Conditions: Acute Myeloid Leukemia Acute Lymphoblastic Leukemia Biphenotypic Acute Leukemia Undifferentiated Leukemia Prolymphocytic Leukemia Myelodysplastic Syndromes Chronic Myelogenous Leukemia Myeloproliferative Neoplasm Relapsed Large Cell Lymphoma Mantle Cell Lymphoma Hodgkin Lymphoma Burkitt Lymphoma Relapsed T-Cell Lymphoma Relapsed Chronic Lymphocytic Leukemia Relapsed Small Lymphocytic Lymphoma Relapsed Marginal B-cell Lymphoma Relapsed Follicular Lymphoma Lymphoplasmacytic Lymphoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 34
Healthy volunteers: no

Brief summary:
This is a single arm, phase II trial of HLA-haploidentical related hematopoietic cells transplant (Haplo-HCT) using reduced intensity conditioning (fludarabine and melphalan and total body irradiation). Peripheral blood is the donor graft source. This study is designed to estimate disease-free survival (DFS) at 18 months post-transplant.

Detailed description:

Arms:
arm 1: All participants will receive a conditioning regimen of Fludarabine, Melphalan and Total Body Irradiation prior to transplantation of HLA-Haploidentical Related Hematopoietic Cells (Haplo-HCT)

Interventions: intervention 1: Fludarabine intervention 2: Melphalan intervention 3: Total Body Irradiation
Intervention descriptions: intervention 1: Fludarabine 30mg/m\^2/day will be administered over 30-60 minutes intravenous infusion on Days -6 through -2 for a total dose of 150 mg/m\^2 intervention 2: Melphalan 70 mg/m\^2 over 45 minutes will be administered Day -6. Melphalan dose will be calculated based on Actual Body Weight. intervention 3: Total Body Irradiation (TBI) will be delivered at a dose of 200 centigray units (cGy)

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
Reduced-Intensity Fludarabine, Melphalan, and Total Body Irradiation 
Conditioning for Transplantation of HLA-Haploidentical Related 
Hematopoietic Cells (Haplo-HCT) For Patients With Hematologic 
Malignancies 
Protocol Number: MCC 20131 
NCT Identified Number: NCI-2019-08483 
 
 
Principal Investigator: 
Nelli Bejanyan, MD 
 
 
IND number: 
144792 Exempt 
Biostatistician: 
Jongphil Kim, PhD 
 
 
Funded by:  Moffitt Cancer Center 
 
 
Version Number: v 10    
 
 
 
 
 
 


  
 
 
ii 
Table of Contents 
1 
PROTOCOL SUMMARY ............................................................................................................................... 1 
1.1 
Synopsis ................................................................................................................................................ 1 
Transplant Related Endpoints ........................................................................................................................... 2 
1.2 
Schema ................................................................................................................................................. 4 
1.3 
Schedule of Activities (SoA) ............................................................................................................... 4 
2 
Study rationale and background .................................................................................................................. 6 
2.1 
introduction ........................................................................................................................................... 6 
2.2 
Haploidentical Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide 7 
2.3 
Relapse in Haplo hct with ptcy ........................................................................................................... 8 
2.4 
Mycophenolate Mofetil Pharmacokinetics ........................................................................................ 9 
2.5 
Cyclopophosphamide Metabolism .................................................................................................... 9 
2.6 
Summary of Rationale ........................................................................................................................ 9 
2.7 
Risk/Benefit Assessment .................................................................................................................. 10 
2.7.1 
Known Potential Risks ................................................................................................... 10 
2.7.2 
Preparative Regimen ..................................................................................................... 10 
2.7.3 
Haploidentical Donor Stem Cell Infusion .................................................................... 12 
2.7.4 
GVHD Prophylaxis ......................................................................................................... 12 
2.7.5 
G-CSF 13 
2.7.6 
Known Potential Benefits .............................................................................................. 14 
2.7.7 
Assessment of Potential Risks and Benefits .............................................................. 14 
3 
OBJECTIVES AND ENDPOINTS .............................................................................................................. 14 
4 
STUDY DESIGN ........................................................................................................................................... 17 
4.1 
Overall Design .................................................................................................................................... 17 
4.2 
Scientific Rationale for Study Design.............................................................................................. 17 
4.3 
Justification for Dose ......................................................................................................................... 17 
4.4 
End of Study Definition ..................................................................................................................... 17 
5 
STUDY POPULATION ................................................................................................................................ 18 
5.1 
Inclusion Criteria ................................................................................................................................ 18 
5.1.2 
Eligible Diseases ............................................................................................................ 18 
5.1.3 
Organ Function Criteria ................................................................................................. 21 
5.2 
Exclusion Criteria ............................................................................................................................... 21 
5.3 
Donor selection .................................................................................................................................. 22 
5.4 
Lifestyle Considerations .................................................................................................................... 23 
5.5 
Screen Failures .................................................................................................................................. 23 
5.6 
STRATEGIES FOR RECRUITMENT AND RETENTION ............................................................ 23 
5.7 
Patient Registration in oncore .......................................................................................................... 24 
6 
STUDY INTERVENTION ............................................................................................................................ 24 
6.1 
Study Intervention(s) Administration ............................................................................................... 24 
6.1.1 
Study Intervention Description ..................................................................................... 24 
Treatment Plan .......................................................................................................................................................... 24 
6.1.2 
Dosing and Administration ............................................................................................ 24 
6.1.3 
GVHD Prophylaxis and Growth Factor Support (begin Day 5) ............................... 26 
6.1.4 
Supportive care .............................................................................................................. 27 
6.1.5 
Follow-up ......................................................................................................................... 27 
6.2 
Measures to Minimize Bias: Randomization and Blinding ........................................................... 27 
6.3 
Study Intervention Compliance ........................................................................................................ 27 


  
 
 
iii 
6.4 
Concomitant Therapy ........................................................................................................................ 27 
6.4.1 
Rescue Medicine ............................................................................................................ 28 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................................................................... 28 
7.1 
Discontinuation of Study Intervention ............................................................................................. 28 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................................... 28 
7.3 
Lost to Follow-Up ............................................................................................................................... 29 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 30 
8.1 
Efficacy Assessments ....................................................................................................................... 30 
8.2 
Safety and Other Assessments ....................................................................................................... 32 
8.3 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES OR OTHER ENDPOINTS ........... 33 
8.3.1 
Mycophenolate Pharmacokinetics ............................................................................... 33 
8.3.2 
Cyclophosphamide Pharmacogenomics .................................................................... 34 
8.4 
Adverse Events and Serious Adverse Events ............................................................................... 34 
8.4.1 
Definition of Adverse Events (AE) ............................................................................... 34 
8.4.2 
Definition of Serious Adverse Events (SAE) .............................................................. 35 
8.4.3 
Classification of an Adverse Event .............................................................................. 35 
8.4.4 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 36 
8.4.5 
Adverse Event Reporting .............................................................................................. 37 
8.4.6 
Serious Adverse Event Reporting ............................................................................... 37 
8.4.7 
Reporting Events to Participants ................................................................................. 37 
8.4.8 
Events of Special Interest ............................................................................................. 37 
8.4.9 
Reporting of Pregnancy ................................................................................................ 37 
8.5 
Unanticipated Problems .................................................................................................................... 37 
8.5.1 
Definition of Unanticipated Problems (UP) ................................................................. 37 
8.5.2 
Unanticipated Problem Reporting ................................................................................ 38 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 39 
9.1 
Statistical Endpoints .......................................................................................................................... 39 
Transplant Related Endpoints ......................................................................................................................... 39 
9.2 
Sample Size Determination .............................................................................................................. 39 
9.3 
Statistical Analyses............................................................................................................................ 40 
9.3.1 
General Approach .......................................................................................................... 40 
9.3.2 
Analysis of the Primary Efficacy Endpoint .................................................................. 40 
9.3.3 
Analysis of the Secondary Endpoints ......................................................................... 40 
9.3.4 
Mycophenolate Pharmacokinetic Analyses................................................................ 41 
9.3.5 
Cyclophosphamide Pharmacogenetic Analyses ....................................................... 41 
9.3.6 
Exploratory Analyses ..................................................................................................... 41 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 42 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................... 42 
10.1.1 
Scientific Review Committee (SRC) ............................................................................ 42 
10.1.2 
The Protocol Monitoring Committee (PMC) ............................................................... 42 
10.1.3 
Corporate Compliance .................................................................................................. 43 
10.1.4 
Internal Monitoring ......................................................................................................... 43 
10.1.5 
Institutional Review Board (IRB) .................................................................................. 43 
10.1.6 
Informed Consent Process ........................................................................................... 43 
10.1.7 
Consent/assent and Other Informational Documents Provided to participants .... 43 


  
 
 
iv 
10.1.8 
Consent Procedures and Documentation .................................................................. 44 
10.2 
Study Discontinuation and Closure ................................................................................................. 44 
10.2.1 
Toxicity Monitoring and Stopping Rules ..................................................................... 45 
10.3 
Future Use of Stored Specimens and Data ................................................................................... 46 
10.3.1 
Key Roles and Study Governance .............................................................................. 46 
10.3.2 
Safety Oversight ............................................................................................................. 47 
10.3.3 
Clinical Monitoring .......................................................................................................... 47 
10.3.4 
Quality Assurance and Quality Control ....................................................................... 47 
10.3.5 
Data Handling and Record Keeping ............................................................................ 47 
10.3.6 
Data Collection and Management Responsibilities................................................... 47 
10.3.7 
Study Records Retention .............................................................................................. 48 
10.3.8 
Protocol Deviations ........................................................................................................ 48 
10.3.9 
Publication and Data Sharing Policy ........................................................................... 48 
10.3.10 
Conflict of Interest Policy .............................................................................................. 49 
10.4 
Additional Considerations ................................................................................................................. 49 
10.5 
Abbreviations ...................................................................................................................................... 49 
10.6 
Protocol Amendment History ........................................................................................................... 51 
11 
REFERENCES ............................................................................................................................................. 52 
Appendix I Cytokine Release Syndrome Grading ................................................................................................ 56 
Appendix II – Karnofsky Performance Status ....................................................................................................... 59 
Appendix III – TBI Guidelines .................................................................................................................................. 60 
 


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1 
 
PROTOCOL SUMMARY 
1.1 SYNOPSIS  
Title: 
Reduced-Intensity Fludarabine,  Melphalan, and Total Body 
Irradiation Conditioning for Transplantation of HLA-Haploidentical 
Related Hematopoietic Cells (Haplo-HCT) For Patients With 
Hematologic Malignancies 
Study Description: 
This is a single arm, phase II trial of HLA-haploidentical related 
hematopoietic cells transplant (Haplo-HCT) using reduced intensity 
conditioning (fludarabine and melphalan and total body irradiation).  
Peripheral blood is the donor graft source. This study is designed to 
estimate disease-free survival (DFS) at 18 months post-transplant.   
Objectives: 
Primary Objective: The primary objective is to estimate probability of 
the 18 months DFS after a HLA-haploidentical related hematopoietic 
cells transplant (Haplo-HCT) using a reduced intensity conditioning 
regimen with fludarabine/melphalan/total body irradiation (TBI) 
conditioning for patients with advanced age or comorbidities.  
 
Secondary Objectives: 
• Incidence of day 100 grade II-IV and grade III-IV acute graft versus-
host-disease (GVHD)  
• Probability of 6 month and 18 months treatment-related mortality 
(TRM) 
• Probability of 18 months relapse incidence 
• Probability of 18 months overall survival (OS) 
 
 
Transplant Related Objectives: 
• Incidence of neutrophil recovery by day +56 
• Incidence of platelet recovery by day +56  
• Donor cell engraftment (chimerism) at day +30, +60, +90, +180 and 
+ 365 
• Incidence of 1 year and 18 months chronic GVHD 
• Probability of 1 year and 18 months GVHD and relapse-free 
survival (GRFS) 
• Incidence of serious fungal and viral infections at day 100 and 1 
year and 18 months post-HCT 
 
Pharmacokinetic Objectives: 
• 
Evaluate pharmacokinetics of mycophenolate mofetil (MMF) 
measured on day 7 after transplant 


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• 
Evaluate single nucleotide polymorphisms (SNPs) in p450, 
aldehyde dehydrogenase, and glutathione S-transferase that 
influence Cyclophosphamide metabolism 
 
Endpoints: 
Primary Endpoint: The primary endpoint is the probability of disease-
free survival (DFS) by 18 months post-transplant.  An event will be 
defined as death or a relapse 
 
Secondary Endpoints:  
• 
Probability of Grade II-IV and Grade III-IV aGVHD at 180 days 
• 
Probability of TRM at 6 months and 18 months  
• 
Probability of relapse at 18 months  
• 
Probability of 18 months year overall survival (OS) 
 
Transplant Related Endpoints 
• 
Probability of neutrophil recovery by day +56 
• 
Probability of platelet recovery by day +56 
• 
Proportion of donor cell engraftment (chimerism) at days +30, 
+60, +90, +180 and +365 
• 
Probability of 18 months chronic GVHD 
• 
Probability of 18 months  GRFS 
• 
Probability of serious fungal and viral infections at day +100, 1 
year and 18 months post-HCT 
 
Pharmacokinetic Endpoints: 
• 
Concentrations of MMF metabolites measured on day 6 after 
transplant 
• 
Prevalence, by ethnicity, of SNPs in p450, aldehyde 
dehydrogenase, and glutathione S-transferase known to 
influence Cyclophosphamide metabolism  
Study Population: 
 
Estimated Sample Size: 34 patients 
• Age > 55 years or HCT-CI>3 
• Karnofsky performance status of ≥70% or Lansky play score ≥ 70% 
• Acute leukemia in complete remission  
or 
• Myelodysplastic syndrome, myeloproliferative neoplasm or chronic 
myelogenous leukemia with <5% blasts in bone marrow by 
morphology;  
or 
• High risk lymphoma in at least a partial remission (PR) 


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• The donor and recipient must be HLA identical for at least one 
haplotype (using high resolution DNA based typing) at the following 
genetic loci: HLA-A, HLA-B, HLA-C, and HLA-DRB1. 
Phase: 
Phase II 
Description of 
Sites/Facilities 
Enrolling Participants: 
H.  Lee Moffitt Cancer Center  - Single Site 
Description of Study 
Intervention: 
Conditioning: 
Day -6: Fludarabine IV 30mg/m2, Melphalan 70 mg/m2 
Day -5: Fludarabine IV 30mg/m2 
Day -4: Fludarabine IV 30mg/m2 
Day -3: Fludarabine IV 30mg/m2 
Day -2: Fludarabine IV 30mg/m2 
Day -1: Total Body Irradiation 2 Gy 
 
Graft: 
PBSCT infusion will be administered on day 0 with a minimal dose of 
2x106 CD34+ cells and a maximum dose of 5x106 CD34+ cells. 
 
GVHD Prophylaxis: 
Cyclophosphamide IV 50 mg/kg will be administered on Day +3 and 
+4. Mycophenolate mofetil (MMF) and sirolimus will be initiated on 
day +5. Sirolimus will be dosed to a goal level of 8-14 ng/ml. In 
absence of GVHD, sirolimus may be tapered after day 90 and should 
be completed by day 180. MMF will be started at a dose of 15 mg/kg 
every 8 hours with a maximum daily dose not to exceed 3 gm. MMF 
will be discontinued on day +35.   
Study Duration: 
36 Months 
Participant Duration: 
18 months 
 
 


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1.2 SCHEMA 
 
 
1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
For explanation of procedures, please see Section 8 (Study Assessments and Procedures). 
 
Pre-BMT work-up evaluations should be completed prior to initiation of conditioning 
chemotherapy within the screening windows defined in the table below. Evaluations done as a 
“standard of care” prior to consent on trial may be used for the trial screening if falling within the 
appropriate window from initiation of conditioning chemotherapy.  
Scheduled evaluations after screening and until engraftment may be performed +/-3 days from the 
targeted date; assessments performed after engraftment and through Day 90 may be done +/-10 
days of the targeted date.  After Day 90 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 
42-90 
Follow-Up ( >Day 90 
through Day 540) 
Consent 
No Window 
 
 
 
Medical History 
Within 30 days 
Daily 
weekly 
X (day 180, 360, 540) 
Physical Exam 
Within 30 days 
Daily 
weekly 
X (day 180, 360, 540) 
RT consultation 
No Window 
 
 
 
Karnofsky/Lansky 
Within 30 days 
 
day 90 
X (day 180, 360, 540) 
GVHD Assessment 
 
weekly start day 7 
weekly, day 90 
X (day 180, 360, 540) 
CBC/diff/plt 
Within 30 days 
Daily 
weekly 
X (day 180, 360, 540) 
-8 
-4 
-5 
-2 
-3 
0 
-1 
+40 
+30 
+20 
+10 
+5 
+60 
+50 
+180 
  Flu 30 mg/m
2/day          CY 50 mg/kg/day 
TBI 2Gy/day 
PBSCT infusion 
Siri
MMF 
G-CSF 
-7 -6 
Mel 70 mg/m2 


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Activity 
Pre-BMT  
Work-Up 
Day 1 To 
Engraftment1 
Follow-Up Days 
42-90 
Follow-Up ( >Day 90 
through Day 540) 
PT/INR 
Within 60 days 
 
 
 
Viral Screen 
Within 60 days 
 
 
 
PRA (Donor Specific 
Antibody) 
Within 60 days 
 
 
 
Basic metabolic panel  
 
Daily 
 
 
Comprehensive 
metabolic panel 
Within 30 days 
2x/wk 
weekly 
X (day 180, 360, 540) 
eGFR for adults with 
creat > 1.2 or hx or 
renal dysfunction 
Within 30 days 
 
 
 
Pregnancy test (females 
of childbearing potential) 
Within 30 days 
 
 
 
BM Biopsy 
Within 60 days 
X (day 30) 
X (day 90) 
X (day 180, 360, 540) 
BM chimerism  
 
BM (day 30) 
BM (day 90) 
BM (day 180, 360, 
540) 
Blood chimerism  
 
PB (day 30) 
PB (day 90) 
PB (day 180, 360, 
540) 
PETCT (lymphoma 
only) 
Within 60 days 
 
 
X 
Minimal Residual 
Disease 
Within 60 days 
BM (day30) 
BM (day 90) 
BM (day 180, 360, 
540) 
T-Cell Immune 
Reconstitution Panel 
Within 60 days 
PB (day 30) 
PB (day 90) 
PB (day 180, 360, 
540) 
CMV PCR (blood) 
 
Weekly 
Weekly 
 
HHV6 PCR (blood) 
 
Weekly 
Weekly 
 
PFT/DLCO 
Within 60 days 
 
 
 
MUGA or Echo 
Within 60 days 
 
 
 
CT Chest/Sinus 
Within 60 days 
 
 
 
Disease Evaluation 
Within 60 days 
X (day 30) 
X (day 90) 
X (day 180, 360, 540) 


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Activity 
Pre-BMT  
Work-Up 
Day 1 To 
Engraftment1 
Follow-Up Days 
42-90 
Follow-Up ( >Day 90 
through Day 540) 
Research Bone 
Marrow and Blood2 
Sample 
No Window 
X (day 30) 
 
X (day 180) 
Blood samples for 
MMF 
 
X (day 7)3 
 
 
1 
Engraftment defined as absolute neutrophil count (ANC) ≥ 5 X 108/L for 3 consecutive measurements  
2 
Research blood samples will be used for cyclophosphamide genomics studies. Research blood samples will be 
collected in EDTA blood collection tubes and research marrow samples will be collected in sodium heparin 
tubes. Excess blood and marrow samples from existing samples (including those collected for MCC 14690) may 
be stored for future correlative studies in lieu of collecting a new sample. 
3 
Blood for MMF pharmacokinetic studies will be obtained on day 7 at the following time points: pre-dose, post-
dose, 1 hour, 2 hour, 4 hour, and 8 hours after dose in EDTA blood collection tubes. Collections may occur +/- 
10 minutes from the scheduled interval.  
NOTE: In certain clinical circumstances (e.g. relapsed or terminally ill patients, risk of undue harm 
to patients, etc.) study tests may be omitted at the physician’s discretion. Additionally, tests may be 
rescheduled as clinically indicated. 
 
2 
 
STUDY RATIONALE AND BACKGROUND 
 
 
2.1 INTRODUCTION 
Allogeneic (allo) hematopoietic cell transplantation (HCT) is widely used as a curative therapy for 
a number of hematological malignancies.  While early conditioning regimens were too toxic for 
many patients, reduced intensity conditioning (RIC) opened opportunities for older patients and 
those with comorbid conditions to be eligible for potentially curable transplantation.[1-5]  
Historically, implementation of allo HCT required the availability of a human leukocyte antigen 
(HLA) matched donor to minimize complications including graft-versus-host disease (GVHD) and 
non-relapse mortality (NRM). An HLA matched sibling donor (MSD) is the preferred donor, but 
only 30% of patients have an MSD.[6] When no MSD exists, HLA matched unrelated donors 
(MUDs) may be identified through volunteer donor databases. However, the likelihood of finding a 
suitable MUD varies dramatically by ethnicity, from <20% for Black populations to ~75% for White 
Caucasian groups.[6] Overall, the likelihood of finding an HLA matched donor is 60%, and falls 
below 50% for many ethnic minority groups.[6, 7]  In addition, data from the National Marrow Donor 
Program (NMDP) indicates that the median time from donor search to adult MUD transplant is 
about 3-4 months.  This time delay increases the risk of malignancy relapse in some patients with 
aggressive diseases.[1, 2]   
Given the absence of a matched donor for many patients, alternative donor strategies that use 
HLA mismatched donors have been developed to expand the donor pool.[8-11] Among the most 
commonly adopted strategies is the use of HLA haploidentical (HLA “half-matched”) related 
donors. Low cost and easy accessibility of haploidentical transplantation (haplo-HCT) make it an 


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attractive alternative graft source. As HLA haplotypes follow Mendelian inheritance, the likelihoods 
of a sibling or offspring being HLA haploidentical to the patient are approximately 50% and 100%, 
respectively. Per prior reports, inclusion of HLA haploidentical donors in HCT donor search 
algorithms increases the likelihood of finding a suitable donor to >90%, even in populations for 
whom unrelated donors are less likely.[7, 12-14] Thus, optimization of haplo HCT protocols allows 
for transplantation for nearly all patients otherwise eligible for the procedure.  
2.2 HAPLOIDENTICAL HEMATOPOIETIC CELL TRANSPLANTATION WITH POST-
TRANSPLANT CYCLOPHOSPHAMIDE 
Initial experience with haplo HCT using T-cell replete allografts resulted in unacceptably high 
incidences of severe graft versus host disease (GVHD) and transplant-related mortality (TRM) in 
about half of the patients.[15-17] A number of strategies have been attempted to reduce the toxicity 
of haplo HCT by depleting T-cells, which facilitate GVHD. [14, 18-27]  Ex vivo depletion of T-cells 
does reduce GVHD, but results in poor engraftment and unacceptably high rates of infection and 
TRM.[14, 18, 19]  
Investigators at the Johns Hopkins University developed a strategy that uses high dose post-
transplant cyclophosphamide (PTCy) to deplete T-cells in vivo.[28]  PTCy after transplant is 
preferentially toxic to the alloreactive T cells that cause GVHD while also sparing the regulatory T 
(Treg) cells that help induce immune tolerance. These effects result in a potent anti-GVHD effect 
that allows for safe transplantation from HLA mismatched donors.[29-31] The original Johns 
Hopkins PTCy platform uses a RIC regimen consisting of Fludarabine (Flu) 30 mg/m2/day IV daily 
from Days -6 to -2, Cy 14.5 mg/kg IV on Day -6 and -5, and 200 cGy total body irradiation (TBI) in 
a single fraction on Day -1 (Flu150Cy29TBI200), bone marrow graft (BMT), and PTCy 50 mg/kg 
given on days +3 and +4.[32-35] Multiple studies have demonstrated acceptable toxicity with this 
platform including rates of TRM ~10-15%, acute GVHD rates ~30%, severe acute GVHD rates of 
~10%, and chronic GVHD rates ~10%.[28, 36-39]  Immune reconstitution is also favorable given 
preservation of memory T-cells when PTCy is used in T-cell replete haplo HCT.[23, 25]  
Prospective comparative trials comparing the Hopkins haplo BMT with PTCy platform to other 
donor platforms are lacking. Results of two parallel Blood and Marrow Transplant Clinical trials 
Network (BMTCTN) multicenter phase 2 trials compared the outcomes of patients with RIC haplo 
BMT with PTCy (BMTCTN 0603, n=50) to RIC umbilical cord blood transplantation (UCBT; 
BMTCTN 0604, n=50).[40]  Recipients of haplo BMT were conditioned with Flu150Cy29TBI200 
and UCBT recipients received Flu 40mg/m2 Days -6 to -2, Cy 50 mg/kg Day -6 and  TBI 200 cGy 
Day -1 (Flu200/Cy50/TBI200).  GVHD prophylaxis for haplo BMTs consisted of Cy 50 mg/kg IV on 
Days +3 and +4 followed by MMF and tacrolimus beginning on Day +5.  UCB recipients received 
MMF and CSA beginning on Day -3 for GVHD prophylaxis. The 1-year probabilities of OS and 
DFS were 54% and 46% after double UCB (dUCB) transplantation (n=50) and 62% and 48%, 
respectively, after haplo BMT (n=50). The cumulative incidence of neutrophil recovery at day 56 
was 94% after dUCB and 96% after haplo BMT. The cumulative incidence of grade II-IV acute 
GVHD at Day 100 was 40% after dUCB and 32% after haplo BMT.  The 1-year cumulative 
incidences of TRM and relapse after dUCB transplantation were 24% and 31%, respectively, and 
those for haplo BMT were 7% and 45%, respectively. A phase III randomized, prospective trial 
comparing haplo BMT with PTCy to UCBT is ongoing (NCT01597778). No studies have 
prospectively compared the Hopkins platform to HLA matched donor transplant, though multiple 


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retrospective studies have demonstrated favorable safety outcomes and comparable OS with the 
haplo regimen.[37, 38, 41, 42]  
Given its safety, accessibility, and low cost, the haplo HCT with PTCy approach has become widely 
used in many transplant centers when a matched donor is not available.[24, 26, 43-50]     
2.3 
RELAPSE IN HAPLO HCT WITH PTCY 
Though Flu150Cy29TBI200 haploidentical BMT with PTCy has safely expanded the donor pool 
with low rates of TRM and GVHD, application has been marred by high rates of disease relapse 
in high risk diseases such as myeloid malignancies, exceeding 40-50% in some studies.[28, 36, 
37, 51] Thus, various modifications have been attempted to optimize haplo BMT with PTCy in 
these disease groups.     
Efforts to reduce relapse by using full intensity conditioning regimens with haplo HCT with PTCy 
in younger patients with AML lowered the risk of post-transplant relapse to 20-45% without a 
substantial increase in TRM in some reports.[45, 50]  However, since myeloablative conditioning 
is not an option for older patients and for those with higher comorbidities (HCT-CI >3) due to an 
unacceptably high risk of TRM,  strategies identifying novel RIC regimens can reduce the risk of 
relapse and improve survival after haplo HCT with PTCy are needed for those >55 years old or 
with comorbidities.   
Recently Flu/Melphalan (Mel) and Flu/Busulfan (Bu) RIC regimens were compared in the matched 
adult donor allo HCT setting for AML/MDS, with the flu/mel regimen yielding significantly improved 
relapse rates and DFS.[52] The group from MD Anderson Cancer Center (MDACC) has attempted 
similarly to implement a melphalan based regimen in the setting of haplo HCT with PTCy. They 
recently reported their experience with haplo HCT with PTCy following conditioning with Flu 40 
mg/m2 Day -6 to -3, Mel 100 mg/m2 Day -8 and either Thiotepa 5 mg/kg Day -7 or TBI 200 cGy 
(FM100) in patients 55 years and older.[49, 50] Despite reported low 1-year relapse rates of 11-
19% with the Flu/Mel regimen in these studies, prolonged courses of intensive immune 
suppression (MMF through Day +90 and Tac through Day +180) were required in order to minimize 
the risk of excessive acute GVHD.[49, 50] Notably, high doses of Mel exposure per kilogram of 
body weight (>3.5mg/kg) has been previously shown to increase the risk of oral mucositis and 
subsequent acute GVHD rates in allo HCT recipients.[53] Intensification of conditioning with the 
addition Mel, though at a lower dose than used at MDACC, may result in a more favorable balance 
of efficacy and toxicity. 
In addition to conditioning, graft source is a modifiable variable that may be optimized in the setting 
of high risk for disease relapse. The original Hopkins haplo HCT with PTCy platform used bone 
marrow (BM) as the graft source. In the setting of MUD HCT, prospective data has shown that 
transplantation from peripheral blood stem cell grafts (PBSCT) results in higher rates of chronic 
GVHD than bone marrow transplantation (BMT), without any benefit in disease control.[54] Noting 
the effectiveness of PTCy in preventing chronic GVHD, the Center for International Blood and 
Marrow Transplant Research (CIBMTR) pursued a large retrospective study to assess outcomes 
of haplo PBSCT with PTCy versus BMT with PTCy.[55]  Though rates of GVHD remained higher 
in the PBSCT group, NRM remained comparable in the two groups. Further, patients receiving 
PBSCT experienced lower relapse rates (RR) and improved disease free survival (DFS). These 
results are bolstered by similar outcomes in a smaller retrospective analysis.[56] Thus, substitution 


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of PBSCT for BMT in patients appears acceptably safe and may improve efficacy of the haplo HCT 
with PTCy platform.  
2.4 
MYCOPHENOLATE MOFETIL PHARMACOKINETICS 
The PTCy platform includes mycophenolate mofetil (MMF) through day +35 after transplant as 
well as either tacrolimus or sirolimus.[28, 31, 57] Tacrolimus/sirolimus levels are monitored and 
dosing is adjusted to ensure consistent therapeutic exposure. In contrast, MMF in this regimen is 
dosed at 15 mg/kg three times daily, up to a maximum of 3 grams per day, and most adult 
patients are treated at the maximum dose of 1000mg three times daily. However, prior studies 
have demonstrated that there is significant pharmacokinetic variability with this drug. Additionally, 
in the setting of allogeneic HCT, relative exposure to MMF has been shown to impact outcomes. 
A study of 85 patients receiving reduced intensity matched unrelated donor (MUD) transplants, 
higher levels of MMF metabolites in the blood correlated with a higher risk of cytomegalovirus 
(CMV) activation and lower T-cell chimerism.[58] Investigators from the University of Minnesota 
found in 87 reduced intensity HCTs including matched related and unrelated donors 
demonstrated that low unbound blood MMF levels were correlated with higher risks of acute 
GVHD and graft failure.[59] Recently, the same group showed that weight-based dosing of MMF 
impacts outcomes, with higher weight-based dosing resulting in lower rates of GVHD but higher 
rates of relapse.[60] In combination with PTCy, the impact of variable MMF exposure and 
pharmacokinetics have not been studied. 
2.5 
CYCLOPOPHOSPHAMIDE METABOLISM 
PTCy for GVHD prevention is dosed at 50mg/kg given on day +3 and day +4 based on a 
reduction in GVHD compared to giving only a single dose on day +3.[28, 31] However, 
pharmacokinetic data with this platform is lacking. In other HCT settings, Cyclophosphamide 
metabolism has proven highly variable with high relative exposure correlating with increased 
toxicity and NRM.[61] Cyclophosphamide is metabolized through the cytochrome p450 system 
and subsequently detoxified by aldehyde dehydrogenases and glutathione S-transferases. 
Polymorphisms in these pathways have been shown to correlate with efficacy and specific drug 
related toxicities in various malignancies, including relapse in the autologous transplant 
setting.[62, 63] Notably, the patterns of expression of these polymorphisms vary across ethnic 
groups, translating into different drug responses in these groups.[64, 65] As haplo HCT helps 
address the challenges of finding a donor for black and hispanic patients, a better understanding 
of the pharmacokinetics of PTCy in these groups is warranted.  
2.6 
SUMMARY OF RATIONALE 
High risk hematologic malignancies are curable with allo HCT, which offers an overall survival 
benefit. Haplo HCT with PTCy has improved access to transplant among patients lacking an HLA 
matched donor. However, this therapy is marred by high rates of relapse. This study seeks to 
optimize the haplo HCT with PTCy platform with a small increase in conditioning intensity and the 
use of PBSCT in lieu of BMT.  


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We hypothesize that intensification of Flu150/Cy29/TBI200 haplo BMT with PTCy to Flu150/Mel 
70mg/m2/TBI200 haplo PBSCT with PTCy can successfully reduce the risk of relapse and improve 
DFS without substantially increasing the risk of TRM. Additionally, we will substitute sirolimus 
instead of tacrolimus given recent phase II data from Moffitt that this drug may confer more 
favorable rates of chronic GVHD when combined with PTCy and peripheral blood stem cell 
grafts.[66] 
If successful, this intervention would further enhance the utility of haplo HCT to expand the donor 
pool to all eligible patients.  
 
 
 
 
 
 
2.7 RISK/BENEFIT ASSESSMENT  
 
2.7.1 KNOWN POTENTIAL RISKS  
 
There are numerous anticipated adverse consequences of transplantation, which include, but are 
not limited to conditioning regimen related toxicity such as severe mucositis, idiopathic 
pneumonia syndrome, hepatic veno-occlusive disease and death, early and late infectious 
complications, potentially severe or fatal acute or chronic graft vs. host disease, and relapse of 
primary disease and its complications. Specific complications are listed below. 
 
2.7.2 PREPARATIVE REGIMEN 
 
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 


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Fludarabine 
Common 
Less Common 
Rare 
• 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 
 
Cyclophosphamide 
Common 
Less Common 
Rare 
• nausea/vomiting 
• mucositis 
• sterility 
• severe suppression of 
• blood counts 
• diarrhea 
• fluid weight gain/edema 
• alopecia 
• hemorrhagic cystitis 
 
• cardiomyopathy 
• skin rash 
• SIADH (Syndrome of Inappropriate 
Anti-diuretic Hormone) 
 
 
Melphalan 
Common 
Less Common 
Rare 
• 
nausea (at higher doses)  
• 
vomiting (at higher doses)  
• 
low white blood cell count 
with increased risk of 
infection  
• 
low platelet count with 
increased risk of bleeding  
• 
anemia (low red blood cell 
count) with symptoms like 
tiredness, paleness, or 
trouble catching breath 
• short-term or long-term 
infertility (inability to have 
children)  
• weakness 
 
• 
severe allergic reaction  
• 
loss of appetite  
• 
scarring (fibrosis) or 
inflammation of lungs  
• 
hair loss, including face and 
body hair  
• 
rash  
• 
itching  
• 
second type of cancer (may 
happen years after 
treatment)  


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Melphalan 
Common 
Less Common 
Rare 
• 
diarrhea 
• 
death from lung damage or 
other causes  
 
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 
• intestinal cramps 
• mucositis (mouth sores) 
• 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 
• veno-occlusive disease (VOD - 
explained below in the damage 
to vital organs section) 
• 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) 
2.7.3 HAPLOIDENTICAL DONOR STEM 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 
• 
Cytokine release syndrome (CRS, see appendix I for grading and management) 
• 
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 
2.7.4 GVHD PROPHYLAXIS 
 


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Sirolimus   
Common 
Less Common 
Rare, but may be serious 
 Pain or body aches 
 Fever 
 High blood pressure 
 kidney problems 
 Swelling of the hands, feet, 
ankles, or lower legs 
 Low red blood cell count 
(anemia) 
 Low platelets 
 Unusual bleeding/bruising 
 Headaches 
 Ulcers of the lips/mouth 
 Shortness of breath 
  
 Blood clots 
 High cholesterol 
 Reduced number of 
platelets, red, and white 
blood cells 
 Hoarse voice 
  
 
Severe liver damage 
 
Increased risk of 
lymphoma or other 
cancers 
 
 
Mycophenolate mofetil (MMF) 
Common 
Less Common 
Rare, but may be serious 
• miscarriage 
• birth defects 
• diarrhea 
• damage to unborn baby 
• limited effectiveness of birth 
control 
• stomach pain 
• upset stomach 
• vomiting 
• headache 
• tremors 
• low white blood cell count 
with increased risk of 
infection 
• increased blood cholesterols 
• swelling of the hands, feet, 
ankles or lower legs 
• anemia 
• rash 
• difficulty falling asleep 
or staying asleep 
• dizziness 
• uncontrollable hand 
shakes 
• difficulty breathing 
• unusual bruising 
• fast heartbeat 
• excessive tiredness 
• weakness 
• blood in stool 
• bloody vomit 
• change in vision 
• secondary cancers, such as 
lymphoproliferative disease or 
lymphoma 
• Progressive Multifocal 
Leukoencephalopathy 
2.7.5 G-CSF 
 
Common 
Less Common 
Rare, but may be serious 
none 
• local irritation at injection site 
• ache or pain inside the bones 
• increased levels of liver enzymes 
• uric acid in the blood 
• low number of platelets in the blood 
• allergic reaction, low fever 
• enlargement of the spleen and even 
splenic rupture  
• worsening of pre-existing skin rashes,  
• hair loss  
• inflammation of a blood vessel in the skin 
 


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2.7.6 KNOWN POTENTIAL BENEFITS  
 
High risk hematologic malignancies are curable with allo HCT, which offers an overall survival 
benefit. Unfortunately, some patients lack an HLA matched donor. Haplo BMT with PTCy has 
improved access to transplant among these patients. However, this therapy is marred by high 
rates of relapse. This study seeks to optimize the haplo HCT with PTCy platform with a small 
increase in conditioning intensity and the use of PBSCT in lieu of BMT. If successful, this 
intervention will improve efficacy without a significant concomitant increase in toxicity. This would 
further enhance the utility of haplo HCT to expand the donor pool to all eligible patients. In 
particular, this would significantly improve outcomes in patients lacking an HLA matched donor 
and are, thus, at high risk of relapse using existing haplo transplant protocols.    
Immediate Benefits: 
• 
Decreased toxicity (GVHD, TRM) in the immediate post-transplant period as compared to 
many standard melphalan based conditioning regimens 
Long-range Potential Benefits: 
• 
Improved disease control and survival as compared to currently standard conditioning 
regimens used prior to haplo HCT with PTCy 
 
2.7.7 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
Allogeneic HCT is the only curative therapy for a number of hematologic malignancies. The long 
term outcomes for patients after HCT can be generally categorized as disease free survival (i.e., 
cure), survival with disease relapse, and death due to transplant. Generally, increasing the 
intensity of pre-transplant conditioning results in lower relapse rates, but at the cost of higher 
rates of transplant related mortality (TRM). Conversely, reduced intensity regimens decrease 
TRM but at cost of higher rates of relapse. Thus, a large proportion of transplant patients 
succumb to either the transplant or disease relapse. The goal of this study is to use a novel 
conditioning regimen to optimize the balance of toxicity and efficacy in patients undergoing 
haploidentical donor HCT with PTCy based GVHD prophylaxis.     
 
 
 
3 
OBJECTIVES AND ENDPOINTS 
 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
FOR ENDPOINTS 
Primary 
 
 
The primary objective is to 
estimate probability of the 
18 month disease free 
survival (DFS) after a HLA-
haploidentical related 
hematopoietic cell 
transplant (Haplo-HCT) 
The primary endpoint is the probability of 
disease-free survival (DFS) by 18 
months post-transplant.  An event will be 
defined as death or a relapse. 
As HCT is intended 
as a curative therapy, 
DFS is an optimal 
endpoint as it 
encompasses both 
elimination of the 


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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
FOR ENDPOINTS 
using a reduced intensity 
fludarabine/melphalan/total 
body irradiation (TBI) 
conditioning in older 
patients in patients with a 
myeloid hematologic 
malignancy.  
disease and overall 
survival.  
 
Secondary 
 
 
• Incidence of day 90 
grade II-IV and grade III-
IV acute graft versus-
host-disease (GVHD)  
• Probability of 6 month 
and 18 month TRM 
• Probability of 18 month 
relapse incidence 
• Probability of 18 month 
OS 
 
• 
Probability of Grade II-IV and Grade 
III-IV aGVHD at 100 days 
• 
Probability of treatment-related 
mortality (TRM) at 6 months and 18 
months  
• 
Probability of relapse at 18 months  
• 
Probability of OS at 18 months 
 
These are standard 
outcomes of interest 
following transplant. 
These outcomes will 
further elucidate 
causes of treatment 
failure contributing to 
the primary outcome 
(DFS). 
Tertiary/Exploratory  
 
 
• Incidence of neutrophil 
recovery by day +30 
• Incidence of platelet 
recovery by day +60  
• Donor cell engraftment 
(chimerism) at day +30, 
+60, +90, +180 and + 
365 
• Incidence of 18 month 
chronic GVHD 
• Probability of 18 month 
year GVHD and relapse-
free survival (GRFS) 
• Incidence of 100 day, 1 
year, and 18 month 
serious fungal and viral 
infection 
• 
Probability of neutrophil recovery by 
day +30 
• 
Probability of platelet recovery by 
day +60 
• 
Proportion of donor cell engraftment 
(chimerism) at days +30, +60, +90, 
+180 and +365 
• 
Probability of 18 month chronic 
GVHD 
• 
Probability of 18 month GVHD and 
relapse-free survival (GFRS) 
• 
Probability of 100 day, 1 year, and 
18 month serious fungal and viral 
infection 
 
These are standard 
outcomes of interest 
following transplant. 
These outcomes will 
further elucidate 
causes of treatment 
failure contributing to 
the primary outcome 
(DFS). 
Pharmacologic  
 
 
• 
Evaluate 
pharmacokinetics of 
mycophenolate 
mofetil (MMF) 
measured on day 6 
after transplant 
• 
Evaluate single 
nucleotide 
polymorphisms 
(SNPs) in p450, 
aldehyde 
• 
Concentrations of MMF 
metabolites measured on day 6 
after transplant 
• 
Prevalence, by ethnicity, of 
SNPs in p450, aldehyde 
dehydrogenase, and glutathione 
S-transferase known to 
influence Cyclophosphamide 
metabolism  
 
• 
Metabolism of 
relevant drugs 
may impact 
clinical 
outcomes.  


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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
FOR ENDPOINTS 
dehydrogenase, 
and glutathione S-
transferase that 
influence 
Cyclophosphamide 
metabolism 
 
 
 


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4 
STUDY DESIGN  
 
4.1 OVERALL DESIGN 
This is a single institution phase II study of a reduced intensity conditioning (RIC) followed by a 
haploidentical hematopoietic cell transplant (haplo-HCT) in persons with diagnosis of 
myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).   
Conditioning will consist of a reduced intensity fludarabine, melphalan and total body irradiation 
(TBI) preparative regimen for patients ≥55 years old or those with HCT Comorbidity Index (CI) >3. 
The graft source will be peripheral blood stem cells.  
 
4.2 SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
This study will be a single arm, phase II study to evaluate the feasibility, efficacy, and safety of a 
modified reduced intensity conditioning regimen of fludarabine, melphalan, and TBI followed by 
haploidentical PBSCT with PTCy based GVHD prophylaxis.[67-69] These regimens are standard 
of care in allogeneic transplant at higher doses, so a phase I portion is not required in this study 
that will use a lower dose to decrease toxicity. This trial will determine the estimated efficacy of 
this regimen based on DFS at 18 months. This will allow a basis for future, larger comparative 
studies.  
 
4.3 JUSTIFICATION FOR DOSE 
Recently Flu/Mel and Flu/Bu RIC regimens were compared in the matched adult donor allo HCT 
setting for AML/MDS, with the Flu/Mel regimen yielding significantly improved relapse rates and 
DFS.[52] The group from MD Anderson Cancer Center (MDACC) has attempted similarly to 
implement a melphalan based regimen in the setting of haplo HCT with PTCy. They recently 
reported their experience with haplo HCT with PTCy following conditioning with Flu 40 mg/m2 Day 
-6 to -3, Mel 100 mg/m2 Day -8 and either Thiotepa 5 mg/kg Day -7 or TBI 200 cGy (FM100) in 
patients 55 years and older.[49, 50] Despite reported low 1-year relapse rates of 11-19% with the 
Flu/Mel regimen in these studies, prolonged courses of intensive immune suppression (MMF 
through Day +90 and Tac through Day +180) were required in order to minimize the risk of 
excessive acute GVHD.[49, 50] Notably, high dose of Mel exposure per kilogram of body weight 
(>3.5mg/kg) has been previously shown to increase the risk of oral mucositis and subsequent 
acute GVHD rates in allo HCT recipients.[53] Thus, a reduction in melphalan dosing may result in 
a more favorable balance of efficacy and toxicity. 
 
4.4 END OF STUDY DEFINITION 
A participant is considered to have completed the study if he or she has completed all phases of 
the study including the last visit or the last scheduled procedure shown in the Schedule of Activities 
(SoA), Section 1.3. 
 
The end of the study is defined as completion of the last visit or procedure shown in the SoA in 
the trial globally. 
 


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5 
STUDY POPULATION 
 
5.1 INCLUSION CRITERIA 
5.1.1 
Age, Performance Status, and Graft Criteria 
• Age ≥ 55 years or HCT Co-Morbidity score (HCT-CI) > 3 
(http://www.qxmd.com/calculate-online/hematology/hct-ci) 
• Lack of a suitable 8/8 HLA-matched sibling donor 
• Adequate performance status is defined as Karnofsky score ≥ 70% (> 16 years 
of age) or Lansky score ≥ 70 (pediatrics) (Appendix II) 
• Patients and selected donor must be HLA typed at high resolution using DNA 
based typing at the following HLA-loci: HLA-A, -B, -C and DRB1. Donors must 
be HLA-haploidentical relatives including, but not limited to, children, siblings, or 
parents, defined as having a shared HLA haplotype between donor and patient 
at HLA-A, -B, -C, and -DRB1.Refer to donor selection in section 5.3.  
5.1.2 
Eligible Diseases 
Acute Myeloid Leukemia (AML):  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. (Refer to exclusion criteria section 3.5 
for more detailed definition).  
• 
Second or greater complete remission (CR) 
• 
First CR (CR1) in patients ≥60 years old  
• 
CR1 in <60 years old that is NOT considered as favorable risk (see 
exclusion criteria).   
o 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 
• 
Recipient age 30 years and 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 


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• 
Slow cytologic response (>10% lymphoblasts in bone marrow on Day 14 of 
induction therapy) 
• 
Evidence of persistent immonophenotypic or molecular MRD at the end of 
induction and consolidation therapy 
Biphenotypic/Undifferentiated/Prolymphocytic 
Leukemias 
in 
first 
or 
subsequent CR. 
Myelodysplastic syndrome: any subtype including refractory anemia (RA) if 
severe pancytopenia or complex cytogenetics. Blasts must be less than 10%. If 
10% or more, then requires chemotherapy for cytoreduction to ≤10% prior to 
transplantation. 
Chronic myelogenous leukemia in chronic or accelerated phase.  Chronic 
phase patients must failed at least two different TKIs, been intolerant to all available 
TKIs or have T315I mutation. Accelerated phase requires remission as defined in 
“AML” section above.  
Myeloproliferative neoplasms/myelofibrosis. Blasts must be less than 5%. If 5% 
or more requires chemotherapy for cytoreduction to ≤5% prior to transplantation. 
Relapsed large-cell lymphoma, mantle-cell lymphoma and Hodgkin 
lymphoma that is chemotherapy sensitive and has failed or ineligible for an 
autologous transplant.  
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.  
Relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma 
(CLL/SLL), marginal zone B-cell lymphoma, follicular lymphoma with any of 
the following:  
• 
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 primary refractory disease.  
 
Note: Bulky disease and an estimated tumor doubling time of less than one 
month require debulking therapy prior to transplant.  
Lymphoplasmacytic lymphoma is eligible after initial therapy if chemotherapy 
sensitive. 
 


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5.1.3 
Organ Function Criteria 
Adequate organ function is defined as:  
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 nether test can be obtained it should be clearly stated in 
the provider’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 or a history of renal dysfunction must 
have estimated creatinine clearance > 40 ml/min/1.73m2. 
5.1.4 
Sexually active females of childbearing potential and males with partners of child-
bearing potential must agree to use adequate birth control during study treatment.   
5.1.5 
Voluntary written consent (adult or parent/guardian with presentation of the minor 
information sheet, if appropriate) 
 
 
5.2 EXCLUSION CRITERIA 
5.2.1 
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.  
5.2.2 
Untreated active infection 
5.2.3 
Active HIV infection  
5.2.4 
Prior allogeneic HCT at any time point or less than 6 months since prior autologous 
transplant (if applicable)  
5.2.5 
Evidence of progressive disease by imaging modalities or biopsy - persistent PET 
activity thought unrelated to lymphoma is not an exclusion criterion in the absence 
of CT changes indicating progression. 
5.2.6 Active central nervous system malignancy 
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• 
t(8,21) without cKIT mutation or evidence of immunophenotypic, cytogenetic 
or molecular minimal residual disease (MRD) 
• 
inv(16) or t(16;16) without cKIT mutation or evidence of MRD 
• 
Normal karyotype with mutated NPM1 but FLT3-ITD wild type without 
evidence of MRD 
• 
Normal karyotype with double mutated CEBPA without evidence of MRD 
5.3 DONOR SELECTION 
 
Donor selection will be in compliance with 21 CFR 1271.  Donors will be evaluated, consented 
and enrolled via standard operating procedures of the Moffitt Cancer Center Department of 
Blood and Marrow Transplantation. However information in this protocol (including match 
criteria, donor selection priority if more than 1 available donor, cell collection target) overrules 
those procedures. 
In addition, the following criteria must be met: 
5.3.1 Must be HLA-haploidentical relatives of the patient (biological parents, siblings, half-
siblings, offspring, or other non-first degree relatives), defined as having a shared 
HLA haplotype between donor and patient at HLA-A, -B, -C, and -DRB1 
5.3.2 14 to 70 years of age 
5.3.4 Negative for HIV and active hepatitis B  
5.3.5 Not pregnant - females of childbearing potential must have a negative pregnancy test 
within 7 days of marrow collection 
Donor Prioritization Schema 
In the event that two or more eligible donors are identified, the following order of priority is 
suggested: 
• 
Medically fit to donate 
• 
Absence of recipient donor-specific anti-HLA antibodies (DSA). Positive DSA is defined 
as a positive crossmatch test of any titer (by complement-dependent cytotoxicity or flow 
cytometric testing) or the presence of DSA to the high expression loci HLA-A, - B, -C, or 
-DRB1 with mean fluorescence intensity >1000 by solid phase immunoassay. 
• 
Donor age 18-40 is prioritized over donor age < 18, then >40-60 years. If multiple 18-40 
year old donors are available, the donor should be selected based on the following 
criteria.  
• 
Lack of major ABO incompatibility 
• 
For cytomegalovirus (CMV) seronegative recipients, a CMV seronegative donor. For 
CMV seropositive recipients, a CMV seropositive donor.  
• 
Lack of minor ABO incompatibility 
• 
Male donor or non-parous female are preferable.  


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5.4 LIFESTYLE CONSIDERATIONS 
 
Patients on trial will be required to follow standard post-transplant care per Moffitt Cancer Center 
BMT/CI standard operating procedures. 
 
5.5 SCREEN FAILURES 
 
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently assigned to the study intervention or entered in the study. A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure participants, to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, screen 
failure details, eligibility criteria, and any serious adverse event (SAE). 
 
Screen failure individuals who do not meet the criteria for participation in this trial because of a 
correctable comorbidity (e.g., active infection, elevated blast percentage, etc.) may be rescreened. 
Rescreened participants should be assigned the same participant number as for the initial 
screening. 
 
5.6 STRATEGIES FOR RECRUITMENT AND RETENTION 
 
All the patients evaluated at Moffitt Cancer Center BMTCI department will be considered for this 
trial if they are otherwise eligible. Women and minorities will be enrolled if they are considered for 
haploidentical related hematopoietic Cells (Haplo-HCT)  and meet eligibility criteria. All efforts will 
be made to conform to NIH Policy on Inclusion of Women and Minorities as Participants in 
Research Involving Human Subjects. This trial is expected to enroll a high proportion of ethnic 
minorities as these patients are less likely to have matched donor options. Demographic 
information regarding ethnicity/race will be collected for future reporting. This information may be 
collected at any time after consent through the end of the trial. Patients will be followed for 1.5 
years from the date of HCT. 
 
To facilitate collection of demographic data, patients will be asked to answer the following 
survey: 
 
“In this trial we want to accurately collect the race and ethnicity of all our patients. Please check 
the race/ethnicity category that you belong to:  
1.White 
2.Black or African American 
3.Hispanic 
4.American Indian or Alaska native 
5.Asian, Hawaiian or pacific islander 
6.Other, not included, please explain:” 
 
 


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5.7 PATIENT REGISTRATION IN ONCORE 
Registration will occur after the patient/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 Moffitt Cancer Center’s Clinical Trial Coordinator(s). 
 
6 
STUDY INTERVENTION 
 
6.1 STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
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 supportive care drug therapy (e.g., 
acetaminophen, diphenhydramine, antimicrobials, etc.). 
The administration of the preparative regimen will follow institutional drug and supportive care 
guidelines. Timing of infusions below may be modified per institutional practice or as clinically 
indicated.   
Dose and/or schedule adjustments to the dosing or administration of the treatment plan may be 
made on an individual patient basis as needed for safety (e.g., for drug-drug interactions or 
toxicity). 
All drugs used in this study are commercially available by prescription. 
 
6.1.2 DOSING AND ADMINISTRATION 
 
Treatment 
Day 
Treatment 
Protocol 
Section  
Day –6 
Fludarabine 30 mg/m2 IV over 30-60 minutes, then 
Melphalan 70 mg/ m2 IV over 45 minutes 
6.1.2.1 
Days -5 
Fludarabine 30 mg/m2 IV over 30-60 minutes, then 
6.1.2.1 
Day -4 
Fludarabine 30 mg/m2 IV over 30-60 minutes 
6.1.2.1 
Day -3 
Fludarabine 30 mg/m2 IV over 30-60 minutes 
6.1.2.1 


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Day -2 
Fludarabine 30 mg/m2 IV over 30-60 minutes 
6.1.2.1 
Day -1 
TBI 200 cGy 
6.1.2.1 
Appendix III 
Day 0 
Peripheral Blood Stem Cell Transplant 
6.1.2.2 
Day 3 
Cyclophosphamide 50 mg/kg IV 
Mesna IV  
6.1.2.3 
Day 4 
Cyclophosphamide 50 mg/kg IV 
Mesna IV  
6.1.2.3 
Day 5 
Begin sirolimus, mycophenolate mofetil, and G-CSF 
6.1.3 
6.1.2.1 CONDITIONING REGIMEN 
Fludarabine 30 mg/m2/day will be administered over 30-60 minutes intravenous infusion on Days 
–6 through –2 for a total dose of 150 mg/m2.  Fludarabine will be dosed according to the recipient’s 
actual body weight.  For patients who have an estimated or measured creatinine clearance < 70 
ml/min/1.73 m2, or either prior CNS disease, prior brain radiation, or prior intrathecal 
chemotherapy, the fludarabine dose should be reduced by 20%.  Fludarabine dosing is based on 
the last creatinine clearance prior to the start of conditioning.  The fludarabine dose should be the 
same on Days -6 to -2, even if the patient’s creatinine changes.   
Melphalan 70 mg/m2 over 45 minutes will be administered on Day –6. Melphalan dose will be 
calculated based on Actual Body Weight. High-dose melphalan will be administered following oral 
cryotherapy per standard institutional practice. High-dose Melphalan is administered via a central 
venous catheter following reconstitution with the provided sterile diluent. High-dose melphalan 
should be administered diluted with sodium chloride and infused over 45 minutes. Vigorous 
maintenance hydration will be administered with high dose melphalan per institutional practice 
(day –6).  
TBI 200 cGy will be administered on Day -1.  Refer to appendix II. 
 
6.1.2.2 HAPLOIDENTICAL PERIPHERAL BLOOD STEM CELL COLLECTION AND INFUSION (DAY 0) 
On day 0, patients will receive a peripheral blood hematopoietic cell graft. Donor peripheral blood 
hematopoietic cells will be collected for a target yield of 5 x 106 CD34+ cells/kg, minimal accepted 
number is 2 x 106 CD34+ cells/kg recipient IBW. The maximum infused cell dose will be 7 x 106 
CD34+ cells/kg. Sample of the infused graft will be sent for flow cytometry to determine the content 
of CD34+, CD3+ cells and for correlative studies.  
6.1.2.3 POST-TRANSPLANT CYCLOPHOSPHAMIDE (DAY 3 AND DAY 4) 


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Hydration will be given according to our institutional standards.  
Cyclophosphamide 50 mg/kg will be given as an IV infusion over 1 hour on Days +3 post-transplant 
(between 62 and 72 hours after start of stem cell infusion) and on Day +4 post-transplant 
(approximately 24 hours after Day +3 cyclophosphamide).   
Mesna 20 mg/kg will be given as an IV infusion over 15 minutes for four doses on Days +3 post-
transplant and for four doses on Day +4 post-transplant. Mesna doses will be given starting 30 
minutes prior to the first dose of cyclophosphamide, then 3, 6, and 9 hours following the start of 
cyclophosphamide infusion each day. 
Both cyclophosphamide and mesna dosing is calculated based on ideal body weight (IBW) unless 
actual body weight (ABW) is < IBW (then ABW should be used).   
Ideal body weight is calculated using 50kg + [2.3kg x (height in inches – 60)] for men; 45.5kg + 
[2.3kg x (height in inches – 60)] for women.   
6.1.3 GVHD PROPHYLAXIS AND GROWTH FACTOR SUPPORT (BEGIN DAY 5) 
All patients will receive prophylaxis for GVHD with two drugs both beginning at Day 5 as follows: 
6.1.3.1 SIROLIMUS 
Sirolimus (SIR) will be administered as a 9 mg oral loading dose on day +5, followed by 4 mg oral 
daily as maintenance to target blood level 5-14 ng/ml. SIR levels will be monitored according to 
BMT program standard operating procedures (BMT-G-103). Serum levels of sirolimus will be 
measured around Day +7 and then should be checked twice weekly thereafter and the dose 
adjusted accordingly to maintain a goal trough level of 8-14 ng/mL. Frequency of sirolimus levels 
may be decreased once the goal target has been achieved. Sirolimus should be continued for at 
least 90 days if tolerated. In absence of GVHD, sirolimus should be discontinued by day 180.   
The goal sirolimus trough may be adjusted as clinically indicated (e.g., for GVHD, infection, graft 
failure, relapse). Tacrolimus (trough level of 5-15 ng/ml) may be substituted for sirolimus if the 
patient is intolerant of sirolimus.  
6.1.3.2 MYCOPHENOLATE MOFETIL (MMF) 
MMF will be initiated at a dose of 15 mg/kg PO TID (based upon actual body weight) with the 
maximum total daily dose not to exceed 3 grams (1 g PO TID). Dosing may be adjusted for toxicity 
or as clinically indicated. MMF prophylaxis will begin on Day +5 post-transplant and will be 
discontinued after the last dose on Day +35 as tolerated or may be continued if active GVHD is 
present.  
 
6.1.3.3 GROWTH FACTOR SUPPORT 


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G-CSF will be given beginning on Day +5 at a dose of 300 mcg if patient weight is ≤ 70 kg or 480 
mcg if the patient weight is >70 kg.(rounding to the nearest vial dose is allowed), until absolute 
neutrophil count (ANC) is ≥ 1,500/mm3 for three consecutive measurements on 3 different days.  
G-CSF may be restarted to maintain ANC > 1,000/mm3.  G-CSF may be given by IV or 
subcutaneously. 
 
 
6.1.4 SUPPORTIVE CARE 
Supportive care will be provided per Moffitt Cancer Center’s 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 Moffitt Cancer Center BMT-CI 
program GVHD protocols  
Antimicrobial prophylaxis directed towards bacteria, fungi and viruses will be per Moffitt Cancer 
Center’s current institutional guidelines for transplant patients.  
 
 
6.1.5 FOLLOW-UP 
 
Patients will be followed for 1.5 years post-transplant per  institutional standard and the schedule 
in section 8.   
Follow-up after 1.5 years will be per the Moffitt Cancer Center standard hematopoietic stem cell 
transplantation protocol for long-term follow-up.  
 
6.2 MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
Not Applicable 
 
6.3 STUDY INTERVENTION COMPLIANCE 
 
Patients will admitted for conditioning and treatment in the inpatient BMT unit at the Moffitt Cancer 
Center from the initiation of conditioning through neutrophil engraftment. Patients will subsequently 
follow-up as outpatient per institutional protocol and the clinical trial calendar. Compliance with 
sirolimus (or tacrolimus) will be assessed via serum levels. Compliance with other medications will 
be confirmed at follow-up visits.  
 
6.4 CONCOMITANT THERAPY 
 
Patients on this trial may not be concomitantly treated on an alternate interventional clinical trial.  


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6.4.1 RESCUE MEDICINE 
 
Not applicable 
 
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 DISCONTINUATION OF STUDY INTERVENTION 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to investigator, funding 
agency, the IND/IDE sponsor and regulatory authorities. If the study is prematurely terminated or 
suspended, the PI will promptly inform the IRB and will provide the reason(s) for the termination 
or suspension. 
 
Circumstances that may warrant termination or suspension include, but are not limited to: 
 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
 
The PMC and/or IRB may vote to suspend or terminate approval of a research study not being 
conducted in accordance with the IRB, the Cancer Center and/or regulatory requirements or that 
has been associated with unexpected problems or serious harm to subjects.  The PMC/IRB will 
notify the PI in wiring of such suspensions or terminations.  It is the responsibility of the PMC/IRB 
Chairperson to ensure prompt written notification of any suspensions or terminations of PMC/IRB 
approval to the relevant Federal Agencies, including OHRP, FDA as applicable. 
 
 
7.2 PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Participants are free to withdraw from participation in the study at any time upon request. An 
investigator may discontinue or withdraw a participant from the study for the following reasons: 
 
• 
Pregnancy 
• 
Significant study intervention non-compliance  
• 
If any clinical adverse event (AE), laboratory abnormality, or other medical condition or 
situation occurs such that continued participation in the study would not be in the best 
interest of the participant 
• 
Disease progression which requires discontinuation of the study intervention 
• 
If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
The reason for participant discontinuation or withdrawal from the study will be recorded within 
the patient’s medical record and OnCore and/or the Clinical Trial Management System 
(CTMS). Subjects who sign the informed consent form but do not receive the study 


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intervention may be replaced.  Subjects may be replaced if they signed the informed consent 
form and received the study intervention, and then were withdrawn or discontinued from the 
study. 
All efforts will be made to continue to follow-up of withdrawn or terminated participants or 
participants who discontinue therapy but remain in the study for follow-up, especially for 
safety and efficacy study endpoints (if applicable). Every effort will be made to undertake 
protocol-specified safety follow-up procedures to capture AEs, serious adverse events 
(SAEs), and unanticipated problems (UPs). 
 
7.3 LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if he or she fails to return for 3 scheduled visits 
and if study site staff are unable to contact the participant.  
 
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
• 
The site will attempt to contact the participant and reschedule the missed visit within 2 
weeks and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether the participant wishes to and/or should continue in the 
study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, by making 3 telephone 
calls and, if necessary, by sending a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented in 
the participant’s medical record or study file.  
• 
A minimum of 2 years should be spent attempting to locate the patient.  If after that period 
of time the coordinator has sufficiently documented all failed attempts to locate the 
patient, including sending a certified letter with no response, then he or she will be 
considered to have withdrawn from the study for the primary reason of being lost to 
follow-up.] 
 
 


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8 
STUDY ASSESSMENTS AND PROCEDURES 
 
 
8.1 EFFICACY ASSESSMENTS  
 
Prior to engraftment, patients will remain in the hospital and study related assessments will be 
performed on an inpatient basis. Post-transplantation study visits occur on day 30, 90, 180, 1 year, 
and 18 months (with acceptable windows as outlined in the study calendar). 
 
All clinic assessments and laboratory studies needed to inform study endpoints captured at these 
time points are part of Moffitt standard practices (with exception of underlined research samples). 
 
1. Day 30 study visit 
- Capture ANC/PLT engraftment data, day 30 disease response assessment and donor 
chimerism, and any occurrence of acute GVHD 
- Monitor AE/SAE throughout observation period 
- Collect day 30 immune deficiency panel IMDFP Tregs. 
- Collect day 30 research blood sample and bone marrow sample 
 
3. Day 90 study visit 
- Capture acute GVHD data, day 90 disease response assessment and donor chimerism, 
and death events. 
- Capture initiation of sirolimus (or tacrolimus) taper. 
- Monitor AE/SAE throughout observation period 
- Collect day 90 immune deficiency panel IMDFP Tregs 
 
4. Day 180 study visit 
- Capture acute and chronic GVHD data, day 180 disease response assessment and donor 
chimerism, mortality events 
- Capture time of sirolimus discontinuation 
- monitor AE/SAE throughout observation period 
- Collect day 180 immune deficiency panel IMDFP Tregs 
- collect day 180 research blood sample and bone marrow sample 
 
5. 1 year and 18 months study visits 
- capture chronic GVHD data, response assessment and donor chimerism, mortality 
 
Pre-BMT work-up evaluations should be completed prior to initiation of conditioning 
chemotherapy within the screening windows defined in the table below. Evaluations done as a 
“standard of care” prior to consent on trial may be used for the trial screening if falling within the 
appropriate window from initiation of conditioning chemotherapy.  
 
Scheduled evaluations after screening and until engraftment may be performed +/-3 days from 
the targeted date; assessments performed after engraftment and through Day 90 may be done 
+/-10 days of the targeted date.  After Day 90 assessments may be done +/- 30 days of the 
targeted date.  In addition, targeted days may be altered as clinically appropriate. 
 


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Activity 
Pre-BMT  
Work-Up 
Day 1 To 
Engraftment1 
Follow-Up Days 
42-90 
Follow-Up ( >Day 90 
through Day 540) 
Consent 
No Window 
 
 
 
Medical History 
Within 30 days 
Daily 
weekly 
X (day 180, 360, 540) 
Physical Exam 
Within 30 days 
Daily 
weekly 
X (day 180, 360, 540) 
RT consultation 
No Window 
 
 
 
Karnofsky/Lansky 
Within 30 days 
 
day 90 
X (day 180, 360, 540) 
GVHD Assessment 
 
weekly start day 7 
weekly, day 90 
X (day 180, 360, 540) 
CBC/diff/plt 
Within 30 days 
Daily 
weekly 
X (day 180, 360, 540) 
PT/INR 
Within 60 days 
 
 
 
Viral Screen 
Within 60 days 
 
 
 
PRA (Donor Specific 
Antibody) 
Within 60 days 
 
 
 
Basic metabolic panel  
 
Daily 
 
 
Comprehensive 
metabolic panel 
Within 30 days 
2x/wk 
weekly 
X (day 180, 360, 540) 
eGFR for adults with 
creat > 1.2 or hx or 
renal dysfunction 
Within 30 days 
 
 
 
Pregnancy test (females 
of childbearing potential) 
Within 30 days 
 
 
 
BM Biopsy 
Within 60 days 
X (day 30) 
X (day 90) 
X (day 180, 360, 540) 
BM chimerism  
 
BM (day 30) 
BM (day 90) 
BM (day 180, 360, 
540) 
Blood chimerism  
 
PB (day 30) 
PB (day 90) 
PB (day 180, 360, 
540) 
PETCT (lymphoma 
only) 
Within 60 days 
 
 
X 
Minimal Residual 
Disease 
Within 60 days 
BM (day 30) 
BM (day 90) 
BM (day 180, 360, 
540) 
T-Cell Immune 
Reconstitution Panel 
Within 60 days 
PB (day 30) 
PB (day 90) 
PB (day 180, 360, 
540) 


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Activity 
Pre-BMT  
Work-Up 
Day 1 To 
Engraftment1 
Follow-Up Days 
42-90 
Follow-Up ( >Day 90 
through Day 540) 
CMV PCR (blood) 
 
Weekly 
Weekly 
 
HHV6 PCR (blood) 
 
Weekly 
Weekly 
 
PFT/DLCO 
Within 60 days 
 
 
 
MUGA or Echo 
Within 60 days 
 
 
 
CT Chest/Sinus 
Within 60 days 
 
 
 
Disease Evaluation 
Within 60 days 
X (day 30) 
X (day 90) 
X (day 180, 360, 540) 
Research Bone 
Marrow and Blood 
Sample2 
No Window 
X (day 30) 
  
X (day 180) 
Blood samples for 
MMF 
 
X (day 7)3 
 
 
 
1 
Engraftment defined as absolute neutrophil count (ANC) ≥ 5 X 108/L for 3 consecutive measurements  
2 
Research blood samples will be used for cyclophosphamide genomics studies. Research blood samples will be 
collected in EDTA blood collection tubes and research marrow samples will be collected in sodium heparin 
tubes. Excess blood and marrow samples from existing samples (including those collected for MCC 14690) may 
be stored for future correlative studies in lieu of collecting a new sample. 
3 
Blood for MMF pharmacokinetic studies will be obtained on day 7 at the following time points: pre-dose, post-
dose, 1 hour, 2 hour, 4 hour, and 8 hours after dose in EDTA blood collection tubes. Collections may occur +/- 
10 minutes from the scheduled interval.  
 
NOTE: 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. 
NOTE: In certain clinical circumstances (e.g.relapsed or terminally ill patients, risk of undue harm to 
patients, etc.) study tests may be omitted at the physician’s discretion. Additionally, tests may be 
rescheduled as clinically indicated. 
 
8.2 SAFETY AND OTHER ASSESSMENTS 
Study participants will be monitored closely by study investigators based on clinical, laboratory 
and imaging studies as outlined in study calendar and per Moffitt institutional standard 
procedures. Adverse events, vital signs, clinical and laboratory tests will be assessed according 
to Schedule of Events until protocol termination. Treatment emergent adverse experiences will 
be summarized based on CTCAE severity grade. 
 


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8.3 BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES OR OTHER 
ENDPOINTS 
 
 
Specimen Type 
Baseline (Pre-
treatment) 
Day 7 
Day 30 
Day 180 
Cyclophosphamide Genomics 
(EDTA blood samples) 
X 
 
 
 
Mycophophenolate 
pharmacokinetics (EDTA blood 
samples) 
 
X 
 
 
Blood and marrow for future 
studies (EDTA tubes for blood, 
heparin tubes for marrow)* 
X 
 
X 
X 
*Blood and marrow samples for future studies may be added on to previously collected (off-trial) samples 
and/or research samples from other protocols (including MCC 14690) if excess sample is available.     
8.3.1 MYCOPHENOLATE PHARMACOKINETICS 
Blood samples for the determination of Mycophenolate mofetil (MMF) and Mycophenolic Acid 
(MPA) concentrations will be collected in the study.  Free and total drug will be determined for 
both. The actual PK sampling times should be recorded accurately in the PK requisition forms.  
Measurements will be taken on post-transplant day 7 at pre-dose and then at the end of the 
infusion, followed by 1, 2, 4, 8 hours after the end of infusion. Collections may occur +/- 10 
minutes from the scheduled interval. If samples are not collected on day 7 (e.g., due to day 7 falling 
on a holiday or weekend), then samples may be collected within 3 days of day 7 (days 8, 9, or 10). 
MMF PK samples should NOT be collected prior to day 7.   
a. Pharmacokinetic Blood Sample Collection and Handling 
At each specified time point, a single 10 mL EDTA tube will be used to collect blood.  
Vacutainers will be kept on crushed ice after blood collection. Within 30 minutes, the tubes will 
be centrifuged for 5 minutes at 1100 x g at 4°C to separate the plasma.  After centrifugation, 
plasma will be transferred into polypropylene screw-cap tubes labeled appropriately for total drug 
assays of MMF and MPA.  Remaining plasma will be added to specialty centrifuge devices to 
create free-fractionate of drug.  These aliquots will be assayed for free concentrations of each 
drug.  All samples will be stored at of -80ºC until analysis.   
Day 
MMF/MPA PK 1 
Day 7 
Pre-dose 


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Day 7 
EOI 
Day 7 
1 hr post +/-10 min 
Day 7 
2 hr post +/-10 min 
Day 7 
4 hr post +/-10 min 
Day 7 
8 hr post +/-10 min 
 
1. All collection time points after administration are relative to the end of infusion, regardless 
of length of administration and dosage. 
b. Analytical Methods 
Concentrations of MMF and MPA will be determined by the Translational Research Core at the 
Moffitt Cancer Center using LC/MS/MS methods that have been validated according to ICH/FDA 
guidelines for bio-analytical analysis. 
8.3.2 CYCLOPHOSPHAMIDE PHARMACOGENOMICS 
In order to assess the presence of single nucleotide polymorphisms (SNPs) in 6 genes of interest 
that influence drug metabolism (CYP2B6, CYP2C19, CYP2C9, CYP3A5, GSTP1, ALDH1A1), 
targeted sequencing will be performed using a Qiagen QiaSeq Pharmacogenomics Panel.  Qiagen 
QiaSeq panels incorporate unique molecular indices (UMIs) which facilitate accurate variant allele 
frequency reporting while also reducing the number of artefactual variants.  Briefly, the sample 
DNA will be enzymatically fragmented, followed by followed by end-repair, A-addition, and adaptor 
ligation. Target enrichment with locus-specific primers and library amplification will be performed, 
and the final libraries will be screened on an Agilent TapeStation (Agilent Technologies, Inc., Santa 
Clara, CA) and quantitated by qPCR with the Kapa Library Quantification Kit (Roche Diagnostics, 
U.S., Indianapolis, IN).  The indexed samples will be sequenced on the NextSeq 500 sequencer 
(Illumina, Inc. San Diego, CA) with150-base paired-end reads.  Data analysis including alignment 
and variant calling will be performed using the QiaSeq data analysis pipeline. 
 
8.4 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.4.1 DEFINITION OF ADVERSE EVENTS (AE) 
 
An adverse event is any unexpected medical occurrence associated with the use of a drug or 
therapy in humans, whether or not considered drug related. It can be any unfavorable and 
unintended sign (e.g., an abnormal laboratory finding), symptom, or disease, temporally 
associated with the use of a drug. Infection, acute and chronic GVHD will not be considered 
adverse events. 
 


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8.4.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
An adverse event or suspected adverse reaction is considered "serious" if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes:  
• 
death,  
• 
a life-threatening adverse event,  
• 
inpatient hospitalization or prolongation of existing hospitalization,  
• 
a persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions, or  
• 
a congenital anomaly/birth defect.  
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered serious when, based upon appropriate medical judgment, they may jeopardize 
the patient or subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the development of drug dependency or drug 
abuse. 
 
 
8.4.3 CLASSIFICATION OF AN ADVERSE EVENT 
 
8.4.3.1 SEVERITY OF EVENT 
 
Toxicity and adverse events will be classified according to NCI's Common Terminology 
Criteria for Adverse Events V 5.0 (CTCAE).  A copy of the CTCAE can be downloaded 
from the CTEP home page http://evs.nci.nih.gov/ftp1/CTCAE/About.html   
8.4.3.2 EVENT DOCUMENTATION 
Transplant related outcomes and events will be recorded in the Blood and Marrow 
Transplantation (BMT) database.   
Events requiring prompt reporting to the Moffitt Cancer Center Protocol Monitoring 
Committee, the Institutional Review Board (IRB), early stopping rule events, and protocol 
deviations will be documented in OnCore.  
8.4.3.3 RELATIONSHIP TO STUDY INTERVENTION 
 
Anticipated toxicity following allogeneic transplantation: 
There are numerous anticipated adverse consequences of transplantation, which include, but are 
not limited to conditioning regimen related toxicity such as severe mucositis, cytokine release 
syndrome, idiopathic pneumonia syndrome, hepatic veno-occlusive disease and death, early and 
late infectious complications, potentially severe or fatal acute or chronic graft vs. host disease, 


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and relapse of primary disease and its complications. Thus, expected complications of 
transplantation will not be collected as adverse events on this trial. 
 
Suspected Adverse Events 
A suspected adverse reaction is any adverse event for which there is a reasonable possibility 
that the drug caused the event. Reasonable possibility means there is evidence to suggest a 
causal relationship between the drug and the event. 
Unexpected 
An adverse event is considered unexpected if it is not listed in the investigator brochure, occurs 
in severity greater than previously described, or - for the purpose of this protocol - if it is not in 
keeping with expected post-transplantation toxicity. 
Adverse event recording: 
Non-serious AE: Only unexpected, grade 3-5 AE will be recorded. 
Serious AE: All SAE will be recorded. 
Adverse event reporting: 
Non-serious AE: Unexpected, grade 3-5 AE will be reported to the IRB in summary form on an 
annual basis. 
8.4.3.4 EXPECTEDNESS  
 
The PI will be responsible for determining whether an AE is expected or unexpected. An AE will 
be considered unexpected if the nature, severity, or frequency of the event is not consistent with 
the risk information previously described for the study agent. 
 
 
8.4.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND 
FOLLOW-UP 
 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the 
attention of study personnel during study visits and interviews of a study participant presenting 
for medical care, or upon review by a study monitor. 
 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a patient. 
 
All AEs, including local and systemic reactions not meeting the criteria for SAEs, will be captured 
on the appropriate case report form (CRF). Information to be collected will include event 
description, time of onset, clinician’s assessment of severity, relationship to study product 
(assessed only by those with the training and authority to make a diagnosis), and time of 
resolution/stabilization of the event. All AEs occurring while on study must be documented 
appropriately regardless of relationship. All AEs will be followed to adequate resolution. 
 


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Any medical condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if the study participant’s condition 
deteriorates at any time during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of 
the event at each level of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
 
All events beginning with start of study intervention until 30 days after the last day of study 
intervention will be reported. At each study visit, the investigator will inquire about the occurrence 
of AE/SAEs since the last visit. Events will be followed for outcome information until resolution or 
stabilization. 
 
8.4.5 ADVERSE EVENT REPORTING  
 
Grade 3 or higher unexpected AEDs will be recorded from initiation of conditioning 
chemotherapy through day +90 after transplant infusion  at each examination on the Adverse 
Event case report forms/worksheets. 
 
8.4.6 SERIOUS ADVERSE EVENT REPORTING  
 
The principal investigator will report each serious adverse event, regardless attribution, within 24 
hours of learning of the occurrence. In the event that the principal investigator does not become 
aware of the serious adverse event immediately (e.g., participant sought treatment elsewhere), 
the principal investigator is to report the event within 24 hours after learning of it and document 
the time of his or her first awareness of the adverse event. The SAE report must include event 
term(s), serious criteria, and the investigator’s determination of both the intensity of the event(s) 
and the relationship of the event(s) to study drug administration. 
 
8.4.7 REPORTING EVENTS TO PARTICIPANTS  
 
Not applicable 
 
8.4.8 EVENTS OF SPECIAL INTEREST  
 
Not applicable 
 
8.4.9 REPORTING OF PREGNANCY  
 
Pregnancy, although not itself a serious adverse event, should also be reported and be followed 
up to determine outcome, including spontaneous or voluntary termination, details of birth, and the 
presence or absence of any birth defects or congenital abnormalities. 
 
8.5 UNANTICIPATED PROBLEMS 
 
8.5.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving 
risks to participants or others to include, in general, any incident, experience, or outcome that 
meets all of the following criteria: 


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• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the Institutional Review 
Board (IRB)-approved research protocol and informed consent document; and (b) the 
characteristics of the participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there 
is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously known 
or recognized.] 
 
 
8.5.2  UNANTICIPATED PROBLEM REPORTING  
  
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review 
Board (IRB) and to the Moffitt Cancer Center Protocol Monitoring Committee. The UP report will 
include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or 
outcome represents an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been 
taken or are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:  
 
• 
UPs that are serious adverse events (SAEs) will be reported to the IRB within 24 hours of 
the investigator becoming aware of the event.  
• 
All UPs should be reported to appropriate institutional officials (as required by an 
institution’s written reporting procedures), the supporting agency head (or designee), and 
the Office for Human Research Protections (OHRP) within 7 days of the IRB’s receipt of 
the report of the problem from the investigator. 
 
 


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9 
STATISTICAL CONSIDERATIONS  
 
9.1 STATISTICAL ENDPOINTS 
 
Primary Endpoint: The primary endpoint is the probability of disease-free 
survival (DFS) by 1.5 years post-transplant.  An event will be defined as 
death or a relapse. 
Secondary Endpoints:  
• Probability of Grade II-IV and Grade III-IV aGVHD at 180 days 
• Probability of TRM at 6 months and 18 months  
• Probability of relapse at 18 months 
• Probability of OS at 18 months 
Transplant Related Endpoints 
• 
Probability of neutrophil recovery by day +30 
• 
Probability of platelet recovery by day +60 
• 
Proportion of donor cell engraftment (chimerism) at days +30, +60, +90, 
+180 and +365 
• 
Probability of 18 months chronic GVHD 
• 
Probability of 18 months overall GVHD 
• 
Probability of 18 months GRFS 
• 
Probability of serious fungal and viral infections at day +100 and 18 
months post-HCT 
 
 
9.2 SAMPLE SIZE DETERMINATION 
 
The primary endpoint of this study is disease-free survival (DFS). The historic DFS at 18 months 
is 40%.[67-69] We assume that the DFS at 18 months in patients treated with Flu/TBI and low 
dose Mel will be 60%, corresponding to a hazard ratio (HR) of 0.557. A total of 18 events will be 
required to have 90.2% power to detect a HR of 0.557 using a log-rank test at a one-sided 
significance level of 0.1. Assuming uniform accrual over an 18-month accrual period and total study 
duration of 36 months, the estimated sample size is 34 subjects.  
 
 


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9.3 STATISTICAL ANALYSES 
 
9.3.1 GENERAL APPROACH 
 
The final analysis for the primary endpoint will be conducted when 18 events are observed. The 
time-to-event endpoint will be analyzed by using the Kaplan-Meier (KM) method as the primary 
analytic tool. The association with time-to-event endpoint will be explored by using Cox 
proportional hazard regression model. If the competing risk exists, the competing risk approach 
and Fine-Gray regression model will be used.  
Cumulative incidence will be used to estimate the probabilities of GVHD, relapse, infection, and 
neutrophil and platelet recovery treating deaths as a competing risk. For GVHD endpoint, relapse 
and death will serve as the competing risks. The Gray test will be used accordingly. The probability 
of TRM will be estimated in a similar manner but treating relapse as a competing risk.  
Ninety-five percent confidence intervals will be estimated from respective standard errors and the 
complementary log-log transformation. The proportion of donor chimerism (classified as ≥70% 
donor cells at various time-points will be estimated among patients who have survived to the 
evaluated time-point). Descriptive plots and measures will also be used to evaluate chimerism as 
a continuous measure. Medians, ranges and inter-quartile ranges will be given for actual 
chimerism values. Analyses will be performed and plots generated using SAS 9.3 (SAS Institute, 
Cary, NC) and/or R 3.0.2.  
 
9.3.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT 
 
The disease-free survival (DFS) is defined as the time from the date of PBSCT to first 
documentation of relapse or death due to any cause, whichever comes first. Patients who do not 
relapse and are still on the study at the time of an analysis, will be censored at the date of the 
last disease assessment documenting absence of relapse. The final statistical analysis will be 
conducted when 18 events (deaths or relapses) are observed. The Kaplan-Meier (KM) method 
and complementary log-log transformation will be used to estimate the DFS and the associated 
confidence interval. If the lower limit of one-sided 90% confidence interval at 18 months is 
greater than 40%, then the null hypothesis will be rejected. As a secondary approach, the Cox 
proportional hazard regression model will be used to explore the association with covariates.    
 
9.3.3 ANALYSIS OF THE SECONDARY ENDPOINTS 
 
 
Overall survival (OS) is defined as the time from the date of PBSCT to the date of death due to 
any cause. OS will be censored at the last date the patient is known to be alive. The GVHD-
free/relapse-free survival (GRFS) is defined as the time from the date of PBSCT to date of 
events which include grade 3-4 acute GVHD, systemic therapy-requiring chronic GVHD, relapse, 
or death, whichever comes first. OS, GRFS, and 95% confidence interval will be computed by 
the KM method and complementary log-log transformation. The cumulative incidence of acute 
GVHD, relapse, and treatment-related mortality will be estimated by the competing risk approach 


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as described in section 9.3.1. As these are secondary endpoints, no multiplicity adjustment is 
considered.  
 
9.3.4 MYCOPHENOLATE PHARMACOKINETIC ANALYSES 
Non-compartmental methods will be used to calculate the pharmacokinetic parameters. The 
parameters will be determined separately for each subject using the concentration at each 
sampling time. PhoenixTM WinNonlin® ver 8.1 (www.Pharsight.com) will be used for the 
pharmacokinetic calculations. The maximum measured concentration, Cmax, and its associated 
time will be used as the Cmax, and Tmax values for each subject.  The area under the plasma 
concentration curve from time zero to the time of the last measurable concentration (AUC0-t) and 
from time zero to infinity (AUC0-∞) will be calculated where applicable. The elimination rate 
constant (ke) clearance (CL), and volume of distribution (Vz) calculated from the terminal 
elimination phase will also be calculated where applicable. The elimination rate constant will be 
converted to the terminal half-life, t1/2, (t1/2 = ln2/ke). The reliability of the pharmacokinetic 
parameters will be determined using the correlation coefficient, r2, for the fit of the elimination 
constant to the terminal data points. Data with good fits are characterized by r2 > 0.9. Subjects 
will be dichotomized by using the median value (i.e., ≤ median vs. > median). The incidence of 
acute GVHD by PK parameters will be estimated by the competing risk approach. The 
association with the incidence of acute GVHD will be explored by the Fine-Gray regression 
model. No multiplicity adjustment is considered. Correlations with clinical endpoints may be 
pursued. 
9.3.5 CYCLOPHOSPHAMIDE PHARMACOGENETIC ANALYSES 
The single nucleotide polymorphisms (SNPs) in the 6 genes (CYP2B6, 
CYP2C19, CYP2C9, CYP3A5, GSTP1, ALDH1A1) known to impact cyclophosphamide 
metabolism will be analyzed by QiaSeq pharmacogenomics panel. The incidence of acute GVHD 
by SNPs will be estimated by the competing risk approach. The association with the incidence of 
acute GVHD will be explored by the Fine-Gray regression model. No multiplicity adjustment is 
considered. Correlations with clinical endpoints may be pursued. 
9.3.6 EXPLORATORY ANALYSES 
 
Not applicable 
 
 


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10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
10.1.1  
SCIENTIFIC REVIEW COMMITTEE (SRC) 
The Cancer Center’s internal SRC provides the review for scientific merit and prioritization and 
monitors scientific progress for all protocols at the Cancer Center. The SRC has a defined 
membership representing all of the major research divisions of the cancer center, including 
biostatisticians. The SRC reviews newly proposed clinical research studies based on the following 
categories: 
a. study significance to evaluate its potential for contribution to medical science. 
b. the adequacy of study objectives, design, specific aims and hypotheses. 
c. the methods to be employed to conduct the study. Ensuring that the study is adequately 
described, including inclusion/exclusion criteria, sample size, procedures and instruments to be 
used. 
d. Feasibility of the study. Ensuring the investigator has adequate staffing and facilities to conduct 
the study. Ensuring that the timeframe for the study and projected annual accrual are adequately 
addressed. 
e. Review of all data and safety monitoring plans. 
The SRC will also evaluate the risk/benefit assessment and corresponding Data & Safety 
Monitoring Plan (DSMP), evaluate and may recommend frequency of monitoring. The SRC will 
identify any potential conflicts of interest related to the proposed research. The SRC may also 
evaluate and recommend the monitoring frequency of clinical trials they approve. 
 
10.1.2 THE PROTOCOL MONITORING COMMITTEE (PMC) 
The Protocol Monitoring Committee (PMC) is a multidisciplinary, peer review, standing committee 
established to oversee clinical research conducted at Moffitt Cancer Center to monitor scientific 
progress and data quality. It also serves as a component of the Data Safety Monitoring Plan 
(DSMP) for oncology trials at MCC. The membership of the PMC includes physicians and scientists 
from various program areas. 
The PMC provides ongoing monitoring of all clinical research studies for safety, validity and 
integrity of data, adverse events, conflicts of interest, and overall compliance with GCP or other 
applicable clinical research guidelines or regulations. In addition to the protocol stopping rules, the 
PMC is authorized to suspend a trial for non-compliance with a DSMP or as a result of audit 
findings deemed unacceptable. 
 
 


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10.1.3 CORPORATE COMPLIANCE 
The Corporate Compliance Office is the coordinating center for internal audits of clinical trials 
conducted at the Cancer Center and its affiliates. These audits will provide for a systematic and 
independent examination of trial-related activities and documents to determine whether the 
evaluated trial-related activities were conducted, and the data was recorded, analyzed and 
accurately reported, according to the Institutional Review Board (IRB) approved protocol, Center’s 
policies, Good Clinical Practices (GCP): Consolidated Guidance, and applicable regulatory 
requirements. 
Audits are conducted by Corporate Compliance in accordance with applicable regulatory 
standards. Corporate Compliance will conduct and report the findings of audits to the PMC. 
The PMC will determine the findings to be: acceptable, acceptable with corrective action, or 
unacceptable. Corporate Compliance will follow up to ascertain whether corrective actions, which 
have been agreed to, are achieving the desired results. The PMC will be informed of all significant 
open follow-up items. For those observations where no action has been taken, Corporate 
Compliance will inform the PMC who may take action as appropriate.  
10.1.4 INTERNAL MONITORING 
Monitoring will be performed regularly by the MCC Clinical Monitoring Core for accuracy, 
completeness, and source verification of data entry, validation of appropriate informed consent 
process, reporting of SAEs, and adherence to the protocol, Good Clinical Practice(GCP) 
guidelines, and applicable regulatory requirements. 
10.1.5 INSTITUTIONAL REVIEW BOARD (IRB) 
The trial will not be initiated without approval of the appropriate Institutional Review Board (IRB). 
All administrative requirements of the governing body of the institution will be fully complied with. 
This protocol, consent procedures, and any amendments will be approved by the IRB in 
compliance with current regulations of the Food and Drug Administration prior to initiation unless 
necessary to protect the safety and welfare of subjects; in which case, the IRB will be notified 
within 24 hours of implementing the change. 
The IRB will be kept informed by the investigator as to the progress of the study as well as to any 
serious or unusual adverse events. 
10.1.6 INFORMED CONSENT PROCESS 
 
10.1.7 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
 
Consent forms describing in detail the study intervention, study procedures, and risks are given to 
the participant and written documentation of informed consent is required prior to starting 
intervention/administering study intervention.  
 


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10.1.8 CONSENT PROCEDURES AND DOCUMENTATION 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent forms will be 
Institutional Review Board (IRB)-approved and the participant will be asked to read and review the 
document.  
 
The investigator will explain the research study to the participant and answer any questions that 
may arise. A verbal explanation will be provided in terms suited to the participant’s comprehension 
of the purposes, procedures, and potential risks of the study and of their rights as research 
participants.  
 
Participants will have the opportunity to carefully review the written consent form and ask questions 
prior to signing. The participants should have the opportunity to discuss the study with their family 
or surrogates or think about it prior to agreeing to participate. The participant will sign the informed 
consent document prior to any procedures being done specifically for the study.  
 
Participants must be informed that participation is voluntary and that they may withdraw from the 
study at any time, without prejudice. A copy of the informed consent document will be given to the 
participants for their records. The informed consent process will be conducted and documented in 
the source document (including the date), and the form signed, before the participant undergoes 
any study-specific procedures. The rights and welfare of the participants will be protected by 
emphasizing to them that the quality of their medical care will not be adversely affected if they 
decline to participate in this study. 
 
 
 
 
10.2 STUDY DISCONTINUATION AND CLOSURE 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to, investigator, funding 
agency, the Investigational New Drug (IND) or Investigational Device Exemption (IDE) sponsor 
and regulatory authorities. If the study is prematurely terminated or suspended, the Principal 
Investigator (PI) will promptly inform study participants, the Institutional Review Board (IRB), and 
sponsor and will provide the reason(s) for the termination or suspension. Study participants will be 
contacted, as applicable, and be informed of changes to study visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping   
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary endpoint has been met 
• 
Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB and/or Food and Drug Administration (FDA). 
 


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10.2.1 TOXICITY MONITORING AND STOPPING RULES 
Sequential boundaries will be used to monitor for TRM, graft failure, and relapse rate. The tables below 
show the stopping boundaries for TRM (Tn), graft failure (Gn), and Relapse (Rn), for a given number of 
patients up to that point. The trial will be halted if at least one of the stopping boundaries is reached, and 
the data will be reviewed by the Moffitt Cancer Center Protocol Monitoring Committee. This is a Pocock-
type stopping boundary proposed by Ivanova et al. that yields the probability of crossing the boundary at 
most 10% if  
• 
TRM rate at day 100 is ≤30%, 
• 
graft failure rate at day 100 is ≤20%,  
• 
relapse rate at day 100 is ≤30%. 
For example, if 2 TRMs are observed in 3 patients, the trial will be halted due to the excessive TRM. Table 
2 contains the probability of early stopping for given true TRM, graft failure, and relapse rates. If the true 
TRM rate, for example, is unacceptably high (30%), the stopping rule has greater than 92% probability of 
early stopping.  
 
Table 1: Early Stopping Boundaries for the TRM (Tn), graft failure (Gn), and Relapse (Rn) 
Number of 
Patients, n 
Stopping Boundaries 
  
Number of 
Patients, n 
Stopping Boundaries 
Tn 
Gn 
Rn 
  
Tn 
Gn 
Rn 
1 
NA 
NA 
NA 
  
18 
10 
8 
10 
2 
NA 
NA 
NA 
 
19 
11 
8 
11 
3 
3 
3 
3 
 
20 
11 
8 
11 
4 
4 
3 
4 
 
21 
11 
9 
11 
5 
5 
4 
5 
 
22 
12 
9 
12 
6 
5 
4 
5 
 
23 
12 
9 
12 
7 
5 
5 
5 
 
24 
13 
10 
13 
8 
6 
5 
6 
 
25 
13 
10 
13 
9 
6 
5 
6 
 
26 
13 
10 
13 
10 
7 
5 
7 
 
27 
14 
10 
14 
11 
7 
6 
7 
 
28 
14 
11 
14 
12 
8 
6 
8 
 
29 
14 
11 
14 
13 
8 
6 
8 
 
30 
15 
11 
15 
14 
9 
7 
9 
 
31 
15 
11 
15 
15 
9 
7 
9 
 
32 
16 
12 
16 
16 
9 
7 
9 
 
33 
16 
12 
16 
17 
10 
8 
10 
  
34 
16 
12 
16 


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Table 2: Probability of early stopping for given true TRM, graft failure, and relapse rates 
Ture TRM 
rate 
Probability of 
Early Stopping 
Ture Graft 
Failure rate 
Probability of 
Early Stopping 
Ture Relapse 
rate 
Probability of 
Early Stopping 
0.3 
0.0984 
0.2 
0.0986 
0.3 
0.0984 
0.4 
0.392 
0.3 
0.454 
0.4 
0.392 
0.5 
0.7867 
0.4 
0.8437 
0.5 
0.7867 
0.6 
0.9721 
0.5 
0.9825 
0.6 
0.9721 
0.7 
0.9991 
0.6 
0.9995 
0.7 
0.9991 
0.8 
1 
0.7 
1 
0.8 
1 
0.9 
1 
0.8 
1 
0.9 
1 
1 
1 
0.9 
1 
1 
1 
 
 
 
10.3 FUTURE USE OF STORED SPECIMENS AND DATA  
 
Data collected for this study will be analyzed and stored at the Moffitt Cancer Center. With the 
participant’s approval and as approved by local Institutional Review Boards (IRBs), de-identified 
biological samples will be stored at the Moffitt Cancer Center. These samples could be used to 
research the causes of hematologic malignancies and/or post-transplant outcomes. The Moffitt 
Cancer Center will also be provided with a code-link that will allow linking the biological specimens 
with the phenotypic data from each participant, maintaining the blinding of the identity of the 
participant. 
 
During the conduct of the study, an individual participant can choose to withdraw consent to have 
biological specimens stored for future research. However, withdrawal of consent with regard to 
biosample storage may not be possible after the study is completed.  
 
 
10.3.1 KEY ROLES AND STUDY GOVERNANCE 
 
Principal Investigator 
Nelli Bejanyan, MD 
Moffitt Cancer Center 
12902 Magnolia Drive 
Tampa, FL 33612 
813-745-6008 
Nelli.Bejanyan@moffitt.org   
 


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10.3.2 SAFETY OVERSIGHT 
 
Serious Adverse Events: Serious Adverse Events (SAEs) from this protocol will be reported 
concurrently to the IRB and the study sponsor. The Protocol Monitoring Committee (PMC) will 
review these SAEs in accordance with the protocol-specific DSMP. The data and safety plan will 
define dose limiting toxicities, rules for escalation of dose, and criteria for stopping the trial and 
defining the Maximum Tolerated Dose (MTD) according to rules set forth by this protocol. This trial 
will be continuously monitored by the PI and the research team and reviewed at monthly BMT 
Research Group meetings. This protocol will be subject to periodic internal audits based on risk or 
as recommended by the PMC. 
 
 
10.3.3 CLINICAL MONITORING 
 
MCC’s Internal Monitors will periodically monitor regulatory documents and case report forms 
according to the protocol specific clinical monitoring plan.  Monitoring will include review of data 
for accuracy, completeness, and source verification, reporting of SAEs, and adherence to the 
protocol, Good Clinical Practice (GCP) guidelines, and applicable regulatory requirements. 
 
10.3.4 QUALITY ASSURANCE AND QUALITY CONTROL 
 
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion. An individualized quality management plan 
will be developed to describe a site’s quality management.] 
 
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution. 
 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical 
trial is conducted and data are generated and biological specimens are collected, documented 
(recorded), and reported in compliance with the protocol, International Conference on 
Harmonization Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., 
Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)).  
 
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities. 
 
 
10.3.5 DATA HANDLING AND RECORD KEEPING  
 
10.3.6 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
The Principal Investigator and the Clinical Trial Coordinator(s) assigned to the case will be primarily 
responsible for maintaining all study related documents including clinical research forms, as 


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applicable. ONCORE is the database of record for all CRF entries and will be verified with source 
documentation. The review of medical records within PowerChart will be done in a manner to 
assure that patient confidentiality is maintained. 
 
Data collected will be stored in Moffitt Cancer Center’s database system, ONCORE. Identifying 
patient information will be kept confidential. Representatives of the IRB and the FDA will have 
access to patient information as it pertains to the study. Privacy and confidentiality of the 
information will be protected to the extent provided by law. 
 
10.3.7 STUDY RECORDS 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.   
10.3.8 PROTOCOL DEVIATIONS  
 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or MOP 
requirements. The noncompliance may be either on the part of the participant, the investigator, or 
the study site staff. As a result of deviations, corrective actions are to be developed by the site and 
implemented promptly. 
These practices are consistent with ICH E6: 
 
• 4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 
• 5.1 Quality Assurance and Quality Control, section 5.1.1 
• 5.20 Noncompliance, sections 5.20.1, and 5.20.2. 
 
It is the responsibility of the site to use continuous vigilance to identify and report deviations within 
10 working days of identification of the protocol deviation, or within 10 working days of the 
scheduled protocol-required activity. Protocol deviations must be sent to the local IRB per their 
guidelines. The site PI/study staff is responsible for knowing and adhering to their IRB 
requirements. 
 
10.3.9 PUBLICATION AND DATA SHARING POLICY 
 
This study will be conducted in accordance with the following publication and data sharing policies 
and regulations: 
 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access 
to the published results of NIH funded research. It requires scientists to submit final peer-reviewed 
journal manuscripts that arise from NIH funds to the digital archive PubMed Central upon 
acceptance for publication. 
 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-
Funded Clinical Trial Information and the Clinical Trials Registration and Results Information 
Submission rule. As such, this trial will be registered at ClinicalTrials.gov, and results information 


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from this trial will be submitted to ClinicalTrials.gov. In addition, every attempt will be made to 
publish results in peer-reviewed journals. Data from this study may be requested from other 
researchers x years after the completion of the primary endpoint by contacting <specify person or 
awardee institution, or name of data repository>.  
 
In addition, this study will comply with the NIH Genomic Data Sharing Policy, which applies to all 
NIH-funded research that generates large-scale human or non-human genomic data, as well as 
the use of these data for subsequent research. Large-scale data include genome-wide association 
studies (GWAS), single nucleotide polymorphisms (SNP) arrays, and genome sequence, 
transcriptomic, epigenomic, and gene expression data. 
 
10.3.10 
CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and 
managed. Furthermore, persons who have a perceived conflict of interest will be required to have 
such conflicts managed in a way that is appropriate to their participation in the design and conduct 
of this trial. The study leadership has established policies and procedures for all study group 
members to disclose all conflicts of interest and will establish a mechanism for the management 
of all reported dualities of interest. 
 
 
10.4  ADDITIONAL CONSIDERATIONS 
 
Not applicable 
 
10.5  ABBREVIATIONS 
 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Science 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
CMS 
Centers for Medicare and Medicaid Services 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CTMS 
Clinical Trial Management System 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data Safety Monitoring Board 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GWAS 
Genome-Wide Association Studies 


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HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
ICH E6 
International Conference on Harmonization Guidance for Industry, Good Clinical Practice: Consolidated 
Guidance 
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
Investigational Review Board 
ISO 
International Organization for Standardization 
MCC 
Moffitt Cancer Center 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
MSDS 
Material Safety Data Sheet 
NIH 
National Institutes of Health 
NIH IC 
NIH Institute & Center 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
PMC 
Protocol Monitoring Committee 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMC 
Safety Monitoring Committee 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
 
 
 


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10.6 PROTOCOL AMENDMENT HISTORY 
The table below is intended to capture changes of IRB-approved versions of the protocol, including a description of 
the change and rationale. A Summary of Changes table for the current amendment is located in the Protocol Title 
Page.  
 
Version 
Date 
Description of Change  
Brief Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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20. Federmann B, Bornhauser M, Meisner C, Kordelas L, Beelen DW, Stuhler G et al. Haploidentical allogeneic 
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23. Munchel A, Kesserwan C, Symons HJ, Luznik L, Kasamon YL, Jones RJ et al. Nonmyeloablative, HLA-haploidentical 
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24. Ciurea SO, Mulanovich V, Saliba RM, Bayraktar UD, Jiang Y, Bassett R et al. Improved early outcomes using a T 
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25. Raiola AM, Dominietto A, Ghiso A, Di Grazia C, Lamparelli T, Gualandi F et al. Unmanipulated haploidentical 
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Blood and Marrow Transplantation.19(1):117-22.  
26. Bashey A, Zhang X, Sizemore CA, Manion K, Brown S, Holland HK et al. T-cell-replete HLA-haploidentical 
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Journal of clinical oncology : official journal of the American Society of Clinical Oncology.31(10):1310-6.  
27. Solomon SR, Sizemore CA, Sanacore M, Zhang X, Brown S, Holland HK et al. Haploidentical transplantation using 
T cell replete peripheral blood stem cells and myeloablative conditioning in patients with high-risk hematologic 
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and Marrow Transplantation.18(12):1859-66.  
28. Luznik L, O'Donnell P, Symons H, Chen A, Leffell M, Zahurak M et al. HLA-haploidentical bone marrow 
transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, 
posttransplantation cyclophosphamide. BBMT. 2008;14(6):641-50.  
29. Mayumi H, Good R. Long-lasting skin allograft tolerance in adult mice induced across fully allogeneic (multimajor 
H-2 plus multiminor histocompatibility) antigen barriers by a tolerance-inducing method using cyclophosphamide. J 
Exp Med. 1989;169(1):213-38.  
30. Eto M, Mayumi H, Tomita Y, Yoshikai Y, Nishimura Y, Nomoto K. Sequential mechanisms of cyclophosphamide-
induced skin allograft tolerance including the intrathymic clonal deletion followed by late breakdown of the clonal 
deletion. J Immunol. 1990;145(5):1303-10.  
31. Luznik L, Jalla S, Engstrom L, Iannone R, Fuchs E. Durable engraftment of major histocompatibility complex–
incompatible cells after nonmyeloablative conditioning with fludarabine, low-dose total body irradiation, and 
posttransplantation cyclophosphamide. Blood. 2001;98:3456-64.  
32. Luznik L, O'Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M et al. HLA-haploidentical bone marrow 
transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, 
posttransplantation cyclophosphamide. Biology of blood and marrow transplantation : journal of the American 
Society for Blood and Marrow Transplantation. 2008;14(6):641-50. doi:10.1016/j.bbmt.2008.03.005. 
33. McCurdy SR, Kanakry JA, Showel MM, Tsai HL, Bolanos-Meade J, Rosner GL et al. Risk-stratified outcomes of 
nonmyeloablative HLA-haploidentical BMT with high-dose posttransplantation cyclophosphamide. Blood. 
2015;125(19):3024-31. doi:10.1182/blood-2015-01-623991. 
34. Showel MM, Fuchs EJ, Varadhan R, Levis MJ, Jones RJ. Related Nonmyeloablative Haploidentical (mini-haplo) 
Blood or Marrow Transplantation (BMT) with High-Dose Post-Transplant Cyclophosphmade (PTCy) for Acute 
Myeloid Leukemia (AML): Donor Age Impacts Outcome Blood (ASH Annual Meeting Abstracts). 2015 126: 151(23).  
35. Kanakry JA, Gocke CD, Bolanos-Meade J, Gladstone DE, Swinnen LJ, Blackford AL et al. Phase II Study of 
Nonmyeloablative Allogeneic Bone Marrow Transplantation for B Cell Lymphoma with Post-Transplantation 
Rituximab and Donor Selection Based First on Non-HLA Factors. Biology of blood and marrow transplantation : 


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journal of the American Society for Blood and Marrow Transplantation. 2015;21(12):2115-22. 
doi:10.1016/j.bbmt.2015.07.012. 
36. Ciurea S, Zhang M, Bacigalupo A, Bashey A, Appelbaum F, Aljitawi O et al. Haploidentical transplant with post-
transplant cyclophosphamide versus matched unrelated donor transplant for acute myeloid leukemia. Blood. 
2015;126(8):1033-40.  
37. McCurdy S, Kanakry J, Showel M, Tsai H, Bolaños-Meade J, Rosner G et al. Risk-stratified outcomes of 
nonmyeloablative HLA-haploidentical BMT with high-dose posttransplantation cyclophosphamide. Blood. 
2015;125(19):3024-31.  
38. McCurdy S, Kasamon Y, Kanakry C, Bolaños-Meade J, Tsai H, Showel M et al. Comparable composite endpoints 
after HLA-matched and HLA-haploidentical transplantation with post-transplantation cyclophosphamide. 
Haematologica. 2017;102(2):391-400.  
39. Bashey A, Zhang X, Sizemore C, Manion K, Brown S, Holland H et al. T-Cell–Replete HLA-Haploidentical 
Hematopoietic Transplantation for Hematologic Malignancies Using Post-Transplantation Cyclophosphamide 
Results in Outcomes Equivalent to Those of Contemporaneous HLA-Matched Related and Unrelated Donor 
Transplantation. JCO. 2013;31(10):1310-6.  
40. 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.118(2):282-8.  
41. Kanate A, Mussetti A, Kharfan-Dabaja M, Ahn K, DiGilio A, Beitinjaneh A et al. Reduced-intensity transplantation 
for lymphomas using haploidentical related donors vs HLA-matched unrelated donors. Blood. 2016;127:938-47.  
42. Ghosh N, Karmali R, Rocha V, Ahn K, DiGilio A, Hari P et al. Reduced-Intensity Transplantation for Lymphomas 
Using Haploidentical Related Donors Versus HLA-Matched Sibling Donors: A Center for International Blood and 
Marrow Transplant Research Analysis. JCO. 2016;34(26):3141-9.  
43. 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. doi:10.1182/blood-2011-03-
344853. 
44. Castagna L, Crocchiolo R, Furst S, Bramanti S, El Cheikh J, Sarina B et al. Bone marrow compared with peripheral 
blood stem cells for haploidentical transplantation with a nonmyeloablative conditioning regimen and post-
transplantation cyclophosphamide. Biology of blood and marrow transplantation : journal of the American Society 
for Blood and Marrow Transplantation. 2014;20(5):724-9. doi:10.1016/j.bbmt.2014.02.001. 
45. Ciurea SO, Zhang MJ, Bacigalupo AA, Bashey A, Appelbaum FR, Aljitawi OS et al. Haploidentical transplant with 
posttransplant cyclophosphamide vs matched unrelated donor transplant for acute myeloid leukemia. Blood. 
2015;126(8):1033-40. doi:10.1182/blood-2015-04-639831. 
46. Bacigalupo A, Dominietto A, Ghiso A, Di Grazia C, Lamparelli T, Gualandi F et al. Unmanipulated haploidentical 
bone marrow transplantation and post-transplant cyclophosphamide for hematologic malignanices following a 
myeloablative conditioning: an update. Bone marrow transplantation. 2015;50 Suppl 2:S37-9. 
doi:10.1038/bmt.2015.93. 
47. Cieri N, Greco R, Crucitti L, Morelli M, Giglio F, Levati G et al. Post-transplantation Cyclophosphamide and 
Sirolimus after Haploidentical Hematopoietic Stem Cell Transplantation Using a Treosulfan-based Myeloablative 
Conditioning and Peripheral Blood Stem Cells. Biology of blood and marrow transplantation : journal of the 
American Society for Blood and Marrow Transplantation. 2015;21(8):1506-14. doi:10.1016/j.bbmt.2015.04.025. 
48. Kanate AS, Mussetti A, Kharfan-Dabaja MA, Ahn KW, DiGilio A, Beitinjaneh A et al. Reduced-intensity 
transplantation for lymphomas using haploidentical related donors vs HLA-matched unrelated donors. Blood. 
2016;127(7):938-47. doi:10.1182/blood-2015-09-671834. 
49. Brammer JE, Khouri I, Gaballa S, Anderlini P, Tomuleasa C, Ahmed S et al. Outcomes of Haploidentical Stem Cell 
Transplantation for Lymphoma with Melphalan-Based Conditioning. Biology of blood and marrow transplantation : 
journal of the American Society for Blood and Marrow Transplantation. 2016;22(3):493-8. 
doi:10.1016/j.bbmt.2015.10.015. 
50. Gaballa S, Ge I, El Fakih RO, Brammer JE, Wang SA, Lee DA et al. Results of a Two-Arm Phase II Clinical Trial Using 
Post-Transplantation Cyclophosphamide for Prevention of Graft-Versus-Host Disease in Haploidentical and 
Mismatched Unrelated Donors Hematopoietic Stem-Cell Transplantation. Blood (ASH Annual Meeting Abstracts). 
2015;126: 152.  


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51. Brunstein C, Fuchs E, Carter S, Karanes C, Costa L, 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.  
52. Damlaj M, Alkhateeb HB, Partain DK, Almasri J, Hefazi M, Hashmi SK et al. Fludarabine Busulfan Compared to 
Fludarabine Melphalan Is Associated with Increased Relapse Risk in Reduced Intensity Conditioning Transplant 
Despite Pharmacokinetic Dosing. Blood (ASH Annual Meeting Abstracts). 2015 126: 736(23).  
53. Vokurka S, Steinerova K, Karas M, Koza V. Characteristics and risk factors of oral mucositis after allogeneic stem 
cell transplantation with FLU/MEL conditioning regimen in context with BU/CY2. Bone Marrow Transplant. 
2009;44(9):601-5. doi:10.1038/bmt.2009.66. 
54. Anasetti C, Logan B, Lee S, Waller E, Weisdorf D, Wingard J et al. Peripheral-Blood Stem Cells versus Bone 
Marrow from Unrelated Donors. NEJM. 2012;367:1487-96.  
55. Bashey A, Zhang M, McCurdy S, StMartin A, Argall T, Anasetti C et al. Mobilized Peripheral Blood Stem Cells 
Versus Unstimulated Bone Marrow As a Graft Source for T-Cell-Replete Haploidentical Donor Transplantation Using 
Post-Transplant Cyclophosphamide. JCO. 2017;35(26):3002-9.  
56. O'Donnell P, Eapen M, Horowitz M, Logan B, DiGilio A, Brunstein C et al. Comparable outcomes with marrow or 
peripheral blood as stem cell sources for hematopoietic cell transplantation from haploidentical donors after non-
ablative conditioning: a matched-pair analysis. BMT. 2016;51:1599-601.  
57. O'Donnell P, Luznik L, Jones R, Vogelsang G, Leffell M, Phelps M et al. Nonmyeloablative bone marrow 
transplantation from partially HLA-mismatched related donors using posttransplantation cyclophosphamide. BBMT. 
2002;8(7):377-86.  
58. L G, JS M, MB M, TA G, BM S, JT S et al. Pharmacodynamics of mycophenolate mofetil after nonmyeloablative 
conditioning and unrelated donor hematopoietic cell transplantation. Blood. 2005;106(13):4381-8.  
59. P J, J R, JN B, K G, J N, D W et al. Relationship of mycophenolic acid exposure to clinical outcome after 
hematopoietic cell transplantation. Clin Pharmacol Ther. 2005;78(5):486-500.  
60. Bejanyan N, Rogosheske J, Cao Q, Lazaryan A, Holtan S, Ustun C et al. Weight-Based Mycophenolate Mofetil 
Dosing Predicts Acute Gvhd and Relapse after Allogeneic Hematopoietic Cell Transplantation. BBMT. 
2018;24(3):s291.  
61. McDonald G, Slattery J, Bouvier M, Ren S, Batchelder A, Kalhorn T et al. Cyclophosphamide metabolism, liver 
toxicity, and mortality following hematopoietic stem cell transplantation. Blood. 2003;101:2043-8.  
62. Pinto N, Ludeman S, Dolan M. Pharmacogenetic studies related to cyclophosphamide-based therapy. 
Pharmacogenomics. 2009;10(12):1897.  
63. Bachanova V, Shanley R, Malik F, Chauhan L, Lamba V, Weisdorf D et al. Cytochrome P450 2B6*5 Increases 
Relapse after Cyclophosphamide-containing Conditioning and Autologous Transplantation for Lymphoma. BBMT. 
2015;21(5):944-8.  
64. Dandara C, Swart M, Mpeta B, Wonkam A, Masimirembwa C. Cytochrome P450 pharmacogenetics in African 
populations: implications for public health. Expert Opinion on Drug Metabolism & Toxicology. 2014;10(6):769-85. 
doi:10.1517/17425255.2014.894020. 
65. Claudio-Campos K, Duconge J, Cadilla CL, Ruaño G. Pharmacogenetics of drug-metabolizing enzymes in US 
Hispanics. Drug metabolism and personalized therapy. 2015;30(2):87-105. doi:10.1515/dmdi-2014-0023. 
66. Bejanyan N, Pidala J, Wang X, Thapa R, Nishihori T, Elmariah H et al. A Phase II Study of Sirolimus-Based 
Calcineurin Inhibitor-Free Gvhd Prophylaxis after Peripheral Blood Haploidentical Transplantation with Post-
Transplant Cyclophosphamide. BBMT. 2019;12(133).  
67. Kroger N, Iacobelli S, Franke G-N, Platzbecker U, Uddin R, Hubel K et al. Dose-Reduced Versus Standard 
Conditioning Followed by Allogeneic Stem-Cell Transplantation for Patients With Myelodysplastic Syndrome: A 
Prospective Randomized Phase III Study of the EBMT (RICMAC Trial). JCO. 2017;35(19):2157-64.  
68. Scott BL, Pasquini MC, Logan BR, Wu J, Devine SM, Porter DL et al. Myeloablative versus reduced-intensity 
hematopoietic cell transplantation for acute myeloid leukemia and myelodysplastic syndromes. Journal of Clinical 
Oncology. 2017;35(11):1154-61.  
69. Eapen M, Brazauskas R, Hemmer M, Perez W, Steinert P, Horowitz M et al. Hematopoietic cell transplant for 
acute myeloid leukemia and myelodysplastic syndrome: conditioning regimen intensity. Blood Advances. 
2018;2:2095-103.  
 
 


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Appendix 
APPENDIX I CYTOKINE RELEASE SYNDROME GRADING 
 


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APPENDIX II – KARNOFSKY PERFORMANCE STATUS 
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. 
 
 
 


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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.