Clinical trial NCT02728895
Conditions: Allogeneic Hematopoietic Stem Cell Transplantation
Keywords: Drug Therapy
Sponsor: Takeda
Start date: 2016-06-15; Completion date: 2018-07-10
Enrollment: 24 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess the initial tolerability, safety and recommended phase 2 dose of vedolizumab intravenous (IV) administered for GvHD prophylaxis along with standard GvHD prophylaxis therapy (in participants undergoing allogeneic hematopoietic stem cell transplantation \[allo-HSCT\]).

Detailed description:
The drug being tested in this study is called Vedolizumab. Vedolizumab (also called MLN0002) is approved for the treatment of adult participants with moderately to severely active ulcerative colitis (UC) and Crohn's disease (CD) who achieved an inadequate response, had a loss of response, or were intolerant to conventional and/or biologic treatments. This study will look at the tolerability and pharmacokinetics of Vedolizumab in participants undergoing allo-HSCT when added to standard GvHD prophylaxis (tacrolimus plus short-term methotrexate) for the prevention of acute GvHD (major complication in allo-HSCT).

The study will enroll approximately 36 participants. Participants will be assigned to different dose-escalating cohorts in order to find out the recommended phase 2 dose (RP2D) of the study:

* Cohort 1: Vedolizumab 75 mg
* Cohort 2: Vedolizumab 300 mg
* Cohort 3: Vedolizumab Dose 1

All participants have to receive 1 injection of Vedolizumab on Day -1 before allo-HSCT and on Days 13 and 42 after allo-HSCT. If none of the participants receiving vedolizumab at 75 mg experience dose-limiting toxicities (DLTs), dose escalation will continue to 300 mg on Day -1 before allo-HSCT and on Days +13 and +42 after allo-HSCT. If the first 3 participants at 300 mg tolerate the treatment without experiencing DLTs, then the decision on whether to increase the vedolizumab IV dose in the next cohort will be guided by the PK results.

Cohorts will be escalated in same manner until the identification of RP2D. The cohort at that dose level may be expanded to include approximately 18 additional participants undergoing myeloablative conditioning or reduced-intensity conditioning (RIC) and receiving either related or unrelated allo-HSCT for the treatment of hematologic malignancies or myeloproliferative neoplasms. This group of participants will allow the further assessment of the tolerability and clinical activity of vedolizumab.

This multi-center trial will be conducted in the United States. The overall time to participate in this study will be approximately 2 years. Following the treatment period, participants who remain in remission will be followed for development of acute and chronic GvHD and safety during clinic visits at 4, 5, 6, 9, and 12 months after allo-HSCT or until death or withdrawal of consent or termination of the study by the sponsor. Participants who complete the study will attend a 12-month follow-up visit. Patients who have been discontinued from treatment will attend an end of treatment visit 30 to 40 days after the last dose of study drug using all study procedures outlined for the 12-month follow-up visit.

Arms: arm 1: Vedolizumab 75 mg, injection, intravenously once on Days -1, 13 and 42. arm 2: Vedolizumab 300 mg, injection, intravenously once on Days -1, 13 and 42. arm 3: Vedolizumab first decided dose as determined from Cohort 1 or 2, injection, intravenously once on Days -1, 13 and 42.
Interventions: intervention 1: Vedolizumab
Intervention descriptions: intervention 1: Vedolizumab Injection.

Protocol documents:
Prot_001.pdf: 


•
Title: An Open-Label, Dose-Finding Study of Vedolizumab IV Plus Standard of Care for Graft-
Versus-Host Disease (GvHD) Prophylaxis in Patients Undergoing Allogeneic Hematopoietic 
Stem Cell Transplantation (HSCT)
NCT Number: NCT02728895
Protocol Approve Date: 13 January 2016
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 (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
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
PROTOCOL
An Open-Label, Dose-Finding Study of Vedolizumab IV Plus Standard of Care for 
Graft-Versus-Host Disease (GvHD) Prophylaxis in Patients Undergoing Allogeneic 
Hematopoietic Stem Cell Transplantation (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-1015
IND Number:
127,634
EudraCT Number:
Not Applicable
Compound:
Vedolizumab IV
Date:
13 January 2016
Amendment History: 
Date
Amendment Number
Amendment Type
Region
04 December 2015
Initial Protocol
Not applicable
Global
13 January 2016
01
Nonsubstantial
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 11.0, 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
Serious adverse event and pregnancy reporting
See Section 11.0


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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.
PPD


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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 11.0 of this 
protocol.

Terms outlined in the Clinical Study Site Agreement.

Appendix B– Responsibilities of the Investigator.
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 No. 01 Summary of Changes
This document describes the changes in reference to the Protocol Incorporating Amendment 
No. 01.
The primary purpose of this amendment is to update the protocol regarding inclusion criteria for 
the expansion phase of the study and the definitions of dose-limiting toxicity (DLT), details on 
End-of-Cohort Meetings, and recording of vital signs on the days of study drug infusion. 
Justification: The changes in the protocol are based upon communication from the United States
Food and Drug Administration received on 28 December 2015.
Minor grammatical and editorial changes are included for clarification purposes only. Full details 
on changes of text are given in Appendix I. The following is a summary of the changes made in the 
amendment:
1. Section 8.1.2: Updated inclusion criterion in the expansion phase of the study.
2. Section 9.2: Clarified the definitions of DLT.
3. Section 10.3.7: Updated details on recording of vital signs.
4. Section 12.1: Provided additional details on End-of-Cohort Meetings.
5. Appendix A: Updated details on recording of vital signs on Study Days –1, +13, and +42.


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TABLE OF CONTENTS
1.0
ADMINISTRATIVE.......................................................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment No. 01 Summary of Changes ...................................................5
2.0
STUDY SUMMARY ....................................................................................................11
3.0
STUDY REFERENCE INFORMATION ......................................................................15
3.1
Study-Related Responsibilities.................................................................................15
3.2
Principal Investigator/Coordinating Investigator ......................................................15
3.3
List of Abbreviations ...............................................................................................16
3.4
Corporate Identification...........................................................................................18
4.0
INTRODUCTION.........................................................................................................19
4.1
Background .............................................................................................................19
4.1.1
Disease Under Treatment ...................................................................................19
4.1.2
Vedolizumab IV.................................................................................................19
4.2
Rationale for the Proposed Study.............................................................................22
5.0
STUDY OBJECTIVES .................................................................................................24
5.1
Primary Objective....................................................................................................24
5.2
Secondary Objectives...............................................................................................24
5.3
Exploratory Objectives ............................................................................................24
6.0
STUDY ENDPOINTS...................................................................................................25
6.1
Primary Endpoints ...................................................................................................25
6.2
Secondary Endpoints ...............................................................................................25
6.3
Exploratory Endpoints .............................................................................................25
7.0
STUDY DESIGN..........................................................................................................27
7.1
Overview of Study Design.......................................................................................27
7.2
Number of Patients ..................................................................................................29
7.3
Duration of Study ....................................................................................................29
8.0
STUDY POPULATION................................................................................................30
8.1
Inclusion Criteria .....................................................................................................30
8.1.1
Dose-Finding Phase ...........................................................................................30
8.1.2
Expansion Phase ................................................................................................31
8.2
Exclusion Criteria ....................................................................................................32
8.2.1
Dose-Finding Phase ...........................................................................................32
8.2.2
Expansion Phase ................................................................................................33


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9.0
STUDY DRUG .............................................................................................................36
9.1
Study Drug Administration......................................................................................36
9.2
Definitions of Dose-Limiting Toxicity.....................................................................36
9.3
Dose Escalation Rules..............................................................................................36
9.4
Excluded Concomitant Medications and Procedures ................................................38
9.5
Permitted Concomitant Medications and Procedures................................................38
9.6
Precautions and Restrictions ....................................................................................38
9.6.1
HSC Source .......................................................................................................38
9.6.2
Criteria for Dosing on Days +13 and +42 After Allo-HSCT...............................38
9.6.3
Reproductive Effects..........................................................................................39
9.7
Management of Clinical Events ...............................................................................39
9.7.1
Hypersensitivity Reactions.................................................................................39
9.7.2
Leukopenia or Lymphopenia..............................................................................40
9.7.3
Cytomegalovirus Colitis.....................................................................................40
9.7.4
Malignancy........................................................................................................40
9.7.5
Other Clinical Events.........................................................................................40
9.8
Dose Modification or Treatment Delay for Vedolizumab-Related Toxicity..............41
9.9
Blinding and Unblinding..........................................................................................41
9.10
Description of Investigational Agent........................................................................41
9.11
Preparation, Reconstitution, and Dispensation..........................................................41
9.12
Packaging and Labeling...........................................................................................41
9.13
Storage, Handling, and Accountability.....................................................................42
9.14
Other Protocol-Specified Materials ..........................................................................42
10.0
STUDY CONDUCT......................................................................................................43
10.1
Study Personnel and Organizations..........................................................................43
10.2
Arrangements for Recruitment of Patients................................................................43
10.3
Study Procedures.....................................................................................................43
10.3.1 Informed Consent...............................................................................................43
10.3.2 Patient Demographics ........................................................................................43
10.3.3 Medical History .................................................................................................43
10.3.4 Physical Examination.........................................................................................44
10.3.5 Neurological Examination..................................................................................44
10.3.6 Patient Height and Weight .................................................................................44
10.3.7 Vital Signs .........................................................................................................44
10.3.8 Progressive Multifocal Leukoencephalopathy Checklist.....................................44


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10.3.9 Pregnancy Test...................................................................................................44
10.3.10
Concomitant Medications and Procedures ....................................................44
10.3.11
Adverse Events ............................................................................................45
10.3.12
Enrollment ...................................................................................................45
10.3.13
Clinical Laboratory Evaluations ...................................................................45
10.3.14
Tuberculosis Screening ................................................................................46
10.3.15
Chimerism Analysis .....................................................................................46
10.3.16
Disease Assessment......................................................................................46
10.3.17
Pharmacokinetic Measurements ...................................................................46
10.3.18
Pharmacodynamic Measurements.................................................................47
10.3.19
Immunogenicity ...........................................................................................47
10.4
Completion of Treatment .........................................................................................47
10.5
Completion of Study................................................................................................47
10.6
Discontinuation of Treatment With Study Drug and Patient Replacement................47
10.7
Withdrawal of Patients From Study .........................................................................48
10.8
Study Compliance....................................................................................................48
10.9
Posttreatment Follow-up Assessments .....................................................................48
11.0
ADVERSE EVENTS ....................................................................................................49
11.1
Definitions...............................................................................................................49
11.1.1 Pretreatment Event Definition............................................................................49
11.1.2 Adverse Event Definition...................................................................................49
11.1.3 Serious Adverse Event Definition ......................................................................49
11.2
Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events........................................................................................................50
11.3
Monitoring of Adverse Events and Period of Observation........................................51
11.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events.........51
11.5
Procedures for Reporting Product Complaints..........................................................51
11.6
Risk Minimization Action Plan for PML (RAMP Program) .....................................52
12.0
STUDY-SPECIFIC COMMITTEES .............................................................................54
12.1
Dose Escalation and Cohort Expansion Plan ............................................................54
13.0
DATA HANDLING AND RECORDKEEPING............................................................55
13.1
eCRFs......................................................................................................................55
13.2
Record Retention .....................................................................................................55
14.0
STATISTICAL METHODS..........................................................................................57
14.1
Statistical and Analytical Plans ................................................................................57
14.1.1 Analysis Sets......................................................................................................57


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14.1.2 Procedures for Handling Missing, Unused, and Spurious Data ...........................57
14.1.3 Analysis of Demographics and Other Baseline Characteristics ...........................57
14.1.4 Efficacy Analysis...............................................................................................57
14.1.5 Pharmacokinetic Analysis ..................................................................................58
14.1.6 Pharmacodynamic Analysis ...............................................................................58
14.1.7 Immunogenicity Analysis...................................................................................58
14.1.8 Safety Analysis ..................................................................................................58
14.2
Interim Analysis and Criteria for Early Termination ................................................59
14.3
Determination of Sample Size..................................................................................59
15.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................60
15.1
Study-Site Monitoring Visits ...................................................................................60
15.2
Protocol Deviations..................................................................................................60
15.3
Quality Assurance Audits and Regulatory Agency Inspections ................................60
16.0
ETHICAL ASPECTS OF THE STUDY........................................................................61
16.1
IRB and/or IEC Approval ........................................................................................61
16.2
Subject Information, Informed Consent, and Subject Authorization .........................62
16.3
Subject Confidentiality ............................................................................................63
16.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................63
16.4.1 Publication and Disclosure.................................................................................63
16.4.2 Clinical Trial Registration..................................................................................64
16.4.3 Clinical Trial Results Disclosure ........................................................................64
16.5
Insurance and Compensation for Injury....................................................................64
17.0
REFERENCES..............................................................................................................65
LIST OF IN-TEXT TABLES
Table 10.a
Clinical Chemistry and Hematology Tests..........................................................45
Table 10.b
Clinical Urinalysis Tests ....................................................................................46
LIST OF IN-TEXT FIGURES
Figure 7.a
Overview of Study Design From Days –1 to +50 ...............................................29
LIST OF APPENDICES
Appendix A
Schedule of Events.............................................................................................68


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Appendix B
Responsibilities of the Investigator.....................................................................74
Appendix C
Investigator Consent to Use of Personal Information..........................................76
Appendix D
Clinical Stages and Grades of Graft-Versus-Host Disease ..................................77
Appendix E
Recommended Tacrolimus + Short-Term Methotrexate Prophylaxis Regimen ...78
Appendix F
Eastern Cooperative Oncology Group (ECOG) Scale for Performance Status.....79
Appendix G
Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) Scores.........80
Appendix H
Grade 4 Regimen-Related Organ Toxicities .......................................................81
Appendix I
Detailed Description of Amendments to Text.....................................................82


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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 
Plus Standard of Care for Graft-Versus-Host Disease 
(GvHD) Prophylaxis in Patients Undergoing Allogeneic 
Hematopoietic Stem Cell Transplantation (HSCT)
IND No.:
127,634
EudraCT No.:
Not Applicable
Study Number: Vedolizumab-1015
Phase: 1b
Study Design:
This is a phase 1b, open-label, dose-finding study designed to evaluate the safety, tolerability, and clinical activity of 
adding vedolizumab to standard graft-versus-host disease (GvHD) prophylaxis (tacrolimus plus short-term 
methotrexate) in adult patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). 
Vedolizumab dose finding will be cohort based and follow a rule-based dose-finding study design with 
pharmacokinetic (PK) guidance. After a tolerated dose with acceptable PK has been identified, the cohort at that dose 
level may be expanded to further assess the tolerability and effectiveness of 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. Study drug will be administered initially on Day –1 before 
allo-HSCT and then on Days +13 and +42 after allo-HSCT.
Approximately 36 evaluable patients will be enrolled in this study. For PK endpoints, an evaluable patient is one who 
receives vedolizumab and has at least 1 PK sample collected.
Patients who remain in remission will be followed for safety and development of acute and chronic GvHD for 1 year 
after allo-HSCT or until the patient’s death or withdrawal of consent or termination of the study by the sponsor. All 
patients will be followed for overall survival (OS) 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. Patients will attend a Day +100 visit 
(±7 days) at which time they will enter posttreatment follow-up.
Dose escalation will start with a low-dose cohort receiving vedolizumab at 75 mg IV on Day –1 and on Days +13 and 
+42 after allo-HSCT. HSC infusion should occur on Day 0 (no sooner than 12 hours after completion of IV infusion of 
vedolizumab on Day –1). The first patient in each dosing cohort will then be monitored for dose-limiting toxicities 
(DLTs) from the start of the first IV infusion of vedolizumab on Day –1 to Day +28 after allo-HSCT (the DLT 
observation period) including assessment for neutrophil recovery by Day +28. If the first patient in the first cohort 
tolerates vedolizumab IV at 75 mg and engraftment occurs, then 2 more patients will be enrolled in the first cohort. If 
none of the first 3 patients experience DLTs, the next cohort will receive vedolizumab 300 mg IV on Day –1 and on 
Days +13 and +42 after allo-HSCT. If the first patient in this cohort tolerates vedolizumab IV at 300 mg and 
engraftment occurs, then 2 more patients will be enrolled in the second cohort. If the first 3 patients at 300 mg tolerate 
the treatment without experiencing DLTs, then the decision on whether to increase the vedolizumab IV dose in the 
next cohort will be guided by the PK results. If 1 of the first 3 patients in the cohort experiences a DLT, then 3 
additional patients will be enrolled at the same dose level and monitored for DLTs from Day –1 until Day +28. If none 
of the additional patients experiences a DLT, then the decision on whether to increase the vedolizumab IV dose in the 
next cohort will be guided by the PK results. If 2 or more patients in a cohort of either 3 or 6 patients experience a 
DLT, then the dose of vedolizumab IV for the next cohort of 3 patients will be reduced. These patients will be 
monitored for DLTs in the same manner that patients in the previous cohort were monitored. 
After a tolerated dose level with acceptable PK has been identified in patients who are undergoing unrelated-donor 
myeloablative transplant for the treatment of hematologic malignancies, the cohort at that dose level may be expanded 
to include approximately 18 additional patients undergoing myeloablative conditioning or reduced-intensity 
conditioning (RIC) and are receiving either related or unrelated allo-HSCT for the treatment of hematologic 
malignancies or myeloproliferative neoplasms. This group of patients will allow the further assessment of the 


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tolerability and clinical activity of vedolizumab IV.
Vital signs, physical and neurological examinations, adverse event (AE) assessments, and laboratory values 
(chemistry, hematology, and urinalysis) will be obtained to evaluate the safety and tolerability of vedolizumab IV. To 
exclude patients with progressive multifocal leukoencephalopathy (PML), a Risk Assessment and Minimization for 
PML (RAMP) questionnaire will be administered at Screening and before vedolizumab IV administration on Days -1 
before allo-HSCT, and on Days +13 and +42 after allo-HSCT.
Serial blood samples for the evaluation of PK of vedolizumab will be obtained at prespecified time points. PK of 
vedolizumab will be analyzed for each of the first 3 patients at each dose level. It is expected that the 
concentration-time profile of vedolizumab will be influenced by the level of α4β7 target saturation. If α4β7 is saturated, 
then vedolizumab clearance would be linear; if α4β7is not saturated, then clearance would be nonlinear indicating rapid 
elimination. If the clearance of vedolizumab is nonlinear at the 300 mg dose, then subsequent dosing for all patients 
will be increased in approximately 150 mg increments (up to a maximum of 600 mg) until linear PK clearance is 
achieved.
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.
Primary Objective:
!
To describe the initial tolerability and safety and identify a recommended phase 2 dose of vedolizumab IV 
administered for GvHD prophylaxis along with standard GvHD prophylaxis therapy (tacrolimus plus short-term 
methotrexate) in patients undergoing allo-HSCT.
Secondary Objectives:
!
To characterize the PK of vedolizumab in patients on Days -1, +13, and +42 after allo-HSCT.
!
To determine the cumulative incidence and severity of acute GvHD at 100 days after allo-HSCT.
!
To determine the distribution of maximum severity of acute GvHD throughout the 100-day period after 
allo-HSCT.
Exploratory Objectives:
 
 
 
CCI
CCI


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Subject Population: Adult patients undergoing allo-HSCT for the treatment of hematologic malignancies or 
myeloproliferative neoplasms.
Number of Subjects:
Approximately 36 evaluable patients
Number of Sites: 
Approximately 3 to 4 in the United States
Dose Level(s):
Vedolizumab: initially 75 mg on Day –1 before allo-HSCT 
and on Days +13 and +42 after myeloablative allo-HSCT
Route of Administration:
Vedolizumab: intravenous (IV)
Duration of Treatment:
Patients will receive up to 3 doses of vedolizumab IV within 
the first 100 days after allo-HSCT.
Period of Evaluation:
Patients who remain in remission will be followed for 
safety and development of acute and chronic GvHD for 
1 year after allo-HSCT 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 until 
death, withdrawal of consent, termination of the study 
by the sponsor, or for a maximum of 1 year after the 
last patient enrolled is enrolled in the study.
Additionally, subjects will be required to participate in 
a long-term follow-up (LTFU) safety survey 6 months 
after the last dose of study drug.
It is anticipated that this study will last for 
approximately 2 to 3 years.
Main Criteria for Inclusion:
In the initial cohort for dose finding, patients who are undergoing unrelated-donor myeloablative transplant for the 
treatment of hematologic malignancies and who are ≤60 years of age will be enrolled. After a recommended phase 2 
dose has been identified, the cohort at that dose level may be expanded to include additional patients receiving 
myeloablative conditioning or RIC (≤75 years of age) who are undergoing either related or unrelated allogeneic HSCT 
for the treatment of hematologic malignancies or myeloproliferative neoplasms.
Main Criteria for Exclusion:
Patients will be excluded from the study who have received prior allogeneic transplants or who are planned to undergo 
umbilical cord blood transplant, receive ex vivo T-cell-depleted hematopoietic stem cells (HSCs), receive any in vivo 
T-cell depleting antibodies, or RIC (in the dose-finding potion only). Patients with active cerebral/meningeal disease, 
active cytomegalovirus (CMV) colitis, or signs and symptoms of progressive multifocal leukoencephalopathy (PML) 
or any history of PML will also be excluded. In addition, patients with nonmalignant hematological disorders (eg, 
aplastic anemia, sickle cell anemia, thalassemias, Fanconi anemia) will be excluded in the both portions of the study.
Main Criteria for Evaluation and Analyses:
The primary endpoint of this study is to determine the recommended phase 2 dose of vedolizumab IV administered for 
GvHD prophylaxis along with standard GvHD prophylaxis therapy as assessed by the frequency of DLTs and the 
number and percentage of patients who experience treatment-emergent adverse events (TEAEs) or serious adverse 
events (SAEs) from administration of the first dose of vedolizumab IV through 18 weeks after administration of the 
last dose of vedolizumab IV. In addition, mean serum concentrations of vedolizumab will help inform the likelihood 
of α4β7 target saturation throughout the first 100 days following allo-HSCT.
Statistical Considerations:
Statistical analyses will be primarily descriptive and graphical in nature. No formal statistical hypothesis testing will 
be performed. A formal statistical analysis plan will be developed and finalized before database lock.


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Sample Size Justification:
Approximately 18 evaluable patients will be enrolled to identify a tolerable vedolizumab dose level with acceptable 
PK. After the dose level has been identified, the cohort at that dose level may be expanded to include approximately 18 
additional patients receiving myeloablative conditioning or RIC who are undergoing either related or unrelated 
allo-HSCT for the treatment of hematologic malignancies or myeloproliferative neoplasms. This group of patients will 
allow the further assessment of the tolerability and clinical activity of vedolizumab IV. The sample size estimates are 
based on the primary objective of determining a recommended phase 2 dose and to describe the initial tolerability and 
safety of vedolizumab IV administered along with standard GvHD prophylaxis.


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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
ALL
acute lymphoblastic leukemia
allo-HSCT
allogeneic hematopoietic stem cell transplantation
AML
acute myeloid leukemia
ANC
absolute neutrophil count
APC
antigen-presenting cell
AUC
area under the serum concentration-time curve
AVA
anti-vedolizumab antibody
BMT CTN
Blood and Marrow Transplant Clinical Trials Network
BuFlu
busulfan + fludaradine
CD
Crohn’s disease
Ctrough
serum concentration before dosing
CMV
cytomegalovirus
CRF
case report form
CRO
contract research organization
CRp
complete remission with incomplete platelet recovery
CTCAE
Common Terminology Criteria for Adverse Events 
CyTBI
cyclophosphamide + total body irradiation
DLT
dose-limiting toxicity
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EU
European Union
FDA
Food and Drug Administration
GALT
gut-associated lymphoid tissue 
GCP
Good Clinical Practice
GCSF
granulocyte-colony stimulating factor
GI
gastrointestinal(ly)
GRFS
GvHD-free, relapse-free survival
GvHD
graft-versus-host disease
HBV
hepatitis B virus surface antigen
HCT-CI
Hematopoietic Cell Transplantation-Specific Comorbidity Index
HCV
hepatitis C virus antigen
HIV
human immunodeficiency virus
HLA
human leukocyte antigen
HSC
hematopoietic stem cell
HSCT
hematopoietic stem cell transplantation
IAC
Independent Adjudication Committee 
IB
Investigator’s Brochure


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Term
Definition
IBD
inflammatory bowel disease
IBMTR
International Bone Marrow Transplant Registry Database
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IL-6
interleukin-6
IL-17
interleukin-17
IPS
idiopathic pneumonia syndrome
IRB
institutional review board
IV
intravenous(ly)
MAdCAM-1
mucosal addressin cell adhesion molecule-1
MedDRA
Medical Dictionary for Regulatory Activities
NCI 
National Cancer Institute 
NOAEL
no-observed-adverse-effect level
OS
overall survival
PCR
polymerase chain reaction
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PML
progressive multifocal leukoencephalopathy
PTE
pretreatment event
PVC
polyvinyl chloride
Q4W
once every 4 weeks
Q8W
once every 8 weeks
RAMP
Risk Assessment and Minimization of PML
RIC
reduced-intensity conditioning
SAE
serious adverse event
SAP
statistical analysis plan
ST2
suppressor of tumorigenicity 2
TB
tuberculosis
TEAE
treatment-emergent adverse event
TNF-α
tumor necrosis factor-alpha 
UC
ulcerative colitis
US
United States
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
Millenium 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 hematological malignant disorders and hematological genetic diseases, but its use is 
limited by the major complication of graft-versus-host disease (GvHD) [1]. The common 
complication of GvHD following an 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]. In patients receiving hematopoietic stem cells from an 
unrelated donor source after myeloablative conditioning, the risk of Grade 2 to 4 acute GvHD is 
approximately 40% to 50% [2,3]. The reduction of GvHD without causing significant systemic 
immunosuppression may improve overall outcomes following allo-HSCT [2,5]. 
GvHD results from an activation of alloreactive donor lymphocytes by histocompatibility antigens 
on host antigen-presenting cells (APCs) [6,7]. It has been postulated that intestinal microflora and 
endotoxin exert a crucial step in APC activation, and that this process occurs in the gut-associated 
lymphoid tissues (GALT). Clinically, GvHD can be reduced through the use of T-cell depletion 
strategies and gut decontamination, highlighting the respective roles of both T cells and 
gastrointestinal (GI) microflora on the development of GvHD. In clinical HSCT, the human 
lymphocyte integrin α4β7 has been shown to be significantly increased on naïve and memory T 
cells in patients who subsequently developed intestinal acute GvHD compared with patients who 
developed skin acute GvHD or no GvHD [8]. Studies in murine models of acute GvHD suggest 
that prevention of T-cell trafficking to GALT via interruption of the interaction between α4β7 and 
mucosal addressin cell adhesion molecule-1 (MAdCAM-1) may prevent GvHD [9-11]. 
4.1.2
Vedolizumab IV
Vedolizumab (also called MLN0002) is a humanized immunoglobulin (Ig) G1 mAb directed 
against the human lymphocyte integrin 47. The 47 integrin mediates lymphocyte trafficking 
to GI mucosa and GALT through adhesive interaction with MAdCAM-1, which is expressed on 
the endothelium of mesenteric lymph nodes and GI mucosa [12-15]. Vedolizumab binds the 47 
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 [16]. 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 which after appropriate reconstitution and 
dilution is intended for intravenous (IV) infusion that has been granted marketing approval in 
several regions, including the United States (US) and European Union (EU). 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 


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intolerant to, or demonstrated dependence on corticosteroids. The approved dosing and 
administration regimen consists of 300 mg vedolizumab infused intravenously 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, pharmacokinetic (PK), pharmacodynamic (PD), and immunogenicity of 
vedolizumab.
4.1.2.1
Nonclinical
Several key nonclinical studies have been published that support the use of vedolizumab for the 
prevention of GvHD (see Section 4.1.1). 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 [16].
4.1.2.2
Human Experience
To date, more than 3400 subjects have received at least 1 dose of vedolizumab across all studies in 
the clinical development program (see current version of Investigator’s Brochure [IB]). Phase 3 
placebo-controlled studies enrolled 2427 subjects with UC or CD, of whom 1434 subjects 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, 1786 subjects in clinical studies have been exposed to 
vedolizumab for ≥12 months, 1379 subjects for ≥24 months, 977 subjects for ≥36 months, 
724 subjects for ≥48 months, and 344 subjects for ≥60 months. Since approval in May 2014, the 
patient exposure of vedolizumab in the postmarketing setting as of May 2015 is estimated to be 
approximately 11,943 patient-years on the basis of drug shipment data.
In subjects with moderately to severely active CD (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 to 
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 (CDAI-100) 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, as well as important secondary endpoints, 
including enhanced clinical response at Week 52 and corticosteroid-free clinical remission at 
Week 52 [18].
In 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 


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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].
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 (t1/2z) 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 have been related to exacerbations or complications of the 
underlying UC or CD. For those infections that were reported more frequently in 
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. 
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Overall, vedolizumab was well tolerated in clinical studies.
4.2
Rationale for the Proposed Study
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 undergoing allo-HSCT because of the specific mechanism of action of 
vedolizumab. Prophylactic administration of vedolizumab to patients undergoing allo-HSCT may 
prevent trafficking of alloreactive T-cells to GALT and GI mucosa, thereby preventing the 
development of acute GvHD. 
Dose and Schedule
The starting dose and schedule of vedolizumab IV administration is 75 mg on Day –1 before 
allo-HSCT and on Days +13 and +42 after allo-HSCT. The first dose will be on Day –1 and the 
allo-HSCT will occur on Day 0, no sooner than 12 hours after completion of the IV infusion of 
vedolizumab to ensure distribution of vedolizumab and to minimize the likelihood of occurrence 
of infusion-related reactions at the time of HSC infusion. If none of the patients receiving 
vedolizumab IV at 75 mg experience dose-limiting toxicities (DLTs), dose escalation will 
continue to 300 mg on Day –1 before allo-HSCT and on Days +13 and +42 after allo-HSCT. A 
dose of 300 mg on Day –1 before allo-HSCT and on Days +13 and +42 is identical to the induction 
dose and schedule of vedolizumab approved for the treatment of UC or CD. 
The no-observed-adverse-effect level (NOAEL) in both pharmacologically responsive species 
(monkeys and rabbits) was 100 mg/kg vedolizumab IV. Collectively, nonclinical studies show that 
doses up to 100 mg/kg vedolizumab IV were well tolerated. This dose was associated with an 
exposure 26 times (rabbits) and 18 times (cynomolgus monkeys) higher than the geometric mean 
clinical area under the serum concentration-time curve [AUC] after a single dose of 300 mg 
vedolizumab IV by 30-minute infusion.
In addition, extensive clinical data exists in healthy volunteers and patients with IBD. 
Vedolizumab IV has been administered as both weight-adjusted doses (0.15-10.0 mg/kg) and 
fixed doses (180-750 mg). The PK of vedolizumab in healthy subjects and patients with UC or CD 
is described by a 2-compartment model with parallel linear and nonlinear elimination. Elimination 
of vedolizumab is linear at serum concentrations higher than 1 to 10 µg/mL, but nonlinear at lower 
serum concentrations [20,21]. The linear elimination kinetics suggest that the α4β7 target is 
saturated at serum concentrations greater than 10 µg/mL, but not saturated at lower serum 
concentrations in healthy subjects and patients with either UC or CD. In addition, serum 
concentrations of vedolizumab needed to provide efficacy in both UC and CD are greater than 
serum concentrations for full receptor occupancy [21]. Based on the 300 mg dose of vedolizumab 
IV administered once every 8 weeks in patients with UC or CD, the serum concentration of 
vedolizumab is expected to maintain >90% α4β7 receptor saturation over the dosing interval in 
>90% of subjects.
Unlike healthy subjects and subjects with UC or CD, subjects undergoing a myeloablative 
conditioning regimen [22] followed by allo-HSCT are expected to have markedly changing T-cell 


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populations with variable 47 integrin expression during the posttransplant period. The 
rule-based dose-finding strategy with PK guidance will ensure that the dose and schedule of 
vedolizumab selected for this patient population are well tolerated and effectively saturate the α4β7
target.
The mechanistic hypothesis for the prevention of GvHD requires sustained α4ß7-blockade at the 
time of hematopoietic stem cell infusion. Given the safety profile for the range of exposure for 
vedolizumab as noted previously, a dose of 300 mg would achieve sustained receptor saturation. 
The kinetics of vedolizumab established in patients with IBD suggest that the intended dosing 
schedule of vedolizumab will result in target saturation throughout the first 100 days following 
HSCT, which is the time period where the vast majority of acute GvHD occurs.


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5.0
STUDY OBJECTIVES
5.1
Primary Objective
The primary objective is:
!
To describe the initial tolerability and safety and identify a recommended phase 2 dose of 
vedolizumab IV administered for GvHD prophylaxis along with standard GvHD prophylaxis 
therapy (tacrolimus plus short-term methotrexate) in patients undergoing allo-HSCT.
5.2
Secondary Objectives
The secondary objectives are:
!
To characterize the PK of vedolizumab in patients on Days -1, +13 and +42 after allo-HSCT.
!
To determine the cumulative incidence and severity of acute GvHD at 100 days after 
allo-HSCT.
!
To determine the distribution of maximum severity of acute GvHD throughout the 100-day
period after allo-HSCT.
5.3
Exploratory Objectives
The exploratory objectives are:
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6.0
STUDY ENDPOINTS
6.1
Primary Endpoints
The primary endpoints to identify the recommended phase 2 dose of vedolizumab IV administered 
for GvHD prophylaxis along with standard GvHD prophylaxis therapy include:
!
Frequency of DLTs from the start of the first IV infusion of vedolizumab on Day –1 until Day 
+28 (the DLT observation period).
!
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 serious adverse events (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 that will help inform the likelihood of α4β7 target 
saturation throughout the first 100 days following allo-HSCT.
6.2
Secondary Endpoints
The secondary endpoints are:
!
Mean time to neutrophil engraftment (recovery of absolute neutrophil count [ANC]) defined 
by an ANC >500/mm3 for 3 consecutive days or >2000/mm3 for 1 day. The first day of the 
3-day period will be considered the day of neutrophil engraftment.
!
Percentage of patients who have developed overall Grade 2 to 4 acute GvHD (compiled from 
individual organ scores of gut, skin, or liver) by 100 days after myeloablative allo-HSCT.
!
The frequency by maximum severity of acute GvHD according to the modified Glucksberg 
criteria and Blood and Marrow Transplant Clinical Trials Network (BMT CTN)-modified 
International Bone Marrow Transplant Registry Database (IBMTR) index (See Appendix D).
!
Mean serum concentrations of vedolizumab before dosing (Ctrough) on Days +13 and +42 after 
myeloablative allo-HSCT.
6.3
Exploratory Endpoints 
The exploratory endpoints are:
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7.0
STUDY DESIGN
7.1
Overview of Study Design
This is a phase 1b, open-label, dose-finding study designed to evaluate the safety, tolerability, and 
clinical activity of adding vedolizumab to standard GvHD prophylaxis (tacrolimus plus short-term 
methotrexate) in adult patients undergoing allo-HSCT. Vedolizumab dose finding will be cohort
based and follow a rule-based dose-finding study design with PK guidance. After a tolerated dose 
with acceptable PK has been identified, the cohort at that dose level may be expanded to further 
assess the tolerability and effectiveness of 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. Study drug 
will be administered initially on Day –1 before allo-HSCT and then on Day +13 and Day +42 after 
allo-HSCT.
Approximately 36 evaluable patients will be enrolled in this study. For PK endpoints, an evaluable 
patient is one who receives vedolizumab IV and has at least 1 PK sample collected.
Patients who remain in remission will be followed for safety and development of acute and chronic 
GvHD for 1 year after allo-HSCT or until the patient’s death or withdrawal of consent or 
termination of the study by the sponsor. Remission will be defined by conventional World Health 
Organization (WHO) criteria: <5% blast cells, count recovery (although complete remission with 
incomplete platelet recovery [CRp] would be allowed), and no evidence of extramedullary 
disease. All patients will be followed for OS 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. 
Patients will attend a Day +100 visit (±7 days) at which time they will enter posttreatment 
follow-up. 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.
Dose escalation will start with a low-dose cohort receiving vedolizumab at 75 mg IV on Day –1 
before allo-HSCT and on Days +13 and +42 after allo-HSCT. HSC infusion should occur on 
Day 0 no sooner than 12 hours after completion of IV infusion of vedolizumab on Day –1. The 
first patient in each dosing cohort will then be monitored for DLTs from the start of the first IV 
infusion of vedolizumab on Day –1 until Day +28 (the DLT observation period) including 
assessment for neutrophil recovery by Day +28. If the first patient in the first cohort tolerates 
vedolizumab IV at 75 mg and engraftment occurs, then 2 more patients will be enrolled in the first 
cohort. If none of the first 3 patients experience DLTs, the next cohort will receive vedolizumab 
300 mg IV on Day –1 before allo-HSCT and on Days +13 and +42 after allo-HSCT. If the first 
patient in this cohort tolerates vedolizumab IV at 300 mg and engraftment occurs, then 2 more 
patients will be enrolled in the second cohort. If the first 3 patients at 300 mg tolerate the treatment 
without experiencing DLTs, then the decision on whether to increase the vedolizumab IV dose in 
the next cohort will be guided by the PK results. If 1 of the first 3 patients in the cohort experiences 
a DLT, then 3 additional patients will be enrolled at the same dose level and monitored for DLTs 
from Day –1 until Day +28. If none of the additional patients experiences a DLT, then the decision 


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on whether to increase the vedolizumab IV dose in the next cohort will be guided by the PK 
results. If 2 or more patients in a cohort of either 3 or 6 patients experience a DLT, then the dose of 
vedolizumab IV for the next cohort of 3 patients will be reduced. These patients will be monitored 
for DLTs in the same manner that patients in the previous cohort were monitored. 
After a tolerated dose level with acceptable PK has been identified in patients who are undergoing 
unrelated-donor myeloablative transplant for the treatment of hematologic malignancies, the 
cohort at that dose level may be expanded to include approximately 18 additional patients 
undergoing myeloablative conditioning or reduced-intensity conditioning (RIC) [22] and are 
receiving either related or unrelated allo-HSCT for the treatment of hematologic malignancies or 
myeloproliferative neoplasms. This group of patients will allow the further assessment of the 
tolerability and clinical activity of vedolizumab IV.
Vital signs, physical and neurological examinations, adverse event (AE) assessments, and 
laboratory values (chemistry, hematology, and urinalysis as specified in Section 10.3.13) will be 
obtained to evaluate the safety and tolerability of vedolizumab IV, as described in the Schedule of 
Events. To exclude patients with progressive multifocal leukoencephalopathy (PML), a Risk 
Assessment and Minimization for PML (RAMP) questionnaire will be administered at Screening
and before vedolizumab IV administration on Days -1 before allo-HSCT and on Days +13 and +42 
after allo-HSCT.
Serial blood samples for the evaluation of PK of vedolizumab will be obtained at prespecified time 
points as described in the Schedule of Events. PK of vedolizumab will be analyzed for each of the 
first 3 patients at each dose level. It is expected that the concentration-time profile of vedolizumab 
will be influenced by the level of α4β7 target saturation. If α4β7 is saturated, then vedolizumab 
clearance would be linear; if α4β7is not saturated, then clearance would be nonlinear indicating 
rapid elimination. If the clearance of vedolizumab is nonlinear at the 300 mg dose, then subsequent 
dosing for all patients will be increased in approximately 150 mg increments (up to a maximum of 
600 mg) until linear PK clearance is achieved.
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 [24]. DLTs are 
defined in Section 9.2.
See Figure 7.a for an overview of the study design from Days -1 to +50.
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Figure 7.a
Overview of Study Design From Days –1 to +50
Allo-HSCT=allogeneic hematopoietic stem cell transplantation, AVA=anti-vedolizumab antibodies, 
DLT=dose-limiting toxicity, GvHD=graft-versus-host disease, IV=intravenous, PK=pharmacokinetic.
PK sampling for patients who have been discharged from the hospital will be aligned to clinic visits, and therefore may 
not be as frequent as represented in this figure. 
7.2
Number of Patients
Approximately 36 evaluable patients will be enrolled in this study from approximately 3 to 4 study 
centers in the United States. Enrollment is defined as when the written informed consent has been 
obtained and the patient’s eligibility has been confirmed per the inclusion and exclusion criteria.
Patients in the dose-finding cohort who are withdrawn from treatment for reasons other than DLT 
during the DLT observation period will be replaced.
7.3
Duration of Study
Patients who remain in remission will be followed for safety and development of acute and chronic 
GvHD for 1 year after allo-HSCT 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 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.
It is anticipated that this study will last for approximately 2 to 3 years.


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8.0
STUDY POPULATION
8.1
Inclusion Criteria
8.1.1
Dose-Finding Phase
Each patient must meet all of the following inclusion criteria to be enrolled in the study:
1. Male or female patients between 18 and 60 years, inclusive.
2. Candidates for human leukocyte antigen (HLA)-matched unrelated donor or 1-locus (antigen 
or allele) HLA-mismatched unrelated donor allo-HSCT, using either peripheral blood stem 
cells or bone marrow as the cell source, for the treatment of acute lymphoblastic leukemia 
(ALL) or acute myeloid leukemia (AML).
3. Disease must be in remission at the time of allo-HSCT. Remission of ALL and AML will be 
defined by conventional WHO criteria: <5% blast cells, count recovery (although CRp would 
be allowed), and no evidence of extramedullary disease.
4. Patients for whom a myeloablative conditioning regimen (such as cyclophosphamide + total 
body irradiation [CyTBI], busulfan + cyclophosphamide, or busulfan + fludaradine [BuFlu]) is 
planned. For definitions of myeloablative conditioning versus RIC regimens refer to 
Bacigalupa et al, 2009 [22].
5. Patients who are planned to receive standard GvHD prophylaxis of tacrolimus + short-term 
methotrexate by the investigator (refer to Appendix E).
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 (refer to Appendix 
F).
7. Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) score of ≤4 (refer to 
Appendix G).
8. Sufficient cognitive ability to reliably complete the RAMP questionnaire 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 2 effective methods of contraception, 
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] and withdrawal are not acceptable methods of contraception.)
Male patients, even if surgically sterilized (ie, status postvasectomy), who:


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
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 for the female partner] and withdrawal are not acceptable methods of 
contraception.)
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 
pharmacodynamic sampling. Patients with a planned central venous access device will be 
allowed.
8.1.2
Expansion Phase
Each patient must meet all of the following inclusion criteria to be enrolled in the study:
1. Male or female adult patients for whom a myeloablative conditioning (between 18 and 
60 years of age, inclusive) or RIC regimen (between 18 and 75 years of age, inclusive) is 
planned [22].
2. Candidates for HLA-matched or 1-locus (antigen or allele) mismatched unrelated or related 
donor allo-HSCT, using either peripheral blood stem cells or bone marrow as the cell source, 
for the treatment of hematologic malignancy or myeloproliferative neoplasm.
3. Disease must be in remission at the time of allo-HSCT. Remission is defined as one of the 
following:

Patients with acute leukemia, chronic myelogenous leukemia, and myelodysplasia with no 
circulating blasts and <5% blasts in the bone marrow.

Patients with chronic lymphocytic leukemia, small lymphocytic lymphoma, or other 
non-Hodgkin lymphoma with chemosensitive disease at time of transplantation.

Patients with myelofibrosis and other myeloproliferative neoplasms with <5% blasts in the 
blood and bone marrow.
4. Patients who are planned to receive standard GvHD prophylaxis of tacrolimus + short-term 
methotrexate by the investigator (refer to Appendix E).
5. ECOG performance status of 0 to 2 (refer to Appendix F).
6. Sufficient cognitive ability to reliably complete the RAMP questionnaire at baseline.
7. Female patients who:

Are postmenopausal for at least 1 year before the screening visit, OR

Are surgically sterile, OR


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
If they are of childbearing potential, agree to practice 2 effective methods of contraception, 
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] and withdrawal are not acceptable methods of contraception.)
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 for the female partner] and withdrawal are not acceptable methods of 
contraception.)
8. 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.
9. Suitable venous access for the study-required blood sampling, including PK and 
pharmacodynamic sampling. Patients with a planned central venous access device will be 
allowed.
8.2
Exclusion Criteria
8.2.1
Dose-Finding Phase
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
1. The patient has a positive PML subjective checklist before the administration of study drug.
2. The patient has a history of any major neurological disorders, including stroke, multiple 
sclerosis, brain tumor, or neurodegenerative disease.
3. Patients with active cytomegalovirus (CMV) colitis.
4. The patient has active or latent tuberculosis (TB), regardless of treatment history, as evidenced 
by any of the following:

History of TB.

A diagnostic TB test performed during screening that is positive, as defined by:
–
A positive QuantiFERON® test or 2 successive indeterminate QuantiFERON tests, OR
–
A tuberculin skin test reaction ≥10 mm (≥5 mm in patients receiving the equivalent of 
>15 mg/day prednisone).
5. The patient has chronic hepatitis B (HBV) or hepatitis C (HCV) infection.


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6. The patient has any identified congenital or acquired immunodeficiency (eg, common variable 
immunodeficiency, human immunodeficiency virus [HIV] infection, organ transplantation).
7. The patient has evidence of active C. difficile infection or other intestinal pathogens during 
Screening.
8. The patient has evidence of an active systemic infection during Screening.
9. Female patients who are breastfeeding or have a positive serum or urine pregnancy test during 
the Screening period or on Day –1 before first dose of study drug.
10. Any serious medical or psychiatric condition that could, in the investigator or medical 
monitor’s opinion, potentially interfere with the completion of treatment according to this 
protocol.
11. Patients who have received a prior allogeneic transplant.
12. Patients planned to undergo umbilical cord blood transplant or to receive in vivo or ex vivo 
T-cell-depleted HSCs.
13. Patients planned for RIC regimen or non-myeloablative regimen [22].
14. Single antigen mismatched patients who have donor-specific antibodies.
15. Prior exposure to vedolizumab, natalizumab, efalizumab, adalimumab, or rituximab, and 
anti-TNF-α or anti-TNF-α receptor antibodies, such as etanercept, lenercept, and infliximab.
16. Prior known exposure of either the donor or transplant recipient to vedolizumab.
17. The patient has 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, would confound the study 
results or compromise patient safety.
18. The patient has a history of hypersensitivity or allergies to vedolizumab or its components.
19. Treatment with anti-T-cell antibody (eg, alemtuzumab, anti-thymocyte globulin) within 
4 months before the first dose of vedolizumab. 
20. Treatment with any live vaccinations within 30 days prior to enrollment.
21. 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.
22. If male, the patient intends to donate sperm during the course of this study or for 18 weeks 
thereafter.
8.2.2
Expansion Phase
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
1. The patient has a positive PML subjective checklist before the administration of study drug.


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2. The patient has a history of any major neurological disorders, including stroke, multiple 
sclerosis, brain tumor, or neurodegenerative disease.
3. Patients with active CMV colitis.
4. The patient has active or latent TB, regardless of treatment history, as evidenced by any of the 
following:

History of TB.

A diagnostic TB test performed during screening that is positive, as defined by:
–
A positive QuantiFERON® test or 2 successive indeterminate QuantiFERON tests, OR
–
A tuberculin skin test reaction ≥10 mm (≥5 mm in patients receiving the equivalent of 
>15 mg/day prednisone).
5. The patient has chronic HBV or HCV infection.
6. The patient has any identified congenital or acquired immunodeficiency (eg, common variable 
immunodeficiency, HIV infection, organ transplantation).
7. The patient has evidence of active C. difficile infection or other intestinal pathogens during 
Screening.
8. The patient has evidence of an active systemic infection during Screening.
9. Female patients who are breastfeeding or have a positive serum or urine pregnancy test during 
the Screening period or on Day –1 before first dose of study drug.
10. Any serious medical or psychiatric condition that could, in the investigator or medical 
monitor’s opinion, potentially interfere with the completion of treatment according to this 
protocol.
11. Patients who have received a prior allogeneic transplant.
12. Patients planned to undergo umbilical cord blood transplant or to receive in vivo or ex vivo 
T-cell-depleted HSCs.
13. Patients undergoing HSCT for the treatment of nonmalignant hematological disorders 
(eg, aplastic anemia, sickle cell anemia, thalassemias, Fanconi anemia).
14. Single antigen mismatched patients who have donor-specific antibodies.
15. Prior exposure to vedolizumab, natalizumab, efalizumab, adalimumab, or rituximab, and 
anti-TNF-α or anti-TNF-α receptor antibodies, such as etanercept, lenercept, and infliximab.
16. Prior known exposure of either the donor or transplant recipient to vedolizumab.
17. The patient has 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, would confound the study 
results or compromise patient safety.


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18. The patient has a history of hypersensitivity or allergies to vedolizumab or its components.
19. Treatment with anti-T-cell antibody (eg, alemtuzumab, anti-thymocyte globulin) within 
4 months before the first dose of vedolizumab. 
20. Treatment with any live vaccinations within 30 days prior to enrollment.
21. 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.
22. If male, the patient intends to donate sperm during the course of this study or for 18 weeks 
thereafter.


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9.0
STUDY DRUG
9.1
Study Drug Administration
All protocol-specific criteria for administration of study drug must be met and documented prior to 
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 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.
Additional reference information and administration instructions can be found in the Pharmacy 
Manual.
9.2
Definitions of Dose-Limiting Toxicity
Toxicity will be evaluated according to the NCI CTCAE, Version 4.03, effective 14 June 2010
[24]. These criteria are provided in the Study Manual. 
The DLT observation period in the proposed phase 1b study is defined as the start of the first IV 
infusion of vedolizumab on Day –1 to Day +28 after allo-HSCT.
A DLT will be any Grade 3 or higher toxicity assessed by the investigator as related to 
vedolizumab treatment. Hypersensitivity reactions and other infusion-related reactions will not be 
considered a DLT. Any patient who discontinues the study due to an infusion-related reaction will 
be replaced in the study.
Grade 4 or higher regimen-related organ toxicities (see Appendix H) will be considered as 
potential DLTs and reviewed as described in Section 12.0 before moving to the next dose level.
Grade 4 laboratory abnormalities that are not considered clinically significant by the investigator 
will not be considered DLTs. 
Engraftment will be defined as ANC >500/mm3 for 3 consecutive days or >2000/mm3 for 1 day. 
Failure to engraft by Day +28 will be considered a DLT. In the event of engraftment failure, the 
third dose of vedolizumab should be withheld. 
9.3
Dose Escalation Rules
The starting dose and schedule of vedolizumab IV administration is 75 mg on Day –1 before 
allo-HSCT and on Days +13 and +42 after allo-HSCT. If none of the patients receiving 
vedolizumab IV at 75 mg experience DLTs, dose escalation will continue to 300 mg on Day –1 
before allo-HSCT and on Days +13 and +42 after allo-HSCT. A dose of 300 mg on Day –1 before 


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allo-HSCT and on Days +13 and +42 is identical to the induction dose and schedule of 
vedolizumab approved for the treatment of UC or CD.
The first patient enrolled will be monitored for engraftment before the second patient is enrolled. 
The dose escalation will start with sentinel dosing for the first cohort, whereby the first patient will 
receive 75 mg vedolizumab IV administration along with standard-of-care tacrolimus and 
short-term methotrexate prophylaxis. The patient will then be monitored for DLTs from the start of 
the first IV infusion of vedolizumab on Day –1 to Day +28 after allo-HSCT (the DLT observation 
period) including assessment for engraftment by Day +28. If the first patient in the first cohort 
tolerates vedolizumab IV at 75 mg and engraftment occurs, then 2 more patients will be enrolled in 
the first cohort. If at any time during the study it appears that vedolizumab might lead to 
unacceptable engraftment delay or failure, then the study design might be revised so that 
vedolizumab prophylaxis is initiated approximately 1 week after hematopoietic stem cell infusion.
If none of the first 3 patients experience DLTs, the next cohort will receive vedolizumab 300 mg 
IV on Day –1 before allo-HSCT and on Days +13 and +42 after allo-HSCT. If the first patient in 
this cohort tolerates vedolizumab IV at 300 mg and engraftment occurs, then 2 more patients will 
be enrolled in the second cohort. If the first 3 patients at 300 mg tolerate the treatment without 
experiencing DLTs, then the decision on whether to increase the vedolizumab IV dose in the next 
cohort will be guided by the PK results. If 1 of the first 3 patients in the cohort experiences a DLT, 
then 3 additional patients will be enrolled at the same dose level and monitored for DLTs from Day 
–1 until Day +28. If none of the additional patients experiences a DLT, then the decision on 
whether to increase the vedolizumab IV dose in the next cohort will be guided by the PK results. 
Serial blood samples for the evaluation of PK of vedolizumab will be obtained at prespecified time 
points as described in the Schedule of Events. PK of vedolizumab will be analyzed for each of the 
first 3 patients at each dose level. It is expected that the concentration-time profile of vedolizumab 
will be influenced by the level of α4β7 target saturation in depots outside of the peripheral blood 
compartment. If α4β7 is saturated, then vedolizumab clearance will be linear; if α4β7is not 
saturated, then clearance will be nonlinear, indicating rapid elimination. If the clearance of 
vedolizumab is nonlinear at the 300 mg dose, then subsequent dosing for all patients will be 
increased in approximately 150 mg increments (up to a maximum of 600 mg) until linear PK 
clearance is achieved. Any dose escalation of vedolizumab IV will be cohort based. Intrapatient 
dose escalation of vedolizumab IV will not be permitted.
If 2 or more patients in a cohort of either 3 or 6 patients experience a DLT, then the dose of 
vedolizumab for the next cohort of 3 patients will be reduced to the dose level in the previous 
cohort or to an interim dose level. These patients will be monitored for DLTs in the same manner 
that patients in the first cohort were monitored. 
After a tolerated dose with acceptable PK has been identified, the cohort at that dose level may be 
expanded to include approximately 18 additional patients undergoing myeloablative conditioning 
or RIC and are receiving either related or unrelated allo-HSCT for the treatment of hematologic 
malignancies or myeloproliferative neoplasms. This group of patients will allow the further 
assessment of the tolerability and clinical activity of vedolizumab.


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9.4
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 case report form (CRF). 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.

All live vaccines during study treatment and for at least 6 months after the last dose of study 
drug.

Either 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) or agents required for treatment of GvHD (and after consultation with 
the medical monitor).
9.5
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 electronic case report form (eCRF).
9.6
Precautions and Restrictions
9.6.1
HSC Source
A back-up plan for the event of primary graft failure must be identified for all patients in the study 
(ie, an alternate stem cell source) before performing the allo-HSCT.
9.6.2
Criteria for Dosing on Days +13 and +42 After Allo-HSCT
After a patient has received the first dose of vedolizumab IV on Day –1 before allo-HSCT, patients 
may not receive the second and/or third dose on Days +13 and +42 after allo-HSCT 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 CMV colitis.
3. The patient has evidence of uncontrolled C. difficile colitis. 
4. The patient experienced an anaphylactic reaction to vedolizumab.
5. If female, the patient is pregnant.


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9.6.3
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 of 
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 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] and withdrawal are not acceptable methods of contraception.)
Male patients, even if surgically sterilized (ie, status postvasectomy) must agree to 1 of the 
following:

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 for the female partner] and withdrawal are not acceptable methods of contraception.)
9.7
Management of Clinical Events 
9.7.1
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 prior to any study drug administration. Corticosteroids, if 
given as a premedication, should be limited to the day of 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 measure 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 


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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 project clinician.
9.7.2
Leukopenia or Lymphopenia
Leukocyte and lymphocyte counts will be monitored for all patients with a hematological panel 
(see Section 10.3.13). If engraftment has not occurred by Day +21 (defined as ANC >500/mm3 for 
3 consecutive days or >2000/mm3 for 1 day), the use of prophylactic myeloid growth factors (ie, 
granulocyte-colony stimulating factor [GCSF]) must be started with the product, dose, and route of 
administration at the discretion of the treating institution.
9.7.3
Cytomegalovirus 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 
suspected of having GvHD for whom the cause of transplantation-associated diarrhea and/or 
enterocolitis is unclear, the subject will require endoscopy and histologic analyses of intestinal 
biopsy specimens as clinically appropriate.
9.7.4
Malignancy
All cases of malignancies that are detected during the study, including relapse of primary disease 
will be reported as AEs.
9.7.5
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 10.3.8) prior to 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.


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9.8
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 9.7 for management of vedolizumab dosing for specific clinical events. The medical 
monitor should be contacted prior to any dose modification in vedolizumab for any patient in the 
study.
9.9
Blinding and Unblinding
Not applicable. This is an open-label study. 
9.10
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 
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.
9.11
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 
starting dose, 300 mg (5.0 mL) will be removed from each vial 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 prior 
to administration, whenever solution and container permit.
9.12
Packaging and Labeling
Vedolizumab IV will be supplied in a 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.


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9.13
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 to 46F). A daily temperature log of the drug 
storage area must be maintained every working day.
9.14
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.

PVC infusion line or alternative infusion line listed in the Pharmacy Manual.


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10.0
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.
10.1
Study Personnel and Organizations
The contact information for the Millennium project clinician for this study, the central laboratory 
and any additional clinical laboratories, the coordinating investigator for each member 
state/country (where applicable), 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.
10.2
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). 
10.3
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. 
10.3.1 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.
10.3.2 Patient Demographics
The date of birth, race, ethnicity, and sex of the patient are to be recorded during Screening.
10.3.3 Medical History
During the Screening period, a complete medical history will be compiled for each patient. The 
history will emphasize the background and progress of the patient’s malignancy and include a 
description of prior therapies for it. In addition, concomitant medications will be recorded as 
specified in Section 10.3.10.


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10.3.4 Physical Examination
Complete physical examinations and symptom-directed physical examinations, as appropriate,
will be completed per standard of care at the times specified in the Schedule of Events.
10.3.5 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. The neurological examination will be performed by the study neurologist. 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.
10.3.6 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.
10.3.7 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. On dosing days, 
vital signs will be obtained before and within 60 minutes of completion of infusion.
10.3.8 Progressive Multifocal Leukoencephalopathy 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 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 11.6 for additional details regarding the RAMP program.
10.3.9 Pregnancy Test
A serum or urine pregnancy test will be performed for women of childbearing potential at 
screening and within 4 days prior to 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.
10.3.10 Concomitant Medications and Procedures
Medications used by the patient and therapeutic procedures completed by the patient will be
recorded in the eCRF from the first dose of study drug through 18 weeks after the last dose of study 


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drug. See Section 9.4 and Section 9.5 for a list of medications and therapies that are prohibited 
and/or allowed during the study.
10.3.11 Adverse Events
Monitoring of AEs, serious and nonserious, will be conducted throughout the study as specified in 
the Schedule of Events. Refer to Section 11.0 for details regarding definitions, documentation, and 
reporting of pretreatment events (PTEs), AEs, and SAEs.
10.3.12 Enrollment
Enrollment is defined as when the written informed consent has been obtained and the patient’s 
eligibility has been confirmed per the inclusion and exclusion criteria. Procedures for completion 
of the enrollment information are described in the Study Manual.
10.3.13 Clinical Laboratory Evaluations
Clinical laboratory evaluations will be performed locally. Handling and shipment 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 10.a and urine samples for analysis of the parameters shown in Table 10.b will be obtained 
as specified in the Schedule of Events.
Table 10.a
Clinical Chemistry and Hematology Tests
Hematology
Chemistry
Hematocrit
Hemoglobin
Leukocytes with differential
Neutrophils ANC
Platelets (count)
Albumin
Alkaline phosphatase (ALP)
ALT
AST
Bilirubin (total)
Blood urea nitrogen (BUN)
Calcium
Carbon dioxide (CO2)
Creatinine
Chloride
Glucose
Lactate dehydrogenase (LDH)
Magnesium
Phosphate
Potassium
Sodium
Uric acid
PCR monitoring for CMV reactivation will be performed on a weekly basis (see Section 9.7.2).
Additionally, blood samples for measurement of anti-vedolizumab antibodies will be obtained as 
specified in the Schedule of Events.


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Table 10.b
Clinical Urinalysis Tests
Urinalysis
Bilirubin
Glucose
Ketones
Leukocytes
Nitrite
Occult blood
pH
Protein
Specific gravity
Turbidity and color
Urobilinogen
10.3.14 Tuberculosis Screening
All patients will complete TB screening to determine eligibility. All patients must complete a 
diagnostic test during screening, either a QuantiFERON® test or a tuberculin skin test. Subjects 
will be excluded from the study if they have active or latent TB, regardless of treatment history, as 
defined in Section 8.2.
10.3.15 Chimerism Analysis
A peripheral blood sample will be collected for chimerism analysis per institutional standards 
according to time points specified in the Schedule of Events
10.3.16 Disease Assessment
Acute GvHD will be assessed as specified in the Schedule of Events using the Glucksberg criteria 
and BMT CTN-modified IBMTR index for staging and grading acute GvHD (see Appendix D).
10.3.17 Pharmacokinetic 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 schedule in 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 prior to the start of 
infusion and end of the infusion samples should be collected within 5 minutes from the end of 
infusion. The exact dates and times of administration of vedolizumab (start and end of infusion) 
and the exact date 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 
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10.3.18 Pharmacodynamic Measurements
Detailed instructions for the handling and shipping of samples are provided in the Laboratory 
Manual.
10.3.19 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. 
Detailed instructions for the handling and shipping of samples are provided in the Laboratory 
Manual.
10.4
Completion of Treatment
Patients will be considered to have completed study treatment if they discontinue study drug for 
any of the reasons outlined in Section 10.6.
10.5
Completion of Study
Patients will be considered to have completed the study if they withdraw from the study for any of 
the reasons outlined in Section 10.7.
10.6
Discontinuation of Treatment With Study Drug and Patient Replacement
Treatment with study drug may be discontinued for any of the following reasons:
!
Adverse event.
!
Protocol violation.
!
Unsatisfactory therapeutic response.
!
Study terminated by sponsor.
!
Withdrawal by subject.
!
Lost to follow-up.
!
Other.
Once study drug has been discontinued, all study procedures outlined for the End of Treatment
visit will be completed as specified in the Schedule of Events. The primary reason for study drug 
discontinuation will be recorded on the eCRF.
Patients in the dose-finding cohort who are withdrawn from treatment for reasons other than DLT 
during the DLT observation period will be replaced.
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10.7
Withdrawal of Patients From Study
A patient may be withdrawn from the study for any of the following reasons:

Lost to follow-up.

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.
10.8
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.
10.9
Posttreatment Follow-up Assessments 
Patients will attend a Day +100 visit (±7 days) at which time patients will enter posttreatment 
follow-up. If subsequent anticancer therapy is required before 30 days after the last dose, the 
Day +100 visit should be conducted before the initiation of subsequent anticancer therapy.
Patients who remain in remission will be followed for development of acute and chronic GvHD 
and safety during clinic visits at 4, 5, 6, 9, and 12 months after allo-HSCT (Day 0) 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 until death, withdrawal of consent, termination of study by the 
sponsor, or for a maximum of 1 year after until the last patient is enrolled in the study. Survivor 
information may be collected by methods that include, but are not limited to, telephone, e-mail, 
mail, or retrieved from online or other databases (eg, social security indexes). 
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 11.0 for details regarding definitions, documentation, 
and reporting of SAEs.


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11.0
ADVERSE EVENTS
11.1
Definitions
11.1.1 Pretreatment Event Definition
A pretreatment event 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.
11.1.2 Adverse Event 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.
11.1.3 Serious Adverse Event 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 11.2 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 [24]. 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.
11.2
Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events
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 11.3 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 pretreatment events (as defined in Section 11.1) must be 
reported (see Section 11.3 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 
pretreatment event may be requested by Takeda. SAE report information must be consistent with 
the data provided on the eCRF.
SAE Reporting Contact Information
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).
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For both serious and nonserious AEs, the investigator must determine both the intensity of the 
event and the relationship of the event to study drug administration. For serious pretreatment 
events, the investigator must determine both the intensity of the event and the relationship of the 
event to study procedures.
Intensity for each AE, including any lab abnormality, will be determined using the NCI CTCAE, 
Version 4.03, effective date 14 June 2010 [24]. The criteria are provided in the Study Manual.
Relationship to study drug administration will be determined by the investigator responding yes 
or no to this question: Is there a reasonable possibility that the AE is associated with the study 
drug?
11.3
Monitoring of Adverse Events 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 pretreatment events will be reported to the Takeda Global Pharmacovigilance 
department or designee from the time of the signing of the ICF up to 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).
11.4
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 11.2). 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 11.2). Every effort 
should be made to follow the pregnancy for the final pregnancy outcome.
11.5
Procedures for Reporting Product Complaints
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 


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identify a potential product complaint situation should immediately report this via the phone 
numbers or email addresses below:
Call center
Phone number
E-mail
Fax
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 11.2).
11.6
Risk Minimization Action Plan for PML (RAMP Program)
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 (JCV) and typically only occurs in patients who are immunocompromised 
[25,26]. 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 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 [27,28]. In contrast, 
vedolizumab binds to the α4β7 integrin only [16] 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.
Patients undergoing HSCT are immunocompromised because of underlying disease, prior 
therapies, HSCT conditioning, and GvHD prophylaxis and treatment. The baseline risk of PML in 
the population of patients undergoing allo-HSCT for the treatment of malignancy can be estimated 
at 35.4 per 100,000 person-years (95% CI: 0.90, 197.29) compared with 0.2 per 100,000 patients 
with autoimmune diseases who did not have HIV or malignancy (including patients with 
IBD).[29,30] To address the theoretical 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. The complete description of the RAMP program, including 
materials and instructions for its implementation and monitoring, is included in the Study Manual.
The RAMP is focused on early clinical detection and management of that specific safety risk, 
including the discontinuation of study drug, if applicable. Patients are assessed for signs and 
symptoms of PML prior to the administration of each dose of study drug using a PML subjective 
symptom checklist. Patients with a positive PML subjective symptom checklist at any time after 
enrollment in a vedolizumab clinical study will be evaluated according to a prespecified algorithm 
(the PML Case Evaluation Algorithm). The next dose of study drug will be held until the 
evaluation is complete and results are available. Subsequent doses of study drug will be 
administered only if the possibility of PML is definitively excluded, as described in the RAMP 
algorithm. An Independent Adjudication Committee (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 patient evaluation and management as defined in the IAC charter.
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To ensure success of the RAMP program, site personnel will be trained to recognize the features of 
PML, and patients will be trained to report specific neurological signs and symptoms without 
delay. Educational materials for teaching site personnel and patients about PML and the RAMP 
procedures will be distributed to all sites and are included in the Study Manual. Formal teaching 
and training will be performed for site personnel prior to the start of the study. Patients will receive 
training and educational materials prior to receiving treatment. The informed consent form will 
contain specific information on the hypothetical risk of PML. Any documented case of PML will 
be reported as an SAE, regardless of whether hospitalization occurs.


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12.0
STUDY-SPECIFIC COMMITTEES
No steering committee, data safety monitoring committee, or clinical endpoint committee will be 
used in this study.
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.
12.1
Dose Escalation and Cohort Expansion Plan
End-of-Cohort Meetings will be held to review safety and PK data before moving to the next dose 
level in subsequent cohorts. The safety review will encompass the following: all available AEs for 
DLTs, appropriate dosing information and patient eligibility/evaluability, dose-toxicity 
relationships, and any other pertinent available safety and PK data. The review committee for the 
End-of-Cohort Meetings will include the sponsor study team, the study investigators, and an 
independent, third-party HSCT expert consultant. The study sponsor team will include, but will 
not be limited to, the following: the study clinician, safety lead, and other members as appropriate 
(biostatistics, clinical pharmacology, and translational medicine to interpret PK, PD, and 
biomarker data). During the dose escalation and expansion phases, review of safety data by the 
above listed parties will occur as needed on the basis of continuous monitoring of safety data, but 
at least quarterly by the study sponsor team, with consideration of the study stopping criteria (see 
Section 14.2).


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13.0
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.
13.1
eCRFs 
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.
13.2
Record Retention
The investigator agrees to keep the records stipulated in Section 13.1 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 informed consent forms, subject authorization forms 
regarding the use of personal health information (if separate from the informed consent 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, 
International Conference on Harmonisation (ICH) E6 Section 4.9.5 requires the investigator to 
retain essential documents specified in ICH E6 (Section 8) until at least 2 years after the last 


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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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14.0
STATISTICAL METHODS
14.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized prior to 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 prior to database lock. This review will assess the 
accuracy and completeness of the study database, patient evaluability, and appropriateness of the 
planned statistical methods.
14.1.1 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.

PK population: Defined as patients from the safety set with at least 1 PK sample collected. 

PD population: Defined as patients from the safety set with at least 1 PD sample collected.
For the primary endpoint, an evaluable patient is one who receives vedolizumab IV and is assessed 
for engraftment on or before Day +28.
14.1.2 Procedures for Handling Missing, Unused, and Spurious Data
All available safety, tolerability, efficacy, PK, and PD 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.
14.1.3 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.
14.1.4 Efficacy Analysis
Secondary efficacy endpoints include:

Percentage of patients who have developed overall Grade 2 to 4 acute GvHD (compiled from 
individual organ scores of gut, skin, or liver) by 100 days after myeloablative allo-HSCT.

The frequency by maximum severity of GvHD according to the modified Glucksberg criteria
and BMT CTN-modified IBMTR index.


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14.1.5 Pharmacokinetic 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 
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.
14.1.6 Pharmacodynamic Analysis 
14.1.7 Immunogenicity Analysis
Immunogenicity (anti-vedolizumab antibodies) will be descriptively summarized. The effect of 
anti-vedolizumab antibodies on safety and efficacy will be explored.
14.1.8 Safety Analysis
For the primary endpoint, an evaluable patient is one who receives vedolizumab IV and is assessed 
for engraftment on or before Day +28.
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 system organ class, high-level terms, and 
preferred terms and will include the following categories:
!
TEAEs.
CCI
CCI


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
Drug-related TEAEs.

Grade 3 or higher TEAEs.

Grade 3 or higher drug-related TEAEs.

The most commonly reported TEAEs (ie, those events reported by ≥10% of all patients).

SAEs.
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.
14.2
Interim Analysis and Criteria for Early Termination
No interim analysis is planned. Toxicities will be continuously monitored during all phases of the 
study.
In addition to ongoing safety reviews of cumulative data, early termination of the study will occur 
if any of the following are observed during the expansion phase of the study:

3 cases of CMV colitis, or

3 cases of engraftment failure; however, if first 2 cases of engraftment failure are in patients 
who received myeloablative conditioning, the study will be stopped.
14.3
Determination of Sample Size
Approximately 18 evaluable patients will be enrolled to identify a tolerable vedolizumab dose 
level with acceptable PK. After the dose level has been identified, the cohort at that dose level may 
be expanded to include approximately 18 additional patients receiving myeloablative conditioning 
or RIC who are undergoing either related or unrelated allo-HSCT for the treatment of hematologic 
malignancies or myeloproliferative neoplasms. This group of patients will allow the further 
assessment of the tolerability and clinical activity of vedolizumab IV.
The sample size estimates are based on the primary objective of determining a recommended 
phase 2 dose and to describe the initial tolerability and safety of vedolizumab IV administered 
along with standard GvHD prophylaxis.


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15.0
QUALITY CONTROL AND QUALITY ASSURANCE
15.1
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 informed consent 
forms), 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.
15.2
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.
15.3
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 15.1.


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16.0
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” that are listed in Appendix B. 
The principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities.
16.1
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 Investigator’s Brochure, a copy of 
the informed consent form, 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, informed consent form) 
reviewed; and state the approval date. The sponsor will {ship drug/notify site once} 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 
[drug/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 informed consent 
form, 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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16.2
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 informed consent form, 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 informed consent form and the subject information sheet (if applicable) 
further explain the nature of the study, its objectives, and potential risks and benefits, as well as the 
date informed consent is given. The informed consent form 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 
informed consent form and if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) must 
be approved by both the IRB or IEC and the sponsor prior to use.
The informed consent form, 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 informed consent 
form, 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 informed consent form 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 prior to 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 informed consent 
form and subject authorization (if applicable) at the time of consent and prior to 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 informed consent form, 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 informed consent form, the signed subject authorization form 
(if applicable), and subject information sheet (if applicable) shall be given to the subject.


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All revised informed consent forms 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 revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form.
16.3
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, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), 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 16.2).
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 [e]CRF).
16.4
Publication, Disclosure, and Clinical Trial Registration Policy
16.4.1 Publication and Disclosure
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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16.4.2 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 before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with investigator’s city, state (for Americas investigators), country, and 
recruiting status will be registered and available for public viewing. 
For some registries, Takeda will assist callers in locating trial sites closest to their homes by 
providing the investigator name, address, and phone number to the 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. 
16.4.3 Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.
16.5
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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17.0
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McDonald GB, Tabellini L, Storer BE, Lawler RL, Martin PJ, Hansen JA. Plasma 
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Murray S. Engraftment. In: Maziarz RT, Slater SS, editors. Blood and Marrow Transplant 
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Gratwohl A, Brand R, Frassoni F, Rocha V, Niederwieser D, Reusser P, et al. Cause of 
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Ferrara JL, Deeg HJ. Graft-versus-host disease. N Engl J Med 1991;324(10):667-74.
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8.
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Murai M, Yoneyama H, Ezaki T, Suematsu M, Terashima Y, Harada A, et al. Peyer's patch 
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10.
Waldman E, Lu SX, Hubbard VM, Kochman AA, Eng JM, Terwey TH, et al. Absence of 
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Butcher EC, Williams M, Youngman K, Rott L, Briskin M. Lymphocyte trafficking and 
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Briskin M, Winsor-Hines D, Shyjan A, Cochran N, Bloom S, Wilson J, et al. Human 
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Soler D, Chapman T, Yang LL, Wyant T, Egan R, Fedyk ER. The binding specificity and 
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Feagan BG, Rutgeerts P, Sands BE, Hanauer S, Colombel JF, Sandborn WJ, et al. 
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Sandborn WJ, Feagan BG, Rutgeerts P, Hanauer S, Colombel JF, Sands BE, et al. 
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Sands B, Feagan B, Rutgeerts P, Colombel J-F, Sandborn W, Sy R, et al. Vedolizumab 
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Sandborn WJ, Colombel JF, Enns R, Feagan BG, Hanauer SB, Lawrance IC, et al. 
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29.
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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30.
Amend KL, Turnbull B, Foskett N, Napalkov P, Kurth T, Seeger J. Incidence of 
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Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, et al. 1994 
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32.
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 
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33.
Mori T, Kato J, Shimizu T, Aisa Y, Nakazato T, Yamane A, et al. Effect of early 
posttransplantation tacrolimus concentration on the development of acute graft-versus-host 
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Biol Blood Marrow Transplant 2012;18(2):229-34.
34.
Ruutu T, Gratwohl A, de Witte T, Afanasyev B, Apperley J, Bacigalupo A, et al. 
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Appendix A
Schedule of Events
Schedule of Events (Screening through Day +20)
Screening
(a)
Day 
–1
Day 
0
Day 
+1
Day 
+3
Day 
+5
Day 
+7
Day 
+9
Day 
+11
Day 
+13
Day 
+14
Day 
+16
Day 
+18
Day 
+20
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
X
X
X
Height
X
Weight
X
X
X
X
Vital signs
X
X (d)
X
X (d)
X
ECOG performance status
X
HCT-CI (dose-finding phase only)
Tuberculosis screening
X (e)
RAMP questionnaire
X
X (b)
X (b)
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 informed consent form through 18 weeks after the last dose of study drug.
Vedolizumab IV administration (g)
X
X
Allo-HSCT (h)
X
Footnotes are on last table page.


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Schedule of Events (Screening through Day +20) (continued)
Screening
(a)
Day 
–1
Day 
0
Day 
+1
Day 
+3
Day 
+5
Day 
+7
Day 
+9
Day 
+11
Day 
+13
Day 
+14
Day 
+16
Day 
+18
Day 
+20
Samples/Laboratory Assessments
Pregnancy test(i)
X1
X1
Hematology/chemistry
X1
X1 
(b)
X1
X1 (b)
X1
Urinalysis
X1
X1
(b)
Blood sample for flow cytometry 
(j,k,l)
X1 
(b)
X1
X1
X1 (b)
X1
Blood sample for anti-vedolizumab 
antibodies (k)
X1 
(b)
X1
Blood sample for PK(n)
See Table A
Allo-HSCT=allogeneic hematopoietic stem cell transplantation, ECOG= Eastern Cooperative Oncology Group, GvHD=graft-verus-host disease, HCT-CI=Hematopoietic Cell 
Transplantation-Specific Comorbidity Index, ICF=informed consent form, IV=intravenous, PK=pharmacokinetic(s), RAMP= Risk Assessment and Minimization for Progressive 
Multifocal Leukoencephalopathy (PML).
(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 
prior to 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) QuantiFERON® test or tuberculin skin test only.
(f) Including serious pretreatment events; see Section 11.2.
(g) Vedolizumab will be administered via a 30-minute intravenous (IV) infusion on Day –1. HSC infusion should occur on Day 0 no sooner than 12 hours after completion of IV 
infusion of vedolizumab on Day –1. Vedolizumab will also be administered via a 30-minute IV infusion on Day +13 after myeloablative allo-HSCT.
(h) Details on the HSC infusion including cell counts and donor CMV status will be recorded on the eCRF.
(i) A serum beta-human chorionic gonadotropin (#-hCG) 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.
(j) Additional specimens may be collected from any patient who experiences an infusion reaction.
(k) 
. 
(l) Includes immunophenotyping and MAdCAM-1 (immunophenotyping includes the cell markers of GvDH).
(m) 
CCI
CCI
CCI


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CONFIDENTIAL
(n) Time points for blood samples for PK analysis will be collected as specified in Table A.
Note: 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.


Vedolizumab IV
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CONFIDENTIAL
Schedule of Events (Day +22 Through End of Study)
Day 
+22
Day 
+26
Day 
+30
Day 
+34
Day 
+36
Day 
+40
Day 
+42
Day 
+100 
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)
12 month 
Follow-up/
EOS/ET
Visit (b)
OS 
Follow
-up
Symptom-directed physical 
examination
X
X
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
X
X
Vital signs
X
X
X (c)
X
X
X
X
X
X
RAMP questionnaire
X (d)
Follow-up phone calls
Q3mo 
(e)
Assessment of GvHD
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 informed consent form through 18 weeks after the last dose of study drug.
Vedolizumab IV administration
(g)
X
Samples/Laboratory Assessments
Hematology/chemistry(h)
X1
X1
X1 
(d)
X1
X1
X1
X1
X1
X1
Urinalysis
Blood sample for chimerism 
analysis
X1
Blood sample for flow cytometry 
(i)
X1
X1
X1 
(d)
X1
X1
Blood sample for 
anti-vedolizumab antibodies (i)
X1
X1
Blood sample for PK(k)
See Table A
CCI


Vedolizumab IV
Study No. Vedolizumab-1015
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CONFIDENTIAL
Complete remission with incomplete platelet recovery=CRp, EOS=end-of-study, ET=early termination, GvHD=graft-verus-host disease, IV=intravenous, OS=overall survival, 
PK=pharmacokinetic(s), World Health Organization=WHO.
(a) Patients will attend a Day +100 visit (±7 days) at which time patients will enter posttreatment follow-up. If subsequent anticancer therapy is required before 30 days after the last 
dose, the Day +100 visit should be conducted before the initiation of subsequent anticancer therapy.
(b) Patients who remain in remission will be followed for development of acute and chronic GvHD and safety during clinic visits at 4, 5, 6, 9, and 12 months after allo-HSCT 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). Patients who
have been discontinued will attend an ET visit 30 to 40 days after the last dose of study drug using all study procedures outlined for the 12-month follow-up visit.
(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 pre-dose.
(e) Patients will be followed for overall survival 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 11.2.
(g) If engraftment is confirmed, vedolizumab will be administered via a 30-minute intravenous (IV) infusion on Day +42 after myeloablative allo-HSCT.
(h) Hepatitis and HIV testing are to be performed only at the Screening visit.
(i) Additional specimens may be collected from any patient who experiences an infusion reaction.
(j) 
.
(k) Time points for blood samples for PK analysis will be collected as specified in Table A.
Note: 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.
CCI


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CONFIDENTIAL
Table A
Pharmacokinetic Sample Breakdown
Day
-1
0
+3
+5
+7
+9
+11
+13
+14
+16
+18
+20
+22
+26
+30
+36
+40
+42
+100
(±7 days)
Serum
PK collection on 
non-dosing days (a)
X1
X1
X1
X1
X1
X1
X1
X1
X1
X1
X1
X1
X1
X1
Predose 
X1
X1
X1
30 min postdose (5 min)
X1
X1
X1
1 hr postdose (10 min)
X1
2 hrs postdose (20 min)
X1
X1
X1
12 hrs postdose (30 min)
X1
X1
24 hrs postdose (60 min)
X1
X1
(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.


Vedolizumab IV
Study No. Vedolizumab-1015
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CONFIDENTIAL
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, prior to 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 informed consent form 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 informed consent form 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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CONFIDENTIAL
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.


Vedolizumab IV
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CONFIDENTIAL
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.


Vedolizumab IV
Study No. Vedolizumab-1015
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Appendix D
Clinical Stages and Grades of Graft-Versus-Host Disease
Acute Graft-versus-Host Disease Clinical Stage 
Stage
Skin
Liver
Intestinal tract
Bilirubin: SI units
(standard units)
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 [31].
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.
Acute Graft-versus-Host Disease Grade (modified Glucksberg)
Grade
Skin
Liver
Intestinal tract
I
Stage 1-2
None
None
II
Stage 3 or 
Stage 1 or 
Stage 1
III
-
Stage 2-3 or 
Stage 2-4
IV
Stage 4 or 
Stage 4
-
From Przepiorka et al., 1995 [31].
ECOG PS=Eastern Cooperative Oncology Group performance status.
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 [32].
IBMTR=International Bone Marrow Transplant Registry Database.


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Study No. Vedolizumab-1015
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Appendix E
Recommended Tacrolimus + Short-Term Methotrexate Prophylaxis Regimen
Tacrolimus (Mori et al, 2012) [33]

Tacrolimus treatment should start during conditioning.

The goal of tacrolimus treatment should be to achieve a trough concentration of 5-10 ng/dL.

Keep at therapeutic levels through Day +100, tapering off after Day +100 if no signs of GvHD 
are observed.

The goal should be to discontinue tacrolimus treatment by Day +180 after allo-HSCT.
Methotrexate (Ruutu et al, 2014) [34]

Administer at 10 mg/m2 IV on Days +1, +3, +6, and +11 after allo-HSCT per institutional 
standards.

Doses may be modified or held based on toxicity.


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Appendix F
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, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response criteria 
of the Eastern Cooperative Oncology Group. American Journal of Clinical Oncology 1982;5(6):649-55.


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CONFIDENTIAL
Appendix G
Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) Scores
Comorbidity
Definitions of Comorbidities
HCT-CI 
Weighted Scores
Arrhythmia
Atrial fibrillation or flutter, sick sinus syndrome, or ventricular 
arrhythmias
1
Cardiac
Coronary artery disease (a), congestive heart failure, myocardial 
infarction, or ejection fraction ≤50%
1
IBD
CD or UC
1
Diabetes (b)
Requiring treatment with insulin or oral hypoglycemics but not 
diet alone
1
Cerebrovascular disease
Transient ischemic attack or cerebrovascular accident
1
Psychiatric disturbance (b)
Depression or anxiety requiring psychiatric consult or treatment
1
Hepatic, mild (b)
Chronic hepatitis, bilirubin >ULN to 1.5 × ULN, or 
AST/ALT >ULN to 2.5 × ULN 
1
Obesity (b)
Patients with a body mass index >35 kg/m2
1
Infection (b)
Requiring continuation of antimicrobial treatment after Day 0
1
Rheumatologic
SLE, RA, polymyositis, mixed CTD, or polymyalgia 
rheumatica
2
Peptic ulcer
Requiring treatment
2
Moderate/severe renal (b)
Serum creatinine >2 mg/dL, on dialysis, or prior renal 
transplantation
2
Moderate pulmonary (b)
DLCO and/or FEV1 66%-80% or dyspnea on slight activity
2
Prior solid tumor
Treated at any time point in the patient’s past history, excluding 
nonmelanoma skin cancer
3
Heart valve disease (b)
Except mitral valve prolapse
3
Severe pulmonary (b)
DLCO and/or FEV1 ≤65% or dyspnea at rest or requiring oxygen
3
Moderate/severe hepatic (b)
Liver cirrhosis, bilirubin >1.5 × ULN, or AST/ALT >2.5 × ULN 
3
Source: Sorror ML, Maris MB, Storb R, Baron F, Sandmaier BM, Maloney DG, Storer B. Hematopoietic cell transplantation 
(HCT)–specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood 2005;106(8):2912-9.
AST=aspartate transaminase, ALT=alanine transaminase, CD=Crohn’s disease, CTD=connective tissue disease, DLCO=diffusion 
capacity of carbon monoxide, FEV1=volume that has been exhaled at the end of the first second of forced expiration, 
HCT-CI=Hematopoietic Cell Transplantation-Comorbidity Index, IBD=inflammatory bowel disease, RA=rheumatoid arthritis, 
SLE=systemic lupus erythematosus, UC=ulcerative colitis, ULN=upper limit of normal.
(a) One or more vessel-coronary artery stenosis requiring medical treatment, stent, or bypass graft.
(b) Comorbidity is currently active or patient required medical treatment.


Vedolizumab IV
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CONFIDENTIAL
Appendix H
Grade 4 Regimen-Related Organ Toxicities
Occurrence of the following Grade 4 regimen-related organ toxicities will be considered as a 
possible DLT. Review of any such regimen-related toxicities will occur at each End-of-Cohort 
Review meeting prior to any dose escalation.

Cardiac toxicity: Cardiac rhythm disturbance with life-threatening consequences, 
hemodynamic compromise requiring urgent intervention, cardiac failure requiring continuous 
IV or mechanical hemodynamic support.

Bladder toxicity: Hemorrhagic cystitis with life-threatening consequences, urgent radiologic 
or operative intervention indicated.

Renal toxicity: Life-threatening consequences, dialysis required.

Pulmonary toxicity: Diffuse alveolar hemorrhage or idiopathic pneumonia syndrome (IPS)
with life-threatening consequences, intubation with ventilatory support indicated.

Hepatic toxicity: Moderate to severe hepatic encephalopathy, coma, ascites requiring operative 
intervention, life-threatening consequences.

CNS toxicity: Life-threatening, prolonged repetitive seizures or coma not explained by other 
medication, infection or bleeding.

Mucositis: Life-threatening airway compromise, urgent intervention indicated (eg, 
tracheotomy or intubation). 

GI toxicity: Life-threatening hemorrhagic enterocolitis requiring urgent intervention, small 
bowel obstruction requiring surgical intervention. 


Vedolizumab IV
Study No. Vedolizumab-1015
Page 82 of 84
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13 January 2016 
CONFIDENTIAL
Appendix I
Detailed Description of Amendments to Text
This document describes changes in reference to Protocol Incorporating Amendment No. 01.
Page 31, Section 8.1.2 Inclusion Criteria: Expansion Phase 
Existing Text
2. Candidates for HLA-matched or 1-locus (antigen or allele) mismatched unrelated or related 
donor allo-HSCT, using either peripheral blood stem cells or bone marrow as the cell source, 
for the treatment of ALL, AML, or myeloproliferative neoplasm.
3. Disease must be in remission at the time of allo-HSCT. Remission is defined as:

Patients with acute leukemia, chronic myelogenous leukemia, and myelodysplasia with no 
circulating blasts and <5% blasts in the bone marrow.

Patients with chronic lymphocytic leukemia, small lymphocytic lymphoma, or other 
non-Hodgkin lymphoma with chemosensitive disease at time of transplantation.

Patients with myelofibrosis and other myeloproliferative neoplasms with <5% blasts in the 
blood and bone marrow.
Revised Text
2. Candidates for HLA-matched or 1-locus (antigen or allele) mismatched unrelated or related 
donor allo-HSCT, using either peripheral blood stem cells or bone marrow as the cell source, 
for the treatment of hematologic malignancy or myeloproliferative neoplasm.
3. Disease must be in remission at the time of allo-HSCT. Remission is defined as one of the 
following:

Patients with acute leukemia, chronic myelogenous leukemia, and myelodysplasia with no 
circulating blasts and <5% blasts in the bone marrow.

Patients with chronic lymphocytic leukemia, small lymphocytic lymphoma, or other 
non-Hodgkin lymphoma with chemosensitive disease at time of transplantation.

Patients with myelofibrosis and other myeloproliferative neoplasms with <5% blasts in the 
blood and bone marrow.
Rationale for Amendment
As non-Hodgkin lymphoma is not classified as a myeloproliferative neoplasm, clarifications were 
made to the text to provide clarity based on the FDA communication received on 
28 December 2015. 
Page 36, Section 9.2 Definitions of Dose-Limiting Toxicity 
Existing Text
A DLT will be any Grade 3 or higher toxicity assessed by the investigator as clearly related to 
vedolizumab treatment. Hypersensitivity reactions and other infusion-related reactions will not be 


Vedolizumab IV
Study No. Vedolizumab-1015
Page 83 of 84
Protocol Incorporating Amendment No. 01
13 January 2016 
CONFIDENTIAL
considered a DLT. Any patient who discontinues the study due to an infusion-related reaction will 
be replaced in the study.
Revised Text
A DLT will be any Grade 3 or higher toxicity assessed by the investigator as related to 
vedolizumab treatment. Hypersensitivity reactions and other infusion-related reactions will not be 
considered a DLT. Any patient who discontinues the study due to an infusion-related reaction will 
be replaced in the study.
Rationale for Amendment
Regarding the DLT definition, a Grade 3 or higher toxicity assessed by the investigator as clearly
related to vedolizumab treatment was not acceptable according to the FDA communication 
received on 28 December 2015; thus, this was removed from the protocol text.
Page 44, Section 10.3.7 Vital Signs
Existing Text
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. On dosing days, 
vital signs will be obtained before the infusion.
Revised Text
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. On dosing days, 
vital signs will be obtained before and within 60 minutes of completion of infusion.
Rationale for Amendment
The recording of vital signs after study drug infusion was added on the basis of the FDA 
communication received on 28 December 2015. The change also appears in the Schedule of 
Events on Days –1, +13, and +42.
Page 54, Section 12.1 Dose Escalation and Cohort Expansion Plan
Existing Text
End-of-Cohort Meetings will be held to review safety and PK data before moving to the next dose 
level in subsequent cohorts. The review committee for the End-of-Cohort Meetings will include 
the sponsor study team, the study investigators, and a third-party HSCT expert consultant. During 
the expansion phase, review of safety data will occur at least quarterly with consideration of the 
study stopping criteria (see Section 14.2).
Revised Text
End-of-Cohort Meetings will be held to review safety and PK data before moving to the next dose 
level in subsequent cohorts. The safety review will encompass the following: all available AEs 
for DLTs, appropriate dosing information and patient eligibility/evaluability, dose-toxicity 
relationships, and any other pertinent available safety and PK data. The review committee for 


Vedolizumab IV
Study No. Vedolizumab-1015
Page 84 of 84
Protocol Incorporating Amendment No. 01
13 January 2016 
CONFIDENTIAL
the End-of-Cohort Meetings will include the sponsor study team, the study investigators, and an
independent, third-party HSCT expert consultant. The study sponsor team will include, but 
will not be limited to, the following: the study clinician, safety lead, and other members as 
appropriate (biostatistics, clinical pharmacology, and translational medicine to interpret 
PK, PD, and biomarker data). During the dose escalation and expansion phases, review of 
safety data by the above listed parties will occur as needed on the basis of continuous 
monitoring of safety data, but at least quarterly by the study sponsor team, with consideration 
of the study stopping criteria (see Section 14.2).
Rationale for Amendment
Language was added to clarify who is responsible for reviewing safety and PK data for the 
purposes of applying the dose escalation and early protocol stopping rules, and how often this 
review is to occur. These modifications were made on the basis of the FDA communication 
received on 28 December 2015.


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SAP_000.pdf: 


• Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: An Open-Label, Dose-Finding Study of Vedolizumab IV Plus Standard of Care for Graft-
Versus-Host Disease (GvHD) Prophylaxis in Patients Undergoing Allogeneic Hematopoietic 
Stem Cell Transplantation (HSCT)
NCT Number: NCT02728895
SAP Approve Date: June 04, 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 (PPD) information 
or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
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.


Vedolizumab-1015
Page 1 of 34
Statistical Analysis Plan Final Version 1.0
June 04, 2018
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: Vedolizumab-1015
An Open-Label, Dose-Finding Study of Vedolizumab IV for Treatment of
Steroid-Refractory Acute Intestinal Graft-Versus-Host Disease (GvHD) Prophylaxis in 
Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)
PHASE 1b
Version: Final v1.0
Date: June 04, 2018
Prepared by:
Based on:
Protocol Version: 2.0
Protocol Date: December 22, 2016
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.
PPD


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1.1
Approval Signatures
Study Title:
An Open-Label, Dose-Finding Study of Vedolizumab IV for Treatment of 
Steroid-Refractory Acute Intestinal Graft-Versus-Host Disease (GvHD) 
Prophylaxis in Patients Undergoing Allogeneic Hematopoietic Stem Cell 
Transplantation (HSCT)
Approvals: Electronic signatures can be found on the last page of this document.


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2.0
TABLE OF CONTENTS
1.1
Approval Signatures ..................................................................................................2
2.0
TABLE OF CONTENTS.................................................................................................3
List of In-Text Tables............................................................................................................4
List of In-Text Figures...........................................................................................................4
3.0
LIST OF ABBREVIATIONS..........................................................................................5
4.0
OBJECTIVES .................................................................................................................7
4.1
Primary Objectives ....................................................................................................7
4.2
Secondary Objectives.................................................................................................7
4.3
Exploratory Objectives ..............................................................................................7
4.4
Study Design .............................................................................................................8
5.0
ANALYSIS ENDPOINTS.............................................................................................11
5.1
Primary Endpoints ...................................................................................................11
5.2
Secondary Endpoints ...............................................................................................11
5.3
Exploratory Endpoints .............................................................................................12
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................13
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................14
7.1
General Principles....................................................................................................14
7.2
Study Definitions and Conventions..........................................................................14
7.2.1
Study Terms.......................................................................................................14
7.2.2
Definition of Study Days....................................................................................15
7.2.3
Definition of Study Visit Windows ....................................................................15
7.2.4
Conventions for Missing Adverse Event Dates...................................................16
7.2.5
Conventions for Missing Concomitant Medication Dates...................................17
7.2.6
Conventions for Clinical Stages and Grades of Graft-Versus-Host Disease ........18
7.3
Populations for Analyses .........................................................................................18
7.4
Disposition of Subjects ............................................................................................18
7.5
Demographic and Other Baseline Characteristics.....................................................19
7.6
Medication History and Concomitant Medications...................................................21
7.7
Study Drug Exposure and Compliance.....................................................................21
7.8
Efficacy Analyses ....................................................................................................21
7.8.1
Primary Efficacy Endpoint.................................................................................21
7.8.2
Secondary Efficacy Endpoints............................................................................21
7.8.3
Exploratory Efficacy Endpoints .........................................................................22
7.8.4
Descriptive Summary of Efficacy Endpoints......................................................23


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7.9
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................23
7.9.1
Pharmacokinetic Analysis ..................................................................................24
7.9.2
Pharmacodynamic Analysis ...............................................................................24
7.9.3
Other Outcomes.................................................................................................24
7.10
Safety Analysis........................................................................................................25
7.10.1 Adverse Events ..................................................................................................25
7.10.2 Clinical Laboratory Evaluations .........................................................................26
7.10.3 Vital Signs .........................................................................................................26
7.11
Interim Analysis ......................................................................................................26
7.12
Changes in the Statistical Analysis Plan...................................................................26
8.0
REFERENCES..............................................................................................................27
9.0
APPENDIXES ..............................................................................................................28
LIST OF IN-TEXT TABLES
Table 5.a
Description of the Primary Endpoints.................................................................11
Table 5.b
Description of the Secondary Endpoints.............................................................11
Table 5.c
Description of the Exploratory Endpoints...........................................................12
Table 7.a
Visit Windows to be used for the summary of the efficacy endpoints. ................15
Table 7.b
Visit Windows to be used for the summary of the PD and biomarker 
endpoints. ..........................................................................................................16
Table 7.c.
Summary of Patients' Baseline and Demographic Characteristics.......................20
LIST OF IN-TEXT FIGURES
Figure 4.a
Overview of Study Design (from day -1 to +50)...................................................9


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3.0
LIST OF ABBREVIATIONS
Term
Definition
AE
adverse event
ALL
acute lymphoblastic leukemia
allo-HSCT
allogeneic hematopoietic stem cell transplantation
AML
acute myeloid leukemia
ANC
absolute neutrophil count
APC
antigen-presenting cell
AUC
area under the serum concentration-time curve
AVA
anti-vedolizumab antibody
BMT CTN
Blood and Marrow Transplant Clinical Trials Network 
BuFlu
busulfan + fludaradine
Ctrough
serum concentration before dosing
CMV
cytomegalovirus
CRF
case report form
CRO
contract research organization
CRp
complete remission with incomplete platelet recovery
CTCAE
Common Terminology Criteria for Adverse Events 
CyTBI
cyclophosphamide + total body irradiation
DLT
dose-limiting toxicity
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EU
European Union
FDA
Food and Drug Administration
GALT
gut-associated lymphoid tissue 
GCP
Good Clinical Practice
GCSF
granulocyte-colony stimulating factor
GI
gastrointestinal(ly)
GRFS
GvHD-free, relapse-free survival
GvHD
graft-versus-host disease
HBV
hepatitis B virus surface antigen
HCT-CI
Hematopoietic Cell Transplantation-Specific Comorbidity Index
HCV
hepatitis C virus antigen
HIV
human immunodeficiency virus
HLA
human leukocyte antigen
HSC
hematopoietic stem cell
HSCT
hematopoietic stem cell transplantation
IAC
Independent Adjudication Committee 
IB
Investigator’s Brochure
IBD
inflammatory bowel disease
IBMTR
International Bone Marrow Transplant Registry Database


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Term
Definition
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IL-6
interleukin-6
IL-17
interleukin-17
IPS
idiopathic pneumonia syndrome
IRB
institutional review board
IV
intravenous(ly)
MAdCAM-1
mucosal addressin cell adhesion molecule-1
MedDRA
Medical Dictionary for Regulatory Activities
NCI 
National Cancer Institute 
NOAEL
no-observed-adverse-effect level
OS
overall survival
PCR
polymerase chain reaction
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PML
progressive multifocal leukoencephalopathy
PTE
pretreatment event
PVC
polyvinyl chloride
Q4W
once every 4 weeks
Q8W
once every 8 weeks
RAMP
Risk Assessment and Minimization of PML
RIC
reduced-intensity conditioning
SAE
serious adverse event
SAP
statistical analysis plan
ST2
suppressor of tumorigenicity 2
TB
tuberculosis
TEAE
treatment-emergent adverse event
US
United States
WHO
World Health Organization


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4.0
OBJECTIVES
4.1
Primary Objectives
The primary objective is:
!
To describe the initial tolerability and safety and identify a recommended phase 2 dose of 
vedolizumab IV administered for GvHD prophylaxis along with standard GvHD 
prophylaxis therapy (tacrolimus plus short-term methotrexate) in patients undergoing 
allo-HSCT.
4.2
Secondary Objectives
The secondary objectives are:
!
To characterize the PK of vedolizumab in patients on Days -1, +13 and +42 after allo-
HSCT.
!
To determine the cumulative incidence and severity of acute GvHD (compiled from 
individual organ scores of gut, skin, or liver) at 100 days after allo-HSCT.
!
To determine the distribution of maximum severity of acute GvHD throughout the 
100-day period after allo-HSCT.
4.3
Exploratory Objectives
The exploratory objectives are:
CCI


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4.4
Study Design
This is a phase 1b, open-label, dose-finding study designed to evaluate the safety, tolerability, 
and clinical activity of adding vedolizumab to standard graft-versus-host disease (GvHD) 
prophylaxis (tacrolimus plus short-term methotrexate) in adult patients (18—75 years old) 
undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Vedolizumab dose 
finding will be cohort based and follow a rule-based dose-finding study design with 
pharmacokinetic (PK) guidance. After a tolerated dose with acceptable PK has been identified, 
the cohort at that dose level may be expanded to further assess the tolerability and effectiveness 
of 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. 
Vedolizumab will be administered initially on Day –1 before allo-HSCT and then on Days +13 
and +42 after allo-HSCT.
Approximately 36 evaluable patients will be enrolled in this study. For PK endpoints, an 
evaluable patient is one who receives vedolizumab and has at least 1 PK sample collected.
Patients will receive up to 3 doses of vedolizumab IV within the first 100 days after allo-HSCT. 
Patients who remain in remission will be followed for safety and development of acute and 
chronic GvHD for 1 year after allo-HSCT or until the patient’s death or withdrawal of consent or 
termination of the study by the sponsor. All patients will be followed for overall survival (OS) 
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. Patients will attend a Day +100 visit (±7 
days) at which time they will enter post treatment follow-up. 
Dose escalation will start with a low-dose cohort receiving vedolizumab at 75 mg IV on Day –1 
and on Days +13 and +42 after allo-HSCT. HSC infusion should occur on Day 0 (no sooner than 
12 hours after completion of IV infusion of vedolizumab on Day –1). The first patient in each 
dosing cohort will then be monitored for dose-limiting toxicities (DLTs) from the start of the 
first IV infusion of vedolizumab on Day –1 to Day +28 after allo-HSCT (the DLT observation 
period) including assessment for neutrophil recovery by Day +28. If the first patient in the first 
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cohort tolerates vedolizumab IV at 75 mg and engraftment occurs, then 2 more patients will be 
enrolled in the first cohort. If none of the first 3 patients experience DLTs, the next cohort will 
receive vedolizumab 300 mg IV on Day –1 and on Days +13 and +42 after allo-HSCT. If the 
first patient in this cohort tolerates vedolizumab IV at 300 mg and engraftment occurs, then 2 
more patients will be enrolled in the second cohort. If the first 3 patients at 300 mg tolerate the 
treatment without experiencing DLTs, then the decision on whether to increase the vedolizumab 
IV dose in the next cohort will be guided by the PK results. If 1 of the first 3 patients in the 
cohort experiences a DLT, then 3 additional patients will be enrolled at the same dose level and 
monitored for DLTs from Day –1 until Day +28. If none of the additional patients experience a 
DLT, then the decision on whether to increase the vedolizumab IV dose in the next cohort will 
be guided by the PK results. If 2 or more patients in a cohort of either 3 or 6 patients experience 
a DLT, then the dose of vedolizumab IV for the next cohort of 3 patients will be reduced. These 
patients will be monitored for DLTs in the same manner that patients in the previous cohort were 
monitored. DLT will be considered as a part of the PK/PD analysis and will be further outlined 
in the Clinical Pharmacology Analysis Plan (CPAP).
The graphical study design is presented on Figure 4.a.
Figure 4.a
Overview of Study Design (from day -1 to +50)
Allo-HSCT=allogeneic hematopoietic stem cell transplantation, AVA=anti-vedolizumab antibodies, 
DLT=dose-limiting toxicity, GvHD=graft-versus-host disease, IV=intravenous, PK=pharmacokinetic.
PK sampling for patients who have been discharged from the hospital will be aligned to clinic visits, and 
therefore may not be as frequent as represented in this figure. 
After a tolerated dose level with acceptable PK has been identified in patients who are 
undergoing unrelated-donor myeloablative transplant for the treatment of hematologic 


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malignancies, the cohort at that dose level may be expanded to include approximately 18 
additional patients undergoing myeloablative conditioning or reduced-intensity conditioning 
(RIC) and are receiving either related or unrelated allo-HSCT for the treatment of hematologic 
malignancies or myeloproliferative neoplasms. This group of patients will allow the further 
assessment of the tolerability and clinical activity of vedolizumab IV.
Vital signs, physical and neurological examinations, adverse event (AE) assessments, and 
laboratory values (chemistry, hematology, and urinalysis) will be obtained to evaluate the safety 
and tolerability of vedolizumab IV. To exclude patients with progressive multifocal 
leukoencephalopathy (PML), a Risk Assessment and Minimization for PML (RAMP) 
questionnaire will be administered at Screening and before vedolizumab IV administration on 
Days -1 before allo-HSCT, and on Days +13 and +42 after allo-HSCT.


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5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoints
The primary endpoints to identify the recommended phase 2 dose of vedolizumab IV 
administered for GvHD prophylaxis along with standard GvHD prophylaxis therapy are listed in 
Table 5.a:
Table 5.a
Description of the Primary Endpoints
Type of the Endpoints
Description of the Endpoints
Primary Safety Endpoints
Frequency of DLTs from the start of the first IV infusion of vedolizumab on 
Day –1 until Day +28 (the DLT observation period).
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 serious adverse 
events (SAEs) from administration of the first dose of vedolizumab IV 
through 18 weeks after administration of the last dose of vedolizumab IV.
Primary PK Endpoint
Mean serum concentrations of vedolizumab that will help inform the 
likelihood of α4β7 target saturation throughout the first 100 days following 
allo-HSCT.
5.2
Secondary Endpoints
The secondary endpoints are listed in Table 5.b:
Table 5.b
Description of the Secondary Endpoints
Type of the Endpoints
Description of the Endpoints
Secondary Efficacy 
Endpoints
Time to neutrophil engraftment.
Percentage of patients who have developed overall Grade 2 to 4 acute GvHD (compiled from 
individual organ scores of gut, skin, or liver) by 100 days after myeloablative allo-HSCT.
The frequency of maximum severity of acute GvHD  throughout the 100 day period after allo-
HSCT(see GvHD assessment schedule in 
Appendix C), defined according to the modified Glucksberg criteria and Blood and Marrow 
Transplant Clinical Trials Network (BMT CTN)-modified International Bone Marrow 
Transplant Registry Database (IBMTR) index (See Appendix D).
Secondary PK Endpoint
Mean serum concentrations of vedolizumab before dosing (Ctrough) on Days +13 and +42 after 
myeloablative allo-HSCT.


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5.3
Exploratory Endpoints
The exploratory endpoints are listed in Table 5.c:
Table 5.c
Description of the Exploratory Endpoints.
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6.0
DETERMINATION OF SAMPLE SIZE
Approximately 18 evaluable patients will be enrolled to identify a tolerable vedolizumab dose 
level with acceptable PK. After the dose level has been identified, the cohort at that dose level 
may be expanded to include approximately 18 additional patients receiving myeloablative 
conditioning or RIC who are undergoing either related or unrelated allo-HSCT for the treatment 
of hematologic malignancies or myeloproliferative neoplasms. This group of patients will allow 
the further assessment of the tolerability and clinical activity of vedolizumab IV.
The sample size estimates are based on the primary objective of determining a recommended 
phase 2 dose and to describe the initial tolerability and safety of vedolizumab IV administered 
along with standard GvHD prophylaxis.


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7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
Statistical analysis plan (SAP) will be prepared and finalized prior to database freeze. After 
cleaning the data, the analyses of the primary, secondary and exploratory endpoints will be 
performed. Additional analysis will be performed after the 12-month follow-up data are locked 
and cleaned.
Statistical analyses will be primarily descriptive and graphical in nature. No formal statistical 
hypothesis testing will be performed. 
All available safety, tolerability, efficacy, PK, and PD 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.
7.2
Study Definitions and Conventions
7.2.1
Study Terms
The definitions of the study terms are provided in the table below:
Term
Definition
Clinical Remission
(for overall design 
and escalation phase
entry)
Defined by conventional WHO criteria: <5% blast cells, count recovery 
(although complete remission with incomplete platelet recovery [CRp] would 
be allowed), and no evidence of extramedullary disease.
Clinical Remission
(for expansion phase)
Defined for patients with one of the following criteria:
a) Acute leukemia, chronic myelogenous leukemia, and myelodysplasia with 
no circulating blasts and <5% blasts in the bone marrow; OR
b)  Chronic lymphocytic leukemia, small lymphocytic lymphoma, or other 
non-Hodgkin lymphoma with chemosensitive disease at time of 
transplantation; OR
c) Myelofibrosis and other myeloproliferative neoplasms with <5% blasts in 
the blood and bone marrow.
Acute GvHD
Defined as clinical evidence of acute GvHD per Glucksberg and IBMTR
Chronic GvHD
Defined as clinical evidence of chronic GvHD by the investigator per Seattle 
and NIH scale
Neutrophil 
Engraftment 
Recovery
Recovery of absolute neutrophil count [ANC], defined by an ANC >500/mm3
for 3 consecutive days or >2000/mm3 for 1 day. The first day of the 3-day 
period will be considered the day of neutrophil engraftment.
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.
GRFS
Defined as Grade 3—4 acute GvHD, chronic GvHD requiring systemic 
immunosuppression, disease relapse or progression, or death due to any cause.


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7.2.2
Definition of Study Days
Study Day 0 is defined as the date on which HSC infusion occurs (no sooner than 12 hours after 
completion of IV infusion of vedolizumab on Day –1). Other study days are defined relative to 
the Study Day 0 with Day +1 being the day after, and Day -1 being the day prior to Study Day 0.
7.2.3
Definition of Study Visit Windows
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). All data will be categorized based on the scheduled and actual 
sampling time at which it was collected, allowing equally distanced windows (See Table 7.a) 
between the scheduled days when applicable. The visit windows should be used to summarize 
the endpoints that are defined to target the scheduled visit days.
Table 7.a
Visit Windows to be used for the summary of the efficacy endpoints.
Scheduled 
Visit Day
Assessment of 
GvHD
Symptom-directed 
physical examination
Vital signs
Weight
Screening
≤-2
≤-2
-1
-1
-1 (b)
0
Allo-HSCT (no sooner than 12 hours after IV vedolizumab infusion)
+1
Blood sample collection (within 24 ±3 hours post-dose from Day 0)
+7±2
+1 — +10
+1 — +10
+1 — +10
+1 — +10
+13±2
+11 — +16
+11 — +16
+11 — +16(b)
+11 — +16
+20±2
+17 — +23
+17 — +23
+17 — +23
+17 — +23
+26±2
+24 — +30
+24 — +30
+24 — +30
+24 — +30
+34±2
+31 — +38
+31 — +38
+31 — +38
+31 — +38
+42±2
+39 — +71
+39 — +71
+39 — +71(b)
+39 — +71
+100±7
+72 — +110
+72 — +110
+72 — +110
+72 — +110
4 month(a)
follow up
+111 — +135
+111 — +135
+111 — +135
+111 — +135
5 month(a)
follow up
+136 — +165  
+136 — +165
+136 — +165
+136 — +165 
6 month(a)
follow up
+166 — +225
+166 — +225
+166 — +225
+166 — +225
9 month(a)
follow up
+226 — +315
+226 — +315
+226 — +315
+226 — +315
12 month(a)
follow up
≥+316
≥+316
≥+316
≥+316
(a) One month here is considered to be 30 days. (b) Vital signs will be obtained before and within 60 minutes of 
completion of IV infusion of vedolizumab. 


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Table 7.b
Visit Windows to be used for the summary of the PD and biomarker 
endpoints.
Scheduled Visit Day
Flow Cytometry
Biomarkers
Screening
-1
≤-1
≤-1
0
Allo-HSCT (no sooner than 12 hours after IV vedolizumab infusion)
+1
+1 — +3
+1 — +3
+7±2
+4 — +10
+4 — +10
+13±2
+11 — +16
+11 — +16
+20±2
+17 — +23
+17 — +23
+26±2
+24 — +30
+24 — +30
+34±2
+31 — +38
+31 — +38
+42±2
+39 — +111
+39 — +71
+100±7
NA
≥+72 
6 month(a) follow up
+112 — +270
NA
12 month(a) follow up
≥+271
NA
(a) One month here is considered to be 30 days. 
The monitoring of concomitant medications and procedures, as well as the adverse event 
reporting is recorded from first dose of study drug (or from signing of the informed consent in 
case of SAE) through 18 weeks after the last dose of study drug, and should be summarized 
based on the reported dates (not following windows).
Subjects disposition tables should be based on the reported dates (not following visit windows).
7.2.4
Conventions for Missing Adverse Event Dates
Every effort will be made to determine the actual onset date for the event or to obtain a reliable 
estimate for the onset date from the investigator.
For AEs or SAEs, a missing or incomplete onset date will be imputed according to the following 
conventions:
1) If an onset date is missing, the derived onset date will be calculated as the first non-
missing valid date from the following list (in order of precedence):
o
First study medication date
o
Consent date (for SAEs only)
2) If an onset date is incomplete, the derived onset date will be calculated following:


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o
Missing day, but month and year present: the day will be imputed as the 15th of 
the month. If the first study medication dose occurs after the imputed date, the 
derived onset date will be set equal to the first study medication date. 
o
Missing day and month, but year present: the day and month will be imputed as 
the 30th June of the year. If the first study medication dose occurs after the 
imputed date, the derived onset date will be set equal to the first study medication 
date.
For AEs or SAEs, a missing or incomplete end date will be imputed according to the following 
conventions:
1) If an end date is missing, the derived end date will be imputed the last assessment date. 
2) If an end date is incomplete, the derived end date will be calculated following:
o
Missing day, but month and year present: the day will be imputed as the last date 
(for example February 2009 will be imputed as 28 February 2009) of the month.   
o
Missing day and month, but year present: the day and month will be imputed as 
the 31st December of the year. 
7.2.5
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 
-
If the year or the entire date is missing or if the medication is “continuing”, the stop 
year will be the year in which the last dose of induction treatment was administered.


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7.2.6
Conventions for Clinical Stages and Grades of Graft-Versus-Host Disease
The clinical Stages and Grades of Graft-Versus-Host Disease will be defined according to the 
modified Glucksberg criteria and Blood and Marrow Transplant Clinical Trials Network (BMT 
CTN)-modified International Bone Marrow Transplant Registry Database (IBMTR) index (See
Appendix D).
The classification the following rules apply:
1) For every organ involvement (skin, liver, or intestinal) if the GvHD involvement is 
marked as “YES” for this organ involvement (skin, liver, or intestinal) on eCRF. and the 
stage of this organ involvement is ≥1, the subjects should to be counted as having GvHD
involvement for this organ (skin, liver, or intestinal respectively). 
2) If the involvement of an organ (Skin, Liver, or Intestinal) is marked as “YES” but the 
stage of involvement is = 0, then the subject should not be counted as having GvHD of 
that organ.
3) A subject should be counted as having overall GvHD if this subject has at least one organ 
involvement with stage ≥1. 
4) To assess the grade level for Liver GvHD involvement, the maximal bilirubin level 
within the visit window should be used (See Table 7.a).
7.3
Populations for Analyses
The following populations will be used for analysis:

Safety population: The population of patients evaluable for vedolizumab safety is 
defined as all patients who receive any amount of vedolizumab IV.

PK population: Defined as patients from the safety set with at least 1 PK sample 
collected. 

PD population: Defined as patients from the safety set with at least 1 PD sample 
collected.
For the primary endpoint, an evaluable patient is one who receives vedolizumab IV and is 
assessed for engraftment on or before Day +28.
Any additional analyses/sub-analyses for cohorts will be outlined in the CPAP, if deemed 
necessary.
7.4
Disposition of Subjects
Summary of the subject disposition will include 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.


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
Summary of Screen Failures. 

Number of subjects enrolled by site and treatment dose group.

Number and percent of subjects completing 28 days

Number and percent of subjects completing 100 days

Number and percent of subjects completing 180 days

Number and percent of subjects completing 1 year

Number and percent of subjects receiving all 3 infusions

Number and percent of subjects receiving 2 infusions

Number and percent of subjects receiving 1 infusions

Number and percent of subject receiving 0 infusions

Number of patients in the Safety population.

Number of patients in the PK population.

Number of patients in the PD population.

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.
7.5
Demographic and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized by dose level using safety analysis 
dataset (see Table 7.c). No baseline comparison will be performed.
Categorical variables (including prior treatment therapies) will be tabulated.  No baseline lab 
values will be tabulated. The number and percentage of the observations for each category will 
be reported. Categories that contain zero observations will be reported as ‘0’, not omitted.
Missing and non-reported observation will be reported as such, not omitted.
Continuous variables should be summarized for each dosing cohort using the following:

Number of observations (n),

Mean,

Standard deviation (SD),

Range of values (Min, Max).


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Table 7.c.
Summary of Patients' Baseline and Demographic Characteristics
Characteristic
Summarized as
Categories and measurement units
Age
Continuous
18—75 years
Age group
Ordinal Categorical
<35
>= 35 years
Gender
Categorical
Female/Male
Race
Categorical
White/Black/Asian/Native American/ 
Asian Pacific/Other
Ethnicity
Categorical
  Hispanic or Latino
  Not Hispanic or Latino
  Not Reported
Weight
Continuous
Kg
Height
Continuous
cm
Baseline ECOG Status
Ordinal Categorical
0, 1, 2, 3, 4
Smoking status
Categorical
Current Smoker
Never Smoked
Former Smoker
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 and 
Continuous
< 1 years 
≥1 — <3 years 
≥ 3 — <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
Donor Relationship to Subject 
Categorical
Related/Not related
HLA Compatability
Categorical
Match/Mismatch
Cytomegalovirus IgG Antibody
Catgorical
Positive/Negative
Source of stem cells
Catgorical
Bone Marrow/Peripheral Blood


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7.6
Medication History and Concomitant Medications
During the Screening period, a complete medical history will be compiled for each patient. The 
history will emphasize the background and progress of the patient’s malignancy and include a 
description of prior therapies for it. Medical and Surgical History will be summarized by system 
organ class and preferred term.
In addition, concomitant medications used by the patient and therapeutic procedures completed 
by the patient will be recorded in the eCRF from the first dose of vedolizumab through 18 weeks 
after the last dose of vedolizumab.
Concomitant medications will be coded using the WHO Drug Dictionary. The number and 
percentage of patients taking concomitant medications will be tabulated by standardized 
medication name in the safety analysis set. Concomitant medications are medications taken 
anytime between 30 days prior to the administration of the first dose of vedolizumab through the 
last dose of the vedolizumab. Medications taken prior to dosing and stopped more than 30 days 
prior to the administration of the first dose of vedolizumab will not be included in the summary 
table. All concomitant medications administered and concomitant procedures will be provided in 
data listings.  
7.7
Study Drug Exposure and Compliance
Vedolizumab 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 vedolizumab receipt and dispensing. The number of doses will be summarized as both 
continuous and ordinal categorical variable. 
Exposure to vedolizumab will be summarized and reasons for discontinuation will be tabulated 
by dose level, as following:







1
,
Dose
Total
Expected
Dose
Total
Actual
Min
*
100
Compliance
%
7.8
Efficacy Analyses
Efficacy endpoints will be analyzed using the safety population.
7.8.1
Primary Efficacy Endpoint
{Not applicable}
7.8.2
Secondary Efficacy Endpoints
Secondary efficacy endpoints are:

Time to neutrophil engraftment (recovery of ANC). The first day of the 3-day period will 
be considered the day of neutrophil engraftment.


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!
Percentage of patients who have developed overall Grade 2 to 4 acute GvHD (compiled 
from individual organ scores of gut, skin, or liver) by 100 days after myeloablative allo-
HSCT.  
!
The frequency of maximum severity of GvHD according to the modified Glucksberg 
criteria and BMT CTN-modified IBMTR index.
7.8.3
Exploratory Efficacy Endpoints
Exploratory efficacy endpoints are:
CCI


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7.8.4
Descriptive Summary of Efficacy Endpoints
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 
will be considered if confounding factors suspected.
Time-to-event (survival) endpoints will be summarized for each dosing cohort and will display:
–
Number and percentage of events,
–
Number and percentage of censored observations,
–
Median time to event and 95% CI,
–
25th percentile of the time to event and 95% CI,
–
75th percentile of the time to event and 95% CI,
–
Range (minimum and maximum time to event),
–
Kaplan-Meier estimates of the event rates (percentage and n) at 6 months,
–
Kaplan-Meier estimates of the event rates (percentage and n) at 12 months,
–
Plots of the Kaplan-Meier estimated survival curves.
The proportion endpoints (percentage of subjects meeting endpoint criteria) will be summarized 
for each dosing cohort and will display:
–
Number (n),
–
Percentage and 95% CI.
Frequency of maximum severity of acute GvHD will be summarized for each dosing cohort 
throughout the 100 day period after allo-HSCT and will display:
–
Number (n) of the acute GvHD cases for each severity category,
–
Percentage and 95% CI for each severity category,
–
Plot of the frequencies for each acute GvHD severity categories.
Unless otherwise noticed, all efficacy endpoints that are defined using GvHD grading scale, will 
be summarized twice: based on the modified Glucksberg criteria, and based on the IBMTR 
criteria, respectively. The appropriate grading scale should be explicitly listed on all related 
summary tables, reports and figures, e.g. “Grade 2—4 acute GvHD-free survival at 6 months 
(using modified Glucksberg criteria)”.
7.9
Pharmacokinetic/Pharmacodynamic 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.
Details of the non-compartmental analysis (NCA) for the PK parameters will be provided in a 


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separate Clinical Pharmacology Analysis Plan (CPAP) and the results of the analysis will be 
reported in the Clinical Study Report.
7.9.1
Pharmacokinetic Analysis
The PK analysis set will be used for all PK analyses. Treatment groups will be presented as 
defined in Section 7.2. Missing PK data will not be imputed. More details on the PK analysis 
will be described in a separate document, i.e., CPAP. 
Measured serum concentrations of vedolizumab will be summarized using descriptive statistics 
by treatment group and visit/time separately. 
The mean serum concentration-time profile of vedolizumab will be plotted by treatment group 
and/or visit/time separately. Individual plot will be also presented.
The PK parameters (ex AUC, Cmax) will be summarized by treatment group and treatment 
period (day -1, day +13 and day +42 after allo-HSCT) separately using descriptive statistics 
(non-missing values, mean, SD, SE, %CV, geometric mean, geometric mean %CV, median, 
minimum and maximum) as appropriate. 
Serum concentration data and PK parameters will also be listed.
7.9.2
Pharmacodynamic Analysis
Summary of pharmacodynamics results and change from baseline will be summarized 
descriptively by visit.
7.9.3
Other Outcomes
Immunogenicity (anti-vedolizumab antibodies, AVA) will be descriptively summarized. The 
AVA status will be summarized descriptively, using AVA positive, AVA negative, and 
Neutralizing AVA positive subgroups. AVA positive subgroup will be summarized descriptively 
by transient positive, persistently positive, and any neutralizing AVA positive subgroups. 
Summary of Anti-vedolizumab Antibody (AVA) Frequency will be summarized by study visit 
and study dose (75mg and 300 mg).
The effect of anti-vedolizumab antibodies on PK (ex, exclude ADA positive patients), safety and 
efficacy will be explored.
AVA positive and negative sample will be defined as follows:
)
Negative AVA: defined as a sample that is evaluated as negative in the AVA screening 
assay. Samples that are determined to be positive in the AVA screening assay but the 
result is not confirmed in the AVA confirmatory assay are considered negative.
CCI


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
Positive AVA: defined as a sample that was evaluated as positive in both the AVA 
screening and confirmatory assays.
o
Transiently positive: defined as patients with confirmed positive AVA in 1 sample.
o
Persistently positive: defined as patients with confirmed positive AVA in 2 or more 
consecutive positive AVA samples. 

Positive neutralizing AVA: defined as a sample that was evaluated as positive in the 
neutralizing AVA assay.
Patient AVA positive at baseline is defined as a positive AVA sample prior to Day -1 dose.
7.10
Safety Analysis
For the primary endpoint, an evaluable patient is one who receives vedolizumab IV and is 
assessed for engraftment on or before Day +28. 
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. 
Hematology results, chemistry results, and urinalysis results (including the appropriate changes 
from baseline) will be summarized by study day.
Vita sign analysis and urine laboratory tests will be summarized by study day.
Shifts in laboratory test results for hematology between low, normal and high levels will be 
summarized for each dose and the total by study visit.  
7.10.1 Adverse Events
Unless specified otherwise, the AEs will be tabulated according to MedDRA by system organ 
class, high-level terms, and preferred terms and will include the following categories:

TEAEs.

Drug-related TEAEs.

Grade 3 or higher TEAEs.

Grade 3 or higher drug-related TEAEs.

The most commonly reported TEAEs (i.e., those events reported by ≥10% of all patients)
by system organ class and preferred term.

SAEs by system organ class and preferred term.

Serious Drug-Related TEAEs by system organ class and preferred term.
Listings of PML checklist data and TEAEs resulting in study drug discontinuation will be 
provided.


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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.
7.10.2 Clinical Laboratory Evaluations
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. Key 
parameters are: Liver function tests (ALT, AST, Total Bilirubin, Alkaline phosphatase), WBC, 
Hemoglobin, Platelets, Eos, Mono, Lymph, Neut, Basophils, calculated ANC. 
Shift tables for laboratory parameters will be generated based on changes in NCI CTCAE grade 
from baseline to the worst postbaseline value. 
7.10.3 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 B), and 
summarized using descriptive statistics. On dosing days, vital signs will be obtained before the 
infusion. 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.
7.11
Interim Analysis
No interim analysis is planned. Toxicities will be continuously monitored during all phases of 
the study.
In addition to ongoing safety reviews of cumulative data, early termination of the study will 
occur if any of the following are observed during the expansion phase of the study:

3 cases of CMV colitis, or

3 cases of engraftment failure; however, if first 2 cases of engraftment failure are in 
patients who received myeloablative conditioning, the study will be stopped.
7.12
Changes in the Statistical Analysis Plan 
Not applicable.


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8.0
REFERENCES
[1] 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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APPENDIXES
Appendix A. Pharmacokinetic Sample Breakdown
Day
-1
0
+3
+5
+7
+9
+11
+13
+14
+16
+18
+20
+22
+26
+30
+36
+40
+42
+100
(±7 days)
Serum
PK collection on non-dosing 
days (a)
X1
X1
X1
X1
X1
X1
X1
X1
X1
X1
X1
X1
X1
X1
Predose 
X1
X1
X1
30 min postdose (5 min)
X1
X1
X1
1 hr postdose (10 min) 
X1
2 hrs postdose (20 min) 
X1
X1
X1
12 hrs postdose (30 min)
X1
X1
24 hrs postdose (60 min)
X1
X1
(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. Schedule of Events (Screening through Day +20)
Screening 
(a)
Day 
–1
Day 
0
Day 
+1
Day 
+3
Day 
+5
Day 
+7
Day 
+9
Day 
+11
Day 
+13
Day 
+14
Day 
+16
Day 
+18
Day 
+20
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
X
X
X
Height
X
Weight
X
X
X
X
Vital signs
X
X(b)
X
X (b)
X
ECOG performance status
X
HCT-CI (dose-finding phase only)
Tuberculosis screening
X(d)
RAMP questionnaire
X
X(b)
X (b)
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 informed consent form through 18 weeks after the last dose of study drug.
Vedolizumab IV administration (f)
X
X
Allo-HSCT (g)
X
Samples/Laboratory Assessments
Pregnancy test (h)
X1
X1
Hematology/chemistry 
X1
X1(b)
X1
X1 (b)
X1
Urinalysis
X1
X1(b)
Blood sample for flow cytometry (i,j,k)
X1(b)
X1
X1
X1 (b)
X1
Blood sample for serum biomarkers (j,l)
X1(b)
X1
X1
X1 (b)
X1
Blood sample for anti-vedolizumab 
antibodies (j)
X1(b)
X1


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Allo-HSCT=allogeneic hematopoietic stem cell transplantation, ECOG= Eastern Cooperative Oncology Group, GvHD=graft-verus-host disease, HCT-
CI=Hematopoietic Cell Transplantation-Specific Comorbidity Index, ICF=informed consent form, IV=intravenous, PK=pharmacokinetic(s), RAMP= 
Risk Assessment and Minimization for Progressive Multifocal Leukoencephalopathy (PML).
(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 prior to 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) QuantiFERON® test or tuberculin skin test only. 
(e) Including serious pretreatment events.
(f) Vedolizumab will be administered via a 30-minute intravenous (IV) infusion on Day –1. HSC infusion should occur on Day 0 no sooner than 12 
hours after completion of IV infusion of vedolizumab on Day –1. Vedolizumab will also be administered via a 30-minute IV infusion on Day +13 after 
myeloablative allo-HSCT.
(g) Details on the HSC infusion including cell counts and donor CMV status will be recorded on the eCRF.
(h) A serum beta-human chorionic gonadotropin (-hCG) 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.
(i) Additional specimens may be collected from any patient who experiences an infusion reaction.
(j) An additional sample may be collected from any patient who develops GvHD. 
(k) Includes immunophenotyping and MAdCAM-1 (immunophenotyping includes the cell markers of GvDH).
(l) To be collected 24 hours (3 hours) postdose from the preceding day.
(m) Time points for blood samples for PK analysis will be collected as specified in Appendix A.


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Appendix C. Schedule of Events (Day +22 through end of study)
Day 
+22
Day 
+26
Day 
+30
Day 
+34
Day 
+36
Day 
+40
Day 
+42
Day 
+100 
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)
12 month 
Follow-
up/EOS/ET 
Visit (b)
OS 
Follow-
up
Symptom-directed physical 
examination
X
X
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
X
X
Vital signs
X
X
X (c)
X
X
X
X
X
X
RAMP questionnaire
X (c)
Follow-up phone calls
Q3mo 
(d)
Assessment of GvHD
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(e) will be reported from signing of the informed consent form through 18 weeks after the last dose of study drug.
Vedolizumab IV administration (f)
X
Samples/Laboratory Assessments
Hematology/chemistry (g)
X1
X1
X1 
(c)
X1
X1
X1
X1
X1
X1
Urinalysis
Blood sample for chimerism 
analysis
X1
Blood sample for flow cytometry (h)
X1
X1
X1 
(c)
X1
X1
Blood sample for serum biomarkers 
(i)
X1
X1
X1 
(c)
X1
Blood sample for anti-vedolizumab 
antibodies (h)
X1
X1
Blood sample for PK (j)
See Appendix A.Error! Reference source not found.


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Complete remission with incomplete platelet recovery=CRp, EOS=end-of-study, ET=early termination, GvHD=graft-verus-host disease, 
IV=intravenous, OS=overall survival, PK=pharmacokinetic(s), World Health Organization=WHO.
(a) Patients will attend a Day +100 visit (±7 days) at which time patients will enter posttreatment follow-up. If subsequent anticancer therapy is required 
before 30 days after the last dose, the Day +100 visit should be conducted before the initiation of subsequent anticancer therapy.
(b) Patients who remain in remission will be followed for development of acute and chronic GvHD and safety during clinic visits at 4, 5, 6, 9, and 12 
months after allo-HSCT 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). Patients who have been discontinued will attend an ET visit 30 to 40 days after the last dose of study drug 
using all study procedures outlined for the 12-month follow-up visit.
(c) Assessment/sample collection should be performed pre-dose.
(d) Patients will be followed for overall survival 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. 
(e) Including serious pretreatment events; see Section 11.2.
(f) If engraftment is confirmed, vedolizumab will be administered via a 30-minute intravenous (IV) infusion on Day +42 after myeloablative allo-HSCT.
(g) Hepatitis and HIV testing are to be performed only at the Screening visit.
(h) Additional specimens may be collected from any patient who experiences an infusion reaction.
(i) An additional sample may be collected from any patient who develops GvHD.
(j) Time points for blood samples for PK analysis will be collected as specified in Appendix A.
Note: 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.


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Appendix D. Clinical Stages and Grades of Graft-Versus-Host Disease
Acute Graft-versus-Host Disease Grade (modified Glucksberg)
Grade
Skin
Liver
Intestinal tract
I
Stage 1-2 and 
None and 
None
II
Stage 3 or 
Stage 1 or 
Stage 1
III
-
Stage 2-3 or 
Stage 2-4
IV
Stage 4 or 
Stage 4
-
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%
and
0
<34
and
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. [1]


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Clinical Stages for Skin, Liver, and Intestinal tract of GvHD.


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%LRVWDWLVWLFV$SSURYDO
-XQ87&
%LRVWDWLVWLFV$SSURYDO
-XQ87&
&OLQLFDO6FLHQFH$SSURYDO
-XQ87&
&OLQLFDO3KDUPDFRORJ\$SSURYDO
-XQ87&
3KDUPDFRYLJLODQFH$SSURYDO
-XQ87&
PPD