Parallel Phase II Trial of IPA Targeted Adoptive Immunotherapy vs Adult Haplo-identical Cell Infusion During Induction of High Risk Leukemia
Phase: PHASE2
Conditions: Acute Myeloid Leukemia, Myelodysplastic Syndrome
Sponsor: Weill Medical College of Cornell University

Title: Parallel Phase II Trial of Adoptive Immunotherapy Targeted Against Inherited Paternal Antigens 
(IPA) vs Adult Haplo-Identical Cell Infusion During Induction of High Risk Leukemia or Myelodysplastic 
Syndrome 
NCT02508324 
Initial IRB Approval Date: 6/17/2015 
 
Amendment History 
• 
Original Protocol Date: 19MAY2015 
• 
Amendment #1: 22JUL2015 
• 
Amendment #2: 09NOV2017 
• 
Amendment #3: 03JUL2018 
• 
Amendment #4: 29OCT2019 
• 
Amendment #5: 26MAY2020 
• 
Amendment #6: 08SEP2020 
• 
Amendment #7: 15JUL2022 

  
i 
 
 
 
 
 
TITLE:  Parallel phase II trial of adoptive immunotherapy targeted against Inherited 
Paternal Antigens (IPA) vs adult haplo-identical cell infusion during induction of high risk 
leukemia or myelodysplastic syndrome; Version Date: July 15, 2022 
 
 
Principal Investigator: 
 
  Alexandra Gomez Arteaga, MD 
 
 
525 East 68th Street, Starr 3 
Telephone: (646) 962-7950 
Fax: (212) 746-6645 
 
 
alg9117@med.cornell.edu 
 
Co-Principal Investigators:  
 
Gail Roboz, MD 
 
 
 
 
 
 
 
525 East 68th Street, Starr 3  
 
 
 
 
Phone: (646) 962-2700  
 
 
 
 
 
Fax: (646) 962-1605 
 
 
 
 
 
 
gar2001@med.cornell.edu  
 
 
 
 
 
 
 
 
 
 
 
 
       
 
 Co-Investigators: 
 
Sebastian Mayer 
 
 
 
 
 
 
525 East 68th Street, Starr 3  
 
 
 
Phone: (646) 962-7950  
 
 
 
 
Fax: (212) 746-6678 
 
 
 
 
 
 
 
 
 
      sam2033@med.cornell.edu  
       
 
Ellen Ritchie, MD  
 
 
 
 
Melissa Cushing, MD 
1305 York Avenue, 7th Floor  
 
 
520 E. 70th St., Ste F-715 
Phone: (646) 962-2700  
 
 
 
Phone: (212) 745-3527 
Fax: (646) 962-1605 
 
 
 
 
Fax: (212) 746-8435 
ritchie@med.cornell.edu  
 
      mec2013@med.cornell.edu 
 
 
Joseph Scandura, MD, PhD  
 
 
Tsiporah Shore, MD 
 
 
 
525 East 68th Street  
 
 
 
 
525 E. 68th Street, Starr 3 
 
 
Payson Pavilion, 3  
 
 
 
 
Phone: (646) 962-7950  
Phone: (646) 962-2700  
 
 
 
Fax: (212) 746-6678 
Fax: (646) 962-1602 
 
 
 
 
Tbs2001@med.cornell.edu 
jms2003@med.cornell.edu  
 
 
 
 
       
 
 
Pinkal Desai, MD  
 
 
 
Adrienne Phillips, MD  
525 East 68th Street  
 
 
 
525 East 68th Street  
Payson Pavilion, 3  
 
 
 
Payson Pavilion, 3 
Phone: (646) 962-2700  
 
 
Phone: (646) 962-7950 
Fax: (212) 746-6645 
 
 
 
Fax: (212) 746-6678 
Pid9006@med.cornell.edu  
 
adp9002@med.cornell.edu 
 
 

 
 
 
 
 
Statistician: 
Study Coordinator: 
Paul Christos, PhD 
Melissa Lewis 
Phone: (646) 962-8018 
435 East 70tht Street, Room 4F 
Pac2001@med.cornell.edu  
Phone: (212) 746-2026 
 
mel2025@med.cornell.edu 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
i
 
 
SCHEMA 
 
STUDY SCHEMA 
 
1. 
INCLUSION/EXCLUSION: See Section 3 
 
ENROLLMENT: All potential recipients will have complete HLA typing (12 loci).  An 
appropriate umbilical cord blood unit (CBU) will be identified or in the absence of an appropriate 
CBU, a haplo-identical donor will be identified.  
 
INDUCTION THERAPY: 
Will be at treating physician’s choice, and could include cytarabine-daunorubicin (3+7). High dose 
cytarabine-mitoxantrone or other appropriate regimens.  For patients with MDS or AML patients 
considered unfit for intensive therapy, it can include treatment with hypomethylating agents.  
 
STEM CELL ADMINISTRATION 
Within 72 hours after completion of the chemotherapy regimen, and no sooner than 24 hours after 
administration of the last dose of chemotherapy, umbilical cord graft or haplo-graft will be 
administered. 
Supportive care and premedications for stem cell administration will be governed by current 
policies of transplant program.   
 
 
The choice between CBU vs Haplo-graft will be based on availability according to the table 
below. It may be further influenced by practical issues such as insurance approval etc.  
 
                                                      Graft selection algorithm 
1 
CBU Unit 5/6 Matched 
1 NIMA match with patient 
2 
CBU Unit 5/6 Matched 
Shared IPA target(s) with patient 
3 
Haplo Identical relative 
 
4 
CBU Unit 4/6 matched  
1-2 NIMA matches with patient 
5 
CBU Unit 4/6 matched 
Shared IPA target(s) with patient 
 
 
 
CBU UNIT     The CBU unit must supply a minimum of 0.5 x107/kg and a maximum of 2.5x107/kg 
nucleated cell dose pre-cryopreservation. The unit must match at a minimum of 4 of 6 at HLA-A, 
-B antigens, -DRB1 alleles with the recipient. Mismatches (0-2) can be at any loci -. Although 
molecular level typing will be available for the patient and the CBU unit, a match is defined at 
intermediate resolution for HLA-A and –B and at high resolution for –DRB1.  The CBU donor 
will also have undergone HLA typing of the mother, thus allowing determination of the CBU-IPA 
and NIMA. 
CBU grafts used in this study will be investigational units that meet all criteria for clinical use. 
Better matching units will be preferred over less matching units as long as the CBU dose exceeds 
0.5 x107 NBC/kg 
 

 
 
ii 
 
ALL RECIPIENTS SHOULD HAVE TESTING FOR CLASS I AND CLASS II HLA 
ANTIBODIES. IF ANTIBODIES ARE PRESENT, CBU SHOULD BE CHOSEN THAT ARE 
NOT TARGETED. THIS MAY REQUIRE DQ AND DP TESTING OF THE CBU.  
 
HAPLO UNIT 
Haplo identical healthy related donor. Ie. Parent, child, sibling, possibly third degree or farther 
removed relative (cousin, aunt, nephew etc…). 
They will be collected using standard methods and approximately 3 x10^6 CD34 cells/kg will be 
infused within 72 hours after completion of the treatment. 
 
Note: Excess cells collected from the haplo-identical donor will be cryopreserved and may be 
reinfused if deemed clinically necessary during subsequent off protocol treatments.  
 
Supportive Care and Management of Side Effects: 
 
Supportive care will follow the institutional standards of care for treatment of leukemia patients. 
(e.g. quinolone prophylaxis, antifungal prophylaxis, antiviral prophylaxis).  
In addition patients will be monitored weekly for CMV reactivation. CMV viremia will be 
treated appropriately. 
 
No GVHD prophylaxis will be administered, but patients will be closely monitored for signs and 
symptoms of GVHD. Suspicion for GVHD will be confirmed by biopsy. GVHD grade II and 
above will preferably be treated with a single dose of cyclophosphamide 50 mg/kg with mesna. 
 
 
 

 
 
iii 
 
 
TABLE OF CONTENTS 
 
 
Page 
SCHEMA ........................................................................................................................................ i 
 
1. OBJECTIVES ..........................................................................................................................1 
1.1 
Primary Objective .......................................................................................................1 
1.2 
Secondary Objectives ..................................................................................................1 
 
2. BACKGROUND ......................................................................................................................1 
2.1 
Acute Leukemia and MDS ..........................................................................................1 
2.2 
Adoptive immunotherapy in AML ............................................................................3 
2.3 
Umbilical Cord Blood Transplant and GVL Effect .................................................4 
2.4 
Rationale for the Current Study: Potential Benefits ................................................5 
2.5 
Rationale for the Current Study: Potential Risks ....................................................7 
2.6 
Preliminary Results November 2017 .........................................................................7 
 
 
3. PATIENT SELECTION .........................................................................................................8 
3.1 
Inclusion Criteria  ........................................................................................................8 
3.2 
Exclusion Criteria ........................................................................................................9 
 
4. ENROLLMENT AND REGISTRATION PROCEDURES ................................................9 
4.1  
Enrollment ....................................................................................................................9 
4.2  
Central Patient Registration .......................................................................................9 
 
5. TREATMENT PLAN ..............................................................................................................9 
5.1 
Induction Therapy .......................................................................................................9 
5.2 
Stem Cell Source and Cell Dose ...............................................................................10 
5.3 
CBU Unit ....................................................................................................................10 
5.4 
Haplo Unit ..................................................................................................................10 
5.5 
Supportive Care and Management of Side Effects .................................................11 
 
6. RECIPIENT PRE-TREATMENT EVALUATION ...........................................................13 
 
7. REQUIRED DATA ................................................................................................................13 
7.1  
Pre-Study Testing Interval ..............................................................................................15 
 
 
 
 
7.2  
CBU Graft Evaluation and Preparation Prior to Infusion ..........................................15 
7.3  
Haplo Donor and Product Evaluation Prior to Infusion ........................................15 
7.4  
Response Assessment .................................................................................................16 
 
8. ADVERSE EVENT REPORTING REQUIREMENTS .....................................................16 
8.1 
Investigational Risks ..................................................................................................16 
8.2 
Adverse Event Characteristics ..................................................................................16 
8.3 
Recording and Reporting of Adverse Events and SAEs ........................................17 

 
 
iv
 
 
9. CRITERIA FOR STUDY EVALUATION..........................................................................17 
 
10.  STATISTICAL CONSIDERATIONS ................................................................................19 
 
10.1    Sample Size Considerations .......................................................................................19 
 
10.2    Stopping Rules .............................................................................................................20 
 
10.3    Screening vs Treating .................................................................................................20 
 
 
11. CRITERIA FOR REMOVAL OF PATIENTS FROM PROTOCOL THERAPY .........21
 
 
11.1 
Duration of Treatment ..............................................................................................21 
 
12. DATA, SAMPLE, AND PROTOCOL MANAGEMENT ..................................................21 
 
 
13. DATA SAFETY MONITORING BOARD..........................................................................22 
 
14.0 REGULATORY CONSIDERATIONS .............................................................................22 
 
14.1    Institutional Review Board / Ethics Committee Approval .....................................22 
 
14.2    Informed Consent Procedures ...................................................................................22 
 
14.3    Protecting Privacy and Confidentiality.....................................................................23 
 
14.4    Study Records Requirements .....................................................................................23 
 
14.5    Protection of Human Rights.......................................................................................23 
 
 
 
 
 
REFERENCES .............................................................................................................................24 
 
 
 

 
 
  
1 
1. OBJECTIVES 
 
     1.1     Primary Objective  
  
To evaluate the safety of adoptive immunotherapy with Non-Inherited Maternal Antigen 
(NIMA) compatible, Inherited Paternal Antigen (IPA) targeted CBU or with haplo-
identical stem cells after conventional induction therapy for very high risk Acute Myeloid 
Leukemia (AML) or Myelodysplastic Syndrome (MDS). 
 
     1.2     Secondary Objectives 
 
a) To assess the incidence and severity of Graft Versus Host Disease (GVHD), after 
conventional induction therapy followed by adoptive immunotherapy with NIMA 
compatible, IPA targeted CBU. 
 
b) To assess the incidence and severity of GVHD, after conventional induction therapy 
followed by adoptive immunotherapy with haplo-identical stem cells. 
 
c) To study kinetics of graft chimerism (including UCBM-microchimerism) after each of 
these treatments 
 
d) To study development of HLA-antibodies after each of these treatments 
 
e) To assess response rates and duration of response after each of these treatments  
 
f) To assess the utilization of unrelated, low cell dose CBU as adoptive immunotherapy 
for AML 
 
 
2. BACKGROUND 
 
2.1     Acute Leukemia and MDS 
 
Acute leukemia and MDS used to be invariably fatal diseases, but over the past 
decades, outcomes have much improved.1-3 Younger patients and those with favorable 
features can often be cured; for older patients and those with unfavorable features 
induction of remission and prolongation of life has become a realistic goal of treatment. 
But survival and quality of life tend to correlate with induction of response. 
Approximately 60% of patients obtain first remission after initial treatment and have a 
reasonable prognosis. Those failing to obtain a first remission have a poor prognosis.  
Well defined unfavorable characteristics include older age, monosomal karyotype and 
complex karyotype.4;5Patients who have achieved an initial CR to conventional therapy 
and relapse within less than a year from diagnosis, also have less than 20% chance of 
obtaining a second remission. 
 

 
 
2
 
Over the past decade hypomethylating agents (azacytidine and deoxyazacytidine) have 
been shown to induce remissions and prolong survival in older patients with AML and 
MDS. But remissions are not durable and upon disease progression, outcomes are poor. 
 
Remission rates upon reinduction with conventional chemotherapy are low and median 
overall survival is in the range of three to four months.    
 
 
Outcome of patients with AML and/or  MDS who fail hypomethylating agents  
Author 
Nr of pts 
Median Survival  
CR/CRp 
Prebet (MDS)6 
435 
5.6 months 
14% 
Prebet(AML)7 
74 
3 months 
none 
Bello8 
25 
3.7 months 
30% 
Jabbour9 
87 
4.3 months 
20% 
Ritchie10 
81* 
5 mo** 
 
*patients who failed induction with hypomethylating agents.** from start of 
hypomethylating agent. 
 
 
In a somewhat similar analysis, the MD Anderson Cancer Center group has analyzed the 
outcome of patients with AML undergoing second salvage therapy, and identified 
prognostic factors associated with remission and survival in a cohort of 594 patients. 
Salvage therapy included Allogeneic Stem Cell Transplantation (SCT) in 74 patients, 
standard-dose ara-C combinations in 30 patients, high-dose ara-C combinations in 171 
patients, non-ara-C combinations in 73 patients, and phase I-II single agents in 246 
patients. Overall, 76 patients (13 %) achieved Complete Remission (CR).  The median 
CR duration was 7 months. The median survival was 1.5 months, and the 1-year survival 
rate was 8 %.  A multivariate analysis of prognostic factors for CR identified the 
following 6 independent adverse factors: (1)CR1 duration < 6 months; (2)CR2 duration < 
6 months; (3) salvage therapy not including allogeneic SCT;  (4)non-inversion 16 AML; 
(5) platelet counts < 50 x 109/L, and (6) leukocytosis > 50 x 109/L. Patients were divided 
into low-risk (1-2 adverse factors; 8 %), intermediate 1 (3 factors; 20 %), intermediate 2 
(4 factors; 38 %), and high-risk groups (5-6 factors; 33 %) with respective CR rates of 
54 %, 26 %, 8 %, and 0 %. The respective 1-year survival rates were 36 %, 21 %, 6 %, 
and 1 %.  A multivariate analysis for survival identified the following 6 independent 
adverse factors: (1) CR1 duration < 12 months; (2) CR2 duration < 6 months; (3) 
bilirubin level ≥ 1 mg/dL; (3) albumin level < 3 g/dL; (4) age > 60 years; (5) bone 
marrow blasts ≥ 50 %; and (6) year of therapy before 1991. Patients were divided into 
low-risk (0-2 adverse factors; 39 %), intermediate (3 factors; 27%), and high-risk groups 
(≥ 4 factors; 34 %) with estimated 1-year survival rates of 22 %, 6 %, and 0 %, 
respectively.  
 
The proposed study will focus on this subgroup of patients who have limited treatment 
options. 
 

 
 
3
 
2.2   Adoptive immunotherapy in AML  
 
Cellular therapy, particularly as used in allogeneic transplantation, is an established 
treatment for AML.11 So-called Graft-Versus-Leukemia (GVL) effects can be powerful 
mediators of anti-leukemic therapy. Unfortunately, because of its associated toxicities 
and the difficulties in finding matching donors, allogeneic transplant is applicable to 
only a minority of patients. Typically, it is offered to those with an excellent 
performance status, who have compatible donors and who have achieved at least some 
disease control, preferably CR. Those who fail to achieve a complete remission are not 
often considered for transplant, and if they are, their outcome is far inferior.12 
 
Several groups have recently reported on the value of adoptive cellular therapy during 
induction. In those circumstances, the graft is thought to mediate transient GVL effects 
and then be rejected. Colvin et al, reported a pilot study of haploidentical cell infusion 
in a Phase I/II nonimmunosuppressive, nonmyeloablative setting.13 A total of 41 
patients with relapsed refractory cancer received 100 cGy of total body irradiation 
(TBI), along with an infusion of haplo-identical cells. There were 26 patients with 
hematologic malignancies with 14 responses, 9 of which were major; there were 5 
durable complete responses and 4 partial responses in 13 patients with acute 
myelogenous leukemia (AML). All responses occurred without overt donor chimerism.  
 
Guo et al reported fifty-eight AML patients aged 60-88 years who were randomly 
assigned to receive induction chemotherapy with cytarabine and mitoxantrone or the 
same chemotherapy plus G-CSF mobilized HLA-haplo-identical stem cells(G-PBSC).14  
Patients who achieved complete remission received another 2 cycles of post remission 
therapy with intermediate-dose cytarabine or the same chemotherapy plus G-PBSCs. 
The complete remission rate was significantly higher in the G-PBSC group than in the 
control group (80.0% vs 42.8%; P < .006). The median recovery times of neutrophils 
and platelets were 11 days and 14.5 days, respectively in the G-PBSC group and 16 
days and 20 days, respectively, in the control group after chemotherapy. The 2-year 
probability of disease-free survival was significantly higher in the G-PBSC group than 
in the control group (38.9% vs 10.0%; P < .01). No graft-versus-host disease was 
observed in any patient. Persistent donor microchimerism was successfully detected in 
the 4 female patients who received cells from male donors.  
 

 
 
4
 
The studies from these groups, 
though preliminary studies, 
suggest that GVL effects can 
contribute to induction of 
remission and that they may be 
operative with minimal or 
transient evidence of chimerism. 
Indeed, transient or mixed 
chimerism may be preferable 
because it is associated with less 
risk for acute or chronic 
GVHD.15;16 
2.3 
Umbilical Cord Blood 
Transplant and GVL Effect 
 
Several groups, including our 
own, have shown decreased rates 
of disease recurrence after 
umbilical cord blood transplantation compared to unrelated donor transplant.17 (and 
Delaney, personal communication). The reasons for the reduced rate of disease 
recurrence after CBU transplant have until recently remained elusive, but may be 
explained by the presence in the umbilical cord graft of a substantial number of 
lymphocytes of maternal origin that are primed against the paternal HLA-haplotype of 
the fetus (the inherited paternal antigen or IPA). The first indication of this mechanism 
came from the observation by Mold et al that fetal lymphoid organs including the 
lymph nodes and blood contain between 0.1% and 0.5% lymphocytes of maternal 
origin.18 These lymphocytes are protected from immune-mediated destruction by the 
presence of a very high number of fetal T-regulatory cells.  Van Rood et al speculated 
that the IPA-primed maternal cells were responsible for the GVL activity of the cord 
and that a similar mechanism explained why haplo-identical transplant from a mother 
to her child is associated with less relapse than that from a father.  In an elegant study, 
they analyzed for a large number of CBU transplants, the HLA type of both mother and 
CBU and deduced the IPA of the CBU.19  Then, they identified transplant cases with 
IPA targeting CBU (i.e cases in which the maternal lymphocytes would be primed 
against the IPA of the CBU and also against the recipient.) They compared their 
outcome with that of the cases where there was no IPA reactivity and found a much 
increased rate of disease recurrence in the latter. This phenomenon was mostly 
observed in recipients of well-matched transplants (5/6 matched). Importantly, the 
decreased recurrence rate after IPA targeted CBU-SCT was not associated with 
increased GVHD.   
 
Another set of HLA molecules, the NIMA (non-inherited maternal antigens, i.e 
antigens absent from the CBU cells, but present in the mother of the fetus), also merit 
consideration. The CBU cells have been exposed to these NIMAs throughout their life 
span (throughout pregnancy), and therefore are tolerant to them. In the setting of CBU 
stem cell transplant, the presence of NIMA in the transplant recipient results in 
 
Figure 1: Time to relapse for patients with myelogenous 
malignancies. Zero HLA mismatch (MM) = 33; one MM/NIMA 
match = 13; two MM/NIMA match = 31; one MM/no-NIMA 
match = 193; two MM/no-NIMA match = 343.  

 
 
5
 
improved transplant outcomes even when grafts with low TNC doses were used.19 
(Figure 1) 
 
 
2.4 Rationale for the Current Study: Potential Benefits 
 
Preliminary data indicates that adoptive cellular therapy with partially matched cells is an 
effective approach that may improve remission rates and survival in AML and MDS. 
Rates of remission and survival for patients with AML and MDS who fail 
hypomethylating agents are extremely poor.  We have focused on this well-defined 
subgroup for our initial studies.  
 
The majority of preliminary data on adoptive immunotherapy derives from infusion of 
haplo-identical cells after induction therapy. Organization of haplo-identical cell therapy 
during remission induction of acute leukemia may pose considerable logistical problems 
in the United States. For example, only a small minority of older patients have siblings 
that can be readily tested. 20 Children, who could serve as haplo-identical donors, are 
often not readily available for a variety of reasons, such as remote distances, socio-
economic issues, health etc.  An increasing number of people- up to 20%- also remain 
childless - a percentage that is likely to increase given recent demographic trends.21  
Logistical, financial and availability issues thus limit the practicality of this type of 
intervention. Lastly, recent data suggest that genomic loss of is an extremely common 
mechanism of escape of tumor surveillance from the GVL effects mediated by partially 
mismatched grafts.22  
 
As an alternative, we are interested in exploring the utility of  umbilical cord blood 
infusion as a means of inducing antileukemic effects. Umbilical cord blood cells are 
banked and readily available and because of IPA-mediated effects have potent 
antileukemic effects and cause less GVHD, and may therefore be superior at inducing 
remissions compared to haplo-identical grafts.  These IPA-mediated GVL effects were 
mostly detected in recipients of 5/6 matched grafts. Low resolution and partial HLA- 
matching is sufficient for identification of an appropriate umbilical cord blood unit. Since  
 
The likelihood of finding CBU grafts of different cellular content and degree of matching 
for various ethnic groups are shown in Table 1 (M Maiers, personal communication). 5/6 
HLA matched cords can be found in up to 75% of patients of most ethnic groups, if 
smaller than customary cell doses are accepted; 4/6 matched CBU can be identified for 
nearly all patients.  
 
Table 1: Likelihood of identifying an CBU graft for various ethnic groups, based on 
current inventory size and cell does requirement. 
 
 
HLA 5/6 matched graft 
HLA 4/6 matched graft 
 
TNC2.5 TNC1.5 
TNC0.5 
TNC2.5 
TNC1.5 
TNC0.5 
AAFA 
0.20 
0.51
0.74
0.77
0.98 
1.00 
AFB 
0.19 
0.51
0.73
0.76
0.98 
1.00 

 
 
6
 
CARB 
0.20 
0.52
0.74
0.76
0.98 
1.00 
SCAMB 
0.23 
0.54
0.74
0.78
0.98 
1.00 
AINDI 
0.35 
0.70
0.86
0.86
0.99 
1.00 
FILII 
0.32 
0.72
0.89
0.83
0.99 
1.00 
HAWI 
0.25 
0.57
0.76
0.78
0.97 
1.00 
JAPI 
0.29 
0.68
0.87
0.83
0.99 
1.00 
KORI 
0.32 
0.70
0.88
0.85
0.99 
1.00 
NCHI 
0.33 
0.72
0.89
0.85
0.99 
1.00 
SCSEAI 
0.30 
0.65
0.83
0.85
0.99 
1.00 
VIET 
0.32 
0.69
0.86
0.83
0.99 
1.00 
MENAFC 
0.42 
0.74
0.88
0.89
0.99 
1.00 
EURCAU 
0.63 
0.89
0.96
0.95
1.00 
1.00 
CARHIS 
0.36 
0.70
0.86
0.87
0.99 
1.00 
MSWHIS 
0.40 
0.75
0.89
0.89
0.99 
1.00 
SCAHIS 
0.40 
0.74
0.88
0.89
0.99 
1.00 
AISC 
0.50 
0.79
0.90
0.91
0.99 
1.00 
ALANAM 
0.42 
0.73
0.88
0.89
0.99 
1.00 
AMIND 
0.50 
0.80
0.92
0.92
1.00 
1.00 
CARIBI 
0.30 
0.62
0.81
0.83
0.99 
1.00 
 
 
 
 
Population 
Broad race 
Description 
AAFA 
AFA (African American) 
African American 
AFB 
African 
CARB 
Black Caribbean 
SCAMB 
Black South or Central American 
AINDI 
API (Asian or Pacific Islander) 
South Asian 
FILII 
Filipino 
HAWI 
Hawaiian/other Pacific Islander 
JAPI 
Japanese 
KORI 
Korean 
NCHI 
Chinese 
SCSEAI 
Other Southeast Asian 
VIET 
Vietnamese 
MENAFC 
CAU (Caucasian) 
Mideast/North Coast of Africa 
EURCAU 
European Caucasian 
CARHIS 
HIS (Hispanic) 
Caribbean Hispanic 
MSWHIS 
Mexican or Chicano 
SCAHIS 
South or Central Amer. Hispanic 
AISC 
NAM (Native American) 
Amer. Indian South or Central America 
ALANAM 
Alaska Native or Aleut 
AMIND 
North American Indian 
CARIBI 
Caribbean Indian 
 

 
 
7
 
In this initial study, we propose to utilize either haplo-identical cells or CBU cells 
depending on availability and our selection criteria. This will allow us to compare in a 
preliminary fashion the toxic (GVHD, myelosuppression, development of HLA 
antibodies to the donor) and therapeutic effects (count recovery, response rate) of each of 
these products.  
 
The biological effects of the CBU infusions is immunologically and largely T-cell mediated. 
Moderate doses of T-cells as low as 0.2-1x106 CD3/kg(recipient) have been associated with 
beneficial effects in the adoptive therapy of viral diseases and likely also mediate GVL effects.23  
Approximately 30 % of the cellular content of a CBU unit consists of Tcells. CBU with a cell 
dose as low as 5x106/kgr  nucleated cells will be permissible.  The highest acceptable nucleated 
cell dose will be 25x106/kgr  
 
2.5 Rationale for the Current Study: Potential Risks 
 
The risks of adoptive cell therapy include the development of graft vs host disease, prolongation 
of myelosuppression and development of donor specific antibodies that may interfere with 
further therapy. A syndrome akin to engraftment syndrome, but seemingly mediated by other 
cytokines and labeded “haplo-immunostorm” has also been described.13 Based on preliminary 
experience by others, we believe that such risks are extremely low.14 Nevertheless, a major goal 
of the proposed studies is to detect toxicities and stopping rules are incorporated in case of 
excessive toxicity.  
 
2.6 Preliminary Results November 2017 
 
As of July 2017, ten patients have been treated with the CBU graft (Table); 8 had AML, 7 with 
primary induction failure (PIF); one had myeloid blast phase CML and one with high risk MDS. 
Nine patients had poor risk karyotype and 4 had prior allografts. Median age was 52 years 
(range: 34-67); median number of prior treatments was 11 (2-15) and median HSCT-CI was 3 
(0-7). 
 
No CBU infusion reactions or cytokine release syndrome were observed. One patient, recipient 
of a prior allograft with no history of GVHD, experienced skin rash 1 week after CBU infusion. 
The skin biopsy was consistent with GVHD. No GVHD was observed in the other 9 patients. 
One patient died of disseminated adenovirus infection early after treatment, viremia was present 
at the initiation of chemotherapy.  
 
Transient CBU chimerism was detected in 5 of the 10 patients as early as one week and as late as 
6 months after CBU infusion. The median bone marrow blast percentage before treatment was 
27% (range: 10-98) and at one month +/- 7 days post treatment was 8% (range: 0-90). Five 
patients had objective hematologic responses, 4 with aplasia and one with a partial response, 
while 5 patients recovered with persistent leukemia. Six patients went on to receive 
hematopoietic stem cell transplants (HSCT). Two subsequently relapsed and one died of 
disseminated adenovirus, while 3 patients remain in remission. These three patients also remain 
in remission as of November 09, 2017. These data will be presented at the ASH meeting in 2017, 
Three additional patients have been treated since then, though follow-up is short, two additional 

 
 
8
 
remissions have been observed in very heavily pretreated patients. One of the latter patients 
developed grade IV GVHD which has been reversed.  
 
 
 
3. PATIENT SELECTION 
 
3.1 Inclusion Criteria (Modified 5/26/2020) 
Patients can be of any race and either gender and must meet all of the following criteria to 
be eligible for participation in this study.  
1. Patients must be 18 years of age or older 
2. Patients with a confirmed diagnosis of AML or MDS, according to WHO classification 
(excluding acute promyelocytic leukaemia) with recurrent or refractory disease as 
defined below.  
a. For AML: 
(1) Primary induction failure (PIF) after ≥ 2 cycles of chemotherapy. 
  
(2) First relapse -only if occurring within 12 months from initial induction therapy. 
(3) Relapse refractory to salvage chemotherapy  
(4) Second or subsequent relapse.  
 
Patients who fail targeted agents including IDH1, IDH2 or FLT3 inhibitors will 
be eligible if they fulfill other eligibility criteria. 
Patients who fail venetoclax based therapy will be eligible if they fulfill other 
eligibility criteria. 
 
b. For MDS, either RAEB I or RAEB II who failed at least one chemotherapy 
regimen including either cytarabine or a hypomethylating agent.  
Failure of cytarabine or hypomethylating agent will include patients who fail to 
achieve PR after four cycles of treatment. 
 
Addendum 5/26/2020 
Patients who fail targeted agents including IDH1, IDH2 or FLT3 inhibitors will be 
eligible if they fulfill other eligibility criteria.  
Patients who fail venetoclax based therapy will be eligible if they fulfill other eligibility 
criteria.  
 
3. Patients must have Karnofsky Performance score of ≥70 
4. Women of child-bearing potential must have a negative serum or urine pregnancy test 
within 2 weeks prior to treatment start  
5. Patients must be capable of understanding and complying with protocol requirements, 
and must be able and willing to sign a written informed consent form 
  
 

 
 
9
 
 
3.2     Exclusion Criteria 
Patients who meet any one of the following criteria will not be eligible for study 
participation 
1. Persistent clinically significant toxicities from previous chemotherapy  
2. Known positive status for human immunodeficiency virus (HIV)  
3. Pregnant and nursing patients 
4. Uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, or 
psychiatric illness/social situations that would limit compliance with study requirements 
5. Impairment of hepatic or renal function to such an extent that the patient, in the opinion 
of the investigator, will be exposed to an excessive risk if entered into this clinical study  
6. Active heart disease including myocardial infarction within previous 3 months, 
symptomatic coronary artery disease, arrhythmias not controlled by medication, or 
uncontrolled congestive heart failure. Any NYHA grade 3 or 4.  
7. Any medical condition which in the opinion of the investigator places the patient at an 
unacceptably high risk for toxicities 
Note: AML and MDS are life-threatening diseases and participation in this protocol may at times 
constitute the treatment option most likely to benefit a particular patient. Therefore, the exclusion 
criteria may be waived if - in the opinion of the referring leukemia specialist and the transplant 
team - this constitutes the best therapeutic option.  
 
 
4.0 ENROLLMENT AND REGISTRATION PROCEDURES 
 
4.1 Enrollment  
 
All potential recipients will have complete HLA typing and determination of HLA 
antibodies.  An appropriate umbilical cord blood unit (CBU) will be identified or in the 
absence of an appropriate CBU, a haplo-identical donor will be identified.  
  
 4.2  Central Patient Registration 
 
Subjects will be registered within the WRG-CT as per the standard operating 
procedure for Subject Registration. 
 
5. TREATMENT PLAN 
 
5.1 Induction therapy  
 
Will be at treating physician’s choice and could include cytarabine-daunorubicin (3+7). 
High dose cytarabine-mitoxantrone or other appropriate regimens.5;24  For patients with 
MDS or AML patients considered unfit for intensive therapy, it can include treatment 
with hypomethylating agents.  

 
 
10
 
5.2 Stem Cell Source and Cell Dose 
Within 72 hours after completion of the chemotherapy regimen, and no sooner than 24 
hours after administration of the last dose of chemotherapy, umbilical cord graft or haplo-
graft will be administered.  
Supportive care and premedications for stem cell administration will be governed by 
current policies of transplant program.   
 
 
 
The choice between CBU vs Haplo-graft will be based on availability according to the table 
below. It may be further influenced by practical issues such as insurance approval etc.  
 
                                                      Graft selection algorithm 
1 
CBU Unit 5/6 Matched 
1 NIMA match with patient 
2 
CBU Unit 5/6 Matched 
Shared IPA target(s) with patient 
3 
Haplo Identical relative 
 
4 
CBU Unit 4/6 matched  
1-2 NIMA matches with patient 
5 
CBU Unit 4/6 matched 
Shared IPA target(s) with patient 
 
 
 
5.3 CBU UNIT     The CBU unit must supply a minimum of 0.5 x107/kg and a maximum of 
2.5x107/kg nucleated cell dose pre-cryopreservation. The unit must match at a minimum of 4 of 6 
at HLA-A, -B antigens, -DRB1 alleles with the recipient. Mismatches (0-2) can be at any loci -. 
Although molecular level typing will be available for the patient and the CBU unit, a match is 
defined at intermediate resolution for HLA-A and –B and at high resolution for –DRB1.  The CBU 
donor will also have undergone HLA typing of the mother, thus allowing determination of the 
CBU-IPA and NIMA. 
CBU grafts used in this study will be investigational units that meet all criteria for clinical use. 
Better matching units will be preferred over less matching units as long as the CBU dose exceeds 
0.5 x107 NBC/kg 
 
ALL RECIPIENTS SHOULD HAVE TESTING FOR CLASS I AND CLASS II HLA 
ANTIBODIES. IF ANTIBODIES ARE PRESENT, CBU SHOULD BE CHOSEN THAT ARE 
NOT TARGETED. THIS MAY REQUIRE DQ AND DP TESTING OF THE CBU.25-27 
 
5.4   HAPLO UNIT 
Haplo-identical healthy related donor. i.e. Parent, child, sibling, possibly third degree or further 
removed relative (cousin, aunt, nephew etc) 
They will be collected using standard methods and approximately 3 x10^6 CD34 cells/kg will be 
infused within 72 hours after completion of the treatment. 
 
Note: Excess cells collected from the haplo-identical donor will be cryopreserved and may be 
reinfused if deemed clinically necessary during subsequent off protocol treatments.  
 

 
 
11
 
5.5   Supportive Care and Management of Side Effects including Engraftment, GVHD and 
Haplo-Immunostorm. Modified 5/26/2020 
 
Supportive care will follow the institutional standards of care for treatment of leukemia patients. 
(e.g. quinolone prophylaxis, antifungal prophylaxis, antiviral prophylaxis).  
In addition patients will be monitored weekly for CMV reactivation. CMV viremia will be 
treated appropriately. 
 
Modified 5/26/2020 
No GVHD prophylaxis will be administered, but patients will be closely monitored for signs and 
symptoms of GVHD. Suspicion for GVHD will be confirmed by biopsy. GVHD grade II and 
above will preferably be treated with a single dose of cyclophosphamide 50 mg/kg.  Subsequent 
treatment, if required, will follow standard transplant SOP and will include high dose steroids 
(0.5 mg/kg-2 mg/kg depending on severity). Administration of high dose cyclophosphamide may 
not always be feasible and in such cases, steroids will be the first line of therapy. 
 
GVHD Prophylaxis and Treatment. Added 5/26/20 
Complete and durable donor chimerism has been observed in minority of patients. This has been 
associated with a high incidence of grade 3 and 4 acute GVHD.  
The observation of >50% donor chimerism at any time after graft infusion will lead to institution 
of GVHD prophylaxis preferably  with calcineurin inhibitors. Alternatives include mTor 
inhibitors, steroids and/or mycophenolate. 
 
Haplo-immunostorm Modified 5.26.20. 
Haplo-immunostorm defined by fever, rash, diarrhea and liver function abnormalities without 
histological evidence for GVHD is a syndrome very similar to cytokine release syndrome.  
It will be graded and managed in a similar fashion. (Lee DW, Santomasso BD, Locke FL, et al. 
ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated 
with Immune Effector Cells. Biol Blood Marrow Transplant 2019;25:625-38.) and Table below 
 
 
 

 
 
12
 
Grading of Cytokine Release Syndrome (CRS) (ASBMT CRS Consensus Grading)13 
 
Parameter 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Fever* 
> 38° 
> 38° 
> 38° 
> 38° 
Hypotension 
None 
Not requiring 
vasopressors 
Requiring 
vasopressors 
with or without 
vasopressin 
Requiring 
multiple 
vasopressors 
(exluding 
vasopressin) 
And/or 
Hypoxia** 
None 
Requring low‐flow 
nasal cannula*** or 
blow‐by 
Requiring high‐
flow nasal 
cannula, 
facemask, 
nonrebreather 
mask, or 
Venturi mask 
Requiring 
positive 
pressure (eg, 
CPAP, BiPAP, 
intubation and 
mechanical 
ventilation) 
 Organ toxicities associated with CRS may be graded according to CTCAE v5.0 but they do not influence CRS grading. 
* Fever is defined as temperature >= 38°C not attributable to any other cause. In patients who have CRS then receive antipyretics or anticytokine 
therapy such as tocilizumab or steroids, fever is no longer required to grade subsequent CRS severity. In this case, CRS grading is driven by 
hypotension and/or hypoxia. 
** CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. For example, a patient with 
temperature of 39.5° C, hypotension requiring 1 vasopressor, and hypoxia requiring low-flow nasal cannula is classified as grade 3 CRS. 
*** Low-flow nasal cannula is defined as oxygen delivered at 6 L/minute. Low flow also includes blow-by oxygen delivery, sometimes used in 
pediatrics. High-flow nasal cannula is defined as oxygen delivered at >6 L/minute. 
Vasopressin is not included in the assignment of CRS grade 
Grade 5 CRS: By convention, grade 5 CRS is defined as death due to CRS in which another 
cause is not the principle factor leading to this outcome 
CRS Management by Grade 
Grade 
Management 
Grade 1 
 Provide symptomatic support: 
- Administer antipyretics around the clock, if necessary 
- Administer oxygen, pain meds, intravenous fluids as needed  
- Empiric broad spectrum antibiotics if neutropenic 
 Consider tocilizumab for persistent (> 3 days) or refractory fever 
Grade 2 
 Provide symptomatic support as in Grade 1 
 Consult ICU Triage 
 Start continuous cardiac telemetry and continuous pulse oximetry  
 Start supplemental oxygen 
 If hypotensive, give fluid bolus of 500-1000 mL 

 
 
13
 
Grade 3 
 Continue Grade 1 and 2 measures 
 Manage hypoxia and hypotension with supportive care measures as needed 
 If hypotensive after 2 boluses, start vasopressors and consider transfer to ICU 
 Consider tocilizumab; repeat up to every 8 hours if not responsive to intravenous 
fluids or supplemental O2. Limit to a maximum of 3 doses in a 24-hour period; 
maximum total of 4 doses 
 If hypotension persists after 1-2 doses of tocilizumab or there are signs of hypo-
perfusion or rapid deterioration, start dexamethasone 10mg Q6hr2 
 Consider G-CSF if neutropenic3 
Grade 4 
 Administer tocilizumab if not done earlier 
 Start methylprednisolone 1000 mg IV Q24H2 
 
 
 
6.0   RECIPIENT PRE-TREATMENT EVALUATION 
. 
1. Medical history, physical examination, vital signs, height and weight. 
2. Karnofsky Performance Status. 
3. CBC with differential and platelet count, serum creatinine, bilirubin, alkaline phosphatase, 
ALT, and AST. 
4. CMV antibody test, hepatitis panel (HepA Ab, HepB Sab, HepB Sag, HepB Core Ab, 
HepCAb), herpes simplex, syphilis, HIV and HTLV 1 antibody, and varicella zoster virus. 
5. High resolution HLA typing, if not already performed. 
6. Bone marrow aspirates for pathology and cytogenetics and/or biopsy, for patients with 
<10% circulating peripheral blasts. 
7. CMV PCR, EBV PCR 
8. HLA antibodies  
9. Assessment of disease status (bone marrow, cytogenetics, molecular testing etc..) within 
30 days prior to start of chemotherapy. 
10. CRP, ESR (erythrocyte sedimentation rate), procalcitonin 
11. Serum cytokine levels (IL1, IL6,TNF,  TNFR1, REG3 alpha, ST2) (Samples to be drawn 
and stored for later analysis) 
 
7.0   REQUIRED DATA 
 
7.1 Pre-Study Testing Intervals 
To be completed within 30 DAYS before infusion of stem cells: 
- All bloodwork 
- History and physical 
- bone marrow 
 
All others to be completed within 42 DAYS before infusion of stem cells: 
 

 
 
14
 
Tests 
& 
Observations 
on 
patient 
Prior 
to 
infusion of 
stem cells 
Day 0-Day 60 
Beyond day 60 
(only if evidence of 
donor chimerism) 
Informed Consent 
X 
 
 
History and Progress Notes 
X 
A ☻ 
E 
Physical Examination 
X 
A☻ 
E 
Height 
X 
 
 
Weight/Body Surface Area 
X 
 
 
Karnofsky Performance Status 
X 
 
E 
Drug Toxicity Assessment 
 
B 
 
GVHD/Engraftment Syndrome 
assessment 
 
B 
E 
Laboratory Studies 
CBC, Differential, Platelets 
X 
A 
E 
Serum Chemistry ** 
X 
B 
E 
Uric Acid 
X 
 
E 
Magnesium 
X 
 
E 
PT (INR), PTT, Fibrinogen 
X 
 
 
Urinalysis 
X 
 
 
EBV PCR 
X 
B 
E 
CMV PCR 
X 
B 
 
Lymphocyte subsets (laboratory 
tests 17603138 and 17603144) 
X 
D 
E 
Chimerism Peripheral Blood 
X 
C 
E 
ESR, CRP, procalcitonin 
X 
D 
E 
HLA antibodies 
X 
 
F 
CMV antibody test, hepatitis 
panel (HepA Ab, HepB Sab, 
HepB Sag, HepB Core Ab, 
HepCAb), 
herpes 
simplex, 
syphilis, HIV and HTLV 1 
antibody, and varicella zoster 
virus 
X 
 
 
 
Chest x-ray or Chest CT 
X 
 
 
Staging 
Bone Marrow Asp,biopsy with 
cytogenetic and Flow  and 
chimerism† 
X*** 
Before day 60 
 
Correlative Laboratory studies 
Microchimerism* 
 
C 
E 
Serum Cytokine level ((IL1, 
IL6,TNF,  TNFR1, REG3 alpha, 
X* 
D* 
E* 

 
 
15
 
Tests 
& 
Observations 
on 
patient 
Prior 
to 
infusion of 
stem cells 
Day 0-Day 60 
Beyond day 60 
(only if evidence of 
donor chimerism) 
ST2) 
(sample 
stored 
for 
subsequent analysis) 
† A bone marrow biopsy is required for response assessment in the event of a dry tap or an 
aspiration that is inadequate for interpretation. 
 
A: At least twice weekly. 
B: At least weekly starting on day of infusion 
C: Weekly until day 60. Every two months thereafter until one year after cell infusion. 
D: Every two weeks until Day 60. Lymphocyte subsets are performed only at Day 28.  
E:  At least monthly until Day 180 and at least every two months thereafter until one year. 
Lymphocyte subsets are performed only at Day 100, Day 180, and 1 year.  
F: Performed only at Day 100☻Physical exam and history will focus on signs and symptoms of 
GVHD 
*microchimerism assays will be performed in selected cases of CBU infusion and based on HLA 
type of recipient, CBU unit and Mother of the CBU donor. 
**Serum chemistry to include BUN, creatinine, electrolytes, alanine aminotransferase, aspartate 
aminotransferase, alkaline phosphatase, total bilirubin, calcium, glucose, total protein, and 
albumin. 
***Not required for subjects with ≥ 10% circulating peripheral blasts observed on manual 
differential. 
 
7.2 CBU Graft Evaluation and Preparation Prior to Infusion: 
Upon thawing and prior to infusion, CBU will be evaluated by  
 Viability testing (including 7AAD, CFU) 
 Cell Subset determination  including at least CD3, CD34 –consider CD19, 
CD4, CD8 
 CBUs will be washed prior to infusion. 
 Sample for microchimerism  (selected cases, based on maternal  and fetal 
HLA type) 
 
7.3 Haplo Donor and Product Evaluation Prior to Infusion. 
Haplo donor evaluation will follow the routine transplant program policies. This 
will include screening for COVID (PCR test) as stipulated in Transplant Policies. 
 
Haplo product may be infused fresh, after washing, or using bedside thaw. 
 
The haplo product will be evaluated: 
 At the time of collection using: 
o Cell subset determination including at least CD3, CD34,-
consider CD19, CD4, CD8  
o Viability testing including Trypan Blue. 
 At the time of cell infusion using 
o Viability testing (including 7AAD, CFU) 

 
 
16
 
o Cell subset determination including at least CD3, CD34. 
 
 
 
 
7.4 Response Assessment 
 
A bone marrow examination to document response must be performed in all 
patients on or before Day 60. Physicians should consider earlier bone marrow exams 
in patients whose peripheral blood counts are not recovering or recovering sluggishly.  
Subsequent treatment (consolidation, salvage therapy, etc) will be at the discretion of 
the treating physician. 
Patients will continue to be followed for survival, and disease status. Samples for 
correlative studies will be collected, if possible at 2 month intervals after day 60, until 
one year after treatment. 
 
 
 
  
 
 
 
 
 
 
 
 
 
8.0 ADVERSE EVENT REPORTING REQUIREMENTS  
 
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, as well as by other 
investigations such as clinical laboratory tests, x-rays, and electrocardiographs. 
 
 
8.1 Investigational Risks 
 
The investigational component of the study is the infusion of allogeneic cells. The 
possible complication of such treatment would be the development of severe GVHD 
and/or prolonged myelosuppression. The chemotherapy preceding adoptive cell 
therapy has numerous side effects and possible complications, but these are not 
considered investigational risks since the chemo is standard of care.  
 
8.2 
Adverse Event Characteristics  
 
 
CTCAE term (AE description) and grade:  The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized for AE reporting.  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 

 
 
17
 
- 
Unrelated – The AE is clearly NOT related to the study treatment 
 8.3      Recording and Reporting of Adverse Events and SAEs 
 
 Safety reporting will be 21 CFR 312.32 compliant. 
 Salvage chemotherapy for AML/MDS is a complex procedure with the possibility of 
prolonged initial admission and numerous immediate and delayed complications as well 
as frequent readmissions. 
 
 Expected toxicities are those listed in the consent form and include regimen-related 
toxicities, myelosuppression, opportunistic infections, haplo-immunostorm, 
engraftment syndrome and GVHD.  These will be captured in the transplant 
database and  reported to the IRB on a quarterly basis 
 
 Unexpected adverse events are those leading to ICU admission or to death. Such 
toxicities will be reported immediately to the designated study chairman. Such events 
will be reported to the local IRB within the institution’s prescribed time period. 
 
 
 
Immediate Reporting 
Report quarterly 
Hematopoietic Toxicity 
Death 
Time to Hematopoietic 
recovery 
Extramedullary Toxicity 
Fatal toxicity and toxicity 
requiring ICU admission 
Grade III-IV toxicities not 
requiring ICU admission 
Infections 
Fatal or requiring ICU 
admission 
Grade II-IV 
Acute GVHD 
Fatal or Grade IV 
Grade II-IV 
Chronic GVHD 
Fatal or requiring ICU 
admission 
Limited and extensive 
Haplo-immunostorm and/or 
engraftment syndrome 
Fatal or requiring ICU 
admission 
All others. 
 
 
 
9.0 CRITERIA FOR STUDY EVALUATION 
 
 
 Responses must be maintained with no evidence of AML/MDS for more than four 
weeks. If chemotherapy continues, there can be no evidence of relapse within four 
weeks. Response assessments will require a bone marrow aspirate to be performed. In 
the event of a dry tap or an aspiration that is inadequate for interpretation, a bone 
marrow biopsy is required for response assessment.  
 
 Complete Remission (CR): Complete remission is defined as all of the following: 
 
o Peripheral Blood Counts: 
 Absolute neutrophil count ≥ 1000/μL 
 Platelet count ≥ 100,000/μL 

 
 
18
 
 No leukemic blasts in the peripheral blood 
 Adequate erythroid recovery so that RBC transfusions are not necessary 
 
o Bone Marrow: 
 Adequate cellularity 
 No Auer rods 
 < 5% blast cells 
 
o No extramedullary leukemia (such as CNS or soft tissue involvement) 
 
OR 
 
o Complete Response with Incomplete Platelet Recovery (CRp): CRp satisfies all 
CR criteria except platelets < 100,000/μL, but platelet transfusions are not 
necessary 
 
 Partial Remission (PR): Must meet all criteria of a CR except that the bone marrow 
may contain 5%-24% blasts 
 
 Treatment Failure: Failure to achieve a CR (by 60 days after initial induction therapy 
started) 
 
o Treatment Failure Due to Resistant Disease: 
 Patients treated appropriately 
 Survived > 30 days after therapy began. 
 Failed to achieve remission due to persistent AML as determined by 
peripheral blood and bone marrow aspirate and biopsy. 
 
o Treatment Failure Due to Death of the Patient: 
 Patient died within 30 days of starting protocol therapy. 
 Record whether the patient died with or without evidence of persistent 
leukemia as determined by peripheral blood and bone marrow aspirate 
and biopsy. 
 
 Relapse - Any of the following, occurring after either CR, CRp, or PR: 
 
o The reappearance of circulating blast cells not attributable to “overshoot” 
following recovery from myelosuppressive therapy 
  
o > 5% blasts in the marrow, not attributable to another cause (e.g., CSF, bone 
marrow regeneration) 
 
o Development of extramedullary leukemia 
 
 
 

 
 
19
 
 Toxicities will be followed using CTCAE criteria. 
Most toxicities will be attributable to the chemotherapy. Toxicity attributed to the cell 
infusions may include occurrence of GVHD and unexpected duration of myelosuppression.  
Severity of myelosuppression (hematologic toxicity) will not be taken into account.  
 
 Time to neutrophil recovery: 
The first of three consecutive days with ANC >5x10^9/L. 
 
 Time to platelet recovery; 
Platelet recovery is reported when the platelet count is ≥ 20 x 109/L seven days after platelet 
transfusion and is maintained for three consecutive lab values obtained on different days. 
 Treatment Related Mortality 
Considered any death that cannot be explained by persistence, relapse or progression of the 
underlying malignancy once the preparative regimen starts.  
 
 Acute GVHD 
Acute GVHD will be scored according to the criteria proposed by Przepiorka et al.28  
Risk score for acute GVHD will be further assigned based on recent publication by Mac 
Millan et al.29 
Chronic GVHD will be scored according to the consensus criteria.30 
 
 
 
10. STATISTICAL CONSIDERATIONS 
 
The primary objective of this study is to evaluate the safety of adoptive immunotherapy with IPA 
targeted CBU or with haplo-identical stem cells after conventional induction therapy for very 
high risk AML or MDS. 
 
The study has 2 cohorts. Patients in cohort 1 will receive CBU cells as adoptive immunotherapy. 
Patients in cohort 2 will receive haplo identical cells. Both cohorts will be evaluated separately 
and no formal statistical comparison between cohorts will be performed in this pilot study. 
 
Reinduction therapy in patients with recurrent AML and MDS is extremely toxic with high 
induction related mortality, which is however justified by the dismal prognosis of patients who 
don’t receive treatment.  Safety of the adoptive immunotherapy will be defined as absence of life 
threatening complications attributable to the adoptive immunotherapy part of the protocol. These 
are restricted to: 1) grade III-IV GVHD; an incidence of >10% of this complication in either 
cohort will be considered unacceptable.  2) Unexplained prolonged myelosuppression, i.e. no 
count recovery for more than 30 days after completion of chemotherapy, without evidence of 
residual or recurrent leukemia/MDS. An incidence of >10% of this complication will also be 
considered unacceptable.  
 
10.1 Sample Size Considerations 
 

 
 
20
 
With a sample size of approximately 20 patients in each cohort, a 95% confidence interval for 
the proportion of patients experiencing grade III-IV GVHD complications or unexplained 
prolonged myelesuppression complications in each cohort can be constructed to be within ± 
13.1% of the observed complication proportions.  This calculation assumes an expected 
prevalence of each of these complication proportions of ≤10%. 
Addendum November 2017 Extension of the UCB cohort 
The preliminary results in the UCB cohort are encouraging (section 2.6). We therefore have 
increased accrual to this cohort to a total of 35 patients treated. This will allow a preliminary 
assessment of efficacy. Patients who are enrolled but do not undergo treatment (defined as 
infusion of stem cell product) will be replaced. 
 
Addendum May 2020: In order to further solidify outcomes in the CBU cohort and pending 
completion  of next protocols, we will further increase accrual to this cohort to a total of 60 
patients treated. This will allow a definitive assessment of efficacy. Patients who are enrolled 
but do not undergo treatment (defined as infusion of stem cell product) will be replaced. 
 
10.2 Stopping Rules 
 
The occurrence of adverse events that are life-threatening, lead to ICU admission or death (as 
defined in section 8.3) will lead to temporary suspension of enrollment and immediate 
assessment of events.  
The study will also be paused if there is death that is directly attributed to infusion of adoptive 
cell therapy; for example severe infusion related reaction, infection from contaminated unit, 
Grade 5 GVHD etc. 
 
Enrollment may resume upon assessment by the investigators that there are no safety issues and 
upon appropriate revision of the protocol – if required.  
 
After 10 patients are enrolled in each group, the incidence of the above-defined life-threatening 
complications will be assessed.  If more than one patient out of 10 enrolled patients (i.e., >10%) 
in a cohort experiences either of these complications, the cohort will be stopped for safety.  Each 
cohort will be evaluated separately with respect to these complications. Additionally, if three or 
more of the first five patients in a particular cohort experiences either of these complications, the 
cohort will also be stopped. This is illustrated in the Table below. 
 
 
N treated subjects 
5 
10 
15 
20 
No with gr III-IV GVHD to 
trigger stopping rules  
2 
2 
3 
4 
No with prolonged 
myelosuppression to trigger 
stopping rules 
2 
2 
3 
4 
No with either Gr III-IV GVHD 
or with prolonged 
myelosuppression to trigger 
stopping rules 
3 
 
 
 
 
 

 
 
21
 
For assessment of secondary objectives, descriptive statistics will be utilized via the method of 
binary proportions and 95% confidence intervals will be calculated to assess the precision of the 
obtained estimates.  All analyses will be performed in SAS Version 9.3 (SAS Institute, Inc., 
Cary, NC) and Stata Version 13.0 (StataCorp, College Station, TX). 
 
Addendum 5/26/2020: To date stopping rules have not been met in the CBU cohort after 
enrolling more than 30 patients.  The Haplo cohort has not accrued.  
10.3 Screening vs Treating 
We anticipate that several patients will be consented and then screened for each patient treated. 
The sample sizes are based on number of patients treated – not on number of patients consented. 
 
 
11. 
 CRITERIA FOR REMOVAL OF PATIENTS FROM PROTOCOL THERAPY 
 
11.1 Duration of Treatment 
 
Patients will continue with the therapy specified in this protocol until one of the 
following occurs: 
 Achievement of protocol endpoint CR or CRp after  induction and cellular therapy 
 Failure to achieve CR or CRp  
 Extraordinary Medical Circumstances: If, at any time the constraints of this 
protocol are detrimental to the patient’s health and/or the patient no longer wishes 
to continue protocol therapy, remove the patient from protocol treatment. In this 
event. 
After removal from protocol therapy, patients will continue to be followed for survival and 
disease status. Samples for correlative studies will continue to be collected every two months 
until one year after cell infusion. 
 
12. DATA, SAMPLE AND PROTOCOL MANAGEMENT 
 
 Protocol Compliance: Patients will be reviewed weekly during admission by the Study 
Investigators who will score the patient for standard endpoints.  
 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 
 

 
 
22
 
 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.  
13.0 DATA SAFETY MONITORING BOARD 
 
The Weill Cornell Medical College Data Safety Monitoring Board (DSMB) is being requested to 
review safety data and to make recommendations regarding continuation, termination, or 
modification to the study.  
The research team will report all adverse events to the DSMB after accrual of successive sets of 
five patient to each arm of the protocol. The report to the DSMB will include a description of 
adverse events attributed to cell infusion and of patient’s outcome.  
 
14.0 
REGULATORY CONSIDERATIONS 
 
 
14.1 
Institutional Review Board/Ethics Committee Approval 
 
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. 
 
The Investigator will be responsible for preparing documents for submission to the 
relevant IRB/EC and obtaining written approval for this study.  The approval will be 
obtained prior to the initiation of the study. 
 
The approval for both the protocol and informed consent must specify the date of 
approval, protocol number and version, or amendment number. 
 
Any amendments to the protocol after receipt of IRB/EC approval must be submitted for 
approval by the Investigator to the IRB/EC.  The Investigator is also responsible for 
notifying the IRB/EC of any serious deviations from the protocol, or anything else that 
may involve added risk to subjects. 
 
Any advertisements used to recruit subjects for the study must be reviewed and approved 
by the IRB/EC prior to use. 
 
 
14.2 
Informed Consent Procedures 
 
The 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. 

 
 
23
 
 
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. 
 
 
14.3 
Protecting Privacy and Confidentiality 
 
Confidentiality will be maintained within the limits of the law. Patient 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 patient 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. 
 
 
14.4 
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. 
 
 
14.5 
Protection of Human Rights 
 
Participation in this trial is voluntary. All patients will be required to sign a statement of 
informed consent, which must conform to Weill Cornell Medical College IRB guidelines.  
 
 
 
Patients will be eligible for this trial regardless of gender or racial/ethnic background.  

 
 
24
 
 
 
 
 
 
 
 
 
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