The Rapid Study: Randomized (RA) Phase (P) II Study To Expedite Allogeneic Transplant With Immediate (I) Haploidentical Plus Unrelated Cord Donor (D) Search Versus Matched Unrelated Donor Search For AML And High-Risk MDS Patients
Phase: PHASE2
Conditions: Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS)
Sponsor: University of Chicago

Randomized (RA) phase (P) II Study to Expedite Allogeneic Transplant with Immediate 
(I) Haploidentical plus Unrelated Cord Donor (D) Search Versus Matched Unrelated 
Donor Search for AML and High-Risk MDS Patients. The RAPID Study 
 
 
Coordinating Center: 
 
The University of Chicago  
5841 S. Maryland Ave., MC2115 
Chicago, IL 60637 USA  
 
Principal Investigators: 
 
Andrew Artz, MD, MS 
 
 
 
 
 
 
 
 
 
 
University of Chicago  
Co-Investigators:   
 
Michael Bishop, MD 
John Cunningham, MD 
Lucy Godley, MD, PhD 
 
Justin Kline, MD 
James LaBelle, MD 
Richard Larson, MD 
Hongtao Liu, MD, PhD  
Toyosi Odenike, MD  
Wendy Stock, MD 
Amittha Wickrema, PhD 
 
 
Weill Cornell Medical College  
Co-Investigators:   
 
Koen Van Besien, MD, PhD 
 
Usama Gergis, MD 
 
Tormer Mark, MD 
Sebastian Mayer, MD 
Tsiporah Shore, MD 
Adrienne Phillips, MD 
 
Statistician:                   
 
Masha Kocherginsky, PhD 
 
Study Coordinator:  
 
TBD  
                                         
 
Data Management: 
 
Brianna Novitsky, CRA 
Alexis Small, CRA 
 
 
Participating Sites: 
 
University of Chicago, Chicago, IL 
Weill Cornell Medical Center, New York, NY 
 
Protocol version date:           
February 16, 2015 
 
University of Chicago  
Institutional Review Board #:  
IRB15-0866 

SCHEMA 
 
 
 
 
                                                               
 
 
                                                                    
 
 
 
Phase I: 
Consent 1 and Search 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phase II:   
Consent 2 and:* 
Transplant 
Transplant 
 
 
 
 
Modified  
Intent To  
Treat 
 
 
Patient has potential related haploidentical donor, AND preliminary search reveals 1) a 
potential 8/8 matched unrelated donor at HLA-A, -B, -C, and DRB1 with 70% probability, 
AND 2) a single 4/6 umbilical cord unit of at least 1 x 10(7) TNC/kg 
Randomization 1:1 
Adults aged ≥18 years old with acute myeloid leukemia (AML) or high or very high 
IPSS-Revised risk MDS requiring allogeneic stem cell transplantation.  No matched 
related donor available at time of randomization. 
MUD Search 
Haplo-Cord Search 
*Patient will register prior to phase II (transplant)  
Undergo Transplant 
MUD 
Transplant 
Haplo-cord Transplant 
Matched Sibling 
Identified:  
Exclude 
Matched Sibling 
Identified: 
Exclude 

2 
Table of Contents 
SCHEMA ....................................................................................................................................... 1 
 
1. 
OBJECTIVES ....................................................................................................................... 5 
1.1. PRIMARY: ...................................................................................................................... 5 
1.2. SECONDARY: ................................................................................................................ 5 
 
2. 
BACKGROUND ................................................................................................................... 5 
2.1.  ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION (HCT) ........................... 5 
2.2.  TRANSPLANT FOR AML ................................................................................................... 5 
2.3.  HIGH-RISK MYELODYSPLASTIC SYNDROMES ................................................................... 6 
2.4.  DONORS AND DONOR SEARCHES ..................................................................................... 6 
2.5.  TRANSPLANT DELAYS FOR MUD .................................................................................... 6 
2.6.  ALTERNATIVE DONORS.................................................................................................... 7 
2.7.  ALTERNATIVE DONORS IN OLDER ADULTS ...................................................................... 8 
2.8.  HAPLO-CORD APPROACH ................................................................................................ 8 
2.9.  PATIENT SELECTION AND GERIATRIC SELECTION ............................................................ 8 
2.10. RATIONALE FOR THIS STUDY ........................................................................................... 9 
2.11. CONDITIONING REGIMENS ............................................................................................... 9 
2.12. T-CELL DEPLETION .......................................................................................................... 9 
2.13. LIMITATIONS. ................................................................................................................ 10 
 
3. 
PATIENT SELECTION .................................................................................................... 10 
3.1. INCLUSION CRITERIA FOR SEARCH PHASE ...................................................................... 10 
3.2. EXCLUSION CRITERIA FOR SEARCH PHASE ..................................................................... 11 
3.3. INCLUSION CRITERIA FOR TRANSPLANT PHASE .............................................................. 11 
3.4. EXCLUSION CRITERIA FOR TRANSPLANT PHASE ............................................................. 12 
 
4. 
ENROLLMENT, RANDOMIZATION, AND REGISTRATION ................................. 12 
4.1. ENROLLMENT AND RANDOMIZATION .............................................................................. 12 
4.2. CENTRAL PATIENT REGISTRATION.................................................................................. 12 
 
5. 
STUDY DESIGN ................................................................................................................. 13 
5.1. GENERAL ORGANIZATION ............................................................................................... 13 
5.2. SEARCH EVALUATION ..................................................................................................... 14 
5.3. CONDITIONING REGIMENS .............................................................................................. 14 
5.4. GVHD PROPHYLAXIS ..................................................................................................... 16 
5.5. SUPPORTIVE CARE .......................................................................................................... 16 
 
6. 
TRANSPLANT STEM CELL SOURCE AND CELL DOSE ........................................ 18 
6.1. HAPLO-CORD .................................................................................................................. 18 
6.2. MATCHED UNRELATED DONOR ...................................................................................... 18 
6.3. INFUSION OF CELLS ......................................................................................................... 19 
6.4. PRIOR TO TRANSPLANT ................................................................................................... 19 
6.5. POST-TRANSPLANT EVALUATIONS ................................................................................. 19 
6.6. STUDY CALENDARS ........................................................................................................ 20 

3 
 
7. 
ADVERSE EVENTS MONITORING AND REPORTING: .......................................... 22 
7.1. INVESTIGATIONAL RISKS ................................................................................................ 22 
7.2. DEFINITIONS ................................................................................................................... 22 
7.3. ADVERSE EVENT CHARACTERISTICS .............................................................................. 24 
7.4. PROTOCOL-SPECIFIC EXPEDITED ADVERSE EVENT REPORTING EXCLUSIONS ................ 24 
7.5. ADVERSE EVENT REPORTING REQUIREMENTS ................................................................ 25 
7.6. SUPPORTIVE THERAPY AND OTHER INVESTIGATIONAL DRUGS....................................... 25 
 
8. 
CORRELATIVE/SPECIAL STUDIES ............................................................................ 26 
 
9. 
CRITERIA FOR STUDY EVALUATION ...................................................................... 26 
9.1. TIME TO TRANSPLANT .................................................................................................... 26 
9.2. PROPORTION UNDERGOING TRANSPLANT ........................................................................ 26 
9.3. LEUKEMIA FREE SURVIVAL ............................................................................................ 26 
9.4. OVERALL SURVIVAL ....................................................................................................... 27 
9.5. GRAFT FAILURE .............................................................................................................. 27 
9.6. TREATMENT RELATED MORTALITY ................................................................................ 27 
9.7. TIME TO NEUTROPHIL RECOVERY ................................................................................... 27 
9.8. TIME TO PLATELET RECOVERY ....................................................................................... 27 
9.9. ACUTE GVHD ................................................................................................................ 27 
9.10.CHRONIC GVHD ............................................................................................................ 27 
9.11.LENGTH OF STAY ........................................................................................................... 27 
9.12.TRANSFUSION SUPPORT .................................................................................................. 27 
 
10. CRITERIA FOR REMOVAL OF PATIENTS FROM STUDY .................................... 28 
 
11. DATA REPORTING / REGULATORY CONSIDERATIONS ..................................... 28 
 
12. STATISTICAL CONSIDERATIONS .............................................................................. 29 
 
13. DATA, SAMPLE AND PROTOCOL MANAGEMENT ................................................ 30 
 
14. DATA SAFETY MONITORING BOARD ...................................................................... 31 
 
15. REGULATORY CONSIDERATIONS ............................................................................ 31 
15.1. INSTITUTIONAL REVIEW BOARD/ETHICS COMMITTEE APPROVALS ....................................... 31 
15.2. INFORMED CONSENT PROCEDURES ....................................................................................... 31 
15.3.PROTECTING PRIVACY AND CONFIDENTIALITY ...................................................................... 32 
15.4. FOOD AND DRUG ADMINISTRATION (FDA) APPROVAL ........................................................ 32 
15.5. STUDY RECORDS REQUIREMENTS .......................................................................................... 32 
15.6. AMENDMENTS TO THE PROTOCOL ......................................................................................... 33 
15.7. ANNUAL IRB RENEWALS, CONTINUING REVIEW AND FINAL REPORTS ................................ 33 
15.8. PROTECTION OF HUMAN RIGHTS ........................................................................................... 33 
 
16. APPENDICES ..................................................................................................................... 35 

4 
APPENDIX A: PRZEPIORKA CRITERIA FOR ACUTE GVHD  ...................................... 36 
APPENDIX B: GERIATRIC ASSESSMENT TOOLS ................................................................... 37 
 
REFERENCES ............................................................................................................................ 38 
 
 
 
 
 

5 
1. 
OBJECTIVES 
1.1. 
PRIMARY: 
 To compare time from formal search to hematopoietic cell transplantation (HCT) for 
patients 18 years and older, randomized between haplo-cord search and matched 
unrelated donor (MUD) search for patients with acute myeloid leukemia (AML) and 
high-risk myelodysplastic syndrome (MDS)  
 
1.2. 
SECONDARY: 
 To compare the percentage of patients who undergo HCT in each study cohort  
 To evaluate overall survival from time to randomization by study cohort 
 For those undergoing transplant compare outcomes by donor type received MUD vs 
haplo-cord for neutrophil engraftment, grade 3-5 day 100 toxicities and chimerism 
 To evaluate non-relapse mortality, rates of acute and chronic GVHD, leukemia-free 
survival and overall survival by donor type  
 To collect correlative samples for future research 
 
 
2. 
BACKGROUND 
2.1. 
Allogeneic Hematopoietic Stem Cell Transplantation (HCT)  
Allogeneic stem cell transplantation (SCT) remains the only potentially curative treatment in 
high-risk and relapsed hematologic malignancies, by inducing a cell-mediated graft-versus 
tumor effect.   Major barriers to more widespread application have been lack of an HLA identical 
donor and transplant related morbidity and mortality.  As outlined below, these are now 
surmountable obstacles. 
 
2.2. 
Transplant for AML 
A meta-analysis of studies indicated a benefit for allogeneic transplant with a matched sibling 
donor compared to non-transplant treatment for AML in first remission in those with 
intermediate or high-risk disease by cytogenetic criteria. (1) Studies were restricted to younger 
adults.   Observational data have shown similar outcomes for matched related and matched 
unrelated donor at HLA-A, B, C and DRB1 (i.e, 8 of 8 HLA match).  
 
The number and proportion of transplants is rising markedly in older patients, particularly for 
AML. Historically, SCT was restricted to patients younger than 50 years of age due to high 
transplant-related mortality (TRM).  Multiple advances, such as availability of reduced intensity 
(RIC) and non-myeloablative conditioning, better supportive care, and high resolution typing 
consequently with less graft-versus-host disease, have enabled extending transplant into the 
eighth decade of life in select groups.   A large number of observational studies now show that 
patients 50 years and older have good outcomes after SCT, with limited or small differences 
compared to younger adults and with improved survival compared to chemotherapy-only 
approaches.(2, 3) In addition, new methods to appropriately assess health status and therefore 
predict tolerance to transplant have been developed for patients 50 and older to help medically 

6 
optimize patients in the peri-transplant period and to circumvent foreseeable complications. (4-
7) 
 
2.3. 
High-risk Myelodysplastic Syndromes 
High-risk myelodysplastic syndromes (MDS) have similar outcomes to AML.  Recent 
prognostic models using the International Prognostic Scoring System provide prognosis such 
that high-risk and very high-risk MDS have median overall survival of 1.6 and 0.8 years and 
median time to AML of 1.4 and 0.7 years respectively. (8) Therefore, moving quickly to 
transplant, similar to AML, is essential.  
 
2.4. 
Donors and Donor Searches 
An HLA matched sibling or related donor at HLA-A, -B, -C and -DRB1 remains the standard 
and optimal transplant donor. However, the majority of patients for whom transplant may be 
indicated lack an HLA matched related donor (MRD).  Thus, matched unrelated donors (MUD) 
have become the most common donor source for allogeneic transplant, particularly with 
cooperative registries of adult donors across the world, allowing quick computer searches for 
potential HLA matched donors.  Furthermore, complication rates of unrelated donor transplant 
has markedly improved with matching at allele level for at least HLA-A, -B, -C and -DRB-1 
(sibling donors harbor similar haplotypes and thus are inherently allele level matches). Recent 
data support the present practice to consider matched unrelated donor as an equivalent stem cell 
source to matched sibling donor for AML. (9).  Increasing data also suggest importance of partial 
matching for HLA DPB1 (permissive haplo types), which may further improve outcomes for 
unrelated donor transplants. (10, 11) 
 
However, the use of HCT remains limited by availability of an appropriately matched donor, 
especially in minority groups. (12-14) In one study of transplant searches in the United Kingdom 
in 2005, Querol et al. found that only 38% of patients in whom unrelated donor search was 
initiated received a transplant. (15) Major reasons for lack of transplant included inability to 
secure a donor in 28%, and disease progression in 33% despite having a donor identified.  
Gragert et al. recently reported on the likelihood of finding a suitable donor in the US registry. 
(16) Whites and those of European descent had the highest chance (75%) of finding a matched 
unrelated donor (MUD).  While those of South and Central American descent had the lowest 
probability of finding a MUD at 16%.   
 
2.5. 
Transplant Delays for MUD 
Even in those fortunate enough to have an identified MUD when a matched sibling is not 
available, delays to transplant are frequent and problematic, as procuring a MUD may take 
additional weeks or months due to donor availability, donor attrition from personal, 
psychosocial, or medical issues. (17-19) Such delays can result in disease relapse or 
administration of additional consolidation chemotherapy that may produce additional toxicities, 
potentially abolishing transplant eligibility or increasing risk of subsequent transplant-related 
mortality (TRM). (17, 20)  
 

7 
Moreover, registry data show that additional cytarabine consolidation for AML in first remission 
prior to transplant does not confer a benefit, further justifying moving to transplant quickly. (21) 
Alternatively, it is possible that patients who undergo one cycle of consolidation and are able to 
proceed to HCT are a select group, as patients with early relapse or toxicity from consolidation 
do not move to transplant. Therefore, equivalent results intimate a benefit among those 
transplanted without consolidation, as the “rapid transplant” group likely includes patients at 
higher risk of relapse or toxicity. 
 
Furthermore, outcomes may suffer with delays.  Craddock et al. performed multivariate and 
univariate analyses on factors impacting overall survival in 168 patients with primary refractory 
acute myeloid leukemia between 1994 and 2006. (22) They found time to transplant to be the 
only manipulable factor to impact outcome after unrelated donor transplantation in primary 
refractory AML.   
 
The untoward consequences of delayed transplant are amplified for older adults with 
hematologic malignancies, particularly AML.  Disease free survival hovers around 8-9 months 
in older AML patients despite intensive induction, and standard consolidation chemotherapy has 
no clear benefit in AML patients 60 years and older who have achieved remission, making 
allogeneic stem cell transplantation the only known curative treatment. (23) Due to shorter 
relapse-free intervals, ability to move more quickly to transplant in eligible older individuals 
could be quite beneficial. 
 
2.6. 
Alternative Donors 
Increasing availability of and experience with alternative donor sources such as haploidentical 
related donors and umbilical cord blood units has expanded access substantially.  Umbilical cord 
blood (UCB) boasts less stringent HLA matching requirements, good graft-versus-leukemia 
effects, and low rates of GVHD. (24-26) In their recent report, Gragert et al. reported that while 
few in US registry searches had an HLA 6/6 matched umbilical cord blood (UCB) unit, UCB 
units mismatched at one or two HLA loci were available for almost all patients < 20 years of age 
and for more than 80% of those > 20 years of age, regardless of race or ethnicity. (16) All 
together, this suggests that most patients who would benefit from SCT are likely to find a suitable 
donor with recent advances. 
 
Advantages of UCB units include no risk to the donor (mother and fetus) and ready availability 
due to storage at cord banks.  Barker et al. retrospectively reviewed their adult and pediatric 
transplants at their institution over one year and found that the median time required to obtain an 
unrelated donor (URD; from formal search to clearance of a donor) was 49 days (range, 32-293 
days) compared to only 13.5 days (range, 2-387 days) for an UCB unit (from formal search to 
donor unit chosen). (27) In patients who underwent both UCB and URD searches, it took 29 
more days (95% confidence interval 21-37 days) to identify and clear an URD compared with a 
UCB unit (p<0.01).   
 
A preliminary review of all allogeneic stem cell transplants at the University of Chicago Medical 
Center (UCMC) during 2013 and 2014 supports these findings, with median time from search to 
transplant 66 days for UCB and 86 days for unrelated peripheral blood stem cells or bone marrow 
in 2013, and 53 and 82 days, respectively, in 2014. [unpublished data].   

8 
 
However, UCB’s relatively low cell doses are associated with delayed engraftment and slow 
immune reconstitution, which contribute to heightened early transplant related mortality (TRM).   
Various studies have compared MUD to cord blood transplant. For example, comparing AML 
at high risk by cytogenetics in first remission, cord blood transplantation and MUD donors had 
equivalent outcomes. (28) 
 
2.7. 
Alternative Donors in Older Adults 
Cord blood and haploidentical transplantations have increasingly been paired with reduced 
intensity conditioning and applied to older adults.  Observational data from the registry 
comparing patients 50 years and older with AML in first remission showed outcomes with MUD 
were better than unrelated cord blood units. (29) However, in the absence of a MUD, UCB 
transplant can provide extended survival, and with less frequent chronic GVHD, which is of 
particular value in older patients.  Alternative donor outcomes are improving rapidly and ready 
availability has prompted some centers to proceed directly to UCB or haploidentical transplant 
instead of MUD, rather than reserving alternative donors only for when no MUD is available, 
particularly for acute leukemias where time is of the essence.   
 
To our knowledge, this strategy has never been prospectively tested. 
 
2.8. 
Haplo-Cord Approach  
The University of Chicago Medical Center (UCMC) and Weil Cornell Medical Center (WCMC) 
groups have advanced an approach to overcome UCB limitations by combining a single cord 
blood unit with relatively low total nucleated cell (TNC) dose of 1.0 x 10(7)/kg compared to the 
traditional requirement of 2.5 – 5.0 x 10(7) TNC/kg, by co-infusing G-CSF mobilized ex vivo 
CD34 selected haplo-identical cells.  Early engraftment of the haplo-identical cells essentially 
protects the patient against prolonged cytopenias until the UCB cells eventually engraft and 
predominate in hematopoiesis and immune function.  This platform incorporates reduced-
intensity conditioning and thymoglobulin pre-transplantation, achieving fast engraftment, low 
rates of acute and chronic GVHD, acceptable risks of opportunistic infection, and promising 
long-term outcomes in adults, including older adults. (30) UCMC and WCMC are now testing 
approaches with cord doses as low as 0.5 x 10^7 TNC/kg, opening a larger menu of available 
cords.  This allows for more refined cord blood selection, such as with allele level matching at 
8/8 loci, non-inherited maternal antigen matching (clinical trial in progress), and optimizing non-
HLA parameters such as cell viability.  
 
2.9. 
Patient Selection and Geriatric Selection  
As the majority of allogeneic transplants occur in patients 50 years and older, adjusting for health 
conditions in select patients who undergo transplant has always presented challenges for 
observational and even prospective studies.  While disease features and donor type can be well-
characterized, validated health measures have now been established in the transplant setting.  
 
Comorbidity, as measured by the hematopoietic-cell transplantation-comorbidity index has 
become an established tool to gauge comorbid conditions and predict transplant related mortality 

9 
and overall survival. (31) Additional prognostic information can be obtained using a Geriatric 
Assessment. Our group has shown in patients 50 years and older, the importance of other factors, 
including pre-transplant c-reactive protein, functional status as measured by instrumental 
activities of daily living (7 questions reported by patients on their ability to function day to day 
without help), and possibly self-reported physical and mental function. (4, 5) Such information 
also provides invaluable data when comparing groups where drop-out may occur after 
randomization, as will occur in this study. 
 
2.10. 
Rationale for this Study  
Pursuing UCB transplant in patients who have potential unrelated donors identified has benefits. 
First, these patients will have more common haplotypes, as having potential unrelated donor 
matches (done by an initial computer search), and render them more likely to have better matched 
cord blood units relative to those without a potential MUD.  Data support finding the optimal 
HLA matched cord blood unit based on data from Eapen and colleagues showing better allele 
level matching in cord blood units, similar to MUD, reduced transplant related mortality. (32)   
 
We hypothesize that planning for a haplo-cord approach immediately relative to pursuing an 8/8 
MUD will: 1) reduce time to transplant, 2) increase the proportion actually proceeding to 
transplant, and 3) subsequently improve outcomes through both more rapid transplantation and 
finding well-matched cord blood units.  This could be of particular value for older patients where 
consolidation chemotherapy affords no clear benefit and relapse and clinical deterioration readily 
occur during transplant delays.    
 
2.11. 
Conditioning Regimens 
Allogeneic transplant requires pre-infusion conditioning chemotherapy and/or radiation to 
suppress host immune cells to facilitate engraftment and control residual hematologic 
malignancy. Historically, standard conditioning regimens not only caused myelosuppression, but 
extra-medullary toxicities to the gut, liver and lungs which may be prohibitive in less fit and/or 
older adults. Reduced intensity regimens employ less myeloablative regimens with parallel 
reduction in extra-medullary toxicities, and have promoted allogeneic HCT in older and less fit 
adults. The optimal regimen has not been established although fludarabine is commonly 
combined with an aklyating agent (e.g., melphalan or busulfan at various doses). The dose range 
of busulfan varies considerably, but higher myeloablative doses may be safely used with 
therapeutic drug monitoring to avoid excessive busulfan exposure and toxicity. (33) We have 
successfully incorporated two regimens at the University of Chicago:  1) fludarabine and 
melphalan at 140 mg/m2 and 2) fludarabine and IV busulfan once daily for four days to achieve 
a target AUC of 4800 umol/min/day (34, 35) for matched related and unrelated donor transplants, 
and primarily fludarabine and melphalan for haplo-cord transplants. (30)  
 
2.12. 
T-cell Depletion 
Graft-versus-host disease persists as one of the most dreaded complications of allogeneic 
transplant.  T-cell depletion reduces risks of graft-versus-host disease, but at the possible expense 
of higher rates of infection and disease recurrence. (36-38) 
 

10 
In vivo T-cell depletion is most commonly accomplished by use of polyclonal anti-T cell 
antibodies, such as anti-thymocyte globulin (ATG), although the exact mechanism and optimal 
dosing remain areas of active research.  Myeloablative transplant with unrelated donors may 
benefit in GVHD-free survival after ATG. (39) In reduced-intensity unrelated donor 
transplantation, observational data shows contradictory conclusions. In some studies, a possible 
detriment was found, while others showed reduction in GVHD with minimal or no effect on 
relapse. (38, 40, 41) A recent prospective randomized study from the Canadian Bone Marrow 
Transplant Group shows reduction in GVHD without impact on relapse rates in both 
myeloablative and RIC regimens (Walker I, ASH 2014, Abstract 38) 
 
In cord blood series, data are particularly limited and observational in nature.  In general, ATG 
appears to confer reduced risk of acute GVHD, but with possible greater risk of infection and 
EBV driven PTLD. (42-45) 
 
We believe that reducing the risk of acute if not chronic GVHD is essential to successful 
transplantation in the growing population of transplant candidates and improves long-term 
quality of life.  This can be accomplished by way of ATG for in vivo T-cell depletion.  However, 
careful attention must be paid to prevent infection with aggressive prophylaxis and monitoring 
of CMV, EBV, and other infections, which are cornerstones to the allogeneic stem cell transplant 
program at our institutions.  Absent clear data on whether T-cell depletion is beneficial or not, 
we believe a standardized approach in this study employing similar conditioning regimen and 
supportive care not only will facilitate comparisons, but will also allow standardization of patient 
care to optimize outcomes in both arms. 
 
2.13. 
Limitations.  
There may be reluctance to randomize subjects to a haplo-cord transplant when they have 
potential matched unrelated donors.  However, our retrospective data preliminarily show no 
difference in outcomes after MUD and haplo-cord HCT for all hematologic malignancies in a 
joint analysis by the WCMC and UCMC recently (Rhodes J et al, ASH 2014).  Other alternative 
donor sources exist, such as haploidentical. The WCMC and UCMC have developed 
considerable expertise in the haplo-cord approach. How haplo-cord transplantation fares relative 
to MUD is an important question. This can most easily be studied by randomization at time of 
transplant. However, we do not favor this approach for several reasons. First, one of the main 
benefits of haplo-cord is ready availability, and thus, study designs must account for this as 
survival from time of donor search is most important from a patient perspective. Secondly, a 
transplant requires considerable planning and cost in the donor search phase. The earlier the 
intended donor is identified, the more likely an optimal donor will be secured. Finally, this study 
is not powered to be definitive and will require a validation should the results show sufficient 
promise.  
 
3. 
PATIENT SELECTION 
3.1. 
Inclusion Criteria for Search Phase 
1. Diagnosis of acute myeloid leukemia (AML) or high or very high-risk MDS by 
international prognostic scoring system revised for whom transplant is recommended 

11 
 
2. 18 years of age or older 
 
3. Subject is likely to be considered for allogeneic transplant in the opinion of the 
transplant physician (based on age of patient, health, cytogenetics, and/or molecular 
characteristics).  
 
4. Karnofsky Performance Status (KPS) >/= 70% at time of enrollment.  An exception 
will be made for those with lower KPS at enrollment with an acute worsening that is 
likely to resolve in the treating physicians judgment (e.g., reversible infection, trauma, 
medication reaction, etc) 
 
5. Ability to understand and the willingness to sign a written informed consent document 
for the Search Phase.  
 
6. Patient willing to consider HCT 
 
7. A preliminary search has identified:  
a) An appropriate minimum 4/6 matched umbilical cord unit at intermediate 
resolution at HLA-A and B, and high resolution at HLA-DRB with a cell dose 
above 1 x 10(7) TNC/kg for a single umbilical cord blood (UCB) transplant AND 
b) At least one potential 8/8 HLA-matched (HLA-A, -B, -C, and –DRB1) unrelated 
donor with a probability of 70% AND 
c) Availability of a potential related haploidentical donor. 
 
3.2. 
 Exclusion Criteria for Search Phase 
1. 
Prior formal search was instituted 
 
2. 
Diagnosis of acute promyelocytic leukemia (APL)  
 
3. 
Known HLA matched related donor without contraindications to donate 
 
4. 
Life expectancy severely limited by concomitant illness or uncontrolled infection 
 
3.3. 
 Inclusion Criteria for Transplant Phase 
It is recognized that only some subjects will undergo transplant. 
 
1. High-risk AML for which transplant is recommend based on cytogenetic, molecular 
and morphologic features. Patients must meet institutional standards for disease control 
prior to transplant.  
 
2. For MDS. IPSS-revised criteria of high or very high at diagnosis.  
 
3. Subject meets institutional criteria for transplant and has acceptable organ and marrow 
function as defined below: 

12 
a) Serum bilirubin < 2.0mg/dL unless Gilberts disease  
b) Creatinine Clearance > 45 mL/min.1.73m2 as estimated by modified MDRD 
equation  
c) Left ventricular function 40% or greater  
d) DLCO corrected for hemoglobin >50% 
e) KPS 70% or greater 
 
 
4. An adequate graft for the defined donor type 
a) Haplo-cord requires a haploidentical adult donor of 14 years of age and at least 50 
kg, and a cord blood unit with at least 1.0 x 10(7) TNC/kg and a match of at least 
4/6 by intermediate resolution for HLA-A and B and high resolution at DRB1. 
Donor provides standard of care consent for harvest following institutional policy. 
Any donor samples or donor research data would be obtained on separate donor 
research protocol. 
b) For MUD requires a 7/8 or 8/8 HLA matched unrelated donor with high resolution 
matching at HLA-A, -B, -C, and DRB1. DP matching or DP permissive should be 
achieved when possible using T-cell epitope strategy.  
 
5. Written informed consent for the transplant phase 
 
3.4. 
 Exclusion Criteria for Transplant Phase 
1. Life expectancy severely limited by concomitant illness or uncontrolled infection 
 
2. HIV-positive 
 
4. 
ENROLLMENT, RANDOMIZATION, AND REGISTRATION 
4.1. 
Enrollment and Randomization 
Subjects at the University of Chicago (UCMC) and at the Weill Cornell Medical College 
(WCMC) will be enrolled simultaneously to reach the end goal of about 180 total subjects across 
both sites for the Search Phase of the trial.  Other sites may be asked to participate in the future. 
 
The study’s biostatistician at the University of Chicago will provide the study randomization 
table, eligibility checklist will be completed for each subject, a study ID will be given, and the 
study arm assigned. 
 
4.2. 
Central Patient Registration 
Subjects will be centrally registered with the University of Chicago (UCMC), Division of 
Hematology and Medical Oncology Clinical Research Office.  To register a subject, fax the 
following documents to the Clinical Research Office at 773-834-0188: 
 
 UCMC Subject registration form 

13 
 First and last page of the fully executed informed consent form, plus additional 
pages if checkboxes for correlative studies are required. 
 Eligibility checklist signed and dated by investigator and research nurse 
 
Central registration information is reviewed and entered into the Hem-Onc centralized research 
database.  Emailing of eligibility to the study PI and staff are acceptable. 
PI email: aartz@medicine.bsd.uchicago.edu 
 
5. 
STUDY DESIGN 
5.1. 
General Organization 
A.  Search Phase 
Subjects with AML or high risk MDS, who may benefit from HCT based on the treating 
physician’s recommendation, ages 18 years and older, with adequate performance status, will be 
eligible.  Those for whom a preliminary computer search identifies a potential matched unrelated 
donor (MUD; 8/8 match with at least 70% probability of matching) and a potential umbilical 
cord blood unit (at least 4/6 match with at least 1.2 x 10(7) TNC/kg), who also have a potential 
haploidentical donor, will be eligible for enrollment.  It is encouraged prior to registration, to 
HLA type available siblings to exclude such patients from the time and effort of formal search 
if a sibling match is available. Having children, parents, or full-siblings who have no known 
health contraindications, even prior to HLA typing, will be considered evidence of a potential 
haplo-identical donor.  Subjects will be randomized 1:1 to proceed with planning for a MUD or 
a haplo-cord HCT.   For those where an HLA sibling or other HLA matched related donor are 
later found, they will be removed from additional study procedures and only be followed to 
determine if they undergo transplant. 
 
B.  Transplant phase 
A second registration will occur for those who proceed to transplant in the Transplant Phase of 
this study.  Due to attrition from health impairments, identification of a related donor, lack of a 
reasonable donor, and lack of disease control, we expect considerable drop-out of 50% or more 
from the Search Phase prior to the Transplant Phase. Patients will be removed from study if 
greater than 1 year has elapsed from enrollment after search phase without a transplant unless 
permission from the PI is granted. We expect accrual of 180 subjects over a course of two years 
at two institutions in the Search Phase to achieve 96 patients who pursue HCT in the Transplant 
Phase. Enrollment will continue until 96 patients have pursued a MUD or haplo-cord HCT on 
study.  If this requires more than 180 subjects to be recruited, an amendment will be submitted 
for additional recruitment. 
 
Eligible subjects who enrolled on this study and are pursuing transplant will be encouraged to 
consent to the transplant phase on this study. Consent with details specific for each donor source 
is warranted and will not be confirmed until the time of transplantation. Additionally, 
correlatively samples will be requested warranting a second consent. Patients will be eligible for 
transplant regimens and post-transplant maintenance as long as ATG is included in the regimen. 
For subjects randomized to the haplo-cord arm who subsequently do not have an adequate 
haploidentical donor or umbilical cord blood unit, a MUD approach will be pursued if available.  

14 
Likewise, subjects randomized to the MUD search arm may proceed with a 7/8 MUD or another 
donor source for transplant such as haplo-cord if no MUD can be procured. Should subjects not 
consent on this protocol but pursue transplant, the data on stem cell source and outcomes will be 
captured. 
 
5.2. 
Search Evaluation  
Subjects will present for a Screening Visit.  After it has been established that the subject has 
consented, is confirmed to be eligible for search phase, he/she will be assigned a study number 
and be “randomized” by REDCap into one of the study groups:  Arm A - the haplo-cord group 
or Arm B - the matched unrelated donor (MUD) group.  The donor search will then proceed 
quickly to identify the best donor following the above criteria and initiate institutional standards 
for potential transplant recipients without delay.  The intent of this protocol is to identify donors 
and prepare patients for transplant as quickly as possible.  
  
Pre-transplant testing: 
The following items are considered standard evaluations for transplant eligibility and should be 
determined within 12 weeks before initiation of conditioning therapy, unless otherwise noted to 
determine transplant eligibility. They are not required to enroll in search phase. 
 
The following tests are required unless otherwise specified below:   
 
1. Medical history, physical examination, vital signs, height and weight. 
2. KPS (Karnofsky Performance Score)  
3. Complete blood count (CBC) with differential and platelet count, serum creatinine, 
bilirubin, alkaline phosphate, Cytomegalovirus (CMV) antibody test * 
4. Infectious disease and hepatitis panel (HepAAb, HepB Sab, HepB Sag, HepB Core Ab, 
HepCAb), herpes simplex, syphilis, HIV and HTLV 1 antibody, & varicella zoster virus.* 
5. Immunoglobulin levels 
6. High resolution HLA typing (at any time per institutional policy) 
7. Electrocardiogram (ECG), and left ventricular ejection fraction or shortening fraction,  
8. Diffusing capacity of the lung  for carbon monoxide (DLCO), Forced Expiratory Volume 
in One Second (FEVI)  
9. Bone marrow aspirates for pathology and cytogenetics and/or biopsy 
10. Beta-HCG serum pregnancy test for females of childbearing potential 
11. Chest CT preferred or chest radiograph  
12. Peripheral blood for pre-transplant restriction fragment length polymorphism (RFLP) 
analysis to establish a reference profile of host hematopoiesis* 
13. HLA antibody testing (panel reactive antibody)* 
 
*within 24 weeks of planned transplant.  
 
5.3. 
Conditioning Regimens  
Two conditioning regimens will be utilized. The fludarabine-melphalan-ATG regimen is 
preferred for adults 55 years and older, KPS 80%, and/or HCT-CI score or 4 or more. For those 

15 
under 55 years of age, or particularly fit patients up to 65 years of age (e.g. comorbidity score < 
3 and KPS 90% or more), the fludarabine-busulfan-ATG regimen may be used. 
 
Fludarabine-Melphalan and ATG: 
Day 
-7 
-6  
-5 
-4 
-3 
-2 
-1 
0 
 1 
Fludarabine 
(mg/m2) 
30  
30  
30  
30  
30 
 
 
Haplo2 
or MUD  
Cord  
Melphalan 1  
 (mg/m2) 
 
 
 
 
 
 
140 
 
 
 
rATG 
(mg/kg) 
 
 
1.5  
 
1.5  
 
1.5  
 
 
TBI* 
(cGY) 
 
 
 
 
 
200 
200 
 
 
 
 
Fludarabine-Busulfan and ATG: 
Day 
-7 
-6  
-5 
-4 
-3 
-2 
-1 
0 
 1 
Fludarabine 
(mg/m2) 
30  
30  
30  
30  
30 
 
 
Haplo2 
or MUD  
Cord  
Busulfan3 
(mg/kg) 
 
3.2 
3.2 
3.2 
3.2 
 
 
 
 
rATG 
(mg/kg) 
 
 
1.5  
 
1.5  
 
1.5  
 
 
 
 
 
1In patients at high risk for graft rejection (i.e., donor-specific HLA antibodies, or those who have 
not received cytotoxic chemotherapy in the 3 months prior to conditioning), the treating 
investigator may use total body irradiation (TBI) for 2 doses at 200 cGy to reduce the risk of graft 
failure in the reduced intensity arm. TBI days may be modified from day 0 prior to stem cells to 
start day -4 to account for scheduling but should be two consecutive days. 
2Haplo-identical grafts will be CD34+ selected by Miltenyi Device. When possible, grafts should 
be administered without cryopreservation. 
 
3Recommended to achieve an AUC of goal of 4800 mcmol/minute/day +/- 20%. The last day of 
busulfan may be moved to day -2 and a test dose may be used to achieve desired ablative AUC. 
The dosing of 3.2 mg/kg is recommended dose prior to obtaining therapeutic drug levels or if no 
drug levels are obtained for adjustment.  Anti-seizure prophylaxis is required Levetiracetam 1000 
mg po BID is recommended starting 12 hours before the first dose of busulfan and continuing for 
48 hours after the last dose. Clonazepam 1 mg po TID starting 12 hours before busulfan and 
continuing for 24 hours after the last dose of busulfan is the recommended alternative 
 
DRUG INFORMATION: 

16 
Fludarabine: 30 mg/m2 /day intravenously x 5 days total dose 150 mg/m2. Fludarabine will be 
dosed according to actual body weight. 
 
Melphalan: 70mg/m2/day intravenously x 2 days or 140 mg/m2 x 1 day. Melphalan will be 
dosed according to actual body weight. Cryotherapy with ice chips will be administered to 
prevent mucositis. 
 
Busulfan:. 3.2 mg/kg/day intravenously x 4 days. This will be dosed on actual body weight. 
Therapeutic drug monitoring is recommended to achieve a target an AUC of 4800/day +/- 20% 
for each day on average, which will be considered equivalent to 3.2 mg/kg/day. Anti-seizure 
prophylaxis is mandatory. 
 
Rabbit ATG (rATG): 1.5 mg/kg/day intravenously x 3 days, total 4.5 mg/kg. ATG will be 
dosed according to actual body weight. The first dose will be infused over at least six hours, and 
subsequent doses over at least 4 hours.  Pre-medications include acetaminophen 650 mg by 
mouth, diphenhydramine 25-50 mg by mouth or intravenously, and methylprednisolone 2 mg/kg 
(1 mg/ kg at the initiation and 1 mg/kg half-way through anti-thymocyte globulin 
administration). 
 
Circumstances may require minor changes in scheduling of chemotherapy. Variations of up to 
24 hours in scheduling will be acceptable. 
 
5.4. 
GVHD Prophylaxis 
Tacrolimus: 0.03 mg/kg/day using continuous intravenous infusion over 24 hour time period or 
equivalent given as a 3 hour infusion every 12 hours from Day -2 until engraftment or when 
subject is able to take by mouth, then tacrolimus approximately 0.09 mg/kg by mouth in 2 
divided doses.  Tacrolimus should be given at full dose to maintain levels of 5-15 ng/mL through 
Day 180, tapered by 20% every week thereafter.  We recommend a level of 10-15 until 
engraftment. Infection, toxicity or other clinical circumstances may prompt earlier 
discontinuation. In the presence of GVHD, a clinical decision by the attending physician will 
determine if tacrolimus can be tapered or should be continued.  PO tacrolimus can be used in the 
pre-engraftment period when IV access for tacrolimus is not available. 
 
Mycophenolate Mofetil (MMF): Will be started on Day -2 and given at a dose of 1000 mg 
every 8 hours until Day 28. Infection, toxicity, very low patient weight (< 50kg) may prompt 
earlier discontinuation or adjustment of doses. 
 
Alternative GVHD prophylaxis: Should tacrolimus require discontinuation in the first 100 
days without ability to restart it, it is strongly encouraged to use another agent such as sirolimus 
or cyclosporine A. 
 
5.5. 
Supportive Care 
Format: Supportive Care Schedule for CMV seropositive patients and/or seropositive MUD or 
haploidentical donors. 
 

17 
Admission to 
Day -2 
Day -1 until 
engraftment 
Engraftment  
until Day 210 
Day 210 
Ganciclovir 5mg/kg 
IV every 12 hrs 
Acyclovir  500mg/m2 
IV every 8hrs (or 
equivalent IV) 
Valaciclovir 2gm by 
mouth four times per 
day 
Acyclovir 400 mg by 
mouth two to three 
times per day (or 
equivalent IV) 
 
Changes and incorporation of alternative medications, unless dictated by clinical circumstances 
(side-effect, intolerance, failure, contra-indication), require discussion with the Principal 
Investigator. 
 
 For patients who are not at risk of CMV (i.e, seronegative recipient and seronegative 
MUD) an alternative CMV strategy of acyclovir alone is acceptable. Cord blood is 
considered at low risk for CMV unless specific testing of CMV virus is available. 
 Cytomegalovirus (CMV) monitoring at least weekly until Day 100 and at least monthly 
until Day 180 regardless of donor/recipient CMV status. We recommend at least monthly 
monitoring if on immune suppression past day 180 or more often if prior CMV 
reactivation. 
 A prophylactic broad-spectrum antifungal with anti-mold activity is strongly 
recommended.  
 Other infection prophylaxis and supportive care will be as per institutional unit policy. 
 All subjects, regardless of disease histology will receive filgrastim (G-CSF) 5 mcg/kg 
(rounded to 300 mcg or 480 mcg, depending on subject weight) SQ daily starting day + 
1 to day + 5 until ANC >1000/uL. 
 Blood transfusions should follow institutional policies.  
 Epstein-Barr virus (EBV) monitoring: 
o EBV monitoring at least weekly until Day 100 and at least monthly until off 
immune suppression is required. 
o Rising EBV titers should warrant investigation for an EBV post-transplant 
lymphoproliferative disorder (PTLD).  
 Evidence of PTLD or consecutive increases in EBV polymerase chain 
reaction should lead to treatment with rituximab. 
 Donor specific antibodies: Patients with donor DSA in high titers may undergo 
therapeutic procedures prior to transplant in order to reduce DSA levels. Such treatments 
may include but are not limited to: bortezomib, intravenous immunoglobulins, rituximab 
and plasma exchange. 
 Cytoreduction for those not in remission. Patients may receive pre transplant treatments 
meant for disease reduction or disease sensitization. This may include, but is not limited 
to clofarabine and hypomethylating agents.   

18 
 
All aspects of care will be identical between the two groups, except for the choice of donor. 
 
Patients may participate in investigational drug studies to prevent infection or preventing relapse 
unless they interfere with time to transplant or engraftment after transplant.  Interventional 
studies designed primarily to mitigate GVHD are prohibited.  
 
6. 
TRANSPLANT STEM CELL SOURCE AND CELL DOSE 
All recipients should be tested for Panel Reactive Antibody (PRA) for Class I and Class II HLA 
antibodies.  If antibodies are present, the donor should be chosen whose antigens are not targeted 
by antibodies present in the recipient (donor specific antibodies; DSA) if possible. This may 
require DQ and DP testing of the donor. 
 
6.1. 
Haplo-cord 
Umbilical Cord Blood (UCB) Unit 
The UCB unit must supply a minimum of 1.0 x107/kg pre-cryopreserved total nucleated cell 
dose. The unit must match at a minimum of 4 of 6 at HLA-A, -B, -DRB1 loci with the recipient. 
This may include 0-2 antigen mismatches at each A or B (at the antigen level) or DRB1 (at the 
allele level) loci. The optimal cord unit will be identified by high-resolution matching at 8/8 
HLA loci, similar to unrelated donors taking preference for the cord blood unit that contains an 
adequate cell dose and the fewest mismatches. (32) Cord viability should be 85% or more by 
tryphan blue or flow cytometry post-processing from the cord bank. 
 
Third Party Donor     
The preferred 3rd party donor will be a young HLA haplo-identical relative. After appropriate 
evaluation per transplant program criteria, the donor will receive G-CSF (filgrastim or 
equivalent) 5 mcg/kg subcutaneous two times per day or 10 mcg/kg subcutaneous daily for four 
to five consecutive days (doses rounded to the nearest vial size). Apheresis will start on the 
morning of the fifth day and proceed until sufficient cells have been collected following 
institutional policies and procedures. Scheduling may require collection on day 4 or 6. 
 
The use of pediatric donors is restricted to donors who are 14 years and older and weigh more 
than 50 kg. After collection and prior to cryopreservation, cells will be T-cell depleted using the 
Milteny Clinimax® depletion device. The target will be to obtain a product containing less than 
1x104CD3+ cells per kg of recipient body weight and no more than 5x106/kg CD34 positive 
cells. The haplo-identical unit may be cryopreserved if required for logistical reasons.  
 
6.2. 
Matched Unrelated Donor 
Matched unrelated donors will be sought through the National Marrow Donor Program.  Suitable 
donors will match at a minimum at HLA-A, -B, -C, and –DRB1 at high-resolution, which has 
been shown to maximize post-transplantation survival.  HLA-DQ matching is encouraged and 
DP permissive matching using a T-cell epitope (TCE) strategy is strongly encouraged. 
 
Peripheral blood or bone marrow harvests will be acceptable. 

19 
 
6.3. 
Infusion of Cells 
 
The infusion of UCB and the haplo-identical units will be separated by at least 1 hour and 
preferably will occur on successive days (Day 0 and Day 1).  The haplo-identical unit is 
preferred, but not required, to be infused first.  
 
An emergency second cord may be given in the haplo-cord arm under extenuating 
circumstances: post-thaw cord viability exceptionally low, HLA matching show that incorrect 
unit or less matched unit was found, or <1.0 x 10(7) TNC/kg was able to be infused due to illness 
or infusion reaction.  
 
MUD infusion: The MUD infusion may occur on day +1 (1 day after planned infusion) when 
products arrive late or require processing. This will not be considered a deviation. 
 
6.4. 
Prior to Transplant 
Patients must consent a second time to undergoing transplant in the Transplant Phase of the 
study. Because transplant has considerable toxicities, a dedicated second consent at the time of 
transplant is optimal to ensure patients are aware of and comprehend the risks and the pre-
transplant evaluation has been completed to properly advise patients of their specific risks.  This 
evaluation may include the following. 
 
1. Additional testing prior to transplant for patients 50 years and older: modified Geriatric 
Assessment (Demographics, Patient reported Karnofsky PS, falls, weight loss, 
hematopoietic-cell transplantation-comorbidity index, OARS comorbidity, OARS 
IADL, OARS physical activity, MHI-17, caregiver support, social activity, blessed 
orientation memory concentration, grip strength and 4 meter walk speed) 
2. Short-form MOS-36 Quality of Life survey (SF-36) 
 
Should patients or clinicians not pursue transplant on study, their choice will be documented 
along with the reason. These patients will still be followed for overall survival and if they do 
eventually undergo transplant off-protocol.  
 
Reasons to not to pursue transplant may include: 
1. Death 
2. Impaired disease control 
3. Impaired patient health, making transplant risks too great 
4. Inability to find a donor 
5. Patient preference 
6. Clinician decision not listed above 
7. One year elapsed since time of search 
 
6.5. 
Post-Transplant Evaluations 
The follow-up schedule for scheduled study visits is outlined in Table 1 below. 

20 
 
Table 1 
Study Visit 
Target Day Post-Transplant (Day 0) 
4 week 
28 + 5 days 
7  week 
56 + 7 days 
100 days 
100 + 7days 
6 month 
180 + 28 days 
12 month 
365 + 28 days 
24 months 
730 +/- 56 days 
36 months 
3 yrs +/- 90 days 
 
6.6. 
Study Calendars 
Table 2. Study calendar for Search Phase 
 
Exam 
Baseline 
Physical exam, height, weight, and  
KPS performance status 
X 
Geriatric Assessment (GA) for pts 50 and 
older* 
X 
*  See Appendix B for GA tools 
 
Table 3:  Transplant Phase including pre and post-transplant testing 
The follow-up schedule for scheduled study visits is outlined in Table 1 and tests also noted in 
section 5.2  Institutional transplant work up guidelines may demand additional testing.  
 
Exam 
Baseline** 
Day 28 
Day 56 
Day 100 
Day 180 
Day 365 
and 730 
Physical exam, 
height, weight, and 
KPS performance 
status 
X 
X 
 
X 
X 
X 
GVHD and other 
morbidity 
assessments5 
 
X 
 
X 
X 
X 
Geriatric Assessment 
(GA) for pts 50 and 
older7 
X 
 
 
 
 
 
Short-form 36 
Quality of Life (SF-
36 ) 
X 
X 
 
X 
X 
X 
Toxicity assessments 
X 
X 
 
X 
X 
X 
Electrocardiogram 
X 
 
 
 
 
 
Infectious disease 
titers3 
X 
 
 
 
 
 
Chest CT or chest x-
ray 
X 
 
 
 
 
 
LVEF, or shortening 
fraction 
X 
 
 
 
 
 

21 
Exam 
Baseline** 
Day 28 
Day 56 
Day 100 
Day 180 
Day 365 
and 730 
DLCO corrected, 
FEV 1 and FVC  
X 
 
 
 
 
 
High Resolution 
HLA typing 
X 
 
 
 
 
 
B-HCG serum 
pregnancy test (pre-
menopausal females 
only) within 4 week 
of conditioning 
X 
 
 
 
 
 
CBC1 , differential, 
platelet count, and 
blood chemistries2 
X 
X 
 
X 
X 
X 
CMV and EBV PCR 
Titres6 
X 
X 
X 
X 
X 
X 
Bone marrow biopsy 
and aspirate for 
pathology 
X 
X 
 
X 
X 
X 
Chimerism 
X 
X 
X 
X 
X 
X 
Lymphocyte Subsets 
and Ig Levels 
X 
X 
 
X 
X 
X 
HLA Antibodies 
X 
 
 
 
 
 
Correlative assays 4, 5 
BM/PB 
BM/PB 
BM/PB 
PB 
BM/PB 
BM/PB 
BM/PB 
 
Note: 
*The exact day of the tests is approximate. Tests can be scheduled several days before or after. 
See table 1 for windows of testing.  
**Baseline tests: see also section 5.2  
 
1. CBC performed at least three times a week from Day 0 until ANC >500 mcL for three 
days after nadir. CBC performed twice weekly until Day 28.  CBC performed 
approximately weekly after Day 28 until 12 weeks post-transplant. 
2. Blood chemistries include: serum creatinine, bilirubin, alkaline phosphatase, AST, and 
ALT, LDH, sodium, magnesium, potassium, chloride, and thyroid function tests (where 
standard of care should be according to institutional guidelines). Blood chemistries 
performed twice weekly if possible until Day 28.  Blood chemistries performed weekly if 
possible after Day 28 until day 100 post-transplant. 
3. Infectious disease titers include: CMV, Hepatitis B and C (HepBSAb, HepBSAg, HepB 
Core Ab, HepCAb), syphilis, HIV, toxoplasmosis, and HTLV antibody 
4. Correlative Assays may include studies of immune reconstitution, novel prognostic 
factors, or minimal residual disease assays.  
a) 
BM: bone marrow: 10 cc green top from marrow. If unavailable, sample may be 
drawn from PB 
b) PB: Peripheral blood. 10 cc serum/plasma red top. 
5. Recommended, not required.  

22 
6. Cytomegalovirus (CMV) and Epstein-Barr Virus (EBV) monitoring at least weekly until 
Day 100 and at least monthly until off immune suppression. 
7. Geriatric assessment. Involves patient report questions and bedside testing by health care 
professional (appendix B for complete list). This may be performed by electronic survey 
through REDCap or paper for patient reported instruments). The GA administered during 
search phase will be used. However, GA may be repeated if additional chemotherapy 
consolidation has been given since the initial GA was administered, clinical change in 
status and/or 3 months have elapsed since initial GA prior to transplant conditioning.  
 
 
7. 
ADVERSE EVENTS MONITORING AND REPORTING:   
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
investigator will be required to provide appropriate information concerning any findings that 
suggest significant hazards, contraindications, side effects, or precautions pertinent to the safe 
use of the drug under investigation.  Safety will be monitored by evaluation of adverse events 
reported by subjects or observed by investigators or research staff, and may require 
investigations such as clinical laboratory tests, x-rays, electrocardiographs, etc. 
 
7.1. 
Investigational Risks 
See consent form. There are no known side-effects related to the use of the Miltenyi CliniMacs 
device to select cells. 
 
There are potential risks to undergoing hematopoietic stem cell transplantation using an 
alternative donor source, such as with a haplo-cord approach in this protocol, in comparison to 
stem cell transplantation using matched unrelated donors.  Risks of using umbilical cord blood, 
which is the intended source of permanent engraftment, include late engraftment with resulting 
prolonged pancytopenia, increased risk of graft failure, and delayed immune reconstitution, 
infection, post-transplant lymphoproliferative disorder and increased treatment related mortality. 
{Eapen, 2010 #109;Laughlin, 2004 #111}(26) 
 
For the unrelated donor arm, relative to haplo-cord, acute and chronic graft-versus-host disease 
may be greater and disease relapse may be greater. Time to transplant may be longer. 
 
7.2. 
Definitions 
 Adverse Event 
An adverse event is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product that does not necessarily have a causal relationship with 
the treatment. An adverse event can be any unfavorable and unintended sign (including a 
laboratory finding), symptom or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product. 
 
At each evaluation patients should be interviewed in a non-directed manner to elicit potential 
adverse reactions from the patient. The occurrence of an adverse event will be based on changes 

23 
in the patient’s physical examination, laboratory results, and/or signs and symptoms, and review 
of the patient’s own record of adverse events. 
 
Adverse events will be followed until resolution while the patient remains on-study. Once the 
patient is removed from study, events thought to be related to the study medication will be 
followed until resolution or stabilization of the adverse event, or until the patient starts a new 
treatment regimen, or death, whichever comes first.  Subjects will be followed for AEs/SAEs for 
100 days after transplant. 
 
 Serious Adverse Event 
An adverse event is considered serious if it results in ANY of the following outcomes:  
 
1) Death 
2) Life-threatening (e.g. places subject at immediate risk of death, this does not include 
events that might have caused death if they occurred a greater severity) 
3) Results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours (see below) 
4) A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions  
5) A congenital anomaly/birth defect.  
 
Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon 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. 
 
 Unexpected Events 
Unexpected events are those not listed at the observed specificity or severity in the protocol 
(Section Error! Reference source not found.), informed consent, FDA-approved drug package 
insert(s).  An event is considered unexpected if it is listed as occurring within the class of drugs 
or otherwise expected from the drug’s pharmacological properties but which has not been 
previously observed with this specific investigational agent. 
 
Events related to transplant as described in Section 7.4 will not be considered unexpected.  
 
 Adverse Reactions 
An adverse event is considered to be an adverse reaction if there evidence to suggest a causal 
relationship to the study agents.  This may include a single occurrence of an event strongly 
associated with drug exposure (e.g. Stevens-Johnson Syndrome), one or more occurrence of an 
event otherwise uncommon is the study population, or an aggregate analysis of specific events 
occurring at greater than expected frequency. 
 

24 
7.3. 
Adverse Event Characteristics  
The National Cancer Institute Common Toxicity Criteria Scale (version 4.0) will be used to 
grade toxicities.  
 
A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov). 
 
 
Attribution of the AE: 
- Definite – The AE is clearly related to the study treatment. 
- Probable – The AE is likely related to the study treatment. 
- Possible – The AE may be related to the study treatment. 
- Unlikely – The AE is doubtfully related to the study treatment. 
- Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.4. 
Protocol-Specific Expedited Adverse Event Reporting Exclusions 
Many toxicities that are grade 3 by CTCAE are expected and routine for transplant. Toxicities 
are common following transplant. Therefore, only unexpected, grades 3-5 adverse events (AEs) 
will be reported via the expedited reporting mechanisms as defined in Section 7.6. 
 
For this protocol only, the AEs/grades listed below do not require expedited reporting to the 
responsible parties listed Section 7.6.  However, they still must be reported through the routine 
reporting mechanism. 
 
Expected Grade 3 -4 Toxicities for 
Transplant (NOT SAE) 
Not Routinely Expected Grade 3-4 for 
Transplant (SAE) 
Fever after engraftment without a source 
requiring several additional hospital days 
Intensive care unit admission 
Fever/infection requiring IV antibiotics 
during neutropenia or related to catheter 
Infection 
requiring 
a 
major 
surgical 
procedure 
Confusion requiring additional monitoring 
in the room 
Seizure 
Atrial fibrillation or flutter or arrhythmias 
monitoring on the transplant floor 
Arrhythmia requiring monitoring outside of 
the transplant unit, a pacemaker, or 
cardioversion 
Electrolyte 
disturbances 
requiring 
IV 
repletion 
 
Poor nutrition requiring parenteral or enteral 
nutrition  
 
Acute or chronic GVHD 
 
VOD (for busulfan treated) 
 
 

25 
7.5. 
Adverse Event Reporting Requirements 
All Adverse Events must be reported in routine study data submissions.  AEs reported using the 
Serious Event Reporting Form and/or MedWatch Form discussed below must also be reported 
in routine study data submissions.   
 
 Serious Adverse Event Reporting to the Coordinating Center 
All serious adverse events except for those routinely expected due to transplant (as defined in 
sections 7.2.2 and 7.4) occurring on this study require expedited reporting to the University of 
Chicago Comprehensive Cancer Center (UC CCC).  The responsible Research Nurse or other 
designated individual at the treating site should report the SAE to the Study Principal Investigator 
and the CCTO by the end of the business day when s/he becomes aware of the event.  Events 
occurring after business hours should be reported to the CCTO by 12pm (noon) the next business 
day.   
 
All unexpected adverse reactions must be reported to the IND holder so that the University of 
Chicago CCTO can inform the FDA.  The responsible Research Nurse or other designated 
individual at the treating site should provide a complete written report using the FDA MedWatch 
3500A form.  The completed form should be sent to the CCTO at qaccto@bsd.uchicago.edu 
within the specified timelines below regardless of whether all information regarding the event is 
available.  If applicable, a follow-up report should be provided to the CCTO if additional 
information on the event becomes available.   
 
Participating sites should not forward any adverse event reports directly to the FDA.  The CCTO 
will report all events to the FDA as per the current FDA guidelines.   
 
Fatal or Life-threatening Events: within 4 calendar days from treating investigator knowledge 
of the event 
 
All Other Reportable Events: within 10 calendar days of treating investigator knowledge of the 
event 
 
All serious adverse events should also be reported to the local IRB of record according to their 
policies and procedures.   
 
 
7.6. 
Supportive Therapy and Other Investigational Drugs 
Symptomatic care may be given as required with medications such as anti-emetics and 
analgesics, according to institution’s standard operating protocols. Investigational drugs that 
may influence time to transplant, engraftment, or rates of GVHD are not permitted. It is 
anticipated patients may participate in supportive care studies such as treatment of GVHD, 
prevention or treatment of CMV etc. 
 

26 
8. 
CORRELATIVE/SPECIAL STUDIES 
In addition to routine clinical tests, we will collect additional samples for possible correlative 
studies. 
 
In addition to the standard immune reconstitution studies including lymphocyte subset panel 3 
and quantitative immunoglobulin levels, an additional 10 cc heparinized (Green Top) from bone 
marrow (or blood if marrow not available) will be cryopreserved at each center.  The samples 
will be batch shipped to the University of Chicago periodically. Samples will be shared with 
Weill Cornell to perform correlative studies. We anticipate several correlative studies.  
 
A. 
Minimal Residual Disease Monitoring.  The presence of minimal residual disease in 
myeloid leukemia or MDS may be assessed by monitoring of WT1 transcript levels in 
blood or bone marrow using a quantitative RT-PCR assay. Briefly, total RNA will be 
extracted from blood and bone marrow and cDNA synthesized using standard 
techniques. Amplifications of patient samples, K562 cell line cDNA, and no template 
controls will be performed in triplicate. WT-1 expression levels will be detected using 
a transcript specific primer and probe set. In order to compensate for differences in 
RNA integrity and cDNA synthesis efficiency, the absolute WT1 transcript copy 
number will be normalized to the endogenous control gene Abl.  
B. 
Additional studies. There may be additional studies geared toward gaining a better 
understanding and predictors of disease relapse, GVHD, and immunologic activity of 
this strategy. 
 
 
 
9. 
CRITERIA FOR STUDY EVALUATION 
9.1. 
Time to Transplant 
Time to transplant will be measured from time of date of formal request to stem cell infusion 
date. We will also capture time from preliminary search to both formal search and transplant 
date. 
 
9.2. 
Proportion undergoing transplant 
The proportion undergoing transplant in 3 months and 1 year from randomization will be 
captured. This will first be captured by transplant to assigned arm and to any transplant. The 
percent adherence to the assigned arm of those transplanted will be measured. 
 
9.3. 
Leukemia Free Survival 
Relapse will be recorded by the day of initial detection of malignant cells if these cells were on 
subsequent testing confirmed to be increasing in number or by unequivocal radiological 
progression.  The diagnosis of disease recurrence will be based on clinical and pathological 
criteria. 
 

27 
9.4. 
Overall Survival 
Overall survival will be recorded from day of enrollment until death by any cause. Overall 
survival from time of transplant in the transplant phase will also be captured. 
 
9.5. 
Graft Failure 
Primary graft failure day 28 will be defined as lack of neutrophil engraftment at day 28. Primary 
graft failure day 48 will be defined as lack of neutrophil engraftment at day 48 
Secondary graft failure will be defined as lack of donor chimerism defined as <5% donor 
chimerism and an absolute neutrophil count below 500/uL .  
 
9.6. 
Treatment Related Mortality 
Treatment related mortality is considered any death that cannot be explained by persistence, 
relapse or progression of the underlying malignancy once the preparative regimen starts.  
 
9.7. 
Time to Neutrophil Recovery 
Neutrophil engraftment will be defined as the first day in which the ANC is > 500/mm3 for three 
consecutive days.  Time to neutrophil recovery will be recorded from the first day of donor cell 
infusion until neutrophil engraftment. 
 
9.8. 
Time to Platelet Recovery 
Platelet engraftment will be defined as the first day the platelet count is > 20,000/mm3 without 
transfusion support for seven consecutive days.  Time to platelet recovery will be recorded from 
the first day of donor cell infusion until platelet engraftment. 
 
9.9. 
Acute GVHD 
Acute GVHD will be scored according to the criteria proposed by Przepiorka et al. (Appendix 
A) 
 
9.10. 
Chronic GVHD 
Chronic GVHD will be scored according to the NIH Consensus Development Project on Criteria 
for Clinical Trials in Chronic Graft-versus-Host Disease:   
I. Diagnosis and Staging Working Report  
 
9.11. 
Length of Stay 
The length of stay will be defined as the number of days spent in the hospital between Day 0 and 
Day 100 after transplant. This will include time spent for readmissions.  
 
9.12. 
Transfusion Support 
The total number of transfusion episodes and the total transfused PLT and RBC units  
 

28 
10. 
CRITERIA FOR REMOVAL OF PATIENTS FROM STUDY 
Disease Progression or Disease Persistence 
Patients with progressive disease or relapse will be removed from protocol therapy and followed 
for survival. 
 
Extraordinary Medical Circumstances 
If, at any time, the constraints of this protocol are detrimental to the subjects’ health and/or the 
subject no longer wishes to continue protocol therapy, protocol therapy shall be discontinued. In 
this event: 
• 
Notify the Study Principal Investigator. 
• 
Document the reason(s) for discontinuation of therapy in patient records. 
• 
Follow the patient for survival, progression, relapse, and secondary malignancy 
 
11. 
DATA REPORTING / REGULATORY CONSIDERATIONS 
A. The University of Chicago or Weil Cornell Medical Center medical records will be utilized 
for all patients.  Data will be entered into a data management file within 3 weeks after each 
evaluation of the patient.  After the patient goes off treatment, follow-up information will 
be collected per the study calendar. .  
 
B. Pathologic diagnosis and HLA typing will be recorded in a conventional way with a record 
being placed in the patient’s permanent record and data management file.  However, 
investigational correlative assay results will not be made part of the medical record.  
 
C. Data and safety monitoring for this trial will be carried out in accordance with the 
University of Chicago Comprehensive Cancer Center Data and Safety Monitoring (DSM) 
Plan.  Briefly, accrual, toxicity, and response data will be reviewed weekly at the transplant 
patient care conference for all patients enrolled at all centers. Adverse events will be 
reported to the principal investigator, IRB, and FDA as described in section 7.  Decisions 
will be made regarding study continuation, amendment, or closure at the weekly meeting 
and a note will be signed by the principal investigator or his designee documenting this 
decision.  External monitoring of accrual is performed by the Accrual Monitoring 
Committee.   
 
D. In addition to the clinical monitoring procedures, the University of Chicago Comprehensive 
Cancer Center will perform routine Quality Assurance Audits of investigator-initiated 
clinical trials as described in the NCI-approved UC CCC DSM Plan. Audits provide 
assurance that trials are conducted and study data are collected, documented and reported 
in compliance with the protocol. Further, quality assurance audits ensure that study data are 
collected, documented and reported in compliance with Good Clinical Practices (GCP) 
Guidelines and regulatory requirements. The audit will review subjects enrolled at the 
University of Chicago in accordance with audit procedures specified in the UC CCC Data 
and Safety Monitoring plan.  
 
A regulatory authority (e.g. FDA) may also wish to conduct an inspection of the study, during its 
conduct or even after its completion. If an inspection has been requested by a regulatory authority, 

29 
the site investigator must immediately inform the University of Chicago Cancer Clinical Trials 
Office and Regulatory Manager that such a request has been made. 
 
12. 
STATISTICAL CONSIDERATIONS 
Blocked randomization will be performed at each participating site with a 1:1 allocation ratio. 
Such randomization will allow for equal numbers of haplo-cord SCT and MUD SCT subjects to 
be enrolled at each participating site. 
 
The primary endpoint is time to transplant, specifically from donor formal request until stem cell 
infusion.  Time to transplant in the standard Arm A (MUD) is expected to be 87 days.  The 
expected difference between the two arms is about 25 days (ie: time to transplant in the haplo-
cord group will be about 25 days faster than in the MUD group). 
 
Group sample sizes of 48 and 48 in the MUD and haplo-cord groups achieve 80% power to 
detect a difference of 25 days between the null hypothesis that both group means are 87 days, 
and the alternative hypothesis that the mean of the haplo-cord group is 62 days, with estimated 
group standard deviations of 43 and 43, and with a significance level (alpha) of 0.050000 using 
a two-sided two-sample t-test.  Standard deviations of both groups is expected to be the same 
given relatively uniform regimens. 
 
Assuming approximately 50% drop-out rate in those enrolled at the Search Phase due to inability 
to undergo transplant, prior to re-consenting for the Transplant Phase, this design will still have 
80% power to detect the hypothesized difference in time to transplant between the two arms.  
We will budget for 180 subjects to achieve 96 total subjects (48 per arm)  
 
Analysis Plan for Endpoints: 
The primary endpoint in both treatment arms is time to transplant as measured from the date of 
formal donor request to the date of stem cell infusion.  Standard deviations, means, and medians 
will be estimated for the time to event measures in both arms in a modified-intent to treat fashion.  
In other words, those who register for the Search Phase of the study, but who are eventually 
unable to proceed to transplant, will be excluded from analysis of the primary endpoint.  
However, they will retained for secondary analyses as discussed below. 
 
Secondary endpoints include the proportion of patients who undergo transplantation by modified 
intention to treat in each arm.  Group sample sizes of 90 in the MUD group and 90 in the haplo-
cord group (before the 50% drop out expected prior to transplant) achieve 80% power to detect 
a difference between the group proportions of 0.2000.  The proportion in the experimental haplo-
cord group who successfully proceed to transplant is assumed to be 0.2000 under the null 
hypothesis, and 0.4000 under the alternative hypothesis.  The proportion in the MUD group 
proceeding to transplant is estimated to be about 0.2000.  The test statistic used is the two-sided 
Fisher’s Exact test.  The significance level of the test is targeted at 0.0500. We will summarize 
subjects who drop-out and primary reason (i.e, disease progression, ineligible due to health, 
patient defers, insurance denial, physician choice) 
 
For those registered to transplant in the Transplant Phase, comparing the two graft sources is of 
considerable interest and will be analyzed by biologic choice (rather than by intent to treat by 

30 
randomization arm) MUD vs haplo-cord. We anticipate some patients, especially those 
randomized to MUD, will ultimately undergo haplo-cord. Occasionally, patients randomized to 
an immediate haplo-cord may pursue MUD. Specifically, we will compare acute toxicities 
including grade 3-5 non-hematologic toxicities, rates of full donor chimerism at day 100, overall 
survival, leukemia-free survival, non-relapse rates of aGVHD and cGVHD, days in the hospital 
and transfusion requirements within the first 100 days post-transplant. 
 
 Progression-free survival (time to relapse or death as a result of any cause) and overall survival 
will be computed using the Kaplan-Meier product-limit estimate and expressed as probabilities 
with a 95% CI.  Acute and chronic GVHD, treatment-related mortality will be estimated by 
cumulative incidence method. Cumulative incidence of treatment-related mortality with relapse 
of the original disease as the competing risk factor will be calculated. In order to compare the 
cumulative incidence curves, we will use Gray’s test.  Log rank test will be used to compare the 
Kaplan Meier curves.  Hazard ratios and appropriate confidence intervals will be estimated from 
Cox regression models. Multivariate models when needed will use Cox proportional hazards 
regression analysis. 
 
 
13. 
DATA, SAMPLE AND PROTOCOL MANAGEMENT 
 PROTOCOL COMPLIANCE:  Subjects will be reviewed weekly during admission 
by the study investigators who will score the patient for standard endpoints. After 
discharge they will be reviewed at least once a month. 
 
 DATA ENTRY: REDCap (Research Electronic Data Capture) is a free data 
management software system that is fully supported by the Weill-Cornell Medical 
Center CTSC.  It is a tool for the creation of customized, secure data management 
systems that include Web-based data-entry forms, reporting tools, and a full array of 
security features including user and group based privileges, authentication using 
institution LDAP system, with a full audit trail of data manipulation and export 
procedures.  REDCap is maintained on CTSC-owned servers that are backed up 
nightly and support encrypted (SSL-based) connections.  Nationally, the software is 
developed, enhanced and supported through a multi-institutional consortium led by 
the Vanderbilt University CTSA. 
 
 ACCURACY OF DATA COLLECTION The Study Chairman will be the final 
arbiter of toxicity should a difference of opinion exist 
 Management of Research samples: Research samples will be cryopreserved after 
ficolling and isolation of viable cells. The serum will be stored separately. Part of the 
product may be stored after DNA extraction. The samples will be stored securely. 
They will coded with the key to identification of the samples kept in a secure location 
and available only to the PI or his delegate. Samples and appropriate clinical 
information may be shared with other investigators at WCMC and elsewhere, but will 
be de-identified. Samples will be kept indefinitely.  
 

31 
14. 
DATA SAFETY MONITORING BOARD 
A Data Safety Monitoring Board (DSMB) is not required.  This protocol will undergo weekly 
review at the transplant program data and safety monitoring teleconference as per procedures 
specified by the UC CCC NCI-approved Data and Safety Monitoring Plan. The conference will 
review: 
 
 Enrollment rate relative to expectations, characteristics of participants 
 Safety of study participants (Serious Adverse Event & Adverse Event reporting) 
 Adherence to protocol (protocol deviations) 
 Completeness, validity and integrity of study data 
 Retention of study participants 
 
 
 
15. 
REGULATORY CONSIDERATIONS 
15.1. 
Institutional Review Board/Ethics Committee Approvals 
The protocol for this study has been designed in accordance with the general ethical principles 
outlined in the Declaration of Helsinki.  The review of this protocol by the IRB/EC and the 
performance of all aspects of the study, including the methods used for obtaining informed 
consent, must also be in accordance with principles enunciated in the declaration, as well as ICH 
Guidelines, Title 21 of the Code of Federal Regulations (CFR), Part 50 Protection of Human 
Subjects and Part 56 Institutional Review Boards. 
 
Unless otherwise specified, each participating institution must obtain its own IRB approval. It is 
expected that the IRB will have the proper representation and function in accordance with 
federally mandated regulations.  The IRB should approve the consent form and protocol.  
 
Any advertisements used to recruit subjects for the study must be reviewed and approved by the 
IRB/EC prior to use. 
 
15.2. 
Informed Consent Procedures 
The Treating Investigator must obtain informed consent of a subject or his/her designee prior to 
any study related procedure as per GCP’s as set forth in the CFR and ICH guidelines. 
 
Documentation that informed consent occurred prior to the subject’s entry into the study and the 
informed consent process should be recorded in the subject’s source documents.  The original 
consent form signed and dated by the subject and by the person consenting the subject prior to 
the subject’s entry into the study, must be maintained in the Investigator’s study files.   At the 
pre-admission consultation, patients will be fully informed as to the purposes and potential risks 
and benefits involved in this study. Patients will have ample opportunity to ask questions before 
consenting. Legal guardians will sign informed consent for legally incompetent patients in 
accordance with hospital policy. 
 

32 
15.3. 
Protecting Privacy and Confidentiality 
Confidentiality will be maintained within the limits of the law. Subject names or any other 
identifying information will not be used in reports or publications resulting from this study. Only 
qualified staff from New York Presbyterian Hospital, Weill Medical College of Cornell 
University, the Food and Drug Administration, or other study support such as the National 
Cancer Institute will be able to review subject medical records. 
 
Should direct access to medical records require a waiver or authorization separate from the 
subject’s statement of informed consent, it is the responsibility of the Investigator to obtain such 
permission in writing from the appropriate individual. 
 
15.4. 
Food and Drug Administration (FDA) Approval 
This study will be conducted under an IND held by Andrew Artz, MD at the University of 
Chicago.  The University of Chicago CCTO will be responsible for facilitating all 
communications with the FDA on behalf of the IND holder.   Participating sites should not 
communicate directly with the FDA.   
 
15.5. 
Study records requirements 
The Investigator must ensure that the records and documents pertaining to the conduct of the 
study and the distribution of the study drug, that is copies of CRFs and source documents 
(original documents, data, and records [e.g., hospital records; clinical and office charts; 
laboratory notes; memoranda; subject’s diaries or evaluation checklists; pharmacy dispensing 
records; recorded data from automated instruments; copies or transcriptions certified after 
verification as being accurate copies; microfiches; photographic negatives, microfilm, or 
magnetic media; x-rays; subject files; and records kept at the pharmacy, at the laboratories, and 
at medico-technical departments involved in the clinical study; documents regarding subject 
treatment and study drug accountability; original signed informed consents, etc.]) be retained by 
the Investigator for as long as needed to comply with national and international regulations 
(generally 2 years after discontinuing clinical development or after the last marketing approval).  
The Investigator agrees to adhere to the document/records retention procedures by signing the 
protocol. 
 
Before the study can be initiated at any site, the following documentation must be provided to 
the Cancer Clinical Trials Office (CCTO) at the University of Chicago Comprehensive Cancer 
Center. 
 
 A copy of the official IRB approval letter for the protocol and informed consent 
 IRB membership list 
 CVs and medical licensure for the principal investigator and any sub-investigators who 
will be involved in the study. 
 Form FDA 1572 appropriately filled out and signed with appropriate documentation  
 CAP and CLIA Laboratory certification numbers and institution lab normal values 
 Investigational drug accountability standard operating procedures 

33 
 Additionally, before the study can be initiated at any site, the required executed research 
contract/subcontract must be on file with the University of Chicago. 
 
15.6. 
Amendments to the Protocol 
All modifications to the protocol, consent form, and/or questionnaires will be submitted to the 
University of Chicago IRB for review and approval. A list of the proposed modifications or 
amendments to the protocol and/or an explanation of the need of these modifications will be 
submitted, along with a revised protocol incorporating the modifications. Only the Study Lead 
PI can authorize any modifications, amendments, or termination of the protocol. Once a protocol 
amendment has been approved by the University of Chicago IRB, the Regulatory Manager 
will send the amended protocol and consent form (if applicable) to the affiliate institutions 
electronically. Upon receipt of the packet the affiliate institution is expected to do the following: 
 
 The affiliate must reply to the email from the Regulatory Manager indicating that the 
amendment was received by the institution and that it will be submitted to the local IRB.  
 
 The amendment should be submitted to the affiliate institution’s IRB as soon as 
possible after receipt. The amendment must be IRB approved by the institution 
within 3 months from the date that it was received.  
 
 The  University  of  Chicago  version  date  and/or  amendment  number  must  appear  
on  the  affiliate consent form and on the affiliate IRB approval letter.  The version 
dates can be found on the footer of every page of the protocol and consent form.  The 
amendment number can be found on the University of Chicago IRB amendment 
approval letter that is sent with the protocol/amendment mailing.  
 
 The IRB approval for the amendment and the amended consent form (if amended 
consent is necessary) for the affiliate institution must be sent to the designated UC 
Regulatory Manager as soon as it is received.  
 
15.7. 
Annual IRB Renewals, Continuing Review and Final Reports 
A continuing review of the protocol will be completed by the University of Chicago IRB and 
the participating institutions’ IRBs at least once a year for the duration of the study. The 
annual IRB renewal approvals for participating institutions should be forwarded promptly to 
the Regulatory Manager. If the institution’s IRB requires a new version of the consent form 
with the annual renewal, the consent form should be included with the renewal letter. 
 
15.8. 
Protection of Human Rights 
Participation in this trial is voluntary. All subjects will be required to sign a statement of informed 
consent, which must conform to Weill Cornell Medical College IRB guidelines.  
 
Subjects will be eligible for this trial regardless of gender or racial/ethnic background.  
 
 

34 
 
 
 
 

35 
16. 
APPENDICES 
 
 
 
 
 

36 
APPENDIX A 
PRZEPIORKA CRITERIAFOR ACUTE GVHD 
 
Consensus Criteria for Grading of Acute GVHD 
 

37 
Appendix B 
Geriatric Assessment Tools 
 
Patient Report 
(P), Health Care 
team (H) 
Items 
Demographic and baseline 
P 
6 
Hematopoietic cell comorbidity index 
H 
17 
OARS Comorbidity 
P 
15-30 
MOS Physical function 
P 
10 
4 meter walk speed 
H 
3 
Grip strength 
H 
3 
Timed up and go 
H 
1 
Nutrition 
P 
3 
KPS patient 
P 
1 
KPS provider 
H 
1 
Polypharmacy 
P 
1-10 
MHI-17 
P 
17 
MOS social Activity Limitation Scale 
P 
4 
MOS social support 
P 
12 
Blessed Orientation Memory Concentration 
H 
6 
Survey feedback 
P 
7 
Medical Outcomes Study (MOS) 
OARS:Older American Resources and Services 
IADL: Instrumental Activities of daily living 
 
 
 

38 
 
 
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