A Phase II Study of Myeloablative and Reduced-Intensity Conditioning Regimens for Children and Young Adults With Acute Myeloid Leukemia or Myelodysplastic Syndrome Undergoing Allogeneic Hematopoietic Stem Cell Transplantation
Phase: PHASE2
Conditions: Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS), Hematopoietic Stem Cell Transplant (HSCT)
Sponsor: Randy Windreich

MAC vs RIC Protocol v5.0, 09/03/2020 
 
 
Page 1 of 37 
 
 
 
 
 
A Phase II Study of Myeloablative and Reduced-Intensity Conditioning Regimens 
for Children and Young Adults with Acute Myeloid Leukemia or Myelodysplastic 
Syndrome Undergoing Allogeneic Hematopoietic Stem Cell Transplantation 
Version 1.1:  August 18, 2014 
Version 2.0:  August 27, 2018 
Version 3.0: February 6, 2018 
Version 4.0: June 07, 2019 
Version 5.0:  September 03, 2020 
 
 
 
 
 
 
 
Principal Investigator/Protocol Chair 
Randy Windreich, MD 
Division of Blood and Marrow Transplantation and Cellular Therapies 
UPMC Children’s Hospital of Pittsburgh  
4401 Penn Avenue, Plaza Building, 4th Floor 
Pittsburgh, PA 15224 
412-692-5225 
Randy.Windreich@chp.edu 
 
 
 
 
 
 
 
 
NCT02626715

MAC vs RIC Protocol v4.0, 09/03/2020 
 
 
 
Page 2 of 37 
 
Protocol Synopsis 
Protocol Title 
A Phase II Study of Myeloablative and Reduced-Intensity Conditioning Regimens for 
Children and Young Adults with Acute Myeloid Leukemia or Myelodysplastic Syndrome 
Undergoing Allogeneic Hematopoietic Stem Cell Transplantation 
Version/Date 
 Version 5.0:  September 03, 2020 
Clinical Phase 
Phase II 
Trial Site 
University of Pittsburgh Medical Center (UPMC) 
• 
UPMC Children's Hospital of Pittsburgh (CHP)  
Primary 
Investigator 
Randy Windreich, MD 
Primary Objective 
To determine the safety and preliminary efficacy of achieving acceptable rates of event-free 
survival at 6 months in pediatric patients receiving a myeloablative preparative regimen 
including Busulfan, Fludarabine and Thiotepa or a reduced-intensity preparative regimen 
including Alemtuzumab, Hydroxyurea, Fludarabine, Melphalan and Thiotepa prior to 
hematopoietic stem cell transplantation for high-risk acute myeloid leukemia and 
myelodysplastic syndrome. 
Secondary 
Objective 
• 
To describe the pace of neutrophil and platelet recovery. 
• 
To describe the incidence of acute GVHD (II-IV, III-IV) and chronic GVHD. 
• 
To determine the treatment-related mortality (TRM), overall survival (OS), and disease-
free survival (DFS) by Days 100 and 180 post-transplant. 
• 
To evaluate the pace of immune reconstitution. 
• 
To measure Day 0 alemtuzumab levels, if available, and correlate with rate of relapse, 
rate of viral infections, and pace of immune reconstitution. 
• 
To compare outcomes with historically-used “standard” conditioning regimen of 
busulfan and cyclophosphamide in terms of above objectives as well as short- and long-
term complications. 
Hypothesis  
We hypothesize that a myeloablative fludarabine/busulfan/thiotepa (FLU/BU/THIO) 
regimen, along with the addition of alemtuzumab for CD52-positive malignancies and 
mismatched grafts, provides improved overall survival and event-free survival rates in 
pediatric patients undergoing myeloablative transplants; the reduced-intensity regimen will 
be well-tolerated and allow pediatric patients with significant comorbidities that would 
otherwise preclude them from transplantation to receive a potentially life-saving allogeneic 
stem cell transplant; and, similar to its action on normal HSCs, pre-transplant G-CSF may 
disrupt the interaction of leukemic stem cells with the marrow microenvironment, thereby 
sensitizing these cells to genotoxic stresses. 
Study Design 
This is a single-center, prospective, non-randomized, dual-arm, phase II study evaluating the 
safety and efficacy of achieving acceptable rates of event-free survival in pediatric patients 
receiving either a myeloablative conditioning (MAC) regimen including Busulfan, 
Fludarabine and Thiotepa or a reduced-intensity conditioning (RIC) regimen including 
Alemtuzumab, Hydroxyurea, Fludarabine, Melphalan and Thiotepa prior to blood and 
marrow transplantation for high-risk acute myeloid leukemia or myelodysplastic syndrome.  

MAC vs RIC Protocol v4.0, 09/03/2020 
 
 
 
Page 3 of 37 
 
Planned Sample 
Size 
Expected accrual to this study is 3-4 patients per year based on the last 5 years’ average. 
We anticipate enrollment of 16 patients receiving stem cell transplant. Total accrual time 
could be as long as 4 years, or more, if the study is not stopped early. 
Duration of 
Treatment 
Subjects will be followed for one year post stem cell transplant, and data may be obtained 
from the subjects’ medical charts for an additional three years, post stem cell transplant. 
Inclusion Criteria: 
Study Entry 
Individuals must meet all the following criteria to be eligible for this study. 
• 
Subject, parent, or legal guardian, if applicable, must have given written informed 
consent. For patients ≤ 17 years of age who are developmentally able, assent or 
affirmation will be obtained.  
• 
Age 0-26, inclusive, at time of consent. 
• 
Diagnosis of myelodysplastic syndrome or acute myeloid leukemia, either high-risk 
(defined below), relapsed or primary refractory, MRD-positive without circulating 
myeloblasts or active extramedullary disease at the time of transplant. Active marrow 
disease is permitted. High-risk AML features are defined by the following:  RAM 
phenotype; adverse cytogenetic abnormalities of monosomy 5, monosomy 7, 5q 
deletion, or other unfavorable prognostic markers according to cytogenetics, FISH, or 
next generation sequencing (NGS); presence of FLT3 positive internal tandem 
duplication (FLT3/ITD+), particularly high allelic ratio; treatment-related AML; or 
positive minimal residual disease (MRD) at end of Induction I. 
• 
Stem cell sources include bone marrow, peripheral blood stem cells, or umbilical cord 
blood.  Related bone marrow, peripheral blood stem cell, or cord blood unit: sibling 
should be HLA-matched at A, B, and DR-B1 loci. Unrelated cord blood unit should be at 
a minimum of 4/6 matched at antigen level on HLA A and B, and allele level at HLA DR-
B1 loci. Unrelated bone marrow or peripheral blood stem cell donor should be HLA 
allele level matched at DR-B1.  
• 
Minimum pre-freezing cell dose for cord blood units: 3 x 10^7 total nucleated cells/kg 
and 1.5 x 10^5 CD34+ cells/kg. If this is not attainable, then double cord blood 
transplant should be considered.  
• 
Subject must have adequate performance status:  Lansky score ≥60% for patients <16 
years, Karnofsky score ≥60% for patients ≥16 years. 
• 
Subject must have adequate pre-transplant organ function to undergo one of the two 
conditioning regimens, either the myeloablative conditioning (MAC) OR reduced-
intensity conditioning (RIC) regimen.  If a subject does not meet the following organ 
function criteria for the MAC regimen, the RIC regimen will be considered if eligibility 
criteria is met. The RIC regimen may also be considered, regardless of MAC eligibility, if 
deemed appropriate by the Principal Investigator and/or treating physician.  
Pre-transplant organ function criteria for Myeloablative Conditioning regimen: 
o 
Renal: creatinine clearance or radioisotope GFR ≥70 mL/min/1.73 m2. 
o 
Hepatic: total bilirubin ≤2.0 mg/dL unless the increase in bilirubin is 
attributable to Gilbert’s syndrome; and SGOT (AST), SGPT (ALT), and Alkaline 
Phosphatase <4 x upper limit of normal (ULN) for age. 
o 
Cardiac: normal cardiac function by echocardiogram or radionuclide scan, as 
defined by left ventricular ejection fraction at rest >45% or shortening fraction 
>26%. 
o 
Pulmonary: FEV1, FVC, and DLCO (corrected for hemoglobin) ≥50% of 
predicted; if unable to perform pulmonary function tests, then oxygen 
saturation ≥92% on room air. 
OR 
Pre-transplant organ function criteria for Reduced-Intensity Conditioning regimen: 
o 
Renal: creatinine clearance or radioisotope GFR ≥70 mL/min/1.73 m2. 

MAC vs RIC Protocol v4.0, 09/03/2020 
 
 
 
Page 4 of 37 
 
o 
Hepatic: total bilirubin ≤2.5 mg/dL unless the increase in bilirubin is 
attributable to Gilbert’s syndrome; and SGOT (AST), SGPT (ALT), and Alkaline 
Phosphatase <5 x upper limit of normal (ULN) for age. 
o 
Cardiac: normal cardiac function by echocardiogram or radionuclide scan, as 
defined by left ventricular ejection fraction at rest >40% or shortening fraction 
>26%. 
o 
Pulmonary: FEV1, FVC, and DLCO (corrected for hemoglobin) ≥40% of 
predicted; if unable to perform pulmonary function tests, then oxygen 
saturation ≥92% on room air. 
 
• 
HIV and HTLV negative, by either PCR or serology. 
• 
Negative pregnancy test for females ≥10 years old or who have reached menarche. 
• 
All females of childbearing potential and sexually active males must agree to use an 
FDA approved method of birth control for up to 12 months after HSCT or for as long as 
they are taking any medication that may harm a pregnancy, an unborn child or may 
cause a birth defect. 
Exclusion Criteria: 
Study Entry 
Individuals who meet any of the following criteria are not eligible for this protocol. 
• 
Uncontrolled bacterial, viral, fungal, or other infection at the time of cytoreduction, 
defined by positive blood cultures and/or fevers >38.0 within 24 hours of start of 
conditioning therapy. 
• 
Females who are pregnant or who are lactating. 
• 
Past or current medical problems or findings from physical examination or laboratory 
testing that are not listed above, which, in the opinion of the investigator, may pose 
additional risks from participation in the study, may interfere with the participant’s 
ability to comply with study requirements or that may impact the quality or 
interpretation of the data obtained from the study. 
Additional Exclusion Criteria for Myeloablative Conditioning (MAC) Only 
Individuals who meet any of the following criteria are not eligible for the MAC regimen. 
• 
Recipient of either an autologous or allogeneic stem cell transplant within 3 months of 
the start of conditioning.  
• 
Patients with any inherited bone marrow failure syndrome including, but not limited 
to, Fanconi anemia, Shwachman-Diamond syndrome, dyskeratosis congenital or Down 
syndrome (defined as either constitutional trisomy 21 or constitutional mosaicism of 
trisomy 21). 
Efficacy Endpoint 
• 
Absence of leukemia or dysplasia at 6 months post-HSCT and beyond. 
• 
Achievement of full donor chimerism. 
 

MAC vs RIC Protocol v4.0, 09/03/2020 
 
 
 
Page 21 of 37 
 
• 
To measure Day 0 Alemtuzumab levels, if available, and correlate with rate of relapse, rate of viral 
infections, and pace of immune reconstitution. 
• 
To compare the outcomes with historically-used “standard” conditioning regimen of Busulfan and 
Cyclophosphamide in terms of above objectives as well as short- and long-term complications. 
 
Efficacy Endpoints 
• 
Absence of leukemia or dysplasia at 6 months post-HSCT and beyond. 
• 
Achievement of full donor chimerism. 
2.5 
STATISTICAL ANALYSIS 
 
Sample Size Determination 
Expected accrual to this study is 3-4 patients per year based on the last 5 years’ average. We anticipate 
enrollment of 16 patients receiving stem cell transplant. Total accrual time could be as long as 4 years, or more, 
if the study is not stopped early.  
 
Efficacy Analysis 
The study sample for efficacy will be patients who receive HSCT (n=12). Efficacy will be defined by the following 
criteria: 
• 
Absence of leukemia or dysplasia at 6 months post-HSCT and beyond. 
• 
Achievement of full donor chimerism. 
Efficacy will be analyzed as a case series, with rates for key efficacy criteria reported with 95% Wilson (score) 
confidence intervals. For example, if 4/12 patients receiving HSCT are leukemia-free by 2-year milestone post-
HSCT, the rate of independence of absence of leukemia would be reported as 0.33 (95% CI 0.14-0.61). 
 
Safety Analysis 
All reported adverse events will be coded using the NCI common toxicity criteria. The number and percent of 
patients reporting adverse events will be quantified for each phase of therapy (HSCT, post-HSCT). 
 
Handling Missing Data 
Standard procedures will be used to ensure that data are as complete and accurate as possible. We will not 
impute values for subjects with missing data. 
 
Data Management  
Data will be generated from standard of care procedures, tests, etc. and will be available in the subjects’ medical 
records.   
3 
SUBJECT POPULATION AND CLINICAL SITES  
3.1 
Eligibility for Study Entry  
 
Inclusion Criteria