Clinical trial NCT02993783
Conditions: Allogeneic Hematopoietic Stem Cell Transplantation
Keywords: Drug Therapy
Sponsor: Millennium Pharmaceuticals, Inc.
Start date: 2017-04-28; Completion date: 2018-05-09
Enrollment: 17 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess the initial activity, tolerability, safety and to identify a recommended dose and regimen of vedolizumab intravenous (IV) administered for treatment of steroid-refractory acute intestinal GvHD in participants who have undergone allo-HSCT.

Detailed description:
The drug being tested in this study is called vedolizumab. This study will look at the tolerability and effectiveness of vedolizumab IV in participants with acute intestinal GvHD who have received no systemic therapy for the treatment of acute GvHD (prophylaxis acceptable) other than corticosteroids.

The study enrolled 17 participants. Participants will be randomly assigned (by chance, like flipping a coin) to one of the two treatment groups:

* Vedolizumab 300 mg
* Vedolizumab 600 mg

All participants will be infused intravenously at the same time each day throughout the study. Vedolizumab IV will be administered on Days 1, 15, 43, 71, and 99. After approximately 10 participants are enrolled at each dose level and have data available from the Day 28 evaluation, safety, tolerability, efficacy, and pharmacokinetic (PK), results will be assessed for each dose level, and the appropriate dose for subsequent participants in the study will be determined.

This multi-center trial will be conducted in multiple countries. The overall time to participate in this study is 32 weeks. Participants will make multiple visits to the clinic after last dose of study drug for a follow-up assessment.

Arms: arm 1: Vedolizumab 300 mg, intravenous (IV) infusion, once on Days 1, 15, 43, 71 and 99. arm 2: Vedolizumab 600 mg, IV infusion, once on Days 1, 15, 43, 71 and 99.
Interventions: intervention 1: Vedolizumab
Intervention descriptions: intervention 1: Vedolizumab IV infusion

Protocol documents:
Prot_001.pdf: 
This may include, but is not limited to, redaction of the following: 


•
Title: An Open-Label, Dose-Finding Study of Vedolizumab IV for Treatment of 
Steroid-Refractory Acute Intestinal Graft-Versus-Host Disease (GvHD) in Patients who Have 
Undergone Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT)
NCT Number: NCT02993783
Protocol Approve Date: November 27, 2017
Certain information within this protocol has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable 
information or company confidential information. 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.


1.0 TITLE PAGE
CONFIDENTIAL
PROTOCOL
An Open-Label, Dose-Finding Study of Vedolizumab IV for Treatment of 
Steroid-Refractory Acute Intestinal Graft-Versus-Host Disease (GvHD) in Patients who 
Have Undergone Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT)
Sponsor:
Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda 
Pharmaceutical Company Limited
40 Landsdowne Street
Cambridge, MA USA 02139
Telephone: +1 (617) 679-7000
Please note: Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda
Pharmaceutical Company Limited, may be referred to in this protocol as 
“Millennium,” “Sponsor,” or “Takeda”.
Study Number:
Vedolizumab-2004 
IND Number:
127,634
EudraCT Number:
2016-002985-30
Compound:
Vedolizumab IV
Date:
17 May 2017
Amendment Number:
01
27 November 2017
02
Amendment History:
Date
Amendment Number
Amendment Type
Region
27 July 2016
Initial protocol
Not applicable
Global
17 May 2017
01
Substantial
Sweden
27 November 2017
02
Substantial
Global
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by 
the recipient that no information contained herein will be published or disclosed without written authorization from 
Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduct of the study.


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1.0
ADMINISTRATIVE 
1.1
Contacts 
A separate contact information list will be provided to each site.
Serious adverse event and pregnancy reporting information is presented in Section 10.0, as is 
information on reporting product complaints.
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site.
Contact Type/Role
North America
Europe
Serious adverse event and pregnancy reporting
See Section 10.2
See Section 10.2
Responsible Medical Officer 
(carries overall responsibility for the conduct of the study)
Protected Personal Data


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1.2
Approval 
REPRESENTATIVES OF TAKEDA 
This study will be conducted with the highest respect for the individual participants in accordance 
with the requirements of this clinical study protocol and also in accordance with the following:
!
The ethical principles that have their origin in the Declaration of Helsinki.
!
International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline.
!
All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations.
SIGNATURES
The signature of the responsible Takeda medical officer (and other signatories, as applicable) can
be found on the signature page.
Electronic Signatures may be found on the last page of this document.
Protected Personal Data


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INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, package 
insert and any other product information provided by the sponsor. I agree to conduct this study in 
accordance with the requirements of this protocol and also to protect the rights, safety, privacy, 
and well-being of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.0 of this 
protocol.

Terms outlined in the Clinical Study Site Agreement.

Responsibilities of the Investigator (Appendix B).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix C of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Provence)
Location of Facility (Country)


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1.3
Protocol Amendment 02 Summary of Changes
Rationale for Amendment 02
This document describes the changes in reference to the protocol incorporating Amendment 
No. 02. The primary reasons for this amendment are to change some of the inclusion and exclusion 
criteria, allowing enrollment of suitable subjects and avoiding unnecessary screen failures, as well 
as to conduct a single interim analysis that fulfills the goals of this study. In addition, changes 
made in the Sweden only protocol amendment 01 have been incorporated into the global 
amendment 02.
Minor grammatical, editorial, and formatting changes are included for clarification purposes only. 
For specific descriptions of text changes and where the changes are located, see Appendix G.
Changes in Amendment 02
1. Clarification that the progressive multifocal leukoencephalopathy (PML) checklist is 
administered per Section 9.4.8.
2. Clarification to the description of patients with steroid-refractory graft-versus-host disease 
(GvHD) who are eligible for enrollment to the study.
3. Deletion of the inclusion criterion specifying a required level of creatinine clearance for 
enrollment in the study.
4. Deletion of the exclusion criterion requiring the occurrence of acute steroid resistant GvHD 
within 28 days from primary treatment.
5. Addition of viral testing procedures to be conducted at the Screening visit.
6. Correction and specification of the pharmacokinetic (PK) postinfusion sampling times. 
7. Correction to the end of treatment (ET) visit.
8. Clarification of the posttreatment follow-up assessments.
9. Clarification to the efficacy analyses.
10. Clarification of the immunogenicity analyses.
11. Deletion of redundant safety analysis text.
12. Modification to the conduct of the interim analysis.
13. Corrections to the Schedule of Events (Appendix A). 
14. Update of the signatories. 


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TABLE OF CONTENTS
1.0
ADMINISTRATIVE.......................................................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 02 Summary of Changes ..........................................................5
2.0
STUDY SUMMARY ....................................................................................................11
3.0
STUDY REFERENCE INFORMATION ......................................................................14
3.1
Study-Related Responsibilities.................................................................................14
3.2
Principal Investigator/Coordinating Investigator ......................................................14
3.3
List of Abbreviations ...............................................................................................15
3.4
Corporate Identification...........................................................................................17
4.0
INTRODUCTION.........................................................................................................18
4.1
Background .............................................................................................................18
4.1.1
Disease Under Treatment ...................................................................................18
4.1.2
Vedolizumab IV.................................................................................................18
4.2
Rationale for the Proposed Study.............................................................................21
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................24
5.1
Objectives................................................................................................................24
5.1.1
Primary Objective ..............................................................................................24
5.1.2
Secondary Objectives.........................................................................................24
5.1.3
Additional/Exploratory Objectives .....................................................................24
5.2
Endpoints.................................................................................................................24
5.2.1
Primary Endpoints .............................................................................................24
5.2.2
Secondary Endpoints..........................................................................................25
5.2.3
Additional/Exploratory Endpoints......................................................................25
6.0
STUDY DESIGN..........................................................................................................27
6.1
Overview of Study Design.......................................................................................27
6.2
Number of Patients ..................................................................................................28
6.3
Duration of Study ....................................................................................................28
6.3.1
Duration of an Individual Patient’s Study Participation ......................................28
6.3.2
End of Study/Study Completion Definition and Planned Reporting....................29
6.3.3
Timeframes for Primary and Secondary Endpoints to Support Disclosures.........29
6.3.4
Total Study Duration..........................................................................................30
7.0
STUDY POPULATION................................................................................................31
7.1
Inclusion Criteria .....................................................................................................31


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7.2
Exclusion Criteria ....................................................................................................32
8.0
STUDY DRUG .............................................................................................................34
8.1
Study Drug Administration......................................................................................34
8.2
Excluded Concomitant Medications and Procedures ................................................34
8.3
Permitted Concomitant Medications and Procedures................................................35
8.4
Precautions and Restrictions ....................................................................................35
8.4.1
Criteria for Dosing on Days 15, 43, 71, and 99...................................................35
8.4.2
Reproductive Effects..........................................................................................35
8.5
Management of Clinical Events ...............................................................................36
8.5.1
Hypersensitivity Reactions.................................................................................36
8.5.2
Leukopenia or Lymphopenia..............................................................................36
8.5.3
CMV Colitis ......................................................................................................36
8.5.4
Malignancy........................................................................................................37
8.5.5
Other Clinical Events.........................................................................................37
8.6
Dose Modification or Treatment Delay for Vedolizumab-Related Toxicity..............37
8.7
Blinding and Unblinding..........................................................................................37
8.8
Description of Investigational Agent........................................................................37
8.9
Preparation, Reconstitution, and Dispensation..........................................................38
8.10
Packaging and Labeling...........................................................................................38
8.11
Storage, Handling, and Accountability.....................................................................38
8.12
Other Protocol-Specified Materials ..........................................................................38
9.0
STUDY CONDUCT......................................................................................................40
9.1
Study Personnel and Organizations..........................................................................40
9.2
Arrangements for Recruitment of Patients................................................................40
9.3
Treatment Group Assignments.................................................................................40
9.4
Study Procedures.....................................................................................................40
9.4.1
Informed Consent...............................................................................................40
9.4.2
Patient Demographics ........................................................................................40
9.4.3
Medical History .................................................................................................41
9.4.4
Physical Examination.........................................................................................41
9.4.5
Neurological Examination..................................................................................41
9.4.6
Patient Height and Weight .................................................................................41
9.4.7
Vital Signs .........................................................................................................41
9.4.8
PML Checklist...................................................................................................41
9.4.9
Pregnancy Test...................................................................................................42


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9.4.10 ECOG Performance Status.................................................................................42
9.4.11 Concomitant Medications and Procedures..........................................................42
9.4.12 Adverse Events ..................................................................................................42
9.4.13 Enrollment .........................................................................................................42
9.4.14 Clinical Laboratory Evaluations .........................................................................42
9.4.15 Disease Assessment ...........................................................................................43
9.4.16 Endoscopy .........................................................................................................43
9.4.17 PK Measurements..............................................................................................44
9.4.18 Healthcare Resource Utilization Data Collection................................................44
9.4.19 Quality of Life Assessments...............................................................................44
9.4.20 Biomarker Measurements...................................................................................44
9.4.21 Immunogenicity.................................................................................................44
9.4.22 Fecal Microbiome Samples................................................................................45
9.5
Completion of Study Treatment (for Individual Patients) .........................................45
9.6
Completion of Study (for Individual Patients)..........................................................45
9.7
Discontinuation of Treatment With Study Drug and Patient Replacement................45
9.8
Withdrawal of Patients From Study .........................................................................45
9.9
Study Compliance....................................................................................................46
9.10
Posttreatment Follow-up Assessments .....................................................................46
10.0
ADVERSE EVENTS ....................................................................................................47
10.1
Definitions...............................................................................................................47
10.1.1 PTE Definition...................................................................................................47
10.1.2 AE Definition ....................................................................................................47
10.1.3 SAE Definition ..................................................................................................47
10.2
Procedures for Recording and Reporting AEs and SAEs..........................................48
10.3
Monitoring of AEs and Period of Observation .........................................................49
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events.........49
10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose) ................................................................................................................50
10.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities...........50
10.7
Risk Minimization Action Plan for PML (RAMP Program) .....................................50
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................52
12.0
DATA HANDLING AND RECORDKEEPING............................................................53
12.1
eCRFs......................................................................................................................53
12.2
Record Retention .....................................................................................................53
13.0
STATISTICAL METHODS..........................................................................................55


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13.1
Statistical and Analytical Plans ................................................................................55
13.1.1 Analysis Sets......................................................................................................55
13.1.2 Procedures for Handling Missing, Unused, and Spurious Data ...........................55
13.1.3 Analysis of Demographics and Other Baseline Characteristics ...........................55
13.1.4 Efficacy Analysis...............................................................................................55
13.1.5 Resource Utilization and Patient-Reported Outcome Analysis............................56
13.1.6 PK Analysis .......................................................................................................56
13.1.7 Biomarker Analysis............................................................................................57
13.1.8 Immunogenicity Analyses..................................................................................57
13.1.9 Safety Analysis ..................................................................................................57
13.2
Interim Analysis ......................................................................................................58
13.3
Determination of Sample Size..................................................................................58
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................59
14.1
Study-Site Monitoring Visits ...................................................................................59
14.2
Protocol Deviations..................................................................................................59
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................59
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................60
15.1
IRB and/or IEC Approval ........................................................................................60
15.2
Subject Information, Informed Consent, and Subject Authorization .........................61
15.3
Subject Confidentiality ............................................................................................62
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................62
15.4.1 Publication.........................................................................................................62
15.4.2 Clinical Trial Registration..................................................................................63
15.4.3 Clinical Trial Results Disclosure ........................................................................63
15.5
Insurance and Compensation for Injury....................................................................63
16.0
REFERENCES..............................................................................................................64
LIST OF IN-TEXT TABLES
Table 6.a
Primary and Secondary Endpoints for Disclosures .............................................29
Table 9.a
Clinical Chemistry and Hematology Tests..........................................................43
Table 9.b
Clinical Urinalysis Tests ....................................................................................43


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LIST OF APPENDICES
Appendix A
Schedule of Events.............................................................................................68
Appendix B
Responsibilities of the Investigator.....................................................................73
Appendix C
Investigator Consent to Use of Personal Information..........................................75
Appendix D
Definitions for Assessing Response in Treatment of Acute GvHD .....................76
Appendix E
Eastern Cooperative Oncology Group (ECOG) Scale for Performance Status.....77
Appendix F
Clinical Stages of Graft-Versus-Host Disease.....................................................78
Appendix G
Amendment 02 Detailed Summary of Changes ..................................................79


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2.0
STUDY SUMMARY
Name of Sponsor(s):
Millennium Pharmaceuticals, Inc.
Compound:
Vedolizumab IV
Title of Protocol: 
An Open-Label, Dose-Finding Study of Vedolizumab IV 
for Treatment of Steroid-Refractory Acute Intestinal
Graft-Versus-Host Disease (GvHD) in Patients who Have 
Undergone Allogeneic Hematopoietic Stem Cell 
Transplantation (allo-HSCT)
IND No.:
127,634
EudraCT No.:
2016-002985-30
Study Number: Vedolizumab-2004
Phase: 2a
Study Design:
This is a phase 2a, open-label, dose-finding study designed to evaluate the safety, tolerability, and clinical activity of 
vedolizumab to treat patients who have developed acute intestinal GvHD that is refractory to primary steroid therapy. 
Clinical GvHD scoring will be used for assessment of response to treatment. Patients with acute intestinal GvHD who 
have received no systemic therapy for the treatment of acute GvHD (prophylaxis acceptable) other than 
corticosteroids will be administered vedolizumab. 
Eligibility will be determined during the Screening period, which may last for up to 28 days before Day 1 (designation 
of the day of the first intravenous [IV] infusion of vedolizumab). Patients who meet all eligibility criteria and provide 
written informed consent will be enrolled in this study. Approximately 38 evaluable patients will be enrolled. 
Patients will be randomized at a ratio of 1:1 to 2 treatment arms to receive either 300 or 600 mg vedolizumab IV on 
Days 1, 15, 43, 71, and 99. After approximately 10 patients are enrolled at each dose level and have data available 
from their Day 28 evaluation, safety, tolerability, efficacy, and pharmacokinetic (PK) results will be assessed from the 
patients at both vedolizumab dose levels (300 and 600 mg), and a Bayesian statistical approach will be used to 
facilitate the determination of an appropriate dose for subsequent patients in the study. The cohort at the chosen dose 
level will then be expanded by approximately 18 additional evaluable patients to further assess the tolerability and 
effectiveness of vedolizumab. Both dose levels may be expanded based on accumulating results, if necessary. 
Upon review and agreement by the medical monitor, patients who respond to and tolerate all 5 planned doses of 
vedolizumab and who develop recurrent symptoms of intestinal GvHD following discontinuation of therapy (ie, after 
the fifth dose) may enter an extension phase where they may receive 300 mg vedolizumab IV every 2 weeks for 
2 doses followed by every 4 weeks for up to 1 year from the first dose of study drug. A dose other than 300 mg and/or 
a frequency of administration other than every 4 weeks may be chosen based on accumulating safety, efficacy, and PK 
results. Patients may receive drug beyond 1 year with the agreement of the investigator and the sponsor if, in the 
opinion of the investigator, the patient is benefitting from treatment. All patients will be followed for overall survival 
(OS) every 3 months until death, withdrawal of consent, termination of the study by the sponsor, or for a maximum of 
1 year after the last patient is enrolled in the study. Additionally, patients will be required to participate in a long-term 
follow-up (LTFU) safety survey 6 months after the last dose of study drug.
Vital signs, physical and neurological examinations, adverse event assessments, and laboratory values (chemistry, 
hematology, and urinalysis) will be obtained to evaluate the safety and tolerability of vedolizumab IV. Another pan-α4 
integrin antagonist (blocking α4β7 and α4β1) has been associated with progressive multifocal leukoencephalopathy 
(PML). α4β7 mediates T cell trafficking to the gastrointestinal tract whereas α4β1 mediates T cell trafficking to the 
central nervous system (CNS) and is therefore involved in CNS immune surveillance. Because vedolizumab binds to 
the α4β7 integrin only, it is anticipated to affect T cell trafficking to the gastrointestinal tract. However, given the
effects of integrin receptor antagonists, there is a potential risk of PML in patients treated with vedolizumab. To date, 
no cases of PML have been reported in clinical studies of vedolizumab; however, health care professionals should 
monitor subjects on vedolizumab for any new onset or worsening of neurological signs and symptoms, and consider 
neurological referral if they occur. To minimize the risk of PML, a PML checklist will be administered at Screening 
and before vedolizumab IV administration on Days 1, 15, 43, 71, and 99. Optional endoscopy will be performed to 
evaluate clinical response to vedolizumab treatment.


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Toxicity will be evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events, 
version 4.03, effective date 14 June 2010. 
Primary Objective:
To describe the initial activity, tolerability, and safety and to identify a recommended dose and regimen of 
vedolizumab IV administered for treatment of steroid-refractory acute intestinal GvHD in patients who have 
undergone allo-HSCT.
Secondary Objectives:
!
To evaluate overall response to vedolizumab treatment at Day 28.
!
To determine the nonrelapse mortality at 6 months after treatment with vedolizumab.
!
To evaluate OS.
!
To determine the GvHD-free, relapse-free survival at 6 and 12 months after treatment with vedolizumab.
!
To characterize the PK in patients treated with vedolizumab.
Exploratory Objectives
!
!
!
!
!
!
!
!
Subject Population: Adult patients with primary steroid-refractory acute intestinal GvHD who have undergone 
allo-HSCT.
Number of Subjects:
Approximately 38 evaluable patients
Number of Sites: 
Approximately 15 in the United States and Europe
Dose Level(s):
Vedolizumab: Initially, patients will be randomized at a 
ratio of 1:1 to 2 treatment arms to receive 300 or 600 mg. 
After approximately 10 patients are enrolled at each dose
level, one or both dose levels may be expanded in 
approximately 18 additional evaluable patients.
Route of Administration:
Vedolizumab: IV
Company Confidential Information
Confidential Company Information


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Duration of Treatment:
Patients will receive up to 5 doses of vedolizumab IV (a 
single dose on each of Days 1, 15, 43, 71, and 99). Upon 
review and agreement by the medical monitor, patients who 
respond to and tolerate all 5 planned doses of vedolizumab 
and who develop recurrent symptoms of intestinal GvHD 
following discontinuation of therapy (ie, after the fifth dose)
may receive 300 mg vedolizumab IV every 2 weeks for 
2 doses followed by every 4 weeks for up to 1 year from the 
first dose of study drug. A dose other than 300 mg and/or a 
frequency of administration other than every 4 weeks may 
be chosen based on accumulating safety, efficacy, and PK 
results. Patients may receive drug beyond 1 year with the 
agreement of the investigator and the sponsor if, in the 
opinion of the investigator, the patient is benefitting from 
treatment.
Period of Evaluation:
Patients may receive vedolizumab unless they 
experience relapse of the underlying malignancy. 
Patients will discontinue treatment if they have an 
unacceptable vedolizumab-related toxicity. All 
patients will be followed for OS every 3 months until 
death, withdrawal of consent, termination of the study 
by the sponsor, or for a maximum of 1 year after the 
last patient is enrolled in the study. Additionally, 
patients will be required to participate in an LTFU 
safety survey 6 months after the last dose of study 
drug.
It is anticipated that this study will last for 
approximately 36 months.
Main Criteria for Inclusion:
Adult patients aged ≥18 years who have received 1 allo-HSCT and have primary steroid-refractory acute GvHD with 
intestinal disease involvement with a severity index of B, C, or D using the Blood and Marrow Transplant Clinical 
Trials Network (BMT CTN)- modified International Bone Marrow Transplant Registry Database (IBMTR) index will 
be enrolled. Patients should have evidence of myeloid engraftment, an Eastern Cooperative Oncology Group 
performance status of 0 to 3, and an estimated creatinine clearance based on the Cockcroft-Gault estimate of 
≥60 mL/minute/1.73 m2.
Main Criteria for Exclusion:
Patients who have chronic GvHD, have relapse of underlying malignancy after allo-HSCT, or have received systemic 
agents other than corticosteroids for treatment of acute GvHD (other than GvHD prophylaxis agents) will be excluded 
from the study. Patients with active CNS disease, active cytomegalovirus colitis, or signs and symptoms of PML or 
any history of PML will also be excluded. In addition, patients with severe hepatic veno-occlusive disease/sinusoidal 
obstruction syndrome will be excluded.
Main Criteria for Evaluation and Analyses:
The primary endpoints of the study are overall response (partial response+very good partial response+complete 
response) at Day 28 and the number and percentage of patients who experience serious adverse events from 
administration of the first dose of vedolizumab IV through Day 28. 
Statistical Considerations:
Statistical analyses will be primarily descriptive and graphical in nature. A Bayesian statistical approach will be used 
for the PK and efficacy data summary to facilitate decision making. A formal statistical analysis plan will be 
developed and finalized before database lock.
Sample Size Justification:
Approximately 38 evaluable patients will be enrolled to identify an active and tolerable vedolizumab dose level with 
sufficient PK sampling to determine the PK parameters in this patient population. Sample size determination is mainly 
based on clinical considerations and on the primary objective of determining a recommended dose and regimen and to 
describe the initial activity, tolerability, and safety of vedolizumab IV administered for the treatment of primary 
steroid-refractory acute intestinal GvHD.


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3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities 
The sponsor will perform all study-related activities with the exception of those identified in the 
Clinical Study Supplier List. The identified vendors in the template for specific study-related 
activities will perform these activities in full or in partnership with the sponsor.
3.2
Principal Investigator/Coordinating Investigator
Takeda will select a Signatory Coordinating Investigator from the investigators who participate in 
the study. Selection criteria for this investigator will include significant knowledge of the study 
protocol, the study medication, their expertise in the therapeutic area and the conduct of clinical 
research as well as study participation. The Signatory Coordinating Investigator will be required to 
review and sign the clinical study report and by doing so agrees that it accurately describes the 
results of the study.


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3.3
List of Abbreviations
Term
Definition
AE
adverse event
allo-HSCT
allogeneic hematopoietic stem cell transplantation
AVA
anti-vedolizumab antibodies
BMT CTN
Blood and Marrow Transplant Clinical Trials Network
CD
Crohn’s disease
CDAI
Crohn’s Disease Activity Index
CMV
cytomegalovirus
CNS
central nervous system
CR
complete response
CRO
contract research organization
Ctrough
observed concentration at the end of a dosing interval
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EOS
end of study
EQ-5D
European Quality of Life 5-Dimensional questionnaire
FACT-BMT
Functional Assessment of Cancer Therapy-Bone Marrow Transplant Scale
FDA
Food and Drug Administration
GALT
gut-associated lymphoid tissue 
GCP
Good Clinical Practice
GI
gastrointestinal(ly)
GvHD
graft-versus-host disease
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HSCT
hematopoietic stem cell transplantation
IAC
independent adjudication committee 
IB
Investigator’s Brochure
IBD
inflammatory bowel disease
IBMTR
International Bone Marrow Transplant Registry Database
ICF
informed consent form
ICH
International Conference on Harmonisation
ID
identification
IEC
independent ethics committee
IL
interleukin
IRB
institutional review board
IRT
interactive voice or web response technology
IV
intravenous(ly)
LTFU
long-term follow-up


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Term
Definition
MAdCAM-1
mucosal addressin cell adhesion molecule-1
MedDRA
Medical Dictionary for Regulatory Activities
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
OS
overall survival
PCR
polymerase chain reaction
PK
pharmacokinetic(s)
PML
progressive multifocal leukoencephalopathy
PR
partial response
PRO
patient-reported outcome
PTE
pretreatment event
PVC
polyvinyl chloride
Q4W
once every 4 weeks
Q8W
once every 8 weeks
RAMP
Risk Assessment and Minimization of PML
SAE
serious adverse event
SAP
statistical analysis plan
SOC
system organ class
SOE
schedule of event(s)
ST2
suppressor of tumorigenicity 2
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment-emergent adverse event
TNF-α
tumor necrosis factor-alpha 
UC
ulcerative colitis
US
United States
VCAM-1
vascular cell adhesion molecule 1
VGPR
very good partial response
WHO
World Health Organization


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3.4
Corporate Identification 
Millennium
Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda 
Pharmaceutical Company Limited
TDC Japan
Takeda Development Center Japan
TDC Asia
Takeda Development Center Asia, Pte Ltd
TDC Europe
Takeda Development Centre Europe Ltd
TDC Americas
Takeda Development Center Americas, Inc
TDC
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable
Takeda
Millennium Pharmaceuticals, Inc, TDC Japan, TDC Asia, TDC Europe and/or TDC 
Americas, as applicable


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4.0
INTRODUCTION
4.1
Background
4.1.1
Disease Under Treatment
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an important therapy that is 
used to treat hematologic malignant disorders and hematologic genetic diseases, but its use is 
limited by the major complication of graft-versus-host disease (GvHD) [1]. The common 
complication of GvHD following allo-HSCT is a major cause of morbidity and mortality. The risk 
of GvHD is variable and depends on patient factors, donor factors, the degree of histocompatibility 
between donor and recipient, the conditioning regimen, and the GvHD prophylaxis strategy 
employed [2-4]. GvHD prophylaxis is employed for all patients undergoing allo-HSCT using 
various strategies such as calcineurin inhibitors, methotrexate, and in vivo or ex vivo T-cell 
depletion; however, despite GvHD prophylaxis, GvHD still develops in 30% to 50% of allo-HSCT 
recipients [2,3]. First-line treatment for patients with acute GvHD (Grade II or higher) is 
corticosteroids such as methylprednisolone. Although first-line treatment is effective in more than
50% of patients, durable responses (defined as a complete response [CR] by Day 28 that remains at 
6 months after onset) are observed in only one-third of patients [5]. In patients who do not respond 
to primary treatment with steroids, acute GvHD is associated with a high rate of morbidity and 
mortality, primarily from infections and/or multi-organ failure [6,7]. Despite this, there are no 
approved or agreed-upon standard treatments for steroid-refractory GvHD, which remains largely 
an untreatable disease with limited survival, representing a major unmet therapeutic need.
Acute GvHD that occurs after allo-HSCT involves the skin, liver, and gut in the most severe and 
life-threatening cases. Acute skin GvHD is generally not life-threatening with existing therapies, 
which are usually effective, and the incidence of Stage 3 or 4 liver GvHD is around 2% [2]. While 
the incidence of Stage 3 or 4 intestinal GvHD has decreased in recent years, most courses of 
treatment remain unsuccessful, with most fatal cases of GvHD involving the gastrointestinal (GI) 
tract [2]. Lower intestinal GvHD presents with secretory, protein-rich diarrhea (in excess of 
1.5 liters per day in severe cases), abdominal pain from gut distention, inflammation of the small 
intestine and colon, mucosal ulceration, and bleeding. A recent study of patients who received 
allo-HSCT showed that 7.9% of patients developed Stage 3 or 4 intestinal GvHD at a median time 
to onset of 35 days after transplant [8]. Of these patients, 73% developed corticosteroid resistance 
before or within 14 days of onset of Stage 3 or 4 intestinal GvHD. Significant risk factors for 
mortality include corticosteroid resistance, age >18 years, increased serum bilirubin, and overt GI 
bleeding.
4.1.2
Vedolizumab IV
Vedolizumab (also called MLN0002) is a humanized immunoglobulin G1 monoclonal antibody 
directed against the human lymphocyte integrin 47. The 47 integrin mediates lymphocyte 
trafficking to GI mucosa and gut-associated lymphoid tissue (GALT) through adhesive interaction 
with mucosal addressin cell adhesion molecule-1 (MAdCAM-1), which is expressed on the 
endothelium of mesenteric lymph nodes and GI mucosa [9-12]. Vedolizumab binds the 47 


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integrin, antagonizing its adherence to MAdCAM-1 and, as such, impairs the migration of 
gut-homing leukocytes into GI mucosa. As a result, vedolizumab acts as a gut-selective 
immunomodulator [13]. Vedolizumab has been developed as a treatment for ulcerative colitis 
(UC) and Crohn’s disease (CD), which are characterized by inflammation of the GI tract.
Vedolizumab IV (Entyvio®) is a lyophilized solid that, after appropriate reconstitution and 
dilution, is intended for intravenous (IV) infusion; it has been granted marketing approval in 
several regions, including the United States (US) and European Union. Vedolizumab IV is 
approved for the treatment of adult patients with moderately to severely active UC or CD who 
have had an inadequate response with, lost response to, or were intolerant to a tumor necrosis 
factor-alpha (TNF-α) blocker or immunomodulator; or had an inadequate response with, were 
intolerant to, or demonstrated dependence on corticosteroids. The approved dosing and 
administration regimen for UC and CD consists of 300 mg vedolizumab infused IV over 
approximately 30 minutes at Weeks 0, 2, and 6, then once every 8 weeks (Q8W) thereafter. 
Previously conducted clinical studies in healthy subjects and patients with UC and CD have 
characterized the efficacy, safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and 
immunogenicity of vedolizumab.
4.1.2.1
Nonclinical
Several key nonclinical studies have been published that support the use of vedolizumab for the 
treatment of GvHD [14-16]. Extensive nonclinical evaluations of the cardiovascular, acute, local 
tolerance, subchronic, chronic, immunologic, and reproductive toxicity of vedolizumab in 
pharmacologically responsive species (New Zealand white rabbits and cynomolgus monkeys) 
have been conducted and support its clinical development. Nonclinical studies also show that 
vedolizumab does not antagonize 4β1 integrin [13], which has been implicated in the 
development of progressive multifocal leukoencephalopathy (PML).
4.1.2.2
Human Experience
As of 19 May 2015, approximately 3600 subjects have received at least 1 dose of vedolizumab 
across all studies in the clinical development program (see current Investigator’s Brochure [IB]). 
Phase 3, placebo-controlled studies enrolled 2427 subjects with UC or CD, of whom 1434 were 
administered 300 mg of vedolizumab for induction followed by once every 4 weeks (Q4W) or 
Q8W for up to a total of 52 weeks, and 488 subjects were administered 300 mg vedolizumab for 
induction only [17-19]. As of May 2015, vedolizumab exposure has extended for ≥12 months in 
1667 subjects, ≥24 months in 1306 subjects, ≥36 months in 935 subjects, ≥48 months in 
676 subjects, ≥60 months in 267 subjects, and ≥72 months in 26 subjects. Based on the most recent 
drug shipment data (19 November 2015), the cumulative patient exposure to vedolizumab since its 
marketing approval in May 2014 is estimated to be approximately 25,831 patient-years.
In subjects with moderately to severely active CD (phase 3 Study C13007), including subjects who 
had failed treatment with 1 or more therapies including TNF-α antagonists, vedolizumab 300 mg 
infusion at Week 0 and Week 2 (induction) followed by either Q4W or Q8W from Week 6 through 
Week 52 (maintenance) demonstrated statistically significant differences in efficacy compared 


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with placebo for both the induction phase and maintenance phase. The study met its primary 
endpoint for the induction phase, clinical remission at Week 6, but did not meet the second primary 
endpoint of enhanced clinical response (Crohn’s Disease Activity Index [CDAI-100]; a
≥100-point decrease in the CDAI score) at Week 6 in the overall population, although the 
treatment difference favored vedolizumab. The study did meet its primary endpoint for the 
maintenance phase, clinical remission at Week 52, and important secondary endpoints, including 
enhanced clinical response at Week 52 and corticosteroid-free clinical remission at Week 52 [18].
In the phase 3 Study C13011, vedolizumab (300 mg infusion at Weeks 0, 2, and 6) was 
administered to subjects with moderately or severely active CD who had failed conventional 
therapies, including TNF-α antagonists. The primary endpoint of clinical remission at Week 6 in 
the TNF-α antagonist failure intent-to-treat population was not met; however, a treatment 
difference was observed at Week 10 in this population. Similar treatment differences favoring 
vedolizumab were also demonstrated for the overall population and in the subgroup of subjects 
who were TNF-α antagonist naïve [19].
Study C13008 is an ongoing, phase 3, open-label, single-arm study. Interim efficacy results with a 
cutoff date of 16 July 2012 were analyzed from 1822 subjects (704 UC and 1118 CD) enrolled 
from previous qualifying vedolizumab studies. Enrolled subjects received 300 mg vedolizumab IV 
Q4W starting at Week 0, and efficacy was assessed using partial Mayo scores (UC subjects) or the 
Harvey-Bradshaw Index (CD subjects). The interim efficacy results suggest persistence of benefit 
with continued maintenance treatment in subjects with UC and CD.
Vedolizumab has shown an acceptable safety profile based on an analysis of safety data from both 
completed and ongoing studies (see current version of the IB). In phase 1 and 2 clinical trials 
(7 completed phase 1 studies in healthy subjects and 8 completed phase 1b/2 studies in UC or CD 
patients), there was no consistent evidence of any dosetoxicity relationships, and vedolizumab 
was well tolerated. The majority of the safety data is from 3 well-controlled, phase 3 clinical 
studies that evaluated the safety of vedolizumab for up to 12 months in subjects with UC (Study 
C13006 [52 weeks]) or CD (Studies C13007 [52 weeks] and C13011 [10 weeks]). In addition, an 
interim assessment of safety was performed for the ongoing, uncontrolled extension study 
(Study C13008).
Vedolizumab exhibits target-mediated drug disposition as characterized by linear and nonlinear 
processes of elimination after single-dose administration. Following IV dosing, vedolizumab 
concentrations fell in a biexponential fashion until concentrations reached approximately 1 to 
10 μg/mL with a serum terminal elimination half-life of approximately 25 days. Thereafter, 
vedolizumab concentrations fell in a nonlinear fashion. Similar PK was observed in healthy 
subjects and in subjects with UC or CD.
Vedolizumab has shown an acceptable and consistent safety profile in clinical trials. In the pivotal 
phase 3 studies (Studies C13006 and C13007), the most common (≥5% and at a higher incidence 
than placebo) adverse reactions in subjects administered vedolizumab were nausea, 
nasopharyngitis, upper respiratory tract infection, arthralgia, pyrexia, fatigue, headache, and 
cough. Most serious adverse events (SAEs) have been related to exacerbations or complications of 
the underlying UC or CD. For those infections that were reported more frequently in 


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vedolizumab-treated subjects, the sites of these infections correlated with the known tissue 
distribution of MAdCAM-1 binding sites. Anal abscess, abdominal abscess, and gastroenteritis 
were the most frequently reported serious infections. Extraintestinal infections (bronchitis, 
pneumonia, urinary tract infection, sepsis) occurred at a low frequency (1). A total of 4% of 
vedolizumab-treated subjects and 3% of placebo-treated subjects experienced an infusion-related 
reaction. In Studies C13006 and C13007, 10% of subjects were positive for anti-vedolizumab 
antibodies 16 weeks following the last dose of vedolizumab. Results from the clinical program to 
date do not suggest an increased risk for malignancy with vedolizumab treatment. Overall, the 
safety profile following long-term treatment with vedolizumab in Study C13008 is consistent with 
safety in the completed studies. 
Concomitant use of corticosteroids and/or conventional immunomodulators did not appear to be 
associated with any increased rate of infections based on the comparative rates of infections in the 
phase 3 trials among subjects who had and had not received these medications. 
Natalizumab (TYSABRI), another integrin receptor antagonist, has been associated with PML, a 
rare and often fatal opportunistic infection of the central nervous system. PML is caused by the 
John Cunningham virus and typically occurs only in patients who are immunocompromised 
[20,21]. MAdCAM-1 is mainly expressed on gut endothelial cells and plays a critical role in the 
homing of T-lymphocytes to tissues within the GI tract, while vascular cell adhesion molecule-1 
(VCAM-1) mediates trafficking to the central nervous system. Natalizumab is a pan-α4 integrin 
antagonist that binds to both the α4β1 and α4β7 integrins and inhibits cellular adhesion to VCAM-1 
and MAdCAM-1 [22,23]. In contrast, vedolizumab binds to the α4β7 integrin only [13] and inhibits 
adhesion to MAdCAM-1 but not VCAM-1. Although no cases of PML have been reported in 
clinical trials with vedolizumab to date, a risk of PML cannot be ruled out. To minimize the risk of 
the development of PML in patients treated with vedolizumab, the sponsor, with input from PML 
experts, has developed a Risk Minimization Action Plan for PML, the RAMP (see Section 10.7).
As of 19 May 2015, a total 26 subjects (0.7%) who participated in vedolizumab clinical studies 
have died during the study or up to 2 years following the last dose of study drug (Studies C13004, 
C13006, C13007, and C13008); 4 of the deaths were considered by the investigator to be related to 
study drug. Twenty-five of the 26 subjects who died were administered vedolizumab, including 
12 subjects each with UC or CD and 1 subject who was diagnosed with both UC and CD. There 
was no pattern or consistent cause of death identified in these patients; detailed information can be 
found in the current version of the IB.
Overall, vedolizumab was well tolerated in clinical studies.
4.2
Rationale for the Proposed Study
Acute GvHD is mediated by immunocompetent donor T cells, which migrate to lymphoid tissues 
soon after infusion, recognize host alloantigens, and become activated upon interaction with host 
antigen-presenting cells [24]. On the basis of the safety profile of vedolizumab that has been 
established in patients with inflammatory bowel disease (IBD), it is expected that vedolizumab 
will have acceptable tolerability in patients with steroid-refractory intestinal GvHD following 
allo-HSCT because of the specific mechanism of action of vedolizumab and targeted effects on 


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lymphocytes in the GI tract. A published case series of 6 patients suggests promising activity and 
tolerability of off-label use of vedolizumab for the treatment of acute steroid-refractory intestinal 
GvHD [25]. In this case series, all patients exhibited clinical responses within 7 to 10 days after 
starting treatment with vedolizumab with a decrease in abdominal pain and watery diarrhea. In 
addition, the patients had gradual macroscopic and histological improvement in the GI tract. In the 
proposed study, administration of vedolizumab to patients who have developed intestinal GvHD 
after undergoing allo-HSCT may reduce trafficking of alloreactive T cells to the GI mucosa, 
reducing ongoing tissue damage from acute intestinal GvHD.
Vedolizumab will be administered to patients with acute intestinal GvHD who have received no 
systemic therapy for the treatment of acute GvHD (prophylaxis acceptable) other than 
corticosteroids. Patients will be randomized at a ratio of 1:1 to 2 treatment arms to receive either 
300 or 600 mg vedolizumab IV on Days 1, 15, 43, 71, and 99. After approximately 10 patients are 
enrolled at each dose level and have data available from their Day 28 evaluation, safety, 
tolerability, efficacy, and PK results will be assessed from the patients at both vedolizumab dose 
levels (300 and 600 mg), and a Bayesian statistical approach will be used to facilitate the 
determination of an appropriate dose for subsequent patients in the study.
The cohort at the chosen dose level will then be expanded by approximately 18 additional 
evaluable patients to further assess the tolerability and effectiveness of vedolizumab. Both dose 
levels may be expanded based on accumulating results, if necessary. 
Upon review and agreement by the medical monitor, patients who respond to and tolerate all 
5 planned doses of vedolizumab and who develop recurrent symptoms of intestinal GvHD
following discontinuation of therapy (ie, after the fifth dose) may receive 300 mg vedolizumab IV 
every 2 weeks for 2 doses and Q4W for up to 1 year. A dose other than 300 mg and/or a frequency 
other than Q4W may be chosen based on accumulating safety, efficacy, and PK results. Patients 
may receive drug beyond 1 year with the agreement of the investigator and the sponsor if, in the 
opinion of the investigator, the patient is benefitting from treatment.
Dose Selection
The dose and schedule of vedolizumab IV approved for the treatment of UC or CD is 300 mg IV at 
Weeks 0, 2, and 6, then Q8W [26]. The doses and schedule of vedolizumab IV proposed for this 
study are 300 and 600 mg IV on Days 1, 15, 43, 71, and 99.
In the phase 2, placebo-controlled, double-blind, multiple dose study in subjects with active UC 
(Study C13002), vedolizumab was administered as weight-adjusted doses, ranging from 2.0 to 
10.0 mg/kg [27,28]. In this study, vedolizumab was administered for 12 weeks to 11 patients at 
10.0 mg/kg which approximates a 760 mg fixed dose, ranging from 420 mg to 950 mg (C13002 
CSR). These patients then entered a long-term safety of vedolizumab in the phase 2, open-label 
Study C13004 in patients with UC or CD. In the combined phase 1b and phase 2 UC and CD 
patient population across the vedolizumab clinical development program, there was no apparent 
dose response in adverse events (AEs) by system organ class (SOC) with weight-adjusted doses up 
to 10.0 mg/kg.


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A published case series of 6 patients suggests promising activity and tolerability of off-label use of 
vedolizumab for the treatment of acute steroid-refractory intestinal GvHD [25]. In this case series, 
results showed that a patient who did not achieve remission early required chronic administration 
of vedolizumab to prevent symptom recurrence whereas patients who were treated effectively with 
vedolizumab early in the acute GvHD course were able to discontinue vedolizumab without 
recurrence of symptoms (personal communication). This suggests that it may be critical that 
clinical remission is achieved early in the course of treatment with vedolizumab.
Exposure/response analysis from the phase 3 Study C13006 in adult patients with active CD at 
Week 6 indicated that higher efficacy can be achieved with higher trough concentrations of 
vedolizumab [18]. 
Based on these considerations, 300 and 600 mg vedolizumab IV administered on Days 1, 15, 43, 
71, and 99 (equivalent to Weeks 0, 2, 6, 10, and 14) are the proposed doses and schedule to test in 
this study.


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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective
The primary objective is to describe the initial activity, tolerability, and safety and to identify a 
recommended dose and regimen of vedolizumab IV administered for treatment of 
steroid-refractory acute intestinal GvHD in patients who have undergone allo-HSCT.
5.1.2
Secondary Objectives
The secondary objectives are:
!
To evaluate overall response to vedolizumab treatment at Day 28.
!
To determine the nonrelapse mortality at 6 months after treatment with vedolizumab.
!
To evaluate overall survival (OS).
!
To determine the GvHD-free, relapse-free survival at 6 and 12 months after treatment with 
vedolizumab.
!
To characterize the PK in patients treated with vedolizumab.
5.1.3
Additional/Exploratory Objectives
The additional/exploratory objectives are:
!
!
!
!
!
!
!
!
5.2
Endpoints
5.2.1
Primary Endpoints
The primary endpoints are:
!
The proportion of subjects with overall response (partial response [PR]+very good partial 
response [VGPR]+CR) at Day 28 (refer to Appendix D).
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!
The number and percentage of patients who experience SAEs from administration of the first 
dose of vedolizumab IV through Day 28.
5.2.2
Secondary Endpoints
The secondary endpoints are:
!
The proportion of subjects who have died in the absence of primary malignancy relapse after 
allo-HSCT at 6 months.
!
The proportion of subjects with CR at Day 28.
!
The proportion of subjects with intestinal overall response at Day 28.
!
OS at 6 and 12 months.
!
The proportion of subjects alive without GvHD or relapse of primary malignancy at 6 and 
12 months.
!
The number and percentage of patients who experience treatment-emergent adverse events 
(TEAEs) from administration of the first dose of vedolizumab IV through 18 weeks after 
administration of the last dose of vedolizumab IV.
!
The number and percentage of patients who experience SAEs from administration of the first 
dose of vedolizumab IV through 18 weeks after administration of the last dose of vedolizumab 
IV.
!
Mean serum concentrations of vedolizumab before dosing (Ctrough) on Day 99.
!
The total dose of steroids administered (mg/kg/day of methylprednisolone or equivalent) from 
the start of the first IV infusion of vedolizumab through both 6 and 12 months.
5.2.3
Additional/Exploratory Endpoints
The exploratory endpoints are:
!
!
!
!
!
!
!
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!
!
!
!
!
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6.0
STUDY DESIGN
6.1
Overview of Study Design
This is a phase 2a, open-label, dose-finding study designed to evaluate the safety, tolerability, and 
clinical activity of vedolizumab to treat patients who have developed acute intestinal GvHD that is 
refractory to primary steroid therapy. Clinical GvHD scoring will be used for assessment of 
response to treatment [31]. Patients with acute intestinal GvHD who have received no systemic 
therapy for the treatment of acute GvHD (prophylaxis acceptable) other than corticosteroids will 
be administered vedolizumab.
Eligibility will be determined during the Screening period, which may last for up to 28 days before 
Day 1 (designation of the day of the first IV infusion of vedolizumab). Patients who meet all 
eligibility criteria and provide written informed consent will be enrolled in this study.
Approximately 38 evaluable patients will be enrolled.
Patients will be randomized at a ratio of 1:1 to 2 treatment arms to receive either 300 or 600 mg 
vedolizumab IV on Days 1, 15, 43, 71, and 99. After approximately 10 patients are enrolled at each 
dose level and have data available from their Day 28 evaluation, safety, tolerability, efficacy, and 
PK results will be assessed from the patients at both vedolizumab dose levels (300 and 600 mg), 
and a Bayesian statistical approach will be used to facilitate the determination of an appropriate 
dose for subsequent patients in the study. The cohort at the chosen dose level will then be 
expanded by approximately 18 additional evaluable patients to further assess the tolerability and 
effectiveness of vedolizumab. Both dose levels may be expanded based on accumulating results, if 
necessary
Upon review and agreement by the medical monitor, patients who respond to and tolerate all 
5 planned doses of vedolizumab and who develop recurrent symptoms of intestinal GvHD
following discontinuation of therapy (ie, after the fifth dose) may enter an extension phase where 
they may receive 300 mg vedolizumab IV every 2 weeks for 2 doses followed by Q4W for up to 
1 year from the first dose of study drug. A dose other than 300 mg and/or a frequency of 
administration other than Q4W may be chosen based on accumulating safety, tolerability, efficacy, 
and PK results. Patients may receive drug beyond 1 year with the agreement of the investigator and 
the sponsor if, in the opinion of the investigator, the patient is benefitting from treatment. All 
patients will be followed for OS every 3 months until death, withdrawal of consent, termination of 
the study by the sponsor, or for a maximum of 1 year after the last patient is enrolled in the study. 
Additionally, patients will be required to participate in a long-term follow-up (LTFU) safety 
survey 6 months after the last dose of study drug.
Vital signs, physical and neurological examinations, AE assessments, and laboratory values 
(chemistry, hematology, and urinalysis as specified in Section 9.4.14) will be obtained to evaluate 
the safety and tolerability of vedolizumab IV, as described in the Schedule of Events (Appendix 
A). Another pan-α4 integrin antagonist (blocking α4β7 and α4β1) has been associated with PML. 
α4β7 mediates T cell trafficking to the GI tract whereas α4β1 mediates T cell trafficking to the 
central nervous system (CNS) and is therefore involved in CNS immune surveillance. Because 
vedolizumab binds to the α4β7 integrin only, it is anticipated to affect T cell trafficking to the 


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gastrointestinal tract. However, given the effects of integrin receptor antagonists, there is a 
potential risk of PML in patients treated with vedolizumab. To date, no cases of PML have been 
reported in clinical studies of vedolizumab; however, health care professionals should monitor 
subjects on vedolizumab for any new onset or worsening of neurological signs and symptoms, and 
consider neurological referral if they occur. To minimize the risk of PML, a PML checklist will be 
administered at Screening and before vedolizumab IV administration on Days 1, 15, 43, 71, and 
99. Optional endoscopy will be performed to evaluate clinical response to vedolizumab treatment 
as described in the Schedule of Events (Appendix A).
Toxicity will be evaluated according to National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI CTCAE), version 4.03, effective date 14 June 2010 [38].
6.2
Number of Patients
Approximately 20 patients will be enrolled to determine the appropriate dose for subsequent 
patients in the study. The cohort at the chosen dose level then will be expanded by approximately 
18 additional evaluable patients to further assess the tolerability and effectiveness of vedolizumab. 
A total of approximately 38 evaluable patients will be enrolled in this study from approximately 
10 to 15 study centers in the United States and Europe. Enrollment is defined as when patients are 
assigned their first dose of study drug in the interactive voice or web response technology (IRT) 
system.
6.3
Duration of Study
6.3.1
Duration of an Individual Patient’s Study Participation
Patients may receive vedolizumab unless they experience relapse of the underlying malignancy. 
Patients will discontinue treatment if they have an unacceptable vedolizumab-related toxicity.
All patients will receive 5 doses of vedolizumab IV (a single dose on each of Days 1, 15, 43, 71, 
and 99); however, some patients who respond to and tolerate vedolizumab and who develop 
recurrent symptoms of intestinal GvHD following discontinuation of therapy (ie, after the fifth 
dose) may enter an extension phase where they may receive 300 mg vedolizumab IV every 
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2 weeks for 2 doses followed by Q4W for up to 1 year from the first dose of study drug (see 
Section 6.1). 
Patients may receive drug beyond 1 year with the agreement of the investigator and the sponsor if, 
in the opinion of the investigator, the patient is benefitting from treatment. All patients will be 
followed for OS every 3 months until death, withdrawal of consent, termination of the study by the 
sponsor, or for a maximum of 1 year after the last patient is enrolled in the study. Additionally, 
patients will be required to participate in an LTFU safety survey 6 months after the last dose of 
study drug.
6.3.2
End of Study/Study Completion Definition and Planned Reporting
The final analyses for the primary endpoint and clinical study report will be conducted following 
the end of the study. The estimated timeframe for study completion (first patient in to last patient
last visit) is approximately 36 months.
6.3.3
Timeframes for Primary and Secondary Endpoints to Support Disclosures
Please refer to Table 6.a for disclosures information for all primary and secondary endpoints.
Table 6.a
Primary and Secondary Endpoints for Disclosures
Endpoint
Maximum Time Frame
Primary: 

The proportion of subjects with overall response (PR+VGPR+CR) at Day 28.
Up to 28 days

The number and percentage of patients who experience SAEs from administration of 
the first dose of vedolizumab IV through Day 28.
Up to 28 days
Secondary: 

The proportion of subjects who have died in the absence of primary malignancy 
relapse after allo-HSCT at 6 months.
Up to 6 months

The proportion of subjects with CR at Day 28.
Up to 28 days

The proportion of subjects with intestinal overall response at Day 28.
Up to 28 days

OS at 6 and 12 months.
Up to 1 year

The proportion of subjects alive without GvHD or relapse of primary malignancy at 
6 and 12 months.
Up to 12 months

The number and percentage of patients who experience TEAEs from administration 
of the first dose of vedolizumab IV through 18 weeks after administration of the last 
dose of vedolizumab IV.
Up to 32 weeks

The number and percentage of patients who experience SAEs from administration of 
the first dose of vedolizumab IV through 18 weeks after administration of the last 
dose of vedolizumab IV.
Up to 32 weeks

Mean serum concentrations of vedolizumab before dosing (Ctrough) on Day 99.
Up to 14 weeks

The total dose of steroids administered (mg/kg/day of methylprednisolone or 
equivalent) from the start of the first IV infusion of vedolizumab through both 6 and 
12 months.
Up to 12 months


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6.3.4
Total Study Duration
It is anticipated that this study will last for approximately 36 months.


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7.0
STUDY POPULATION
7.1
Inclusion Criteria
Each patient must meet all the following inclusion criteria to be enrolled in the study:
1. Male or female patients aged 18 years or older.
2. Recipient of 1 allo-HSCT but not more than 1 allo-HSCT.
3. Patients with primary steroid-refractory GvHD. Steroid-refractory disease is defined as 
worsening or no improvement in 5 to 7 days of treatment with methylprednisolone 2 mg/kg or 
equivalent or lack of a CR after 14 days of primary treatment with methylprednisolone 2 mg/kg 
or equivalent. Note that patients who develop intestinal GvHD while receiving systemic 
therapy for other GvHD are still eligible after 5 to 7 days, even if the intestinal GvHD has not 
been present for the entire duration. Patients who may have received an increase in their steroid 
dose treatment (eg, increased methylprednisolone from 1 mg/kg to 2 mg/kg) before enrollment 
will be eligible, provided the patient has met the definition of steroid refractory above. Patients 
who develop toxicity on corticosteroids or who are otherwise medically unable to be dosed to 
this level, will also be eligible.
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 3 (refer to Appendix 
E). 
5. Acute GvHD with intestinal disease involvement with a severity index of B, C, or D using the 
Blood and Marrow Transplant Clinical Trials Network (BMT CTN)-modified International 
Bone Marrow Transplant Registry Database (IBMTR) index (See Appendix F). Note that 
other organ involvement from acute GvHD is also allowed.
6. Evidence of myeloid engraftment defined by absolute neutrophil count ≥0.5×109/L on 
3 consecutive days.
7. This inclusion criterion is deleted in amendment 02. 
8. Sufficient cognitive ability to reliably complete the PML checklist at Baseline.
9. Female patients who:

Are postmenopausal for at least 1 year before the Screening visit, OR

Are surgically sterile, OR

If they are of childbearing potential, agree to practice one highly effective method of 
contraception and one additional effective (barrier) method at the same time, from the time 
of signing the informed consent through 18 weeks after the last dose of study drug, or

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle 
of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.)


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Male patients, even if surgically sterilized (ie, status postvasectomy), who:

Agree to practice effective barrier contraception during the entire study treatment period 
and through 18 weeks after the last dose of study drug, or

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle 
of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.)
10. Voluntary written consent must be given before 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.
11. Suitable venous access for the study-required blood sampling, including PK and biomarker 
sampling. Patients with a planned central venous access device will be allowed.
7.2
Exclusion Criteria
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
1. Presence of chronic GvHD at Screening (including acute-chronic overlap syndrome).
2. Relapsed disease after allo-HSCT.
3. Patients with hyperacute GvHD defined as onset of GvHD within the first 15 days following 
hematopoietic stem cell infusion.
4. Received systemic agents other than corticosteroids for treatment of acute GvHD. GvHD 
prophylaxis agents (eg, calcineurin inhibitors) may be continued.
5. This exclusion criterion is deleted in amendment 02. 
6. Patients with a positive PML subjective checklist must be evaluated by a neurologist for 
possible PML before enrollment (see Section 10.7). Patients will be excluded if PML cannot 
be ruled out.
7. Evidence of encephalopathy at Screening.
8. Evidence of severe hepatic veno-occlusive disease/sinusoidal obstruction syndrome.
9. Life expectancy of <3 weeks.
10. History of any major neurological disorders, including multiple sclerosis or neurodegenerative 
disease. Patients with a history of stroke or brain tumor within the past 3 years are also 
excluded.
11. Patients with active cytomegalovirus (CMV) colitis (see Section 8.5.3).
12. The patient has chronic hepatitis B (HBV) or hepatitis C (HCV) infection indicated by testing 
for positive HBV surface antigen, and/or HCV RNA.


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13. Any identified congenital or acquired immunodeficiency (eg, common variable 
immunodeficiency, human immunodeficiency virus [HIV] infection, organ transplantation).
14. Positive Clostridium difficile toxin test on a stool sample or evidence of other intestinal 
pathogens (eg, adenovirus) during Screening.
15. Evidence of uncontrolled active systemic infection.
16. Any serious medical or psychiatric condition that could, in the investigator’s or medical 
monitor’s opinion, potentially interfere with the completion of treatment according to this 
protocol.
17. Any unstable or uncontrolled cardiovascular, pulmonary, hepatic, renal, GI, genitourinary, 
hematological, coagulation, immunological, endocrine/metabolic, neurologic, or other 
medical disorder that, in the opinion of the investigator or medical monitor, would confound 
the study results or compromise patient safety.
18. History of hypersensitivity or allergies to vedolizumab or its components.
19. If female, the patient is pregnant or lactating or intending to become pregnant before, during, 
or within 18 weeks after participating in this study; or intending to donate ova during such time 
period.
20. If male, the patient intends to donate sperm during the course of this study or for 18 weeks 
thereafter.


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8.0
STUDY DRUG
8.1
Study Drug Administration
All protocol-specific criteria for administration of study drug must be met and documented before
drug administration. Study drug will be administered only to eligible patients under the 
supervision of the investigator or identified subinvestigator(s).
The study sites will be supplied by the sponsor with the following medication in an open-label 
manner: vedolizumab IV 300 mg/vial, for single use, in 20 mL vials. The study medication will be 
provided in a glass vial as a lyophilized solid formulation for reconstitution using sterile water for 
injection. Each vial will be packaged in an appropriately labeled single vial carton. 
Each carton will have a single-panel or multi-language booklet label that will contain, but will not 
be limited to, the following: sponsor’s name and address, protocol number, packaging job/lot 
number, name and strength of the product, medication identification number, patient information, 
caution statement, directions for use, and storage conditions.
All infusions will be administered IV over approximately 30 minutes. Longer infusion times of up 
to 60 minutes may be used based on study observations. Subjects should be observed for 2 hours 
following the first 2 infusions, at a minimum, and 1 hour after each subsequent infusion in a room 
where appropriate treatment for infusion-related reactions is available. The subject should be 
considered clinically stable by the investigator or designee prior to discharge.
Additional reference information and administration instructions can be found in the Pharmacy 
Manual. 
8.2
Excluded Concomitant Medications and Procedures
All prescription and over-the-counter medications, including influenza vaccines, taken by a patient 
as of the first study drug administration through 18 weeks from the last dose will be recorded on 
the designated electronic case report form (eCRF). Patients must be instructed not to take any 
medications, including over-the-counter medications and herbal supplements, without first 
consulting with the investigator.
The following medications and procedures are prohibited during the study:

Any investigational agent other than vedolizumab.

Any additional systemic agent other than vedolizumab or corticosteroids for the treatment of 
acute GvHD. GvHD prophylaxis agents (eg, calcineurin inhibitors) may be continued. 

Approved or investigational biological agents for the treatment of other conditions (eg, 
rheumatoid arthritis), other than localized injections (eg, intra-ocular injections for wet 
macular degeneration).


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8.3
Permitted Concomitant Medications and Procedures
Other medications considered necessary for the safety and wellbeing of the patient may be 
administered at the discretion of the investigator. Any concomitant medications added or 
discontinued during the study should be recorded on the eCRF.
8.4
Precautions and Restrictions
8.4.1
Criteria for Dosing on Days 15, 43, 71, and 99
After receiving the first dose of vedolizumab IV on Day 1, patients may not receive the second, 
third, fourth, and/or fifth dose on Days 15, 43, 71, and 99 if they meet any of the following criteria:
1. The patient has a positive PML subjective checklist before the administration of study drug.
2. The patient has suspected CMV colitis. If suspected, endoscopic biopsy is required to rule out 
CMV colitis before the next dose.
3. The patient has a positive Clostridium difficile test on a stool sample or evidence of other 
intestinal pathogens (eg, adenovirus).
4. The patient experienced an anaphylactic reaction to vedolizumab.
Patients may continue to receive vedolizumab IV after these criteria have been resolved (refer to 
Section 8.5).
8.4.2
Reproductive Effects
It is not known what effects vedolizumab has on human pregnancy or development of the embryo 
or fetus. Therefore, female patients participating in this study should avoid becoming pregnant, 
and male patients should avoid impregnating a female partner. Nonsterilized female patients in the 
reproductive age group and male patients should use effective methods of contraception through 
defined periods during and after study treatment as specified in the following.
Female patients must meet 1 of the following:

Postmenopausal for at least 1 year before the Screening visit, or

Surgically sterile, or

If they are of childbearing potential, agree to practice 2 effective methods of contraception 
from the time of signing of the informed consent form (ICF) through 18 weeks after the last 
dose of study drug, or

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.)
Male patients, even if surgically sterilized (ie, status postvasectomy) must agree to 1 of the 
following:


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
Practice effective barrier contraception during the entire study treatment period and through 
18 weeks after the last dose of study drug, or

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.)
8.5
Management of Clinical Events
8.5.1
Hypersensitivity Reactions
Currently, there is no evidence to support the routine prophylactic administration of premedication 
(eg, antihistamines, corticosteroids) to patients receiving vedolizumab; hence, such 
premedications are unlikely to be necessary or beneficial. At the discretion of the investigator, 
however, patients may be administered premedication before any study drug administration. 
Vedolizumab should be administered by a health care professional prepared to manage 
hypersensitivity reactions, including anaphylaxis, if they occur. Appropriate monitoring and 
medical support measures should be available for immediate use. Patients should be observed 
during the infusion and until the infusion is complete.
Patients should be instructed to report the development of rash, hives, pruritus, flushing, urticaria, 
etc that may represent an infusion-related reaction to study medication. If signs or symptoms of 
infusion-related reaction are observed during the administration of study drug, it should be 
immediately discontinued and the patient treated as medically appropriate. In the case of a mild 
reaction, study drug administration may be reinitiated (with appropriate premedication) at the 
discretion of the investigator. Patients with severe or serious infusion-related reactions (eg, stridor, 
angioedema, life-threatening change in vital signs) must be withdrawn from the study.
In all cases of administration-related reaction, the medical monitor must be informed as soon as 
practical. The disposition of patients with less severe infusion-related reactions should be 
discussed with the medical monitor.
8.5.2
Leukopenia or Lymphopenia
Leukocyte and lymphocyte counts will be monitored for all patients with a hematological panel 
(see Section 9.4.14). Blood samples for analysis of hematological parameters will be obtained as 
specified in the Schedule of Events (Appendix A).
8.5.3
CMV Colitis
Regular assessments will include symptom-directed assessment for GI toxicity and weekly 
polymerase chain reaction (PCR) monitoring for CMV reactivation. Preemptive CMV therapy 
will be initiated per institutional standards for patients with CMV titers ≥500 copies/mL and rising 
on serial PCR. Subjects with active CMV colitis during Screening will be excluded from the study, 
and subjects with confirmed CMV colitis during the study will require dosing hold. In patients 


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with suspected CMV colitis, the subject will require endoscopy and histologic analyses of 
intestinal biopsy specimens before any additional dosing with vedolizumab.
8.5.4
Malignancy
All cases of malignancies that are detected during the study, including relapse of primary disease, 
will be reported as AEs.
8.5.5
Other Clinical Events
All patients will be screened for new neurological signs and symptoms potentially consistent with 
PML using the PML subjective symptom checklist (see Section 9.4.8) before dosing with 
vedolizumab. Any patients reporting signs or symptoms of PML will undergo objective testing. If 
a patient demonstrates a neurologic deficit related to PML upon administration of the specific 
test(s) on the objective checklist, no further doses of vedolizumab should be administered to that 
patient. The patient should be referred to the study neurologist for further testing, and the sponsor 
must be notified of this action.
Subsequent doses of study drug will be administered only if the possibility of PML is definitively 
excluded, as described in the RAMP algorithm.
8.6
Dose Modification or Treatment Delay for Vedolizumab-Related Toxicity
Dosing of vedolizumab should be withheld for Grade 3 or higher vedolizumab-related toxicities. 
See Section 8.5 for management of vedolizumab dosing for specific clinical events. The medical 
monitor should be contacted before any vedolizumab dose modification for any patient in the 
study.
8.7
Blinding and Unblinding
This is an open-label study. Patients will be randomized at a ratio of 1:1 to 2 treatment arms to 
receive either 300 or 600 mg vedolizumab IV on Days 1, 15, 43, 71, and 99. The investigator or 
investigator’s designee will access the IRT system at Screening to obtain the subject study number. 
The investigator or the investigator’s designee will use the IRT to randomize the subject into the 
study. During this contact, the investigator or designee will provide the necessary 
subject-identifying information, including the subject number assigned at Screening. The 
medication identification (ID) number of the investigational drug to be dispensed will then be 
provided by the IRT. If sponsor-supplied drug is lost or damaged, the site can request a 
replacement from IRT. Refer to the IRT manual provided separately. At subsequent 
drug-dispensing visits, the investigator or designee will again contact the IRT to request additional 
investigational drug for a subject. The medication ID number of the investigational drug to be 
dispensed will be provided by the IRT.
8.8
Description of Investigational Agent
Vedolizumab IV drug product is a sterile lyophilized solid formulation provided in a single vial, 
where each vial nominally contains 300 mg of vedolizumab antibody. Reconstituted 


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vedolizumab IV drug product contains 60 mg/mL of active vedolizumab antibody, 50 mM 
histidine/histidine HCl, 125 mM arginine HCl, 100 mg/mL sucrose, and 0.6 mg/mL 
polysorbate 80, with a pH of 6.3.
Each vial will be reconstituted with sterile water for injection according to the instructions in the 
Pharmacy Manual.
8.9
Preparation, Reconstitution, and Dispensation
The investigational pharmacist will prepare the study treatment under standard aseptic conditions. 
For preparation of the active vedolizumab treatment, each vial of vedolizumab will be 
reconstituted according to the Pharmacy Manual with 4.8 mL of sterile water for injection. For the 
300 mg dose, 5.0 mL will be removed from each vial and diluted into 0.9% sodium chloride to an 
approximate volume of 250 mL. For the 600 mg dose, 5.0 mL will be removed from each of 2 vials 
and diluted into 0.9% sodium chloride to an approximate volume of 250 mL. Additional details on 
the preparation of vedolizumab are provided in the Pharmacy Manual.
Because vedolizumab is a biological protein and, therefore, subject to denaturation upon shaking, 
reconstituted vials and IV solution bags should not be shaken. Vials are for single-use 
administration.
Parenteral drug products should be inspected visually for particulate matter and discoloration 
before administration, whenever solution and container permit.
8.10
Packaging and Labeling
Vedolizumab IV will be supplied in single-use, 20 mL vials. The injection vials will be packaged 
into individual kits containing one 20 mL vial of active vedolizumab. Both the primary and 
secondary label information will fulfill all requirements specified by local governing regulations. 
Additional details are provided in the Pharmacy Manual.
8.11
Storage, Handling, and Accountability
Investigational drug must be kept in an appropriate, limited-access, secure place until it is used or 
returned to the sponsor or designee for destruction. Investigational drug must be stored under the 
conditions specified on the label, and remain in the original container until dispensed.
Vedolizumab IV must be stored at 2C to 8C (36F-46F). A daily temperature log of the drug 
storage area must be maintained every working day. 
8.12
Other Protocol-Specified Materials
The following supplies will also be required for study treatment administration and are to be 
provided by the clinical study center:

Bottled sterile water for injection (for vedolizumab reconstitution).

250 mL 0.9% sodium chloride for injection in polyvinyl chloride (PVC) IV bag(s) or 250 mL 
0.9% sodium chloride in alternative IV bags or bottles listed in the Pharmacy Manual.


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
PVC infusion line or alternative infusion line listed in the Pharmacy Manual.


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9.0
STUDY CONDUCT
This trial will be conducted in compliance with the protocol, Good Clinical Practice (GCP), 
applicable regulatory requirements, and International Conference on Harmonisation (ICH) 
guidelines.
9.1
Study Personnel and Organizations
The contact information for the medical monitor for this study, the central laboratory and any 
additional clinical laboratories, the coordinating investigator for each member state/country, the 
IRT provider, and the contract research organization (CRO) team may be found in the Study 
Manual. A full list of investigators is available in the sponsor’s investigator database.
9.2
Arrangements for Recruitment of Patients
Recruitment and enrollment strategies for this study may include recruitment from the 
investigator’s local practice or referrals from other physicians. If advertisements become part of 
the recruitment strategy, they will be reviewed by the institutional review board (IRB)/
independent ethics committee (IEC). 
9.3
Treatment Group Assignments
Patients will be randomized at a ratio of 1:1 to 2 treatment arms to receive either 300 or 600 mg 
vedolizumab IV on Days 1, 15, 43, 71, and 99. The investigator or investigator’s designee will 
access the IRT system at Screening to obtain the subject study number (see Section 8.7). If a 
patient discontinues from study drug, the randomization code will not be reused, and the patient 
will not be allowed to re-enter the study. The sponsor may opt to replace patients who discontinue 
before Day 28 for reasons other than vedolizumab-related safety events.
9.4
Study Procedures
Refer to the Schedule of Events (Appendix A) for timing of assessments. Additional details are 
provided as necessary in the sections that follow. Evaluations during the Screening period are to be 
conducted within 28 days before administration of the first dose of study drug. Unless otherwise 
noted, evaluations during the Treatment period must occur before study drug administration. Tests 
and procedure should be performed on schedule for all visits. The timing of PK assessments is 
specified in the Pharmacokinetic Sample Breakdown table.
9.4.1
Informed Consent
Each patient must provide written informed consent before any study-required procedures are 
conducted, unless those procedures are performed as part of the patient’s standard care.
9.4.2
Patient Demographics
The date of birth or age, race (where allowed), ethnicity, and sex of the patient are to be recorded 
during Screening.


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9.4.3
Medical History
During the Screening period, a complete medical history will be compiled for each patient. The 
history will include the background of the patient’s malignancy and prior therapies for it, and the 
background of the patient’s transplant and post-transplant course. In addition, concomitant 
medications will be recorded as specified in Section 9.4.10.
9.4.4
Physical Examination
Physical examinations will be completed per standard of care at the times specified in the Schedule 
of Events (Appendix A).
9.4.5
Neurological Examination
A neurological examination, including assessments of cranial nerves, motor and sensory function, 
coordination, and mental status, will be performed at the time points specified in the Schedule of 
Events (Appendix A). Completed neurological forms will be stored by the sponsor and sent to the 
CRO. Clinically significant findings from the neurological examination will be recorded as 
medical history during Screening, and new clinically significant findings will be recorded as AEs 
after the first dose of study drug.
9.4.6
Patient Height and Weight
Height will be recorded only during Screening (within 28 days before the first dose of 
vedolizumab). Body weight will be recorded at the visits specified in the Schedule of Events 
(Appendix A).
9.4.7
Vital Signs
Vital signs, including heart rate, respiratory rate, systolic and diastolic blood pressure, and 
temperature, will be recorded at the visits specified in the Schedule of Events (Appendix A). On 
dosing days, vital signs will be obtained before and within 60 minutes of completion of the 
infusion.
9.4.8
PML Checklist
Clinic staff will administer the subjective PML checklist during Screening to exclude patients with 
positive responses from enrolling into the study. The subjective PML checklist will be 
administered (before dosing, if applicable) at the time points specified in the Schedule of Events 
(Appendix A) to probe for symptoms suggestive of PML. The checklist must be administered by 
appropriate clinic staff as it is not designed as a patient questionnaire. A patient who reports a new 
and persistent change(s) per the subjective checklist must have the corresponding objective test(s) 
administered and may be referred to a neurologist for a full evaluation, as described in the RAMP 
algorithm. The PML checklist and the RAMP algorithm and tools are included in the Study 
Manual. See Section 10.7 for additional details regarding the RAMP program.


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9.4.9
Pregnancy Test
A serum or urine pregnancy test will be performed for women of childbearing potential at 
Screening and within 4 days before the first dose of study drug. The results from these tests must 
be available and negative before the first dose of study drug is administered. 
9.4.10 ECOG Performance Status
The ECOG performance status (see Appendix E) will be assessed at the times specified in the 
Schedule of Events (Appendix A).
9.4.11 Concomitant Medications and Procedures
Medications used by the patient and therapeutic procedures completed by the patient will recorded 
in the eCRF from the first dose of study drug through 18 weeks after the last dose of study drug. 
See Section 8.2 and Section 8.3 for a list of medications and therapies that are prohibited and/or 
allowed during the study.
9.4.12 Adverse Events
Monitoring of AEs, serious and nonserious, will be conducted throughout the study as specified in 
the Schedule of Events (Appendix A). Refer to Section 10.0 for details regarding definitions, 
documentation, and reporting of pretreatment events (PTEs), AEs, and SAEs.
9.4.13 Enrollment
Enrollment is defined as when patients are assigned their first dose of study drug in the IRT 
system. Procedures for completion of the enrollment information are described in the Study 
Manual.
9.4.14 Clinical Laboratory Evaluations
Clinical laboratory evaluations will be performed locally. Results of hematology and clinical 
chemistry safety labs must be available and reviewed by the investigator before enrollment and 
administration of any study drug. Handling of clinical laboratory samples will be outlined in the 
Study Manual. Clinical laboratory evaluations will be performed as outlined below.
Blood samples for analysis of the clinical chemistry and hematological parameters shown in Table 
9.a and urine samples for analysis of the parameters shown in Table 9.b will be obtained as 
specified in the Schedule of Events (Appendix A). Hepatitis and human immunodeficiency virus 
testing are to be performed only at the Screening visit. 


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Table 9.a
Clinical Chemistry and Hematology Tests
Hematology
Serum Chemistry
Hematocrit
Hemoglobin
Leukocytes with differential
Neutrophils (absolute neutrophil 
count [ANC])
Platelet (count)
Albumin
Alkaline phosphatase (ALP)
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
Bilirubin (total)
Blood urea nitrogen (BUN) (a)
Calcium
Carbon dioxide (CO2)
Creatinine
Chloride
Gamma glutamyl transferase (GGT)
Glucose
Lactate dehydrogenase (LDH)
Magnesium
Phosphate
Potassium
Sodium
Urate
(a) Blood urea (in mmol/L)=BUN(in mg/dL)×0.357.
PCR monitoring for CMV reactivation will be performed on a weekly basis (see Section 8.5.3) per 
standard of care. Additionally, blood samples for measurement of anti-vedolizumab antibodies 
will be obtained as specified in the Schedule of Events (Appendix A).
Table 9.b
Clinical Urinalysis Tests
Urinalysis
Bilirubin
Glucose
Ketones
Leukocytes
Nitrite
Occult blood
pH
Protein
Specific gravity
Turbidity and color
Urobilinogen
9.4.15
Disease Assessment
Acute GvHD will be assessed as specified in the Schedule of Events (Appendix A) using the BMT 
CTN-modified IBMTR index for staging and grading acute GvHD (see Appendix F). All cases of 
malignancies that are detected during the study, including relapse of primary disease, will be 
reported as AEs (see Section 8.5.4). In addition, other measures such as stool volume, oral intake, 
and total parenteral nutrition requirement will be collected.
9.4.16
Endoscopy
Endoscopy (optional) will be performed as specified in the Schedule of Events (Appendix A) only 
for patients already planned for the procedure and will be read locally for efficacy analysis. Biopsy 
specimens, if available, will be collected for these patients for other histologic analyses, including 
changes in lymphocyte recruitment patterns.
Detailed instructions for handling and shipping samples are provided in the Laboratory Manual.


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9.4.17
PK Measurements
Blood samples (one 5 mL sample per scheduled time) for PK analysis of vedolizumab will be 
collected into red stopper vacutainers according to the Pharmacokinetic Sample Breakdown table. 
Note: if done via peripheral vein, PK samples should not be collected from the arm where the 
vedolizumab infusion was administered. All PK samples should be collected within 10% of 
nominal time; however, samples collected outside this margin will not be considered protocol 
deviations. Predose samples should be collected within 0.5 hours before the start of infusion and 
end of infusion samples should be collected at 30 ( 5 minutes, 1 hour ( 10 minutes; 2 hours ( 20 
minutes; 12 ( 2 hours; and 24 hours ( 60 minutes. The exact dates and times of administration of 
vedolizumab (start and end of infusion) and the exact dates and times of collection of all PK 
samples will be recorded on the appropriate eCRF. 
Detailed instructions for the handling and shipping of samples are provided in the Laboratory 
Manual.
9.4.18
9.4.19
9.4.20
9.4.21
Immunogenicity 
A blood sample will be taken to evaluate the presence of anti-vedolizumab antibodies in serum at 
the time points specified in the Schedule of Events (Appendix A). 
Detailed instructions for the handling and shipping of samples are provided in the Laboratory 
Manual.
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9.4.22
Fecal Microbiome Samples
9.5
Completion of Study Treatment (for Individual Patients)
Patients will be considered to have completed study treatment if they received all 5 intended doses 
of vedolizumab IV on Days 1, 15, 43, 71, and 99. In addition, patients will be considered to have 
completed study treatment if they discontinue study drug for any of the reasons outlined in Section 
9.7.
9.6
Completion of Study (for Individual Patients)
In addition to completion or discontinuation of study drug treatment, patients will be considered to 
have completed the study if they withdraw from the study for any of the reasons outlined in 
Section 9.8.
For all subjects receiving study medication, the investigator must complete the end-of-study 
(EOS) eCRF page.
9.7
Discontinuation of Treatment With Study Drug and Patient Replacement
Treatment with study drug may be discontinued for any of the following reasons:
!
AE.
!
Protocol deviation. 
!
Unsatisfactory therapeutic response.
!
Progression of underlying malignancy.
!
Study terminated by sponsor.
!
Withdrawal by subject.
!
Lost to follow-up.
!
Other.
The sponsor may opt to replace patients who discontinue before Day 28 for reasons other than 
those related to safety. Once study drug has been discontinued, all study procedures outlined for 
the ET visit will be completed as specified in the Schedule of Events (Appendix A). The primary 
reason for study drug discontinuation will be recorded on the eCRF.
9.8
Withdrawal of Patients From Study
A patient may be withdrawn from the study for any of the following reasons:
!
Lost to follow-up.
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
Study terminated by sponsor.

Withdrawal by subject.

Other.
The consequence of study withdrawal is that no new information will be collected from the 
withdrawn patient and added to the existing data or any database.
9.9
Study Compliance
Study drug will be administered or dispensed only to eligible patients under the supervision of the 
investigator or identified subinvestigator(s). The appropriate study personnel will maintain records 
of study drug receipt and dispensing.
9.10
Posttreatment Follow-up Assessments 
Patients will be followed for survival and assessment of symptoms of acute and chronic GvHD or 
relapse of primary malignancy during clinic visits at 4, 5, 6, 9, and 12 months or until the patient’s 
death or withdrawal of consent, or termination of the study by the sponsor. Patients who complete 
the study will attend a 12-month follow-up visit (EOS).
All patients will be followed for OS every 3 months after the 12 month follow-up visit, until death, 
withdrawal of consent, termination of study by the sponsor, or for a maximum of 1 year after the 
last patient is enrolled in the study. In addition, the start of another systemic therapy for treatment 
of GvHD or for the primary malignancy will be collected. The EOS visit is to be completed when 
the patient discontinues from the follow-up period. Additionally, patients will be required to 
participate in an LTFU safety survey 6 months after the last dose of study drug. See the Schedule 
of Events (Appendix A) for appropriate assessments during follow-up.
NOTE: Related SAEs must be reported to the Global Pharmacovigilance department or designee. 
This includes deaths that the investigator considers related to study drug that occur during the 
posttreatment follow-up. Refer to Section 10.0 for details regarding definitions, documentation, 
and reporting of SAEs.


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10.0
ADVERSE EVENTS
10.1
Definitions
10.1.1 PTE Definition
A PTE is any untoward medical occurrence in a patient or subject who has signed informed 
consent to participate in a study but before administration of any study medication; it does not 
necessarily have to have a causal relationship with study participation.
10.1.2 AE Definition
AE means any untoward medical occurrence in a patient or subject administered a pharmaceutical 
product; the untoward medical occurrence does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product whether or not it is related to the medicinal product. This includes any 
newly occurring event, or a previous condition that has increased in severity or frequency since the 
administration of study drug.
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is considered 
by the investigator to be a clinically significant change from baseline.
10.1.3 SAE Definition
SAE means any untoward medical occurrence that at any dose:

Results in death.

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).

Requires inpatient hospitalization or prolongation of an existing hospitalization (see 
clarification in the paragraph in Section 10.2 on planned hospitalizations).

Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions).

Is a congenital anomaly/birth defect.

Is a medically important event. 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 1 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 


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development of drug dependency or drug abuse; any organism, virus, or infectious particle 
(eg, prion protein transmitting transmissible spongiform encephalopathy), pathogenic or 
nonpathogenic, is considered an infectious agent.
In this study, intensity for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE, version 4.03, effective date 14 June 2010 [38]. Clarification should be made 
between an SAE and an AE that is considered severe in intensity (Grade 3 or 4), because the terms 
serious and severe are NOT synonymous. The general term severe is often used to describe the 
intensity (severity) of a specific event; the event itself, however, may be of relatively minor 
medical significance (such as a Grade 3 headache). This is NOT the same as serious, which is 
based on patient/event outcome or action criteria described above, and is usually associated with 
events that pose a threat to a patient’s life or ability to function. A severe AE (Grade 3 or 4) does 
not necessarily need to be considered serious. For example, a white blood cell count of 1000/mm3
to less than 2000 is considered Grade 3 (severe) but may not be considered serious. Seriousness 
(not intensity) serves as a guide for defining regulatory reporting obligations.
10.2
Procedures for Recording and Reporting AEs and SAEs
All AEs 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 will be 
recorded on the appropriate page of the eCRF (see Section 10.3 for the period of observation). Any 
clinically relevant deterioration in laboratory assessments or other clinical finding is considered an 
AE. When possible, signs and symptoms indicating a common underlying pathology should be 
noted as 1 comprehensive event.
Regardless of causality, SAEs and serious PTEs (as defined in Section 10.1) must be reported (see 
Section 10.3 for the period of observation) by the investigator to the Takeda Global 
Pharmacovigilance department or designee (contact information provided below). This should be 
done by faxing the SAE Form within 24 hours after becoming aware of the event. The SAE Form, 
created specifically by Takeda, will be provided to each clinical study site. A sample of the SAE 
Form may be found in the Study Manual. Follow-up information on the SAE or serious PTE may 
be requested by Takeda. SAE report information must be consistent with the data provided on the 
eCRF.
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Planned hospital admissions or surgical procedures for an illness or disease that existed before the 
patient was enrolled in the trial are not to be considered AEs unless the condition deteriorated in an 
unexpected manner during the trial (eg, surgery was performed earlier or later than planned).
For both serious and nonserious AEs, the investigator must determine both the severity (toxicity 
grade) of the event and the relationship of the event to study drug administration. For serious 
pretreatment events, the investigator must determine both the severity (toxicity grade) of the event 
and the causality of the event in relation to study procedures.
Severity (toxicity grade) for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE, version 4.03, effective date 14 June 2010 [38]. The criteria are provided in the Study 
Manual.
Relationship of the event to study drug administration (ie, its causality) will be determined by the 
investigator responding yes (related) or no (unrelated) to this question: “Is there a reasonable 
possibility that the AE is associated with the study drug?”
10.3
Monitoring of AEs and Period of Observation
AEs, both nonserious and serious, will be monitored throughout the study as follows:

AEs will be reported from the first dose of study drug through 18 weeks after administration of 
the last dose of study drug and recorded in the eCRFs.

Serious PTEs will be reported to the Takeda Global Pharmacovigilance department or 
designee from the time of the signing of the ICF up to the first dose of study drug, but will not 
be recorded in the eCRF.

Related and unrelated SAEs will be reported to the Takeda Global Pharmacovigilance 
department or designee from the first dose of study drug through 18 weeks after administration 
of the last dose of study drug and recorded in the eCRF. After this period, only related SAEs 
must be reported to the Takeda Global Pharmacovigilance department or designee. SAEs 
should be monitored until they are resolved or are clearly determined to be due to a patient’s 
stable or chronic condition or intercurrent illness(es).
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events
If a woman becomes pregnant or suspects that she is pregnant while participating in this study, she 
must inform the investigator immediately and permanently discontinue study drug. The sponsor 
must also be contacted immediately by faxing a completed Pregnancy Form to the Takeda Global 
Pharmacovigilance department or designee (see Section 10.2). The pregnancy must be followed 
for the final pregnancy outcome.
If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, the sponsor must also be contacted immediately by faxing a completed Pregnancy Form 
to the Takeda Global Pharmacovigilance department or designee (see Section 10.2). Every effort 
should be made to follow the pregnancy for the final pregnancy outcome.


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10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose)
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 report this via the phone 
numbers or email addresses provided below.
A medication error is a preventable event that involves an identifiable patient and that leads to 
inappropriate medication use, which may result in patient harm. Whereas overdoses and 
underdoses constitute medication errors, doses missed inadvertently by a patient do not. 
Individuals who identify a potential medication error (including overdose) situation should 
immediately report this via the phone numbers or email addresses provided below.
Call center
Phone number
E-mail
Fax
DLSS
Product complaints in and of themselves are not AEs. If a product complaint results in an SAE, an 
SAE form should be completed and sent to 
 (refer to Section 10.2).
10.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, including the European 
Medicines Agency, investigators and IRBs or IECs, as applicable, in accordance with national 
regulations in the countries where the study is conducted. Relative to the first awareness of the 
event by/or further provision to the sponsor or sponsor’s designee, SUSARs will be submitted to 
the regulatory authorities as an expedited report within 7 days for fatal and life-threatening events 
and 15 days for other serious events, unless otherwise required by national regulations. The 
sponsor will also prepare an expedited report for other safety issues where these might materially 
alter the current benefit-risk assessment of an investigational medicinal product or that would be 
sufficient to consider changes in the investigational medicinal product’s administration or in the 
overall conduct of the trial. The investigational site also will forward a copy of all expedited 
reports to his or her IRB or IEC in accordance with national regulations.
10.7
Risk Minimization Action Plan for PML (RAMP Program)
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11.0
STUDY-SPECIFIC COMMITTEES
No steering committee, data safety monitoring committee, or clinical endpoint committee will be 
used in this study. Review of patient safety throughout the study will occur during regular 
meetings between the sponsor and investigators. 
An IAC has been identified as part of the RAMP program to review new neurological signs and 
symptoms potentially consistent with PML, and will provide input regarding subject evaluation 
and management as defined in the IAC charter.


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12.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
If selected for coding, AEs, PTEs, medical history, and concurrent conditions will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the 
World Health Organization (WHO) Drug Dictionary.
12.1
eCRFs 
Completed eCRFs are required for each subject who receives study drug.
The sponsor or its designee will supply investigative sites with access to eCRFs and will make 
arrangements to train appropriate site staff in the use of the eCRF. These forms are used to transmit 
the information collected in the performance of this study to the sponsor, CRO partners, and 
regulatory authorities. Investigative sites must complete eCRFs in English.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site.
Any change of, modification of, or addition to the data on the eCRFs should be made by the 
investigator or appropriate site personnel. Corrections to eCRFs are recorded in an audit trail that 
captures the old information, the new information, identification of the person making the 
correction, the date the correction was made, and the reason for change.
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the principal investigator must retain 
full responsibility for the accuracy and authenticity of all data entered on the eCRFs.
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed eCRFs 
are the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor.
12.2
Record Retention
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated ICFs, subject authorization forms regarding the use of 
personal health information (if separate from the ICFs forms), electronic copy of eCRFs, including 
the audit trail, and detailed records of drug disposition to enable evaluations or audits from 
regulatory authorities, the sponsor or its designees. Any source documentation printed on 
degradable thermal sensitive paper should be photocopied by the site and filed with the original in 
the subject’s chart to ensure long term legibility. Furthermore, ICH E6 Section 4.9.5 requires the 
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after the last approval of a marketing application for a specified drug indication being investigated 
or, if an application is not approved, until at least 2 years after the investigation is discontinued and 
regulatory authorities are notified. In addition, ICH E6 Section 4.9.5 states that the study records 
should be retained until an amount of time specified by applicable regulatory requirements or for a 
time specified in the Clinical Study Site Agreement between the investigator and sponsor.
Refer to the Clinical Study Site Agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of any 
such documents.


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13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized before database lock. This 
document will provide further details regarding the definition of analysis variables and analysis 
methodology to address all study objectives.
A targeted data review will be conducted before database lock. This review will assess the 
accuracy and completeness of the study database, patient evaluability, and appropriateness of the 
planned statistical methods.
13.1.1 Analysis Sets
The populations used for analysis will include the following:

Safety population: The population of patients evaluable for vedolizumab safety is defined as 
all patients who receive any amount of study drug.

Efficacy population: Defined as all patients from the safety set who have completed their Day 
28 assessment.

Per-protocol population: Defined as all patients from the efficacy set who do not violate the 
terms of the protocol in a way that would affect the study outcome significantly, as determined 
by the medical monitor.

PK population: Defined as patients from the safety set with at least 1 postdose PK sample 
collected. 

Biomarker population: Defined as patients from the safety set with at least 1 biomarker sample 
collected.
13.1.2 Procedures for Handling Missing, Unused, and Spurious Data
All available safety, tolerability, efficacy, PK, and biomarker data will be included in data listings 
and tabulations. No imputation of values for missing data will be performed. The relevance of 
missing sample data will be assessed. 
Data that are potentially spurious or erroneous will be examined according to standard data 
management operating procedures.
13.1.3 Analysis of Demographics and Other Baseline Characteristics
Demographic (age, sex, and other parameters as appropriate) and baseline characteristics (weight, 
height, and other parameters, as appropriate) will be summarized by dose level.
13.1.4 Efficacy Analysis
The primary efficacy endpoint is the proportion of subjects with overall response 
(PR+VGPR+CR) in GvHD at Day 28.


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Secondary efficacy endpoints include:
!
The proportion of subjects who have died in the absence of primary malignancy relapse after 
allo-HSCT at 6 months.
!
The proportion of subjects with acute GvHD CR at Day 28.
!
The proportion of subjects with intestinal overall response at Day 28. Symptoms of acute 
intestinal GvHD will be measured using the BMT CTN-modified IBMTR index (See 
Appendix F). 
!
OS at 6 and 12 months.
!
The proportion of subjects alive without GvHD or relapse of primary malignancy at 6 and 
12 months.
!
The total dose of steroids administered (mg/kg/day of methylprednisolone or equivalent) from 
the start of the first IV infusion of vedolizumab through both 6 and 12 months.
Safety, PK, and efficacy data will be used in decision making. For efficacy evaluation, a Bayesian 
statistical approach will be used where posterior probability that PR+VGPR+CR rate is at least 
70% will be derived from this distribution. If this probability is at least 75% (“75% level of proof 
at 70%”), this will be considered a positive proof-of-concept in efficacy. Efficacy signals will be 
evaluated using the initial cohorts and will be updated using the expansion cohort. A flat 
noninformative prior probability distribution will be assumed in the Bayesian analysis.
In addition, patients will be followed for OS. OS is defined as the time from the date of enrollment 
to the date of death. Patients without documentation of death at the time of analysis will be 
censored at the date last known to be alive.
13.1.5 Resource Utilization and Patient-Reported Outcome Analysis
13.1.6 PK Analysis
Concentrations of vedolizumab will be summarized by dose level and by nominal time using 
descriptive statistics. Individual concentration∃time profiles will be presented in data listings. PK 
parameters will be derived using standard noncompartmental methods. PK parameters of 
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vedolizumab will be summarized using descriptive statistics. Other PK parameters may be 
calculated if necessary.
PK parameters will be summarized by dose level. A detailed plan will be provided in the SAP.
13.1.7 Biomarker Analysis 
13.1.8 Immunogenicity Analyses 
Immunogenicity (anti-vedolizumab antibodies [AVA]) will be descriptively summarized. The 
effect of anti-vedolizumab antibodies on safety and efficacy will be explored. The proportion of 
subjects with positive AVA (transient and persistent) and proportion of subjects with positive 
neutralizing AVA during the study will be summarized at each visit. Further information about the 
immunogenicity analyses will be provided in the SAP.
13.1.9 Safety Analysis
Safety will be evaluated by the incidence of AEs, severity and type of AEs, and by changes from 
baseline in the patient’s vital signs, weight, and clinical laboratory results using the safety analysis 
set. Exposure to study drug will be summarized, and reasons for discontinuation will be tabulated. 
Safety will be summarized by dose level. 
TEAEs will be tabulated. Treatment-emergent is defined as any AE that occurs after 
administration of the first dose of study drug and up through 18 weeks after the last dose of study 
medication.
AEs will be tabulated according to MedDRA by SOC, high-level terms, and preferred terms and 
will include the following categories:
!
TEAEs.
!
Drug-related TEAEs.
!
Grade 3 TEAEs.
!
Grade 4 TEAEs.
!
Grade 5 TEAEs.
!
Grade 3 or higher drug-related TEAEs.
!
The most commonly reported TEAEs.
!
SAEs.
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Listings of PML checklist data and TEAEs resulting in study drug discontinuation will be 
provided.
Descriptive statistics for the actual values of clinical laboratory parameters (and/or change from 
baseline in clinical laboratory parameters) will be presented for all scheduled measurements over 
time. Mean laboratory values over time will be plotted for key laboratory parameters. Descriptive 
statistics for the actual values (and/or the change from baseline) of vital signs, weight, and blood 
pressure time will be tabulated by scheduled time point.
Shift tables for laboratory parameters will be generated based on changes in NCI CTCAE grade 
from baseline to the worst postbaseline value. 
Concomitant medications will be coded using the WHO Drug Dictionary. The number and 
percentage of patients taking concomitant medications will be tabulated by WHO drug generic 
term in the safety analysis set. In addition, the number and percentage of patients receiving blood 
transfusions will be tabulated in the safety analysis set.
13.2
Interim Analysis
There will be 1 interim analysis when all patients in the dose finding phase have reached Day 28.
13.3
Determination of Sample Size
Approximately 38 evaluable patients will be enrolled to identify an active and tolerable 
vedolizumab dose level with sufficient PK sampling to determine the PK parameters in this patient 
population. Sample size determination is mainly based on clinical considerations and on the 
primary objective of determining a recommended dose and regimen and to describe the initial 
activity, tolerability, safety, and activity of vedolizumab IV administered for the treatment of 
primary steroid-refractory acute intestinal GvHD.


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14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or its 
designee (CRO) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or designee 
(as long as blinding is not jeopardized), including but not limited to the Investigator’s Binder, 
study medication, subject medical records, informed consent documentation, documentation of 
subject authorization to use personal health information (if separate from the ICFs), and review of 
eCRFs and associated source documents. It is important that the investigator and other study 
personnel are available during the monitoring visits and that sufficient time is devoted to the 
process.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
The site should document all protocol deviations in the subject’s source documents. In the event of 
a significant deviation, the site should notify the sponsor or its designee (and IRB or EC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of primary study 
assessment. A Protocol Deviation Form should be completed by the site and signed by the sponsor 
or designee for any significant deviation from the protocol.
14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the US Food and Drug Administration [FDA], the United 
Kingdom Medicines and Healthcare products Regulatory Agency, the Pharmaceuticals and 
Medical Devices Agency of Japan). If the study site is contacted for an inspection by a regulatory 
body, the sponsor should be notified immediately. The investigator and institution guarantee 
access for quality assurance auditors to all study documents as described in Section 14.1.


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15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the Responsibilities of the Investigator listed in Appendix B. The 
principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities.
15.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable state and federal/local requirements 
of each participating region. The sponsor or designee will require documentation noting all names 
and titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC 
has direct participation in this study, written notification regarding his or her abstinence from 
voting must also be obtained. Those American sites unwilling to provide names and titles of all 
members due to privacy and conflict of interest concerns should instead provide a Federal Wide 
Assurance Number or comparable number assigned by the Department of Health and Human 
Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the IB, a copy of the ICF, and, if 
applicable, subject recruitment materials and/or advertisements and other documents required by 
all applicable laws and regulations, must be submitted to a central or local IRB or IEC for 
approval. The IRB’s or IEC’s written approval of the protocol and subject informed consent must 
be obtained and submitted to the sponsor or designee before commencement of the study (ie, 
before shipment of the sponsor-supplied drug or study specific screening activity). The IRB or IEC 
approval must refer to the study by exact protocol title, number, and version date; identify versions 
of other documents (eg, ICF) reviewed; and state the approval date. The sponsor will ship drug the 
sponsor has confirmed the adequacy of site regulatory documentation and, when applicable, the 
sponsor has received permission from competent authority to begin the trial. Until the site receives 
notification no protocol activities, including screening, may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the ICF, recruitment 
materials intended for viewing by subjects, local safety reporting requirements, reports and 
updates regarding the ongoing review of the study at intervals specified by the respective IRB or 
IEC, and submission of the investigator’s final status report to IRB or IEC. All IRB and IEC 
approvals and relevant documentation for these items must be provided to the sponsor or its 
designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor.


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15.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The ICF, subject authorization form (if applicable), and subject 
information sheet (if applicable) describe the planned and permitted uses, transfers, and 
disclosures of the subject’s personal and personal health information for purposes of conducting 
the study. The ICF and the subject information sheet (if applicable) further explain the nature of 
the study, its objectives, and potential risks and benefits, and the date informed consent is given. 
The ICF will detail the requirements of the participant and the fact that he or she is free to 
withdraw at any time without giving a reason and without prejudice to his or her further medical 
care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the ICF 
and if applicable, the subject authorization form. The ICF, subject authorization form (if 
applicable), and subject information sheet (if applicable) must be approved by both the IRB or IEC 
and the sponsor before use.
The ICF, subject authorization form (if applicable), and subject information sheet (if applicable) 
must be written in a language fully comprehensible to the prospective subject. It is the 
responsibility of the investigator to explain the detailed elements of the ICF, subject authorization 
form (if applicable), and subject information sheet (if applicable) to the subject. Information 
should be given in both oral and written form whenever possible and in the manner deemed 
appropriate by the IRB or IEC. In the event the subject is not capable of rendering adequate written 
informed consent, then the subject’s legally acceptable representative may provide such consent 
for the subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the study and (2) decide whether or not to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines he or she will participate in 
the study, then the ICF and subject authorization form (if applicable) must be signed and dated by 
the subject, or the subject’s legally acceptable representative, at the time of consent and before the 
subject entering into the study. The subject or the subject’s legally acceptable representative 
should be instructed to sign using their legal names, not nicknames, using blue or black ballpoint 
ink. The investigator must also sign and date the ICF and subject authorization (if applicable) at 
the time of consent and before subject entering into the study; however, the sponsor may allow a 
designee of the investigator to sign to the extent permitted by applicable law.
Once signed, the original ICF, subject authorization form (if applicable), and subject information 
sheet (if applicable) will be stored in the investigator’s site file. The investigator must document 
the date the subject signs the informed consent in the subject’s medical record. Copies of the 
signed ICF, the signed subject authorization form (if applicable), and subject information sheet (if 
applicable) shall be given to the subject.
All revised ICFs must be reviewed and signed by relevant subjects or the relevant subject’s legally 
acceptable representative in the same manner as the original informed consent. The date the 


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revised consent was obtained should be recorded in the subject’s medical record, and the subject 
should receive a copy of the revised ICF.
15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, US FDA, United Kingdom Medicines and Healthcare products 
Regulatory Agency, Pharmaceuticals and Medical Devices Agency of Japan), the sponsor’s 
designated auditors, and the appropriate IRBs and IECs to review the subject’s original medical 
records (source data or documents), including, but not limited to, laboratory test result reports, 
ECG reports, admission and discharge summaries for hospital admissions occurring during a 
subject’s study participation, and autopsy reports. Access to a subject’s original medical records 
requires the specific authorization of the subject as part of the informed consent process (see 
Section 15.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF).
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1 Publication 
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail.


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15.4.2 Clinical Trial Registration
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other 
publicly accessible websites on or before start of study, as defined in Takeda Policy/Standard. 
Takeda contact information, along with investigator’s city, state (for America’s investigators), 
country, and recruiting status will be registered and available for public viewing. 
As needed Takeda and Investigator/site contact information may be made public to support 
participant access to trials via registries. In certain situations/registries, Takeda may assist 
participants or potential participants to find a clinical trial by helping them locate trial sites closest 
to their homes by providing the investigator name, address, and phone number via email/phone or 
other methods callers requesting trial information. Once subjects receive investigator contact 
information, they may call the site requesting enrollment into the trial. The investigative sites are 
encouraged to handle the trial inquiries according to their established subject screening process. If 
the caller asks additional questions beyond the topic of trial enrollment, they should be referred to 
the sponsor.
Any investigator who objects to Takeda providing this information to callers must provide Takeda 
with a written notice requesting that their information not be listed on the registry site. 
15.4.3 Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites (including the Takeda corporate site) and registries, as required by Takeda 
Policy/Standard, applicable laws and/or regulations. 
15.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to clinical study subjects. 
Refer to the Clinical Study Site Agreement regarding the sponsor’s policy on subject 
compensation and treatment for injury. If the investigator has questions regarding this policy, he or 
she should contact the sponsor or sponsor’s designee.


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16.0
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27. Parikh A, Fox I, Leach T, Xu J, Scholz C, Patella M, et al. Long-term clinical experience with 
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39. Bharat A, Xie F, Baddley JW, Beukelman T, Chen L, Calabrese L, et al. Incidence and risk 
factors for progressive multifocal leukoencephalopathy among patients with selected 
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Appendix A
Schedule of Events
Schedule of Events for Dose Finding and Expansion Phases (Screening Through Day 32)
Screening (a)
Day
1
Day 
2
Day 
3
Day 
5
Day 
7
Day 
9
Day 
11
Day 
15
Day 
16
Day 
18
Day 
20
Day 
22
Day 
24
Day 
28
Day 
32
Informed consent
X
Inclusion/exclusion criteria
X
X (b)
Demographics
X
Medical history
X
X (c)
Complete physical examination and 
neurological assessment
X
Symptom-directed physical 
examination
X (b)
X
X (b)
X
X
Height
X
Weight
X
X
X
X
X
Vital signs
X
X (d)
X
X (d)
X
X
ECOG performance status
X
X
X
X
X
X
PML checklist
X
X (b)
X (b)
PML wallet card
X
EQ-5D
X
X
FACT-BMT
X
X
Assessment of GvHD
X
X
X
X
X
X
Monitoring of concomitant 
medications and procedures
Recorded from first dose of study drug through 18 weeks after the last dose of study drug
Adverse event reporting
Recorded from first dose of study drug through 18 weeks after the last dose of study drug
Serious adverse events (e) will be reported from signing of the ICF through 18 weeks after the last dose of study drug.
Vedolizumab IV administration (f)
X
X
Samples/Laboratory Assessments
Pregnancy test(g)
X1
X1 (b)
Footnotes are on last table page.


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Schedule of Events for Dose Finding and Expansion Phases (Screening Through Day 32) (continued)
Screening (a)
Day
1
Day 
2
Da
y 3
Day 
5
Day 
7
Day 
9
Day 
11
Day 
15
Day 
16
Day 
18
Day 
20
Day 
22
Day 
24
Day 
28
Day 
32
Hematology/chemistry(l)
X1 (l)
X1 (b)
X1
X1 (b)
X1
X1
Urinalysis
X1 (b)
Fecal sample for microbiome 
analysis (h)
X1
X1
X1
X1
Blood sample for flow cytometry (i)
X1 (b)
X1
X1
X1 (b)
X1
X1
Blood sample for serum biomarkers
X1 (b)
X1(j)
X1
X1 (b)
X1
X1
Blood sample for anti-vedolizumab 
antibodies (i) 
X1 (b)
X1
Blood sample for PK(k)
See Pharmacokinetic Sample Breakdown Table
ECOG=Eastern Cooperative Oncology Group, EQ-5D=European Quality of Life 5-Dimensional, FACT-BMT=Functional Assessment of Cancer Therapy-Bone Marrow Transplant 
Scale, GvHD=graft-versus-host disease, ICF=informed consent form, IV=intravenous, PK=pharmacokinetic(s), PML=progressive multifocal leukoencephalopathy, X#=the number 
of samples required (eg, 2 samples=X2).
Tests and procedures should be performed on schedule, but occasional changes are allowable (±2 days, except where otherwise specified) with permission from the medical monitor 
for holidays, vacations, and other administrative reasons. If extenuating circumstances prevent a patient from beginning treatment or completing a scheduled procedure or 
assessment within this time, the patient may continue the study only with the written permission from the medical monitor.
(a) Unless otherwise noted, the Screening visit must occur within 28 days before the day of the first dose of study drug (Day 1); however, the ICF may be signed more than 28 days 
before Day 1.
(b) Assessment/sample collection should be performed predose.
(c) The Day 1 medical history is not required if the screening medical history was obtained within 4 days before administration of the first dose of study drug (Day 1).
(d) Vital signs will be obtained before and within 60 minutes of completion of IV infusion of vedolizumab.
(e) Including serious pretreatment events; See Section 10.2.
(f) Vedolizumab will be administered via an approximately 30 minute IV infusion on Days 1 and 15. 
(g) A serum or urine beta-human chorionic gonadotropin pregnancy test will be performed only for patients of childbearing potential during Screening and again on Day 1 (Baseline) 
if the screening test was performed more than 4 days before the first dose of any study drug. Additional pregnancy testing may be performed during the study at the discretion of the 
investigator, upon request of an IEC/IRB, or if required by local regulations.
(h) Sample must be taken from the first bowel movement of the day.
(i) Additional specimens may be collected from any patient who experiences an infusion reaction.
(j) To be collected 24 hours (3 hours) postdose from the preceding day.
(k) Time points for blood samples for PK analysis will be collected as specified in the Pharmacokinetic Sample Breakdown table.
(l) Hepatitis and human immunodeficiency virus testing are to be performed only at the Screening visit. Negative results of all such tests are required for subject enrollment.


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Schedule of Events (Day 36 Through End of Study)
Day 
36
Day 
40
Day 
43 
Day 
71
Day 
99 
Ex-
tension 
Dose 
Visit (a)
4 
Month 
Follow-
up 
Visit (b)
5 Month 
Follow-up 
Visit (b)
6 Month 
Follow-up 
Visit (b)
9 Month 
Follow-up 
Visit (b)
Un-
scheduled 
Visit
12 Month 
Follow-
up/ 
EOS/ET 
Visit (b)
OSFU
Symptom-directed physical 
examination
X
X(d)
X(d)
X(d)
X (d)
X
Weight
X
X
X
X
X
X
X
X
X
X
X
Vital signs
X
X (c)
X (c)
X (c)
X
X
X
X
X
X
X
ECOG performance status
X
X
X
X
X
X
X
X
X
X
PML checklist
X (d)
X (d)
X (d)
X (d)
Follow-up phone calls
Q3mo 
(e)
PML wallet card
X
EQ-5D
X
X
X
X
X
X
X
X
X
FACT-BMT
X
X
X
X
X
X
X
X
X
Assessment of GvHD
X
X
X
X
X
X
X
X
X
X
X
Monitoring of concomitant 
medications and procedures
Recorded from first dose of study drug through 18 weeks after the last dose of study drug
Adverse event reporting
Recorded from first dose of study drug through 18 weeks after the last dose of study drug
Serious adverse events (f) will be reported from signing of the ICF through 18 weeks after the last dose of study drug.
Vedolizumab IV 
administration (g)
X
X 
X 
X
Endoscopy (h)
X
Samples/Laboratory Assessments
Hematology/chemistry
X1 (d)
X1 (d)
X1 (d)
X1 (d)
X1
X1
X1
X1
Fecal sample for microbiome 
analysis (j)
X1
X1
X1
X1
Footnotes are on last table page.


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Schedule of Events (Day 36 Through End of Study) (continued)
Day 
36
Day 
40
Day 
43 
Day 
71
Day 
99 
Ex-
tension 
Dose 
Visit (a)
4 Month 
Follow-up 
Visit (b)
5 Month 
Follow-up 
Visit (b)
6 Month 
Follow-up 
Visit (b)
9 Month 
Follow-up 
Visit (b)
Un-
scheduled 
Visit
12 Month 
Follow-up/ 
EOS/ET 
Visit (b)
OSFU
Blood sample for flow cytometry
X1
X1 
(d,k)
X1
(d,k)
X1
(d,k)
Blood sample for 
anti-vedolizumab antibodies (d,k)
X1 
(k)
X1 
(k)
X1
LTFU Safety Survey
Safety survey completed for patients in long-term follow-up 6 months after the last dose of study drug.
Blood sample for PK(l)
See Pharmacokinetic Sample Breakdown table
ECOG=Eastern Cooperative Oncology Group, EOS=end-of-study, EQ-5D=European Quality of Life 5-Dimensional, ET=early termination, FACT-BMT=Functional Assessment of 
Cancer Therapy-Bone Marrow Transplant Scale, GvHD=graft-versus-host disease, ICF=informed consent form, IV=intravenous, LTFU)long-term follow-up; OSFU=overall 
survival follow-up, PK=pharmacokinetic(s), PML=progressive multifocal leukoencephalopathy, Q3mo=every 3 months, X#=the number of samples required (eg, 2 samples=X2).
Tests and procedures should be performed on schedule, but occasional changes are allowable (±2 days, except where otherwise specified) with permission of the medical monitor for 
holidays, vacations, and other administrative reasons. If extenuating circumstances prevent a patient from beginning treatment or completing a scheduled procedure or 
assessment within this time, the patient may continue the study only with the written permission of the medical monitor.
(a) Upon review and agreement by the medical monitor, patients who respond to and tolerate all 5 planned doses of vedolizumab and who develop recurrent symptoms of intestinal 
GvHD following discontinuation of therapy (ie, after the fifth dose) may enter an extension phase where they may receive 300 mg vedolizumab IV every 2 weeks for 2 doses followed 
by every 4 weeks for up to 1 year from the first dose of study drug. A dose other than 300 mg and/or a frequency of administration other than every 4 weeks may be chosen based on 
accumulating safety, tolerability, efficacy, and PK results. Patients may receive drug beyond 1 year with the agreement of the investigator and the sponsor if, in the opinion of the 
investigator, the patient is benefitting from treatment.
(b) Symptoms of acute and chronic GvHD and safety will be assessed during clinic visits at 4, 5, 6, 9, and 12 months after Day 1 or until the patient’s death or withdrawal of consent 
or termination of the study by the sponsor. Patients who complete the study will attend a 12-month follow-up visit (EOS). 
(c) Vital signs will be obtained before and within 60 minutes of completion of IV infusion of vedolizumab.
(d) Assessment/sample collection should be performed predose.
(e) Patients will be followed for overall survival (OS) every 3 months after the 12-month follow-up visit until death, withdrawal of consent, termination of study by the sponsor, or for 
a maximum of 1 year after the last patient is enrolled in the study. OS is defined as the time from the date of enrollment to the date of death.
(f) Including serious pretreatment events; see Section 10.2.
(g) Vedolizumab will be administered via an approximately 30 minute IV infusion on Days 43, 71, and 99. 
(h) Endoscopy will be performed to assess response to treatment. This procedure is optional and will only be performed for patients already planned for endoscopy. Biopsy specimens, 
if available, will be collected for these patients for other histologic analyses, including changes in lymphocyte recruitment patterns.
(i) This footnote is deleted from this schedule of events (SOE) and was moved to appear in the Screening visit.
(j) Sample must be taken from the first bowel movement of the day.
(k) Additional specimens may be collected from any patient who experiences an infusion reaction.
(l) Time points for blood samples for PK analysis will be collected as specified in the Pharmacokinetic Sample Breakdown table.
Company Confidential Information


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Pharmacokinetic Sample Breakdown
Day
1
2
3
5
7
9
11
15
16
18
20
22
24
28
32
36
40
43
71
99
Serum
PK collection on 
nondosing days (a)
X1
X1
X1
X1
X1
X1
X1
X1
X1
X1
X1
X1
X1
Predose 
X1
X1
X1
X1
X1
30 min postdose (5 min)
X1
X1
X1
X1
1 h postdose (10 min)
X1
X1
X1
2 h postdose (20 min)
X1
X1
X1
X1
X1
12 h postdose (2 h)
X1
X1
24 h postdose (60 min)
X1
X1
PK=pharmacokinetic, X#=the number of samples required (eg, 2 samples=X2).
(a) Once the patient completes the inpatient period (as determined by the investigator), sample collection may be aligned with clinic visits. All PK samples should 
be collected within 10% of nominal time; however, samples collected outside this margin will not be considered protocol deviations. The total number of collected 
PK samples should be no greater than the amount outlined in this table.


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Appendix B
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this study.
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff who will assist in the protocol.
3. Ensure that study related procedures, including study specific (non routine/non standard panel) 
screening assessments are NOT performed on potential subjects, before the receipt of written 
approval from relevant governing bodies/authorities.
4. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
5. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
21 CFR Part 56, ICH, and local regulatory requirements.
6. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
7. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met.
8. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each ICF should contain a subject authorization section that 
describes the uses and disclosures of a subject’s personal information (including personal 
health information) that will take place in connection with the study. If an ICF does not include 
such a subject authorization, then the investigator must obtain a separate subject authorization 
form from each subject or the subject’s legally acceptable representative.
9. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents.
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.


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11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied
drugs, and return all unused sponsor-supplied drugs to the sponsor.
12. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.


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Appendix C
Investigator Consent to Use of Personal Information
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.


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Appendix D
Definitions for Assessing Response in Treatment of Acute GvHD
Terminology
Definition
CR
Resolution of all signs and symptoms of acute GvHD.
VGPR
Skin: No rash, or residual erythematous rash involving <25% of the body surface, without bullae 
(excluding residual faint erythema and hyperpigmentation).
Liver: Total serum bilirubin concentration <2 mg/dL or <25% of baseline at enrollment.
Gut:

Patient tolerates food or enteral feeding.

Predominantly formed stools.

No overt gastrointestinal bleeding or abdominal cramping.

No more than occasional nausea or vomiting.
PR
Improvement of 1 GvHD stage in 1 or more organs without progression in any organ.
Source: Martin PJ, et al, 2009 [31].


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Appendix E
Eastern Cooperative Oncology Group (ECOG) Scale for Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all predisease performance without restriction.
1
Symptoms but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to 
carry out work of a light or sedentary nature (eg, light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry out any work 
activities. Up and about more than 50% of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair.
5
Dead
Source: Oken MM, et al, 1982 [41].


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Appendix F
Clinical Stages of Graft-Versus-Host Disease
Acute Graft-Versus-Host Disease Clinical Stage 
Stage
Skin
Liver
Bilirubin: SI Units
(Standard Units)
Intestinal Tract
Diarrhea/Day
1
Maculopapular rash <25% of body 
surface (a)
34-50 µmol/L
(2-3 mg/dL)
>500 mL diarrhea/day
2
Maculopapular rash 25%-50% of body 
surface
51-102 µmol/L
(3.1-6 mg/dL)
>1000 mL diarrhea/day
3
Rash >50% of body surface
103-225 µmol/L
(6.1-15 mg/dL)
>1500 mL diarrhea/day
4
Generalized erythroderma with bullous 
formation
>255 µmol/L
(>15 mg/dL)
Severe abdominal pain, 
with or without ileus
From Przepiorka et al, 1995 [42].
SI=International System of Units (Système Internationale d’Unités).
(a) Use the “Rule of Nines” or burn chart to determine the extent of the rash.
Criteria for IBMTR Severity Index for Acute Graft-Versus-Host Disease
Index
Skin
Liver
Intestinal Tract
Stage 
(max)
Extent of 
Rash
Stage 
(max)
Total Bilirubin 
(μmol/L)
Stage 
(max)
Volume of Diarrhea 
(mL/day)
A
1
<25%
0
<34
0
<500
B
2
25-50%
or
1-2
34-102
or
1-2
550-1500
C
3
>50%
or
3
103-255
or
3
>1500
D
4
Bullae
or
4
>255
or
4
Severe pain and ileus
From Rowlings et al, 1997 [43].
IBMTR=International Bone Marrow Transplant Registry Database.


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Appendix G
Amendment 02 Detailed Summary of Changes
THE PRIMARY SECTIONS OF THE PROTOCOL AFFECTED BY THE CHANGES IN 
AMENDMENT 02 ARE INDICATED. THE CORRESPONDING TEXT HAS BEEN REVISED 
THROUGHOUT THE PROTOCOL.
Change 1: Clarification that the progressive multifocal leukoencephalopathy (PML) checklist is 
administered per Section 9.4.8.
The primary change occurs in Section 6.1 Overview of Study Design:
Initial 
wording:
To minimize the risk of PML, a RAMP questionnaire will be administered at Screening 
and before vedolizumab IV administration on Days 1, 15, 43, 71, and 99.
Amended or 
new 
wording:
To minimize the risk of PML, a RAMP questionnaire PML checklist will be 
administered at Screening and before vedolizumab IV administration on Days 1, 15, 43, 
71, and 99. 
Rationale for Change:
To clarify that it is the PML checklist that is administered to patients and that this named reference is 
used consistently throughout the protocol and in the SOEs.
The following sections also contain this change:

Section 2.0 STUDY SUMMARY

Section 7.1 Inclusion Criteria.

Section Appendix A Schedule of Events.


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Change 2: Clarification to the description of patients with steroid-refractory graft-versus-host 
disease (GvHD) who are eligible for enrollment to the study.
The primary change occurs in Section 7.1 Inclusion Criteria
Added text: Patients who develop toxicity on corticosteroids or who are otherwise medically 
unable to be dosed to this level, will also be eligible.
Rationale for Change:
To allow patients who have developed sensitivity to corticosteroids and can’t be dosed at the 
designated dose to be enrolled to the study.
Change 3: Deletion of the inclusion criterion specifying a required level of creatinine clearance for 
enrollment in the study.
The primary change occurs in Section 7.1 Inclusion Criteria:
Initial 
wording:
7. Creatinine clearance based on the Cockcroft-Gault estimate of ≥60 mL/minute/1.73 
m2 for patients with serum creatinine concentrations above institutional limits (see 
Section 9.4.14). 
Amended or 
new 
wording:
7. This inclusion criterion is deleted in amendment 02. Creatinine clearance based 
on the Cockcroft-Gault estimate of ≥60 mL/minute/1.73 m2 for patients with serum 
creatinine concentrations above institutional limits (see Section 9.4.14). 
Rationale for Change:
To prevent unnecessary screen failures for a criterion considered irrelevant to the study.
Section 9.4.14 Clinical Laboratory Evaluations also contains this change (removal of the estimation 
of creatinine clearance). 


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Change 4: Deletion of the exclusion criterion requiring the occurrence of acute steroid resistant 
GvHD within 28 days from primary treatment.
The primary change occurs in Section 7.2 Exclusion Criteria:
Initial 
wording:
5. Acute steroid-resistant GvHD beyond 28 days from primary treatment.
Amended or 
new 
wording:
5. This exclusion criterion is deleted in amendment 02. Acute steroid-resistant 
GvHD beyond 28 days from primary treatment.
Rationale for Change:
To allow patients beyond 28 days of primary treatment of acute GvHD to enter the study. 
Change 5: Addition of viral testing procedures to be conducted at the Screening visit.
The primary change occurs in Section 9.4.14 Clinical Laboratory Evaluations:
Added text: Hepatitis and human immunodeficiency virus testing are to be performed only at 
the Screening visit.
Rationale for Change:
Improve consistency between the procedure section and the SOE.
Section Appendix A Schedule of Events also contains this change in footnote (l). 
Change 6: Correction and specification of the pharmacokinetic (PK) postinfusion sampling times.
The primary change occurs in Section 9.4.17 PK Measurements:
Initial 
wording:
Predose samples should be collected within 0.5 hours before the start of infusion, and 
end of the infusion samples should be collected within 5 minutes after the end of 
infusion.
Amended or 
new 
wording:
Predose samples should be collected within 0.5 hours before the start of infusion, and 
end of the infusion samples should be collected within 5 minutes after the end of 
infusion at 30 5 minutes, 1 hour 10 minutes; 2 hours 20 minutes; 
12 2 hours; and 24 hours 60 minutes.
Rationale for Change:
Improve consistency between the procedure section and the SOE.


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Change 7: Correction to the end of treatment (ET) visit.
The primary change occurs in Section 9.7 Discontinuation of Treatment With Study Drug and 
Patient Replacement:
Initial 
wording:
Once study drug has been discontinued, all study procedures outlined for the EOS visit 
will be completed as specified in the Schedule of Events (Appendix A).
Amended or 
new 
wording:
Once study drug has been discontinued, all study procedures outlined for the EOS ET
visit will be completed as specified in the Schedule of Events (Appendix A).
Rationale for Change:
To correct that the ET visit will be conducted (and all associated procedures) when study drug is 
discontinued. 
Change 8: Clarification of the posttreatment follow-up assessments.
The primary change occurs in Section 9.10 Posttreatment Follow-up Assessments
Initial 
wording:
Patients will be followed for survival and assessment of GvHD or relapse of primary 
malignancy for 1 year after enrollment or until the patient’s death or withdrawal of 
consent, or termination of the study by the sponsor.
All patients will be followed for OS every 3 months until death, withdrawal of consent, 
termination of study by the sponsor, or for a maximum of 1 year after the last patient is 
enrolled in the study.
Amended or 
new 
wording:
Patients will be followed for survival and assessment of symptoms of acute and 
chronic GvHD or relapse of primary malignancy during clinic visits at 4, 5, 6, 9, and 
12 months for 1 year after enrollment or until the patient’s death or withdrawal of 
consent, or termination of the study by the sponsor. Patients who complete the study 
will attend a 12-month follow-up visit (EOS).
All patients will be followed for OS every 3 months after the 12 month follow-up 
visit, until death, withdrawal of consent, termination of study by the sponsor, or for a 
maximum of 1 year after the last patient is enrolled in the study.
Rationale for Change:
To clarify that posttreatment follow-up assessments for survival and GvHD status would be made at 
4, 5, 6, 9, and 12 months.


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Change 9: Clarification to the efficacy analyses.
The primary change occurs in Section 13.1.4 Efficacy Analysis:
Initial 
wording:
Safety, PK, and efficacy data will be used in decision making. For efficacy evaluation, a 
Bayesian statistical approach will be used where posterior probabilities that (a)
PR+VGPR+CR rate is >54%, and (b) PR+VGPR+CR rate is at least 70% will be 
derived from this distribution. If (a) is at least 85% probability (”85% level of proof at 
54%”), and (b) is at least 75% (“75% level of proof at 70%”), then this will be 
considered a positive proof-of-concept in efficacy. Efficacy signals will be evaluated 
using the initial cohorts and will be verified using the expansion cohort.
Amended or 
new 
wording:
Safety, PK, and efficacy data will be used in decision making. For efficacy evaluation, a 
Bayesian statistical approach will be used where posterior probability probabilities that 
(a) PR+VGPR+CR rate is >54%, and (b) PR+VGPR+CR rate is at least 70% will be 
derived from this distribution. If (a) is at least 85% this probability (”85% level of proof 
at 54%”), and (b) is at least 75% (“75% level of proof at 70%”), then this will be 
considered a positive proof-of-concept in efficacy. Efficacy signals will be evaluated 
using the initial cohorts and will be verified updated using the expansion cohort.
Rationale for Change:
To clarify the conduct of the efficacy analyses.
Change 10: Clarification of the immunogenicity analyses.
The primary change occurs in Section 13.1.8 Immunogenicity Analyses:
Initial 
wording:
Immunogenicity (anti-vedolizumab antibodies [AVA]) will be descriptively 
summarized. The effect of anti-vedolizumab antibodies on safety and efficacy will be 
explored. The proportion of subjects with positive AVA (transient and persistent) and 
proportion of subjects with positive neutralizing AVA during the study will be 
summarized at each visit.
A positive AVA subject is defined as a subject who has at least 1 positive AVA result in 
any post-baseline sample, and is further categorized as:
•
Transiently positive: defined as subjects with confirmed positive AVA in 1 sample at 
a post-dose visit.
•
Persistently positive: defined as subjects with confirmed positive AVA in 2 or more 
consecutive positive AVA samples at post-dose visits.
Amended or 
new 
wording:
Immunogenicity (anti-vedolizumab antibodies [AVA]) will be descriptively 
summarized. The effect of anti-vedolizumab antibodies on safety and efficacy will be 
explored. The proportion of subjects with positive AVA (transient and persistent) and 
proportion of subjects with positive neutralizing AVA during the study will be 
summarized at each visit. Further information about the immunogenicity analyses 


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will be provided in the SAP.
A positive AVA subject is defined as a subject who has at least 1 positive AVA result in 
any post-baseline sample, and is further categorized as:
•
Transiently positive: defined as subjects with confirmed positive AVA in 1 sample at 
a post-dose visit.
•
Persistently positive: defined as subjects with confirmed positive AVA in 2 or more 
consecutive positive AVA samples at post-dose visits.
Rationale for Change:
To clarify the conduct of the immunogenicity analyses. 
Change 11: Deletion of redundant safety analysis text.
The primary change occurs in Section 13.1.9 Safety Analysis:
Deleted 
text:
Patients will be randomized at a ratio of 1:1 to 2 treatment arms to receive either 300 or 
600 mg vedolizumab IV on Days 1, 15, 43, 71, and 99. After approximately 10 patients 
are enrolled at each dose level and have data available from their Day 28 evaluation, 
safety, tolerability, efficacy, and PK results will be assessed from the patients at both 
vedolizumab dose levels (300 and 600 mg), and a Bayesian statistical approach will be 
used to facilitate the determination of an appropriate dose for subsequent patients in the 
study (See Section 13.2). The cohort at the chosen dose level will then be expanded by 
approximately 18 additional evaluable patients to further assess the tolerability and 
effectiveness of vedolizumab. Both dose levels may be expanded based on 
accumulating results, if necessary.
Rationale for Change:
To delete redundant text.


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Change 12: Modification to the conduct of the interim analysis.
The primary change occurs in Section 13.2 Interim Analysis:
Initial 
wording:
There will be 1 interim analysis with early stopping rules for futility when at least 50% 
of patients in the dose finding phase have reached Day 28, based on preliminary 
efficacy and biological activity as follows: 
•
The posterior probability for the treatment effect to be greater than the 54% target 
effect will be estimated using the data from the interim analysis. 
•
If the estimated posterior probability is less than 0.3 then stopping for futility will be 
considered for this dose regimen following review of all the data collected in this 
initial cohort (eg, biological activity, PK and tolerability). 
•
If the estimated posterior probability is greater than or equal to 0.3 then this dose 
regimen will be considered for continued enrollment.
Amended or 
new
wording:
There will be 1 interim analysis with early stopping rules for futility when at least 50% 
of all patients in the dose finding phase have reached Day 28 based on preliminary 
efficacy and biological activity as follows: 
•
The posterior probability for the treatment effect to be greater than the 54% target 
effect will be estimated using the data from the interim analysis. 
•
If the estimated posterior probability is less than 0.3 then stopping for futility will be 
considered for this dose regimen following review of all the data collected in this 
initial cohort (eg, biological activity, PK and tolerability). 
•
If the estimated posterior probability is greater than or equal to 0.3 then this dose 
regimen will be considered for continued enrollment.
Rationale for Change:
To modify the conduct of the interim analysis to occur when all patients have reached Day 28 in the 
dose finding phase. This change deleted the need for early stopping rules for futility that had been 
added in the Sweden only amendment 01. 


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Change 13: Corrections to the Schedule of Events (Appendix A).
The primary changes occur in Section Appendix A Schedule of Events:
Description 
of change:
In the SOE for Dose Finding, PML checklist replaces the previous RAMP 
questionnaire. The same change was made in the SOE for Day 36 and beyond.
Description 
of change:
In the SOE for Dose Finding, in the row Hematology/chemistry, added footnote (l) to 
this heading and to the Screening visit. 
Description 
of change:
In the SOE for Dose Finding, added text for footnote (l): Hepatitis and human 
immunodeficiency virus testing are to be performed only at the Screening visit. 
Negative results of all such tests are required for subject enrollment.
Description 
of change:
In the SOE for Dose Finding, in the row Symptom-directed physical examination, 
footnote (b) was added to Day 1 and Day 15 to align the global amendment 02 with a 
change made in the Sweden only amendment 01.
Description 
of change:
In the SOE for Dose Finding, in the row Blood sample for serum biomarkers, footnote 
(j) was deleted next to the header and moved to be collected at Day 2 only. 
Description 
of change:
In the SOE for Day 36 and beyond, in the row PML checklist, X (d) was added to the 
Extension Dose Visit. 
Description 
of change:
In the SOE for Day 36 and beyond, in the row Hematology/chemistry, footnote (i) has 
been deleted and moved to the SOE for Dose Finding, in the row 
Hematology/chemistry because it refers to a sample collected at the Screening visit. 
Description 
of change:
In the SOE for Day 36 and beyond, in the row Blood sample for flow cytometry, 
footnote (d) has been added to Day 43, Day 71, and Day 99 visits to indicate that these 
assessments/samples should be collected predose. 
Description 
of change:
In the SOE for Day 36 and beyond, a row for LTFU Safety Survey has been added, 
along with text: Safety survey completed for patients in long-term follow-up 
6 months after the last dose of study drug.
Description 
of change:
In the SOE describing pharmacokinetic sampling, the window for collection of the 
12 hour postdose sample was changed from (30 min) to (2 h). 
Rationale for Change:
Various changes to the SOEs were made to clarify the procedures or to improve consistency between 
the SOE and procedure sections. 


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Change 14: Update of the signatories.
The primary change occurs in Section 1.2 Approval
Initial 
wording:
Amended or
new 
wording:
Rationale for Change:
To update the signatories, reflecting a change in study personnel.
Protected Personal Data
Protected Personal Data


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SAP_000.pdf: 
This may include, but is not limited to, redaction of the following: 


•
Title: An Open-Label, Dose-Finding Study of Vedolizumab IV for Treatment of Steroid-Refractory 
Acute Intestinal Graft-Versus-Host Disease (GvHD) in Patients who Have Undergone Allogeneic 
Hematopoietic Stem Cell Transplantation (allo-HSCT) 
NCT Number: NCT02993783
SAP Approve Date: September 13, 2018
Certain information within this statistical analysis plan has been redacted (ie, specific 
content is masked irreversibly from view with a black/blue bar) to protect either 
personally identifiable information or company confidential information. 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.


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Vedolizumab-2004 
Page 3 of 32
Statistical Analysis Plan Final 1.0 
14 September 2018
CONFIDENTIAL 
TABLE OF CONTENTS 
Approval Signatures...................................................................................................................2 
TABLE OF CONTENTS .................................................................................................................3 
List of In-Text Tables ................................................................................................................4 
LIST OF ABBREVIATIONS ..........................................................................................................5 
1.0 
OBJECTIVES ......................................................................................................................6 
1.1 
Primary Objectives.........................................................................................................6 
1.2 
Secondary Objectives.....................................................................................................6 
1.3 
Additional Objectives ....................................................................................................6 
1.4 
Study Design ..................................................................................................................6 
2.0 
ANALYSIS ENDPOINTS ..................................................................................................8 
2.1 
Efficacy Endpoints .........................................................................................................8 
2.1.1 Primary efficacy endpoint ........................................................................................8 
2.1.2 Secondary Efficacy Endpoints .................................................................................8 
2.1.3 Exploratory Efficacy Endpoint ................................................................................9 
2.2 
Safety Endpoints ..........................................................................................................10 
2.2.1 Primary Safety Endpoint ........................................................................................10 
2.2.2 Secondary Safety Endpoints ..................................................................................10 
2.2.3 Additional Safety Endpoints ..................................................................................11 
2.3 
Pharmacokinetic Endpoints .........................................................................................11 
2.4 
Biomarker Endpoints ...................................................................................................11 
3.0 
DETERMINATION OF SAMPLE SIZE ..........................................................................12 
4.0 
METHODS OF ANALYSIS AND PRESENTATION .....................................................13 
4.1 
General Principles ........................................................................................................13 
4.1.1 Study Definitions ...................................................................................................13 
4.1.2 Definition of Study Days .......................................................................................14 
4.1.3 Definition of Study Visit Windows .......................................................................14 
4.1.4 Conventions for Missing Concomitant Medication Dates .....................................15 
4.1.5 Conventions for Missing Scores in FACT-BMT ...................................................16 
4.2 
Analysis Sets ................................................................................................................16 
4.3 
Disposition of Subjects ................................................................................................17 
4.4 
Demographic and Other Baseline Characteristics .......................................................17 
4.5 
Medical History and Concurrent Medical Conditions .................................................19 
4.6 
Medication History and Concomitant Medications .....................................................19 
4.7 
Study Drug Exposure and Compliance ........................................................................20 


Vedolizumab-2004 
Page 4 of 32
Statistical Analysis Plan Final 1.0 
14 September 2018
 
CONFIDENTIAL 
4.8 
Efficacy Analysis .........................................................................................................20 
4.9 
Pharmacokinetic/Pharmacodynamic Analysis .............................................................21 
4.10 
Other Outcomes ...........................................................................................................21 
4.10.1 Biomarker Analysis ...............................................................................................21 
4.10.2 Immunogenicity .....................................................................................................22 
4.11 
Safety Analysis ............................................................................................................22 
4.11.1 Adverse Events ......................................................................................................22 
4.11.2 Clinical Laboratory Evaluations ............................................................................25 
4.11.3 Vital Signs ..............................................................................................................26 
4.12 
Interim Analysis ...........................................................................................................26 
4.13 
Changes in the Statistical Analysis Plan ......................................................................26 
5.0 
REFERENCES ..................................................................................................................27 
6.0 
APPENDICES ...................................................................................................................28 
 
 
LIST OF IN-TEXT TABLES 
Table 1. Visit windows for scheduled visit related to efficacy and safety assessment ..................14 
Table 2. Summary of the Demographic and Baseline Characteristics...........................................18 
Table 3. Clinical Chemistry and Hematology Tests ......................................................................25 
Table 4. Clinical Urinalysis Tests ..................................................................................................25 
 
 
 


Vedolizumab-2004 
Page 5 of 32
Statistical Analysis Plan Final 1.0 
14 September 2018
 
CONFIDENTIAL 
LIST OF ABBREVIATIONS 
 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
ANOVA 
analysis of variance 
AST 
aspartate aminotransferase 
BMI 
body mass index 
BUN 
blood urea nitrogen 
CPK 
creatine phosphokinase 
CRF 
case report form 
ECG 
electrocardiogram 
FAS 
full analysis set 
GGT 
-glutamyl transferase 
HIV 
human immunodeficiency virus 
ICH 
International Conference on Harmonisation 
IVRS 
Interactive Voice Response System 
LDH 
lactate dehydrogenase 
LLN 
lower limit of normal 
LOCF 
last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
PD 
pharmacodynamics 
PK 
pharmacokinetics 
QOL 
quality-of-life 
PRO 
patient-reported outcome 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SDB 
standard database 
TLGs 
tables, listings, and graphs 
ULN 
upper limit of normal 
WHODrug 
World Health Organization Drug Dictionary 
 


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Vedolizumab-2004 
Page 7 of 32
Statistical Analysis Plan Final 1.0 
14 September 2018
 
CONFIDENTIAL 
of response to treatment. Patients with acute intestinal GvHD who have received no systemic 
therapy for the treatment of acute GvHD (prophylaxis acceptable) other than corticosteroids will 
be administered vedolizumab. 
Patients will be randomized at a ratio of 1:1 to two treatment arms to receive either 300 mg or 
600 mg of vedolizumab IV on Days 1, 15, 43, 71, and 99.  
 


Vedolizumab-2004 
Page 8 of 32
Statistical Analysis Plan Final 1.0 
14 September 2018
 
CONFIDENTIAL 
2.0 
ANALYSIS ENDPOINTS 
2.1 
Efficacy Endpoints 
2.1.1 Primary efficacy endpoint 
The primary efficacy endpoint of the study is the proportion of subject with overall response 
(OR) at Day 28. A patient is considered to have an OR if there is either a complete response 
(CR), or a very good partial response (VGPR), or a partial response (PR), i.e. OR = PR + VGPR 
+ CR. The definition of CR, VGPR, and PR are shown in the table below: 
Response 
Skin 
 
Liver 
 
Intestinal tract 
CR 
Skin involvement = No 
and 
Hepatic involvement 
= No 
and 
Intestinal tract involvement =No  
VGPR 
No rash, or residual 
erythematous rash involving 
<25% of the body surface 
without bullae. 
and 
Total serum bilirubin 
< 2 mg/dL or < 25% 
of baseline at 
enrollement 
(chemistry linked to 
eCRF) 
and 
Patient tolerates food or enternal 
feeding, and 
Predominantly formed stool (or 
fully formed), and no overt GI 
bleeding or abdominal 
cramping, and no more than 
occasional nausea/vomiting. 
PR 
Improvement of at least 1 
GvHD stage since baseline 
and 
No progression (no 
worsening in stage) 
and 
No progression 
No progression 
and 
Improvement of at 
least 1 GvHD stage 
since baseline 
and 
No progression 
No progression 
and 
No progression 
and 
Improvement of at least 1 
GvHD stage since baseline 
Improvement of at least 1 
GvHD stage since baseline 
and 
Improvement of at 
least 1 GvHD stage 
since baseline 
and 
No progression 
Improvement of at least 1 
GvHD stage since baseline 
and 
No progression 
and 
Improvement of at least 1 
GvHD stage since baseline 
No progression 
and 
Improvement of at 
least 1 GvHD stage 
since baseline 
and 
Improvement of 1 at least 
GvHD stage since baseline 
Improvement of at least 1 
GvHD stage since baseline 
and 
Improvement of at 
least 1 GvHD stage 
since baseline 
and 
Improvement of at least 1 
GvHD stage since baseline 
 
The stages for GvHD improvement are listed in Appendix B. Unless otherwise noted the Acute 
Graft-Versus-Host Disease Clinical Stage table is used (Przepiorka et al, 1995 [2]). 
 
2.1.2 Secondary Efficacy Endpoints 
Secondary efficacy endpoints include: 


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Vedolizumab-2004 
Page 12 of 32
Statistical Analysis Plan Final 1.0 
14 September 2018
 
CONFIDENTIAL 
3.0 
DETERMINATION OF SAMPLE SIZE 
Approximately 38 evaluable patients were planned to be enrolled to identify an active and 
tolerable vedolizumab dose level with sufficient PK sampling to determine the PK parameters in 
this patient population. Sample size determination was mainly based on clinical considerations 
and on the primary objective of determining a recommended dose and regimen and to describe 
the initial activity, tolerability, safety, and activity of vedolizumab IV administered for the 
treatment of primary steroid-refractory acute intestinal GvHD. 


Vedolizumab-2004 
Page 13 of 32
Statistical Analysis Plan Final 1.0 
14 September 2018
 
CONFIDENTIAL 
4.0 
METHODS OF ANALYSIS AND PRESENTATION 
4.1 
General Principles  
All data will be provided in data listings sorted by treatment group and subject number. Tabular 
summaries will be presented by treatment group. 
For any variable, unless otherwise noted, the baseline values are defined as the last non-missing 
measurement prior to or on the date of the first dose of study drug administration, which is 
defined as study Day 1. 
A windowing convention will be used to determine the analysis value for a given study visit for 
the analyses of the data with scheduled visit days. Subjects disposition and the summary of tables 
for non-scheduled events (such as TEAE, concomitant medication use, etc.) will be based on the 
reported dates, not following the windowing convention. 
Continuous data will be summarized using number of subjects with non-missing values, 
arithmetic mean, standard deviation, median, minimum, and maximum. Categorical data will be 
summarized using the number and percentage of subjects for each possible category where 
appropriate. The denominator for the proportion will be based on the number of subjects in each 
treatment group (column total) unless otherwise specified.  
Means and medians will be presented to 1 more decimal place than the recorded data. The 
standard deviations (SDs) will be presented to 2 more decimal places than the recorded data. 
Confidence intervals about a parameter estimate will be presented using the same number of 
decimal places as the parameter estimate.  
All available safety, tolerability, efficacy, PK, and biomarker data will be included in data 
listings and tabulations. No imputation of values for missing data will be performed. The 
relevance of missing sample data will be assessed. 
Data that are potentially spurious or erroneous will be examined according to standard data 
management operating procedures. 
All statistical analyses will be conducted using SAS® version 9.2 or higher. 
4.1.1 Study Definitions 
The definitions of the study terms are provided in the table below: 
Term 
Definition 
Overall Response (OR) 
Defined for a patient with either a complete response (CR), or a very 
good partial response (VGPR), or a partial response (PR), i.e. OR = 
PR+VGPR+CR. 
Complete Response (CR) 
See Appendix A.                                                                                            
Very Good Partial Response 
(VGPR) 
See Appendix A. 
Partial Response (PR) 
See Appendix A. 
Overall Survival (OS) 
Defined as the time from the date of enrollment to the date of death. 
Patients without documentation of death at the time of analysis will be 


Vedolizumab-2004 
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CONFIDENTIAL 
censored at the date last known to be alive. 
Acute GvHD 
As reported in the eCRF.  
Chronic GvHD 
As reported in the eCRF.  
Durable Overall Response 
Defined as proportion of patients in each arm who achieve OR at Day 
28 and maintain OR at Day 56. 
Durable Intestinal Overall 
Response 
Defined as proportion of patients in each arm who achieve intestinal OR 
at Day 28 and maintain OR at Day 56. 
Overall Survival (OS) 
Defined as the time from the date of enrollment to the date of death. 
Patients without documentation of death at the time of analysis will be 
censored at the date last known to be alive. 
 
4.1.2 Definition of Study Days 
Study Day 1 is defined as the designation date of the first intravenous [IV] infusion of 
vedolizumab. Other study days are defined relative to the Study Day 1 with Day 2 being the day 
after, and Day -1 being the day prior to Study Day 1.  
Baseline is defined as the last non-missing measurement prior to or on the date of the first dose 
of study drug (Study Day -1). 
4.1.3 Definition of Study Visit Windows 
For any variable, unless otherwise noted, the baseline values are defined as the last non-missing 
measurement prior to or on the date of the first dose of study drug administration, which is 
defined as study Day 1. All data will be categorized based on the scheduled and actual sampling 
time at which it was collected, allowing equally distanced windows (See Table 1) between the 
scheduled days when applicable. If a subject has more than one assessment visit within a 
window, the assessment closest to the target day will be used. In case of ties between the 
observations located on different sides of the target day, the later assessment will be used. In case 
when two or more assessments were done on the same day, the average value will be used. 
Table 1. Visit windows for scheduled visit related to efficacy and safety assessment 
Scheduled 
Visit Day 
Question-
naires 
Assessment 
of GvHD 
Symptom-
directed 
physical 
examinatio
n 
Vital signs(b) 
Hematology 
/chemistry 
Blood 
samples for 
serum 
biomarkers 
Weight 
Screening(a) 
≤ -1 
 
 
≤ -1 
≤ -1 
 
≤ -1 
+1 
 
+1 – +4  
+1 – +4 
+1 – +4  
+1 – +4  
≤ +1  
 
+2 
 
 
 
 
 
+2 – +4 
 
+7 
 
+5 – +11 
+5 – +11 
+5 – +11 
+5 – +11 
+5 – +11 
+1 – +11 
+15 
 
+12 – +18 
+12 – +18 
+12 – +18 
+12 – +18 
+12 – +16  
+12 – +18 
+18 
 
 
 
 
 
+17 – +23 
 


Vedolizumab-2004 
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CONFIDENTIAL 
+22 
 
+19 – +25 
+19 – +25 
+19 – +25 
+19 – +25 
 
+19 – +25 
+28 
+1 – +35  
+26 – +32 
+26 – +32 
+26 – +32 
+26 – +35 
+24 – +32 
+26 – +32 
+36 
 
+33 – +39 
+33 – +39 
+33 – +39 
 
+33 – +39 
+33 – +39 
+43 
+36 – +57 
+40 – +57 
+40 – +57 
+40 – +57 
+36 – +57 
+40 – +57 
+40 – +57 
+71 
+58 – +85 
+58 – +85 
+58 – +85 
+58 – +85 
+58 – +85 
+58 – +85 
+58 – +85 
+99 
+86 – +109 
+86 – +109 
+86 – +109 
+86 – +109 
+86 – +109 
+86 –  +139 
+86 – +109 
4 months 
follow up 
+110 – +135 
+110 – +135 
 
+110 – +135 
+110 – +135 
 
+110 – +135 
5 months 
follow up 
+136 – +165 
+136 – +165 
 
+136 – +165 
+136 – +165 
 
+136 – +165  
6 months 
follow up 
+166 – +225 
+166 – +225 
 
+166 – +225 
+166 – +315 
+140 - +315 
+166 – +225 
9 months 
follow up 
+226 – +315 
+226 – +315 
 
+226 – +315 
 
 
+226 – +315 
12 months 
follow up/ 
EOS/ET 
≥ +316 
≥ +316 
≥ +316 
≥ +316 
≥ +316 
≥ 316 
≥ +316 
(a) Unless otherwise noted, the Screening visit must occur within 28 days before the day of the first dose of the 
study drug (Day 1). (b) Vital signs will be obtained before and within 60 minutes of completion of IV infusion of 
vedolizumab.  
4.1.4 Conventions for Missing Concomitant Medication Dates 
Start and stop dates for all concomitant medications are collected on the CRF. However, in case 
of missing or partial information in these dates, the following rules will be used: 
If the start date is missing or partial: 
- 
If the day is missing, the start day will be the first day of the month 
- 
If the month is missing, the start month will be the month corresponding to 90 days prior 
to the first study medication date 
- 
If the year is missing, the start year will be the year of the entry visit (or consent date, for 
those missing entry visit) 
- 
If the entire date is missing, the start date will be the date of first study drug 
administration 
If the stop date is missing, partial or “continuing:” 
- 
If the day is missing, the stop day will be the last day of the month reported 
- 
If the month is missing, the stop month will be the month during which the last dose of 
induction treatment was administered 


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Vedolizumab-2004 
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CONFIDENTIAL 
ii. 
Did not meet exclusion criteria #1, 3, 4, and 5. 
iii. 
Received at least the first two does of study medication as assigned. 
Per-protocol population will be used for sensitivity analysis.  
 PK population is defined as patients from the safety set with at least 1 postdose PK 
sample collected. PK population will be used for the PK parameters analysis. 
 Biomarker population: Defined as patients from the safety set with at least 1 biomarker 
sample collected. Biomarker population will be used for Biomarker analysis. 
4.3 
Disposition of Subjects 
Summary of the subject disposition will be summarized by dose level including the following: 
 Study Information, including date first subject signed ICF, date of last subject’s last 
visit/contact, date of last subject’s last procedure for collection of data for primary 
endpoint (when applicable). 
 Summary of screen failures. If no subjects failed the screening, the number of screened 
and the number of eligible patients should be reported.  
 Summary of eligibility for randomization into phase 2a. 
 Summary of study subjects randomized by site, country, dose level and regimen. 
 Summary of patients for each pre-defined population: efficacy population, safety 
population, PP population, PK population, and biomarker population. 
 Summary of subjects completing 15 days. 
 Summary of subjects completing 43 days. 
 Summary of subjects completing 71 days. 
 Summary of subjects completing 99 days. 
 Summary of subjects completing 6 months. 
 Disposition of subjects based on the reasons for discontinuation of treatment and for 
failing to complete the study. 
 Significant protocol deviations, captured on the eCRF will be summarized descriptively. 
 
4.4 
Demographic and Other Baseline Characteristics 
The following demographic and baseline characteristics will be summarized by dose level using 
Safety Population (See Table 2). 


Vedolizumab-2004 
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CONFIDENTIAL 
Table 2. Summary of the Demographic and Baseline Characteristics 
Characteristic 
Summarized as 
Categories and measurement units 
Age 
Continuous 
18—75 years 
Age group 
Categorical 
<35 and >= 35 years 
<65, and ≥65 years 
Gender 
Categorical 
Female/Male/Missing 
Race 
Categorical 
White/ Black or African American/ 
Native Hawaiian or Other Pacific Islander/ 
Asian/ American Indian or Alaska Native/ 
Other/ Not reported 
Ethnicity 
Categorical 
  Hispanic or Latino 
  Not Hispanic or Latino 
  Not Reported 
Weight 
Continuous 
kg 
Height 
Continuous 
cm 
Baseline ECOG Status 
Ordinal Cetegorical 
0, 1, 2, 3, 4, 5 
Underlying disease diagnosis 
Categorical  
Myeloproliferative Neoplasm, 
   Myelodysplastic or Myelofroliferative 
Neoplasm, 
   Myelodysplastic syndrome, 
   Acute myeloid leukaemia or related 
precursor neoplasm, 
   Precursor lymphoid neoplasm, 
   Mature B-cell neoplasm, 
   Mature T-cell and NK-cell neoplasm 
Underlying disease duration 
since diagnosis 
Ordinal Categorical 
< 1 years 
≥1 and < 3 years 
≥ 3 and, 7 years 
≥ 7 years 
Conditioning Regimen 
Categorical 
  Myeloablative Transplant, 
Reduced-intensity Transplant 
Donor-recipient Gender Match 
Categorical 
Female Subject-Female Donor 
Female Subject-Male Donor 
Male Subject-Female Donor 
Male Subject-Male Donor 
Transplant characteristics: 
   Donor Relationship to Subject  
   HLA Compatability 
   Source of stem cells 
  
Categorical 
Categorical 
Categorical 
  
Related/Not related 
Match/Mismatch 
Bone Marrow/Peripheral Blood Stem Cell 


Vedolizumab-2004 
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CONFIDENTIAL 
Characteristic 
Summarized as 
Categories and measurement units 
Cytomegalovirus IgG Antibody 
Categorical 
Positive/Negative 
GvHD characteristics (Staging 
by organ involved) 
Categorical 
Organ: Liver, Intestinal, Skin 
Stage: 0, 1, 2, 3, 4 
GvHD characteristics (Grade by 
organ involved) 
 
Categorical 
By IBMTR 
By modified Glucksberg 
 
For the categorical variables the counts and proportions of each possible value will be tabulated 
by treatment group. No baseline laboratory values will be tabulated. Categories that contain zero 
observations will be reported as ‘0’, not omitted. Missing and non-reported observation will be 
reported as such, not omitted. The denominator for proportion will be based on the number of 
subjects in each group (column total), unless otherwise specified. 
Continuous variables will be tabulated by treatment group using the using the following: 
 Number of subjects with non-missing values (n), 
 Arithmetic mean, 
 Median, 
 Standard deviation (SD), 
 Minimum and maximum observed values (Min, Max). 
No baseline comparison will be performed. 
 
4.5 
Medical History and Concurrent Medical Conditions 
During the Screening period, a complete medical history will be compiled for each patient. The 
history will include the background of the patient’s malignancy and prior therapies for it, and the 
background of the patient’s transplant and post-transplant course. 
Medical and Surgical History will be summarized by system organ class and preferred term. 
4.6 
Medication History and Concomitant Medications 
In addition, concomitant medications used by the patient and therapeutic procedures completed 
by the patient will recorded in the eCRF from the first dose of study drug through 18 weeks after 
the last dose of study drug. 
Concomitant medications will be coded using WHODrug. The number and percentage of 
patients taking concomitant medications will be tabulated by standardized medication name 
WHO drug generic term in the Safety Population, and categorized as follows: 
• Concomitant medications that started and stopped prior to baseline. 


Vedolizumab-2004 
Page 20 of 32
Statistical Analysis Plan Final 1.0 
14 September 2018
 
CONFIDENTIAL 
• Concomitant medications that started prior to and were ongoing at baseline and those that 
started after baseline. 
In addition, the number and percentage of subjects receiving blood transfusions will be tabulated 
in the Safety Population. GvHD prophylaxis at baseline may be summarized as well.   
All concomitant medications administered and concomitant procedures will be provided in data 
listings. 
4.7 
Study Drug Exposure and Compliance 
Vedolizumab will be administered or dispensed only to eligible patients under the supervision of 
the investigator or identified sub-investigator(s). The appropriate study personnel will maintain 
records of vedolizumab receipt and dispensing. 
Exposure to vedolizumab will be summarized and reasons for discontinuation will be tabulated 
by dose level.  
 
Compliance will be calculated as percentage of infusions (both completed and partial) out of the 
total number of infusions. “Partial infusions” is defined as an infusion with less than the 
scheduled amount. 
Extent of Exposure for vedolizumab is calculated as the duration between the first and last dose 
of study drug +18 weeks, i.e.:  
(Date of last dose of Vedolizumab) – (Date of first dose of Vedolizumab) + 1 + (126 days). 
 
4.8 
Efficacy Analysis 
Statistical analyses will be primarily descriptive and graphical in nature. Efficacy signals will be 
evaluated using the initial cohorts and will be updated using the expansion cohort (if applicable) 
using Efficacy Population. In addition, the analysis for primary efficacy endpoint will be 
repeated using the PPS for sensitivity analysis.  
Efficacy data will be summarized as observed. Missing data will not be imputed. 
No formal statistical tests will be performed for this open-label study. The description of the 
statistical methods to analyze the endpoints is provided below. Additional exploratory analysis 
may be considered if confounding factors suspected. The proportion-based endpoints (percentage 
of subjects meeting endpoint criteria) will be summarized for each dosing cohort using 
descriptive statistics (count, percentage and associated 95% CI using normal approximation). If 
the number of responses is too small (i.e., ≤ 5), the exact method will be used instead (e.g., the 
Clopper-Pearson method).   
 
Continuous endpoints will be descriptively summarized (number of subjects with non-missing 
values, arithmetic mean, median, SD, minimum, and maximum) by visit for each dosing cohort. 


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Vedolizumab-2004 
Page 23 of 32
Statistical Analysis Plan Final 1.0 
14 September 2018
 
CONFIDENTIAL 
– Where a patient has the same AE, based on preferred terminology, reported multiple 
times in a single analysis period, the patient will only be counted once at the preferred 
terminology level in AE tables. 
– When a patient has the same AE, based on preferred terminology, reported multiple times 
in a single analysis phase, the following criteria, in order of precedence, will be used to 
select the event to be included in summary tables.  
• Relationship to study medication. 
• Intensity of event. 
• Onset date and time (where applicable). 
– When reporting AEs by intensity, in addition to providing a summary table based on the 
event selection criteria detailed in Item 2 above, summary tables will also be provided 
based on the most intense event during the analysis phase – independent of relationship to 
study medication. For these tables, the following criteria, in order of precedence, will be 
used to select the event to be included in summary tables. 
• Intensity of event. 
• Onset date and time (where applicable). 
4.11.1.1 Serious Adverse Events (SAE) 
The number and percentage of subjects experiencing the SAEs will be summarized by system 
organ class (SOC), high level term (HLT), and preferred term (PT) and by treatment group. 
SAEs from administration of the first dose of vedolizumab IV through Day 28 and SAEs from 
administration of the first dose of vedolizumab IV through 18 weeks after administration of the 
last dose of vedolizumab IV will be summarized separately. All SAEs will be listed.  
– SAEs by SOC, HLT and PT. 
– SAEs by severity* and by SOC, HLT and PT. 
– SAEs by relationship to the investigational product and by SOC, HLT, and PT. 
4.11.1.2 TEAEs 
The number and percentage of subjects experiencing the TEAEs will be summarized by SOC, 
HLT, and PT and by treatment groups.  
– TEAEs by SOC, HLT and PT. 
– TEAEs by severity* and by SOC, HLT and PT. 
                                                 
* Missing severity needs to be confirmed with the vendor. During the data cleaning proces the clinical cites need to 
be queried for missing severity. 


Vedolizumab-2004 
Page 24 of 32
Statistical Analysis Plan Final 1.0 
14 September 2018
 
CONFIDENTIAL 
– TEAEs by relationship to relationship to the investigational product and by SOC, HLT, 
and PT. 
– The most commonly reported TEAEs (i.e., TEAEs occurring in ≥ 10% of all subjects) by 
PT in descending order of frequency. 
– Grade 3 TEAEs. 
– Grade 4 TEAEs. 
– Grade 5 TEAEs. 
– Grade 3 or higher drug-related TEAEs. 
– All drug-related TEAEs. 
4.11.1.3 Deaths 
All on-study deaths recorded on the AE page, or death page (with a death date, cause of death, 
and outcome) of the CRF will be considered a death in the analysis.  
All deaths will be listed, and summarized by PT. 
4.11.1.4 TEAEs Resulting in Discontinuation of Study Drug 
TEAEs resulting in permanent discontinuation of study drug will be listed and summarized by 
SOC, HLT and PT and by treatment group.  
4.11.1.5 TEAEs of Special Interest 
Based on the mechanism of action of Vedolizumab, certain adverse events of special interest 
have been predefined. These AEs of special interest will be summarized by SOC, HLT and PT 
and by treatment group. 
The categories of AEs of special interest are as follows (see Appendix C for details): 
– Gastrointestinal infections 
– Malignancies  
– Infections 
– Infusion Related Reactions 
– Hypersensitivity Reactions 
– Suspected PML 
– Liver Injury. 
4.11.1.6 Other Observations Related to Safety 
In addition, PML checklist data will be presented in data listings. 
 


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4.11.2 Clinical Laboratory Evaluations 
Blood samples for analysis of the clinical chemistry and hematological parameters shown in 
Table 3 and urine samples for analysis of the parameters shown in Table 4 will be obtained as 
specified in the Schedule of Events as described in Study Protocol. Hepatitis and human 
immunodeficiency virus testing are to be performed only at the Screening visit. 
Table 3. Clinical Chemistry and Hematology Tests 
 
Table 4. Clinical Urinalysis Tests 
 
The analysis of the laboratory data will include parameters tabulation for each assessment visit 
by dose level, using the following: 
 
Number of subjects with non-missing values (n), 
 
Arithmetic mean, 
 
Median, 
 
Standard deviation (SD), 
 
Minimum and maximum observed values (Min, Max). 
For the post-baseline assessments, the summary will also include the change from baseline 
values.  


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Mean laboratory values over time will be plotted for key laboratory parameters (hematology, 
chemistry, and LFTs). Shift tables for laboratory parameters will be generated based on changes 
in NCI CTCAE grade from baseline to the worst postbaseline value. 
Elevated hepatic parameters, and subject mappings for the number and percentage of subjects 
with elevated hepatic parameters summarized. 
 
4.11.3 Vital Signs 
Vital signs, including heart rate, respiratory rate, systolic and diastolic blood pressure, and 
temperature will be summarized descriptively following the windowing convention for visits 
specified events. 
4.12 
Interim Analysis 
The protocol prespecified one interim analysis when all patients in the dose finding phase have 
reached Day 28.  Takeda has decided to terminate the Vedolizumab-2004 study early. Therefore, 
the performance of the Bayesian interim analysis is not applicable. There will not be separate 
analyses for interim or final database lock. 
 
4.13 
Changes in the Statistical Analysis Plan  
1. Additional efficacy endpoints that were not defined in the protocol were added in Section 
2.1.3, including durable overall response rate, durable intestinal overall response rate, 
time to overall response, and time to intestinal overall response. 
2. Additional safety endpoints AESIs were added in Section 2.2.3 and Appendix C. 
3. The protocol defined Efficacy population includes all patients from the safety population 
who have completed their Day 28 assessment. The Efficacy population was revised to 
include all patients from the safety population who have baseline efficacy assessment and 
at least one post-baseline efficacy assessment. Refer to Section 4.2 for details.  
4. Sponsor has decided to terminate the study early. There will not be separate analyses for 
interim or final database lock. 


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5.0 
REFERENCES 
[1] Martin PJ, Bachier CR, Klingemann HG, McCarthy PL, Szabolcs P, Uberti JP, et al. 
Endpoints for clinical trials testing treatment of acute graft-versus-host disease: a joint 
statement. Biol Blood Marrow Transplant 2009;15(7):777-84. 
[2] Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, et al. 1994 
Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 
1995;15(6):825-8. 
[3] Rowlings PA, Przepiorka D, Klein JP, Gale RP, Passweg JR, Henslee-Downey PJ, et al. 
IBMTR Severity Index for grading acute graft-versus-host disease: retrospective 
comparison with Glucksberg grade. Br J Haematol 1997;97(4):855-64. 


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6.0 
APPENDICES 
Appendix A. Definitions for Assessing Response in Treatment of Acute GvHD 
 
Source: Martin PJ, et al., 2009 [1] 
Appendix B. Clinical Stages of Graft-Versus-Host Disease 
 
Source: Przepiorka et al, 1995 [2] 
SI=International System of Units (Système Internationale d’Unités). 
(a) Use the “Rule of Nines” or burn chart to determine the extent of the rash. 
 
From Rowlings et al, 1997 [3]. 
IBMTR=International Bone Marrow Transplant Registry Database. 


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Appendix C 
AEs of Special Interest 
Based on the mechanism of action of vedolizumab, certain adverse events of special interest 
(AESIs) have been predefined. The categories of adverse events of special interest, and other 
planned analyses, are described below.  
Events 
MedDRA Terms or definitions 
Gastrointestinal Infections 
The infection reports retrieved from the clinical database were evaluated for GI 
infections during the reporting period using the MedDRA 20.0 search criteria of:  
- 
Abdominal and gastrointestinal infections HLT in the Infections and 
Infestations SOC. 
- 
Gastrointestinal infections HLT of the Gastrointestinal SOC. 
 
Malignancies 
SOC: NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS 
AND POLYPS) 
 
Infections 
The infection reports retrieved from the clinical database, not classified as GI 
infections, or suspected PML will be searched using the MedDRA 20.0 search criteria 
of: Infections and Infestations SOC 
 
The following reports will then be excluded: 
     Abdominal and gastrointestinal infections HLT. 
     URTI HLT. 
     Bronchitis PT. 
     Influenza PT. 
     Human polyomavirus infection PT. 
     JC virus infection PT. 
     JC virus test positive PT. 
     Leukoencephalopathy PT. 
     Polyomavirus test positive PT. 
     Progressive multifocal leukoencephalopathy PT. 
 
Infusion Related Reactions 
Analysis for these AEs will occur on two levels: 
• 
Investigator defined Infusion Related Reactions (as indicated on the AE 
CRF). 
• 
All AEs that occur on or one calendar day after the infusion date. 
 
Hypersensitivity Reactions 
Anaphylactic/anaphylactoid shock conditions SMQ (broad). 
Angioedema SMQ (broad). 
Hypersensitivity SMQ (broad). 
 
Suspected PML 
The protocol incorporates an active screening program in order to identify and 
manage any case of PML. This program is known as the Risk Assessment and 
Minimization for PML (RAMP). The clinical database will be searched for suspected 
PML reports received within the Infection and Infestation SOC using the MedDRA 
20.0 search criteria of:  
• 
Human polyomavirus infection PT. 


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Events 
MedDRA Terms or definitions 
• 
JC virus infection PT. 
• 
JC virus test positive PT. 
• 
Leukoencephalopathy PT. 
• 
Polyomavirus test positive PT. 
• 
Progressive multifocal leukoencephalopathy PT. 
 
Liver injury 
Cholestasis and jaundice of hepatic origin SMQ (Broad)  
Hepatic failure, fibrosis and cirrhosis and other liver damage-related conditions SMQ 
(Broad) 
Hepatitis, non-infectious SMQ (Broad)  
Liver related investigations, signs and symptoms SMQ (Narrow)  
Liver infections SMQ (Broad) 
 
 
Appendix D 
Criteria for Identification of Markedly Abnormal Laboratory Values 
Hematology—Criteria for Markedly Abnormal Values 
Parameter 
Low Abnormal 
High Abnormal 
Red blood cells 
<0.8 x LLN 
>1.2 x ULN 
White blood cells 
<0.5 x LLN 
>1.5 x ULN 
Neutrophils 
<0.5 x LLN 
>1.5 x ULN 
Eosinophils 
-- 
>2 x ULN 
Basophils 
-- 
>3 x ULN 
Lymphocytes 
<0.5 x LLN 
>1.5 x ULN 
Monocytes 
-- 
>2 x ULN 
Hemoglobin 
<0.8 x LLN 
>1.2 x ULN 
Hematocrit 
<0.8 x LLN 
>1.2 x ULN 
Platelets (conventional) 
<75 x 103/L 
>600 x 103/L 
Platelets (SI) 
<75 x 109/L 
>600 x 109/L 
HbA1c (conventional) 
-- 
>7% 
HbA1c (SI) 
-- 
>0.07 
 


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Criteria for Abnormal Changes from Baseline of Vital Signs 
Vital Sign 
Criterion Value 
Change Relative to Baseline 
Systolic arterial blood pressure 
>180 mm Hg 
Increase of 20 mm Hg 
 
<85 mm Hg 
Decrease of 20 mm Hg 
Diastolic arterial blood pressure 
>110 mm Hg 
Increase of 15 mm Hg 
 
<50 mm Hg 
Decrease of 15 mm Hg 
Pulse 
>120 bpm 
 
 
<50 bpm 
 
Body Temperature 
>37.7 degrees Celsius 
 
 
<35.6 degrees Celsius 
 
Weight 
 
Change of greater than 7% body weight 
 
Both the criterion value and the change from Baseline must be met. 
 
Urinalysis – Criteria for Markedly Abnormal Values 
Parameter 
Low Abnormal 
High Abnormal 
pH 
N/A 
N/A 
Specific Gravity 
N/A 
N/A 
Protein 
N/A 
N/A 
Glucose 
N/A 
N/A 
Blood 
N/A 
N/A 
Nitrite 
N/A 
N/A 
 


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Chemistry—Criteria for Markedly Abnormal Values 
Parameter 
Low Abnormal 
High Abnormal 
ALT 
-- 
>3 x ULN 
Alkaline phosphatase 
-- 
>3 x ULN 
AST 
-- 
>3 x ULN 
Total bilirubin (conventional) 
-- 
>2.0 mg/dL 
Total bilirubin (SI) 
-- 
>34.2 mol/L 
Direct bilirubin 
-- 
>2 x ULN 
GGT 
-- 
>3 x ULN 
Total protein 
<0.8 x LLN 
>1.2 x ULN 
Albumin (conventional) 
<2.5 g/dL 
-- 
Albumin (SI) 
<25 g/L 
-- 
Creatinine (conventional) 
-- 
>2 mg/dL 
Creatinine (SI) 
-- 
>177 mol/L 
Blood urea nitrogen (conventional) 
-- 
>30 mg/dL 
Blood urea nitrogen (SI) 
-- 
>10.7 mmol/L 
Potassium (conventional) 
<3.0 mEq/L 
>6.0 mEq/L 
Potassium (SI) 
<3.0 mmol/L 
>6.0 mmol/L 
Sodium (conventional) 
<130 mEq/L 
>150 mEq/L 
Sodium (SI) 
<130 mmol/L 
>150 mmol/L 
Glucose (conventional) 
<50 mg/dL 
>350 mg/dL 
Glucose (SI) 
<2.8 mmol/L 
>19.4 mmol/L 
Calcium (conventional) 
<7.0 mg/dL 
>11.5 mg/dL 
Calcium (SI) 
<1.75 mmol/L 
>2.88 mmol/L 
Thyroid Stimulating Hormone (TSH) 
<0.8 x LLN 
>2.0 x ULN 
Vitamin B12 (conventional) 
<125 pg/mL 
-- 
Vitamin B12 (SI) 
<92 pmol/L 
-- 
Folate (conventional) 
<2.2 pg/dL 
>17.5 pg/dL 
Folate (SI) 
<5.0 nmol/L 
>39.7 nmol/L 
Parathyroid hormone (PTH) 
<0.8 x LLN 
>2.0 x ULN 
Free thyroxine (Free T4) 
<0.8 x LLN 
>2.0 x ULN 
Rapid plasma reagin (RPR) 
positive 
positive 
Bicarbonate 
<8.0 mmol/L 
-- 
Chloride 
<75 mmol/L 
>126 mmol/L 
Phosphorous 
<0.52 mmol/L 
>2.10 mmol/L 
CPK 
-- 
>5x ULN 
ALT=alanine aminotransferase, AST=aspartate aminotransferase, GGT=-glutamyl transferase, LLN=lower limit of 
normal, N/A=not applicable, ULN=upper limit of normal 


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