Clinical trial NCT02722668
Conditions: Acute Leukemia Acute Myeloid Leukemia Acute Lymphoblastic Leukemia/Lymphoma Burkitt's Lymphoma Natural Killer Cell Malignancies Chronic Myelogenous Leukemia Myelodysplastic Syndrome Large-cell Lymphoma Hodgkin Lymphoma Multiple Myeloma Relapsed Chronic Lymphocytic Leukemia Relapsed Small Lymphocytic Lymphoma Marginal Zone B-cell Lymphoma Follicular Lymphoma Lymphoplasmacytic Lymphoma Mantle-cell Lymphoma Prolymphocytic Leukemia Bone Marrow Failure Syndromes Myeloproliferative Neoplasms/Myelofibrosis Biphenotypic/Undifferentiated/Prolymphocytic Leukemias MRD Positive Leukemia Leukemia or MDS in Aplasia Relapsed T-Cell Lymphoma Relapsed Multiple Myeloma Plasma Cell Leukemia
Keywords: AML ALL CML CLL SLL
Sponsor: Masonic Cancer Center, University of Minnesota
Start date: 2017-05-15; Completion date: 2024-02-22
Enrollment: 15 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a phase II trial using a non-myeloablative cyclophosphamide/ fludarabine/total body irradiation (TBI) preparative regimen with modifications based on factors including diagnosis, disease status, and prior treatment. Single or double unit selected according to current University of Minnesota umbilical cord blood graft selection algorithm.

Detailed description:

Arms: arm 1: Hematologic malignancy patients who have received a previous autologous transplant or ≥ 2 cycles of multi-agent chemotherapy within the 3 months previous to umbilical cord blood transplantation. arm 2: Hematologic malignancy patients who have not been treated with prior autologous transplant or ≤ 1 cycle of chemotherapy in the 3 months previous to umbilical cord blood transplantation, should receive Anti-thymocyte Globulin (ATG) as part of their conditioning regimen.
Interventions: intervention 1: Fludarabine intervention 2: Cyclophosphamide intervention 3: MMF intervention 4: Sirolimus intervention 5: TBI intervention 6: Umbilical cord blood cell infusion intervention 7: ATG
Intervention descriptions: intervention 1: Both Arms: 30 mg/m\^2 IV over 1 hour Day -6 to Day -2 intervention 2: Arm 1: 50 mg/kg IV over 2 hours Day -6 intervention 3: Both Arms:

Mycophenolate mofetil (MMF) 3 gram/day IV/PO for patients who are ≥ 40 kg divided in 2 or 3 doses. In obese patients (\>125% IBW) 15 mg/kg every 12 hours may be considered. Pediatric patient (\<40 kilograms) will receive MMF at the dose of 15 mg/kg/dose every 8 hours beginning Day -3. MMF dosing will be monitored and altered as clinically appropriate based on institutional guidelines. Patients will be eligible for MMF dosing and pharmacokinetics studies.

Stop MMF at Day +30 or 7 days after engraftment, whichever day is later, if no acute graft versus host disease (GVHD). (Definition of engraftment is 1st day of 3 consecutive days of absolute neutrophil count \[ANC) ≥ 0.5 x 109 /L\]). If no donor engraftment, do not stop MMF. intervention 4: Both Arms:

Adult Dosing: Sirolimus will be administered starting at Day -3 with 8-12 mg oral loading dose followed by single dose 4 mg/day with a target serum concentration of 3 to 12 mg/mL by high-performance liquid chromatography (HPLC) and will be monitored per institutional guidelines. In the absence of acute GVHD sirolimus may be tapered starting at Day +100 and eliminated by Day +180 post-transplantation.

Pediatric Dosing: Sirolimus will be administered starting on Day -3 with an oral loading dose of 10 mg followed by maintenance dosing of 2.5 mg/m\^2/day (Maximum total daily dose of 4mg) as per institutional guidelines. Target serum concentration goals are 3 to 12 mg/mL by high-performance liquid chromatography (HPLC) and will be monitored per institutional guidelines. intervention 5: Both Arms: 200 cGy on Day -1 intervention 6: Both Arms: Day 0 intervention 7: Arm 2: 15 mg/kg IV every 12 hours Day -6 to Day -4

Protocol documents:
Prot_SAP_000.pdf: 
Masonic Cancer Center, University of Minnesota 
Blood and Marrow Transplantation Program 
 
 
 
Transplantation of Umbilical Cord Blood from Unrelated Donors in 
Patients With Hematological Diseases Using a Non-Myeloablative 
Preparative Regimen 
MT2015-17 
CPRC #2015LS149 
 
 
 
Principal Investigator: 
 
Margaret L.MacMillan, MD 
 
 
Collaborators: 
John E. Wagner, MD 
 
 
Bruce R. Blazar, MD 
Kathryn Dusenbery, MD 
Jeffrey Miller, MD 
Daniel J. Weisdorf, MD 
David McKenna, Jr, MD 
 
 
Biostatistician: 
Qing Cao, MS 
 
 
Version Date: 
April 25, 2022 
 
Confidential 
 
 


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Revision History 
 
Revision 
Number 
Version 
Date 
Revision Summary 
Consent 
Change? 
 
10/27/2015 original to CPRC 
 
 
1/27/2016 
In response to CPRC stips, original to IRB 
n/a 
 
12/29/2016 Updated disease eligibility and general study 
inclusion/exclusion criteria to match institutional 
standard language 
Updated link to Cancer Center DSMP 
Yes 
 
2/22/2018 
Section 2: Updated to clarify standard of care 
procedures  
 
 
04/25/2022 Updated Study committee 
Minor template edits: removed eligibility checklist, 
updated dsmp link, updated reference to cord blood 
IND sponsor 
Yes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PI Contact Information: 
Margaret L. MacMillan, MD, MSc, FRCPC 
Professor of Pediatrics 
Blood and Marrow Transplant Program  
University of Minnesota  
MMC 484   
420 Delaware Street SE 
Minneapolis, MN 55455 
612 626-2961 (phone) 
612-626-2815 (fax) 
macmi002@umn.edu (email) 
 


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Table of Contents 
 
Study Synopsis .................................................................................................................................... 5 
Treatment Plan ..................................................................................................................................... 7 
1 
Study Objectives .......................................................................................................................... 8 
1.1 
Primary Objective................................................................................................................. 8 
1.2 
Secondary Objectives ......................................................................................................... 8 
1.3 
Transplant Related Objectives ........................................................................................... 8 
2 
Background and Rationale ......................................................................................................... 8 
3 
Study Design .............................................................................................................................. 11 
4 
Patient Selection ........................................................................................................................ 11 
4.1 
Inclusion Criteria ................................................................................................................ 11 
4.1.1 
Age, Performance Status, and Graft Criteria ......................................................... 11 
4.1.2 
Eligible Diseases ........................................................................................................ 12 
4.1.3 
Additional Criteria for Bulky Disease (lymphomas) .............................................. 14 
4.1.4 
Organ Function Criteria ............................................................................................. 14 
4.2 
Exclusion Criteria ............................................................................................................... 15 
5 
Patient Registration In OnCore ................................................................................................ 16 
6 
Treatment Plan ........................................................................................................................... 16 
6.1 
Preparative Regimen (Arm 1 - no ATG) ......................................................................... 17 
6.2 
Preparative Regimen with ATG ....................................................................................... 18 
6.3 
GVHD Prophylaxis (begin Day -3) .................................................................................. 19 
6.3.1 
Sirolimus ...................................................................................................................... 19 
6.3.2 
Mycophenolate Mofetil (MMF) ................................................................................. 20 
6.4 
Umbilical Cord Blood Thaw and Infusion (Day 0) ......................................................... 20 
6.5 
Supportive Care ................................................................................................................. 21 
6.6 
Management of Slow Engraftment or Graft Failure ...................................................... 21 
6.7 
Follow-up ............................................................................................................................. 21 
7 
Expected Toxicities of the Treatment Plan ............................................................................ 21 
7.1 
Preparative Regimen......................................................................................................... 21 
7.2 
GVHD Prophylaxis ............................................................................................................. 23 


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7.3 
UCB Cell Infusion............................................................................................................... 24 
8 
Clinical Care Activities............................................................................................................... 25 
9 
Adverse Event Monitoring, Documentation and Reporting ................................................. 26 
9.1 
Event Documentation ........................................................................................................ 26 
9.2 
Adverse Event Reporting .................................................................................................. 26 
10 
Study Data Collection and Monitoring ................................................................................ 27 
10.1 
Data Collection ................................................................................................................... 27 
10.2 
Data and Safety Monitoring .............................................................................................. 27 
10.3 
Study Related Monitoring ................................................................................................. 27 
10.4 
Record Retention ............................................................................................................... 27 
11 
Statistical Considerations ..................................................................................................... 28 
11.1 
Primary, Secondary and Transplant-Related Endpoints and Study Design ............. 28 
11.2 
Statistical Analysis ............................................................................................................. 28 
11.2.1 
Analysis of Primary Endpoint ................................................................................... 28 
11.2.2 
Analysis Of Secondary and Transplant Related Objectives ............................... 29 
11.3 
Rationale for Sample Size ................................................................................................ 29 
11.4 
Safety Monitoring ............................................................................................................... 30 
12 
Conduct of the Study ............................................................................................................. 30 
12.1 
Record Retention ............................................................................................................... 30 
12.2 
Ethical Considerations ...................................................................................................... 30 
12.3 
Informed Consent .............................................................................................................. 30 
13 
References .............................................................................................................................. 31 
Appendix I – Eligibility Checklist ...................................................................................................... 34 
Appendix II – Karnofsky Performance Status and Lansky Play Score ...................................... 35 
Appendix III – TBI Guidelines .......................................................................................................... 36 
 
 
 


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Study Synopsis 
Transplantation of Umbilical Cord Blood from Unrelated Donors in Patients 
With Hematological Diseases Using a Non-Myeloablative Preparative Regimen 
MT2015-17 
Study Design: 
This is a phase II trial using a non-myeloablative cyclophosphamide/ 
fludarabine/total body irradiation (TBI) preparative regimen with 
modifications based on factors including diagnosis, disease status, and 
prior treatment.  Single or double unit selected according to current 
University of Minnesota umbilical cord blood graft selection algorithm. 
 
This study uses a Minimax two-stage phase II design.  Stage 1 will enroll 
110 patients.  If 54 or fewer develop GVHD, 45 additional patients will be 
enrolled.  After stage 2, if 71 or fewer out of 155 enrolled develop GVHD, 
CSA/Sirolimus will be considered worthy of further consideration. 
 
Primary Objective: 
Estimate probability of grade II-IV acute GVHD at Day 100 
 
Secondary Objectives: 
• Incidence of Day 100 grade III-IV acute GVHD 
• Transplant related mortality (TRM) at 6 months 
• Chimerism at Day 21, 100,180 and 365 
• Incidence of neutrophil engraftment by Day 42 
 
Transplant Related 
Objectives: 
• Incidence of platelet engraftment by six months  
• Incidence of one year chronic GVHD 
• Probability of one and two year overall survival 
• Probability of one and two year progression free survival (PFS) 
• Incidence of one and two year relapse or disease progression  
 
Eligible Diseases: 
All diseases listed below are advanced hematologic malignancies not 
curable by conventional chemotherapy.  Refer to section 4.1.2 for specific 
criteria. 
• Acute Leukemias 
• Acute myeloid leukemia  
• Acute lymphoblastic leukemia/lymphoma  
• Biphenotypic/Undifferentiated/Prolymphocytic Leukemias  
• MRD positive leukemia  
• Leukemia or MDS in aplasia 
• Burkitt’s lymphoma 
• Relapsed T-Cell Lymphoma 
• Natural killer cell malignancies 
• Chronic myelogenous leukemia in chronic or accelerated phase, or 
CML blast crisis in morphological remission (<5% blasts)    
• Myelodysplastic syndrome 
• Large-cell lymphoma, Hodgkin lymphoma and multiple myeloma  
• Relapsed Chronic lymphocytic leukemia/small lymphocytic lymphoma 
(CLL/SLL), marginal zone B-cell lymphoma, follicular lymphoma  
• Lymphoplasmacytic lymphoma, mantle-cell lymphoma, prolymphocytic 
leukemia  
• Relapsed Multiple Myeloma 
• Plasma Cell Leukemia 
• Bone marrow failure syndromes, except for Fanconi anemia 
• Myeloproliferative Neoplasms/Myelofibrosis 


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• Other Leukemia Subtypes -  with the approval of two members of the 
study committee   
Age. PS, and UCB 
Graft Requirements: 
• <70 years old with no matched 5/6 or 6/6 sibling donor - patients ≥ 70 
but ≤ 75 are eligible if the co-morbidity score is ≤ 2 
(http://www.qxmd.com/calculate-online/hematology/hct-ci) 
• Karnofsky score ≥ 70% (≥ 16 years) or Lansky score ≥ 50 (< 16 years) 
• UCB graft to be selected according to current University of Minnesota 
umbilical cord blood graft selection algorithm 
 
 
Other Inclusion Criteria: 
• adequate liver and renal function per section 4.1.4 
• absence of decompensated congestive heart failure, or uncontrolled 
arrhythmia and left ventricular ejection fraction ≥ 40% 
• DLCO, FEV1, FVC > 40% predicted, and absence of O2 requirements 
 
Exclusion Criteria: 
• 
pregnant or breastfeeding 
• 
untreated active infection 
• 
Active HIV infection or known HIV positive serology 
• 
Less than 3 months since prior myeloablative transplant 
• 
Evidence of progressive disease by imaging modalities or biopsy 
- persistent PET activity, though possibly related to lymphoma, is 
not an exclusion criterion in the absence of CT changes 
indicating progression. 
• 
CML in blast crisis 
• 
large cell lymphoma, mantle cell lymphoma and Hodgkin 
lymphoma that is progressive on salvage therapy  
• 
Active central nervous system malignancy 
 
Enrollment: 
15-25 patients per year over 6-10 years for a total of 163 patients 
 
 
 


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Treatment Plan 
Disease/Prior Treatment Status  
 
Preparative Regimen 
CY/FLU/TBI, no ATG 
hematological diseases with prior autologous 
transplant, ≥ 2 cycles of multi-agent 
chemotherapy or severely 
immunosuppressive therapy in the last 3 
months 
 
 
• cyclophosphamide 50 mg/kg Day -6 
• fludarabine 30 mg/m2 Days -6 to -2  
• TBI 200cGy Day -1 
 
 
CY/FLU/TBI, ATG  
hematological diseases with prior autologous 
transplant > 12 months or ≤ 1 cycle of multi-
agent chemotherapy or no 
immunosuppressive chemotherapy in the last 
3 months 
 
 
• cyclophosphamide 50 mg/kg Day -6 
• fludarabine 30 mg/m2 Days -6 to -2 
• TBI 200cGy Day -1 
• equine ATG 15 mg/kg bid Days -6 to -4 
 
 
 
 
 
 
 
UCB 
 
 
 
 
 
Infusion           key follow-up time points 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day -6      -5      -4      -3      -2      -1       0        21      28       42       60        180     360     720 
 
 
GVHD prophylaxis: 
 
MMF through Day +30 or 7 days after engraftment (whichever is earlier) 
 
 
 
Sirolimus through Day +100, taper until Day +180 
 
Preparative Regimen from above 


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1 
Study Objectives 
1.1 
Primary Objective 
The primary objective is to estimate the probability of grade II-IV acute 
GVHD at Day 100 after unrelated donor umbilical cord blood 
transplantation using a non-myeloablative preparative regimen along 
with Sirolimus/MMF for GVHD prophylaxis in persons with hematologic 
malignancies.  
1.2 
Secondary Objectives 
Secondary objectives are: 
• Incidence of grade III-IV acute GVHD at 100 days 
• Transplant related mortality (TRM) at 6 months 
• Chimerism at Day 21, 100,180 and 365 
• Incidence of neutrophil engraftment by Day 42 
1.3 
Transplant Related Objectives 
• Incidence of platelet engraftment by six months 
• Incidence of one year chronic GVHD 
• Probability of one and two year overall survival (OS) 
• Probability of one and two year progression free survival (PFS)  
• Incidence of one and two year relapse or disease progression  
2 
Background and Rationale 
Umbilical cord blood (UCB) is now an established alternative donor type for 
allogeneic transplantation.  The advantages of UCB transplantation included, 
but not limited to, rapid availability, less restrictive HLA-selection criteria, no 
risk for the donor, and relative low risk of graft-versus-host disease (GVHD). 
The main limitations of UCB are limited stem cell content, delayed engraftment 
potentially increasing the risk of infections and morbidity.  
Our institution has led several critical advances in the UCB transplant field. Our 
approach and clinical outcomes have now been reproduced worldwide as 
evidenced by reports from Center for International Blood and Marrow 
Transplant and Research (CIBMTR)(1) the Blood and Marrow Transplant 
Clinical Trials Network (BMT-CTN) (2) and by the Societé Française de Greffe 
de Moelle Osseuse et Therapie Cellulaire and Eurocord (3-5).  In one of these 
reports, the outcomes after UCB transplantation were shown to be similar to 
other donor types (1).  
 


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The University of Minnesota platform consists of cyclophosphamide 50 mg/m2, 
fludarabine 200 mg/m2 divided in 5 days and total body irradiation (TBI) 200 
cGy with cyclosporine A (CsA) and mycophenolate mofetil (MMF) immune 
suppression.  This treatment platform has been shown to support single and 
double UCB transplantation resulting in sustained donor engraftment > 90%, 
transplant related mortality (TRM) between 20-30%, and long term disease free 
survival (DFS) in 25-50% depending on disease stage and the presence of co-
morbid condition prior to transplantation.(6)  Building upon this platform our 
groups has focused our research efforts on methods that will ultimately result 
in improved immune reconstitution (7-9).  Our hypothesis is that reducing the 
risk of GVHD after UCB transplantation would facilitate the reconstitution of 
lymphocyte subsets and result in lower risk of infections and relapse, potentially 
improving survival. Recent reports by our group demonstrated the critical 
influence of therapeutic cyclosporine A level in the first month post-
transplantation (7), the superior effectiveness in suppressing acute GVHD of 
MMF 3g/day(8), and the promising early results of the adoptive transfer of UCB-
derived natural regulatory T cells (nTreg) (9).  More recently we studied the 
safety and efficacy of the combination of sirolimus and MMF as immune 
suppressive regimen in a subset of patients.  
The mTor inhibitor sirolimus has potential anti-leukemia (10) and anti-viral 
activity (11).  As compared to calcineurin inhibitors, sirolimus has a different 
toxicity profile with low risk of kidney dysfunction, hypertension and seizures 
but it may cause hypertriglyceridemia, skin rash and, at least in lung transplant 
cases, interstitial pneumonia.  
In matched related donors and in UCB transplantation the combination of 
sirolimus with tacrolimus and rabbit ATG resulted on a risk of GVHD of < 20% 
(12, 13).  In unrelated donor transplantation the combination of sirolimus with 
tacrolimus and MMF resulted in a risk of acute GVHD of 47% (14). In haplo-
identical transplantation, sirolimus with MMF and rabbit ATG results in 35% risk 
of acute GVHD and showed rapid reconstitution of nTreg cells (15).  In contrast, 
studies combining sirolimus with CsA (16) or sirolimus with MMF (17) in adult 
donors were terminated due to excessive acute GVHD.  The combination of 
sirolimus with tacrolimus has a high risk of thrombotic microangiopathy (12) 
and, when used in combination with busulfan based conditioning regimen, with 
excessive risk of veno-occlusive disease of the liver (12, 18).  Taken together, 
these data suggest that sirolimus/MMF with or without ATG may be a suitable 
immune suppression regimen in specific subsets.  
 


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In pilot in the setting of UCB transplantation, recipients of ex vivo expanded 
UCB derived-nTreg were treated with sirolimus/MMF immune suppression that 
favors the survival of this important T-cell subset (19).  As the combination of 
sirolimus/MMF has potential advantages over calcineurin inhibitor-based 
regimens, we modified our local protocol to incorporate this immune 
suppression regimen and monitored patients for increased risk of severe 
GVHD.  As per our institutional practice we allowed for the co-administration of 
equine ATG in a subset of patients who were considered high risk for graft 
rejection.  Our preliminary data comparing sirolimus/MMF ± ATG vs CsA/MMF 
± ATG is summarized in the table below. Overall this immune suppression 
regimen resulted in similar incidence of engraftment, acute GVHD and non-
relapse mortality.  However, before we can definitively adopt this immune 
suppression regimen as our new standard of care, we need better define its 
safety and efficacy profile in larger numbers of patients.  
Group 
N 
Grade II-IV 
AGVHD  
(95% CI) 
ANC 
(95% CI) 
NRM 
(95% CI) 
Cy/Flu(40mg)/TBI±ATG + 
CsA/MMF 
157 42% (34-50%) 
95% (92-98%) 
24% (17-31%) 
Cy/Flu(40mg)/TBI±ATG + 
Siro/MMF 
11 
27% (2-52%) 
82% (59-100%) 
27% (2-52%) 
Cy/Flu(30mg)/TBI±ATG + 
Siro/MMF 
37 
35% (19-54%) 
81% (69-93%) 
35% (17-53%) 
 
Experimental Component  
Our non-myeloablative UCB transplant platform is well established.  Despite 
outcomes similar to other donor types there is ample room for improvement. 
Our preliminary data on the sirolimus/MMF ± ATG are promising.  The rationale 
for the development of this immune suppression is that in contrast to CsA-
based regimens, sirolimus is supportive of nTreg cells survival potentially 
reducing risk of acute and chronic GVHD and ultimately promoting immune 
reconstitution.  Consistent with our approach of progressive changes to our 
platform we will further characterize the safety and efficacy of sirolimus/MMF 
immune suppression in the setting of non-myeloablative UCB transplantation.  
Standard of Care  
All pre-and post-transplant testing, graft source, chemotherapy and supportive 
measures listed in this protocol are standard of care but are part of the data 


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elements necessary to determine the long-term outcomes of the sirolimus/MMF 
immune suppression regimen.  
3 
Study Design 
This is a single institution phase II study of minimally manipulated umbilical 
cord blood transplantation after a non-myeloablative chemo/radiation 
preparative regimen in persons with one of several hematologic malignancies. 
 
This study uses a Minimax two-stage phase II design.  Stage 1 will enroll 110 
patients. If 54 or fewer develop GVHD, 45 additional patients will be enrolled.  
After stage 2, if 71 or fewer out of 155 enrolled develop GVHD,  CSA/Sirolimus 
will be considered worthy of further consideration. 
The primary objective of this study is to estimate the probability of grade II-IV 
acute GVHD at Day 100 and provide support that use of Sirolimus/MMF is not 
worse at preventing GVHD than CsA/MMF after unrelated donor umbilical cord 
blood transplantation.  Secondary objectives include incidence of neutrophil 
engraftment by Day 42, incidence of grade III-IV acute GVHD, incidence of 
transplant-related mortality and chimerism at Day 21 and 3, 6 and 12 months 
post-transplant. 
4 
Patient Selection 
Study entry is open to persons less than 70 years of age (refer to for additional 
eligibility ≥ 70 years, but ≤75 years of age), regardless of gender, race or ethnic 
background.  While there will be every effort to seek out and include females 
and minority patients, the patient population is expected to be no different than 
that of similar studies at the University of Minnesota. 
4.1 
Inclusion Criteria 
4.1.1 Age, Performance Status, and Graft Criteria 
• <70 years of age with no matched 5/6 or 6/6 sibling donor - 
patients ≥ 70 and ≤ 75 years of age may be eligible if they have 
a Co-Morbidity score ≤ 2 - (http://www.qxmd.com/calculate-
online/hematology/hct-ci) 
• Karnofsky score ≥ 70% (≥ 16 years) or Lansky score ≥ 50 (< 16 
years) - refer to appendix II 
• UCB graft selected according to current University of Minnesota 
umbilical cord blood graft selection algorithm 


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4.1.2 Eligible Diseases 
All diseases listed below are advanced hematologic malignancies 
not curable by conventional chemotherapy.  Responses to 
conventional treatment range from zero to 30% but are typically 
short lived [25]. 
Acute Leukemias: Must be in remission by morphology (<5% 
blasts). Note cytogenetic relapse or persistent disease without 
morphologic relapse is acceptable.  Also a small percentage of 
blasts that is equivocal between marrow regeneration vs. early 
relapse are acceptable provided there are no associated 
cytogenetic markers consistent with relapse. 
Acute 
Myeloid 
Leukemia 
(AML) 
and 
related 
precursor 
neoplasms: 2nd or greater complete remission (CR); first 
complete remission (CR1) in patients > 60 years old; CR1 in ≤ 60 
years old that is NOT considered as favorable-risk.  
Favorable risk AML is defined as having one of the following: 
• 
t(8,21) without cKIT mutation 
• 
inv(16) or t(16;16) without cKIT mutation  
• 
Normal karyotype with mutated NPM1 and wild type FLT-ITD 
• 
Normal karyotype with double mutated CEBPA 
• 
Acute prolymphocytic leukemia (APL) in first molecular 
remission at the end of consolidation 
Acute lymphoblastic leukemia (ALL)/lymphoma: second or 
greater CR; CR1 unable to tolerate consolidation chemotherapy 
due to chemotherapy-related toxicities; CR1 high-risk ALL.  
High risk ALL is defined as having one of the following: 
• 
Evidence of high risk cytogenetics, e.g. t(9;22), t(1;19), 
t(4;11), other MLL rearrangements, IKZF1 
• 
30 years of age or older at diagnosis 
• 
White blood cell counts of greater than 30,000/mcL (B-ALL) 
or greater than 100,000/mcL (T-ALL) at diagnosis 
• 
CNS leukemia involvement during the course of disease 
• 
Slow cytologic response (>10% lymphoblasts in bone 
marrow on Day 14 of induction therapy) 
• 
Evidence of persistent immonophenotypic or molecular 
minimal residual disease (MRD) at the end of induction and 
consolidation therapy 


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Biphenotypic/Undifferentiated/Prolymphocytic Leukemias in 
first or subsequent CR. 
Chronic myelogenous leukemia in chronic or accelerated 
phase, or CML blast crisis in morphological remission (<5% 
blasts): Chronic phase patients must have failed at least two 
tyrosine kinase inhibitors been intolerant to all available TKIs or 
have T315I mutation. 
Myelodysplastic syndrome: IPSS INT-2 or High Risk; R-IPSS 
High or Very High; WHO classification: RAEB-1, RAEB-2; Severe 
Cytopenias: ANC < 0.8, Anemia or thrombocytopenia requiring 
transfusion; Poor or very poor risk cytogenetics based on IPSS 
or R-IPSS definitions; therapy-related MDS. Blasts must be < 5% 
by bone marrow aspirate morphology. If ≥5% blasts, patient 
requires chemotherapy for cytoreduction to <5% blasts prior to 
transplantation.  
MRD positive leukemia (AML, ALL or accelerated/blast 
phase CML). Selected patients in morphologic CR, but with 
positive immunophenotypic (flow cytometry) or molecular 
evidence of MRD may be eligible if recent chemotherapy has not 
resulted in MRD negative status.  
Leukemia or MDS in aplasia. These patients may be taken to 
transplant if after induction therapy they remain with aplastic bone 
marrow and no morphological or flow-cytometry evidence of 
disease ≥ 28 days post-therapy. These high risk patients will be 
analyzed separately. 
Burkitt’s lymphoma in CR2 or subsequent CR 
Relapsed T-Cell Lymphoma that is chemotherapy sensitive in 
CR/PR that has failed or ineligible for an autologous transplant. 
Natural killer cell malignancies 
Large-cell lymphoma, Hodgkin lymphoma and multiple 
myeloma with chemotherapy sensitive disease who are ineligible 
for an autologous transplant.  
Relapsed Chronic lymphocytic leukemia/small lymphocytic 
lymphoma (CLL/SLL), Marginal Zone B-Cell Lymphoma, 


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Follicular Lymphoma which have progressed within 12 months 
of achieving a partial or complete remission.  Patients who had 
remissions lasting > 12 months, are eligible after at least two prior 
therapies.  Patients with bulky disease should be considered for 
debulking chemotherapy before transplant.  Patients with 
refractory disease are eligible, unless bulky disease and an 
estimated tumor doubling time of less than one month.  
Lymphoplasmacytic lymphoma, mantle-cell lymphoma, 
prolymphocytic leukemia are eligible after initial therapy if 
chemotherapy sensitive.  
Relapsed Multiple Myeloma that is chemotherapy sensitive and 
has failed or ineligible for an autologous transplant.  
Plasma Cell Leukemia after initial therapy if achieved at least in 
partial remission; or relapsed and achieved subsequent 
remission (CR/PR) 
Acquired Bone marrow failure syndromes, except for 
Fanconi anemia 
Myeloproliferative Neoplasms/Myelofibrosis. 
Other Leukemia Subtypes:  A major effort in the field of 
hematology is to identify patients who are of high risk for 
treatment failure so that patients can be appropriately stratified 
to either more (or less) intensive therapy.  This effort is 
continually ongoing and retrospective studies identify new 
disease features or characteristics that are associated with 
treatment outcomes.  Therefore, if new features are identified 
after the writing of this protocol, patients can be enrolled with 
the approval of two members of the study committee. 
4.1.3 Additional Criteria for Bulky Disease (lymphomas)   
if stable disease is best response, the largest residual nodal 
mass must < 5 cm (approximately) 
If response to previous therapy, the largest residual mass must 
represent a 50% reduction and be < 7.5 cm (approximately) 
4.1.4 Organ Function Criteria 
Adequate organ function is defined as: 


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Cardiac: Absence of decompensated congestive heart failure, or 
uncontrolled arrhythmia and left ventricular ejection fraction > 
40%.  For children that are not able to cooperate with MUGA and 
echocardiography, such should be clearly stated in the 
physician’s note 
Pulmonary: DLCO, FEV1, FVC ≥ 40% predicted, and absence of 
O2 requirements. For children that are not able to cooperate with 
PFTs, a pulse oximetry with exercise should be attempted.  If 
neither test can be obtained it should be clearly stated in the 
physician’s note.  
Liver:  Transaminases ≤ 5 x upper limit of normal (ULN) and total 
bilirubin ≤ 2.5 mg/dL except for patients with Gilbert’s syndrome 
or hemolysis  
Renal:  Creatinine ≤ 2.0 mg/dl (adults) and creatinine clearance ≥ 
40 mL/min (pediatrics).    Adults with a creatinine > 1.2 mg/dl or a 
history of renal dysfunction must have estimated creatinine 
clearance ≥ 40 ml/min/1.73m2. 
Adequate performance status is defined as Karnofsky score ≥ 
70% (≥ 16 years of age) or Lansky score ≥ 50 (pediatrics) 
4.1.5 Sexually active females of childbearing potential and males with 
partners of child-bearing potential must agree to use adequate 
birth control during study treatment.   
4.1.6 Voluntary written consent (adult or parent/guardian with 
presentation of the minor information sheet, if appropriate) 
4.2 
Exclusion Criteria 
4.2.1 Pregnant or breast feeding. The agents used in this study include 
Pregnancy Category D: known to cause harm to a fetus.  Females 
of childbearing potential must have a negative pregnancy test 
prior to starting therapy.  
4.2.2 Untreated active infection 
4.2.3 Active HIV infection or known HIV positive serology 
4.2.4 Less than 3 months since prior myeloablative transplant  


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4.2.5 Evidence of progressive disease by imaging modalities or biopsy 
- persistent PET activity, though possibly related to lymphoma, is 
not an exclusion criterion in the absence of CT changes indicating 
progression. 
4.2.6 CML in blast crisis 
4.2.7 Large cell lymphoma, mantle cell lymphoma and Hodgkin 
disease that is progressing on salvage therapy. 
4.2.8 Active central nervous system malignancy 
5 
Patient Registration In OnCore 
Registration will occur after the patient/parent/guardian has signed the subject 
consent and eligibility is confirmed.  To be eligible for registration to this study, 
the patient must meet each criteria listed on the eligibility checklist based on 
the eligibility assessment documented in the patient’s medical record.  A copy 
of the eligibility checklist is under attachments within the study in OnCore. 
Patients will be registered in OnCore by the Masonic Cancer Center’s Clinical 
Data Associates (CDA’s). 
At the time of registration in OnCore, the treatment arm related to statistical 
analysis will be recorded using the following definitions: 
Arm 1 (no ATG) - hematologic malignancy patients who have received a 
previous autologous transplant or ≥ 2 cycles of multi-agent chemotherapy 
within the 3 months previous to UCBT  
Arm 2 (ATG) - hematologic malignancy patients who have not been treated 
with prior autologous transplant or ≤ 1 cycle of chemotherapy in the 3 months 
previous to UCBT, should receive ATG as part of their conditioning regimen  
If one or both of the cord blood units used for the graft is unlicensed, the 
participant will co-enroll on University of Minnesota protocol MT2011-13R 
“Infusion of Cell Populations from Unlicensed Umbilical Cord Blood Units” as 
the units used for the transplant will be minimally manipulated.  
6 
Treatment Plan 
In order to provide optimal patient care and to account for individual medical 
conditions, investigator discretion may be used in the prescribing of all 


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supportive care drug therapy (i.e. acetaminophen, diphenhydramine, 
antimicrobials, etc.). 
 
All patients will receive allopurinol 300 mg/day (for peds -150 mg/m2/day) PO, 
unless known allergy ending one day after the last dose of chemotherapy or 
TBI (may continue longer if clinically indicted). 
All drugs used in this study are commercially available by prescription. 
6.1 
Preparative Regimen (Arm 1 - no ATG) 
The administration of the preparative regimen will follow institutional drug and 
supportive care guidelines.  Dose and/or schedule adjustments consistent with 
the standard of care may be made on an individual patient basis as needed for 
safety. 
 
 
 
 
 
 
 
 
 
Fludarabine will be administered as a 1 hour infusion per institutional 
guidelines on Day -6 through Day -2.  Dose adjustments will be made for adult 
patients with renal impairment defined as CrCL < 70mL/minute. Fludarabine 
dose MAY also be reduced to this dose if there is prior malignancy involvement 
of the central nervous system with intrathecal chemotherapy and/or cranio-
spinal irradiation 
Cyclophosphamide will be administered as a 2 hour intravenous infusion with 
a high volume fluid flush and mesna per institutional guidelines on Day -6.   
Dosing is based on Actual Body Weight (ABW) unless ABW > 150% above 
Ideal Body Weight (IBW), in which case the dose should be computed using 
adjusted body weight. 
Treatment Day 
Treatment 
Day -7 
Begin allopurinol (Day -7 to Day 0) 
Day -6 
Fludarabine 30 mg/m2 IV over 1 hour 
Cyclophosphamide 50 mg/kg IV over 2 hours 
Antiemetics and fluid flush per institutional guidelines 
Day -5 
Fludarabine 30 mg/m2 IV over 1 hour 
Day -4 
Fludarabine 30 mg/m2 IV over 1 hour 
Day -3 
Fludarabine 30 mg/m2 IV over 1 hour 
Begin MMF and Sirolimus per section 6.3 
Day -2 
Fludarabine 30 mg/m2 IV over 1 hour 
Day -1 
TBI 200 cGy 
Day 0 
UCB cell infusion (transplant) 


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Steroids and/or other medications may be used as needed per the discretion 
of the treating physician. 
TBI will be administered as a single treatment on Day -1.  Refer to appendix III. 
6.2 
Preparative Regimen with ATG 
Patients who have had a prior autologous transplant or who have had ≤ 1 cycle 
of chemotherapy in the previous 3 months should receive ATG as part of their 
conditioning regimen. 
 
The administration of the preparative regimen will follow institutional drug and 
supportive care guidelines.  Dose and/or schedule adjustments consistent with 
the standard of care may be made on an individual patient basis as needed for 
safety. 
Fludarabine will be administered as a 1 hour infusion per institutional 
guidelines on Day -6 through Day -2.  Dose adjustments will be made for adult 
patients with renal impairment defined as CrCL < 70mL/minute. Fludarabine 
dose MAY also be reduced to this dose if there is prior malignancy involvement 
of the central nervous system with intrathecal chemotherapy and/or cranio-
spinal irradiation 
Cyclophosphamide will be administered as a 2 hour intravenous infusion with 
a high volume fluid flush and mesna per institutional guidelines on Day -6.   
Treatment Day 
Treatment 
Day -7 
Begin allopurinol (day -7 to day 0) 
Day -6 
Fludarabine 30 mg/m2 IV over 1 hour 
Cyclophosphamide 50 mg/kg IV over 2 hours 
ATG 15 mg/kg IV every 12 hours   
Antiemetics and fluid flush per institutional guidelines 
Day -5 
Fludarabine 30 mg/m2 IV over 1 hour 
ATG 15 mg/kg IV every 12 hours 
Day -4 
Fludarabine 30 mg/m2 IV over 1 hour 
ATG 15 mg/kg IV every 12 hours 
Day -3 
Fludarabine 30 mg/m2 IV over 1 hour 
Begin MMF and Sirolimus per section 6.3 
Day -2 
Fludarabine 30 mg/m2 IV over 1 hour 
Day -1 
TBI 200 cGy 
Day 0 
UCB cell infusion (transplant) 


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Dosing is based on Actual Body Weight (ABW) unless ABW > 150% above 
Ideal Body Weight (IBW), in which case the dose should be computed using 
adjusted body weight. 
Steroids and/or other medications may be used as needed per the discretion 
of the treating physician. 
Equine ATG (ATGAM) 15 mg/kg IV will be administered every 12 hours 
beginning on Day -6 and continuing on Day -5 and Day -4 (for a total of 6 doses) 
per institutional guidelines.  Methylprednisone 1 mg/kg IV will be administered 
prior to each dose of ATG per institutional guidelines.  Additional steroids 
and/or other medications may be used as needed per the discretion of the 
treating physician.  
TBI will be administered as a single treatment on Day -1.  Refer to appendix III. 
6.3 
GVHD Prophylaxis (begin Day -3) 
All patients will receive prophylaxis for GVHD with two drugs both beginning 
at Day -3 as follows: 
6.3.1 Sirolimus 
Adult Dosing:  Sirolimus will be administered starting at Day -3 with 8-12 
mg oral loading dose followed by single dose 4 mg/day with a target serum 
concentration of 3 to 12 mg/mL by high-performance liquid chromatography 
(HPLC) and will be monitored per institutional guidelines.  In the absence of 
acute GVHD sirolimus may be tapered starting at Day +100 and eliminated 
by Day +180 post-transplantation. 
Pediatric Dosing:  Sirolimus will be administered starting on Day -3 with 
an oral loading dose of 10 mg followed by maintenance dosing of 2.5 
mg/m2/day (Maximum total daily dose of 4mg) as per institutional 
guidelines. Target serum concentration goals are 3 to 12 mg/mL by high-
performance liquid chromatography (HPLC) and will be monitored per 
institutional guidelines.   
Due to the long and variable half-life in pediatric patients, it is recommended 
that sirolimus dosing changes must not be made until 3 days after a dose 
change or using best clinical judgment.  In the absence of acute GVHD 
sirolimus may be tapered starting at Day +100.   
Sirolimus is available as 0.5 mg tablet, 1 mg tablet, 2 mg tablet and 1mg/ml 
oral suspension.  The oral tablets and oral suspension are not bio-
equivalent.  No IV formulation is available. 


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6.3.2 Mycophenolate Mofetil (MMF) 
Mycophenolate mofetil (MMF) 3 gram/day IV/PO for patients who are ≥ 40 
kg divided in 2 or 3 doses.  In obese patients (>125% IBW) 15 mg/kg every 
12 hours may be considered.  Pediatric patient (<40 kilograms) will receive 
MMF at the dose of 15 mg/kg/dose every 8 hours beginning Day -3.  MMF 
dosing will be monitored and altered as clinically appropriate based on 
institutional guidelines.  Patients will be eligible for MMF dosing and 
pharmacokinetics studies. 
Stop MMF at Day +30 or 7 days after engraftment, whichever day is later, if 
no acute GVHD. (Definition of engraftment is 1st day of 3 consecutive days 
of absolute neutrophil count [ANC) ≥ 0.5 x 109 /L]).  If no donor engraftment, 
do not stop MMF.  
If the patient has acute GVHD requiring systemic therapy, MMF may be 
stopped 7 days after initiation of systemic therapy for acute GVHD (e.g. 
resolution of skin rash, vomiting, and diarrhea).  
6.4 
Umbilical Cord Blood Thaw and Infusion (Day 0) 
Cord blood products are thawed and filtered (170-micron) in the Molecular and 
Cellular Therapeutics (MCT) Lab using the method of Rubinstein et al.[20] 
There will be no processing of the UCB. 
Note:  Unlicensed UCB units will be covered by University of Minnesota IND 
BB 14797 (J. Wagner MD – sponsor/investigator) and therefore will be in 
compliance with mandatory reporting to the FDA for minimally manipulated 
UCB units. 
Cord blood products are thawed and filtered (170-micron) in the Molecular and 
Cellular Therapeutics (MCT) Lab using the method of Rubinstein et al.  
Pre-medications and UCB infusion will be per current institutional 
policies/guidelines.  The infusion of the first UCB unit should begin within 15 
minutes, and no later than 30 minutes after arrival on the Unit.  If 2 units are 
used, both cords will be infused within 30-60 minutes of each other as deemed 
clinically safe by the BMT attending or designee. 
Vital signs will be checked before and after the infusion, and one hour post 
infusion per University Of Minnesota transplant guidelines.  More frequent vital 
signs may be required depending on reactions to the product infusion.   


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6.5 
Supportive Care 
Supportive care will be provided per University Of Minnesota institutional 
guidelines for transplant patients including any supportive care research 
protocols. 
All patients will receive standard supportive transfusion care according to 
transfusion committee guidelines or as modified based on clinical parameters. 
Acute and chronic GVHD will be staged and treated using current University of 
Minnesota BMT program GVHD protocols  
Antimicrobial prophylaxis directed towards bacteria, fungi and viruses will be 
per University Of Minnesota current institutional guidelines for transplant 
patients.  
6.6 
Management of Slow Engraftment or Graft Failure 
Patients with ANC < 1000 any time after cord infusion will be started on G-CSF 
support at 5 mcg/kg (IV/SQ)(round to vial size) daily until ANC > 2500/μL for 2 
consecutive days. Once a patient has met these criteria, the ANC will be 
monitored and G-CSF restarted if ANC falls to < 1000. 
If no evidence of donor engraftment on the Day +21/28 bone marrow biopsy, 
notify the unrelated donor (URD) search coordinator to pursue back-up graft 
and arrange a follow-up bone marrow biopsy per current institutional slow 
engraftment guidelines. 
6.7 
Follow-up  
Patients will be followed for 2 years post-transplant per the standard of care 
schedule in section 8.   
Follow-up after 2 years will be per the University of Minnesota standard 
hematopoietic stem cell transplantation protocol for long-term follow-up.  
7 
Expected Toxicities of the Treatment Plan 
7.1 
Preparative Regimen 
Cyclophosphamide 
Common 
Less Common 
Rare 
nausea/vomiting 
mucositis 
sterility 
severe suppression of 
blood counts 
diarrhea 
hemorrhagic cystitis 
 
cardiomyopathy 
skin rash 
SIADH (Syndrome of Inappropriate Anti-
diuretic Hormone) 
 


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Cyclophosphamide 
Common 
Less Common 
Rare 
fluid weight gain/edema 
alopecia 
 
Fludarabine 
Common 
Less Common 
Rare 
• severe suppression of 
• blood counts 
• diarrhea 
• anorexia 
• mucositis 
• nausea/vomiting 
• stomatitis 
• osteoporosis 
• dysuria 
• chills 
• fever 
• GI bleeding 
• peripheral edema 
 
• neurotoxicity 
- 
agitation and confusion 
- 
blurred vision 
- 
peripheral neuropathy 
- 
hearing loss 
- 
headache 
- 
cerebellar syndrome 
- 
blindness 
- 
coma 
- 
weakness 
• depression 
• insomnia 
• hemorrhagic cystitis (except in FA) 
• abnormal renal function test 
• autoimmune hemolytic anemia 
• deep venous thrombosis 
• aneurysms 
• pruritic skin rash 
• abnormal liver function/liver failure 
• constipation 
• transient ischemic attack 
• dysphagia 
• myalgia 
• arthralgia 
• renal failure 
 
Total Body Irradiation 
Common  
Less Common 
Rare 
• nausea and vomiting 
• diarrhea 
• cataracts 
• sterility (inability to have 
children) 
• endocrinopathies 
(hormone imbalance due 
to damage to the 
endocrine gland)  
• stunted growth in children 
• parotitis (swelling and 
inflammation of the parotid 
gland) 
• interstitial pneumonitis 
(explained below in the 
damage to vital organs 
section) 
• generalized mild reddening of 
the skin 
• dysphagia (difficulty 
swallowing) 
• deformities of the backbone 
(vertebrae)  
• nephropathy (numbness or 
tingling in hands and/or 
feet) 
• risk of 2nd malignancy years 
later (when given along 
with chemotherapy) 


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Total Body Irradiation 
Common  
Less Common 
Rare 
• intestinal cramps 
• mucositis (mouth sores) 
• veno-occlusive disease (VOD - 
explained below in the damage 
to vital organs section) 
 
Anti-Thymocyte Globulin (ATG) – ARM 2 ONLY 
Common 
Less Common 
Rare 
• fever 
• chills 
• leukopenia 
• pain 
• headache 
• abdominal pain 
• diarrhea 
• hypertension 
• nausea 
• thrombocytopenia 
• peripheral edema 
• dyspnea 
• asthenia 
• hyperkalemia 
• tachycardia  
• malaise 
• dizziness  
 
• severe allergic reaction 
(anaphylaxis) 
 
 
7.2 
GVHD Prophylaxis 
Mycophenolate Mofetil (MMF) 
Sirolimus 
• pancytopenia 
• headache 
• insomnia 
• electrolyte imbalances 
• leg cramps/bone pain 
• hypertension 
• dizziness 
• hyperglycemia 
• rash 
• nausea/diarrhea 
• fast heart rate 
• pain when breathing, feeling short of breath 
• chest pain, feeling weak or tired 
• coughing up blood or mucus 
• feeling like you might pass out 
• pale skin, easy bruising or bleeding, weakness 
• fever, chills, body aches, flu symptoms 
• night sweats, weight loss 
• swelling of face, stomach, hands or feet 
• rapid weight gain 
• pain or burning when urinating 
• slow healing of a wound 
• joint pain 
• nausea, vomiting, diarrhea, constipation, 
stomach pain 
• headache 
• acne or skin rash 
• high triglycerides and cholesterol 


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CPRC #2015LS149 
 
7.3 
UCB Cell Infusion  
With the cell infusion 
• nausea and vomiting  
• possible allergic reaction (including itching, hives, flushing [red face], 
shortness of breath, wheezing, chest tightness, skin rash, fever, chills, stiff 
muscles, or trouble breathing) 
 
General transplant related risks  
• slow recovery of blood counts   
• graft failure 
• Graft-Versus-Host Disease (GVHD)  
• other complications including: 
o damage to the vital organs  
o serious infections  
o relapse of disease or a new blood cancer  
o risk to the unborn 
 
Risks related to using a UCB stem cell source  
• Bacterial/Endotoxin Contamination of cellular therapy products may 
occur, but rarely cause acute, severe or life threatening effects. However, 
the onset of high fever (>2ºC or >3.5ºF rise in temperature), severe chills, 
hypotension, or circulatory collapse during or immediately after infusion 
should suggest the possibility of bacterial contamination and/or the 
presence of endotoxin in the product. 
• Transmission of Infectious Disease may occur because cellular therapy 
products are collected from human body and/or tissues. The donor selection 
criteria do not totally eliminate the risk of transmitting the agents currently 
tested such as HIV, HTLV, HBV, HCV, CMV, T. pallidum (Syphilis), West 
Nile Virus, and Trypanosome (Chagas).   For some other infectious disease 
there are no routine tests to prevent disease transmission including 
Parvovirus spp., Plasmodium spp. (Malaria), the coronavirus associated 
with severe acute respiratory syndrome (SARS), and the agents of human 
transmissible spongiform encephalopathies (TSEs). 
 
 


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8 
Clinical Care Activities 
Scheduled evaluations after screening and until engraftment may be performed +/-
3 days from the targeted date; assessments performed after engraftment and 
through Day 100 may be done +/-7 days of the targeted date.   After Day 100 
assessments may be done +/- 30 days of the targeted date.  In addition, targeted 
days may be altered as clinically appropriate. 
Activity 
Pre-BMT 
Work-Up 
Day 1 To 
Engraftment1 
Follow-Up Days 
42-100 
Follow-Up ( >Day 100 
through Day 720) 
Consent 
X 
 
 
 
Medical History 
X 
daily 
weekly 
X (day 180, 360, 720) 
Physical Exam 
X 
daily 
weekly 
X (day 180, 360, 720) 
RT consultation 
X 
 
 
 
Karnofsky/Lansky 
X 
 
day 100 
X (day 180, 360, 720) 
GVHD Assessment 
 
weekly start day 7 
weekly, day 100 
X (day 180, 360) 
CBC/diff/plt 
X 
daily 
weekly 
X (day 180, 360, 720) 
PT/INR 
X 
 
 
 
Viral Screen 
X 
 
 
 
Basic metabolic panel  
 
daily 
 
 
Comprehensive 
metabolic panel 
X 
2x/wk 
weekly 
X (day 180, 360, 720) 
Testing for anti-HLA 
antibodies3  
X 
 
 
 
Urinalysis 
X 
 
 
 
eGFR for adults with 
creat > 1.2 or hx or 
renal dysfunction 
X 
 
 
 
Pregnancy test for 
FOCBP 
X 
 
 
 
BM Biopsy chimerism  
 
BM (day 21/28) 
BM (day 100) 
BM (day 360, 720) 
Blood chimerism  
Patient and UCB 
PB (day 21, 28) 
PB (day 60) 
 
Quantitative 
Immunoglobulins4 
X 
 
X (day 100) 
X (day 360) 
PFT/DLCO 
X 
 
 
 
MUGA or Echo 
X 
 
 
 
Chest CT 
X2 
 
 
 
Disease Evaluation 
X 
X(day 21 to 28) 
X (day 100) 
X (day 360, 720) 
1 
engraftment defined as absolute neutrophil count (ANC) ≥ 5 X 108/L for 3 consecutive measurements  
2 
Patients with a history of MDS or a history of 2 or more consecutive inductions/re-inductions to treat 
acute leukemia or CML blast crisis or prolonged neutropenia of at least 2 months immediately preceding 
transplant should have a chest CT without contrast to exclude occult fungal infection prior to transplant. 
3 
obtain as soon as possible once the patient is determined to be a candidate for UCB transplantation in 
order to guide unit selection 
4 
May be omitted at the physician’s discretion 
NOTE: In certain clinical circumstances (e.g. relapsed or terminally ill patients) study tests may be omitted at the 
physician’s discretion). 


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9 
Adverse Event Monitoring, Documentation and Reporting 
Toxicity and adverse events will be classified according to NCI's Common 
Terminology Criteria for Adverse Events V 4.0 (CTCAE).  A copy of the CTCAE 
can 
be 
downloaded 
from 
the 
CTEP 
home 
page 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html   
FOR UNLICENSED UCB UNITS ONLY: Selected expected adverse reactions 
determined to be caused by or at least possibly caused by the UCB units based 
on objective evidence will be reported in an expedited manner to the FDA under 
University of Minnesota IND BB-14797 (J. Wagner, MD – sponsor/investigator). 
9.1 
Event Documentation  
Transplant related outcomes and events will be recorded in the Blood and 
Marrow Transplantation (BMT) database. Events requiring prompt reporting to 
the University of Minnesota Institutional Review Board (IRB), early stopping 
rule events, and protocol deviations will be documented in OnCore.  
9.2 
Adverse Event Reporting  
The SAE Coordinator will provide the Masonic Cancer Center’s Data and 
Safety Monitoring Council (DSMC) with the SAE in an appropriate format 
depending on the individual SAE (as reported or in a summary format). 
 
 
 
Agency 
Criteria for reporting 
Timeframe 
Form to 
Use 
Submission 
address/ fax 
numbers 
Copy to: 
U of MN IRB 
Events requiring prompt reporting including, but not 
limited to unanticipated death of a locally enrolled 
subject(s); new or increased risk; any adverse event  
that require a change to the protocol or consent 
form or any protocol deviation that resulting in harm  
For a complete list refer to 
http://www.research.umn.edu/irb/guidance/ae.htm
l#.VC7xraI0-sh  
Within 5 
business 
days of 
event 
discovery 
 
Report 
Form 
irb@umn.edu 
 
SAE Coordinator 
mcc-saes@umn.edu 
Masonic 
Cancer 
Center SAE 
Coordinator 
Events that impact the early study stopping rules. 
At time of 
reporting 
Event 
Form 
SAE Coordinator 
mcc-
saes@umn.edu 
n/a 


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10 
Study Data Collection and Monitoring 
10.1 
Data Collection  
This study will track SAE’s, stopping rule events, and clinical deviations using 
The Online Enterprise Research Management Environment (OnCoreTM), a web 
based Oracle® database utilizing study specific electronic case report forms.   
All transplant related outcomes and complications will be recorded in the Blood 
and Marrow Transplantation (BMT) database. 
10.2 
Data and Safety Monitoring  
The study’s Data and Safety Monitoring Plan will be in compliance with the 
University of Minnesota Masonic Cancer Center's Data & Safety Monitoring 
Plan (DSMP), which can be accessed at https://z.umn.edu/dsmp. 
For the purposes of data and safety monitoring, this phase II study is classified 
as moderate risk.  Therefore, the following requirements will be fulfilled: 
 The Masonic Cancer Center Data and Safety Monitoring Council (DSMC) 
will review the trial’s progress twice yearly 
 The PI will comply with at least twice yearly monitoring of the project by the 
Masonic Cancer Center monitoring services. 
 The PI will oversee the submission of all reportable adverse events per the 
definition of reportable in section 9.2 to the Masonic Cancer Center’s SAE 
Coordinator and the University of Minnesota IRB.   
 
In addition, at the time of the continuing review with the University of Minnesota 
IRB, a copy of the report with any attachments will be submitted to the Cancer 
Protocol Review Committee (CPRC). 
10.3 Study Related Monitoring  
The investigator will permit study-related monitoring, audits, and inspections by 
the IRB, government regulatory bodies, and University of Minnesota 
compliance groups.  The investigator will make available all study related 
documents (e.g. source documents, regulatory documents, data collection 
instruments, study data, etc.).  The investigator will ensure the capability for 
inspections of applicable study-related facilities (e.g. pharmacy, diagnostic 
laboratory, etc.) will be available for trial related monitoring, audits, or regulatory 
inspections. 
10.4 Record Retention  
The investigator will retain study records for at 6 years after the study file is 
closed with the IRB and FDA.   


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In addition, the Clinical Trials Office (CTO) will keep a master log of all patients 
participating in the study with sufficient information to allow retrieval of the 
medical records for that patient.  
Please contact the CTO before destroying any study related records. 
11 
Statistical Considerations 
We have extensive experience with the use of Cy/Flu/TBI as a non-myeloablative 
conditioning regimen in conjunction with the use of transplantation of umbilical cord 
blood from unrelated donors in patients with hematological disease. We also have 
extensive experience using CsA/MMF as a GVHD prophylaxis. However, we have 
limited experience with the use of Sirolimus/MMF, showing safety and potential 
efficacy. Our principal objective in this study is to estimate the rate of grade II-IV 
AGVHD using Sirolimus/MMF as a GVHD prophylaxis. Sirolimus/MMF is preferable 
to CsA/MMF due to its ability to support nTreg cells which can potentially reduce 
GVHD and promote immune reconstitution.  
11.1 Primary, Secondary and Transplant-Related Endpoints and Study 
Design 
Our primary endpoint is the probability of grade II-IV acute GVHD by Day 100. 
Secondary endpoints include transplant related mortality at 6 months, the 
incidence of grade III-IV acute GVHD at 100 days, chimerism at Day 21, 
100,180 and 365 and the Incidence of neutrophil engraftment by Day 42. Other 
transplant related endpoints include the Incidence of platelet engraftment by 
six months, the incidence of Day 100 grade II-IV and III-IV acute GVHD, the 
incidence of one year chronic GVHD, the probability of one and two year 
progression free survival, the probability of one and two year survival and the 
incidence of one and two year relapse or disease progression.  
This is a Minimax two-stage phase II design. Stage 1 will enroll 110 patients. If 
54 or fewer develop GVHD, 45 additional patients will be enrolled. After stage 
2, if 71 or fewer out of 155 enrolled develop GVHD, CSA/Sirolimus will be 
considered worthy of further consideration.  
 
11.2 Statistical Analysis 
11.2.1 Analysis of Primary Endpoint 
Simple proportions will be used to estimate the probability of grade II-IV 
AGVHD. We do not expect competing risk but if necessary AGVHD will 
be estimated by cumulative incidence treating non-event death as a 


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competing risk. Ninety-five percent confidence intervals will help provide 
inference as well as show a potential upper bound for the primary 
endpoint around the benchmark rate of 42%.  
11.2.2 Analysis Of Secondary and Transplant Related Objectives 
Analyses of the secondary and transplant related endpoints emphasize 
estimation along w/ a measure of precision which includes 95% 
confidence intervals. Grade III-IV acute and chronic GVHD will be 
estimated by cumulative incidence treating non-GVHD death as a 
competing risk. Transplant-related mortality will be estimated by 
cumulative incidence treating relapse as a competing risk.  Kaplan-
Meier curves will be used to estimate overall and disease-free survival. 
Engraftment will also be estimated by cumulative incidence treating non-
event death as a competing risk. Ninety-five percent confidence 
intervals will help provide inference for all endpoints. Chimerism 
(percentage donor) will be summarized among evaluable patients 
surviving to each time-point at Days 21, 100, 180 and 365 with 
descriptive box-plots and statistics such as medians, ranges and 
interquartile ranges.  
Estimation of endpoints is the primary emphasis in this study. However, in the 
event that investigators desire to compare primary and/or secondary endpoints 
to an external cohort or wish to look for various risk factors within the cohort, 
regression methods will be employed. Cox regression will be used for the 
endpoints of survival and disease-free survival. Fine and Gray regression will 
be employed for all endpoints that include competing risks. Logistic regression 
will be employed for binary endpoints. SAS 9.3 (SAS Institute, Cary, NC) and 
R 3.0.2 (R foundation for Statistical Computing, Vienna, Austria) will be used 
for all statistical analyses. 
11.3 Rationale for Sample Size 
The sample size is based on the Minimax two-stage design with a type-I error 
of 5% and a power of 80%. Using prior data and on advice by investigators, we 
used a benchmark rate of 42% GVHD to be considered effective and a rate of 
52% or higher to be considered ineffective. Based on our design, there is less 
than a 5% probability of concluding effectiveness if the true rate is ≥ 52%. 
GVHD less than equal to 42% is considered effective and there is an 80% 
probability of concluding effectiveness if the true proportion is ≤ 42%. If the trial 
reaches stage 2, there will be 155 patients enrolled. We do not expect early 
competing risk for the primary endpoint but if up to 5% of patients have an early 
competing risk of non-event death, we will conservatively add an additional 8 
patients to the study sample for a total enrollment of 163. Based on enrollment 


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in the similar trial, MT2005-02, we can expect to enroll approximately 15-25 
patients per year so enrollment should be complete between 6 and 10 years. 
11.4 Safety Monitoring 
Sirolimus/MMF has been shown to be safe in protocol MT2005-02 therefore 
continuous monitoring will not be in place during this study. Instead, safety will 
be the responsibility of the DSMC committee and the principal investigator. The 
committee will review safety twice a year with particular attention paid to graft 
failure by Day 42 post-transplant. Graft failure should be estimated at each 
review. A failure rate exceeding 25% should raise concern. If this rate is 
exceeded, the principal investigator and any others deemed necessary by the 
DSMC committee should be notified. 
12 
Conduct of the Study 
12.1 Record Retention  
The study will be conducted in accordance with the appropriate regulatory 
requirement(s).  Essential clinical documents will be maintained to demonstrate 
the validity of the study and the integrity of the data collected.  Master files 
should be established at the beginning of the study, maintained for the duration 
of the study and retained according to the appropriate regulations.   
12.2 Ethical Considerations  
The study will be conducted in accordance with ethical principles founded in 
the Declaration of Helsinki.  The IRB will review all appropriate study 
documentation in order to safeguard the rights, safety and well-being of the 
patients.  The study will only be conducted at sites where IRB approval has 
been obtained.  The protocol, consent, written information given to the patients, 
safety updates, annual progress reports, and any revisions to these documents 
will be provided to the IRB by the investigator.   
12.3 Informed Consent  
All potential study participants will be given a copy of the IRB-approved consent 
to review. The investigator or designee will explain all aspects of the study in 
lay language and answer all questions regarding the study. If the participant 
decides to participate in the study, he/she will be asked to sign and date the 
consent document. In the case of minor patients, the parent/guardian will be 
required to sign and date the parental consent form and the minor, if 8 years or 
older will be presented with a minor information sheet. 
Patients who refuse to participate or who withdraw from the study will be treated 
without prejudice.  


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13 
References 
1. Brunstein CG, Eapen M, Ahn KW, Appelbaum FR, Ballen KK, Champlin RE, et al. 
Reduced-intensity conditioning transplantation in acute leukemia: the effect of source of 
unrelated donor stem cells on outcomes. Blood. 2012;119(23):5591-8. 
2. Brunstein CG, Fuchs EJ, Carter SL, Karanes C, Costa LJ, Wu J, et al. Alternative donor 
transplantation after reduced intensity conditioning: results of parallel phase 2 trials 
using partially HLA-mismatched related bone marrow or unrelated double umbilical cord 
blood grafts. Blood. 2011;118(2):282-8. 
3. Rio BC, S.; Vigouroux, S.; Chevallier, P.; Furst, S.; Sirvent, A.; Bay, J.O.; Socie, G.; 
Ceballos, P.; Huynh, A.; Cornillon, J.; Francois, S.; Legrand, F.; Yakoub-Agha, I.; Michel, 
M.; Maillard, N.; Margueritte, M.; Maury, S.; Uzunov, M.; Bulabois, C.E.; Michallet, M.; 
Clement, L.; Dauriac, C.; Bilger, K.;  Simon, T.; Gluckman, E.; Milpied, N.; Rocha, V. . 
Reduced Intensity Conditioning Regimen Prior to Unrelated Cord Blood Transplantation 
In Patients with Acute Myeloid leukemia : Preliminary Analysis of a Prospective Phase II 
Multicentric Trial on Behalf of Societe Française De Greffe De Moelle Osseuse Et 
Therapie Cellulaire (SFGM-TC) and Eurocord. . Blood (ASH Annual Meeting Abstracts). 
2010;116: 911. 
4. Wallet HL, Sobh M, Morisset S, Robin M, Fegueux N, Furst S, et al. Double umbilical 
cord blood transplantation for hematological malignancies: a long-term analysis from the 
SFGM-TC registry. Experimental hematology. 2013;41(11):924-33. 
5. Rio B, Chevret S, Vigouroux S, Chevallier P, Furst S, Sirvent A, et al. Decreased 
Nonrelapse Mortality after Unrelated Cord Blood Transplantation for Acute Myeloid 
Leukemia Using Reduced-Intensity Conditioning: A Prospective Phase II Multicenter 
Trial. Biology of blood and marrow transplantation : journal of the American Society for 
Blood and Marrow Transplantation. 2015;21(3):445-53. 
6. Brunstein CG, Barker JN, Weisdorf DJ, DeFor TE, Miller JS, Blazar BR, et al. Umbilical 
cord blood transplantation after nonmyeloablative conditioning: impact on transplantation 
outcomes in 110 adults with hematologic disease. Blood. 2007;110(8):3064-70. 
7. Rogosheske JR, Fargen AD, DeFor TE, Warlick E, Arora M, Blazar BR, et al. Higher 
therapeutic CsA levels early post transplantation reduce risk of acute GVHD and 
improves survival. Bone Marrow Transplant. 2014;49(1):122-5. Epub 2013/09/17. 
8. Bejanyan N, Rogosheske J, DeFor T, Lazaryan A, Esbaum K, Holtan S, et al. Higher 
Dose of Mycophenolate Mofetil Reduces Acute Graft-versus-Host Disease in Reduced-
Intensity Conditioning Double Umbilical Cord Blood Transplantation. Biol Blood Marrow 
Transplant. 2015;21(5):926-33. Epub 2015/02/07. 
9. Brunstein CG, Miller JS, Cao Q, McKenna DH, Hippen KL, Curtsinger J, et al. Infusion of 
ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: 
safety profile and detection kinetics. Blood. 2011;117(3):1061-70. Epub 2010/10/19. 


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10. Yang X, He G, Gong Y, Zheng B, Shi F, Shi R. Mammalian target of rapamycin inhibitor 
rapamycin enhances anti-leukemia effect of imatinib on Ph+ acute lymphoblastic 
leukemia cells. Eur J Haematol. 2014;92(2):111-20. Epub 2013/10/12. 
11. Marty FM, Bryar J, Browne SK, Schwarzberg T, Ho VT, Bassett IV, et al. Sirolimus-
based graft-versus-host disease prophylaxis protects against cytomegalovirus 
reactivation after allogeneic hematopoietic stem cell transplantation: a cohort analysis. 
Blood. 2007;110(2):490-500. Epub 2007/03/30. 
12. Cutler C, Logan B, Nakamura R, Johnston L, Choi S, Porter D, et al. 
Tacrolimus/sirolimus vs tacrolimus/methotrexate as GVHD prophylaxis after matched, 
related donor allogeneic HCT. Blood. 2014;124(8):1372-7. Epub 2014/07/02. 
13. Cutler C, Stevenson K, Kim HT, Brown J, McDonough S, Herrera M, et al. Double 
umbilical cord blood transplantation with reduced intensity conditioning and sirolimus-
based GVHD prophylaxis. Bone Marrow Transplant. 2011;46(5):659-67. Epub 
2010/08/11. 
14. Kornblit B, Maloney DG, Storer BE, Maris MB, Vindelov L, Hari P, et al. A randomized 
phase II trial of tacrolimus, mycophenolate mofetil and sirolimus after non-myeloablative 
unrelated donor transplantation. Haematologica. 2014;99(10):1624-31. Epub 
2014/08/03. 
15. Peccatori J, Forcina A, Clerici D, Crocchiolo R, Vago L, Stanghellini MT, et al. Sirolimus-
based graft-versus-host disease prophylaxis promotes the in vivo expansion of 
regulatory T cells and permits peripheral blood stem cell transplantation from 
haploidentical donors. Leukemia. 2015;29(2):396-405. Epub 2014/06/05. 
16. Furlong T, Kiem HP, Appelbaum FR, Carpenter PA, Deeg HJ, Doney K, et al. Sirolimus 
in combination with cyclosporine or tacrolimus plus methotrexate for prevention of graft-
versus-host disease following hematopoietic cell transplantation from unrelated donors. 
Biol Blood Marrow Transplant. 2008;14(5):531-7. Epub 2008/04/16. 
17. Johnston L, Florek M, Armstrong R, McCune JS, Arai S, Brown J, et al. Sirolimus and 
mycophenolate mofetil as GVHD prophylaxis in myeloablative, matched-related donor 
hematopoietic cell transplantation. Bone Marrow Transplant. 2012;47(4):581-8. Epub 
2011/05/10. 
18. Cutler C, Stevenson K, Kim HT, Richardson P, Ho VT, Linden E, et al. Sirolimus is 
associated with veno-occlusive disease of the liver after myeloablative allogeneic stem 
cell transplantation. Blood. 2008;112(12):4425-31. Epub 2008/09/09. 
19. Brunstein CG, Miller JS, Cao Q, McKenna DH, Hippen KL, Curtsinger J, et al. Infusion of 
ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: 
safety profile and detection kinetics. Blood. 2011;117(3):1061-70. 


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20. Rubinstein, P., et al., Outcomes among 562 recipients of placental-blood transplants 
from unrelated donors. N Engl J Med, 1998. 339(22): p. 1565-77. 
 


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Appendix I – Eligibility Checklist 
Eligibility Checklists are now kept in Oncore 
 


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Appendix II – Karnofsky Performance Status and Lansky Play Score 
For patients 16 years of age and older: 
Karnofsky Performance Scale 
Percent 
Description 
100 
Normal, no complaints, no evidence of disease. 
90 
Able to carry on normal activity; minor signs or symptoms of disease. 
80 
Normal activity with effort; some signs or symptoms of disease. 
70 
Cares for self, unable to carry on normal activity or to do active work. 
60 
Requires occasional assistance, but is able to care for most of his/her needs. 
50 
Requires considerable assistance and frequent medical care. 
40 
Disabled, requires special care and assistance. 
30 
Severely disabled, hospitalization indicated.  Death not imminent. 
20 
Very sick, hospitalization indicated. Death not imminent. 
10 
Moribund, fatal processes progressing rapidly. 
0 
Dead. 
 
For patients < 16 years of age: 
Lansky 
Score 
Play Score 
100 
Fully active, normal 
90 
Minor restrictions in physically strenuous activity 
80 
Active, but tires more quickly 
70 
Both greater restriction of and less time spent in play activity 
60 
Up and around, but minimal active play; keeps busy with quieter activities 
50 
Gets dressed but lies around much of the day, no active play but able to participate 
in all quiet play and activities 
40 
Mostly in bed; participates in quiet activities 
30 
In bed; needs assistance even for quiet play 
20 
Often sleeping; play entirely limited to very passive activities 
10 
No play; does not get out of bed 
0 
Unresponsive 
 
 


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Appendix III – TBI Guidelines 
 
All patients who have had previous radiation therapy or TBI will be seen by Radiation Oncology 
prior to entrance on the protocol for approval for additional 200 cGy of TBI. TBI may be 
delivered by local guidelines provided the effective dose is equivalent to what is recommended 
in the TBI Guidelines. 
Patients ineligible for this protocol include those who have had previous irradiation to areas of 
the body such that the Radiation Oncologist feels that even a relatively small dose of total body 
irradiation (TBI) cannot safely be given.   
The dose of TBI will be 200 cGy given in a single fraction on Day -1. 
The dose rate will be between 10-19 cGy/minute prescribed to the midplane of the patient at the 
level of the umbilicus. 
The TBI will be delivered with right and left lateral fields with the patient semi-recumbent in a 
semi-fetal position with their arms at their sides. 
Based on measurement of transverse thickness, aluminum compensators will be used to ensure 
that the dose homogeneity across the fields is within 10% of the prescribed dose. Usually head/ 
neck, leg and lung compensators are used (although based on calculated mid-mediastinal 
doses, lung compensators are often not needed if the thickness of the arms, which partially 
shield the lung, are taken into the thickness consideration). 
TBI will be delivered with a linear accelerator using 6, 10, or 18 MV photons. The energy used 
will be based on the calculated dose to midline at points along the patient's torso. The lowest 
energy that gives 90-100% of the prescriptions point dose will be used. 
A beam "spoiler" will be used to ensure a full skin dose. 
Half value layer lung and kidney blocks will not be utilized for patients who have not previously 
received total body irradiation. 
Updated 10/2015 by Kathryn Dusenbery, MD 
 
 
 
 
 
 
 

ICF_001.pdf: