A Phase II Study of Thiotepa Added to Fludarabine and Melphalan as the Preparative Regime for Alternative Donor Transplantation
Phase: PHASE2
Conditions: Leukemia
Sponsor: Case Comprehensive Cancer Center



CASE xxxx10Z17 
 
 
 
Page 2  
 
 
Version date: 
02.21.2023 
 
 
 
 
SUPPORT/FUNDING: 
 
List any support/grants or any funding source (partial or 
full) here 
 
IND #:  
 
 
 
Exempt 
 
 
 
 
OTHER AGENT(S): 
 
Thiotepa / Melphalan / Fludarabine  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

CASE xxxx10Z17 
 
 
 
Page 3  
 
 
Version date: 
02.21.2023 
 
SUMMARY OF CHANGES 
 
Protocol 
Date 
Section 
Change 
09/14/17 
 
Initial IRB approval 
12/19/17 
Cover page 
Added Clinical Trials.gov NCT #; updated version date and contact 
information for study coordinator 
 
Protocol Summary 
Inclusion criteria revised to be consistent with Section 4.1.2 
 
11.1.2 
Revised to indicate timing of follow-up tests and procedures 
 
 
11.2 
Footnotes added to the Study Calendar to indicate timing of tests and 
procedures 
03.22.18 
Cover page 
Updated version date 
 
Protocol Summary 
Corrected typographical error 
 
4.2.1 
Changed Pulmonary function: DLCOcorr < 40% normal to 
Pulmonary function:  DLCOc <40% normal 
 
8.2.2 
Corrected typographical error 
04.13.18 
Cover page 
Updated version date 
 
8.2.3 
Updated CTCAE version to 5.0 
 
11.1.2 
Text has been added to clarify the timing of the bone marrow 
aspiration 
 
11.2 
Footnotes have been revised to clarify the timing of the bone marrow 
aspiration 
10.31.18 
Cover page 
Updated version date 
 
Cover page 
KGF added to other agents 
 
Fig. 2 
work  
 
Protocol summary 
Added: KGF 60mcg/kg IV on day -11, -10, and -9 and 0, +1, and +2. 
 
3.4 
Day -8 changed to day -11 
 
6.2 
Added: Keratinocyte Growth Factor (Palifermin, Kepivance, K) will 
be given at a dose of 60mcg/kg IV on day -11, -10, and -9 and 0, +1, 
and +2 for both haplo-identical transplants and dUCBT. 
 
8.1.7 
Added: 8.1.7 Palifermin (Kepivance) 
Palifermin may cause rash, itching, redness, or discoloration of the 
skin. It may cause edema, an increase in pancreatic enzymes. It may 
cause arthralgia. It may cause tongue discoloration or tongue edema. 
 
8.1.8 
Renumbered from 8.1.7 
 
9.1.4 
Added Kepivance, Palifermin, KGF, Keratinocyte Growth Factor 
Pharmacologic information 

CASE xxxx10Z17 
 
 
 
Page 4  
 
 
Version date: 
02.21.2023 
 
Protocol 
Date 
Section 
Change 
 
11.1.2 
Added:  
T-11, -10, -9 
• Keratinocyte Growth Factor (Palifermin, Kepivance, K) will 
be given at a dose of 60mcg/kg  
T +0 
• Infusion of graft source: dUCBT or Haplo-Identical Donor 
• Keratinocyte Growth Factor (Palifermin, Kepivance, K) will 
be given at a dose of 60mcg/kg IV after the infusion of the 
hematopoietic stem cells 
T +1 
• Keratinocyte Growth Factor (Palifermin, Kepivance, K) will 
be given at a dose of 60mcg/kg IV 
T +2 
• Keratinocyte Growth Factor (Palifermin, Kepivance, K) will 
be given at a dose of 60mcg/kg IV 
 
11.2 
Study calendar updated to include KGF 
12.13.18 
Figure 2 
Protocol summary 
6.2 
Corrected dose of rabbit ATG (A) to 1 mg/kg on day -3 and 2 
mg/kg on day -2 
 
11.2 
Correct study calendar to indicate Palifermin on days -11, -10, -9 
(not -8) 
2.7.2020 
Through 
out document 
Minor grammatical & typographical corrections 
Updated protocol version date in footer 
Figures updated to correspond with text updates 
 
Title page 
Updated version date 
Updated study nurse  
 
1.3 
Added: Alternative donor transplant have acceptable clinical 
outcomes comparable to matched unrelated donors, therefore 
anyone without a matched related donor may be a candidate for 
this trial 
 
2.1 
Changed leukemia-free survival to disease-free survival 
 
4.1.1 
Added intermediate risk to inclusion criteria: Complete Remission 
(CR1) with poor or intermediate-risk cytogenetics or molecular 
markers (e.g. Flt 3 mutation, 11q23, del 5, del 7, complex 
cytogenetics) 
 
4.1.1 
Added treatment related MDS to inclusion criteria: Myelodysplastic 
syndromes (MDS), Intermediate, High or Very High Risk by the 
revised international prognostic scoring system (IPSS-R; See 
Appendix B) or treatment related MDS. 
 
4.1.1 
Added Intermediate one to inclusion criteria: Myelofibrosis (MF): 
Intermediate-1, Intermediate-2 or high risk by DIPSS-plus 
 
4.1.1 
Added inclusion criteria: Chronic Myelomonocytic Leukemia 

CASE xxxx10Z17 
 
 
 
Page 5  
 
 
Version date: 
02.21.2023 
 
Protocol 
Date 
Section 
Change 
 
4.1.4 
Removed unrelated from inclusion criteria: Patients without a 
matched related donor 
 
8.2.3 
Added clarification: exempting those previously mentioned in section 
8.2.2 
 
8.2.3 
Added clarification: Attribution is required for the treatment as a 
whole, not individual components of the treatment. 
 
8.4 
Added clarification: expected adverse events listed in Sec. 8.2.2 above 
(not collected at all). 
 
11.1 
Added differential to Complete Blood Count and Differential  
 
11.1.2 
Treatment Period corrected from day -8 to: 
Treatment time will begin the day -11  
 
11.2 
Corrected study calendar to indicate testing window of 2 weeks 
Added clarifications to footer 
5/13/20 
Through-out 
document 
Updated protocol version date in footer  
 
4.0 
Added missing OR to inclusion criteria 
o Relapsed or Refractory Lymphoid Malignancies 
(including 
non-Hodgkin 
Lymphoma, 
Hodgkin 
Lymphoma) meeting the following criteria: 
 Disease 
status: 
Stable 
Disease, 
Partial 
Remission or Complete Remission OR 
 Have relapsed after autologous transplant or 
who have failed to collect for an autologous 
transplant.  
 
7/22/20 
Through-out 
document 
Updated protocol version date in footer  
 
Cover page 
Updated version date 
 
7.0 
Revised to specify that the fludarabine dose may be reduced for 
patients at an increased risk for neurotoxicity, including those with 
impaired renal function, prior high dose cytarabine, intrathecal 
therapy, or cranial irradiation and prior HSCT with fludarabine 
conditioning. 
1/8/2021 
Through-out 
document 
Updated protocol version date in footer  
 
Cover page 
Updated version date; updated study staff 
 
7.0 
Revised  thiotepa dose modification to add or has comorbidities that 
may increase the risk of morbidity or mortality with conditioning 
chemotherapy, the dosage of thiotepa may be reduced to 7.5mg/kg or 
5mg/kg at the discretion of the treating physician. 
 
7.0 
Added: If a patient develops a reaction to KGF that significantly 
impacts the care, health, and/or functionality of the patient, further 
doses may be omitted from the preparative regimen. 

CASE xxxx10Z17 
 
 
 
Page 6  
 
 
Version date: 
02.21.2023 
 
Protocol 
Date 
Section 
Change 
3/31/21 
Through-out 
document 
Updated protocol version date in footer  
 
Through-out 
document 
Minor corrections to spelling, grammar, and document formatting 
 
Study Schema 
Figure 1: “Decision Tree on how donor sources are decided for 
patients enrolled in CASE 10Z17” revised 
 
Study Schema 
Study Summary 
ATG for cord blood transplants removed as a treatment option for this 
protocol. We will not be utilizing ATG in cord blood transplants per 
ASTCT guidelines. 
 
Table of abbrevia-
tions 
Abbreviations added, table reorganized into alphabetical order for 
ease of use 
 
1.3 
ATG for cord blood transplants removed as a treatment option for this 
protocol per ASTCT guidelines 
 
1.3 
Removed ATG dosing, added We will not be utilizing ATG in cord 
blood transplants per ASTCT guidelines. 
 
3.4 
Clarification: Added definition of treatment failure 
 
4.1.2 
Upper age limit lowered from 75 years to 65 years 
 
4.2.1 
Creatinine clearance changed from <30 to <50 ml/min 
AST(SGOT) & ALT(SGPT) changed from > 2X to >3X ULN 
DLCOc  changed from <40 to < 60% normal 
Ejection fraction changed from < 35% to <50% 
KPS<80 
 
Thus, revised section is: 
Patients with inadequate Organ Function as defined by: 
o Creatinine clearance < 50ml/min 
o BilirubinS > 2X institutional upper limit of normal 
o AST (SGOT) > 3X institutional upper limit of normal 
o ALT (SGPT) > 3X institutional upper limit of normal 
o Pulmonary function: DLCOc < 60% normal 
o Cardiac: left ventricular ejection fraction < 50% 
o KPS < 80 
 
6.1 
Figure 1: “Decision tree for choosing of a graft” revised 
 
6.2 
Removed ATG dosing, ATG no longer utilized in cord blood 
transplants per ASTCT guidelines 
 
8.1.6 
Removed ATG risks, ATG no longer utilized in cord blood 
transplants per ASTCT guidelines 
 
8.1 
Sections re-numbered after deletion of section 8.1.6 
 
11.1.2 
Removed ATG as treatment options, ATG no longer utilized in cord 
blood transplants per ASTCT guidelines 
 
Appendix A 
Karnofsky Performance Status added 
 
Appendix B 
Revised 

CASE xxxx10Z17 
 
 
 
Page 7  
 
 
Version date: 
02.21.2023 
 
Protocol 
Date 
Section 
Change 
6/22/21 
Through-out 
document 
Updated protocol version date in footer  
References re-numbered as needed 
 
Cover page 
Study coordinator updated 
 
decision tree 
Updated 
 
1.3 
Added: 9. Cord blood selection will be based on ASTCT guidelines as 
well10. 
 
4.1.3 
ECOG performance status removed, Karnofsky Performance Status 
(KPS) added as protocol relies on KPS 
 
4.1.5 
Inclusion criteria update to match ASTCT current guidelines 
 
11.2 
ECOG performance status removed, Karnofsky Performance Status 
(KPS) added as protocol relies on KPS 
 
Appendix A 
ECOG performance status removed as protocol relies on KPS 
 
References 
References revised 
10/26/22 
4.1 
Added inclusion criteria: Mixed Phenotypic Leukemia / Biphenotypic 
Leukemia in CR 
2/21/23 
Cover page 
Study Schema 
Protocol Summary 
Abbreviations 
6.2 
7.0 
8.1.6 
9.1.4 
11.1 
11.2 
Palifermin (Kepivance or Keratinocyte Growth Factor (KGF)) is no 
longer manufactured, thus is no longer available and is being removed 
from the protocol.  
 

CASE xxxx10Z17 
 
 
 
Page 8  
 
 
Version date: 
02.21.2023 
 
STUDY SCHEMA  
 
Figure 1. Decision Tree on how donor sources are decided for patients enrolled in 
CASE 10Z17 
 
 
 

CASE xxxx10Z17 
 
 
 
Page 9  
 
 
Version date: 
02.21.2023 
 
 
Figure 2. Preparative Regimen and Thiotepa Dosing for Double Umbilical Cord 
Transplant (dUCBT) and haplo-identical transplant (Haplo).  

CASE xxxx10Z17 
 
 
 
Page 11  
 
 
Version date: 
02.21.2023 
 
PROTOCOL SUMMARY 
 
Protocol Number/Title 
CASE 10Z17 A Phase II Study of Thiotepa added to 
Fludarabine and Melphalan as the Preparative Regime for 
Alternative Donor Transplantation 
Study Phase 
II  
Brief Background/Rationale 
 
 
 
In the United States, thiotepa has been utilized in reduced 
intensity conditioning regimens for alternative donor courses 
(double umbilical cord blood transplant (dUCBT) and haplo-
identical transplants). 
Our hypothesis is that thiotepa at a dose of 10mg/kg, in 
combination with melphalan (100mg/m2) and fludarabine 
(160mg/m2) as a reduced intensity conditioning regimen for 
alternative donor transplant is safe and effective in patients 
with hematologic malignancies 
Given that this regimen has been investigated extensively, 
and the current study proposes to confirm those previous 
observations with a small modification (melphalan dose 
reduction due to previous mucositis rates with higher doses), 
this will be a phase II study designed to measure disease-
free-survival.   
Primary Objective  
To assess the effectiveness of Thiotepa, Fludarabine, and 
Melphalan in alternative donor transplants as measured by 
leukemia free survival. 
Secondary Objective(s) 
To assess the 1- year OS, Relapse, TRM, aGVHD and 
cGVHD, rates of neutrophil and platelet engraftment. 
Sample Size 
Approximately 39 males and females 1 year  to 75 years of 
age 
Disease sites/Conditions 
Acute Myelogenous Leukemia (AML), Acute Lymphocytic 
Leukemia (ALL), Chronic Myelogenous Leukemia (CML), 
Myelodysplastic syndrome (MDS), Myelofibrosis and 
Lymphoma 
Interventions 
Melphalan 100 mg/m2 on day −8 
Thiotepa 10 mg/kg on day -7  
Fludarabine 160 mg/m2 in divided doses given on days −6, 
−5, −4 and −3.  
 
 
 
If the patient undergoes a haplo-identical transplant, post-
transplant cyclophosphamide will be added as 50 mg/kg 
given on each of days +3 and +4. 

CASE xxxx10Z17 
 
 
 
Page 12  
 
 
Version date: 
02.21.2023 
 
ABBREVIATIONS  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE 
Adverse event 
aGVHD Acute Graft Versus Host Disease 
AML 
Acute Myelogenous Leukemia 
ALL 
Acute Lymphocytic Leukemia 
ASTCT 
American Society for Transplantation and Cellular Therapy 
CCCC 
Case Comprehensive Cancer Center 
CCF 
Cleveland Clinic Foundation 
cGVHD Chronic Graft Versus Host Disease  
CML 
Chronic Myelogenous Leukemia  
CNS 
Central Nervous System 
CR 
Complete Remission 
CRF 
Case Report Form 
CTCAE NCI Common Terminology Criteria for Adverse Events 
DCRU 
Dahm’s Clinical Research Unit 
DFS 
Disease Free Survival 
DSTC 
Data Safety and Toxicity Committee 
dUCBT 
Double Umbilical Cord Blood Transplant 
FDA 
Food and Drug Administration 
ICF 
Informed Consent Form 
IPS 
Idiopathic Pneumonia Syndrome 
IPSS-R 
Revised International Prognostic Scoring System 
IRB 
Institutional Review Board 
GVHD 
Graft Versus Host Disease 
GVL 
Graft Versus Leukemia 
 
 
KPS 
Karnofsky Performance Statue 
LFS 
Leukemia Free Survival 
MDS 
Myelodysplastic Syndrome 
MMF 
Mycophenolate Mofetil 
OS 
Overall Survival 
PRMC 
Protocol Review and Monitoring Committee 
RIC 
Reduced Intensity Conditioning 
SAE 
Severe Adverse Event 
SOC 
Standard of Care 
TBI 
Total Body Irradiation  
TRM 
Transplant Mortality Rate  
UCB 
Umbilical Cord Blood 
UH 
University Hospitals 
VOD 
Veno-occlusive Disease of the Liver 

CASE xxxx10Z17 
 
 
 
Page 13  
 
 
Version date: 
02.21.2023 
 
TABLE OF CONTENTS 
 
1.0  
INTRODUCTION  
 
1.1 
Study Diseases  
1.2  
Name/description of Investigational Agents 
1.3  
Rationale   
 
2.0 
OBJECTIVES 
2.1 
Primary Objective 
 
2.2  
Secondary Objective(s) 
 
3.0 
STUDY DESIGN 
3.1 
Study design 
3.2 
Number of Subjects 
3.3 
Replacement of Subjects 
3.4 
Expected Duration of Treatment and Subject Participation 
 
 
4.0  
SUBJECT SELECTION 
4.1 
Inclusion Criteria 
4.2  
Exclusion Criteria 
4.3 
Inclusion of Women and Minorities 
 
5.0 
REGISTRATION  
 
 
6.0  
TREATMENT PLAN 
6.1 
Donor Selection  
6.2 
Conditioning Regimen  
6.3  
General Concomitant Medications and Supportive Care Guidelines 
6.4 
Criteria for Removal from Study 
6.5 
Duration of Follow-Up 
 
7.0 
DOSE DELAYS / DOSE MODIFICATIONS 
 
8.0 
POTENTIAL RISKS, ADVERSE EVENTS, REPORTING 
REQUIREMENTS 
8.1  
Potential Risks 
8.2 
Definitions 
8.3 
Serious Adverse Event Report Form 
8.4 
Reporting Procedures for Serious Adverse Event  
8.5 
Serious Adverse Events and OnCoreTM    
8.6 
Data Safety Toxicity Committee 
8.7 
Data and Safety Monitoring Plan 
 
9.0 
PHARMACEUTICAL INFORMATION  
9.1 
Agent(s) 
 
 

CASE xxxx10Z17 
 
 
 
Page 14  
 
 
Version date: 
02.21.2023 
 
10.0 
EXPLORATORY/CORRELATIVE  
n/a 
 
11.0 
STUDY PARAMETERS AND CALENDAR 
11.1 
Study Parameters 
11.2 
Calendar 
 
12.0 
MEASUREMENT OF EFFECT  
 
13.0 
RECORDS TO BE KEPT/REGULATORY CONSIDERATIONS 
13.1 
Data Reporting 
13.2 
Regulatory Considerations  
 
 
14.0 
STATISTICAL CONSIDERATIONS 
14.1 
Design and Sample Size 
14.2 
Analysis Plan 
 
REFERENCES 
 
  
APPENDICES  
 
 
 
APPENDIX A:  
Karnofsky Performance Score 
 
APPENDIX B: 
Revised International Prognostic Scoring System (IPSS-R) 
 
APPENDIX C: 
Acute GVHD staging per Blood and Marrow Transplant Clinical Trials Network Manual 
of Operations (BMT MOP) 
 
APPENDIX D: 
Acute GVHD grading per Blood and Marrow Transplant Clinical Trials Network Manual 
of Operations (BMT MOP) 
 
APPENDIX E: 
Acute GVHD clinical assessment per Blood and Marrow Transplant Clinical Trials 
Network Manual of Operations (BMT MOP) 
 
 
APPENDIX F: 
 
 
Chronic GVHD severity scoring per Blood and Marrow Transplant Clinical Trials 
Network Manual of Operations (BMT MOP)

CASE xxxx10Z17 
 
 
 
Page 15  
 
 
Version date: 
02.21.2023 
 
1.0 
Introduction  
 
1.1 
Study Diseases  
Acute Myelogenous Leukemia (AML), Acute Lymphocytic Leukemia (ALL), Chronic 
Myelogenous Leukemia (CML), Myelodysplastic syndrome (MDS), Myelofibrosis and 
Lymphoma 
 
1.2  
Name and Description of Investigational Agents  
Thiotepa / Melphalan / Fludarabine in Alternative Donor Transplants  
 
1.3 
Rationale  
Reduced intensity conditioning (RIC) regimens have expanded availability of allogeneic 
transplantation and therefore cure to a greater number of patients who would not be 
otherwise eligible for myeloablative transplantation based on age or organ function1. 
However, the rates of relapse with such regimens remain high and thus there have been 
attempts to intensify RIC with a number of chemotherapeutic or immunologic agents2,3. 
Thiotepa, an alkylating agent with very good central nervous system penetration, has been 
studied in a number of phase II trials as a way to intensify RIC and achieve better outcomes 
for patients with hematologic malignancies4,5.  
 
Thiotepa has been shown to be safe and effective as an additional chemotherapeutic to 
conditioning regimens. In an European Society for Blood and Marrow Transplant (EBMT) 
retrospective analysis of the use of thiotepa as a part of the conditioning regimen in 
allogeneic transplant for AML, which included matched related donors, matched unrelated 
donors, and cord blood transplants, the majority of the conditioning regimens were 
myeloablative and consisted of: fludarabine, busulfan, and thiotepa; fludarabine and 
thiotepa (+/- TBI); and cyclophosphamide and thiotepa (+/- TBI)6. The overall leukemia 
free survival at 3 years was 41% in patients in CR1; non-relapse mortality at 3 years was 
19%. The rates of mucositis were 47% and the rate of VOD was 4%, even with the high 
percentage of myeloablative conditioning within the cohort.  
 
In the United States, thiotepa has been utilized in reduced intensity conditioning regimens 
for alternative donor courses (double umbilical cord blood transplant (dUCBT) and haplo-
identical transplants). In a retrospective analysis of dUCBT for AML, thiotepa at 10mg/kg 
was added to melphalan 140mg/m2 and fludarabine 160mg/m2 4. Forty-three of 47 patients 
engrafted (91%); and 1-year treatment related mortality was 28%. One year overall survival 
was 59%. The major toxicity was GI (nausea / vomiting / mucositis / diarrhea) and there 
was no veno-occlusive disease diagnosed in this cohort. In a retrospective analysis of 
haplo-identical transplants for AML, thiotepa at 10mg/kg was added to melphalan 
140mg/m2 and fludarabine 160mg/m25. Haplo-identical grafts were CD34+ selected.  
Although there was a high rate of graft failure (22%), many patients had donor-specific 
antibodies (3 out of 22 patients). The major toxicity was GI (nausea / vomiting / mucositis 
/ diarrhea) and there was no veno-occlusive disease diagnosed in this cohort. The non-
relapse mortality was 32% and there was a high rate of relapse in these high risk patients 
(44% by day 72 post-transplant).  
 

CASE xxxx10Z17 
 
 
 
Page 16  
 
 
Version date: 
02.21.2023 
 
Besides utilizing chemotherapy to reduce relapse, another mechanism by which one can 
affect disease control is through the graft versus leukemia (GVL) effect. Recently Milano 
et al published data in support of superior GVL with cord blood grafts7. There is not similar 
data in regards to haplo-identical transplants. 
 
Our hypothesis is that thiotepa at a dose of 10mg/kg, in combination with melphalan 
(100mg/m2) and fludarabine (160mg/m2) as a reduced intensity conditioning regimen for 
alternative donor transplant is safe and effective in patients with hematologic malignancies. 
Alternative donor transplant have acceptable clinical outcomes comparable to matched 
unrelated donors, therefore anyone without a matched related donor may be a candidate for 
this trial8. We have decided to reduce the melphalan dose to limit GI toxicity associated 
with the combination of melphalan (at 140mg/m2), fludarabine (160mg/m2) and thiotepa 
(10mg/kg). We will not be utilizing ATG in cord blood transplants per ASTCT guidelines9. 
Cord blood selection will be based on ASTCT guidelines as well10. Haplo-identical 
transplants will undergo post-transplant cyclophosphamide for GVHD prophylaxis. 
 
Given that this regimen has been investigated extensively, and the current study proposes 
to confirm those previous observations with a small modification (Melphalan dose 
reduction due to previous mucositis rates with higher doses), this will be a phase II study 
designed to measure disease-free-survival.   
 
 
2.0  
Objectives 
 
2.1  
Primary Objective  
To assess the effectiveness of Thiotepa, Fludarabine, and Melphalan in alternative donor 
transplants as measured by disease free survival. 
 
2.2 
Secondary Objective(s) 
To assess the 1- year OS, Relapse, TRM, aGVHD and cGVHD rates and the rates of 
neutrophil and platelet engraftment. 
 
 
3.0 
Study Design 
 
3.1  
Study design  
This is a Phase II study of Thiotepa, Fludarabine, and Melphalan in alternative donor 
transplants. 
 
Subjects will be assessed for safety and tolerability (including adverse events, serious 
adverse events, and clinical/laboratory assessments) using a continuous monitoring 
approach. Subjects will be followed for up to 1 year or until progression of disease, relapse, 
or death.  
 
3.2 
Number of Subjects 
Approximately 39 subjects will be enrolled in this trial.  

CASE xxxx10Z17 
 
 
 
Page 17  
 
 
Version date: 
02.21.2023 
 
 
 
3.3 
Replacement of Subjects  
There may be replacement of subjects if a patient is enrolled but does not start treatment 
before they come off study.  
 
3.4  
Expected Duration of Treatment and Subject Participation 
Treatment time will begin the day -11 before transplant and continued until the 
conditioning regimen is completed; for dUCBT this is T+0 and for haplo-identical 
transplant this is T+4. 
 
Patients will be followed for 12 months post-transplant, unless treatment failure. Treatment 
failure is defined by disease  relapse, graft failure, or death. Patients will  continue to be 
followed for safety for up to 30 days afterwards. 
 
Patients will be followed for toxicity for 30 days after therapy has been completed or until 
death, whichever occurs first.  
 
The clinical course of each event will be followed until resolution, stabilization, or until it 
has been determined that the study treatment or participation is not the cause. 
 
Serious adverse events that are still ongoing at the end of the study period will necessitate 
follow-up to determine the final outcome. Any serious adverse event that occurs after the 
study period and is considered to be possibly related to the study treatment or study 
participation will be recorded and reported immediately. 
 
 
4.0 
Subject Selection 
Each of the criteria in the sections that follow must be met in order for a subject to be 
considered eligible for this study. Use the eligibility criteria to confirm a subject’s 
eligibility.  
 
Subject’s Name 
_____________________________________________________________ 
 
Medical Record # 
___________________________________________________________ 
 
Research Nurse / Study Coordinator Signature: 
____________________________________________ 
Date __________ 
 
Treating Physician [Print] 
____________________________________________________ 
 
Treating Physician Signature: 
______________________________________________ Date __________ 

CASE xxxx10Z17 
 
 
 
Page 18  
 
 
Version date: 
02.21.2023 
 
 
 
 
4.1 
Inclusion Criteria 
 
 
Subjects must meet all of the following inclusion criteria to be eligible for enrollment:  
 
 
 
4.1.1 Patients with the following hematologic malignancies: 
o Acute myelogenous leukemia (AML): High-risk AML including: 
 Antecedent hematological disease (e.g., myelodysplasia (MDS)) 
 Treatment-related leukemia 
 Complete Remission (CR1) with poor or intermediate-risk 
cytogenetics or molecular markers (e.g. Flt 3 mutation, 11q23, del 
5, del 7, complex cytogenetics) 
 CR2 or CR3 
 Induction failure or 1st relapse with < 10% blasts in the marrow  
o Acute lymphoblastic leukemia (ALL) 
 High-risk CR1 including: 
• Poor-risk cytogenetics (e.g., Philadelphia chromosome 
t(9;22)or 11q23 rearrangements) 
• Presence of minimal disease by flow cytometry after 2 or 
more cycles of chemotherapy 
 No CR within 4 weeks of initial treatment 
 Induction failure with <  10% blasts in the marrow 
 CR2 or CR3  
o Myelodysplastic syndromes (MDS), Intermediate, High or Very High Risk 
by the revised international prognostic scoring system (IPSS-R; See 
Appendix B) or treatment related MDS. 
o Mixed Phenotypic Leukemia / Biphenotypic Leukemia in CR 
o Chronic Myelogenous Leukemia (CML) in second chronic phase after 
accelerated or blast crisis.  
o Myelofibrosis (MF): 
 Intermediate-1, Intermediate-2 or high risk by DIPSS-plus 
(Appendix D) OR  
 Monosomal karyotype OR  
 Presence of inv(3)/i(17q) abnormalities OR  
 Other unfavorable karyotype OR leukocytes  ≥40 × 10(9) /L AND 
 Circulating blasts =< 9% 
o Chronic Myelomonocytic Leukemia 
o Relapsed or Refractory Lymphoid Malignancies (including non-Hodgkin 
Lymphoma, Hodgkin Lymphoma) meeting the following criteria: 
 Disease status: Stable Disease, Partial Remission or Complete 
Remission  OR  
 Have relapsed after autologous transplant or who have failed to 
collect for an autologous transplant.  
 

CASE xxxx10Z17 
 
 
 
Page 19  
 
 
Version date: 
02.21.2023 
 
 
 
4.1.2 Age > 1 years, < 65yrs  
 
 
 
4.1.3 KPS Performance status  ≥80 [See Appendix A] 
 
 
 
4.1.4 Patients without a matched related donor 
 
 
 
4.1.5 Patient with either one or both: 
 
 
o A related haplo-identical donor 
o Two 4/8 HLA or better high resolution matched UCB grafts with a cell dose 
of 1.5x107 TNC/kg each and 1x105CD34+ cells/ kg each. 
 
 
 
4.1.6 Concurrent Therapy for Extramedullary Leukemia or CNS Lymphoma: 
Concurrent therapy or prophylaxis for testicular leukemia, CNS leukemia, and CNS 
lymphoma including standard intrathecal chemotherapy and/or radiation therapy 
will be allowed as clinically indicated. Such treatment may continue until the 
planned course is completed. Subjects must be in CNS remission at the time of 
protocol enrollment if there is a history of CNS involvement. Maintenance therapy 
after transplant is allowed. 
 
 
 
4.1.7 Subjects must have the ability to understand and the willingness to sign a 
written informed consent document. 
 
4.2 
Exclusion Criteria 
 
The presence of any of the following will exclude a subject from study enrollment. 
 
 
 
4.2.1 Patients with inadequate Organ Function as defined by: 
o Creatinine clearance < 50ml/min 
o Bilirubin > 2X institutional upper limit of normal 
o AST (SGOT) > 3X institutional upper limit of normal 
o ALT (SGPT) > 3X institutional upper limit of normal 
o Pulmonary function: DLCOc < 60% normal 
o Cardiac: left ventricular ejection fraction < 50% 
o KPS < 80 
 
 
 
4.2.2 Patients with uncontrolled inter-current illness including, but not limited to 
ongoing or active infection, symptomatic congestive heart failure, unstable angina 
pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit 
compliance with study requirements. 
 
 
 
4.2.3 Pregnant or breastfeeding women are excluded from this study because 
chemotherapy involved with RIC have the significant potential for teratogenic or 
abortifacient effects. 
 

CASE xxxx10Z17 
 
 
 
Page 20  
 
 
Version date: 
02.21.2023 
 
 
 
4.2.4 Any condition that would, in the investigator's judgment, interfere with full 
participation in the study, including administration of study drug and attending 
required study visits; pose a significant risk to the subject; or interfere with 
interpretation of study data. 
 
 
 
4.2.5 Known allergies, hypersensitivity, or intolerance to any of the study 
medications, excipients, or similar compounds. 
 
 
 
4.2.6 Presence of donor-specific antibodies against chosen graft source. 
 
4.3 
Inclusion of Women and Minorities  
Men, women and members of all races and ethnic groups are eligible for this trial. 
 
 
5.0 
Registration 
All subjects who have been consented are to be registered in the OnCore™ Database. For 
those subjects who are consented, but not enrolled, the reason for exclusion must be 
recorded. 
 
All subjects will be registered through University Hospitals Cleveland Medical Center and 
will be provided a study number by contacting the study coordinator listed on the cover 
page.  
 
 
 

CASE xxxx10Z17 
 
 
 
Page 21  
 
 
Version date: 
02.21.2023 
 
6.0  
Treatment Plan 
 
6.1 
Donor Selection 
Figure 1: Decision tree for choosing of a graft 
 
 
 
 
6.2 
Conditioning Regimen 
The conditioning regimen would consist of:  
Melphalan 100 mg/m2 on day −8  
Thiotepa 10 mg/kg on day -7  
Fludarabine 40mg/m2/day on days -6, -5, -4 and -3 
 
If the patient undergoes a haplo-identical transplant, post-transplant cyclophosphamide 
will be added as 50 mg/kg given on each of days +3 and +4.All monitoring is done per 
standard of care. 
 
CTCAE v 5.0 will be used as the criteria for evaluating infusion-related events. We will 
attribute acute toxic effects noted during and within 60 minutes of the infusion to 
administration of that cellular product.  
 
6.3 
General Concomitant Medications and Supportive Care Guidelines 
6.3.1 Graft versus host disease prophylaxis 
1. 
For dUCBT:  

CASE xxxx10Z17 
 
 
 
Page 22  
 
 
Version date: 
02.21.2023 
 
a. Tacrolimus will be initiated on the day –5 before the transplant. Tacrolimus will 
be administered IV at 0.02 mg/kg/dose over 24 hours. Subsequently doses will be 
adjusted according to trough levels monitored at least biweekly and/or upon 
symptoms or alteration in renal function. When appropriate, the treating physician 
may transition the patient to oral tacrolimus.  The target range for serum tacrolimus 
levels will be 7 ng/mL to 15 ng/mL, or as clinically indicated. This dose of 
tacrolimus will continue until day +100, and then will be tapered as long as the 
severity of GVHD is less than grade II.  
b. Mycophenolate mofetil (MMF) will be given at 1g intravenously or orally twice 
daily from day -5 to +100, or as clinically indicated. 
2. 
For haplo-identical transplants: 
a. Tacrolimus will be initiated on the day + 5 after the transplant. Tacrolimus will 
be administered IV at 0.02 mg/kg/dose over 24 hours. Subsequently doses will be 
adjusted according to trough levels monitored at least biweekly and/or upon 
symptoms or alteration in renal function. When appropriate, the treating physician 
may transition the patient to oral tacrolimus. The target range for serum tacrolimus 
levels will be 7 ng/mL to 15 ng/mL, or as clinically indicated. This dose of 
tacrolimus will continue until day +100, and then will be tapered as long as the 
severity of GVHD is less than grade II.  
b. Mycophenolate mofetil (MMF) will be given at 1g intravenously or orally twice 
daily from day +5 to +35, or as clinically indicated. 
 
6.3.2 Growth factor support: Per standard of care. 
 
6.4 
Criteria for Removal from Study 
In the absence of treatment delays due to adverse events, treatment may continue until one 
of the following criteria applies: 
 
• Disease progression, 
• The investigator considers it, for safety reasons, to be in the best interest of the subject.  
• Subject decision to withdraw from treatment (partial consent) or from the study (full 
consent), 
• Pregnancy during the course of the study for a child-bearing participant 
• Death, or 
• Sponsor reserves the right to temporarily suspend or prematurely discontinue this study. 
The date and reason for discontinuation must be documented. Every effort should be made 
to complete the appropriate assessments.  
 
6.5 
Duration of Follow Up 
Patients will be followed as outpatient per standard of care with their transplant physician. 
Patients will be followed for this study for 1 year following the allogeneic transplant, 
relapse, or death, whichever comes first. 
 
The clinical course of each adverse event will be followed until resolution, stabilization, or 
until it has been determined that the study treatment or participation is not the cause.  
 

CASE xxxx10Z17 
 
 
 
Page 23  
 
 
Version date: 
02.21.2023 
 
Maintenance therapy post hematopoietic stem cell transplant is allowed if clinically 
indicated or patient is eligible for another trial. 
 
Serious adverse events, such as chronic infection or grade III-IV GVHD, that are still 
ongoing at the end of the study period will necessitate follow-up to determine the final 
outcome. Any serious adverse event that occurs after the study period and is considered to 
be possibly related to the study treatment or study participation will be recorded and 
reported immediately.  
 
 
7.0  
Dose Delays/Dose Modifications 
If patient is over the age of 60 or has comorbidities that may increase the risk of morbidity 
or mortality with conditioning chemotherapy, the dosage of thiotepa may be reduced to 
7.5mg/kg or 5mg/kg at the discretion of the treating physician. 
 
In patients with an increased risk for neurotoxicity, including those with impaired renal 
function, prior high dose cytarabine, intrathecal therapy, cranial irradiation, or prior HSCT 
with fludarabine conditioning, the fludarabine dose may be reduced to 30 mg/m2 on days -
6, -5, -4 and -3 instead of 40mg/m2. 
 
If a patient develops toxicity attributed to the chemotherapy the nurse and physician will 
adhere to institutional guidelines for infusion toxicity / reaction. 
 
 
8.0 
Potential Risks, Adverse Events, Reporting Requirements 
 
8.1 
Potential Risks  
8.1.1 Thiotepa  
Thiotepa may cause a lowering of the white blood cell, red blood cell, or platelet counts, 
leading to an increased risk of infection and frequent bruising or bleeding. It may cause 
damage to the GI tract causing mouth sores, nausea, vomiting, and diarrhea. Other side 
effects may include loss of appetite, liver abnormalities, hair loss, swelling, fatigue, 
sleepiness, skin rash. 
 
8.1.2 Melphalan 
Melphalan may cause a lowering of the white blood cell, red blood cell, or platelet counts, 
leading to an increased risk of infection and frequent bruising or bleeding. It may cause 
damage to the GI tract causing mouth sores, nausea, vomiting, and diarrhea. Other side 
effects may include loss of appetite, liver abnormalities, hair loss, swelling, fatigue, 
sleepiness, skin rash. 
 
8.1.3 Fludarabine 
Fludarabine may cause a lowering of the white blood cell, red blood cell, or platelet counts, 
leading to an increased risk of infection and frequent bruising or bleeding. Other side 
effects may include loss of appetite, liver abnormalities, hair loss, swelling, fatigue, 
sleepiness, skin rash, and lower limb weakness. 

CASE xxxx10Z17 
 
 
 
Page 24  
 
 
Version date: 
02.21.2023 
 
 
8.1.4 Mycophenolate Mofetil (MMF, Cellcept) 
MMF may cause a lowering of the white blood cell, red blood cell, or platelet counts. This 
may lead to an increase in the risk of infections or bleeding. Other side effects include 
headache, rash, fever, nausea, vomiting, allergic reaction, liver abnormalities, kidney 
abnormalities, thyroid dysfunction, fatigue, and swelling.   
 
8.1.5 Tacrolimus 
Tacrolimus may cause a lowering of the white blood cell, red blood cell, or platelet counts. 
This may lead to an increase in the risk of infections or bleeding. Other side effects include 
headache, rash, fever, nausea, vomiting, allergic reaction, high blood pressure, high blood 
sugar, mental status changes, liver abnormalities, kidney abnormalities, thyroid 
dysfunction, fatigue, and swelling.   
 
8.1.7 Risks of Transplant 
Risks of Transplant include fever, nausea and vomiting, fatigue, weakness, malaise, 
diarrhea, dark stools, sores in the mouth, headache, low blood counts, cough, swelling, 
rash, hives, allergic reaction, muscle pain, loss of appetite, painful urination, red urine, 
kidney damage, liver damage, serious infection, and death. Specific risks discussed below: 
 
 
Graft rejection: First, the UCB or Haplo-Identical cells may not grow after they are 
infused. This problem is termed graft rejection, occurs rarely, and is reduced by giving 
high-dose chemotherapy. The high-dose chemotherapy is not only given to get rid of the 
cancer cells, but it will get rid of the immune system and prevent graft rejection. 
 
Graft-versus-host disease (GVHD): GVHD is the most common complication following 
allogeneic stem cell transplant. Development of GVHD can result in damage to the skin, 
intestine, liver, immune system, and occasionally bone marrow. Following an allogeneic 
stem cell transplant UCB, the risk of GVHD is roughly between 20 and 30%. Methotrexate, 
and/or prednisone and/or mycophenolate mofetil, and/or cyclosporine/tacrolimus may be 
given to prevent the development of GVHD. On the other hand, there is some benefit to 
the development of GVHD; the T-lymphocytes present in the cells obtained from an HLA 
matched UCB may kill any remaining cancer cells, a process called the graft-versus-tumor 
(GVT) effect. GVHD and GVT can occur despite the preventative medications. GVHD 
can be serious enough to cause death. Most common symptoms are skin rash diarrhea, 
yellowing of the skin, and also dry eyes, mouth sores and changes of the finger and toe 
nails. GVHD may also affect the lung, tendons and joints. 
 
Veno-occlusive disease of the liver (VOD): VOD is damage to the blood vessels of the 
liver that can be caused by the chemotherapy given before stem cell transplant. In VOD 
the flow of blood into the liver is impaired. This causes a painful enlargement of the liver, 
an increase in body fluid and weight, and an increase in blood bilirubin. In severe cases the 
liver fails, which can result in death. 
 

CASE xxxx10Z17 
 
 
 
Page 25  
 
 
Version date: 
02.21.2023 
 
Damage to the kidneys: Kidney damage may occur due to medicines used as part of the 
transplant and to prevent GVHD. Kidney function will be monitored carefully during and 
after the transplant procedure. 
 
Damage to the lungs: Lung damage may occur due to the chemotherapy used prior to stem 
cell transplant or as a result of the transplant itself. Lung inflammation that occurs early 
after transplant, in the absence of infection, is known as idiopathic pneumonia syndrome 
or IPS. IPS occurs in less than 10% of patients that received allogeneic stem cell transplant. 
However, if/when it occurs, IPS can be fatal.  Prednisone will be given to reduce the 
inflammation should IPS occur. Other IPS treatment options may be used at the discretion 
of the treating physician. 
 
Serious infections: Infections in the blood stream or other organs are more likely to occur 
because the immune system is weakened for a period of time by the stem cell transplant 
and the medicines used to prevent GVHD. These infections are sometimes fatal. 
 
These side effects, alone or in combination with other problems, may be severe enough to 
cause death. 
 
8.2 
Definitions  
 
8.2.1 
Adverse Event   
An adverse event (AE) is any unfavorable or unintended event, physical or psychological, 
associated with a research study, which causes harm or injury to a research participant as 
a result of the participant’s involvement in a research study. The event can include 
abnormal laboratory findings, symptoms, or disease associated with the research study. 
The event does not necessarily have to have a causal relationship with the research, any 
risk associated with the research, the research intervention, or the research assessments.  
 
Adverse events may be the result of the interventions and interactions used in the research; 
the collection of identifiable private information in the research; an underlying disease, 
disorder, or condition of the subject; and/or other circumstances unrelated to the research 
or any underlying disease, disorder, or condition of the subject.  
 
 
8.2.2   Serious Adverse Events  
A serious adverse event (SAE) is any adverse experience occurring at any dose that results 
in any of the following outcomes:  
• Results in death.  
• Is a life-threatening adverse experience.  The term life-threatening in the 
definition of serious refers to an adverse event in which the subject was at risk 
of death at the time of the event.  It does not refer to an adverse event which 
hypothetically might have caused death if it were more severe.  
• Requires 
inpatient 
hospitalization 
or 
prolongation 
of 
existing 
hospitalization.  Any adverse event leading to hospitalization or prolongation 

CASE xxxx10Z17 
 
 
 
Page 26  
 
 
Version date: 
02.21.2023 
 
of hospitalization will be considered as Serious, UNLESS at least one of the 
following expectations is met: 
o The admission results in a hospital stay of less than 24 hours OR 
o The admission is pre-planned (e.g., elective or scheduled surgery 
arranged prior to the start of the study) OR 
o The admission is not associated with an adverse event (e.g., social 
hospitalization for purposes of respite care. 
However it should be noted that invasive treatment during any hospitalization may 
fulfill the criteria of “medically important” and as such may be reportable as a 
serious adverse event dependent on clinical judgment.  In addition where local 
regulatory authorities specifically require a more stringent definition, the local 
regulation takes precedent.  
• Results in persistent or significant disability/incapacity.  The definition of 
disability is a substantial disruption of a person’s ability to conduct normal life’s 
functions. 
• Is a congenital anomaly/birth defect.  
• Is an important medical event.  Important medical events that may not result 
death, be life-threatening, or require hospitalization may be considered a serious 
adverse experience when, based upon appropriate medical judgment, they may 
jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition.  Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood disease or disorders, or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency 
or drug abuse. The development of a new cancer is always considered an 
important medical event. 
 
Neutropenic fever, thrombocytopenia and anemia, electrolyte disturbances, elevations of 
enzymes, LDH, gamma GT, alkaline phosphatase are expected side effects of stem cell 
transplantation and will not be considered regimen-related toxicity.   
 
8.2.3 Adverse Event Evaluation  
The investigator or designee is responsible for ensuring that all reportable adverse events 
(both serious and non-serious, exempting those previously mentioned in section 8.2.2) 
observed by the clinical team or reported by the subject which occur after the subject has 
signed the informed consent are fully recorded in the subject’s medical records. Source 
documentation must be available to support all adverse events.  
 
A laboratory test abnormality considered clinically relevant (e.g., causing the subject to 
withdraw from the study, requiring treatment or causing apparent clinical manifestations, 
result in a delay or dose modification of study treatment, or judged relevant by the 
investigator), should be reported as an adverse event.   
 
The investigator or sub-investigator (treating physician if applicable) will provide the 
following for all adverse events (both serious and non-serious): 

CASE xxxx10Z17 
 
 
 
Page 27  
 
 
Version date: 
02.21.2023 
 
• Event term (as per CTCAE) 
• Description of the event 
• Date of onset and resolution 
• Expectedness of the toxicity 
• Grade of toxicity  
• Attribution of relatedness to the investigational agent- (this must be assigned 
by an investigator, sub-investigator, or treating physician) 
• Action taken as a result of the event, including but not limited to; no changes, dose 
interrupted, reduced, discontinued, etc. or action taken with regard to the event, i.e. 
no action, received conmed or other intervention, etc. 
• Outcome of event 
 
Descriptions and grading scales found in the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting.  
 
GVHD grading scales and assessment forms are included in Appendices C-F. 
 
An expected adverse event is an event previously known or anticipated to result from 
participation in the research study or any underlying disease, disorder, or condition of the 
subject. The event is usually listed in the Investigator Brochure, consent form or research 
protocol.  
 
An unexpected adverse event is an adverse event not previously known or anticipated to 
result from the research study or any underlying disease, disorder, or condition of the 
subject.  
 
Attribution is the relationship between an adverse event or serious adverse event and the 
study drug.  Attribution will be assigned as follows: 
 
• Definite – The AE is clearly related to the study drug. 
• Probable – The AE is likely related to the study drug. 
• Possible – The AE may be related to the study drug. 
• Unlikely – The AE is doubtfully related to the study drug. 
• Unrelated – The AE is clearly NOT related to the study drug. 
 
Protocol must specify if attribution is required for individual components of the treatment 
regimen or the treatment regimen as a whole. 
Attribution is required for the treatment as a whole, not individual components of the 
treatment. 
 
8.3  
SAE Report Form 
SAEs will be recorded on the FDA Form 3500A (MedWatch) but should only be reported 
as instructed below.  The electronic FDA SAE reporting forms should not be used.   
 
8.4  
Reporting Procedures for Serious Adverse Events 

CASE xxxx10Z17 
 
 
 
Page 28  
 
 
Version date: 
02.21.2023 
 
For this study, only grade 3 and greater (according to CTCAE 5.0) AEs will be collected 
and reported, with the exception of infusion site reactions (all grades will be collected) and 
the expected adverse events listed in Sec. 8.2.2 above (not collected at all). 
 
For the purposes of safety reporting, serious adverse events that occur beginning with the 
signing of the informed consent form, during treatment, or within 30 days of the last dose 
of treatment must be reported. Adverse events, both serious and non-serious, and deaths 
that occur during this period will be recorded in the source documents. All SAEs should 
be monitored until they are resolved or are clearly determined to be due to a subject’s stable 
or chronic condition or intercurrent illness(es). Related AEs will be followed until 
resolution to baseline or grade 1 or stabilization.  
 
8.4.1 SAE Reporting Requirements 
• All serious adverse events must be reported to the Sponsor-Investigator within 24 
hours of discovery or notification of the event.  
o Leland Metheny, 216-844-0139, Leland.Metheny@uhhospitals.org 
• The Sponsor-Investigator will review the SAE and report the event to external 
collaborator(s), and IRB as applicable. 
 
Institutional Review Board Reporting Requirements: 
• Adverse events will be reported to the IRB of record according to the local IRB’s 
policies and procedures in reporting adverse events.  
 
8.5 
SAEs and OnCore 
• All SAEs will be entered into OnCore.   
• A copy of the completed SAE form (FDA Form 3500A) is also uploaded into 
Oncore. 
 
8.6  
Data Safety and Toxicity Committee 
ALL SAEs occurring on this trial must be reported to the Case Comprehensive Cancer 
Center’s Data and Safety Toxicity Committee. This submission is simultaneous with 
OnCoreTM.  
 
The Sponsor-Investigator is responsible for submitting an annual report to the DSTC as per 
CCCC Data and Safety Monitoring Plan. 
  
8.7 
Data and Safety Monitoring Plan (DSMP) 
This protocol will adhere to the policies of the Case Comprehensive Cancer Center Data 
and Safety Monitoring Plan in accordance with NCI guidelines.  
 
9.0 
PHARMACEUTICAL INFORMATION  
A list of the adverse events and potential risks associated with the investigational or 
commercial agents administered in this study can be found in Section 8.0.  
 
9.1 Agents 

CASE xxxx10Z17 
 
 
 
Page 29  
 
 
Version date: 
02.21.2023 
 
9.1.1  Thiotepa 
 
Product description: Thiotepa is an alkylating agent which produces cross-linking of 
DNA strands leading to inhibition of DNA, RNA, and protein synthesis; thiotepa is cell-
cycle independent. 
 
Solution preparation: Thiotepa for Injection, USP, for single use only, is available in vials 
containing 15 mg of nonpyrogenic, sterile lyophilized powder. 
 
Thiotepa for injection should be reconstituted with 1.5 mL of sterile water for injection 
resulting in a drug concentration of approximately 10 mg/mL. The reconstituted solution 
is hypotonic and should be further diluted with sodium chloride injection (0. 9% sodium 
chloride) before use. When reconstituted with sterile water for injection, solutions of 
thiotepa should be stored in a refrigerator and used within 8 hours.  
 
Reconstituted solutions further diluted with sodium chloride injection should be used 
immediately. In order to eliminate haze, filter solutions through a 0.22 micron filter* prior 
to administration. Filtering does not alter solution potency. Reconstituted solutions should 
be clear. Solutions that remain opaque or precipitate after filtration should not be used. 
 
Storage requirements: As for other antineoplastic agents Thiotepa should be handled by 
trained personnel using procedures for proper handling. The use of gloves and protective 
glasses is recommended to avoid exposure upon accidental spillage. 
 
Route of administration: intravenous infusion over 30-60 minutes 
 
Drug Procurement: Thiotepa must be obtained from commercial sources.  
 
9.1.2 Melphalan 
Product description: Alkylating agent which is a derivative of mechlorethamine that 
inhibits DNA and RNA synthesis via formation of carbonium ions; cross-links strands of 
DNA; acts on both resting and rapidly dividing tumor cells. 
 
Solution preparation: ALKERAN for Injection is supplied as a sterile, nonpyrogenic, 
freeze-dried powder. Each single-use vial contains melphalan hydrochloride equivalent to 
50 mg melphalan and 20 mg povidone. ALKERAN for Injection is reconstituted using the 
sterile diluent provided. Each vial of sterile diluent contains sodium citrate 0.2 g, propylene 
glycol 6.0 mL, ethanol (96%) 0.52 mL, and Water for Injection to a total of 10 mL.  
 
As for other antineoplastic agents Melphalan should be handled by trained personnel using 
procedures for proper handling. The use of gloves and protective glasses is recommended 
to avoid exposure upon accidental spillage. 
 
Route of administration: intravenous infusion over 30-60 minutes 
 
Drug Procurement: Melphalan must be obtained from commercial sources.  

CASE xxxx10Z17 
 
 
 
Page 30  
 
 
Version date: 
02.21.2023 
 
 
9.1.3 Fludarabine 
Product description: Antineoplastic fluorinated nucleoside analog. After phosphorylation 
to fluoro-ara-ATP [adenosine triphosphate] the drug appears to incorporate into DNA and 
inhibit DNA polymerase alpha, ribonucleotide reductase and DNA primase, thus inhibiting 
DNA synthesis. The half-life of the activated compound is approximately 10 hours but the 
pharmacology is incompletely understood. Excretion is impaired in patients with impaired 
renal function. 
 
Solution preparation: Each vial contains 50 mg lyophilized drug, to be reconstituted with 
2 mL sterile water to a solution that is 25 mg/mL for intravenous administration. Solution 
Preparation: mix each vial with 2 mL sterile pyrogen-free water to a clear solution, which 
is 25 mg/mL for intravenous administration only. Reconstituted solution should be used 
within 8 hours. 
 
As for other antineoplastic agents Melphalan should be handled by trained personnel using 
procedures for proper handling. The use of gloves and protective glasses is recommended 
to avoid exposure upon accidental spillage. 
 
Route of administration: intravenous infusion over 30-60 minutes 
 
Drug Procurement: Fludarabine must be obtained from commercial sources.  
 
 
10.0 
EXPLORATORY or CORRELATIVE STUDIES 
N/A 
 
11.0  STUDY PARAMETERS AND CALENDAR  
 
11.1 
Study Parameters 
Laboratory Studies: 
• Serum Chemistries: albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, 
calcium, chloride, creatinine, glucose, potassium, SGOT [AST], SGPT [ALT], 
sodium.  
• Complete Blood Count and Differential  
• Additional lab studies (Screening only) 
• PT, PTT. 
• Urinalysis 
• CMV IgG and IgM, EBV panel, Hep B sAg, Hep B sAb, Hep B cAb, Hep 
C Ab, HIV I/II, HSV I/II, HTLV I/II, Syphilis, Toxo IgG (and if positive 
IgM), VZV IgG 
 
Vital signs include: blood pressure, pulse, respiratory rate, percent oxygen saturation and 
temperature 
 

CASE xxxx10Z17 
 
 
 
Page 31  
 
 
Version date: 
02.21.2023 
 
Bone marrow aspiration; flow cytometry, cytogenetics, and molecular studies as clinically 
appropriate  
 
11.1.1 Screening Evaluation  
Screening studies and evaluations will be used to determine the eligibility of each subject 
for study inclusion. All evaluations must be completed < 60 days prior to administration 
of protocol therapy.  
 
11.1.2 Treatment Period 
Treatment time will begin the day -11 before transplant and continued until the 
conditioning regimen is completed; for dUCBT this is T+0 and for haplo-identical 
transplant this is T+4. 
 
 
 
If the patient undergoes a haplo-identical transplant, post-transplant cyclophosphamide 
will be added as 50 mg/kg given on each of days +3 and +4. 
T-8 
• Melphalan 100 mg/m2 
 
T-7 
• Thiotepa (T) 10 mg/kg  
 
T-6 
• Fludarabine 40mg/m2 
 
T -5 
• Fludarabine 40mg/m2 
 
T -4 
• Fludarabine 40mg/m2 
 
T -3 
• Fludarabine 40mg/m2 
 
 
T +0 
• Infusion of graft source: dUCBT or Haplo-Identical Donor 
 
 
T +6 to +30 
• Continue GVHD prophylaxis per standard of care 
• Bone Marrow Aspiration may be performed following between T+6 and T+30 if 
engraftment has not been demonstrated or if loss of graft is suspected;  flow cytometry, 
cytogenetics, and molecular studies as clinically appropriate 
 
T +30 to +60 

CASE xxxx10Z17 
 
 
 
Page 32  
 
 
Version date: 
02.21.2023 
 
• Bone Marrow Aspiration may be performed following T+30 bone marrow if 
engraftment has not been demonstrated or if loss of graft is suspected; flow 
cytometry, cytogenetics, and molecular studies as clinically appropriate. If a bone 
marrow aspiration has been already performed between T+6 and T+30, this does not 
need to be repeated. 
 
Follow up:  Outpatient, up to T+100, 6, 9, and 12 months post-transplant (+/- 
2weeks) 
 
Bone marrow aspiration; flow cytometry, cytogenetics, and molecular studies as 
clinically appropriate. 
 
Acute GVHD 
Acute GVHD will be graded and staged according to the BMT CTN Manual of 
Operations (BMT CTN MOP) (Appendixes C, D, and E).  
 
Chronic Graft Versus Host Disease 
Chronic GVHD is scored according to the BMT CTN MOP (Appendix F). The first day 
of cGVHD onset will be used to calculate cumulative incidence curves. 

CASE xxxx10Z17 
 
 
 
Page 33  
 
 
Version date: 02.21.2023 
 
11.2 
Calendar  
 
 
* Bone Marrow Aspiration may be performed following T+30 bone marrow if engraftment has not been demonstrated or if loss of graft is suspected; flow cytometry, 
cytogenetics, and molecular studies as clinically appropriate. It may be repeated as clinically appropriate  
Study Days 
Screening 
T -11, -10, -9 
T -8 
T -7 
T -6 
T -5 
T -4 
T -3 
T -2 
T -1 
T +0 
T +1, 
T +2 
T +6  to 
T +30 
T +30 to 
T +60 
T+100, 6, 9, and 
12mo f/u 
Required Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
Vitals (section 11.1) 
X 
 
X1 
X1 
 
 
 
 
 
 
 
 
 
 
 
Physical exam 
X 
 
 
X1 
 
 
 
 
 
 
 
 
 
 
 
Con Med Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
KPS 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X2 
Baseline Symptoms Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events Assessment 
 
 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X‡ 
CBC/diff/Platelets  
X 
 
X1 
X1 
 
 
 
 
 
 
 
 
 
 
X2 
Chemistries (section 11.1) 
X 
 
X1 
X1 
 
 
 
 
 
 
 
 
 
 
X2 
Additional Lab Studies (section 11.1) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ß-HCG for women of childbearing potential3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2-D ECHO or MUGA  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulmonary function testing (including 
DLCO) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT, PET, for lymphoma 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiology consult 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone Marrow Aspiration (see section 11.1) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X* 
X2 
(T+100 only) 
Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Melphalan 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Thiotepa 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Fludarabine 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 

CASE xxxx10Z17 
 
 
 
Page 34  
 
 
Version date: 02.21.2023 
 
‡ Follow-up of adverse events that are still ongoing after the 30 day reporting period 
1These studies may have a window to +/-3 days. 
2 These studies may have a window of 2 weeks. 
3 ß-HCG test should be performed within 7 days before admission.  

CASE xxxx10Z17 
 
 
 
Page 35  
 
 
Version date: 
02.21.2023 
 
12.0  MEASUREMENT OF EFFECT  
 
 
 
Disease Free Survival (DFS) at 1 year is the percentage of patients alive and without 
evidence of hematologic malignancy at 1 year after transplant. 
 
Overall Survival (OS) at 1 year is the percentage of patients alive at 1 year after transplant. 
 
Relapse incidence at 1 year is the percentage of patients who experience relapse of their 
hematologic malignancy up to 1 year after transplant. 
 
Treatment Related Mortality (TRM) at 1 year is the percentage of patients who expire from 
treatment related toxicity attributed to transplant up to 1 year after transplant. 
 
Acute graft versus host disease (aGVHD) 1 year cumulative incidence is the percentage of 
patients who experience any aGVHD up to 1 year after transplant. 
 
Chronic graft versus host disease (cGVHD) 1-year cumulative incidence is the percentage 
of patients who experience any cGVHD up to 1 year after transplant. 
 
Neutrophil engraftment will be calculated as the days from transplant where the absolute 
neutrophil count (ANC) reaches >500cells/ul x 3 days. 
 
Platelet engraftment will be calculated as the days from transplant where the platelet count 
reaches 20,000 platelets /ul without the need of transfusion of platelets for 7 days. 
 
13.0 
DATA REPORTING / REGULATORY CONSIDERATIONS  
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 
8.0 (Adverse Events: List and Reporting Requirements). 
 
13.1 
Data Reporting  
The OnCore™ Database will be utilized, as required by the Case Comprehensive Cancer 
Center, to provide data collection for both accrual entry and trial data management. 
OnCore™ is a Clinical Trials Management System housed on secure servers maintained at 
Case Western Reserve University. OnCore™. Access to data through OnCore™ is 
restricted by user accounts and assigned roles. Once logged into the OnCore™ system with 
a user ID and password, OnCore™ defines roles for each user which limits access to 
appropriate data. User information and password can be obtained by contacting the 
OnCore™ Administrator at OnCore-registration@case.edu. 
 
OnCore™ is designed with the capability for study setup, activation, tracking, reporting, 
data monitoring and review, and eligibility verification.  A calendar of events and required 
forms are available in OnCore™. 
 

CASE xxxx10Z17 
 
 
 
Page 36  
 
 
Version date: 
02.21.2023 
 
This study will utilize electronic Case Report Form completion in the Overture database 
system, a part 11 compliant electronic data capture system.  Approved users will received 
access independently from the OnCoreTM system used for clinical trial management. 
 
13.2 
Regulatory Considerations 
The study will be conducted in compliance with ICH guidelines and with all applicable 
federal (including 21 CFR parts 56 & 50), state or local laws. 
13.2.1 Written Informed consent 
Provision of written informed consent must be obtained prior to any study-related 
procedures. The Principal Investigator will ensure that the subject is given full and 
adequate oral and written information about the nature, purpose, possible risks and benefits 
of the study as well as the subject’s financial responsibility. Subjects must also be notified 
that they are free to discontinue from the study at any time. The subject should be given 
the opportunity to ask questions and be allowed time to consider the information provided.  
The original, signed written Informed Consent Form must be kept with the Research Chart 
in conformance with the institution’s standard operating procedures. A copy of the signed 
written Informed Consent Form must be given to the subject. Additionally, documentation 
of the consenting process should be located in the research chart. 
13.2.2 Subject Data Protection 
In accordance with the Health Information Portability and Accountability Act (HIPAA), a 
subject must sign an authorization to release medical information to the sponsor and/or 
allow the sponsor, a regulatory authority, or Institutional Review Board access to subject’s 
medical information that includes all hospital records relevant to the study, including 
subjects’ medical history.  
 
13.2.3  Retention of records 
The Principal Investigator of The Case Comprehensive Cancer Center supervises the 
retention of all documentation of adverse events, records of study drug receipt and 
dispensation, and all IRB correspondence for as long as needed to comply with local, 
national and international regulations. No records will be destroyed until the Principal 
Investigator confirms destruction is permitted.  
 
13.2.4  Audits and inspections  
Authorized representatives of the sponsor, a regulatory authority, an Independent Ethics 
Committee (IEC) or an Institutional Review Board (IRB) may visit the site to perform 
audits or inspections, including source data verification. The purpose of an audit or 
inspection is to systematically and independently examine all study-related activities and 
documents to determine whether these activities were conducted, and data were recorded, 
analysed, and accurately reported according to the protocol, Good Clinical Practice (GCP), 
guidelines of the International Conference on Harmonization (ICH), and any applicable 
regulatory requirements.  For multi-center studies, participating sites must inform the 
sponsor-investigator of pending audits.  
 

CASE xxxx10Z17 
 
 
 
Page 37  
 
 
Version date: 
02.21.2023 
 
14.0  STATISTICAL CONSIDERATIONS  
 
14.1 
Design and Sample Size: 
The one year leukemia free survival (LFS) is the primary endpoint for the phase II study. 
One year LSF is measured is the percentage of patients alive and without evidence of 
hematologic malignancy at 1 year after transplant. We are particularly interested in the rate 
of LFS within one year after transplant.   The 1-year LFS rate for this study population 
under standard care is about 40% (P0 = 0.4). We expect the target 1-year LFS rate of the 
investigation therapy to be 60% (P1 = 0.60). R. Simon’s minimax two-stage phase II 
design11 with type I error of 0.05 and power of 80% will be used on 1-year LFS. Thirty-
four patients will be enrolled on stage one. If there are 17 or less alive without relapse 
beyond 1 year, the trial will be stopped and the treatment will be considered not effective 
for this patient population. If there are 18 or more alive without relapse after 1 year, 5 
additional patients will be enrolled. If 20 or fewer are alive without relapse after 1 year are 
observed in the total 39 patients, then the trial will be considered to be not effective. On 
the other hand, if there are more than 20 patients alive without relapse after 1 year, then 
the treatment will be considered to be effective. 
 
14.2 
Analysis Plan 
AEs and SAEs from this phase II study will be tabulated. For time-to-event endpoints, such 
as overall survival, the Kaplan-Meier method12 will be used to estimate survivor function. 
The cumulative incidence of acute GVHD, chronic GVHD, and the rate of neutrophil and 
platelet engraftment will be estimated by the method that accommodates competing risks13. 
As part of exploratory data analysis, the predictive value of laboratory correlates on time-
to-event data will be estimated using Cox models14. 
 

CASE xxxx10Z17 
 
 
 
Page 38  
 
 
Version date: 
02.21.2023 
 
REFERENCES 
1. 
Mohty M, de Lavallade H, El-Cheikh J, et al. Reduced intensity conditioning 
allogeneic stem cell transplantation for patients with acute myeloid leukemia: long term 
results of a 'donor' versus 'no donor' comparison. Leukemia. Jan 2009;23(1):194-196. 
2. 
Sengsayadeth S, Savani BN, Blaise D, Malard F, Nagler A, Mohty M. Reduced 
intensity conditioning allogeneic hematopoietic cell transplantation for adult acute myeloid 
leukemia in complete remission - a review from the Acute Leukemia Working Party of the 
EBMT. Haematologica. Jul 2015;100(7):859-869. 
3. 
Mawad R, Lionberger JM, Pagel JM. Strategies to reduce relapse after allogeneic 
hematopoietic cell transplantation in acute myeloid leukemia. Current hematologic 
malignancy reports. Jun 2013;8(2):132-140. 
4. 
Ciurea SO, Saliba RM, Hamerschlak N, et al. Fludarabine, melphalan, thiotepa and 
anti-thymocyte globulin conditioning for unrelated cord blood transplant. Leukemia & 
lymphoma. May 2012;53(5):901-906. 
5. 
Ciurea SO, Saliba R, Rondon G, et al. Reduced-intensity conditioning using 
fludarabine, melphalan and thiotepa for adult patients undergoing haploidentical SCT. 
Bone marrow transplantation. Mar 2010;45(3):429-436. 
6. 
Eder S, Labopin M, Finke J, et al. Safety and efficacy of thiotepa-based 
conditioning for allogeneic transplantation in AML: a survey from the ALWP of the 
EBMT. Bone marrow transplantation. Feb 2017;52(2):238-244. 
7. 
Milano F, Gooley T, Wood B, et al. Cord-Blood Transplantation in Patients with 
Minimal Residual Disease. The New England journal of medicine. Sep 8 
2016;375(10):944-953. 
8. 
Simon R. Optimal two-stage designs for phase II clinical trials. Controlled clinical 
trials. Mar 1989;10(1):1-10. 
9. 
Kaplan EL, Meier P. Nonparametric Estimation from Incomplete Observations. J 
Am Stat Assoc. 1958;53(282):457-481. 
10. 
Pepe MS, Mori M. Kaplan-Meier, Marginal or Conditional-Probability Curves in 
Summarizing Competing Risks Failure Time Data. Stat Med. Apr 30 1993;12(8):737-751. 
11. 
Cox DR. Regression Models and Life-Tables. Journal of the Royal Statistical 
Society Series B-Statistical Methodology. 1972;34(2):187-&. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

CASE xxxx10Z17 
 
 
 
Page 39  
 
 
Version date: 
02.21.2023 
 
APPENDIX A 
 
 
 
Karnofsky DA Burchenal JH. (1949). "The Clinical Evaluation of Chemotherapeutic Agents in Cancer." In: 
MacLeod CM (Ed), Evaluation of Chemotherapeutic Agents. Columbia Univ Press. Page 196 
 
 
 
 
 
 
 

CASE xxxx10Z17 
 
 
 
Page 41  
 
 
Version date: 
02.21.2023 
 
IPSS-R Prognostic Risk Categories/Scores* 
RISK CATEGORY 
RISK SCORE 
Very Low 
<=1.5 
Low 
>1.5 - 3 
Intermediate 
>3 - 4.5 
High 
>4.5 - 6 
Very High 
>6 
*Greenberg, Tuechler, Schanz et al, Revised International Prognostic Scoring System 
(IPSS-R) for Myelodysplastic Syndrome, Blood 120: 2454, 2012. 
**Schanz J et al, J Clin Oncology 2012; 30:820 
 
 
 

CASE xxxx10Z17 
 
 
 
Page 45  
 
 
Version date: 
02.21.2023 
 
 
 
 
 
1. 
Mohty M, de Lavallade H, El-Cheikh J, et al. Reduced intensity conditioning 
allogeneic stem cell transplantation for patients with acute myeloid leukemia: long 
term results of a 'donor' versus 'no donor' comparison. Leukemia. 2009;23(1):194-
196. 
2. 
Sengsayadeth S, Savani BN, Blaise D, Malard F, Nagler A, Mohty M. Reduced 
intensity conditioning allogeneic hematopoietic cell transplantation for adult acute 
myeloid leukemia in complete remission - a review from the Acute Leukemia 
Working Party of the EBMT. Haematologica. 2015;100(7):859-869. 
3. 
Mawad R, Lionberger JM, Pagel JM. Strategies to reduce relapse after allogeneic 
hematopoietic cell transplantation in acute myeloid leukemia. Current hematologic 
malignancy reports. 2013;8(2):132-140. 
4. 
Ciurea SO, Saliba RM, Hamerschlak N, et al. Fludarabine, melphalan, thiotepa and 
anti-thymocyte globulin conditioning for unrelated cord blood transplant. Leukemia 
& lymphoma. 2012;53(5):901-906. 
5. 
Ciurea SO, Saliba R, Rondon G, et al. Reduced-intensity conditioning using 
fludarabine, melphalan and thiotepa for adult patients undergoing haploidentical 
SCT. Bone marrow transplantation. 2010;45(3):429-436. 
6. 
Eder S, Labopin M, Finke J, et al. Safety and efficacy of thiotepa-based 
conditioning for allogeneic transplantation in AML: a survey from the ALWP of 
the EBMT. Bone marrow transplantation. 2017;52(2):238-244. 
7. 
Milano F, Gooley T, Wood B, et al. Cord-Blood Transplantation in Patients with 
Minimal 
Residual Disease. 
The 
New 
England 
journal 
of 
medicine. 
2016;375(10):944-953. 
8. 
Baron F, Labopin M, Ruggeri A, et al. Impact of Donor Type in Patients with AML 
Given Allogeneic Hematopoietic Cell Transplantation After Low-Dose TBI-Based 
Regimen. Clinical cancer research : an official journal of the American 
Association for Cancer Research. 2018;24(12):2794-2803. 
9. 
Metheny L, Politikos I, Ballen KK, et al. Guidelines for Adult Patient Selection and 
Conditioning Regimens in Cord Blood Transplant Recipients with Hematologic 
Malignancies and Aplastic Anemia. Transplant Cell Ther. 2021;27(4):286-291. 
10. 
Politikos I, Davis E, Nhaissi M, et al. Guidelines for Cord Blood Unit Selection. 
Biology of blood and marrow transplantation : journal of the American Society for 
Blood and Marrow Transplantation. 2020. 
11. 
Simon R. Optimal two-stage designs for phase II clinical trials. Controlled clinical 
trials. 1989;10(1):1-10. 
12. 
Kaplan EL, Meier P. Nonparametric Estimation from Incomplete Observations. J 
Am Stat Assoc. 1958;53(282):457-481. 
13. 
Pepe MS, Mori M. Kaplan-Meier, Marginal or Conditional-Probability Curves in 
Summarizing Competing Risks Failure Time Data. Stat Med. 1993;12(8):737-751. 
14. 
Cox DR. Regression Models and Life-Tables. Journal of the Royal Statistical 
Society Series B-Statistical Methodology. 1972;34(2):187-&.