A Phase 1b/2 Study of TAK-981 Plus Pembrolizumab to Evaluate the Safety, Tolerability, and Antitumor Activity of the Combination in Patients With Select Advanced or Metastatic Solid Tumors
Phase: PHASE1
Conditions: Advanced or Metastatic Solid Tumors
Sponsor: Takeda

NCT Number: NCT04381650
Title: A Phase 1b/2 Study of TAK-981 Plus Pembrolizumab to Evaluate the Safety, 
Tolerability, and Antitumor Activity of the Combination in Patients With Select 
Advanced or Metastatic Solid Tumors
Study Number: TAK-981-1502
Document Version and Date: Amendment 6, 22 Jun 2023
Certain information within this document has been redacted (ie, specific content is masked 
irreversibly from view) to protect either personally identifiable information or company 
confidential information. 
Clinical Study Protocol

PROTOCOL 
A Phase 1b/2 Study of TAK-981 Plus Pembrolizumab to Evaluate the Safety, Tolerability, 
and Antitumor Activity of the Combination in Patients With Select Advanced or Metastatic 
Solid Tumors 
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-981-1502 
EudraCT Number: 
2020-004325-23 
Compound: 
TAK-981 
Date: 
22 June 2023 
Amendment Number: 
6 
Date 
Amendment Number 
Region 
22 June 2023 
Amendment 6 
Global 
01 July 2022 
Amendment 5 
Global 
09 September 2021 
Amendment 4 
Global 
23 April 2021 
Amendment 3 
Global 
10 February 2021 
Amendment 2 
Global 
22 April 2020 
Amendment 1 
Global 
19 February 2020 
Original protocol 
Global 
CONFIDENTIAL PROPERTY OF TAKEDA 
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement 
by the recipient that no information contained herein will be published or disclosed without written authorization 
from Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her 
staff, and applicable institutional review committee and regulatory agencies to enable conduct of the study. 

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CONFIDENTIAL 
1.0 
ADMINISTRATIVE INFORMATION 
1.1 
Contacts 
A separate contact information list will be provided to each site. 
Serious adverse event (SAE) and pregnancy reporting information is presented in Section 10.0, 
as is information on reporting product complaints. 
TDC-Americas–sponsored investigators per individual country requirements will be provided 
with emergency medical contact information cards to be carried by each patient. 
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site. 
The names and contact information for the medical monitor and responsible medical officer are 
in the study manual. 

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CONFIDENTIAL 
1.2 
Approval 
REPRESENTATIVES OF TAKEDA 
This study will be conducted with the highest respect for the individual participants in 
accordance with the requirements of this clinical study protocol and also in accordance with the 
following: 
• The ethical principles that have their origin in the Declaration of Helsinki. 
• International Council for Harmonisation (ICH) E6 Good Clinical Practice (GCP): 
Consolidated Guideline. 
• All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations. 
SIGNATURES  
The signature of the responsible Takeda medical officer (and other signatories, as applicable) can 
be found on the signature page. 
Electronic Signatures may be found on the last page of this document. 
, MD 
 
Oncology Clinical Research 
Date 
, PhD 
 
(or designee) 
Date 
, PhD 
, 
Quantitative Clinical Pharmacology 
(or designee) 
Date 
 
PPD
PPD
PPD
PPD
PPD
PPD

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CONFIDENTIAL 
1.3 
Protocol Amendment 6 Summary of Changes and Rationale 
Rationale for Amendment 6 
This section describes the changes in reference to the protocol incorporating Amendment 6.  
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 the Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
1 
Section 2.0 STUDY SUMMARY 
Section 6.3 Phase 2–Expansion 
in Select Indications 
Removed small cell lung cancer 
(SCLC) population. 
 
Removed Cohort H.  
Reflecting changes in 
study design, the SCLC 
population and Cohort 
H were removed. 
2 
Section 2.0 STUDY SUMMARY 
Section 6.3 Phase 2–Expansion 
in Select Indications 
Changed selection and timing of 
dosing. 
Clarification added to 
reflect changes in study 
design.  
3 
Section 2.0 STUDY SUMMARY 
Section 6.3.1 Early Stopping 
Rules 
Added stopping rules for Cohort F.  
 
Removed Cohorts G and H. 
Stopping rules updated 
for Cohort F to reflect 
change in Cohort F. 
 
Cohorts G and H have 
been removed from the 
study. 
4 
Section 2.0 STUDY SUMMARY 
Section 6.4 Number of Patients 
Section 13.3 Determination of 
Sample Size 
Updated number of patients. 
Number of patients was 
updated to account for 
removal of Cohorts G 
and H, and change for 
Cohort F. 
5 
Section 2.0 STUDY SUMMARY 
Section 7.1 Inclusion Criteria 
Added clarification for inclusion 
criterion #3F that patients with driver 
mutations are not eligible. 
 
Removed criteria #3G and #3H.  
Added for clarification. 
 
Head and neck 
squamous cell 
carcinoma (HNSCC) 
and microsatellite 
instability, high 
levels/mismatch-repair-
deficient (MSI-
H/dMMR) colorectal 
cancer (CRC) 
populations were 
removed from the 
study.  

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CONFIDENTIAL 
Protocol Amendment 6 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
6 
Section 2.0 STUDY SUMMARY 
Section 7.2 Exclusion Criteria 
Removed exclusion criterion #2.  
Palliative radiation in 
patients on treatment 
with TAK-981 and 
pembrolizumab has 
showed no safety 
signals, therefore 
radiation within 4 
weeks from cycle 1 day 
1 is no longer 
considered a safety 
concern.  
7 
Section 2.0 STUDY SUMMARY 
Section 13.3 Determination of 
Sample Size 
Removed Cohorts G and H. 
 
Added sample size calculation for 
Cohort F and clarified that Cohort F 
will have 2 dose levels.  
Cohorts G and H have 
been removed from the 
study. 
 
Added to provide 
rationale for sample 
size calculation in 
Cohort F.  
8 
Section 4.1.2 Cervical Cancer 
Section updated.  
Updated to reflect latest 
clinical data.  
9 
Section 4.1.3 Colorectal Cancer 
Section updated.  
Updated to reflect latest 
clinical data.  
10 
Section 4.1.4 Small Cell Lung 
Cancer 
Section removed.  
The SCLC population 
was removed from the 
study. 
11 
Section 4.1.5 Head and Neck 
Squamous Cell Carcinoma 
Section removed. 
The HNSCC population 
was removed from the 
study. 
12 
Section 4.2.6 Clinical Experience 
Section updated.  
Updated clinical data 
from the investigator’s 
brochure (IB) were 
available.  
13 
Section 4.3 Pembrolizumab 
Updated prescribing information (PI) 
reference from 2018 to 2023. 
Updated to latest PI. 
14 
Section 4.4 Rationale for the 
Proposed Study 
Updated study rationale. 
Study rationale was 
updated to reflect 
change in study design. 
15 
Section 4.5 Rationale for the 
Proposed Patient Population 
Section updated to remove 
nonsquamous non-small cell lung 
cancer (NSCLC), SCLC, and MSI-
H/dMMR CRC populations. 
The removed 
populations will not be 
part of the study as of 
Amendment 6.  

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CONFIDENTIAL 
Protocol Amendment 6 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
16 
Section 4.5.1 Rationale for the 
TAK-981 Starting Dose and 
Schedule 
Section removed. 
Rationale for starting 
dose is no longer 
necessary given 
available clinical data. 
17 
Section 4.5.1 Rationale for the 
Phase 2 Dose of TAK-981 in 
TAK-981-1502 
Removed reference to Cohorts G and 
H. 
Cohorts G and H have 
been removed from the 
study. 
18 
Section 4.6.2.1 Lymphoid and 
Hematopoietic Effects 
Updated section with latest data to 
align with IB Edition 5. 
Updated to align with 
IB Edition 5. 
19 
Section 4.6.3 Potential Effects of 
TAK-981 Based on TAK-981 
Clinical Studies 
Updated section with latest data to 
align with IB Edition 5. 
Updated to align with 
IB Edition 5. 
20 
Section 4.6.4 Potential Effects of 
Pembrolizumab 
Updated PI reference from 2018 to 
2023. 
Updated to latest PI. 
21 
Section 4.6.5 Potential 
Overlapping Toxicities 
Updated PI reference from 2018 to 
2023. 
Updated to latest PI. 
22 
Section 6.1 Overview of Study 
Design 
Updated Figure 6.a. 
Figure 6.a was updated 
to reflect changes in 
study design.  
23 
Section 6.5 Patient Replacement 
Section 9.7.2 Patient 
Replacement 
Removed “patients enrolled in Phase 
2 will not be replaced”.  
Updated to reflect 
changes in study 
design.  
24 
Section 6.6.3 Timeframes for 
Primary and Secondary 
Endpoints to Support Disclosures 
Updated duration of study. 
Changed to align with 
changes in study 
design.  
25 
Section 6.6.4 Total Study 
Duration 
Updated approximate total study 
duration from 48 months to 60 
months. 
Changed to align with 
changes in study 
design.  
26 
Section 8.1.1 TAK-981 
Updated criteria for patient discharge 
after study drug administration. 
Added as a clarification 
that in Phase 2 patients 
can be discharged 1 
hour after the 
administration of study 
drug.  
 
27 
Section 8.1.2 Pembrolizumab 
Updated PI reference from 2018 to 
2023. 
Updated to latest PI. 
28 
Section 8.5.3 Criteria for Dose 
Interruption or Dose Reduction 
Updated PI reference from 2018 to 
2023. 
Updated to latest PI. 
29 
Section 8.5.3.2 Pembrolizumab 
Dose Modification Guidelines 
Updated PI reference from 2018 to 
2023. 
Updated to latest PI. 

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CONFIDENTIAL 
Protocol Amendment 6 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
30 
Section 9.4.7 Pregnancy Test 
Added clarification that screening 
result for pregnancy must be available 
and negative before enrollment and 
dosing.  
Added for clarification.  
31 
Section 9.4.12.1 Clinical 
Chemistry, Hematology, and 
Urinalysis 
Removed assessment of turbidity and 
color from urinalysis tests.  
Assessment of turbidity 
and color is not 
necessary.  
32 
Section 9.4.13 Disease 
Assessment 
Added PET. 
Added for clarification. 
33 
Section 9.4.14.1 Primary 
Specimen Collection 
Updated Table 9.e.  
Plasma collection is 
mandatory in both 
Phase 1 and Phase 2. 
34 
Section 9.4.14.2 Tumor Biopsies 
Updated wording for collection of 
tumor biopsies.  
Wording was updated 
for clarity.  
35 
Section 9.4.14.4 Fresh Paired 
Tumor Biopsy 
Removed redundant wording for 
collection of tumor biopsies. 
Wording was updated 
for clarity.  
36 
Section 9.4.17 DNA 
Measurements 
Clarified wording for assessment of 
tumor mutations. 
Changed for 
clarification. 
37 
Section 13.2 Interim Analysis 
and Criteria for Early 
Termination 
Specified that Cohorts A to F will be 
examined for overall response rate 
below the futility boundary.  
Specified criteria to 
stop enrollment.  
38 
Appendix A 
Schedule of 
Events Table 1.b 
Added footnote for end-of-treatment 
visit.  
Added for clarification.  
39 
Appendix A 
Schedule of 
Events Table 1.b 
Added clarification for footnote p. 
Clarification to allow 
CT scans collected 
before screening as 
valid for screening. 
40 
Appendix A 
Schedule of 
Events Table 1.b 
Added columns for Cycle 4 and 
onwards.  
Added for clarification.  
41 
Appendix A 
Schedule of 
Events Table 2.b 
Added pharmacokinetics (PK) 
sampling timepoint.  
Added to evaluate the 
robustness of PK 
results.  
42 
Appendix A 
Schedule of 
Events Table 3.b 
Adjusted biomarker sampling.  
Adjusted to align with 
the biomarker sampling 
schedule. 
 

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CONFIDENTIAL 
INVESTIGATOR AGREEMENT  
I confirm that I have read and that I understand this protocol, the investigator’s brochure, 
prescribing information, and any other product information provided by the sponsor. I agree to 
conduct this study in accordance with the requirements of this protocol and also to protect the 
rights, safety, privacy, and well-being of study patients in accordance with the following: 
• The ethical principles that have their origin in the Declaration of Helsinki. 
• International Council for Harmonisation, E6 Good Clinical Practice: 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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CONFIDENTIAL 
TABLE OF CONTENTS 
1.0 
ADMINISTRATIVE INFORMATION ..............................................................................2 
1.1 
Contacts..........................................................................................................................2 
1.2 
Approval ........................................................................................................................3 
1.3 
Protocol Amendment 6 Summary of Changes and Rationale .......................................4 
2.0 
STUDY SUMMARY.........................................................................................................16 
3.0 
STUDY REFERENCE INFORMATION .........................................................................24 
3.1 
Study-Related Responsibilities ....................................................................................24 
3.2 
Coordinating Investigator ............................................................................................24 
3.3 
List of Abbreviations ...................................................................................................25 
3.4 
Corporate Identification ...............................................................................................28 
4.0 
INTRODUCTION .............................................................................................................29 
4.1 
Solid Tumors ................................................................................................................29 
4.1.1 
Lung Cancer ........................................................................................................30 
4.1.2 
Cervical Cancer ...................................................................................................30 
4.1.3 
Colorectal Cancer ................................................................................................31 
4.1.4 
Cutaneous Melanoma ..........................................................................................31 
4.2 
TAK-981 ......................................................................................................................32 
4.2.1 
Protein SUMOylation Biology in Cancer ............................................................32 
4.2.2 
Mechanism of Action ..........................................................................................32 
4.2.3 
TAK-981 in Combination With Checkpoint Inhibitors .......................................33 
4.2.4 
Nonclinical Pharmacokinetics .............................................................................35 
4.2.5 
Nonclinical Toxicology .......................................................................................35 
4.2.6 
Clinical Experience .............................................................................................36 
4.3 
Pembrolizumab ............................................................................................................38 
4.4 
Rationale for the Proposed Study ................................................................................38 
4.5 
Rationale for the Proposed Patient Population ............................................................39 
4.5.1 
Rationale for the Phase 2 Dose of TAK-981 in TAK-981-1502 .........................39 
4.5.2 
Rationale for the Tumor and Blood Tissues Collection ......................................41 
4.5.2.1 
Tumor Biopsies ...........................................................................................41 
4.5.2.2 
Blood ...........................................................................................................41 
4.6 
Potential Risks and Benefits ........................................................................................41 
4.6.1 
Potential Drug Interactions ..................................................................................41 
4.6.2 
Potential Effects of TAK-981 Based on TAK-981 Nonclinical Studies .............42 
4.6.2.1 
Lymphoid and Hematopoietic Effects ........................................................42 

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CONFIDENTIAL 
4.6.2.2 
Effects in Renal Pelvis ................................................................................43 
4.6.2.3 
IRRs and Potential for CRS ........................................................................43 
4.6.2.4 
Injection Site Reactions...............................................................................44 
4.6.2.5 
Reproductive and Development Toxicity ...................................................44 
4.6.2.6 
Genotoxicity ................................................................................................45 
4.6.3 
Potential Effects of TAK-981 Based on TAK-981 Clinical Studies ...................45 
4.6.4 
Potential Effects of Pembrolizumab ....................................................................46 
4.6.5 
Potential Overlapping Toxicities .........................................................................46 
4.6.6 
Coronavirus Disease 2019 Pandemic ..................................................................46 
5.0 
STUDY OBJECTIVES AND ENDPOINTS .....................................................................47 
5.1 
Objectives ....................................................................................................................47 
5.1.1 
Primary Objectives ..............................................................................................47 
5.1.2 
Secondary Objectives ..........................................................................................47 
5.1.3 
Exploratory Objectives ........................................................................................47 
5.2 
Endpoints .....................................................................................................................48 
5.2.1 
Primary Endpoints ...............................................................................................48 
5.2.2 
Secondary Endpoints ...........................................................................................48 
5.2.3 
Exploratory Endpoints .........................................................................................49 
6.0 
STUDY DESIGN...............................................................................................................49 
6.1 
Overview of Study Design ...........................................................................................49 
6.2 
Phase 1b–Dose Escalation ...........................................................................................50 
6.3 
Phase 2–Expansion in Select Indications .....................................................................51 
6.3.1 
Early Stopping Rules ...........................................................................................52 
6.4 
Number of Patients ......................................................................................................53 
6.5 
Patient Replacement.....................................................................................................53 
6.6 
Duration of Study .........................................................................................................53 
6.6.1 
Duration of an Individual Patient’s Study Participation ......................................54 
6.6.2 
End of Study/Study Completion Definition and Planned Reporting...................54 
6.6.3 
Timeframes for Primary and Secondary Endpoints to Support Disclosures .......54 
6.6.4 
Total Study Duration ...........................................................................................55 
6.6.5 
Posttrial Access ...................................................................................................55 
7.0 
STUDY POPULATION ....................................................................................................55 
7.1 
Inclusion Criteria .........................................................................................................55 
7.2 
Exclusion Criteria ........................................................................................................58 
8.0 
STUDY DRUG ..................................................................................................................60 

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CONFIDENTIAL 
8.1 
Study Drug Administration ..........................................................................................60 
8.1.1 
TAK-981 ..............................................................................................................61 
8.1.2 
Pembrolizumab ....................................................................................................62 
8.1.3 
Additional Instructions for Treatment Administration ........................................62 
8.2 
Definitions of DLT ......................................................................................................62 
8.3 
Definition of DLT-Evaluable Patients in Phase 1b ......................................................64 
8.4 
Phase 1b Dose Escalation Rules ..................................................................................64 
8.5 
Dose Management and Modification Guidelines ........................................................67 
8.5.1 
Intrapatient Dose Escalation ................................................................................67 
8.5.2 
Criteria for Beginning or Delaying a Subsequent Treatment Cycle ....................67 
8.5.3 
Criteria for Dose Interruption or Dose Reduction ...............................................68 
8.5.3.1 
TAK-981 Dose Modification Guidelines ....................................................68 
8.5.3.2 
Pembrolizumab Dose Modification Guidelines ..........................................71 
8.5.4 
Criteria for Discontinuation of Treatment With Study Drugs .............................76 
8.5.4.1 
TAK-981 .....................................................................................................76 
8.5.4.2 
Pembrolizumab ...........................................................................................76 
8.5.4.3 
COVID-19 Infection ...................................................................................77 
8.6 
Excluded Concomitant Medications and Procedures ..................................................77 
8.7 
Permitted Concomitant Medications and Procedures ..................................................78 
8.8 
Precautions and Restrictions ........................................................................................79 
8.9 
Management of Clinical Events ...................................................................................80 
8.9.1 
Nausea or Vomiting .............................................................................................80 
8.9.2 
Diarrhea ...............................................................................................................80 
8.9.3 
Anemia, Thrombocytopenia, or Neutropenia ......................................................81 
8.9.4 
Infusion Site Care ................................................................................................81 
8.9.5 
Lymphopenia and Opportunistic Infection Prophylaxis ......................................81 
8.9.6 
IRRs .....................................................................................................................82 
8.9.7 
CRS ......................................................................................................................82 
8.9.8 
Management of Immune-Mediated AEs .............................................................84 
8.10 
Blinding and Unblinding..............................................................................................84 
8.11 
Description of Investigational Agents .........................................................................84 
8.12 
Preparation, Reconstitution, and Dispensation ............................................................84 
8.13 
Packaging and Labeling ...............................................................................................85 
8.14 
Storage, Handling, and Accountability ........................................................................85 
8.15 
Other Protocol-Specified Materials .............................................................................86 

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9.0 
STUDY CONDUCT ..........................................................................................................86 
9.1 
Study Personnel and Organizations .............................................................................86 
9.2 
Arrangements for Recruitment of Patients ..................................................................86 
9.3 
Treatment Group Assignments ....................................................................................86 
9.4 
Study Procedures .........................................................................................................86 
9.4.1 
Informed Consent ................................................................................................87 
9.4.2 
Patient Demographics ..........................................................................................87 
9.4.3 
Medical History ...................................................................................................87 
9.4.4 
Physical Examination ..........................................................................................87 
9.4.5 
Patient Height and Weight ...................................................................................87 
9.4.6 
Vital Signs ...........................................................................................................87 
9.4.7 
Pregnancy Test ....................................................................................................88 
9.4.8 
Concomitant Medications and Procedures ..........................................................88 
9.4.9 
AEs ......................................................................................................................88 
9.4.10 
Enrollment ...........................................................................................................88 
9.4.11 
Cardiac Monitoring .............................................................................................88 
9.4.12 
Clinical Laboratory Evaluations ..........................................................................88 
9.4.12.1 Clinical Chemistry, Hematology, and Urinalysis .......................................88 
9.4.12.2 Immunosafety Markers ...............................................................................90 
9.4.13 
Disease Assessment .............................................................................................90 
9.4.13.1 Modified RECIST, Version 1.1 for Immune-Based Therapeutics 
(iRECIST) and Treatment Beyond Progression:.........................................91 
9.4.14 
Biomarker, Pharmacodynamic, and PK Samples ................................................93 
9.4.14.1 Primary Specimen Collection .....................................................................93 
9.4.14.2 Tumor Biopsies ...........................................................................................94 
9.4.14.3 Banked Tumor .............................................................................................94 
9.4.14.4 Fresh Paired Tumor Biopsy ........................................................................94 
9.4.15 
PK Measurements ................................................................................................95 
9.4.16 
Pharmacodynamic Measurements .......................................................................95 
9.4.17 
DNA Measurements ............................................................................................95 
9.5 
Completion of Study Treatment (for Individual Patients) ...........................................96 
9.6 
Completion of Study (for Individual Patients).............................................................96 
9.7 
Discontinuation of Treatment With Study Drugs and Patient Replacement ...............96 
9.7.1 
Treatment Beyond Progression ...........................................................................97 
9.7.2 
Patient Replacement ............................................................................................97 
9.8 
Study Compliance ........................................................................................................98 

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CONFIDENTIAL 
9.9 
Posttreatment Follow-up Assessments (Survival) .......................................................98 
10.0 
ADVERSE EVENTS .........................................................................................................98 
10.1 
Definitions....................................................................................................................98 
10.1.1 
Pretreatment Event Definition .............................................................................98 
10.1.2 
AE Definition ......................................................................................................98 
10.1.3 
SAE Definition ....................................................................................................99 
10.1.4 
Adverse Event of Special Interests Definition ....................................................99 
10.2 
Procedures for Recording and Reporting AEs and SAEs ..........................................100 
10.3 
Monitoring of AEs and Period of Observation ..........................................................101 
10.4 
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events ........102 
10.5 
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose) ...................................................................................................................102 
10.6 
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities .........102 
11.0 
STUDY-SPECIFIC COMMITTEES ...............................................................................103 
11.1 
Safety Monitoring Committee ...................................................................................103 
11.2 
Independent Data Monitoring Committee .................................................................103 
11.3 
Independent Review Committee ................................................................................103 
12.0 
DATA HANDLING AND RECORD KEEPING ...........................................................103 
12.1 
eCRFs .........................................................................................................................103 
12.2 
Record Retention .......................................................................................................104 
13.0 
STATISTICAL METHODS ............................................................................................105 
13.1 
Statistical and Analytical Plans ..................................................................................105 
13.1.1 
Analysis Sets .....................................................................................................105 
13.1.2 
Analysis of Demographics and Other Baseline Characteristics ........................106 
13.1.3 
Efficacy Analysis ...............................................................................................106 
13.1.3.1 Primary Efficacy Analysis ........................................................................106 
13.1.3.2 Secondary Efficacy Analysis ....................................................................106 
13.1.4 
PK Analysis .......................................................................................................107 
13.1.5 
Pharmacodynamic Analysis ..............................................................................108 
13.1.6 
PK/Pharmacodynamic Analysis ........................................................................108 
13.1.7 
Safety Analysis ..................................................................................................109 
13.2 
Interim Analysis and Criteria for Early Termination .................................................110 
13.3 
Determination of Sample Size ...................................................................................110 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE ...............................................113 
14.1 
Study-Site Monitoring Visits .....................................................................................113 
14.2 
Protocol Deviations ....................................................................................................113 

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CONFIDENTIAL 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections ................................114 
15.0 
ETHICAL ASPECTS OF THE STUDY .........................................................................114 
15.1 
IRB and/or IEC Approval ..........................................................................................114 
15.2 
Patient Information, Informed Consent, and Patient Authorization ..........................115 
15.3 
Patient Confidentiality ...............................................................................................116 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy ................................117 
15.4.1 
Publication .........................................................................................................117 
15.4.2 
Clinical Trial Registration .................................................................................117 
15.4.3 
Clinical Trial Results Disclosure .......................................................................118 
15.5 
Insurance and Compensation for Injury .....................................................................118 
16.0 
REFERENCES ................................................................................................................119 
 
LIST OF IN-TEXT TABLES 
Table 4.a 
Most Frequent (≥10% of All Patients) TEAEs in Studies TAK-981-1002, 
TAK-981-1501, TAK-981-1502, and TAK-981-1503 ..........................................37 
Table 6.a 
Primary and Secondary Endpoints for Disclosures ...............................................54 
Table 8.a 
General Dose Modification Recommendations for TAK-981 Nonhematologic 
Drug-Related AEs ..................................................................................................69 
Table 8.b 
TAK-981 Dose Adjustments for Hematologic Toxicities .....................................70 
Table 8.c 
TAK-981 Dose Modification Guidelines for CRS ................................................71 
Table 8.d 
Pembrolizumab Dose Modification Guidelines for irAEs .....................................73 
Table 8.e 
CRS Management Recommendations ...................................................................83 
Table 9.a 
Clinical Chemistry and Hematology Tests ............................................................89 
Table 9.b 
Clinical Urinalysis Tests ........................................................................................89 
Table 9.c 
Tumor Prognostic Markers ....................................................................................90 
Table 9.d 
Immunosafety Determinations in Serum ...............................................................90 
Table 9.e 
Primary Specimen Collection ................................................................................93 
Table 13.a 
Sample Size for Each Cohort and Each Stage (Cohorts A-C, and E) ..................111 
Table 13.b 
Sample Size for Each Cohort and Each Stage (Cohort D)...................................112 
Table 13.c 
CPI Primary Refractory: Sample Size for Each Cohort and Each Stage 
(Cohort F: 90 mg BIW & 120 QW) .....................................................................113 
 

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LIST OF IN-TEXT FIGURES 
Figure 4.a 
Survival Curves for the Combination of TAK-981 With Anti-PD-1 Antibody ....34 
Figure 4.b 
Survival Curves for the Combination of TAK-981 With Anti-CTLA4 
Antibody ................................................................................................................34 
Figure 6.a 
TAK-981-1502 Study Design ................................................................................50 
Figure 8.a 
Phase 1b Dose Escalation Schema .........................................................................66 
 
LIST OF APPENDICES 
Appendix A 
Schedule of Events ...............................................................................................124 
Appendix B 
Responsibilities of the Investigator ......................................................................135 
Appendix C 
Investigator Consent to Use of Personal Information ..........................................137 
Appendix D 
ECOG Scale for Performance Status ...................................................................138 
Appendix E 
Drugs That Interact With the CYP3A Family of CYPs .......................................139 
Appendix F 
Examples of Clinical Inhibitors of Pgp ................................................................141 
Appendix G 
Contraception Methods ........................................................................................142 
Appendix H 
BOIN Design .......................................................................................................144 
Appendix I 
Protocol History ...................................................................................................146 
 

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2.0 
STUDY SUMMARY  
Name of Sponsor(s): Takeda Development Center 
Americas, Inc. (TDC Americas) 
Compound: TAK-981 
Title of Protocol: A Phase 1b/2 Study of TAK-981 Plus 
Pembrolizumab to Evaluate the Safety, Tolerability, and 
Antitumor Activity of the Combination in Patients With 
Select Advanced or Metastatic Solid Tumors 
EudraCT No.: 
2020-004325-23 
Study Number: TAK-981-1502 
Phase: 1b/2 
Study Design: 
The study consists of 2 phases, Phase 1b (dose escalation) and Phase 2 (expansion in select indications). 
The study will consist of a screening period (Day –28 to −1), a treatment period, an end of treatment (EOT) visit, 
2 follow-up visits at 30 and 90 days after the last dose occurring when treatment is discontinued for any reason, 
and a survival follow-up period lasting for a maximum of 12 months for each patient after their last dose of study 
drug to monitor disease and survival status. Day 1 of the study (baseline) will be defined as the first day a patient 
receives TAK-981. One cycle of treatment will be defined as 21 days. Patients will be asked to attend clinic 
visits at regular intervals during the study for safety and efficacy assessments. 
Patients will receive treatment with TAK-981 and pembrolizumab for up to 24 months or until confirmed disease 
progression, unacceptable toxicity, or any criterion for withdrawal from the study or study drugs occurs. 
Treatment may be continued beyond disease progression, with sponsor approval, if, in the opinion of the 
investigator, the patient continues to experience clinical benefit.  
Phase 1b: Dose Escalation 
The Phase 1b portion of the study is a dose escalation of TAK-981 in combination with pembrolizumab at a 
fixed dose in patients with nonsquamous non-small lung cancer (NSCLC), cervical cancer, or microsatellite 
stable colorectal cancer (MSS-CRC). Dose escalation of TAK-981 will be guided by a Bayesian Optimal Interval 
Design (BOIN) to guide the recommended Phase 2 dose (RP2D) for the combination therapy. The RP2D will be 
determined from the collective experience in the clinic considering the safety data including the pattern of 
immune-related adverse event across all patients beyond the dose-limiting toxicity (DLT) window, preliminary 
pharmacokinetic (PK) data, preliminary pharmacodynamic data, preliminary translational data, and any early 
antitumor activity observed along with the decision boundaries from the BOIN design. 
A safety monitoring committee composed of the principal investigators, and sponsor clinician will regularly 
review safety data to ensure patients’ safety throughout the Phase 1b portion of the study and make decisions on 
dose escalation. 
Phase 2: Expansion in Select Indications 
The Phase 2 portion of the study will explore the efficacy and safety of TAK-981 in combination with 
pembrolizumab in patients with select cancers. The following cohorts will be enrolled: 
• 
Cohort A: Non-squamous NSCLC. 
• 
Cohort B: Cervical cancer. 
• 
Cohort C: MSS-CRC. 
• 
Cohort D: Cutaneous melanoma.  
• 
Cohort E: Squamous NSCLC. 
• 
Cohort F: checkpoint inhibitor (CPI) refractory squamous or nonsquamous NSCLC.  
Enrollment will be initiated in Cohorts A through D. Enrollment to Cohort E will be initiated after positive 
readouts in Stage 1 from any of Cohorts A through D. Enrollment to Cohort F will be initiated after positive 
readouts in Stage 1 from any of the lung cancer cohorts (Cohorts A or E). 
Cohorts A to E will be assessed separately using an adaptive 2-stage design for a single proportion. For Stage 1, 

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each cohort will be analyzed when a prespecified number of patients have been enrolled and had the potential to 
have at least 1 post-treatment scan (ie, after the first disease assessment, 2 months from Cycle 1, Day 1 [C1D1]). 
Enrollment will be paused at the end of Stage 1 for each arm. If the prespecified minimal response rate is not 
achieved in the first stage for a given cohort, that cohort will be closed to enrollment. If the required response 
rate during Stage 1 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 to complete the 6-month disease assessment.  
The preliminary safety and efficacy of TAK-981 in combination with pembrolizumab in primary refractory 
NSCLC will be assessed in Cohort F, which includes 2 dose-expansion levels following Simon’s 2-stage design. 
For Stage 1, each cohort will be analyzed when a prespecified number of patients (as defined in Section 13.0) 
have been enrolled and had the potential to have at least 1 posttreatment scan (ie, after the first disease 
assessment, 2 months from C1D1). However, in the absence of significant safety signals and conditional to 
passing the futility analysis in Cohorts A or E, enrollment to Cohort F may continue (up to 15 subjects in each 
dose level) after the completion of enrollment of Stage1 patients and before response evaluation of these patients. 
Cohorts A, E, and F are independent study cohorts and will be separately evaluated for efficacy.  
In Phase 2, TAK-981 will be evaluated using 2 dose regimens:  
• 
A dose of 90 mg twice weekly (BIW) (a lower biologically active dose; BIW will be on Days 1, 4, 8, and 
11) during the first 3 cycles followed by 90 mg weekly (QW) (on Days 1 and 8), both in combination with a 
fixed dose of pembrolizumab.  
• 
A dose regimen of 120 mg QW (Days 1 and 8) in a 21-day cycle (the highest, safe dose level studied in 
Phase 1, but with exposures below the maximum tolerated dose [MTD] in the first-in-human Phase 1 study 
of TAK-981 [120 mg BIW] as a single agent) in combination with a fixed dose of pembrolizumab in 
patients with NSCLC.  
Considering the totality of the data from this study (TAK-981-1502) and factoring in safety, PK, and 
pharmacodynamics data from the first-in-human single-agent study (Study TAK-981-1002), upon 
implementation of Amendment 6, TAK-981 dose of 90 mg BIW will be evaluated in Phase 2 expansion Cohorts 
A to F, while the TAK-981 dose of 120 mg QW will be initially evaluated in Cohorts A and F. Additional 
cohorts of TAK-981 at 120 mg QW may be opened in the protocol-specified cohorts to generate supplementary 
efficacy, safety, and exposure/response data to inform dose selection for further development of TAK-981.  
During Phase 2, an independent data monitoring committee will be established to monitor safety and assess 
benefit/risk throughout the conduct of the Phase 2 portion of the study. 
Primary Objectives: 
Phase 1b: 
• 
To determine the safety and tolerability of TAK-981 in combination with pembrolizumab in patients with 
select solid tumor indications. 
• 
To establish the RP2D. 
Phase 2: 
• 
To evaluate the preliminary efficacy of TAK-981 at the RP2D in combination with pembrolizumab in 
patients with select solid tumor indications. 
Secondary Objectives: 
Phase 1b: 
• 
To characterize the PK of TAK-981 in combination with pembrolizumab. 
• 
To determine the MTD and/or pharmacologically active dose of TAK-981 when administered in 
combination with pembrolizumab. 
• 
To assess the preliminary antitumor activity of TAK-981-pembrolizumab combination. 
• 
To assess target engagement of TAK-981 (small ubiquitin-like modifier [SUMO]-TAK-981 adduct 

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formation) and SUMOylation pathway inhibition in blood. 
Phase 2: 
• 
To evaluate the efficacy of TAK-981 in combination with pembrolizumab in select solid tumors as 
measured by disease control rate (DCR), durable response rate (DRR), duration of response (DOR), time to 
response (TTR), time to progression (TTP), progression-free survival (PFS), and overall survival (OS). 
• 
To evaluate the safety and tolerability of TAK-981 in combination with pembrolizumab. 
• 
To collect PK data to contribute to population PK and exposure-response (safety/efficacy) analysis. 
Patient Population:  
Male and female patients, aged 18 years or older with a histologically or cytologically documented, locally 
advanced or metastatic solid tumors in selected indications will be enrolled. 
Number of Patients: 
A total of approximately 231 patients will be enrolled in 
this study: approximately 32 patients in the Phase 1b 
dose escalation and approximately 76 to 199 patients in 
the Phase 2 portion of the study (approximately 9-23 
patients for Cohorts A-C, and E, approximately 11-36 
patients for Cohort D, and approximately 10-24 for 
Cohort F).  
Number of Sites:  
Estimated total: approximately 60, globally (United 
States, Canada, Europe, Asia, and South America). 
Dose Level(s): 
Phase 1:  
The proposed starting dose level for TAK-981 in 
combination with pembrolizumab for this Phase 1b/2 
study will be 40 mg, which is 1 dose level below the 
monotherapy dose that has cleared the DLT period in the 
ongoing first in human single-agent study 
TAK-981-1002. 
Phase 2: 
• 
Cohorts A and F: 90 mg TAK-981 BIW (on Days 1, 
4, 8, and 11) or 120 mg TAK-981 QW (on Days 1 
and 8) of each 21-day cycle. 
• 
Cohorts B, C, D, and E, each: 90 mg TAK-981 BIW 
(on Days 1, 4, 8, and 11) of each 21-day cycle. 
Patients on the TAK-981 BIW schedule in combination 
with pembrolizumab 200 mg every 21 days will be 
treated with an induction treatment period of at least 3 
cycles with the BIW schedule, followed by the QW 
schedule. 
Route of Administration: 
TAK-981: Intravenous (IV) 
Pembrolizumab: IV 
Duration of Treatment: 
Treatment with TAK-981 with pembrolizumab will be 
administered for up to 24 months or until patients meet 
any of the discontinuation criteria. 
Period of Evaluation:  
The expected period of evaluation for this study is 
48 months; approximately 24 months for enrollment 
and approximately 24 months for treatment and/or 
follow-up. 

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Main Criteria for Inclusion: 
1. Adult male or female patients aged 18 years or older. 
2. Be willing and able to provide written informed consent for the study. 
3. Have a histologically or cytologically documented, advanced (metastatic and/or unresectable) cancer as 
listed below that is incurable: 
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 prior to the 
current tumor recurrence. 
A. Non-squamous NSCLC for which prior standard first-line treatment containing an anti-PD-(1/L1) 
checkpoint inhibitor alone or in combination has failed and that has progressed on no more than 1 
prior systemic therapy. In Phase 2, patients with nonsquamous NSCLC must have not received 
more than 1 prior systemic therapy and must not have presented with disease progression during the 
first 6 months of treatment with first-line CPI/anti-PD-(1/L1)-containing therapy. 
Note: In Phase 1, patients with nonsquamous NSCLC and 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 ALK rearrangements) must have also shown progressive disease after treatment with a 
commercially available targeted therapy. In Phase 2, patients with driver mutations are not eligible. 
B. CPI-naïve cervical cancer (squamous cell carcinoma, adenosquamous carcinoma or 
adenocarcinoma of the cervix) patients for whom prior standard first-line treatment has failed and 
who have received no more than 1 prior systemic line of therapy for recurrent or Stage IVB cervical 
cancer. 
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 for whom prior standard first-line treatment has failed and who have 
progressed on/after no more than 3 chemotherapy regimens/lines. 
Note: Patients must have received prior treatment with fluoropyrimidine-, oxaliplatin-, and 
irinotecan-containing regimens if indicated. 
D. Unresectable Stage III or Stage IV cutaneous melanoma that has not received prior therapy in the 
metastatic setting. 
Note: Patients with acral melanoma are not eligible. Patients who have presented with disease 
relapse after ≥6 months of the last dose of CPI or BRAF-MEK inhibitor in the adjuvant setting are 
eligible. 
E. Squamous NSCLC for which prior standard first-line treatment containing an anti-PD-(1/L1) 
checkpoint inhibitor alone or in combination has failed. Patients must have not received more than 
1 prior systemic therapy and must not have presented with disease progression during the first 6 
months of treatment with first-line CPI/anti-PD-(1/L1)-containing therapy. 
F. Squamous or nonsquamous NSCLC for which prior standard first-line treatment containing an anti-
PD-(1/L1) checkpoint inhibitor alone or in combination has failed within 6 months from the 
initiation of the CPI. Patients must have not received more than 1 prior systemic therapy in the 
metastatic setting. 
Note: patients with driver mutations are not eligible. 
4. Have at least 1 radiologically measurable lesion based on RECIST, Version 1.1. Tumor lesions situated in a 

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previously irradiated area are considered measurable if progression has been demonstrated in such lesions. 
5. Patients in Phase 2 expansion cohorts must have a PD-L1 result in tumor tissue obtained from an FDA-
approved, or Conformité Européene (CE)-marked, or locally equivalent PD-L1 test. 
6. Willing to consent to mandatory pretreatment fresh tumor biopsy for Phase 2. 
Note: Pretreatment fresh tumor biopsy at screening can be replaced by a recent (≤12 months old) formalin-
fixed, paraffin-embedded tumor specimen. For fresh tumor biopsies, the lesion must be accessible for a low-
risk biopsy procedure (those occurring outside the brain, lung/mediastinum, and intra-abdominal space, or 
those obtained with endoscopic procedures beyond the stomach or bowel). 
7. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance 
Scale. 
8. Demonstrate adequate organ function as described below: 
A. Platelet count ≥75.0 × 109/L.  
B. Absolute neutrophil count (ANC) ≥1.0 × 109/L.  
C. Hemoglobin ≥85 g/L (red blood cell [RBC] transfusion allowed ≥14 days before assessment). 
D. Calculated creatinine clearance ≥30 mL/min using the Cockcroft-Gault formula.  
E. Aspartate aminotransferase (AST, GOT) and alanine aminotransferase (ALT, GPT) ≤3.0 times the 
upper limit of normal (ULN), <5.0 times the ULN if liver enzyme elevations are due to liver 
metastases; bilirubin ≤1.5 times the ULN. Patients with Gilbert’s syndrome may have a bilirubin 
level >1.5 times the ULN, per discussion between the investigator and the medical monitor. 
9. Left ventricular ejection fraction (LVEF) ≥40%; as measured by echocardiogram (ECHO) or multiple-gated 
acquisition (MUGA) scan. 
10. Have recovered to Grade 1 or baseline from all toxicity associated with previous therapy or have the toxicity 
established as sequela. 
Note: Neuropathy Grade ≤2, any grade alopecia, or autoimmune endocrinopathies with stable replacement 
therapy are permitted. 
11. Women of childbearing potential must have a negative serum/urine pregnancy test within 72 hours prior to 
receiving the first dose of study medication. 
12. 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 
informed consent form through 6 months after the last dose of study, or 
D. Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the 
patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], 
withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of 
contraception. Female and male condoms should not be used together.) 
13. Male patients, even if surgically sterilized (ie, status postvasectomy) 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 
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.) 
14. Must be willing and able to comply with clinic visits and procedures outlined in the study protocol. 

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Main Criteria for Exclusion: 
1. 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 ≤10 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. 
2. History of uncontrolled brain metastasis (evidence of progression by imaging over a period of 4 weeks 
and/or neurologic symptoms that have not returned to baseline). Patients with treated brain metastases are 
allowed provided they are radiologically stable, without evidence of progression for at least 4 weeks by 
repeat imaging, clinically stable, and without requirement of steroid treatment for at least 14 days prior to 
first dose of study treatment. Note: For asymptomatic patients, screening brain imaging is not required. 
3. 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. 
4. Major surgery ≤14 days from the first dose of study drug and not recovered fully from any complications 
from surgery. 
5. Prior treatment with TAK-981. 
6. Hypersensitivity to TAK-981, pembrolizumab, or any component of the drug product. 
7. Baseline prolongation of the QT interval corrected using Fridericia’s formula (QTcF) (eg, repeated 
demonstration of QTcF interval >480 ms, history of congenital long QT syndrome, or torsades de pointes). 
8. History of immune-related AEs related to treatment with immune CPIs that required treatment 
discontinuation. 
9. Receiving or requires the continued use of medications that are known to be strong or moderate inhibitors 
and inducers of cytochrome P-450 (CYP) CYP3A4/5 and strong P-glycoprotein (Pgp) inhibitors. To 
participate in this study, such patients should discontinue use of such agents for at least 2 weeks (1 week for 
CYP3A4/5 and Pgp inhibitors) before receiving a dose of TAK-981. 
10. Receipt of any live vaccine within 4 weeks of initiation of study treatment. 
11. 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 
replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for thyroid, 
adrenal or pituitary insufficiency) for endocrinopathies are not considered prohibited forms of systemic 
treatment of an autoimmune disease. 
12. History of noninfectious pneumonitis that required steroids or a history of interstitial lung disease. 
13. Has evidence of active, noninfectious pneumonitis. 
14. History of allogeneic tissue or solid organ transplant. 
15. Has active infection requiring systemic therapy. 
16. Known history of HIV infection or any other relevant congenital or acquired immunodeficiency. 
17. 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. 
18. 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 

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disease, uncontrolled hypertension despite appropriate medical therapy, ongoing symptomatic cardiac 
arrhythmias >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. 
19. 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. 
20. Female patients who are pregnant or lactating and breastfeeding. 
Main Criteria for Evaluation and Analyses: 
Primary: 
Phase 1b: 
• 
Frequency, severity, and duration of TEAEs and laboratory abnormalities for all dose groups 
according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE), Version 5.0, except cytokine release syndrome (CRS) that will be graded according to 
American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading for CRS. 
• 
Occurrence of dose-limiting toxicities (DLTs) within the first 21 days of treatment in Cycle 1. 
Phase 2: 
• 
Overall response rate (ORR) (CR + PR) as assessed by the investigator according to 
RECIST, Version 1.1). 
Secondary: 
Phase 1b: 
• 
ORR, DCR, DRR, DOR, TTR, TTP, and PFS as assessed by the investigator according to RECIST, 
Version 1.1 and the RECIST consensus guideline developed by the RECIST Working Group for the 
use of modified RECIST, Version 1.1 in cancer immunotherapy trials (iRECIST). 
• 
TAK-981-SUMO adduct formation and SUMO pathway inhibition in blood. 
• 
TAK-981 plasma concentration-time data.  
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 that will be graded according to ASTCT 
Consensus Grading for CRS. 
• 
DCR, DRR, DOR, TTR, TTP, PFS, and OS as assessed by the investigator according to RECIST, 
Version 1.1 and iRECIST; ORR as assessed by the investigator according to iRECIST. 
Statistical Considerations: 
Dose Escalation Phase (Phase 1b): 
The BOIN design will be implemented for dose escalation phase. Approximately 4 patients will be initially 
enrolled in the first cohort. 
It is estimated that up to approximately 32 DLT-evaluable patients will be enrolled in this study for the 
dose escalation phase to evaluate dose escalation for 2 dosing schedules of TAK-981 (ie, Days 1, 4, 8, and 11 or 
Days 1 and 8 in 21-day cycles).  
Efficacy Evaluation Phase (Phase 2): 
After select Phase 2 doses are identified, up to approximately 199 response-evaluable patients with select 
indications and dose levels in 8 cohorts will be enrolled in the Phase 2 study to evaluate the antitumor efficacy of 
the combination of TAK-981 and pembrolizumab.  
The primary endpoint for the Phase 2 portion is ORR (CR + PR) as assessed by the investigator according to 
RECIST, Version 1.1. The sample size consideration for Cohorts A through E is an adaptive design based on 

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Simon’s 2-stage design for a single proportion with the specified hypotheses of ORR. The sample size 
consideration for cohort F is a standard Simon’s 2-stage design. 
Sample Size Justification: 
It is anticipated that approximately 231 patients will be enrolled in this study, including the Phase 1b portion 
dose escalation phase and the Phase 2 preliminary evaluation of the antitumor efficacy of the combination at the 
select Phase 2 doses in patients with select advanced or metastatic solid tumors, such as NSCLC, cervical, MSS-
CRC, and melanoma. 
 

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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 
ADR 
adverse drug reaction 
AE 
adverse event 
AESI 
adverse event of special interest 
ALK 
anaplastic lymphoma kinase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
ASTCT 
American Society for Transplantation and Cellular Therapy 
AUC∞ 
area under the plasma concentration-time curve from time 0 to infinity 
BOIN 
Bayesian Optimal Interval Design 
BRAF V600E 
B-Raf proto-oncogene mutation V600E 
BIW 
twice weekly 
C1D1 
Cycle 1, Day 1 
cfDNA 
cell-free DNA 
COVID-19 
coronavirus disease 2019 
CPI 
checkpoint inhibitor 
CR 
complete response 
CRC 
colorectal cancer 
CRO 
contract research organization 
CRS 
cytokine release syndrome 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P-450 
DC 
dendritic cell 
DCR 
disease control rate 
DLT 
dose-limiting toxicity 
dMMR 
mismatch-repair-deficient 
DOR 
duration of response 
DRR 
durable response rate 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EGFR 
epidermal growth factor receptor 
EOT 
end of treatment 
FDA 
Food and Drug Administration 
FIH 
first-in-human 

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GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HR 
hazard ratio 
iCD 
immune confirmed progressive disease 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
iCPD 
immune-confirmed progressive disease 
iCR 
immune complete response 
IDMC 
independent data monitoring committee 
IEC 
independent ethics committee 
IFN 
interferon 
IL 
interleukin 
IP-10 
interferon gamma-induced protein 10 
iPR 
immune partial response 
irAE 
immune-related adverse event 
IRB 
institutional review board 
IRC 
independent review committee 
iRECIST 
consensus guideline developed by the RECIST Working Group for the use of modified RECIST, 
Version 1.1 in cancer immunotherapy trials 
IRR 
infusion-related reaction 
iSD 
immune stable disease 
iUPD 
immune unconfirmed progressive disease 
IV 
intravenous 
LVEF 
left ventricular ejection fraction 
mAb 
monoclonal antibody 
MCP-1 
monocyte chemotactic protein-1 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare products Regulatory Agency 
MRI 
magnetic resonance imaging 
MSI-H 
microsatellite instability, high levels 
MSI-L 
microsatellite instability, low levels 
MSS-CRC 
microsatellite stable colorectal cancer 
MTD 
maximum tolerated dose 
MUGA 
multiple-gated acquisition 
NCI 
National Cancer Institute 
NK 
natural killer 
NLNT 
new lesion-non-target 
NLT 
new lesions-target 
NRTK 
neurotrophic receptor tyrosine kinase 
NSCLC 
non-small cell lung cancer 
ORR 
overall response rate 

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OS 
overall survival 
PAD 
pharmacologically active dose 
PBMC 
peripheral blood mononuclear cell 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PD-1 
programmed cell death protein 1 
PD-L1 [PD-L2] 
programmed cell death protein 1 ligand [programmed cell death protein 2 ligand] 
PET 
positron emission tomography 
PFS 
progression-free survival 
Pgp 
P-glycoprotein 
PJP 
Pneumocystis jirovecii pneumonia  
PK 
pharmacokinetic 
PMDA 
Pharmaceuticals and Medical Devices Agency of Japan 
PR 
partial response 
PRR 
pattern recognition receptor 
QTcF 
QT interval corrected using Fridericia’s formula 
QW 
once weekly 
RANKL 
receptor activator of nuclear factor kappa-Β ligand 
RANTES 
regulated upon activation normal T-cell expressed and secreted 
RBC 
red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
ROS1 
ROS proto-oncogene 1 
RP2D 
recommended Phase 2 dose 
SAE 
serious adverse event 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SD 
stable disease 
SMC 
safety monitoring committee 
SmPC 
Summary of Product Characteristics 
SOE 
schedule of events 
SUMO 
small ubiquitin-like modifier 
TEAE 
treatment-emergent adverse event 
TME 
tumor microenvironment 
TTP 
time to progression 
TTR 
time to response 
UBC9 
ubiquitin carrier protein 9 
ULN 
upper limit of normal 
US 
United States 
Vss 
volume of distribution at steady state  

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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 
Solid Tumors 
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 CTLA-4 and programmed cell death protein 1 (PD-1)/PD-L1 (PD-1 ligand) inhibitors 
have changed the therapeutic paradigm in a growing number of indications. Overcoming T-cell 
inhibition in the tumor microenvironment (TME) 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 (Jenkins et al. 2018; Minn and Wherry 2016; Sharma et al. 
2017). 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], 
granulocytes, eosinophils, neutrophils, or monocytes/macrophages, as well as lymphoid cells 
including gamma/delta T-cells, natural killer [NK] cells, and NK T-cells) to condition the TME, 
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 which act upon multiple cell types to mold both innate and adaptive 
immunity. They directly enhance NK cell cytotoxicity and stimulate interleukin (IL)-15 
production by DCs to promote NK cell activation (Lee et al. 2000; Lucas et al. 2007). They also 
directly act upon T-cells to stimulate survival, clonal expansion, and the development of T-cell 
effector function (Curtsinger et al. 2005; Marrack et al. 1999). 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 (Diamond et al. 2011; Fuertes et al. 2011). Indeed, 
innate immune responses have been implicated in tumor surveillance via sensing of tumor DNA 
through the pattern recognition receptor (PRR) pathway (Woo et al. 2014), activation of which 
induces production of Type I IFNs, and propagation of an adaptive antitumor response as 
described above. 

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4.1.1 
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) (Siegel et al. 2019). More than 80% of lung cancers 
are classified as 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. However, 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, 
the advanced disease is incurable and will eventually progress. In the Phase 1b KEYNOTE-001 
trial of pembrolizumab in patients with advanced NSCLC, the 5-year OS rate in treatment-naive 
patients with PD-L1 expression ≥50% was 29.6%, 15.7% if PD-L1 was <50%. In patients 
previously treated whose PD-L1 expression levels were ≥50%, 1% to 49% and <1%, the 5-year 
OS rate was 25%, 12.6% and 3.5%, respectively. 
The introduction of frontline immunotherapy has changed previous treatment paradigms in 
NSCLC. In patients whose tumors progressed after CPI-based therapy, the choice of treatment 
with platinum-doublets or docetaxel depends on the chemotherapy regimen associated to the CPI 
in frontline therapy. Treatment with docetaxel plus ramucirumab in second-line therapy shows 
an overall response rate (ORR) of 23%, median progression-free survival (PFS) of 4.5 months 
(hazard ratio [HR]: 0.76, 95% CI, 0.68-0.86), and median OS of 10.5 months (HR: 0.86, 95% CI 
0.75-0.98) (Garon et al. 2014). Combination of CPI with the activation of the Type I IFN 
pathway may reinvigorate the pre-existing immune response and initiate a new antitumor 
immune response, and it has the potential to improve outcomes in NSCLC including patients 
with negative PD-L1 expression tumors. 
4.1.2 
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 (Siegel et al. 2019). 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 PFS and median OS: 5 months and 10 to 13 months, respectively (Long et al. 
2005; Monk et al. 2009; Moore et al. 2004). The addition of bevacizumab to standard first-line 
chemotherapy significantly improved median PFS (8.2 vs 5.9 months; HR: 0.67, 95% CI, 
0.54-0.82) and median OS (17.0 vs 13.3 months; HR: 0.71, 95% CI, 0.54-0.95) compared with 
chemotherapy alone. More recently, the anti-PD-1 monoclonal antibody (mAb) pembrolizumab, 
has received approval for treatment of patients with persistent or recurrent cervical cancer whose 
tumors express PD-L1 (combined positive score ≥1) either in first line of the metastatic setting in 
combination with chemotherapy with or without bevacizumab, or as a single agent in the second 
line.  

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Combinations with pembrolizumab to reinvigorate the preexisting CD8 effector population plus 
the initiation of a novel immune response may translate into a significantly higher ORR and a 
greater clinical benefit. 
4.1.3 
Colorectal Cancer 
Colorectal cancer (CRC) is the second-leading cause of cancer death worldwide, with 
51,020 deaths estimated during 2019 in the US (Siegel et al. 2019). Advanced Stage IV 
metastatic disease is the initial presentation in approximately 25% of patients with CRC, and a 
further 25% to 50% present with 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 (VEGFA)-directed mAbs, the prognosis for patients with metastatic 
CRC remains poor, with a median 5-year survival of only 12.5% in the US (Siegel et al. 2014). 
Unfortunately, current CPIs are ineffective in tumors that are mismatch-repair-proficient and 
microsatellite stable or have low levels of microsatellite instability (MSI-L). In these tumors, low 
tumor mutation burden and the lack of immune cell infiltration have been posited as mechanisms 
of immune resistance. Once the tumor has progressed to mAb-based chemo regimens, the 
2 available therapeutic options, regorafenib and trifluridine-tipiracil, have shown poor ORR 
(1.6% to 3%), with median PFS and median OS of 2 and 7 months, respectively (Mayer et al. 
2015; Van Cutsem et al. 2012).  
4.1.4 
Cutaneous Melanoma 
The worldwide incidence of melanoma has risen rapidly over the course of the past few decades. 
About 100,350 new cases and 6850 deaths are expected in 2020 in the US (Siegel et al. 2020). 
Two cytokines have shown evidence of the activity in melanoma. IFNα2b was approved by the 
FDA in the adjuvant setting in patients with high-risk malignant melanoma, and high-dose 
interleukin-2 (IL-2) in patients with metastatic melanoma. More recently, ipilimumab, 
nivolumab, the combination of both agents, and pembrolizumab have been approved by the FDA 
for the adjuvant treatment of melanoma patients. 
In the metastatic setting, CPIs as single agents, the combination of nivolumab and ipilimumab or 
nivolumab and relatlimab, and the combination of an MAPK inhibitor with the anti-PD-L1 
atezolizumab have been approved for treatment of unresectable Stage III or Stage IV melanoma. 
The Phase III KEYNOTE-006 trial conducted in patients with advanced melanoma naïve to 
immunotherapy, has shown improved median OS (33 months vs 16 months), median PFS 
(8.4 months vs 3.4 months) and higher ORR (42% vs 17%), for pembrolizumab compared with 
ipilimumab (Robert et al. 2019; Robert et al. 2015; Schachter et al. 2017). However, despite the 
remarkable improvement in survival, the prevailing unmet needs in first-line unresectable or 
metastatic malignant melanoma therapies still consolidate around the improvements in efficacy, 
creating a significant clinical opportunity to extend patients’ lives. 

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4.2 
TAK-981 
4.2.1 
Protein SUMOylation Biology in Cancer 
SUMOylation is a post-translational modification that attaches a small ubiquitin-like modifier 
(SUMO) protein to protein substrates, regulating their activity, subcellular localization, and 
stability (Geiss-Friedlander and Melchior 2007; Oken et al. 1982). There are 3 functional 
mammalian paralogues of the SUMO proteins: small ubiquitin-like modifier 1 (SUMO1), small 
ubiquitin-like modifier 2 (SUMO2), and small ubiquitin-like modifier 3 (SUMO3) (Gareau and 
Lima 2010; Geiss-Friedlander and Melchior 2007), which are attached to their substrate proteins 
as monomers (SUMO1) or poly-SUMO chains (SUMO2/3). The SUMOylation process is 
mediated by an enzymatic cascade similar to that described for ubiquitination (Geiss-Friedlander 
and Melchior 2007; Seeler and Dejean 2017). An E1 activating enzyme consisting of a 
SUMO-activating enzyme subunit 1/SUMO-activating enzyme subunit 2 heterodimer binds 
SUMO, generating a SUMO-SUMO-activating enzyme subunit 2 thioester that is transferred to 
SUMO-conjugating enzyme (ubiquitin carrier protein 9 [UBC9]), the sole E2 conjugating 
enzyme in the pathway. SUMO is then covalently attached to a lysine residue on target proteins 
by an E3 ligase. TAK-981 interrupts this cascade by forming a covalent adduct with SUMO, 
preventing its transfer from SUMO-activating enzyme to UBC9. 
SUMOylation has been reported to regulate cellular processes important for tumor cell 
proliferation and survival (Gareau and Lima 2010; Geiss-Friedlander and Melchior 2007; He et 
al. 2017; Seeler and Dejean 2017). In addition, SUMOylation has been reported to play a key 
role in the regulation of Type I IFN signaling and the innate immune response by transcriptional 
repression of Type I IFNs, 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 (Crowl and Stetson 2018; Decque et al. 
2016). 
Initiation of a Type I IFN response represents a strategy for modulating the cancer immunity 
cycle at its inception, differentiated from the currently approved immuno-oncology therapies, the 
immune CPIs, which function to disinhibit cytotoxic T-cell activity at more distal parts of the 
cycle (Chen and Mellman 2013). The full potential of leveraging Type I 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 I IFN by stimulating 
the PRR pathway through administration of agonists (such as stimulator of IFN genes protein 
[STING] or toll-like receptor agonists) have been largely limited to delivery by intratumoral 
injection, or topical application, indicative of toxicities associated with systemic administration 
(Adams 2009). Inhibition of SUMOylation represents a novel therapeutic strategy for initiating 
Type I IFN responses and promoting antitumor immune responses. 
4.2.2 
Mechanism of Action 
TAK-981 is a first-in-class small molecule inhibitor of SUMOylation. Biochemical and 
cell-based assays demonstrated that TAK-981 is a potent and selective mechanism-based 
inhibitor of SUMO-activating enzyme that inhibits SUMOylation by forming a covalent adduct 

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with SUMO when it is bound to SUMO-activating enzyme. Central to the antitumor mechanism 
of action of TAK-981 is its ability to induce expression of the potent immunomodulatory 
molecules Type I IFNs. Ex vivo assays demonstrated that TAK-981 promoted the activation of 
DCs, NK cells, and macrophages in a Type I IFN-dependent manner. In both mouse and human 
NK cells, TAK-981 promoted upregulation of the T-cell costimulatory markers CD40, CD80, 
and CD86, as well as production of inflammatory cytokines. In vivo vaccination studies with 
ovalbumin protein demonstrated enhancement of antigen cross presentation and T-cell priming 
by TAK-981. In vivo antitumor activity in a mouse syngeneic A20 tumor model was shown to be 
fully dependent on Type I IFN signaling and capable of generating CRs (defined as the absence 
of palpable tumor) dependent on the presence of CD8+ T-cells. CRs were resistant to 
re-challenge with the same (A20) but not a different (CT26) tumor, indicative of a tumor-specific 
protective immune response.  
A pharmacodynamic study assessing the response of lymphocyte populations in circulation and 
in lymphoid organs after TAK-981 administration to immune-competent BALB/c mice 
demonstrated depletion of B lymphocytes in the blood, spleen, and lymph nodes. T lymphocyte 
numbers were also decreased in the blood and spleen within 24 hours of treatment, but showed a 
marked trend toward an increase in the lymph nodes, indicative of a TAK-981-mediated T-cell 
redistribution from the periphery to the lymph nodes, consistent with previous observations of 
Type I IFN-induced T-cell redistribution (Gresser et al. 1981; Kamphuis et al. 2006; O'Neil et al. 
2017; Shiow et al. 2006). 
4.2.3 
TAK-981 in Combination With Checkpoint Inhibitors 
Combination with immune CPIs demonstrated enhanced antitumor responses in the CT26 
(combination with anti-PD-1) (Figure 4.a) and MC38 (combination with anti-CTLA4) 
(Figure 4.b) tumor models. In the CT26 tumor model, which did not show single-agent 
responsiveness to either TAK-981 or an anti-mouse PD-1 antibody, combination treatment 
resulted in a significant survival benefit relative to either single-agent treatment. Flow cytometry 
analysis revealed that those CT-26 tumors exhibiting marked growth inhibition in response to 
treatment with the TAK-981 and anti-PD-1 combination showed enhanced activation of 
CD8+ T-cells and NK cells compared to vehicle or single-agent treated tumors. 

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Figure 4.a 
Survival Curves for the Combination of TAK-981 With Anti-PD-1 Antibody 
 
PD-1: programmed cell death protein 1. 
BALB/c mice inoculated subcutaneously with CT26 tumor cells were treated with vehicle on Days 0, 3, 7, and 10, 
or with 7.5 mg/kg TAK-981 on Day 0 and 3 (blue arrows), or with 10 mg/kg anti-mouse PD-1 antibody on Days 0, 
3, 7, and 10 (green arrows), or with a combination of TAK-981 (Day 0 and 3) and anti-PD-1 antibody (Days 0, 3, 7, 
and 10). The combination of TAK-981 with anti-PD-1 resulted in significantly improved survival relative to either 
single-agent treatment (p <0.001). P-values were calculated by Weibull regression analysis. 
Figure 4.b 
Survival Curves for the Combination of TAK-981 With Anti-CTLA4 
Antibody 
 
C57BL/6 mice inoculated subcutaneously with MC38 tumor cells were treated with vehicle, TAK-981 (blue 
arrows), anti-mouse CTLA4 antibody (olive green arrows) or TAK-981 combined with anti-mouse CTLA4 on 
Days 0, 3, 7, 10, 14, and 17. The combination of TAK-981 with anti-CTLA4 resulted in significantly improved 
survival relative to TAK-981 alone (p <0.001) or anti-CTLA4 alone (p = 0.0019). P-values were calculated by 
Weibull regression analysis. 

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4.2.4 
Nonclinical Pharmacokinetics 
TAK-981 has an acceptable nonclinical pharmacokinetic (PK) profile for continuing evaluation 
and development in humans. 
• In plasma, after single intravenous (IV) administration, TAK-981 showed moderate to high 
plasma clearance and volume of distribution at steady state (Vss) after IV administration in 
mice, rats, dogs, and monkeys with half-lives varying from 2 to 6 hours among species. 
4.2.5 
Nonclinical Toxicology 
The nonclinical toxicology profile of TAK-981 has been fully characterized in a comprehensive 
toxicology program that included single- and repeat-dose studies in rats and dogs. Repeat daily 
dosing resulted in unacceptable toxicity due to multiorgan failure in rats and fever (increased 
body temperature) in dogs. Increased body temperature was observed in dogs after a single dose 
of TAK-981 at ≥3 mg/kg and was dose limiting at 12 mg/kg with body temperature reaching up 
to 40.3ºC (compared to baseline body temperature of 37.8ºC to 38.9ºC). Increased body 
temperature (0.5°C to 2.0°C) was also observed in dogs at ≥3 mg/kg in a single-dose 
cardiovascular assessment study and after repeat once-daily or once-weekly (QW) dosing. 
Increased body temperature in the cardiovascular assessment study was not associated with 
effects on blood pressure or electrocardiogram (ECG) morphology but was associated with 
increased heart rate. Because intermittent dosing on a QW or twice-weekly (BIW) schedule was 
demonstrated to be efficacious in mouse models, both QW and BIW schedules were examined in 
Good Laboratory Practices (GLP) toxicology studies. Once per week 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, twice-weekly 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. In the Phase 1 clinical trial, patients 
have been dosed on either a QW or BIW schedule.  
The primary toxicity with BIW dosing was dose-dependent mild to marked decreases in 
peripheral blood lymphocyte counts that affected T cells, T-cell subsets (helper, cytotoxic, 
activated, memory, regulatory), B cells, and NK cells approximately equally. Decreases in 
lymphocyte count were associated with decreases in lymphoid cellularity in the primary and 
secondary lymphoid organs including the thymus, spleen, lymph nodes, and gut-associated 
lymphoid tissue. Decreases in other circulating cell types including neutrophils, monocytes, 
basophils, and/or eosinophils were also observed, but were of decreased severity compared to 
decreases in lymphocyte counts. Additional effects observed with twice-weekly 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), IFN gamma-induced 
protein 10 (IP-10) (rats only), and RANTES (regulated upon activation normal T-cell expressed 
and secreted) (rats only) at ≥0.5 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 

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once-weekly 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 considered to be monitorable, except for 
inflammation and vascular necrosis in the renal pelvis in dogs. All target organ toxicities were 
completely or partially reversible. 
An in vitro cytokine release assay was performed to evaluate the risk of TAK-981 to produce 
clinically significant CRS, and results were considered negative. TAK-981 was not mutagenic in 
a GLP-compliant Ames assay; however, TAK-981 was associated with genotoxicity at ≥5 mg/kg 
in an in vivo micronucleus assay in rats and was clastogenic in an in vitro chromosomal 
aberration assay with human peripheral blood lymphocytes. Reproductive and developmental 
toxicity studies have not been conducted; however, there were no TAK-981–related reproductive 
findings in rats or dogs with BIW dosing or in dogs with QW dosing. In the rat study with QW 
dosing, there were partially to fully reversible microscopic findings in reproductive tissues; in a 
non–GLP-compliant 7-day repeat-dose toxicity study in male rats, there were microscopic and 
organ weight changes in reproductive tissues in animals that had significant systemic toxicity. 
TAK-981 did not demonstrate phototoxic potential in an in vitro assay. 
4.2.6 
Clinical Experience 
TAK-981 is being evaluated in 4 clinical studies: 1 first-in-human (FIH) Phase 1/2 study in 
patients with advanced or refractory solid tumors or lymphomas (Study TAK-981-1002), 1 Phase 
1/2 clinical study in combination with rituximab in patients with relapsed/refractory indolent or 
aggressive CD20+ non-Hodgkin lymphomas (Study TAK-981-1501), 1 Phase 1b/2 clinical study 
in combination with pembrolizumab in patients with select advanced or metastatic solid tumors 
(Study TAK-981-1502), and 1 Phase 1b/2 study in combination with anti-CD38 monoclonal 
antibodies in adult patients with relapsed/refractory multiple myeloma (Study TAK-981-1503). 
As of the 28 June 2022 data cutoff for the investigator’s brochure (IB), 194 patients have been 
treated with TAK-981 across 4 clinical trials; 92 patients have received single agent TAK-981, 
and 102 patients have received TAK-981 as part of a combination regimen. Overall, TAK-981 
has been well tolerated, and the type of treatment-emergent adverse events (TEAEs) are 
consistent with induction of interferon signaling or were consistent with the patients’ underlying 
cancer disease (see Section 4.6.2 and Section 8.9 for more details). The most common TEAEs 
(>20%) in the total population in Studies TAK-981-1002, TAK-981-1501, TAK-981-1502, and 
TAK-981-1503 are fatigue, pyrexia, nausea, diarrhoea, chills, headache, vomiting, decreased 
appetite, anaemia, and dyspnoea (Table 4.a). Overall, preliminary efficacy is being observed, and 
efficacy evaluations are ongoing. (Refer to current TAK-981 IB for details).  

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Table 4.a 
Most Frequent (≥10% of All Patients) TEAEs in Studies TAK-981-1002, 
TAK-981-1501, TAK-981-1502, and TAK-981-1503 
Preferred Term 
Number of Patients (%) 
Total (N = 194) 
Fatigue 
90 (46.4) 
Pyrexia 
79 (40.7) 
Nausea 
70 (36.1) 
Diarrhoea 
67 (34.5) 
Chills 
65 (33.5) 
Headache 
59 (30.4) 
Vomiting 
50 (25.8) 
Decreased appetite 
49 (25.3) 
Anaemia 
42 (21.6) 
Dyspnoea 
39 (20.1) 
Hypokalaemia 
36 (18.6) 
Arthralgia 
33 (17.0) 
Abdominal pain 
31 (16.0) 
Back pain 
26 (13.4) 
Oedema peripheral 
26 (13.4) 
Constipation 
25 (12.9) 
Stomatitis 
23 (11.9) 
Hypomagnesaemia 
22 (11.3) 
Insomnia 
21 (10.8) 
Cough 
20 (10.3) 
Source: TAK-981 IB Edition 5, Table 5.e (data cutoff date: 28 June 2022). 
IB: investigator’s brochure; TEAE: treatment-emergent adverse event. 
 
In Study TAK-981-1002, the maximum tolerated dose (MTD) was determined to be 120 mg; the 
recommended Phase 2 dose (RP2D) for single agent TAK-981 is 90 mg given BIW (Days 1, 4, 
8, and 11) in a 21-day cycle. Out of the 92 patients, 4 dose-limiting toxicities (DLTs) 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 2 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 (3-120 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, anaemia, and dyspnoea. 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 

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IV fluids for low blood pressure). No patient with CRS required vasoactive drug support or 
anti-IL-6 directed therapies. 
Refer to the TAK-981 IB for additional details. 
Overall, TAK-981 has been well tolerated. The majority of the observed adverse events (AEs) 
were consistent with the patients’ underlying cancer disease. 
4.3 
Pembrolizumab 
Pembrolizumab is a humanized immunoglobulin G4 (IgG4) mAb with high specificity of 
binding to the PD-1 receptor, thus inhibiting its interaction with PD-L1 and programmed cell 
death protein 2 ligand (PD-L2) (Keytruda (pembrolizumab) Injection for Intravenous Use 2023). 
Preclinical data demonstrated the high affinity and potent receptor blocking activity for PD-1. 
Pembrolizumab has an acceptable clinical safety profile as an IV immunotherapy for advanced 
malignancies. Pembrolizumab is indicated for treatment across several indications (Keytruda 
(pembrolizumab) Injection for Intravenous Use 2023). 
4.4 
Rationale for the Proposed Study 
Encouraging clinical data emerging in the field of tumor immunotherapy have demonstrated that 
therapies focused on enhancing T-cell responses against cancer can result in a significant 
survival benefit in patients with Stage IV cancer (Hodi et al. 2010; Kantoff et al. 2010). 
However, currently only a minority of patients respond to immunotherapeutics.  
Combination strategies to help increase antigen release and T-cell priming, promote T-cell 
activation and homing, or improve the tumor microenvironment can help overcome the tumor 
immune-evasive mechanisms and maximize efficacy to ultimately benefit the majority of 
patients. Currently, interest on the cellular elements participating in the initiation of the tumor 
immunity cycle, has emerged as a key combination strategy to overcome intrinsic resistance to 
CPIs. 
Triggering the release of modulators of the innate immune response such as Type I IFNs may 
activate DCs and induce pro-inflammatory cytokines and chemokines that lead to increased 
antigen cross presentation, T-cell activation and recruitment to the tumor sites, or the modulation 
of the TME. In addition, most of the antigen-presenting cells, tumor-associated macrophages, 
and NK cells in the TME are considered dysfunctional (Broz et al. 2014), which can lead to 
ineffective activation and recruitment of antitumor-specific T-cells and resistance to CPIs. 
Therefore, the induction of Type I IFN signal in cells of the innate immune response may be 
required to generate optimal DC activation, cross-priming and recruitment of CD8 T-cells, and to 
reinvigorate the adaptive immune response.  
Preclinical evidence supports the above synergy. In the CT26 syngeneic tumor model, which did 
not show single agent responsiveness to either TAK-981 or an anti-mouse PD-1 antibody, 
combination treatment resulted in a significant survival benefit. Similar observations were noted 
in the MC38 tumor model in combination with anti-mouse CTLA4. Flow cytometry analysis 
revealed that those CT-26 tumors exhibiting marked growth inhibition in response to treatment 

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with the TAK-981 and anti-PD-1 combination showed enhanced activation of CD8+ T-cells 
compared to vehicle or single-agent treated tumors (sponsor data on file). 
Therefore, the induction of a Type I IFN signal in the cells of the innate immune response in 
combination with the reinvigoration of the CD8 effector population with a CPI may translate into 
a significantly higher clinical benefit in a broader patient population than treatment with CPIs 
alone. 
The pharmacodynamic studies performed to date at dose levels ranging from 3 to 120 mg 
provide evidence of dose-dependent target engagement (TAK-981-SUMO adduct) and 
SUMOylation pathway inhibition in blood and skin; induction of a Type I IFN response assessed 
by several complementary methods, including gene expression in blood and increase in plasma 
cytokines and chemokines; and activation of an innate and adaptive response observed by an 
increase in the proportion of CD69-positive NK and T-cytotoxic cells in the circulation, 
respectively. In total, the evidence for Type I IFN response is most convincing beginning at the 
60 mg cohort and onwards.  
4.5 
Rationale for the Proposed Patient Population 
The objective of this study is to determine the safety and tolerability of TAK-981 in combination 
with pembrolizumab, and whether the combination leads to a higher objective response rate than 
current treatment options in patients with select solid tumor types. 
This is a multicenter, nonrandomized, multi-cohort study of TAK-981 in combination with 
pembrolizumab in patients with advanced solid tumors. Patients with any of the 4 specified solid 
tumor types (NSCLC, cervical, microsatellite stable colorectal cancer [MSS-CRC], cutaneous 
melanoma) will be enrolled. These tumor types were selected because (1) each represents a 
significant unmet medical need in the metastatic/refractory setting, (2) there is some evidence of 
limited clinical response to checkpoint blockade for these indications (Brahmer et al. 2015; 
Chung et al. 2019; Gadgeel et al. 2019; Gandhi et al. 2018; Herbst et al. 2016; Horn et al. 2017; 
Le et al. 2015; O'Neil et al. 2017; Overman et al. 2018; Overman et al. 2017; Reck et al. 2019; 
Rittmeyer et al. 2017; West et al. 2019), and (3) these indications broadly represent different 
immune contextures (inflamed, immune excluded, and immune desert). This approach will 
permit the assessment of the impact of TAK-981 on the tumor microenvironment of different 
tumors and the ability to induce and/or enhance an anti-tumor immune response. 
4.5.1 
Rationale for the Phase 2 Dose of TAK-981 in TAK-981-1502 
Traditionally, the RP2D of cytotoxic anticancer agents was determined by DLTs given the 
assumption that the highest tolerable dose could result in better therapeutic activity. For some 
current drugs, such as TAK-981, with new mechanisms of action, the classical approach using 
only toxicity to define a RP2D may not be sufficient (Hansen et al. 2017). With targeted drugs, 
increasing doses beyond a certain level may not enhance the therapeutic activity, DLTs and a 
MTD may not be observed, and more serious TEAEs may only occur after multiple cycles of 
therapy (Shah et al. 2021). In addition to safety and tolerability, biological results, such as PK, 
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with these molecularly targeting agents, for which clinical benefit is not necessarily dose 
dependent. Therefore, the optimal method to define Phase 2 dose remains unclear in this setting 
(Shah et al. 2021) (Hansen et al. 2017).  
As per protocol in Study TAK-981-1502, the dose to be evaluated in the Phase 2 expansion 
could be the MTD, based on observed DLTs following Bayesian logistic regression modeling 
guidance; alternatively, the expansion dose could be a dose below MTD considering other 
non-DLT safety and tolerability information as well as other data, including but not limited to 
PK, pharmacodynamic, and exposure/response findings. Further, the dose and schedule for the 
combination of TAK-981 and pembrolizumab to be taken forward for future efficacy studies 
could be determined either at the end of Phase 1 or Phase 2, considering all these circumstances. 
Overall, the Phase 2 dose will be determined from the collective experience in the clinic, 
considering the safety data, preliminary PK data, preliminary pharmacodynamics data, and any 
observed early antitumor activity.  
In study TAK-981-1502, other parameters in addition to toxicity, such as PK, 
pharmacodynamics, and efficacy, were considered in the decision regarding the dose(s) to be 
evaluated in the Phase 2 expansion. Dose-dependent pharmacological effects, defined by target 
engagement and Type I IFN signaling, have been reported with similar magnitude and duration 
of pharmacodynamic responses when administered alone or in combination with 
pembrolizumab. These pharmacodynamic readouts were observed from the TAK-981 dose level 
of 60 mg and up to the dose level of 120 mg. Across the doses evaluated in this study, the PK of 
TAK-981 was linear with approximately dose-proportional increases in area under the plasma 
concentration-time curve from time 0 to infinity (AUC∞). There was no accumulation of 
TAK-981 from C1D1 to C1D8 after either QW or BIW dosing, and plasma exposures were 
similar when TAK-981 was administered alone or in combination with pembrolizumab. 
PK/pharmacodynamics relationship modeling show dose-dependent target engagement that 
begins to plateau approximately at the 60 mg dose with a near maximal pharmacodynamic effect 
in terms of Type 1 IFN effector cell activation at the 120 mg dose of TAK-981. The currently 
available data in the dose- or exposure-response analyses have not been able to inform a dose 
selection, likely because of the small heterogenous sample sizes in some of the dose cohorts in 
this Phase 1 dose escalation phase. As previously noted, in this study combining TAK-981 with 
pembrolizumab, MTD was not identified, and antitumor activity has been seen across 90 BIW 
and 120 mg QW dose levels.  
Therefore, considering the totality of the data from this study (TAK-981-1502) and factoring in 
safety, PK, and pharmacodynamics data from the FIH single-agent study (Study 
TAK-981-1002), upon implementation of Amendment 6, TAK-981 dose of 90 mg BIW will be 
evaluated in Phase 2 expansion Cohorts A to F, while the TAK-981 dose of 120 mg QW will be 
initially evaluated in Cohort A and F. Additional cohorts of TAK-981 at 120 mg QW may be 
opened in the protocol-specified cohorts to generate supplementary efficacy, safety, and 
exposure/response data to inform dose selection for further development of TAK-981. 

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4.5.2 
Rationale for the Tumor and Blood Tissues Collection 
4.5.2.1 
Tumor Biopsies 
For patients in Phase 2, baseline (pretreatment) tumor collection is mandatory. Either a fresh 
tumor biopsy or banked tumor taken within 12 months of enrollment is required. This sample 
will be assessed for features of the tumor and/or tumor microenvironment including immune cell 
content and tumor mutations. 
The collection of paired tumor biopsies at screening and on treatment will be encouraged (but 
optional) for all patients enrolled in the study. When provided, paired tumor biopsies will be 
used to determine TAK-981-SUMO adduct formation and SUMO pathway inhibition, as well as 
expressional and functional modulation of the immune response in the tumor/TME. Induction of 
an innate and/or adaptive immune response and checkpoint modulation in the tumor and TME 
will be assessed by measuring levels of IFN-regulated gene transcripts (messenger RNA) as well 
as by measuring levels of PD-1 and PD-L1 expression and activation state of tumor-infiltrating 
lymphocytes and myeloid cells, including NK cells and macrophages. 
4.5.2.2 
Blood 
Blood samples will be collected to demonstrate TAK-981-SUMO adduct formation, SUMO 
pathway inhibition, and activation of an innate and/or adaptive immune response. This will be 
assessed by measuring levels of select plasma chemokines and cytokines (eg, CXCL10, MCP-1, 
and macrophage inflammatory protein MIP-1β), by detection of up-regulation of Type 1 IFN 
pathway-related genes, and by cellular markers of NK and T cell activation, T cell proliferation, 
and exhaustion. Plasma samples will be collected for evaluation of cell-free DNA (cfDNA) for 
assessment of tumor mutation burden. 
4.6 
Potential Risks and Benefits 
TAK-981 is currently being evaluated as a single agent in the FIH study TAK-981-1002, in 
combination with rituximab in the Phase 1b/2 study TAK-981-1501, and in combination with 
anti-CD38 monoclonal antibodies in the Phase 1b/2 study TAK-981-1503, and, as such, the 
clinical benefits and risks have not yet been completely determined. The only serious adverse 
reaction considered expected for safety reporting purposes across the ongoing TAK-981 studies 
is pyrexia. Preliminary safety information in described in Section 4.2.6. 
During this study, risk mitigation strategies include but are not limited to the following: 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. 
4.6.1 
Potential Drug Interactions 
TAK-981 is metabolized by cytochrome P-450 (CYP)2C9, 2C19, 2D6, 3A4, and aldehyde 
oxidase. CYP3A4/5 and aldehyde oxidase were the major contributors to the metabolism of 
TAK-981 with 70% to 76% and 19.1% contribution, respectively. 

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Pembrolizumab undergoes catabolism to small peptides and single amino acids via general 
protein degradation routes and does not rely on metabolism for clearance (Longoria and Tewari 
2016). 
Therefore, the potential risk for drug-drug interactions in patients treated with a combination of 
TAK-981 and pembrolizumab is very unlikely. 
4.6.2 
Potential Effects of TAK-981 Based on TAK-981 Nonclinical Studies 
The potential risks listed below are based on findings from GLP repeat-dose nonclinical 
toxicology studies with QW or BIW dosing in rats and dogs, and a single-dose safety 
pharmacology study in dogs. These events may or may not develop in human patients treated 
with TAK-981. 
Clinical study protocols for TAK-981 will include monitoring for the potential AEs specified for 
this compound using routine laboratory evaluations, urinalysis, cardiac monitoring, physical 
examinations, and disease assessment. The timing of these tests and evaluations is detailed in the 
schedule of events (SOE) (Appendix A). Additional tests and evaluations will be considered 
based on symptoms and findings observed in the study. 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. 
Further details for TAK-981 administration and safety event management can be found in the 
Guidance for Investigator section of the IB. 
4.6.2.1 
Lymphoid and Hematopoietic Effects 
Dose-dependent reversible or partially reversible lymphoid/hematopoietic effects, including 
peripheral lymphopenia and decreased cellularity in lymph nodes, spleen, thymus, gut-associated 
lymphoid tissue, and bone marrow were observed in rats and dogs. Decreased cellularity of 
lymphoid tissues contributed to decreases in leukocyte counts. These findings 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 standard of care. 
As of the data cutoff for the IB Edition 5 in the ongoing clinical studies (N = 194), instances of 
lymphocyte count decreased (6.2%) related to TAK-981 have been reported. No serious 
infections or opportunistic infections associated with lymphocyte count decrease have been 
reported to date. Herpes simplex viral infections have been observed (2.6% related to TAK-981) 
and 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 

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Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] Grade ≥3) 
is the strongest predictor for opportunistic infections. The initiation of Pneumocystis jirovecii 
pneumonia (PJP) prophylaxis and herpes virus prophylaxis will be considered at the discretion of 
the investigator. 
4.6.2.2 
Effects in Renal Pelvis 
TAK-981–related effects were observed in the kidney in dogs following repeat daily to BIW 
dosing at higher doses and consisted of inflammation and arteriolar fibrinoid necrosis localized 
to the renal pelvis. There were no effects in the renal cortex or medulla; there were no 
repercussions on kidney function or conventional urinary test parameters. After a 10-day 
nondosing period, arteriolar fibrinoid necrosis was completely reversed and inflammation was 
partially reversed. Lesions in the renal pelvis could be associated with alterations in urinary 
sediment and susceptibility to urinary infections in the clinic, although these potential effects 
were not observed in dogs. 
Inflammation in the renal pelvis suggests a local effect of concentrated drug or a metabolite. 
Patients will be asked to maintain adequate hydration (1.5 to 2 L/day) 48 hours before initiating 
therapy, and IV fluid administration on Cycle 1, Day 1 (C1D1) will be recommended for those 
who cannot maintain adequate oral hydration. Patients will be monitored for renal function, and 
in patients with significant alterations in urinalysis, urine sediment analysis will be required. 
4.6.2.3 
IRRs and Potential for CRS 
The mechanism of action of TAK-981 involves Type I IFN signaling. Thus, the potential for 
IRRs and CRS was examined in the twice-weekly GLP toxicity studies in rats and dogs. Modest 
increases in MCP-1, IP-10 (rats only), and RANTES (rats only) were observed while no 
increases in cytokines related to CRS were observed. 
An in vitro cytokine release assay was performed with human whole blood for hazard 
identification of clinically significant CRS. There were no effects on cytokines typically 
associated with CRS; TAK-981-related effects were limited to moderate increases in IP-10 at 
≥0.5 µM. 
In a single-dose safety pharmacology study, acute and transient mild increases in body 
temperature and reactive increases in heart rate without changes in blood pressure were observed 
in dogs from 6 to 24 hours after the infusion. In a single-dose non-GLP-compliant dog toxicity 
study, fever was considered a DLT at the high dose of 12 mg/kg. Non-dose-limiting increases in 
body temperatures were noted in studies with daily and once weekly dosing at ≥3 mg/kg. No 
changes in body temperature, heart rate, or respiratory rate were observed in the GLP-compliant 
twice-weekly dog study. 
 
 
 
 
As a precaution for IRRs/CRS, patients in dose escalation will be monitored for a minimum of 
6 hours after the first infusion of TAK-981. For the remaining infusions during Cycle 1 (and only 
CCI

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in case no IRR AEs are being observed), the patient will be observed a minimum of 2 hours after 
the end of infusion of the last study drug and can only be discharged if clinically stable. 
As an additional precaution measure, for the first cohort in dose escalation only, patient 
enrollment will be staggered between the first and second patients by 7 days. The second and 
third patients can be dosed concurrently if the first patient in the cohort has gone through the 
Day 8 visit without clinically significant acute toxicities. Subsequent cohorts will not require 
staggering between patients. 
4.6.2.4 
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. 
4.6.2.5 
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 rat and dog 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 

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• 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 
• 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 postvasectomy) 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.) 
4.6.2.6 
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. TAK-981 was 
considered clastogenic in an in vitro chromosomal aberration test using human peripheral blood 
lymphocytes. In compliance with International Council for Harmonisation (ICH) S9 guidance 
(2009), 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. 
4.6.3 
Potential Effects of TAK-981 Based on TAK-981 Clinical Studies 
The safety of TAK-981 as single agent has been evaluated in patients with solid tumors or 
lymphomas in the FIH clinical Study TAK-981-1002, in combination with rituximab in patients 
with lymphomas in the clinical Study TAK-981-1501, in combination with pembrolizumab in 
patients with select solid tumor types in Study TAK-981-1502, and in combination with 
anti-CD38 mAbs in patients with relapsed and/or refractory multiple myeloma in Study 
TAK-981-1503 (Section 4.2.6). Refer to current IB for more details.  

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4.6.4 
Potential Effects of Pembrolizumab 
Pembrolizumab toxicities are generally associated with the activation of autoreactive T-cells 
resulting in immune-related adverse events (irAEs) and embryofetal toxicity. The safety of 
pembrolizumab at 200 mg every 3 weeks has been evaluated in multiple clinical studies, and the 
most common adverse drug reactions (ADRs) (≥20%) were fatigue, diarrhea, and nausea. The 
majority of ADRs reported were of Grade 1 or 2 in severity. For detailed information regarding 
the safety of pembrolizumab administration, please refer to the FDA-approved package insert 
(Keytruda (pembrolizumab) Injection for Intravenous Use 2023). 
4.6.5 
Potential Overlapping Toxicities 
Nonclinical toxicology studies evaluating the combination of TAK-981 and pembrolizumab were 
not conducted and are not warranted per ICH S9 (2009). Pembrolizumab is a mAb that binds to 
the human PD-1 receptor and blocks the interaction of PD-1 with PD-L1/PD-L2. 
Compared to treatment with TAK-981 alone, synergistic toxicity as assessed by increased 
mortality or more significant decreases in body weight was not observed in mouse tumor-bearing 
models administered TAK-981 in combination with an antimurine PD-1 antibody. TAK-981 and 
pembrolizumab both activate the immune system, so known PD-1 immunotherapy-related 
toxicities (eg, pneumonitis, colitis, hepatitis, dermatitis, IRRs, endocrinopathies, and nephritis) 
observed following the administration of pembrolizumab may be enhanced when combined with 
TAK-981. Details regarding the full safety profile of pembrolizumab can be found in the FDA 
approved package insert (Keytruda (pembrolizumab) Injection for Intravenous Use 2023). 
To minimize the risk to patients treated with TAK-981 and pembrolizumab, the proposed starting 
dose for TAK-981, in combination with pembrolizumab, will be at least 1 dose level below the 
clinically tested highest safe dose defined in the single-agent FIH study (Study TAK-981-1002) 
and will be determined by the sponsor and participating investigators after review of the 
emerging safety data from the ongoing FIH single-agent study. Pembrolizumab will be 
administered at the approved dose and schedule of 200 mg IV once every 3 weeks to maximize 
the possibility of observing clinical benefit. 
4.6.6 
Coronavirus Disease 2019 Pandemic 
The coronavirus disease 2019 (COVID-19) pandemic has affected health care and specifically 
cancer care broadly across the globe. Based on current knowledge, the benefit/risk assessment 
for patient participation in this study remains favorable. The benefit/risk considerations for 
patient participation should be evaluated by the investigator on a patient-by-patient basis taking 
into consideration the current local situation, guidelines, and recommendations. Investigators 
should follow local recommendations and guidelines with regards to COVID-19 precautions, 
vaccination, and treatment. 

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5.0 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
5.1.1 
Primary Objectives 
The primary objectives are: 
Phase 1b: 
• To determine the safety and tolerability of TAK-981 in combination with pembrolizumab 
in patients with select solid tumor indications. 
• To establish the recommended Phase 2 dose (RP2D). 
Phase 2: 
• To evaluate the preliminary efficacy of TAK-981 at the RP2D in combination with 
pembrolizumab in patients with select solid tumor indications. 
5.1.2 
Secondary Objectives 
The secondary objectives are: 
Phase 1b: 
• To characterize the PK of TAK-981 in combination with pembrolizumab. 
• To determine the MTD and/or pharmacologically active dose (PAD) of TAK-981 when 
administered in combination with pembrolizumab. 
• To assess the preliminary antitumor activity of TAK-981-pembrolizumab combination. 
• To assess target engagement of TAK-981 (SUMO-TAK-981 adduct formation) and 
SUMOylation pathway inhibition in blood. 
Phase 2: 
• To evaluate the efficacy of TAK-981 in combination with pembrolizumab in select solid 
tumors as measured by disease control rate (DCR), durable response rate (DRR), DOR, time 
to response (TTR), time to progression (TTP), PFS, and OS. 
• To evaluate the safety and tolerability of TAK-981 in combination with pembrolizumab. 
• To collect PK data to contribute to population PK and exposure-response (safety/efficacy) 
analysis. 
5.1.3 
Exploratory Objectives 
The exploratory objectives are: 
• To assess pharmacodynamic biomarkers in peripheral blood such as immune cell activation 
and gene and protein expression. 

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• To assess pharmacodynamic biomarkers in tumors such as SUMO pathway inhibition, gene 
expression and tumor-infiltrating immune cells. 
• To explore potential predictive biomarkers of response to combination therapy by exploring 
correlations between baseline molecular and cellular characterization of peripheral blood and 
tumor biomarkers (this may include genomic/transcriptomic/proteomic approaches) with 
efficacy and other clinical endpoints of interest.  
• To explore mechanisms of resistance in peripheral blood samples collected from patients 
who initially respond to TAK-981 in combination with pembrolizumab therapy and then 
exhibit disease progression. 
• Exploratory endpoints, such as evaluating circulating serum proteins, cell-free DNA 
(cfDNA), exosomes, and mRNA signatures associated with response or resistance to TAK-
981 in combination with pembrolizumab treatment, will be executed as warranted to further 
understand TAK-981 mechanism of action and potential responsive patient populations. 
5.2 
Endpoints 
5.2.1 
Primary Endpoints 
The primary endpoints are: 
Phase 1b: 
• Frequency, severity, and duration of TEAEs and laboratory abnormalities for all dose 
groups according to the NCI CTCAE, Version 5.0, except CRS that will be graded 
according to American Society for Transplantation and Cellular Therapy (ASTCT) 
Consensus Grading for CRS. 
• Occurrence of DLTs within the first 21 days of treatment in Cycle 1. 
Phase 2: 
• ORR (CR + PR) as assessed by the investigator according to Response Evaluation 
Criteria in Solid Tumors Version 1.1 (RECIST, Version 1.1). 
5.2.2 
Secondary Endpoints 
The secondary endpoints are: 
Phase 1b: 
• ORR, DCR, DRR, DOR, TTR, TTP, and PFS as assessed by the investigator according to 
RECIST, Version 1.1 and the RECIST consensus guideline developed by the RECIST 
Working Group for the use of modified RECIST, Version 1.1 in cancer immunotherapy 
trials (iRECIST). 
• TAK-981-SUMO adduct formation and SUMO pathway inhibition in blood.  
• TAK-981 plasma concentration-time data.  

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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 that will be graded 
according to ASTCT Consensus Grading for CRS. 
• DCR, DRR, DOR, TTR, TTP, PFS, and OS as assessed by the investigator according to 
RECIST, Version 1.1 and iRECIST; ORR as assessed by the investigator according to 
iRECIST. 
5.2.3 
Exploratory Endpoints  
The exploratory endpoints are: 
• TAK-981-SUMO adduct formation and SUMO pathway inhibition in tumor tissue. 
• Changes in pharmacodynamic biomarkers in peripheral blood such as immune cell activation 
and gene and protein expression. 
• Changes in pharmacodynamic biomarkers in tumors such as gene expression and 
tumor-infiltrating immune cells. 
• Correlative studies to explore predictive biomarkers of response to combination therapy. 
• Correlative studies to explore mechanisms of resistance to combination therapy. 
• Exploratory endpoints such as evaluating circulating serum proteins, cfDNA, and mRNA 
signatures associated with response or resistance to TAK-981 in combination with 
pembrolizumab treatment will be executed as warranted. 
6.0 
STUDY DESIGN 
6.1 
Overview of Study Design 
The study consists of 2 phases: 
• Phase 1b: Dose escalation. 
• Phase 2: Expansion in select indications. 
The study will consist of a screening period (Day –28 to −1), a treatment period, an end of 
treatment (EOT) visit, and 2 follow-up visits at 30 and 90 days after the last dose occurring when 
treatment is discontinued for any reason, and a survival follow-up period lasting for a maximum 
of 12 months for each patient after their last dose of study drug to monitor disease and survival 
status. Day 1 of the study (baseline) will be defined as the first day a patient receives TAK-981. 
One cycle of treatment will be defined as 21 days. Patients will be asked to attend clinic visits at 
regular intervals during the study for safety and efficacy assessments. 
Patients will receive treatment with TAK-981 and pembrolizumab for up to 24 months or until 
confirmed disease progression, unacceptable toxicity, or any criterion for withdrawal from the 
study or study drugs occurs. Treatment may be continued beyond disease progression, with 

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sponsor approval, if, in the opinion of the investigator, the patient continues to experience 
clinical benefit. 
A study design scheme is provided in Figure 6.a. 
Figure 6.a 
TAK-981-1502 Study Design 
 
CPI: checkpoint inhibitor; DLT: dose-limiting toxicity; FIH: first in human; IV: intravenous; MSS: microsatellite 
stable; MTD: maximum tolerated dose; NSCLC: non-small cell lung cancer; PD-1: programmed cell death protein 
1; PD-L1: programmed cell death protein 1 ligand; q21d: every 21 days; RP2D: recommended Phase 2 dose. 
 
6.2 
Phase 1b–Dose Escalation 
The Phase 1b portion of the study is a dose escalation of TAK-981 in combination with 
pembrolizumab at a fixed dose in patients with nonsquamous NSCLC, cervical cancer, or MSS-
CRC. Dose escalation of TAK-981 will be guided by a Bayesian Optimal Interval Design 
(BOIN) to guide the RP2D for the combination therapy. The RP2D will be determined from the 
collective experience in the clinic considering the safety data including the pattern of irAEs 
across all patients beyond the DLT window, preliminary PK data, preliminary pharmacodynamic 
data, preliminary translational data, and any early antitumor activity observed along with the 
decision boundaries from the BOIN design. 
In the first cohort, patient enrollment will be staggered between the first and second patients by 
7 days during dose escalation. The second and third patients can be dosed concurrently if the first 
patient in the cohort has gone through the Day 8 visit without clinically significant acute 
toxicities. Subsequent cohorts will not require staggering between patients. 

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A safety monitoring committee (SMC) composed of the principal investigators, and sponsor 
clinician will regularly review safety data to ensure patients’ safety throughout the Phase 1b 
portion of the study and make decisions on dose escalation. 
Circumstances that may warrant enrollment hold include: any death or ≥ 2 Grade 4 events not 
clearly related to underlying disease, progression of disease, or intercurrent illness, and at least 
possibly related to the investigational product. 
The stop will result in an immediate halt in enrollment and may also necessitate the halting of 
treatment of ongoing patients. The decision to halt treatment of ongoing patients, resume 
enrollment, terminate the study, or amend the protocol will be made only after a full review of 
the safety data by the SMC and the safety management team. 
6.3 
Phase 2–Expansion in Select Indications 
The Phase 2 portion of the study will explore the efficacy and safety of TAK-981 in combination 
with pembrolizumab in patients with select cancers. The following cohorts will be enrolled: 
• Cohort A: Non-squamous NSCLC. 
• Cohort B: Cervical cancer. 
• Cohort C: MSS-CRC. 
• Cohort D: Cutaneous melanoma.  
• Cohort E: Squamous NSCLC. 
• Cohort F: CPI refractory squamous or nonsquamous NSCLC.  
Enrollment will be initiated in Cohorts A through D. Enrollment to Cohort E will be initiated 
after positive readouts in Stage 1 from any of Cohorts A through D. Enrollment to Cohort F will 
be initiated after positive readouts in Stage 1 from any of the lung cancer cohorts (Cohorts A or 
E). 
Cohorts A to E 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 (as 
defined in Section 13.0) have been enrolled and had the potential to have at least 1 post-
treatment scan (ie, after the first disease assessment, 2 months from C1D1). Enrollment will be 
paused at the end of Stage 1 for each arm. If the prespecified minimal response rate is not 
achieved in the first stage for a given cohort, that cohort will be closed to enrollment. If the 
required response rate during Stage 1 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 13.0). The final analysis of the primary endpoints for each cohort will take place when 
all ongoing patients have had the opportunity to complete the 6-month disease assessment.  
The preliminary safety and efficacy of TAK-981 in combination with pembrolizumab in primary 
refractory NSCLC will be assessed in Cohort F, which includes 2 dose-expansion levels 

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following Simon’s 2-stage design. For Stage 1, each cohort will be analyzed when a prespecified 
number of patients (as defined in Section 13.0) have been enrolled and had the potential to have 
at least 1 posttreatment scan (ie, after the first disease assessment, 2 months from C1D1). 
However, in the absence of significant safety signals and conditional to passing the futility 
analysis in Cohorts A or E, enrollment to Cohort F may continue (up to 15 subjects in each dose 
level) after the completion of enrollment of Stage1 patients and before response evaluation of 
these patients. Cohorts A, E, and F are independent study cohorts and will be separately 
evaluated for efficacy.  
In Phase 2, TAK-981 will be evaluated using 2 dose regimens:  
• A dose of 90 mg BIW (a lower biologically active dose; BIW will be on Days 1, 4, 8, and 11) 
during the first 3 cycles followed by 90 mg QW (on Days 1 and 8), both in combination with 
a fixed dose of pembrolizumab.  
• A dose regimen of 120 mg QW (Days 1 and 8) in a 21-day cycle (the highest, safe dose level 
studied in Phase 1, but with exposures below the MTD in the first-in-human Phase 1 study of 
TAK-981 [120 mg BIW] as a single agent) in combination with a fixed dose of 
pembrolizumab in patients with NSCLC.  
The safety and preliminary efficacy of TAK-981 120 mg QW will be evaluated in a lead-in 
safety cohort that will initially enroll 6 patients with an enrollment pause until the 6 patients have 
had the opportunity to complete the first 3 cycles (Cohort A). Enrollment in the 120 mg cohort of 
nonsquamous non-small cell lung cancer will be discontinued if ≥4 out of 6 treated patients 
require dose reduction or drug withdrawals due to TAK-981–related AEs within the first 
3 cycles. If dose reduction or drug withdrawals due to TAK-981–related AEs within the first 
3 cycles are observed in ≤3 out of 6 treated patients, enrollment will be expanded to 
9 response-evaluable patients to complete Stage 1. Should the 120 mg dose be considered safe in 
nonsquamous-NSCLC, additional cohorts of TAK-981 at 120 mg on Days 1 and 8 in 
combination with pembrolizumab may be opened in the protocol-defined cohorts without the 
need for an enrollment pause after the first 6 patients.  
For all cohorts, the criteria to proceed to Stage 2 are provided in Section 6.3.1.  
During Phase 2, patients will be concurrently enrolled, and the sponsor/designee will assign 
patients to a respective cohort and, for Cohort A and F only, to a respective TAK-981 dose group 
(120 mg QW or 90 mg BIW). 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. 
6.3.1 
Early Stopping Rules 
In the Phase 2 portion of the study, Grade 4 or higher drug-related AEs will be monitored. 
For Cohorts A to C, and E, starting from the first 9 response-evaluable patients and then every 

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4 response-evaluable patients up to the approximate maximum number of 24 patients, accrual to 
the study will be suspended if: 
• Grade 4 drug-related AEs meet the stopping bounds of the number of ≥3/9, ≥4/13, ≥5/17, 
≥6/21, ≥6/24; or  
• At any time if 1 or more patients present with fatal drug-related AEs. 
For Cohort D, starting from the first 11 response-evaluable patients and then every 4 response 
evaluable patients up to the approximate maximum number of patients 36, accrual to the study 
will be suspended if: 
• Grade 4 drug-related AEs meet the stopping bounds of the number of ≥4/11, ≥4/15, ≥5/19, 
≥6/23, ≥7/27, ≥7/31, ≥8/35, ≥8/36; or  
• At any time if 1 or more patients present with fatal drug-related AEs. 
For Cohort F, starting from the first 10 response-evaluable patients and then every 4 response-
evaluable patients up to the approximate maximum number of patients 24, accrual to the study 
will be suspended if: 
• Grade 4 drug-related AEs meet the stopping bounds of the number of ≥3/10, ≥4/14, ≥5/18, 
≥6/22, ≥6/24; or  
• At any time if 1 or more patients present with fatal drug-related AEs. 
After review and consideration by the IDMC, a decision will be made as to whether accrual can 
be resumed. 
The stopping bounds for Grade 4 drug-related AEs are based on a Bayesian strategy to monitor 
outcomes in clinical trials. If the stopping rule is met, there is 80% probability that the true 
toxicity rate is greater than 16% with a prior beta distribution with parameters 0.4 and 1.6 for the 
binomially distributed toxicity rate (Thall and Sung 1998). 
6.4 
Number of Patients 
A total of approximately 231 patients will be enrolled in this study: approximately 32 patients in 
the Phase 1b dose escalation and approximately 76 to 199 patients in the Phase 2 portion of the 
study (approximately 9-23 patients for Cohorts A-C, and E, approximately 11-36 patients for 
Cohort D, and approximately 10-24 for Cohort F). 
6.5 
Patient Replacement 
In the Phase 1b part of the study, patients who are considered to not be evaluable for DLT 
assessment (as defined in Section 8.3) will be replaced.  
6.6 
Duration of Study 
The expected duration for this study is 48 months: approximately 24 months for enrollment and 
approximately 24 months for treatment and/or follow-up. 

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6.6.1 
Duration of an Individual Patient’s Study Participation 
Patient participation will include screening, treatment, and follow-up. Screening will last up to 
28 days before the first dose of study drug, during which the patient’s eligibility and baseline 
characteristics will be determined. Treatment with TAK-981 and pembrolizumab will be 
administered for up to 24 months or until patients meet any of the discontinuation criteria in 
Section 8.5.4. Patients who have completed treatment or have discontinued treatment will be 
followed for survival for up to 12 months. 
6.6.2 
End of Study/Study Completion Definition and Planned Reporting 
The end of study will occur when all patients have had the opportunity to complete 24 months of 
treatment; have been followed for survival for a minimum of 12 months after the last patient has 
been discontinued or completes treatment; until all patients have died, withdrawn consent, or are 
lost to follow-up; or the study is terminated (whichever occurs first). 
6.6.3 
Timeframes for Primary and Secondary Endpoints to Support Disclosures 
Table 6.a 
Primary and Secondary Endpoints for Disclosures 
Endpoint 
Definition 
Maximum Time Frame 
Primary (Phase 1):  
 
 
Frequency of TEAEs overall and per DL 
Standard safety assessments 
Up to 48 months 
Number of patients with DLTs per DL 
Standard safety assessments 
Up to 48 months 
Number/percentage of patients with Grade 
≥3 TEAEs 
Standard safety assessments 
Up to 48 months 
Number/percentage of patients with 1 or 
more SAEs 
Standard safety assessments 
Up to 48 months 
Number/percentage of patients with 1 or 
more TEAEs leading to dose modifications 
(delay, interruption, or reduction) and 
treatment discontinuations 
Standard safety assessments 
Up to 48 months 
Number/percentage of patients with 
clinically significant laboratory values 
Standard safety assessments 
Up to 48 months 
Primary (Phase 2): 
 
 
ORR as assessed by the investigator 
according to RECIST, Version 1.1 
Standard efficacy assessments 
Up to 60 months 
Secondary:  
 
 
Data permitting, PK parameters after the 
dose administration of TAK-981 on C1D1 
and C1D8: 
Cmax, tmax, AUCt, AUC∞, t1/2z, CL, Vss 
Standard PK parameters to allow 
determination of PK profile 
Up to 60 months 
ORR as defined by the investigator 
according to iRECIST modification. 
ORR 
Up to 60 months 
DCR 
DCR 
Up to 60 months 

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Table 6.a 
Primary and Secondary Endpoints for Disclosures 
Endpoint 
Definition 
Maximum Time Frame 
DRR 
DRR 
Up to 60 months 
DOR 
DOR 
Up to 60 months 
PFS  
PFS 
Up to 60 months 
TTR 
TTR 
Up to 60 months 
TTP 
TTP 
Up to 60 months 
OS 
OS 
Up to 60 months 
TAK-981-SUMO adduct formation and 
SUMO pathway inhibition 
TAK-981-SUMO adduct 
formation and SUMO pathway 
inhibition in blood 
Up to 48 months 
AUCt: area under the plasma/blood/serum concentration-time curve from time 0 to time t; AUC∞: area under the 
plasma concentration-time curve from time 0 to infinity; CxDx; Cycle x, Day x; CL: total clearance after 
intravenous administration; Cmax: maximum observed plasma concentration; DCR: disease control rate; DL: dose 
level; DLT: dose limiting toxicity; DOR: duration of response; DRR: durable response rate; iRECIST: consensus 
guideline developed by the RECIST Working Group for the use of modified RECIST, Version 1.1 in cancer 
immunotherapy trials; ORR: overall response rate; OS: overall survival; PFS: progression-free survival; PK: 
pharmacokinetic; RECIST: Response Evaluation Criteria in Solid Tumors; SAE: serious adverse event; SUMO: 
small ubiquitin-like modifier; TEAE: treatment-emergent adverse event; t1/2z: terminal disposition phase half-life; 
tmax: time of first occurrence of Cmax; TTP: time to progression; TTR: time to response; Vss: volume of distribution 
at steady state after intravenous administration. 
 
6.6.4 
Total Study Duration 
It is anticipated that this study will last for approximately 60 months. 
6.6.5 
Posttrial Access 
Treatment with TAK-981 and/or pembrolizumab will be administered for up to 24 months. 
Patients that have completed the protocol defined course of therapy will no longer receive 
treatment administration and will be followed for survival as defined in Section 6.6.1. 
7.0 
STUDY POPULATION 
7.1 
Inclusion Criteria 
Each patient must meet all the following inclusion criteria to be enrolled in the study: 
1. Adult male or female patients aged 18 years or older. 
2. Be willing and able to provide written informed consent for the study. 

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3. Have a histologically or cytologically documented, advanced (metastatic and/or unresectable) 
cancer as listed below that is incurable: 
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 prior to the current tumor recurrence. 
A. Non-squamous NSCLC for which prior standard first-line treatment containing an 
anti-PD-(1/L1) checkpoint inhibitor alone or in combination has failed and that has 
progressed on no more than 1 prior systemic therapy. In Phase 2, patients with 
nonsquamous NSCLC must have not received more than 1 prior systemic therapy and 
must not have presented with disease progression during the first 6 months of treatment 
with first-line CPI/anti-PD-(1/L1)-containing therapy. 
Note: In Phase 1, patients with nonsquamous NSCLC and 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 ALK rearrangements) must have also 
shown progressive disease after treatment with a commercially available targeted 
therapy. In Phase 2, patients with driver mutations are not eligible. 
B. CPI-naïve cervical cancer (squamous cell carcinoma, adenosquamous carcinoma or 
adenocarcinoma of the cervix) patients for whom prior standard first-line treatment has 
failed and who have received no more than 1 prior systemic line of therapy for recurrent 
or Stage IVB cervical cancer. 
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 for whom prior standard first-line treatment has failed and 
who have progressed on/after no more than 3 chemotherapy regimens/lines. 
Note: Patients must have received prior treatment with fluoropyrimidine-, oxaliplatin-, 
and irinotecan-containing regimens if indicated. 
D. Unresectable Stage III or Stage IV cutaneous melanoma that has not received prior 
therapy in the metastatic setting. 
Note: Patients with acral melanoma are not eligible. Patients who have presented with 
disease relapse after ≥6 months of the last dose of CPI or BRAF-MEK inhibitor in the 
adjuvant setting are eligible. 

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E. Squamous NSCLC for which prior standard first-line treatment containing an 
anti-PD-(1/L1) checkpoint inhibitor alone or in combination has failed. Patients must 
have not received more than 1 prior systemic therapy and must not have presented with 
disease progression during the first 6 months of treatment with first-line 
CPI/anti-PD-(1/L1)-containing therapy. 
F. Squamous or nonsquamous NSCLC for which prior standard first-line treatment 
containing an anti-PD-(1/L1) checkpoint inhibitor alone or in combination has failed 
within 6 months from the initiation of the CPI. Patients must not have received more than 
1 prior systemic therapy in the metastatic setting.  
Note: patients with driver mutations are not eligible. 
4. Have at least 1 radiologically measurable lesion based on RECIST, Version 1.1. Tumor 
lesions situated in a previously irradiated area are considered measurable if progression has 
been demonstrated in such lesions. 
5. Patients in Phase 2 expansion cohorts must have a PD-L1 result in tumor tissue obtained 
from an FDA-approved, or Conformité Européene (CE)-marked, or locally equivalent PD-L1 
test.  
6. Willing to consent to mandatory pretreatment fresh tumor biopsy for Phase 2. 
Note: Pretreatment fresh tumor biopsy at screening can be replaced by a recent (≤12 months 
old) formalin-fixed, paraffin-embedded tumor specimen. For fresh tumor biopsies, the lesion 
must be accessible for a low-risk biopsy procedure (those occurring outside the brain, 
lung/mediastinum, and intra-abdominal space, or those obtained with endoscopic procedures 
beyond the stomach or bowel). 
7. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) 
Performance Scale. 
8. Demonstrate adequate organ function as described below: 
A. Platelet count ≥75.0 × 109/L.  
B. Absolute neutrophil count (ANC) ≥1.0 × 109/L.  
C. Hemoglobin ≥85 g/L (red blood cell [RBC] transfusion allowed ≥14 days before 
assessment). 
D. Calculated creatinine clearance ≥30 mL/min using the Cockcroft-Gault formula.  
E. Aspartate aminotransferase (AST, GOT) and alanine aminotransferase (ALT, GPT) 
≤3.0 times the upper limit of normal (ULN), <5.0 times the ULN if liver enzyme 
elevations are due to liver metastases; bilirubin ≤1.5 times the ULN. Patients with 
Gilbert’s syndrome may have a bilirubin level >1.5 times the ULN, per discussion 
between the investigator and the medical monitor. 
9. Left ventricular ejection fraction (LVEF) ≥40%; as measured by echocardiogram (ECHO) or 
multiple-gated acquisition (MUGA) scan. 

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10. Have recovered to Grade 1 or baseline from all toxicity associated with previous therapy or 
have the toxicity established as sequela. 
Note: Neuropathy Grade ≤2, any grade alopecia, or autoimmune endocrinopathies with stable 
replacement therapy are permitted. 
11. Women of childbearing potential must have a negative serum/urine pregnancy test within 
72 hours prior to receiving the first dose of study medication. 
12. 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, or 
D. Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are 
not acceptable methods of contraception. Female and male condoms should not be used 
together.) 
13. Male patients, even if surgically sterilized (ie, status postvasectomy) 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 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.) 
14. Must be willing and able to comply with clinic visits and procedures outlined in the study 
protocol. 
7.2 
Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not to be enrolled in the study: 
1. 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 ≤10 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. 

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2. History of uncontrolled brain metastasis (evidence of progression by imaging over a period 
of 4 weeks and/or neurologic symptoms that have not returned to baseline). Patients with 
treated brain metastases are allowed provided they are radiologically stable, without evidence 
of progression for at least 4 weeks by repeat imaging, clinically stable, and without 
requirement of steroid treatment for at least 14 days prior to first dose of study treatment. 
Note: For asymptomatic patients, screening brain imaging is not required. 
3. 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. 
4. Major surgery ≤14 days from the first dose of study drug and not recovered fully from any 
complications from surgery. 
5. Prior treatment with TAK-981. 
6. Hypersensitivity to TAK-981, pembrolizumab, or any component of the drug product. 
7. Baseline prolongation of the QT interval corrected using Fridericia’s formula (QTcF) (eg, 
repeated demonstration of QTcF interval >480 ms, history of congenital long QT syndrome, 
or torsades de pointes). 
8. History of immune-related AEs related to treatment with immune CPIs that required 
treatment discontinuation. 
9. Receiving or requires the continued use of medications that are known to be strong or 
moderate inhibitors and inducers of CYP3A4/5 and strong P-glycoprotein (Pgp) inhibitors. 
To participate in this study, such patients should discontinue use of such agents for at least 
2 weeks (1 week for CYP3A4/5 and Pgp inhibitors) before receiving a dose of TAK-981. 
10. Receipt of any live vaccine within 4 weeks of initiation of study treatment. 
11. 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 replacement therapy (eg, thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for thyroid, adrenal or pituitary insufficiency) 
for endocrinopathies are not considered prohibited forms of systemic treatment of an 
autoimmune disease. 
12. History of noninfectious pneumonitis that required steroids or a history of interstitial lung 
disease. 
13. Has evidence of active, noninfectious pneumonitis. 
14. History of allogeneic tissue or solid organ transplant. 
15. Has active infection requiring systemic therapy. 
16. Known history of HIV infection or any other relevant congenital or acquired 
immunodeficiency. 

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17. 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. 
18. 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, uncontrolled hypertension despite appropriate medical 
therapy, ongoing symptomatic cardiac arrhythmias >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. 
19. 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. 
20. Female patients who are pregnant or lactating and breastfeeding. 
8.0 
STUDY DRUG 
Patients enrolled in the study will receive TAK-981 in combination with pembrolizumab. 
8.1 
Study Drug Administration 
All protocol-specific criteria for administration of study drug must be met and documented 
before drug administration. Study drug will be administered only to eligible patients under the 
supervision of the investigator or identified subinvestigator(s). All patients will receive TAK-981 
and pembrolizumab as specified in the SOE (Appendix A). 
Two treatment schedules will be evaluated. Each 21-day treatment cycle will consist of 
TAK-981 administration on Days 1, 4, 8, and 11 or Days 1 and 8. Alternative TAK-981 dosing 
schedules (eg, Day 1, or Days 1, 8, and 15 in 21-day cycles) may be permissible only after 
discussions between the sponsor and the investigators. The TAK-981 starting dose in the less 
dense schedule must not be higher than the dose level being tested in the Days 1, 4, 8, and 11 
dosing schedule. Also, in patients with maximal clinical benefit, the TAK-981 dosing schedule 
can be changed after 6 months of therapy to a less frequent schedule after discussion with the 
sponsor. 
Pembrolizumab will be dosed at the clinically approved dose of 200 mg on Day 1 of a 21-day 
cycle. 
TAK-981 will be administered before pembrolizumab on days on which both TAK-981 and 
pembrolizumab are given on the same visit day. At least 30 minutes should elapse between the 
completion of the infusion of the first study drug and the initiation of the infusion of the second 
study drug. 

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8.1.1 
TAK-981 
TAK-981 Injection (Solution for Infusion) is supplied in a single use vial containing 100 mg of 
TAK-981 sterile solution. TAK-981 is stored frozen at -25˚C to -15˚C. For specific information 
about the storage and handling of TAK-981 drug product, refer to the Pharmacy Manual. 
TAK-981 must be thawed then diluted in 5% Dextrose or 0.9% Saline prior to use. TAK-981 
vials and prepared dilutions should be protected from light. The prepared dilution must be 
administered within 4 hours if stored at ambient temperature, or within 24 hours if stored at 2˚C 
to 8˚C. Detailed thawing and dosage preparation instructions are provided in the Directions for 
Use located in the Pharmacy Manual. The diluted product will be administered by IV infusion 
over 1 hour. After the end of the infusion the IV line should be flushed accordingly to local 
standards. 
The TAK-981 dose for each dose level in Phase 1b and for Phase 2 will be decided by the SMC 
composed of the principal investigators, and sponsor clinician at each end-of-cohort meeting. 
TAK-981 will be administered as a 60 ±10-minute IV infusion. If infusion reactions are 
observed, the length of the infusion can be extended up to 2 hours for all patients without 
requiring a protocol amendment. 
During dose escalation, all patients at a given dose level will be monitored for C1D1 for drug 
administration and observation for a minimum of 6 hours after the end of infusion of TAK-981. 
Patients can be discharged after the 6-hour observation period only if there are no signs and 
symptoms of acute toxicity like fever or significant changes in blood pressure and/or heart rate. 
Patients who experience any treatment-related AEs during the 6-hour observation period should 
be further monitored as clinically indicated. If no infusion reaction is observed on C1D1, 
subsequent monitoring for that patient during Cycle 1 can be reduced to 2 hours after the end of 
infusion of the last study drug. 
In Phase 2, patients can be discharged after 1-hour observation if there are no signs of acute 
toxicity after the end of infusion of the last study drug.  
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. 
Note: Fever is a common TEAE associated with the TAK-981 administration. Consider 
prescribing postinfusion antipyretic medications for up to 24 hours after the end of the TAK-981 
infusion as a preventative measure. For any patient that has an infusion-related fever, consider 
prophylaxis with an antipyretic medication. Investigator may consider reducing, even 
discontinuing, predose and postdose antipyretics if the patient experiences no major 
infusion-related fever. The clinical site is responsible for sourcing any pre- and postmedications 
outlined in the protocol. 

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8.1.2 
Pembrolizumab 
Pembrolizumab is available as single-use vials of 50 or 100 mg of drug substance (Keytruda 
(pembrolizumab) Injection for Intravenous Use 2023). 
The approved dose of pembrolizumab is 200 mg every 3 weeks (21-day cycle). Dose escalations 
or dose reductions of pembrolizumab are not allowed in this study. Pembrolizumab will be 
administered as a 30 ±10-minute IV infusion. 
8.1.3 
Additional Instructions for Treatment Administration 
Vital signs will be monitored throughout study drug administration according to the SOE 
(Appendix A). All patients will be monitored for at least 2 hours after the end of infusion of the 
last study drug. After the administration of TAK-981 or pembrolizumab, the patient should be 
considered clinically stable by the investigator or designee before the next study drug is 
administered or the patient is discharged. From Cycle 2 onwards, if no infusion reaction is 
observed in the first cycle, post-infusion monitoring may not be required and the patient can be 
discharged from the site per investigator discretion.  
In all cases, the administration of TAK-981 or pembrolizumab should occur in an area with 
access to resuscitating equipment and medications such as antihistamines, acetaminophen, 
corticosteroids, epinephrine, and bronchodilators readily available. Treatment must be stopped if 
the patient experiences symptoms compatible with an infusion reaction of Grade 2 or greater. 
The management of infusion reactions and CRS is detailed in Section 8.9.6 and Section 8.9.7, 
respectively. 
Dose administration of TAK-981 and pembrolizumab should be performed on schedule; 
however, a dose delay of up to 3 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 8.7). For 
patients in the DLT-evaluation period (Cycle 1) rescheduling is allowed for a maximum of 
1 dose. At least 3 days should elapse between consecutive doses of TAK-981. On days on which 
both TAK-981 and pembrolizumab are administered, should the treatment day be rescheduled, 
both TAK-981 and pembrolizumab doses will be rescheduled. 
As with other potentially toxic compounds, caution should be exercised in handling this drug. 
The use of gloves is recommended. Following topical exposure, events could include redness or 
blistering. Given the possibility of extravasation, it is advisable to closely monitor the infusion 
site for possible infiltration during drug administration. Administration through a central port is 
always preferred versus a peripheral line. 
8.2 
Definitions of DLT 
Toxicity will be evaluated according to the NCI CTCAE, Version 5.0 (NCI 2017), except CRS 
that will be graded according to ASCST Consensus Grading for CRS (Lee et al. 2019). In Phase 
1b, DLT will be defined as any of the following events occurring through the first 21 days of 

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treatment (Cycle 1) unless they are considered by the investigator to be clearly unrelated to 
therapy: 
1. Any Grade 5 AE. 
2. Any Grade 4 hematologic AE will be considered DLTs except for: 
• Grade 4 lymphopenia that has no clinical sequela, or recovers to Grade ≤2 within 
14 days. 
• Grade 4 neutropenia (ANC <0.5 × 109/L) lasting <48 hours that is not associated with 
fever (defined as a single temperature >38.3°C or sustained temperature of 38°C for more 
than 1 hour) or other clinically significant symptoms. 
• Grade 4 hematologic AEs that last <7 days. 
3. Platelet count <10.0 × 109/L, at any time. 
4. Febrile neutropenia: Grade ≥3 neutropenia (ANC <1.0 × 109/L) with fever and/or infection. 
5. Grade 3 thrombocytopenia lasting longer than 14 days or accompanied by Grade 2 bleeding 
or requiring transfusion. 
6. Any Grade 3 immune-related adverse events such as pericarditis, pneumonitis, 
cardiotoxicity, hepatitis or neurotoxicity. 
7. Grade ≥3 nonhematologic toxicity with the following exceptions: 
• Grade 3 fatigue lasting less than 7 days. 
• Grade 3 arthralgia/myalgia that responds to nonsteroidal anti-inflammatory drugs within 
7 days. 
• Grade 3 endocrine disorder that is managed with or without therapy and the patient is 
asymptomatic. 
• Grade 3 inflammatory reaction attributed to a local antitumor response (tumor flare). 
• 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. 
• Asymptomatic nonhematological laboratory changes that are otherwise asymptomatic 
and that can be controlled to Grade ≤1 or baseline in 7 days with appropriate treatment or 
with dose interruption and does not result in a delay of >7 days of planned treatment. In 
this setting, a course of action will be determined jointly by the investigator and the 
sponsor clinician. 
• Grade 3 elevation in ALT, AST, or alkaline phosphatase that resolves to Grade ≤2 with 
supportive care within 7 days and is not associated with other clinically significant 
consequences. 

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• Isolated Grade 3 electrolyte abnormalities that resolve to Grade ≤2 with supportive care 
within 7 days and are not associated with other clinically significant consequences. 
• Grade ≥3 diarrhea that can be controlled to Grade ≤1 or baseline in 7 days with optimal 
supportive therapy. 
• Grade ≥3 nausea and/or emesis that can be controlled to Grade ≤1 or baseline in 7 days 
with the use of optimal antiemetics (defined as an antiemetic regimen that employs both a 
5-hydroxytryptamine 3 serotonin receptor antagonist and a corticosteroid given in 
standard doses and according to standard schedules). 
• Grade 3 rash lasting ≤7 days after treatment that includes topical steroid treatment, oral 
administration of antihistamines, and pulse oral steroids (if necessary). 
8. Grade 2 nonhematologic toxicities that are considered by the investigator to be related to 
study drug and dose-limiting. 
9. Delay in the initiation of Cycle 2 by more than 14 days due to a lack of adequate recovery of 
treatment-related hematological or nonhematological toxicities. 
10. Missed at least 1 planned dose of TAK-981 or planned dose of pembrolizumab in Cycle 1 
due to treatment-related AEs.  
8.3 
Definition of DLT-Evaluable Patients in Phase 1b 
Patients enrolled in Phase 1b are considered evaluable for assessment of a DLT if either of the 
following criteria is met during the DLT assessment period of 21 days following the first dose of 
treatment (Cycle1): 
• The patient experienced a DLT at any time after receiving the first dose of TAK-981 during 
the DLT assessment period (Cycle 1). 
or 
• The patient received all planned TAK-981 doses and 1 administration of pembrolizumab in 
Cycle 1. 
For the Phase 1b part of the study, patients who withdraw before completing the 21-day DLT 
assessment period for reasons other than a DLT, or who do not fulfill either of the criteria above, 
will not be evaluable for assessment of DLT and will be replaced. 
8.4 
Phase 1b Dose Escalation Rules  
In the Phase 1b portion of the study, only the dosing of TAK-981 will be escalated. 
Pembrolizumab will be administered at a fixed dose of 200 mg for each scheduled infusion.  
The starting dose level of TAK-981 in combination with pembrolizumab will be 40 mg which is 
1 dose level below the monotherapy dose that has cleared the DLT period in the ongoing FIH 
single-agent study (Study TAK-981-1002). The following dose levels of TAK-981 will be 
potentially considered: 25, 40, 60, 90, 120, and 160 mg. TAK-981 cannot be escalated above the 

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MTD defined in the FIH study or to a maximum dose level of 160 mg, which-ever is lower. 
Evaluation of lower or intermediate dose levels are permissible following discussions between 
the sponsor and the investigators, if such measures are needed for patient safety or for a better 
understanding of toxicity, exposure, or pharmacodynamics of TAK-981.  
Dose escalation will follow a BOIN design (Yuan et al. 2016). Approximately 4 patients will be 
enrolled in the first cohort. The decision to escalate or de-escalate the dose of TAK-981 will be 
based on the cumulative DLT rate at the current dose level and the predetermined DLT rate 
threshold for dose escalation/de-escalation boundaries as defined by the BOIN model. The target 
DLT rate for this study is 0.3. The dose escalation and de-escalation rules for TAK-981 are as 
follows. 
1. If the observed DLT rate at the current dose level is ≤0.236, escalate. 
2. If the observed DLT rate at the current dose level is ≥0.33, de‑escalate. 
3. Otherwise, stay at the same dose level. 
The schema of the dose escalation is presented in Figure 8.a.  

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Figure 8.a 
Phase 1b Dose Escalation Schema 
 
DLT: dose-limiting toxicity; MTD: maximum tolerated dose. 
 
It is estimated that up to approximately 32 DLT-evaluable patients will be enrolled to evaluate 
dose escalation for 2 dosing schedules of TAK-981. For each cohort of patients enrolled at a 
given dose level, the observed DLT rate will be calculated for that dose level. If the observed 
DLT rate at the current dose is ≤0.236, the next cohort of patients will be treated at the next 
higher dose level; if it is ≥0.33, the next cohort of patients will be treated at the next lower dose 
level. The boundary guiding the number of patients treated at the current dose is displayed in 
Appendix H in which the operating characteristics of the BOIN design based on 
1000 simulations of each scenario are presented. 

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Alternative dosing schedules for TAK-981 (eg, Day 1, or Days 1, 8, and 15 in 21-day cycles) 
may be explored in agreement between the investigators and sponsor. TAK-981 escalation for 
different TAK-981 schedules will be evaluated separately. 
Dose escalation and cohort expansion decisions will be determined by the SMC. The SMC will 
review the Cycle 1 safety of all treated patients and will take into consideration the pattern of 
irAEs beyond the DLT window across all patients enrolled and make decisions regarding dose 
escalation. In addition, the available PK and pharmacodynamic information will also be 
evaluated to support the dose escalation. 
8.5 
Dose Management and Modification Guidelines 
8.5.1 
Intrapatient Dose Escalation 
Patients in the Phase 1b part of the study with Grade ≤2 toxicity during the previous treatment 
cycle at the initially assigned dose may have their doses of TAK-981 increased in subsequent 
cycles of treatment only if all patients in the next dose level cohort have completed assessment 
for Cycle 1 and a decision has been made that this dose level does not exceed the MTD after 
agreement between the investigator and the sponsor. The maximal intrapatient dose escalation 
level will be 1 dose level. Patients in Phase 2 will not have their dose escalated. 
8.5.2 
Criteria for Beginning or Delaying a Subsequent Treatment Cycle 
A treatment cycle in this study is 21 days. For a new cycle of TAK-981 in combination with 
pembrolizumab treatment to begin, the patient must meet the following criteria: 
• ANC ≥1.0 × 109/L. 
• Platelet count ≥75.0 × 109/L. 
Before starting a new treatment cycle for TAK-981 in combination with pembrolizumab, drug-
related AEs or laboratory abnormalities must have returned to Grade ≤1 or baseline or become 
clinically insignificant as determined by the investigator (unless otherwise specified). If the 
patient fails to meet the above-cited criterion for retreatment, initiation of the next cycle of 
treatment of TAK-981 in combination with pembrolizumab 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 be delayed for more than 28 days 
from the last TAK-981 administration because of incomplete recovery from treatment-related 
toxicity, the patient must discontinue treatment with TAK-981 unless there is clinical benefit as 
assessed by the investigator, with agreement by the sponsor. 
In case of permanent discontinuation of TAK-981 due to a treatment-related AE as defined in 
Sections 8.5.3.1 and 8.5.4.1, patients can continue treatment with pembrolizumab alone if the 
criteria for reinitiating treatment defined in Section 8.5.3.2 are met. 

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8.5.3 
Criteria for Dose Interruption or Dose Reduction 
All toxicities that occur during the study will be actively managed following standard of care 
and/or institutional guidelines unless otherwise specified in the protocol. Patients experiencing 
AEs attributed to TAK-981, pembrolizumab, or the combination, may continue study treatment 
with the same dose, may have the treatment held, or may be permanently discontinued from the 
study. Patients who have study drugs held because of treatment-related or possibly related AEs 
should resume study drug treatment according to the dose modification guidelines below. If the 
dose of 1 study drug is delayed or modified because of toxicity attributed to its use, the dose of 
the other study drug may be administered as scheduled. If the causality of toxicity is attributed to 
both study drugs by the investigator, both study drugs should be modified following the dose 
modification guidelines shown in Table 8.a, Table 8.b, and Table 8.c. 
For additional information, refer to the TAK-981 IB and the pembrolizumab Summary of 
Product Characteristics (SmPC) (Keytruda (pembrolizumab) Injection for Intravenous Use 
2023). 
8.5.3.1 
TAK-981 Dose Modification Guidelines 
Dosing of TAK-981 should be interrupted during a treatment cycle or reduced according to the 
dose modification recommendations listed in Table 8.a for nonhematologic toxicity and 
Table 8.b for hematologic toxicities. When the dose of TAK-981 is withheld based on the listed 
criteria, clinical and laboratory reevaluation should be repeated weekly or more frequently, 
depending on the nature of the toxicity observed until the toxicity resolves to the grade specified 
in Table 8.a and Table 8.b. If indicated, the TAK-981 dose should be reduced by at least 1 dose 
level.  
If TAK-981 alone or in combination with pembrolizumab cannot be administered within a cycle 
in a 48-hour window because of an AE, the dose will be missed, and the patient will be 
scheduled for the next administration per SOE. 
In general, after a dose is reduced, it should not be re-escalated even if there is minimal or no 
toxicity with the reduced dose. However, if further evaluation reveals that the AE that led to the 
dose reduction was not study drug related, or there were other circumstances contributing to the 
AE that are unlikely to recur, the dose may be re-escalated to the original dose level. If more than 
2 dose-level reductions of TAK-981 are needed to manage TAK-981-related AEs, treatment with 
TAK-981 should be discontinued. 

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Table 8.a 
General Dose Modification Recommendations for TAK-981 
Nonhematologic Drug-Related AEs 
Criteria 
Action 
Grade 1 AEs 
No dose reductions or interruptions. 
Grade 2 AEs 
Treat according to local practice.  
Patients experiencing Grade 2 AEs considered related to study treatment that 
are not easily managed or corrected and are not tolerable to the patient, or AEs 
that are not acceptable in the investigator’s judgment, should have study 
treatment interrupted until the AE resolves to Grade ≤1 or baseline and then 
restarted at the same dose or, depending on the toxicity, at the previous safe DL. 
Grade 3 and Grade 4 non-life-
threatening AEs 
Hold TAK-981 until resolution to Grade ≤1 or baseline level, and then resume 
treatment at the next lower DL, except for the following instances that do not 
require dose reduction: 
• 
Grade ≥3 nausea, vomiting, and/or diarrhea resolved to Grade ≤1 or 
baseline within 72 hours with optimal antiemetics and/or antidiarrheal 
following local practice. 
• 
Transient Grade 3 fatigue (lasting <72 hours) and asymptomatic Grade ≤4 
laboratory abnormalities that the investigator considers not clinically 
significant following agreement between sponsor and investigators. 
Note: Permanently discontinue treatment if Grade ≥3 QTcF prolongation, or 
Grade ≥3 pneumonitis. 
Grade 4 life-threatening AEs 
Permanently withdraw the patient from treatment with TAK-981. 
AEs of all grades 
If treatment has been held for >21 consecutive days without resolution of the 
toxicity (to baseline level 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 sponsorʼs approval. Treatment 
should be resumed at a reduced DL after resolution of AEs to Grade ≤1 or 
baseline. 
AE: adverse event; DL: dose level. 
 

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Table 8.b 
TAK-981 Dose Adjustments for Hematologic Toxicities 
Criteria 
Action 
Neutropenia (ANC) 
 
Grade 1 (ANC <LLN-1.5 × 109 cells/L) 
Continue TAK-981 at the same DL. 
Grade 2 (ANC 1.0- <1.5 × 109 cells/L) 
Continue TAK-981 at the same DL. 
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 
DL. 
• 
If resolved in >7 days, resume treatment at the next 
lower DL (ie, reduce by 1 DL). 
Grade 4 (ANC <0.5 × 109 cells/L) without 
fever 
Withhold dose until resolved to Grade ≤2 or baseline, then 
resume treatment at the lower DL (ie, reduce by 1 DL). 
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 
lower DL (ie, reduce by 1 DL). 
Thrombocytopenia (PLT) 
 
Grade 1 (PLT <LLN-75.0 109 cells/L) 
Continue TAK-981 at the same DL. 
Grade 2 (PLT <75.0 - 50.0 × 109 cells/L) 
Continue TAK-981 at the same DL. 
Grade 3 (PLT <50.0 - 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 
DL. 
• 
If resolved in >7 days, resume treatment at the lower 
DL (ie, reduce by 1 DL). 
Grade 4 (PLT <25.0 × 109 cells/L) without 
bleeding 
Withhold dose until resolved to Grade ≤1 or baseline, then 
resume treatment at the lower DL (ie, reduce by 1 DL). 
Platelets <10.0 × 109 cells/L, thrombocytopenia 
Grade ≥3 associated clinically significant 
bleeding 
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 lower DL 
(ie, reduce by 1 DL). 
ANC: absolute neutrophil count; DL: dose level; LLN: lower limit of normal; PLT: platelet. 
 

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Table 8.c 
TAK-981 Dose Modification Guidelines for CRS 
ASTCT Grade 
TAK-981 Dose Modification 
Grade 1: 
Fever a (≥38°C) 
Continue TAK-981 at the same dose. 
Grade 2: 
Fever a (≥38°C) 
with hypotension not requiring 
vasopressors;  
and/or b hypoxia requiring low-flow c 
nasal cannula 
Withhold dose until resolved to Grade ≤1, then: 
• 
If resolved in ≤14 days, maintain DL. 
• 
If resolved in >14 days or repeat event, reduce by 1 DL. 
• 
If >2 consecutive doses of TAK-981 are skipped due to CRS, 
permanently discontinue treatment with TAK-981. 
Grade 3: 
Fever a (≥38°C) 
with hypotension requiring a 
vasopressor with or without 
vasopressin;  
and/or b hypoxia requiring high-flow c 
nasal cannula, facemask, 
nonrebreather mask, or Venturi mask 
Withhold dose until resolved to Grade ≤1, then: 
• 
If resolved in ≤14 days, reduce by 1 DL and if toxicity does not 
recur, consider re-escalating to original DL. 
• 
If resolved in >14 days or repeat event, reduce by 1 DL. 
• 
If >2 consecutive doses of TAK-981 are skipped due to CRS, 
permanently discontinue treatment with TAK-981. 
Grade 4: 
Fever a (≥38°C) 
with hypotension requiring multiple 
vasopressors (excluding vasopressin);  
and/or b hypoxia requiring positive 
pressure (eg, CPAP, BiPAP, 
intubation, and mechanical 
ventilation) 
Permanently discontinue TAK-981. 
ASTCT: American Society for Transplantation and Cellular Therapy; BiPAP: bilevel positive airway pressure; 
CPAP: continuous positive airway pressure; CRS: cytokine release syndrome; DL: dose level. 
ASTCT consensus grade adapted from Lee et. Al. 2019 (Lee et al. 2019); CRS management recommendations are 
adapted from Neelapu et al, 2018 (Neelapu et al. 2018) and should be implemented at the investigator’s 
discretion. 
a Fever is defined as temperature ≥38°C not attributable to any other cause. In patients who have CRS then 
receive antipyretic or anticytokine therapy such as tocilizumab or steroids, fever is no longer required to grade 
subsequent CRS severity. In this case, CRS grading is driven by hypotension and/or hypoxia. 
b CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. 
For example, a patient with temperature of 39.5°C, hypotension requiring 1 vasopressor, and hypoxia requiring 
low-flow nasal cannula is classified as Grade 3 CRS. 
c Low-flow nasal cannula is defined as oxygen delivered at ≤6 L/minute. High-flow nasal cannula is defined as 
oxygen delivered at >6 L/minute. 
 
8.5.3.2 
Pembrolizumab Dose Modification Guidelines 
In this study the dose of pembrolizumab cannot be modified. Depending on the toxicity 
observed, the infusion of pembrolizumab can be interrupted (in case of IRR, for example), 
delayed, or discontinued. If hypersensitivity or infusion-related events develop, the infusion 

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should be temporarily slowed or interrupted, but dose modifications are not allowed. The patient 
should be treated according to the appropriate standard of care. Patients who discontinue 
pembrolizumab for reasons described in the pembrolizumab label (Keytruda (pembrolizumab) 
Injection for Intravenous Use 2023) other than irAEs may continue TAK-981 treatment. 
General instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade ≤1 and continue to 
taper over at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after 
the AE severity has been reduced to Grade 1 or baseline level and corticosteroid has been 
tapered. Pembrolizumab should be permanently discontinued if the AE does not resolve 
within 12 weeks of last dose or corticosteroids cannot be reduced to ≤10 mg prednisone or 
equivalent per day within 12 weeks. 
3. For severe and life-threatening irAEs, IV corticosteroid treatment should be initiated first 
followed by oral steroid therapy. Other immunosuppressive treatment should be initiated if 
irAEs cannot be controlled by corticosteroids. 

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Table 8.d 
Pembrolizumab Dose Modification Guidelines for irAEs 
Immune-Related 
AEs 
Toxicity Grade or 
Conditions 
(CTCAE v5.0) 
Action Taken 
with 
Pembrolizumab 
Immune-Related AE 
Management with 
Corticosteroid and/or Other 
Therapies 
Monitor and Follow-Up 
Pneumonitis 
Grade 2  
Withhold 
Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper. 
Monitor patients for signs and symptoms of 
pneumonitis. 
Evaluate patients with suspected pneumonitis 
with radiographic imaging and initiate 
corticosteroid treatment. 
Add prophylactic antibiotics for opportunistic 
infections. 
Grade 3 or 4, or 
recurrent Grade 2 
Permanently 
discontinue 
Diarrhea/colitis 
Grade 2 or 3 
Withhold 
Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper. 
Monitor patients for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, blood 
or mucus in stool with or without fever) and of 
bowel perforation (ie, peritoneal signs and ileus). 
Patients with Grade ≥2 diarrhea suspecting colitis 
should consider GI consultation and performing 
endoscopy to rule out colitis. 
Patients with diarrhea/colitis should be advised to 
drink liberal quantities of clear fluids. If 
sufficient oral fluid intake is not feasible, fluid 
and electrolytes should be substituted via IV 
infusion. 
Grade 4 
Permanently 
discontinue 
AST/ALT elevation 
or increased bilirubin 
Grade 2  
Withhold 
Administer corticosteroids (initial 
dose of 0.5-1 mg/kg prednisone 
or equivalent) followed by taper. 
Monitor with liver function tests (consider 
weekly or more frequently) until liver enzyme 
value returned to baseline or is permanently 
stable. 
Grade 3 or 4 
Permanently 
discontinue 
Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper. 

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Table 8.d 
Pembrolizumab Dose Modification Guidelines for irAEs 
Immune-Related 
AEs 
Toxicity Grade or 
Conditions 
(CTCAE v5.0) 
Action Taken 
with 
Pembrolizumab 
Immune-Related AE 
Management with 
Corticosteroid and/or Other 
Therapies 
Monitor and Follow-Up 
Type 1 diabetes 
mellitus or 
hyperglycemia 
Newly onset Type 1 
diabetes mellitus or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-cell 
failure 
Withhold  
Initiate insulin replacement 
therapy for patients with Type 1 
diabetes mellitus. 
Administer antihyperglycemic in 
patients with hyperglycemia. 
Monitor patients for hyperglycemia or other 
signs and symptoms of diabetes. 
Hypophysitis 
Grade 2  
Withhold 
Administer corticosteroids and 
initiate hormonal replacements as 
clinically indicated. 
Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal 
insufficiency) 
Grade 3 or 4 
Withhold or 
permanently 
discontinue a 
Hyperthyroidism 
Grade 2 
Continue 
Treat with nonselective 
beta-blockers (eg, propranolol) or 
thionamides as appropriate. 
Monitor for signs and symptoms of thyroid 
disorders. 
Grade 3 or 4 
Withhold or 
permanently 
discontinue 
Hypothyroidism 
Grade 2 to 4 
Continue 
Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper. 
Monitor changes of thyroid function 
Nephritis and renal 
dysfunction 
Grade 2 or 3 
Withhold 
Administer corticosteroids 
(prednisone 1 to 2 mg/kg or 
equivalent) followed by taper. 
Monitor changes in renal function 
Grade 4 
Permanently 
discontinue 
Myocarditis 
Grade 1 
Withhold 
Based on severity of AE, 
administer corticosteroids. 
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes 
Grade 2, 3 or 4 
Permanently 
discontinue 

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Table 8.d 
Pembrolizumab Dose Modification Guidelines for irAEs 
Immune-Related 
AEs 
Toxicity Grade or 
Conditions 
(CTCAE v5.0) 
Action Taken 
with 
Pembrolizumab 
Immune-Related AE 
Management with 
Corticosteroid and/or Other 
Therapies 
Monitor and Follow-Up 
Exfoliative 
dermatologic 
conditions 
Suspected SJS, TEN, 
or DRESS  
Confirmed SJS, TEN, 
or DRESS 
Withhold b 
 
Permanently 
discontinue 
As clinically indicated. 
Monitor changes 
All other immune-
related AEs 
Intolerable/persistent 
Grade 2 
Withhold 
Based on type and severity of AE 
administer corticosteroids. 
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes. 
Grade 3 
Withhold or 
discontinue based 
on the type of 
event. Events that 
require 
discontinuation 
include and not 
limited to: 
Guillain-Barre 
syndrome, 
encephalitis 
Grade 4 or recurrent 
Grade 3 
Permanently 
discontinue 
 
 
AE: adverse event; ALT: alanine aminotransferase; AST: aspartate aminotransferase; CTCAE: Common Terminology Criteria for Adverse Events; DRESS: 
drug rash with eosinophilia and systemic symptoms; GI: gastrointestinal; irAE: immune-related adverse event; IV: intravenous; SJS: Stevens-Johnson 
syndrome; TEN: toxic epidermal necrolysis; ULN: upper limit normal. 
For patients with Grade 3 or 4 immune-related endocrinopathy where withholding of pembrolizumab is required, pembrolizumab may be resumed when the 
AE resolves to Grade ≤2 and is controlled with hormonal replacement therapy or when metabolic control has been achieved (in case of Type 1 diabetes). 
a Withholding or permanently discontinuing pembrolizumab is at the discretion of the investigator or treating physician. 
b Resume in patients with complete or partial resolution (Grades 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution 
within 12 weeks of initiating steroids or inability to reduce prednisone to 10 mg per day or less (or equivalent) within 12 weeks of initiating steroids. 
 

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8.5.4 
Criteria for Discontinuation of Treatment With Study Drugs 
Patients should discontinue treatment with either TAK-981 or pembrolizumab or both, if they 
meet the criteria listed below. Patients who discontinue pembrolizumab may continue TAK-981 
treatment as a single agent if TAK-981 discontinuation criteria are not met; patients who 
discontinue TAK-981 may continue pembrolizumab as a single agent if pembrolizumab 
discontinuation criteria are not met. In the event of discontinuation of study therapy (TAK-981 
and pembrolizumab), patients will undergo the EOT visit. 
8.5.4.1 
TAK-981 
Treatment with TAK-981 must be discontinued for any of the following reasons: 
• Occurrence of a DLT in dose escalation during the first cycle (exceptions to this criterion 
may be made after discussion and agreement between the investigator and the sponsor based 
on the benefit/risk assessment). 
• Occurrence of drug-related AEs that require study drug discontinuation per dose 
modification guidelines in Section 8.5. 
• If subsequent cycle is delayed by >21 days for treatment-related AEs despite supportive 
treatment per standard clinical practice. (Exceptions to this criterion may be made after 
discussion and agreement between the investigator and the sponsor based on the benefit/risk 
assessment.) 
• If more than 2 dose-level reductions of TAK-981 are required for a patient. (Exceptions to 
this criterion may be made after discussion and agreement between the investigator and the 
sponsor based on the benefit/risk assessment.) 
• Occurrence of AEs resulting in discontinuation of study drug that is desired or considered 
necessary by the investigator and/or the patient (if applicable). 
8.5.4.2 
Pembrolizumab 
Pembrolizumab will be discontinued if any of the criteria described in dose modification 
Table 8.d or the SmPC have been met. Additionally, pembrolizumab may be discontinued for 
other reasons if it is considered in the best interest of the patient and discussed with the medical 
monitor. 
Permanently discontinue pembrolizumab for any of the following: 
• Any life-threatening adverse reaction (excluding endocrinopathies controlled with hormone 
replacement therapy). 
• Grade 3 or 4 pneumonitis or recurrent pneumonitis of Grade 2 severity. 
• Grade 3 or 4 nephritis. 
• Grade 4 severe skin reactions or confirmed Stevens-Johnson syndrome or toxic epidermal 
necrolysis. 

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• AST or ALT greater than 5 times the ULN or total bilirubin greater than 3 times the ULN. 
– For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST 
or ALT increases by greater than or equal to 50% relative to baseline and lasts for at least 
1 week. 
• Grade 3 or 4 IRRs. 
• Inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day 
within 12 weeks. 
• Persistent Grade 2 or 3 adverse reactions (excluding endocrinopathies controlled with 
hormone replacement therapy) that do not recover to Grade ≤1 within 12 weeks after last 
dose of pembrolizumab. 
• Any severe or Grade 3 treatment-related adverse reaction that recurs. 
8.5.4.3 
COVID-19 Infection  
If a patient is diagnosed with COVID-19 infection while on study, study treatment must be 
withheld until resolution of the infection. A patient may restart study treatment if the following 
criteria are met; otherwise the patient must discontinue treatment: 
• The infection must have resolved without ongoing clinical sequalae. 
• There should be 2 sequential negative SARS CoV-2 tests 12 hours apart. If necessary, 
discuss a path forward with sponsor considering PCR tests may continue to be positive for 
prolonged period of time (Qu et al. 2020) (Plebani 2021) (cdc.gov/coronavirus/2019-
ncov/hcp/duration-isolation.html, Center for Disease Control. Ending Isolation and 
Precautions for People with COVID-19: Interim Guidance. Jan 14, 2022. Access 22 April 
2022). 
• The patient must be asymptomatic, and the investigator must believe, with agreement of the 
sponsor, that the patient would benefit from resuming study treatment. 
8.6 
Excluded Concomitant Medications and Procedures 
The following medications and procedures are prohibited during the study: 
• Prophylactic use of myeloid growth factors (eg, G-CSF) is not allowed in Cycle 1 during 
dose escalation. Patients who experience severe (ie, Grade 4) neutropenia or febrile 
neutropenia can be managed with growth factor support, if needed, in accordance with 
American Society of Clinical Oncology (ASCO) guidelines and/or institutional practices. 
GCSF 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. 
• 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. 

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• Any investigational agent other than TAK-981 or pembrolizumab. 
• Any concurrent antineoplastic therapy (eg, chemotherapy, hormonal therapy, 
immunotherapy, or radiation therapy except for palliative radiation therapy and once 
progressive disease [PD] is ruled out) or standard or investigational agents other than 
pembrolizumab for treatment of cancer. 
• Concomitant corticosteroid administration of >10 mg of prednisone or equivalent unless 
given as treatment or prophylaxis for IRRs or de novo irAEs, 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 and moderate CYP3A4/5 inhibitors and inducers (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. 
These patients can resume treatment with TAK-981 approximately 1 week after 
discontinuing the use of these strong and moderate inhibitors CYP3A4/5, and approximately 
2 weeks after discontinuing the use of strong and moderate inducers of CYP3A4/5. 
• Strong inhibitors of Pgp (Appendix F). 
• Because the safety of immunization with live viral vaccines following TAK-981 therapy has 
not been studied, vaccination with live virus vaccines is not recommended while the patient 
is being treated on study. 
• For patients enrolled in Phase 1, vaccination during Cycle 1 is not permitted as this may 
confound the evaluation of safety and the determination of DLTs. 
8.7 
Permitted Concomitant Medications and Procedures  
All prescription and over-the-counter medications, including influenza vaccines, taken by a 
patient from their informed consent through the 30 (+10) days follow-up visit after the last dose 
of study drug 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 over the counter medications and herbal supplements, without 
first consulting with the investigator. 
The following medications and procedures are permitted while the patient is receiving the study 
drug: 
• Myeloid growth factors (eg, granulocyte colony-stimulating factor, granulocyte macrophage 
colony-stimulating factor) and/or erythropoietin support, as clinically indicated. 
• Topical, intranasal, or inhaled steroids (eg, for the treatment of asthma). 
• Patients should be transfused with RBCs and platelets as clinically indicated. 

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• Concomitant treatment with bisphosphonates will be allowed for patients with evidence of 
lytic destruction of bone or with osteopenia, according to the ASCO Clinical Practice 
guidelines or institutional practice in accordance with the product label, unless specifically 
contraindicated. 
• Local radiation of isolated lesions for palliative intent (for example, pain control) is 
acceptable provided that the requirement for radiation does not represent a progression of the 
disease and that the radiated lesion is not a target lesion. 
• Narrow therapeutic range Pgp substrates such as digoxin or dabigatran may be used with 
caution, and patients requiring use of these drugs will be closely monitored. 
• COVID-19 vaccination is generally allowed for patients enrolled in the study with the 
exception of live attenuated vaccines which must be completed at least 4 weeks prior to 
treatment initiation. COVID-19 vaccination should follow local guidances and regulations. 
Ideally, patients will have completed vaccination prior to treatment initiation. For patients 
enrolled in Phase 1, vaccination during Cycle 1 is not permitted as this may confound the 
evaluation of safety and the determination of DLTs. Vaccination should be avoided within 
±3 days of TAK-981 administration and should be administered after the last dose of TAK-
981 of a given cycle; study treatment may be delayed for up to 7 days to accommodate a 
vaccine dose administration after discussion with the Sponsor. Vaccination should be 
captured as a concomitant medication. 
Additional concomitant medications and procedures are permitted during the study to prevent 
and actively manage AEs related or not related to the study drug(s) unless prohibited as specified 
in this protocol. Supportive measures consistent with optimal patient care may be given 
throughout the study. 
8.8 
Precautions and Restrictions 
It is not known 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. 
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 patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 

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methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.) 
Male patients, even if surgically sterilized (ie, status postvasectomy) must agree to 1 of the 
following: 
• Agree to practice effective barrier contraception during the entire study treatment period and 
through 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.) 
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. 
8.9 
Management of Clinical Events 
Therapies that are required to manage AEs and control cancer symptoms are allowed based on 
standard clinical practice, unless specifically excluded. Supportive care agents, such as 
erythropoietin, granulocyte colony stimulating factor, blood products (RBC and platelet 
transfusions), and pain medications are permitted as needed per American Society of 
Hematology/ASCO guidelines or local institutional practice. If dose alterations are necessary as 
a result of the events detailed below, refer to Section 8.5. 
The sections below provide guidance for the management of some expected AEs based on 
observations in nonclinical toxicology or other AEs that have not been substantiated in these 
experiments but that could be expected because of the mechanism of action of TAK-981, and 
warnings and precautions in the pembrolizumab SmPC. This guidance is not expected to replace 
investigator judgment in the management of AEs. 
8.9.1 
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. 
8.9.2 
Diarrhea 
This study will not initially employ prophylactic antidiarrheals. Patients in this study must be 
monitored for immune-mediated colitis and treated per local guidance. 

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8.9.3 
Anemia, Thrombocytopenia, or Neutropenia 
Please refer to Table 8.b for dose delay and reduction recommendations for hematologic 
toxicities. TAK-981 should be withheld if a significant treatment-emergent cytopenia or bleeding 
is suspected to be related to, or could be worsened by, study treatment. Precautionary measures 
should be taken to prevent bleeding and overwhelming infections. Blood transfusions (RBCs or 
platelet) and hematopoietic or thrombopoietic stimulating factors may be used to treat 
cytopenia/thrombocytopenia at the discretion of the investigator per standard clinical practice. 
Use of myeloid growth factor (eg, granulocyte colony stimulating factor) support to treat Grade 
≥3 neutropenia and/or febrile neutropenia is recommended per regional guidelines or local 
institutional practice; prophylaxis is permitted per regional guidelines or local institutional 
practice. 
8.9.4 
Infusion Site Care 
Skin lesions, which may include inflammation or necrosis, represent a potential risk of TAK-981 
and were observed at the injection site in rats. Local institutional guidelines must be applied to 
stress proper administration and prevention of accidental extravasation of TAK-981. Usage of an 
IV port is highly recommended. The IV line should be flushed at the end of the infusion 
according to local procedures. Monitoring at the beginning of 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.  
8.9.5 
Lymphopenia and Opportunistic Infection Prophylaxis 
Because lymphopenia is an expected TAK-981-related AE, patients may be at an increased risk 
of opportunistic pathogens. Follow-up with standard hemograms and serial immunophenotyping 
will help to make clinical decisions about the risk of immunosuppression.  
Prophylaxis for PJP should be initiated if the following is present: 
• Absolute CD4+ T-cell count of <200/mm3. 
• Percent CD4+ T-cells <20%. 
• Prior episode of PJP in medical history. 
For older patients or patients who, in the investigator’s opinion, are more susceptible to 
opportunistic infection at baseline, PJP prophylaxis should be considered at the start of study 
treatment. When steroids or any immunomodulatory agents need to be used to manage AEs 
during the study, PJP prophylaxis should be considered when the study treatment resumes or is 
co-administered. Trimethoprim-sulfamethoxazole is recommended as the treatment of choice for 
PJP prophylaxis unless contraindicated; however, investigator discretion in selecting a more 
appropriate prophylaxis regimen for their patients is permitted. 

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In the event of long-lasting lymphopenia, pneumocystis, or herpes zoster infection, prophylaxis 
can be started at the investigator’s discretion. 
8.9.6 
IRRs 
Although TAK-981 is not a biologic drug, its immune-activating properties may also produce 
AEs in the category of IRRs. If such reactions were to occur, they might manifest with fever, 
chills, rigors, headache, rash, pruritus, arthralgias, hypotension or hypertension, bronchospasm, 
or other symptoms. Treatment and monitoring of patients presenting with IRRs to TAK-981 or 
pembrolizumab until symptoms resolve should be consistent with institutional standards and 
guidelines as appropriate. If an IRR develops during the TAK-981 or pembrolizumab infusion, 
the patient should be closely monitored until recovery of symptoms. 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 on days on which just TAK-981 is given, and at investigator discretion, 
premedication can be instituted for the remaining TAK-981 doses. 
8.9.7 
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 and graded following ASTCT Consensus Grading for CRS 
(Lee et al. 2019). Investigators should try to differentiate CRS from other IRRs. 
Recommendations for management of CRS are shown in Table 8.e and can be implemented at 
the investigator’s discretion. Table 8.c also provides indications for dose modifications after a 
CRS event. 

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Table 8.e 
CRS Management Recommendations 
ASTCT Consensus Grade  
CRS Management Recommendations 
Grade 1: 
Fever a (≥38°C)  
Monitor fluid status. 
Supportive care: antipyretics, analgesics.  
Grade 2: 
Fever a (≥38°C) 
with hypotension not requiring 
vasopressors;  
and/or b hypoxia requiring low-flow c 
nasal cannula  
As per Grade 1 and: 
• 
Closely monitor all organ functions, including cardiac function. 
• 
IV fluid bolus. 
• 
Supportive care. 
Grade 3: 
Fever a (≥38°C) 
with hypotension requiring a 
vasopressor with or without 
vasopressin;  
and/or b hypoxia requiring high-flow c 
nasal cannula, facemask, nonrebreather 
mask, or Venturi mask  
As Grade 2 and: 
• 
Closely monitor all organ functions, including cardiac function. 
• 
Tocilizumab (8 mg/kg IV; maximum dose 800 mg) can be 
repeated after 6 hours. 
• 
If refractory to tocilizumab, dexamethasone 10 mg IV every 6 
hours; if refractory, increase to 20 mg every 6 hours or equivalent 
methylprednisolone. 
• 
Vasopressors as needed. 
• 
Supplemental oxygen as needed for hypoxia (including high-flow 
O2 and CPAP). 
• 
Transfer to ICU. 
Grade 4: 
Fever a (≥38°C) 
with hypotension requiring multiple 
vasopressors (excluding vasopressin);  
and/or b hypoxia requiring positive 
pressure (eg, CPAP, BiPAP, intubation 
and mechanical ventilation) 
As per Grade 3 and: 
• 
Substitute dexamethasone with methylprednisolone 1 g IV per 
day. 
• 
Mechanical ventilation. 
ASTCT: American Society for Transplantation and Cellular Therapy; BiPAP: bilevel positive airway pressure; 
CPAP: continuous positive airway pressure; CRS: cytokine release syndrome; ICU: intensive care unit; 
IV: intravenous; O2: supplemental oxygen. 
ASTCT consensus grade adapted from Lee et al, 2019 (Lee et al. 2019); CRS management recommendations are 
adapted from Neelapu et al, 2018 (Neelapu et al. 2018) and should be implemented at the investigator’s 
discretion. 
a Fever is defined as temperature ≥38°C not attributable to any other cause. In patients who have CRS then 
receive antipyretic or anticytokine therapy such as tocilizumab or steroids, fever is no longer required to grade 
subsequent CRS severity. In this case, CRS grading is driven by hypotension and/or hypoxia. 
b CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. 
For example, a patient with temperature of 39.5°C, hypotension requiring 1 vasopressor, and hypoxia requiring 
low-flow nasal cannula is classified as Grade 3 CRS. 
c Low-flow nasal cannula is defined as oxygen delivered at ≤6 L/minute. High-flow nasal cannula is defined as 
oxygen delivered at >6 L/minute. 
 

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8.9.8 
Management of Immune-Mediated AEs 
Pembrolizumab and TAK-981 can cause pneumonitis, colitis, hepatitis, endocrinopathies, 
nephritis, skin adverse reactions, IRRs, and other immune-mediated AEs. Monitoring of these 
AEs is required in both the dose escalation and expansion cohorts in the combination arm. 
Patients with AEs that are suspected to be related to pembrolizumab or TAK-981 should be 
evaluated by appropriate methodology, including physical examinations, laboratory tests, and 
imaging. These irAEs will be treated based on SOC, local institutional guidance, the 
WARNINGS AND PRECAUTIONS section of the package insert, and the proper use guidance 
of pembrolizumab and TAK-981 dose modifications. 
8.10 
Blinding and Unblinding 
This is an open-label study.  
8.11 
Description of Investigational Agents 
TAK-981 
TAK-981 drug product has been developed as an injection, for IV use (solution for infusion). 
 
 It is packaged in a glass vial 
containing 10 mL of TAK-981 sterile solution, with 0.5 mL excess volume. 
For specific information about the storage and handling of TAK-981 drug product, refer to the 
study or pharmacy manual associated with a given study protocol or the Instructions for Use 
contained in the shipping package. 
Full details are available in the IB. 
Pembrolizumab 
Pembrolizumab solution for injection consists of 100 mg/4 mL (25 mg/mL) in a single-dose vial 
or powder for solution for infusion 50 mg (1 vial contains 50 mg pembrolizumab). Please refer to 
the pharmacy manual and the most recent pembrolizumab SmPC for details. 
8.12 
Preparation, Reconstitution, and Dispensation 
TAK-981 
The reconstituted product will be administered by IV infusion over 1 hour (±10 minutes). After 
the end of the infusion the IV line should be flushed accordingly to local standards. Detailed 
reconstitution and dosage preparation instructions are provided in the directions for use located 
in the pharmacy manual. 
In the absence of compatibility studies, this medicinal product must not be mixed with other 
medicinal products. 
TAK-981 is an anticancer drug and, as with other potentially toxic compounds, caution should be 
exercised when handling TAK-981. 
CCI

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Reconstituted study products should be inspected visually for particulate matter and 
discoloration before administration, whenever solution and container permit. 
Pembrolizumab 
Please refer to the pharmacy manual and/or the most recent SmPC for preparation, 
reconstitution, and administration instructions. 
A commercially available IV formulation of pembrolizumab background therapy will be used. 
The sponsor will provide commercial supplies of pembrolizumab for IV administration, labeled 
appropriately for investigational use as per the regulations of the relevant country health 
authority. Patients enrolled in countries where pembrolizumab is designated as 
non-investigational product, should obtain commercially available product through the local 
hospital pharmacy or licensed distributor. Patients enrolled in countries where pembrolizumab is 
designated as investigational product, will have pembrolizumab supplied and packaged by the 
sponsor. 
8.13 
Packaging and Labeling 
All label information will fulfill requirements specified by local governing regulations. 
Additional details are provided in the pharmacy manual. 
8.14 
Storage, Handling, and Accountability 
TAK-981 
Complete receipt, inventory, accountability, reconciliation, and destruction records will be 
maintained for all used and unused study drug vials. A drug dispensing log, including records of 
drug received from the sponsor and drug dispensed to patients, will be provided and kept at the 
study site. Disposal instructions are provided in the pharmacy manual.  
The required storage condition for TAK-981 study drug is -20°C ± 5°C. Study drug must be 
stored under the conditions specified on the label and remain in the original container until 
dispensed. The investigator or designee must confirm that appropriate temperature conditions 
have been maintained for all TAK-981 received and that any discrepancies are reported and 
resolved before use of TAK-981. 
Pembrolizumab 
Pembrolizumab must be stored in a secure, limited-access location, according to conditions 
specified on the drug label. The investigator or designee must confirm that appropriate 
temperature conditions have been maintained and that any discrepancies are reported and 
resolved before use. Refer to the pharmacy manual and/or the most recent SmPC for additional 
details. 

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8.15 
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 trial will be conducted in compliance with the protocol, Good Clinical Practice (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, they will be reviewed by the institutional review board (IRB). Prisoners 
(or other populations that might be subject to coercion or exploitation) will not be enrolled into 
this study. 
9.3 
Treatment Group Assignments 
This is not a randomized study. Patient assignment to a specific schedule will be decided jointly 
by the investigator and sponsor with the aim of maximizing enrollment efficiency in the study. 
Details can be found in the cohort management plan.  
9.4 
Study Procedures 
Patients will be evaluated at scheduled visits over the following study periods: screening, 
treatment, EOT visit, two follow-up visits at 30 and 90 days (+10 days) after the last dose, PFS 
follow-up visits for patients who discontinued for reasons other than PD, and follow-up for OS 
for patients in Phase 2, for a maximum of 12 months for each patient after their last dose of study 
drug to monitor disease and survival status. Evaluations during the screening period are to be 
conducted within 28 days before administration of the first dose of the study drug. Procedures 
conducted during the screening period that are performed within 3 days of C1D1 may also be 
used as the predose evaluation and do not need to be repeated, unless otherwise specified. 
Unless otherwise noted, evaluations during the treatment period must occur before drug 
administration on scheduled visits. Tests and procedures should be performed on schedule for all 
visits. The timing of PK and pharmacodynamic assessments is specified in the SOE 

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(Appendix A). Laboratory assessments and procedures may occur up to 3 days before the 
scheduled day. For image tests (CT scan, positron emission tomography [PET] with 
18fluorodeoxyglucose [FDG-PET], MUGA, ECG), a ±7-day window is allowed. 
Refer to the SOE (Appendix A) for timing of assessments. Additional details are provided as 
necessary in the sections that follow. 
9.4.1 
Informed Consent 
Each patient must provide written informed consent before any study-required procedures are 
conducted, unless those procedures are performed as part of the patient’s standard care. 
9.4.2 
Patient Demographics 
The date of birth, race, ethnicity, and sex of the patient are to be recorded during screening. 
9.4.3 
Medical History 
During the screening period, a complete medical history will be compiled for each patient. The 
history will emphasize the background and progress of the patient’s malignancy and include a 
description of prior therapies for it and the best response achieved by each one. In addition, 
concomitant medications will be recorded as specified in Section 9.4.8. 
Available tumor pathology/cytogenetic/mutational information, such as driver 
mutations/alterations (eg, EGFR, ALK, ROS1, RET, MET, ATM, BRCA1/2, NTRK, KRAS, 
BRAF), HPV status, and tumor mutational burden, and PD-L1 results among others, should be 
reported for all patients in the eCRF.  
PD-L1 tumor status is required from all patients in Phase 2. If the patient requires immediate 
treatment and PD-L1 testing result is not available before the start of treatment, medical monitor 
or designee approval for initiation of protocol treatment is required; in this case, submission of 
an appropriate sample (either archival tissue or pretreatment biopsy) for local testing is required. 
9.4.4 
Physical Examination 
A physical examination will be completed per standard of care at the times specified in the SOE 
(Appendix A). Any clinically relevant findings are to be documented. 
9.4.5 
Patient Height and Weight 
Height and body weight will be measured at the times specified in the SOE. 
9.4.6 
Vital Signs 
Vital signs (blood pressure, heart rate, and temperature) will be monitored as specified in the 
SOE (Appendix A).  

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9.4.7 
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. The screening result must be available and 
negative before enrollment and dosing. For women of childbearing potential, if menstrual period 
is delayed during the study, absence of pregnancy must be confirmed by serum pregnancy test. 
9.4.8 
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 follow-up visit 30 days 
(+10 days) after the last dose of study drug in case of treatment discontinuation, or the start of 
subsequent antineoplastic therapy, whichever occurs first. See Section 8.6 for a list of 
medications and therapies that are prohibited during the study. 
9.4.9 
AEs 
Monitoring of AEs, serious and nonserious, will be conducted from the time of informed consent 
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. 
9.4.10 
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. 
9.4.11 
Cardiac Monitoring 
A single 12-lead standard safety ECG will be performed to assess eligibility as specified in the 
SOE (Appendix A). ECG assessments are to be performed with the patient rested for at least 
5 minutes before collection. A qualified person will interpret the ECGs locally. Additional ECGs 
may be obtained as clinically indicated at the discretion of the investigator.  
The assessment of LVEF measured by echocardiography or MUGA will be performed as 
indicated in SOE. From Cycle 3 onwards, a ±7-day window is allowed for this test. When the 
timing of ECG or vital sign measurements coincides with the timing of a blood draw 
(eg, PK sample), the ECG measurements and vital signs measurements should be completed first 
followed by blood sampling. 
9.4.12 
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. 
9.4.12.1 
Clinical Chemistry, Hematology, and Urinalysis 
Blood samples for analysis of the chemistry and hematology parameters shown in Table 9.a, 
urine samples for analysis of the parameters shown in Table 9.b, and tumor prognostic markers 

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shown in Table 9.c will be obtained as specified in the SOE (Appendix A). They will be 
performed locally only.  
Table 9.a 
Clinical Chemistry and Hematology Tests 
Hematology 
Serum Chemistry 
Coagulation 
Hematocrit 
Hemoglobin 
Leukocytes with differential 
ANC 
CD4/CD8 count and ratio 
Platelets (count) 
 
Albumin 
Alkaline phosphatase 
Alanine aminotransferase 
Aspartate aminotransferase 
Bilirubin (total) 
(Blood) Urea nitrogen (BUN) 
Calcium 
Bicarbonate (HCO3-) or Carbon 
dioxide (CO2) 
Creatinine  
(Standard) C Reactive protein 
Chloride 
Glucose 
Lactate dehydrogenase (LDH) 
Magnesium 
Phosphate 
Potassium 
Sodium 
Protein (total) 
Urate 
Activated partial thromboplastin 
time (aPTT) 
Prothrombin time (PT) 
Fibrinogen 
ANC: absolute neutrophil count. 
 
Table 9.b 
Clinical Urinalysis Tests 
Urinalysis 
Bilirubin 
Glucose 
Ketones 
Leukocytes 
Nitrite 
Occult blood 
Urine pH 
Protein 
Specific gravity 
Urobilinogen 
 

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Table 9.c 
Tumor Prognostic Markers 
Colon Cancer 
Cervical Cancer 
Carcinoembryonic antigen (CEA) 
Cancer antigen 19-9 (CA 19-9) 
Cancer antigen 15-3 (CA 15-3) 
Cancer antigen 125 (CA 125) 
Blood sample collection for tumor markers during Phase 2 only. 
 
Hematology, chemistry, coagulation testing, and urinalysis samples may be taken up to 3 days 
before the visit (unless otherwise specified) and may be conducted 24 hours before the visit. All 
results must be evaluated before dosing. Microscopic analysis of urine sediment should be 
performed if significant abnormalities are detected in proteins, leukocytes, or blood. 
Serum creatinine clearance is to be estimated by the Cockcroft-Gault formula (Cockcroft and 
Gault 1976) as follows: 
Estimated creatinine clearance 
= [(140 −Age) ∗Mass(kg) ] / [72 ∗serum creatinine(mg/dL)]  
For female patients, the result of the formula above should be multiplied by 0.85.  
9.4.12.2 
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. Results 
may be evaluated after dosing. 
Table 9.d 
Immunosafety Determinations in Serum 
Serum Chemistry 
Thyrotropin (TSH) 
Free thyroxine (FT4) 
Adrenocorticotropic hormone (ACTH) 
 
9.4.13 
Disease Assessment 
Patients will undergo CT and/or magnetic resonance imaging (MRI) scans, and/or FDG-PET 
imaging to assess disease response and progression, using RECIST, Version 1.1 (Eisenhauer et 
al. 2009). 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 imaging 
modalities used for a patient should remain consistent throughout the study. If contrast-enhanced 
CT scans are contraindicated for a particular patient, a non-contrast CT of the chest, in addition 
to contrast-enhanced abdomen, and pelvis MRI images should be acquired, if possible. 
Anatomical measurements (individually and summed across target lesions) will be collected at 
baseline and each subsequent evaluation. In addition, non-measurable disease and new lesions 
will be documented and their status evaluated. 

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Bone and PET scans should be collected as clinically indicated. Objective assessments of the 
disease burden: target, non-target, and potential new lesions, will be performed at each time 
point (a ±7-day window is allowed for image tests) as described in the SOE (Appendix A). For 
Phase 2, radiographic images will be collected centrally. Test results and physician findings will 
be filed in patient source documents. In the event of antitumor response, the sponsor may request 
electronic images for those patients who demonstrate tumor reduction. Objective response data 
collected for the clinical study report will be based on investigator assessment. 
Imaging tests performed before the screening consent date may be used as screening tests if 
C1D1 is planned within the 28 days after the date of the test. 
9.4.13.1 
Modified RECIST, Version 1.1 for Immune-Based Therapeutics (iRECIST) and 
Treatment Beyond Progression: 
For patients who have initial radiological evidence of PD by RECIST, Version 1.1 as determined 
by the site, the investigator may elect to continue a patient on study treatment until repeat 
imaging is obtained (iRECIST-based management) (Seymour et al. 2017). This clinical judgment 
decision by the investigator should only be made if the patient is clinically stable, based on 
clinical factors including performance status, clinical symptoms, and laboratory data. Such 
patients may continue to receive study treatment and an imaging-based tumor assessment should 
be repeated ≥ 4 weeks later in order to reassess PD per investigator assessment. 
Clinical stability is defined by the following: 
• Absence of signs and symptoms of clinically significant progression of disease, including 
worsening of laboratory values. 
• No decline in ECOG performance status. 
• Absence of rapid progression of disease. 
• Absence of tumor progression at critical anatomical sites that requires urgent alternative 
medical intervention (eg, central nervous system metastasis with potential for cord 
compression). 
Note: Patients exhibiting toxicity from study treatment as outlined in Section 8.5.4 may NOT 
continue to receive trial therapy. 
In determining whether or not the tumor burden has increased or decreased per iRECIST, the 
investigator should consider all target and non-target lesions as well as any incremental new 
lesion(s). 
iRECIST defines unconfirmed progressive disease (iUPD) on the basis of RECIST, Version 1.1 
principle; however, iUPD requires confirmation obtained by repeat imaging at least 4 weeks, but 
no longer than 8 weeks after.  

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9.4.13.1.1 
Confirming Progression 
Confirmatory scans should be performed at least 4 weeks, but no longer than 8 weeks after 
iUPD. 
A. Immune-confirmed progressive disease (iCPD) is confirmed if further increase in tumor 
burden, compared to the last assessment, is seen as evidenced by 1 or more of the 
following: 
• Continued increase in tumor burden (from iUPD) where RECIST, Version 1.1 
definitions of progression had been met (from nadir) in target, non-target disease 
or new lesions. 
• Progression in target disease worsens with an increase of at least 5 mm in the 
absolute value of the sum. 
• Continued unequivocal progression in non-target disease with an increase in 
tumor burden. 
• Increase in size of previously identified new lesion (s) (an increase of at least 5 
mm in the absolute value of the sum of those considered to be target new lesions) 
or additional new lesions. 
OR 
B. RECIST, Version 1.1 criteria are met in lesion types (target or non-target or new lesions) 
where progression was not previously identified, including the appearance of additional 
new lesions. 
If iUPD is not confirmed at the next assessment, then the appropriate response will be 
assigned (iUPD if the criteria are still met, but no worsening, or immune stable disease (iSD), 
immune partial response (iPR) or immune complete response (iCR) if those criteria are met 
compared to baseline). The prior documentation of iUPD does not preclude assigning iCR, 
iPR, or iSD in subsequent time-point assessments or as best overall response providing that 
iCPD is not documented at the next assessment after iUPD (Seymour et al. 2017). 
9.4.13.1.2 
New Lesions 
New lesions should be assessed and measured as they appear using RECIST, Version 1.1 criteria 
(maximum of 5 lesions, no more than 2 per site, at least 10 mm in long axis (or 15 mm in short 
axis for nodal lesions), and recorded as new lesions-target (NLT) and new lesion-non-target 
(NLNT) to allow clear differentiation from baseline target and non-target lesions. 
New lesions may either meet the criteria of NLT or NLNT to drive iUPD (or iCPD). However, 
the measurements of target lesions should NOT be included in the sum of measures of original 
target lesions identified at baseline. Rather, these measurements will be collected on a separate 
table in the eCRF. 
PD is confirmed in the new lesion category if the next imaging assessment, conducted at least 
4 weeks (but not more than 8 weeks) after iUPD confirms further progression from iUPD with 

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either an increase of at least 5 mm in the absolute value of the sum of NLT, an increase (but not 
necessarily unequivocal increase) in the size of NLNT lesions or the appearance of additional 
new lesions. 
9.4.14 
Biomarker, Pharmacodynamic, and PK Samples 
9.4.14.1 
Primary Specimen Collection 
The primary specimens to be collected are shown in Table 9.e. Collection of samples for 
exploratory endpoints are dependent upon 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 
≤12 months 
Fresh tumor tissue 
biopsy sample at 
Screening 
Fresh tumor 
tissue 
FFPE 
block/slides 
DNA 
RNA 
Biomarker 
measurements 
Mandatory. 
Paired fresh tumor 
tissue biopsy sample 
Fresh tumor 
tissue 
FFPE 
block/slides 
DNA 
RNA 
Biomarker 
measurements 
Optional. 
Plasma sample for 
chemokines 
Plasma 
 
 
Biomarker 
measurements 
Mandatory 
Blood cells for 
immunophenotyping 
Blood 
Cells 
 
Biomarker 
measurements 
Mandatory 
PBMCs sample for 
immunophenotyping a 
Blood 
Cells 
 
Biomarker 
measurements 
Mandatory in 
Phase 1b 
Blood sample for flow 
cytometry 
(adduct/conjugate) 
Blood 
Cells 
 
Biomarker 
measurements 
Mandatory in 
Phase 1b 
Blood sample for RNA 
Blood 
RNA 
 
Biomarker 
measurements 
Mandatory 
Serum sample for 
circulating biomarkers 
Serum 
 
 
Biomarker 
measurements 
Mandatory in 
Phase 1b 
Blood sample for DNA 
Blood 
DNA 
 
Biomarker 
measurements 
Mandatory in 
Phase 1b 
Blood sample for 
cfDNA 
Plasma 
DNA 
 
Biomarker 
measurements 
Mandatory  
Plasma sample for 
TAK-981 PK 
Plasma 
 
 
PK measurements 
Mandatory 
cfDNA: cell-free DNA; FFPE: formalin-fixed, paraffin-embedded; PK: pharmacokinetic; PBMC: peripheral 
blood mononuclear cell. 
a This term has been updated from “Blood sample for immunophenotyping” to “PBMCs sample for 
immunophenotyping” for the purpose of standardization; however, the previous term may continue to be utilized 
by the central laboratory in the labeling of these samples. 

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9.4.14.2 
Tumor Biopsies 
For patients in Phase 2, baseline (pretreatment) tumor collection is mandatory. Pretreatment fresh 
tumor biopsy at screening can be replaced by a recent (≤12 months old) formalin fixed paraffin 
embedded tumor specimen. For fresh tumor biopsies, the lesion must be accessible for a low-risk 
biopsy procedure (those occurring outside the brain, lung/mediastinum, and intra-abdominal, or 
obtained with endoscopic procedures beyond the stomach or bowel). Either a fresh tumor biopsy 
or banked tumor taken within 12 months of enrollment is required. This sample will be assessed 
for other features of the tumor and/or tumor microenvironment including immune cell content 
and tumor mutations. 
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 biopsy for patients who have provided a fresh tumor tissue sample during 
screening will be encouraged but optional. The on-treatment biopsy will be obtained after 
TAK-981 infusion on C2D8 (+7 days). The accessible lesion biopsy (screening and on-
treatment) should not have been previously designated as the only target lesion for measurable 
disease or located in a previously irradiated area. Ideally, the same lesion should be biopsied 
before treatment and on treatment whenever possible. On-treatment biopsy collection visit day 
may be changed if data emerges that would be supportive of such change. 
When provided, paired tumor biopsies will be used to determine TAK-981-SUMO adduct 
formation and SUMO pathway inhibition in the tumor, as well as activation markers and markers 
of functional modulation of the immune response in the tumor/TME. Induction of an innate 
and/or adaptive immune response and check point modulation in the tumor and TME will be by 
measuring levels of PD-1 and PD-L1 expression and activation state of tumor-infiltrating 
lymphocytes and myeloid cells, including NK cells and macrophages. 
Hematology and coagulation tests including platelet counts, international normalized ratio and 
activated partial thromboplastin time (aPTT) should be performed prior to a biopsy procedure 
being performed and the risk of bleeding associated with the procedure must be assessed by the 
investigator. 
9.4.14.3 
Banked Tumor 
Archival (banked) tumor tissue sample block or approximately 10 unstained slides collected 
within 12 months of study initiation will be collected when available from all enrolled patients to 
assess baseline features such as gene mutations, gene signatures, gene expression, tumor 
mutation burden, immune cell content and their spatial relationships, or biomarkers of response 
or resistance to TAK-981, pembrolizumab or their combination that may emerge from future 
nonclinical or clinical studies. See the laboratory manual for details. 
9.4.14.4 
Fresh Paired Tumor Biopsy 
Paired screening and on-treatment biopsies are highly encouraged (but optional) for all patients 
in 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 

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study drug. The on-treatment biopsy will be obtained post-TAK-981 infusion on C2D8 
(+7 days). The accessible lesion biopsy (screening and on-treatment) should not have been 
previously designated as the only target lesion for measurable disease or located in a previously 
irradiated area. Ideally, the same lesion should be biopsied before treatment and on treatment 
whenever possible. On-treatment biopsy collection visit day may be changed should data emerge 
that would be supportive of such change.  
9.4.15 
PK Measurements 
Details regarding the preparation, handling, and shipping of the PK samples are provided in the 
laboratory manual. Plasma samples for TAK-981 PK will be collected at the time points 
specified in Appendix A. Blood/plasma samples should be collected from the contralateral arm 
(not the arm which was used for drug infusion). 
The timing but not the total number of plasma samples may be modified during the study based 
on emerging PK data if a change in sampling scheme is considered necessary to better 
characterize the PK of TAK-981. A protocol amendment is not necessary for such modifications. 
9.4.16 
Pharmacodynamic Measurements 
The pharmacodynamics specimen collection time points are displayed in the SOE (Appendix A). 
Details regarding the preparation, handling, and shipping of samples are provided in the 
laboratory manual. 
The following pharmacodynamic measures will be tested: 
• TAK-981-SUMO adduct formation and SUMO2/3 inhibition in blood, and paired tumor 
biopsies (when collected). 
• Chemokines and cytokine analysis in plasma, including those in the IFN pathway. 
• Immunophenotyping in whole blood, peripheral blood mononuclear cells (PBMCs, when 
collected), and paired tumor biopsies (when collected). 
• Gene expression analysis, including IFN pathway, in whole blood  
9.4.17 
DNA Measurements  
As detailed in the SOE (Appendix A), whole blood will be collected predose on C1D1 as a 
germline control sample for DNA mutation analysis from banked tumor and/or fresh tumor 
biopsies. Plasma samples will be collected as per SOE for evaluation of cfDNA to assess tumor 
mutations over time. In addition, the extracted DNA from such samples may be used in 
pharmacogenomic evaluation to study the impact of genetic polymorphism in drug metabolizing 
enzymes and/or transporters that may be implicated in the disposition of TAK-981 or response to 
anti-PD-1 therapies. The data resulting from such analyses, if performed, may be pooled with 
similar data from other clinical studies for eventual population PK analysis purposes and as such 
will be reported separately and not within the clinical study report for this study. 

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9.5 
Completion of Study Treatment (for Individual Patients) 
Patients will be considered to have completed study treatment when they have discontinued 
treatment with both study drugs, TAK-981 and pembrolizumab. 
9.6 
Completion of Study (for Individual Patients) 
Patients will be considered to have completed the study if they are discontinued from both study 
drugs and 1 or more of the following situations occur: 
• Death. 
• PD per iRECIST. 
• Start of new systemic treatment. 
• Withdrawal by patient. 
• Study terminated by the sponsor. 
• Lost to follow-up. 
• Transfer of patient to a TAK-981 long-term safety study, single-patient investigational new 
drug application, or similar program. 
The consequence of patient withdrawal is that no new information will be collected from the 
withdrawn patient and added to the existing data or any database. 
9.7 
Discontinuation of Treatment With Study Drugs 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. It is possible that 1 study drug is permanently 
discontinued due to treatment-related AEs, while the patient continues to receive the other study 
drug and remains on treatment. Discontinuation of treatment occurs only when both study drugs 
are required to be discontinued due to AEs or upon the occurrence of any of the other non-AE 
criteria. 
Treatment with study drug may be discontinued for any of the following reasons: 
• Withdrawal by patient. 
• 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/risk assessment).  
• AE that leads to TAK-981 and pembrolizumab discontinuation. 
• Occurrence of drug-related AEs that require discontinuation of study drug(s) per dose 
modification guidelines in Section 8.5.3.1.  
• Treatment interruption of more than 63 days (3 cycles) for study drug-related or possibly 
related AEs. 

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• Symptomatic deterioration. 
• PD per iRECIST. 
• Death. 
• Pregnancy. 
• Major protocol deviation. 
• Initiation of another systemic anticancer treatment. 
• Study terminated by sponsor. 
• Treatment completion. 
• Lost to follow-up. 
9.7.1 
Treatment Beyond Progression 
Immunotherapeutic agents may produce antitumor effects by potentiating endogenous cancer-
specific immune responses. The response patterns seen with such an approach can manifest as a 
clinical response after an initial apparent increase in tumor burden (ie, pseudoprogression) or 
even the appearance of new lesions. Standard RECIST, Version 1.1-based assessment of disease 
progression may, thus, not provide an accurate assessment of response to immunotherapeutic 
agents. For this reason, the modified iRECIST criterion of iCPD will be required before 
treatment discontinuation. Therefore, in the event of PD by RECIST, Version 1.1 that is also 
considered iUPD, repeat disease imaging will be performed at 4 to 8 weeks, and if the 
investigator determined that the patient is clinically stable, treatment with study drugs should not 
be discontinued until iCPD is declared. 
Once TAK-981 and pembrolizumab have been discontinued, all study procedures outlined for 
the EOT visit will be completed as specified in the SOE (Appendix A). The primary reason for 
study drug discontinuation will be recorded on the eCRF. After the EOT, each patient will be 
followed for 30 and 90 days (+10) as outlined in the SOE (Appendix A).  
9.7.2 
Patient Replacement 
Note that some patients may discontinue study drug for reasons other than PD before completing 
the full treatment course; these patients will remain in the study for posttreatment assessments as 
outlined in the SOE (Appendix A) until PD occurs. 
During dose escalation, patients who are withdrawn from treatment during Cycle 1 for reasons 
other than DLTs will be replaced.  
In the case of study termination by the sponsor, eligible patients may have continued access to 
TAK-981 as described in Section 6.6.5. 

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9.8 
Study Compliance 
Study drug will be administered or dispensed only to eligible patients under the supervision of 
the investigator or identified subinvestigator(s). The appropriate study personnel will maintain 
records of study drug receipt and dispensing. 
9.9 
Posttreatment Follow-up Assessments (Survival)  
Patients who complete treatment or stop treatment for any reason other than PD will continue to 
have PFS follow-up visits. The PFS follow-up visit should be conducted at the site every 
12 ± 1 weeks from last dose of study drug until the occurrence of PD, loss to follow-up, consent 
withdrawal, death, the start of subsequent systemic antineoplastic therapy, or study termination 
(Section 9.6), whichever occurs first.  
The duration of follow-up for PFS, and OS (Phase 2 only) for a patient will be for up to 
12 months. 
NOTE: During this period, related SAEs must be reported to the Global Pharmacovigilance 
department or designee. This includes deaths or SAEs that the investigator considers related to 
study drug that occur during posttreatment follow-up. Refer to Section 10.0 for details regarding 
definitions, documentation, and reporting of SAEs. 
10.0 
ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 
Pretreatment Event Definition 
A pretreatment event is any untoward medical occurrence in a patient or subject who has signed 
informed consent to participate in a study but before administration of any study medication; it 
does not necessarily have to have a causal relationship with study participation. 
10.1.2 
AE Definition 
AE means any untoward medical occurrence in a patient or subject administered a 
pharmaceutical product; the untoward medical occurrence does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product whether or not it is related to the medicinal product. 
This includes any newly occurring event or a previous condition that has increased in severity or 
frequency since the administration of study drug. 
All abnormal laboratory values will be reviewed by the investigator but only those abnormal 
values that lead to discontinuation or delay in treatment, dose modification, therapeutic 
intervention, or are considered by the investigator to be a clinically significant change from 
baseline, will be assessed as AEs. 

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10.1.3 
SAE Definition 
SAE means any untoward medical occurrence that at any dose: 
• Results in death. 
• Is life-threatening (refers to an AE in which the patient was at risk of death at the time of the 
event. It does not refer to an event which hypothetically might have caused death if it were 
more severe). 
• Requires inpatient hospitalization or prolongation of an existing hospitalization (see 
clarification in the paragraph in Section 10.2 on planned hospitalizations). 
• Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions). 
• Is a congenital anomaly/birth defect. 
• Is a medically important event. This refers to an AE that may not result in death, be 
immediately life-threatening, or require hospitalization, but may be considered serious when, 
on the basis of appropriate medical judgment, it may jeopardize the patient, require medical 
or surgical intervention to prevent one of the outcomes listed above, or involves suspected 
transmission via a medicinal product of an infectious agent. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse; any organism, virus, or infectious particle 
(eg, prion protein transmitting transmissible spongiform encephalopathy), pathogenic or 
nonpathogenic, is considered an infectious agent. 
In this study, intensity for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE, Version 5.0, effective 27 November 2017 (NCI 2017), except CRS that will be 
graded according to ASTCT Consensus Grading for CRS (Lee et al. 2019). Clarification should 
be made between an SAE and an AE that is considered severe in intensity (Grade 3 or 4) because 
the terms serious and severe are NOT synonymous. The general term severe is often used to 
describe the intensity (severity) of a specific event; the event itself, however, may be of 
relatively minor medical significance (such as a Grade 3 headache). This is NOT the same as 
serious, which is based on patient/event outcome or action criteria described above and is usually 
associated with events that pose a threat to a patient’s life or ability to function. A severe AE 
(Grade 3 or 4) does not necessarily need to be considered serious. For example, a white blood 
cell count of 1000/mm3 to less than 2000/mm3 is considered Grade 3 (severe) but may not be 
considered serious. Seriousness (not intensity) serves as a guide for defining regulatory reporting 
obligations. 
10.1.4 
Adverse Event of Special Interests 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 
investigator to Takeda may be appropriate. Such events may require further investigation in 

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order to characterize and understand them. Communication between the sponsor and other 
parties (eg, regulators) will follow regular reporting timelines (ie, 7 days for fatal or 
life-threatening SUSARs [suspected unexpected serious adverse reactions] and 15 days for other 
serious events). 
A list of AESIs specific to study drugs are provided in Section 10.2. 
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 trial or before study drug was given are not to be considered AEs 
unless the condition deteriorated in an unexpected manner during the trial (eg, surgery was 
performed earlier or later than planned). 
For both serious and nonserious AEs, the investigator must determine both the severity (toxicity 
grade) of the event and the relationship of the event to study drug administration.  
Severity (toxicity grade) for each AE, including any lab abnormality, will be determined using 
the NCI CTCAE, Version 5.0, effective 27 November 2017 (NCI 2017), except CRS that will be 
graded according to ASTCT Consensus Grading for CRS (Lee et al. 2019). The criteria are 
provided in the study manual. 

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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? 
AESI Reporting: 
The below list of immune-mediated AEs will be treated as AESIs. 
• Pneumonitis. 
• Hepatitis. 
• Colitis. 
• Endocrinopathies. 
– Thyroid disorders. 
– Adrenal insufficiency. 
– Type 1 diabetes mellitus. 
– Hypophysitis. 
• Nephritis. 
• Dermatologic reactions. 
All AESIs regardless of seriousness and causality must be reported by the investigator to the 
sponsor within 72 hours of becoming aware of the event. This will be done by transmitting an 
EDC. 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 becoming aware of the event. 
All non-serious AESIs are captured only in the clinical database. 
The investigator must follow institutional guidelines to manage immune-mediated AEs. 
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 or start of a new systemic treatment, 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 from C1D1 through the 90-day visit or until resolved. 

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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. 
A medication error is a preventable event that involves an identifiable patient and leads to 
inappropriate medication use, which may result in patient harm. Whereas overdoses and 
underdoses constitute medication errors, doses missed inadvertently by a patient do not.  
Individuals who identify a potential medication error (including overdose) situation should 
immediately report this via the email address provided below. 
Product 
Call Center 
Email 
TAK-981 
Takeda 
ctmcomplaint@takeda.com  
 
Product complaints and medication errors in and of themselves are not AEs. If a product 
complaint or a medication error results in an SAE, the SAE should be reported.  
10.6 
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities 
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
and any other applicable SAEs to regulatory authorities, including investigators and IRBs, as 
applicable, in accordance with national regulations. Relative to the first awareness of the event 
by/or further provision to the sponsor or sponsor’s designee, suspected unexpected serious 
adverse reactions will be submitted to the regulatory authorities as expedited reports within 
7 days for fatal and life-threatening events and within 15 days for other serious events, unless 
otherwise required by national regulations. The sponsor will also prepare an expedited report for 
other safety issues where these might materially alter the current benefit/risk assessment of an 

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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 
Safety Monitoring Committee 
During Phase 1b, an SMC composed of the principal investigators, and sponsor clinician will 
regularly review safety data to ensure patients’ safety throughout the study and make decisions 
on dose escalation as defined in the SMC charter. 
11.2 
Independent Data Monitoring Committee 
During Phase 2, an IDMC will be established to monitor safety and assess benefit/risk 
throughout the conduct of the Phase 2 portion of the study. The IDMC will consist of 3 to 
5 members not associated with the conduct of the study and/or the sponsor with the exception of 
the compensation to IDMC members related to their IDMC activities. The IDMC members will 
be a multidisciplinary group that will include at least 2 oncologists with extensive experience in 
clinical study conduct and a biostatistician with substantial experience in the IDMC process. The 
committee will perform data review to monitor safety and assess benefit/risk throughout the 
conduct of the Phase 2 portion of the study. IDMC meetings will be held on a periodic basis as 
defined in the IDMC charter and at the end of each stage of the Phase 2. Ad hoc IDMC meetings 
may also be held if a significant issue should arise. 
11.3 
Independent Review Committee  
All imaging performed to assess response to treatment will be submitted to a central core 
imaging repository. An independent review committee (IRC) will be established to 
independently review efficacy imaging endpoints once any cohort in Phase 2 meets the efficacy 
threshold in Stage 1 and begins enrolling patients in Stage 2. Please refer to the imaging manual 
and/or IRC charter for further details. 
12.0 
DATA HANDLING AND RECORD KEEPING  
The full details of procedures for data handling will be documented in the data management plan. 
If selected for coding, AEs, medical history, and concurrent conditions will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the World 
Health Organization (WHO) Drug Dictionary. 
12.1 
eCRFs  
Completed eCRFs are required for each patient who signs an ICF. 
The sponsor or its designee will supply investigative sites with access to eCRFs and will make 
arrangements to train appropriate site staff in the use of the eCRF. These forms are used to 

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transmit the information collected in the performance of this study to the sponsor, contract 
research organization (CRO) partners, and regulatory authorities. Investigative sites must 
complete eCRFs in English. 
After completion of the entry process, computer logic checks will be run to identify items such 
as inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designee) and will be answered by the site. 
Any change of, modification of, or addition to the data on the eCRFs should be made by the 
investigator or appropriate site personnel. Corrections to eCRFs are recorded in an audit trail that 
captures the old information, the new information, identification of the person making the 
correction, the date the correction was made, and the reason for the change.  
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the principal investigator must retain 
full responsibility for the accuracy and authenticity of all data entered on the eCRFs. 
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor (or designee) will be permitted to review the patient’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed 
eCRFs are the sole property of the sponsor and should not be made available in any form to third 
parties, except for authorized representatives of appropriate governmental health or regulatory 
authorities, without written permission of the sponsor. 
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 patients, medical records, temporary media such as thermal-sensitive paper, source 
worksheets, all original signed and dated ICFs, patient authorization forms regarding the use of 
personal health information (if separate from the ICFs), electronic copies of eCRFs including the 
audit trail, and detailed records of drug disposition to enable evaluations or audits from 
regulatory authorities and the sponsor (or designees). Any source documentation printed on 
degradable thermal-sensitive paper should be photocopied by the site and filed with the original 
in the patient’s chart to ensure long-term legibility. Furthermore, ICH E6 Section 4.9.5 requires 
the investigator to retain essential documents specified in ICH E6 (Section 8) until at least 
2 years after the last approval of a marketing application for a specified drug indication being 
investigated or, if an application is not approved, until at least 2 years after the investigation is 
discontinued and regulatory authorities are notified. In addition, ICH E6 Section 4.9.5 states that 
the study records should be retained until an amount of time specified by applicable regulatory 
requirements or for a time specified in the clinical study site agreement between the investigator 
and sponsor. 
Refer to the clinical study site agreement for the sponsor’s requirements for record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of 
any such documents. 

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13.0 
STATISTICAL METHODS 
13.1 
Statistical and Analytical Plans 
A statistical analysis plan will be prepared and finalized before database lock. This document 
will provide further details regarding the definition of analysis variables and analysis 
methodology to address all study objectives. 
13.1.1 
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 all DLT-evaluable 
patients as specified in Section 8.3. The DLT-evaluable population will be used to inform 
RP2D/MTD selection. 
Response-evaluable analysis set: Patients who have received at least 1 dose of study drug, 
have sites of measurable disease at baseline, and have undergone 1 postbaseline disease 
assessment or were discontinued due to symptomatic deterioration or death before a 
postbaseline evaluation happens, will be used for analyses of response. 
Phase 2 efficacy analysis set: All patients who received at least 1 dose of study drug in 
Phase 2 portion will be included in the Phase 2 efficacy analysis. 
Pharmacodynamic analysis sets:  
Pharmacodynamic analysis sets to assess target engagement of TAK-981 and SUMOylation 
pathway inhibition:  
• Patients who have provided evaluable paired tumor biopsies (screening and postdose) 
will be included in the tumor 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. 
For exploratory biomarkers, the following may be included in the analysis sets: 
• Patients who have provided evaluable plasma samples (C1D1 predose sample and at least 
1 postdose sample) may be included in the plasma chemokine/cytokine pharmacodynamic 
analysis dataset.  
• Patients who have provided evaluable paired tumor biopsies (screening and postdose) 
may be included in the tumor immunophenotyping and/or tumor gene expression 
pharmacodynamic analysis dataset.  

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• Patients who have provided evaluable blood samples (C1D1 predose sample and at least 
1 postdose sample) may be included in the blood/PBMCs immunophenotyping and/or 
blood gene expression pharmacodynamic analysis dataset. 
13.1.2 
Analysis of Demographics and Other Baseline Characteristics 
Patient demographic and baseline characteristics will be summarized descriptively. Variables to 
be analyzed include sex, age, race, medical history, prior medications/therapies, ECG findings, 
and other parameters as appropriate. For continuous variables, descriptive statistics (number, 
mean, standard deviation, median, minimum, and maximum) will be provided. For categorical 
variables, patient counts and percentages will be provided. Categories for missing data will be 
presented as needed. 
13.1.3 
Efficacy Analysis 
13.1.3.1 
Primary Efficacy Analysis 
Phase 1b: 
Efficacy is not the primary objective for this study in the Phase 1b portion. The efficacy analysis 
will mainly focus on the Phase 2 portion of this study. 
In the Phase 1b portion of this study, efficacy parameters such as ORR, DCR, DRR, DOR, TTR, 
TTP, and PFS, may be summarized as appropriate. Disease response will be categorized and 
presented in listings. 
Phase 2: 
The primary endpoint for Phase 2 portion is ORR (CR + PR) as defined by the investigator 
according to RECIST, Version 1.1. 
ORR is defined as the proportion of patients who achieve CR and PR (determined by the 
investigator) during the study according to RECIST, Version 1.1. 
The primary efficacy analysis will be based on the Phase 2 efficacy analysis set. 
Estimates of the ORR (CR + PR) will be presented with 2-sided 95% exact binomial confidence 
intervals. Additional confidence intervals may also be provided as appropriate. 
13.1.3.2 
Secondary Efficacy Analysis 
Secondary efficacy endpoints include DCR, DRR, DOR, TTR, TTP, PFS, and OS (Phase 2 only) 
as assessed by the investigator according to both RECIST, Version 1.1 and iRECIST; and ORR 
as assessed by the investigator according to iRECIST.  
DCR is defined as the proportion of patients who achieve stable disease (SD) or better 
(CR+PR+SD determined by the investigator) during the study. 
DRR is defined as the rate of objective responses (CR and PR as determined by the investigator) 
maintained for at least 6 months initiating at any time within 12 months of commencing therapy. 

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DOR is the time from the date of first documentation of a PR or better to the date of first 
documentation of PD for responders (PR or better). Responders without documentation of PD 
will be censored at the date of the last response assessment that is SD or better. 
TTR is defined as the time from the date of the first dose to the date of the first documentation of 
objective tumor response (CR and PR as determined by the investigator).  
TTP is defined as the time from the date of the first dose to the date of the first documentation of 
PD as defined by standard disease criteria. 
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 the investigator for both RECIST, Version 1.1 and iRECIST. Patients without documentation 
of PD 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. 
ORR is defined as the proportion of patients who achieve CR and PR (determined by the 
investigator) during the study according to iRECIST. 
Estimates of ORR, DCR, and DRR will be presented with 2-sided 95% exact binomial 
confidence intervals. Additional confidence intervals may also be provided as appropriate. 
PFS, OS, DOR, and TTP will be analyzed using Kaplan-Meier method for the Phase 2 efficacy 
analysis set. TTR will be summarized for responders. 
All efficacy endpoints may be analyzed for the overall study population as appropriate.  
13.1.4 
PK Analysis  
The PK of TAK-981 will be characterized in this study on Day 1 and Day 8 of the dose 
escalation phase of the study. PK of pembrolizumab will not be characterized.  
PK parameters for TAK-981 will be estimated using noncompartmental methods with Phoenix 
WinNonlin software. The PK parameters will be estimated from the concentration-time profiles 
for the PK population. The following PK parameters will be estimated, as permitted by data: 
• Maximum observed concentration (Cmax). 
• Time of first occurrence of Cmax (tmax). 
• AUC∞. 
• Area under the concentration-time curve from time 0 to time of the last quantifiable 
concentration (AUClast). 
• Terminal disposition phase half-life (t1/2z). 
• Clearance (CL). 

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• Vss. 
PK parameters will be summarized using descriptive statistics. Individual TAK-981 
concentration-time data and individual PK parameters will be presented in listings and tabulated 
using summary statistics by dose cohort. Individual and mean concentration-time profiles will be 
plotted by dose cohort. The above parameters will not be estimated for the sparse PK samples 
collected during the Phase 2 portion of study. 
The serial and sparse PK data collected in this study are intended to contribute to future 
population PK analyses of TAK-981. These population PK analyses may include data collected 
in other TAK-981 clinical studies. The analysis plan for the population PK analysis will be 
separately defined, and the results of these analyses will be reported separately. 
13.1.5 
Pharmacodynamic Analysis 
The analysis of tumor and blood 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 the TAK-981 biological activity range and duration of 
pharmacodynamic effects, and to help determine the PAD/RP2D for the 
TAK-981/pembrolizumab combination. In addition, candidate response biomarkers will be 
evaluated. 
13.1.6 
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 in combination with 
pembrolizumab. Such analyses may be performed on an ongoing basis to assess the 
appropriateness of dose and dosing schedule of TAK-981 in combination with pembrolizumab 
and for determination of PAD. 
To determine the appropriateness of the PAD/MTD and schedule, a totality of evidence approach 
will be used that will integrate all available data from the dose escalation and the Phase 2 
portions of the study, including:  
1. Multicycle safety/tolerability of TAK-981 in combination with pembrolizumab. 
2. Single- and multiple-dose PK of TAK-981. 
3. Single- and multiple-dose pharmacodynamic biomarkers of TAK-981 (in circulation and 
tumor when available) including target engagement (adduct formation), SUMO2/3 inhibition, 
Type 1 IFN response gene signature, cytokines/chemokines in circulation, and blood 
immunophenotyping. 
4. Antitumor response with TAK-981 in combination with pembrolizumab administration. 
5. Relative dose intensity. 
Dose-exposure-response relationships will be explored to describe the PK-safety, 
PK-pharmacodynamics, and PK-antitumor response relationships of TAK-981, and the results of 

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such quantitative pharmacology analyses will be used to inform selection of the RP2D/dosing 
schedule of TAK-981 in combination with pembrolizumab. 
In addition, PK-pharmacodynamic data collected in the study during dose escalation may be used 
to inform the quantitative systems pharmacology model that may be used to further refine the 
dose/dosing schedule for TAK-981. Furthermore, the PK-pharmacodynamic data collected in 
this study may be pooled with similar data from other clinical studies for population analysis 
purposes. The results of such PK-pharmacodynamic and population PK-pharmacodynamic 
analyses and quantitative systems pharmacology modeling may not be presented in the clinical 
study report for this study but will be presented in a separate report. 
13.1.7 
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 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. 
• SAEs (related and regardless of relationship). 
• AESIs 
• TEAE leading to study drug modification and discontinuation. 
The incidence of DLTs will be tabulated using the DLT-evaluable analysis set. 
Descriptive statistics for the actual values of clinical laboratory parameters (and/or change from 
baseline in clinical laboratory parameters) will be presented for all scheduled measurements over 
time. Mean laboratory values over time will be plotted for key laboratory parameters. 
Descriptive statistics for the actual values (and/or the changes from baseline) of vital signs and 
weight will be tabulated by scheduled time point. ECOG performance scores will be summarized 
using a shift table. 
Shift tables for laboratory parameters will be generated for changes in NCI CTCAE grade from 
baseline to the worst postbaseline value. Graphical displays of key safety parameters, such as 

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scatter plots of baseline versus worst postbaseline values, may be used to understand the safety 
profile of TAK-981 in combination with pembrolizumab. 
All concomitant medications collected from the first dose of study drug throughout the study 
period will be classified to preferred terms according to the World Health Organization drug 
dictionary. 
Additional safety analyses may be performed to most clearly enumerate rates of toxicities and to 
further define the safety profile of TAK-981 in combination with pembrolizumab. 
13.2 
Interim Analysis and Criteria for Early Termination 
Although no formal interim analysis is planned, investigators and sponsor representatives will 
review accruing data to determine dose escalation and number of patients per cohort in the dose 
escalation phase (see Section 8.4).  
During the Phase 2 part of the study, if any arms in Cohorts A to F shows an ORR below the 
futility boundary in the first stage, then the enrollment in that specific arm will be stopped (see 
Section 13.3). 
13.3 
Determination of Sample Size 
It is anticipated that approximately 231 patients will be enrolled in this study, including the 
Phase 1b portion dose escalation phase and the Phase 2 preliminary evaluation of the antitumor 
efficacy of the combination at the select Phase 2 doses in patients with select advanced or 
metastatic solid tumors, such as NSCLC, cervical, MSS-CRC, and melanoma. 
Dose Escalation Phase (Phase 1b): 
The BOIN design will be implemented for the dose escalation phase. It is estimated that up to 
approximately 32 DLT-evaluable patients will be enrolled to evaluate dose escalation for 
2 dosing schedules of TAK-981 (ie, Days 1, 4, 8, and 11 or Days 1 and 8 in 21-day cycles).  
Efficacy Evaluation Phase (Phase 2): 
After select Phase 2 doses are identified, up to approximately 199 response-evaluable patients 
with select indications and dose levels in 8 cohorts will be enrolled in the Phase 2 study to 
evaluate the antitumor efficacy of the combination of TAK-981 and pembrolizumab.  
The primary endpoint for the Phase 2 portion is ORR (CR + PR) as assessed by the investigator 
according to RECIST, Version 1.1. The sample size consideration for disease-specific patient 
populations is an adaptive design based on Simon’s 2-stage design for a single proportion (Lin 
and Shih 2004) with the following hypotheses of ORR. 
For Cohorts A through C and Cohort E, the hypotheses for Stage 1 are: 
H0: ORR <p0 where p0 = 15% 
H1: ORR ≥p0 where p0 = 15% 
where p0 is a very low, undesirable ORR. 

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If H0 is rejected (and H1 is accepted at Stage 1), further 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 for the cohorts above (Cohorts A-C, and E) at the end of Stage 2 for a low 
desirable ORR, p1, are: 
a) H1 is accepted at Stage 1, and 
b) H0: ORR ≤p1 where p1 = 35% 
H1: ORR >p1 where p1 = 35% 
The hypotheses for the cohorts above (Cohorts A-C, and E) at the end of Stage 2 for a high 
desirable response, p2, are: 
a) H1 is accepted at Stage 1, and 
b) H0: ORR ≤ p2 where p2 = 45% 
H1: ORR > p2 where p2 = 45% 
In order to have higher power for detecting more improvement of the new combination therapy 
(p2 vs p0) assuming a power of 90% for high-desirable response, 80% 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 
Sample Size for Each Cohort and Each Stage (Cohorts A-C, and E) 
 
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 
9 
23 
23 
0.1/80% 
Number of responses a 
≥2 and ≤5 
≥6 
 
 
High response at the end of Stage 1 
 
 
 
 
Number of patients 
9 
15 
15 
0.1/90% 
Number of responses 
≥6 
≥7 
 
 
a Number of patients needed to respond in order 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 the 
end of Stage 2 in order to claim treatment effect. 
 
For Cohort D (Figure 6.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. 

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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 for Cohort D 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 for Cohort D 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 Cohort D, assuming a power of 90% for high desirable response and 80% 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 (Cohort D) 
 
Stage 
Total Number of 
Patients in 
Cohort 
1-Sided Alpha 
Level/Power 
 
Stage 1 
Stage 2 b 
All cohorts 
 
 
 
 
Low response at the end of Stage 1 
 
 
 
 
Number of patients 
11 
36 
36 
0.1/80% 
Number of responses a 
≥6 and ≤9 
≥20 
 
 
High response at the end of Stage 2 
 
 
 
 
Number of patients 
11 
19 
19 
0.1/90% 
Number of responses 
≥10 
≥14 
 
 
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 CPI refractory NSCLC cohort (Cohort F with 2 dose levels: 90 mg BIW & 120 mg QW), 
Simon’s 2-stage design (Simon 1989) will be used for sample size calculation. The null 
hypothesis that the true response rate is (p0 ≤ 5%) will be tested against a 1-sided alternative.  
In the first stage, 10 evaluable patients will be accrued. If there are 0 responses observed in these 
10 patients, the cohort will be stopped; otherwise, 14 additional patients will be accrued for a 
total of 24.  

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The null hypothesis will be rejected if 4 or more responses are observed in the total of 
24 patients. This design yields power of 85% and 1-sided Type I error rate of 0.05 when the true 
response rate is ≥25%. 
Table 13.c 
CPI Primary Refractory: Sample Size for Each Cohort and Each Stage 
(Cohort F: 90 mg BIW & 120 QW) 
 
Stage 
Total Number of Patients in 
Each Cohort 
One-Sided Alpha 
Level/Power 
 
Stage I 
Stage II b 
Response at the end of stage I 
Number of patients 
10 
24 
24 
0.05/85% 
Number of responses a 
≥1 
≥4 
 
 
BWI: twice weekly; CPI: checkpoint inhibitor; QW: once weekly. 
a Number of patients needed to respond to continue into Stage II or have a positive result at the end of Stage II. 
b Maximum number of patients required for each cohort and number of responders that should be presented at end 
of Stage II 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, COVID-19), remote electronic medical records access visits may be made 
(where allowed by sites). Source documents will be reviewed for verification of data recorded on 
the eCRFs. Source documents are defined as original documents, data, and records. The 
investigator and institution guarantee access to source documents by the sponsor or its designee 
(CRO) and by the IRB or IEC. 
All aspects of the study and its documentation will be subject to review by the sponsor or 
designee (as long as blinding is not jeopardized) including, but not limited to, the investigator’s 
binder, study medication, patient medical records, informed consent documentation, 
documentation of patient authorization to use personal health information (if separate from the 
ICFs), and review of eCRFs and associated source documents. It is important that the 
investigator and other study personnel are available during the monitoring visits and that 
sufficient time is devoted to the process. 
14.2 
Protocol Deviations 
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study patients. Should other unexpected circumstances arise that will 
require deviation from protocol-specified procedures, the investigator should consult with the 
sponsor or designee (and IRB or IEC, as required) to determine the appropriate course of action. 

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There will be no exemptions (a prospectively approved deviation) from the inclusion or 
exclusion criteria. 
The site should document all protocol deviations in the patient’s source documents. In the event 
of a significant deviation, the site should notify the sponsor or its designee (and IRB or EC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the patient, or confound interpretation of the primary 
study assessment. 
The sponsor will assess any protocol deviation; if it is likely to affect to a significant degree the 
safety and rights of a patient or the reliability and robustness of the data generated, it may be 
reported to regulatory authorities as a serious breach of GCP and the protocol. 
The investigator should document all protocol deviations. 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections 
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, 
including those of foreign governments (eg, the US FDA, the United Kingdom [UK] Medicines 
and Healthcare products Regulatory Agency [MHRA], the Pharmaceuticals and Medical Devices 
Agency of Japan [PMDA]). If the study site is contacted for an inspection by a regulatory body, 
the sponsor should be notified immediately. The investigator and institution guarantee access for 
quality assurance auditors to all study documents as described in Section 14.1. 
15.0 
ETHICAL ASPECTS OF THE STUDY 
This study will be conducted with the highest respect for the individual participants (ie, patients) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the responsibilities of the investigator that are listed in Appendix B. 
The principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities. 
15.1 
IRB and/or IEC Approval 
IRBs and IECs must be constituted according to the applicable state and federal/local 
requirements of each participating region. The sponsor or designee will require documentation 
noting all names and titles of members who make up the respective IRB or IEC. If any member 
of the IRB or IEC has direct participation in this study, written notification regarding his or her 
abstinence from voting must also be obtained. Those American sites unwilling to provide names 
and titles of all members because of privacy and conflict of interest concerns should instead 

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provide a Federalwide 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, patient recruitment materials and advertisements and other documents required by all 
applicable laws and regulations must be submitted to a central or local IRB or IEC for approval. 
The IRB’s or IEC’s written approval of the protocol and patient informed consent must be 
obtained and submitted to the sponsor or designee before commencement of the study, ie, before 
shipment of the sponsor-supplied drug or study-specific screening activity. The IRB or IEC 
approval must refer to the study by its exact protocol title, number, and version date; identify 
versions of other documents (eg, ICF) reviewed; and state the approval date. If required by 
country or regional regulations or procedures, approval from the competent regulatory authority 
will be obtained before commencement of the study or implementation of a substantial 
amendment. The sponsor will ship drug/notify site once the sponsor has confirmed the adequacy 
of site regulatory documentation and, when applicable, the sponsor has received permission from 
the competent authority to begin the trial. Until the site receives drug/notification, no protocol 
activities, including screening, may occur. 
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the ICF, recruitment 
materials intended for viewing by patients, local safety reporting requirements, reports and 
updates regarding the ongoing review of the study at intervals specified by the respective IRB or 
IEC, and submission of the investigator’s final status report to IRB or IEC. All IRB and IEC 
approvals and relevant documentation for these items must be provided to the sponsor (or 
designee). 
Patient incentives should not exert undue influence for participation. Payments to patients must 
be approved by the IRB or IEC and sponsor. 
15.2 
Patient Information, Informed Consent, and Patient Authorization 
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The ICF, patient authorization form (if applicable), and patient 
information sheet (if applicable) describe the planned and permitted uses, transfers, and 
disclosures of the patient’s personal and personal health information for purposes of conducting 
the study. The ICF and the patient information sheet (if applicable) further explain the nature of 
the study, its objectives, and potential risks and benefits, and the date informed consent is given. 
The ICF will detail the requirements of the participant and the fact that he or she is free to 
withdraw at any time without giving a reason and without prejudice to his or her further medical 
care. 
The investigator is responsible for the preparation, content, and IRB or IEC approval of the ICF 
and, if applicable, the patient authorization form. The ICF, patient authorization form (if 

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applicable), and patient information sheet (if applicable) must be approved by both the IRB or 
IEC and the sponsor before use. 
The ICF, patient authorization form (if applicable), and patient information sheet (if applicable) 
must be written in a language fully comprehensible to the prospective patient. It is the 
responsibility of the investigator to explain the detailed elements of the ICF, patient authorization 
form (if applicable), and patient information sheet (if applicable) to the patient. Information 
should be given in both oral and written form whenever possible and in the manner deemed 
appropriate by the IRB or IEC. If the patient is not capable of rendering adequate written 
informed consent, then the patient’s legally acceptable representative may provide such consent 
for the patient in accordance with applicable laws and regulations. 
The patient, or the patient’s legally acceptable representative, must be given ample opportunity 
to (1) inquire about details of the study and (2) decide whether to participate in the study. If the 
patient, or the patient’s legally acceptable representative, determines that he or she will 
participate in the study, then the ICF and patient authorization form (if applicable) must be 
signed and dated by the patient, or the patient’s legally acceptable representative, at the time of 
consent and before the patient enters into the study. The patient or the patient’s legally 
acceptable representative should be instructed to sign using their legal names, not nicknames, 
using a ballpoint pen with either blue or black ink. The investigator must also sign and date the 
ICF and patient authorization (if applicable) at the time of consent and before the patient enters 
into the study; however, the sponsor may allow a designee of the investigator to sign to the 
extent permitted by applicable law. 
Once signed, the original ICF, patient authorization form (if applicable), and patient information 
sheet (if applicable) will be stored in the investigator’s site file. The investigator must document 
the date the patient signs the informed consent in the patient’s medical record. Copies of the 
signed ICF, the signed patient authorization form (if applicable), and patient information sheet (if 
applicable) shall be given to the patient. 
All revised ICFs must be reviewed and signed by relevant patients or the relevant patient’s 
legally acceptable representative in the same manner as the original informed consent. The date 
the revised consent was obtained should be recorded in the patient’s medical record, and the 
patient should receive a copy of the revised ICF. 
15.3 
Patient Confidentiality 
The sponsor and designees affirm and uphold the principle of the patient’s right to protection 
against invasion of privacy. Throughout this study, a patient’s source data will be linked to the 
sponsor’s clinical study database or documentation only via a unique identification number. As 
permitted by all applicable laws and regulations, limited patient attributes, such as sex, age, or 
date of birth, and patient initials may be used to verify the patient and accuracy of the patient’s 
unique identification number. 
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
sponsor requires the investigator to permit its monitor or designee’s monitor, representatives 
from any regulatory authority (eg, US FDA, UK MHRA, Japan PMDA), the sponsor’s 

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designated auditors, and the appropriate IRBs and IECs to review the patient’s original medical 
records (source data or documents) including, but not limited to, laboratory test result reports, 
ECG reports, admission and discharge summaries for hospital admissions occurring during a 
patient’s study participation, and autopsy reports. Access to a patient’s original medical records 
requires the specific authorization of the patient as part of the informed consent process (see 
Section 15.2). 
Copies of any patient source documents that are provided to the sponsor must have certain 
identifying personal information removed, eg, patient name, address, and other identifier fields 
not collected on the patient’s eCRF. 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy 
15.4.1 
Publication  
The investigator is obliged to provide the sponsor with complete test results and all data derived 
by the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and advertisements, is the sole responsibility of the sponsor. 
The sponsor may publish any data and information from the study (including data and 
information generated by the investigator) without the consent of the investigator. Manuscript 
authorship for any peer-reviewed publication will appropriately reflect contributions to the 
production and review of the document. All publications and presentations must be prepared in 
accordance with this section and the clinical study site agreement. In the event of any 
discrepancy between the protocol and the clinical study site agreement, the clinical study site 
agreement will prevail. 
15.4.2 
Clinical Trial Registration 
To ensure that information on clinical trials reaches the public in a timely manner and to comply 
with applicable laws, regulations, and guidance, Takeda will, at a minimum, register 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other 
publicly accessible websites on or before start of study, as defined by Takeda policy/standards. 
Takeda contact information, along with investigator’s city, state (for Americas investigators), 
country, and recruiting status will be registered and available for public viewing.  
As needed, Takeda and investigator/site contact information may be made public to support 
participant access to trials via registries. In certain situations/registries, Takeda may assist 
participants or potential participants in finding a clinical trial by helping them locate trial sites 
closest to their homes by providing the investigator name, address, and phone number via 
email/phone or other methods preferred by callers requesting trial information. Once patients 
receive investigator contact information, they may call the site requesting enrollment into the 
trial. The investigative sites are encouraged to handle the trial inquiries according to their 

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established patient screening process. If the caller asks additional questions beyond the topic of 
trial enrollment, they should be referred to the sponsor.  
Any investigator who objects to Takeda providing this information to callers must provide 
Takeda with a written notice requesting that their information not be listed on the registry site.  
15.4.3 
Clinical Trial Results Disclosure 
Takeda will post the results of clinical trials on ClinicalTrials.gov, and 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 patient in the study must be insured in accordance with the regulations applicable to the site 
where the patient is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to clinical study patients. 
Refer to the clinical study site agreement regarding the sponsor’s policy on patient compensation 
and treatment for injury. If the investigator has questions regarding this policy, he or she should 
contact the sponsor or sponsor’s designee. 

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16.0 
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Appendix A Schedule of Events 
 

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Table 1.a 
Schedule of Events for Treatment Cycles (21-Day Cycle) (Phase 1) 
 
 
Cycle 1 
Cycle 2 
Cycle 3 and Onward 
 
30 and 90 
(+10) Days 
After Last 
Dose 
 
 
 
Days 
Days 
Days 
 
Survival 
Procedure/Assessment 
Screening a 
1 
2 
4 
8 
9 
11 15 
1 
4 
8 
11 
15 
1 
4 
8 
11 
15 EOT 
Follow-up b 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Available tumor 
genomic/cytogenetic/mutational 
information c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor PD-L1 status c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Symptom-directed physical 
examination e 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
 
ECOG performance status e 
X 
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 
X 
 
12-lead safety ECG i 
X 
X2 
 
 
X2 
 
 
 
X2 
 
X2 
 
 
X2 
 
 
 
 
X 
 
 
Echocardiography/MUGA (LVEF) 
scan j 
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. 
 
Adverse event reporting 
Recorded from the signing of ICF through 30 days after the last dose of study drug or start of a new systemic treatment. 
 
SAEs will be reported from the signing of the ICF through 30 days after the last dose of study drug or any moment after EOT for 
related SAEs. AESIs will be reported from the C1D1 through 90 days after the last dose of study drug or any moment after EOT. 
 
TAK-981 administration k 
 
X 
 
X g X 
 
X g X h 
X 
X g 
X 
X g 
X h 
X 
X g 
X 
X g 
X h 
 
 
 
Pembrolizumab administration k 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
Samples/Laboratory Assessments 
Pregnancy test, β-HCG (urine or 
serum) l 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
Hematology/chemistry m 
X 
X 
 
X g X 
 
X g X h 
X 
 
  
 
 
X 
 
  
 
 
X 
 
 
Coagulation m 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
Urinalysis m, n 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
Tumor prognostic markers o 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 

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Table 1.a 
Schedule of Events for Treatment Cycles (21-Day Cycle) (Phase 1) 
 
 
Cycle 1 
Cycle 2 
Cycle 3 and Onward 
 
30 and 90 
(+10) Days 
After Last 
Dose 
 
 
 
Days 
Days 
Days 
 
Survival 
Procedure/Assessment 
Screening a 
1 
2 
4 
8 
9 
11 15 
1 
4 
8 
11 
15 
1 
4 
8 
11 
15 EOT 
Follow-up b 
Immunosafety markers 
(hormones) p 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
Disease assessment q, r 
X 
PK samples 
 
Refer to Table 2.a (Phase 1b). 
 
 
 
 
 
 
 
 
Biomarker samples  
Refer to Table 3.a (Phase 1b). 
 
 
 
AESI: adverse event of special interest; COVID-19: coronavirus disease 2019; CT: computed tomography; CxDx: Cycle x, Day x; ECG: electrocardiogram, 
ECOG: Eastern Cooperative Oncology Group; eCRF: electronic case report form; EOI: end of infusion; EOT: end of treatment; FDG: fluorodeoxyglucose; HCG: 
human chorionic gonadotropin; ICF: informed consent form; LVEF: left ventricular ejection fraction; MRI: magnetic resonance imaging; MUGA: multiple-gated 
acquisition; PD: progressive disease; PD-L1: programmed cell death protein 1 ligand; PET: positron emission tomography; PFS: progression-free survival; PK: 
pharmacokinetic; RECIST: Response Evaluation Criteria in Solid Tumors; SAE: serious adverse event. 
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. 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 a treatment visit is delayed, associated tests and procedures should also be delayed. 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 The survival status of patients who permanently discontinue all study treatment for reasons specified in Section 9.7, with the exception of death, or withdrawal 
by the patient, or PD by iRECIST, will be assessed through medical charts or by telephone following the last administration of the study drugs. 
c Any available pathology/cytogenetic/mutational information for all patients should be reported in the eCRF. Tumor PD-L1 status is required from all patients in 
Phase 2. For more information, see Protocol, Section 9.4.3. 
d Complete physical exam at screening. If screening is performed more than 4 days before C1D1, the exam should be performed again before dosing.  
e The symptom-directed physical examination and ECOG will be conducted within 3 days before dosing on Day 1 of each treatment cycle and at the EOT/early 
termination 30 and 90 days after last dose visit. The symptom-directed physical examination may be performed at other visits during the treatment cycle at the 
discretion of the investigator. 
f Perform vital signs measurement before and after dosing. Blood pressure, heart rate, and temperature will be measured immediately before the start of the 
infusion and at the end of the infusion of each study drug. Blood pressure should be determined after the patient has been resting for 5 minutes.  
g For patients enrolled in the dosing schedule of TAK-981 on Days 1, 4, 8, and 11 every 21 days. 

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h For patients enrolled in the dosing schedule of TAK-981 on Days 1, 8, and 15 every 21 days. 
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 Cycles 1 and Cycle 2. From 
Cycle 3 onwards, pre-TAK-981 dose 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 with the patient rested for 5 minutes. 
j The MUGA (LVEF) scan should be performed at screening to ensure patient eligibility. Echocardiographic estimate of the left ventricular ejection fraction can 
be measured as an alternative to MUGA scans. From Cycle 3 onwards, MUGA (LVEF) scan will be repeated every 3 cycles and at EOT. From Cycle 3 onwards, 
a ±7-day window is allowed for this test.  
k On days on which the infusion of TAK-981 and pembrolizumab coincide, TAK-981 is administered first. At least 30 minutes should elapse between the 
completion of the first study drug and the initiation of the second study drug. Patients with clinical benefit can be changed to a less frequent schedule if the 
investigator, in agreement with the sponsor, considers that continuing with the intensive schedule would negatively impact the patient’s well-being. Dose 
administration of TAK-981 and pembrolizumab should be performed on schedule; however, a dose delay of up to 3 days may occur because of inclement 
weather, holidays, vacations, or administrative reasons; a dose delay of up to 7 days is allowed to accommodate for COVID-19 vaccine administration after 
discussion with the sponsor. If a treatment visit is delayed, associated tests and procedures should also be delayed. 
l A serum or urine choriogonadotropin beta (β-hCG) pregnancy test will be performed only for women of childbearing potential during screening, again at C1D1 
(baseline) if the screening test was performed more than 72 hours before the first dose of any study drug. From Cycle 2 onwards, serum or urine pregnancy test 
samples should be collected on Day 1 or within 72 hours prior to Day 1 of each subsequent cycle. The results must be negative within 72 hours before TAK-981 
is administered or as otherwise required by local regulations.  
m Hematology, chemistry, coagulation, and urinalysis may be taken up to 3 days prior to the Day 1 visit. Day 4, 8, 11, 15 hematology and chemistry assessments 
are to be performed on dosing days depending on treatment schedule (these assessments may be discontinued during Phase 2). 
n Urinalysis includes tests for pH, protein, glucose, ketones, urobilinogen, bilirubin, leukocytes, erythrocytes, nitrites, and density. In the event significant 
abnormalities are detected in proteins, leukocytes or blood, a microscopic analysis of urine sediment should be performed. From C1 onwards, urine tests will be 
taken only on Day 1 of each cycle and at EOT. 
o Tumor prognostic markers (CEA and CA 19-9 in colon cancer patients, CA 15-3 and CA 125 in cervical cancer patients, and only in Phase 2) may be 
performed up to 3 days prior to D1 visit. For specifics, see Section 9.4.12.1.  
p Immunosafety determinations include thyroid-stimulating hormone, free thyroxine, and adrenocorticotropic hormone measured in blood at screening and 
repeated at the beginning of each cycle from C3 until C6, every other cycle afterwards, and at the EOT. 
q A baseline contrast-enhanced CT or MRI scan of the chest, abdomen, and pelvis must be acquired at screening. Subsequent assessments must be performed by 
using the same imaging modality (contrast-enhanced CT or MRI). 
r Contrast-enhanced CT or MRI and FDG-PET should be performed every 2 months from C1D1 (62 days ± 7 days), or more frequently if clinically indicated. 
After 6 months, imaging frequency should be reduced to every 3 months (93 days ±7 days) until occurrence of progression of disease. Imaging timing should 
follow calendar days and should not be adjusted for delays in cycle starts (ie, administration of TAK-981 or pembrolizumab). The same imaging modality 
(contrast-enhanced CT or MRI, and FDG-PET scan) should be used on a patient at the screening visit and throughout the study. Bone scans may be performed on 
patients as clinically indicated. Response will be determined according to RECIST, Version 1.1 criteria.  
 

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Table 1.b 
Schedule of Events for Treatment Cycles (21-Day Cycle) (Phase 2) 
 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 and 
Onwards 
 
30 and 90 
(+10) 
Days 
After Last 
Dose 
 
 
 
Days 
Days 
Days 
Days 
 
Survival 
Procedure/Assessment 
Screening a 
1 
2 4 
8 9 11 
1 
4 
8 
11 
1 
4 
8 
11 1 2 4 
8 9 
11 
EOT  
Follow-
up b 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Available tumor 
genomic/cytogenetic/mutational 
information c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor PD-L1 status c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Symptom-directed physical 
examination e 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X  
 
 
 
 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X  
 
 
 
 
X 
X 
 
ECOG performance status e 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X  
 
 
 
 
X 
X 
 
Vital signs f 
X 
X 
 X g X 
 X g X X g X X g X X g X X g X  X g X  
X g 
X 
X 
 
12-lead safety ECG h 
X 
X2  
 
X2  
 
X2 
 
X2 
 
X2 
 
 
 
 
 
 
 
 
 
X 
 
 
Echocardiography/MUGA (LVEF) 
scan i 
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 
 
Adverse event reporting 
Recorded from the signing of ICF through 30 days after the last dose of study drug or start of a new systemic treatment 
 
SAEs will be reported from the signing of the ICF through 30 days after the last dose of study drug or any moment after EOT 
for related SAEs. AESIs will be reported from the C1D1 through 90 days after the last dose of study drug or any moment after 
EOT. 
 
TAK-981 administration j 
 
X 
 X g X 
 X g X X g X X g X X g X X g X  X g X  
X g 
 
 
 
Pembrolizumab administration j 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X  
 
 
 
 
 
 
 
Samples/Laboratory Assessments 
Pregnancy test, β-HCG (urine or 
serum) k 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X  
 
 
 
 
X 
 
 
Hematology/chemistry l 
X 
X 
 X g X 
 X g X 
 
X  
 
X 
 
X  
 
X  
 
X  
 
X 
 
 
Coagulation l 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X  
 
 
 
 
X 
 
 
Urinalysis l,m 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X  
 
 
 
 
X 
 
 

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Table 1.b 
Schedule of Events for Treatment Cycles (21-Day Cycle) (Phase 2) 
 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 and 
Onwards 
 
30 and 90 
(+10) 
Days 
After Last 
Dose 
 
 
 
Days 
Days 
Days 
Days 
 
Survival 
Procedure/Assessment 
Screening a 
1 
2 4 
8 9 11 
1 
4 
8 
11 
1 
4 
8 
11 1 2 4 
8 9 
11 
EOT  
Follow-
up b 
Tumor prognostic markers n 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X  
 
 
 
 
 
 
 
Immunosafety markers (hormones) o 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X  
 
 
 
 
X 
 
 
Disease assessment p,q 
X 
PK samples 
 
Refer to Table 2.b (Phase 2) 
 
 
 
 
Refer to Table 2.b 
(Phase 2) 
 
 
 
Biomarker samples  
Refer to Table 3.b (Phase 2) 
 
 
 
 
AESI: adverse event of special interest; COVID-19: coronavirus disease 2019; CT: computed tomography; CxDx: Cycle x, Day x; ECG: electrocardiogram, 
ECOG: Eastern Cooperative Oncology Group; eCRF: electronic case report form; EOI: end of infusion; EOT: end of treatment; FDG: fluorodeoxyglucose; HCG: 
human chorionic gonadotropin; ICF: informed consent form; LVEF: left ventricular ejection fraction; MRI: magnetic resonance imaging; MUGA: multiple-gated 
acquisition; PD-L1: programmed cell death protein 1 ligand; PET: positron emission tomography; PFS: progression-free survival; PK: pharmacokinetic; 
RECIST: Response Evaluation Criteria in Solid Tumors; SAE: serious adverse event. 
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. 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 a treatment visit is delayed, associated tests and procedures should also be delayed. 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. 
EOT procedures to be completed by all patients at the time of study drug discontinuation. For patients who discontinue, the EOT visit should be performed 
instead of the scheduled trial visit at time of discontinuation.  
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 The survival status of patients in Phase 2 who permanently discontinue all study treatment for reasons specified in Section 9.7, with the exception of death, or 
withdrawal by the patient, will be assessed through medical charts or by telephone following the last administration of the study drugs. 
c Any available pathology/cytogenetic/mutational information for all patients should be reported in the eCRF. Tumor PD-L1 status is required from all patients in 
Phase 2. For more information, see Protocol, Section 9.4.3. 
d Complete physical exam at screening. If screening is performed more than 4 days before C1D1, the exam should be performed again before dosing.  

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e The symptom-directed physical examination and ECOG will be conducted within 3 days before dosing on Day 1 of each treatment cycle and at the EOT/early 
termination 30 and 90 days after last dose visit. The symptom-directed physical examination may be performed at other visits during the treatment cycle at the 
discretion of the investigator. 
f Perform vital signs measurement before and after dosing. Blood pressure, heart rate, and temperature will be measured immediately before the start of the 
infusion and at the end of the infusion of each study drug. Blood pressure should be determined after the patient has been resting for 5 minutes.  
g For patients enrolled in the dosing schedule of TAK-981 on Days 1, 4, 8, and 11 every 21 days. 
h 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 Cycles 1 and Cycle 2. From 
Cycle 3 onwards, pre-TAK-981 dose 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 with the patient rested for 5 minutes. 
i The MUGA (LVEF) scan should be performed at screening to ensure patient eligibility. Echocardiographic estimate of the left ventricular ejection fraction can 
be measured as an alternative to MUGA scans. From Cycle 3 onwards, MUGA (LVEF) scan will be repeated every 3 cycles and at EOT. From Cycle 3 onwards, 
a ±7-day window is allowed for this test.  
j On days on which the infusion of TAK-981 and pembrolizumab coincide, TAK-981 is administered first. At least 30 minutes should elapse between the 
completion of the first study drug and the initiation of the second study drug. Patients with clinical benefit can be changed to a less frequent schedule if the 
investigator, in agreement with the sponsor, considers that continuing with the intensive schedule would negatively impact the patient’s well-being. Dose 
administration of TAK-981 and pembrolizumab should be performed on schedule; however, a dose delay of up to 3 days may occur because of inclement 
weather, holidays, vacations, or administrative reasons; a dose delay of up to 7 days is allowed to accommodate for COVID-19 vaccine administration after 
discussion with the sponsor. If a treatment visit is delayed, associated tests and procedures should also be delayed. 
k A serum or urine choriogonadotropin beta (β-hCG) pregnancy test will be performed only for women of childbearing potential during screening, again at C1D1 
(baseline) if the screening test was performed more than 72 hours before the first dose of any study drug. From Cycle 2 onwards, serum or urine pregnancy test 
samples should be collected on Day 1 or within 72 hours prior to Day 1 of each subsequent cycle. The results must be negative within 72 hours before TAK-981 
is administered or as otherwise required by local regulations.  
l Hematology, chemistry, coagulation, and urinalysis may be taken up to 3 days before the Day 1 visit. Hematology and chemistry assessments on Days 4, 8, and 
11 (Cycle 1) and Days 1 and 8 (Cycle 2 and onwards) are to be performed on dosing days depending on treatment schedule (these assessments may be 
discontinued during Phase 2). 
m Urinalysis includes tests for pH, protein, glucose, ketones, urobilinogen, bilirubin, leukocytes, erythrocytes, nitrites, and density. In the event significant 
abnormalities are detected in proteins, leukocytes or blood, a microscopic analysis of urine sediment should be performed. From C1 onwards, urine tests will be 
taken only on Day 1 of each cycle and at EOT. 
n Tumor prognostic markers (CEA and CA 19-9 in colon cancer patients, CA 15-3 and CA 125 in cervical cancer patients, and only in Phase 2) may be 
performed up to 3 days prior to D1 visit. For specifics, see Section 9.4.12.1.  
o Immunosafety determinations include thyroid-stimulating hormone (TSH), free thyroxine (FT4), adrenocorticotropic hormone (ACTH) measured in blood at 
screening and repeated at the beginning of each cycle from C3 until C6, every other cycle afterwards, and at the EOT. 
p A baseline contrast-enhanced CT or MRI scan of the chest, abdomen, and pelvis must be acquired at screening or within 28 days from C1D1. Subsequent 
assessments must be performed by using the same imaging modality (contrast-enhanced CT or MRI). 

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q Contrast-enhanced CT or MRI and FDG-PET should be performed every 2 months from C1D1 (62 days ± 7 days), or more frequently if clinically indicated. 
After 6 months, imaging frequency should be reduced to every 3 months (93 days ±7 days) until occurrence of progression of disease. Imaging timing should 
follow calendar days and should not be adjusted for delays in cycle starts (ie, administration of TAK-981 or pembrolizumab). The same imaging modality 
(contrast-enhanced CT or MRI, and FDG-PET scan) should be used on a patient at the screening visit and throughout the study. Bone scans may be performed on 
patients as clinically indicated. Response will be determined according to RECIST, Version 1.1 criteria. 

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Table 2.a 
Plasma PK Sampling Schedule During Phase 1b 
 
Cycle 1 
Cycle 2 
 
Day 1 
Day 4 
Day 8 
Day 11 
Day 1 
Day 8 
PK (Plasma) 
PK (Plasma) 
PK (Plasma) 
PK (Plasma) 
PK (Plasma) 
PK (Plasma) 
Pre-TAK-981 dose (within 1 h before the start of infusion) 
X 
 
X 
 
 
 
End of TAK-981 infusion (±10 min) 
X 
X a 
X 
X a 
X 
X 
2 h after end of TAK-981 infusion (±30 min) 
X 
 
X 
 
X 
X 
4 h after end of TAK-981 infusion (±30 min) 
X 
 
X 
 
 
 
6 h after end of TAK-981 infusion (±30 min) 
X 
 
X 
 
 
 
24 h after end of TAK-981 infusion (±60 min) 
X 
 
X 
 
 
 
Total time points/samples 
6 
1 
6 
1 
2 
2 
h: hour; PK: pharmacokinetic. 
a For patients enrolled in the dosing schedule of TAK-981 on Day 1, or Days 1 and 8, or Days 1, 8, and 15 every 21 days, this test or procedure may not be performed. 
Table 2.b 
Plasma PK Sampling Schedule During Phase 2 
 
Cycle 1 
Cycle 2 
Day 1 
Day 8  
Day 1 
Day 8  
PK (Plasma) 
PK (Plasma) 
PK (Plasma) 
PK (Plasma) 
Pre-TAK-981 dose (within 1 h before the start of infusion) 
X 
X 
X 
X 
End of TAK-981 infusion (±10 min) 
X 
X 
X 
X 
1-4 h after end of TAK-981 infusion (±30 min) 
X 
X  
X 
X 
24 h after end of TAK-981 infusion (±3 h) 
X 
X 
 
 
Total time points/samples 
4 
4 
3 
3 
h: hour; PK: pharmacokinetic. 

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Table 3.a 
Biomarker Sample Collection During Phase 1b 
Screening 
C1D1 
C1D8 
C2D1 
C2D8 
C3D1, 
C6D1, 
C9D1 
C3D8, 
C6D8, 
C9D8 
Pre-
dose 
1 h 
4 h 6-8 h 24 h 
Pre-
dose 
1 h 
4 h 6-8 h 24 h 
Pre-
dose 
Pre-
dose 
1 h  
4 h  6-8 h  
Pre-
dose 
Pre-
dose 
Post-
EOI 
Post-
EOI 
Post-
EOI 
Post-
EOI 
Post-
EOI 
Post-
EOI 
Post-
EOI 
Post-
EOI 
Post-
EOI 
Post-
EOI 
Post-
EOI 
Window period 
 
 
+20 
min 
±30 
min 
 
±60 
min 
 
+20 
min 
±30 
min 
 
±60 
min 
 
 
+20 
min 
±30 
min 
 
 
 
Archival (banked) tumor tissue sample a 
X 
 
 
 
Fresh tumor tissue biopsy sample b 
X 
 
X 
 
 
Plasma sample for chemokine/cytokine analysis c 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Blood cells for immunophenotyping c 
X 
X 
X 
X 
 
X 
X 
X 
X 
PBMCs sample for immunophenotyping c 
 
X 
 
 
 
X 
X 
 
 
 
X 
 
X 
 
 
 
 
 
Whole blood sample for adducts/conjugates 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
Blood sample for RNA c 
 
X 
 
 
X 
X 
X 
 
 
X 
X 
 
X 
 
 
X 
X 
X 
Serum sample for circulating biomarkers 
X 
X 
 
 
 
Blood sample for DNA  
X 
 
 
 
Blood sample for cfDNA c  
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
aPTT: activated partial thromboplastin time; cfDNA: cell-free DNA; CxDx: Cycle x, Day x; EOI: end of infusion; INR: international normalized ratio; PBMC: 
peripheral blood mononuclear cell. 
“Predose” and “Post-EOI” refers to predose and end of TAK-981 infusion, respectively. 
a Archival (banked) tumor tissue sample collected within 12 months of study initiation will be collected when available from all patients. 
b Screening and on-treatment biopsies are encouraged (but optional) for all patients in Phase 1b. 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. The on-treatment biopsy 
will be obtained post TAK-981 infusion on C2D8 (+7 days). The accessible lesion biopsy (screening and on-treatment) should not have been previously 
designated as the only target lesion for measurable disease or being located in a previously irradiated area. Ideally, the same lesion should be biopsied before 
treatment and on treatment whenever possible. Hematology and coagulation tests including platelet counts, INR and aPTT should be performed prior to a biopsy 
procedure being performed and the risk of bleeding associated with the procedure must be assessed by the investigator. On-treatment biopsy collection visit day 
may be changed should data emerging would be supportive of such change. 
c A decision to stop collection of plasma samples for chemokine/cytokine analysis, blood cells and PBMCs samples for immunophenotyping, blood sample for 
RNA, and blood sample for cfDNA may take place should sufficient data be generated. 

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Table 3.b 
Biomarker Sample Collection During Phase 2 
Screening 
C1D1 
C1D8 
C2D1 
C2 Biopsy  
(C2D8 +7 days) 
C3 
C4D1 
C4D8 
C6, and C9 
Predose 
24h 
Predose 
24h 
Predose 
Pre-
Biopsy 
Biopsy 
Predose Predose 
24h 
Predose 
24h 
Predose 
Post-
EOI 
Post-
EOI 
Post-
EOI 
Post-
EOI 
Archival (banked) tumor tissue sample if 
available a 
X 
 
 
 
 
 
 
 
Tumor biopsy b 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fresh paired tumor tissue biopsy sample c 
X 
 
X 
 
 
 
 
 
 
Plasma sample for chemokine/cytokine 
analysis d  
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
Blood cells for immunophenotyping d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood sample for RNA d 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
Blood sample for cfDNA d  
 
X 
 
 
 
X  
 
 
  
X  
 
 
 
X 
aPTT: activated partial thromboplastin time; cfDNA: cell-free DNA; CxDx: Cycle x, Day x; EOI: end of infusion; INR: international normalized ratio. 
“Predose” and “Post-EOI” refers to predose and end of TAK-981 infusion, respectively. 
Samples will only be collected if on-treatment biopsies are collected. 
a Archival (banked) tumor tissue sample collected within 12 months of study initiation will be collected when available from all patients. 
b Pretreatment fresh tumor biopsy at screening can be replaced by a recent (≤12 months old) formalin-fixed, paraffin-embedded tumor specimen. For fresh tumor biopsies, the 
lesion must be accessible for a low-risk biopsy procedure (those occurring outside the brain, lung/mediastinum, and intra-abdominal space, or those obtained with endoscopic 
procedures beyond the stomach or bowel). 
c Screening and on-treatment biopsies are encouraged (but optional) for all patients in 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. The on-treatment biopsy will be obtained post TAK-981 
infusion on C2D8 (+7 days). The accessible lesion biopsy (screening and on-treatment) should not have been previously designated as the only target lesion for measurable disease 
or being located in a previously irradiated area. Ideally, the same lesion should be biopsied before treatment and on treatment whenever possible. Hematology and coagulation tests 
including platelet counts, INR and aPTT should be performed prior to a biopsy procedure being performed and the risk of bleeding associated with the procedure must be assessed 
by the investigator. On-treatment biopsy collection visit day may be changed should data emerging would be supportive of such change.  
d A decision to stop collection of plasma samples for cfDNA, chemokine/cytokine analysis, blood samples for immunophenotyping, and blood sample for RNA may take place 
should sufficient data be generated.  

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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 trial-
related duties and functions, the investigator/institution should ensure that this individual or 
party is qualified to perform those trial-related duties and functions and should implement 
procedures to ensure the integrity of the trial-related duties and functions performed and any 
data generated. 
4. Ensure that study-related procedures, including study-specific (nonroutine/nonstandard 
panel) screening assessments, are NOT performed on potential patients before the receipt of 
written approval from relevant governing bodies/authorities. 
5. Ensure that all colleagues and employees assisting in the conduct of the study are informed 
of these obligations. 
6. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform 
to 21 CFR Part 56, ICH and local regulatory requirements. 
7. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and 
approval of the protocol. Promptly report to the IRB/IEC all changes in research activity and 
all anticipated risks to patients. Make at least yearly reports on the progress of the study to 
the IRB/IEC, and issue a final report within 3 months of study completion. 
8. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met. 
9. Obtain valid informed consent from each patient who participates in the study, and document 
the date of consent in the patient’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each ICF should contain a patient authorization section 
that describes the uses and disclosures of a patient’s personal information (including personal 
health information) that will take place in connection with the study. If an ICF does not 
include such a patient authorization, then the investigator must obtain a separate patient 
authorization form from each patient or the patient’s legally acceptable representative. 
10. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
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 
UK, 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 MM, 1982 (Oken et al. 1982). 
ECOG: Eastern Cooperative Oncology Group. 

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Appendix E Drugs That Interact With the CYP3A Family of CYPs 
Drugs listed below which 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. 

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Drugs Inducing or Inhibiting CYP3A Metabolism That Are Prohibited Concomitant 
Medications With TAK-981 
Strong CYP3A Inducers a 
Strong CYP3A Inhibitors b 
apalutamide 
carbamazepine 
enzalutamide 
mitotane 
phenytoin 
rifampin 
St John’s Wort 
boceprevir 
clarithromycin 
cobicistat 
danoprevir and ritonavir 
elvitegravir and ritonavir 
grapefruit juice 
idelalisib  
indinavir and ritonavir 
itraconazole 
ketoconazole 
lopinavir and ritonavir 
nefazodone 
nelfinavir 
paritaprevir and ritonavir and (ombitasvir and/or dasabuvir) 
posaconazole 
ritonavir 
saquinavir and ritonavir 
telaprevir 
telithromycin 
tipranavir and ritonavir 
troleandomycin 
voriconazole 
Moderate CYP3A Inducers a 
Moderate CYP3A Inhibitors b 
bosentan  
efavirenz  
etravirine  
phenobarbital  
primidone  
 
aprepitant  
ciprofloxacin  
conivaptan  
crizotinib  
cyclosporine  
diltiazem  
dronedarone  
erythromycin  
fluconazole  
fluvoxamine  
imatinib  
tofisopam  
verapamil  
CYP: cytochrome P450. 
a fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-
inducers#table3-3 (Accessed 27 May 2022). 
b fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-
inducers#table3-2 (Accessed 27 May 2022). 

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Appendix F Examples of Clinical Inhibitors of Pgp 
Drugs listed below that are inhibitors of Pgp are prohibited as concomitant medications with 
TAK-981. 
Transporter 
Gene 
Inhibitor 
Pgp 
ABCB1 
amiodarone 
carvedilol 
clarithromycin 
dronedarone  
itraconazole 
lapatinib 
lopinavir and ritonavir 
propafenone 
quinidine 
ranolazine 
ritonavir 
saquinavir and ritonavir 
telaprevir 
tipranavir and ritonavir 
verapamil 
Source: fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-
inhibitors-and-inducers#table5-2 (Accessed 27 May 2022). 
Pgp: P-glycoprotein. 

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Appendix G Contraception Methods 
Male patients: We do not know if using TAK-981 will affect sperm or an unborn baby. 
Therefore, due to potential risk, you should not get your partner pregnant while taking TAK-981, 
and for 6 months after the last dose of study drug. Even if you are surgically sterilized (ie, have 
had a vasectomy), if you are sexually active with a woman who is pregnant or could get 
pregnant, you must agree to use an appropriate method of barrier contraception (latex condom 
with a spermicidal agent) each time you have sex from the time of signing the informed consent 
form, and throughout the entire study drug treatment period, and for 6 months after the last dose 
of study drug. Or, you should completely avoid having heterosexual intercourse. 
If your partner does become pregnant while you are taking part in the study, you must tell your 
study doctor immediately who will be able to advise you. In this situation, your partner should be 
under medical supervision during her pregnancy, and the baby should be under supervision after 
it is born. Your partner may be asked to give her consent to the collection of information related 
to both herself as well as the baby.  
Female patients: We do not know if the study drug TAK-981 will affect mother’s milk or an 
unborn child. Therefore, breast-feeding and pregnant women are not allowed to take part in the 
study. Due to unknown risks and potential harm to the unborn child/infant, you must agree not to 
become pregnant or breastfeed a baby during the study and for 6 months after you stop taking 
TAK-981.  
You must have a negative pregnancy test prior to enrolling in the study. This test will be repeated 
just before you start taking TAK-981 and then regularly throughout the study. If you become 
pregnant while on this study, the study drug will be stopped immediately, and the pregnancy will 
be followed until conclusion. 
Unless you cannot have children because of surgery or other medical reasons (you had an 
effective tubal ligation, or had the ovaries or the uterus removed; or you are postmenopausal), 
and if you are sexually active with a male partner who has not been sterilized, you must use 
1 highly effective method of contraception and 1 additional effective barrier method of 
contraception at the same time from the time of signing the informed consent form, throughout 
the entire study drug treatment period, and for 6 months following the last dose of study drug. A 
postmenopausal state is defined as no menses (menstrual periods) for 12 months without an 
alternate medical cause.  

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Highly Effective Methods 
Additional Effective Methods 
Combined (estrogen and progestogen containing) 
hormonal contraception associated with inhibition of 
ovulation 
• 
Oral. 
• 
Intravaginal. 
• 
Transdermal. 
Male or female condom with or without spermicide 
(female and male condoms should not be used 
together). 
Progestogen-only hormonal contraception associated 
with inhibition of ovulation 
• 
Oral. 
• 
Injectable. 
• 
Implantable. 
Cap, diaphragm, or sponge with spermicide. 
Intrauterine device (IUD). 
Progestogen-only oral hormonal contraception, where 
inhibition of ovulation is not the primary mode of 
action. 
Intrauterine hormone-releasing system (IUS). 
Bilateral tubal occlusion. 
Vasectomised partner. 
Sexual abstinence. 
You must use birth control methods as directed above unless you completely avoid having heterosexual intercourse. 
 
All patients (male or female): If you or your partner becomes pregnant while you are taking part 
in the study, you must tell your study doctor immediately who will be able to advise you 
regarding the possible risks to your unborn child and discuss options for managing the 
pregnancy. You will be asked for the results of any tests and procedures carried out during your 
pregnancy and up to the birth. You may also be asked for the results from any evaluation of the 
baby after the birth. 
All patients considering having children in the future should consider autologous gamete 
cryopreservation (freezing their eggs or sperm) prior to enrolling in this study with TAK-981. 

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Appendix H BOIN Design 
It is estimated that up to approximately 32 DLT-evaluable patients will be enrolled to evaluate 
dose escalation for 2 dosing schedules of TAK-981. Dose escalation will follow a BOIN design 
(Yuan et al. 2016). Approximately up to 4 patients will be enrolled in the first cohort. According 
to the BOIN design, the decision to escalate or de-escalate dose of TAK-981 is based on the 
cumulative DLT rate at the current dose level and the predetermined DLT rate threshold for dose 
escalation/de-escalation boundaries. The target DLT rate for this study is 0.3. The dose 
escalation and de-escalation rules for TAK-981 are as follows. 
1. If the observed DLT rate at the current dose level is ≤0.236, escalate. 
2. If the observed DLT rate at the current dose level is ≥0.33, de-escalate. 
3. Otherwise, stay at the same dose level. 
The boundary guiding the number of patients treated at the current dose is displayed in the table 
below: 
 
Number of Patients Treated at the Current Dose 
Action 
1 
2 
3 
4 
5 
6 
7 
8 
9 10 11 12 13 14 15 16 17 18 19 20 
Escalate if # of DLT ≤0.236 
0 
0 
0 
0 
1 
1 
1 
1 
2 
2 
2 
2 
3 
3 
3 
3 
4 
4 
4 
4 
De-escalate if # of DLT ≥0.33 1 
1 
1 
2 
2 
2 
3 
3 
3 
4 
4 
4 
5 
5 
5 
6 
6 
6 
7 
7 
 
The operating characteristics of the BOIN design based on 1000 simulations of each scenario are 
presented in the following table:  
 
1 
2 
3 
4 
5 
Number of Patients 
% Early Stopping 
Scenario 1 
 
 
 
 
 
 
 
True DLT Rate 
0.3 
0.46 
0.5 
0.54 
0.58 
 
 
Selection % 
71.4 
13.2 
1.2 
0.1 
0 
 
14.1 
% pts. Treated 
83.7 
15.5 
0.8 
0.1 
0 
18.3 
 
Scenario 2 
 
 
 
 
 
 
 
True DLT Rate 
0.16 
0.3 
0.47 
0.54 
0.6 
 
 
Selection % 
29.2 
57.8 
10.8 
0.7 
0 
 
1.5 
% pts. Treated 
54.6 
36.9 
8.2 
0.3 
0 
19.8 
 
Scenario 3 
 
 
 
 
 
 
 
True DLT Rate 
0.04 
0.15 
0.3 
0.48 
0.68 
 
 
Selection % 
1.6 
37.2 
50.8 
10 
0.4 
 
0 
% pts. Treated 
28.2 
40.3 
26.6 
4.8 
0.1 
20 
 
Scenario 4 
 
 
 
 
 
 
 
True DLT Rate 
0.02 
0.07 
0.12 
0.3 
0.45 
 
 
Selection % 
0.1 
5.5 
39 
46.2 
9.2 
 
0 
% pts. Treated 
22.7 
27.8 
30.2 
17 
2.3 
20 
 

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1 
2 
3 
4 
5 
Number of Patients 
% Early Stopping 
Scenario 5 
 
 
 
 
 
 
 
True DLT Rate 
0.02 
0.06 
0.1 
0.13 
0.3 
 
 
Selection % 
0.1 
4 
24.3 
45.7 
25.9 
 
0 
% pts. Treated 
22.5 
26.4 
27.5 
17.8 
5.8 
20 
 
DLT: dose-limiting toxicity. 
 
The operating characteristics show that the proposed BOIN design selects the true MTD, if any, 
with high probability and allocates more patients to the dose levels with the DLT rate closest to 
the target of 0.3. For example, in scenario 1, the first dose is the true MTD, and the BOIN design 
yields the high selection percentage of 71.4% with 16.7 patients allocated to this dose level. 

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Appendix I 
Protocol History 
Date 
Amendment Number 
Region 
22 June 2023 
Amendment 6 
Global 
01 July 2022 
Amendment 5 
Global 
09 September 2021 
Amendment 4 
Global 
23 April 2021 
Amendment 3 
Global 
10 February 2021 
Amendment 2 
Global 
22 April 2020 
Amendment 1 
Global 
19 February 2020 
Original protocol 
Global 
 
Rationale for Amendment 5 
This section describes the changes in reference to the protocol incorporating Amendment 5. The 
primary reason for this amendment was to expand Phase 2 enrollment in Cohort A to evaluate 
the dose regimen of TAK-981 at 120 mg once weekly (QW) in addition to the 90 mg twice 
weekly (BIW) dose regimen. This would add an additional 23 patients to the Phase 2 portion of 
the study. These data would be used to generate supplementary efficacy, safety, and 
exposure/response data to inform dose selection for further development of TAK-981.  
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification and administrative purpose only. 
Protocol Amendment 5 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
1 
Section 4.2.5 Nonclinical 
Toxicology 
• 
Clarified that TAK-981–related 
effects after repeat daily or QW 
dosing, were observed in lung, 
endocrine systems and glandular 
organs in “rats only.” 
• 
Corrected dose of TAK-981 
administered in rats. 
Changes made to align 
with TAK-981 IB. 
2 
Section 4.2.6 Clinical Experience 
Added details of Study TAK-981-
1503 to the list of ongoing studies in 
TAK-981 program. 
Addition made to 
reflect latest update in 
the program. 
3 
Section 4.4 Rationale for the 
Proposed Study 
Updated details on DLTs observed in 
patients receiving TAK-981. 
Update made to reflect 
information available in 
Recommended Phase 2 
Dose Report for Study 
TAK-981-1002 (data 
cut off 30 April 2021). 
4 
Section 4.5.2 Rationale for the 
Phase 2 Dose of TAK-981 in 
TAK-981-1502 
Added subsection on rationale for 
selection of Phase 2 dose of TAK-981 
in this study. 
Addition done to 
provide latest 
information available. 

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5 
Section 4.5.3.2 Blood 
Section 9.4.17 DNA 
Measurements  
Appendix A SOE Table 3.b 
Biomarker Sample Collection 
During Phase 2 
Added plasma sample collection for 
cell-free DNA evaluation. 
Addition of samples to 
assess tumor mutation 
burden. 
6 
Section 2.0 STUDY SUMMARY 
Figure 6.a TAK-981-1502 Study 
Design 
Section 6.3 Phase 2–Expansion 
in Select Indications 
 
Section 6.4 Number of Patients 
Section 13.3 Determination of 
Sample Size 
Expansion of Phase 2 enrollment in 
Cohort A to evaluate the dose regimen 
of TAK-981 120 mg QW in addition 
to the 90 mg BIW dose regimen and 
addition of 23 more patients to Phase 
2. 
Addition done to 
generate supplementary 
efficacy, safety, and 
exposure/response data 
to inform dose selection 
for further development 
of TAK-981. 
7 
Section 7.1 Inclusion Criteria 
• 
For inclusion criterion #3 A, E, 
and G, patients must have not 
received more than 1 prior 
systemic therapy and must not 
have presented with disease 
progression during the first 6 
months of treatment with first-line 
checkpoint inhibitor/anti-
programmed cell death protein 
1/protein 1 ligand–containing 
therapy, not 5 months. 
• 
For inclusion criterion #8 E, 
correction made to clarify the 
AST/ALT limits in patients with 
liver metastases. 
Typographical error 
correction in criterion 
#3 E and G: 6 months is 
now listed, corrected 
from 5 months. The 
rationale is to align 
with the criteria for 
secondary resistance 
from the Society for 
Immunotherapy of 
Cancer Immunotherapy 
Resistance Taskforce. 
Typographical error 
correction in criterion 
#8 E to align summary 
and text. 
8 
Section 8.2 Definitions of DLT 
Clarified that DLT definitions are 
applicable in Phase 1b. 
Change made for more 
clarity. 

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Table 8.a General Dose 
Modification Recommendations 
for TAK-981 Nonhematologic 
Drug-Related AEs 
Modified dose modification 
recommendations for TAK-981 in 
case of Grade 3 and Grade 4 non–life-
threatening AEs (nonhematologic 
drug-related AEs). Added below 
exceptions that would not require 
TAK-981 dose reduction: 
• 
Grade ≥3 nausea, vomiting, 
and/or diarrhea resolved to Grade 
≤1 or baseline within 72 hours 
with optimal antiemetics and/or 
antidiarrheal following local 
practice. 
• 
Transient Grade 3 fatigue (lasting 
<72 hours) and asymptomatic 
Grade ≤4 laboratory 
abnormalities that the investigator 
considers not clinically 
significant following agreement 
between sponsor and 
investigators. 
Exceptions included to 
prevent dose 
modifications in case of 
transient and 
manageable non–life- 
threatening AEs, such 
as nausea and fatigue.  
10 
Section 8.5.4.3 COVID-19 
Infection 
Added subsection on coronavirus 
disease 2019 (COVID-19) infection.  
Addition made to 
provide information on 
action to be taken if 
patient on study/study 
treatment is diagnosed 
with COVID-19 
infection. 
11 
Section 8.7 Permitted 
Concomitant Medications and 
Procedures 
Changed the time of recording 
concomitant medications in the 
electronic case report form (eCRF) 
from the time of first study drug 
administration to the time of patient’s 
informed consent through the 30 
(+10) days follow-up visit after the 
last dose of study drug. 
Change made to align 
with eCRF guidelines 
and Appendix A SOE 
Table 1.a. 
12 
Appendix A SOE Table 1.a 
Schedule of Events for Treatment 
Cycles (21-Day Cycle) (Phase 1) 
Updated footnote b. 
Modification done for 
clarification of survival 
follow-up in Phase 1 
patients. 

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Appendix A SOE Table 1.b 
Schedule of Events for Treatment 
Cycles (21-Day Cycle) (Phase 2) 
Correction made in footnote l. 
 
 
 
Removed column for Day 15 in all 
Cycles, deleted footnote h and 
reordered subsequent footnotes. 
Correction made to 
reflect correct days of 
performing hematology 
and chemistry 
assessments. 
Change made as Day 
15 is not applicable in 
Phase 2. 
14 
Appendix A SOE Table 3.b 
Biomarker Sample Collection 
During Phase 2 
Addition of new column for Predose 
Cycles 3, 6 and 9.  
Modified footnote a to provide 
information on which patients will 
have biomarker samples collected. 
 
 
Rationale for Amendment 4 
This section describes the changes in reference to the protocol incorporating Amendment 4. The 
primary reason for this amendment was to update the translational strategy for sample collection 
for analysis of biomarkers in Phase 2.  
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification and administrative purpose only. 
Protocol Amendment 4 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
1 
Section 4.2.2 Mechanism of 
Action 
Corrected cross reference citations. 
Correction. 
2 
Section 4.2.5 Nonclinical 
Toxicology 
Section 4.2.6 Clinical Experience 
Section 4.5.1 Rationale for the 
TAK-981 Starting Dose and 
Schedule 
Section 4.6.3 Potential Effects of 
TAK-981 Based on TAK-981 
Clinical Studies 
Updated clinical sections to include 
information from the latest 
investigator’s brochure (IB) edition 
(Edition 4, data cutoff 28 June 2021). 
Updated clinical data 
from the IB were 
available. 

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Section 4.5.2 Rationale for the 
Tumor and Blood Tissues 
Collection 
Section 9.4.14.4 Fresh Paired 
Tumor Biopsy 
Defined tumor collection as 
mandatory. 
Clarified trial 
instructions for sites. 
4 
Section 5.1.3 Exploratory 
Objectives 
Revised the following exploratory 
objective to:  
“To explore potential predictive 
biomarkers of response to 
combination therapy by exploring 
correlations between baseline 
molecular and cellular 
characterization of peripheral blood 
and tumor biomarkers (this may 
include 
genomic/transcriptomic/proteomic 
approaches) with efficacy and other 
clinical endpoints of interest.” 
Updated for clarity. 
5 
Section 8.1.1 TAK-981 
Antipyretic medication treatment 
added for TAK-981 post-dose fevers. 
Updated safety 
precautions. 
6 
Section 8.5.2 Criteria for 
Beginning or Delaying a 
Subsequent Treatment Cycle 
Corrected cross references to sections 
describing treatment-emergent adverse 
events leading to permanent 
discontinuation of TAK-981 and 
criteria for reinitiation of 
pembrolizumab treatment. 
Correction. 
7 
Table 8.a General Dose 
Modification Recommendations 
for TAK-981 Nonhematologic 
Drug-Related AEs 
Added discontinuation of treatment in 
cases of Grade 3+ QTcF prolongation. 
Updated safety 
precautions. 
8 
Table 8.d Pembrolizumab Dose 
Modification Guidelines for 
irAEs 
Grade 3 nephritis and myocarditis 
reclassified with instructions to 
withhold drug. 
Addition of exfoliative dermatologic 
conditions. 
Modification made as 
per pembrolizumab 
prescription sheet. 
9 
8.5.4.1 TAK-981 Criteria for 
Discontinuation 
Criteria for Discontinuation for 
pembrolizumab were removed from 
criteria for discontinuation for TAK-
981. 
Clarification of the 
TAK-981 
discontinuation criteria. 
10 
Table 9.e Primary Specimen 
Collection 
Aligned order of specimens with the 
order of assessments in Appendix A, 
Table 3.a and clarified which 
specimens are mandatory during 
Phase 1 only. 
Updated list of 
biomarker specimens 
for consistency. 

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11 
Section 9.4.16 Pharmacodynamic 
Measurements 
Deletion of plasma cfDNA analysis. 
Biomarkers sampling 
was streamlined. 
12 
Section 13.1.6 
PK/Pharmacodynamic Analysis 
Clarified which pharmacodynamic 
biomarkers are to be analyzed.  
Clarification. 
13 
Appendix A Schedule of Events 
Table 1.a Schedule of Events for 
Treatment Cycles (21-Day Cycle) 
(Phase 1) 
Table 1.b Schedule of Events for 
Treatment Cycles (21-Day Cycle) 
(Phase 2) 
Table 2.a Plasma PK Sampling 
Schedule During Dose Escalation 
Table 2.b Plasma PK Sampling 
Schedule During Phase 2 
Table 3.a Biomarker Sample 
Collection During Phase 1b 
Table 3.b Biomarker Sample 
Collection During Phase 2 
Updated Appendix A schedule of 
event (SOE) table numbers as Tables 
1.a, 2.a, 2.b, 3.a, and 3.b instead of 
Tables A-1, A-1.a, A-1.b, A-2, and A-
3; added Table 1.b. 
Updated Table 1.a to add cross 
references to Tables 1.a through 3.b 
instead of showing sample collection 
times within the table; removed 
associated footnotes referring to the 
separate pharmacokinetic (PK) and 
pharmacodynamic SOEs. 
Updated Table 1.b and added 
Table 3.b to reflect streamlined PK 
and pharmacodynamic sample 
collection strategies, respectively, for 
Phase 2. 
Clarified that Table 3.a is for Phase 1b 
only and removed any Phase 2-
specific sample collections and 
language. 
Updates of SOE tables 
for consistency, Takeda 
style, and clarification. 
Update of PK SOE for 
Phase 2 and addition of 
pharmacodynamic SOE 
for Phase 2, reflecting 
streamlined sample 
collection strategy. 
14 
Appendix F Examples of Clinical 
Inhibitors of Pgp 
Corrected source. 
Correction. 
 
Rationale for Amendment 3 
This section describes the changes in reference to the protocol incorporating Amendment 3. The 
primary reasons for this amendment were to incorporate additional local laboratory assessments 
for safety during Cycle 1, to update contraception requirements throughout the protocol, 
including in inclusion and exclusion criteria that specify contraception timelines, and to provide 
guidance on coronavirus disease 2019 (COVID-19) vaccination and procedures during the study.  
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification and administrative purpose only. 

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Description 
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1 
Section 2.0 STUDY 
SUMMARY 
Study Design 
Section 6.3 Phase 2–Expansion 
in Select Indications 
In the Phase 2 section, the paragraph 
describing the 2-stage design was 
reorganized for clarity and the sentence 
including “Cohorts E through G” was 
corrected to include “Cohorts E through 
H.”  
Edits for clarity and 
correction. 
2 
Section 2.0 STUDY 
SUMMARY 
Secondary Objectives 
Main Criteria for Evaluation 
and Analyses 
Section 5.1.2 Secondary 
Objectives 
Section 5.2.2 Secondary 
Endpoints 
Moved assessment of TAK-981-small 
ubiquitin-like modifier (SUMO) adduct 
formation and SUMO pathway 
inhibition in blood to Phase 1b 
objectives and endpoints. 
Deleted pharmacokinetic endpoint from 
Phase 2; this endpoint is listed for both 
phases. 
Update to limit target 
engagement 
assessments to Phase 1 
dose escalation only. 
Edit to reduce 
redundancy. 
3 
Section 2.0 STUDY 
SUMMARY 
Main Criteria for Inclusion 
Section 4.6.2.5 Reproductive 
and Development Toxicity 
Section 7.1 Inclusion Criteria 
Section 8.8 Precautions and 
Restrictions 
Appendix G Contraception 
Methods 
Updated text throughout the protocol to 
require patients to practice effective 
contraception through 6 months after the 
last dose of study drug (instead of 
120 days after the last dose of study 
drug).  
Compliance with local 
guidelines. 
4 
Section 2.0 STUDY 
SUMMARY 
Main Criteria for Evaluation 
and Analyses 
Sections 5.2.2 Secondary 
Endpoints 
Section 9.4 Study Procedures 
Section 9.9 Posttreatment 
Follow-up Assessments 
(Survival) 
Section 13.1.3.1 Primary 
Efficacy Analysis 
Section 13.1.3.2 Secondary 
Efficacy Analysis 
Removed overall survival (OS) from list 
of secondary endpoints in Phase 1b. 
Added text to clarify that follow-up 
visits for progression-free survival (PFS) 
are to be conducted for any patients who 
discontinued for reasons other than 
progressive disease and follow-up for 
OS is to be done in Phase 2 only.  
Modification to limit 
the OS analysis to 
patients on the 
pharmacodynamically 
optimal dose in 
Phase 2. 

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Section 2.0 STUDY 
SUMMARY 
Main Criteria for Evaluation 
and Analyses 
Section 5.2.1 Primary 
Endpoints  
Section 5.2.2 Secondary 
Endpoints 
Section 8.2 Definitions of DLT 
Table 8.c TAK-981 Dose 
Modification Guidelines for 
CRS 
8.9.7 CRS 
Table 8.e CRS Management 
Recommendations 
Section 10.1.3 SAE Definition 
Section 10.2 Procedures for 
Recording and Reporting AEs 
and SAEs 
Changed criteria for grading cytokine 
release syndrome (CRS) from the 
National Cancer Institute (NCI) 
Common Terminology Criteria for 
Adverse Events (CTCAE) to American 
Society for Transplantation and Cellular 
Therapy (ASTCT) Consensus Grading 
for CRS. 
Added guidelines for dose modification 
and CRS management based on ASTCT, 
including addition of corresponding 
references. 
Alignment with other 
TAK-981 studies. 
6 
Section 4.6.6 Coronavirus 
Disease 2019 Pandemic 
Added a section on benefit/risk 
assessment of participation in the study 
during the coronavirus disease 2019 
(COVID-19) pandemic, indicating that 
the benefit/risk assessment remains 
favorable and that considerations for 
patient participation should be evaluated 
by the investigator on a patient by 
patient basis taking into consideration 
the current local situation, guidelines, 
and other recommendations. 
Guidance on 
benefit/risk assessment 
for patient participation 
in the study during the 
COVID-19 pandemic. 
7 
Section 8.1.1 TAK-981 
Updated text to indicate that if infusion 
reactions are observed, the length of the 
infusion can be extended up to 2 hours 
(instead of up to 4 hours) for all patients 
without requiring a protocol amendment. 
Compliance with the 
TAK-981 stability at 
room temperature.  
8 
Section 8.1.3 Additional 
Instructions for Treatment 
Administration 
Added that a dose delay of up to 7 days 
is allowed to accommodate for 
COVID-19 vaccine administration after 
discussion with the sponsor. 
Guidance on 
COVID-19 vaccination 
timing and procedures 
during the study. 

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Section 8.6 Excluded 
Concomitant Medications and 
Procedures 
Added that vaccination during Cycle 1 is 
not permitted for patients in Phase 1. 
Vaccination during 
Cycle 1 in Phase 1 
would confound safety 
evaluation and 
determination of 
dose-limiting toxicities. 
10 
Section 8.7 Permitted 
Concomitant Medications and 
Procedures 
Added guidance on timing of COVID-
19 vaccination during the study 
including live attenuated vaccine must 
be completed at least 4 weeks prior to 
treatment initiation, vaccination not 
permitted during Cycle 1 in Phase 1, 
vaccination to be avoided within ±3 days 
of TAK-981 administration, and 
allowing a 7-day dose delay to 
accommodate vaccination. 
Guidance on 
COVID-19 vaccination 
timing and procedures 
during the study. 
11 
Section 10.4 Procedures for 
Reporting Drug Exposure 
During Pregnancy and Birth 
Events 
Updated reporting period for 
pregnancies to 6 months after the last 
dose of study drug (instead of 12 months 
after the last dose of study drug.) 
Alignment with 
updated contraception 
requirements per local 
guidelines. 
12 
Section 10.5 Procedures for 
Reporting Product Complaints 
or Medication Errors 
(Including Overdose) 
Updated contact information for 
reporting medication errors. 
Administrative update. 
13 
Section 13.1.3.2 Secondary 
Efficacy Analysis 
Updated the definition of overall 
survival to be “the time from the date of 
the first dose administration to the date 
of death” instead of “the time from the 
date of randomization to the date of 
death”. 
Correction. 

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14 
Appendix A Schedule of 
Events 
Table 1 Schedule of Events 
for Treatment Cycles (21-Day 
Cycle) 
Renamed the column header “PFS 
Follow-up” as “Survival Follow-up” and 
added the following footnote b to this 
header: “The survival status of patients 
in Phase 2 who permanently discontinue 
all study treatment for reasons specified 
in Section 9.7, with the exception of 
death, or withdrawal by the patient, will 
be assessed through medical charts or by 
telephone following the last 
administration of the study drugs.”  
Added hematology and chemistry 
assessments on Days 4, 8, 11, and 15 of 
Cycle 1 with footnote m (previously 
footnote j) updated with the following 
text: “Day 4, 8, 11, 15 hematology and 
chemistry assessments are to be 
performed on dosing days depending on 
treatment schedule (these assessment 
may be discontinued during Phase 2).” 
Added that if a treatment visit is 
delayed, associated tests and procedures 
should also be delayed. 
Updated footnote k (previously footnote 
h) to include allowances for dose delays, 
including a dose delay of up to 7 days to 
accommodate for COVID-19 
vaccination. 
Updated footnote r (previously footnote 
o) to clarify that imaging frequency after 
6 months should be reduced to every 
3 months until occurrence of progression 
of disease. 
Rearranged order of pharmacodynamic 
biomarker sample collections to match 
that in the pharmacodynamic biomarker 
table in Appendix A (Table 2) and 
aligned sample collection times with 
those in Table 2. 
Allowance of additional 
monitoring measures 
for platelets and red 
blood cells during 
treatment. 
Guidance on 
COVID-19 vaccination 
timing and procedures 
during the study. 
Clarification of 
follow-up procedures. 

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15 
Appendix A Schedule of 
Events 
Table 2 Biomarker Sample 
Collection 
Added columns for Cycle 3 and beyond 
to show sample collection predose on 
Days 1 and 8. 
Added samples at Cycle 2 Day 8 for 
chemokines/cytokines and RNA 
(pre-dose and 6-8 hours post-end of 
infusion [EOI]) and removed peripheral 
blood mononuclear cells sample for 
immunophenotyping from 6-8 hours 
post-EOI. 
Updates to biomarker 
collection schedule at 
Cycle 2 Day 8 and 
addition of columns for 
sample collection at 
Cycles 3 and beyond. 
16 
Appendix E Drugs That 
Interact With the CYP3A 
Family of CYPs 
Under strong cytochrome P450 (CYP) 
3A inhibitors, corrected spelling of 
nefazodone and telithromycin and 
deleted grapefruit. Updated source table 
number in footnote a and added footnote 
b to separate sources for CYP3A 
inducers and inhibitors. 
Update to align with 
current Food and Drug 
Administration 
guidance. 
 
Rationale for Amendment 2 
This section describes the changes in reference to the protocol incorporating Amendment 2. The 
primary reason for this amendment was to incorporate additional tumor histologies in Phase 2.  
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification and administrative purpose only. 
Protocol Amendment 2 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
1 
Section 2.0 STUDY SUMMARY 
Section 6.1 Overview of Study 
Design 
Clarified that the follow-up period 
includes monitoring of both disease 
and survival status. 
Clarification. 

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2 
Section 2.0 STUDY SUMMARY 
Section 4.5 Rationale for the 
Proposed Patient Population 
Figure 6.a TAK-981-1502 Study 
Design 
Section 6.3 Phase 2–Expansion 
in Select Indications 
Updated the list of cohorts to be 
evaluated in Phase 2 to the following 
8 cohorts: Cohort A: non-squamous 
non-small cell lung cancer (NSCLC); 
Cohort B: cervical cancer; Cohort C: 
microsatellite stable colorectal cancer 
(MSS-CRC); Cohort D: cutaneous 
melanoma; Cohort E: squamous 
NSCLC; Cohort F: small cell lung 
cancer (SCLC); Cohort G: head and 
neck squamous cell carcinoma 
(HNSCC); and Cohort H: 
microsatellite instability high/ 
mismatch repair deficient colorectal 
cancer (MSI-H/dMMR CRC). 
Conditioned opening of Cohorts E, F, 
G, and H to a positive Stage 1 
readout for Cohorts A, B, C, or D. 
Further evaluation of the 
activity of TAK-981 in 
combination with 
pembrolizumab at the 
recommended Phase 2 
dose (RP2D) in 
additional tumor types. 
3 
Section 2.0 STUDY SUMMARY 
Section 6.3 Phase 2–Expansion 
in Select Indications 
Added text that enrollment may be 
paused at the end of Stage 1 of each 
arm and deleted text on possible 
enrollment into Stage 2 in case of 
potential clinical benefit. 
Clarification on process 
of initiating enrollment 
in Stage 2. 
4 
Section 2.0 STUDY SUMMARY 
Section 5.1.2 Secondary 
Objectives 
Added durable response rate (DRR) 
and time to response (TTR) as part of 
the secondary efficacy objective for 
Phase 2. 
Update of efficacy 
endpoints for Phase 2. 
5 
Section 2.0 STUDY SUMMARY 
Section 6.4 Number of Patients 
Section 13.3 Determination of 
Sample Size 
Increased the estimated number of 
enrolled patients from 101 to 242 and 
increased the number of sites from 30 
to 60 to account for additional 
cohorts in Phase 2. 
Incorporation of 
additional cohorts during 
Phase 2.  
6 
Section 2.0 STUDY SUMMARY 
Section 7.1 Inclusion Criteria 
Edited inclusion criterion 3 to update 
entry criteria for NSCLC and to add 
entry criteria for squamous NSCLC, 
SCLC, HNSCC, cutaneous 
melanoma, and MSI-H/dMMR CRC. 
Updates for further 
evaluation of the activity 
of TAK-981 in 
combination with 
pembrolizumab at the 
RP2D in additional 
tumor types. 

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Rationale 
7 
Section 2.0 STUDY SUMMARY 
Section 7.1 Inclusion Criteria 
Added the following as inclusion 
criterion 5: 
Patients in Phase 2 expansion cohorts 
must have a programmed cell death 
protein 1 ligand (PD-L1) result in 
tumor tissue obtained from a Food 
and Drug Administration 
(FDA)-approved PD-L1 test. 
Characterization of the 
molecular and 
histological profile of the 
tumor tissues of patients 
enrolled in Phase 2. 
8 
Section 2.0 STUDY SUMMARY 
Section 7.1 Inclusion Criteria 
Renumbered inclusion criterion 6 to 
inclusion criterion 7 and updated it to 
include a screening creatinine 
clearance requirement of 
≥30 mL/min (instead of ≥45 mL/min) 
per Cockcroft-Gault formula. 
The creatinine clearance 
requirement was lowered 
based on recent 
pharmacokinetic (PK) 
analysis that showed 
minimal renal 
elimination of TAK-981. 
9 
Section 2.0 STUDY SUMMARY 
Section 7.2 Exclusion Criteria 
In exclusion criterion 10, added that 
the washout period for 
P-glycoprotein inhibitors is 1 week 
before TAK-981 dosing. 
Clarification. 
10 
Section 2.0 STUDY SUMMARY 
Section 7.2 Exclusion Criteria 
Deleted examples of live vaccine 
from exclusion criterion 11. 
Clarification. 
11 
Section 2.0 STUDY SUMMARY 
Section 5.2.2 Secondary 
Endpoints 
Added DRR and TTR as secondary 
endpoints. 
Update of secondary 
efficacy endpoints. 
12 
Section 2.0 STUDY SUMMARY 
Section 4.5.1 Rationale for the 
TAK-981 Starting Dose and 
Schedule 
Section 8.1 Study Drug 
Administration 
Section 8.4 Phase 1b Dose 
Escalation Rules 
Section 13.3 Determination of 
Sample Size 
Updated the dosing schedules to be 
evaluated to include a schedule of 
Days 1 and 8 in 21-day cycles in 
addition to the schedule of Days 1, 4, 
8, and 11 in 21-day cycles. Two 
alternative TAK-981 dosing 
schedules were also added: Day 1 or 
Days 1, 8, and 15 in 21-day cycles. 
Update to allow 
additional dosing 
schedules within the 
dose escalation phase in 
order to evaluate safety 
and 
pharmacodynamics/PK 
characteristics of 
TAK-981. 
13 
Section 4.1.3 Colorectal Cancer 
Section 4.1.4 Small Cell Lung 
Cancer 
Section 4.1.5 Head and Neck 
Squamous Cell Carcinoma 
Section 4.1.6 Cutaneous 
Melanoma 
Added background information for 
added indications. 
Update information on 
the added tumor types. 

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Description of Each Change and Rationale 
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Description 
Rationale 
14 
Section 4.2.6 Clinical Experience 
Updated clinical section to include 
text from the latest investigator’s 
brochure (Edition 3, data cutoff 
28 June 2020). 
Updated clinical data 
from the investigator’s 
brochure were available. 
15 
Section 4.5.2.2 Blood 
Updated the description of the types 
of blood biomarkers to be evaluated 
to include cellular markers of natural 
killer and T cell activation.  
Clarification. 
16 
Section 5.1.3 Exploratory 
Objectives 
Updated exploratory objectives to 
indicate that potential predictive 
biomarkers are to be explored and 
that certain exploratory endpoints 
were to be evaluated to further 
understand the TAK-981 mechanism 
of action and potential responsive 
patient populations. 
Clarification. 
17 
Section 6.3.1 Early Stopping 
Rules 
Added early stopping rules for 
enrollment of cohorts in Phase 2. 
Alignment with 
TAK-981 study 
protocols. 
18 
Section 6.6.1 Duration of an 
Individual Patient’s Study 
Participation  
Clarified that patients will be 
followed for survival (rather than 
progression-free survival [PFS]) for 
up to 12 months after the last dose of 
study drug. 
Alignment with the 
overall survival (OS) 
objective in Phase 2. 
19 
Table 6.a Primary and Secondary 
Endpoints for Disclosures 
Added disease control rate (DCR), 
DRR, time to progression (TTP), and 
OS as secondary endpoints for 
disclosure for Phase 2. 
Alignment with 
secondary objectives in 
Phase 2. 
20 
Section 8.1.1 TAK-981 
Updated the storage temperature for 
TAK-981. 
Alignment with the 
requirements in the 
TAK-981 Pharmacy 
Manual.  
21 
Table 8.d Pembrolizumab Dose 
Modification Guidelines for 
irAEs 
Corrected the monitoring of 
hypothyroidism to include 
monitoring of thyroid function 
instead of renal function. 
Correction. 

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22 
Section 9.4.3 Medical History 
Clarified which disease-related 
medical history data were to be 
collected, including tumor 
pathology/cytogenetic/mutational 
information, human papillomavirus 
status, and tumor mutational burden, 
and PD-L1 results. Clarified that 
PD-L1 tumor status was required 
from all patients in Phase 2. 
Clarification. 
23 
Table 9.c Tumor Prognostic 
Markers 
Added a table of prognostic markers 
for colon cancer and cervical cancer. 
To better evaluate 
complete responses per 
Response Evaluation 
Criteria in Solid Tumors 
(RECIST) v1.1 criteria. 
24 
Table 9.e Primary Specimen 
Collection 
The list of specimens to be collected 
was updated to change the sample 
name from “blood sample for 
immunophenotyping” to “peripheral 
blood mononuclear cell (PBMC) 
sample for immunophenotyping” and 
to add a sample called “blood cells 
for immunophenotyping.” 
Clarification on 
specimen collection. 
25 
Section 9.4.16 Pharmacodynamic 
Measurements 
Updated the list of pharmacodynamic 
measures to include 
immunophenotyping in PBMCs and 
analyses of pharmacodynamic 
measures in the interferon pathway. 
Clarification. 
26 
Section 10.1.4 AESI Definition 
Section 10.2 Procedures for 
Recording and Reporting AEs 
and SAEs 
Clarified reporting procedures for 
adverse events (AEs) of special 
interest. 
Clarification. 
27 
Section 10.3 Monitoring of AEs 
and Period of Observation 
Aligned reporting period for AEs 
with schedule of events. 
Clarification. 
28 
Section 13.1.1 Analysis Sets 
Section 13.1.3.1 Primary 
Efficacy Analysis 
Renamed an analysis set from “Phase 
2 primary analysis set” to “Phase 2 
efficacy analysis set” and clarified 
definition. 
Clarification. 

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Section 13.1.3.1 Primary 
Efficacy Analysis 
For the Phase 2 analysis, defined 
overall response rate (ORR) as based 
on RECIST, Version 1.1 instead of 
iRECIST (consensus guideline 
developed by the RECIST Working 
Group for the use of modified 
RECIST, Version 1.1 in cancer 
immunotherapy trials). 
Alignment with the 
primary objective. 
30 
Section 13.1.3.1 Primary 
Efficacy Analysis 
Added DRR and TTR to the list of 
efficacy parameters that may be 
summarized in Phase 1b. For 
estimates of ORR, added that 
additional confidence intervals may 
also be provided as appropriate. 
Clarification and 
addition of DRR and 
TTR. 
31 
Section 13.1.3.2 Secondary 
Efficacy Analysis 
Added DRR and TTR to the list of 
secondary endpoints and reordered 
the list to align with other protocol 
sections. Added definitions for DRR, 
TTR, TTP, and OS. Added that 
estimates of ORR, DCR, and DRR 
will be presented with 2-sided 95% 
exact binomial confidence intervals, 
with additional confidence intervals 
provided as appropriate, that PFS, 
OS, duration of response, and TTP 
will be analyzed using Kaplan-Meier 
method for the Phase 2 efficacy 
analysis set and TTR summarized for 
responders, and that all efficacy 
endpoints may be analyzed for the 
overall study population as 
appropriate.  
Clarification and 
addition of DRR and 
TTR. 
32 
Section 13.3 Determination of 
Sample Size 
The alpha level for sample size 
calculations for all cohorts was 
changed from 2-sided to 1-sided. 
Correction of text to 
align with other 
TAK-981 protocols. 
33 
Section 13.3 Determination of 
Sample Size 
Added sample size calculations for 
the additional Cohorts D and H. 
Incorporation of 
additional cohorts in 
Phase 2. 
34 
Section 14.1 Study-Site 
Monitoring Visits  
Text was added to allow for potential 
remote monitoring of sites due to the 
COVID-19 (coronavirus disease 
2019) pandemic. 
Clarification. 

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Rationale 
35 
Appendix A Schedule of Events 
The schedules of events for Cycle 1 
was updated to add alternative dosing 
schedules with associated changes in 
assessments, to add an Eastern 
Cooperative Oncology Group 
(ECOG) assessment 90 days after the 
last dose visit, to add flexibility for 
timing of vital sign measurements 
before and after dosing of each study 
drug, and to clarify timing of 
pregnancy testing and cell-free DNA 
(cfDNA) sample collection.  
Modifications to 
simplify vital signs 
assessment and 
procedures across the 
TAK-981 clinical 
studies. 
36 
Appendix A Schedule of Events 
The schedule of events for Cycle 2 
and Cycles 3 and subsequent cycles 
was updated to remove collection of 
the hematology/chemistry sample on 
Day 8 of Cycle 3 and subsequent 
cycles, to add collection of 
immunosafety markers at end of 
treatment, to add collections of 
PBMCs samples for 
immunophenotyping and blood 
samples for cfDNA, and to add 
flexibility for timing of vital sign 
measurements before and after 
dosing of each study drug. 
Modifications to 
simplify vital signs 
assessment and central 
and local laboratory 
assessments across the 
TAK-981 clinical 
studies. 
37 
Appendix E Drugs That Interact 
With the CYP3A Family of 
CYPs 
The list of CYP3A inhibitors and 
inducers was updated based on the 
most recent recommendations from 
FDA (3 March 2020).  
Alignment with recent 
FDA recommendations. 
38 
Appendix H BOIN Design 
Renumbered tables and deleted 
2 references included in the 
appendix. 
Editorial changes. 
 
Rationale for Amendment 1 
This section describes the changes in reference to the protocol incorporating Amendment 01. The 
primary reason for this amendment was to incorporate requirements by the United States Food 
and Drug Administration (FDA).  
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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Sections Affected by Change 
Description 
Rationale 
Location 
1. Clarified that starting dose for 
TAK-981 will be 40 mg. 
Clarification provided in response 
to FDA request. 
Section 4.5.1 Rationale for the TAK-
981 Starting Dose and Schedule 
Section 8.4 Phase 1b Dose Escalation 
Rules  
Section 2.0 STUDY SUMMARY  
2. Modified inclusion criteria to 
require NSCLC patients with 
driver mutations/genomic 
aberrations must have 
progressed after therapy with 
FDA-approved targeted therapy. 
Change made in response to FDA 
request. 
Section 7.1 Inclusion Criteria, 
criterion #3A 
Section 2.0 STUDY SUMMARY 
3. Modified inclusion criteria to 
clarify that CPI-naïve MSS-
CRC patients must have 
received prior treatment with 
fluoropyrimidine-, oxaliplatin-, 
and irinotecan-containing 
regimens if indicated. 
Change made in response to FDA 
request. 
Section 7.1 Inclusion Criteria, 
criterion #3C 
Section 2.0 STUDY SUMMARY 
4. Removed inclusion criterion #5 
and note in the inclusion 
criterion #4 that required 
mandatory tumor biopsy from 
patients in Phase 2, Stage I. 
Change made in response to FDA 
request. 
Section 4.5.2.1 Tumor Biopsies 
Section 7.1 Inclusion Criteria  
Section 9.4.14.2 Tumor Biopsies 
Section 9.4.14.4 Fresh Paired Tumor 
Biopsy  
Section 9.4.16 Pharmacodynamic 
Measurements  
Table 9.d Primary Specimen 
Collection 
Appendix A: Table 1, footnote “q”; 
Table 2, footnote “b” 
Section 2.0 STUDY SUMMARY 
5. Added criteria to exclude 
patients with baseline 
prolongation of the QT interval 
Change made in response to FDA 
request. 
Section 7.2 Exclusion Criteria, 
criterion #8. 
Section 2.0 STUDY SUMMARY 
6. Added study-stopping rules 
during dose escalation. 
Change made in response to FDA 
request. 
Section 6.2 Phase 1b–Dose 
Escalation 
7. Modified definitions of DLT. 
Change made in response to FDA 
request. 
Section 8.2 Definitions of DLT 

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Description 
Rationale 
Location 
8. Added language for 
precautionary measures to be 
taken during dose escalation 
phase by staggering the 
enrollment. 
Change made in response to FDA 
request. 
Section 4.6.2.3 IRRs and Potential 
for CRS 
Section 6.2 Phase 1b–Dose 
Escalation 
Section 2.0 STUDY SUMMARY 
9. Added a 90-day follow up visit 
after last dose with the study 
treatment to capture any late-
onset immune-related adverse 
events (irAE). 
Change made in response to FDA 
request. 
Section 6.1 Overview of Study 
Design. 
Section 9.4 Study Procedures 
Section 9.7.1 Treatment Beyond 
Progression 
Section 10.3 Monitoring of AEs and 
Period of Observation 
Section 2.0 STUDY SUMMARY 
Appendix A, Table 1 
10. Amended language to remove 
treatment beyond 24 months. 
Change made in response to FDA 
request. 
Section 6.6.1 Duration of an 
Individual Patient’s Study 
Participation 
Section 6.6.2 End of Study/Study 
Completion Definition and Planned 
Reporting 
Section 6.6.5 Posttrial Access 
Section 2.0 STUDY SUMMARY 
11. Amended language for 
intrapatient dose escalation. 
Change made in response to FDA 
request. 
Section 8.5.1 Intrapatient Dose 
Escalation 
12. Added adverse event of special 
interest (AESI) definition, 
procedure for recording and 
reporting AESIs, and 
monitoring of AESIs. 
Change made in response to FDA 
request. 
Section 10.0 ADVERSE EVENTS 
Section 13.1.7 Safety Analysis  
Appendix A, Table 1 
13. Added text to perform 
hematology and coagulation 
tests prior to biopsy procedure 
to assess the risk of bleeding 
associated with biopsy 
procedure. 
Change made in response to FDA 
request. 
Section 9.4.14.4 Fresh Paired Tumor 
Biopsy 
Appendix A, Table 1 and Table 2 

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Sections Affected by Change 
Description 
Rationale 
Location 
14. Specified the names of 
countries and regions in which 
this study might be conducted. 
Clarification provided in response 
to FDA request. 
Section 2.0 STUDY SUMMARY 
15. Added details on TAK-981 
preparation. 
Addition made in response to 
FDA request. 
Section 8.1.1 TAK-981 
16. Amended and added text in 
rationale for the proposed 
study.  
Change made to provide current 
data.  
Section 4.4 Rationale for the 
Proposed Study 
17. Added exploratory endpoint of 
TAK-981-SUMO adduct 
formation and SUMO pathway 
inhibition in tumor tissue. 
Change made in response to FDA 
request regarding fresh paired 
tumor biopsies. 
Section 5.2.3 Exploratory Endpoints 
18. Modified figure for study 
design. 
Change made to reflect study 
design. 
Figure 6.a TAK-981-1502 Study 
Design 
19. Amended number of patients to 
be enrolled in the study. 
Change made in response to FDA 
request. 
Section 6.4 Number of Patients 
Section 13.3 Determination of 
Sample Size 
Section 2.0 STUDY SUMMARY 
20. Amended upper bound for the 
targeted toxicity interval for 
maximum tolerated dose 
(MTD) not to exceed 33% and 
provided the operating 
characteristics of the Bayesian 
optimal interval design (BOIN) 
that will be used for dose-
escalation in the phase 1b part 
of study. 
Change made in response to FDA 
request. 
Section 8.4 Phase 1b Dose Escalation 
Rules  
Appendix H BOIN design 
21. Added definition of Phase 2 
primary analysis set. 
Addition made in response to 
FDA request. 
Section 13.1.1 Analysis Sets 
22. Amended that ECOG will be 
conducted within 3 days before 
dosing on Day 1 of each 
treatment cycle. 
Clarification provided per 
Investigator’s recommendation. 
Appendix A, Table 1 
 
23. Added language to address 
study conduct during the 
Coronavirus Disease 2019 
(COVID-19) pandemic. 
Change made to facilitate conduct 
of study activities during COVID-
19 pandemic.  
Appendix A, Table 1 footnotes 

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Description 
Rationale 
Location 
24. Removed the requirement of 
patient to stay in supine 
position for ECGs and blood 
pressure measurements. 
Change made per Investigator's 
request. 
Section 9.4.11 Cardiac Monitoring 
Appendix A, Table 1 footnotes “e” 
and “h” 
25. Clarified that blood sample for 
DNA will be collected on 
Cycle 1 Day 1 predose 
Change made per Investigator’s 
request. 
Section 9.4.17 DNA Measurements 
Appendix A, Table 1 and Table 2 
26. Added window periods for 
biomarker samples collection at 
1h, 4h and 24 h in Cycle 1 Day 
1 and Cycle 1 Day 8 and at 1h 
and 4h in Cycle 2 Day 8. 
Change made to facilitate sample 
collection at the clinical site. 
Appendix A, Table 2 
27. Added blood sample collection 
for cfDNA. 
Addition made to assess potential 
biomarkers for monitoring disease 
status 
Appendix A, Table 1 (and footnote 
“u”) and Table 2 (and footnote “d”) 
 

Signature Page for TAK-981-1502 Protocol Amend 6 2023-06-22
Title: A Phase 1b/2 Study of TAK-981 Plus Pembrolizumab to Evaluate the Safety, 
Tolerability, and Antitumor Activity of the Combination in Patients With Select 
Advanced or Metastatic Solid Tumors
Document Number: TDN-000182163 v1.0
Approval
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27-Jun-2023 20:02:18 GMT+0000
Approval
Statistics
27-Jun-2023 20:12:17 GMT+0000
Approval
Clinical
27-Jun-2023 20:13:50 GMT+0000
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