from MD Anderson Cancer Center (MDACC) sources will be maintained 
on a password protected server compliant with HIPAA. Study staff will have role based 
restricted access to directories and files on the server, according to project responsibilities. 
Only those with data entry permissions can add records. The PI or a delegate will review the 
conditions under which data will be released to recipient- investigators. Each application for 
use will need IRB approval and consents, if appropriate. The level of identifiability will 
determine the process for review and approval as well as the way information is shared. 
Any study data or records maintained in paper documents will be stored in the offices of the 
PI or other delegated study staff, in a locked cabinet or other comparable controlled 
environment, and will be accessible only to authorized study team members or authorized 
inspectors.   
 
Duration of Study Record Storage 
 
The study participant’s contact information will be securely stored at each clinical site for 

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internal use during the study. At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by the reviewing IRB, Institutional policies, or 
sponsor/funding agency requirements. 
 
Sharing of Study Records 
 
There are no plans to share study identifiable data with entities external to MD Anderson 
Cancer Center, aside from authorized inspectors as applicable (i.e. authorized representatives 
of the sponsor or funding agency, representatives of the Institutional Review Board (IRB), 
regulatory agencies or representatives from companies or organizations supplying the 
product).  If data will be shared, IRB approval will be sought, and applicable inter-
institutional agreements executed, prior to data sharing.   
 
12.0 STUDY OVERSIGHT  
This protocol is monitored at several levels, as described elsewhere in this section. The 
Protocol Principal Investigator is responsible for monitoring the conduct and progress of the 
clinical trial, including the ongoing review of accrual, patient-specific clinical and laboratory 
data, and routine and serious adverse events; reporting of expedited adverse events; and 
accumulation of reported adverse events from other trials testing the same drug(s).  The 
Protocol Principal Investigator and statistician always have access to the data. 
 
Required: All Study Investigators at participating sites who register/enroll patients on a 
given protocol are responsible for timely submission of data via the mechanism described 
elsewhere in this section.  All studies are also reviewed in accordance with the enrolling 
institution’s data safety monitoring plan. 
 
12.1 Data and Safety Monitoring  
Data and Safety Monitoring is the process for reviewing data collected as research progresses 
to ensure the continued safety of current and future participants as well as the scientific 
validity and integrity of the research.  Studies conducted at MD Anderson will follow the 
DSMP that has been approved by the NCI.   
 
The Principal Investigator is ultimately responsible for the conduct and monitoring of all 
aspects of the study on an ongoing basis. The Principal Investigator will provide an annual 
review and report of the study, including all adverse events, accrual information, efficacy and 
response data, along with overall study progress and continuation plans to MD Anderson’s 
Data and Safety Monitoring committees responsible for study oversight.  
 
For this study, MD Anderson’s Data and Safety Monitoring Committee is responsible for 
study oversight. 
 
12.2 Clinical Trial Monitoring 
Regular monitoring of trial conduct will be conducted to ensure that the rights and well-being 
of trial participants are protected, that the reported trial data are accurate, complete, and 
verifiable, and that the conduct of the trial is in compliance with the currently approved 
protocol/amendment(s), with ICH GCP, and with applicable regulatory requirement(s).  
 

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12.3  Consent Process and Documentation  
This protocol will follow the SOP 04_Informed Consent Process. SOP 04 has been read by 
the research staff and investigators.  Informed consent may be obtained using the following 
methods: Remote consent, In-person consent. 
 
13.0 STATEMENT OF COMPLIANCE  
Each engaged institution must have a current Federal-Wide Assurance (FWA) issued by the 
Office for Human Research Protections (OHRP) and must provide this protocol and the 
associated informed consent documents and recruitment materials for review and approval by 
an appropriate Institutional Review Board (IRB) or Ethics Committee (EC) registered with 
OHRP. Any amendments to the protocol or consent materials must also be approved before 
implementation.  
 
 

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14.0 REFERENCES 
 
1. 
Estey EH, et. al. Therapy for Acute Myeloid Leukemia. In: Hoffmann R BE, Shattil SJ, 
Furie B, Cohen HJ, Silberstein LE, McGlave P, ed. Hematology, Basic Principles and 
Practice (3rd edition). Vol. 3rd Edition. New York, Edinburgh, London, Philadelphia, 
San Francisco: Churchill Livingston; 2000:1025. 
2. 
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