Clinical trial NCT04552704
Conditions: Advanced Malignant Solid Neoplasm
Sponsor: Tianhong Li
Start date: 2020-10-30; Completion date: 2022-01-26
Enrollment: 3 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This phase I/II trial investigates the side effects and how well CD24Fc works in treating immune related adverse events in patients with solid tumors that have spread to other places in the body (advanced). CD24Fc may prevent autoimmune reactions due to the tissue damage induced by cancer treatment. CD24Fc binds to injured cell components and prevents inflammatory responses. CD24Fc also acts to turn off the immune system after it has been activated ("immune checkpoint"). Adding CD24Fc to standard treatment may shorten the recovery time and reduce the severity of side effects from immunotherapy.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the safety and tolerability of CD24 extracellular domain-IgG1 Fc domain recombinant fusion protein CD24Fc (CD24Fc) in patients with advanced solid tumors who developed debilitating immune-related adverse events (irAEs) from immune check point inhibitors (ICIs). (Phase I) II. To determine if CD24Fc shortens the recovery time of irAE and increases the recovery rate of irAE in cancer patients with grade (G)2 or 3 irAEs. (Randomized phase II)

SECONDARY OBJECTIVES:

I. Time to irAE reduction by at least 1 grade. (Phase I) II. Time to all irAEs reduced to grade =\< 1. (Phase I) III. Time to resume ICI treatment. (Phase I) IV. Recovery rate (as defined by reduction of irAE by one grade) at day (D)42. (Phase I) V. To estimate the time to all irAEs reduced to =\< 1. (Randomized phase II) VI. To record the use of steroids (drug, dose, duration) and other treatment for irAE. (Randomized phase II) VII. To record the time to resume ICI treatment. (Randomized phase II) VIII. To estimate the preliminary overall response rate (ORR), progression free survival (PFS), and 1-year overall survival (OS) after treatment with or without CD24Fc. (Randomized phase II) IX. To determine if CD24Fc treatment changes the levels of inflammatory markers in the plasma. (Randomized phase II)

OUTLINE:

PHASE I: Patients receive CD24Fc intravenously (IV) over 60 minutes on days 1, 14, and 28 with standard of care (i.e., steroids per treating physician and best supportive care) in the absence of disease progression or unacceptable toxicity.

PHASE II: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive CD24Fc IV over 60 minutes on days 1, 14, and 28 in addition to standard of care treatment for irAE in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive placebo IV over 60 minutes on days 1, 14, and 28 in addition to standard of care treatment for irAE in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at days 42 and 60 and then every 3 months for up to 1 year.

Arms: arm 1: Patients receive CD24Fc IV over 60 minutes on days 1, 14, and 28 with standard of care (i.e., steroids per treating physician and best supportive care) in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive CD24Fc IV over 60 minutes on days 1, 14, and 28 in addition to standard of care treatment for irAE in the absence of disease progression or unacceptable toxicity. arm 3: Patients receive placebo IV over 60 minutes on days 1, 14, and 28 in addition to standard of care treatment for irAE in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: CD24 Extracellular Domain-IgG1 Fc Domain Recombinant Fusion Protein CD24Fc intervention 2: Placebo Administration
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
TIRAEC 
 
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UC Davis Comprehensive Cancer Center 
 
 
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Treatment of Immune Related Adverse Events with CD24Fc (TIRAEC) 
 
Protocol Number: 
UCDCC#292 
CD24Fc-006 
NCT04552704 
Indication: 
Patients with advanced solid tumors who have treatment 
interruption due to grade 2 or 3 irAEs from immune check point 
inhibitors (ICIs)  
Phase: 
I/II 
Funding Source: 
UCDCCC, OncoImmune, Inc. 
Agent: 
Immunomodulator 
Principal Investigator: 
Tianhong Li, MD, PhD 
UC Davis Comprehensive Cancer Center 
Division of Hematology & Oncology 
 
 
Coordinating Center: 
UC Davis Comprehensive Cancer Center 
 
 
 
 
Co-Investigator(s): 
James Liu, MD 
Primo N. Lara, Jr, MD 
Karen Kelly, MD 
David R. Gandara, MD 
Jonathan Riess, MD 
Edward Kim, MD PhD 
May Cho, MD 
Kit Tam, MD 
Mamta Parikh, MD 
Joyce Lee, Pharm D 
Aaron Paul Steele, Pharm D 
Jennifer Murphy, PharmD, BCOP 
Weijie Ma, MD 


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Statistician: 
Shuai Chen, PhD 
Division of Biostatistics 
Department of Public Health Sciences 
 
 
  
 
 
 
Participating 
Center(s): 
UC Davis Comprehensive Cancer Center 
Protocol History: 
Version 1.5 / October 20, 2020 
 
IND #: 
 
IND Sponsor:  
OncoImmune, Inc. 
 
 


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PROTOCOL SIGNATURE PAGE 
 
Protocol Number: UCDCC#292, CD24Fc-006, NCT04552704 
Protocol Title: Treatment of Immune Related Adverse Events with CD24Fc (TIRAEC) 
I have read this protocol and agree that it contains all necessary details for carrying out this 
study. I will conduct the study as outlined herein and will complete the study within the time 
designated, in accordance with all stipulations of the protocol and in accordance with Good 
Clinical Practices, local regulatory requirements, and the Declaration of Helsinki.  
I will provide copies of the protocol and all pertinent information to all individuals responsible to 
me who assist in the conduct of this study. I will discuss this material with them to ensure that 
they are fully informed regarding the study agent(s) and the conduct of the study. 
 
Tianhong Li, MD PhD 
__________________________________ 
Investigator Name (print) 
 
__________________________________ 
Investigator Signature  
 
__________________ 
Date  
 
 
__________________________________ 
Signature of Chief Medical Officer  
 
Dr. Pan Zheng_______________________ 
Name  
 
__________________ 
Date  
 
 


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PROTOCOL SYNOPSIS 
Study Title: 
Treatment of Immune Related Adverse Events with CD24Fc (TIRAEC) 
Protocol No.: 
UCDCC#292, CD24Fc-006, NCT04552704 
Phase of 
Development: 
Phase I/II 
Investigational 
Product, Dosage 
Form, Route, and 
Dose Regimen 
CD24Fc: 480 mg on day 1; then 240 mg on day 14 and day 28 i.v. (a 
total course of 28 days). 
Primary Objective: 
Phase I study: To determine the safety and tolerability of CD24Fc in 
patients with advanced solid tumors who have treatment interruption due 
to grade 2 or 3 irAEs (by NCI CTCAEv5.0) from immune check point 
inhibitors (ICIs). 
Phase II randomized double-blind placebo controlled study: To 
determine if CD24Fc shortens the recovery time and increases recovery 
rate of irAEs in cancer patients with grade 2 or 3 irAEs. 
Secondary 
Objectives 
Phase I study: Time to irAE reduction by at least 1 grade from CD24Fc. 
To estimate the time to all irAEs reduced to grade ≤1. Time to resume 
ICI treatment from the initiation of CD24Fc. To estimate the recovery 
rate as defined by reduction on irAE by at least one grade. To determine 
if CD24Fc treatment changes the levels of inflammatory markers in the 
plasma. 
Phase II study: To estimate the time to all irAEs reduced to grade ≤1. To 
record the use of steroids (drug, dose, duration) and other treatment for 
irAE. To estimate the preliminary overall response rate (ORR), 
progression free survival (PFS), and 1-year overall survival (OS) after 
treatment with or without CD24Fc. To determine if CD24Fc treatment 
changes the levels of inflammatory markers in the plasma 
Study Design and 
Investigational Plan 
/ Methodology: 
Phase I study: Patients with advanced solid tumors who have treatment 
interruption due to grade 2 or 3 irAEs from ICI will be treated with 
CD24Fc along with standard of care (SOC) treatment for irAE.Phase II 
randomized double blind placebo controlled study: Patient with 
advanced solid tumors who have treatment interruption due to grade 2 or 
3 irAEs will be randomized (1:1) to receive CD24 Fc vs placebo in 
addition to SOC treatment for irAE. Patient will be stratified randomized 
by study statistician based on whether steroid was used for irAE at 
enrollment. Placebo is 100 ml normal saline, which is used to dilute 
CD24Fc.   


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Study Schema:  
Phase I 
Study Schema:  
Phase II 
Study Population 
and Sample Size: 
Cancer patients who have treatment interruption due to grade 2 or 3 
irAEs on ICI therapy. Phase I: n=6; Phase II: n=72 
Eligibility Criteria:  
Patients who developed grade 2-3 irAEs to ICI for treatment of 
metastatic or unresectable solid tumor leading to therapy hold. Patients 
should be naïve to CD24Fc therapy. 
Patients who have grade 4 irAEs or any grade 4 toxicity based on 
CTCAE v5.0 will be excluded.  
The detailed inclusion and exclusion criteria are listed in Section 5.0.  
Endpoints: 
Phase I study:  
Primary endpoint:  Any new AE of ≥grade 3 that are outside the 
spectrum of irAEs when CD24Fc is given in cancer patients who 
developed grade 2-3 irAEs.  
Secondary endpoints: 1) time to irAE reduction by at least 1 grade; 2) 
time to all irAEs reduced to ≤1 (by NCI CTCAEv5.0); 3) time to resume 
ICI treatment; 4) recovery rate (as defined by reduction of irAE by one 
grade) at D42. 
Phase II randomized study: 
Co-primary endpoints:  
1). Recovery rate (as defined by reduction of irAE by one grade) at D42 
2). Kaplan Meier Estimate of time to recovery from grade 2 or 3 irAE 
(as defined by reduction of irAE by at least one grade in severity).  
Secondary endpoints:  
1) Time to all irAEs reduced to ≤1 after treatment with CD24Fc; 2) the 
use of steroids and other drugs (drug, dose, duration) as SOC for irAEs; 
3) time to resume ICI treatment; 4) ORR; 5) PFS; and 6) 1-year OS  


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Statistical 
Considerations 
Statistical Analysis 
Demographic and background characteristics obtained at enrollment will 
be listed and summarized. Descriptive statistics will be used to 
summarize changes of biomarkers from baseline in clinical laboratory 
parameters for this cohort, and use of steroids (drug, dose, duration) and 
other treatment for irAE.  
To assess toxicity: Toxicity is evaluated by NCI CTCAEv5.0. The type, 
grade, frequency and proportion of toxicities noted during the treatment 
period will be reported, along with associated 95% confidence interval 
of proportion. All adverse events noted by the investigator will be 
tabulated according to the affected body system. In phase I lead-in 
study, dose limiting toxicity is defined as any new AE of ≥grade 3 that 
are outside the spectrum of irAEs.  
To assess time to recovery from irAE (time to reduction of irAE by at 
least one grade), time to all irAEs reduced to ≤1, and time to resume ICI 
treatment: The date of staring treatment (i.e., Day 1) will be used for all 
time events in the study. Kaplan-Meier plots and confidence intervals 
will be used to summarize outcomes. Medians and associated 95% 
confidence intervals will be calculated, and comparisons between groups 
will be performed by log-rank tests. Cox proportional hazard models 
will be used to explore association between covariates and outcomes.  
To assess recovery rate of irAE by CD24Fc (reduction of irAE by one 
grade) at D42 and response rate of ICI: The fractions will be reported 
along with 95% two-sided confidence intervals. Comparisons between 
arms will be performed by Fisher’s Exact tests. We will also 
characterize the proportion who remain that either respond or have 
stable disease, compared to those who progress.  
To assess PFS and OS: Kaplan-Meier plots and confidence intervals will 
be used to summarize PFS, and OS; 1-year OS rate will be reported; 
medians and associated 95% confidence intervals will be calculated, and 
comparisons between groups will be performed by log-rank tests. Cox 
PH models will be used to explore association between outcomes and 
covariates. 
As exploratory analysis, we will summarize descriptively the 
relationship of response rates to tumor type (lung, GI, melanoma, breast, 
prostate) and to cellular immune response and explore the relationship 
using logistic regression. 


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The possibility of bias from missing data will be addressed. Missing 
pattern and mechanism will be evaluated, and sensitivity analyses will 
be performed using imputation methods for use of steroid, irAE type, 
cancer type, etc., if such might affect point estimates and study 
conclusions. 
Sample Size Justification 
Phase I study:  
We plan to enroll 6 patients in the phase I study. The objective of this 
phase I study is to confirm the safety of CD24Fc in ICI-treated cancer 
patients who have treatment interruption due to grade 2 or 3 irAEs and 
to estimate the median time to recovery and resumption of ICI after 
treatment interruption due to irAE. The primary endpoint is new AE of 
≥grade 3 that are outside the spectrum of irAEs when CD24Fc is given 
to treat irAEs. We expect the rate of this event will be less than 33.3%. 
With a sample size of 6 patients, we would have 74-91% chance to 
observe at least one occurrence if the true event rate is 20-30%. Hence 
the sample size is adequate for this pilot study for safety.  
Randomized phase II study:  
Previous studies suggested that response rate at 42 days for control 
group will be about 50%. We hypothesize CD24Fc will increase 
recovery rate from 50% to 80 %. A sample size of 72 patients (36 in 
each arm) will have 81% power to detect an increase of recovery rate 
from 50% of control group to 80% of CD24Fc group. This result is 
based on one-sided Fisher’s Exact test and significance level of 0.05. 
Group-sequential design will be used with interim analysis to monitor 
the trial by a cohort size of 24 (12 in each group), with maximum 
sample size of 72, average sample size of 46 if null hypothesis is true, 
and 58 if alternative hypothesis is true. 
Steroids is the most commonly used SOC therapy for irAEs. It affects 
the severity and duration of irAE, which are the key endpoints of this 
study. We thus will stratify the subjects based on the status of steroids 
use at registration and will adjust steroids use in analyses. Few patients 
might start on steroids as SOC before starting the study treatment, and 
the patients will be moved to the steroid stratum. 
Estimated 
Accrual/Enrollment 
Period: 
Six patients in the phase I study and 72 patients in phase II randomized 
study. Of about 50 cancer patients received ICI per month at UCD, 8 
patients (15%) develops grade 2 and 3 irAE that require treatment 
interruption. We estimate 4-5 patients will be enrolled each month.  


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Estimated Study 
Duration:  
Estimated Duration 
of Participation: 
Total duration of the study is estimated to be approximately 3 months 
for phase I, 18 months for phase II, and 3 months for follow-up, data 
collection, and analysis.  
Anticipated FPFV / 
LPLV: 
 
Correlatives: 
To evaluate tissue damage-associated molecular pattern (DAMP) 
signaling contributes to the pathogenesis of irAEs, we will explore the 
association of pretreatment plasma HMGB1 level with the grade of irAE 
from all study patients. To test if CD24Fc ameliorates inflammatory 
response to DAMPs, we will compare plasma levels of inflammatory 
cytokines in the placebo and the CD24Fc arms.  
 
 
 


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Figure 1: Phase I Study Schema 
 
 
 
 
END OF SURVIAL FOLLOWUP 
 DEATH OR CUT-OFF DATE 
FOLLOW-UP PERIOD 
Every 3 months by chart checks until death or up to 1 year 
N=6 
TREATMENT 
CD24Fc, 480 mg on day 1, 240 mg on day 14 and 
day 28 i.v. (a total course of 28 days) 
SCREENING  
Within 2 weeks 
END OF STUDY 
Evaluation of all AE at day 60 
POST-TREATMENT 
Evaluation of irAE at day 42 


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Table 1. Flow Chart for Phase I Study 
CD24Fc 480 mg on day 1, 240 mg on day 14, and 240 mg on day 28 i.v. (a total course=28 days)  
Trial Period 
Screening 
Treatments 
Post-
Treatment 
End of 
Study 
Post-
Study 
Dose/Treatment Number 
  
1 
2 
3 
2-week 
Evaluation 
Safety 
Follow Up 
Survival 
Follow Up  
Day 
-14 to -1 
1 
14 ± 
3 
28 ± 
3 
42 ± 3 
60 ± 3 
Every 3 
months to 
1 year1 
Drug Dispensation 
CD24Fc 
 
X 
X 
X 
 
 
 
Administrative Procedures 
Eligibility evaluation, informed 
consent, medical history 
X 
 
 
 
 
 
 
Medication review 
X 
X 
X 
X 
X 
X 
X 
Post-study status, survival status 
 
 
 
 
 
 
X 
Clinical Procedures 
Full physical exam 
X 
 
 
 
X 
X 
 
Directed physical exam 
 
X 
X 
X 
 
 
 
ECOG PS, vital signs, EKG2, 
acute AE monitoring3 
X 
X 
X 
X 
X 
X 
 
Evaluation for ICI retreatment 
 
 
 
 
X 
 
 
Toxicity assessment (NCI 
CTCAE V5.0) 
X 
X 
X 
X 
X 
X 
X4 
Laboratory Procedure/Assessment 
CBC with differential, CMP 
X 
X5 
X5 
X5 
X 
X 
 
Pharmacokinetics/Pharmacodyna
mics, ADA, correlative blood 
sample collection6 
 
X6 
X6 
X6 
X 
X 
 
Pregnancy test (urine or serum b-
HCG)7 
X 
 
 
 
 
 
 
1. 
Frequency of follow-up office visits at the discretion of treating physician. Chart check every 3 months for post 
treatment and survival status. To continue until death or up to 1 year after completion of the study.  
2. 
On days of CD24Fc administration, vitals and EKG will be obtained prior to and post infusion of study drug.  
3. 
All patients will be monitored for 1-hour post infusion with are registered nurse or nurse practitioner within immediate 
proximity. 
4. 
If irAE has not resolved to ≤grade 1 at day 60, check on primary oncologist’s document for the grade of AE at every 
visit until resolution. 
5. 
CBC and CMP blood draw should be within 3 days prior to CD24 Fc administration  
6. 
The PK/PD, ADA, correlative blood sample collection: 2x 10ml EDTA samples at each time point. The samples should be 
collected pre-dosing and 30±10 min after each IV infusion. Sample collection must be from the opposite arm to that used for 
study drug infusion.   
7. 
Women of childbearing age only 


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Figure 2: Phase II Randomized, Placebo Controlled Study Schema 
 
END OF SURVIAL FOLLOWUP 
 DEATH OR CUT-OFF DATE 
Treatment (N=36): 
CD24Fc x 3 doses  
Control (N=36): 
Placebo x 3 doses  
FOLLOW UP PERIOD 
Every 3 months by chart checks until death or up to 1 year 
N=72 
SCREENING  
Within 2 weeks 
Randomization 
END OF STUDY 
Evaluation of all AE at day 60 
POST-TREATMENT 
Evaluation of irAE at day 42 


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Table 2. Flow Chart for Phase II Study (CD24Fc Group vs Placebo Group) 
CD24Fc 480 mg on day 1, 240 mg on day 14, and 240 mg on day 28 i.v. (a total course=28 days)  
Trial Period 
Screening 
Treatments 
Post-
Treatment 
End of 
Study 
Post-
Study 
Dose/Treatment Number 
  
1 
2 
3 
2-week 
Evaluation 
Safety 
Follow Up 
Survival 
Follow Up  
Day 
-14 to -1 
1 
14 ± 
3 
28 ± 
3 
42 ± 3 
60 ± 3 
Every 3 
months to 
1 year1 
Drug Dispensation 
CD24Fc 
 
X 
X 
X 
 
 
 
Placebo 
 
X 
X 
X 
 
 
 
Administrative Procedures 
Eligibility evaluation, informed 
consent, medical history 
X 
 
 
 
 
 
 
Medication review 
X 
X 
X 
X 
X 
X 
X 
Post-study status, survival status 
 
 
 
 
 
 
X 
Clinical Procedures 
Full physical exam 
X 
 
 
 
X 
X 
 
Directed physical exam 
 
X 
X 
X 
 
 
 
ECOG PS, vital signs, EKG2, 
acute AE monitoring3 
X 
X 
X 
X 
X 
X 
 
Evaluation for ICI retreatment 
 
 
 
 
X 
 
 
Toxicity assessment (NCI 
CTCAE V5.0) 
X 
X 
X 
X 
X 
X 
X4 
Laboratory Procedure/Assessment 
CBC with differential, CMP 
X 
X5 
X5 
X5 
X 
X 
 
Correlative blood and plasma 
sample collection, PK/ADA 
samples6 
 
X6 
X6 
X6 
X 
X 
 
Pregnancy test (urine or serum 
b-HCG)7 
X 
 
 
 
 
 
 
 
1. 
Frequency of follow-up office visits at the discretion of treating physician. Chart check every 3 months for post 
treatment and survival status. To continue until death or up to 1 year after completion of the study.  
2. 
On days of CD24Fc administration, vitals and EKG will be obtained prior to and post infusion of study drug.  
3. 
All patients will be monitored for 1-hour post infusion with are registered nurse or nurse practitioner within immediate 
proximity. 
4. 
If irAE has not resolved to ≤grade 1 at day 60, check on primary oncologist’s document for the grade of AE at every 
visit until resolution. 
5. 
CBC and CMP blood draw should be within 3 days prior to CD24 Fc administration 
6. 
The PK/PD, ADA, correlative blood sample collection: 2x 8 ml EDTA samples at each time point. For all infusions, 
the samples should be collected pre-dosing and 30±10 min after IV infusion and the end of study visit. Sample 
collection must be from the opposite arm to that used for study drug infusion.   
7. 
Women of childbearing age only 


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LIST OF ABBREVIATIONS AND TERMS 
Abbreviation/ 
Term 
Definition 
°C 
Degrees Celsius 
ACVP 
American College of Veterinary Pathologists 
ADA 
Anti-drug antibodies 
AE 
adverse event 
ALT 
alanine transaminase 
ANC 
absolute neutrophil count 
APC 
Antigen-presenting cell  
AST 
aspartate transaminase 
AUC0-∞  
Area under the plasma drug concentration-time curve from 0 to infinity 
AUC0-t 
Area under the plasma drug concentration-time curve from time 0 to last measurable 
time 
CD24Fc 
CD24 IgG1 Fc fusion protein 
cGMP 
Current Good Manufacturing Practices 
CL 
Plasma clearance 
Cmax 
Maximum plasma concentration 
CNS 
Central nervous system 
CPU 
Clinical Pharmacology Unit 
CR 
complete response 
CRA 
Clinical Research Associate 
CRC 
clinical research coordinator 
CRF 
case report form 
CRF 
Case report form 
CT 
computed tomography 
CTCAE 
(NCI) Common Terminology Criteria for Adverse Events 
DAMP 
Danger-associated molecular pattern 
DC 
Dendritic cell 
DLT 
dose-limiting toxicity 
DSMB 
Data and Safety Monitoring Board 
DSMC 
Data and Safety Monitoring Committee 
DSMP 
Data and Safety Monitoring Plan 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GLP 
Good Laboratory Practice 


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GVHD 
Graft vs host diseases 
HBsAg 
Hepatitis B virus surface antigen 
HCT 
Hematopoietic stem cell transplantation 
HED 
Human equivalent dose 
HIV 
Human immunodeficiency virus 
ICH 
International Council for Harmonisation 
ICH 
International Conference on Harmonization 
IEC 
independent ethics committee 
IND 
Investigational New Drug 
irAE 
immune related adverse event 
irAE 
Immune-related adverse events 
IRB 
institutional review board 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IV 
intravenous 
IV 
Intravenous 
Kel 
Elimination rate of constant 
KLH 
Keyhole limpet hemocyanin 
LDH 
lactate dehydrogenase 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
mM 
micromolar 
MRI 
magnetic resonance imaging 
MRSD 
Maximum recommended starting dose 
MS 
Multiple sclerosis 
MTD 
maximum tolerated dose 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
NOAEL 
No observed adverse event level 
OCR 
Office of Clinical Research 
OS 
overall survival 
PAMP 
Pathogen-associated molecular pattern 
PBML 
Peripheral blood mononuclear leukocytes 
PD 
progressive disease 
PD 
Pharmacodynamics 
PET 
positron emission tomography 
PI 
principal investigator 
PK 
Pharmacokinetics 
PML 
Progressive multifocal leukoencephalopathy 
PPB 
Plasma protein binding 


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PR 
partial response 
QD 
Once daily 
RA 
Rheumatoid Arthritis 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RP2D 
Recommended phase II dose 
SAE 
serious adverse event 
SAE 
Serious adverse event 
SOC 
Standard of Care 
SOP 
Standard operation procedures 
SRC 
Scientific Review Committee 
t1/2 
Elimination half life 
TBI 
Total body irradiation 
TEAE 
Treatment-emergent adverse event 
tmax 
Time to maximum plasma concentration 
UCD 
University of California, Davis (UC Davis) 
UCDCCC 
UC Davis Comprehensive Cancer Center 
US 
United States 
WHO 
World Health Organization 
 
 
 


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TABLE OF CONTENTS  
PROTOCOL SIGNATURE PAGE .............................................................................................................. 3 
PROTOCOL SYNOPSIS .............................................................................................................................. 4 
LIST OF ABBREVIATIONS AND TERMS ............................................................................................. 13 
TABLE OF CONTENTS ............................................................................................................................ 16 
LIST OF TABLES ...................................................................................................................................... 18 
LIST OF FIGURES .................................................................................................................................... 18 
0. 
OBJECTIVES ................................................................................................................................ 20 
0.0 
Phase I study: .................................................................................................................................. 20 
0.0.0 Primary Objective: ............................................................................................................... 20 
0.0.1 Secondary Objectives: ......................................................................................................... 20 
0.1 
Randomized phase II study: ............................................................................................................ 20 
0.1.0 Primary Objective: ............................................................................................................... 20 
0.1.1 Secondary Objectives: ......................................................................................................... 20 
1. 
BACKGROUND ........................................................................................................................... 20 
1.0 
Overview for immune-related adverse events (irAE) ..................................................................... 20 
1.1 
Treatment for immune-related adverse events ................................................................................ 21 
1.2 
Host Defense to Tissue Damage ..................................................................................................... 22 
1.3 
Preclinical studies on irAEs ............................................................................................................ 23 
1.3.0 A preclinical mouse model to recapitulate irAEs reported in human experience ................ 23 
1.3.1 CD24Fc Reduces irAE by Ipilimumab and Anti-PD-1 Antibody ....................................... 24 
1.3.2 The impact of CD24Fc in immunotherapy anti-tumor efficacy. .......................................... 25 
1.3.3 High plasma HMGB1 level in NSCLC Patients with irAEs ............................................... 27 
1.3.4 Rationale to allow COVID-19 infected cancer patients to receive CD24Fc ........................ 28 
1.4 
Clinical Experience of CD24Fc in Humans .................................................................................... 29 
1.4.0 Phase I Summary: ................................................................................................................ 29 
1.4.1 Phase IIa Summary: ............................................................................................................. 29 
1.5 
Rationale ......................................................................................................................................... 31 
2. 
SAFETY IN HUMANS ................................................................................................................. 31 
2.0.0 Phase 1 Safety Data ............................................................................................................. 31 
2.0.1 Phase IIa safety Data ........................................................................................................... 32 
2.0.2 Treatment Emergent SAEs (TESAEs) ................................................................................. 32 
2.1 
Pharmacokinetics in Humans .......................................................................................................... 34 
2.1.0 Phase I PK ........................................................................................................................... 34 
2.1.1 Phase IIa PK ........................................................................................................................ 35 
2.2 
Immunogenicity in Humans ............................................................................................................ 37 
2.2.0 Phase 1 ADA ....................................................................................................................... 37 
2.2.1 Phase IIa ADA ..................................................................................................................... 37 
3. 
STUDY MEDICATION ................................................................................................................ 37 
3.0 
Study drug: CD24Fc or CD24 IgG (OncoImmune, Inc.) and placebo ............................................ 37 
3.0.0 Molecular Formula and Formulation ................................................................................... 37 
3.0.1 Packaging, Ordering, and Inventory Management .............................................................. 37 
3.0.2 Administration ..................................................................................................................... 38 
3.0.3 Disposal and Destruction ..................................................................................................... 38 
4. 
TOXICITIES MONITERED ......................................................................................................... 38 
4.0 
Treatment-Related Toxicities .......................................................................................................... 38 
4.1 
Phase I Dose Limiting Toxicities .................................................................................................... 38 


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4.2 
Managing Infusion Reactions ......................................................................................................... 39 
4.3 
Ventricular Tachycardia .................................................................................................................. 39 
5. 
SUBJECT SELECTION ................................................................................................................ 39 
5.0 
Inclusion Criteria ............................................................................................................................ 39 
5.1 
Exclusion Criteria ........................................................................................................................... 40 
6. 
STUDY DESIGN AND RULES FOR INFUSION SERIES CONTINUATION ......................... 41 
6.0 
Screening Phase .............................................................................................................................. 41 
6.1 
Treatment Phase .............................................................................................................................. 41 
6.1.0 Phase I Safety Study ............................................................................................................ 42 
6.1.1 Phase II Randomized Double Blind Placebo Controlled Study ........................................... 42 
6.2 
Serum Sample Collection ................................................................................................................ 42 
6.3 
Drug Administration and Monitoring ............................................................................................. 42 
6.4 
Dose modification based on laboratory values................................................................................ 43 
6.4.0 Renal Function ..................................................................................................................... 43 
6.4.1 Hepatic Function.................................................................................................................. 43 
6.4.2 Hematologic laboratory values ............................................................................................ 43 
6.4.3 Dose adjustment .................................................................................................................. 43 
6.5 
Concomitant Therapy ...................................................................................................................... 43 
6.6 
Toxicity ........................................................................................................................................... 43 
6.7 
Criteria for Removal from Protocol Treatment ............................................................................... 44 
6.8 
Replacement of Removed Patients .................................................................................................. 44 
6.9 
Criteria for Premature Study Termination for Phase II Study ......................................................... 44 
7. 
STUDY CALENDAR ................................................................................................................... 44 
8. 
CRITERIA FOR EVALUATION AND ENDPOINTS DEFINITIONS ....................................... 45 
8.0 
Definitions....................................................................................................................................... 45 
8.0.0 Evaluable For Toxicity ........................................................................................................ 45 
8.0.1 Acute Toxicity ..................................................................................................................... 45 
8.0.2 Evaluable For Response ...................................................................................................... 45 
8.1 
Response and Evaluation Endpoints ............................................................................................... 45 
8.1.0 Measurable Disease ............................................................................................................. 45 
8.1.1 Non-Measurable Disease ..................................................................................................... 45 
8.1.2 Target Lesions ..................................................................................................................... 45 
8.1.3 Non-Target Lesions ............................................................................................................. 46 
8.1.4 Response .............................................................................................................................. 46 
9. 
SPECIAL INSTRUCTIONS ......................................................................................................... 47 
10. 
STATISTICAL CONSIDERATIONS ........................................................................................... 47 
10.0 
Endpoints ........................................................................................................................................ 47 
10.0.0 Primary Endpoints ............................................................................................................... 47 
10.0.1 Secondary Endpoints ........................................................................................................... 47 
10.1 
Randomization for Phase II Study .................................................................................................. 48 
10.2 
Statistical Analysis .......................................................................................................................... 48 
10.3 
Sample Size Justification ................................................................................................................ 49 
10.4 
Safety Monitoring and Stopping Rule ............................................................................................. 49 
10.5 
Emergency Unblinding ................................................................................................................... 50 
11. 
SAFETY AND REPORTING REQUIREMENTS ........................................................................ 51 
11.0 
Adverse Events ............................................................................................................................... 51 
11.0.0 Severity of Adverse Events ................................................................................................. 51 
11.0.1 Causality (Attribution) of Adverse Events .......................................................................... 51 
11.0.2 Serious Adverse Events ....................................................................................................... 52 
11.1 
Procedures for Reporting Adverse Events ...................................................................................... 52 


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11.1.0 Methods and Timing for Assessing and Recording Safety Variables .................................. 52 
11.1.1 Adverse Event Reporting Period ......................................................................................... 52 
11.1.2 Procedures for SAE Reporting ............................................................................................ 53 
12. 
ETHICAL CONSIDERATIONS AND ADMINISTRATIVE PROCEDURES ........................... 54 
12.0 
Ethics and Good Clinical Practice ................................................................................................... 54 
12.1 
Institutional Review Board ............................................................................................................. 54 
12.2 
Patient Information and Informed Consent ..................................................................................... 54 
12.3 
Patient Confidentiality .................................................................................................................... 54 
12.4 
Study Registration ........................................................................................................................... 55 
12.5 
Protocol Compliance and Deviations .............................................................................................. 55 
12.6 
Record Retention ............................................................................................................................ 55 
12.7 
Quality Assurance and Control ....................................................................................................... 55 
13. 
OVERSITE AND MONITORING ................................................................................................ 55 
13.0 
Data and Safety Monitoring ............................................................................................................ 55 
13.1 
Investigator Monitoring Guidelines ................................................................................................ 56 
14. 
PATHOLOGY REVIEW............................................................................................................... 56 
15. 
REFERENCES .............................................................................................................................. 57 
16. 
APPENDICES ............................................................................................................................... 60 
Appendix 1. ECOG and Karnofsky Performance Status Scores1,2 ................................................................ 60 
Appendix 2. Study Registration .................................................................................................................... 61 
Appendix 3. Data Collection Forms .............................................................................................................. 62 
Appendix 4. NCI CTCAE Version 5.0 .......................................................................................................... 63 
Appendix 5: List of Proarrhymic Drugs ........................................................................................................ 64 
17. 
SUMMARY OF CHANGES ......................................................................................................... 65 
LIST OF TABLES 
Table 1. Flow Chart for Phase I Study .......................................................................................... 10 
Table 2. Flow Chart for Phase II Study (CD24Fc Group vs Placebo Group) .............................. 12 
Table 3: Clinical observations recapitulated in Ctlah/h mouse model ........................................... 23 
Table 4: Evaluation for tumor response ........................................................................................ 46 
LIST OF FIGURES 
Figure 1: Phase I Study Schema ..................................................................................................... 9 
Figure 2: Phase II Study Schema .................................................................................................. 11 
Figure 3: Immune-related adverse events (irAE) associated with cancer immunotherapy with 
immune checkpoint inhibitors..................................................................................... 21 
Figure 4: Mechanisms of the Siglec-CD24 pathway and CD24Fc in suppressing the DAMPs 
triggered innate immune response .............................................................................. 22 
Figure 5: Immunotherapy related AE presented as growth retardation in mouse model. ............ 24 
Figure 6: CD24Fc reduces immunotherapy related adverse events (irAE) in mouse model. ....... 25 
Figure 7: CD24Fc has synergistic anti-tumor effect with ipilimumab in melanoma model. ....... 26 
Figure 8: CD24Fc enhance therapeutic effect of anti-PD-1+anti-CTLA-4. ................................. 26 


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Figure 9: Plasma HMGB1 levels in NSCLC patients who underwent and responded to 
immunotherapy. .......................................................................................................... 28 
Figure 10: Plot of Mean (±SD) Plasma CD24Fc Concentration by Treatment – PK Evaluable 
Population ................................................................................................................... 34 
Figure 11: Plot of Mean (±SD) Plasma CD24Fc Concentration by Treatment – PK Evaluable 
Population. .................................................................................................................. 36 
 
 


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0. 
OBJECTIVES 
0.0 
Phase I study: 
0.0.0 
Primary Objective:  
To determine the safety and tolerability of CD24Fc in patients with advanced solid tumors who 
developed debilitating irAEs from immune check point inhibitors (ICIs) 
0.0.1 
Secondary Objectives:  
1) time to irAE reduction by at least 1 grade 
2) time to all irAEs reduced to grade ≤1 
3) time to resume ICI treatment 
4) recovery rate (as defined by reduction of irAE by one grade) at D42 
0.1 
Randomized phase II study:  
0.1.0 
Primary Objective:  
To determine if CD24Fc shortens the recovery time of irAE and increases the recovery rate of 
irAE in cancer patients with G2 or 3 irAEs 
0.1.1 
Secondary Objectives:  
1) To estimate the time to all irAEs reduced to ≤1 
2) To record the use of steroids (drug, dose, duration) and other treatment for irAE 
3) To record the time to resume ICI treatment  
4) To estimate the preliminary overall response rate (ORR), progression free survival (PFS), 
and 1-year overall survival (OS) after treatment with or without CD24Fc 
5) To determine if CD24Fc treatment changes the levels of inflammatory markers in the 
plasma  
 
1. 
BACKGROUND  
1.0 
Overview for immune-related adverse events (irAE) 
First-generation immune checkpoint inhibitors (ICIs) targeting programed cell death protein 1 (PD-1) or its 
ligand PD-L1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) pathways have become the most 
potent and durable cancer immunotherapy for patients with many cancer types. Currently, FDA-approved 
ICIs include the anti-PD-1 monoclonal antibodies (mAbs) nivolumab and pembrolizumab; the anti-PD-L1 
mAbs atezolizumab, durvalumab and avelumab; and the anti-CTLA-4 mAb ipilimumab [1-6]. These ICIs 
have been approved as first-line, second-line or consolidation treatment for patients with non-small cell 
lung cancer (NSCLC), first-line therapy for patients with metastatic small cell lung cancer (SCLC), 
melanoma [7-10] and is promising for mesothelioma [11, 12].   
However, immune-related adverse events (irAEs) due to the ICIs, especially combinational regimens, are 
frequent and potentially severe and even fatal, leading to early treatment discontinuation in ~18% of 
NSCLC patients [6]. Clinical data showed that greater than 50% of melanoma patients with combination 
of anti-CTLA4 and anti-PD-1 therapy developed grade 3 and 4 toxicity and many patients could not 
complete the therapy due to these serious toxicities [9, 10]. Even with the less toxic single anti-PD1/L1 


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therapy, rare but life-threatening complications 
have been described [13, 14]. A systematic review 
including 5,744 NSCLC patients from 23 studies 
treated with PD-1 or PD-L1 ICIs reported a global 
incidence of AEs of 64% (14% grade ≥3) with anti-
PD-1 and 66% (21% grade ≥3) with anti-PD-L1 
mAbs [15]. The incidence of grade 3 or 4 toxicity 
with the combination was increased compared with 
either single agent (59 versus 21 and 28 percent, 
respectively, for nivolumab and ipilimumab) in 
cancer patients [16, 17]. These irAEs can affect any 
organ (Figure 3), which including but not limited to 
skin, gastrointestinal tracts, lung, liver, heart, bone 
marrow, have unique features and require new 
management strategies that are distinct from those 
of chemotherapy and molecularly targeted therapy 
[18]. Of note, those patients who develop severe 
irAEs might benefit the most from ICIs [19, 20]. 
Among all irAEs captured in the largest World 
Health Organization (WHO) database VigiBase 
(N=24,079), pneumonitis and colitis are the most 
common observed irAEs with median time of irAE 
onset (IQR) of 48 (16-114) and 51 (24-105) days, respectively [21]. Little is known at this point regarding 
the safety and efficacy of retreatment with immunotherapy after an irAE.  Much of the information available 
is based on retrospective studies [22-24].  In the largest observational WHO database VigiBase (N=6123), 
28.8% of the initial irAE leading to the discontinuation of ICI therapy were observed again after a 
rechallenge with the same ICI [21]. In a rechallenge, colitis, hepatitis, and pneumonitis had higher 
recurrence rates compared with other irAEs. Thus, irAE represents a major hurdle in the clinical application 
of ICIs. For many patients this could mean delay, and potentially discontinuation, from life-prolonging 
treatment. Success in reducing irAE could make a transformative impact in the outcome of cancer 
immunotherapy, however, the mechanism of irAE related to ICIs is still not well understood, hinders the 
development of strategies to treat and prevent these toxicities. 
1.1 
Treatment for immune-related adverse events 
Several professional societies have established the practice guidelines for the diagnosis and management 
of irAEs (NCCN, SITC, and ASCO) [25-27]. Standard of care for the treatment of irAE at this time is 
limited to high dose steroids, and infliximab for refractory disease [26].  Use of steroids and withholding 
ICI is considered standard of care for most irAEs though timing intervention varies from grade and site of 
AE.  In general, most guidelines recommend withholding ICI for irAE greater than grade 2 (colitis, 
pneumonitis, uveitis, episcleritis, transaminitis, pancreatitis). Some organ specific irAE allow for 
continuation of ICI up until grade 3 (rash, pruritis, inflammatory arthritis). Early recognition of initiation 
of ICI is heavily emphasized in these guidelines. First line treatment involves initiation of high dose 
corticosteroids at 0.5-1mg/kg with long taper, over 4-8 weeks [26]. The immunosuppressive effect of 
steroids is the main mechanism for treating irAE although the exact mechanisms are unknown [28, 29]. 
However, high dose glucocorticoids for the treatment of irAE has been associated with decreased survival 
in patients with melanoma [30]. In addition, prolonged steroid use can result in significant morbidity 
including infection, adrenal suppression, osteoporosis, psychosis, and hyperglycemia.  Thus, there is unmet 
need to explore new treatment option to replace or reduce the steroids use. The objective of this study is to 
 
Figure 3: Immune-related adverse events 
(irAE) associated with cancer immunotherapy 
with immune checkpoint inhibitors. 


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determine safety and tolerability of CD24Fc, a novel therapy with the intent to reduce the severity and 
duration of irAE. A 28-day course of 3 CD24Fc treatment will reduce the treatment duration and side effects 
of steroids. 
1.2 
Host Defense to Tissue Damage 
Danger associated molecular patterns (DAMPs) play an important role in regulating tissue damages. 
Autoimmunity occurs when disruption in immune tolerance, triggered by aberrant innate and adaptive 
immune cell activation, results in tissue degradation and organ failure [31]. Innate immune response is 
initiated by pattern recognition receptors (PRR) such as Toll or Toll-like receptors (TLRs), that respond to 
injured cells (DAMPs) or pathogens (pathogen-associated molecular patterns, PAMPs) [32, 33]. The classic 
DAMP high-mobility group box 1 (HMGB1) has been shown to trigger inflammation and exacerbate 
autoimmune diseases [34]. Tissue necrosis is associated with cancer development and cancer therapy, 
resulting in release of DAMPs. Studies have shown that attenuating host response to DAMPs may not 
negatively affect development of cancer immunity, as deletion of DAMPs gp96 in macrophages reduced 
tumor in a colitis- associated colon cancer model [35].  
Siglec-CD24 signaling pathway suppresses inflammation triggered by DAMPs but not PAMPs. 
Previous work by our groups indicated that 
sialic-acid–binding 
immunoglobulin-like 
lectins (Siglec) is a distinct class of PRR that 
down regulate innate immunity [36], and 
have 
immunoreceptor 
tyrosine-based 
inhibitory 
motifs 
(ITIMs) 
in 
their 
intracellular domains [37]. DAMPs such as 
HMGB1, HSP70 and -90 are presented to 
Siglec by binding to their high affinity 
ligand CD24, which leads to activation of 
the ITIM Siglec10 (human) / G (mouse) and 
subsequent abrogation of inflammatory 
cytokine signals through blockade of NF-κB 
activation [38], including suppression of 
TNF-α, IL-1β and IL-6 (Figure 4). CD24 
also binds to several DAMPs and represses 
host response to these DAMPs. Siglec-G 
deletion in mice (Siglec-G−/−) exacerbated 
the production of inflammatory cytokines 
and acute organ failure in response to 
DAMPs [39, 40], but not PAMPs. Loss of 
CD24 in the context of exogenously 
introduced insult resulted in an HMGB1-
driven dendritic cell (DC) inflammatory 
response. The CD24 inflammatory axis is 
specific to signaling initiated by DAMPs, as 
the PAMP LPS response did not differ 
between CD24 knockout (KO) and wild-
type (WT) cells [39]. CD24 has been shown to be essential for the development of experimental 
autoimmune encephalomyelitis in the mice [41, 42], and is associated with a number of autoimmune 
diseases [43-48]. CD24 deletion in gp96 lupus prone mice reduces the lupus like disease by expansion of 
myeloid-derived suppressor cells (MDSC) [49]. Recently, in mouse models of graft-versus-host disease 
 
  
 
Figure 4: Mechanisms of the Siglec-CD24 pathway 
and CD24Fc in suppressing the DAMPs triggered 
innate immune response 


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(GVHD), Siglec-G expression on host APCs, specifically on hematopoietic cells, was found to negatively 
regulate GVHD, and rescue experiments with novel CD24 fusion protein (CD24Fc) demonstrate that 
enhancing the interaction between Siglec-G on host APCs with CD24 on donor T cells attenuates GVHD 
[50]. These data suggest that enhancing this interaction may represent a novel strategy for mitigating 
GVHD. 
 
1.3 
Preclinical studies on irAEs  
1.3.0 
A preclinical mouse model to recapitulate irAEs reported in human experience 
Our collaborators have developed the human CTLA-4 knock in mouse model to study the irAE. Very young 
mice (10 days post birth) are given ipilimumab (clinical approved anti-CTLA 4 antibody drug) together 
with anti-mouse PD-1 antibody. The model can successfully recapitulate a large spectrum of irAEs that 
have been reported in human clinical trials and real-world experience. Table 3 listed the irAEs in the model 
and in human experience.  
Table 3: Clinical observations recapitulated in Ctlah/h mouse model 
Select AEs/Organ Category 
Clinical observation 
Ctlah/h pups model 
Gastrointestinal select AEs 
Diarrhea, ulceration, 
inflammation 
inflammation in mucosal layers 
mild ulceration 
Hepatic select AEs 
ALT/AST increase 
inflammation 
ALT increase 
Inflammation 
Pulmonary select AEs 
Pneumonitis (CT) 
severe inflammation 
Renal select AEs 
Creatinine increase, swelling 
(CT), inflammation 
No function damage, 
Inflammation 
Heart select AEs 
Myocarditis 
T cell infiltration 
Myocarditis, Organ Morphology  
T cell infiltration 
Hematologic select AEs 
Hemolytic Anemia, 
Pure Red-Cell Aplasia 
Anemia, BM failure 
Sicca syndrome 
dry mouth symptoms  
severe salivary hypofunction 
Sever inflammation 
pathologic structural damage in SG 
Skin select AEs 
Rash, Pruritus 
No rash, hair loss or scratch, 
slight inflammatory cells infiltration 
Endocrine select AEs 
Hypothyroidism, Adrenal 
insufficiency, hypophysitis 
ACTH increase, delayed adrenal 
development 
Ovary abnormal 
No report 
Less mature follicles, hypogonadism 
Our collaborators have tested whether CD24Fc could be applied to prevent or treat irAE without affecting 
T cell anti-tumor function upon immunotherapy. The emphasis was on the effect of short term CD24Fc 
administration on the long term irAE prevention. They have published our mouse model for irAE with 
confidence that giving young mice anti-CTLA 4 (Ipilimumab) and anti-PD-1 antibodies can reliably induce 
growth retardation and irAE in different organs[51].   
 


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1.3.1 
CD24Fc Reduces irAE by Ipilimumab and Anti-PD-1 Antibody 
The young 10-days old CTLA4h/h mice were treated with the following four regimen, intraperitoneal 
injection, at day 10, 13, 16, and 19 for total four injections of 100 µg/mouse/injection for each reagent.  (1). 
Human IgG-Fc. (2). CD24Fc. (3). Ipilimumab + anti-PD-1 (clone RMP 1-14, from Bio-X Cell, Inc.) + 
human IgG-Fc; (4). Ipilimumab + anti-PD-1 + CD24Fc. We monitored the growth closely with body weight 
measurement every three days. The mice in group 1 and 2 have body weight increase as expected for normal 
mice. On day 40 after birth, the body weight of the mice increased from 4.5 – 5.0 grams to 15 to 16 grams. 
In contrast, the mice in group 3 with Ipilimumab and anti-PD-1 antibody injections had growth retardation 
starting from day 22 after birth (3 days after last injection). At day 40 after birth, the average body weights 
for this group of mice were 11.0 grams, significantly lower than the group 1 and 2. Group 4 mice were 
injected with Ipilimumab and anti-PD-1, plus CD24Fc, rescued mice with accelerated growth from day 30 
to day 40 to reach the body weights of 14 grams (60-70% recovery) (Figure 5). 
 
Figure 5: Immunotherapy related AE presented as growth retardation in mouse model.  
C57BL/6 Ctla4h/h mice were treated, respectively, with control human IgG-Fc, CD24Fc, anti-PD-1 + 
Ipilimumab + hIgG-Fc or anti-PD-1 + Ipilimumab + CD24Fc at a dose of 100 μg/mouse/injection on days 
10, 13, 16 and 19. The left panel is the body weight measurement. The right panel is the percent change 
the body weights before first injection at day 10 after birth.  
 
 
The Complete Blood Counts (CBC) were measured on Day 41. As our collaborators showed in their recent 
publication [51] Ipilimumab + anti-PD-1 induced hematological abnormalities. These abnormalities were 
confirmed here with decreased RBC number, HCT and Hb. Surprisingly, the lymphocyte numbers were 
also significantly reduced. Adding CD24Fc completely reversed the hematological abnormalities.  
 
They examined three different organs for lymphocyte infiltration and tissue destruction for irAE scoring. 
The scoring system was described in previous paper. The H&E sections from liver, lung and salivary glands 
are examined and scored (Figure 6). Ipilimumab + anti-PD-1 combination induced more severe 
inflammation and lymphocyte infiltrations. CD24Fc reduced the severity of the irAE in all three organs.   
  
 


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Figure 6: CD24Fc reduces immunotherapy related adverse events (irAE) in mouse model.  
C57BL/6 Ctla4h/h mice were treated with different combination drugs, and the organs and tissues were 
taken on Day 42 for histology examination.  
 
 
1.3.2 
The impact of CD24Fc in immunotherapy anti-tumor efficacy. 
It has been reported by our group and others that B16 melanoma in mice are difficult to treat. Figure 7 
shows that 4 injections of 10 – 30 µg/mouse/injection of Ipilimumab could reject MC38 colon cancer in 
Ctla4h/m mice, and 100 – 150 µg/mouse/injection of Ipilimumab could reject CT26 colon cancer in 
Ctla4h/m mice. However, for B16 melanoma, the dose of Ipilimumab had to increase to 250 
µg/mouse/injection for 4 injections to induce tumor rejection, which would be 12.5 mg/kg, a dose that was 
much higher than clinical human dosing of 3 mg/kg or 1mg/kg (Figure 7).  
The investigators next performed the tumor rejection experiment with B16F1 tumor cell line adding the 
groups with CD24Fc. The Ipilimumab dose was the same as before using 250 µg/mouse/injection for 3 
injections to induce tumor rejection. CD24Fc dose was 100 µg/mouse/injection for 3 injections. The 
antibody and CD24Fc were given three days after tumor inoculation. The experiment groups are as follows. 
(1). Human IgG-Fc. (100 µg/mouse/injection); (2). CD24Fc. (100 µg/mouse/injection); (3). Ipilimumab 
(250 µg/mouse/injection) + human IgG-Fc (100 µg/mouse/injection); (4). Ipilimumab (250 
µg/mouse/injection) + CD24Fc (100 µg/mouse/injection). 


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As expected, high dose of Ipilimumab given earlier (day 3, 6, 9) prevented the B16 tumor formation. Adding 
CD24Fc to Ipilimumab did not affect the anti-tumor efficacy of Ipilimumab. Of note, CD24Fc alone 
reduced the tumor size considerably (Figure 7). This is unexpected as growing tumor cells in the culture 
medium containing CD24Fc in vitro had not shown anti-tumor effect by CD24Fc.  
Figure 7: CD24Fc has synergistic anti-tumor effect with ipilimumab in melanoma model.  
1x10^5 B16-F1 tumor cells were injected (s.c.) into Ctla4h/h mice (n=6), and treated (i.p.) with 100 μg 
control hIgGFc or CD24Fc, 250 μg Ipilimumab plus 100 μg human IgGFc or CD24Fc, on days 3, 6, and 
9. Data represent mean ± S.E.M. of 6 mice per group. 
 
To determine the effect of CD24Fc on combination therapy with anti-PD-1 and anti-CTLA-4 antibodies, 
we treated B16-F1 tumor-bearing Ctla4h/h mice with control IgG1 Fc, IgG1 Fc+anti-mouse PD-
1+Ipilimumab, or CD24Fc+anti-mouse PD-1+Ipilimumab and followed tumor growth kinetics and mouse 
survival.  As shown in Figure 8, CD24Fc promoted therapeutic effect of anti-PD-1+anti-CTLA-4 
immunotherapy, as it reduced tumor growth and promoted mouse survival. 
Figure 8: CD24Fc enhance therapeutic effect of anti-PD-1+anti-CTLA-4.   
1x105 B16-F1 tumor cells were injected (s.c.) on Ctla4h/h mice (n=12-13), and treated (i.p.) with 200 μg 
Ipilimumab plus 200 μg αPD-1 (RMP1-14) together with 200 μg of hIgFc or CD24Fc on day 8, 11 and 
14.. Tumor growth kinetics or 4 weeks and mouse survival curve over 60 days (B) are shown.  Data 
shown were pooled from two independent experiments.  Survival endpoints are defined as tumor volume 
reaching 2000 mm3, death or moribund per institutional guidelines. 
 
Days after tumor inoculation 


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These results support clinical testing of CD24Fc in combination with Ipilimumab + anti-PD-1, not only 
for reduction of irAE, but also the synergistic anti-tumor effects.  
1.3.3 
High plasma HMGB1 level in NSCLC Patients with irAEs 
HBGB1 is a representative DAMP.  HMGB1 is a multifunctional redox sensitive protein with various roles 
in different cellular compartments. In the nucleus is one of the major chromatin-associated non-histone 
proteins and acts as a DNA chaperone involved in replication, transcription, chromatin remodeling, V(D)J 
recombination, DNA repair and genome stability. HMGB1 promotes host inflammatory response to sterile 
and infectious signals and is involved in the coordination and integration of innate and adaptive immune 
responses. HMGB1 contribute to the pathogenesis of various chronic inflammatory and autoimmune 
diseases, and cancer. High serum levels are found in several inflammatory events including sepsis, 
rheumatoid arthritis, atherosclerosis, chronic kidney disease, systemic lupus erythematosus (SLE)[52].  
Using banked serum samples from NSCLC patients who received ICI treatment, we established the ELISA 
to measure the HMGB1 protein levels in the plasma samples (Figure 9). Our preliminary data showed that 
patients with irAEs had relatively higher plasma HMGB1 level compared to those patients who did not 
have irAEs. Further study is warranted to verify this finding and correlate the level of plasma HBGB1 with 
the severity of irAE.   
0
20
40
60
80
0
50
100
Days after first treatment
Percent survival
hIgFc
Ipi+αPD1
Ipi+αPD1+CD24Fc
**
*
P=0.07


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Figure 9: Plasma HMGB1 levels in NSCLC patients who underwent and responded to 
immunotherapy.  
There are 7 patients with irAEs and 3 patients without irAEs during treatment period. 
 
1.3.4 
Rationale to allow COVID-19 infected cancer patients to receive CD24Fc 
The COVID-19 pandemic has presented unprecedent challenges and learning opportunities to the global 
community and all health care providers to patients, especially elderly cancer patients on active treatment 
with compromised immune systems. A small retrospective analysis showed the cancer patients with 
COVID-19 infection have much higher death rate than those infected but without cancer diagnoses.  It also 
suggested that the cancer survivors are more vulnerable than the general population [53]. With the ongoing 
COVID-19 pandemic and accumulation of asymptomatic carriers in the general population, we expect to 
see more cancer patients tested positive for SARS-CoV-2 infection. At this time, no specific 
recommendations can be made by professional societies such as American Society of Clinical Oncology 
(ASCO) and National Comprehensive Cancer Network (NCCN) [54, 55] for delaying life-saving cancer 
directed therapy such as immune checkpoint inhibitor therapy in patients who are asymptomatic or 
recovered from SARS-CoV2 infection.  
Preclinical and clinical studies have demonstrated that CD24Fc effectively address the major challenges 
associated with COVID-19.  First, a Phase I clinical trial on heathy volunteers not only demonstrated safety 
of CD24Fc, but also demonstrated its biological activity in suppressing expression of multiple inflammatory 
cytokines.  Second, in Phase II clinical trial in leukemia patients undergoing hematopoietic stem cell 
transplantation (HCT), three doses of CD24Fc effectively eliminated severe (Grade 3-4) acute graft vs host 
diseases (GVHD), which is caused by transplanted T cells attacking recipient target tissues.  Third, in 
preclinical models of HIV/SIV infections, CD24Fc ameliorated production of multiple inflammatory 
cytokines, reversed the loss of T lymphocytes as well as functional T cell exhaustion and reduced the 
leukocyte infiltration of multiple organs.  It is particularly noteworthy that CD24Fc reduced the rate of 
pneumonia in SIV-infected Chinese rhesus monkey from 83% to 33%.  Therefore, CD24Fc maybe a prime 
candidate for non-antiviral biological modifier for COVID-19 therapy.  On April 8, 2020, OncoImmune 
received FDA approval for conducting a Phase III clinical trial for the treatment of severe COVID-19 
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patients (NCT04317040). The first interim analysis of 71 subjects on safety and futility demonstrated that 
the overall 14-day mortality rate is remarkably low in 4% (3/71) in this Phase III randomized double blind 
placebo controlled clinical trial for severe and critical COVID-19 patients. The drug is safe without any 
adverse events directly related to it. There is no infusion reaction or allergic reaction to the drug.  With the 
increasing testing ability for SARS-CoV2 infection and immunity at UC Davis Health, we anticipate 
identifying cancer patients who have recovered from COVID-19 or are asymptomatic carriers for SARS-
CoV2 virus. Since CD24Fc are being evaluated as a non-antiviral-based immune modulator to treat patients 
with COVID-19, we will allow cancer patients who have recovered from COVID-19 or who are 
asymptomatic carriers for SARS-CoV2 virus in this protocol after they are cleared by infectious disease 
physicians for transmission risk.   
 
1.4 
Clinical Experience of CD24Fc in Humans 
1.4.0 
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 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), 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.  
1.4.1 
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 100 days post-HCT on Apr. 5, 2018. Data was locked and unblinded on May 
17, 2018. 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.  
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 


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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-IV (> 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 2a study, compared to 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),  
3. Better 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. Higher cumulative incidence of Grade II to IV acute GVHD by Day 100 (38.9% in CD24Fc 
treatment group, 16.7% in placebo) (hazard ratio = 2.6),  
9. Slightly higher Grade II to IV acute GFS rate at Day 180 (61.1% in CD24Fc treatment group, 
50.0% in placebo) (hazard ratio = 0.8), 
10. Slightly higher 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), 
11. 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). 
 
An open label single arm Phase II expansion cohort with 20 subjects was initiated in June 2019. The study 
completed the enrollment of 20 patients in Dec. 2019. The dosing schedule is 480-240-240 mg at Day -1, 
Day 14 and Day 28 post-hematopoietic cell transplantation. All patients had the first dosing of 480 mg 
CD24Fc. There was no infusion reaction. There was no adverse event that can be attributed to CD24Fc. All 
subjects have completed the 180-day primary endpoint follow up time on June 16, 2020. There are no Grade 


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III-IV acute GVHD in this cohort. The preliminary outcome data is in consistent with the Phase IIa results, 
confirming the efficacy of CD24Fc in reduction of acute GVHD, reduction of leukemia relapse.    
In summary, the preclinical data and the human clinical trial experience on CD24Fc have provided solid 
scientific foundation for the proposed Phase Ib/II clinical trial. Based on the reported phase I and phase II 
data, the CD24Fc regimen to be tested in this study is 480 mg on day 1, 240 mg on day 14 and day 28 i.v. 
(a total course of 28 days).  
 
1.5 
Rationale 
We hypothesize that tissue damage-associated molecular pattern (DAMP) signaling contributes to the 
pathogenesis of irAEs. CD24Fc binds to DAMPs such as HMGB1, HSP70, and HSP90, preventing them 
from associating with TLRs to activate downstream NF-κB. In addition, CD24Fc binds to and activates 
murine Siglec-10 (Siglec-G in humans), whose signaling also results in suppression of NF-κB. Both actions 
inhibit NF-κB-mediated aspects of the DAMP response, such as secretion of inflammatory cytokines. Thus, 
CD24Fc given to patients developed irAEs to ICI could selectively reduce autoimmunity triggered by tissue 
damage and ameliorate irAEs, without interference to the mechanistically distinct, anti-tumor action of 
ICIs. Of note, there are paradoxical effect of steroids on the PRR signaling. Low concentrations of 
endogenous glucocorticoids sensitize the innate immune system by upregulating PRRs, cytokine receptors 
and complement factors, thus allowing for rapid responses to danger signals. High concentrations of 
glucocorticoids, by contrast, suppress signals that are mediated by PRRs and cytokine receptors, thereby 
preventing excessive and/or prolonged immune responses [29].   
This pilot, phase I/II trial aims to obtain preliminary safety and efficacy data of CD24Fc for treating grade 
2 or 3 irAEs in patients with advanced/metastatic solid tumors who required treatment interruption on ICIs. 
Based on the reported phase I and phase II data, the CD24Fc regimen is 480 mg on day 1, 240 mg on day 
14 and day 28 i.v. (a total course of 28 days).  
The knowledge gained from this pilot project will support further investigation of the mechanism of irAEs 
and provide the basis for a phase III clinical trial to formally evaluate the efficacy and safety of CD24Fc in 
treating irAEs in patients with advanced/metastatic solid tumors who required treatment interruption on 
ICIs and allowing the patients to resume the ICI treatment safely. 
 
2. 
SAFETY IN HUMANS 
2.0.0 
Phase 1 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). 


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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 (16.7%) 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. 
2.0.1 
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 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. 
2.0.2 
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 


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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). No patients experienced a study drug-
related treatment-emergent SAE. 
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 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%). TEAEs of blood cholesterol increased were only reported by patients in 
the 480/240/240 mg CD24Fc multiple dose cohort (11%). 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 


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80.9% donor cells for patients who received CD24Fc and 73.8% donor cells for patients who received 
placebo. 
The mean CD33 cell chimerism on Day 28/Day 30 was 100.0% donor cells for patients who received 
CD24Fc and 100.0% donor cells for patients who received placebo. The mean CD33 cell chimerism on 
Day 100 was 99.4% donor cells for patients who received CD24Fc and 96.6% donor cells for patients who 
received placebo.  
 
2.1 
Pharmacokinetics in Humans 
2.1.0 
Phase I PK 
The PK of CD24Fc in healthy human subjects was determined from the single dose Phase 1 study. The 
mean plasma concentration of CD24Fc increased proportionally to the dose of CD24Fc administered 
(Figure 10). For all dose groups except 120 mg, the maximum mean plasma concentration of CD24Fc was 
reached at 1 hour post-dose. The maximum mean plasma concentration of CD24Fc for the 120 mg group 
was reached at 2 hours post-dose. By Day 42 (984 hours), the mean plasma concentration of CD24Fc for 
all groups had decreased to between 2% and 4% of the maximum mean plasma concentration. The plasma 
CD24Fc reached Tmax at 1.34 hours. The t½ of plasma CD24Fc range was 280.83 to 327.10 hours. 
Figure 10: Plot of Mean (±SD) Plasma CD24Fc Concentration by Treatment – PK Evaluable 
Population 
 
PK = pharmacokinetic; SD = standard deviation. 
Source: Investigators Brochure.  
. 
 


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2.1.1 
Phase IIa PK 
The PK of CD24Fc in human subjects undergoing HCT has been determined from the Phase IIa study from 
the two single dose cohorts and one multi-dose cohort. With the 240 mg single dose, the mean plasma 
concentration of CD24Fc is similar to the 120 mg single dose in Phase I human volunteers. The 480 mg 
dose shows a proportional increase of CD24Fc at all time points (Figure 11, upper panel). The 480/240/240 
mg multi-dose maintains the CD24Fc plasma concentration over 10,000 ng/ml over the period of Day-1 to 
Day 42 post-HCT (Figure 11, lower panel).  
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 11: Plot of Mean (±SD) Plasma CD24Fc Concentration by Treatment – PK Evaluable 
Population.  
(Upper). Single dose cohorts, 240mg (n=6); 480mg (n=6). (lower). multi-dose cohort. 480-240-240mg 
(n=6).  
 
 
 
 


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2.2 
Immunogenicity in Humans 
2.2.0 
Phase 1 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. 
2.2.1 
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. All samples 
are negative for ADA in the Phase IIa study. 
 
3. 
STUDY MEDICATION 
3.0 
Study drug: CD24Fc or CD24 IgG (OncoImmune, Inc.) and placebo 
CD24Fc (CD24 IgG) is a fusion protein consisting of the extracellular domain of mature human CD24 
linked to the human immunoglobulin G1 (IgG1) Fc domain. 
The placebo is 0.9% Sodium Chloride Solution for IV infusion.  
3.0.0 
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.   
Name 
CD24Fc for IV infusion. 
Vial content 
120mg/12mL 
Formulation 
Liquid formulation for IV infusion. 
Route 
IV Infusion 
Storage 
-20℃, avoid light.  
Manufacturer 
Catalent, Inc. 
Provider 
OncoImmune, Inc 
3.0.1 
Packaging, Ordering, and Inventory Management 
CD24Fc is supplied in clear borosilicate glass vials with chlorobutyl rubber stoppers and aluminum flip 
off seals.  Drug product vials are stored at OncoImmune’s clinical distribution site, ALMAC Clinical 


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Services, at 25 Fretz Road, Souderton, PA. Study site (UCDCC) IDX pharmacy will order the drug 
for onsite storage after the study activation.     
Availability, Storage and Stability 
CD24Fc is supplied as a sterile, clear, colorless, preservative-free aqueous solution for parenteral 
administration. CD24Fc will be stored at -20° C until removed for use.  Remove the CD24Fc vials from 
the freezer and thaw immediately prior to dose preparation. The CD24Fc infusion should begin within 3 
hours after reconstitution.  
3.0.2 
Administration 
CD24Fc at doses of 480 mg or 240 mg will 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 as 
specified in Section 6.2 
3.0.3 
Disposal and Destruction 
Responsibility for drug accountability is on the investigator and the assigned pharmacist or designee. Drug 
supply will be disposed of according to institutional standard operating procedures. Accurate records of all 
investigational product received at and dispensed from the study site should be recorded on the Drug Log.  
 
4. 
TOXICITIES MONITERED 
4.0 
Treatment-Related Toxicities 
The toxicity scale, definitions, and specific criteria for each toxicity level will be those as outlined in the 
guidelines defined by the NCI CTCAE version 5.0. (Appendix 4).  If the patient develops any grade 3 or 
greater hematologic or non-hematologic toxicity that is possibly, probably, or definitely related to the 
CD24Fc, no further drug administration will be given to that patient and the patient will be removed from 
protocol therapy (see Section 4.1). Treatment delay within 3 scheduled days is allowed.  Dose 
modification based on the renal and hepatic function values and hematologic laboratory values (see 
Section 6.4).  
4.1 
Phase I Dose Limiting Toxicities 
1) Grade 4 non-hematologic toxicity (not laboratory). 
2) Grade 4 hematologic toxicity including Grade 4 neutrophil count decrease, Grade 4 platelet 
count decrease or Grade 4 anemia regardless of duration.  
3)  Grade 3 Neutrophil count decrease lasting > 1 week, or febrile neutropenia. 
4) Grade 3 Platelet count decrease lasting > 1 week, or Grade 3+ thrombocytopenia with bleeding. 
5) Grade 3 non-hematologic toxicity (not laboratory) will be considered a DLT with the 
following exceptions: grade 3 fatigue, Grade 3 nausea, vomiting, or diarrhea lasting < 72 
hours, (Grade 3 nausea, vomiting, or diarrhea lasting >72 hours despite optimal supportive 
care is a DLT). 
6) Any Grade 3 non-hematologic laboratory value if: 
• 
Associated with clinical symptoms or signs, or 
• 
Medical intervention is required to treat the patient, or 
• 
The abnormality leads to hospitalization, or 
• 
The abnormality persists for >1 week. 
7) AST and/or ALT elevation >20 x ULN with concurrent total bilirubin elevation to >5 x ULN 


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without initial evidence of cholestasis. 
8) Grade 5 toxicity (i.e., death). 
 
The treatment related toxicities should be evaluated as CD24Fc treatment emergent AE that is not 
associated to irAEs defined in enrollment. The DLT monitoring period is the 14 days after the first dose 
of CD24Fc at 480 mg. If DLT occurred in 2 patients during the first dose of CD24Fc dosing in the 14-day 
period, CD24Fc will be reduced to 240 mg as first dose, or 120 mg until no more than 1/6 patients 
developed DLT. The study will be terminated if >2 patients have DLT at this reduced dosing. In Phase I, 
patients will be dosed at least two hours apart and no more than two patients will be enrolled in the same 
day.  
4.2 
Managing Infusion Reactions 
Although infusion reactions were not observed in the Phase 1 and Phase IIa clinical trials, there is a 
theoretical potential for CD24Fc to result in infusion reaction. CD24Fc, which includes a human portion 
IgG1 may induce FcγR cross-linking, which has been associated with infusion reactions for some 
therapeutics.  
Supportive care and vitals monitoring (including but not limited to supplemental oxygen, 
diphenhydramine, acetaminophen, ibuprofen, steroids and fluids) in the event of infusion reaction will be 
allowed and be dictated per institutional standards and policies.  Depending on the severity of the infusion 
reactions, patient might be resumed the study drug at the discrepancy of the treatment physician. Patient 
will be permanently discontinued from the study if infusion reactions recur despite of pre-medications.  
4.3 
Ventricular Tachycardia 
In the phase 1 first in human clinical trial a SAE of ventricular tachycardia was observed in one healthy 
individual that received 60mg of CD24Fc.  Though this was considered mild in severity by the 
investigator and did not result in discontinuation of the subject from study, patient undergoing CD24Fc 
will be closely monitored for cardiac SAE.   
Vital signs will be checked at immediately before and after each infusion of CD24Fc. EKG will be done 
before and after receiving CD24Fc. If at any time an episode of arrythmia develops during treatment, 
study drug should be held until resolution of SAE.  If the reaction is considered severe (e.g. symptomatic, 
hypotension requiring urgent intervention) study drug should be discontinued. 
 
5. 
SUBJECT SELECTION 
Subjects with advanced/metastatic or recurrent solid tumors (stage IV) of any primary site, with emphasis 
on non-small cell lung cancer, melanoma, bladder, and breast cancer that is incurable with available 
therapies will be recruited from the UC Davis Comprehensive Cancer Center (Appendix 5). 
5.0 
Inclusion Criteria 
Patients must meet all of the following criteria to be eligible for study entry. 
1) Ability to understand and willingness to sign an informed consent form. 
2) At least 18 years of age. 
3) Histologically confirmed advanced solid tumors.  


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4) Patients must have grade 2 or 3 irAEs from at least one ICI-containing regimen. Both newly 
emerging and persistent irAEs are allowed. Systemic steroid therapy or any other form of 
immunosuppressive therapy for irAEs is allowed. The specific irAEs are:  
a. Grade 2-3 Diarrhea/Colitis: Patients with >4 stools per day or moderate-severe increase 
in ostomy output compared to baseline but not life-threatening diarrhea;  
b. Grade 2-3 Pneumonitis: Mild to moderate (grade 2) or severe (grade 3) symptoms 
(including hypoxia, shortness of breath, requiring oxygen) but not life-threatening 
respiratory compromise requiring urgent intervention (e.g., tracheostomy or intubation) 
c. Grade 2-3 Renal irAE: Creatine increased between 1.6-6.0 x ULN or ≤3.0 x baseline if 
baseline was abnormal, eGFR or creatinine clearance ≥15 ml/min/1.73m2 but not life-
threatening consequences or requiring dialysis.  
d. 
Grade 2-3 Hepatic irAE: AST/ALT/ALP levels 3-20 x ULN, and T bilirubin increased <5 
x ULN  
e. Grade 2-3 Skin Rash: moderate (10-30% body surface area, BSA) to severe (>30% BSA) 
but not life-threatening skin lesions or Stevens-Johnson syndrome. 
5) ECOG performance status <2. (Appendix 1). 
6) Life expectancy of ≥ 3 months at the time of enrollment. 
7) All patients must have a pretreatment absolute neutrophil count (ANC) ≥ 1,000 /µL, hemoglobin 
≥ 8 gm/dL and a pretreatment platelet count of ≥ 75,000 /µL obtained within 14 days prior to 1st 
dose of treatment. 
8) Female subjects who are of non-reproductive potential (i.e., post-menopausal by history – no 
menses for ≥1 year; OR history of hysterectomy; OR history of bilateral tubal ligation; OR 
history of bilateral oophorectomy). Or, female subjects of childbearing potential must have a 
negative serum or urine pregnancy test within 72 hours prior to the first study drug 
administration. 
9) Male and female subjects who agree to use highly effective method of birth control (e.g., 
implants, injectables, birth control pills with two hormones, intrauterine devices [IUDs], complete 
abstinence or sterilized partner, and female sterilization) and a barrier method (e.g., condoms, 
vaginal ring, sponge, etc.) during the period of therapy and for 90 days after the last dose of study 
drug. 
5.1 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry.  
1) Prior CD24Fc Therapy.  
2) Any known active hepatitis B (HBV), hepatitis C (HCV), or human immunodeficiency virus 
(HIV) or acquired immunodeficiency syndrome (AIDS)-related illness, including patients who 
have an active infection requiring systemic therapy. History of COVID-19 or known 
asymptomatic carrier of SARS-CoV-2 virus is allowed. 
3) Pregnant or lactating women. 
4) Any medical condition including additional laboratory abnormalities, or psychiatric illness that 
would, in the opinion of the investigator, prevent the subject from participating and adhering to 
study related procedures.  
5) Any known severe bacterial, fungal, or viral infection that in the opinion of the investigator 
would interfere with patient safety or compliance on trial within 2 weeks prior to enrollment.   


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6) Patients with concomitant proarrhythmic medications. (Appendix 6). 
7) Patients with heart failure in NY Heart Association class IV.  
8) Any grade 4 irAE symptoms and CTCAE v5.0 grade 4 toxicity. (Appendix 4) 
9) Renal, liver and cardiac toxicities as defined below: 
Hepatic 
AST, ALT, GGT, or ALP 
>20.0 x ULN regardless of baseline 
 
Blood Bilirubin 
>5.0 x ULN regardless of baseline 
Renal 
Creatinine 
> 6.0 x ULN or creatinine clearance <15 
ml/min/1.73m2 
 
Urine: Anuria 
<140 ml in 24 hours 
Electrolytes 
Hyponatremia, sodium 
<120 mmol/L 
 
Hypokalemia, potassium 
<2.5 mmol/L 
Cardiac 
CPK 
>10.0 ULN 
 
ECG  
Prolonged QT interval ≥480mS, 
corrected by Fridericia’s formula. 
Torsade de pointes; polymorphic 
ventricular tachycardia; signs/symptoms 
of serious arrythmia. 
 
6. 
STUDY DESIGN AND RULES FOR INFUSION SERIES CONTINUATION 
This is a study at the University of California, Davis Comprehensive Cancer Center (UCDCCC). 
Registration and assignment to the repeated infusions will be done centrally at UCD. (Appendix 2 and 
Appendix 3). 
Rules for dosage/infusion continuation and termination are given below. 
6.0 
Screening Phase 
All patients being considered for this trial will be pre-screened prior to protocol therapy for the following: 
Patients who meet the above criteria (in addition to those outlined in section 3.0) will be deemed eligible 
for protocol therapy. 
6.1 
Treatment Phase 
This is a phase I/II study to determine the safety, tolerability, and efficacy of CD24Fc in patients who 
needed treatment interruption from irAE with ICI. This study will be divided into two studies. Phase I 
study is to evaluate safety and tolerability of CD24Fc for treatment of irAE. Phase II consists of a 
randomized control study evaluating efficacy of CD24Fc in reducing duration of irAE and rate of 
recovery from irAE.  


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6.1.0 
Phase I Safety Study 
In the Phase I study, patients with unresectable or metastatic solid tumors who developed grade 2-3 irAEs 
and treatment interruption to immunotherapy will be selected for treatment.  Once enrolled, CD24Fc will 
be administered every 2 weeks along with standard of care (i.e., steroids per treating physician and best 
supportive care) for 3 treatments.  All 6 patients shall complete 3 treatments. For treatment dosing and 
schedule see Table 1 and Figure 1.  Patients may receive steroids at the discretion of the treating 
physician prior to and during treatment with CD24Fc. Two weeks after completing dose 3 of CD24Fc 
(Day 42) patients will be re-evaluated for resolution of irAE. At the discretion of the treating physician 
patient can be evaluated for retreatment with ICI at this time. Patient will undergo end of study evaluation 
on day 60.  Post study irAE and survival follow up will consists of chart check every 3 months for up to 1 
year.   
6.1.1 
Phase II Randomized Double Blind Placebo Controlled Study 
Phase II study will consist of a randomized double blind placebo controlled study involving patients who 
have treatment interruption due to grade 2 or 3 irAEs.  Patients may receive steroids at the discretion of 
the treating physician prior to and during treatment with CD24Fc. As the steroids is the most commonly 
used SOC therapy for irAEs and it affects the severity and duration of irAE, we will separate the subjects 
into two groups based on the status of steroids use at registration.   Each group of patients will be 
randomized (1:1) to receive CD24Fc vs placebo in addition to SOC treatment for irAE. Patients who are 
randomized to treatment with CD24Fc will receive treatment every 2 weeks for total of three treatments. 
Placebo group will receive 100 mL of normal saline every 2 weeks for total of three treatments.  Refer to 
Table 2 and Figure 2 for treatment schedule. All patients shall complete 3 treatments.  
Two weeks after completing the third treatment dose, patients will be re-evaluated for retreatment with 
ICI at the discretion of the treating physician and post treatment re-evaluation. Thereafter, patients will 
continue to end of treatment safety follow up on day 60.  After the end of treatment, we will follow 
patients with irAE and survival by chart check every 3 months for up to 1 year.  
 
6.2 
Serum Sample Collection 
During active treatment with CD24Fc CBC and CMP will be collected based on schedule see Tables 1 
and 2.  
 
6.3 
Drug Administration and Monitoring 
CD24Fc or placebo will be administrated by intravenous infusion over 60 minutes.  
Vital sign monitoring before the dosing, during and 1-hour post infusion by registered nurse per 
institutional standard.  
If the patient misses a dose, an infusion would be rescheduled within 3 days. Otherwise, the dose will be 
omitted.  
 


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6.4 
Dose modification based on laboratory values 
6.4.0 
Renal Function 
If estimated GFR is less than 15 mL/min on the scheduled day of dosing, then the dose be held.  If GFR 
recovers to greater than 15 mL/min within the protocol defined treatment period window (up to day +3), 
then CD24Fc may be resumed.  
6.4.1 
Hepatic Function 
CD24Fc will be administered on the scheduled day if AST or ALT is <20x ULN and total bilirubin is < 
5x ULN.  
6.4.2 
Hematologic laboratory values 
CD24Fc will be administered on the scheduled day if absolute neutrophil count (ANC) ≥ 1,000 /µL, 
hemoglobin ≥ 8 gm/dL and a pretreatment platelet count of ≥ 75,000 /µL. 
6.4.3 
Dose adjustment 
There should be a one level dose reduction (i.e., CD24Fc 240 mg on day 1, 120 mg on day 14, and 120 
mg on day 28 i.v.) if any ≥G3 hematologic due to CD24Fc that requires < 2 week to recover to grade 1 or 
less.  There will be no dose reduction according to irAEs.  
6.5 
Concomitant Therapy 
Concomitant ICI and chemotherapies are not allowed during the study period. 
Patients may receive ongoing supportive and palliative care (e.g., nutritional support, pain control) as 
clinically indicated throughout the study. Bisphosphonate therapy is allowed as part of supportive care 
before or after the study. Steroids are permitted in the study as outline in section 6.2. Patients enrolled to 
the study will receive steroid treatment as well as other recommended treatment for a given irAE if 
recommended per the treating physician. Patients who develop urgent complications in previously 
documented sites of disease may receive palliative radiation therapy. Continuation on the protocol therapy 
will be determined by discussions with the sponsor and the investigator, if medically appropriate.  
 
6.6 
Toxicity 
A brief written summary documenting the toxicity or adverse reactions after the 6th patient (phase I 
study) has received his/her 3th dose will be prepared with input from the UCD clinical PI. The brief 
report will summarize and define if the study should continue or be terminated. At the end of Phase II 
study, a summary will likewise be completed to address the same issues. A recommendation whether to 
continue onto a Phase II clinical trial will also be included. 
Toxicity assessments will be done by the treating physician or their licensed representative (such as nurse 
practitioner) on the days of therapy. 
Patients with progressive disease will be counseled as to the option of exiting the study. They will be 
advised on their disease progress and future options, and their response, if any, to the therapy.  
 


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6.7 
Criteria for Removal from Protocol Treatment 
• 
Unacceptable toxicity (as determined by the treating physician and/or the patient), or toxicity 
requiring discontinuation of treatment (See sections 4.0 and 4.1). 
• 
Elevation in AST or ALT >20x ULN on bloodwork prior to CD24Fc treatment.  
• 
Elevation of total bilirubin >5x ULN on bloodwork prior to CD24Fc treatment.  
• 
If the recovery of any ≥G3 hematologic or non-hematological toxicity due to CD24Fc to grade 1 or 
less requires > 2 weeks. 
• 
Patients may choose to withdraw from the study at any time for any reason. 
• 
Patients may be withdrawn from the protocol at the investigator’s discretion if the investigator feels 
that continuation is not in the patient’s best medical interest or if the patient is non-compliant with 
treatment. 
• 
Completion of treatment CD24Fc. 
• 
All reasons for discontinuation of treatment must be documented in the case report forms. 
• 
Therapy after Protocol Treatment is stopped: If patients fail to respond to the protocol treatment 
and/or are removed from the therapy because of toxic effects or “disease progression”, further 
treatment, if any, is at the discretion of the investigator. 
Follow-up off Protocol Treatment: After removal from protocol treatment, all patients will be followed 
for late toxicities. Patients will be seen 4 weeks, 4 months and 7 months after coming off therapy. If 
ongoing toxicities have not resolved to ≤ grade 1 within the first 4 weeks, patients are to be seen every 
month until toxicity resolves to ≤ grade 1. No new toxicities after the 4-week follow-up will be re-ported 
unless considered related to protocol treatment by the investigator.  
 
6.8 
Replacement of Removed Patients 
Additional patients are allowed to replace patients who choose to withdraw from the study before or 
within 28-day course of drug administration or patients who were withdrawn from the study at the 
investigator’s discretion. Patients who are removed due to CD24Fc related DLT will not be replaced. 
 
6.9 
Criteria for Premature Study Termination for Phase II Study 
Patients will be enrolled on the study as outlined above. If, at any time during the study, there is sufficient 
evidence suggesting an excessive Grade 3 or Grade 4 toxicity rate related to treatment, the study will be 
terminated. An excessive Grade 3 toxicity rate will be taken to be 20% (or 4 patients) and an excessive 
Grade 4 toxicity rate will be taken to be 10% (or 2 patients) of the patients enrolled to that date. Evidence 
that the toxicity rate is excessive will be considered sufficient if the lower limit of the 90% one-sided 
confidence interval for the estimate of the toxicity rate exceeds the appropriate limit (20% for Grade 3, 
10% for Grade 4). 
 
7. 
STUDY CALENDAR  
Baseline evaluations are to be conducted within 14 days prior to 1st infusion unless otherwise noted. 
Please see Tables 1 and 2.   


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8. 
CRITERIA FOR EVALUATION AND ENDPOINTS DEFINITIONS 
8.0 
Definitions 
8.0.0 
Evaluable For Toxicity 
All patients will be evaluable for toxicity from the time of their first treatment with CD24Fc up to 30 days 
after completion of last dose of treatment. 
8.0.1 
Acute Toxicity 
All patients will be evaluable for toxicity from the drug. All patients will be monitored for 1-hour post 
infusion with are registered nurse or nurse practitioner within immediate proximity. 
8.0.2 
Evaluable For Response 
8.0.2.0 
Tumor Evaluation 
All patients will be considered evaluable for response according to RECIST 1.1.  For this study, PSA-
only disease is included in Non-Measurable disease.  
 
8.1 
Response and Evaluation Endpoints 
Response and progression will be evaluated in this study using the new international criteria proposed by 
RECIST committee. Changes in only the largest diameter (unidimensional measurement) of the tumor 
lesions are used in the RECIST 1.1 criteria. 
8.1.0 
Measurable Disease 
Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest 
diameter to be recorded) as ≥ 20 mm with conventional techniques (PE, CT, XR, MRI) or as ≥ 10 mm 
with spiral CT scan. All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
8.1.1 
Non-Measurable Disease 
All other lesions (or sites of disease), including small lesions (longest diameter < 20 mm with 
conventional techniques or < 10 mm with spiral CT scan) are considered non-measurable disease. Bone 
lesion, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pneumonitis, 
inflammatory beast disease, abdominal masses (not followed by CT or MRI) and cystic lesions are all 
non-measurable. Prostate cancer patients may also have PSA-only disease. 
8.1.2 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total representative of all 
involved organs should be identified as target lesions and be recorded and measured at baseline. Target 
lesions should be selected on the basis of their size (lesions with the longest diameter) and their suitability 
for accurate repetitive measurements (either by imaging techniques or clinically). A sum of the longest 
diameter (LD) for all target lesions will be calculated and reported as the baseline sum LD. The baseline 
sum LD will be used as reference to further characterize the objective tumor response of the measurable 
dimension of the disease. If there are > 10 measurable lesions, those not selected as target lesions will be 
considered together with non-measurable disease as non-target lesions (see section 10.2.4). 


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8.1.3 
Non-Target Lesions 
All non-measurable lesions (or sites of disease) plus any measurable lesions over and above the 10 listed 
as target lesions. Measurements are not required but these lesions should be noted at baseline and should 
be followed as “present” or “absent”. The exception for this requirement is the serial evaluation of 
prostate specific antigen (PSA) levels in the serum. Although PSA values constitute “non-target” disease, 
in this study which includes a population of patients with hormone refractory prostate cancer, PSA levels 
are expected to be the principal measure of disease activity and response to therapy, if any. 
8.1.4 
Response 
All patients will have their BEST RESPONSE on study classified as outlined below: 
Complete Response (CR): disappearance of all clinical and radiological evidence of tumor (both 
target and non-target).  
Partial Response (PR): at least a 30% decrease in the sum of LD of target lesions taking as 
reference the baseline sum LD. Patients may not demonstrate clinical or radiographic evidence of 
progression of measurable or non-measurable disease during this time period. 
Stable Disease (SD): steady state disease. Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD. 
Progressive Disease (PD): at least a 20% increase in the sum of LD of measured lesions taking as 
reference the smallest LD recorded since the treatment started or the appearance of one or more 
new lesions.  
In exceptional circumstances unequivocal progression of non-target lesions may be accepted as evidence 
of disease progression. 
Table 4: Evaluation for tumor response  
 
NOTE: Patients with global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be reported as “symptomatic deterioration”. Every effort should 
be made to document the objective progression even after discontinuation of treatment. 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Response For This Category Also 
Requires 
CR 
CR 
No 
CR 
≥ 4 weeks confirmation 
CR 
Non-CR/Non-PD No 
PR 
≥ 4 weeks confirmation 
PR 
Non-PD 
No 
PR 
≥ 4 weeks confirmation 
SD 
Non-PD 
No 
SD 
Documented at least ≥ 4 weeks from baseline; 
> 8 weeks for PSA-only disease 
PD 
Any 
Yes or No 
PD 
No prior SD, PR, or CR 
Any 
PD 
Yes or No 
PD 
No prior SD, PR, or CR 
Any 
Any 
Yes 
PD 
No prior SD, PR, or CR 


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8.1.4.0 
Response Duration 
Response duration will be measured from the time measurement criteria for CR/PR (whichever is first 
recorded) are first met until the first date that recurrent or progressive disease is objectively documented.  
8.1.4.1 
Stable Disease Duration 
Stable disease duration will be measured from the time of start of therapy until the criteria for progression 
are met, taking as reference the smallest measurements recorded since the treatment started.  
8.1.4.2 
Methods of Measurement 
The same method of assessment and the same technique should be used to characterize each identified 
and reported lesion at baseline and during follow-up. 
 
9. 
SPECIAL INSTRUCTIONS 
A blood sample of 20-30 ml is to be drawn as outlined in study flow charts (Table 1 and Table 2). Each 
sample will be collected into a non-heparinized vacutainer with a 20 g or larger needle. Blood samples 
will be shipped at room temperature until processed to separate the plasma. Serological studies will be 
performed in all patients during the course of this study to assess the changes in HMGB1 level before, 
during and after the treatment. The sample should be sent to for on-site processing and storage: 
Tianhong Li, M.D., Ph.D. 
 
 
 
 
10. 
STATISTICAL CONSIDERATIONS  
10.0 
Endpoints 
10.0.0 
Primary Endpoints 
Phase I: Event of new AE of ≥grade 3 that are outside the spectrum of irAEs when CD24Fc is given in 
cancer patients who developed grade 2-3 irAEs. 
Phase II: Co-primary endpoints:  
• 
Recovery rate (as defined by reduction of irAE by one grade) at Day 42. 
• 
Time to recovery from grade 2 or 3 irAE (as defined by reduction of at least 1 grade in irAE 
severity) from the initiation of CD24Fc treatment. Patients who have not been documented to 
have event (reduction of at least 1 grade) will be censored at the date of the latest clinical 
assessment that documented as being free of event. 
10.0.1 
Secondary Endpoints 
Phase I:  
• 
Time to irAE reduction by at least 1 grade from the initiation of CD24Fc treatment.  


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• 
Time to all irAEs reduced to ≤1 (by NCI CTCAEv5.0) from the initiation of CD24Fc treatment.  
• 
Time to resume ICI treatment from the initiation of CD24Fc treatment.  
• 
Recovery rate (reduction of irAE by one grade) at D42. 
Patients who have not been documented to have above events will be censored at the date of the latest 
clinical assessment that documented as being free of events. 
Phase II:  
• 
Time to all irAEs reduced to ≤1 (by NCI CTCAEv5.0) from the initiation of CD24Fc treatment. 
Patients who have not been documented to have the event will be censored at the date of the latest 
clinical assessment that documented as being free of event. 
• 
The use of steroids and other drugs (drug, dose, duration). 
• 
Overall response rate (ORR) after retreatment with ICI with or without CD24Fc after resolution 
of irAE.  
• 
Progression free survival (PFS) will be calculated as the time from initiation of ICI to first 
documented evidence of disease progression or death, whichever comes first. Alive patients who 
have not been documented to have progression will be censored at the date of the latest clinical 
assessment that documented as being free of progression.  
• 
Overall survival (OS) will be calculated as the time from diagnosis to death. Alive patients will 
be censored at the date of the latest follow-up visit.  
10.1 
Randomization for Phase II Study 
Steroids is the most commonly used SOC therapy for irAEs. It affects the severity and duration of irAE, 
which are the key endpoints of this study. We thus will stratify the subjects based on the status of steroids 
use at registration, Stratified block randomization will be used. Randomization codes will be generated in 
a permuted block design, stratified by the status of steroids use at registration. The block size will be 
balanced within each block to maintain a 1:1 ratio between the two groups. For patient who have no 
steroids use at registration but start on steroids before starting CD24Fc treatment, the patient will be 
moved to the steroid stratum. If a subject withdraws from participation in the study or changed to steroids 
use group, his or her randomization code will not be re-used.  
10.2 
Statistical Analysis 
Demographic and background characteristics obtained at enrollment will be listed and summarized. 
Descriptive statistics will be used to summarize changes of biomarkers from baseline in clinical 
laboratory parameters for this cohort, and use of steroids (drug, dose, duration) and other treatment for 
irAE. We will adjust steroids use in analyses. Subgroup analyses will be performed separately by the 
status of Steroids use.  
To assess toxicity: Toxicity is evaluated by NCI CTCAEv5.0. The type, grade, frequency and proportion 
of toxicities noted during the treatment period will be reported, along with associated 95% confidence 
interval of proportion. All adverse events noted by the investigator will be tabulated according to the 
affected body system. In phase I lead-in study, dose limiting toxicity is defined as any new AE of ≥grade 
3 that are outside the spectrum of irAEs.  
To assess time to recovery from irAE (time to reduction of irAE by at least one grade), time to all irAEs 
reduced to ≤1, and time to resume ICI treatment:  All time points will be started from Day 1 of CD24Fc 
treatment. Kaplan-Meier plots and confidence intervals will be used to summarize outcomes. Medians 
and associated 95% confidence intervals will be calculated, and comparisons between groups will be 


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performed by log-rank tests. Cox proportional hazard models will be used to explore association between 
covariates and outcomes. 
To assess recovery rate of CD24Fc (reduction of irAE by at least one grade) at D42 and response rate of 
ICI: The fraction of patients who experience a PR or CR will be determined by dividing the number of 
responders by the total evaluable patients. The fraction will be reported along with 95% two-sided 
confidence intervals. Comparisons between groups will be performed by Fisher’s Exact tests. We will 
also characterize the proportion who remain that either respond or have stable disease, compared to those 
who progress.  
To assess PFS and OS: Kaplan-Meier plots and confidence intervals will be used to summarize PFS, and 
OS; 1-year OS rate will be reported; medians and associated 95% confidence intervals will be calculated, 
and comparisons between groups will be performed by log-rank tests. Cox PH models will be used to 
explore association between outcomes and covariates. 
As exploratory analysis, we will summarize descriptively the relationship of response rates to tumor type 
(lung, breast, prostate) and to cellular immune response, and explore the relationship using logistic 
regression. 
The possibility of bias from missing data will be addressed. Missing pattern and mechanism will be 
evaluated, and sensitivity analyses will be performed using imputation methods for use of steroid, irAE 
type, cancer type, etc., if such might affect point estimates and study conclusions. 
The study design in the Phase II portion allows steroids and other systemic treatments prior to and during 
study enrollment. CD24Fc/placebo will be added in addition to standard of care.  We will perform a 
sensitivity test for data from the Phase II study.  We will consider isolating the effect of CD24Fc in the 
future Phase III clinical study. 
 
10.3 
Sample Size Justification 
Phase I study: We plan to enroll 6 patients in the phase I study. The objective of this phase I study is to 
confirm the safety of CD24Fc in ICI-treated cancer patients who have treatment interruption due to grade 
2 or 3 irAEs and to estimate the median time to recovery and resumption of ICI after treatment 
interruption due to irAE. The primary endpoint is new AE of ≥grade 3 that are outside the spectrum of 
irAEs when CD24Fc is given to treat irAEs. We expect the rate of this event will be less than 33.3%. 
With a sample size of 6 patients, we would have 74-91% chance to observe at least one occurrence if the 
true event rate is 20-30%. Hence the sample size is adequate for this pilot study for safety. 
Randomized phase II study:  Previous studies suggested that recovery rate at 42 days for control group 
will be about 50% [22, 56]. We hypothesize CD24Fc will increase recovery rate from 50% to 80 %. A 
sample size of 72 patients (36 in each arm) will have 81% power to detect an increase of response rate 
from 50% of control group to 80% of CD24Fc group. This result is based on one-sided Fisher’s Exact test 
and significance level of 0.05.  
 
10.4 
Safety Monitoring and Stopping Rule 
The Phase II study is a randomized, double blind, placebo-controlled study. To ensure the safety of the 
patients enrolled in the Phase II study, Bayesian stopping boundaries are used to allow early stopping at 
any given time in the combined population. The objective response rate (ORR) and toxicity of CD24Fc 
during the whole study will be monitored simultaneously using the Bayesian stopping boundaries 
calculated based on beta-binomial distribution. Toxicity is defined as new AE of ≥grade 3 that are 


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outside the spectrum of irAEs. ORR is defined as partial response and complete response by RECIST 
V1.1 after retreatment with ICI. 
The regimen will be considered safe if the ORR is at least 20% in all patients in both arms and the 
toxicity rate is maintained at most 33.3% for the CD24Fc arm.  Previous studies for controls suggested 
the ORR after retreatment with ICI is about 20-40%, and therefore we consider a response rate <20% in 
all patients in both arms as unacceptable, which will indicate an effect of CD24Fc on promoting tumor 
growth. The prior probabilities of response and toxicity for the regimen are modeled by beta distributions 
[Beta(0.8, 1.2) and Beta(0.3, 1.7), respectively], and response and toxicity are assumed to be independent. 
Denoting the probabilities of response for both arms and toxicity for CD24Fc arm by {θRES, θTOX}, and 
they are compared to fixed targets of response and toxicity rates.  The following decision criteria will be 
applied: 
1)   stop if Prob{ θRES < 0.2 | data} > 0.97, and 
2)   stop if Prob{ θTOX > 0.333 | data} > 0.97 
We will have randomization box of 6 patients and thus ensure that 3 patients have been dosed for each 6 
subjects enrolled. Patients will be monitored by a cohort size of 6 patients (3 for the CD24Fc arm and 3 
for the placebo arm) according to the following stopping boundary for toxicity during the whole study. To 
be conservative, we attribute all AEs to CD24Fc. 
Number of Patients 
Evaluated in All Enrolled 
Patients (half control and 
half CD24Fc) 
Stop if Number of 
ORR Observed 
Stop if Number of 
AE Observed 
6 
Never stop with these 
many patients 
Never stop with these 
many patients 
12 
Never stop with these 
many patients 
≥5 
18 
0 
≥7 
24 
≤1 
≥8 
30 
≤2 
≥10 
36 
≤2 
≥11 
42 
≤3 
≥12 
48 
≤4 
≥14 
54 
≤5 
≥15 
60 
≤6 
≥16 
66 
≤7 
≥17 
72 
Always stop with this number of patients 
 
10.5 
Emergency Unblinding 
In situations where the Investigator believes that knowledge of the subject’s treatment assignment is 
required to select appropriate continuing therapy for the disease under study, the Investigator may unblind 


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the patient’s treatment assignment. The Investigator should make every effort to contact the medical 
monitor before unblinding a patient’s treatment assignment unless the urgency of the case requires 
immediate action.  All other members of the study team should remain blinded to treatment assignment. 
 
11. 
SAFETY AND REPORTING REQUIREMENTS 
11.0 
Adverse Events 
An adverse event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting 
medical condition in a clinical investigation participant administered study drug and that does not 
necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of investigational product, whether or not considered related to the investigational product.  
11.0.0 
Severity of Adverse Events 
The severity of an AE is graded based on the NCI CTCAE version 5.0. The guideline is as follows: 
Grade 1 (Mild): 
Asymptomatic or mild symptoms. Requires clinical or 
diagnostic observations only. Intervention not indicated.  
Grade 2 (Moderate): 
Moderate symptoms. Minimal, local or non-invasive 
intervention indicated. Limits age-appropriate activities of 
daily living. 
Grade 3 (Severe): 
Severe or medically significant symptoms, but not life-
threatening. Limits self-care activities of daily living. 
Requires hospitalization or prolongation of hospitalization.  
Grade 4 (Life-threatening): 
Life-threatening consequences. Requires urgent intervention. 
Grade 5 (Fatal): 
The event caused death. 
11.0.1 
Causality (Attribution) of Adverse Events  
The investigator is to assess the causal relation of all AEs (i.e., whether there is a reasonable possibility 
that the study drug caused the event) using the following definitions: 
Not Related: 
Another cause of the AE is more plausible; a temporal sequence cannot be 
established with the onset of the AE and administration of the investigational 
product; or, a causal relationship is considered biologically implausible. 
Unlikely: 
The current knowledge or information about the AE indicates that a relationship 
to the investigational product is unlikely. 
Possibly Related: 
There is a clinically plausible time sequence between onset of the AE and 
administration of the investigational product, but the AE could also be attributed 
to concurrent or underlying disease, or the use of other drugs or procedures.  
Possibly related should be used when the investigational product is one of several 
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Probably Related: 
Related: 
The AE is likely related to investigational product. 
The AE is clearly related to use of the investigational product. 
Any other AE not listed as an expected event in the Investigator’s Brochure or in this protocol will be 
considered unexpected. 
11.0.2 
Serious Adverse Events 
Serious adverse event (SAE) means any untoward medical occurrence that at any dose: 
• 
Results in death. 
• 
Is life-threatening (Note: the term “life-threatening” refers to an event/reaction in which the 
patient was at risk of death at the time of the event/reaction.  It does not refer to an 
event/reaction which hypothetically might have caused death if it were more severe). 
• 
Requires inpatient hospitalization or prolongation of an existing hospitalization  
• 
Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions). 
• 
Is a congenital anomaly/birth defect. 
• 
Is a medically important event or reaction. Medical and scientific judgment should be 
exercised in deciding whether other situations should be considered serious, such as 
important medical events that might not be immediately life-threatening or result in death or 
hospitalization, but might jeopardize the patient or might require intervention to prevent one 
of the other outcomes listed in the definition above. 
 
11.1 
Procedures for Reporting Adverse Events   
11.1.0 
Methods and Timing for Assessing and Recording Safety Variables 
The investigator is responsible for ensuring that all AEs and SAEs that are observed or reported during 
the study are collected and reported to the IRB and to the FDA in accordance with CFR 312.32 (IND 
Safety Reports).  
11.1.1 
Adverse Event Reporting Period 
The study period during which all AEs and SAEs must be reported begins at initiation of study treatment 
and ends 30 days following the last administration of study treatment or study 
discontinuation/termination, whichever is earlier. After this period, investigators should only report SAEs 
that are attributed to prior study treatment. 
Investigators are not obligated to actively seek information regarding the occurrence of new SAEs 
beginning after the 30-day post last dose period. However, if the investigator learns of such an SAE and 
that event is deemed relevant to the use of study treatment, he/she should promptly document and report 
the event. A longer reporting period applies in the case of pregnancy. 


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11.1.2 
Procedures for SAE Reporting 
11.1.2.0 
Reporting to the FDA 
Sponsor of studies conducted under an IND are required to report all serious, unexpected, and related 
adverse events directly to the FDA on a MedWatch Form FDA 3500A within 7 (if fatal or life-
threatening) or 15 calendar days of first awareness, as described below.  
Before submitting this report, the sponsor needs to ensure that the event meets all three of the definitions 
contained in the requirement:  
• 
Suspected adverse reaction  
• 
Serious  
• 
Unexpected  
The Sponsor will notify the FDA according to the following timelines: 
within 7 calendar days of any unexpected fatal or life-threatening adverse event with 
possible relationship to study drug; 
within 15 calendar days of any event that is considered: 1) serious, 2) unexpected, and 3) at 
least possibly related to study participation. 
FDA fax number for IND Safety Reports: (800) FDA-0178 or (800) 332-0178 
If the adverse event does not meet all three of the definitions, it should not be submitted as an expedited 
IND safety report to the FDA.  For adverse events that are either serious but don’t meet the criteria for 
expedited reporting or are not serious, the FDA will be notified at the time of the IND Annual Report. 
MedWatch Form FDA 3500A Reporting Guidelines  
In addition to completing appropriate demographic and suspect medication information, the report should 
include the following information within the Event Description of the MedWatch Form FDA 3500A: 
• 
Treatment regimen (dosing, frequency, combination therapy) 
• 
Protocol description (include number if assigned) 
• 
Description of event, severity, treatment, and outcome, if known 
• 
Supportive diagnostic and laboratory results 
• 
Investigator’s assessment of the relationship of the SAE to each investigational product and 
suspect medication 
• 
Follow-up information: 
• 
Additional information may be added to a previously submitted report by any of the 
following methods: 
• 
Adding to the original MedWatch Form FDA 3500A and submitting it as follow-up 
• 
Adding supplementary summary information and submitting it as follow-up with the original 
MedWatch Form FDA 3500A 


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• 
Summarizing new information and faxing it with a cover letter including subject identifiers 
(i.e., DOB, initials, subject number), protocol description and number, suspect drug, brief 
adverse event description, and notation that additional or follow-up information is being 
submitted 
11.1.2.1 
Reporting to the Institutional Review Board 
Both serious and non-serious adverse events will be reported in accordance with UCD IRB 
Administration and UCD Comprehensive Cancer Center’s (UCDCCC) Office of Clinical Research 
(OCR) policies. The UC Davis IRB can be reached at (916) 703-9151.  
Participating site(s) will report adverse events per institution’s IRB guidelines.  
 
12. 
ETHICAL CONSIDERATIONS AND ADMINISTRATIVE PROCEDURES  
12.0 
Ethics and Good Clinical Practice 
This study must be carried out in compliance with the protocol and Good Clinical Practice, as described 
in:  
1. International Council for Harmonisation (ICH) Harmonized Tripartite Guidelines for Good 
Clinical Practice 1996. 
2. Directive 91/507/EEC, The Rules Governing Medicinal Products in the European Community. 
3. US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 and 56 
concerning informed consent and IRB regulations). 
4. Declaration of Helsinki, concerning medical research in humans (Recommendations Guiding 
Physicians in Biomedical Research Involving Human Subjects, Helsinki 1964, amended Tokyo 
1975, Venice 1983, Hong Kong 1989, Somerset West 1996). 
The investigator agrees, when signing the protocol, to adhere to the instructions and procedures described 
in it and thereby to adhere to the principles of Good Clinical Practice that it conforms to. 
12.1 
Institutional Review Board 
Before implementing this study, the protocol, the proposed informed consent form and other information 
to subjects, must be reviewed by a properly constituted Institutional Review Board (IRB). 
12.2 
Patient Information and Informed Consent 
After the study has been fully explained, written informed consent will be obtained from either the patient 
or his guardian or legal representative prior to study participation.  The method of obtaining and 
documenting the informed consent and the contents of the consent will comply with ICH-GCP and all 
applicable regulatory requirement(s).  In accordance with UCD OCR policy an original signed and dated 
participant Informed Consent document will reside in a secured location within the UCD OCR.  Copies of 
the signed and dated Informed Consent document will be provided to the study participant and UCD 
Health System Information Management for inclusion in the participant’s UCD Health System Medical 
Record or per the participating site’s policies. 
12.3 
Patient Confidentiality 
In order to maintain patient privacy, all study reports and communications will identify the patient by 
initials and the assigned patient number.  Data capture records and drug accountability records will be 
stored in secure cabinets in the UCD CCC OCR or at the participating institutions.  Medical records of 
patients will be maintained in strict confidence according to legal requirements.  The patient’s 


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confidentiality will be maintained and will not be made publicly available to the extent permitted by the 
applicable laws and regulations. 
12.4 
Study Registration 
Once signed, informed consent has been obtained and all pretreatment evaluations have been performed, 
patients will be entered on study according to UCD Office of Clinical Research (OCR) policy. To register 
a patient, the data manager or designee must complete the Eligibility Checklist and the Patient 
Registration Form.  After verifying the eligibility, the OCR coordinator will register the patient onto the 
study and assign a patient accession.  Administration of study drug may not be initiated until the patient is 
registered (See Appendix Registration Guidelines).  
12.5 
Protocol Compliance and Deviations 
The investigator will conduct the study in compliance with the protocol given approval/favorable opinion 
by the IRB and the appropriate regulatory authority(ies).   
All protocol deviations will be reported in accordance with UCD IRB Administration and UCD Cancer 
Center OCR policies and the participating site’s IRB policies. Any departures from the protocol must be 
fully documented in the source documents.   
12.6 
Record Retention 
The investigator will maintain all study records according to ICH-GCP and applicable regulatory 
requirement(s).  
12.7 
Quality Assurance and Control 
Quality assurance audits of select patients and source documents may be conducted by the UC Davis 
Comprehensive Cancer Center Quality Assurance Committee as outlined in the UC Davis Cancer Center 
Data and Safety Monitoring plan. Quality control will be maintained by the OCR Quality Assurance team 
according to OCR policy. 
 
13. 
OVERSITE AND MONITORING 
13.0 
Data and Safety Monitoring 
In addition to the requirements for adverse event reporting, this protocol is also subject to the UC Davis 
Comprehensive Cancer Center (UCDCCC) Data and Safety Monitoring Plan. The UCDCCC is 
committed to pursuing high-quality patient-oriented clinical research and has established mechanisms to 
ensure both scientific rigor and patient safety in the conduct of clinical research studies. The UCDCCC 
relies on a multi-tiered committee system that reviews and monitors all cancer clinical trials and ensures 
the safety of its participants, in compliance with institutional and federal requirements on adverse event 
(AE) reporting, verification of data accuracy, and adherence to protocol eligibility requirements, 
treatment guidelines, and related matters. The Scientific Review Committee (SRC) assumes overall 
oversight of cancer studies, with assistance and input from two independent, but interacting, committees: 
the Quality Assurance Committee and the Data Safety Monitoring Committee. A multi-level review 
system strengthens the ability of the UCDCCC to fulfill its mission in conducting high quality clinical 
cancer research. 
As per UCDCCC Office of Clinical Research (OCR) standard operating procedures the principal 
investigator (PI) and clinical research coordinator (CRC) meet at least monthly for ongoing study 
information, to discuss patient data and adverse events, and to determine if dose escalation is warranted, 
when applicable. 


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According to the UCDCCC Data and Safety Monitoring Plan (DSMP), UCDCCC Data and Safety 
Monitoring Committee (DSMC) monitors all at risk studies, including this study, being conducted at the 
UCDCCC.  The DSMC is responsible for reviewing study accrual logs, adverse event information, and 
dose escalation meeting minutes (where applicable) to ensure subject safety and compliance with protocol 
defined guidelines. The DSMC meets monthly. All serious adverse events experienced by study 
subjects will be discussed and appropriate action taken.  If serious adverse events occur between 
these standing meetings and/or calls, all investigators will be informed by email. The UCDCCC 
Scientific Review Committee (SRC) determines if an additional Data and Safety Monitoring Board 
(DSMB) is required for a study.  If required, the DSMC will appoint an additional DSMB. 
 
13.1 
Investigator Monitoring Guidelines 
Investigators will conduct continuous review of patient safety. Patients will be monitored bi-weekly 
during the study.  All patients on active treatment will be discussed at weekly conferences that are held at 
the University of California, Davis 
 
14. 
PATHOLOGY REVIEW 
Not applicable. 
 
 
 


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Piotrowski, P., et al., CD24 Ala57Val gene polymorphism and the risk of systemic lupus 
erythematosus. Tissue Antigens, 2010. 75(6): p. 696-700. 
47. 
Sánchez, E., et al., Association of a CD24 gene polymorphism with susceptibility to systemic 
lupus erythematosus. Arthritis & Rheumatism, 2007. 56(9): p. 3080-3086. 
48. 
Sánchez, E., et al., Investigating the role of <em>CD24</em> gene polymorphisms in 
rheumatoid arthritis. Annals of the Rheumatic Diseases, 2008. 67(8): p. 1197-1198. 
49. 
Thaxton, J.E., et al., Deletion of CD24 Impairs Development of Heat Shock Protein gp96–Driven 
Autoimmune Disease through Expansion of Myeloid-Derived Suppressor Cells. The Journal of 
Immunology, 2014. 192(12): p. 5679-5686. 
50. 
Toubai, T., et al., Siglec-G–CD24 axis controls the severity of graft-versus-host disease in mice. 
Blood, 2014. 123(22): p. 3512-3523. 
51. 
Du, X., et al., Uncoupling therapeutic from immunotherapy-related adverse effects for safer and 
effective anti-CTLA-4 antibodies in CTLA4 humanized mice. Cell Res, 2018. 28(4): p. 433-447. 
52. 
Gorgulho, C.M., et al., Johnny on the Spot-Chronic Inflammation Is Driven by HMGB1. Front 
Immunol, 2019. 10: p. 1561. 
53. 
Liang, W., et al., Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China. 
Lancet Oncol, 2020. 21(3): p. 335-337. 
54. 
COVID-19 Provider & Practice Information. 2020  [cited 2020 April 8]; Available from: 
https://www.asco.org/asco-coronavirus-information/provider-practice-preparedness-covid-19. 
55. 
Ueda, M., et al., Managing Cancer Care During the COVID-19 Pandemic: Agility and 
Collaboration Toward a Common Goal. J Natl Compr Canc Netw, 2020: p. 1-4. 
56. 
Tarhini, A., Immune-mediated adverse events associated with ipilimumab ctla-4 blockade 
therapy: the underlying mechanisms and clinical management. Scientifica (Cairo), 2013. 2013: p. 
857519. 
 
 
 


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16. 
APPENDICES 
Appendix 1. ECOG and Karnofsky Performance Status Scores1,2 
http://ecog-acrin.org/resources/ecog-performance-status  
ECOG PERFORMANCE STATUS 
KARNOFSKY PERFORMANCE STATUS 
0—Fully active, able to carry on all pre-
disease performance without restriction 
100—Normal, no complaints; no evidence of 
disease 
 90—Able to carry on normal activity; minor 
signs or symptoms of disease 
1—Restricted in physically strenuous 
activity but ambulatory and able to carry 
out work of a light or sedentary nature, 
e.g., light house work, office work 
 80—Normal activity with effort, some signs or 
symptoms of disease 
 70—Cares for self but unable to carry on normal 
activity or to do active work 
2—Ambulatory and capable of all selfcare 
but unable to carry out any work 
activities; up and about more than 50% 
of waking hours 
 60—Requires occasional assistance but is able to 
care for most of personal needs 
 50—Requires considerable assistance and 
frequent medical care 
3—Capable of only limited selfcare; 
confined to bed or chair more than 50% 
of waking hours 
 40—Disabled; requires special care and 
assistance 
 30—Severely disabled; hospitalization is 
indicated although death not imminent 
4—Completely disabled; cannot carry on 
any selfcare; totally confined to bed or 
chair 
 20—Very ill; hospitalization and active 
supportive care necessary 
 10—Moribund 
5—Dead 
  0—Dead 
1. Karnofsky D, Burchenal J, The clinical evaluation of chemotherapeutic agents in cancer. In: 
MacLeod C, ed. Evaluation of Chemotherapeutic Agents. New York, NY: Columbia University 
Press; 1949:191–205. 
2. Zubrod C, et al. Appraisal of methods for the study of chemotherapy in man: Comparative therapeutic 
trial of nitrogen mustard and thiophosphoramide. Journal of Chronic Diseases; 1960:11:7-33. 
 
 


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Appendix 2. Study Registration 
Once signed, informed consent has been obtained; patients will be entered on study.  To register a patient, 
the study coordinator must complete the Eligibility Checklist. The study coordinator will register the 
patient onto the study and assign a unique patient number.    
 
 
 


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Appendix 3. Data Collection Forms  
All data will be collected using UC Davis data collection forms. Any and all source documentation shall 
be maintained. 
 
 
 
 
 
 


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Appendix 4. NCI CTCAE Version 5.0 
Toxicity will be scored using NCI CTCAE Version 5.0 for toxicity and adverse event reporting.  A copy 
of the NCI CTCAE Version 5.0 can be downloaded from the CTEP homepage: (http://ctep.info.nih.gov).  
All appropriate treatment areas have access to a copy of the CTCAE version. 
 
 
 
 


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Appendix 5: List of Proarrhymic Drugs 
Konstantopoulou A, et al, World J Cardiol 2013 June 26; 5(6): 175-185.  
Category 
Drugs 
Antianginal 
Bepridil 
  
Antiarrhythmic 
Disopyramide, 
procainamide, 
quinidine, 
mexiletine, 
  
propafenone, 
flecainide, 
d,l-sotalol, 
amiodarone, 
  
dronedarone, 
bretylium, 
dofetilide, 
ibutilide, 
  
azimilide, 
ajmaline 
  
Anticancer 
Tamoxifen, 
lapatinib, 
vandetanib, 
nilotinib, 
  
arsenic trioxide 
  
Antifungal 
Itraconazole, 
ketoconazole, 
fluconazole, 
voriconazole 
Antimicrobial 
Erythromycin, 
clarithromycin, 
azithromycin, 
  
  
spiramycin, 
telithromycin, 
levofloxacin, 
moxifloxacin, 
  
sparfloxacin, 
gatifloxacin, 
grepafloxacin, 
  
  
gemifloxacin, 
ofloxacin, 
trimethoprim-sulfamethoxazole, 
  
pentamidine, 
quinine, 
chloroquine, 
  
  
mefloquine, 
halofantrine 
  
Antiviral 
Foscarnet 
  
Antihistamine 
Astemizole, 
diphenhydramine, 
ebastine, 
terfenadine, 
  
hydroxyzine 
  
Antidepressant 
Doxepin, 
venlafaxine, 
fluoxetine, 
desipramine, 
  
imipramine, 
clomipramine, 
paroxetine, 
sertraline, 
  
citalopram, 
escitalopram 
  
Antipsychotic 
Chlorpromazine, 
prochlorperazine, 
trifluoperazine, 
  
  
fluphenazine, 
felbamate, 
haloperidol, 
  
  
thioridazine, 
droperidol, 
mesoridazine, 
pimozide, 
  
risperidone, 
quetiapine, 
ziprasidone, 
lithium, 
  
chloral hydrate 
pericycline, 
sertindole, 
sultopride, 
  
zimeldine, 
maprotiline, 
tiapride 
  
Antimigraine 
Naratriptan, 
sumatriptan, 
zolmitriptan 
  
Bronchodilators 
Albuterol, 
salmeterol 
  
Diuretics 
Indapamide, 
thiazide, 
furosemide 
  
Gastrointestinal stimulants Cisapride, 
metoclopramide, 
domperidone 
  
Hormones 
Octreotide, 
vasopressin 
  
Others 
Probucol, 
methadone, 
cocaine, 
amantadine, 
  
veratridine, 
vincamine, 
terodiline, 
budipine, 
  
tizanidine, 
aconitine 
organophosphorus compounds 
 
 
 


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17. 
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 header 
(all pages) 
Protocol version number updated to 1.5, dated October 20, 2020. 
Page 1 and Page 4 
Add the clinicaltrial.gov registration number as a protocol number: 
NCT04552704 
Table 1 and 2 
Clarify the window of study visit, and blood draw schedule and amount.  
Section 6.4 
Clarify dose modification criteria. 
Administrative 
changes 
Several grammatical changes that were lost between the different versions.