A Phase IIa Study of Recombinant Human Interleukin-22 IgG2-Fc (F 652) in Combination With Systemic Corticosteroids for the Treatment of Newly Diagnosed Grade II-IV Lower Gastrointestinal Acute Graft-versus-Host Disease (aGVHD) in Hematopoietic Stem Cell Transplantation Recipients (HSCT)
Phase: PHASE1
Conditions: Acute Graft vs Host Disease
Sponsor: EVIVE Biotechnology



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INTRODUCTORY AND CONFIDENTIALITY STATEMENT 
This protocol has been prepared according to the International Conference on 
Harmonisation (ICH) Harmonised Tripartite Guidelines for Good Clinical Practice 
issued in June 1996, with an implication date of January 17, 1997 and Food and Drug 
Administration (FDA) Good Clinical Practice (GCP) guidelines and Code of Federal 
Regulations (CFR): 21 CFR 312, 21 CFR 50, 21 CFR 56.  
This document contains confidential information of the Generon (Shanghai) 
Corporation that should not be disclosed to anyone other than the recipient study staff, 
members of the Ethics Committee, or Institutional Review Board, and Regulatory 
Authorities. This information cannot be used for any purpose other than the evaluation 
or conduct of the clinical study without the prior written consent of Generon (Shanghai) 
Corporation. 
PRINCIPAL INVESTIGATOR'S STATEMENT 
I, the undersigned, have reviewed this protocol, including appendices, and I agree to 
conduct the clinical study as described (subject to any amendments). Any changes in 
procedure will only be made if necessary to protect the safety, rights or welfare of study 
subjects. 
I agree to conduct in person or to supervise the study. I agree to ensure that all who 
assist me in the conduct of the study are aware of their obligations. 
 
Site Investigator: 
Site Number: 
 
 
…………………………………. 
……………………………………. 
Signature 
Date 

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Sponsor Approval and Medical Expert for the Trial: 
 
Tom Tang, MD,  
Regulatory and Clinical Affairs 
Building 9, 787 Kangqiao Road,  
Shanghai, PRC 201315 
Tel: 86 21-61760866 
Fax: 86 21-61760865 
 
 
 
 
…………………………………. 
……30 May 2017………………………… 
Signature 
Date 
 
 

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TABLE OF CONTENTS 
1 
INTRODUCTION ........................................................................................................................ 13 
1.1 
Acute GVHD and Current Therapy .................................................................................... 13 
1.1.1 
Recombinant Human IL-22 (F-652) and Reduction of GVHD ............................ 14 
1.1.2 
Clinical Studies and Previous Human Usage ....................................................... 16 
1.1.3 
Potential Risks and Benefits ................................................................................. 17 
2 
STUDY OBJECTIVES ................................................................................................................. 18 
2.1 
Study Objective .................................................................................................................. 18 
2.2 
Study Endpoints .................................................................................................................. 18 
Safety Endpoints ........................................................................................................................... 18 
Primary Efficacy Endpoint ............................................................................................................ 18 
Secondary Efficacy Endpoints ...................................................................................................... 18 
3 
INVESTIGATIONAL PLAN ....................................................................................................... 20 
3.1 
Overall Study Design .......................................................................................................... 20 
3.2 
Rationale for Study Design ................................................................................................. 24 
3.2.1 
F-652 Dosing ........................................................................................................ 24 
3.3 
Study Duration and Dates ................................................................................................... 24 
3.3.1 
Duration of Subject Participation ......................................................................... 24 
3.3.2 
Hold and Stop Rules ............................................................................................. 25 
3.3.2.1 
Hold and Discontinuation Rules for the Clinical Trial ........................ 25 
3.3.2.2 
Reasons for Subject Study Drug Discontinuation ................................ 25 
3.3.3 
End of Treatment and Follow-up Visits ............................................................... 25 
4 
STUDY POPULATION SELECTION ......................................................................................... 27 
4.1 
Study Population ................................................................................................................. 27 
4.2 
Inclusion Criteria ................................................................................................................ 27 
4.3 
Exclusion Criteria ............................................................................................................... 27 
5 
STUDY TREATMENTS .............................................................................................................. 29 
5.1 
Description of Treatments .................................................................................................. 29 
5.1.1 
Study Drug: F-652 (Recombinant human IL-22) ................................................. 29 
5.1.2 
Preparation 
 ............................................................................ 29 
5.2 
Treatments Administered .................................................................................................... 29 
5.2.1 
F-652 .................................................................................................................... 29 
5.2.1.1 
Pre-Treatment Criteria and Dose Modification Guidelines ................. 30 
5.2.2 
Systemic Corticosteroids ...................................................................................... 31 
5.2.3 
Prophylaxis Against Infection .............................................................................. 31 
5.2.4 
Supportive Care .................................................................................................... 31 
5.3 
 ....................................................................................... 32 
5.4 
Investigational Product at Study Site .................................................................................. 32 
5.5 
Test Article Accountability ................................................................................................. 32 
5.6 
Investigational Product at Study Site at Study Conclusion ................................................ 32 
5.7 
Selection and Timing of Dose for Each Subject ................................................................. 33 
5.8 
Method of Assigning Treatment to Subjects ...................................................................... 33 
6 
TRIAL PROCEDURES ................................................................................................................ 34 
6.1 
Measures to Avoid Bias ...................................................................................................... 34 
6.1.1 
Randomization ..................................................................................................... 34 
6.1.2 
Blinding ................................................................................................................ 34 

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6.1.3 
Simultaneous Utilization of All Arms .................................................................. 34 
6.2 
Concomitant Therapy ......................................................................................................... 34 
6.2.1 
Approved Medications ......................................................................................... 34 
6.2.2 
Change from Baseline in Medications ................................................................. 35 
6.3 
Restrictions ......................................................................................................................... 35 
6.3.1 
Medications Not Permitted ................................................................................... 35 
6.4 
Treatment Compliance ........................................................................................................ 35 
7 
STUDY PROCEDURES .............................................................................................................. 36 
7.1 
Informed Consent ............................................................................................................... 36 
7.2 
Medical History .................................................................................................................. 36 
7.3 
Physical Examination ......................................................................................................... 36 
7.4 
Vital Signs .......................................................................................................................... 36 
7.5 
Clinical Laboratory Tests ................................................................................................... 36 
7.5.1 
Laboratory Parameters ......................................................................................... 37 
7.5.1.1 
Sample Collection, Storage, and Shipping........................................... 37 
7.5.1.2 
Blood Volume ...................................................................................... 38 
7.5.2 
Urinalysis ............................................................................................................. 38 
7.5.3 
Assessment of aGVHD ........................................................................................ 38 
7.6 
Efficacy Assessments ......................................................................................................... 38 
7.6.1 
Methods and Timing for Assessing Acute Graft-Versus-Host Disease 
(aGVHD) .............................................................................................................. 38 
7.7 
Safety Assessments ............................................................................................................. 39 
7.7.1 
Standard Safety Parameters .................................................................................. 39 
7.7.2 
Adverse Events Assessments ............................................................................... 40 
7.7.2.1 
Procedures for Eliciting Reports of and Recording Adverse 
Events and Inter-current Illnesses ........................................................ 40 
7.7.2.2 
Timing and Duration of Follow-up of Subjects after Adverse 
Events Reported ................................................................................... 40 
7.7.3 
Defining, Grading, and Reporting Adverse Events .............................................. 40 
7.7.3.1 
Adverse Events .................................................................................... 40 
7.7.3.2 
Serious Adverse Events ....................................................................... 41 
7.7.3.3 
Severity and Grading ........................................................................... 42 
7.7.3.4 
Relationship ......................................................................................... 42 
7.7.3.5 
Clinical Significance ............................................................................ 43 
7.7.3.6 
Clinical Laboratory Adverse Events .................................................... 43 
7.7.3.7 
Reporting Adverse Events (Serious and Non-serious)......................... 43 
7.7.3.8 
Exposure In Utero ................................................................................ 45 
7.7.4 
Toxicity (Adverse Event) Management ............................................................... 46 
7.7.4.1 
Hematologic Toxicity .......................................................................... 46 
7.7.4.2 
Skin Toxicity ........................................................................................ 47 
7.7.4.3 
Other Toxicities ................................................................................... 47 
7.8 
Concomitant Medication Assessments ............................................................................... 48 
7.9 
Removal of Subjects from the Trial or Study Drug ............................................................ 48 
7.9.1 
Criteria for Subject Withdrawal ........................................................................... 48 
7.9.2 
Procedures for Subject Withdrawal ...................................................................... 49 
7.9.3 
Replacements for Withdrawn Subjects ................................................................ 49 
7.9.4 
Follow-Up of Withdrawn Subjects ....................................................................... 49 
7.9.5 
Documentation ..................................................................................................... 49 

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8 
QUALITY CONTROL AND ASSURANCE ............................................................................... 50 
9 
PLANNED STATISTICAL METHODS...................................................................................... 51 
9.1 
General Considerations ....................................................................................................... 51 
9.2 
Determination of Sample Size ............................................................................................ 51 
9.3 
Analysis Populations .......................................................................................................... 51 
9.3.1 
Safety Population ................................................................................................. 51 
9.3.2 
Efficacy Evaluable Population ............................................................................. 51 
9.3.3 
................................................................................. 51 
9.4 
Demographics and Baseline Characteristics ....................................................................... 52 
9.5 
Study Endpoints .................................................................................................................. 52 
9.6 
Statistical Methods.............................................................................................................. 52 
9.6.1 
Safety Analysis ..................................................................................................... 52 
9.6.2 
Primary Efficacy Analysis .................................................................................... 52 
9.6.3 
Secondary Efficacy Analysis ................................................................................ 52 
9.6.4 
 ............................................................................................ 53 
9.6.5 
 ................................................................................... 53 
9.6.6 
Criteria for Termination and Sponsor Discontinuation Criteria ........................... 53 
9.6.7 
Level of Significance............................................................................................ 53 
9.6.8 
Procedure for Accounting for Missing, Unused and Spurious Data .................... 53 
10 ADMINISTRATIVE CONSIDERATIONS ................................................................................. 54 
10.1 Investigators and Study Administrative Structure .............................................................. 54 
10.2 Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
Approval ............................................................................................................................. 54 
10.3 Ethics .................................................................................................................................. 54 
10.3.1 
Treatment Considerations ..................................................................................... 54 
10.3.2 
Ethical Conduct of the Study ................................................................................ 55 
10.4 Subject Information and Consent ....................................................................................... 55 
10.5 Subject Confidentiality ....................................................................................................... 55 
10.6 Study Monitoring ................................................................................................................ 55 
10.7 Case Report Forms and Study Records .............................................................................. 55 
10.7.1 
Electronic Case Report Forms .............................................................................. 56 
10.8 Protocol Interpretation and Compliance ............................................................................. 56 
10.9 Access to Source Documentation ....................................................................................... 56 
10.10 Data Generation and Analysis ............................................................................................ 56 
10.11 Records Retention and Retention of Data ........................................................................... 57 
10.12 Financial Disclosure ........................................................................................................... 57 
10.13 Publication and Disclosure Policy ...................................................................................... 57 
11 REFERENCE LIST ...................................................................................................................... 58 
 

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LIST OF IN-TEXT TABLES 
Table 3.3.2.1. 
Stopping criteria for excessive mortality based on a Pocock boundary. ...25 
Table 5.2.1.1. 
F-652 administration schedule ...................................................................30 
Table 5.2.1.2. 
 ..............................................................................31 
Table 7.5.1.1. 
List of Laboratory Tests .............................................................................37 
Table 7.7.3.1. 
Attribution of Adverse Events ...................................................................43 
Table 7.7.4.1. 
Hematology Toxicity Management ...........................................................46 
Table 7.7.4.2. 
Skin Toxicity Management ........................................................................47 
Table 7.7.4.3. 
Other Toxicity Management ......................................................................47 
 

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LIST OF IN-TEXT FIGURES 
Figure 1. 
Post-BMT ISC Survival Curve in IL-22-Deficient Mice ..........................15 
Figure 2. 
Post-BMT Survival Curve .........................................................................16 
Figure 3. 
......................................................................22 
Figure 4. 
 ................................................................................23 
Figure 5. 
 .....................................................................32 
 

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LIST OF APPENDICES 
Appendix 1 
Trial Procedures and Study Activities .......................................................62 
Appendix 2 
Schedule of Procedures and Events ...........................................................65 
Appendix 3 
 .........................................................66 
Appendix 4 
 ......................................................................................67 
Appendix 5 
aGVHD Diagnosis and Grading Tables .....................................................69 
Appendix 6 
Criteria for Therapeutic Response/Outcome Assessment ..........................70 
Appendix 7 
List of Abbreviations and Definitions of Terms ........................................72 
 

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STUDY SYNOPSIS 
Protocol Number: 
GC-652-02 
Title: 
A Phase IIa Study of Recombinant Human Interleukin-22-IgG2-Fc (F-652) in 
Combination with Systemic Corticosteroids for the Treatment of Newly 
Diagnosed Grade II-IV Lower Gastrointestinal Acute Graft-versus-Host Disease 
in Hematopoietic Stem Cell Transplantation Recipients 
Study Phase: 
Phase IIa 
Name of Product: 
F-652 
Name of Active 
Ingredient: 
Recombinant human interleukin (IL)-22 and human immunoglobulin (Ig) 
IgG2-Fc fusion protein (rhIL-22 IgG2 Fc). 
Indication: 
Gastrointestinal (GI) Acute Graft-versus-Host Disease (aGVHD) in 
Hematopoietic Stem Cell Transplantation (HSCT) Recipients.  
Sponsor: 
Generon (Shanghai) Corporation  
Building 9, 787 Kang Qiao Road, 
Shanghai, PRC 201315 
Tel: 8621-61760866 
Fax: 8621-61760865 
Name of Sponsor 
Contact: 
Tom Tang, MD 
Generon (Shanghai) Corporation 
Name of Principal 
Investigators: 
Doris M. Ponce, M.D. 
Alan Hanash, M.D., PhD 
Juliet N. Barker, MBBS 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue, 
New York, NY 10065  
Test Product, Dose, and 
Mode of Administration:  
F-652 is to be administered intravenously (IV) once a week for a total of 4 doses 
at 45 μg/kg each. Dose reduction is permitted depending on individual subject 
safety and tolerability. Reduced doses permitted in de-escalation order: 30 μg/kg 
and then 10 μg/kg. 
Concurrent Control: 
No concurrent control 
Objectives and Study 
Endpoints: 
Objective:  
The objective of the study is to assess the safety, efficacy, and pharmacokinetics 
(PK) of F-652 in combination with systemic corticosteroids for the treatment of 
newly diagnosed grade II-IV lower GI aGVHD in HSCT recipients. GVHD 
cytokines and biomarkers will be explored. 
Safety Endpoints: 
1. Adverse event (AE) reporting. 
2. Vital sign measurements 
3. Laboratory measurements 
4. Physical Examination 
Primary Efficacy Endpoint: 
To assess the lower GI aGVHD treatment response rate at Day 28. 
Secondary Efficacy Endpoints: 

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liver) will be allowed if grade II-IV lower GI aGVHD is concurrently present. 
Subjects will have an absolute neutrophil count (ANC) ≥500/mm3 and serum 
creatinine ≤3 mg/dL. A biopsy of the GI tract is required for study entry; 
However, results are not needed to initiate treatment. If GVHD is not confirmed 
histologically, treatment with F-652 will be discontinued and the subject will be 
withdrawn and replaced in the study. The severity of aGVHD will be graded 
using the International Bone Marrow Transplant Registry (IBMTR) criteria.  
Duration of Treatment: 
The duration of study treatment will be a total of approximately 4 weeks with a 
screening phase and a post treatment phase. All post treatment visits are 
scheduled after the initial F-652 treatment. 
Clinical assessments will occur during the screening period (up to 5 days), study 
entry (Day 0, first dose of F-652), and on Days 7, 14, 21, 28, 56, 180, and 365. 
Clinical visits will also occur according to the PK sampling schedule.  
PK sampling will occur on dosing Days 0, 7, 14, and 21 as follows (all post-dose 
sampling time points are after the start of the infusion): 
Day 0: 60 min pre-dose and post-dose 30 min, 1 hr, 8 hr, and 72 hrs. 
Days 7 and 14: 60 min pre-dose and post dose 30 min and 72 hrs. 
Days 21: 60 min pre-dose and post-dose 30 min, 1 hr, 8 hr, 24 hrs, 48 hrs, 
72 hrs, and 96 hrs. 
PK sampling will occur during follow-up on Days 28 and 56 as follows: 
Days 28 and 56: during the visit. 
. 
Subject Assignment: 
All eligible subjects will be given open label F-652. There will be no 
randomization in this single arm study. 
Efficacy Assessments: 
The efficacy of F-652 in combination with systemic corticosteroids for the 
treatment of grade II-IV lower GI aGVHD will be assessed by evaluating 
therapy response rate by Day 28.  
Safety Assessments: 
• 
AEs and serious adverse events (SAEs) 
• 
Vital signs 
• 
Clinical laboratory tests (to include hematology, serum chemistry, and 
urinalysis)  
• 
Physical examination 
Data Analyses: 
• 
Safety analysis will be assessed by a review of all safety parameters 
including AEs, SAEs, laboratory safety parameters, and vital signs. 
• 
Efficacy will be evaluated by treatment response along with 
immunosuppressive use and overall survival. In addition, GVHD 
biomarkers and cytokines will be explored. 
• 
Non-compartmental analysis of PK parameters, such as Cmax and AUC will 
be performed. 
Date 
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1 
INTRODUCTION 
1.1 
Acute GVHD and Current Therapy 
Acute graft versus host disease (aGVHD) is a frequent and, at times, unpredictable and severe 
complication of hematopoietic stem cell transplantation (HSCT).2-4 Organs affected in 
GVHD include the skin, liver, and/or the gastrointestinal (GI) tract, and is a common cause of 
transplant-related mortality (TRM).2,5 While calcineurin-inhibitor based GVHD prophylaxis 
has decreased the incidence and mortality associated with aGVHD, it provides inadequate 
protection since this disease commonly affects more than 50% of HSCT recipients.6,7 
Although several clinical factors have been associated with aGVHD risk, such as recipients 
of sex-mismatched HSCT, donor-recipient human leukocyte antigen-mismatch, peripheral 
blood stem cell graft and myeloablative conditioning,8,9 and omission of anti-thymocyte 
globulin (ATG) in the conditioning regimen,10 it is currently unknown which patients will 
develop this complication post-allograft. Ponce et al. demonstrated that GVHD frequently 
occurs after unmodified unrelated donor and cord blood transplantation; the incidence of 
grade II-IV aGVHD at Day 100 was found to be 56% and 55%, respectively.11 GVHD was 
the most common cause of transplant-related death in T-replete and T-cell depleted unrelated 
donor and cord blood transplant recipients. In this study and others, the GI tract was the organ 
most commonly associated with lethal GVHD.12-14 These findings support the investigation 
of new GVHD treatment strategies specifically targeting the GI tract. 
The standard treatment for grade II-IV aGVHD is systemic corticosteroids at a daily dose of 
2 mg/kg.15 However, treatment with systemic corticosteroids is non-target specific and can be 
associated with several and potential life-threatening side effects including lethal infections.16 
Approximately 50% of the patients will not achieve a sustained complete response (CR) to 
therapy with corticosteroids,6 and for those patients who fail to respond or are unable to 
maintain aGVHD control upon tapering corticosteroid therapy, escalation of 
immunosuppressive therapy is necessary.17,18 While several immunosuppressive agents can 
be added for second-line therapy, such as ATG, alemtuzumab, monoclonal antibodies against 
CD3, tumor-necrosis factor (TNF)-α inhibitor and pentostatin,19-24 they are usually associated 
with a very low durable CR rate and profound immunosuppression that may cause severe 
sequelae of infection and abrogation of graft-versus-tumor effect increasing the risk of 
disease relapse or progression.25,26 If clinical response is achieved to these agents, duration of 
remission is typically short. Therefore, survival is poor in corticosteroid-resistant aGVHD 
and approximately only 15% of the patients will be alive after 2 years.27 Thus, the ideal 
treatment of aGVHD is one that can preserve overall immunity and have low risk of infection 
complications while maintaining graft-versus-tumor effect to preserve the protection against 
malignant relapse. 
Better understanding of the mechanisms involved in the development of aGVHD could 
potentially reveal a targeted-specific therapy. Acute GVHD is caused by the allorecognition 
of host antigens by donor lymphocytes. The affected host organs may initially undergo injury 
from the direct toxicity of the conditioning regimen, which also leads to local entry of 
microbial products such as endotoxin or bacterial DNA. This injury and the subsequent 
signals generated by cytokines and microbial products could be the initial trigger for the 
production of further inflammatory cytokines which induce more efficient antigen processing 
and presentation by local dendritic cells (DC). This consequently leads to recruitment and 
activation of alloreactive naïve donor T-cells in secondary lymphoid tissues and proliferation. 
End-organ damage to targeted tissue (GI tract, skin, and liver) is subsequently mediated by 
the direct cytotoxic actions of activated donor effector T-cells as well as the actions of local 
cytokines. In animal models, cytokines up-regulation or down-regulation have been identified 

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as a manifestation of aGVHD.12,28-30 In the GI tract specifically, inflammatory cytokines can 
promote tissue injury causing an alteration of the intestinal stem cell (ISC) and progenitor cell 
niche that may result in gut GVHD.31,32 However, there is currently no treatment available to 
promote the recovery of the epithelial tissue that has been damaged by GVHD. 
GVHD involves complex interactions between innate and adaptive immunity, culminating in 
tissue damage by inflammatory mediators and cellular effectors. Acute GVHD is a 
proinflammatory process mediated in part by donor T-cells. Cytokines and chemokines 
influence T-cell differentiation pathways and trafficking to GVHD target organs and also 
mediate direct tissue damage. Notably, in murine studies, proinflammatory cytokines 
expressed in GVHD have been reported to regulate homing molecule expression on 
alloreactive donor activated T-cells.33-35 At Memorial Sloan Kettering Cancer Center 
(MSKCC), Hanash et al evaluated the effects of interleukin (IL)-21 signaling in donor T-cells 
in a murine model of bone marrow transplant.31 Using IL-21 receptor deficient donor T-cells 
they demonstrated that abrogation of IL-21 signaling led to decreased GVHD mortality and 
GI GVHD pathology. IL-21 receptor deficient T-cells showed decreased gut infiltration and 
reduction in inflammatory cytokine production within the mesenteric lymph nodes. IL-23 has 
similarly been implicated in experimental GI GVHD. This cytokine is produced by antigen 
presenting cells post-bone marrow treatment (BMT),35 and has been reported as a major 
regulator of IL-22 production.36-38 Donor bone marrow deficient in IL-23 reduced GI GVHD 
compared with animals receiving wild-type grafts. In DCs purified from the colon, levels of 
IL-23 and its receptor were elevated, but not at other GVHD target sites. Increased interferon 
(IFN)-γ CD4+ T-cells appear to mediate these inflammatory effects.35 
New insights into the roles played by cytokines in GVHD biology may provide novel targets 
for the prevention and treatment of aGVHD. 
1.1.1 
Recombinant Human IL-22 (F-652) and Reduction of GVHD 
IL-22 is an IL-10-family cytokine produced by innate lymphoid cells (ILCs) and T-cells.39,40 
The IL-22 receptor is present in many epithelial tissues and expression of IL-22 reduces the 
severity of multiple experimental injury models including colitis, hepatitis, and thymic 
radiation injury.41-43 Murine models of allogeneic HSCT have provided clinically relevant 
experimental systems for assessing mechanisms of immune-mediated intestinal damage and 
regeneration.44-46 Hanash et al studied the role of IL-22 in murine gut GVHD.32 They showed 
that intestinal IL-22 can be produced by intestinal lamina propia ILCs post-BMT, but that GI 
GVHD leads to loss of gut ILCs and impaired IL-22 production due to the elimination of 
IL-22 producing cells by the donor immune system. Deficiency of IL-22 led to increased 
GVHD in HSCT recipients (Figure 1). Additionally, mice deficient for IL-22 demonstrated 
increased gut pathology due to GVHD including intestinal crypt apoptosis, depletion of ISCs 
in the small intestine, and loss of epithelial integrity. 

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Pharmacokinetic Endpoints 
• Total exposure (AUC) 
• Cmax 
• Other parameters, such as CL, Vd, and λz maybe estimated. 

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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design  
This Phase IIa open label single arm study will enroll up to 27 subjects to investigate the 
safety, efficacy, and PK of F-652 (recombinant human IL-22) in combination with systemic 
corticosteroids for the treatment of newly diagnosed grade II-IV lower GI aGVHD in HSCT 
recipients. Acute GVHD will be initially diagnosed clinically and staged accordingly.1 
Grading of aGVHD will be based on International Bone Marrow Transplant Registry 
(IBMTR) criteria52. This clinical trial will investigate if the use of F-652 enhances the 
recovery of the GI tract after aGVHD mediated-injury. The safety endpoints of this study are 
to assess the incidence of AEs and SAEs, along with other safety. The primary efficacy 
endpoint is to assess F-652 treatment response at Day 28 in subjects with lower GI aGVHD. 
Candidates for this trial will include subjects ≥18 years and ≤80 years of age who are 
recipients of allogeneic HSCT using bone marrow, peripheral blood stem cells, or umbilical 
cord blood. Subjects must have stage 1-4 aGVHD of the lower GI tract at screening which 
will be determined by the maximum stool output in the preceding 3 days. Subjects with 
concurrent involvement of liver or skin aGVHD will be allowed but not as the sole organ 
affected. Biopsy of the GI tract is required for GVHD confirmation; however, results are not 
needed to initiate treatment. If GVHD is not confirmed histologically, treatment with F-652 
will be discontinued and the subject will be replaced. 
Eligible subjects will be consented and enter the study screening period. During this period, 
screening samples and tests will be obtained. A GI biopsy will be performed (if not done 
prior to study entry) for aGVHD disease histologic confirmation. The first dose of F-652 is to 
occur within 5 days after the subject’s initial administration of systemic corticosteroids. 
The expected duration of treatment for each subject is 4 weeks. F-652 weekly will be 
administered once a week for a total of 4 doses. Study enrollment will begin with 16 subjects 
dosed at 45 μg/kg of F-652. These subjects will be evaluated for treatment response at 
Day 28. If ≤6 of the first 16 subjects demonstrate a treatment response (i.e., response ≥PR), 
the clinical trial will be closed due to a lack of efficacy. If 7 or more subjects of the first 16 
subjects have a treatment response, an additional 11 subjects will be required to complete 
enrollment into the study for a total sample size of 27 patients (Figure 3). 
All subjects will be followed for efficacy through Day 56, safety through Day 180, and 
subject survival status will be collected at Day 365 (1 year from the date of initial dosing of 
F-652). 
Prior to each dosing of F-652, subjects are required to meet the following criteria: ANC 
≥500/mm3, serum creatinine ≤3.0 mg/dl, and all non-hematologic toxicity (except alopecia) 
attributed to the study drug as probable or greater to resolved to ≤ Grade 1 or returned to the 
subject’s baseline condition. Failure to meet these criteria will result in treatment delay, dose 
reduction, or withdrawal from the study, as outlined in Section 3.3.2 (Hold and Stop Rules). 
A review of excess subject mortality at Day 56 will occur for every 6 subjects accrued into 
the study. 
During the course of the study, systemic corticosteroids (prednisone or methylprednisolone 
equivalent) will be administered concurrently with F-652. Tapering of corticosteroids is 
permitted as outlined in Section 5.2 (Treatment Administrations); however, tapering should 
result in no less than 0.25 mg/kg/day of prednisone (or IV equivalent) by Day 28, after which 
tapering may be according to local institutional guidelines. 

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All subjects should be treated to the institutional allogeneic BMT standard of care guidelines 
for prophylaxis against infection. This includes, Pneumocystis carinii, Herpes simplex, 
Herpes Zoster, and fungal infections. Subjects will be closely monitored for cytomegalovirus 
(CMV) reactivation according to the each local center standard practice. 
The study drug will be administered on an inpatient or outpatient basis, depending on the 
subject’s clinical condition. The route of administration of F-652 is IV and will be 
administered once a week on Days 0, 7, 14, and 21. Following infusion of F-652, vital signs 
will be obtained and nursing assessment will be performed according to the BMT 
institutional standard of care. PK sampling will occur as per the schedule listed in Appendix 3 
and serum samples to test the immunogenicity of F-652 will be taken. Subjects will be 
evaluated for grade 3-4 toxicities, graded by the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE). A complete description of the study 
procedures for each clinical visit is presented in Appendix 1. 
GVHD biomarkers will be assessed at baseline and post-treatment. Baseline assessment of 
GVHD markers in the peripheral blood and GI tissue will be performed at the time of GVHD 
diagnosis, pending specimen availability. Due to the extensive processing of the peripheral 
blood for the assessment of GVHD cytokine markers, cytokine samples are optional for 
subjects participating in this study.  The biomarker panel will include ST2 and REG3α 
whereas the cytokine panel will include IL-21, IL-22, and IL-23 levels. A stool sample will 
be collected for intestinal microbiota analysis and GVHD biology, including histology and 
epithelial gene expression, will also be analyzed in biopsy samples from the GI tract as the 
specimen allows. Post-treatment evaluation of GVHD biomarkers/cytokines in the peripheral 
blood, stool sample for intestinal microbiota, and GI tract biopsies will be performed 
approximately 28 days after study drug initiation or at least 3 days after receiving last dose of 
study drug (subject and sample availability permitting). Sampling may be withheld in patients 
who are critically ill. 
A study visit schematic is provided in Figure 4 and a complete schedule of study procedures 
and events are presented in Appendix 2 (Schedule of Procedures and Events). 
 

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3.2 
Rationale for Study Design 
Acute GVHD is a frequent complication following HSCT and a leading cause of TRM. The 
mainstay of treatment of aGVHD is corticosteroids. Although effective for some, the overall 
initial response rate is only 50% which decreases to 42% when the GI tract is affected. GI 
aGVHD produces direct epithelial tissue injury causing intestinal damage and inflammation. 
Murine models have shown that GI aGVHD particularly targets the ISC compartment and 
results in the loss of ILCs. These ILCs produce cytokine IL-22, which mediates a variety of 
protective effects including maintenance of tissue homeostasis, epithelial barrier integrity, 
and inducer of antimicrobial peptides in the GI tract. However, with the loss of ILCs in GI 
aGVHD, the production of IL-22 is impaired. While there is no current approved therapy that 
enhances the recovery of the human intestinal damage caused by aGVHD, treatment with 
IL-22 in vivo has emerged as a novel therapy in murine GI aGVHD. These studies have 
demonstrated that IL-22 administration promoted healing of the GI tract through its trophic 
effects on the intestinal epithelium and increased the ISC recovery. 
This study is designed to determine the efficacy, safety, tolerability, and PK of F-652 in 
subjects with lower GI grade II-IV aGVHD. Based on the safety profile of F-652 observed in 
the Phase I trial and the lack of serious side effects and toxicity observed, this trial has been 
designed for the treatment of lower GI aGVHD with F-652 at a dose of 45 μg/kg in 
combination with systemic corticosteroids. 
All subjects will be dosed with single administration of 45 μg/kg of F-652 weekly for a total 
of 4 doses. Safety of the subjects will be m nitored throughout the study. An assessment of a 
subject’s ability to continue treatment before each dosing of F-652 will be made, with a dose 
reduction permitted (Section 5.2.1.1), as determined by the treating physician. The potential 
benefits of F-652 for the treatment of aGVHD in a clinical setting are to be evaluated in order 
to determine if expansion of F-652 in a clinical program is warranted. The design of this 
study ensures an incremental evaluation of subjects with aGVHD to ensure subject safety. 
3.2.1 
F-652 Dosing  
The dose chosen, 45 μg/kg, was the highest dose of F-652 tested in healthy male subjects 
with a demonstrated tolerable safety profile. The most common TEAEs identified were dry 
skin and eye pruritus. The PK results from the previous study indicated a once a week 
treatment regimen administered for 4 weeks, is appropriate. Study drug preparation is 
detailed in Appendix 4. 
3.3 
Study Duration and Dates 
3.3.1 
Duration of Subject Participation  
The duration of the study participation consists of an initial screening period, followed by 4 
weeks of treatment, and  4 post-treatment clinical visits (Days 28, 56, 180, and Day 365). 
Prior to study admission, there is a screening period of up to 5 days for the completion of the 
study consent form, the collection of medical history, signs and symptoms, laboratory tests, 
and biopsy sampling. After completion of therapy, subsequent evaluations will consist of a 
physical exam, blood tests, aGVHD assessment, and a post-treatment GI biopsy (as permitted 
by subject). 
Subjects will be required to provide samples for the PK and immunogenicity evaluation of 
F-652. PK sampling will occur as per the schedule listed in Appendix 3. 

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3.3.2 
Hold and Stop Rules 
3.3.2.1 
Hold and Discontinuation Rules for the Clinical Trial  
Subjects will be closely monitored for clinical deterioration (i.e., disease progression) by the 
study Investigators, the study Medical Monitor, and the Sponsor’s medical expert. In addition 
to standard toxicities such as alterations in blood chemistries or hematology, this monitoring 
will also include disease progression and treatment efficacy. 
Clinical Trial Termination: 
The study includes stopping criteria in the event that excessive Day 56 TRM is observed. The 
historical rate of TRM deaths is approximately 15-20%.53 A TRM of 40% at Day 56 would 
be considered unexpected and an unacceptable number of excess deaths. TRM is defined as 
death at any time from the commencement of pre-transplant conditioning due to any cause 
other than disease relapse with the exception of automobile or other accidents. 
In this study, there will be an ongoing review for excessive TRM. The study will be stopped 
for interim evaluation if the number of deaths is 3 or more in the first 5 subjects treated, 4 or 
more in the first 9 subjects treated, etc. as per Table 3.3.2.1. This evaluation will occur for the 
subject’s Day 56 visit (post their initial F-652 dosing). Subjects removed from the study due 
to negative biopsy for aGVHD will not be accountable for the mortality rate rule analysis. 
Table 3.3.2.1. Stopping criteria for excessive mortality based on a Pocock boundary. 
Failure Type 
Mortality Rate Rule for 
Study Termination 
Death rate in the 
population 
Probability boundary 
is crossed  
Transplant-Related 
Mortality (day +56)   
3 deaths in the first 5 
subjects treated 
0.15 
0.10 
4 deaths in the first 9 
subjects treated 
5 deaths in the first 13 
subjects treated 
0.40 
0.93 
6 deaths in the first 18 
subjects treated 
7 deaths in the first 23 
subjects treated 
8 deaths at any point   
From Ivanova A, Qaqish BF and Schell MJ (2005).54 
 
3.3.2.2 
Reasons for Subject Study Drug Discontinuation 
A subject may withdraw from the trial at any time at his/her own request, or he/she may be 
withdrawn at any time at the discretion of the Investigator or Sponsor for safety, behavioral, 
or administrative reasons. The list of reasons for subject withdrawal is provided in 
Section 7.9.1.  
3.3.3 
End of Treatment and Follow-up Visits 
All subjects will receive an End of Treatment assessment on Day 28. Subjects withdrawing 
from the study early will have their End of Treatment assessment visit and will be asked to 

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participate in a follow-up phone call. All AEs and concomitant medications will be recorded 
through 28 days after the last dose of study drug (Study Day 56) and only related SAEs (and 
associated concomitant medications)will be recorded through its stabilization, resolution, or 
the end of the study.   
For subjects completing treatment, follow up visits will occur on Days 56, 180, and 365 from 
the first dose of F-652. The 365-day follow up visit will evaluate the subject’s general health 
and aGVHD status. Subjects will be discharged from the study following the Day 365 
Follow-up Visit. 

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4 
STUDY POPULATION SELECTION 
4.1 
Study Population 
The study population will consist of adult male and female subjects aged ≥18 to ≤80 years of 
age with newly diagnosed stage I-IV lower GI aGVHD1 following allogeneic HSCT.  
Eligible subjects must meet all entry criteria prior to receiving study medication, except for 
histologic confirmation of disease, as outlined below. If lower GI aGVHD is not confirmed 
histologically, the subject will be withdrawn from the study and replaced. 
4.2 
Inclusion Criteria 
Each subject must meet the following criteria to be enrolled in this study: 
1. Age ≥18 years and ≤80.  
2. Newly diagnosed stage 1-4 lower GI aGVHD1 with a minimum stool volume 
>500 mL/day (determined by the maximum stool output in the preceding 3 days) 
following allogeneic HSCT using bone marrow or peripheral blood stem cells, or cord 
blood. 
3. Subjects are willing to undergo a biopsy to confirm lower GI aGVHD. Biopsy results are 
not needed to initiate treatment. However, if aGVHD is not confirmed histologically, 
treatment with F-652 will be discontinued. 
4. Female subjects of childbearing potential who: agree to practice 2 effective methods of 
contraception at the same time from the time of signing the informed consent form (ICF) 
through 90 days after the last dose of study drug, OR are postmenopausal for at least 1 
year before the screening visit, OR are surgically sterile, OR agree to practice true 
abstinence when this is in line with the preferred and usual lifestyle of the subject 
(periodic abstinence and withdrawal are not acceptable methods of contraception). 
5. Male subjects, even if surgically sterilized (i.e. status post-vasectomy) must agree to one of 
the following: agree to practice effective barrier contraception during the entire study 
treatment period and through 90 days after the last dose of study drug, OR agree to 
practice true abstinence when this is in line with the preferred and usual lifestyle of the 
subject (periodic abstinence and withdrawal are not acceptable methods of contraception). 
6. Have adequate renal function (Serum creatinine <3 mg/dL). 
7. ANC >500/mm3. 
8. Show evidence of a personally signed and dated informed consent document indicating 
that the subject (or legally acceptable representative) has been informed of all pertinent 
aspects of the trial.  
4.3 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from the study. 
1. Evidence of relapse or progression of hematologic malignancy at the time of study 
enrollment. 
2. Active uncontrolled infection. Subjects with a controlled infection receiving definitive 
therapy for 48 hours prior to enrollment are eligible. 
3. Subjects requiring vasopressors or mechanical ventilation. 
4. Subjects who have received previous systemic corticosteroids for the treatment of acute 
GI GVHD for longer than 5 days. Subjects who were treated with systemic 
corticosteroids for aGVHD for a prior allogeneic HSCT >12 months ago are eligible. 

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5. Subjects who received any corticosteroid therapy (for non-GVHD) at doses 
>0.5 mg/kg/day prednisone (or IV equivalent) within 7 days prior to the onset of GVHD 
therapy. 
6. Subjects who developed aGVHD after unplanned donor lymphocyte infusion. 
7. Subjects with chronic GVHD features (i.e., acute/chronic GVHD overlap syndrome or 
classical chronic GVHD). 
8. History of psoriasis. 
9. History of epithelial malignancies including melanoma or any carcinomas. 
10. History or diagnosis of mantle cell lymphoma or anaplastic large cell lymphoma. 
11. Subject is pregnant or breast-feeding. 
12. Evidence of current uncontrolled cardiovascular conditions, including uncontrolled 
hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, 
unstable angina, or myocardial infarction within the past 6 months. 
13. The subject or guardian is unable to give informed consent or unable to comply with the 
treatment protocol including appropriate supportive care, follow-up, and research tests. 
14. The subject has tested positive for the Clostridium difficile toxin within 7 days of study 
entry. 
15. Cytotoxic, biologic, or investigational agents are not permitted throughout the study. 
These include, but are not limited to, antithymocyte globulin, alemtuzumab, rituximab, 
photopheresis, and thalidomide. Subjects who participated in any other investigational 
drug trial or had exposure to any other investigational agent, device or procedure, within 
4 weeks prior to screening and throughout the entire trial, except for trials of 
investigational drugs administered prophylactically for GVHD or CMV post allogeneic 
HSCT. In this exception, the other investigational drug must be discontinued upon 
enrolling (i.e., screening/sign ICF) into this study. 
16. Any serious medical or psychiatric illness that could, in the Investigator’s opinion, 
potentially interfere with the completion of treatment according to this protocol. 

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action being taken with study medication after the study is completed, the Investigator will 
contact the Sponsor or the contracted research organization for approval of such action. 
5.7 
Selection and Timing of Dose for Each Subject 
Once a subject has met the eligibility criteria, dosing will commence as specified in 
Section 5.2.  
5.8 
Method of Assigning Treatment to Subjects  
Study site personnel will assign the investigational drug to each subject via IWRS. The IWRS 
system will identify which study drug vial is to be used for reconstitution and administered to 
a subject using its unique identification number. 

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6.2.2 
Change from Baseline in Medications  
Systemic corticosteroid therapy may be tapered, as indicated in Section 5.2.2. No tapering of 
systemic immunosuppression will be allowed sooner than Study Day 3. Taper after Study 
Day 3 is allowed at the discretion of the treating physician. The treating physician may adjust 
tacrolimus, CSA, MMF, and sirolimus medications, as necessary. 
6.3 
Restrictions 
6.3.1 
Medications Not Permitted 
Besides those medications specified in the exclusion criteria (see Section 4.3), addition of 
other systemic immunosuppression agents would result in subject withdrawal from the study. 
Cytotoxic, biologic, or investigational agents are not permitted throughout the study. 
6.4 
Treatment Compliance 
Subject compliance will be monitored by obtaining the study medication accountability 
inventory and a record of any delayed doses, along with a list of concomitant medications 
according to the institutional policy, at each visit. 

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7 
STUDY PROCEDURES 
7.1 
Informed Consent 
The Investigator will obtain and document an ICF for each subject screened in this study. 
Prior to the initiation of any study procedures, all subjects will be informed in writing of the 
nature of the protocol and investigational therapy, its possible hazards, and their right to 
withdraw at any time, and will sign a form indicating their consent to participate. The 
subject’s medical records should contain written documentation indicating that informed 
consent was obtained. The ICF must be reviewed and approved by the Investigator’s 
designated Institutional Review Board (IRB)/Independent Ethics Committee (IEC) and by the 
Sponsor. The ICF should include all the elements as outlined in Section 4.8.10 of the ICH 
guideline for GCP (E6). 
7.2 
Medical History 
Medical history will be collected at screening evaluation and clinical symptomatology will be 
assessed by subject interview at each scheduled visit post-initial dose of F-652 therapy. 
Concomitant medications, dose of corticosteroids, illnesses, AEs, and participation in other 
investigational drug studies will also be recorded. If other unscheduled activities are 
performed up to Study Day 56, such as physical examination or laboratory studies, the results 
should be recorded in the subject’s eCRF. 
7.3 
Physical Examination 
Physical examination including height and body weight will be performed at screening. 
Height will be recorded at screening only; if it is not possible to measure height at screening, 
a historical record of height may be used (e.g., height as measured at hospital admission). 
Physical exam will be done on visit Days 0, 28, 56, 180, and 365 post-initial dose of F-652 
therapy. Any change from baseline will be evaluated and assessed by the Investigator. Any 
clinically significant findings from an abbreviated physical exam for any unscheduled visit up 
to Study Day 56, as deemed necessary by medical staff must be included in the eCRFs.  
7.4 
Vital Signs 
Blood pressure, heart rate, body temperature, and respiratory rate will be measured according 
to Appendix 2 (Schedule of Procedures and Events) or following early termination of the 
study.  If multiple vital signs measurements are taken for a subject on the day of a study visit, 
the results of the first vital signs measurement of the day will be recorded on the CRFs. Vital 
signs are to be taken 15 minutes after the start of infusion, at the completion of infusion, and 
1 hour after the end of the infusion for each dose of F-652. 
7.5 
Clinical Laboratory Tests 
Blood will be collected to assess hematology and serum chemistry profiles at screening and 
on Days 0, 7, 14, 21, 28, and 56 as per Appendix 2 (Schedule of Procedures and Events). For 
each subject, all clinical laboratory assessments will be reported in the eCRF. 
Immunogenicity serum samples will be taken on Days 0, 7, 14, 21, 28, and 56, pre-dosing of 
F-652, where applicable. All immunogenicity samples will be shipped to the Sponsor or its 
agent, as directed in the study laboratory manual.  

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7.5.1.2 
Blood Volume 
Total blood volume for all research tests will be approximately 200 mL. 
7.5.2 
Urinalysis 
Urinalysis parameters for clinical laboratory tests will be obtained at screening and Day 28 
and will include the following assessments: 
appearance 
occult blood 
bilirubin 
pH 
glucose 
protein 
ketones 
specific gravity 
leukocyte esterase 
urobilinogen 
7.5.3 
Assessment of aGVHD 
A complete assessment of aGVHD will be conducted at Screening (baseline) and at Study 
Visit Days 7, 14, 21, 28, 56, 180, and 365 post-initial dose of F-652 therapy.  
7.6 
Efficacy Assessments 
The aim of this study is to assess the safety, efficacy, and PK of F-652 in combination with 
systemic corticosteroids for the treatment of newly diagnosed grade II-IV lower GI aGVHD 
in allogeneic HSCT recipients. The efficacy primary endpoint is to assess the lower GI 
aGVHD response rate at Day 28. 
7.6.1 
Methods and Timing for Assessing Acute Graft-Versus-Host Disease (aGVHD) 
Acute GVHD will be diagnosed clinically and staged according to modified Keystone criteria 
(Appendix 5). Grading of aGVHD will be based on IBMTR criteria52 (Appendix 5). Biopsy 
samples will be obtained prior to therapy initiation for confirmation of clinical diagnosis. 
Acute GVHD assessments will be obtained at Screening (baseline) and on Days 7, 14, 21, 28, 
56, 180, and 365 post-initial dose of F-652 therapy.  
Responses to aGVHD therapy will be determined using published definitions6 of GVHD 
response and will be assessed on Days 14, 28, and 56. 
Acute lower GI GVHD Response Criteria: 
Scoring of CR, VGPR, PR, progression, and NR will be in comparison to the participant’s 
lower GI aGVHD stage prior to treatment with F-652. Response will be based on the 
following response definitions: 
• CR: stage of 0 for all aGVHD symptomatology in the lower GI tract with no 
additional intervening aGVHD therapy. 
• VGPR: tolerating food or enteral feeding, predominantly formed stools, no overt GI 
bleeding or abnormal cramping. 
• PR: improvement by at least 1 stage in lower GI aGVHD symptomatology with no 
additional intervening therapy for their GVHD. 
• Progression: deterioration in lower GI tract aGVHD. 
• NR/stable: absence of any improvement in aGVHD stage. Subjects receiving 
secondary therapy (including need to re-escalate corticosteroid dose to 

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≥2.5 mg/kg/day of prednisone (or methylprednisolone equivalent) will be classified 
as non-responders. 
Response for All Organs Involved with aGVHD: 
Treatment response defined as CR, VGPR, PR, MR, progression, and NR will be in 
comparison to the subject’s aGVHD stage prior to treatment with F-652. Response will be 
based on the following response definitions: 
• CR: stage of 0 of all aGVHD symptomatology in all GVHD target organs with no 
additional intervening GVHD therapy. 
• VGPR: tolerating food or enteral feeding, predominantly formed stools, no overt GI 
bleeding or abnormal cramping, no more than occasional nausea or vomiting. 
• PR: improvement in aGVHD stage in all initial GVHD target organs without 
complete resolution and without worsening in any other GVHD target organs 
• MR: improvement in 1 or more GVHD target organs with deterioration in another 
organ manifesting symptoms of aGVHD or development of symptoms of aGVHD 
in a new organ. 
• Progression: worsening of GVHD in at least 1 organ without any improvement in 
others. 
• NR/stable: absence of any improvement in aGVHD stage.  Subjects receiving 
secondary therapy (including need to re-escalate corticosteroid dose to 
≥2.5 mg/kg/day of prednisone [or methylprednisolone equivalent of 2 mg/kg/day]) 
will be classified as non-responders. 
Treatment Failure: 
The following will be considered as treatment failures: 
• NR/stable after 14 days of therapy. 
• Progression after 7 days of therapy. 
• Administration of additional systemic therapy for aGVHD (or re-escalation of 
corticosteroids dose to ≥ 2.5 mg/kg/day of prednisone (or methylprednisolone 
equivalent) 
• TRM 
7.7 
Safety Assessments 
7.7.1 
Standard Safety Parameters 
Standard safety parameters include hematology, blood chemistry, urinalysis, vital signs, 
physical examination, and symptom/toxicity assessment as outlined in Section 7 and 
according to the schedule of events presented in Appendix 2 (Schedule of Procedures and 
Events).  
The NCI CTCAE will be used to grade potential AEs (see Section 7.7.3.3).  

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7.7.2 
Adverse Events Assessments 
7.7.2.1 
Procedures for Eliciting Reports of and Recording Adverse Events and 
Inter-current Illnesses 
The Investigator is to document  on the eCRFall directly observed AEs and all AEs 
spontaneously reported by the trial subject through Study Day 56 (or approximately 28 days 
after last dose of study drug). After Study Day 56, only SAEs deemed possibly, probably, or 
definitely related to the investigational product are required to be recorded through to the end 
of the study (Day 365).   
Each trial subject will be questioned about AEs at each clinic visit. AEs can be discovered by 
observing the subject, questioning the subject objectively, and/or receiving an unsolicited 
complaint from the subject. For all study visits, up to and including a subject’s Day 56 study 
visit,, a history of any AEs occurring since the last visit are to be recorded in the study the 
eCRF pages.  Only SAEs deemed possibly, probably, or definitely related to the 
investigational product are required to be recorded from study Day 56 through to the end of 
the study (Day 365).  Specimens are to be collected for specified laboratory tests as needed 
and results will be reviewed. Physical examinations will be performed as appropriate. 
7.7.2.2 
Timing and Duration of Follow-up of Subjects after Adverse Events 
Reported 
The subject is routinely followed up for 4 weeks after termination of drug dosing for 
identification of potential AEs. Any Grade 3 or 4 AEs or SAE is to be followed until it has 
resolved or stabilized. Sponsor must be advised of all Grade 3 or 4 AEs within one week of 
their identification and of all SAEs within 24 hours of identification. Subjects will be 
followed until the AE resolves or stabilizes. 
7.7.3 
Defining, Grading, and Reporting Adverse Events 
7.7.3.1 
Adverse Events 
All AEs, whether observed by researchers or reported by subjects, regardless of treatment 
group or suspected causal relationship to the investigational product(s), will be documented 
on the AE page(s) of the eCRF up to and including Study Day 56.  After Day 56,  SAEs 
deemed possibly, probably, or definitely related to the investigational product are required to 
be recorded through to the end of the study (Day 365).   
For all AEs, the Investigator must obtain information adequate to determine the cause and 
outcome of the AE and to assess whether it meets the criteria for classification as an SAE, 
which require immediate notification to Sponsor and its designated representative (see 
Section 7.7.3.7). The Investigator is required to assess causality and record that assessment 
on the eCRF. Follow-up of the AE after the date of therapy discontinuation is required if the 
AE or its sequelae persist. Follow-up is required until the event or its sequelae is resolved 
and/or stabilized at a level acceptable to the Investigator and the Sponsor clinician and safety 
officer. 
DEFINITION 
An AE is any occurrence or worsening (from baseline) of an undesirable or unintended sign, 
symptom (including an abnormal laboratory finding), or disease temporally associated with 
the use of a medicinal product, whether or not considered related to the medicinal product. 
Worsening of underlying disease will not be considered to be an AE, since it will be 

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classified as a treatment failure. Pregnancy will not be considered to be an AE, but will be 
collected separately. However if the resultant child has a birth defect, this will be considered 
to be an SAE. 
Throughout the study, the Investigator must record all AEs on the eCRF through Study Day 
56, regardless of the severity or relationship to study medication or procedure. The 
Investigator should treat subjects with AEs appropriately and observe them at suitable 
intervals until the events resolve or stabilize. 
AEs will be regarded as ‘pre-treatment’ if they occur between the Screening Visit (signing of 
ICF) and the time of administration of the first dose of study medication. All events reported 
following the first study medication administration will be recorded as treatment emergent 
AEs (TEAE). AEs that are unresolved at the time of study termination will be followed until 
they resolve or stabilize. 
7.7.3.2 
Serious Adverse Events 
An SAE is defined by federal regulation as any AE occurring at any dose that results in any 
of the following outcomes: 
• Death: A death occurring during the study or which comes to the attention of the 
Investigator during the protocol-defined follow-up after the completion of therapy, 
whether or not considered treatment-related, must be reported. 
• Life-threatening: Any adverse therapy experience that places the subject, in the 
view of the Investigator, at immediate risk of death from the reaction as it occurred. 
• Inpatient hospitalization (i.e. the event required at least a 24-hour hospitalization or 
prolonged hospitalization beyond the expected length of stay). Hospitalization 
admissions and/or surgical operations scheduled to occur during the study period, 
but planned prior to study entry are not considered SAEs if the illness or disease 
existed before the person was enrolled in the trial, provided that it did not 
deteriorate in an unexpected manner during the trial. 
• Persistent or significant disability/incapacity. 
• Congenital anomaly/birth defect. 
 
Additionally, any AEs occurring at any dose that suggests a significant hazard, 
contraindication, side effect, or precaution may be considered an SAE. This includes, but 
may not be limited to any of the following events:  
• Spontaneous abortion or death of the infant within 1 month of birth. 
• An event that required intervention to prevent permanent impairment or damage. 
 
An important medical event that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, 
it may jeopardize the subject and may require medical or surgical intervention to prevent one 
of the outcomes listed above. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
Pregnancy is NOT considered an SAE (see Section 7.7.3.8). 

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SAEs will be collected from the time of study entry until 30 days after completion of the trial 
or 30 days after premature withdrawal of a subject from the trial. 
If an event meets any of the criteria listed above, it must be reported on the eCRFs as an SAE 
regardless of its presumed relationship to the study drug. However, after Study Day 56, only 
SAEs deemed possibly, probably, or definitely related to the investigational product are 
required to be reported through to the end of the study (Day 365). 
7.7.3.3 
Severity and Grading 
Toxicity grades are assigned by the study site to indicate the severity of AEs occurring in 
study participants. To do this, the NCI CTCAE grading system will be used in AE reporting. 
The purpose of using the CTCAE system is to provide a standard language to describe 
toxicities, to facilitate tabulation and analysis of the data, and to facilitate the assessment of 
the clinical significance of all AEs. AEs should be recorded and graded 1 to 5 according to 
the CTCAE grades provided below: 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental Activities of Daily Living (ADL)*. 
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL**. 
Grade 4: Life-threatening consequences; urgent intervention indicated. 
Grade 5: Death related to AE. 
*Activities of Daily Living (ADL):  
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, 
etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden. 
If an AE term cannot be found in the CTCAE, the AE should be graded based on the verbiage 
provided for the grades above. 
7.7.3.4 
Relationship 
The relationship between an AE and an investigational product is determined by the site 
Investigator and recorded on the appropriate eCRF and/or SAE Report Form. The CTCAE 
provides the following descriptors and definitions. (See Table 7.7.3.1.) 
The Investigator’s determination of drug-relatedness (attribution) for each AE should be 
recorded in the source documentation.  
For additional information, please consult the CTCAE and the Common Toxicity Criteria 
Document at the following URL: http://ctep.cancer.gov/reporting/ctc.html. 

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If an SAE occurs, the Generon Safety Officer and/or his/her agent are to be notified within 
24 hours of awareness of the event by the Investigator. In particular, if the SAE is fatal or 
life-threatening, notification must be made to the Generon Safety Officer or his/her agent 
immediately, irrespective of the extent of available AE information. This time frame also 
applies to additional new information (follow-up) on previously forwarded SAE reports. 
In the rare event that the Investigator does not become aware of the occurrence of an SAE 
immediately (e.g., if an outpatient trial subject initially seeks treatment elsewhere), the 
Investigator is to report the event within 24 hours after learning of it and document the time 
of his/her first awareness of the AE. 
For all SAEs, the Investigator is obligated to provide information to the Generon Safety 
Officer and his/her agent in accordance with the time frames for reporting specified above. In 
addition, Generon study clinician or the Generon Safety Officer may request an Investigator 
to obtain specific follow-up information in an expedited fashion. This information may be 
more detailed than that captured on the AE eCRF. This will include a description of the AE in 
sufficient detail to allow for a complete medical assessment of the case and independent 
determination of possible causality. Information on other possible causes of the event, such as 
concomitant medications and illnesses must be provided. In the case of a subject death, a 
summary of available autopsy findings must be submitted as soon as possible to Generon 
Safety Officer and his/her designated representative. 
The Investigator’s causality assessment must be included in all reports of SAEs. An 
Investigator’s causality assessment is the determination of whether there exists a reasonable 
possibility that the investigational product caused or contributed to an AE. If the 
Investigator’s final determination is that causality is unknown and the Investigator cannot 
determine whether the event is related to study drug, then the event will be handled as 
“related to study drug” for reporting purposes. If the Investigator's causality assessment is 
"unknown but not related to study drug", this should be clearly documented on study records. 
In addition, if the Investigator determines the AE is associated with trial procedures, the 
Investigator must record this causal relationship in the source documents and eCRF, as 
appropriate and report such an assessment in accordance with the SAE reporting 
requirements. 
 
It should be noted that the form for collection of SAE information is not the same as the AE 
eCRF. Where the same data are collected, the forms must be completed in a consistent 
manner. For example, the same AE term should be used on both forms. AEs should be 
reported using concise medical terminology on the eCRFs as well as on the form for 
collection of SAE information. 
If a subject begins a new therapy (i.e., is discontinued from the study and completes the end 
of study assessment), the AE reporting period will end at the time of the new treatment is 
started. Death must be reported if it occurs within 30 days after the date of last dose of 
investigational product, irrespective of any intervening treatment. 
Since the study population (patients with aGVHD) is expected to have a relatively high 
background of AEs, anticipated AEs that are serious will not be reported in an expedited 
manner to the FDA, as they are anticipated to occur at a frequency independent of drug 
exposure. Examples include events related to the disease/condition under study (e.g., 
symptoms, disease progression), events unlikely to be related to the underlying disease or 
condition under investigation but common in the study population independent of drug 

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therapy, and events anticipated from any background treatment. These events do not warrant 
expedited reporting as individual cases because it is not possible, based on a single case, to 
determine that there is a reasonable possibility that the drug caused the event. An IND safety 
report will be submitted only if an aggregate analysis indicates that such events are occurring 
more frequently than expected in the drug treatment group. 
7.7.3.8 
Exposure In Utero 
For investigational products within clinical trials and for marketed products, an exposure 
in-utero (EIU) occurs if a female becomes, or is found to be pregnant either while receiving 
or having been exposed to (e.g., environmental toxin) an investigational medication or 
product, or the female becomes or is found to be pregnant after discontinuing and/or being 
exposed to the investigational medication or product. 
If any trial subject becomes or is found to be pregnant while receiving an investigational 
medication/product, the Investigator must submit this information to the Generon Safety 
Officer or sponsor designee (using the SAE reporting contact fax number) on a Pregnancy 
Report Form. This must be done irrespective of whether an AE has occurred, and within 
24 hours of awareness of the pregnancy. 
The information submitted should include the anticipated date of delivery (see below for 
information related to induced termination of pregnancy). 
The Investigator will follow the subject until completion of the pregnancy or until pregnancy 
termination (i.e., induced abortion) and then notify Generon (Shanghai) Corporation Medical 
Officer or Sponsor’s designee of the outcome.  
The Investigator will provide this information as a follow up to the initial Pregnancy Report 
Form. The reason(s) for an induced abortion should be specified. A pregnancy report is not 
created when an ectopic pregnancy report is received since this pregnancy is not usually 
viable. Rather, an SAE is to be submitted with the event of ectopic pregnancy. 
If the outcome of the pregnancy meets the criteria for immediate classification as a SAE (i.e., 
spontaneous abortion, stillbirth, neonatal death, or congenital anomaly [including that in an 
aborted fetus, stillbirth or neonatal death]), the Investigator should follow the procedures for 
reporting SAEs. 
In the case of a live birth, the “normality” of the newborn can be assessed at the time of birth 
(i.e., no minimum follow-up period of a presumably normal infant is required before a 
Pregnancy Report Form can be completed). The “normality” of an aborted fetus can be 
assessed by gross visual inspection, unless pre-abortion test findings are suggestive of a 
congenital anomaly. 
Additional information about pregnancy outcomes that are classified as SAEs follows: 
• “Spontaneous abortion” includes miscarriage and missed abortion. 
• All neonatal deaths that occur within 1 month of birth should be reported, without 
regard to causality, as SAEs. In addition, any infant death after 1 month that the 
Investigator assesses as possibly related to the in utero exposure to the investigational 
medication should be reported. 

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7.7.4 
Toxicity (Adverse Event) Management 
Subjects should receive full supportive care per institutional guidelines including blood 
products, antibiotics, and antiemetics at the discretion of the provider. Suggested guidelines 
for potential toxicities are detailed in the subsections below, including when and how long 
study drug should be withheld and when subjects should be discontinued from the study.  
Re-initiation of the study drug that was withheld cannot occur until drug-related toxicity 
(probably or definitely related) decreases to ≤grade 1 or baseline condition. Subjects who 
require >14 days recovering from a potential drug-related toxicity will be taken off study 
treatment. Dose modification or delay may occur in the setting of lower grade toxicity if the 
Investigator believes that is in the interest of a subject safety. In the event of a grade 1-2 toxic 
event, re-treatment with F-652 is permitted in the presence of the toxicity. 
If a probably related or definitely related AE occurs again after resumption of study drug, 
subject will hold drug until resolution to ≤grade 1 or baseline condition and then resume 
study drug at a reduce dose as outlined in Table 7.7.4.3Error! Reference source not found.. 
If resolution of an initial AE takes >7 days but <14 days and has no other explanation, then 
the study drug will be restarted at a reduced dose upon resolution ≤grade 1 or baseline 
condition. If resolution of an initial AE takes >7 days and has an alternative explanation not 
related to study, F-652 may be restarted at the original dose at the discretion of the 
Investigator. If resolution of an initial AE takes >14 days and has no other explanation, then 
the subject will be removed from the study treatment.  
Study drug will be held immediately at the identification of a study-related SAE. If an SAE 
resolves to CTCAE ≤grade 1 or baseline in <7 days, then a subject may resume study drug at 
the original dose. If an SAE does not resolve but is determined to be unrelated to study drug, 
treatment can be restarted at the original dose at the discretion of the Investigator.  
7.7.4.1 
Hematologic Toxicity 
Blood counts should be checked at each treatment visit. Granulocyte colony stimulating 
factor (G-CSF) is not routinely included in the care of these subjects but can be used at the 
discretion of the Investigator. G-CSF treatment is strongly recommended if ANC 
<1000 mm3.  
No primary prophylactic use of white blood cell growth factor support is recommended, but 
may be used as secondary prophylaxis at the discretion of the Investigator. 
Hematology toxicity related to F-652 treatment should be managed as outlined in 
Table 7.7.4.1Error! Reference source not found.. 
Table 7.7.4.1. Hematology Toxicity Management 
Blood Counts (ANC/mm3) 
Administer % of Full Dose 
>500 
100% 
<500 and subject afebrile (temp <38.0ºC) 
Hold F-652 and give G-CSF support. Give 100% of dose 
once ANC >500 mm3. 
<500 and subject febrile (>38ºC) 
Hold F-652. Treatment of neutropenic fever per institutional 
guidelines. Restart at full dose after 1 week if ANC 
>500 mm3 (G-CSF support is allowed). 
 

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7.7.4.2 
Skin Toxicity 
Skin dryness was the most common side effect reported with F-652 use. Skin erythema was 
also observed, but was less common. Baseline skin findings including rash should be 
documented prior to initiation of each treatment dose. Given that the differential diagnosis 
also includes skin aGVHD, histologic evaluation is recommended for assessment of etiology 
at any grade of presentation. Skin toxicity related to F-652 treatment is to be managed as 
outlined in Table 7.7.4.2Error! Reference source not found.. 
Table 7.7.4.2. Skin Toxicity Management 
Skin Rash 
Administer % of Full DoseF-652 dose 
Comments 
Grade 1 
100% 
Obtain skin biopsy, start topical 
corticosteroids and/or moisturizer 
Grade 2 
Scattered but not 
generalized erythema  
100% 
Obtain skin biopsy, start topical 
corticosteroids and/or moisturizer 
Grade 3 
Generalized 
erythroderma, ulcerative 
dermatitis or skin 
changes with pain 
interfering with function  
Withhold dose until toxicity is <Grade 1 
or has returned to baseline. If subject has 
a second grade 3 toxicity or if resolution 
of the first takes >7 days, withhold dose 
until toxicity is <grade 1, then reduce dose 
by one dose level and resume treatment. 
Obtain skin biopsy. 
If a 3rd Grade 3 event occurs, 
subjects will be discontinued from 
the study. 
Grade 4 
Life-threatening, 
disabling 
Withhold dose until toxicity is <grade 1, 
then reduce dose by one dose level and 
resume treatment, or discontinue at the 
discretion of the PI after discussion with 
treating physician. 
Obtain skin biopsy.  
If a 2nd Grade 4 event occurs, 
subjects will be discontinued from 
the study. 
 
7.7.4.3 
Other Toxicities 
All other Grade 3-4 toxicities (except hematologic and skin) considered probably or 
definitely related to F-652 should be managed as outlined in Table 7.7.4.3Error! Reference 
source not found.. 
Table 7.7.4.3. Other Toxicity Management 
Toxicity 
Administer % of Full DoseF-652 dose 
Comments 
Grade 1 
100% 
 
Grade 2 
100% 
 
Grade 3 
Withhold dose until toxicity is <grade 1 or has returned 
to baseline. If subject has a second grade 3 toxicity or 
if resolution of the first takes >7 days, withhold dose 
until toxicity grade is <1, then reduce dose by one dose 
level and resume treatment. 
If a 3rd Grade 3 event occurs, 
subjects will be discontinued 
from the study. 
Grade 4 
Withhold dose until toxicity is <grade 1 or has returned 
to baseline, then reduce dose by one dose level and 
resume treatment, or discontinue at the discretion of the 
PI after discussion with treating physician. 
If a 2nd Grade 4 event occurs, 
subjects will be discontinued 
from the study. 
 

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7.8 
Concomitant Medication Assessments 
All concomitant medications (over the counter or prescribed) taken by subjects during the 
screening period and throughout the duration of the study will be documented in the patient’s 
medical/source records. Concomitant medications are to be recorded in the eCRFs as 
described below, up to Study Day 56. Common medications typical for treatment of aGVHD 
and/or transplant are to be documented on the “Common aGVHD/Transplant Medications” 
eCRF and will include the medication name and start/stop date of the medication regardless 
of dose changes. All other medications not common to aGVHD/transplant therapy are to be 
documented on the “Concomitant Medication” eCRF page and must include medication 
name, indication (reason for use), start/stop date, dose, route, and frequency. 
After Study Day 56, only concomitant medications related to a SAE will be documented on 
the eCRFs. 
7.9 
Removal of Subjects from the Trial or Study Drug 
A subject may withdraw from the trial at any time at his/her own request, or he/she may be 
withdrawn at any time at the discretion of the Investigator or Sponsor for safety, behavioral, 
or administrative reasons. The Investigator will document the reason for a subject’s 
withdrawal from the study. 
7.9.1 
Criteria for Subject Withdrawal 
The following are criteria for subject discontinuation from the study: 
1. Subject withdraws study consent.  
2. Subject is found to be ineligible for the protocol as per the Inclusion/Exclusion criteria. 
3. Subject’s lower GI acute GVHD is not confirmed histologically. 
4. Subject has aGVHD progression after 7 days of therapy (dose 2) or at any subsequent 
point or NR/stable aGVHD after 14 days of therapy (dose 3). The Investigator may 
withdraw the subject from the study and treat the subject per the standard of care.  
5. Subject requires more than 2 investigational drug (F-652) dose reductions. 
6. Failure of the subject to comply with protocol requirements. 
7. Subject is initiated on protocol-prohibited medications. 
8. Exhibition of unacceptable toxicity (adverse event), which would make it difficult or 
dangerous to comply with further protocol requirements such as study visits, blood draws, 
etc. 
9. Subject experiences an acute infection that is either not identified or controlled by the 
next scheduled infusion. 
10. Subject develops serious infusion reaction (such as bronchospasm with wheezing or 
requires ventilatory support) or serum sickness-like reactions manifesting 1 to 14 days 
after drug administration. 
11. Subject experiences a recurrent Grade 4 AE related to study treatment. 
12. Subject develops malignancy, including skin cancer or relapse of the disease for which 
the allogeneic HSCT was performed. 
13. Subject requires tapering of systemic corticosteroids (<2 mg/kg/day) before Study Day 3. 
14. Subject requires an increase in their current immunosuppression therapy or the addition of 
systemic immunosuppression therapies due to active aGVHD. 
15. There are changes in medical status of the subject such that the Investigator believes that 
subject safety will be compromised or that it would be in the best interest of the subject to 
stop participation in the study. 

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16. Death of the subject. 
17. Subjects with a test consistent with pregnancy such as a positive beta-hCG. 
18. Subject is lost to follow-up. 
7.9.2 
Procedures for Subject Withdrawal 
At the time of study withdrawal, subjects, if capable, will be asked to complete all of the 
procedures that would normally be performed at the Day 28 (End of Treatment) assessment. 
Collection of research/exploratory samples is at the discretion of the Investigator. If the End 
of Treatment Visit for early withdrawal overlaps with another study visit (within 1-2 days), 
only one set of laboratory and research samples will be collected during the visit. If the End 
of Treatment Visit occurs between regularly planned study visits, a 1-2 day window is 
allowed for the visit and sample collection relative to the withdrawal date. All assessments 
for the visit must be completed and samples collected prior to the subject starting a new 
treatment. Withdrawn subjects will have a 30-day follow-up phone call after their last clinical 
assessment. 
7.9.3 
Replacements for Withdrawn Subjects 
Subjects withdrawn from the study due to a failure of aGVHD histologic confirmation will be 
replaced. 
7.9.4 
Follow-Up of Withdrawn Subjects 
At the time of withdrawal from study, the reasons for the withdrawal should be ascertained 
and recorded. If it is for a medical procedure, the outcome should be recorded. 
If the subject withdraws consent to continue in the study, the subject will be requested at a 
minimum to participate in a post-treatment follow-up phone call (30 days after the last dose). 
If the subject declines, no further evaluations are to be performed and no attempts should be 
made to contact the subject or collect additional data. If the subject is withdrawn from the 
study prior to initiation of the study drug, no follow-up will be conducted. 
If a subject does not return for scheduled visits, every effort should be made to re-establish 
contact. Attempts made to reach the subject should be clearly documented. If the subject 
cannot be contacted, every effort should be made to document subject outcome as far as 
possible.  
7.9.5 
Documentation 
For any subject who withdraws, the date and the reason for the withdrawal must be recorded 
on the appropriate eCRF. 

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8 
QUALITY CONTROL AND ASSURANCE 
During trial conduct, Generon or its agents will conduct periodic monitoring visits to ensure 
that the protocol and GCP are being followed. The monitors may review source documents to 
confirm that the data recorded on eCRFs are accurate. The investigators and institutions will 
allow Generon’s monitors or its agents and appropriate regulatory authorities direct access to 
source documents to perform this verification. 
The trial sites may be subject to review by the IRB/IEC, quality assurance audits performed 
by Generon, and/or inspection by appropriate regulatory authorities from the US or other 
countries. 
Investigators and their relevant personnel must be available during the monitoring visits and 
audits or inspections. Sufficient time must be devoted to these inspections. 
The Investigator is required to keep accurate records to ensure the conduct of the study is 
fully documented. The Investigator is required to ensure that all eCRFs are complete and 
accurate for every subject entered in the trial. 
The Sponsor is responsible for regular inspection of the conduct of the trial, for verifying 
adherence to the protocol, and for confirming the completeness, consistency, and accuracy of 
all documented data. 

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9 
PLANNED STATISTICAL METHODS 
9.1 
General Considerations 
Detailed methodology for summary and statistical analyses of the data collected in this trial 
will be documented in a Statistical Analysis Plan (SAP), which will be signed and maintained 
by the Sponsor. This document will expand upon and may modify the plans outlined in the 
protocol; however, any major modifications of the primary endpoint definition and/or its 
analysis will also be reflected in a protocol amendment. In this exploratory Phase IIa study, 
all statistical tests will be two-sided with no adjustment for multiplicity.  
Descriptive summaries of variables will be provided where appropriate. For continuous 
variables, the number of non-missing values (n) and the median, mean, standard deviation, 
minimum, and maximum will be summarized. For categorical variables, the number and 
percent of each variable will be summarized. All collected data will be presented in listings. 
9.2 
Determination of Sample Size 
As described in Section 9.6.1, this study is designed to distinguish between an unpromising 
Day+28 treatment response rate of 35% and a promising treatment response rate of 60% 
using a Simon’s two-stage optimal design. With a maximum sample of 27 patients, this study 
has a type I error of 0.10 and a type II error of 0.10. 
9.3 
Analysis Populations  
Three study populations are defined for the study: a Safety Population, an Efficacy Evaluable 
Population, and a PK Population. Additional study populations may be defined to further 
explore study data. Any additional study populations will be defined in either the SAP or in 
the final clinical study report. 
9.3.1 
Safety Population 
All enrolled subjects receiving any study treatment will be included in the Safety analysis set, 
which will be used for all safety analyses. 
9.3.2 
Efficacy Evaluable Population  
All subjects who receive study treatment and provide at least one post-treatment assessment 
for aGVHD treatment response will be included in the Efficacy Evaluable Population, which 
will be used for all efficacy analyses. Missing aGVHD treatment response will be imputed as 
non-response for this analysis. 
9.3.3 
Pharmacokinetic Population 
All subjects who receive study treatment and provide sufficient samples for PK parameter 
estimation will be included in the PK Population, which will be used for all PK analyses. 
Subjects who have reported protocol deviations, which may have a significant impact on the 
estimation of the PK parameters, will be removed from the PK population. Subjects with 
partial serum concentration data will be evaluated to determine whether sufficient data is 
available for meaningful analysis. 

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9.4 
Demographics and Baseline Characteristics 
All baseline subject characteristics and demographic data (including age, height, weight, race, 
ethnicity), medical history, physical examination (abnormalities only), and prior/concomitant 
medications will be listed for all subjects. Demographic data will be summarized and 
tabulated. 
9.5 
Study Endpoints 
Study endpoints are provided in Section 2.2. 
9.6 
Statistical Methods  
9.6.1 
Safety Analysis 
Safety will be assessed based on AE reporting, physical examination, vital sign measurement, 
and clinical laboratory test results.  
AEs will be tabulated by body system and preferred term according to a standardized 
thesaurus (Medical Dictionary for Regulatory Activities [MedDRA]). The severity of AEs 
will be classified using the NCI-CTCAE toxicity scale as detailed in Section 7.7.3.3. 
Summaries will be provided in separate tables for SAEs, treatment-related AEs, and AEs 
leading to study discontinuation. AEs will also be summarized by maximum severity and 
relationship to the study drug for each treatment group and overall.  
Concomitant medications including baseline medications will be tabulated by subject with 
drug category and preferred term. 
Physical examination findings will be provided as subject listings. Descriptive statistics for 
vital sign measurements, by treatment and time (after dose) will be provided. Hematological 
data and blood chemistry will be graded according to NCI CTCAE severity grade. Shift 
tables from the screening visit to the end of study visit will be presented for clinical 
laboratory measurements (serum chemistry, hematology, and urinalysis). 
9.6.2 
Primary Efficacy Analysis 
The primary endpoint of aGHVD treatment response rate 28 days following the initiation of 
therapy will be reported as the proportion of subjects who provide a response as defined in 
Appendix 6. 
9.6.3 
Secondary Efficacy Analysis 
Secondary efficacy endpoints will be analyzed as follows: 
1. Response to therapy will be explored by examining the proportion of subjects with a 
CR, VGPR, PR or have NR/stable or progression of lower GI aGVHD 
symptomatology at 14 and 56 days post treatment initiation. 
2. Overall aGVHD response to therapy will be explored by examining the proportion of 
subjects with a CR, VGPR, PR, MR, NR/stable or who have progression of aGVHD at 
Days 14, 28, and 56 post-treatment initiation. 
3. The proportion of subjects who have stopped immunosuppressive medication at 
Day 180 and 1 year will be estimated. 
4. Immune recovery will be evaluated through the B and T lymphocytes recovery and 
will be measured on Study Days 0 and 28 post-initial dose of F-652. Graphical and 
summary measures will be used to describe the CD3+CD4+, CD3+CD8+, and CD19+ 
populations. 

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10 ADMINISTRATIVE CONSIDERATIONS 
10.1 Investigators and Study Administrative Structure 
The PI and study staff has the responsibility of maintaining a comprehensive and centralized 
filing system containing all study-related documentation. These files must be available for 
inspection by the sponsor, representatives of the sponsor, the IRB/IEC, and regulatory 
authorities (i.e., FDA or international regulatory authorities) at any time, and should consist 
of the following elements: 
• Subject files, supporting source documentation from the medical record including 
laboratory data and the ICF. 
• Regulatory files, containing the protocol with all amendments and Investigator signature 
pages, copies of all other regulatory documentation, and all correspondence between the 
site and the IRB/IEC and Sponsor; and drug accountability files, including a complete 
account of the receipt and disposition of the study medication (test article). 
Records are to be available for 2 years after marketing application approval, or if the 
application is not approved or never submitted, 2 years after the last shipment and delivery of 
the material and the appropriate competent regulatory authorities are notified. The Sponsor 
will provide written notification when it is appropriate for the Investigator to discard the 
study-specific documents referenced above. 
10.2 Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
Approval 
It is the responsibility of the Investigator to obtain prior approval of the trial protocol, 
protocol amendments, ICFs, and other relevant documents (e.g., advertisements) if 
applicable, from the IRB/IEC. All correspondence with the IRB/IEC should be retained in the 
Investigator File. Copies of IRB/IEC approvals should be forwarded to Generon or its 
designees. 
The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects. In that 
event, the Investigator must notify the IRB/IEC and Generon or its designees in writing 
within 5 working days after the implementation. 
10.3 Ethics 
10.3.1 
Treatment Considerations 
The final study protocol, including the final version of the ICF, must be approved or given a 
favorable opinion in writing by an IRB or IEC as appropriate. The Investigator must submit 
written approval to the Sponsor or its designee before he or she can enroll any subject into the 
study. 
The PI is responsible for informing the IRB or IEC of any amendment to the protocol in 
accordance with local requirements. In addition, the IRB or IEC must approve all advertising 
used to recruit subjects for the study. The protocol must be re-approved by the IRB or IEC 
upon receipt of amendments and annually, as local regulations require. 

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The PI is also responsible for providing the IRB/IEC with reports of any reportable serious 
adverse drug reactions from any other study conducted with the investigational product. The 
Sponsor or its designee will provide this information to the PI. 
Progress reports and notifications of serious adverse drug reactions will be provided to the 
IRB or IEC according to local regulations and guidelines. 
10.3.2 
Ethical Conduct of the Study 
The trial will be performed in accordance with the protocol, International Conference on 
Harmonisation (ICH) GCP guidelines, and applicable local regulatory requirements and laws. 
10.4 Subject Information and Consent 
The ICF must be agreed to by Generon and the IRB/IEC and must be in compliance with 
ICH-GCP, local regulatory requirements, and legal requirements. 
The Investigator must ensure that each trial subject, or his/her legally acceptable 
representative, is fully informed about the nature and objectives of the trial and possible risks 
associated with participation. The Investigator will obtain written ICF each subject or the 
subject's legally acceptable representative before any study-specific activity is performed. 
The ICF used in this trial, and any changes made to it during the course of the trial, must be 
approved by both the IRB/IEC and Sponsor before use. The Investigator will retain a copy of 
each subject's signed consent form. 
A Sponsor recommended sample informed consent form will be provided to the 
investigational site as a separate document. Modifications to the consent required by ethics 
committee/IRB should be reviewed by the Sponsor. 
10.5 Subject Confidentiality 
All information obtained during the conduct of the study with respect to the subjects’ state of 
health will be regarded as confidential. This is detailed in the written information provided to 
the subject. An agreement for disclosure of any such information will be obtained in writing 
and is included in both copies of the ICF signed by the subject. The study data shall not be 
disclosed to a third party without the written consent of the sponsor. 
10.6 Study Monitoring 
The Sponsor or a sponsor representative will visit the study center periodically to monitor 
adherence to the protocol, compliance with ICH guidelines, adherence to applicable 
regulations, and the maintenance of adequate and accurate clinical records. eCRFs will be 
reviewed to ensure that key safety and efficacy data are collected and recorded as specified 
by the protocol. The monitor will be permitted to access subjects’ complete medical records, 
laboratory data, and other source documentation as needed to monitor the trial appropriately. 
10.7 Case Report Forms and Study Records 
Each site is responsible for collecting and maintaining the source documentation describing 
the clinical information.  
eCRFs are required and should be completed in a timely manner for each included subject. 
The completed original eCRFs are the sole property of Generon and should not be made 

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available in any form to third parties, except for authorized representatives of Generon or 
appropriate regulatory authorities, without written permission from Generon. 
It is the Investigator's responsibility to ensure completion and to review and approve all 
eCRFs. eCRFs must be signed by the Investigator or by an authorized staff member. These 
signatures serve to attest that the information contained on the eCRFs is correct and 
complete. At all times, the Investigator has final personal responsibility for the accuracy and 
authenticity of all clinical and laboratory data entered on the eCRFs. Subject source 
documents are the physician's subject records maintained at the trial sites. In most cases, the 
source documents will be the hospital's or the physician's charts. In cases where the source 
documents are the hospital or the physician's charts, the information collected on the eCRFs 
must match those charts. 
All information recorded in the electronic Case Report Forms must be documented in the 
source document. To leave as is implies that the Investigator may document directly into the 
eCRF and not record in the clinic record. If a policy or standard operating procedure requires 
the present language, it must be specified what information can be documented directly into 
the eCRF. 
10.7.1 
Electronic Case Report Forms 
eCRFs are to be completed using the iDataFax electronic data capture system. Sites will 
receive training and guidelines for appropriate eCRF completion.  
All eCRFs should be completed by designated, trained, data entry personnel or the study 
coordinator as appropriate. The eCRF should be reviewed and electronically signed and dated 
by the Investigator. 
In addition, at the end of the study, the Investigator will receive subject data for his or her site 
in a read-only format on a compact disc that must be kept with the study records. 
10.8 Protocol Interpretation and Compliance 
To ensure accurate interpretation and implementation of the study, the procedures and 
endpoints defined in the protocol will be carefully reviewed by the PI and his or her staff 
prior to the time of study initiation. The Sponsor and PI will follow all reasonable means to 
resolve any differences of opinion of matters of eligibility, toxicity and other endpoints. In 
the event that a resolution cannot be reached then one or both parties may seek to terminate 
the study following the provisions outlined in the Clinical Trials Agreement. 
10.9 Access to Source Documentation 
The PI and the Investigator’s institution must permit trial-related monitoring, audits, IRB/IEC 
review, and regulatory inspections by providing direct access to source data/documents. 
10.10 Data Generation and Analysis 
The eCRF data will be verified by a series of computerized edit checks, and all relevant data 
queries will be resolved on an ongoing basis. When the eCRFs are complete, they will be 
reviewed and signed by the Investigator. All elements of data entry (i.e., time, date, verbatim 
text, and the person performing the data entry) are recorded in an electronic audit trail to 
allow all data changes in the database to be monitored and maintained in accordance with 
federal regulations. 

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10.11 Records Retention and Retention of Data 
To enable evaluations and/or audits from regulatory authorities or Generon, the Investigator 
agrees to keep complete records, including the identity of all participating subjects (sufficient 
information to link records, e.g., eCRFs and hospital records), all original signed ICFs, copies 
of all eCRFs, source documents, and detailed records of treatment disposition. The records 
must be retained by the Investigator according to ICH and local regulations as well as the 
Clinical Trials Agreement. 
If the Investigator relocates, retires, or for any reason withdraws from the trial, Generon 
should be notified in advance. The trial records must be transferred to an acceptable designee, 
such as another Investigator, another agreed-upon institution, or to Generon. The Investigator 
must obtain written permission from Generon before disposing of any records, even if 
retention requirements have been met. 
10.12 Financial Disclosure 
The Sponsor, Generon, will provide adequate insurance for trial conduct.  
10.13 Publication and Disclosure Policy 
Publication of study results is discussed in the Clinical Trials Agreement. All publications to 
be submitted to scientific journals or presentations to be given at scientific meetings must be 
submitted to the Generon (Shanghai) Corporation at least one month prior to submission. 
Planned presentations must include all slides. This includes presentations given at the 
presenter’s own institution (such as Grand Rounds). However, presentations given to the 
study team are not required to be approved in advance. 

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17. Deeg HJ. How I treat refractory acute GVHD. Blood. 2007;109(10):4119-4126. 
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clinical trial of ABX-CBL versus ATG as secondary therapy for steroid-resistant acute 
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20. Van Lint MT, Milone G, Leotta S, et al. Treatment of acute graft-versus-host disease with 
prednisolone: significant survival advantage for day +5 responders and no advantage for 
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21. Gomez-Almaguer D, Ruiz-Arguelles GJ, del Carmen Tarin-Arzaga L, et al. 
Alemtuzumab for the treatment of steroid-refractory acute graft-versus-host disease. Biol 
Blood Marrow Transplant. 2008;14(1):10-15. 
22. Anasetti C, Martin PJ, Storb R, et al. Treatment of acute graft-versus-host disease with a 
nonmitogenic anti-CD3 monoclonal antibody. Transplantation. 1992;54(5):844-851. 
23. Busca A, Locatelli F, Marmont F, Ceretto C, Falda M. Recombinant human soluble tumor 
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2007;82(1):45-52. 
24. Alam N, Atenafu EG, Tse G, et al. Limited benefit of pentostatin salvage therapy for 
steroid-refractory grade III-IV acute graft-versus-host disease. Clin Transplant. 
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25. Martin PJ, Schoch G, Fisher L, et al. A retrospective analysis of therapy for acute graft-
versus-host disease: secondary treatment. Blood. 1991;77(8):1821-1828. 
26. Soiffer RJ, Lerademacher J, Ho V, et al. Impact of immune modulation with anti-T-cell 
antibodies on the outcome of reduced-intensity allogeneic hematopoietic stem cell 
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27. Westin JR, Saliba RM, De Lima M, et al. Steroid-Refractory Acute GVHD: Predictors 
and Outcomes. Adv Hematol. 2011;2011:601953. 
28. Hill GR, Crawford JM, Cooke KR, Brinson YS, Pan L, Ferrara JL. Total body irradiation 
and acute graft-versus-host disease: the role of gastrointestinal damage and inflammatory 
cytokines. Blood. 1997;90(8):3204-3213. 
29. Reddy P, Negrin R, Hill GR. Mouse models of bone marrow transplantation. Biol Blood 
Marrow Transplant. 2008;14(1 Suppl 1):129-135. 
30. Robb RJ, Hill GR. The interferon-dependent orchestration of innate and adaptive 
immunity after transplantation. Blood. 2012;119(23):5351-5358. 
31. Hanash AM, Kappel LW, Yim NL, et al. Abrogation of donor T-cell IL-21 signaling 
leads to tissue-specific modulation of immunity and separation of GVHD from GVL. 
Blood. 2011;118(2):446-455. 
32. Hanash AM, Dudakov JA, Hua G, et al. Interleukin-22 Protects Intestinal Stem Cells 
from Immune-Mediated Tissue Damage and Regulates Sensitivity to Graft versus Host 
Disease. Immunity. 2012;37(2):339-350. 
33. Schmaltz C, Alpdogan O, Muriglan SJ, et al. Donor T cell-derived TNF is required for 
graft-versus-host disease and graft-versus-tumor activity after bone marrow 
transplantation. Blood. 2003;101(6):2440-2445. 
34. Kappel LW, Goldberg GL, King CG, et al. IL-17 contributes to CD4-mediated graft-
versus-host disease. Blood. 2009;113(4):945-952. 
35. Das R, Chen X, Komorowski R, Hessner MJ, Drobyski WR. Interleukin-23 secretion by 
donor antigen-presenting cells is critical for organ-specific pathology in graft-versus-host 
disease. Blood. 2009;113(10):2352-2362. 
36. Zheng Y, Danilenko DM, Valdez P, et al. Interleukin-22, a T(H)17 cytokine, mediates IL-
23-induced dermal inflammation and acanthosis. Nature. 2007;445(7128):648-651. 
37. Kreymborg K, Etzensperger R, Dumoutier L, et al. IL-22 is expressed by Th17 cells in an 
IL-23-dependent fashion, but not required for the development of autoimmune 
encephalomyelitis. J Immunol. 2007;179(12):8098-8104. 
38. Cella M, Fuchs A, Vermi W, et al. A human natural killer cell subset provides an innate 
source of IL-22 for mucosal immunity. Nature. 2009;457(7230):722-725. 
39. Sonnenberg GF, Fouser LA, Artis D. Border patrol: regulation of immunity, 
inflammation and tissue homeostasis at barrier surfaces by IL-22. Nat Immunol. 
2011;12(5):383-390. 
40. Sanos SL, Diefenbach A. Innate lymphoid cells: from border protection to the initiation 
of inflammatory diseases. Immunol Cell Biol. 2013;91(3):215-224. 
41. Zheng Y, Valdez PA, Danilenko DM, et al. Interleukin-22 mediates early host defense 
against attaching and effacing bacterial pathogens. Nat Med. 2008;14(3):282-289. 

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42. Sawa S, Lochner M, Satoh-Takayama N, et al. RORgammat+ innate lymphoid cells 
regulate intestinal homeostasis by integrating negative signals from the symbiotic 
microbiota. Nat Immunol. 2011;12(4):320-326. 
43. Sabat R, Ouyang W, Wolk K. Therapeutic opportunities of the IL-22-IL-22R1 system. 
Nat Rev Drug Discov. 2014;13(1):21-38. 
44. Shlomchik WD. Graft-versus-host disease. Nat Rev Immunol. 2007;7(5):340-352. 
45. Ferrara JL, Levine JE, Reddy P, Holler E. Graft-versus-host disease. Lancet. 
2009;373(9674):1550-1561. 
46. Blazar BR, Murphy WJ, Abedi M. Advances in graft-versus-host disease biology and 
therapy. Nat Rev Immunol. 2012;12(6):443-458. 
47. Lindemans CA, Mertelsmann AM, O’Connor MH, et al. Interleukin-22 Is an Intestinal 
Stem Cell Growth Factor, and IL-22 Administration in Vivo Reduces Morbidity and 
Mortality in Murine GVHD. Blood. 2015; 124(21):651a. 
48. Takashima S, Kadowaki M, Aoyama K, et al. The Wnt agonist R-spondin1 regulates 
systemic graft-versus-host disease by protecting intestinal stem cells. J Exp Med. 
2011;208(2):285-294. 
49. Jenq RR, Ubeda C, Taur Y, et al. Regulation of intestinal inflammation by microbiota 
following allogeneic bone marrow transplantation. J Exp Med. 2012;209(5):903-911. 
50. Eriguchi Y, Takashima S, Oka H, et al. Graft-versus-host disease disrupts intestinal 
microbial ecology by inhibiting Paneth cell production of alpha-defensins. Blood. 
2012;120(1):223-231. 
51. Barker N, van Oudenaarden A, Clevers H. Identifying the stem cell of the intestinal crypt: 
strategies and pitfalls. Cell Stem Cell. 2012;11(4):452-460. 
52. Rowlings PA, Przepiorka D, Klein JP, et al. IBMTR Severity Index for grading acute 
graft-versus-host disease: retrospective comparison with Glucksberg grade. British 
Journal of Haematology. 1997;97(4):855-864. 
53. Levine JE, Logan B, Wu J, et al. Graft-versus-host disease treatment: predictors of 
survival. Biol Blood Marrow Transplant. 2010;16(12):1693-1699 
54. Ivanova A, Qaqish BF and Schell MJ. (2005). Continuous Toxicity Monitoring in Phase 
II Trials in Oncology. Biometrics 61, 540-545. 
 

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Appendix 1 
Trial Procedures and Study Activities 
Screening (begins with consent): 
• Informed Consent is signed 
• Registration of Subject into the IWRS system 
• Relevant Medical history 
• Listing of all treatments and current therapies over the past 1 month and any 
chemotherapy regimens in the past 1 year from the date of informed consent 
• Concomitant medications 
• Physical examination 
• Height and body weight 
• Vital Signs (BP and heart rate, respiratory rate, body temperature) 
• Complete blood count (CBC) with Differential  
• Blood chemistry (Sodium, Potassium, BUN, Serum Creatinine, Chloride, Carbon 
Dioxide, Calcium, Phosphorus, Glucose, Bilirubin total and direct, ALT, AST, ALP, 
CRP, LDH, Albumin, Fibrinogen, Total Protein, Total Cholesterol, Triglycerides) 
• Urinalysis  
• ECG-12 lead 
• Stool sample for C. diff testing (if not tested in the last 7 days) 
• Stool sample for microbiota testing 
• aGVHD baseline scoring and grading (by IBMTR scoring system) 
• GI evaluation and biopsy*: flexible sigmoidoscopy (preferred) or colonoscopy and 
upper endoscopy, according to local center practice. 
• Skin biopsy for evaluation of rash, optional in the absence of rash 
• Collection of adverse events (AEs) 
• Serum pregnancy test as appropriate  
* If no biopsy for GI aGVHD confirmation has been performed before study entry. GI 
evaluation to be done within 5 days of initial systemic corticosteroid administration 
Study Day 0, Initial Dose of F-652 (to be within 5 days of initial systemic corticosteroid 
administration): 
• Body weight 
• Physical examination  
• Vital Signs (BP and heart rate, respiratory rate, body temperature). Vital signs are 
to be taken 15 min. after the start of F-652 infusion, at the completion, and 1 hour 
after the end of the initial infusion. 
• Serum sample for F-652 antibody testing (prior to administration of F-652) 
• PK testing samples 
• Collection of AEs and toxicity assessments 
• Concomitant medications  
• Administration of F-652 
• aGVHD blood research samples (cytokine samples optional) 
 
Study Days 7*, 14*, and 21*:  
• Body weight 

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• Collect vital signs (BP and heart rate, respiratory rate, body temperature). Vital 
signs are to be taken 15 min. after the start of F-652 infusion, at the completion, 
and 1 hour after the end of the initial infusion. 
• CBC with Differentials 
• Blood chemistry (Sodium, Potassium, BUN, Serum Creatinine, Chloride, Carbon 
Dioxide, Calcium, Phosphorus, Glucose, Bilirubin total and direct, ALT, AST, ALP, 
CRP, LDH, Albumin, Fibrinogen, Total Protein, Total Cholesterol, Triglycerides) 
• Serum sample for F-652 antibody testing (prior to administration of F-652) 
• PK testing samples (see schedule for Day 21+ sampling) 
• Collection of AEs and toxicity assessments 
• Concomitant medications  
• Administration of F-652 
• aGVHD scoring and grading (by IBMTR scoring system) 
• Skin biopsy if rash develops during treatment, optional in the absence of rash 
(Day 14) 
• aGVHD treatment response (only for visit Day 14)  
*Actual study day may vary as per the allowed window for visit due to each subject’s 
individual schedule. 
Study Day 28* (End of Treatment Visit): 
• Body weight 
• Physical examination  
• Collect vital signs (BP and heart rate, respiratory rate, body temperature) 
• CBC with Differential 
• Blood chemistry (Sodium, Potassium, BUN, Serum Creatinine, Chloride, Carbon 
Dioxide, Calcium, Phosphorus, Glucose, Bilirubin total and direct, ALT, AST, ALP, 
CRP, LDH, Albumin, Fibrinogen, Total Protein, Total Cholesterol, Triglycerides) 
• Serum sample for F-652 antibody testing 
• Urinalysis 
• PK testing samples 
• Collection of AEs and toxicity assessments 
• Concomitant medications  
• aGVHD scoring and grading (by IBMTR scoring system) 
• aGVHD treatment response 
• aGVHD blood research samples (cytokine samples optional) 
• Stool sample for microbiota testing 
• Skin biopsy if rash develops during treatment, optional in the absence of rash  
• ECG-12 lead 
• GI evaluation and biopsy*: flexible sigmoidoscopy (preferred) or colonoscopy and 
upper endoscopy with biopsy according to local center practice. (1 sample 
required, subject permitting, 4 others collected). 
*Actual study day may vary as per the allowed window for visit due to each subject’s 
individual schedule. 
Study Follow up Day 56*: 

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• Relevant medical history 
• Body weight 
• Physical examination  
• Collect vital signs (BP and heart rate, respiratory rate and body temperature) 
• CBC with Differential 
• Blood chemistry (Sodium, Potassium, BUN, Serum Creatinine, Chloride, Carbon 
Dioxide, Calcium, Phosphorus, Glucose, Bilirubin total and direct, ALT, AST, ALP, 
CRP, LDH, Albumin, Fibrinogen, Total Protein, Total Cholesterol, Triglycerides) 
• Serum sample for F-652 antibody testing 
• Current therapy and concomitant medications  
• Collection of AEs and toxicity assessments 
• aGVHD scoring and grading (by IBMTR scoring system) 
• aGVHD treatment response 
• PK testing sample 
*Actual study day may vary as per the allowed window for visit due to each subject’s 
individual schedule. 
Study Follow up Days 180 and 365*: 
• Relevant medical history 
• Body weight 
• Physical examination  
• Collect vital signs (BP, heart rate, respiratory rate, body temperature) 
• aGVHD scoring and grading (by IBMTR scoring system) 
• SAEs (possibly, probably, or definitely related to the investigational drug) 
• Current therapy and concomitant medications (only for subjects with SAEs reported 
after Day 56) 
 
*Actual study day may vary as per the allowed window for visit due to each subject’s 
individual schedule. 

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Appendix 2 
Schedule of Procedures and Events 
Assessments 
Screening 
Day 0 
Day 7 
Day 14 
Day 21 
Day 28* 
Day 56 
Day 180 
Day 365 
Window for visit (days) 
(5) days 
  
(±) 2 
(±) 2 
(±) 2  
(±) 4 
(±) 14 
(±) 30 
(±) 30 
Signing of Informed Consent 
X 
 
 
 
 
 
 
 
 
Relevant Medical History 
X 
 
 
 
 
 
X 
X 
X 
Body Temperature, Weight, Vital Signs (BP, heart rate, respiratory rate) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
X 
 
 
 
X 
X 
X 
X 
CBC1 
X 
  
X 
X 
X 
X 
X 
 
 
Blood chemistry1 
X 
  
X 
X 
X 
X 
X 
 
 
Urinalysis  
X 
 
 
 
 
X 
 
 
 
Immune recovery (per institutional standard)2 
 
X 
 
 
 
X 
 
 
 
Serum for F-652 antibody testing (pre dosing of F-652)  
 
X 
X 
X 
X 
X 
X 
 
 
ECG 
X 
 
 
 
 
X 
 
 
 
Stool C. Difficile testing (if not done within 7 days) 
X 
 
 
 
 
 
 
 
 
Stool microbiota test 
X 
 
 
 
 
X 
 
 
 
Pregnancy test3 
X 
 
 
 
 
 
 
 
 
Current therapy and concomitant medications4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
GI Biopsy5 
X 
 
 
    
 
X 
 
 
 
PK Testing6 (see additional schedule) 
 
X 
X 
X 
X 
X 
X 
 
 
Administration of F-6527 (within 5 days of consent)  
 
X 
X 
X 
X 
 
 
 
 
Collection of AEs and toxicity assessment8 
X 
X 
X 
X 
X 
X 
X 
 
 
aGVHD blood research samples ( cytokine samples optional) 
 
X 
 
 
 
X 
 
 
 
Skin biopsy, subject permitting or if skin rash develops during treatment 
X 
 
 
X 
 
X 
 
 
 
GVHD treatment response 
 
 
 
X 
 
X 
X 
 
 
aGVHD evaluation  
X 
 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: aGVHD = acute graft-versus-host disease; BP = blood pressure; ECG = electrocardiogram; GVHD = graft-versus-host disease; PK = pharmacokinetics.* End of treatment visit 
1 Blood samples are taken predose at Screening and Days 7, 14, 21, 28, and 56, and at 72 hours post-dose for CRP determination only at Screening and Days 7, 14, and 21. 
2 Immune recovery assessed on Day 0 as baseline and Days 28, post initial dose of F-652. Testing can be withheld if the patient has very low circulating white blood cells. 
3 For females with reproductive potential, serum test. 
4 Concomitant medications will be collected at each visit, scheduled or unscheduled. Collection of concomitant medications after Day 56 is required only for subjects with reported SAEs. 
5 Screening: for those subjects where no previous biopsy sample has been taken for GVHD confirmation. Day 28 Biopsy: subject permitting.  
6 See schedule for details (Appendix 3).  
7 Intravenous (IV) solution prepared per protocol.  
8 Collected at each scheduled or unscheduled visit. All AEs will be collected and documented on the study eCRF page through Study Day 56 (28 days after last dosing of F-652). After Study 
Day 56, only SAEs deemed possibly, probably, or definitely related to the investigational product are recorded through to the end of the study (Day 365). 

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Appendix 5 
aGVHD Diagnosis and Grading Tables 
Appendix Table 2. 
Modified Keystone Criteria 
 
Stage 0 
Stage 1 
Stage 2 
Stage 3 
Stage 4 
Skin 
No Rash 
Rash <25% BSA 
25-50% BSA 
>50% BSA 
Generalized 
erythroderma with 
bullae and/ or 
desquamation  
GI Tract* 
<500 ml/day 
stool volume 
501-1000 ml/day 
stool volume 
1001-1500 
ml/day stool 
volume 
>1500 
ml/day stool 
volume 
Severe abdominal 
pain +/- ileus, with or 
without 
hematochezia 
Upper GI 
 
Severe nausea, 
vomiting, or 
anorexia 
 
 
 
Liver 
Total 
bilirubin 
<2.0 mg/dL 
2.1-3 mg/dl 
3.1-6 mg/dl 
6.1-15 
mg/dl 
>15 mg/dl 
Abbreviations: BSA = body surface area; GI = gastrointestinal 
* If stool sample is not quantified in mL, each episode of diarrhea will be estimated to be a volume of 200 mL. 
 
Appendix Table 3. 
IBMTR Severity Index for Grading aGVHD 
 
Skin 
Liver 
GI 
I 
Stage 1 
0 
0 
II 
Stage 2 
Stage 1-2 
Stage 1-2 
III 
Stage 3  
Stage 3  
Stage 3 
IV 
Stage 4  
Stage 4 
Stage 4 
 

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Appendix 6 
Criteria for Therapeutic Response/Outcome Assessment 
Acute lower GI GVHD Response Criteria: 
• Complete Response (CR): stage of 0 of all aGVHD symptomatology in the lower GI tract 
with no additional intervening GVHD therapy. 
• Very good partial response (VGPR): tolerating food or enteral feeding, predominantly 
formed stools, no overt GI bleeding or abnormal cramping. 
• Partial Response (PR): improvement by at least 1 stage in lower GI GVHD 
symptomatology with no additional intervening therapy for their GVHD. 
• No Response (NR)/stable: absence of any improvement in GVHD stage. Subjects 
receiving secondary therapy (including need to re-escalate corticosteroid dose to 
≥2.5 mg/kg/day of prednisone (or methylprednisolone equivalent) will be classified as 
non-responders.  
• Progression: deterioration in lower GI tract. 
 
Response for All Organs Involved with Acute GVHD: 
• Complete Response (CR): stage of 0 of all aGVHD symptomatology in all GVHD target 
organs with no additional intervening GVHD therapy. 
• Very good partial response (VGPR): tolerating food or enteral feeding, predominantly 
formed stools, no overt GI bleeding or abnormal cramping, no more than occasional 
nausea or vomiting. 
• Partial response (PR): improvement in GVHD stage in all initial GVHD target organs 
without complete resolution and without worsening in any other GVHD target organs.  
• Mixed response (MR): improvement in 1 or more GVHD target organs with deterioration 
in another organ manifesting symptoms of GVHD or development of symptoms of 
GVHD in a new organ. 
• No response (NR)/stable: absence of any improvement in GVHD stage. Subjects 
receiving secondary therapy (including need to re-escalate corticosteroid dose to 
≥2.5 mg/kg/day of prednisone or methylprednisolone equivalent) will be classified as 
non-responders.  
• Progression: deterioration in at least 1 organ without any improvement in others.  
 
Treatment Failure: 
The following will be considered as treatment failures: 
• NR/stable after 14 days of therapy. 
• Progression after 7 days of therapy. 
• Administration of additional systemic therapy for GVHD (or re-escalation of 
corticosteroid dose to ≥2.5 mg/kg/day of prednisone (or methylprednisolone equivalent) 
• Transplant-related mortality (TRM) 
 

F-652 Version: Amendment 3 
 
Generon (Shanghai) Corporation 
Protocol: GC-652-02 
 
26 January 2017 
 
Confidential 
Page 71 of 73 
Discontinuation of Immunosuppressive Medications. 
• Discontinuation of immunosuppression will be assessed over time. The date of 
discontinuation of corticosteroids will be recorded. In addition, dates for discontinuation 
of all other systemic immunosuppressive medications (including CSA, tacrolimus, 
sirolimus, etc.) for treatment or prevention of aGVHD will be assessed.  
 
Transplant related mortality (TRM) 
• TRM is defined as death at any time from the commencement of pre-transplant 
conditioning due to any cause other than disease relapse with the exception of automobile 
or other accidents. The incidence of TRM at Day 56 is the primary safety endpoint. 

F-652 Version: Amendment 3 
 
Generon (Shanghai) Corporation 
Protocol: GC-652-02 
 
26 January 2017 
 
Confidential 
Page 72 of 73 
Appendix 7 
List of Abbreviations and Definitions of Terms 
z 
Elimination half-life 
ADL 
Activities of daily living 
AE 
Adverse event 
aGVHD 
Acute Graft-versus-Host Disease 
ALP 
Alkaline Phosphatase 
ALT (SGOT) 
Alanine aminotransferase 
ANC 
Absolute neutrophil counts 
AST (AGPT) 
Aspartate aminotransferase 
ATG 
Anti-thymocyte globulin 
AUC 
Area under the plasma concentration vs. time curve 
BMT 
Bone marrow transplant 
BUN 
Blood Urea Nitrogen 
Cmax 
Concentration Maximum 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations 
CL 
Clearance 
CMV 
Cytomegalovirus 
CR 
Complete response 
CRP 
C-reactive Protein  
CSA 
Cyclosporine 
CTCAE 
Common Terminology Criteria for Adverse Events 
D5W 
5% dextrose in water 
DC 
Dendritic cell 
DP 
Drug product 
DS 
Drug substance 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EIU 
Exposure in utero 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GMP 
Good Manufacturing Practices 

F-652 Version: Amendment 3 
 
Generon (Shanghai) Corporation 
Protocol: GC-652-02 
 
26 January 2017 
 
Confidential 
Page 73 of 73 
hCG 
Human chorionic gonadotropin 
Hgb 
Hemoglobin 
HSCT 
Hematopoietic stem cell transplantation 
IBMTR 
International Bone Marrow Transplant Registry 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IL 
Interleukin 
ILC 
Innate lymphoid cell 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ISC 
Intestinal stem cell 
IV 
Intravenous 
IWRS 
Interactive web based response system 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHC 
Major histocompatibility complex 
MMF 
Mycophenolate mofetil 
MR 
Mixed response 
NCI 
National Cancer Institute 
NR 
No response 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PR 
Partial response 
rh 
Recombinant human 
rm 
Recombinant murine 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
t1/2 
Half-life 
tmax 
Maximum concentration (of a drug in bloodstream) 
TEAE 
Treatment-emergent adverse event 
TRM 
Transplant-related mortality 
Vd 
Volume of distribution 
VGPR 
Very Good Partial Response