Clinical trial NCT04128319
Conditions: Steroid-Refractory Acute Graft Versus Host Disease
Keywords: Steroid-refractory acute GVHD Acute GVHD GVHD treatment
Sponsor: Xenikos
Start date: 2019-11-21; Completion date: 2020-02-17
Enrollment: 3 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The study is designed as an open-label, single arm Phase III, multicenter trial to evaluate the efficacy and safety of T-Guard treatment in patients with Steroid-Refractory acute Graft versus Host Disease (SR-aGVHD).

Detailed description:
Allogeneic Hematopoietic Cell Transplantation (allo-HSCT) is a potent immunotherapy with curative potential for several hematological disorders. Improvements in survival following allo-HSCT have led to its increasing use, but the leading cause of non-relapse mortality (NRM) remains graft-versus-host-disease (GVHD. Despite recent advances in the understanding of transplantation immune tolerance, aGVHD is a frequent and major complication of allo-HSCT involving activation of donor T-lymphocytes, which ultimately causes host tissue damage. T-Guard has a rapid onset, preferential killing of activated T cells, and short half-life, leading to depletion of allo-reactive T cells and quick post-treatment reconstitution of the immune system.

Arms: arm 1: Patients will receive T-Guard for treatment of steroid-refractory acute GVHD.
Interventions: intervention 1: T-Guard
Intervention descriptions: intervention 1: Patients will receive 4 doses of T-Guard treatment, administered intravenously as four 4-hour infusions at least two calendar days (no less than 40 hours) apart. Each dose consists of 4 mg/m\^2 Body Surface Area (BSA).

Protocol documents:
Prot_SAP_000.pdf: 


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PROTOCOL SYNOPSIS – BMT CTN 1802 PROTOCOL 
 
 
An Open-Label, Single-Arm, Multicenter Study of T-Guard for Steroid-Refractory 
Acute Graft-versus-Host Disease 
 
Co-Chairs: 
 John Levine, M.D. 
Gabrielle Meyers, 
M.D. 
 
Study Design: 
The study is an open-label, single arm Phase III, multicenter  
 
trial, which has been designed to evaluate the efficacy and  
safety of T-Guard treatment in patients with Steroid-Refractory 
acute Graft versus Host Disease (SR-aGVHD). 
 
The primary analysis will include all patients that initiate T-
Guard treatment. 
 
Primary Objective: 
To assess the rate of Day 28 complete response (CR) in 
SR-aGVHD patients treated with T-Guard therapy. 
 
Secondary Objectives: 
Secondary objectives are the following: 
1. Evaluate the duration of complete response (DoCR) 
2. Estimate the overall survival (OS) at Days 90 and 180 
3. Estimate the overall response rate (CR or partial 
response (PR)) at Days 14, 28, and 56 
4. Describe proportions of CR, PR, mixed response (MR), no 
response (NR), and progression of aGVHD at Days 7, 14, 
28, and 56 
5. Estimate the cumulative incidence of non-relapse 
mortality (NRM) at Days 100 and 180 
6. Estimate relapse-free survival at Day 180 
7. Estimate GVHD-free survival at Days 90 and 180 
8. Estimate   the cumulative incidence of chronic
GVHD (cGVHD) at Day 180 
9. Estimate 
the 
cumulative 
incidence 
of
disease relapse/progression at Day 180 
10. Describe the incidence of systemic infections 
11. Describe the incidence of toxicities 
12. Assess the pharmacokinetics of T-Guard 
13. Assess the immunogenicity of T-Guard 
 
Exploratory Objectives: 
1. Describe corticosteroid-dose (measured in   prednisone- 
equivalent) at baseline, Days 28 and 56 post initiation of 
T- Guard therapy. 
2. Estimate the rate of near-CR (i.e. CR in GI and Liver with 
only Stage 1 Skin) at Days 28 and 56 post initiation of T- 
Guard therapy. 
3. Describe discontinuation of systemic steroids by Day 180 
post initiation of T-Guard therapy. 


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4. Estimate the incidence of CMV reactivation requiring 
therapy by Day 180 post initiation of T-Guard Therapy. 
5. Estimate the incidence of Epstein-Barr Virus (EBV)- 
associate lymphoproliferative disorder or EBV reactivation 
requiring therapy with rituximab by Day 180 post initiation 
of T-Guard therapy. 
6. Describe the incidence of Investigational Medicinal Product 
(IMP) related SAEs. 
7. Evaluate T-cell subsets and Natural Killer (NK) cells at 
baseline and at Days 0, 2, 4, 6 (just prior to and 4 hours 
after each T-Guard infusion) and then subsequently at 
Days 14, 28, 56, 180. 
8. Evaluate aGVHD biomarkers at baseline and at Days 7, 14, 
and 28 post initiation of T-Guard therapy. 
9. Describe changes in patient-reported outcomes (PROs) 
from baseline to Days 28, 56, and 180 post initiation of T- 
Guard therapy. 
 
Correlatives: 
The pharmacokinetics and immunogenicity of T-Guard will    
be evaluated as referenced in the secondary and exploratory 
objectives. 
 
Eligibility Criteria: 
Adolescents and adults at least 12 years of age at the time 
of consent who have undergone first allogeneic hematopoietic 
stem cell transplantation (allo-HSCT) from any donor source 
using bone marrow, peripheral blood stem cells, or cord blood 
will be included in this study. Recipients of nonmyeloablative, 
reduced intensity, and myeloablative conditioning regimens 
are eligible. Patients must be diagnosed with SR-aGVHD. 
Steroid refractory (SR) is defined as aGVHD that progressed 
after 3 days of primary treatment with prednisone (or 
equivalent) of greater than or equal to 2 mg/kg/day; no 
improvement after 7 days of primary treatment with prednisone 
(or equivalent) of greater than or equal to 2 mg/kg/day; or 
previously was treated with prednisone (or equivalent) of 
greater than or equal to 1 mg/kg/day and aGVHD has 
developed in a previously uninvolved organ system. Patients 
with visceral (GI and/or liver) plus skin aGVHD at prednisone 
(or equivalent) initiation with improvement in skin GVHD 
without any improvement in visceral GVHD after 7 days of 
primary treatment with prednisone (or equivalent) of greater 
than or equal to 2 mg/kg/day are eligible. Patients must also 
have evidence of myeloid engraftment (e.g., absolute 
neutrophil count greater than or equal to 0.5 × 109/L for 3 
consecutive days if ablative therapy was previously used). Use 
of growth factor supplementation is allowed. Patients or an 
impartial witness (in case the patient is capable to provide 
verbal consent but not capable to sign the informed consent) 
should have given written informed consent. 
 
 


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Exclusion Criteria: Patients will be excluded from study entry 
if any of the following exclusion criteria exist: Diagnosis of 
overlap syndrome, that is, with any concurrent features of 
cGVHD; patients requiring mechanical ventilation, requiring 
vasopressor support, or requiring hemodialysis; patients who 
have received any systemic treatment, besides steroids, as 
upfront treatment of aGVHD OR as treatment for SR-aGVHD; 
  
patients with severe hypoalbuminemia, with an albumin of less 
than or equal to 1 g/dl, a creatine kinase (CK) level greater 
than 5 times the upper limit of normal; patients with an 
uncontrolled infection (infections are considered controlled if 
appropriate therapy has been instituted and, at the time of 
enrollment, no signs of progression are present). Patients with 
evidence of relapsed, progressing, or persistent malignancy, or 
with evidence of minimal residual disease requiring withdrawal 
of systemic immune suppression are not eligible for this trial. 
Patients with known hypersensitivity to any of the components 
murine monoclonoal antibodies (mAb), or Recombinant Ricin 
Toxin A-chain (RTA), or have received more than one allo-
HSCT, or who have known human immunodeficiency virus 
infection are also excluded from this trial. Pregnant or 
breastfeeding females, and females of childbearing potential 
unwilling to use effective birth control from start of treatment 
until 30 days after the last infusion of T-Guard are not eligible 
to participate. Male patients who are sexually active and 
unwilling to use effective birth control from start of treatment 
until 65 days after the last infusion of T-Guard are not eligible. 
 
Interim Analysis: 
This trial will include one interim analysis for futility after 
21 patients become evaluable for the primary endpoint. There 
will be no interim analyses for efficacy. 
 
 
Treatment Description: 
Patients will receive 4 doses of T-Guard treatment, 
administered intravenously as four 4-hour infusions at least two 
calendar days apart. Each dose consists of 4 mg/m2 Body 
Surface Area (BSA). 
 
Accrual Objective: 
The target accrual is 47 patients initiating T-Guard treatment. 
 
Accrual Period: 
Approximately 1 year is expected for accrual. 
 
Study Duration: 
Patients will be followed for 180 days for a total study duration 
of approximately 1.5 years. 
 
Safety Monitoring: 
The rates of overall mortality and CTCAE Grade 4 or higher 
capillary leak syndrome (CLS) at Day 30 post treatment 
initiation will be monitored separately using sequential 
probability ratio tests (SPRT) for binary data. The SPRTs will 
contrast a mortality rate of 15% vs. a 30% rate and a Grade 4 
or higher CLS rate of 5% vs. a 15% rate. 


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TABLE OF CONTENTS 
CHAPTER 1 .................................................................................................................... 1 
1 BACKGROUND AND RATIONALE .......................................................................... 1 
1.1 
Introduction ............................................................................................................... 1 
1.2 
Therapies for Acute GVHD ....................................................................................... 2 
1.2.1 
First Line Therapy: Corticosteroids ............................................................. 2 
1.2.2 
Second Line Therapies Background ........................................................... 2 
1.2.3 
New Emerging Therapies ........................................................................... 3 
1.3 
T-Guard .................................................................................................................... 4 
1.3.1 
Pre-Clinical Data ........................................................................................ 5 
1.3.2 
Clinical data ................................................................................................ 7 
1.3.3 
Justification for the Proposed Dose Regimen for this Phase III Clinical Trial 
Using T-Guard as First Line SR-GvHD Treatment ...................................................11 
1.4 
Study Rationale .......................................................................................................12 
1.5 
Inclusion of children age 12-17 ................................................................................14 
CHAPTER 2 .................................................................................................................. 15 
2 STUDY DESIGN ...................................................................................................... 15 
2.1 
Study Overview ........................................................................................................15 
2.2 
Hypothesis and Specific Objectives .........................................................................15 
2.2.1 
Primary Hypothesis ...................................................................................15 
2.3 
Study Objectives ......................................................................................................15 
2.3.1 
Primary Objective ......................................................................................15 
2.3.2 
Secondary Objectives ...............................................................................15 
2.3.3 
Exploratory Objectives ...............................................................................16 
2.4 
Patient Eligibility.......................................................................................................16 
2.4.1 
Inclusion Criteria........................................................................................16 
2.4.2 
Exclusion Criteria ......................................................................................17 
2.5 
Treatment Plan ........................................................................................................18 
2.5.1 
T-Guard Treatment ....................................................................................18 
2.5.2 
Storage, Handling, and Dispensing of T-Guard .........................................18 
2.5.3 
Drug Accountability ...................................................................................18 
2.5.4 
Dose and Administration of T-Guard .........................................................19 
2.5.5 
Toxicities and Guidelines for Withholding T-Guard ....................................20 
2.5.6 
T-Guard Discontinuation ............................................................................21 


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2.5.7 
Acute GVHD Progression or Non-response ...............................................21 
2.5.8 
Supportive Care ........................................................................................21 
2.5.9 
Follow-Up Post Treatment Discontinuation ................................................23 
2.6 
Study Conduct .........................................................................................................23 
CHAPTER 3 .................................................................................................................. 24 
3 STUDY ENDPOINTS ............................................................................................... 24 
3.1 
Acute GVHD Response Definitions ..........................................................................24 
3.2 
Relapse Definition ....................................................................................................24 
3.3 
Primary Endpoint .....................................................................................................26 
3.4 
Secondary Endpoints ...............................................................................................26 
3.4.1 
Key Secondary Endpoints: ........................................................................26 
3.4.2 
Other Secondary Endpoints:......................................................................26 
3.5 
Exploratory Endpoints ..............................................................................................28 
3.5.1 
Corticosteroid Dose ...................................................................................28 
3.6 
Endpoint Review Process ........................................................................................29 
CHAPTER 4 .................................................................................................................. 31 
4 PATIENT ENROLLMENT AND EVALUATION ....................................................... 31 
4.1 
Approaching Patients, Eligibility Screening, and Obtaining Consent ........................31 
4.2 
Enrollment ...............................................................................................................31 
4.2.1 
Treatment] .................................................................................................31 
4.3 
Study Monitoring ......................................................................................................31 
4.3.1 
Follow-up Schedule ...................................................................................31 
4.3.2 
Assessments .............................................................................................32 
4.4 
Adverse Event Reporting .........................................................................................37 
4.4.1 
Definitions .................................................................................................37 
4.4.2 
Classification of Adverse Events by Severity .............................................38 
4.4.3 
Classification of Adverse Events by Relationship to Investigational Product
 
38 
4.4.4 
Required Adverse Event Reporting ...........................................................39 
4.4.5 
Procedure in Case of Pregnancy ...............................................................39 
4.5 
Infusion Delays ........................................................................................................40 
CHAPTER 5 .................................................................................................................. 42 
5 STATISTICAL CONSIDERATIONS ........................................................................ 42 
5.1 
Study Design and Objective .....................................................................................42 


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5.1.1 
Accrual and Study Duration .......................................................................42 
5.1.2 
Randomization and Blinding ......................................................................42 
5.1.3 
Analysis Populations .................................................................................42 
5.1.4 
Primary Hypothesis ...................................................................................42 
5.1.5 
Sample Size and Power Considerations ....................................................43 
5.2 
Interim Analysis and Stopping Guidelines ................................................................44 
5.2.1 
Interim Analysis for Futility .........................................................................44 
5.2.2 
Guidelines for Safety Monitoring ................................................................45 
5.2.3 
Demographic and Baseline Characteristics ...............................................48 
5.3 
Analysis of Primary Endpoint ...................................................................................48 
5.4 
Analysis of Secondary Endpoints .............................................................................48 
5.4.1 
Duration of Complete Response (DoCR) ...................................................48 
5.4.2 
Overall Survival (OS) .................................................................................49 
5.4.3 
Overall Response Rate (ORR) ..................................................................49 
5.4.4 
Proportion of Response .............................................................................49 
5.4.5 
Non-relapse Mortality (NRM) .....................................................................49 
5.4.6 
Relapse-free Survival (RFS) ......................................................................49 
5.4.7 
GVHD-free Survival ...................................................................................49 
5.4.8 
Chronic GVHD (cGVHD) ...........................................................................49 
5.4.9 
Relapse/progression of the Underlying Malignancy ...................................50 
5.4.10 
Incidence of Systemic Infections ...............................................................50 
5.4.11 
Incidence of Toxicities ...............................................................................50 
5.4.12 
Pharmacokinetics ......................................................................................50 
5.4.13 
Immunogenicity .........................................................................................50 
5.4.14 
Subgroup Analyses of Day 28 CR Rate .....................................................50 
5.5 
Analysis of Exploratory Endpoints ............................................................................51 
5.5.1 
Corticosteroid Dose ...................................................................................51 
5.5.2 
Near Complete Response (Near CR) ........................................................51 
5.5.3 
Discontinuation of Systemic Steroids .........................................................51 
5.5.4 
CMV Reactivation ......................................................................................51 
5.5.5 
EBV-associated Lymphoproliferative Disorder ...........................................51 
5.5.6 
Incidence of Investigational Medical Product (IMP)-related Serious Adverse 
Events (SAEs) .........................................................................................................51 
5.5.7 
T-cell Subsets and NK-cells.......................................................................51 
5.5.8 
GVHD-related Biomarkers .........................................................................52 
5.5.9 
Patient-reported Outcomes .......................................................................52 


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APPENDIX A:  HUMAN SUBJECTS ............................................................................ 53 
APPENDIX B:  LABORATORY PROCEDURES .......................................................... 54 
APPENDIX C:  STAGING AND GRADING OF ACUTE GVHD (HARRIS, YOUNG ET 
AL. 2016) ...................................................................................................................... 59 
APPENDIX D:  GRADING OF CHRONIC GVHD (NIH CRITERIA, (JAGASIA, GREINIX 
ET AL. 2015) ................................................................................................................. 60 
APPENDIX E:  PATIENT REPORTED OUTCOMES.................................................... 63 
APPENDIX F:  LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............. 68 
APPENDIX G:  REFERENCES .................................................................................... 70 
 
 


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CHAPTER 1 
1 
BACKGROUND AND RATIONALE 
1.1 
INTRODUCTION 
Allogeneic Hematopoietic Cell Transplantation (allo-HSCT) is a potent immunotherapy with 
curative potential for several hematological disorders (Magenau, Runaas et al. 2016). 
Improvements in survival following allo-HSCT have led to its increasing use, but the leading 
cause of non-relapse mortality (NRM) remains graft-versus-host-disease (GVHD) (Alousi, 
Weisdorf et al. 2009, Major-Monfried, Renteria et al. 2018). Serious infections and impairment of 
generalized immune function are responsible for GVHD mortality. GVHD incidence and severity 
depends primarily on donor and recipient matching for human leukocyte antigens and the 
regimen used for post-grafting immune suppression. The National Institutes of Health (NIH) 
consensus development project working group recognized 2 main categories of GVHD, each 
with 2 subcategories. The acute GVHD (aGVHD) category is defined in the absence of 
diagnostic or distinctive features of chronic GVHD (cGVHD) and includes (1) classic aGVHD 
occurring within 100 days after transplantation and (2) persistent, recurrent, or late aGVHD 
(features of GVHD occurring beyond 100 days, often during withdrawal of immune 
suppression). The broad category of cGVHD includes (1) classic cGVHD (without features or 
characteristics of aGVHD) and (2) an overlap syndrome in which diagnostic or distinctive 
features of cGVHD and aGVHD appear together. (Filipovich, Weisdorf et al. 2005, Jagasia, 
Greinix et al. 2015) 
Despite recent advances in the understanding of transplantation immune tolerance, aGVHD is a 
frequent and major complication of allo-HSCT involving activation of donor T-lymphocytes, which 
ultimately causes host tissue damage (Holtan SG 2014, LaQuisa 2018). Serious infections, 
organ failure and impairment of generalized immune function are responsible for aGVHD 
mortality. The condition involves three target organs, the skin (presenting as inflammatory, 
maculopapular, erythematous rash), the liver (presenting as hyperbilirubinemia due to 
cholestatic jaundice) and the gastro-intestinal (GI) tract (presenting as upper and/or lower GI 
tract manifestations: anorexia with weight loss, nausea, vomiting, diarrhea, severe pain, GI 
bleeding and/or ileus) (Schoemans, Lee et al. 2018). The diagnosis must occur in absence of 
cGVHD symptoms (Filipovich, Weisdorf et al. 2005, Jagasia, Greinix et al. 2015). Despite 
immune suppression prophylaxis, up to 50% of hematopoietic cell transplantation (HCT) 
recipients will experience grade II-IV aGVHD (Zakias PD 2014, Zeiser, Socie et al. 2016). 
Complete responses (CR) to upfront treatment at day 28 of therapy have been reported in 25% 
to 41% of patients, as defined as regression of skin rash or decrease in the volume of diarrhea 
and the extent of liver function abnormalities (Hings, Severson et al. 1994, MacMillan, Weisdorf et 
al. 2002, Deeg 2007). When performing a meta-analysis of prospective studies, including the 
recently completed REACH1 Study, and of patients reported in the MAGIC database, the 
expected CR rate at day 28 of therapy is more in the range of 25%-30% (Section 5.1.5). The 
likelihood of GVHD treatment response decreases with increasing severity of the disease. 
(Martin, Schoch et al. 1990, Weisdorf, Haake et al. 1990). Treatment responses differ between 
target organs and may differ considerably between patients. Of particular interest are patients 
with both visceral and skin aGVHD who have CR of GI or liver GVHD but have persistence of 
skin rash at less than 25% body surface area (BSA). These patients, who would be considered 


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to have partial response (PR) by current staging, likely have superior outcomes compared to 
those patients with persistence of visceral aGVHD. We hypothesize this patient group, with 
visceral and skin GVHD who meet the criteria for CR except for persistent, low volume skin 
rash (what we will call near-CR), will have identical outcomes compared to those patients with 
CR. The response to primary therapy is of central importance, as responses correlate with post-
HCT survival. 
1.2 
THERAPIES FOR ACUTE GVHD 
1.2.1 First Line Therapy: Corticosteroids 
The mainstay of treatment of aGVHD for over three decades has been high-dose 
corticosteroids, typically dosed at the prednisone equivalent of 1-2 mg/kg per day (Weisdorf, 
Haake et al. 1990, Bolanos-Meade and Vogelsang 2004, Bacigalupo 2007, Deeg 2007). 
However, high dose corticosteroid therapy has several shortcomings, including toxicity issues, 
such as infection, diabetes, hypertension, osteoporosis, myopathy and avascular necrosis, as 
well as less than optimal efficacy. This has led to interest for alternate first line therapies e.g. the 
development of the BMT CTN 1501 clinical trial “A Randomized, Phase II, Multicenter, Open 
Label, Study Evaluating Sirolimus and Prednisone in Patients with Refined Minnesota Standard 
Risk, Ann Arbor 1/2 Confirmed Acute Graft-Versus-Host Disease”, comparing outcomes of a 
non-steroid first-line therapy (sirolimus) for aGVHD. This trial completed enrollment in February 
2018 and results are pending publication. While this and other trials are evaluating alternate first 
line therapies, in the interim and near future, steroids are still expected to be the primary first 
line therapy for aGVHD. While steroids are considered first line therapy for aGVHD, a significant 
fraction of the aGVHD population (10-50%) fail to have a clinical response, deeming them 
steroid refractory (SR). (Deeg 2007, MacMillan, Robin et al. 2015). 
1.2.2 Second Line Therapies Background 
If the manifestations of GVHD in any organ worsen over 3 days of high-dose steroid treatment 
or if the involved organs do not improve by 7 days of high-dose steroids therapy, it is unlikely 
that a response will be achieved in a timely fashion, and secondary therapy should be 
considered (Deeg 2007). Patients meeting the above criteria are classified as having steroid- 
refractory aGVHD (SR-aGVHD), and in these patients steroid dosing is not increased since it 
does not improve survival, (Bacigalupo, van Lint et al. 1983) but rather another 
immunosuppressive agent is added to the treatment regimen. 
Though substantial progress has been made in the field the last decade due to a) advances in 
selection of patient and donor, b) selection of the most appropriate preparative regimen and c) 
earlier identification of subpopulations by using biomarkers (Paczesny 2013, Major- Monfried, 
Renteria et al. 2018), there are still a vast number of patients which end up with SR- aGVHD. 
The long-term prognosis for this population is unfortunately very poor, with a mortality rate of 
approximately 70-80% (Weisdorf, Haake et al. 1990, Levine, Logan et al. 2010), because 
response rates with second-line treatment are low (Deeg 2007, Pidala, Kim et al. 2010, Castilla-
Llorente, Martin et al. 2014) and infectious complications due to profound immunosuppression 
are common. 


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1.2.3 New Emerging Therapies 
Given the dismal overall outcomes in patients with SR-aGVHD many innovative therapies are 
currently under development (Hill, Alousi et al. 2018). We may conclude that more effective 
aGVHD immunosuppressive agents will improve remission rates and decrease toxicities, 
especially in the SR-aGVHD patients, which will result in better survival after allo-HSCT. Ideally, 
agents should be targeted (i.e. not broadly immunosuppressive), have a favorable side effect 
profile, should be effective upfront to avoid severe and irreversible tissue damage, and should 
provide complete and durable responses, without impacting graft versus tumor effects and/or 
infection risk. 
The most promising agents currently being studied include inhibitors of the Janus Kinase 
pathway (JAK), cytokine modulators, and monoclonal antibodies (mAbs) among others. 
Ruxolitinib 
The dual JAK1 and JAK2 inhibitor ruxolitinib as well as the JAK1 inhibitor itacitinib have shown 
efficacy and tolerability in the upfront treatment of aGVHD and SR-aGVHD. The pivotal phase II 
study of ruxolitinib for SR-aGVHD and steroid-dependent aGVHD showed an overall response 
rate (ORR) at Day 28 of 57% and 31% CR rate (Jagasia, Zeiser et al. 2018), leading to the FDA 
approval of this agent on May 24, 2019. The main complications seen with this agent include 
hematologic toxicity and infections, with 31% of patients discontinuing this agent on trial due to 
adverse reactions. Larger studies of this agent for SR-aGVHD are underway (REACH 2, 
ClinicalTrials.gov identifier:NCT0291326). 
Early studies of the JAK1 inhibitor itacitinib for aGVHD shows tolerability and suggestion of 
activity. The Phase I trial of itacitinib combined with steroids for treatment naïve and SR- aGVHD 
was reported at the 2016 American Society of Hematology Meeting (Schroeder et al, Blood 
2016, Abstract 390), with ORR of 64.7% in SR-aGVHD. GRAVITAS-301 is a phase III trial 
currently 
enrolling 
for 
front-line 
treatment 
of 
aGVHD 
(ClinicalTrials.gov 
identifier: 
NCT03139604). 
AAT 
The serine protease inhibitor alpha-1 antitrypsin (AAT) has been shown to impact T cell 
repertoire and inflammatory cytokines, and levels of the naturally occurring AAT in donors was 
found to impact GVHD outcomes (Marcondes, Karoopongse et al. 2014). This data led to the 
Phase I/II dose escalation study of AAT for treatment of SR-aGVHD, which showed optimistic 
Day 28 response rates (ORR 65%, CR 35%) and good tolerance, supporting additional trials 
with this agent (Marcondes, Hockenbery et al. 2016). 
mAbs 
Finally, our experience and ability to manufacture (mAbs) has rapidly expanded, with multiple 
immunomodulatory mAbs (Floisand, Lundin et al. 2017, Hill, Alousi et al. 2018) currently under 
investigation for the treatment of aGVHD. 
The goal of any new therapy for aGVHD is to improve remission rates and minimize toxicities, 
especially in the SR patient, thereby leading to improved survival after allo-HSCT. Each of the 
agents highlighted above, and others being studied for SR-aGVHD, have certain advantages 


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and disadvantages, but maintain a suboptimal response rate. Therefore, a very high priority 
remains for development of an effective and well tolerated therapy for SR-aGVHD. 
In the proposed study a new immunotoxin is investigated in patients with SR-aGVHD that may 
meet all of the criteria for an ideal agent based on immunosuppressive profile reported on 20 
patients in a Phase I/II clinical trial (Groth, van Groningen et al. 2017). Anti-CD3/anti-CD7 
antibody treatment in patients with severe SR-aGVHD resulted in high day 28 CR rate of 50%, 
which compares favorably with historical controls (20-30%), and a high Day 180 overall survival 
(OS). In addition, the short treatment course (4 treatments given every 48 hours) allows for a 
rapid response and fast restoration of the immune system. 
1.3 
T-GUARD 
The investigational medicinal product (IMP) in this study, T-Guard, is an immunotoxin- 
combination, consisting of two equal amounts (w/w) of the murine mAbs SPV-T3a (anti-CD3, 
IgG2b) and WT1 (anti-CD7, IgG2a), each conjugated to the Ricin Toxic A (RTA) chain: SPV-
T3a-RTA and WT1-RTA. This particular immunotoxin-combination harbors multiple 
mechanisms of action (Figure 1-1). 
Both the anti-CD3 and anti-CD7 mAbs act as chaperones that bring the toxic RTA payload into 
the target cells after binding to the surface antigens on T cells (CD3+ and CD7+) and Natural 
Killer (NK) cells (CD7+ and CD3-). Once inside the cell, the bond between these mAbs and RTA 
toxin is broken, thereby releasing free RTA into the cytoplasm. The RTA toxin then irreversibly 
inhibits protein synthesis by means of a catalytic reaction culminating in programmed cell death 
(apoptosis) of T cells, with a preference for the recently-activated ones, and NK cells (see also 
1.3.1 Pre-clinical data). RTA toxin does not enter the cell autonomously. Because the RTA toxin 
is unable to bind or enter the cell autonomously, immunotoxins are only hazardous to cells 
capable of binding and internalizing the mAbs (Wayne, Fitzgerald et al. 2014), therefore 
mitigating toxicity to bystander cells (van Oosterhout, van Emst et al. 2000). 
Additionally, two other anti-T-cell immunotoxins have been clinically tested as a single-agent for 
the in vivo prevention/treatment of aGVHD: anti-CD5 immunotoxin H65-RTA (Xomazyme CD5), 
which was constructed with RTA chain, and anti-CD25 directed denileukin diftitox (Ontak), a 
recombinant fusion protein linking cytokine interleukin (IL)-2 to truncated diphtheria toxin. 
Although these single-agent immunotoxins showed promising initial results, when tested as 
second-line treatment for SR-aGVHD, they appeared not to be superior than available aGVHD 
treatments. (Byers, Henslee et al. 1990, Krance, Heslop et al. 1993, Hings, Severson et al. 1994, 
Phillips, Nevill et al. 1995, Martin, Nelson et al. 1996, Ho, Zahrieh et al. 2004, Shaughnessy, 
Bachier et al. 2005). 
One of the reasons T-Guard might be more successful is that the simultaneous targeting of two 
or more antigens on the same target cell may result in a synergistic toxicity (see also 1.3.1 Pre-
clinical data). Moreover, CD3 antibody binding to the CD3/T cell receptor (CD3/TCR) complex 
results in competitive inhibition and internalization of the antibody-receptor complex, thus 
blocking T cell activation directly and may trigger activation-induced cell death of activated T 
cells. 


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Figure 1-1: T-Guard Mechanism of Action 
1.3.1 Pre-Clinical Data 
We hypothesize that T-Guard might have a role in treatment and/or prevention of clinical GVHD 
based on the pre-clinical immunological profile. 
1.3.1.1 
Synergistic Apoptosis of a Combination of Anti-T-Cell Immunotoxins  
Several anti-T cell mAbs were conjugated to RTA and evaluated for their efficacy, alone and in 
combination, to eliminate or neutralize activated T cells in vitro. These experiments led to the 
selection of an immunotoxin-combination consisting of SVP-T3a-RTA (anti-CD3) and WT1-RTA 
(anti-CD7). This particular combination, having the working name ‘T-Guard’, was more effective 
at inducing T cell apoptosis than each of the individually tested immunotoxins. Figure 1-2 shows 
% cells viability of Jurkat cells treated with either SPV-T3a-RTA and WT1- RTA or in combination 
(half a dose each). 
1.3.1.2 
Cytokine Modulation by T-Guard 
Both SPV-T3a and WT1 deliver the toxic RTA-payload inside the T cells, and the SPV-T3a 
modulates the CD3/TCR complex (see above). Notably, SPV-T3a is particularly well suited for 
in vivo use, as this anti-CD3 mAb does not stimulate T cells (Land, Hillebrand et al. 1988, Smely, 
Weschka et al. 1990, Frenken, Koene et al. 1991, Woodle, Thistlethwaite et al. 1991, Anasetti, 
Martin et al. 1992, Knight, Kurrle et al. 1994). This strongly reduces the occurrence of cytokine 
release syndrome (CRS), a potentially life-threatening complication frequently associated with 
the clinical use of non-conjugated immunosuppressive anti-CD3 mAbs or Anti- Thymocyte 
Globulin (ATG). 


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Figure 1-2: Synergistic cell kill by the T-Guard combination 
 
1.3.1.3 
Preferential Targeting of Activated T Cells over Non-Activated and Anti-
Viral T cells 
The SPV-T3a-RTA and WT1-RTA immunotoxin-combination preferentially kills recently 
activated T cells (van Oosterhout, van Emst et al. 2000). Figure 1-3 depicts the outcome of an 
ex vivo experiment, in which non-activated and phytohemagglutinin (PHA)-activated Peripheral 
Blood Mononuclear Cells s were incubated with various concentrations of T-Guard. Incubation 
with clinically relevant T-Guard concentrations (10-9 M – 10-8 M) results in a reduction of the 
number of activated T cells to less than 1%, while 35% of their non-activated counterparts 
survived. Flow cytometric analysis revealed that the higher vulnerability of recently activated T 
cells could most likely be attributed to a strong increase in CD7 membrane expression. This 
upregulation of CD7 expression upon recent T cell activation with either PHA, anti-CD3 mAbs 
or in a Mixed Lymphocyte Reaction has been described by others as well (Heinrich, Gram et 
al. 1989, Akbar, Amlot et al. 1990, Amlot, Tahami et al. 1996). 
 
 
 


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Figure 1-3: Preferential targeting of activated T cells (ex vivo experiment) 
 
 
It is also noteworthy that, apart from recent T cell activation, CD7 expression also seems to be 
regulated by differentiation stage, with lower CD7 expression on mature effector memory T 
cells (Reinhold, Abken et al. 1993, Amlot, Tahami et al. 1996, Aandahl, Sandberg et al. 2003, 
Appay, van Lier et al. 2008). This may portend clinical benefit given that virus-specific T cells 
reside primarily in the effector memory compartments (Gamadia, Rentenaar et al. 2001, Aandahl, 
Quigley et al. 2004, Appay, van Lier et al. 2008, Shindo, Kim et al. 2013), and may therefore 
be relatively spared by T-Guard treatment. 
1.3.1.4 
NK Cells Apoptosis 
Aside from T cells, the immunotoxin-antibody combination WT1-RTA also targets NK cells 
(CD3-/CD7+). In the Phase I/II clinical study using T-Guard, NK cells demonstrated the same 
depletion pattern as T cells, an early and quick depletion during the seven-day treatment period, 
followed by a rapid repopulation of the NK cell compartment (Groth, van Groningen et al. 2018). 
The NK cell depletion is thought to contribute to controlling established aGVHD disease, as NK 
cells may aggravate the severity of aGVHD through cytokine production, e.g. Interferon (IFN)-
gamma (Gill, Olson et al. 2009). 
1.3.2 Clinical data 
1.3.2.1 
Clinical Experience with T-Guard in Patients with SR-aGVHD 
T-Guard has been evaluated in two clinical trials: as third-line therapy in an investigator-initiated 
dose escalation-study in seven patients suffering from SR-aGVHD (van Oosterhout, van Emst 
et al. 2000, van Oosterhout, van Emst et al. 2001) and as second-line therapy in a Phase I/II 
study in 20 patients with SR-aGVHD (Groth, van Groningen et al. 2017). Results from these 
studies are summarized below. 


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1.3.2.2 
T-Guard Dose Escalation Study as Third Line for SR-aGVHD Patients 
The main purpose of the investigator-initiated dose escalation study was to test the safety and 
pharmacokinetics (PK) of T-Guard. A total of seven male Caucasian patients, with a median 
age of 47 with SR-aGVHD that had failed second line therapy were included.  Three of these 
patients (43%) had aGVHD Grade IV, 3 patients (43%) Grade III and 1 patient Grade II (14%). 
Six patients (86%) had visceral organ involvement, including four patients (57%) with liver 
involvement and two patients (29%) with GI involvement. One patient (14%) had grade IV 
aGVHD of the skin. Before T-Guard treatment, all patients received an initial course of steroids 
at 1-2mg/kg/day for at least 7 days, followed by 1 gram of methylprednisolone equivalent per 
day or at least 3 days to treat SR-aGVHD. The first two patients started with T-Guard 2mg/m2 
infused every 48 hours x 2 doses, followed by 4mg/m2 every 48 hours x 2 doses. There were 
no toxicities associated with the T-Guard treatment, and therefore the next five patients were 
scheduled to receive 4mg/m2 every 48 hours x 4 doses. 
The infusions were well tolerated, and biologic and clinical responses, as further described 
below, were achieved. Given the activity and tolerance of the 4mg/m2 every 48 hours x 4 doses 
schema, no further dose escalation was completed. The study team was concerned for capillary 
leak syndrome (CLS), which is a known complication of ricin-based immunotoxins. However, 
none of the patients had any severe toxic side effects (grade 3 or higher Common Terminology 
Criteria for Adverse Events (CTCAE) 4.3) associated with RTA-based immunotoxins, like severe 
CLS and rhabdomyolysis. Regarding Treatment Emerging Adverse Events (TEAE), the most 
frequent reported adverse events (AE) were: pyrexia (43%) and headache (29%) followed by 
pain, edema, aphasia, dizziness, epilepsia, diarrhea, hemorrhoids, paralytic ileus and protein 
losing gastroenteropathy (all 14%). 
PK analysis showed that the 4mg/m2 every 48 hours x 4 doses schedule resulted in T-Guard in 
vivo serum peak concentration (Cmax) of around 1.5 µg/ml (~10-8M). On the basis of in vitro 
experiments, the Cmax attained results in a 60-80% occupation of the target antigens CD3 and 
CD7 and corresponds with the optimal in vitro concentration for a specific elimination of antigen-
positive target cells (Figure 1-3). 
Four patients were evaluated for biologic response with flow cytometric quantitation of NK and T 
cell levels. All of these patients showed a rapid and profound reduction in circulating T cells and 
NK cells, with additional doses leading to further reduction (less than 10-20%) of initial levels of 
circulating NK and T cells. With this prompt and marked decline in NK and T cells there was 
clinical improvement in GVHD, with four of the seven patients having clinically meaningful and 
rapid reduction in their GVHD. Five out of 7 patients (71%) responded. One patient (14%) was 
in complete remission, 4 patients (57%) had a PR. To date 6 patients died, two during the first 
eight days of treatment with T-Guard. All patient deaths were related to multisystem organ failure 
and opportunistic infections. 
Since the dose level of T-Guard at 4 mg/m2 x 4 doses generated biologically relevant serum 
concentrations (Cmax of 1.36 ± 0.27 µg/mL) which resulted in clear biological and clinical 
responses without inducing severe acute toxicities, the dosage was not further increased to 
prevent potentially dangerous dose limiting toxicities (DLTs). 


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1.3.2.3 
Single-arm, Phase 1/2 Clinical trial in second line SR-aGVHD Patients 
Following the promising results of T-Guard for the indication SR-aGVHD in the investigator- 
initiated dose escalation study, a Phase 1/2 study XEN/TG-001 was conducted (Groth, van 
Groningen et al. 2018). The study was designed to evaluate the safety and efficacy of T- Guard 
in treating SR-aGVHD patients who were refractory to first-line therapy. Regarding the IMP (T-
Guard), a switch was made to non-glycosylated bacterial produced recombinant RTA. In total 20 
patients were treated with T-Guard with a dose of 4 mg/m2 every other day x 4 doses. All patients 
had SR grade II to IV aGVHD. Seventeen of these patients (85%) had severe SR-aGVHD, and 
all 20 patients had visceral involvement; 18 GI (90%) and 5 liver (25%) involvement. Sixteen 
patients (80%) had 2 or more organs involved. A validated two biomarker algorithm classified 
the majority of patients (11/20) as high-risk. 
The Day 28 ORR (primary endpoint), defined as having a CR or PR without the need for initiation 
of other treatments due to insufficient response, was 60%. Day 28 CR was 50% and PR 10%. 
The Day 180 OS was 60%. The outcomes achieved were very favorable compared with the 
historical standard of care (SoC) data at the participating centers (Day 28 CR less than 20% and 
Day 180 OS 29%). 
1.3.2.4 
Safety 
The most common side-effects described for RTA-based immunotoxins are vascular leakage 
and myalgia, the latter being often associated with an increase in serum creatine kinase (CK). 
Moreover, the systemic administration of anti-CD3 antibodies may result in the activation of T- 
cells leading to CRS. In both trials T-Guard was overall well-tolerated. Mild infusion related 
reactions, such as mild chills, were documented. However, no acute toxicity reactions seen were 
greater than Grade 1. The most commonly reported AEs considered to be related to T- Guard 
administration were hypoalbuminemia and thrombocytopenia. 
The potentially drug-associated side effects occurring in more than one patient consisted of 
(further) decrease in platelet count (thrombocytopenia), hypoalbuminemia and thrombotic 
microangiopathy. Regarding thrombocytopenia and hypoalbuminemia, the patients in the study 
already had a low platelet count and albumin level due to aGVHD and medication. Nevertheless, 
in several patients, a further decrease was observed during the treatment period. According to 
the Principal Investigators, thrombocytopenia and hypoalbuminemia were well-manageable. 
TEAEs from the overall study are outlined in Table 1-1 from the Phase I/II Trial. 
Table 1-1: Most Frequently Reported System Organ Class (≥10 Patients in Total) and 
Preferred Term (≥5 Patients in Total) for TEAEs, Overall Study 
 
System organ class/ Preferred term 
Total (N=20) n (%) 
Any adverse event 
20 (100.0%) 
Infections and infestations 
19 (95.0%) 
Upper respiratory tract infection 
5 (25.0%) 
Metabolism and nutrition disorders 
17 (85.0%) 


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System organ class/ Preferred term 
Total (N=20) n (%) 
Hypoalbuminemia 
8 (40.0%) 
Hyperglycemia 
7 (35.0%) 
Hypokalemia 
5 (25.0%) 
Hypophosphatasemia 
5 (25.0%) 
General disorders and administration site conditions 
16 (80.0%) 
Edema peripheral 
8 (40.0%) 
Pyrexia 
8 (40.0%) 
Fatigue 
6 (30.0%) 
Gastrointestinal disorders 
15 (75.0%) 
Nausea 
5 (25.0%) 
Investigations 
13 (65.0%) 
Blood bilirubin increased 
6 (30.0%) 
White blood cell count decreased 
5 (25.0%) 
Musculoskeletal and connective tissue disorders 
13 (65.0%) 
Muscular weakness 
5 (25.0%) 
Myopathy 
5 (25.0%) 
Vascular disorders 
12 (60.0%) 
Capillary leak syndrome 
8 (40.0%) 
Blood and lymphatic system disorders 
11 (55.0%) 
Anemia 
6 (30.0%) 
Thrombocytopenia 
6 (30.0%) 
Nervous system disorders 
11 (55.0%) 
 
In total 29 Serious Adverse Events (SAE) were reported in 14 patients (Table 1-2). Of those 
SAEs, 23 were reported as severe, 4 as moderate and 2 as mild. Eight (8) patients died during 
the course of the trial. The causes of death were determined to be refractory aGVHD, infections 
or the combination of the two. All deaths were reported as not related to T-Guard. No deaths 
occurred before 6 months (Day 180) due to relapse of the underlying disease. 
Table 1-2: Summary of Adverse Events Potentially Related to Treatment (Groth, van 
Groningen et al. 2018) 
 
Grade 2a 
Grade 3 
Grade 4 
Anemia (1)b 
Thrombocytopenia (3) 
Thrombocytopenia (5) 
Abdominal pain (1) 
Neutropenia (1) 
Thrombocytopenia (1) 
Elevated bilirubin (2) 
Neutropenia (1) 
Myopathy (1) 
Microangiopathy (1) 
Microangiopathy (1) 


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Grade 2a 
Grade 3 
Grade 4 
Chills (2) 
Hypoalbuminemia (1) 
Capillary leak syndrome (1) 
Hypoalbuminemia (1) 
 
Grading of each AE is based on version 4.0 of the CTCAE, with the exception of CLS, which 
was graded using the system described by Messmann et al. (Messmann, Vitetta et al. 2000) 
The numbers in parentheses refer to the number of patients who experienced the indicated 
adverse event. 
The overall conclusion of the Phase 1/2 study is that T-Guard was well tolerated and can be 
safely administered in patients with SR-aGVHD. Additionally, the response rates, in particular 
CR rates, at Day 28 were markedly superior (CR 50%) to historical controls and the results of 
emerging therapies (CR 20-35%). 
1.3.3 Justification for the Proposed Dose Regimen for this Phase III Clinical Trial 
Using T-Guard as First Line SR-GvHD Treatment 
The proposed dose for the T-Guard Phase 3 study is 4 mg/m2 / dose q 48 hours x 4 doses. This 
dose is based on the following data: 
In the investigator-initiated dose-escalation study (van Oosterhout, van Emst et al. 2000, van 
Oosterhout, van Emst et al. 2001) it was determined that the second dose level of 4 mg/m2/dose 
q 48 hours x 4 doses delivered positive biological and clinical responses, without inducing any 
severe acute toxicities. 
PK analysis showed that the 4 mg/m2 x 4 doses schedule led to T-Guard in vivo serum Cmax of 
around 1.5 µg/ml (~10-8M). On basis of in vitro experiments, the Cmax attained results in a 60-
80% occupation of the target antigens CD3 and CD7. It has been shown in in vitro studies that 
this concentration is very effective in specifically eliminating antigen-positive target cells by RTA-
based immunotoxins (Derocq, Laurent et al. 1987, Preijers, De Witte et al. 1988, Preijers, Tax 
et al. 1988, Preijers, Tax et al. 1988, Herrera, Farah et al. 2000). 
Given the 50% Day 28 CR rate observed in the T-Guard Phase 1/2 study, it could be argued 
that the clinical benefit may be further optimized by administering a higher T-Guard dose. When 
judging the response rate, though, consideration is given to the high incidence of serious 
comorbidities in this severely ill population. Four of the 20 patients of the T-Guard Phase 1/2 
study died before Day 28 due to comorbidities; two patients died from sepsis (non- treatment 
related), one patient died in the treatment week with uncontrolled viral infections, and another 
patient had vanishing bile duct syndrome with very rare aberrant bile ducts at treatment start 
suggestive for co-existing liver disease of different etiology. When these four patients are 
censored, the Day 28 response rate increases to 63% CR (10/16) and 75% ORR (12/16), 
respectively. In the Phase 1/2 study, the adverse events judged to be potentially treatment-
related were clinically manageable and included 7 mild cases (35%) and 1 moderate case (5%) of 
CLS. 
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determined for similar RTA-based immunotoxins typically lies between 4 and 8 mg/m2 with 
capillary leakage being the most common dose limiting toxicity (Amlot, Stone et al. 1993, Stone, 
Sausville et al. 1996, Engert, Diehl et al. 1997, Messmann, Vitetta et al. 2000, Schnell, Staak et 
al. 2002, Schindler, Gajavelli et al. 2011). Thus, given concern for increased toxicity due to the 
immunotoxin at higher doses, the Food and Drug Administration was in agreement with the 
proposed dose selection. In conclusion, the observed positive benefit-risk profile of the proposed 
dose regimen is considered sufficient to focus on confirming the safety and efficacy of T-Guard’s 
current 4 x 4 mg/m2 dose in a pivotal Phase 3 clinical study. In the proposed pivotal Phase 3 
study, further data will be collected to investigate if biomarkers can be identified that correlate 
with clinical efficacy and safety. 
1.4 
STUDY RATIONALE 
T-Guard has a rapid onset, preferential killing of activated T cells, and short half-life, leading to 
depletion of allo-reactive T cells and quick post-treatment reconstitution of the immune system. 
In the Phase 1/ 2 trial with T-Guard, peripheral blood samples were analyzed before and after 
treatment. As expected, treatment with T-Guard led to profound depletion of T cells and NK 
cells, with rapid recovery starting as early as 14 days following treatment. (Figure 1- 4). No 
specific treatment-induced changes in the relative proportions of naïve, memory, effector and 
effector memory type of T-cells were found before and after treatment, and regulatory T cells 
showed normal variation throughout the study. The study of T cell diversity found low T-cell 
diversity before T-Guard treatment, which further declined by month one post- treatment, likely 
due to reduction in T cell numbers. This was followed, at months two through six, with a steady 
rebound in the T-cell diversity. By 180 days post-treatment the T-cell repertoire was both diverse 
and expanded, with several new polyclonal T cell populations found. 
The proposed model is that immunodepleting the vast majority of alloreactive T cells will shift 
the immune balance to a more tolerogenic state in SR-aGVHD patients, resulting in better 
disease control and an improved survival. We hypothesize depleting NK cells will contribute to 
the tolerogenic state by suppressing cytokine release and inflammation. 
Given the high mortality and limited treatment options for patients with SR-aGVHD, we propose 
conducting a Phase III single arm open label multicenter trial to evaluate the safety and efficacy 
of T-Guard. A single arm study is justified given that this is a rare disease without an established 
SoC, yet with compelling historical data on response and survival rates. The 50% Day 28 CR 
rate observed in the T-Guard Phase I/II study compares favorably to the 31% CR rate seen with 
ruxolitinib in the REACH1 trial. This well-controlled Phase III trial will evaluate the hypothesized 
improvement in Day 28 CR rates in combination with the proposed PK, immunogenicity, and 
biomarker studies while evaluating durability of CR and OS. 


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Figure 1-4: T-Guard Observed Immune Reconstitution 
T-Guard induces rapid immune reconstitution with a diverse T cell repertoire. (A-C) Time course 
of the median T cell count (A), median NK cell count (B), and median B cell count (C) for all 
patients. In each plot, the blue line represents the median value, and the lower and upper gray 
dotted lines represent the 25th and 75th percentiles, respectively. (D) Summary of the absolute 
number of unique T cell clones before administration of T-Guard (Pre) and at 30, 90, and 180 
days after treatment. The number of unique T cell clones was measured using the total number 
of unique CDR3 sequences. The P values are based on the Wilcoxon matched-pairs signed-
rank test. The significant increase in unique T cell clones at Day 180 after T-Guard treatment 
reflects an increase in the diversity of expanded T cells. (E-H) Representative histograms 


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showing the T cell repertoires in a single patient before T-Guard treatment (E) and at 30 days 
(F), 90 days (G), and 180 days (H) after therapy. 
1.5 
INCLUSION OF CHILDREN AGE 12-17 
This study allows children aged 12-17 to enroll. This study will be a first in the evaluation of the 
safety and effectiveness of T-Guard in a pediatric population. Only adolescent children, who are 
most similar to adult patients, will be treated to mitigate risk. As in adults, SR-aGVHD is a highly 
morbid and life-threatening complication of transplant. Ruxolitinib is now FDA- approved for 
treatment of SR-aGVHD in ages 12 and above. However, the 50% Day 28 CR rate observed in 
the T-Guard Phase 1/2 study compares favorably to the 31% CR rate seen with ruxolitinib in the 
REACH1 trial. Ruxolitinib is also only available as an oral compound and given as an extended 
treatment course, which may not be tolerable for SR-aGVHD patients with GI involvement. Given 
the high rates of GI involvement in SR-aGVHD and short IV course of T-Guard, enrollment of 
children ages 12 and above on this trial is justified. 


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CHAPTER 2 
2 
STUDY DESIGN 
2.1 
STUDY OVERVIEW 
This is a Phase III, open label, single arm, multicenter trial designed to evaluate the efficacy of T-
Guard treatment in patients with SR-aGVHD. 
2.2 
HYPOTHESIS AND SPECIFIC OBJECTIVES 
2.2.1 Primary Hypothesis 
The primary hypothesis is that T-Guard treatment will improve the Day 28 complete remission (CR) 
rate in patients with steroid-refractory (SR) acute GVHD (aGVHD). 
2.3 
STUDY OBJECTIVES 
2.3.1 Primary Objective 
The primary objective of this trial is to assess the rate of Day 28 CR in SR acute GVHD patients treated 
with T-Guard treatment. 
2.3.2 Secondary Objectives 
1. Evaluate the duration of complete response (DoCR). 
2. Estimate overall survival (OS) at Days 90 and 180 post initiation of T-Guard treatment. 
3. Estimate the overall response rate (CR or partial response (PR)) at Days 14, 28, and 56 post 
initiation of T-Guard treatment. 
4. Describe proportions of CR, PR, mixed response (MR), no response (NR), and progression of 
aGVHD at Days 7, 14, 28, and 56 post initiation of T-Guard treatment. 
5. Estimate the cumulative incidence of NRM at Days 100 and 180 post initiation of T- Guard 
treatment. 
6. Estimate relapse-free survival at Day 180 post initiation of T-Guard treatment. 
7. Estimate GVHD-free survival at Days 90 and 180 post initiation of T-Guard treatment. 
8. Estimate the cumulative incidence of cGVHD at Day 180 post initiation of T-Guard treatment. 
9. Estimate the cumulative incidence of disease relapse/progression at Day 180 post initiation of 
T-Guard treatment. 
10. Describe the incidence of systemic infections. 
11. Describe the incidence of toxicities. 
12. Assess the pharmacokinetics of T-Guard. 
13. Assess the immunogenicity of T-Guard. 
 


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2.3.3 Exploratory Objectives 
1. Describe corticosteroid-dose (measured in prednisone-equivalent) at baseline, Days 28 and 
56 post initiation of T-Guard treatment. 
2. Estimate the rate of near-CR (i.e. CR in GI and Liver with only Stage 1 Skin) at Days 28 and 
56 post initiation of T-Guard treatment. 
3. Describe discontinuation of systemic steroids by Day 180 post initiation of T-Guard treatment. 
4. Estimate the incidence of CMV reactivation requiring treatment by Day 180 post initiation of T-
Guard treatment. 
5. Estimate the incidence of EBV-associated lymphoproliferative disorder or EBV reactivation 
requiring treatment with rituximab by Day 180 post initiation of T-Guard treatment. 
6. Describe the incidence of IMP related SAEs. 
7. Evaluate T-cell subsets and NK-cells at baseline and at Days 0, 2, 4, 6 (just prior to and 4 hours 
after each T-Guard infusion) and then subsequently at Days 14, 28, 56, and 180. 
8. Evaluate aGVHD Biomarkers at baseline and at Days 7, 14 and 28 post initiation of T- Guard 
treatment. 
9. Describe changes in patient-reported outcomes (PROs) from baseline to Days 28, 56 and 180 
post initiation of T-Guard treatment. 
2.4 
PATIENT ELIGIBILITY 
2.4.1 Inclusion Criteria 
To be eligible to participate in this study, patients must meet the following eligibility criteria: 
1. Patient must be at least 12.0 years of age at the time of consent. 
2. Patient has undergone first allo-HSCT from any donor source using bone marrow, peripheral 
blood stem cells, or cord blood. Recipients of nonmyeloablative, reduced intensity, and 
myeloablative conditioning regimens are eligible. 
3. Patients diagnosed with SR-aGVHD after allo-HSCT.  SR is defined as aGVHD that: 
• 
Progressed after 3 days of primary treatment with prednisone (or equivalent) of greater 
than or equal to 2 mg/kg/day 
• 
No improvement after 7 days of primary treatment with prednisone (or equivalent) 
of greater than or equal to 2mg/kg/day 
• 
Patients with visceral (GI and/or liver) plus skin aGVHD at prednisone (or equivalent) 
initiation with improvement in skin GVHD without any improvement in visceral GVHD 
after 7 days of primary treatment with prednisone (or equivalent) of greater than or 
equal to 2mg/kg/day 
• 
Previously was treated with prednisone (or equivalent) of greater than or equal to 
1mg/kg/day and aGVHD has developed in a previously uninvolved organ system 


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Progression and no improvement are defined in Section 3.1. Improvement or progression in 
organs is determined by comparing current organ staging to staging at initiation of prednisone 
(or equivalent) treatment. Staging is performed per MAGIC criteria (Appendix C). 
4. Evidence of myeloid engraftment (e.g., absolute neutrophil count greater than or equal to 0.5 × 
109/L for 3 consecutive days if ablative therapy was previously used). Use of growth factor 
supplementation is allowed. 
5. Patients or an impartial witness (in case the patient is capable of providing verbal consent but 
not capable of signing the informed consent form (ICF)) should have given written informed 
consent. For patients less than 18 years of age, a written informed consent of the parents or 
guardian and written assent of the patient will be obtained, per the local requirements. 
2.4.2 Exclusion Criteria 
Patients will be excluded from study entry if they meet any of the following exclusion criteria: 
1. Patients who have been diagnosed with overlap syndrome, that is, with any concurrent features 
of cGVHD. 
2. Patients requiring any of the following: mechanical ventilation, vasopressor support, or 
hemodialysis. 
3. Patients who have received any systemic treatment, besides steroids, as upfront treatment of 
aGVHD OR as treatment for SR-aGVHD. 
4. Patients who have severe hypoalbuminemia, with an albumin of less than or equal to 1 g/dl. 
5. Patients who have a CK level of greater than 5 times the upper limit of normal. 
6. Patients with uncontrolled infections. Infections are considered controlled if appropriate therapy 
has been instituted and, at the time of enrollment, no signs of progression are present. 
Progression of infection is defined as hemodynamic instability attributable to sepsis, new 
symptoms, worsening physical signs or radiographic findings attributable to infection. Persisting 
fever without other signs or symptoms will not be interpreted as progressing infection. 
7. Patients with evidence of relapsed, progressing or persistent malignancy. 
8. Patients with evidence of minimal residual disease requiring withdrawal of systemic immune 
suppression. 
9. Patients with known hypersensitivity to any of the components murine monoclonal 
antibodies (mAb) or Recombinant Ricin Toxin A-chain (RTA). 
10. Patients who have received more than one allo-HSCT. 
11. Patients with known human immunodeficiency virus infection. 
12. Female patients who are pregnant, breast feeding, or, if sexually active and of childbearing 
potential, unwilling to use effective birth control from start of treatment until 30 days after the 
last infusion of T-Guard. 
13. Male patients who are, if sexually active and with a female partner of childbearing potential, 
unwilling to use effective birth control from start of treatment until 65 days after the last infusion 
of T-Guard. 
14. Patients with any condition that would, in the investigator's judgment, interfere with full 


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participation in the study, including administration of study drug and attending required study 
visits; pose a significant risk to the patient; or interfere with interpretation of study data. 
15. Patients whose decision to participate might be unduly influenced by perceived expectation of 
gain or harm by participation, such as patients in detention due to official or legal order. 
2.5 
TREATMENT PLAN 
2.5.1 T-Guard Treatment 
T-Guard product will be supplied as 2 separate liquids for infusion, i.e.: 
SPV-T3a-RTA, having a protein concentration of 0.2 mg/ml, and filled in 12.5 ml fractions in 20 
RDIN (20 ml) Type I glass bottles with rubber stop and pull-off aluminum cap that are to be stored 
at -20°C. 
WT1-RTA, having a protein concentration of 0.2 mg/ml, and filled in 12.5 ml fractions in 20 RDIN 
(20 ml) Type I glass bottles with rubber stop and pull-off aluminum cap that are to be stored at -
20°C. 
All medication used in this study will be prepared and labeled according to the rules of Good 
Manufacturing Practice, International Conference on Harmonization (ICH)-Good Clinical Practice 
(GCP) and local regulatory requirements. Since this is an open label trial, blinding procedures are 
not applicable. 
2.5.2 Storage, Handling, and Dispensing of T-Guard 
T-Guard will be prepared for infusion by the pharmacy of the participating centers. 
The liquids for infusion containing either SPV-T3a-RTA or WT1-RTA are provided at a 
concentration of 0.2 mg protein/ml in vials containing 12.5 ml of infusion liquid in -20 °C. The vials 
are to be stored immediately at -20 °C freezer until use. A certificate of analysis will be provided 
indicating the expiry date. 
Before administration to the patient, the medication is brought to room temperature for 1.5 h, mixed 
and transferred to a syringe. Before the start of administration, the prepared infusion syringe can 
be stored for up to 4 hours, at room temperature (20 ± 5 °C), in a controlled environment. 
Detailed directions for use can be found in the Pharmacy Manual.  
2.5.3 Drug Accountability 
T-Guard will be delivered at the Investigational Pharmacy per the Pharmacy Manual. The 
Investigational Pharmacist at each site will be responsible for receiving, storing, distributing and 
accounting of the study drug. All study medication supplied for the study should be kept in a locked 
secure place with appropriate pharmaceutical precautions. 
A “Drug Accountability” record for T-Guard should be maintained by the person responsible for 
dispensing the trial medication to the patient. This record should contain which supplies are issued 
to which patients, including the times of dosing, and any drugs returned unused. Details of any 
supplies that are inadvertently damaged should be reported on this record.  Further information on 


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study drug accountability is provided in the Pharmacy Manual. Study drug accountability logs will 
be monitored per the clinical monitoring plan. 
All unused study medication should be kept and added to the drug accountability record. All study 
medication in these categories will be inventoried by the monitor during and at the conclusion of 
the study. The monitor will arrange for their secure disposal at the end of the study. 
The drugs supplied for this study are only intended for use by patients enrolled in this study. They 
must not be diverted for use by others. 
2.5.4 Dose and Administration of T-Guard 
T-Guard will be administered at a dose of 4mg/m2 (actual body weight) over 4 hours every 2 
calendar days on Days 0, 2, 4, and 6. Infusions of T-Guard that exceed 4 hours are not considered 
deviations. Pauses in the infusion due to a patient reaction need to be documented. 
The maximum BSA to be used in dose calculation is 2.5 m2. If the patient’s BSA is more than  
2.5 m2, the dose calculation should use 2.5 m2.  The patient’s weight on the day of the first dose will 
determine the dose for the remaining infusions (dose adjustments for changes in weight during the 
treatment period will not be made). 
Premedication with diphenhydramine 50 mg by mouth or 25 mg IV should be administered 30 
minutes prior to each dose. For pediatric patients, the diphenhydramine dose should not exceed 1 
mg/kg. Premedication with acetaminophen is permitted. 
It is recommended that T-Guard be infused via a central catheter using a dedicated line or can be 
administered via a peripheral line, if needed. If a multi-lumen central venous catheter is used, T-
Guard and crystalloid or total parenteral nutrition should be administered through different lumens 
of the catheter. PK samples should be drawn from the central catheter using a different lumen than 
the lumen used for infusion. 
Before the infusion, connect the syringe with the in-line filter and luer-lock extension tube to a 
central venous catheter (recommended) or peripheral line. The contents of the syringe will then be 
administered by means of an automated infusion device, over a period of 4 hours. Once the infusion 
syringe is empty, the administration tubes will be flushed. 
Vital signs (temperature, pulse, respiratory rate, blood pressure), should be checked at the 
following timepoints with each infusion: just before starting the infusion, 15 minutes after the start 
of the infusion, 30 minutes after the start of the infusion, then every 30 minutes during the infusion, 
and at 1-hour post-infusion. Deviation of +/- 5 minutes may occur for all vital sign collection 
timepoints. 
Infusion-related reactions are a potential risk with this medication. If the patient experiences a grade 
3 or 4 infusion related reaction, the infusion should be held, and the reaction managed per 
institutional standards. Once the reaction has resolved the infusion can be restarted at half the 
rate. Subsequent infusions should be managed with an escalation in premedication based on type 
of reaction and initiated at the half rate. After 15 minutes, if no reactions are noted, then the infusion 
rate can be escalated to the full rate as tolerated. 


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Patients should receive a maximum of 4 doses. The minimal interval between doses is 2 days (no 
less than 40 hours apart). If required for logistics, a delay of up to 1 day can occur between one of 
the doses during the treatment course. If toxicity occurs, then dosing can be delayed until toxicity 
improves, but all dosing must be completed within 14 days. 
2.5.5 Toxicities and Guidelines for Withholding T-Guard 
The following are expected toxicities that may impact administration of T-Guard. 
Allergic reactions: 
Each of the following well-recognized allergic reactions to foreign protein may follow the 
administration of a monoclonal antibody including urticaria, bronchospasm, anaphylaxis, Arthus 
reaction, vasculitis, and serum sickness. Symptoms will be monitored closely and should be treated 
per SoC. Appropriate medications should be readily available at the bedside, including epinephrine, 
hydrocortisone and diphenhydramine. 
Anaphylactic reaction: 
Administration of xenogeneic proteins may be accompanied by anaphylactic reactions that are 
mostly IgE mediated. The most probable time of onset, if occurring, is within 10 minutes after 
starting T-Guard infusions. This acute hypersensitivity reactions may be characterized by: 
cardiovascular collapse, cardiorespiratory arrest, loss of consciousness, hypotension, pulmonary 
edema especially in patients with volume overload, seizures or coma, tachycardia, pruritus, 
urticaria, tingling, angioedema including laryngeal, pharyngeal or facial edema, dyspnea, 
bronchospasm, and airway obstruction. 
 
Capillary Leak Syndrome (CLS): 
Manifested as hypotension, fluid overload, weight gain or edema, dyspnea, anorexia, nausea, and 
in some cases confusion, and muscle damage. Investigative findings, may include, hypoxia, 
hypoalbuminemia, pulmonary edema, pleural effusion. Patients experiencing severe CLS 
(requiring pressors, dialysis, mechanical ventilator support) related to study treatment should have 
their treatment held until 72 hours after cessation of pressors, dialysis, or mechanical ventilator 
support. 
Hypoalbuminemia: 
Severe hypoalbuminemia is a risk for CLS. Therefore, if the albumin level is less than or equal to 1 
g/dL, dosing should be held until the albumin level is greater than1 g/dL. Dosing can be based on 
the albumin level within 48 hours of dosing. If the treating physician feels that there has been 
benefit from dosing, then further dosing can be discussed with the protocol chairs. 
Myalgia and serum CK-elevation: 
If an anaphylactic reaction is suspected, T-Guard administration should be 
discontinued immediately. Therapy should not be resumed, nor should the patient be 
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There is an association of myositis with Ricin-based immunotoxicity. Therefore, patients should 
be monitored for signs of myositis. If patients experience muscle pain, then a serum CK should 
be performed. The next dosage of T-Guard should be withheld in case of a CK elevation greater 
than 5 times ULN. Dosing can resume if the CK decreases to less than or equal to 5 ULN and 
symptoms of myositis has improved to Grade 2 or less by CTCAE v.5. Dosing can proceed at the 
investigator’s discretion if deemed in the best interest of the patient. 
Other toxicities: 
Patients with another non-hematologic grade 3 or higher toxicity which is not attributable to an 
expected post-transplant event may have their study drug held at the attending physician’s 
discretion. Expected post-transplant events include steroid-related toxicity and chemotherapy 
toxicity. T-Guard should be restarted after recovery of related toxicities to grade 2 or lower or 
identification of an alternative cause for these toxicities. 
Infection: 
Patients with severe infections resulting in hemodynamic instability requiring use of vasopressor 
medication may have study drug held at the discretion of the treating physician. 
2.5.6 T-Guard Discontinuation 
T-Guard treatment must be completed within 14 days of the first study drug dose. Patients who 
have missed doses may re-start T-Guard provided it is within the 14-day treatment window. 
2.5.7 Acute GVHD Progression or Non-response 
If additional systemic acute GVHD treatment, other than steroids, is added for lack of response or 
progression, T-Guard treatment must be discontinued and not re-instituted. 
2.5.8 Supportive Care 
2.5.8.1 
Corticosteroid Dosing 
For patients with SR-aGVHD a gradual taper of steroids rather than an abrupt discontinuation of 
steroids is recommended. Corticosteroid taper may be done per institutional practice or may follow 
the suggested schedule below for responding patients. Patients on 1 mg/kg/day may follow the 
taper beginning on week 2. 
 
 


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Table 2-1: Suggested Steroid Taper Protocol 
 
Week (After study initiation) 
Steroid Dose 
Week 1 
1.5 mg/kg/day 
Week 2 
1.0 mg/kg/day 
Week 3 
0.5 mg/kg/day 
Week 4 
0.25 mg/kg/day 
Week 5 
0.2 mg/kg/day 
Week 6 
0.1 mg/kg/day 
Week 7 
0.1 mg/kg/every other day 
2.5.8.2 
GVHD Prophylaxis Medications 
Medications such as cyclosporine, tacrolimus, mycophenolate mofetil (MMF), sirolimus (if used as 
GVHD prophylaxis prior to the development of acute GVHD) may be continued, resumed, or 
increased to therapeutic doses per provider discretion, and adjusted/discontinued as necessary for 
renal, central nervous system (CNS) or other toxicity using institutional management guidelines. 
Resumption of a GVHD prophylaxis agent is not considered the addition of a second agent. 
2.5.8.3 
Topical and Ancillary GVHD Therapies 
Topical treatment for acute GVHD is allowed and should be used according to institutional 
practices. Topical treatment, including corticosteroid creams, topical tacrolimus, oral 
beclomethasone or budesonide, topical azathioprine and ophthalmic glucocorticoids, is not 
considered as secondary systemic treatment. 
Ancillary/supportive care measures for acute GVHD such as the use of anti-motility agents for 
diarrhea, including octreotide, is allowed at the discretion of the treating physician. Use of ursodiol 
to prevent/reduce gall bladder sludging or prevent hepatic transplant complications is also allowed 
according to institutional guidelines. 
2.5.8.4 
Other Supportive Care Guidelines 
In addition to T-Guard, all patients should receive the following per institutional practice: 
• 
Transfusion support 
• 
Anti-infective prophylaxis against herpes viruses, Pneumocystis jiroveci, bacterial and 
fungal infections. 
• 
Routine CMV antigenemia/viral load testing by hybrid capture or PCR based methods (with 
preemptive treatment in patients who develop a positive assay). CMV testing is 
recommended weekly through at least Day +100 post-transplant. Prophylaxis against CMV 
is allowed. 
• 
In addition to the required monitoring for EBV according to the study calendar, monitoring 
for viral infections such as EBV, adenovirus, and HHV6 is encouraged for patients at high 
risk in accordance with institutional practice. 


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• 
Co-enrollment onto supportive care and infectious disease protocols will be allowed on case-
by-case basis and requires approval by study chair or officer and sponsor. 
2.5.9 Follow-Up Post Treatment Discontinuation 
Patients may withdraw from treatment at any time for any reason. The reason should be 
documented by the study team. However, patients that have received at least one treatment dose 
are evaluable for all endpoints of the study and should continue with protocol-specific follow-up and 
data collection unless consent to study is withdrawn. Enrolled patients that do not receive any study 
treatment may be replaced. Patients that receive at least one treatment dose remain on study and 
are evaluable for all endpoints as above. 
2.6 
STUDY CONDUCT 
This study will be conducted in accordance with the protocol, the BMT CTN MOP, and the following: 
• 
Consensus ethical principles derived from international guidelines including the Declaration 
of Helsinki 
• 
Applicable ICH Good Clinical Practice (GCP) Guidelines 
• 
Applicable laws and regulations 
The National Marrow Donor Program (NMDP) single Institutional Review Board (IRB) of Record will 
oversee this study and conduct the study-specific reviews as required by federal regulations and per 
the NMDP IRB Standard Operating Procedures (SOPs). 
Site personnel will enter data in the electronic case report form (eCRF) in Advantage eClinical as 
described in the BMT CTN 1802 eCRF Completion Guide. Source documentation should be made 
available for monitoring visits, audits and regulatory inspections as described in the BMT CTN MOP.  
Participating Principal Investigators bear ultimate responsibility for training of site staff as well as the 
scientific, technical, and administrative aspects of conduct of the protocol, even when certain tasks 
have been delegated to coinvestigators, sub-investigators, or staff. The PIs have a responsibility to 
protect the rights and welfare of participants and comply with all requirements regarding the clinical 
obligations and all other pertinent requirements in 21 CFR part 312. In addition to following 
applicable federal, state, and local regulations, investigators are expected to follow ethical principles 
and standards and receive training in GCP every three years and human subjects training within the 
past 3 years and thereafter as per institutional requirements.


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CHAPTER 3 
3 
STUDY ENDPOINTS 
3.1 
ACUTE GVHD RESPONSE DEFINITIONS 
Scoring of aGVHD response on a given day is in comparison to the patient’s aGVHD staging on 
the day of initial T-Guard treatment. Organ staging will be assessed using the Harris criteria 
(Appendix C) and response will be scored as defined below: 
Complete response (CR) is defined as a score of 0 for the GVHD staging in all evaluable organs. 
For example, for a response to be scored as CR, the patient must still be in CR on that day and 
have had no intervening additional systemic therapy for treatment of aGVHD. 
Near-CR is defined as a score of 0 for the GI and/or liver GVHD staging, but with persistence of 
skin rash at less than 25% BSA (Stage 1 skin GVHD). Near CR can only occur in patients with 
both visceral and skin aGVHD. 
Partial response (PR) is defined as improvement in one or more organs involved with GVHD 
symptoms without progression in others. For example, for a response to be scored as PR, the 
patient must still be in PR on that day and have had no intervening additional systemic therapy 
for treatment of aGVHD. 
Mixed response (MR) is defined as improvement in one or more organs with deterioration in 
another organ manifesting symptoms of GVHD or development of symptoms of GVHD in a new 
organ. 
No response (NR) is defined as absence of any improvement or progression as defined. 
Patients receiving additional systemic therapy will be classified as non-responders. 
Progression is defined as deterioration in at least one organ without any improvement in others. 
Loss of CR or near-CR is defined as progression of aGVHD symptoms requiring additional 
systemic therapy; death; or if the patient develops new target organ symptoms that could qualify 
as being from either aGVHD or cGVHD (if the new symptoms are only associated with cGVHD 
then this is not considered a loss of CR). 
3.2 
RELAPSE DEFINITION 
Malignancy relapse is defined as follows: 
Relapse is defined by either morphological or cytogenetic evidence of acute leukemia or MDS 
consistent with pre-transplant features, or radiologic evidence of lymphoma, documented or not 
by biopsy. Progression of disease applies to patients with lymphoproliferative diseases 
(lymphoma or chronic lymphocytic leukemia) not in remission prior to transplantation. The event 
is defined as increase in size of prior sites of disease or evidence of new sites of disease, 
documented or not by biopsy. 
Acute leukemia, CML and MDS – Relapse will be diagnosed when there is: 
• 
Reappearance of leukemia blast cells in the peripheral blood; or, 


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• 
Greater than 5% blasts in the bone marrow, not attributable to another cause (e.g. bone 
marrow regeneration) 
• 
The appearance of previous or new dysplastic changes (MDS specific) within the bone 
marrow with or without falling donor chimerism; or 
• 
The development of extramedullary leukemia or leukemic cells in the cerebral spinal fluid 
or 
• 
The reappearance of cytogenetic abnormalities present prior to transplantation 
 
Lymphoproliferative Diseases – Relapse or progression will be diagnosed when there is: 
• 
Appearance of any new lesion more than 1.5 cm in any axis during or at the end of 
therapy, even if other lesions are decreasing in size. Increased fluoro- deoxyglucose 
(FDG) uptake in a previously unaffected site will only be considered relapsed or 
progressive disease (PD) after confirmation with other modalities. In patients with no 
prior history of pulmonary lymphoma, new lung nodules identified by CT are mostly 
benign. Thus, a therapeutic decision should not be made solely on the basis of the 
positron emission tomography (PET) without histologic confirmation. 
• 
At least a 50% increase from nadir in the sum of the product diameters of any previously 
involved nodes, or in a single involved node, or the size of other lesions (e.g., splenic or 
hepatic nodules). To be considered PD, a lymph node with a diameter of the short axis 
of less than 1.0 cm must increase by ≥ 50% and to a size of 1.5 x 1.5 cm or more than 1.5 
cm in the long axis. 
• 
Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the lesion 
was PET positive before therapy unless the lesion is too small to be detected with current 
PET systems (less than 1.5 cm in its long axis by CT). 
• 
In addition to the criteria above, patients with chronic lymphocytic leukemia (CLL) who 
present in complete remission prior to transplantation may fulfill the relapse definition if 
there is reappearance of circulating malignant cells that are phenotypically characteristic 
of CLL. 
Multiple myeloma – Clinical relapse is defined as meeting one or more of the following criteria: 
• 
Direct indicators of increasing disease and/or end organ dysfunction (CRAB features) 
related to the underlying clonal plasma-cell proliferative disorder. It is not used in 
calculation of time to progression or progression-free survival but is listed as something 
that can be reported optionally or for use in clinical practice; 
• 
Development of new soft tissue plasmacytomas or bone lesions (osteoporotic fractures 
do not constitute progression); 
• 
Definite increase in the size of existing plasmacytomas or bone lesions. A definite 
increase is defined as a 50% (and greater than or equal to1 cm) increase as measured 
serially by the SPD§§ of the measurable lesion; 
• 
Hypercalcaemia (greater than 11 mg/dL); 
• 
Decrease in haemoglobin of greater than or equal to 2 g/dL not related to therapy or 
other non-myeloma-related conditions; 
• 
Rise in serum creatinine by 2 mg/dL or more from the start of the therapy and attributable 
to myeloma; 
• 
Hyperviscosity related to serum paraprotein. 
For the purposes of assessing relapse free survival (RFS), if the patient is in a CR, any one or 
more of the following will be considered a relapse: 


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• 
Reappearance of serum or urine M-protein by immunofixation or electrophoresis; 
• 
Development of greater than or equal to 5% plasma cells in the bone marrow; 
• 
Appearance of any other sign of progression (i.e., new plasmacytoma, lytic bone 
lesion, or hypercalcaemia see above). 
Myeloproliferative Neoplasms: Relapse from CR is defined as: 
• 
Reappearance of bone marrow disease, including blasts, monocytic blast equivalents, 
or fibrosis 
• 
New extramedullary disease, including new or reappearance of splenomegaly, 
hepatomegaly, skin lesions, etc. 
*Institution of any therapy to treat persistent, progressive or relapsed malignancy, 
including the withdrawal of immunosuppressive therapy or donor lymphocyte infusion, 
will be considered evidence of relapse/progression regardless of whether the criteria 
described above were met. 
Non-malignant Diseases: Non-malignant diseases will be considered to have a transplant 
status of persistent/active disease. Graft failures will be considered recurrence. 
3.3 
PRIMARY ENDPOINT 
The primary endpoint is the proportion of patients with a CR at Day 28 after start of T-Guard 
treatment (first infusion). 
3.4 
SECONDARY ENDPOINTS 
3.4.1 Key Secondary Endpoints: 
3.4.1.1 
Duration of Complete Response (DoCR) 
DoCR is defined as the time from first observation of CR until loss of CR or the date of 
additional systemic therapy for treatment of aGVHD. DoCR will be evaluated both in the set of 
all patients who achieve a CR and only in those patients who are in CR at Day 28 post- initiation 
of T-Guard treatment. 
3.4.1.2 
Overall Survival (OS) 
OS will be assessed at Days 90 and 180 post initiation of T-Guard treatment. An event for this 
analysis is death from any cause and time will be calculated from initiation of T-Guard treatment 
until date of death. 
3.4.2 Other Secondary Endpoints: 
3.4.2.1 
Overall Response Rate (ORR) 
ORR is defined as having a complete or partial response (CR+PR). The ORR will be estimated at 
Days 14, 28, and 56 post T-Guard initiation. 
 


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3.4.2.2 
Proportion of Response 
The proportion of patients in each aGVHD response category will be described at Days 7, 14, 
28 and 56 post initiation of T-Guard. 
3.4.2.3 
Non-relapse mortality (NRM) 
Events for NRM are death from any cause other than relapse/progression of the underlying 
malignancy. Relapse will be considered a competing risk. Time for NRM will be from time of T-
Guard initiation until the earlier of death from a non-relapse cause or relapse (competing risk). 
NRM will be estimated at Days 100 and 180 post initiation of T-Guard. 
3.4.2.4 
Relapse free survival (RFS) 
Events for RFS are death from any cause or relapse/progression of the underlying malignancy. 
Time will be calculated from the initiation of T-Guard treatment until the earlier of death or 
relapse/progression of the underlying malignancy. RFS will be estimated at Day 180 post 
initiation of T-Guard. 
3.4.2.5 
GVHD-free Survival 
Patients alive, in CR and without cGVHD will be considered a success for this endpoint. GVHD 
free survival will be estimated at Days 90 and 180 post initiation of T-Guard treatment. 
3.4.2.6 
Chronic GVHD (cGVHD) 
cGVHD is defined per NIH Consensus Criteria (see Appendix D). Time will be calculated from 
the initiation of T-Guard treatment until the earlier of diagnosis of cGVHD or death from any 
cause, with death treated as a competing risk. The cumulative incidence of cGVHD at Day 180 
post T-Guard initiation will be estimated and maximum severity (mild/moderate/severe) will be 
described. 
3.4.2.7 
Relapse/Progression of Underlying Malignancy 
The cumulative incidence of malignancy relapse/progression will be estimated with death prior to 
relapse/progression considered a competing risk. The cumulative incidence of 
relapse/progression at Day 180 post T-Guard initiation will be described. 
3.4.2.8 
Incidence of Systemic Infections 
All Grade 2-3 infections (as defined by the BMT CTN MOP) from initiation of T-Guard treatment 
will be reported by site of disease, date of onset, and severity. Incidence of systemic infections 
will be described in patients from the initiation of T-Guard treatment to 28 days post last dose. 
3.4.2.9 
Incidence of Toxicities 
All grade 3-5 toxicities according to CTCAE v5 occurring from the initiation of T-Guard treatment 
to 28 days post last dose will be described. 
3.4.2.10 Pharmacokinetics of T-Guard 
A population pharmacokinetic model will be developed for T-Guard based on the SPV-T3a- RTA 
and WT1-RTA levels measured in samples obtained before each infusion and at the following 
post-infusion timepoints: 4, 5, 6, 8, and 24 hours for the first infusion, 4, 6, and 24 hours for the 


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second and third infusions, and 4, 6, 24 and 48 hours for the fourth infusion. The time points for 
blood sampling were based on the t1/2 and Cmax values as determined in the previous studies.  
The Population PK model will be used to describe the following metrics: 
• 
Cinf: Observed and model-predicted concentration at the end of infusion 
• 
CL: Systemic clearance 
• 
AUC: Model-predicted area under the curve from the start of the current infusion 
until the next infusion or until 48 hours following for the last infusion 
• 
t1/2: Model-predicted terminal half-life 
• 
Vc: Volume of the central compartment 
 
Additionally, the impact of various factors on these measures will be evaluated, including age, 
weight, BSA, BMI, disease status, and anti-drug-antibodies (ADA). 
3.4.2.11 Immunogenicity of T-Guard 
ADA responses in the form of human anti-SPV-T3a-RTA and anti-WT1-RTA -antibodies will be 
evaluated in serum samples obtained at baseline and at Days 7, 14, 28, 90, and 180 following 
initiation of T-Guard treatment validated bioluminescence assays. 
3.5 
EXPLORATORY ENDPOINTS 
3.5.1 Corticosteroid Dose 
The steroid dose administered (measured in prednisone equivalent) at baseline, Days 28 and 56 
will be described. 
3.5.1.1 
Near Complete Response (Near CR) 
Near CR is defined as having stage 1 skin GVHD only (persistence of skin rash at less than 
25% BSA) with a score of 0 in other target organs. The proportion of patients with a near CR will 
be evaluated at Day 7, 14, 28, and 56 post-initiation of T-Guard treatment. The OS rates at Day 
180 will also be described for patients that attain a near CR or better and those who do not. 
3.5.1.2 
Discontinuation of Systemic Steroids 
The proportion of patients that are free of systemic steroid therapy at Day 180 post- T-Guard 
initiation will be described. 
3.5.1.3 
Incidence of CMV Reactivation 
The proportion of patients requiring new systemic treatment for a CMV PCR level per 
institutional practice (patients receiving only SoC viral prophylaxis will not be included in this 
assessment) for cytomegalovirus (CMV)-reactivation by Day 180 post-T-Guard initiation will be 
described. 
3.5.1.4 
Incidence of EBV-associated Lymphoproliferative Disorder 
The proportions of patients with EBV-associated lymphoproliferative disorder and EBV 
reactivation requiring therapy with rituximab by Day 180 post-T-Guard initiation will be 
described. 


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3.5.1.5 
Incidence of IMP-related Serious Adverse Events (SAEs) 
SAEs that are deemed to be related to T-guard treatment will be summarized by type, 
frequency, and number of patients affected. 
3.5.1.6 
T-cell Subsets and NK-cells 
The evolution of specific cell populations over the 180-day follow-up period and, in particular, T-
Guard’s effect in depleting targeted T cell and NK cell subsets as well as its impact on relevant 
non-target populations (B cells, monocytes and dendritic cells), will be evaluated. 
The Phase 1/2 study showed that when using a pan T cell marker, there is no direct correlation 
between the T cell depletion patterns and clinical responses. This might be explained by the 
observed responses being induced by a shift in the composition of the T cell compartment 
towards more tolerogenic subpopulations, rather than by just grossly (but temporarily) reducing 
the total number of circulating T cells (and NK cells). 
The flow cytometry analysis as proposed below, with a more refined and detailed set of 
markers, might help to further elucidate T-Guard’s MoA and identify a surrogated biomarker for 
response. 
Blood samples will be taken during the infusion week at Days 0, 2, 4, 6 (just prior to and 4 hours 
after each T-Guard infusion) and then subsequently at Days 14, 28, 56, and 180. These samples 
will be assessed by to measure the following cell populations: Inflammatory Monocytes & 
Dendritic Cells, Recent Thymic Emigrants, CD4+, CD8+ Naïve & Memory Cells, CD4+ T 
Regulatory Cells, NK Cells, γδ T Cells, and B cells. 
3.5.1.7 
GVHD-related biomarkers 
Serum ST2 and Regenerating Family Member 3 Alpha (REG3α) concentrations and urine 3- 
Indoxyl Sulfate (3-IS) concentrations at baseline and at Day 7, 14, and 28 post-initiation of T- 
Guard treatment will be used to estimate the probability of NRM at Day 180 post-assessment for 
each patient, using the NRM risk model from (Major-Monfried, Renteria et al. 2018). The 
proportion of patients with high risk biomarker status (defined as estimated NRM greater than 
0.29) will be described at each time point. 
3.5.1.8 
Patient Reported Outcomes (PROs) 
Patient reported outcomes will be assessed using a subset of the PROMIS measures described 
in Appendix F. PROs will be assessed at baseline and Days 28, 56, and 180 post initiation of T-
Guard treatment. 
3.6 
ENDPOINT REVIEW PROCESS 
Upon completion of patient follow-up, an Endpoint Review Committee (ERC) will conduct an 
independent review of site-reported data on a key study endpoint, Day 28 aGVHD response, in 
order to determine the data to be presented in the primary manuscript and final analysis. This 
Committee will consist of members of the protocol team, including the Protocol Chairs, Protocol 
Officer, Operational Statistician, and Protocol Coordinator. Each patient’s data will be reviewed 
by ERC clinicians. The adjudicated Day 28 aGVHD response data for each patient will be 
determined by consensus of the reviewers. 
 


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Data will be obtained from the relevant electronic case report forms (eCRFs) and source 
documents and will be provided to reviewers in a blinded manner with respect to treatment 
center and patient identifier. These data will be kept confidential and will not be discussed 
outside the Committee or presented in a public forum. The ERC charter will provide further 
details on the ERC membership and adjudication process.


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CHAPTER 4 
4 
PATIENT ENROLLMENT AND EVALUATION 
4.1 
APPROACHING PATIENTS, ELIGIBILITY SCREENING, AND OBTAINING 
CONSENT 
Patients with SR-aGVHD will be approached as soon as possible after diagnosis. Patients at 
least 18 years of age and willing to participate in the trial will sign an Institutional Review Board 
(IRB) approved ICF, and eligibility for enrollment will be further evaluated. For patients at least 
12 but less than 18 years of age and willing to participate, assent will be obtained in addition to 
parent or guardian consent. The process of obtaining informed consent must comply with 
applicable ICH GCP E6 guidelines as implemented in US guidelines, GCP guidelines and 
national regulatory requirements. 
4.2 
ENROLLMENT 
Patients will be enrolled onto the study using Advantage eClinical. The following procedures 
shall be followed: 
1. An authorized user at the clinical center completes the initial screening by entering 
patient demographics and Segment A information (consent date, inclusion/exclusion 
criteria) on the Eligibility Form. 
2. If the patient is eligible, a patient ID number is generated. 
If a connection is interrupted during an enrollment session, the process is completely canceled 
and logged. A backup manual enrollment system will also be available to provide for short- term 
system failure or unavailability. 
4.2.1 Treatment] 
Treatment should be initiated as soon as possible after enrollment. A maximum of 72 hours (3 
days) is allowable. 
4.3 
STUDY MONITORING 
4.3.1 Follow-up Schedule 
The Follow-up Schedule for scheduled study visits is outlined in Table 4.1. The timing of follow-
up visits is based on the date of first T-Guard infusion (Day 0) A detailed description of each of 
the forms and the procedures required for forms completion and submission can be found in the 
Data Management Handbook and User’s Guide. 
Table 4.1: Follow-up Schedule 
 
Assessment Time 
Target Day1 
(Days Post-Enrollment) 
1 week 
7 days 
2 weeks 
14 days 
3 weeks 
21 days 


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Assessment Time 
Target Day1 
(Days Post-Enrollment) 
4 weeks 
28 days 
5 weeks 
35 days 
6 weeks 
42 days 
7 weeks 
49 days 
8 weeks 
56 days 
10 weeks 
70 days 
90 days 
90 days 
6 months 
180 days 
1Target day range = ±3 days for Day 7 (subsequent visits through Day 56 
must be scheduled weekly and within ±3 days of target date). Target day 
range ±14 days for Days 70, 90, and 180 
 
Criteria for Forms Submission: Criteria for timeliness of submission for all study forms are 
detailed in the Data Management Handbook and User’s Guide. Forms that are not entered in 
Advantage eClinical within the specified time will be considered delinquent. Transplant Centers 
can view past due forms via Advantage eClinical. A missing form will continue to appear until 
the form is entered into Advantage eClinical, or until an exception is granted and entered into 
the Missing Form Exception File, as detailed in the Data Management Handbook and User’s 
Guide. 
Reporting Patient Deaths: The Recipient Death Information must be entered into Advantage 
eClinical within 24 hours of knowledge of a patient’s death even if the cause of death is unknown 
at that time. Once the cause of death is determined, the form must be updated. 
Center for International Blood and Marrow Transplant Research (CIBMTR) Data 
Reporting: Centers participating in BMT CTN trials must register pre and post-transplant 
outcomes on all consecutive HCTs done at their institution during their time of participation to 
the CIBMTR. Registration is done using procedures and forms of the Stem Cell Transplant 
Outcomes Database (SCTOD). (Note: Federal legislation requires submission of these forms 
for all US allotransplant recipients.) CIBMTR post- transplant Report Forms must continue to be 
submitted for all patients enrolled on this trial. Long-term follow-up of patients on this study will 
continue through routine CIBMTR mechanisms. 
4.3.2 Assessments 
Assessment and/or reporting of the following is required for patients enrolled on this study. All 
assessments are considered standard-of-care unless identified below by “*” below. 
Assessments indicated by “*” are for research purposes. 
Prior to Enrollment 
The following pre-enrollment assessments must be completed prior to enrolling the patient in 
Advantage eClinical and within the designated timeframe listed below. 
1. Complete acute GVHD staging and grading information including assessments of rash, 
diarrhea, nausea/vomiting, and bilirubin, within 24 hours prior to enrollment. Biopsy 
results of involved tissue, if performed as SoC, should also be reported. 


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2. Albumin, platelet count, and CK level within 24 hours prior to enrollment 
3. Complete blood count (CBC) with differential within 24 hours prior to enrollment 
4. Pregnancy test (urine or serum) for females of child-bearing potential within 30 days prior to 
enrollment  
Baseline Assessments 
Baseline assessments listed below must be completed post-enrollment and within 24 hours prior 
to the first dose of study therapy unless otherwise specified. 
1. Karnofsky or Lansky Performance Status (may be completed pre- or post-enrollment) 
2. Baseline patient-reported outcome measures (Appendix F) 
3. Peripheral blood for EBV and CMV viral load (within 72 hours prior to first T-Guard dose) 
4. Peripheral blood* for EBV, CMV-specific and alloreactive T-cells (See Appendix B) 
5. CBC with differential and platelet count* (must be collected at the same time as the 30mL 
peripheral blood for alloreactive T-cells) 
6. Peripheral blood* for humoral response (ADA) and immunophenotyping (See Appendix 
B) 
7. Peripheral blood* and urine sample* for GVHD biomarker testing (See Appendix B) 
8. Recording of all systemic immune suppressive therapy (as appropriate: tacrolimus, 
cyclosporine, etc.), as well as topical agents 
9. History and physical exam including height and weight, patient disease/transplantation 
baseline variables (may be completed pre- or post-enrollment but must be within 7 days 
prior to first T-Guard dose) 
 
At Each Infusion of T-Guard Therapy 
1. Complete acute GVHD staging and grading information including assessments of rash, 
diarrhea, nausea/vomiting, and bilirubin 
2. Vital signs (temperature, pulse, respiratory rate, blood pressure) just before starting the 
infusion, 15 minutes after the start of the infusion, 30 minutes after the start of the 
infusion, then every 30 minutes during the infusion, and at 1-hour post-infusion*. 
Deviation of +/- 5 minutes may occur for all vital sign collection timepoints. 
3. Albumin and platelet count prior to each dose of T-Guard 
4. CBC with differential 
5. Peripheral blood* for immunophenotyping studies pre-infusion and at 4 hours after the 
start of infusion. Pre-infusion samples should be drawn prior to T-Guard administration 
and a window of +/- 15 minutes is allowed for the sample drawn 4 hours after the start of 
infusion. 
6. Peripheral blood* for PK at the following timepoints 
a. 1st  infusion: pre-infusion, and at 4, 5, 6, 8, and 24 hours after start of infusion 
b. 2nd  infusion: pre-infusion, and at 4, 6, and 24 hours after start of infusion 
c. 3rd  infusion: pre-infusion, and at 4, 6, and 24 hours after start of infusion 
d. 4th  infusion: pre-infusion, and at 4, 6, 24, and 48 hours after start of infusion 
 
Pre-infusion samples should be drawn prior to T-Guard administration. A window of +/- 15 
minutes for samples drawn at 4,5, or 6 hours after the start of infusion, and a window of +/-30 


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minutes for the sample drawn 8 hours after the start of infusion is allowed. A window of +/- 2 
hours for samples drawn 24 or 48 hours after the start of infusion is also allowed. Every effort 
should be made to collect PK samples at all timepoints, however, the treatment schedule should 
not be altered to accommodate PK sampling. For example, if T-Guard administration is 
scheduled for a weekend and PK sampling is not possible then administration should occur on 
schedule. In the event weekend PK sample collection is missed, collection of PK samples should 
be resumed at the next T-Guard infusion. Please refer to Section 4.5 for more information 
regarding infusion delays. 
Post-Initiation of T-Guard Therapy 
The following assessments and observations must be completed at the timepoints designated 
below. 
1. Complete acute GVHD staging and grading information including assessments of rash, 
diarrhea, nausea/vomiting, and bilirubin at Days 7, 14, 21, 28, 35, 42, 49, 56, 70, 90, and 
180 
2. Albumin and platelet count at Days 28, 56, 90, and 180 
3. CBC with differential at Days 28, 56, 90, and 180 (must be collected at the same time 
as the 30mL peripheral blood for alloreactive T-cell sample on Days 28 and 180) 
4. Karnofsky or Lansky performance status at Days 28, 56, 90, and 180 
5. Peripheral blood for EBV and CMV viral load at Days 28 and 180 with monitoring of EBV 
and CMV continuing per institutional practice post Day 28 through 180 days post initiation 
of T-Guard 
6. Peripheral blood* for EBV, CMV-specific and alloreactive T-cells at Days 28 and 180 
7. Patient reported outcomes at Days 28, 56 and 180 post initiation of T-Guard 
8. cGVHD evaluation (if present) Day 28, 56, 90, and 180 
9. Peripheral blood* for ADA testing at Days 7, 14, 28, 90, and 180 
10. Peripheral blood* for immunophenotyping studies at Days 14, 28, 56, and 180 
11. Peripheral blood* and urine sample* at Days 7, 14, and 28 for GVHD biomarker 
testing 
12. Recording of all systemic immune suppressive therapy (as appropriate: tacrolimus, 
cyclosporine, etc.), as well as topical agents, and all anti-infectives used for prophylaxis or 
treatment at Days 7, 14, 21, 28, 35, 42, 49, 56, 70, 90, and 180 
13. Recording of toxicities on Days 56, 70, 90, and 180 
14. Recording of AE/SAEs as described in Section 4.4 Adverse Event Reporting 
15. Recording of infections through Day 180 
16. Recording of primary disease relapse through Day 180 
 
 
 
 
 


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Table 4.2: Assessment Schedule 
1Baseline assessments must be completed post enrollment and within 24 hours prior to the first dose of study 
treatment unless otherwise specified. 
2If patients experience muscle pain, then a serum CK should be performed. 
3The CBC with differential and platelet count must be taken at the same time as the peripheral blood is drawn for EBV, 
CMV-specific and alloreactive T-cells at baseline, day 28, and day 180. 
4Pharmcokinetic blood samples directly pre-infusion, and at 4, 5, 6, 8, and 24 hours after start of 1st infusion, pre-
infusion, and at 4, 6, and 24 hours after the 2nd and 3rd infusion, and pre-infusion, and at 4, 6, 24 and 48 hours after the 
4th T-Guard infusion. 
Pre-infusion samples should be drawn prior to T-Guard administration. A window of +/- 15 minutes for samples drawn at 
4,5, or 6 hours after the start of infusion, and a window of +/-30 minutes for the sample drawn 8 hours after the start of 
infusion is allowed. A window of +/- 2 hours for samples drawn 24 or 48 hours after the start of infusion is also allowed. 
Every effort should be made to collect PK samples at all timepoints, however, the treatment schedule should not be 
altered to accommodate PK sampling. For example, if T-Guard administration is scheduled for a weekend and PK 
Pre- 
Enrollment 
Baseline1 Days of T-Guard 
Infusion 
Days Post Initiation of T-Guard 
Baseline 
0 
2 4 6 
7 
14 21 28 35 42 
49 
56 70 
90 
180 
Acute GVHD evaluation, 
including bilirubin 
X 
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chronic GVHD evaluation 
X 
X 
X 
X 
Recording of all systemic 
immune suppression, 
including steroid dose 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
History and physical exam 
X 
CBC with differential 
X3 
X 
X X X 
X3 
X 
X 
X3 
Platelet count 
X 
X3 
X 
X X X 
X3 
X 
X 
X3 
Albumin 
X 
X 
X X X 
X 
X 
X 
X 
CK levels2 
X 
Pregnancy test (if applicable) 
X 
Karnofsky/Lansky 
performance status 
X 
X 
X 
X 
X 
Pre- 
Enrollment 
Baseline1 Days of T-Guard 
Infusion 
Days Post Initiation of T-Guard 
Baseline 
0 
2 4 6 
7 
14 21 28 35 42 
49 
56 70 
90 
180 
Peripheral blood for CMV and 
EBV viral load 
X 
X 
X 
Peripheral blood for 
EBV, CMV-specific 
and alloreactive T-
cells3 
X 
X 
X 
Pharmacokinetics4 
X 
X X X 
Peripheral blood for ADA 
X 
X 
X 
X 
X 
X 
Peripheral blood for GVHD 
biomarkers REG3α and ST2 
X 
X 
X 
X 
Peripheral blood for 
immunophenotyping5 
X 
X 
X X X 
X 
X 
X 
X 
Urine sample for GVHD 
biomarker 3-IS 
X 
X 
X 
X 
Vital signs (temperature, 
pulse, respiratory rate, blood 
pressure)6 
X 
X X X 
AE/SAE assessment7 
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Toxicity assessment 
X 
X 
X 
X 
Patient-reported outcomes: 
PROMIS 
X 
X 
X 
X 
Infection monitoring 
Reporting of infections at time of occurrence from time of enrollment through Day 180 
Primary disease relapse 
reporting 
Reporting of relapse at time of occurrence from time of enrollment through Day 180 


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sampling is not possible then administration should occur on schedule. In the event weekend PK sample collection is 
missed, collection of PK samples should be resumed at the next T- Guard infusion. 
5Peripheral blood for immunophenotyping should be collected pre-infusion and at 4 hours after the start of each infusion. Pre- 
infusion samples should be drawn prior to T-Guard administration and a window of +/- 15 minutes is allowed for the sample 
drawn 4 hours after the start of infusion. 
6Vital signs should be taken directly pre-infusion, 15 minutes after the start of the infusion, 30 minutes after the start of the 
infusion, then every 30 minutes during the infusion, and at 1-hour post-infusion. Deviation of +/- 5 minutes may occur for all 
vital sign collection timepoints. 
7 AEs and SAEs will be reported as described in Section 4.4 Adverse Event Reporting 
 


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4.4 
ADVERSE EVENT REPORTING 
AE reporting requirements are summarized below. 
4.4.1 Definitions 
Adverse Event: An AE is any untoward medical occurrence in a patient administered an 
investigational product or has undergone study procedures and which does not necessarily 
have a causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease that is 
temporally associated with the use of a medicinal (investigational) product, whether or not 
related to the medicinal (investigational) product. 
An abnormality identified during a medical test (e.g., laboratory parameter, vital sign, ECG data, 
physical exam) should be defined as an AE only if the abnormality meets 1 of the following 
criteria: 
• 
Induces clinical signs or symptoms. 
• 
Requires active intervention. 
• 
Requires interruption or discontinuation of study medication. 
• 
The abnormality or investigational value is clinically significant in the opinion of the 
investigator. 
 
Serious Adverse Event: An SAE, as defined by per 21 CFR 312.32, is any adverse event that 
results in one of the following outcomes, regardless of causality and expectedness: 
• 
Results in death 
• 
Is life-threatening. Life-threatening means that the person was at immediate risk of 
death from the reaction as it occurred, i.e., it does not include a reaction which 
hypothetically might have caused death had it occurred in a more severe form. 
• 
Requires or prolongs inpatient hospitalization (i.e., the event required at least a 24-
hour hospitalization or prolonged a 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 (e.g., surgery performed earlier than 
planned). 
• 
Results in persistent or significant disability/incapacity. Disability is defined as 
a substantial disruption of a person’s ability to conduct normal life functions. 
• 
Is a congenital anomaly or birth defect; or 
• 
Is an important medical event when, based upon appropriate medical judgment, 
it may jeopardize the patient and 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. 
 
Medical and scientific judgment should be exercised in deciding whether expected reporting is 
also appropriate in situations other than those listed above. For example, important medical 
events may not be immediately life threatening or result in death or hospitalization but may 


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jeopardize the patient or may require intervention to prevent one of the outcomes listed in the 
definition above (e.g., suspected transmission of an infectious agent by a medicinal product is 
considered an SAE). Any event is considered a SAE if it is associated with clinical signs or 
symptoms judged by the investigator to have a significant clinical impact. 
An adverse event can be Anticipated or Unanticipated: 
• 
Anticipated adverse events are those that have been previously identified as resulting 
from the underlying disease, the HCT, or acute GVHD and not related to study drug. 
• 
Unanticipated adverse events are those that vary in nature, intensity or frequency from 
information in the current anticipated event list, the Investigator’s Brochure, the package 
insert, or when it is not included in the informed consent document as a potential risk. 
Unanticipated events would also include those that have not been previously described 
as a result of the underlying disease requiring HCT, the HCT or acute GVHD 
4.4.2 Classification of Adverse Events by Severity 
The severity refers to the intensity of the reported event. The Investigator must categorize the 
severity of each unanticipated SAE according to the NCI CTCAE version 5.0. CTCAE guidelines 
can be referenced at the following website: http://ctep.cancer.gov/reporting/ctc.html. For any 
term that is not specifically listed in the CTCAE scale, intensity will be assigned a grade of one 
through five using the following CTCAE guidelines: 
• 
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 
• 
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self- care 
activities of daily living 
• 
Grade 4: Life-threatening consequences; urgent intervention indicated 
• 
Grade 5: Death related to AE 
4.4.3 Classification of Adverse Events by Relationship to Investigational Product 
The relationship of each reported event to the study treatment will be assessed by the 
Investigator; after careful consideration of all relevant factors such as (but not limited to) the 
underlying study indication, coexisting disease, concomitant medication, relevant history, 
pattern of the SAE, temporal relationship to any study treatment interventions and dechallenge 
or rechallenge according to the following guidelines: 
• 
Possibly, Probably, or Definitely Related: there is a reasonable possibility that the 
study treatment caused the event. A relationship of possibly, probably or definitely 
related to the investigational product is considered related for the purposes of regulatory 
authority reporting. 
• 
Unlikely, or Not Related: There is no reasonable possibility that the investigational 
product caused the event.  An unlikely or not related relationship to the investigational 
product is not considered related for the purposes of regulatory authority reporting.  One 
or more of the following criteria apply: 


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4.4.4 Required Adverse Event Reporting 
Any unanticipated SAEs from time of enrollment through the study defined follow up are required 
to be reported following the BMT CTN Administrative MOP Chapter 6. Additionally, any grade 4 
anticipated event not collected on the calendar-driven toxicity or specified event- driven form 
must also be reported through the expedited AE reporting system in Advantage eClinical. 
Chapter 6 of the BMT CTN MOP defines reporting based on the terms Unexpected and 
Expected; however, for this study, the reporting will be based on the terms Unanticipated and 
Anticipated All adverse events, including SAEs, must be reported from the 1st dose of T- Guard 
through 30 days after the last dose. In addition, any SAEs occurring after that 30-day period, but 
assessed as related to the investigational product, must be reported. All SAEs are to be followed 
up until resolved, judged to be no longer clinically significant, or until they become chronic to the 
extent that they can be fully characterized. 
Infections are collected separately in eClinical as this is a study endpoint; however, should an 
infection meet the SAE criteria the infection must also be reported following the SAE reporting 
criteria outlined above. 
GVHD and underlying disease relapse events are also collected separately in eClinical because 
they are part of the endpoint analysis. Events of GVHD and underlying disease relapse are not 
to be reported as AEs/SAEs for this study. 
The Sponsor has a list of events classified as Special Situations. These events are 1) medication 
error, 2) overdose and 3) pregnancy. These events must be reported following the reporting for 
SAEs. 
SAEs that require reporting will be reported through an expedited AE reporting system via an 
EDC. All SAEs, as well as Special Situations, must be reported within 24 hours of 
knowledge of the event. Events entered in EDC will be reported using NCI’s CTCAE Version 
5.0. If there are network outages, a paper copy of the AE form must be completed and emailed to 
Emmes to initiate Sponsor review. Once the system is available, the event information must be 
entered into the system. 
Anticipated AEs will be reported using NCI’s CTCAE Version 5.0 at regular intervals as defined on 
the Form Submission Schedule, including calendar-driven eCRFs (e.g., Toxicity and GVHD) or 
event-driven eCRFs (e.g., Relapse/Progression, Infection, Secondary Graft Failure and Death). 
The Data and Safety Monitoring Board (DSMB) will receive reports of all unanticipated and 
unexpected SAEs upon review by the BMT CTN Medical Monitor and the Xenikos Medical 
Monitor. Summary reports for all reported SAEs will be reviewed by the DSMB on a semi- annual 
basis. 
4.4.5 Procedure in Case of Pregnancy 
If a female patient becomes pregnant during the study dosing period or within 90 days from the 
last dose of study drug, the investigator should report the information through an expedited AE 
reporting system via Advantage eClinical. The expected date of delivery or expected date of the 
end of the pregnancy, last menstruation, estimated conception date, pregnancy result, neonatal 
data and other related information will be requested. If a patient becomes pregnant during the 
study dosing period, the investigational product will be discontinued. 


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The investigator will follow the medical status of the mother, as well as the fetus, as if the 
pregnancy is an SAE and will report the outcome. Additional information regarding the outcome 
of a pregnancy (which is categorized as an SAE) is mentioned below. 
• 
“Spontaneous abortion” includes miscarriage, abortion and missed abortion 
• 
Death of an infant within 30 days after birth should be reported as an SAE regardless of 
its relationship with the study drug 
• 
If an infant dies more than 30 days after birth, it should be reported if a relationship 
between the death and intrauterine exposure to the study drug is judged as “possible” 
by the investigator 
• 
In the case of a delivery of a living newborn, the “normality” of the infant is evaluated at the 
birth 
• 
Unless a congenital anomaly is identified prior to spontaneous abortion or miscarriage, 
the embryo or fetus should be assessed for congenital defects by visual examination 
Information will be collected at the time of delivery/birth and 180 and 360 days after birth. 
4.5 
INFUSION DELAYS 
The visit schedule in eClinical is set up to allow patients a timeline of two days between each 
infusion visit and a +1-day window for logistics. In the event dosing must be delayed due to 
occurrence of toxicity, the protocol allows up to 14 days to receive all four infusions. Therefore, 
instances may occur where a visit falls outside the windows in eClinical that overlap with the visit 
window for the Day 7 and Day 14 visits. If the infusion visits are delayed, then the assessments 
for each infusion should still be done and entered into the corresponding visits’ forms. Note that 
the Day 2, 4, and 6 visits directly correlate to Infusion #2, 3, and 4. 
For example, if the third infusion (Day 4) is received five days after the second infusion (Day 2), 
then all the assessments scheduled for the third infusion must be completed. Data for the third 
infusion would still be entered on the Day 4 forms even though the third infusion occurred on a 
later day. Similarly, the data for the fourth infusion (Day 6) would be entered on the Day 6 forms 
although the fourth infusion occurred on a later day. 
If an infusion is delayed and occurs on Day 7, then the infusion day assessments must be done 
while the Day 7 assessments can either be done on the same day or on another day within 
window, per PI discretion. If all assessments for the infusion (Day 4 or 6) and Day 7 are combined 
to be completed on the same day, the following should occur: 
• 
Acute GVHD form and Acute GVHD Medications form should be collected and entered in 
eClinical for the Day 7 visit. A missing form exception should be requested for the Acute 
GVHD assessment for the infusion visit forms (Day 4 or 6). When requesting a missing 
form exception, select “Other” as the reason for the missing form exception and specify 
“Form no longer required, combined with Day [XX] visit”. 
• 
The specimen acquisition forms should be completed for both the Day 7 visit and the 
infusion visit forms (Day 4 or 6) as different samples are required. 
o Day 7: Peripheral blood for ADA, Peripheral blood for GVHD biomarkers REG3α 
and ST2, and a urine sample for GVHD biomarker 3-IS are to be collected prior to 
infusion. If the samples can’t be drawn pre-infusion, they may be collected the day 


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after. 
o Infusion Visit: CBC with differential, platelet count with differential, and albumin, 
pharmacokinetics, and Peripheral blood for immunophenotyping are to be 
collected per protocol. 
• 
The above would still apply if an infusion was delayed to Day 8-10 and the Day 7 visit had 
not yet been completed. 
 
If an infusion is delayed and occurs on Day 14, then the infusion day assessments must be done 
while the Day 14 assessments can either be done on the same day or on another day within 
window, per PI discretion. If all assessments for the infusion (Day 4 or 6) and Day 14 are combined 
to be completed on the same day, the following should occur: 
• 
Acute GVHD form and Acute GVHD Medications form should be collected and entered in 
eClinical for the Day 14 visit. A missing form exception should be requested for the Acute 
GVHD assessment for the infusion visit forms (Day 4 or 6). When requesting a missing 
form exception, select “Other” as the reason for the missing form exception and specify 
“Form no longer required, combined with Day [XX] visit”. 
• 
The specimen acquisition forms should be completed for both the Day 14 visit and the 
infusion visit forms (Day 4 or 6) as different samples are required. 
o Day 14: Peripheral blood for ADA, Peripheral blood for GVHD biomarkers REG3α 
and ST2, and a urine sample for GVHD biomarker 3-IS are to be collected prior to 
infusion. If the samples can’t be drawn pre-infusion, they may be collected the day 
after. 
o Infusion Visit: CBC with differential, platelet count with differential, and albumin, 
and pharmacokinetics per protocol 
o Both visits: Peripheral blood for immunophenotyping – this should be entered 
under the infusion visit as it is to be collected pre-infusion and 4 hours post 
o If an infusion is delayed to Day 11-13, the Day 14 visit can be combined as 
appropriate. 
 
Note: 
• 
There is a 3-day window for the Day 7 and Day 14 visits and visits should be combined 
when appropriate. However, it’s ideal for the assessments to be completed on Day 7 and 
Day 14. 
• 
Sites are to be mindful of the max blood draw volumes per day for participants and to 
combine sample collection to avoid unnecessary needle sticks. 
• 
There should be at least 4 but preferably 7 days between the biomarker samples. 


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CHAPTER 5 
5 
STATISTICAL CONSIDERATIONS 
5.1 
STUDY DESIGN AND OBJECTIVE 
This study is designed as an open-label, single arm, non-comparative, multi-center Phase III 
study to investigate the efficacy and safety of T-Guard in adult and adolescent patients with SR-
aGVHD. A total of 47 patients will be enrolled from approximately 20 transplant centers and 
treated with T-Guard. The primary objective is to assess the Day 28 CR rate with all patients 
followed through Day 180 to assess longer term secondary outcomes. As this is a single arm 
open label study, the analysis will be descriptive, with the target sample size based on ruling out 
CR rates based on historical data in comparable populations. The target enrollment is 47 
patients treated with at least one T-Guard infusion. If any enrolled patients do not initiate T-
Guard treatment, additional patients will be enrolled until the goal of 47 treated patients is met. 
The basis for the sample size, including the underlying meta-analysis, is described in the 
sequel. 
5.1.1 Accrual and Study Duration 
Accrual is estimated to require 365 days to complete with a total study duration of 545 days. 
5.1.2 Randomization and Blinding 
No randomization or blinding will occur as this is a single arm open label trial. 
5.1.3 Analysis Populations 
The primary analysis population will consist of all patients who are enrolled and initiate T- Guard 
treatment. Patients who are enrolled but do not initiate treatment of T-Guard will be described 
separately. 
A PK analysis population will be defined for the assessment of pharmacokinetic and 
immunogenicity endpoints. This will consist of the set of patients in the primary analysis 
population from whom samples have been collected and evaluated for these endpoints. 
A secondary, supportive analysis of a per protocol (PP) population is planned. The PP 
population will consist of all enrolled patients who: 
• 
Received four T-Guard infusions 
• 
Met all inclusion and exclusion criteria, with the exceptions of the use of contraceptive 
and the informed consent (provided a prospective ICF can be obtained) 
5.1.4 Primary Hypothesis 
The primary endpoint is the Day 28 CR rate among all patients. Historical control data indicates 
a Day 28 CR rate of 25-30% is expected under currently available treatment strategies for SR-
aGVHD. The primary hypothesis is that the Day 28 CR rate under T-Guard treatment will be 
superior to historical rates. This will be evaluated by comparing the null hypothesis that the Day 
28 CR rate under T-Guard treatment is 30% to the alternative hypothesis that this rate exceeds 
30% using a one-sided test at a significance level of 2.5%. 


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5.1.5 Sample Size and Power Considerations 
Based on the results of the Phase I/II study (Groth, van Groningen et al. 2018), we expect a Day 
28 CR rate of 50% under T-Guard treatment. A literature review suggests a Day 28 CR rate of 
25-30% in historical controls, summarized below: 
• 
A random-effects meta-analysis of the 11 prospective studies on second line treatment 
for aGVHD reported in Martin et al. 2012 (see Figure 5-1) resulted in a CR rate of 29.5% 
(95% CI 24.0 – 35.3%). However, in seven of the 11 studies CRs that were achieved 
after Day 28 were included, and one study used CR assessment shorter than 28 days. 
In addition, eight of the 11 studies did not specify whether addition of another therapy to 
the protocol-defined treatments would result in classification of response as a non-
responder. 
• 
The recently published REACH1 study (Jagasia, Zeiser et al. 2018) with the JAK 1/2 
inhibitor ruxolitinib (Jakafi/Jakavi) resulted in a CR rate at Day 28 of 26.8%. 
• 
A meta-analysis of the 20 T-Guard treated patients of the Phase I/II study, 42 institutional 
control patients from that study’s two centers, 77 matched control patients from the 
MAGIC database, and 71 patients from the REACH1 study resulted in Day 28 CR rates 
of 49.6% (95% CI 28.8 – 70.4%) in the T-Guard patients and 23.0% (95% CI 17.2 – 
28.9%) in the control patients, adjusted for Harris acute GVHD grade (Table 5-1). CR 
rates were adjusted at the same ratio as observed in the T-Guard arm (3:10:7 for grades 
II:III:IV) using a generalized linear model adjusted for Harris grade and data source 
(Phase I/II, institutional controls / MAGIC / REACH1). 
 
Figure 5-1: Forest Plot of CR Rates from the Meta-analysis on Second Line aGVHD 
Therapy from (Martin, Rizzo et al. 2012) [numbers next to study treatment name refer to 
the references in that paper]. 
 
 
 
 
 
 
Martin 2012 - Prospective studies - CR rate 
Study 
Alemtuzumab [26] 
Alemtuzumab [27] 
Basiliximab [38] 
Dacliz + etanercept [47] 
Daclizumab [39] 
Daclizumab [40] 
CR 
(95% CI) 
% Weight 
0.20  (  0.01, 0.51) 
0.33  (  0.13, 0.57) 
0.17  (  0.04, 0.36) 
0.38  (  0.18, 0.60) 
0.37  (  0.23, 0.52) 
0.08  (  0.00, 0.32) 
4.1 
7.0 
8.7 
8.0 
15.2 
4.8 
Overall 
0.29  (  0.24,  0.35)   100.0 
 
0.05    0.1     0.15    0.2    0.25     0.3    0.35     0.4    0.45     0.5 
0.55    0.6 


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Table 5-1: Observed and Adjusted Day 28 CR Rates from Meta-analysis of Phase I/II 
Study, MAGIC Controls, and REACH1 Study 
 
Harris Grade 
Phase I/II T- 
Guard arm 
Combined 
controls 
Institutional 
controls 
MAGIC 
controls 
REACH1 
study 
II 
2/3 (66.7%) 
17/35 (48.6%) 
- 
6/12 (50.0%) 
11/23 (47.8%) 
III 
5/10 (50.0%) 
19/88 (21.6%) 
3/20 (15.0%) 
9/34 (26.5%) 
7/34 (20.6%) 
IV 
3/7 (42.9%) 
10/67 (14.9%) 
5/22 (22.7%) 
4/31 (12.9%) 
1/14 (7.1%) 
All 
10/20 (50.0%) 
46/190 
8/42 (19.0%) 
19/77 (24.7%) 
19/71 (26.8%) 
(24.2%) 
Adjusted CR 
49.6% 
23.0% 
25.7% 
20.2% 
24.6% 
Rate (95% CI) 
(28.8 – 
(17.2 – 
(13.2 – 
(10.5 – 
(15.4 – 
70.4%) 
28.9%) 
38.2%) 
29.8%) 
33.8%) 
 
The primary hypothesis will be evaluated by comparing the proportion of patients attaining a 
Day 28 CR to a historical rate of 30%, targeting 80% power to see a CR rate of 50% under T- 
Guard treatment. In addition, one interim analysis for futility will be incorporated. To generate 
the required sample size and futility and efficacy boundaries for this test, we used a Simon’s 
two-stage minimax design. A sample size of 47 patients is required under this design to 
compare a null rate of 30% to an alternative rate of 50% with a one-sided type I error rate of 
2.5% and 80% power. 
5.2 
INTERIM ANALYSIS AND STOPPING GUIDELINES 
5.2.1 Interim Analysis for Futility 
This trial will include one interim analysis for futility. At the interim analysis, the number of Day 28 
CRs will be compared to a futility boundary determined by Simon’s two-stage minimax design 
comparing a null rate of 30% to an alternative rate of 50% with a one-sided type I error rate of 
2.5% and 80% power. This is a non-binding stopping rule, in that the type I error rate will be 
controlled at 2.5% even if the rule is not followed exactly. If the number of CRs fails to exceed 
the boundary, the DSMB will be consulted on the appropriate course of action, including 
whether to declare futility and close the trial early. 
The futility boundaries and operating characteristics of this design are displayed in Table 5- 2A. 
The interim analysis will be conducted when 21 patients are evaluable for Day 28 CR. If the 
number of CRs is 6 or below, the boundary is crossed. At the final analysis, the futility boundary 
is 20 CRs and efficacy is declared only if the observed number of CRs exceeds this boundary, 
i.e. the observed rate is at least 21/47 (44.6%). 
 
 
 
 
 


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Table 5-2A: Single Boundary Non-Binding Futility Stopping Thresholds from Simon’s 
Two-stage Minimax Design with One-Sided Type I Error 2.5% and Power 80% 
 
Analysis 
Number of 
Evaluable 
Patients 
Futility 
Boundary - 
# of CRs 
(CR rate) 
Probability of Stopping Early 
Under True CR Rate Below 
30% 
50% 
Interim 
21 
6 (28.5%) 
55.1% 
3.9% 
Final 
47 
20 (42.6%) 
- 
- 
 
5.2.2 Guidelines for Safety Monitoring 
Monitoring of key safety endpoints will be conducted monthly, and if their rates significantly 
exceed pre-set thresholds, the NHLBI will be notified in order that the DSMB can be advised. 
Policies and composition of the DSMB are described in the BMT CTN's Manual of Procedures. 
These stopping guidelines serve as triggers for consultation with the DSMB for additional review 
and are not formal “stopping rules” that mandate automatic closure of study enrollment. The 
number of enrolled patients that fail to receive any T-Guard treatment and the occurrence of 
toxicity, adverse events, and other safety endpoints will be monitored regularly. These data will 
be reported to the DSMB at semi-annual meetings at a minimum; in the event that any safety 
concerns arise, these data will be conveyed to the DSMB expeditiously. Additionally, the DSMB 
will conduct a full review of study endpoint and safety data after 10 and 30 participants are 
evaluable for Day 28 CR. 
One key safety endpoint for this study is Day 30 overall mortality. The rate of mortality within 30 
days following T-Guard initiation will be monitored in patients who initiate this treatment. Based 
on historical data from MAGIC, the expected probability of Day 30 mortality in SR- aGVHD 
patients after initiating second line treatment is 15%, while a rate of 30% is considered to be 
unacceptable. A sequential probability ratio test (SPRT) for binary data that compares a rate of 
15% under the null hypothesis to a rate of 30% under the alternative hypothesis will be used for 
monthly monitoring of the Day 30 overall mortality rate in this study. 
This sequential testing procedure preserves the type I error rate at a prespecified level across all 
of the monthly examinations. The binary SPRT can be represented graphically. At each month, 
the number of evaluable patients is plotted against the cumulative number of events. 
The continuation region of the SPRT is defined by two parallel lines. Only the upper boundary 
will be used for monitoring in order to protect against excessive Day 30 mortality. If the 
cumulative number of deaths falls above the upper boundary the SPRT rejects the null 
hypothesis and concludes that more deaths occurred than should be expected in the observed 
number of evaluable patients. Otherwise, the SPRT continues until enrollment reaches the 
target sample size of 47 patients. The SPRT can be displayed in a tabular form, as shown in 
Table 5-2B. This table gives the rejection boundaries for the number of Day 30 mortality events 
corresponding to the number of evaluable patients. At least three deaths must be observed in 
order to trigger review. Figure 5-2A displays the same information in a graphical format. 
 
 


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Table 5-2B: Sequential Monitoring Plan of Day 30 Overall Mortality in 47 Patients 
Number of Evaluable Patients Rejection Boundary for Number of Day 30 Deaths 
1-2 
3-5 
3 
6-10 
4 
11-14 
5 
15-19 
6 
20-24 
7 
25-28 
8 
29-33 
9 
34-37 
10 
38-42 
11 
43-46 
12 
47 
13 
 
Figure 5-2A: Rejection Boundary for Day 30 Overall Mortality Monitoring in 47 Patients 
 
The actual operating characteristics of the truncated test are shown in Table 5-2C, obtained 
from a simulation study that assumed uniform accrual of 47 patients over a 365-day period with 
395 days of monitoring. 
 
 
 


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Table 5-2C: Operating Characteristics of the Binary SPRT for Day 30 Overall Mortality 
from a Simulation Study with 100,000 Replicates 
 
True Day 30 Mortality Rate 
15% 
20% 
25% 
30% 
Probability Reject Null 
0.096 
0.299 
0.579 
0.814 
Mean Month Stopped 
12.3 
11.0 
9.2 
7.3 
Mean # Deaths by Day 30 
6.6 
7.9 
8.1 
7.4 
Mean # Patients Enrolled 
44.7 
40.5 
34.4 
27.9 
 
The testing procedure rejects the null hypothesis in favor of the alternative 9.6% of the time 
when the true Day 30 mortality rate is 15% and 81.4% of the time when the rate is 30%. This 
corresponds to a type I error rate of 9.6% and a type II error rate of 18.6%. If the true Day 30 
mortality rate is 30%, the DSMB will be consulted 220 days after opening on average, when 7 
events have been observed in 28 patients. 
CTCAE Grade 4 or higher capillary leak syndrome (CLS) is another key safety endpoint that will 
be monitored during this study. The rate of Grade 4 or higher CLS occurring within 30 days 
following T-Guard initiation will be monitored in patients who initiate this treatment. This 
monitoring will compare a null rate of 5% to an alternative rate of 15%, considered to be 
unacceptable, using a sequential probability ratio test (SPRT) for binary data. The SPRT can be 
displayed in a tabular form, as shown in Table 5-2D. This table gives the rejection boundaries 
for the number of Day 30 CLS events corresponding to the number of evaluable patients. At 
least two events must be observed in order to trigger review. Figure 5-2B displays the same 
information in a graphical format. 
Table 5-2D: Sequential Monitoring Plan of Day 30 Grade 4 or Higher Capillary Leak 
Syndrome in 47 Patients 
 
Number of Evaluable Patients Rejection Boundary for Number of Day 30 Events 
1 
2-7 
2 
8-18 
3 
19-29 
4 
30-39 
5 
40-47 
6 
 
The actual operating characteristics of the truncated test are shown in Table 5-2E, obtained 
from a simulation study that assumed uniform accrual of 47 patients over a 365-day period with 
395 days of monitoring. 
 
 
 


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Table 5-2E: Operating Characteristics of the Binary SPRT for Day 30 Grade 4 or Higher 
Capillary Leak Syndrome from a Simulation Study with 100,000 Replicates 
 
True Day 30 Grade 4 or Higher CLS Rate 
5% 
10% 
15% 
20% 
Probability Reject Null 
0.094 
0.466 
0.807 
0.954 
Mean Month Stopped 
12.3 
9.9 
7.3 
5.4 
Mean # CLS events by Day 30 
2.2 
3.5 
3.7 
3.5 
Mean # Patients Enrolled 
44.7 
36.8 
27.8 
21.1 
 
The testing procedure rejects the null hypothesis in favor of the alternative 9.4% of the time 
when the true Day 30 Grade 4 or higher CLS rate is 5% and 80.7% of the time when the rate is 
15%. This corresponds to a type I error rate of 9.7% and a type II error rate of 19.3%. If the true 
Day 30 Grade 4 or higher CLS rate is 15%, the DSMB will be consulted 220 days after opening 
on average, when 4 events have been observed in 28 patients. 
5.2.3 Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized for all patients. Characteristics to 
be examined are: age, gender, race/ethnicity, performance status, primary disease, primary 
disease status, disease risk index (DRI), time from steroid initiation to enrollment, acute GVHD 
grade and organ staging, graft source, GVHD prophylaxis, conditioning regimen, time from 
disease diagnosis to transplant, time from transplant to enrollment, and time from acute GVHD 
onset to enrollment. 
Counts and percentages will be used to describe categorical variables, while the median, mean, 
standard deviation, and range will be used to summarize continuous variables. 
5.3 
ANALYSIS OF PRIMARY ENDPOINT 
The primary endpoint of this trial is the proportion of patients that attain a Day 28 CR. Patients in 
a CR at Day 28 post-initiation of T-Guard treatment will be considered a success while all other 
patients will be considered a failure for this endpoint. The CR rate at Day 28 will be estimated in 
the primary analysis population (all patients that initiate T-Guard treatment) using the sample 
proportion and a 95% Wilson score or Clopper-Pearson CI, where appropriate. 
The primary determination of efficacy of T-Guard treatment on Day 28 CR will be evaluated 
using efficacy and futility boundaries from the Simon’s two-stage minimax design described in 
Section 5.2.1. 
5.4 
ANALYSIS OF SECONDARY ENDPOINTS 
All secondary endpoints will be reported for the primary and PP analysis groups. 
Key Secondary Endpoints 
5.4.1 Duration of Complete Response (DoCR) 
DoCR is defined in Section 3.4. DoCR will be evaluated both in the set of all patients who 
achieve a CR and only in those patients who are in CR at Day 28 post-initiation of T-Guard 


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treatment. Estimates and 95% CIs for the median and quartiles of DoCR will be obtained using 
the Kaplan-Meier estimator. 
5.4.2 Overall Survival (OS) 
OS is defined as survival of death from any cause. The time from initiation of T-Guard treatment 
until death from any cause will be described using the Kaplan-Meier estimator. An estimate and 
95% CI for OS at Days 90 and 180 post-initiation of T-Guard will be provided. 
Other Secondary Endpoints: 
5.4.3 Overall Response Rate (ORR) 
Overall response is defined as either a complete or patient response (CR+PR). The ORR will be 
estimated at Days 14, 28, and 56 post T-Guard initiation using sample proportions and 95% 
Wilson score or Clopper-Pearson CIs, as appropriate. 
5.4.4 Proportion of Response 
The proportion of patients in each aGVHD response category (CR, PR, MR, NR, or progression) 
will be described at Days 7, 14, 28, and 56 using sample proportions. 
5.4.5 Non-relapse Mortality (NRM) 
NRM is defined as death from any cause other than malignancy relapse/progression. The time 
from initiation of T-Guard until NRM will be described using the Aalen-Johansen estimator, with 
malignancy relapse/progression treated as a competing risk. Estimates and 95% CIs of the 
cumulative incidence of NRM will be provided at Days 100 and 180 post- initiation of T-Guard. 
5.4.6 Relapse-free Survival (RFS) 
RFS is defined as being alive and free of malignancy relapse/progression. The time from 
initiation of T-Guard until malignancy relapse/progression or death will be described using the 
Kaplan-Meier estimator. An estimate and 95% CI for RFS at Day 180 post-initiation of T- Guard 
will be provided. 
5.4.7 GVHD-free Survival 
GVHD-free survival is defined as being alive, in CR, and free of cGVHD. The proportion of 
patients with GVHD-free survival at Days 90 and 180 post-initiation of T-Guard will be estimated 
using the sample proportion and 95% Wilson score or Clopper-Pearson CIs, as appropriate, if 
no censoring occurs prior to Day 180. If censoring does occur, Days 90 and 180 GVHD-free 
survival will be assessed using the Aalen-Johansen estimator in an illness- death multi-state 
model. 
5.4.8 Chronic GVHD (cGVHD) 
cGVHD severity is defined per the 2014 NIH Consensus Criteria (see Appendix D). The time 
from initiation of T-Guard treatment until onset of cGVHD of any severity (mild, moderate, or 
severe) will be described using the Aalen-Johansen estimator, with death prior to cGVHD onset 
treated as a competing risk. An estimate and 95% CI of the cumulative incidence of cGVHD will 
be provided at Day 180 post-initiation of T-Guard. The maximum severity of cGVHD through 
Day 180 post-initiation of T-Guard will be tabulated. 


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5.4.9 Relapse/progression of the Underlying Malignancy 
The time from initiation of T-Guard until malignancy relapse/progression will be described using 
the Aalen-Johansen estimator, with death prior to relapse/progression treated as a competing 
risk. An estimate and 95% CI of the cumulative incidence of malignancy relapse/progression will 
be provided at Day 180 post-initiation of T-Guard. 
5.4.10 Incidence of Systemic Infections 
The frequency of Grade 2-3 infections occurring from the initiation of T-Guard treatment until 28 
days post-last dose will be tabulated by disease site, date of onset, and severity, with Grade 
defined per the BMT CTN Technical MOP. The cumulative incidence of Grade 2-3 infections at 
28 days post-last dose will be described using the Aalen-Johansen estimator and its 95% CI, 
with death prior to infection treated as a competing risk. 
5.4.11 Incidence of Toxicities 
The frequency of Grade 3-5 toxicities per CTCAE version 5 occurring from the initiation of T- 
Guard treatment until 28 days post-last dose will be tabulated by organ system. The maximum 
severity of reported toxicities during that period will also be summarized. 
5.4.12 Pharmacokinetics 
A population pharmacokinetic model will be developed for T-Guard based on the SPV-T3a- RTA 
and WT1-RTA levels measured in samples obtained before each infusion and at pre- defined 
timepoints after infusion (Table 4.2). The model will be used to evaluate the following metrics: 
• 
Cinf: Observed and model-predicted concentration at the end of infusion 
• 
CL: Systemic clearance 
• 
AUC: Model-predicted area under the curve from the start of the current infusion until 
the next infusion or until 48 hours following for the last infusion 
• 
t1/2: Model-predicted terminal half-life 
• 
Vc: Volume of the central compartment 
 
Additionally, the impact of various factors on these measures will be evaluated, including age, 
weight, BSA, BMI, disease status, and ADA. 
5.4.13 Immunogenicity 
ADA responses in the form of anti-SPV-T3a-RTA and anti-WT1-RTA antibodies will be 
evaluated using serum samples obtained at baseline and at Days 7, 14, 28, 90, and 180 
following initiation of T-Guard treatment. Antibody levels will be described using descriptive 
statistics at each time point. Changes in levels from baseline will be evaluated using Wilcoxon 
signed rank tests. 
5.4.14 Subgroup Analyses of Day 28 CR Rate 
In a secondary analysis of the primary endpoint, the CR rate at Day 28 will be evaluated 
separately by age group (adulthood vs. adolescence), aGVHD grade, and DRI. Point estimates 
and 95% Wilson score or Clopper-Pearson CIs will be provided for each subgroup, as 
appropriate. 


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5.5 
ANALYSIS OF EXPLORATORY ENDPOINTS 
The analysis of exploratory endpoints will be based on the primary analysis population. 
5.5.1 Corticosteroid Dose 
The current steroid dose being administered (measured in prednisone equivalent) will be 
described by mean, median, range, and quartiles at baseline and Day 28 and 56 post T-Guard 
initiation. 
5.5.2 Near Complete Response (Near CR) 
The proportion of patients with a near CR (having isolated stage 1 skin GVHD) will be estimated 
at Day 7, 14, 28, and 56 using sample proportions and 95% Wilson score or Clopper-Pearson 
CIs, where appropriate. 
Estimates and 95% CIs of OS at Day 180 post-initiation of T-Guard treatment will also be 
obtained from the Kaplan-Meier estimator separately for two subsets of patients: those that attain 
a near CR or CR, and those who fail to reach a (near) CR. 
5.5.3 Discontinuation of Systemic Steroids 
The proportion of patients that are free of systemic steroids above physiological replacement at 
Day 180 post-T-Guard initiation will be described. 
5.5.4 CMV Reactivation 
Among patients that were CMV positive at enrollment, the cumulative incidence of initiation of 
systemic treatment for CMV-reactivation will be described using the Aalen-Johansen estimator, 
with death treated as a competing risk. An estimate and 95% CIs of the cumulative incidence of 
CMV reactivation will be provided at Day 180 post-initiation of T-Guard. 
5.5.5 EBV-associated Lymphoproliferative Disorder 
The cumulative incidence of either EBV-associated lymphoproliferative disorder or EBV 
reactivation requiring therapy with rituximab will be described using the Aalen-Johansen 
estimator, with death treated as a competing risk. An estimate and 95% CIs of the cumulative 
incidence of EBV-associated lymphoproliferative disorder/EBV reactivation will be provided at 
Day 180 post-initiation of T-Guard. 
5.5.6 Incidence of Investigational Medical Product (IMP)-related Serious Adverse 
Events (SAEs) 
SAEs that are deemed to be related to T-guard treatment will be summarized by type, frequency, 
and number of patients affected. 
5.5.7 T-cell Subsets and NK-cells 
The following cell populations will be measured by flow cytometry analysis: Inflammatory 
Monocytes & Dendritic Cells, Recent Thymic Emigrants, CD4+, CD8+ Naïve & Memory Cells, 
CD4+ T Regulatory Cells, NK Cells, γδ T Cells, and B cells. These cells will be obtained from 
blood samples drawn at Days 0, 2, 4, 6 (just prior to and 4 hours after each T-Guard infusion) 
and at Days 14, 28, 56, and 180. The level of each population will be summarized using 
descriptive statistics at each assessment time considered. Changes in levels from baseline will 
be evaluated using Wilcoxon signed rank tests. 


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5.5.8 GVHD-related Biomarkers 
Using the biomarker risk model from (Major-Monfried, Renteria et al. 2018), the serum levels of 
REG3α and ST2, and the 3-IS urine levels at enrollment and Day 7, 14, and 28 post-initiation of 
T-Guard will be used to estimate NRM probabilities for each patient at Day 180 following each 
assessment time point. The proportions of patients with high risk (defined as an estimated NRM 
greater than 0.29) will be described at each assessment time. 
Moreover, the proportions of patients experiencing a Day 28 CR will be described separately for 
patients with high risk vs. not using sample proportions and 95% Wilson score or Clopper- 
Pearson CIs, as appropriate. 
5.5.9 Patient-reported Outcomes 
Patient self-reported measures will be assessed using selected PROMIS subscales for GI 
symptoms, physical function and satisfaction with participation in social roles. These instruments 
will be scored according to the recommendations of the developers. Scores at baseline and at 
Day 28, 56, and 180 will be described using descriptive statistics. Wilcoxon signed rank tests 
will be used to evaluate changes from baseline to each post-enrollment time point.


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APPENDIX A:  HUMAN SUBJECTS 
 
1. Subject Consent 
Candidates for the study will be identified as described in Chapter 4 of the protocol. The 
Prinicipal Investigator or his/her designee at each transplant center will contact the candidates, 
provide the patient with information about the purpose of the study, and obtain consent. The 
BMT CTN will provide a template of the consent form to each center. Each center will customize 
the templates according to their local requirements and submit for review by the DCC for 
adequacy prior to submitting to the NMDP IRB of Record. Each center must provide evidence 
of IRB approval to the DCC. 
2. Confidentiality 
Confidentiality will be maintained by individual names being masked and assigned a patient 
identifier code. The code relaying the patient’s identity with the ID code will be kept separately 
at the center. The ID code will be generated by and kept on file at the BMT CTN Data and 
Coordinating Center upon enrollment. 
3. Participation of Children, Women and Minorities 
Women, ethnic minorities, children at least 12 and less 18 years of age, and other populations 
will be included in this study. Children less than 12 years of age are not eligible for this study 
given lack of applicable safety and PK data with T-Guard. Accrual of women and minorities at 
each center will be monitored to determine whether their rates of enrollment are reflective of 
the distribution of potentially eligible women and minorities expected from data reported to the 
CIBMTR and from published data on incidence of high risk acute GVHD in these groups. 
Centers will be notified if their rates differ significantly from those expected and asked to 
develop appropriate recruitment reports.


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APPENDIX B:  LABORATORY PROCEDURES 
Collection of Mandatory Research Samples for Protocol-Defined Correlative Studies Research 
samples will be collected for patients who consent to the BMT CTN 1802 study. Required research 
samples for study-specific exploratory endpoints include the collection of peripheral blood and urine 
samples as summarized in the table below. The following planned studies will be performed and 
remaining biospecimens made available to approved investigators for meritorious ancillary correlative 
laboratory studies with the potential to extend the findings of the current study portfolio. 
• 
Analysis of serum cytokines before and after T-Guard infusions 
• 
Evaluation of serum and urine biomarkers associated with acute GVHD 
• 
PK of T-Guard - development of a population pharmacokinetic model 
• 
Evaluation of potential humoral responses (ADA) to T-Guard infusions 
• 
Evaluation of T-Guard treatment on targeted and non-target immune cell subsets and 
presence of alloreactive and CMV/EBV specific T-cells 
Once the samples are collected at specified time points they will either be shipped on the day of 
collection directly to specified project laboratory for testing or to the BMT CTN Biorepository for 
processing/long-term aliquot storage. In some cases, the samples will be transferred internally to a 
laboratory for local processing and freezing and then periodically batch shipped to the BMT CTN 
Biorepository for long-term storage and distribution for planned and approved studies. The collection 
and shipment of these blood and urine samples will be tracked using the network’s GlobalTrace sample 
management system. Detailed procedures regarding specimen collection schedules, sample 
handling/processing procedures and shipping instructions will be found in the BMT CTN 1802 Research 
Sample Information Guide. 
 
 


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Subjects 
Sample Type 
Sample 
Collection 
Time Points 
Sample Collection 
and Sample 
Processing Summary 
Shipping 
Specifications 
Shipping 
and Testing 
Locations 
Collect the blood sample 
and place 5 mL in SST 
Vacutainer tube 
containing no 
anticoagulant. Allow 
Patients 
Peripheral Blood 
(SST Clot Tube) 
5 mL 
Humoral Response 
Serum Anti-Drug 
Antibodies 
Pre-treatment 
initiation 
Day -3 to Day 0 
Post-treatment 
initiation 
Days 7, 14, 28, 
90 and 180 
blood samples to clot 
upright for 30-60 minutes 
in a tube rack prior to 
centrifugation. Once 
centrifuged, the tube will 
be packaged for same- 
day shipping to 
Biorepository. 
Refer to the BMT CTN 
1802 Research Specimen 
Centrifuged blood 
sample tube will be 
shipped at 2-8⁰C on 
the day of 
collection, to the 
BMT CTN 
Biorepository by 
priority overnight 
FedEx® delivery. 
BMT CTN 
Biorepository 
Information Guide for 
details related to sample 
centrifugation and 
shipping. 
Day 0 
(1st T-Guard 
infusion) 
Collect the blood sample 
and place 5 mL in SST 
Patients 
Peripheral Blood1 
(SST Clot Tube) 
5 mL 
Serum 
Prior to study 
drug infusion and 
4, 5, 6, 8, and 24 
hours after start 
of infusion 
Days 2 & 4 
(2nd & 3rd 
infusions) 
Vacutainer tube 
containing no 
anticoagulant. Allow 
blood samples to clot 
upright for 30-60 minutes 
in a tube rack prior to 
centrifugation, serum 
removal and serum 
aliquot storage at -80⁰C. 
Frozen serum 
sample aliquots will 
be periodically 
batched-shipped to 
the BMT CTN 
Biorepository by 
priority overnight 
BMT CTN 
Biorepository 
Pharmacokinetic 
Testing 
Prior to study 
drug infusion and 
4, 6, and 24 
hours after start 
of infusion 
Refer to the BMT CTN 
1802 Research Specimen 
Information Guide for 
details related to sample 
processing, aliquot 
labeling, storing and 
FedEx® delivery. 
Day 6 
shipping. 
(4th infusion) 
Prior to study 
drug infusion and 


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Required Research Sample Summary 
 
Subjects 
Sample Type 
Sample 
Collection 
Time Points 
Sample Collection and 
Sample Processing 
Summary 
Shipping 
Specifications 
Shipping 
and 
Testing 
Locations 
 
Collect the blood sample 
 
and place 5 mL in SST 
 
Vacutainer tube 
 
containing no 
 
anticoagulant. Allow 
 
Peripheral Blood 
blood samples to clot 
 
 
 
Patients 
(SST Clot Tube) 
10 mL 
Serum 
Pre-treatment 
initiation 
Day -3 to Day 0 
Post-treatment 
initiation 
upright for 30-60 minutes 
in a tube rack prior to 
centrifugation. Once 
centrifuged, the tube will 
be packaged for same- 
day shipping to 
Biorepository. 
Centrifuged blood 
sample tube will 
be shipped at 2-
8⁰C on the day of 
collection, to the 
BMT CTN 
Biorepository by 
priority overnight 
BMT CTN 
Biorepository 
 
Cytokines and 
GVHD 
Biomarkers 
Days 7, 14 and 
28 
Refer to the BMT CTN 
1802 Research Specimen 
FedEx® delivery. 
 
Information Guide for 
 
details related to sample 
 
centrifugation and 
 
shipping. 
 
Patients 
Peripheral Blood 
(Sodium 
Heparin 
Vacutainer 
Tubes) 
Pre-treatment 
initiation 
Blood sample 
tubes will be 
shipped at 2- 8⁰C 
on the day of 
collection, to the 
BMT CTN 
Biorepository 
4, 6, 24, and 48 
hours after start of 
infusion 


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30 mL 
Peripheral blood 
mononuclear 
cells (PBMC) 
CMV/EBV 
and 
Alloreactive 
T- Cells 
Day -3 to Day 0 
Post-treatment 
initiation 
Days 28 and 180 
Collect the blood sample 
and place 10 mL into each 
of three Vacutainer tubes 
containing sodium heparin 
anticoagulant. 
Gently mix sample by 
inversion 8-10 times to 
mix sample well with 
anticoagulant. 
BMT CTN 
Biorepository 
by 
priority 
overnight 
FedEx® 
delivery. 
 
 


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Subjects 
Sample Type 
Sample 
Collection 
Time Points 
Sample Collection and 
Sample Processing 
Summary 
Shipping 
Specifications 
Shipping 
and 
Testing 
Locations
 
 
 
 
 
 
Patients 
Urine 
(sterile transport 
tube) 
10 mL 
GVHD Related 
Biomarkers 
Pre-treatment 
initiation 
Day -3 to Day 0 
Post-treatment 
initiation 
Days 7, 14, and 
28 
Collect 10 mL urine and 
place in sterile transport 
tube for same-day shipping 
to Biorepository. 
Refer to the BMT CTN 
1802 Research Specimen 
Information Guide for 
details related to sample 
centrifugation and shipping. 
Urine sample tube 
will be shipped at 
2- 8⁰C on the day 
of collection, to 
the BMT CTN 
Biorepository 
by 
priority 
overnight 
FedEx® 
delivery. 
BMT CTN 
Biorepository 
 
 
 
 
 
 
 
 
 
 
Patients 
Peripheral Blood2 
(Cyto-Chex BCT) 
10 mL 
Immunophenotypi 
ng 
Pre-treatment 
initiation 
Day -3 to Day 0 
Day 0, 2, 4 and 6 
1st through 4th 
T-Guard 
infusion 
Prior to study 
drug infusion and 
4 hours after 
infusion 
Post-treatment 
initiation 
Days 14, 28, 56, 
and 180 
Collect the blood sample 
and place 5 mL into each 
of two Cyto-Chex tubes 
containing EDTA 
anticoagulant and cell 
fixative. Gently mix sample 
by inversion 8-10 times to 
mix sample well with 
anticoagulant and cell 
fixative reagent. 
Cyto-Chex blood 
tubes will be 
shipped at 2-8⁰C 
on the day of 
collection to the 
RPCI project 
laboratory by 
priority overnight 
FedEx® delivery. 
Project 
Laborator
y 
(RPCI) 
1Pharmcokinetic blood samples directly pre-infusion, and at 4, 5, 6, 8, and 24 hours after start of 1st infusion, pre-infusion, and at 4, 6, 
and 24 hours after the 2nd and 3rd infusion, and pre-infusion, and at 4, 6, 24 and 48 hours after the 4th T-Guard infusion. 
Pre-infusion samples should be drawn prior to T-Guard administration. A window of +/- 15 minutes for samples drawn at 4,5, or 6 hours 
after the start of infusion, and a window of +/-30 minutes for the sample drawn 8 hours after the start of infusion is allowed. A window of 
+/- 2 hours for samples drawn 24 or 48 hours after the start of infusion is also allowed. Every effort should be made to collect PK 
samples at all timepoints, however, the treatment schedule should not be altered to accommodate PK sampling. For example, if T-
Guard administration is scheduled for a weekend and PK sampling is not possible then administration should occur on schedule. In the 
event weekend PK sample collection is missed, collection of PK samples should be resumed at the next T- Guard infusion. 
  2 Peripheral blood for immunophenotyping should be collected pre-infusion and at 4 hours after the start of each infusion. Pre- infusion 
samples should be drawn prior to T-Guard administration and a window of +/- 15 minutes is allowed for the sample drawn 4 hours after 
the start of infusion. 
 


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APPENDIX C:  STAGING AND GRADING OF ACUTE GVHD (HARRIS, YOUNG ET AL. 
2016) 
 


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APPENDIX D:  GRADING OF CHRONIC GVHD (NIH CRITERIA, (JAGASIA, 
GREINIX ET AL. 2015) 
 
Organ scoring of chronic GVHD. ECOG indicates Eastern Cooperative Oncology Group; KPS, Karnofsky Performance 
Status; LPS, Lansky Performance Status; BSA, body surface area; ADL, activities of daily living; LFTs, liver function tests; 
AP, alkaline phosphatase; ALT, alanine aminotransferase; ULN, normal upper limit. *Weight loss within 90 days. Skin scoring 
should use both percentage of BSA involved by disease signs and the cutaneous features scales. When a discrepancy exists 
between the percentage of total body surface (BSA) score and the skin feature score, OR if superficial sclerotic features are 
present (Score 2), but there is impaired mobility or ulceration (Score 3), the higher level should be used for the final skin scoring. 
To be completed by specialist or trained medical providers. **Lung scoring should be performed using both the symptoms 
and FEV1 scores whenever possible. FEV1 should be used in the final lung scoring where there is discrepancy between 
symptoms and FEV1 scores. 


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APPENDIX E:  PATIENT REPORTED OUTCOMES 
 
In general, would you say your health is…. 
1. Poor 
2. Fair 
3. Good 
4. Very good 
5. Excellent 
 
In the past 7 days, how often did you have nausea—that is, a feeling like you could vomit? 
1. Never (skip next question) 
2. Rarely 
3. Sometimes 
4. Often 
5. Always 
 
In the past 7 days, how often did you know that you would have nausea before it happened? 
1. Never 
2. Rarely 
3. Sometimes 
4. Often 
5. Always 
 
In the past 7 days, how often did you have a poor appetite? 
1. Never 
2. Rarely 
3. Sometimes 
4. Often 
5. Always 
 
In the past 7 days, how often did you throw up or vomit? 
1. Never 
2. One day 
3. 2-6 days 
4. Once a day 
5. More than once a day 
In the past 7 days, how often did you have belly pain? 
1. Never 
2. One day 
3. 2-6 days 
4. Once a day 
5. More than once a day 
 
 
 
 


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In the past 7 days, how many days did you have loose or watery stools? 
1. No days 
2. One day 
3. Two days 
4. 3-5 days 
5. 6-7 days 
In the past 7 days, how often did you feel like you needed to empty your bowels right away 
or else you would have an accident? 
1. Never 
2. One time during the past 7 days 
3. 2-6 days during the past 7 days 
4. Often once a day 
5. More than once a day 
In the past 7 days, how often did you have bowel incontinence—that is, have an accident 
because you could not make it to the bathroom in time? 
1. No days 
2. One day 
3. 2-3 days 
4. 4-5days 
5. 6-7 days 
Are you able to dress yourself, including tying shoelaces and buttoning your clothes? 
1. Without any difficulty 
2. With a little difficulty 
3. With some difficulty 
4. With much difficulty 
5. Unable to do 
Are you able to get out of bed into a chair? 
1. Without any difficulty 
2. With a little difficulty 
3. With some difficulty 
4. With much difficulty 
5. Unable to do 
Are you able to go for a walk of at least 15 minutes? 
1. Without any difficulty 
2. With a little difficulty 
3. With some difficulty 
4. With much difficulty 
5. Unable to do 
Are you able to go up and down stairs at a normal pace? 
1. Without any difficulty 
2. With a little difficulty 
3. With some difficulty 
4. With much difficulty 
5. Unable to do 


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In the past 7 days, I feel fatigued 
1. Not at all 
2. A little bit 
3. Somewhat 
4. Quite a bit 
5. Very much 
In the past 7 days, I have trouble starting things because I am tired 
1. Not at all 
2. A little bit 
3. Somewhat 
4. Quite a bit 
5. Very much 
In the past 7 days, how run-down did you feel on average? 
1. Not at all 
2. A little bit 
3. Somewhat 
4. Quite a bit 
5. Very much 
In the past 7 days, how fatigued were you on average? 
1. Not at all 
2. A little bit 
3. Somewhat 
4. Quite a bit 
5. Very much 
In the past 7 days, how much did pain interfere with your day to day activities? 
1. Not at all 
2. A little bit 
3. Somewhat 
4. Quite a bit 
5. Very much 
In the past 7 days, how much did pain interfere with your enjoyment of life? 
1. Not at all 
2. A little bit 
3. Somewhat 
4. Quite a bit 
5. Very much 
 
 


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In the past 7 days, how would you rate your pain on average? 
0. No pain 0 1.  
1 
2.  2 
3.  3 
4.  4 
5.  5 
6.  6 
7.  7 
8.  8 
9.  9 
10. Worst imaginable pain, 10 
In the past 7 days, how bothered were you by sores on your skin? 
1. Not at all 
2. Slightly 
3. Moderately 
4. Quite a bit 
5. Extremely 
In the past 7 days, how intense was your itch in general? 
1. Had no itch 
2. Mild 
3. Moderate 
4. Severe 
5. Very severe 
In the past 7 days, I felt worthless 
1. Never 
2. Rarely 
3. Sometimes 
4. Often 
5. Always 
In the past 7 days, I felt helpless 
1. Never 
2. Rarely 
3. Sometimes 
4. Often 
5. Always 
In the past 7 days, I felt depressed 
1. Never 
2. Rarely 
3. Sometimes 
4. Often 
5. Always 
 
 
In the past 7 days, I felt hopeless 


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1. Never 
2. Rarely 
3. Sometimes 
4. Often 
5. Always 
 
In the past 7 days, my sleep quality was… 
1. Very poor 
2. Poor 
3. Fair 
4. Good 
5. Very good 
In the past 7 days, my sleep was refreshing 
1. Not at all 
2. A little bit 
3. Somewhat 
4. Quite a bit 
5. Very much 
In the past 7 days, I had a problem with my sleep 
1. Not at all 
2. A little bit 
3. Somewhat 
4. Quite a bit 
5. Very much 
In the past 7 days, I had difficulty falling asleep 
1. Not at all 
2. A little bit 
3. Somewhat 
4. Quite a bit 
5. Very much 
 
 


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APPENDIX F:  LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
AAT 
Alpha-1 Antitrypsin 
ADA 
Anti-Drug-Antibody 
AE 
Adverse Event 
Allo-HSCT 
Allogeneic Hematopoietic Stem Cell Transplantation 
ATG 
Anti-Thymocyte Globulin 
AUC 
Areas Under the Time-Concentration Curves 
B-cells 
B Lymphocytes 
BSA 
Body Surface Area 
Cmax 
Peak Concentration 
CBC 
Complete Blood Count 
CD3/TCR 
CD3 T-Cell Receptor 
CI 
Confidence Interval 
CIBMTR 
Center for International Blood and Marrow Transplant Research 
CK 
Creatine Kinase 
CLL 
Chronic Lymphocytic Leukemia 
CLS 
Capillary Leak Syndrome 
CMV 
Cytomegalovirus 
CR 
Complete Response, the disappearance of symptoms in all organ 
systems 
CRS 
Cytokine Release Syndrome 
eCRFs 
electronic Case Report Forms 
CTCAE 
Common Terminology Criteria for Adverse Events 
DoCR 
Duration of Complete Response 
DRI 
Disease Risk Index 
DSMB 
Data and Safety Monitoring Board 
EBV 
Epstein-Barr Virus 
EDC 
Electronic Data Capture 
ERC 
Endpoint Review Committee 
GCP 
Good Clinical Practice 
GI 
Gastro-intestinal 
GVHD 
Graft-Versus-Host Disease 
aGVHD 
(acute) Graft-Versus-Host Disease 
cGVHD 
(chronic) Graft-Versus-Host Disease 
SR-aGVHD 
Steroid-refractory (acute) Graft-Versus-Host Disease 
FDG 
Fluoro-deoxyglucose 
HCT 
Hematopoietic Cell Transplantation 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IFN 
Interferon 
Ig 
Immunoglobulin 


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List of Abbreviations and Definitions of Terms 
 
IL 
Interleukin 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
JAK 
Janus Kinase 
mAb 
Monoclonal Antibody 
NIH 
National Institutes of Health (USA) 
NK cells 
Natural Killer Cells 
NR 
Non-Responder; No Response, Progression/Relapse of aGVHD or 
death by the end of Day 28 
NRM 
Non-Relapse Mortality 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PBMC 
Peripheral Blood Mononuclear Cells 
PD 
Progressive Disease, progression in 1 or more organ-systems resulting 
in a worsening of overall at least one Grade, without improvement in any 
other organs 
PET 
Positron Emission Tomography 
PHA 
Phytohemagglutinin 
PK 
Pharmacokinetics 
PP 
Per Protocol 
PR 
Partial Response, the improvement of 1 or more organs, with no 
worsening in other organs 
Progression/Malignancy 
Relapse 
The time from the date of the start of treatment to the date of 
hematologic malignancy relapse/progression. 
`α 
Regenerating Family Member 3 Alpha 
RFS 
Relapse Free Survival 
RTA 
Ricin Toxin A-chain 
SAE 
Serious Adverse Event 
SoC 
Standard of Care 
SPRT 
Sequential Probability Ratio Test 
SPV-T3a 
Anti-CD3, IgG2b 
SR 
Steroid refractory 
ST2 
Interleukin 1 receptor-like 1 
TEAE 
Treatment Emergent Adverse Event 
t1/2 
Terminal-phase Elimination Half-life 
T cells 
T Lymphocytes 
TCR 
T-cell Receptor 
WT1 
Anti-CD7, IgG2a 
3-IS 
3-Indoxyl Sulfate 


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APPENDIX G:  REFERENCES 
 
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F. M. Hecht, S. G. Deeks, M. G. Rosenberg, D. F. Nixon and J. K. Sandberg (2004). "Expansion of 
CD7(low) and CD7(negative) CD8 T-cell effector subsets in HIV-1 infection: correlation with antigenic 
load and reversion by antiretroviral treatment." Blood 104(12): 3672-3678. 
Aandahl, E. M., J. K. Sandberg, K. P. Beckerman, K. Tasken, W. J. Moretto and D. F. Nixon (2003). "CD7 
is a differentiation marker that identifies multiple CD8 T cell effector subsets." J Immunol 170(5): 2349-
2355. 
Akbar, A. N., P. L. Amlot, K. Ivory, A. Timms and G. Janossy (1990). "Inhibition of alloresponsive naive 
and memory T cells by CD7 and CD25 antibodies and by cyclosporine." Transplantation 50(5): 823-829. 
Alousi, A. M., D. J. Weisdorf, B. R. Logan, J. Bolanos-Meade, S. Carter, N. Difronzo, M.   Pasquini, 
S. C. Goldstein, V. T. Ho, B. Hayes-Lattin, J. R. Wingard, M. M. Horowitz and J. E. Levine (2009). 
"Etanercept, mycophenolate, denileukin, or pentostatin plus corticosteroids for acute graft-versus- host 
disease: a randomized phase 2 trial from the Blood and Marrow Transplant Clinical Trials Network." Blood 
114(3): 511-517. 
Amlot, P. L., M. J. Stone, D. Cunningham, J. Fay, J. Newman, R. Collins, R. May, M. McCarthy, J. 
Richardson, V. Ghetie and et al. (1993). "A phase I study of an anti-CD22-deglycosylated ricin A chain 
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Amlot, P. L., F. Tahami, D. Chinn and E. Rawlings (1996). "Activation antigen expression on human T cells. 
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Exp Immunol 105(1): 176-182. 
Anasetti, C., P. J. Martin, R. Storb, F. R. Appelbaum, P. G. Beatty, J. Davis, K. Doney, H. F. Hill, P. 
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Appay, V., R. A. van Lier, F. Sallusto and M. Roederer (2008). "Phenotype and function of human T 
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Bacigalupo, A. (2007). "Management of acute graft-versus-host disease. ." Br J Haematol 137(2): 87- 98. 
Bacigalupo, A., M. T. van Lint, F. Frassoni, M. Podesta, G. Veneziano, G. Avanzi, V. Vitale and  A. 
M. Marmont (1983). "High dose bolus methylprednisolone for the treatment of acute graft versus host 
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Bolanos-Meade, J. and G. Vogelsang (2004). "Acute graft-versus-host-diseas. ." Clinical Advances in 
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Byers, V. S., P. J. Henslee, N. A. Kernan, B. R. Blazar, R. Gingrich, G. L. Phillips, C. F. LeMaistre, 
G. Gilliland, J. H. Antin, P. Martin and et al. (1990). "Use of an anti-pan T-lymphocyte ricin a chain 
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Castilla-Llorente, C., P. J. Martin and G. McDonald (2014). "Prognostic factors and outcomes of severe 
gastrointestinal GVHD after allogeneic hematopoietic cell transplantation." Bone Marrow Transplant 49: 
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Deeg, H. J. (2007). "How I treat refractory acute GVHD." Blood 109(10): 4119-4126. 
Derocq, J. M., G. Laurent, P. Casellas, H. Vidal, P. Poncelet, A. Fauser, C. Demur and F. Jansen (1987). 
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