Clinical trial NCT04074330
Conditions: Lymphoma, Non-Hodgkin
Keywords: Drug Therapy
Sponsor: Takeda
Start date: 2019-10-15; Completion date: 2023-04-26
Enrollment: 38 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This study is about a medicine called TAK-981 given with rituximab, used to treat adults with relapsed or refractory CD20-positive non-Hodgkin lymphoma.

This study has 2 parts.

The main aims of the study are:

* To check for side effects from treatment with TAK-981 given with rituximab.
* To check how much TAK-981 participants can tolerate.
* To check if participants with diffuse large B-cell lymphoma or follicular lymphoma respond well to treatment.

Participants will receive TAK-981 and rituximab in 21-day cycles. They will continue treatment for about 12 months unless their condition gets worse (disease progression), they cannot tolerate the treatment, or they leave the study for certain reasons.

Detailed description:
The drug being tested in this study is called TAK-981 in combination with rituximab. The study will include a dose escalation phase (Phase 1) and an expansion phase in select non-Hodgkin lymphoma (NHL) indications (Phase 2).

The study will enroll approximately 180 participants, approximately 35 participants in Phase 1 and approximately 145 participants in Phase 2. The participants with indolent or aggressive relapsed or refractory (r/r) NHL in Phase 1 will identify the maximum tolerated dose (MTD) and/or pharmacologically active dose (PAD). PAD can be defined retrospectively once MTD is reached and it can below MTD or coincide with it. In the dose escalation phase, the starting dose of TAK-981 will be 10 mg. The RP2D will be determined based on the available safety, preliminary pharmacokinetic (PK), pharmacodynamic information data, and after any early antitumor activity observed along with the statistical inference from the Bayesian logistic regression modeling (BLRM).

Participants in the Phase 2 will be enrolled once the Phase 1 of the study is completed, and MTD and/or PAD is determined. Phase 2 will explore the efficacy and safety of TAK-981 in combination with rituximab in participants with select NHL types and indications. Participants in Phase 2 will be enrolled in one of the three treatment arms based on Cohorts:

* Phase 2, Cohort A r/r DLBCL Progressed after CAR T-cell therapy:TAK-981+Rituximab
* Phase 2, Cohort B:r/r DLBCL;no CAR T-cell Therapy;2-3 Prior Lines: Two Dose Levels of TAK-981+Rituximab
* Phase 2, Cohort C:r/r FL;no CAR T-cell Therapy;2-3 Prior Lines: Two Dose Levels of TAK-981+Rituximab

This multi-center trial will be conducted worldwide. The overall time to participate in this study is approximately 72 months. Participants will make multiple visits to the clinic, and will attend the end of treatment (EOT) visit 30 days after receiving their last dose of drug or before the start of subsequent systemic anticancer therapy, whichever occurs first for a follow-up assessment.

Arms: arm 1: Participants with indolent or aggressive non-Hodgkin lymphoma (NHL) received TAK-981 10 mg, infusion, intravenously (IV), once weekly (QW) on Days 1 and 8 every 21 days in each 21-day treatment cycle in combination with rituximab 375 milligram per square meter (mg/m\^2), infusion, IV, once on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or disease progression (PD) or unacceptable toxicity. arm 2: Participants with indolent or aggressive NHL received TAK-981 40 mg, infusion, IV, QW on Days 1 and 8 every 21 days in each 21-day treatment cycle in combination with rituximab 375 mg/m\^2, infusion, IV, once on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or PD or unacceptable toxicity. arm 3: Participants with indolent or aggressive NHL received TAK-981 60 mg, infusion, IV, QW on Days 1 and 8 every 21 days in each 21-day treatment cycle in combination with rituximab 375 mg/m\^2, infusion, IV, once on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or PD or unacceptable toxicity. arm 4: Participants with indolent or aggressive NHL received TAK-981 90 mg, infusion, IV, QW on Days 1 and 8 every 21 days in each 21-day treatment cycle in combination with rituximab 375 mg/m\^2, infusion, IV, once on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or PD or unacceptable toxicity. arm 5: Participants with indolent or aggressive NHL received TAK-981 90 mg, infusion, IV, BIW on Days 1, 4, 8, and 11 every 21 days in each 21-day treatment cycle in combination with rituximab 375 mg/m\^2, infusion, IV, once on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or PD or unacceptable toxicity. arm 6: Participants with indolent or aggressive NHL received TAK-981 120 mg, infusion, IV, QW on Days 1 and 8 every 21 days in each 21-day treatment cycle in combination with rituximab 375 mg/m\^2, infusion, IV, once on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or PD or unacceptable toxicity. arm 7: Japanese participants with indolent or aggressive NHL received TAK-981 60 mg, infusion, IV, QW on Days 1 and 8 every 21 days in each 21-day treatment cycle in combination with rituximab 375 mg/m\^2, infusion, IV, once on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or PD or unacceptable toxicity. arm 8: Japanese participants with indolent or aggressive NHL received TAK-981 60 mg, infusion, IV, BIW on Days 1, 4, 8, and 11 every 21 days in each 21-day treatment cycle for up to 12 months or PD or unacceptable toxicity. arm 9: Participants with relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL) received TAK-981 120 mg, infusion, IV, QW on Days 1 and 8 every 21 days in each 21-day treatment cycle in combination with rituximab infusion, intravenously, once on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or PD or unacceptable toxicity. arm 10: Participants with follicular lymphoma (FL) received TAK-981 120 mg, infusion, IV, QW on Days 1 and 8 every 21 days in each 21-day treatment cycle in combination with rituximab infusion, intravenously, once on Days 1, 8, and 15 of Cycle 1 and then on Day 1 of each 21-day treatment cycle from Cycle 2 for up to 12 months or PD or unacceptable toxicity.
Interventions: intervention 1: TAK-981 intervention 2: Rituximab
Intervention descriptions: intervention 1: TAK-981 intravenous infusion. intervention 2: Rituximab intravenous infusion.

Protocol documents:
Prot_000.pdf: 
For non-commercial use only


 
 
PROTOCOL
Phase 1/2 Study of TAK-981 in Combination With Rituximab in Patients With 
Relapsed/Refractory CD20-Positive Non-Hodgkin Lymphoma
Sponsor:
Takeda Development Center Americas, Inc. (TDC Americas) 
95 Hayden Avenue
Lexington, MA 02421
Please note: Takeda Development Center Americas, Inc. (TDC Americas) may be 
referred to in this protocol as “sponsor” or “Takeda”.
Study Number:
TAK-981-1501
EudraCT Number:
2020-003946-36
Compound:
TAK-981
Date:
20 May 2022
Amendment Number:
8
Date
Amendment Number
Region
20 May 2022
Amendment 8
Global
04 October 2021
Amendment 7
Global
02 September 2021
Amendment 6
Global
31 March 2021
Amendment 5
Global
20 January 2021
Amendment 4
Global
18 June 2020 
Amendment 3
Global
27 January 2020
Amendment 2
Global
19 July 2019
Amendment 1
Global
04 June 2019
Original protocol
United States and Canada
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by 
the recipient that no information contained herein will be published or disclosed without written authorization from 
Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduct of the study.
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1.0
ADMINISTRATIVE 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 subject.
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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1.3
Protocol Amendment 8 Summary of Changes and Rationale for Amendment
This section describes the changes to the protocol incorporating Amendment 8.
The primary reason for this amendment was to expand Phase 2 enrollment in Cohorts B and C in 
order to evaluate two dose levels, 120 mg and 60 mg QW. This will add an additional 50 patients to 
the original Phase 2 (25 patients each to Cohort B and C). This data will be used to generate 
supplementary efficacy, safety, and exposure/response data to inform dose selection for further 
development of TAK-981. New study schematics for Phase 2 of the TAK-981-1501 study are
provided in Figure 6.d (Cohort A), Figure 6.e (Cohort B), and Figure 6.f (Cohort C).
Patients enrolled in China will join Phase 2 part of the study, details about China-specific 
requirements are integrated into this amendment. The major difference between patients enrolled 
in China and patients enrolled from rest of the world is that selected exploratory assessments are 
removed for patients enrolled in China, related changes are listed in the following table.
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification and administrative purposes only.
Protocol Amendment 8
Summary of Changes Since the Last Version of the Approved Protocol
Change 
Number
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
Expansion of Phase 2 Enrollment in Cohorts B and C
1
Section 2.0 STUDY 
SUMMARY, Study Design
Section 8.2 Definitions of DLT
for Phase 1 Only
Section 8.3 Definition of 
DLT-Evaluable Patients for 
Phase 1 Only
Section 8.5 Dose-Escalation 
Rules for Phase 1 Only
Removed itemized list of dose-limiting 
toxicities (DLT) criteria and added 
reference to the protocol for details.
Added “for Phase 1 Only” to the title of 
Section 8.2, 8.3, and 8.5.
Update 
2
Section 4.2.5 Clinical 
Experience
Updated clinical experience with Phase 1 
data to support the Phase 2 design.
Update
3
Section 4.4.1.1 TAK-981, 
Rationale for the RP2D of 
TAK-981 in this Combination 
Study:
Updated to provide the rationale for the 
2 dose levels, 60 mg and 120 mg once 
weekly (QW), selected for the Phase 2 
Cohorts B and C.
Update
4
Section 2.0 STUDY 
SUMMARY, Study Design, and
Dose Levels (in Phase 1 and 
Phase 2)
Added text describing that the Phase 2 
design will include 2 dose levels of 
TAK-981 only for Cohorts B and C. 
Update
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Protocol Amendment 8
Summary of Changes Since the Last Version of the Approved Protocol
Change 
Number
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
5
Section 6.3 Phase 2 Study 
Design
Figure 6.b TAK-981-1501: 
Schedule for TAK-981 Once 
Weekly and Rituximab Dosing
Figure 6.c TAK-981-1501 Study 
Schematic of Phase 1 and Phase 
2
Figure 6.d TAK-981-1501 Study 
Schematic for Phase 2 Cohort A
Figure 6.e TAK-981-1501 Study 
Schematic for Phase 2 Cohorts B
120 mg and B 60 mg
Figure 6.f TAK-981-1501 Study 
Schematic for Phase 2 Cohorts C 
120 mg and C 60 mg
Updated and clarified the overview of the 
study design in Figure 6.b and Figure 6.c. 
Added new Figure 6.d, Figure 6.e, and 
Figure 6.f, for the study design of Cohort 
A, Cohorts B 120 mg and B 60 mg, and 
Cohorts C 120 mg, and C 60 mg, 
respectively.
Clarification
6
Section 2.0 STUDY 
SUMMARY, Number of 
Subjects, and
Sample Size Justification
Section 6.4 Number of Patients 
and Sites
Section 13.3 Determination of 
Sample Size
Added text noting the addition of 
approximately 25 patients to each of the 
2 new doses within Cohorts B and C. 
Updated the total number of patients to 
180 accordingly.
Update
7
Section 13.3 Determination of 
Sample Size, 
Efficacy-Evaluation Phase 
(Phase 2)
Added text to clarify the number of 
patients for Cohorts B and C considering 
evaluation of a second dose-level.
Update
Requirements for Patients enrolled in China versus in the Global Study
8
Section 2.0 STUDY 
SUMMARY, Study Design
Inclusion Criteria, #11
Section 4.4.2.1 Tumor Biopsies
Section 6.3 Phase 2 Study 
Design
Section 7.1 Inclusion Criteria, 
criterion #11
Section 9.4.16.1 Tumor Biopsies
(Global Study; Not Applicable 
to Patients Enrolled in China)
Added text that patients in China will 
participate only in the Phase 2 part.
Updated text to clarify that tumor 
tissue/archival tissue will not be 
applicable for patients in China.
Clarification 
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INVESTIGATOR AGREEMENT
I confirm that I have read and that I understand this protocol, the investigator’s brochure (IB), 
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 study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Council for Harmonisation (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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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 8 Summary of Changes and Rationale for Amendment ............4
2.0
STUDY SUMMARY ....................................................................................................15
3.0
STUDY REFERENCE INFORMATION ......................................................................22
3.1
Study-Related Responsibilities.................................................................................22
3.2
Principal Investigator...............................................................................................22
3.3
List of Abbreviations ...............................................................................................23
3.4
Corporate Identification...........................................................................................25
4.0
INTRODUCTION.........................................................................................................26
4.1
Non-Hodgkin Lymphoma ........................................................................................26
4.1.1
Follicular Lymphoma ......................................................................................26
4.1.2
Diffuse Large B-Cell Lymphoma.....................................................................27
4.2
TAK-981 .................................................................................................................27
4.2.1
Protein SUMOylation Biology in Cancer.........................................................27
4.2.2
Nonclinical Pharmacology...............................................................................28
4.2.3
Nonclinical PK ................................................................................................31
4.2.4
Nonclinical Toxicology ...................................................................................32
4.2.5
Clinical Experience..........................................................................................33
4.3
Rituximab................................................................................................................35
4.4
Rationale for the Proposed Study.............................................................................36
4.4.1
Rationale for the Starting Dose and Schedule...................................................36
4.4.2
Rationale for Tumor, Skin, and Blood Tissues Collection ................................38
4.5
Potential Risks and Benefits.....................................................................................39
4.5.1
Potential Effects of TAK-981 Based on TAK-981 Nonclinical and Clinical 
Studies.............................................................................................................39
4.5.2
Potential Effects of Rituximab .........................................................................43
4.5.3
TAK-981 in Combination with Rituximab .......................................................43
4.5.4
Coronavirus Disease 2019 Pandemic ...............................................................43
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................44
5.1
Objectives................................................................................................................44
5.1.1
Primary Objectives ..........................................................................................44
5.1.2
Secondary Objectives ......................................................................................44
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5.1.3
Additional/Exploratory Objectives...................................................................45
5.2
Endpoints.................................................................................................................45
5.2.1
Primary Endpoints ...........................................................................................45
5.2.2
Secondary Endpoints .......................................................................................46
5.2.3
Additional/Exploratory Endpoints....................................................................46
6.0
STUDY DESIGN..........................................................................................................47
6.1
Overview of Study Design.......................................................................................47
6.2
Phase 1 Study Design...............................................................................................48
6.3
Phase 2 Study Design...............................................................................................50
6.4
Number of Patients and Sites ...................................................................................55
6.5
Duration of Study ....................................................................................................56
6.5.1
Duration of an Individual Patient’s Study Participation....................................56
6.5.2
End of Study/Study Completion Definition and Planned Reporting..................56
6.5.3
Timeframes for Primary and Secondary Endpoints to Support Disclosures ......56
6.5.4
Total Study Duration .......................................................................................57
6.5.5
Poststudy Access .............................................................................................57
7.0
STUDY POPULATION................................................................................................58
7.1
Inclusion Criteria .....................................................................................................58
7.2
Exclusion Criteria ....................................................................................................61
8.0
STUDY DRUG .............................................................................................................62
8.1
Study Drug Administration......................................................................................62
8.1.1
Rituximab........................................................................................................63
8.1.2
TAK-981 .........................................................................................................64
8.1.3
Additional Instructions for Treatment Administration......................................64
8.2
Definitions of DLT for Phase 1 Only .......................................................................65
8.3
Definition of DLT-Evaluable Patients for Phase 1 Only...........................................67
8.4
Definition of PAD....................................................................................................67
8.5
Dose-Escalation Rules for Phase 1 Only ..................................................................67
8.6
Dose Management and Modification Guidelines......................................................69
8.6.1
Intrapatient Dose Escalation.............................................................................69
8.6.2
Criteria for Beginning or Delaying a Subsequent Treatment Cycle...................69
8.6.3
Criteria for Dose Interruption or Dose Reduction.............................................69
8.6.4
Criteria for Discontinuation of Study Treatment Due to AEs............................74
8.7
Excluded Concomitant Medications and Procedures ................................................75
8.8
Permitted Concomitant Medications and Procedures................................................75
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8.9
Precautions and Restrictions ....................................................................................76
8.10
Management of Clinical Events ...............................................................................77
8.10.1
Nausea or Vomiting.........................................................................................78
8.10.2
Diarrhea...........................................................................................................78
8.10.3
Anemia, Thrombocytopenia, or Neutropenia....................................................78
8.10.4
Infusion Site Care............................................................................................78
8.10.5
Lymphopenia and Opportunistic Infection Prophylaxis....................................79
8.10.6
IRRs ................................................................................................................79
8.10.7
CRS.................................................................................................................80
8.10.8
TLS .................................................................................................................82
8.11
Blinding and Unblinding..........................................................................................82
8.12
Description of Investigational Agents ......................................................................83
8.13
Preparation, Reconstitution, and Dispensation..........................................................83
8.14
Packaging and Labeling...........................................................................................84
8.15
Storage, Handling, and Accountability.....................................................................84
8.16
Other Protocol-Specified Materials ..........................................................................84
9.0
STUDY CONDUCT......................................................................................................84
9.1
Study Personnel and Organizations..........................................................................85
9.2
Arrangements for Recruitment of Patients................................................................85
9.3
Treatment Group Assignments.................................................................................85
9.4
Study Procedures.....................................................................................................85
9.4.1
Informed Consent ............................................................................................85
9.4.2
Patient Demographics......................................................................................86
9.4.3
Medical History...............................................................................................86
9.4.4
Physical Examination ......................................................................................86
9.4.5
Patient Height and Weight ...............................................................................86
9.4.6
ECOG Performance Status...............................................................................86
9.4.7
Vital Signs.......................................................................................................86
9.4.8
Viral Serologies...............................................................................................86
9.4.9
Pregnancy Test ................................................................................................86
9.4.10
Concomitant Medications and Procedures........................................................87
9.4.11
AEs .................................................................................................................87
9.4.12
Enrollment.......................................................................................................87
9.4.13
Cardiac Monitoring..........................................................................................87
9.4.14
Clinical Laboratory Evaluations.......................................................................88
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13.1.5
Pharmacodynamic Analysis...........................................................................104
13.1.6
PK/Pharmacodynamic Analysis.....................................................................105
13.1.7
..............................................................................105
13.1.8
Safety Analysis..............................................................................................105
13.2
Interim Analysis and Criteria for Early Termination ..............................................106
13.3
Determination of Sample Size................................................................................107
14.0
QUALITY CONTROL AND QUALITY ASSURANCE.............................................110
14.1
Study-Site Monitoring Visits .................................................................................110
14.2
Protocol Deviations................................................................................................110
14.3
Quality Assurance Audits and Regulatory Agency Inspections ..............................111
15.0
ETHICAL ASPECTS OF THE STUDY......................................................................111
15.1
IRB Approval ........................................................................................................111
15.2
Patient Information, Informed Consent, and Patient Authorization.........................112
15.3
Patient Confidentiality ...........................................................................................113
15.4
Publication, Disclosure, and Clinical Trial Registration Policy...............................114
15.4.1
Publication.....................................................................................................114
15.4.2
Clinical Trial Registration..............................................................................114
15.4.3
Clinical Trial Results Disclosure....................................................................114
15.5
Insurance and Compensation for Injury..................................................................115
16.0
REFERENCES............................................................................................................116
LIST OF IN-TEXT TABLES
Table 4.a
TAK-981 (All Clinical Studies): Most Frequent (≥10% of All Patients) TEAEs
..........................................................................................................................34
Table 6.a
Primary and Secondary Endpoints for Disclosures .............................................57
Table 8.a
General Dose Modification Recommendations for TAK-981 Nonhematologic 
Drug-Related AEs..............................................................................................71
Table 8.b
Dose Adjustments for TAK-981 Hematologic Drug-Related AEs ......................72
Table 8.c
TAK-981 Dose Modification Guidelines for CRS ..............................................73
Table 8.d
CRS Management Recommendations ................................................................81
Table 9.a
Clinical Chemistry and Hematology Tests..........................................................89
Table 9.b
Clinical Urinalysis Tests ....................................................................................89
Table 9.c
Immunosafety Determinations in Serum.............................................................90
Table 13.a
............................................................108
Table 13.b
.......................109
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Table 13.c
...........................110
LIST OF IN-TEXT FIGURES
Figure 6.a
TAK-981-1501: Schedules for TAK-981 Twice or Once Weekly and 
Rituximab Dosing ..............................................................................................49
Figure 6.b
TAK-981-1501: Schedule for TAK-981 Once Weekly and Rituximab Dosing ...51
Figure 6.c
TAK-981-1501 Study Schematic of Phase 1 and Phase 2 ...................................52
Figure 6.d
......................................53
Figure 6.e
...54
Figure 6.f
...55
LIST OF APPENDICES
Appendix A
Schedule of Events...........................................................................................119
Appendix B
Responsibilities of the Investigator...................................................................133
Appendix C
Investigator Consent to Use of Personal Information........................................135
Appendix D
ECOG Scale for Performance Status ................................................................136
Appendix E
Drugs That Interact With the CYP3A Family of CYPs.....................................137
Appendix F 
Examples of Clinical Inhibitors of Pgp.............................................................138
Appendix G
Examples of QTc Interval-Prolonging Agents (Phase 1 Only) ..........................139
Appendix H
Bayesian Logistic Regression Model................................................................141
Appendix I
Rituximab Prescribing Information ..................................................................144
Appendix J
Methods of Contraception Considered to be Effective......................................145
Appendix K
Recommendations for Initial Management of Electrolyte Abnormalities and 
Prevention of TLS............................................................................................146
Appendix L
Definition of TLS.............................................................................................149
Appendix M
Protocol History...............................................................................................150
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2.0
STUDY SUMMARY
Name of Sponsor(s): Takeda Development Center 
Americas, Inc. (TDC Americas)
Compound: TAK-981
Title of Protocol: Phase 1/2 Study of TAK-981 in 
Combination With Rituximab in Patients With 
Relapsed/Refractory CD20-Positive Non-Hodgkin 
Lymphoma
EudraCT No.:
2020-003946-36
Study Number: TAK-981-1501
Phase: 1/2
Study Design:
The study consists of 2 phases: Phase 1 (Dose Escalation) and Phase 2 (Expansion in select non-Hodgkin lymphoma 
[NHL] indications).
The study will consist of a screening period (Day -28 to -1), a treatment period, an end-of-treatment (EOT) visit 30 
(+10) days after the last dose occurs when treatment is discontinued for any reason, and a progression-free survival 
(PFS) follow-up period lasting until disease progression, start of the patient’s next line of therapy, or up to a maximum 
of 12 months for each patient, whichever is soonest, to monitor participants disease progression status. After the 
occurrence of progressive disease (PD) or start of alternative therapy, patients will continue to have overall survival 
(OS) follow-up visits that may be performed by phone contact. The OS information will be collected every 12 weeks 
(±1 week) after the last dose of study drug until death or the conclusion of the study, whichever occurs first.
Day 1 of the study (baseline) will be defined as the first day a patient receives TAK-981. One cycle of treatment will 
be defined as 21 days. Patients will be asked to attend clinic visits at regular intervals during the study for safety and 
efficacy assessments.
Patients will receive treatment with TAK-981 and rituximab for up to 12 months or until confirmed disease 
progression, unacceptable toxicity, or any criterion for withdrawal from the study or study drugs occurs. Treatment 
may be continued beyond disease progression, with sponsor approval, if, in the opinion of the investigator, the patient 
continues to experience clinical benefit.
Phase 1: Dose Escalation
The Phase 1 portion of the study consists of dose escalation of TAK-981 in combination with rituximab at a fixed dose 
in patients with indolent or aggressive relapsed or refractory (r/r) NHL, to identify the maximum tolerated dose 
(MTD) and/or pharmacologically active dose (PAD) and schedule of the combination. PAD can be defined 
retrospectively once MTD is reached and it can be below MTD or coincide with it (see Section 8.5).
Upon agreement with TAK-981-1501 investigators, and based on the review of the safety data of TAK-981 from the 
ongoing TAK-981-1002 single-agent study, the selected starting dose of TAK-981 in this study will be 10 mg. (Note, 
as of Protocol Amendment 6, patients are enrolling into the ≥90 mg twice weekly cohort). TAK-981 will be 
administered as a 1-hour intravenous (IV) infusion on Days 1 and 8 or Days 1, 4, 8, and 11 in cycles of 21 days. 
Alternative dosing schedules may be investigated.
Rituximab will be administered on a weekly schedule at 375 mg/m2 x 3 doses, followed by 375 mg/m2 on Day 1 of 
subsequent 21-day cycles for both indolent non-Hodgkin lymphoma (iNHL) and aggressive non-Hodgkin lymphoma 
(aNHL) patients in cycles of 21 days. Rituximab and TAK-981 will be administered IV until disease progression or 
unacceptable toxicity.
Dose escalation of TAK-981 will be guided by a Bayesian logistic regression modeling (BLRM) design with overdose 
control. The recommended Phase 2 dose (RP2D) will be determined from the collective experience in the clinic 
considering the safety data, preliminary pharmacokinetic (PK) data, preliminary pharmacodynamic data, and any 
early antitumor activity observed along with the statistical inference from the BLRM.
Toxicity will be evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE) Version 5.0, except cytokine release syndrome (CRS), which will be graded according to 
American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading for CRS. During the Phase 
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1 part of the study, dose-limiting toxicity (DLT) was defined as outlined in the protocol.
A Safety Monitoring Committee (SMC) composed of the principal investigators and sponsor clinician will regularly 
review safety data to ensure patients’ safety throughout the Phase 1 portion of the study and make decisions on dose 
escalation. Dose-escalation decisions will be made based on the DLTs meeting the criteria above that occur during the 
first 3 weeks of treatment for each patient.
For the first infusion Cycle 1, Day 1 (C1D1) of TAK-981 in combination with rituximab during dose escalation, every 
patient must be hospitalized for drug administration and observation (for a minimum of 18 hours after the end of 
TAK-981 infusion). Hospitalization is not required after the first 3 patients at a dose level or expansion of previously 
cleared dose level, and only if the risk of infusion reactions is considered low based on previous experience. If Grade 
3 or greater infusion-related reaction (IRR) or CRS are not observed at PAD or MTD, or if the safety data from the 
ongoing first-in-human TAK-981-1002 study support the removal of the requirement of hospitalization for the first 
dose of TAK-981, the decision will be made by the SMC.
Patient enrollment will be staggered between the first and second patients by 72 hours during dose escalation at all 
dose levels. At each dose level, the second and third patients can be dosed concurrently if the first patient in the cohort 
has gone through Cycle 1 Day 4 (72 hours) without clinically significant acute toxicities. If more than 3 patients are to 
be enrolled in a dose level or if de-escalation is indicated, staggering will not be required unless indicated by safety 
findings.
If infusion reactions or CRS of Grade 2 or greater are not observed at RP2D, the requirement of hospitalization for the 
first dose will be removed for the Phase 2 study.
Phase 2: Expansion in Select Indications
The Phase 2 portion of the study will explore the efficacy and safety of TAK-981 in combination with rituximab in 
patients with select r/r NHL types and indications. The following cohorts will be enrolled:

Cohort A: r/r diffuse large B-cell lymphoma (DLBCL) progressed or relapsed after chimeric antigen receptor 
(CAR) T-cell therapy (CAR-T).

Cohort B: r/r DLBCL progressed or relapsed after 2-3 prior lines of systemic therapy and no prior therapy with 
CAR T-cells.

Cohort C: r/r follicular lymphoma (FL) progressed or relapsed after 2-3 prior lines of systemic therapies.
Each cohort will be assessed separately using an adaptive 2-stage design for a single proportion. For Stage 1, each 
cohort will be analyzed when a prespecified number of patients have been enrolled and had the potential to have at 
least 1 post-treatment radiologic evaluation of the disease. If the prespecified minimal response rate is not achieved in 
the first stage for a given cohort, that cohort will be closed to enrollment. However, if a clear clinical benefit has been 
observed for patients in the cohort (eg, a majority of patients have recorded stable disease at Week 8 and no complete 
response [CR] or partial response [PR] is recorded) then enrollment into Stage 2 may be allowed for this cohort. If the 
required response rate during Stage 1 or a good clinical benefit is observed for a particular cohort as mentioned above, 
then additional patients will be enrolled in the second stage of the corresponding cohort until a predetermined number 
of additional patients for that cohort has been reached. The final analysis of the primary endpoints for each cohort will 
take place when all ongoing patients have completed the 6-month disease assessment/survival follow-up.
TAK-981 will be evaluated at a dose of 120 mg once weekly (QW) (the upper dose tested in Phase 1) as well as at the 
dose of 60 mg QW (a lower yet biologically active dose) in a 21-day cycle, both in combination with a fixed dose of 
rituximab, in the Phase 2 expansion. The dose cohorts will be: Cohorts B 120 mg/C 120 mg and Cohorts B 60 mg/C 60 
mg. This data will be used to generate supplementary efficacy, safety, and exposure/response data to inform dose 
selection for further development of TAK-981.
During Phase 2, an Independent Data Monitoring Committee will be established to monitor safety and assess 
benefit/risk throughout the conduct of the Phase 2 portion of the study.
Patients enrolled in sites in China will participate in Phase 2 of the study.
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Primary Objectives:
Phase 1:

To determine the safety and tolerability of TAK-981 in combination with rituximab in patients with r/r CD20+ 
NHL.

To establish the RP2D of TAK-981 in combination with rituximab.
Phase 2:

To evaluate the efficacy of TAK-981 in combination with rituximab in select r/r NHL indications.
Secondary Objectives:

To characterize the PK profile of TAK-981 in combination with rituximab.
Phase 1:

To determine the MTD and/or PAD of TAK-981 when administered in combination with rituximab.

To assess the preliminary antitumor activity of TAK-981-rituximab combination.

To assess target engagement of TAK-981 (small ubiquitin-like modifier [SUMO]-TAK-981 adduct formation) 
and SUMOylation pathway inhibition in blood and skin.
Phase 2:

To evaluate the efficacy of TAK-981 in combination with rituximab in select r/r NHL as measured by disease 
control rate (DCR), duration of response (DOR), time to progression (TTP), and PFS.

To evaluate the safety and tolerability of TAK-981 in combination with rituximab. 
Patient Population: Patients with r/r CD20+ aggressive NHL that have progressed on at least 1 prior regimen, or 
patients with r/r CD20+ indolent NHL that have progressed on at least 1 prior regimens and are refractory to any 
anti-CD20 monoclonal antibody.
Number of Subjects: A total of up to approximately 
180 patients will be enrolled in the study.
Phase 1: Approximately 35 DLT-evaluable patients.
Phase 2: Approximately 145 response-evaluable patients.
Number of Sites:
Estimated total: Approximately 12 sites in Phase 1 
and up to a total of approximately 70 sites in the 
United States, Canada, European Union, Asia, and/or 
globally.
Dose Levels:
Phase 1: TAK-981 at 10, 15, 25, 40, 60, 90, 120, and 160 mg. 
Intermediate dose levels can be explored in escalation or 
de-escalation without amending the protocol.
Phase 2: 

Cohort A: 120 mg TAK-981 QW on Days 1 and 8 of
each 21-day cycle

Cohorts B and C, each: 60 or 120 mg TAK-981 QW 
on Days 1 and 8 of each 21-day cycle
Rituximab: 375 mg/m2.
Route of Administration:
TAK-981: IV
Rituximab: IV
Duration of Treatment:
Patients will continue treatment until any of the 
discontinuation criteria are met. If no discontinuation 
criterion is met, patients can continue receiving TAK-981 for 
1 year. After 1 year, patients with clinical benefit can 
continue treatment if approved by the sponsor.
Period of Evaluation: Approximately 72 months.
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Main Criteria for Inclusion:
1.
Adults ≥18 years old.
2.
Patient populations:
a)
For Phase 1 Dose Escalation:

aNHL including mantle cell lymphoma and DLBCL histologies such as transformed DLBCL from 
low-grade lymphoma (follicular or others), DLBCL associated with small-cell infiltration in bone 
marrow, B-cell lymphoma with intermediate features between DLBCL and Burkitt’s lymphoma or with 
intermediate features between DLBCL and Hodgkin lymphoma, FL Grade 3B, and aggressive B-cell 
lymphoma unclassifiable who must have previously received rituximab, cyclophosphamide, doxorubicin 
(hydroxydaunorubicin), vincristine (Oncovin) and prednisone (R-CHOP) (or equivalent anti-CD20 
containing therapy) and 1 additional line of therapy in the r/r setting.

iNHL (including FL of Grades 1-3A and marginal zone lymphoma) refractory to rituximab or to any 
other anti-CD20 monoclonal antibody, who have received at least 1 prior systemic therapy for r/r iNHL:
–
Rituximab or anti-CD20 refractoriness is defined as failure to respond to, or progression during, any 
previous rituximab/anti–CD20-containing regimen (monotherapy or combined with chemotherapy), 
or progression within 6 months of the last rituximab or anti-CD20 dose.
NOTE: The minimum qualifying rituximab/anti-CD20 dose is 1 full cycle (ie, weekly x 4 doses 
monotherapy or 1 complete dose if combined with chemotherapy). Prior anti-CD20 antibody or 
cytotoxic drugs may have been administered as single agents or as components of combination
therapies. Each repeated course of the same single agent or combination is considered an 
independent regimen.
b)
For Phase 2, the following confirmed CD20 positive:

r/r DLBCL progressed or relapsed after a prior CAR-T that has received approval by a health authority 
for the treatment of DLBCL (Cohort A).

r/r DLBCL that has progressed or relapsed after at least 2 but no more than 3 prior lines of systemic 
therapy and has not received prior cellular therapy. At least one prior line of therapy must have included 
a CD20-targeted therapy (Cohort B).

r/r FL that has progressed or relapsed after at least 2 but no more than 3 prior lines of systemic therapy. At 
least one prior line of therapy must have included a CD20-targeted therapy (Cohort C).
3.
Patients must be considered ineligible for, in the opinion of the investigator, or must have refused autologous 
stem-cell transplantation (ASCT).
4.
Eastern Cooperative Oncology Group performance score of ≤2.
5.
Adequate bone marrow function per local laboratory reference range at screening as follows:

Platelet count ≥75.0 × 109/L, Grade 2 thrombocytopenia (platelet count ≥50.0 × 109/L) is allowed if it is 
clearly due to marrow involvement with no evidence of myelodysplastic syndrome or hypoplastic bone 
marrow if found. Absolute neutrophil count (ANC) ≥1.0 × 109/L. Hemoglobin ≥85 g/L (red blood cell 
transfusion allowed ≥14 days before assessment).
6.
Adequate renal and hepatic function, per local laboratory reference range at screening as follows:

Calculated creatinine clearance ≥30 mL/min calculated with Cockcroft–Gault formula.

Potassium levels ≥ lower limit of normal. For potassium > upper limit of normal (ULN) discussion with 
Takeda medical monitor/designee recommended.

Aspartate aminotransferase and alanine aminotransferase ≤3.0× the ULN of the institution’s normal range; 
bilirubin ≤1.5 × ULN. Patients with Gilbert’s syndrome may have a bilirubin level >1.5 × ULN, per 
discussion between the investigator and the medical monitor.
7.
Left ventricular ejection fraction ≥40%; as measured by echocardiogram or multiple gated acquisition scan.
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8.
Suitable venous access for safe drug administration and the study-required PK and pharmacodynamic sampling.
9.
Have at least 1 bidimensionally measurable lesion per Lugano Classification (eg, measurable node >1.5 cm in its 
largest dimension; measureable extranodal lesion >1.0 cm in longest diameter) by computed tomography (CT). 
Tumor lesions situated in a previously irradiated area are considered measurable if progression has been 
demonstrated in such lesions.
10. Willing to consent to 1 mandatory pretreatment and 1 on-treatment skin biopsy during Phase 1. The skin biopsy 
entry requirement may be discontinued by the sponsor once there is enough pharmacodynamic evidence of target 
engagement.
11. For patients enrolled in Phase 2, if available, mandatory submission of archival tumor tissue acquired ≤12 months 
prior to screening. Tumor tissue, including archival tissue, is not applicable to patients enrolled in China.
12. Recovered to Grade 1, baseline or established as sequela, from all toxic effects of previous therapy (except 
alopecia, neuropathy, autoimmune endocrinopathies with stable endocrine replacement therapy, neurotoxicity 
[Grade 1 or 2 permitted], or bone marrow parameters [any of Grade 1, 2, permitted if directly related to bone 
marrow involvement]).
13. Women of childbearing potential participating in this study should avoid becoming pregnant, and male patients 
should avoid impregnating a female partner. Nonsterilized female patients of reproductive age and male patients 
should use effective methods of contraception through defined periods during and after study treatment as 
specified below. Female patients must meet 1 of the following:

Postmenopausal for at least 1 year before the screening visit, or

Surgically sterile, or

If they are of childbearing potential, agree to practice 1 highly effective method and 1 additional effective 
(barrier) method of contraception at the same time, from the time of the signing of the informed consent form 
through 12 months after the last dose of study drug, or

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. 
(Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], withdrawal, 
spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male 
condoms should not be used together.)
14. Male patients, even if surgically sterilized (ie, status postvasectomy) must agree to 1 of the following:

Agree to practice effective barrier contraception during the entire study treatment period and through 
12 months after the last dose of study drug, or

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. 
(Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], withdrawal, 
spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male 
condoms should not be used together.)
15. Subject has provided informed consent.
16. Must be willing and able to comply with clinic visits and procedures outlined in the study protocol.
Main Criteria for Exclusion:
1.
Central nervous system lymphoma; active brain or leptomeningeal metastases, as indicated by positive cytology 
from lumbar puncture or CT scan/magnetic resonance imaging.
2.
Hypersensitivity to TAK-981, rituximab, or any component of the drug product.
3.
History of Grade ≥3 IRR that lead to permanent discontinuation of previous rituximab treatment.
4.
Previous participation in the TAK-981-1002 clinical study.
5.
Posttransplantation lymphoproliferative disease except relapsed NHL after ASCT.
6.
Undergone ASCT or treatment with cellular therapy including CAR T within ≤12 weeks of TAK-981 dosing.
7.
Prior allogeneic hematopoietic stem-cell transplantation.
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8.
Lymphomas with leukemic expression.
9.
Prior anticancer therapy including chemotherapy, hormonal therapy, or investigational agents within 2 weeks or 
within at least 5 half-lives before TAK-981 dosing, whichever is shorter. Low dose steroids (oral prednisone or 
equivalent ≤20 mg per day), hormonal therapy for prostate cancer or breast cancer (in adjuvant situation), and 
treatment with bisphosphonates and RANKL (receptor activator of nuclear factor kappa-B ligand) inhibitors are 
allowed.
10. Major surgery within 14 days before the first dose of study drug and not recovered fully from any complications 
from surgery.
11. Significant medical diseases or conditions, as assessed by the investigators and sponsor that would substantially 
increase the risk-benefit ratio of participating in the study. This includes but is not limited to acute myocardial 
infarction or unstable angina within the last 6 months; uncontrolled diabetes mellitus; significant active bacterial, 
viral, or fungal infections; severely immunocompromised state; severe non-compensated hypertension and 
congestive heart failure New York Heart Association Class III or IV; ongoing symptomatic cardiac arrhythmias 
of >Grade 2, pulmonary embolism, or symptomatic cerebrovascular events; or any other serious cardiac condition 
(eg, pericardial effusion or restrictive cardiomyopathy). Chronic atrial fibrillation on stable anticoagulant therapy 
is allowed.
12. Known chronic hepatitis C and/or positive serology (unless due to vaccination or passive immunization due to 
immunoglobulin therapy) for chronic hepatitis B. Known HIV infection.
13. Second malignancy within the previous 3 years, except treated basal cell or localized squamous skin carcinomas, 
localized prostate cancer, cervical carcinoma in situ, resected colorectal adenomatous polyps, breast cancer in 
situ, or other malignancy for which the patient is not on active anticancer therapy as defined in Exclusion 
Criterion 9.
14. Receipt of any live vaccine within 4 weeks of initiation of study treatment.
15. Active, uncontrolled autoimmune disease requiring >20 mg of prednisone or equivalent, cytotoxics, or 
biologicals.
16. Corticosteroid use within 1 week before first dose of study drug, except as indicated for other medical conditions 
such as inhaled steroid for asthma, topical steroid use, or as premedication for administration of study drug or 
contrast. Patients requiring steroids at daily doses >20 mg prednisone equivalent systemic exposure daily, or 
those who are administered steroids for lymphoma control or white blood cell count lowering are not eligible.
17. History of medical or psychiatric illness likely to interfere with ability to comply with protocol requirements or 
give informed consent.
18. Patients with baseline prolongation of the QT interval with Fridericia correction method (QTcF) (eg, >470 ms for 
women and >450 ms for men and a history of congenital long QT syndrome or torsades de pointes).
19. Receiving or requiring the continued use of medications that are known to be strong or moderate inhibitors and 
inducers of cytochrome P-450 (CYP)3A4/5 and strong P-glycoprotein (Pgp) inhibitors. To participate in this 
study, such patients should discontinue use of such agents for at least 2 weeks (1 week for CYP3A4/5 and Pgp 
inhibitors) before receiving a dose of TAK-981.
20. Female patients who are lactating and breastfeeding or have a positive urine or serum pregnancy test during the 
screening period or a positive urine pregnancy test on Day 1 before first dose of study drug.
21. Patients in Germany who are committed to an institution by virtue of an order issued either by judicial or 
administrative authorities as required by German law.
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Main Criteria for Evaluation and Analyses:
The primary endpoints are:
Phase 1:

Frequency, severity, and duration of treatment-emergent adverse event (TEAEs) and laboratory abnormalities for 
all dose groups according to the NCI CTCAE, Version 5.0; except CRS which will be graded according to 
ASTCT Consensus Grading for CRS.

Occurrence of DLTs within the first 21 days of treatment in Cycle 1.
Phase 2:

Overall response rate (ORR) (CR + PR) as defined by the investigator according to Lugano Classification for 
lymphomas.
Secondary endpoints for this study are:

PK parameters after the first dose of TAK-981 on C1D1 and C1D8 (data permitting):
–
Maximum observed plasma concentration (Cmax).
–
Time of first occurrence of Cmax (tmax).
–
Area under the plasma concentration-time curve from time 0 to time t.
–
Area under the plasma concentration-time curve from time 0 to infinity.
–
Terminal disposition phase half-life.
–
Total clearance after IV administration.
–
Volume of distribution at steady state after IV administration.
Phase 1:

ORR, DCR, DOR, TTP, and PFS as assessed by the investigator according to Lugano Classification for 
lymphomas.

TAK-981-SUMO adduct formation and SUMO pathway inhibition in skin/blood.
Phase 2:

Frequency, severity, and duration of TEAEs and laboratory abnormalities for all dose groups according to the 
NCI CTCAE, Version 5.0; except CRS which will be graded according to ASTCT Consensus Grading for CRS.

DCR, DOR, TTP, and PFS as assessed by the investigator according to Lugano Classification for lymphomas. 
Statistical Considerations:
In Phase 1, only TAK-981 will be escalated. Dose escalation of TAK 981 will be cohort-based with an adaptive 
Bayesian logistic regression modeling (BLRM) guided by escalation with overdose control principle that is based on 
the posterior probability of having a DLT. The final decision on escalating to the next dose level will be taken jointly 
by the sponsor and the participating investigators according to the BLRM along with safety, clinical, PK, and 
pharmacodynamic data.
In Phase 2, the primary endpoint is ORR (CR + PR) as assessed by the investigator according to Lugano criteria for 
patients with lymphoma. The sample sizes for disease-specific patient populations will be estimated using an adaptive 
design based on Simon’s 2-stage design for a single proportion with the different hypotheses assumptions of ORR for 
disease-specific cohorts.
Sample Size Justification:
It is anticipated that up to approximately 180 patients will be enrolled in this study, including the dose-escalation phase 
(approximately 35 patients), and the 5 expansion dose cohorts for Phase 2 (up to approximately 
145 response-evaluable patients) to evaluate efficacy in patients with select lymphoma.
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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
Principal Investigator
Takeda will select a signatory coordinating investigator from the investigators who participate in 
the study. Selection criteria for this investigator will include significant knowledge of the study 
protocol, the study medication, their expertise in the therapeutic area and the conduct of clinical 
research, and study participation. The signatory coordinating investigator will be required to 
review and sign the clinical study report and by doing so agrees that it accurately describes the 
results of the study.
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3.3
List of Abbreviations
ADCC
antibody-dependent cell-mediated cytotoxicity
ADCP
antibody-dependent cell-mediated phagocytosis
AE
adverse event
ANC
absolute neutrophil count
aNHL
aggressive Non-Hodgkin Lymphoma
ASCT
autologous stem-cell transplant
ASTCT
American Society for Transplantation and Cellular Therapy
AUC0-∞
area under the plasma concentration-time curve from time 0 to infinity
AUC0-t
area under the plasma concentration-time curve from time 0 to time t
BCRP
breast cancer resistance protein
BIW
twice weekly
BLRM
Bayesian logistic regression modeling
BSA
body surface area
C1D1
Cycle 1, Day 1
C1D2
Cycle 1, Day 2
C1D8
Cycle 1, Day 8
CAR
chimeric antigen receptor
CAR-T
chimeric antigen receptor T cell therapy
CL
total clearance after intravenous administration
COVID-19
coronavirus disease 2019
CNS
central nervous system
Cmax
maximum observed plasma concentration
CR
complete response
CRA
cytokine release assay
CRS
cytokine release syndrome
CT
computed tomography
CYP
cytochrome P-450
DC
dendritic cells
DCR
disease control rate
DLBCL
diffuse large B-cell lymphoma
DLT
dose-limiting toxicity
DOR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EOT
end-of-treatment
FDA
Food and Drug Administration
FDG-PET
18fluorodeoxyglucose positron emission tomography 
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FIH
first-in-human
FL
follicular lymphoma
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
IB
investigator’s brochure
IC50
50% inhibitory concentration
ICF
informed consent form
ICH
International Council for Harmonisation
IDMC
independent data monitoring committee
IEC
independent ethics committee
IFN
interferon
Ig
immunoglobulin
IL
interleukins
iNHL
indolent non-Hodgkin lymphoma
IRB
institutional review board
IRC
independent review committee
IRR
infusion-related reaction
IV
intravenous
LVEF
left ventricular ejection fraction
MCP-1
monocyte chemotactic protein-1
MHRA
Medicines and Healthcare products Regulatory Agency
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
MUGA
multiple gated acquisition scan
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NHL
non-Hodgkin lymphoma
NK
natural killer
ORR
overall response rate
OS
overall survival
PAD
pharmacologically active dose
PBMC
peripheral blood mononuclear cell
PD
progressive disease
PET
positron emission tomography
PET-CT
positron emission tomography-computed tomography
PFS
progression-free survival
Pgp
P-glycoprotein
PJP
Pneumocystis jirovecii pneumonia
PK
pharmacokinetic(s)
PMDA
Pharmaceuticals and Medical Devices Agency, Japan
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PR
partial response
QTc
corrected QT interval
QTcF
Fridericia-corrected QT interval
QW
once weekly
R-CHOP
rituximab, cyclophosphamide, doxorubicin (hydroxydaunorubicin), vincristine (Oncovin) and 
prednisone
RANKL
receptor activator of nuclear factor kappa-B ligand
RANTES
regulated upon activation normal T-cell expressed and secreted
RBC
red blood cell
RP2D
recommended Phase 2 dose
r/r
relapsed or refractory
SAE
serious adverse event
SMC
Safety Monitoring Committee
SOE
schedule of events
STAT
within 1-hour immediately
SUMO
small ubiquitin-like modifier
SUMO1
small ubiquitin-like modifier 1
SUMO2
small ubiquitin-like modifier 2
SUMO3
small ubiquitin-like modifier 3
t1/2z
terminal disposition phase half-life
TEAE
treatment-emergent adverse events
TLS
tumor lysis syndrome
tmax
time of first occurrence of Cmax
TTP
time to progression
ULN
upper limit of normal
Vss
volume of distribution at steady state after intravenous administration
3.4
Corporate Identification
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
Non-Hodgkin Lymphoma
Non-Hodgkin lymphoma (NHL) is among the most common cancers in the United States and 
Europe with more than 70,000 and 93,000 new cases diagnosed every year, respectively (Ferlay et 
al. 2018; Siegel et al. 2018). NHL is a heterogeneous group of malignancies with varying clinical 
characteristics that are optimally managed through a range of different treatment modalities. The 
spectrum of NHL includes more indolent variants such as follicular lymphoma (FL) and marginal 
zone lymphomas, to more aggressive subtypes such as diffuse large B-cell lymphoma (DLBCL). 
While systemic chemotherapy is a mainstay of treatment for most NHL variants, antitumor 
directed monoclonal antibodies have an important role in the treatment of this disease (Oflazoglu 
and Audoly 2010). Monoclonal antibodies such as rituximab, which targets the B-cell antigen 
CD20, are now part of the standard treatment regimens for many B-cell NHLs (Keating 2010). 
However, once NHL becomes refractory to standard chemotherapy and antibody-based therapies, 
the overall prognosis is poor, with limited long-term survival. Thus, novel and effective therapies 
are needed to address this high unmet medical need.
This study will explore clinical proof of concept of the combination of TAK-981 with rituximab to 
treat FL and DLBCL.
4.1.1
Follicular Lymphoma
Indolent NHL (iNHL) represents 40% of all NHL subtypes, with FL occurring with the greatest 
frequency (Harris et al. 1999). iNHL presents with a broad spectrum of disease characteristics. 
Patients with FL often experience a chronic relapsing and remitting disease course and are exposed 
to several successive treatment regimens, resulting eventually in death due to disease progression. 
In general, treatment is reserved for patients who develop significant symptoms or who are 
sufficiently high-risk to merit early therapy (Gribben 2007). The most common frontline therapies 
include a combination of alkylators (including cyclophosphamide, doxorubicin, vincristine, and 
prednisone [CHOP] or bendamustine) in combination with the anti-CD20 monoclonal antibody 
rituximab. In addition, single-agent rituximab is also often administered as frontline therapy, 
particularly in patients with lower disease burden or who may not tolerate combination 
chemo-immunotherapy (Sousou and Friedberg 2010). Rituximab was originally approved for use 
in patients with relapsed and refractory FL and low-grade lymphoma.
For patients with FL who initially respond (complete response [CR] or partial response [PR]) with 
a time to progression (TTP) of at least 6 months and then experience relapse after single-agent 
rituximab, retreatment with either rituximab alone or in combination with chemotherapy is 
frequently given (Gribben 2007; Kahl et al. 2014; National Comprehensive Cancer Network 2019). 
Patients who become refractory to rituximab alone or in combination with chemotherapy have 
limited options for effective treatment. In the third line setting, treatment with phosphoinositide-3 
kinase delta inhibitors are available but are associated with significant toxicities (Gopal et al. 
2014).
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4.1.2
Diffuse Large B-Cell Lymphoma
Aggressive non-Hodgkin Lymphoma (aNHL) accounts for approximately 30% to 40% of all NHL 
(The Non-Hodgkin's Lymphoma Classification Project 1997) and DLBCL is the most common 
histological subtype (Beham-Schmid 2017). Combination chemotherapy with the addition of 
rituximab is standard of care for patients with newly diagnosed DLBCL. However, approximately 
40% of patients with DLBCL relapse following initial immunochemotherapy (Vaidya and Witzig 
2014). For eligible patients, high-dose chemotherapy, including salvage regimens such as 
rituximab, ifosfamide, carboplatin, etoposide (R-ICE), and autologous stem-cell transplantation 
(ASCT) are the treatments of choice for some patients with relapsed disease. For patients with 
disease relapse following ASCT, cell therapy with autologous chimeric antigen receptor (CAR)
T-cell targeti ng CD19 has emerged as an option, however with significant toxicity including 
cytokine release syndrome (CRS) and neurotoxicity (Neelapu et al. 2017; Schuster et al. 2019).
While various salvage regimens comprising combination chemotherapy are available for 
relapsed/refractory disease, no standard salvage regimen exists currently. An international, 
multicohort retrospective research study evaluated outcomes in relapsed or refractory (r/r) DLBCL 
(Crump et al. 2017). The overall response rate (ORR) was 26% to the next line therapy (rituximab 
containing polychemotherapy regimens), and the median overall survival (OS) was 6.3 months. 
Apart from anti-CD20 monoclonal antibodies, the development of new therapies for r/r NHL has 
been limited to immune checkpoint inhibitors in primary mediastinal B-cell lymphoma (Armand 
et al. 2018), and ibrutinib and lenalidomide in mantle cell lymphoma (Witzig et al. 2017), both low 
prevalent diseases. Therefore, there remains an unmet need for patients with DLBCL that relapse 
following cellular therapy and for those have relapsed or who are not responsive to anti-CD20 
treatment regimens. The development of more effective treatments for relapsed/refractory 
DLBCL represents a high unmet medical need.
4.2
TAK-981
TAK-981 is a first in class small molecule inhibitor of small ubiquitin-like modifier 
(SUMO)ylation.
4.2.1
Protein SUMOylation Biology in Cancer
SUMOylation is a post-translational modification that attaches a SUMO protein to protein 
substrates, regulating their activity, subcellular localization and stability (Geiss-Friedlander and 
Melchior 2007). There are 3 functional mammalian paralogues of the SUMO proteins, small 
ubiquitin-like modifier 1 (SUMO1), small ubiquitin-like modifier 2 (SUMO2), and small 
ubiquitin-like modifier 3 (SUMO3) (Gareau and Lima 2010; Geiss-Friedlander and Melchior 
2007), which are attached to their substrate proteins as monomers (SUMO1) or poly SUMO chains 
(SUMO2, SUMO3). The SUMOylation process is mediated by an enzymatic cascade similar to 
that described for ubiquitination (Geiss-Friedlander and Melchior 2007; Seeler and Dejean 2017). 
An E1 activating enzyme consisting of an SUMO-activating enzyme subunit 1/SUMO-activating 
enzyme subunit 2 heterodimer binds SUMO, generating a SUMO-SUMO-activating enzyme 
subunit 2 thioester that is transferred to SUMO-conjugating enzyme (UBC9), the sole E2 
conjugating enzyme in the pathway, following which SUMO is then covalently attached to a lysine 
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residue on target proteins by an E3 ligase. TAK-981 interrupts this cascade by forming an 
irreversible covalent adduct with SUMO, preventing its transfer from SUMO-activating enzyme to 
UBC9.
SUMOylation has been reported to regulate cellular processes important for tumor cell 
proliferation and survival (He et al. 2017; Seeler and Dejean 2017). In addition, SUMOylation has 
also been shown to play a key role in regulating innate immune responses. A net inhibitory effect 
of SUMOylation on type 1 interferon (IFN) expression has been demonstrated (Decque et al. 
2016), such that inhibiting SUMOylation by genetic means resulted in enhanced basal expression 
levels and sensitization of induction of type 1 IFNs, promoting enhanced innate immune responses 
to pathogenic stimuli. The pattern recognition receptor pathway, upstream of the transcription 
factors which promote expression of type I IFNs, has been shown to play a key role in the body’s 
tumor surveillance mechanism, activating innate immune responses that can bridge to an adaptive 
antitumor response (Woo et al. 2014). Production of type 1 IFNs promotes maturation of dendritic 
cells (DCs) and cross presentation of tumor antigens to naïve T-cells eliciting cytotoxic T-cells and 
thereby propagating an adaptive antitumor response. Central to the mechanism of action of 
TAK-981 is production of type 1 IFNs and induction of an innate immune response with activation 
of both natural killer (NK) cells and macrophages.
Initiation of a type 1 IFN response represents a strategy for modulating the cancer immunity cycle 
at its inception, differentiated from the currently approved immuno-oncology therapies, the 
immune checkpoint inhibitors, which function to disinhibit cytotoxic T-cell activity at more distal 
parts of the cycle (Chen and Mellman 2013). The full potential of leveraging type 1 IFN responses 
to stimulate antitumor immunity has yet to be realized. Direct systemic administration of IFNα is 
hampered by serious clinical toxicity. Alternative strategies to induce type 1 IFN by stimulating 
the pattern recognition receptor pathway through administration of agonists (such as stimulator of 
IFN genes protein or toll-like receptor agonists) have been largely limited to delivery by 
intratumoral injection, or topical application, indicative of toxicities associated with systemic 
administration (Adams 2009). Inhibition of SUMOylation represents a novel therapeutic strategy 
for initiating type 1 IFN responses and promoting antitumor immune responses.
Brief summaries of nonclinical pharmacology, pharmacokinetic (PK), and toxicity studies are 
provided below. More detailed information is provided in the IB.
4.2.2
Nonclinical Pharmacology
Biochemical assays demonstrated that TAK-981 is a mechanism-based inhibitor of 
SUMO-activating enzyme that potently inhibits enzyme activity by forming a covalent adduct 
with SUMO. Strong selectivity for SUMO-activating enzyme was observed over the other closely 
related ubiquitin-activating enzymes ubiquitin-activating enzyme, Nedd8-activating enzyme, and 
autophagy related 7 enzyme. Selective and potent inhibition of SUMO-activating enzyme and 
SUMOylation by TAK-981 was also demonstrated in cultured mouse and human tumor cell lines 
and the antiproliferative activity of TAK-981 was determined in a panel of 7 mouse hematologic 
and solid tumor cell lines. In ex vivo assays evaluating the activity of TAK-981 on the function of 
human monocyte derived macrophages and human NK cells (both derived from peripheral blood 
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mononuclear cells), TAK-981 increased the phagocytic activity of monocyte derived macrophages 
and increased the cytotoxicity of NK cells in both the absence and presence of the anti-CD20 
antibody rituximab. In addition, TAK-981 upregulated inflammatory markers on macrophages 
(CD80, CD86) and the activation marker CD69 and degranulation marker CD107 on NK cells. 
These activities were dependent on type 1 IFN signaling, demonstrating that TAK-981-mediated 
SUMO-activating enzyme inhibition leads to the functional activation of human macrophages and 
human NK cells via type 1 IFN signaling ex vivo. In a mouse model bearing the human OCI-Ly10 
DLBCL tumor xenograft, TAK-981 demonstrated target engagement (formation of the 
TAK-981-SUMO adduct) and pathway inhibition, inducing robust, durable, and dose-responsive 
inhibition of SUMO2/SUMO3 conjugates in tumor cells. Significant antitumor activity was 
demonstrated against OCI-Ly10 xenografts in severe combined immunodeficiency mice (lacking 
B and T cells, but with intact innate immune response) following administration of single-agent 
TAK-981 or the anti-CD20 antibody rituximab. Combination of TAK-981 with rituximab resulted 
in CRs, defined as absence of palpable tumors, in every tumor-bearing mouse treated with the 
combination. The ability of TAK-981 to promote activation of macrophages and NK cells, key 
innate effector cells which mediate the activity of anti-tumor antibodies such as rituximab, 
suggests that enhancement of antibody-dependent cell-mediated cytotoxicity (ADCC) and/or 
antibody-dependent cell-mediated phagocytosis (ADCP) may provide a mechanistic rationale for 
this synergistic combination activity.
Ex vivo characterization of mouse bone marrow-derived DCs and human DCs isolated from 
peripheral blood mononuclear cells demonstrated that TAK-981 promoted DC maturation as 
assessed by upregulation of the T cell co-stimulatory markers CD40, CD80, and CD86. Consistent 
with these findings, TAK-981 also induced release of type 1 IFNs and pro-inflammatory 
chemokines from human DCs in vitro. Antitumor activity of TAK-981 was demonstrated in fully 
immune-competent BALB/c mice bearing syngeneic A20 lymphoma tumors. CRs were achieved 
most frequently after treatment with 7.5 mg/kg TAK-981 twice weekly (BIW) but also after 
treatment with 15 mg/kg TAK-981 once weekly (QW). Re-challenge of mice that had achieved 
CRs with either the same (A20) or a different (CT26, colorectal) tumor type demonstrated 
protection from A20, but not CT26, tumor growth, indicative of a protective antitumor immune 
response in mice with CRs. TAK-981 treatment of B and T cell-deficient BALB/c Rag2 knockout 
mice bearing A20 lymphoma isografts resulted in diminished tumor growth inhibition compared 
to treatment in wild type BALB/c mice and CR was not achieved, demonstrating dependency of 
TAK-981 antitumor activity on lymphocytes. Treatment of the tumor-bearing Rag2 knockout 
mice with the type 1 IFN receptor IFNAR1 neutralizing antibody before administration of 
TAK-981 resulted in a marked decrease in TAK-981 antitumor activity, indicative of a key role for 
type I IFN signaling in the antitumor mechanism of action of TAK-981.
A pharmacodynamic study assessing the response of lymphocyte populations in circulation and in 
lymphoid organs after TAK-981 administration to immune-competent BALB/c mice 
demonstrated marked, moderate, and trending toward depletion of B lymphocytes in the blood, 
spleen, and bone marrow respectively. T lymphocyte numbers were also decreased in the blood 
within 24 hours of treatment, but showed a clear trend towards increased numbers in the lymph 
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physiologically based PK simulations. However, there is drug-drug interaction potential with 
CYP3A4/5 inhibitors or inducers with TAK-981 as a victim.

TAK-981 is a substrate of P-glycoprotein (Pgp) but not of breast cancer resistance protein
(BCRP) and is an inhibitor of Pgp (IC50 of 30.4 μM) and BCRP (IC50 of 24.4 μM). The 
drug-drug interaction potential with Pgp and BCRP substrates with TAK-981 as a perpetrator 
is low; however, there is a drug-drug interaction potential with Pgp inhibitors or inducers with 
TAK-981 as a victim.

Allometric scaling was used to project human PK parameters based on PK parameters from 
rats, dogs, and monkeys. For a 70-kg human, the projected plasma clearance was moderate 
(0.62 L/h/kg), with a Vss of 4.04 L/kg, volume of distribution during the terminal disposition 
phase of 6.51 L/kg, and a half-life of 7.3 hours.
4.2.4
Nonclinical Toxicology
The nonclinical toxicology profile of TAK-981 has been fully characterized in a comprehensive 
toxicology program that included single- and repeat-dose studies in rats and dogs. Repeat daily 
dosing resulted in unacceptable toxicity due to multiorgan failure in rats and fever (increased body 
temperature) in dogs. Increased body temperature was observed in dogs after a single dose of 
TAK-981 at ≥3 mg/kg and was dose-limiting at 12 mg/kg with body temperature reaching up to 
40.3ºC (compared to baseline body temperature of 37.8ºC to 38.9ºC). Increased body temperature 
(0.5°C to 2.0°C) was also observed in dogs at ≥3 mg/kg in a single-dose cardiovascular assessment 
study and after repeat once daily or QW dosing. Increased body temperature in the cardiovascular 
assessment study was not associated with effects on blood pressure or ECG morphology but was 
associated with increased heart rate. Because intermittent dosing on a QW or BIW schedule was 
demonstrated to be efficacious in mouse models, both QW and BIW schedules were examined in 
GLP toxicology studies. QW dosing (5 doses) was associated with multiorgan failure in rats at ≥20 
mg/kg, but was well-tolerated in dogs up to the top dose of 6 mg/kg. BIW dosing (4 doses) was 
well-tolerated in both species up to the top dose of 10 mg/kg in rats and 4 mg/kg in dogs; therefore,
in the Phase 1 study TAK-981-1002, patients were dosed with TAK-981 on either the QW (2 
weeks on and 1 week off) or the BIW schedule.
The primary toxicity with BIW dosing was dose-dependent mild to marked decreases in peripheral 
blood lymphocyte counts that affected T cells, T-cell subsets (helper, cytotoxic, activated, memory, 
regulatory), B cells, and NK cells approximately equally. Decreases in lymphocyte count were 
associated with decreases in lymphoid cellularity in the primary and secondary lymphoid organs 
including the thymus, spleen, lymph nodes, and gut-associated lymphoid tissue. Decreases in other 
circulating cell types including neutrophils, monocytes, basophils, and/or eosinophils were also 
observed, but were of decreased severity compared to decreases in lymphocyte counts. Additional 
effects observed with BIW dosing were limited to myeloid hyperplasia in the bone marrow in rats 
at 10 mg/kg and in dogs at 4 mg/kg; modest increases in serum monocyte chemotactic protein-1 
(MCP-1), IP-10 (rats only), and regulated upon activation normal T-cell expressed and secreted
(RANTES) (rats only) at ≥0.5 mg/kg (with no increases in cytokines typically associated with 
CRS); injection site reactions in rats at ≥0.5 mg/kg; single cell necrosis in the stomach in dogs at 
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≥2 mg/kg; and renal pelvis inflammation and fibrinoid vascular necrosis (without involvement of 
the renal parenchyma or alterations in renal parameters) in dogs at 4 mg/kg. Additional 
TAK-981-related effects after repeat daily or QW dosing, often at non-tolerated doses only, were 
observed in the bone marrow, liver, kidney, urinary bladder (dog only), gastrointestinal tract, heart, 
musculoskeletal system, lung (rat only), endocrine system (rat only), glandular organs (rat only), 
and reproductive tract (rat only). All target organ toxicities at tolerated doses were considered to be 
monitorable, except for inflammation and vascular necrosis in the renal pelvis in dogs. All target 
organ toxicities were completely or partially reversible.
An in vitro cytokine release assay (CRA) was performed to evaluate the risk of TAK-981 to 
produce clinically significant CRS. TAK-981 was incubated with human whole blood (n = 10) at 
up to 20 µM for 24 hours. There were no effects on IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, 
IL-12(p70), tumor necrosis factor-alpha, IFNγ, or granulocyte colony stimulating factor levels.
TAK-981-related increases in IP-10 levels were noted at ≥0.5 µM (8- to 50-fold compared to 
negative control). Increases were dose-dependent from 0.5 to 5.0 µM, while increases at >5 µM 
were not dose-dependent. TAK-981–related effects were limited to moderate increases in IP-10 at 
≥0.5 µM. Based on these results, this CRA can be considered negative. TAK-981 was not 
mutagenic in a GLP-compliant Ames assay; however, it was associated with genotoxicity at 
≥5 mg/kg in an in vivo micronucleus assay in rats, and was clastogenic in an in vitro chromosomal 
aberration assay with human peripheral blood lymphocytes. Reproductive and developmental 
toxicity studies have not been conducted. There were no TAK-981–related reproductive findings 
in rats or dogs with BIW dosing or in dogs with QW dosing. In the rat study with QW dosing, there 
were partially to fully reversible microscopic findings in reproductive tissues. In a non-GLP
compliant, 7-day repeat-dose toxicity study in male rats, there were microscopic and organ weight 
effects in reproductive tissues in animals that had significant systemic toxicity. TAK-981 did not 
demonstrate phototoxic potential in an in vitro assay.
4.2.5
Clinical Experience
TAK-981 is currently being evaluated in this ongoing Phase 1/2 clinical efficacy and safety study 
of the combination with rituximab in patients with relapsed/refractory indolent or aggressive 
CD20+ NHLs (Study TAK-981-1501), in the ongoing first-in-human (FIH) Phase 1/2 study in 
patients with advanced or refractory solid tumors or relapsed/refractory hematologic malignancies 
(Study TAK-981-1002), in one ongoing Phase 1b/2 clinical efficacy and safety study of the 
combination with pembrolizumab in patients with advanced or metastatic solid tumors (Study 
TAK-981-1502), and in one ongoing Phase 1b/2 safety and efficacy study of the combination with 
monoclonal antibodies in patients with relapsed and/or refractory multiple myeloma (Study 
TAK-981-1503).
As of the 28 June 2021 data cutoff for the IB, 135 patients were treated with TAK-981 across 
4 clinical trials; 81 patients received TAK-981 as a single agent, and 54 patients received 
TAK-981 as part of a combination regimen. Overall, TAK-981 has been well-tolerated, with 
treatment-emergent adverse events (TEAEs) consistent with induction of IFN signaling or with the 
patients’ underlying cancer disease (see Section 4.5.1 and Section 8.10 for more details). The most 
common TEAEs (>20%) in the total population in Studies TAK-981-1002, TAK-981-1501, and 
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TAK-981-1502 included fatigue, pyrexia, nausea, diarrhea, chills, and headache (Table 4.a). 
Overall, preliminary efficacy is being observed, and efficacy evaluations are ongoing. (Refer to 
current TAK-981 IB for details).
Table 4.a
TAK-981 (All Clinical Studies): Most Frequent (≥10% of All Patients) TEAEs
Preferred Term
Number of Patients (%)
Total (N = 135)
Fatigue
49 (36.3)
Pyrexia
46 (34.1)
Nausea
45 (33.3)
Diarrhea
39 (28.9)
Chills
36 (26.7)
Headache
35 (25.9)
Vomiting
27 (20.0)
Decreased appetite
26 (19.3)
Dyspnea
22 (16.3)
Abdominal pain
21 (15.6)
Hypokalemia
21 (15.6)
Anemia
19 (14.1)
Oedema peripheral
17 (12.6)
Constipation
14 (10.4)
Source: Investigator’s Brochure Edition 4, data cut-off date: 28 June 2021, Table 5.g.
NCI CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events; 
TEAE: treatment-emergent adverse event.
Adverse events graded according to NCI CTCAE Version 5.0.
The TAK-981 studies reported some pharmacologically active dose (PAD) at ≥60 mg. In study 
TAK-981-1002, pharmacodynamic activity, including SUMO pathway inhibition and activation 
of IFN-I signaling, was most consistently detected at doses ≥60 mg. The maximum tolerated dose 
(MTD) was determined to be 120 mg; the recommended Phase 2 dose (RP2D) for single-agent 
TAK-981 was 90 mg, when administered BIW (Days 1, 4, 8, and 11) in a 21-day cycle. Out of the 
81 patients, 4 dose-limiting toxicities (DLTs) were reported in the single-agent study: transient 
Grade 3 serum alanine aminotransferase and aspartate aminotransferase elevations at 60 mg BIW; 
Grade 3 recurrent pneumonitis after a previous pneumonitis with an anti–PD-1 inhibitor at 90 mg 
BIW, and 2 DLTs at 120 mg BIW; transient Grade 3 stomatitis; and transient Grade 3 cognitive 
disturbance with Grade 2 lethargy. The most common (≥20%) TEAEs in Study TAK-981-1002 
across 10 dose levels (3 mg to 120 mg) and 3 dosing schedules (Days 1, 4, 8, and 11; Days 1 and 8; 
and Days 1, 8, and 15 in a 21-day cycle) were fatigue, nausea, headache, diarrhea, pyrexia, 
dyspnea, vomiting, and decreased appetite. Reversible CRS was reported in 9 patients with 5 
patients experiencing Grade 1 events (Grade 1 or 2 fever only) and 4 patients experiencing Grade 2 
events (ie, fever and low peripheral oxygen saturation or low blood pressure). Grade 2 CRS was 
managed symptomatically (eg, oral antipyretics for fever, in addition to oxygen for hypoxia or IV 
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fluids for low blood pressure). No patient with CRS required vasoactive drug support or anti-IL-6
directed therapies.
The preliminary analysis of available corrected QT interval (QTc) data is consistent with a low risk 
of QTc prolongation after IV administration of TAK-981 alone at doses of 3 to 120 mg 
(Study TAK-981-1002) or in combination with rituximab at doses of 10 to 120 mg 
(Study TAK-981-1501). A separate QTc report is on file with the sponsor.
In Phase 1 of this study, TAK-981-1501, patients were treated in cohorts with increasing doses of 
TAK-981 (10, 40, 60, 90, and 120 weekly [QW, Days 1 and 8]), with fixed doses of rituximab (375 
mg/m2 [QW Days 1, 8, 15 during Cycle 1 and on Day 1 of each subsequent cycle]). One alternative 
schedule of TAK-981 was implemented, as allowed per protocol; this was a 90 mg twice weekly 
(BIW) cohort where TAK-981 was administered on Days 1, 4, 8, and 11, with rituximab 
administered as described above. Cycle duration in all cohorts was 21 days. As of 07 Feb 2022, a 
total of 31 patients with relapsed/refractory CD20-positive NHL were enrolled in this study.
Pharmacodynamic activity, including SUMO pathway inhibition and activation of IFN-I signaling, 
was most consistently detected at doses ≥60 mg and up to the dose level of 120 mg. 
PK/pharmacodynamics relationship modeling showed dose-dependent target engagement that 
begins to plateau approximately at the 60 mg dose of TAK-981, and a near maximal effect in terms 
of Type 1 IFN effector cell activation at the 120 mg dose of TAK-981. 
In this study, TAK-981-1501, combining TAK-981 with rituximab, as of the data cut-off of 
07 Feb 2022, no DLTs were reported, an MTD was not identified, and dose modifications have 
been infrequent and similar across the QW Phase 1 dose cohorts. The most common (≥20%) 
TEAEs in Study TAK-981-1501 across 5 dose levels (10 mg to 120 mg) and 2 dosing schedules 
(Days 1 and 8; and Days 1, 4, 8, and 11; both in 21-day cycles) were fever, chills, diarrhea, fatigue, 
headache, hypokalemia, and nausea. These TEAEs could be characterized as transient flu-like 
symptoms temporally associated to TAK-981 administration and consistent with induction of IFN 
signaling. CRS (Grade 1) was reported in 1 patient in the 120 mg QW cohort who complained of 
fever and chills; no anti-IL-6 directed therapy was needed. Rates of TEAE, including TAK-981 
related TEAEs, Grade ≥3 adverse events (AEs), and SAEs, were generally similar across QW 
dosing cohorts ≥60 mg. In this Phase 1 study, safety was the primary endpoint while efficacy was 
predominantly signal seeking, as such a heterogeneous patient population, ie patients with various 
subtypes of aggressive and indolent non-Hodgkin’s lymphoma, were enrolled. As of the data 
cutoff date, 7 patients out of 26 response evaluable patients have achieved an objective response (2 
CRs and 5 PRs). These objective responses were investigator-assessed and occurred in patients 
across the dose cohorts and across NHL disease subtypes.
Overall, TAK-981 was well-tolerated. The majority of the observed AEs were consistent with the 
patients’ underlying cancer disease and/or IFN signaling. Refer to the TAK-981 IB for additional 
details.
4.3
Rituximab
Rituximab is a chimeric murine/human immunoglobulin (Ig) G1 kappa monoclonal antibody that 
targets CD20. Its mechanisms of actions are thought to be ADCC, complement-dependent 
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cytotoxicity, and induction of apoptosis and ADCP after binding to the CD20 antigen on the cell 
surface. The biological effect is manifested by B-cell depletion in peripheral blood, lymph nodes, 
and bone marrow. Rituximab is the first commercially available monoclonal antibody for the 
treatment of lymphoma and is currently approved for several NHL indications, including FL, 
chronic lymphocytic leukemia, and DLBCL. Rituximab is widely used in frontline and salvage 
regimens in B-cell NHL, either alone or in combination with chemotherapy. The estimated median 
terminal elimination half-life is 22 days (range 6.1 to 52 days), based on a population PK analysis 
of data from 298 NHL patients who received rituximab QW or once every 3 weeks (Appendix I) 
(Rituxan (rituximab) Injection for Intravenous Use 2019).
4.4
Rationale for the Proposed Study
One approach to enhancing the efficacy of rituximab is the addition of other agents that could 
potentiate its activity. There is strong nonclinical evidence demonstrating that TAK-981 can 
synergize with rituximab to eliminate CD20+ NHL cells (Section 4.2.2).
TAK-981 has been shown to activate macrophages and NK cells. In the case of macrophages, 
TAK-981 induces human melatonin receptor (M1) polarization, upregulates Fc gamma receptors, 
and enhances phagocytosis and ADCP in an ex vivo assay. In the case of NK cells, TAK-981 
promotes upregulation of the activation marker CD69 and the degranulation marker CD107, 
increases the number of IFNγ + NK cells in tumors, and enhances cytotoxicity and ADCC in an ex 
vivo assay. This mechanistic cooperation with ADCP and ADCC supports the combination of 
TAK-981 with IgG1 therapeutic monoclonal antibodies.
In vivo studies have demonstrated robust antitumor activity when TAK-981 is combined with 
rituximab in severe combined immunodeficient mice bearing human DLBCL xenograft models. 
Specifically, in the OCI-Ly-10 and TMD8 models the combination can reproducibly result in 
complete regression of all treated tumors at doses at which no CRs were achieved for either 
single-agent treatment. In the PHTX-166L PDX (patient derived xenograft) model, single agent 
TAK-981 and single agent rituximab showed only very modest tumor growth delay, but 
combination treatment resulted in longer-term growth delay and 1 complete regression out of 
6 mice.
Although these tumor models lack lymphocytes, they retain an intact innate immune system, and 
the demonstrated activation by TAK-981 of macrophages and NK cells, key innate effector cells 
required for the antitumor activity of tumor-targeting antibodies such as rituximab, suggests that 
enhancement of ADCP and/or ADCC may provide a mechanistic rationale for the synergistic 
combination activity achieved in these models.
4.4.1
Rationale for the Starting Dose and Schedule
4.4.1.1
TAK-981
TAK-981 has been extensively characterized in preclinical studies (Sections 4.2.2 and 4.2.3) and is 
currently being evaluated as a single agent in the FIH study TAK-981-1002. The starting dose for 
the FIH study was based on minimum anticipated biological effect level with 3 mg of TAK-981 
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administered IV on Days 1, 4, 8, and 11 of a 21-day dosing cycle. As of 02 May 2019, 5 patients 
have received at least 1 dose of TAK-981 at the starting dose of 3 mg, administered as a single 
agent. No incidences of infusion-related reactions (IRRs) or CRS have been reported after a total 
of 22 doses (16 in Cycle 1 and 6 in Cycle 2).
After consideration of the emerging safety data from the ongoing FIH single-agent study (Study 
TAK-981-1002), with the agreement of the Study TAK-981-1501 investigators, the starting dose 
level for TAK-981 in combination with rituximab for this Phase 1 study is 10 mg administered on 
Days 1 and 8 of each 21-day dosing cycle. This dose level represents a 50% lower dose intensity 
than the 10 mg dose level in the FIH single-agent study. Alternative dosing schedules (eg, Day 1, 
or Days 1, 4, 8, and 11, or Days 1, 8, and 15 in 21-day cycles) may be investigated.
Rationale for the Phase 2 Dose of TAK-981 in This Combination Study:
Traditionally, the RP2D of cytotoxic anticancer agents was determined by DLT given the 
assumption that the highest tolerable dose could result in better therapeutic activity. For some 
current drugs, such as TAK-981, with new mechanisms of action (ie, drugs that target specific 
molecules involved in the proliferation and metastasis of cancer cells as the mechanism to kill or 
inhibit proliferation), the classical approach using only toxicity to define a RP2D may not be 
sufficient (Hansen et al. 2017). With targeted drugs, increasing doses beyond a certain level may 
not enhance the therapeutic activity, DLTs and a MTD may not be observed, and more serious 
TEAEs may only occur after multiple cycles of therapy (Shah et al. 2021). In addition to safety and 
tolerability, biological results such as PK, pharmacodynamics, and efficacy may also be useful in 
identifying a dose to evaluate in Phase 2 with these molecularly targeting agents, for which clinical 
benefit is not necessarily dose dependent. Therefore, the optimal method to define RP2D remains 
unclear in this setting (Shah et al. 2021) (Hansen et al. 2017). 
As per protocol in study TAK-981-1501, the dose to be evaluated in the Phase 2 expansion could 
be the MTD based on observed DLTs following Bayesian logistic regression modeling (BLRM)
guidance or a dose below MTD considering other non-DLT safety and tolerability information as 
well as other data, including but not limited to PK, pharmacodynamic, and exposure/response 
findings. Further, the TAK-981 + rituximab combination dose and schedule to be taken forward 
for future efficacy studies could be determined either at the end of Phase 1 or Phase 2, considering 
all these circumstances. Overall, the RP2D will be determined from the collective experience in 
the clinic, considering the safety data, preliminary PK data, preliminary pharmacodynamics data, 
and any observed early antitumor activity. 
In Study TAK-981-1501, in addition to toxicity, other parameters such as PK, pharmacodynamics, 
and efficacy were considered in the decision regarding the dose(s) to be evaluated in the Phase 2 
expansion. Dose-dependent pharmacological effects, defined by target engagement and Type 1 
IFN signaling, have been reported with similar magnitude and duration of pharmacodynamic
responses when administered alone or in combination with rituximab. These pharmacodynamic
readouts were observed from the TAK-981 dose level of 60 mg and up to the dose level of 120 mg. 
Across the doses evaluated in this study, the PK of TAK-981 was linear with approximately 
dose-proportional increases in area under the plasma concentration-time curve from time 0 to 
infinity (AUC0-∞). There was no accumulation of TAK-981 from C1D1 to C1D8 after either QW 
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diarrhea, chills, and headache; TEAEs consistent with induction of IFN signaling. The only 
serious adverse reaction considered expected for safety reporting purposes across the ongoing 
TAK-981 studies is pyrexia. The single agent MTD (in Study TAK-981-1002) has been identified 
as 120 mg with evaluation continuing in the ongoing studies of TAK-981 in combination with 
pembrolizumab or a monoclonal antibody (studies TAK-981-1502 and TAK-981-1503, 
respectively) as well as from this study (TAK-981-1501). For additional details, refer to Section 
4.2.5 and the TAK-981 IB.
Further details for TAK-981 administration and safety events management can be found in 
Section 8.1, Section 8.10, and the Guidance for Investigator section of the IB.
Lymphoid and Hematopoietic Effects
Dose-dependent reversible or partially reversible lymphoid/hematopoietic effects, including 
peripheral lymphopenia and decreased cellularity in lymph nodes, spleen, thymus, and 
gut-associated lymphoid tissue were observed in repeat-dose toxicity studies in rats and dogs. 
Decreased cellularity of lymphoid tissues contributed to decreases in white blood cell counts. 
These findings could be associated with increased susceptibility to certain forms of infection that 
were not observed in the GLP toxicology studies.
In this study, absolute lymphocyte counts and subpopulations will be monitored. Prophylaxis for 
Pneumocystis jirovecii pneumonia and herpes virus is recommended for prolonged CD4 counts 
below 200/µL.
As of the IB data cutoff for this report and the ongoing clinical studies, transient decrease 
lymphocyte count related to TAK-981 has been reported (3.7%). Opportunistic infections have not 
been reported to date; however, herpes virus reactions have been observed (1.5% related to 
TAK-981). These reactions are self-limited and resolve within 14 days. (Refer to the IB for current 
details.)
Effects in Renal Pelvis
In dogs, at the higher doses following repeat daily or BIW dosing, there was reversible to partially 
reversible inflammation and arteriolar fibrinoid necrosis localized at the renal pelvis; this did not 
involve either renal cortex or medulla. The lesions had no repercussion on kidney function or 
conventional urinary test parameters.
Inflammation in the renal pelvis suggests a local effect of concentrated drug or a metabolite. No 
clinically significant safety concerns have been reported as of the IB data cutoff date of 
28 June 2021. Patients will be asked to maintain adequate hydration (1.5-2 L/day) 48 hours before 
initiating therapy; IV fluid administration on C1D1 will be recommended for those who cannot 
maintain adequate oral hydration. Patients will be monitored for renal function, and in patients 
with significant alterations in urinalysis, urine sediment analysis will be required.
IRRs and Potential for CRS
The mechanism of action of TAK-981 involves type 1 IFN signaling; as a result, there is potential 
for infusion reactions and CRS. Serum cytokine levels were examined in the BIW GLP toxicity 
studies in rats and dogs. Modest increases in MCP-1, IFN gamma-induced protein 10 (rats only), 
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Injection Site Reactions
Partially reversible effects at the injection site, including potentiation of procedure-related 
subcutaneous perivascular hemorrhage, inflammation, and necrosis, were observed in rats only. 
The shorter needle length and frequent movement of conscious rats likely resulted in extravasation, 
and chemical irritation due to the acid pH (3.5) of the dosing solution could have been a 
contributing factor. Injection site reactions related to TAK-981 have been infrequently reported 
(1.5%; all Grade 1) in the ongoing clinical studies.
Sites will be informed to enforce careful observation of the infusion site in case a peripheral vein is 
used for administration. In general, infusion through a central line or subcutaneous reservoir is 
preferred for TAK-981 administration (see Section 8.1). (Refer to the IB for further details)
Reproductive and Development Toxicity
Reproductive and developmental toxicity studies have not yet been conducted; therefore, the 
effects of TAK-981 on fertility and the developing fetus are currently unknown. Reproductive 
tissues were weighed and examined microscopically as part of the GLP-compliant repeat-dose 
toxicity studies with QW or BIW dosing in sexually mature rats and dogs of both sexes. 
TAK-981–related reproductive findings were not observed in either rats or dogs with BIW dosing, 
or in dogs with QW dosing. However, in the rat study with QW dosing, at ≥20 mg/kg there was 
reversible single-cell necrosis in multiple male and female reproductive tissues and inflammation 
in the prostate gland. In addition, there was partially reversible acinar cell atrophy in the male 
mammary gland at ≥5 mg/kg. Additionally, in a non−GLP-compliant, 7-day repeat-dose toxicity 
study in male rats, TAK-981−related effects were noted in multiple reproductive tissues in animals 
that also had significant systemic toxicity, including minimal to mild single-cell necrosis of the 
epithelium (≥10 mg/kg), and, at 40 mg/kg, minimal to mild atrophy, karyomegaly, increased 
mitotic figures, and/or degeneration/necrosis.
Female partners of male patients participating and female patients participating in this study 
should avoid becoming pregnant.
Genotoxicity
TAK-981 was not mutagenic in an in vitro bacterial mutagenesis Ames assay. In an in vivo rat 
bone marrow micronucleus assay, TAK-981 increased induction of micronuclei and was 
considered to be positive for in vivo genotoxicity at ≥5 mg/kg. TAK-981 was considered 
clastogenic in an in vitro chromosomal aberration test using human peripheral blood lymphocytes. 
In compliance with ICH S9 guidance [ich.org/products/guidelines/safety/ 
article/safety-guidelines.html]), a carcinogenicity assessment is not planned.
The potential effects listed above are based on toxicology findings in the nonclinical studies and 
the emerging safety data from ongoing clinical studies with TAK-981. The nonclinical data may or 
may not present with similar severity in humans. It is possible that administration of TAK-981 will 
result in toxicities that were not observed or predicted from the completed nonclinical studies 
conducted in animals or previously observed in ongoing clinical studies. To mitigate the inherent 
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risks in clinical studies of TAK-981, patients will be carefully monitored closely for signs and 
symptoms of adverse reactions with appropriate management of these events.
4.5.2
Potential Effects of Rituximab
Rituximab toxicities are generally associated with B cell depletion, infusion reactions, and/or 
tumor lysis syndrome (TLS). For detailed information regarding the safety of rituximab 
administration please refer to the United States Food and Drug Administration (FDA)-approved 
package insert (Appendix I) (Rituxan (rituximab) Injection for Intravenous Use 2019).
4.5.3
TAK-981 in Combination with Rituximab
Nonclinical toxicology studies with the combination of TAK-981 and rituximab, or other 
anti-CD-20 agents, were not conducted and are not warranted per ICH S9 
(ich.org/products/guidelines/safety/article/safety-guidelines.html). Compared to TAK-981 alone, 
synergistic toxicity, as assessed by increased mortality or significant decreases in body weight, 
was not observed in mouse tumor-bearing models administered TAK-981 in combination with 
rituximab. Based on the safety profile of TAK-981 (nonclinical) and rituximab (clinical) described 
above, there is potential for some toxicity overlap between the IRR of rituximab and the potential 
for IFN signaling induced IRR/ CRS of TAK-981. However, based on the non-clinical CRA, the 
CRS risk of TAK-981 can be considered low. In this study, on C1D1, rituximab will be 
administered per standard of care administration guidance before TAK-981 and with a separation 
of 1 hour. Another potential overlap for the 2 drugs is the effects on the immune system, 
specifically on the B-cell arm of adaptive immunity. It is well-known that rituximab can produce 
profound and prolonged B cell depletion with no major effect on T cells. 
Lymphocyte subpopulations will be monitored frequently during the study to assess the potential 
impact on the cellular immunity.
Finally, due to the risk for TLS associated with rituximab monotherapy and the expected 
enhancement of treatment efficacy with the proposed combination, TLS risk stratification, 
monitoring, and precautions will be observed.
As of 28 Jun 2021, the most common TEAE was pyrexia in this study (TAK-981-1501). Other 
common TEAEs were diarrhea, chills, dizziness, fatigue, and nausea. There were no reports of 
CRS or DLTs as of this data cutoff. Refer to current IB for more details.
Altogether, the potential overlap of risks for the combination are considered to be low and will be 
monitored throughout the study.
4.5.4
Coronavirus Disease 2019 Pandemic
The coronavirus disease 2019 (COVID-19) pandemic has affected health care and specifically 
cancer care broadly across the globe. Based on current knowledge, the benefit/risk assessment for 
patient participation in this study remains favorable. The benefit/risk considerations for patient 
participation should be evaluated by the investigator on a patient-by-patient basis taking into 
consideration the current local situation, guidelines, and recommendations. Investigators should 
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follow local recommendations and guidelines with regards to COVID-19 precautions, vaccination, 
and treatment, see Section 8.6.3.3 and 8.8.
5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objectives
The primary objectives are:
Phase 1:

To determine the safety and tolerability of TAK-981 in combination with rituximab in patients
with r/r NHL.

To establish the RP2D of TAK-981 in combination with rituximab.
Phase 2:

To evaluate the efficacy of TAK-981 in combination with rituximab in select r/r NHL 
indications.
5.1.2
Secondary Objectives
The secondary objectives are:

To characterize the PK profile of TAK-981 in combination with rituximab.
Phase 1:

To determine the MTD and/or PAD of TAK-981 when administered in combination with 
rituximab.

To assess the preliminary antitumor activity of TAK-981-rituximab combination.

To assess target engagement of TAK-981 (SUMO-TAK-981 adduct formation) and 
SUMOylation pathway inhibition in blood and skin.
Phase 2:

To evaluate the efficacy of TAK-981 in combination with rituximab in select r/r NHL as 
measured by disease control rate (DCR), duration of response (DOR), TTP, and 
progression-free survival (PFS).

To evaluate the safety and tolerability of TAK-981 in combination with rituximab.
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
Occurrence of DLTs within the first 21 days of treatment in Cycle 1.
Phase 2:

ORR (CR + PR) as defined by the investigator according to Lugano Classification for 
lymphomas.
5.2.2
Secondary Endpoints
The secondary endpoints for this study are:

PK parameters after the first dose of TAK-981 on C1D1 and Cycle 1, Day 8 (C1D8) (data 
permitting):
–
Cmax.
–
Time of first occurrence of Cmax (tmax).
–
Area under the plasma concentration-time curve from time 0 to time t (AUC0-t).
–
AUC0-∞.
–
Terminal disposition phase half-life (t1/2z).
–
Total clearance (CL) after IV administration.
–
Vss.
Phase 1:

ORR, DCR, DOR, TTP, and PFS as assessed by the investigator according to Lugano 
Classification for lymphomas.

TAK-981-SUMO adduct formation and SUMO pathway inhibition in skin/blood.
Phase 2:

Frequency, severity, and duration of TEAEs and laboratory abnormalities for all dose groups 
according to the NCI CTCAE, Version 5.0; except CRS, which will be graded according to 
ASTCT Consensus Grading for CRS.

DCR, DOR, TTP, and PFS as assessed by the investigator according to Lugano Classification 
for lymphomas.
5.2.3
Additional/Exploratory Endpoints
5.2.3.1
Exploratory Endpoints (Global Study; Not Applicable to Patients Enrolled in China)
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study or study drugs occurs. Treatment may be continued beyond disease progression, with 
sponsor approval, if, in the opinion of the investigator, the patient continues to experience clinical 
benefit.
6.2
Phase 1 Study Design
The dose-finding, dose-escalation part of the study will enroll patients with aNHL (mantle cell 
lymphoma patients are also allowed) and iNHL. Patients will be treated in cohorts with increasing 
doses of TAK-981 administered IV as a 1-hour infusion on Days 1 and 8 followed by a fixed dose 
of rituximab of 375 mg/m2 administered IV on Days 1, 8, and 15 during Cycle 1 and on Day 1 of 
each subsequent cycle (from Cycle 2 Day 1 onwards). Cycle duration is 21 days. (Study drug 
administration details in Section 8.1.) Evaluation of alternative TAK-981 dosing schedules (eg, 
Days 1, 4, 8, and 11 in 21-day cycles) may be permissible after discussions between the sponsor 
and the investigators, based on data emerging across the program.
Dose-escalation intervals progress from 10 mg to 160 mg. The starting dose for TAK-981 is 
justified in Section 4.4.1. As of Amendment 6, Phase 1 patients are being enrolled to the 90 mg of 
TAK-981 BIW and 120 mg of TAK-981 QW (2 weeks on and 1 week off) cohorts in a 21-day 
cycle.
TAK-981 in combination with rituximab will be administered until a discontinuation criterion is 
met (Section 8.6.4).
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Figure 6.a
TAK-981-1501: Schedules for TAK-981 Twice or Once Weekly and 
Rituximab Dosing
Note: Evaluation of alternative TAK-981 dosing schedules (ie, twice weekly on Days 1, 4, 8, and 11; or once weekly
on Days 1 and 8 in 21-day cycles) may be permissible only after discussions between the sponsor and the 
investigators.
Dose escalation will be cohort-based with an adaptive design using a BLRM model with 
Escalation with Overdose Control (see Appendix H for details). Approximately 35 patients will be 
enrolled until either MTD or a PAD is identified. A minimum of 3 patients will be enrolled in the 
dose level 1 cohort. Dose escalation and cohort expansion decisions are reviewed and approved by 
the Safety Monitoring Committee (SMC) consisting of sponsor representatives and investigators.
For the first infusion (C1D1) of TAK-981 every patient needs to be hospitalized for drug 
administration and observation for a minimum of 18 hours after the end of infusion of 
TAK-981. Hospitalization is not required if expansion after 3 patients in a dose level or expansion 
of previously cleared dose level and only if infusion reaction risk is considered low based on 
previous experience. If grade 3 or greater IRR or CRS are not observed at PAD or MTD, or if the 
safety data from the ongoing FIH TAK-981-1002 study support the removal of the requirement of 
hospitalization for the first dose of TAK-981, the decision will rely on the SMC.
Patient enrollment will be staggered between the first and second patients by 72 hours during dose 
escalation at all dose levels. At each dose level, the second and third patients can be dosed 
concurrently if the first patient in the cohort has gone through Day 4 (72 hours) without clinically 
significant acute toxicities. If more than 3 patients are to be enrolled in a dose level or if 
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de-escalation is indicated, staggering will not be required unless indicated by safety findings. 
Dose-escalation decisions will be made by the SMC as defined in Section 8.5.
Toxicity will be evaluated according to the NCI CTCAE, Version 5.0; except CRS which will be 
graded according to ASTCT Consensus Grading for CRS (Lee et al. 2019). A DLT will be defined 
as any of the events described in detail in Section 8.2 occurring during Cycle 1 unless they are 
considered by the investigator to be clearly unrelated to therapy with TAK-981 in combination 
with rituximab. TEAEs meeting DLT definitions occurring in later cycles will determine the 
suitability of the PAD/MTD as the RP2D.
Intrapatient dose escalation will be permitted only when patients in the next dose level cohort have 
completed assessment for Cycle 1 and a decision has been made that this dose level does not 
exceed the MTD.
The SMC will select the dose to be used for the Phase 2 part of the study. It can be primarily the 
MTD based on the observation of DLTs, and following BLRM guidance as detailed in Section 8.5. 
A dose below the MTD can be selected for Phase 2 if it is recommended by other non-DLT safety 
and tolerability information. PK and pharmacodynamic information may also recommend using a 
dose below the MTD. The TAK-981/rituximab combination MTD, PAD, and schedule to be taken 
forward for our future efficacy studies will be determined either at the end of Phase 1 or Phase 2 
considering all these circumstances.
6.3
Phase 2 Study Design
The Phase 2 part of the study uses a non-randomized, open-label, uncontrolled, parallel arm design 
that will enroll 1 cohort of patients with FL and another 2 cohorts of patients with DLBCL, one 
with patients that have relapsed after a chimeric antigen receptor T-cell therapy (CAR-T) that has 
been approved by a health authority, and another one for patients that have progressed after 2 or 3 
lines of systemic therapy and have not received prior therapy with commercially available CAR 
T-cells. The primary objective during Phase 2 is to assess the efficacy of TAK-981 in combination 
with rituximab as measured by ORR per Lugano criteria using an adaptive 2 stage design for a 
single proportion. For Stage 1, each cohort will be analyzed when a prespecified number of 
patients (as defined in Section 13.3) have been enrolled and had the potential to have a least 1 
post-treatment radiologic evaluation of the disease. If the prespecified minimal response rate is not 
achieved in the first stage for a given cohort, that cohort will be closed to enrollment. However, if 
a clear clinical benefit has been observed for patients in the cohort (eg, a majority of patients have 
recorded stable disease at Week 8 and no CR or PR is recorded) then enrollment into Stage 2 may 
be allowed for this cohort. If the required response rate during Stage 1 or a good clinical benefit is 
observed for a particular cohort as mentioned above, then additional patients will be enrolled in the 
second stage of the corresponding cohort until a predetermined number of additional patients for 
that cohort has been reached (as defined in Section 13.3). The final analysis of the primary 
endpoints for each cohort will be performed when all ongoing patients have completed the 
6-month disease assessment/survival follow-up.
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TAK-981 will be evaluated at a dose of 120 mg QW (the upper dose tested in Phase 1) as well as at 
the dose of 60 mg QW (a lower yet biologically active dose) in a 21-day cycle, both in combination 
with a fixed dose of rituximab, in the Phase 2 expansion. The dose cohorts will be: Cohorts B 120 
mg/C 120 mg and Cohorts B 60 mg/C 60 mg. This data will be used to generate supplementary 
efficacy, safety, and exposure/response data to inform dose selection for further development of 
TAK-981.
Figure 6.b
TAK-981-1501: Schedule for TAK-981 Once Weekly and Rituximab Dosing
Note: Evaluation of TAK-981 dosing schedule, ie, once weekly on Days 1 and 8 in 21-day cycles.
During the Phase 2 portion, patients will be concurrently enrolled and the sponsor/designee will 
assign patients to a respective cohort and, for Cohorts B and C only, to a respective TAK-981 dose 
group (B 120 mg, B 60 mg, C 120 mg, or C 60 mg). All patients in Cohort A will receive the same 
120 mg dose. Hospitalization for C1D1 TAK-981 administration is not required.
During Phase 2, an Independent Data Monitoring Committee (IDMC) will be established to 
monitor safety and assess benefit/risk throughout the conduct of the Phase 2 portion of the study.
Patients enrolled in sites in China will participate in Phase 2 of the study.
The overall study schematic is displayed in Figure 6.c.
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Figure 6.c
TAK-981-1501 Study Schematic of Phase 1 and Phase 2
aNHL: aggressive Non-Hodgkin Lymphoma; CAR: chimeric antigen receptor; DLBCL: diffuse large B-cell 
lymphoma; FIH: first-in-human; FL: follicular lymphoma; iNHL: indolent Non-Hodgkin Lymphoma; MCL: mantle 
cell lymphoma; MZL: marginal zone lymphoma; NHL: non-Hodgkin lymphoma; QW: once weekly; R-CHOP: 
rituximab, cyclophosphamide, doxorubicin (hydroxydaunorubicin), vincristine (Oncovin) and prednisone; r/r: 
relapse/refractory.
For more details on Cohorts A, B, and C, please refer to Figure 6.d, Figure 6.e, and Figure 6.f, respectively.
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6.5
Duration of Study
6.5.1
Duration of an Individual Patient’s Study Participation
Patient participation will include screening, treatment, and follow-up. Screening will last up to 28 
days before the first dose of study drug, during which the patient’s eligibility and baseline 
characteristics will be determined. Treatment with TAK-981 with rituximab will be administered 
for up to 12 months or until patients meet any of the discontinuation criteria in 
Section 8.6.4. Patients with demonstrated clinical benefit may continue treatment beyond 
12 months with the agreement of the sponsor. These patients can continue receiving treatment in 
this study or any of the poststudy access modalities described in Section 6.5.5. Patients who 
discontinue rituximab for reasons described in Appendix I (Rituxan (rituximab) Injection for 
Intravenous Use 2019) may continue TAK-981 treatment; however, patients cannot remain on 
rituximab as a single agent once TAK-981 has been discontinued. In that case, patients will 
undergo the EOT visit.
Patients should attend the EOT visit 30 days (+10 days) after receiving their last dose of TAK-981 
or before the start of subsequent systemic anticancer therapy, whichever occurs first, to permit 
detection of any delayed TEAEs and resolution of ongoing events. Patients with unresolved
TEAEs will continue the periodic safety follow-up until complete resolution or stabilization 
(established as sequelae) occurs. Patients who discontinue study treatment for reasons other than 
PD will continue PFS follow-up every 12 weeks ±1 week from last dose of study drug until the 
occurrence of PD, loss to follow-up, consent withdrawal, death, the start of subsequent systemic 
antineoplastic therapy, or study termination (Section 9.6), whichever occurs first. During Phase 2, 
patients who stop treatment due to PD will be followed every 12 weeks (±1 week) after 
documented PD for OS until death, loss to follow-up, consent withdrawal, or study termination for 
up to 12 months following the last day the patient discontinues or completes treatment, or until 50% 
of patients have died, whichever occurs first. (Additional detail in Section 9.9)
6.5.2
End of Study/Study Completion Definition and Planned Reporting
The final data cutoff for the clinical study report will be conducted after all patients have been 
discontinued from treatment or transferred to a long-term safety study, a single-patient 
investigational new drug application, or a similar program (Section 6.5.5). The estimated time 
frame for study completion is approximately 72 months.
6.5.3
Timeframes for Primary and Secondary Endpoints to Support Disclosures
Refer to Table 6.a for disclosures information for all primary and secondary endpoints.
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Table 6.a
Primary and Secondary Endpoints for Disclosures
Endpoint
Definition
Maximum Time Frame
Primary (Phase 1): 
Frequency, severity, and duration of TEAEs overall 
and per dose level
Standard safety assessments
Up to 72 months
Number of patients with DLTs per dose level
Standard safety assessments
Up to 72 months
Number/percentage of patients with clinically 
significant laboratory values
Standard safety assessments
Up to 72 months
Primary (Phase 2): 
ORR as defined by the investigator according to 
Lugano classification for lymphomas
Standard efficacy assessments
Up to 72 months
Secondary: 
Data permitting, PK parameters after the dose 
administration of TAK-981 on C1D1 and C1D8:
Cmax, tmax, AUC0-t, AUC0-∞, t1/2z, CL, Vss
Standard PK parameters to 
allow determination of PK 
profile
Up to 72 months
DCR
DCR
Up to 72 months
DOR
DOR
Up to 72 months
PFS
PFS
Up to 72 months
TTP
TTP
Up to 72 months
TAK-981–SUMO adduct formation; SUMO 
pathway inhibition
TAK-981–SUMO adduct 
formation; SUMO pathway 
inhibition in either skin tissue or 
in blood (Phase 1 only).
Up to 72 months
AUC0-t: area under the plasma concentration-time curve from time 0 to time t; AUC0-∞: area under the plasma 
concentration-time curve from time 0 to infinity; C1D1: Cycle 1, Day 1; C1D8: Cycle 1, Day 8; CL: total clearance 
after intravenous administration; Cmax: maximum observed plasma concentration; DCR: disease control rate; 
DLT: dose-limiting toxicity; DOR: duration of response; ORR: overall response rate; PFS: progression-free survival; 
PK: pharmacokinetic; SUMO: small ubiquitin-like modifier; TEAE: treatment-emergent adverse event; t1/2z: terminal 
disposition phase half-life; TTP: time to progression; tmax: time of first occurrence of Cmax; Vss: volume of distribution 
at steady state after intravenous administration.
6.5.4
Total Study Duration
It is anticipated that this study will last for approximately 72 months.
6.5.5
Poststudy Access
Subjects who have met the primary (and secondary) endpoints of the study and, in the opinion of 
the investigator and confirmed by the sponsor, experienced a clinically important benefit from 
TAK-981 in combination with rituximab may continue to receive TAK-981 or the combination in 
an extension phase of this study or will be given the opportunity to enroll in a separate open-label 
rollover study or have the possibility of using an individual patient investigational new drug to 
continue receiving both study drugs, where permitted by local regulations.
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Additionally, these patients should have no alternative therapeutic option and would be harmed 
without continued access.
Duration of Poststudy Access
Continued access to TAK-981 or the combination with rituximab for subjects will be terminated 
for those individuals who no longer benefit from TAK-981 or the combination (eg, they have 
completed the recommended course of therapy or their disease has resolved), the benefit-risk no 
longer favors the individual, if TAK-981 ± rituximab becomes available either commercially or 
via some other access mechanism, or when an alternative appropriate therapy becomes available. 
Poststudy access may be terminated in a country or geographical region where marketing 
authorization has been rejected, the development of TAK-981 has been suspended or stopped by 
the sponsor, or the TAK-981 can no longer be supplied.
7.0
STUDY POPULATION
7.1
Inclusion Criteria
Each patient must meet all the following inclusion criteria to be enrolled in the study:
1. Adults ≥18 years old.
2. Patient populations:
a) For Phase 1 Dose Escalation:

aNHL including mantle cell lymphoma and DLBCL histologies such as transformed 
DLBCL from low-grade lymphoma (follicular or others), DLBCL associated with 
small-cell infiltration in bone marrow, B-cell lymphoma with intermediate features 
between DLBCL and Burkitt’s lymphoma or with intermediate features between 
DLBCL and Hodgkin lymphoma, FL grade 3B, and aggressive B-cell lymphoma 
unclassifiable who must have previously received rituximab, cyclophosphamide, 
doxorubicin (hydroxydaunorubicin), vincristine, (Oncovin) and prednisone (R-CHOP) 
(or equivalent anti-CD20 containing therapy) and 1 additional line of therapy in the r/r 
setting.

iNHL (including FL of grades 1–3A and marginal zone lymphoma) refractory to 
rituximab or to any other anti-CD20 monoclonal antibodies, who have received at least 
1 prior systemic therapy for r/r iNHL:
–
Rituximab or anti-CD20 refractoriness is defined as failure to respond to, or 
progression during, any previous rituximab/anti-CD20-containing regimen 
(monotherapy or combined with chemotherapy), or progression within 6 months of 
the last rituximab or anti-CD20 dose.
Note: The minimum qualifying rituximab/anti-CD20 dose is 1 full cycle 
(ie, weekly x 4 doses monotherapy or 1 complete dose if combined with 
chemotherapy). Prior anti-CD20 antibody or cytotoxic drugs may have been 
administered as single agents or as components of combination therapies. Each 
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repeated course of the same single agent or combination is considered an 
independent regimen.
b) For Phase 2, the following confirmed CD20 positive:

r/r DLBCL progressed or relapsed after a prior CAR T-cells therapy that has received 
approval by a health authority for the treatment of DLBCL (Cohort A).

r/r DLBCL that has progressed or relapsed after at least 2, but no more than 3 prior 
lines of systemic therapy and has not received prior cellular therapy. At least one prior 
line of therapy must have included a CD20-targeted therapy (Cohort B).

r/r FL that has progressed or relapsed after at least 2, but no more than 3 prior lines of 
systemic therapy. At least 1 prior line of therapy must have included a CD20-targeted 
therapy (Cohort C).
3. Patients must be considered ineligible for, in the opinion of the investigator, or must have 
refused ASCT.
4. Eastern Cooperative Oncology Group (ECOG) performance score of ≤2.
5. Adequate bone marrow function per local laboratory reference range at screening as follows:

Platelet count ≥75.0 × 109/L, Grade 2 thrombocytopenia (platelet count ≥50.0 × 109/L) is 
allowed if it is clearly due to marrow involvement with no evidence of myelodysplastic 
syndrome or hypoplastic bone marrow if found. Absolute neutrophil count (ANC)
≥1.0 × 109/L. Hemoglobin ≥85 g/L (RBC transfusion allowed ≥14 days before 
assessment).
6. Adequate renal and hepatic function, per local laboratory reference range at screening as 
follows:

Calculated creatinine clearance ≥30 mL/min calculated with Cockcroft-Gault formula.

Potassium levels ≥lower limit of normal. For potassium > upper limit of normal (ULN) 
discussion with Takeda medical monitor/designee recommended.

Aspartate aminotransferase and alanine aminotransferase ≤3.0× the ULN of the 
institution’s normal range; bilirubin ≤1.5 × ULN. Patients with Gilbert’s syndrome may 
have a bilirubin level >1.5 × ULN, per discussion between the investigator and the medical 
monitor.
7. Left ventricular ejection fraction (LVEF) ≥40%; as measured by echocardiogram or multiple 
gated acquisition (MUGA) scan.
8. Suitable venous access for safe drug administration and the study-required PK and 
pharmacodynamic sampling.
9. Have at least 1 bidimensionally measurable lesion per Lugano Classification (eg, measurable 
node >1.5 cm in its largest dimension; measureable extranodal lesion >1.0 cm in longest 
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diameter) by computed tomography (CT). Tumor lesions situated in a previously irradiated 
area are considered measurable if progression has been demonstrated in such lesions.
10. Willing to consent to 1 mandatory pretreatment and 1 on-treatment skin biopsy during Phase 1. 
The skin biopsy entry requirement may be discontinued by the sponsor once there is enough 
pharmacodynamic evidence of target engagement.
11. For patients enrolled in Phase 2, if available, mandatory submission of archival tumor tissue 
acquired ≤12 months prior to screening. Tumor tissue, including archival tissue, is not 
applicable to patients enrolled in China.
12. Recovered to Grade 1, baseline or established as sequela, from all toxic effects of previous 
therapy (except alopecia, neuropathy, autoimmune endocrinopathies with stable endocrine 
replacement therapy, neurotoxicity [Grade 1 or 2 permitted], or bone marrow parameters [any 
of Grade 1, 2, permitted if directly related to bone marrow involvement]).
13. Women of childbearing potential participating in this study should avoid becoming pregnant, 
and male patients should avoid impregnating a female partner. Nonsterilized female patients of 
reproductive age and male patients should use effective methods of contraception through 
defined periods during and after study treatment as specified below. Female patients must meet 
1 of the following:

Postmenopausal for at least 1 year before the screening visit, or

Surgically sterile, or

If they are of childbearing potential, agree to practice 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 12 months after the last dose of study 
drug, or

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle 
of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together).
14. Male patients, even if surgically sterilized (ie, status postvasectomy) must agree to 1 of the 
following:

Agree to practice effective barrier contraception during the entire study treatment period 
and through 12 months after the last dose of study drug, or

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle 
of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.)
15. Subject has provided informed consent.
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16. Must be willing and able to comply with clinic visits and procedures outlined in the study 
protocol.
7.2
Exclusion Criteria
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
1. CNS lymphoma; active brain or leptomeningeal metastases, as indicated by positive cytology 
from lumbar puncture or CT scan/magnetic resonance imaging (MRI).
2. Hypersensitivity to TAK-981, rituximab, or any component of the drug product.
3. History of Grade ≥3 IRR that lead to permanent discontinuation of previous rituximab 
treatment.
4. Previous participation in the TAK-981-1002 clinical study.
5. Posttransplantation lymphoproliferative disease except relapsed NHL after ASCT.
6. Undergone ASCT or treatment with cellular therapy including CAR T within ≤12 weeks of 
TAK-981 dosing.
7. Prior allogeneic hematopoietic stem-cell transplantation.
8. Lymphomas with leukemic expression.
9. Prior anticancer therapy including chemotherapy, hormonal therapy, or investigational agents 
within 2 weeks or within at least 5 half-lives before TAK-981 dosing, whichever is shorter. 
Low dose steroids (oral prednisone or equivalent ≤20 mg per day), hormonal therapy for 
prostate cancer or breast cancer (in adjuvant situation), and treatment with bisphosphonates 
and receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitors are allowed.
10. Major surgery within 14 days before the first dose of study drug and not recovered fully from 
any complications from surgery.
11. Significant medical diseases or conditions, as assessed by the Investigators and Sponsor that 
would substantially increase the risk-benefit ratio of participating in the study. This includes 
but is not limited to acute myocardial infarction or unstable angina within the last 6 months; 
uncontrolled diabetes mellitus; significant active bacterial, viral, or fungal infections; severely 
immunocompromised state; severe non-compensated hypertension and congestive heart 
failure New York Heart Association Class III or IV; ongoing symptomatic cardiac arrhythmias 
of >Grade 2, pulmonary embolism, or symptomatic cerebrovascular events; or any other 
serious cardiac condition (eg, pericardial effusion or restrictive cardiomyopathy). Chronic 
atrial fibrillation on stable anticoagulant therapy is allowed.
12. Known chronic hepatitis C and/or positive serology (unless due to vaccination or 
passive immunization due to Ig therapy) for chronic hepatitis B. Known HIV infection.
13. Second malignancy within the previous 3 years, except treated basal cell or localized 
squamous skin carcinomas, localized prostate cancer, cervical carcinoma in situ, resected 
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colorectal adenomatous polyps, breast cancer in situ, or other malignancy for which the patient 
is not on active anticancer therapy as defined in Exclusion Criterion 9.
14. Receipt of any live vaccine within 4 weeks of initiation of study treatment.
15. Active, uncontrolled autoimmune disease requiring >20 mg of prednisone or equivalent, 
cytotoxics, or biologicals.
16. Corticosteroid use within 1 week before the first dose of study drug, except as indicated for 
other medical conditions such as inhaled steroid for asthma, topical steroid use, or as 
premedication for administration of study drug or contrast. Patients requiring steroids at daily 
doses >20 mg prednisone equivalent systemic exposure daily, or those who are administered 
steroids for lymphoma control or white blood cell count lowering are not eligible.
17. History of medical or psychiatric illness likely to interfere with the ability to comply with
protocol requirements or give informed consent.
18. Patients with baseline prolongation of the QT interval with Fridericia correction method 
(QTcF) (eg, >470 ms for women and >450 ms for men and a history of congenital long QT 
syndrome, or torsades de pointes).
19. Receiving or requiring the continued use of medications that are known to be strong or 
moderate inhibitors and inducers of CYP3A4/5 and strong Pgp inhibitors. To participate in this 
study, such patients should discontinue use of such agents for at least 2 weeks (1 week for 
CYP3A4/5 and Pgp inhibitors) before receiving a dose of TAK-981.
20. Female patients who are lactating and breastfeeding or have a positive urine or serum 
pregnancy test during the screening period or on Day 1 before first dose of study drug.
21. Patients in Germany who are committed to an institution by virtue of an order issued either by 
judicial or administrative authorities as per German law.
8.0
STUDY DRUG
8.1
Study Drug Administration
All protocol-specific criteria for administration of study drug must be met and documented before 
drug administration. Study drug will be administered only to eligible patients under the 
supervision of the investigator or identified subinvestigator(s). All patients will receive TAK-981 
and rituximab as specified in the schedule of events (SOEs) (Appendix A).
Each 21-day treatment cycle will consist of TAK-981 administration on Day 1 and Day 8 (2 weeks 
on and 1 week off) or on Days 1, 4, 8, and 11 (BIW) every 21 days as per the assigned cohort. 
During Cycle 1 only, rituximab will be dosed in a loading regimen that consists of rituximab at the 
clinically approved dose of 375 mg/m2 on Days 1, 8, and 15 of a 21-day cycle. From Cycle 2 
onwards, TAK-981 will be administered as per the assigned schedule, ie, Days 1 and 8 or Days 1, 
4, 8, and 11, and rituximab only on Day 1 of each 21-day cycle. During Phase 1 of this study, 
alternative dosing schedules for TAK-981 (eg, Day 1, or Days 1, 4, 8, and 11, or Days 1, 8, and 15 
in 21-day cycles) were explored, only after discussions between sponsor and the investigators. For 
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patients initially treated with TAK-981 in a more dense schedule, such as on Days 1, 4, 8, and 11 or 
Days 1, 8, and 15 for at least 6 cycles; and that present with an objective response, a less dense 
schedule of TAK-981 (eg, on Day 1, or on Days 1 and 8) may be considered upon discussion and 
agreement between the investigator and sponsor.
On C1D1 only, rituximab will be administered first (before TAK-981 infusion). Starting at C1D8 
onwards, TAK-981 will be administered before rituximab on days on which both TAK-981 and 
rituximab are given on the same visit day. At least 1 hour should elapse between the completion of 
the infusion of the first study drug and the initiation of the infusion of the second study drug.
The rationale for dosing rituximab before TAK-981 on C1D1 is that most of the infusion reactions 
due to rituximab in patients have been reported primarily during the first infusion with time to 
onset of 30 to 120 minutes (Appendix I) (Rituxan (rituximab) Injection for Intravenous Use 2019). 
The proportion of patients experiencing acute IRRs decreases with subsequent courses of 
rituximab (van Vollenhoven et al. 2010; van Vollenhoven et al. 2015). Although most 
rituximab-related reactions are mild to moderate in severity, there is a theoretical risk that when 
combined with TAK-981 any such reactions could be more severe. Therefore, rituximab is 
administered after premedication and before TAK-981 infusion on C1D1. Subsequent rituximab 
infusions are administered after TAK-981 infusion to facilitate PK/pharmacodynamic sampling.
Should no Grade 3 or greater IRR be observed at the PAD or MTD, the SMC may determine that 
TAK-981 be administered before the rituximab infusion on C1D1 of subsequent patients enrolled 
in the study.
Note: Fever is a common TEAE associated with the TAK-981 infusion. Consider prescribing
postinfusion antipyretic medications for up to 24 hours after the end of the TAK-981 infusion as a 
preventative measure. For any patient that has an infusion related fever, consider premedication 
with an antipyretic medication as prophylaxis. Investigator may consider reducing, even 
discontinuing, predose and postdose antipyretics if the patient experiences no major 
infusion-related fever. The clinical site is responsible for sourcing any pre- and post-medications 
outlined in the protocol.
8.1.1
Rituximab
Rituximab is available as single-use vials of 100 mg/10 mL and 500 mg/50 mL of drug substance 
(refer to Appendix I) (Rituxan (rituximab) Injection for Intravenous Use 2019).
The dose of rituximab will be calculated based on actual weight at enrollment. The total doses of 
rituximab throughout therapy should be based on the pretreatment body surface area (BSA) 
calculated using the Du Bois formula (BSA = 0.007184 × Weight0.425 × Height0.725) without 
consideration of fluctuations in body weight during treatment. Dose escalations or dose reductions 
of rituximab are not allowed in this study.
Premedication with an antihistamine and acetaminophen is required before rituximab dosing, in 
accordance with local best practice.
The first rituximab infusion (C1D1), will be initiated at a rate of 50 mg/hour and the infusion rate 
will be increased by 50 mg/hour increments every 30 minutes to a maximum of 400 mg/hour in the 
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Vital signs will be monitored throughout study drug administration according to the SOE 
(Appendix A). All patients will be monitored for 2 hours after the end of infusion of the last study 
drug. After the administration of TAK-981 or rituximab, the patient should be considered 
clinically stable by the investigator or designee before the next study drug is administered or the 
patient is discharged. If no infusion reaction is observed in the first 2 cycles, postinfusion 
monitoring may not be required and the patient can be discharged from the site per investigator 
discretion.
In all cases, the administration of TAK-981 or rituximab should occur in an area with access to 
resuscitating equipment and medications such as antihistamines, acetaminophen, corticosteroids, 
epinephrine, and bronchodilators readily available. Treatment must be stopped if the patient 
experience symptoms compatible with an infusion reaction of Grade 2 or greater. The 
management of infusion reactions and CRS is detailed in Section 8.10.6 and Section 8.10.7.
Dose administration of TAK-981 and rituximab should be performed on schedule; however, a 
dose delay of up to 4 days may occur because of inclement weather, holidays, vacations, or 
administrative reasons; a dose delay of up to 7 days is allowed to accommodate for COVID-19 
vaccine administration after discussion with the sponsor (see Section 8.8). For patients in the 
DLT-evaluation period (Cycle 1) rescheduling is allowed for a maximum of 1 dose. At least 7 days 
should elapse between consecutive doses of rituximab. On days on which both TAK-981 and 
rituximab are administered, should the treatment day be rescheduled, both TAK-981 and 
rituximab doses will be rescheduled.
As with other potentially toxic compounds, caution should be exercised in handling this drug. The 
use of gloves is recommended. Following topical exposure, events could include redness or 
blistering. Given the possibility of extravasation, it is advisable to closely monitor the infusion site 
for possible infiltration during drug administration. Administration through a central port is always 
preferred versus a peripheral line.
8.2
Definitions of DLT for Phase 1 Only
Toxicity will be evaluated according to the NCI CTCAE, Version 5.0; except CRS, which will be 
graded according to ASTCT Consensus Grading for CRS (Lee et al. 2019). During the Phase 1 part 
of the study, a DLT will be defined as any of the following AEs that occur during Cycle 1 unless 
they are considered by the investigator to be clearly unrelated to therapy:
1. Any Grade 5 AE.
2. Grade 4 neutropenia (ANC <0.5 × 109/L) lasting ≥7 consecutive days.
3. Febrile neutropenia: Grade ≥3 neutropenia (ANC <1 × 109/L) with fever and/or infection, 
where fever is defined as a single temperature >38.3°C or sustained temperature of ≥38°C for 
more than 1 hour.
4. Grade 4 thrombocytopenia lasting ≥7 consecutive days.
5. Grade 3 thrombocytopenia lasting ≥14 days or accompanied by ≥Grade 2 bleeding.
6. A platelet count <10,000/mm3 at any time.
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7. Grade ≥3 nonhematologic toxicity with the following exceptions:

Grade 3 fatigue lasting less than 7 days.

Grade 3 arthralgia/myalgia that responds to nonsteroidal anti-inflammatory drugs within 1 
week.

Grade 3 endocrine disorder that is managed with or without therapy and the patient is 
asymptomatic.

Grade 3 or 4 inflammatory reaction attributed to a local antitumor response.

Grade 3 IRR that resolves within 6 hours with appropriate clinical management.

Nonhematological laboratory changes that are otherwise asymptomatic and that can be 
controlled to ≤Grade 1 or baseline in 7 days with appropriate treatment or with dose 
interruption, and does not result in a delay of >7 days of planned treatment. In this setting, 
a course of action will be determined jointly by the investigators and the sponsor clinician.

Grade 3 elevation in alanine aminotransferase, aspartate aminotransferase, or alkaline 
phosphatase that resolves to ≤Grade 2 with supportive care within 7 days and is not 
associated with other clinically significant consequences.

Isolated Grade 3 electrolyte abnormalities that resolve to ≤Grade 2 with supportive care 
within 7 days and are not associated with other clinically significant consequences.

Grade 3 TLS or related electrolyte disturbances (hyperkalemia, hypophosphatemia, 
hyperuricemia) that resolve to ≤Grade 2 within 7 days.

≥Grade 3 diarrhea that can be controlled to ≤Grade 1 or baseline in 7 days with optimal 
supportive therapy.

≥Grade 3 nausea and/or emesis that can be controlled to ≤Grade 1 or baseline in 7 days 
with the use of optimal antiemetics (defined as an antiemetic regimen that employs both a 
5-hydroxytryptamine 3 serotonin receptor antagonist and a corticosteroid given in standard 
doses and according to standard schedules).

Grade 3 rash lasting ≤7 days after treatment that includes topical steroid treatment, oral 
administration of antihistamines, and pulse oral steroids (if necessary).
8. Delay in the initiation of Cycle 2 by more than 14 days from the scheduled Cycle 2 Day 1 date 
due to a lack of adequate recovery of treatment-related hematological or nonhematologic 
toxicities.
9. Grade 2 nonhematologic toxicities that are considered by the investigator to be related to study 
drug and dose-limiting.
DLTs for dose-escalation purposes will be evaluated during Cycle 1. Although DLT-like events 
may occur at any point during treatment, only DLTs observed during the DLT-evaluation period 
(Cycle 1) will necessarily influence dose-escalation decisions and MTD determination per BLRM. 
While the primary escalation schema is designed to determine MTD based on DLTs during its 
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evaluation period, cumulative toxicity beyond the DLT-evaluation period will be considered in 
assessing the overall tolerability of a given dose and consequently influence the dose escalation 
decision and selection of the RP2D. Patients will be monitored through all cycles of therapy for 
treatment-related toxicities.
Patients experiencing a DLT may continue in the study if they are deriving clinical benefit upon 
agreement by the sponsor, but they will be administered reduced doses of TAK-981 as appropriate.
8.3
Definition of DLT-Evaluable Patients for Phase 1 Only
Patients assigned to a particular dose cohort in Phase 1 are considered evaluable for assessment of 
a DLT if either of the following criteria are met during the DLT assessment period:

The patient experienced a DLT at any time after initiation of the first infusion of TAK-981.
OR

The patient completed all planned infusions of TAK-981 and 3 infusions of rituximab.
For the Phase 1 part of the study, patients who withdraw before completing the 3-week DLT 
assessment period for reasons other than a DLT, or who do not fulfill either of the criteria above, 
will not be evaluable for assessment of DLT for dose review decisions and will be replaced in the 
cohort.
8.4
Definition of PAD
The PAD of TAK-981 is defined as the dose at which there is evidence of pharmacodynamic 
effects (which may include the induction of cytokines/chemokines or type 1 IFN signature in 
blood, or evidence of activation of immune cells or antitumor activity). The PAD can be defined 
retrospectively once MTD is reached and it can be below MTD or coincide with it. 
8.5
Dose-Escalation Rules for Phase 1 Only
In the Phase 1 portion of the study, only TAK-981 will be escalated. Rituximab is administered at 
a fixed dose of 375 mg/m2 for each scheduled infusion. The following dose levels of TAK-981 are 
considered a priori:10, 15, 25, 40, 60, 90, 120, and 160 mg. Evaluation of intermediate doses, and 
expansion of an existing dose level are all permissible following discussions between the sponsor 
and the investigators, if such measures are needed for patient safety or for a better understanding of 
the relationships between dose and toxicity, exposure, or pharmacodynamics.
Initially, a minimum of 3 patients will be enrolled at the starting dose level. A provision of cohorts 
of 4 patients is contemplated during dose escalation to have an extra patient in case 1 of the 3 
earlier patients is unevaluable, or, if a patient within the cohort experiences a DLT, requiring 
cohort expansion to 6 patients. The following rules will be used only for this initial dose level:

If none of the 3 patients experiences a DLT during the first cycle, the dose may be escalated for 
the next planned dose level.
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
If 1 of the 3 patients exhibits a DLT, then that cohort will be expanded to a total of 6 patients.
–
If no more than 1 patient out of the 6 total patients has a Cycle 1 DLT, 3 patients will be 
enrolled at the next dose level.
–
If 3 or more of the 6 patients experience a Cycle 1 DLT, the starting dose level will be 
considered not tolerated and the dose will be de-escalated to 1 mg.
–
If 2 of the 6 patients have a Cycle 1 DLT, 3 additional patients will be enrolled. If any of 
those 3 additional patients have a Cycle 1 DLT, the starting dose will be considered not 
tolerated and dose will be de-escalated to 1 mg. If none of the 3 additional patients have a 
Cycle 1 DLT, the starting dose may be considered the MTD or escalated to the next dose 
level along with consideration of other safety, clinical, PK, and pharmacodynamic data.

If 2 or more patients of the 3 patients exhibit a DLT, then the starting dose level is considered 
too toxic, and the dose will be de-escalated to the 1 mg dose.
Alternative dosing schedules for TAK-981 (eg, Day 1, or Days 1, 4, 8, and 11, or Days 1, 8, and 15) 
may be explored in agreement between the investigators and sponsor. TAK-981 escalation for 
different TAK-981 schedules will be evaluated separately.
Dose-escalation and cohort expansion decisions will be determined by the SMC. The SMC will 
review the Cycle 1 safety of all treated patients and make decisions regarding dose escalation. In 
addition, the available PK and pharmacodynamic information from this study as well as emerging 
safety, PK, and pharmacodynamic data from the FIH study (TAK-981-1002) will be evaluated to 
support the dose-escalation decisions by the SMC.
Starting from the second dose of patients, the BLRM will be used for dose recommendations as 
well as information from the FIH study TAK-981-1002. However, at the End of Cohort meeting 
the SMC will make the final decision on the next dose level based on the evaluation of all evidence 
available. The recommended dose by BLRM will be the one that has the highest posterior 
probability of having a DLT rate that falls into the interval [0.16, 0.33]. In the meantime, following 
the Escalation With Overdose Control principle, the posterior probability of the recommended 
dose having a DLT rate above 0.33 must not exceed 35% (see Section 13.3 and Appendix H). 
Escalation may continue until 1 of the following stopping rules is met:
At least 6 patients are enrolled at the current dose and the current dose is the recommended 
dose for the next cohort,
OR
At least 9 patients are enrolled at the next recommended dose level and the posterior 
probability of the next recommended dose level having a DLT rate that falls into the 
interval [0.16, 0.33] exceeds 50%.
Once either of the above rules has been met, MTD may be declared. The study team may decide to 
stop dose escalation without identifying MTD based on pharmacodynamic markers, antitumor 
activity, non-DLT AEs, PK, or a combination of all or some of these factors. More conservative 
dose escalation, evaluation of intermediate doses, and expansion of an existing dose level are all 
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permissible following discussions between the sponsor and the investigators, if such measures are 
needed for patient safety or for a better understanding of the dose-related toxicity, exposure, or 
pharmacodynamics of TAK-981.
8.6
Dose Management and Modification Guidelines
Patients will be evaluated according to the SOE (Appendix A) for possible toxicities. Toxicities 
are to be assessed according to the NCI CTCAE Version 5.0; except CRS which will be graded 
according to ASTCT Consensus Grading for CRS (Lee et al. 2019).The causal relationship of each 
AE should be assessed in relation to TAK-981 and to rituximab so that dose modifications can be 
made accordingly.
Dose management and modification guidelines for toxicities are described below for TAK-981 
based on the nature and severity of AEs and causality determination by investigators. Further 
clarification can be obtained in consultation with the sponsor clinician (or designee). In this study 
the dose of rituximab cannot be modified. Depending on the toxicity observed the infusion of 
rituximab can be interrupted (in case of IRR, for example), delayed, or discontinued.
8.6.1
Intrapatient Dose Escalation
Patients who have tolerated treatment at the initially assigned dose may have their doses of 
TAK-981 increased in subsequent cycles of treatment only if all patients in the next dose level
cohort have completed assessment for Cycle 1 and a decision has been made that this dose level
does not exceed the MTD.
8.6.2
Criteria for Beginning or Delaying a Subsequent Treatment Cycle
A treatment cycle in this study is 21 days. For a new cycle of treatment to begin, the patient must 
meet the following criteria:

ANC ≥1.0 × 109/L.

Platelet count ≥75.0 × 109/L (platelet count ≥50.0 × 109/L if no change on the baseline 
platelets level from the screening visit and it is clearly due to marrow involvement).
Before starting a new treatment cycle, TAK-981/rituximab-related AEs or laboratory 
abnormalities must have returned to ≤Grade 1 or baseline (unless otherwise specified). If the 
patient fails to meet the criteria cited above for retreatment, initiation of the next cycle of treatment 
should be delayed for 1 week. At the end of that time, the patient should be re-evaluated to 
determine whether the criteria for retreatment have been met. Should the start of the next cycle 
need to be delayed for more than 2 weeks because of incomplete recovery from treatment-related 
toxicity, the patient may be withdrawn from treatment unless there is clinical benefit as assessed 
by the investigator, with agreement by the sponsor’s medical monitor.
8.6.3
Criteria for Dose Interruption or Dose Reduction
All toxicities that occur during the study will be actively managed following the standard of care 
unless otherwise specified in the protocol. Patients experiencing AEs attributed to TAK-981, 
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rituximab, or the combination may continue study treatment with the same dose, may have the 
treatment held or may be permanently discontinued from the study. Patients who have study drugs 
held because of treatment-related or possibly related AEs should resume study drug treatment 
according to the dose modification guidelines below.
8.6.3.1
TAK-981
Dosing of TAK-981 should be interrupted during a treatment cycle or reduced according to the 
dose modification recommendations listed in Table 8.a for nonhematologic toxicity and Table 8.b
for hematologic toxicities. When the dose of TAK-981 is withheld based on the listed criteria, 
clinical and laboratory reevaluation should be repeated at QW or more frequently, depending on 
the nature of the toxicity observed until the toxicity resolves to the Grade specified in Table 8.a and 
Table 8.b. If indicated, TAK-981 dose should be reduced by at least 1 dose level (or by 50% if the 
patient is receiving the first dose level).
If TAK-981 alone or in combination with rituximab cannot be administered within a cycle in a 
48-hour window, because of an AE, the dose will be missed and the patient will be scheduled for 
the next administration per SOE.
In general, after a dose is reduced, it should not be re-escalated even if there is minimal or no 
toxicity with the reduced dose. However, if further evaluation reveals that the AE that led to the 
dose reduction was not study drug related, or there were other circumstances contributing to the 
AE that are unlikely to recur, the dose may be re-escalated to the original dose level. Up to 2 dose 
level reductions of TAK-981 due to AEs are permitted. If more than 2 dose-level reductions of 
TAK-981 are needed to manage TAK-981 related AEs, treatment with TAK-981 should be 
discontinued.
In the Phase 1 portion of the study, intrapatient dose reductions of TAK-981 are not permitted in 
Cycle 1 unless the patient experiences a DLT attributed to TAK-981. DLTs are defined in 
Section 8.2. Patients experiencing a DLT in Cycle 1 may continue in the study upon resolution of 
the toxicity; however, a dose reduction by at least 1 dose level of TAK-981 should be considered 
based on the toxicity and discussion between investigator and sponsor.
Refer to the Pharmacy manual for dose level reduction table.
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Table 8.a
General Dose Modification Recommendations for TAK-981 Nonhematologic 
Drug-Related AEs
Criteria
Action
Grade 1 AEs
No dose reductions or interruptions.
Grade 2 AEs
Treat according to local practice.
Patients experiencing Grade 2 AEs considered related to study treatment that are not easily 
managed or corrected and are not tolerable to the patient, or AEs that are not acceptable in the 
investigator’s judgment, should have study treatment interrupted until the AE resolves to 
≤Grade 1 or baseline and then restarted at the same dose or, depending on the toxicity, resume 
treatment at the next lower dose level.
Grade 3 and Grade 
4 
non – life-threateni
ng AEs
Hold TAK-981 until resolution to ≤Grade 1 or baseline, and then resume treatment at the next 
lower dose level, except for the following instances that do not require dose reduction:

≥Grade 3 nausea, vomiting, and/or diarrhea resolved to ≤Grade 1 or baseline within 72 
hours with optimal antiemetics and/or antidiarrheal following local practice.

Transient Grade 3 fatigue (lasting <72 hours) and asymptomatic ≤Grade 4 laboratory 
abnormalities that the investigator considers not clinically significant following agreement 
between sponsor and investigators.
–
*Note: for QTcF ≥501 ms or >60 ms change from baseline, consult a cardiologist, 
manage according to standard clinical practice. For Grade 3 events treatment 
withdrawal should be evaluated; discuss with Takeda/designee. For Grade 4 events,
study drug should be permanently discontinued 
(oncologypro.esmo.org/education-library/esmo-handbooks/oncological-emergencies/
introduction, Chapter 1: Cardiac Complications of Cancer and Anticancer Treatment,
in ESMO Handbook of Oncological Emergencies, Accessed 22 April 2022).
Grade 4 
life-threatening 
AEs
Permanently withdraw the patient from the study.
AEs of all grades
If treatment has been held for >14 consecutive days without resolution of the toxicity (to 
baseline or ≤Grade 1 or if considered a sequela), consider permanently discontinuing study 
treatment unless there is clinical benefit for the patient as assessed by the investigator and with 
sponsor’s approval. Treatment should be resumed at a reduced dose level after resolution of 
AEs to ≤Grade 1 or baseline.
AE: adverse event; CRS: cytokine release syndrome; QTcF: QT interval with Fridericia correction method.
For specific instructions in case of CRS, consult Section 8.10.7.
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Table 8.b
Dose Adjustments for TAK-981 Hematologic Drug-Related AEs
Criteria
Action
Neutropenia (ANC)
Grade 1 (ANC <LLN-1.5 × 109 cells/L).
Continue TAK-981 at the same dose level.
Grade 2 (ANC 1.0- <1.5 × 109 cells/L).
Continue TAK-981 at the same dose level.
Grade 3 (ANC 0.5- <1 × 109 cells/L) without 
fever.
Withhold dose until resolved to ≤Grade 2 or baseline, then:
If resolved in ≤7 days, resume treatment at the same dose 
level.
If resolved in >7 days, resume treatment at the previous safe 
lower dose level (ie, reduce by 1 dose level).
Grade 4 (ANC <0.5 × 109 cells/L) without fever.
Withhold dose until resolved to ≤Grade 2 or baseline, then if 
resolved in ≤7 days, resume treatment at the same dose level. 
If recovered in >7 days, second Grade 4 neutropenia event, 
ANC >0.1 × 109/L, or concomitant occurrence of mucositis or 
thrombocytopenia, resume treatment at the previous safe dose 
level.
Febrile neutropenia (ANC <1.0 × 109 cells/L, 
with a single temperature of >38.3°C or sustained 
temperature of ≥38°C for more than 1 hour).
Withhold dose until fever/infection have recovered and ANC 
≤Grade 2 or baseline, then resume treatment at the previous 
safe lower dose level (ie, reduce by 1 dose level).
Thrombocytopenia (PLT)
Grade 1 (PLT < LLN-75.0 109 cells/L)
Grade 2 (PLT <75.0 – 50.0 × 109 cells/L)
Grade 3 (PLT <50.0 – 25.0 × 109 cells/L) without 
bleeding. 
Continue TAK-981 at the same dose level.
Continue TAK-981 at the same dose level.
Withhold dose until resolved to ≤Grade 1 or baseline, then:
If resolved in ≤7 days, resume treatment at the same dose 
level.
If resolved in >7 days, resume treatment at the previous safe 
lower dose level (ie, reduce by 1 dose level).
Grade 4 (PLT <25.0 × 109 cells/L) without 
bleeding.
Withhold dose until resolved to ≤Grade 1 or baseline, then if 
resolved in ≤7 days, resume treatment at the same dose level, 
if resolved in >7 days, then resume treatment at the previous 
safe lower dose level.
PLTs <10.0 × 109 cells/L, thrombocytopenia 
≥Grade 3 associated clinically significant 
bleeding, second event of Grade 4 
thrombocytopenia >7 days.
Consider permanently withdrawing the patient from the study, 
except when there is clinical benefit for the patient as assessed 
by the investigator and with sponsor’s approval. In this case, 
treatment should be resumed at a reduced dose level after 
resolution of AEs to ≤Grade 1 or baseline.
AE: adverse event; ANC: absolute neutrophil count; LLN: lower limit of normal; PLT: platelet.
Observation of isolated Grade 3/4 lymphopenia during Cycle 1 is not sufficient to hold the administration of 
TAK-981.
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Table 8.c
TAK-981 Dose Modification Guidelines for CRS
ASTCT Consensus Grade
TAK-981 Dose Modification
Grade 1:
Fever a (≥38°C)
Continue TAK-981 at the same dose.
Grade 2:
Fever a (≥38°C)
with hypotension not requiring 
vasopressors; 
and/or b hypoxia requiring low-flow c
nasal cannula
Withhold dose until resolved to ≤Grade 1, then:

If resolved in ≤14 days, maintain dose level.

If resolved in >14 days or repeat event, reduce by 1 dose level.

If >2 consecutive doses of TAK-981 are skipped due to CRS, 
permanently discontinue treatment with TAK-981.
Grade 3:
Fever a (≥38°C)
with hypotension requiring a 
vasopressor with or without 
vasopressin; 
and/or b hypoxia requiring high-flow c
nasal cannula, facemask, 
nonrebreather mask, or Venturi mask
Withhold dose until resolved to ≤Grade 1, then:

If resolved in ≤14 days, reduce by 1 dose level and if toxicity does not 
recur, consider re-escalating to original dose level.

If resolved in >14 days or repeat event, reduce by 1 dose level.

If >2 consecutive doses of TAK-981 are skipped due to CRS, 
permanently discontinue treatment with TAK-981.
Grade 4:
Fever a (≥38°C)
with hypotension requiring multiple 
vasopressors (excluding vasopressin); 
and/or b hypoxia requiring positive 
pressure (eg, CPAP, BiPAP, 
intubation, and mechanical 
ventilation)
Permanently discontinue TAK-981.
ASTCT: American Society for Transplantation and Cellular Therapy; BiPAP: bilevel positive airway pressure; CPAP: 
continuous positive airway pressure; CRS: cytokine release syndrome.
ASTCT consensus grade adapted from Lee et. Al. 2019 (Lee et al. 2019); CRS management recommendations are 
adapted from Neelapu et al, 2018 (Neelapu et al. 2018) and should be implemented at the investigator’s discretion.
a Fever is defined as temperature ≥38°C not attributable to any other cause. In patients who have CRS and 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. High-flow nasal cannula is defined as oxygen 
delivered at >6 L/minute.
8.6.3.2
Rituximab
In this study the dose of rituximab cannot be modified. Depending on the toxicity observed the 
infusion of rituximab can be interrupted (in case of IRR, for example), delayed, or discontinued. If 
hypersensitivity or infusion-related events develop, the infusion should be temporarily slowed or 
interrupted, but dose modifications are not allowed. The patient should be treated according to the 
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appropriate standard of care. Patients who discontinue rituximab for reasons described in 
Appendix I (Rituxan (rituximab) Injection for Intravenous Use 2019) may continue TAK-981 
treatment.
8.6.3.3
COVID-19 Infection 
If a patient is diagnosed with COVID-19 infection while on study, study treatment must be 
withheld until resolution of the infection. A patient may restart study treatment if the following 
criteria are met; otherwise the patient must discontinue treatment:

The infection must have resolved without ongoing clinical sequalae.

There should be 2 sequential negative severe acute respiratory syndrome coronavirus 2 (SARS 
CoV-2) tests 12 hours apart. Discuss with sponsor if needed considering polymerase chain 
reaction tests may continue to be positive for a prolonged period of time (Qu et al. 2020)
(Plebani 2021) (cdc.gov/coronavirus/2019-ncov/hcp/duration-isolation.html, Center for 
Disease Control. Ending Isolation and Precautions for People with COVID-19: Interim 
Guidance. Updated 14 January 2022. Accessed 22 April 2022).

The patient must be asymptomatic and the investigator believes, with agreement of the sponsor, 
that the patient would benefit from resuming study treatment.
8.6.4
Criteria for Discontinuation of Study Treatment Due to AEs
Treatment with study drug must be discontinued for any of the following reasons:

Occurrence of a DLT in dose escalation during the first cycle (exceptions to this criterion may 
be made after discussion and agreement between the investigator and the sponsor based on the 
benefit and risk assessment).

Occurrence of drug-related AEs that require study drug discontinuation per dose modification 
guidelines in Section 8.6 and the rituximab United States Package Insert (Appendix I) 
(Rituxan (rituximab) Injection for Intravenous Use 2019).

If subsequent cycle is delayed by >14 days for treatment-related AEs despite supportive 
treatment per standard clinical practice. (Exceptions to this criterion may be made after 
discussion and agreement between the investigator and the sponsor based on the benefit-risk 
assessment.)

If more than 2 dose reductions of TAK-981 are required for a patient. (Exceptions to this 
criterion may be made after discussion and agreement between the investigator and the sponsor 
based on the benefit-risk assessment.)

Occurrence of AEs, resulting in discontinuation of study drug that is desired or considered 
necessary by the investigator and/or the patient (if applicable).
It is possible that rituximab is permanently discontinued due to drug-related AEs, while the patient 
continues to receive TAK-981 and remains on treatment. Discontinuation of treatment occurs only 
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report form (eCRF). Patients must be instructed not to take any medications, including 
over-the-counter medications and herbal supplements, without first consulting with the 
investigator.
The following medications and procedures are permitted while the patient is receiving the study 
drug:

Myeloid growth factors (eg, granulocyte colony-stimulating factor, granulocyte-macrophage 
colony-stimulating factor) and/or erythropoietin support as clinically indicated are permitted.

Topical or inhaled steroids (eg, for the treatment of asthma) are permitted.

Patients should be transfused with RBCs and platelets as clinically indicated.

Concomitant treatment with bisphosphonates or RANKL inhibitors will be allowed for 
patients with evidence of lytic destruction of bone or with osteopenia, according to the 
American Society of Clinical Oncology Clinical Practice guidelines or institutional practice in 
accordance with the product label, unless specifically contraindicated.

Narrow therapeutic range Pgp substrates such as digoxin or dabigatran may be used with caution, 
and patients requiring use of these drugs will be closely monitored.

COVID-19 vaccination is generally allowed for patients enrolled in the study with the 
exception of live attenuated vaccines which must be completed at least 4 weeks prior to 
treatment initiation. COVID-19 vaccination should follow local guidance and regulations. 
Ideally, patients will have completed vaccination prior to treatment initiation as treatment with 
rituximab may negatively affect the efficacy of vaccination. For patients enrolled in Phase 1, 
vaccination during Cycle 1 is not permitted as this may confound the evaluation of safety and 
the determination of DLTs. Vaccination should be avoided within ± 3 days of TAK-981 
administration and should be administered after the last dose of TAK-981 of a given cycle; 
study treatment may be delayed for up to 7 days to accommodate a vaccine dose administration 
after discussion with the Sponsor. Vaccination should be captured as a concomitant 
medication.
Additional concomitant medications and procedures are permitted during the study to prevent and 
actively manage AEs related or not related to the study drug(s) unless prohibited as specified in the 
protocol. Supportive measures consistent with optimal patient care may be given throughout the 
study unless prohibited as specified in the protocol.
8.9
Precautions and Restrictions
Precautions and requirements for a safe administration of TAK-981 and/or rituximab are detailed 
in Section 8.1.
It is not known what effects TAK-981 or rituximab has on human pregnancy or development of the 
embryo or fetus; therefore, female patients participating in this study should avoid becoming 
pregnant, and male patients should avoid impregnating a female partner. Nonsterilized female 
patients of reproductive age and male patients should use effective methods of contraception 
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through defined periods during and after study treatment as specified below (see also Appendix J
for acceptable methods of contraception).
Female patients must meet 1 of the following:

Postmenopausal for at least 1 year before the screening visit, or

Surgically sterile, or

If they are of childbearing potential, agree to practice 1 highly effective method and 1 
additional effective (barrier) method of contraception at the same time, from the time of 
signing of the 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 subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.)
Male patients, even if surgically sterilized (ie, status postvasectomy) must agree to 1 of the 
following:

Agree to practice effective barrier contraception during the entire study treatment period and 
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 subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation 
methods), withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.
Before starting treatment, male patients should be advised to seek counseling on sperm storage, 
and female patients should be advised to seek counseling on egg storage.
8.10
Management of Clinical Events
Therapies that are required to manage AEs and control cancer symptoms are allowed based on 
standard clinical practice, unless specifically excluded. Supportive care agents, such as 
erythropoietin, granulocyte colony-stimulating factor, blood products (RBC and platelet 
transfusions), and pain medications are permitted as needed per American Society of 
Hematology/American Society of Clinical Oncology guidelines or local institutional practice. If 
dose alterations are necessary as a result of the events detailed below, refer to Section 8.6.
In the sections below guidance for the management of some expected AEs based on observations 
in nonclinical toxicology or other AEs that have not been substantiated in these experiments but 
that could be expected because of the mechanism of action of TAK-981, and warnings and 
precautions in the rituximab label. This guidance is not expected to replace investigator judgment 
in the management of AEs. Additional information on the potential risks can be found in 
Sections 4.2.5 and 4.5.1, and the current IB.
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8.10.1
Nausea or Vomiting
This study will not initially employ prophylactic antiemetics before the first dose of the study drug 
during dose escalation. However, a patient who develops nausea or vomiting will be actively 
managed by employing optimal antiemetic treatment based on local standard practice. 
Additionally, antiemetics may be used prophylactically as clinically indicated following the 
occurrence of a first event of study drug-related or possibly related nausea and/or vomiting. An 
optimal antiemetic regimen is defined as one that employs both a 5-hydroxytryptamine 3 serotonin 
receptor antagonist and a short course of corticosteroid given in standard doses and according to 
standard schedules. If these are inadequate, an NK-1 antagonist may be added.
8.10.2
Diarrhea
This study will not initially employ prophylactic antidiarrheals; however, there is no prohibition 
against their use in the management of a patient who develops diarrhea. Patients will be instructed 
to take antidiarrheal medication(s) (ie, loperamide) at the physician’s discretion until they are 
diarrhea-free for at least 12 hours. Fluid intake should be maintained to avoid dehydration.
8.10.3
Anemia, Thrombocytopenia, or Neutropenia
Please refer to Table 8.b for dose delay and reduction recommendations for hematologic toxicities. 
TAK-981 should be held if a significant treatment-emergent cytopenia or bleeding is suspected to 
be related to, or can be worsened by, study treatment. Precautionary measures should be taken to 
prevent bleeding and overwhelming infections. Blood transfusions (RBCs or platelet) and 
hematopoietic or thrombopoietic stimulating factors may be used to treat 
cytopenia/thrombocytopenia at the discretion of the investigator per standard clinical practice. Use 
of myeloid growth factor (eg, granulocyte colony-stimulating factor) support to treat ≥Grade 3 
neutropenia and/or febrile neutropenia is recommended per regional guidelines or local 
institutional practice; prophylaxis is permitted per regional guidelines or local institutional 
practice.
8.10.4
Infusion Site Care
Skin lesions, which may include inflammation or necrosis, represent a potential risk of TAK-981 
and were observed at the injection site in rats. Local institutional guidelines must be applied to 
stress proper administration and prevention of accidental extravasation of TAK-981. Usage of 
IV port is highly recommended. IV line should be flushed at the end of the infusion accordingly to 
local procedures. Monitoring at the beginning and during infusion must be ensured. If 
extravasation occurs, the infusion must be discontinued immediately and institutional guidelines 
applied. Treatment and monitoring of patients until symptoms resolve should be consistent with 
institutional standards and guidelines as appropriate. Patients should be instructed to report any 
discomfort, pain, or swelling at the infusion site.
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8.10.5
Lymphopenia and Opportunistic Infection Prophylaxis
Because lymphopenia is one of the most common AEs associated with the use of rituximab and is 
also an expected TAK-981–related AE, patients may be at an increased risk of opportunistic 
pathogens. Follow-up with standard hemograms and serial immunophenotyping will help to make 
clinical decisions about the risk of immunosuppression.
Prophylaxis for Pneumocystis jiroveci pneumonia should be initiated if the following is present:

Absolute CD4+ T-cell count of <200/mm3.

Percent CD4+ T-cells <20%.

Prior episode of PJP in medical history.
For older patients; patients with recent exposure to steroids, rituximab, cyclophosphamide, or 
immunosuppressive agents; or patients who, in the investigator’s opinion, are more susceptible to 
opportunistic infection at baseline, PJP prophylaxis should be considered at the start of study 
treatment. When steroids or any immunomodulatory agents need to be used to manage AEs during 
the study, PJP prophylaxis should be considered when the study treatment resumes or is 
co-administered. Trimethoprim-sulfamethoxazole is recommended as the treatment of choice for 
PJP prophylaxis unless contraindicated; however, investigator discretion in selecting a more 
appropriate prophylaxis regimen for their patients is permitted.
In the event of long-lasting lymphopenia, pneumocystis, or herpes zoster infection, prophylaxis 
can be started at investigator’s discretion.
8.10.6
IRRs
Rituximab can cause severe, including fatal, infusion reactions. Severe reactions typically occurred 
during the first infusion with time to onset of 30 to 120 minutes. Premedication with an 
antihistamine and acetaminophen is required before rituximab dosing, in accordance with local 
best practices. Should infusion-related events develop during rituximab infusion, the infusion 
should be temporarily slowed or interrupted. The patient should be treated according to the 
appropriate standard of care. The infusion can be continued at one-half the previous rate when 
symptoms resolve. If, in accordance with local clinical guidelines, a 90-minute rituximab infusion 
is given and the patient experiences an infusion reaction, refer to local prescribing information for 
infusion adjustments (Appendix I) (Rituxan (rituximab) Injection for Intravenous Use 2019).
Although TAK-981 is not a biological drug, its immune activating properties may also produce 
AEs in the category of IRRs. If such reactions were to occur, it might manifest with fever, chills, 
rigors, headache, rash, pruritus, arthralgias, hypotension or hypertension, bronchospasm, or other 
symptoms. Treatment and monitoring of patients until symptoms resolve should be consistent with 
institutional standards and guidelines as appropriate. If an IRR develops during the TAK-981 
infusion, the patient should be closely monitored until recovery of symptoms. The patient will be 
permanently discontinued from the study in case of a Grade 4 life-threatening reaction. All Grade 
3 or 4 infusion reactions should be reported within 24 hours to the medical monitor and 
communicated as an SAE if criteria are met. Concomitant medications administered for infusion 
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reaction treatment should be collected in the eCRF. Investigator may consider reducing, even 
discontinuing, predose and postdose antipyretics if the patient experiences no major 
infusion-related fever. If a patient presents signs and symptoms compatible with infusion reaction 
on days on which just TAK-981 is given, and at investigator discretion, premedication can be 
instituted for the remaining TAK-981 doses.
8.10.7
CRS
CRS should be diagnosed and managed following institutional guidelines and graded following 
ASTCT Consensus Grading for CRS (Lee et al. 2019). Recommendations for management of CRS 
are shown in Table 8.d and can be implemented at the investigator’s discretion. Please refer to 
Table 8.c for dose modifications after a CRS event.
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Table 8.d
CRS Management Recommendations
ASTCT Consensus Grade 
CRS Management Recommendations
Grade 1:
Fever a (≥38°C)
Monitor fluid status.
Supportive care: antipyretics, analgesics.
Grade 2:
Fever a (≥38°C) with hypotension 
not requiring vasopressors; and/or b
hypoxia requiring low-flow c nasal 
cannula
As per Grade 1 and:

Closely monitor all organ functions, including cardiac function.

IV fluid bolus.

Supportive care.
Grade 3:
Fever a (≥38°C) with hypotension 
requiring a vasopressor with or 
without vasopressin; and/or b
hypoxia requiring high-flow c
nasal cannula, facemask, 
nonrebreather mask, or Venturi 
mask 
As Grade 2 and:

Closely monitor all organ functions, including cardiac function.

Tocilizumab (8 mg/kg IV; maximum dose 800 mg) can be repeated after 6 
hours.

If refractory to tocilizumab, dexamethasone 10 mg IV every 6 hours; if 
refractory, increase to 20 mg every 6 hours or equivalent 
methylprednisone.

Vasopressors as needed.

Supplemental oxygen as needed for hypoxia (including high-flow O2 and 
CPAP).

Transfer to ICU.
Grade 4:
Fever a (≥38°C) with hypotension 
requiring multiple vasopressors 
(excluding vasopressin); and/or b
hypoxia requiring positive pressure 
(eg, CPAP, BiPAP, intubation and 
mechanical ventilation)
As per Grade 3 and:

Substitute dexamethasone with methylprednisone 1 g IV per day.

Mechanical ventilation.
ASTCT: American Society for Transplantation and Cellular Therapy; BiPAP: bilevel positive airway pressure; CPAP: 
continuous positive airway pressure; CRS: cytokine release syndrome; ICU: intensive care unit; IV: intravenous; O2: 
supplemental oxygen.
ASTCT consensus grade adapted from Lee et. Al. 2019 (Lee et al. 2019); CRS management recommendations are 
adapted from Neelapu et al, 2018 (Neelapu et al. 2018) and should be implemented at the investigator’s discretion.
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. High-flow nasal cannula is defined as oxygen 
delivered at >6 L/minute.
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8.10.8
TLS
Rituximab rapidly decreases the number of benign and malignant CD20+ cells, which can result in 
TLS (as defined in Appendix L). TLS has been reported to occur within 12 to 24 hours after the 
first rituximab infusion in patients with NHL. The risk of TLS is a continuum based on multiple 
factors, including comorbidities. Patients with high tumor burden are at greater risk of TLS. 
Reduced renal function further increases the risk.
Tumor burden assessments, including radiographic evaluation (eg, CT scan) should be performed 
at screening as well as blood chemistry assessments (creatinine, uric acid, potassium, phosphorus, 
calcium, albumin, and corrected calcium, if available) in all patients. Preexisting abnormalities 
should be corrected before initiation of treatment.
During C1D1, the prophylaxis measures listed below should be followed and more intensive 
measures (including hospitalization) should be employed as overall risk increases:
Hydration: Ensure adequate hydration (1.5-2 L) 48 hours before initiating therapy. 
Administer IV fluids as indicated based on overall risk of TLS or for those who cannot 
maintain adequate oral hydration.
Antihyperuricemic agents: Consider administration of allopurinol 72 hours before initiation. 
Rasburicase is recommended for patients at high-risk, especially those with high tumor 
burden.
Laboratory Assessments:
Predose: Assess blood chemistries before initiating treatment to evaluate kidney function and 
correct preexisting abnormalities.
Postdose: Monitor blood chemistries at 6 to 8 hours and at 24 hours after the rituximab dose. 
In Phase 2, the 24 hour sample is not required but may be collected based on the 
physician’s assessment of the patient’s TLS risk. Electrolyte abnormalities should be 
corrected. For hospitalized patients due to high-risk TLS, monitor blood chemistries at 4, 8, 
12, and 24 hours, and, as needed, after the rituximab dose.
Hospitalization: Based on investigator assessment, patients with high tumor burden (at least 1 
lesion >10 cm; or at least 1 lesion >5 cm and circulating lymphocytes >25,000 cells/mm3) 
and/or creatinine clearance <60 mL/min, are at greater risk of TLS and hospitalization 
should be considered for the first 24 to 48 hours of treatment for more intensive 
prophylaxis and monitoring. Consider hospitalization for subsequent doses based on 
reassessment of risk.
Correct electrolyte abnormalities, monitor renal function and fluid balance, and administer 
supportive care, including dialysis as clinically indicated.
8.11
Blinding and Unblinding
This is an open-label study.
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Commercially available IV formulation of rituximab background therapy will be used. The 
Sponsor will provide commercial supplies of rituximab for IV administration, labeled 
appropriately for investigational use as per the regulations of the relevant country health authority. 
Subjects enrolled in countries where rituximab is designated as non-investigational product, 
should obtain commercially available product through the local hospital pharmacy or licensed 
distributor. Subjects enrolled in countries where rituximab is designated as investigational product, 
will have rituximab supplied and packaged by the sponsor.
8.14
Packaging and Labeling
All label information will fulfill requirements specified by local governing regulations. Additional 
details are provided in the pharmacy manual.
8.15
Storage, Handling, and Accountability
TAK-981
Complete receipt, inventory, accountability, reconciliation, and destruction records will be 
maintained for all used and unused study drug vials. A drug dispensing log, including records of 
drug received from the sponsor and drug dispensed to patients will be provided and kept at the 
study site. Disposal instructions are provided in the pharmacy manual.
The required storage condition for TAK-981 study drug is -20°C ± 5°C. Study drug must be stored 
under the conditions specified on the label, and remain in the original container until 
dispensed. The investigator or designee must confirm that appropriate temperature conditions 
have been maintained for all TAK-981 received and that any discrepancies are reported and 
resolved before use of TAK-981.
Rituximab
Rituximab vials (100 mg/10 mL single-use vials and 500 mg/50 mL single-use vials) are stable at 
2°C to 8°C (36°F to 46°F). Rituximab vials should be protected from direct sunlight. Diluted 
rituximab solution should be stored at 2°C to 8°C because there is no preservative. The diluted 
solution is stable for 24 hours at 2°C to 8°C.
8.16
Other Protocol-Specified Materials
Information on supplies required by the site for drug administration is provided in the pharmacy 
manual. Clinical supplies other than study drug to be provided by the sponsor or designee are 
specified in the study manual.
9.0
STUDY CONDUCT
This study will be conducted in compliance with the protocol, GCP, applicable regulatory 
requirements, and ICH guidelines.
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9.1
Study Personnel and Organizations
The contact information for the project clinician for this study, the central laboratory and any 
additional clinical laboratories, the coordinating investigator, 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, please 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 IRB. Prisoners (or other populations that 
might be subject to coercion or exploitation) will not be enrolled into this study.
9.3
Treatment Group Assignments
This is not a randomized study. Patient assignment to a specific schedule will be decided jointly by 
the investigator and sponsor with the aim of maximizing enrollment efficiency in the study. Details 
can be found in the cohort management plan.
9.4
Study Procedures
Patients will be evaluated at scheduled visits over the following study periods: Screening, 
treatment, EOT, follow-up, and end of study. Evaluations during the screening period are to be 
conducted within 28 days before administration of the first dose of the study drug. Procedures 
conducted during the screening period that are performed within 3 days of C1D1 may also be used 
as the predose evaluation and do not need to be repeated, unless otherwise specified.
Unless otherwise noted, evaluations during the treatment period must occur before drug 
administration on scheduled visits. Tests and procedures should be performed on schedule for all 
visits. The timing of PK and pharmacodynamics assessment is specified in the SOE (Appendix A). 
Laboratory assessments may occur up to 3 days before the scheduled day. An additional window 
for testing procedure due to extenuating circumstances (ie, inclement weather, holidays, vacations, 
or other administrative reasons) is specified in the SOE. For image tests (CT scan, positron 
emission tomography [PET] with 18fluorodeoxyglucose [FDG-PET], MUGA scan, 
echocardiography), a ±7-day window is allowed.
Refer to the SOE (Appendix A) for timing of assessments. Additional details are provided as 
necessary in the sections that follow.
9.4.1
Informed Consent
Each patient must provide written informed consent before any study-required procedures are 
conducted, unless those procedures are performed as part of the patient’s standard care.
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9.4.2
Patient Demographics
The date of birth, race, ethnicity, and sex of the patient are to be recorded during screening.
9.4.3
Medical History
During the screening period, a complete medical history will be compiled for each patient. The 
history will emphasize the background and progress of the patient’s malignancy and include a 
description of prior therapies for it and the best response achieved by each one. In addition, 
concomitant medications will be recorded as specified in Section 9.4.10.
Available tumor genomic information obtained at the site will be collected.
9.4.4
Physical Examination
A physical examination will be completed per standard of care at the times specified in the SOE 
(Appendix A). Any clinically relevant findings are to be documented.
9.4.5
Patient Height and Weight
Height will be measured only during screening. Body weight should be recorded as specified in the 
SOE (Appendix A).
9.4.6
ECOG Performance Status
Performance status is to be assessed using the ECOG scale (see Appendix D for a description of 
the scale) at the times specified in the SOE (Appendix A).
9.4.7
Vital Signs
Vital signs (blood pressure, heart rate, and temperature) will be monitored as specified in the SOE 
(Appendix A).
9.4.8
Viral Serologies
Serological tests for hepatitis B (hepatitis B surface antigen [HBsAg] and IgG anti-hepatitis B core 
antibody), hepatitis C virus ([HCV]-antibody, also HCV-RNA by polymerase chain reaction if the 
patient is HCV-antibody positive), and HIV at screening period. For patients who show evidence 
of prior hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative 
but anti-hepatitis B core antibody [anti-HBc] positive), consult with physicians with expertise in 
managing hepatitis B regarding monitoring.
9.4.9
Pregnancy Test
A serum/urine pregnancy test will be obtained for women of childbearing potential at screening, 
C1D1, on Day 1 of each cycle, and at the EOT. The screening results must be available and 
negative before enrollment. For women of childbearing potential, if menstrual period is delayed 
during the study, absence of pregnancy must be confirmed by serum pregnancy test.
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Table 9.a
Clinical Chemistry and Hematology Tests
Hematology
Serum Chemistry
Coagulation
Hematocrit
Hemoglobin
Leukocytes with differential a
ANC
CD4/CD8 count and ratio
Platelet count
Albumin
Alkaline phosphatase
Alanine aminotransferase
Aspartate aminotransferase
Bilirubin (total)
(Blood) Urea nitrogen
Calcium
Bicarbonate or Carbon dioxide
Creatinine
(Standard) C Reactive protein
Chloride
Glucose
Lactate dehydrogenase
Magnesium
Phosphate
Potassium
Sodium
Protein (total)
Urate
Activated partial thromboplastin time
Prothrombin time
Fibrinogen
ANC: absolute neutrophil count.
a Differential laboratory results may be entered in unit types of “Absolute,” “Percent,” “Both,” or “Not applicable.”
“Absolute” values are preferred when available.
The chemistry laboratory parameters for TLS monitoring will include the following: creatinine, 
uric acid, potassium, phosphorus, calcium, albumin, and corrected calcium, if available.
Table 9.b
Clinical Urinalysis Tests
Urinalysis
Bilirubin
Glucose
Ketones
Leukocytes
Nitrite
Occult blood
Urine pH
Protein
Specific gravity
Turbidity and color
Urobilinogen
Hematology, chemistry, coagulation and urine samples may be taken up to 3 days before the visit 
(unless otherwise specified). All results must be evaluated before dosing. Microscopic analysis of 
urine sediment should be performed if significant abnormalities are detected in proteins, 
leukocytes, or blood.
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Serum creatinine clearance is to be estimated by the Cockcroft-Gault formula (Cockcroft and 
Gault 1976) as follows:
	
 
	
 
		
 
= [(140 −
) ∗	() ] / [72 ∗
! 
	
(/")]
For female patients, the result of the formula above should be multiplied by 0.85.
9.4.14.2
Immunosafety Markers
Blood samples for the analysis of autoimmune endocrinopathies as shown in Table 9.c will be 
obtained as specified in the SOE (Appendix A). They will be performed locally only. Results may 
be evaluated after dosing.
Table 9.c
Immunosafety Determinations in Serum
Serum Chemistry
Thyrotropin
Free thyroxine
Adrenocorticotropic hormone
9.4.14.3
Complement System Proteins
Blood samples for the analysis and quantification of the complement proteins C1q, C3, C4, and 
CH50 will be obtained as specified in the SOE (Appendix A). They will be performed locally only. 
Results may be evaluated after dosing.
9.4.15
Disease Assessment
9.4.15.1
Imaging
Appropriate cancer staging assessments should be performed (eg, MRI, FDG-PET-CT). Imaging 
assessments should be conducted according to Lugano Classification for staging and response 
assessment (Cheson et al. 2014). A baseline contrast-enhanced CT or MRI scan of the chest, 
abdomen, and pelvis in addition to an FDG-PET scan must be acquired at screening. Subsequently, 
the same imaging modality used at screening should be used throughout the study whenever 
possible. It is understood that some circumstances may require a different imaging modality. An 
alternate imaging modality is acceptable and may be performed at the investigator’s 
discretion. Objective assessments of the disease burden: target, non-target, and potential new 
lesions will be performed at each time point (a ±7-day window is allowed for image tests) as 
described in the SOEs (Appendix A). Radiographic images will be maintained at the site and can 
be requested by the sponsor at a later date. For Phase 2, radiographic images must be submitted to 
a centralized repository for future centralized review should that be required or desired. Imaging 
tests performed before the screening consent date may be used, if of diagnostic quality, as 
screening tests if the C1D1 is planned within the 28 days after the date of the test.
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9.7
Discontinuation of Treatment With Study Drug and Patient Replacement
Patients will be informed that they have the right to discontinue study treatment at any time for any 
reason, without prejudice to their medical care.
Treatment with study drug must be discontinued for any of the following reasons:

Pregnancy.

Withdrawal by patient.

AE that leads to TAK-981 discontinuation.

Death.

Initiation of another systemic anticancer treatment.

Study terminated by sponsor.

Treatment completion, ie, the patient completes 1 year of treatment and continuation is 
not approved.
Treatment with study drug may be discontinued for any of the following reasons:

Symptomatic deterioration.

Clinical progression.

PD.

CR (after discussion with sponsor).

Major protocol deviation.

Lost to follow-up.

Lack of benefit.
Once TAK-981 has been discontinued, all study procedures outlined for the EOT visit will be 
completed as specified in the SOE (Appendix A). The primary reason for study drug 
discontinuation will be recorded on the eCRF.
Note that some patients may discontinue study drug for reasons other than PD before completing 
the full treatment course (Section 9.9); these patients will remain in the study for posttreatment 
assessments as outlined in the SOE (Appendix A) until death occurs.
During dose escalation, patients who are withdrawn from treatment during Cycle 1 for reasons 
other than DLTs will be replaced.
In the case of study termination by the sponsor, eligible patients may have continued access to 
TAK-981 as described in Section 6.5.5.
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9.8
Study Compliance
Study drug will be administered or dispensed only to eligible patients under the supervision of the 
investigator or identified subinvestigator(s). The appropriate study personnel will maintain records 
of study drug receipt and dispensing.
9.9
Posttreatment Follow-up Assessments
Patients who stop treatment for any reason other than PD will continue to have PFS follow-up 
visits. The PFS follow-up visit should be conducted at the site every 12 weeks ±1 week from the 
last dose of study drug until the occurrence of PD, loss to follow-up, consent withdrawal, death, 
the start of subsequent systemic antineoplastic therapy, or study termination (Section 9.6), 
whichever occurs first. The duration of follow-up for PFS will be up to a maximum of 12 months 
for each patient, or until 50% of patients have progressed, whichever occurs first.
During Phase 2, patients who stop treatment due to PD will be followed every 12 weeks (±1 week) 
after documented PD for OS until death, loss to follow-up, consent withdrawal, or study 
termination for up to 12 months after the last patient discontinues or completes treatment, or until 
50% of patients have died, whichever occurs first. Survival information and death details 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). In addition, the start of another anticancer 
therapy for the disease under study will be collected.
Subsequent follow-up for PFS and OS, respectively, will be calculated from last contact.
Note: Related SAEs must be reported to the Global Pharmacovigilance department or designee; 
this includes deaths or SAEs 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.
9.10
Early Study Termination
The study may be terminated early by the sponsor at any time for reasons that may include a 
potential health hazard to patients, poor enrollment of patients (thus, making completion of the 
trial in an acceptable timeframe unlikely), or modification or discontinuation of study drug 
development.
The study may be stopped or terminated in a country if the favorable opinion or the approval in that 
country is revoked by that country’s ethics committee as mandated by German law.
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10.0
ADVERSE EVENTS
10.1
Definitions
10.1.1
Pretreatment Event Definition
A pretreatment event is any untoward medical occurrence in a patient or subject who has signed 
informed consent to participate in a study but before administration of any study medication; it 
does not necessarily have to have a causal relationship with study participation.
10.1.2
AE Definition
AE means any untoward medical occurrence in a patient or subject administered a pharmaceutical 
product; the untoward medical occurrence does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product whether or not it is related to the medicinal product. This includes any 
newly occurring event or a previous condition that has increased in severity or frequency since the 
administration of study drug.
All abnormal laboratory values will be reviewed by the investigator but only those abnormal 
values that lead to discontinuation or delay in treatment, dose modification, therapeutic 
intervention, or are considered by the investigator to be a clinically significant change from 
baseline will be assessed as AEs.
Disease progression of the malignancy under study assessed by measurement of malignant lesions 
on radiographs or other methods should not be reported as an AE. However, worsening of signs 
and symptoms of the malignancy under study should be reported as AEs in the appropriate section 
of the eCRF.
10.1.3
SAE Definition
SAE means any untoward medical occurrence that at any dose:

Results in death.

Is life-threatening (refers to an AE in which the patient was at risk of death at the time of the 
event. It does not refer to an event which hypothetically might have caused death if it were 
more severe).

Requires inpatient hospitalization or prolongation of an existing hospitalization (see 
clarification in the paragraph in Section 10.2 on planned hospitalizations).

Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions).

Is a congenital anomaly/birth defect.
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
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 1 of the outcomes listed above, or involves suspected 
transmission via a medicinal product of an infectious agent. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
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; except CRS which will be graded according to ASTCT 
Consensus Grading for CRS (Lee et al. 2019). 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.
Any death, whether due to side effects of the treatment, PD, or other causes is considered an SAE.
Hospitalization for previously planned procedure(s) or convenience will not be considered as a 
reportable SAE.
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 (see Section 10.3 for the period of observation). Any 
clinically relevant deterioration in laboratory assessments or other clinical finding is considered an 
AE. When possible, signs and symptoms indicating a common underlying pathology should be 
noted as a single comprehensive event.
Regardless of causality, SAEs must be reported (see 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 electronic data capture (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.
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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).
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.
Severity (toxicity grade) for each AE, including any laboratory abnormality, will be determined 
using the NCI CTCAE, Version 5.0; except CRS which will be graded according to ASTCT 
Consensus Grading for CRS (Lee et al. 2019). The criteria are provided in the study manual.
Relationship of the event to study drug administration (ie, its causality) will be determined by the 
investigator responding yes (related) or no (unrelated) to this question: is there a reasonable 
possibility that the AE is associated with the study drug?
10.3
Monitoring of AEs and Period of Observation
AEs, both nonserious and serious, will be monitored throughout the study as follows:

AEs will be reported from the signing of informed consent through 30 days after 
administration of the last dose of study drug and recorded in the eCRFs. AEs ongoing at EOT 
should be monitored until they are resolved, return to baseline, are clearly determined to be due 
to a patient’s stable or chronic condition or intercurrent illness(es), the start of second line 
alternative therapy, or 6 months after PD has occurred, whichever comes first.

SAEs will be reported to the Takeda Global Pharmacovigilance department or designee from 
the signing of informed consent through 30 days after administration of the last dose of study 
drug and recorded in the eCRF. After this period, only related SAEs must be reported to the 
Takeda Global Pharmacovigilance department or designee. SAEs should be monitored until 
they are resolved or are clearly determined to be due to a patient’s stable or chronic condition 
or intercurrent illness(es).
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events
If a woman becomes pregnant or suspects that she is pregnant while participating in this study, she 
must inform the investigator immediately and permanently discontinue study drug. The sponsor 
must also be contacted immediately by 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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If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, the sponsor must also be contacted immediately by sending a completed pregnancy 
form to the Takeda Global Pharmacovigilance department or designee. Every effort should be 
made to follow the pregnancy for the final pregnancy outcome. If transmission of a pregnancy 
report is not feasible, then a facsimile of the completed Takeda paper-based pregnancy form will 
be sent.
Pregnancies are to be reported through 12 months after the last dose of study drug.
10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose)
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product. Individuals who 
identify a potential product complaint situation should immediately report this via the phone 
numbers or email addresses provided below.
A medication error is a preventable event that involves an identifiable patient and leads to 
inappropriate medication use, which may result in patient harm. Whereas overdoses and 
underdoses constitute medication errors, doses missed inadvertently by a patient do not.
Individuals who identify a potential medication error (including overdose) situation should 
immediately report this via the email address provided below.
Product
Call Center
Email
TAK-981
Takeda
ctmcomplaint@takeda.com
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.
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 
and any other applicable SAEs to regulatory authorities, including investigators and IRBs, as 
applicable, in accordance with national regulations. Relative to the first awareness of the event 
by/or further provision to the sponsor or sponsor’s designee, suspected unexpected serious adverse 
reactions 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 in accordance with national regulations.
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11.0
STUDY-SPECIFIC COMMITTEES
11.1
SMC
During Phase 1, an SMC composed of the principal investigators and sponsor clinician will 
regularly review safety data to ensure patient safety throughout the study and make decisions on 
dose escalation as defined in the SMC charter.
11.2
IDMC
During Phase 2, an IDMC will be established to monitor safety and assess benefit/risk throughout 
the conduct of the Phase 2 portion of the study. The IDMC will consist of 3 to 5 members not 
associated with the conduct of the study and/or the sponsor with the exception of the compensation 
to IDMC members related to their IDMC activities. The IDMC members will be a 
multidisciplinary group that will include at least 2 hematologists with extensive experience in 
clinical study conduct and a biostatistician with substantial experience in the IDMC process. The 
committee will perform data review to monitor safety and assess benefit/risk throughout the 
conduct of the Phase 2 portion of the study. IDMC meetings will be held at the end of each stage 
for each of the respective arms in Phase 2. Ad-hoc IDMC meetings may also be held if a 
significant issue should arise.
11.3
Independent Review Committee
All imaging performed to assess response to treatment will be submitted to a central core imaging 
repository. An independent review committee (IRC) will be established to independently review 
efficacy imaging endpoints once any cohort in Phase 2 meets the efficacy threshold in Stage 1 and 
begins enrolling patients in Stage 2. Please refer to the imaging manual and/or IRC charter for 
further details.
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 World Health 
Organization Drug Dictionary.
12.1
eCRFs
Completed eCRFs are required for each subject 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.
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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 subject’s medical and 
hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed eCRFs are 
the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor.
12.2
Record Retention
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal-sensitive paper, source 
worksheets, all original signed and dated ICFs, subject authorization forms regarding the use of 
personal health information (if separate from the ICFs), electronic copies of eCRFs including the 
audit trail, 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 
subject’s chart to ensure long-term legibility. Furthermore, ICH E6 Section 4.9.5 requires the 
investigator to retain essential documents specified in ICH E6 (Section 8) until at least 2 years 
after the last approval of a marketing application for a specified drug indication being investigated 
or, if an application is not approved, until at least 2 years after the investigation is discontinued and 
regulatory authorities are notified. In addition, ICH E6 Section 4.9.5 states that the study records 
should be retained until an amount of time specified by applicable regulatory requirements or for a 
time specified in the clinical study-site agreement between the investigator and sponsor.
Refer to the clinical study-site agreement for the sponsor’s requirements for record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of any 
such documents.
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13.1.2
Analysis of Demographics and Other Baseline Characteristics
Patient demographic and baseline characteristics will be summarized descriptively. Variables to be 
analyzed include gender, age, race, medical history, prior medications/therapies, ECG findings, 
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.
13.1.3
Efficacy Analysis
13.1.3.1
Primary Efficacy Analysis
Phase 1:
Efficacy is not the primary objective for this study in the Phase 1 portion. The efficacy analysis 
will mainly focus on the Phase 2 portion of this study.
In the Phase 1 portion of this study, efficacy parameters such as ORR, DOR, and PFS may be 
summarized as appropriate. Disease response will be categorized and presented in listings.
Phase 2:
The primary endpoint for Phase 2 portion is ORR (CR + PR) as defined by the investigator 
according to Lugano criteria for lymphoma response, from Cheson 2014 (Cheson et al. 2014).
ORR is defined as the proportion of patients who achieve CR and PR (determined by the 
investigator) during the study.
The primary efficacy analysis will be based on the response-evaluable population in the Phase 2 
portion of the study.
Estimates of the ORR (CR + PR) will be presented with 2-sided 95% exact binomial confidence 
intervals.
13.1.3.2
Secondary Efficacy Analysis
Secondary efficacy endpoints include DCR, DOR, TTP, and PFS.
DCR is defined as the proportion of patients who achieve CR, PR, or SD (determined by the 
investigator) during the study.
DOR is the time from the date of first documentation of a PR or better to the date of first 
documentation of PD for responders (PR or better). Responders without documentation of PD will 
be censored at the date of last response assessment that is stable disease or better.
TTP is defined as the time from the date of first study drug administration to the date of first 
documented disease progression by the investigator.
PFS is defined as the time from the date of the first dose administration to the date of first 
documentation of PD or death due to any cause, whichever occurs first. PD will be determined by 
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Response Evaluation Criteria in Lymphoma for patients with lymphoma. Patients without 
documentation of PD will be censored at the date of the last response assessment that is stable 
disease or better.
PFS will be analyzed descriptively using Kaplan-Meier method for safety analysis set. DOR will 
be analyzed using Kaplan-Meier method for response-evaluable analysis set.
13.1.4
PK Analysis
The PK of TAK-981 will be characterized in this study (ie, rituximab PK will not be 
characterized).
PK parameters for TAK-981 will be estimated using noncompartmental methods with Phoenix 
WinNonlin software. The PK parameters will be estimated from the concentration-time profiles 
for the PK population. The following PK parameters will be estimated, as permitted by data, for 
samples collected during C1D1 and C1D8:

Cmax.

tmax.

AUC0-∞.

AUC0-t.

t1/2z.

CL.

Vss.
PK parameters will be summarized using descriptive statistics. Individual TAK-981 
concentration-time data and individual PK parameters will be presented in listings and tabulated 
using summary statistics by dose cohort. Individual and mean concentration-time profiles will be 
plotted by dose cohort. The above parameters will not be estimated for the sparse PK samples 
collected during the Phase 2 portion of study.
The serial and sparse PK data collected in this study are intended to contribute to future population 
PK analyses of TAK-981. These population PK analyses may include data collected in other 
TAK-981 clinical studies. The analysis plan for the population PK analysis will be separately 
defined, and the results of these analyses will be reported separately.
13.1.5
Pharmacodynamic Analysis
The analysis of blood and skin biomarker profiles for each dose and timepoint tested will be 
tabulated. When possible, the dynamic range for each biomarker and fold change will be 
determined to better understand TAK-981 biological activity range and duration of 
pharmacodynamic effect, and to help determine the PAD/RP2D for the TAK-981/rituximab 
combination. 
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Exposure to study drug and reasons for discontinuation will be tabulated.
TEAEs that occur after administration of the first dose of study drug and through 30 days after the 
last dose of study drug will be tabulated.
AEs will be tabulated according to the Medical Dictionary for Regulatory Activities and will 
include the following categories:

TEAEs.

Drug-related TEAEs.

Grade 3 or higher TEAEs.

Grade 3 or higher drug-related TEAEs.

The most commonly reported TEAEs (ie, those reported by 10% of all patients).

SAEs (related and regardless of relationship).

TEAE leading to study drug modification and discontinuation.
The incidence of DLTs will be tabulated using the DLT-evaluable analysis set.
Descriptive statistics for the actual values of clinical laboratory parameters (and/or change from
baseline in clinical laboratory parameters) will be presented for all scheduled measurements over 
time. Mean laboratory values over time will be plotted for key laboratory parameters.
Descriptive statistics for the actual values (and/or the changes from baseline) of vital signs and 
weight will be tabulated by scheduled time point. ECOG Performance Scores will be summarized 
using a shift table.
Shift tables for laboratory parameters will be generated for changes in NCI CTCAE grade from 
baseline to the worst postbaseline value. Graphical displays of key safety parameters, such as 
scatter plots of baseline versus worst postbaseline values, may be used to understand the TAK-981 
safety profile.
All concomitant medications collected from the first dose of study drug throughout the study 
period will be classified to preferred terms according to the World Health Organization drug 
dictionary.
Additional safety analyses may be performed to most clearly enumerate rates of toxicities and to 
further define the safety profile of TAK-981.
13.2
Interim Analysis and Criteria for Early Termination
In Phase 1, investigators and sponsor representatives will review accruing data to determine dose 
escalation and number of patients per cohort in the dose-escalation phase (see Section 8.5).
During the Phase 2 part of the study, interim analysis for futility will be performed for each of the 
cohorts upon completion of the respective Stage 1.
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misconduct, increase the health risk to the subject, 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 subject 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.
14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the United States FDA, the United Kingdom Medicines and 
Healthcare products Regulatory Agency [MHRA], the Pharmaceuticals and Medical Devices 
Agency [PMDA] for 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, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of Helsinki, 
and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct the study 
according to applicable local or regional regulatory requirements and align his or her conduct in 
accordance with the responsibilities of the investigator that are listed in Appendix B. The 
principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities.
15.1
IRB 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 
Federalwide Assurance number or comparable number assigned by the United States Department 
of Health and Human Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the IB, a copy of the ICF, and, if 
applicable, subject recruitment materials and advertisements and other documents required by all 
applicable laws and regulations must be submitted to a central or local IRB or IEC for approval. 
The IRB’s or IEC’s written approval of the protocol and subject informed consent must be 
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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 notify sites 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, no protocol activities, including screening, 
may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the ICF, recruitment 
materials intended for viewing by subjects, local safety reporting requirements, reports and 
updates regarding the ongoing review of the study at intervals specified by the respective IRB or 
IEC, and submission of the investigator’s final status report to IRB or IEC. All IRB and IEC 
approvals and relevant documentation for these items must be provided to the sponsor (or 
designee).
Subject incentives should not exert undue influence for participation. Payments to subjects 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, subject authorization form (if applicable), and subject 
information sheet (if applicable) describe the planned and permitted uses, transfers, and 
disclosures of the subject’s personal and personal health information for purposes of conducting 
the study. The ICF and the subject information sheet (if applicable) further explain the nature of 
the study, its objectives, and potential risks and benefits, and the date informed consent is given. 
The ICF will detail the requirements of the participant and the fact that he or she is free to 
withdraw at any time without giving a reason and without prejudice to his or her further medical 
care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the ICF 
and, if applicable, the subject authorization form. The ICF, subject authorization form (if 
applicable), and subject information sheet (if applicable) must be approved by both the IRB or IEC 
and the sponsor before use.
The ICF, subject authorization form (if applicable), and subject information sheet (if applicable) 
must be written in a language fully comprehensible to the prospective subject. It is the 
responsibility of the investigator to explain the detailed elements of the ICF, subject authorization 
form (if applicable), and subject information sheet (if applicable) to the subject. Information 
should be given in both oral and written form whenever possible and in the manner deemed 
appropriate by the IRB or IEC. If the subject is not capable of rendering adequate written informed 
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consent, then the subject’s legally acceptable representative may provide such consent for the 
subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to 
(1) inquire about details of the study and (2) decide whether to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines that he or she will participate 
in the study, then the ICF and subject authorization form (if applicable) must be signed and dated 
by the subject, or the subject’s legally acceptable representative, at the time of consent and before 
the subject enters into the study. The subject or the subject’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 subject authorization 
(if applicable) at the time of consent and before the subject enters into the study; however, the 
sponsor may allow a designee of the investigator to sign to the extent permitted by applicable law.
Once signed, the original ICF, subject authorization form (if applicable), and subject information 
sheet (if applicable) will be stored in the investigator’s site file. The investigator must document 
the date the subject signs the informed consent in the subject’s medical record. Copies of the 
signed ICF, the signed subject authorization form (if applicable), and subject information sheet (if 
applicable) shall be given to the subject.
All revised ICFs must be reviewed and signed by relevant subjects or the relevant subject’s legally 
acceptable representative in the same manner as the original informed consent. The date the 
revised consent was obtained should be recorded in the subject’s medical record, and the subject 
should receive a copy of the revised ICF.
15.3
Patient Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will 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 subject attributes, such as sex, age, or date 
of birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, United States FDA, United Kingdom MHRA, Japan PMDA), the 
sponsor’s designated auditors, and the appropriate IRBs and IECs to review the subject’s original 
medical records (source data or documents) including, but not limited to, laboratory test result 
reports, ECG reports, admission and discharge summaries for hospital admissions occurring 
during a subject’s study participation, and autopsy reports. Access to a subject’s original medical 
records requires the specific authorization of the subject as part of the informed consent process 
(see Section 15.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
identifying personal information removed, eg, subject name, address, and other identifier fields 
not collected on the subject’s eCRF.
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15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1
Publication
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study-site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the clinical study-site agreement. In the event of any discrepancy between the 
protocol and the clinical study-site agreement, the clinical study-site agreement will prevail.
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 subjects 
receive investigator contact information, they may call the site requesting enrollment into the trial. 
The investigative sites are encouraged to handle the trial inquiries according to their established 
subject screening process. If the caller asks additional questions beyond the topic of trial 
enrollment, they should be referred to the sponsor.
Any investigator who objects to Takeda providing this information to callers must provide Takeda 
with a written notice requesting that their information not be listed on the registry site.
15.4.3
Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov, and other publicly accessible 
websites (including the Takeda corporate site) and registries, as required by Takeda 
policy/standards, applicable laws, and/or regulations.
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Data Sharing
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.
15.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to clinical study subjects. 
Refer to the clinical study-site agreement regarding the sponsor’s policy on subject compensation 
and treatment for injury. If the investigator has questions regarding this policy, he or she should 
contact the sponsor or sponsor’s designee.
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16.0
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Lymphoma. N Engl J Med, 377(26), 2531-44.
Neelapu, S. S., Tummala, S., Kebriaei, P., Wierda, W., Gutierrez, C., Locke, F. L., et al. 2018. 
Chimeric antigen receptor T-cell therapy - assessment and management of toxicities. Nat 
Rev Clin Oncol, 15(1), 47-62.
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approach to phase I cancer trials. Statistics in Medicine, 27(13), 2420-39.
Oflazoglu, E. and Audoly, L. P. 2010. Evolution of anti-CD20 monoclonal antibody therapeutics 
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Oken, M. M., Creech, R. H., Tormey, D. C., Horton, J., Davis, T. E., McFadden, E. T., et al. 1982. 
Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin 
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Plebani, M. 2021. Persistent viral RNA shedding in COVID-19: Caution, not fear. EBioMedicine,
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Qu, Y. M., Kang, E. M. and Cong, H. Y. 2020. Positive result of Sars-Cov-2 in sputum from a 
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Schuster, S. J., Bishop, M. R., Tam, C. S., Waller, E. K., Borchmann, P., McGuirk, J. P., et al. 2019. 
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D. E., et al. 2010. Longterm safety of patients receiving rituximab in rheumatoid arthritis 
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Longterm Safety of Rituximab: Final Report of the Rheumatoid Arthritis Global Clinical 
Trial Program over 11 Years. J Rheumatol, 42(10), 1761-6.
Witzig, T. E., Luigi Zinzani, P., Habermann, T. M., Tuscano, J. M., Drach, J., Ramchandren, R., et 
al. 2017. Long-term analysis of phase II studies of single-agent lenalidomide in 
relapsed/refractory mantle cell lymphoma. Am J Hematol, 92(10), E575-E83.
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STING-dependent cytosolic DNA sensing mediates innate immune recognition of 
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Appendix A
Schedule of Events
SOEs for patients enrolled in the global study (except for those enrolled in China) are:

Phase 1: Table A-1, Table A-3 (PK assessments), and Table A-5 (biomarker sample collection).

Phase 2: Table A-2, Table A-4 (PK assessments), and Table A-6 (biomarker sample collection).
SOEs for patients enrolled in China (Phase 2 only) are:

Table A-2, Table A-4 (PK assessments), and Table A-7 (biomarker sample collection).
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Table A-1
SOE for Phase 1 (Global Patients Only; Excluding Patients Enrolled in China)
Procedure/Assessment
Screening a
Cycle 1
Cycle 2 and Subsequent Cycles
EOT
Follow-up b
Day
Day
30 (+10) d 
after Last 
TAK-981 
Dose
Every 
12 Wks
1
2
4
8
9
11
15
1
4
8
11
15
PFS
OS
Informed consent
X
Inclusion/exclusion criteria
X
Demographics
X
Medical history including available 
tumor information c
X
Physical examination d
X
Symptom-directed physical examination
X
X
Height
X
Weight d
X
X
X
ECOG performance status
X
X
X
X
Vital signs e
X
X
X f
X
X f
X f
X
X f
X
X f
X f
X
12-lead safety ECG (single record) g
X
X2
X2
X2
X
Echocardiography/MUGA (LVEF) scan 
i
X
X j
X
Monitoring of concomitant medications 
and procedures
Recorded from the signing of ICF through 30 days after the last dose of study drug.
X
AE reporting
Recorded from the signing of ICF through 30 days after the last dose of study drug or start of a new 
systemic treatment.
X
SAEs will be reported from signing of the ICF through 30 days after the last dose of study drug or any 
moment after EOT for related SAEs g
X
Treatment Administration
TAK-981 administration k
X
X f
X
X f
X f
X
X f
X
X f
X f
Rituximab administration k
X
X
X
X
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Procedure/Assessment
Screening a
Cycle 1
Cycle 2 and Subsequent Cycles
EOT
Follow-up b
Day
Day
30 (+10) d 
after Last 
TAK-981 
Dose
Every 
12 Wks
1
2
4
8
9
11
15
1
4
8
11
15
PFS
OS
Samples/Laboratory Assessments
Viral serologies l
X
Pregnancy test m
X
X
X
X
Hematology/Chemistry n
X
X
X
X
X
X j
X
TLS laboratory assessments o
X
X
Coagulation n
X
X
X
Urinalysis n, p
X
X
X
X
Immunosafety markers (hormones) q
X
X
X
Complement serum proteins n
X
X
X
X
X
Disease Assessment/Survival Follow-up
Imaging r
X
Every 2 months from C1D1 for the first 6 months, and every 12 weeks thereafter.
X
X
Bone marrow biopsy s
X Refer to Section 9.4.15.2 for details.
X
X
Investigator assessment of disease 
response
Every 2 months from C1D1 for the first 6 months, and every 12 weeks thereafter.
X
X
Survival follow-up
X
Subsequent therapy
X
Central Laboratory Sample Collection
PK sample collection
Refer to Phase 1 Table A-3.
Biomarker sample collection
Refer to Phase 1 Table A-5.
AE: adverse event; anti-HBc: anti-hepatitis B core antibody; COVID-19: coronavirus disease 2019; C1D1: Cycle 1 Day 1; C1D8: Cycle 1 Day 8; CT: computed tomography; ECG: 
electrocardiogram; ECOG: Eastern Cooperative Oncology Group; eCRF: electronic case report form; EOI: end of infusion; EOT: end of treatment; FDG-PET: 18fluorodeoxyglucose 
positron emission tomography; HBsAg: hepatitis B surface antigen; HCV: hepatitis C virus; HCV-Ab: hepatitis C virus antibody; ICF: informed consent form; IEC: independent 
ethics committee; IRB: institutional review board; LVEF: left ventricular ejection fraction; mos: months; MRI: magnetic resonance imaging; MUGA: multiple gated acquisition; OS: 
overall survival; PD: progressive disease; PFS: progression-free survival; PK: pharmacokinetic; SAE: serious adverse event; SOE: schedule of events; TLS: tumor lysis syndrome; 
X2: two timepoints.
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Tests and procedures should be performed on schedule (unless otherwise specified in Section 9.0); occasional changes are allowable up to a 4-day window for inclement weather, 
holidays, vacations, and other administrative reasons. From Cycle 2 onwards, laboratory assessments may occur up to 3 days before the scheduled day. Unless otherwise noted, 
evaluations during the treatment period must occur before drug administration on scheduled visits. For individual instances where assessments or procedures are not able to be 
performed as defined in the protocol, the reasons for failing to perform those should be documented (eg, identifying the specific limitation imposed by COVID-19 leading to the 
inability to perform the protocol-specified visit, assessment, or procedure). 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 visit or procedure cannot be performed within the window, then the 
Takeda project clinician or designee should be consulted if a longer window is necessary. If the study schedule, especially including dosing, is shifted, assessments should be shifted 
to align with the new schedule. A cycle of therapy begins when a patient receives a dose of TAK-981 or of rituximab. 
a Unless otherwise noted, the screening visit must occur within 28 days before the day of the first dose of study drug (C1D1). Signed informed consent must be obtained before 
performing any protocol-specific procedure. Informed consent must be documented before initiating any screening procedures that are for research purposes only. Tests and the 
resultant findings, which are done before consent for standard of care reasons, may count towards a screening procedure if done within 28 days of the first dose of TAK-981.
b Patients who stop treatment for any reason other than PD will continue to have PFS follow-up visits. The PFS follow-up visit should be conducted at the site every 12 weeks from last 
dose of study drug until PD. Response to treatment will also continue to be assessed in PFS follow-up every 12 weeks for patients who discontinue treatment for reasons other than PD 
until occurrence of PD, start of alternative therapy, or conclusion of the study. After the occurrence of PD or start of alternative therapy, patients will continue to have OS follow-up 
visits that may be performed by phone contact. The OS information will be collected every 12 weeks after the last dose of study drug until death or the conclusion of the study, 
whichever occurs first.
c Available pathology/cytogenetic/mutational information for all patients should be reported in the eCRF.
d Complete physical examination at screening. If the assessment was performed more than 3 days before C1D1, the examination should be performed again. Weight should be 
recorded during screening.
e Perform vital signs measurements before and after dosing. Blood pressure, heart rate, and temperature will be measured immediately before the start of the infusion and at the end of 
the infusion of each study drug. Blood pressure should be determined with the patient in a supine position after the patient has been quiet for 5 minutes. Outside C1D1, all patients will 
be monitored for 2 hours after the end of infusion of the last study drug. After the administration of TAK-981 or rituximab, the patient should be considered clinically stable by the 
investigator or designee before the next study drug is administered or the patient is discharged. If no infusion reaction is observed in the first 2 cycles, post-infusion monitoring may 
not be required and the patient can be discharged from the site per investigator discretion.
f During Phase 1 of this study, if alternative dosing schedules for TAK-981 (eg, TAK-981 on Day 1, or Days 1, 4, 8 and 11, or Days 1, 8, and 15 every 21 days) were employed, this 
test, dose administration, or procedure were performed on dosing days. For patients enrolled in a less dense schedule (eg, TAK-981 on Day 1 every 21 days), this test, procedure, or 
dosing was not performed.
g Predose and post-EOI (+1 h window) 12-lead ECG will be collected on C1D1, C1D8, and on Day 1 of every other subsequent cycle (Cycles 2, 4, 6, 8, etc). Additional ECGs may be 
obtained as clinically indicated at the discretion of the investigator. ECG assessments are to be performed after the patient has rested for 5 minutes.
h
i The MUGA (LVEF) scan should be performed at the screening to ensure patient eligibility. Echocardiographic estimate of the LVEF can be measured as an alternative to MUGA
scans. 
j Cycle 2 only.
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k On C1D1 only, rituximab will be administered first (before TAK-981 infusion). At least 1 hour should elapse between the completion of the infusion of the first study drug and the 
initiation of the infusion of the second study drug. For the first infusion (C1D1) of TAK-981 in combination with rituximab during dose escalation in Phase 1, every patient must be 
observed for 4 hours after the EOI. From C1D8 onwards, TAK-981 will be administered before rituximab on the days on which both agents are administered on the same day visit and 
the patient can be discharged from observation after a minimum of 2 hours after the end of infusion only if there are no signs and symptoms of acute toxicity like fever, significant 
changes in blood pressure and/or heart rate. Dose administration should be performed on schedule; however, a dose delay of up to 4 days may occur because of inclement weather, 
holidays, vacations, or administrative reasons; a dose delay of up to 7 days is allowed to accommodate for COVID-19 vaccine administration after discussion with the sponsor. If a 
treatment visit is delayed, associated tests and procedures should also be delayed. At least 7 days should elapse between consecutive doses of rituximab. For further details on 
TAK-981 or rituximab administration refer to Section 8.1.
l HBsAg, IgG anti-HBc, HCV-Ab serology (also HCV-RNA by polymerase chain reaction if the patient is HCV-antibody positive), and HIV-Ab. For patients who show evidence of 
prior hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult with physicians with expertise in managing hepatitis B 
regarding monitoring.
m A serum/urine choriogonadotropin beta (β-hCG) pregnancy test will be performed only for patients of childbearing potential during screening and again at C1D1 (baseline) if the 
screening test was performed more than 3 days before the first dose of any study drug. The results must be negative within 3 days before the first dose of TAK-981/rituximab is 
administered (ie, within the 3 days before C1D1), or as otherwise required by local regulations. Additional pregnancy testing may be performed during the study at the discretion of 
the investigator, if the menstrual period is delayed, upon request of an IEC/IRB, or if required by local regulations.
n Hematology, CD4/CD8-T-cells count and ratio, chemistry, coagulation, complement serum protein, and urine samples may be taken up to 3 days before the visit.
o For patients hospitalized due to high TLS risk, monitor blood chemistries at 4, 8, 12, and 24 hours and, as needed, after rituximab dose (Sections 8.10.8 and 9.4.14).
p Urinalysis includes tests for pH, proteins, glucose, ketone bodies, urobilinogen, bilirubin, leukocytes, erythrocytes, nitrites, density, and sediment. From Cycle 2 onwards, urine tests 
will be taken only the first day of each cycle and at EOT.
q Immunosafety determinations include thyroid-stimulating hormone, free thyroxine, and adrenocorticotropic hormone measured in blood and repeated at the beginning of each cycle 
until Cycle 6, every other cycle afterwards, and at the end of study treatment.
r A baseline contrast-enhanced CT or MRI scan of the chest, abdomen, and pelvis in addition to an FDG-PET scan must be acquired at screening. Subsequently, the same imaging 
modality (contrast-enhanced CT or MRI, and FDG-PET scan) should be performed. Imaging tests performed before the screening consent date may be used as screening tests if the 
C1D1 is planned within the 28 days after the date of the test. Refer to Section 9.4.15.1 for details.
s In Phase 1, bone marrow biopsy will be performed at screening per investigator discretion and Lugano guidelines to assess bone marrow involvement.
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Table A-2
SOE for Phase 2 (All Patients, Including Patients Enrolled in China)
Procedure/Assessment
Screening a
Cycle 1
Cycle 2 and Subsequent Cycles
EOT
Follow-up b
Day
Day
30 (+10) 
d after 
Last 
TAK-98
1 Dose
Every 3 Mos
1
2
4
8
9
11
15
1
4
8
11
15
PFS
OS
Informed consent
X
Inclusion/exclusion criteria
X
Demographics
X
Medical history including available 
tumor information c
X
Physical examination d
X
Symptom-directed physical examination
X
X
Height
X
Weight d
X
X
X
X
ECOG performance status
X
X
X
X
Vital signs e
X
X
X
X f
X
X
X
12-lead safety ECG (single record) g
X
X2
X2
X2
X2
X
Echocardiography/MUGA (LVEF) scan 
h
X
X i
X
Monitoring of concomitant medications 
and procedures
Recorded from the signing of ICF through 30 days after the last dose of study drug.
X
AE reporting
Recorded from the signing of ICF through 30 days after the last dose of study drug or start of a new 
systemic treatment.
X
SAEs will be reported from signing of the ICF through 30 days after the last dose of study drug or any 
moment after EOT for related SAEs
X
Treatment Administration
TAK-981 administration j
X
X
X
X
Rituximab administration j
X
X
X
X
Samples/Laboratory Assessments
Viral serologies k
X
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Procedure/Assessment
Screening a
Cycle 1
Cycle 2 and Subsequent Cycles
EOT
Follow-up b
Day
Day
30 (+10) 
d after 
Last 
TAK-98
1 Dose
Every 3 Mos
1
2
4
8
9
11
15
1
4
8
11
15
PFS
OS
Pregnancy test β-HCG (urine or serum) l
X
X
X
X
Hematology/Chemistry m
X
X
X
X
X
X i
X
TLS laboratory assessments n
X
X
Coagulation m
X
X
X
Urinalysis m, o
X
X
X
Immunosafety markers (hormones) p
X
X
X
Complement serum proteins m
X
X
X
X
X
Disease Assessment/Survival Follow-up
Imaging q
X
Every 2 months from C1D1 for the first 6 months, and every 12 weeks thereafter.
X
X
Disease Assessment
X
Every 2 months from C1D1 for the first 6 months, and every 12 weeks thereafter.
Xn
X
Bone marrow biopsy r
X
X Refer to Section 9.4.15.2 for details.
X
X
Survival follow-up
X
Subsequent therapy
X
Central Laboratory Sample Collection
PK sample collection
Refer to Phase 2 Table A-4.
Biomarker sample collection
Refer to Phase 2 Table A-6 (global study) and Table A-7 (for patients enrolled in China)
AE: adverse event; anti-HBc: anti-hepatitis B core antibody; COVID-19: coronavirus disease 2019; C1D1: Cycle 1 Day 1; C1D8: Cycle 1 Day 8; CT: computed tomography; ECG: 
electrocardiogram; ECOG: Eastern Cooperative Oncology Group; eCRF: electronic case report form; EOI: end of infusion; EOT: end of treatment; FDG-PET: 18fluorodeoxyglucose 
positron emission tomography; HBsAg: hepatitis B surface antigen; HCV: hepatitis C virus; HCV-Ab: hepatitis C virus antibody; ICF: informed consent form; IEC: independent 
ethics committee; IRB: institutional review board; LVEF: left ventricular ejection fraction; mos: months; MRI: magnetic resonance imaging; MUGA: multiple gated acquisition; OS: 
overall survival; PD: progressive disease; PFS: progression-free survival; PK: pharmacokinetic; q12w: every 12 weeks; SAE: serious adverse event; SOE: schedule of events; TLS: 
tumor lysis syndrome; X2: two timepoints.
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Tests and procedures should be performed on schedule (unless otherwise specified in Section 9.0); occasional changes are allowable up to a 4-day window for inclement weather, 
holidays, vacations, and other administrative reasons. Laboratory assessments may occur up to 3 days before the scheduled day. Unless otherwise noted, evaluations during the 
treatment period must occur before drug administration on scheduled visits. For individual instances where assessments or procedures are not able to be performed as defined in the 
protocol, the reasons for failing to perform those should be documented (eg, identifying the specific limitation imposed by COVID-19 leading to the inability to perform the 
protocol-specified visit, assessment, or procedure). 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 visit or procedure cannot be performed within the window, then the Takeda project clinician or 
designee should be consulted if a longer window is necessary. If the study schedule, especially including dosing, is shifted, assessments should be shifted to align with the new 
schedule. A cycle of therapy begins when a patient receives a dose of TAK-981 or of rituximab. 
a Unless otherwise noted, the screening visit must occur within 28 days before the day of the first dose of study drug (C1D1). Signed informed consent must be obtained before 
performing any protocol-specific procedure.
b Patients who stop treatment for any reason other than PD will continue to have PFS follow-up visits. The PFS follow-up visit should be conducted at the site every 12 weeks from last 
dose of study drug until PD. Response to treatment will also continue to be assessed in PFS follow-up every 12 weeks for patients who discontinue treatment for reasons other than PD 
until occurrence of PD, start of alternative therapy, or conclusion of the study. After the occurrence of PD or start of alternative therapy, patients will continue to have OS follow-up 
visits that may be performed by phone contact. The OS information will be collected every 12 weeks after the last dose of study drug until death or the conclusion of the study, 
whichever occurs first.
c Available pathology/cytogenetic/mutational information for all patients should be reported in the eCRF.
d Complete physical examination at screening. If the assessment was performed more than 3 days before C1D1, the examination should be performed again. Weight should be 
recorded during screening.
e Perform vital signs measurements before and after dosing. Blood pressure, heart rate, and temperature will be measured immediately before the start of the infusion and at the end of 
the infusion of each study drug. Blood pressure should be determined with the patient in a supine position after the patient has been quiet for 5 minutes. Outside C1D1, all patients will 
be monitored for 2 hours after the end of infusion of the last study drug. After the administration of TAK-981 or rituximab, the patient should be considered clinically stable by the 
investigator or designee before the next study drug is administered or the patient is discharged. If no infusion reaction is observed in the first 2 cycles, post-infusion monitoring may 
not be required and the patient can be discharged from the site per investigator discretion.
f During Phase 1 of this study, if alternative dosing schedules for TAK-981 (eg, TAK-981 on Day 1, or Days 1, 4, 8 and 11, or Days 1, 8, and 15 every 21 days) were employed, this 
test, dose administration, or procedure were performed on dosing days. For patients enrolled in a less dense schedule (eg, TAK-981 on Day 1 every 21 days), this test, procedure, or 
dosing was not be performed.
g Predose and post-EOI (+1 h window) 12-lead ECG will be collected on C1D1, C1D8, and on Day 1 of every other subsequent cycle (Cycles 2, 4, 6, 8, etc). Additional ECGs may be 
obtained as clinically indicated at the discretion of the investigator. ECG assessments are to be performed after the patient has rested for 5 minutes.
h The MUGA (LVEF) scan should be performed at the screening to ensure patient eligibility. Echocardiographic estimate of the LVEF can be measured as an alternative to MUGA
scans.
i Cycle 2 only.
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j On C1D1 only, rituximab will be administered first (before TAK-981 infusion). At least 1 hour should elapse between the completion of the infusion of the first study drug and the 
initiation of the infusion of the second study drug. For the first infusion (C1D1) of TAK-981 in combination with rituximab, every patient must be observed for 4 hours after the EOI. 
From C1D8 onwards, TAK-981 will be administered before rituximab on the days on which both agents are administered on the same day visit and the patient can be discharged from 
observation after a minimum of 2 hours after the end of infusion only if there are no signs and symptoms of acute toxicity like fever, significant changes in blood pressure and/or heart 
rate. Dose administration should be performed on schedule; however, a dose delay of up to 4 days may occur because of inclement weather, holidays, vacations, or administrative 
reasons; a dose delay of up to 7 days is allowed to accommodate for COVID-19 vaccine administration after discussion with the sponsor. If a treatment visit is delayed, associated 
tests and procedures should also be delayed. At least 7 days should elapse between consecutive doses of rituximab. For further details on TAK-981 or rituximab administration refer 
to Section 8.1.
k HBsAg, IgG anti-HBc, HCV-Ab serology (also HCV-RNA by polymerase chain reaction if the patient is HCV-antibody positive), and HIV-Ab. For patients who show evidence of 
prior hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult with physicians with expertise in managing hepatitis B 
regarding monitoring.
l A serum/urine choriogonadotropin beta (β-hCG) pregnancy test will be performed only for patients of childbearing potential during screening and again at C1D1 (baseline) if the 
screening test was performed more than 3 days before the first dose of any study drug. The results must be negative within 3 days before the first dose of TAK-981/rituximab is 
administered (ie, within the 3 days before C1D1), or as otherwise required by local regulations. Additional pregnancy testing may be performed during the study at the discretion of 
the investigator, if the menstrual period is delayed, upon request of an IEC/IRB, or if required by local regulations.
m Hematology, CD4/CD8-T-cells count and ratio, chemistry, coagulation, complement serum protein, and urine samples may be taken up to 3 days before the visit.
n For patients hospitalized due to high TLS risk, monitor blood chemistries at 4, 8, 12, and 24 hours and, as needed, after rituximab dose (see Sections 8.10.8 and 9.4.14 for non-high 
risk patients).
o Urinalysis includes tests for pH, proteins, glucose, ketone bodies, urobilinogen, bilirubin, leukocytes, erythrocytes, nitrites, density, and sediment. From Cycle 2 onwards, urine tests 
will be taken only the first day of each cycle and at EOT.
p Immunosafety determinations include thyroid-stimulating hormone, free thyroxine, and adrenocorticotropic hormone measured in blood and repeated at the beginning of each cycle 
until Cycle 6, every other cycle afterwards, and at the end of study treatment.
q A baseline contrast-enhanced CT or MRI scan of the chest, abdomen, and pelvis in addition to an FDG-PET scan must be acquired at screening. Subsequently, the same imaging 
modality (contrast-enhanced CT or MRI, and FDG-PET scan) should be performed. Informed consent must be documented before initiating any screening procedures that are for 
research purposes only. Tests, including imaging, and the resultant findings, which are done before consent for standard of care reasons may count towards a screening procedure if 
done within 28 days of the first dose of TAK-981. Refer to Section 9.4.15.1 for details. 
r A bone marrow biopsy will be performed at screening during Phase 2 to assess bone marrow involvement only in patients with baseline PET-CT indicating negative bone marrow 
involvement. and to confirm complete response in all patients that are assessed as having a complete response. Refer to Section 9.4.15.2 for details.
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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 
study-related duties and functions, the investigator/institution should ensure that this 
individual or party is qualified to perform those study-related duties and functions and should 
implement procedures to ensure the integrity of the study-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 subjects 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 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 subjects. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
8. Ensure that requirements for informed consent, as outlined in 21 Code of Federal Regulations 
Part 50, ICH, and local regulations, are met.
9. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each ICF should contain a subject authorization section that 
describes the uses and disclosures of a subject’s personal information (including personal 
health information) that will take place in connection with the study. If an ICF does not include 
such a subject authorization, then the investigator must obtain a separate subject authorization 
form from each subject or the subject’s legally acceptable representative.
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. In general, study records 
should be retained until an amount of time specified by applicable regulatory requirements or 
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for a time specified in the clinical study-site agreement between the investigator and the 
sponsor. The investigator should 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, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
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
ECOG Scale for Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all predisease performance without restriction.
1
Symptoms but ambulatory. Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature (eg, light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to bed or
chair.
5
Dead.
Source: Oken MM, 1982 (Oken et al. 1982).
ECOG: Eastern Cooperative Oncology Group.
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Appendix E
Drugs That Interact With the CYP3A Family of CYPs
Drugs listed below that are strong or moderate inducers or inhibitors of the CYP3A family of 
CYPs are generally prohibited as concomitant medications with TAK-981. This list is not intended 
to be exhaustive, and a similar restriction will apply to other agents that are known to strongly 
modulate CYP3A activity. Appropriate medical judgment is required. Please contact the sponsor’s 
medical monitor with any queries.
Drugs Inducing or Inhibiting CYP3A Metabolism That are Prohibited Concomitant 
Medications With TAK-981
Strong CYP3A Inducers a
Strong CYP3A Inhibitors b
apalutamide
carbamazepine
enzalutamide
mitotane
phenytoin
rifampin
St John’s Wort
boceprevir
clarithromycin
cobicistat
danoprevir and ritonavir
elvitegravir and ritonavir
grapefruit juice
idelalisib
indinavir and ritonavir
itraconazole
ketoconazole
lopinavir and ritonavir
nefazodone
nelfinavir
paritaprevir and ritonavir and (ombitasvir and/or dasabuvir)
posaconazole
ritonavir
saquinavir and ritonavir
telaprevir
telithromycin
tipranavir and ritonavir
troleandomycin
voriconazole
Moderate CYP3A Inducers a
Moderate CYP3A Inhibitors b
bosentan
efavirenz
etravirine
phenobarbital
primidone
aprepitant
ciprofloxacin
conivaptan
crizotinib
cyclosporine
diltiazem
dronedarone
erythromycin
fluconazole
fluvoxamine
imatinib
tofisopam
verapamil
CYP: cytochrome P-450; FDA: Food and Drug Administration.
a fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers#table
3-3 (accessed 26 August 2021).
b fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers#table
3-2 (accessed 26 August 2021).
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Appendix F
Examples of Clinical Inhibitors of Pgp
Drugs listed below that are inhibitors of Pgp are generally prohibited as concomitant medications 
with TAK-981.
Transporter
Gene
Inhibitor
Pgp
ABCB1
amiodarone
carvedilol
clarithromycin
dronedarone
itraconazole
lapatinib
lopinavir and ritonavir
propafenone
quinidine
ranolazine
ritonavir
saquinavir and ritonavir
telaprevir
tipranavir and ritonavir
verapamil
Source: fda.gov/fddrugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibito
rs-and-inducers#table5-2 (accessed 06 August 2021).
Pgp: P-glycoprotein. 
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Appendix G
Examples of QTc Interval-Prolonging Agents (Phase 1 Only)
Common concomitant medications can prolong the QT interval (eg, antiemetics, antifungals, 
quinolone antibiotics). Electrolyte disturbances such as hypokalemia and hypomagnesemia caused 
by GI toxicities may also increase the risk for QT prolongation. The use of drugs known to prolong
the QTc interval should not be initiated on C1D1, but will be allowed from C1D2 onwards.
The drugs noted in the table below are examples of only some of the more common drugs and may 
not be comprehensive. It is the investigator's responsibility to ensure that drugs under 
consideration have not been newly identified as causing QT prolongation. The website 
crediblemeds.org provides a list of drugs known to cause QT prolongation that may be used as a 
guide for healthcare providers.
Patients taking such drugs need not stop if their baseline QTc <480 ms.
Drug Class
Examples of Drugs That Increase Risk of TdP, Name (Brand Name)
Antiarrhythmic
amiodarone (Cordarone, Pacerone)
bepridil (Vascor)
disopyramide (Norpace)
dofetilide (Tikosyn)
flecainide (Tambocor)
ibutilide (Corvert)
procainamide (Pronestyl, Procan)
quinidine (Cardioquin, Quinaglute)
sotalol (Betapace)
Antibiotic
azithromycin (Zithromax)
clarithromycin (Biaxin)
erythromycin (Erythrocin, EES)
moxifloxacin (Avelox)
pentamidine (NebuPent, Pentam)
sparfloxacin (Zagam)
Anticancer
arsenic trioxide (Trisenox)
vandetanib (Caprelsa)
Antidepressant
citalopram (Celexa)
Antiemetic a
domperidone (Motilium)
droperidol (Inapsine)
ondansetron
granisetron
Antihistamine
astemizole (Hismanal)
terfenadine (Seldane)
Antilipemic/
Hypercholesterolemia
probucol (Lorelco)
Antimalarial
chloroquine (Aralen)
halofantrine (Halfan)
Antipsychotic
chlorpromazine (Thorazine)
haloperidol (Haldol)
mesoridazine (Serentil)
pimozide (Orap)
thioridazine (Mellaril)
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Drug Class
Examples of Drugs That Increase Risk of TdP, Name (Brand Name)
Gastrointestinal 
stimulant/Heartburn
cisapride (Propulsid)
Opiate agonist
levomethadyl (Orlaam)
methadone (Dolophine,
Methadose)
QTc: corrected QT interval; TdP: torsade de pointes.
a Palonosetron is permissible antiemetic.
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Appendix H
Bayesian Logistic Regression Model
It is anticipated that up to approximately 180 patients will be enrolled in this study including the 
dosing-escalation phase (up to approximately 35 patients) and efficacy evaluation phase (up to 
approximately 145 patients).
An adaptive BLRM with overdose control will be used to guide dose escalation starting with the 
second dose level. BLRM with overdose control principle (Babb et al. 1998; Neuenschwander et al. 
2008) informs dose-escalation decisions and MTD estimation, along with consideration of other 
safety, clinical, PK, and pharmacodynamic data.
The 2-parameter logistic regression model used is as follows:
logit(()) =  log(*) +  , log-
./012
./013456 , * > 0, , > 0 where πi is the DLT rate for dose I and 
doseref is a reference dose. A quantile-based, weakly informative, bivariate normal prior will be 
used for ln(α) and ln(β). This prior will be assigned based on pre-study estimates of median DLT 
rate (0.011,0.021, 0.053, 0.084, 0.105, 0.126, 0.210, 0.263, 0.315, and 0.630) at provisional dose 
levels (3,6, 10, 15, 25, 40, 60, 90, 120, and 160 mg), as described in Neuenschwander 2008 
(Neuenschwander et al. 2008).
The model will be updated after each group of approximately 3 patients are enrolled in the current 
dose level. Each subject will participate in only 1 dose cohort. A cohort size other than 3 may also 
be considered as appropriate. For each subsequent dose level after the initial dose level, the 
posterior probability of having DLT rates that fall into the following intervals will be estimated:

[0, 0.16]: underdosing.

[0.16, 0.33]: target toxicity.

[0.33, 1.00]: excessive toxicity.
The next recommended dose will be selected as described in Section 8.5.
The simulation to evaluate the operating characteristics is performed based on provisional dose 
levels (3, 6, 10, 15, 25, 40, 60, 90, 120, and 160 mg). The cohort size of 3 is assumed in the 
simulation. The simulation is performed based on 6 scenarios of the assumed true DLT rates at 
dose levels (3, 6, 10, 15, 25, 40, 60, 90, 120, and 160 mg), representing various distributions of 
toxicity across dose levels, detailed as shown in Table H-1.
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Table H-1
Dose-Escalation Simulation Study of the Probability of DLT
Dose Level
True P(DLT) at Each Scenario
1
2
3
4
5
6
3 mg a
0.001
0.005
0.01
0.08
0.25
0.50
6 mg
0.005
0.01
0.02
0.12
0.31
0.55
10 mg
0.015
0.03
0.07
0.19
0.45
0.60
15 mg
0.03
0.05
0.12
0.25
0.50
0.65
25 mg
0.04
0.07
0.19
0.30
0.55
0.70
40 mg
0.05
0.10
0.22
0.45
0.60
0.75
60 mg
0.06
0.13
0.25
0.50
0.70
0.80
90 mg
0.08
0.17
0.28
0.60
0.80
0.90
120 mg
0.10
0.21
0.45
0.70
0.90
0.95
160 mg
0.11
0.25
0.60
0.75
0.99
0.99
DLT: dose-limiting toxicity; P(DLT): probability of a DLT at each dose level.
a Starting dose.
The trend of the dose-DLT relationship becomes steeper and MTD is reached earlier from 
Scenario 1 to Scenario 6. The operating characteristic results are shown in Table H-2. In Scenario 
1 where all true DLT rates are below 0.33, the probabilities of recommending the highest dose 
level (160 mg) and the second highest dose level (120 mg) are 30.4% and 53.6%, respectively. In 
Scenario 1, the average number of patients required is approximately 31.7 with 1.6 DLTs expected 
on average. The true DLT rates in Scenario 2 increase faster than Scenario 1 but are still all below 
0.33, and the BLRM has 78.3% chance of successfully recommending target dose levels. The 
average number of patients required is approximately 30.8, with approximately 3 DLTs expected 
on average. In Scenario 3, there is 5.4% chance of recommending a lower dose as MTD, 89.7% 
chance of successfully recommending target dose levels. The average number of patients required 
is approximately 27.6, with approximately 4.3 DLTs expected on average. In Scenario 4, with 
further faster increase of DLT rate over doses, there is a 73.1% probability of recommending target 
dose levels, whereas the probability of recommending toxic doses is 12.8%. The average number 
of patients required is approximately 22.8 with 5.2 DLTs expected on average. In Scenario 5, there 
is 46.2% chance of claiming the target doses as MTD, 14.2% chance of recommending a toxic 
dose, and approximately 39.6% chance of claiming all doses are toxic. Most of the patients 
(around 70.7%) do not receive doses above the MTD dose. The average number of patients 
required is approximately 13.5 with 4.4 DLTs expected on average. In Scenario 6 when all doses 
are toxic, there is a 92.7% chance of successfully claiming all doses are toxic. The average number 
of patients required is approximately 6 and 3.1 DLTs are expected on average.
The accuracy of the BLRM recommendation relies on the true DLT rate; thus, the safety, clinical, 
PK, and pharmacodynamic data evaluation are combined to support the dose escalation. As an 
example, a hypothetical dose escalation step is shown in Table H-3 to illustrate how BLRM guides 
dose escalation.
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Table H-2
Operating Characteristics for BLRM Dose-Escalation Rule
Scenario
Probability of Recommending a:
Average Proportion of 
Patients Receiving a:
Average Number of 
Patients
Low 
Dose
Target 
Dose
High 
Dose
Low 
Dose
Target 
Dose
High 
Dose
Per 
Study
Experiencing 
DLT Per 
Study
1
100%
NA
NA
100%
NA
NA
31.7
1.6
2
21.7%
78.3%
NA
72.6%
27.4%
NA
30.8
3.0
3 
5.4%
89.7%
4.8%
45.5%
50.8%
3.5%
27.6
4.3
4 a
11.0%
73.1%
12.8%
33.1%
54.3%
12.8%
22.8
5.2
5 b
NA
46.2%
14.2%
NA
70.7%
29.2%
13.5
4.4
6 c
NA
NA
7.3%
NA
NA
100%
6.0
3.1
BLRM: Bayesian logistic regression modeling; DLT: dose-limiting toxicity; MTD: maximum tolerated dose; NA: Not 
available.
Low Dose = true DLT rate is [0, 0.16]; Target Dose = true DLT rate is [0.16, 0.33]; High Dose = true DLT rate is [0.33, 
1.00].
a Probability of 3.1 % to claim all doses are toxic.
b Probability of 39.6% to claim all doses are toxic.
c Probability of 92.7% to claim all doses are toxic.
Table H-3
Hypothetical Dose-Escalation Step
Step
Dose (mg)
#Patients
#DLTs
Next Recommended Dose (mg)
1
3
3
0
6
2
3
3
0
6
3
1
10
3
3
3
0
6
10
3
3
1
0
15
4
3
3
0
6
3
1
10
15
3
3
0
2
10
5
3
3
0
6
3
1
10
6
1
15
3
2
10 mg is claimed as the MTD
BLRM: Bayesian logistic regression modeling; DLT: dose-limiting toxicity; MTD: maximum tolerated dose.
In addition, BLRM is flexible in handling late-onset toxicities and can be fed with events meeting DLT criteria but 
occurring in later cycles to modulate dose escalation, as needed. The DLT information from a single-agent study may 
also be used in the dose-escalation phase as prior information for the BLRM.
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Appendix I
Rituximab Prescribing Information
accessdata.fda.gov/drugsatfda_docs/label/2019/103705s5454lbl.pdf (Rituxan (rituximab) 
Injection for Intravenous Use 2019)
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Appendix J
Methods of Contraception Considered to be Effective
A. 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.

Vasectomised partner 2,3.

Sexual abstinence 4.
B. 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_Co
ntraception.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 Vasectomised 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 subject.
5 A combination of male condom with either 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 K
Recommendations for Initial Management of Electrolyte Abnormalities and 
Prevention of TLS
Section 1: First Dose of Rituximab
Within the first 24 hours after either the first dose, if any laboratory criteria below are met, the 
patient should be hospitalized for monitoring and the investigator notified. No additional 
rituximab doses should be administered until resolution. A rapidly rising serum potassium is a 
medical emergency.
Nephrology (or other acute dialysis service) should be contacted/consulted (per institutional 
standards to ensure emergency dialysis is available) on admission for any patient hospitalized 
prophylactically or in response to laboratory changes.
IV fluids (eg, dextrose 5% in half-normal saline) should be initiated at a rate of at least 1 mL/kg/h 
rounded to the nearest 10 mL (target, 150 to 200 mL/h; not <50 mL/h). Modification of fluid rate 
should also be considered for individuals with specific medical needs.
Monitor for symptoms or signs of TLS (eg, fever, chills, tachycardia, nausea, vomiting, diarrhea, 
diaphoresis, hypotension, muscle aches, weakness, paresthesias, mental status changes, confusion, 
seizures). If any clinical features are observed, recheck potassium, phosphorus, uric acid, calcium, 
and creatinine within 1-hour immediately (STAT).
Vital signs should be taken at time of all blood draws or any Intervention.
The management recommendations below focus on the minimum initial responses required. If a 
diagnosis of TLS is established, ongoing intensive monitoring and multidisciplinary management 
will be per institutional protocols.
In addition to the recommendations in the table below:
For potassium increase ≥0.5 mmol/L from baseline, or any value >5.0 mmol/L, recheck potassium, 
phosphorus, uric acid, calcium, and creatinine within 1-hour STAT and follow first guideline.
For phosphorus increase of >0.5 mg/dL AND >4.5 mg/dL, administer phosphate binder and 
recheck potassium, phosphorus, uric acid, calcium, and creatinine within 1-hour STAT.
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Abnormality
Management Recommendations 
(Cairo and Bishop 2004; Coiffier et al. 2008)
Hyperkalemia (including rapidly rising potassium)
Potassium ≥0.5 mmol/L increase from 
prior value (even if potassium within 
normal limits)
Recheck potassium, phosphorus, uric acid, calcium, and creatinine in 
1 hour STAT. If further ≥0.2 mmol/L increase in potassium, but still 
<ULN, manage as per potassium ≥ULN. Otherwise recheck in 1 hour.
Resume per protocol testing if change in potassium is 
<0.2 mmol/L, and potassium <ULN, and no other evidence of tumor 
lysis.
At discretion of investigator, may recheck prior to hospitalization. If 
stable or decreased, and still within normal limits, hospitalization is at the 
discretion of the investigator. Potassium, phosphorus, uric acid, calcium 
and,
Creatinine must be rechecked within 24 hours.
Potassium >ULN
Perform STAT ECG and commence telemetry.
Nephrology notification with consideration of initiating dialysis.
Administer kayexalate 60 g (or resonium A 60 g).
Administer furosemide 20 mg IV × 1.
Administer calcium gluconate 100-200 mg/kg IV slowly if there is 
ECG/telemetry evidence of life-threatening arrhythmias.
Recheck potassium, phosphorus, uric acid, calcium, and creatinine in 
1 hour STAT.
If potassium <ULN 1 hour later, repeat potassium, phosphorus, uric acid, 
calcium, and creatinine 1, 2, and 4 hours, if no other evidence of tumor 
lysis.
Potassium ≥6.0 mmol/L (6.0 mEq/L) 
and/or symptomatic (eg, muscle cramps, 
weakness, paresthesias, nausea, vomiting, 
diarrhea)
Perform STAT ECG and commence telemetry.
Nephrology (or other acute dialysis service) assessment with 
consideration of initiating dialysis.
Administer kayexalate 60 g (or Resonium A 60 g).
Administer furosemide 20 mg IV × 1.
Administer insulin 0.1 U/kg IV + D25 2 mL/kg IV.
Administer sodium bicarbonate 1 to 2 mEq/kg IV push.
If sodium bicarbonate is used, rasburicase should not be used as this may 
exacerbate calcium phosphate precipitation.
Administer calcium gluconate 100 to 200 mg/kg IV slowly if there is 
ECG/telemetry evidence of life-threatening arrhythmias. Do not 
administer in same IV line as sodium bicarbonate.
Recheck potassium, phosphorus, uric acid, calcium, and creatinine every 
hour STAT.
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Abnormality
Management Recommendations 
(Cairo and Bishop 2004; Coiffier et al. 2008)
Hyperuricemia
Uric acid ≥8.0 mg/dL (476 μmol/L)
Consider rasburicase (0.2 mg/kg as an IV infusion over 30 minutes).
If rasburicase is used, sodium bicarbonate should not be used as this may 
exacerbate calcium phosphate precipitation.
Recheck potassium, phosphorus, uric acid, calcium, and creatinine in 
1 hour STAT.
Uric acid ≥10 mg/dL (595 μmol/L)
OR
Uric acid ≥8.0 mg/dL (476 μmol/L) with 
25% increase and creatinine increase 
≥0.3 mg/dL (≥0.027 mmol/L) from 
predose level
Administer rasburicase (0.2 mg/kg as an IV infusion over 30 minutes).
If rasburicase is used, sodium bicarbonate should not be used as this may 
exacerbate calcium phosphate precipitation.
Consult Nephrology (or other acute dialysis service).
Recheck potassium, phosphorus, uric acid, calcium, and creatinine in 
1 hour STAT.
If uric acid <8.0 mg/dL 1 hour later, repeat potassium, phosphorus, uric 
acid, calcium, and creatinine 2 and 4 hours later, if no other evidence of 
tumor lysis.
Hypocalcemia
Calcium ≤7.0 mg/dL (1.75 mmol/L)
AND
Patient symptomatic (eg, muscle cramps, 
hypotension, tetany, cardiac arrhythmias)
Administer calcium gluconate 50 to 100 mg/kg IV slowly with ECG 
monitoring.
Telemetry.
Recheck potassium, phosphorus, uric acid, calcium, and creatinine in 
1 hour STAT.
If calcium normalized 1 hour later, repeat potassium, phosphorus, uric 
acid, calcium, and creatinine 2 and 4 hours later, if no other evidence of 
tumor lysis. Calculate corrected calcium and check ionized calcium if 
albumin low.
Hyperphosphatemia
Phosphorus ≥5.0 mg/dL (1.615 mmol/L) 
with ≥0.5 mg/dL (0.16 mmol/L) increase
Administer a phosphate binder (eg, aluminum hydroxide, calcium 
carbonate, sevelamer hydroxide, or lanthanum carbonate).
Nephrology (or other acute dialysis service) notification (dialysis 
required for phosphorus ≥10 mg/dL).
Recheck potassium, phosphorus, uric acid, calcium, and creatinine in 
1 hour STAT.
If phosphorus <5.0 mg/dL 1 hour later, repeat potassium, phosphorus, 
uric acid, calcium, and creatinine 2 and 4 hours later, if no other evidence 
of tumor lysis.
Creatinine
Increase ≥25% from baseline
Start or increase rate of IV fluids.
Recheck potassium, phosphorus, uric acid, calcium, and creatinine in 1 to 
2 hours STAT.
ECG: electrocardiogram; IV: intravenous; STAT: within 1-hour within 1-hour; ULN: upper limit of normal.
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Appendix L
Definition of TLS
The following features are used to define TLS:
Parameter
Value
Laboratory TLS
(TWO of)
Uric acid
Potassium
Phosphorus
Calcium (corrected)
≥476 μmol/L
≥6.0 mmol/L
≥1.45 mmol/L
≤1.75 mmol/L
Clinical TLS
(Lab TLS + one of)
Renal insufficiency (increase of 0.3 mg/dL in creatinine)
Cardiac arrhythmias
Sudden death
Seizures
TLS: tumor lysis syndrome.
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Protocol Amendment 6
Summary of Changes Since the Last Version of the Approved Protocol
Change 
Number
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
14
Appendix E Drugs That Interact 
With The CYP3A Family of CYPs
Appendix F Examples of Clinical 
Inhibitors of Pgp
Updated citations.
Editorial updates and 
corrections.
15
Appendix H Bayesian Logistic 
Regression Model
Updated Appendix H table 
numbers as Tables H-1 through 
H-3 instead of Tables 6 through 
8.
Editorial update.
Rationale for Amendment 5
This section describes the changes to the protocol incorporating Amendment 5.
The primary reason for this amendment was to provide guidance on coronavirus disease 2019 
(COVID-19) vaccination timing and procedures during the study.
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 the Last Version of the Approved Protocol
Change 
Number
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
1
Title page
Section 2.0 STUDY SUMMARY
Updated sponsor legal entity name.
Correction and alignment 
with other TAK-981 
protocols.
2
Section 2.0 STUDY SUMMARY
Main Criteria for Exclusion
Section 7.2 Exclusion Criteria.
In Exclusion Criterion 18 in the 
study summary and body, added an 
abbreviation for QTcF 
(Fridericia-corrected QT interval). 
In Exclusion Criterion 18 in the 
study summary, deleted the 
fragment “QT interval with 
Fridericia correction method;” 
edited term “QTcT” to “QTc,” and 
added a definition for QTc.
Alignment of exclusion 
criterion in protocol 
summary and body.
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Protocol Amendment 5
Summary of Changes Since the Last Version of the Approved Protocol
Change 
Number
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
3
Section 4.5.4 Coronavirus Disease 
2019 Pandemic
Added a section on benefit/risk 
assessment of participation in the 
study during the coronavirus disease 
2019 (COVID-19) pandemic, 
indicating that the benefit/risk 
assessment remains favorable and 
that considerations for patient 
participation should be evaluated by 
the investigator on a patient by 
patient basis taking into 
consideration the current local 
situation, guidelines, and other 
recommendations.
Guidance on benefit/risk 
assessment for patient 
participation in the study 
during the COVID-19 
pandemic.
4
Section 8.1.3 Additional 
Instructions for Treatment 
Administration
Appendix A
Schedule of Events
Table 1 SOE for Treatment Cycle 
1 (21-Day Cycle) During Phase 1 
and Phase 2
footnote j
Table 2 SOEs for Treatment 
Cycle 2 (21-Day Cycle) Through 
End of Study
footnote h
Added that a dose delay of up to 
7 days is allowed to accommodate 
for COVID-19 vaccine 
administration after discussion with 
the sponsor.
Added that if a treatment visit is 
delayed, associated tests and 
procedures should also be delayed.
Guidance on COVID-19 
vaccination timing and 
procedures during the study
5
Section 8.7 Excluded Concomitant 
Medications and Procedures
Added that vaccination during 
Cycle 1 is not permitted for patients 
in Phase 1.
Vaccination during Cycle 1 
in Phase 1 would confound 
safety evaluation and 
determination of 
dose-limiting toxicities.
6
Section 8.8 Permitted Concomitant 
Medications and Procedures
Added guidance on timing of
COVID-19 vaccination during the 
study including live attenuated 
vaccine must be completed at least 4 
weeks prior to treatment initiation, 
vaccination not permitted during 
Cycle 1 in Phase 1, vaccination to be 
avoided within ± 3 days of TAK-981 
administration, and allowing a 7-day 
dose delay to accomodate
vaccination.
Guidance on COVID-19 
vaccination timing and 
procedures during the study
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Protocol Amendment 5
Summary of Changes Since the Last Version of the Approved Protocol
Change 
Number
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
7
Appendix A
Schedule of Events
Table 1
SOE for Treatment 
Cycle 1 (21-Day Cycle) During 
Phase 1 and Phase 2
footnote e
Table 2
SOEs for Treatment 
Cycle 2 (21-Day Cycle) Through 
End of Study
footnote d
Updated footnotes with additional 
text as follows:
“If alternative more dense dosing 
schedules for TAK-981 (eg, 
TAK-981 on Days 1, 4, 8 and 11, or 
Days 1, 8, and 15 every 21 days), 
this test, dose administration, or 
procedure should be performed on 
dosing days.”
Clarification.
8
Appendix A
Schedule of Events
Table 2
SOEs for Treatment 
Cycle 2 (21-Day Cycle) Through 
End of Study
Deleted footnote k and updated 
subsequent footnote letters.
Correction.
9
Appendix E
Drugs That Interact 
With the CYP3A Family of CYPs
Under strong cytochrome P450 
(CYP) 3A inhibitors, corrected 
spelling of nefazodone and 
telithromycin, and added 
clarithromycin. Updated source 
table number in footnote a and 
added footnote b to separate sources 
for CYP3A inducers and inhibitors.
Update to align with current 
Food and Drug 
Administration guidance.
Rationale for Amendment 4
This section describes the changes to the protocol incorporating Amendment 4.
The primary reason for this amendment was to allow additional dosing schedules within the dose 
escalation phase in order to assess the safety and preliminary efficacy of TAK-981 in combination 
with rituximab.
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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Protocol Amendment 4
Summary of Changes Since the Last Version of the Approved Protocol
Change 
Number
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
1
Title page
Updated sponsor legal entity and 
added EudraCT number.
Administrative updates.
2
Section 2.0 STUDY SUMMARY
Section 7.1 Inclusion Criteria
In Inclusion Criterion 6, updated 
screening creatinine clearance 
requirement to ≥30 mL/min (instead of 
≥45 mL/min) per Cockcroft-Gault 
formula.
The creatinine clearance 
requirement was lowered 
based on recent 
pharmacokinetic (PK) 
analysis that showed 
minimal renal elimination 
of TAK-981.
3
Section 2.0 STUDY SUMMARY
Section 7.1 Inclusion Criteria
In Inclusion Criterion 11, clarified that 
tumor biopsy collection was for 
patients in Phase 2, Stage 1.
Clarification.
4
Section 2.0 STUDY SUMMARY
Section 7.2 Exclusion Criteria
In Exclusion Criterion 9, clarified that 
the washout period for prior anticancer 
therapy is within 2 weeks or 
5 half-lives before dosing, whichever 
is shorter; the fragment “(up to a 
maximum of 4 weeks)” was deleted.
Clarification.
5
Section 2.0 STUDY SUMMARY
Section 7.2 Exclusion Criteria
Deleted examples of live vaccine from 
Exclusion Criterion 14.
Clarification.
6
Section 2.0 STUDY SUMMARY
Section 7.2 Exclusion Criteria
In Exclusion Criterion 19, added that 
the washout period for P-glycoprotein 
inhibitors is 1 week before TAK-981 
dosing.
Clarification.
7
Section 4.2.5 Clinical Experience
Updated clinical section to include text 
from the latest investigator’s brochure 
(IB) edition (Edition 3, data cutoff 28 
June 2020).
Updated clinical data 
from the IB were 
available.
8
Section 4.4.1.1 TAK-981
Section 6.2 Phase 1 Study Design
Section 8.1 Study Drug 
Administration
Section 8.5 Dose-Escalation Rules
Appendix A Schedule of Events
Updated alternative dosing schedules 
to include Day 1, or Days 1, 4, 8, and 
11, or Days 1, 8, and 15 every 21 days.
Update to allow 
additional dosing 
schedules within the dose 
escalation phase in order 
to assess the safety and 
preliminary efficacy of 
TAK-981 in combination 
with rituximab.
9
Section 8.1.1 Rituximab
Clarified that body surface area used to 
determine rituximab dosing was to be 
calculated using the Du Bois formula.
Clarification on method 
of calculation of body 
surface area across 
participating sites.
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Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification and administrative purposes only.
For specific descriptions of text changes and where the changes are located, see Appendix M.
Changes in Amendment 3
1. Updated information of the preliminary clinical experience.
2. Changed the title of the study from Phase 1b/2 to Phase 1/2.
3. Modified the Phase 2 patient population.
4. Added text to further describe the study design.
5. Added at least 30 additional recruiting sites and clarified that the study may be conducted 
outside of North America.
6. Modified Section 6.3 to describe Phase 2 treatment cohorts.
7. Modified Section 6.5.2 to extend the duration of the study.
8. Added an Independent Data Monitoring Committee (IDMC) to the Phase 2 study.
9. Added an Independent Review Committee (IRC) to the Phase 2 study.
10. Updated study schematic figure with the specific tumor types and indications during Phase 2.
11. Deleted measured creatinine clearance from the inclusion criterion and renal function testing.
12. Modified the inclusion criterion regarding radiologically measurable lesions.
13. Replaced Clinical Study Team (CST) with Study Monitoring Committee (SMC), and added a 
description of the SMC.
14. Removed LYRIC criteria for the evaluation of response.
15. Changed the window for image testing from +10 days to ±7 days.
16. Modified the coagulation testing and urinalysis window period on Cycle 1 Day 1.
17. Changed the tumor and skin biopsy window.
18. Updated Adverse Event (AE) definition.
19. Updated serious adverse event (SAE) definition.
20. Modified language to perform either serum or urine pregnancy test for women of childbearing 
potential at screening, Day 1 of each cycle, and at the end-of-treatment (EOT) visit.
21. Amended the statistical description of determination of sample size for Phase 2.
22. Modified language to clarify risks and prophylaxis of patients with lymphopenia.
23. Modified the length of infusion time.
24. Added a permitted concomitant treatment.
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25. Clarified tumor and skin biopsy inclusion criteria.
26. Modified the starting dose based on emerging safety data from the TAK-981-1002 
single-agent study.
27. Modified the staggering period within each cohort in dose escalation from 7 days to 72 h.
28. Modified the grading of cytokine release syndrome (CRS) to ASTCT Consensus Grading for 
CRS.
29. Updated information on Diffuse Large B-cell lymphoma.
30. Updated study objectives and endpoints.
31. Clarified exclusion criteria for patients that have undergone ASCT or cellular therapy.
32. Added text on alternative dosing schedules for TAK-981.
33. Added timepoints for serum and plasma sample collection.
34. Corrected the list of moderate CYP3A inhibitors and inducers in Appendix E.
Rationale for Amendment 2
This document describes the changes to the protocol incorporating Amendment 02. 
The primary reason for this amendment was to incorporate recent requirements by the Food and 
Drug Administration (FDA) (clarification on dose limiting toxicity [DLT] criteria, addition of 
reference under statistical considerations for sample size calculation, and addition of appropriate 
language for safety procedures in tumor biopsies). 
The dose escalation of TAK-981 as single agent in the first-in-human (FIH) study 
(Study TAK-981-1002) in patients with solid tumors or lymphoma is advancing fast. The sponsor 
now has more insight on dose escalation steps from the safety and pharmacodynamic data 
available from the FIH study, so the dose escalation steps are also refined in this amendment. 
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification and administrative purpose only. 
For specific descriptions of text changes and where the changes are located, see Appendix M. 
Changes in Amendment 2 
1. DLT definitions: In response to FDA’s request for clarifying the DLT criteria due to 
inconsistency in DLT definitions in the Study Summary and Section 8.2, current language was 
incorporated in the Study Summary and Section 8.2 of the protocol amendment. 
2. Corrected the typographical error in inclusion criteria no. 8; replaced “ECG” 
(electrocardiogram) with “echocardiogram”. 
3. Added statement in inclusion criteria no. 11, that for fresh tumor biopsies, the lesion must be 
accessible for a low risk biopsy procedure (those occurring outside the brain, 
lung/mediastinum, and intra-abdominal, or obtained with endoscopic procedures beyond the 
stomach or bowel). 
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3. Increased the number of sites to approximately 9 sites in phase 1b and up to approximately 20 
sites total in North America and/or globally.
4. Added language regarding adequate hydration.
5. Added an appendix that defines tumor lysis syndrome (TLS).
6. Added statement that, for laboratory assessments, blood chemistries should be monitored at 
6 to 8 hours and at 24 hours after the first rituximab dose, and that electrolyte abnormalities 
should be corrected.
7. Added statement that for patients who show evidence of prior hepatitis B infection (hepatitis B 
surface antigen [HBsAg] positive [regardless of antibody status] or HBsAg negative but 
anti-hepatitis B core antibody positive), they should consult with physicians with expertise in 
managing hepatitis B regarding monitoring.
8. Added that hematology/chemistry assessments should be made at end of treatment.
9. Added an appendix: Recommendations for Initial Management of Electrolyte Abnormalities 
and Prevention of TLS.
10. Modified inclusion criterion number 3 to require only 1 prior systemic therapy instead of 2.
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CONFIDENTIAL
Amendment History:
Date
Version Number
Amendment Type
03 Mar 2023
Final Version 2.0
Substantial
18 June 2020
Initial SAP 1.0
Not applicable
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2.0
TABLE OF CONTENTS 
1.0
TITLE PAGE ..................................................................................................................1
1.1
Approval Signatures ..................................................................................................2
2.0
TABLE OF CONTENTS.................................................................................................4
3.0
LIST OF ABBREVIATIONS..........................................................................................6
4.0
OBJECTIVES .................................................................................................................8
4.1
Primary Objectives ....................................................................................................8
4.2
Secondary Objectives.................................................................................................8
4.3
Exploratory Objectives ..............................................................................................9
4.3.1
Exploratory Objectives (Global Study; Not Applicable to Patients Enrolled 
in China)............................................................................................................9
4.3.2
Exploratory Objectives (China-Specific)............................................................9
4.4
Study Design ...........................................................................................................10
5.0
ANALYSIS ENDPOINTS.............................................................................................14
5.1
Primary Endpoints ...................................................................................................14
5.2
Secondary Endpoints ...............................................................................................15
5.3
Exploratory Endpoints .............................................................................................15
5.3.1
Exploratory Endpoints (Global Study; Not Applicable to Patients Enrolled in 
China)..............................................................................................................15
5.3.2
Exploratory Endpoints (China-Specific)...........................................................16
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................16
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................20
7.1
General Principles....................................................................................................20
7.1.1
Definition of Study Visit Windows..................................................................20
7.1.2
Conventions for Missing/Partial Dates in Screening Visit ................................20
7.1.3
Conventions for Missing Adverse Event Dates ................................................21
7.1.4
Conventions for Missing Concomitant Medication/Therapy Dates...................22
7.1.5
Conventions for Missing Subsequent Medication/Therapy Dates.....................22
7.2
Analysis Sets ...........................................................................................................23
7.3
Disposition of Subjects ............................................................................................24
7.4
Demographic and Other Baseline Characteristics.....................................................24
7.5
Medical History and Concurrent Medical Conditions...............................................25
7.6
Medication History and Concomitant Medications...................................................25
7.7
Study Drug Exposure and Compliance.....................................................................25
7.8
Efficacy Analysis.....................................................................................................26
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7.8.1
Primary Efficacy Endpoint(s)...........................................................................26
7.8.2
Secondary Efficacy Endpoint(s).......................................................................26
7.8.3
Additional Efficacy Endpoint(s).......................................................................27
7.9
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................27
7.9.1
Pharmacokinetic (PK) Analysis .......................................................................27
7.9.2
Pharmacodynamic (PD) Analysis.....................................................................28
7.10
Other Outcomes.......................................................................................................28
7.10.1
PK/PD Analysis...............................................................................................28
7.10.2
PK/ QTc Interval Analysis...............................................................................29
7.11
Safety Analysis........................................................................................................30
7.11.1
Dose Limiting Toxicities (DLTs).....................................................................30
7.11.2
Adverse Events................................................................................................30
7.11.2.1
Adverse Events........................................................................................30
7.11.2.2
Serious Adverse Events ...........................................................................31
7.11.2.3
Deaths .....................................................................................................32
7.11.2.4
Adverse Events Resulting in Discontinuation of Study Drug....................32
7.11.3
Clinical Laboratory Evaluations.......................................................................32
7.11.4
Vital Signs.......................................................................................................33
7.11.5
12-Lead ECGs.................................................................................................34
7.11.6
Eastern Cooperative Oncology Group (ECOG) Performance Status.................34
7.12
Interim Analysis ......................................................................................................34
7.13
Changes in the Statistical Analysis Plan...................................................................34
8.0
REFERENCES..............................................................................................................35
LIST OF IN-TEXT TABLES
Table 6.a
..............................................................18
Table 6.b
.........................19
Table 6.c
.............................19
Table 7.a
Clinical Chemistry and Hematology Tests..........................................................33
LIST OF IN-TEXT FIGURES
Figure 4.a
TAK-981-1501: TAK-981 Study Schematic.......................................................14
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Statistical Analysis Plan Final V2.0
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CONFIDENTIAL
3.0
LIST OF ABBREVIATIONS 
Abbreviation
Term
ANC
absolute neutrophil count
AE
adverse event
AUC0-∞
area under the plasma/blood/serum concentration-time curve from time 
0 to infinity
AUC0-t
area under the plasma concentration versus time curve from time 0 to 
time t
BLRM
Bayesian Logistic Regression Modeling
CL
total clearance after intravenous administration
Cmax
maximum observed concentration
CR
complete response 
CRS
cytokine release syndrome
DCR
disease control rate 
DLBCL
diffuse large B-cell lymphoma
DL
dose level
DLT
dose-limiting toxicity
DOR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
FL
follicular lymphoma
GGT
gamma glutamyl transferase
IFN
interferon
IRR
infusion-related reaction
IV
intravenous
LDH
lactate dehydrogenase
MAD
maximally administered dose
MedDRA
Medical Dictionary for Regulatory Activities
MTD
maximum tolerated dose
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse 
Events
NHL
non-Hodgkin lymphoma
ORR
overall response rate
PAD
pharmacologically active dose
PD
progressive disease (disease progression)
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Abbreviation
Term
PFS
progression-free survival
PK
pharmacokinetic(s)
PR
partial response 
QTc
corrected QT interval
RBC
red blood cell
R-CHOP
rituximab, cyclophosphamide, doxorubicin (hydroxydaunorubicin), 
vincristine (Oncovin) and prednisone
RP2D
recommended phase 2 dose
SMC
Safety Monitoring Committee
SUMO
small ubiquitin-like modifier
SUMO1
small ubiquitin-like modifier 1
SUMO2
small ubiquitin-like modifier 2
SUMO3
small ubiquitin-like modifier 3
t1/2z
terminal disposition phase half-life
tmax
first time to reach maximum (peak) plasma concentration
TEAE
treatment-emergent adverse events
TLS
tumor lysis syndrome
TTP
time to progression
WHO
World Health Organization
Vss
volume of distribution at steady state after intravenous administration
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4.0
OBJECTIVES
The study will be conducted in 2 parts:

Phase 1 dose escalation guided by Bayesian Logistic Regression Modeling (BLRM), and 
a Japan-Specific Lead-in in patients with both indolent and aggressive CD20+ r/r Non-
Hodgkin Lymphoma (NHL).

Phase 2 study with 3 treatment arms with select r/r Follicular Lymphoma (FL) and r/r 
Diffuse large B-cell lymphoma (DLBCL) indications, conducted according an adaptive 2 
stage design for a single proportion.
The study objectives will be separated based on the phase of the study.
4.1
Primary Objectives
Phase 1 Dose Escalation:

To determine the safety and tolerability of TAK-981 in combination with rituximab in 
patients with r/r NHL.

To establish the recommended Phase 2 dose (RP2D) of TAK-981 in combination with 
rituximab.
Phase 1 Japan-Specific Lead-in Expansion:

To evaluate the safety and tolerability of TAK-981 in Japanese patients with r/r CD20+ 
NHL.
Phase 2:

To evaluate the efficacy of TAK-981 in combination with rituximab in select r/r NHL.
4.2
Secondary Objectives

To characterize the PK profile of TAK-981 in combination with rituximab, for both 
Phase 1 and 2.
Phase 1:

To determine the maximum tolerated dose (MTD) and/or pharmacologically active dose 
(PAD) of TAK-981 when administered in combination with rituximab.

To assess the preliminary antitumor activity of TAK-981-rituximab combination.

To assess target engagement of TAK-981 (SUMO-TAK-981 adduct formation) and 
SUMOylation pathway inhibition in blood and skin.
Phase 1 Japan-Specific Lead-in Expansion:

To characterize the PK profile of TAK-981 in Japanese patients.
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Dose escalation of TAK-981 will be guided by a Bayesian Logistic Regression Modeling 
(BLRM) design with overdose control. Approximately 35 patients will be enrolled until either 
MTD or a PAD is identified. A minimum of 3 patients will be enrolled in the dose level 1 cohort.
The recommended phase 2 dose (RP2D) will be determined from the collective experience in the 
clinic considering the safety data, preliminary pharmacokinetic (PK) data, preliminary 
pharmacodynamic data, and any early antitumor activity observed along with the statistical 
inference from the BLRM.
A Safety Monitoring Committee (SMC) composed of the principal investigators, and sponsor 
clinician will regularly review safety data to ensure patients’ safety throughout the phase 1 
portion of the study and make decisions on dose escalation. Dose escalation decisions will be 
made based on the DLTs meeting the criteria above that occur during the first 3 weeks of 
treatment for each patient.
For the first infusion Cycle 1, Day 1 (C1D1) of TAK-981 in combination with rituximab during 
dose escalation every patient must be hospitalized for drug administration and observation (for a 
minimum of 18 hours after the end of TAK-981 infusion). Hospitalization is not required after 
the first 3 patients at a dose level (DL) or expansion of previously cleared DL, and only if the 
risk of infusion reactions is considered low based on previous experience. If Grade 3 or greater 
IRR or cytokine release syndrome (CRS) are not observed at PAD or MTD, or if the safety data 
from the ongoing first-in-human TAK-981-1002 study support the removal of the requirement of 
hospitalization for the first dose of TAK-981, the decision will be made by the SMC.
Patient enrollment will be staggered between the first and second patients by 72h during dose 
escalation at all DLs. At each DL, the second and third patients can be dosed concurrently if the 
first patient in the cohort has gone through the Day 4 (72h) without clinically significant acute 
toxicities. If more than 3 patients are to be enrolled in a DL or if de-escalation is indicated, 
staggering will not be required unless indicated by safety findings. 
Phase 1: Japan-Specific Lead-in Expansion Study Design
The Japan-Specific Safety Lead-in is an open-label study to evaluate the tolerability of Phase 2 
dose levels and schedule of TAK-981 in combination with rituximab determined during Dose 
Escalation in the TAK-981-1501 study. 
The Japan-Specific Lead-in will consist of 2 cohorts:

TAK-981 single agent cohort: Patients will be treated with TAK-981 at 60 mg 
administered as a 1-hour IV infusion on Days 1, 4, 8 and 11 in cycles of 21 days. TAK-
981 will be administered until disease progression or unacceptable toxicity. Following a 
rule-based 3 + 3 + 3 design for the single agent cohort, a lower dose level of 40 mg will 
be considered if 60 mg is not tolerated. The Japan Safety Monitoring Committee (JSMC) 
consisting of sponsor clinician and Japanese investigators, will determine whether the 
TAK-981 starting dose is tolerable in Japanese patients, and will determine the initiation 
of the combination cohorts in Japan-Specific Lead-in. Additional dose levels are not 
planned to be evaluated in the single agent cohorts.
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
Patients in the combination cohorts will be treated with escalating doses of TAK-981 
with fixed dose of rituximab up to the upper dose level of the Phase 2 doses determined 
in the global Dose Escalation. TAK-981 dose escalation will follow a rule-based 3 + 3 + 
3 design, starting from the dose level considered safe in the single agent cohort in Japan-
Specific Lead-in with a fixed dose of rituximab of 375 mg/m2 administered IV on Days 
1, 8, and 15 during Cycle 1 and on Day 1 from Cycle 2 Day 1 onwards. TAK-981 will be 
administered as a 1-hour IV infusion, and the dosing schedule will be considered upon 
discussion and agreement between Japanese investigators and sponsor referring to the 
Phase 2 dose schedule selected in global Dose Escalation. The Phase 2 dose levels in 
Japanese subjects will be determined from the collective experience in the clinic 
considering the safety data, preliminary PK data, preliminary pharmacodynamic data, and 
any early antitumor activity. Rituximab and TAK-981 will be administered intravenously 
as per dosing schedule until disease progression or unacceptable toxicity. 
In combination with rituximab, TAK-981 dose escalation and cohort expansion decisions are 
reviewed and approved by the JSMC. The combination cohorts will be initiated after the JSMC 
review and approval of the safety data, considering no significant toxicity observed for TAK-981 
in combination with rituximab based on the latest safety data from dose escalation part and 
single agent cohort of Japan-Specific Lead-in. The JSMC may require the enrollment of 
additional patients to any of the single agent or combination cohorts to develop PK and/or 
pharmacodynamic data in Japanese patients. The JSMC may decide to further expand dose levels 
to support the potential development of other regimens and/or NHL indications.
Japan-Specific Lead-in will enroll patients with indolent or aggressive CD20+ r/r NHL. Patients 
who participated in Japan-Specific Lead-in will receive TAK-981 under inpatient hospitalization 
during Cycle 1. During Cycle 1, patients will be hospitalized for 21 days (Cycle 1). Patient 
enrollment will be staggered between the first and second patients by 72 hours at all dose levels. 
At each dose level, the second and third patients can be dosed concurrently if the first patient in 
the cohort has gone through Day 4 (72 hours) without clinically significant acute toxicities. If 
more than 3 patients are to be enrolled in a dose level or if de-escalation is indicated, staggering 
will not be required unless indicated by safety findings.
Intrapatient dose escalation will be permitted only when patients in the next dose level cohort 
have completed assessment for Cycle 1 and a decision has been made that this dose level does 
not exceed the MTD. Patients in the single-agent cohort will be permitted to be treated with the 
combination when patients in the subsequent combination cohort have completed assessment for 
Cycle 1 and JSMC has decided that the dose of TAK-981 combination with rituximab is 
tolerable in Japanese patients.
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Phase 2: Expansion in Select Indications
The Phase 2 portion of the study will explore the efficacy and safety of TAK-981 in combination 
with rituximab in patients with select r/r NHL types and indications. The following cohorts will 
be enrolled:

Cohort A: r/r diffuse large B-cell lymphoma (DLBCL) progressed or relapsed after chimeric 
antigen receptor (CAR) T-cell therapy (CAR-T).

Cohort B: r/r DLBCL progressed or relapsed after 2-3 prior lines of systemic therapy and no 
prior therapy with CAR T-cells.

Cohort C: r/r follicular lymphoma (FL) progressed or relapsed after 2-3 prior lines of 
systemic therapies.
Each cohort will be assessed separately using an adaptive 2-stage design for a single proportion. 
For Stage 1, each cohort will be analyzed when a prespecified number of patients have been 
enrolled and had the potential to have at least 1 post-treatment radiologic evaluation of the 
disease. If the prespecified minimal response rate is not achieved in the first stage for a given 
cohort, that cohort will be closed to enrollment. However, if a clear clinical benefit has been 
observed for patients in the cohort (eg, a majority of patients have recorded stable disease at 
Week 8 and no complete response [CR] or partial response [PR] is recorded) then enrollment 
into Stage 2 may be allowed for this cohort. If the required response rate during Stage 1 or a 
good clinical benefit is observed for a particular cohort as mentioned above, then additional 
patients will be enrolled in the second stage of the corresponding cohort until a predetermined 
number of additional patients for that cohort has been reached. The final analysis of the primary
endpoints for each cohort will take place when all ongoing patients have completed the 6-month 
disease assessment/survival follow-up.
TAK-981 will be evaluated at a dose of 120 mg once weekly (QW) (the upper dose tested in 
Phase 1) as well as at the dose of 60 mg QW (a lower yet biologically active dose) in a 21-day 
cycle, both in combination with a fixed dose of rituximab, in the Phase 2 expansion. The dose 
cohorts will be: Cohorts B 120 mg/C 120 mg and Cohorts B 60 mg/C 60 mg. This data will be 
used to generate supplementary efficacy, safety, and exposure/response data to inform dose 
selection for further development of TAK-981.
During Phase 2, an Independent Data Monitoring Committee will be established to monitor 
safety and assess benefit/risk throughout the conduct of the Phase 2 portion of the study.
Patients enrolled in sites in China will participate in Phase 2 of the study.
The overall study schematic is displayed in Figure 4.a. 
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Figure 4.a
TAK-981-1501: TAK-981 Study Schematic
aNHL: aggressive Non-Hodgkin Lymphoma; BIW: twice weekly; CAR: chimeric antigen receptor; DLBCL: diffuse 
large B-cell lymphoma; FIH: first-in-human; FL: follicular lymphoma; iNHL: indolent Non-Hodgkin Lymphoma; 
MCL: mantle cell lymphoma; MZL: marginal zone lymphoma; NHL: non-Hodgkin lymphoma; QW: once weekly; 
R-CHOP: rituximab, cyclophosphamide, doxorubicin (hydroxydaunorubicin), vincristine (Oncovin ®) and 
prednisone; r/r: relapsed or refractory.
5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoints

Phase 1:
–
Frequency, severity, and duration of TEAEs and laboratory abnormalities for all dose 
groups according to the NCI CTCAE, Version 5.0; except CRS which will be graded 
according to American Society for Transplantation and Cellular Therapy (ASTCT) 
Consensus Grading for CRS.
–
Occurrence of DLTs within the first 21 days of treatment in Cycle 1.

Phase 2:
–
ORR (CR + PR) as defined by the investigator according to Lugano Classification for 
lymphomas.
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7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
In general, summary tabulations will display the number of observations, mean, standard 
deviation (SD), median, minimum, and maximum for continuous variables, and the number and 
percent (of non-missing values) per category for categorical data. 
All available efficacy and safety data will be included in data listings and tabulations as needed. 
Data that are potentially spurious or erroneous will be examined under the auspices of standard 
data management operating procedures.
Baseline values are defined as the last observed value before the first dose of study medication. 
Means and medians will be presented to 1 more decimal place than the recorded data. The SDs 
will be presented to 2 more decimal places than the recorded data. Confidence intervals about a 
parameter estimate will be presented using the same number of decimal places as the parameter 
estimate.
The summary tables will be presented separately for escalation phase (include escalation cohort, 
overall for dose escalation phase), expansion phase (by expansion cohort and overall for 
expansion phase and overall for expansion phase). Summary tables with subjects with the same 
dose/regimen pooled across escalation and expansion phase may also be provided. In addition, 
selected summary tables for Japan-specific lead-in phase may be provided separately.
Screen failure subjects will be grouped and listed.
At the time of the SAP amendment, the expansion phase portion is being terminated with limited 
number of patients and an abbreviated CSR will be written for this study, therefore certain 
analyses described in this SAP may not be conducted. Details will be documented in the CSR.
All statistical analyses will be conducted using SAS® Version 9.4, or higher.
7.1.1
Definition of Study Visit Windows
All data will be categorized based on the scheduled visit at which it was collected unless 
otherwise specified. These visit designators are predefined values that appear as part of the visit 
tab in the eCRF.
7.1.2
Conventions for Missing/Partial Dates in Screening Visit
The following rules apply to dates recorded during the screening visits. 

If only the day-component is missing, the first day of the month will be used if the year 
and the month are the same as those for the first dose of study drug. Otherwise, the 
fifteenth will be used. 

If only the year is present, and it is the same as the year of the first dose of study drug, the 
fifteenth of January will be used unless it is later than the first dose, in which case the 
date of the first of January will be used, unless other data indicate that the date is earlier.
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
If only the year is present, and it is not the same as the year of the first dose of study 
drug, the fifteenth of June will be used, unless other data indicates that the date is earlier.
7.1.3
Conventions for Missing Adverse Event Dates
Adverse events with start dates that are completely or partially missing will be analyzed as 
follows:

If month and year are known but day is missing 
–
If month and year are the same as month and year of first dose date, then impute to 
first dose date 
–
If month and year are different than month and year of first dose date, then impute to 
first date of the month 

If year is known but day and month are missing 
–
If year is same as year of 1st dose date, then 1st dose date will be used instead
–
If year is different than year of 1st dose date, then 1st of January of the year will be 
imputed. 

If all is missing, then it is imputed with 1st dose date.
Imputing missing AE start date is mandatory. After the imputation, all imputed dates are checked 
against the stop dates to ensure the stop date does not occur before start date 
Adverse events with stop dates that are completely or partially missing will be analyzed as 
follows:

If “ongoing” is checked, no imputation is necessary.

If month and year are known but day is missing, the last day of the month will be 
imputed 

If year is known, but day and month are missing,
–
If YYYY < year of last dose, then 31st of December will be imputed
–
If YYYY = year of last dose, then 31st of December will be imputed 
–
If YYYY > year of last dose, then 1st of January will be imputed 

If all are missing, then impute date to 31st of December, in the year of last dose. 
Imputing missing AE stop date is not mandatory if AE is regarded as ongoing. However, if it is 
to be done, the rules are outlined above. If the imputed stop date occurs prior to start date, then 
keep the imputed date same as the start date. If subject dies, then use death date for AE stop date.
After the imputation, all imputed dates are checked against the start dates to ensure the stop date 
does not occur before start date. If the imputed stop date occurs prior to start date, then keep the 
imputed date the same as the start date. 
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7.1.4
Conventions for Missing Concomitant Medication/Therapy Dates
Concomitant medications/therapies with start dates that are completely or partially missing will 
be analyzed as follows:

If month and year are known, but day is missing, then impute day to first of the month
–
If year is known, but day and month are missing, then 1st of January of the year will 
be imputed

If all is missing, then impute date to Date of Birth (DOB) 
–
If DOB is not available but age is available, then estimate DOB by using screening 
date and age (age = screening date – DOB) 
Concomitant therapies with stop dates that are completely or partially missing will be analyzed 
as follows:

If “ongoing” is checked, no imputation is necessary.

If month and year are known but day is missing, the last day of the month will be 
imputed 

If year is known, but day and month are missing, 
–
If YYYY < year of last dose, then 31st of December will be imputed 
–
If YYYY = year of last dose, then 31st of December will be imputed 
–
If YYYY > year of last dose, then 1st of January will be imputed 

If all is missing, then impute date to 31st of December in the year of last dose 
Imputing missing concomitant therapies is optional. However, if it is to be done, the rules are 
outlined above. If subject dies, then use death date for concomitant therapies stop date. After the 
imputation, all imputed dates are checked against the start dates to ensure stop date does not 
occur before start date. If the imputed stop date occurs prior to start date, then keep the imputed 
date same as the start date.
7.1.5
Conventions for Missing Subsequent Medication/Therapy Dates
Subsequent therapies with start dates that are completely or partially missing will be analyzed as 
follows:

When month and year are present and the day of the month is missing, 
–
If the onset month and year are the same as the month and year of last dose with study 
drug, the day of last dose + 1 will be imputed.
–
If the onset month and year are not the same as the month and year of last dose with 
study drug, the first day of the month is imputed.
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7.5
Medical History and Concurrent Medical Conditions
Medical history will be presented in a by-patient listing, including the medical and surgical 
history, date of onset and the status (whether it is resolved or ongoing).
7.6
Medication History and Concomitant Medications
A separate table will summarize the numbers and percentages of patients who received prior 
therapy, including prior anticancer, prior radiation, prior surgery or procedure, and best response 
to the last prior anticancer therapy.
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Dictionary. The number and percentage of patients taking concomitant medications will be 
tabulated by ATC Pharmacological Subgroup and WHO drug generic term for the safety 
population, the signing of ICF through 30 days after the last dose of study treatment, or to the 
start of subsequent systemic anticancer therapy, whichever occurs first. 
Concomitant medications will also be presented in a by-patient listing.
Concomitant procedures will not be coded but will be presented in a by-patient listing.
7.7
Study Drug Exposure and Compliance
Extent of Exposure: 
The exposure to study drugs (TAK-981 and rituximab) will be characterized by total amount of 
dose taken in mg, total number of doses taken, relative dose intensity (%), number of treated 
cycles, numbers and percentages of patients who had ≥1, ≥2, …, ≥6, ≥9, ≥12 and ≥15 treated 
cycles for patients in the safety population. A treated cycle is defined as a cycle in which the 
patient received any amount of study drug. 
Duration of treatment (days), and number and percentages of patients who had >=3, >=6, … 
weeks of treatment will be summarized for patients in the safety population. 
Relative dose intensity (RDI) (%) for will be presented overall and by cycle for each IP (TAK-
981 and rituximab).
Overall RDI (%) is defined as 100 x (Total amount of dose taken) / (Total prescribed dose of all 
treated cycles), where a treated cycle is defined as a cycle in which the patient received any 
amount of any study drug. 
For RDI by cycle the similar formula is used as overall relative dose intensity and will be 
calculated for treated cycles. 
Cycle RDI (%) is defined as 100 x (Total amount of dose in cycle) / (Total prescribed dose of in 
cycle)
Prescribed dose is determined by the dose level to which a patient is scheduled to receive and 
will take into consideration of planned dose reduction or escalation during the study. 
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Relative dose intensity will also be displayed as <50%, 50% - <= 80%, 80% - < 100%, = 100%, 
and > 100%.
The extent of exposure will be summarized by escalation cohort, overall for dose escalation 
phase, by safety expansion cohort, and overall in safety expansion phase.
Dosing data will also be presented in a by-patient listing.
Action on Study Drug:
Action on study drug will be summarized by Cycles 1- 6, Cycle 7- 12, Cycles 13-18, Cycle ≥19 
and total, for each dose escalation cohort, overall for dose escalation phase, for each safety 
expansion cohort, and overall in safety expansion phase.
Summary for extent exposure and action on study drug in Japan-specific lead-in phase will be 
provided separately by dose cohort and overall.
7.8
Efficacy Analysis
7.8.1
Primary Efficacy Endpoint(s)
Phase 1:
Efficacy is not the primary objective for this study in the phase 1 portion. The efficacy analysis 
will mainly focus on the phase 2 portion of this study.
In the phase 1 portion of this study, efficacy parameters such as ORR, DOR and PFS will also be 
summarized as appropriate. Disease response will be categorized and presented in listings.
Phase 2:
The primary endpoint for phase 2 portion is ORR (CR + PR) as defined by the investigator 
according to Lugano criteria for lymphoma response, from Cheson 2014 [3].
ORR is defined as the proportion of patients who achieve CR and PR (determined by the 
investigator) during the study. 
The primary efficacy analysis will be based on the response-evaluable population.
Estimates of the ORR (CR + PR) will be presented with 2-sided 95% exact binomial confidence 
intervals.
7.8.2
Secondary Efficacy Endpoint(s)
Secondary efficacy endpoints include ORR, DCR, DOR, TTP and PFS. No formal statistical 
tests will be performed for these secondary endpoints. 
DCR is defined as the proportion of patients who achieve stable disease (SD) or better 
(CR+PR+SD determined by the investigator) during the study in response-evaluable population.
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DOR is the time from the date of first documentation of a PR or better to the date of first 
documentation of PD for responders (PR or better). Responders without documentation of PD 
will be censored at the date of last response assessment that is SD or better.
PFS is defined as the time from the date of the first dose administration to the date of first 
documentation of PD or death due to any cause, whichever occurs first. PD will be determined 
by Response Evaluation Criteria in Lymphoma for patients with lymphoma. Patients without 
documentation of PD will be censored at the date of the last response assessment that is SD or 
better.
Patients who received any subsequent anticancer therapy without a prior reported progression 
will be censored at the last response assessment prior to or on the date of initiation of the 
subsequent anticancer therapy.
TTP is defined as the time from the date of the first dose administration to the date of first 
documented progress disease (PD). Patients without documentation of PD at the time of analysis 
will be censored at the date of last response assessment that is SD or better. Patients who die 
during treatment without PD will also be censored at the date of last response assessment that is 
SD or better. Patients who received any subsequent anticancer therapy without a prior reported 
progression will be censored at the last response assessment that is SD or better prior to or on the 
date of initiation of the subsequent anticancer therapy.
ORR will be summarized using descriptive statistics with 95% confidence interval for response-
evaluable analysis set. 
DCR will be summarized is a similar way as ORR.
PFS will be analyzed descriptively using Kaplan-Meier (K-M) method for safety analysis set. 
The K-M survival curves, 25th, 50th (median), and 75th percentiles (if estimable), along with 
their 2-sided 95% confidence intervals will be provided.
DOR and TTP will also be analyzed using K-M method for response-evaluable analysis set.
Waterfall plot of best %change of target lesion size from baseline and swimmer plot of response 
with duration will be provided.
Efficacy endpoints will be presented in individual subject listings for Japan-specific lead-in
phase. 
7.8.3
Additional Efficacy Endpoint(s)
Not applicable.
7.9
Pharmacokinetic/Pharmacodynamic Analysis
7.9.1
Pharmacokinetic (PK) Analysis 
The PK of TAK-981 will be characterized in this study (ie, rituximab PK will not be 
characterized).
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PK parameters will be estimated using noncompartmental methods with Phoenix WinNonlin. 
The PK parameters will be estimated from the concentration-time profiles for the PK population. 
The following PK parameters will be determined, as permitted by data:

Cmax.

tmax.

AUC0-∞.

AUC0-t.

T1/2z.

CL.

Vss.
PK parameters will be summarized using descriptive statistics. Individual TAK-981 
concentration-time data and individual PK parameters will be presented in listings and tabulated
using summary statistics by dose cohort. Individual and mean concentration-time profiles will be 
plotted by dose cohort. The above parameters will not be estimated for the sparse PK samples 
collected during the phase 2 portion of study.
The PK data collected in this study are intended to contribute to future population PK analyses of 
TAK-981. These population PK analyses may include data collected in other TAK-981 clinical 
studies. The analysis plan for the population PK analysis will be separately defined, and the 
results of these analyses will be reported separately.
7.9.2
Pharmacodynamic (PD) Analysis
The analysis of blood and skin biomarker profiles for each dose and timepoint tested will be 
tabulated. When possible, the dynamic range for each biomarker and fold change will be 
determined to better understand TAK-981 biological activity range and duration of 
pharmacodynamic effect, and help to determine the PAD/RP2D for the TAK-981/rituximab 
combination. 
7.10
Other Outcomes
7.10.1
PK/PD Analysis 
Data permitting, the PK and pharmacodynamic data collected in this study will be analyzed to 
understand the exposure-response relationship for TAK-981 in combination with rituximab. 
Such analysis may be performed on an ongoing basis to assess the appropriateness of dose and 
schedule of TAK-981 in combination with rituximab and for determination of PAD.
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events will be tabulated according to MedDRA by system organ class, high level term, and 
preferred term and will include the following categories: 

Treatment-emergent AEs.

Drug-related treatment-emergent AEs.

Grade 3 or higher treatment-emergent AEs.

Grade 3 or higher drug-related treatment-emergent AEs.

The most commonly reported treatment-emergent AEs (ie, those events reported by 10% of 
all patients).

SAEs (related and regardless of relationship).

Treatment-emergent AEs leading to study drug modification and discontinuation.
Patients with the same AE more than once will have that event counted only once within each 
body system, once within each high-level term, and once within each preferred term.
Treatment-emergent AEs will also be summarized by CTCAE grade (or ASTCT grade for CRS). 
Patients with the same AE more than once will have the maximum intensity of that event 
counted within each body system, once within each high-level term, and once within each 
preferred term. 
The most commonly reported treatment-emergent AEs (ie, those events reported by 10% of all 
patients) will be tabulated by preferred term. Patients with the same AE more than once will 
have that event counted only once within each preferred term.
An overall summary treatment-emergent AE table will include numbers and percentages of 
patients who had any treatment-emergent AE, drug-related treatment-emergent AE, grade 3 or 
higher treatment-emergent AE, grade 3 or higher drug-related treatment-emergent AE, serious 
AE (SAE), drug-related SAE, treatment-emergent AE resulting in dose modification of study 
drug, treatment-emergent AE resulting in discontinuation of study drug, and on-study deaths. 
In addition, Summary of AEs in Japan-specific lead-in phase will be provided separately by dose 
cohort and overall.
By-patient listing of grade 3 or higher treatment-emergent AE will also be provided, where the 
cycle day information for the AE onset and end dates will be included in the listing.
7.11.2.2
Serious Adverse Events
The number and percentage of subjects experiencing at least 1 treatment emergent serious AE 
(SAE) will be summarized by MedDRA primary system organ class, high-level term, and 
preferred term. Drug-related SAEs will be summarized similarly.
In addition, a by-subject listing of the SAEs will be presented (the subject listing will contain all 
SAEs regardless of treatment emergent AE status).
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7.11.2.3
Deaths
A by-subject listing of the deaths will be presented. All deaths occurring on-study and during 
follow-up will be displayed (regardless of treatment-emergent AE status).
On-study death is defined as the death that occurs between the first dose of any study drug and 
within 30 days of the last dose of any study drug.
7.11.2.4
Adverse Events Resulting in Discontinuation of Study Drug
A by-patient listing of treatment-emergent AEs resulting in discontinuation of study drug will be 
presented. All AEs resulting in discontinuation of study drug occurring on-study and during 
follow-up will be displayed (regardless of treatment-emergent AE status). 
7.11.3
Clinical Laboratory Evaluations
For the purposes of summarization in both the tables and listings, all laboratory values will be 
converted to standardized units. If a lab value is reported using a non-numeric qualifier (e.g., less 
than (<) a certain value, or greater than (>) a certain value), the given numeric value will be used 
in the summary statistics, ignoring the non-numeric qualifier.
Laboratory test results from the central laboratory will be used when they are available.
Laboratory test results from local laboratories will be used only when no central laboratory test 
results exist at the same scheduled sample collection time point.
If a patient has repeated laboratory values for a given time point, the value from the last 
evaluation will be used.
The actual values of laboratory test results and percent change from baseline will be summarized 
according to the scheduled sample collection time point. Laboratory data will also be presented 
in listings. Unscheduled laboratory test results will be listed and included in laboratory shift 
tables.
Shift tables will be constructed for laboratory parameters to tabulate changes in NCI CTCAE 
v5.0 for toxicity from baseline to post baseline worst on study CTCAE grade, if available.
Parameters to be tabulated are included in Table 7.a.
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Table 7.a
Clinical Chemistry and Hematology Tests
Hematology
Serum Chemistry
Coagulation
Hematocrit
Hemoglobin
Leukocytes with differential
ANC
CD4/CD8 count and ratio
Platelet count
Albumin
Alkaline phosphatase
Alanine aminotransferase
Aspartate aminotransferase
Bilirubin (total)
(Blood) Urea nitrogen (BUN)
Calcium
Bicarbonate (HCO3-) or Carbon 
dioxide (CO2)
Creatinine 
(Standard) C Reactive protein
Chloride
Glucose
Lactate dehydrogenase (LDH)
Magnesium
Phosphate
Potassium
Sodium
Protein (total)
Urate
Activated partial thromboplastin 
time (aPTT)
Prothrombin time (PT)
Fibrinogen
ANC: absolute neutrophil count.
The chemistry laboratory parameters for TLS monitoring will include the following: creatinine, 
uric acid, potassium, phosphorus, calcium, albumin, and corrected calcium, if available.
By-patient listings to be presented include hematology, clinical chemistry, clinically significant 
laboratory values, etc.
Mean laboratory values over time will be plotted for key lab parameters, including hemoglobin, 
leukocytes with differential, neutrophils, platelet count, alkaline phosphatase, alanine 
aminotransferase, aspartate aminotransferase, bilirubin, creatinine, and standard C-reactive 
protein. The analysis for other lab parameters may be performed as needed.
The number and percentage of patients with clinically significant laboratory values will also be
tabulated as appropriate.
7.11.4
Vital Signs
The actual values of vital sign parameters (blood pressure, heart rate, oxygen saturation
[Japanese specific lead-in only] and temperature) and weight will be summarized over time.
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Change of vital signs from baseline values will also be summarized over time. Vital sign values 
will also be presented in a by-patient listing.
The number and percentage of patients with clinically significant vital sign measurements will be
tabulated as appropriate.
7.11.5
12-Lead ECGs
Descriptive statistics for the actual values and changes from values at baseline in 
Electrocardiograms (ECGs) will be listed by time point.
QTc interval will be calculated using Bazett’s correction and Fridericia’s correction, if necessary.
The formulas are:
QTc (Bazett) = QT / (RR0.5)
QTc (Fridericia) = QT / (RR0.33)
where RR = 60 / heart rate (bpm)
In addition, a categorical analysis of QTc intervals will be performed for each time point. The 
number and percentage of patients in each QTc interval (< 450 msec, 450-480 msec, > 480-
<500 msec, and ≥500msec) will be summarized at baseline and each of the subsequent time 
points. Categories of changes from baseline (≥30 msec and ≥60 msec) will be summarized as 
well. Maximum QTc intervals and maximum changes from baseline will also be summarized 
similarly in a separate display.
ECGs abnormalities will be presented in a data listing.
7.11.6
Eastern Cooperative Oncology Group (ECOG) Performance Status
ECOG Group Performance Status and shifts from baseline to post baseline assessment over time, 
and ECOG score frequency table over time will be summarized. Shifts from baseline to the worst 
post baseline score will be tabulated.
7.12
Interim Analysis
Not applicable.
7.13
Changes in the Statistical Analysis Plan 
To be updated as needed.
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8.0
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For non-commercial use only


For non-commercial use only