Conditions: Hematologic Malignancies
Keywords: Graft-versus-host disease
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 51
Healthy volunteers: no

Brief summary:
This is a phase 2 open-label trial designed to evaluate the efficacy of tildrakizumab in improving graft-versus-host disease (GVHD)-free relapse-free survival after myeloablative allogeneic hematopoietic cell transplantation (alloHCT) for hematologic malignancy.

Detailed description:
Study Rationale: GVHD remains a major cause of morbidity and mortality following myeloablative conditioning (MAC) alloHCT. Proinflammatory cytokines play a central role in initiation and development of acute GVHD and as such, inhibition of these cytokines has been examined for both prevention and treatment of GVHD. Interleukin (IL)-23 is a proinflammatory cytokine which the investigators' lab has shown to have a unique and selective role in induction of colonic inflammation during acute GVHD and that this cytokine serves as a critical mediator linking conditioning regimen-induced mucosal injury and endotoxin lipopolysaccharide (LPS) translocation to subsequent proinflammatory cytokine production and GVHD-associated pathological damage. Moreover, additional studies have demonstrated that blocking the IL-23 signaling pathway has not abrogated the graft-versus-tumor effect. Tildrakizumab is a commercially available anti-IL-23 antibody FDA approved for the treatment of moderate to severe psoriasis with good tolerance. The investigators hypothesize that blocking IL-23, with tildrakizumab, will reduce GVHD rates for patients undergoing MAC alloHCT without having an impact on relapse rates, thus improving GVHD-free relapse-free survival (GRFS).

Arms:
arm 1: Tildrakizumab (IluymaTM) is a humanized monoclonal antibody that specifically binds to the IL-23p19 subunit of IL-23 to neutralize its function.

Interventions: intervention 1: Tildrakizumab
Intervention descriptions: intervention 1: 100 mg will be injected subcutaneously on Day -1, Day 28 ± 3, Day 112 ± 7, Day 196 ± 14, and Day 280 ± 14.

Protocol document:
Prot_SAP_000.pdf: 
Official Title:  A Phase II Trial of Tildrakizumab for Prevention of Acute Graft-Versus-Host 
Disease 
NCT Number:  NCT04112810 
Protocol Date:  10-31-2022 


 
 
 MCW Protocol No: PRO00035737 
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A Phase II Trial of Tildrakizumab for Prevention of 
 Acute Graft-Versus-Host Disease 
 
 
 
William Drobyski, MD 
Lyndsey Runaas, MD 
 
 
Current Version Number and Date 
 
Version 1.0, Version date: 08-08-2019 
 
Version 2.0, Version date:  09-16-2019 
 
Version 3.0, Version date:  05-19-2020 
 
Version 4.0, Version date:  08-07-2020 
 
Version 5.0, Version date:  09-08-2021 
 
Version 6.0, Version date:  09-07-2022 
 
Version 7.0, Version date:  10-31-2022 
 
 
 
 
 
 
 
 
 
Proprietary and Confidential 
The information in this document is considered privileged and confidential and may not 
be disclosed to others except to the extent necessary to obtain Institutional Review 
Board approval and informed consent, or as required by federal and state laws. Persons 
to whom this information is disclosed should be informed that this information is 
privileged and confidential and that it should not be further disclosed.  


 
 
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Title:  A Phase II Trial of Tildrakizumab for Prevention of Acute Graft-Versus-Host 
Disease 
MCW OnCore® No.:  PRO00035737  
 
 
FDA IND No.: 145778  
 
Principal Investigator  
Lyndsey Runaas, MD 
Assistant Professor 
Division of Hematology and Oncology 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
Phone: (414) 805-4600 
Email: lrunaas@mcw.edu  
Principal Investigator [Study PI] 
William R. Drobyski, MD 
Professor 
Medical College of Wisconsin 
8701 Watertown Plank Road 
Milwaukee, WI 53226 
Phone: (414) 805-4600 
Email: wdrobysk@mcw.edu  
 
 
 
Sub-investigator: 
Bryon D. Johnson, PhD 
Professor 
Director of BMT and Cell Therapy 
Laboratory 
Medical College of Wisconsin 
8701 Watertown Plank Road 
Milwaukee, WI  53226 
Research Lab Phone: (414) 955-4123 
Email:  bjohnson@mcw.edu 
Biostatistician: 
Aniko Szabo, PhD 
Associate Professor of Biostatistics 
Medical College of Wisconsin 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
Email: aszabo@mcw.edu    
 
Funding Sponsor:  
Sun Pharmaceutical Industries, Inc. 
2 Independence Way 
Princeton NJ 08540 
(609) 720-8021 
www.sunpharma.com 
 
DSMC Manager:  
Jennifer Bollmer, PhD 
Medical College of Wisconsin  
9200 W. Wisconsin Ave. 
Milwaukee, WI   53226 
Phone: (414) 805-1947  
Email: jbollmer@mcw.edu  
 
 
 
 
 
 
 
 
 
 
 


 
 
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VERSION HISTORY 
Version 1, Version Date 08/08/2019 
Initial submission of the protocol.  
Version 
Date 
Version 1 
08-08-2019 
Version 2 
09-16-2019 
Version 3 
05-19-2020 
Version 4 
08-07-2020 
Version 5 
09-08-2021 
Version 6 
09-07-2022 
Version 7 
10-31-2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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TABLE OF CONTENTS 
PROTOCOL SUMMARY ............................................................................................................ 7 
STUDY SCHEMA ..................................................................................................................... 12 
STUDY CALENDAR ................................................................................................................. 13 
1  BACKGROUND .................................................................................................................... 19 
1.1  GRAFT-VERSUS-HOST DISEASE ........................................................................................19 
1.2  INTERLEUKIN-23 ...............................................................................................................20 
1.3  IL-23 AND GVHD .............................................................................................................20 
1.4  TILDRAKIZUMAB ...............................................................................................................20 
1.5  TILDRAKIZUMAB AND TREATMENT OF GVHD .....................................................................21 
1.6  CORRELATIVE STUDIES.....................................................................................................21 
1.7 STUDIES OF THE MICROBIOME IN TRANSPLANT PATIENTS .....................................................21 
1.7.1  Microbiome and Outcomes after Allogeneic Transplantation using Tildrakizumab as GVHD Prophylaxis . 22 
2  HYPOTHESIS, OBJECTIVES, AND ENDPOINTS ............................................................... 22 
2.1  PRIMARY OBJECTIVES .......................................................................................................22 
2.2  SECONDARY OBJECTIVES .................................................................................................23 
2.3  RATIONALE FOR THE OUTCOME MEASURES SELECTION ......................................................23 
2.4  PRIMARY ENDPOINT ..........................................................................................................23 
2.5  SECONDARY ENDPOINT(S) ................................................................................................23 
2.6  CORRELATIVE STUDIES .....................................................................................................26 
3  STUDY DESIGN ................................................................................................................... 26 
3.1  GENERAL DESCRIPTION ....................................................................................................26 
3.2  TREATMENT SCHEMA .......................................................................................................26 
3.3  RATIONALE FOR TREATMENT SCHEMA...............................................................................26 
3.4  STUDY COMPLETION .........................................................................................................27 
4  SUBJECT PARTICIPATION, DISCONTINUATION, AND WITHDRAWAL ........................... 27 
4.1  SUBJECT STATUS .............................................................................................................27 
4.2  PRESCREENING AND SCREENING LOG ...............................................................................27 
4.3  CONSENT .........................................................................................................................28 
4.4  SCREENING PROCEDURES ................................................................................................28 
4.5  ELIGIBILITY CONFIRMATION ...............................................................................................29 
4.6  DISCONTINUATION OF STUDY TREATMENT, WITHDRAWAL, AND COMPLIANCE ......................32 
4.7  LOST TO FOLLOW-UP ........................................................................................................33 
4.8  ACCRUAL SUSPENSION AND CLOSURE ..............................................................................33 
4.9  STUDY DISCONTINUATION AND CLOSURE ...........................................................................33 
5  STUDY ENTRY AND WITHDRAWAL; STUDY PROCEDURES .......................................... 33 
5.1  REQUIRED PREREGISTRATION SCREENING TESTS AND PROCEDURES .................................33 
5.2  REGISTRATION PROCESS ..................................................................................................34 
5.3  PRETREATMENT PERIOD ...................................................................................................34 
5.4  STUDY PROCEDURES DURING TREATMENT ........................................................................35 
5.5  GVHD ASSESSMENT ........................................................................................................35 
6  TREATMENT PLAN ............................................................................................................. 36 


 
 
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6.1  INVESTIGATIONAL AGENT ADMINISTRATION ........................................................................36 
6.2  STANDARD GVHD PROPHYLAXIS ADMINISTRATION ............................................................36 
6.2.1  Tacrolimus ................................................................................................................................................ 36 
6.2.2  Methotrexate ............................................................................................................................................ 37 
6.3  GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES ........................37 
6.4  DIETARY RESTRICTIONS ....................................................................................................37 
6.5  SUPPORTIVE CARE GUIDELINES ........................................................................................37 
6.6  FOLLOW-UP PERIOD .........................................................................................................37 
7  ADVERSE EVENTS: DEFINITIONS AND REPORTING ...................................................... 37 
7.1  DEFINITIONS .....................................................................................................................37 
7.1.1  Adverse Event ........................................................................................................................................... 37 
7.1.2  Serious Adverse Event (SAE) .................................................................................................................. 38 
7.1.3 Attribution of an Adverse Event ............................................................................................................... 38 
7.1.4  Expectedness of an Adverse Event .......................................................................................................... 39 
7.2  COLLECTION AND REPORTING REQUIREMENTS FOR ADVERSE EVENTS AND SERIOUS 
ADVERSE EVENTS ........................................................................................................39 
7.2.1  Reporting of Adverse Events and Serious Adverse Events ..................................................................... 39 
7.2.2  Reporting Instructions ............................................................................................................................. 40 
7.3  UNANTICIPATED PROBLEM INVOLVING RISK TO SUBJECT OR OTHER (UPIRSO) ..................41 
7.4  REPORTING OF PREGNANCY .............................................................................................41 
7.5  SUBJECT COMPLAINTS .....................................................................................................41 
7.6  KNOWN AES LIST .............................................................................................................42 
8  PHARMACEUTICAL INFORMATION .................................................................................. 42 
8.1  AGENT DESCRIPTION ........................................................................................................42 
8.2  ABSORPTION ....................................................................................................................42 
8.3  DISTRIBUTION ..................................................................................................................43 
8.4  METABOLISM ...................................................................................................................43 
8.5  ELIMINATION ....................................................................................................................43 
8.6  CONTRAINDICATIONS ........................................................................................................43 
8.7  SIDE EFFECTS ..................................................................................................................43 
8.8  STORAGE REQUIREMENTS AND STABILITY .........................................................................43 
8.9  AGENT DESTRUCTION AND RETURN ..................................................................................43 
9  CORRELATIVE STUDIES/SPECIAL STUDIES ................................................................... 43 
9.1  DESCRIPTION ...............................................................................................................43 
9.2  INSTRUCTIONS REGARDING SAMPLE COLLECTION FOR CORRELATIVES ...............................44 
10  STATISTICAL CONSIDERATIONS .................................................................................... 44 
10.1  STUDY ENDPOINTS .........................................................................................................44 
10.2  STUDY DESIGN ...............................................................................................................45 
10.2.1  Determination of Sample Size and Accrual Rate .................................................................................... 45 
10.2.2  Accrual Estimates ................................................................................................................................... 45 
10.3  ANALYSIS POPULATION ..................................................................................................45 
10.3.1  Primary Analysis (or Analysis of Primary Endpoints) ......................................................................... 46 
10.3.2  Secondary Analysis (or Analysis of Secondary Endpoints) .................................................................. 46 
10.3.3  Other Analyses/Assessments .................................................................................................................. 46 
10.4  EVALUATION OF SAFETY .................................................................................................46 
10.5  STOPPING RULES ...........................................................................................................46 
11  DATA AND SAFETY MONITORING PLAN (DSMP) .......................................................... 48 
11.1  STUDY TEAM ..................................................................................................................48 


 
 
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11.2  QUALITY ASSURANCE .....................................................................................................49 
11.3  CLINICAL TRIALS OFFICE ................................................................................................49 
11.4  DSMC ...........................................................................................................................49 
12 REGULATORY COMPLIANCE, ETHICS AND STUDY MANAGEMENT ............................ 49 
12.1  ETHICAL STANDARD ........................................................................................................49 
12.2  REGULATORY COMPLIANCE .............................................................................................49 
12.3  PRESTUDY DOCUMENTATION ...........................................................................................50 
12.4  INSTITUTIONAL REVIEW BOARD .......................................................................................50 
12.5 SUBJECT CONFIDENTIALITY AND ACCESS TO SOURCE DOCUMENTS/DATA ..........................51 
12.6  PROTECTION OF HUMAN SUBJECTS .................................................................................51 
12.6.1  Protection from Unnecessary Harm ...................................................................................................... 52 
12.6.2  Protection of Privacy .............................................................................................................................. 52 
12.6.3  Changes in the Protocol ......................................................................................................................... 52 
12.7  INVESTIGATOR COMPLIANCE ...........................................................................................52 
13  DATA HANDLING AND RECORD KEEPING .................................................................... 52 
13.1  OVERVIEW .....................................................................................................................52 
13.2  DATA MANAGEMENT RESPONSIBILITIES ...........................................................................53 
13.2.1  Principal Investigator............................................................................................................................. 53 
13.2.2  Research Coordinator ............................................................................................................................ 53 
13.2.3  Research Nurse/Medical Staff ............................................................................................................... 53 
13.2.4  Biostatistician ......................................................................................................................................... 53 
13.3  HANDLING AND DOCUMENTATION OF CLINICAL SUPPLIES .................................................53 
13.4  SOURCE DOCUMENTS .....................................................................................................53 
13.5  CASE REPORT FORMS ....................................................................................................54 
13.6  STUDY RECORD RETENTION ............................................................................................54 
APPENDIX 1.  PERFORMANCE STATUS CRITERIA ............................................................. 56 
APPENDIX 2.  GVHD ASSESSMENT ...................................................................................... 57 
APPENDIX 3. MEDICATION GUIDE ........................................................................................ 61 
REFERENCES ......................................................................................................................... 67 
 
 
 
 
 
 
 
 
 
 


 
 
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PROTOCOL SUMMARY 
Title 
 
A Phase II Trial of Tildrakizumab for Prevention of Acute Graft-Versus-Host 
Disease 
IND Sponsor 
Sponsor-investigator  
Principal 
Investigator  
William Drobyski, MD, and Lyndsey Runaas, MD  
Clinical Trial 
Phase 
Phase II 
Study 
Population 
Adult patients undergoing a myeloablative allogeneic HSCT for hematologic 
malignancies. 
Main Eligibility 
Criteria 
Inclusion Criteria: 
1. $JH\HDUV. 
2. Patients with any hematologic malignancy for which alloHCT is 
indicated. Patients with acute myeloid leukemia (AML) and acute 
lymphoblastic leukemia (ALL) must be in complete remission at the 
time of alloHCT.* 
3. Myeloablative conditioning (MAC) regimen, based on CIBMTR 
criteria.*  
4. T cell-replete peripheral blood graft.  
5. Patients must have a matched related or unrelated donor (at least 
6/6 match at HLA-A, -B and -C for related donors and at least 8/8 
match at HLA-A, -B, -C and -DRB1 for unrelated donors). 
6. &DUGLDFIXQFWLRQ/HIWYHQWULFXODUHMHFWLRQIUDFWLRQ. 
7. (VWLPDWHGFUHDWLQLQHFOHDUDQFHP/PLQXWHXVLQJWKH&RFNFURIW-
Gault formula and actual body weight). 
8. 3XOPRQDU\IXQFWLRQ'/&2DGMXVWHGIRUKHPRJORELQDQG
)(9.  
9. Liver function: total bilirubin <3 x upper limit of normal and ALT/AST 
<5 x upper normal limit. 
10. Female subjects must meet one of the following*:  
x 
Postmenopausal for at least one year before enrollment,  
OR  
x 
Surgically sterile (i.e., undergone a hysterectomy or bilateral 
oophorectomy), OR  
x 
If subject is of childbearing potential (defined as not satisfying 
either of the above two criteria), agrees to practice two 
acceptable methods of contraception from the time of signing 
of the informed consent form through 90 days after the last 
dose of study agent, OR 
o Agrees to practice true abstinence when this is in line 
with the preferred and usual lifestyle of the subject.  
11. Male subjects, even if surgically sterilized (i.e., status post 
vasectomy), must agree to one of the following*: 
 


 
 
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x 
Practice effective barrier contraception during the entire study 
period and through 60 calendar days after the last dose of 
study agent,  
OR 
x 
Agrees to practice true abstinence when this is in line with the 
preferred and usual lifestyle of the subject.  
12. Signed informed consent: Voluntary written consent must be given 
before patient registration and performance of any study-related 
procedure not part of standard medical care, with the understanding 
that consent may be withdrawn by the patient at any time without 
prejudice to future medical care. 
13. Planned posttransplant maintenance therapy is allowed. 
14. Prior autologous transplant is allowed. 
 
Exclusion Criteria 
 
1. Prior allogeneic HCT. 
2. Active CNS involvement with malignancy. 
3. Patients receiving cord blood or haploidentical allograft.  
4. Patients undergoing in vivo or ex vivo T cell-depleted alloHCT. 
5. Karnofsky performance sFRUH or ECOG > or = 2.  
6. Patients with uncontrolled bacterial, viral, or fungal infections 
(currently on treatment and with progression of infectious disease or 
no clinical improvement) at time of enrollment.  
7. Active hepatitis B or C virus infection or known human 
immunodeficiency virus (HIV) positive. 
8. Use of rituximab, alemtuzumab, anti-thymocyte globulin (ATG), or 
other monoclonal antibody planned as part of conditioning regimen 
for GVHD prophylaxis.  
9. Participation in another GVHD prophylaxis clinical trial. 
10. Any current uncontrolled cardiovascular conditions, including 
uncontrolled ventricular arrhythmias, NYHA class III or IV congestive 
heart failure, uncontrolled angina, or electrocardiographic evidence 
of active ischemia or active conduction system abnormalities. 
11. Any serious medical or psychiatric illness that could, in the 
investigator’s opinion, potentially interfere with the completion of 
treatment according to this protocol.  
 
Eligibility criteria will be determined prior to transplant. If a patient meets 
criteria during this pretransplant period but is no longer eligible at time of first  
administration of tildrakizumab, they will be removed and replaced on study.   
*Further defined in Section 4.5. 
Study Rationale 
GVHD remains a major cause of morbidity and mortality following MAC 
alloHCT. Proinflammatory cytokines play a central role in initiation and 
development of acute GVHD and as such, inhibition of these cytokines has 
been examined for both prevention and treatment of GVHD. IL-23 is a 
proinflammatory cytokine, which our lab has shown to have a unique and 
selective role in induction of colonic inflammation during acute GVHD and 
that this cytokine serves as a critical mediator linking conditioning regimen-


 
 
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induced mucosal injury and endotoxin lipopolysaccaraide (LPS) 
translocation to subsequent proinflammatory cytokine production and 
GVHD-associated pathological damage. Moreover, additional studies have 
demonstrated that blocking the IL-23 signaling pathway has not abrogated 
the graft-versus-tumor effect. Tildrakizumab is a commercially available anti-
IL23 antibody FDA approved for the treatment of moderate to severe 
psoriasis with good tolerance. We hypothesize that blocking IL23, with 
tildrakizumab, will reduce GVHD rates for patients undergoing MAC alloHCT 
without having an impact on relapse rates, thus improving GVHD-free 
relapse-free survival (GRFS).  
Primary 
Objectives 
Probability of GVHD-free relapse-free survival (GRFS). An event for this 
outcome is defined as either: 
x 
grade III–IV acute GVHD 
x 
systemic therapy requiring chronic GVHD 
x 
relapse 
x 
or death at 12 months  
after matched related/unrelated donor peripheral blood HSCT using 
myeloablative conditioning regimen.  
Primary 
Endpoint 
GVHD-free relapse-free survival (GRFS).  
Secondary 
Objectives 
1. Cumulative incidence of mild, moderate, and severe chronic GVHD,  
according to the NIH criteria, and limited or extensive GVHD by 
conventional criteria.  
2. Cumulative incidence of grade III–IV acute GVHD at days 100 and 
180. 
3. Probability of lower GI tract GVHD. 
4. Incidence of primary and secondary graft failure. 
5. Probability of non-relapse mortality (NRM) post HSCT.  
6. Cumulative incidence of relapse/progression of the primary 
malignancy.  
7. Probability of overall survival (OS) post HSCT.  
8. Assess the pharmacokinetic (PK) profile of multi-dose tildrakizumab. 
9. Incidence of infections. 
10. Donor cell chimerism. 
11. Effect of GVHD prophylaxis on gut microbiome diversity:  difference 
in the level of microbiome diversity during transplant and association 
of baseline gut microbiome diversity with development of aGVHD, 
cGVHD and overall survival. 
 
Secondary 
Endpoint(s) 
1. Chronic GVHD. 
2. Acute GVHD. 
o Grade II–IV. 
o Grade III–IV. 
3. Acute GI GVHD. 
4. Graft failure and hematopoietic recovery. 
5. Non-relapsed mortality (NRM). 
6. Disease relapse or progression. 
7. Progression-free survival. 
8. Overall survival. 
9. Pharmacokinetics. 


 
 
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10. Infectious risk.  
11. Donor cell chimerism. 
12. Microbiome diversity pre-engraftment and evolution during 
transplant. 
Study Design 
This is a phase II open-label trial designed to evaluate the efficacy of 
tildrakizumab in improving GRFS after myeloablative allogeneic 
hematopoietic cell transplantation for hematologic malignancy.  
Study Agent/ 
Intervention 
Description 
Patients enrolled on this clinical trial will receive tacrolimus initiating at day -
3 at doses to maintain therapeutic levels per institutional preference and 
continued until at least day +90 post-transplant. Methotrexate will be 
administered intravenously and dosed at 15 mg/m2 days +1, and 10 mg/mg2 
on days +3, +6, and +11. Tildrakizumab will be administered 
subcutaneously at a dose of 100 mg on day -1, day 28 ± 3, day 112 ± 7, day 
196 ± 14, and day 280 ± 14. 
Number of 
Subjects 
55 patients 
Subject 
Participation 
Duration 
Patients will be followed for at least 12 months following alloHCT. 
Duration of 
Follow-up 
Patients will be followed for at least 12 months following alloHCT. 
Estimated Time 
for Study 
Completion: 
The study will reach study completion 30 months from the time the study 
opens to accrual. 
Statistical 
Methodology: 
The study will test the primary hypothesis that GRFS at 12 months exceeds 
WKHKLVWRULFDOFRQWUROYDOXHRIDWDWZR-VLGHGVLJQLILFDQFHOHYHO7KH
target sample size will be 55 patients with a known outcome (i.e., GVHD, 
relapse, or death status at 12 months). With this sample size the study will 
KDYHSRZHUWRGHWHFWDQLQFUHDVHLQ*5)6DWPRQWKVWR
SRZHUWRGHWHFWDQLQFUHDVHWRDQGSRZHUWRGHWHFWDQLQcrease to 
 -XVWLILFDWLRQIRUWKHLQFUHDVHLQ*5)6SUREDELOLW\DVD clinically 
meaningful endpoint derives from the recently published BMT Clinical Trials 
Network 1203 GVHD prevention trial which compared three different 
prophylaxis regimens to standard therapy with tacrolimus and methotrexate 
and was powered to detect a LQFUHDVHLQ*5)67RDFKLHYHWKHWDUJHW
VDPSOHVL]HZHZLOOHQUROOSDWLHQWVWRDOORZIRUDORVVWRIROORZ-up. It 
is estimated that 30 months of accrual will be adequate. This is based on 
our historical rate of approximately 50 myeloablative allogeneic stem cell 
transplants per year over the past three years. Assuming a conservative 


 
 
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HQUROOPHQWUDWHDSSUR[LPDWHO\PRQWKVVKRXOGEHVXIILFLHQWWRHQUROO
our target of 55 patients. 
 
Analysis of primary endpoint 
The GRFS will be estimated using the Kaplan-Meier estimator and plotted 
ZLWKDFRQILGHQFHEDQG. An event for this outcome is defined as grade 
III–IV acute GVHD, chronic GVHD requiring systemic therapy, relapse, or 
death. Patients who are alive without GVHD will be censored at the last 
follow-up. The 12-month GRFS will be compared to the prespecified 
KLVWRULFDOFRQWUROYDOXHRIXVLQJDRQH-sided z-test. 
Analysis of secondary endpoints 
Demographic and other baseline data, such as disease characteristics, as 
well as outcome measures, will be presented overall and separately for URD 
and MRD patients. Categorical data, such as gender, race, etc., will be 
presented by frequencies and percentages. Descriptive summary statistics 
(e.g., frequency, mean, median, range and standard deviation) will be used 
to present numeric data. 
Time-to-event outcomes with and without competing risks will be analyzed 
using Kaplan-Meier and Nelson-Aalen estimates, respectively, and 
SUHVHQWHGZLWKFRQILGHQFHLQWHUYDOV%LQDU\RXWFRPHVZLOOEHDQDO\]HG
XVLQJSURSRUWLRQVZLWKFRQILGHQFHLQWHUYals. 
Bacterial community composition will be characterized using OTU counts 
generated, as described above. OTU counts will be converted to measures 
of relative abundance to account for variation in sequencing coverage 
between samples. Statistical analysis will be carried out using the statistical 
software package R (www.r-project.org$OSKDĮGLYHUVLW\ULFKQHVVDQG
evenness of taxa within a population) will be reported using the Shannon 
Index 46 and Chao1 richness estimator.47 %HWDȕGLYHUVLW\RYHUODSLQWD[D
shared between populations) will be analyzed using the Bray-Curtis 
dissimilarity metric48 in conjunction with multivariate statistical analysis 
methods that will include Principal Components Analysis (PCA) and 
Permutational Multivariate Analysis of Variance (PERMANOVA).49 Changes 
in abundance of individual taxa will also be analyzed using traditional 
univariate statistical methods. 
 
 
 
 
 
 


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STUDY SCHEMA
Consent
(N=55) 
Patients receiving:
x
Myeloablative Conditioning Regimen
x
GVHD prophylaxis (Methotrexate + 
Tacrolimus)
x
Peripheral Blood Stem Cell (PBSC)
Day 0
(Date of Transplant)
Tildrakizumab (100 mg) on:

Day 28±3

Day 112±7

Day 196±14

Day 280±14
Tildrakizumab
(100 mg on Day-1)
12-month follow-up post 
last dose of the study drug
Outcomes assessed


 
 
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STUDY CALENDAR 
 
Study Assessments 
Baseline 
 
Pre-
Transplant 
 (Post-Transplant) 
(in Days) 
Follow-Up 
 
Day – 30 
to -1 
Day -1 
28± 
3 
56 +/- 
7 days 
100 +/- 
14 
days 
112± 7 
180+/- 
14 days 
196± 14 
280± 14 
12 month post 
HCT (+/- 30 
days) 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Tildrakizumab administration – 
100 mg subcutaneously 
 
X 
X 
 
 
X 
 
X 
X 
 
 
History, physical exam, weight, 
height* 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECOG Performance Status and 
HCT-CI* 
X 
 
 
 
 
 
 
 
 
 
 
HLA typing (donor and 
recipient)*  
X 
 
 
 
 
 
 
 
 
 
 
CBC with differential1, 
Comprehensive metabolic 
panel2* 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Infectious disease markers3*
 
 
X 
 
 
 
 
 
 
 
 
 
 
LVEF4* 
X 
 
 
 
 
 
 
 
 
 
 
DLCO and FEV14* 
X 
 
 
 
 
 
X 
 
 
X 
 
Disease evaluation5* 
X 
 
 
 
X 
 
 
 
 
X 
 
Pregnancy test6* 
X 
 
 
 
 
 
 
 
 
 
 
GVHD assessments7* 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
AE assessments8 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Chimerism9* 
 
 
X 
 
 
 
 
 
 
 
 
CMV NAAT peripheral blood* 
 
 
X 
X 
X 
X 
 
 
 
 
 
EBV PCR peripheral blood 
 
 
X 
X 
X 
X 
 
 
 
 
 
Immune reconstitution* 
 
 
X 
 
X 
 
X 
 
 
X 
 


 
 
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STUDY CALENDAR 
 
Study Assessments 
Baseline 
 
Pre-
Transplant 
 (Post-Transplant) 
(in Days) 
Follow-Up 
 
Day – 30 
to -1 
Day -1 
28± 
3 
56 +/- 
7 days 
100 +/- 
14 
days 
112± 7 
180+/- 
14 days 
196± 14 
280± 14 
12 month post 
HCT (+/- 30 
days) 
 
Pharmacokinetic Labs 
and ADA testing 
 
 
See footnote 10 for details and timepoints 
Research (stool) sample 
collection 
 
x 
 
See footnote 11 for details and timepoints 
Research blood and plasma 
X 
 
See footnote 12 for details and timepoints 
 
*Indicates evaluations are currently performed as standard of care at the MCW BMT program. 
1. CBC with differential will be performed as appropriate during hospitalization for alloHCT on clinic visits and at minimum performed on 
days indicated on the schedule of events. 
2. Comprehensive metabolic panel will be performed as appropriate during hospitalization for alloHCT, on clinic visits and at minimum 
performed on days indicated on the schedule of events. 
3. Infectious disease titers include: CMV, hepatitis panel (hepA ab, hepB SAb, hepB SAg, hepB Core Ab, hepC Ab), HIV and HTLV I/II 
antibody. 
4. May be performed within three months of transplant. 
5. Evaluation of the malignant disease: for acute leukemia, CML, and MDS, these include a bone marrow aspirate and biopsy for 
morphology, cytogenetics/FISH and molecular testing as appropriate.  
6. Pregnancy test must be performed <30 days before the start of the transplant conditioning for females of childbearing potential and 
may be performed per institutional practices. 
7. GVHD assessments performed per the standard operating procedures at the MCW BMT Program and at minimum on days listed 
above. The GVHD assessment will include a review of all abnormalities experienced during the entire assessment period and the 
highest grade for each abnormality during the assessment period will be recorded. 
8. The AE assessment will include a review of all toxicities experienced during the entire assessment period and the highest grade for 
each AE during the assessment period will be recorded on the AE forms. 
9. Chimerism in whole blood fractionated as CD3 and CD33. 
10. PK labs should be drawn prior to drug administration (prior to D-1) during initial admission, D+30 +/- 2 days, D+60 +/- 7 days and D+90 
+/- 14 days. Each PK analysis requires five tubes of blood, each with 2–3 mL for a total of 10–15 mL blood drawn per PK analysis. 
Samples should stored at -70 degrees and batched prior to transmission to Labcorp Drug Development. 
ADA/NAB testing will be run off same samples as necessary to allow for better understanding of the PK profile differences seen.   
11. First stool sample for microbiome studies will be collected after admission in the hospital pre-transplant (d-1) Subsequent stool samples 
will be collected on D+1 +/-2 days, D+7 +/- 2 days, , and every seven days thereafter through neutrophil engraftment (defined as three 
consecutive days of ANC >500). The last stool sample should be collected AFTER neutrophil engraftment. Stool sample will also be 
collected at the time of onset of acute or chronic GVHD. 


 
 
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STUDY CALENDAR 
 
Study Assessments 
Baseline 
 
Pre-
Transplant 
 (Post-Transplant) 
(in Days) 
Follow-Up 
 
Day – 30 
to -1 
Day -1 
28± 
3 
56 +/- 
7 days 
100 +/- 
14 
days 
112± 7 
180+/- 
14 days 
196± 14 
280± 14 
12 month post 
HCT (+/- 30 
days) 
 
12. Blood samples will be collected at the following time points: Baseline (screening) and days 7±3, 14±3, 21±3, 28±7, 60±14, 90±14, 
196±30, 365±30 post-transplants and at the time of development of GVHD (if it occurs). For each time point, one 10-ml red top tube 
and one 10-ml purple top tube will be collected. 
 


 
 
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LIST OF ABBREVIATIONS 
ADA 
AE 
Anti-drug antibodies 
Adverse Event 
aGVHD 
Acute Graft-Versus-Host Disease 
ALP 
Alkaline Phosphatase 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
BUN 
Blood Urea Nitrogen 
CDK 
Cyclin-Dependent Kinases 
cGVHD 
Chronic Graft-Versus-Host Disease 
CR 
Complete Response 
CRC 
Clinical Research Coordinator 
CRF 
Case Report Form 
CSF 
Cerebral Spinal Fluid 
CT 
Computerized Tomography 
CTCAE  
Common Terminology Criteria for Adverse Events 
CTL 
Cytotoxic T Cell 
CTO 
Clinical Trials Office 
DFS 
Disease-Free Survival 
DLT 
Dose-Limiting Toxicity 
DSMP 
Data and Safety Monitoring Plan 
FDA 
Food and Drug Administration 


 
 
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GI 
Gastrointestinal 
 
 
GVHD 
Graft-Versus-Host Disease 
GVL 
Graft-Versus-Leukemia 
HCT 
Hematocrit 
HGB 
Hemoglobin 
HSCT 
Hematopoietic Stem Cell Transplantation  
IL-23 
Interleukin-23 
IP 
Investigational Product 
IRB 
Institutional Review Board 
LDH 
Lactate Dehydrogenase 
MCWCC 
Medical College of Wisconsin Cancer Center 
NCI 
National Cancer Institute 
NRM 
Non-Relapsed Mortality  
ORR 
Overall Response Rate 
PBMC 
Peripheral Blood Mononuclear Cells 
PD 
Disease Progression 
PK 
Pharmacokinetics 
PR 
Partial Response 
PRRs 
Pattern Recognition Receptors  
ROS 
Reactive Oxygen Species 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SD 
Standard Deviation 
ULN 
Upper Limit of Normal 
UP 
Unanticipated Problem 


 
 
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UPIRSO   
Unanticipated Problems Involving Risks to Subjects or Others 
WBC 
White Blood Cell (Count) 


 
 
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1  BACKGROUND 
Allogeneic hematopoietic stem cell transplantation (HSCT) is an intensive treatment modality that 
often represents the only curative therapy for patients with aggressive hematologic malignancies 
or other marrow failure syndromes. More than 8,000 allogeneic HSCTs were performed in the 
United States in 2016.1 Despite this, the procedure continues to carry a high morbidity and 
mortality rate. One of the principal contributors to transplant-related mortality is graft-versus-host 
disease (GVHD).2 GVHD develops in approximately 40– RI SDWLHQWV XQGHUJRLQJ DQ +/$
matched related HSCT and 50–RIUHFLSLHQWVUHFHLYLQJDPDWFKHGXQUHODWHGGRQRU+6&7. 3,4 
This is despite standard GVHD prophylactic medications administered to all transplant recipients. 
Once established, GVHD proves resistant to frontline therapies with corticosteroids in more than 
RISDWLHQWV,5 and survival is significantly diminished for these patients. 6,7 
 
1.1  Graft-versus-Host Disease 
 
GVHD is an immunological phenomenon whereby donor lymphocytes respond to host peptides 
expressed on polymorphic human leukocyte antigens (HLA) molecules. This results in a clinical 
syndrome which can be described as an inflammatory response directed predominantly against 
the skin, intestine, and liver. The interaction between donor lymphocytes and polymorphic HLAs 
on host tissues is amplified by the significant tissue damage that occurs in transplant recipients 
as a result of the conditioning regimen. This leads to a significant cytokine and chemokine 
signaling, which furthers this destructive cascade.  
 
GVHD has been divided into two phases, termed acute and chronic, which are distinguishable 
based on both temporal characteristics as well as unique clinical and pathological manifestation.8-
10 Acute GVHD (aGVHD) typically occurs in the first 100 days of transplant and targets a restricted 
set of organs including the skin, gastrointestinal (GI) tract, and liver, leading to cell apoptosis.11 
Chronic GVHD, alternatively, tends to occur after the first 100 days of transplant and can impact 
almost any organ system, with protean manifestations that have similarities to what occurs during 
autoimmune diseases.  
 
The pathophysiology underlying acute GVHD is often considered a “cytokine storm” with a three-
phase process:  (1) the conditioning regimen results in systemic inflammation due to release of 
pro inflammatory cytokines such as IL-1, IL-6, TNF-D, and INF-J; (2) donor T-cell priming and 
differentiation as a response to presentation by host antigens to APC;  (3) effector phase of tissue 
apoptosis mediated by inflammatory cytokines and T/NK cells effectors.2 
 
Compelling data in experimental models have shown that the GI tract plays a primary role in the 
amplification of acute GVHD.12,13 Damage to the gastrointestinal mucosa from the conditioning 
regimen results in the release of damage- and pathogen-associated molecular patterns (DAMPs 
and PAMPs),13,14 which activate cells of the innate immune system through the ligation of pattern 
recognition receptors (PRRs).15 This ultimately leads to the generation of clonally expanded 
alloreactive T cells, which mediate further damage, creating an inflammatory positive feedback 
loop. From a clinical perspective, involvement of the GI tract is a major cause of morbidity and 
can result in significant complications, including protracted diarrhea, requirement for parenteral 
nutrition, and infectious complications due to translocation of bacteria across a damaged mucosal 
barrier.16 Given the pivotal role that the GI tract plays in GVHD biology, strategies designed to 
reduce inflammation in this target organ have the potential to significantly decrease morbidity and 
mortality associated with this disease. 
 
Owing to the central role of proinflammatory cytokines in the initiation and development of acute 


 
 
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graft-versus-host disease, inhibiting these cytokines has been looked at for both prevention and 
treatment of GVHD.  
 
1.2  Interleukin-23  
 
IL-23 is a member of the IL-12 family, signals through STAT3, and is secreted by dendritic cells 
(DCs), as well as other antigen presenting cells (APCs) such as macrophages and monocytes.i 
17 This cytokine shares a p40 subunit with IL-12, but also contains an IL-23-specific p19 
component. The p19/p40 complex binds to the IL-12RE1 subunit that is also a component of the 
IL-12 receptor along with a unique IL-23 receptor subunit that together is present on 
memory/activated T cells, DCs and macrophages.18 Early studies demonstrated that IL-23 plays 
a critical role in disorders such as experimental allergic encephalomyelitis (EAE),19 collagen-
induced arthritis,20 and inflammatory bowel disease21 implicating this cytokine as a pivotal 
mediator in the pathogenesis of inflammatory disorders and autoimmunity.  
 
1.3  IL-23 and GVHD 
 
Studies in our laboratory using preclinical murine bone marrow transplantation models have 
demonstrated that IL-23 has a unique and selective role in the induction of colonic inflammation 
during acute GVHD and serves as a critical mediator linking conditioning regimen-induced 
mucosal injury and lipopolysaccharide (LPS) translocation to subsequent proinflammatory 
cytokine production and GVHD-associated pathological damage.11,22 Specifically, transplantation 
of IL-23–deficient marrow grafts or administration of a p19-specific antibody significantly reduced 
the severity of acute GVHD, which was attributable to the preferential reduction in colonic GVHD, 
and a decrease in the production of proinflammatory cytokines within this tissue site. Secretion of 
IL-23 by donor, and not host, APCs was shown to be a critical event in the induction of GVHD of 
the colon. In subsequent studies, we identified that the proinflammatory effects of IL-23 were 
mediated through CD4+ T cells that expressed the IL-23 receptor.23 Specifically, these studies 
identified a unique colitogenic CD4+ IL-23R+ T-FHOOSRSXODWLRQWKDWFRQVWLWXWLYHO\H[SUHVVHVWKHȕ
integrin, CD11c, has a biased central memory phenotype and memory T-cell transcriptional 
profile, possesses innate-like properties by gene expression analysis, and has increased 
expression of the gut-KRPLQJ PROHFXOHV Įȕ DQG &&5. Adoptive transfer of these cells 
resulted in increased overall mortality, proinflammatory cytokine production and pathology 
specifically in the colon. Collectively, these findings defined a novel organ-specific role for IL-23 
in the pathophysiology of GVHD and demonstrated that IL-23 could direct tissue-specific 
pathology within the context of a systemic inflammatory disorder. Moreover, additional studies 
demonstrated that blockade of the IL-23 signaling pathway did not abrogate the graft-versus-
leukemia effect when tested in both acute and chronic models of leukemia.23 Thus, targeting the 
IL-23 pathway for GVHD prevention in murine models resulted in separation of GVH and GVL 
reactivity. Thus, with a series of publications in well-characterized mouse models, we believe that 
we have established that IL-23 has a pivotal role in the pathophysiology of GVHD in the GI tract. 
In addition, there have been a number of studies that have suggested that donors with IL23R 
polymorphisms which result in attenuated IL-23 secretion have a protective effect on the 
occurrence of moderate-to-severe acute GVHD in transplant recipients.24   
 
1.4  Tildrakizumab 
 
Tildrakizumab (IluymaTM) is a humanized monoclonal antibody that specifically binds to the IL-
23p19 subunit of IL-23 to neutralize its function.25 The drug has been evaluated in clinical trials 
for patients with moderate to severe psoriasis with good effect.25,26 The drug was well tolerated, 
with maximum-tolerated dose (MTD) of 10 mg/kg-1 once monthly. The responses were achieved 


 
 
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at all dose level (0.05–10 mg/kg-1), maximum responses were achieved at dose level 3 and 10 
mg/kg-1.  
 
The most common adverse events reported were headache, nasopharyngitis, upper respiratory 
infection, and cough. There was no dose increase related adverse events. Among the serious 
adverse events reported was convulsion, which was attributed secondary to tildrakizumab, 
occurred 17 days after the 10 mg/kg-1 doses, but there were several reported confounding factors; 
alcohol consumption, lack of sleep and use of benzodiazepines. In terms of pharmacokinetic, the 
drug had slow systemic clearance with long half-life of around three weeks. Another significant 
finding of the study was that the IL-23p19 expression almost completely disappeared from the 
affected tissue after tildrakizumab treatment, suggesting that the drug possesses direct effect on 
IL-23 producing cells. Based on this data, tildrakizumab was FDA approved for treatment of 
moderate to severe plaque psoriasis in March 2018. 
 
1.5  Tildrakizumab and Treatment of GVHD 
 
To date, tildrakizumab has not been tested for prevention or treatment of GVHD but based on 
aforementioned data suggesting a pivotal role for IL-23 in the pathophysiology of GVHD, coupled 
with the very favorable safety profile of tildrakizumab; we propose to conduct a phase II study 
evaluating the efficacy of tildrakizumab plus standard immunosuppressive therapy in preventing 
GVHD in patients undergoing a myeloablative HSCT. The FDA approval for use of this agent in 
patients with plaque psoriasis, with a well-reported safety profile, justifies not embarking on a 
phase I study in this population. However, as we were well aware that patients undergoing MAC 
alloHCT patients represent a uniquely vulnerable patient population with potential for unexpected 
and potentially life-threatening adverse effects, we initially proposed a safety run-in phase of six 
patients to ensure these patients appropriately engrafted and did not experience any unexpected 
adverse events before proceeding to the full phase II study. 
 
 
1.6  Correlative Studies 
 
Given the known cytokine dysregulation that is seen in the setting of allogeneic HSCT, especially 
in acute GVHD,27 we intend to perform correlative studies to understand the impact of anti-IL-23 
antibody treatment on the proinflammatory cytokine milieu that is typically seen post-allogeneic 
HSCT. This testing may help us better understand the changes that are happening within the 
immune system to inhibit graft-versus-host disease (GVHD).  
 
1.7 Studies of the Microbiome in Transplant Patients 
 
The microbiome, consisting of a varied community of microbes (bacteria, viruses, fungi, 
microeukaryotes, and sometimes multicellular parasites), exists in niches across the human 
body. The skin, lung, nares, vagina, and gastrointestinal tract are among the most heavily 
colonized, with the largest number of microorganisms inhabiting the colonic lumen. While the 
majority of the over trillion organisms that live within a healthy human colon are nonpathogenic 
members of the phyla Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria, alterations 
in the balance of these microorganisms have been associated with adverse outcomes ranging 
from GVHD and infection to relapse post-HCT. 28 This clinical association between intestinal 
microorganisms and HCT outcomes has been investigated for decades and has informed the 
still controversial practices of infection prophylaxis, gut decontamination, the “neutropenic diet,” 
and isolation of patients in laminar air flow rooms. Single-institution studies have demonstrated 
that low microbial diversity in the stool after allogeneic HCT is associated with poor survival. 29,30 


 
 
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Additionally, specific alterations have been associated with increased risk of acute GVHD, 
infectious outcomes and most recently, relapse. 31-33 While these findings are compelling, the 
generalizability of these proposed microbial biomarkers is unclear. This is particularly important 
as there is known geographic variation of the intestinal microbiome and practice variability in 
antibiotic use for prophylaxis and treatment from institution to institution, in part due to different 
antibiograms. 
 
Novel methods in microbiome research are likely to facilitate translational breakthroughs — 
these methods allow (1) detailed taxonomic classification of microorganisms at the strain level, 
(2) metabolic characterization of the small molecules and proteins that a microbial community 
makes, (3) measurement of microbial genomic evolution in clinical time courses, and (4) 
culturing of previously fastidious organisms from the microbiome for in vitro investigation and 
cultivation as potential therapeutic live bacterial clinical interventions. Given recent reports 
suggesting that alterations in the microbiome can impact the efficacy of immunologic therapies, 
it is imperative that the link between the microbiome and transplant outcomes is 
investigated.34,35  
 
 
1.7.1  Microbiome and Outcomes after Allogeneic Transplantation using Tildrakizumab as 
GVHD Prophylaxis 
The study will test the secondary hypothesis that the use of IL-23 blockage (tildrakizumab), 
which has been shown to lower gastrointestinal GVHD rates, preserves the gut microbiome 
diversity (determined by 16s rRNA sequencing analysis of the sequential stool sample collected 
pre- and post-transplant until neutrophil engraftment). Additional analyses on patient samples 
will be conducted to answer the key question concerning the impact of the gut microbiome on 
transplant outcome. Aliquots preserved additionally will establish a cohort of stool samples 
collected prospectively for future sequencing by shotgun metagenomic sequencing and 
metabolomic analysis. Previous GVHD prophylaxis studies performed at this institution have 
also evaluated microbiome diversity in this setting. Continuing these important exploratory 
evaluations will help to add to our knowledge base in this arena and will contribute importantly 
to future research. 
 
2  HYPOTHESIS, OBJECTIVES, AND ENDPOINTS 
In this study, we hypothesize that IL-23 inhibition through repeated treatment with tildrakizumab, 
when added to standard GVHD prophylaxis, will result in an improvement in GVHD-free 
relapse-free survival (GRFS) for adult patients undergoing a myeloablative allogeneic HSCT for 
hematologic malignancies.  
 
2.1  Primary Objectives 
The primary endpoint of this trial is to determine the probability of GVHD-free relapse-free survival 
(GRFS). An event for this outcome is defined as either grade III–IV acute GVHD, systemic 
therapy-requiring chronic GVHD, relapse, or death at 12 months after matched related/unrelated 
donor peripheral blood HSCT using myeloablative conditioning regimen. Patients who are alive 
without GVHD will be censored at the last follow-up.  
 


 
 
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2.2  Secondary Objectives 
 
1. Cumulative incidence of mild, moderate and severe chronic GVHD according to the NIH 
criteria and limited or extensive GVHD by conventional criteria.  
2. Cumulative incidence of grade II–IV acute GVHD at days 100 and 180.  
3. Cumulative incidence of grade III–IV acute GVHD at days 100 and 180. 
4. Probability of lower GI tract GVHD. 
5. Incidence of primary and secondary graft failure. 
6. Probability of non-relapse mortality (NRM) post HSCT.  
7. Cumulative incidence of relapse/progression of the primary malignancy.  
8. Probability of overall survival (OS) post HSCT.  
9. Assess the pharmacokinetic (PK) profile of multi-dose tildrakizumab. 
10. Incidence of infections. 
11. Donor cell chimerism. 
12. Effect of GVHD prophylaxis on gut microbiome diversity:  difference in level of 
microbiome diversity during transplant and association of baseline gut microbiome 
diversity with development of aGVHD, cGVHD and overall survival. 
 
 
2.3  Rationale for the Outcome Measures Selection 
Ample evidence suggests that IL-23 has a pivotal role in the pathophysiology of GVHD and 
preclinical studies suggest that blocking the IL-23 pro-inflammatory pathway can prevent GVHD. 
In this study, we will treat patients with tildrakizumab, which is a humanized monoclonal antibody 
that specifically binds to the IL-23p19 subunit of IL-23. We hypothesize that targeting IL-23 will 
reduce the incidence of GVHD and improve morbidity and mortality after transplantation.  
2.4  Primary Endpoint 
The primary endpoint of this trial is GRFS. An event for this outcome is defined as grade III–IV 
acute GVHD, chronic GVHD requiring systemic therapy, relapse or death. Patients who are alive 
without GVHD will be censored at the last follow-up. 
2.5  Secondary Endpoint(s) 
1. Chronic GVHD 
The cumulative incidence of chronic GVHD by NIH Consensus criteria (Appendix 2) will 
be determined. Development of chronic GVHD will be considered an event for this 
endpoint. The highest grade of chronic GVHD will be recorded. In addition, the time of 
onset of chronic GVHD and the time to highest chronic GVHD grade will be recorded. 
Death but not disease relapse will be considered a competing event. 
 
 
2. Acute GVHD 
Cumulative incidences of grades II–IV and III–IV acute GVHD will be determined at day 
+100 and day +180 post-HCT. Acute GVHD will be graded according to Appendix 2. The 
time of onset of grade II–IV acute GVHD and time to development of the highest grade 
until day +180 will be recorded. Development of acute GVHD will be considered an event 
for this endpoint. Death but not disease relapse will be considered a competing event. 
 


 
 
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3. Graft failure 
Graft failure will be assessed as a secondary endpoint, including primary and secondary 
JUDIWIDLOXUH3ULPDU\JUDIWIDLOXUHLVGHILQHGDVQRQHXWURSKLOUHFRYHU\WR!FHOOVȝ/E\
day 28 post-HCT. Secondary graft failure will be assessed according to neutrophil count 
after initial hematologic recovery. Secondary graft failure is defined as initial neutrophil 
engraftment followed by subsequent decline in absolute neutrophil counts <500 FHOOVȝ/
unresponsive to growth factor therapy, but cannot be explained by disease relapse or 
drugs. 
 
4. Hematopoietic recovery 
Hematopoietic recovery will be assessed according to neutrophil and platelet counts 
recovery after HSCT. Neutrophil recovery or engraftment is defined as achieving an 
DEVROXWHQHXWURSKLOFRXQW$1&PP3 for three consecutive measurements on three 
different days. The first of the three days will be designated the day of neutrophil 
engraftment. The competing event is death without engraftment. Platelet recovery is 
defined by either the first day of a sustained platelet count >20,000/mm3 for three days 
with no platelet transfusion in the preceding seven days. The first day of sustained platelet 
count above these thresholds will be designated the day of platelet engraftment. 
 
5. Non-relapsed Mortality (NRM) 
NRM is defined as death after alloHCT without relapse. The cumulative incidence of NRM 
will be estimated at day +100 and one year after alloHCT. An event for this endpoint is 
death without evidence of disease progression or relapse. Disease progression or relapse 
will be considered a competing event. 
 
6. Disease Relapse or Progression 
Relapse is defined by either morphological, cytogenetic or radiologic evidence of the 
pretransplant hematologic malignancy. Institution of any therapy to treat persistent, 
progressive or relapsed disease, including the withdrawal of immunosuppressive therapy 
or donor lymphocyte infusion, will be considered evidence of relapse/progression. NRM 
will be considered a competing event. 
 
7. Progression-Free Survival 
The event for this endpoint is relapse/progression or death. The time to this event is 
measured from transplant to death or relapse/progression, whichever comes first. Patients 
who are alive and disease-free will be censored at last follow-up. 
 
8. Overall Survival 
The event for this endpoint is death from any cause. The time to this event is measured 
from the time of transplant to death from any cause or for surviving patients, to last follow-
up. Survivors will be censored at last follow-up. 
 
 
9. Pharmacokinetics and ADA/NAB testing 
Pharmacokinetic sampling will be performed by Sun Pharmaceutical Industries Ltd., 
which will outsource these samples to Labcorp Drug Development. Given the long half-
life of tildrakizumab, samples will be collected on week 0 (prior to administration of 
tildrakizumab), and then on days 30, 60, and 90. Each PK analysis draw requires five 
tubes of blood, each with 2–3 mL per tube, for a total of 10–15 mL of blood per PK 
analysis. PK samples should be stored at -70 degrees. Samples can be batched and 
shipped to Labcorp Drug Development. 


 
 
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ADA testing is testing for anti-drug antibodies, while Nab testing is testing for neutralizing 
antibodies to give a more complete picture along with the PK testing. ADA testing 
typically includes 3 tiers- screen, confirm and titer where screen/confirm are qualitative 
(positive or negative) and titer is semi-quantitative. The Nab method for tildrakizumab is 
screen tier only and qualitative (positive or negative), in which only samples that test 
positive are confirmed in the ADA assay. The purpose of having ADA/Nab testing 
alongside the PK testing is to better understand the PK profile differences seen. For 
instance, if PK serum concentrations are lower for an individual then a high ADA 
response would provide more clarity regarding the serum levels. Nab testing then would 
give additional insight into the mode of action of the immunogenicity.  
 
10. Incidence of infections 
The incidence of grade  &7&$( Y5) viral, fungal, and bacterial infections will be 
determined. The cumulative incidence of CMV viremia post-alloHCT will be described. 
 
11. Donor cell chimerism 
Chimerism will be evaluated using sorted whole blood in CD3+ and CD33+ fractions. 
Mixed chimerism is defined as the presence of donor cells, as a proportion of total cells to 
EH!DQG)XOOGRQRUFKLPHULVPLVGHILQHGDVRIGRQRUFHOOV'RQRUFHlls 
RIZLOOEHFRQVLGHUHGDVJUDIWUHMHFWLRQ'RQRUFHOOFKLPHULVPZLOOEHDVVHVVHGIRUDOO
patients at day +28 (baseline) for both CD3+ and CD33+ fractions. The proportion of 
patients with each level of chimerism listed above will be described. CD3+ donor cell 
chimerism will be used to define the donor/recipient chimerism status. 
 
12. Microbiome 
To address this question, we will obtain stool samples from each patient prior to 
transplantation as a baseline and then at weekly intervals through the period of 
engraftment (defined as an absolute neutrophil count >500/mm3 for three consecutive 
days). In addition, stool samples will be obtained at the time of GVHD onset in any affected 
patients. Fresh fecal samples will be collected and immediately preserved in RNAlater 
solution to facilitate optimal sample preservation, consistency of sample quality and ease 
of sample transport. Genomic DNA will be isolated from 200 mg of fecal sample using the 
Qiagen Powerlyzer Powersoil® kit as described.40 Bacterial composition and abundance 
will be validated by quantitative PCR analysis. Composition of the microbiota will be 
determined through sequencing of the 16S rRNA gene V4 region (Diversigen, Baylor 
College of Medicine, Waco, TX). PCR products will be generated using a dual-indexing 
amplification strategy, then sequenced on the MiSeq platform (Illumina, San Diego, CA). 
  
RNA gene sequence data will be utilized for bioinformatic analysis. 16S primers will be 
removed from the Illumina reads with the Trimmomatic program. Paired-end sequences 
will then be assembled using the FLASH algorithm,42 and chimeric sequences will be 
removed using UCHIME.43 The remaining clean 16S sequences will be clustered into 
operational taxonomic units (OTUs) using the UPARSE pipeline.44 A sequence identity of 
ZLOOEHXVHGWRJHQHUDWH278VUHSUHVHQWLQJGLVWLQFWEDFWHULDOVSHFLHV7KHWD[RQRPLF
LGHQWLW\RIUHIHUHQFHVHTXHQFHVZLOOEHGHWHUPLQHGXVLQJWKH5'3&ODVVLILHUZLWKDQ
confidence threshold. Bacterial community composition will be characterized using OTU 
counts generated as described above. OTU counts will be converted to measures of 
relative abundance to account for variation in sequencing coverage between samples. 
Statistical analysis will be carried out using the statistical software package R (www.r-
project.org$OSKDĮGLYHUVLW\ULFKQHVVDQGHYHQQHVVRIWD[DZLWKLQDSRSXODWLRQZLOOEH
reported using the Shannon Index46 and Chao1 richness estimator.47 %HWDȕGLYHUVLW\


 
 
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(overlap in taxa shared between populations) will be analyzed using the Bray-Curtis 
dissimilarity metric48 in conjunction with multivariate statistical analysis methods that will 
include Principal Components Analysis (PCA) and Permutational Multivariate Analysis of 
Variance (PERMANOVA).49 Changes in abundance of individual taxa will also be analyzed 
using traditional univariate statistical methods. 
 
2.6  Correlative Studies 
We intend to perform correlative studies to understand the impact of anti-IL-23 antibody treatment 
post allogeneic hematopoietic progenitor cell transplantation. This testing should help us better 
understand the changes that are happening within the immune system to inhibit graft-versus-host 
disease (GVHD). We propose obtaining labs at a minimum of nine time points as follows: 
 
I) 
Baseline blood and plasma samples (at screening). 
II) 
Blood and plasma samples at the following time points:  days 7±3, 14±3, 21±3, 28±7, 
60±14, 90±14, 196±30, 365±30 post-transplant. 
III) 
Samples at the time of development of GVHD (if it occurs). 
3  STUDY DESIGN 
3.1  General Description 
This is a phase II, open-label, single-arm trial designed to evaluate the efficacy of tildrakizumab 
in improving GVHD relapse-free survival. 
 
Prior to embarking on the phase II portion of the study, we proposed a run-in of six patients to 
assess the safety and tolerability of tildrakizumab in patients undergoing MAC alloHCT. These 
six patients received the same dosing schema as the other patients in our proposed phase II 
study. The first three patients were followed through day 28 to ensure no evidence of primary 
graft failure. We saw no evidence of primary graft failure, thus, an additional three patients (similar 
to a 3+3 trial design) were treated on study and again, monitored through day 28 for evidence of 
primary graft failure. No evidence of graft failure was seen in these six patients. Thus, additional 
patients will be enrolled in the trial until the trial has reached full accrual or activated a stopping 
rule. 
 
 
3.2  Treatment Schema 
 
Patients enrolled on this clinical trial will receive tacrolimus initiating at day -3 at doses to maintain 
therapeutic levels per institutional preference and continued until at least day +90 post-transplant. 
Methotrexate will be administered intravenously and dosed at 15 mg/m2 days +1, and 10 mg/mg2 
on days +3, +6 and +11. Tildrakizumab will be administered subcutaneously at a dose of 100 mg 
on day -1, day 28±3, day 112±7, day 196±14, and day 280±14. 
 
Number of patients who will be enrolled in the study:  55. 
 
3.3  Rationale for Treatment Schema 
 
We propose early administration of tildrakizumab for acute GVHD prevention based on the fact 


 
 
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that immediately following MAC, tissue injury ensues resulting in release of inflammatory 
mediators that provoke acute GVHD. We hypothesize that it is critical to have tildrakizumab 
present in order to block this inflammatory milieu, as outlined in Section 1.3. We propose 
continued administration of tildrakizumab to mediate a beneficial effect not only on the risk of 
aGVHD but also on cGVHD. The FDA-approved dosing of tildrakizumab for moderate to severe 
plaque psoriasis, based on a half-life of 21 to 24 days, is week 0, week 4 and every 12 weeks 
thereafter. We have maintained this dosing schedule [day -1 = week 0, day 28=week 4, day 112, 
day 196, day 280 are on the every-12-week schedule] and continued the tildrakizumab dosing 
through the period at highest risk for development of acute GVHD, conventionally thought to occur 
prior to day 100, and into the period of time during which chronic GVHD can occur, traditionally 
after day 100. 
 
3.4  Study Completion 
The study will reach study completion 24 months from the time the study opens to accrual. 
4  SUBJECT PARTICIPATION, DISCONTINUATION, AND  
    WITHDRAWAL 
MCW must follow all MCW IRB requirements and policies regarding subject participation, found 
here: 
 
https://www.mcw.edu/HRPP/Policies-Procedures.htm 
 
4.1  Subject Status 
 
Subject statuses throughout the trial are defined as follows:   
 
x 
Prescreening: preconsent (subject considering trial or study staff considering patient for 
the trial per institutional recruitment methods). 
x 
Screening: period after consent, but prior to eligibility confirmation. 
x 
Consented: consented, prior to eligibility confirmation. 
x 
Eligible: the local investigator confirms all eligibly criteria apply. 
x 
On study/enrolled: date eligibility is confirmed. 
x 
On arm: date of enrollment. 
x 
On treatment: first day treatment was given to the last day treatment was given. 
x 
Off treatment: the last day treatment was given. 
x 
On follow-up: from last day of treatment to the end of follow-up period. 
x 
Off study: follow-up period completed, with no additional data gathered. 
x 
Withdrawn: subject fully withdraws consent (i.e., refuses ALL follow-up, even survival) or 
is taken off study by the local PI. 
 
4.2  Prescreening and Screening Log 
 
The MCW study principal investigator regularly reviews screen failure reasons to understand 
barriers to accrual and consider amending eligibility criteria. Screen failures are defined as 
participants who were considered for the trial to participate in the clinical trial with or without 
consent but are not subsequently assigned to the study intervention or enrolled in the study. 


 
 
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MCWCC CTO will follow its SOPs regarding prescreening and screening tracking. 
 
4.3  Consent  
 
Investigators or their appropriate designees will identify potentially eligible subjects from their 
clinics, subject self-referrals, referrals from other clinicians and/or other IRB-approved recruitment 
methods. No study conduct, including subject prescreening, can occur until after IRB approval. 
 
A written, signed informed consent form (ICF) must be obtained before any study-specific 
assessments are initiated. A signed ICF copy will be given to the subject and a copy will be filed 
in the medical record (per local IRB policies and SOPs). The original will be kept on file with the 
study records.  
 
4.4  Screening Procedures 
 
Refer to study calendar of events. 
 
Visit procedures that were performed as standard of care prior to consent (without the specific 
intent to make the subject eligible for the trial), may count towards screening tests and eligibility 
if they are within the screening window.


Subject Initials: _________   Subject Study ID: ______________    Enrolling Physician___________ 
 
 
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4.5  Eligibility Confirmation 
 
Study staff must adhere to MCWCC CTO SOPs regarding eligibility review/confirmation.  
 
Patients must have baseline evaluations performed prior to the first study drug dose and must 
meet all inclusion and exclusion criteria. In addition, the patient must be thoroughly informed about 
all study aspects, including the study visit schedule and required evaluations and all regulatory 
requirements for informed consent. The written informed consent must be obtained from the 
patient prior to enrollment. The following criteria apply to all patients enrolled onto the study, 
unless otherwise specified. 
 
In the unlikely event that a patient meets criteria during the pretransplant period but is no longer 
eligible at time of first administration of tildrakizumab, they will be removed and replaced on 
study.   
 
No waivers of protocol eligibility will be granted, but when clinical factors relating to an eligibility 
item are unclear or questionable, the study principal investigator (Lyndsey Runaas, MD 
lrunaas@mcw.edu) can only provide guidance or clarification on eligibility.  
Inclusion Criteria 
1. $JH\HDUV. 
2. Patients with any hematologic malignancy for which alloHCT is indicated. Patients with 
acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) must be in 
FRPSOHWH UHPLVVLRQ DW WKH WLPH RI DOOR+&7  EODVWV LQ WKH ERQH PDUURZ QRUPDO
maturation of all cellular components in the bone marrow and absence of extramedullary 
disease). Patients with P\HORG\VSODVWLFV\QGURPH0'6PXVWKDYHEODVWVLQWKH
bone marrow, no circulating blasts. 
3. Myeloablative conditioning (MAC) regimen, based on CIBMTR criteria (total body 
irradiation [TBI] *\VLQJOHGRVHRU*\IUDFWLRQDWHGRUEXVXOIDQ[Bu] dose >8 mg/kg 
oral or >6.4 mg/kg intravenous).39  
4. T cell-replete peripheral blood graft.  
5. Patients must have a matched related or unrelated donor (at least 6/6 match at HLA-A, -
B and -C for related donors and at least 8/8 match at HLA-A, -B, -C and -DRB1 for 
unrelated donors). 
6. &DUGLDFIXQFWLRQ/HIWYHQWULFXODUHMHFWLRQIUDFWLRQIRUP\HORDEODWLYHFRQGLWLRQLQJ 
7. (VWLPDWHGFUHDWLQLQHFOHDUDQFHP/PLQXWHXVLQJWKH&RFNFURIW-Gault formula and 
actual body weight). 
8. 3XOPRQDU\IXQFWLRQ'/&2DGMXVWHGIRUKHPRJORELQDQG)(9.  
9. Liver function: total bilirubin <3 x upper limit of normal and ALT/AST <5 x upper normal 
limit. 
10. Female subjects must meet one of the following:  
Postmenopausal for at least one year before enrollment, OR  
a. Surgically sterile (i.e., undergone a hysterectomy or bilateral oophorectomy), OR 
 
CRC Initials:___________                                                              Date:_______________ 
 
 
 
Investigator/Enrolling Physician Initials:___________                    Date:_________________ 


Subject Initials: _________   Subject Study ID: ______________    Enrolling Physician___________ 
 
 
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b. If subject is of childbearing potential (defined as not satisfying either of the above 
two criteria), she must agree to practice two acceptable methods of contraception 
(combination methods require use of two of the following: diaphragm with 
spermicide, cervical cap with spermicide, contraceptive sponge, male or female 
condom, hormonal contraceptive) from the time of signing of the informed consent 
form through 90 days after the last dose of study agent, OR 
c. Agrees to practice true abstinence when this is in line with the preferred and usual 
lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, 
symptothermal, post ovulation methods] and withdrawal are not acceptable 
contraception methods.) 
11. Male subjects, even if surgically sterilized (i.e., status postvasectomy), must agree to one 
of the following: 
a. Practice effective barrier contraception during the entire study period and through 
60 calendar days after the last dose of study agent, OR 
b. Agree to practice true abstinence when this is in line with the preferred and usual 
lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, 
symptothermal, post ovulation methods] and withdrawal are not acceptable 
methods of contraception.) 
12. Signed informed consent: Voluntary written consent must be given before patient 
registration and performance of any study-related procedure not part of standard medical 
care, with the understanding that consent may be withdrawn by the patient at any time 
without prejudice to future medical care. 
13. Planned post-transplant maintenance therapy is allowed. 
14. Prior autologous transplant is allowed. 
 
Exclusion Criteria 
1. Prior allogeneic HCT. 
2. Active CNS involvement with malignancy. 
3. Patients receiving cord blood or haploidentical allograft.  
4. Patients undergoing in vivo or ex vivo T cell-depleted alloHCT. 
5. Karnofsky performance sFRUH or ECOG > or = 2.  
6. Patients with uncontrolled bacterial, viral or fungal infections (currently on treatment and 
with progression of infectious disease or no clinical improvement) at time of enrollment.  
7. Active hepatitis B or C virus infection or known human immunodeficiency virus (HIV) 
positive. 
8. Use of rituximab, alemtuzumab, anti-thymocyte globulin (ATG), or other monoclonal 
antibody planned as part of conditioning regimen for GVHD prophylaxis.  
9. Participation in another GVHD prophylaxis clinical trial. 
 
 
CRC Initials:___________                                                              Date:_______________ 
 
 
 
Investigator/Enrolling Physician Initials:___________                    Date:_________________ 
 
 
 


Subject Initials: _________   Subject Study ID: ______________    Enrolling Physician___________ 
 
 
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10. Any current uncontrolled cardiovascular conditions, including uncontrolled ventricular 
arrhythmias, NYHA class III or IV congestive heart failure, uncontrolled angina, or 
electrocardiographic evidence of active ischemia or active conduction system 
abnormalities. 
11. Any serious medical or psychiatric illness that could, in the investigator’s opinion, 
potentially interfere with the completion of treatment according to this protocol.  
 
 
 
“I have reviewed all inclusion and exclusion criteria and confirm the subject is eligible.” 
 
 
 
 
______________________________________         
 
_______________ 
                   (CRC Signature)                                                                   (Date) 
 
 
 
 
 
_____________________________________         
 
_______________ 
   (Investigator/Enrolling Physician Signature)                                           (Date) 


 
 
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4.6  Discontinuation of Study Treatment, Withdrawal, and Compliance 
Discontinuation from the study treatment does not mean discontinuation from the study. Subject 
will be considered in follow-up, study procedures should still be completed as indicated by the 
study protocol and AEs/SAEs will continue to be reported according to this protocol. 
 
In the absence of treatment delays due to adverse events, study treatment/intervention may 
continue until:  
 
x 
Disease (relapse or progression of the primary malignancy) for which treatment is 
indicated. 
x 
Donor leukocyte infusion (DLI) prior to planned redose of tildrakizumab for any 
indication: infection, disease control or to address mixed chimerism. 
x 
Grade III–IV acute GVHD. Patients with grade I–II acute GVHD and on topical or 
V\VWHPLFFRUWLFRVWHURLGVWKHUDS\HTXLYDOHQWWRSUHGQLVRQHPJGFDQUHFHLYH
further doses of tildrakizumab. 
x 
Active chronic GVHD requiring systemic therapy. 
x 
General or specific changes in the subject’s condition renders the subject 
unacceptable for further treatment in the investigator’s judgment.  
x 
Inter-current illness that prevents further treatment administration.  
x 
Subject decides to withdraw from the study.  
x 
The subject has significant noncompliance with the protocol (see below).   
x 
Unacceptable adverse event(s) beyond requirements as detailed in this protocol.  
 
 
Subjects who sign the informed consent form, and are enrolled and receive the study intervention, 
but subsequently withdraw, or are withdrawn or discontinued from the study will not be replaced. 
 
Consent Withdrawal 
 
A subject may decide to withdraw from the study at any time. MCWCC CTO will follow its IRB of 
record’s SOPs regarding consent withdrawal.  
 
If a subject intends on withdrawing consent, staff should confirm which of the following options 
the subject chooses and document the discussion: 
 
x 
Full consent withdrawal, with no study follow-up. 
x 
Selective consent withdrawal from interventional portion of the study, but agrees to 
continued follow-up of associated clinical outcome information. 
Investigator-initiated Withdrawal 
The investigator will withdraw a subject whenever continued participation is no longer in the 
subject’s best interests. Reasons for withdrawing a subject include, but are not limited to, disease 
progression, the occurrence of an adverse event or a concurrent illness, a subject’s request to 
end participation, a subject’s noncompliance or simply significant uncertainty on the part of the 
investigator that continued participation is prudent. The reason for study withdrawal and the date 
the subject was removed from the study must be documented. 
 
 


 
 
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4.7  Lost to Follow-up 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit and/or is unable to be reached for follow-up: 
 
x 
The investigator or designee must make every effort to regain contact and/or reschedule a 
missed visit with the participant. 
x 
A participant is deemed lost to follow-up if his/her status cannot be obtained after all of the 
following occurs at two consecutive scheduled protocol calendar timepoints: 
o Three telephone calls (at least one day apart) from the study team are unanswered.  
AND  
o A letter to the participant’s last known mailing address goes unanswered.  
AND 
o These contact attempts must be documented in the participant’s medical record or 
study file.  
x 
Update OnCore® (follow-up tab and eCRF) when a participant is officially considered lost to 
follow-up. 
x 
If a subject is considered lost to follow-up, but subsequently contacts the study team, the 
subject should be considered in follow-up again. 
 
4.8  Accrual Suspension and Closure 
 
The MCW PI facilitates the suspension and closing of accrual in the following manner: 
 
x 
OnCore® tracks accrual throughout the study. 
x 
If the study must be suspended, OnCore® is updated to a ‘suspended’ status. 
x 
When the accrual number is reached, OnCore® notifies staff of study closure. 
 
4.9  Study Discontinuation and Closure 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause (as determined by the MCW Study PI, DSMC, sponsor, and/or IRB). Written 
notification, documenting the reason for study suspension or termination, will be provided by the 
suspending or terminating party to study participants, investigator, funding agency, the 
Investigational New Drug (IND) sponsor and regulatory authorities. If the study is prematurely 
terminated or suspended, the MCW Principal Investigator (PI) will promptly inform the MCW 
Institutional Review Board (IRB), and sponsor and will provide the reason(s) for the termination 
or suspension. Study participants will be contacted, as applicable, and be informed of changes. 
5  STUDY ENTRY AND WITHDRAWAL; STUDY PROCEDURES 
5.1  Required Preregistration Screening Tests and Procedures 
The study-specific assessments are detailed in this section and outlined in the Study Calendar. 
A written, signed informed consent form (ICF) must be obtained before any study-specific 
assessments are initiated. A signed ICF copy will be given to the subject and a copy will be filed 
in the medical record. The original will be kept on file with the study records.  


 
 
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All patients who are consented will be registered in OnCore®, the MCW Cancer Center Clinical 
Trial Management System. The system is password protected and meets HIPAA requirements. 
5.2  Registration Process 
Patients will be approached for this study after the decision to proceed with transplant is made 
and a suitable HLA-matched donor is identified. Transplant physicians will evaluate the patient 
eligibility into this study. All source documents that support eligibility include a signed informed 
consent/HIPAA and signed eligibility checklist. These must be available for review and 
verification.  
At the point of registration, the study staff will register the patient in the electronic database (where 
applicable), including demographic, consent and on-study information. The patient will be 
assigned a unique sequence number for the study. 
Patients will be enrolled on this trial within 30 days preceding the conditioning regimen for 
alloHCT. 
5.3  Pretreatment Period 
Pretransplant Evaluations 
The following observations must be completed within 30 days before the initiation of the 
conditioning regimen. 
x 
History, physical examination, height, and weight. 
x 
CBC with differential will be performed as appropriate during hospitalization for 
alloHCT on clinic visits and at minimum performed on days indicated on the 
schedule of events. 
x 
Comprehensive metabolic panel will be performed as appropriate during 
hospitalization for alloHCT, on clinic visits and at minimum performed on days 
indicated on the schedule of events. 
 
x 
HLA typing (donor and recipient). 
x 
Adverse events assessments. 
x 
Karnofsky Performance Status Scale and HCT-Specific Comorbidity Index score. 
x 
Infectious disease markers: CMV antibody, hepatitis panel (HepA Ab, HepB SAb, 
HepB SAg, HepB Core Ab, HepC Ab), HIV and HTLV I/II antibody. 
x 
EKG and LVEF (may be performed <30 days prior to patient enrollment).  
x 
Pulmonary function tests, including DLCO and FEV1 (may be performed <30 days 
prior to patient enrollment). 
x 
Disease evaluation of the malignant disease: For acute leukemia, CML and MDS, 
this includes a bone marrow aspirate and biopsy for pathology and cytogenetics.  


 
 
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x 
Pregnancy test per institutional practices for females of childbearing potential. 
NOTE: pregnancy test must be performed <30 days before initiation of the 
conditioning regimen. 
x 
Pretransplant blood samples for future research. 
Research (stool) sample will be collected pretransplant after admission to the 
hospital during the (pretransplant) conditioning period. Samples will be collected 
from each patient as a baseline and then at weekly intervals through the period 
of engraftment. In addition, stool samples will be obtained at the time of GVHD 
onset in any affected patients. Fresh fecal samples will be collected and 
immediately preserved in RNAlater solution, to facilitate optimal sample 
preservation, consistency of sample quality and ease of sample transport. 
Genomic DNA will be isolated from 200 mg of fecal sample using the Qiagen 
Powerlyzer Powersoil kit as described.40 Bacterial composition and abundance 
will be validated by quantitative PCR analysis. Composition of the microbiota will 
be determined through sequencing of the 16S rRNA gene V4 region (Diversigen, 
Baylor College of Medicine, Waco, TX). PCR products will be generated using a 
dual-indexing amplification strategy, then sequenced on the MiSeq platform 
(Illumina, San Diego, CA).  
 
5.4  Study Procedures during Treatment 
Patients must meet eligibility criteria eligible on day -1 to be treated.  
5.5  GVHD Assessment 
Patients will be monitored for development of acute and chronic GVHD, per standard operating 
procedures at the MCW BMT Program, but at minimum on days +28 (+/-7), +56 (+/-7), +100 (+/-
14), +180 (+14), +365 (+/-28) post-HCT. Diagnosis of acute GVHD may not necessitate biopsy 
confirmation in at least one involved organ but would be preferred. When more than one organ is 
involved, biopsy confirmation of all involved organs is recommended but not necessary. With liver-
only GVHD, biopsy confirmation is strongly recommended. Acute GVHD will be assessed by 
consensus criteria (Appendix 2),  and chronic GVHD diagnosis and grading will be according to 
NIH Criteria (please see Appendix 2).  
Independent GVHD adjudication is mandated in the study. Acute and chronic GVHD will be 
adjudicated by an independent Faculty Research Committee (FRC)-appointed review panel. 
Protocol PIs will be blinded to the adjudication panel and will not be permitted to grade or modify 
GVHD assessments. GVHD case report forms (CRFs) will be completed by treating 
MDs/NPs/APPs in real time, as indicated in study calendar. FRC adjudication panel will grade 
GVHD, using a calendar-driven approach (days +100 and +180 for aGVHD and days +180 and 
+365 for chronic GvHD). 


 
 
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6  TREATMENT PLAN 
6.1  Investigational Agent Administration 
Treatment will be administered on an inpatient or outpatient basis depending on patient status. 
Treatment cannot be self-administered. Allow prefilled syringe in original carton to sit and reach 
room temperature (30 minutes) before injecting subcutaneously. Inject a site with clear skin and 
easy access (e.g., abdomen, thighs, or upper arm); do not administer two inches around navel 
or where skin is tender, bruised, erythematous, indurated, or affected by psoriasis; do not inject 
into scars, stretch marks, or blood vessels. 
Study Drug 
Premedication; 
precautions 
Dose 
Route 
Schedule 
(Day pre or post-
transplant) 
Tildrakizumab 
None 
100 mg 
Subcutaneously 
Day -1, Day 28 ± 
3, Day 112 ± 7, 
Day 196 ± 14, and 
Day 280 ± 14. 
 
The following are contraindications for tildrakizumab dosing beyond the first dose: 
1) Grade 4 (according to CTCAE version 5 hematologic or nonhematologic events 
(which have life-threatening consequences and require urgent treatment). Dosing will 
EHDOORZHGXSRQUHFRYHU\WRJUDGH7UDQVIXVLRQWRLQFUHDVHSODWHOHWDQG
hemoglobin is allowed.  
2) Disease (relapse or progression of the primary malignancy) for which treatment is 
indicated. 
3) Donor leukocyte infusion (DLI) prior to planned redose of tildrakizumab for any 
indication: infection, disease control or to address mixed chimerism. 
4) Grade III–IV acute GVHD. Patients with grade I–II acute GVHD and on topical or 
V\VWHPLFFRUWLFRVWHURLGVWKHUDS\HTXLYDOHQWWRSUHGQLVRQHPJGFDQUHFHLYHD
second dose of tildrakizumab. 
5) Active chronic GVHD requiring systemic therapy. 
 
6.2  Standard GVHD Prophylaxis Administration 
6.2.1  Tacrolimus 
Tacrolimus will be given per standard operating procedures from the MCW BMT program, 
intravenously at a dose of 0.03 mg/kg/day starting day –3. Subsequent dosing will be based on 
blood levels. The dose should be adjusted accordingly to maintain a suggested level of 5–10 
ng/mL. The dose of tacrolimus may be switched to oral at a 1:3 dose equivalence and rounded to 
the nearest 0.5 mg at the discretion of the treating physician. If patients are on medications which 
alter the metabolism of tacrolimus (e.g., azoles), the initial starting dose and subsequent doses 
should be altered, as per institutional practices. Tacrolimus taper can be initiated at a minimum 
of 90 days post-HSCT, if there is no evidence of active GVHD. The rate of tapering will be done 
according institutional practices, but patients should be off tacrolimus by day 180 post-HSCT. 
 


 
 
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6.2.2  Methotrexate 
Methotrexate will be administered, per institutional practices, at the doses of 15 mg/m2 IV bolus 
on day +1, and 10 mg/m2 IV bolus on days +3, +6 and +11 after hematopoietic cell infusion. Dose 
reduction of MTX due to worsening creatinine clearance after initiation of conditioning regimen, 
high serum levels or development of oral mucositis is allowed, according to institutional practices.  
 
6.3  General Concomitant Medication and Supportive Care Guidelines 
There are no restricted concomitant medications. 
Patients should avoid live vaccines until at least two years post-transplant as per institutional 
protocol.   
6.4  Dietary Restrictions 
 
There are no dietary restrictions for this study.  
 
6.5  Supportive Care Guidelines 
 
All supportive therapy for optimal medical care will be given during the study period at the 
discretion of the attending physician(s) within the parameters of the protocol and documented on 
source documents as concomitant medication. 
 
Concurrent or concomitant use of medication is not restricted during protocol therapy. However, 
subjects are not permitted to take any anti-cancer medications or supplements during study 
treatment. 
 
6.6  Follow-up Period 
Patients will be followed for a total 12 months or until death, whichever occurs first. All patients 
who receive at least one dose of the study drug will be followed.  
7  ADVERSE EVENTS: DEFINITIONS AND REPORTING  
    REQUIREMENTS 
 
7.1  DEFINITIONS 
 
7.1.1  Adverse Event  
 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship with 
this treatment. (International Conference on Harmonisation [ICH], E2A, E6). This study will utilize 
the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, located on the 
CTEP web site: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm  
AEs may be spontaneously reported by the patient and/or in response to an open question from 
study personnel or revealed by observation, physical examination or other diagnostic 
procedures. 


 
 
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7.1.2  Serious Adverse Event (SAE)  
 
Serious Adverse Event (SAE) means any untoward medical occurrence that results in any of the 
following outcomes: 
x 
Death. Results in death. 
x 
Life-threatening. Is life-threatening (refers to an AE in which the patient was at risk of 
death at the time of the event. It does not refer to an event which hypothetically might have 
caused death if it were more severe). 
x 
Hospitalization. Requires inpatient hospitalization or prolongation of an existing 
hospitalization. 
x 
Disability/incapacity. Results in persistent or significant disability or incapacity. 
(Disability is defined as a substantial disruption of a person’s ability to conduct normal life 
functions). 
x 
Pregnancy. 
x 
Medically important event. This refers to an AE that may not result in death, be 
immediately life threatening, or require hospitalization, but may be considered serious 
when, based on appropriate medical judgment, may jeopardize the patient, require 
medical or surgical intervention to prevent one of the outcomes listed above, or involves 
suspected transmission via a medicinal product of an infectious agent. 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; any organism, 
virus, or infectious particle (e.g., prion protein transmitting transmissible spongiform 
encephalopathy), pathogenic or nonpathogenic, is considered an infectious agent. 
7.1.3 Attribution of an Adverse Event 
An assessment of the relationship between the adverse event and the medical intervention, using 
the following categories:  
Definitely Related: The AE is clearly related to the intervention. There is clear evidence to 
suggest a causal relationship, and other possible contributing factors can be ruled out.  
Probably Related: The AE is likely related to the intervention. There is evidence to suggest a 
causal relationship, and the influence of other factors is unlikely.  
Possibly Related: The AE may be related to the intervention. There is some evidence to suggest 
a causal relationship (e.g., the event occurred within a reasonable time after administration of the 
trial medication). However, the influence of other factors may have contributed to the event (e.g., 
the subject’s clinical condition, other concomitant events).  
Unlikely: The AE is doubtfully related to the intervention. A clinical event, including an abnormal 
laboratory test result, whose temporal relationship to drug administration makes a causal 
relationship improbable (e.g., the event did not occur within a reasonable time after administration 


 
 
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of the trial medication) and in which other drugs or chemicals or underlying disease provides 
plausible explanations (e.g., the subject’s clinical condition, other concomitant treatments).  
Unrelated: The AE is clearly NOT related to the intervention. The AE is completely independent 
of study drug administration, and/or evidence exists that the event is definitely related to another 
etiology.  
7.1.4  Expectedness of an Adverse Event 
 
Study investigator or treating physician will be responsible for determining whether an AE is 
expected or unexpected, as indicated in the protocol, informed consent form and/or drug 
information brochure. An AE will be considered unexpected if the nature, severity, or frequency 
of the event is NOT consistent with the risk information previously described for the study 
intervention. 
7.2  Collection and Reporting Requirements for Adverse Events and Serious Adverse 
Events 
 
Only grade 3,4 and 5 adverse events (including SAEs) must be recorded in OnCore® and/or an 
adverse event log. All AEs required to be collected must be graded according to the CTCAE v5. 
When possible, signs and symptoms indicating a common underlying pathology should be noted 
as one comprehensive event. Investigator’s or treating physician’s assessment of AE attributions 
must also be documented.  
AEs will be collected from the time the subject signs the consent form through 30 days post last 
dose of study drug(s). AEs will be tracked and followed until resolution, subject withdraws 
consent, or is lost to follow-up (including subjects who discontinue early). All adverse events 
collected per the protocol will be followed with appropriate medical management until they are 
resolved, if they are related to the study treatment, or until the investigator deems the event to be 
chronic. Please see section 7.2.2 and Table 1 to identify the adverse events that need to be 
reported.  
7.2.1  Reporting of Adverse Events and Serious Adverse Events 
Please refer to Table 1 below to identify adverse events that meet reporting requirements.  
All serious adverse events (SAEs) that occur after the subject has signed the consent form 
through 30 days post last dose of study drug(s) will be reported. All SAEs will be followed until 
satisfactory resolution, or until the investigator deems the event to be chronic. All serious adverse 
events (SAEs) must also be documented in OnCore®. 
Table 1 
Attribution 
SAE 
AE 
Grade 1, 2 & 3 
Grade 4 and 5 
Grade 3 
Grade 4  
Expected 
Unexpected 
Expected 
Unexpected 
Unexpected 
Expected 
Unexpected 


 
 
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1. Guidance on adverse event reporting to the IRB is available online at MCW IRB Policies 
and Procedures.  
2. For expedited DSMC reporting, study coordinator/research nurse must notify the DSMC 
via email including the subject ID, date of event, grade, relatedness, expectedness, and a 
short narrative. DSMC will review data entered into OnCore®. Non-hematological grade 4, 
unexpected hematological grade 4 and all grade 5 events must be reported to the DSMC 
within five calendar days of study staff’s knowledge. Expected hematological grade 4 
adverse events will be routine reported. 
3. For routine reporting, the events will be reported to IRB as part of the annual continuing 
progress report and the DSMC will review data entered into OnCore® at the time of 
scheduled monitoring. 
4. Fatal or life-threatening SAEs meeting the criteria indicated in the above table will be 
reported to FDA no later than seven calendar days after study staff’s initial awareness of 
the event. If the SAE is not fatal or life-threatening and meets the above criteria, the 
timeline for submitting an IND safety report to FDA is no later than 15 calendar days after 
study staff’s initial awareness of the event. See section 7.2.2 for detailed reporting 
instructions. 
5. Sun Pharmaceutical Industries Ltd. reporting requirements will be same as FDA (see 
footnote 4 above). For the purpose of reporting to Sun Pharmaceutical Industries Ltd, 
study staff should submit the MedWatch form and a deidentified OnCore® SAE report.  
 
7.2.2  Reporting Instructions  
x 
Food and Drug Administration  
An IND safety report will be submitted for any adverse event that meets all three 
definitions: possibly related to the study drug, unexpected and serious. If the adverse 
event does not meet one of the above definitions, it should not be submitted as an 
expedited IND safety report.  
Any relevant additional information that pertains to a previously submitted IND safety 
report will be submitted to FDA as a Follow-up IND Safety Report without delay, as soon 
as the information is available (21 CFR 312.32(d)(2)).  
Unrelated 
Unlikely 
IRB1 and 
DSMC2- 
Routine 
Review3 
 
 
 
IRB1 and 
DSMC2- 
Routine 
Review3 
 
 
IRB1- 
Routine 
Review3 
 
DSMC2-
Within 5 
calendar 
days 
 
 
 
IRB1- 
Routine 
Review3 
 
DSMC2-
Within 5 
calendar 
days 
DSMC2- 
Routine 
Review3 
 
DSMC2- 
Heme: 
Routine 
review 
 
Non-
Heme: 
Within 5 
calendar 
days 
DSMC2- 
Within 5 
calendar 
days 
 
Possible 
Probable 
Definite 
IRB1 and 
DSMC2- 
Within 5 
calendar 
days 
 
FDA4 
 
Sun 
Pharma5 
IRB1 and 
DSMC2- 
Within 5 
calendar 
days 
 
FDA4 
 
Sun 
Pharma5 


 
 
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Suggested Reporting Form: 
US FDA MedWatch 3500A:  
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm        
x 
Sun Pharmaceutical Industries Ltd. (Sponsor) 
Serious adverse events (SAEs) as per the table above must be reported to Sun 
Pharmaceutical Industries Ltd.’s local safety representative by FAX at 609-720-8505 
(preferred) or by email:  drug.safetyUSA@sunpharma.com. 
 
7.3  Unanticipated Problem Involving Risk to Subject or Other (UPIRSO) 
The investigator and his or her team will follow the Medical College of Wisconsin policies related 
to unanticipated problems involving risks to subjects or others. This information may be found on 
the Human Research Protection Program website.  
7.4  Reporting of Pregnancy 
Female subjects who become pregnant during treatment and 30 days post the last dose of the 
study drug should discontinue the study treatment immediately. Study staff should report the 
pregnancy in OnCore® as a grade 3 SAE and email the PDF report to the study PI and DSMC 
coordinator within 24 hours of staff awareness.  
If a male subject impregnates his partner during treatment and 30 days post last dose of the study 
drug, the study team should report the pregnancy in OnCore® as a grade 3 SAE and email the 
pdf report to the study PI and DSMC coordinator within 24 hours of staff awareness. 
Whenever possible, a pregnancy (for either a subject or male subject’s partner as described 
above and according to IRB policies regarding consent of this partner) should be followed to term, 
any premature termination reported, and the status of the mother and child should be reported. 
Data on fetal outcome and breastfeeding are to be collected for regulatory reporting and drug 
safety evaluation. 
7.5  Subject Complaints 
If a complaint is received by anyone on the study staff, it will be discussed with the study staff and 
will be addressed on a case-by-case basis. The PI will be notified of any complaints. Complaints 
will be reported to the IRB if indicated.  
If the subject has questions about his or her rights as a study subject, wants to report any 
problems or complaints, obtain information about the study or offer input, the subject can call the 
Medical College of Wisconsin/Froedtert Hospital research subject advocate at 414-955-8844. 
This information is provided to the subject in their consent.  
A product complaint is a verbal, written or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality or stability of a drug product. Individuals who identify 
a potential product complaint situation should immediately contact the drug manufacturer and 
report the event. Whenever possible, the associated product should be maintained in accordance 
with the label instructions pending further guidance from a drug manufacturer representative. 


 
 
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Product complaints in and of themselves are not reportable events. If a product complaint results 
in an SAE, an SAE form should be completed. 
7.6  Known AEs List 
 
Tildrakizumab 
 
Tildrakizumab side effects include: 
x 
Nasopharyngitis 
x 
Diarrhea 
x 
Injection site reaction 
 
 
Tacrolimus 
 
Tacrolimus side effects include:  
x 
Neurologic: confusion, dizziness, insomnia, seizures, tremors, changes in how clearly 
one can think 
x 
Cardiovascular: hypertension 
x 
Gastrointestinal: nausea, vomiting 
x 
Hematologic: microangiopathic hemolytic anemia, thrombocytopenia 
x 
Endocrine and metabolic: hypomagnesemia, hypokalemia, hypocalcemia, 
hyperlipidemia 
x 
Miscellaneous: unwanted hair growth, changes in vision, liver problems, reversible renal 
insufficiency, infections and posttransplant lymphoproliferative disorders 
 
Methotrexate 
 
The most frequently reported adverse reactions associated with methotrexate use as GVHD 
prophylaxis include: 
x 
Neurologic: fever, dizziness, chills, undue fatigue 
x 
Gastrointestinal: ulcerative stomatitis, nausea, abdominal distress, diarrhea 
x 
Hematologic:  leucopenia, anemia and suppressed hematopoiesis (leading to infection) 
 
 
Miscellaneous  
x 
Abnormal liver tests, kidney failure and pulmonary complications after transplantation 
8  PHARMACEUTICAL INFORMATION 
Tildrakizumab 
8.1  Agent Description:  Tildrakizumab is a high affinity (297 pM), humanized immunoglobulin 
G1/kappa ,J*ț DQWLERG\ WKDW VSHFLILFDOO\ ELQGV DQG QHXWUDOL]HV KXPDQ ,/-23 (SN 08197 
[Addendum 1]). This antibody has been shown in Phase 1, Phase 2, and Phase 3 studies to 
reduce the clinical signs and symptoms of psoriasis. 
8.2  Absorption:  Absolute bioavailability is 73–ZLWKVORZabsorption with time to reach 
maximum concentration at 6.2 days after SC injection. Tildrakizumab exposure increased 


 
 
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proportionally with dose and did not exhibit time-dependent PK. Steady-state is achieved by 16 
weeks with the clinical regimen (dosing on Week 0 and Week 4 and Q12W thereafter) with 1.1- 
fold accumulation in Cmax. Tildrakizumab has low to moderate PK variability (33-&9 
 
8.3  Distribution:  Tildrakizumab has limited extravascular distribution with an apparent volume 
of distribution (Vd/F) of 10.8 L, which was found to depend on the body weight. Plasma protein 
binding is not expected to impact tildrakizumab exposure. 
 
8.4  Metabolism:  Tildrakizumab is catabolized by general protein degradation processes; typical 
small-molecule metabolic pathways (e.g., CYPs), glucuronosyltransferases) do not contribute to 
its clearance. 
 
8.5  Elimination: Tildrakizumab is catabolized into component amino acids by general protein 
degradation processes and is not eliminated by renal or hepatic pathways. Apparent clearance is 
independent of dose. Apparent elimination half-OLIH&9LVGD\V  
 
8.6  Contraindications:  As tildrakizumab is eliminated by protein catabolism, not affected by 
hepatic drug metabolizing enzymes and not eliminated by renal or hepatic pathways, no dose 
adjustments for tildrakizumab are necessary when co-administered with other therapies. 
8.7  Side Effects:  Complete and updated adverse event information is available in the 
Investigational Drug Brochure and/or product package insert. 
8.8  Storage Requirements and Stability:  Ongoing stability studies have shown that 
tildrakizumab solution DP in PFS is stable under refrigerated storage conditions (2ºC to 8°C). 
Please refer to the package insert for additional storage and stability information.  
8.9  Agent Destruction and Return:  Used, and any unused study drug will be destroyed and 
documented, as per institutional standards.  
8.10 Availability 
This drug is commercially available for the indication of psoriasis. For the purpose of this study, 
it will be paid for and supplied by the funding sponsor, Sun Pharmaceutical Industries Ltd. For 
drug ordering, fill out the drug supply form request form provided by Sun Pharmaceutical 
Industries Ltd.  
9  CORRELATIVE STUDIES/SPECIAL STUDIES 
9.1  DESCRIPTION 
We intend to perform correlative studies to understand the impact of anti-IL-23 antibody treatment 
post allogeneic hematopoietic progenitor cell transplantation. This testing should help us better 
understand the changes that are happening within the immune system to inhibit graft-versus-host 
disease (GVHD). 
 
We plan to perform the analysis of immune cells subsets from fresh or frozen peripheral blood 
mononuclear cells by flow cytometry, with the hypothesis that treatment with anti-IL-23 antibody 
will prevent alterations in circulating immune cell subsets and cytokines/biomarkers that are 
associated with development of GVHD.  


 
 
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Analysis of immune cell subsets from fresh or frozen peripheral blood mononuclear cells (PBMCs) 
by flow cytometry 
 
As a measure of systemic immunity (using PBMCs), the relative percentage of circulating immune 
cells will be assessed by multiparametric flow cytometry. Multiparametric flow cytometry will allow 
for identification of immune cell subsets by recording the simultaneous expression of biomarkers 
unique to that cell subset. Flow cytometry will be performed on a MACS Quant flow cytometer in 
the Cell Therapy Laboratory at the Medical College of Wisconsin. We will use flow cytometry of 
antibody stained PBMCs to evaluate the relative percentage of cell types including T, B, NK and 
myeloid cells. Correlating changes in immune cell subsets upon anti-IL-23 therapy will facilitate 
the identification of a peripheral immune signature that correlates with absence or presence of 
GVHD. We will test for the expression of the following immune cell markers: T cell marker panel 
(includes regulatory T cell markers): CD3, CD4, CD8, CD25, CD44, CD62L, CD56, CD127, Foxp3 
(intracellular), phospho-STAT3 (intracellular); NK cell marker panel: CD56, CD16, CD3; Myeloid 
cell marker panel: CD11b, CD33, CD14; B cell marker panel: CD19, CD20. 
 
We also intend to perform the analysis of cytokines and biomarkers in blood plasma. Plasma, or 
serum, cytokine and biomarker signatures can provide important information regarding peripheral 
immune responses. Changes in serum cytokines and other biomarkers have been reported during 
GVHD and in cancer patients. However, currently, there are no defined cytokine signatures that 
are predictive of outcome following allogeneic hematopoietic progenitor cell transplantation.  
Analysis of cytokines and biomarkers in blood plasma (Luminex® platform) 
 
For this study, plasma cytokines and other biomarkers will be analyzed longitudinally before and 
after immune therapy with anti-IL-23 antibody. Serum cytokines will be quantified using 
customized Luminex® bioplex assays. For the cytokine array, we will analyze the following: IL-1, 
IL-2, IL-4, IL-6, IL-10, IL-17, IL-23, TNFD, GM-CSF, IFNJ. The biomarker array will analyze the 
following: ST2, REG3A, BAFF, CCL15, MMP3, CXCL9, CXCL10, osteopontin, soluble CD163. 
 
9.2  Instructions Regarding Sample Collection for Correlatives: 
For each time point, one 10 ml red top tube and one 10 ml purple top tube will be collected. 
Once the samples are collected, study coordinator will contact the BMT and Cell Therapy 
Laboratory (414-805-6143). 
The samples will be transferred to Dr. Bryon Johnson’s lab once collected (no spinning or other 
special handling). They can be at room temperature. If they were to be collected on weekends 
or holidays, the samples should be stored at 4°C until they are transferred to the lab. 
10  STATISTICAL CONSIDERATIONS 
10.1  Study Endpoints 
The endpoints are defined with more detail in Sections 2.3 through 2.5. 
Primary endpoint 
The primary endpoint is the 12-month probability of GVHD-free relapse-free survival (GRFS). An 
event for this outcome is defined as either grade III–IV acute GVHD, systemic therapy-requiring 
chronic GVHD, relapse, or death at 12 months.  


 
 
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Secondary endpoints 
 
1. Cumulative incidence of mild, moderate and severe chronic GVHD according to the NIH 
criteria and limited or extensive GVHD by conventional criteria.  
2. Cumulative incidence of grade II–IV acute GVHD at days 100 and 180.  
3. Cumulative incidence of grade III–IV acute GVHD at days 100 and 180. 
4. Incidence of primary and secondary graft failure. 
5. Hematopoietic recovery will be assessed according to neutrophil and platelet counts 
recovery after HSCT.  
6. Cumulative incidence of non-relapse mortality (NRM) post HSCT.  
7. Cumulative incidence of relapse/progression of the primary malignancy.  
8. Overall survival (OS) post HSCT.  
9. Assess the pharmacokinetic (PK) profile of multi-dose tildrakizumab. 
10. Probability of lower GI tract GVHD. 
 
Exploratory endpoints 
1. Longitudinal trajectory of serum cytokines. 
2. Longitudinal trajectory of serum biomarkers. 
3. Longitudinal trajectory of immune cell markers. 
 
10.2  Study Design 
10.2.1  Determination of Sample Size and Accrual Rate 
Dr. Aniko Szabo will assist with the statistical analyses in the trial. The study will test the primary 
K\SRWKHVLVWKDW*5)6DWPRQWKVH[FHHGVWKHKLVWRULFDOFRQWUROYDOXHRIDWDWZR-sided 
VLJQLILFDQFHOHYHO7KHWDUJHWVDPSOHVL]HZLOOEH5 patients with a known outcome (i.e., 
*9+'UHODSVHRUGHDWKVWDWXVDWPRQWKV:LWKWKLVVDPSOHVL]HWKHVWXG\ZLOOKDYH
SRZHUWRGHWHFWDQLQFUHDVHLQ*5)6DWPRQWKVWRSRZHUWRGHWHFWDQLQFUHDVHWR
DQGSRZHUWRGHWHFWDQLQcrHDVHWR. -XVWLILFDWLRQIRUWKHLQFUHDVHLQ*5)6
probability as a clinically meaningful endpoint derives from the recently published BMT Clinical 
Trials Network 1203 GVHD prevention trial which compared three different prophylaxis 
regimens to standard therapy with tacrolimus and methotrexate and was powered to detect a 
LQFUHDVHLQ*5)67RDFKLHYHWKHWDUJHWVDPSOe size, we will enroll 55 patients to allow for 
DORVVWRIROORZ-up. 
 
10.2.2  Accrual Estimates 
 
It is estimated that 30 months of accrual will be adequate. This is based on our historical rate of 
approximately 50 myeloablative allogeneic stem cell transplants per year over the past three  
years. $VVXPLQJDFRQVHUYDWLYHHQUROOPHQWUDWHDSSUR[LPDWHO\PRQWKVVKRXOGEH
sufficient to enroll our target of 55 patients.   
 
10.3  Analysis Population 
The full analysis set will include all patients enrolled in the study. 
The efficacy analysis set will include all patients in the full analysis set who receive at least 
one dose of tildrakizumab. 


 
 
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The biomarker analysis set will include all patients in the efficacy analysis set who have at 
least one evaluable biomarker sample. 
10.3.1  Primary Analysis (or Analysis of Primary Endpoints) 
The primary endpoint will be evaluated in the efficacy analysis set. The GRFS will be estimated 
using the Kaplan-Meier estimator and plotted with a 90 FRQILGHQFH EDQG. An event for this 
outcome is defined as grade III–IV acute GVHD, chronic GVHD requiring systemic therapy, 
relapse or death. Patients who are alive without GVHD or relapse will be censored at the last 
follow-up. The 12-month GRFS will be compared to the prespecified historical control value of 
XVLQJDRQH-sided z-test DWDVLJQLILFDQFHOHYHO. 
 
 
 
10.3.2  Secondary Analysis (or Analysis of Secondary Endpoints) 
The secondary endpoints will be evaluated in the efficacy analysis set. Time-to-event outcomes 
with and without competing risks will be analyzed using Kaplan-Meier and Nelson-Aalen 
HVWLPDWHVUHVSHFWLYHO\DQGSUHVHQWHGZLWKFRQILGHQFHLQWHUYDOV. Binary outcomes will be 
analyzed using proportions and presented ZLWKFRQILGHQFHLQWHUYDOV.  
 
Bacterial community composition will be characterized using OTU counts generated as described 
above. OTU counts will be converted to measures of relative abundance to account for variation 
in sequencing coverage between samples. Statistical analysis will be carried out using the 
statistical software package R (www.r-project.org$OSKDĮGLYHUVLW\ULFKQHVVDQGHYHQQHVVRI
taxa within a population) will be reported using the Shannon Index46 and Chao1 richness 
estimator.47 %HWDȕGLYHUVLW\RYHUODSLQWD[DVKDUHGEHWZHHQSRSXODWLRQVZLOOEHDQDO\]HGXVLQJ
the Bray-Curtis dissimilarity metric48 in conjunction with multivariate statistical analysis methods 
that will include Principal Components Analysis (PCA) and Permutational Multivariate Analysis of 
Variance (PERMANOVA).49 Changes in abundance of individual taxa will also be analyzed using 
traditional univariate statistical methods. 
 
10.3.3  Other Analyses/Assessments 
Demographic and other baseline data, such as disease characteristics, as well as outcome 
measures, will be presented for the full analysis set overall and separately for unrelated and 
matched related donor patients. Categorical data, such as gender, race, etc. will be presented by 
frequencies and percentages. Descriptive summary statistics (e.g., frequency, mean, median, 
range and standard deviation) will be used to present numeric data.  
10.4  Evaluation of Safety 
 
Analyses will be performed for all patients having received at least one dose of study drug. The 
study will use the NCI CTCAE v5. The frequency and proportion of patients experiencing an 
6$(ZLOOEHUHSRUWHGZLWKFRQILGHQFHLQWHUYDOVRYHUDOODVZHOODVFODVVLILHGE\JUDGHDQG
organ system. 
10.5  Stopping Rules 
Formal statistical monitoring will be in place for 100-day overall mortality and 100-day grade 3–4 
aGVHD rate. Based on program experience, a 100-GD\PRUWDOLW\UDWHand a 100-day 
D*9+'UDWHRIDUH expected in the study population. Using a Bayesian approach to 


 
 
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toxicity monitoring as implemented by J. Jack Lee, Ying-Wei Kuo, Diane Liu and Nan Chen 
(http://www.trialdesign.org/one-page-shell.html#BTOX), we derived a stopping boundary that 
SDXVHVWKHWULDOLIZHDUHFRQILGHQWWKDWWKHSUREDELOLW\RIthe monitored event exceeds the 
historical value, i.e., 100-GD\PRUWDOLW\H[FHHGV or 100-day grade 3–4 aGVHD rate 
H[FHHGV. A Beta prior distribution with effective sample size of 1 and mean equal to the 
historical value was used with a maximum of 37 patients, and a continuous evaluation starting 
at two patients. The following tables show the number of 100-day mortality and grade 3–4 
aGVHD events that would trigger a safety review depending on the number of evaluable 
patients. For the purposes of the safety monitoring patients in the safety set who are alive with 
at least 100 days of follow-up or have experienced the monitored event within 100 days are 
considered evaluable.  
 
Number of Evaluable 
Patients 
Boundary for excessive 
100-day mortality 
1 
- 
2–6 
2+ 
7–12 
3+ 
13–18 
4+ 
19–25 
5+ 
26–33 
6+ 
34–37 
7+ 
41–48 
8+ 
49–54 
9+ 
 
 
Number of Evaluable 
Patients 
Boundary for excessive 
grade 3–4 aGVHD 
1 
- 
2–4 
2+ 
5–8 
3+ 
9–13 
4+ 
14–17 
5+ 
18–22 
6+ 
23–27 
7+ 
28–33 
8+ 
34–37 
9+ 
39–43 
10+ 


 
 
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44–49 
11+ 
50–54 
12+ 
 
The following table shows the probability of finding excessive 100-day mortality and 100-day 
grade 3–4 aGVHD rate during the study for several underlying true values of the outcomes. 
 
 
Underlying 100-day 
event rate 
Probability of crossing 
mortality boundary 
Probability of crossing 
aGVHD boundary 
 
4.8 
 
 
24 
 
 
53 
 
20 
78 
 
25 
92 
 
 
 
 
 
If a stopping rule is triggered based on excessive 100-day mortality or 100-day grade III–IV 
aGVHD, the trial will be paused. The DSMC will meet and review all relevant data. They will 
determine the relevant next steps in terms of permanent discontinuation of the trial versus 
additional safety modifications needed to allow the trial to continue.  
11  DATA AND SAFETY MONITORING PLAN (DSMP) 
Data and Safety Management Overview 
The Medical College of Wisconsin (MCW) Data and Safety Monitoring Committee (DSMC) and 
the MCW Institutional Review Board (IRB) will approve protocol-specific DSM plans. A local, 
investigator-initiated trial will be required to be continuously monitored by the principal investigator 
of the study with safety and progress reports submitted to the DSMC.  
The DSMP for this study will involve the following entities: 
11.1  Study Team 
The study team minimally consists of the principal investigator, the clinical research coordinator, 
regulatory specialist and the study biostatistician. While subjects are on study, the principal 
investigator will meet regularly with the research coordinator and the study biostatistician to review 
study status. This review will include but not be limited to reportable SAEs and UPIRSOs and an 
update of the ongoing study summary that describes study progress in terms of the study schema. 
The appropriateness of further subject enrollment and the specific intervention for a next subject 
enrollment is addressed. All meetings, including attendance, are documented.  


 
 
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11.2  Quality Assurance 
This protocol was classified as high risk and will be reviewed internally by the MCW Cancer 
Center Clinical Trials Office Quality Assurance Staff according to the MCWCC Data and Safety 
Monitoring Plan and current version SOP, 6.5.2 Internal Quality Assurance Reviews. 
 
11.3  Clinical Trials Office 
The MCWCC Clinical Trials Office [CTO] provides administrative assistance and support to the 
DSMC.  
11.4  DSMC 
The Medical College of Wisconsin Cancer Center places the highest priority on ensuring the 
safety of patients participating in clinical trials. Every cancer interventional trial conducted at 
MCW includes a plan for safety and data monitoring. 
More information can be found related to the MCWCC Data and Safety Monitoring Plan at the 
MCWCC website (Data and Safety Monitoring Plan).  
This study will be reviewed by the Medical College of Wisconsin Cancer Center Data and Safety 
Monitoring Committee (MCWCC DSMC). A summary of the MCWCC DSMC activities are as 
follows:  
 
Review the clinical trial for data integrity and safety.  
 
Review all DSM reports.  
 
Submit a summary of any recommendations related to study conduct.  
 
Terminate the study if deemed unsafe for patients.  
A copy of the MCWCC Data and Safety Monitoring Plan and membership roster will be maintained 
in the study research file and updated as membership changes. The committee will review reports 
from the study PI twice annually (or more frequently if needed) and provide recommendations on 
trial continuation, suspension or termination, as necessary.  
Any available DSMC letters will be submitted to the IRB of record as required. 
12 REGULATORY COMPLIANCE, ETHICS AND STUDY MANAGEMENT 
12.1  Ethical Standard 
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki, as stated in 21 CFR §312.120(c)(4); consistent with GCP and all 
applicable regulatory requirements. 
12.2  Regulatory Compliance 
This study will be conducted in compliance with: 
 
The protocol. 


 
 
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 
Federal regulations, as applicable, including: 21 CFR 50 (Protection of Human 
Subjects/Informed Consent); 21 CFR 56 (Institutional Review Boards) and §312 
(Investigational New Drug Application; and 45 CFR 46 Subparts A (Common Rule), B 
(Pregnant Women, Human Fetuses and Neonates), C (Prisoners), and D (Children), 
GCP/ICH guidelines, and all applicable regulatory requirements. The IRB must comply 
with the regulations in 21 CFR §56 and applicable regulatory requirements. 
12.3  Prestudy Documentation 
Prior to implementing this protocol at MCWCC, the protocol, informed consent form and any other 
information pertaining to participants must be approved by the MCW IRB.  
12.4  Institutional Review Board 
The protocol, the proposed informed consent form and all forms of participant information related 
to the study (e.g., advertisements used to recruit participants) will be reviewed and approved by 
the MCW Institutional Review Board. Prior to obtaining MCW approval, the protocol must be 
approved by the Medical College of Wisconsin Cancer Center Scientific Review Committee. The 
initial protocol and all protocol amendments must be approved by the IRB prior to implementation.  
Informed Consent Process 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continues throughout the individual’s study participation. Extensive discussion of 
risks and possible benefits of this therapy will be provided to the subjects and their families. 
Consent forms describing in detail the study interventions/products, study procedures and risks 
are given to the subject and written documentation of informed consent is required prior to starting 
intervention/administering study product. 
Potential subjects will be told, and a statement will be included that this study is designed to 
determine both safety and effectiveness. The consent forms will include the approved MCW IRB 
template language. 
Consent forms will be IRB-approved and the subject (and legally authorized representative, if 
necessary) will be asked to read and review the document. The treating physician or the 
investigator will explain the research study to the subject and answer any questions that may 
arise. The study coordinator may complete the consenting process. In accordance with 46 CR 
46.111, the subject will sign and date the informed consent document prior to any procedures 
being done specifically for the study.  
A witness should only sign when required, per FH/MCW IRB policy. If a witness signs the 
document when not required, the study staff should document in the legal medical record (or note 
to file) the relationship to the patient and why a witness signed. (For example, “Although not 
required, the subject’s spouse was present during the consenting process and signed as the 
witness.” Or “Although not required, hospital staff was present for consenting process and signed 
as a witness.”) 
The subjects will have the opportunity to discuss the study with their surrogates or think about it 
prior to agreeing to participate. The subjects may withdraw consent at any time throughout the 
course of the trial.  


 
 
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A copy of the informed consent document will be given to the subjects for their records. The rights 
and welfare of the subjects will be protected by emphasizing to them that the quality of their 
medical care will not be adversely affected if they decline to participate in this study. If there are 
changes to the consent form, all revisions will be reviewed with study subject at the next 
appropriate opportunity. Patients that require reconsenting will be defined in the IRB approved 
amendment submission. The process for obtaining informed consent will again be performed. 
Study subjects will not be reconsented for continuing reviews. The MCWCC CTO will follow the 
MCW/FH IRB’s policy for subjects who demonstrate limited English proficiency or limited literacy.  
After the subject’s visit in which the consent is signed, it is documented in the clinic chart that the 
consent has been signed and that all questions have been answered to the subject’s satisfaction 
after adequate time for review of the consent. It is also documented that a copy of the consent is 
given to the subject. The original consent is kept with the subject’s study file, and a copy of the 
consent is sent to the OCRICC office, which will then submit to HIM a copy of the signed consent 
to be scanned into EPIC, the legal medical record. 
12.5 Subject Confidentiality and Access to Source Documents/Data 
Subject confidentiality is strictly held in trust by the sponsor-investigator, participating 
investigators, and any staff, and the sponsor. This confidentiality includes the clinical information 
relating to participating subjects, as well as any genetic or biological testing. 
The study protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study, or the data will be released to any unauthorized 
third party without prior written approval of the principal investigator. 
The conditions for maintaining confidentiality of the subjects’ records are required for the life of 
the data. These rules apply equally to any and all MCWCC projects.  
One risk of taking part in a research study is that more people will handle the personal health 
information collected for this study. The study team will make every effort to protect the information 
and keep it confidential, but it is possible that an unauthorized person might see it. Depending on 
the kind of information being collected, it might be used in a way that could embarrass the subject 
or affect his/her ability to get insurance. 
While data are being collected and after all data have been collected but are still in the process 
of being analyzed, the subject’s data/PHI are stored in the locked Clinical Research Office in the 
Clinical Trials Office. Databases in which the study subject information is stored and accessed 
are password protected, allowing for limited access by authorized personnel only. Data/PHI kept 
in the Case Report Forms contain the study identifiers, subject initials, date of birth and date of 
service.  
Personal identifiers, such as name and medical record number, will be removed from 
accompanying lab reports and test results. Any data/PHI that are not stored for the purposes of 
the study are shredded in the Clinical Trials Office. 
After all study queries and analyses are completed, the data/PHI will not be destroyed but will be 
archived in a secure long-term storage site in order to keep an accurate record of screened and 
enrolled subjects for the sponsor and potential audit purposes only specific for this study.  
12.6  Protection of Human Subjects 


 
 
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12.6.1  Protection from Unnecessary Harm 
Each clinical site is responsible for protecting all subjects involved in human experimentation. This 
is accomplished through the IRB mechanism and the informed consent process. The IRB reviews 
all proposed studies involving human experimentation and ensures that the subject’s rights and 
welfare are protected and that the potential benefits and/or the importance of the knowledge to 
be gained outweigh the risks to the individual. The IRB also reviews the informed consent 
document associated with each study in order to ensure that the consent document accurately 
and clearly communicates the nature of the research to be done and its associated risks and 
benefits. 
12.6.2  Protection of Privacy 
As noted, patients will be informed of the extent to which their confidential health information 
generated from this study may be used for research purposes. Following this discussion, they 
will be asked to sign informed consent documents. The original signed document will become 
part of the patient’s medical records, and each patient will receive a copy of the signed 
document.  
12.6.3  Changes in the Protocol 
 
Once the protocol has been approved by the MCW IRB, any changes to the protocol must be 
documented in the form of an amendment. The amendment must be signed by the investigator 
and approved by IRB prior to implementation.  
If it becomes necessary to alter the protocol to eliminate an immediate hazard to patients, an 
amendment may be implemented prior to IRB approval. In this circumstance, however, the 
investigator must then notify the IRB in writing within five working days after implementation.  
The IRB may provide, if applicable regulatory authority(ies) permit, expedited review and 
approval/favorable opinion for minor change(s) in ongoing studies that have the approval 
/favorable opinion of the IRB. The investigator will submit all protocol modifications to the sponsor 
and the regulatory authority(ies) in accordance with the governing regulations. 
Changes to the protocol may require approval from the sponsor. 
Any departures from the protocol must be fully documented in the source documents. 
12.7  Investigator Compliance  
The investigator will conduct the study in compliance with the protocol given approval/favorable 
opinion by the IRB and the appropriate regulatory authority(ies).  
13  DATA HANDLING AND RECORD KEEPING 
13.1  Overview 
Every effort is made to uphold the integrity of the project, the research, the institution, and the 
researchers involved. Data collection guidelines and methodologies are carefully developed 
before the research begins. Investigators focus on the following to ensure data integrity:  well-
trained data collectors/recorders to ensure consistency and quality, well-designed data collection 


 
 
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protocols and ongoing monitoring. In this way, study rigor and validity are maintained. Data is 
protected from physical damage as well as from tampering, loss or theft. This project’s data 
management is a multidisciplinary activity that includes investigators, research coordinators and 
nurses, data mangers, support personnel, biostatisticians and database programmers. Quality 
control will be applied to each stage of data handling to ensure that all data are reliable and have 
been processed correctly.  
13.2  Data Management Responsibilities 
13.2.1  Principal Investigator 
The principal investigator oversees the management of patient records/case report forms and 
ensures that a) complete and accurate data will be obtained and provided to the sponsor; b) 
patient records are maintained to include history, prescribed medication and investigational 
product(s), measurements, exams, evaluations and adverse events; c) corrections are applied to 
clinical research data according to principles of good research practice (i.e., single-line delete, 
date and initial). He or she will ensure that there is correlation between the case report forms and 
the source documents.  
13.2.2  Research Coordinator 
 
A research coordinator creates, collects and organizes clinical trial documentation. He or she 
ensures that source documentation and data abstraction and entry are being done at protocol 
specified time points. 
 
13.2.3  Research Nurse/Medical Staff 
 
The research nurse and medical staff documents protocol-required care or assessment of the 
subject’s outcomes, adverse events and compliance to study procedures. 
13.2.4  Biostatistician 
 
The biostatistician may assist in CRF development (content and design), dataset specifications 
(annotation of CRFs and record layout) and validation. 
13.3  Handling and Documentation of Clinical Supplies 
The MCWCC Principal Investigator will maintain complete records showing the receipt, 
dispensation, return, or other disposition of all investigational drugs. The date, quantity and batch 
or code number of the drug, and the identification of patients to whom study drug has been 
dispensed by patient number and initials will be included. The sponsor-investigator will maintain 
written records of any disposition of the study drug. 
The principal investigator shall not make the investigational drug available to any individuals other 
than to qualified study patients. Furthermore, the principal investigator will not allow the 
investigational drug to be used in any manner other than that specified in this protocol. 
 
13.4  Source Documents 
Source documents for clinical information (patient history, diagnosis, clinical and diagnostic test 
reports, etc.) are maintained in the patient’s clinical file.  


 
 
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All source documents will be written following ALCOA standards:  
ALCOA Attribute 
Definition 
Attributable 
Clear who has documented the data. 
Legible 
Readable and signatures identifiable. 
Contemporaneous 
Documented in the correct time frame along with the flow of 
events. If a clinical observation cannot be entered when made, 
chronology should be recorded. Acceptable amount of delay 
should be defined and justified. 
Original  
Original, if not original should be exact copy; the first record made 
by the appropriate person. The investigator should have the 
original source document. 
Accurate 
Accurate, consistent and real representation of facts. 
Enduring 
Long-lasting and durable. 
Available and 
accessible 
Easily available for review by treating physicians and during 
audits/inspections. The documents should be retrievable in 
reasonable time. 
Complete 
Complete until that point in time. 
Consistent 
Demonstrate the required attributes consistently. 
Credible 
Based on real and reliable facts. 
Corroborated 
Data should be backed up by evidence. 
 
13.5  Case Report Forms 
The principal investigator and/or his/her designee will prepare and maintain adequate and 
accurate participant case histories with observations and data pertinent to the study. Study-
specific Case Report Forms (CRFs) will document safety and treatment outcomes for safety 
monitoring and data analysis. All study data will be entered into OnCore® via standardized CRFs, 
in accordance with the study calendar, using single data entry with a secure access account. The 
Clinical Research Coordinator will complete the CRFs as soon as possible upon completion of 
the study visit; the investigator will review and approve the completed CRFs.  
The information collected on CRFs shall be identical to that appearing in original source 
documents. Source documents will be found in the patient’s medical records maintained by 
MCWCC personnel. All source documentation should be kept in separate research folders for 
each patient. 
In accordance with federal regulations, the Investigator is responsible for the accuracy and 
authenticity of all clinical and laboratory data entered onto CRFs. The principal investigator will 
approve all completed CRFs to attest that the information contained on the CRFs is true and 
accurate.  
All source documentation and data will be available for review/monitoring by the MCWCC DSMC 
and regulatory agencies. 
13.6  Study Record Retention 
The principal investigator is required to maintain adequate records of the disposition of the drug, 
including dates, quantity and use by subjects, as well as written records of the disposition of the 
drug when the study ends.  


 
 
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The principal investigator is required to prepare and maintain adequate and accurate case 
histories that record all observations and other data pertinent to the investigation on each 
individual administered the investigational drug or employed as a control in the investigation. Case 
histories include the case report forms and supporting data including, for example, signed and 
dated consent forms and medical records including, for example, progress notes of the physician, 
the individual's hospital chart(s), and the nurses' notes. The case history for each individual shall 
document that informed consent was obtained prior to participation in the study. 
Study documentation includes all CRFs, data correction forms or queries, source documents, 
sponsor-investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, IRB correspondence and approval, signed patient consent forms). 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study. 
In accordance with FDA regulations, the investigator shall retain records for a period of two years 
following the date a marketing application is approved for the drug for the indication for which it is 
being investigated; or, if no application is to be filed or if the application is not approved for such 
indication, until two years after the investigation is discontinued and FDA is notified. 
 
 
 


 
 
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APPENDIX 1. PERFORMANCE STATUS CRITERIA 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity 
Fully active, able to carry on all 
pre-disease performance 
without restriction 
100 
Normal, no complaints, no evidence 
of disease 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease 
1 
Symptoms, but ambulatory 
Restricted in physically 
strenuous activity, but 
ambulatory and able to carry out 
work of a light or sedentary 
nature (e.g., light housework, 
office work) 
80 
Normal activity with effort; some 
signs or symptoms of disease 
70 
Cares for self, unable to carry on 
normal activity or to do active work 
2 
In bed < RIWKHWLPH 
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities 
8SDQGDERXWPRUHWKDQRI
waking hours 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs 
50 
Requires considerable assistance 
and frequent medical care 
3 
In bed > RIWKHWLPH 
Capable of only limited self-
care, confined to bed or chair 
more WKDQRIZDNLQJKRXUV 
40 
Disabled, requires special care and 
assistance 
30 
Severely disabled, hospitalization 
indicated 
Death not imminent 
4 
EHGULGGHQ 
Completely disabled 
Cannot carry on any self-care 
Totally confined to bed or chair 
20 
Very sick, hospitalization indicated 
Death not imminent 
10 
Moribund, fatal processes 
progressing rapidly 
5 
Dead 
0 
Dead 
 
 
 


 
 
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APPENDIX 2. GVHD ASSESSMENT 
ACUTE GVHD ASSESSMENT 
 
 


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Grading of Chronic GVHD (NIH Criteria)


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APPENDIX 3. MEDICATION GUIDE 
 
ILUMYA™ - tildrakizumab-asmn injection, solution  
Sun Pharmaceutical Industries, Inc. 
 
Medication Guide 
 
ILUMYA™ (“e-loom’-me-a”) (tildrakizumab-asmn) 
 
injection, for subcutaneous use 
 
What is the most important information I should know about ILUMYA™ ? 
ILUMYA™  may cause serious side effects, including: 
 
Serious allergic reactions. Get emergency medical help right away if you get any of the 
following symptoms of a serious allergic reaction: 
 
x 
feel faint  
x 
swelling of your face, eyelids, lips, mouth, tongue or throat  
x 
skin rash 
x 
trouble breathing or throat tightness 
x 
chest tightness 
 
Infections. ILUMYA™  is a medicine that may lower the ability of your immune system to fight 
infections and may increase your risk of infections. Your healthcare provider should check you 
for infections and tuberculosis (TB) before starting treatment with ILUMYA™  and may treat you 
for TB before you begin treatment with ILUMYA™  if you have a history of TB or have active TB. 
Your healthcare provider should watch you closely for signs and symptoms of TB during and 
after treatment with ILUMYA™ . 
 
Tell your healthcare provider right away if you have an infection or have symptoms of an 
infection, including: 
 
x 
fever, sweats, or chills 
x 
cough 
x 
shortness of breath 
x 
blood in your phlegm (mucus) 
x 
muscle aches 
x 
warm, red or painful skin or sores on your body different from your psoriasis 
x 
weight loss 
x 
diarrhea or stomach pain 
x 
burning when you urinate or urinating more often than normal 
 
See “What are the possible side effects of ILUMYA™ ?” for more information about side 
effects. 
 
What is ILUMYA™ ? 
ILUMYA™ is a prescription medicine used to treat adults with moderate to severe plaque 
psoriasis who may benefit from taking injections, pills (systemic therapy) or treatment using 
ultraviolet or UV light (phototherapy). 


 
 
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It is not known if ILUMYA™  is safe and effective in children under 18 years of age. 
 
Do not use ILUMYA™  if you have had a severe allergic reaction to tildrakizumab or any of the 
other ingredients in ILUMYA™ . See the end of this Medication Guide for a complete list of 
ingredients in ILUMYA™ . 
 
Before receiving ILUMYA™ , tell your healthcare provider about all of your medical 
conditions, including if you: 
 
x 
have any of the conditions or symptoms listed in the section “What is the most important 
information I should know about ILUMYA™ ?”  
x 
have an infection that does not go away or that keeps coming back.  
x 
have TB or have been in close contact with someone with TB.  
x 
recently received or are scheduled to receive a vaccine (immunization). You should avoid 
receiving live vaccines during treatment with ILUMYA™.  
x 
are pregnant or plan to become pregnant. It is not known if ILUMYA™  can harm your 
unborn baby.  
x 
are breastfeeding or plan to breastfeed. It is not known if ILUMYA™ passes into your breast 
milk. 
 
Tell your healthcare provider about all the medicines you take, including prescription and 
over-the-counter medicines, vitamins, and herbal supplements. 
 
How will I receive ILUMYA™ ? 
x 
ILUMYA™  should only be given to you by a healthcare provider.  
x 
ILUMYA™  is given as an injection under your skin (subcutaneous injection) in areas of your 
body such as your thighs, stomach area (abdomen), or upper arm.  
x 
If you miss a follow-up appointment and do not receive your dose of ILUMYA™ , schedule 
another appointment as soon as possible. 
 
What are the possible side effects of ILUMYA™ ? 
ILUMYA™  may cause serious side effects. See “What is the most important information I 
should know about ILUMYA™ ?” 
The most common side effects of ILUMYA™  include: 
x 
upper respiratory infections 
x 
injection site reactions 
x 
diarrhea 
 
These are not all of the possible side effects of ILUMYA™ . Call your doctor for medical advice 
about side effects. You may report side effects to the FDA at 1-800-FDA-1088. 
 
General information about the safe and effective use of ILUMYA™ . 
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. 
You can ask your healthcare provider for information about ILUMYA™ that is written for health 
professionals. 
 
What are the ingredients in ILUMYA™ ? 
Active ingredient: tildrakizumab-asmn 
Inactive ingredients: L-histidine, L-histidine hydrochloride monohydrate, polysorbate 80, 
sucrose, and water for Injection, USP. 


 
 
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Manufactured by: Sun Pharma Global FZE, Inc. 
Sharjah, U.A.E. 
U.S. License No. 2092 
At: MSD Ireland (Carlow), County Carlow, Ireland 
Tildrakizumab-asmn (active ingred.) Product of The Netherlands. 
Distributed by: Sun Pharmaceutical Industries, Inc., Cranbury, NJ 08512 
ILUMYA™ is a trademark of Sun Pharma Global FZE 
Copyright © 2018 Sun Pharma Global FZE 
All rights reserved 
usmg-tildrakizumab-pfs-00001 
 
 
This Medication Guide has been approved by the U.S. Food and Drug Administration. Issued: 
08/2018 
 
 
 
 
 


 
 
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Impact on metabolism and efficacy of therapeutics. Maturitas 2018;112:53-63. 
36. 
Walters W, Hyde ER, Berg-Lyons D, et al. Improved Bacterial 16S rRNA 
Gene (V4 and V4-5) and Fungal Internal Transcribed Spacer Marker Gene Primers for 
Microbial Community Surveys. mSystems 2016;1. 
37. 
Kuczynski J, Stombaugh J, Walters WA, Gonzalez A, Caporaso JG, Knight 
R. Using QIIME to analyze 16S rRNA gene sequences from microbial communities. 
Curr Protoc Microbiol 2012;Chapter 1:Unit 1E 5. 
38. 
Taur Y, Jenq RR, Perales MA, et al. The effects of intestinal tract bacterial 
diversity on mortality following allogeneic hematopoietic stem cell transplantation. 
Blood 2014;124:1174-82. 
39. 
Bacigalupo A, Ballen K, Rizzo D, et al. Defining the intensity of conditioning 
regimens: working definitions. Biol Blood Marrow Transplant 2009;15:1628-33. 
40. 
Liu TC, Gurram B, Baldridge MT, Head R, Lam V, Luo C, Cao Y, Simpson P, 
Hayward M, Holtz ML, Bousonis P, Noe J, Lerner D, Cabrera J, Biank V, Stephens M, 
Huttenhower C, McGovern DP, Xavier RJ, Stappenbeck TS, Salzman NH. Paneth cell 
defects in Crohn’s disease patients promote dysbiosis.  JCI Insight 2016; 1: e86907. 
41. 
Bolger AM, Lohse M, Usadel B, 2014.  Trimmomatic: a flexible trimmer for 
Illumina sequence data. Bioinformatics. 2014; 30: 2114-2120. 
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Magoc T, Salzberg SL. FLASH: fast length adjustment of short reads to 
improve genome assemblies.  Bioinformatics 2011; 27: 2957-2963. 


 
 
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Edgar RC, Haas BJ, Clemente JC, Quince C, Knight R. 2011 UCHIME 
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Edgar RC. UPARSE: highly accurate OTU sequences from microbial 
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Wang Q, Garrity GM, Tiedje JM, Cole JR. Naïve Bayesian classifier for rapid 
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Chao. Nonparametric estimation of the number of classes in a population. 
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Bray JR, Curtis JT. An Ordination of the Upland Forest Communities of 
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Anderson MJ. A new method for non-parametric multivariate analysis of 
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ICF_001.pdf: 
Official Title:  A Phase II Trial of Tildrakizumab for Prevention of Acute Graft-Versus-Host 
Disease 
NCT Number:  NCT04112810 
Date:  December 13, 2022 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: 35737 
IRB Approval Period: 12/13/2022 – 8/14/2023 
 
Page 1 of 15 
MCW Version: 12-06-2022 
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December 13, 2022 
 
MCW/FH IRB
Medical College of Wisconsin and Froedtert Hospital 
INTRODUCTION TO THE INFORMED CONSENT 
 
Name of Subject: ____________________________ 
 
IIT-Runaas-Tildrakizumab- A Phase II Trial of Tildrakizumab for Prevention of Acute Graft-
Versus-Host Disease 
 
Lyndsey Runaas, MD 
Froedtert & Medical College of Wisconsin 
Division of Hematology and Oncology 
9200 W. Wisconsin Avenue 
Milwaukee, WI 53226 
414-805-6700 
 
 
You are invited to take part in this research. You can decide whether to take part in this project 
or not. You are free to say yes or no. If there is anything that you do not understand, please ask 
questions. 
 
 
Definitions 
 
Allogenic HCT: unrelated donor bone marrow transplant 
GVHD: Graft versus Host Disease: a complication that can occur after an  
allogeneic bone marrow transplant 
HLA: human Leukocyte antigen. Proteins that help the body’s immune system tell the 
difference between its own cells and foreign, harmful substances 
PFT: Pulmonary function test 
 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: 35737 
IRB Approval Period: 12/13/2022 – 8/14/2023 
 
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December 13, 2022 
 
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Purpose 
This project is being done to find out if giving 
Tildrakizumab in combination with standard 
GVHD prophylaxis; Tacrolimus and 
Methotrexate will help prevent acute and 
chronic GVHD.  
Length 
1. You will be in this research project for 
about 12 months following your bone 
marrow transplant.   
Risks 
This is a brief list of the most commonly seen 
side effects. The full consent form after this 
introduction contains a more complete list of 
potential research risks. 
 
Tildrakizumab and Standard GVHD 
Prophylaxis risks: 
 
Tildrakizumab: 
x 
Hypersensitivity reactions: allergic 
reactions 
x 
Respiratory: upper respiratory tract 
infections, pharyngitis 
x 
Gastrointestinal: Nausea 
x 
Hepatic: abnormal liver tests elevation 
x 
Neurologic: headache, dizziness, 
lethargy (lack of energy) 
x 
Cardiovascular: hypertension 
x 
Insomnia-not able to sleep 
x 
Dermatologic: skin rash, injection site 
erythema (reddening of the skin as a 
result of the injection) 
 
Tacrolimus & Methotrexate: 
Discussed in C2 
Procedures 
You will receive Tildrakizumab in combination 
with standard GVHD prophylaxis. 
 
List of visits: 
 
Screening Visit  
- Total Number: 1 
- Total Time: approximately 2 to 4 
hours 
 
Study drug Treatment Visits 
- Total Number: __5__ 
- Total Time: __approximately 1 
hour each visit__ 
 
End of Treatment Visits 
- Total Number: 1 
- Total Time: approximately 2 to 4 
hours 
 
Procedures that will occur at various 
visits: 
 
Invasive Procedures 
- Drug administration, blood sample 
collection, and bone marrow/aspirate 
collection  
 
 
Non-invasive Procedures 
- Full medical history exam, physical 
exam, pulmonary function tests 
 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: 35737 
IRB Approval Period: 12/13/2022 – 8/14/2023 
 
Page 3 of 15 
MCW Version: 12-06-2022 
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December 13, 2022 
 
MCW/FH IRB
 
My Other Options 
You do not have to join this project. Your other 
options may include: 
1. Joining a different project 
2. Routine care for this condition  
3. Getting no treatment for this condition 
 
Benefits 
We don’t know if this project will help you. Your 
condition may get better but it could stay the 
same or even get worse. 
If you have more questions about this project at any time, you can call Dr. Runaas at 414-
805-6700. 
 
If you have questions about your rights as a participant, want to report any problems or 
complaints, or offer input, you can call the MCW/Froedtert Hospital Research Subject 
Advocate at 414-955-8844. 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: 35737 
IRB Approval Period: 12/13/2022 – 8/14/2023 
 
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MCW Version: 12-06-2022 
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December 13, 2022 
 
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CONSENT TO PARTICIPATE IN RESEARCH 
A1. INTRODUCTION – WHY ARE WE ASKING YOU TO PARTICIPATE? 
You are being invited to participate in this research because you have a type of cancer that will 
be treated with an allogenic HCT.  Developing acute GVHD is a risk of this type of transplant.  
Because of your condition, you may be eligible for a research project using an investigational 
drug, Tildrakizumab, and standard GVHD prophylaxis to treat your disease.  
 
A total of about 55 people are expected to participate in this research at the Medical College of 
Wisconsin/Froedtert Hospital. 
 
The Director of the project is Lyndsey Runaas, MD in the Division of Hematology & Oncology. A 
research team works with Dr. Runaas. You can ask who these people are.  
 
Sun Pharmaceuticals is providing support for this study. 
 
A2. DO I HAVE TO PARTICIPATE? 
You can decide whether to take part in this research or not. You are free to say yes or no. If you 
say no, your regular medical care will not change. Even if you join this project, you do not have 
to stay in it. You may stop at any time.  
 
A research project is different from routine medical care in three ways: 1) there are extra risks 
that we will tell you about in this form; 2) you may have some extra medical tests and visits; 3) 
the research procedures, tests and visits follow a set plan that must be kept. 
 
A3. WHY IS THIS PROJECT BEING DONE? 
In this study we want to find out if giving Tildrakizumab (100 mg) as a subcutaneous injection on 
Day -1 in combination with the standard GVHD prophylaxis; Tacrolimus and Methotrexate will 
help prevent acute and chronic GVHD. Tildrakizumab (100 mg) subcutaneous injection will also 
be given on Day +28, Day +112, Day +196 and Day +280 after your bone marrow transplant. 
We also want to find out whether the investigational drug combination is safe to use and 
whether it reduces the symptoms of acute and chronic GVHD. 
 
Everyone in this study will receive the combination of Tildrakizumab and standard GVHD 
prophylaxis. This research and your samples will help us in creating controls and active drug 
levels for future research studies. The combination of Tildrakizumab and standard GVHD 
prophylaxis is still experimental and is not approved by the U.S. Food and Drug Administration.   
 
 
 
 
 
 
 
 
 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: 35737 
IRB Approval Period: 12/13/2022 – 8/14/2023 
 
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EFFECTIVE 
 
December 13, 2022 
 
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B1. WHAT WILL HAPPEN IF I PARTICIPATE? 
Treatment Schedule 
 
Before the research starts (screening):   
After signing this consent form, you will be asked to undergo some screening tests or 
procedures to find out if you can be in the research study.  Many of these tests and procedures 
are likely to be part of regular cancer care and may be done even if it turns out that you do not 
take part in the research study.  If you have had some of these tests or procedures recently, 
they may or may not have to be repeated.   
 
Screening procedures:  
If the screening information shows that you meet the requirements, then you will complete the 
following:   
x 
Medical History, which includes questions about your health, current medications. 
x 
Physical Exam, which includes your height, weight 
x 
Your performance status, which evaluates how you are able to carry on with your usual 
activities.  
x 
Routine Blood tests (about 4 tablespoons)  
x 
Pregnancy test if you are able to have children 
x 
Infections disease markers 
x 
HLA typing  
x 
PFT: to test the function of your lungs 
x 
Bone marrow biopsy and/or aspirate, to evaluate the extent of your disease. For this 
test, a sample of bone marrow cells is taken by a needle inserted into a bone in your 
body. If a bone marrow biopsy is needed, a small piece of bone and the attached bone 
marrow is removed. These tests may be done under local anesthesia.  
x 
Research blood samples (approximately 4 teaspoons) to help understand the changes 
that are happening with your immune system to prevent GVHD  
 
If the screening information shows that you cannot be in the research, the research doctor will 
discuss other options with you and/or refer you back to your regular doctor.  
 
Days 
 
Pre-
transpl
ant 
-1 
0 
+1 
+3 
+5 
+6 
+11 
+28 
+35 
+90 
+100 
+112 
+180 
+196 
+280 
Conditioning 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Transplant 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Methotrexate 
 
 
 
X 
X 
 
X 
X 
 
 
 
 
 
 
 
 
Tildrakizumab 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
Tacrolimus 
X 
 
 
 
X 
 
 
 
 
 
Taper* 
X 
X 
Stop* 
 
 
G-CSF 
 
 
 
 
 
Start^ 
 
 
 
 
 
 
 
 
 
 
*If there is no evidence of GVHD 
^G-CSF begins on day +5 after stem cell infusion and continues until engraftment is seen 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: 35737 
IRB Approval Period: 12/13/2022 – 8/14/2023 
 
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Summary of Procedures: Day 0 to 365 
(See Table 1 for more detail) 
x 
Physical Exam, which includes your weight  
x 
Review of any side effects that you may be experiencing 
x 
Routine Blood tests about 1 to 4 tablespoons at each timepoint listed on Table 1. 
x 
Chimerism (engraftment analysis) 
x 
PFT: to test the function of your lungs 
x 
Bone marrow biopsy and/or aspirate, to evaluate the extent of your disease. For this 
test, a sample of bone marrow cells is taken by a needle inserted into a bone in your 
body. If a bone marrow biopsy is needed, a small piece of bone and the attached bone 
marrow is removed. These tests may be done under local anesthesia. Any time a bone 
marrow exam is done in the study, a sample will also be sent to a laboratory for research 
studies 
x 
GVHD Assessments will be performed to determine if you are developing side effects as 
a result of the treatment you have been given. This assessment will be part of the 
physical exam. 
x 
Research blood samples (approximately 32 teaspoons) to help understand the changes 
that are happening with your immune system to prevent GVHD 
x 
Research stool samples to help understand the changes that are happening with your 
gut microbiome during study treatment 
x 
Blood samples for pharmacokinetic labs and anti-drug antibody (ADA) testing 
(approximately 2 teaspoons) to help understand the way the drug is used and processed 
by your body 
x 
Tildrakizumab subcutaneous injection: Day-1, Day+28, Day + 112, Day + 196, Day +280  
 
 
 
 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: 35737 
IRB Approval Period: 12/13/2022 – 8/14/2023 
 
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December 13, 2022 
 
MCW/FH IRB
Table 1 
 
Study Assessments 
Baseline 
 
Pre-
Trans
-plant 
 (Post-Transplant) 
(in Days) 
Follow-up 
Screening 
Within 30 
days prior 
to infusion 
Day -
1 
28± 3 
days 
56 +/- 
7 days 
100 
+/- 14 
days 
112± 
7 
180+/
- 14 
days 
196± 
14 
280± 
14 
12 month 
post HCT (+/- 
30 days) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Tildrakizumab administration – 
100 mg subcutaneously 
 
X 
X 
 
 
X 
 
X 
X 
 
History, physical exam, weight, 
height 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
HLA typing (donor and 
recipient) 
X 
 
 
 
 
 
 
 
 
 
CBC with differential, 
Comprehensive metabolic 
panel 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Infectious disease markers^ 
X 
 
 
 
 
 
 
 
 
 
LVEF 
X 
 
 
 
 
 
 
 
 
 
DLCO and FEV1 
X 
 
 
 
 
 
X 
 
 
X 
Disease evaluation 
X 
 
 
 
X 
 
 
 
 
X 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
 
GVHD assessments 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
AE assessments 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Chimerism 
 
 
X 
 
 
 
 
 
 
X 
CMV NAAT peripheral blood 
 
 
X 
X 
X 
X 
 
 
 
 
EBV PCR peripheral blood 
 
 
X 
X 
X 
X 
 
 
 
 
Immune reconstitution 
 
 
X 
 
X 
 
X 
 
 
X 
Research blood and plasma 
X 
Baseline (screening) and Days 7±3, 14±3, 21±3, 28±7, 60±14, 90±14, 196±30, 
365±30 post-transplants and at the time of development of GVHD (if it occurs). 
Research stool samples 
 
Days -1, 1±2, 7±2, 15±2, 21±2, until neutrophil engraftment with final stool 
sample collected after neutrophil engraftment. Will also be collected at the time 
of development of GVHD (if it occurs). 
Pharmacokinetic labs and ADA 
testing 
X 
Days 30±2, 60±7, and 90±14 
 
 
*For acute leukemia, CML, and MDS, this includes a bone marrow aspirate and 
biopsy and cytogenetics.  
^CMV antibody, Hepatitis panel (HepA, HepB Sab, Hep B) 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: 35737 
IRB Approval Period: 12/13/2022 – 8/14/2023 
 
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B2. HOW LONG WILL I BE IN THE PROJECT? 
You will be in this research project for about 12 months following your bone marrow transplant. 
 
B3. CAN I STOP BEING IN THE PROJECT?   
You are free to withdraw from the project at any time. If you leave, your regular medical care will 
not change. If you are thinking about leaving, please tell the research doctor.  
 The research doctor can tell you about the effects of stopping, and you and the research 
doctor can talk about what follow-up care would help you the most. 
 You might be asked to come back for one more visit to check your health. 
 
The research doctor may take you out of this project at any time. This would happen if: 
x 
They think it is in your best interest. 
x 
You do not follow the project rules. 
x 
The whole project is stopped. 
If this happens, the research doctor will tell you. 
 
B4. ARE THERE ANY SPECIAL INSTRUCTIONS WHILE I AM IN THE PROJECT?  
x 
While you are participating in this study (during treatment), you can participate in other 
research studies as long as they are NOT GVHD prevention or treatment.  
 
x 
You should also report to your doctor any changes in your health or side effects that you 
may be experiencing.  
 
x 
You will be asked to receive all study-required treatments and complete all study-required 
procedures.  
 
C1. WHAT HEALTH RISKS OR PROBLEMS CAN I EXPECT FROM THE PROJECT? 
There are risks to taking part in any research project. There is a risk that you may get a drug 
combination that does not help your condition or may make it worse.  There also may be 
problems (side effects) we do not know about yet, from the combination of Tildrakizumab and 
standard GVHD prophylaxis themselves, or how they combine with other drugs you are taking. 
If we learn about new important side effects, we will tell you.  
 
We watch everyone in the project for problems (side effects). You need to tell the research 
doctor or a member of the research team immediately if you experience any problems, 
side effects, or changes in your health. If you have signs of fever or other new abnormal 
symptoms, call Dr. Runaas immediately at 414-805-6700. In an emergency, call 911. 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: 35737 
IRB Approval Period: 12/13/2022 – 8/14/2023 
 
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C2. RISKS OF TILDRAKIZUMAB IN COMBINATION WITH STANDARD GVHD 
PROPHYLAXIS 
The research drugs themselves may cause problems (side effects).  Side effects may be mild or 
very serious.  Some can last a long time or never go away.   
 
The side effects that other people have experienced so far with the drug combination are:  
 
Tildrakizumab: 
 
x 
Hypersensitivity reactions: allergic reactions 
x 
Respiratory: upper respiratory tract infections, pharyngitis 
x 
Gastrointestinal: Nausea 
x 
Hepatic: abnormal liver tests elevation 
x 
Neurologic: headache, dizziness, lethargy (lack of energy) 
x 
Cardiovascular: hypertension 
x 
Insomnia-not able to sleep 
x 
Dermatologic: skin rash, injection site erythema (reddening of the skin as a result of the 
injection) 
 
Tacrolimus:  
x 
Cardiovascular: hypertension 
x 
Neurologic: confusion, dizziness, insomnia, seizures, tremors, changes in how clearly 
one can think 
x 
Gastrointestinal: nausea, vomiting 
x 
Hematologic: microangiopathic hemolytic anemia (possible destruction of red blood 
cells), thrombocytopenia 
x 
Endocrine and metabolic: hypomagnesemia (low blood level of magnesium), 
hypokalemia (low blood level of potassium), hypocalcemia (low blood level of calcium), 
hyperlipidemia (increase lipid level in blood) 
x 
Miscellaneous: unwanted hair growth, changes in vision, liver problems, reversible renal 
insufficiency, infections and posttransplant lymphoproliferative disorders 
 
Methotrexate: 
x 
Neurologic: fever, dizziness, chills, undue fatigue 
x 
Gastrointestinal: ulcerative stomatitis (painful swelling and sores inside the mouth), 
nausea, abdominal distress, diarrhea 
x 
Hematologic:  leucopenia (decreased number of white blood cells), anemia (decreased 
number of red blood cells) 
x 
Miscellaneous: abnormal liver tests, kidney failure and pulmonary complications after 
transplantation 
 
C3. OTHER RISKS OF THIS RESEARCH PROJECT 
Other procedures that are part of the research also involve some risks: 


Medical College of Wisconsin & Froedtert Hospital 
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IRB Protocol Number: 35737 
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Blood Draws (for research blood and plasma, and pharmacokinetic labs) 
Having your blood drawn can be uncomfortable and can sometimes cause a bruise. In rare 
cases, a blood draw can cause fainting. If you have fainted before when your blood was drawn 
please let the person drawing your blood know. Only trained people will draw your blood. 
 
Bone marrow biopsy and bone marrow aspirate 
Bone marrow aspirate and/or biopsy are each performed using a hollow needle to remove a small 
sample of bone marrow.  Before the biopsy, a local anesthetic is used to numb the area where the 
needle(s) will be inserted.  The sterile procedure may cause discomfort, pain, bleeding, scarring 
or infection at the site of the aspirate and/or biopsy. 
 
 
 
C4. REPRODUCTIVE RISKS 
Risks to women who could become pregnant 
The drugs in this project might affect a baby, before or after the baby is born. We do not know if 
the drugs cause(s) harm to a baby, so we do not want anyone who might be pregnant to enter 
the project. You should not become pregnant or nurse a baby while in this project. You must tell 
the research doctor right away if you think you are pregnant. You will be asked to have a 
pregnancy test to be sure you are not pregnant at the start of the project.  
 
If you become pregnant during the project, you will be dropped from participation for safety 
reasons. If you become pregnant while you are taking this experimental drug we ask that you 
inform the research doctor immediately. The research doctor will ask you for written permission 
to obtain information from you or your obstetrician on your pregnancy and the health of the 
baby. 
 
Risks of fathering a child 
You should not father a baby while taking part in this project because it is unknown if the drugs 
could affect a baby. If your partner is able to become pregnant, one or both of you must use 
some form of effective birth control.  You must tell the research doctor right away if you think 
your partner is pregnant. 
 
If you think that you have fathered a baby while you are taking this experimental drug, we ask 
that you inform the research doctor immediately. At that time, the research doctor will ask 
permission of your partner for the use and disclosure of her health information regarding the 
pregnancy. She will be asked to sign a separate consent form. She can choose to do this or not. 
She will be asked to sign this form to allow your research doctor to contact her obstetrician to 
collect information on the progress of the pregnancy and its outcome. The research doctor will 
make this information available to the sponsor for safety monitoring. 
 
Birth control methods for all subjects 
Check with the research doctor about the birth control methods needed for this project and how 
long to use them. Some methods might not be good enough for this project. If you are having 
sex that could lead to pregnancy, you should use birth control while you are in this project.   
This may include: 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: 35737 
IRB Approval Period: 12/13/2022 – 8/14/2023 
 
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x 
Not having vaginal sex (abstinence) 
x 
Taking birth control pills orally 
x 
Having birth control shots or patches such as Depo-Provera 
x 
Surgical sterilization (hysterectomy or tubal ligation) 
x 
Use of an intrauterine device (IUD) 
x 
Use of diaphragm with contraceptive jelly 
x 
Use of condoms with contraceptive foam 
x 
Use of diaphragm with condoms (“double barrier”) 
x 
Limiting sexual activity to a male partner who has had a vasectomy 
 
C5. ARE THERE ANY BENEFITS TO TAKING PART IN THE PROJECT? 
We don’t know if this study will help you. Your condition may get better but it could stay the 
same or even get worse. We hope the information from this study will help us develop better 
treatments for acute GVHD. 
 
D1. ARE THERE ANY COSTS TO BEING IN THE PROJECT? 
Most of the medical care that you will receive in this project is considered routine care for your 
condition and would be recommended whether or not you join the project.  Costs for routine 
care will be billed to you or your insurance carrier.   
 
Activities / costs that are part of the project will not be billed to you or your insurance company. 
These are the study drug, Tildrakizumab, research samples and the process and shipping of 
research samples. Some insurers will not pay for drugs, tests or hospitalization that are part of 
research, so check with your insurer before you join this project. If you have questions regarding 
costs, please contact Dr. Runaas. 
 
If you participate in this research, the costs of any necessary emergency medical treatment in 
the event of a research-related injury will be billed to you or your health insurance. 
 
D2. WILL I BE PAID FOR PARTICIPATING IN THE PROJECT? 
There is no payment for being in this project. 
 
D3. WHAT OTHER HEALTHCARE CHOICES DO I HAVE? 
You do not have to join this project. You are free to say yes or no. If you do not join this project, 
your research doctor can discuss other healthcare choices with you.  
Your other choices may include: 
x 
Joining a different research project 
x 
The procedure or drug offered to you may also be available without being in any 
research project. 
 
The research doctor can explain both the possible benefits and the risks of other options that 
are available to you. 
 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: 35737 
IRB Approval Period: 12/13/2022 – 8/14/2023 
 
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MCW/FH IRB
D4. WILL I BE GIVEN NEW INFORMATION ABOUT THE PROJECT? 
If we learn any important new information about the drugs that might change your mind about 
being in the project, we will tell you about it right away.  You can then decide if you want to stay 
in the project. 
 
D5. WHAT HAPPENS IF I AM INJURED BECAUSE I TOOK PART IN THE PROJECT?  
Emergency medical treatment for injuries directly related to your participation in this research 
project will be provided to you. You or your health insurance will be billed for the costs of this 
emergency treatment.  MCW will decide on a case by case basis if they will reimburse you or 
your insurer for emergency treatment costs.  If your research-related injury requires medical 
care beyond this emergency treatment, you or your insurer will be responsible for the costs of 
this follow-up care.  
 
At this time, there is no plan for any additional financial payments. 
 
If you believe that you have been injured because of your participation in this project, contact 
the research doctors right away.  Contact information: Dr. Runaas, 414-805-6700.  
 
Nothing in this consent form affects any legal rights you may have nor does it release the 
investigator, the sponsor, the institution, or its agents from liability for negligence. 
 
D6. WHO CAN ANSWER MY QUESTIONS ABOUT THE PROJECT? 
 
If you have more questions about this project at any time, you can call Dr. Runaas at 414-
805-6700 
 
If you have questions about your rights as a research participant, want to report any 
problems or complaints, or offer input, you can call the MCW/Froedtert Hospital Research 
Subject Advocate at 414-955-8844. 
 
E. PERMISSION TO COLLECT, USE AND SHARE HEALTH INFORMATION 
 
E1. What health information will be collected and used for this project? 
To be in this research project, the research team needs your permission to access, collect and 
use some of your health information. If you say no, you cannot be in the project. This 
information may come from questions we ask, forms we ask you to fill out, or your medical 
record, as described below. We will only collect and use information needed for the project. 
 
The protected health information (PHI) originates from services you will or have received at one 
or more of the following locations: the Medical College of Wisconsin (MCW); BloodCenter of 
Wisconsin (BCW); Children’s Hospital of Wisconsin (CHW); any Froedtert Health Affiliate- 
Froedtert Memorial Lutheran Hospital (FMLH), Inc.; Community Memorial Hospital (CMH) 
Menomonee Falls, Inc.;  St. Joseph’s Community Hospital (SJH) West Bend, Inc.;  Froedtert & 
The Medical College of Wisconsin Community Physicians Clinics, Inc. (FMCWCP); the West 
Bend Surgery Center, LLC; and the Froedtert Surgery Center, LLC.  
 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: 35737 
IRB Approval Period: 12/13/2022 – 8/14/2023 
 
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The health information to be collected and used for this project is:  
• 
Hospital/Medical Records 
• 
Physician/Clinical Records 
• 
Lab and/or Pathology Reports  
• 
Radiology Reports 
• 
Biological Samples 
 
E2. Who will see the health information collected for this project? 
The only MCW/Froedtert Hospital employees allowed to handle your health information are 
those on the research team, those on the Institutional Review Board (IRB) and those who check 
on the research activities to make sure the hospital’s rules are followed. 
 
If the costs of any necessary emergency medical treatment in the event of a research-related 
injury are billed to your health insurance, your health information may need to be disclosed to 
the insurer for billing purposes. 
 
The research team may share your information with people who don’t work at MCW/Froedtert 
Hospital because they planned, pay for, or work with us on this project.  The federal Privacy 
Rule may no longer protect your health information once it leaves MCW/Froedtert Hospital.  For 
this project, we plan to share information with those doctors, researchers or government 
representatives working with us on this project at the institutions or companies listed here: 
 
 
x 
The U.S. Food and Drug Administration (FDA) 
x 
Covance Laboratories and affiliates 
x 
Sun Pharmaceutical Industries, Inc.   
x 
Federal agencies such as the Department of Health and Human Services (the DHHS), 
the National Cancer Institutes / National Institutes of Health (the NCI/NIH) and the 
Office of Human Research Protections (the OHRP) 
x 
Other regulatory agencies and/or their Designated Representatives  
x 
Any independent ethics committee, which approved this study 
x 
Those required by law 
 
Because this project involves the use of drugs and/or devices, the FDA also has the right to 
inspect all project records. 
 
We may record your research information, including results of tests and procedures done for 
research, in your Froedtert Hospital and/or Medical College of Wisconsin medical record.  As a 
result, this research information may be seen by people allowed to see your medical records for 
healthcare operations or treatment, by those you allow to see your medical records by giving 
written permission, and by others when required by law. 
 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: 35737 
IRB Approval Period: 12/13/2022 – 8/14/2023 
 
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MCW/FH IRB
We will not use your personal health information for a different project without your permission 
or the permission of a hospital research review board (IRB). Once all personal identification is 
removed from your health information, the information may be used for future research or 
distributed to another investigator for future research without additional informed consent from 
you or your legally authorized representative. The information might also be used or released 
for other purposes without asking you. Results of the project may be presented in public talks or 
written articles, but no information will be presented that identifies you. 
  
E3. What are the risks of sharing this health information? 
One risk of taking part in a research project is that more people will handle your personal health 
information collected for this project. The research team will make every effort to protect the 
information and keep it confidential, but it is possible that an unauthorized person might see it. 
Depending on the kind of information being collected, it might be used in a way that could 
embarrass you or affect your ability to get insurance. If you have questions, you can talk to the 
research doctor about whether this could apply to you.  
 
E4. How long will you keep the health information for this project? 
If you sign this form, we plan to keep your information without any end-date in case we need to 
check it again for this project. 
 
E5. Can I cancel my permission to share this health information? 
If you change your mind later and do not want us to collect or share your health information, you 
need to send a letter to: 
Lyndsey Runaas, MD  
Froedtert & the Medical College of Wisconsin 
Division of Hematology and Oncology 
9200 W. Wisconsin Avenue 
Milwaukee WI 53226 
 
The letter must say that you have changed your mind and do not want the researcher to collect 
and share your health information. At that time, we may decide that you cannot continue to be 
part of the project. We may still use the information we have already collected.  
 
F1. FOR MORE INFORMATION ABOUT THE PROJECT 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov as required by 
U.S. Law. This Web site will not include information that can identify you. At most, the Web site 
will include a summary of the results. You can search this Web site at any time. 
 
You can look up this project by referring to the ClinicalTrials.gov number NCT04112810 or by 
asking the research team for a printed copy.    
 
 
 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: 35737 
IRB Approval Period: 12/13/2022 – 8/14/2023 
 
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CONSENT TO PARTICIPATE 
 
By signing my name below, I confirm the following: 
x 
I have read (or had read to me) this entire consent document.  
All of my questions have been answered to my satisfaction. 
x 
The project’s purpose, procedures, risks and possible benefits have been explained to me.   
x 
I agree to let the research team use and share the health information and other information 
gathered for this project. 
x 
I voluntarily agree to participate in this research project. I agree to follow the procedures as 
directed. I have been told that I can stop at any time. 
 
IMPORTANT: You will receive a signed and dated copy of this consent form.  Please keep it 
where you can find it easily.  It will help you remember what we discussed today. 
 
 
 
 
Subject's Name please print  
Subject's Signature 
Date   
 
 
 
Name of Witness (if applicable) 
please print  (for short form consent 
process, or consent of blind or 
illiterate subject) 
Signature of Witness 
 
Date 
Rationale for Use of Witness 
 Subject has limited/no literacy 
 Subject has limited English 
proficiency 
 Subject has limited/no vision 
 
 Sponsor requirement 
 Other ____________________ 
 
 
 
 
 
* Name of person discussing/ 
obtaining consent please print  
Signature of person 
discussing/obtaining consent 
Date 
* A member of the research team trained and authorized by the Principal Investigator to act on 
her/his behalf in obtaining informed consent according to the protocol.  The Principal 
Investigator is responsible and accountable for the research project.