Conditions: Acute Myeloid Leukemia
Keywords: acute myeloid leukemia high dose cytarabine HiDAC consolidation chemotherapy schedule bone marrow elderly
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 5
Healthy volunteers: no

Brief summary:
This phase 2, open label, non-randomized study will evaluate the safety of administering high dose cytarabine (HiDAC) consolidation therapy on days 1-3 of each cycle, as compared to standard administration on days 1, 3, and 5 of each cycle, in patients 61 years and older with de novo acute myeloid leukemia (AML).

Detailed description:

Arms:
arm 1: Subject on this arm will be treated with HiDAC prospectively. arm 2: Subjects on this arm will be historical controls who have previously received treatment with HiDAC.

Interventions: intervention 1: Cytarabine intervention 2: Cytarabine
Intervention descriptions: intervention 1: Subjects on this arm will prospectively receive consolidation therapy with cytarabine. Subjects will be treated with 1000 mg/m2 cytarabine intravenously every 12 hours on Days 1-3 of each consolidation cycle. Subjects will receive up to four consolidation cycles. intervention 2: Subjects on this arm will have received consolidation therapy with cytarabine between 2/1/2017 and 2/1/2019. Subjects will have received 1000 mg/m2 cytarabine intravenously every 12 hours on days 1, 3, and 5 of each consolidation cycle and will have received up to 4 consolidation cycles.

Protocol document:
Prot_SAP_000.pdf: 
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Accelerated dose schedule of cytarabine consolidation therapy for older 
patients with acute myeloid leukemia (AML) in complete remission 
 
Protocol Number: 
UF-HEM-009 
 
Protocol Version Number: 
4.1 
 
Coordinating Center: 
 
University of Florida 
 
Principal Investigator:  
 
Jack W. Hsu, MD 
University of Florida 
1600 SW Archer Road 
Gainesville, FL 32608 
Telephone: 352-672-0704 
Email: jack.hsu@medicine.ufl.edu   
 
Co-Investigator (Proxy):                Brooke Adams, PharmD, BCOP 
UF Health Shands Hospital 
Email: cada0002@shands.ufl.edu  
 
Translational Co-Investigator:  Jatinder Lamba, PhD 
University of Florida 
Telephone: 352-273-6425 
Email: jlamba@cop.ufl.edu  
 
Other Co-Investigators: 
 
Sarah Wheeler, PharmD, BCPS, BCOP 
UF Health Shands Hospital 
Email: whees@shands.ufl.edu 
  
Statistician:  
 
 
Ji-Hyun Lee, DrPH 
University of Florida 
Telephone: 352-273-9079 
Email: jihyun@ufl.edu  
  
Protocol Manager(s): 
             UFHCC Project Management Office  
              
 
 
 
PMO@cancer.ufl.edu  
 
Clinical Phase: 
Phase II 
 
IND Status: 
N/A 
 
NCT#: 
NCT04914676 
 
Investigational Agent(s):  
N/A 


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Keywords: 
acute myeloid leukemia (AML), high dose cytarabine 
(HiDAC), consolidation, chemotherapy schedule, bone 
marrow, elderly 
 
CONFIDENTIAL 
This protocol was designed and developed by the University of Florida Health Cancer Center.  The information contained in this document is regarded as confidential and, 
except to the extent necessary to obtain informed consent, may not be disclosed to another party unless law or regulations require such disclosure.  Persons to whom the 
information is disclosed must be informed that the information is confidential and may not be further disclosed by them. 


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TABLE OF CONTENTS 
Page 
STUDY SCHEMA .................................................................................................................................................. 11 
PROTOCOL SYNOPSIS ...................................................................................................................................... 12 
1. 
BACKGROUND ........................................................................................................................................... 18 
1.1      Acute Myeloid Leukemia Cancer Therapy ........................................................................... 18 
1.2 
Overview of Non-Clinical Studies ........................................................................................... 20 
1.3 
Overview of Clinical Studies ..................................................................................................... 21 
1.4 
Rationale for Regimen/Doses/Schedule .............................................................................. 22 
2. 
OBJECTIVES ................................................................................................................................................ 22 
2.1 
Primary ........................................................................................................................................... 22 
2.1.1 Primary objective .......................................................................................................................... 22 
2.1.2 Primary endpoint .......................................................................................................................... 23 
2.2 
Secondary ...................................................................................................................................... 23 
2.2.1  Secondary objectives ................................................................................................................... 23 
2.2.2  Secondary endpoint(s) ............................................................................................................... 23 
2.3 
Exploratory ................................................................................................................................... 24 
2.3.1 Exploratory objectives ................................................................................................................. 24 
2.3.2  Exploratory endpoints ................................................................................................................ 24 
3. 
STUDY DESIGN .......................................................................................................................................... 25 
3.1 
Study Overview ............................................................................................................................ 25 
4. 
SELECTION OF SUBJECTS ..................................................................................................................... 25 
4.1 
Number of Subjects ..................................................................................................................... 25 
4.2 
Inclusion Criteria ......................................................................................................................... 26 
4.3 
Exclusion Criteria ........................................................................................................................ 26 
4.4 
Inclusion of Women and Minorities ...................................................................................... 27 
5. 
REGISTRATION PROCEDURES ............................................................................................................ 27 
6. 
STUDY PROCEDURES .............................................................................................................................. 27 
6.1 
Schedule of Events ...................................................................................................................... 28 
6.2 
End of Treatment Evaluations ................................................................................................. 30 
6.3 
Follow up Evaluations ............................................................................................................... 30 
7. 
STUDY TREATMENT ............................................................................................................................... 31 
7.1 
Treatment Schedule/Administration .................................................................................... 31 


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7.2 
Dose Calculations ........................................................................................................................ 32 
7.3 
Supportive Care ........................................................................................................................... 32 
7.3.1 
Supportive Care Guidelines ............................................................................................. 32 
7.3.2 
Concomitant Therapy ........................................................................................................ 32 
7.3.3 
Infections ................................................................................................................................ 33 
7.3.4 
Prohibited Concomitant Therapy .................................................................................. 33 
7.3.5 
Hematopoietic Stem Cell Transplantation Treatment .......................................... 33 
7.4 
Dose Modifications...................................................................................................................... 33 
7.4.1 
Non- Hematologic Toxicity .............................................................................................. 33 
7.4.2 
Hematologic Toxicity ......................................................................................................... 33 
8. 
TREATMENT DISCONTINUATION ..................................................................................................... 34 
8.1 
Screen Failures ............................................................................................................................. 34 
8.2 
Criteria for Study Treatment Discontinuation ................................................................... 34 
8.3 
Replacement of Subjects ........................................................................................................... 35 
9. 
BIOLOGICAL SPECIMENS AND CORRELATIVES .......................................................................... 35 
9.1 
Source of Specimens ................................................................................................................... 35 
9.2 
Correlative Studies ...................................................................................................................... 35 
9.3 
Preparation, Shipment and Storage of Specimens ............................................................ 36 
10. 
STUDY DRUG INFORMATION14 ....................................................................................................... 36 
10.1 Study Drug Name ........................................................................................................................ 36 
10.2    Identification ................................................................................................................................ 36 
10.3   Packaging and Labeling .............................................................................................................. 36 
10.4 Drug Supply ................................................................................................................................... 36 
10.5 Storage, Handling and Dispensing ......................................................................................... 36 
10.6 Drug Ordering and Accountability ......................................................................................... 36 
10.7 Infusion Reactions....................................................................................................................... 37 
10.8 Contraindications ........................................................................................................................ 37 
10.9 Special Warnings and Precautions for Use .......................................................................... 37 
10.10 Adverse Event Profile ................................................................................................................ 37 
11. 
ADVERSE EVENTS ................................................................................................................................ 38 
11.1 Definitions ..................................................................................................................................... 38 
11.1.1 
Adverse Event ....................................................................................................................... 38 


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11.1.2 
Serious Adverse Event ....................................................................................................... 39 
11.1.3 
Non-Serious Adverse Event ............................................................................................. 40 
11.2 Period of Observation ................................................................................................................ 40 
11.3 Documenting and Reporting of Adverse Events by Investigator .................................. 40 
11.3.1 
Assessment of Causal Relationship of Study Drug ................................................. 41 
11.3.2 
Intensity of Adverse Events ............................................................................................. 42 
11.3.3 
Action Taken with Study Drug ....................................................................................... 42 
11.3.4 
Definition of Outcome ........................................................................................................ 42 
11.4 Reportable Events ....................................................................................................................... 43 
11.4.1 
Serious Adverse Events ..................................................................................................... 43 
12. 
STATISTICAL METHODS .................................................................................................................... 43 
12.1 Data collection and management plan .................................................................................. 43 
12.2 Sample Size Justification ........................................................................................................... 43 
12.3 Analysis of Primary Endpoint .................................................................................................. 44 
12.4 Analysis of Secondary Endpoints ........................................................................................... 44 
12.5 Analysis of Exploratory Endpoints ........................................................................................ 44 
12.6 Analysis of Safety Data ............................................................................................................... 44 
12.7 Interim Analysis and Stopping Rules .................................................................................... 44 
12.8 Data Integrity and Safety Committee .................................................................................... 45 
12.9 Data Monitoring ........................................................................................................................... 46 
12.10 Principal Investigator Responsibilities ................................................................................. 46 
13. 
EMERGENCY PROCEDURES .............................................................................................................. 47 
13.1 Emergency Contact ..................................................................................................................... 47 
13.2 Emergency Treatment ............................................................................................................... 47 
14. 
ADMINISTRATIVE, ETHICAL, and REGULATORY CONSIDERATIONS ............................. 47 
14.1 Good Clinical Practice ................................................................................................................ 47 
14.2 Institutional Review Board ...................................................................................................... 48 
14.3 Compliance with Laws and Regulations ............................................................................... 48 
14.4 Delegation of Investigator Responsibilities ........................................................................ 48 
14.5 Subject Information and Informed Consent ........................................................................ 49 
14.6 Confidentiality .............................................................................................................................. 49 
14.7 Protocol Amendments ............................................................................................................... 49 


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14.8 Case Report Forms ...................................................................................................................... 50 
14.9 Record Retention ......................................................................................................................... 50 
15. 
REFERENCES .......................................................................................................................................... 52 
16. 
APPENDICES ........................................................................................................................................... 55 
Appendix A: Infection Definitions ...................................................................................................... 56 
Appendix B: UF Health Shands/BMT Program Blood Product Support Guidelines – Adult
 
64 
Appendix C: AML Response Criteria According to European Leukemia Net (ELN) ............ 65 
Appendix D: Protocol Version History / Summary of Changes ................................................. 66 
 
 
 
 
 
 
 
 


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ABBREVIATIONS  
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine transaminase (also SGPT) 
AML 
Acute myeloid leukemia 
ANC 
absolute neutrophil count 
AST 
BAL 
aspartate transaminase (also SGOT) 
bronchoalveolar lavage  
BSA 
BSI 
body surface area 
bloodstream infection 
BUN 
blood urea nitrogen 
CBC 
CG 
complete blood count 
cytogenetics  
CML 
CMV 
Chronic myeloid leukemia 
Cytomegalovirus 
CNS 
central nervous system 
CR 
complete remission 
CRF 
CT 
case report form 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTMS 
clinical trials management system 
CTO 
Clinical Trials Office 
DISC 
Data Integrity and Safety Committee 
DLT 
dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 
ECOG 
Eastern Cooperative Oncology Group 
EOT 
FISH 
FC 
End of Treatment 
fluorescence in situ hybridization 
flow cytometry 
FLT3 
FMS-like tyrosine kinase 3 
GCP 
Good Clinical Practice 
HiDAC 
HCT 
High-dose cytarabine 
Hematopoietic stem cell transplant 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IDH 
Isocitrate dehydrogenase 
IRB 
IFI 
Institutional Review Board 
invasive fungal infection 
IV 
Intravenous 


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kg  
kilogram(s) 
LDH 
lactic dehydrogenase 
LFS 
LOS 
LRTD 
Leukemia-free survival 
length of stay 
lower respiratory tract disease 
MDS 
Myelodysplastic syndrome 
MRD 
Minimal residual disease 
NCI 
National Cancer Institute 
NGS 
Next-generation sequencing 
NSAE 
non-serious adverse event 
ORR 
overall response rate 
OS 
overall survival 
PB 
PCR 
Peripheral blood 
Polymerase chain reaction  
PD 
progressive disease 
PFS 
progression free survival 
PMO 
Project Management Office 
PI 
principal investigator 
PK 
Pharmacokinetics 
PO  
By mouth 
PR 
partial remission 
PRN 
As needed 
PS 
performance status 
RBC 
red blood cells 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RR 
RVI 
Relapse rate 
Respiratory viral infection 
SAE 
serious adverse event 
SNP 
Single nucleotide polymorphism 
SCR 
Serum creatinine 
SOC 
Standard of care 
SQ 
Subcutaneous 
SD 
stable disease 
SGOT 
serum glutamic oxaloacetic transaminase (also AST) 
SGPT 
TNFα 
serum glutamic pyruvate transaminase (also ALT) 
tumor necrosis factor alpha 
UF 
University of Florida 
UFHCC 
University of Florida Health Cancer Center 
ULN 
upper limit of normal 
US 
United States 


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USA 
United States of America 
WBC 
white blood cell  
WHO 
World Health Organization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Protocol Signature Page 
 
Accelerated dose schedule of cytarabine consolidation therapy for older patients with 
acute myeloid leukemia (AML) in complete remission 
 
 
Principal Investigator: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
Jack W. Hsu, MD 
 
Date 
 
 
 
Printed Name of Investigator 
 
University of Florida 
 
 
 
Name of Facility 
 
FL 
 
 
 
Location of Facility (City/State) 
 
 
 
By my signature, I agree to personally supervise the conduct of 
this study and to ensure its conduct in compliance with the 
protocol, informed consent, IRB procedures, the Declaration of 
Helsinki, ICH Good Clinical Practices guidelines, and the 
applicable parts of the United States Code of Federal Regulations 
or local regulations governing the conduct of clinical studies. 
 
 
 
 
 
 
 


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STUDY SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle = 28 days 
Accrual Goal= 29 subjects 
 
 
Standard AML induction of physician’s 
choice 
Diagnosis of de novo AML and age > 61 years 
Disease re-assessment by bone marrow 
biopsy after recovery of blood counts 
Consent to study:  
consolidation with HiDAC 1,2,3 
for up to 4 cycles 
Exploratory analysis: <5 mL PB 
collected once prior to starting 
Not eligible for study 
Disease re-assessment will 
only be performed as 
clinically indicated, i.e., 
suspicion of relapse, 
according to standard of care 
Longitudinal Follow-Up:  
Subjects will be followed 
clinically (in terms of safety and 
labs) as long as they remain on 
study (while receiving HiDAC 
until recovery of last cycle) or 
up to 6 months after starting 
consolidation (whichever 
comes first); patients may end 
consolidation early if they 
proceed to HCT or 
consolidation ends earlier than 
planned. Subjects will be 
followed every 3 months (+ 28 
days) for up to 48 months after 
start of induction to describe 
long-term outcomes. 


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PROTOCOL SYNOPSIS 
Title: 
Accelerated dose schedule of cytarabine consolidation therapy for 
older patients with acute myeloid leukemia (AML) in complete 
remission 
Funding Source(s): All services will be provided by University of Florida CRO, if 
applicable. 
Investigational 
Agent Source: 
N/A                                                                                             
Rationale: 
Various chemotherapy regimens have been used in the treatment of 
AML, and common agents used include anthracyclines and 
pyrimidine/purine analogs. Once complete remission is confirmed 
after induction chemotherapy, a common regimen for AML patients 
to receive is standard HiDAC chemotherapy consolidation 
(cytarabine ≥ 1000 mg/m2 up to 3000 mg/m2 IV q12h on Days 1,3,5) 
x 3-4 cycles in the USA. Doses depend on age, renal function, 
performance status (PS) and institution/provider. UF Health Shands 
Hospital routinely uses HiDAC consolidation as above.  Recently 
published results from two European trials showing that a modified 
HiDAC consolidation regimen (given on Days 1,2,3) reduced the 
duration of neutropenia and number of blood product transfusions 
in younger AML patients.1 Another recent publication of a 
retrospective study confirmed the result of reduced hematologic 
recovery and less days of hospitalizations between the two regimens 
in subjects 60 years or less, however they did not see a reduced 
number of blood products.2 Due to differences in induction treatment 
strategies and differences in patterns of health care systems it is not 
clear that similar benefits and reductions in health care resource 
utilization would be seen in patients treated in the US. Also, many 
patients with AML are diagnosed over the age of 60 years, and 
currently this abbreviated HiDAC consolidation has not been studied 
in the elderly population. In older patients cytarabine is given as 
1000 mg/m2 IV q12h for 6 doses. In this trial, we will evaluate the 
safety of this abbreviated regimen in our AML patient population 
who are age 61 years or older, and try to reproduce the hematologic 
toxicity results seen in the younger population using standard 
practices here in the US. We would like to adopt this practice as a 
standard regimen if we are able to confirm the results of these 
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length of stay, infections, transfusions and other potentially-related 
complications for AML patients.      
Objectives: 
Primary:                                                                           
 
To determine the duration of neutropenia after consolidation 
chemotherapy with HiDAC 123 compared to matched historical 
controls who received HiDAC 135. Neutropenia is defined in 
days, as the first day of absolute neutrophil count (ANC) < 500 
after chemotherapy to day of recovery [ANC > 500 (defined as 
first day above 500 if consecutive x 2)]. 
Secondary:  
 
To define duration of thrombocytopenia after consolidation 
chemotherapy with HiDAC 123 compared to matched historical 
controls who received HiDAC 135. Thrombocytopenia is defined 
as the interval between the first day of platelets <50x103/uL 
after consolidation chemotherapy to the first day of recovery 
(defined as first day of platelets >20x103/uL if consecutive x 2 
and not transfused). 
 
To determine the safety of HiDAC 123 compared to standard 
HiDAC 135 in case controls by evaluating the differences in:  
o duration of neutropenia and thrombocytopenia 
o incidence of documented infections (e.g., bloodstream 
infection (BSI), pneumonia, invasive fungal infection (IFI), 
Clostridium difficile infection (CDI), typhlitis, (see Appendix 
A) and rates of febrile neutropenia (defined as 
temperature ≥ 38.3 C° once or ≥ 38 C° for more than 1 
hour and ANC less than 500/mm3 or expected to fall 
below 500/mm3 in next 48 hours)  
o number of RBC and platelet transfusions given per cycle 
will be recorded in units  
o readmission rates (incidence and reason for admission) 
and LOS recorded in days (total, including chemotherapy 
administration, and readmission days) 
o non-hematologic toxicity: focus on CNS/cerebellar and 
ocular as these are specific to high dose cytarabine, but 
will record incidences of any other grade 3-5 organ 
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o time to next treatment (next chemotherapy cycle, 
transplant, etc.; if chemotherapy was discontinued prior 
to planned date, what was the reason).  
Exploratory:   
 
Relapse rate (RR). Relapse rate defined as incidence of confirmed 
relapse by peripheral blood flow or bone marrow biopsy results. 
Patients will be monitored up to 48 months after starting 
induction and will be reported if available.  
 
Overall survival (OS) and leukemia-free survival (LFS). Overall 
survival defined as the time from date of complete remission (CR) 
to death from any cause. Leukemia-free survival defined as time 
from CR to AML relapse or death, whichever comes first. Cause of 
death will be recorded. Patients will be monitored up to 48 
months after starting induction and will be reported if available. 
 
Examine minimal residual disease (MRD) positivity after 
recovery from induction prior to study entry. The following 
modalities on bone marrow biopsy and aspirate will be used: flow 
cytometry (FC), karyotyping utilizing cytogenetics (CG), and 
fluorescence in situ hybridization (FISH). Patients with evidence 
of disease by any technique above will be classified as being 
MRDpos, FC will be performed on bone marrow specimens using 
monoclonal antibodies either as a large panel if the patient was 
newly evaluated or as a limited but targeted panel based on 
previously known patient-specific leukemia immune phenotype. 
MRD will be reported as a percentage of CD45 positive white 
blood cells (WBCs) and will be labeled MRDpos if leukemic cells 
account for ≥0.1% of the analyzed total WBCs. CG will be 
performed using standard G-banding methods on 20 metaphase 
cells. FISH will be reported as a percentage of abnormal nuclei 
among the examined 300 interphase nuclei. MRDpos by CG will 
be defined as abnormal karyotype seen in at least two metaphase 
cells, or less than two cells if it was a previously known 
abnormality for the given patient. FISH positivity of a prior 
known abnormality will be labeled MRDpos.4  
 
Pharmacogenomics: Dr. Lamba’s group has developed an Ara-C 
SNP score (ACSS) consisting of 4 SNPs that is predictive of 
intracellular leukemic cell ara-CTP levels and thus impacts 
toxicity and efficacy to cytarabine containing regimens.5 We will 
genotype SNPs of relevance (already established in Dr. Lamba’s 


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lab) and based on the ACSS score classify into two groups having 
ACSS score ≥ 0 or <0). ACSS score will be evaluated for 
association with certain endpoints (duration of neutropenia, 
thrombocytopenia, RR and OS).  Peripheral blood samples will 
be collected and analyzed through Dr. Lamba’s lab at the 
University of Florida and NGS results will be used to calculate 
the ACSS score.   
 
Study Design: 
This is a non-randomized, open-label, single group phase II study for 
the prospective arm. These subjects will be compared to matched 
historical controls who received Day 135 consolidation for the 
primary and secondary objectives.  Historical controls will be 
matched with prospective subjects for age (+/- 3 years), gender 
(male or female), Karnofsky PS (90-100/70-80/50-60), and number 
of HiDAC cycles received.  
Accrual Goal: 
A total of 29 subjects in HiDAC 123 arm. Data collected from these 
subjects will be compared to data from 29 matched historical 
controls who received standard HiDAC 135 consolidation. 
Inclusion Criteria: 
Individuals eligible for study participation must meet the following 
criteria:  
A. Both males and females ≥ 61 years of age  
B. A clinical diagnosis of de novo, non-M3 acute myeloid 
leukemia (AML) confirmed by greater than 20% blasts in 
peripheral blood or on diagnostic bone marrow biopsy who 
have completed intensive induction chemotherapy and are 
confirmed in complete remission #1 (defined by < 5% 
myeloblasts on recovery BM biopsy (ANC > 1000/uL and 
platelets > 100x103/uL) and able to receive HiDAC 
consolidation #1. 
C. Patients on the prospective arm must be willing to have 
labs/clinic visits at UF Health Shands after discharge from 
chemotherapy approximately every 48 hours +/- 24 hours 
until neutrophil and platelet count recovery after each 
chemotherapy cycle per standard of care to be included.  
- 
If prospective subjects cannot be followed at the UF site 
then telephone visits are allowed to follow for toxicity and 
transfusions. Records can be requested from subject’s 
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D. Written informed consent obtained from the subject and the 
subject agrees to comply with all the study-related 
procedures as stated above. For subjects on the historical arm, 
there will be a waiver of informed consent (as these patients 
may be deceased or not be available for retrospective 
consent). 
Exclusion Criteria: 
Subjects with any of the following will not be eligible for study 
participation:  
A. Age < 61 years 
B. Patients unable to provide informed consent for prospective 
arm 
C. Secondary AML (documented history of antecedent 
hematological disorder, such as myelodysplastic syndrome 
or therapy-related AML) or CML in blast crisis 
D. Patients receiving, received, or who will receive a FLT3 
inhibitor 
E. Patients receiving, received, or who will receive an IDH1 or 
IDH2 inhibitor 
F. SCr greater than 2 mg/dL 
G. Karnofsky PS of 40 or less at study entry 
H. History of any other disease, metabolic dysfunction, physical 
examination finding, or clinical laboratory finding giving 
reasonable suspicion of a disease or condition that 
contraindicates the use of protocol therapy or that might 
affect the interpretation of the results of the study or that puts 
the subject at high risk for treatment complications, in the 
opinion of the treating physician   
I. Prisoners or subjects who are involuntarily incarcerated, or 
subjects who are compulsorily detained for treatment of 
either a psychiatric or physical illness 
J. For historical arm, subjects will be excluded if adequate data 
is not available in electronic medical record (e.g., if patient 
was followed by their local oncologist between 
chemotherapy cycles and labs/transfusions/clinic notes, etc. 
are not available) 


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Efficacy 
Assessments: 
 
Duration of neutropenia after consolidation chemotherapy is 
primary efficacy endpoint. Neutropenia is defined in days, as the 
interval between the first recorded day of ANC < 500 after 
chemotherapy started to recovery [ANC > 500 (recorded as first day 
above 500 if consecutive x 2)]. Primary analysis will be with first 
consolidation cycle; however, data will be collected for all 
consolidation cycles up to six months after starting consolidation. 
Duration of thrombocytopenia will be a secondary efficacy endpoint. 
Thrombocytopenia is defined as interval between the first recorded 
day of platelets < 50x103/uL after consolidation to recovery 
(recorded as first day of platelets > 20x103/uL if consecutive x 2 and 
not transfused within the past 7 days). Analysis will be with first 
consolidation cycle; however, subjects will be monitored for up to six 
months after start of consolidation.  
Statistical 
Considerations: 
Group sample sizes of 23 subjects from a prospective cohort and 23 
subjects from historical baseline group will achieve 81% statistical 
power to reject the null hypothesis of equal means when the 
population mean difference in neutropenia duration is three days (16 
vs 19 days) with a standard deviation for both groups of four days 
and statistical significance level (alpha) of 0.05 using a one-sided, 
two sample, equal-variance t-test. Including a 20% drop out rate, we 
will accrue 29 subjects per cohort.  
The primary outcome will be analyzed using one-sided t-test with 
equal variance or the corresponding non-parametric statistical 
method, depending on the validation of the assumptions. 
Estimated 
Enrollment Period: 36 months 
Estimated Study 
Duration: 
60 months 


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1. BACKGROUND 
Cytarabine is a standard chemotherapy agent used in the treatment of AML. Cytarabine is an 
antimetabolite, specifically a pyrimidine nucleoside analog that is converted inside cells to 
an active metabolite that ultimately results in inhibition of DNA synthesis. It is used in 
various doses and can be used alone or in combination with other chemotherapy agents for 
the treatment of AML. High doses of cytarabine, known as HiDAC (doses > 1000 mg/m2 IV), 
are given in many different regimens. A standard AML consolidation regimen given after 
induction chemotherapy is HiDAC 1000-3000 mg/m2 IV q12 hours on Days 1, 3, and 5. 
HiDAC can also be given daily as an induction chemotherapy regimen in AML as HiDAC IV 
q12h x 12 doses (Days 1-6).  This dose schedule was not based on a pharmacologic basis but 
has been widely used.  Common side effects of cytarabine are nausea and/or vomiting, bone 
marrow suppression and associated toxicities (such as infection), rash, and mucositis. 
Specific to high-dose cytarabine only, ocular and neurologic toxicity can occur and patients 
are monitored closely for these adverse effects. Patients are provided with eye drops during 
and after chemotherapy, and given tests to evaluate for cerebellar toxicity (such as signing 
their name prior to each dose). 
1.1      Acute Myeloid Leukemia Cancer Therapy 
Acute myeloid leukemia (AML) is a rare type of cancer (1.1% of all new cancer cases); AML 
affects 4.3 people per 100,000 men and women per year.6 Patients undergo treatment to 
induce a complete remission if fit to receive chemotherapy. Once complete remission is 
confirmed after induction chemotherapy, AML patients receive consolidation chemotherapy. 
A standard AML consolidation regimen is HiDAC (cytarabine 1000-3000 mg/m2 IV q12h on 
Days 1, 3, 5 every 28 days) x 3-4 cycles in USA.7 Many institutions use HiDAC as consolidation 
chemotherapy or as a bridge to hematopoietic stem cell transplantation. Dosing of 
cytarabine varies for treatment of AML; for consolidation, some regimens may include 
cytarabine 100-200 mg/m2 continuous IV infusion Days 1-5 given in combination with 
anthracycline or HiDAC alone for 3-4 cycles. For induction regimens, often HiDAC is 
incorporated into various regimens, including cytarabine >1000 mg/m2 IV q12h x 8-12 
doses. Doses depend on age, renal function, performance status and institution/provider. 
Generally, patients over the age of 60 years receive cytarabine 1000 mg/m2for HiDAC 
consolidation.8 UF Health Shands Hospital routinely uses cytarabine 1000 mg/m2 IV q12h 
on Days 1, 3, and 5 up to 4 cycles (if tolerated) for standard chemotherapy consolidation in 
older AML patients.  Jaramillo et al recently published results from two European trials 
showing that a modified consolidation regimen of HiDAC on Days 1, 2 and 3 reduced the 
duration of neutropenia and number of blood product transfusions in younger AML patients 
compared to standard HiDAC consolidation on Days 1, 3 and 5 with no adverse effects on 
long-term outcomes.1 Dumas et al subsequently published a retrospective study of centers 
in France showing that adult patients age 18 to 60 years old with de novo or secondary AML 


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treated with the condensed HiDAC regimen showed 3 days less of neutropenia compared to 
the standard HiDAC regimen without any negative effect on OS, relapse or non-relapse 
mortality.2 After these two trials were published, the NCCN guidelines recommended HiDAC 
123 for AML patients ages 60 and under as another consolidation option.9  Since European 
centers use a different induction strategy often with two induction courses before 
consolidation and with a different health care system, it is not clear if similar findings of 
safety and less health care utilization would be seen in US centers. Both published trials 
included only patients 60 years or younger. However, the median age at diagnosis of AML is 
68 years old in the US.6 We will evaluate this abbreviated regimen and compare it to the 
standard of care regimen on Days 1, 3, and 5 in our older AML patient population, to try to 
reproduce the hematologic toxicity results seen in younger individuals using standard 
practices here in the US. We do not anticipate non-hematologic safety concerns since twice 
daily high dose cytarabine regimens are commonly used for patients who receive a second 
induction regimen if leukemia is not cleared by day 14 or at recovery after the first induction 
chemotherapy regimen and doses are routinely given for 6 continuous days rather than the 
3 days of this regimen.10 Patients older than 50 years received cytarabine 2,000 mg/m2 IV 
q12h D1-6 for induction chemotherapy, and this study only reported 7% severe 
neurotoxicity in this population. 
  
In the proposed exploratory analysis, we will genotype patients for SNPs of relevance to 
cytarabine that can generate Ara-CTP SNP scores (ACSS as described in recent publication5). 
Given small sample size we will consider dividing patients into two groups (ACSS ≥0 and <0) 
and will evaluate for association with toxicity and response to cytarabine that may be able 
to provide a model to identify patients who could be at higher risk for cytarabine toxicity. 
These SNPs are used in conjunction with next-generation sequencing (NGS) results to 
quantify the leukemia-associated variant allele frequencies. We hope to validate the clinical 
utility of ACSS to apply this score to explore if there is an association with relapse rate and 
risk of adverse effects in older adult AML patients undergoing HiDAC consolidation 
chemotherapy. This is an exploratory analysis to see if it is feasible to use this ACSS score 
and deep genetic sequencing to eventually be used in clinical practice and provide a patient-
specific treatment plan. For example, we may be able to identify patients more at risk for 
adverse effects if he/she has high ACSS score and/or predict treatment failure in patients 
with low ACSS scores that could help guide different dosing strategies for dose optimization 
for individualized patients to decrease cytarabine toxicity without compromising cytarabine 
effectiveness. This approach could lead to the development of clinical research aimed at 
enhancing the adoption of best practices in the community if it is later evaluated in a larger 
population if we find this approach feasible.  
 


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1.2 
Overview of Non-Clinical Studies 
Cytarabine is a prodrug requiring activation to ara-CTP for its anti-leukemic effect. 
Intracellular levels of ara-CTP vary among AML patients and are critical for achieving 
significant leukemic cell death.5 One of the mechanisms underlying ara-C resistance is 
insufficient intracellular levels of ara-CTP, which may be due to: a) inefficient cellular uptake 
due to transporter levels; b) reduced activation due to alterations in enzymes as DCK, 
CMPK1; c) increased inactivation due to NT5C2, SAMDH1, CDA, or DCTD; d) increased 
cellular dCTP pools (regulated by ribonucleotide reductases), that can compete with DNA 
incorporation of ara-CTP and also inhibit DCK activity.  
Dr. Lamba’s group has previously reported association of SNPs in DCK, NT5C2 and RRMs 
with intracellular levels of ara-CTP in leukemic cells.11-13 Using the most informative SNPs 
within the ara-C metabolic pathway, we have recently developed a comprehensive Ara-CTP 
SNP score (ACSS) that is predictive of intracellular levels of ara-CTP within leukemic cells. 
See Figure 2. A comprehensive ara-CTP-SNP-score (ACSS) developed from top 4 SNPs 
classified patients into 3 groups: High-ACSS (score>0), Intermediate-ACSS (score=0) and 
Low-ACSS (score<0). ACSS designation significantly predicted with intracellular ara-CTP 
levels (p=0.00012), suggesting a cumulative or synergistic effect of the significant SNPs.5 
More recently a study (unpublished results) with Moffitt Cancer Center, we observed 
significant correlation between induction 1 response being significantly (p<0.0001) better 
in patients with high ACSS score (≥0) vs low ACSS score (0). These results open up 
opportunities for the clinical utility of ACSS score to help identify patients who may be high 
risk of treatment failure or toxicity based on the ACSS scores.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 2 


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1.3 
Overview of Clinical Studies 
For more detail refer to the prescribing information for cytarabine.14  
Historically, poor outcomes were reported when conventional doses of cytarabine were used 
as post-remission therapy in AML, so groups studied higher doses of cytarabine for post-
remission therapy. The Cancer and Leukemia Group B (CALGB) compared various doses of 
cytarabine consolidation in AML patients in CR after induction therapy.7 Subjects in this trial 
were randomized into three groups (each planned to receive 4 cycles of consolidation of the 
following): 1.) 100 mg/m2 continuous IV x 5 days, 2.) 400 mg/m2 IV daily x 5 days or 3.) 
3000 mg/m2 IV q12h x 6 doses on Days 1, 3, and 5. These authors found that subjects who 
received high dose cytarabine were more likely to remain in CR and lived longer than 
patients who received lower doses of cytarabine. This trial was pivotal in establishing HiDAC 
as the standard post-remission/consolidation chemotherapy in the USA, as it was the first to 
show superior efficacy outcomes compared to anthracycline and conventional dose 
cytarabine for consolidation. Hematologic toxicity was main adverse effect, and 71% of 
patients were hospitalized due to infection or febrile neutropenia. Growth factors were not 
used in the trial. After excluding subjects over the age of 60 years after seeing higher rates of 
CNS toxicity (32%), severe CNS toxicity was recorded in 12% of subjects aged 60 years or 
younger.  
However more than half of patients are diagnosed over the age of 60 years with lower rates 
of CR compared to younger patients, so Sperr and colleagues designed a trial evaluating 
lower doses of cytarabine as consolidation chemotherapy in elderly AML subjects in CR.8 In 
this trial, patients received up to four cycles of cytarabine 1000 mg/m2 IV q12h on Days 1, 
3, and 5. Prophylactic growth factor was not routinely used. Neutropenic fever was recorded 
in 44-72% of cycles. No severe CNS adverse effects were reported. Drug fever was seen in 
32% and rash occurred in 17% of cycles. The results of this trial demonstrated that elderly 
AML patients can tolerate attenuated doses of HiDAC, which became the standard 
consolidation regimen for many institutions in the US.  
In 2006, the American Society of Clinical Oncology published guidelines that recommended 
prophylactic white blood cell growth factors after AML consolidation chemotherapy 
regimens. Bradley, et al published results of patients who did or did not receive prophylactic 
growth factor after first cycle of consolidation chemotherapy with at least 1000 mg/m2 
cytarabine q12h D1, 3, 5.15 Patients who received granulocyte colony stimulating factor 
(GCSF) had less readmissions for febrile neutropenia vs patients who did not receive GCSF 
(14% vs 37%).   
In general, the neutrophil nadir starts around Days 7-10 after HiDAC consolidation, and most 
patients start to recover neutrophils between Day 21 and 24, but hematologic recovery 


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depends on various factors, such as age, amount of prior treatments, prior antecedent 
hematologic disorder, etc. The use of GCSF has decreased the time to hematologic recovery. 
Sierra, et al showed median time to neutrophil recovery after HiDAC consolidation therapy 
to be 17 days if given GCSF.16 In Jaramillo, et al, the median time to neutrophil recovery after 
1-3 HiDAC consolidation(s) was 21-22 days in HiDAC 135 cohort compared to 17-18 days 
for subjects in the HiDAC 123 arm.1 Dumas, et al reported a median time of neutrophil 
recovery of 14-16 days with HiDAC 123 compared to 17-19 days with HiDAC 135.2  
1.4 
Rationale for Regimen/Doses/Schedule 
This condensed schedule described by Jaramillo1 and Dumas 2 will lessen the duration of 
chemotherapy inpatient admission by three days if older patients tolerate this new regimen. 
The authors also showed this modified HiDAC consolidation regimen reduced the duration 
of neutropenia and number of blood product transfusions in younger AML patients, so the 
benefits of this abbreviated regimen may be even greater than just three days less 
hospitalization. Patients were given pegfilgrastim as primary prophylaxis to prevent febrile 
neutropenia, however in the Jaramillo trial it was given on Day 10 in patients receiving 
HiDAC 135 and Day 8 in patients receiving HiDAC 123; this is typically later than many 
institutions in the US, as it is typically given or started approximately 24 hours after 
chemotherapy ends. The timing of GCSF prophylaxis described by Dumas et al more closely 
resembles to what we do in our practice, and the median time to recovery of neutrophils was 
slightly shorter compared to the results recorded by Jaramillo and colleagues. However, even 
in the trial described by Dumas, they described practices different than at this institution. 
For example, patients were routinely admitted on Days 10-12 according to blood cell counts 
and patients were not given bacterial prophylaxis. These trials were performed in Europe, 
which induction chemotherapy and supportive care measures are different than institutions 
in the US. Additionally, since AML patients are typically over 60 years with the median age 
at diagnosis of 68 years old6, we would like to study this patient population to potentially 
reproduce these reported results similar to the above trials. By reproducing these results 
seen in the aforementioned trials, it would make the benefits more generalizable to the AML 
population, especially to other institutions in the USA.  
2. OBJECTIVES 
2.1 
Primary 
2.1.1 Primary objective 
• To determine the duration of neutropenia in older patients with de novo AML after 
consolidation chemotherapy with HiDAC 123 compared to historical controls with HiDAC 
135.  We expect to see a shorter duration of neutropenia in subjects who receive HiDAC 
123 compared to subjects who received HiDAC 135. 


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2.1.2 Primary endpoint   
• To determine duration of neutropenia after HiDAC123 compared to HiDAC 135. Duration 
of neutropenia is defined as the number of days between first absolute neutrophil count 
(ANC) < 500 after chemotherapy to day of recovery, defined as first day when ANC > 500 
for two consecutive days.  
2.2 
Secondary 
2.2.1  Secondary objectives  
• To define duration of thrombocytopenia in older patients with de novo AML after 
consolidation chemotherapy with HiDAC 123 compared to historical controls with HiDAC 
135.  
• To determine the safety of HiDAC 123 compared to standard HiDAC 135 in case controls 
2.2.2  Secondary endpoint(s)    
 
To determine the safety of HiDAC 123 compared to standard HiDAC 135 in case controls 
by evaluating the differences in:  
o duration of neutropenia and thrombocytopenia (see neutropenia definition 
above). Thrombocytopenia is defined as the interval between the first day of 
platelets < 50x103/uL after consolidation chemotherapy to the first day of 
recovery (defined as first day of platelets > 20x103/uL if consecutive x 2 and not 
transfused) 
o incidence of documented infections (bloodstream infection (BSI), pneumonia, 
invasive fungal infection (IFI), Clostridium difficile infection (CDI), typhlitis, (see 
Appendix A) and rates of febrile neutropenia (defined as temperature ≥ 38.3 C° 
once or ≥ 38 C° for more than 1 hour and ANC less than 500/mm3 or expected to 
fall below 500/mm3 in next 48 hours)  
o number of RBC and platelet transfusions given per cycle will be recorded in units  
o readmission rates (incidence and reason for admission) and LOS recorded in days 
(total, including chemotherapy administration, and readmission days) 
o non-hematologic toxicity: focus on CNS/cerebellar and ocular as these are specific 
to high dose cytarabine, but will record incidences of any other grade 3-5 organ 
systems according to CTCAE v5 criteria  
o time to next treatment (next chemotherapy cycle, transplant, etc.; if chemotherapy 
was discontinued prior to planned date, what was the reason)  
 


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2.3 
Exploratory 
2.3.1 Exploratory objectives 
 
Pharmacogenomics: to evaluate impact of ACSS score for association with toxicity and 
efficacy in HiDAC 123 arm 
 
Describe RR, LFS and OS in each cohort  
2.3.2  Exploratory endpoints 
 
Record pharmacogenomic profiles if results available from next generation sequencing 
(NGS)/GatorSeq on bone marrow (BM) biopsies for both arms (collected at diagnosis as 
standard of care). 
 
Compute ACSS SNP score using the genotype data for subjects in HiDAC 123 arm. We 
will genotype SNPs of relevance and based on the ACSS score classify into two groups 
having ACSS score ≥ 0 or <0). ACSS score will be evaluated for association with certain 
endpoints (duration of neutropenia, thrombocytopenia, RR and OS).  Peripheral blood 
samples will be collected and analyzed through Dr. Lamba’s lab at the University of 
Florida and NGS results will be used to calculate the ACSS score.   
 
Describe relapse rate (RR). Relapse rate defined as incidence of confirmed relapse by 
peripheral blood flow or bone marrow biopsy results. Patients will be monitored up to 
48 months after starting induction and will be reported if available. 
 
Describe overall survival (OS) and leukemia-free survival (LFS). Overall survival defined 
as the time from date of complete remission (CR) to death from any cause. Leukemia-
free survival defined as time from CR to AML relapse or death, whichever comes first. 
Cause of death will be recorded. Patients will be monitored up to 48 months after 
starting induction and will be reported if available. These are not expected to be different 
between the two cohorts.1,2   
 
Examine minimal residual disease (MRD) positivity after recovery from induction prior 
to study entry. The following modalities on bone marrow biopsy and aspirate will be 
used: flow cytometry (FC), karyotyping utilizing cytogenetics (CG), and fluorescence in 
situ hybridization (FISH). Patients with evidence of disease by any technique above will 
be classified as being MRDpos, FC will be performed on bone marrow specimens using 
monoclonal antibodies either as a large panel if the patient was newly evaluated or as a 
limited but targeted panel based on previously known patient-specific leukemia immune 
phenotype. MRD will be reported as a percentage of CD45 positive white blood cells 
(WBCs) and will be labeled MRDpos if leukemic cells account for ≥0.1% of the analyzed 
total WBCs. CG will be performed using standard G-banding methods on 20 metaphase 
cells. FISH will be reported as a percentage of abnormal nuclei among the examined 300 
interphase nuclei. MRDpos by CG will be defined as abnormal karyotype seen in at least 


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two metaphase cells, or less than two cells if it was a previously known abnormality for 
the given patient. FISH positivity of a prior known abnormality will be labeled MRDpos.  
 
3. STUDY DESIGN 
3.1 
Study Overview 
This is a single center, open-label, non-randomized phase II study.  Twenty nine (29) subjects 
are planned to be enrolled in this study.  Each subject will be administered cytarabine 1000 
mg/m2 IV q12h x 6 doses on Days 1-3 in the hospital during the consolidation treatment 
phase. Subject may receive up to four consolidation cycles. Subjects will have laboratory and 
toxicity assessments as clinically indicated (at baseline, then daily while inpatient and ideally 
every 48 hours after hospital discharge +/- 24 hours until count recovery from each cycle). 
These subjects will be compared to 29 historical controls [matched by age (within 3 years), 
gender (male or female), PS (Karnofsky: 90-100, 70-80, or 50-60) and number of HiDAC 
cycles received] who received HiDAC 135 from the time period of 2/1/2017-2/1/2019.  
Screening data will be reviewed to determine subject eligibility. Subjects who meet all 
inclusion criteria and none of the exclusion criteria and who have consented will be entered 
into the study. The following treatment regimen will be used for prospective arm: cytarabine 
1000mg/m2 IV q12h x 6 doses (Days 1-3) for up to four cycles. 
Historical arm subjects will have received cytarabine 1000 mg/m2 IV q12h x 6 doses (Days 
1, 3, and 5) for up to four cycles from the time period of 2/1/2017-2/1/2019.  
Total duration of subject participation will be up to six months from start of first 
consolidation cycle (each cycle is 28 days, but more time may be required allowing extra 
time for delayed count recovery in some patients); study participation will end when subject 
recovers neutrophils and platelets after last administered cycle of chemotherapy, is admitted 
for conditioning chemotherapy for HCT, dies, or withdraws consent (whichever comes first).  
However, subjects will be followed every 3 months (+ 28 days) for up to 48 months after 
start of induction to determine long-term outcomes. Total duration of the study is expected 
to be 60 months. 
4. SELECTION OF SUBJECTS 
Subjects with a clinical diagnosis of de novo acute myeloid leukemia in CR1 who meet the 
following inclusion and exclusion criteria will be eligible for participation in this study.  
4.1 
Number of Subjects 
Twenty nine (29) subjects are expected to participate in the prospective arm of the study. 


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4.2 
Inclusion Criteria  
Subjects must meet all of the following criteria to be eligible for study participation:  
A. Both males and females ≥ 61 years of age  
B. A clinical diagnosis of de novo, non-M3 acute myeloid leukemia (AML) confirmed 
by greater than 20% blasts in peripheral blood or on diagnostic bone marrow 
biopsy who have completed intensive induction chemotherapy and are confirmed 
in complete remission #1 (defined by   < 5% myeloblasts on recovery BM biopsy, 
ANC > 1000/uL and platelets > 100x103/uL) and able to receive HiDAC 
consolidation #1 
C. Patients on the prospective arm must be willing to have labs/clinic visits at UF 
Health Shands approximately every 48 hours +/- 24 hours after discharge from 
chemotherapy admission to be included 
- 
If prospective subjects cannot be followed at the UF site then telephone visits are 
allowed to follow for toxicity and transfusions. Records can be requested from 
subject’s local physician office. 
D. Written informed consent obtained from the subject and the subject agrees to 
comply with all the study-related procedures. For subjects on the historical arm, 
there will be a waiver of informed consent (as these patients may be deceased or not 
be available for retrospective consent). 
4.3 
Exclusion Criteria 
Subjects with any of the following will not be eligible for study participation:  
A. Age < 61 years 
B. Patients unable to provide informed consent for prospective arm 
C. Secondary AML (documented history of antecedent hematological disorder, e.g., 
myelodysplastic syndrome or therapy-related AML) or CML in blast crisis 
D. Patients receiving, received, or who will receive a FLT3 inhibitor 
E. Patients receiving, received, or who will receive an IDH1 or IDH2 inhibitor 
F. SCr greater than 2 mg/dL 
G. Karnofsky PS of 40 or less at study entry 
H. History of any other disease, metabolic dysfunction, physical examination finding, or 
clinical laboratory finding giving reasonable suspicion of a disease or condition that 
contraindicates the use of protocol therapy or that might affect the interpretation of 
the results of the study or that puts the subject at high risk for treatment 
complications, in the opinion of the treating physician   
I. Prisoners or subjects who are involuntarily incarcerated, or subjects who are 
compulsorily detained for treatment of either a psychiatric or physical illness 


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J. For historical arm, subjects will be excluded if adequate data is not available in 
electronic medical record (e.g., if patient was followed by their local oncologist 
between chemotherapy cycles and labs/transfusions/clinic notes, etc. are not 
available) 
4.4 
Inclusion of Women and Minorities 
Both men and women and members of all races and ethnic groups are eligible for this trial. 
5. REGISTRATION PROCEDURES 
All subjects must be registered with the UF Health Cancer Center prior to participation in 
this trial and must meet all subject eligibility requirements and complete informed consent. 
All consented subjects must be entered into a secured electronic data base that is encrypted 
and password protected. 
All eligible and enrolled subjects will receive a unique subject number. This number will be 
used to identify the subject throughout the study. Subjects withdrawn from the study will 
retain their subject number.   
6. STUDY PROCEDURES 
Written informed consent must be obtained prior to performing any study-specific 
evaluations or tests. Tests or evaluations performed as standard of care within the specified 
screening period, but prior to informed consent, may be accepted for this study and need not 
be repeated.  Screening measurements below will be obtained within 60 days prior to 
registration into the study.  After registering a subject into this study, study treatment 
must begin within 30 days or subject will need to be re-screened: 
• Demographic data, including date of birth, gender, race, ethnicity and zip code 
• Medical history, including h/o MDS or other conditions that could cause secondary or 
treatment-related AML or other conditions that may have major psychiatric or medical 
illness(es) that may impact if subject able to consent or be monitored for cerebellar 
toxicity 
• Previous diagnostic assessments and treatment(s) for AML including regimens and dates 
• Medications that may exclude subject (such as FLT3 inhibitors, e.g. midostaurin, 
sorafenib, gilteritinib, or any investigational FLT3 inhibitor as well as IDH1 and IDH2 
inhibitors, e.g., ivosidenib, enasidenib or any investigational IDH inhibitor 
• Bone marrow aspirate and/or biopsy for clinical classification, flow cytometry, 
cytogenetic classification, molecular markers, NGS for identification of commonly tested 
mutations in AML at diagnosis and at hematologic recovery after induction 
chemotherapy 


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• Hematology laboratory evaluations: 
o Complete blood count (CBC) including hemoglobin, hematocrit, white blood cell 
(WBC) absolute with differential, and platelet count 
• Blood chemistry laboratory evaluations: serum creatinine 
• Blood transfusions, growth factors, anti-infective medications, eye drops 
 
6.1 
Schedule of Events 
                              Visit: 
 
 
 
 
 
 
Procedure: 
SCREENING 
(≤ 60 days 
prior to 
Day 1) 
CYCLE 1 
CYCLES 2 TO 4 IF SUBJECT 
CONTINUES 
END OF 
TREATMENT8  
(+/- 14 DAYS) 
FOLLOW UP 
(UP TO 48 
MONTHS AFTER  
START OF 
INDUCTION)9 
 
EVERY 3 MONTHS 
(+/- 28 DAYS) 
Day 
1 
At each clinic 
visit per SOC  
(as clinically 
indicated  ideally 
q48h+/- 24h) 
Day 1 
At each clinic 
visit per SOC  
(as clinically 
indicated ideally 
q48h+/- 24h) 
Informed Consent 
X 
 
 
 
 
 
 
Demographic 
Information 
X 
 
 
 
 
 
 
Medical and Cancer 
Treatment History1 
X 
 
 
 
 
 
 
Medication History2 
X 
 
 
 
 
 
 
Bone Marrow Biopsy 
and/or Aspirate3 
X 
 
 
 
 
As clinically 
indicated 
 
Interval 
History/Physical 
Exam10 
X 
X 
PRN SOC 
X 
PRN SOC 
PRN SOC 
 
Karnofsky 
Performance Status4 
 
X 
 
 
 
 
 
BSA Used for 
Chemotherapy 
 
X 
 
X 
 
 
 
Vital Signs 
X 
X 
PRN SOC 
X 
PRN SOC 
X 
 
Pharmacogenomic 
Sample Collection 
 
X 
 
 
 
 
 
Blood Chemistry 
Evaluations5 
X 
X  
(+/- 72 
HOURS 
AS SOC) 
PRN SOC 
X  
(+/- 72 
HOURS 
AS SOC) 
PRN SOC 
PRN SOC 
 
CBC w/Diff 
X 
X 
 (+/- 72 
HOURS 
AS SOC) 
PRN SOC 
X  
(+/- 72 
HOURS 
AS SOC) 
PRN SOC 
PRN SOC 
 
Administration of 
Blood and Platelet 
Transfusions 
 
PRN SOC 
PRN SOC 
PRN 
SOC 
PRN SOC 
PRN SOC 
 
Administer 
Cytarabine Inpatient 
(q12h Days 1-3) 
 
X 
 
X 
 
 
 
Concomitant 
Medication Review6 
 
PRN SOC 
PRN SOC 
PRN 
SOC 
PRN SOC 
PRN SOC 
 


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Adverse Event 
Review/Toxicity 
Assessment7 
 
PRN SOC 
PRN SOC 
PRN 
SOC 
PRN SOC 
PRN SOC 
 
RR and Survival 
Status (LFS and OS) 
 
 
 
 
 
X 
X 
1) 
The bone marrow assessment, cytogenetics NGS, and/or molecular markers at diagnosis will be documented. 
2) 
Document specific medications that may exclude patient that have been taken during the 30 days prior to screening. 
3) 
The screening bone marrow assessment must be performed within 30 days after start of induction therapy, and must be reviewed at 
UF. This must confirm a diagnosis of AML, non-M3 in CR1 (less than 5% blasts on BM biopsy when ANC >1000 and platelets greater 
than 100). Results will be recorded, including cytogenetics and NGS and/or molecular markers.  
4) 
Performance status will be collected on Day 1 of Cycle 1; however, if this is not documented on this admission progress note, the last 
documented value within the screening periods will be used for baseline Karnofsky performance status. 
5) 
Blood chemistries including blood urea nitrogen, creatinine, alkaline phosphatase, AST, ALT, total bilirubin 
6) 
Document supportive care medications (pegfilgrastim or equivalent 48 hours +/- 24 hours after chemo ends; antimicrobial prophylaxis 
when neutropenic and other anti-infectives needed, eye drops until 48 hours after cytarabine ends, etc.) Supportive care medications 
and blood transfusions should be documented throughout and for 28 days after last treatment. 
7) 
Monitoring for SAEs at the time of consent and AEs collection will start the day patient starts cycle 1 of consolidation chemotherapy 
and continuing throughout the study. Subjects who have received at least one dose of study drug and  discontinue prematurely  
(regardless of reason) will be monitored for any adverse events that occur during study until 28 days following the most recent  dose 
of study treatment or initiation of a new chemotherapy regimen (whichever comes first). If a SAE or AE that is deemed related to the 
study intervention and ongoing at the end of the monitoring period the event will be monitored until; resolution, event returns to 
baseline or in the investigator’s opinion, deems the event is unlikely to resolve due to the patients underlying disease. 
8) 
End of treatment visit will occur in subjects who complete 3-4 cycles of consolidation or at study withdrawal (for example, at HCT 
conditioning, relapsed disease or if ended earlier than planned due to toxicity or physician discretion).  Other assessments will be 
performed as necessary by the treating physician. Outside lab results may be collected if subject unavailable to travel to the institution. 
9) 
All subjects will be followed for long term outcomes until: relapse, death, or until closure of study. 
10) This data may be collected via telephone interview. 
 
Abbreviations:   
SOC= standard of care; PRN = as needed; BSA = OS = overall survival; SAE = severe adverse effects, AEs = adverse effects; HCT = 
hematopoietic stem cell transplant 
 


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6.2 
End of Treatment Evaluations 
The End of Treatment date will be the date the subject has met one of the following: 
- 
3-4 cycles of planned consolidation treatment 
- 
Study withdrawal  
- 
HCT conditioning 
- 
Treatment ended earlier than planned (due to toxicity or physician discretion) 
-  
Relapsed disease 
 
All subjects will have the following procedures documented: 
• Reason for end of treatment (relapse or transplant, etc.) 
• Supportive care medications and transfusions if needed 
• AE assessment 
• Hematology laboratory evaluations (unless recovery was documented in a previous 
visit): complete blood count (CBC) including hemoglobin, hematocrit, white blood cell 
(WBC) including differential and platelet count 
• Assessed for complete hematologic recovery  
o Reference Appendix C. ELN Guidelines 
6.3 
Follow up Evaluations 
Subjects will have follow-up visits for the evaluation of adverse events, labs, etc. per standard 
of care (after discharge from chemotherapy administration, generally every 48 hours +/- 24 
hours until neutrophil and platelet recovery after each consolidation chemotherapy cycle). 
Patients will be evaluated prior to starting next chemotherapy cycle, then admitted for 
chemotherapy and monitored while inpatient.   
If the subject is unavailable to travel to the institution (if situation changes from study 
inclusion criteria after subject starts first consolidation cycle), the visit may be made via 
telephone interview to review for adverse event resolution or the occurrence of any new 
adverse events, and outside labs reviewed if collected. Additionally, medical records may be 
requested with permission of the subject to complete remote visit reporting e.g., if admitted 
to an outside institution due to complications of chemotherapy. 
If the subject is at the treating facility and the physician decides to hold, reduce, or omit the 
dose completely, the following procedures should be performed:  
• Document reason for delay, decreased or missed doses 
• AE assessment 
• Hematology laboratory evaluations: complete blood count (CBC) including 
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If study therapy is discontinued before planned, disease assessments will be performed as 
clinically indicated, such as suspicion of relapse. Reason for discontinuation should be 
documented, e.g., relapse, proceeding to HCT, unexpected toxicity/poor tolerance of 
chemotherapy, etc. Subjects will continue to be followed every 3 months (+ 28 days) for 
survival data up to 48 months after induction chemotherapy is started, or until relapse or 
death (whichever comes first). Following discontinuation of study therapy for any reason, 
report the date as appropriate (date of confirmed relapse, date of death, date of start of HCT 
conditioning, or recovery from last planned or unplanned cycle). 
If a subject becomes unreachable during the course of the study, the investigator or study 
team will make a reasonable effort to contact the subject and document each attempt.  If 
these attempts are not successful, the subject may be declared “lost to follow up.”  For 
subjects lost to follow-up, the termination date will be the date of last contact with the 
subject. 
7. STUDY TREATMENT 
7.1 
Treatment Schedule/Administration 
Cytarabine administration will be recorded including, but not limited to, date of 
administration, dose (total and mg/m2) and any changes in dose administration (e.g., 
interruption or reduction in dose due to an adverse event). Cytarabine will be scheduled to 
be given IV q12h on the first three days of each 28-day treatment cycle, unless there has been 
a scheduled modification of administration due to not meeting treatment parameters, such 
as hematologic recovery or toxicity.  The product will be administered per institutional 
standard in terms of nursing administration and pharmacy preparation. Antiemetic 
medication(s) should be given 30-60 minutes prior to administration of cytarabine per 
institutional guidelines, and agents may be modified for individual patients based on risk 
factors and previous antiemetic responses. Eye drops (steroid or artificial tears) should be 
given prior to cytarabine and continued for 48 hours after last dose of cytarabine given. 
Prophylactic antimicrobials should be given as standard of care. Pegfilgrastim 6 mg SQ (or 
equivalent) should be given once 48 hours +/- 24 hours after completion of chemotherapy. 
Filgrastim (or equivalent) may be given as an alternative (5 mcg/kg rounded to vial size daily 
until WBC recovery). If patient is unable to receive these aforementioned medications, the 
reason should be documented. 
Patients will be monitored for cerebellar toxicity using NCI CTCAE v5 toxicity grades while 
admitted for high dose cytarabine. Patients will be asked to sign his/her name prior to each 
dose of chemotherapy. If there is suspicion of neurotoxicity, a provider should assess the 
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7.2 
Dose Calculations 
Chemotherapy will be dosed according to institutional standard, unless otherwise specified. 
Generally, cytarabine will be dosed on actual/total body weight, and body surface area (BSA) 
will be capped at 2.4 m2. 
BSA will be documented per Mosteller formula.  
BSA (m2) = √height (cm) x weight (kg)/3600 
7.3 
Supportive Care 
7.3.1 Supportive Care Guidelines 
Subjects should receive full supportive care, including transfusions of blood products, 
antimicrobials, antiemetics, antidiarrheals, eye drops, analgesics, etc., when appropriate.  
Supportive care will be administered to all study subjects per institutional guidelines.  
Subjects will be counseled on the expected side effects of cytarabine and what to do if/when 
these occur. 
Growth factors (granulocyte-colony stimulating factor [G-CSF]) should be given if able, 
according to the institutional standard of care.17 Pegfilgrastim (or biosimilar product) 6 mg 
SQ once 48 hours +/- 24 hours (or on-body injector on the last day of chemotherapy) is 
generally used for primary prophylaxis of febrile neutropenia. If patient is unable to obtain 
pegfilgrastim, then filgrastim (or biosimilar) 5 mcg/kg rounded to vial size shall be 
administered SQ daily until ANC recovery.  
Antiviral, antifungal, and antibacterial prophylaxis and treatment should follow 
conventional guidelines and institutional guidelines.18 In general, levofloxacin, fluconazole 
(or mold-active azole if patient has history of IFI), and valacyclovir (or acyclovir) are started 
when ANC is approximately 500/mm3 or below and continued until count recovery. See 
Appendix B for UF Health Shands Hospital transfusion guidelines.  
7.3.2 Concomitant Therapy  
Relevant medical history should be obtained at screening and include prior AML treatment 
history. Medications will be reviewed at screening for FLT3 and IDH 1/2 inhibitors to assess 
exclusion criteria. 
The use of concomitant therapy will be collected, such as supportive care (e.g., growth 
factors, antimicrobials, eye drops) throughout consolidation therapy and will be 
administered per institutional guidelines or patient-specific treatments per the treating 
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7.3.3 Infections 
Chemotherapy puts the patient at higher risk for bacterial, viral, or fungal infections, which 
are potentially life-threatening. Prophylactic antimicrobial medications and prophylactic 
granulocyte colony stimulating factor will be initiated per institutional guidelines if able, and 
patients will be closely monitored for signs of infections and will receive early and 
appropriate treatment per standard of care. Infections will be scored according to infections 
listed in Appendix A. 
7.3.4 Prohibited Concomitant Therapy 
Supportive care measures consistent with optimal subject care will be permitted throughout 
the study, as long as the therapy is not included in this section as prohibited. 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this trial:   
• FLT3 inhibitors, e.g., midostaurin, sorafenib, gilteritinib, or any investigational FLT3 
inhibitor) 
• IDH 1 and IDH2 inhibitors, e.g., ivosidenib, enasidenib or any investigational IDH 
inhibitor 
7.3.5 Hematopoietic Stem Cell Transplantation Treatment 
Subjects may undergo allogeneic stem cell transplant after study entry; at the start time of 
conditioning therapy, the subject will be removed from the study. The time to next treatment 
(date of conditioning) will be recorded. The conditioning regimen, donor type and graft 
source during the allogeneic HCT period will be recorded.  
7.4 
Dose Modifications 
The National Cancer Institute (NCI) Common Toxicity Criteria (v5.0) for Adverse Events 
(CTCAE) will be used to grade toxicity (http://evs.nci.nih.gov/ftp1/CTCAE/About.html).3    
Subjects will generally receive cytarabine 1000 mg/m2 IV q12h x 6 doses. Dose 
modifications may occur per physician discretion.  If dose or duration is different than stated 
above, the reason should be recorded.  
7.4.1 Non- Hematologic Toxicity 
Dose modifications or interruptions may occur per standard of care or per the treating 
physician based on patient tolerability.  
7.4.2 Hematologic Toxicity 
Dose modifications or interruptions may occur per standard of care or per the treating 
physician based on patient tolerability.  


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8. TREATMENT DISCONTINUATION 
8.1 
Screen Failures  
Subjects who sign informed consent, but do not meet eligibility criteria, or withdraw prior 
to eligibility being verified, and undergo at least some of the screening procedures will be 
considered screening failures. Subjects who sign informed consent and are verified as 
eligible, but do not proceed to formal registration will be considered “unregistered.”  A 
record of screen failures and unregistered subjects will be maintained by the study site. 
8.2 
Criteria for Study Treatment Discontinuation 
Subjects who discontinue participation in the clinical study on their own or subjects who are 
withdrawn by the investigator, for reasons other than completion of treatment, proceeding 
to HCT, relapse or toxicity, will be defined as premature withdrawals. The end of treatment 
data will be collected if available at last visit if confirmed relapse, death, or proceeding to 
HCT. For those with toxicity that end before planned last cycle, data will be collected up to 
the end of treatment date and AE data will be collected until 28 days following the most 
recent  dose of study treatment or initiation of a new chemotherapy regimen (whichever 
comes first). 
Subjects will be followed for long term data every 3 months (+ 28 days) until relapse, death 
or until 48 months after induction therapy (whichever comes first).  
A subject will be discontinued from protocol therapy under the following circumstances: 
• Any adverse event which, in the Investigator’s opinion, requires termination of the 
chemotherapy 
• Disease relapse 
• If subject proceeds to allogeneic HCT 
• The subject uses illicit drugs or other substances, or takes part in activities that may, in 
the opinion of the Investigator, have a reasonable chance of contributing to toxicity or 
otherwise interfering with results 
• The subject is lost to follow-up 
• Death 
• Development of an intercurrent illness or situation which would, in the judgment of the 
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The Investigator will make every reasonable effort to keep each subject in the study unless 
it is in the subject’s best interests to discontinue participation.  If a subject is removed from 
the study or declines further participation, all EOT evaluations should be performed if the 
subject is willing and able to be assessed.  A description of the reason(s) for withdrawal from 
the study must be recorded on the case report form (CRF).  The Investigator should also 
ensure that all subjects are followed up for survival status after the Final Visit. 
Subjects who discontinue following entry will have relevant information completed and 
recorded on the CRF.  All subjects who discontinue because of adverse events or clinically 
significant laboratory abnormalities should be followed up until they recover or stabilize, 
and the subsequent outcome will be recorded. If any subject should experience an 
unexpected serious adverse event during the trial or within 28 days of stopping study 
treatment, the Investigator will inform the UF Health Data Integrity and Safety Committee.   
8.3 
Replacement of Subjects 
Subjects will be replaced if they have not received any doses of study drug prior to their 
withdrawal. 
9. BIOLOGICAL SPECIMENS AND CORRELATIVES 
9.1 
Source of Specimens 
Peripheral blood (<5 mL) will be collected in subjects on the prospective arm for exploratory 
analysis. Only one sample is needed, and this will be during the pre-admission labs prior to 
first consolidation chemotherapy cycle. 
All correlative studies will be performed in Dr. Lamba’s laboratory at University of Florida.  
Peripheral blood samples will be collected and analyzed in Dr. Lamba’s laboratory. We will 
use genotype patient samples for the 4 SNPs that are part of ACSS score and compute ACSS 
score for each patient and patients will be classified into having a low (<0) or high ACSS 
(>=0).   
9.2 
Correlative Studies 
We will compare the ACSS score for association with clinical endpoints using appropriate 
statistical tests as used in our previous work. Statistical analysis will be performed to 
compare overall-survival (OS), between ACSS groups using Cox regression and Fisher’s exact 
test for toxicity endpoints and Wilcoxon test for association of ACSS score with duration or 
neutropenia/thrombocytopenia. 


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9.3 
Preparation, Shipment and Storage of Specimens 
Three to five mL of peripheral blood will be collected in EDTA tube on pre-admission or 
admission day of C1D1 of HiDAC consolidation. Storage in -80 deg C is preferred but sample 
can be kept at 40 deg C to send to the laboratory.  Specimens will be processed after funding 
is obtained.  
 
10. STUDY DRUG INFORMATION14 
10.1 
Study Drug Name 
Cytarabine (Cytosar®); multiple manufacturers; aka cytosine arabinoside, Ara-C. 
10.2    Identification 
Cytarabine, initially developed by Pfizer, is a standard of care chemotherapy used for 
intravenous administration in the management of AML patients. Cytarabine is a colorless 
solution that is diluted in 0.9% sodium chloride. At high doses, it is usually diluted in 250 mL 
IV and given over 2-3 hours.  Preparation and administration is per institutional guidelines 
and policies as applicable. 
10.3   Packaging and Labeling 
Vials are supplied from institution’s wholesaler via commercial supply. Preparation and 
labeling of IV infusion will follow institutional policies and procedures. 
10.4 
Drug Supply 
Vials are supplied from institution’s wholesaler via commercial supply.  
10.5 
Storage, Handling and Dispensing 
Storage, handling and dispensing of cytarabine and other supportive care medications will 
follow institution’s policies and procedures. This product will be given per SOC except for 
the interval/days for the HiDAC 123 arm. The pharmacist will verify and dispense the 
medication(s) and nursing will administer medications as above per institutional policies 
and procedures.  
10.6 
Drug Ordering and Accountability 
Drug product ordering and accountability will follow institutional policies and procedures. 


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10.7 
Infusion Reactions 
Severe allergic reactions are very rare with cytarabine (<1%). Nurses should monitor the 
patient for any signs/symptoms of anaphylaxis and notify provider if these occur. Patient 
should be treated per conventional and institutional guidelines for treatment of anaphylaxis. 
Two adverse effects that patients should be monitored for while receiving cytarabine and 
shortly after are ocular and neurotoxicity as stated previously in protocol. 
10.8 
Contraindications 
Allergy to cytarabine, patients unable to monitor for ocular or neurotoxicity or any other 
condition that the treating physician feels is a contraindication to receiving high doses of 
cytarabine.  
10.9 
Special Warnings and Precautions for Use 
Bone marrow suppression and associated complications (e.g., bleeding and infection), 
chemical conjunctivitis, and cerebellar toxicity are the most significant complications of 
high-dose cytarabine. Cytarabine is a chemotherapy agent, so standard universal 
precautions should be followed in terms of handling and administering the product and 
handling any bodily secretions and blood of patients receiving cytarabine per SOC and 
institutional policies and procedures.  
There are no clinically significant drug interactions with single agent cytarabine regimens.  
10.10 Adverse Event Profile 
Most Frequent Adverse Reactions 
Anorexia 
fever 
thrombocytopenia 
Nausea 
rash 
anemia 
Vomiting 
thrombophlebitis 
neutropenia 
Diarrhea 
oral mucositis 
infections 
 
Less Frequent Adverse Reactions 
Sepsis 
esophageal ulceration 
shortness of breath 
Bleeding 
esophagitis 
alopecia 
conjunctivitis 
chest pain 
anaphylaxis 
urinary retention 
pericarditis 
allergic edema 
renal dysfunction 
bowel necrosis 
pruritis 


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Neuritis 
abdominal pain 
urticaria 
neurotoxicity 
pancreatitis 
hand-foot syndrome 
Headache 
hepatic dysfunction 
skin ulceration 
Dizziness 
jaundice 
 
 
11. ADVERSE EVENTS 
11.1 
Definitions 
11.1.1 Adverse Event 
The term “adverse event” (AE) includes any sign, symptom, syndrome, or illness that appears 
or worsens in a subject during the period of observation in the clinical study and that may 
impair the wellbeing of the subject. The term also covers laboratory findings or results of 
other diagnostic procedures that are considered to be clinically significant (e.g., that requires 
unscheduled diagnostic procedures or treatment measures, or result in withdrawal from the 
study).  An AE is therefore any unfavorable and unintended symptom or disease temporally 
associated with the administration of an investigational product, whether or not related to 
that investigational product. 
The adverse event may be: 
• A new illness/condition; 
• Worsening of a sign or symptom of the condition under treatment, or of a concomitant 
illness/condition; 
• An effect of the study drug; or 
• A combination of 2 or more of these factors. 
No causal relationship with the study drug or with the clinical study itself is implied by the 
use of the term “adverse event.” 
The Investigator or his/her designee will assess for occurrence of AEs during hospitalization 
and each outpatient visit (or via telephone survey if patient is unable to return to clinic at 
the planned time).  AEs related to cytarabine will be recorded in the subject CRF.  AEs will be 
described by duration (start and stop dates and times), severity, outcome, treatment and 
relation to study drug, or if unrelated, the cause. 
Surgical procedures themselves are not adverse events; they are therapeutic measures for 
conditions that require surgery. The condition(s) for which the surgery is required may be 
an adverse event. Planned surgical measures permitted by the clinical study protocol and the 
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When a clear diagnosis is available that explains the abnormal objective findings, this 
diagnosis will be recorded as an adverse event and not the abnormal objective findings (e.g., 
viral hepatitis will be recorded as the adverse event and not the transaminase elevation). If 
a definitive diagnosis is not available, then the sign(s) (e.g., clinically significant elevation of 
transaminase levels) or symptom(s) (e.g., abdominal pain) will be recorded as the adverse 
event. 
Adverse events fall into the categories “serious” and “non-serious.” 
11.1.2 Serious Adverse Event 
A serious adverse event is one that at any time during the period of observation: 
• Results in death 
• Is life-threatening (defined as an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe) 
• Requires inpatient hospitalization or causes prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is an important medical event, defined as a medical event that may not be 
immediately life-threatening or result in death or hospitalization but, based on 
appropriate medical and scientific judgment, may jeopardize the subject or may 
require intervention (e.g., medical, surgical) to prevent one of the other serious 
outcomes listed above. Examples of such events include but are not limited to 
intensive treatment in an emergency department or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization. 
“Medically important” should be marked only if no other serious criteria are met. 
An “unexpected SAE” is any SAE for which the nature, specificity or severity is not consistent 
with the currently known adverse event profile of cytarabine. 
Clarification of the difference in meaning between “severe” and “serious” 
The term “severe” is often used to describe the intensity (severity) of a specific event (as in 
mild, moderate, or severe myocardial infarction); the event itself, however, may be of 
relatively minor medical significance (such as severe headache). Any grade ≥ 3 adverse event 
per CTCAE is generally considered severe AE. This is not the same as “serious,” which is 
based on the outcome or action criteria usually associated with events that pose a threat to 
life or functioning. Seriousness (not severity) serves as a guide for defining regulatory 
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11.1.3 Non-Serious Adverse Event 
A non-serious adverse event is any adverse event not meeting any of the serious adverse 
event criteria. 
11.2 
Period of Observation 
Following the subject’s written consent to participate in the study, all SAEs must be collected, 
including those thought to be associated with protocol-specified procedures. Collection of all 
SAEs must continue for at least 28 days after the last dose of study treatment or until 
initiation of new chemotherapy regimen (whichever comes first).  
The investigator will begin collecting ocular or neurologic toxicities of any grade related to 
cytarabine and other grade 3-5 non-hematologic and hematologic toxicities and associated 
toxicities, such as bleeding and infection once administration of cytarabine is initiated.  
Treated subjects, including those who were prematurely discontinued from the study, will 
be monitored for any adverse events that occur during the study until 28 days following the 
most recent dose of study treatment or initiation of a new chemotherapy treatment 
(whichever occurs first).  If another course of anti-cancer therapy is initiated prior to the 28 
day follow-up period visit, collection of adverse events will no longer be performed, with the 
exception of events that may be possibly, probably, or definitely related to cytarabine or are 
clinically significant. If AE is deemed related to the study intervention and ongoing at the end 
of the monitoring period, the event will be monitored until resolution, returns to baseline or 
in the investigator’s opinion, deems the event is unlikely to resolve due to the patients 
underlying disease. 
11.3 
Documenting and Reporting of Adverse Events by Investigator 
Ocular or neurologic adverse events of any grade related to cytarabine and other grade 3-5 
non-hematologic and hematologic toxicities and associated toxicities, such as bleeding and 
infection must be fully recorded in the subject’s case record form. 
Revise documentation and recording requirements as required. 
A laboratory test abnormality considered clinically relevant, e.g., causing the subject to 
withdraw from the study, requiring treatment or causing apparent clinical manifestations, 
or judged relevant by the investigator, should be reported as an adverse event.  Each event 
should be described in detail along with start and stop dates, severity, relationship to 
cytarabine, action taken and outcome. 
Every attempt should be made to describe the adverse event in terms of a diagnosis that 
encompasses the component signs and symptoms. If only nonspecific signs or symptoms are 
present, then these should be recorded as separate diagnoses on the pages of the case report 
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All subjects who have adverse events, whether considered associated with the use of study 
drug or not, must be monitored to determine the outcome. The clinical course of the adverse 
event will be followed according to accepted standards of medical practice, even after the 
end of the period of observation, until a satisfactory explanation is found or the Principal 
Investigator considers it medically justifiable to terminate follow-up. Should the adverse 
event result in death, a full pathologist’s report should be supplied, if possible. 
11.3.1 Assessment of Causal Relationship of Study Drug 
The Investigator will provide an assessment of the potential causal relationship between 
adverse events and study medication by determining whether or not there is a reasonable 
possibility that the event was caused by the study medication. The relationship or 
association of the adverse event to the study medication will be characterized as not related, 
unlikely related, possibly related, probably related, or related:   
Not Related: There is not a temporal relationship to the study drug administration or the 
adverse event is clearly due only to the progression of the underlying disease state, 
intercurrent illness, concomitant medication, concurrent therapy or other known cause. 
Unlikely Related:  There is little or no chance that the study drug administration caused the 
adverse event; the event is most likely due to another competing cause, including 
intercurrent illness, progression or expression of the disease state, or a reaction to a 
concomitant medication or concurrent therapy appearing to explain the reported adverse 
event.  
Possibly Related:  The association of the adverse event with the study drug administration 
is unknown; however, the adverse event is not reasonably attributed to any other condition.  
Probably Related:  When a reasonable temporal relationship exists between the adverse 
event and the study drug administration; significant symptoms abate upon discontinuation 
of the study drug and there is a reasonable explanation based on known characteristics of 
the study drug and there is no clear association with preexisting disease or therapy, 
intercurrent illness, concurrent therapy or other factor(s). 
Related:  When the adverse event is a known side effect of the study drug or there is a 
temporal relationship to the administration of the study drug; or the adverse event 
reappears upon re-administration of the study drug (rechallenge); or the significant 
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11.3.2 Intensity of Adverse Events 
The intensity of adverse changes in physical signs or symptoms will be graded according to 
the most up-to-date CTCAE version. For all other adverse events not described in the CTCAE, 
the intensity will be assessed by the Investigator using the following categories: 
Mild (Grade 1) – transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required. 
Moderate (Grade 2) – mild to moderate limitation in activity, some assistance may be 
needed; no or minimal medical intervention/therapy required. 
Severe (Grade 3) – marked limitation in activity, some assistance usually required; medical 
intervention/therapy required, hospitalization is possible. 
Life-threatening (Grade 4) – extreme limitation in activity, significant assistance required; 
significant medical intervention/therapy required, hospitalization or hospice care probable. 
Death (Grade 5) – the event resulted in death. 
 
11.3.3 Action Taken with Study Drug 
The action the Investigator took with study drug as a result of the event should be recorded 
as one of the following: 
None – No action was taken with regard to chemotherapy as a result of the adverse event. 
Interrupted – Chemotherapy was stopped due to the adverse event, but was later resumed 
at the same dose. 
Dose decreased – The dose of cytarabine was decreased as a result of the adverse event. 
Permanently discontinued – The subject was withdrawn from the study due to the adverse 
event. 
Only one item should be chosen. If multiple actions apply, the following “worst case” scenario 
hierarchy should be used to determine the preferred entry:  
permanently discontinued > dose decreased > interrupted. 
11.3.4 Definition of Outcome 
The outcome of the AE should be recorded as one of the following: 
Resolved without sequelae – The subject fully recovered from the adverse event with no 
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Resolved with sequelae – The subject recovered from the adverse event with observable 
residual effects. 
Not resolved – The adverse event was present at the time of last observation. 
Death – The subject died as a result of the adverse event. 
 
11.4 
Reportable Events 
11.4.1 Serious Adverse Events 
Serious (requiring hospitalization and/or increased level of care) adverse events (SAE's) 
that are unexpected (not in informed consent) and most likely related to cytarabine must be 
reported to the IRB within five working days. If there are more than three grade 3-5 
neurologic adverse events, these will be reported to the IRB within 5 working days, and 
enrollment will be suspended until each case is evaluated for causality. If only limited details 
are known, these should be reported within that time frame and follow up reports can be 
submitted for elaboration, clarifications, or corrections.  Any email correspondence must be 
kept in the trial file at the study site. The site investigator is responsible for informing the 
IRB and/or the Regulatory Authority of the SAE as per local requirements.   
Follow-up information will be submitted to the IRB stating that this is a follow-up to a 
previously reported SAE and giving the date of the original report. Each re-occurrence, 
complication, or progression of the original event should be reported as a follow-up to that 
event regardless of when it occurs. The follow-up information should describe whether the 
event has resolved or continues, if and how it was treated, and whether the participant 
continued or withdrew from study participation. 
12. STATISTICAL METHODS 
The sections below provide an overview of the statistical considerations and analyses. 
12.1 
Data collection and management plan  
Data will be collected using a CRF managed by the Oncology Clinical Pharmacy Specialists 
under the supervision of the PI. Information collected from the CRF will be entered into a 
secure, encrypted, password protected that only the PI and co-investigators have. Regulatory 
specialists and managers will be involved with the protocol once IRB application is 
submitted and while the protocol remains open with the IRB.  
12.2 
Sample Size Justification 
This is a prospective single group study to determine the duration of neutropenia after 
consolidation chemotherapy with HiDAC 123. A historical control group will be selected by 
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2/1/2019 by propensity matching factors: age (+/- 3 years), gender (male or female), 
Karnofsky PS (90-100/70-80/50-60), and number of HiDAC cycles. The hypothesis is that 
patients with HiDAC123 treatment schema have a shorter duration of neutropenia after 
consolidation chemotherapy, compared to matched historical controls who received HiDAC 
135.  Group sample sizes of 23 subjects from a prospective cohort and 23 subjects from 
historical baseline group will achieve 81% statistical power to reject the null hypothesis of 
equal means when the population mean difference in neutropenia duration is three days (16 
vs. 19 days) with a standard deviation for both groups of four days and statistical significance 
level (alpha) of 0.05 using a one-sided, two sample, equal-variance t-test. Including 20% 
drop out rate, we will accrue 29 subjects per cohort. 
12.3 
Analysis of Primary Endpoint 
When the required assumptions are met, duration of neutropenia will be analyzed by a one-
sided, two sample, equal-variance t-test.  If the normal distribution and equal variance are 
not validated, the corresponding non-parametric method will be used. Primary analysis will 
be for cycle 1 of consolidation only. Other cycles will be recorded and use descriptive 
statistics.  Further, multivariable linear regression model of the neutropenia in days with 
group as the primary independent variable of interest will be fitted, while adjusting for some 
potential confounding variables, including AML type (WHO and FAB), documented infection 
in consolidation #1 (yes or no), ELN risk category (favorable, intermediate, high) and MRD 
positivity (yes or no), WBC at diagnosis (<50,000 or > 50,000), delay between induction 
course and consolidation #1 (less than or more than 40 days), allogeneic HCT (yes or no). 
12.4 
Analysis of Secondary Endpoints 
All secondary endpoints will be summarized by descriptive statistics.  Group comparisons 
will be carried out using appropriate statistical tests in an exploratory fashion.  
12.5 
Analysis of Exploratory Endpoints 
Exploratory endpoints will be descriptive.   
12.6 
Analysis of Safety Data 
Safety data will be descriptive as we expect a low number of non-hematologic adverse 
effects. Hematologic adverse effects and associated infections are common with this regimen 
in standard practice, including hospitalizations. We do not expect any additional adverse 
effects with the change in this schedule.       
12.7 
Interim Analysis and Stopping Rules 
No interim analysis for efficacy will be planned. However, the study will be monitored and 
stopped following statistical rules.  Sequential boundaries will be used to monitor 
neurological dose-limiting toxicities (DLT) (Grade 3-5) rate. The accrual will be halted if 


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excessive numbers of DLTs are seen, that is, if the number of DLT is equal to or exceeds the 
Boundary (bn) out of the accrued subjects (n) with full follow-up (see table 12.7.1). This is a 
Pocock-type stopping boundary that yields the probability of crossing the boundary at most 
5% when the rate of DLT is equal to the acceptable rate 10%.  This boundary is equivalent 
to testing the null hypothesis, after each subject, that the event rate is equal to 10%, using a 
one-sided level 0.01 test. 
Table 12.7.1  
The trial will be stopped if the number of neurological DLT (grade 3-5) is equal to or exceeds 
the Boundary (bn) out of the total Number of Subjects (n) participating in the trial with 
completed follow-up.  
Number of subjects (n) 
1 
2 
3-6 
7-10 
11-16 
17-21 
22-28 
29 
30 
Boundary (bn) 
- 
2 
3 
4 
5 
6 
7 
8 
- 
12.8 
Data Integrity and Safety Committee 
This protocol will be reviewed and monitored by the University of Florida Health Cancer 
Center Data Integrity and Safety Committee (UFHCC DISC) in accordance with their policies 
and procedures.  They will review and monitor study progress, toxicity, safety and other data 
from this trial. Questions about subject safety or protocol performance will be addressed 
with the sponsor-investigator, statistician and study team members. Should any major 
concerns arise, the DISC will offer recommendations regarding whether or not to suspend 
the trial. 
UFHCC DISC data and safety monitoring activities include:  
• Review of clinical trial conducted for progress and safety  
• Review of all adverse events requiring expedited reporting as defined in the protocol  
• Review of reports generated by data quality control review process  
• Notification of the sponsor-investigator of recommended action  
• Notification of sites coordinated by the UFHCC of adverse events requiring expedited 
reporting and subsequent committee recommendations for study modifications 
In compliance with the UFHCC data and safety monitoring plan, the PI will provide a Data 
Integrity and Safety Committee Report to DISC at the predetermined timelines for the level 
of risk category assigned during the initial SRMC (Scientific Review and Monitoring 
Committee) review, which occurs prior to initial IRB approval. 
UFHCC investigator-initiated protocols will be classified into one of the following categories 


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of risk by the SRMC (see SRMC manual for further details): 
 
Level 1 – Low risk Investigator Initiated interventional trials.  
Level 2 – Moderate risk Investigator Initiated or externally sponsored interventional 
(such as drug, biologic or device) trials using FDA approved or commercially available 
compounds or interventions. 
Level 3 –  High risk Investigator Initiated or externally sponsored interventional 
trials (such as investigator-sponsored INDs, Phase I trials, studies requiring biosafety 
approval, or other areas that may be designated by NIH as high risk). 
Level 4 – Complex trials involving very high risk to subjects and a high level of 
complexity such as first in human or gene transfer studies.  
The risk level assigned by SRMC will determine the appropriate level of DISC monitoring 
required, with increased monitoring required for higher-risk trials.  
Findings will be communicated to all study sites by UFHCC CRO. 
12.9 
Data Monitoring 
UFHCC (University of Florida Health Cancer Center) Quality Assurance team and/or project 
management officers will perform remote monitoring and may make monitoring visits to the 
trial sites periodically during the trial to confirm that all sites are complying with the 
protocol. Source documents will be reviewed for completion and validated against data 
submitted electronically via Electronic Data Capture. The site investigator/institution 
guarantee access to source documents by UFHCC or its designee and appropriate regulatory 
agencies.  As part of the responsibilities assumed by conducting this study, the Principal 
Investigator (PI) agrees to maintain and have available for monitoring adequate case records 
(accurate source documents and CRFs) for the subjects treated under this protocol. 
The trial site may also be subject to quality assurance audit by any collaborating sponsors or 
their designee as well as inspection by appropriate regulatory agencies.  
It is important for the site investigator and their relevant personnel to be available during 
the monitoring visits and possible audits and for sufficient time to be devoted to the process. 
12.10 Principal Investigator Responsibilities 
Per UF IRB requirements, the PI is personally responsible for conducting and supervising the 
conduct of human research subjects by “protecting the rights, safety, and welfare of subjects 
under the investigator’s care.” The PI also must ensure that all the research conducted is 
done so in an ethical manner and in accordance with all federal, state, and local laws and 
regulations, institutional policies, and the requirements of the IRB. 


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Oversight is defined as “management by overseeing the performance or operation of a 
person or group; watchful care, superintendence, general supervision”. Any person serving 
as a PI has voluntarily accepted these responsibilities and is expected to fully comply with 
these requirements, as outlined in the UFHCC Guidance: Principal Investigator 
Responsibilities and Oversight. 
The PI will be primarily responsible for continuous monitoring of adverse events, protocol 
violations, and other immediate protocol issues. The study coordinator will collect 
information on subjects enrolled through the use of electronic or paper adverse event (AE) 
forms, CRFs, and Informed Consent forms.  
13. EMERGENCY PROCEDURES 
13.1 
Emergency Contact 
In emergency situations, the treating physician should contact the Principal Investigator by 
telephone at the number listed on the title page of the protocol. 
13.2 
Emergency Treatment 
During and following a subject’s participation in the study, the treating physician and/or 
institution should ensure that adequate medical care is provided to a subject for any adverse 
events, including clinically significant laboratory values, related to the study. 
14. ADMINISTRATIVE, ETHICAL, AND REGULATORY CONSIDERATIONS 
14.1 
Good Clinical Practice 
The procedures set out in this study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that the Principal Investigator and Co-
Investigators abide by Good Clinical Practice (GCP), as described in International Conference 
on Harmonization (ICH) Guideline E6 and in accordance with the general ethical principles 
outlined in the Declaration of Helsinki.  
The study will be conducted in compliance with the protocol. The protocol, any amendments, 
and the subject informed consent will receive Institutional Review Board (IRB) approval 
before initiation of the study.  
The Principal Investigator will conduct all aspects of this study in accordance with applicable 
national, state, and local laws of the pertinent regulatory authorities. 


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All potential serious breaches must be reported immediately to the UFHCC Project 
Management Office (PMO, pmo@cancer.ufl.edu, who will then report the breach to UFHCC 
DISC) and the IRB of record, if applicable. A serious breach is a breach of the conditions and 
principles of GCP in connection with the study or the protocol, which is likely to affect, to a 
significant degree, the safety or physical or mental integrity of the subjects of the study or 
the scientific value of the study. 
14.2 
Institutional Review Board 
Before study initiation, the investigator must have written and dated approval from the IRB 
for the protocol, consent form, subject recruitment materials/process (e.g., advertisements), 
and any other written information to be provided to subjects. The investigator should also 
provide the IRB with a copy of the Investigator Brochure or product labeling, information to 
be provided to subjects, and any updates. The investigator should provide the IRB with 
reports, updates, and other information (e.g., amendments, and administrative letters) 
according to regulatory requirements or institution procedures. 
14.3 
Compliance with Laws and Regulations 
It is intended that the proposed study be conducted according to the International 
Conference on Harmonization E6 Guideline for Good Clinical Practice (GCP) and the 
Declaration of Helsinki.   
Please refer to the International Conference on Harmonization and GCP:  
http://www.fda.gov/oc/gcp/guidance.html; Declaration of Helsinki:   
http://www.fda.gov/oc/health/helsinki89.html; Code of Federal Regulations, Title 
21: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch. cfm]  
All UF Health Cancer Center investigator-initiated trials, meeting the criteria of the FDAAA’s 
applicable clinical trials, will be registered with ClinicalTrials.gov by the Project Management 
Officer (PMO) or assigned designee.  All studies must be registered prior to enrollment of the 
first participant.  The Project Management Officer or assigned designee will maintain the 
responsibility of updating trials registered with ClinicalTrials.gov.  Per FDA requirement, 
information must be updated at least every twelve months and the registry must be updated 
within thirty days of any changes in recruitment status or completion of the study. The PMO 
will determine if registration and updates to the NCI CTRP are required. 
14.4 
Delegation of Investigator Responsibilities 
The Principal Investigator will ensure that all persons assisting with the study are 
adequately informed about the protocol, any amendments to the protocol, the study 
treatments, and their study-related duties and functions. The Principal Investigator will 
maintain a list of Co-Investigators and other appropriately qualified persons to whom he has 
delegated significant study-related duties.  


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Study personnel involved in conducting this study will be qualified by education, training, 
and experience to perform their respective tasks. This study will not use the services of study 
personnel where sanctions have been invoked or where there has been scientific misconduct 
or fraud (e.g., loss of medical licensure; debarment). Systems with procedures that ensure 
the quality of every aspect of the study will be implemented. 
14.5 
Subject Information and Informed Consent 
Before being enrolled in this clinical trial, the subject must consent to participate after the 
nature, scope, and possible consequences of the clinical study have been explained in a form 
understandable to him or her. An informed consent document that includes both information 
about the study and the consent form will be prepared and given to the subject. This 
document will contain all ICH, GCP, and locally required regulatory elements. The document 
must be in a language understandable to the subject and must specify the person who 
obtained informed consent. 
After reading the informed consent document, the subject must give consent in writing. The 
written informed consent will be obtained prior to conducting any study-related procedures 
or tests. The subject’s consent must be confirmed at the time of consent by the personally 
dated signature of the person conducting the informed consent discussions and a copy of the 
consent form (preferably signed) must be given to the subject for their records.  
The PI will retain the original signed consent document. The PI will not undertake any 
measures specifically required only for the clinical study until valid consent has been 
obtained. 
14.6 
Confidentiality 
All records identifying the subject will be kept confidential and, to the extent permitted by 
the applicable laws and/or regulations, will not be made publicly available. 
Should direct access to medical records require a waiver or authorization separate from the 
subject’s statement of informed consent, it is the responsibility of the Investigator to obtain 
such permission in writing from the appropriate individual.   
Subjects will be told that the IRB, UF Health DISC, or regulatory authorities may inspect their 
medical records to verify the information collected, and that all personal information made 
available for inspection will be handled in strictest confidence and in accordance with local 
data protection law. 
14.7 
Protocol Amendments 
Once the study has started, amendments should be made only in exceptional cases.  Protocol 
amendments will not be implemented without prior written IRB approval. All amendments 


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will be submitted to the IRB and SRMC (as applicable), and written verification that the 
amendment was submitted and subsequently approved is to be obtained, and notification 
will sent out to the applicable study teams, prior to implementing the amendment.   
On an emergency-basis, to eliminate an immediate safety hazard to a subject, a protocol 
deviation may be implemented immediately, provided the IRB and UFHCC CRO PMO 
(pmo@cancer.ufl.edu) are notified within 5 business days with a full justification and 
description of the event.    
14.8 
Case Report Forms 
The Principal Investigator and/or his/her designee, will prepare and maintain adequate and 
accurate participant case histories with observations and data pertinent to the study.  Study 
specific Case Report Forms (CRFs) will document protocol-required outcomes for safety 
monitoring and data analysis.  All study data will be entered electronically in an Electronic 
Data Capture system in accordance with the protocol schedule of events and guidelines 
developed in the Data Management Plan for the study, using a secure access account.   
All protocol data is the sole property of UFHCC and should not be made available in any form 
to third parties, except for authorized representatives of appropriate Health/Regulatory 
Authorities, without written permission from UFHCC. 
14.9 
Record Retention 
Study documentation includes all eCRFs, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory 
documents (e.g., protocol and amendments, IRB correspondence and approval, signed 
subject consent forms). 
Source documents include all recordings of observations or notations of clinical activities 
and all reports and records necessary for the evaluation and reconstruction of the clinical 
research study. 
Government agency regulations and directives require that all study documentation 
pertaining to the conduct of a clinical trial must be retained by the study investigator. In the 
case of a study with a drug seeking regulatory approval and marketing, these documents 
shall be retained for at least two years after the last approval of marketing application in an 
International Conference on Harmonization (ICH) region. In all other cases, study documents 
should be kept on file until three years after the completion and final study report of this 
investigational study. 
UF Health Cancer Center requires that all study documentation be maintained for at least 6 
years from the date of final study publication.  No study records may be destroyed without 


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prior authorization from UF. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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15. REFERENCES 
1. Jaramillo S, Benner A, Krauter J, Martin H, Kindler T, Bentz M, et al. Condensed versus 
standard schedule of high-dose cytarabine consolidation therapy with pegfigrastim 
growth factor support in acute myeloid leukemia. Blood Cancer Journal 2017;7(e564): 
doi:10.1038/bcj.2017.45. 
2. Dumas P, Bertoli S, Berard E, Leguay T, Tavitian S, Galtier J, et al. Delivering HDAC over 3 
or 5 days as consolidation in AML impacts health care resource consumption but not 
outcome. Blood Advances 2020;4(16):3840-9. 
3. US Department of Health and Human Services/National Cancer Institute. Common 
Terminology Criteria for Adverse Events (CTCAE) version 5. November 27, 2017. 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html. Accessed 10/20/2018.  
4. Norkin M, Katragadda L, Zou F, Xiong S, Chang M, Dai Y, et al. Minimal residual disease by 
either flow cytometry or cytogenetics prior to an allogeneic hematopoietic stem cell 
transplant is associated with poor outcome in acute myeloid leukemia. Blood Cancer 
Journal  2017;7:634. 
5. Elsayed AH, Cao X, Crews KR, Ghandi V, Plunkett W, Rubnitz J. Comprehensive Ara-C SNP 
score predicts leukemic cell intracellular ara-CTP levels in pediatric acute myeloid 
leukemia patients. Pharmacogenomics 2018; 2018-0086; epub ahead of print. ISSN1462-
2416. 
6. National Cancer Institute. Cancer Stat Facts: Leukemia- Acute Myeloid Leukemia (AML) 
https://SEER.cancer.gov/statfacts/html/amyl.html. Accessed on 11/05/18. 
7. Mayer RJ, Davis RB, Schiffer CA, Berg DT, Powell BL, Schulman P, et al. Intensive 
postremission chemotherapy in adults with acute myeloid leukemia. N Engl J Med 
1994;896-903. 
8. Sperr WG, Piribauer M, Wimazal F, Fonatsch C, Thalhammer-Scherrer R, et al. A novel 
effective and safe consolidation for patients over 60 years with acute myeloid leukemia: 
intermediate dose cytarabine (2x 1 g/m2 on Days 1, 3, and 5. Clin Cancer Research 2004; 
10: 3965-71 
9. National 
Comprehensive 
Cancer 
Network. Acute 
Myeloid 
Leukemia 
(Version 
3.2020).  https://www.nccn.org/professionals/physician_gls/pdf/AML.pdf.  Accessed 
September 20, 2020. 
10. Karanes C, Kopecky KJ, Head DR, Grever MR, Hynes HE, Kraut EH, et al. A phase III 
comparison of high dose ARA-C (HIDAC) versus HIDAC plus mitoxantrone in the 
treatment of first relapsed or refractory acute myeloid leukemia Southwest Oncology 
Group Study. Leuk Res 1999;23:787-94. 
11. Cao X, Mitra AK, Pounds S, et al: RRM1 and RRM2 pharmacogenetics: association with 
phenotypes 
in 
HapMap 
cell 
lines 
and 
acute 
myeloid 
leukemia 
patients. 
Pharmacogenomics 14:1449-66, 2013 
12. Lamba JK, Crews K, Pounds S, et al: Pharmacogenetics of deoxycytidine kinase: 
identification and characterization of novel genetic variants. J Pharmacol Exp Ther 
323:935-45, 2007. 


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13.  Mitra AK, Crews KR, Pounds S, et al: Genetic variants in cytosolic 5'-nucleotidase II are 
associated with its expression and cytarabine sensitivity in HapMap cell lines and in 
patients with acute myeloid leukemia. J Pharmacol Exp Ther 339:9-23, 2011. 
14. Cytarabine 
injection 
product 
information. 
Hospira, 
Inc. 
Lake 
Forest 
IL. 
http://labeling.pfizer.com/ShowLabeling.aspx?id=4400 Accessed 11/13/2018.  
15.  Bradley AM, Deal AM, Buie LW, van Deventer H. Neutropenia-associated outcomes in 
adults with acute myeloid leukemia receiving cytarabine consolidation chemotherapy 
with 
or 
without 
granulocyte 
colony-stimulating 
factor. 
Pharmacotherapy 
2012;32(12):1070-7. 
16.  Sierra J, Szer J, Kassis J, Herrmann R, Lazzarino M, Thomas X, et al A single dose of 
pegfilgrastim compared with daily filgrastim for supporting neutrophil recovery in 
patients treated for low-to-intermediate risk acute myeloid leukemia: results from a 
randomized, double-blind, phase 2 trial. BMC Cancer 2008;8:195-205. 
17.  National Comprehensive Cancer Network. Hematopoietic Growth Factors (Version 
2.2020). https://www.nccn.org/professionals/physician_gls/pdf/growthfactors.pdf.  
Accessed September 20, 2020. 
18. National Comprehensive Cancer Network. Prevention and Treatment of Cancer-Related 
Infections. (Version 2.2020). 
https://www.nccn.org/professionals/physician_gls/pdf/infections.pdf. Accessed 
September 20, 2020. 
19. Fopp M, Fey MF, Bacchi M, Cavalli F, Gmuer J, Jacky E et al. Post-remission therapy of adult 
acute myeloid leukaemia: one cycle of high-dose versus standard-dose cytarabine.  Ann 
of Oncol 1997;8:251-7. 
20.  National 
Healthcare 
Safety 
Network. 
Bloodstream 
Infection 
Event 
http://www.cdc.gov/nhsn/PDFs/pscManual/4PSC_CLABScurrent.pdf 
 
Accessed 
September 21, 2020. 
21.  Kalil AC, Metersky ML, Klompas M, et al. Management of adults with hospital-acquired 
and ventilator-associated pneumonia: 2016 Clinical Practice Guidelines by the Infectious 
Diseases Society of America and the American Thoracic Society. Clin Infect Dis 2016 Sep 
1;63(5):e61- e111. 
22.  Ljungman P, Boeckh M, Hirsch HH, et al. Definitions of cytomegalovirus infection and 
disease in transplant patients for use in clinical trials. Clin Infect Dis 2016;64:87-91. 
23.  Seo S, Campbell AP, Kuypers JM, et al. Parainfluenza virus lower respiratory tract disease 
after hematopoietic cell transplant: viral detection in the lung predicts outcome. Clin 
Infect Dis 2014;58:1357-68. 
24. De Pauw B, Walsh TJ, Donnelly JP, et al; European Organization for Research and 
Treatment of Cancer/Invasive Fungal Infections Cooperative Group; National Institute of 
Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. 
Revised definitions of invasive fungal disease from the European Organization for 
Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and 
the National Institute of Allergy and Infectious Diseases Mycoses Study Group 
(EORTC/MSG) Consensus Group. Clin Infect Dis 2008;46:1813-21. 
25.  Stuart H, Cohen MD, Dale N, et al. Practice guidelines for C. difficile infection in adults. 


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Infect Control Hosp Epidemiol 2010; 31:431-55. 
26.  Nesher L, Rolston KV. Neutropenic enterocolitis, a growing concern in the era of 
widespread use of aggressive chemotherapy. Clin Infect Dis 2013;56:711-7. 
27.  Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of 
antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious 
Diseases Society of America. Clin Infect Dis 2011;52:e56–e93. 
28.  Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus 
Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016;315:801-10. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16. APPENDICES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix A: Infection Definitions  
Type of Infection 
Clinical/Radiographic 
Criteria 
Laboratory/Microbiological 
Major Infections 
Primary Blood BSI 20 
 
Organism(s) identified in 
blood is not related to an 
infection at another site 
• Pathogen cultured from ≥ 1 
blood cultures  
• Cultured organism(s) are 
other than common skin 
contaminants  
Primary BSI with 
Skin Colonizers20 
• Patient has at least one of 
the following signs or 
symptoms: fever (> 
38.0°C), chills, or 
hypotension AND  
• Organism(s) identified 
from blood is not related 
to an infection at another 
site  
AND  
• The same common 
commensal (i.e., 
diphtheroids 
[Corynebacterium spp. not 
C. diphtheriae], Bacillus 
spp. [not B. anthracis], 
Propionibacterium spp., 
coagulase-negative 
staphylococci [including S. 
epidermidis], viridans 
group streptococci, 
Aerococcus spp., and 
Micrococcus spp.) is 
identified 
• ≥ 2 blood specimens drawn 
on separate occasions 
(collected on the same or 
consecutive calendar days)  
• Collected in a manner which 
suggests that 2 separate 
blood draw site preparations 
were performed (e.g., 
different venipunctures, a 
combination of venipuncture 
and lumen withdrawal, or 
different lumens of the same 
central line) 
Pneumonia21 
All of the following criteria 
are met:  
• Chest imaging (either 
chest X-ray or computed 
tomography scan) 
consistent with 
pneumonia; AND  
• The presence of the clinical 
pneumonia syndrome in 
conjunction with the 
isolation of a probable 
pulmonary pathogen from 
the blood, sputum, BAL fluid, 
or lung tissue. 


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Type of Infection 
Clinical/Radiographic 
Criteria 
Laboratory/Microbiological 
• No evidence of pulmonary 
edema based on 
echocardiographic and 
pulmonary artery catheter 
data, fluid balance, and 
radiographic response to 
diuresis; AND  
• Temperature greater than 
38°C*, OR dyspnea, OR 
cough with purulent 
sputum  
 
*Fever may be absent in a 
minority of patients and some 
may even be hypothermic. 
• Coagulase-negative 
Staphylococcus and Candida 
species will be excluded 
unless there is biopsy-proven 
invasion or concomitant 
isolation of the organism in 
respiratory secretions and 
blood in the absence of a 
more likely pulmonary 
pathogen.  
• A virus will be considered a 
pathogen if it is detected by 
antibody or culture or 
polymerase chain reaction 
from respiratory secretions 
in the absence of a more 
likely etiologic agent 
CMV Pneumonia 
(Proven)20 
• Clinical symptoms and/or 
signs of pneumonia such 
as new infiltrates on 
imaging, hypoxia, 
tachypnea, and/or 
dyspnea  
AND  
• CMV documentation in 
lung tissue 
CMV documented in lung tissue 
by virus isolation, rapid culture, 
histopathology, 
immunohistochemistry, or DNA 
hybridization techniques 
CMV Pneumonia 
(Probable)22 
• Clinical symptoms and/or 
signs of pneumonia  
AND  
• Detection of CMV 
CMV by viral isolation, rapid 
culture of BAL fluid, or the 
quantitation of CMV DNA in BAL 
fluid. A definite cut-off for CMV 
DNA load is not established 
Proven Lower RVI23 
New pulmonary infiltrates per 
CT chest or chest X-ray with 
or without lower respiratory 
tract symptoms 
Respiratory virus detected with 
BAL or biopsy specimen by 
multiplex-PCR 
Probable Lower 
RVI23 
No new pulmonary infiltrates 
per CT chest or chest X-ray 
with lower respiratory tract 
symptoms, with or without 
pulmonary function decline 
Respiratory virus detected in 
BAL or lung biopsy sample by 
multiplex-PCR 


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Type of Infection 
Clinical/Radiographic 
Criteria 
Laboratory/Microbiological 
Proven IFI24 
Only laboratory/ 
microbiological 
criteria 
Microscopic analysis  
Mold: Histopathologic, 
cytopathologic, or direct 
microscopic examination of a 
specimen obtained by needle 
aspiration or biopsy in which 
hyphae or melanized yeast-
like forms are seen 
accompanied by evidence of 
associated tissue damage  
Yeast: Histopathologic, 
cytopathologic, or direct 
microscopic examination of a 
specimen obtained by needle 
aspiration or biopsy from a 
normally sterile site (other 
than mucous membranes) 
showing yeast cells—for 
example, Cryptococcus spp. 
indicated by encapsulated 
budding yeasts or Candida 
spp. showing pseudohyphae 
or true hyphae 
Culture (sterile material)  
Mold: Recovery of a mold or 
“black yeast” by culture of a 
specimen obtained by a 
sterile procedure from a 
normally sterile and clinically 
or radiologically abnormal 
site consistent with an 
infectious disease process, 
excluding BAL fluid, a cranial 
sinus cavity specimen, and 
urine  
• Blood culture that yields a 
mold (e.g., Fusarium species) 
in the context of a compatible 
infectious disease process  
• Blood culture that yields 
yeast (e.g., Cryptococcus or 
Candida spp.) or yeast like 
fungi (e.g., Trichosporon 
species)  
• Cryptococcal antigen in CSF 
indicates disseminated 
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Type of Infection 
Clinical/Radiographic 
Criteria 
Laboratory/Microbiological 
Yeast: Recovery of a yeast by 
culture of a sample obtained 
by a sterile procedure 
(including a freshly placed 
[<24 h ago] drain) from a 
normally sterile site showing 
a clinical or radiological 
abnormality consistent with 
an infectious disease process 
Probable IFI24 
Subjects MUST have 
one each (at a 
minimum) of host, 
clinical, and 
microbiologic criteria 
Host criteria:  
• Recent history of 
neutropenia (< 500 
cells/mm3 for > 10 days) 
temporally related to 
onset of fungal disease; 
OR 
• Received an allogeneic 
HSCT; OR  
• Corticosteroid use for > 3 
weeks (average dose 0.3 
mg/kg/d prednisone 
equivalent); OR  
• Treatment with T-cell 
immune suppressants 
(e.g., cyclosporine, TNFα 
blocker, specific 
monoclonal antibodies or 
nucleoside analogues) 
within the last 90 days; 
OR  
• Inherited severe 
immunodeficiency; 
Clinical criteria:  
• Lower respiratory 
tract fungal disease (1 
of 3 on CT scan):  
o Dense, well 
circumscribed 
lesion(s) with 
or without a 
halo sign; OR  
Microbiologic criteria  
• Mold in sputum, BAL fluid, 
bronchial brush, or sinus 
aspirate samples, indicated 
by 1 of either presence of 
fungal elements indicating a 
mold or recovery of a mold 
by culture (e.g., Aspergillus, 
Fusarium, Zygomycetes, or 
Scedosporium spp.); OR 
• Positive evidence of GM in 
serum, BAL or CSF; OR  
• Positive evidence of β-D-
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Type of Infection 
Clinical/Radiographic 
Criteria 
Laboratory/Microbiological 
o Air-crescent 
sign; OR 
o Cavity;  
OR 
• Tracheobronchitis 
(mark the finding(s) 
per bronchoscopic 
evaluation)  
o Tracheobronchi
al ulceration; 
OR  
o Nodule; OR  
o Pseudo-
membrane; OR  
o Plaque or 
eschar;  
OR  
• Sinonasal Infection 
(imaging showing 
sinusitis plus 1 of the 
following 3 signs):  
o Acute localized 
pain (including 
pain radiating 
to the eye); OR 
o Nasal ulcer with 
black eschar; 
OR  
o Extension of the 
paranasal sinus 
process across 
bony barriers; 
OR  
• CNS Infection (1 of the 
following): 
o Focal lesions on 
imaging; OR  
o Meningeal 
enhancement on 
MRI or CT;  


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Type of Infection 
Clinical/Radiographic 
Criteria 
Laboratory/Microbiological 
OR  
• Disseminated candidiasis 
(at least 1of the followings 
after an episode of 
candidemia within the 
previous 2 weeks):  
o Small target-like 
abscesses (bull’s 
eye lesions) in liver 
or spleen; OR 
o Progressive retinal 
exudates on 
ophthalmologic 
examination 
Clostridium difficile 
infection (CDI)25 
Diagnosis will be if 
the clinical criterion is 
met AND there is 
microbiological 
confirmation 
Presence of at least 3 
unformed bowel movements 
in a 24-hour period or fewer 
consecutive hours 
• A stool test result positive for 
the presence of toxigenic C. 
difficile or its toxins or 
colonoscopic OR 
histopathologic findings 
demonstrating 
pseudomembranous colitis  
• Patients presenting with 
ileus or megacolon will need 
a perianal specimen test 
positive for C. difficile or its 
toxins 
Typhilitis26 
Diagnosis will be if 
the clinical criteria 
are met AND there is 
microbiological 
confirmation 
• Patients with fever > 
38.3°C) * or > 38°C 
sustained for 1 hour, 
neutropenia and 
abdominal signs such as 
abdominal cramping, 
abdominal pain (> 3 on 
VAS), abdominal 
distention, diarrhea, GI 
bleeding AND  
• Exclusion of other 
diagnoses such as C. 
difficile associated colitis 
or other biopsy proven 
diagnosis  
• ANC ≤ 500/mm3 AND  
• Bowel wall thickening on CT 
exam or US exam > 4 mm 
(transverse scan) thickening 
in any segment of the bowel 
for at least 30 mm length 
(longitudinal scan) 


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Type of Infection 
Clinical/Radiographic 
Criteria 
Laboratory/Microbiological 
*Fever may be absent in a 
minority of patients and some 
may even be hypothermic.  
Other Infections 
Febrile 
Neutropenia27   
Both clinical and 
laboratory criteria 
should be met 
• A single oral temperature 
of > 38.3°C (101°F) OR  
• A temperature of > 38.0°C 
(100.4°F) sustained for > 1 
hour 
• ANC < 500 cells/mm3 OR  
• ANC that is expected to 
decrease to < 500 cells/mm3 
during the next 48 hours 
Upper RVI23 
• No new pulmonary 
infiltrates per CT chest or 
chest X-ray 
• Symptoms of upper 
respiratory tract infection 
Respiratory virus detected in a 
nasopharyngeal swab or sputum 
by multiplex-PCR 
Possible Lower 
RVI23 
New pulmonary infiltrates per 
CT chest or chest X-ray (but 
without confirmation of 
respiratory virus in the lower 
respiratory tract) with or 
without LRTD signs or 
symptoms (e.g., cough, 
wheezing, rales, tachypnea, 
shortness of breath, dyspnea, 
or hypoxia). 
Respiratory virus detected in a 
nasopharyngeal swab or sputum 
by multiplex-PCR 
Catheter-associated 
BSI for Non-skin 
common skin 
contaminants20  
BOTH clinical and 
microbiological 
criteria should be met 
• A CVC must be present at 
the time of the BSI or 
removed within the 48 
hours prior to onset, 
unless clinical evidence 
links the BSI to a catheter 
removed > 48 hours 
before onset (e.g., 
purulent 
thrombophlebitis) AND  
• Absence of other focus of 
infection as a source of the 
BSI 
Recognized pathogen cultured 
(other than skin contaminants) 
from one or more blood cultures, 
unrelated to infection at another 
site 
Septic Shock28 
• Any documented infection 
AND 
Lactate >2 mmol/L (>18 mg/dL) 


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Type of Infection 
Clinical/Radiographic 
Criteria 
Laboratory/Microbiological 
• Requirement of 
vasopressors and have a 
lactate >2 mmol/L (>18 
mg/dL) 
Catheter associated 
BSI for common skin 
contaminants20 (e.g. 
diphtheroids, Bacillus 
spp, 
Propionibacterium 
spp, coagulase 
negative 
staphylococci, and 
micrococci) BOTH 
clinical and 
microbiological 
criteria should be met 
At least one of the 
following:  
• Fever (> 38°C)  
• Chills 
• Hypotension 
• Signs of infection of 
catheter insertion site or 
tunnel 
• Organisms (diphtheroids, 
Bacillus spp., 
Propionibacterium spp., 
coagulase negative 
staphylococci, and 
micrococci) cultured from:  
o At least two separate 
blood draws collected 
on the same or 
consecutive calendar 
days, OR  
• Collected in a manner which 
suggests that 2 separate 
blood draw site preparations 
were performed (e.g., 
different venipunctures, a 
combination of venipuncture 
and lumen withdrawal, or 
different lumens of the same 
central line) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix B: UF Health Shands/BMT Program Blood Product Support Guidelines – Adult 
 
Product: 
 
Situation: 
Current BMT Program 
Recommendations: 
Platelet 
Leukemia – Routine 
≤ 10,000/µL 
No change for fevers 
Platelet 
• Bleeding – Not CNS 
• Prior to and post-invasive 
procedure (not CNS) 
>50,000/µL for LP 
Platelet 
• CNS bleeding 
• Prior to and post-invasive CNS 
procedure 
≤100,000/µL 
Platelet 
Subjects receiving therapeutic 
anticoagulation 
≤50,000/µL 
Red Cells 
Routine 
Hct ≤ 20% 
Red Cells 
Asymptomatic with history of 
cardiovascular disease 
Hct ≤ 25% 
Red Cells 
Symptomatic cardiovascular or 
pulmonary disease 
Hct 26-30% 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix C: European Leukemia Net (ELN) Guidelines 
 


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Appendix D: Protocol Version History / Summary of Changes 
Protocol 
Version  
Change History 
Date of Changes 
v1.0 
N/A – Original Protocol 
v1.1 
Protocol Signature Page 
• PI name and site information added. 
Exploratory Objectives 
• Monitoring time period after starting 
induction has been updated to match 
other areas of the protocol.  
4.3 Exclusion Criteria 
• Criteria (G) has been added to match 
the exclusion criteria listed under the 
Protocol Synopsis section.  
14-Sep-2021 
V2.0 
Protocol Synopsis 
• Inclusion criteria language added to 
(B), and a sub-paragraph regarding 
usage of non-site collected laboratory 
sample results added under criteria 
(C) 
4.2 Inclusion Criteria 
• Sub-paragraph below criteria (C) has 
been added to match Inclusion 
Criteria listed in Protocol Synopsis 
section 
• Minor language updates to criteria (B) 
6.1 Schedule of Events 
• Foot note 8 had language added 
•  New footnote (10) created and 
superscript placed on ‘Interval 
History/Physical Exam’ 
09-May-2022 
V3.0 
Protocol Schema 
• Updated subject pool to adults aged 
55 years and older 
Protocol Synopsis/Inclusion 
Criteria/Exclusion Criteria 
• Updated study recruitment criteria to 
adults aged 55 years and older 
6.1 Schedule of events 
08-February-2023 


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• Footnote #7: Amended language to 
avoid a scenario where subject is 
indefinitely followed for an Adverse 
Event 
Section 6.2 End of Treatment Evaluations 
• Clarified language regarding what 
defines End of Treatment date. 
• Defined hematologic recovery 
V4.0 
Protocol Synopsis / Rationale / Inclusion 
Criteria / Exclusion Criteria / Efficacy 
Assessment 
• Updated definition of ‘recovery’ to 
incomplete hematologic recovery  
• Updated transfusion language to 
match REDCap  
• Returned subject age inclusion criteria 
to >= 61 years of age 
Section 6.1 Schedule of Events 
• Created (+/- 14 days) window for End 
of Treatment visit 
• Added +/- to 28 day window in 
Follow-Up visits 
• Amended footnote 7 to adjust AE 
collection period 
• Amended footnote 8 to include 
relapsed disease 
Sections 6.2 End of Treatment Evaluations 
• Clarified EOT criteria to be met. 
• Added ‘Relapsed disease’  
• Clarified hematologic recovery 
defined as complete or incomplete 
• Added reference to Appendix C. ELN 
guideline 
Section 8.2 Criteria for Study Treatment 
Discontinuation 
• Clarified treatment discontinuation 
procedures for subjects in complete 
hematologic recovery 
Section 11.2 Period of Observation 
• Redefined Period of Observation SAE 
collection to go until 28 days after last 
06-April-2023 


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infusion or ‘subject starts new chemo 
therapy treatment’ (whichever comes 
first) 
Appendix C 
• Addition of new appendix for ELN 
Guideline