A Phase 2, Open-label, Multicenter Study of the Safety and Efficacy of TAK-007 in Adult Patients With Relapsed or Refractory B-cell Non-Hodgkin Lymphoma
Phase: PHASE2
Conditions: Relapsed or Refractory (r/r) B-cell Non-Hodgkin Lymphoma (NHL)
Sponsor: Takeda

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PROTOCOL 
A Phase 2, Open-label, Multicenter Study of the Safety and Efficacy of TAK-007 in 
Adult Patients With Relapsed or Refractory B-cell Non-Hodgkin Lymphoma 
Sponsor: 
Takeda Development Center Americas, Inc. 
500 Kendall Street 
Cambridge, MA 02142 USA 
Please note: Takeda Development Center Americas, Inc. (TDC Americas) may be 
referred to in this protocol as “sponsor” or “Takeda”. 
Study Number: 
TAK-007-2001 
IND Number: 
027322 
EudraCT Number: 
2021-002086-18 
Compound: 
TAK-007 
Date: 
03 June 2024 
Amendment Number: 
5 
Amendment History: 
Date 
Amendment Number 
Amendment Type 
Region 
03 June 2024 
Amendment 5 
Substantial 
Global 
20 December 2023 
Amendment 4 
Substantial 
Global 
29 April 2022 
Amendment 3 
Substantial 
Global 
21 December 2021 
Amendment 2 
Substantial 
Global 
12 July 2021 
Amendment 1 
Substantial 
Global 
05 May 2021 
Initial protocol 
Not applicable 
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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TAK-007 
Study No. TAK-007-2001 
Page 2 of 144 
Protocol Incorporating Amendment No. 5 
03 June 2024 
CONFIDENTIAL 
1.0 
ADMINISTRATIVE INFORMATION 
1.1 
Contacts 
A separate contact information list will be provided to each site. 
Serious adverse event (SAE) and pregnancy reporting information is presented in Section 10.0, 
as is information on reporting product complaints.  
Takeda Development Center–sponsored investigators per individual country requirements will 
be provided with emergency medical contact information cards to be carried by each patient. 
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. 
The names and contact information for the medical monitor and responsible medical officer are 
in the study manual. 
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TAK-007 
 
Study No. TAK-007-2001 
Page 3 of 144 
Protocol Incorporating Amendment No. 5 
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CONFIDENTIAL 
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 Council for Harmonisation (ICH) E6 Good Clinical Practice (GCP): 
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 can be found on the signature page. 
 
, MD 
, Cellular Therapies 
Date 
, PhD 
, Cellular Therapies 
Date 
, PhD 
, Cellular Therapies 
Date 
 PhD  
, Cellular Therapies 
Date 
, MD 
, Cellular Therapies 
Date 
 
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TAK-007 
 
Study No. TAK-007-2001 
Page 4 of 144 
Protocol Incorporating Amendment No. 5 
03 June 2024 
 
CONFIDENTIAL 
INVESTIGATOR AGREEMENT  
I confirm that I have read and that I understand this protocol, the investigator’s brochure, 
prescribing information, 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 patients in accordance with the following: 
• The ethical principles that have their origin in the Declaration of Helsinki. 
• ICH, E6 GCP: Consolidated Guideline. 
• All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations. 
• Regulatory requirements for reporting SAEs defined in Section 10.0 of this protocol. 
• Terms outlined in the clinical study site agreement. 
• Responsibilities of the investigator (Appendix B). 
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix C of this protocol. 
 
Signature of Investigator 
Date 
Investigator Name (print or type) 
Investigator’s Title 
Location of Facility (City, State/Province) 
Location of Facility (Country) 
 
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TAK-007 
Study No. TAK-007-2001 
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Protocol Incorporating Amendment No. 5 
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CONFIDENTIAL 
1.3 
Protocol Amendment 5 Summary of Changes  
Protocol Amendment 5 Summary and Rationale 
This section describes the changes to the protocol incorporating Amendment 5. 
On 11 April 2024, Takeda communicated to the FDA the decision to discontinue the 
development of TAK-007 in B-cell non-Hodgkin lymphoma. This decision was not due to 
changes in the safety profile of TAK-007. 
The purpose of this amendment is to confirm that: 
•
All activities to implement TAK-007-2001 Protocol Amendment 4 should be stopped.
•
Patient screening will remain closed for new patients, permanently.
•
Enrolled patients should continue to be followed per Protocol Amendment 5.
•
Secondary follow-up was amended to focus on safety assessments.
•
Protocol will implement the long-term follow-up (LTFU) phase for enrolled patients for up
to 15 years after TAK-007 administration.
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification and administrative purposes only. 
Protocol Amendment 5 
Summary of Changes Since Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by 
Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
1. 
• Section 6.2 Number
of Patients
• Section 13.2
Determination of
Sample Size
Confirm that the planned number of 
patients enrolled in study is 45 as of 
Amendment 5  
To clarify that no additional 
patients will be enrolled in the 
study. 
2 
• Section 1.2
Approval
Added Global Safety Lead as 
signatory. 
Added signatory because this is 
largely a safety-related 
amendment. 
3. 
• Section 1.3 Protocol
Amendment 5
Summary of
Changes
Updated this section with Protocol 
Amendment 5-specific changes. 
To summarize major changes in 
this amendment. 
4. 
• Section 2.0 STUDY
SUMMARY
• Section 6.2 Number
of Patients
Revised number of participating sites 
and countries 
To update that the sites will only 
be US only since Part 2 will no 
longer be conducted. 
5. 
• Section 2.0 STUDY
SUMMARY
Deleted all references to “Part 1” and 
“Part 2” of the study, including: 
To clarify that Part 2 is no longer 
part of the study and that 
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TAK-007 
 
Study No. TAK-007-2001 
Page 6 of 144 
Protocol Incorporating Amendment No. 5 
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CONFIDENTIAL 
Protocol Amendment 5  
Summary of Changes Since Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by 
Change 
Description of Each Change and Rationale 
 
Location 
Description 
Rationale 
• Section 5.1.1 
Primary Objective 
• Section 5.1.2 
Secondary 
Objectives 
• Section 5.1.3 
Exploratory 
Objectives 
• Section 5.2.1 
Primary Endpoint 
• Section 5.2.2 
Secondary 
Endpoints 
• Section 5.2.3 
Exploratory 
Endpoints 
• Section 6.1 
Overview of Study 
Design 
• Table 6.b Primary 
and Secondary 
Endpoints for 
Disclosures 
• Section 8.7 
Enrollment Pausing 
Criteria 
• Section 9.3 
Treatment Group 
Assignments 
• Section 9.4.17 
Disease Assessment 
• Section 9.7 
Discontinuation of 
Treatment With 
Study Drug and 
Patient Replacement 
• Section 9.10 
Posttreatment 
Follow-up 
Assessments (DOR, 
PFS, OS, and 
Safety) 
• Section 11.1 IDMC 
• Section 13.2 
Determination of 
• 
Revision of post-treatment 
follow-up assessments. 
• 
Revisions in efficacy, safety, 
and CK analyses. 
• 
Deletion of healthcare resource 
utilization and analyses. 
• 
Deletion of patient-reported 
outcomes (PROs) and analyses. 
• 
Deletion of the IDMC 
Committee. 
• 
Deletion of central IRC. 
assessments and analyses have 
been deleted or revised, 
accordingly. 
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TAK-007 
 
Study No. TAK-007-2001 
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Protocol Incorporating Amendment No. 5 
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CONFIDENTIAL 
Protocol Amendment 5  
Summary of Changes Since Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by 
Change 
Description of Each Change and Rationale 
 
Location 
Description 
Rationale 
Sample Size  
• Section 13.5 
Efficacy Analyses 
• Section 13.5.1 
Efficacy Analysis of 
the Primary 
Endpoint 
• Section 13.5.2 
Efficacy Analyses of 
the Secondary 
Endpoints 
• Schedule of Events 
(Appendix A  
Table A 1) 
• Section 13.6 Safety 
Analysis  
• Section 13.7 CK 
Analysis 
• Section 13.11.1 
Population CK-
Pharmacodynamic 
Analysis 
• Schedule of Events 
(Appendix A  
Table A 2) 
6. 
• Section 2.0 STUDY 
SUMMARY 
• Table 6.b Primary 
and Secondary 
Endpoints for 
Disclosures 
• Section 6.3.1 
Duration of an 
Individual Patient’s 
Study Participation 
• Section 6.3.4 Total 
Study Duration 
• Section 9.4.3 
Treatment and 
Follow-up Phases 
(Day 0 to Month 24) 
• Section 9.4.17 
Disease Assessment 
• Section 9.10 
Reduced secondary follow-up phase 
from 60 months to 24 months, 
including: 
• 
Reducing the number of 
scheduled visits. 
• 
Removing all efficacy-related 
assessments after Month 6. 
To clarify that LTFU phase will 
begin after Month 24 instead of 
Month 60, and for up to 
13 additional years. 
 
To reduce the assessment burden 
on patients. 
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Study No. TAK-007-2001 
Page 8 of 144 
Protocol Incorporating Amendment No. 5 
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CONFIDENTIAL 
Protocol Amendment 5  
Summary of Changes Since Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by 
Change 
Description of Each Change and Rationale 
 
Location 
Description 
Rationale 
Posttreatment 
Follow-up 
Assessments (DOR, 
PFS, OS, and 
Safety) 
• Section 10.3 
Monitoring of AEs 
and Period of 
Observation 
• Schedule of Events 
(Appendix A  
Table A 1) 
• Schedule of Events 
(Appendix A  
Table A 2) 
7. 
• Section 2.0 STUDY 
SUMMARY 
Reduced enrollment period from 4 to 
5 years to 3 years. 
To clarify that study enrollment is 
closed and no additional patients 
are to be enrolled in the study. 
8. 
• Section 2.0 STUDY 
SUMMARY 
• Section 6.1 
Overview of Study 
Design 
• Section 7.1 Inclusion 
Criteria, criterion #6  
• Section 8.1 Study 
Drug Administration 
• Section 8.7 
Enrollment Pausing 
Criteria 
• Section 9.3 
Treatment Group 
Assignments 
• Section 13.2 
Determination of 
Sample Size 
Revised the number of expansion 
cohorts  
To reflect discontinuation of 
enrollment to multiple dosing 
cohorts and non-implementation 
of Part 2 of the study. 
9. 
• Section 2.0 STUDY 
SUMMARY 
• Section 13.1 General 
Considerations 
Revised primary analysis to not 
involve any statistical inference. 
To clarify how primary analysis 
will now be assessed. 
10. 
• Section 8.1 Study 
Drug Administration 
• Section 9.4.3 
Deleted all references to multiple 
doses of TAK-007. 
Deleted the Day 17 scheduled visit 
To clarify that patients received 
only a single dose of TAK-007. 
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TAK-007 
Study No. TAK-007-2001 
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Protocol Incorporating Amendment No. 5 
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CONFIDENTIAL 
Protocol Amendment 5 
Summary of Changes Since Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by 
Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
Treatment and 
Follow-up Phases 
(Day 0 to Month 24) 
• Section 9.5
Completion of Study
Treatment (for
Individual Patients)
• Section 9.7
Discontinuation of
Treatment With
Study Drug and
Patient Replacement
• Schedule of Events
(Appendix A
Table A 1)
since it is associated with multiple 
doses of TAK-007. 
11. 
• Section 8.4
Precautions and
Restrictions
• Section 10.4
Procedures for
Reporting Drug
Exposure During
Pregnancy and Birth
Events
Revised pregnancy precautions and 
restrictions language. 
To clarify and ensure consistency 
current Takeda wording. 
12. 
• Section 9.4.4.1 RCR
Testing
• Section 9.4.4.2
TAK-007
Persistence
• Section 9.4.19.2
Blood Samples for
RCR
• Schedule of Events
(Appendix A
Table A 2)
• Schedule of Events
(Appendix A
Table A 3)
Revised RCR Testing and TAK-007 
persistence testing  
To clarify reduced testing 
procedures. 
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Study No. TAK-007-2001 
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Protocol Incorporating Amendment No. 5 
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CONFIDENTIAL 
Protocol Amendment 5  
Summary of Changes Since Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by 
Change 
Description of Each Change and Rationale 
 
Location 
Description 
Rationale 
13. 
• Section 10.3 
Monitoring of AEs 
and Period of 
Observation 
• Schedule of Events  
(Appendix A  
Table A 3) 
Revised AE monitoring and 
observation period.  
To update new monitoring and 
observation period during the 
secondary and long-term 
follow-up. 
14. 
• Section 2.0 STUDY 
SUMMARY 
• Section 6.1 
Overview of Study 
Design 
• Figure 6.a Study 
Schematic for TAK-
007-2001 Protocol 
• Section 6.3.1 
Duration of an 
Individual Patient’s 
Study Participation 
• Section 6.3.4 Total 
Study Duration 
• Figure 6.a Study 
Schematic for TAK-
007-2001 Protocol 
• Table 8.a CAR-T 
Toxicity Assessment 
and Management 
Guidelines 
• Section 9.4.1 
Screening Phase 
(Day -33 to Day -6) 
• Section 9.4.3 
Treatment and 
Follow-up Phases 
(Day 0 to Month 24) 
• Section 9.4.4 LTFU 
Phase (Ongoing – up 
to Year 15 
Following TAK-007 
Administration) 
• Section 9.4.18.3 
Blood Sample for 
DNA and Flow 
Cytometry (CK) 
Implement LFTU phase of the study  
 
To clarify that the LTFU phase 
will begin for all patients who 
have completed the 2-year 
secondary follow-up and will 
continue for up to 15 years after 
TAK 007 administration to ensure 
compliance with FDA LTFU 
guidance for cell therapies studies 
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CONFIDENTIAL 
Protocol Amendment 5  
Summary of Changes Since Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by 
Change 
Description of Each Change and Rationale 
 
Location 
Description 
Rationale 
• Section 9.6 
Completion of Study 
(for Individual 
Patients) 
• Section 13.1 General 
Considerations 
• Schedule of Events 
(Appendix A  
Table A 3) 
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TAK-007 
 
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CONFIDENTIAL 
TABLE OF CONTENTS 
1.0 
ADMINISTRATIVE INFORMATION ..............................................................................2 
1.1 
Contacts..........................................................................................................................2 
1.2 
Approval ........................................................................................................................3 
1.3 
Protocol Amendment 5 Summary of Changes...............................................................5 
2.0 
STUDY SUMMARY.........................................................................................................18 
3.0 
STUDY REFERENCE INFORMATION .........................................................................23 
3.1 
Study-Related Responsibilities ....................................................................................23 
3.2 
Coordinating Investigator ............................................................................................23 
3.3 
List of Abbreviations ...................................................................................................24 
3.4 
Corporate Identification ...............................................................................................27 
4.0 
INTRODUCTION .............................................................................................................28 
4.1 
Background ..................................................................................................................28 
4.1.1 
Large B-Cell Lymphoma .....................................................................................28 
4.1.2 
Indolent Non-Hodgkin Lymphoma (FL and MZL) .............................................29 
4.1.3 
TAK-007 and Rationale for Development in Patients With r/r B-cell NHL .......31 
4.1.4 
Nonclinical Experience .......................................................................................32 
4.1.5 
Clinical Experience .............................................................................................33 
4.1.6 
Known and Potential Benefits and Risks to Patients ...........................................34 
4.2 
Rationale for the Proposed Study ................................................................................35 
5.0 
STUDY OBJECTIVES AND ENDPOINTS .....................................................................36 
5.1 
Objectives ....................................................................................................................36 
5.1.1 
Primary Objective ................................................................................................36 
5.1.2 
Secondary Objectives ..........................................................................................36 
5.1.3 
Exploratory Objectives ........................................................................................36 
5.2 
Endpoints .....................................................................................................................36 
5.2.1 
Primary Endpoint .................................................................................................36 
5.2.2 
Secondary Endpoints ...........................................................................................36 
5.2.3 
Exploratory Endpoints .........................................................................................37 
6.0 
STUDY DESIGN...............................................................................................................37 
6.1 
Overview of Study Design ...........................................................................................37 
6.2 
Number of Patients ......................................................................................................42 
6.3 
Duration of Study .........................................................................................................42 
6.3.1 
Duration of an Individual Patient’s Study Participation ......................................42 
6.3.2 
EOS/Study Completion Definition and Planned Reporting ................................42 
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CONFIDENTIAL 
6.3.3 
Time Frames for Primary and Secondary Endpoints to Support Disclosures .....42 
6.3.4 
Total Study Duration ...........................................................................................44 
7.0 
STUDY POPULATION ....................................................................................................45 
7.1 
Inclusion Criteria .........................................................................................................45 
7.2 
Exclusion Criteria ........................................................................................................48 
8.0 
STUDY DRUG ..................................................................................................................49 
8.1 
Study Drug Administration ..........................................................................................49 
8.2 
Prohibited Concomitant Medications and Procedures .................................................49 
8.3 
Permitted Concomitant Medications and Procedures ..................................................50 
8.4 
Precautions and Restrictions ........................................................................................50 
8.5 
Management and Mitigation of AEs Associated With CAR Cell Therapy .................51 
8.6 
Definition of DLTs ......................................................................................................54 
8.7 
Enrollment Pausing Criteria .........................................................................................54 
8.8 
Blinding and Unblinding..............................................................................................55 
8.9 
Description of TAK-007 ..............................................................................................55 
8.10 
Preparation ...................................................................................................................55 
8.11 
Packaging and Labeling ...............................................................................................56 
8.12 
Storage, Handling, and Accountability ........................................................................56 
8.13 
Other Protocol-Specified Materials .............................................................................56 
8.13.1 
Fludarabine ..........................................................................................................56 
8.13.2 
Cyclophosphamide ..............................................................................................56 
9.0 
STUDY CONDUCT ..........................................................................................................57 
9.1 
Study Personnel and Organizations .............................................................................57 
9.2 
Arrangements for Recruitment of Patients ..................................................................57 
9.3 
Treatment Group Assignments ....................................................................................57 
9.4 
Study Procedures .........................................................................................................57 
9.4.1 
Screening Phase (Day -33 to Day -6) ..................................................................57 
9.4.2 
Conditioning Phase (Day -5 to Day -1) ...............................................................59 
9.4.3 
Treatment and Follow-up Phases (Day 0 to Month 24) ......................................60 
9.4.4 
LTFU Phase (Ongoing – up to Year 15 Following TAK-007 Administration) ..61 
9.4.4.1 
RCR Testing ................................................................................................62 
9.4.4.2 
TAK-007 Persistence ..................................................................................62 
9.4.5 
Informed Consent ................................................................................................62 
9.4.6 
Patient Demographics ..........................................................................................62 
9.4.7 
Medical History ...................................................................................................63 
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9.4.8 
Physical Examination ..........................................................................................63 
9.4.9 
Height and Weight ...............................................................................................63 
9.4.10 
Vital Signs ...........................................................................................................63 
9.4.11 
Pregnancy Test ....................................................................................................63 
9.4.12 
Concomitant Medications and Procedures ..........................................................63 
9.4.13 
AEs ......................................................................................................................63 
9.4.14 
Enrollment ...........................................................................................................64 
9.4.15 
12-Lead ECGs and ECHO/MUGA Scans ...........................................................64 
9.4.16 
Clinical Laboratory Evaluations ..........................................................................64 
9.4.17 
Disease Assessment .............................................................................................66 
9.4.18 
CK, Immunogenicity, and Biomarker Samples ...................................................67 
9.4.18.1 Primary Specimen Collection .....................................................................67 
9.4.18.2 Tumor and Bone Marrow Biopsies and Aspirates ......................................69 
9.4.18.3 Blood Sample for DNA and Flow Cytometry (CK) ...................................70 
9.4.18.4 Plasma Sample for Pharmacodynamics: Cytokines ....................................70 
9.4.18.5 Blood Samples for T/B/NK Absolute Counts and B-cell Aplasia ..............71 
9.4.19 
Biomarker and Pharmacodynamic Measurements ..............................................71 
9.4.19.1 Blood Sample for HLA and KIR Typing ....................................................71 
9.4.19.2 Blood Samples for RCR ..............................................................................71 
9.4.19.3 Blood Samples for Immunophenotyping ....................................................71 
9.4.19.4 Plasma Samples for ctDNA ........................................................................72 
9.4.19.5 Immunogenicity Sample Collection ............................................................72 
9.4.20 
Sample Retention .................................................................................................72 
9.4.21 
Sample Use for Research Purposes .....................................................................72 
9.5 
Completion of Study Treatment (for Individual Patients) ...........................................72 
9.6 
Completion of Study (for Individual Patients).............................................................73 
9.7 
Discontinuation of Treatment With Study Drug and Patient Replacement .................73 
9.8 
Withdrawal of Patients From Study .............................................................................73 
9.9 
Study Compliance ........................................................................................................73 
9.10 
Posttreatment Follow-up Assessments (DOR, PFS, OS, and Safety)..........................73 
10.0 
ADVERSE EVENTS .........................................................................................................74 
10.1 
Definitions....................................................................................................................74 
10.1.1 
Pretreatment Event Definition .............................................................................74 
10.1.2 
AE Definition ......................................................................................................74 
10.1.3 
SAE Definition ....................................................................................................75 
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CONFIDENTIAL 
10.2 
Procedures for Recording and Reporting AEs and SAEs ............................................76 
10.3 
Monitoring of AEs and Period of Observation ............................................................76 
10.4 
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events ..........77 
10.5 
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose) .....................................................................................................................78 
10.6 
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities ...........78 
11.0 
STUDY-SPECIFIC COMMITTEES .................................................................................79 
11.1 
Steering Committee .....................................................................................................79 
12.0 
DATA HANDLING AND RECORDKEEPING ..............................................................79 
12.1 
eCRFs ...........................................................................................................................79 
12.2 
Record Retention .........................................................................................................80 
13.0 
STATISTICAL METHODS ..............................................................................................80 
13.1 
General Considerations ................................................................................................80 
13.2 
Determination of Sample Size .....................................................................................81 
13.3 
Analysis Sets ................................................................................................................81 
13.4 
Analysis of Demographics and Other Baseline Characteristics ..................................81 
13.5 
Efficacy Analyses ........................................................................................................81 
13.5.1 
Efficacy Analysis of the Primary Endpoint .........................................................82 
13.5.2 
Efficacy Analyses of the Secondary Endpoints ...................................................82 
13.6 
Safety Analysis ............................................................................................................83 
13.7 
CK Analysis .................................................................................................................84 
13.8 
Pharmacodynamic Analysis .........................................................................................84 
13.9 
Immunogenicity Analyses ...........................................................................................84 
13.10 RCR Analyses ..............................................................................................................84 
13.11 Exploratory Analyses ...................................................................................................84 
13.11.1 Population CK-Pharmacodynamic Analysis .......................................................84 
13.11.2 Biomarker Analyses ............................................................................................84 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................85 
14.1 
Study-Site Monitoring Visits .......................................................................................85 
14.2 
Protocol Deviations ......................................................................................................85 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections ..................................85 
15.0 
ETHICAL ASPECTS OF THE STUDY ...........................................................................86 
15.1 
IRB and/or IEC Approval ............................................................................................86 
15.2 
Patient Information, Informed Consent, and Patient Authorization ............................87 
15.3 
Patient Confidentiality .................................................................................................88 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy ..................................88 
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CONFIDENTIAL 
15.4.1 
Publication ...........................................................................................................88 
15.4.2 
Clinical Trial Registration ...................................................................................89 
15.4.3 
Clinical Trial Results Disclosure .........................................................................89 
15.5 
Insurance and Compensation for Injury .......................................................................90 
16.0 
REFERENCES ..................................................................................................................91 
 
LIST OF IN-TEXT TABLES 
Table 6.a 
Dose Escalation/De-escalation Rule for the BOIN Design ...................................38 
Table 6.b 
Primary and Secondary Endpoints for Disclosures ...............................................43 
Table 8.a 
CAR-T Toxicity Assessment and Management Guidelines ..................................52 
Table 9.a 
Hematology, Clinical Chemistry, and Serum Immunoglobulin Tests ...................65 
Table 9.b 
Primary Specimen Collection ................................................................................67 
Table 9.c 
Prioritized Sequence for Specimen Collection ......................................................69 
 
LIST OF IN-TEXT FIGURES 
Figure 6.a 
Study Schematic for TAK-007-2001 Protocol ......................................................41 
 
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LIST OF APPENDICES 
Appendix A 
Schedule of Events .................................................................................................96 
Appendix B 
Responsibilities of the Investigator ......................................................................105 
Appendix C 
Investigator Consent to Use of Personal Information ..........................................107 
Appendix D 
IWG 2014 (Lugano) Response Criteria for Lymphoma ......................................108 
Appendix E 
ECOG Scale for Performance Status ...................................................................111 
Appendix F 
Methods of Contraception Considered to Be Effective .......................................112 
Appendix G 
ASTCT CRS Consensus Grading ........................................................................113 
Appendix H 
ASTCT ICANS Consensus Grading for Adults ..................................................114 
Appendix I 
Definition of Acute and Chronic GvHD ..............................................................115 
Appendix J 
Target Organ Staging of Acute GvHD in Adults.................................................116 
Appendix K 
Overall Clinical Grading of Acute GvHD ...........................................................117 
Appendix L 
Organ Scoring of Chronic GvHD ........................................................................118 
Appendix M Global Severity of Chronic GvHD ......................................................................121 
Appendix N 
BOIN Design .......................................................................................................122 
Appendix O 
CARTOX Guidelines for the Management of CRS and ICANS .........................124 
Appendix P 
Protocol History ...................................................................................................132 
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2.0 
STUDY SUMMARY 
Name of Sponsor(s): Takeda Development Center 
Americas, Inc. 
Compound: TAK-007 
Title of Protocol: A Phase 2, Open-label, Multicenter 
Study of the Safety and Efficacy of TAK-007 in Adult 
Patients With Relapsed or Refractory B-cell 
Non-Hodgkin Lymphoma 
IND No.: 
027322 
EudraCT No.: 2021-002086-18 
Study Number: TAK-007-2001 
Phase: 2 
Study Design: 
This phase 2, open-label, multicenter study will investigate the safety and efficacy of TAK-007 (anti-CD19 
chimeric antigen receptor [CAR]+ natural killer [NK] cellular product) administered intravenously (IV) in adult 
patients with relapsed or refractory (r/r) B-cell non-Hodgkin lymphoma (NHL), including large B-cell lymphoma 
(LBCL) patients who have failed ≥2 prior systemic therapies (ie, third or higher line [3L+] treatment) and 
indolent non-Hodgkin lymphoma (iNHL) patients who have failed ≥2 prior systemic therapies (3L+). Eligible 
patients are required to have previously received an anti-CD20 monoclonal antibody (mAb) and chemotherapy 
regimen. 
At the beginning of the study, the dose escalation phase will be conducted to assess the acute safety profile, 
cellular kinetics (CK), and pharmacodynamics of the TAK-007 cell product at 2 dose levels (200 × 106 [30%] 
and 800 × 106 [25%] CD19 CAR+ viable NK cells per patient). A sequential dose escalation guided by Bayesian
Optimal Interval (BOIN) design will be used, followed by expansion cohorts to select the recommended phase 2 
dose (RP2D). Separate expansion cohorts for LBCL and iNHL (Cohorts 1 [LBCL 3L+] and 2 [iNHL 3L+]), with 
approximately 15 patients each may be initiated for dose level(s) selected based on the dose escalation part, to 
further evaluate the safety, tolerability, efficacy, and CK and to allow the selection of the RP2D to be used in the 
rest of the study.  
During dose escalation, a 21-day observation period will be placed between the first and the second patient in 
each dose level, in addition to a 28-day interval between the 2 dose cohorts to allow for dose-limiting toxicity 
(DLT) assessment.  
The sponsor and investigators will select the RP2D. This decision will be based on a review of the preliminary 
safety and efficacy data generated in the dose escalation and expansion phases.  
The study consists of 5 phases: screening, conditioning (lymphodepleting chemotherapy), treatment and primary 
follow-up (safety and efficacy when patients have had the opportunity to be evaluated for at least 6 months after 
TAK-007 administration), secondary follow-up (bi-annual safety evaluations for an additional 18 months), and 
after 2 years, the long-term follow up (LTFU) phase, during which patients will be contacted at least annually for 
continued monitoring of relevant new safety events. The total duration that an individual patient will participate 
in this study is 15 years following TAK-007 administration.  
Eligible patients will receive lymphodepleting chemotherapy on Days -5, -4, and -3, before receiving a single 
IV administration of TAK-007 on Day 0.  
After TAK-007 administration, response will be assessed locally by computed tomography (CT) and/or 
18F-fluorodeoxyglucose positron emission tomography (FDG-PET) according to Lugano classification at Months 
1, 3, and 6 or per local guidelines until the end of study (EOS).  
Clinical evaluations and laboratory studies will be performed on Days 1, 3, and 7 after TAK-007 administration. 
Clinical evaluation and laboratory studies will be further performed on Days 10, 14, 21, 28, and depending on a 
patient's response to treatment, Months 2, 3, 4, and 6. After 6 months, during secondary follow up and LTFU, 
clinical evaluations and laboratory studies will follow an abbreviated Schedule of Events (SOE).  
For patients who receive TAK-007, all adverse events (AEs) will be monitored and recorded continuously from 
signed informed consent through Month 6. After 6 months, during secondary follow-up and LTFU, all related 
SAEs, deaths, and new incidences of Grade ≥3 AEs that are relevant to the potential risks of TAK-007 will be 
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collected. 
For patients who receive lymphodepleting chemotherapy and do not receive TAK-007, all AEs (regardless of 
causality) will be collected for the first 30 days following lymphodepleting chemotherapy.  
Safety evaluations will include the incidence of AEs, severity and type of AEs, electrocardiograms (ECGs), and 
changes from baseline in the patient’s vital signs and clinical laboratory results at the time points noted in the 
Schedule of Events (Appendix A).  
Grading of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome will be 
performed following the definition provided in the American Society for Transplantation and Cellular Therapy 
consensus. Management of immune effector cell therapy-related toxicities will follow the MD Anderson Cancer 
Center (MDACC) guidelines for the management of CAR-T–cell therapy–associated TOXicity (CARTOX) 
recommendations.  
The overall study schema for TAK-007-2001 is illustrated in Figure 6.a. 
Primary Objective: 
• 
To evaluate the safety and tolerability of TAK-007 in adult patients with r/r B-cell NHL to determine the 
RP2D. 
Secondary Objectives: 
• 
To evaluate efficacy endpoints (overall response rate (ORR), complete response [CR], duration of 
response [DOR], progression-free survival [PFS], and overall survival [OS]). 
• 
To further evaluate the safety and tolerability of TAK-007 in adult patients with r/r LBCL and iNHL. 
• 
To characterize CK of TAK-007.  
• 
To assess pharmacodynamics of TAK-007. 
• 
To assess immunogenicity of TAK-007. 
Patient Population: Adult patients with histologically proven B-cell NHL, including LBCL patients who have 
failed ≥2 prior systemic therapies (ie, 3L+) and iNHL (FL and MZL), including the types defined by the World 
Health Organization (WHO), who have failed ≥2 prior lines of systemic therapy (3L+). 
Number of Patients:  
Approximately 42 patients will be enrolled.  
Number of Sites:  
Estimated total: Approximately 15 sites in the 
United States.  
Investigational Therapy: 
Dose Escalation: Patients will receive lymphodepleting chemotherapy consisting of IV fludarabine (30 mg/m2 
body surface area [BSA] per day) and cyclophosphamide (300 mg/m2 BSA per day) on Days -5, -4, and -3 before 
a single IV administration of TAK-007 (allogeneic cord blood-derived CD19 CAR+ NK cells) at a dose of 
200 × 106 (30%) or 800 × 106 (25%) CD19 CAR+ viable NK cells on Day 0 of the study.  
Dose Expansion Cohort 1 (LBCL 3L+) and Cohort 2 (iNHL 3L+): Patients will receive the lymphodepleting 
chemotherapy on Days -5, -4, and -3 before the single IV administration of TAK-007 at a dose of 200 × 106 
(30%) or 800 × 106 (25%) CAR+ viable NK cells on Day 0 of the study. 
Period of Evaluation: 
Study enrollment: Approximately 3 years. 
Core study (conditioning phase + treatment and primary follow-up phase):  
After every patient has had the opportunity to complete at least 6 months of follow-up after TAK-007 
administration. 
Secondary follow-up phase: After every patient has had the opportunity to complete 24 months of follow-up 
after TAK-007 administration. Visits will occur at Months 9, 12, 18, and 24.  
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Long-term follow-up phase: After completion of the 24-month secondary follow-up phase, patients will enter 
long-term follow-up for up to 13 additional years, for a total duration of up to 15 years after TAK-007 
administration.  
Main Inclusion Criteria:  
1. Patients aged ≥18 years or meeting country definition of adult, whichever is older, at the time of signing the 
informed consent. 
2. Patients who have a life expectancy ≥12 weeks. 
3. Patients who have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
4. Patients with a diagnosis of previously treated r/r histologically proven CD19-expressing disease of the 
following types: 
a. 
LBCL, including the following subtypes defined by the WHO: 
i. Diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS). 
ii. High-grade B-cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 rearrangement. 
iii. HGBL NOS without translocations. 
iv. DLBCL arising from iNHL including FL or MZL. 
v. T-cell/histiocyte-rich large B-cell lymphoma. 
vi. DLBCL associated with chronic inflammation. 
vii. Epstein-Barr virus–positive DLBCL-NOS. 
viii. Primary cutaneous DLBCL, leg type. 
ix. Primary mediastinal large B-cell lymphoma.  
x. FL Grade 3B. 
b. iNHL, including the following subtypes defined by the WHO: 
i. 
FL Grade 1, 2, 3A.  
ii. 
MZL (nodal, extranodal, and splenic). 
5. Patients who have measurable disease, defined as at least 1 lesion per the Lugano classification. Lesions 
situated in a previously irradiated area are considered measurable if radiographic progression has been 
documented in such lesions following completion of radiation therapy. LBCL should have a positron-
emission tomography–positive disease per the Lugano classification. 
6. Patients who have r/r LBCL or r/r iNHL after ≥2 prior lines of systemic therapy (Expansion Cohorts 1 
[LBCL 3L+], and 2 [iNHL 3L +]):  
a) Patients with r/r LBCL must have received an anti-CD20 mAb and an anthracycline-containing 
chemotherapy regimen and failed or be ineligible for high-dose chemotherapy and autologous stem cell 
transplantation (ASCT). 
b) Patients with iNHL must have received an anti-CD20 mAb and an alkylating agent (eg, bendamustine or 
cyclophosphamide). 
c) Preinduction salvage chemotherapy and ASCT should be considered 1 line of therapy. 
d) Any consolidation/maintenance therapy after a chemotherapy regimen (without intervening relapse) 
should be considered 1 line of therapy with the preceding combination therapy. Maintenance antibody 
therapy should not be considered a line of therapy. 
e) Single-agent anti-CD20 mAb therapy should not be considered a line of therapy.  
f) 
Bridging chemotherapy given just prior to CAR-T cell therapy treatment should be considered one line 
of therapy together with cell therapy. 
g) Patients who have received prior CD19-targeting CAR-T cell therapy must have achieved at least a 
partial response to the most recent CD19-targeting CAR-T cell therapy. 
7. Patients who have adequate bone marrow function defined as follows: 
a) Absolute neutrophil count >500/µL. 
b) Platelet count of >50,000/µL at screening. Patients with transfusion-dependent thrombocytopenia are 
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excluded. 
8. Patients who have adequate renal, hepatic, cardiac, and pulmonary function as defined in the study protocol. 
Full inclusion criteria are described within the body of the protocol. 
Main Criteria for Exclusion: 
1. Patients with total body weight of <40 kg. 
2. Patients with primary or secondary central nervous system (CNS) involvement by lymphoma. Patients with a 
history of secondary CNS involvement by lymphoma without evidence of CNS involvement at screening 
may be included. 
3. Burkitt lymphoma, mantle cell lymphoma, lymphoplasmocytic lymphoma, or transformation from chronic 
lymphocytic leukemia/small lymphocytic lymphoma (Richter transformation). 
4. Patients with a history of malignancy other than nonmelanoma skin cancer, carcinoma in situ (eg, cervix, 
bladder, breast), low-grade tumors deemed to be cured and not treated with systemic therapy (eg, by gastro-
endoscopy curatively removed gastric cancer) or unless disease free for ≥3 years at screening. 
5. Patients who have undergone autologous or allogeneic transplant or CAR-T- or CAR-NK cell therapy within 
3 months of planned enrollment. Patients after allogeneic transplant have to be off systemic 
immunosuppressive therapy and without the evidence of clinically relevant acute or chronic graft-versus-host 
(GvHD) disease at the time of enrollment. 
6. Treatment with any investigational products or any systemic anticancer treatment within 14 days or 
2 half-lives of the treatment (whichever is longer) before conditioning therapy. For rituximab, a half-life of 
22 days should be considered.  
7. Patients with active infection, including fungal, bacterial, viral, or other infection that is uncontrolled or 
requiring IV antimicrobials for management within 3 days before enrollment. 
8. Patients with active HIV, hepatitis B virus or hepatitis C virus infection at screening (positive DNA/RNA 
test). 
9. Patients with a history or presence of active or clinically relevant CNS disorder such as seizure, 
encephalopathy, cerebrovascular ischemia/hemorrhage, severe dementia, cerebellar disease, or any 
autoimmune disease with CNS involvement. For CNS disorders that recover or are in remission, patients 
without recurrence within 2 years of planned study enrollment may be included. 
10. Patients with any of the following within 6 months of enrollment: myocardial infarction, cardiac angioplasty 
or stenting, unstable angina, symptomatic congestive heart failure (ie, New York Heart Association Class II 
or greater), clinically significant arrythmia (including uncontrolled atrial fibrillation), or any other clinically 
significant cardiac disease. 
11. Patients with a history of autoimmune disease or solid organ transplantation, requiring systemic 
immunosuppression and/or systemic disease modifying agents within the last 2 years. 
12. Patients who have received a live vaccine ≤6 weeks before the start of the conditioning regimen. 
Full exclusion criteria are described within the body of the protocol. 
Main Criteria for Evaluation and Analyses: 
The primary analyses of the primary, secondary, and selected exploratory endpoints will be performed at a time 
when all patients have had the opportunity to be evaluated for at least 6 months after TAK-007 administration. 
Analyses of the primary, secondary, and exploratory endpoints will also be assessed in the final analysis, if 
applicable.  
Primary Endpoint: 
• 
Incidence of AEs and clinically significant laboratory values and vital signs. 
Secondary Endpoints: 
• 
ORR per investigator. 
• 
CR per investigator. 
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• 
DOR per investigator. 
• 
PFS per investigator. 
• 
OS. 
• 
CK parameters (eg, maximum observed concentration [Cmax], time of first occurrence of Cmax, 
persistence (time of last measurable concentration above the lower limit of quantitation), area under the 
concentration-time curve from time 0 to time of the last quantifiable concentration), and other 
parameters as appropriate.  
• 
Pharmacodynamic biomarker assessments utilizing B cell quantification and levels of cytokines in 
circulation over time. 
• 
Prevalence and incidence of antidrug antibodies (ie, anti–human leukocyte antigens, anti-CAR). 
• 
Prevalence and incidence of replication competent retrovirus positive test results. 
Statistical Considerations:  
The efficacy analyses will use the modified intent-to-treat (mITT) set to inform the RP2D decision. The analyses 
of primary and secondary endpoints will be summarized by dose levels in dose escalation cohorts, and by disease 
cohorts and dose regimens in expansion cohorts.  
Sample Size Justification:  
The primary analysis for the study does not involve any statistical inference. Consequently, the sample size was 
determined based on feasibility considerations instead of a formal statistical evaluation. Approximately 
42 patients at levels of either 200 × 106 (30%) or 800 × 106 (25%) CD19 CAR+ viable NK cells per patient 
will be enrolled. 
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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 supplier list in the study manual. The identified vendors will perform specific 
study-related activities either in full or in partnership with the sponsor. 
3.2 
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, expertise in the therapeutic area and the conduct of clinical 
research, and study participation. The signatory coordinating investigator will be required to 
review and sign the clinical study report (CSR) and by doing so agrees that it accurately 
describes the results of the study. 
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3.3 
List of Abbreviations 
2L 
second line treatment 
3L+ 
third or >3rd line treatment 
AE 
adverse event 
ASCT 
autologous stem cell transplantation 
ASTCT 
American Society for Transplantation and Cellular Therapy 
AUClast 
area under the concentration-time curve from time 0 to time of the last quantifiable concentration 
BFI 
Brief Fatigue Inventory 
BOIN 
Bayesian Optimal Interval 
BPI 
Brief Pain Inventory 
BSA 
body surface area 
BTKi 
Bruton tyrosine kinase inhibitor 
CAR 
chimeric antigen receptor 
CAR-T 
chimeric antigen receptor T cells 
CARTOX 
CAR-T–cell therapy–associated TOXicity 
CB 
cord blood 
CFR 
Code of Federal Regulation 
CK 
cellular kinetic(s) 
CLL 
chronic lymphocytic leukemia 
Cmax 
maximum observed concentration 
CMV 
cytomegalovirus 
CNS 
central nervous system 
CR 
complete response 
CRF 
case report form 
CRS 
cytokine release syndrome 
CSR 
clinical study report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
circulating tumor DNA 
DLBCL 
diffuse large B-cell lymphoma 
DLT 
dose-limiting toxicity 
DMSO 
dimethylsulfoxide 
DOR 
duration of response 
ECG 
electrocardiogram 
ECHO 
echocardiogram/echocardiography 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EMA 
European Medicines Agency 
EORTC-
QLQ-C30 
European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 
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EOS 
end of study 
EQ-5D-5L 
European Quality of Life 5-Dimension 5-Level Scale 
FACT-GP5 
Functional Assessment of Cancer Therapy – General  
FDA 
[United States] Food and Drug Administration 
FDG-PET 
18F-fluorodeoxyglucose–positron emission tomography 
FL 
follicular lymphoma 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
GHS/QOL 
global health status/quality of life 
GI 
gastrointestinal 
GvHD 
graft-versus-host disease 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HGBL 
high-grade B-cell lymphoma 
HLA 
human leukocyte antigen 
HRQOL 
health-related quality of life 
ICANS 
immune effector cell-associated neurotoxicity syndrome 
iCas9 
inducible caspase 9 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
IL-15 
interleukin-15 
IND 
Investigational New Drug 
iNHL 
indolent non-Hodgkin lymphoma 
IRB 
institutional review board 
IRC 
independent review committee 
IRR 
infusion-related reactions 
ITT 
intent-to-treat 
IV 
intravenous(ly) 
IWG 
International Working Group 
KIR 
killer immunoglobulin-like receptor 
LBCL 
large B-cell lymphoma 
LTFU 
long-term follow-up 
LVEF 
left ventricular ejection fraction 
mAb 
monoclonal antibody 
MDACC 
MD Anderson Cancer Center 
MDRD 
Modification of Diet in Renal Disease 
mITT 
modified intent-to-treat 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
MUGA 
multigated acquisition scan 
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MZL 
marginal zone lymphoma 
NCI 
National Cancer Institute  
NHL 
non-Hodgkin lymphoma 
NIH 
National Institutes of Health 
NK 
natural killer (cells) 
NOS 
not otherwise specified 
ORR 
overall response rate 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cell 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PET 
positron emission tomography 
PFS 
progression-free survival 
PI3Ki 
phosphatidylinositol 3 kinase inhibitor 
PMBCL 
primary mediastinal large B-cell lymphoma 
PP 
per-protocol set 
PRO 
patient reported outcomes 
PRO-CTCAE 
Patient-Reported Outcomes Version of the Common Term Criteria for Adverse Events 
r/r 
relapsed or refractory 
RP2D 
recommended phase 2 dose 
RCR 
replication competent retrovirus 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SCT 
stem cell transplantation 
SOE 
Schedule of Events 
SUSAR 
suspected unexpected serious adverse reaction 
TCR 
T-cell receptor 
TEAE 
treatment-emergent adverse event 
TLS 
tumor lysis syndrome 
Tlast 
time of last measurable concentration 
tmax 
time of first occurrence of Cmax 
ULN 
upper limit of the normal range 
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 
Millennium Pharmaceuticals, Inc, TDC Japan, TDC Asia, TDC Europe and/or TDC 
Americas, as applicable 
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4.0 
INTRODUCTION 
4.1 
Background 
Lymphomas account for a heterogeneous group of lymphoid neoplasms with different cellular 
origins, including B, T, and natural killer (NK) cells. With an incidence of 3% among all cancer 
entities, lymphomas are considered to be the most prevalent hematological malignancy and 
responsible for 3% of all cancer-related deaths worldwide (Bray et al. 2018). According to the 
2016 revised World Health Organization (WHO) classification of lymphoid neoplasms, 
lymphomas can be classified into mature B-cell neoplasms, mature T-cell and NK-cell 
neoplasms, Hodgkin lymphoma, and posttransplant lymphoproliferative disorders, as well as 
histiocytic and dendritic cell neoplasms (Swerdlow et al. 2016). Within the mature B-cell 
neoplasms, it can be further distinguished between aggressive (eg, diffuse large B-cell lymphoma 
[DLBCL] and primary mediastinal large B-cell lymphoma [PMBCL]) and indolent lymphomas 
(eg, follicular lymphoma [FL] and marginal zone lymphoma [MZL]). 
4.1.1 
Large B-Cell Lymphoma 
DLBCL is the most frequent lymphoma subtype and accounts for approximately one-third of all 
NHL cases (Sant et al. 2010). It is estimated that approximately 66,000 new cases of NHL and, 
consequently, approximately 20,000 new cases of DLBCL are diagnosed annually in the United 
States (US) (Ferlay et al. 2013). Besides the conventional DLBCL not otherwise specified 
(NOS), several other aggressive large B-cell lymphomas are receiving similar treatment 
approaches and are together often referred to as large B-cell lymphoma (LBCL). This includes 
high-grade B-cell lymphoma (HGBL), DLBCL arising from indolent lymphoma including FL or 
MZL, T-cell/histiocyte-rich LBCL, FL Grade 3B, and PMBCL. As an aggressive lymphoma, 
LBCL is considered as curable with chemoimmunotherapy (Tilly et al. 2015).  
While up to 60% of patients with DLBCL may be cured in the first-line setting with R-CHOP 
(rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone)-based 
chemoimmunotherapy, the remaining become refractory to treatment or relapse, and the 
prognosis for these patients is poor (Sehn and Gascoyne 2015). Among patients with progressive 
disease (PD) during first-line treatment or early relapse after initial response, only 30% to 40% 
will respond to salvage chemoimmunotherapy and may undergo autologous stem cell 
transplantation (ASCT) that is necessary for long-term disease control in the relapsed or 
refractory (r/r) setting (Crump et al. 2014), (Gisselbrecht et al. 2010), (Van Den Neste et al. 
2016). The prognosis for patients experiencing failure of second-line salvage therapy is poor, 
with a median overall survival (OS) of 4.4 months and corresponding 1-year and 2-year OS rates 
of 23% and 16%, respectively (Van Den Neste et al. 2016).  
Even in patients responding to salvage therapy, long-term remissions are only seen in up to 50% 
(Hamadani et al. 2014), (Gisselbrecht et al. 2012). Furthermore, for patients with refractory 
DLBCL, the overall response rate (ORR) is 26% and complete response (CR) is 7% to the next 
line of therapy, with median OS of 6.3 months. Twenty percent of patients are alive at 2 years 
(Crump et al. 2017). Consolidation of r/r DLBCL patients in remission with allogeneic stem cell 
transplantation (SCT) may achieve long-term disease control; however, high rates of nonrelapse 
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mortality and long-term morbidity are expected (Rigacci et al. 2012), (Van Den Neste et al. 
2017). 
Autologous chimeric antigen receptor T-cell (CAR-T) therapies targeting CD19 have 
demonstrated efficacy in r/r LBCL after 2 or more prior treatment lines in several phase 2 studies 
with ORRs and CRs of 72% and 51%, respectively, in the ZUMA-1 study evaluating 
axicabtagene ciloleucel (Neelapu et al. 2017); 52% and 40%, respectively, in the JULIET study 
evaluating tisagenlecleucel (Schuster et al. 2019); and 73% and 53%, respectively, in the 
TRANSCEND NHL 001 study evaluating lisocabtagene maraleucel (Abramson et al. 2020). 
Two-year follow-up data from the ZUMA-1 study showed a median progression-free survival 
(PFS) of 5.9 months, and 58% (59 of 101) of patients achieved CR (Locke et al. 2019). 
Importantly, these outcomes are focusing on patients treated with CAR-T cells and not the 
complete intent-to-treat (ITT) population with patients who were not treated in the study (eg, due 
to manufacturing failure, PD, or death while waiting for the cell therapy product). Furthermore, 
Grade ≥3 cytokine release syndrome (CRS) occurred in 11% of patients, and Grade ≥3 
neurological events occurred in 32% of patients. As evidenced by the results of these published 
studies, the wide application of autologous CAR-T adoptive cell therapy is limited by significant 
toxicities (including but not limited to CRS and neurotoxicity), reimbursement issues, and 
significant logistical challenges of autologous cell collection, manufacturing, and infusion.  
Allogeneic, off-the-shelf, CAR-T cells might overcome the logistical limitations of autologous 
CAR-Ts but pose other critical challenges, including risk of graft-versus-host disease (GvHD) 
and graft rejection; CAR-T cells also require complex gene editing procedures to reduce toxicity. 
Importantly, the outcome of patients failing CD19-targeted CAR-Ts is poor with a median OS of 
only 5.3 months (Chow et al. 2019). Recent data indicate the potential benefit of retreatment of 
CD19 CAR-T therapies in a minority of patients and only with limited response duration in 
LBCL (Gauthier et al. 2021).  
Meanwhile, noncellular therapy in heavily pretreated patients with LBCL has made variable 
progress. Monotherapies, as well as drug combinations, may achieve decent response rates in this 
heavily pretreated patient population. Examples include selinexor (ORR 28%) (Kalakonda et al. 
2020), loncastuximab tesirine (ORR 48%) (Caimi et al. 2020), polatuzumab 
vedotin/bendamustine/rituximab (ORR 63%) (Sehn et al. 2020), and tafasitamab/lenalidomide 
(ORR 60%) (Salles et al. 2020). Nevertheless, new treatment options are still needed for patients 
to achieve long-term benefit with an improved safety profile.  
In summary, there remains a significant medical need for patients with r/r LBCL, and novel 
treatment approaches are needed to improve outcomes for these patients. 
4.1.2 
Indolent Non-Hodgkin Lymphoma (FL and MZL) 
FL and MZL are considered to be incurable indolent mature B-cell malignancies, affecting 
approximately 30,000 new patients annually in the US. FL and MZL are heterogeneous diseases 
with varying prognoses, owing to differences in clinical, laboratory, and disease parameters.  
Localized FL is treated with radiation in curative intent (Lowry et al. 2011). Treatment of 
systemic disease is indicated in the presence of lymphoma-related symptoms (eg, B symptoms, 
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hematopoietic insufficiency, rapid lymphoma progression, and organ compression). Treatment 
goals in advanced indolent non-Hodgkin lymphoma (iNHL) are to provide a durable remission 
and to contribute to improved outcomes by offering longer PFS, with minimum side effects. 
Current standard of care in the first-line setting for fit patients is chemoimmunotherapy including 
a CD20 antibody (eg, rituximab, obinutuzumab) and an alkylating agent (eg, bendamustine, 
cyclophosphamide). Definitive management of r/r iNHL remains controversial due to the large 
number of available treatment options, such as chemotherapy, radioimmunotherapy, targeted 
therapies, ASCT, and allogeneic SCT.  
Recent data identified that one of the strongest predictors of long-term FL outcomes is length of 
first remission after first-line therapy. Patients with progression of disease within 24 months of 
completing induction chemoimmunotherapy (POD24), who make up approximately 20% of 
patients, have significantly poorer outcomes than those with longer remission durations (5-year 
OS: 50% versus 90%, respectively) (Casulo et al. 2015). The prognosis for patients with iNHL 
relapsing or refractory to second-line and third-line of therapy is poor, with 5 year OS dropping 
to 40% to 45%. Use of phosphatidylinositol 3 kinase inhibitors (PI3Ki) in patients relapsing after 
2 or more previous lines of therapy has demonstrated encouraging ORRs (copanlisib, 59%; 
duvelisib, 42%; idelalisib, 56%); however, with median PFS of 12.5, 9.5, and 11 months, 
respectively, the duration of response (DOR) is relatively limited (Dreyling et al. 2020), (Flinn et 
al. 2019), (Gopal et al. 2014). The EZH2 inhibitor tazemetostat displayed only limited activity in 
EZH2 wild-type FL (ORR 34%) (Morschhauser et al. 2020). For those patients who achieve 
remission with salvage therapy, ASCT may be considered. For subsequent remissions or one 
requiring more than 2 lines of therapy, allogeneic SCT may be discussed depending on younger 
patient age and the absence of comorbidities. FL management in the r/r disease setting is 
influenced by initial first-line therapy and the duration and quality of the response. 
MZL is subdivided into 3 major categories: extranodal MZL of mucosa-associated lymphoid 
tissue, nodal MZL, and splenic MZL representing 70%, 20%, and 10% of all MZL, respectively 
(Bertoni et al. 2011). For localized disease, recommended therapies include triple therapy for 
Helicobacter pylori in gastric extranodal MZL, splenectomy for splenic MZL, and radiotherapy 
for nodal MZL. For disseminated disease with low tumor burden, a watch-and-wait approach or 
single-agent rituximab may be applied. For symptomatic disease, however, a similar approach to 
FL is used with chemoimmunotherapy approaches such as bendamustine and rituximab. Patients 
with relapsing disease after at least 1 CD20-targeted therapy have chemotherapy-free options 
available, including the Bruton tyrosine kinase inhibitor (BTKi), ibrutinib (ORR 48%) (Noy et 
al. 2017), the PI3Ki umbralisib (ORR 49%) (Fowler et al. 2021), and the immunomodulatory 
agent lenalidomide in combination with rituximab (ORR 65%) (Leonard et al. 2019). 
Transformation from an indolent to more aggressive disease is also a well-recognized 
complication of iNHL in the natural disease history. Transformation is defined by histologic 
evidence of DLBCL or other high-grade morphology, usually accompanied by rapid progression 
of lymphadenopathy, extranodal disease outside the marrow, B symptoms, and elevated serum 
lactate dehydrogenase.  
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Cellular immunotherapy, such as CD19-targeted CAR-T cells, may be a treatment option for 
r/r iNHL. In the ongoing phase 2 ZUMA-5 study of axicabtagene ciloleucel with 96 evaluable 
patients (80 patients with FL and 16 patients with MZL), ORR was 93% with 80% CR (Jacobson 
et al. 2020). The median PFS was 23.5 months for all patients (23.5 months and 11.8 months for 
patients with FL and MZL, respectively). Furthermore, in the ongoing phase 2 ELARA study of 
tisagenlecleucel with 98 FL patients, ORR was 83% with 65% CR (Fowler et al. 2020).  
Published reports suggest that CAR-Ts may be an option for multiply relapsed patients. 
However, significant toxicities, including CRS and neurotoxicity, and significant challenges to 
logistics of autologous cell collection, manufacturing, and infusion have limited wide application 
of autologous CAR-T therapy.  
Taken together, there is still a significant medical need for patients with iNHL. Novel treatment 
approaches are necessary to improve outcomes in these patients. 
4.1.3 
TAK-007 and Rationale for Development in Patients With r/r B-cell NHL 
TAK-007 is a cryopreserved allogeneic cellular product comprising human umbilical cord 
blood-derived natural killer (CB-NK) cells genetically modified with retroviral vector 
SFG.iC9.2A.CAR.CD19-28-3zeta.2A.IL15 encoding the transgenes for anti-CD19 chimeric 
antigen receptor (CAR), the CD28 endodomain, the ζ-chain of the T-cell receptor (TCR) 
complex, interleukin-15 (IL-15), and inducible caspase 9 (iCas9)-based safety switch. TAK-007 
is designed to be administered in conjunction with lymphodepleting chemotherapy in patients 
with r/r CD19+ B-lymphoid malignancies (eg, LBCL, FL, MZL). A phase 1/2 study of anti-
CD19 CAR+ NK cells derived from cord blood (CB) in adult patients with r/r CD19+ cancers 
was conducted using fresh formulation of this cellular product at the MD Anderson Cancer 
Center (MDACC) (refer to NCT03056339 for details). 
NK cells are highly cytotoxic effectors of innate immunity, killing their targets in a 
nonantigen-specific manner, whereas the adaptive cytotoxic functions of T cells depend on 
antigen activation. Unlike allogeneic T cells that carry a significant risk of GvHD mediated 
through the TCR activation, NK cells are characterized by a lack of TCR, hence, have limited 
potential to cause GvHD. CD19 CAR+ NK cells can target lymphoma cells via CD19 
antigen-specific CAR-driven and innate nonantigen-specific mechanisms and may become a 
novel therapy. CB offers an attractive source of allogeneic and off-the-shelf NK cells for 
immunotherapy. Transduced CB-NK cells expressing CD19 CAR and IL-15 have demonstrated 
killing of CD19-expressing cell lines and primary leukemia cells in vitro, with prolongation of 
survival in a xenograft Raji lymphoma murine model. IL-15 production by the transduced 
CB-NK cells increased their persistence and tumor control (Liu et al. 2018).  
Treatment goals in r/r NHL are to provide a durable remission by offering longer PFS with 
minimal side effects. However, currently available treatment options for patients with 
r/r aggressive and indolent B-cell lymphoma are unsatisfactory resulting in continued major 
unmet medical need.  
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4.1.4 
Nonclinical Experience 
TAK-007 uses the genetically identical CAR construct transduced with the same viral vector 
used in the MDACC CD19 CAR+ NK study (Clinical Protocol 2016-0641) but differs in that it 
uses a semi-closed and scalable manufacturing process and is developed as a cryoformulation. 
The nonclinical studies conducted in support of TAK-007 include a series of in vitro and in vivo 
studies to investigate efficacy, pharmacodynamics, cellular kinetics (CK), and safety. 
In vitro studies conducted with TAK-007 characterized the CAR expression, the cellular 
composition, IL-15 secretion, iCas9 functionality and cytolytic activity of TAK-007. These 
studies confirmed the presence of a high percentage of NK cells, CAR-expression on NK cells, 
IL-15 secretion, and low levels of non-NK cells in the composition of TAK-007. In addition, 
TAK-007 demonstrated cytolytic activity against both CD19+ and CD19− cells. 
CAR-independent killing of cancer cells was robust and could be augmented by addition of the 
CAR. CAR-independent killing of primary B cells was minimal, in line with low to undetectable 
levels of stress ligands expressed by these cells.  
In vivo efficacy and tolerability/toxicity studies with TAK-007 were conducted using the 
aggressive systemic luciferase-expressing Raji human Burkitt’s lymphoma xenograft model in 
whole body irradiated nonobese diabetic severe combined immunodeficient gamma (NSG) mice. 
Doses in the in vivo studies bracket the clinical doses based on a total cells/kg basis and 
represent the doses of total NK cells required for nonclinical efficacy in this model. TAK-007 
demonstrated anti-tumor activity; maximum whole blood TAK-007 CAR+ cells concentrations 
were dose dependent and observed on Day 1 postdose; TAK-007 CAR+ cells were detected in 
tissues on Days 14 and 22; and plasma concentrations of human IL-15 were below the 
quantification limit at all timepoints in all groups. No TAK-007-related toxicity findings were 
observed.  
The risk of genotoxicity is low based on the safety features included in the design of the viral 
vector, the absence of replication-competent retroviral vector in the drug product, a highly 
polyclonal viral vector integration profile, and normal karyotype of TAK-007. Furthermore, 
TAK-007 did not demonstrate IL-2/IL-15 independent proliferation, and low levels of cellular 
impurities including CD34+ and universal antigen-presenting cells that may carry a risk of 
second primary malignancy are being controlled during the manufacturing process. 
Nonclinical data show that TAK-007 (i) expresses the CD19 CAR on the cell surface, (ii) is 
functional with regards to IL-15 secretion, killing of CD19+ and CD19- tumor cells, and iCas9 
elimination of CAR+ cells, (iii) has an impact on CD19+ tumor growth in an 
immunocompromised mouse model of human Burkitt's lymphoma, (iv) is generally 
well-tolerated in vivo, and (v) has a low risk of tumorigenicity.  
Nonclinical study results and detailed nonclinical study information are provided in the 
TAK-007 Investigator’s Brochure. 
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4.1.5 
Clinical Experience 
MDACC conducted a phase 1/2 CD19 CAR+ NK study (Clinical Protocol 2016-0641) entitled, 
“Dose Escalation Study Phase I/II of Umbilical Cord Blood -Derived CAR-Engineered NK Cells 
in Conjunction with Lymphodepleting Chemotherapy in Patients with Relapsed/Refractory 
B-Lymphoid Malignancies.” This study used fresh CD19 CAR+ NK product with CB-derived 
NK cells engineered to express anti-CD19 CAR, IL-15, and iCas9-based safety switch. 
Postremission therapy was permitted after the Day 30 assessment at the treating physician’s 
discretion. The first 9 patients received a CAR+ NK product that was partially human leukocyte 
antigen (HLA)-matched with the recipient (4/6 HLA molecules: HLA-A, B, and DRβ1); the 
protocol was then amended to permit treatment with no consideration for HLA matching 
(infused Patients 10 and 11). When possible, a CB unit with killer immunoglobulin-like receptor 
(KIR)-ligand mismatch was selected for CAR+ NK production. 
Initial results from this ongoing study were reported by Liu and colleagues (Liu et al. 2020). 
From June 2017 to February 2019, 11 patients were treated; the median age was 60 years (range, 
47 to 70 years). Five patients had chronic lymphocytic leukemia (CLL) (2 had Richter’s 
transformation or accelerated CLL) and all had failed ibrutinib plus a minimum of 3 prior lines 
of therapy. All 5 patients had high-risk cytogenetic characteristics. Six patients had lymphoma, 
including 2 with DLBCL and 4 with the FL; 3 of these patients underwent transformation to 
high-grade lymphoma. Of the 6 patients with lymphoma, 4 had undergone disease progression 
after autologous hematopoietic stem-cell transplantation and 2 had refractory disease. 
None of the patients developed CRS, immune effector cell-associated neurotoxicity syndrome 
(ICANS), or hemophagocytic lymphohistiocytosis. Moreover, no cases of GvHD were noted 
despite the HLA mismatch between the patients and their CAR+ NK cell products. As expected, 
all patients had hematologic toxicity secondary to the lymphodepleting chemotherapy. No cases 
of tumor lysis syndrome (TLS) or Grade III/IV nonhematological toxicity attributable to the 
CAR+ NK product were observed. The maximum tolerated CAR+ NK cell dose was not reached. 
No patient required admission to an intensive care unit for management of CAR+ NK cell 
toxicity, and there was no need for steroids or anti-IL-6 therapy (tocilizumab), and no need to 
activate the iCas9 safety switch. Patient 2, however, required intensive care for progressive 
lymphoma and died of the malignancy.  
At a median follow-up of 13.8 months, 8 of the 11 treated patients (73%) had objective responses 
(4 of 5 CLL and 4 of 6 NHL) with 7 (64%) achieving a CR. Responses were rapid, usually 
within 30 days of administration, and seen at all 3 dose levels examined. Despite the limitations 
imposed by a small sample size, these results compare favorably to those reported for anti-CD19 
CAR T-cells in the same patient population. 
In summary, these early results of a first-in-human phase 1/2 study of CB-derived NK cells 
engineered to express an anti-CD19 CAR, IL-15 and an iCas9 safety switch is well tolerated with 
preliminary evidence of activity in heavily pretreated patients with multiply r/r CLL or NHL.  
Since this January 2020 publication, MDACC continued to enroll and treat patients on the 
2016-0641 study. Patients have continued to show responses, and the ongoing tolerance and 
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safety experiences have been generally favorable and consistent with the initial report. So far, 
there has been no need to activate the iCas9 safety switch; 1 instance of Grade 1 CRS lasting 
approximately 24 hours was reported, and there have been no reported cases of neurotoxicity or 
GvHD (communication with MDACC). 
TAK-007-2001 is the only study to date of the TAK-007 cryopreserved allogeneic CAR-NK cell 
therapy in humans that uses CB-derived NK cells. The first patient was dosed in August 2022 
and the study has enrolled 21 patients with LBCL and iNHL as of 8 July 2023. Nine patients 
received TAK-007 during the dose escalation phase, including 3 patients who received TAK-007 
at the 200 M CAR+ NK cell dose level, and 6 patients at the 800 M CAR+ NK cell dose level. A 
further 12 patients were dosed in the expansion phase at 800 M CAR+ NK cells. 
4.1.6 
Known and Potential Benefits and Risks to Patients 
This is the first study in which TAK-007 therapy will be given to humans. Nonclinical laboratory 
testing and clinical studies with fresh CD19 CAR NK cell therapy have not identified any serious 
risks. The safety profile of fresh CD19 CAR NK cell therapy in humans is still evolving. Safety 
data from the initial Dose Escalation and Expansion cohorts of this study are available in the 
Investigator’s Brochure.  
The following risks are based on those observed in patients receiving CD19 CAR-T therapies. 
TAK-007 is expected to have a lower toxicity profile compared with CD19 CAR-T therapies, 
and the following events are expected to be less frequent and less severe, but still may occur in 
patients receiving TAK-007 therapy: 
• CRS, which can be associated with serious events, including cardiac failure, kidney 
dysfunction, capillary leak syndrome, hypoxia, and very rare events such as hemophagocytic 
lymphohistiocytosis and macrophage activation syndrome. 
• GvHD. 
• Neurological syndromes, including ICANS. Associated symptoms may include altered or 
decreased consciousness, delirium, confusion, agitation, seizures, difficulty speaking and 
understanding, loss of balance, and/or encephalopathy. 
• TLS. 
• Hypersensitivity reactions and infusion-related reactions (IRRs). Symptoms of allergic 
reaction may include a rash, hives, pyrexia, shortness of breath, and hypotension, which can 
be confused with CRS. Signs and symptoms of IRRs may also include wheezing, chest pain, 
pruritis, rigors, and gastrointestinal (GI) symptoms. 
• Replication competent retrovirus (RCR) positivity and risk of second primary malignancy. 
TAK-007 is administered after lymphodepleting chemotherapy, and therefore TAK-007 therapy 
includes risks associated with fludarabine and cyclophosphamide. The risks associated with 
lymphodepleting chemotherapy include the following:  
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• Viral reactivation, including hepatitis B virus (HBV), hepatitis C virus (HCV), herpes 
simplex virus, varicella zoster virus, and cytomegalovirus (CMV) reactivation (potential 
risk). 
• Severe or prolonged cytopenias resulting in anemia (fatigue, shortness of breath), 
neutropenia (severe infections), and thrombocytopenia (bleeding, hemorrhage). 
• GI disturbances (nausea, vomiting, diarrhea). 
TAK-007 toxicities are expected to be less severe compared to the currently approved CAR-T 
therapies and manageable according to standard medical practices and published guidelines, 
including the MDACC guidelines for the management of CAR-T–cell therapy–associated 
TOXicity (CARTOX) (The University of Texas MD Anderson Cancer Center 2019). 
Standard-of-care treatments for cell-therapy toxicities are effective for the management of safety 
concerns in commercially available CAR-T therapies, which have a high risk of CRS and 
ICANS compared to CAR-NK cells. 
4.2 
Rationale for the Proposed Study 
As mentioned previously, the use of autologous CAR-T cells is accompanied with significant 
challenges in logistics for personalized and timely cell product manufacture and administration. 
Allogeneic CAR-T cells with encouraging results in early-stage development can help to 
improve the logistic challenge, but the risk of GvHD is still of concern. TAK-007, an allogeneic, 
off-the-shelf, CD19 CAR+ NK cell product, presents a potential novel NHL therapy via CD19 
antigen-specific and innate nonantigen-specific mechanisms with a favorable safety profile 
compared with CAR-T therapies. MDACC investigators have conducted Investigational New 
Drug (IND)-enabling nonclinical studies of umbilical CB-NK cells transduced with a viral vector 
incorporating the genes for CD19 CAR, IL-15, and iCas9-based suicide gene. This group’s early 
phase 1 data demonstrate clinical efficacy in r/r LBCL and iNHL patients without evidence of 
clinically relevant GvHD, CRS, or neurotoxicity (Liu et al. 2020).  
On the basis of these early findings, it is expected that TAK-007 (allogeneic 
SFG.iCas9.2A.CAR.CD19-28-3zeta.2A.IL15-transduced CB-NK cells with cryopreservation) 
administered after lymphodepleting chemotherapy in patients with r/r LBCL and iNHL will 
provide equivalent or higher rates of disease response than expected with current standard of 
care. Occurrence of CRS and neurotoxicity complications like those associated with current 
autologous CAR-T therapies are also expected to be significantly lower, representing a 
meaningful clinical benefit for patients with r/r LBCL and iNHL. Occurrence of GvHD is 
expected to be significantly lower compared with allogeneic CAR-T. This allogeneic CAR+ NK 
approach should greatly improve the logistics of delivering this therapy to large numbers of 
patients, a major limitation of current autologous CAR-T therapies, hence the rationale for the 
proposed clinical study.  
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5.0 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
5.1.1 
Primary Objective 
• To evaluate the safety and tolerability of TAK-007 in adult patients with r/r B-cell NHL to 
determine the recommended phase 2 dose (RP2D). 
5.1.2 
Secondary Objectives  
The secondary objectives are: 
• To evaluate efficacy endpoints (ORR, CR, DOR, PFS, and OS). 
• To further evaluate the safety and tolerability of TAK-007 in adult patients with r/r LBCL 
and iNHL. 
• To characterize CK of TAK-007. 
• To assess pharmacodynamics of TAK-007. 
• To assess immunogenicity of TAK-007. 
5.1.3 
Exploratory Objectives  
The exploratory objectives are: 
– To conduct population CK/pharmacodynamics modeling to further evaluate the 
relationship between exposure and response (safety, efficacy, pharmacodynamics, and 
product attributes). 
– To explore biomarkers of clinical response including predictive biomarkers, mechanism 
of action, mechanism of resistance, and product performance. 
5.2 
Endpoints 
5.2.1 
Primary Endpoint 
• Incidence of adverse events (AEs) and clinically significant laboratory values and vital signs. 
5.2.2 
Secondary Endpoints 
The secondary endpoints are: 
• ORR per investigator. 
• CR per investigator. 
• DOR per investigator. 
• PFS per investigator. 
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• OS. 
• CK parameters (eg, maximum observed concentration [Cmax], time of first occurrence of Cmax 
[tmax], persistence (time of last measurable concentration above the lower limit of quantitation 
[tlast]), area under the concentration-time curve from time 0 to time of the last quantifiable 
concentration [AUClast]), and other parameters as appropriate. 
• Pharmacodynamic biomarker assessments utilizing B cell quantification and levels of 
cytokines in circulation over time. 
• Prevalence and incidence of antidrug antibodies (ie, anti-HLA, anti-CAR). 
• Prevalence and incidence of RCR positive test results. 
5.2.3 
Exploratory Endpoints 
The exploratory endpoints are: 
• Characterization and evaluation of predictive biomarkers, as well as molecular mechanisms 
of action and resistance to TAK-007 utilizing (including but not limited to) quantitative and 
phenotypic evaluation of immune cells and cellular product characteristics, as well as HLA 
and KIR characterization. 
• Assessment of circulating tumor DNA (ctDNA). 
• Assessment of standardized uptake value, metabolic tumor volume, tumor volume computed 
tomography (CT)/magnetic resonance imaging (MRI), volumetric tumor assessment, and 
total lesion glycolysis assessed by 18F-fluorodeoxyglucose–positron-emission tomography 
(FDG-PET) and volumetric tumor assessments by CT/MRI. 
6.0 
STUDY DESIGN 
6.1 
Overview of Study Design 
This phase 2, open-label, multicenter study will investigate the safety and efficacy of TAK-007 
administered intravenously (IV) in adult patients with r/r B-cell NHL, including LBCL patients 
who have failed ≥2 prior systemic therapies (ie, third or higher line [3L+] treatment) and iNHL 
patients who have failed ≥2 prior systemic therapies (3L+). Eligible patients are required to have 
previously received an anti-CD20 monoclonal antibody (mAb) and chemotherapy regimen. 
At the beginning of the study, the dose escalation phase will be conducted to assess the acute 
safety profile, CK, and pharmacodynamics of the TAK-007 cell product at 2 dose levels 
(200 × 106 [30%] and 800 × 106 [25%] CD19 CAR+ viable NK cells per patient). Previous 
clinical experience with CD19 CAR NK cells suggests that both proposed dose levels are likely 
to be clinically active (Liu et al. 2020). A sequential dose escalation guided by Bayesian Optimal 
Interval (BOIN) design (Liu and Yuan 2015; Yuan et al. 2016; Zhou et al. 2018) will be used 
(see additional details in Appendix N), followed by expansion cohorts to select the RP2D.  
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During the dose escalation, only patients who received TAK-007 will be considered as 
dose-limiting toxicity (DLT)-evaluable. Each dose level will enroll at least 3 patients. The target 
toxicity rate for the maximum tolerated dose (MTD) is ϕ = 0.25, and the maximum sample size is 
12 total patients for dose escalation. As shown in Table 6.a, the BOIN design uses the following 
rule to guide dose escalation/ de-escalation: 
• If the observed DLT rate at the current dose is ≤0.197, escalate the dose to the next higher 
dose level; if the current dose is the highest dose, treat the new patients at the highest dose. 
• If the observed DLT rate at the current dose is >0.298, de-escalate the dose to the next lower 
dose level; if the current dose is the lowest dose and the rule indicates dose de-escalation, 
treat the new patients at the lowest dose unless the number of DLTs reaches the elimination 
boundary (as shown in Table 6.a), at which point the dose escalation will be terminated for 
safety. 
• Otherwise, stay at the current dose. 
• Repeat above until the maximum sample size of 12 is reached, or until the number of 
evaluable patients treated at the current dose reaches 6 and the decision according to above is 
to stay at the current dose. 
For the purpose of overdose control, doses j and higher levels will be eliminated from further 
examination if Pr(p_j>0.25 |data) >0.95 and at least 3 evaluable patients have been treated at 
dose level j, where p_j is the true DLT rate of dose level j, j = 1, 2.  
Table 6.a 
Dose Escalation/De-escalation Rule for the BOIN Design 
Number of Evaluable Patients 
Treated at Current Dose 
1 
2 
3 
4 
5 
6 
Escalate if # of DLT ≤ 
0 
0 
0 
0 
0 
1 
De-escalate if # of DLT ≥ 
1 
1 
1 
2 
2 
2 
Eliminate if # of DLT ≥ 
NA 
NA 
3 
3 
3 
4 
BOIN: Bayesian Optimal Interval; DLT: dose-limiting toxicity. 
“# of DLT” is the number of patients with at least 1 DLT. When none of the actions (ie, escalate, de-escalate or 
eliminate) is triggered, stay at the current dose for treating the next cohort of patients. “NA” means that a dose 
cannot be eliminated before treating 3 evaluable patients. 
 
Enrollment into the lower dose level may be continued during exploration of the higher dose 
level in the dose escalation phase if deemed appropriate by the sponsor and the investigators. In 
this case, if additional DLTs are identified when additional patients are enrolling, the dose 
escalation decision will be re-examined using the cumulative DLT rate at this dose level. 
Separate expansion cohorts for LBCL and iNHL (Cohorts 1 [LBCL 3L+] and 2 [iNHL 3L+]), 
with approximately 15 patients each may be initiated for dose level(s) selected based on the dose 
escalation part, to further evaluate the safety, tolerability, efficacy, and CK and to allow the 
selection of the RP2D to be used in the rest of the study.  
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During dose escalation, a 21-day observation period will be placed between the first and the 
second patient in each dose level, in addition to a 28-day interval between the 2 dose cohorts to 
allow for DLT assessment.  
The sponsor and investigators will select the RP2D for subsequent studies. The decision for 
RP2D will be based on a review of the preliminary safety and efficacy data during the dose 
escalation and expansion phase.  
The study consists of 5 phases: screening, conditioning (lymphodepleting chemotherapy), 
treatment and primary follow-up (safety and efficacy when patients have had the opportunity to 
be evaluated for at least 6 months after TAK-007 administration), secondary follow-up (safety 
and efficacy evaluations for an additional 18 months), and, at the end of 2 years, a long-term 
follow up phase for up to 13 additional years. The total duration that an individual patient will 
participate in this study is 15 years following TAK-007 administration.  
Eligible patients will receive lymphodepleting chemotherapy on Days -5, -4, and -3, before 
receiving a single IV administration of TAK-007 on Day 0.  
After TAK-007 administration, response will be assessed locally by CT and/or FDG-PET 
according to Lugano classification (Appendix D) at Months 1, 3, and 6. Clinical evaluations and 
laboratory studies will be performed on Days 1, 3, and 7 after TAK-007 administration. Clinical 
evaluation and laboratory studies will be further performed on Days 10, 14, 21, and 28; followed 
by Months 2, 3, 4, and 6, depending on how the patient responds to the treatment.  
Safety Evaluations 
Safety evaluations will include the incidence of AEs, severity and type of AEs, 
electrocardiograms (ECGs), and changes from baseline in the patient’s vital signs and clinical 
laboratory results at the time points noted in the Schedule of Events (SOE) (Appendix A  
Table A 1). Additional details regarding the scope and timing of AE monitoring are provided in 
Section 9.4.13 and Section 10.3, respectively. 
Toxicity grading and management will be conducted as follows: 
• For most AEs, toxicity grades will be evaluated according to the National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 (NCI 2017). 
• Grading of CRS and ICANS will be performed following the definitions provided in the 
ASTCT consensus (Lee et al. 2019) (Appendix G and Appendix H). 
• Grading of acute cell-therapy-associated GvHD will follow recommendations by the Mount 
Sinai Acute GvHD International Consortium (Harris et al. 2016), and grading of chronic 
cell-therapy-associated GvHD will follow recommendations by the 2014 National Institutes 
of Health (NIH) Consensus Conference (Jagasia et al. 2015) (Appendix I to Appendix M). 
• Management of other immune effector cell therapy-related toxicities (not including CRS, 
ICANS, or GvHD) will follow CARTOX recommendations (Appendix O). 
For each set of grading criteria, a higher (later) version of the criteria may be applied. 
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Patients who complete study treatment will continue to have follow-up visits for 6 months 
(Section 9.10). After 6 months, an abbreviated follow-up assessment schedule will be used 
(Appendix A Table A 3).  
The overall study schema for TAK-007-2001 is illustrated in Figure 6.a. 
 
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6.2 
Number of Patients 
The expected total number of patients to be enrolled in the study is approximately 42 patients in 
the dose escalation and expansion phase.  
6.3 
Duration of Study 
6.3.1 
Duration of an Individual Patient’s Study Participation 
Patients will receive TAK-007 and be followed for approximately 2 years in the core study and 
will then enter the long-term follow-up (LTFU) phase for safety assessments for up to 
13 additional years for a total of 15 years after TAK-007 administration per recommendation for 
genetically modified cell therapy products. 
6.3.2 
EOS/Study Completion Definition and Planned Reporting 
The primary analysis for the primary and secondary endpoints will be conducted and 
documented in a CSR after all dosed patients in the study have had the opportunity to be 
assessed for response and safety at least 6 months after TAK-007 administration. The data cutoff 
for final analysis for the CSR addendum will be conducted after all dosed patients have had the 
opportunity to complete LFTU or if the study has been terminated by the sponsor. EOS is 
defined as either the date of the last visit of the last patient, or the date of the last follow-up, or 
the receipt of the last data point from the last patient that is required for at least primary and 
secondary analyses, as prespecified in the protocol, whichever is the later date. 
6.3.3 
Time Frames for Primary and Secondary Endpoints to Support Disclosures 
Refer to Table 6.b for disclosures information for all primary and secondary endpoints. 
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Table 6.b 
Primary and Secondary Endpoints for Disclosures 
Endpoint 
Definition 
Maximum Time Frame 
Primary Endpoint: 
Incidence of AEs and clinically 
significant laboratory values and 
vital signs 
 
Up to 24 months 
Secondary Endpoints: 
ORR per investigator 
CR + PR as best response to treatment 
per the Lugano criteria (Appendix D) 
after TAK-007 administration 
Up to 6 months 
CR per investigator 
Incidence of CR as best response to 
treatment per the Lugano 
Classification Revised Staging 
System for nodal non-Hodgkin and 
Hodgkin lymphomas (Appendix D) 
after TAK-007 administration 
Up to 6 months 
DOR per investigator 
Only for patients who experience an 
objective response and is the time 
from the date of first objective 
response to disease progression per 
Lugano classification (Appendix D) 
or death, whichever comes first 
Up to 6 months 
PFS per investigator 
Time from enrollment date to the date 
of disease progression per Lugano 
classification (Appendix D) or death 
from any cause, whichever comes 
first 
Up to 6 months 
OS 
Time from enrollment to the date of 
death from any cause 
Up to 24 months 
CK parameters 
• 
Parameters determined using 
non-compartmental 
pharmacokinetic analysis. 
• 
Cmax 
• 
tmax 
• 
tlast 
• 
AUClast 
Up to 24 months 
CK parameters 
• 
Additionally, periodic blood 
samples are planned to determine 
TAK-007 levels using a validated 
ddPCR. 
Up to 15 years post-dose 
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Table 6.b 
Primary and Secondary Endpoints for Disclosures 
Endpoint 
Definition 
Maximum Time Frame 
Safety and pharmacodynamic 
biomarkers 
Concentration of IL-15 and soluble 
immune factors (eg, IFN-γ, IL-1β, 
IL-2, IL-4, IL-6, IL-8, IL-10, 
IL-12p70, IL-13, TNFα, GM-CSF) in 
plasma over time 
B cell quantification over time 
Up to 6 months 
Prevalence and incidence of 
antidrug antibodies (ie, anti-HLA, 
anti-CAR) 
Percent of patients with detectable 
anti-HLA and anti-CAR antibodies 
over time 
Prevalence – before TAK-007 
administration 
Incidence – after TAK-007 
administration 
Up to 12 months 
 
Dependent on previous 
testing 
Prevalence and incidence of 
RCR positive test results 
Percent of patients with positive 
RCR test results over time 
Prevalence – before TAK-007 
administration 
Incidence – after TAK-007 
administration 
Up to 60 a months 
AE: adverse event; AUClast: area under the concentration-time curve from time 0 to time of the last quantifiable 
concentration; CAR: chimeric antigen receptor; CK: cellular kinetic(s); Cmax: last measurable concentration; 
CR: complete response; CR: complete response; DOR: duration of response; GM-CSF: granulocyte-macrophage 
colony-stimulating factor; HLA: human leukocyte antigen; IFN: interferon; IL-: interleukin; ORR: objective 
response rate; OS: overall survival; PFS: progression-free survival; PR: partial response; RCR: replication 
competent retrovirus; SOE: Schedule of Events; tlast: time of last measurable concentration above the lower limit 
of normal; tmax: time of first occurrence of Cmax; TNFα: tumor necrosis factor alpha. 
a Additionally, periodic blood samples are planned for up to 15 years post-dose to determine TAK-007 transgene 
levels, RCR testing, and immunogenicity assessment (See SOE, Table A 3). 
 
6.3.4 
Total Study Duration 
The estimated time frame for study completion of primary and secondary follow-up is 5 years 
including approximately 3 years enrollment and 2-year follow-up. 
Patients completing the study follow-up through 2 years will continue in LTFU for up to 
13 additional years, for a total of up to 15 years. 
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7.0 
STUDY POPULATION 
7.1 
Inclusion Criteria 
Each patient must meet all the following inclusion criteria to be enrolled in the study: 
1. Patients aged ≥18 years or meeting country definition of adult, whichever is older, at the time 
of signing the informed consent. 
2. Patients who have a life expectancy ≥12 weeks. 
3. Patients who have an Eastern Cooperative Oncology Group (ECOG) performance status of 
0 or 1 (Appendix E). 
4. Patients with a diagnosis of previously treated, r/r histologically proven CD19 expressing 
disease of the following types: 
a. LBCL, including the following subtypes defined by the WHO: 
i. 
DLBCL NOS. 
ii. 
HGBL with MYC and BCL2 and/or BCL6 rearrangement. 
iii. 
HGBL NOS without translocations. 
iv. 
DLBCL arising from iNHL including FL or MZL. 
v. 
T-cell/histiocyte-rich LBCL. 
vi. 
DLBCL associated with chronic inflammation. 
vii. 
Epstein-Barr virus–positive DLBCL-NOS. 
viii. 
Primary cutaneous DLBCL, leg type. 
ix. 
PMBCL.  
x. 
FL Grade 3B. 
b. iNHL, including the following subtypes defined by the WHO: 
i. 
FL Grades 1, 2, 3A.  
ii. 
MZL (nodal, extranodal, and splenic). 
5. Patients who have measurable disease, defined as at least 1 lesion per the Lugano 
classification (Appendix D). Lesions situated in a previously irradiated area are considered 
measurable if radiographic progression has been documented in such lesions following 
completion of radiation therapy. LBCL should have positron emission tomography 
(PET)-positive disease per the Lugano classification (Appendix D). 
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6. Patients who have r/r LBCL or r/r iNHL after ≥2 prior lines of systemic therapy 
(Expansion Cohorts 1 [LBCL 3L+], and 2 [iNHL 3L +]):  
a. Patients with r/r LBCL must have received an anti-CD20 mAb and an anthracycline-
containing chemotherapy regimen and failed or be ineligible for high-dose chemotherapy 
and ASCT. 
b. Patients with iNHL must have received an anti-CD20 mAb and an alkylating agent 
(eg, bendamustine or cyclophosphamide). 
c. Preinduction salvage chemotherapy and ASCT should be considered 1 line of therapy. 
d. Any consolidation/maintenance therapy after a chemotherapy regimen (without 
intervening relapse) should be considered 1 line of therapy with the preceding 
combination therapy. Maintenance antibody therapy should not be considered a line of 
therapy. 
e. Single-agent anti-CD20 mAb therapy should not be considered a line of therapy.  
f. Bridging chemotherapy given just prior to CAR-T cell therapy treatment should be 
considered one line of therapy together with cell therapy. 
g. Patients who have received prior CD19-targeting CAR-T cell therapy must have achieved 
at least a partial response to the most recent CD19-targeting CAR-T cell therapy. 
7. Patients who have adequate bone marrow function defined as follows: 
a. Absolute neutrophil count >500/µL.  
b. Platelet count of >50,000/µL at screening. Patients with transfusion-dependent 
thrombocytopenia are excluded. 
8. Patients who have adequate renal, hepatic, cardiac, and pulmonary function as defined in the 
study protocol: 
a. Estimated glomerular filtration rate (GFR; Modification of Diet in Renal Disease 
[MDRD] equation) ≥30 mL/min. 
b. Serum alanine aminotransferase/aspartate aminotransferase ≤5 times the upper limit of 
normal range (ULN), as long as patient is asymptomatic.  
c. Total bilirubin ≤2 mg/dL. Patients with Gilbert’s syndrome may have a bilirubin level 
>2 × ULN, per discussion between the investigator and the medical monitor. 
d. Left ventricular ejection fraction (LVEF) ≥40% as determined by an echocardiogram 
(ECHO) or multigated acquisition (MUGA) scan performed within 1 month of 
determination of eligibility. 
e. No evidence of clinically relevant pericardial effusion, and no acute clinically significant 
ECG findings. 
f. Absence of Grade ≥2 pleural effusion. Grade 1 stable pleural effusions are allowed. 
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g. Baseline oxygen saturation >92% on room air. 
9. Patients are required to consent to provide either sufficient archived formalin-fixed paraffin 
embedded (at least 10 unstained slides, ideally 20 unstained slides) or fresh tumor tissue 
obtained after the last relapse (see laboratory manual for details). Exception may be granted 
by sponsor medical monitor per discussion with investigator.  
10. Female patients who:  
a. Are postmenopausal for at least 1 year before the screening visit, or 
b. Are surgically sterile, or 
c. If they are of childbearing potential, agree to practice 1 highly effective method of 
contraception and 1 additional effective (barrier) method at the same time, from the time 
of signing the informed consent through at least 12 months following TAK-007 
administration, or 
d. Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the patient (periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are 
not acceptable methods of contraception). Female and male condoms should not be used 
together, or 
e. Agree not to breastfeed a baby or donate an egg or eggs (ova) during the study and until 
at least 12 months following TAK-007 administration. 
11. Male patients, even if surgically sterilized (ie, status postvasectomy), who: 
a. Agree to practice effective barrier contraception from the time of signing the informed 
consent through at least 12 months following TAK-007 administration, or 
b. Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the patient (periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are 
not acceptable methods of contraception). Female and male condoms should not be used 
together, or 
c. Agree not to donate sperm during the study and at least until 12 months following 
TAK-007 administration. 
12. Patients must give voluntary written consent 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. 
13. Patients who have the willingness and ability to comply with scheduled visits and study 
procedures. 
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7.2 
Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not to be enrolled in the study: 
1. Patients with total body weight of <40 kg. 
2. Patients with primary or secondary central nervous system (CNS) involvement by 
lymphoma. Patients with a history of secondary CNS involvement by lymphoma without 
evidence of CNS involvement at screening may be included.  
3. Patients with Burkitt lymphoma, mantle cell lymphoma, lymphoplasmocytic lymphoma, or 
transformation from CLL/small lymphocytic lymphoma (Richter transformation). 
4. Patients with a history of malignancy other than nonmelanoma skin cancer, carcinoma in situ 
(eg, cervix, bladder, breast), low-grade tumors deemed to be cured and not treated with 
systemic therapy (eg, by gastro-endoscopy curatively removed gastric cancer) or unless 
disease free for ≥3 years at screening. 
5. Patients who have undergone autologous or allogeneic transplant or CAR-T or CAR-NK cell 
therapy within 3 months of planned enrollment. Patients after allogeneic transplant have to be 
off systemic immunosuppressive therapy and without the evidence of clinically relevant 
acute or chronic GvHD at the time of enrollment. 
6. Treatment with any investigational products or any systemic anticancer treatment within 
14 days or 2 half-lives of the treatment (whichever is longer) before conditioning therapy. 
For rituximab, a half-life of 22 days should be considered. 
7. Patients with active infection, including fungal, bacterial, viral, or other infection that is 
uncontrolled or requires IV antimicrobials for management within 3 days before enrollment. 
8. Patients with active HIV, HBV, or HCV infection at screening (positive DNA/RNA test). 
9. Patients with a history or presence of active or clinically relevant CNS disorder, such as 
seizure, encephalopathy, cerebrovascular ischemia/hemorrhage, severe dementia, cerebellar 
disease, or any autoimmune disease with CNS involvement. For CNS disorders that recover 
or are in remission, patients without recurrence within 2 years of planned study enrollment 
may be included. 
10. Patients with any of the following within 6 months of enrollment: myocardial infarction, 
cardiac angioplasty or stenting, unstable angina, symptomatic congestive heart failure (ie, 
New York Heart Association Class II or greater), clinically significant arrythmia (including 
uncontrolled atrial fibrillation), or any other clinically significant cardiac disease. 
11. Patients with a history of autoimmune disease or solid organ transplantation, requiring 
systemic immunosuppression and/or systemic disease modifying agents within the last 
2 years. 
12. Patients who have received a live vaccine ≤6 weeks before the start of the conditioning 
regimen. 
13. Patients with admission or evidence of current illicit drug use, drug abuse, or alcohol abuse. 
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14. Patients with the history of severe immediate hypersensitivity reaction to any of the agents 
used in this study, including cyclophosphamide and fludarabine. 
15. Female patients who are lactating and breastfeeding. 
16. Female patients who have a positive serum pregnancy test.  
17. Patients with any serious medical or psychiatric illness that could, in the investigator’s 
opinion, potentially interfere with the completion of treatment according to this protocol. 
8.0 
STUDY DRUG 
The TAK-007 investigational product will be provided as a cryopreserved suspension of living 
cells that will be thawed by clinical staff immediately before administration. The doses of 
TAK-007 are 200 × 106 (±30%) and 800 × 106 (±25%) CD19 CAR+ viable NK cells per patient. 
Patients must meet all inclusion and exclusion criteria before initiation of lymphodepleting 
chemotherapy. Study drug will be administered only to eligible patients under the supervision of 
the investigator or identified subinvestigator(s). 
8.1 
Study Drug Administration 
If an enrolled patient becomes ineligible to receive TAK-007 due to development of medical 
complications, such as systemic infection, sepsis, hemodynamic instability, or altered mental 
status during/immediately after lymphodepleting chemotherapy but before TAK-007 
administration, the administration of TAK-007 may be delayed for up to 7 days on investigator’s 
decision. Any dose that requires >7 days delay should result in discontinuation of the patient 
from TAK-007 treatment. Day 0 will be defined as the actual day of TAK-007 administration 
after lymphodepleting chemotherapy. In addition, the investigator is required to consult with the 
sponsor medical monitor in case of delayed TAK-007 administration.  
TAK-007 administration will follow lymphodepleting chemotherapy (fludarabine 30 mg/m2 
body surface area [BSA] per day IV on Days -5, -4, and -3 and cyclophosphamide 300 mg/m2 
BSA per day IV on Days -5, -4, and -3). At least 2 days must elapse between the end of 
lymphodepleting chemotherapy and the first TAK-007 administration. 
The outpatient setting is preferred for the administration of TAK-007.  
The instructions for administration of lymphodepleting chemotherapy are outlined in the cell 
handling manual. Details for handling (eg, shipping, receipt, thaw) and administration of 
TAK-007 are contained in the cell handling manual. 
8.2 
Prohibited Concomitant Medications and Procedures 
The following medications are prohibited during the treatment (starting from the signed informed 
consent) and primary follow-up phase (6 months after TAK-007 administration) unless there is 
considerable medical need or approval per sponsor’s medical monitor: 
• Administration of systemic steroids and other immunosuppressant drugs is strictly forbidden 
48 hours before, during, or after any TAK-007 administration unless required for physiologic 
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replacement (up to 35 mg/day of hydrocortisone equivalent) or for the treatment of a critical 
medical condition, or progression of disease following TAK-007. Recent or current use of 
inhaled or topical steroids is not exclusionary.  
• Granulocyte colony-stimulating factors (G-CSF) for 7 days after the first TAK-007 
administration.  
• Granulocyte macrophage colony-stimulating factors. 
• Live vaccines. 
• Other systemic antilymphoma therapies, including but not limited to venetoclax, rituximab, 
and lenalidomide, are prohibited before disease progression. 
8.3 
Permitted Concomitant Medications and Procedures 
Supportive treatment and premedication, per investigator’s discretion and/or institutional 
guidelines for management of patients receiving lymphodepleting conditioning and TAK-007, 
except the prohibited concomitant medications, is allowed. The patient must be told to notify the 
investigational site about any new medications taken after TAK-007 administration. Bacterial, 
fungal, viral prophylaxis, and appropriate management of infections and antibiotics are allowed 
as needed per investigator’s discretion and/or institutional guidelines. In addition, supportive 
care measures (eg, use of antiemetics and antimotility agents for diarrhea management) are 
permitted at the investigator’s discretion and/or per institutional guidelines. 
All medications and significant nondrug therapies (including physical therapy, herbal/natural 
medications, and blood products) administered during the study must be listed on the 
Concomitant Medications, Surgeries, and Procedures case report forms (CRFs). Any prior 
medication received up to 28 days before the administration of lymphodepleting chemotherapy 
will also be recorded in the appropriate CRF. Patients will be instructed not to take any 
additional medications (including over-the-counter products) during the primary follow-up phase 
of the study without consultation with the investigator. 
8.4 
Precautions and Restrictions 
Considering potential CAR-related toxicities (See Section 8.5), appropriate safety measures 
should be taken when treating patients with TAK-007. Assessment and grading of CRS and 
ICANS will be performed following the definition provided in the ASTCT consensus (Lee et al. 
2019) [Appendix G and Appendix H]. Toxicity management will follow the recommendation of 
the CARTOX Working Group (Appendix O) or be performed according to institutional 
guidelines. Other recommended mitigation strategies for each of the potential risks are provided 
in the study manual or equivalent. 
It is not known what effects TAK-007 has on human pregnancy or development of the embryo or 
fetus; therefore, patients participating in this study should avoid becoming pregnant or 
impregnating a partner for 1 year after the dose of TAK-007. Patients who are able to become 
pregnant or impregnate a partner should use effective methods of contraception through defined 
periods during and after study treatment as specified below. 
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Female patients must meet 1 of the following (see Appendix F): 
• Postmenopausal for at least 1 year before the screening visit, or 
• Surgically sterile, or 
• If they are of childbearing potential, agree to one of the following: 
– Agree to practice 1 highly effective method and 1 additional effective (barrier) method of 
contraception at the same time, from the time of signing of the informed consent form 
(ICF) through 1 year 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 patient (periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are 
not acceptable methods of contraception). Female and male condoms should not be used 
together, or 
– Agree not to breastfeed a baby or donate an egg or eggs (ova) during the study and until 
at least 12 months following TAK-007 administration. 
Male patients, even if surgically sterilized (ie, status postvasectomy), must agree to 1 of the 
following: 
• Agree to practice effective barrier contraception with partners who can become pregnant 
from the time of signing of the informed consent through 1 year after the last dose of study 
drug, or 
• Agree to practice true abstinence with partners who can become pregnant, when this is in line 
with the preferred and usual lifestyle of the patient (periodic abstinence [eg, calendar, 
ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and 
lactational amenorrhea are not acceptable methods of contraception). Female and male 
condoms should not be used together, or 
• Agree not to donate sperm during the study and at least until 12 months following TAK-007 
administration. 
Before starting treatment, patients should be advised to seek counseling on sperm or egg storage. 
8.5 
Management and Mitigation of AEs Associated With CAR Cell Therapy 
Investigators should use clinical judgement and refer to the following treatment Guidelines on 
Chimeric Antigen Receptor (CAR) Cell Therapy Toxicity Assessment and Management as 
needed (Table 8.a).  
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Table 8.a 
CAR-T Toxicity Assessment and Management Guidelines 
Toxicity 
Monitoring, Assessment, and Management Guidelines  
CRS 
• 
Close monitoring of patients during and after TAK-007 administration according to 
the study protocol. 
• 
Grading will follow ASTCT Consensus Grading for CRS and Neurologic Toxicity 
Associated with Immune Effector Cells. 
• 
Toxicity management will follow Immune Effector Cell Therapy Toxicity 
Assessment and Management (also known as CARTOX). 
ICANS 
• 
Close monitoring of patients after TAK-007 administration according to the study 
protocol. 
• 
Monitoring for PML according to PML diagnostic criteria, and monitoring for other 
neurotoxicities according to study protocol. 
• 
Grading will follow ASTCT Consensus Grading for CRS and Neurologic Toxicity 
Associated with Immune Effector Cells. 
• 
Toxicity management will follow Immune Effector Cell Therapy Toxicity 
Assessment and Management (also known as CARTOX). 
GvHD 
• 
Close monitoring of patients after TAK-007 administration according to the study 
protocol. 
• 
If any Grade ≥2 acute GvHD is observed after administration of TAK-007 drug 
product exceeding 1.3 × 106 residual T-cells per single high dose of 800 × 106 CAR+ 
NK cells, the following actions will be taken: 
– 
All batches with >1.3 × 106 total residual T cells per single high dose of 
800 × 106 CAR+ NK cells, will be immediately quarantined. 
– 
The batch release acceptance criterion of residual T cells will be revised to 
≤1.3 × 106 T cells per single high dose of 800 × 106 CAR+ NK cells to ensure 
that the total residual T cell remain below 4.0 × 106 for the entire three dose 
regimen. 
– 
For any batch that is >1.3 × 106 T cells per single high dose of 800 × 106 CAR+ 
NK cells, the sponsor may release a dose on an individual patient basis after 
confirmation that the total CD3+ T cells from three doses meets the criterion of 
≤1.0 × 105/kg body weight. 
• 
Grading for acute cell therapy associated GvHD will follow Mount Sinai Acute 
GvHD International Consortium grading for acute cell-therapy associated GvHD. 
• 
Grading for chronic cell therapy associated GvHD will follow 2014 National 
Institutes of Health Consensus Conference grading for chronic cell therapy 
associated GvHD. 
• 
Toxicity management will follow Immune Effector Cell Therapy Toxicity 
Assessment and Management (also known as CARTOX). 
TLS 
• 
Close monitoring before and after lymphodepleting chemotherapy and TAK-007 
administration according to study protocol. 
• 
For patients who are at an increased risk of TLS, hydration and prophylactic 
treatment should be provided. TLS events should be treated aggressively. 
Hypersensitivity and 
IRRs 
• 
Close monitoring of patients for symptoms of hypersensitivity or IRRs during and 
after administration of TAK-007 according to study protocol. 
• 
Administration of supportive therapy, such as oxygen, bronchodilators, epinephrine, 
antihistamines, and corticosteroids, per study protocol. 
• 
Continued monitoring of patients until complete resolution of signs and symptoms. 
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Table 8.a 
CAR-T Toxicity Assessment and Management Guidelines 
Toxicity 
Monitoring, Assessment, and Management Guidelines  
Generation of RCR 
and risk of second 
primary malignancy  
• 
Monitoring for development of any second primary malignancies. 
• 
Adherence to FDA Guidance on Long-Term Follow-Up After Administration of 
Human Gene Therapy Products (FDA 2018). Takeda will implement a LTFU phase 
to further assess the long-term risk profile of TAK-007 therapy; study participants 
will be followed for up to 15 years. 
• 
Monitoring for clonality according to the study protocol (Section 9.4.19.1, 
 Appendix A). 
• 
Monitoring for RCR positivity according to study protocol. 
HBV reactivation 
• 
Hepatitis virus testing at screening and throughout the conduct of the study as 
clinically indicated. HBV testing will include HBsAg, HBsAb, and HBcAb. For 
patients who are HBsAg negative but HBsAb and/or HBcAb positive, HBV DNA 
will also be assessed at screening. 
• 
American Gastroenterological Association Institute Guideline on the Prevention and 
Treatment of Hepatitis B Virus Reactivation During Immunosuppressive Drug 
Therapy (and/or local guidelines) 
• 
For patients with evidence of viral replication [ie, HBsAg (+), HBV DNA increases, 
or reverse conversion HBsAg (-) to (+)], consult a specialist to assess the higher risk 
of hepatic damage and fulminant hepatitis. Antiviral treatment is recommended per 
clinical guidelines. Hepatic safety monitoring and follow-up for at least 12 months is 
also recommended. 
• 
Antiviral prophylaxis per institutional guidelines is recommended for patients with 
history of HBV infection. 
Lymphodepletion-
associated toxicities  
Management of lymphodepletion-associated toxicities according to product labeling. 
ASTCT: American Society for Transplantation and Cellular Therapy; CAR: chimeric antigen receptor; 
CARTOX: CAR-T–cell therapy–associated TOXicity; CRS: cytokine release syndrome; FDA, Food and Drug 
Administration; GvHD: graft-versus-host disease; HBcAb: hepatitis B core antibody; HBsAb: hepatitis B surface 
antibody; HBsAg: hepatitis B surface antigen; HBV: hepatitis B virus; ICANS: immune effector cell-associated 
neurotoxicity syndrome; IRR: infusion-related reaction; LTFU: long-term follow-up; PML: progressive 
multifocal leukoencephalopathy; RCR: replication competent retrovirus; TLS: tumor lysis syndrome. 
 
As an additional risk mitigation measure, patients will be required to carry a patient emergency 
card detailing treatment site and investigator contact information, clinical study information, and 
a back-up 24-hour emergency number for 6 months after TAK-007 administration. This card is 
intended to provide relevant contact information should a patient be treated by a nonstudy 
healthcare provider or emergency medical services. It will also alert nonstudy healthcare 
providers to evaluate patients for the potential risks related to the investigational product 
administration and provide them with the contact information of the treating site and/or obtain 
important study information relevant to the patient’s care. This card will also remind patients of 
concerning signs or symptoms for which they should seek immediate medical attention. 
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8.6 
Definition of DLTs 
DLTs are defined as events occurring during the Dose Escalation phase of this study, that meet 
the criteria below that occur by Day 28 after administration of TAK-007 infusion (Day 0).  
1. Nonhematologic treatment-emergent adverse events (TEAEs) Grade ≥3 clearly unrelated to 
the underlying disease and at least possibly related to the investigational therapy (TAK-007 
and/or lymphodepletion) will be considered DLTs with the following exceptions:  
• Asymptomatic laboratory changes (other than renal and hepatic laboratory values) that 
can be successfully managed (reversal of Grade 4 events to Grade ≤2; reversal of Grade 3 
events to Grade ≤1 or baseline) within 72 hours. 
• Grade 3 nausea/vomiting that can be managed subsequently with antiemetics (Grade 3 
nausea or vomiting that persists beyond 72 hours with or without appropriate medical 
intervention will be considered a DLT). 
• Grade 3 fatigue lasting <7 days. 
• Grade 3 diarrhea lasting <72 hours. 
• Grade 3 renal and hepatic toxicity that improves to Grade ≤2 within 7 days. 
• Grade 3 IRR that responds to symptomatic treatment, without recurrence of Grade 3 
symptoms. 
• Grade 3 TLS lasting ≤14 days and Grade 4 TLS lasting ≤7 days. 
2. Hematologic TEAEs Grade ≥3 that are clearly not attributable to previous lymphoma 
therapy, and/or marrow infiltration related to the underlying disease, and at least possibly 
related to the investigational therapy (TAK-007 and/or lymphodepletion) will be considered 
DLTs with the following exceptions: 
• Grade ≥3 neutropenia lasting <21 consecutive days. 
• Grade 3 febrile neutropenia lasting <14 days. 
• Grade ≥3 thrombocytopenia lasting <21 consecutive days. 
• Cytopenia except neutropenia and thrombocytopenia as described above. 
3. Acute GvHD Grade 2 requiring systemic steroids and not resolving within 7 days. 
8.7 
Enrollment Pausing Criteria 
Enrollment will be paused and investigators and health authorities notified if any of the 
following events occur: 
• Death suspected to be at least possibly related to TAK-007 therapy. 
• Life-threatening (Grade 4) toxicity that is unmanageable and unrelated to chemotherapy or 
underlying disease, and at least possibly related to the investigational therapy (TAK-007 
therapy). 
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• Occurrence of two Grade 4 DLTs in 2 patients at the lower dose level during the Dose 
Escalation phase, that are at least possibly related to the investigational therapy (TAK-007 
and/or lymphodepletion). 
• Oligoclonal or monoclonal CAR-NK cell proliferation beyond 6 months from TAK-007 cell 
product administration. 
• Detectable RCR after TAK-007 administration. 
If a higher than expected incidence of Grade ≥3 neurotoxicity or Grade ≥3 CRS is observed 
(incidence threshold defined as >33% incidence after at least 6 patients have been administered 
TAK-007), then the following events will be considered additional enrollment pausing criteria: 
• Grade ≥3 neurotoxicity event. 
• Grade 4 CRS event. 
• Grade 3 CRS that lasts >72 hours with no improvement to a lower grade. 
The pause in enrollment may also necessitate a pause in dosing or termination of the study, 
depending on the nature and severity of the safety risk. A final decision to resume enrollment 
and/or amend the protocol will be made by the safety management team after a full review of the 
safety data.  
The study may be halted if any regulatory body decides for any reason that patient safety may be 
compromised by continuing the study. The study or specific cohort may also be stopped if the 
sponsor decides to discontinue the development of TAK-007. 
8.8 
Blinding and Unblinding 
This is an open-label study.  
8.9 
Description of TAK-007 
TAK-007 is an unrelated, HLA-agnostic (not selected based on recipient HLA genotype), 
allogeneic donor umbilical CB-derived SFG.iCas9.2A.CAR.CD19-28-3zeta.2A.IL15 transduced 
NK cell product. 
8.10 
Preparation 
TAK-007 should be prepared in accordance with the cell handling manual. 
Management and premedication for cryopreserved product administration is per institutional 
practice, including acetaminophen/paracetamol and an H1 antihistamine. Premedication may be 
based on patient risk of hypersensitivity reactions and IRRs. Steroids should not be used for 
premedication.  
Toxicities potentially associated with the administration of TAK-007 (containing 
dimethylsulfoxide [DMSO]) include changes in heart rate or heart rhythm, chest tightness, 
changes in blood pressure, fever, chills, sweats, nausea/vomiting, diarrhea, abdominal cramping, 
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fluid overload, headache, dyspnea, presence of DMSO taste and odor, hemoglobinuria, allergic 
reaction, and acute renal failure. These toxicities are unlikely. 
If the patient develops a medical condition including, but not limited to, infection, fever, sepsis, 
hypotension, or cardiac arrhythmia during/immediately after lymphodepleting chemotherapy but 
before TAK-007 administration, TAK-007 administration may be delayed for up to 7 days on 
investigator’s decision (Section 8.1). Medical management will be provided per institutional 
guidelines. Decision to administer the drug in this setting will be made in consultation with the 
sponsor’s medical monitor.  
TAK-007 will be shipped to the clinical site in a proper container that can maintain and control 
the cryopreserved condition. 
Parenteral drug products should be inspected visually for particulate matter and discoloration 
before administration whenever solution and container permit. 
The final product will be shipped to the clinical site as 1 dose of cryopreserved cells at 
appropriate concentration for administration without further manipulation. Trained medical staff 
will thaw the product using appropriate equipment and administer the product intravenously to 
the patients.  
Refer to the cell handling manual for details. 
8.11 
Packaging and Labeling 
Product packaging should include the product label, which includes dose information (number of 
CAR+ NK cells), product release information, and any other necessary product information. 
Refer to the cell handling manual for details. 
8.12 
Storage, Handling, and Accountability 
The final product should be stored in a vessel with controlled temperature at or below -140°C 
and stored in the vapor phase of liquid nitrogen or other sponsor-approved equipment. 
Refer to the cell handling manual for details.  
8.13 
Other Protocol-Specified Materials 
8.13.1 
Fludarabine 
The purine antagonist antimetabolite fludarabine phosphate is a synthetic purine nucleoside that 
differs from physiologic nucleosides in that the sugar moiety is arabinose instead of ribose or 
deoxyribose.  
8.13.2 
Cyclophosphamide 
The nitrogen mustard-derivative cyclophosphamide possesses potent immunosuppressive 
activity. Following conversion to active metabolites in the liver, cyclophosphamide functions as 
an alkylating agent.  
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9.0 
STUDY CONDUCT 
This study will be conducted in compliance with the protocol, GCP, applicable regulatory 
requirements, and ICH guidelines. 
9.1 
Study Personnel and Organizations 
The contact information for the project clinician for this study, the central laboratory and any 
additional clinical laboratories, and other vendors such as the interactive response technology 
provider, may be found in the study manual. A full list of investigators is available in the 
sponsor’s investigator database. 
For 24-hour contact information, refer to the study manual or equivalent. 
9.2 
Arrangements for Recruitment of Patients 
Recruitment and enrollment strategies for this study may include recruitment from the 
investigator’s local practice or referrals from other physicians. If advertisements become part of 
the recruitment strategy, they will be reviewed by the institutional review board 
(IRB)/independent ethics committee (IEC).  
9.3 
Treatment Group Assignments 
Patients will be enrolled in dose escalation cohorts followed by expansion cohorts, as outlined 
below: 
Dose Escalation cohorts: Eligible patients will be assigned to receive lymphodepleting 
chemotherapy consisting of IV fludarabine (30 mg/m2 body surface area [BSA] per day) and 
cyclophosphamide (300 mg/m2 BSA per day) on Days -5, -4, and -3 before a single IV 
administration of TAK-007 at a dose of 200 × 106 (±30%) or 800 × 106 (±25%) CD19 CAR+ 
viable NK cells on Day 0. 
Dose Expansion Cohort 1 (LBCL 3L+) and Cohort 2 (iNHL 3L+): Eligible patients will be 
assigned to receive a single IV administration of TAK-007 at a dose of 200 × 106 (30%) or 
800 × 106 (25%) CAR+ viable NK cells on Day 0 of the study. 
9.4 
Study Procedures 
Refer to the SOE (Appendix A Table A 1) for timing of assessments. Additional details are 
provided as necessary in the sections that follow. 
9.4.1 
Screening Phase (Day -33 to Day -6) 
The screening phase begins on the date the patient (or legally acceptable representative) signs the 
IRB/IEC-approved ICF and continues through confirmation of eligibility. The screening visit 
must occur within 28 days before lymphodepleting chemotherapy.  
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Screening tests will include: 
Evaluation of eligibility criteria, disease assessment, and collection of tumor tissue: 
• Patients are required to consent to provide either archived diagnostic formalin-fixed paraffin 
embedded tumor tissue from a sample obtained after the last lymphoma treatment or a 
pretreatment fresh tumor biopsy to perform tumor and microenvironment assessments 
including but not limited to immunohistochemistry; this requirement may be waived at the 
discretion of the sponsor. Central confirmation of diagnosis and CD19 expression is not 
mandatory for enrollment. 
• Routine assessment: height and weight, vital signs, physical examination, medical history 
including concomitant medications, complete blood count (differential), blood chemistries, 
serum immunoglobulins, and coagulation test, serum beta-human chorionic gonadotropin 
(for women). 
• ECOG performance status (Appendix E). 
• Disease assessment per Lugano criteria (Appendix D) including: FDG-PET and/or contrast-
enhanced CT of neck, chest, abdomen, and pelvis (contrast in CT may be replaced by MRI in 
patients with contraindication). 
• Lymph node evaluation (aspiration/biopsy, as clinically indicated): immunohistochemistry, 
flow cytometry, morphology, and molecular studies. 
• Bone marrow (aspiration/biopsy): immunohistochemistry, flow cytometry, morphology, and 
molecular studies. Archived bone marrow biopsy sample (and assessment) within 42 days 
before the start of lymphodepleting chemotherapy is acceptable if no antitumor therapy was 
given after bone marrow evaluation. Bone marrow biopsy assessment will be performed 
locally.  
• Assessment of physiologic reserves including: 12-lead ECG, ECHO or MUGA scan for 
ejection fraction, and pulse oximetry on room air. 
• Infectious disease tests (according to institutional guidelines) to include at a minimum: 
serology tests for CMV, HIV-1, HBV, and HCV. 
Patients should not be enrolled if they are unwilling to participate in the secondary follow-up 
phase (through Month 24) and the LTFU phase (through Year 15) of this study.  
• Each patient will be informed of the purpose and duration of the LTFU phase, including time 
intervals, schedule of visits (or contact), and details as to what those contacts will involve.  
TAK-007 administration should occur within 6 weeks of written informed consent. 
• Informed consent for participation in the screening phase must be obtained before completion 
of any study-specific procedures. Procedures that are part of standard of care are not 
considered study-specific procedures and may be performed before obtaining consent and 
used to confirm eligibility. 
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• After written informed consent has been obtained, patients will be screened to confirm study 
eligibility and participation. Only patients who meet the eligibility criteria listed in 
Section 7.1 and Section 7.2 will proceed to further study procedures.  
Enrollment is defined as the time when a patient meets the eligibility criteria during the 
screening phase and is registered in the study. If at any time the patient fails to meet the 
eligibility criteria during the screening phase, the patient should be designated as a screen failure 
on the patient screening log with the reasons for failing screening. Screen failures will be 
captured and tracked in the interactive response technology and electronic data capture (EDC). 
Procedures and assessments to be conducted during the screening phase are shown in the SOE 
(Appendix A Table A 1). 
Patients who fail to meet the eligibility criteria will be allowed to be rescreened once. Patients 
will undergo the assessment that initially resulted in the patient failing screening including any 
other procedures that fell outside of the designated screening window (eg, laboratory 
assessments). 
9.4.2 
Conditioning Phase (Day -5 to Day -1) 
The conditioning phase is defined as the period from lymphodepleting chemotherapy 
administration to the day before the first TAK-007 administration. Informed consent for study 
participation with study drug administration must be obtained before lymphodepleting 
chemotherapy is initiated. Patients must meet all inclusion and exclusion criteria before the 
treatment with lymphodepleting chemotherapy.  
Delivery date of TAK-007 to the study site will be confirmed by the sponsor before start of 
lymphodepleting chemotherapy. For details, see the cell handling manual. 
Patients with symptomatic SARS-CoV-2 infection must not initiate lymphodepleting 
chemotherapy until recovery from symptomatic infection. 
During the conditioning phase: 
• The outpatient setting is preferred for the application of lymphodepleting chemotherapy.  
• Vital signs are evaluated on Days -5, -4, and -3 during the conditioning phase. 
• Anti-infective prophylaxis is provided per institutional practices. Antiviral (aciclovir for all 
patients, lamivudine for patients with prior history of HBV) and antifungal (fluconazole) 
prophylaxes are recommended given expected duration of immunosuppression after 
administration of lymphodepleting chemotherapy and should be continued for a minimum of 
3 months after TAK-007 administration. Pneumocystis jiroveci pneumonia (cotrimoxazole) 
prophylaxis is recommended for 6 months after TAK-007 administration.  
• Lymphodepleting chemotherapy administration includes: 
– Fludarabine 30 mg/m2 BSA per day will be administered IV on Days -5, -4, and -3. 
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NOTE: Patients with estimated GFR between 30 and 70 mL/min should have a 20% dose 
reduction of each daily dose of fludarabine. The MDRD formula should be used to 
calculate GFR. 
In the event of fludarabine shortage, the actual dose administered may be rounded down, 
as long as the actual dose is within 10% of the calculated dose. Every attempt must be 
made to secure the full dose of fludarabine. 
– Cyclophosphamide 300 mg/m2 BSA per day will be administered IV on Days -5, -4, 
and-3.  
Supportive care before, during, and immediately after administration of lymphodepleting 
chemotherapy is provided per institutional practices. In case of any relevant delay in the 
administration of lymphodepleting chemotherapy, continued treatment administration must be 
discussed with the sponsor’s medical monitor. There has to be at least 2 chemotherapy-free days 
between the last day of lymphodepleting chemotherapy and TAK-007 administration.  
Procedures and assessments to be conducted during the conditioning phase are shown in the SOE 
(Appendix A Table A 1). Patients should not experience significant change in clinical status 
compared with initial eligibility criteria that would, in the opinion of the treating physician, 
increase the risk of AEs associated with experimental cell infusion. 
9.4.3 
Treatment and Follow-up Phases (Day 0 to Month 24)  
The treatment and follow-up phases begin with TAK-007 administration on Day 0 and continue 
up to Month 24. 
• Primary follow-up analysis period: up to 6 months after TAK-007 administration of the last 
patient enrolled in the study.  
• Secondary follow-up analysis period: up to 24 months after TAK-007 administration of the 
last patient enrolled in the study. 
After 24 months, patients will be followed within the LTFU phase for up to 13 additional years, 
for a total duration of up to 15 years following TAK-007 administration. 
Patients must not experience significant deterioration following lymphodepleting chemotherapy 
and before treatment with TAK-007. Refer to Section 8.10 and Section 8.1 for a description of 
TAK-007 preparation and administration procedures. 
Day 0: On Day 0, TAK-007 will be administered IV. Premedication may include acetaminophen 
and an H1-antihistamine according to institutional standards for DMSO-containing cell therapy 
products. Premedication may be based on the patient’s risk of hypersensitivity reactions and 
IRRs. The use of steroids is contraindicated unless required for physiologic replacement. In case 
of unexpected clinical or logistic reasons, for example, patients experiencing toxicities from the 
preceding lymphodepleting chemotherapy or delays in TAK-007 delivery, TAK-007 
administration may be delayed for up to 7 days (Section 8.1). There has to be at least 
2 chemotherapy-free days between the last day of lymphodepleting chemotherapy and the first 
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TAK-007 administration. In case of delayed TAK-007 administration, Day 0 will be defined as 
the day of actual TAK-007 administration.  
The outpatient setting is preferred for the administration of TAK-007.  
Vital signs (temperature, heart rate, blood pressure, and respiratory rate) will be obtained for all 
patients per institutional standard of care for cellular therapy. At a minimum, these 
measurements should be obtained before each TAK-007 administration and until the patient is 
clinically stable, with minimum assessment time points as follows: 
• 15, 30, 45, and 60 minutes (±5 minutes) after start of TAK-007 administration. 
• 1.5, 2, and 3 hours (±10 minutes) after start of TAK-007 administration. 
Day +1 to Month 24: Following TAK-007 administration, all patients will be followed to at least 
Month 24 during the secondary follow-up phase of the study. Posttreatment evaluations will be 
conducted during the treatment and follow-up phases as shown in the SOE (Appendix A  
Table A 1 for the period up to 6 months and Appendix A, Table A 3 for the period after 6 
months, including secondary follow up and LTFU).  
The outpatient setting for assessments in the first week following TAK-007 dose administration 
is recommended. Evaluations may be withheld if the treating physician feels that there is a strong 
contraindication to perform the study assessments (eg, the patient has relapsed and is terminally 
ill). Additional tests and procedures may be performed as clinically indicated. 
A patient may complete study participation at any time (Section 9.6). With completion of study 
participation, the patient will proceed directly to the EOS visit (Appendix A, Table A 1). 
Transfusion Support 
Following initiation of the lymphodepleting chemotherapy, all blood products for transfusion, 
with the exception of TAK-007, must be irradiated to 3000 cGy to inactivate lymphocytes 
capable of initiating transfusion-associated GvHD. Blood products are irradiated per institutional 
guidelines.  
9.4.4 
LTFU Phase (Ongoing – up to Year 15 Following TAK-007 Administration)  
Upon implementation of Protocol Amendment 5, the LTFU phase will begin for all patients who 
have completed the 2-year secondary follow-up and will continue for up to 15 years after 
TAK-007 administration. 
The SOEs for this LTFU phase is provided in Appendix A, Table A 3. 
Collection of LTFU data may commence with a site-based approach if the patient continues 
follow up at the same site where TAK-007 treatment was administered. It is possible that over 
time, there may be a transition to a centralized approach where a research coordinating center 
may serve as a central site and manage subsequent LTFU data collection. 
The purpose of LTFU is to identify and mitigate the long-term risks of TAK-007 treatment and 
to understand the persistence of TAK-007 in patients after treatment. 
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After 2 years on study and up to 15 years after administration of TAK-007, relevant patient 
histories should be collected at least once a year to document the following: 
• Unexpected illnesses and hospitalizations: 
– The focus should be on new incidences of infections (including opportunistic pathogens), 
new hematological disorders, new incidences or exacerbations of prior neurological, 
rheumatological, or autoimmune disorders, and new malignancies. (See Section 10.3 for 
additional details) 
– Appropriate follow-up for the events listed above must be conducted and recorded in 
order to assess whether the event is associated with TAK-007 treatment. 
– Investigators should consider CK DNA and/or RCR testing of clinical samples, if 
appropriate. 
• Subsequent cancer therapies and exposures to mutagenic agents. 
• Results of any ongoing testing per protocol (eg, blood for CK DNA and RCR testing).  
9.4.4.1 
RCR Testing 
If all post-treatment RCR samples are negative for the first year or after 2 negative consecutive 
tests (which ever comes later), collection of samples may be discontinued in that patient. 
However, if a previously RCR-negative patient develops an AE suggestive of retrovirus-
associated disease (ie, new malignancy, new or significant exacerbations of neurological diseases 
or hematological diseases), relevant clinical samples should be collected and tested for RCR. 
If a positive RCR assay result is obtained, the investigator will be informed, and the patient will 
be scheduled for a confirmatory RCR retest. If the retest is positive, the result must be submitted 
as an SAE within the timeline described in Section 10.2 of the protocol. If deemed necessary, a 
more extensive patient monitoring plan will be developed in consultation with health authorities 
such as the US Food and Drug Administration (FDA). 
9.4.4.2 
TAK-007 Persistence  
To detect the presence of a transgene in patients, periodic blood samples are planned for up to 
15 years post-dose (See Appendix A, Table A 3). These samples will be analyzed using a 
validated ddPCR assay with adequate sensitivity. Furthermore, additional confirmatory testing 
may be conducted for samples with detectable transgene prior to confirming those as positive. 
9.4.5 
Informed Consent 
Each patient must provide written informed consent before any study-required procedures are 
conducted, unless those procedures are performed as part of the patient’s standard care. 
9.4.6 
Patient Demographics 
The date of birth, race, ethnicity, and sex of the patient are to be recorded, as local laws permit, 
during the screening phase. 
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9.4.7 
Medical History 
During the screening phase, 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 and the best response achieved by each one. In addition, 
concomitant medications will be recorded as specified in Section 9.4.12.  
9.4.8 
Physical Examination 
A physical examination will be completed per standard of care at the times specified in the SOE 
(Appendix A Table A 1). Any clinically relevant findings will be documented. 
9.4.9 
Height and Weight 
Height will be measured only during the screening phase. Body weight will be measured at the 
times specified in the SOE (Appendix A Table A 1). 
9.4.10 
Vital Signs 
Vital sign measurements, including (after 3 to 5 minutes in the sitting or supine position) 
measurements of diastolic and systolic blood pressure, heart rate, and body temperature will be 
assessed as specified in the SOE. Percutaneous oxygen saturation will also be measured 
according to the SOE (Appendix A Table A 1). 
9.4.11 
Pregnancy Test 
A serum pregnancy test will be performed for all women of childbearing potential at screening. 
Urine pregnancy tests are allowed for the rest of the visits. The results must be available and 
negative before lymphodepleting chemotherapy and treatment with TAK-007. For women of 
childbearing potential, if menstrual period is delayed during the study, absence of pregnancy 
must be confirmed by serum pregnancy test. 
9.4.12 
Concomitant Medications and Procedures 
Medications used by the patient and therapeutic procedures completed by the patient will be 
recorded in the electronic case report form (eCRF) from the time of informed consent through 
the EOS visit. Refer to Section 8.2 and Section 8.3 for a list of medications and therapies that are 
prohibited or allowed during the study. 
9.4.13 
AEs 
Monitoring of AEs, serious and nonserious, will be conducted throughout the study as specified 
in the SOE (Appendix A Table A 1) and in Section 10.3. For patients who receive 
lymphodepleting chemotherapy and do not receive TAK-007, all AEs (regardless of causality) 
will be collected for the first 30 days following lymphodepleting chemotherapy. 
Refer to Section 10.0 for details regarding definitions, documentation, and reporting 
requirements of AEs.  
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9.4.14 
Enrollment 
Enrollment is defined as the time when a patient meets the eligibility criteria and is registered in 
the study.  
9.4.15 
12-Lead ECGs and ECHO/MUGA Scans 
A single 12-lead standard safety ECG will be performed to assess eligibility as specified in the 
SOE (Appendix A Table A 1). ECG assessments are to be performed with the patient supine and 
rested for 3 to 5 minutes. A qualified person will interpret the ECGs locally. Additional ECGs 
may be obtained as clinically indicated at the discretion of the investigator. 
The assessment of LVEF measured by ECHO or MUGA scan will be performed during 
screening as indicated in SOE. 
9.4.16 
Clinical Laboratory Evaluations 
Clinical laboratory evaluations will be performed locally and will be performed as outlined 
below. 
Blood samples for analysis of the clinical chemistry and hematology parameters shown in  
Table 9.a and urine samples for analysis of the parameters will be obtained as specified in the 
SOE (Appendix A Table A 1).  
SARS-CoV-2 testing should be conducted per institutional standards for any suspicion of 
SARS-CoV-2 infection or known exposure. SARS-CoV-2 testing should follow ASTCT 
published guidelines for cellular therapy during the COVID-19 pandemic (Bachanova et al. 
2020).  
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Table 9.a 
Hematology, Clinical Chemistry, and Serum Immunoglobulin Tests 
Hematology 
Serum Chemistry 
Coagulation 
Serum 
Immunoglobulin 
Hematocrit 
Hemoglobin 
Leukocytes with differential 
Absolute lymphocyte count 
Absolute neutrophil count 
Platelet count 
Albumin 
Alkaline phosphatase 
Alanine aminotransferase 
Aspartate aminotransferase 
Bilirubin (total) 
Bilirubin (direct) 
Blood urea nitrogen/urea 
Calcium 
C-reactive protein 
Creatinine  
eGFR (MDRD) 
Ferritin 
Glucose 
Lactate dehydrogenase 
Magnesium 
Phosphate 
Potassium 
Sodium 
Total protein 
Uric acid 
β2 microglobulin 
(only at screening) 
aPTT 
Prothrombin time 
International 
normalized ratio 
IgA 
IgG 
IgM 
aPTT: activated partial thromboplastin time; eGFR: estimated glomerular filtration rate; Ig: immunoglobulin; 
MDRD: Modification of Diet in Renal Disease. 
 
Hematology and serum chemistry samples may be taken within the windows specified for each 
visit according to the SOE (Appendix A, Table A 1), and coagulation testing may be conducted 
24 hours before a visit. All results must be evaluated before dosing. On the day of TAK-007 
administration, an additional hematology sample will be drawn at 1 hour (±15 minutes) after the 
start of TAK-007 administration (Appendix A, Table A 1, footnote h). 
GFR will be estimated using the MDRD equation. As a backup, creatinine clearance can be 
determined based on 12 hours or 24 hours collection of a urine specimen. If creatinine clearance 
is measured for inclusion, it cannot be replaced by the calculated one, if it is more favorable. 
In addition to standard clinical chemistry and hematology, virus tests will be performed locally 
for CMV, HIV, HBV, and HCV according to the SOE (Appendix A, Table A 1). For patients 
with a medical history of HBV/HCV infection, HBV DNA or HCV RNA must be monitored 
after TAK-007 administration as described in the SOE (Appendix A, Table A 1). Patients who 
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are HIV-positive but have a negative viral load at screening must continue to have HIV viral load 
monitored per institutional guidelines for the duration of the study. Handling of clinical 
laboratory samples will be outlined in the laboratory manual. 
9.4.17 
Disease Assessment 
Patients will undergo radiographic evaluation consisting of FDG-PET imaging and/or 
contrast-enhanced CT of neck, chest, abdomen, and pelvis to monitor and assess disease 
response. In case of contraindications against contrast-enhanced CT, MRI can be used instead. 
Bone marrow biopsy to confirm CR in the bone marrow will be performed for iNHL patients at 
the time of radiographic CR and initial bone marrow involvement. Response will be assessed 
locally using the International Working Group (IWG) 2014 Lugano classification and according 
to the IWG 2014 Lugano classification (Cheson et al. 2014) (Appendix D). 
The disease burden is recorded at baseline and at Months 1, 3, and 6 using FDG-PET and/or 
contrast-enhanced CT/MRI. An FDG-PET scan extending from the base of the skull through the 
mid-thighs will be performed at baseline for all patients enrolled to determine FDG avidity. For 
FDG -avid patients, FDG-PET scans should be acquired additionally at 3 subsequent response 
assessments (Months 1, 3, and 6). Additional PET assessments should be conducted on 
FDG-avid patients who did not achieve CR at the abovementioned schedule, and may be used to 
confirm assessment of CR on CT/MRI, to confirm recurrence or progression of disease, or as 
clinically indicated per investigator discretion.  
Disease assessment will be done using contrast-enhanced CT/MRI at other time points. For 
patients who are not FDG-avid, disease assessment should be done with contrast-enhanced 
CT/MRI as per the above imaging schedule. The CT portion of an FDG-PET scan may be used 
as the source of the CT scan, but the CT scan will need to be of diagnostic quality and contain IV 
contrast. If the CT portion of the PET scan is not of diagnostic quality, additional 
contrast-enhanced, diagnostic quality CT/MRI should also be obtained. The same imaging 
modality should be used consistently throughout the study to monitor the disease status. Disease 
assessment will be performed for all patients who received TAK-007.  
Vaccination against the SARS-CoV-2 virus has been shown to cause transient, reactive 
adenopathy in about 10% to 15% of patients. Enlarged axillary, cervical, and supraclavicular 
lymph nodes in the vicinity of drainage areas of sites of vaccine injection have been reported 
(Lehman et al. 2021; Su et al. 2022), with some of the affected lymph nodes appearing to be 
PET-avid. It is possible that this phenomenon can mimic cancer-related adenopathy and may 
have a confounding effect in the interpretation of efficacy among oncology patients undergoing 
serial follow-up on imaging scans. For this reason, it is not recommended to schedule baseline or 
follow-up imaging scans within 2 weeks of SARS-CoV-2 vaccination, where possible. If 
vaccination has already occurred close to the imaging visit, the original disease assessment 
schedule should be followed, and patient treatment should not be delayed. In the event of 
confounding findings on imaging that are assessed as likely due to the effects of vaccination, a 
follow-up scan 8 to 12 weeks after vaccination should be considered. 
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9.4.18 
CK, Immunogenicity, and Biomarker Samples 
9.4.18.1 
Primary Specimen Collection 
Blood samples will be collected via venipuncture or indwelling catheter at the time points 
detailed in the SOE (Appendix A Table A 2 and Table A 3) for CK of TAK-007, serum cytokine 
measurements, and biomarker assessments. On days when lymphodepleting chemotherapy is 
administered, blood samples should be drawn before dosing. The primary specimen collection is 
presented in Table 9.b. 
Table 9.b 
Primary Specimen Collection 
No. 
Specimen Name in 
Schedule of Procedures 
Primary 
Specimen 
Primary 
Specimen 
Derivative 
Description of Intended 
Use 
Endpoint 
1 
Blood sample for CK 
Blood 
DNA 
CK 
Secondary 
2 
Plasma sample for IL-15 
and other cytokines 
Blood 
Plasma 
CK, PD, and biomarker 
measurements 
Secondary 
3 
Blood sample for B cell 
aplasia and T/B/NK cell 
counts 
Blood 
-- 
Biomarker 
measurements 
Secondary 
4 
Serum sample for 
anti-HLA Ab AND 
anti-CAR 
immunogenicity testing 
Blood 
Serum 
Humoral 
immunogenicity 
evaluation 
Secondary 
5 
Blood sample for RCR 
testing 
Blood 
DNA 
RCR testing for safety 
Secondary 
6 
Sample for HLA and 
KIR typing 
Blood 
DNA 
Biomarker measurement 
Exploratory 
7 
Blood sample for flow 
cytometry (CAR+ NK 
enumeration) 
Blood 
-- 
Exploratory assay for 
CK 
Exploratory 
8 
Plasma sample 
for ctDNA 
Blood 
Plasma ctDNA, 
buffy coat 
DNA 
Exploratory ctDNA 
assessment 
Exploratory 
9 
Blood sample for 
immunophenotyping 
Blood 
PBMC 
Biomarker 
measurements 
Exploratory 
10  
Blood sample for cellular 
immunogenicity 
Blood 
PBMC 
Cellular immunogenicity 
evaluation 
Exploratory 
11 
Bone marrow aspirate 
Bone Marrow 
Cells and DNA 
CK and 
immunophenotyping 
Exploratory 
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Table 9.b 
Primary Specimen Collection 
No. 
Specimen Name in 
Schedule of Procedures 
Primary 
Specimen 
Primary 
Specimen 
Derivative 
Description of Intended 
Use 
Endpoint 
12 
Fresh tumor tissue biopsy 
sample 
a) Excisional or core 
needle biopsy 
OR 
b) LN aspirate 
Tumor tissue 
biopsy, LN 
and/or BM as 
clinically 
indicated 
FFPE block 
(preferred) or 
FFPE slides 
(for excisional 
or core needle 
biopsy) 
Cells, DNA (for 
LN aspirate) 
CD19 expression 
evaluation, 
biodistribution, 
biomarker 
measurements, NGS 
Exploratory 
Ab: antibody; BM: bone marrow; CAR: chimeric antigen receptor; CK: cellular kinetics; ctDNA: circulating 
tumor DNA; FFPE: formalin-fixed, paraffin embedded; HLA, human leukocyte antigen; IL-15: interleukin-15; 
KIR: killer immunoglobulin-like receptor; LDC: lymphodepleting chemotherapy; LN: lymph node; NGS: 
next-generation sequencing; NK: natural killer; PBMC: peripheral blood mononuclear cell; PD: 
pharmacodynamics; RCR: replication competent retrovirus. 
 
If required, blood samples collected for secondary endpoints can be used for exploratory 
endpoint analyses only after final CK analysis has been completed. Collection of samples for 
exploratory endpoints are dependent upon local guidelines and regulations (including feasibility 
of sample export), as well as IRB/EC approval and may not be required on discussion with 
medical monitor. If under some circumstances of unmet blood collection, the prioritized 
assessments are listed in Table 9.c. 
Details on sample handling, storage, shipment, and analysis are provided in the laboratory 
manual. 
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Table 9.c 
Prioritized Sequence for Specimen Collection 
Priority 
Primary Specimen 
Specimen Name in Schedule of Events (Assessments) 
1 
Blood 
Blood sample for DNA (CK, RCR) 
2 
Plasma 
Plasma sample for pharmacokinetics (IL-15) 
Plasma sample for cytokines (cytokine panels) 
3 
Blood 
Blood sample for T/B/NK cell counts 
4 
Serum 
Serum sample for anti-HLA Ab testing (humoral immunogenicity) 
Serum sample for anti-CAR Ab testing (humoral immunogenicity) 
5 
Blood 
Blood sample for HLA and KIR typing 
Blood sample for flow cytometry (CAR+ NK enumeration) 
6 
Plasma 
Plasma sample for ctDNA 
7 
Blood 
Blood sample for immunophenotyping 
8 
Blood 
Blood sample for cellular immunogenicity 
Ab: antibody; CAR: chimeric antigen receptor; CK: cellular kinetics; ctDNA: circulating tumor DNA; HLA, 
human leukocyte antigen; IL-15: interleukin-15; KIR: killer immunoglobulin-like receptor; NK: natural killer; 
RCR: replication competent retrovirus. 
 
In addition, patients with CD19 CAR+ allelic frequency >1% of the housekeeping gene control at 
6 months from TAK-007 administration will be asked to return for a confirmatory blood test 
before the next visit within 3 months. If the confirmatory test is positive, then genomic vector 
integration sites will be determined. If integration site analysis reveals monoclonality or 
oligoclonality pattern and/or integration at or near an oncogenic locus, this information will be 
submitted as an information amendment to the IND within 30 days. In addition, a monitoring 
plan (including follow-up molecular analyses) that is specific for the healthcare risks anticipated, 
given the nature of the integration site and vector target cell type, will be developed in 
collaboration among the principal investigator, and according to local regulations. 
If no evidence of oligoclonality or monoclonality is observed, a summary of all analyses for the 
pattern of vector integration sites will be presented in the annual report. 
9.4.18.2 
Tumor and Bone Marrow Biopsies and Aspirates 
Tumor biopsies, according to the treating institution’s guidelines, will be obtained at prespecified 
time points, as outlined in the SOE (Appendix A, Table A 1).  
Screening lymph node and/or bone marrow biopsy (archived): An archived tumor biopsy will 
be tested to assess the expression level of CD19 and other biomarkers in tumor cells. If relevant 
to initial patient disease assessment, the molecular subtype of the disease will be reviewed. 
Exploratory biomarker analyses including but not limited to sequencing and immunochemistry 
will be performed to assess predictive biomarkers, mechanism of action, and mechanism of 
resistance. A fresh biopsy/aspirate will be required in the absence of archived tissue. Excisional 
biopsy is preferred over core needle biopsy or fine needle aspirate, unless clinically 
contraindicated. This requirement may be waived by the study medical monitor. 
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Posttreatment lymph node and/or bone marrow biopsy (fresh): For patients who sign the 
optional portion of the consent form, a fresh tumor biopsy (core needle biopsy preferred over 
fine needle aspirate) and bone marrow aspirate will be collected between Days 7 to 14 to assess 
tissue concentration and mechanism of action of TAK-007, unless the lesion is inaccessible or 
the procedure is clinically contraindicated. In addition, a lymph node biopsy (excisional biopsy 
preferred over core needle biopsy or fine needle aspirate) and bone marrow aspirate are 
recommended with disease relapse or when disease progression is observed with 2 consecutive 
radiologic assessments, unless medically contraindicated. If possible, biopsy should be obtained 
from a nontarget lesion. The posttreatment biopsy and/or aspirate will be used for exploratory 
biomarker analyses including, but not limited to immunohistochemistry, targeted sequencing, 
and gene expressions analyses. 
New Tumor Sample Biopsy for Second Primary Malignancy Assessment 
If second primary malignancy is suspected, a fresh tumor biopsy may be collected for potential 
analysis of CAR transgene and insertional site analysis including CK and Pharmacodynamic 
Measurements 
9.4.18.3 
Blood Sample for DNA and Flow Cytometry (CK) 
TAK-007 CK will be evaluated in blood and bone marrow samples by a validated polymerase 
chain reaction (PCR) method. For all patients treated with TAK-007, the CK profile and 
parameters, including but not limited to Cmax, tmax, tlast, and AUClast, will be reported. In addition, 
the number of TAK-007–expressing cells in the blood may be tracked by flow cytometry as an 
exploratory endpoint. The assessment of TAK-007 CK will be used to examine the 
exposure-response relationship, as well as the possible correlation of persistence and expansion 
of TAK-007 with safety and efficacy endpoints. Peripheral blood for CK will be collected as 
indicated in Appendix A,Table A 2.and Table A 3. In addition, bone marrow samples for 
assessment of CK will be obtained at all time points where bone marrow biopsy/aspirate is 
prescribed in the SOE (Appendix A, Table A 1). Details of the sample collection procedures for 
these assays are provided in the laboratory manual. 
The timing may be adjusted and the total number of samples may be reduced during the study on 
the basis of emerging CK data. Additional confirmatory testing may be performed for patients 
with detectable transgene during long term follow-up. 
9.4.18.4 
Plasma Sample for Pharmacodynamics: Cytokines 
Plasma samples will be collected to monitor the TAK-007–induced changes in cytokines, 
including IL-15. Additional soluble factor analyses may be conducted with emerging data. 
Sample collections for plasma cytokines, and inflammatory and safety biomarkers are mandated 
during the first 28 days following TAK-007 administration. However, the time-course and 
rapidity of CRS development and other toxicities, such as TLS, varies among patients. 
Additional unscheduled samples to better inform these individual differences may also be 
collected as needed, if it is clinically feasible. Any unscheduled inflammatory markers or 
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laboratory results will be recorded. In addition to cytokines defined in the protocol, an 
exploratory analyses of plasma using multiplexed proteomic approaches may be conducted. 
9.4.18.5 
Blood Samples for T/B/NK Absolute Counts and B-cell Aplasia 
Blood samples will be collected for absolute quantification and frequency determination of 
lymphocytes (T cells, B cells, and NK cells) during the primary follow-up phase of the study.  
9.4.19 
Biomarker and Pharmacodynamic Measurements 
In this study, several biomarker measurements will be assessed to test for correlations with safety 
and efficacy. These biomarkers will be used to identify potential pharmacodynamic activity in 
patients who have a greater likelihood of response or adverse reactions. The biomarker and 
pharmacodynamic specimen collection time points are displayed in Appendix A,Table A 2. 
Details regarding the preparation, handling, and shipping of samples are provided in the 
laboratory manual. 
9.4.19.1 
Blood Sample for HLA and KIR Typing 
A blood sample will be collected to extract DNA for sequencing, the analyses will include, but 
may not be limited to, KIR genotyping and HLA typing. 
9.4.19.2 
Blood Samples for RCR 
Blood samples will be collected to examine RCR during the course of the study. RCR testing 
will be done at pretreatment and at 3, 6, and 12 months for the first year after TAK-007 
administration or until 2 consecutive negative results, whichever comes later. If all 
post-treatment assays for an individual patient are negative during the first year, collection of the 
yearly follow-up samples may be discontinued for that individual (Appendix A, Table A 2 and 
Table A 3). 
If a positive RCR assay result is obtained from a blood specimen, the investigator will be 
informed, and the patient will be scheduled for an RCR retest. All positive RCR tests must be 
submitted as an SAE within the timeline described in Section 10.2 of the protocol. If deemed 
necessary, a more extensive patient monitoring plan will be developed in consultation with 
health authorities such as the US Food and Drug Administration (FDA). 
9.4.19.3 
Blood Samples for Immunophenotyping 
Blood samples will be collected for assessment of CAR-NK phenotype and host 
immunophenotypic changes induced by TAK-007. These blood samples will be analyzed for the 
presence and changes in immune cell phenotype and/or function, including but not limited to, by 
flow cytometry and/or RNAseq. 
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9.4.19.4 
Plasma Samples for ctDNA 
Plasma samples from peripheral blood will be collected for assessment of tumor burden and 
genetic profiles using ctDNA over the course of the study. In addition to plasma, buffy coat cells 
will be collected for isolating cellular DNA to filter out germline variants. 
9.4.19.5 
Immunogenicity Sample Collection 
Serum samples for the assessment of humoral immunogenicity and blood samples for the 
assessment of cellular immunogenicity will be collected. Samples must be collected before 
lymphodepleting chemotherapy, and as specified in the SOE (Appendix A, Table A 1 and  
Table A 3) and at unscheduled visits for a patient who experiences an AE considered by the 
investigator to be consistent with hypersensitivity/IRR. Antidrug antibody serum sample will be 
saved for future characterization if applicable. In addition, blood samples will also be collected if 
IRR/hypersensitivity is observed.  
9.4.20 
Sample Retention 
Tumor tissue and bone marrow samples, peripheral blood mononuclear cells (PBMCs), serum 
and plasma samples collected as part of the study will be stored and may be used for research 
purposes up to 15 years after the date of study completion. Samples will be destroyed by a 
third-party vendor per company standard operating procedures. Samples will be stored according 
to the laboratory manual. If a patient withdraws consent, the investigator needs to inform the 
sponsor immediately, the samples will be discarded following the local procedure (ie, where the 
sample resides at the time of withdrawal. The tests performed with these samples are not 
intended to make determinations about a patient’s health or the likelihood that a patient will 
develop any disease, so no test results will be provided to the investigator or put into a patient’s 
medical record, except in the case of positive RCR results for safety reporting purposes. Test 
results should not be discussed with a patient unless required by local law. 
9.4.21 
Sample Use for Research Purposes 
The function of TAK-007 cells is not fully elucidated because CAR+ NK cell therapy is an 
evolving field. Tumor tissue biopsy samples, PBMCs, and serum/plasma samples collected as 
part of the study under sample retention (Section 9.4.20) may be analyzed using new assays or 
platforms to test hypotheses relevant to disease biology, immuno-oncology, and cell therapy 
outside of TAK-007 clinical study. Research analyses may include, but are not limited to, cell 
functional assays, targeted DNA and RNA sequencing, immunohistochemistry, and/or flow 
cytometry. 
9.5 
Completion of Study Treatment (for Individual Patients) 
Patients will be considered to have completed study treatment if they receive one dose of 
TAK-007.  
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9.6 
Completion of Study (for Individual Patients) 
Patients will be considered to have completed the study if they have completed the 15-year 
LTFU phase, or if the patient has been withdrawn from the study (see Section 9.8). 
9.7 
Discontinuation of Treatment With Study Drug and Patient Replacement 
For patients who receive a single dose of TAK-007, discontinuation of treatment is applicable 
only to the conditioning phase of the study and during TAK-007 administration and not after 
TAK-007 was completely administered.  
For patients who passed the screening phase but could not receive lymphodepleting therapy or 
TAK-007 (including incomplete administration), the reasons will be documented on the eCRF. 
Patients who passed the screening phase but could not receive lymphodepleting therapy or 
TAK-007 may be replaced in the study. Additional patients may be enrolled if deemed 
appropriate. 
9.8 
Withdrawal of Patients From Study 
A patient may be withdrawn from the study for any of the following reasons: 
• Death. 
• Lost to follow-up. 
• Study terminated by sponsor. 
• Consent withdrawal. 
• 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. All data that has been collected 
to that point will remain in the database and can be subsequently used for analyses. 
9.9 
Study Compliance 
Study drug will be administered or dispensed only to eligible patients under the supervision of 
the investigator or identified subinvestigator(s). The appropriate study personnel will maintain 
records of lymphodepleting chemotherapy and study cell product receipt and dispensing. 
9.10 
Posttreatment Follow-up Assessments (DOR, PFS, OS, and Safety) 
Patients who complete study treatment will continue to have PFS and OS follow-up visits. The 
primary treatment follow-up visits should be conducted per the SOE listed in Appendix A,  
Table A 1 and Table A 2 for up to 6 months after TAK-007 administration.  
Patients who experience PD or start a new systemic anticancer treatment will return for the 
subsequent visits with a smaller set of assessments. For example, a patient with documented 
disease progression at the Day28/Month 1 visit should still follow the assessments listed for the 
Day 28/Month 1 visit, will not return for the regular Month 2 and Month 4 visits, but will return 
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at Month 3 and Month 6 for assessments. Patients who receive subsequent new systemic 
anticancer therapy without documented disease progression should continue to undergo 
radiologic disease assessments as per Appendix A, Table A 1, until documented disease 
progression. Patients who have not yet experienced disease progression at the time of 
implementation of Protocol Amendment 5 will no longer have to undergo additional radiological 
disease assessments outside of standard of care. 
The OS follow-up should be conducted according to Appendix A, Table A 1 and Table A 3, even 
outside the scheduled follow-up visits in the SOE, and also for patients with PD or who received 
new anticancer treatment. Survival information and death details may be collected by methods 
that include, but are not limited to, telephone, email, mail, review of medical records at the site, 
or retrieval from online or other databases (eg, Social Security indexes). 
The EOS visit is to be completed when the patient discontinues from the follow-up phase. See 
the SOE (Appendix A, Table A 1) for appropriate assessments during follow-up. 
NOTE: Related SAEs must be reported to the Global Pharmacovigilance department or designee. 
This includes deaths that the investigator considers related to study drug that occur during 
posttreatment follow-up. Refer to Section 10.0 for details regarding definitions, documentation, 
and reporting of SAEs.  
10.0 
ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 
Pretreatment Event Definition 
A pretreatment event is any untoward medical occurrence in a patient who has signed informed 
consent to participate in a study but before administration of any study medication; it does not 
necessarily have to have a causal relationship with study participation. 
10.1.2 
AE Definition 
AE means any untoward medical occurrence in a patient or patient 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 therapeutic 
intervention or is considered by the investigator to be a clinically significant change from 
baseline. 
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10.1.3 
SAE Definition 
SAE means any untoward medical occurrence that at any dose: 
• Results in death. 
• Is life-threatening (refers to an AE in which the patient was at risk of death at the time of the 
event. It does not refer to an event which hypothetically might have caused death if it were 
more severe). 
• Requires inpatient hospitalization (after the initial treatment hospitalization period) or 
prolongation of an existing hospitalization (see clarification in the paragraph in 
Section 10.2 on planned hospitalizations). 
• Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions.) 
• Is a congenital anomaly/birth defect. 
• Is a medically important event. This refers to an AE that may not result in death, be 
immediately life-threatening, or require hospitalization, but may be considered serious when, 
on the basis of appropriate medical judgment, it may jeopardize the patient, require medical 
or surgical intervention to prevent one of the outcomes listed above, or involves suspected 
transmission via a medicinal product of an infectious agent. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse; any organism, virus, or infectious particle 
(eg, prion protein transmitting transmissible spongiform encephalopathy), pathogenic or 
nonpathogenic, is considered an infectious agent. 
In this study, intensity for each AE, including any laboratory abnormality, will be determined 
using the NCI CTCAE, version 5.0, effective 27 November 2017 (NCI 2017). In addition, 
grading of CRS and ICANS will follow the ASTCT guidelines (Lee et al. 2019) (Appendix G 
and Appendix H); grading of acute GvHD will follow the recommendations by the Mount Sinai 
Acute GvHD International Consortium (Harris et al. 2016); and grading of chronic GvHD will 
follow the 2014 NIH Consensus (Jagasia et al. 2015) (Appendix I to Appendix M). For each set 
of grading criteria, a later version of the criteria may be applied. 
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/mm3 is considered Grade 3 
(severe) but may not be considered serious. Seriousness (not intensity) serves as a guide for 
defining regulatory reporting obligations. 
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10.2 
Procedures for Recording and Reporting AEs and SAEs 
All AEs spontaneously reported by the patient 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 (refer to Section 10.3 for the period of 
observation). Any clinically relevant deterioration in laboratory assessments or other clinical 
finding is considered an AE. When possible, signs and symptoms indicating a common 
underlying pathology should be noted as a single comprehensive event. 
SAEs must be reported (refer to Section 10.3 for the period of observation) by the investigator to 
the Takeda Global Pharmacovigilance department or designee within 24 hours of becoming 
aware of the event. This will be done by transmitting an EDC SAE report. If transmission of an 
EDC SAE report is not feasible, then a facsimile of the completed Takeda paper-based SAE form 
will be sent. A sample of the paper-based SAE form and processing directions are in the study 
manual. Information in the SAE report or form must be consistent with the data provided on the 
eCRF. 
If information not available at the time of the first report becomes available at a later date, then 
the investigator will transmit a follow-up EDC SAE report (or a paper-based SAE form if an 
EDC SAE report is not feasible) or provide other documentation immediately within 24 hours of 
receipt. Copies of any relevant data from the hospital notes (eg, ECGs, laboratory tests, discharge 
summary, postmortem results) should be sent to the addressee, if requested. 
All SAEs should be followed up until resolution or permanent outcome of the event. The 
timelines and procedure for follow-up reports are the same as those for the initial report. 
Planned hospital admissions or surgical procedures for an illness or disease that existed before 
the patient was enrolled in the study are not to be considered AEs unless the condition 
deteriorated in an unexpected manner during the study (eg, surgery was performed earlier or later 
than planned). 
RCR positivity is considered an SAE for this study and must be reported as such.  
For both serious and nonserious AEs, the investigator must determine both the severity (toxicity 
grade) of the event and the relationship of the event to study drug administration.  
Relationship of the event to study drug administration (ie, the causality assessment) will be 
determined by the investigator responding yes (related) or no (unrelated) to this question: Is there 
a reasonable possibility that the AE is associated with (1) the investigational product (TAK-007) 
or (2) conditioning (lymphodepleting) chemotherapy. The relationship is indicated by a yes or no 
response and entered into the eCRF. 
10.3 
Monitoring of AEs and Period of Observation 
AEs, both nonserious and serious, will be monitored throughout the study as follows: 
• AEs will be reported from the signing of informed consent and recorded in the eCRFs.  
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• SAEs will be reported to the Takeda Global Pharmacovigilance department or designee from 
the signing of informed consent through the EOS visit and recorded in the eCRF.  
From signed informed consent through Month 6: 
• For patients who receive TAK-007, including patients who experience disease progression 
and receive new anticancer systemic therapy, all AEs, both nonserious and serious, 
regardless of causality, will be continuously monitored and recorded.  
• For patients who receive lymphodepleting chemotherapy and do not receive TAK-007, all 
AEs, both nonserious and serious, regardless of causality, will be collected for the first 
30 days following lymphodepleting chemotherapy. 
After Month 6 until EOS (ie, up to 15 years after TAK-007 administration), for all patients who 
receive TAK-007, including patients who experience disease progression and receive new 
anticancer systemic therapy, all AEs that meet the following criteria will be collected. 
• All SAEs that are at least possibly related to TAK-007, lymphodepleting chemotherapy, or 
study procedures; these should be recorded on the appropriate page of the eCRF and reported 
to Takeda as directed in Section 10.2. 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. 
• All events leading to death. 
• All new incidences of Grade ≥3 infections, including opportunistic infections, that are at least 
possibly related to TAK-007 or lymphodepleting chemotherapy. 
• All new incidences of Grade ≥3 hematologic disorders that are at least possibly related to 
TAK-007 or lymphodepleting chemotherapy. 
• All new incidences OR Grade ≥3 exacerbations of prior neurological, rheumatological, or 
autoimmune disorders. 
• Any new malignancy, other than the primary malignancy. 
• Positive RCR results (always report as serious).  
10.4 
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events 
Patients and their partners must agree not to become pregnant, breastfeed a baby, or donate an 
egg or eggs (ova) during the study and until at least 12 months following TAK-007 
administration. If a patient or partner of a patient becomes pregnant or suspects that they are 
pregnant while participating in this study, they must inform the investigator immediately. The 
sponsor must also be contacted immediately by sending a completed pregnancy form to the 
Takeda Global Pharmacovigilance department or designee. The pregnancy must be followed for 
the final pregnancy outcome. 
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10.5 
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose) 
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, function or stability of a drug product. 
An investigator who is made aware of or identifies a potential product complaint should 
immediately report the event to Takeda in accordance with the contact list provided to the site 
and recorded in the eCRF. Whenever possible, the associated product should be maintained in 
accordance with the instructions pending further guidance from a Takeda representative. Refer to 
the appropriate study manual provided separately for additional information (depending on local 
regulations). 
A medication error is a preventable event that involves an identifiable patient and that leads to 
inappropriate medication use, which may result in patient harm, whereas overdoses and 
underdoses constitute medication errors, doses missed inadvertently by a patient do not. 
An overdose is defined as a known deliberate or accidental administration of investigational drug 
or the lymphodepleting chemotherapy, to or by a study patient, at a dose above that which is 
assigned to that individual patient according to the study protocol. All cases of overdose (with or 
without associated AEs) will be documented on an Overdose page of the eCRF, to capture this 
important safety information consistently in the database. In the event of drug overdose, the 
patient should be treated symptomatically. 
Product complaints and medication errors in and of themselves are not AEs. If a product 
complaint or a medication error results in an SAE, the SAE should be reported per Section 10.2. 
The sponsor will also evaluate whether there is a risk that would lead to deaths or SAEs due to 
the complaint. As a result of the evaluation, the sponsor may ask the investigator(s) for 
additional investigation. The investigators will need to submit requested follow-up information 
to the sponsor.  
10.6 
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities 
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, including the EMA, 
investigators, and IRBs and IECs, as applicable, in accordance with national regulations in the 
countries where the study is conducted. Relative to the first awareness of the event by/or further 
provision to the sponsor or sponsor’s designee, SUSARs will be submitted to the regulatory 
authorities as expedited reports within 7 days for fatal and life-threatening events and within 
15 days for other serious events, unless otherwise required by national regulations. The sponsor 
will also prepare an expedited report for other safety issues where these might materially alter 
the current benefit-risk assessment of an investigational medicinal product or that would be 
sufficient to consider changes in the investigational medicinal product’s administration or in the 
overall conduct of the study. The investigational site also will forward a copy of all expedited 
reports to his or her IRB or IEC in accordance with national regulations.  
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11.0 
STUDY-SPECIFIC COMMITTEES 
11.1 
Steering Committee 
The steering committee will comprise medical experts involved in the study and the sponsor. The 
steering committee will oversee the conduct and reporting of the study, ensuring expert clinical 
guidance and a high standard of scientific quality, and making any necessary modifications 
deemed necessary to the protocol. The steering committee will oversee publications emanating 
from study results. The steering committee charter will define the responsibilities of the 
committee. 
12.0 
DATA HANDLING AND RECORDKEEPING  
The full details of procedures for data handling will be documented in the data management plan. 
If selected for coding, AEs, medical history, and concurrent conditions will be coded using the 
Medical Dictionary for Regulatory Activities. Drugs will be coded using the WHO Drug 
Dictionary. 
12.1 
eCRFs  
Completed eCRFs are required for each patient who signs an ICF. 
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, contract 
research organization 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 designee) 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 the 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 designee) will be permitted to review the patient’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. 
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12.2 
Record Retention 
The investigator and the head of the institution agree to keep the records stipulated in 
Section 12.1 and those documents that include (but are not limited to) the study-specific 
documents and records such as cell manipulation and storage, the identification log of all 
participating patients, medical records, temporary media such as thermal-sensitive paper, source 
worksheets, all original signed and dated ICFs, patient authorization forms regarding the use of 
personal health information (if separate from the ICFs), electronic copies of eCRFs, including 
the audit trails, and detailed records of drug disposition to enable evaluations or audits from 
regulatory authorities and the sponsor (or designees). Any source documentation printed on 
degradable thermal-sensitive paper should be photocopied by the site and filed with the original 
in the patient’s chart to ensure long-term legibility.  
Furthermore, ICH E6 Section 4.9.5 requires the investigator and the head of the institution to 
retain essential documents specified in ICH E6 (Section 8) until at least 2 years after the last 
approval of a marketing application for a specified drug indication being investigated or, if an 
application is not approved, until at least 2 years after the investigation is discontinued and 
regulatory authorities are notified. In addition, ICH E6 Section 4.9.5 states that the study records 
should be retained until an amount of time specified by applicable regulatory requirements or for 
a time specified in the clinical study site agreement between the investigator and/or the head of 
the institution and sponsor. 
The sponsor will establish and maintain a system ensuring that the individual product can be 
traced through the sourcing, manufacture, packaging, storage, transport, and delivery to the 
hospital, institution, or private practice where the product is used. The sponsor will keep these 
data for a minimum of 30 years after the expiry date of the product. 
Refer to the clinical study site agreement for the sponsor’s requirements for record retention. The 
investigator and the head of the institution should contact and receive written approval from the 
sponsor before disposing of any such documents. 
13.0 
STATISTICAL METHODS 
13.1 
General Considerations 
A statistical analysis plan (SAP) will be prepared and finalized before database lock. This 
document will provide further details regarding the definition of analysis variables and analysis 
methodology to address study objectives. 
The primary analysis will be conducted and documented in a CSR after all dosed patients in the 
study have had the opportunity to be assessed for response and safety for at least 6 months after 
TAK-007 administration. Additional analyses may occur after the primary analyses have been 
completed. These additional analyses will be descriptive. The data cutoff for final analysis for 
the CSR addendum will be conducted after all dosed patients have had the opportunity to 
complete LTFU or if the study has been terminated by the sponsor. 
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All the endpoints (by dose levels in dose escalation, and by disease cohorts and dose regimens in 
expansion cohorts) will be summarized separately, unless specified otherwise. 
13.2 
Determination of Sample Size 
Approximately 42 patients at dose levels of either 200 × 106 (30%) or 800 × 106 (25%) CD19 
CAR+ viable NK cells per patient will be enrolled.  
13.3 
Analysis Sets 
The analysis sets will include the following: 
• ITT set: All enrolled patients in the TAK-007 study. This set will primarily be used for 
disposition of patients.  
• Safety analysis and modified intent-to-treat (mITT) sets: Patients who have received 
TAK-007 administration. This set will be used for safety analyses (safety set), and efficacy 
analysis to inform RP2D.  
• Response-evaluable analysis set: Patients who have received TAK-007 administration, have 
had measurable disease at baseline, and at least 1 posttreatment radiologic assessment of 
disease response. This set will primarily be used for sensitivity analyses of efficacy 
endpoints, ORR and CR.  
• CK analysis set: Patients receiving treatment with TAK-007 administration and sufficient 
data to estimate 1 or more CK parameters will be used for CK analyses. 
• Pharmacodynamic analysis set: The pharmacodynamic analysis set will include those 
patients from the safety analysis set who have baseline and at least 1 postbaseline sample 
assessment. 
• Per-protocol (PP) set: The PP set will include all enrolled patients who do not have a major 
protocol violation. All decisions to exclude patients from the PP set will be made before the 
database lock.  
13.4 
Analysis of Demographics and Other Baseline Characteristics 
Patient disposition, demographic, and baseline characteristics will be summarized descriptively 
based on the ITT set and the mITT set. Variables to be analyzed include sex, age, race and other 
parameters, as appropriate. For continuous variables, descriptive statistics (number, mean, 
standard deviation, median, minimum, and maximum) will be provided. For categorical 
variables, patient counts, and percentages will be provided. Categories for missing data will be 
presented as needed. 
13.5 
Efficacy Analyses 
The mITT set will be used to inform the RP2D decision. The analyses of primary and secondary 
endpoints will be summarized by dose levels in dose escalation cohorts, and by disease cohorts 
and dose regimens in expansion cohorts.  
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In the event a patient undergoes an SCT or any other systemic anticancer therapy while on study, 
the patient’s best response will be derived only based on evaluation before SCT or initiation of a 
new therapy, whichever occurs earlier. All patients who do not meet the criteria for an objective 
response by the analysis cutoff date will be considered nonresponders within the response-related 
analyses. 
13.5.1 
Efficacy Analysis of the Primary Endpoint 
No longer applicable to the study as of Protocol Amendment 5. 
13.5.2 
Efficacy Analyses of the Secondary Endpoints 
The analysis of the secondary efficacy endpoints includes ORR by investigator, CR by 
investigator, DOR by investigator, PFS by investigator, and OS.  
ORR and CR and the corresponding exact 2-sided 95% CIs will be provided.  
The time-to-event endpoints will include the following:  
• DOR is defined only for patients who experience an objective response and is the time from 
the date of first documented objective response to the date of first documented disease 
progression per Lugano classification (Appendix D) or death, whichever comes first. Patients 
not meeting the criteria for progression or death will be censored at the last disease 
assessment. 
• PFS in the ITT set is defined as the time from enrollment date to the date of disease 
progression per Lugano classification (Appendix D) or death from any cause, whichever 
comes first. PFS in the mITT set is defined as the time from TAK-007 administration to the 
date of disease progression or death from any cause, whichever comes first. Patients who do 
not have disease progression or die will be censored at the last disease assessment. 
• OS in the ITT set is defined as the time from enrollment to the date of death from any cause. 
OS in the mITT set is defined as the time from TAK-007 administration to the date of death. 
Patients who do not die will be censored at the last contact date. 
For time-to-event endpoints, including DOR, PFS, and OS, Kaplan-Meier plots, estimates and 
median values (if estimable) along with their 2-sided 95% CIs, will be computed. Estimates of 
the proportion of patients event-free at 3-month intervals will be provided. The censoring rules 
will be detailed in the SAP.  
For the primary and secondary efficacy endpoints, subgroup analyses will be performed by 
disease subtypes, prespecified baseline, or other potential prognostic factors, which will be 
detailed in the SAP. 
Further details of the analyses of the primary and secondary efficacy endpoints, including 
sensitivity analyses, will be prespecified in the SAP. 
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13.6 
Safety Analysis 
The safety set will be used for all safety analyses. TEAEs are defined as any AE that begins on 
or after the start date of lymphodepleting chemotherapy. 
AEs will be tabulated for the following observation periods: 
• Pretreatment: the period from signed informed consent to the day before lymphodepleting 
chemotherapy. 
• Treatment: the period from administration of lymphodepleting chemotherapy to EOS. 
The incidence and percentages of TEAEs will be summarized by System Organ Class and 
Preferred Term of the ICH Medical Dictionary for Regulatory Activities and by grade according 
to the NCI CTCAE version 5.0. In addition, grading of CRS and ICANS will follow the ASTCT 
guidelines (Lee et al. 2019) (Appendix G and Appendix H), grading of acute GvHD will follow 
the recommendations by the Mount Sinai Acute GvHD International Consortium (Harris et al. 
2016) and grading of chronic GvHD will follow the 2014 NIH Consensus (Jagasia et al. 2015) 
(Appendix I to Appendix M). For each set of grading criteria, a later version of the criteria may 
be applied. 
Tabulated AEs will include the following categories:  
• TEAEs.  
• Drug-related TEAEs.  
• Grade ≥3 TEAEs.  
• Grade ≥3 drug related TEAEs.  
• The most commonly reported TEAEs (ie, those events reported by ≥10% of patients). 
• SAEs.  
• Drug-related SAEs. 
• Deaths. 
• Drug-related deaths. 
• AEs of clinical interest as defined in the SAP. 
The incidence of DLTs will be tabulated by dose levels using the safety set.  
Descriptive statistics for the actual values of clinical laboratory parameters will be presented for 
all scheduled measurements over time. Mean laboratory values over time will be plotted for key 
laboratory parameters. Shift tables for laboratory parameters will be generated for changes in 
NCI CTCAE grade from baseline to worst postbaseline value.  
Descriptive statistics for the actual values (and/or the changes from baseline) of vital signs and 
ECGs will be tabulated by scheduled time point. ECOG performance scores will also be 
summarized using shift tables.  
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All concomitant medications will be collected and classified to preferred terms according to the 
WHO Drug Dictionary.  
13.7 
CK Analysis 
CK-related parameters will be estimated using noncompartmental methods. As permitted by 
data, CK parameters (eg, Cmax, tmax, tlast, AUClast) will be estimated from the TAK-007 
concentration time profiles using the CK analysis set. CK parameters will be summarized using 
descriptive statistics, as permitted by data by dose level and indication.  
Individual TAK-007 concentration-time data and individual CK parameters may be presented in 
listings and also tabulated using summary statistics by dose cohort and indication. Individual and 
mean concentration-time profiles will be plotted by dose cohort. 
13.8 
Pharmacodynamic Analysis 
Frequency and percentage of patients with B-cell aplasia will be summarized before and after 
TAK-007 administration by scheduled time point using the pharmacodynamic analysis set.  
Concentration of soluble immune factors in circulation (eg, IL-15, IFN-γ, IL-1β, IL-2, IL-4, IL-6, 
IL-8, IL-10, IL-12p70, IL-13, tumor necrosis factor alpha, granulocyte macrophage colony-
stimulating factor) in plasma will be tabulated using summary statistics over scheduled time 
point. Individual and mean concentration-time profiles may also be plotted. 
13.9 
Immunogenicity Analyses 
Frequency and percentage of patients with detectable anti-HLA and anti-CAR antibodies will be 
summarized by scheduled time point using the safety analysis set. Impact of anti-HLA and 
anti-CAR immunogenicity on CK parameters, safety and efficacy may be assessed, as 
appropriate based on the available data. 
13.10 
RCR Analyses 
Frequency and percentage of patients with positive RCR test results will be summarized by 
scheduled time point before and after TAK-007 administration using safety analysis set. 
13.11 
Exploratory Analyses 
13.11.1 
Population CK-Pharmacodynamic Analysis 
The relationship between TAK-007 systemic exposure and safety, efficacy, and 
pharmacodynamic response (eg, B cell aplasia, time to B cell recovery, changes in 
cytokines/chemokines) will be evaluated to understand the CK-pharmacodynamic relationship of 
TAK-007. The results from this PK/PD analysis will be presented in a separate report. 
13.11.2 
Biomarker Analyses 
Exploratory biomarker analyses will be separately defined in biomarker analysis plan and the 
results of these analyses may be reported separately from the CSR. 
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14.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
Study-Site Monitoring Visits 
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. If monitors are not allowed to visit sites for data verification due to a 
pandemic (eg, coronavirus disease 2019 [COVID-19]), remote electronic medical records access 
visits may be made (where allowed by sites). 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 contract research organization and by the IRB or IEC. 
All aspects of the study and its documentation will be subject to review by the sponsor or 
designee including, but not limited to, the investigator’s binder, study medication, patient 
medical records, informed consent documentation, documentation of patient authorization to use 
personal health information (if separate from the ICFs), and review of eCRFs and associated 
source documents. It is important that the investigator and other study personnel are available 
during the monitoring visits and that sufficient time is devoted to the process. 
14.2 
Protocol Deviations 
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study patients. 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 patient’s source documents. In the event 
of a significant deviation, the site should notify the sponsor or its designee (and IRB or IEC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the patient, or confound interpretation of the primary 
study assessment. 
The sponsor will assess any protocol deviation; if it is likely to affect to a significant degree the 
safety and rights of a patient or the reliability and robustness of the data generated, it may be 
reported to regulatory authorities as a serious breach of GCP and the protocol. 
The investigator should document all protocol deviations. 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections 
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
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addition, there is the possibility that this study may be inspected by regulatory agencies, 
including those of foreign governments (eg, the US FDA, the EMA, and the Pharmaceuticals and 
Medical Devices Agency of Japan). If the study site is contacted for an inspection by a 
regulatory body, the sponsor should be notified immediately. The investigator and institution 
guarantee access for quality assurance auditors to all study documents as described in 
Section 14.1. 
15.0 
ETHICAL ASPECTS OF THE STUDY 
This study will be conducted with the highest respect for the individual participants (ie, patients) 
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. 
15.1 
IRB and/or IEC Approval 
IRBs and IECs must be constituted according to the applicable state and federal/local 
requirements of each participating region. The sponsor or designee will require documentation 
noting all names and titles of members who make up the respective IRB or IEC. If any member 
of the IRB or IEC has direct participation in this study, written notification regarding his or her 
abstinence from voting must also be obtained. Those American sites unwilling to provide names 
and titles of all members because of privacy and conflict of interest concerns should instead 
provide a Federal-wide Assurance number or comparable number assigned by the US 
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 ICF, and, if applicable, patient recruitment materials and 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 patient 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 its exact protocol title, number, and version date; 
identify versions of other documents (eg, ICF) reviewed; and state the approval date. If required 
by country or regional regulations or procedures, approval from the competent regulatory 
authority will be obtained before commencement of the study or implementation of a substantial 
amendment. 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 
the competent authority to begin the study. 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 ICF, recruitment 
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materials intended for viewing by patients, 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 
designee). 
Patient incentives should not exert undue influence for participation. Payments to patients must 
be approved by the IRB or IEC and sponsor. 
15.2 
Patient Information, Informed Consent, and Patient Authorization 
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The ICF, patient authorization form (if applicable), and patient 
information sheet (if applicable) describe the planned and permitted uses, transfers, and 
disclosures of the patient’s personal and personal health information for purposes of conducting 
the study. The ICF and the patient information sheet (if applicable) further explain the nature of 
the study, its objectives, and potential risks and benefits, and the date informed consent is given. 
The ICF will detail the requirements of the participant and the fact that he or she is free to 
withdraw at any time without giving a reason and without prejudice to his or her further medical 
care. 
The investigator is responsible for the preparation, content, and IRB or IEC approval of the ICF 
and, if applicable, the patient authorization form. The ICF, patient authorization form (if 
applicable), and patient information sheet (if applicable) must be approved by both the IRB or 
IEC and the sponsor before use. 
The ICF, patient authorization form (if applicable), and patient information sheet (if applicable) 
must be written in a language fully comprehensible to the prospective patient. It is the 
responsibility of the investigator to explain the detailed elements of the ICF, patient authorization 
form (if applicable), and patient information sheet (if applicable) to the patient. Information 
should be given in both oral and written form whenever possible and in the manner deemed 
appropriate by the IRB or IEC. If the patient is not capable of rendering adequate written 
informed consent, then the patient’s legally acceptable representative may provide such consent 
for the patient in accordance with applicable laws and regulations. 
The patient, or the patient’s legally acceptable representative, must be given ample opportunity 
to (1) inquire about details of the study and (2) decide whether to participate in the study. If the 
patient, or the patient’s legally acceptable representative, determines that he or she will 
participate in the study, then the ICF and patient authorization form (if applicable) must be 
signed and dated by the patient, or the patient’s legally acceptable representative, at the time of 
consent and before the patient enters into the study. The patient or the patient’s legally 
acceptable representative should be instructed to sign using their legal names, not nicknames, 
using a ballpoint pen with either blue or black ink. The investigator must also sign and date the 
ICF and patient authorization (if applicable) at the time of consent and before the patient enters 
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into the study; however, the sponsor may allow a designee of the investigator to sign to the 
extent permitted by applicable law. 
Once signed, the original ICF, patient authorization form (if applicable), and patient information 
sheet (if applicable) will be stored in the investigator’s site file. The investigator must document 
the date the patient signs the informed consent in the patient’s medical record. Copies of the 
signed ICF, the signed patient authorization form (if applicable), and patient information sheet (if 
applicable) shall be given to the patient. 
All revised ICFs must be reviewed and signed by relevant patients or the relevant patient’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 patient’s medical record, and the 
patient should receive a copy of the revised ICF. 
15.3 
Patient Confidentiality 
The sponsor and designees affirm and uphold the principle of the patient’s right to protection 
against invasion of privacy. Throughout this study, a patient’s source data will be linked to the 
sponsor’s clinical study database or documentation only via a unique identification number. As 
permitted by all applicable laws and regulations, limited patient attributes, such as sex, age, or 
date of birth, and patient initials may be used to verify the patient and accuracy of the patient’s 
unique identification number. 
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
sponsor requires the investigator to permit its monitor or designee’s monitor, representatives 
from any regulatory authority (eg, US FDA, United Kingdom Medicines and Healthcare 
products Regulatory Agency, Japan Pharmaceuticals and Medical Devices Agency of Japan), the 
sponsor’s designated auditors, and the appropriate IRBs and IECs to review the patient’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 patient’s study participation, and autopsy reports. Access to a patient’s original medical 
records requires the specific authorization of the patient as part of the informed consent process 
(Section 15.2). 
Copies of any patient source documents that are provided to the sponsor must have certain 
identifying personal information removed, eg, patient name, address, and other identifier fields 
not collected on the patient’s eCRF. 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy 
15.4.1 
Publication  
The investigator is obliged to provide the sponsor with complete test results and all data derived 
by the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
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disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and advertisements, is the sole responsibility of the sponsor. 
The sponsor may publish any data and information from the study (including data and 
information general packaging 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. 
15.4.2 
Clinical Trial Registration 
To ensure that information on clinical trials reaches the public in a timely manner and to comply 
with applicable laws, regulations, and guidance, Takeda will, at a minimum, register 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other 
publicly accessible websites on or before start of study, as defined by Takeda policy/standards. 
Takeda contact information, along with investigator’s city, state (for Americas investigators), 
country, and recruiting status will be registered and available for public viewing.  
As needed, Takeda and investigator/site contact information may be made public to support 
participant access to trials via registries. In certain situations/registries, Takeda may assist 
participants or potential participants in finding a clinical trial by helping them locate trial sites 
closest to their homes by providing the investigator name, address, and phone number via 
email/phone or other methods preferred by callers requesting trial information. Once patients 
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 patient screening process. If the caller asks additional questions beyond the topic of 
trial enrollment, they should be referred to the sponsor.  
Any investigator who objects to Takeda providing this information to callers must provide 
Takeda with a written notice requesting that their information not be listed on the registry site. 
15.4.3 
Clinical Trial Results Disclosure 
Takeda will post the results of clinical trials on ClinicalTrials.gov and clinicaltrialsregister.eu, 
and other publicly accessible websites (including the Takeda corporate site) and registries, as 
required by Takeda policy/standards, applicable laws, and/or regulations.  
The sponsor is committed to responsible sharing of clinical data with the goal of advancing 
medical science and improving patient care. Qualified independent researchers will be permitted 
to use data collected from patients during the study to conduct additional scientific research, 
which may be unrelated to the study drug or the patient’s disease. The data provided to external 
researchers will not include information that identifies patients personally. 
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15.5 
Insurance and Compensation for Injury 
Each patient in the study must be insured in accordance with the regulations applicable to the site 
where the patient 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 patients. 
Refer to the clinical study site agreement regarding the sponsor’s policy on patient compensation 
and treatment for injury. If the investigator has questions regarding this policy, he or she should 
contact the sponsor or sponsor’s designee. 
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16.0 
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Appendix A Schedule of Events 
Table A 1 
Schedule of Events for All Patients up to Month 6 ...............................................97 
Table A 2 
Schedule of Events for All Patients up to Month 6 (Treatment and Primary 
Follow-up Phase) – Biomarker Sampling ............................................................101 
Table A 3 
Schedule of Events for All Patients from Month 6 onwards ...............................103 
 
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Table A 1 
Schedule of Events for All Patients up to Month 6  
Phase 
Screening  
Phase a 
Conditioning 
Phase 
LDC 
Treatment and Primary Follow-up Phase 
Days 
≤28 days 
Before 
LDC 
D -5, -4, -3 
D0 b 
D1 
D3 
D7 
D10 
D14 
D21 
D28/ 
M1 
M2 
M3 
M4 
M6 
Visit window 
 
 
 
±1 d 
±1 d 
±1 d 
±1 d 
±2 d 
±2 d 
±4 d 
±4 d 
±14 d 
±14 d ±14 d 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history and patient 
demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECHO or MUGA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG performance status 
X 
Day -5 
(before LDC) 
 
 
 
 
 
 
 
X 
Xc 
Xc 
Xc 
Xc 
12-lead ECG 
X 
Day -5 
(before LDC) 
 
 
 
 
 
 
 
 
 
 
 
Xc 
Pregnancy tests d 
X 
Day -5 
(before LDC) 
As clinically indicated 
Height and weight e 
X 
Day -5 
(before LDC) 
 
 
 
 
 
 
 
X 
Xc 
X 
 
X 
Safety assessments 
Physical examination 
X 
Day -5 
(before LDC) 
X 
X 
X 
X 
X 
X 
X 
X 
Xc 
X 
Xc 
X 
Vital signs and SpO2 
X 
D -5 to D -3 
X f 
X 
X 
X 
X 
X 
X 
X 
Xc 
X 
Xc 
X 
Hematology, serum 
chemistry, coagulation, 
serum immunoglobulins g 
X 
Day -5 
(before LDC) 
X h 
X 
X 
X 
X 
X 
X 
X 
Xc 
Xc 
Xc 
Xc 
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Table A 1 
Schedule of Events for All Patients up to Month 6  
Phase 
Screening  
Phase a 
Conditioning 
Phase 
LDC 
Treatment and Primary Follow-up Phase 
Days 
≤28 days 
Before 
LDC 
D -5, -4, -3 
D0 b 
D1 
D3 
D7 
D10 
D14 
D21 
D28/ 
M1 
M2 
M3 
M4 
M6 
Visit window 
 
 
 
±1 d 
±1 d 
±1 d 
±1 d 
±2 d 
±2 d 
±4 d 
±4 d 
±14 d 
±14 d ±14 d 
Safety assessments (continued) 
Virus tests (CMV, HBV, 
HCV, HIV) 
X 
For patients with evidence of prior exposure to HBV or HCV: HBV DNA or HCV RNA at D28/M1, M2, M3, M4, and M6. 
For all other cases: Test as clinically indicated OR if ALT > 3 × ULN. 
Patients who are HIV-positive but have a negative viral load at screening must continue to have HIV viral load monitored per 
institutional guidelines for the duration of the study. Not required for a patients with documented disease progression and/or 
begins a new systemic anticancer treatment at the prior visit. 
Concomitant medications 
and procedures 
<------------------------------------------------------------------  X  -----------------------------------------------------------------------> 
AE i 
<-------------------------------------------------------------------  X  -----------------------------------------------------------------------> 
Survival follow-up j 
 
X 
 
X 
Study Intervention 
LDC 
 
D -5, -4, -3 
 
 
 
 
 
 
 
 
 
 
 
 
TAK-007 Administration 
 
 
X b 
 
 
 
 
 
 
 
 
 
 
 
Disease assessments 
Lymphoma tissue collection 
X 
 
 
 
 
(Range of D7-D14) 
 
 
 
 
 
 
Disease assessment per 
Lugano classification l 
X 
 
 
 
 
 
 
 
 
X 
 
Xc 
 
Xc 
BM biopsy m 
X 
 
 
 
 
 
 
 
 
Mandatory for iNHL at the time of CR in imaging 
(for patients with previous BM involvement) 
BM aspirate n 
X 
 
 
 
 
(Range of D7-D14) 
 
Recommended for iNHL at the time of CR in 
imaging (for patients with previous 
BM involvement) and recommended at relapse 
(for all patients) 
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Table A 1 
Schedule of Events for All Patients up to Month 6  
Phase 
Screening  
Phase a 
Conditioning 
Phase 
LDC 
Treatment and Primary Follow-up Phase 
Days 
≤28 days 
Before 
LDC 
D -5, -4, -3 
D0 b 
D1 
D3 
D7 
D10 
D14 
D21 
D28/ 
M1 
M2 
M3 
M4 
M6 
Visit window 
 
 
 
±1 d 
±1 d 
±1 d 
±1 d 
±2 d 
±2 d 
±4 d 
±4 d 
±14 d 
±14 d ±14 d 
AE: adverse event; ALT: alanine aminotransferase; BM: bone marrow; CMV: cytomegalovirus; CR: complete response; CT: computed tomography; D: day; 
ECG: electrocardiogram; ECHO: echocardiogram; ECOG: Eastern Cooperative Oncology Group; EOS: end of study; FFPE: formalin-fixed paraffin embedded; HBV: 
hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; iNHL: indolent non-Hodgkin lymphoma; IWG: International Working Group; LBCL: 
large B-cell lymphoma; LDC: lymphodepleting chemotherapy; M: month; MUGA: multigated acquisition scan; PD: progressive disease; PET: positron emission 
tomography; RNA: ribonucleic acid; SpO2: oxygen saturation; ULN: upper limit of normal. 
Tests and procedures should be performed on schedule for all visits. Evaluations and procedures identified in the schedule of events may be performed at unscheduled 
visits, as clinically indicated, at the investigator’s discretion in consultation with the sponsor. If a patient is not able to visit the study site, then a telehealth visit should be 
considered to ensure appropriate oversight and safety monitoring. In addition to this, if the patient is able to visit a local doctor and/or laboratory, then appropriate 
assessments may be performed at a local laboratory or doctor’s office, per investigator discretion. 
Day 0 will be defined as the actual day of first TAK-007 administration, hence the reference of all subsequent dates. 
After the Day 28 visit, each month will count as 30 days. 
a The screening visit must occur within 28 days before the day of LDC. Signed informed consent must be obtained before performing any protocol-specific procedure. 
b All assessments must be completed and evaluated before dosing.  
c Not required for a patient with documented disease progression and/or begins a new systemic, anticancer therapy at the prior visit. 
d For women of childbearing potential, a serum pregnancy test will be performed at screening. A urine pregnancy test will be allowed for all other visits. A negative 
pregnancy test result on Day -5 is necessary before initiation of LDC. If menstrual period is delayed during the study, absence of pregnancy must be confirmed by serum 
pregnancy test. 
e Height to be measured at screening only.  
f Vital signs and SpO2: Before TAK-007 administration and until the patient is clinically stable, at a minimum, 15, 30, 45, 60 minutes (±5 minutes) and 1.5, 2, and 3 
hours (±10 minutes) after start of TAK-007 administration.  
g Coagulation will only be assessed at screening and as clinically indicated. Immunoglobulins will not be assessed between Day 0 and Day 21.  
h Hematology samples will be collected before TAK-007 administration and 1 hour (±15 minutes) after start of TAK-007 administration. 
i Details on monitoring of AEs and period of observation during the primary follow-up phase are summarized in Section 10.3. 
j Survival will be followed up for patients who receive TAK-007 administration. Survival will be followed-up every 3 months. If a patient misses a scheduled visit, or if 
the time-point does not align with a scheduled visit, survival status may be collected by methods that include, but are not limited to, telephone, email, mail, or retrieval 
from online or other databases (eg, Social Security indexes). 
k A lymphoma biopsy at screening is mandatory unless archived tumor lymphoma tissue (at least 10 unstained FFPE slides) collected after the last therapy is available. 
Sponsor waiver may be given on a case by case basis. For all patients, Days 7 to 14 biopsies will be optional. Biopsies at relapse are recommended. There should be no 
clinical contraindication and lymphoma should be easily accessible. 
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Table A 1 
Schedule of Events for All Patients up to Month 6  
Phase 
Screening  
Phase a 
Conditioning 
Phase 
LDC 
Treatment and Primary Follow-up Phase 
Days 
≤28 days 
Before 
LDC 
D -5, -4, -3 
D0 b 
D1 
D3 
D7 
D10 
D14 
D21 
D28/ 
M1 
M2 
M3 
M4 
M6 
Visit window 
 
 
 
±1 d 
±1 d 
±1 d 
±1 d 
±2 d 
±2 d 
±4 d 
±4 d 
±14 d 
±14 d ±14 d 
l Disease assessment per IWG 2014 guidelines will be performed until PD by imaging, or additional lymphoma therapy except consolidating autologous or allogeneic 
stem cell transplantation. Assessments will be performed per local guidance.  
m Baseline BM evaluation is required for all patients at screening except for patients with LBCL with confirmed BM involvement in PET-CT. Archived BM biopsy 
sample (and assessment) within 42 days before start of lymphodepleting chemotherapy is acceptable if no antitumor therapy was given after BM evaluation. After 
baseline evaluation, BM will be evaluated in patients with iNHL who had initial BM involvement and in whom, treatment achieved CR in imaging. There should be no 
clinical contraindication for BM evaluation. 
n Optional BM aspiration for pharmacokinetics will be performed between Days 7 and 14. Based on the emerging data, collection from additional patients may be 
waived or made optional. BM aspirate is also recommended at relapse. There should be no clinical contraindication for BM evaluation. 
 
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Table A 2 
Schedule of Events for All Patients up to Month 6 (Treatment and Primary Follow-up Phase) – 
Biomarker Sampling 
Procedure 
Conditioning 
Phase 
Treatment and Primary Follow-up Phase 
LDC 
TAK-007 
Administration 
Post-treatment Follow-up 
D -5  
(before LDC 
Administration) 
D0 
D1 
D3 
D7 
D10 
D14 
D21 
D28/ 
M1 
M2, M3, M4  
and M6 a 
Visit window 
-4d 
  
±1 d 
±1 d 
±1 d 
±1 d 
±2 d 
±2 d 
±4 d 
±4 d (M2 only)/ 
±14 d 
Blood for DNA (CK) 
  
Xb 
X 
X 
X 
X 
X 
X 
X 
X 
Blood for flow cytometry (CK) 
X 
Xb 
  
X 
X 
X 
X 
X 
X 
M2 and M6c 
Blood (HLA and KIR typing) 
X 
  
  
  
  
  
  
  
  
  
Blood for DNA (RCR) 
X 
  
  
  
  
  
  
  
  
M3 and M6 
Blood for T/B/NK cells absolute 
counts 
X 
X 
(before TAK-007 
administration 
  
  
X 
  
  
  
X 
M2, M3 and M6c 
Blood for immunophenotyping 
X 
  
  
  
X 
  
X 
  
X 
M3 and M6c 
Plasma for IL-15 and cytokine panel d 
X 
X 
(before TAK-007 
administration) 
X 
  
X 
  
X 
X 
X 
M2 and M6c 
Serum for humoral immunogenicity 
(anti-HLA and anti-CAR antibody)  
X 
  
  
  
  
  
  
  
X 
Xc 
Plasma for ctDNA 
X 
X 
(before TAK-007 
administration) 
  
  
  
  
X 
  
X 
M3 and M6c 
Blood for cellular immunogenicity  
X 
  
  
  
  
  
  
  
X 
Xc 
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Table A 2 
Schedule of Events for All Patients up to Month 6 (Treatment and Primary Follow-up Phase) – 
Biomarker Sampling 
Procedure 
Conditioning 
Phase 
Treatment and Primary Follow-up Phase 
LDC 
TAK-007 
Administration 
Post-treatment Follow-up 
D -5  
(before LDC 
Administration) 
D0 
D1 
D3 
D7 
D10 
D14 
D21 
D28/ 
M1 
M2, M3, M4  
and M6 a 
Visit window 
-4d 
  
±1 d 
±1 d 
±1 d 
±1 d 
±2 d 
±2 d 
±4 d 
±4 d (M2 only)/ 
±14 d 
 
CAR: chimeric antigen receptor; CK: cellular kinetics; ctDNA: circulating tumor DNA; D: day; HLA: human leukocyte antigens; IL 15 interleukin-15; KIR: killer 
immunoglobulin-like receptor; LDC: lymphodepleting chemotherapy; M: month; NK: natural killer; RCR: replication competent retrovirus. 
Unless otherwise noted, evaluations during the conditioning and treatment phases must occur before LDC administration or TAK-007 administration. Tests and 
procedures should be performed on schedule for all visits. If extenuating circumstances prevent a patient from completing a scheduled procedure or assessment within 
this time, the patient may continue the study only with the written permission of the medical monitor. 
After the Day 28 visit, each month will count as 30 days. 
a For patients who have documented progression at a prior visit and/or begin a new systemic anticancer treatment at a prior visit, only M3 and M6 samples are required 
where indicated. 
b Samples will be collected before and after (1 hour ±15 minutes) TAK-007 administration. 
c Sample is not required if patient has documented progression and/or begin a new systemic anticancer treatment at a prior visit. 
d Additional samples may be collected during safety assessment if patient develops Grade 3 toxicity. 
 
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Table A 3 
Schedule of Events for All Patients from Month 6 onwards 
Procedure 
Secondary Follow-up 
Long Term Follow-up 
M12, M18, and M24 
Annually after M24 until 15 years 
±2 months 
±3 months 
Adverse events a,b 
<----------------------------------- X -----------------------------------> 
Second primary malignancy evaluation 
X 
X 
Survival follow-up c 
X 
X 
New anticancer therapy 
X 
Xd 
Blood for DNA (CK) e 
X 
X 
Blood for DNA (RCR) 
M12 and M24f 
Xf 
Serum for humoral immunogenicity  
(anti HLA and anti-CAR antibody)  
M12 
 
Pregnancy test 
As clinically indicated until M12 
 
 
AE: adverse event; CAR: chimeric antigen receptor; CK: cellular kinetic(s); D: Day; M: Month; PD: progressive disease; RCR: replication competent retrovirus; SAE: 
serious adverse event; SCT: stem cell transplantation. 
Tests and procedures should be performed within the specified windows for all visits. If extenuating circumstances prevent a patient from completing a scheduled 
procedure or assessment within this time, the patient may continue the study only with the written permission of the medical monitor. If a patient is not able to visit the 
study site, then a telehealth visit should be considered to ensure appropriate oversight and safety monitoring. In addition to this, if the patient is able to visit a local 
doctor and/or laboratory, then appropriate assessments may be performed at a local laboratory or doctor’s office, per investigator discretion. 
Each month will count as 30 days. 
a During secondary follow-up, all AEs with onset date more than 6 months until 24 months after TAK-007 administration should be reported according to criteria listed 
in Section 10.3. 
b During LTFU, all related SAEs, all deaths, and new incidences of Grade ≥3 AEs that are at least possibly related to TAK-007 and/or lymphodepletion and relevant to 
the potential risks of TAK-007 will be collected (see Section 10.3). 
c Survival follow-up should be conducted every 6 months in secondary and at least annually during the long-term follow-up phases. If a patient misses a scheduled visit, 
or if the time-point does not align with a scheduled visit, survival status may be collected by methods that include, but are not limited to, medical records review, 
telephone, email, mail, or retrieval from online or other databases (eg, Social Security indexes). 
d New anticancer therapy need not be collected if samples for CK (DNA) are no longer being taken after Month 24. 
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Table A 3 
Schedule of Events for All Patients from Month 6 onwards 
Procedure 
Secondary Follow-up 
Long Term Follow-up 
M12, M18, and M24 
Annually after M24 until 15 years 
±2 months 
±3 months 
e If CAR transgene is detectable at Months 24, 36, or 48, additional samples will be collected within the next 6 months ie, at Months 30, 42, and 54, respectively, for 
further clonality assessment. 
f If all post-treatment assays for an individual patient are negative during the first year, collection of the yearly follow-up samples may be discontinued for that 
individual. 
 
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Appendix B Responsibilities of the Investigator 
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the Statement of Investigator (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this study. 
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572: 
1. Conduct the study in accordance with the protocol. 
2. Personally conduct or supervise the staff who will assist in the protocol. 
3. If the investigator/institution retains the services of any individual or party to perform 
trial-related duties and functions, the investigator/institution should ensure that this 
individual or party is qualified to perform those trial-related duties and functions and should 
implement procedures to ensure the integrity of the trial-related duties and functions 
performed and any data generated. 
4. Ensure that study-related procedures, including study-specific (nonroutine/nonstandard 
panel) screening assessments, are NOT performed on potential patients before the receipt of 
written approval from relevant governing bodies/authorities. 
5. Ensure that all colleagues and employees assisting in the conduct of the study are informed 
of these obligations. 
6. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform 
to 21 Code of Federal Regulations (CFR) Part 56, ICH and local regulatory requirements. 
7. 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 patients. 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. 
8. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met. 
9. Obtain valid informed consent from each patient who participates in the study and document 
the date of consent in the patient’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each ICF should contain a patient authorization section 
that describes the uses and disclosures of a patient’s personal information (including personal 
health information) that will take place in connection with the study. If an ICF does not 
include such a patient authorization, then the investigator must obtain a separate patient 
authorization form from each patient or the patient’s legally acceptable representative. 
10. 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 
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contact and receive written approval from the sponsor before disposing of any such 
documents. 
11. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents. 
12. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor.  
13. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours. 
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Appendix C Investigator Consent to Use of Personal Information 
Takeda will collect and retain personal information of the investigator, including his or her name, 
address, and other identifying personal information. In addition, the investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, US, 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. 
The 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 the 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. 
The 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 the 
investigator’s own country. 
The investigator acknowledges and consents to the use of his or her personal information by 
Takeda and other parties for the purposes described above. 
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Appendix D IWG 2014 (Lugano) Response Criteria for Lymphoma 
Response and Site 
PET-CT–Based Response 
CT-Based Response 
Complete 
Complete metabolic response 
Complete radiologic response (all the 
following) 
Lymph nodes and 
extralymphatic sites 
Score 1, 2, or 3, with or without a residual 
mass on the 5-point scale a 
Target nodes/nodal masses must regress to 
≤1.5 cm in the longest transverse diameter 
of all lesions 
 
No extralymphatic sites of disease 
 
It is recognized that in Waldeyer’s ring or 
extranodal sites with high physiologic uptake 
or with activation within spleen or marrow 
(eg, with chemotherapy or myeloid colony-
stimulating factors), uptake may be greater 
than normal mediastinum and/or liver. In this 
circumstance, complete metabolic response 
may be inferred if uptake at sites of initial 
involvement is no greater than surrounding 
normal tissue even if the tissue has high 
physiologic uptake. 
 
Nonmeasured lesion Not applicable 
Absent 
Organ enlargement 
Not applicable 
Regress to normal 
New lesions 
None 
None 
Bone marrow 
No evidence of FDG-avid disease in marrow Normal by morphology; if indeterminate, 
immunohistochemistry negative 
Partial 
Partial metabolic response 
Partial remission (all the following) 
Lymph nodes and 
extralymphatic sites 
Score of 4 or 5 a with reduced uptake 
compared with baseline and residual mass(es) 
of any size 
≥50% decrease in sum of the product of the 
perpendicular diameters of up to 6 target 
measurable nodes and extranodal sites 
 
At interim, these findings suggest responding 
disease 
When a lesion is too small to measure on 
CT, assign 5 mm × 5 mm as the default 
value 
 
At end of treatment, these findings indicate 
residual disease 
When no longer visible, 0 × 0 mm 
 
 
For a node >5 mm × 5 mm, but smaller 
than normal, use actual measurement for 
calculation 
Nonmeasured lesion Not applicable 
Absent/normal, regressed, but no increase 
Organ enlargement 
Not applicable 
Spleen must have regressed by >50% in 
length beyond normal 
New lesions 
None 
None 
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Response and Site 
PET-CT–Based Response 
CT-Based Response 
Bone marrow 
Residual uptake higher than uptake in normal 
marrow but reduced compared with baseline 
(diffuse uptake compatible with reactive 
changes from chemotherapy allowed). If 
there are persistent focal changes in the 
marrow in the context of a nodal response, 
consideration should be given to further 
evaluation with MRI or biopsy or an interval 
scan 
Not applicable 
No response or stable 
disease 
No metabolic response 
Stable disease 
Target nodes/nodal 
masses, extranodal 
lesions 
Score 3, 4 or 5 with no significant change in 
FDG uptake from baseline at interim or end 
of treatment 
<50% decrease from baseline in sum of the 
product of the perpendicular diameters of 
up to 6 dominant, measurable nodes and 
extranodal sites; no criteria for progressive 
disease are met 
Nonmeasured 
lesions 
Not applicable 
No increase consistent with progression 
Organ enlargement 
Not applicable 
No increase consistent with progression 
New lesions 
None 
None 
Bone marrow 
No change from baseline 
Not applicable 
Progressive disease 
Progressive metabolic disease 
Progressive disease requires at least 1 of 
the following 
Individual target 
nodes/nodal masses 
Score 3, 4 or 5 with an increase in intensity 
of uptake from baseline and/or 
PPD progression: 
Extranodal lesions 
New FDG-avid foci consistent with 
lymphoma at interim or end-of-treatment 
assessment 
An individual node/lesion must be 
abnormal with: 
Longest transverse diameter of a lesion 
>1.5 cm and 
Increase by ≥50% from nadir cross product 
of the longest transverse diameter and 
perpendicular diameter and 
An increase in longest transverse diameter 
of a lesion or SDi from nadir 
0.5 cm for lesions ≤2 cm 
1.0 cm for lesions >2 cm 
In the setting of splenomegaly, the splenic 
length must increase by >50% of the extent 
of its prior increase beyond nadir (eg, a 
15-cm spleen must increase to >16 cm). If 
no prior splenomegaly, must increase by at 
least 2 cm from nadir. 
New or recurrent splenomegaly 
Nonmeasured 
lesions 
None 
New or clear progression of preexisting 
nonmeasured lesions 
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Response and Site 
PET-CT–Based Response 
CT-Based Response 
New lesions 
New FDG-avid foci consistent with 
lymphoma rather than another etiology 
(eg, infection, inflammation). If uncertain 
regarding etiology of new lesions, biopsy or 
interval scan may be considered 
Regrowth of previously resolved lesions 
A new node >1.5 cm in any axis 
A new extranodal site >1.0 cm in any axis; 
if <1.0 cm in any axis, its presence must be 
unequivocal and must be attributable to 
lymphoma 
Assessable disease of any size 
unequivocally attributable to lymphoma 
Bone marrow 
New or recurrent FDG-avid foci 
New or recurrent involvement 
Source: Adapted from (Cheson et al. 2014). 
a PET 5-point scale: 1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake > mediastinum but ≤ liver; 
4, uptake moderately > liver; 5, uptake markedly higher than liver and/or new lesions; X, new areas of uptake 
unlikely to be related to lymphoma. 
CT: computed tomography; FDG: fluorodeoxyglucose; IHC: immunohistochemistry; LDi: longest transverse 
diameter of a lesion; IWG: International Working Group; MRI: magnetic resonance imaging; PET: positron 
emission tomography; PPD: cross product of the LDi and perpendicular diameter; SDi: shortest axis perpendicular 
to the LDi; SPD: sum of the products of the perpendicular diameters for multiple lesions. 
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Appendix E 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 et al. 1982). 
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Appendix F Methods of Contraception Considered to Be Effective 
Acceptable Methods Considered Highly Effective 
Birth control methods that can achieve a failure rate of less than 1% per year when used consistently and correctly 
are considered as highly effective. Such methods include: 
• 
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of 
ovulation (1): 
– Oral. 
– Intravaginal. 
– Transdermal. 
• 
Progestogen-only hormonal contraception associated with inhibition of ovulation (1): 
– Oral. 
– Injectable. 
– Implantable (2) 
• Intrauterine device (2). 
• Intrauterine hormone-releasing system (2). 
• Bilateral tubal occlusion (2). 
• Vasectomized partner (2, 3). 
• Sexual abstinence (4). 
Methods That are Considered Less Highly Effective 
Acceptable birth control methods that result in a failure rate of more than 1% per year include: 
• Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary mode of 
action. 
• Male or female condom with or without spermicide (5). 
• Cap, diaphragm or sponge with spermicide (5). 
__________________________________________________ 
Source: European Heads of Medicines Agencies (HMA) Clinical Trial Facilitation Group (CTFG); see 
hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/CTFG/2014_09_HMA_ 
CTFG_Contraception.pdf 
(1) Hormonal contraception may be susceptible to interaction with the investigational medicinal product, which 
may reduce the efficacy of the contraception method. 
(2) Contraception methods that in the context of this guidance are considered to have low user dependency. 
(3) Vasectomized partner is a highly effective birth control method provided that partner is the sole sexual partner 
of the woman of childbearing potential participant of the study and that the vasectomized partner has received 
medical assessment of the surgical success. 
(4) In the context of this guidance sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the 
preferred and usual lifestyle of the patient. 
(5) A combination of male condom with cap, diaphragm, or sponge with spermicide (double-barrier methods) are 
also considered acceptable, but not highly effective, birth control methods. 
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Appendix G ASTCT CRS Consensus Grading 
CRS 
Parameter 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Fever a 
Temperature 
≥38°C 
Temperature 
≥38°C 
Temperature ≥38°C 
Temperature ≥38°C 
 
With 
Hypotension None 
Not requiring 
vasopressors 
Requiring a vasopressor 
with or without vasopressin 
Requiring multiple 
vasopressors (excluding 
vasopressin) 
And/or b 
Hypoxia 
None 
Requiring low-
flow nasal 
cannula c or blow-
by 
Requiring high-flow nasal 
cannula d, facemask, 
nonrebreather mask, or 
Venturi mask 
Requiring positive pressure 
(eg, CPAP, BiPAP, intubation 
and mechanical ventilation) 
Source: (Lee et al. 2019). 
BiPAP: bilevel positive airway pressure; CPAP: continuous positive airway pressure; CRS: cytokine release 
syndrome; CTCAE: Common Terminology Criteria for Adverse Events. 
Organ toxicities associated with CRS may be graded according to CTCAE v5.0 but they do not influence CRS 
grading. 
a Fever is defined as temperature ≥38°C not attributable to any other cause. In patients who have CRS then receive 
antipyretic or anticytokine therapy, such as tocilizumab or steroids, fever is no longer required to grade subsequent 
CRS severity. In this case, CRS grading is driven by hypotension and/or hypoxia. 
b CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. For 
example, a patient with temperature of 39.5°C, hypotension requiring 1 vasopressor, and hypoxia requiring low-flow 
nasal cannula is classified as Grade 3 CRS. 
c Low-flow nasal cannula is defined as oxygen delivered at ≤6 L/minute. Low flow also includes blow-by oxygen 
delivery.  
d High-flow nasal cannula is defined as oxygen delivered at >6 L/minute. 
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Appendix H ASTCT ICANS Consensus Grading for Adults 
Neurotoxicity Domain 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
ICE score a 
7-9 
3-6 
0-2 
0 (patient is unarousable and 
unable to perform ICE) 
Depressed level of 
consciousness b 
Awakens 
spontaneously 
Awakens 
to voice 
Awakens only to tactile 
stimulus 
Patient is unarousable or requires 
vigorous or repetitive tactile 
stimuli to arouse; stupor or coma 
Seizure 
N/A 
N/A 
Any clinical seizure 
focal or generalized that 
resolves rapidly or 
nonconvulsive seizures 
on EEG that resolve 
with intervention 
Life-threatening prolonged 
seizure (>5 min) or repetitive 
clinical or electrical seizures 
without return to baseline in 
between 
Motor findings c 
N/A 
N/A 
N/A 
Deep focal motor weakness such 
as hemiparesis or paraparesis 
Elevated ICP/cerebral 
edema 
N/A 
N/A 
Focal/local edema on 
neuroimaging d 
Diffuse cerebral edema on 
neuroimaging; decerebrate or 
decorticate posturing; or cranial 
nerve VI palsy; or papilledema; 
or Cushing’s triad 
Source: (Lee et al. 2019). 
CTCAE: Common Terminology Criteria for Adverse Events; ICANS: immune effector cell-associated neurotoxicity 
syndrome; ICE: immune effector cell-associated encephalopathy; ICP: intracranial pressure; NA: not applicable.  
a patient with an ICE score of 0 may be classified as Grade 3 ICANS if awake with global aphasia, but a patient with 
an ICE score of 0 may be classified as Grade 4 ICANS if unarousable. 
ICE Categories:  
• 
Orientation: orientation to year, month, city, hospital: 4 points. 
• 
Naming: ability to name 3 objects (eg, point to clock, pen, button): 3 points. 
• 
Following commands: ability to follow simple commands (eg, “Show me 2 fingers” or  “Close your eyes 
and stick out your tongue”): 1 point. 
• 
Writing: ability to write a standard sentence (eg, “Our national bird is the bald eagle”): 1 point. 
• 
Attention: ability to count backwards from 100 by 10: 1 point. 
b Depressed level of consciousness should be attributable to no other cause (eg, no sedating medication).  
c Tremors and myoclonus associated with immune cell therapies may be graded according to CTCAE v5.0, but they 
do not influence ICANS grading. 
d Intracranial hemorrhage with or without associated edema is not considered a neurotoxicity feature and is excluded 
from ICANS grading. It may be graded according to CTCAE v5.0. 
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Appendix I 
Definition of Acute and Chronic GvHD 
Category 
Time of GvHD 
Manifestation 
Acute GvHD 
Features a 
Chronic GvHD 
Features a 
Acute GvHD 
Classic acute GvHD  
<100 d 
Yes 
No 
Persistent, recurrent, or late-onset acute GvHD 
>100 d 
Yes 
No 
Chronic GvHD 
Classic chronic GvHD  
No time limit 
No 
Yes 
Overlap syndrome  
No time limit 
Yes 
Yes 
Source:  Adapted from (Filipovich et al. 2005). 
GvHD: graft-versus-host disease. 
a See Appendix J and Appendix K for acute and chronic GvHD features. 
 
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Appendix J 
Target Organ Staging of Acute GvHD in Adults 
Stage 
Skin (Active Erythema Only) a 
Liver (Bilirubin) b 
Gut (Stool Output/Day) c 
0 
No active (erythematous) 
GvHD rash 
<2 mg/dL 
<500 mL/day or <3 episodes/day 
1 
Maculopapular rash 
<25% BSA 
2-3 mg/dL 
500-999 mL/day or 3-4 episodes/day or 
prolonged nausea d 
2 
Maculopapular rash 
25-50% BSA 
3.1-6 mg/dL 
1000-1500 mL/day or 5-7 episodes/day 
3 
Maculopapular rash 
>50% BSA 
6.1-15 mg/dL 
>1500 mL/day or >7 episodes/day 
4 
Generalized erythroderma (>50% 
BSA) plus bullous formation and 
desquamation >5% BSA 
>15 mg/dL 
Severe abdominal pain with or without ileus or 
grossly bloody stool (regardless of stool 
volume) 
Source: Adapted from (Harris et al. 2016). 
BSA: body surface area; GvHD: graft-versus-host disease. 
a Use “rule of nines” to determine BSA (head 9%, each arm 9%, front and back torso 18% each, each leg 18%). 
b Range given as total bilirubin. Downgrade by 1 stage if an additional cause of elevated bilirubin has been 
c Downgrade by 1 stage if an additional cause of diarrhea has been documented. 
d With histological signs of GvHD in stomach or duodenum biopsy.  
 
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Appendix K Overall Clinical Grading of Acute GvHD 
Grade 
Skin 
Liver 
Gut 
0 
None 
None 
None 
1 
Stage 1-2 
None 
None 
2 
Stage 3 and/or 
Stage 1 and/or 
Stage 1 
3 
Stage 0-3 and 
Stage 2-3 and/or 
Stage 2-3 
4 
Stage 4 and/or 
Stage 4 and/or 
Stage 4 
Source: Adapted from (Harris et al. 2016). 
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Appendix L Organ Scoring of Chronic GvHD 
Scoring of organ involvement by chronic GvHD will be performed according to the revised NIH 
criteria of 2014 (Jagasia et al. 2015). Evaluation using a systematic form is recommended: 
 
Source: (Jagasia et al. 2015). 
 
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Source: (Jagasia et al. 2015). 
 
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Source: (Jagasia et al. 2015). 
 
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Appendix M Global Severity of Chronic GvHD 
Overall 
Mild 
Moderate 
Severe 
Number of involved organs 
1-2 
≥3 
≥3 
Severity of organ manifestation 
No more than score 1 and 
lung score 0 
Score 2 or  
lung score 1 
Score 3 or  
lung score 2-3 
Source: Adapted from (Jagasia et al. 2015). 
Key points: 
• 
In skin: higher of the 2 scores to be used for calculating global severity.  
• 
In lung: FEV1 (forced expiratory volume in 1 second) is used instead of clinical score for calculating global 
severity. 
• 
If the entire abnormality in an organ is noted to be unequivocally explained by a non–graft-versus-host disease 
(GvHD) documented cause, that organ is not included for calculation of the global severity. 
• 
If the abnormality in an organ is attributed to multifactorial causes (GvHD plus other causes), the scored organ 
will be used for calculation of the global severity regardless of the contributing causes (no downgrading of 
organ severity score). 
 
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Appendix N BOIN Design 
The Bayesian optimal interval (BOIN) design (Liu and Yuan 2015), (Yuan et al. 2016), (Zhou et 
al. 2018) will be used to guide the dose escalation and the MTD estimation. This study was 
designed and will be conducted using the software BOIN that is available at trialdesign.org 
(trialdesign.org, Integrated Platform for Designing Clinical Trials, Accessed 21 June 2021). 
The target toxicity rate for the MTD is 𝜙= 0.25 and the maximum sample size is 12. Each time 
we will enroll and treat patients in a cohort size of approximately 3. The BOIN design uses the 
following rule, optimized to minimize the probability of incorrect dose assignment, to guide dose 
escalation/de-escalation: 
• If the observed DLT rate at the current dose is ≤ 0.197, escalate the dose to the next higher 
dose level; if the current dose is the highest dose, treat the new patients at the highest dose. 
• If the observed DLT rate at the current dose is > 0.298, de-escalate the dose to the next lower 
dose level; if the current dose is the lowest dose and the rule indicates dose de-escalation, 
treat the new patients at the lowest dose unless the number of DLTs reaches the elimination 
boundary (as shown in Table 6.a), at which point the dose escalation will be terminated for 
safety. 
• Otherwise, stay at the current dose. 
• Repeat above until the maximum sample size of 12 is reached, or until the number of 
evaluable patients treated at the current dose reaches 6 and the decision according to above is 
to stay at the current dose. 
For the purpose of overdose control, doses 𝑗 and higher levels will be eliminated from further 
examination if Pr(𝑝𝑗> 0.25 | data) > 0.95 and at least 3 evaluable patients have been treated at 
dose level 𝑗, where 𝑝𝑗 is the true DLT rate of dose level 𝑗, 𝑗= 1,⋯, 2. This posterior probability 
is evaluated based on the beta-binomial model 𝑦𝑗∣𝑝𝑗∼binomial(𝑝𝑗) with 𝑝𝑗∼uniform(0,1), 
where 𝑦𝑗 is the number of patients experienced DLT at dose level 𝑗. When the lowest dose is 
eliminated, stop the dose escalation for safety. The above dose escalation/de-escalation and 
elimination rule can be equivalently presented in Table 6.a (Section 6.1), which will be used to 
conduct the study. 
After the dose escalation is complete, the MTD is selected based on isotonic regression as 
specified in Liu and Yuan (Liu and Yuan 2015). Specifically, the dose is selected as the MTD for 
which the isotonic estimate of the toxicity rate is closest to the target toxicity rate. If there are 
ties, the higher dose level is selected when the isotonic estimate is lower than the target toxicity 
rate; the lower dose level is selected when the isotonic estimate is greater than or equal to the 
target toxicity rate. 
The operating characteristics of the BOIN design are evaluated with simulations assuming 
various distributions of toxicity across dose levels shown in Table T 1 below. 
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Table T 1: 
Simulation Scenarios 
 
True DLT Rate 
TAK-007 Dose Level 
Scenario 1 
Scenario 2 
Scenario 3 
200M 
0.05 
0.25 
0.08 
800M 
0.15 
0.43 
0.25 
 
The operating characteristics calculated from the simulations are shown in Table T 2 below. 
Table T 2: 
Operating Characteristics 
TAK-007  
Dose Level 
Scenario 1 
Scenario 2 
Scenario 3 
Selection 
% 
% Patients 
Treated 
Selection 
% 
% Patients 
Treated 
Selection 
% 
% Patients 
Treated 
200M 
9.6 
44.6 
76.97 
67.8 
29.27 
50.7 
800M 
90.4 
55.4 
18.03 
32.2 
70.70 
49.3 
% Early Stopping 
0 
5 
0.03 
Expected # of Patients 
10.4 
9.2 
10.7 
Note: Out of 3,000 simulations, “% early stopping”" refers to the percentage of early stopping due to excessive 
DLT; “Selection %” refers to the percentage of selecting this dose as the MTD. 
 
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Appendix O CARTOX Guidelines for the Management of CRS and ICANS 
Management of CRS 
CRS Grade 
CRS 
Parameter 
Management 
Diagnostic Work-Up 
Supportive Care 
Anti-IEC Therapies 
Grade 1 
Fever 
• Assess for infection with 
blood and urine cultures, 
and chest radiography 
• Cardiac telemetry and 
pulse oximetry 
• Acetaminophen and hypothermia 
blanket as needed for the 
treatment of fever 
• Ibuprofen if fever is not controlled 
with above; use with caution or 
avoid with thrombocytopenia or 
renal dysfunction 
• Empiric broad-spectrum 
antibiotics and consider filgrastim 
products if neutropenic 
• Maintenance IV fluids for 
hydration 
• Symptomatic management of 
constitutional symptoms and 
organ toxicities as per standard 
guidelines 
• If not on seizure prophylaxis, 
initiate levetiracetam 500 mg PO 
twice daily 
• Consider tocilizumab1 for 
1 dose for persistent fever 
lasting greater than 3 days 
Grade 2 
Hypotension 
• Cardiac telemetry  
• Fever work-up if not 
previously performed 
o Assess for infection 
with blood and urine 
cultures, and chest 
radiography 
• IV fluid bolus of 500 – 1,000 mL 
normal saline; repeat once as 
needed to maintain normal BP 
• If hypotension persists after IV 
fluids, tocilizumab, and 
dexamethasone, start 
vasopressors, transfer patient to 
IC, obtain ECHO, and refer to 
further management as in Grade 3 
or 4 CRS 
• Symptomatic management of 
fever as in Grade 1 CRS 
• Symptomatic management of 
constitutional symptoms and 
organ toxicities as per standard 
guidelines 
• Administer tocilizumab1 for 
1 dose and consider 
dexamethasone 4 – 10 mg IV 
for 1 dose (or 
methylprednisolone 
equivalent) and reassess in 
6 hours or earlier if clinically 
indicated 
o Tocilizumab may be 
repeated every 8 hours for 
up to 3 doses in a 24-hour 
period 
Hypoxia 
• Pulse oximetry  
• Fever work-up if not 
previously performed 
o Assess for infection 
with blood and urine 
cultures, and chest 
radiography 
• Use supplemental oxygen as 
needed 
• If hypoxia persists after above 
interventions, but oxygen 
requirement is stable with low-
flow nasal cannula, continue close 
monitoring. If oxygen requirement 
increases to high-flow nasal 
cannula, face mask, or positive 
pressure ventilation, refer to 
further management as in Grade 3 
or 4 CRS 
• Symptomatic management of 
fever as in Grade 1 CRS 
• Symptomatic management of 
constitutional symptoms and 
organ toxicities as per standard 
guidelines 
• Administer tocilizumab1 for 
1 dose and consider 
dexamethasone 4 – 10 mg IV 
for 1 dose (or 
methylprednisolone 
equivalent) and reassess in 
6 hours or earlier if clinically 
indicated 
• Tocilizumab may be repeated 
every 8 hours for up to 
3 doses in a 24-hour period 
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CRS Grade 
CRS 
Parameter 
Management 
Diagnostic Work-Up 
Supportive Care 
Anti-IEC Therapies 
Grade 3 
Hypotension 
• Obtain ECHO if not 
performed already 
• Cardiac telemetry  
• Fever work-up if not 
previously performed 
o Assess for infection 
with blood and urine 
cultures, and chest 
radiography 
• Transfer patient to ICU 
• IV fluid boluses as needed in 
Grade 2 CRS 
• Use vasopressors as needed 
• Symptomatic management of 
constitutional symptoms and 
organ toxicities as per standard 
guidelines 
• Tocilizumab1 as in Grade 2 if 
not administered previously; 
tocilizumab may be repeated 
every 8 hours for up to 
3 doses in a 24-hour period 
• If on 1 vasopressor: 
tocilizumab as in Grade 2 
CRS and dexamethasone 
10 mg IV every 6 hours (or 
methylprednisolone 
equivalent) 
• If vasopressin and 
norepinephrine equivalent2 is 
≥15 µg/minute, follow as in 
Grade 4 CRS 
• Once CRS improves to 
Grade 1 or less, taper and/or 
stop corticosteroids depending 
on clinical situation 
Hypoxia 
• Pulse oximetry  
• Fever work-up if not 
previously performed 
o Assess for infection 
with blood and urine 
cultures, and chest 
radiography 
• Supplemental oxygen including 
high-flow nasal cannula, face 
mask, non-rebreather mask, or 
Venturi mask as needed 
• Symptomatic management of 
fever as in Grade 1 CRS 
• Symptomatic management of 
constitutional symptoms and 
organ toxicities as per standard 
guidelines 
• Tocilizumab1 as in Grade 2 
CRS if not administered 
previously; tocilizumab may 
be repeated every 8 hours for 
up to 3 doses in a 24-hour 
period 
• Methylprednisolone 
1,000 mg/day in divided 
doses IV for 3 days followed 
by rapid taper as per clinical 
situation 
• If hypoxia is refractory 
for >24 hours or if patient is 
deteriorating rapidly, consider 
additional therapies (see 
below) 
Grade 4 
Hypotension 
• Obtain ECHO if not 
performed already 
• Cardiac telemetry  
• Fever work-up if not 
previously performed 
o Assess for infection 
with blood and urine 
cultures, and chest 
radiography 
• Transfer patient to ICU 
• IV fluid boluses as needed in 
Grade 2 CRS 
• Vasopressors as in Grade 3 CRS 
• Use vasopressors as needed 
• Symptomatic management of 
fever as in Grade 1 CRS 
• Symptomatic management of 
constitutional symptoms and 
organ toxicities as per standard 
guidelines 
• Tocilizumab1 as in Grade 2 if 
not administered previously; 
tocilizumab may be repeated 
every 8 hours for up to 
3 doses in a 24-hour period 
• Methylprednisolone 
1,000 mg/day in divided 
doses IV for 3 days followed 
by rapid taper as per clinical 
situation 
• If hypotension is refractory 
for >24 hours or if patient is 
deteriorating rapidly, consider 
additional therapies (see 
below) 
Hypoxia 
• Monitor oxygen 
saturation while on 
mechanical ventilation 
• Fever work-up if not 
previously performed 
o Assess for infection 
with blood and urine 
• Transfer patient to ICU 
• Positive pressure ventilation 
including CPAP, BiPAP, 
mechanical ventilation 
• Symptomatic management of 
fever as in Grade 1 CRS 
• Supplemental oxygen including 
• Tocilizumab1 as in Grade 2 
CRS if not administered 
previously; tocilizumab may 
be repeated every 8 hours for 
up to 3 doses in a 24-hour 
period 
• Methylprednisolone 
1,000 mg/day in divided 
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CRS Grade 
CRS 
Parameter 
Management 
Diagnostic Work-Up 
Supportive Care 
Anti-IEC Therapies 
cultures, and chest 
radiography 
high-flow nasal cannula, face 
mask, non-rebreather mask, or 
Venturi mask as needed 
• Symptomatic management of 
constitutional symptoms and 
organ toxicities as per standard 
guidelines 
doses IV for 3 days followed 
by rapid taper as per clinical 
situation 
• If hypoxia is refractory 
for >24 hours or if patient is 
deteriorating rapidly, consider 
additional therapies (see 
below) 
 
Management of ICANS 
ICANS 
Grade 
Sign or Symptom 
Management 
Diagnostic Work-Up 
Supportive Care 
Anti-IEC Therapies 
Grade 1 
Encephalopathy 
and/or depressed 
level of 
consciousness 
• MRI imaging of the brain 
with and without 
contrast: CT of brain 
without contrast may be 
performed if MRI is not 
feasible: MRI spine if 
focal deficits are noted 
• Neurology consultation 
• ICE Score assessment 
every 6 hours or more 
frequently if clinically 
indicated 
• EEG 
• Consider diagnostic 
lumbar puncture if other 
causes of encephalopathy 
are suspected (eg, 
infections, autoimmune, 
leptomeningeal disease) 
o Add a meningitis-
encephalitis panel 
from CSF in patients 
with neurologic 
symptoms that persist 
or worsen after 
ICANS therapy 
and/or if symptoms 
start after 
corticosteroids 
• Vigilant supportive care; 
aspiration precautions ; IV 
hydration 
• Withhold oral intake of 
food/medications/fluids and 
assess swallowing; convert all 
oral medications and/or nutrition 
to IV if swallowing is impaired 
• Avoid medications that cause 
central nervous system 
depression 
• Low doses of lorazepam after 
EEG is performed (0.25 – 0.5 mg 
IV every 8 hours) or haloperidol 
(0.5 mg IV every 6 hours) may 
be used with careful monitoring 
for agitated patients 
• If no seizures on EEG, continue 
prophylactic levetiracetam 
• If EEG shows focal or 
generalized convulsive or non-
convulsive seizure or convulsive 
status epilepticus, refer to further 
management as in Grade 3 or 4 
ICANS 
• Dexamethasone 10 mg IV for 
1 dose (or methylprednisolone 
equivalent) and reassess in 
6 hours or earlier if clinically 
indicated 
o 
If associated with 
concurrent CRS, add 
tocilizumab1 
Grade 2 
Encephalopathy 
and/or depressed 
level of 
consciousness 
• Neurological work-up as 
in Grade 1 ICANS 
• Supportive care as in Grade 1 
ICANS 
• Dexamethasone 10 mg IV 
every 12 hours (or 
methylprednisolone 
equivalent) 
o If associated with 
concurrent CRS, add 
tocilizumab1 
• Once ICANS improves to 
Grade 1 or less, taper and/or 
stop corticosteroids 
depending on clinical 
situation 
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ICANS 
Grade 
Sign or Symptom 
Management 
Diagnostic Work-Up 
Supportive Care 
Anti-IEC Therapies 
Grade 3 
Encephalopathy 
and/or depressed 
level of 
consciousness 
• Neurological work-up as 
in Grade 1 ICANS 
• Consider repeat neuro-
imaging (CT or MRI) 
every 2-3 days for 
persistent ≥Grade 3 
encephalopathy 
• Consider diagnostic 
lumbar puncture if 
Grade 3 encephalopathy 
persists ≥2 days or earlier 
if other causes are 
suspected (eg, infections, 
autoimmune, 
leptomeningeal disease) 
o Add a meningitis-
encephalitis panel 
from CSR in 
patients with 
neurologic 
symptoms that 
persist or worsen 
after ICANS therapy 
and/or symptoms 
start after 
corticosteroids 
• Supportive care as in Grade 1 
ICANS 
• Consider ICU transfer 
• IF there are new abnormal 
findings on brain imaging3 not 
related to primary malignancy, 
control hypertension with the 
goal of maintaining mean arterial 
pressure (MAP) within 20-25 
mmHg of baseline MAP, correct 
any uremia (dialysis if needed) 
and/or coagulopathy (transfuse 
to keep platelets >20-50 K/µL, 
fibrinogen >200 mg/dL and INR 
<1.5) 
• Dexamethasone 10 mg IV 
every 6 hours (or 
methylprednisolone 
equivalent) 
o If associated with 
concurrent CRS, add 
tocilizumab1 
• If Grade 3 encephalopathy is 
persistent for >24 hours, 
increase dexamethasone to 
20 mg IV every 6 hours (or 
methylprednisolone 
equivalent) 
• Once ICANS improves to 
Grade 1 or less, taper and/or 
stop corticosteroids 
depending on clinical 
situation 
Seizure 
• Neurological work-up as 
in Grade 1 ICANS 
• EEG if clinically 
indicated (eg, ongoing 
seizures, depressed level 
of consciousness) 
• Rule out other potential 
causes of seizure (ie, 
beta-lactams, etc.) 
• Transfer to ICU 
• Supportive care as in Grade 1 
ICANS 
• For focal or generalized 
convulsive seizures, or non-
convulsive seizures, treat as 
summarized below 
• Dexamethasone 20 mg IV 
every 6 hours (or 
methylprednisolone 
equivalent) 
o If associated with 
concurrent CRS, add 
tocilizumab1 
• Once ICANS improves to 
Grade 1 or less, taper and/or 
stop corticosteroids 
depending on clinical 
situation 
Focal cerebral 
edema 
• Neurological work-up as 
in Grade 1 ICANS 
• Consider repeat neuro-
imaging (CT or MRI) 
every 24 hours until 
edema resolves or more 
frequently if clinically 
indicated 
• Transfer to ICU 
• Supportive care as in Grade 1 
ICANS 
• If focal edema is in brain stem 
or thalamus 
methylprednisolone 
1,000 mg/day in divided 
doses for IV for 3 days 
followed by taper depending 
on clinical situation 
o If associated with 
concurrent CRS, add 
tocilizumab1 
• If focal edema is in other 
areas of brain, 
methylprednisolone 
1,000 mg/day in divided 
doses IV for 1 day; assess 
daily and continue or taper 
depending on clinical 
situation 
• If associated with 
concurrent CRS, add 
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ICANS 
Grade 
Sign or Symptom 
Management 
Diagnostic Work-Up 
Supportive Care 
Anti-IEC Therapies 
tocilizumab1 
Grade 4 
Encephalopathy 
and/or depressed 
level of 
consciousness 
• Neurological 
work-up as in 
Grade 1 ICANS 
• Repeat neuro-
imaging and 
lumbar puncture 
as in Grade 3 
ICANS 
• Transfer to ICU 
• Supportive care as in Grade 1 
ICANS 
• Consider mechanical ventilation 
for airway protection 
• If there are new abnormal 
findings on brain imaging1 not 
related to primary malignancy, 
control hypertension with the 
goal of maintaining mean arterial 
pressure (MAP) within 20-25 
mmHg of baseline MAP, correct 
any uremia (dialysis if needed) 
and/or coagulopathy (transfuse to 
keep platelets >20-50 K/µL, 
fibrinogen >200 mg/dL and INR 
<1.5) 
• Methylprednisolone 1,000 mg/day in 
divided doses IV for 3 days followed 
by taper as clinically indicated; if 
associated with concurrent CRS, add 
tocilizumab2 
• Continue corticosteroids until 
improvement to less than or equal to 
Grade 1 ICANS and then taper and 
stop corticosteroids depending on 
clinical situation 
• If Grade 4 ICANS is refractory 
for >24 hours or if patient is 
deteriorating rapidly, consider 
additional therapies (see below) 
including activation of safety 
switches if applicable 
Seizure 
• Neurological 
work-up as in 
Grade 1 ICANS 
• Rule out other 
potential causes 
of seizure (ie, 
beta-lactams, 
etc.) 
• Transfer to ICU 
• Supportive care as in Grade 1 
ICANS 
• For focal or generalized 
convulsive seizures, or non-
convulsive seizures or convulsive 
status epilepticus, treat as listed 
below 
• Methylprednisolone 1,000 mg/day in 
divided doses IV for 3 days followed 
by taper as clinically indicated; if 
associated with concurrent CRS, add 
tocilizumab2 
• If Grade 4 ICANS is refractory 
for >24 hours or if patient is 
deteriorating rapidly, consider 
additional therapies (see below) 
including activation of safety 
switches if applicable 
Motor Weakness 
• Neurological 
work-up as in 
Grade 1 ICANS 
• MRI with and 
without contrast 
of the spine 
• Transfer to ICU 
• Supportive care as in Grade 1 
ICANS 
• Methylprednisolone 1,000 mg/day in 
divided doses IV for 3 days followed 
by taper as clinically indicated; if 
associated with concurrent CRS, add 
tocilizumab2 
• If Grade 4 ICANS is refractory 
for >24 hours or if patient is 
deteriorating rapidly, consider 
additional therapies (see below) 
including activation of safety 
switches if applicable 
Diffuse Cerebral 
Edema or Raised 
Intracranial 
Pressure 
• Neurological 
work-up as in 
Grade 1 ICANS 
• Consider repeat 
neuro-imaging as 
in focal cerebral 
edema from 
Grade 3 ICANS 
• Transfer to ICU 
• Supportive care as in Grade 1 
ICANS 
• For diffuse cerebral edema or 
signs of raised intracranial 
pressure, treat as summarized 
below 
• Methylprednisolone 1,000 mg/day in 
divided doses IV for 3 days followed 
by taper as clinically indicated; if 
associated with concurrent CRS, add 
tocilizumab2 
• If Grade 4 ICANS is refractory 
for >24 hours or if patient is 
deteriorating rapidly, consider 
additional therapies (see below) 
including activation of safety 
switches if applicable 
 
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TAK-007 
 
Study No. TAK-007-2001 
Page 129 of 144 
Protocol Incorporating Amendment No. 5 
03 June 2024 
 
CONFIDENTIAL 
Recommendations for Use of IL IL-6 Antagonists and Alternative Agents for Management of 
CRS and ICANS 
Drug 
Recommended 
Dose for CRS 
and/or ICANS 
Maximum Dose 
Mechanism of Action 
Comments 
Tocilizumab 
8 mg/kg IV 
Maximum 800 mg 
per dose 
IL-6 receptor antagonist 
• Maximum of 4 doses total over the entire 
course of CRS and ICANS 
• Dose may be repeated every 8 hours for up 
to 3 doses in a 24-hour period 
Siltuximab 
11 mg/kg IV once 
-- 
IL-6 antibody 
• Recommended primarily for patients who 
are intolerant to tocilizumab 
• No more than 1 dose in a 3-week period 
Anakinra 
100 mg 
subcutaneously 
daily for 7 days 
-- 
IL-1 receptor antagonist 
• Renal dose adjustment may be needed for 
creatinine clearance <30 mL/minute 
Cyclophosphamide 
1,500 mg/m2 IV 
for 1 dose 
-- 
Alkylating agent 
• Give with mesna 1,500 mg/m2 IV over 
24 hours for 1 dose 
Anti-thymocyte 
globulin (rabbit) 
1-2 mg/kg IV daily 
for 3 days 
-- 
Immunosuppressant 
• Hypersensitivity reactions can occur; 
premedicated with diphenhydramine and 
schedule dose of corticosteroid 
• No more than 1dose in 3-week period 
 
Management of Focal or Generalized Convulsive or Non Non-Convulsive Seizures 
• Assess CAB / consider airway protection / check blood glucose 
• Consult Neurology 
• For focal and generalized convulsive seizures, lorazepam 1-2 mg IV and repeat as needed (to a maximum cumulative dose of 4 mg) 
• For electrographical seizures, including non-convulsive status epilepticus, lorazepam 0.5 mg IV and repeat every 5 minutes as needed (to a 
maximum cumulative dose of 2 mg) 
• Levetiracetam 500-1,500 mg IV bolus (in addition to maintenance dose) 
• Replete with magnesium as needed to maintain magnesium level >2 mg/dL 
• Thiamine 100 mg IV every 8 hours for 5 days 
• If non-convulsive seizures persist, transfer to ICU and add phenobarbital loading dose of 60 mg IV (monitor for respiratory depression, 
bradycardia and hypotension) 
• Maintenance doses after resolution of non-convulsive status epilepticus 
o 
Lorazepam 0.5 mg IV every 8 hours for 3 doses 
o 
Levetiracetam 1,000-1,500 mg IV every 12 hours 
o 
Phenobarbital 30 mg IV every 12 hours (~0.5 mg/kg every 12 hours) 
- 
Monitor for respiratory depression, bradycardia and hypotension 
- 
Assess for drug-drug interactions (ie, may induce metabolism of azole antifungals or other CYP3A4 substrates) and consider 
alternative therapy if drug interactions are significant 
- 
Target serum trough levels 15-40 µg/mL 
 
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TAK-007 
 
Study No. TAK-007-2001 
Page 130 of 144 
Protocol Incorporating Amendment No. 5 
03 June 2024 
 
CONFIDENTIAL 
Management of Convulsive Status Epilepticus 
• Assess circulation, airway, breathing (CAB) / consider airway protection / check blood glucose 
• Transfer to ICU 
• Consult Neurology 
• Lorazepam 0.1 mg/kg (maximum 4 mg/dose) given at a maximum rate of 2 mg/minute; may repeat in 5 to 10 minutes 
• Levetiracetam 500-1,500 mg IV bolus (in addition to maintenance dose) 
• Replete with magnesium as needed to maintain magnesium level >2 mg/dL 
• Thiamine 100 mg IV every 8 hours for 5 days 
• If seizures persist, add phenobarbital loading dose of 15 mg/kg IV (monitor for respiratory depression, bradycardia and hypotension) 
• If refractory, consider additional therapies (see below) 
• Maintenance doses after resolution of non-convulsive status epilepticus 
o 
Levetiracetam 1,000-1,500 mg IV every 12 hours 
o 
Phenobarbital 0.5 mg/kg IV every 12 hours 
- 
Monitor for respiratory depression, bradycardia and hypotension 
- 
Assess for drug-drug interactions (ie, may induce metabolism of azole antifungals or other CYP3A4 substrates) and consider 
alternative therapy if drug interactions are significant 
- 
Target serum trough levels 15-40 µg/mL 
• Continuous EEG monitoring if seizures are refractory to treatment 
 
Management of Diffuse Cerebral Edema and or Raised Intracranial Pressure 
For papilledema without diffuse 
cerebral edema or other signs of raised 
intracranial pressure 
• 
Acetazolamide 1,000 mg IV followed by 250-1,000 mg IV every 12 hours (monitor renal 
function and acid/base balance once or twice daily and adjust dose accordingly) 
• 
Dexamethasone 20 mg IV every 6 hours (or methylprednisolone equivalent) and start taper 
after resolution of papilledema 
For diffuse cerebral edema on 
neuroimaging or signs of raised 
intracranial pressure such as 
decerebrate or decorticate posturing, 
cranial nerve VI palsy, or Cushing’s 
triad 
• 
Methylprednisolone 1,000 mg/day in divided doses IV for 3 days followed by taper as 
clinically indicated 
• 
Elevate head end of patient’s bed to an angle of 30 degrees 
• 
Hyperventilation to achieve target PaCO2 of 28-30 mmHg, but maintained for no longer 
than 24 hours 
• 
Hyperosmolar therapy with either mannitol (20 g/dL solution) or hypertonic saline (3% or 
23.4% as detailed below) 
o 
Mannitol: initial dose 0.5-1 g/kg IV; maintenance dose 0.25-1 g/kg IV every 6 hours 
while monitoring metabolic profile and serum osmolality every 6 hours; and withhold 
mannitol if serum osmolality is ≥320 mOsm/kg or osmolality gap is ≥40) 
o 
Hypertonic 3#saline: initial dose 250 mL IV over 15 minutes, maintenance dose of 
50-75 mL/hour IV while monitoring electrolytes every 4 hours; withhold infusion if 
serum sodium levels reach ≥155 mEq/L) 
o 
Hypertonic 23.4% saline (for patients with imminent herniation): dose to be 
administered by physician; initial dose of 30 mL IV; repeat after 15 minutes, if needed 
• 
If patient as Ommaya reservoir, drain CSF to target OP <20 mmHg 
• 
Control hypertension with the goal of maintaining mean arterial pressure (MAP) within 
20-25 mmHg of baseline MAP; correct any uremia (dialysis if needed) and/or coagulopathy 
(transfuse to keep platelets >20-50 K/µL, fibrinogen >200 mg/dL and INR <1.5) 
• 
Consider neurosurgery consultation and IV anesthetics for burst-suppression pattern on 
EEG; transfuse to keep platelets ≥100 K/µL if possible and correct coagulopathy in case of 
surgical intervention 
• 
Consider additional therapies (see below) 
• 
Metabolic profile every 6 hours and daily CT scans of head without contrast, with 
adjustments in usage of aforementioned medications to prevent rebound cerebral edema, 
renal failure, electrolyte abnormalities, hypovolemia and hypotension 
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TAK-007 
 
Study No. TAK-007-2001 
Page 131 of 144 
Protocol Incorporating Amendment No. 5 
03 June 2024 
 
CONFIDENTIAL 
Adapted from IEC Therapy Toxicity Assessment and Management (also known as CARTOX) -Adult V4 
mdanderson.org/documents/for-physicians/algorithms/clinical-management/clin-management-cytokine-release-web-algorithm.pdf  
BiPAP: bilevel positive airway pressure; BP: blood pressure; CAB: circulation, airway, breathing; CPAP: continuous positive airway 
pressure; CRS: cytokine release syndrome; CSF: cerebrospinal fluid; CT: computed tomography; CYP: cytochrome P450; ECHO: 
echocardiogram; EEG: electroencephalogram; FiO2: fraction of inspired oxygen; ICANS: immune effector cell–associated neurotoxicity 
syndrome; ICE: IEC-Associated Encephalopathy; ICU: intensive care unit; IEC: immune effector cell; INR: international normalized ratio; 
IV: intravenous; MAP: mean arterial pressure; MRI: magnetic resonance imaging; PO: oral; VASST: Vasopressin and Septic Shock Trial. 
1See Dosing of IL 6 Antagonists and Alternative Agents. 
2VASST Trial vasopressor equivalent equation : norepinephrine equivalent dose = [norepinephrine (µg/minute)] + [dopamine (µg/kg minute) / 
2] + [epinephrine (µg/minute)] + [phenylephrine (µg/minute) / 10] 
3Abnormal findings on imaging where correction of hypertension, uremia, and/or coagulopathy should be performed include changes 
suggestive of typical or atypical posterior reversible encephalopathy syn drome (PRESPRES), temporal lobe and limbic system encephalitis 
(autoimmune or infection), acute disseminated encephalomyelitis, emboli, vasculitis, strokes, and/or seizure-related changes. 
 
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TAK-007 
 
Study No. TAK-007-2001 
Page 132 of 144 
Protocol Incorporating Amendment No. 5 
03 June 2024 
 
CONFIDENTIAL 
Appendix P Protocol History 
Date 
Amendment Number 
Amendment Type 
Region 
03 June 2024 
Amendment 5 
Substantial 
Global 
20 December 2023 
Amendment 4 
Substantial 
Global 
29 April 2022 
Amendment 3 
Substantial 
Global 
21 December 2021 
Amendment 2 
Substantial 
Global 
12 July 2021 
Amendment 1 
Substantial 
Global 
05 May 2021 
Initial protocol 
Not applicable 
Global 
 
Protocol Amendment 4 Summary and Rationale 
This section describes the changes to the protocol incorporating Amendment 4.  
The primary reason for this amendment is to update the study design of Part 1 with two 
additional expansion cohorts to evaluate the administration of >1 dose of TAK-007, after a single 
cycle of lymphodepleting chemotherapy, including appropriate safety and tolerability risk 
mitigation. This amendment also opens enrollment to patients with relapsed or refractory (r/r) 
large B-cell lymphoma (LBCL) who have failed one prior line of systemic anticancer therapy, 
removes the requirement for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 
testing at screening, and clarifies monitoring of AEs and period of observation for all patients 
during posttreatment follow-up. 
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification and administrative purposes only. 
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TAK-007 
 
Study No. TAK-007-2001 
Page 133 of 144 
Protocol Incorporating Amendment No. 5 
03 June 2024 
 
CONFIDENTIAL 
Protocol Amendment 4  
Summary of Changes Since Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by 
Change 
Description of Each Change and Rationale 
 
Location 
Description 
Rationale 
1. 
Section 2.0 STUDY 
SUMMARY 
Section 6.1 Overview 
of Study Design  
Figure 6.a Study 
Schematic for 
TAK-007-2001 
Protocol  
Section 8.2 Prohibited 
Concomitant 
Medications and 
Procedures 
Section 9.4.3 Treatment 
and Follow-up Phases 
(Day 0 to Month 24)  
 
Appendix A, Schedule 
of Events Table A 1, 
Table A 2, Table A 3 
The design of the expansion phase of 
Part 1 was updated to include 
2 additional expansion cohorts for 
patients with r/r LBCL, evaluating the 
administration of >1 dose of  
TAK-007. In addition, r/r LBCL 
patients after 1 prior line of systemic 
anticancer therapy will be included.  
The administration of 3 weekly doses 
of TAK-007 after a single cycle of 
lymphodepletion is not expected to 
cause a clinically significant increase 
in toxicity; however, in addition to the 
robust TAK-007-2001 study safety 
management plan that is already in 
place, additional safety measures 
(14-day observation period and 
staggering between the first 2 patients; 
enrollment pausing criteria; and 
exclusionary safety criteria for 
patients who will not be eligible to 
receive their Day 7 and/or Day 14 
dose of TAK-007) were added 
specifically for these 2 multi-dose 
expansion cohorts to mitigate any 
possible additional toxicity. 
Based on the safety and 
tolerability profile of TAK-007 
(no dose-limiting toxicities 
[DLTs], graft-versus-host disease 
[GvHD], or immune effector cell-
associated neurotoxicity syndrome 
[ICANS], and very few events of 
low-grade cytokine release 
syndrome [CRS], the most 
common toxicities were 
hematological and related to 
lymphodepletion), the 
administration of up to 3 single 
doses of 800 × 106 CAR+ NK cells 
(on Days 0, 7, and 14) following a 
single cycle of lymphodepletion 
may further enhance the clinical 
response rate without the additive 
risks associated with repeat 
lymphodepletion cycles. 
2. 
Section 2.0 STUDY 
SUMMARY 
Section 6.2 Number of 
Patients 
Section 13.2 
Determination of 
Sample Size 
The number of patients in Part 1 of 
the study was increased for the 
planned patients in the multi-dose 
expansion cohorts. 
Updated for revised study design 
3. 
Section 2.0 STUDY 
SUMMARY 
Section 6.3.4 Total 
Study Duration 
Updated duration of enrollment to 
account for the increased observation 
time and staggered design of the 
multi-dose expansion cohorts of 
Part 1.  
Updated for revised study design 
4. 
Section 2.0 STUDY 
SUMMARY 
Section 7.1 Inclusion 
Criteria, #6 
Added specifications on which 
patients with CD19-targeted therapies 
are eligible 
Revised for clarification because 
of the evolving treatment 
landscape in LBCL with 
CD19-targeted therapies. 
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TAK-007 
 
Study No. TAK-007-2001 
Page 134 of 144 
Protocol Incorporating Amendment No. 5 
03 June 2024 
 
CONFIDENTIAL 
Protocol Amendment 4  
Summary of Changes Since Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by 
Change 
Description of Each Change and Rationale 
 
Location 
Description 
Rationale 
5. 
Section 6.1 Overview 
of Study Design  
Restricted enrollment of patients with 
prior CD19-targeting CAR-T cell 
therapy to ≤7 patients for Cohort 1B. 
Updated for revised study design 
6. 
Section 2.0 STUDY 
SUMMARY 
Section 7.2 Exclusion 
Criteria, #6 
Specified exclusionary time frame for 
rituximab treatment before initiation 
of conditioning therapy. 
Revised for clarification 
7. 
Section 2.0 STUDY 
SUMMARY 
Section 8.1 Study Drug 
Administration 
Section 9.3 Treatment 
Group Assignments 
Section 9.4.3 Treatment 
and Follow-up Phases 
(Day 0 to Month 24)  
Appendix A, Schedule 
of Events Table A 1 
Study drug administration details 
were updated for the multi-dose 
expansion cohorts, including a delay 
for up to 7 days each before the 
second and third TAK-007 dose to 
allow for recovery from AEs and the 
addition of exclusionary safety criteria 
for patients who will not be eligible to 
receive their second and/or third dose 
of TAK-007, including possible dose 
reduction for subsequent TAK-007 
dose administration in patients with 
Grade ≥3 cardiac or pulmonary 
toxicity at least possibly related to 
TAK-007, after resolution to baseline.  
Updated for revised study design 
8. 
Section 2.0 STUDY 
SUMMARY 
Section 9.4.13 AEs 
Section 9.10 
Posttreatment Follow-
up Assessments (DOR, 
PFS, OS, and Safety) 
Section 10.3 
Monitoring of AEs and 
Period of Observation 
Appendix A, Schedule 
of Events Table A 1, 
Table A 3. 
The monitoring of AEs and period of 
observation for all patients during 
posttreatment follow-up was adapted 
to detail the proper safety follow up 
phase for patients with disease 
progression with or without new 
systemic anticancer therapy, and for 
patients who received 
lymphodepletion therapy, but did not 
receive TAK-007. In addition, the 
types of AEs and the period of 
collection was limited to reduce 
excessive reporting and unnecessary 
AE collection. 
Revised for clarification. Also 
refined and clarified AE collection 
to reduce excessive reporting and 
for better characterization of the 
expected short-term and long-term 
risks of TAK-007. 
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TAK-007 
 
Study No. TAK-007-2001 
Page 135 of 144 
Protocol Incorporating Amendment No. 5 
03 June 2024 
 
CONFIDENTIAL 
Protocol Amendment 4  
Summary of Changes Since Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by 
Change 
Description of Each Change and Rationale 
 
Location 
Description 
Rationale 
9. 
Section 2.0 STUDY 
SUMMARY 
Section 13.1 General 
Considerations 
Section 13.5 Efficacy 
Analyses 
Added specifications for summarizing 
endpoints in Part 1 (dose escalation 
and dose expansion phase) and the 
primary analysis assessment of Part 2 
by an independent review committee.  
Updated for revised study design 
and clarification. 
10. 
Section 4.1.5 Clinical 
Experience 
Updated information and added 
current status of the study. 
Clarification 
11. 
Section 6.3.1 Duration 
of an Individual 
Patient’s Study 
Participation 
Revised to include the multi-dose 
cohorts in the dose expansion phase of 
Part 1. 
Updated for revised study design 
12. 
Section 8.5 
Management and 
Mitigation of AEs 
Associated With CAR 
Cell Therapy 
Table 8.a CAR-T 
Toxicity Assessment 
and Management 
Guidelines 
Revised to include monitoring, 
assessment, and management 
guidelines for handling TAK-007 
product batches in the multi-dose 
expansion cohorts, after the 
occurrence of a Grade ≥2 acute GvHD 
AE. Revised monitoring, assessment, 
and management guidelines for tumor 
lysis syndrome. 
Updated for revised study design 
and clarification. 
13. 
Section 8.6 Definition 
of DLTs 
Specified that DLTs occur only in the 
Dose Escalation phase of Part 1 
Revised for clarification 
14. 
Section 8.7 Enrollment 
Pausing Criteria 
Revised enrollment pausing criteria to 
include pausing during the dose 
escalation phase and the dose 
expansion phase (for multi-dose 
cohorts) of Part 1 
Updated for revised study design 
15. 
Section 9.4.1 Screening 
Phase (Day -33 to 
Day -6) 
Section 9.4.16 Clinical 
Laboratory Evaluations 
Removed requirement for SARS-
CoV-2 testing from infectious disease 
test at screening. 
Updated due to endemicity of 
COVID-19.  
16. 
Section 9.4.16 Clinical 
Laboratory Evaluations 
Appendix A, Schedule 
of Events Table A 1 
Added requirements for HIV-positive 
patients with negative viral load at 
screening 
Revised for clarification. 
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TAK-007 
 
Study No. TAK-007-2001 
Page 136 of 144 
Protocol Incorporating Amendment No. 5 
03 June 2024 
 
CONFIDENTIAL 
Protocol Amendment 4  
Summary of Changes Since Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by 
Change 
Description of Each Change and Rationale 
 
Location 
Description 
Rationale 
17.  
Section 9.4.18.1 
Primary Specimen 
Collection 
Table 9.b Primary 
Specimen Collection 
Table 9.c Prioritized 
Sequence for Specimen 
Collection 
The priority of plasma sample for 
ctDNA was changed to number 8 in 
Table 9.b, and to number 6 in  
Table 9.c. 
Revised to increase probability of 
sample collection.  
18. 
Section 9.4.18.2 Tumor 
and Bone Marrow 
Biopsies and Aspirates 
Appendix A, Schedule 
of Events Table A 1 
Removed mandatory bone marrow 
aspiration at Month 3. 
Revised to reduce patient burden. 
19. 
Section 9.4.21 
Healthcare Resource 
Utilization 
Added clarification that healthcare 
resource utilization will only be 
evaluated in Part 2 of this study. 
Revised for clarification. 
20. 
Section 9.5 Completion 
of Study Treatment (for 
Individual Patients) 
Section 9.7 
Discontinuation of 
Treatment With Study 
Drug and Patient 
Replacement 
Updated to include definitions for the 
added cohorts with multi-dose 
regimen of TAK-007. 
Updated for revised study design 
 
Protocol Amendment 3 Summary and Rationale 
This section describes the changes to the protocol incorporating Amendment 3.  
The primary reason for this amendment is to modify several exclusion criteria to broaden the 
enrollment of eligible patients into the study. This amendment also removes all Day 5 laboratory 
evaluations as Day 5 will likely take place on a weekend day, which is logistically impractical 
for this study. Imaging requirements have also been updated to reduce patient exposure to 
positron emission tomography (PET) scans beyond 6 months posttreatment. 
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification and administrative purposes only. 
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TAK-007 
 
Study No. TAK-007-2001 
Page 137 of 144 
Protocol Incorporating Amendment No. 5 
03 June 2024 
 
CONFIDENTIAL 
Protocol Amendment 3 
Summary of Changes Since Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by 
Change 
Description of Each Change and Rationale 
 
Location 
Description 
Rationale 
1. 
Section 2.0 STUDY 
SUMMARY 
Section 6.1 Overview 
of Study Design  
Appendix A, 
Schedule of Events 
Tables 1 and 2  
Removed all Day 5 laboratory 
evaluations and research sampling. 
Revised because of the increased 
likelihood of the Day 5 visit 
occurring on a weekend; this visit 
is removed for site resourcing and 
laboratory practicality reasons. 
2. 
Section 2.0 STUDY 
SUMMARY 
Section 7.2 Exclusion 
Criteria, #2 
Reworded this exclusion criterion to 
clarify that patients with a history of 
secondary involvement by lymphoma 
without evidence of central nervous 
system (CNS) involvement at screening 
can be enrolled. 
Revised for clarity. 
3. 
Section 2.0 STUDY 
SUMMARY 
Section 7.2 Exclusion 
Criteria, #3 
Created a separate exclusion criterion 
for patients with Burkitt lymphoma, 
mantle cell lymphoma, 
lymphoplasmacytic lymphoma, or 
transformation from chronic 
lymphocytic leukemia (CLL)/small 
lymphocytic lymphoma (Richter 
transformation). 
Revised for clarity. 
4. 
Section 2.0 STUDY 
SUMMARY 
Section 7.2 Exclusion 
Criteria #3 
(Amendment 2 
numbering) 
Removed the criterion excluding 
patients with a history of anti-CD19 
therapy (eg, CD19-targeted chimeric 
antigen receptor [CAR] T cells or 
monoclonal antibodies). 
Revised because of the evolving 
treatment landscape in large 
B-cell lymphoma (LBCL) with 
CD19 targeted therapies moving 
into the second line setting. 
Additionally, natural killer (NK) 
cells are hypothesized to kill 
tumor cells upon target antigen 
downregulation via innate 
immune receptor-mediated 
killing. 
5. 
Section 2.0 STUDY 
SUMMARY 
Section 7.2 Exclusion 
Criteria, #5 
Added to this criterion the exclusion of 
patients who have undergone chimeric 
antigen receptor T-cell (CAR-T) 
therapy within 3 months of planned 
enrollment. 
Revised to allow sufficient time 
for patients to recover after 
CAR-T therapy. 
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TAK-007 
 
Study No. TAK-007-2001 
Page 138 of 144 
Protocol Incorporating Amendment No. 5 
03 June 2024 
 
CONFIDENTIAL 
Protocol Amendment 3 
Summary of Changes Since Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by 
Change 
Description of Each Change and Rationale 
 
Location 
Description 
Rationale 
6. 
Section 2.0 STUDY 
SUMMARY 
Section 7.2 Exclusion 
Criteria, #6 
Reworded this criterion to (1) exclude 
patients who receive any systemic 
anticancer treatment within 14 days 
before conditioning therapy and (2) 
revise the 14-day time frame to include 
2 half-lives of the treatment (whichever 
is longer) before conditioning therapy. 
Revised to allow adequate 
washout periods for patients who 
may have received prior systemic 
anticancer treatments. In addition, 
included a half-life–based 
washout period for agents with 
long half-lives. 
7. 
Section 2.0 STUDY 
SUMMARY 
Section 7.2 Exclusion 
Criteria, #7 
Reworded this criterion for emphasis on 
active fungal, bacterial, and viral 
infections. 
Revised for clarity and to remove 
redundancy. 
8. 
Section 2.0 STUDY 
SUMMARY 
Section 7.2 Exclusion 
Criteria, #8 
Removed severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2) 
infection from this criterion. 
Revised to eliminate redundancy 
with exclusion criterion #7. 
9. 
Section 2.0 STUDY 
SUMMARY 
Section 7.2 Exclusion 
Criteria, #9 
Reworded this criterion to exclude 
patients with active or clinically 
relevant CNS disorders and severe 
dementia.  
Reworded this criterion to permit 
enrollment of patients without 
recurrence of a CNS disorder within 2 
years of planned study enrollment. 
Revised for clarity. 
 
 
Revised as limited risk of CNS 
events expected with CAR-NK 
cell therapy. 
10. 
Section 2.0 STUDY 
SUMMARY 
Section 7.2 Exclusion 
Criteria, #10 
Reduced the time frame from 12 months 
within enrollment to 6 months within 
enrollment for patients with specified 
exclusionary cardiac events.  
Revised as a limited risk of 
cardiac events is expected with 
CAR-NK cell therapy. 
11. 
Section 2.0 STUDY 
SUMMARY 
Section 7.2 Exclusion 
Criteria, #12 
(Amendment 2 
numbering) 
Removed exclusion criterion #12. 
Revised as a limited risk of 
thromboembolic events is 
expected with CAR-NK cell 
therapy. 
12. 
Section 5.2.3 
Exploratory 
Endpoints  
Added tumor volume on computed 
tomography (CT)/magnetic resonance 
imaging (MRI) and volumetric tumor 
assessment. 
Revised to provide additional 
details on endpoints that will be 
assessed. 
13. 
Section 9.4.1 
Screening Phase 
(Day -33 50 Day -6)  
Section 9.4.16 
Disease Assessments  
Removed wording that excludes 
marginal zone lymphoma (MZL) from 
positron emission tomography (PET) 
imaging. 
Revised as MZL may have 
fluorodeoxyglucose (FDG) 
avidity. 
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TAK-007 
 
Study No. TAK-007-2001 
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Protocol Incorporating Amendment No. 5 
03 June 2024 
 
CONFIDENTIAL 
Protocol Amendment 3 
Summary of Changes Since Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by 
Change 
Description of Each Change and Rationale 
 
Location 
Description 
Rationale 
14. 
Section 9.4.2 
Conditioning Phase 
(Day -5 to Day -1)  
Added wording that patients with 
symptomatic SARS-CoV2 infection 
must not initiate lymphodepleting 
chemotherapy. 
Revised for clarity. 
15. 
Section 9.4.2 
Conditioning Phase 
(Day -5 to Day -1)  
Section 9.4.15 
Clinical Laboratory 
Evaluations  
Replaced creatinine clearance with 
estimated glomerular filtration rate 
(GFR) in the “NOTE” defining 
lymphodepleting chemotherapy 
administration in Section 9.4.2 and in 
text in Section 9.4.15. 
Revised for accuracy. 
16. 
Section 9.4.16 
Disease Assessments  
Removed mention of response 
assessment by independent central 
review as it is not being done in Part 1 
of this study. 
Updated text to reduce exposure to PET 
scans beyond 6 months posttreatment. 
Added recommendation to avoid 
scheduling imaging scans and SARS-
CoV-2 vaccination or booster within 
2 weeks of each other. 
Revised for clarity regarding 
timing of imaging for disease 
assessment and what scans to 
perform. 
 
Revised to reduce exposure to 
PET imaging for patients who do 
not have FDG-avid disease. 
Added recommendation to avoid 
possible confounding observations 
on imaging scans, as SARS-CoV-
2 vaccination has been shown to 
cause transient lymphadenopathy 
that may make mimic that of 
lymphoma. 
17. 
Section 9.4.17.1 
Primary Specimen 
Collection  
Added language that blood samples 
should be drawn before dosing on days 
when lymphodepleting chemotherapy is 
administered. 
Revised for clarity. 
18. 
Appendix A, 
Schedule of Events 
Tables 1  
Reduced vital signs and oxygen 
saturation (SpO2) assessments from 
daily to Day (D)1, D2, D3, and D7. 
Revised as a limited risk of acute 
toxicity by CAR-NK treatment is 
expected and to reduce patient 
burden. 
19. 
Appendix A, 
Schedule of Events 
Tables 2 
Removed Month (M)36 and M48 
circulating tumor DNA (ctDNA) sample 
collection. 
Revised to reduce sampling. 
20. 
Appendix A, 
Schedule of Events 
Tables 2, Footnote d 
Added new footnote for additional 
ctDNA sample to be drawn at time of 
documented progression of disease. 
Revised for clarity. 
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Study No. TAK-007-2001 
Page 140 of 144 
Protocol Incorporating Amendment No. 5 
03 June 2024 
 
CONFIDENTIAL 
Protocol Amendment 3 
Summary of Changes Since Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by 
Change 
Description of Each Change and Rationale 
 
Location 
Description 
Rationale 
21. 
Appendix J IWG 
2014 (Lugano) 
Response Criteria for 
Lymphoma 
Replaced baseline with nadir and added 
PET 5-point scale.  
Revised for accuracy and clarity.  
 
Protocol Amendment 2 Summary and Rationale: 
This section describes the changes to the protocol incorporating Amendment 2.  
The primary reason for this amendment is to provide additional guidance for severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2) testing and management in cellular therapy 
patients.  
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification and administrative purpose only. 
Protocol Amendment 2 
Summary of Changes Since Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by 
Change 
Description of Each Change and Rationale 
 
Location 
Description 
Rationale 
1. 
Section 8.3 Permitted 
Concomitant 
Medications and 
Procedures 
Added premedications to permitted 
medications and procedures. 
Revised for clarity. 
2. 
Section 9.4.1 
Screening Phase (Day 
-33 to Day -6) 
Section 9.4.15 
Clinical Laboratory 
Evaluations 
Appendix A Schedule 
of Events (SOE) 
Extended polymerase chain reaction 
(PCR) test window for SARS-CoV-2 
from within 7 days to within 10 days of 
lymphodepleting chemotherapy 
initiation and included guidance for 
SARS-CoV-2 testing prior to cellular 
therapy. 
Revised to allow better planning 
of treatment schedules and 
included guidance for SARS-
CoV-2 testing prior to cellular 
therapy. 
3. 
Section 10.3 
Monitoring of AEs 
and Period of 
Observation 
Revised adverse event (AE) collection 
language to specify that, for patients 
who receive lymphodepletion 
chemotherapy but do not go on to 
receive TAK-007, all AEs will be 
collected for the first 30 days following 
lymphodepleting chenotherapy and that 
after that, only treatment-related AEs 
would be collected. 
Revised for clarity. 
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TAK-007 
 
Study No. TAK-007-2001 
Page 141 of 144 
Protocol Incorporating Amendment No. 5 
03 June 2024 
 
CONFIDENTIAL 
Protocol Amendment 2 
Summary of Changes Since Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by 
Change 
Description of Each Change and Rationale 
 
Location 
Description 
Rationale 
4. 
Section 14.1 Study-
Site Monitoring 
Visits 
Added statement regarding remote site 
monitoring. 
Revised to allow improved site 
monitoring. 
5. 
Appendix A Schedule 
of Events Tables 1, 2, 
and 3 
Deleted statement in table notes 
regarding visit windows. 
Revised for clarity. 
 
Protocol Amendment 1 Summary and Rationale: 
This section describes the changes to the protocol incorporating Amendment 1. 
The primary reason for this amendment was to address the changes requested by United States 
(US) Food and Drug Administration (FDA) during the Investigational New Drug (IND) 
application 27322 review.  
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification and administrative purpose only. 
Protocol Amendment 1 
Summary of Changes Since Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by 
Change 
Description of Each Change and Rationale 
 
Location 
Description 
Rationale 
1. 
Throughout protocol  
TAK-007 dose of 800 × 106 (30%) 
was revised to 800 × 106 (25%) 
 
 
 
Removed “safety run-in” from Part 1 
references as Part 1 includes 
assessments other than safety 
assessments. 
Changes made in response to 
Food and Drug Administration’s 
(FDA’s) request for a tighter dose 
range. 
 
Changes made for accuracy. 
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TAK-007 
 
Study No. TAK-007-2001 
Page 142 of 144 
Protocol Incorporating Amendment No. 5 
03 June 2024 
 
CONFIDENTIAL 
Protocol Amendment 1 
Summary of Changes Since Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by 
Change 
Description of Each Change and Rationale 
 
Location 
Description 
Rationale 
2. 
Section 2.0 STUDY 
SUMMARY 
Section 6.1 Overview 
of Study Design 
Section 9.3 Treatment 
Group Assignments 
Part 1 of study is redesigned to be a 
sequential dose escalation guided by 
Bayesian Optimal Interval (BOIN) 
design followed by expansion cohorts 
to select the recommended phase 2 
dose (RP2D). Separate expansion 
cohorts for large B-cell lymphoma and 
indolent non-Hodgkin lymphoma with 
approximately 15 patients each may be 
initiated for dose level(s) selected 
based on the dose escalation part, to 
further evaluate the safety, tolerability, 
efficacy and cellular kinetics and to 
allow the selection of the RP2D to be 
used in the rest of the study. 
Changes made in response to 
FDA’s request for a sequential, 
dose escalation study design. 
3. 
Section 2.0 STUDY 
SUMMARY 
Section 6.1 Overview 
of Study Design 
Part 1 of the study, the 7-day interval 
between the first and second patient in 
each dose level has been increased to a 
21-day interval, and a new 28-day 
interval has been added between the 
2 dose cohorts in Part 1 to allow for 
dose-limiting toxicity (DLT) 
assessment.  
Changes made in response to 
FDA’s request for additional time 
between the first 2 patients dosed 
and between dose cohorts to 
allow for safety monitoring and 
DLT assessment. 
4. 
Section 2.0 STUDY 
SUMMARY 
Section 7.1 Inclusion 
Criteria 
Revised inclusion criterion # 6.e and 
deleted #6.f to indicate that single 
agent anti-CD20 mAb therapy is not 
considered a line of therapy for all 
patients (ie, both LBCL and iNHL). 
Changes made per FDA 
recommendation. 
5. 
Section 2.0 STUDY 
SUMMARY 
Section 6.1 Overview 
of Study Design 
Section 8.4 
Precautions and 
Restrictions 
All references to the use of institutional 
guidelines have been removed from the 
protocol and only CAR-T cell therapy-
associated TOXicity (CARTOX) 
guidelines will be used for the 
management of cytokine release 
syndrome (CRS) and immune effector 
cell-associated neurotoxicity syndrome 
(ICANS). 
Changes made to simplify and 
standardize CRS and ICANS 
management. 
6. 
Section 2.0 STUDY 
SUMMARY 
Section 6.2 Number 
of Patients 
Section 13.2 
Determination of 
Sample Size 
Number of patients in Part 1 has been 
revised to reflect BOIN dose escalation 
design followed by expansion cohorts. 
Changes made in response to 
FDA’s request for sequential, 
dose escalation design. 
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TAK-007 
 
Study No. TAK-007-2001 
Page 143 of 144 
Protocol Incorporating Amendment No. 5 
03 June 2024 
 
CONFIDENTIAL 
Protocol Amendment 1 
Summary of Changes Since Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by 
Change 
Description of Each Change and Rationale 
 
Location 
Description 
Rationale 
7. 
Section 2.0 STUDY 
SUMMARY 
Study enrollment period was revised to 
match the study enrollment period in 
Section 6.3. 
Change was made to correct prior 
error in the Study Summary. 
8. 
Section 2.0 STUDY 
SUMMARY 
Section 13.2 
Determination of 
Sample Size 
Sample size was revised to reflect the 
dose escalation design followed by 
expansion cohorts. 
Changes made per FDA 
recommendation. 
9. 
Section 8.6 Definition 
of DLTs 
DLT definition revised to clarify and 
include nonhematologic treatment-
emergent adverse events (TEAEs) 
Grade ≥3 clearly unrelated to the 
underlying disease and at least possibly 
related to the investigational therapy 
(TAK-007 and/or lymphodepletion). 
 
Added acute graft-versus-host disease 
(GvHD) Grade 2 requiring systemic 
steroids and not resolving within 7 
days to definition of DLTs. 
Change made in response to 
FDA’s request for inclusion of 
TEAEs at least possibly related 
to TAK-007 and/or 
lymphodepletion. 
 
 
 
 
 
Change made in response to 
FDA's request for inclusion of 
Grade 2 acute GvHD not 
resolving within 7 days to 
definition of DLTs.  
10. 
Section 8.7 
Enrollment Pausing 
Criteria 
Revised enrollment pausing criteria. 
Changes made in response to 
FDA’s request for clarification 
and revision of enrollment 
pausing criteria. 
11. 
Section 13.3 Analysis 
Sets 
Added per-protocol set 
Change made to clarify that per-
protocol set would be used for 
additional supportive analysis of 
overall response rate (ORR) in 
Part 2 of the study. 
12. 
Section 13.5 Efficacy 
Analyses 
Added statement regarding ORR 
analysis in Part 2 of study. 
Change made to clarify that ORR 
in Part 2 will be analyzed in the 
per-protocol set as supportive 
analysis. 
13. 
Section 13.6 Safety 
Analysis 
 
Deleted “TEAEs leading to study 
discontinuation” bullet from tabulated 
AEs categories. 
Added sentence to reflect the DLT 
assessment during the dose escalation. 
Change made as this does not 
apply to this study. 
 
Changes made per FDA 
recommendation. 
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TAK-007 
 
Study No. TAK-007-2001 
Page 144 of 144 
Protocol Incorporating Amendment No. 5 
03 June 2024 
 
CONFIDENTIAL 
Protocol Amendment 1 
Summary of Changes Since Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by 
Change 
Description of Each Change and Rationale 
 
Location 
Description 
Rationale 
14. 
Section 13.12 
Statistical 
Considerations for 
Dose Selection at the 
End of Part 1 
Deleted this section. 
Change made as it no longer 
applies to the new study design to 
address the comments by the 
FDA. 
15. 
Appendix T BOIN 
Design 
Added BOIN Design appendix to 
provide further details regarding BOIN 
study design. 
Change made as part of response 
to FDA’s request for revised Part 
1 study design. 
16. 
Appendix U 
CARTOX Guidelines 
for the Management 
of CRS and ICANS 
Added CARTOX Guidelines appendix. 
Change made for investigator 
convenience. 
 
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Signature Page for TAK-007-2001 Protocol Amend 5
Title: TAK-007-2001 Protocol Amend 5
Document Number: TDN-000350636 v3.0
Approval
Research
10-Jul-2024 16:51:05 GMT+0000
Approval
Statistics
10-Jul-2024 16:58:52 GMT+0000
Approval
Clinical
10-Jul-2024 17:34:20 GMT+0000
Approval
Pharmacovigilance
10-Jul-2024 18:01:15 GMT+0000
Approval
Clinical
11-Jul-2024 07:00:13 GMT+0000
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