Conditions: Hematopoietic Stem Cell Transplantation Acute Graft Versus Host Disease Acute Myeloid Leukemia Acute Lymphoblastic Leukemia Myelodysplastic Syndromes
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 11
Healthy volunteers: no

Brief summary:
The study compares two acute graft-versus-host disease (aGVHD) prophylaxis regimens: efprezimod alfa vs placebo with the standard GVHD prophylaxis of tacrolimus / methotrexate.

The study compares two acute graft-versus-host disease (aGVHD) prophylaxis regimens: efprezimod alfa/tacrolimus / methotrexate (efprezimod alfa/Tac/MTX) versus placebo/tacrolimus / methotrexate (placebo/Tac/MTX) in the setting of myeloablative conditioning (MAC), matched unrelated donor (MUD) allogeneic hematopoietic stem cell transplantation in participants with acute leukemia (AML/ALL) or myelodysplastic syndrome (MDS). The study agent, efprezimod alfa, will be administered through IV infusion on days -1, 14, and 28 at the dose of 480mg, 240 mg and 240mg, respectively. The placebo will be 100 ml normal saline intravenous (IV) solution.

Detailed description:
The Sponsor decided to discontinue screening and enrollment in this study on 18 May 2021 for business reasons. This decision was not related to any new or unexpected safety or efficacy findings.

Arms:
arm 1: Efprezimod alfa: IV infusion, 480 mg (day -1), 240 mg (day +14) and 240 mg (day +28); Tacrolimus: begin on day -3. IV \[0.03 mg/kg/day\] or by mouth (PO) \[0.045 mg/kg/dose\] dosing is permitted; Methotrexate: given IV at a dose of 15 mg/m\^2/dose once daily on Day 1 after hematopoietic cell transplantation (HCT), and at a dose of 10 mg/m\^2/dose on days 3, 6, and 11 after HCT. arm 2: Placebo (Saline solution): 100 ml IV infusion, Day -1, Day 14, Day 28. Tacrolimus: begin on day -3. IV \[0.03mg/kg/day\] or PO \[0.045 mg/kg/dose\] dosing is permitted; Methotrexate: given IV at a dose of 15 mg/m\^2/dose once daily on Day 1 after HCT, and at a dose of 10 mg/m\^2/dose on days 3, 6, and 11 after HCT.

Interventions: intervention 1: Efprezimod alfa intervention 2: Placebo intervention 3: Methotrexate intervention 4: Tacrolimus
Intervention descriptions: intervention 1: IV infusion: 480 mg at Day -1, 240 mg at Day 14, 240 mg at Day 28. intervention 2: IV infusion, 100 ml at Day -1, Day 14, and Day 28. intervention 3: IV, 15 mg/m\^2/dose at Day 1, then 10 mg/m2/dose at Day 3, 6, 11. intervention 4: Begin on day -3. IV \[0.03 mg/kg/day\] or PO \[0.045 mg/kg/dose\] dosing is permitted

Protocol document:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT04095858  
Document Date: 
17-Aug-2020
A Randomized, Double blind, Placebo-controlled, Multi-center, 
Phase III Study of CD24Fc for Prevention of Acute Graft-versus-
Host Disease Following Myeloablative Allogeneic Hematopoietic 
Stem Cell Transplantation


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OncoImmune Inc. 
Clinical Trial Protocol (CATHY) 
IND 127,363 
CD24Fc-005 
2 
 
CD24Fc for GVHD Prevention; v1.5: August 17, 2020 
1 SYNOPSIS 
A Randomized, Double-blind, Placebo-controlled, Multi-Center, Phase III Study of 
CD24Fc for Prevention of Acute Graft-versus-Host Disease Following 
Myeloablative Allogeneic Hematopoietic Stem Cell Transplant (CATHY) 
Principal Investigator:  
John Magenau, MD 
Study Design: 
The study is designed as a randomized, placebo-controlled, 
double blind, multicenter, Phase III trial comparing two acute 
graft-versus-host disease (aGVHD) prophylaxis regimens: 
CD24Fc/tacrolimus/methotrexate (CD24Fc/Tac/MTX) versus 
placebo/tacrolimus/methotrexate (placebo/Tac/MTX) in the 
setting of myeloablative conditioning (MAC), matched 
unrelated donor (MUD) allogeneic hematopoietic stem cell 
transplantation in patients with acute leukemia (AML/ALL).   
Primary Objective: 
To establish the efficacy of CD24Fc in combination with 
standard prophylaxis for preventing acute GVHD after 
allogeneic HCT. 
Secondary Objectives: 
To improve the relapse free survival (RFS) and overall 
survival (OS) in leukemia patients after allogeneic HCT 
through (1) reduction of the myeloablative conditioning 
toxicity; (2) reduction of severe acute GVHD; and (3) reduction 
of relapse. 
Primary Endpoint: 
180 day grade III-IV acute GVHD free survival (aGFS), event 
defined as the earlier time of GVHD or death within 180 days 
of HCT. 
Secondary Endpoints: 
Disease Free Survival (DFS), event defined as the earlier time 
of leukemia relapse or death after HCT. 
Overall Survival (OS), event defined as time of all-cause 
mortality after HCT. 
180 day grade II-IV acute GVHD free survival (aGFS), the 
earlier time of event defined as Grade II-IV GVHD or death 
within 180 days of HCT. 
180 day grade III-IV acute GVHD relapse-free survival 
(aGRFS), the earlier time of event defined as GVHD, relapse 
or death within 180 days of HCT. 
Eligibility Criteria: 
Eligible patients are at least 18 years of age undergoing 
allogeneic HCT (bone marrow or PBSC) for the treatment of 
AML/ALL with less than 5% blasts in the bone marrow. 
Patients will undergo myeloablative conditioning regimens. 
06CPP7
07ZKR8


OncoImmune Inc. 
Clinical Trial Protocol (CATHY) 
IND 127,363 
CD24Fc-005 
3 
 
CD24Fc for GVHD Prevention; v1.5: August 17, 2020 
Patients must have a matched unrelated donor. Unrelated 
donor must be an 8/8 match at HLA-A, -B, -C, and -DRB1 at 
high resolution using DNA-based typing; must be willing to 
donate BM or PBSCs; and be medically eligible to donate 
stem cells according to NMDP criteria. 
Treatment Description:  The study will be randomized and double blind. Patients will 
be randomized 1:1 to receive one of the following GVHD 
prophylaxis regimens:  
Arm A: CD24Fc/Tac/MTX,  
Arm B:  placebo/Tac/MTX, 
CD24Fc or placebo will be given at the dose level of 480mg, 
240mg and 240mg on Day -1, +14 and +28. 
MTX will be dosed at 15 mg/m2 Day +1, and 10 mg/m2 Days 
+3, +6, and +11.  
Tacrolimus will begin on day -3. For intravenous dosing the 
recommended starting dose is 0.03 mg/kg/day based on 
adjusted body weight as a continuous infusion. For oral 
dosing the recommended starting dose is 0.045 mg/kg/dose 
twice daily. In the absence of GVHD or relapse, it is 
recommended that tacrolimus tapering begin on day +100 
post-transplant. 
Accrual Objective: 
The clinical trial will enroll 180 patients, or 90 per arm. 
Accrual Period: 
The estimated accrual period is 24 months. 
Study Duration: 
Patients will be followed for 180 days for primary endpoint, 
and 1 year for other secondary and exploratory endpoints. 
Interim Analysis: 
The study will include one interim analysis for efficacy and 
futility, for the primary endpoint at the time when the required 
number of events is reached. A sample size re-estimation will 
also be conducted at this interim analysis. 
Data Monitoring Committee: The DMC consists of experts outside of the Sponsor will 
be responsible for the planned interim analyses.  
 
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07ZKR8


OncoImmune Inc. 
Clinical Trial Protocol (CATHY) 
IND 127,363 
CD24Fc-005 
 
5 
 
CD24Fc for GVHD Prevention; v1.5: August 17, 2020 
TABLE 1: STUDY CALENDAR FOR PHASE III STUDY 
 
PRE-HCT 
PRE-HCT 
POST-HCT 
Observations  
Day -28 to -2  
(Screening and 
Randomization) 
- 1 
PRE 
Drug 
-1 
- 1 
2 hr 
POST 
Drug 
0 
 
+7 
(± 2) 
 
+14 
(± 4) 
 
+ 28 
(± 4) 
Weekly 
from 
+ 0 to +100 
(± 3) 
 
Informed Consent 
x 
 
 
 
 
 
 
 
 
Medical History and Examination 
x 
x 
 
 
x 
x 
x 
x 
x 
Pre-HCT organ function and infectious disease testing1 
x 
 
 
 
 
 
 
 
 
Pregnancy test (if applicable) 
x 
 
 
 
 
 
 
 
 
Karnofsky Performance Status 
x 
x 
 
 
 
 
 
 
 
Laboratory testing2  
x 
x 
 
 
 
x 
x 
x 
 
ECG monitoring3 
 
x 
 
x 
 
 
x 
x 
 
CD24Fc (Study Agent) 4 
 
 
x 
 
 
 
x 
x 
 
Hematopoietic Stem Cell Transplant (HCT) 
 
 
 
 
x 
 
 
 
 
Vital Sign monitoring5  
 
x 
 
x 
 
 
x 
x 
 
Acute GVHD assessment6 
 
 
 
 
 
x 
x 
x 
x 
Chronic GVHD assessment 
 
 
 
 
 
 
 
 
 
Concomitant Medications  
x 
x 
 
 
x 
x 
x 
x 
x 
AE Assessment (NCI CTCAE V5.0) 
 
 
 
x 
x 
x 
x 
x 
x 
Assess  Engraftment 
 
 
 
 
 
 
 
x 
 
Bone marrow aspirate & biopsy7 
x 
 
 
 
 
 
 
 
 
Chimerism 
 
 
 
 
 
 
 
 
 
Fasting Lipid Panel including LDL 
 
x 
 
 
 
 
x 
 
 
Survival Follow-Up 
 
 
 
 
 
 
 
 
 
 
 
 
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OncoImmune Inc. 
Clinical Trial Protocol (CATHY) 
IND 127,363 
CD24Fc-005 
 
6 
 
CD24Fc for GVHD Prevention; v1.5: August 17, 2020 
TABLE 1 (CONT): STUDY CALENDAR FOR PHASE III STUDY CONTINUED. 
 
FOLLOW-UP PERIOD 
SURVIVAL 
FOLLOW-UP8 
  Observations  
+ 100 
(± 7) 
Monthly from  
+100 to +180 
(± 7) 
+270 
(± 14) 
+365 
(± 14) 
GVHD Onset 
(± 3) 
Every 6 months 
post +365 
(± 3 months) 
Informed Consent 
 
 
 
 
 
 
Medical History and Examination 
x 
x 
x 
x 
x 
 
Pre-HCT organ function and infectious disease testing1 
 
 
 
 
 
 
Pregnancy test (if applicable) 
 
 
 
 
 
 
Karnofsky Performance Status 
 
 
 
 
 
 
Laboratory testing2  
x 
x 
 
 
 
 
ECG monitoring3 
 
 
 
 
 
 
CD24Fc (Study Agent)4 
 
 
 
 
 
 
Vital Sign monitoring5  
 
 
 
 
 
 
Acute GVHD assessment6 
x 
x 
 
 
x 
 
Chronic GVHD assessment 
x 
x 
x 
x 
 
 
Concomitant Medications  
x 
 
 
 
x 
 
AE Assessment (NCI CTCAE V5.0) 
x 
x 
 
 
 
 
Assess  Engraftment 
 
 
 
 
 
 
Bone marrow aspirate & biopsy7 
 
 
 
 
 
 
Chimerism 
x 
 
 
 
 
 
Fasting Lipid Panel including LDL 
 
 
 
 
 
 
Survival Follow-Up 
 
 
 
 
 
x 
 
 
 
06CPP7
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OncoImmune Inc. 
Clinical Trial Protocol (CATHY) 
IND 127,363 
CD24Fc-005 
7 
 
CD24Fc for GVHD Prevention; v1.5: August 17, 2020 
NOTE: Pre and Post-transplant observations. Patient condition and scheduling issues may impact the time of post-HCT observations. The acceptable 
time frame for completing these observations is ± 3 days through day 60, ± 5 days for observations from day 61 until day 100, and ± 7 to 14 days for 
observations from day 100 to day 365.  
1) 
Per institution practice guidelines: Recipient organ function testing will include MUGA or Echocardiography, Electrocardiogram, and Pulmonary 
Function Testing. Donor safety and eligibility assessments and screening for infectious disease markers will be performed according to national marrow 
donor program (NMDP) guidelines.  These include but are not limited to screening for HIV, Hepatitis B and C, HTLV I/II, HSV antibody, Trypanosoma 
cruzi, west nile virus, syphilis and CMV.  The organ function testing may be collected up to 10 weeks prior to enrollment.   
2) 
Laboratory tests include CBC with differential, serum chemistries with creatinine, AST, ALT, and total bilirubin in pre-HCT period. CBC with differential, 
serum electrolytes with creatinine, AST, ALT, and total bilirubin will be performed at a minimum on the day of CD24Fc infusion and three times weekly 
from day 0 until ANC > 500/ul, while hospitalized for HCT. Tacrolimus levels will be monitored per institution clinical practice guidelines. Laboratory 
testing may be more frequent per standard HCT practice.   
3) 
ECG monitoring will be performed on treatment days (Day -1, Day 14 and Day 28).  The ECG should be measured within four hours of the start of 
study drug infusion and 2 hours ± 15 min after the start of infusion. 
4) 
Per protocol, CD24Fc will be administered on day -1, day 14± 4 and day 28± 4.  See protocol section 7.1 for instructions on identifying and managing 
infusion reactions.  
5) 
Vital signs will be recorded prior to infusion and after CD24Fc infusion (+/- 30 min).   
6) 
Assessment for acute GVHD will occur weekly through day 100. The weekly visits and the follow up visits can be done through telemedicine to decrease 
the exposure risk of COVID-19.  Following day 100 acute and chronic GVHD assessments will occur monthly. The follow up visits can be done through 
telemedicine in case of COVID-19.  MAGIC acute GVHD grading will be used to report disease severity (APPENDIX C). NIH Consensus chronic GVHD 
grading will be used to report chronic GVHD (APPENDIX F). 
7) 
The Pre-HCT bone marrow biopsy may be assessed up to 6 weeks prior to enrollment. 
8) 
The follow up of relapse and survival will be up to 3 years after HCT.  If a subject withdraws from the study and does not consent to continued follow-
up of associated clinical outcome information, a public records search can be performed for survival. 
06CPP7
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OncoImmune Inc. 
Clinical Trial Protocol (CATHY) 
IND 127,363 
CD24Fc-005 
9 
 
 
 
 
 
 
 
 
 
TABLE OF CONTENTS 
1 
SYNOPSIS ............................................................................................. 2 
CD24Fc-005 PROTOCOL SIGNATURE ..................................................... 8 
2 
STUDY OBJECTIVES ......................................................................... 15 
2.1 
Primary Objectives .................................................................................... 15 
2.2 
Secondary Objectives ............................................................................... 15 
2.3 
Phase III CATHY STUDY Endpoints ......................................................... 15 
2.3.1 
Primary Efficacy Endpoint .......................................................................... 15 
2.3.2 
Secondary Efficacy Endpoints ................................................................... 15 
2.3.3 
Other Exploratory Evaluations ................................................................... 15 
3 
BACKGROUND AND SIGNIFICANCE ................................................ 16 
3.1 
Importance of Improving GVHD Prevention .............................................. 16 
3.2 
Pathogenesis of GVHD ............................................................................. 17 
3.3 
Current Therapeutic Approaches for GVHD .............................................. 17 
3.4 
Role of Siglec-G in APC mediated Response to Tissue Injury .................. 18 
3.5 
CD24-Siglec Interactions in the Host Response to Tissue Injury .............. 18 
3.6 
Preclinical Studies of CD24Fc for Prevention of GVHD ............................ 19 
3.7 
Rationale for Clinical Study of CD24Fc for GVHD Prevention .................. 20 
3.8 
Clinical Experience of CD24Fc in Humans ............................................... 20 
3.8.1 
Phase I Summary: ..................................................................................... 20 
3.8.2 
Phase IIa Summary: .................................................................................. 21 
3.8.3 
Conclusion and Plans for Clinical Development ........................................ 32 
3.8.4 
Rationale for a Randomized, double blind, placebo-controlled Phase III Trial
 .................................................................................................................. 33 
4 
ELIGIBILITY ......................................................................................... 34 
4.1 
Inclusion Criteria ....................................................................................... 34 
4.2 
Exclusion criteria ....................................................................................... 35 
5 
PHASE III STUDY ................................................................................ 36 
5.1 
Overview ................................................................................................... 36 
5.2 
screening Procedures ............................................................................... 36 
5.3 
Treatment Schema .................................................................................... 36 
5.4 
Rationale for Treatment Schema .............................................................. 36 
5.5 
Administration of GVHD Prophylaxis ......................................................... 37 
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OncoImmune Inc. 
Clinical Trial Protocol (CATHY) 
IND 127,363 
CD24Fc-005 
10 
 
 
 
 
 
 
 
 
 
5.5.1 
CD24Fc ..................................................................................................... 37 
5.5.2 
Tacrolimus ................................................................................................. 37 
5.5.3 
Methotrexate .............................................................................................. 37 
5.6 
Myeloablative Conditioning Regimens ...................................................... 38 
5.6.1 
Busulfan and Fludarabine (Bu/Flu) ............................................................ 38 
5.6.2 
Busulfan and cyclophosphamide (Bu/Cy) .................................................. 38 
5.6.3 
Cyclophosphamide and total body irradiation (Cy/TBI) .............................. 38 
5.6.4 
Etoposide and total body irradiation (VP16/TBI) ........................................ 38 
5.6.5 
Other Myeloablative Conditioning .............................................................. 38 
5.7 
Donor Eligibility, Selection, and Related Procedures ................................ 39 
5.8 
Post-transplant Supportive Care ............................................................... 39 
5.8.1 
Growth Factors .......................................................................................... 39 
5.8.2 
Seizure Prophylaxis ................................................................................... 39 
5.8.3 
Blood Products .......................................................................................... 40 
5.8.4 
Prophylaxis Against Infections ................................................................... 40 
5.8.5 
Sinusoidal Obstruction Syndrome (SOS) / Veno-occlusive Disease (VOD) of 
the Liver .................................................................................................... 41 
5.8.6 
Donor Lymphocyte Infusions – Viral-specific cytotoxic T-Lymphocytes 
(CTLs) ....................................................................................................... 41 
5.8.7 
Intravenous Immune Globulin (IVIG). ........................................................ 41 
6 
STUDY DEFINITIONS ......................................................................... 41 
6.1 
Screening .................................................................................................. 41 
6.2 
Randomization .......................................................................................... 41 
6.3 
Treatment Period ...................................................................................... 41 
6.4 
Follow Up Period ....................................................................................... 41 
6.5 
On Study ................................................................................................... 42 
6.6 
Off Treatment ............................................................................................ 42 
6.7 
Definition of engraftment and engraftment failure ..................................... 42 
7 
MANAGING TOXICITIES ..................................................................... 43 
7.1 
Managing Infusion Reactions .................................................................... 43 
7.2 
Managing Acute GVHD ............................................................................. 44 
8 
DOSE MODIFICATIONS BASED ON LABORATORY VALUES ........ 44 
8.1 
Hepatic Function ....................................................................................... 44 
9 
REQUIRED OBSERVATIONS (STUDY CALENDAR): ....................... 45 
9.1 
Special considerations for COVID-19 ........................................................ 45 
10 PHARMACEUTICAL INFORMATION ................................................. 49 
10.1 
CD24Fc or CD24IgG (OncoImmune, Inc.), Study Agent ........................... 49 
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OncoImmune Inc. 
Clinical Trial Protocol (CATHY) 
IND 127,363 
CD24Fc-005 
11 
 
 
 
 
 
 
 
 
 
10.1.1 Molecular Formula and Formulation .......................................................... 49 
10.1.2 Packaging, Ordering, and Inventory Management .................................... 49 
10.1.3 Availability, Storage and Stability ............................................................... 49 
10.1.4 Administration ............................................................................................ 49 
10.1.5 Safety in Humans ...................................................................................... 51 
10.1.6 Treatment Emergent SAEs (TESAEs) ....................................................... 52 
10.1.7 Pharmacokinetics in Humans .................................................................... 54 
10.1.8 Immunogenicity in Humans ....................................................................... 57 
10.2 
Placebo ..................................................................................................... 57 
10.3 
Methotrexate ............................................................................................. 57 
10.3.1 Formulation ................................................................................................ 57 
10.3.2 Availability and administration ................................................................... 58 
10.3.3 Potential Side Effects ................................................................................ 58 
10.3.4 Potential Drug Interactions ........................................................................ 58 
10.4 
Tacrolimus (Prograf, FK506) ..................................................................... 58 
10.4.1 Formulation ................................................................................................ 58 
10.4.2 Availability and administration ................................................................... 59 
10.4.3 Potential Side Effects ................................................................................ 59 
10.5 
Cyclosporine (Sandimmune, Neoral) ........................................................ 60 
10.5.1 Oral or Intravenous Availability .................................................................. 60 
10.5.2 Storage and Handling ................................................................................ 60 
10.5.3 Sirolimus or other prevention regimen ....................................................... 61 
10.5.4 Potential drug interactions ......................................................................... 61 
10.5.5 Excretion .................................................................................................... 61 
11 ADVERSE EVENTS AND REPORTING CRITERIA ............................ 62 
11.1 
Definition of Adverse Events ..................................................................... 62 
11.2 
Definition of AE Severity ........................................................................... 64 
11.3 
AE and SAE Reporting Requirements ...................................................... 64 
11.3.1 AE Reporting ............................................................................................. 64 
11.3.2 Pregnancy Reporting ................................................................................. 66 
11.3.3 Emergency Unblinding............................................................................... 66 
12 DATA SAFETY MONITORING PLAN (DSMP) ................................... 66 
12.1 
Trained and Certified Personnel ................................................................ 67 
12.2 
Storage and Dissemination of Reports ...................................................... 67 
12.3 
Clinical Monitoring Procedures .................................................................. 67 
12.4 
Independent Data Monitoring Committee (DMC) ...................................... 68 
13 QUALITY ASSURANCE AND AUDITS ............................................... 68 
14 REMOVAL FROM STUDY ................................................................... 69 
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15 STATISTICAL CONSIDERATIONS ..................................................... 69 
15.1 
Study Design ............................................................................................. 69 
15.2 
Accrual ...................................................................................................... 70 
15.3 
Randomization and stratification ............................................................... 70 
15.4 
Primary Endpoint ....................................................................................... 70 
15.5 
Sample Size and Power Considerations ................................................... 71 
15.5.1 Power Calculation for the Primary Endpoint .............................................. 71 
15.5.2 Power Calculation for the Secondary Endpoints ........................................ 71 
15.6 
Interim Analysis and Stopping Guidelines ................................................. 72 
15.6.1 Interim Analysis for Efficacy ....................................................................... 72 
15.6.2 Operating Characteristics of the Design .................................................... 73 
15.7 
Guidelines for Safety Monitoring ............................................................... 73 
15.8 
Demographic and Baseline Characteristics............................................... 73 
15.9 
Analysis Populations ................................................................................. 74 
15.9.1 Primary Population .................................................................................... 74 
15.9.2 Safety Population ....................................................................................... 74 
15.9.3 Transplant Population ................................................................................ 74 
15.10 
Analysis of the Primary Endpoint: 180 day aGFS ..................................... 74 
15.10.1 Censoring rules for time to event efficacy endpoints ................................. 74 
15.11 
Analysis of Secondary Endpoints .............................................................. 75 
15.11.1 The secondary endpoints (1) Disease (Relapse) Free Survival; (2) Overall 
Survival; (3) 180 days grade II-IV acute GVHD free survival will be included 
in a formal testing procedure after the primary analysis is statistically 
significant and (4) 180 Day Grade III-IV acute GVHD and Relapse-free 
survival. The multiplicity adjustment will be a gate-keeping method in the 
order described above. Disease-free Survival ........................................... 75 
15.11.2 Overall Survival ......................................................................................... 75 
15.11.3 180 Day Grade II-IV GVHD-Free Survival ................................................. 75 
15.11.4 180 Day Grade III-IV GVHD and Relapse-Free Survival (aGRFS) ............ 75 
15.12 
Analysis of Exploratory Endpoints ............................................................. 75 
15.12.1 Chronic GVHD ........................................................................................... 75 
15.12.2 Disease Relapse or Progression ............................................................... 76 
15.12.3 Non-relapse Mortality................................................................................. 76 
15.12.4 Mucositis .................................................................................................... 76 
15.12.5 Infections ................................................................................................... 76 
15.12.6 Safety Analysis .......................................................................................... 76 
15.13 
Missing Data and Sensitivity Analysis ....................................................... 76 
16 REFERENCES ..................................................................................... 78 
17 APPENDIX A: KARNOFSKY PERFORMANCE SCALE .................... 83 
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18 APPENDIX B: CIBMTR OPERATIONAL GUIDELINES ..................... 84 
19 APPENDIX C: ORGAN STAGING OF ACUTE GVHD ........................ 85 
20 APPENDIX D: DISEASE RISK INDEX FOR AML/ALL ....................... 86 
21 APPENDIX E: HCT-SPECIFIC COMORBIDITY INDEX SCORE ........ 87 
22 APPENDIX F: CHRONIC GVHD ASSESSMENT ................................ 88 
23 SUMMARY OF CHANGES .................................................................. 90 
 
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LIST OF FIGURES 
Figure 1:  Study Diagram .............................................................................................. 4 
Figure 2:  Randomization.............................................................................................. 4 
Figure 3: 
 Incidence of grade iii-iv acute gvhd following unrelated donors hct ........... 16 
Figure 4:  Tissue injury after allo-HCT. ....................................................................... 17 
Figure 5:  Loss of Siglec-G signaling results in exacerbation of GVHD. ..................... 18 
Figure 6:  CD24-Siglec G (10) interaction discriminates between pathogen associated 
molecular patterns (PAMPs) such as lipopolysaccharide (LPS) and DAMPs.
 ................................................................................................................... 19 
Figure 7:  CD24Fc prevents experimental acute GVHD. ............................................ 19 
Figure 8:  CD24Fc treatment significantly improves 180 AGFS. ................................. 28 
Figure 9:  180 DAY GRADE II-IV GVHD-FREE SURVIVAL. CD24FC-TREATED VS MATCHED CIBMTR 
HISTORICAL CONTROLS (CM68). ..................................................................... 29 
Figure 10:  CD24Fc treatment improves 1 year Relapse Free Survival (RFS). ............ 29 
Figure 11:  CD24Fc treatment shows trend in improvement of 1 year Overall Survival 
(OS). ........................................................................................................... 30 
Figure 12: 180 DAY GRADE III-IV GVHD-FREE AND RELAPSE-FREE SURVIVAL. CD24FC VS 
MATCHED CIBMTR CONTROL (CM68). ........................................................... 31 
Figure 13: Mucositis scores calculated as multiple of severe mucositis grade >3 and 
duration (grade-days). ................................................................................ 32 
Figure 14: Plot of Mean (±SD) Plasma CD24Fc Concentration by Treatment – PK 
Evaluable Population.  PK = pharmacokinetic; SD = standard deviation. ... 54 
Figure 15: Plot of Mean (±SD) Plasma CD24Fc Concentration by Treatment – PK 
Evaluable Population. ................................................................................. 56 
LIST OF TABLES 
Table 1: Study Calendar for Phase III study .................................................................... 5 
Table 2: Univariate Results from the CD24Fc Phase IIa study ..................................... 24 
Table 3: Characteristics of patients: Cases vs. Controls ............................................... 25 
Table 4: Univariate analysis of 180 days grade III-IV acute GVHD-free survival, 180 days 
acute (grades II-IV and III-IV) GVHD, 1 year chronic GVHD, 1 year relapse, 1 
year non-relapse mortality, 1 year disease-free survival, and 1 year overall 
survival. Controls (CIBMTR Reference Group) vs. Cases. .............................. 27 
Table 5: Eligibility According to Pre HCT Organ Function ............................................. 34 
Table 6: Study Calendar for Phase III study .................................................................. 46 
Table 7: Efficacy Stopping Thresholds with Type I Error 0.05, and an Effect Size of Hazard 
Ratio 0.446 ...................................................................................................... 72 
Table 8: Summary of Operating Characteristics ............................................................ 73 
 
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2 STUDY OBJECTIVES 
The primary goal of the Phase III CATHY study is to confirm the safety and efficacy of 
CD24Fc in combination with standard prophylaxis for preventing acute GVHD after 
allogeneic HCT.  The CATHY study is a Phase III randomized, double blind, placebo-
controlled, multi-center trial comparing CD24Fc vs placebo with standard Tac/MTX acute 
GVHD prophylaxis in patients with controlled AML/ALL receiving a matched unrelated 
donor allogeneic HCT after a myeloablative conditioning regimen.  
2.1 PRIMARY OBJECTIVES 
• To establish the efficacy of CD24Fc in combination with standard prophylaxis 
for preventing acute GVHD after allogeneic HCT.  
2.2 SECONDARY OBJECTIVES 
• To improve the relapse free survival (RFS) and overall survival (OS) in patients 
with AML/ALL after allogeneic HCT through (1) reduction of the myeloablative 
conditioning toxicity; (2) reduction of severe acute GVHD; and (3) reduction of 
relapse.   
2.3 PHASE III CATHY STUDY ENDPOINTS 
2.3.1 Primary Efficacy Endpoint 
• 180 day grade III-IV acute GVHD free survival (aGFS), event defined as time 
of GVHD or death within 180 days of HCT.  
2.3.2 Secondary Efficacy Endpoints 
• Disease Free Survival (DFS), event defined as the earlier of time of leukemia 
relapse or death after HCT. 
• Overall Survival (OS), event defined as time of all-cause mortality after HCT. 
• 180 day grade II-IV acute GVHD free survival (aGFS), the earlier time of event 
defined as Grade II-IV GVHD or death within 180 days of HCT.  
• 180 day grade III-IV acute GVHD relapse-free survival (aGRFS), the earlier 
time of event defined as GVHD, relapse or death within 180 days of HCT. 
2.3.3 Other Exploratory Evaluations  
• To describe incidence of chronic GVHD at one year. 
• To describe incidence of relapse at one year. 
• To describe incidence of non-relapse mortality (NRM) at one year. 
• To describe incidence and rate of infection at day 100.  
• To describe incidence of Grade 3-4 oral mucositis at Day 28 or when patient is 
discharged, whichever comes first.  
• To estimate the OS and DFS at 3 year. 
 
 
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3 BACKGROUND AND SIGNIFICANCE 
3.1 IMPORTANCE OF IMPROVING GVHD PREVENTION 
Allogeneic HCT is an expanding therapeutic modality for a growing number of malignant 
and non-malignant conditions. Each year allogeneic HCT is performed in greater than 
21,000 patients worldwide as a potentially curative option for hematologic diseases.[1] 
However, its success is limited by transplantation related mortality (TRM), particularly 
when utilizing unrelated or non-HLA matched donors. Acute GVHD is the most frequent 
life threatening complication after HCT and often contributes to mortality related to 
infection.[2, 3] Because GVHD is the principle contributor to TRM, it poses a fundamental 
barrier to improving outcomes after HCT.[4, 5]  
For over 20 years, the combination of a calcineurin inhibitor (e.g. cyclosporine and 
tacrolimus) with methotrexate has remained the standard of care for the prevention of 
GVHD.[2] Despite routine administration of immune prophylaxis, clinically significant 
GVHD (Grade II-IV) occurs in approximately 50 to 80% of patients receiving unrelated 
donor HCT.[6-10]  
Several recent single center or large CIBMTR data analyses suggest that moderate, 
Grade II severity, which comprises the majority of  acute GVHD events, may have less 
demonstrable effects on overall survival [11, 12].  Nonetheless, in patients with very 
severe Grade III-IV GVHD (Figure 3), mortality rates are 50-90%.[4, 13, 14] One 
explanation for this is that, once grade III-IV GVHD is established, ineffective responses 
occur to front-line therapy with high dose corticosteroids in greater than 50% of 
patients.[15] Survival is significantly diminished for patients who demonstrate steroid 
refractoriness or who require prolonged treatment.[14, 16, 17] Even when successful, 
high doses of corticosteroids are a major source of morbidity due to increased infections 
and deconditioning that places patients at significant risk for TRM.[18, 19] These factors 
highlight the importance of improving our current approaches for the prevention of grade 
III-IV acute GVHD.[13-15]
FIGURE 3: INCIDENCE OF GRADE III-IV 
ACUTE GVHD FOLLOWING UNRELATED 
DONORS HCT  
(as reported by CIBMTR; Jagasia et al: Blood 
2012, 119: 296-307).  
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3.2 PATHOGENESIS OF GVHD 
Acute GVHD results from immunologically-mediated injury to host tissues.[20] 
Experimental data have shown that GVHD stems from allogeneic donor lymphocytes 
responding to host tissues that express polymorphic human leukocyte antigens,[10] that 
culminate in clinical manifestations, namely inflammatory responses that primarily involve 
the skin, intestine, and liver. These 
events 
are 
driven 
by 
interactions 
between 
antigen 
presenting 
cells 
(APCs), specifically dendritic cells that 
activate 
donor 
T cells.[21-23] 
The 
subsequent 
immunologic 
cascade 
results in the release of pro-inflammatory 
cytokines and expansion of antigen 
specific allo-reactive T cells that target 
host tissues. A key inciting event is 
believed to be direct tissue damage from 
pre HCT conditioning regimens,[24, 25] 
which 
are 
routinely 
employed 
for 
immune-ablation of host immunity and 
control 
of 
primary 
malignancy. 
Unfortunately, conditioning therapy also 
causes broad tissue injurious effects that 
result in the release of pro-inflammatory 
cytokines, 
and 
damage-associated 
molecular patterns (DAMPs) capable of 
initiating 
and 
propagating 
the 
inflammatory cascade of GVHD (Figure 
4).  
3.3 CURRENT THERAPEUTIC APPROACHES FOR GVHD 
To date, treatment and prevention of GVHD has predominantly focused on either 
pharmacologic inhibition[2, 26] or depletion of T cells through in vitro[27] or in vivo 
approaches to limit expansion of alloreactive T cells that mediate tissue injury.[28] While 
non-selective T-cell depleting strategies (e.g. anti-thymocyte globulin (ATG)) are 
efficacious in preventing GVHD, they do not improve survival due to offsetting risks for 
relapse, infection and graft rejection.[19, 29, 30] A recent prospective, randomized, 
double-blind, placebo controlled, Phase III clinical trial comparing adding ATG to standard 
GVHD prophylaxis showed that although ATG reduced the incidence of Grade II-IV acute 
GVHD and chronic GVHD, ATG may have an overall negative impact on neutrophil and 
platelet engraftment, increased rates of CMV reactivation, as well as significantly reduced 
overall survival and relapse free survival [31]. Conversely, more selective inhibition by 
targeting single pro-inflammatory cytokines to prevent GVHD has not demonstrated 
clinical benefit on overall survival and relapse free survival [32, 33] [34, 35]. 
FIGURE 4: TISSUE INJURY AFTER ALLO-HCT.  
DAMAGE-ASSOCIATED MOLECULAR PATTERNS (DAMPS) 
INTERACT WITH PATTERN RECOGNITION RECEPTORS (PRRS) 
TO PROMOTE APC (DENDRITIC CELL) ACTIVATION (+) THAT 
ACTIVATES DONOR LYMPHOCYTES THAT RESULT IN GVHD. 
INTERACTIONS OF DAMPS WITH SIGLECS CAN PROMOTE 
NEGATIVE REGULATION (-) CAPABLE OF OVERCOMING PRR 
MEDIATED ACTIVATION. ATP, ADENOSINE TRIPHOSPHATE; 
HMGB1, HIGH-MOBILITY GROUP BOX 1 PROTEIN. (ADAPTED 
FROM BRENNEN ET AL. FRONT. IMM. 6(101): 1-9)   
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macrophages.[47] When expressed on T cells, CD24 is essential for down-modulating 
immune stimulation by DAMPs.[48, 49] It has been shown that CD24 directly associates 
with DAMPs thereby ameliorating their stimulatory activity (Figure 6). The interaction of 
CD24 with Siglecs (murine Siglec-G or human Siglec 10) also results in inhibition of 
nuclear factor kappaB (NF-kappaB), facilitating an attenuated damage response.[49] It is 
postulated that the CD24-Siglec G/10 pathway affords the host protection against 
exaggerated responses to pathological cell death, and most importantly discriminates 
between tissue damage (i.e. DAMP) versus pathogen (i.e. PAMP) immune activation. 
Since HCT is associated with tissue injury from conditioning and GVHD, and places 
immune deficient hosts at risk for infectious complications, the CD24 - Siglec G/10 
pathway is a compelling therapeutic target for more selectively mitigating GVHD while 
leaving the pathogen-specific immune 
responses intact and thus addressing one 
of the limitations of T cell directed 
therapy. 
 
3.6 PRECLINICAL 
STUDIES 
OF 
CD24FC FOR PREVENTION OF 
GVHD  
Consistent with the loss of Siglec-G, in 
murine models of allogeneic HCT we 
observed that lack of CD24 expression on 
T cells promotes greater GVHD severity. 
This provides evidence of a crucial 
interaction between Siglec-G and CD24 
in modulating immune response. CD24Fc 
(CD24 Ig) is a fusion protein consisting of 
the extracellular domain of mature human 
CD24 
linked 
to 
the 
human 
immunoglobulin G1 (IgG1) Fc domain (OncoImmune, Inc.). Similar to native CD24, in 
HMGB1/HSP70/90
CD24
SIglec G
TLR 
SHP1
MYD88
NFkB
Inflammatory cytokines
B
TLR-Ligand
TLR 
MYD88
NFkB
Inflammatory cytokines
A
PAMP
DAMP
Science 2009
Trends Immunol 2009
FIGURE 6: CD24-SIGLEC G (10) INTERACTION 
DISCRIMINATES BETWEEN PATHOGEN ASSOCIATED 
MOLECULAR PATTERNS (PAMPS) SUCH AS 
LIPOPOLYSACCHARIDE (LPS) AND DAMPS.  
A) HOST RESPONSE TO PAMPS WAS UNAFFECTED 
BY CD24-SIGLEC G(10) INTERACTION. B) CD24-
SIGLEC G (10) INTERACTION REPRESSES HOST 
IMMUNE RESPONSE TO DAMPS. THIS IS PROPOSED 
TO OCCUR THROUGH DIRECT INTERACTION OF CD24
WITH DAMPS, AND INHIBITION OF TLR SIGNALING BY 
SHP-1. SHP-1, SRC HOMOLOGY REGION 2 DOMAIN-
CONTAINING 
PHOSPHATASE-1; NFKB, 
NUCLEAR 
FACTOR KAPPA B; TLR, TOLL LIKE RECEPTOR;
MYD88, 
MYELOID 
DIFFERENTIATION 
PRIMARY 
RESPONSE GENE 88. 
FIGURE 7: CD24FC PREVENTS EXPERIMENTAL ACUTE 
GVHD.  
B6 
MICE 
WERE 
ADMINISTERED 
MYELOABLATIVE XRT
FOLLOWED 
BY 
INFUSION 
OF CD24-/-T 
CELLS 
FROM 
ALLOGENEIC AND SYNGENEIC DONORS. RECIPIENTS WERE 
INJECTED WITH CD24FC (5MG/KG) OR PLACEBO ON DAY -1
BEFORE HCT. 
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vitro studies demonstrate that CD24Fc binds to murine Siglec-G (and its human 
orthologue, Siglec 10).[48] CD24Fc also stimulates tyrosine-phosphorylation of, and 
SHP-1 association to Siglec G. In preclinical models of HCT, administration of exogenous 
CD24Fc restores Siglec G signaling and reverses the exaggerated GVHD observed with 
CD24-/- T cells (Figure 7) [43]. Moreover, CD24Fc also ameliorates GVHD from wild type 
allogeneic T cells by enhancing CD24 – Siglec-G signaling. Taken together, these 
multiple lines of experimental evidence support suppression of innate immune responses, 
specifically by enhancing CD24-Siglec-G interactions that are capable of regulating 
severe tissue damage mediated inflammatory disorders such as GVHD. The availability 
of clinical grade  
3.7 RATIONALE FOR CLINICAL STUDY OF CD24FC FOR GVHD PREVENTION 
Several lines of evidence provide compelling rationale to support clinical investigation of 
CD24Fc for GVHD prevention. First, preclinical evidence in several well-established HCT 
models suggest that CD24Fc is effective in preventing GVHD. Second, the mechanism 
of immune modulation by CD24Fc is ideally suited to the inflammatory state immediately 
preceding HCT, which results from exacerbated immunologic responses to DAMPs that 
are released through generalized tissue damage by myeloablative conditioning, a 
necessary component of the HCT procedure for reducing leukemic relapse [64]. As 
opposed to standard GVHD therapies that directly inhibit T cell responses, targeting 
Siglec-10 – CD24 interactions with CD24Fc provides a completely novel strategy for 
preventing GVHD by directly interrupting the immune response to chemotherapy-
associated inflammatory signaling or DAMPs, a major GVHD initiating event. Third, 
CD24Fc has demonstrated initial safety in healthy human subjects and a Phase IIa dose 
finding clinical trial in patients undergoing allogeneic HCT, coupled with a good 
tolerability, making it suitable for additional study in this vulnerable population. Fourth, 
GVHD occurs at a high incidence and is associated with significant morbidity and mortality 
thus reflecting an unmet clinical need. Therefore, improving standard of care GVHD 
prevention strategies could expand the curative potential of HCT. Finally, establishing 
proof-of-concept and efficacy in a prototypical immune disorder would provide key 
evidence for further definitive investigations of CD24Fc for the treatment and prevention 
of GVHD and other inflammatory conditions.    
3.8 CLINICAL EXPERIENCE OF CD24FC IN HUMANS 
3.8.1 Phase I Summary: 
OncoImmune Inc. has developed and manufactured clinical grade CD24Fc for use in 
humans. CD24Fc has been tested in a Phase I clinical trial in healthy human subjects, 
and this study showed preliminary safety of single dose CD24Fc by IV administration. A 
total of 40 subjects were randomized in 5 cohorts of 8 subjects, and 39 subjects 
completed the study. CD24Fc was administered via IV infusion over 1 hour at doses 
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ranging from 10 to 240 mg, and the subjects were followed over a six-week period. A 
MTD was not encountered.  
In general, adverse events were mild to moderate in severity. The most common AEs 
were headache (6 [15.0%] subjects), accidental burns second degree (3 [7.5%] subjects), 
non-sustained ventricular tachycardia (2 [5.0%] subjects), and upper respiratory tract 
infection (2 [5.0%] subjects). The rates of the AEs were similar in the placebo control 
group. The SAE of ventricular tachycardia was considered mild in severity by the 
investigator and did not lead to discontinuation of the subject from the study. This SAE 
was considered to be drug related due to its close temporal proximity to dosing, though 
similar short, isolated episodes of non-sustained ventricular tachycardia may be seen in 
up to 4% of normal, healthy populations. No deaths or adverse events leading to 
discontinuation occurred during the study.  
3.8.2  Phase IIa Summary: 
A Phase IIa prospective randomized double-blind clinical trial of CD24Fc for acute GVHD 
prophylaxis in myeloablative matched unrelated donor HCT was initiated in July 2016. 
The first patient was enrolled in Sept 2016. A total of 24 patients were enrolled in three 
cohorts, 240mg single dose given at day -1, 480mg single dose at day -1, 480-240-240mg 
multi-dose given on day -1, day 14 and day 28, with 6 patients receiving CD24Fc and 2 
patients receiving placebo in each cohort. The last patient was enrolled in Dec 2017. The 
last patient reached one year post-HCT in December 2018. Data was locked and the final 
clinical study report (CSR) was submitted to FDA in April 2019. In total there are 18 
patients in the CD24Fc group and 6 patients in the placebo group (3:1 randomization).  
All planned dosages were delivered on schedule.   
3.8.2.1 Phase IIa Clinical Study Overview 
The primary objectives of the Phase IIa are to assess the safety and tolerability of CD24Fc 
in combination with methotrexate and tacrolimus prophylaxis in subjects undergoing 
matched unrelated donor HCT following myeloablative conditioning, and to define the 
recommended Phase II dose (RP2D) or maximum tolerated dose (MTD). In addition, 
secondary efficacy objectives in the Phase IIa include: 
• assessing grade II – IV aGVHD free survival (GFS) at day 180 after HCT,  
• assessing the incidence of chronic GVHD (cGVHD) at one year following HCT 
• assessing the incidence of relapse one year following HCT 
• assessing the incidence of transplant-related mortality (TRM) one year following 
HCT 
• assessing infection rates at day 100 following HCT 
• evaluating overall survival (OS), absence of grade III-IV GVHD, and relapse-free 
survival one year following HCT 
• evaluating conditioning toxicity including oral mucositis and organ failure 
Other exploratory objectives include assessment of the pharmacokinetic (PK) profile of 
CD24Fc, examining the immune cell profile and functional responses of APCs and T cells 
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after HCT in the CD24Fc and placebo groups, and assessing pharmacodynamics (PD) 
biomarkers such as the plasma concentrations of pro-inflammatory cytokines, DAMPs, 
lipids, and GVHD biomarkers in the CD24Fc and placebo groups. 
Subjects between the ages of 18-70 years old undergoing matched unrelated donor 
allogeneic HCT for a malignant hematologic condition (AML, ALL, CML, CMML, MDS) 
with a Karnofsky performance score  70% were eligible for the trial. An 8/8 HLA allelic 
match between the unrelated donor and the recipient at HLA-A, HLA-B, HLA-C, and HLA-
DRB1 was required. All subjects received myeloablative conditioning and standard of 
care GVHD prophylaxis with methotrexate and tacrolimus per the Phase IIa protocol. 
Patients received a myeloablative conditioning regimen consisting of either fludarabine 
and busulfan (Flu/Bu) or cyclophosphamide and total body irradiation (Cy/TBI), as 
decided by the treating physician, followed by an infusion of stem cells on day 0. The 
source of donor stem cells was either peripheral blood stem cells (PBSC) or bone marrow 
(BM). GVHD prophylaxis was administered to all subjects and consisted of tacrolimus 
(initiated Day -3 before transplant) and methotrexate (initiated Day +1 after transplant) in 
combination with CD24Fc in the treatment arms, and tacrolimus/methotrexate plus saline 
solution in the placebo arm. In the absence of GVHD, tacrolimus tapering started on day 
+100.  
Overall, CD24Fc was well tolerated in the Phase IIa study. There were no infusion-related 
toxicities. There was one possible drug related treatment emergent adverse event (TEAE) 
of  grade III-IV hyperglycemia in the 480 mg CD24Fc group, which was managed with 
insulin. One dose-limiting toxicity (DLT) was observed in the placebo group, and no DLTs 
were observed in the CD24Fc group. There were no adverse events leading to death in 
subjects administered CD24Fc within the 180 days. There was one adverse event of 
pneumonia that led to the death of a subject at Day 48 in the placebo group. The 
development of anti-drug antibodies (ADA) were not detected in any of the 24 subjects at 
any point out to day 100 after HCT. 
The most common TEAEs  grade III (> 10%) included a decrease in platelet counts 
(83.3% placebo and 94.4% CD24Fc), decrease in WBC counts (66.7% placebo and 
88.9% CD24Fc), decrease in neutrophil counts (50% placebo and 83.3% CD24Fc), 
decrease in lymphocyte counts (50% placebo and 77.8% CD24Fc), anemia (50% placebo 
and 66.7% CD24Fc), stomatitis (83.3% placebo and 50% CD24Fc), and nausea (0% 
placebo and 11.1% CD24Fc). These are expected SAEs were anticipated as they were 
hematologic in nature and were otherwise considered related to the myeloablative 
conditioning regimen of HCT. 
In the Phase IIa study summarized in Table 2, compared to treatment with placebo, 
treatment with CD24Fc resulted in trends toward:  
1. Higher Grade III to IV acute GFS rate at Day 180 (94.4% in CD24Fc treatment group, 
50.0% in placebo) (hazard ratio = 0.1),  
2. Higher DFS rate at 1 year (83.3% in CD24Fc treatment group, 50.0% in placebo) 
(hazard ratio = 0.2),  
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3. Higher OS rate at 1 year (83.3% in CD24Fc treatment group, 50.0% in placebo) 
(hazard ratio = 0.2),  
4. Higher Grade III to IV acute GRFS rate at Day 180 (83.3% in CD24Fc treatment 
group, 33.3% in placebo) (hazard ratio = 0.2), 
5. Lower incidence of Grade III-IV acute GVHD by Day 180 (5.6% in CD24Fc treatment 
group, 33.3% in placebo) (hazard ratio = 0.1),  
6. Lower cumulative incidence of leukemia relapse at 1 year (11.1% in CD24Fc 
treatment group, 33.3% in placebo) (hazard ratio = 0.3), 
7. Lower incidence of non-relapse mortality at 1 year (5.6% in CD24Fc treatment group, 
16.7% in placebo) (hazard ratio = 0.3), 
8. Similar cumulative incidence of Grade II to IV acute GVHD by Day 180 (38.9% in 
CD24Fc treatment group, 33.3% in placebo) (hazard ratio = 2.6),  
9. Similar 1 year GRFS (Grade III-IV acute GVHD / chronic GVHD requiring systemic 
immunosuppressive treatment /relapse free survival) (32.4% in CD24Fc treatment 
group, 33.3% in placebo) (hazard ratio = 0.7), 
10. Higher cumulative incidence of all grade chronic GVHD at 1 year (63.3% in CD24Fc 
treatment group, 33.3% in placebo) (hazard ratio = 2.1).  
 
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TABLE 2: UNIVARIATE RESULTS FROM THE CD24FC PHASE IIA STUDY 
Outcome 
Placebo/Tac/MTX 
N=6 
CD24Fc/Tac/MTX 
N=18 
Grade III-IV Acute GVHD Free 
Survival (aGFS) 
HR 
(90% CI) 
1.00 
0.1 
(0.0-0.7) 
Incidence at 6 mo 
(95%CI) 
50% 
(11-80%) 
94% 
(67-99%) 
Relapse 
HR 
(90% CI) 
1.00 
0.3 
(0.1-1.4) 
Incidence at 12 mo 
(95%CI) 
33% 
(2.9-71%) 
11% 
(1.7-30%) 
Overall Survival 
HR 
(90% CI) 
1.00 
0.2 
(0.1-1.0) 
Probability at 12 mo 
(95%CI) 
50% 
(11-80%) 
83% 
(57-94%) 
Disease free survival 
HR 
(90% CI) 
1.00 
0.2 
(0.1-0.9) 
Probability at 12 mo 
(95%CI) 
50% 
(11-80%) 
83% 
(57-94%) 
Chronic GVHD 
HR 
(90% CI) 
1.00 
2.1 
(0.6-7.4) 
Probability at 12 mo 
(95%CI) 
33% 
(2.5-72%) 
63% 
(34-82%) 
HR=Hazard Ratio, CI=Confidence Interval. The event for overall survival was death and the event for 
disease free survival was death or relapse. A hazard ratio (HR) less than 1 implies that CD24Fc group has 
less events at any time compared to the Tac+MTX Control reference group (indicated by a HR of 1.00). 
 
3.8.2.1.1 Historical Control From the Phase IIa Study Sites: UM/OSU Control.  
Considering the limited sample size of available placebo controls in the Phase IIa portion, 
a post-hoc analysis of patients was conducted at the highest enrolling centers involved in 
this trial (UM, OSU) the relapse incidence in 92 similarly treated patients receiving 
myeloablative unrelated donor HCT using tacrolimus and methotrexate GVHD 
prophylaxis. The rates of 180 day Grade III-IV acute GVHD free survival, 1 year relapse 
free survival and 1 year overall survival are compared with CD24Fc group (see Figure 8, 
Figure 10, and Figure 11). 
3.8.2.1.2 Registered Matched Control from the CIBMTR 
In order to better evaluate the efficacy of novel approaches for GVHD prophylaxis, a 
registered matched control analysis was performed using data from the Center for 
International Blood and Marrow Transplant Research (CIBMTR) for patients with 
myeloablative matched unrelated donor hematopoietic cell transplantation and with 
TAC/MTX as GVHD prophylaxis.  
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The Center for International Blood and Marrow Transplant Research (CIBMTR) is an 
observational registry for allogeneic and autologous transplantations since 1972.  
Transplant centers report consecutive transplants and patients are followed longitudinally 
until death or lost to follow up. In person audits and continuous process improvement for 
all centers ensure data accuracy and completeness of follow up of transplanted patients. 
Eligibility criteria were identical to the Phase IIa portion of the trial and included recipients 
of HLA-matched unrelated donor hematopoietic cell transplantation (HCT), from 2015 to 
2017, for treatment of acute myeloid leukemia, acute lymphoblastic leukemia, chronic 
myelogenous leukemia, myelodysplastic syndrome, and chronic myelomonocytic 
leukemia.  Potential controls were restricted to those with a performance score ≥ 70, 
myeloablative conditioning regimens (busulfan + fludarabine or cyclophosphamide + total 
body irradiation) and tacrolimus with methotrexate for graft-versus-host disease (GVHD) 
prophylaxis. 
Up to 4 Controls per Case was selected from the CIBMTR’s database at the CRF level, 
matched on age (±5 years), HCT-comorbidity score, and disease status (1st complete 
remission or 2nd complete remission or primary induction failure for acute leukemia, 1st 
and 2nd chronic phase or blast phase for chronic myelogenous leukemia, refractory 
anemia, refractory cytopenia, refractory anemia with excess blasts I or II for 
myelodysplastic syndrome, and CPSS score for chronic myelomonocytic leukemia). 
Most Cases (N=16) were matched to 4 CIBMTR Controls.  Two Cases were matched to 
2 CIBMTR Controls. The final study population compared 18 Cases to their 68 matched 
CIBMTR Controls. 
The primary objective was grade III-IV acute GVHD-free survival (aGFS) and secondary 
objectives included grades II-IV and III-IV acute GVHD, chronic GVHD, relapse, disease 
free survival and overall survival.  
Table 3 describes the study population in Cases vs. CIBMTR Controls. Table 4 presents 
the 180 day probabilities and the hazard ratio (95% confidential interval) generated from 
marginal Cox regression models to accommodate Case-Control matching. Multivariate 
adjusted models were not done due to the small sample size and low even rate. 
Probability estimates for acute and chronic GVHD and relapse were considered 
competing events.   
TABLE 3: CHARACTERISTICS OF PATIENTS: CASES VS. CONTROLS 
 
Cases 
Controls 
Number of patients 
18 
68 
Number of centers 
2 
34 
Age at transplant 
 
 
Median (range) 
64 (24-69) 
64 (23-70) 
18-29 
3 (17) 
8 (12) 
30-39 
1 (6) 
5 (7) 
40-49 
2 (11) 
3 (4) 
50-59 
0 
10 (15) 
60-69 
12 (67) 
42 (62) 
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Cases 
Controls 
Age at transplant (cutoff at 65 
years) 
 
 
 >65 
11 (61) 
39 (57) 
 ≤65 
7 (39) 
29 (43) 
Sex 
 
 
Male 
11 (61) 
42 (62) 
Female 
7 (39) 
26 (38) 
Race 
 
 
Caucasian 
17 (94) 
62 (91) 
African-American 
0 
1 (1) 
Asian 
0 
3 (4) 
Native American 
0 
1 (1) 
Not reported 
1 (6) 
1 (1) 
Ethnicity 
 
 
Hispanic or Latino 
1 (6) 
2 (3) 
Non-Hispanic 
or 
non-
Latino 
17 (94) 
63 (93) 
Not reported 
0 
3 (4) 
Disease 
 
 
AML 
7 (39) 
19 (28) 
ALL 
3 (17) 
12 (18) 
CML 
2 (11) 
2 (3) 
MDS 
5 (28) 
32 (47) 
CMMol 
1 (6) 
3 (4) 
Disease status 
 
 
Early stage a 
10 (56) 
40 (59) 
Late stage b 
8 (44) 
28 (41) 
Disease Risk Stratification 
(DRI) 
 
 
Low to Intermediate 
10 (56) 
34 (50) 
High 
8 (44) 
34 (50) 
Karnofsky score 
 
 
70 
0 
5 (7) 
80 
17 (94) 
24 (35) 
90 
0 
22 (32) 
100 
1 (6) 
17 (25) 
HCT comorbidity index 
 
 
0 
6 (33) 
22 (32) 
1-2 
5 (28) 
20 (29) 
≥ 3 
7 (39) 
26 (38) 
Donor/recipient CMV 
serostatus 
 
 
+/+ 
5 (28) 
19 (28) 
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Cases 
Controls 
+/- 
1 (6) 
7 (10) 
-/+ 
4 (22) 
22 (32) 
-/- 
8(44) 
20 (29) 
Conditioning intensity 
 
 
Myeloablative 
18 
68 
Conditioning regimen 
 
 
TBI + cyclophosphamide 
3 (17) 
12 (18) 
TBI + cyclophosphamide 
+ thiotepa 
0 
1 (1) 
TBI + other(s) 
1 (6) 
0 
Fludarabine + busulfan 
14 (78) 
55 (81) 
Transplant year 
 
 
2015 
0 
23 (34) 
2016 
5 (28) 
31 (46) 
2017 
13 (72) 
14 (21) 
 
 
 
Median follow-up of survivors 
(range), months 
(Oct. 2018) 
13 (9-21) 
24 (6-37) 
a MDS early stage: Refractory Anemia; CML early stage: Hematologic CR or First chronic phase;  
CMMol late stage: CPSS score = 0; AML early stage: CR1; ALL early stage: CR1 or CR2 
b MDS late stage: RAEB-I, RAEB-II; CML late stage: Accelerated or Blastic phase; CMMol late stage: CPSS 
score > 0; AML late stage: PIF; ALL late stage: PIF 
 
TABLE 4: UNIVARIATE ANALYSIS OF 180 DAYS GRADE III-IV ACUTE GVHD-FREE SURVIVAL, 180 
DAYS ACUTE (GRADES II-IV AND III-IV) GVHD, 1 YEAR CHRONIC GVHD, 1 YEAR RELAPSE, 1 
YEAR NON-RELAPSE MORTALITY, 1 YEAR DISEASE-FREE SURVIVAL, AND 1 YEAR OVERALL 
SURVIVAL. CONTROLS (CIBMTR REFERENCE GROUP) VS. CASES.  
 
Cases (N=18) 
Controls (N=68) 
HR: Ctr=1 
P-value 
Outcomes 
Events/Eval 
Prob 
(95% CI) Events/Eval 
Prob  
(95% CI) 
(95% CI) 
Grade III-IV acute GVHD-
free survival at 180 days 
1/18 
94% 
(80-100)% 
22/68 
68% 
(56-78)% 
0.34  
(0.13-0.91) 
0.03 
Grade II-IV acute GVHD-
free survival at 180 days 
7/18 
61% 
(38-84)% 
43/68 
37% 
(25-48)% 
0.54  
(0.28-1.02) 
0.06 
Grade III-IV acute GVHD-
free relapse free survival at 
180 days 
3/18 
83% 
(57-94)% 
30/68 
56% 
(44-68)% 
0.44  
(0.20-0.96) 
0.04 
Grade II-IV acute GVHD at 
180 days 
7/18 
39% 
(18-62)% 
36/68 
53% 
(41-65)% 
0.57 
(0.25-1.28) 
0.17 
Grade III-IV acute GVHD at 
180 days 
1/18 
6% 
(0-20)% 
13/68 
19% 
(11-30)% 
0.27 
(0.03-1.96) 
0.21 
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Figure 9: 180 DAY GRADE II-IV GVHD-FREE SURVIVAL. CD24FC-TREATED VS MATCHED CIBMTR HISTORICAL 
CONTROLS (CM68). 
The 1 year probability of disease free survival (DFS) was 83% for the CD24Fc Cases and 
48% for the CIBMTR Controls (HR=0.39, 95% CI: 0.18-0.81, P=0.01) as shown in Figure 
10. The DFS for placebo is 50% and for UM/OSU control group of 92 patients is 61%.  
 
FIGURE 10: CD24FC 
TREATMENT IMPROVES 1 
YEAR RELAPSE FREE 
SURVIVAL (RFS). 
CD24Fc treatment 
compared with CIBMTR 
matched control group: 
p=0.011 (HR=0.386); 
CD24Fc treatment 
compared with placebo 
group: p=0.05; CD24Fc 
treatment compared with 
UM/OSU control group 
of 92 patients: p=0.04.  
 
 
 
 
0
10
20
30
40
50
60
70
80
90
100
180D24AGFS
0
1
2
3
4
5
6
Time
Number at risk
Group: CD24Fc
18
17
13
11
11
11
11
Group: CM68
68
44
33
29
26
26
25
G1
CD24Fc
CM68
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The 1 year probability of overall survival (OS) was 83% for the CD24Fc Cases and 58% 
for the CIBMTR Controls (HR=0.42, 95% CI: 0.19-0.96, P=0.04) as shown in Figure 11. 
The OS for placebo is 50% and for UM/OSU control group of 92 patients is 68%.  
 
FIGURE 11: CD24FC 
TREATMENT SHOWS 
TREND IN IMPROVEMENT 
OF 1 YEAR OVERALL 
SURVIVAL (OS). 
CD24Fc treatment 
compared with 
CIBMTR matched 
control group: p=0.04 
(HR=0.425); CD24Fc 
treatment compared 
with placebo group: 
p=0.07; CD24Fc 
treatment compared 
with UM/OSU control 
group of 92 patients: 
p=0.06.  
 
 
 
The 180 days probability of grade III-IV acute GVHD and relapse-free survival was 83% 
for the CD24Fc Cases and 56% for the CIBMTR Controls (HR=0.443, 95% CI: 0.196-
0.974, P=0.04) as shown in Figure 12.  
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Figure 12: 180 DAY GRADE III-IV GVHD-FREE AND RELAPSE-FREE SURVIVAL. CD24FC VS MATCHED CIBMTR 
CONTROL (CM68). 
 
3.8.2.1.3 Reduction of Conditioning Related Mucositis 
Myeloablative conditioning for HCT is often associated with severe regimen related 
toxicity including organ failure. Grade 3-4 mucositis occurs in approximately 90% of 
patients receiving radiation containing regimens [50], which can promote mucosal barrier 
injury and infection, utilization of opioid analgesia and parenteral nutrition, and 
prolongation of hospitalization. In the CD24Fc group of 18 patients, none died within the 
first 100 days post HCT, while 1 out of 6 in the placebo group died on Day 48 due to 
pulmonary toxicity with respiratory failure. Severe oral mucositis has been reported by 
HCT patients as the most distressing symptom they experienced [51]. We calculated the 
grade-day score of severe grade 3-4 mucositis (total number of days patients had grade 
3-4 mucositis) in the placebo cohort and three CD24Fc treatment cohorts. CD24Fc multi-
dosing had a significant reduction of severe mucositis grade-day score (placebo vs. 960 
multi-dose: P=0.03) (Figure 13).  
0
10
20
30
40
50
60
70
80
90
100
180D34GRFS
0
1
2
3
4
5
6
Time
Number at risk
Group: CD24Fc
18
17
17
17
16
16
15
Group: CM68
68
56
52
48
43
43
35
G1
CD24Fc
CM68
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aGVHD that are associated with increased risk of non-relapse mortality [55].  A trend of 
reduction in the incidence of relapse is also observed in subjects who received CD24Fc 
(11.1%) as compared to subjects who did not, both as compared to the placebo group 
(33.3%) and two sets of internal and external (CIBMTR) contemporary controls (both 
23%), demonstrating that CD24Fc does not affect the GVT effects of the graft and may 
contain salutary properties that prevent leukemia relapse. The benefit of including 
CD24Fc in standard GVHD prophylaxis regimens is further supported by the better NRM 
in CD24Fc exposed subjects (6%) as compared to placebo (17%), better 1-year overall 
survival (83% versus 50%, CD24Fc versus placebo), a statistically significant 
improvement in grade III – IV aGFS (94% versus 50%, CD24Fc versus placebo, 
respectively), a dose-dependent reduction in severe mucositis, and a favorable overall 
safety profile.   
3.8.4 Rationale for a Randomized, double blind, placebo-controlled Phase III Trial 
This multicenter Phase III clinical trial will evaluate adding CD24Fc to standard of care 
TAC/MTX acute GVHD prophylaxis for the efficacy in improving the proportion of patients 
who survive to 180 days without developing severe (Grade III-IV) acute GVHD. The 
randomized, double blind and placebo-controlled study will provide the most rigorous 
analysis to assess the efficacy of the novel biological agent CD24Fc in reduction of severe 
acute GVHD with clear advantage in improvement of relapse free survival and overall 
survival.  
 
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4 ELIGIBILITY 
4.1 INCLUSION CRITERIA  
4.1.1 A prospective patient for allogeneic HCT for a malignant hematologic disorder (see 
section 4.1.3 for eligible diagnoses).  
4.1.2 The donor and recipient must have an HLA-8/8 allelic match at the HLA-A, -B, -C, 
and – DRB1 loci. High-resolution typing is required for all alleles for unmatched 
donors. Only matched unrelated donors are acceptable for this trial.  
4.1.3 The following diagnoses are to be included in the Phase III study: 
Acute Myeloid Leukemia (AML) or Acute Lymphoblastic Leukemia (ALL) in 
remission. Remission is defined as the absence of blasts in the peripheral 
circulation at the time of enrollment, < 5% blasts in the bone marrow and absence 
of extramedullary disease including CNS involvement. 
4.1.4 Males or non-pregnant, non-lactating females, ≥ 18 years of age. Note there is no 
defined upper age limited, so long as deemed appropriate candidate for 
myeloablative conditioning.  
4.1.5 Karnofsky Performance Status ≥70%, see Appendix A.  
4.1.6 Patients must have normal or near normal organ function as defined by their 
treating institutions BMT program clinical practice guidelines. In addition, for 
purposes of this protocol minimum organ function criteria within 30 days of 
beginning conditioning are listed in Table 5 below: 
TABLE 5: ELIGIBILITY ACCORDING TO PRE HCT ORGAN FUNCTION 
Total bilirubin 
≤2.0 x ULN (unless from Gilbert’s disease or 
disease-related) 
AST(SGOT)/ALT(SGPT) 
<3.0 X institutional upper limit of normal 
Estimated or actual GFR 
>50 mL/min/1.73 m2 for patients with creatinine 
levels above institutional normal 
(GFR should be corrected for BSA) 
Pulmonary Function Tests* 
DLCO, FEV1, FVC > 50% 
DLCO should be corrected for hemoglobin 
Ejection Fraction* 
>50% 
Hematopoietic Cell 
Transplantation-Specific 
Comorbidity Index (HCT-CI)# 
< 5 
*May be assessed up to 10 weeks prior to the date of enrollment. 
#The HCT-Specific Comorbidity Index (HCT-CI) found in Appendix E which states “Prior 
solid tumor” “requiring treatment with chemotherapy” (HCI-CI score=3) is modified to: 
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“Prior solid tumor” “requiring treatment with chemotherapy, if the solid tumor 
chemotherapy is documented to be complete and the tumor has not progressed in the 
two years before the HCT, the BMT physician may take this into consideration and adjust 
the HCI-CI score to < 3.” 
4.1.7 Ability to understand and the willingness to sign a written informed consent 
document. 
4.1.8 Women of child bearing potential and men must agree to use contraception prior 
to study entry and through day 100 post HCT (hormonal or barrier method of birth 
control; abstinence). Should a woman become pregnant or suspect she is 
pregnant while she or her partner is on treatment in this study, she should inform 
her study physician immediately. Men treated or enrolled on this protocol must also 
agree to use adequate contraception prior to the study until day 100 post HCT 
(See section 6.0).  
4.2 EXCLUSION CRITERIA 
4.2.1 Subjects may not have presence of active CNS disease or extramedullary disease.  
4.2.2 Prior cytotoxic chemotherapy within 21 days from the initiation of HCT conditioning 
(i.e. intensive induction / consolidation for AML). Note, certain low intensity 
treatments not intended to induce remission but rather stabilize disease are 
acceptable up to 24 hours prior to initiation of HCT conditioning (i.e. Sorafenib). 
4.2.3 Matched sibling donor, cord blood and haploidentical donors are not eligible.  
4.2.4 HLA-mismatch at the HLA-A, -B, -C, and – DRB1 loci. Note, HLA-DQ mismatches 
are permissible.  
4.2.5 Pregnant and nursing mothers are excluded from this study. This is because the 
risk to the fetus is unknown.  
4.2.6 Any physical or psychological condition that, in the opinion of the investigator, 
would pose unacceptable risk to the patient or raise concern that the patient would 
not comply with protocol procedures. 
4.2.7 Uncontrolled infections. Patients still under therapy for presumed or proven 
infection are eligible provided there is clear evidence (radiologic, clinical and/or 
culture) that the infection is well controlled. Patients testing positive for SARS-CoV-
2, whether symptomatic or asymptomatic, are excluded. Patients recovering from 
COVID-19 and viral testing negative for SARS-CoV-2 are eligible.  
4.2.8 Patients seropositive or PCR positive for the human immunodeficiency virus (HIV). 
Patients with evidence of active Hepatitis B or Hepatitis C PCR positivity. 
4.2.9 Prior HCT (allograft or autograft). 
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4.2.10 Use of T cell depletion either ex vivo or in vivo (such as ATG or alemtuzumab or 
ex vivo CD34+ selected HCT) is prohibited. 
4.2.11 Current or prior diagnosis of antecedent Myelofibrosis is excluded. 
5 PHASE III STUDY 
5.1 OVERVIEW  
The prospective, randomized, double blind, placebo controlled, multi-center Phase III 
study is designed to assess the safety, tolerability and efficacy of the addition of CD24Fc 
to standard tacrolimus and methotrexate GVHD prophylaxis in myeloablative matched 
unrelated donor HCT. The goal of the study is to confirm that adding CD24Fc to standard 
tacrolimus and methotrexate will improve the 180 day Grade III-IV aGFS. To further limit 
the heterogeneity to assess the potential toxicity and to facilitate statistical estimates of 
GVHD and relapse incidence, the Phase III study will restrict the study to AML and ALL 
patients with matched unrelated donors receiving myeloablative conditioning regimen.   
5.2 SCREENING PROCEDURES 
The CRO Medpace will serve as the multi-site study coordinator. An IRB-approved 
informed consent must be obtained from patients (or legal guardians) prior to the initiation 
of treatment on this protocol. Patient demographics, including the patient’s age, gender, 
race, ethnicity, underlying disease, disease risk index (DRI) (Appendix D) [56], disease 
remission status, conditioning regimen, cell source, donor/recipient CMV status, HCT-CI, 
KPS, transplant center and donor age/gender, and eligibility criteria will be recorded at 
entry into the study. All screening evaluations will be completed as part of the local 
institutions standard work up for HCT.  
5.3 TREATMENT SCHEMA 
Based on the Phase IIa clinical safety results and the pharmacokinetic data, the 
recommended Phase III dose has been determined to be multi-dose 480-240-240 mg 
administered on day -1, day 14 and day 28, respectively. This regimen will provide 
biologically active levels of CD24Fc through the acute GVHD peak risk period (median 
30 days). The Phase III study schema is shown in Figure 1.  Dosing is based on a fixed 
amount and not based on weight or BSA. 
5.4 RATIONALE FOR TREATMENT SCHEMA  
We propose early administration of CD24Fc for acute GVHD prevention based on the 
following rationale: 1) during or immediately following HCT myeloablative conditioning 
tissue injury ensues resulting in release of inflammatory mediators, including exaggerated 
levels of DAMPs, that have been implicated in the initiation of acute GVHD; 2) through 
direct blockade of DAMPs and enhancing Siglec-10 / CD24 interactions, CD24Fc is 
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capable of markedly reducing the inflammatory responses to DAMPs that initiate acute 
GVHD; and 3) multiple established models of acute GVHD demonstrate that early 
administration of exogenous human CD24Fc, prior to infusion of donor cells, attenuates 
acute GVHD and improves survival after HCT.  
5.5 ADMINISTRATION OF GVHD PROPHYLAXIS  
5.5.1 CD24Fc  
CD24Fc will be administered intravenously on day -1 (480 mg) prior to HCT (day 0), and 
on day 14 (240 mg) and day 28 (240 mg) post HCT. Subjects will also receive standard 
of care GVHD prophylaxis with methotrexate and tacrolimus. Attempts should be made 
to administer the CD24Fc on schedule and to ensure that at least 14 days of interval 
between dosing. The dose may not be delayed for the first intended administration but 
may be delayed for up to 4 days for the second (i.e. on day 14 + 4) and the third 
administration (day 28 + 4 post HCT) for unanticipated events such as toxicity from 
preceding conditioning chemotherapy, severe infection or scheduling 
5.5.2 Tacrolimus  
a. Tacrolimus will begin on day -3. IV or PO dosing is permitted. For intravenous dosing 
the recommended starting dose is 0.03 mg/kg/day based on adjusted body weight as a 
continuous infusion. For oral dosing the recommended starting dose is 0.045 mg/kg/dose 
twice daily. 
b. Patients who cannot tolerate tacrolimus, then cyclosporine at a dose of 100x the 
intravenous tacrolimus dose (e.g., 3 mg/kg/day starting dose) is recommended. For oral 
dosing the recommended conversion is 3x the intravenous dose. When Neoral brand is 
used, because of greater bioavailability, the conversion is 2x the IV dose. 
c. Tacrolimus will be switched to oral administration when applicable based on the 
patient’s ability to take oral medication generally at a daily dose of three times the IV dose.  
d. In the absence of GVHD, levels will be monitored for therapeutic dosing only during the 
first 100 days post-transplant. The therapeutic target trough level for tacrolimus is 5-15 
ng/mL. Tacrolimus levels outside of the desired range are not considered protocol 
deviations. 
e. In the absence of GVHD or relapse, it is recommended that tacrolimus tapering begin 
on day +100 post-transplant.  
f. In the presence of GVHD, it is recommended that tacrolimus be continued at the 
therapeutic dosing. 
5.5.3  Methotrexate 
Methotrexate will be used in combination with tacrolimus for standard GVHD prophylaxis. 
Methotrexate will be given intravenously at a dose of 15 mg/m2/dose once daily on Day 1 
after HCT, and at a dose of 10 mg/m2/dose on days 3, 6, and 11 after HCT. Attempts 
should be made to deliver all four doses, however, methotrexate may be omitted or 
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reduced doses at the discretion of the treating physician according to institutional 
guidelines.  Leucovorin rescue may also be administered according to local institutional 
practice guidelines.  Reduced Methotrexate per institutional practice guidelines is 
allowed, but should inform the study PI.  
 
5.6 MYELOABLATIVE CONDITIONING REGIMENS 
Pre HCT conditioning will be selected by the local investigator. Examples of 
acceptable regimens with dose ranges are outlined below: 
5.6.1 Busulfan and Fludarabine (Bu/Flu) 
Days -5 to -2: Busulfan (3.2 mg/kg/day IV or 130 mg/m2/day; total dose of 12.8 mg/kg or 
520 mg/m2, respectively).  
Days -5 to -2: Flu (30 to 45 mg/m2/day, total dose of 120 - 180 mg/m2) 
The specific sequence and timing of busulfan and fludarabine administration in MAC 
regimens will be done according to institutional standards.  
5.6.2 Busulfan and cyclophosphamide (Bu/Cy) 
Days -7 to -4: Busulfan (3.2 mg/kg/day IV or 130 mg/m2/day, total dose of 12.8 mg/kg or 
520 mg/m2, respectively). 
Days -3 to -2: cyclophosphamide (60 mg/kg/day, total dose of 120 mg/kg). 
5.6.3 Cyclophosphamide and total body irradiation (Cy/TBI) 
Days -7 to -4: TBI (1200-1420 cGy) 
Days -3 to -2: Cy (60 mg/kg/day, total dose of 120 mg/kg) 
The sequence of cyclophosphamide, and TBI administration practices for myeloablative 
regimens will be done according to institutional standards. 
5.6.4 Etoposide and total body irradiation (VP16/TBI) 
Days -7 to -4 (or Day -6 to -4): TBI (1200 – 1320 cGy) 
Day -3: Etoposide (VP16) (60mg/kg, IV infusion in 4 hours). 
The sequence of etoposide, and TBI administration practices for myeloablative regimens 
will be done according to institutional standards. 
5.6.5 Other Myeloablative Conditioning 
This trial is designed to study GVHD prevention in the general context of myeloablative 
conditioning, thus other myeloablative conditioning regimens are acceptable and do not 
constitute protocol deviation so long as they fulfill CIBMTR myeloablative criteria 
(APPENDIX B). Incorporation of T cell depletion either ex vivo or in vivo (such as ATG, 
alemtuzumab or ex vivo CD34+ selected HCT) is prohibited.   
 
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5.7 DONOR ELIGIBILITY, SELECTION, AND RELATED PROCEDURES 
Donor selection will be conducted according to local institution’s BMT clinical practice 
guidelines.  Participating HCT centers are registered and must remain in compliance with 
the U.S. Department of Health and Human Services FDA 21 CFR 1271. Donors shall be 
assessed per National Marrow Donor Program (NMDP) Donor Center and Apheresis 
Collection Center Procedures of Interaction that will determine compliance with FDA 
donor eligibility regulations. Matched unrelated donor products undergo comprehensive 
medical screening to determine that the donor is free of risk factors for infection due to 
relevant communicable diseases, as well as testing for relevant communicable disease 
agents prior to administration.  Donors are not research subjects. 
• No sibling, cord, haploidentical or syngeneic donors are eligible.  
• The source of donor stem cells will be peripheral blood stem cells (PBSC) or bone 
marrow (BM). 
• BM or PBSC should be infused into the patient within the time frame according to 
the institutional guidelines of each BMT site. Due to the COVID-19 situation, the 
NMDP strongly recommends cryopreservation of all donor products as far in 
advance of the initiation of patient conditioning as is feasible, dictated by the 
clinical situation of the patient. 
• For PBSC: The recommended stem cells dose is ≥ 5.0 x 106, up to 10 x 106 CD34 
cells/kg recipient weight. 
• For BM infusions: The recommended cell dose is ≥ 2.0 x 108 mononuclear cells/kg 
recipient weight. 
Note: The day of the stem cell/marrow infusion will be defined as day 0. If more than one 
day of infusion is required, then these days are defined as day 0a, day 0b accordingly. 
The first day after the last stem cell infusion will be defined as day 1.  
5.8 POST-TRANSPLANT SUPPORTIVE CARE 
Post-transplant supportive care outside of the scope of what is delineated in this protocol, 
for instance infection prophylaxis, will be conducted as per the local institution’s BMT 
clinical practice guidelines. 
5.8.1 Growth Factors 
G-CSF may be given per institutional guidelines. 
5.8.2 Seizure Prophylaxis 
Keppra (Levetiracetam) will be administered for the prevention of busulfan-associated 
seizures to all subjects receiving busulfan. Typically, this will involve initiation of 
Levetiracetam 12 hours prior to Busulfan through 48 hours after last dosage. Specifics of 
Dosing of Levetiracetam will be administered as per the institutions BMT guidelines. 
Alternatively, Phenytoin or another similar seizure prophylaxis agents may be 
administered starting prior to starting busulfan for the prevention of busulfan-associated 
seizures, according to institutional practices. 
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5.8.3 Blood Products 
Transfusion thresholds for blood product support will be consistent with the standard 
institutional guidelines. All blood products will be irradiated. 
5.8.4 Prophylaxis Against Infections 
Patients will receive infection prophylaxis according to institutional guidelines. Infection 
prophylaxis should include, but is not limited to, agents or strategies (e.g., PCR screening 
and preemptive therapy) to reduce the risk of bacterial, Herpes simplex, CMV, EBV, 
Pneumocystis jiroveci and fungal infections: 
5.8.4.1 Antifungal therapy: 
Prophylaxis with fluconazole or other antifungal agents will be given as per local 
institutional guidelines. Fluconazole, voriconazole and other azoles are expected to 
increase serum cyclosporine or tacrolimus levels, therefore, dosages of cyclosporine or 
tacrolimus should be adjusted accordingly. 
5.8.4.2 Cytomegalovirus (CMV):  
CMV monitoring will be done according to institutional guidelines. It is recommended that 
at minimum weekly assessment for CMV be done through Day 100 post-transplant, and 
then at each clinical assessment until day 180 post-transplant. Any reactivation of CMV 
necessitating treatment and/or CMV end organ disease (enteritis, pneumonitis) will be 
captured in this study. Preemptive treatment (early treatment of CMV viremia detected by 
PCR) is the preferred strategy for the majority of patients.  Patients receiving CMV 
prophylaxis with FDA approved agents (Letermovir) will be recorded. Other 
investigational agents for CMV prevention should be avoided while on study treatment.   
It is recommended that the threshold to initiate preemptive therapy will be according to a 
value determined by the assay being performed at the institution or a rising trend on 
successive measurements from patient’s baseline. As an example, when using an FDA 
approved assay that has been calibrated, using WHO CMV standards, a threshold of 
3000 international units (IU)/mL may be used. 
5.8.4.3 Epstein-Barr Virus (EBV): 
EBV monitoring will be done according to institutional guidelines. Any reactivation of EBV 
necessitating treatment and/or EBV-related post-transplant lymphoproliferative disease 
will be captured in this study. 
5.8.4.4 Pneumocystis jiroveci: 
Prophylaxis with Bactrim or other agents directed against Pneumocystis jiroveci must be 
administered where clinically feasible per local institutional guidelines. 
5.8.4.5 Herpes Virus (HSV or VZV): 
Patients must receive acyclovir or valacyclovir through Day 365 post-transplant as 
standard prophylaxis against HSV and VZV per institutional guidelines or until the CD4 
T-cell count has normalized. 
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5.8.5 Sinusoidal Obstruction Syndrome (SOS) / Veno-occlusive Disease (VOD) of 
the Liver 
Prophylaxis against SOS/VOD with ursodiol will be administered according to local 
institutional standard practice. 
5.8.6 Donor Lymphocyte Infusions – Viral-specific cytotoxic T-Lymphocytes 
(CTLs) 
Donor lymphocyte infusions (DLI) should only be performed for therapeutic reasons, 
including but not limited to relapsed or persistent disease or refractory infections. DLI 
should not be administered for mixed chimerism only before Day 180.  
5.8.7 Intravenous Immune Globulin (IVIG).  
IVIG administration for treatment and prevention of infection will be per local institutional 
practice. 
6 STUDY DEFINITIONS 
6.1 SCREENING 
A patient is considered to be in the “Screening” period from the time they sign consent 
until the date the eligibility criteria has been determined as either “eligible” or “ineligible” 
(screen failure). Patients may be consented to this trial based on disease control at the 
time of consent, but later removed from the trial prior to initiation of transplant conditioning 
regimen if disease status confirmation between consenting and transplant changes. In 
the event this occurs, these patients will be replaced. 
6.2 RANDOMIZATION 
A patient is considered to be “Randomized” onto the study once they have been assigned 
to one of the treatment arms through randomization process.  All patients will be 
randomized within 48 hours prior to the treatment of first dosing of either CD24Fc or 
placebo at day -1 (one day before transplantation).  
6.3 TREATMENT PERIOD 
The “Treatment Period” is defined as the first day of treatment with CD24Fc until 60 days 
after HCT. The assessment and reporting period for adverse events (AE) potentially 
related to the study drug (CD24Fc) extend through day 100 post HCT. Based upon PK 
data for CD24Fc this time period will allow for passage of greater than two half-lives.   
6.4 FOLLOW UP PERIOD 
The “Follow Up” period is defined as the first day the patient is no longer within the 
treatment period (i.e. day 101) until the subject comes off study.  The follow-up period 
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can be up to 3 years post HCT. During this time subjects will be followed for acute or 
chronic GVHD, relapse, and survival.  Data collection after one year post HCT will be 
minimal and can be an office visit, phone contact or review of the subject’s medical chart.   
6.5 ON STUDY 
The “On Study” period is defined as the day the patient signs the protocol consent 
document, meets the protocol eligibility criteria and is randomized to a study arm, until 
the subject comes off study. Patients can be taken off study at any time at their own 
request, or they may be withdrawn at the discretion of the investigator for safety, 
behavioral or administrative reasons. 
6.6 OFF TREATMENT 
The “Off Treatment” period is generally defined as the time period where the patient 
completes the study drug treatment period (Day 100) or if one or more of the following 
criteria are met: 
• Death 
• Lost to follow up 
• Withdrawal of consent by the patient or clinical PI for any further treatment and 
follow up observations 
• Grade III-IV Acute GVHD requiring high dose corticosteroid therapy  
• Relapse of the underlying malignancy or development of new malignancy 
• Unacceptable or dose limiting toxicity or complication 
Note: Subjects will be continuously monitored for all grade adverse events per local 
institutional guidelines within 24 hours and severe grade 3 to 5 adverse events through 
100 days post-HCT (e.g. for routine post HCT care and measurement of primary clinical 
endpoint of acute GVHD) and then at minimum quarterly through one year. Severe 
adverse events occurring beyond day 100 post-HCT will be evaluated, monitored and 
recorded but not be reported unless related (probably or definitely) to the study drug 
(CD24Fc). The survival and disease relapse status will be followed for up to 3 years.  
6.7 DEFINITION OF ENGRAFTMENT AND ENGRAFTMENT FAILURE 
Engraftment: Engraftment for neutrophils is defined as the first of three consecutive days 
in which the absolute neutrophil count (ANC) is > 500/L. Engraftment for platelets is 
defined as the first of three consecutive days in which the platelet count is > 20,000/L, 
without transfusion support. 
Primary engraftment failure: will be defined as ongoing ANC <500/L by day 28 post HCT.  
Failure to attain platelet count ≥ 20,000/L will not be considered engraftment failure. 
Patients who engraft prior to day 28 and later have ANC <500/L or platelet transfusion 
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requirements, as frequently occurs in HCT patients due to infection and other 
complications will not be considered to have engraftment failure. 
7 MANAGING TOXICITIES 
7.1 MANAGING INFUSION REACTIONS 
Infusion reactions were not observed in the Phase I and Phase IIa clinical trials which 
involved 84 patients. Infusion reactions were not observed in an ongoing Phase III clinical 
trial in COVID-19 treatment which more than 180 patients have been dosed. However, 
the administration of any recombinant protein has the potential to elicit infusion reactions. 
CD24Fc includes the Fc portion of human IgG1. After target binding, CD24Fc may induce 
FcγR cross-linking, which has been associated with infusion reactions for some 
therapeutics. 
Infusion reactions may include events such as changes in vital signs, fever, difficulty 
breathing, hypotension, generalized or facial edema, nausea, chills, mental status 
changes, urticaria or vomiting during or up to 2 hours following infusion. 
Outlined below are generalized procedures designed to closely monitor, minimize and 
manage any potential infusion reactions:  
1) CD24Fc dosing can be administered in an inpatient or an outpatient hospital unit.  
Premedications do not need to be administered prior to the infusion of CD24Fc to prevent 
infusion reactions but patients should be closely monitored during CD24Fc administration.  
Sites should also follow-up with the patient within 24 hours post CD24Fc administration.  
2) The duration of the infusion will be over a minimum of 60 minutes. The IV rate may be 
reduced to prolong the duration of infusion at the discretion of the investigator and clinical 
team based upon symptoms suggestive of a Grade 2 infusion-related reaction. If an 
infusion reaction is deemed severe (e.g. severe hypotension, hypoxemia) the infusion 
should be stopped. Patients who develop a grade 3 or higher infusion reaction will be 
taken off study drug but continued on study follow up.  
3) Supportive care will be provided as clinically indicated and commiserate with the 
intensity of the infusion reaction. The grade 2 or above infusion reaction can be treated 
following NCI CTEP guidelines, such as supplemental oxygen, diphenhydramine, 
acetaminophen, ibuprofen, IV corticosteroids (i.e. hydrocortisone) and iv fluids.  
4) If a subject experiences a grade 2 infusion reaction but responds promptly to 
symptomatic treatment, premedication with diphenhydramine up to 4 hours prior to study 
drug infusion is recommended for the subsequent treatment. 
5) In accordance with the preparedness for treatment of hypersensitivity reactions, severe 
infusion reactions, and/or cytokine release syndrome emergency resuscitation 
equipment, advanced cardiac life support equipment, and medications (e.g. epinephrine 
kit) must be readily available during CD24Fc administration. 
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7.2 MANAGING ACUTE GVHD 
a. Acute GVHD will be graded and recorded according to MAGIC score system [57] 
(APPENDIX C). Patients are evaluable for the primary endpoint of acute GVHD following 
receipt of HCT on day 0 until day 180 after HCT. Assessment for the secondary endpoints 
of late onset acute GVHD or chronic GVHD endpoints will continue until one year after 
HCT. Acute GVHD secondary to disease relapse treatments such as reduction of 
immunosuppressive agents or administration of immunotherapy drugs and targeted 
therapy drugs should be graded and recorded until day 180 after HCT. However the study 
primary endpoint analysis will not include the acute GVHD secondary to the treatment to 
leukemia relapse.   
b. The diagnosis and severity of GVHD will be determined clinically (see APPENDIX C, 
adults). If stool volumes are incomplete or not recorded stool frequency may be 
considered in grading assessment [57]. Biopsies of affected organs are strongly 
encouraged whenever possible.  Overall acute GVHD will be assessed and graded 
weekly through day +100 after transplant, then at minimum monthly from Day 100 to Day 
180 with quarterly thereafter. If the acute GVHD is diagnosed, the assessment and 
grading should be weekly until GVHD is resolved. The first day of GVHD of a certain 
clinical grade will be counted as the day of onset. The first day of maximum GVHD 
severity will also be recorded.  
c. Individual organ stages will be scored by the attending physician. Stages will be 
reviewed by the PI, including reasons for declaring an individual organ potentially un-
evaluable. For example, elevated indirect bilirubin consistent with acute hemolysis may 
impede liver specific GVHD grading.  
d. If a patient develops acute GVHD, treatment with standard of care is recommended 
according to institutional BMT program clinical practice guidelines (e.g. 2 mg/kg/day of 
prednisone or equivalent). Other GVHD therapy, including immunosuppressives can be 
added at the discretion of the treating physician.  
8 DOSE MODIFICATIONS BASED ON LABORATORY VALUES 
8.1 HEPATIC FUNCTION 
Patients receiving HCT with myeloablative conditioning may have transient elevations in 
LFTs and total bilirubin. However, if ALT or AST is greater than 20 times above the upper 
limit of normal (≥ grade 4 CTCAE v4.0 ALT/ST elevation) OR total bilirubin ≥ 5 mg/dl, 
CD24Fc will be temporarily suspended. If ALT, AST, and total bilirubin fall to < 5 x upper 
limit of normal (< grade 2 CTCAEv4.0) OR total bilirubin falls to < 2.5mg/dl within the 
protocol defined treatment period (up to Day +1) then CD24Fc may be administered.  
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9 REQUIRED OBSERVATIONS (STUDY CALENDAR): 
In general, pre- and post- HCT care will follow local BMT program clinical practice 
guidelines for myeloablative conditioning. For example, routine history, physical, organ 
function testing (PFT, Echocardiogram), and laboratory evaluations (including serologic 
and/or PCR based viral studies) will follow institutional practice guidelines. The following 
assessments/samples will be obtained pre-therapy and post-therapy (Table 6). These 
procedures will be conducted as required observations for study unless indicated 
otherwise.  
9.1 SPECIAL CONSIDERATIONS FOR COVID-19 
The study sites should follow the ASTCT and NMDP guidelines for HCT during the 
COVID-19 pandemic. The study schedule has been adjusted to minimize the SARS-CoV-
2 exposure risk. The post-HCT visits can be in person or by telemedicine. When a patient 
has acute GVHD, it is recommended that they have in person visits for more accurate 
assessment and grading.   
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TABLE 6: STUDY CALENDAR FOR PHASE III STUDY 
 
PRE-HCT 
PRE-HCT 
POST-HCT 
Observations  
Day -28 to -2 
(Screening and 
Randomization) 
- 1 
PRE 
Drug 
-1 
- 1 
2 hr POST 
Drug 
0 
 
+7 
(± 2) 
 
+14 
(± 4) 
 
+ 28 
(± 4) 
Weekly 
from 
+ 0 to 
+100 
(± 3) 
 
Informed Consent 
x 
 
 
 
 
 
 
 
 
Medical History and Examination 
x 
x 
 
 
x 
x 
x 
x 
x 
Pre-HCT organ function and infectious disease testing1 
x 
 
 
 
 
 
 
 
 
Pregnancy test (if applicable) 
x 
 
 
 
 
 
 
 
 
Karnofsky Performance Status 
x 
x 
 
 
 
 
 
 
 
Laboratory testing2  
x 
x 
 
 
 
x 
x 
x 
 
ECG monitoring3 
 
x 
 
x 
 
 
x 
x 
 
CD24Fc (Study Agent) 4 
 
 
x 
 
 
 
x 
x 
 
Hematopoietic Stem Cell Transplant (HCT) 
 
 
 
 
x 
 
 
 
 
Vital Sign monitoring5  
 
x 
 
x 
 
 
x 
x 
 
Acute GVHD assessment6 
 
 
 
 
 
x 
x 
x 
x 
Chronic GVHD assessment 
 
 
 
 
 
 
 
 
 
Concomitant Medications  
x 
x 
 
 
x 
x 
x 
x 
x 
AE Assessment (NCI CTCAE V5.0) 
 
 
 
x 
x 
x 
x 
x 
x 
Assess  Engraftment 
 
 
 
 
 
 
 
x 
 
Bone marrow aspirate & biopsy7 
x 
 
 
 
 
 
 
 
 
Chimerism 
 
 
 
 
 
 
 
 
 
Fasting Lipid Panel including LDL 
 
x 
 
 
 
 
x 
 
 
Survival Follow-Up 
 
 
 
 
 
 
 
 
 
 
 
 
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TABLE 6 (CONT): STUDY CALENDAR FOR PHASE III STUDY CONTINUED. 
 
FOLLOW-UP PERIOD 
SURVIVAL 
FOLLOW-UP8 
  Observations  
+ 100 
(± 7) 
Monthly from 
+100 to +180 
(± 7) 
+270 
(± 14) 
+ 365 
(± 14) 
GVHD Onset 
(± 3) 
Every 6 months 
post +365 
(± 3 months) 
Informed Consent 
 
 
 
 
 
 
Medical History and Examination 
x 
x 
x 
x 
x 
 
Pre-HCT organ function and infectious disease testing1 
 
 
 
 
 
 
Pregnancy test (if applicable) 
 
 
 
 
 
 
Karnofsky Performance Status 
 
 
 
 
 
 
Laboratory testing2  
x 
x 
 
 
 
 
ECG monitoring3 
 
 
 
 
 
 
CD24Fc (Study Agent)4 
 
 
 
 
 
 
Vital Sign monitoring5  
 
 
 
 
 
 
Acute GVHD assessment6 
x 
x 
 
 
x 
 
Chronic GVHD assessment 
x 
x 
x 
x 
 
 
Concomitant Medications  
x 
 
 
 
x 
 
AE Assessment (NCI CTCAE V5.0) 
x 
x 
 
 
 
 
Assess  Engraftment 
 
 
 
 
 
 
Bone marrow aspirate & biopsy7 
 
 
 
 
 
 
Chimerism 
x 
 
 
 
 
 
Fasting Lipid Panel including LDL 
 
 
 
 
 
 
Survival Follow-Up 
 
 
 
 
 
x 
 
 
 
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NOTE: Pre and Post-transplant observations. Patient condition and scheduling issues may impact the time of post-HCT observations. The acceptable time frame 
for completing these observations is ± 3 days through day 60, ± 5 days for observations from day 61 until day 100, and ± 7 to 14 days for observations from day 
100 to day 365.  
1) 
Per institution practice guidelines: Recipient organ function testing will include MUGA or Echocardiography, Electrocardiogram, and Pulmonary Function Testing. 
Donor safety and eligibility assessments and screening for infectious disease markers will be performed according to national marrow donor program (NMDP) 
guidelines.  These include but are not limited to screening for HIV, Hepatitis B and C, HTLV I/II, HSV antibody, Trypanosoma cruzi, west nile virus, syphilis and 
CMV.  The organ function testing may be collected up to 10 weeks prior to enrollment.   
2) 
Laboratory tests include CBC with differential, serum chemistries with creatinine, AST, ALT, and total bilirubin in pre-HCT period. CBC with differential, serum 
electrolytes with creatinine, AST, ALT, and total bilirubin will be performed at a minimum on the day of CD24Fc infusion and three times weekly from day 0 until 
ANC > 500/ul, while hospitalized for HCT. Tacrolimus levels will be monitored per institution clinical practice guidelines. Laboratory testing may be more frequent 
per standard HCT practice.   
3) 
ECG monitoring will be performed on treatment days (Day -1, Day 14 and Day 28).  The ECG should be measured within four hours of the start of study drug 
infusion and 2 hours ± 15 min after the start of infusion. 
4) 
Per protocol, CD24Fc will be administered on day -1, day 14±4 and day 28±4.  See protocol section 7.1 for instructions on identifying and managing infusion 
reactions.  
5) 
Vital signs will be recorded prior to infusion and after CD24Fc infusion (+/- 30 min).   
6) 
Assessment for acute GVHD will occur weekly through day 100. The weekly visits and the follow up visits can be done through telemedicine to decrease the 
exposure risk of COVID-19.  Following day 100 acute and chronic GVHD assessments will occur monthly. The follow up visits can be done through telemedicine 
in case of COVID-19.  MAGIC acute GVHD grading will be used to report disease severity (APPENDIX C). NIH Consensus chronic GVHD grading will be used 
to report chronic GVHD (APPENDIX F). 
7) 
The Pre-HCT bone marrow biopsy may be assessed up to 6 weeks prior to enrollment. 
8) 
The follow up of relapse and survival will be up to 3 years after HCT.  If a subject withdraws from the study and does not consent to continued follow-up of 
associated clinical outcome information, a public records search can be performed for survival. 
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10 PHARMACEUTICAL INFORMATION 
10.1 CD24FC OR CD24IGG (ONCOIMMUNE, INC.), STUDY AGENT 
CD24Fc (CD24 Ig) is a fusion protein consisting of the extracellular domain of mature 
human CD24 linked to the human immunoglobulin G1 (IgG1) Fc domain. 
10.1.1 Molecular Formula and Formulation 
The complete molecular formula of CD24Fc has not been determined at this time.  The 
mature protein is 261 amino acids long and each CD24Fc molecule includes the 30 amino 
acid CD24 extracellular domain. CD24Fc forms a disulfide-linked homodimer with a 
predicted mass of 57.7 kilodaltons (kDa) based on the homodimer amino acid sequence.  
However, the apparent molecular weight of the intact dimer is approximately 80 KDa 
based on non-reduced SDS-PAGE. The CD24 domain is highly glycosylated with both N-
linked and O-linked oligosaccharides, which comprise approximately 80% of the mass of 
the CD24 domain.   
CD24Fc has been formulated as single dose injection solution, at a concentration of 10 
mg/mL in phosphate buffered saline at pH 7.2.  Each CD24Fc Drug Product vial contains 
120 mg of CD24Fc in a volume that allows for extractable 12 ml. Each vial will be labeled 
according to Title 21 of the U.S. Code of Federal Regulations with product name 
“CD24Fc” and “Caution: New Drug – Limited by Federal (or United States) Law to 
Investigational Use”.  
10.1.2 Packaging, Ordering, and Inventory Management 
CD24Fc Drug Product is supplied in clear borosilicate glass vials with chlorobutyl rubber 
stoppers and aluminum flip off seals. Vials are further packaged into 8 vial patient kit 
boxes comprising labeled paperboard boxes outfitted with cardstock box dividers and 
tamper evident seals.  Drug product vials are stored at OncoImmune’s clinical distribution 
site, Almac Clinical Services, at 25 Fretz Road, Souderton, PA. On site inventory will be 
managed by Medpace and additional drug will be ordered by Medpace and shipped 
directly to the drug site from Almac. 
10.1.3 Availability, Storage and Stability 
CD24Fc is supplied as a sterile, clear, colorless, preservative-free aqueous solution for 
parenteral administration. CD24Fc is stored at -20° C until use.  CD24Fc should be 
thawed and equilibrated to room temperature prior to administration.  CD24Fc Drug 
Product used in the Phase I and Phase IIa trials (Lot 09MM-036) is stable for at least 66 
months at -20oC, for 6 months at 5°C and 3 months at 25oC. New CD24Fc Drug Product 
has been manufactured as “Lot 0118-002”. Stability studies for Lot 0118-002 are ongoing 
and it has demonstrated to be stable for 24 months at the intended storage temperature, 
-20oC, for 6 months at 5oC and 1 month at 25°C. 
10.1.4 Administration 
CD24Fc at doses 480 mg or 240 mg should be prepared in a diluent comprising 0.9% 
Sodium Chloride in a volume of 100 ml and be administrated by intravenous infusion over 
a minimum of 60 minutes.  
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CD24Fc is intended for use under the guidance and supervision of a physician.  
• CD24Fc is formulated as single dose injection solution, at a concentration of 10 mg/mL 
at pH of 7.2. Each CD24Fc vial contains 120 mg of the fusion protein in 12 mL injection 
solution.  
• CD24Fc is stored at -20° C until use. CD24Fc should be thawed to room temperature 
prior to administration.  
• No precipitation or visible particulates were observed when the CD24Fc Drug Product 
was formulated with saline for 72 hours at 2 - 8°C or at room temperature. 
The constituted infusion solution should be prepared by a trained medical professional 
using aseptic technique by the following procedure:  
1. Parenteral drug products should be inspected visually before and after reconstitution 
for particulate matter and discoloration prior to administration, whenever solution and 
container permit. If visibly opaque particles, discoloration or other foreign particulates 
are observed, the solution should not be used. 
2. For the first treatment, 4 vials of CD24Fc is required for 480mg, with a total of 48 ml 
in volume. 52 ml sterile 0.9% Sodium Chloride Injection, USP, is required to reach a 
final volume of 100 ml for the dose of 480 mg CD24Fc. Using an empty IV bag, add 
52 ml sterile 0.9% Sodium Chloride followed by 48 ml CD24Fc solution. Gently mix. 
3. For second and third treatments, 2 vials of CD24Fc is required for 240mg, with a total 
of 24 ml in volume. 76 ml sterile 0.9% Sodium Chloride Injection, USP, is required to 
reach a final volume of 100 ml for the dose of 240 mg CD24Fc. Using an empty IV 
bag, add 76 ml sterile 0.9% Sodium Chloride followed by 24 ml CD24Fc solution. 
Gently mix. 
4. The CD24Fc infusion should begin within 3 hours of reconstitution and dilution. The 
infusion must be administered over a period of not less than 60 minutes (≤ 100 mL/hr). 
A latex-free DEHP-free infusion set with an in-line, sterile, non-pyrogenic, low-protein-
binding filter (pore size of 1.2 μm or less) must be used.  
5. At the end of infusion, add a small amount of saline (25 ml) according to institution 
guideline for the flushing of the line to ensure the entire volume of study drug is 
infused. The 25 ml saline solution flushing should be given at the same infusion rate. 
The vials do not contain antibacterial preservatives. Therefore, any unused portion of the 
infusion solution should not be stored for reuse.  
No physical biochemical compatibility studies have been conducted to evaluate the co-
administration of CD24Fc with other agents. CD24Fc should not be infused concomitantly 
in the same intravenous line with other agents.  
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10.1.5 Safety in Humans  
10.1.5.1 
Phase I Safety Data 
A Phase I, randomized, double-blind, placebo-controlled, single ascending dose study to 
assess the safety, tolerability, and PK of CD24Fc in healthy male and female adult 
subjects was conducted. Details are also provided in section 3.8 A total of 40 subjects 
were randomized in 5 cohorts of 8 subjects each, and 39 subjects completed the study. 
CD24Fc was administered via IV infusion over 1 hour. In total, 18 (45.0%) subjects had 
a treatment-emergent adverse event (TEAE) during the study: 6 (60.0%) subjects in the 
placebo group, 2 (33.3%) subjects in the CD24Fc 10 mg group, 3 (50.0%) subjects in the 
CD24Fc 30 mg group, 2 (33.3%) subjects in the CD24Fc 60 mg group, 3 (50.0%) subjects 
in the CD24Fc 120 mg group, and 2 (33.3%) subjects in the CD24Fc 240 mg group. 
All TEAEs in the study were considered mild to moderate in severity by the Investigator 
except for 1 subject in the placebo group who experienced a severe headache. The most 
common TEAEs were headache (6 [15.0%] subjects), burns second degree (3 [7.5%] 
subjects), non-sustained ventricular tachycardia (2 [5.0%] subjects), and upper 
respiratory tract infection (2 [5.0%] subjects). 
Overall, 5 (12.5%) subjects had a study drug-related TEAE: 1 (10.0%) subject in the 
placebo group, 2 (33.3%) subjects in the CD24Fc 10 mg group, 1 (16.7%) subject in the 
CD24Fc 30 mg group, and 1 (16.7%) subject in the CD24Fc 60 mg group. The study 
drug-related TEAEs during the study were headache (4 [10.0%] subjects) and ventricular 
tachycardia (1 [2.5%] subject). A drug-related SAE of ventricular tachycardia was 
experienced by 1 subject in the CD24Fc 60 mg group. This SAE occurred at a rate 
comparable with normal populations, was considered mild by the Investigator, and did not 
lead to discontinuation from the study. No subjects died during the study and no subjects 
discontinued from the study due to an adverse event. There were no clinically meaningful 
changes from baseline in laboratory parameters, vital signs, ECGs, or physical exams 
during the study. 
10.1.5.2 
Phase IIa Safety Data 
The number of subjects with TEAEs from Day -1 to 30 or 60 days after the last dosing 
was the same between all treatment groups: 6 (100.0%) patients in the 240 mg CD24Fc 
single dose cohort, 6 (100.0%) patients in the 480 mg CD24Fc single dose cohort, 
6 (100.0%) patients in the 480/240/240 mg multiple dose cohort, and 6 (100.0%) patients 
who received placebo experienced TEAEs.  
The most common TEAEs were stomatitis (6 [100.0%] patients in the 240 mg CD24Fc 
single dose cohort, 6 [100.0%] patients in the 480 mg CD24Fc single dose cohort, 5 
[83.3%] patients in the 480/240/240 mg CD24Fc multiple dose cohort, and 6 [100.0%] 
patients who received placebo); platelet count decreased (6 [100.0%] patients in the 240 
mg CD24Fc single dose cohort, 6 [100.0%] patients in the 480 mg CD24Fc single dose 
cohort, 5 [83.3%] patients in the 480/240/240 mg CD24Fc multiple dose cohort, and 5 
[83.3%] patients who received placebo); white blood cell count decreased (6 [100.0%] 
patients in the 240 mg CD24Fc single dose cohort, 6 [100.0%] patients in the 480 mg 
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CD24Fc single dose cohort, 5 [83.3%] patients in the 480/240/240 mg CD24Fc multiple 
dose cohort, and 4 [66.7%] patients who received placebo). Severe stomatitis ( Grade 
3) occurred in 3 (50.0%) patients in the 240 mg CD24Fc single dose cohort, 
4 (66.7%) patients in the 480 mg CD24Fc single dose cohort, 2 (33.3%) patients in the 
480/240/240 mg CD24Fc multiple dose cohort, and 5 (83.3%) patients who received 
placebo, with a clear inverse correlation between CD24Fc doses and duration of severe 
stomatitis. 
One (16.7%) patient in the 480 mg CD24Fc single dose cohort and 2 (33.3%) patients 
who received placebo experienced a study drug-related TEAE. The most common study 
drug-related TEAE was diarrhea (1 [16.7%] patient in the 480 mg CD24Fc single dose 
cohort and 2 [33.3%] patients who received placebo). No patients in other cohorts 
experienced a study drug-related TEAE. 
The incidence of Grade 3/4/5 TEAEs was the same between all treatments: 6 (100.0%) 
patients in the 240 mg CD24Fc single dose cohort, 6 (100.0%) patients in the 480 mg 
single dose cohort, 6 (100.0%) patients in the 480/240/240 mg multiple dose cohort, and 
6 (100.0%) patients who received placebo. One (16.7%) patient in the 480 mg CD24Fc 
single dose cohort experienced hyperglycemia that was considered a study drug-related 
Grade 3/4/5 TEAE. 
No patients receiving CD24Fc experienced a DLT during the study.  One dose-limiting 
toxicity (DLT) was observed in the placebo group 
In total, 1 (4.2%) patient died during the study. Patient 103-001 received placebo and 
experienced Grade 4 pneumomediastinum and Grade 5 pneumonia TEAEs that resulted 
in death. Per the Investigator, it was considered unlikely that these TEAEs were related 
to study drug. 
10.1.6 Treatment Emergent SAEs (TESAEs) 
In total, 9 (37.5%) patients experienced TESAEs from Day -1 to 30/60 days after the last 
dosing: 2 (33.3%) patients in the 240 mg CD24Fc single dose cohort (30 days), 
1 (16.7%) patient in the 480 mg CD24Fc single dose cohort (30 days), 4 (66.7%) patients 
in 
the 
480/240/240 
mg 
CD24Fc 
multiple 
dose 
cohort 
(60 
days), 
and 
2 (33.3%) patients who received placebo (30, 30, 60 days). Treatment-emergent SAEs 
reported for patients who received CD24Fc (some patients had more than one condition) 
were nausea (2), stomatitis (1), abdominal pain (1), dehydration(1), decreased appetite 
(1), device related infection (1), pain (1), weight decreased (1), arthritis (1), cognitive 
disorder (1), and embolism (1).  
In total, 1 patient experienced a TEAE that led to discontinuation of study drug: this patient 
received placebo. Patient 103-001 experienced a Grade 4 pneumonia TEAE that led to 
discontinuation of study drug (ie, placebo). Per the Investigator, it was considered unlikely 
that this TEAE was related to study drug. 
In Chemistry laboratory tests, the incidence of TEAEs of alanine aminotransferase 
increased or blood alkaline phosphatase increased were similar between patients who 
received CD24Fc and patients who received placebo (ALT: 44% vs 50%; ALP 22% vs 
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17%). The incidence of TEAEs of aspartate aminotransferase increased was higher for 
patients who received CD24Fc compared to patients who received placebo (28% vs 
18%). Treatment-emergent adverse events of blood creatinine increased were only 
reported by patients who received placebo (33.3%). A TEAE of blood bilirubin increased 
was reported by 1 (16.7%) patient who received placebo. In general, TEAEs were 
consistent with toxicities normally associated with HCT conditioning and did not appear 
associated with investigational therapy or placebo.   
Hematologic Effects: 
In total, the incidence of TEAEs of white blood cell count decreased, lymphocyte count 
decreased, and neutrophil count decreased were higher in patients who received CD24Fc 
compared to patients who received placebo (white blood cells decrease 94% vs 67%, 
lymphocyte decrease 83% vs 50%, neutrophil decrease 89% vs 50%). The incidence of 
TEAEs of platelet count decreased was similar between patients who received CD24Fc 
and patients who received placebo (94% vs 83%). 
No patient had a laboratory abnormality that was considered an SAE or resulted in 
discontinuation of study drug.  
No patients who received either single or multiple dosing of CD24Fc had positive ADA 
results at any time point sampled pre- or post-infusion. 
A TEAE of weight increased was reported by 1 (16.7%) patient who received placebo 
and a TEAE of weight decreased was reported by 3 (16.7%) patients who received 
CD24Fc. A TEAE of ECG QT prolonged was reported by 1 (16.7%) patient who received 
placebo. 
Donor Cell Engraftment and Chimerism: 
In total, 18 (100.0%) patients who received CD24Fc and 6 (100.0%) patients who 
received placebo experienced neutrophil engraftment. The median time to neutrophil 
engraftment was 13.5 days for patients in the 240 mg CD24Fc single dose cohort, 13.5 
days for patients in the 480 mg CD24Fc single dose cohort, 13.0 days for patients in the 
480/240/240 mg CD24Fc multi-dose cohort, and 15.5 days for patients who received 
placebo.  
In total, 18 (100.0%) patients who received CD24Fc and 5 (83.3%) patients who received 
placebo experienced platelet engraftment. The median time to platelet engraftment was 
15.5 days for patients in the 240 mg CD24Fc single dose cohort, 13.0 days for patients 
in the 480 mg CD24Fc single dose cohort, 12.0 days for patients in 480/240/240 mg 
CD24Fc multiple dose cohort, and 15.0 days for patients who received placebo. No 
patients experienced primary engraftment failure. 
The mean CD3 cell chimerism on Day 28/Day 30 was 73.0% donor cells for patients who 
received CD24Fc and 77.4% donor cells for patients who received placebo. The mean 
CD3 cell chimerism on Day 100 was 80.9% donor cells for patients who received CD24Fc 
and 73.8% donor cells for patients who received placebo. 
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CD24Fc plasma concentration over 10,000 ng/ml over the period of Day-1 to Day 42 post-
HCT.  
Following a single IV administration of CD24Fc (240 and 480 mg CD24Fc single dose 
cohorts), the geometric mean plasma exposure (Cmax,-1d, AUC0-42d, and AUC0-inf) 
increased with increasing CD24Fc doses. The mean t½ and λz were similar between the 
240 and 480 mg doses of CD24Fc. The mean values of t½ were 414.739 and 406.648 h 
and the mean values of λz were 0.0018 and 0.0017 h-1 for the 240 and 480 mg CD24Fc 
single dose cohorts, respectively. Additionally, there was an increase in the mean Vz and 
CL between the 240 and 480 mg doses of CD24Fc. 
Following multiple IV administrations of CD24Fc (480/240/240 mg CD24Fc multi-dose 
cohort), the exposure of CD24Fc was sustained over time. Additionally, the mean plasma 
CD24Fc concentration on Day 100 was higher for the 480/240/240 mg CD24Fc multi-
dose cohort (850.84 ng/mL) compared to the single dose cohorts (216.38 ng/mL and 
330.96 ng/mL for the 240 and 480 mg CD24Fc single dose cohorts, respectively). 
Furthermore, the geometric mean AUC0-last,overall value was higher for the 480/240/240 mg 
CD24Fc multi-dose cohort (37,363,953.5 ngh/mL) compared to the single dose cohorts 
(10,156,549.9 ngh/mL and 15,522,686.2 ngh/mL for the 240 and 480 mg CD24Fc single 
dose cohorts, respectively). 
The median tmax,-1d (2.10 h for both the 240 and 480 mg CD24Fc single dose cohorts and 
2.13 h for the 480/240/240 mg CD24Fc multiple dose cohort) remained consistent across 
all of the CD24Fc doses. For the 480/240/240 mg CD24Fc cohort, the median tmax,-1d and 
tmax,28d were similar (2.13 and 2.52 h, respectively). 
 
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FIGURE 15: PLOT OF MEAN (±SD) PLASMA CD24FC CONCENTRATION BY TREATMENT – PK EVALUABLE 
POPULATION.  
UPPER PANEL: PK IN LINEAR SCALE. LOWER PANEL: PK IN SEMI-LOG SCALE. SINGLE DOSE COHORTS, 240MG (N=6); 
480MG (N=6); MULTI-DOSE COHORT, 480-240-240MG (N=6). 
 
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10.1.8 Immunogenicity in Humans 
10.1.8.1 
Phase I ADA 
Serum samples in the Phase I study were screened for anti-drug antibodies. Anti-CD24Fc 
antibodies were detectable at Day 28 and Day 42 in 1 subject in each of the 5 dose 
cohorts; however, for the subject in the CD24Fc 120 mg group and the subject in the 
CD24Fc 240 mg group, anti-CD24Fc antibodies were also detectable pre-dose at levels 
higher than post-dose levels. Except for those subjects with significant pre-dose anti-
CD24Fc antibody levels, all post-dose anti-CD24Fc antibody levels were modest. No 
deviations in PK were found in any subjects with detectable anti-CD24Fc antibody levels. 
10.1.8.2 
Phase IIa ADA 
In the Phase IIa allogeneic HCT context, given the immunoablation and 
immunosuppression of host immunity at time of CD24Fc administration, ADA responses 
were monitored but unlikely to be elicited.  
For the two single dose cohorts, the samples were collected at 7 time points from Day-1 
to Day 100. For the multi-dose cohort, the samples were collected at 13 time points from 
Day-1 to Day 100. As expected, all samples are negative for ADA in the Phase IIa study. 
10.2 PLACEBO 
The placebo will consist of 100 ml of 0.9% Sodium Chloride.  
CD24Fc is supplied as a sterile, clear, colorless, preservative-free aqueous, solution and 
thus is indistinguishable from placebo (saline). Since CD24Fc has not been associated 
with infusion reactions and is a clear, colorless liquid, saline should be an effective 
placebo. 
The study drug (CD24Fc or placebo) will be labeled anonymously in order to maintain the 
study blind.  
The Phase III study will randomize patient in 1:1 ratio to receive either CD24Fc or 
Placebo.  
10.3 METHOTREXATE 
10.3.1 Formulation 
Methotrexate: 
N-[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-L-glutamic 
acid, is an antimetabolite used in the treatment of certain neoplastic diseases, severe 
psoriasis, adult rheumatoid arthritis, and prevention of acute GVHD. Methotrexate inhibits 
dihydrofolic acid reductase. Dihydrofolates must be reduced to tetrahydrofolates by this 
enzyme before they can be utilized as carriers of one-carbon groups in the synthesis of 
purine nucleotides and thymidylate. Therefore, methotrexate interferes with DNA 
synthesis, repair, and cellular replication. 
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10.3.2 Availability and administration 
Methotrexate sodium for injection is available in 25 mg/ml solution. The appropriate 
amount is drawn into a syringe for administration.  Store at controlled room temperature, 
20°-25° C (68°-77° F); excursions permitted to 15°-30° C (59°-86° F). Protect from light. 
10.3.3 Potential Side Effects 
The most frequently reported adverse reactions associated with methotrexate use as 
GVHD prophylaxis include ulcerative stomatitis, leucopenia and suppressed 
hematopoiesis, nausea, and abdominal distress. Other frequently reported adverse 
effects are malaise, undue fatigue, chills and fever, dizziness and decreased resistance 
to infection. Methotrexate may be associated with increased rates of pulmonary 
complications after transplantation. The risk of infections is due to the suppression of 
hematopoiesis after transplantation. 
10.3.4 Potential Drug Interactions 
Methotrexate is partially bound to serum albumin, and toxicity may be increased because 
of displacement by certain drugs, such as salicylates, phenylbutazone, phenytoin, and 
sulfonamides. Renal tubular transport is also diminished by probenecid; use of 
methotrexate with this drug should be carefully monitored. Oral antibiotics such as 
tetracycline, chloramphenicol, and nonabsorbable broad-spectrum antibiotics, may 
decrease intestinal absorption of methotrexate or interfere with the enterohepatic 
circulation by inhibiting bowel flora and suppressing metabolism of the drug by bacteria. 
Penicillins may reduce the renal clearance of methotrexate; increased serum 
concentrations of methotrexate with concomitant hematologic and gastrointestinal toxicity 
have been observed with high and low dose methotrexate. Use of methotrexate with 
penicillins should be carefully monitored. 
10.4 TACROLIMUS (PROGRAF, FK506) 
10.4.1 Formulation 
Tacrolimus, previously known as FK506, is the active ingredient in Prograf. Tacrolimus is 
a macrolide immunosuppressant produced by Streptomyces tsukubaensis. Tacrolimus 
appears as white crystals or crystalline powder. It is practically insoluble in water, freely 
soluble in ethanol, and very soluble in methanol and chloroform. Tacrolimus inhibits T-
lymphocyte activation, although the exact mechanism of action is not known. 
Experimental evidence suggests that tacrolimus binds to an intracellular protein, FKBP-
12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin is then 
formed and the phosphatase activity of calcineurin inhibited. This effect may prevent the 
generation of nuclear factor of activated T-cells (NF-AT), a nuclear component thought to 
initiate gene transcription for the formation of lymphokines (interleukin-2, gamma 
interferon). The net result is the inhibition of T-lymphocyte activation (i.e., 
immunosuppression). 
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10.4.2 Availability and administration 
Prograf is available for oral administration as capsules (tacrolimus capsules) containing 
the equivalent of 0.5 mg, 1 mg or 5 mg of anhydrous tacrolimus. Inactive ingredients 
include lactose, hydroxypropyl methylcellulose, croscarmellose sodium, and magnesium 
stearate. The 1-mg capsule shell contains gelatin and titanium dioxide, and the 0.5 mg 
and 5-mg capsules shell contains gelatin, titanium dioxide and ferric oxide. Prograf is also 
available as a sterile solution (tacrolimus injection) containing the equivalent of 5 mg 
anhydrous tacrolimus in 1 mL for administration by intravenous infusion only. Each mL 
contains polyoxyl 60 hydrogenated castor oil (HCO-60), 200 mg, and dehydrated alcohol, 
USP, 80.0% v/v. Prograf injection must be diluted with 0.9% sodium chloride injection or 
5% dextrose injection before use. Intravenous administration will be given by continuous 
infusion. Oral preparation will be administered on empty stomach every 12 hours. 
10.4.3 Potential Side Effects 
a. Increased susceptibility to infection and the possible development of lymphoma may 
result from immunosuppression. 
b. Nephrotoxicity has been noted in 40% and 33% of liver transplantation patients 
receiving Prograf in the U.S. and European randomized trials, respectively. The risk 
appears to be related to the intensity and duration of immunosuppression rather than to 
the use of any specific agent. A lymphoproliferative disorder (LPD) related to Epstein - 
Barr virus (EBV) infection has been reported in immunosuppressed organ transplant 
recipients. The risk of LPD appears greatest in young children who are at risk for primary 
EBV infection while immunosuppressed or who are switched to Prograf following long-
term immunosuppression therapy. 
c. Mild to severe hyperkalemia has been noted in 44% and 10% of liver transplant 
recipients treated with Prograf in the U.S. and European randomized trials and may 
require treatment. 
d. Neurotoxicity, including tremor, headache, and other changes in motor function, mental 
status, and sensory function were reported in approximately 55% of liver transplant 
recipients in the two randomized studies. Tremor and headache have been associated 
with high whole-blood concentrations of tacrolimus and may respond to dosage 
adjustment. Seizures have occurred in adult and pediatric patients receiving Prograf. 
Coma and delirium also have been associated with high plasma concentrations of 
tacrolimus. 
e. Hypertension is a common adverse effect of Prograf therapy. Mild or moderate 
hypertension is more frequently reported than severe hypertension. Antihypertensive 
therapy may be required; the control of blood pressure can be accomplished with any of 
the common antihypertensive agents. Since tacrolimus can cause hyperkalemia, 
potassium-sparing diuretics should be avoided. While calcium-channel blocking agents 
can be effective in treating Prograf-associated hypertension, care should be taken since 
interference with tacrolimus metabolism may require a dosage reduction. 
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f. Hyperglycemia was associated with the use of Prograf in 47% and 29% of liver 
transplant recipients in the U.S. and European randomized studies, respectively and may 
require treatment. 
10.5 CYCLOSPORINE (SANDIMMUNE, NEORAL) 
NOTE: Per protocol Cyclosporine will only be administered as a second line agent in 
cases where tacrolimus is no longer indicated due to intolerance (i.e. CNS toxicity) or 
unavailable commercially. Cyclosporine is a cyclic polypeptide immunosuppressant agent 
produced by the fungus species Beauveria nivea. While the molecular structure of 
cyclosporine is distinct from tacrolimus, their mechanism of action is almost 
indistinguishable and involves inhibition of calcineurin and the resulting activation 
cascade leads to inhibition of T cell signaling. Cyclophilin is the cytosolic binding protein 
for cyclosporine that is distinct from FK binding protein. Refer to the FDA-approved 
package insert for more information 
10.5.1 Oral or Intravenous Availability 
a. Cyclosporine is most commonly prescribed as soft gelatin capsules (neoral) or modified 
oral solution (Neoral Oral Solution) that have increased bioavailability in comparison to 
the less commonly used Sandimmune formulations. Neoral and Sandimmune cannot be 
used interchangeably and care must be exercised when converting from high doses of 
Sandimmune to Neoral. Neoral capsules are available in two strengths: 25 mg (oval, blue-
gray) or 100 mg (oblong, blue-gray) imprinted in red. Neoral Oral solution is available in 
50 mL bottles of yellow liquid containing 100 mg/mL of cyclosporine. Both neural 
formulations contain 11.9% v/v alcohol. Sandimmune capsules are available in two 
strengths: 25 mg (oblong, pink) or 100 mg (oblong, dusty rose), in unit dose packages of 
30 capsules that should be stored at 25°C (77°F). Sandimmune Oral solution is available 
in 50 mL bottles of yellow liquid containing 100 mg/mL of cyclosporine. Both Sandimmune 
formulations contain ~12.5% v/v alcohol. 
b. Sandimmune IV solution is supplied in 5 mL ampoules that contain 50 mg of 
cyclosporine per mL, Cremaphor and 32.9% alcohol v/v.  
c. Neoral or Sandimmune is available through the hospital pharmacy during all inpatient 
admissions and through the local pharmacy for outpatient management. 
10.5.2 Storage and Handling 
Sandimmune should be stored in the original container below 25°C (77°F). Neural 
capsules and oral solution should be stored at 20°C-25°C (68°F-77°F) and not in the 
refrigerator. Sandimmune intravenous solution should be stored at temperatures below 
30°C (86°F) but not in the refrigerator and should be protected from light. 
Oral or Intravenous Administration 
a. Do not administer liquid from plastic or Styrofoam cup. May dilute Neoral oral solution 
with orange juice or apple juice. May dilute Sandimmune oral solution with milk, chocolate 
milk, or orange juice. Avoid changing diluents frequently. Mix thoroughly and drink at 
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once. Use syringe provided to measure dose. Mix in a glass container and rinse container 
with more diluent to ensure total dose is taken. Do not rinse syringe before or after use 
(may cause dose variation). 
b. Intravenous administration will be given by continuous infusion. Discard solution after 
24 hours. Anaphylaxis has been reported with intravenous use; reserve for patients who 
cannot take oral form. Patients should be under continuous observation for at least the 
first 30 minutes of the infusion, and should be monitored frequently thereafter. Maintain 
patient airway; other supportive measures and agents for treating anaphylaxis should be 
present when intravenous drug is given. 
10.5.3 Sirolimus or other prevention regimen 
If patient cannot tolerant either Tacrolimus or Cyclosporine, Sirolimus or other GVHD 
prevention regimen should be given per institution practice guideline. The change of 
GVHD prophylaxis regimen should get approval by the PI and protocol chair.  
10.5.4 Potential drug interactions 
Cyclosporine is extensively metabolized by the cytochrome P450 (CYP3A4) system. 
Drugs that may increase cyclosporine blood concentrations include: calcium channel 
blockers (e.g., diltiazem, nicardipine, nifedipine, verapamil), antifungal agents (e.g., 
ketoconazole, clotrimazole, fluconazole, itraconazole, voriconazole, pozaconazole), 
macrolide antibiotics (e.g., clarithromycin, erythromycin, troleandomycin), gastrointestinal 
prokinetic agents (e.g., cisapride, metoclopramide), and/or other drugs (e.g., 
bromocriptine, 
cimetidine, 
tacrolimus, 
danazol, 
ethinyl 
estradiol, 
omeprazole, 
nefazodone, HIV-protease inhibitors. Drugs that may decrease cyclosporine 
concentrations include: anticonvulsants (e.g., carbamazepine, phenobarbital, phenytoin), 
antibiotics (e.g., rifabutin, rifapentine), and/or herbal preparations (e.g., St. John’s Wort 
[hypericum perforatum]). Refer to http://medicine.iupu.edu/clinpharm/ddis/table.aspx for 
current information about drug interactions with calcineurin inhibitors. 
10.5.5 Excretion 
The absorption of cyclosporine after oral administration is incompletely dependent on the 
individual patient, patient population and the formulation. Cyclosporine is extensively 
metabolized by CYP3A4 and to a lesser extent in the gastrointestinal tract and kidney. At 
least 25 metabolites have been identified in bile, feces, blood and urine but the parent 
compound is primarily responsible for the immunosuppressive activity. Elimination is 
primarily biliary with only 6% of the dose excreted in urine. The mean terminal elimination 
half-life (T1/2) of cyclosporine is 8.4 hours (range 5-18 hours). The mean T1/2 was 
reduced by 2-3 fold in patients with impaired hepatic function. Dosage reduction is 
recommended for patients with mild to moderate hepatic impairment. 
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11 ADVERSE EVENTS AND REPORTING CRITERIA 
11.1 DEFINITION OF ADVERSE EVENTS 
Adverse Event (AE): An AE is any untoward medical occurrence in a clinical 
investigation subject administered a pharmaceutical product regardless of causality 
assessment. An adverse event can be an unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, syndrome or disease temporarily associated with 
or occurring during the use of an investigational product whether or not considered related 
to the investigational product. As such, the AEs will be continuously followed and reported 
after the study subjects have been started on the investigational drug and recorded on 
the appropriate electronic case report form (eCRF). 
Wherever possible, a specific disease or syndrome rather than individual associated 
signs and symptoms should be identified by the Investigator and recorded on the eCRF.  
However, if an observed or reported sign or symptom is not considered a component of 
a specific disease or syndrome by the Investigator, it should be recorded as a separate 
adverse event on the eCRF.  Additionally, the condition that led to a medical or surgical 
procedure (e.g. surgery, endoscopy, tooth extraction, or transfusion) should be recorded 
as an adverse event, not the procedure. 
Any medical condition already present at screening should not be reported as an adverse 
event unless the medical condition or signs or symptoms present at baseline changes in 
severity or seriousness at any time during the study.  In this case, it should be reported 
as an adverse event. 
Clinically significant abnormal laboratory or other examination (e.g. electrocardiogram) 
findings that are detected during the study or are present at screening and significantly 
worsen during the study should be reported as AEs.  The Investigator will exercise his or 
her medical or scientific judgment in deciding whether an abnormal laboratory finding or 
other abnormal assessment is clinically significant.  Clinically significant abnormal 
laboratory values occurring during the clinical study will be followed until repeat tests 
return normal, stabilize, or are no longer clinically significant.  Any abnormal test that is 
determined to be an error does not require reporting as an AE.           
These events may be: 
• Related: clearly or likely associated with study drug/treatment 
• Not related: unlikely or definitely not related to the study drug/treatment 
For reporting purposes, an AE should be regarded as related to the study drug if the 
Investigator believes that at least one of the Number 1 or Number 2 criteria plus at least 
one of the Number 3 or Number 4 criteria are met: 
1. There is a clinically plausible time sequence between onset of the AE and the 
administration of the study drug or treatment. 
2. There is a biologically plausible mechanism for the study drug or treatment causing 
or contributing to the AE. 
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OncoImmune Inc. 
Clinical Trial Protocol (CATHY) 
IND 127,363 
CD24Fc-005 
63 
 
CD24Fc for GVHD Prevention; v1.5: August 17, 2020 
3. The AE cannot be attributed solely to concurrent/underlying illness, other drugs, or 
procedures. 
4. A potential alternative cause does not exist.  
Serious Adverse Experience (SAE): Any adverse drug experience occurring at any 
dose that results in any of the following outcomes: 
• death, 
• a life-threatening adverse drug experience, 
Note: An adverse event or adverse reaction is considered ‘life-threatening’ if, in 
view of either the Investigator or Sponsor, its occurrence places the subject at 
immediate risk of death.  It does not include an event that, had it occurred in a 
more severe form, might have caused death. 
• inpatient hospitalization or prolongation of existing hospitalization, 
Note: Any hospital admission that is >24 hours is considered an inpatient 
hospitalization.  An emergency room visit without hospital admission will not be 
recorded as an SAE under this criterion, nor will hospitalization for a procedure 
scheduled or planned before signing of informed consent. However, unexpected 
complications and/or prolongation of hospitalization that occur during elective 
surgery should be recorded as AEs and assessed for seriousness.  Admission to 
the hospital for social or situational reasons (e.g. no place to stay, live too far away 
to come for hospital visits) will not be considered inpatient hospitalizations.   
• a persistent or significant disability/incapacity, 
• or a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Expected Events: - An adverse event (AE) is considered “expected” if: 
• 
For approved and marketed drugs or devices, those adverse events are described 
in the approved Package Insert (Label).  
• 
For investigational new drugs or devices, those adverse events are described in 
the FDA Investigator’s Brochure.  
• 
In clinical research studies, information on expected adverse events is also 
summarized in the protocol and in the consent document.  See section for the list 
of expected adverse events related to the drug under study. 
Unexpected adverse events: - An adverse event (AE) is considered “unexpected” if it is 
not described in the Package Insert, Investigator’s Brochure, in published medical 
literature, in the protocol, or in the informed consent document.  
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OncoImmune Inc. 
Clinical Trial Protocol (CATHY) 
IND 127,363 
CD24Fc-005 
 
64 
 
CD24Fc for GVHD Prevention; v1.5: August 17, 2020 
 
11.2 DEFINITION OF AE SEVERITY  
The severity or grade of an adverse event may be measured using the following 
definitions: 
Event grading: The NCI Common Terminology Criteria (CTCAE Version 5.0) will be used 
to grade intensity of adverse events and assist in reporting adverse events. 
Mild: Noticeable to the subject, but does not interfere with the subject’s expected daily 
activities, usually does not require additional therapy or intervention, dose reduction, or 
discontinuation of the study. In the transplant setting CTCAE version 5.0 grades 1 and 2. 
Moderate: Interferes with the subject’s expected daily activities, may require some 
additional therapy or intervention but does not require discontinuation of the study. In the 
transplant setting using the CTCAE version 5.0 some grade 2 and most grade 3. 
Severe: Extremely limits the subject’s daily activities and may require discontinuation of 
study therapy, and/or additional treatment or intervention to resolve. In the transplant 
setting using the CTCAE version 5.0 some grades 3 and all grade 4. 
 
11.3 AE AND SAE REPORTING REQUIREMENTS 
11.3.1 AE Reporting 
Reports of AEs and SAEs will be sent by the clinical site PI or PI designated clinical 
coordinator directly to the CRO, which will be disseminated to the Sponsor, PI, IRB, 
FDA and other regulatory bodies, as appropriate.  
In order to maintain the safety of subjects, the following study specific AE / SAE 
reporting plan has been devised.  
Reporting to Sponsor: 
As the expectation of a high rate of low grade adverse events associated with conditioning 
regimen and HCT procedure, only Grade 3 to 5 AEs (regardless attribution) will be 
recorded in the patient’s source and entered into the electronic data capture system from 
the time of CD24Fc or placebo infusion through day 100 post HCT.   
All grade AE will be recorded only within 24 hours of start of an infusion of 
CD24Fc/placebo.  
The acute GVHD is the study primary endpoint. Infections and leukemia relapse are study 
endpoints. The CMV reactivation, myeloablative conditioning regimen associated 
myelosuppression, anemia, thrombocytopenia, mucositis will not be considered as AE as 
these are expected events in HCT. The post-HCT hospital re-admission due to these 
conditions will be recorded.   
Reporting of SAEs to the IRB 
The Investigator must comply with the applicable regulatory requirements related to the 
report of SAEs to their Institutional Review Board (IRB). The IRB must be informed in a 
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07ZKR8


OncoImmune Inc. 
Clinical Trial Protocol (CATHY) 
IND 127,363 
CD24Fc-005 
67 
 
CD24Fc for GVHD Prevention; v1.5: August 17, 2020 
12.1 TRAINED AND CERTIFIED PERSONNEL 
All of the research protocol personnel who will work with study subjects, study subject 
data or subjects’ research samples have completed training in the protection of human 
research subjects per guidelines issued by the U. S. Department of Health and Human 
Services, Office of Human Research Protections. The investigator and designated 
associates have attended an IRB sponsored HIPAA research presentation in accordance 
with the policy of the study site. Each participant in this research trial will be listed by study 
specific numbers, without initials or date of birth; however, the date of transplant may be 
included when corresponding with the IRB or outside agencies. 
Designation of Responsibilities: The Clinical Principal Investigator(s) are solely 
responsible for the implementation, conduct and safety of human subjects enrolled in this 
trial. The Clinical Principal Investigator has however, designated associates to assist with 
the protocol implementation which includes but is not limited to the following: 
1. BMT Physicians – have been designated to assist with participant education, informed 
consent process, study implementation and compliance, recording of primary source 
documentation, AE assessment and reporting, adherence to all regulations. 
2. BMT Research Nurse(s) - have been designated to assist with participant education, 
informed consent process, study implementation and compliance, recording of primary 
source documentation and adherence to all regulations. 
3. BMT Data Manager(s) - have been designated to assist with patient 
enrollment/eligibility, verification of protocol compliance, all data collection and recording 
from primary source, AE reporting, DSM reports and adherence to all regulations. 
4. BMT Clinical Team - The members of the BMT clinical team that have been designated 
to assist the investigator in any aspect of this protocol will be listed on the protocol specific 
designation log. 
12.2 STORAGE AND DISSEMINATION OF REPORTS 
Medpace is responsible for collecting all safety data in the electronic Case Report Forms 
(eCRFs) from all participating institutions and providing the data to the independent DMC.   
12.3 CLINICAL MONITORING PROCEDURES 
Clinical studies must be conducted in accordance with the ethical principles that are 
consistent with Good Clinical Practices and in compliance with other applicable regulatory 
requirements. The following measures have been taken to ensure the safe conduct of this 
clinical trial: 
This study will be continuously monitored by medical monitor from Sponsor and from the 
CRO. Monitoring visits will be made during the conduct of the study and at study close-
out. Monitoring visits can be conducted remotely.  
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Clinical Trial Protocol (CATHY) 
IND 127,363 
CD24Fc-005 
68 
 
CD24Fc for GVHD Prevention; v1.5: August 17, 2020 
Prior to subject recruitment, a site initiation meeting will be conducted by the Sponsor or 
the CRO through teleconference. The PI and the study staff should make every effort to 
attend the site initiation meeting. Study-related questions or issues identified during the 
site initiation meeting will be followed by the appropriate personnel until they have been 
answered and resolved. 
Monitoring of the study site will be performed by the CRO. The purpose is to verify: 
a. 
Adherence to the protocol 
b. 
Completeness and accuracy of study data and samples collected 
c. 
Proper storage, dispensing, and inventory of study medication 
d. 
Compliance with regulations 
Monitoring may be in the form of a site visit or a remote review of the documents. During 
a monitoring visit, access to relevant hospital and clinical records must be given by the 
clinical site PI to the CRO representative conducting the monitoring visit to verify 
consistency of data collected on the CRFs with the original source data. While most 
patient cases will be selected from patients accrued since the previous monitoring visit, 
any patient case has the potential for review. At least one or more unannounced cases 
will be reviewed, if the total accruals warrant selection of unannounced cases. 
The CRO expects the relevant investigational staff to be available to facilitate the conduct 
of the visit, that source documents are available at the time of the visit, and that a suitable 
environment will be provided for review of study-related documents. Any issues identified 
during these visits will be communicated and are expected to be resolved in a timely 
manner. 
At close-out visit will occur upon completion, termination, or cancellation of a study to 
ensure fulfillment of study obligations during the conduct of the study, and the clinical site 
PI will be informed of his / her ongoing responsibilities.  
12.4 INDEPENDENT DATA MONITORING COMMITTEE (DMC) 
An independent DMC has been convened for the Phase III study. The purpose of the 
DMC is to safeguard the interests of study subjects, assess the safety of the interventions, 
and monitor the overall conduct of the study. The DMC acts as an advisory to the clinical 
study leadership team of OncoImmune. The clinical study leadership will have 
responsibility for overall conduct of the study including managing the communication of 
study data. The leadership team will be responsible for promptly reviewing the DMC 
recommendations, for providing guidance regarding the continuation or termination of the 
trial, and for determining whether amendments to the protocol or changes to the study 
conduct are required. 
13 QUALITY ASSURANCE AND AUDITS 
Audits provide assurance that trials are conducted in compliance with the protocol. 
Further, they ensure that study data are collected, documented and reported in 
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OncoImmune Inc. 
Clinical Trial Protocol (CATHY) 
IND 127,363 
CD24Fc-005 
69 
 
CD24Fc for GVHD Prevention; v1.5: August 17, 2020 
compliance with Good Clinical Practices (GCP) Guidelines and regulatory requirements. 
All audit findings are reported to the DMC and the sponsor. 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, the site 
investigator must immediately inform the CRO and Sponsor that such a request has been 
made.  
14 REMOVAL FROM STUDY 
Patients have the right to withdraw from the study at any time for any reason. The clinical 
site PI also has the right to withdraw patients from the study in the event of intercurrent 
illness, adverse events, treatment failure, protocol violation, or other reasons. Should a 
patient (or a patient’s legally authorized guardian or representative) decide to withdraw, 
all efforts will be made to complete and report the observations as thoroughly as possible. 
A complete final evaluation should be made at the time of the patient’s withdrawal with 
an explanation of why the patient is withdrawing. Patients may be removed from the study 
treatment if one or more of the following events occur: 
• Significant protocol violation or noncompliance, either on the part of the patient or 
the clinical site PI. 
• Refusal of the patient to continue treatment and / or observations. 
• Unacceptable or dose-limiting toxicity. 
• Decision by the clinical site PI that removal from the study is in the patient’s medical 
interest. 
• Unrelated medical illness or complication. 
• Lost to follow-up. 
• Disease relapse or progression. 
In the event a subject fails to appear for a scheduled follow-up visit, Institution and/or 
Principal Investigator shall use reasonable efforts contact the subject within ten (10) days 
after the date of the scheduled visit regarding the failure to keep the appointment.  If a 
subject withdraws from the Study, Institution and Principal Investigator shall use 
reasonable measures to follow up with the subject in person or by telephone (if possible), 
otherwise by certified mail, to determine the reason for the discontinuance. 
15 STATISTICAL CONSIDERATIONS 
15.1 STUDY DESIGN  
The study is designed as a Phase III randomized, double blind, placebo controlled, 
multicenter trial to compare CD24Fc/Tac/MTX with Placebo/Tac/MTX in the setting of 
myeloablative conditioning (MAC), matched unrelated donor (MUD) allogeneic 
hematopoietic stem cell transplantation (HCT) in patients with acute myeloid leukemia 
(AML) or acute lymphoblastic leukemia (ALL).  
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OncoImmune Inc. 
Clinical Trial Protocol (CATHY) 
IND 127,363 
CD24Fc-005 
70 
 
CD24Fc for GVHD Prevention; v1.5: August 17, 2020 
The primary endpoint is 180 day grade III-IV acute GVHD-free survival (aGFS). An event 
for this time-to-event outcome is defined as grade III-IV aGVHD, or death by any cause, 
whichever occurs first.  
The target enrollment is 180 patients in total, with 90 patients on each of the two treatment 
arms.  
15.2 ACCRUAL  
It is estimated that 24 months of accrual will be necessary to enroll the targeted sample 
size with an accrual rate of approximately 8 patients per month. Approximately 15 clinical 
sites will enroll patients on this study. Accrual will be reported by race, ethnicity, gender, 
and age.  
15.3 RANDOMIZATION AND STRATIFICATION  
All patients will be randomized within 48 hours prior to the first dosing of either CD24Fc 
or placebo at Day -1 of HCT.  
Randomization will be performed in a 1:1 ratio using permuted block randomization 
stratified by disease type: AML vs. ALL.  
15.4 PRIMARY ENDPOINT  
The primary endpoint is time to grade III-IV acute GVHD or death (aGFS) in 180 days 
after HCT. This endpoint is chosen based on large retrospective analyses showing that 
grade II acute GVHD does not affect the overall survival in HCT patients [58, 59]. 
The primary endpoint is aGFS from the HCT, treated as a time to event variable. All 
transplanted patients will be followed for the primary endpoint for 180 days after 
transplantation. The aGFS will be compared between groups in the ITT population using 
the stratified log-rank test, with the randomization factor of disease type (AML or ALL) 
used as stratification variables. 
The aGFS event is defined as Grade III-IV acute GVHD, or the death by any cause. Since 
leukemia relapse leads to treatment that can induce GVHD, the subject will be censored 
at relapse. 
The primary estimation of aGFS event rate at 180 days based on the Kaplan-Meier 
estimates will be accompanied by the corresponding two-sided 95% confidence interval 
calculated using Greenwood’s formula.  
The primary test null hypothesis of  
 
H0: HR = 1.0  
will be rejected in favor of  
 
Ha: HR < 1.0 
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OncoImmune Inc. 
Clinical Trial Protocol (CATHY) 
IND 127,363 
CD24Fc-005 
71 
 
CD24Fc for GVHD Prevention; v1.5: August 17, 2020 
if the p-value based on the stratified log-rank test (two sided) with stratification factor of 
disease type is less than the significance level of 5%. 
15.5 SAMPLE SIZE AND POWER CONSIDERATIONS  
15.5.1 Power Calculation for the Primary Endpoint 
Sample size and power considerations are based on an accrual period of 24 months and 
a 6-month follow-up period with a 5% drop-out rate. We further assume that the drop-out 
and time-to-event are exponentially distributed.  
From our preliminary study (Figure 8), we assume that the rate of 180 days aGFS for the 
CD24Fc group is set at 84.2% (10.2% lower that the Phase IIa CD24Fc aGFS of 94.4%) 
while the rate for placebo group is 68%, i.e., HR=0.446. A total of 65 aGFS events will be 
required to maintain a two-sided type I error of 5% while providing about 90% statistical 
power which corresponds to approximately 180 patients (90 per arm). There will be a 
sample size re-estimation at the planned interim analysis. 
15.5.2 Power Calculation for the Secondary Endpoints 
The sample size of the Phase III trial is based on the primary endpoint.  The sample size 
allows adequate power for most secondary endpoints, as detailed below. 
DFS The proposed trial period has two years of enrollment period and 1 year of follow 
up for the last patient.  The relapse will be observed over 3 years period.  Our Phase IIA 
data suggest an HR=0.39 (0.18-0.81) when CD24Fc-dosed patients were compared to 
68 matched control patients from CIBMTR.  Assuming 10% drop out and HR of 0.5 for 
the Phase III trial, the pre-specific sample size of 180 is sufficient to achieve 83% power 
for DFS. 
OS 
The proposed trial period has two years of enrollment period and 1 year of follow 
up for the last patient.  The relapse will be observed over 3 years period.  Our Phase IIA 
data suggest an HR=0.42 (0.19-0.96) when CD24Fc-dosed patients were compared to 
68 matched control patients from CIBMTR.  Assuming 10% drop out and HR of 0.5 for 
the Phase III trial, the pre-specific sample size of 180 is sufficient to achieve 81% power 
for OS. 
180 day Grade II-IV GVHD-free survival.  Our Phase IIA data suggest an HR=0.538 
(0.284-0.102) when CD24Fc-dosed patients were compared to 68 matched control 
patients from CIBMTR.  Using the same HR of 0.5, pre-specific sample size of 180 is 
insufficient to achieve 80% power for 180 day Grade II-IV GVHD-free survival. 
180 day Grade III-IV GVHD-free, Relapse-free survival.  Our Phase IIA data suggest 
an HR=0.434 (0.196-0.964) when CD24Fc-dosed patients were compared to 68 matched 
control patients from CIBMTR.  Using the same HR of 0.446, pre-specific sample size of 
180 is sufficient to achieve 91% power for 180 day Grade II-IV GVHD-free survival. 
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Clinical Trial Protocol (CATHY) 
IND 127,363 
CD24Fc-005 
 
72 
 
CD24Fc for GVHD Prevention; v1.5: August 17, 2020 
15.6 INTERIM ANALYSIS AND STOPPING GUIDELINES  
The study will consist of one interim analysis for efficacy after observing a total of 46 
events, at a 70% information fraction. The final analysis will be conducted when the 
targeted number of events of 65 occurs.  
A sample size re-estimation will be performed at this interim analysis by the DMC to 
support a decision to increase the target number of aGFS events. Except for the DMC, 
there are no other parties who will have access to unblinded data. The DMC has been 
contracted by another CRO, ACI, that is completely independent from the clinical CRO, 
Medpace. A Reporting Statistician has been appointed for the DMC and the Reporting 
Statistician will have access to the clinical database and to the randomization code. The 
Reporting Statistician will report to the DMC Chair and will support presentation of the 
data during sessions that are closed to anyone else associated with the study. The 
Reporting Statistician is permitted and empowered to disclose unblinded study data to 
the DMC members. The method based on Chen et al. [60] will be used for the sample 
size re-estimation. If the conditional power is < 50% or >85%, the trial will continue without 
a sample size increase; whereas if the conditional power is between 50% to 85%, the 
sample size will be re-calculated to have 85% power. To maintain trial integrity, the DMC 
will pick a sample size in a nearest interval with 5 patients. For example, if the re-
estimated sample size is 240, the DMC could pick any number in the interval of 237 to 
242. Also, the maximum increased sample size will not be more than 70 patients above 
what is needed to observe 65 events. No new sites will be added after sample size is 
adjusted. 
15.6.1 Interim Analysis for Efficacy  
Analyses will be performed as described below for the primary endpoint. At the interim 
analysis time point, a Z test for comparing the two treatments will be compared to the 
critical values with non-binding boundary for efficacy as shown in Table 7. All patients 
with follow-up post randomization prior to the time of the interim analyses will be used to 
compute this statistic. If the test statistic is outside the continuation range, the DMC will 
discuss the continuation of the trial. 
Efficacy stopping rules are based on O'Brien-Fleming-type error spending function. A P-
value less than 0.0147 at the interim analysis would indicate a statistically significant 
result.  
TABLE 7: EFFICACY STOPPING THRESHOLDS WITH TYPE I ERROR 0.05, AND AN EFFECT SIZE OF 
HAZARD RATIO 0.446  
Analysis 
Time 
Information 
Fraction 
Cumulative Sample 
Size Under Alternative  
Cumulative Events 
Under Alternative 
Cumulative 
Alpha 
Interim 
0.7 
126 
46 
0.0147 
Final 
1 
180 
65 
0.045 
 
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OncoImmune Inc. 
Clinical Trial Protocol (CATHY) 
IND 127,363 
CD24Fc-005 
73 
 
CD24Fc for GVHD Prevention; v1.5: August 17, 2020 
15.6.2 Operating Characteristics of the Design  
The statistical power to reject the null hypothesis under various hazard ratio treatment 
effect sizes using the Z test for comparing treatments is shown in Table 8. This table 
shows that the target sample size of 180 patients has 90% power (unstratified) or 81% 
(stratified) power to detect a hazard ratio of 0.446.   
TABLE 8: SUMMARY OF OPERATING CHARACTERISTICS 
Hazard Ratio  
Expected Events 
Overall Cumulative Power 
0.4 
63 
0.952 
0.446 
65 
0.9 
0.5 
67 
0.807 
0.6 
71 
0.572 
0.7 
75 
0.336 
1 
83 
0.05 
15.7 GUIDELINES FOR SAFETY MONITORING  
Monitoring of the safety endpoint will be conducted by the Sponsor and CRO in a blinded 
fashion The CRO will collect the data and share this with the DMC at the planned interim 
analysis or call a meeting with the DMC at other times if needed.  In the trial, the most 
important safety factors are acute GVHD events and death, which are collected as the 
primary efficacy endpoint. Since there are no other adverse events of special interest in 
the trial, the CRO will monitor adverse events, and other safety endpoints and call a 
meeting with DMC as soon as there are safety concerns. 
15.8 DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
Demographics and baseline characteristics will be summarized for all patients. 
Characteristics to be examined are: age, gender, race/ethnicity, performance status, 
primary disease, disease-specific risk categories, DRI, hematopoietic cell transplant 
comorbidity index (HCT CI), donor type and HLA matching, donor/recipient CMV status, 
donor/recipient sex match, donor/recipient ABO match, and conditioning regimen. 
Between group comparisons will be performed for continuous variables via a Kruskal-
Wallis test and for categorical variables, via the chi-square test.  
Subgroup analyses by age, gender, race, region and other baseline disease 
characteristics will be performed for the primary and key secondary endpoints. 
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15.9 ANALYSIS POPULATIONS 
15.9.1 Primary Population 
The intention-to-treat population will serve as the population for the primary analysis. All 
randomized patients will be included in this population. Patients will be included in the 
treatment group to which they are randomized. Intention-to-treat population consists of 
all randomized patients whether or not treatment was administered. 
15.9.2 Safety Population 
The safety analysis population in this study will comprise of all patients “as treated” in the 
study. This population will be used for the analysis of safety data. The “as treated” 
population consists of all randomized patients who received a HCT with one of the two 
randomized GVHD prophylaxis regimens. Patients will be included in the treatment group 
corresponding to the study treatment (GVHD prophylaxis) they actually received for the 
analysis of safety data using the “as treated” population. For most patients this will be the 
treatment group to which they are randomized. 
15.9.3 Transplant Population 
The transplant population will include all patients who have received a transplant after 
randomization. 
15.10 ANALYSIS OF THE PRIMARY ENDPOINT: 180 DAY AGFS 
Kaplan-Meier curves along with 95% confidence intervals will be constructed to estimate 
grade III-IV aGFS probabilities at 180 days for each treatment group. The primary analysis 
will be a stratified log-rank test with stratification factor of disease type: AML vs. ALL. . A 
significance level of 0.05 (two-sided, appropriately adjusted for an interim analysis) will 
be used to test the null hypothesis of no difference between the treatments. 95% 
confidence intervals for the hazard ratio of the CD24Fc vs placebo treatment will also be 
constructed using a stratified Cox proportional hazard model with exact method of tie 
handling.  
15.10.1 
Censoring rules for time to event efficacy endpoints 
For the primary endpoint, subjects who have not dropped out or experienced the event 
(grade III-IV GVHD or death) will be censored at the time of leukemia relapse or Day 180 
after HCT. Subjects going off study drug without prior documentation of an event will 
continue to be followed for acute GVHD or death, and this additional follow-up will be 
included in the primary analysis. Subjects without an event but lost to follow-up will be 
censored at last date of follow-up. 
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15.11 ANALYSIS OF SECONDARY ENDPOINTS 
15.11.1 
The secondary endpoints (1) Disease (Relapse) Free Survival; (2) 
Overall Survival; (3) 180 days grade II-IV acute GVHD free survival will be 
included in a formal testing procedure after the primary analysis is 
statistically significant and (4) 180 Day Grade III-IV acute GVHD and 
Relapse-free survival. The multiplicity adjustment will be a gate-keeping 
method in the order described above. Disease-free Survival 
Kaplan-Meier curves will be constructed to estimate disease free survival probabilities for 
each treatment group. The efficacy analysis will be a stratified log-rank test with 
stratification factor of disease type, and a stratified Cox proportional hazard model with 
exact method of tie handling will be used to estimate HR and its 95% CI.  
15.11.2 
 Overall Survival 
Kaplan-Meier curves will be constructed to estimate overall survival probabilities for each 
treatment group. The efficacy analysis will be a stratified log-rank test with stratification 
factor of disease type, and a stratified Cox proportional hazard model with exact method 
of tie handling will be used to estimate HR and its 95% CI.  
15.11.3 
180 Day Grade II-IV GVHD-Free Survival 
Kaplan-Meier curves along with 95% confidence intervals will be constructed to estimate 
grade II-IV aGFS probabilities at 180 days for each treatment group. The efficacy analysis 
will be a stratified log-rank test with stratification factor of disease type, and a stratified 
Cox proportional hazard model with exact method of tie handling will be used to estimate 
HR and its 95% CI.  
15.11.4 
180 Day Grade III-IV GVHD and Relapse-Free Survival (aGRFS) 
Kaplan-Meier curves along with 95% confidence intervals will be constructed to estimate 
aGRFS at 180 days for each treatment group. The efficacy analysis will be a stratified log-
rank test with stratification factor of disease type, and a stratified Cox proportional hazard 
model with exact method of tie handling will be used to estimate HR and its 95% CI.  
15.12 ANALYSIS OF EXPLORATORY ENDPOINTS 
15.12.1 
Chronic GVHD 
Incidence of chronic GVHD at 1 year will be estimated with 95% confidence intervals for 
each treatment group using the cumulative incidence estimate, treating death prior to 
chronic GVHD as a competing event. Comparison of cumulative incidence will be done 
using Gray’s test. A multivariate Cox regression model for the cause-specific hazard of 
chronic GVHD will be used to compare the treatment groups, after adjustment for baseline 
characteristics as described for the primary endpoint. 
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15.12.2 
Disease Relapse or Progression 
Incidence of disease relapse at 1 year will be estimated with 95% confidence intervals for 
each treatment group using the cumulative incidence estimate, treating death prior to 
disease relapse as a competing event. A multivariate Cox regression model for the cause-
specific hazard of relapse will be used to compare the treatment groups with the control 
group, after adjustment for baseline characteristics as described for the primary endpoint. 
15.12.3 
Non-relapse Mortality 
Incidence of non-relapse mortality (NRM) at 1 year will be estimated for each treatment 
group using the cumulative incidence estimate, treating disease relapse or progression 
as a competing event. A multivariate Cox regression model for the cause-specific hazard 
of TRM will be used to compare the treatment groups with the control group, after 
adjustment for baseline characteristics as described for the primary endpoint. 
15.12.4 
Mucositis 
All Grade mucositis will be tabulated by grade for each randomized treatment arm, by 
duration of mucositis as well as the grade. Mucositis will be scored up to 28 days.   
15.12.5 
Infections 
The number of infections and the number of patients experiencing infections will be 
monitored and tabulated for each randomized treatment arm by type of infection, severity, 
site and through 100 days after transplant.  
15.12.6 
Safety Analysis 
Adverse events will be graded according to the NCI Common Terminology Criteria for 
Adverse Events Version 5.0.  
15.13 MISSING DATA AND SENSITIVITY ANALYSIS 
For our primary analysis, we will use the following rules to deal with missing data: 
Subjects who have not dropped out or experienced the event (grade III-IV GVHD or death) 
will be censored at the end of the trial. Subjects going off study drug without prior 
documentation of an event will continue to be followed for acute GVHD or death until the 
end of the trial, and this additional follow-up will be included in the primary analysis. 
Subjects without an event but lost to follow-up will be censored at last date of follow-up. 
As a supplemental analysis, a Restricted Mean Survival Time (RMST) method will be 
used to estimate hazard ratio in case the proportionality assumptions do not hold. The 
pre-specified cutoff point to evaluate the RMST will be minimum of a) 2 times expected 
median GVHD survival time for the experimental arm, b) the largest observed GVHD 
survival time for the experimental arm, and c) the largest observed GVHD survival time 
for control arm. 
As another supplemental analysis, the primary endpoint will be defined as time from 
transplantation to acute GVHD of grade III or IV severity, treatment for acute GVHD with 
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systemic agents other than corticosteroids, or death, whichever occurs first, up to day 
180. 
For key secondary endpoints, we will use the same rules to deal with missing data.  
We will perform three more analyses on the following sets for the purpose of sensitivity 
analysis: 
First: Subjects who have not dropped out or experienced the event are censored at the 
end of the trial. Subjects going off study drug without prior documentation of an event will 
be censored at the last disease assessment before going off treatment. Subjects without 
an event but lost to follow-up will be censored at last date of follow-up. When the event is 
documented, the time to the event is the length of time from the randomization to the 
event observed if at most one missed disease assessment before the event is 
documented.  If more than one missed disease assessment before the event is 
documented, it censors at the last disease assessment without acute GVHD. 
Second: Subjects who have not dropped out or experienced the event and are followed 
at the end of the trial will be included. Subjects going off study drug will be excluded. 
Subjects who have documented the event and no missing disease assessment(s) will be 
included. 
Third, we will use time from randomization instead of time from HCT for analysis of 
primary and secondary endpoints. We will compare the results of primary analysis with 
the results from sensitivity tests. The impact of missing data and robustness of the 
primary analysis will be evaluated. 
 
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Matsui WH, Swinnen LJ et al: Development of Grade II Acute Graft-versus-Host Disease Is 
Associated with Improved Survival after Myeloablative HLA-Matched Bone Marrow 
Transplantation using Single-Agent Post-Transplant Cyclophosphamide. Biol Blood Marrow 
Transplant 2019, 25(6):1128-1135. 
60. 
Chen YH, DeMets DL, Lan KK: Increasing the sample size when the unblinded interim result is 
promising. Stat Med 2004, 23(7):1023-1038. 
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17 APPENDIX A: KARNOFSKY PERFORMANCE SCALE 
% 
Description 
100  
Normal, no complaints, no evidence of disease  
90  
Able to carry on normal activity, minor symptoms of disease  
80  
Normal activity with effort, some signs of symptoms of disease  
70  
Cares for self (consistent with age), unable to carry on normal activity or do active 
work/school/play  
60  
Requires occasional assistance (beyond age-appropriate care), but is able to care 
for most of their needs  
50  
Requires considerable assistance and frequent medical care  
40  
Disabled, requires special care and assistance  
30  
Severely disabled, hospitalization is indicated although death is not imminent  
20  
Hospitalization is necessary, very sick, active support treatment is necessary  
10  
Moribund, fatal processes progressing rapidly 
 
 
 
 
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18 APPENDIX B: CIBMTR OPERATIONAL GUIDELINES 
EXAMPLES 
OF 
MYELOABLATIVE, 
REDUCED 
INTENSITY, 
AND 
NON 
– 
MYELOABLATIVE REGIMENS. 
 
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19 APPENDIX C: ORGAN STAGING OF ACUTE GVHD 
 
From Harris AC, et al: BBMT 22:4-10, 2016. 
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21  APPENDIX E: HCT-SPECIFIC COMORBIDITY INDEX SCORE 
 
#The “Prior solid tumor” “requiring treatment with chemotherapy” (HCI-CI score=3) is 
modified to “Prior solid tumor” “requiring treatment with chemotherapy, if the solid tumor 
chemotherapy is documented to be complete and the tumor has not progressed in the 
two years before the HCT, the BMT physician may take this into consideration and adjust 
the HCI-CI score to < 3.” 
 
# 
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22 APPENDIX F: CHRONIC GVHD ASSESSMENT 
 
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23 SUMMARY OF CHANGES 
Substantive changes to the Protocol are outlined in the Table below. In cases where the 
change involves the insertion or deletion of one or a few words, the text may be underlined 
for ease of reviewing. Additional typographical corrections or edits may also be made 
throughout the Protocol but not detailed in the Table.  
 
Section 
of 
the 
document 
Revision and Justification 
Title 
page 
and 
footer (all pages) 
Protocol version number updated to 1.5, dated August 17, 2020 
Title page 
Multi-site coordinator information updated. 
Clinical Sites and Principal Investigators information removed. 
Study Statistician information updated. 
 
Study Synopsis: 
Primary Objective  
(Page 2) 
Primary Objective changed from: 
The primary objective of the trial is to compare the rate of 180 days grade III-IV 
acute GVHD-free survival (aGFS) between the two GVHD prophylaxis regimens. 
An event for this time-to-event outcome is defined as grade III-IV aGVHD, or death 
by any cause, whichever occurs first.  
To: 
To establish the efficacy of CD24Fc in combination with standard prophylaxis for 
preventing acute GVHD after allogeneic HCT. 
  
Study Synopsis: 
Secondary 
Objectives  
(Page 2) 
Secondary Objectives changed from: 
Secondary objectives are to compare, for each treatment arm, rates of disease free 
survival (DFS), overall survival (OS), and 180 days grade II-IV aGVHD free survival 
(aGFS). Other exploratory evaluations will be rates of chronic GVHD at 1 year, 
relapse rate at 1 year, non-relapse mortality (NRM) at 1 year, incidence and rate 
of infections at 100 days, and mucositis rate at 28 days. 
To: 
To improve the relapse free survival (RFS) and overall survival (OS) in leukemia 
patients after allogeneic HCT through (1) reduction of the myeloablative 
conditioning toxicity; (2) reduction of severe acute GVHD; and (3) reduction of 
relapse 
 
Study Synopsis: 
Study 
Endpoints: 
(Page 2) 
Primary Endpoint added: 
180 day grade III-IV acute GVHD free survival (aGFS), event defined as the earlier 
time of GVHD or death within 180 days of HCT. 
 
Secondary Endpoints added: 
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Section 
2.3.1 
Primary 
Efficacy 
Endpoints 
(Page 15) 
Section 
2.3.2 
Secondary 
Efficacy Endpoints 
(Page 15) 
Disease Free Survival (DFS), event defined as the earlier time of leukemia relapse 
or death after HCT. 
Overall Survival (OS), event defined as time of all-cause mortality after HCT. 
180 day grade II-IV acute GVHD free survival (aGFS), the earlier time of event 
defined as Grade II-IV GVHD or death within 180 days of HCT. 
180 day grade III-IV acute GVHD relapse-free survival (aGRFS), the earlier time of 
event defined as GVHD, relapse or death within 180 days of HCT. 
 
Study Synopsis: 
Data 
Monitoring 
Committee: 
(Page 3) 
 
Stopping Guidelines language removed and replaced with Data Monitoring 
Committee language: 
The DMC consists of experts outside of the Sponsor will be responsible for the 
planned interim analyses. 
 
Study Synopsis: 
(Page 4) 
 
Figures 1 and 2 showing the Study Diagram and Randomization scheme, 
respectively, added. 
Study Synopsis: 
(Pages 5-7) 
 
Phase III Study Calendar added. 
CD24Fc 
Protocol 
Signature page 
(Page 8) 
 
Signature line for Sponsor representative added. 
Table 4  
(Page 27) 
Data for the following outcomes added: 
Grade II-IV acute GVHD-free survival at 180 days 
Grade III-IV acute GVHD-free relapse free survival at 180 days 
 
Figure 9  
(Pages 28 and 29) 
 
Figure showing 180 days probability of grade II-IV acute GVHD-free survival and 
description added. 
Figure 12  
(Pages 30 and 31) 
 
Figure showing 180 days probability of grade III-IV acute GVHD and relapse-free 
survival and description added. 
Table 5 
(Page 34) 
 
Eligibility criteria for Total Bilirubin changed from ≤2.5 mg% to ≤2.0 x ULN 
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Section 
4.2 
Exclusion Criteria 
(Pages 35 and 36) 
 
4.2.7 changed from: 
Uncontrolled infections. Patients still under therapy for presumed or proven 
infection are eligible provided there is clear evidence (radiologic, clinical and/or 
culture) that the infection is well controlled. 
To: 
Uncontrolled infections. Patients still under therapy for presumed or proven 
infection are eligible provided there is clear evidence (radiologic, clinical and/or 
culture) that the infection is well controlled. Patients testing positive for SARS-
CoV-2, whether symptomatic or asymptomatic, are excluded. Patients recovering 
from COVID-19 and viral testing negative for SARS-CoV-2 are eligible. 
 
4.2.8 changed from: 
Patients seropositive or PCR positive for the human immunodeficiency virus 
(HIV). Patients with evidence of Hepatitis B or Hepatitis C PCR positivity. 
To: 
Patients seropositive or PCR positive for the human immunodeficiency virus 
(HIV). Patients with evidence of active Hepatitis B or Hepatitis C PCR positivity. 
 
4.2.10 changed from: 
Use of T cell depletion either ex vivo or in vivo (i.e.ATG, alemtuzumab) is 
prohibited. 
To: 
Use of T cell depletion either ex vivo or in vivo (such as ATG or alemtuzumab or 
ex vivo CD34+ selected HCT) is prohibited. 
 
Section 
5.2 
Screening 
Procedures 
(Page 36) 
The following language was deleted and the CRO is identified as Medpace: 
This multi-site study will be conducted at the University of Michigan, The Ohio 
State University, Karmanos Cancer Institute and Indiana University with the 
potential to recruit 10-15 additional sites. 
 
Section 
5.3 
Treatment Schema 
(Page 36) 
 
Figure 10 moved to Study Synopsis section as Figure 1. 
Section 
5.5.2 
Tacrolimus 
(Page 37) 
 
The following language is deleted: 
g. Patients who are unable to initiate standard or alternative prophylaxis 
(calcineurin inhibitor) will be removed from the study and replaced. 
 
Section 
5.5.3 
Methotrexate 
Language changed from: 
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(Pages 37 and 38) 
 
Methotrexate will be used in combination with tacrolimus for standard GVHD 
prophylaxis. Methotrexate will be given intravenously at a dose of 15 mg/m2/dose 
once daily on Day 1 after HCT, and at a dose of 10 mg/m2/dose on days 3, 6, and 
11 after HCT. Attempts should be made to deliver all four doses, however, 
methotrexate may be omitted at the discretion of the treating physician. Missed 
doses of methotrexate will be recorded as a deviation, but will not constitute a 
protocol violation. Leucovorin rescue may also be administered according to local 
institutional practice guidelines.  Reduced Methotrexate per institutional practice 
guidelines is allowed, but should inform the study PI.  
To: 
Methotrexate will be used in combination with tacrolimus for standard GVHD 
prophylaxis. Methotrexate will be given intravenously at a dose of 15 mg/m2/dose 
once daily on Day 1 after HCT, and at a dose of 10 mg/m2/dose on days 3, 6, and 
11 after HCT. Attempts should be made to deliver all four doses, however, 
methotrexate may be omitted or reduced doses at the discretion of the treating 
physician according to institutional guidelines.  Leucovorin rescue may also be 
administered according to local institutional practice guidelines.  Reduced 
Methotrexate per institutional practice guidelines is allowed, but should inform the 
study PI.  
 
Section 
5.6.5 
Other 
Myeloablative 
Conditioning  
(Page 38) 
Prohibited T cell depletion changed from: 
i.e.ATG, alemtuzumab. 
To: 
such as ATG or alemtuzumab or ex vivo CD34+ selected HCT. 
 
Section 5.7 Donor 
Eligibility, 
Selection, 
and 
Related 
Procedures 
(Page 39) 
 
The following language was added: 
Due to the COVID-19 situation, the NMDP strongly recommends 
cryopreservation of all donor products as far in advance of the initiation of patient 
conditioning as is feasible, dictated by the clinical situation of the patient. 
 
Section 
5.8.4.2 
Cytomegalovirus 
(CMV) 
(Page 40) 
 
Monitoring period changed from Day 60 to Day 100. 
Section 
6.2 
Randomization  
(Page 41) 
Language changed from: 
A patient is considered to be “Enrolled” onto the study once they have signed 
consent and have successfully met all screening criteria, as documented by the 
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inclusion/exclusion document, and the CRO confirms these data.  The date of 
enrollment will be documented as date of notification from the CRO. 
To: 
A patient is considered to be “Randomized” onto the study once they have been 
assigned to one of the treatment arms through randomization process.  All 
patients will be randomized within 48 hours prior to the treatment of first dosing of 
either CD24Fc or placebo at day -1 (one day before transplantation). 
 
Section 
6.3 
Treatment Period 
(Page 41) 
Language changed from: 
The “Treatment Period” is defined as the first day of treatment with CD24Fc until 
60 days after HCT.  The exact days may vary depending on the last day of 
administration of study drug without constituting a deviation. The assessment and 
reporting period for adverse events (AE) including dose limiting toxicities 
potentially related to the study drug (CD24Fc) will extend through day 60 post 
HCT. Based upon PK data for CD24Fc this time period will allow for passage of 
greater than two half-lives.   
To: 
The “Treatment Period” is defined as the first day of treatment with CD24Fc until 
60 days after HCT. The assessment and reporting period for adverse events (AE) 
potentially related to the study drug (CD24Fc) extend through day 100 post HCT. 
Based upon PK data for CD24Fc this time period will allow for passage of greater 
than two half-lives.   
 
Section 6.4 Follow 
up Period 
(Pages 41 and 42) 
Language changed from: 
The “Follow Up” period is defined as the first day the patient is no longer within 
the treatment period (i.e. day 61) until the subject comes off study.  The follow-up 
period can be up to 3 years post HCT. During this time subjects will be followed 
for acute or chronic GVHD, relapse, and survival.  Data collection after one year 
post HCT will be minimal and can be an office visit, phone contact or review of 
the subject’s medical chart.  Outcome information collected on other BMT 
program clinical research studies may be analyzed in relation to patients 
participating in this study. 
To: 
The “Follow Up” period is defined as the first day the patient is no longer within 
the treatment period (i.e. day 101) until the subject comes off study.  The follow-
up period can be up to 3 years post HCT. During this time subjects will be 
followed for acute or chronic GVHD, relapse, and survival.  Data collection after 
one year post HCT will be minimal and can be an office visit, phone contact or 
review of the subject’s medical chart.   
 
Section 
6.5 
On 
Study  
(Page 42) 
Language changed from: 
The “On Study” period is defined as the day the patient signs the protocol 
consent document and meets the protocol eligibility criteria (“Enrolled”), until the 
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subject comes off study. Patients can be taken off study at any time at their own 
request, or they may be withdrawn at the discretion of the investigator for safety, 
behavioral or administrative reasons. 
To: 
The “On Study” period is defined as the day the patient signs the protocol 
consent document, meets the protocol eligibility criteria and is randomized to a 
study arm, until the subject comes off study. Patients can be taken off study at 
any time at their own request, or they may be withdrawn at the discretion of the 
investigator for safety, behavioral or administrative reasons. 
 
Section 
6.6 
Off 
Treatment 
(Page 426) 
 
The treatment period is changed from Day 60 to Day 100. 
Language changed from: 
Note: Subjects will be continuously monitored for adverse events per local 
institutional guidelines through day 60 post-HCT (e.g. for routine post HCT care 
and measurement of primary clinical endpoint of acute GVHD) and then at 
minimum quarterly through one year. Adverse events occurring beyond day 60 
post-HCT will be evaluated, monitored and recorded but not be reported unless 
related (probably or definitely) to the study drug (CD24Fc). The survival and 
disease relapse status will be followed for up to 3 years. 
To: 
Note: Subjects will be continuously monitored for all grade adverse events per 
local institutional guidelines  within 24 hours and severe grade 3 to 5 adverse 
events through 100 days post-HCT (e.g. for routine post HCT care and 
measurement of primary clinical endpoint of acute GVHD) and then at minimum 
quarterly through one year. Severe adverse events occurring beyond day 100 
post-HCT will be evaluated, monitored and recorded but not be reported unless 
related (probably or definitely) to the study drug (CD24Fc). The survival and 
disease relapse status will be followed for up to 3 years.  
 
Section 
7.1 
Managing Infusion 
Reactions 
(Page 43) 
Specific language relating to the management of infusion reactions added: 
nfusion reactions were not observed in the Phase I and Phase IIa clinical trials 
which involved 84 patients. Infusion reactions were not observed in an ongoing 
Phase III clinical trial in COVID-19 treatment which more than 180 patients have 
been dosed. 
Premedications do not need to be administered prior to the infusion of CD24Fc to 
prevent infusion reactions 
Patients who develop a grade 3 or higher infusion reaction will be taken off study 
drug but continued on study follow up. 
The grade 2 or above infusion reaction can be treated following NCI CTEP 
guidelines 
 
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Section 
7.2 
Managing 
Acute 
GVHD 
(Pages 43 and 44) 
 
The language was changed from: 
Overall acute GVHD will be assessed and graded weekly through day +60 after 
transplant, then at minimum monthly from Day 60 to Day 180 with quarterly 
thereafter. 
To: 
Overall acute GVHD will be assessed and graded weekly through day +100 after 
transplant, then at minimum monthly from Day 100 to Day 180 with quarterly 
thereafter. 
 
The following language was added: 
However the study primary endpoint analysis will not include the acute GVHD 
secondary to the treatment to leukemia relapse. 
The following language was deleted: 
Diagnosis of Stage I GVHD of the gut (grade II overall) that involves the 
upper GI tract (e.g. with stool volumes < 500ml/day) requires biopsy with 
histologic evidence of GVHD for confirmation. 
d. Discrepant GVHD scores will be reviewed by at least 1 investigator who will 
resolve the discrepancies (which may/may not include the use of a third, 
independent evaluation adjudication committee). 
 
Section 8.1 Renal 
Function 
 
Section deleted - dose modification based on renal function removed. 
Section 9.1 Special 
Considerations for 
COVID-19  
(Page 45) 
 
New section added. 
Table 
5 
Study 
Calendar 
for 
Phase III Study 
(Pages 46-48) 
A number of changes were made to the Table and footnotes reflect changes in 
the protocol, most notably the following: 
Assessment period for GVHD and AEs changed from weekly through Day 60 to 
weekly through Day 100, and monthly from Day 100 to Day 180. 
Concomitant Medications not assessed beyond Day 100. 
Frequency of Vital Signs monitoring reduced to prior to infusion and after infusion 
(+/- 30 min). 
Telemedicine visits allowed to minimize COVID-19 exposure. 
If a subject withdraws from the study and does not consent to continued follow-up 
of associated clinical outcome information, a public records search can be 
performed for survival. 
 
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Section 
10.1 
Pharmaceutical 
Information 
(Page 49) 
 
Reference to a specific lot number removed as this may change. 
CRO identified as Medpace. 
Section 
10.1.4 
Administration 
(Pages 49 and 50) 
 
Specific information relating the preparation, storage and administration of the 
drug product added. 
Section 
11.1 
Definition 
of 
Adverse Events  
(Page 62) 
 
Language changed from: 
These events may be: 
• 
Definitely related: clearly associated with study drug/treatment 
• 
Probably related: likely associated with study drug/treatment 
• 
Possibly related: may be associated with study drug or other treatment 
• 
Unlikely to be related, or 
• 
Definitely not related to the study drug/treatment 
For reporting purposes, an AE should be regarded as definitely or probably 
related to the study drug if the Investigator believes that at least one of the 
Number 1 or Number 2 criteria plus at least one of the Number 3 or Number 4 
criteria are met: 
To: 
These events may be: 
• 
Related: clearly or likely associated with study drug/treatment 
• 
Not related: unlikely or definitely not related to the study drug/treatment 
For reporting purposes, an AE should be regarded as related to the study drug if 
the Investigator believes that at least one of the Number 1 or Number 2 criteria 
plus at least one of the Number 3 or Number 4 criteria are met: 
 
Section 11.3.1 AE 
Reporting 
(Page 64) 
 
Language changed from: 
Reporting to Sponsor: 
All AEs (regardless of grade and attribution) will be recorded in the patient’s 
source and entered into the electronic data capture system from the time of 
CD24Fc infusion through day 60 post HCT (the treatment period).  Any AE that is 
reported after the treatment period has ended and is considered related to 
treatment (possibly, probably, definitely) should also be entered in the electronic 
data capture system. 
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Expedited Reporting (the following need to be added into the electronic 
data capture system and reported to the Sponsor within 24 hours of 
knowledge): 
• 
All AEs (regardless of grade) from time of CD24Fc infusion through 24 
hours after CD24Fc infusion including subjects receiving blinded 
placebo. 
• 
All grade 3-5 AEs (except as defined in Section 11.1 Expected Events) 
occurring after the 24 hour post CD24Fc infusion period has elapsed on 
day 0 through the treatment period will be recorded and reported to the 
Sponsor and CRO. Note: this duration allows for over two half-lives of 
CD24Fc to elapse (t1/2 is 11 -14 days).   
• 
Events resulting in death during the treatment period. 
To: 
As the expectation of a high rate of low grade adverse events associated with 
conditioning regimen and HCT procedure, only Grade 3 to 5 AEs (regardless 
attribution) will be recorded in the patient’s source and entered into the electronic 
data capture system from the time of CD24Fc or placebo infusion through day 
100 post HCT.   
All grade AE will be recorded only within 24 hours of start of an infusion of 
CD24Fc/placebo.  
The acute GVHD is the study primary endpoint. Infections and leukemia relapse 
are study endpoints. The CMV reactivation, myeloablative conditioning regimen 
associated myelosuppression, anemia, thrombocytopenia, mucositis will not be 
considered as AE as these are expected events in HCT. The post-HCT hospital 
re-admission due to these conditions will be recorded. 
 
Section 11.3.1 AE 
Reporting 
(Page 65) 
 
Language changed from: 
Reporting of SAES to the FDA 
In accordance with FDA REPORTING REQUIREMENTS FOR SERIOUS 
ADVERSE EVENTS (21 CFR Part 312): In this trial, serious, unexpected adverse 
events believed to be definitely, probably or possibly related to the study 
treatment will be reported to the FDA. 
To: 
In accordance with FDA REPORTING REQUIREMENTS FOR SERIOUS 
ADVERSE EVENTS (21 CFR Part 312): In this trial, serious, unexpected adverse 
events believed to be definitely, probably or possibly related to the study 
treatment will be reported to the FDA as applicable. 
 
Section 11.3.1 AE 
Reporting 
Language changed from: 
SAE Reporting-Procedures for Investigators 
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07ZKR8


OncoImmune Inc. 
Clinical Trial Protocol (CATHY) 
IND 127,363 
CD24Fc-005 
 
101 
 
CD24Fc for GVHD Prevention; v1.5: August 17, 2020 
The CRO will be responsible for notifying the Sponsor within 24 hours of 
knowledge. 
A subject becoming pregnant prior to administration of study drug will 
immediately be withdrawn from the study and early termination study procedures 
will be performed. 
To: 
If the subject participating in the study becomes pregnant during the study or 
within 30 days of discontinuing study drug, the Investigator should report the 
pregnancy to the CRO within 24 hours of being notified.  
A subject becoming pregnant prior to administration of study drug will 
immediately be withdrawn from the study. 
 
Section 
11.3.3 
Events reports as 
Adverse 
Events 
Routinely 
in 
Tabular Format 
 
Section deleted 
Section 
11.3.3 
Emergency 
Unblinding 
(Page 66) 
 
New section added 
Section 12 Data 
Safety Monitoring 
Plan (DSMP) 
(Page 66) 
 
Language changed from: 
The following are the procedures for data and safety monitoring of this clinical 
trial to be coordinated by the CRO and sponsored by OncoImmune, Inc. This is to 
ensure the safety of participants, the validity of research data, and the 
appropriate termination of studies for which significant benefits or risks have been 
uncovered or when it appears that the trial cannot be concluded successfully. 
This protocol will conduct a data and safety monitoring process as described in 
the plan below.  
To: 
The CRO Medpace will collect the data and provide the data to an independent 
DMC at the planned safety monitoring meetings and the pre-specified interim 
analysis. . This is to ensure the safety of subjects, the validity of research data, 
and the appropriate termination of studies for which significant benefits or risks 
have been uncovered or when it appears that the trial cannot be concluded 
successfully. This protocol will conduct a data and safety monitoring process as 
described in the plan below. 
 
06CPP7
07ZKR8


OncoImmune Inc. 
Clinical Trial Protocol (CATHY) 
IND 127,363 
CD24Fc-005 
 
102 
 
CD24Fc for GVHD Prevention; v1.5: August 17, 2020 
Section 
12.2 
Storage 
and 
Dissemination 
of 
Reports 
(Page 67) 
 
Language changed form: 
The CRO is responsible for collating all the Data and Safety Monitoring Reports 
from all participating institutions and providing this information to independent 
DSMB. The CRO will coordinate the reporting process between the Investigators, 
the Sponsor, the IRB, as well as other applicable reporting agencies (FDA and 
study sponsors). Copies of all related correspondence and reporting documents 
will be maintained by the CRO and the research data file will be maintained in a 
file by the BMT data management team. 
To: 
Medpace is responsible for collecting all safety data in the electronic Case Report 
Forms (eCRFs) from all participating institutions and providing the data to the 
independent DMC.   
 
Section 
12.3 
Clinical Monitoring 
Procedures 
(Pages 67 and 68) 
Language added to allow remote monitoring and site initiation through 
teleconference. 
 
The following language was deleted: 
The first monitoring visit at each site should occur after the first subject enrolled 
completes the Day 30 visit. At a minimum, a central and/or on-site monitoring visit 
will be done at least quarterly. 
And replaced with: 
Monitoring of the study site will be performed by the CRO. 
 
The following language was deleted: 
Weekly teleconferences will be conducted among investigators from participating 
study sites, the CRO, the principal investigator (PI), study statistician and medical 
monitor from the sponsor and / or its designee (i.e. CRO). At these meetings 
safety events, DLTs, withdrawals, subjects’ progress and other relevant events 
on trial will be reviewed and appropriate actions will be taken including amending 
or suspending the trial. Safety reports generated by the CRO will also be 
submitted to the DSMB and the medical monitor from the sponsor monthly. The 
DSMB and Sponsor will both be responsible for reviewing these reports monthly 
and if necessary taking appropriate steps to ensure the safety of subjects and 
compliance with this protocol (i.e. inquiries, suspension, or termination of trial).  
Finally, whenever an unanticipated data, safety and monitoring board meeting 
takes place or when a new development occurs the medical monitor from the 
sponsor and / or its designee (i.e. CRO) and IRB will be notified of the 
occurrence. 
In general, close-out is conducted during a site visit. However, a site close-out 
can occur without a site visit. 
 
06CPP7
07ZKR8


OncoImmune Inc. 
Clinical Trial Protocol (CATHY) 
IND 127,363 
CD24Fc-005 
 
103 
 
CD24Fc for GVHD Prevention; v1.5: August 17, 2020 
Section 13 Quality 
Assurance 
and 
Audits 
(Pages 68 and 69) 
Language changed from: 
The CRO will perform quality assurance audits. Audits provide assurance that 
trials are conducted in compliance with the protocol. Further, they ensure that 
study data are collected, documented and reported in compliance with Good 
Clinical Practices (GCP) Guidelines and regulatory requirements. All audit 
findings are reported to the DSMB and the sponsor. The DSMB can also request 
a ‘for cause’ quality audit of the trial if the Committee identifies a need for a more 
rigorous evaluation of study-related issues. 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, the 
site investigator must immediately inform the CRO and Sponsor that such a 
request has been made. 
To: 
Audits provide assurance that trials are conducted in compliance with the 
protocol. Further, they ensure that study data are collected, documented and 
reported in compliance with Good Clinical Practices (GCP) Guidelines and 
regulatory requirements. All audit findings are reported to the DMC and the 
sponsor. 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, the site investigator must immediately 
inform the CRO and Sponsor that such a request has been made. 
 
Section 
14 
Removal 
from 
Study 
(Page 69) 
 
The following language was deleted: 
and every effort should be made to perform follow-up evaluations 
 
The following language was added: 
In the event a subject fails to appear for a scheduled follow-up visit, Institution 
and/or Principal Investigator shall use reasonable efforts contact the subject 
within ten (10) days after the date of the scheduled visit regarding the failure to 
keep the appointment.  If a subject withdraws from the Study, Institution and 
Principal Investigator shall use reasonable measures to follow up with the subject 
in person or by telephone (if possible), otherwise by certified mail, to determine 
the reason for the discontinuance. 
Section 15 
Section deleted 
Section 
15 
Statistical 
Considerations 
(Pages 69 to 77) 
 
Substantial changes were made to this section to reflect changes in the study 
analyses. The most notable changes include: 
Patients will be randomized with 48 hours prior to the first dosing. 
Power calculations for the Secondary Endpoints were added. 
The Interim Analysis will test for efficacy (not futility) when 46 events (70%) of 
information occurs (previously 39 events and 60%). 
Details regarding the sample size re-estimation process are added. 
180 Day Grade III-IV acute GVHD and Relapse-free survival added as a 
secondary endpoint. 
06CPP7
07ZKR8


OncoImmune Inc. 
Clinical Trial Protocol (CATHY) 
IND 127,363 
CD24Fc-005 
 
104 
 
CD24Fc for GVHD Prevention; v1.5: August 17, 2020 
Supplement analyses were added including (1) a Restricted Mean Survival Time 
(RMST) method used to estimate hazard ratio in case the proportionality 
assumptions do not hold, and (2) defining the primary endpoint as time from 
transplantation to acute GVHD of grade III or IV severity, treatment for acute 
GVHD with systemic agents other than corticosteroids, or death, whichever 
occurs first, up to day 180. 
 
 
06CPP7
07ZKR8