Conditions: Neoplasms Lymphoma Hematologic Neoplasms
Keywords: Drug therapy
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 109
Healthy volunteers: no

Brief summary:
This study is in 2 parts.

The main aims of the 1st part of the study are to check if people with advanced solid tumors or cancers in the immune system (lymphomas) have side effects from TAK-981, and to check how much TAK-981 they can receive without getting side effects from it.

The main aims of the 2nd part of the study are to learn if the condition of people with specific cancers improves after treatment with TAK-981. Another aim is to check for side effects from TAK-981.

In the 1st part of the study, participants will receive TAK-981. In the 2nd part of the study, participants with specific tumor types will receive TAK-981 at the recommended phase 2 dose determined during the 1st part of the study.

In both parts of the study, participants can receive TAK-981 for up to 1 year or longer if their condition stays improved. Participants will receive TAK-981 through vein.

Detailed description:
The drug being tested in this study is called TAK-981. TAK-981 is being tested to evaluate safety, tolerability, preliminary efficacy and PK in participants with advanced or metastatic solid tumors or relapsed/refractory hematologic malignancies. The study will include 2 phases: Phase 1 dose escalation and Phase 2 dose expansion cohorts (cancer treatment expansions).

The study will enrol approximately 202 participants, approximately 70 participants in the dose escalation phase, approximately 132 participants in cancer treatment expansion phase.

In the dose escalation, dose levels will be escalated based on safety, and available PK and pharmacodynamic data and will also determine the single agent RP2D. Participants in dose expansion phase will be enrolled, once RP2D is determined. There will be 6 cohorts in cancer treatment expansions.

* Cohort A: Nonsquamous NSCLC
* Cohort B: Cervical cancer
* Cohort C: MSS-CRC
* Cohort D: Relapsed/refractory DLBCL progressed or relapsed after CAR T-cells therapy
* Cohort E: Relapsed/refractory DLBCL that have not received prior cellular therapy
* Cohort F: Relapsed/refractory FL

This multi-center trial will be conducted in European Union, China and United States. The overall time to participate in this study is approximately 2 years. The overall time to receive treatment in the dose escalation and cancer treatment is approximately 1 year. Based on decision of sponsor, participants with demonstrated clinical benefit can continue treatment beyond 1 year. Participants will make multiple visits to the clinic and will make a final visit 30 days after receiving their last dose of drug or before the start of subsequent anticancer therapy, whichever occurs first for a follow-up assessment.uroped

Arms:
arm 1: TAK-981, intravenously, administered as 60 minute-infusion, once on Days 1, 4, 8, and 11 in a 21-day treatment cycle for up to approximately 12 months or until discontinuation from the study. If clinical safety, pharmacokinetics, and pharmacodynamics are supportive, the dosing schedule may be modified to evaluate a less intensive administration of TAK-981 on Day 1, or Days 1 and 8, or Day 1, Day 8, and Day 15 in 21-day cycles in participants with advanced or metastatic solid tumors or lymphomas. Dose levels will be escalated based on the Bayesian logistic regression modeling (BLRM). The dose escalation phase will determine the RP2D of TAK-981. arm 2: TAK-981 intravenously administered as 60 minute-infusion in a 21-day treatment cycle for up to approximately 12 months or until discontinuation from the study in participants with nonsquamous non-small cell lung cancer (NSCLC). arm 3: TAK-981 intravenously administered as 60 minute-infusion in a 21-day treatment cycle for up to approximately 12 months or until discontinuation from the study in participants with cervical cancer. arm 4: TAK-981 intravenously administered as 60 minute-infusion in a 21-day treatment cycle for up to approximately 12 months or until discontinuation from the study in participants with microsatellite-stable colorectal cancer (MSS-CRC). arm 5: TAK-981 intravenously administered as 60 minute-infusion in a 21-day treatment cycle for up to approximately 12 months or until discontinuation from the study in participants with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) after prior chimeric antigen receptor (CAR) T-cells therapy. arm 6: TAK-981 intravenously administered as 60 minute-infusion in a 21-day treatment cycle for up to approximately 12 months or until discontinuation from the study in participants with relapsed/refractory DLBCL that have not received prior cellular therapy. arm 7: TAK-981 intravenously administered as 60 minute-infusion in a 21-day treatment cycle for up to approximately 12 months or until discontinuation from the study in participants with relapsed/refractory follicular lymphoma (FL).

Interventions: intervention 1: TAK-981
Intervention descriptions: intervention 1: Intravenous infusion.

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


 
 
CONFIDENTIAL
PROTOCOL
An Open Label, Dose-Escalation, Phase 1/2 Study to Evaluate the Safety, Tolerability, 
Preliminary Efficacy, and Pharmacokinetics of TAK-981 in Adult Patients With Advanced 
or Metastatic Solid Tumors or Relapsed/Refractory Hematologic Malignancies 
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-981-1002
EudraCT Number:
2020-003947-27
Compound:
TAK-981
Date:
09 November 2021
Amendment Number:
7
Date
Amendment Number
Amendment Type
Region
09 November 2021
Amendment 7
Substantial
Global
14 December 2020
Amendment 6
Substantial
Global
28 August 2020
Amendment 5
Substantial
Global
10 April 2020
Amendment 4
Substantial
United States and Canada
31 March 2020
Amendment 3
Substantial
United States and Canada
26 March 2019
Amendment 2
Substantial
United States and Canada
10 July 2018
Amendment 1
Nonsubstantial
United States and Canada
07 May 2018
Initial protocol
Not applicable
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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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.

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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1.3
Protocol Amendment 7 Summary of Changes
Protocol Amendment 7 Summary and Rationale:
This section describes the changes to the protocol incorporating Amendment 7. The primary 
reason for this amendment was to incorporate updated language around pregnancy and lactation to 
align with the IB.
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.
Protocol Amendment 7 
Summary of Changes Since Last Version of the Approved Protocol
Change
Number
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
1
Section 2.0 STUDY SUMMARY
Section 5.1.2 Secondary Objectives
Section 5.2.2 Secondary Endpoints
Table 6.a Primary and Secondary Endpoints 
for Disclosures
Deleted overall response 
rate (ORR) from secondary 
objective/endpoint in 
Phase 2. 
Correction: ORR is the 
primary endpoint, not a 
secondary endpoint, for 
Phase 2.
2
Section 4.2.4 Preliminary Clinical Experience
Added a clinical 
experience section with 
data from the latest 
Investigator’s Brochure
(IB).
Update of the clinical data.
3
Section 2.0 STUDY SUMMARY
Section 5.2.2 Secondary Endpoints
Table 6.a Primary and Secondary Endpoints 
for Disclosures
Deleted overall survival 
(OS) from the list of 
endpoints to be assessed by 
the investigator according 
to Response Evaluation 
Criteria in Solid Tumors 
Version 1.1 (RECIST 
v1.1) criteria for solid 
tumors or Lugano 
classification for 
lymphomas. 
Correction: OS is not 
assessed by the 
investigator according to 
RECIST v1.1 criteria for 
solid tumors or Lugano 
classification for 
lymphomas.
4
Section 2.0 STUDY SUMMARY
Section 7.1 Inclusion Criteria
Section 8.5 Precautions and Restrictions
Section 10.4 Procedures for Reporting Drug 
Exposure During Pregnancy and Birth Events
Updated the duration of the 
contraception and 
pregnancy reporting period 
from 120 days to 6 months.
Alignment with the IB. 
5
Section 4.4.1.1 Lymphoid and Hematopoietic 
Effects
Updated the language 
around lymphoid and 
hematopoietic effects.
Alignment with other 
TAK-981 protocols.
6
Section 4.4.1.2 Effects in Renal Pelvis
Updated the language 
around effects in the renal 
pelvis.
Alignment with other 
TAK-981 protocols.
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Protocol Amendment 7 
Summary of Changes Since Last Version of the Approved Protocol
Change
Number
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
7
Section 4.4.1.4 Injection Site Reactions
Updated the language 
around injection site 
reactions.
Alignment with other 
TAK-981 protocols.
8
Section 4.4.1.5 Reproductive and 
Development Toxicity
Updated the language 
around reproductive and 
development toxicity.
Alignment with other 
TAK-981 protocols.
9
Section 4.4.2 COVID-19 Pandemic
Added information about 
the benefit-risk assessment 
regarding study 
participation.
Updated information.
10
Section 5.2.2 Secondary Endpoints
Added time to response 
(TTR) to a Phase 2 
secondary endpoint. 
Correction because TTR is 
listed elsewhere in the 
Phase 2 secondary 
endpoints.
11
Section 6.1.2 Phase 2 Expansion in Select 
Cancer Indications
Added information on 
recommended Phase 2 
dosing.
Update of the clinical 
information.
12
Section 2.0 STUDY SUMMARY
Section 7.2 Exclusion Criteria
Updated the exclusion 
criteria to clarify that 
patients should discontinue 
using cytochrome P450 
(CYP)3A4/5 and 
P-glycoprotein inhibitors 
at least 1 week before 
starting TAK-981 therapy.
Alignment with other 
TAK-981 protocols.
13
Section 8.2 Phase 1 Dose Escalation and 
Phase 2 Cancer Treatment Expansion Cohorts
Section 8.4 Permitted Concomitant 
Medications and Procedures
Added information 
regarding COVID-19 
vaccination.
Updated information.
14
Table 8.b General Dose Modification 
Recommendations for TAK-981 
Nonhematologic Drug-Related AEs
Clarification added for 
discontinuing treatment if 
Grade ≥3 prolongation of 
the QT interval with 
Fridericia correction 
method occurs.
Alignment with other 
TAK-981 protocols.
15
Section 8.5 Precautions and Restrictions
Updated the language 
around pregnancy and 
lactation.
Alignment with the IB.
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 7 Summary of Changes............................................................5
2.0
STUDY SUMMARY ....................................................................................................15
3.0
STUDY REFERENCE INFORMATION ......................................................................22
3.1
Study-Related Responsibilities.................................................................................22
3.2
Coordinating Investigator.........................................................................................22
3.3
List of Abbreviations ...............................................................................................23
3.4
Corporate Identification...........................................................................................25
4.0
INTRODUCTION.........................................................................................................26
4.1
Immunotherapy in Cancer........................................................................................26
4.1.1
Solid Tumors...................................................................................................26
4.1.1.1
Lung Cancer............................................................................................26
4.1.1.2
Cervical Cancer .......................................................................................27
4.1.1.3
Colorectal Cancer ....................................................................................27
4.1.2
Non-Hodgkin Lymphoma................................................................................27
4.1.2.1
Follicular Lymphoma ..............................................................................28
4.1.2.2
DLBCL ...................................................................................................28
4.2
Background .............................................................................................................29
4.2.1
Nonclinical Pharmacology...............................................................................30
4.2.2
Nonclinical PK ................................................................................................32
4.2.3
Nonclinical Toxicology ...................................................................................33
4.2.4
Preliminary Clinical Experience.......................................................................34
4.2.4.1
Study TAK-981-1002 ..............................................................................36
4.2.4.2
Study TAK-981-1501 ..............................................................................44
4.3
Rationale for the Proposed Study.............................................................................44
4.3.1
Rationale for the Starting Dose and Schedule...................................................45
4.3.2
Rationale for 
 Skin, and Blood Tissue Sample Collection .....................46
4.3.2.1
.......................................................................................46
4.3.2.2
Skin Biopsies...........................................................................................46
4.3.2.3
Blood.......................................................................................................46
4.4
Potential Risks and Benefits.....................................................................................46
4.4.1
Potential Effects Based on Nonclinical Studies ................................................47
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4.4.1.1
Lymphoid and Hematopoietic Effects......................................................47
4.4.1.2
Effects in Renal Pelvis.............................................................................48
4.4.1.3
IRRs and Potential for CRS .....................................................................48
4.4.1.4
Injection Site Reactions ...........................................................................49
4.4.1.5
Reproductive and Development Toxicity.................................................49
4.4.1.6
Genotoxicity............................................................................................50
4.4.2
COVID-19 Pandemic.......................................................................................50
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................51
5.1
Objectives................................................................................................................51
5.1.1
Primary Objectives ..........................................................................................51
5.1.2
Secondary Objectives ......................................................................................51
5.1.3
Exploratory Objectives ....................................................................................51
5.2
Endpoints.................................................................................................................52
5.2.1
Primary Endpoints ...........................................................................................52
5.2.2
Secondary Endpoints .......................................................................................52
5.2.3
Exploratory Endpoints .....................................................................................53
6.0
STUDY DESIGN..........................................................................................................53
6.1
Overview of Study Design.......................................................................................53
6.1.1
Phase 1 Dose Escalation ..................................................................................55
6.1.2
Phase 2 Expansion in Select Cancer Indications...............................................56
6.2
Number of Patients ..................................................................................................57
6.2.1
Phase 1 Dose Escalation and Phase 2 Cancer Treatment Expansion Cohorts....57
6.3
Patient Replacement ................................................................................................57
6.4
Duration of Study ....................................................................................................57
6.4.1
Duration of an Individual Patient’s Study Participation....................................57
6.4.1.1
Phase 1 Dose Escalation and Phase 2 Cancer Treatment Expansion 
Cohorts....................................................................................................57
6.4.2
End of Study/Study Completion Definition and Planned Reporting..................58
6.4.2.1
Phase 1 Dose Escalation and Phase 2 Cancer Treatment Expansion 
Cohorts Primary Completion/Study Completion ......................................58
6.4.3
Timeframes for Primary and Secondary Endpoints to Support Disclosures ......58
6.4.4
Total Study Duration .......................................................................................60
6.4.5
Poststudy Access .............................................................................................60
6.4.5.1
Phase 1 Dose Escalation and Phase 2 Cancer Treatment Expansion 
Cohorts....................................................................................................60
7.0
STUDY POPULATION................................................................................................60
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7.1
Inclusion Criteria .....................................................................................................60
7.2
Exclusion Criteria ....................................................................................................63
8.0
STUDY DRUG .............................................................................................................65
8.1
Study Drug Administration......................................................................................65
8.2
Phase 1 Dose Escalation and Phase 2 Cancer Treatment Expansion Cohorts ............66
8.2.1
Definitions of DLT for Dose Escalation...........................................................67
8.2.2
Dose Escalation Rules .....................................................................................68
8.2.3
Definition of BED ...........................................................................................70
8.2.4
Dose Modification Guidelines for Phase 1 Dose Escalation and Phase 2 
Cancer Treatment Expansion Cohorts..............................................................70
8.3
Excluded Concomitant Medications and Procedures ................................................74
8.3.1
Excluded Concomitant Medications and Procedures for Phase 1 Dose 
Escalation and Phase 2 Cancer Treatment Expansion Cohorts..........................74
8.4
Permitted Concomitant Medications and Procedures................................................74
8.5
Precautions and Restrictions ....................................................................................75
8.6
Management of Clinical Events ...............................................................................76
8.6.1
Nausea or Vomiting.........................................................................................77
8.6.2
Diarrhea...........................................................................................................77
8.6.3
Anemia, Thrombocytopenia, or Neutropenia....................................................77
8.6.4
Infusion Site Care............................................................................................77
8.6.5
Lymphopenia and Opportunistic Infection Prophylaxis....................................77
8.6.6
IRRs ................................................................................................................78
8.6.7
CRS.................................................................................................................78
8.7
Blinding and Unblinding..........................................................................................80
8.8
Description of Investigational Agents ......................................................................80
8.9
Preparation, Reconstitution, and Dispensation..........................................................80
8.10
Packaging and Labeling...........................................................................................80
8.11
Storage, Handling, and Accountability.....................................................................80
8.12
Other Protocol-Specified Materials ..........................................................................81
9.0
STUDY CONDUCT......................................................................................................81
9.1
Study Personnel and Organizations..........................................................................81
9.2
Arrangements for Recruitment of Patients................................................................81
9.3
Treatment Group Assignments.................................................................................81
9.4
Study Procedures.....................................................................................................81
9.4.1
Procedures for Phase 1 Dose Escalation and Phase 2 Cancer Treatment 
Expansion Cohorts...........................................................................................81
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9.4.1.1
Informed Consent ....................................................................................82
9.4.1.2
Patient Demographics..............................................................................82
9.4.1.3
Medical History.......................................................................................82
9.4.1.4
Physical Examination ..............................................................................82
9.4.1.5
Patient Height and Weight .......................................................................82
9.4.1.6
ECOG Performance Status.......................................................................82
9.4.1.7
Vital Signs...............................................................................................82
9.4.1.8
Pregnancy Test ........................................................................................82
9.4.1.9
Concomitant Medications and Procedures................................................83
9.4.1.10
AEs .........................................................................................................83
9.4.1.11
Enrollment...............................................................................................83
9.4.1.12
Posttreatment Follow-up..........................................................................83
9.4.1.13
Cardiac Monitoring..................................................................................84
9.4.1.14
Clinical Laboratory Evaluations...............................................................85
9.4.1.15
Disease Assessment.................................................................................86
9.4.1.16
Biomarker, Pharmacodynamic, and PK Samples......................................88
9.5
Completion of Study Treatment (for Individual Patients) .........................................91
9.6
Completion of Study (for Individual Patients)..........................................................91
9.7
Discontinuation of Treatment With Study Drug and Patient Replacement................92
9.8
Study Compliance....................................................................................................93
10.0
ADVERSE EVENTS ....................................................................................................93
10.1
Definitions...............................................................................................................93
10.1.1
Pretreatment Definition....................................................................................93
10.1.2
AE Definition ..................................................................................................93
10.1.3
SAE Definition................................................................................................93
10.1.4
Adverse Events of Special Interest Definition ..................................................94
10.2
Procedures for Recording and Reporting AEs and SAEs..........................................95
10.3
Monitoring of AEs and Period of Observation .........................................................96
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events.........96
10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose) ................................................................................................................96
10.6
Safety Reporting to Investigators, IRBs, and Regulatory Authorities........................97
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................97
11.1
SMC........................................................................................................................97
11.2
IDMC ......................................................................................................................97
11.3
Independent Review Committee ..............................................................................98
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12.0
DATA HANDLING AND RECORDKEEPING............................................................98
12.1
eCRFs......................................................................................................................98
12.2
Record Retention .....................................................................................................99
13.0
STATISTICAL METHODS..........................................................................................99
13.1
Statistical and Analytical Plans ................................................................................99
13.2
Phase 1 Dose Escalation and Phase 2 Cancer Treatment Expansion Cohorts ............99
13.2.1
Analysis Sets ...................................................................................................99
13.2.2
Analysis of Demographics and Other Baseline Characteristics.......................100
13.2.3
Efficacy Analysis...........................................................................................101
13.2.3.1
Primary Efficacy Analysis .....................................................................101
13.2.3.2
Secondary Efficacy Analysis .................................................................101
13.2.4
PK Analysis...................................................................................................102
13.2.5
Pharmacodynamic Analysis...........................................................................102
13.2.6
PK/Pharmacodynamic Analysis.....................................................................103
13.2.7
..............................................................................103
13.2.8
Safety Analysis..............................................................................................104
13.3
Interim Analysis ....................................................................................................104
13.4
Determination of Sample Size................................................................................105
13.4.1
Phase 1 Dose Escalation and Phase 2 Cancer Treatment Expansion Cohorts..105
14.0
QUALITY CONTROL AND QUALITY ASSURANCE.............................................107
14.1
Study-Site Monitoring Visits .................................................................................107
14.2
Protocol Deviations................................................................................................108
14.3
Quality Assurance Audits and Regulatory Agency Inspections ..............................108
15.0
ETHICAL ASPECTS OF THE STUDY......................................................................108
15.1
IRB Approval ........................................................................................................109
15.2
Subject Information, Informed Consent, and Subject Authorization .......................109
15.3
Subject Confidentiality ..........................................................................................111
15.4
Publication, Disclosure, and Clinical Trial Registration Policy...............................111
15.4.1
Publication.....................................................................................................111
15.4.2
Clinical Trial Registration..............................................................................111
15.4.3
Clinical Trial Results Disclosure....................................................................112
15.5
Insurance and Compensation for Injury..................................................................112
16.0
REFERENCES............................................................................................................113
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LIST OF IN-TEXT TABLES
Table 4.a
TAK-981 (All Clinical Studies): Most Frequent (≥10% of All Patients) TEAEs
..........................................................................................................................35
Table 4.b
Study TAK-981-1002: Patient Enrollment Per Dose Level.................................36
Table 4.c
Study TAK-981-1002: TEAEs Reported in ≥10% of Patients.............................37
Table 4.d
Study TAK-981-1002: Grade ≥3 TEAEs............................................................38
Table 4.e
Study TAK-981-1002: TESAEs.........................................................................41
Table 4.f 
Study TAK-981-1002: On-Study Deaths............................................................43
Table 6.a
Primary and Secondary Endpoints for Disclosures .............................................59
Table 8.a
Planned Dose Levels..........................................................................................70
Table 8.b
General Dose Modification Recommendations for TAK-981 Nonhematologic 
Drug-Related AEs..............................................................................................72
Table 8.c
Dose Adjustments for Hematologic Toxicities ...................................................73
Table 8.d
CRS Management Recommendations and TAK-981 Dose Modification ............79
Table 9.a
Chemistry, Hematology, and Coagulation Tests .................................................85
Table 9.b
Urinalysis Tests .................................................................................................86
Table 9.c
Serum Tumor Markers .......................................................................................86
Table 9.d
Immunosafety Determinations in Serum.............................................................86
Table 9.e
Primary Specimen Collection.............................................................................88
Table 13.a
Sample Size for Each Cohort and Each Stage (Solid Tumor Cohorts A, B, and C 
and Lymphoma Cohort D) ...............................................................................106
Table 13.b
Sample Size for Each Cohort and Each Stage (Lymphoma Cohorts E and F)....107
LIST OF IN-TEXT FIGURES
Figure 6.a
TAK-981-1002 Study Design.............................................................................54
Figure 6.b
TAK-981 Dosing Regimen.................................................................................55
LIST OF APPENDICES
Appendix A
SOE.................................................................................................................118
Appendix B
Responsibilities of the Investigator...................................................................131
Appendix C
Investigator Consent to Use of Personal Information........................................133
Appendix D
ECOG Scale for Performance Status ................................................................134
Appendix E
Drugs that Interact With the CYP3A Family of CYPs ......................................135
Appendix F
Examples of Clinical Inhibitors of P-gp............................................................137
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Appendix G
BLRM (for Phase 1 Dose Escalation and Phase 2 Cancer Expansion Cohorts) .138
Appendix H
Examples of QTc Interval Prolonging Agents (Phase 1 Only) ..........................142
Appendix I
Protocol History...............................................................................................143
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STUDY SUMMARY 
Name of Sponsor(s): Takeda Development Center Americas, Inc. 
(TDC Americas)
Compound: TAK-981
Title of Protocol: An Open Label, Dose-Escalation, Phase 1/2 Study 
to Evaluate the Safety, Tolerability, Preliminary Efficacy, and 
Pharmacokinetics of TAK-981 in Adult Patients With Advanced or 
Metastatic Solid Tumors or Relapsed/Refractory Hematologic 
Malignancies
EudraCT No.:
2020-003947-27
Study Number: TAK-981-1002
Phase: 1/2
Study Design:
This is a Phase 1/2, open-label, dose escalation and dose expansion study designed to evaluate safety, tolerability, 
preliminary efficacy, and pharmacokinetics (PK) of single-agent TAK-981 in adult patients with advanced or 
metastatic solid tumors or relapsed/refractory hematologic malignancies.
The study will be conducted in 2 main parts:
1.
Phase 1 dose escalation, guided by Bayesian logistic regression modeling (BLRM), in patients with solid tumors 
or lymphomas.
2.
Phase 2 cancer treatment dose expansion with 6 treatment arms: 3 with select solid tumor indications and 3 with 
CD20+ relapsed/refractory non-Hodgkin lymphoma (NHL) indications.
The study will consist of a screening period (Days -28 to -1), a treatment period, an end-of-treatment visit up to 
30 (+10) days after the last dose occurring when treatment is discontinued for any reason, and a posttreatment 
follow-up period lasting for a maximum of 12 months for each patient who discontinued TAK-981 for reasons other 
than progressive disease in dose escalation, to monitor survival status after their last dose of TAK-981. 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 for up to 1 year or until confirmed disease progression, unacceptable 
toxicity, or any criterion for withdrawal from the study or discontinuation of study drug 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.
In Phase 1 (dose escalation), patients will be treated in cohorts with increasing doses of TAK-981, administered as a 
1-hour intravenous (IV) infusion on Days 1, 4, 8, and 11 of a 21-day cycle until a discontinuation criterion is met. If 
clinical safety, PK, and pharmacodynamics are supportive, the protocol schedule can be modified to evaluate a less 
intensive administration of TAK-981 (eg, Day 1; Days 1 and 8; or Days 1, 8, and 15 in 21-day cycles). Dose escalation 
intervals progress from 3 mg to 160 mg (with a provision of a dose level -1 of 1 mg). Patient enrollment will be 
staggered between the first and second patients 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 the Day 4 visit 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 may not be required if there are no clinically significant safety findings suggestive of infusion 
reaction or cytokine release syndrome (CRS).
Dose escalation of TAK-981 will be cohort-based with an adaptive design using BLRM. Approximately 50 patients 
will be enrolled until the recommended Phase 2 dose (RP2D) of TAK-981 is identified. Single-agent RP2D could be 
based either on the maximum tolerated dose (MTD) based on the observation of dose-limiting toxicities (DLTs) or a 
biologically effective dose (BED) that is ≤MTD.
Once the RP2D is defined, Phase 2 of the study will explore the efficacy and safety of TAK-981 in patients with select 
cancers. The following cohorts will be enrolled:

Cohort A: Nonsquamous non–small cell lung cancer (NSCLC).

Cohort B: Cervical cancer.
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
Cohort C: Microsatellite-stable colorectal cancer (MSS-CRC).

Cohort D: Relapsed/refractory diffuse large B-cell lymphoma (DLBCL) progressed or relapsed after chimeric 
antigen receptor (CAR) T-cell therapy.

Cohort E: Relapsed/refractory DLBCL that have not received prior cellular therapy.

Cohort F: Relapsed/refractory follicular lymphoma (FL).
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 posttreatment scan (ie, after the first disease assessment, 2 months from Cycle 1 Day 1 [C1D1]). 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 clinical benefit has been observed for patients in the cohort (eg, the majority of patients have 
recorded stable disease at Week 8 and per investigator assessment are benefiting from treatment), then enrollment into 
stage 2 may be allowed for this cohort with agreement from participating investigators. 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 had the opportunity complete the 6 months disease assessment.
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.
Primary Objectives:
Phase 1:

To determine the safety and tolerability of TAK-981 as a single agent in patients with advanced or metastatic solid 
tumors and lymphomas.

To establish the RP2D of TAK-981.
Phase 2:

To evaluate preliminary efficacy of TAK-981 in patients with select solid tumors or relapsed/refractory CD20+ 
NHL indications.
Secondary Objectives:
Phase 1:

To assess the preliminary antitumor activity of TAK-981.

To assess target engagement of TAK-981 (small ubiquitin-like modifier [SUMO]–TAK-981 adduct formation) 
and SUMOylation pathway inhibition in skin and peripheral blood cells.

To characterize the PK profile of TAK-981.
Phase 2:

To evaluate the efficacy of TAK-981 in select solid tumor and CD20+ NHL indications as measured by time to 
response (TTR), duration of the response (DOR), disease control rate (DCR), time to progression (TTP), and 
progression-free survival (PFS).

To evaluate overall survival (OS).

To evaluate the safety and tolerability of TAK-981. 

To collect plasma concentration-time data for TAK-981.
Subject Population: 
Phase 1 and Phase 2: Adult patients ≥18 years old with locally advanced or metastatic solid tumor or 
relapsed/refractory lymphoma with no standard therapeutic alternative with established clinical benefit.
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Number of Subjects:
Phase 1 dose escalation: ~70 patients
Phase 2 cancer treatment expansion: ~132 patients 
Number of Sites: 
Approximately 60 sites (United States, 
Canada, and globally)
Anticipated Dose Levels:
3, 6, 10, 15, 25, 40, 60, 90, 120, and 160 mg of TAK-981. A starting 
dose level of 1 mg will be used if 3 mg is not tolerated.
Route of Administration: 
IV in 1-hour infusion
Duration of Treatment:
Up to 1 year. Patients with clinical benefit can continue treatment if 
approved by the sponsor.
Period of Evaluation:
Approximately 48 months.
Inclusion Criteria:
1.
Adult male or female patients ≥18 years old. 
2.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
3.
Patient population for Phase 1 dose escalation:
a.
Have a histologically or cytologically confirmed advanced (local regionally recurrent not amenable to 
curative therapy) or metastatic solid tumors who have no standard therapeutic option with a proven clinical 
benefit, are intolerant, or have refused them. 
OR
b.
Have a relapsed/refractory lymphoma not amenable to therapies with proven clinical benefit or who are 
intolerant or who refuse them. Patients with low-grade lymphomas such as FL, small lymphocytic 
lymphoma, lymphoplasmacytoid lymphoma, and marginal zone lymphomas may not need to exhaust all 
available therapy. These patients can be enrolled after failure of at least 2 prior systemic therapies, provided 
that there is not an immediate need for cytoreduction. In these cases, patients who need immediate therapy for 
tumor bulk are not eligible for this trial.
4.
Patient population for Phase 2 dose expansion cohorts:
Have a histologically or cytologically documented, advanced (metastatic and/or unresectable) cancer as listed 
below, which is incurable and for which prior standard first-line treatment has failed:
Note: Prior neoadjuvant or adjuvant therapy included in initial treatment may not be considered first- or 
later-line, standard-of-care treatment unless such treatments were completed less than 12 months before the 
current tumor recurrence.
a.
Nonsquamous NSCLC that has progressed to 1 prior systemic immune checkpoint inhibitor 
(CPI)/anti-PD-(1/L1)-containing therapy and no more than 2 lines of therapy. Patients must have not shown 
evidence of tumor progression during the first 5 months of treatment with first-line 
CPI/anti-PD-(1/L1)-containing therapy (cohort A). 
Note: Patients with known driver mutations/genomic aberrations (eg, epidermal growth factor receptor, 
B-Raf proto-oncogene mutation V600E [BRAF V600E], and ROS proto-oncogene 1 [ROS1] sensitizing 
mutations, neurotrophic receptor tyrosine kinase [NRTK] gene fusions, and anaplastic lymphoma kinase 
[ALK] rearrangements) must have also shown progressive disease after treatment with a commercially 
available targeted therapy. 
b.
CPI-naïve cervical cancer (squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the 
cervix) patients who have received no more than 1 prior systemic line of therapy for recurrent or Stage IVB 
cervical cancer (cohort B).
Note: The following cervical tumors are not eligible: minimal deviation/adenoma malignum, gastric-type 
adenocarcinoma, clear-cell carcinoma, and mesonephric carcinoma. Histologic confirmation of the original 
primary tumor is required via pathology report.
Note: First-line treatment must have consisted of platinum-containing doublet. Chemotherapy administered 
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concurrently with primary radiation (eg, weekly cisplatin) is not counted as a systemic chemotherapy 
regimen.
c.
CPI-naïve MSS-CRC patients who have progressed on no more than 3 chemotherapy regimens (cohort C).
Note: Patients must have received prior treatment with fluoropyrimidine-, oxaliplatin-, and 
irinotecan-containing regimens if indicated.
d.
Relapsed/refractory DLBCL progressed or relapsed after a prior CAR T-cell therapy that has received 
approval by a health authority for the treatment of DLBCL (cohort D).
e.
Relapsed/refractory 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 E).
f.
Relapsed/refractory 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 F).
5.
In Phase 2 only, have at least 1 radiologically measurable lesion based on Response Evaluation Criteria in Solid 
Tumors Version 1.1 (RECIST v1.1) for patients with solid tumors or Lugano criteria for lymphoma. Tumor 
lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in 
such lesions.
Note: In Phase 2 stage 1, have an additional lesion for pretreatment and on-treatment biopsy.
6.
In Phase 2 stage 1, willing to consent to mandatory pretreatment and on-treatment tumor biopsy.
Note: For fresh tumor biopsies, the lesion must be accessible for a biopsy procedure as assessed by the 
investigator.
7.
Is willing to provide archival tumor tissue sample, if available.
8.
Adequate bone marrow reserve and renal and hepatic function based on the following laboratory parameters: 
a.
Absolute neutrophil count ≥1.0 × 109/L, hemoglobin ≥85 g/L (red blood cell transfusion allowed ≥14 days 
before assessment), and platelet count ≥75.0 × 109/L(platelet count ≥50.0 × 109/L is allowed for patients 
with lymphoma if it is clearly due to marrow involvement with no evidence of myelodysplastic syndrome or 
hypoplastic bone marrow, if found). 
b.
Total bilirubin ≤1.5 times the institutional upper limit of normal (ULN); or total bilirubin <3.0 times 
the ULN with direct bilirubin within normal range in patients with well documented Gilbert’s syndrome.
c.
Serum alanine aminotransferase or aspartate aminotransferase ≤3.0 times the ULN (<5 times the ULN if liver 
enzyme elevations are due to liver metastases).
d.
Estimated creatinine clearance using the Cockcroft-Gault formula ≥45 mL/min.
9.
Recovered to Grade 1 or baseline or established as sequelae from all toxic effects of previous therapy (except 
alopecia, neuropathy, or autoimmune endocrinopathies with stable endocrine replacement therapy, or bone 
marrow parameters [any of Grade 1/2 permitted if directly related to bone marrow involvement]).
10. Consented to undergo serial skin punch biopsies (dose escalation only). 
11. Voluntary written consent must be given before performance of any study-related procedure not part of standard 
medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice 
to future medical care.
12. Suitable venous access for safe drug administration and the study-required PK and pharmacodynamic sampling.
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:
a.
Postmenopausal for at least 1 year before the screening visit, or
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b.
Surgically sterile, or
c.
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 6 months after the last dose of study drug, or
d.
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 post vasectomy) must agree to 1 of the following:
a.
Agree to practice effective barrier contraception during the entire study treatment period and through 
6 months after the last dose of study drug, or
b.
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.)
Exclusion Criteria:
1.
Phase 1 dose escalation and Phase 2 cancer treatment expansion cohorts:
a.
Have received treatment with systemic anticancer treatments or investigational products within 14 days 
before the first dose of study drug or 5 half-lives, whichever is shorter.
Note: Low-dose steroids (oral prednisone or equivalent ≤20 mg per day), hormonal therapy for prostate 
cancer or breast cancer (as adjuvant treatment), and treatment with bisphosphonates and receptor activator of 
nuclear factor kappa-Β ligand (RANKL) inhibitors are allowed.
b.
Have received extended field radiotherapy ≤4 weeks before the start of treatment (≤2 weeks for limited field 
radiation for palliation) and have not recovered to Grade 1 or baseline from related side effects of such 
therapy (except for alopecia).
2.
Have a history of uncontrolled brain metastasis. Patients with brain metastases are allowed if they are previously 
treated with surgery, whole-brain radiation, or stereotactic radiosurgery and the patients are receiving a 
corticosteroid dose ≤10 mg/day of prednisone equivalent at the time of receiving the first dose of TAK-981. For 
asymptomatic patients, screening brain imaging is not required.
3.
Patient is receiving any live vaccine (eg, varicella, pneumococcus) within 4 weeks of initiation of study treatment.
4.
History of any of the following ≤6 months before first dose: congestive heart failure New York Heart Association 
Grade III or IV, unstable angina, myocardial infarction, unstable symptomatic ischemic heart disease, severe 
noncompensated hypertension despite appropriate medical therapy, 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. 
5.
Baseline prolongation of the QT interval with Fridericia correction method (QTcF) (eg, repeated demonstration of 
QTcF interval >480 ms, history of congenital long QT syndrome, or torsades de pointes).
6.
Psychiatric illness/social circumstances that would limit compliance with study requirements and substantially 
increase the risk of adverse events (AEs) or has compromised ability to provide written informed consent.
7.
Admission or evidence of illicit drug use, drug abuse, or alcohol abuse.
8.
History of autoimmune disease requiring systemic immunosuppressive therapy with daily doses of prednisone 
>10 mg/day or equivalent doses, or any other form of immunosuppressive therapy. Hormone therapy (eg, 
thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not 
considered an excluded form of systemic treatment of an autoimmune disease
9.
History of immune-related AEs related to treatment with immune checkpoint inhibitors that required treatment 
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discontinuation.
10. History of noninfectious pneumonitis that required steroids or a history of interstitial lung disease.
11. Has evidence of active, noninfectious pneumonitis.
12. Have a significant active infection.
13. Known history of human immunodeficiency virus infection or any other relevant congenital or acquired 
immunodeficiency.
14. Known hepatitis B virus surface antigen seropositive or detectable hepatitis C infection viral load.
Note: Patients who have positive hepatitis B core antibody or hepatitis B surface antigen antibody can be enrolled 
but must have an undetectable hepatitis B viral load.
15. Receiving or requiring the continued use of medications that are known to be strong or moderate inhibitors and 
inducers of cytochrome P450 (CYP)3A4/5 (Appendix E) or are strong P-glycoprotein (P-gp) inhibitors 
(Appendix F). To participate in this study, such patients should discontinue use of such agents for at least 2 weeks 
(1 week for CYP3A4/5 and P-gp inhibitors) before receiving a dose of TAK-981.
16. Patient requires the use of drugs known to prolong corrected QT interval (during History of allogeneic tissue or 
solid organ transplant.
18. 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. 
19. Female patients who are lactating and breastfeeding or have a positive serum pregnancy test during the screening 
period or a positive urine pregnancy test on Day 1 before first dose of study drug.
Main Criteria for Evaluation and Analyses:
Primary Endpoints 
Phase 1:

Frequency, severity, and duration of treatment-emergent adverse events (TEAEs) and laboratory abnormalities 
for all dose groups according to the National Cancer Institute Common Terminology Criteria for Adverse Events 
(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 [1].

DLTs within the first 21 days of treatment in Cycle 1.
Phase 2:

Overall response rate (ORR) (complete response [CR] + partial response [PR]) as defined by the investigator 
according to RECIST v1.1 criteria for solid tumors or Lugano classification for lymphomas.
Secondary Endpoints 

PK parameters after the first dose of TAK-981 on C1D1 and Cycle 1, Day 8 (data permitting):
–
Maximum observed plasma concentration (Cmax).
–
Time of first occurrence of maximum observed plasma concentration.
–
Area under the plasma concentration-time curve from time 0 to the last measurable concentration.
–
Area under the plasma concentration-time curve from time 0 to infinity.
–
Terminal disposition phase half-life.
–
Total clearance (CL) after IV administration.
–
Volume of distribution at steady state after intravenous administration.
Phase 1:

ORR, DCR, DOR, TTP, and PFS as assessed by the investigator according to RECIST v1.1 criteria for solid 
tumors or 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.
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
DCR, DOR, TTR, TTP, and PFS as assessed by the investigator according to RECIST v1.1 criteria for solid 
tumors or Lugano classification for lymphomas and OS.
Statistical Considerations:
In Phase 1, dose escalation of TAK-981 will be cohort-based with an adaptive BLRM guided by the 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 of ORR (CR + PR) will be assessed by the investigator according to RECIST v1.1 
criteria for solid tumors or Lugano classification for lymphomas. 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 
different hypotheses of ORR for disease-specific cohorts.
Sample Size Justification: 
Phase 1 Dose Escalation and Phase 2 Cancer Treatment Expansion Cohorts:
It is estimated that up to approximately 70 DLT-evaluable patients will be enrolled in this study for the dose escalation 
phase (Phase 1).
Once the MTD/BED is defined, up to approximately 132 response-evaluable patients with 6 specified types of solid 
tumors and lymphomas will be enrolled in parallel in the Phase 2 portion of the study to evaluate the efficacy of 
TAK-981.
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3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities 
The sponsor will perform all study-related activities with the exception of those identified in the
clinical supplier list in the study manual. The identified vendors will perform specific 
study-related activities either in full or in partnership with the sponsor.
3.2
Coordinating Investigator
Takeda will select a signatory coordinating investigator from the investigators who participate in 
the study. Selection criteria for this investigator will include significant knowledge of the study 
protocol, the study medication, 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
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASCT
autologous stem-cell transplantation
AST
aspartate aminotransferase
ASTCT
American Society for Transplantation and Cellular Therapy
AUC24
area under the plasma concentration-time curve from time 0 to 24 hours
AUC∞
area under the plasma concentration-time curve from time 0 to infinity
AUClast
area under the plasma concentration-time curve from time 0 to the last measurable 
concentration
BED
biologically effective dose
BIW
twice weekly
BLRM
Bayesian logistic regression modeling
BCRP
breast cancer resistance protein
C1D1
Cycle 1, Day 1
C1D8
Cycle 1, Day 8
C2D8
Cycle 2, Day 8
CAR
chimeric antigen receptor
CFR
[United States] Code of Federal Regulations
CL
total clearance
CLp
plasma clearance
Cmax
maximum observed plasma concentration
CNS
central nervous system
CPI
checkpoint inhibitor
CR
complete response
CRA
cytokine release assay
CRC
colorectal cancer
CRS
cytokine release syndrome
CT
computed tomography
CTLA-4
cytotoxic T-lymphocyte–associated protein 4
CV
cardiovascular
CYP
cytochrome P450
DC
dendritic cell
DCR
disease control rate
DDI
drug-drug interaction
DLBCL
diffuse large B-cell lymphoma
DLT
dose-limiting toxicity
DOR
duration of response
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EC20
concentration producing 20% activation
ECG
electrocardiogram, electrocardiographic, electrocardiography
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EGFR
epidermal growth factor receptor
EOT
end of treatment
FDA
[United States] Food and Drug Administration
FDG-PET
18fluorodeoxyglucose–positron emission tomography
FIH
first-in-human
FL
follicular lymphoma
G-CSF
granulocyte colony-stimulating factor
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
HNSTD
highest nonseverely toxic dose
HR
hazard ratio
IB
Investigator’s Brochure
IC50
50% inhibitory concentration
ICF
informed consent form
ICH
International Council for Harmonisation
ICU
intensive care unit
IDMC
Independent Data Monitoring Committee
IEC
independent ethics committee
IFN
interferon
IRB
institutional review board
IRC
independent review committee
IRR
infusion-related reaction
IV
intravenous(ly)
LVEF
left ventricular ejection fraction
MABEL
minimum anticipated biological effect level
MCP-1
monocyte chemotactic protein-1
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
MSS-CRC
microsatellite-stable colorectal cancer
MTD
maximum tolerated dose
MUGA
multiple-gated acquisition
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NHL
non-Hodgkin lymphoma
NK
natural killer
NSCLC
non–small cell lung cancer
ORR
overall response rate
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OS
overall survival
PBMC
peripheral blood mononuclear cell
PD-L1
programmed death ligand 1
PFS
progression-free survival
P-gp
P-glycoprotein
PK
pharmacokinetic(s)
PR
partial response
PRR
pattern recognition receptor
QSP
quantitative systems pharmacology
QTc
heart rate–corrected QT interval
QTcF
QT interval with Fridericia correction method
QW
once weekly
RANKL
receptor activator of nuclear factor kappa-Β ligand
RBC
red blood cell
RECIST v1.1
Response Evaluation Criteria in Solid Tumors Version 1.1
RP2D
recommended Phase 2 dose
SAE
serious adverse event
SD
stable disease
SMC
Safety Monitoring Committee
SOC
standard of care
SOE
schedule of events
STD10
severely toxic dose in 10% of animals tested
STING
stimulator of interferon genes
SUMO
small ubiquitin-like modifier
t1/2z
terminal disposition phase half-life
tmax
time of first occurrence of maximum observed plasma concentration
TEAE
treatment-emergent adverse event
TTR
time to response
ULN
upper limit of normal
US
United States
Vss
volume of distribution at steady state after intravenous administration
WHO
World Health Organization
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
Immunotherapy in Cancer
Immuno-oncology has emerged as the major driver of anticancer therapeutics in both solid tumors 
and hematologic malignancies. Clinical data from immune checkpoint inhibitors (CPIs), such as 
cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), and programmed cell death protein 1 
(PD-1)/programmed death ligand 1 (PD-L1) inhibitors have changed the therapeutic paradigm in a 
growing number of indications. Overcoming T cell inhibition in the tumor microenvironment with 
CPIs has proven to be a successful strategy to produce long-term benefit in a significant number of 
patients with metastatic solid tumors.
However, despite these advances, many advanced cancer patients are either refractory to CPIs or 
relapse after a period of tumor control, eventually succumbing to their disease. Some predictive 
biomarkers of CPI response (PD-L1 expression, microsatellite instability, or tumor mutational 
burden) have been clinically validated, but it remains incompletely understood why most human 
tumors do not respond to CPIs. Evolving data suggest that reduced interferon (IFN) signaling, 
immune escape through human leukocyte antigen loss, as well as altered antigen presentation may 
contribute to CPI resistance [2-4]. Furthermore, an emerging consensus acknowledges that CPI 
resistance (relapse or refractory in nature) may also be driven by tumor immunophenotype, 
specifically those tumors harboring an immunosuppressive or “immune desert” phenotype.
Accordingly, one possible strategy to overcome these elements of resistance is to stimulate innate 
immune cells (myeloid cells including antigen-presenting dendritic cells [DCs] and 
monocytes/macrophages), as well as lymphoid cells and natural killer [NK] cells, to condition the 
tumor microenvironment, thus turning a “cold” tumor into a “hot” tumor in which adaptive 
immune responses can be effectively activated.
Type I IFNs, such as IFNα and IFNβ, are potent immunomodulatory cytokines induced early in the 
innate immune response that act upon multiple cell types to mold both innate and adaptive 
immunity. They directly enhance NK cell cytotoxicity and stimulate IL-15 production by DCs to 
promote NK cell activation [5-8]. They also directly act upon T cells to stimulate survival, clonal 
expansion, and the development of T cell effector function [7,8]. Importantly, type I IFNs play a 
central role in propagating adaptive immune responses by promoting maturation of DCs and 
cross-presentation of antigens to T cells [9,10]. Indeed, innate immune responses have been 
implicated in tumor surveillance, via sensing of tumor DNA through the stimulator of interferon
genes (STING)–controlled pathway [11], activation of which induces production of type I IFNs 
and propagation of an adaptive antitumor response as described above.
4.1.1
Solid Tumors
4.1.1.1
Lung Cancer
Lung cancer is the leading cause of cancer-related mortality worldwide, with 142,670 deaths 
estimated in 2019 in the United States (US) [12]. More than 80% of lung cancers are classified as 
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non–small cell lung cancer (NSCLC). Although targeted therapies have redefined treatment 
options for patients with molecularly defined locally advanced or metastatic NSCLC (eg, 
epidermal growth factor receptor [EGFR]-mutant, anaplastic lymphoma kinase [ALK]-rearranged 
NSCLC), these therapies are ineffective in those whose tumors lack such genetic alterations, who 
comprise the majority of NSCLC patients. By contrast, immunotherapy has become integrated 
into the first-line treatment of such patients, which has led to improvements in survival. However, 
despite the overall survival (OS) benefit of CPI in NSCLC, treatment in the advanced disease 
setting is palliative.
4.1.1.2
Cervical Cancer
Cervical cancer is the fourth leading cause of cancer-related mortality in women worldwide, with 
13,170 new cases and 4250 deaths in 2019 in the US [12]. In contrast to patients with early-stage 
cervical cancer, the prognosis of patients with recurrent or metastatic disease is poor. Over the past 
30 years, cisplatin-based combination chemotherapy has been shown to produce the best 
progression-free survival (PFS) and median OS: 5 months and 10 to13 months, respectively 
[13-15]. The addition of bevacizumab to standard first-line chemotherapy significantly improved 
median PFS (8.2 months vs 5.9 months; hazard ratio [HR], 0.67; 95% CI, 0.54-0.82) and modified 
OS (17.0 months vs 13.3 months; HR, 0.71; 95% CI, 0.54-0.95) compared with chemotherapy 
alone. Treatment after platinum failure is a big challenge, and currently available single agents, 
such as topotecan, vinorelbine, gemcitabine, docetaxel, nab-paclitaxel, and pembrolizumab, have 
shown unsatisfactory activity.
4.1.1.3
Colorectal Cancer
Colorectal cancer (CRC) is the second leading cause of cancer death worldwide, with 51,020 
deaths estimated during 2019 in the US [12]. Advanced Stage IV metastatic disease is the initial 
presentation in approximately 25% of patients with CRC, and a further 25% to 50% present with 
an early-stage disease but go on to develop metastatic disease. Despite the development of several 
chemotherapy regimens and the addition of EGFR/vascular endothelial growth factor A–directed 
monoclonal antibodies, the prognosis for patients with metastatic CRC remains poor, with a 
median 5-year survival of only 12.5% in the US [16].
4.1.2
Non-Hodgkin Lymphoma
Non-Hodgkin lymphoma (NHL) is among the most common cancers in the US and Europe with 
more than 70,000 and 93,000 new cases diagnosed every year, respectively [17,18]. 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 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 [19]. 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 [20]. 
However, once NHL becomes refractory to standard chemotherapy and antibody-based therapies, 
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the overall prognosis is poor with limited long-term survival. Thus, novel and effective therapies 
are needed to address this high unmet medical need.
4.1.2.1
Follicular Lymphoma
Indolent NHL represents 40% of all NHL subtypes, with follicular lymphoma (FL) occurring with 
the greatest frequency [21]. FL presents with a broad spectrum of disease characteristics. Patients 
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 [22]. The most common frontline therapies include a combination of 
alkylators (including cyclophosphamide, doxorubicin, vincristine, and prednisone [or 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 [23]. 
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 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 [22,24,25]. 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 [26-28].
4.1.2.2
DLBCL
Aggressive NHL accounts for approximately 30% to 40% of all NHL cases [29], and DLBCL is 
the most common histological subtype [30]. Combination chemotherapy with the addition of 
rituximab is standard of care (SOC) for patients with newly diagnosed DLBCL. However, 
approximately 40% of patients with DLBCL relapse following initial immunochemotherapy [31]. 
For eligible patients, salvage chemotherapy regimens, such as R-ICE (rituximab, ifosfamide, 
carboplatin, etoposide) and R-DHAP (rituximab, dexamethasone, cytarabine, cisplatin) followed 
by autologous stem cell transplantation (ASCT), are the treatments of choice for patients with 
relapsed/refractory disease. Unfortunately, 40% to 50% of patients will not be eligible for ASCT 
due to chemorefractory disease, and the other 50% who undergo the procedure are at risk of 
disease relapse and significantly high nonrelapse mortality [32]. For patients with disease relapse 
following transplant or for patients not eligible for transplant, treatment with CD19-directed 
chimeric antigen receptor (CAR) T-cell therapy has shown overall response rates (ORRs) of 52% 
to 82% with a median duration of response (DOR) of >9 months [33,34].
Currently, there is no SOC for patients that are not eligible or progressed after CAR T-cell therapy. 
Multiple chemotherapy regimens and investigational agents in clinical trials are being used for 
such patients. However, clinically meaningful benefit is rarely achieved in patients with 
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progressive disease following multiple regimens. DLBCL therefore remains a significant unmet 
medical need.
4.2
Background
TAK-981 is an intravenous (IV) first-in-class small molecule inhibitor of SUMOylation, a 
posttranslational modification that attaches a small ubiquitin-like modifier (SUMO) protein to 
protein substrates, regulating their activity, subcellular localization and stability [35]. There are 
3 functional mammalian paralogues of the SUMO proteins: SUMO1, SUMO2, and SUMO3 
[35,36], which are attached to their substrate proteins as monomers (SUMO1) or poly SUMO 
chains (SUMO2/3). The SUMOylation process is mediated by an enzymatic cascade similar to 
that described for ubiquitination [35,37]. The SUMO-activating enzyme, consisting of a 
SUMO-activating enzyme subunit 1/SUMO-activating enzyme subunit 2 heterodimer, binds 
SUMO, generating a SUMO thioester that is transferred to the sole SUMO-conjugating enzyme 
(UBC9) in the pathway, following which SUMO is covalently attached to a lysine residue on 
target proteins through a process facilitated by an E3 ligase. TAK-981 interrupts this cascade by 
forming an irreversible covalent adduct with SUMO when bound to SUMO-activating enzyme, 
preventing its transfer to UBC9.
SUMOylation has been reported to regulate cellular processes important for tumor cell 
proliferation and survival [37,38]. 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 I IFN 
expression has been demonstrated [39], such that inhibiting SUMOylation by genetic means 
resulted in enhanced basal expression levels and sensitization of induction of type I IFNs, 
promoting enhanced innate immune responses to pathogenic stimuli. The sponsor’s studies have 
similarly demonstrated upregulation of Type I IFNs following pharmacological inhibition of 
SUMOylation with TAK-981 and generation of innate and adaptive antitumor immune responses. 
Indeed, a key role for Type I IFNs in stimulating anti-tumor immune responses has been 
documented in work demonstrating that sensing of tumor DNA through the pattern recognition 
receptor (PRR) pathway, resulting in activation of production of Type I IFNs, plays an important 
role in tumor surveillance [11].
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 [40]. 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 PRR pathway 
through administration of agonists (such as the STING 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 [41]. Inhibition of SUMOylation represents a 
novel therapeutic strategy for initiating type 1 IFN responses and enhancing antitumor immune 
responses.
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Brief summaries of nonclinical pharmacology, pharmacokinetics (PK), and toxicity studies are 
provided below. More detailed information is provided in the IB.
4.2.1
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 (or UAE), Nedd8-activating 
enzyme (or NAE), and autophagy related 7 (or ATG7) 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. In ex vivo assays evaluating the activity of TAK-981 on the 
function of human monocyte derived macrophages (MDMs) and human NK cells (both derived 
from peripheral blood mononuclear cells [PBMCs]), 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 the 
activation marker CD69 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 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 induced robust, durable, and 
dose-responsive inhibition of SUMO2/3 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 potential for TAK-981 to promote type-I-IFN–dependent 
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 and/or antibody-dependent cell-mediated phagocytosis provides the 
mechanistic rationale for this synergistic combination activity.
Ex vivo characterization of mouse bone marrow-derived DCs and human DCs isolated from 
PBMCs demonstrated that TAK-981 promoted DC maturation as assessed by upregulation of the 
T cell costimulatory markers CD40, CD80, and CD86. Consistent with these findings, TAK-981 
also induced release of type I IFNs and proinflammatory 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 upon twice-weekly 
(BIW) treatment with TAK-981, but once-weekly (QW) treatment at the same total weekly dose 
was also typically comparably effective. Rechallenge 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 
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potential with P-gp and BCRP substrates with TAK-981 as a perpetrator is low; however, there 
is a DDI potential with P-gp 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 CLp 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.
4.2.3
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 with 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 CV 
assessment study and after repeat once daily or QW dosing. Increased body temperature in the CV 
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 once or BIW schedule was 
demonstrated to be efficacious in mouse models, both once 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. However, 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, patients will be dosed BIW in the Phase 1 clinical trial.
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 with 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), interferon-inducible protein-10 (IP-10) (rats only), and RANTES 
(rats only) at ≥5 mg/kg (with no increases in cytokines typically associated with cytokine release 
syndrome [CRS]); injection site reactions in rats at ≥0.5 mg/kg; single cell necrosis in the stomach 
in dogs at ≥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 nontolerated 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 
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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.
TAK-981 was not mutagenic in an in vitro bacterial mutagenesis Ames assay. However, in an 
in vivo rat bone marrow micronucleus assay, TAK-981 administered on 2 consecutive days 
increased induction of micronuclei and was therefore considered to be positive for in vivo 
genotoxicity at ≥5 mg/kg. It was not determined whether TAK-981 induces clastogenic or 
aneugenic genotoxicity. In compliance with ICH S9 guidance [42], a carcinogenicity assessment is 
not planned.
Reproductive and developmental toxicity studies have not been conducted. Reproductive tissues 
(ovaries, uterus, cervix, vagina, testes, epididymis, and prostate gland) 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. TAK-981–related reproductive effects were not 
observed in these studies. However, in a non–GLP-compliant 7-day repeat dose toxicity study in 
rats with daily dosing, TAK-981–related reproductive effects included minimal to mild single cell 
necrosis of epithelium in the prostate gland and epididymis, mild atrophy of prostate epithelium, 
mild karyomegaly of epididymis epithelium, minimal to mild increases in mitotic figures in the 
epididymis, moderate to marked increases in debris in the epididymis, and minimal to mild 
degeneration and necrosis of seminiferous tubules in the testis. Reproductive effects correlated 
with decreased prostate gland, epididymis, and testis weights. There were no effects on female 
reproductive tissues in this study. 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), TNFα, IFNg, or granulocyte colony-stimulating factor 
(G-CSF) levels. TAK-981–related increases in IP-10 levels were noted at ≥0.5 µM (8- to 50-fold 
compared with 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 as negative.
4.2.4
Preliminary Clinical Experience 
TAK-981 is currently being evaluated in this ongoing first-in-human (FIH) Phase 1 study in 
patients with advanced or refractory solid tumors or lymphomas (Study TAK-981-1002), in 1 
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), and in 1 
ongoing Phase 1b/2 clinical efficacy and safety study of the combination with pembrolizumab in 
patients with advanced or metastatic solid tumors.
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. The most common TEAEs (>20%) in the total population in Studies 
TAK-981-1002, TAK-981-1501, and TAK-981-1502 included fatigue, pyrexia, nausea, diarrhea, 
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chills, and headache (Table 4.a). Overall, preliminary efficacy is being observed, and efficacy 
evaluations are ongoing. (Refer to the 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, Table 5.g. Data cutoff date: 28 June 2021.
AE: adverse event; NCI CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events; 
TEAE: treatment-emergent adverse event.
AEs graded according to NCI CTCAE Version 5.0.
The TAK-981 studies revealed some pharmacologically active doses at ≥60 mg. In Study 
TAK-981-1002, pharmacodynamic activity, including SUMO pathway inhibition 
 
, was most consistently detected at doses ≥60 mg. The maximum tolerated dose 
(MTD) was determined to be 120 mg; the RP2D for single-agent TAK-981 was 90 mg, when 
administered BIW (Days 1, 4, 8, and 11) in a 21-day cycle. Of the 81 patients, 4 had DLTs, which
were reported in the single-agent study: transient Grade 3 serum alanine aminotransferase (ALT)
and aspartate aminotransferase (AST) elevations at 60 mg BIW; Grade 3 recurrent pneumonitis 
after a previous pneumonitis with an anti–PD-1 inhibitor at 90 mg BIW; and, 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 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 fluids for low blood pressure). No 
patient with CRS required vasoactive drug support or anti–IL-6 –directed therapies.
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Results of the preliminary analysis of available data for the heart rate–corrected QT interval (QTc) 
are consistent with a low risk of QTc prolongation after IV administration of TAK-981 alone  
 or in combination with rituximab at doses of 10 to 90 
mg (Study TAK-981-1501).
Overall, TAK-981 was well tolerated. The majority of the observed adverse events (AEs) were 
consistent with the patients’ underlying cancer disease and/or IFN signaling. Refer to the 
TAK-981 IB for additional details.
4.2.4.1
Study TAK-981-1002
The TAK-981-1002 study is evaluating the safety, tolerability, and efficacy of TAK-981 at the 
following dose levels: 3, 6, 10, 15, 25, 40, 60, 90, 120, and 160 mg on Days 1, 4, 8, and 11 every 3 
weeks. As of 28 June 2021, a total of 81 patients have been treated with TAK-981. Number of 
patients enrolled at each dose level and dosage regimen are shown in Table 4.b.
Table 4.b
Study TAK-981-1002: Patient Enrollment Per Dose Level
Dose Level of TAK-981
Dosing Schedule
Number of Patients
3 mg
Days 1, 4, 8, and 11
5
6 mg
Days 1, 4, 8, and 11
3
10 mg
Days 1, 4, 8, and 11
4
15 mg
Days 1, 4, 8, and 11
3
25 mg
Days 1, 4, 8, and 11
4
40 mg
Days 1, 4, 8, and 11
4
60 mg
Days 1 and 8
6
60 mg
Days 1, 4, 8, and 11
7
75 mg
Days 1 and 8
6
75 mg
Days 1, 4, 8, and 11
6
90 mg
Days 1 and 8
7
90 mg
Days 1, 4, 8, and 11
8
90 mg
Days 1, 8, and 15
4
120 mg
Days 1 and 8
6
120 mg
Days 1, 4, 8, and 11
8
Source: Investigator’s Brochure Edition 4, Table 5.h. Data cutoff date: 28 June 2021.
As of 28 June 2021, 76 (93.8%) of the 81 patients presented with at least 1 TEAE. Table 4.c
displays the most common TEAEs reported in ≥10% of patients, regardless of causality. The most 
commonly reported TEAE was fatigue. Other common TEAEs were nausea, headache, diarrhea, 
pyrexia, vomiting, dyspnea, and decreased appetite. Grade 1 CRS were reported in 7 patients and 4 
patients experienced Grade 2 CRS.
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Table 4.c
Study TAK-981-1002: TEAEs Reported in ≥10% of Patients 
TEAE
Preferred Term
Number of Patients (%)
Total (N = 81)
Fatigue
34 (42.0)
Nausea
33 (40.7)
Headache
26 (32.1)
Diarrhea
24 (29.6)
Pyrexia
23 (28.4)
Dyspnea
18 (22.2)
Vomiting
18 (22.2)
Decreased appetite
17 (21.0)
Chills
16 (19.8)
Abdominal pain
15 (18.5)
Hypokalemia
15 (18.5)
Oedema peripheral
15 (18.5)
Constipation
12 (14.8)
Abdominal distension
10 (12.3)
Insomnia
10 (12.3)
Anemia
9 (11.1)
Back pain
9 (11.1)
Cytokine release syndrome
9 (11.1)
Dehydration
9 (11.1)
Hypophosphatemia
9 (11.1)
Source: Table 15.3.1.7 Most Frequent (at least 10% of all patients) TEAEs. Data cutoff date: 28 June 2021.
AE: adverse event; NCI CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events; 
TEAE: treatment-emergent adverse event. 
AEs graded according to NCI CTCAE Version 5.0.
Overall, 43 (53.1%) patients reported Grade ≥3 TEAEs. Most commonly reported Grade ≥3 
TEAEs were hypokalemia, anemia, decreased lymphocyte count, abdominal pain, dyspnea, small 
intestine obstruction, vomiting, and fatigue. Table 4.d describes all that Grade ≥3 TEAEs.
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Table 4.d
Study TAK-981-1002: Grade ≥3 TEAEs 
TEAE
System Organ Class
Preferred Term
Number of Patients (%)
Total (N = 81)
Gastrointestinal disorders
Abdominal pain
4 (4.9)
Small intestinal obstruction
3 (3.7)
Vomiting
3 (3.7)
Nausea
1 (1.2)
Rectal obstruction
1 (1.2)
Diarrhea
1 (1.2)
Rectal hemorrhage
1 (1.2)
Esophagitis
1 (1.2)
Stomatitis
1 (1.2)
Glossodynia
1 (1.2)
Incarcerated umbilical hernia
1 (1.2)
General disorders and administration site conditions
Fatigue
3 (3.7)
Pyrexia
1 (1.2)
Performance status decreased
1 (1.2)
Pain
1 (1.2)
Metabolism and nutrition disorders
Hypokalemia
7 (8.6)
Dehydration
2 (2.5)
Hypercalcemia
1 (1.2)
Hyperuricemia 
1 (1.2)
Hyperglycemia
1 (1.2)
Hypomagnesemia
1 (1.2)
Hypophosphatemia
1 (1.2)
Investigations
Lymphocyte count decreased
5 (6.2)
Blood bilirubin increased
2 (2.5)
Alanine aminotransferase increased
1 (1.2)
Aspartate aminotransferase increased
1 (1.2)
Platelet count decreased
1 (1.2)
Blood creatinine increased
1 (1.2)
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Table 4.d
Study TAK-981-1002: Grade ≥3 TEAEs 
TEAE
System Organ Class
Preferred Term
Number of Patients (%)
Total (N = 81)
Respiratory, thoracic, and mediastinal disorders
Dyspnea
4 (4.9)
Pneumonitis
2 (2.5)
Pleural effusion
2 (2.5)
Pulmonary embolism
1 (1.2)
Dysphonia
1 (1.2)
Blood and lymphatic system disorders
Anemia
6 (7.4)
Pancytopenia
1 (1.2)
Thrombocytopenia
1 (1.2)
Infections and infestations
Cystitis
1 (1.2)
Urinary tract infection
1 (1.2)
Appendicitis
1 (1.2)
Pneumonia
1 (1.2)
Neoplasms benign, malignant, and unspecified (incl cysts and polyps)
Malignant neoplasm progression
1 (1.2)
Pancreatic carcinoma
1 (1.2)
Small cell lung cancer
1 (1.2)
Renal and urinary disorders
Acute kidney injury
2 (2.5)
Urinary tract obstruction
1 (1.2)
Hematuria
1 (1.2)
Injury, poisoning, and procedural complications
Fall
1 (1.2)
Lumbar vertebral fracture
1 (1.2)
Vascular disorders
Hypertension
1 (1.2)
Hypotension
1 (1.2)
Cardiac disorders
Mitral valve incompetence
1 (1.2)
Hepatobiliary disorders
Bile duct obstruction
1 (1.2)
Musculoskeletal and connective tissue disorders
Back pain
1 (1.2)
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Table 4.d
Study TAK-981-1002: Grade ≥3 TEAEs 
TEAE
System Organ Class
Preferred Term
Number of Patients (%)
Total (N = 81)
Nervous system disorders
Cognitive disorder 
1 (1.2)
Peripheral sensory neuropathy 
1 (1.2)
Psychiatric disorders
Confusional state
1 (1.2)
Skin and subcutaneous tissue disorders
Dermatitis acneiform
1 (1.2)
Source: Table 15.3.1.4 Grade 3 or Higher TEAEs. Data cutoff date: 28 June 2021.
AE: adverse event; NCI CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events; 
TEAE: treatment-emergent adverse event. 
AEs graded according to NCI CTCAE Version 5.0.
Fourteen (17.3%) patients experienced Grade ≥3 TEAEs that were considered related to TAK-981 
as assessed by the investigator. TAK-981–related Grade ≥3 TEAEs were lymphocyte count 
decreased in 4 (4.9%) patients; hypokalemia and pneumonitis in 2 (2.5%) patients each; and ALT
increased, AST increased, platelet count decreased, anemia, pancytopenia, thrombocytopenia, 
vomiting, stomatitis, cognitive disorder, and dermatitis acneiform in 1 (1.2%) patient each.
Of 65 (80.2%) patients who had discontinued treatment, 8 (9.9%) patients discontinued treatment 
due to a TEAE. TEAEs that lead to study drug discontinuations were Grade 3 cognitive 
disturbance and Grade 1 sinus bradycardia in 1 patient, Grade 3 small intestinal obstruction, Grade 
3 pneumonitis, Grade 3 bilateral pulmonary embolism, progression of small cell lung cancer, 
Grade 3 dyspnea, Grade 3 pneumonitis, and Grade 2 fatigue.
All treatment-emergent serious adverse events (TESAEs) are displayed in Table 4.e. Thirty-four 
(42.0%) of 81 patients experienced TESAEs. Most commonly reported TESAEs were vomiting, 
small intestinal obstruction, dyspnea, abdominal pain, pneumonia, CRS, and blood bilirubin 
increased.
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Table 4.e
Study TAK-981-1002: TESAEs 
TEAE
System Organ Class
Preferred Term
Number of Patients (%)
Total (N = 81)
Gastrointestinal disorders
Vomiting
3 (3.7)
Small intestinal obstruction
3 (3.7)
Abdominal pain
2 (2.5)
Rectal obstruction
1 (1.2)
Rectal hemorrhage
1 (1.2)
Glossodynia
1 (1.2)
Incarcerated umbilical hernia
1 (1.2)
Respiratory, thoracic, and mediastinal disorders
Dyspnea
3 (3.7)
Pneumonitis
2 (2.5)
Pleural effusion
2 (2.5)
Hypoxia
1 (1.2)
Pulmonary embolism
1 (1.2)
Infections and infestations
Pneumonia
2 (2.5)
Appendicitis
1 (1.2)
Cystitis
1 (1.2)
General disorders and administration site conditions
Fatigue
1 (1.2)
Oedema peripheral
1 (1.2)
Pain
1 (1.2)
Injury, poisoning, and procedural complications
Subdural hematoma
1 (1.2)
Fall
1 (1.2)
Infusion related reaction
1 (1.2)
Lumbar vertebral fracture
1 (1.2)
Neoplasms benign, malignant, and unspecified (incl cysts and polyps)
Malignant neoplasm progression
1 (1.2)
Pancreatic carcinoma
1 (1.2)
Small cell lung cancer
1 (1.2)
Nervous system disorders
Dizziness postural
1 (1.2)
Presyncope
1 (1.2)
Cognitive disorder 
1 (1.2)
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Table 4.e
Study TAK-981-1002: TESAEs 
TEAE
System Organ Class
Preferred Term
Number of Patients (%)
Total (N = 81)
Immune system disorders
Cytokine release syndrome
2 (2.5)
Investigations
Blood bilirubin increased
2 (2.5)
Metabolism and nutrition disorders
Hyperglycemia
1 (1.2)
Dehydration
1 (1.2)
Renal and urinary disorders
Acute kidney injury
1 (1.2)
Hematuria
1 (1.2)
Cardiac disorders
Sinus bradycardia
1 (1.2)
Hepatobiliary disorders
Bile duct obstruction
1 (1.2)
Musculoskeletal and connective tissue disorders
Back pain
1 (1.2)
Skin and subcutaneous tissue disorders
Dermatitis acneiform
1 (1.2)
Source: Table 15.3.1.5 TESAEs. Data cutoff date: 28 Jun 2021.
AE: adverse event; NCI CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events; 
TESAE: treatment-emergent serious adverse event. 
AEs graded according to NCI CTCAE Version 5.0.
Seven patients (9 events) experienced TESAEs that were considered related to study treatment as 
assessed by the investigator (1 patient experienced Grade 3 pneumonitis, 1 patient experienced 
Grade 2 CRS, 1 patient experienced Grade 3 cognitive disorder and Grade 1 sinus bradycardia, 1 
patient had Grade 3 dermatitis acneiform, 1 patient developed Grade 2 CRS and Grade 2 infusion 
related reactions, 1 patient experienced Grade 2 hypoxia, 1 patient experienced Grade 3 
pneumonitis).
Seven deaths (8.6%) reported during the study are displayed in Table 4.f. All of these deaths were 
considered related to underlying disease progression, and none were considered related to study 
treatment as assessed by the investigator.
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Table 4.f
Study TAK-981-1002: On-Study Deaths
TEAE
Preferred Term
Number of Patients (%)
Total (N = 81)
Dose of TAK-981
Rectal hemorrhage
1 (1.2)
3 mg
Pancreatic carcinoma
1 (1.2)
40 mg
Dehydration (dehydration, ascites, disease progression)
1 (1.2)
60 mg
Small cell lung cancer
1 (1.2)
75 mg
Malignant neoplasm progression (renal cell carcinoma)
1 (1.2)
90 mg
Dyspnea
1 (1.2)
90 mg
Metastatic renal cell carcinoma
1 (1.2)
90 mg
Source: Investigator’s Brochure Edition 4, Table 5.l. Data cutoff date: 28 June 2021.
AE: adverse event; NCI CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events; 
TEAE: treatment-emergent adverse event. 
AEs graded according to NCI CTCAE Version 5.0.
On-study death is defined as the death that occurs between the first dose of study drug and 30 days after the last dose of 
study drug (AEs with an outcome of death).
As of 30 April 2021, overall 4 patients had DLTs in this study:

One DLT was observed in the dose level 7 cohort of TAK-981 60 mg BIW in which transient 
Grade 3 serum ALT and AST elevations with normal bilirubin were observed in a 
 
patient after the third dose of TAK-981. The ALT and AST elevations resolved within 
72 hours, and TAK-981 treatment was resumed at the previous dose level of 40 mg; no liver 
function test abnormalities were observed following the subsequent 4 doses of TAK-981.

One DLT was observed in the dose level 8 cohort of TAK-981 90 mg BIW in which Grade 3 
recurrent pneumonitis was observed in a 
 patient after 4 doses of TAK-981. The 
patient had a history of Grade 2 pneumonitis during prior treatment with a dual-affinity 
re-targeting (DART) anti-CTLA-4 and anti-PD-1 antibody. The Grade 3 recurrence of 
pneumonitis, which was considered an SAE, required treatment with oxygen and steroids; and 
the patient was discharged after 12 days of hospitalization on a tapering dose of oral steroids 
and no supplemental oxygen. As a result of this DLT, the Cycle 2 TAK-981 dose 90 mg BIW 
study medication was withdrawn. 

Two DLTs were observed in the dose level 9 cohort of TAK-981 120 mg BIW.
–
Grade 3 stomatitis was observed in a 
 patient after the second dose of 
TAK-981. The event, which did not require hospitalization, was treated with mouthrinse 
solution for stomatitis and resolved within 96 hours. The patient received 3 subsequent 
doses of TAK-981 at 120 mg with no recurrence of the mucositis. From Cycle 2 Day 4, the 
TAK-981 dose was reduced to 90 mg with no evidence of stomatitis after 6 additional 
cycles.
–
A Grade 3 cognitive disturbance with Grade 2 lethargy was observed in a 
 
patient after the first dose of TAK-981. The Grade 3 cognitive disturbance was not 
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associated with CV instability or abnormal findings in brain magnetic resonance imaging
(MRI) and cerebrospinal fluid tests. After 12 days of treatment with IV steroids, symptoms 
resolved with no sequela. As a result of this DLT, TAK-981 treatment was discontinued.
On 27 May 2021, the 120 mg was determined as the TAK-981 single-agent MTD. TAK-981 90 
mg (Days 1, 4, 8, and 11 dosing regimen) regimen was considered as recommended Phase 2 dose 
(RP2D) and schedule for the subsequent phase 2 portion of the single-agent study. Such dosing 
regimen will be implemented for 3 cycles of treatment, and subsequent tapering down to TAK-981 
90 mg (Days 1 and 8 dosing regimen) will be determined upon sponsor’s agreement.
4.2.4.2
Study TAK-981-1501
The study is evaluating the safety, tolerability, and preliminary efficacy of TAK-981 on Days 1 
and 8 every 3 weeks. The study is enrolling patients at the starting dose of 10 mg of TAK-981. 
In Study TAK-981-1501, as of 28 June 2021, 22 of the 24 patients presented with at least one 
TEAE. The most common TEAE was pyrexia. Other common TEAEs were diarrhea, chills, 
dizziness, fatigue, and nausea. There were no reports of CRS as of this data cutoff. Grade ≥3 
TEAEs were reported in 9 (37.5%) patients. Two patients experienced Grade ≥3 TEAEs that were 
considered related to TAK-981 as assessed by the investigator. TAK-981 related Grade ≥3 TEAEs 
were Grade 4 neutropenia and Grade 3 atrial fibrillation (in patient with ongoing cardiac medical 
history) in 1 patient each; both the were in 40 mg QW cohort and transient.
Two patients discontinued treatment due TEAEs (1 patient discontinued due to Grade 2 infusion 
related reaction and 1 patient discontinued due to progression of lymphoma); the events were 
considered not related to TAK-981 as assessed by the investigator.
More detailed information is provided in the IB.
Overall, TAK-981 has been well tolerated. The majority of the observed AEs were consistent with 
the patients’ underlying cancer disease.
4.3
Rationale for the Proposed Study
Study TAK-981-1002 is the FIH, dose escalation study of TAK-981 in patients with solid tumors 
or lymphoma followed by a nonrandomized multicohort Phase 2 study in patients with select solid 
tumor types or NHL indications. TAK-981 is a first-in-class inhibitor of SUMOylation. 
Nonclinical investigation has demonstrated that TAK-981 promotes production of type I IFNs, 
inducing an innate immune response capable of bridging to an adaptive antitumor immune 
response, representing a novel therapeutic strategy for enhancing antitumor immune responses. 
For the purposes of dose escalation and for evaluating anticancer effects, the study will initially 
enroll patients with histologically confirmed advanced (loco regionally recurrent, not amenable to 
curative therapy) or metastatic solid tumors/lymphomas that have no standard therapeutic option 
with a proven clinical benefit, are intolerant, or patients have refused them.
The study design and patient selection in Phase 1 is adequate to evaluate the initial safety, PK, and 
pharmacodynamic effects of TAK-981 in patients with cancer.
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relapsed/refractory indolent or aggressive CD20+ NHLs (Study TAK-981-1501). Preliminary 
safety information in described in Section 4.2.4.
During this study, risk mitigation strategies include, but are not limited to, strict application of the 
study inclusion and exclusion criteria, frequent monitoring of clinical and laboratory results, 
guidelines for management and prophylaxis of potential toxicities, criteria for dose modification, 
and regular monitoring of TEAEs and SAEs by the sponsor.
4.4.1
Potential Effects Based on Nonclinical Studies
Potential risks based on a non-GLP repeat dose nonclinical toxicology study with daily dosing in 
rats; GLP repeat dose, nonclinical toxicology studies with once or BIW dosing in rats and dogs; a 
single dose safety pharmacology study in dogs; a PK study in cynomolgus macaques; an in vitro 
assessment of mutagenicity and an in vivo assessment of genotoxicity in rats; and a non-GLP in 
vitro CRA in human PBMCs, are summarized below. Further details for TAK-981 administration, 
safety events, and management can be found in Section 8.1, Section 8.6, and the Guidance for 
Investigator section of the IB.
4.4.1.1
Lymphoid and Hematopoietic Effects
Dose-dependent reversible or partially reversible lymphoid/hematopoietic effects including 
peripheral lymphopenia and decreased cellularity in lymph nodes, spleen, gut-associated lymphoid 
tissue, and thymus were observed in rats and dogs. Decreased cellularity of lymphoid tissues 
contributed to decreases in leukocyte counts. Prolonged lymphopenia could be associated with 
increased susceptibility to certain forms of infection that were not observed in GLP toxicology 
studies.
Lymphopenia may predispose patients to certain forms of infection that were not observed in the 
GLP-compliant toxicology studies. Prolonged lymphopenia and CD4 counts below 200/µL have 
been associated with opportunistic infections. Prophylaxis for pneumocystis pneumonia or herpes 
zoster is not required; however, in cases of prolonged lymphopenia, or in patients with a previous 
history of shingles, it might be initiated per SOC.
As of the data cutoff for this report in the ongoing clinical studies, transient decrease lymphocyte 
count (3.7%) related to TAK-981 has been reported. Opportunistic infections have not been 
reported to date; however, herpesvirus reactions have been observed (1.5% related to TAK-981) 
but were self-limited, resolving within 14 days.
In this study, absolute lymphocyte counts will be monitored, and subpopulations will be assessed 
regularly, especially CD4 and CD8 counts. A prolonged CD4 count below 200/µL (National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] ≥Grade 3) is 
the strongest predictor for opportunistic infections. The initiation of Pneumocystis jirovecii
pneumonia prophylaxis and herpes virus prophylaxis will be considered at the discretion of the 
investigator.
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As an additional precautionary measure, during dose escalation, patient enrollment is staggered 
between the first and second patients 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 the Day 4 visit 
without clinically significant acute toxicities (Section 6.1).
4.4.1.4
Injection Site Reactions
The local irritancy potential of TAK-981 was evaluated at the IV administration site in the 
GLP-compliant repeat-dose toxicity studies in rats and dogs. Effects at the injection site, including 
potentiation of procedure-related subcutaneous hemorrhage, inflammation, and necrosis, were 
observed in rats only. The shorter needle length and frequent movement of conscious rats likely 
resulted in extravasation. Of note, TAK-981 is a solution with low pH that should be diluted, as 
defined in the pharmacy manual.
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).
4.4.1.5
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 not known at this time. 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. TAK-981–related 
reproductive findings were not observed in the studies with BIW dosing and in the dog study 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, inflammation in the prostate gland, 
and (at ≥5 mg/kg) partially reversible acinar cell trophy in the male mammary gland. 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.
Therefore, female patients and female partners of male patients participating in this study should 
avoid becoming pregnant. Nonsterilized female patients of reproductive age group and male 
patients should use effective methods of contraception through defined periods during and after 
study treatment as specified 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 6 months after the last dose of study drug, 
or
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
Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.)
Male patients, even if surgically sterilized (ie, status post vasectomy) must agree to 1 of the 
following:
–
Agree to practice effective barrier contraception during the entire study treatment period 
and through 6 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 patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.)
4.4.1.6
Genotoxicity
TAK-981 was not mutagenic in an in vitro bacterial mutagenesis Ames assay. However, in an 
in vivo rat bone marrow micronucleus assay, TAK-981 increased induction of micronuclei and 
was therefore considered to be positive for in vivo genotoxicity at ≥5 mg/kg. It was not determined 
whether TAK-981 induces clastogenic or aneugenic genotoxicity. In compliance with ICH S9 
guidance (ich.org/products/guidelines/safety/article/safety-guidelines.html), carcinogenicity 
assessment is not planned.
The potential effects listed above are based on toxicology findings in the nonclinical studies with 
TAK-981; they 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.
During this study, risk mitigation strategies include, but are not limited to, strict application of the 
study inclusion and exclusion criteria, frequent monitoring of clinical and laboratory results, 
guidelines for management and prophylaxis of potential toxicities, criteria for dose modification, 
and regular monitoring of TEAEs and SAEs by the sponsor. In addition, the Safety Monitoring 
Committee (SMC) will continuously monitor patients in dose escalation and cancer treatment 
expansions; the Independent Data Monitoring Committee (IDMC) will monitor patients in the 
Phase 2 study.
4.4.2
COVID-19 Pandemic
The 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 follow local 
recommendations and guidelines with regards to COVID-19 precautions, vaccination, and 
treatment.
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Figure 6.a
TAK-981-1002 Study Design
CAR: chimeric antigen receptor; CPI: checkpoint inhibitor; DLBCL: diffuse large B-cell lymphoma; FL: follicular lymphoma; HA: health authority; 
IV: intravenous administration; MSS: microsatellite-stable; NHL: non-Hodgkin lymphoma; NSCLC: non–small cell lung cancer; r/r: relapsed/refractory; 
PD-(1/L1): programmed cell death protein 1/programmed death ligand 1; q21d: every 21 days.
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6.1.1
Phase 1 Dose Escalation
Patients will be treated in cohorts with increasing doses of TAK-981, administered as a 1-hour IV 
infusion on Days 1, 4, 8, and 11 of a 21-day cycle until a discontinuation criterion is met. The 
overall dosing regimen is displayed in Figure 6.b.
Figure 6.b
TAK-981 Dosing Regimen
The study will begin with a dose escalation. Dose escalation intervals progress from 3 mg to 
160 mg (with a provision of 1 mg at dose level 1). The upper dose level corresponds 
approximately to the human equivalent dose of the MTD in dogs. Patient enrollment will be 
staggered between the first and second patients 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 the Day 4 visit 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 may not be 
required if there are no clinically significant safety findings suggestive of infusion reaction or 
CRS. 
Dose escalation of TAK-981 will be cohort-based with an adaptive design using Bayesian logistic 
regression modeling (BLRM) (see Appendix G for details). Approximately 70 patients will be 
enrolled until the RP2D of TAK-981 is identified. Single agent RP2D could be based either on the 
MTD based on the observation of DLTs (Section 8.2.1) or a BED that is ≤MTD. 
A minimum of 3 patients will be enrolled in the starting dose cohort. Dose escalation and cohort 
expansion decisions are reviewed and approved by the SMC, composed of the sponsor clinician 
and the investigators, which may decide that a fourth patient can be recruited to the same cohort 
before the first 3 patients complete the DLT assessment period. While the first 3 evaluable patients 
will be used to determine dose expansion, if the fourth patient experiences a DLT, their respective 
AE(s) will be taken into consideration regarding cohort determination, during the end of cohort 
meeting. The rationale for such an addition is to have an extra patient in the cohort should 1 of the 
3 earlier patients be unevaluable, or if a patient within the cohort experiences a DLT, which would 
require cohort expansion to 6 patients. From dose level 2 onwards, an adaptive BLRM guided by 
the Escalation with Overdose Control principle will be used in successive escalation cohorts 
(Section 8.2.2).
Single agent RP2D will be based either on the MTD determined by the BLRM (Section 8.2.1) or a 
BED that is ≤ MTD. The BED of TAK-981 is defined as the dose at which there is evidence of 
pharmacodynamic effects including the presence of SUMO-TAK-981 adducts and inhibition of 
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However, if a clinical benefit has been observed for patients in the cohort (eg, the majority of 
patients have recorded stable disease (SD) at Week 8 and per investigator assessment are 
benefiting from treatment), then enrollment into stage 2 may be allowed for this cohort with 
agreement from participating investigators. 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 take place when all ongoing patients have had the 
opportunity complete the 6 months disease assessment.
On 27 May 2021, a regimen of 90 mg TAK-981 with dosing on Days 1, 4, 8, and 11 was 
considered to be theRP2D and schedule for the subsequent phase 2 portion of the single-agent 
study. This dosing regimen will be implemented for 3 cycles of treatment, and subsequent tapering 
down to 90 mg TAK-981 (Days 1 and 8 dosing regimen) will be determined on the sponsor’s 
agreement.
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.
6.2
Number of Patients
Up to approximately 202 patients will be enrolled in the study. 
6.2.1
Phase 1 Dose Escalation and Phase 2 Cancer Treatment Expansion Cohorts
During the dose escalation phase, approximately 70 DLT-evaluable patients will be enrolled at 
approximately 7 to 12 study centers in the US and Canada. 
During Phase 2, up to approximately 19 to 28 patients will be enrolled in each of the solid tumor or 
the CD20+ relapsed/refractory NHL cohorts.
6.3
Patient Replacement
In Phase 1 part of the study, patients who are withdrawn from treatment during Cycle 1 for reasons 
other than DLT may be replaced. Patients in Phase 2 will not be replaced.
6.4
Duration of Study
6.4.1
Duration of an Individual Patient’s Study Participation
6.4.1.1
Phase 1 Dose Escalation and Phase 2 Cancer Treatment Expansion Cohorts
Patients may receive TAK-981 up to 1 year. Patients with demonstrated clinical benefit can 
continue treatment beyond this point if approved by the sponsor. These patients can continue 
receiving treatment in this study or in any of the poststudy access modalities described in 
Section 6.4.5. Patients may discontinue treatment if they meet any of the discontinuation criteria in 
Section 8.2.4.1.3.
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All patients will attend an end-of-treatment (EOT) visit 30 days (+10 days) after receiving their 
last dose of study drug 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 in Phase 1 who discontinue study treatment 
for reasons other than progressive disease in dose escalation will continue PFS follow-up every 12 
(±1) weeks from the EOT visit for up to 12 months or until a discontinuation criterion is met 
(Section 9.7). Patients in Phase 2 who discontinue or complete treatment will be followed for 
survival every 12 (±1) weeks from the EOT visit for up to 12 months after the last patient in the 
cohort discontinues or completes treatment, or until loss of follow-up, consent withdrawal, death, 
study termination, or until >70% of patients in the cohort have progressed, whichever occurs first.
6.4.2
End of Study/Study Completion Definition and Planned Reporting
6.4.2.1
Phase 1 Dose Escalation and Phase 2 Cancer Treatment Expansion Cohorts Primary 
Completion/Study Completion
The primary analyses for the primary endpoint will be conducted after all patients enrolled in the 
study have had the opportunity to complete 9 cycles of treatment with TAK-981. 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 6.4.5). The estimated time frame for study completion is 
up to 48 months.
6.4.3
Timeframes for Primary and Secondary Endpoints to Support Disclosures
Table 6.a shows 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
Phase 1 
Primary Endpoint: 
Frequency and severity of TEAEs overall and 
per dose level
Standard safety assessments
Up to 48 months
Number of patients with DLTs per dose level
Standard safety assessments
Up to 48 months
Number/percentage of patients with clinically 
significant laboratory values
Standard safety assessments
Up to 48 months
Secondary Endpoints:
PK parameters after the first dose of TAK-981 
on C1D1 and C1D8 (data permitting): Cmax, 
tmax, AUClast, AUC∞, t1/2z, CL, Vss
Standard PK parameters to allow 
determination of PK profile
Up to 48 months
Response assessments based on RECIST v1.1 
for solid tumors or Lugano classification for 
lymphomas: ORR, DOR, DCR, TTR, TTP, 
PFS
Standard efficacy assessments
Up to 48 months
TAK-981-SUMO adduct formation and 
SUMO pathway inhibition
TAK-981-SUMO adduct formation 
and SUMO pathway inhibition on 
skin tissues/blood
Up to 48 months
Phase 2
Primary Endpoint:
ORR (CR + PR) as defined by the investigator 
according to RECIST v1.1 for solid tumors or 
Lugano classification for lymphomas
Standard efficacy assessments
Up to 48 months
Secondary Endpoints:
Plasma TAK-981 concentration-time profile
Standard PK parameters to allow 
determination of PK profile
Up to 48 months
Frequency and severity of TEAEs 
Standard safety assessments
Up to 48 months
Response assessments based on RECIST v1.1 
for solid tumors or Lugano classification for 
lymphomas:
DOR, DCR, TTR, TTP, PFS
Standard efficacy assessments
Up to 48 months
OS
Standard efficacy assessments
Up to 48 months
AUClast: area under the plasma/blood/serum concentration-time curve from time 0 to the last measurable 
concentration; AUC∞: area under the plasma/blood/serum 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; CR: complete response; DCR: disease control rate; DLT, dose-limiting toxicity; DOR: duration 
of response; ORR: overall response rate; OS: overall survival; PFS: progression-free survival; PK, pharmacokinetic; 
PR: partial response; RECIST v1.1: Response Evaluation Criteria in Solid Tumors Version 1.1; SUMO, small 
ubiquitin-like modifier; t1/2z: terminal disposition phase half-life; TEAE: treatment-emergent adverse event; tmax: time 
of first occurrence of maximum observed plasma concentration; TTP: time to progression; TTR: time to response; Vss:
volume of distribution at steady state after intravenous administration.
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6.4.4
Total Study Duration
Phase 1 and Phase 2: It is anticipated that this study will last for approximately up to 48 months.
6.4.5
Poststudy Access
6.4.5.1
Phase 1 Dose Escalation and Phase 2 Cancer Treatment Expansion Cohorts
Participants 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 may continue to receive TAK-981 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 TAK-981. 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 for participants will be terminated for those individuals who no 
longer benefit from TAK-981 (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 becomes 
available either commercially or via another 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
Male or female patients aged 18 years or older with histologically or cytologically confirmed solid 
tumors or relapsed/refractory hematologic malignancies.
7.1
Inclusion Criteria
Each patient must meet all of the following inclusion criteria to be enrolled in the study:
1. Adult male or female patients ≥18 years old. 
2. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
3. Patient population for Phase 1 dose escalation:
a.
Have a histologically or cytologically confirmed advanced (local regionally recurrent not 
amenable to curative therapy) or metastatic solid tumors who have no standard therapeutic 
option with a proven clinical benefit, are intolerant, or have refused them. 
OR
b. Have a relapsed/refractory lymphoma not amenable to therapies with proven clinical 
benefit or who are intolerant or who refuse them. Patients with low-grade lymphomas such 
as FL, small lymphocytic lymphoma, lymphoplasmacytoid lymphoma, and marginal zone 
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lymphomas may not need to exhaust all available therapy. These patients can be enrolled 
after failure of at least 2 prior systemic therapies, provided that there is not an immediate 
need for cytoreduction. In these cases, patients who need immediate therapy for tumor bulk 
are not eligible for this trial.
4. Patient population for Phase 2 dose expansion cohorts:
Have a histologically or cytologically documented, advanced (metastatic and/or 
unresectable) cancer as listed below, that is incurable and for which prior standard first-line 
treatment has failed:
Note: Prior neoadjuvant or adjuvant therapy included in initial treatment may not be 
considered first- or later-line SOC treatment unless such treatments were completed less 
than 12 months before the current tumor recurrence.
a.
Nonsquamous NSCLC that has progressed to 1 prior systemic immune 
CPI/anti-PD-(1/L1)-containing therapy and no more than 2 lines of therapy. Patients must 
have not shown evidence of tumor progression during the first 5 months of treatment with 
first-line CPI/anti-PD-(1/L1)-containing therapy (cohort A). 
Note: Patients with known driver mutations/genomic aberrations (eg, EGFR, B-Raf 
proto-oncogene mutation V600E [BRAF V600E], and ROS proto-oncogene 1 [ROS1] 
sensitizing mutations, neurotrophic receptor tyrosine kinase [NRTK] gene fusions, and 
anaplastic lymphoma kinase [ALK] rearrangements) must have also shown progressive 
disease after treatment with a commercially available targeted therapy. 
b. CPI-naïve cervical cancer (squamous cell carcinoma, adenosquamous carcinoma or 
adenocarcinoma of the cervix) patients who have received no more than 1 prior systemic 
line of therapy for recurrent or Stage IVB cervical cancer (cohort B).
Note: The following cervical tumors are not eligible: minimal deviation/adenoma 
malignum, gastric-type adenocarcinoma, clear-cell carcinoma, and mesonephric 
carcinoma. Histologic confirmation of the original primary tumor is required via pathology 
report.
Note: First-line treatment must have consisted of platinum-containing doublet. 
Chemotherapy administered concurrently with primary radiation (eg, weekly cisplatin) is 
not counted as a systemic chemotherapy regimen.
c.
CPI-naïve MSS-CRC patients who have progressed on no more than 3 chemotherapy 
regimens (cohort C).
Note: Patients must have received prior treatment with fluoropyrimidine-, oxaliplatin-, and 
irinotecan-containing regimens if indicated.
d. Relapsed/refractory DLBCL progressed or relapsed after prior CAR T-cell therapy that has 
received approval by a health authority for the treatment of DLBCL (cohort D).
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e.
Relapsed/refractory 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 E).
f.
Relapsed/refractory 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 F).
5. In Phase 2 only, have at least 1 radiologically measurable lesion based on RECIST v1.1 for 
patients with solid tumors or Lugano criteria for lymphoma. Tumor lesions situated in a 
previously irradiated area are considered measurable if progression has been demonstrated in 
such lesions.
Note: In Phase 2 stage 1, have an additional lesion for pretreatment and on-treatment biopsy.
6. In Phase 2 stage 1, willing to consent to mandatory pretreatment and on-treatment tumor 
biopsy.
Note: For fresh tumor biopsies, the lesion must be accessible for a biopsy procedure as 
assessed by the investigator.
7. Is willing to provide archival tumor tissue sample, if available. 
8. Adequate bone marrow reserve and renal and hepatic function based on the following 
laboratory parameters: 
a.
Absolute neutrophil count (ANC) ≥1.0 × 109/L, hemoglobin ≥85 g/L (RBC transfusion 
allowed ≥14 days before assessment), and platelet count ≥75.0 × 109/L (platelet count 
≥50.0 × 109/L is allowed for patients with lymphoma if it is clearly due to marrow 
involvement with no evidence of myelodysplastic syndrome or hypoplastic bone marrow, 
if found). 
b. Total bilirubin ≤1.5 times the institutional upper limit of normal (ULN); or total bilirubin 
<3.0 times the ULN with direct bilirubin within normal range in patients with 
well-documented Gilbert’s syndrome.
c.
Serum ALT or AST ≤3.0 times the ULN (<5 times the ULN if liver enzyme elevations are 
due to liver metastases).
d. Estimated creatinine clearance using the Cockcroft-Gault formula ≥45 mL/minute.
9. Recovered to Grade 1 or baseline or established as sequelae from all toxic effects of previous 
therapy (except alopecia, neuropathy, or autoimmune endocrinopathies with stable endocrine 
replacement therapy, or bone marrow parameters [any of Grade 1/2 permitted if directly 
related to bone marrow involvement]).
10. Consented to undergo serial skin punch biopsies (dose escalation only).
11. Voluntary written consent must be given before performance of any study-related procedure 
not part of standard medical care, with the understanding that consent may be withdrawn by 
the patient at any time without prejudice to future medical care.
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12. Suitable venous access for safe drug administration and the study-required PK and 
pharmacodynamic sampling.
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:
a.
Postmenopausal for at least 1 year before the screening visit, or
b. Surgically sterile, or
c.
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 6 months after the last dose of study drug, or
d. 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 post vasectomy) must agree to 1 of the 
following:
a.
Agree to practice effective barrier contraception during the entire study treatment period 
and through 6 months after the last dose of study drug, or
b. 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.)
7.2
Exclusion Criteria
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
1. Phase 1 dose escalation and Phase 2 cancer treatment expansion cohorts:
a.
Have received treatment with systemic anticancer treatments or investigational products 
within 14 days before the first dose of study drug or 5 half-lives, whichever is shorter.
Note: Low-dose steroids (oral prednisone or equivalent ≤20 mg per day), hormonal therapy 
for prostate cancer or breast cancer (as adjuvant treatment), and treatment with 
bisphosphonates and receptor activator of nuclear factor kappa-Β ligand (RANKL) 
inhibitors are allowed.
b. Have received extended field radiotherapy ≤4 weeks before the start of treatment (≤2 
weeks for limited field radiation for palliation), and who has not recovered to grade 1 or 
baseline from related side effects of such therapy (except for alopecia).
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2. Have a history of uncontrolled brain metastasis. Patients with brain metastases are allowed if 
they are previously treated with surgery, whole-brain radiation, or stereotactic radiosurgery 
and the patients are receiving a corticosteroid dose ≤10 mg/day of prednisone equivalent at the 
time of receiving the first dose of TAK-981. For asymptomatic patients, screening brain 
imaging is not required.
3. Patient is receiving any live vaccine (eg, varicella, pneumococcus) within 4 weeks of initiation 
of study treatment.
4. History of any of the following ≤6 months before first dose: congestive heart failure New York 
Heart Association Grade III or IV, unstable angina, myocardial infarction, unstable 
symptomatic ischemic heart disease, severe noncompensated hypertension despite appropriate 
medical therapy, 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. 
5. Baseline prolongation of the QT interval with Fridericia correction method (QTcF) (eg, 
repeated demonstration of QTcF interval >480 ms, history of congenital long QT syndrome, or 
torsades de pointes).
6. Psychiatric illness/social circumstances that would limit compliance with study requirements 
and substantially increase the risk of AEs or has compromised ability to provide written 
informed consent.
7. Admission or evidence of illicit drug use, drug abuse, or alcohol abuse.
8. History of autoimmune disease requiring systemic immunosuppressive therapy with daily 
doses of prednisone >10 mg/day or equivalent doses, or any other form of immunosuppressive 
therapy. Hormone therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency) is not considered an excluded form of systemic 
treatment of an autoimmune disease.
9. History of immune-related AEs related to treatment with immune checkpoint inhibitors that 
required treatment discontinuation.
10. History of noninfectious pneumonitis that required steroids or a history of interstitial lung 
disease.
11. Has evidence of active, noninfectious pneumonitis.
12. Have a significant active infection.
13. Known history of HIV infection or any other relevant congenital or acquired 
immunodeficiency.
14. Known hepatitis B virus surface antigen seropositive or detectable hepatitis C infection viral 
load. Note: Patients who have positive hepatitis B core antibody or hepatitis B surface antigen 
antibody can be enrolled but must have an undetectable hepatitis B viral load.
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15. Receiving or requiring the continued use of medications that are known to be strong or 
moderate inhibitors and inducers of CYP3A4/5 (Appendix E) or are strong P-gp inhibitors 
(Appendix F). To participate in this study, patients should discontinue use of such agents for at 
least 2 weeks (1 week for CYP3A4/5 and P-gp inhibitors) before receiving a dose of TAK-981.
16. Patient requires the use of drugs known to prolong QTc interval (during Phase 1 only) 
(Appendix H).
17. History of allogeneic tissue or solid organ transplant.
18. 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.
19. Female patients who are lactating and breastfeeding or have a positive serum pregnancy test 
during the screening period or a positive urine pregnancy test on Day 1 before first dose of 
study drug.
8.0
STUDY DRUG
Patients enrolled in the study will receive TAK-981 as a single agent.
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).
TAK-981 will be provided as a Solution for Infusion containing 10 mg/mL TAK-981 drug 
substance (refer to the pharmacy manual). 
TAK-981 will be administered as 60 (±10) minute IV infusion. In case infusion reactions are 
observed, the length of the infusion can be extended up to 2 hours for all patients without needing 
a protocol amendment.
TAK-981 administration should occur in an area with resuscitating equipment and medications 
such as antihistamines, acetaminophen, corticosteroids, epinephrine, and bronchodilators readily 
available. Patients’ vital signs must be monitored before, during the, and at the end of 
administration of TAK-981. Treatment must be stopped if the patient experiences symptoms 
compatible with an infusion reaction of Grade 2 or greater. The management of infusion reactions 
and CRS is detailed in Sections 8.6.6 and 8.6.7, respectively.
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.
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8.2
Phase 1 Dose Escalation and Phase 2 Cancer Treatment Expansion Cohorts
In Phase 1 dose escalation and Phase 2 cancer treatment expansion, each 21-day treatment cycle 
will consist of a single dose TAK-981 administration on Days 1, 4, 8, and 11. Evaluation of 
alternative TAK-981 dosing schedules (eg, Day 1, or Day 1 and Day 8, or Day 1, Day 8, and Day 
15 in 21-day cycles) may be permissible only after discussions between the sponsor and the 
investigators.
Patients will be asked to maintain adequate hydration (1.5-2 L/day) 48 hours before initiating 
therapy and during C1D1, and IV fluid administration on C1D1 is recommended for those who 
cannot maintain adequate oral hydration. On C1D1 in Phase 1, patients will abstain from eating 
food or having anything to drink except water from a minimum of 2 hours before collection of the 
predose ECGs until after collection of the 1-hour postinfusion ECGs. A low calorie and low 
sodium light meal is permitted immediately after the 1-hour postinfusion ECG has been collected. 
No diet restriction will be required during Phase 2.
During Phase 1, for the first infusion (C1D1) of TAK-981 during dose escalation every patient 
needs to be hospitalized for drug administration and overnight observation (a minimum of 
18 hours after the end of infusion). The patient can be discharged from overnight observation only 
if there are no signs and symptoms of acute toxicity like fever or significant changes in blood 
pressure and/or heart rate. Prophylaxis for IRRs is not recommended for the first dose of 
TAK-981. Hospitalization is not required if expansion after the first 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 no infusion reaction is observed in C1D1, subsequent infusions 
(C1D4 infusion onwards) can be administered in an outpatient basis.
During Phase 1 C1D1 administration, vital signs (blood pressure, heart rate, and temperature) 
should be monitored for at least 6 hours after infusion and again before discharging the patient or 
at any time if the patient complains of symptoms. If an AE is observed, extended monitoring of 
vital signs can be added as medically indicated. Outside C1D1, vital signs need to be monitored as 
stated above and up to 4 hours after the end of the infusion. From Cycle 2 onwards, if no infusion 
reaction is observed in the first cycle, the patient can be discharged from the site per investigator 
discretion.
During Phase 2 C1D1, vital signs should be monitored up to 4 hours after the end of the infusion. 
Outside C1D1, vitals will be monitored immediately before the start of infusion and after the end 
of infusion, and patients will be discharged per investigator discretion.
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 (see Section 8.4). For patients in the DLT-evaluation period (Cycle 1), 
rescheduling is allowed for a maximum of 1 dose. At least 72 hours should elapse between 
consecutive doses of TAK-981. 
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8.2.1
Definitions of DLT for Dose Escalation
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 [1]. 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 with TAK-981:
1. Any Grade 5 AE.
2. Nonfebrile Grade 4 neutropenia (ANC <0.5 × 109/L) lasting more than 7 consecutive days. If 
myeloid growth factors are used, the event will be considered as DLT irrespective of the 
duration.
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 more than 7 consecutive days. A platelet count <10 × 109/L 
at any time is a DLT.
5. Grade 3 thrombocytopenia lasting longer than 14 days or accompanied by Grade 2 bleeding or 
requiring transfusion.
6. Delay in the initiation of Cycle 2 by more than 14 days due to a lack of adequate recovery of 
treatment-related hematological or nonhematologic toxicities.
7. Grade ≥3 nonhematologic toxicity with the following exceptions:
–
Grade 3 arthralgia/myalgia that responds to nonsteroidal anti-inflammatory drugs within 1 
week.
–
Grade 3 fatigue lasting fewer than 7 days.
–
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.
–
Grade 3 CRS that resolves to ≤Grade 1 in less than 7 days without end-organ damage.
–
Asymptomatic laboratory changes (other than renal and hepatic laboratory values) that can 
be successfully supplemented (reversion of Grade 4 events to Grade ≤2, reversion of Grade 
3 events to Grade ≤1 or baseline) within 72 hours.
–
Grade 3 elevation in ALT, AST, and/or alkaline phosphatase that resolves to Grade ≤2 or 
baseline with supportive care within 7 days and is not associated with other clinically 
relevant consequences.
–
Grade 3 nausea and/or emesis that can be controlled to <Grade 3 in ≤3 days with the use of 
optimal antiemetics (defined as an antiemetic regimen that employs both a 
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5-hydroxytryptamine 3 serotonin receptor antagonist and a corticosteroid given in standard 
doses and according to standard schedules).
–
Grade 3 diarrhea that can be controlled to <Grade 3 in ≤3 days with appropriate treatment.
–
Grade 3 rash lasting ≤7 days after treatment that includes topical steroid treatment, 
oral antihistamines, and pulse oral steroids (if necessary).
8. Grade 2 nonhematologic toxicities that are considered by the investigator to be related to study 
drug and dose-limiting.
AEs meeting the DLT definition may occur at any point during treatment. Primarily, only DLTs 
occurring during Cycle 1 of treatment will influence decisions regarding dose escalation; however, 
BLRM also will take into consideration DLTs occurring at later treatment cycles. For the selection 
of RP2D, the total frequency of DLTs and DLT-like AEs should be <33%. If a patient in the dose 
escalation phase does not receive all planned doses for Cycle 1 for reasons other than a DLT, that 
patient will be replaced.
8.2.2
Dose Escalation Rules
Dose escalation of TAK-981 will be cohort-based. Initially, 3 patients will be enrolled at the 
starting dose level. When Cycle 1 safety data are available from the first 3 evaluable patients in the 
current cohort, the final decision on next dose level will be taken by the SMC. The SMC may 
decide that a fourth patient can be recruited before the first 3 patients complete the DLT 
assessment period. The rationale for such an addition is to have an extra patient in the cohort 
should 1 of the 3 earlier patients be 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.

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 has a Cycle 1 DLT, the starting dose will be considered not 
tolerated and the dose will be de-escalated to 1 mg. If none of the 3 additional patients has 
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. 
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While the first 3 evaluable patients will be used to determine dose expansion, if the fourth patient 
experiences a DLT, their respective AE(s) will be taken into consideration regarding cohort 
determination, during the end of cohort meeting.
Starting from the second dose level, the BLRM with overdose control along with consideration of 
other safety, clinical, PK, and pharmacodynamic data, will be used for all subsequent dose 
recommendations. Starting from the second dose level, the size of the cohort will be approximately 
3 subjects. More conservative dose escalation, 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 
DLT, exposure, or pharmacodynamics. 
Before initiating the dosing of the next cohort, when Cycle 1 safety data are available for all 
patients in the current cohort, an end of cohort meeting will be held. The SMC will review the 
Cycle 1 safety data of all treated patients, the available PK and pharmacodynamic information, 
and make decisions regarding dose escalation. Any decision to modify the dose escalation scheme 
or infusion schedule (with the exception of de-escalation, escalation to intermediate doses, or 
reduction in the administration frequency [eg, Day 1, or Day 1 and Day 8, or Day 1, Day 8, and 
Day 15]) will be introduced as a protocol amendment and will need to be approved by the 
institutional review boards (IRBs) before being implemented. All decisions will be documented in 
writing.
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 Appendix G). Escalation will 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 and the posterior probability of 
the next recommended dose 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 SMC may decide to stop 
dose escalation without identifying MTD based solely on pharmacodynamic markers. In this case 
BED will be declared (Section 8.2.3). More conservative dose escalation, 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 dose-related toxicity, exposure, or pharmacodynamics of 
TAK-981.
Patients not receiving all doses of TAK-981 in Cycle 1 for reasons other than DLTs will be 
replaced within the cohort.
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8.2.4.1.2
Criteria for Beginning or Delaying a Subsequent Treatment Cycle
Treatment with TAK-981 will use a cycle length of 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 in patients with lymphoma if no 
change in the baseline platelet level from the screening visit and it is clearly due to marrow 
involvement).
Before starting a new treatment cycle, TAK-981–related AEs or laboratory abnormalities must 
have returned to ≤Grade 1/baseline (other than those stated above). If the patient fails to meet the 
above-cited criteria 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, this will be considered a 
DLT (if considered as possibly related and happens in Cycle 1) and 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. If clinical benefit for the individual patient is confirmed, recovery 
period can be extended or retreatment at the same or reduced dose can be started without complete 
recovery. TAK-981 dosing may be continued at the previously established safe dose level or 
below.
8.2.4.1.3
Criteria for Dose Interruption, Dose Reduction, and Discontinuation
All toxicities that occur during the study will be actively managed following the SOC unless 
otherwise specified in the protocol. Patients experiencing AEs attributed to TAK-981 may 
continue study treatment with the same dose, may have TAK-981 treatment held or may be 
permanently discontinued from the study. Patients who have study drug held because of 
treatment-related or possibly related AEs should resume study drug treatment after resolution of 
the AE to Grade ≤1 or baseline (or Grade 2 for some specified hematological AEs as shown in 
Table 8.c), at the next lower dose level.
Dosing of TAK-981 should be interrupted or reduced according to the dose modification 
recommendations listed in Table 8.b for nonhematologic toxicity and Table 8.c for hematologic 
toxicities. When the dose of TAK-981 is withheld based on the listed criteria, clinical and 
laboratory reevaluation should be repeated at least weekly or more frequently, depending on the 
nature of the toxicity observed until the toxicity resolves to the Grade specified in Table 8.b and 
Table 8.c. 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 cannot be administered 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 the schedule of events (SOE) (Appendix A).
If initial dose adjustment does not provide sufficient relief, the dose of TAK-981 can be further 
reduced by another dose level if the treating physician considers that the patient is receiving 
benefit. In general, after a dose is reduced, it should not be re-escalated even if there is minimal or 
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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. A patient can 
receive up to 2 dose level reductions of TAK-981 due to AEs but further reductions are not 
permitted (the patient should discontinue study drug in this case).
In dose escalation, the dose of TAK-981 will not be reduced for an individual patient during Cycle 
1 unless a DLT has been declared and it is still possible for the patient to receive treatment within 
the remaining dosing period scheduled. In this case, the patient can complete Cycle 1 at a reduced 
dose level.
Table 8.b
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, at the previous safe dose level
Grade 3 and Grade 4 non–
life-threatening AEs
Hold TAK-981 until resolution to Grade ≤1 or baseline, and then resume treatment 
at the next lower dose level.
Note: Permanently discontinue treatment if Grade ≤3 QTcF prolongation occurs.
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; QTcF: QT interval with Fridericia correction method.
For specific instructions in case of CRS, refer to Table 8.d.
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Table 8.c
Dose Adjustments for Hematologic Toxicities
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.
PLT <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 the investigator determines that the patient is 
obtaining clinical benefit and has discussed this with the 
sponsor, then resume treatment at the previous safe lower dose 
level (ie, reduce by 1 dose level).
ANC: absolute neutrophil count; LLN: lower limit of normal; PLT: platelet.
Criteria for Discontinuation of TAK-981
In dose escalation, TAK-981 should be discontinued in patients experiencing an AE in Cycle 1 
meeting criteria for a DLT for which the investigator considers that retreatment of the patient could 
be dangerous. For Grade 4, life-threatening nonhematologic TEAEs, permanently withdraw the 
patient from the study.
If more than 2 dose reductions are required, or if the next cycle of TAK-981 is delayed for 
>14 days because of TAK-981–related toxicities, then the patient should have study treatment 
discontinued unless the investigator considers that the patient will receive benefit from continuing 
in the study. If treatment discontinuation is determined, the EOT visit should be completed within 
30 (+10) days of the last administration of TAK-981 and before the start of subsequent anticancer 
therapy.
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8.3
Excluded Concomitant Medications and Procedures
The following medications and procedures are prohibited during the study:

Strong and moderate CYP3A4/5 inhibitors and inducers (see list in Appendix E). During the 
study, should patients require the use of medications that are known to be strong and moderate 
inhibitors/inducers of CYP3A4/5, they should temporarily discontinue the use of TAK-981. 
Patients in dose escalation or cancer treatment expansions can resume treatment with 
TAK-981 approximately 2 weeks or 5 times the half-life (whichever is shorter) after 
discontinuing the use of these strong and moderate inhibitors and inducers of CYP3A4/5.
8.3.1
Excluded Concomitant Medications and Procedures for Phase 1 Dose Escalation 
and Phase 2 Cancer Treatment Expansion Cohorts

Concomitant corticosteroid administration of >20 mg of prednisone or equivalent unless given 
as treatment or prophylaxis for IRRs, as premedication for administration of certain blood 
products (80 mg methylprednisolone is accepted) or short courses (<96 hours) for 
exacerbations of respiratory tract disorders or for acute control of emerging tumor pain.

Strong inhibitors of P-gp (see list in Appendix F).

In Phase 1, initiation of prophylactic use of myeloid growth factors (eg, G-CSF) are not 
allowed in the first cycle before confirmation of DLT but may be administered to manage 
patients who experience Grade 4 and/or febrile neutropenia if clinically indicated in 
accordance with American Society of Clinical Oncology guidelines and/or institutional 
practices. For the first episode of neutropenia, dose reduction is preferred. 

Patients currently on chronic erythropoietin support for anemia may continue to receive 
erythropoietin, but initiation of new erythropoietin therapy is not allowed during the first cycle.

Any investigational agent other than TAK-981.

Any concurrent antineoplastic therapy (eg, chemotherapy, hormonal therapy, immunotherapy, 
radiation therapy except for palliative radiation therapy and once progressive disease is ruled
out) or standard or investigational agents for treatment of cancer.

Drugs known to prolong QTc interval, during Phase 1 only (see list in Appendix H).

Because the safety of immunization with live viral vaccines following TAK-981 therapy has 
not been studied, vaccination with live virus vaccines is prohibited while the patient is being 
treated on study.
8.4
Permitted Concomitant Medications and Procedures
All prescription and over-the-counter medications, including influenza vaccines, taken by a patient 
as of the first study drug administration through the EOT visit or before initiation of new 
anticancer therapy (whichever comes first) will be recorded in the designated electronic case 
report form (eCRF). Patients must be instructed not to take any medications, including 
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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:

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 P-gp 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 before
treatment initiation. COVID-19 vaccination should follow local guidances and regulations. 
Ideally, patients will have completed vaccination before treatment initiation. For patients 
enrolled in Phase 1, vaccination during Cycle 1 is not permitted because 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. COVID-19 vaccine should be captured 
as a concomitant medication. 
Additional concomitant medications and procedures are permitted during the study to prevent and 
actively manage AEs. Treatment of AEs with prohibited concomitant medications (except 
anticancer treatments) is allowed per the investigator’s judgment. In this situation, treatment with 
TAK-981 must be interrupted. Treatment with TAK-981 may be resumed, if the patients meets 
criteria for resuming treatment with TAK-981, once treatment with the prohibited medication is 
stopped and a washout period (7 days or 5 half-lives whichever is shorter) is completed. This 
situation requires discussion between the investigator and the medical monitor. Supportive 
measures consistent with optimal patient care may be given throughout the study.
8.5
Precautions and Restrictions 
Precautions and requirements for a safe TAK-981 administration are detailed in Section 8.1.
It is unknown what effects TAK-981 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 through defined 
periods during and after study treatment as specified below. If a female patient becomes pregnant 
during TAK-981 treatment, TAK-981 should be stopped, and the patient should be informed about
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the potential hazards to the fetus. If a male patient’s partner becomes pregnant during TAK-981 
treatment, she should be informed of the potential hazards to the fetus. In either case, the 
pregnancy should be followed until the final pregnancy outcome is known.
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 6 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.)
Male patients, even if surgically sterilized (ie, status post vasectomy) must agree to 1 of the 
following:

Agree to practice effective barrier contraception during the entire study treatment period and 
through 6 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.)
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.
8.6
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, G-CSF, 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. However, these agents should not be used in this study in 
a manner that would either help establish eligibility for the study or support escalation of study 
drug dose during dose escalation. If dose alterations are necessary as a result of the events detailed 
below, refer to Section 8.2.4.
In the sections below is 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. This 
guidance is not expected to replace investigator judgment in the management of AEs.
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8.6.1
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.
8.6.2
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) at the physician’s discretion until they are diarrhea-free for at 
least 12 hours. Fluid intake should be maintained to avoid dehydration.
8.6.3
Anemia, Thrombocytopenia, or Neutropenia
Please refer to Table 8.c 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. It 
should be noted that initiation of myeloid growth factors (eg, G-CSF) for patient enrolled in dose 
escalation are not allowed in Cycle 1 before confirmation of DLT. In case of a first event, a dose 
reduction is preferred over the usage of myeloid growth factors.
8.6.4
Infusion Site Care
Skin lesions, which may include inflammation or necrosis, represent a potential risk 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 ports is highly 
recommended. The 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.
8.6.5
Lymphopenia and Opportunistic Infection Prophylaxis
Because lymphopenia is an expected AE, patients may be at an increased risk of opportunistic 
pathogens. TAK-981 lymphopenia is expected to be fully reversible and limited in time, therefore 
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no antibiotic or antiviral primary prophylaxis is indicated. It is also not known if all lymphocyte 
populations or just a subset are affected. Follow up with standard hemograms and serial CD4/8 
counts will help to make clinical decisions about the risk of immunosuppression. However, in the 
event of long lasting lymphopenia, pneumocystis, or herpes zoster infection, prophylaxis can be 
started at investigator’s discretion.
8.6.6
IRRs
Although TAK-981 is not a biological, its immune activating properties may produce AEs in the 
category of IRRs. If they 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. The patient should be closely monitored until recovery of 
symptoms. The patient will be permanently discontinued from the trial 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 reaction treatment should be collected in the eCRF. If a patient presents 
signs and symptoms compatible with infusion reaction, and at investigator discretion, 
premedication can be instituted for the rest of the treatment.
8.6.7
CRS
CRS is a disorder characterized by fever, tachypnea, headache, tachycardia, hypotension, rash, 
and/or hypoxia caused by the release of cytokines. CRS should be diagnosed and managed 
following institutional guidelines. CRS should be graded following the ASTCT Consensus 
Grading for CRS [1]. Investigators should try to differentiate CRS syndrome from other IRRs. 
Recommendations for management of CRS are shown in Table 8.d and can be implemented at the 
investigator’s discretion.
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Table 8.d
CRS Management Recommendations and TAK-981 Dose Modification
ASTCT Consensus Grade 
CRS Management Recommendations and TAK-981 Dose Modification
Grade 1:
Fever a (≥38°C) 

Monitor fluid status.

Supportive care: antipyretics, analgesics. 
TAK-981 dosing

Continue TAK-981 at the same dose level.
Grade 2:
Fever a (≥38°C)
with hypotension not requiring 
vasopressors; 
and/or b requiring low-flow c nasal 
cannula 
As per Grade 1 and:

Closely monitor all organ functions, including cardiac function.

IV fluid bolus.

Supportive care.
TAK-981 dosing

Withhold TAK-981 until recovers to ≤Grade 1.

Once recovered, restart TAK-981 at the same dose level.
A maximum of 2 consecutive TAK-981 doses can be skipped; otherwise 
TAK-981 must be permanently discontinued.
Grade 3:
Fever a (≥38°C)
with hypotension requiring a 
vasopressor with or without 
vasopressin; 
and/or b 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.
TAK-981 dosing

Withhold TAK-981 until recovers to ≤Grade 1.

If recovered within 2 weeks, reduce TAK-981 by 1 dose level.
A maximum of 2 consecutive TAK-981 doses can be skipped; otherwise TAK-981 
must be permanently discontinued.
Grade 4:
Fever a (≥38°C)
with hypotension requiring multiple 
vasopressors (excluding vasopressin); 
and/or b 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.
TAK-981 dosing

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; ICU: intensive care unit; O2: supplemental oxygen.
ASTCT consensus grade adapted from Lee et. al. 2019[1]; CRS management recommendations are adapted from Neelapu et al, 
2018 [59] 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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8.12
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.
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, the advertisements 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 an open-label study. After written informed consent has been obtained and preliminary 
eligibility has been established, the study site will submit documentation supporting eligibility to 
the sponsor and obtain the sponsor’s approval to enroll the patient. Once the sponsor reviews and 
approves the patient for enrollment, the patient cohort and treatment group will be assigned via 
interactive response technology.
9.4
Study Procedures
9.4.1
Procedures for Phase 1 Dose Escalation and Phase 2 Cancer Treatment Expansion 
Cohorts
Patients will be evaluated at scheduled visits over the following study periods: screening, 
treatment, EOT visit, and follow-up visit, 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 
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visits. The timing of PK and pharmacodynamics assessment is specified in the SOE (Appendix A). 
Laboratory assessments and procedures may occur up to 3 days before the scheduled day due to 
extenuating circumstances (ie, inclement weather, holidays, vacations, or other administrative 
reasons). 
Refer to the SOE (Appendix A) for timing of assessments. Additional details are provided as 
necessary in the sections that follow.
9.4.1.1
Informed Consent
Each patient must provide written informed consent before any study-required procedures are 
conducted, unless those procedures are performed as part of the patient’s standard care.
9.4.1.2
Patient Demographics
The date of birth, race, ethnicity, and sex of the patient are to be recorded during screening.
9.4.1.3
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 9.4.1.9.
Any available pathology/cytogenetic/mutational and tumor genomic information for all patients 
should be reported in the eCRF.
9.4.1.4
Physical Examination
A physical examination will be completed per SOC at the times specified in the SOE 
(Appendix A). Any clinically relevant findings are to be documented.
9.4.1.5
Patient Height and Weight
Height and body weight will be measured at the times specified in the SOE (Appendix A).
9.4.1.6
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).
9.4.1.7
Vital Signs
Vital sign measurements, including systolic and diastolic blood pressure, heart rate, and 
temperature, will be assessed as specified in the SOE (Appendix A).
9.4.1.8
Pregnancy Test
A serum or urine pregnancy test will be obtained for women of childbearing potential at screening, 
Day 1 of each cycle, and at the EOT visit. The screening results must be available and negative 
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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.
9.4.1.9
Concomitant Medications and Procedures
Medications used by the patient and therapeutic procedures completed by the patient will be 
recorded in the eCRF from the time of informed consent through the EOT visit or the start of 
subsequent antineoplastic therapy, whichever occurs first. See Section 8.3 for a list of medications 
and therapies that are prohibited during the study.
9.4.1.10
AEs
Monitoring of AEs, serious and nonserious, will be conducted throughout the study as specified in 
the SOE (Appendix A). Refer to Section 10.0 for details regarding definitions, documentation, and 
reporting of AEs and SAEs.
9.4.1.11
Enrollment
Enrollment is defined as the time of initiation of the first dose of study drug.
Procedures for completing enrollment information are described in the study manual.
9.4.1.12
Posttreatment Follow-up
Patients in Phase 1 who discontinue study treatment for reasons other than disease progression will 
continue PFS follow-up every 12 (±1) weeks from the EOT visit for up to 12 months or until a 
discontinuation criterion is met (Section 9.7). Patients in follow-up will continue with disease 
assessment as described in Section 9.4.1.15. Follow-up visits for patients who discontinue study 
treatment for reasons other than disease progression (PFS follow-up) should be conducted at the 
site when possible.
Patients in Phase 2 who discontinue or complete treatment will be followed for survival every 12 
(±1) weeks from the EOT visit for up to 12 months after the last patient in the cohort discontinues 
or completes treatment, or until loss of follow-up, consent withdrawal, death, study termination, or 
until >70% of patients in the cohort have progressed, whichever occurs first. Patients who 
discontinue study treatment for reasons other than disease progression or initiation of new 
anticancer treatment will be followed for PFS and will continue with disease assessment as 
described in Section 9.4.1.15. Visits for patients in follow-up who have not progressed or initiated 
new anticancer treatment should be conducted at the site when possible. For patients who have 
who have progressed or initiated new anticancer treatment, survival status and collection of new 
anticancer therapy will be obtained remotely. For all patients, information on new anticancer 
therapy will be collected.
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9.4.1.14
Clinical Laboratory Evaluations
Clinical laboratory evaluations will be performed locally. Additional handling and shipment of 
clinical laboratory samples will be outlined in the study manual.
9.4.1.14.1
Chemistry, Hematology, Coagulation, Urinalysis, and Tumor Markers
Blood samples for analysis of the chemistry and hematology parameters (Table 9.a), urine samples 
for analysis of the parameters (Table 9.b), and tumor markers (Table 9.c) will be obtained as 
specified in the SOE (Appendix A). They will be performed locally only.
Table 9.a
Chemistry, Hematology, and Coagulation Tests
Hematology
Serum Chemistry
Coagulation
Hematocrit
Hemoglobin
Leukocytes with differential
Neutrophils
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
Urate
Activated partial thromboplastin time 
(aPTT)
Prothrombin time (PT)
Fibrinogen
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Table 9.b
Urinalysis Tests
Urinalysis
Bilirubin
Glucose
Ketones
Leukocytes
Nitrite
Occult blood
pH
Protein
Specific gravity
Turbidity and color
Urobilinogen
Microscopic analysis of urine sediment should be performed if significant abnormalities are 
detected in proteins, leukocytes, or blood.
Serum creatinine clearance is to be estimated by the Cockcroft-Gault formula [60] as follows:
	
 
	
 
		
 
= [(140 −
) ∗	() ] / [72 ∗
! 
	
(/")] 
For female patients, the result of the formula above should be multiplied by 0.85. 
Table 9.c
Serum Tumor Markers
Colon Cancer
Carcinoembryonic antigen (CEA)
Cancer antigen 19-9 (CA 19-9)
Cervical Cancer
Cancer antigen 15-3 (CA 15-3)
Cancer antigen 125 (CA 125)
Blood sample collection for tumor markers during Phase 2 only. 
9.4.1.14.2
Immunosafety Markers
Blood samples for the analysis of autoimmune endocrinopathies as shown in Table 9.d will be 
obtained as specified in the SOE (Appendix A). They will be performed locally only.
Table 9.d
Immunosafety Determinations in Serum
Serum Chemistry
Thyroid-stimulating hormone (TSH)
Free thyroxine (FT4)
Adrenocorticotropic hormone (ACTH)
9.4.1.15
Disease Assessment
Patients will undergo computed tomography (CT) and/or MRI scans, and 18fluorodeoxyglucose–
positron emission tomography (FDG-PET) imaging to assess disease response and progression, 
using RECIST v1.1 criteria for solid tumors [61] or the Lugano criteria for lymphoma response 
from the Cheson 2014 [62]. For this study CT and/or MRI scans should be acquired with at least 
IV contrast. CT scans of the chest, abdominal cavity, and pelvis will be obtained at screening. The 
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imaging modalities used for a patient should remain consistent throughout the study. If 
contrast-enhanced CT scans are contraindicated for a particular patient, a noncontrast CT of the 
chest, in addition to contrast-enhanced abdomen and pelvis MRIs should be acquired, if possible. 
Anatomical measurements (summed across target lesions) will be collected at baseline and each 
subsequent evaluation. In addition, nonmeasurable disease and new lesions will be documented 
and their status evaluated. For lymphoma patients FDG-PET imaging is required so that the avidity 
of the disease burden can also be scored according to the Lugano classification. Objective 
assessments of the disease burden (target, nontarget, and potential new lesions) will be performed 
at each time point as described in the SOE (Appendix A). Radiographic images will be maintained 
at the site and can be requested by the sponsor at a later date for centralized review of the images.
Bone scans should be collected as clinically indicated.
Imaging tests performed before the screening consent date, if of diagnostic quality, may be used as 
screening tests if the C1D1 is planned within the 28 days after the date of the test.
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9.4.1.16
Biomarker, Pharmacodynamic, and PK Samples
9.4.1.16.1
Primary Specimen Collection
The primary specimen to be collected are shown in Table 9.e. Collection of samples 
 
 are dependent on local guidelines and regulations (including feasibility of 
sample export), as well as IRB/independent ethics committee (IEC) approval.
Table 9.e
Primary Specimen Collection
Specimen Name in Schedule of 
Procedures
Primary 
Specimen
Primary 
Specimen 
Derivative 1
Primary 
Specimen 
Derivative 2
Description of 
Intended Use
Sample Collection
Archival (Banked) Tumor Tissue 
Sample
FFPE 
block
FFPE 
slides
DNA
RNA
Biomarker 
measurements
Required if sample is 
available
Fresh Tumor Tissue Biopsy Sample
Fresh 
tumor 
tissue
FFPE 
block/slides
DNA
RNA
Biomarker 
measurements
Mandatory during 
Phase 2 stage 1 a
Fresh Skin Tissue Biopsy Sample
Fresh Skin 
Tissue
FFPE block
FFPE slides
Biomarker 
measurements
Mandatory Phase 1 
only
Blood Sample for Flow Cytometry
Blood
Cells
Biomarker 
measurements
Mandatory Phase 1 
only
Blood Sample for TAK-981 PK
Blood
PK 
Measurements
Mandatory 
Plasma Sample for TAK-981 PK
Plasma
PK 
Measurements
Mandatory
Urine Sample for TAK-981 PK
Urine
PK 
Measurements
Mandatory b
; FFPE: formalin-fixed, paraffin-embedded; 
; PK:
pharmacokinetic.
a Except for Phase 2 stage 1, paired tumor biopsies are optional. 
b Whole blood and urine collection will only be collected in dose levels 60 mg and 120 mg.
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Once study has been completed, all study procedures outlined for the EOT visit will be completed 
as specified in the SOE (Appendix A).
The consequence of study withdrawal is that no new information will be collected from the 
withdrawn patient and added to the existing data or any database after the EOT visit 30 days after 
last dose is completed.
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 may be discontinued for any of the following reasons:

AE that leads to TAK-981 discontinuation.

Major protocol deviation.

Study terminated by sponsor.

Withdrawal by patient.

Lost to follow-up.

Death.

Progressive disease.

Occurrence of a DLT for patients in dose escalation (exceptions to this criterion may be made 
after discussion and agreement between the investigator and the sponsor based on the benefit 
and risk assessment). 

Symptomatic deterioration.

Initiation of another systemic anticancer treatment.

Treatment completion: the patient completes 1 year of treatment and continuation is 
not approved.

CR (after discussion with sponsor).

Lack of benefit.

Clinical progression.
The primary reason for study drug discontinuation will be recorded on the eCRF.
Note that some patients enrolled in Phase 1 dose escalation may discontinue study drug for reasons 
other than progressive disease before completing the full treatment course; these patients will 
remain in the study for posttreatment assessments as outlined in the SOE (Appendix A) until 
progressive disease occurs. All patients in Phase 2 will be followed for OS as outlined in the SOE 
(Appendix A).
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During Phase 1 dose escalation, patients who are withdrawn from treatment during Cycle 1 for 
reasons other than DLTs will be replaced. Patients will not be replaced during the Phase 2 part of 
the study.
In the case of study termination by the sponsor, eligible patients in dose escalation or cancer 
treatment expansion may have continued access to TAK-981 as described in Section 6.4.5. 
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.
10.0
ADVERSE EVENTS
10.1
Definitions
10.1.1
Pretreatment 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.
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
Is life-threatening (refers to an AE in which the patient was at risk of death at the time of the 
event. It does not refer to an event which hypothetically might have caused death if it were 
more severe).

Requires inpatient hospitalization or prolongation of an existing hospitalization (see 
clarification in the paragraph in Section 10.2 on planned hospitalizations).

Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions).

Is a congenital anomaly/birth defect.

Is a medically important event. This refers to an AE that may not result in death, be 
immediately life-threatening, or require hospitalization, but may be considered serious when, 
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 addition to the above examples, any event 
that the investigator considers to be medically important will be considered an SAE.
Note that any death, whether due to side effects of the treatment, progressive disease, or other 
causes, is considered an SAE.
Hospitalization for previously planned procedure or convenience will not be considered a 
reportable SAE. 
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 [1]. 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.
10.1.4
Adverse Events of Special Interest Definition
An adverse event of special interest (AESI) is an AE of scientific and medical concern specific to 
the compound or program for which ongoing monitoring and rapid communication by the 
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investigator to Takeda may be appropriate. Such events may require further investigation to 
characterize and understand them, and instructions regarding how and when AESIs should be 
reported to Takeda are provided in Section 10.2. CRS will be treated as an AESI.
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.
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 [1]. 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?
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AESI Reporting:
All AESIs regardless of seriousness or causality must be reported by the investigator to the sponsor 
within 72 hours of the investigator’s becoming aware of the event. This will be done by 
transmitting an EDC form. If the AESI meets any of the seriousness criteria mentioned in Section 
10.1.3, the event will be reported to the sponsor within 24 hours of the investigator’s becoming 
aware of the event. All nonserious AESIs are captured in only the clinical database.
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.

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). 

AESIs will be reported and monitored as stated in the SAE section.
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.
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 6 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.
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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
Contact
Email
TAK-981
Takeda
ctmcompliance@takeda.com 
Product complaints and medication errors in and of themselves are not AEs. If a product complaint 
or medication error results in an SAE, the SAE should be reported.
10.6
Safety Reporting to Investigators, IRBs, 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.
11.0
STUDY-SPECIFIC COMMITTEES
11.1
SMC
During Phase 1, an SMC composed of the principal investigators, study medical monitor, and 
sponsor safety monitor will regularly review safety data to ensure patients’ safety throughout the 
study and make decisions on dose escalation, safety lead-in, and continued enrollment. 
11.2
IDMC
For Phase 2 cancer treatment expansion cohort, an IDMC will be established to monitor safety and 
assess benefit/risk throughout the conduct of these portions 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 physicians 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 Phase 2 cancer treatment expansion cohorts. IDMC meetings will be held on a periodic 
basis as defined in the IDMC charter, at the end of each stage of the Phase 2, and for the interim 
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analysis for safety. Ad hoc IDMC meetings will be held to evaluate safety 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 
MedDRA. Drugs will be coded using the World Health Organization (WHO) 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.
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 its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed eCRFs 
are the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor.
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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 its designee. 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.
13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A statistical and analytical plan (SAP) for dose escalation and cancer treatment expansion will be 
prepared and finalized before database lock. This document will provide further details regarding 
the respective definition of analysis variables and analysis methodology to address all study 
objectives.
13.2
Phase 1 Dose Escalation and Phase 2 Cancer Treatment Expansion Cohorts
13.2.1
Analysis Sets
The analysis sets will include the following:
Safety analysis set: Patients who have received at least 1 dose, even if incomplete, of study 
drug will be used for all safety analyses and for some efficacy analyses.
PK analysis set: Patients with sufficient dosing and PK data to reliably estimate 1 or more PK 
parameters will be used for PK analyses.
DLT-evaluable analysis set: The DLT-evaluable analysis set will include patients in dose 
escalation who receive all Cycle 1 doses of TAK-981 without experiencing a DLT or who have 
a DLT during Cycle 1 of the study. The DLT-evaluable population will be used to determine 
the RP2D/MTD.
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13.2.3 Efficacy Analysis
13.2.3.1
Primary Efficacy Analysis 
Phase 1:
Efficacy is not the primary objective for this study in the Phase 1 portion. 
In the Phase 1 portion of this study, efficacy parameters such as ORR, DCR, DOR, TTR, TTP, and 
PFS will 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 response assessments based on RECIST v1.1 for solid tumors or Lugano 
classification for lymphomas [62]. The formal hypotheses (see Section 13.4.1) of ORR will be 
tested for each cancer type.
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 analysis set.
Estimates of the ORR (CR + PR) will be presented with 2-sided 95% exact binomial CIs.
13.2.3.2
Secondary Efficacy Analysis
ORR is a secondary efficacy endpoint for the Phase 1 portion only. Similarly, with the primary 
analysis for the Phase 2 portion, estimates of the ORR (CR + PR) will be presented with 2-sided 
95% exact binomial CIs.
Other secondary efficacy endpoints for both Phase 1 and Phase 2 portions include DCR, DOR, 
TTR, TTP, PFS, and OS.
DOR is the time from the date of first documentation of a PR or better to the date of first 
documentation of progressive disease for responders (PR or better). Responders without 
documentation of progressive disease will be censored at the date of last response assessment that 
is SD or better.
DCR is defined as the proportion of patients who achieve SD or better (determined by the 
investigator) >6 weeks during the study in the response-evaluable population.
TTR is defined as the time from the date of first study drug administration to the date of first 
documented PR or better by the investigator for responders. Patients without documentation of 
progressive disease will be censored at the date of the last response assessment that is PR or better.
TTP is defined as the time from the date of the first dose administration to the date of first 
documented progressive disease. Patients without documentation of progressive disease at the 
time of analysis will be censored at the date of last response assessment. Patients who take 
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alternative antineoplastic therapy before progression or who die during treatment will also be 
censored at the date of last response assessment. 
PFS is defined as the time from the date of the first dose administration to the date of first 
documentation of progressive disease or death due to any cause, whichever occurs first. Patients 
without documentation of progressive disease will be censored at the date of the last response 
assessment that is SD or better.
OS is defined as the time from the date of the first dose administration to the date of death. Patients 
without documentation of death at the time of analysis will be censored at the date last known to be 
alive. 
DOR, TTP, TTR, PFS and OS will be summarized descriptively using Kaplan-Meier method. 
TTP, PFS, and OS will be analyzed for the safety analysis set. DCR will be analyzed using a 
method similar to that used for ORR. 
13.2.4
PK Analysis
In Phase 1, 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.

AUClast.

AUC∞.

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 sparse PK data collected after Cycle 1 will be presented in listings and 
tabulated using summary statistics.
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.
13.2.5
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 
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13.2.8
Safety Analysis
Safety will be evaluated by the frequency of AEs, severity and types of AEs, and by changes from 
baseline in patients’ vital signs, weight, and clinical laboratory results using the safety analysis set. 
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 MedDRA 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 statuses 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. The number and percentage of patients with clinically significant laboratory values 
will also be tabulated as appropriate.
All concomitant medications collected from the first dose of study drug throughout the study 
period will be classified to preferred terms according to the WHO 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.
13.3
Interim Analysis 
The SMC will review accruing data to determine dose escalation and number of patients per cohort 
in the dose escalation phase (see Section 8.2.2). 
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13.4
Determination of Sample Size
13.4.1
Phase 1 Dose Escalation and Phase 2 Cancer Treatment Expansion Cohorts
It is anticipated that up to approximately 70 patients will be enrolled in Phase 1 (dose escalation) 
and up to approximately 132 patients will be enrolled in Phase 2 cancer treatment expansion 
cohorts. 
Dose Escalation Phase (Phase 1)
It is estimated that up to approximately 70 DLT-evaluable patients will be enrolled in this study for 
the dosing escalation of TAK-981 in Phase 1. A minimum of 3 patients per cohort will be enrolled 
in the starting dose cohort. In case of no DLT, an adaptive BLRM guided by the Escalation With 
Overdose Control principle will be used in successive escalation cohorts for purposes of dose 
escalation recommendations and estimation of the MTD. The logistic regression model will be 
adapted and updated after each group of patients enrolled in the current dose level cohort. For each 
dose level, the posterior probability of having DLT rates that fall into the following intervals will 
be estimated:

[0, 0.16): under-dosing.

[0.16, 0.33): target toxicity.

[0.33, 1.00]: excessive toxicity.
The selection of the next recommended dose will be determined from BLRM along consideration 
of other safety, clinical, PK, and pharmacodynamic data.
The details of the BLRM are included in Appendix G. The details of dose-escalation are specified 
in Section 8.2.2.
Efficacy Evaluation Phase (Phase 2)
Once the MTD/BED is defined, up to approximately 132 response-evaluable patients with 6 
specified types of solid tumors and lymphomas will be enrolled in parallel in a Phase 2 study to 
evaluate the efficacy of TAK-981.
The primary endpoint for the Phase 2 portion is ORR (CR + PR) as assessed by the investigator 
according to RECIST v1.1 [61] for patients with solid tumors and Lugano criteria [62] for patients 
with lymphoma. The sample size consideration for disease-specific patient populations is adaptive 
design based on Simon’s 2-stage design for a single proportion [63] with the following hypotheses 
of ORR.
For solid tumor cohorts A, B, and C and lymphoma cohort D (Figure 6.a):
The hypotheses for stage 1 are the following:
H0: ORR < p0 where p0 = 15%
H1: ORR ≥ p0 where p0 = 15%
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where p0 is a very low, undesirable ORR.
If H0 is rejected (and H1 is accepted) at stage 1, additional patients will be enrolled 
based on the number of responders in stage 1 and their data will be collected in the 
second stage.
The hypotheses at the end of stage 2 for a low desirable ORR, p1, are the following:
a) H1 is accepted at stage 1, and
b) H0: ORR ≤ p1 where p1 = 35%
H1: ORR > p1 where p1 = 35%
The hypotheses at the end of stage 2 for a high desirable response, p2, are the following:
a) H1 is accepted at stage 1, and
b) H0: ORR ≤ p2 where p2 = 45%
H1: ORR > p2 where p2 = 45%
Because it is desirable to have higher power for detecting more improvement of the new therapy 
(p2 versus p0), for solid tumor cohorts A, B, and C and lymphoma cohort D (Figure 6.a), assuming 
a power of 80% for high desirable response and 70% for low desirable response and 1-sided alpha 
of 0.1, the following number of patients is required for each cohort at each stage (Table 13.a).
Table 13.a
Sample Size for Each Cohort and Each Stage (Solid Tumor Cohorts A, B, 
and C and Lymphoma Cohort D)
Stage
Total Number of 
Patients in Each 
Cohort
1-Sided Alpha 
Level/Power
Stage 1
Stage 2 b
All cohorts
Low response at the end of stage 1
Number of patients
7
19
19
0.1/70%
Number of responses a
≥2 and ≤4
≥5
High response at the end of stage 1
Number of patients
7
13
13
0.1/80%
Number of responses
≥5
≥6
a Number of patients needed to respond to continue into stage 2 or have a positive result at the end of stage 2.
b Maximum number of patients required for each cohort and number of responders that should be presented at end 
of stage 2 in order to claim treatment effect.
For lymphoma cohorts E and F (Figure 6.a):
The hypotheses for stage 1 are the following:
H0: ORR < p0 where p0 = 45%
H1: ORR ≥ p0 where p0 = 45%
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where p0 is a very low, undesirable ORR.
If H0 is rejected (and H1 is accepted) at stage 1, additional patients will be enrolled 
based on the number of responders in stage 1 and their data will be collected in the 
second stage.
The hypotheses at the end of stage 2 for a low desirable ORR, p1, are the following:
a) H1 is accepted at stage 1, and
b) H0: ORR ≤ p1 where p1 = 65%
H1: ORR > p1 where p1 = 65%
The hypotheses at the end of stage 2 for a high desirable response, p2, are the following:
a) H1 is accepted at stage 1, and
b) H0: ORR ≤ p2 where p2 = 75%
H1: ORR > p2 where p2 = 75%
Similarly, for lymphoma cohorts E and F, assuming a power of 80% for high desirable response 
and 70% for low desirable response and 1-sided alpha of 0.1, the following number of patients is 
required for each cohort at each stage (Table 13.b).
Table 13.b
Sample Size for Each Cohort and Each Stage (Lymphoma Cohorts E and F)
Stage
Total Number of 
Patients in Each 
Cohort
1-Sided Alpha 
Level/Power
Stage 1
Stage 2 b
All cohorts
Low response at the end of stage 1
Number of patients
10
28
28
0.1/70%
Number of responses a
≥6 & ≤7
≥16
High response at the end of stage 2
Number of patients
10
16
16
0.1/80%
Number of responses
≥8
≥9
a Number of patients needed to respond to continue into stage 2 or have a positive result at the end of stage 2.
b Maximum number of patients required for each cohort and number of responders that should be presented at end 
of stage 2 in order to claim treatment effect.
14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. If monitors are not allowed to visit sites for data verification 
due to pandemic (eg, coronavirus disease 2019 [COVID-19]), remote electronic medical records 
access visits may be made (where allowed by sites). Source documents will be reviewed for 
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verification of data recorded on the eCRFs. Source documents are defined as original documents, 
data, and records. The investigator and institution guarantee access to source documents by the 
sponsor or its designee and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or designee, 
including but not limited to the investigator’s binder, study medication, subject medical records, 
informed consent documentation, documentation of subject authorization to use personal health 
information (if separate from the ICFs), and review of eCRFs and associated source documents. It 
is important that the investigator and other study personnel are available during the monitoring 
visits and that sufficient time is devoted to the process.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB as required) to determine the appropriate course of action. There will be no 
exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
The site should document all protocol deviations in the subject’s source documents. In the event of 
a significant deviation, the site should notify the sponsor or its designee (and IRB or ethics 
committee, as required). Significant deviations include, but are not limited to, those that involve 
fraud or misconduct, increase the health risk to the subject, or confound interpretation of 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 US Food and Drug Administration [FDA], the United 
Kingdom Medicines and Healthcare Products Regulatory Agency, the Pharmaceuticals and 
Medical Devices Agency of Japan). If the study site is contacted for an inspection by a regulatory 
body, the sponsor should be notified immediately. The investigator and institution guarantee 
access for quality assurance auditors to all study documents as described in Section 14.1.
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 
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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 must be constituted according to the applicable state and federal requirements of each 
participating region. The sponsor or designee will require documentation noting all names and 
titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC has 
direct participation in this study, written notification regarding his or her abstinence from voting 
must also be obtained. Those American sites unwilling to provide names and titles of all members 
because of privacy and conflict of interest concerns should instead provide a Federal wide 
Assurance number or comparable number assigned by the US Department of Health and Human 
Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the 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 for approval. The 
IRB’s written approval of the protocol and subject informed consent must be obtained and 
submitted to the sponsor or designee before commencement of the study, ie, before shipment of the 
sponsor-supplied drug or study-specific screening activity. The IRB approval must refer to the 
study by its exact protocol title, number, and version date; identify versions of other documents 
(eg, ICF) reviewed; and state the approval date. If required by country or regional regulations or 
procedures, approval from the competent regulatory authority will be obtained before 
commencement of the study or implementation of a substantial amendment. The sponsor will ship 
drug 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. This may include 
notification to the IRB 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. All IRB and IEC approvals and relevant 
documentation for these items must be provided to the sponsor or its designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor.
15.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The ICF, subject authorization form (if applicable), and subject 
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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 
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.
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15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, US FDA, the United Kingdom’s Medicines and Healthcare products 
Regulatory Agency, Japan’s Pharmaceuticals and Medical Devices Agency), the sponsor’s 
designated auditors, and the appropriate IRBs and IECs to review the subject’s original medical 
records (source data or documents) including, but not limited to, laboratory test result reports, 
ECG reports, admission and discharge summaries for hospital admissions occurring during a 
subject’s study participation, and autopsy reports. Access to a subject’s original medical records 
requires the specific authorization of the subject as part of the informed consent process (see 
Section 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.
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 
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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 or other publicly accessible 
websites (including the Takeda corporate site) and registries, as required by Takeda 
policy/standards, applicable laws, and/or regulations. 
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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56. Guidance for Industry: S9 Nonclinical Evaluation for Anticancer Pharmaceuticals. U.S. 
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Appendix A
SOE
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Table A-1
SOE for Phase 1 Dose Escalation Treatment Cycles (21-Day Cycle)
Cycle
Cycle 1
Cycle 2
Cycle 3 and Subsequent 
Cycles
EOT 
b
PFS
Follow-up c
Day
Screening a
1
2
3
4
8
9
11
15
1
4
8
11
15
1
4
8
11
15
Informed consent
X
Inclusion/exclusion 
criteria
X
Demographics
X
Medical history
X
Physical examination d
X
Symptom-directed 
physical examination e
X
X
X
Height
X
Weight
X
X
X
X
ECOG performance 
status
X
X
X
X
X
Vital signs f
X
X
X
X g
X
X g
X h
X
X g
X
X g
X h
X
X g
X
X g
X h
X
12-Lead safety ECG i
X
X2
X
Echocardiography/MUG
A (LVEF) scan k
X
X
X
X
Concomitant 
medications and 
procedures
Recorded from the signing of ICF through 30 days after the last dose of study drug or the start of subsequent anticancer therapy, 
whichever occurs first.
X
AE reporting
AEs will be recorded from the signing of ICF through 30 days after the last dose of study drug or start of subsequent anticancer 
therapy.
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
X
Samples/Laboratory Assessments
Pregnancy test l
X
X
X
X
X
Hematology/chemistry m
X
X
X g
X
X g
X
X g
X
X g
X
X g
X
X g
X
Coagulation m
X
X
X
X
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Cycle
Cycle 1
Cycle 2
Cycle 3 and Subsequent 
Cycles
EOT 
b
PFS
Follow-up c
Day
Screening a
1
2
3
4
8
9
11
15
1
4
8
11
15
1
4
8
11
15
Urinalysis m
X
X
X g
X
X g
X
X g
X
X g
X
X
Immunosafety markers 
(hormones) n
X
X
X
Whole blood sample for 
adducts/conjugates (flow 
cytometry) o
X
X
X
X p
X p
Urine collection for PK 
assessment q
X
X
Disease Assessment and Procedures
Disease assessment r
X
Every 8 weeks ±7 days (from C1D1 for the first 6 months and every 12 weeks ±7 days thereafter
X s
X t
Tissue Samples
Fresh skin punch biopsy u
X
X
Fresh tumor tissue biopsy
v
X
X
Banked tumor tissue w
X
Study Drug Administration
TAK-981 administration 
x
X
X g
X
X g
X h
X
X g
X
X g
X h
X
X g
X
X g
X h
AE: adverse event; COVID-19: coronavirus disease 2019; CT: computed tomography; CxDx: Cycle x, Day x; DLT: dose-limiting toxicity; ECG: electrocardiography; ECOG: 
Eastern Cooperative Oncology Group; eCRF: electronic case report form; EOT: end-of-treatment; FDG-PET: 18fluorodeoxyglucose–positron emission tomography; ICF: informed 
consent form; MRI: magnetic resonance imaging; MUGA: multiple-gated acquisition; PFS: progression-free survival; PK: pharmacokinetics; LVEF: left ventricular ejection fraction; 
MUGA: multiple-gated acquisition; RECIST v1.1: Response Evaluation Criteria in Solid Tumors Version 1.1; SAE: serious adverse event; SOE: schedule of events; X2: assessment 
performed twice.
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m Hematology, chemistry, coagulation tests, and urinalysis may be performed up to 3 days prior to C1D1 during the screening period unless otherwise notified. From C1D4 onwards, 
hematology, chemistry, and coagulation tests and urinalysis may be performed 24 hours before the visit. From Cycle 3 onwards, urine tests will be taken only the first day of each 
cycle and at end-of-treatment. For specifics, see Section 9.4.1.14.1.
n Immunosafety determinations include thyroid-stimulating hormone, free thyroxine, and adrenocorticotropic hormone measured in blood on C1D1 and repeated at the beginning of 
each cycle from C3 until C6, every other cycle afterwards, and at the EOT.
o Time points for blood and plasma samples for candidate biomarkers will be collected as specified in Table A-3.
p Samples will be collected on Cycles 3, 6, and 9 only.
q Time points for plasma, whole blood, and urine samples for PK analysis will be collected as specified in Table A-2. Whole blood and urine only to be collected from patients enrolled 
in dose levels 60 mg and 120 mg, in the Day 1, Day 4, Day 8 and Day 11 every 21 days, dosing schedule.
r A baseline contrast-enhanced CT or MRI scan of the chest, abdomen, and pelvis in addition to an FDG-PET scan for lymphoma patients must be acquired at screening. 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. Contrast-enhanced CT or MRI and 
FDG-PET (for lymphoma patients) should be performed every 8 weeks (±7 days) from C1D1 for the first 6 months and every 12 weeks (±7 days) thereafter, or more frequently if 
clinically indicated. Imaging timing should follow calendar days and should not be adjusted for delays in cycle starts (ie, administration of TAK-981) The same imaging modality 
(contrast-enhanced CT or MRI and FDG-PET scan) should be used on a patient as at the screening visit and throughout the study. Bone scans may be performed on patients as 
clinically indicated. See Section 9.4.1.15. Response will be determined according to RECIST v1.1 for patients with solid tumors or Lugano criteria for patients with lymphoma.
s At EOT, tumor assessments will be performed only on patients who have not previously demonstrated disease progression in the study unless completed within the previous 
4 weeks.
t During PFS follow-up, disease assessment will be performed every 12 weeks (±7 days), or more frequently if clinically indicated. See Section 9.4.1.15. 
u The skin punch at screening should be performed within 14 days before the first dose of study drug on C1D1 for all patients in the Phase 1 cancer dose-escalation portion of the study. 
The C1D8 skin punch biopsy should be done 2 (±1) hour after the end of TAK-981 infusion. A decision to stop skin punch biopsies collection may take place should sufficient data 
related to target engagement and SUMO2/3 inhibition be generated.
v Screening and on-treatment paired tumor biopsies are encouraged but optional for patients enrolled during Phase 1. The screening/pretreatment tumor tissue biopsy should be 
performed at least 2 days after the last dose of any prior antineoplastic therapy and within 14 days before the first dose of drug. On-treatment tumor biopsies should be collected on 
C2D8 (+7 days). Refer to Section 9.4.1.16.3 for details.
w Banked formalin-fixed paraffin-embedded tumor tissue or unstained slides of the tumor tissue. Please refer to Section 9.4.1.16.3 for details.
x Initially, TAK-981 will be administered intravenously on Days 1, 4, 8, and 11 of a 21-day cycle. Less intensive schedules of TAK-981 (eg, on Day 1, or Day 1 and Day 8, or Day 1, 
Day 8, and Day 15 every 21 days). For the first infusion (C1D1) of TAK-981 during dose escalation, every patient needs to be hospitalized for drug administration and overnight 
observation. The patient can be discharged from overnight observation (a minimum of 18 hours after the end of infusion) only if there are no signs and symptoms of acute toxicity, 
such as fever or significant changes in blood pressure and/or heart rate. Hospitalization is not required if the patient is part of an expanded dose cohort after the first 3 patients in a dose 
level or expansion of a previously cleared dose level and if the infusion reaction risk is considered low based on previous experience. 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. For patients in the DLT-evaluation period 
(Cycle 1) a maximum of 1 dose reschedule is allowed. At least 72 hours should elapse between consecutive doses of TAK-981. For further details on TAK-981 administration, refer 
to Section 8.1.
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Table A-4
SOE for Phase 2 Cancer Treatment Expansion Cohorts Treatment Cycles (21-Day Cycle)
Cycle
Cycle 1
Cycle 2
Cycle 3 and Subsequent Cycles
EOT 
b
Survival
Follow-up c
Day
Screening a
1
2
3
4
8
9
11
15
1
4
8
11
15
1
4
8
11
15
Informed consent
X
Inclusion/exclusion 
criteria
X
Demographics
X
Medical history 
X
X
Survival Status
X
Next anticancer treatment
X
Physical examination d
X
Symptom-directed 
physical examination e
X
X
X
Height
X
Weight
X
X
X
X
ECOG performance status
X
X
X
X
X
Vital signs f
X
X
X g
X
X g
X h
X
X g
X
X g
X h
X
X g
X
X g
X h
X
12-Lead safety ECG i
X
X2
X2
X2
X2
X2
X
Echocardiography/MUG
A (LVEF) scan j
X
X
X
X
Monitoring of 
concomitant medications 
and procedures
Recorded from the signing of ICF through 30 days after the last dose of study drug or the start of subsequent anticancer therapy, 
whichever occurs first
X
AE reporting
AEs will be recorded from the signing of ICF through 30 days after the last dose of study drug or start of subsequent anticancer 
therapy.
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
X
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Cycle
Cycle 1
Cycle 2
Cycle 3 and Subsequent Cycles
EOT 
b
Survival
Follow-up c
Day
Screening a
1
2
3
4
8
9
11
15
1
4
8
11
15
1
4
8
11
15
Samples/Laboratory Assessments
Pregnancy test k
X
X
X
X
X
Hematology/chemistry l
X
X
X
X
X
Coagulation l
X
X
X
X
Urinalysis l
X
X
X
X
X
Tumor markers l
X
X
X
Immunosafety markers 
(hormones) m
X
X
X
Plasma samples for PK
X
X
X
X
X
Disease Assessment and Procedures
Disease assessment r
X
Every 8 weeks ±7 days (from C1D1 for the first 6 months and every 12 weeks ±7 days thereafter
X s
X t
Tissue Samples
Fresh tumor tissue biopsy 
u
X
X
Banked tumor tissue v
X
Study Drug Administration
TAK-981 administration 
w
X
X g
X
X g
X h
X
X g
X
X g
X h
X
X g
X
X g
X h
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AE: adverse event; 
; COVID-19: coronavirus disease 2019; CT: computed tomography; CxDx: Cycle x, Day x; ECG: electrocardiogram, electrocardiographic, 
electrocardiography; ECOG: Eastern Cooperative Oncology Group; eCRF: electronic case report form; EOT: end-of-treatment; FDG-PET: 18fluorodeoxyglucose–positron emission 
tomography; ICF: informed consent form; LVEF: left ventricular ejection fraction; MRI: magnetic resonance imaging; MUGA: multiple-gated acquisition; 
 
; PK: pharmacokinetics; RECIST v1.1: Response Evaluation Criteria in Solid Tumors Version 1.1; SAE: serious adverse event; SOE: schedule of events; 
X2:, assessment performed twice.
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 Laboratory assessments and procedures may occur up to 3 days before the scheduled day due to extenuating circumstances (ie, inclement weather, holidays, 
vacations, or other administrative reasons). 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.
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 discontinue TAK-981 treatment early should complete the EOT visit 30 (+10) days after the last dose of TAK-981 or before starting a new systemic treatment. See 
Section 9.6.
c Patients who discontinue or complete treatment will be followed for survival every 12 (±1) weeks from the EOT visit for up to 12 months after the last patient in the cohort 
discontinues or completes treatment, or until loss of follow-up, consent withdrawal, death, study termination, or until > 70% of patients in the cohort have progressed, whichever 
occurs first. Patients who discontinue study treatment for reasons other than disease progression or initiation of new anticancer treatment will be followed for PFS and will continue 
with disease assessment as described in Section 9.4.1.15 and in the SOE; follow-up visits for patients these patients should be conducted at the site when possible. For patients who 
have who have progressed or initiated new anticancer treatment, survival status and collection of new anticancer therapy will be obtained remotely. See Section 9.7. 
d Complete physical exam at screening. If a complete physical exam was performed more than 3 days before C1D1, the exam should be performed again.
e The symptom-directed physical examination will be conducted within 3 days before dosing on Day 1 of each treatment cycle and at the EOT/early termination visit. The 
symptom-directed physical examination may be performed at other visits during the treatment cycle at the discretion of the investigator.
f On C1D1,vital signs (blood pressure, heart rate, and temperature) will be measured and documented immediately before the start of the infusion and immediately after the end of 
infusion. Patients will be monitored for up to 4 hours after the end of infusion. Outside C1D1, vitals will be monitored immediately before the start of infusion and after the end of 
infusion, and if no infusion reaction is observed, patients will be discharged from the site per investigator discretion Blood pressure should be determined with the patient in a supine 
position after the patient has been quiet for 5 minutes.
g For patients enrolled on a less dense schedule (eg, TAK-981 on Day 1, or Day 1 and Day 8, or Day 1, Day 8, and Day 15 every 21 days), this test, procedure, or dosing may not be 
performed.
h For patients enrolled in the Day 1, Day 8, and Day 15 every 21 days only, this test or procedure must be performed.
i Single safety ECGs will be collected at screening, pre-TAK-981 dose and post-TAK-981 EOI (+1-h window) on Days 1 and 8 of Cycle 1 and Cycle 2. From Cycle 3 onward,
pre-TAK-981 dosing and post-TAK-981 EOI (+1-h window) ECGs will be collected on Day 1 of every other cycle. 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.
j The MUGA (LVEF) scan should be performed at screening to ensure patient eligibility. Echocardiographic estimate of the LVEF can be measured as an alternative to MUGA scans. 
From C3 onwards, the assessment of LVEF will be repeated every 3 cycles and at EOT. From C3 onwards, a ±7-day window is allowed for this test. 
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k A serum or 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 is administered (ie, 
within the 3 days before C1D1), or as otherwise required by local regulations. From C2 onwards, serum or urine pregnancy test will be performed on Day 1 of each cycle and at the 
EOT visit.
l Hematology, chemistry, coagulation, tumor markers (CEA and CA 19-9 in colon cancer patients, CA 15-3 and CA 125 in cervical cancer patients), and urinalysis may be performed 
up to 3 days prior to C1D1 during the screening period unless otherwise notified. From C2 onwards, hematology, chemistry, tumor markers, coagulation tests and urinalysis may be 
performed 24 hours before the visit. For specifics, see Section 9.4.1.14.1
m Immunosafety determinations include thyroid-stimulating hormone, free thyroxine, and adrenocorticotropic hormone measured in blood on C1D1 and repeated at the beginning of 
each cycle from C3 until C6, every other cycle afterwards, and at the EOT.
 
o Samples will be collected on Cycles 3, 6, and 9 only.
p Samples will be collected on Cycle 3 only.
q Time points for samples for PK analysis will be collected as specified in Table A-5. 
r A baseline contrast-enhanced CT or MRI scan of the chest, abdomen, and pelvis in addition to an FDG-PET scan for lymphoma patients must be acquired at screening. 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. Contrast-enhanced CT or MRI and 
FDG-PET (for lymphoma patients) should be performed every 8 weeks (±7 days) from C1D1 for the first 6 months and every 12 weeks (±7 days) thereafter, or more frequently if 
clinically indicated. Imaging timing should follow calendar days and should not be adjusted for delays in cycle starts (ie, administration of TAK-981). The same imaging modality 
(contrast-enhanced CT or MRI and FDG-PET scan) should be used on a patient as at the screening visit and throughout the study. Bone scans may be performed on patients as 
clinically indicated. See Section 9.4.1.15. Response will be determined according to RECIST v1.1 for patients with solid tumors or Lugano criteria for patients with lymphoma.
s At EOT, tumor assessments will be performed only on patients who have not previously demonstrated disease progression in the study unless completed within the previous 
4 weeks.
t Patients in PFS follow-up (patients who discontinued treatment for any reason other than disease progression or new anticancer treatment), disease assessment will be performed 
every 12 weeks (±7 days), or more frequently if clinically indicated. See Section 9.4.1.15.
u Screening and on-treatment paired tumor biopsies are mandatory for patients enrolled during Phase 2 Stage 1 of the study and are encouraged from (but optional for) patients 
enrolled during Phase 2 stage 2 of the study. The screening/pretreatment tumor tissue biopsy should be performed at least 2 days after the last dose of any prior antineoplastic therapy 
and within 14 days before the first dose of study drug. On-treatment tumor biopsies should be collected on C2D8 (+7 days). Refer to Section 9.4.1.16.3 for details.
v Banked formalin-fixed paraffin-embedded tumor tissue or unstained slides of the tumor tissue. Please refer to Section 9.4.1.16.3 for details.
w TAK-981 will be administered in a 21-day cycle at the dose level and dosing schedule determined at the end of Phase 1. TAK-981 will be administered on Day 1; Days 1 and 8; or 
Days 1, 4, 8, and 11. 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. At least 72 hours should elapse between consecutive doses of TAK-981. For further details on TAK-981 administration, refer to Section 8.1.
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Table A-5
Phase 2 Cancer Treatment Expansion Cohorts: Plasma PK Sampling Schedule
Cycle 1
Cycle 2
Day 1
Day 4
Day 8
Day 1
Day 8
PK (Plasma)
PK (Plasma)
PK (Plasma)
PK (Plasma)
PK (Plasma)
Before TAK-981 dose (within 1 h before the start of 
infusion)
X
X
X
X
X
End of TAK-981 infusion (10 min)
X
X a
X
X
X
2 h after end of TAK-981 infusion (30 min)
X
X
X
4 h after end of TAK-981 infusion (30 min)
X
X
PK: pharmacokinetic.
a If TAK-981–related cumulative toxicity, PK, or pharmacodynamics support the modification of TAK-981 dosing from Days 1, 4, 8, and 11 every 21 days to Day 1, or Day 1 and 
Day 8, or Day 1, Day 8, and Day 15 of every 21-day dosing cycle, this test or procedure should not be performed.
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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 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 that conform to 
21 Code of Federal Regulations (CFR) Part 56, ICH, and local regulatory requirements.
7. Ensure that the IRB will be responsible for initial review, continuing review, and approval of 
the protocol. Promptly report to the IRB 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, and issue 
a final report within 3 months of study completion.
8. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH, and local 
regulations, are met.
9. Obtain valid informed consent from each 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. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents.
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11. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
12. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor.
13. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.
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Appendix C
Investigator Consent to Use of Personal Information
Takeda will collect and retain personal information of the investigator, including his or her name, 
address, and other identifying personal information. In addition, the investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, US, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
The investigator’s personal information may be retained, processed, and transferred by Takeda 
and these other parties for research purposes including the following:

Assessment of the suitability of the investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
The investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in the investigator’s 
own country.
The investigator acknowledges and consents to the use of his or her personal information by 
Takeda and other parties for the purposes described above.
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Appendix D
ECOG Scale for Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all predisease performance without restriction.
1
Symptoms but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to 
carry out work of a light or sedentary nature (eg, light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry out any work 
activities. Up and about more than 50% of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair.
5
Dead.
Source: Oken et al, 1982 [64].
ECOG: Eastern Cooperative Oncology Group.
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Appendix E
Drugs that Interact With the CYP3A Family of CYPs
Drugs listed in the table that are strong or moderate inducers or inhibitors of the CYP3A family of 
CYPs are 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
cobicistat
danoprevir and ritonavir
elvitegravir and ritonavir
grapefruit juice
indinavir and ritonavir
itraconazole
ketoconazole
lopinavir and ritonavir
paritaprevir and ritonavir and (ombitasvir and/or 
dasabuvir)
posaconazole
ritonavir
saquinavir and ritonavir
telaprevir
tipranavir and ritonavir
telithromycin
troleandomycin
voriconazole
clarithromycin
idelalisib
nefazodone
nelfinavir
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Drugs Inducing or Inhibiting CYP3A Metabolism That Are Prohibited Concomitant 
Medications With TAK-981
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 P450.
a Reference: 
fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-in
ducers#table3-3 (accessed 13 October 2021).
b Reference: 
fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-in
ducers#table3-2 (accessed 13 October 2021).
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Appendix F
Examples of Clinical Inhibitors of P-gp
Drugs listed below that are inhibitors of P-gp are prohibited as concomitant medications with 
TAK-981. 
Transporter
Gene
Inhibitor
P-gp
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/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors
-and-inducers#table5-2 (accessed 13 October 2021)..
P-gp: P-glycoprotein.
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Appendix G
BLRM (for Phase 1 Dose Escalation and Phase 2 Cancer Expansion Cohorts)
It is anticipated that up to approximately 132 patients will be enrolled including up to 
approximately 70 patients in Phase 1 (dose escalation) and up to approximately 132 patients in the 
6 expansion cohorts in Phase 2 to evaluate the efficacy in patients with select solid tumors and 
lymphoma.
An adaptive BLRM with overdose control will be used to guide dose escalation. BLRM guided by 
Escalation With Overdose with Control principle [65,66] 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- .
)
.
/01
2, * > 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 (0.01,0.02, 0.05, 0.08, 0.1, 0.12, 0.2, 0.25, 0.3, 
and 0.6) at provisional dose levels (3, 6, 10, 15, 25, 40, 60, 90, 120, and 160 mg), as described in 
Neuenschwander 2008 [65]. 
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 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 8.2.2.
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 the following table.
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Dose Escalation Simulation Study of the Probability of Dose-Limiting Toxicity 
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 following table shows the operating characteristic results. 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 35.3% and 50.3%,
respectively. In Scenario 1, the average number of patients required is approximately 32 with 
1.7 DLTs expected on average. The true DLT rates in Scenarios 2 increase faster than Scenario 1 
but are still all below 0.33, and the BLRM has 74.8% chance of successfully recommending target 
dose levels. The average number of patients required is approximately 31, with approximately 3.1 
DLTs expected on average. In Scenario 3, there is 6.2% chance of recommending a lower dose as 
MTD, 90.2% chance of successfully recommending target dose levels. The average number of 
patients required is approximately 28, with approximately 4.6 DLTs expected on average. In 
Scenario 4, with further faster increase of DLT rate over doses, there is a 73.2% probability of 
recommending target dose levels, whereas the probability of recommending toxic doses is 11.8%. 
The average number of patients required is approximately 23 with 5.3 DLTs expected on average. 
In Scenario 5, there is 48.3% chance of claiming the target doses as MTD, 10.8% chance of 
recommending a toxic dose, and approximately 40.9% chance of claiming all doses are toxic. Most 
of the patients (approximately 72.0%) do not receive doses above the MTD dose. The average 
number of patients required is approximately 13 with 4.4 DLTs expected on average. In Scenario 6 
when all doses are toxic, there is a 91.6% chance of successfully claiming all doses are toxic. The 
average number of patients required is approximately 6 and 3 DLTs are expected on average.
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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
32.0
1.7
2
25.2%
74.8%
NA
72.5%
27.5%
NA
31.0
3.1
3 
6.2%
90.2%
3.6%
45.5%
51.2%
3.7%
27.9
4.6
4 (a)
11.8%
73.2%
11.8%
33.1%
53.3%
13.6%
22.9
5.3
5 (b)
NA
48.3%
10.8%
NA
72.0%
28.0%
13.4
4.4
6 (c)
NA
NA
8.4%
NA
NA
100%
6.1
3.1
BLRM: Bayesian logistic regression modeling; DLT: dose-limiting toxicity; MTD: maximum tolerated dose.
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 3.2% to claim all doses are toxic.
b Probability of 40.9% to claim all doses are toxic.
c Probability of 91.6% to claim all doses are toxic.
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 the following table to illustrate how 
BLRM guides dose escalation.
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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
3
1
10
3
0
15
4
3
3
0
6
3
1
10
3
0
15
3
2
10
5
3
3
0
6
3
1
10
6
2
15
3
2
6
6
3
3
0
6
6
1
6 mg is claimed as the MTD
10
6
2
15
3
2
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.
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Appendix H
Examples of QTc Interval Prolonging Agents (Phase 1 Only)
The use of the following drugs known to prolong QTc interval are prohibited during Phase 1. In 
Phase 2, patients taking such medications need not to discontinue if their baseline QTcF <480 
msec.
Drug Class
Examples of Drugs that Increase the 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 (Caprelsaa)
Antidepressant
citalopram (Celexa)
Antiemetic
domperidone (Motilium)
droperidol (Inapsine)
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)
GI stimulant/heartburn
cisapride (Propulsid)
Opiate agonist
levomethadyl (Orlaam)
methadone (Dolophine, Methadose)
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Appendix I
Protocol History
Date
Amendment Number
Amendment Type
Region
09 November 2021
Amendment 7
Substantial
Global
14 December 2020
Amendment 6
Substantial
Global
28 August 2020
Amendment 5
Substantial
Global
10 April 2020
Amendment 4
Substantial
United States and Canada
31 March 2020
Amendment 3
Substantial
United States and Canada
26 March 2019
Amendment 2
Substantial
United States and Canada
10 July 2018
Amendment 1
Nonsubstantial
United States and Canada
07 May 2018
Initial protocol
Not applicable
United States and Canada
Rationale for Amendment 6 
This section describes the changes to the protocol incorporating Amendment 6. 
The primary reason for this amendment was to address the United States (US) Food and Drug 
Administration (FDA) request to remove coronavirus disease 2019 (COVID-19) expansion 
cohort. 
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification and administrative purpose only.
Protocol Amendment 6 
Summary of Changes Since Last Version of the Approved Protocol
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
The study title on the title page
Section 2.0 STUDY SUMMARY
Removed details of COVID-19 
population from study title. 
Change made to incorporate FDA 
feedback to remove COVID-19 
expansion.
Section 2.0 STUDY SUMMARY
Change in number of sites.
The study will be conducted in 
approximately 60 sites globally.
Section 4.1 Immunotherapy in 
Cancer
Section 4.2 Background
Section 4.2.1 Nonclinical 
Pharmacology
Section 4.2.4 Preliminary Clinical 
Experience 
Section 4.3 Rationale for the 
Proposed Study
Updated clinical and nonclinical 
data.
Section updated to align with data 
provided in latest Investigator 
Brochure (IB) (Edition 3).
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Protocol Amendment 6 
Summary of Changes Since Last Version of the Approved Protocol
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
Section 4.3 Rationale for the 
Proposed Study
Removed rationale for use of 
TAK-981 in patients with locally 
advanced or metastatic solid tumors 
or relapsed/refractory hematologic 
malignancies with COVID-19. Also 
removed complete subsection on 
rationale for COVID-19 expansion.
Change made to incorporate FDA 
feedback to remove COVID-19 
expansion.
Section 2.0 STUDY SUMMARY
Section 4.3.1 Rationale for the 
Starting Dose and Schedule
Section 6.1.1 Phase 1 Dose 
Escalation
Appendix A SOE
Added less intensive TAK-981 
dosing schedule of Day 1, Day 8, and 
Day 15 in 21-day cycle.
To provide more clarity on potential 
change in cycles in patients with 
clinical benefit. 
Section 2.0 STUDY SUMMARY
Section 5.1 Objectives
Section 5.2 Endpoints
Section 6.1 Overview of Study 
Design
Section 6.2 Number of Patients
Section 6.4 Duration of Study
Section 7.0 STUDY POPULATION
Section 8.0 STUDY DRUG
Section 9.4 Study Procedures
Section 11.0 STUDY-SPECIFIC 
COMMITTEES
Section 13.0 STATISTICAL 
METHODS
Section 16.0 REFERENCES
Appendix A SOE
Removed COVID-19 expansion 
details from all the sections of the 
protocol, references, and appendices.
Change made to incorporate FDA 
feedback to remove COVID-19 
expansion.
Section 2.0 STUDY SUMMARY
Section 6.1 Overview of Study 
Design
Section 6.2 Number of Patients
Increased number of subjects in 
dose-escalation phase.
Change incorporated to facilitate 
testing of alternative dosing 
schedules in dose escalation phase.
Section 2.0 STUDY SUMMARY
Section 6.1 Overview of Study 
Design
For Phase 2 cancer treatment 
expansion, revised population for 
Cohort E (relapsed/refractory 
DLBCL that have not received prior 
cellular therapy).
To align with the pre-existing 
inclusion criterion.
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Protocol Amendment 5
Summary of Changes Since Last Version of the Approved Protocol
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
Title page
Section 2.0: STUDY SUMMARY
Addition of EudraCT number.
EudraCT number is obtained as a part 
of plan to expand the study conduct 
globally. 
Section 1.2 Approval
Changed the name of 1 signatory.
To update the document with the 
current Takeda function that is 
accountable for the study protocol.
Section 2.0: STUDY SUMMARY
Change in number of sites.
The study will be conducted in 
approximately 50 sites globally.
Section 4.1: Immunotherapy in 
Cancer
Added background information 
about immunotherapy in cancer, 
solid tumors (lung cancer, cervical 
cancer, colorectal cancer), and 
non-Hodgkin lymphoma (NHL) 
(indolent NHL, aggressive NHL).
To provide background information 
on the incidence, therapeutic 
landscape, and medical need of the 
tumor histologies and indications 
selected for the Phase 2 portion of the 
study.
Section 4.3 Rationale for the 
Proposed Study
Restructured text to create a section 
for a rationale for the proposed 
patient population. 
To provide a rationale for the 
proposed patient population.
Section 4.3.1 Rationale for the 
Starting Dose and Schedule
Clarified that patients with clinical 
benefits can be changed to less 
frequent dosing schedule after Cycle 
9 upon discussion and agreement 
between the investigator and 
sponsor.
To provide more clarity on potential 
change in cycles in patients with 
clinical benefit. 
Section 4.4 Potential Risks and 
Benefits
Added details about ongoing trials in 
which TAK-981 is being 
investigated.
To provide current data available.
Section 4.4.1.1 Lymphoid and 
Hematopoietic Effects
Modified language regarding 
potential lymphoid and 
hematopoietic effects based on 
nonclinical studies.
To align the risk of transient 
lymphopenia with the modifications 
applied in Section 7 and Section 8.
Section 4.4.1.2 Effects in Renal 
Pelvis
Modified language regarding 
potential renal pelvis effects based on 
nonclinical studies.
To include a more flexible hydration 
requirement for patients based on 
principal investigator guidance and 
experience.
Section 4.4.1.3 IRRs and Potential 
for CRS
Modified language regarding 
infusion related reactions and 
potential for cytokine release 
syndrome.
To clarify that these precautions are 
for dose escalation Phase 1.
Section 4.4.1.5 Reproductive and 
Development Toxicity
Added data for potential reproductive 
and development toxicity based on 
nonclinical studies.
To incorporate additional prevention 
of risks based on emerging 
preclinical data.
Section 4.4.1.6 Genotoxicity
Added data for potential genotoxicity 
based on nonclinical studies.
To incorporate emerging preclinical 
data.
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Protocol Amendment 5
Summary of Changes Since Last Version of the Approved Protocol
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
Section 2.0: STUDY SUMMARY
Section 7.1 Inclusion Criteria
Modified inclusion criterion to 
include patient population with 
cytologically confirmed advanced or 
metastatic solid tumors that have no 
standard therapeutic option with a 
proven clinical benefit, are intolerant, 
or have refused them.
To allow the enrollment of patients 
with metastatic solid tumors 
diagnosed by cytology.
Section 2.0: STUDY SUMMARY
Section 7.1 Inclusion Criteria
Added inclusion criteria on patient 
population to be included in Phase 2
cohorts.
To clarify the different tumor types 
and indications to be enrolled during 
Phase 2.
Section 2.0: STUDY SUMMARY
Section 7.1 Inclusion Criteria
Modified inclusion criterion for 
radiologically measurable lesions in 
Phase 2.
To clarify that irradiated tumor 
lesions can be considered measurable 
lesions if progressive disease has 
been demonstrated in that particular 
lesion.
Section 2.0: STUDY SUMMARY
Section 7.1 Inclusion Criteria
Added inclusion criterion for 
willingness to consent to mandatory 
pretreatment and on treatment biopsy 
in Phase 2 stage 1.
To restrict the mandatory collection 
of paired tumor biopsies to Phase 2 
stage 1.
Section 2.0: STUDY SUMMARY
Section 7.1 Inclusion Criteria
Added inclusion criterion for 
willingness to provide archival tumor 
tissue sample, if available, in all 
patients except those in coronavirus 
disease 2019 (COVID-19) 
expansion.
To confirm subject’s willingness to 
provide archival tumor tissue sample 
for biomarker analysis, if available.
Section 2.0: STUDY SUMMARY
Section 7.1 Inclusion Criteria
For COVID-19 expansion, modified 
the inclusion criterion to increase the 
peripheral capillary oxygen 
saturation requirement to >93% on 
room air.
Change is made to follow Food and 
Drug Administration’s (FDA’s) 
definition of COVID-19 infected 
patients with moderate disease.
Section 2.0: STUDY SUMMARY
Section 7.1 Inclusion Criteria
For COVID-19 expansion, modified 
the inclusion criterion to include 
patients with moderate disease 
(National Early Warning Score ≤6).
Changed term “moderately severe” 
to “moderate” to clarify that only 
patients with moderate COVID-19 
disease will be eligible for enrollment 
in COVID-19 expansion. 
Section 2.0: STUDY SUMMARY
Section 7.1 Inclusion Criteria
Lowered the lower limit of absolute 
neutrophil count requirement (≥1.0 × 
109/L) for inclusion in study and 
modified language for the 
hemoglobin and platelet count 
requirements.
To comply with American Society of 
Clinical Oncology guidelines 
published in the Journal Clinical of 
Oncology 2017 and the 
recommendations from principal 
investigators.
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Protocol Amendment 5
Summary of Changes Since Last Version of the Approved Protocol
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
Section 2.0: STUDY SUMMARY
Section 7.1 Inclusion Criteria
Deleted inclusion criterion related to 
absolute lymphocyte count.
This change was made in agreement 
with principal investigators, who 
concurred that low lymphocyte 
counts did not appear to correlate 
with severe clinical outcomes in 
multiple examples of 
immunomodulatory and 
chemoradiotherapeutic regimens. In 
addition, the baseline lymphopenia in 
lymphoma patients and patients with 
solid tumors who progressed to 
multiple lines of therapies would 
preclude the eligibility of this patient 
population for the study.
Section 2.0: STUDY SUMMARY
Section 7.1 Inclusion Criteria
Modified inclusion criterion recovery 
from all toxic effects of previous 
therapy.
To allow the enrollment of patients 
with lymphoma and Grade 2 
thrombocytopenia to comply with the 
American Society of Clinical 
Oncology guidelines regarding 
eligibility criteria in clinical trials as 
described in the Journal of Clinical 
Oncology, October 2017, as well as 
per the recommendation of principal 
investigators.
Section 2.0: STUDY SUMMARY
Section 7.1 Inclusion Criteria
Deleted inclusion criterion regarding 
screening and postdose tumor 
biopsies.
To avoid redundancy with other 
exclusion criteria.
Section 2.0: STUDY SUMMARY
Section 7.1 Inclusion Criteria
Clarified that use of low-dose 
steroids (oral prednisone or 
equivalent ≤20 mg per day) within 14 
days before first dose of the study 
drug is allowed.
To homogenize allowed doses across 
the TAK-981 protocols.
Section 2.0: STUDY SUMMARY
Section 7.2 Exclusion Criteria
Modified the exclusion criterion by 
deleting language on recovering from 
previous treatment toxicity and 
adding exceptions.
Text was deleted to avoid repetition 
since it is also mentioned in inclusion 
criterion; exceptions were added to 
align this exclusion criterion across 
TAK-981 protocols.
Section 2.0: STUDY SUMMARY
Section 7.2 Exclusion Criteria
Modified the exclusion criterion by 
clarifying patients who have not 
recovered to Grade 1 or baseline after 
extended field radiotherapy are 
excluded.
To avoid redundancy across the study 
protocol.
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Protocol Amendment 5
Summary of Changes Since Last Version of the Approved Protocol
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
Section 2.0: STUDY SUMMARY
Section 7.2 Exclusion Criteria
Section 8.4.2 Excluded Concomitant 
Medications and Procedures for 
COVID-19 Expansion
Section 8.5 Permitted Concomitant 
Medications and Procedures
Section 9.4.2.10.1 SOC for 
COVID-19
Appendix A SOE
Removed the allowance of 
hydroxychloroquine and chloroquine 
use in COVID-19 expansion.
Change is made to follow FDA’s 
guidance for treatment of COVID-19 
infected patients.
Section 2.0: STUDY SUMMARY
Section 7.2 Exclusion Criteria
Modified the exclusion criterion 
regarding uncontrolled hypertension.
To clarify the type of hypertension in 
this exclusion criterion.
Section 2.0: STUDY SUMMARY
Section 7.2 Exclusion Criteria
Modified the exclusion criterion by 
replacing “baseline prolongation of 
the QTc interval” with “baseline 
prolongation of the QTcF interval.”
To further clarify that corrected QT 
interval must be calculated with 
Fridericia method.
Section 2.0: STUDY SUMMARY
Section 7.2 Exclusion Criteria
Added/modified exclusion criteria to 
exclude patients with history of 
autoimmune disease and those with 
immune-related adverse events 
(AEs), noninfectious pneumonitis, or 
active noninfectious pneumonitis.
To adapt the exclusion criteria to the 
relevant TAK-981–mediated 
toxicities observed during trial 
conduct and align with the TAK-981 
program protocols.
Section 2.0: STUDY SUMMARY
Section 7.2 Exclusion Criteria
Modified exclusion criterion from 
“active infection” to “significant 
active infection.”
To further clarify the exclusion 
criterion.
Section 2.0: STUDY SUMMARY
Section 7.2 Exclusion Criteria
Section 8.3.1 Excluded Concomitant 
Medications and Procedures for 
Phase 1 Dose Escalation and Phase 2 
Cancer Treatment Expansion 
Cohorts
Added that the exclusion criterion 
regarding use of drugs known to 
prolong QTc interval was for Phase 1 
only.
To clarify that the restriction applies 
to Phase 1 only.
Section 2.0: STUDY SUMMARY
Section 7.2 Exclusion Criteria
Added exclusion criterion for 
secondary malignancy within 
previous 3 years, with exceptions to 
certain types of cancers.
To state that with some exceptions, 
patients with second malignancies 
are not eligible.
Section 2.0: STUDY SUMMARY
Section 7.2 Exclusion Criteria
Added exclusion criterion for prior 
allogeneic tissue and solid organ 
transplant.
To align the exclusion criteria across 
all the TAK-981 study protocols.
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Protocol Amendment 5
Summary of Changes Since Last Version of the Approved Protocol
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
Section 8.0 STUDY DRUG, Section 
8.1 Study Drug Administration 
Section 8.2 Phase 1 Dose Escalation 
and Phase 2 Cancer Treatment 
Expansion Cohorts
Elaborated details on TAK-981 
administration in Phase 1 and Phase 2 
and removed redundant language.
To provide further clarification of 
TAK-981 administration 
requirements during Phase 1 and 
Phase 2 and to avoid redundancy.
Section 8.2.1 Definitions of DLT for 
Dose Escalation
Modified dose-limiting toxicity 
(DLT) definitions.
To reflect the consensus of the 
principal investigators in this regard, 
as baseline lymphocyte counts are 
significantly variable, intermittent 
lymphocytopenia lacks clinical 
significance, and baseline 
lymphocytopenia observed in 
multiple lymphoma and solid tumor 
patients may be aggravated by 
procedures and conditions other than 
treatment with study drug. In this 
study, prophylaxis for opportunistic 
infections is initiated as per 
investigator discretion.
Section 8.2.2 Dose Escalation Rules
Clarified dose escalation rules.
To clarify that the 3 + 3 design rules 
apply to cohort 1 only; the number of 
patients in each cohort from cohort 2 
and above is approximately 3. Also, 
esthetic modifications have been 
applied to avoid redundancy.
Section 8.2.4.1.2 Criteria for 
Beginning or Delaying a Subsequent 
Treatment Cycle
Modified platelet count criterion and 
deleted lymphocyte count as one of 
the criteria for beginning or delaying 
a subsequent treatment cycle.
To align the criteria for beginning a 
new cycle with the baseline 
hematologic Grade 1 or Grade 2 
alterations allowed in Section 7.
Section 8.2.4.1.3 Criteria for Dose 
Interruption, Dose Reduction, and 
Discontinuation
Deleted language regarding acute 
toxicity in the criteria for dose 
interruption, dose reduction, and 
discontinuation.
To avoid overexplaining.
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Protocol Amendment 5
Summary of Changes Since Last Version of the Approved Protocol
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
Section 8.2.4.1.3 Criteria for Dose 
Interruption, Dose Reduction, and 
Discontinuation
Deleted lymphocytopenia as a 
criterion for dose adjustments for 
hematologic toxicities.
To reflect the consensus of the 
principal investigators in this regard, 
as intermittent lymphopenia lacks 
clinical significance or value as a 
potential pharmacodynamic 
biomarker, and baseline 
lymphocytopenia is observed in 
multiple lymphoma and solid tumor 
patients; as a mitigation of risk, 
prophylaxis for opportunistic 
infections is initiated as per 
investigator discretion.
Section 8.4.1 Excluded Concomitant 
Medications and Procedures for 
Phase 1 Dose Escalation and Phase 2 
Cancer Treatment Expansion 
Cohorts
Modified definition of a short course 
of concomitant corticosteroids from 
<48 hours to <96 hours.
To allow a more prolonged course of 
steroids in alignment with current 
guidance on the approach to certain 
clinical conditions.
Section 8.4.1 Excluded Concomitant 
Medications and Procedures for 
Phase 1 Dose Escalation and Phase 2 
Cancer Treatment Expansion 
Cohorts
Modified language regarding 
prophylactic use of myeloid growth 
factors.
To further clarify that the initiation of 
primary prophylaxis of cytopenia 
with myeloid growth factors is not 
allowed during Cycle 1.
Section 8.4.1 Excluded Concomitant 
Medications and Procedures for 
Phase 1 Dose Escalation and Phase 2 
Cancer Treatment Expansion 
Cohorts
Added immunization with live viral 
vaccines as one of the excluded 
concomitant medications and 
procedures during the study.
To align prohibited medications 
across TAK-981 study protocols.
Section 8.5 Permitted Concomitant 
Medications and Procedures
Included receptor activator of nuclear 
factor kappa-Β ligand inhibitors as a 
permitted concomitant medication.
To align across TAK-981 protocols.
Section 8.5 Permitted Concomitant 
Medications and Procedures
Added language clarifying that 
additional concomitant medications 
and procedures are permitted during 
the study to prevent and actively 
manage AEs unless specifically 
prohibited in the protocol.
To further clarify the permitted 
concomitant medications.
Section 8.7.5 Lymphopenia and 
Opportunistic Infection Prophylaxis
Changed the follow-up for 
lymphopenia and opportunistic 
infection prophylaxis from 
 to “CD4/8 
counts.”
To clarify the type of follow-up that 
will help investigators in making 
clinical decisions about the risk of 
immunosuppression.
Section 8.7.7 CRS
Modified language regarding 
cytokine release syndrome.
To provide further information on 
signs and symptoms of cytokine 
release syndrome.
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Summary of Changes Since Last Version of the Approved Protocol
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
Section 9.4 Study Procedures
Modified general language regarding 
study procedures and deleted 
language regarding image tests.
To clarify language and to avoid 
redundancy since this is described in 
the schedule of events (SOE) table.
Section 9.4.1.3 Medical History
Clarified that any available
pathology/cytogenetic/mutational 
and tumor genomic information 
should be reported in the electronic 
case report form (eCRF).
To further clarify collected 
information must be reported in 
eCRF.
Section 9.4.1.5 Patient Height and 
Weight
Modified language regarding patient 
height and weight.
To avoid conflicts with the SOE 
table.
Section 9.4.1.8 Pregnancy Test
Appendix A SOE
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 visit.
To clarify that pregnancy tests are 
required on Day 1 of each cycle in 
women with childbearing potential.
Section 9.4.1.12 Post-Treatment 
Follow-up
Section 9.4.2.1.13 Posttreatment 
Follow-up
Modified language regarding 
posttreatment follow-up assessments 
and separated the sections for 
posttreatment follow-up for Phase 1 
dose escalation and Phase 2 cancer 
treatment expansion, and COVID-19 
expansion.
To avoid redundancy within Section 
9 and to provide separated sections
specific for each cohort.
Section 9.4.1.13 Cardiac Monitoring
Modified language regarding 12-lead 
electrocardiograms (ECGs), left 
ventricular ejection fraction and 
.
To avoid conflicts with the SOE table 
and to clarify that 
will not be collected during Phase 2.
Section 9.4.1.14.1 Chemistry, 
Hematology, Coagulation, and 
Urinalysis
Modified language regarding 
chemistry, hematology, coagulation, 
and urinalysis.
To homogenize the window period 
for sample collection.
Section 9.4.1.15 Disease Assessment
Section 13.2.3 Efficacy Analysis
Removed Response Evaluation 
Criteria in Lymphoma (RECIL) 
throughout the protocol and added 
Lugano criteria for lymphoma 
response to assess disease response 
and progression.
To align the criteria to evaluate 
response in lymphoma patients 
across TAK-981 studies.
Section 9.4.1.16 Biomarker, 
Pharmacodynamic, and PK Samples
Added detailed procedure for tumor 
biopsies, banked tumor, and fresh 
paired tumor biopsy.
To provide flexible window periods 
for the collection of paired tumor 
biopsies and to align the biopsy 
procedure with the requirements 
requested by FDA in the Study 
TAK-981-1501 protocol.
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Summary of Changes Since Last Version of the Approved Protocol
Sections Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
Appendix E Drugs that Interact with 
the CYP3A Family of Cytochromes 
P450
Updated lists of drugs that are strong 
or moderate inducers or inhibitors of 
the CYP3A family of cytochrome 
P450.
To align with FDA’s most current list 
of strong or moderate inducers or 
inhibitors of the CYP3A.
Rationale for Amendment 04 
This document describes the changes to the protocol incorporating Amendment 04. The primary 
reason for this amendment was to incorporate changes requested by United States Food and Drug 
Administration (FDA) during the review of protocol incorporating Amendment 03 that intended to 
explore potential of TAK-981 to control severe acute respiratory syndrome coronavirus 2 
(SARS-CoV-2) infection in patients with cancer by modulating Type I interferon response. 
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 J [of
Protocol Amendment 4].
Changes in Amendment 04
1. Amended the title of the study to accurately describe the patient population of this study.
2. Added a section on rationale for coronavirus disease 2019 (COVID-19) expansion design.
3. Amended the study design in the COVID-19 expansion to include safety lead-in and 
randomized COVID-19 proof of concept cohorts. 
4. Added figure for overall TAK-981-1002 study design.
5. Interchanged the text under potential risks and benefits and preliminary clinical experience.
6. Added details on inclusion of Independent Data Monitoring Committee. 
7. Replaced term “Phase 1” with “dose escalation and cancer treatment expansion” throughout 
protocol for more clarity.
8. Modified primary objective for COVID-19 expansion to clarify that change in SARS-CoV-2 
viral load will be assessed within 8 days of TAK-981 administration.
9. Modified primary endpoint for COVID-19 expansion.
10. Clarified that time to discharge or the maintenance of a National Early Warning Score of ≤3 for 
24 hours, whichever occurs first, is the key secondary endpoint and added another new key 
secondary endpoint.
11. Added duration of supplemental oxygen requirement as a secondary endpoint.
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21. Modified inclusion criteria for patient enrollment in the study by adding specific criteria for 
COVID-19 expansion.
22. Modified exclusion criteria for patient enrollment in the study by adding specific criteria for 
COVID-19 expansion.
23. Added details for TAK-981 administration in COVID-19 expansion.
24. Modified text for hydration and vital signs during C1D1 administration.
25. Clarified that dose adjustments criteria under lymphocytopenia are applicable for patients 
enrolled in dose escalation or cancer treatment expansions only.
26. Restructured list of excluded concomitant medications and procedures.
27. Added list of concomitant medications and procedures permitted in COVID-19 expansion.
28. Added a separate sub-section elaborating on all study procedures for COVID-19 expansion 
cohort.
29. Rearranged criteria for completion of study to distinguish situations for overall study and those 
for dose escalation and cancer treatment cohort only.
30. Rearranged criteria for discontinuation of treatment with TAK-981 to distinguish 
discontinuation criteria for overall study and those for dose escalation and cancer treatment 
cohort only.
31. Added details on posttreatment follow-up assessments for patients in COVID-19 expansion 
cohort.
32. Modified definition for SAE to include criteria for COVID-19 patients.
33. Clarified that a separate statistical analysis plan (SAP) will prepared for COVID-19 expansion. 
34. Added details about COVID-19 response evaluable analysis set.
35. Added details about antiviral efficacy analysis for COVID-19 expansion.
36. Added language for remote monitoring visits for COVID-19 expansion. 
37. Added sample size calculation for COVID-19 expansion cohort.
38. Added 2 tables (Schedule of events and PK and biomarker sample collection) for COVID-19 
expansion in Appendix A. 
39. Added Appendix F for National Early Warning Score.
40. Added footnotes in SOE tables to incorporate language for documentation of reasons for 
missed assessments or procedures.
Rationale for Amendment 2
This document describes the changes to the protocol incorporating Amendment 02. The primary 
reasons for this amendment are to modify the lymphopenia limit inclusion criteria and to clarify 
how and when various tests and procedures should be performed.
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Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification and administrative purpose only.
Changes in Amendment 02
1. Added that the dosing schedule may be modified to a less intense one without a protocol 
amendment if TAK-981–related cumulative toxicity is observed or if supported by emerging 
pharmacokinetic (PK)/pharmacodynamic data.
2. Increased the estimated number of sites to be used in the study.
3. Removed language stating that the screening biopsy could be replaced by an archival biopsy.
4. Removed examples of blood pressure levels from exclusion criterion #5.
5. Changed the length of time that on Cycle 1, Day 1 (C1D1), patients will abstain from eating 
food or having anything to drink except water from a minimum of 2 hours before collection of 
the predose electrocardiograms (ECGs) until after collection of the 1-hour postinfusion ECGs 
and that a low calorie and low sodium light meal is permitted immediately after the 1-hour 
post-infusion ECG has been collected.
6. Ensured that the primary endpoints in the protocol and study summary matched.
7. Updated background information on how TAK-981 affects the small ubiquitin-like modifier 
(SUMO)ylation process based on more recent nonclinical research.
8. Added 3 safety primary endpoints to the list to be reported to Disclosures.
9. Among the inclusion criteria that define adequate bone marrow reserve and renal and hepatic 
function in the inclusion criteria, modified absolute lymphocyte thresholds and include a 
minimum requirement of CD4 lymphocytes for patients with absolute lymphopenia.
10. Modified the lymphocyte count criterion that patients must meet to begin a new cycle of 
treatment.
11. Added that a dose delay of up to 4 days may occur under certain conditions and that 72 hours 
should elapse between consecutive doses of TAK-981.
12. Clarified that Grade 3 fatigue will not be considered a dose-limiting toxicity (DLT) if it lasts 
fewer than 7 days.
13. Added that Grade 3 cytokine release syndrome will not be considered a DLT.
14. Added that if TAK-981 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 
schedule of events (SOE).
15. Clarified how to adjust dose if the patient experiences Grade 4 neutropenia.
16. Clarified how to adjust dose if the patient experiences Grade 4 thrombocytopenia.
17. Clarified how to treat lymphopenia.
18. Added a 7-day window for image tests.
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21. Added that if transmission of a pregnancy report is not feasible, then a facsimile of the 
completed Takeda paper-based pregnancy form will be sent.
22. Clarified definitions of various pharmacodynamic analysis datasets.
23. Made multiple changes in SOE and footnotes to match new protocol sample collection 
requirements, and to provide clarifications or correct typos. 
24. Added language stating that a decision to stop the collection of skin punch biopsies may take 
place should sufficient data related to target engagement and small ubiquitin-like modifier 2
(SUMO2)/ small ubiquitin-like modifier 3 (SUMO3) inhibition be generated.
25. Added language stating that a decision to omit the collection of the 8-hour post–
end-of-infusion blood sample for flow cytometry may occur should sufficient data related to 
target engagement and SUMO2/3 inhibition in peripheral blood in earlier collection time 
points be generated.
26. Added grapefruit to list of prohibited concomitant medications.
27. Added “lack of benefit” and “clinical progression” to the list of reasons that treatment with 
study drug may be discontinued.
28. Added that the same lesion should be biopsied before treatment and on treatment whenever 
possible.
29. Added that 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.
30. Modified the amount of fluid intake from 2 liters to 1 liter in the 4 hours after the infusion, and 
clarified that if the patient cannot drink this amount of fluid, extra IV fluid supplementation 
should be considered at the investigator’s discretion.
31. Day 11 PK samples have been moved to Day 8.
32. Day 11 blood samples have been moved to Day 8.
33. Removed stipulation that vital signs should be assessed every 30 minutes during the 2 hours 
following infusions.
34. Modified the number of patients to be enrolled in cohorts during the dose escalation phase.
Rationale for Amendment 1
This document describes the changes to the protocol incorporating Amendment 01. The primary 
reason for this amendment is to incorporate changes requested by the United States (US) Food and 
Drug Adminsitration during review of the protocol.
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification and administrative purpose only.
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Changes in Amendment 01
1. Added to the study design that for a certain dose level (DL) to be considered as a potential 
recommended phase 2 dose (RP2D), the percentage of adverse events (AEs) meeting the 
dose-limiting toxicity (DLT) definition at any cycle should be <33%.
2. Added the circumstances related to the determination of an overall excess of toxicity that may 
warrant enrollment hold.
3. Modified an inclusion criterion to state that patients must not have a therapy with proven 
clinical benefit available to them to be enrolled in the study.
4. Added to an inclusion criterion that patients with low-grade lymphomas may not need to 
exhaust all available therapy to be enrolled in the study under certain conditions.
5. Modified an exclusion criterion exclude patients who use moderate inhibitors and inducers of 
cytochrome P450 (CYP) 3A4/5. 
6. Modified the definition of DLT to:
a) Clarify that the listed AEs must be clearly unrelated to TAK-981 to not be considered a 
DLT.
b) Include “any Grade 5 AE”.
c) Define a maximum allowable duration for uncomplicated Grade 3 thrombocytopenia.
d) Indicate that AEs meeting the DLT definition happening outside Cycle 1 will be taken into 
consideration by bayesian logistic regression modeling (BLRM) for determination of the 
RP2D.
7. Added clarifications to the criteria for dose interruptions and reductions.
8. Modified the general dose modification recommendations for TAK-981 nonhematologic 
drug-related AEs to reflect changes to criteria for dose interruptions, reductions, and 
discontinuation. 
9. Clarified that patients who require use of strong and moderate inhibitors/inducers of 
CYP3A4/5 during the study should temporarily discontinue use of TAK-981.
10. Added that narrow therapeutic range P-glycoprotein (P-gp) substrates such as digoxin or 
dabigatran may to be used with caution, and patients requiring use of these drugs will be closely 
monitored.
11. Relocated the dose adjustments for hematologic toxicities table and made the levels of dose 
reductions more explicit.
12. Clarified what kinds of pharmacokinetic (PK) and pharmacodynamic evidence will be used to 
determine the RP2D.
13. Added a list of moderate CYP3A inducers and inhibitors to the appendix that describes 
prohibited concomitant medications with TAK-981.
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14. Added that the 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.
15. Clarified in the exclusion criteria that patients should not have received treatment with 
anticancer treatments or investigational products within 14 days before first dose of study 
drug.
16. Aligned time points for multiple-gated acquisition (MUGA) scans/echocardiograms in the 
schedules of events (SOEs) and study procedures sections.
17. Clarified that predose/postdose tumor biopsies are optional for patients in dose escalation until 
there is evidence of TAK-981 pharmacodynamic effect from multiple patients or evidence of 
antitumor effect.
18. Added that all skin punch biopsies should be obtained from the upper back.
19. Clarified that patient enrollment will be staggered between the first and second patients during 
dose escalation at all DLs, and that 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 visit without clinically 
significant acute toxicities.
20. Clarified that screening and postdose tumor biopsies are required from all patients in the 
expansion cohorts and are optional during dose escalation, but will be required from certain 
patients once a DL for which there is consistent evidence of TAK-981 pharmacodynamic 
effect has been established.
21. Added an exclusion criterion for patients who require the use of drugs known to prolong heart 
rate–corrected QT (QTc) interval.
22. Updated the excluded concomitant medications prohibit concomitant use of drugs known to 
prolong the QTc interval during the study.
23. Added examples of drugs that are known to prolong the QTc interval.
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SAP_001.pdf: 
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Amendment History:
Date
Version Number
Amendment Type
14 April 2023
Version 2.0
Substantial
12 May 2020
Initial SAP
Not applicable
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2.0
TABLE OF CONTENTS 
1.0
TITL PAGE.....................................................................................................................1
1.1
Approval Signatures ..................................................................................................3
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 ..............................................................................................8
4.4
Study Design .............................................................................................................9
4.4.1
Phase 1 Dose Escalation ..................................................................................11
4.4.2
Phase 2 Expansion in Select Cancer Indications...............................................12
5.0
ANALYSIS ENDPOINTS.............................................................................................13
5.1
Primary Endpoints: ..................................................................................................13
5.2
Secondary Endpoints: ..............................................................................................13
5.3
Exploratory Endpoints: ............................................................................................14
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................14
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................17
7.1
General Principles....................................................................................................17
7.1.1
Definition of Study Visit Windows..................................................................18
7.1.2
Conventions for Missing/Partial Dates in Screening Visit ................................18
7.1.3
Conventions for Missing Adverse Event Dates ................................................18
7.1.4
Conventions for Missing Concomitant Medication/Therapy Dates...................19
7.1.5
Conventions for Missing Subsequent Medication/Therapy Dates.....................20
7.2
Analysis Sets ...........................................................................................................20
7.3
Disposition of Subjects ............................................................................................21
7.4
Demographic and Other Baseline Characteristics.....................................................21
7.5
Medical History and Concurrent Medical Conditions...............................................22
7.6
Medication History and Concomitant Medications...................................................22
7.7
Study Drug Exposure and Compliance.....................................................................22
7.8
Efficacy Analysis.....................................................................................................23
7.8.1
Primary Efficacy Endpoint(s)...........................................................................23
7.8.2
Secondary Efficacy Endpoint(s).......................................................................23
7.8.3
Additional Efficacy Endpoint(s).......................................................................26
7.9
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................27
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7.9.1
Pharmacokinetic (PK) Analysis .......................................................................27
7.9.2
Pharmacodynamic Analysis.............................................................................28
7.10
Other Outcomes.......................................................................................................28
7.10.1
PK/Pharmacodynamic Analysis.......................................................................28
7.10.2
................................................................................29
7.11
Safety Analysis........................................................................................................30
7.11.1
Dose Limiting Toxicities (DLTs).....................................................................31
7.11.2
Adverse Events................................................................................................31
7.11.2.1
Adverse Events........................................................................................31
7.11.2.2
Serious Adverse Events ...........................................................................32
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.......................................................................................................34
7.11.5
12-Lead Electrocardiograms (ECGs) ...............................................................34
7.11.6
Eastern Cooperative Oncology Group (ECOG) Performance Status.................34
7.11.7
Other Observations Related to Safety...............................................................34
7.12
Interim Analysis ......................................................................................................35
7.13
Changes in the Statistical Analysis Plan from the Protocol.......................................35
8.0
REFERENCES..............................................................................................................36
LIST OF IN-TEXT TABLES
Table 6.a
Sample Size for Each Cohort and Each Stage (Solid Tumor Cohorts A, B, and 
C and Lymphoma Cohort D)..............................................................................16
Table 6.b
Sample Size for Each Cohort and Each Stage (Lymphoma Cohorts E and F)......17
Table 7.a
Examples of best confirmed response derivation ................................................26
Table 7.b
Chemistry, Hematology, and Coagulation Tests .................................................33
LIST OF IN-TEXT FIGURES
Figure 4.a
TAK-981-1002 Study Design.............................................................................10
Figure 4.b
TAK-981 Dosing Regimen.................................................................................11
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3.0
LIST OF ABBREVIATIONS 
Abbreviation
Term
AUC
change in area under the concentration-time curve
AE
adverse event
ALC
absolute lymphocyte count
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
AUCτ
area under the concentration-time curve during a dosing interval 
AUCτ/Dose
steady-state, dose-normalized area under the concentration-time curve 
during a dosing interval 
BED
biologically effective dose
BUN
blood urea nitrogen
CL/F
apparent clearance after extravascular administration, calculated using 
the observed value of the last quantifiable concentration
Cmax
maximum observed concentration
CO2
carbon dioxide
CPK
creatine phosphokinase
CR
complete response 
Ctrough
observed concentration at the end of a dosing interval
DCR
disease control rate
DLBCL
diffuse large B-cell lymphoma
DLT
dose-limiting toxicity
DOR
duration of response
DOSD
duration of stable disease
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
FL
follicular lymphoma
GGT
gamma glutamyl transferase
IDMC
independent data monitoring committee
LDH
lactate dehydrogenase
LVEF
left ventricular ejection fraction 
MAD
maximally administered dose
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Abbreviation
Term
MedDRA
Medical Dictionary for Regulatory Activities
MTD
maximum tolerated dose
MUGA
multiple gated acquisition
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse 
Events
NHL
non-Hodgkin lymphoma
ORR
overall response rate
OS
overall survival
PD
progressive disease (disease progression)
PFS
progression free survival
PK
pharmacokinetic(s)
PR
partial response 
PTR
peak-trough ratio during a dosing interval, at steady state
QD
once daily
Rac
accumulation ratio
RP2D
recommended Phase 2 dose
SAE
serious adverse event
SD
stable disease
SMC
Safety Monitoring Committee
t1/2
terminal disposition half-life
tmax
first time to reach maximum (peak) plasma concentration
TTP
time to progression
TTR
time to response
WHO
World Health Organization
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Figure 4.a
TAK-981-1002 Study Design
Abbreviations: CAR, chimeric antigen receptor; CPI, checkpoint inhibitor; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; HA, health 
authority; IV, intravenous; NHL, non-Hodgkin lymphoma; NSCLC, non–small cell lung cancer; r/r, relapsed/refractory; q21d, every 21 days; SOC, standard of 
care.
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4.4.1
Phase 1 Dose Escalation
Patients will be treated in cohorts with increasing doses of TAK-981, administered as a 1-hour IV 
infusion on Days 1, 4, 8, and 11 of a 21-day cycle until a discontinuation criterion is met. The overall 
dosing regimen is displayed in Figure 4.b.
Figure 4.b
TAK-981 Dosing Regimen
The study will begin with a dose escalation. Dose escalation intervals progress from 3 mg to 160 mg 
(with a provision of 1 mg at dose level 1). The upper dose level corresponds approximately to the 
human equivalent dose of the maximum tolerated dose (MTD) in dogs. Patient enrollment will be 
staggered between the first and second patients 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 the Day 4 visit 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 may not be required if there are no 
clinically significant safety findings suggestive of infusion reaction or CRS. 
Dose escalation of TAK-981 will be cohort-based with an adaptive design using Bayesian logistic 
regression modeling (BLRM) (see Appendix G for details). Approximately 70 patients will be enrolled 
until the RP2D of TAK-981 is identified. Single agent RP2D could be based either on the MTD based 
on the observation of DLTs (Section 8.2.1 in the protocol) or a biologically effective dose (BED) that 
is ≤MTD. 
A minimum of 3 patients will be enrolled in the starting dose cohort. Dose escalation and cohort 
expansion decisions are reviewed and approved by the Safety Monitoring Committee (SMC), 
composed of the sponsor clinician and the investigators, which may decide that a fourth patient can be 
recruited to the same cohort before the first 3 patients complete the DLT assessment period. While the 
first 3 evaluable patients will be used to determine dose expansion, if the fourth patient experiences a 
DLT, their respective AE(s) will be taken into consideration regarding cohort determination, during the 
end of cohort meeting. The rationale for such an addition is to have an extra patient in the cohort 
should 1 of the 3 earlier patients be unevaluable, or if a patient within the cohort experiences a DLT, 
which would require cohort expansion to 6 patients. From dose level 2 onwards, an adaptive BLRM 
guided by the Escalation with Overdose Control principle will be used in successive escalation cohorts 
(Section 8.2.2 in the protocol).
Single agent RP2D will be based either on the MTD determined by the BLRM (Section 8.2.1 in the 
protocol) or a BED that is ≤ MTD. The BED of TAK-981 is defined as the dose at which there is 
evidence of pharmacodynamic effects including the presence of SUMO-TAK-981 adducts and 
inhibition of SUMO2/3 conjugates, 
 
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However, if a clinical benefit has been observed for patients in the cohort (eg, the majority of patients 
have recorded stable disease (SD) at Week 8 and per investigator assessment are benefiting from 
treatment), then enrollment into stage 2 may be allowed for this cohort with agreement from 
participating investigators. 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 of the protocol). The final analysis of the primary 
endpoints for each cohort will take place when all ongoing patients have had the opportunity complete 
the 6 months disease assessment.
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.
5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoints:
The primary endpoints are:
Phase 1:

Frequency, severity, and duration of TEAEs and laboratory abnormalities for all dose groups 
according to the National Cancer Institute Common Terminology Criteria for Adverse Events (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.

DLTs within the first 21 days of treatment in Cycle 1.
Phase 2:

Overall response rate (ORR) (Complete Response[CR] + Partial Response [PR]) as defined by the 
investigator according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) 
criteria for solid tumors or Lugano classification for lymphomas.
5.2
Secondary Endpoints:
The secondary endpoints are:

PK parameters after the first dose of TAK-981 on Cycle 1 Day 1 (C1D1) and Cycle 1, Day 8 (data 
permitting):
– maximum observed plasma concentration (Cmax).
– Time of first occurrence of Cmax (tmax).
– Area under the plasma concentration versus time curve from time 0 to the last measurable 
concentration (AUClast).
– Area under the plasma concentration-time curve from time 0 to infinity (AUC∞).
– Terminal disposition phase half-life (t1/2z).
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updated after each group of patients enrolled in the current dose level cohort. For each dose level, the 
posterior probability of having DLT rates that fall into the following intervals will be estimated:

[0, 0.16): under-dosing.

[0.16, 0.33): target toxicity.

[0.33, 1.00]: excessive toxicity.
The selection of the next recommended dose will be determined from BLRM along consideration of 
other safety, clinical, PK, and pharmacodynamic data.
The details of the BLRM are included in Appendix G of the protocol. The details of dose-escalation 
are specified in Section 8.2.2.
Efficacy Evaluation Phase (Phase 2)
Once the MTD/BED is defined, up to approximately 132 response-evaluable patients with 6 specified 
types of solid tumors and lymphomas will be enrolled in parallel in a Phase 2 study to evaluate the 
efficacy of TAK-981.
The primary endpoint for the Phase 2 portion is ORR (CR + PR) as assessed by the investigator 
according to RECIST v1.1 for patients with solid tumors and Lugano criteria for patients with 
lymphoma. The sample size consideration for disease-specific patient populations is adaptive design 
based on Simon’s 2-stage design for a single proportion with the following hypotheses of ORR.
For solid tumor cohorts A, B, and C and lymphoma cohort D (Figure 4.a):
The hypotheses for stage 1 are the following:
H0: ORR < p0 where p0 = 15%
H1: ORR ≥ p0 where p0 = 15%
where p0 is a very low, undesirable ORR.
If H0 is rejected (and H1 is accepted) at stage 1, additional patients will be enrolled based on 
the number of responders in stage 1 and their data will be collected in the second stage.
The hypotheses at the end of stage 2 for a low desirable ORR, p1, are the following:
a) H1 is accepted at stage 1, and
b) H0: ORR ≤ p1 where p1 = 35%
H1: ORR > p1 where p1 = 35%
The hypotheses at the end of stage 2 for a high desirable response, p2, are the following:
a) H1 is accepted at stage 1, and
b) H0: ORR ≤ p2 where p2 = 45%
H1: ORR > p2 where p2 = 45%
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Because it is desirable to have higher power for detecting more improvement of the new therapy (p2
versus p0), for solid tumor cohorts A, B, and C and lymphoma cohort D (Figure 4.a), assuming a power 
of 80% for high desirable response and 70% for low desirable response and 1-sided alpha of 0.1, the 
following number of patients is required for each cohort at each stage (Table 6.a).
Table 6.a
Sample Size for Each Cohort and Each Stage (Solid Tumor Cohorts A, B, and C 
and Lymphoma Cohort D)
Stage
Total Number of 
Patients in Each 
Cohort
1-Sided Alpha 
Level/Power
Stage 1
Stage 2 b
All cohorts
Low response at the end of stage 1
Number of patients
7
19
19
0.1/70%
Number of responses a
≥2 and ≤4
≥5
High response at the end of stage 1
Number of patients
7
13
13
0.1/80%
Number of responses
≥5
≥6
a Number of patients needed to respond to continue into stage 2 or have a positive result at the end of stage 2.
b Maximum number of patients required for each cohort and number of responders that should be presented at end of stage 
2 in order to claim treatment effect.
For lymphoma cohorts E and F (Figure 4.a):
The hypotheses for stage 1 are the following:
H0: ORR < p0 where p0 = 45%
H1: ORR ≥ p0 where p0 = 45%
where p0 is a very low, undesirable ORR.
If H0 is rejected (and H1 is accepted) at stage 1, additional patients will be enrolled based on 
the number of responders in stage 1 and their data will be collected in the second stage.
The hypotheses at the end of stage 2 for a low desirable ORR, p1, are the following:
a) H1 is accepted at stage 1, and
b) H0: ORR ≤ p1 where p1 = 65%
H1: ORR > p1 where p1 = 65%
The hypotheses at the end of stage 2 for a high desirable response, p2, are the following:
a) H1 is accepted at stage 1, and
b) H0: ORR ≤ p2 where p2 = 75%
H1: ORR > p2 where p2 = 75%
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Similarly, for lymphoma cohorts E and F, assuming a power of 80% for high desirable response and 70% 
for low desirable response and 1-sided alpha of 0.1, the following number of patients is required for 
each cohort at each stage (Table 6.b).
Table 6.b
Sample Size for Each Cohort and Each Stage (Lymphoma Cohorts E and F)
Stage
Total Number of 
Patients in Each 
Cohort
1-Sided Alpha 
Level/Power
Stage 1
Stage 2 b
All cohorts
Low response at the end of stage 1
Number of patients
10
28
28
0.1/70%
Number of responses a
≥6 & ≤7
≥16
High response at the end of stage 2
Number of patients
10
16
16
0.1/80%
Number of responses
≥8
≥9
a Number of patients needed to respond to continue into stage 2 or have a positive result at the end of stage 2.
b Maximum number of patients required for each cohort and number of responders that should be presented at end of stage 
2 in order to claim treatment effect.
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.
In general, the summary tables for efficacy endpoints will be provided by escalation cohort, overall for 
dose escalation phase, and by expansion cohort and overall for expansion phase; the summary tables 
for non-efficacy endpoints (disposition, baseline and demographics, medical history, medication 
history, exposure, safety analysis) will be provided by escalation cohort, overall for dose escalation 
phase, by expansion cohort and overall for expansion phase, and overall for both phases combined 
unless specified otherwise.
Screen failure subjects will be grouped and listed at the end.
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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.

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. 
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 
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–
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 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. 
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.
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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. 

When only a year is present, 
–
If the onset year is the same as the year of last dose with study drug, the date of last dose + 1 
will be imputed.
–
If the onset year is not the same as the year of last dose with study drug, the first day of the year 
is imputed. 

If no components of the onset date are present the date of last dose + 1 will be imputed.
7.2
Analysis Sets
The Analysis Sets (Analysis Populations) will include the following:
Safety analysis set: Patients who have received at least 1 dose, even if incomplete, of study drug will 
be used for all safety analyses and for some efficacy analyses.
PK analysis set: Patients with sufficient dosing and PK data to reliably estimate 1 or more PK 
parameters will be used for PK analyses.
DLT-evaluable analysis set: The DLT-evaluable analysis set will include patients who receive all 
Cycle 1 doses of TAK-981 without experiencing a DLT or who have a DLT during Cycle 1 of the 
study. The DLT-evaluable population will be used to determine the RP2D/MTD.
Tumor response-evaluable analysis set: Patients who have received at least 1 dose of study drug, 
have sites of measurable disease at baseline, and 1 postbaseline disease assessment, or was 
discontinued due to symptomatic deterioration or death before a postbaseline evaluation happens, will 
be used for analyses of response.
Pharmacodynamic analysis set: Pharmacodynamic analysis sets to assess target engagement of 
TAK-981 and SUMOylation pathway inhibition:

Patients who have provided evaluable skin biopsies (screening sample and at least 1 on-treatment
sample) will be included in the skin pharmacodynamic analysis dataset.

Patients who have provided evaluable blood samples (C1D1 predose sample and at least 1 postdose 
sample) will be included in the blood pharmacodynamic analysis dataset.
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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 systemic therapy, prior radiation, prior surgery, prior transplant procedure and best 
response to the last prior systemic 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 WHO 
drug generic term for the safety population, from ICF signature dose of study treatment and 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 TAK-981 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, ≥3, ≥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, where duration of treatment (days) 
is calculated as (last dose date of study drug – first dose date of study drug + 1).
Descriptive statistics for Relative dose intensity (RDI) (%) and categorical summary of RDI (<50%, 50% 
to <80%, 80% to < 100%, >100%, =100%) will be summarized will be presented overall and by cycle.
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 in cycle)
The extent of exposure will be summarized by escalation cohort, overall for dose escalation phase, by 
expansion cohort, and overall in expansion phase, and overall for both phases combined.
Dosing data will also be presented in a by-patient listing.
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Action on 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 dose expansion cohort, 
and overall in dose expansion phase, and overall for both phases combined.
7.8
Efficacy Analysis
Analysis of efficacy measures will be descriptive for each escalation cohort, overall for dose escalation 
phase, for each expansion cohort, overall in expansion phase. All efficacy analyses will be based on 
investigator assessments. Investigators will assess responses using the Lugano classification for 
lymphomas and RECIST version 1.1 for solid tumors.
7.8.1
Primary Efficacy Endpoint(s)
Phase 1:
Efficacy is not the primary objective for this study in the Phase 1 portion. 
In the Phase 1 portion of this study, efficacy parameters such as ORR, DCR, DOR, TTR, TTP, and 
PFS will 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 response assessments based on RECIST v1.1 for solid tumors or Lugano classification for 
lymphomas. 
Overall Response Rate (ORR)
The ORR is defined as the proportion of patients who achieved CR and PR during the study as defined 
by the investigator according to response assessments based on RECIST v1.1 for solid tumors or 
Lugano classification for lymphomas. Response evaluations after the start of alternative anti-cancer
therapy will not be taken into account in the calculation of ORR.
The primary efficacy analysis will be provided by expansion cohort, and overall in expansion phase
using the tumor response-evaluable analysis set.
The ORR (CR + PR) will be summarized by frequencies and percentages and estimates of the ORR
will be presented with 2-sided 95% exact binomial confidence intervals.
7.8.2
Secondary Efficacy Endpoint(s)
Phase 1:

ORR, DCR, DOR, TTP, TTR and PFS as assessed by the investigator according to RECIST v1.1 
criteria for solid tumors or Lugano classification for lymphomas and OS.
Phase 2:

DCR, DOR, TTP, TTR and PFS as assessed by the investigator according to RECIST v1.1 criteria 
for solid tumors or Lugano classification for lymphomas and OS.
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Overall Response Rate (ORR)
Similar to analysis of ORR for phase 2 in Section 7.8.1, analysis of ORR will be provided based on the 
tumor response-evaluable analysis set by each escalation cohort, overall for dose escalation phase.
Duration of Response (DOR)
The DOR will be calculated for responders with a PR or better in the tumor response-evaluable 
analysis set. DOR is the time from the date of first documentation of a PR or better to the date of first 
documentation of PD. Responders without documentation of PD will be censored at the date of last 
response assessment that is SD or better.
DOR (months) = (date of progression or censor – date of response + 1)/30.4375.
The Kaplan-Meier method will be used to estimate the distribution of DOR when data allows. The 
25th, 50th (median), and 75th percentiles, and the corresponding 2-sided 95% confidence intervals 
(CIs) based on Brookmeyer and Crowley method will be presented. The number of patients with 
events and the number of patients censored will be summarized.
Disease Control Rate (DCR)
DCR is defined as the proportion of patients who achieve SD or better (determined by the 
investigator) >6 weeks during the study in the response-evaluable population.
The DCR will be summarized by frequencies and percentages based on response-evaluable analysis set 
by escalation cohort, overall for dose escalation phase, by expansion cohort, and overall in expansion 
phase. Estimates of the CBR will be presented with 2-sided 95% exact binomial confidence intervals.
Progression Free Survival (PFS) 
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 
RECIST version 1.1 for patients with solid tumor and Lugano classification 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. Patients with no post baseline response assessment will 
be censored on date of first dose.
PFS (months) = (earliest date of progression or death or censor – date of first dose + 1)/30.4375.
The analysis of PFS will be based on the safety analysis set by escalation cohort, overall for dose 
escalation phase, by expansion cohort, and overall in expansion phase. The Kaplan-Meier method will 
be used to estimate the distribution of PFS. Kaplan-Meier survival curves, the 25th, 50th (median), and 
75th percentiles, along with associated 2-sided 95% confidence intervals (CIs) based on Brookmeyer 
and Crowley method, and Kaplan-Meier PFS probability estimates with 95% CIs at 3, 6 and 12 months 
(or later time points if data permits) will be presented. The number of patients with events along with 
the type of events (death or progressive disease) and the number of patients censored will be 
summarized.
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The analysis of PFS may be repeated for tumor response-evaluable analysis set.
Time to Response (TTR)
TTR is defined as the time from the date of first study drug administration to the date of first 
documentation of objective response (PR or better) by the investigator. 
Patients with no PR or better will be censored on the last date of adequate response assessment. 
Patients with no post baseline response assessment will be censored on date of first dose.
TTR (months)= (date of response or censor – date of first dose + 1)/30.4375).
The analysis of TTR will be based on response-evaluable analysis set. The Kaplan-Meier method will 
be used to estimate the distribution of TTR (if data allows) by escalation cohort, overall for dose 
escalation phase, by expansion cohort, and overall in expansion phase. Kaplan-Meier curves, the 25th, 
50th (median), and 75th percentiles, along with associated 2-sided 95% confidence intervals (CIs) 
based on Brookmeyer and Crowley, and Kaplan-Meier estimates with 95% CIs at 3 and 6 months (or 
later time points if data permits) will be presented. The number of patients with events and the number 
of patients censored will be summarized.
Time to Progression (TTP)
TTP is defined as the time from the date of the first dose to the date of the first documentation of PD as 
assessed by the investigator. Patients without documentation of PD at the time of analysis will be 
censored at the date of last response assessment. Patients who die during treatment without PD will 
also be censored at the date of last response assessment. 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.
The analysis of TTP will be based on safety analysis set by escalation cohort, overall for dose 
escalation phase, by expansion cohort, and overall in expansion phase. The Kaplan-Meier method will 
be used to estimate the distribution of TTP. The 25th, 50th (median), and 75th percentiles, and the 
corresponding 2-sided 95% confidence intervals (CIs) based on Brookmeyer and Crowley method will 
be presented. The number of patients with events and the number of patients censored will be 
summarized.
Overall Survival (OS)
OS is defined as the time from the date of the first dose to the date of death. Patients without 
documentation of death at the time of analysis will be censored at the date last known to be alive.
The analysis of OS will be based on safety analysis set by escalation cohort, overall for dose escalation 
phase, by expansion cohort, and overall in expansion phase. The Kaplan-Meier method will be used to 
estimate the distribution of OS. Kaplan-Meier survival curves, the 25th, 50th (median), and 75th 
percentiles, along with associated 2-sided 95% confidence intervals (CIs) based on Brookmeyer and 
Crowley method, and Kaplan-Meier OS probability estimates with 95% CIs at 3 and 6 months (or later 
time points if data permits) will be presented. The number of patients with events and the number of 
patients censored will be summarized.
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
tmax.

AUC∞.

AUClast.

Terminal disposition phase half-life (t1/2z).

CL.

Vss.
Additional PK parameters, such as accumulation ratio (RAC), may be estimated as data permit. Details 
for additional PK parameters and detailed analysis will be specified in clinical pharmacology analysis 
plan (CPAP).
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 escalation cohort for dose escalation phase, by expansion cohort for expansion phase. Individual 
and mean concentration-time profiles will also be plotted by cohort for each phase.
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 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 single agent RP2D. In addition, candidate response biomarkers will be evaluated.
7.10
Other Outcomes
7.10.1
PK/Pharmacodynamic Analysis 
Data permitting, the PK and pharmacodynamic data collected in this study will be analyzed to 
understand the exposure-response relationship for TAK-981. Such analysis may be performed on an 
ongoing basis to assess the appropriateness of dose and schedule of TAK-981 and for determination of 
BED.
To determine the appropriateness of the BED/schedule as an RP2D/schedule, a totality of evidence 
approach will be used that will integrate all available data from the dose escalation and expansion 
phases of the study including: 
1. Multicycle safety/tolerability of TAK-981.
2. Single and multiple dose PK of TAK-981.
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7.11.1
Dose Limiting Toxicities (DLTs)
The incidence of DLTs will be tabulated for each dose group. In addition, to assess the relationship 
between toxicities and TAK-981 doses, the preferred term of individual toxicities will be summarized 
by frequency and intensity for each dose group. 
A by-subject listing of DLTs which occur during the treatment will be presented by schedule and dose 
level for all subjects enrolled during the dose escalation portion of this study. Subjects will be grouped 
by the dose level to which they were originally assigned, including those who receive subsequent 
treatment at a lower dose level. 
The DLT-evaluable analysis set will be used for the analysis of DLT.
7.11.2
Adverse Events
7.11.2.1
Adverse Events
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). All 
AEs will be presented in a by-patient listing. Treatment-emergent AEs are AEs that occur after 
administration of the first dose of any study drug and through 30 days after the last dose of any study 
drug. 
Adverse events will be tabulated according to MedDRA using system organ class and preferred term 
by escalation cohort, overall for dose escalation phase, and by expansion cohort and overall for 
expansion phase. Summary of AEs 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, and once within each preferred term.
Treatment-emergent AEs will also be summarized by the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. Patients with the same AE more 
than once will have the maximum intensity of that event counted within each body system, and once 
within each preferred term. 
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The most commonly reported treatment-emergent AEs (ie, those events reported by 10% of any 
treatment arm) 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 discontinuation, and on-study deaths. 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.
In addition, TEAEs will be summarized by each dose group.
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, 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).
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.
Clinical laboratory test results from local laboratories will be used as there are no central laboratory 
test results available for this study.
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If a patient has repeated laboratory values for a given time point, the value from the last evaluation will 
be used.
By-patient listings to be presented include hematology, serum chemistry, coagulation (Table 7.b), 
urinalysis tests(Table 9.b in the protocol), serum tumor markers for phase 2 expansion cohorts (Table 
9.c in the protocol), and immunosafety markers (Table 9.d in the protocol).
The actual values of quantitative laboratory test results (hematology, serum chemistry, coagulation, 
serum tumor markers for phase 2 expansion cohorts, immunosafety markers) and percent change from 
baseline will be summarized according to the scheduled sample collection time point by escalation 
cohort, overall for dose escalation phase, and by expansion cohort and overall for expansion phase. 
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 for shift tables are included in Table 7.b: In addition, shift table will also be constructed for 
immunosafety markers to tabulate changes in baseline categories (below normal range, within normal 
range, above normal range) to post baseline worst on study categories (below normal range, within 
normal range, above normal range).
Table 7.b
Chemistry, Hematology, and Coagulation Tests
Hematology
Serum Chemistry
Coagulation
Hematocrit
Hemoglobin (Hgb)
Leukocytes with differential (WBC)
Neutrophils (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
Urate
Activated partial thromboplastin time 
(aPTT)
Prothrombin time (PT)
Fibrinogen
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Mean laboratory values over time will be plotted for key lab parameters, including Hgb, WBC, 
lymphocytes, ANC, platelets, and liver function tests (ALT, AST, alkaline phosphatase, total bilirubin), 
LDH, creatinine; CD4, CD8 and CD4/8 ratio as well). The analysis for other lab parameters may be 
performed as needed.
7.11.4
Vital Signs
The actual values of vital sign parameters (blood pressure and heart rate) and weight will be 
summarized over time by escalation cohort, overall for dose escalation phase, and by expansion cohort 
and overall for expansion phase. 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 Electrocardiograms (ECGs)
Descriptive statistics for the actual values and changes from values at baseline in 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 study entry 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 study entry assessment over time, 
and ECOG score frequency table over time will be summarized. Shifts from study entry to the worst 
post study entry score will be tabulated by escalation cohort, overall for dose escalation phase, and by 
expansion cohort and overall for expansion phase.
7.11.7
Other Observations Related to Safety
The assessment of left ventricular ejection fraction (LVEF) measured by echocardiography or MUGA 
scan will be performed at screening, Cycle 2 Day 1, Cycle 3 Day 1 then repeated every 3 cycles from 
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C3 onwards and at the end of treatment. The summary of LVEF will be tabulated as appropriate. A by-
patient listing will be presented.
7.12
Interim Analysis
The SMC will review accruing data to determine dose escalation and number of patients per cohort in 
the dose escalation phase (see Section 8.2.2 of the protocol). 
For Phase 2 cancer treatment expansion cohorts, an IDMC will be established to monitor safety and 
assess benefit/risk throughout the conduct of these portions of the study (see Section 11.2 of the 
protocol).
7.13
Changes in the Statistical Analysis Plan from the Protocol
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8.0
REFERENCES
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For non-commercial use only


For non-commercial use only