An Open-label, Dose Escalation and Expansion, Phase 1/2 Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Antitumor Activity of TAK-500, a Novel Stimulator of Interferon Genes Agonist, as a Single Agent and in Combination With Pembrolizumab in Adult Patients With Select Locally Advanced or Metastatic Solid Tumors
Phase: PHASE1
Conditions: Pancreatic Cancer, Hepatocellular Cancer, Mesothelioma, Breast Cancer, Gastric Cancer, Esophageal Cancer, Nasopharyngeal Cancer, Kidney Cancer, Squamous Cell Cancer of Head and Neck (SCCHN), Non-small Cell Lung Cancer (NSCLC), Non-squamous
Sponsor: Takeda

For non-commercial use only

 
 
 
PROTOCOL 
An Open-label, Dose Escalation and Expansion, Phase 1/2 Study to Evaluate the Safety, 
Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Antitumor Activity 
of TAK-500, a Novel Stimulator of Interferon Genes Agonist, as a Single Agent and in 
Combination With Pembrolizumab in Adult Patients With Select Locally Advanced or 
Metastatic Solid Tumors 
Phase 1/2 Study of TAK-500 as a Single Agent and in Combination With Pembrolizumab 
in Patients With Select Locally Advanced or Metastatic Solid Tumors  
Sponsor: 
Takeda Development Center Americas, Inc. 
95 Hayden Avenue 
Lexington, MA 02421 
Please note: Takeda Development Center Americas, Inc. may be 
referred to in this protocol as “sponsor” or “Takeda.” 
Study Number: 
TAK-500-1001 
EU Clinical Trial 
Number: 
2023-505374-15 
Compound: 
TAK-500 
Date: 
13 June 2023 
Amendment Number: 
3 
Amendment History: 
Date 
Amendment Number 
Region 
13 June 2023 
Amendment 3 
Global 
25 October 2022 
Amendment 2 
United States 
21 September 2021 
Amendment 1 
United States 
15 July 2021 
Initial Protocol 
United States 
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. 
For non-commercial use only

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CONFIDENTIAL 
1.0 
ADMINISTRATIVE INFORMATION 
1.1 
Contacts 
A separate contact information list, for relevant contract research organization and sponsor 
contacts, 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.  
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. 
For non-commercial use only

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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, PhD 
 
Clinical Science Oncology 
Date 
, PhD 
 
Statistical and Quantitative Sciences 
Date 
, PhD 
  
Quantitative Clinical Pharmacology 
Date 
 
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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. 
• ICH, E6 GCP: Consolidated Guideline. 
• All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations. 
• Regulatory requirements for reporting SAEs defined in Section 10.0 of this protocol. 
• Terms outlined in the clinical study site agreement. 
• Responsibilities of the investigator (Appendix B). 
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix C of this protocol. 
 
Signature of Investigator 
Date 
Investigator Name (print or type) 
Investigator’s Title 
Location of Facility (City, State/Province) 
Location of Facility (Country) 
  
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CONFIDENTIAL 
1.3 
Protocol Amendment 3 Summary of Changes 
Protocol Amendment 3 Summary and Rationale: 
This section describes the changes in reference to the protocol incorporating Amendment 2.  
The primary reasons for this amendment are to: 
• Describe the study design for the phase 2 dose expansion phase of the study, as summarized 
in Figure 6.b. 
• Add the respective inclusion criteria for the single indication cohorts of the dose expansion 
phase. 
• Adapt the objectives and endpoints to include the phase 2 dose expansion phase.  
• Update the sample size calculation for the expansion phase. 
 
 
 
.  
 
 
  
In this amendment, minor grammatical, editorial, formatting, and administrative changes not 
affecting the conduct of the study are included for clarification and administrative purposes only. 
Protocol Amendment 3 
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. 
Study Protocol Title 
Changed phase 1a/1b to 
phase 1/2. 
Updated to reflect objectives 
and endpoints specific to 
phase 1 dose escalation and 
phase 2 dose expansion. 
2. 
Title page 
2.0 STUDY SUMMARY 
Added European Union (EU) 
clinical trial number 
Added according to EU 
Clinical Trial Regulation 
(CTR) guidelines. 
3. 
2.0 STUDY SUMMARY, Study 
Design, TAK-500 SA Dose 
Escalation, and Dose Levels(s) 
6.1.2 TAK-500 Dose Escalation 
Appendix F 
BOIN Design 
Added intermediary dose level 
of 24 μg/kg. 
Updated to reflect intermediary 
dose level added for use in the 
phase 1 dose escalation. 
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CONFIDENTIAL 
Protocol Amendment 3 
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 
4. 
2.0 STUDY SUMMARY, Study 
Design  
6.1 Overview of Study Design 
6.1.3 TAK-500 Dose Expansion 
and Randomized Dose 
Comparison 
6.1.3.1 Expansion Cohort Tumor 
Type Selection  
6.1.3.2 Dose Expansion in 
Nonsquamous NSCLC 
6.1.3.3 TAK-500 SA and in 
Combination With 
Pembrolizumab Dose Expansion 
in 2L Pancreatic 
Adenocarcinoma 
6.1.3.4 Combination TAK-500 
With Pembrolizumab Dose 
Expansion in 3L RCC 
Updated with all study design 
details of dose expansion, 
including the 3 cancer types 
selected for dose expansion; 
updated Figure 6.a Overview 
of Study Design – Dose 
Escalation; and added Figure 
6.b Schematic of Study Design 
– Dose Expansion. 
Protocol updated to reflect 
planned dose expansion in 
3 indications, including 
nonsquamous non-small cell 
lung cancer (NSCLC), renal 
clear cell carcinoma (RCC), 
and pancreatic 
adenocarcinoma. This replaces 
the prior language around 
potential planned expansion in 
triple-negative breast cancer. 
Dose expansion plans now 
include potential for 
randomized dose comparison 
(dose optimization) in 2 
different dose levels. 
5. 
2.0 STUDY SUMMARY, 
Primary and Secondary 
Objectives and Endpoints 
5.1.1 Primary Objectives 
5.1.2 Secondary Objectives 
5.2.1 Primary Endpoints 
5.2.2 Secondary Endpoints 
 
Updated to reflect objectives 
and endpoints specific to phase 
2 expansion. These include 
evaluation of preliminary 
antitumor activity of TAK-500 
SA and combination with 
pembrolizumab and 
identification of the dose for 
further development. Primary 
and secondary endpoints 
adjusted include overall 
response rate, progression-free 
survival, and overall survival 
(OS).  
6. 
2.0 STUDY SUMMARY 
6.1.2.1 TAK-500 SA Dose 
Escalation 
6.1.2.2 TAK-500 in Combination 
With Pembrolizumab Dose 
Escalation 
Updated wording around 
pharmacologically active dose 
(PAD) determination.  
Clarified circumstances under 
which a dose level meets the 
PAD when a response is 
observed, and proceedings 
when the minimum PAD is 
confirmed. 
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CONFIDENTIAL 
Protocol Amendment 3 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
7. 
2.0 STUDY SUMMARY, 
Number of Patients, Number of 
Sites 
6.2 Number of Patients 
Updated to include all patients 
in the dose expansion phase of 
this study. 
Numbers now include all 
patients in planned phase 2 
escalation and expansion phase 
of protocol. This is increased 
according to the inclusion of 
multiple single-indication 
expansion cohorts. 
8. 
2.0 STUDY SUMMARY, Period 
of Evaluation 
6.3.4 Total Study Duration 
Updated overall study 
duration, including definition 
of study start and study end. 
Study duration now includes 
dose escalation and multiple 
expansion cohorts, and timing 
has been adjusted to take into 
consideration additional length 
of recruitment and treatment of 
the additional patients 
associated with expansion 
cohorts. 
9. 
2.0 STUDY SUMMARY, 
Inclusion Criteria 
7.1 Inclusion Criteria 
Updated inclusion criterion #3 
to include the eligibility 
requirements for the patients 
from the 3 indications and 
other dose expansion phase 
details. 
Details the criteria around 
eligibility of patients for the 
nonsquamous NSCLC, RCC, 
and pancreatic adenocarcinoma 
expansion cohorts. 
10. 
2.0 STUDY SUMMARY, 
Inclusion Criteria 
7.1 Inclusion Criteria 
8.8 Precautions and Restrictions 
Updated inclusion criteria #12 
and #13 and section on 
precautions and restrictions. 
Contraception duration was 
updated from 120 to 180 days. 
Change to be consistent with 
prior requests from EU 
regulatory authorities. 
11. 
2.0 STUDY SUMMARY 
Added potential risks and 
benefits summary to the 
protocol summary. 
Added according to EU CTR 
guidelines. 
12. 
2.0 STUDY SUMMARY 
Exclusion Criteria 
7.2 Exclusion Criteria 
Removed exclusion criteria #6 
and #7. 
Patients who smoke or use 
vaping products will not be 
excluded from this study, as 
there has been no evidence of 
pneumonitis from 
administration of TAK-500 or 
the small molecule STING 
payload TAK-676. 
13. 
2.0 STUDY SUMMARY, 
Exclusion Criteria 
7.2 Exclusion Criteria 
Updated exclusion criterion #9 
to include more detailed 
specifications for excluding 
patients with a history of 
leptomeningeal disease and 
brain metastases. 
Patients with leptomeningeal 
disease excluded due to 
concern for rapid progression 
and lack of evidence regarding 
blood-brain barrier penetration 
of TAK-500. 
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CONFIDENTIAL 
Protocol Amendment 3 
Summary of Changes Since the Last Version of the Approved Protocol 
Change 
Number 
Sections Affected by Change 
Description of Each Change and Rationale 
Location 
Description 
Rationale 
14. 
2.0 STUDY SUMMARY, 
Sample Size Justification  
13.3 Determination of Sample 
Size 
Updated to include sample size 
calculation for the expansion 
phase of the study. 
Numbers now include all 
patients in planned escalation 
and expansion phase of 
protocol. This is increased 
according to the inclusion of 
multiple single-indication 
expansion cohorts. Dropout 
rate changed to 10% from 15% 
to reflect current assumptions 
for enrollment.  
15. 
2.0 STUDY SUMMARY, Study 
Design, Determination of PAD 
8.4 Definition of PAD  
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
.  
16. 
4.2 Rationale for the Proposed 
Study 
4.2.1.2 Pancreatic 
Adenocarcinoma 
4.2.1.4 Nonsquamous NSCLC 
4.2.1.8 RCC 
Updated to include paragraph 
on dose expansion, and 
updated background 
information on the 3 
indications NSCLC, pancreatic 
adenocarcinoma, and RCC. 
Expanded rationale for 
selection of expansion 
indications included for better 
background and understanding. 
17. 
4.2.3 Rationale for European 
Union Auxiliary Medicinal 
Products for CRS Mitigation 
Added rationale for use of 
auxiliary medicinal products 
(AxMP). 
Added according to EU CTR 
guidelines. 
18. 
4.2.4.1 Tumor Biopsies 
Clarified the evaluation of 
immune cell infiltration within 
the tumor (secondary 
endpoint). 
Clarified that secondary 
endpoint includes changes in 
immune cell infiltration. 
19. 
4.3.4 Risks Associated With the 
AxMPs 
Added section on risks and 
benefits of AxMP. 
Added according to EU CTR 
guidelines. 
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CONFIDENTIAL 
Protocol Amendment 3 
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 
20. 
5.1.3 Exploratory Objectives 
5.2.3 Exploratory Endpoints 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
21. 
6.1.1 Premedication 
Appendix A SOEs 
Updated text and moved 
premedication section to 
Section 6.1.1 because it applies 
to both the dose escalation and 
the dose expansion part of this 
study. 
 
 
  
 
 
. 
Moved to earlier section to 
clarify that premedication 
applies to both SA and 
combination arms. 
22. 
8.1.1 TAK-500 
Added text on premedication 
use. 
Clarification.  
23. 
8.1.4 List of European Union 
Auxiliary Medicinal Products 
Table 8.a 
Added justification for AxMPs 
and details on their use. 
Added according to EU CTR 
guidelines. 
24. 
9.4.6 Vital Signs 
9.4.6.3 
 
 
Appendix A SOEs 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
25. 
9.4.14.2 Tumor Biopsies 
Updated to include a possible 
waiver for the mandatory 
paired biopsies.  
Updated to allow possible 
exception to mandatory 
biopsies outside of safety 
concerns as long as there is 
initial discussion and approval 
with sponsor. 
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CONFIDENTIAL 
Protocol Amendment 3 
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 
26. 
9.4.19 Collection, Storage, and 
Future Use of Biological Samples 
From Clinical Trial Subjects 
Text was added describing the 
collection, storage, and future 
use of biological samples.  
Added according to EU CTR 
guidelines. 
27. 
9.4.20 
 
 
9.4.20.1 
 
 
9.4.20.2 
 
 
9.4.20.3 
 
 
 
9.4.20.4 
 
 
Appendix A SOEs 
 
 
 
 
 
 
 
 
 
 
  
28. 
9.9 Completion of Study (for 
Individual Patients) 
Updated to include paragraph 
on dose expansion. 
Clarifies that for expansion, 
patients will be followed 
through end of life for 
evaluation of OS. 
29. 
10.1.4 Special Situation Report 
Definition 
Added definitions for special 
situation reports. 
Added according to EU CTR 
guidelines. 
30. 
10.2.1 Recording and Reporting 
AEs and SAEs Related to AxMPs 
Added reporting requirements 
for AEs and SAEs (serious 
adverse events) that are 
considered related to AxMP(s) 
by the investigator. 
Added according to EU CTR 
guidelines. 
31. 
10.5 Procedures for Reporting 
Product Complaints or SSRs 
Clarified and updated product 
complaints and special 
situation reporting. 
Added according to EU CTR 
guidelines. 
32. 
13.1.3 Efficacy Analysis 
Added the definition for OS. 
Definition for OS. 
33. 
13.1.11 
 
  
 
 
 
 
 
 
 
 
34. 
13.1.12 
 
13.1.12.1 
 
 
13.1.12.2 
 
 
 
 
 
 
 
 
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Protocol Amendment 3 
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 
35. 
14.2 Protocol Deviations 
Clarified that it is mandatory to 
report serious breach of Good 
Clinical Practice or the 
protocol to regulatory 
authorities. 
Added according to EU CTR 
guidelines. 
36. 
15.3 Patient Confidentiality 
Added clarification on serious 
breach affecting personal data. 
Added according to EU CTR 
guidelines. 
37. 
Appendix A SOEs 
Added footnote to selectively 
decrease pharmacokinetic and 
pharmacodynamic biomarker 
samples during planned visits 
of the dose expansion phase. 
Decreases patient burden in 
expansion phase. 
 
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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 3 Summary of Changes...............................................................5 
2.0 
STUDY SUMMARY.........................................................................................................21 
3.0 
STUDY REFERENCE INFORMATION .........................................................................39 
3.1 
Study-Related Responsibilities ....................................................................................39 
3.2 
Principal Investigator/Coordinating Investigator .........................................................39 
3.3 
List of Abbreviations ...................................................................................................39 
3.4 
Corporate Identification ...............................................................................................43 
4.0 
INTRODUCTION .............................................................................................................44 
4.1 
Background ..................................................................................................................44 
4.1.1 
Nonclinical Background ......................................................................................45 
4.1.1.1 
Nonclinical Pharmacology ..........................................................................46 
4.1.1.2 
Nonclinical PK ............................................................................................47 
4.1.1.3 
Nonclinical Toxicology ...............................................................................48 
4.1.2 
Clinical Background ............................................................................................50 
4.1.2.1 
TAK-202 .....................................................................................................50 
4.1.2.2 
TAK-676 .....................................................................................................51 
4.1.2.3 
TAK-500 .....................................................................................................53 
4.2 
Rationale for the Proposed Study ................................................................................55 
4.2.1 
Rationale for the Patient Population Selection ....................................................56 
4.2.1.1 
Gastroesophageal Adenocarcinoma ............................................................57 
4.2.1.2 
Pancreatic Adenocarcinoma ........................................................................57 
4.2.1.3 
HCC ............................................................................................................58 
4.2.1.4 
Nonsquamous NSCLC ................................................................................58 
4.2.1.5 
SCCHN .......................................................................................................59 
4.2.1.6 
Mesothelioma ..............................................................................................60 
4.2.1.7 
TNBC ..........................................................................................................60 
4.2.1.8 
RCC .............................................................................................................60 
4.2.1.9 
NPC .............................................................................................................61 
4.2.2 
Rationale for the Starting Dose, Dose Range, and Schedule ..............................61 
4.2.2.1 
Maximum Recommended Starting Dose Based on Nonclinical 
Toxicology Findings in Monkeys ...............................................................62 
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4.2.2.2 
Recommended Starting Dose Based on MABEL .......................................62 
4.2.2.3 
Selection of Final Recommended Starting Dose for the Study...................63 
4.2.2.4 
Dose Range .................................................................................................64 
4.2.2.5 
Dosing Schedule of TAK-500 .....................................................................64 
4.2.3 
Rationale for European Union Auxiliary Medicinal Products for CRS 
Mitigation ............................................................................................................65 
4.2.4 
Rationale for Tumor and Blood Tissues Collection ............................................65 
4.2.4.1 
Tumor Biopsies ...........................................................................................65 
4.2.4.2 
Blood ...........................................................................................................66 
4.2.5 
Rationale for PK Assessments .............................................................................66 
4.3 
Potential Risks and Benefits ........................................................................................66 
4.3.1 
Potential Risks and Effects of TAK-500 .............................................................66 
4.3.1.1 
CRS .............................................................................................................67 
4.3.1.2 
Pulmonary Edema .......................................................................................67 
4.3.1.3 
Immune/Lymphoid System Toxicity ..........................................................68 
4.3.1.4 
Liver Toxicity..............................................................................................68 
4.3.1.5 
CV Toxicity .................................................................................................68 
4.3.2 
Risks and Effects of TAK-500 in Combination With Pembrolizumab ...............69 
4.3.3 
Risks Associated With Same Class of Compound ..............................................69 
4.3.4 
Risks Associated With the AxMPs ......................................................................70 
4.3.5 
Additional Safety Concerns .................................................................................71 
4.3.5.1 
Infusion-Related Reactions .........................................................................71 
5.0 
STUDY OBJECTIVES AND ENDPOINTS .....................................................................71 
5.1 
Objectives ....................................................................................................................71 
5.1.1 
Primary Objectives ..............................................................................................71 
5.1.2 
Secondary Objectives ..........................................................................................72 
5.1.3 
Exploratory Objectives ........................................................................................72 
5.2 
Endpoints .....................................................................................................................73 
5.2.1 
Primary Endpoints ...............................................................................................73 
5.2.2 
Secondary Endpoints ...........................................................................................74 
5.2.3 
Exploratory Endpoints .........................................................................................75 
6.0 
STUDY DESIGN...............................................................................................................76 
6.1 
Overview of Study Design ...........................................................................................76 
6.1.1 
Premedication ......................................................................................................76 
6.1.2 
TAK-500 Dose Escalation ...................................................................................77 
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6.1.2.1 
TAK-500 SA Dose Escalation ....................................................................78 
6.1.2.2 
TAK-500 in Combination With Pembrolizumab Dose Escalation .............80 
6.1.2.3 
General Rules for Dose Escalation .............................................................80 
6.1.3 
TAK-500 Dose Expansion and Randomized Dose Comparison .........................81 
6.1.3.1 
Expansion Cohort Tumor Type Selection ...................................................83 
6.1.3.2 
Dose Expansion in Nonsquamous NSCLC .................................................83 
6.1.3.3 
TAK-500 SA and in Combination With Pembrolizumab Dose 
Expansion in 2L Pancreatic Adenocarcinoma ............................................85 
6.1.3.4 
Combination TAK-500 With Pembrolizumab Dose Expansion in 3L 
RCC .............................................................................................................86 
6.1.4 
Study Assessments ..............................................................................................86 
6.2 
Number of Patients ......................................................................................................87 
6.3 
Duration of Study .........................................................................................................88 
6.3.1 
Duration of an Individual Patient’s Study Participation ......................................88 
6.3.2 
EOS and Study Completion Definition and Planned Reporting .........................89 
6.3.3 
Timeframes for Primary and Secondary Endpoints to Support Disclosures .......89 
6.3.4 
Total Study Duration ...........................................................................................91 
6.3.5 
Poststudy Access .................................................................................................91 
6.3.5.1 
Duration of Poststudy Access .....................................................................91 
7.0 
STUDY POPULATION ....................................................................................................91 
7.1 
Inclusion Criteria .........................................................................................................91 
7.2 
Exclusion Criteria ........................................................................................................96 
8.0 
STUDY DRUG ..................................................................................................................98 
8.1 
Study Drug Administration ..........................................................................................98 
8.1.1 
TAK-500 ..............................................................................................................98 
8.1.2 
Pembrolizumab ..................................................................................................100 
8.1.3 
TAK-500 in Combination With Pembrolizumab ..............................................100 
8.1.4 
List of European Union Auxiliary Medicinal Products .....................................101 
8.2 
Definitions of DLT ....................................................................................................103 
8.3 
Dose Escalation Rules................................................................................................104 
8.3.1 
BOIN Dose Escalation ......................................................................................104 
8.3.2 
Stopping Rules ...................................................................................................105 
8.4 
Definition of PAD ......................................................................................................105 
8.5 
Dose Modification Guidelines ...................................................................................106 
8.5.1 
Intrapatient Dose Escalation ..............................................................................106 
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CONFIDENTIAL 
8.5.2 
Criteria for Crossover From SA to Combination Treatment .............................107 
8.5.3 
Criteria for Administering a Subsequent Dose/Starting a New Treatment 
Cycle ..................................................................................................................107 
8.5.4 
Criteria for Dose Modification ..........................................................................108 
8.5.5 
Criteria for Discontinuation of TAK-500 ..........................................................113 
8.5.6 
Criteria for Discontinuation of Pembrolizumab ................................................114 
8.6 
Excluded Concomitant Medications and Procedures ................................................114 
8.7 
Permitted Concomitant Medications and Procedures ................................................116 
8.8 
Precautions and Restrictions ......................................................................................116 
8.9 
Management of Clinical Events .................................................................................118 
8.9.1 
CRS ....................................................................................................................119 
8.9.2 
Pulmonary Edema .............................................................................................122 
8.9.3 
Skin Conditions/Rash ........................................................................................123 
8.9.4 
Infusion Site Care ..............................................................................................124 
8.9.5 
Nausea and/or Vomiting ....................................................................................124 
8.9.6 
Fluid Deficit .......................................................................................................124 
8.9.7 
Infusion-Related Reactions ...............................................................................125 
8.9.8 
Management of Pembrolizumab Immune-Mediated AEs .................................125 
8.9.9 
Management of COVID-19–Positive Patients ..................................................126 
8.9.10 
CV Toxicity .......................................................................................................126 
8.10 
Blinding and Unblinding............................................................................................127 
8.11 
Description of Investigational Agents .......................................................................127 
8.11.1 
TAK-500 ............................................................................................................127 
8.11.2 
Pembrolizumab ..................................................................................................128 
8.12 
Preparation, Reconstitution, and Dispensation ..........................................................128 
8.12.1 
TAK-500 ............................................................................................................128 
8.12.2 
Pembrolizumab ..................................................................................................128 
8.13 
Packaging and Labeling .............................................................................................128 
8.13.1 
TAK-500 ............................................................................................................128 
8.13.2 
Pembrolizumab ..................................................................................................128 
8.14 
Storage, Handling, and Accountability ......................................................................129 
8.14.1 
TAK-500 ............................................................................................................129 
8.14.2 
Pembrolizumab ..................................................................................................129 
8.15 
Other Protocol-Specified Materials ...........................................................................129 
9.0 
STUDY CONDUCT ........................................................................................................129 
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9.1 
Study Personnel and Organizations ...........................................................................129 
9.2 
Arrangements for Recruitment of Patients ................................................................129 
9.3 
Treatment Group Assignments ..................................................................................130 
9.4 
Study Procedures .......................................................................................................130 
9.4.1 
Informed Consent ..............................................................................................130 
9.4.2 
Patient Demographics ........................................................................................130 
9.4.3 
Medical History .................................................................................................130 
9.4.4 
Physical Examination ........................................................................................130 
9.4.5 
ECOG Performance Status ................................................................................131 
9.4.6 
Vital Signs .........................................................................................................131 
9.4.6.1 
Patient Diary..............................................................................................131 
9.4.6.2 
Pulse Oximetry ..........................................................................................132 
9.4.6.3 
 ....................................132 
9.4.7 
Pregnancy Test ..................................................................................................132 
9.4.8 
Concomitant Medications and Procedures ........................................................133 
9.4.9 
AEs ....................................................................................................................133 
9.4.10 
Enrollment .........................................................................................................133 
9.4.11 
Cardiac Monitoring ...........................................................................................133 
9.4.11.1 Safety 12-Lead ECGs and LVEF ..............................................................133 
9.4.11.2 Triplicate ECGs (With PK Sampling) ......................................................134 
9.4.12 
Clinical Laboratory Evaluations ........................................................................134 
9.4.12.1 Clinical Chemistry, Hematology, Tumor Markers, Coagulation, and 
Thyroid Function .......................................................................................135 
9.4.13 
Disease Assessment ...........................................................................................136 
9.4.13.1 RECIST v1.1 and Treatment Beyond Progression ...................................136 
9.4.14 
Biomarker, Pharmacodynamics, and PK Samples ............................................137 
9.4.14.1 Primary Specimen Collection ...................................................................137 
9.4.14.2 Tumor Biopsies .........................................................................................139 
9.4.15 
PK Measurements ..............................................................................................140 
9.4.16 
Biomarker and Pharmacodynamic Measurements ............................................140 
9.4.16.1 
 ..............................................140 
9.4.16.2 
 ....................................................140 
9.4.16.3 
 .............................................................................141 
9.4.16.4 
 ...................................................141 
9.4.16.5 
 ................................................................................141 
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9.4.16.6 
 ...........................................................141 
9.4.16.7 
 .................................................141 
9.4.16.8 
 ...........................................................141 
9.4.17 
DNA Analyses ...................................................................................................141 
9.4.18 
Immunogenicity Sample Collection ..................................................................142 
9.4.19 
Collection, Storage, and Future Use of Biological Samples From Clinical 
Trial Subjects .....................................................................................................142 
9.4.20 
 ...........................................................142 
9.4.20.1 
 .....................................................142 
9.4.20.2 
 ..........................143 
9.4.20.3 
 
 ................................................................................................143 
9.4.20.4 
 ....................................................................143 
9.5 
Documentation of Patient Screen Failures .................................................................144 
9.6 
Completion of Study Treatment (EOT for Individual Patients), 90-Day Safety 
Check, and Crossover Option ....................................................................................144 
9.7 
Discontinuation of Treatment With Study Drug and Patient Replacement ...............145 
9.8 
Posttreatment Follow-up Assessments ......................................................................146 
9.9 
Completion of Study (for Individual Patients)...........................................................146 
9.10 
Withdrawal of Patients From Study/Early Termination or EOS ...............................146 
9.11 
Study Compliance ......................................................................................................147 
10.0 
AES ..................................................................................................................................147 
10.1 
Definitions..................................................................................................................147 
10.1.1 
Pretreatment Event Definition ...........................................................................147 
10.1.2 
AE Definition ....................................................................................................147 
10.1.3 
SAE Definition ..................................................................................................148 
10.1.4 
Special Situation Report Definition ...................................................................148 
10.2 
Procedures for Recording and Reporting AEs and SAEs ..........................................149 
10.2.1 
Recording and Reporting AEs and SAEs Related to AxMPs ...........................150 
10.3 
Monitoring of AEs and Period of Observation ..........................................................150 
10.4 
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events ........151 
10.5 
Procedures for Reporting Product Complaints or SSRs ............................................151 
10.6 
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities .........152 
11.0 
STUDY-SPECIFIC COMMITTEES ...............................................................................152 
11.1 
Independent Data Monitoring Committee .................................................................152 
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12.0 
DATA HANDLING AND RECORDKEEPING ............................................................152 
12.1 
eCRFs .........................................................................................................................152 
12.2 
Record Retention .......................................................................................................153 
13.0 
STATISTICAL METHODS ............................................................................................154 
13.1 
Statistical and Analytical Plans ..................................................................................154 
13.1.1 
Analysis Sets .....................................................................................................154 
13.1.2 
Analysis of Demographics and Other Baseline Characteristics ........................155 
13.1.3 
Efficacy Analysis ...............................................................................................155 
13.1.4 
PK Analysis .......................................................................................................156 
13.1.4.1 PK Noncompartmental Analysis ...............................................................156 
13.1.4.2 PK Sampling Intended for Population PK Analysis .................................156 
13.1.5 
Immunogenicity Analysis ..................................................................................156 
13.1.6 
Pharmacodynamic Analysis ..............................................................................157 
13.1.7 
PK/Pharmacodynamic Analysis ........................................................................157 
13.1.8 
PK/QTc Analysis ...............................................................................................157 
13.1.9 
Safety ECG Analysis .........................................................................................157 
13.1.10 Safety Analysis ..................................................................................................157 
13.1.11 
 ..............................................................158 
13.1.12 
 ....................................................................................................159 
13.1.12.1 
 .................................................159 
13.1.12.2 
 ...................................159 
13.2 
Interim Analysis and Criteria for Early Termination .................................................159 
13.3 
Determination of Sample Size ...................................................................................159 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE ...............................................161 
14.1 
Study-Site Monitoring Visits .....................................................................................161 
14.2 
Protocol Deviations ....................................................................................................161 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections ................................161 
15.0 
ETHICAL ASPECTS OF THE STUDY .........................................................................162 
15.1 
IRB and/or IEC Approval ..........................................................................................162 
15.2 
Patient Information, Informed Consent, and Patient Authorization ..........................163 
15.3 
Patient Confidentiality ...............................................................................................164 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy ................................165 
15.4.1 
Publication .........................................................................................................165 
15.4.2 
Clinical Trial Registration .................................................................................165 
15.4.3 
Clinical Trial Results Disclosure .......................................................................166 
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15.5 
Insurance and Compensation for Injury .....................................................................166 
16.0 
REFERENCES ................................................................................................................167 
 
LIST OF IN-TEXT TABLES 
Table 4.a 
 .................................53 
Table 6.a 
Primary and Secondary Endpoints for Disclosures ...............................................90 
Table 8.a 
 .......................................102 
Table 8.b 
Guidelines for TAK-500 Dose Modification and/or Discontinuation for 
Nonhematologic Toxicity ....................................................................................109 
Table 8.c 
Guidelines for TAK-500 Dose Modification and/or Discontinuation for 
Hematologic Toxicity ..........................................................................................113 
Table 8.d 
NCCN Guidelines v1.2021*: Management of CAR T-Cell–Related Toxicities .120 
Table 8.e 
Pulmonary Toxicity Clinical Management Recommendations ...........................123 
Table 8.f 
TAK-500 Drug Product Excipients .....................................................................127 
Table 9.a 
Clinical Chemistry, Hematology, Tumor Markers, Coagulation, and Thyroid 
Function Tests ......................................................................................................135 
Table 9.b 
 ..............................................................................138 
 
LIST OF IN-TEXT FIGURES 
Figure 6.a 
Overview of Study Design – Dose Escalation (Phase 1) .......................................78 
Figure 6.b 
Schematic of Study Design – Dose Expansion (Phase 2) ......................................82 
 
LIST OF APPENDICES 
Appendix A 
SOEs ....................................................................................................................175 
Appendix B 
Responsibilities of the Investigator ......................................................................212 
Appendix C 
Investigator Consent to Use of Personal Information ..........................................214 
Appendix D 
Clinical Inhibitors of OATP1B1 and OATP1B3 .................................................215 
Appendix E 
Potential Risks of TAK-676.................................................................................216 
Appendix F 
BOIN Design .......................................................................................................219 
Appendix G 
ECOG Scale for Performance Status ...................................................................224 
Appendix H 
Cockcroft-Gault Equation ....................................................................................225 
Appendix I 
RECIST v1.1 ........................................................................................................226 
Appendix J 
 ................................................................................228 
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Appendix K 
 ..................................................................................232 
Appendix L 
 ................................................................................233 
Appendix M 
 ....................................................................................234 
Appendix N 
Protocol History ...................................................................................................235 
 
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2.0 
STUDY SUMMARY 
Name of Sponsor(s): Takeda Development Center 
Americas, Inc. 
Compound: TAK-500 
Title of Protocol: An Open-label, Dose Escalation and 
Expansion, Phase 1/2 Study to Evaluate the Safety, 
Tolerability, Pharmacokinetics, Pharmacodynamics, and 
Preliminary Antitumor Activity of TAK-500, a Novel 
Stimulator of Interferon Genes Agonist, as a Single 
Agent and in Combination With Pembrolizumab in Adult 
Patients With Select Locally Advanced or Metastatic 
Solid Tumors 
EU Clinical Trial No.: 2023-505374-15 
Study Number: TAK-500-1001 
Phase: 1/2 
Study Design: 
TAK-500-1001 is a phase 1/2, open-label, dose escalation and expansion study designed to determine the safety, 
tolerability, antitumor activity, pharmacokinetics (PK), pharmacodynamics, and preliminary antitumor activity of 
TAK-500, a novel Stimulator of Interferon Genes (STING) agonist, as a single agent (SA) and in combination 
with pembrolizumab. This information will be used to determine the pharmacologically active dose (PAD) range 
and the dose for further development of TAK-500 as an SA and in combination with pembrolizumab. The study 
will proceed in 2 main sections: (1) a phased dose escalation of each treatment arm (TAK-500 as an SA and in 
combination with pembrolizumab) and (2) the evaluation of TAK-500 in combination with pembrolizumab in 
single tumor type expansion cohorts, with possible exploration of once every 3 weeks (Q3W) versus once every 
2 weeks (Q2W) administration of TAK-500. Additional expansion cohorts in the same or other select tumor 
types may be warranted based on safety, pharmacodynamics, and clinical activity. Approximately 313 patients in 
total will be enrolled in this study. In the dose escalation phase (phase 1), approximately 82 patients will be 
enrolled with the following 9 types of locally advanced or metastatic solid tumors: gastroesophageal (esophageal, 
gastroesophageal junction, and gastric) adenocarcinoma, pancreatic adenocarcinoma, hepatocellular carcinoma 
(HCC), nonsquamous non–small cell lung cancer (NSCLC), squamous-cell carcinoma of the head and neck 
(SCCHN), mesothelioma, triple-negative breast cancer (TNBC), renal clear cell carcinoma (RCC), and 
nasopharyngeal carcinoma (NPC). In the dose expansion phase (phase 2), approximately 231 patients will be 
enrolled with the following 3 types of locally advanced or metastatic solid tumors: nonsquamous NSCLC, 
pancreatic adenocarcinoma, and RCC. 
TAK-500 SA Dose Escalation:  
The proposed explorable dose range of TAK-500 is from 4 to 480 μg/kg (4, 8, 16, 24, 40, 80, 160, 240, 360, and 
480 μg/kg) administered Q3W in a 21-day cycle. Q2W administration of TAK-500 in a 42-day cycle may also be 
explored once the PAD range has been established. See Figure 6.a for an overview of phase 1 dose escalation 
design. 
All patients will be hospitalized for 24 (±4) hours (after the first 2 doses of TAK-500 (Cycle [C]1 Day [D]1 and 
C2D1 for Q3W TAK-500; C1D1 and C1D15 for Q2W TAK-500). Regardless of the treatment cycle, if a 
Grade ≥2 cytokine release syndrome (CRS) or infusion-related reaction occurs during or after administration of 
study drug, hospitalization is required for 24 (±4) hours after the end of the next 2 TAK-500 infusions. For 
patients without evidence of Grade ≥2 CRS after 2 consecutive doses of TAK-500, subsequent administrations of 
TAK-500 may be performed in the outpatient setting with monitoring in clinic for at least 6 hours after the end of 
infusion (EOI). Patients who do not experience an infusion-related reaction or Grade ≥2 CRS after 4 consecutive 
administrations of TAK-500 may have their subsequent postinfusion in-clinic monitoring reduced to 1 hour. 
Patient evaluation including a complete set of vital signs is required before discharge home from either the 
hospital or clinic.  
SA dose escalation/de-escalation will continue until full determination of the PAD range. PAD determination is 
based on observation of peripheral pharmacodynamic activity, including, but not limited to peripheral biomarkers 
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evaluating both 
. Although clinical activity is not necessary to 
confirm PAD, observation of a partial response (PR) or complete response (CR) is sufficient to declare PAD 
regardless of other translational data. To confirm the minimum PAD, 2 dose levels (DLs) must each meet PAD 
criteria, and, consequently, the minimum PAD and PAD +1 DLs may be confirmed simultaneously. In the 
circumstance where a radiographic response (PR or CR) is observed at a given dose level, that dose level may be 
declared as meeting PAD requirements without waiting for confirmation of PAD in a subsequent dose level. 
Once PAD is confirmed, additional patients (approximately 3 to 6 additional patients per DL) may be enrolled at 
the minimum PAD and PAD +1 DLs in order to establish a more robust statistical basis for comparison of 
pharmacodynamic biomarkers across the TAK-500 SA DLs. Additional patients may be added to other DLs 
above the minimum PAD as required to identify the DL with optimal pharmacodynamic activity and inform 
determination of the dose for further development. Backfill cohorts may or may not be enriched for specific 
tumor type(s) selected from those included in dose escalation. 
TAK-500 SA dose escalation may continue past minimum PAD and PAD +1 DLs as dictated by the Bayesian 
Optimal Interval (BOIN) design until either (1) the SA maximum tolerated dose (MTD) is determined, (2) 
peripheral pharmacodynamic biomarkers demonstrate a marked decrease in 
 
 in comparison to prior DLs, or (3) the maximum planned DL of 480 μg/kg is completed. 
In the SA arm, approximately 52 patients will be enrolled to achieve about 46 dose-limiting toxicity (DLT) 
evaluable patients. 
TAK-500 in Combination With Pembrolizumab Dose Escalation:  
While the potential explorable dose range of TAK-500 in combination with pembrolizumab is also from 4 to 
480 μg/kg, by default the combination arm will begin at a TAK-500 DL of 80 µg/kg, triggered upon safety 
clearance of the 80 µg/kg TAK-500 SA DL. If it is determined during the conduct of the SA dose escalation that 
the TAK-500 SA minimum PAD is ≤40 µg/kg, the combination TAK-500 plus pembrolizumab dose escalation 
will begin at a dose no higher than the TAK-500 SA minimum PAD DL. The determination to initiate the 
combination dose escalation arm will be based on the accumulated safety and pharmacodynamic data from all 
TAK-500 SA cohorts available at that time. The combination dose escalation may begin at a DL of TAK-500 
that is below the TAK-500 SA PAD if this is determined to be necessary from the evaluation of safety and 
toxicity data. 
Each combination DL will enroll at least 3 patients initially. A cohort size different from 3 is permissible 
thereafter. There will be at least a 24-hour dosing delay between the first patient of any new combination DL and 
subsequent patients enrolled at the same DL. The dose escalation/de-escalation decisions will follow the same 
BOIN design as the TAK-500 SA arm. If a DL of TAK-500 SA is considered to be too toxic in the SA arm, it 
and any higher DLs will be excluded from the explorable dose range of the combination arm. 
Pembrolizumab will be administered at the fixed DL of 200 mg Q3W, to be administered on the same day as 
TAK-500 on a Q3W schedule in a 21-day cycle, or if Q2W dosing of TAK-500 is explored, pembrolizumab will 
be administered on Days 1 and 22 in a 42-day cycle.  
As with the TAK-500 SA arm, dose escalation/de-escalation for the combination arm will continue until 
determination of its minimum PAD and PAD +1 DL. Once the minimum PAD is confirmed in the combination 
arm, additional patients (approximately 3 to 6 additional patients per DL) may be enrolled to both the minimum 
PAD and PAD +1 DLs to establish a more robust statistical basis for comparison across DLs. Additional patients 
may be added to other DLs above the minimum PAD as required to identify the DL with optimal 
pharmacodynamic activity and inform determination of the dose for further development. Backfill cohorts may 
or may not be enriched for specific tumor type(s) selected from those included in dose escalation. The criteria for 
the determination of minimum PAD and PAD +1 DLs are the same for both the SA and combination arms. 
In the combination arm, the number of patients will depend on the starting DL. Assuming the starting DL is 
80 μg/kg, about 30 patients will be enrolled to achieve a maximum of 27 DLT-evaluable patients.  
Determination of PAD: 
Determination of the PAD dose range for TAK-500 will be used to inform decision-making regarding selection 
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of the starting dose for the combination with pembrolizumab dose escalation and for dose selection for both the 
SA and combination dose expansion cohorts. PAD for TAK-500 is defined as any dose at which there is 
evidence of TAK-500–mediated pharmacodynamic effects and may include, but is not limited to: 
– 
Evidence of 
 activation in peripheral blood. 
– 
Evidence of 
 in peripheral blood. 
OR 
– 
Clinical evidence of antitumor activity (eg, PR or CR) as determined by Response Evaluation Criteria in 
Solid Tumors (RECIST) Version (v)1.1. 
To enhance and refine PAD and dose selection for expansion cohorts, additional peripheral and tumoral 
pharmacodynamic biomarkers will be assessed. Peripheral pharmacodynamic biomarkers may 
 
 
.  
The relationship between TAK-500, total antibody, and/or deconjugated TAK-676 exposure and 
pharmacodynamic response (
 
) will be explored on an ongoing basis as PK and pharmacodynamic data become available to understand 
the PK-pharmacodynamic relationship of TAK-500 and to help in estimation of the PAD range.  
BOIN Dose Escalation: 
Except for the initial 2 TAK-500 SA 1 + 2 + 3 accelerated titration cohorts, dose escalation of TAK-500 in both 
the SA and combination arms will follow the BOIN design to inform dose escalation decisions and potential 
MTD estimation. Each DL of TAK 500 following the BOIN dose escalation will enroll at least 3 patients 
initially. A cohort size different from 3 is permissible thereafter per the escalation/de-escalation guidelines. There 
will be a 24-hour dosing delay between the first patient of any new DL and subsequent patients enrolled at the 
same DL. The target toxicity rate is ϕ = 0.3. To guide dose escalation decisions, if the observed DLT rate at the 
current dose is ≤0.236, the next cohort of patients will be treated at the next higher DL; if it is ≥0.358, the next 
cohort of patients will be treated at the next lower DL; if it is within 0.236 and 0.358, additional patients will be 
enrolled in this DL. For the purpose of overdose control, dose j and higher levels will be eliminated from further 
examination if Pr(pj>0.3 | data) >0.95, where pj is the true DLT rate of DL j. If the lowest dose is eliminated, the 
dose escalation will be stopped for safety. Dose escalation will continue until either: (1) the maximum sample 
size is reached, or (2) the number of patients treated at the current DL reaches 9 and the recommendation is to 
retain at the current DL.  
In the SA dose escalation, after the BOIN escalation starts, the maximum number of DLT evaluable patients to 
be enrolled is 42 (40 rounded up to the nearest multiple of 3). In the combination escalation, the maximum 
number of DLT-evaluable patients to be enrolled depends on the starting DL. In principle, we plan an average of 
about 5 patients per DL from the starting DL to 480 µg/kg. For example, if the starting DL is 80 µg/kg, the 
maximum number of DLT-evaluable patients to be enrolled is 27 (25 rounded up to the nearest multiple of 3). 
Isotonic regression will be used on the cumulative DLT rate for each DL to determine the MTD, defined as the 
highest TAK-500 dose as an SA or in combination with pembrolizumab that does not result in unacceptable 
toxicity. Note that dose escalation cohorts treated with a specific premedication regimen will be analyzed 
separately from cohorts treated without premedication or with other premedication regimens. 
Intrapatient Dose Escalation: 
Intrapatient dose escalation will not be permitted as part of the DLT-evaluable dose escalation set, but patients 
treated at TAK-500 SA DLs below minimum PAD will be allowed to escalate to minimum PAD once the 
minimum PAD DL has been confirmed and cleared from a safety perspective. 
For patients to be eligible for intrapatient dose escalation, they must continue on study without interruption and 
without evidence of progressive disease by imaging or clinical deterioration. 
TAK-500 Dose Expansion and Randomized Dose Comparison  
In addition to TAK-500 SA and TAK-500 plus pembrolizumab combination dose escalation, the preliminary 
antitumor activity along with the safety, tolerability, PK, and PD of TAK-500 will be further evaluated in single-
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indication expansion cohorts. Dose expansion may proceed with both TAK-500 SA and TAK-500 with 
pembrolizumab and include the opportunity to simultaneously explore 2 dose levels of TAK-500 (recommended 
dose for expansion [RDE] 1 and RDE 2) to provide additional data for identification of the dose for further 
development. See Figure 6.b for an overview of phase 2 dose expansion design. 
As noted above, dose escalation in both the SA and pembrolizumab combination arms will proceed beyond 
identification of PAD, until either (1) the respective MTD is determined, (2) peripheral pharmacodynamic 
biomarkers demonstrate a marked decrease in 
 in comparison to prior 
DLs, or (3) the maximum planned DL of 480 μg/kg is completed. Once complete, the totality of data from dose 
escalation will be utilized to identify the RDE(s) and dosing schedule of TAK-500 (Q2W and/or Q3W, both in a 
42-day cycle) for single-indication dose expansion cohorts. The RDE(s) of TAK-500 may be the same as the 
MTD or may be below the MTD if the totality of data (safety and tolerability, PK and PD, and clinical antitumor 
activity) suggest a lower dose is favorable. Additionally, the RDE(s) for dose expansion may or may not be 
different for the TAK-500 SA versus the TAK-500 plus pembrolizumab combination expansion cohorts. For all 
combination TAK-500 plus pembrolizumab cohorts, pembrolizumab administration will remain constant at 
200 mg intravenous (IV) Q3W in a 42-day cycle. 
To accommodate the possible comparison between the Q3W and Q2W schedules, all expansion cohorts will be 
administered in a 42-day cycle. Any Q2W DL evaluated in dose expansion must be at or below a Q2W DL 
previously shown to be tolerated in dose escalation. 
Expansion Cohort Tumor Type Selection:  
Selection of tumor types and line of therapy for single-indication dose expansion cohorts was based primarily on 
scientific rationale for targeting with TAK-500, including 
 
. High unmet 
clinical need and clinical tractability were also considered. Based on this analysis, 3 tumor types were prioritized 
for initial dose expansion cohorts: nonsquamous NSCLC, pancreatic adenocarcinoma, and RCC. These 
cohorts may begin simultaneously, or one or two indications may be prioritized over the other(s). Other single 
indication expansion cohorts may be explored instead of, or in addition to, these indications, if anti-tumor 
activity is seen during dose escalation in a given tumor.  
Dose Expansion in Nonsquamous NSCLC 
The preliminary antitumor activity, safety, tolerability, PK, and PD of TAK-500 SA and/or in combination with 
pembrolizumab will be evaluated in treatment-refractory nonsquamous NSCLC patients without driver mutations 
in both the second-line (2L) and third-line (3L) settings. 
Combination TAK-500 With Pembrolizumab Dose Expansion With Randomized Dose Comparison 
in 2L NSCLC 
Enrollment in 2L NSCLC cohorts will include patients with treatment-refractory nonsquamous NSCLC (without 
targetable driver mutations) with recurrent locally advanced or metastatic disease that has previously progressed 
while on or following 1 prior line of therapy. Patients must have had disease progression while on or following at 
least 6 weeks of 1 prior anti-PD-(L)1 therapy in the recurrent locally advanced or metastatic setting or must have 
had disease progression/recurrence within 6 months of the completion of anti-PD-(L)1 therapy if administered in 
the adjuvant/neoadjuvant setting. Anti-PD-(L)1 therapy may have been given in combination with an anti-
CTLA4 antibody or chemotherapy (eg, carboplatin and pemetrexed). Patients are eligible to enroll regardless of 
PD-L1 status. 
The combination TAK-500 plus pembrolizumab dose expansion in 2L NSCLC will proceed as outlined below 
with concurrent start of early randomized dose comparison.  
– 
Expansion in 2L NSCLC will proceed simultaneously at 2 separate DLs of TAK-500 following a 2:1 
randomized approach, to RDE 1 and RDE 2, respectively. The 2 DLs will be chosen such that adequate 
dose/response and exposure/response analyses can be performed to support the selection of the dose for 
further development. RDE 1 and RDE 2 selection will be made on the totality of data, including safety, 
antitumor activity, PK, and pharmacodynamic analysis, with both doses having a positive benefit-risk 
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ratio for further study at the time of selection. Neither RDE 1 nor RDE 2 will be higher than the highest 
dose level assessed in the dose escalation phase or the MTD, whichever is lower. 
– 
Approximately 59 patients will enroll in this cohort, with up to 39 patients randomized to RDE 1 (to 
achieve an approximate total of 35 response-evaluable patients, assuming a 10% drop-out rate) and up 
to 20 patients randomized to RDE 2 (to achieve an approximate total of 18 response-evaluable patients 
assuming a 10% drop-out rate). A futility analysis will be performed based on overall response rate 
(ORR) at the time when there are 21 response-evaluable patients in RDE 1 and each of these 21 patients 
has experienced at least 1 of the following: (1) shown a clinical response (cPR or cCR), (2) had at least 
2 posttreatment response assessments, or (3) had documented PD or death. If a partial response or 
complete response is initially observed at the second posttreatment response assessment, a third 
posttreatment response assessment will be performed to confirm the response before the patient may be 
included in the futility analysis. If there are ≥5 responders among the first 21 response-evaluable 
patients treated at RDE 1, then the futility analysis is successful, and the enrollment will continue to 35 
response-evaluable patients. Enrollment may or may not pause while the response assessments needed 
for the futility analysis are pending.  
– 
If RDE 1 enrollment is terminated due to failing futility at the stage 1 analysis or fails to meet the 
number of responses needed for proof of concept at final analysis, additional patients may be enrolled to 
RDE 2 in a nonrandomized manner to include 21 response-evaluable patients. A futility analysis will 
then be performed based on ORR as described for RDE 1. If there are ≥5 responders among the first 21 
response-evaluable patients treated at RDE 2, then the enrollment will continue to 35 response-
evaluable patients. Otherwise, the cohort will be terminated for futility. Enrollment may or may not 
pause while the response assessments needed for the futility analysis are pending. 
TAK-500 SA Dose Expansion With Randomized Dose Comparison in 3L NSCLC 
Enrollment in 3L NSCLC cohorts will include patients with treatment-refractory nonsquamous NSCLC (without 
targetable driver mutations) with recurrent locally advanced or metastatic disease that has previously progressed 
while on or following 2 prior lines of therapy. Patients must have had disease progression while on or following 
at least 6 weeks of 1 prior anti-PD-(L)1 therapy in the recurrent locally advanced or metastatic setting or must 
have had disease progression/recurrence within 6 months of the completion of anti-PD-(L)1 therapy if 
administered in the adjuvant/neoadjuvant setting. Anti-PD-(L)1 therapy may have been given in combination 
with an anti-CTLA4 antibody or chemotherapy (eg, carboplatin and pemetrexed). Patients must have had disease 
progression while on or after 1 or 2 lines of chemotherapy in the recurrent locally advanced or metastatic setting. 
If the anti-PD-(L)1 therapy is given in combination with chemotherapy, the patient must have progressed on an 
additional line of chemotherapy. Patients are eligible to enroll regardless of PD-L1 status.  
– 
Expansion in 3L NSCLC will proceed simultaneously at two separate dose levels of TAK-500 following 
a 1:1 randomized approach, to RDE 1 and RDE 2, respectively. The 2 dose levels will be chosen such 
that adequate dose/response and exposure/response analyses can be performed to support the selection 
of the dose for further development. RDE 1 and RDE 2 selection will be made on the totality of data, 
including safety, antitumor activity, PK and pharmacodynamic analysis, with both doses having a 
positive benefit-risk ratio for further study at the time of selection. Neither RDE 1 nor RDE 2 will be 
higher than the highest dose level assessed in the dose escalation phase or the MTD, whichever is lower.  
– 
The 3L nonsquamous NSCLC expansion cohorts will be based on a single-stage design.  
– 
Approximately 48 patients will enroll in this cohort, with 24 patients randomized to RDE 1 and RDE 2 
each (to achieve an approximate total of 21 response-evaluable patients assuming a 10% drop-out rate in 
each dose level). 
TAK-500 SA and in Combination With Pembrolizumab Dose Expansion in 2L Pancreatic 
Adenocarcinoma 
The preliminary antitumor activity, safety, tolerability, PK, and pharmacodynamics of TAK-500 SA or in 
combination with pembrolizumab will be evaluated in treatment-refractory pancreatic adenocarcinoma with 1 
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prior line of therapy.  
Enrollment in the 2L pancreatic adenocarcinoma expansion will include patients with treatment-refractory 
pancreatic adenocarcinoma with recurrent locally advanced or metastatic disease that has previously progressed 
while on or following 1 prior line of therapy. Patient must have had disease progression while on or following 1 
prior line of fluorouracil or gemcitabine-based chemotherapy (eg, FOLFIRINOX, FOLFOX, FOLFIRI, 
gemcitabine/nab-paclitaxel) in the metastatic/recurrent locally advanced setting. Prior chemotherapy in the 
neoadjuvant/adjuvant setting does not qualify unless the patient had progression of disease within 6 months of 
completion of neoadjuvant/adjuvant chemotherapy. Patients cannot have had prior exposure to anti-PD-(L)1 
therapy. Patients are eligible to enroll regardless of PD-(L)1 status. Patients with MSI-H/dMMR disease are not 
eligible. 
– 
Expansion in 2L pancreatic adenocarcinoma will randomize TAK-500 SA and TAK-500 in combination 
with pembrolizumab. Both arms will include TAK-500 at the TAK-500 RDE 1 identified during 
combination TAK-500 plus pembrolizumab dose escalation, unless the RDE 1 for the combination is 
below the PAD established during the TAK-500 SA dose escalation. In this instance, the RDE 1 for 
TAK-500 SA would be utilized for the corresponding arm.  
– 
The 2L pancreatic adenocarcinoma expansion cohorts will be based on Simon’s 2-stage design with 
ORR as an endpoint and separate futility analyses for the TAK-500 SA and TAK-500 combination 
cohorts.  
– 
Approximately 45 patients will be enrolled in each arm to achieve an approximate total of 40 response-
evaluable patients, assuming a 10% drop-out rate per cohort. A futility analysis will be performed at the 
time when there are 25 response-evaluable patients. The same futility criteria will be applied for each 
arm. If there are ≥4 responders among the first 25 response-evaluable patients, then the futility analysis 
is successful, and the enrollment will continue to 40 response-evaluable patients in the respective 
cohort. Otherwise, the cohort will be terminated for futility. Enrollment may or may not pause while the 
response assessments needed for the futility analysis are pending.  
Combination TAK-500 With Pembrolizumab Dose Expansion in 3L RCC 
The preliminary antitumor activity, safety, tolerability, PK, and PD of TAK-500 in combination with 
pembrolizumab will be evaluated in treatment-refractory RCC with 2 prior lines of therapy. 
Enrollment in the 3L RCC cohort will include patients with treatment-refractory RCC with recurrent locally 
advanced or metastatic disease that has previously progressed while on or following at least 2 prior lines of 
therapy. Patients must have had disease progression while on or following at least 6 weeks of 1 prior anti-PD-
(L)1 therapy in the recurrent locally advanced or metastatic setting or must have had disease 
progression/recurrence within 6 months of the completion of anti-PD-(L)1 therapy if administered in the 
adjuvant/neoadjuvant setting. Anti-PD-(L)1 therapy may have been given with or without an anti-CTLA4 
antibody and/or an anti-vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) (eg, 
cabozantinib). Patients must have had prior therapy with 1 or 2 lines of VEGFR TKIs in the metastatic/recurrent 
locally advanced setting. If anti-PD-(L)1 therapy was given in combination with a VEGFR TKI, the patient must 
have had progressive disease on an additional line of therapy (eg, VEGFR TKI or VEGFR TKI-containing 
combination). Patients are eligible to enroll regardless of PD-L1 status. 
– 
Expansion in 3L RCC will occur at the RDE 1 of TAK-500 identified during combination TAK-500 
plus pembrolizumab dose escalation. 
– 
The 3L RCC expansion cohorts will be based on a single-stage design, with enrollment of up to 
approximately 34 patients to achieve a total of 30 response-evaluable patients (assuming a 10% drop-out 
rate).  
Study Conduct: 
TAK-500 administration will occur in facilities with readily available resuscitation equipment, diagnostic 
equipment and supportive care/medications, such as oxygen, antihistamines, acetaminophen, corticosteroids, 
epinephrine, anti–interleukin (IL)-6 agents, and bronchodilators.  
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All patients will be hospitalized for 24 (±4) hours (after the first 2 doses of TAK-500 (C1D1 and C2D1 for Q3W 
TAK-500; C1D1 and C1D15 for Q2W TAK-500). Regardless of the treatment cycle, if a Grade ≥2 CRS or 
infusion-related reaction occurs during or after administration of study drug, hospitalization is required for 24 
(±4) hours after the end of the next 2 TAK-500 infusions. For patients without evidence of Grade ≥2 CRS after 2 
consecutive doses of TAK-500, subsequent administrations of TAK-500 may be performed in the outpatient 
setting with monitoring in clinic for at least 6 hours after the EOI. Patients who do not experience an infusion-
related reaction or Grade ≥2 CRS after 4 consecutive administrations of TAK-500 may have their subsequent 
postinfusion in-clinic monitoring reduced to 1 hour. Patient evaluation including assessment of a complete set of 
vital signs is required before discharge home from either the hospital or clinic. 
During hospitalization, vital signs will be taken no less frequently than every 6 hours until discharge. Before 
discharge from the hospital and/or clinic, a symptom-directed physical examination including assessment of the 
respiratory and neurologic systems and complete set of vital signs will be required. 
At the time of discharge from the hospital, patients and their caregivers will be educated about potential 
symptoms including but not limited to fever, edema, lightheadedness, dizziness, tachypnea, dyspnea, confusion, 
aphasia, dysphasia, ataxia, or tremor. If patients develop any of these symptoms, they should be instructed to 
immediately contact the principal investigator, who may recommend immediate medical attention. 
The required hospitalization for the phase 2 dose expansion portion of the study may be decreased or removed if 
an adequate safety profile is demonstrated in the dose escalation phase of the study for the dose level(s) and 
premedication regimen(s) included in expansion. If hospitalization is not required for dose expansion, outpatient 
monitoring will be required as outlined in the above paragraph.  
Adverse events (AEs) will be assessed, and laboratory values, vital signs, electrocardiograms (ECGs), and other 
clinically indicated examinations will be obtained to evaluate the safety and tolerability of the study treatment. 
Toxicity will be evaluated according to National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE) v5.0. A DLT will be defined as any of the treatment-emergent adverse events (TEAEs) 
described in the Section 8.2 that occurs during the first 21 days on study (C1D21) and are considered by the 
investigator to be at least possibly related to TAK-500 alone or in combination with pembrolizumab. TEAEs 
meeting DLT definitions occurring in later cycles will be considered in the determination of the dose for further 
development of TAK 500. Radiological evaluations (computed tomographic scan and/or magnetic resonance 
imaging as clinically indicated) will be used to assess the status of the patient’s underlying disease. 
 
 tumor tissue or a minimum number of unstained slides of the tumor tissue will 
be collected, if available, from all enrolled patients to assess baseline features such as 
 
 
. All patients with a safely 
accessible lesion enrolling at or above DLs where TAK-500 has previously shown pharmacodynamic activity 
will have mandatory tumor biopsies performed per the schedules of events (SOEs). 
Once peripheral evidence of TAK-500 pharmacodynamic modulation of the 
 
 is observed in the blood and/or clinical response (PR or CR) is observed in at least 1 patient, subsequent 
paired biopsies will be required for all patients with a safely accessible lesion and in whom a fresh tumor biopsy 
would not place the patient at an unjustifiable risk, in the opinion of the investigator.  
Serial blood samples will be collected for circulating biomarkers (
 
). An evaluation of disease response will be performed using the RECIST v1.1 (as 
determined by the investigator) and per the SOEs. Clinically validated peripheral tumor markers will also be 
collected for patients with appropriate tumor types (AFP, CA 27.29, and CA 19-9). Serial blood samples for 
determination of the serum concentration of TAK-500 and related metabolites to understand TAK-500 
metabolism and excretion mechanisms will be obtained at prespecified time points as described in the SOEs. 
In the setting of disease progression while on TAK-500 SA, crossover to the TAK-500 with pembrolizumab 
combination arm is optional and at the discretion of the investigator, in agreement with the sponsor. Patients in 
the TAK-500 SA treatment arm with objective evidence of PD may cross over to the TAK-500 and 
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pembrolizumab combination arm into the last DL that is or was accruing patients. Crossover treatment should 
begin within 28 days of documented disease progression and after the EOT visit; additionally, it is recommended 
that the first pembrolizumab dose be administered on a regularly scheduled TAK-500 dosing day. Crossover 
patients will proceed to a second EOT visit within 30 days of last TAK-500 dose after the combination treatment.  
The sponsor may stop or halt enrollment or treatment of ongoing patients, depending on the nature and severity 
of a safety-related event. A final decision to terminate the study or a protocol amendment will be made only after 
a full review of the safety data by the sponsor’s Safety Management Team and the investigators. 
Primary Objectives: 
The primary objective for phase 1 dose escalation phase is: 
• 
To determine the safety and tolerability of TAK-500 administered as an SA and in combination with 
pembrolizumab in patients with select locally advanced or metastatic solid tumors, including 
gastroesophageal (esophageal, gastroesophageal junction, and gastric) adenocarcinoma, pancreatic 
adenocarcinoma, HCC, nonsquamous NSCLC, SCCHN, mesothelioma, TNBC, RCC, and NPC. 
The primary objectives for phase 2 dose expansion phase are: 
• 
To assess the preliminary antitumor activity of TAK-500 in combination with pembrolizumab in 2L 
recurrent locally advanced or metastatic nonsquamous NSCLC. 
• 
To assess the preliminary antitumor activity of TAK-500 SA in 3L recurrent locally advanced or metastatic 
nonsquamous NSCLC. 
• 
To assess the preliminary antitumor activity of TAK-500 in combination with pembrolizumab in 2L 
recurrent locally advanced or metastatic pancreatic adenocarcinoma. 
• 
To assess the preliminary antitumor activity of TAK-500 SA in 2L recurrent locally advanced or metastatic 
pancreatic adenocarcinoma. 
• 
To assess the preliminary antitumor activity of TAK-500 in combination with pembrolizumab in 3L 
recurrent locally advanced or metastatic RCC. 
• 
To determine the dose for further development of TAK-500 administered as SA and in combination with 
pembrolizumab. 
Secondary Objectives: 
The secondary objectives for the phase 1 dose escalation are: 
• 
To determine the RDEs of TAK-500 administered as SA and in combination with pembrolizumab. 
• 
To characterize the single and multiple dose PK of TAK-500 administered as SA and in combination with 
pembrolizumab. 
• 
To evaluate the preliminary antitumor activity of TAK-500 administered as SA and in combination with 
pembrolizumab. 
• 
To evaluate the dose-responsive impact on T-cell infiltration into the tumor following TAK-500 
administered as SA and in combination with pembrolizumab. 
• 
To determine the immunogenicity of TAK-500. 
The secondary objectives for the phase 2 dose expansion are: 
• 
To determine the safety and tolerability of TAK-500 as SA and in combination with pembrolizumab in 
patients with previously treated recurrent locally advanced or metastatic nonsquamous NSCLC. 
• 
To determine the safety and tolerability of TAK-500 as SA and in combination with pembrolizumab in 
patients with previously treated recurrent locally advanced or metastatic pancreatic adenocarcinoma. 
• 
To determine the safety and tolerability of TAK-500 combination with pembrolizumab in patients with 
previously treated recurrent locally advanced or metastatic RCC. 
Patient Population: Male or female patients aged 18 years or older, at the time of consent, with the following 
pathologically confirmed (cytological diagnosis is adequate) locally advanced or metastatic solid tumors, whose 
disease has progressed on or are intolerant to all standard therapy: gastroesophageal (esophageal, 
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gastroesophageal junction, and gastric) adenocarcinoma, pancreatic adenocarcinoma, HCC, nonsquamous 
NSCLC, SCCHN, mesothelioma, TNBC, RCC, and NPC. Patients who are intolerant to all standard therapies are 
those who have developed clinical or laboratory abnormalities that prevent continued drug administration as 
evaluated by the principal investigator at the time of screening. 
Number of Patients: 
Approximately 313 patients in total will be enrolled in this study.  
For the phase 1 dose escalation phase, in the SA arm, about 52 patients 
will be enrolled to achieve about 46 DLT-evaluable patients (includes 
cohorts treated with and without premedication). In the combination 
arm, the number of patients will depend on the starting DL. Assuming 
the combination starting DL is 80 μg/kg, about 30 patients will be 
enrolled to achieve a maximum of 27 DLT-evaluable patients. 
Additional patients may be enrolled for the evaluation of Q2W 
administration of TAK-500 if this schedule is explored in the dose 
escalation phase.  
For the phase 2 dose expansion phase, assuming only 1 TAK-500 
administration schedule is expanded, approximately 231 patients will be 
enrolled to achieve a total of approximately 205 response-evaluable 
patients. This number may increase if more than 1 TAK-500 
administration schedule is explored. 
Number of Sites:  
Approximately 70 sites globally. 
Dose level(s): 
Pembrolizumab: 200 mg Q3W 
TAK-500: 4 to 480 μg/kg (4, 8, 16, 24, 40, 80, 160, 240, 360, and 
480 μg/kg) Q3W or Q2W 
Route of Administration: 
Pembrolizumab: IV infusion over 
30 minutes 
TAK-500: IV infusion as described in 
pharmacy manual 
Duration of Treatment: up to 1 year. Patients with demonstrated 
clinical benefit will continue treatment beyond this point if approved by 
the sponsor. 
Period of Evaluation:  
It is anticipated that this study will 
last for approximately 50 months. 
Potential Risks and Benefits 
TAK-500 is currently being evaluated in an ongoing first-in-human (FIH) phase 1/2 study in patients with solid 
tumors (Study TAK-500-1001) and the clinical benefits and risks have not been fully determined. Possible risks, 
based on nonclinical studies, include CRS, pulmonary edema, and toxicities for immune/lymphoid system, liver, 
and cardiovascular system.  
Pembrolizumab prescribing information (USPI dated November 2020) includes warnings for severe and fatal 
immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic hematopoietic stem 
cell transplantation (both before and after treatment), and embryo-fetal toxicities. In addition, the most common 
AEs after pembrolizumab administered as an SA, as reported in ≥20% of patients, were fatigue, musculoskeletal 
pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and 
abdominal pain. The most current prescribing information for pembrolizumab should be consulted. 
 
 
 
 
 
 
 
 
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. 
Inclusion Criteria: 
1. Male or female patients aged 18 years or older. 
2. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1. 
3. Patients with the following pathologically confirmed (cytological diagnosis is adequate) locally advanced or 
metastatic solid tumors, whose disease has progressed on or are intolerant to standard therapy: 
a. 
For dose escalation with TAK-500 SA and combination TAK-500 with pembrolizumab: 
• 
Patients with the following pathologically confirmed (cytological diagnosis is adequate) 
locally advanced or metastatic solid tumors, whose disease has progressed on or are 
intolerant to all standard therapy: gastroesophageal (esophageal, gastroesophageal 
junction, and gastric) adenocarcinoma, pancreatic adenocarcinoma, HCC, nonsquamous 
NSCLC, SCCHN, mesothelioma, TNBC, RCC, and NPC. Patients who are intolerant to all 
standard therapies are those who have developed clinical or laboratory abnormalities that 
prevent continued drug administration as evaluated by the principal investigator at the time 
of screening. 
b. For dose expansion in 2L nonsquamous NSCLC (TAK-500 plus pembrolizumab): 
• 
Patients with pathologically confirmed (cytological diagnosis is adequate) locally 
advanced or metastatic nonsquamous NSCLC.  
• 
Patients may not have a known targetable driver mutation, rearrangement or amplification 
(eg, EGFR, ALK, MET, ROS1, BRAF, KRASG12C, etc.). 
• 
Must have had disease progression while on or following 1 prior line of therapy:  
1. Disease progression while on or following at least 6 weeks of 1 prior anti-PD-(L)1 
therapy in the recurrent locally advanced or metastatic setting. 
OR 
Disease progression/recurrence within 6 months of the completion of anti-PD-(L)1 
therapy if administered in the adjuvant/neoadjuvant setting.  
Prior anti-PD-(L)1 therapy may have been given with or without an anti-CTLA4 
antibody and/or chemotherapy (eg, carboplatin and pemetrexed). 
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• 
Patients are eligible regardless of PD-L1 status. 
c. 
For dose expansion in 3L nonsquamous NSCLC (TAK-500 SA): 
• 
Patients with pathologically confirmed (cytological diagnosis is adequate) locally 
advanced or metastatic nonsquamous NSCLC.  
• 
Patients may not have a known targetable driver mutation, rearrangement or amplification 
(eg, EGFR, ALK, MET, ROS1, BRAF, KRASG12C). 
• 
Must have had disease progression while on or following 2 prior lines of therapy:  
1. Disease progression while on or following at least 6 weeks of 1 prior anti-PD-(L)1 
therapy in the recurrent locally advanced or metastatic setting. 
OR 
Disease progression/recurrence within 6 months of the completion of anti-PD-(L)1 
therapy if administered in the adjuvant/neoadjuvant setting.  
Prior anti-PD-(L)1 therapy may have been given with or without an anti-CTLA4 
antibody and/or chemotherapy (eg, carboplatin and pemetrexed). 
2. Patients must have had disease progression while on or after ≥1, but not > 2, lines 
of chemotherapy in the recurrent locally advanced or metastatic setting. If the anti-
PD-(L)1 therapy is given in combination with chemotherapy, patient must have 
progressed on an additional line of chemotherapy. 
• 
Patients are eligible regardless of PD-L1 status. 
d. For dose expansion in 2L pancreatic adenocarcinoma (TAK-500 SA and TAK-500 plus 
pembrolizumab): 
• 
Patients with pathologically confirmed (cytological diagnosis is adequate) locally 
advanced or metastatic pancreatic adenocarcinoma.  
• 
Must have had disease progression while on or following 1 prior line of therapy:  
1. One prior line of fluorouracil- or gemcitabine-based chemotherapy (eg, 
FOLFIRINOX, FOLFOX, FOLFIRI, gemcitabine/nab-paclitaxel) in the 
metastatic/recurrent locally advanced setting. 
Prior chemotherapy in the neoadjuvant/adjuvant setting does not qualify unless the 
patient had progression of disease within 6 months of completion of 
neoadjuvant/adjuvant chemotherapy. 
• 
Must not have had prior exposure to anti-PD-(L)1 therapy.  
• 
Patients with MSI-H/dMMR disease are not eligible.  
• 
Patients are eligible regardless of PD-L1 status. 
e. 
For dose expansion in 3L RCC (TAK-500 plus pembrolizumab): 
• 
Patients with pathologically confirmed (cytological diagnosis is adequate) locally 
advanced or metastatic RCC.  
• 
Must have had disease progression while on or following 2 prior lines of therapy:  
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1. Disease progression while on or following at least 6 weeks of 1 prior anti-PD-(L)1 
therapy in the recurrent locally advanced or metastatic setting. 
OR 
Disease progression/recurrence within 6 months of the completion of anti-PD-(L)1 
therapy if administered in the adjuvant/neoadjuvant setting.  
Prior anti-PD-(L)1 therapy may have been given with or without an anti-CTLA4 
antibody and/or an anti-VEGFR TKI.  
2. Patients must have had prior therapy with 1 or 2 lines of VEGFR TKIs in the 
metastatic/recurrent locally advanced setting. If anti-PD-(L)1 therapy was given in 
combination with a VEGFR TKI, the patient must have had progressive disease on 
an additional line of therapy (eg, VEGFR TKI or VEGFR TKI-containing 
combination). 
• 
Patients are eligible regardless of PD-L1 status. 
4. Patients must have at least 1 RECIST v1.1 measurable lesion. Lesions in previously irradiated areas (or other 
local therapy) should not be selected as measurable/target lesions unless there has been demonstrated 
radiographic progression in that lesion. RECIST v1.1 target lesions must include at least 1 lesion that was 
not previously irradiated.  
5. Once a DL is reached where evidence of TAK-500 stimulation of the 
 
has been observed in the blood and/or a clinical response (PR or CR) measured in at least 1 patient, 
subsequent patients treated at the equivalent or higher DL will be required to have 2 biopsies (at screening 
and on treatment), assuming the potential morbidity of the procedures is deemed acceptable by the treating 
physician. 
6. Adequate bone marrow, renal, and hepatic functions, as determined by the following laboratory parameters: 
• 
Absolute neutrophil count (ANC) ≥1000/μL, platelet count ≥75,000/μL, and hemoglobin ≥8.0 g/dL 
without growth factor support for ANC or transfusion support for platelets within 14 days before the 
first study treatment dose. 
• 
Total bilirubin ≤1.5 times the institutional upper limit of normal (ULN). For patients with Gilbert’s 
disease or HCC, ≤3 mg/dL. 
• 
Serum alanine aminotransferase and aspartate aminotransferase ≤3.0 × ULN or ≤5.0 × ULN with liver 
metastases or HCC. 
• 
Albumin ≥3.0 g/dL. 
• 
Calculated creatinine clearance using the Cockcroft-Gault formula ≥30 mL/minute. 
7. For patients with HCC only: Child-Pugh score less than or equal to 7 (Child-Pugh A or B7). 
8. Left ventricular ejection fraction >50%, as measured by echocardiogram or multiple-gated acquisition scan 
within 4 weeks before receiving the first dose of study drug. 
9. Clinically significant toxic effects of previous therapy have recovered to Grade 1 (per NCI CTCAE v5.0) or 
baseline, except for alopecia, Grade 2 peripheral neuropathy, and/or autoimmune endocrinopathies with 
stable endocrine replacement therapy. 
10. Patients previously treated with fully human/humanized antineoplastic monoclonal antibodies must not have 
received treatment with such antibodies for at least 4 weeks or the time period equal to the dosing interval, 
whichever is shorter. No washout period is required for prior treatment with pembrolizumab or other anti– 
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programmed cell death protein 1 (PD-1) antibodies, although the first study dose of these drugs must not 
occur at an interval less than standard of care (ie, 3 weeks for 200 mg of IV pembrolizumab). 
11. Suitable venous access for the collection of study-required blood sampling, including PK and 
pharmacodynamic blood samples. 
12. Female patients must be: 
• 
Postmenopausal (natural amenorrhea and not due to other medical reasons) for at least 1 year before the 
screening visit, or 
• 
Surgically sterile, or 
• 
If they are of childbearing potential, agree to practice 2 effective methods of contraception at the same 
time, from the time of signing the informed consent through 180 days after the last dose of study 
drug(s), or 
• 
Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the 
patient. 
– 
Note: Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods), 
withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of 
contraception. 
13. Male patients, even if surgically sterilized (ie, status postvasectomy), must: 
• 
Agree to practice effective barrier contraception during the entire study treatment period and through 
180 days 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. 
– 
Note: Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods), 
withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of 
contraception. 
14. Voluntary written consent must be given before performance of any study-related procedure not part of 
standard medical care, with the understanding that consent may be withdrawn by the patient at any time 
without prejudice to future medical care. 
15. Patients must be eligible for treatment with pembrolizumab at the dose(s) and schedule(s) recommended in 
the label/prescribing information, where applicable. 
Exclusion Criteria: 
1. History of any of the following ≤6 months before first dose of study drug(s): congestive heart failure New 
York Heart Association Grade III or IV, unstable angina, myocardial infarction, persistent hypertension 
≥160/100 mm Hg despite optimal medical therapy, ongoing cardiac arrhythmias of Grade >2 (including 
atrial flutter/fibrillation or intermittent ventricular tachycardia), other ongoing serious cardiac conditions (eg, 
Grade 3 pericardial effusion or Grade 3 restrictive cardiomyopathy), or symptomatic cerebrovascular events. 
Chronic, stable atrial fibrillation on stable anticoagulation therapy, including low molecular-weight heparin, 
is allowed. 
2. QT interval with Fridericia correction method >450 milliseconds (men) or >475 milliseconds (women) on a 
12-lead ECG during the screening period. 
3. Grade ≥2 hypotension (ie, hypotension for which nonurgent intervention is required) at screening or during 
C1D1 predose assessment. 
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4. Oxygen saturation <92% on room air at screening or during C1D1 predose assessment. 
5. Patients treated with other STING agonists/antagonists, Toll-like receptor agonists, or CCR2 
agonist/antagonist within the past 6 months. 
6. Exclusion criterion removed 
7. Exclusion criterion removed 
8. Active diagnosis of pneumonitis, interstitial lung disease, severe chronic obstructive pulmonary disease, 
idiopathic pulmonary fibrosis, other restrictive lung diseases, acute pulmonary embolism, or Grade ≥2 
pleural effusion not controlled by tap or requiring indwelling catheters. 
9. History of brain metastasis or leptomeningeal disease unless: 
• 
Brain metastases are stable on cranial imaging (ie, ≥4 weeks) following prior surgery, whole-brain 
radiation, or stereotactic radiosurgery, and 
• 
Off corticosteroids for brain metastases. 
10. Grade ≥2 fever of malignant origin. 
11. Systemic infection requiring IV antibiotic therapy or other serious infection within 14 days before the first 
dose of study drug. Patients are specifically excluded if they have active, severe infections such as 
tuberculosis (screening per local practice and epidemiology), sepsis, cytomegalovirus (including 
cytomegalovirus colitis), listeriosis, and opportunistic infections (including Clostridium difficile) until the 
infections are controlled. 
12. Patients with either/both of: 
• 
Uncontrolled, known or suspected, autoimmune disease. Patients with vitiligo, type I diabetes mellitus, 
residual hypothyroidism due to an autoimmune condition only requiring hormone replacement, psoriasis 
not requiring systemic treatment, or conditions not expected to recur in the absence of an external 
trigger are permitted to enroll. 
• 
A diagnosis of an identified congenital or acquired immunodeficiency (eg, common variable 
immunodeficiency, uncontrolled HIV infection, organ transplantation). 
13. Chronic, active hepatitis (eg, patients with known hepatitis B surface antigen seropositive and/or detectable 
hepatitis C virus [HCV] RNA). 
• 
Note: Patients who have positive hepatitis B core antibody can be enrolled but must have an 
undetectable serum hepatitis B virus-DNA. Patients who have positive HCV antibody must have an 
undetectable HCV-RNA serum level. 
14. History of hepatic encephalopathy. 
15. Prior or current clinically significant ascites, as measured by physical examination, that requires active 
paracentesis for control. 
16. Any pre-existing condition or illness, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding that give reasonable suspicion of a disease or condition that would contraindicate the use 
of an investigational drug or that would limit compliance with study requirements or compromise ability to 
provide written informed consent. 
17. Treatment with any investigational products or other anticancer therapy (including chemotherapy, targeted 
agents, and immunotherapy), within 14 days or 5 half-lives, whichever is shorter, before C1D1 of study 
drug(s). 
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18. Concurrent chemotherapy, immunotherapy (except for pembrolizumab in the combination arm), biologic, or 
hormonal therapy (except for adjuvant endocrine therapy for a history of breast cancer). Concurrent use of 
hormones for noncancer-related conditions is acceptable (except for corticosteroid hormones). 
19. Radiation therapy within 14 days (42 days for radiation to the lungs) and/or systemic treatment with 
radionuclides within 42 days before C1D1 of study drug(s). Patients with clinically relevant ongoing 
pulmonary complications from prior radiation therapy are not eligible. 
20. Use of systemic corticosteroids or other immunosuppressive therapy, concurrently or within 7 days of C1D1 
of study drug(s), with the following exceptions: 
• 
Topical, intranasal, inhaled, ocular, intra-articular, and/or other nonsystemic corticosteroids.  
• 
Physiological doses of replacement steroid therapy (eg, for adrenal insufficiency), not to exceed the 
equivalent of 10 mg prednisone daily. 
21. Use of medications that are known clinical organic anion transporting polypeptide (OATP)1B1 and/or 
OATP1B3 inhibitors, concurrently or within 14 days of C1D1 of study drug(s). 
22. Receipt of live attenuated vaccine (eg, tuberculosis Bacillus Calmette-Guerin vaccine, oral polio vaccine, 
measles, rotavirus, yellow fever) within 28 days of C1D1 of study drug(s). Nonlive, approved vaccines are 
allowed (eg, coronavirus disease 2019 [COVID-19] vaccine). 
Note: COVID-19 vaccination should not be given ±3 days of systemic study treatments. 
23. Recipients of allogeneic or autologous stem cell transplantation or organ transplantation.  
24. Female patients who are lactating or have a positive serum/urine pregnancy test during the screening period 
or a positive serum/urine pregnancy test on Day 1 before first dose of study drug. 
Note: Female patients who are lactating will be eligible if they choose to discontinue breastfeeding before 
the first dose of study drug. 
Additional criteria specific for patients in TAK-500 and pembrolizumab combination arm only: 
25. Contraindication to the administration of pembrolizumab or prior intolerance to pembrolizumab or other 
anti–PD-1 or anti–programmed cell death protein ligand 1 antibody.  
26. History of intolerance to any component of the study treatment agents or known serious or severe 
hypersensitivity reaction to any of the study drugs or their excipients. (Pembrolizumab is formulated with 
L-histidine, polysorbate 80, and sucrose.) 
Main Criteria for Evaluation and Analyses: 
The primary endpoints for the phase 1 dose escalation are: 
• 
Frequency and severity of TEAEs. 
• 
Number of patients with DLTs. 
• 
Number/percentage of patients with 1 or more treatment-emergent serious adverse event (SAE). 
• 
Number/percentage of patients with 1 or more TEAE leading to dose modifications and treatment 
discontinuations. 
The primary endpoints for the phase 2 dose expansion are: 
• 
Response assessments made by the investigator per RECIST v1.1 for both the SA and combination 
treatment. Preliminary antitumor activity will be described as follows: 
– 
ORR: cCR + cPR. 
 
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The secondary endpoints are: 
– 
PK parameters of TAK-500: 
– 
Cmax. 
– 
tmax. 
– 
Area under the serum concentration-time curve from time 0 to time t. 
– 
Area under the serum concentration-time curve from time 0 to infinity. 
– 
Terminal disposition phase half-life. 
– 
Total clearance after intravenous administration. 
– 
Volume of distribution at steady state after intravenous administration. 
• 
Intratumoral T-cell infiltration upon TAK-500 treatment. 
• 
Incidence of patients who are antidrug antibody–positive and acquired immunogenicity.  
Additional secondary endpoints for the phase 1 dose escalation only: 
• 
Response assessments made by the investigator per RECIST v1.1 for both the SA and combination 
treatment. Preliminary antitumor activity will be described as follows: 
– 
ORR: cCR + cPR. 
– 
Disease control rate (DCR): cCR + cPR + stable disease >6 weeks. 
– 
Duration of response (DOR): the time from the date of first documentation of a cPR or better to the date 
of first documentation of PD for responders (cPR or better). 
– 
Time to response (TTR): the time from the date of first dose administration to the date of first 
documented cPR or better by the investigator. 
Additional secondary endpoints for the phase 2 dose expansion only: 
• 
Response assessments made by the investigator per RECIST v1.1 for both the SA and combination 
treatment. Preliminary antitumor activity will be described as follows: 
– 
DCR: cCR + cPR + stable disease (SD) >6 weeks. 
– 
DOR: the time from the date of first documentation of a cPR or better to the date of first documentation 
of PD for responders (cPR or better). 
– 
TTR: the time from the date of first dose administration to the date of first documented cPR or better by 
the investigator. 
– 
Progression-free survival (PFS). 
– 
Overall survival (OS). 
• 
Frequency and severity of TEAEs. 
• 
Number of patients with DLTs. 
• 
Number and percentage of patients with 1 or more treatment-emergent SAE. 
• 
Number and percentage of patients with 1 or more TEAE leading to dose modifications and treatment 
discontinuations. 
Statistical Considerations: 
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 of observations, 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. 
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 Status will be summarized using a shift table. Shift tables for laboratory parameters will be 
generated for changes in NCI CTCAE grade from baseline to worst postbaseline value. Graphical displays of key 
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safety parameters, such as scatter plots of baseline vs worst postbaseline values, may be used to understand the 
TAK-500 safety profile. 
For the dose escalation phase, antitumor activity is not the primary endpoint; secondary antitumor activity 
endpoints include ORR, DCR, DOR, and TTR. In the dose expansion phase, ORR is the primary endpoint; 
secondary antitumor activity endpoints include DCR, DOR, TTR, PFS, and OS. No formal statistical tests will be 
performed for these efficacy endpoints in the study. ORR and DCR will be summarized using descriptive 
statistics with 95% CI. DOR and TTR will be analyzed using Kaplan-Meier method for response-evaluable 
analysis set. PFS and OS will be analyzed using Kaplan-Meier method for the safety analysis set in dose 
expansion cohorts only. 
Patients in the SA arm who cross over to the combination arm will be analyzed separately using all the post-
crossover data, repeating the main analyses as appropriate, to show long-term safety and antitumor activity. 
These crossover patients will still be included in the main analyses, in which their post-crossover data will be 
excluded. Patients treated with a specific premedication regimen will be analyzed separately from cohorts treated 
without premedication or with other premedication regimens. 
PK parameters will be summarized using descriptive statistics. Individual TAK-500 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.  
Sample Size Justification:  
Approximately 313 patients will be enrolled in the study, including approximately 82 in the dose escalation 
phase and approximately 231 in the dose expansion phase (assuming only 1 DL and dose schedule will be 
expanded). 
In the phase 1 dose escalation phase, approximately 52 patients will be enrolled to achieve about 46 DLT-
evaluable patients in the SA arm, and approximately 30 patients will be enrolled to achieve a maximum of 27 
DLT-evaluable patients in the combination arm (assuming a drop-out rate of 10%). In the SA arm, a maximum of 
42 DLT-evaluable patients is planned for BOIN escalation to cover 8 DLs and an additional 4 DLT-evaluable 
patients for the two 1 + 2 + 3 escalation DLs. In the combination arm, the number of patients will depend on the 
starting DL. Assuming the escalation starts at 80 μg/kg, a maximum of 27 DLT-evaluable patients will be 
enrolled. Additional patients may be enrolled for the evaluation of Q2W administration of TAK-500 if this 
schedule is explored in the dose escalation phase (in either the SA or combination arm). 
In the phase 2 dose expansion phase, each cohort’s sample size is based on Simon’s 2-stage design or an exact 
binomial one-stage design with ORR as the endpoint, a one-sided alpha equal to 0.1, and an assumed dropout 
rate of 10%. In the following cohort-specific design specifications, H0 represents the “null hypothesis,” HA 
represents the “alternative hypothesis,” RE represents “response-evaluable,” and power represents “statistical 
power.” Note that some design scenarios are dependent on the results from preceding scenarios and may or may 
not be realized. 
• 
2L NSCLC TAK-500 + pembrolizumab RDE 1 versus RDE 2 [2:1 randomization]:  
– 
Based on Simon’s 2-stage design, approximately 39 patients will be enrolled in the RDE 1 cohort, 
allowing for 35 RE patients. H0: ORR ≤ 23%, HA: ORR ≥40%, and power = 80%. The futility analysis 
will occur at 21 RE patients, where ≥5 responders are required for successfully passing futility.  
– 
Approximately 20 patients will be enrolled in the RDE 2 cohort allowing for 18 RE patients. If the 
futility analysis in RDE 1 fails, additional enrollment will be initiated to increase the RDE 2 RE sample 
size to 21 patients and Simon’s 2-stage design will be applied in the same manner as planned for RDE 1. 
Given this, the total number of RE patients for RDE 2 may be 18, 21, or 35.  
• 
3L NSCLC TAK-500 SA RDE 1 versus RDE 2 [1:1 randomization]: 
– 
Based on a single-stage exact binomial design, approximately 24 patients will be enrolled each in the 
RDE 1 cohort and the RDE 2 cohort, allowing for 21 RE patients per cohort. For each cohort, H0: ORR 
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≤ 5%, HA: ORR ≥20%, and power = 82%. The total RE sample size across the 2 cohorts will be 42 
patients.  
• 
2L pancreatic adenocarcinoma TAK-500 + pembrolizumab RDE 1 versus 2L pancreatic adenocarcinoma 
TAK-500 SA RDE 1 [1:1 randomization]: 
– 
Based on Simon’s 2-stage design, approximately 45 patients will be enrolled each in the combination 
cohort and the SA cohort, allowing for 40 RE patients per cohort. For each cohort, H0: ORR ≤ 16%, HA: 
ORR ≥30%, and power = 80%. For each cohort, a futility analysis will occur at 25 RE patients, where 
≥4 responders are required for successfully passing futility.  
• 
3L RCC TAK-500 + Pembrolizumab RDE 1:  
– 
Based on a single-stage exact binomial design, approximately 34 patients will be enrolled, allowing for 
30 RE patients. H0: ORR ≤ 8%, HA: ORR ≥25%, and power = 90%.  
 
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3.0 
STUDY REFERENCE INFORMATION 
3.1 
Study-Related Responsibilities 
The sponsor will perform all study-related activities with the exception of those identified in the 
clinical supplier list in the study manual. The identified vendors will perform specific 
study-related activities either in full or in partnership with the sponsor. 
3.2 
Principal Investigator/Coordinating Investigator 
The sponsor 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. 
3.3 
List of Abbreviations 
5-HT3 
serotonin type 3 receptor 
2L 
second-line  
3L 
third-line 
ADA 
antidrug antibody 
ADC 
antibody-drug conjugate 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
AUC 
area under the serum concentration-time curve 
AUC336 
area under the serum concentration-time curve from time 0 to 336 hours 
AUC∞ 
area under the serum concentration-time curve from time 0 to infinity 
AUCt 
area under the serum concentration-time curve from time 0 to time t 
AxMP 
auxiliary medicinal product 
BOIN 
Bayesian Optimal Interval 
BQL 
below the quantifiable limit 
cCR 
confirmed complete response 
CCR2 
cysteine-cysteine chemokine receptor type 2 
CDN 
cyclic dinucleotide 
CFR 
Code of Federal Regulations 
cGAS 
cyclic GMP-AMP (guanosine monophosphate–adenosine monophosphate) synthase 
CL 
total clearance after intravenous administration 
Cmax 
maximum observed serum concentration 
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CNS 
central nervous system 
COVID-19 
coronavirus disease 2019 
CPI 
checkpoint inhibitor 
cPR 
confirmed partial response 
CRS 
cytokine release syndrome  
CT 
computed tomographic, computed tomography 
CV 
cardiovascular 
CxDx 
Cycle x Day x 
DC 
dendritic cell 
DCR 
disease control rate 
DILI 
drug-induced liver injury 
DL 
dose level 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
DPV 
during planned visit 
EC50 
half-maximal effective concentration  
ECG 
electrocardiogram, electrocardiographic, electrocardiography 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOI 
end of infusion 
EOS 
end of study 
EOT 
end of treatment 
 
 
 
 
FDA 
Food and Drug Administration 
FIH 
first-in-human 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
GIT 
gastrointestinal tract 
GLP 
Good Laboratory Practice 
HCC 
hepatocellular carcinoma 
HCV 
hepatitis C virus 
HER2 
human epidermal growth factor receptor-2 
IC50 
50% inhibitory concentration 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
IFN 
interferon 
Ig 
immunoglobulin 
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IL 
interleukin 
IO 
immuno-oncology 
IP-10 
induced protein 10 
IRB 
institutional review board 
IV 
intravenous(ly) 
LiMT 
liver microtissue 
LVEF 
left ventricular ejection fraction 
MABEL 
minimum anticipated biological effect level 
mCCR2-TAK-676 
mouse surrogate for TAK-500 
MCP-1 
monocyte chemotactic protein-1 
MDSC 
myeloid derived suppressor cell 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare products Regulatory Agency 
MIP 
macrophage inflammatory protein 
M-MDSC 
monocytic-myeloid derived suppressor cell 
MOA 
mechanism of action 
mOS 
median overall survival 
mPFS 
median progression-free survival 
MRI 
magnetic resonance imaging 
MRSD 
maximum recommended starting dose 
MTD 
maximum tolerated dose 
MUGA 
multiple-gated acquisition scan 
NCCN 
National Comprehensive Cancer Network 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NK 
natural killer 
NOAEL 
no-observed-adverse-effect level 
NPC 
nasopharyngeal carcinoma 
NSCLC 
non–small cell lung cancer 
OATP 
organic anion transporting polypeptide 
ORR 
overall response rate 
OS 
overall survival 
PAD 
pharmacologically active dose 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PD-1 
programmed cell death protein 1 
PD-L1 
programmed cell death ligand 1 
PD-(L)1 
programmed cell death protein 1 or ligand 1 
PDAC 
pancreatic ductal adenocarcinoma  
PFS 
progression-free survival 
PK 
pharmacokinetic(s)  
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PMDA 
Pharmaceuticals and Medical Devices Agency 
POC 
proof-of-concept 
 
 
 
 
 
Q2W 
once every 2 weeks 
Q3W 
once every 3 weeks 
QTc 
corrected QT interval 
QTcF 
QT interval with Fridericia correction method 
RCC 
renal clear cell carcinoma 
RDE 
recommended dose for expansion 
RE 
response-evaluable (patient) 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RO 
receptor occupancy 
SA 
single agent 
SAE 
serious adverse event 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus-2 
SCCHN 
squamous cell carcinoma of the head and neck 
SD 
stable disease 
SITC 
Society for Immunotherapy of Cancer  
SOE 
schedule of events 
SSR 
special situation report 
STING 
Stimulator of Interferon Genes 
SUSAR 
suspected unexpected serious adverse reaction 
t1/2z 
terminal disposition phase half-life 
TAM 
tumor-associated macrophage 
TCR 
T-cell receptor 
TEAE 
treatment-emergent adverse event 
TKI 
tyrosine kinase inhibitor 
tmax 
time of first occurrence of the maximum observed serum concentration 
TME 
tumor microenvironment 
TNBC 
triple-negative breast cancer 
TNF-α 
tumor necrosis factor-alpha 
TTR 
time to response 
UK 
United Kingdom 
ULN 
upper limit of normal  
US 
United States 
v 
Version 
VEGFR 
vascular endothelial growth factor receptor 
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Vss 
volume of distribution at steady state after intravenous administration 
WHO 
World Health Organization 
 
3.4 
Corporate Identification 
Millennium 
Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda 
Pharmaceutical Company Limited 
TDC Japan 
Takeda Development Center Japan 
TDC Asia 
Takeda Development Center Asia, Pte Ltd 
TDC Europe 
Takeda Development Centre Europe Ltd 
TDC Americas 
Takeda Development Center Americas, Inc 
TDC 
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable 
Takeda 
Millennium Pharmaceuticals, Inc, TDC Japan, TDC Asia, TDC Europe and/or TDC 
Americas, as applicable 
 
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4.0 
INTRODUCTION 
4.1 
Background 
Immuno-oncology has emerged as a major driver of anticancer therapeutics in both solid tumors 
and hematologic malignancies. Clinical data from immune checkpoint inhibitors (CPIs) such as 
CTLA-4 (cytotoxic T-lymphocyte-associated antigen-4) and programmed cell death protein 1 
(PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors have changed the therapeutic 
paradigm in a growing number of indications. Overcoming T-cell inhibition in the tumor 
microenvironment (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 patients with advanced cancer are either refractory to CPIs or relapse after a 
period of tumor control, eventually succumbing to their disease. Some predictive biomarkers of 
CPI response, such as PD-L1 expression, microsatellite instability, and tumor mutational burden, 
have been clinically validated, but why some tumors are resistant or become refractory to CPIs 
remains less well-understood. 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 an 
immunosuppressive or “immune desert” phenotype (Liu et al. 2019). Accordingly, a possible 
strategy to overcome these elements of resistance is to stimulate innate immune cells 
(eg, 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 converting 
immunologically “cold” tumors into “hot” tumors in which adaptive immune responses can be 
effectively activated.  
Stimulator of Interferon Genes (STING) is a cytosolic protein critical for the induction of type I 
IFN-dependent innate immunity (Ishikawa et al. 2009) and is specifically activated in the 
presence of cyclic dinucleotides (CDNs) derived from bacteria or produced by cyclic GMP-AMP 
(guanosine monophosphate–adenosine monophosphate) synthase (cGAS) (Sun et al. 2013; Wu et 
al. 2018). Emerging evidence indicates that the cGAS-STING pathway plays an important role 
specifically in driving tumor surveillance (Corrales and Gajewski 2015). The presence of 
cytosolic DNA in tumor cells leads to cGAS-dependent production of the second messenger 
cGAMP (2′,3′-cyclic guanosine monophosphate–adenosine monophosphate), which can 
subsequently transfer to professional antigen-presenting cells in the TME. Ultimately, this leads 
to induction of type I IFNs in DCs (Marcus et al. 2018). Type I IFNs and downstream regulated 
cytokines/chemokines serve as a potent “alert” to immune cells, including T cells and NK cells 
that may prime antitumor responses. Down-regulation of cGAS via epigenetic silencing has been 
reported in some human tumors, underscoring the potential significance of STING signaling in 
immune evasion (Konno et al. 2018). Additionally, recent studies have shown that STING 
(TMEM173)-deficient mice are susceptible to immunogenic tumors that wild type mice can 
reject, consistent with earlier studies demonstrating that tumor rejection in mice is dependent on 
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IFN alpha receptor 1 expression in DCs (Diamond et al. 2011). In immune-competent mice, 
administration of STING agonists activates DCs, which in turn generate a cytotoxic CD8+ T-cell 
response. In mouse models, synthetic STING agonists have demonstrated both single-agent (SA) 
antitumor efficacy and synergistic activity in combination with CPIs, including in aggressive 
tumor models (Sivick et al. 2018). 
Cysteine-cysteine chemokine receptor type 2 (CCR2) is expressed on monocytes and other 
immune subsets of cells and is known to play an important role in the recruitment of 
monocytes/macrophages and T cells (Bakos et al. 2017). CCR2 and its ligand, chemokine CCL2, 
are elevated in certain types of advanced solid tumors and may influence survival in cancer 
patients (Lim et al. 2016). In the TME, CCR2 is most expressed in tumor-infiltrating myeloid 
cells, including tumor-associated macrophages (TAMs) and myeloid derived stromal cells. The 
presence of CCR2+ monocytic-myeloid derived suppressor cells (M-MDSCs) and TAMs 
promotes immune escape by limiting activated CD8 T-cell infiltration (Lesokhin et al. 2012), 
thereby decreasing the efficacy of immunotherapy (Kim et al. 2019). Nonclinical data and early 
clinical trial data suggest blockade of CCR2 may decrease the infiltration of myeloid derived 
suppressor cells (MDSCs) and TAMs and regulatory T cells in the TME (Flores-Toro et al. 2020; 
Lim et al. 2016; Loyher et al. 2016). 
TAK-500 is an immunostimulatory antibody-drug conjugate (ADC) consisting of 3 parts: (1) a 
genetically engineered humanized monoclonal antibody of the immunoglobulin (Ig)G1 class that 
is a potent specific antagonist of CCR2, (2) a CDN STING agonist exhibiting highly selective 
binding and activation of STING proteins from various species including mouse, rat, monkey, 
and human, and (3) a self-immolating maleimide-containing protease-cleavable peptide linker. 
The CDN agonist payload of TAK-500, referred to in this document as “conjugated TAK-676” 
or “TAK-676 payload”, is structurally based on TAK-676, a potent early clinical stage CDN 
STING agonist currently in phase 1 clinical studies. The IgG1 anti-CCR2 antibody used, referred 
to in this document as “TAK-202”, is based on TAK-202, previously evaluated in phase 1 
clinical studies.  
In recent years, there is emerging evidence showing an important role of MDSCs in tumor 
metastasis, drug resistance, and cancer immunosuppression (Hinshaw and Shevde 2019). The 
presence of CCR2+ M-MDSCs promotes immune escape by limiting activated CD8 T-cell 
infiltration, thereby decreasing the efficacy of immunotherapy (Lesokhin et al. 2012). By 
targeting both the STING pathway and CCR2, TAK-500 offers enhanced potency via improved 
pharmacokinetics (PK) and selective delivery in the preclinical models. As such, there are 
3 potential anticancer mechanisms of action associated with TAK-500: (1) activation of IFN 
response via the TAK-676 payload, (2) reprogramming of intratumoral CCR2+ myeloid cells to 
an inflammatory phenotype, and (3) blockade of TAM recruitment via blockade of CCR2. 
4.1.1 Nonclinical Background 
Detailed information regarding the nonclinical pharmacology and toxicology of TAK-500 may 
be found in the investigator’s brochure. 
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4.1.1.1 
Nonclinical Pharmacology 
TAK-500 was found to elevate the expression level of CD69 and activate CD4 and CD8 T cells 
and NK cells in a dose-dependent manner, with similar sensitivity and activation potential among 
the 3 cell populations tested. TAK-500–mediated activation of human monocyte-derived DCs 
induced the expression of all activation markers tested (CD40, CD80, CD86, and HLA-DR) in a 
concentration-dependent manner. TAK-500 and the mouse surrogate for TAK-500 
(
-TAK-676) had a comparable level of potency enhancement of 
 
 that was much improved when compared with 
TAK-676 alone. Additionally, TAK-202 and mouse 
 
. In vitro receptor occupancy 
(RO) of 
-TAK-676 in murine whole blood and TAK-500 in monkey and human whole 
blood was demonstrated on 
. Half-maximal effective concentrations (EC50s) 
of RO for TAK-500 in monkey and human blood were consistent with results of the on-cell 
binding assay of TAK-202. 
In an in vitro cytokine release assay at 24 hours, TAK-500 induced the production of 
proinflammatory cytokines in the plasma of human peripheral whole blood. In vitro incubation 
of human peripheral blood mononuclear cells with TAK-500 resulted in the dose-dependent 
induction of monocyte populations, shown by increased expression of CD80 in monocytes, as 
well as a corresponding dose-dependent increase in the percentage of CD80 positive monocytes. 
This effect was most pronounced in both the total and classical monocyte populations, with 
additional moderate activation of CD80 in the intermediate monocytes. In intermediate 
monocytes, there was modest increased expression of the activation marker CD86, as well as 
modestly increased frequencies of CD86+ cells, after treatment with TAK-500. 
In a PK study, mCCR2-TAK-676 exposure increased in a greater than dose-proportional manner 
in plasma and tumors after a single intravenous (IV) administration at 2, 10, and 50 µg/kg (based 
on TAK-676 payload) to C57BL/6 mice bearing MC38 syngeneic tumors. Deconjugated 
TAK-676 was below the quantifiable limit (BQL) in plasma, except for 1 animal at 50 µg/kg at 
6 hours postdose, but was detectable in tumor samples at 10 and 50 µg/kg, starting at 6 hours 
postdose, and increased in a less than dose-proportional manner.  
Significant activation and proliferation of immune cells within the TME, whole blood, and local 
tumor-associated lymphoid tissue were observed after administration of mCCR2-TAK-676 to 
female C57BL/6 mice bearing MC38 tumors. Significant antitumor activity was demonstrated 
after a single IV administration of mCCR2-TAK-676 to female C57BL6 mice bearing MC38 
xenografts at 5, 10, and 25 µg/kg based on TAK-676 payload. Reduced antitumor activity was 
observed when mCCR2-TAK-676 was administered 24 hours after administration of anti–mouse 
IFNAR1 antibody at 1.0 mg/mouse, suggesting that type I IFN signaling plays a key role in the 
observed antitumor activity. 
In vitro secondary pharmacology and cardiovascular (CV) liability assessments were not 
completed for TAK-500; however, these were completed for TAK-676. TAK-676 demonstrated 
no significant activity on a panel of various pharmacological targets (78 receptors, transporters, 
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ion channels, and enzymes) and no CV liabilities were identified at concentrations up to 30 μM 
on the basis of in vitro results from a human ether-à-go-go–related gene assay and a human stem 
cell cardiomyocyte calcium transient proarrhythmia assay; TAK-676 was considered to be low 
risk for CV liabilities. It is important to note that circulating levels of deconjugated TAK-676 
were low or undetectable in the TAK-500 Good Laboratory Practice (GLP)–compliant 
repeat-dose toxicity study in monkeys.  
Safety pharmacology assessments were not performed on the non-GLP repeat-dose toxicity 
study in monkeys; however, in animals that underwent unscheduled removal from study, 
minimal microscopic findings in the heart and moribund clinical observations related to the CV 
system, central nervous system (CNS), and/or respiratory system were attributed to systemic 
immune stimulation. CV, CNS, and respiratory safety pharmacology assessments were 
completed as part of the GLP-compliant repeat-dose toxicity study in monkeys. There were no 
TAK-500–related changes in qualitative electrocardiology parameters, and, in animals surviving 
to scheduled necropsy, there were no CNS or respiratory clinical observations (including 
evaluation of respiration rates) and no microscopic findings in related tissues/organs. 
Microscopic findings of minimal neutrophilic infiltrates in the heart at scheduled necropsy were 
considered associated with a systemic pro-inflammatory response. In quantitative 
electrocardiology parameters, a moderate statistically significant TAK-500 RR-derived heart rate 
compared with pretreatment and vehicle control was observed on Day 1 at 0.9 mg/kg and was 
associated with an expected inverse correlation of shortened RR and QT intervals. These 
findings were still present but of a lesser magnitude on Day 8, indicative of partial recovery, and 
were considered likely to be associated with increases in serum cytokines. In the 2 female 
animals at 0.9 mg/kg euthanized in moribund condition (see Section 4.1.1.3), clinical 
observations included decreased activity, prolonged capillary refill time, pale skin, hunched 
posture, hypothermia and/or bradycardia at the time of euthanasia, and, microscopically, 
pulmonary edema with low numbers of inflammatory cells within alveoli, a finding not noted in 
animals surviving to scheduled necropsy. Cytokine concentrations in these animals ranged from 
higher than or similar to those in animals receiving TAK-500 that survived to scheduled 
necropsy. These findings support immune-mediated effects as the primary cause of moribundity, 
with pulmonary edema contributing to the clinical decline. 
4.1.1.2 
Nonclinical PK 
In vitro catabolite identification with acidified monkey liver S9, acidified human liver S9, 
recombinant human cathepsin B, papain, and human liver lysosomes identified 2 catabolites. The 
major catabolite was identified as deconjugated TAK-676, generated through hydrolysis of the 
amide bond. C1 was a minor metabolite that was determined to be TAK-676–linker fragment 
(2-[(methylamino)methyl]benzaldehyde) and addition of C7H9N. The location of the addition of 
C7H9N and the mechanism of formation of C1 is currently unknown. 
After single IV administration of TAK-500 to monkeys, plasma exposure of total antibody and 
conjugated TAK-676 increased with increasing doses in a greater than dose-proportional manner 
between 0.1 and 0.5 mg/kg, and in a dose-proportional manner between 0.5 and 3 mg/kg. Plasma 
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exposure of deconjugated TAK-676 was not quantifiable or low across all doses, and PK 
parameters were not estimated. 
Completed as part of the GLP-compliant repeat-dose toxicity study in monkeys, toxicokinetic 
analysis after each dose on Days 1, 15, and 29 showed that the time of first occurrence of the 
maximum observed serum concentration (tmax) for both TAK-500 and conjugated TAK-676 
occurred at 0.083 hours postdose in all animals tested. The maximum observed serum 
concentration (Cmax) and the area under the serum concentration-time curve (AUC) values 
increased with increasing IV DLs of TAK-500 in a dose-proportional and greater than 
dose-proportional manner, respectively. There were no apparent sex-related differences. Repeat 
administration of TAK-500 was associated with the development of antidrug antibodies (ADAs) 
in 35 of 36 animals at 1 or more time points after Day 15, resulting in lower exposure on Day 29 
of TAK-500 and conjugated TAK-676. Deconjugated TAK-676 plasma concentrations were low 
or BQL for all dose groups and toxicokinetic parameters were not estimated. 
Nonclinical PK studies with TAK-676 demonstrated that TAK-676 is mainly eliminated as a 
parent compound through biliary and urinary excretion in rats and monkeys. The contribution of 
metabolism to TAK-676 clearance pathways is anticipated to be minimal. TAK-676 is a 
substrate for organic anion transporting polypeptide (OATP)1B1, OATP1B3, and multidrug 
resistance associated protein 2 but is not likely a substrate for P-glycoprotein and breast cancer 
resistance protein. While the OATP inhibitors may affect plasma drug levels of the TAK-676, 
the impact of OATP1B1 polymorphism on TAK-676 exposure is anticipated to be low. 
Nevertheless, as a precautionary measure, concomitant use of clinical inhibitors of OATP1B1 
and OATP1B3 should be avoided before the first dose of study drug(s) and during the study as 
detailed in Section 7.2, Section 8.6, and Appendix D. 
4.1.1.3 
Nonclinical Toxicology 
No single-dose toxicity studies have been conducted with TAK-500. 
In a non-GLP cynomolgus monkey repeat-dose toxicity study (0.3, 1, or 3 mg/kg; slow IV bolus 
Q2W for 3 doses), TAK-500 was well tolerated at 0.3 mg/kg. Although the first administration 
was well tolerated up to 3 mg/kg, repeat dosing at ≥1 mg/kg was not tolerated, resulting in early 
euthanasia (2) or death (1) out of a total of 12 animals receiving TAK-500. In the early 
euthanasia animals and in animals surviving to scheduled euthanasia, findings were primarily 
attributed to immune-mediated effects of uncertain pathophysiology, either directly related to 
TAK-500 administration and/or secondary to immunogenicity/hypersensitivity, as well as 
hepatocellular effects that included minimal, focal to multifocal hepatocellular necrosis. Repeat 
dosing was associated with a high incidence of ADA and a partial reduction in exposure at all 
doses in most animals by the third dose. Levels of deconjugated TAK-676 were low or 
undetectable after administration of TAK-500 in monkeys. 
In a GLP-compliant monkey repeat-dose toxicity study (0.1, 0.3, or 0.9 mg/kg; slow IV bolus 
Q2W for 3 doses), TAK-500 was well tolerated up to 0.3 mg/kg but resulted in early euthanasia 
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of 2 female animals due to moribundity (adverse clinical observations) at 0.9 mg/kg 
approximately 6 to 7 hours after receiving a dose (1 animal each on Days 1 and 15).  
The majority of TAK-500–related findings were present in both early euthanasia and scheduled 
euthanasia animals at ≥0.1 mg/kg and were considered attributable to direct immune-mediated 
effects of TAK-500, although secondary effects of immunogenicity and/or nonspecific 
infusion-related reactions may have contributed to the underlying pathophysiology. Additionally, 
minimal to mild pulmonary edema was uniquely observed in early euthanasia animals and was 
also considered to have contributed to the clinical decline in these animals. 
Immune-mediated findings observed at ≥0.1 mg/kg TAK-500 included a number of dose-related, 
transient clinical signs generally noted 4 to 8 hours after dosing, which consisted of vomiting 
and, at ≥0.3 mg/kg, decreased activity, hunched posture, and/or red face. Increased RR-derived 
heart rate was found after a single dose of 0.9 mg/kg in jacketed telemetry-designated animals, 
and was considered likely to be associated with increases in serum cytokines. In addition, clinical 
pathology changes consistent with an acute phase response were noted on Day 3 only. 
Microscopic findings at ≥0.1 mg/kg consisted of generally minimal neutrophilic infiltrates in the 
spleen, liver, adrenal cortex, and/or atrioventricular valves of the heart; scattered inflammatory 
foci with degeneration/necrosis in the liver, decreased cellularity or lymphoid necrosis in spleen 
and thymus; and at ≥0.3 mg/kg, minimal adrenocortical hemorrhage. Transient cytokine 
elevations consisted of increases in interleukin (IL)-1 receptor antagonist, IL-6, and tumor 
necrosis factor-alpha (TNF-α) concentrations at 6 hours postdose on Days 1, 15, and/or 29. Other 
TAK-500–related findings observed at ≥0.1 mg/kg were consistent with expected pharmacology 
and included decreases in circulating monocytes on Day 3 and increases in serum monocyte 
chemotactic protein-1 (MCP-1) and induced protein 10 (IP-10) concentrations peaking at 6 hours 
postdose on Days 1, 15, and 29. Additional hepatocellular effects consisted of increases in serum 
chemistry liver parameters (on Day 3 only), and there were minor organ weight changes that 
lacked histologic correlates in the spleen, liver, adrenal gland, and thymus at scheduled necropsy. 
All findings were completely reversible after a 2-week recovery period (Day 43), with the 
exception of histologic findings in the adrenal gland and spleen, which partially recovered. In 
addition to effects on exposure, the ADA that developed in all animals administered TAK-500 
likely correlated with attenuation of clinical pathology findings and findings attributable to 
pharmacology by Day 29 (effects on monocytes and MCP-1 and IP-10 concentrations). 
Nonclinical toxicity studies with TAK-676 included in vitro studies for genotoxicity, cytokine 
release in human whole blood, and in vivo studies in Sprague Dawley rats and cynomolgus 
monkeys. TAK-676 was nongenotoxic in in vitro genotoxicity tests and stimulated cytokine 
release in human whole blood. In the rat GLP toxicity study, the predominant finding was 
single-cell necrosis across multiple tissues and organs that was consistent with death of 
lymphocytes and leukocytes, while in the monkey GLP study pulmonary edema was considered 
the dose-limiting toxicity (DLT). The amount of circulating deconjugated TAK-676 was found 
to be low to BQL after administering repeat doses of TAK-500; the toxicities noted in rats and 
monkeys after IV administration of TAK-676 are unlikely to translate to that after TAK-500 
administration. Tissue cross reactivity studies with a surrogate for the TAK-202 antibody portion 
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of TAK-500 in monkey and human tissues showed similar 
 immunoreactivity patterns 
between species that were consistent with published data. TAK-202 was safe and well tolerated 
in cynomolgus monkeys for up to 6 months of dosing after single and once weekly IV or 
subcutaneous administration and the no-observed-adverse-effect level (NOAEL) was the high 
dose (100 mg/kg) in each study (Katschke et al. 2001; Millennium Pharmaceuticals Inc 2003; 
Ruth et al. 2001). 
4.1.2 Clinical Background 
This study (Study TAK-500-1001) is the first-in-human (FIH) dose escalation and expansion 
study with TAK-500, administered both as an SA and in combination with pembrolizumab in 
patients with select locally advanced or metastatic solid tumors. Potential safety concerns and/or 
biological activity may be extrapolated from preclinical efficacy and GLP toxicology studies 
with TAK-500, as detailed in Sections 4.1.1.1 and 4.1.1.3. There are no prior reports of clinical 
trials involving STING ADCs and only limited reports from clinical trials involving nontargeted 
STING agonists for comparison. 
The dose escalation of TAK-500 in combination with pembrolizumab is included as part of the 
FIH study based on the mechanism of action (MOA) of TAK-500 and evidence of synergistic 
antitumor activity when STING agonists are administered in combination with anti–PD-1 
antibodies in nonclinical models. This synergy is currently being explored in phase 1 studies 
with TAK-676. Pertinent clinical experience with the components of TAK-500 (TAK-202 and 
TAK-676) are summarized in Sections 4.1.2.1 and 4.1.2.2. 
4.1.2.1 
TAK-202 
TAK-202 doses administered in prior clinical studies of TAK-202 are 20 to 300 times higher 
than the maximum planned dose in the dose escalation phase of TAK-500-1001. Consequently, it 
is unlikely that the adverse events (AEs) previously reported for TAK-202 will be reproduced in 
the current study. Regardless, for informational purposes, the pertinent clinical findings from 
prior TAK-202 studies are summarized below. 
Final data from 5 completed clinical studies are the primary basis for characterizing the safety, 
PK, and pharmacodynamic profile of TAK-202 (also known as MLN1202) in humans. These 
5 clinical studies included 2 phase 1 studies (Studies MLN120202-046 and C06002) and 3 phase 
2 studies (Studies C06004, MLN120203-055, and MLN120204-063), in which 187 subjects were 
treated with TAK-202, including 60 healthy subjects, 23 patients with rheumatic arthritis, 
54 patients with risk factors for atherosclerotic CV disease, and 50 patients with 
relapsing-remitting multiple sclerosis. Subjects in these trials received single IV doses ranging 
from 0.1 to 10.0 mg/kg, or subcutaneous doses of 75 or 150 mg. 
In addition, 9 patients with advanced melanoma received TAK-202 in combination with 
nivolumab. Two patients discontinued the study due to AEs, 1 patient withdrew consent, and 
6 patients discontinued treatment due to progressive disease (PD). There were no on-study deaths 
reported and only 1 patient reported treatment-related AE of Grade 3 (alanine aminotransferase 
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[ALT] increase). Fatigue and nausea were the most commonly reported treatment-related AEs. 
No convincing antitumor effect was seen in this study. 
The nonclinical and clinical experience to date suggests that TAK-202 is well tolerated and 
suitable for further investigation in human clinical studies. 
4.1.2.2 
TAK-676 
As of 27 February 2022, 50 patients are enrolled and TAK-676 has been evaluated in a total of 
49 patients across 2 ongoing studies:  
1. Study TAK-676-1002, a phase 1 FIH study evaluating TAK-676 as an SA and in 
combination with pembrolizumab in adult patients with advanced or metastatic solid tumors. 
2. Study TAK-676-1003, a phase 1 dose escalation study to evaluate the safety, tolerability, and 
preliminary antitumor activity of TAK-676 and pembrolizumab following radiation therapy 
in the treatment of non–small cell lung cancer (NSCLC), triple-negative breast cancer 
(TNBC), or squamous-cell carcinoma of the head and neck (SCCHN) patients who have 
progressed on CPIs. 
Study TAK-676-1002 
As of 27 February 2022, a total of 44 patients had received at least 1 dose of TAK-676: 
25 patients had received at least 1 dose of TAK-676 administered as an SA and 19 patients had 
received at least 1 dose of TAK-676 in combination with pembrolizumab. As an SA, TAK-676 
has been administered to patients at the following doses: 0.1 mg (1 patient), 0.2 mg (3 patients), 
0.4 mg (3 patients), 0.8 mg (4 patients), 1.2 mg (4 patients), 1.6 mg (3 patients), 2.0 mg 
(3 patients), and 2.5 mg (4 patients). TAK-676 has been administered in combination with 
pembrolizumab to patients at the following doses: 0.2 mg (3 patients), 0.4 mg (4 patients), 
0.8 mg (5 patients), 1.2 mg (4 patients), and 1.6 mg (3 patients). As of 27 February 2022, 
23 (92.0%) patients receiving TAK-676 SA experienced treatment-emergent adverse events 
(TEAEs). The most common TEAEs were fatigue (8 [32.0%] patients), nausea (6 [24.0%] 
patients), and vomiting (5 [20.0%] patients). Thirteen (52.0%) patients experienced TEAEs 
considered related to study drug by the investigators. Six (24.0%) patients receiving TAK-676 
SA experienced Grade 3 or higher TEAEs. TEAEs that led to study drug discontinuation in 
3 (12.0%) patients in the TAK-676 SA arm were the following: Grade 4 small intestinal 
obstruction (considered not related to TAK-676), Grade 2 infusion-related reaction (considered 
related to TAK-676), and Grade 3 alanine aminotransferase increased (considered related to 
TAK-676). Seven (28.0%) patients experienced treatment-emergent SAEs; SAEs included 
dyspnea, pulmonary embolism, pneumonia, small intestinal obstruction (resulting in death in 
1 patient), abdominal pain, pancreatitis, hypercalcemia, cancer pain, and confusional state. None 
of these SAEs were considered to be related to study drug. There was 1 death, considered 
unrelated to study drug, due to a Grade 5 small bowel obstruction. There were no DLTs among 
patients receiving TAK-676 SA. 
As of 27 February 2022, 19 (100%) patients receiving TAK-676 in combination with 
pembrolizumab experienced TEAEs. The most common TEAEs were cough (7 [36.8%] 
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patients), fatigue (6 [31.6%] patients), diarrhea (6 [31.6%] patients), and nausea (5 [26.3%] 
patients). Sixteen (84.2%) patients experienced TEAEs considered related to study drug by the 
investigators. Nine (47.4%) patients receiving TAK-676 in combination with pembrolizumab 
experienced Grade 3 or higher TEAEs. TEAEs that led to study drug discontinuation in 
2 patients (10.5%) in TAK-676 in combination with pembrolizumab arm were Grade 3 
clostridium difficile colitis and Grade 4 sepsis; both were considered as not related to TAK-676. 
Eight (42.1%) patients experienced treatment-emergent SAEs; SAEs included acute respiratory 
failure (resulting in death), pleural effusion, sepsis (resulting in death), coronavirus disease 2019 
(COVID-19), Clostridium difficile colitis, conduction disorder, electrocardiogram T wave 
abnormality, and bone pain. One patient experienced electrocardiogram T wave abnormality of 
Grade 2 severity that was considered related to TAK-676 administration though the patient 
remained asymptomatic throughout the course of treatment. There were no DLTs among patients 
receiving TAK-676 in combination with pembrolizumab.  
To date, the preliminary PK of TAK-676 has been evaluated in Study TAK-676-1002 (n = 37). 
Across the dose range of 0.1 to 1.6 mg, the PK of TAK-676 was linear with an approximately 
dose-proportional increase in area under the concentration-time curve from time 0 to infinity 
(AUC∞) and biphasic decline in plasma concentrations. Following repeated administration, the 
PK of TAK-676 remained similar suggesting little to no accumulation after repeated 
administration. Similar Cmax, AUC∞ and terminal elimination half-life for TAK-676 were 
observed when TAK-676 was administered as an SA or in combination with pembrolizumab. 
Evaluation of the TAK-676–mediated 
 is observed in peripheral 
blood collected from 1.2 mg SA and 0.8 mg combination treated patients. This data is consistent 
with TAK-676 target engagement 
 regulated by 
 
. 
There has been 1 confirmed partial response (cPR) as of the data cutoff date in a 
-year-old 
 patient with metastatic sebaceous carcinoma dosed at 0.8 mg TAK-676 + 
pembrolizumab. The patient was αPD-(L)1–naïve and received 4 prior lines of therapy. 
 has 
tolerated the study treatment well and remains on study in Cycle 9 as of the data cutoff.  
Study TAK-676-1003 
As of 27 February 2022, 6 patients are enrolled in the study and received radiation therapy and 
5 patients have received at least 1 dose of TAK-676 in combination with pembrolizumab 
following radiation therapy. TAK-676 has been administered to patients at 0.2 mg (4 patients) 
and 0.4 mg (2 patients). 
Four (66.7%) patients receiving TAK-676 experienced TEAEs. The most common TEAEs were 
cough and esophagitis (2 [33.3%] patients each). None of the patients experienced TEAEs 
related to TAK-676. None of TEAEs were of Grade 3 or higher severity. There were no DLTs or 
treatment-emergent SAEs reported. 
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4.1.2.3 
TAK-500 
Currently, TAK-500 is being investigated only in this ongoing FIH study (TAK-500-1001) as an 
SA and in combination with pembrolizumab for the treatment of adult patients with select 
advanced solid tumors. 
As of data cutoff date of 14 September 2022, 7 patients have received TAK-500 administered as 
an SA at doses of 8 μg/kg (3 patients) and 16 μg/kg (4 patients). 
 
.  
Table 4.a 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 4.a 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 4.a 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
. 
 
4.2 
Rationale for the Proposed Study 
TAK-500-1001 is an FIH, dose escalation and dose expansion study with TAK-500 administered 
as an SA and in combination with pembrolizumab. 
In the TAK-500 SA dose escalation arm, the study will enroll adult patients with select 
histologically or cytologically confirmed select locally advanced or metastatic solid tumors 
(gastroesophageal [esophageal, gastroesophageal junction, and gastric] adenocarcinoma, 
pancreatic adenocarcinoma, hepatocellular carcinoma [HCC], nonsquamous NSCLC, SCCHN, 
mesothelioma, TNBC, RCC, and NPC) with no available standard therapeutic options, either due 
to disease progression or intolerance to therapy. Patients who are intolerant to therapy are those 
who have developed clinical or laboratory abnormalities that prevent continued drug 
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administration as evaluated by the principal investigator at the time of screening. This patient 
population represents a traditional cohort for an FIH phase 1 study, where the investigational 
agent lacks a well-defined, biomarker-driven, or clearly defined tumor-specific target. As such, a 
broad locally advanced or metastatic solid tumor patient population presents the most favorable 
balance between patient risk and benefit. 
The TAK-500 and pembrolizumab combination dose escalation arm will enroll the same 
population as the TAK-500 SA dose escalation arm. Pembrolizumab is a humanized monoclonal 
IgG4 kappa PD-1–blocking antibody approved for use by the United States (US) Food and Drug 
Administration (FDA) in numerous tumor types. 
In dose expansion, both TAK-500 SA and TAK-500 in combination with pembrolizumab will be 
explored in nonsquamous NSCLC, RCC, and pancreatic adenocarcinoma. These tumor types 
were selected for expansion due to the immune contexture of their tumor microenvironment and 
unmet clinical need. For detailed rationale behind indication selection for TAK-500 dose 
expansion cohorts, see Sections 4.2.1.2, 4.2.1.4, and 4.2.1.8. 
There is nonclinical evidence that TAK-500 has antitumor synergy when combined with an anti–
PD-1 antibody. However, it is also established that CPIs have SA antitumor activity across a 
wide range of tumor types, even when these antitumor effects were not sufficiently robust to 
support a label indication. As such, the patient selection for this combination approach will 
include the following 2 broad groups:  
• Patients who are refractory to or have developed resistance to prior anti–PD-1/anti–PD-L1 
therapy. This set includes patients with malignancies that have relapsed on or are refractory 
to anti–PD-1/anti–PD-L1 therapy and will include, but is not limited to, patients with the 
following tumor types: locally advanced or metastatic gastroesophageal adenocarcinoma, 
pancreatic adenocarcinoma, HCC, nonsquamous NSCLC, SCCHN, mesothelioma, TNBC, 
RCC, and NPC.  
• Patients who are CPI-naïve. This set includes patients with malignancies that have not yet 
been exposed to anti–PD-1/anti–PD-L1 and will include, but is not limited to, patients with 
pancreatic adenocarcinoma. 
4.2.1 Rationale for the Patient Population Selection 
This study will enroll adult patients with histologically confirmed select locally advanced or 
metastatic solid tumors. This patient population represents a traditional cohort for phase 1 studies 
containing a new regimen without a well-defined, biomarker-driven or tumor-specific target. 
This patient population often has the most favorable balance between patient risk and benefit for 
a phase 1 study. During dose escalation, this study will collect tumor tissue and blood samples to 
identify potential pharmacodynamic biomarkers to support future patient selection or 
enrichment.  
Eligible patients for this study include both patients who are CPI-naïve and those who are 
refractory to or have developed resistance to anti–PD-1/anti–PD-L1 therapies. There is 
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preclinical evidence that the addition of a STING agonist may reverse the mechanisms of 
resistance in tumors with prior exposure to anti–PD-1/anti–PD-L1 therapies (see 
Section 4.1.1.1). While it is unknown whether the combination of anti–PD-1 antibody and 
TAK-500 will provide meaningful clinical benefit, this regimen represents a promising approach 
to addressing CPI recalcitrance. Tumor responses in this group of patients may provide early 
insight into the clinical benefit produced by the combination of TAK-500 and pembrolizumab 
for patients in which CPI alone is not sufficient to drive or maintain a sustained clinical response. 
The tumor types identified in Sections 4.2.1.1 to 4.2.1.7 were selected on the basis of clinical 
unmet need and the presence of the following biomarkers: 
 
 
. 
4.2.1.1 
Gastroesophageal Adenocarcinoma 
Gastroesophageal adenocarcinomas are malignant tumors arising in the upper gastrointestinal 
tract (GIT; esophagus, gastroesophageal junction, stomach). Both in gastric and esophageal 
cancers, patients with advanced stage disease have poor survival rates. The American Cancer 
Society estimates that about 26,560 cases of stomach cancer and 19,260 cases of esophageal 
cancer will be diagnosed in 2021 (Siegel et al. 2021). In 2020, studies showed that the 
combination of nivolumab plus chemotherapy improved overall survival in some patients with 
advanced gastric or gastroesophageal junction cancer (Moehler et al. 2020). Conversely, 
pembrolizumab plus chemotherapy failed to show an overall survival benefit over chemotherapy 
alone (Shitara et al. 2020). Further clinical trials to investigate immunotherapy-based 
combinations are needed for patients with tumors refractory or resistant to CPI. 
4.2.1.2 
Pancreatic Adenocarcinoma  
Pancreatic cancer is one of the deadliest of all types of cancer. In 2021, 60,430 Americans are 
estimated to be diagnosed with pancreatic cancer, and about 48,220 are expected to die of the 
disease (Siegel et al. 2021). The mainstay of curative treatment for pancreatic cancer is surgery. 
The prognosis of locally advanced or metastatic pancreatic cancer remains poor (Siegel et al. 
2022). Overall response rates (ORRs) to second-line (2L) combination chemotherapy ranges 
from 13% to 17%, with median progression-free survival (mPFS) of 3.1 to 5.8 months and 
median OS (mOS) of 6.1 to 9.9 months (Huh et al. 2021; Mita et al. 2019; Wang-Gillam et al. 
2019; Zaibet et al. 2022). In the third-line (3L) or later setting, ORRs range from 0% to 3.9%, 
with mPFS of 1.6 to 2.4 months and mOS of 3.9 to 4.6 months (Chun et al. 2022; Mie et al. 
2021; Yu et al. 2021).  
4.2.1.2.1 
Role of Immunotherapy in the Treatment of Pancreatic Adenocarcinoma 
Despite advances in immunotherapy in many tumor types, the role of immunotherapy in 
pancreatic cancer remains limited. Pembrolizumab is currently only approved for the patients 
with the microsatellite-high/DNA mismatch repair–deficient tumors (Marabelle et al. 2020), 
which accounts for only 1% to 2% of all pancreatic adenocarcinoma (Cancer Genome Atlas 
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Research et al. 2017; Luchini et al. 2021). Multiple studies conducted to investigate CPIs in 
pancreatic cancer have reported disappointing results (Henriksen et al. 2019; O’Reilly et al. 
2019; Renouf et al. 2022; Ullman et al. 2022). 
4.2.1.2.2 
STING Signaling, CCR2 Expression, and Myeloid Infiltration in Pancreatic 
Adenocarcinoma  
Pancreatic adenocarcinoma is characterized by an immunosuppressive TME with a fibrous 
stroma and prominent myeloid cell infiltration. The high density of myeloid subpopulations, such 
as MDSCs and TAMs, have been associated with worse prognosis (Morrison et al. 2018; Murray 
2017; Vayrynen et al. 2021). Moderate CCR2 expression is found in pancreatic adenocarcinoma 
by bulk RNA-seq (Cancer Genome Atlas Research et al. 2017) and by scRNA-seq in myeloid 
populations in the pancreatic adenocarcinoma TME (Cheng et al. 2021). Despite their lack of 
CPI-responsiveness, pancreatic adenocarcinoma tumors span the range of immunological “cold” 
to “hot,” likely due to tumor heterogeneity (Rubin et al. 2022; Ullman et al. 2022). Tumor RNA-
seq analysis showed moderate to high STING and interferon-related gene expression (Cancer 
Genome Atlas Research et al. 2017). Furthermore, STING agonists have been shown to activate 
antitumor immunity in preclinical pancreatic cancer models (Kabashima et al. 2022; Mohseni et 
al. 2021). Given the high myeloid content and potential of STING pathway–mediated immune 
activation, systemic administration of TAK-500 may hypothetically provide clinical antitumor 
activity in pancreatic adenocarcinoma.  
4.2.1.3 
HCC 
In 2021, an estimated 42,230 new cancers of the liver and intrahepatic bile duct are expected to 
be diagnosed in the US, and 30,230 people will die of the disease (Siegel et al. 2021). The most 
common form of primary liver cancer is HCC. In 2020, FDA approved atezolizumab plus 
bevacizumab as first-line therapy with advanced HCC (Finn et al. 2020). Pembrolizumab and 
ipilimumab with nivolumab are also approved for 2L or later use in HCC, but therapeutic options 
after progression while on a CPI are limited. 
4.2.1.4 
Nonsquamous NSCLC 
NSCLC is the leading cause of cancer mortality in the US with an estimated 140,000 patients 
dying of the disease this year, which is greater than the number of cancer mortalities from colon, 
breast, and prostate cancer combined (Siegel et al. 2021). The majority of NSCLC patients 
present with metastatic disease. NSCLC can be subcategorized as nonsquamous (up to 80%) and 
squamous (up to 30%) histological types. Lung adenocarcinoma makes up the majority of 
nonsquamous NSCLC and is viewed as a distinct entity compared with squamous NSCLC 
(Oliver et al. 2015).  
4.2.1.4.1 
Role of Immunotherapy in the Treatment of Nonsquamous NSCLC 
Recently, immunotherapy with or without chemotherapy (depending on PD-L1 expression) has 
become the proven preferred first-line or 2L systemic therapy in patients without actionable 
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tumor driver mutations (Borghaei et al. 2019; Gandhi et al. 2018; Reck et al. 2019). Even though 
a number of CPIs are approved for the treatment in the later-line settings, as CPIs become the 
standard of care in first-line nonsquamous NSCLC, most 2L and later patients will likely have 
developed resistance to CPI therapy and have to undergo a chemotherapy-based regimen. In the 
REVEL study, in 2L after disease progression on a platinum-based regiment ramucirumab (an 
anti-vascular endothelial growth factor [VEGFR] tyrosine kinase inhibitor [TKI]) + docetaxel 
showed an ORR of 23%, mPFS of 4.5 months, and mOS of 10.5 months (Garon et al. 2014). For 
3L and later patients, treatment options are limited to chemotherapy, such as docetaxel SA, for 
which ORRs have been reported to range from 5% to 7% with mPFS of approximately 
3.5 months and mOS of 8 to 9 months. Despite the overall success of CPIs in patients with 
NSCLC, the majority of patients eventually develop resistance to immunotherapy and have 
disease progression (Schoenfeld and Hellmann 2020). Novel treatment options, both as initial 
approach and upon development of resistance to CPI therapy, are needed. 
4.2.1.4.2 
STING Signaling, CCR2 Expression, and Myeloid Infiltration in Nonsquamous 
NSCLC  
The NSCLC TME is complex and harbors both tumor-promoting and tumor-suppressive 
activities (Altorki et al. 2019). Various studies have identified enriched myeloid-derived cells, 
such as MDSCs, TAMs, and neutrophils, in the NSCLC TME (Lavin et al. 2017; Singhal et al. 
2019; Zilionis et al. 2019), and their presence or associated transcriptional signatures have been 
associated with clinical outcomes (Gentles et al. 2015; Jackute et al. 2018; Messmer et al. 2015). 
High CCR2 expression is found in the NSCLC TME by bulk RNA-seq (Cancer Genome Atlas 
Research et al. 2017) and by scRNA-seq in myeloid populations (Cheng et al. 2021). Tumor 
RNA-seq analysis shows high STING and interferon-related gene expression (Cancer Genome 
Atlas Research et al. 2017). The immune TME with high CCR2+ myeloid cells and STING 
activity, combined with the CPI responsiveness, leads to the hypothesis that TAK-500 can 
induce antitumor activity in nonsquamous NSCLC. 
4.2.1.5 
SCCHN 
In 2021, an estimated 54,010 new cancers of the oral cavity and pharynx are expected to be 
diagnosed, and 10,850 people will die of the disease (Siegel et al. 2021). Key risk factors for 
SCCHN are smoking, alcohol consumption, and history of human papillomavirus and 
Epstein-Barr virus infection. Only 29% of patients are diagnosed with localized disease that is 
curable by surgery alone. SCCHN has a predominantly locoregional pattern of recurrence, with 
only 25% of patients presenting with distant metastases at recurrence, and this mostly to the 
lungs. Recently, pembrolizumab was FDA approved in the first-line setting for the treatment of 
metastatic or unresectable SCCHN as monotherapy for patients with positive PD-L1 expression 
and in combination with platinum and fluorouracil in patients whose tumors are PD-L1 negative. 
Nivolumab is also approved for use in the 2L setting after progression on a platinum-containing 
agent. There is an unmet clinical need for those patients who have PD while on CPI and 
chemotherapy. 
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4.2.1.6 
Mesothelioma 
Mesothelioma is a rare and aggressive cancer, accounting for less than 0.3% of all cancer 
diagnoses in the US. About 3000 new cases are diagnosed each year (Carbone et al. 2019). The 
average life expectancy of patients with advanced stage mesothelioma is usually less than 1 to 
2 years (Shavelle et al. 2017). In 2020, FDA approved nivolumab in combination with 
ipilimumab for the first-line treatment of adults with unresectable malignant pleural 
mesothelioma (Wright 2020). Pembrolizumab was also approved for patients with a high tumor 
mutational burden. Given the modest overall effectiveness under immunotherapy, there is an 
unmet medical need for patients with refractory and resistant disease under CPI treatment. 
4.2.1.7 
TNBC 
In 2021, an estimated 284,200 new breast cancers are expected to be diagnosed, and 
44,130 people will die of the disease (Siegel et al. 2021). TNBC, defined by the lack of estrogen 
receptors, progesterone receptors, and human epidermal growth factor receptor-2 (HER2)/neu, 
represents 10% to 20% of all breast cancers. Patients with TNBC do not benefit from hormone 
therapy or HER2 monoclonal antibody. Therefore, TNBC is more aggressive and has poorer 
prognosis than other types of breast cancers. In recent years, the introduction of immunotherapy 
brings some promising results in metastatic TNBC (Cortes et al. 2020). On the basis of the 
IMPASSION 130 phase 3 trial, atezolizumab in combination with nab-paclitaxel is now 
approved for first-line use in patients with metastatic TNBC and positive PD-L1 expression 
levels (Schmid et al. 2018). In 2020, FDA also granted accelerated approval to pembrolizumab 
in combination with chemotherapy for the treatment of patients with locally recurrent resectable 
or metastatic TNBC whose tumors express PD-L1 (Slater 2020). Unmet medical need remains in 
metastatic TNBC, given the short progression-free survival (PFS; <10 month) in first-line 
therapy, and primary and acquired resistance to CPIs. 
4.2.1.8 
RCC 
RCC comprises approximately 5% of all new diagnoses of malignancy with an estimated 
80,000 new cases and almost 14,000 deaths in 2021 in the US 
(seer.cancer.gov/statfacts/html/kidrp.html, Cancer Stat Facts: Kidney and Renal Pelvis Cancer). 
Clear cell RCC accounts for 70% to 80% of RCC cases with about 20% of new diagnoses being 
locally advanced or metastatic while 30% of nonmetastatic disease will develop metastases 
(Lalani et al. 2019).  
4.2.1.8.1 
Role of Immunotherapy in the Treatment of RCC 
The systemic treatment paradigm for metastatic RCC has been dynamically changing 
(Gkolfinopoulos et al. 2021). Antiangiogenic drugs, such as sorafenib, axitinib, cabozantinib, 
lenvatinib, and pazopanib, all small molecule TKIs of VEGFR, have shown significant antitumor 
activity in the first-line and 2L settings (Choueiri et al. 2016; Escudier et al. 2007; Kudo et al. 
2018; Motzer et al. 2013). Recently, drug combinations that include CPIs and TKIs have shown 
improved benefit and emerged as the standard of care in the first-line setting (Choueiri et al. 
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2021; Lombardi et al. 2022; Motzer et al. 2021; Motzer et al. 2019; Rini et al. 2019). However, 
for RCC patients whose disease progresses following initial CPI/TKI combination therapy, 
treatment options in later lines remain limited. In the 3L setting, TKIs, such as tivozanib and 
sorafenib, remain the standard of care with ORRs ranging from 8% to 18%, mPFS of 3.9 to 
5.6 months, and mOS of 16.4 to 19.2 months (Rini et al. 2020).  
4.2.1.8.2 
STING Signaling, CCR2 Expression, and Myeloid Infiltration in RCC 
Large-scale transcriptome analyses showed that RCC tumors are among the most highly 
immune-rich tumor types, with abundant myeloid cell infiltration and high levels of CCR2 
expression (Becht et al. 2016; Chevrier et al. 2017; Ricketts et al. 2018). Various immune 
signatures have shown correlation with disease progression and treatment response (Au et al. 
2021; Helmink et al. 2020; Rappold et al. 2022; Ricketts et al. 2018). Notably, high T cell/low 
myeloid infiltration are reported to be enriched in responders to anti-PD-1/PD-L1 (Helmink et al. 
2020; McDermott et al. 2018). RCC also shows high expression levels of STING and genes 
involved in the cGAS-STING and interferon pathways, likely partially related to the abundant 
immune infiltration (Ricketts et al. 2018). Given RCC’s responsiveness to immunotherapy, high 
level of CCR2 expression and myeloid-rich TME, we hypothesize that TAK-500’s 
CCR2-mediated STING activation represents a promising agent for patients in RCC. 
4.2.1.9 
NPC 
NPC is an epithelial carcinoma arising from the nasopharyngeal mucosal lining. In 2018, there 
were about 129,000 worldwide new cases of NPC, with 70% of cases in East and Southeast Asia. 
Infection with EBV is a major etiologic factor in the development of NPC (Chen et al. 2019). 
Most NPC patients present with advanced disease and chemotherapy (plus radiation therapy for 
locoregional disease) was previously the standard of care. Recently, CPIs (eg, toripalimab, 
camrelizumab, and tislelizumab) in combination with chemotherapy have been approved as 
first-line treatment for metastatic NPC in China. The CPI/chemotherapy combination will likely 
become the new first-line standard of care with significant improvement in efficacy.  
NPC shows high levels of infiltration of exhausted CD8 T-cells, myeloid cells, and expression of 
STING and CCR2. Furthermore, high levels of CCR2 expression and myeloid-derived 
suppressor cells are associated with poor prognosis (Chen et al. 2021; Yang et al. 2016) making 
NPC an opportunity to test TAK-500’s ability to induce immune-mediated tumor elimination.  
4.2.2 Rationale for the Starting Dose, Dose Range, and Schedule 
To appropriately balance the potential risk of developing acute AEs from immune stimulation in 
the cancer patient population and the potential for pharmacologic activity at the starting dose, the 
NOAEL from the GLP-compliant 28-day repeat-dose monkey toxicity study and the minimum 
anticipated biological effect level (MABEL) were considered in selecting the starting dose of 
TAK-500 as an SA.  
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4.2.2.1 
Maximum Recommended Starting Dose Based on Nonclinical Toxicology Findings 
in Monkeys 
In the GLP repeat-dose toxicity study in monkeys (described in Section 4.1.1.3), TAK-500 was 
administered Q2W for 3 doses at 0.1, 0.3, or 0.9 mg/kg via IV slow bolus injection. TAK-500 
was well tolerated up to 0.3 mg/kg, but resulted in early euthanasia of 2 females with adverse 
clinical observations at 0.9 mg/kg. Major findings at early euthanasia and in animals that 
survived to scheduled necropsy were attributable to immune-mediated processes consisting of 
increased serum cytokines, a systemic pro-inflammatory response, and a possible contribution of 
effects secondary to immunogenicity. These findings were noted at all doses and included 
dose-responsive, transient clinical signs considered likely related to increases in serum cytokine 
concentrations, clinical pathology endpoints consistent with a transient acute phase response, and 
microscopic findings including generally minimal to mild inflammatory cell infiltrates in several 
organs/tissues. Pulmonary edema was present in early euthanasia animals only, which 
contributed to clinical decline. Increases in heart rate in jacketed telemetry animals (0.9 mg/kg) 
were considered likely related to increases in serum cytokines. Based on these findings, the 
NOAEL and highest nonseverely toxic dose in this repeat-dose study was 0.3 mg/kg. Using this 
dose, the estimated maximum recommended starting dose (MRSD) in humans was 16 µg/kg. 
This estimation was based on body surface area calculations, and includes a one-sixth safety 
factor calculation per ICH S9. 
4.2.2.2 
Recommended Starting Dose Based on MABEL 
As an alternate approach to estimate the starting dose in humans, the MABEL dose of TAK-500 
was estimated using 3 different approaches that included: 
• The application of in vitro–to–in vivo extrapolation from in vitro 
 in human whole 
blood using predicted human Cmax (Approach 1). 
• An in vitro–to–in vivo extrapolation from in vitro human 
 
 using predicted 
Cmax (Approach 2). 
• An in vitro–to–in vivo extrapolation from an in vitro human whole blood cytokine release 
study, using predicted human Cmax (Approach 3). 
The MABEL was defined as the 20% maximal effective concentration for RO and EC50 for other 
pharmacological responses, since potent agonists produce pharmacodynamic responses with a 
smaller fraction of RO (Kenakin 2004). These thresholds correspond to the recommended 
threshold of 20% to 80% by Saber et al (Saber et al. 2016) for MABEL dose estimation based on 
a summary of the starting dose and clinical maximum tolerated dose (MTD) of 32 immune 
agonistic therapeutics for cancer therapy in the clinic. The dose in humans predicted to result in 
the MABEL at Cmax was projected as the MABEL dose. 
Among the tested pharmacological readouts for MABEL, the lowest projected relevant MABEL 
dose was derived from in vitro monocyte activation, which is estimated to reach EC50 at Cmax 
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with 2.63 µg/kg of TAK-500 through 1 hour IV infusion (Approach 2). The dose is similar to the 
lowest end of the MABEL dose derived from TAK-500 RO (4.11 µg/kg) (Approach 1) and 
lower than MABEL dose obtained from detection of relevant in vitro cytokine release in human 
whole blood (IFN-β release, 231 µg/kg) (Approach 3). Although TAK-500–related induction of 
MCP-1, IP-10, macrophage inflammatory protein (MIP)-1β, and IL-29/IFN-λ1 in the in vitro 
human whole blood assay was observed at a lower concentration than other cytokines, these 
responses were not considered relevant for the MABEL dose associated with acute immune 
toxicity. While these cytokines are useful as pharmacodynamic markers for 
 
activation, in the preclinical models there is a lack of an obvious association between release of 
these cytokines and CRS or other adverse effects. 
4.2.2.3 
Selection of Final Recommended Starting Dose for the Study 
To further promote safety in the study patient population while avoiding treating a large number 
of patients with locally advanced or metastatic solid tumors with potentially non-PADs, an FIH 
starting dose of 8 µg/kg was selected on the basis of consideration of the TAK-500 MABEL and 
MRSD, as well as prior nonclinical and clinical experience with TAK-676 and other STING 
agonists (Harrington et al. 2018; Meric-Bernstam et al. 2019; Zandberg et al. 2020). The 
proposed starting dose is approximately 3-fold higher than the starting dose (2.6 µg/kg) based on 
a MABEL approach, one-half of the MRSD from the GLP monkey toxicology study (16 µg/kg), 
and represents a safety factor of one-twelfth of the NOAEL human equivalent dose scaled by 
body surface area. The starting dose of 8 µg/kg is projected to result in less than 35% RO on 
monocytes and below the 80% maximal effective concentration for monocyte activation at Cmax. 
Exposure multiples at the NOAEL (0.3 mg/kg) from the GLP repeat-dose toxicity study in 
monkeys (Day 1 conjugated TAK-676 area under the serum concentration-time curve from time 
0 to 336 hours [AUC336] of 1680 h*ng/mL and concentration of drug at time 0 of 142 ng/mL 
after a slow IV bolus administration) compared with the projected human AUC336 and Cmax 
values for conjugated TAK-676 at a starting dose of 8 µg/kg TAK-500 (69.3 h*ng/mL and 
3.62 ng/mL, respectively, with 1-hour infusion) are approximately 24- and 39-fold, respectively. 
As described in Section 4.1.2.2, the clinical IV dose of TAK-676 has been escalated to 2.5 mg 
from the MRSD/MABEL-based TAK-676 starting dose of 0.2 mg without any observed DLTs. 
The proposed starting dose of 8 µg/kg for TAK-500 is equivalent to 9.4 µg of TAK-676 
contained in the ADC payload, after adjusting for the molecular weight of TAK-500, a 
drug-antibody ratio of 4, and a body weight of 60 kg. Following this, the TAK-676 payload dose 
associated with the administration of 8 μg/kg of TAK-500 is approximately 21-fold lower than 
the TAK-676 MRSD of 0.2 mg. The lower payload dose reflects the higher potency/improved 
PK of TAK-500 noted in Sections 4.1.1.1 and 4.1.1.2. The clinical tolerability profile of 
TAK-676, coupled with the projected safety multiples of the TAK-500 MRSD, the low to 
nondetectable circulating free payload (deconjugated TAK-676) in monkeys, and the dose and 
exposure of both TAK-500 and associated conjugated TAK-676 at the NOAEL, provide 
confidence in selecting a starting dose that is above the MABEL, while also below the MRSD. 
As such, the TAK-500 starting dose of 8 µg/kg balances the risk of acute toxicity while avoiding 
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treating a larger number of patients at doses that are not projected to be pharmacologically 
active. 
4.2.2.4 
Dose Range 
The proposed dose range for TAK-500 SA in the initial dose escalation phase is 4 to 480 µg/kg 
administered on Day 1 of every 21-day cycle (once every 3 weeks [Q3W]). The default starting 
dose for SA dose escalation will be 8 µg/kg. A 4 µg/kg DL may be explored if unacceptable 
toxicity is observed at the 8 µg/kg DL as either an SA or in combination with pembrolizumab. 
The rationale for the highest dose of TAK-500 (480 µg/kg) was based on consideration of the 
projected human exposures and observed exposures in monkey GLP toxicology studies after 
administration of 0.9 mg/kg, which were associated with early mortalities. The predicted human 
serum exposure of TAK-500 at the proposed highest dose of 480 µg/kg (AUC336 of 
5570 ng*h/mL) is expected to be approximately 83% of the exposures at which toxicity was seen 
in monkeys at a dose of 0.9 mg/kg (AUC336 of 6700 ng*h/mL). 
The TAK-500 therapeutic hypothesis is premised on the ability to augment the adaptive immune 
system–mediated anticancer potential when combined with an anti–PD-1 antibody. Nonclinical 
experiments in mouse models indicate that lower doses of TAK-500 are sufficient to induce 
antitumor activity when combined with an anti–PD-1 antibody as compared with TAK-500 SA. 
The intent in this study is to inform the selection of an optimal dose and schedule of TAK-500 
that produces the desirable immune-activated state for combination with pembrolizumab. 
While the potential explorable dose range for TAK-500 in the pembrolizumab combination arm 
is the same as for the SA dose escalation (4 to 480 µg/kg), the proposed initial DL for the 
pembrolizumab combination arm is 80 µg/kg, to be initiated after safety clearance of the 
TAK-500 SA 80 µg/kg DL. If it is determined during the conduct of the SA dose escalation that 
the TAK-500 SA minimum PAD is ≤40 µg/kg, the combination TAK-500 plus pembrolizumab 
dose escalation will begin enrollment at a dose no higher than the TAK-500 SA minimum PAD 
DL. The combination dose escalation may begin at a dose level of TAK-500 that is below the 
TAK-500 SA PAD if this is determined to be necessary from the evaluation of safety and 
toxicity data. It is anticipated that this approach, combined with evaluating all available data for 
each dosing cohort (such as PK, pharmacodynamics, determination of the PAD range, clinical 
safety, and antitumor activity), will provide an optimal balance between potential antitumor 
activity and safety. The decision regarding which DL of TAK-500 will be used as starting dose 
for the combination is explained in detail in Section 6.1. 
4.2.2.5 
Dosing Schedule of TAK-500 
In the dose escalation phase, TAK-500 will be administered in a Q3W schedule (Day 1 of every 
21-day cycle) for the SA and combination arms. As described in Section 6.1.1, TAK-500 SA will 
be administered at a starting dose of 8 µg/kg on a Q3W 21-day cycle. The maximum DL for 
TAK-500 escalation is 480 µg/kg. The proposed explorable TAK-500 dose escalation levels are 
as follows: 4, 8, 16, 24, 40, 80, 160, 240, 360, and 480 μg/kg. As described in Section 6.1.2.2, 
TAK-500 in combination with pembrolizumab may also explore the dose range from 4 to 
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480 µg/kg, on an initial dosing schedule of TAK-500 administered Q3W in 21-day cycles; 
however, the default starting dose of TAK-500 in the combination arm will be 80 µg/kg, and the 
combination arm will not begin enrollment until after safety clearance of the TAK-500 SA 
80 µg/kg DL or determination of an TAK-500 SA minimum PAD that is ≤40 µg/kg. In the latter 
instance, the starting TAK-500 DL for the combination arm will be the TAK-500 SA minimum 
PAD. While Q3W dosing of TAK-500 will be explored initially, Q2W administration of 
TAK-500 in a 42-day cycle may also be explored once the Q3W PAD range has been 
established. 
In the dose expansion phase of TAK-500 plus pembrolizumab (Section 6.1.3), TAK-500 will be 
administered in a Q3W schedule with the additional option of pursuing a Q2W dosing schedule 
of TAK-500 if inadequate immune activation or clinical activity is observed with Q3W dosing. 
All expansion cohorts will be administered in a 42-day cycle. The Q3W and any Q2W expansion 
cohorts will be administered TAK-500 at DLs that have previously been proven to be 
pharmacologically active in combination with pembrolizumab. 
During the conduct of the study, should a determination be made that the totality of the data 
derived from PK, pharmacodynamics, and safety are supportive of an alternative dosing 
schedule, the TAK-500 schedule of administration or cycle length may be adjusted accordingly. 
For all cohorts in dose escalation and expansion, pembrolizumab will be administered at 200 mg 
Q3W as an IV infusion according to the most current prescribing information. 
4.2.3 
Rationale for European Union Auxiliary Medicinal Products for CRS Mitigation  
 may be utilized as 
auxiliary medicinal products (AxMPs) to mitigate the risk of CRS before and after infusion of 
TAK-500, as described in Section 6.1.1, Section 8.9.1, and Table 8.d. For details on CRS and 
CRS management, please refer to Section 4.3.1.1 and Section 8.9.1, respectively. 
For an overview on the AxMPs, please refer to Section 8.1.4 and Table 8.a. 
4.2.4 Rationale for Tumor and Blood Tissues Collection 
Tumor and blood tissues will be collected to assess pharmacodynamic and potential predictive 
biomarkers supportive of TAK-500’s MOA and PAD determination. 
4.2.4.1 Tumor Biopsies 
Tumor biopsies at baseline and on-treatment will be collected to determine 
 
 within the tumor, as well as the functional modulation of the 
 
 within the TME. To minimize the risk of performing invasive procedures on 
patients at TAK-500 DLs with no measurable pharmacodynamic activity, biopsies will be 
required once TAK-500 is shown to demonstrate peripheral evidence of pharmacodynamic 
activity in the blood or clinical antitumor response in at least 1 patient. However, if the lesions 
are safely accessible, paired biopsies are highly desired in all patients. The pharmacodynamic 
and mechanistic information gained from patient biopsies will be required to demonstrate clinical 
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proof-of-concept (POC) for TAK-500 and to evaluate changes in immune cell infiltration within 
the tumor (secondary endpoint). On-study biopsies are needed to identify possible signals of 
 at DLs below MTD and to help in the identification of the PAD 
range. Additionally, this strategy enables the determination of the dynamic range of the 
pharmacodynamic activity. These data will be essential to establish the dose for further 
development of TAK-500. 
 
 
 
 
. 
4.2.4.2 Blood 
Blood samples will be collected to evaluate 
 
 
. The TAK-500–mediated impact on the immune system will be assessed by 
measuring concentrations of select 
 
 
 
. These samples will also be used to help in the identification of the PAD range, 
recommended dose for expansion (RDE), the dose for further development, and POC. 
4.2.5 Rationale for PK Assessments 
Serial serum sample collections will enable the characterization of TAK-500, total antibody, 
consisting of conjugated and deconjugated monoclonal antibody, and deconjugated TAK-676 
PK, released from TAK-500 on cleavage of the linker-payload bond. The PK data collected on 
these occasions will generally coincide with pharmacodynamic assessments. PK data in 
conjunction with pharmacodynamic data can help in the understanding of the 
PK-pharmacodynamic relationship of TAK-500. Such data will be used to build mathematical 
models to describe the PK-pharmacodynamic and/or PK-safety/antitumor activity relationship of 
TAK-500 to help predict the time course of PK and pharmacodynamic effects of TAK-500. This 
information will provide context for safety findings from the study and will be helpful in 
identifying the PAD range, the dose for further development, and schedule for TAK-500. 
4.3 
Potential Risks and Benefits 
TAK-500 is currently being evaluated in an ongoing FIH phase 1/2 study in patients with solid 
tumors (Study TAK-500-1001) and the clinical benefits and risks have not been fully 
determined. 
4.3.1 Potential Risks and Effects of TAK-500 
The potential effects listed below are primarily based on the findings from nonclinical studies 
with TAK-500 and publicly available data on CDN STING agonists that are currently in clinical 
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development. These events may or may not develop in human patients treated with TAK-500. It 
is also possible that the administration of TAK-500 during a clinical study will result in AEs that 
were not observed or predicted from the completed nonclinical studies conducted in animals. 
Clinical study protocols for TAK-500 will include monitoring for the potential AEs specified for 
this compound using physical and laboratory examinations, vital signs, electrocardiograms 
(ECGs), and imaging as clinically indicated. The timing of these tests and evaluations is detailed 
in the schedules of events (SOEs) (Appendix A). Additional tests and evaluations will be 
considered on the basis of symptoms and findings observed in the study. Details on the 
mitigation for and monitoring of these potential toxicities are included in Section 8.9. 
4.3.1.1 
CRS 
Findings in the in vitro cytokine release assay in human whole blood and the repeat-dose toxicity 
studies in monkeys suggest a potential for CRS in patients treated with TAK-500. 
Systemic increases of pro-inflammatory cytokines including TNF-α, IL-1ra, and IL-6, as well as 
secretion of the IFN pathway biomarker cytokines IP-10 and MCP-1, were observed in the non-
GLP and GLP toxicity studies in cynomolgus monkeys after administration of TAK-500. In the 
non-GLP study, similar magnitudes of cytokine elevations were observed in early euthanasia and 
scheduled euthanasia animals to those found in the GLP study (described below). In the GLP 
toxicity study, these increases peaked at 6 hours after each administered dose on Days 1, 15, 
and/or 29 at all DLs (0.1, 0.3, or 0.9 mg/kg) and returned or partially returned to baseline at 
24 hours postdose. These changes were of the highest magnitude observed on study in the 
1 animal administered 0.9 mg/kg TAK-500 that was euthanized on Day 1 at 7 hours postdose. In 
the other early euthanasia animal that was removed from study 8 hours postdose on Day 15, the 
alterations were more comparable to animals surviving to scheduled euthanasia. In animals 
surviving to scheduled euthanasia on the GLP toxicity study, these increases in cytokines were 
considered likely correlated with increased heart rate, as noted in jacketed external telemetry 
animals; clinical signs of vomiting, hunched posture, decreased activity, and/or red face that 
were observed from 4 to 8 hours after each administered dose; and changes in clinical pathology 
consistent with an acute phase response. In the cytokine release assay in human whole blood, 
TAK-500 induced the production of pro-inflammatory cytokines and chemokines including 
IFN-β, IFN-α2a, IFN-γ, TNF-α, IL-1β, IL-4, IL-6, IL-12p70, MCP-1, IP-10, MIP-1α, MIP-1β 
and IL-29/IFN-λ1. 
CRS has been observed in patients receiving TAK-500 in SA dose escalation (refer to 
Section 4.1.2.3 for details). Management of CRS is described in Sections 6.1.1 and 8.9.1.  
4.3.1.2 
Pulmonary Edema 
Findings in the toxicity studies in monkeys suggest a potential for pulmonary edema in patients 
treated with TAK-500.  
In the non-GLP study, there was no evidence of pulmonary edema in the early euthanasia 
animals that were removed from study on Days 15 (2 animals at 3 mg/kg) or 29 (1 animal at 
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1 mg/kg) and no evidence of pulmonary edema or other respiratory findings in animals surviving 
to scheduled euthanasia. However, in the GLP monkey toxicology study, minimal to mild 
pulmonary edema was observed in the 2 early euthanasia animals at 0.9 mg/kg in which 1 was 
removed from the study on Day 1 and the other on Day 15. The primary cause of early 
euthanasia in these animals was attributed to immune-mediated processes, but the pulmonary 
edema was considered to have contributed to these animals’ early decline. This microscopic 
finding was not associated with in-life evidence (clinical observations) of respiratory distress, 
elevations in respiratory rate, or macroscopic findings, and there was no evidence of pulmonary 
edema or other findings in the lungs of animals that survived to early euthanasia. 
Management of this potential risk is described in Section 8.9.2. 
4.3.1.3 
Immune/Lymphoid System Toxicity 
Findings in the toxicity studies in monkeys suggest a potential for immune/lymphoid toxicity in 
patients treated with TAK-500. 
In the non-GLP toxicity study, minimally decreased cellularity of bone marrow (all cellular 
lineages) was observed in 2 animals at ≥0.1 mg/kg, which correlated with mild reductions in red 
cell mass and in 1 animal, markedly decreased lymphocytes. In addition, in the GLP cynomolgus 
monkey toxicity study, minimal to mild, multifocal lymphoid necrosis was observed in the 
germinal centers of splenic lymphoid follicles and minimal lymphoid necrosis within the thymic 
cortex was observed at ≥0.1 mg/kg TAK-500. These findings lacked clinical pathology correlates 
on hematology, and nonspecific stress may have contributed to the underlying pathophysiology. 
4.3.1.4 
Liver Toxicity 
Findings in the toxicity studies in monkeys suggest a potential for liver toxicity in patients 
treated with TAK-500. 
In the non-GLP study, on Day 3, at ≥0.3 mg/kg, transient minimal to moderate elevations in 
ALT, aspartate aminotransferase (AST), glutamate dehydrogenase, and creatine kinase were 
observed, consistent with muscle and/or hepatocellular origin. Similar elevations in ALT, AST, 
and glutamate dehydrogenase were observed in the GLP study on Day 3 at 0.9 mg/kg as well as 
in a single female at 0.1 mg/kg. Minimal to mild foci of inflammation and/or hepatocellular 
degeneration/necrosis were observed at low incidence of ≥0.3 mg/kg in the non-GLP study and 
at ≥0.1 mg/kg in the GLP study at scheduled necropsy; however, there were no correlative 
increases in liver serum chemistry parameters at that time. Additionally, minimal neutrophilic 
infiltrates were noted within hepatic sinusoids in males and females at ≥0.1 mg/kg in the GLP 
study that were considered related to the systemic pro-inflammatory response. 
4.3.1.5 
CV Toxicity 
Findings in the toxicity studies in monkeys suggest a potential for CV effects in patients treated 
with TAK-500. 
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In the non-GLP toxicity study, microscopic findings in the heart consisted of mild 
epicardial/myocardial hemorrhage in 1 animal at 1 mg/kg. In early mortality animals at 3 mg/kg, 
there was additionally minimal myocardial degeneration in the left ventricle and auricle 
associated with minimal to mild mononuclear cell infiltrates. These CV findings were considered 
immune-mediated in nature.  
In the GLP toxicity study, an increase in RR-derived heart rate was observed from approximately 
3.75 hours postdose through the 21-hour recording period in animals administered 0.9 mg/kg 
TAK-500 (the only DL tested) and were considered likely to be associated with increases in 
serum cytokines (as observed in main study animals; cytokines were not specifically measured in 
CV safety satellite animals). There were no TAK-500–related changes in the PR interval, QRS 
interval, or the individual rate-corrected QT interval. Microscopic findings of minimal mixed cell 
infiltrates in the heart valves or chordae tendineae were present at ≥0.1 mg/kg TAK-500 and 
were considered related to a systemic proinflammatory response. 
4.3.2 
Risks and Effects of TAK-500 in Combination With Pembrolizumab 
The pembrolizumab prescribing information (USPI dated November 2020), includes warnings 
for severe and fatal immune-mediated adverse reactions, infusion-related reactions, 
complications of allogeneic hematopoietic stem cell transplantation (both before and after 
treatment), and embryo-fetal toxicities. In addition, the most common AEs after pembrolizumab 
administered as an SA, as reported in ≥20% of patients, were: fatigue, musculoskeletal pain, 
decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, 
and abdominal pain. The most current prescribing information for pembrolizumab should be 
consulted. 
Nonclinical toxicology studies evaluating the combination of TAK-500 and pembrolizumab were 
not conducted and are considered not warranted per ICH S9. Pembrolizumab is a monoclonal 
antibody that binds to the human PD-1 receptor and blocks the interaction of PD-1 with 
PD-L1/PD-L2 (programmed cell death ligand 2). TAK-500 and pembrolizumab both activate the 
immune system, so known PD-1 immunotherapy-related toxicities (such as pneumonitis, colitis, 
hepatitis, endocrinopathies, nephritis with renal dysfunction, dermatologic adverse reactions, and 
solid organ transplant rejection) associated with the administration of pembrolizumab may be 
enhanced when combined with TAK-500. 
Details on the mitigation for and monitoring of these potential toxicities are included in 
Section 8.9.8. 
4.3.3 
Risks Associated With Same Class of Compound 
Potential risks related to exposure to the payload and antibody portions of TAK-500 (TAK-676 
and TAK-202, respectively) are considered to be negligible as circulating levels of deconjugated 
TAK-676 were low to undetectable in monkeys administered TAK-500, and TAK-202 was 
extremely well tolerated. For informational purposes, the potential risks identified after 
administration of TAK-676 are listed in Appendix E. Clinical background information is 
provided in Section 4.1.2. 
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There were no relevant findings from TAK-676 nonclinical toxicology studies indicating a 
potential for skin-related toxicities. Grade 2 erythema multiforme, assessed as lichenoid/bullous 
drug eruption, was reported with the use of another STING agonist. Patients with congenital 
STING activating mutations (STING-associated vasculopathy with onset in infancy-like 
disorder) have skin lesions, including telangiectatic lesions on nose and cheeks and violaceous, 
scaling atrophic plaques on hands, and vascular inflammation in skin biopsy (Jeremiah et al. 
2014; Liu et al. 2014).  
Vascular toxicity at the injection site, including injection site pain (Grade 3) and skin necrosis 
(Grade 3), have been reported with other STING agonists. 
Details on the mitigation for and monitoring of potential toxicities associated with same class of 
compound are included in Section 8.9. 
4.3.4 Risks Associated With the AxMPs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
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4.3.5 Additional Safety Concerns  
4.3.5.1 
Infusion-Related Reactions 
An infusion-related reaction is a disorder characterized by an adverse local or general response 
from exposure to an allergen. Such reactions are common in patients treated with IV anticancer 
medications and typically occur during the infusion or shortly thereafter. 
TAK-500’s immune-activating properties may produce AEs in the category of infusion-related 
reactions. If an infusion-related reaction were to occur, it could present as fever, chills, rigors, 
headache, rash, flushing, pruritus, arthralgias, hypotension or hypertension, bronchospasm, or 
other symptoms. 
Details on the mitigation for and monitoring of infusion-related reactions are included in 
Section 8.9.7. 
5.0 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
5.1.1 
Primary Objectives 
The primary objective for the phase 1 dose escalation phase is: 
• To determine the safety and tolerability of TAK-500 administered as SA and in combination 
with pembrolizumab in patients with select locally advanced or metastatic solid tumors, 
including gastroesophageal (esophageal, gastroesophageal junction, and gastric) 
adenocarcinoma, pancreatic adenocarcinoma, HCC, nonsquamous NSCLC, SCCHN, 
mesothelioma, TNBC, RCC, and NPC. 
The primary objectives for the phase 2 dose expansion phase are: 
• To assess the preliminary antitumor activity of TAK-500 in combination with 
pembrolizumab in 2L recurrent locally advanced or metastatic nonsquamous NSCLC. 
• To assess the preliminary antitumor activity of TAK-500 SA in 3L recurrent locally 
advanced or metastatic nonsquamous NSCLC. 
• To assess the preliminary antitumor activity of TAK-500 in combination with 
pembrolizumab in 2L recurrent locally advanced or metastatic pancreatic adenocarcinoma. 
• To assess the preliminary antitumor activity of TAK-500 SA in 2L recurrent locally 
advanced or metastatic pancreatic adenocarcinoma. 
• To assess the preliminary antitumor activity of TAK-500 in combination with 
pembrolizumab in 3L recurrent locally advanced or metastatic RCC. 
• To determine the dose for further development of TAK-500 administered as SA and in 
combination with pembrolizumab. 
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5.1.2 
Secondary Objectives 
The secondary objectives for the phase 1 dose escalation are: 
• To determine the RDE of TAK-500 administered as SA and in combination with 
pembrolizumab. 
• To characterize the single and multiple dose PK of TAK-500 administered as SA and in 
combination with pembrolizumab. 
• To evaluate the preliminary antitumor activity of TAK-500 administered as SA and in 
combination with pembrolizumab. 
• To evaluate the dose-responsive impact on T-cell infiltration into the tumor following 
TAK-500 administered as SA and in combination with pembrolizumab. 
• To determine the immunogenicity of TAK-500. 
The secondary objectives for the phase 2 dose expansion are: 
• To determine the safety and tolerability of TAK-500 as SA and in combination with 
pembrolizumab in patients with previously treated recurrent locally advanced or metastatic 
nonsquamous NSCLC. 
• To determine the safety and tolerability of TAK-500 as SA and in combination with 
pembrolizumab in patients with previously treated recurrent locally advanced or metastatic 
pancreatic adenocarcinoma. 
• To determine the safety and tolerability of TAK-500 combination with pembrolizumab in 
patients with previously treated recurrent locally advanced or metastatic RCC. 
5.1.3 
Exploratory Objectives 
The exploratory objectives are: 
• To assess 
 induced by TAK-500 as an SA and in 
combination with pembrolizumab in blood as evidence of pharmacodynamic modulation. 
• To determine whether TAK-500 as an SA and in combination with pembrolizumab results in 
changes in peripheral blood and/or tumor consistent with 
 
. 
• To examine whether the combination of TAK-500 as an SA and in combination with 
pembrolizumab results in blockade of 
 and 
activation of 
. 
• To explore relationships between serum concentrations of TAK-500, total antibody, and 
deconjugated TAK-676 in combination with pembrolizumab with pharmacodynamics, 
antitumor activity, and safety endpoints. 
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• To assess the relationship between 
 
.  
• To characterize 
 of TAK-500 as an SA and in combination with pembrolizumab 
and relationship to dose. 
• To characterize 
, including 
, for 
correlations with clinical outcome, pharmacodynamics, and PK, including future 
pharmacogenomic exploration of 
 
. 
 
 
 
 
 
 
 
 
 
 
5.2 
Endpoints 
5.2.1 
Primary Endpoints 
The primary endpoints for the phase 1 dose escalation are: 
• Frequency and severity of TEAEs. 
• Number of patients with DLTs. 
• Number and percentage of patients with 1 or more treatment-emergent SAE. 
• Number and percentage of patients with 1 or more TEAE leading to dose modifications and 
treatment discontinuations. 
The primary endpoints for the phase 2 dose expansion are: 
• Response assessments made by the investigator per Response Evaluation Criteria in Solid 
Tumors (RECIST) Version (v)1.1 for both the SA and combination treatment. Preliminary 
antitumor activity will be described as follows: 
– ORR: confirmed complete response (cCR) + cPR. 
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5.2.2 
Secondary Endpoints 
The secondary endpoints for dose escalation and dose expansion are: 
• PK parameters of TAK-500: 
– Cmax. 
– tmax. 
– Area under the serum concentration-time curve from time 0 to time t (AUCt). 
– AUC∞. 
– Terminal disposition phase half-life (t1/2z). 
– Total clearance after intravenous administration (CL). 
– Volume of distribution at steady state after intravenous administration (Vss). 
• Intratumoral T-cell infiltration upon TAK-500 treatment. 
• Incidence of patients who are ADA-positive and have acquired immunogenicity. 
• Additional secondary endpoints for the phase 1 dose escalation only: 
• Response assessments made by the investigator per RECIST v1.1 for both the SA and 
combination treatment. Preliminary antitumor activity will be described as follows: 
– ORR: cCR + cPR. 
– Disease control rate (DCR): cCR + cPR + stable disease (SD) >6 weeks. 
– Duration of response (DOR): the time from the date of first documentation of a cPR or 
better to the date of first documentation of PD for responders (cPR or better). 
– Time to response (TTR): the time from the date of first dose administration to the date of 
first documented cPR or better by the investigator. 
Additional secondary endpoints for the phase 2 dose expansion only: 
• Response assessments made by the investigator per RECIST v1.1 for both the SA and 
combination treatment. Preliminary antitumor activity will be described as follows: 
– DCR: cCR + cPR + stable disease (SD) >6 weeks. 
– DOR: the time from the date of first documentation of a cPR or better to the date of first 
documentation of PD for responders (cPR or better). 
– TTR: the time from the date of first dose administration to the date of first documented 
cPR or better by the investigator. 
– PFS.  
– OS. 
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•
Frequency and severity of TEAEs.
•
Number of patients with DLTs.
•
Number and percentage of patients with 1 or more treatment-emergent SAE.
•
Number and percentage of patients with 1 or more TEAE leading to dose modifications and
treatment discontinuations.
5.2.3 
Exploratory Endpoints 
The exploratory endpoints include: 
•
Changes in 
 between
pretreatment and on-treatment peripheral blood samples.
•
The following endpoints will be assessed to evaluate changes in peripheral blood and/or
tumor:
–
Changes in concentrations of plasma biomarkers, including 
.
–
Changes between pretreatment and on-treatment peripheral blood samples in 
.
.
•
Relationship between 
.
•
Relationship between serum concentrations of TAK-500, total antibody, and deconjugated
TAK-676 in combination with pembrolizumab with pharmacodynamics, antitumor activity,
and safety endpoints.
.
•
 assessed
by sequencing of tumor and normal tissue.
 
 
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6.0 
STUDY DESIGN 
6.1 
Overview of Study Design 
TAK-500-1001 is a phase 1/2, open-label, dose escalation and expansion study designed to 
determine the safety, tolerability, antitumor activity, PK pharmacodynamics, and preliminary 
antitumor activity of TAK-500 as SA and in combination with pembrolizumab. This information 
will be used to determine the PAD range, RDE, and the dose for further development of TAK-
500 as an SA and in combination with pembrolizumab. The study will proceed in 2 main phases: 
(1) a phased dose escalation of each treatment arm (TAK-500 as SA and in combination with 
pembrolizumab), and (2) the evaluation of TAK-500 as SA and in combination with 
pembrolizumab in select single tumor type expansion cohorts.  
Approximately 313 patients with the following 9 types of locally advanced or metastatic solid 
tumors will be enrolled: gastroesophageal (esophageal, gastroesophageal junction, and gastric) 
adenocarcinoma, pancreatic adenocarcinoma, HCC, nonsquamous NSCLC, SCCHN, 
mesothelioma, TNBC, RCC, and NPC.  
6.1.1 
Premedication 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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. 
6.1.2 
TAK-500 Dose Escalation 
The proposed explorable dose range of TAK-500 is from 4 to 480 μg/kg (4, 8, 16, 24, 40, 80, 
160, 240, 360, and 480 μg/kg) administered Q3W in a 21-day cycle. Q2W administration of 
TAK-500 in a 42-day cycle may also be explored once the PAD range has been established 
(Figure 6.a). All patients will be hospitalized for 24 (±4) hours after the first 2 doses of TAK-500 
(Cycle [C]1 Day [D]1 and C2D1 for Q3W TAK-500; C1D1 and C1D15 for Q2W TAK-500). 
Regardless of the treatment cycle, if a Grade ≥2 CRS or infusion-related reaction occurs during 
or after the administration of study drug, hospitalization is required for 24 (±4) hours after the 
end of the next 2 TAK-500 infusions. For patients without evidence of Grade ≥2 CRS after 
2 consecutive doses of TAK-500, subsequent administrations of TAK-500 may be performed in 
the outpatient setting with monitoring in the clinic for at least 6 hours after the end of infusion 
(EOI). Patients who do not experience an infusion-related reaction or Grade ≥2 CRS after 
4 consecutive administrations of TAK-500 may have their subsequent postinfusion in-clinic 
monitoring reduced to 1 hour. Patient evaluation including a complete set of vital signs is 
required before their discharge home from either the hospital or clinic. 
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Figure 6.a 
Overview of Study Design – Dose Escalation (Phase 1) 
 
BOIN: Bayesian Optimal Interval; DL: dose level; Q2W: once every 2 weeks; Q3W: once every 3 weeks; PAD: 
pharmacologically active dose; RDE: recommended dose for expansion; SA: single agent. 
PAD in figure refers to the minimum PAD. 
Detailed dose escalation rules are found in Section 8.3.  
Scheme assumes that TAK-500 SA PAD is ≥80 μg/kg. Designation of PAD, PAD +1, and RDE in combination are for 
illustrative purposes only. 
 
6.1.2.1 
TAK-500 SA Dose Escalation 
SA dose escalation will begin at 8 μg/kg. The first 2 DLs (8 and 16 μg/kg) will be evaluated 
using a 1 + 2 + 3 accelerated titration design without intrapatient dose escalation as described by 
Simon et al (Simon et al. 1997). 
Rules for this rapid titration are as follows:  
• The cohort will expand to 3 patients if the single patient dosed at 8 or 16 μg/kg Q3W 
experiences a DLT or any of the following Grade ≥2 AEs considered by the investigator to 
be at least possibly related to TAK-500: fever, hypotension, arrhythmia, tachycardia, 
delirium, dyspnea, hypoxia, pulmonary edema, or symptoms or signs consistent with 
capillary leak syndrome. If a DLT is observed in any of those 3 patients, a 3 + 3 design will 
be used to further evaluate the safety of this DL. Note that any AEs in which the relationship 
to study drug cannot be ruled out will be considered possibly related to the study drug. 
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• If the single patient dosed at either 8 or 16 μg/kg Q3W completes Cycle 1 of treatment 
without a DLT or any Grade ≥2 event listed above, the TAK-500 SA dose escalation will 
proceed to the next highest DL. 
• Once a DLT or any Grade ≥2 AE is observed at a given DL, all higher DLs will enroll with a 
minimum of 3 patients, following the Bayesian Optimal Interval (BOIN) design as detailed in 
Section 8.3.1 (Liu and Yuan 2015). 
• Intrapatient dose escalation will not be permitted as part of the DLT-evaluable dose 
escalation set, but patients treated at TAK-500 SA DLs below minimum PAD (as discussed 
in Section 6.1.2.2 and in Section 8.4) will be allowed to escalate to minimum PAD once the 
minimum PAD DL has been confirmed and cleared from a safety perspective by the sponsor 
and investigators. 
Once the DL of 16 μg/kg is cleared, further dose escalation/de-escalation decisions will follow 
the BOIN design (Liu and Yuan 2015) (see Section 8.3.1 and Appendix F for more detail of the 
BOIN design). Each DL will enroll at least 3 patients initially. A cohort size different from 3 is 
permissible thereafter. There will be a 24-hour dosing delay between the first patient of any new 
DL and subsequent patients enrolled at the same DL. 
SA dose escalation/de-escalation will continue until full determination of the PAD range. As 
defined in Section 8.4, PAD determination is based on observation of peripheral 
pharmacodynamic activity, including peripheral biomarkers evaluating both 
 
. Although clinical activity is not necessary to confirm SA PAD, 
observation of a PR or CR is sufficient to declare PAD regardless of other translational data. To 
confirm the minimum PAD, 2 DLs must each meet PAD criteria, and consequently the minimum 
PAD and PAD +1 DLs may be confirmed simultaneously. In the circumstance where a 
radiographic response (PR or CR) is observed at a given dose level, that dose level may be 
declared as meeting PAD requirements without waiting for confirmation of PAD in a subsequent 
dose level. Once PAD is confirmed, additional patients (approximately 3 to 6 additional patients 
per DL) may be enrolled at the minimum PAD and PAD +1 DLs to establish a more robust 
statistical basis for comparison of pharmacodynamic biomarkers across the TAK-500 SA DLs. 
Additional patients may be added to other DLs above the minimum PAD, as required, to identify 
the DL with optimal pharmacodynamic activity and inform determination of the RDE. Backfill 
cohorts may or may not be enriched for specific tumor type(s) selected from those included in 
dose escalation. 
TAK-500 SA dose escalation may continue past the minimum PAD and PAD +1 DLs as dictated 
by the BOIN design until either (1) the SA MTD is determined, (2) peripheral pharmacodynamic 
biomarkers demonstrate a marked decrease in 
 in 
comparison to prior DLs, or (3) the maximum planned DL of 480 μg/kg is completed. 
Safety clearance of the 80 µg/kg TAK-500 SA DL will trigger initiation of the TAK-500 plus 
pembrolizumab dose escalation at a TAK-500 DL of 80 µg/kg as described in Section 6.1.2.2.  
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6.1.2.2 
TAK-500 in Combination With Pembrolizumab Dose Escalation 
While the potential explorable dose range of TAK-500 in combination with pembrolizumab is 
also from 4 to 480 μg/kg, by default the combination arm will begin at a TAK-500 dose level of 
80 µg/kg, triggered upon safety clearance of the 80 µg/kg TAK-500 SA DL. If it is determined 
during the conduct of the SA dose escalation that the TAK-500 SA minimum PAD is ≤40 µg/kg, 
the combination TAK-500 plus pembrolizumab dose escalation will begin at a dose no higher 
than the TAK-500 SA minimum PAD DL. The determination to initiate the combination dose 
escalation arm will be based on the accumulated safety and pharmacodynamic data from all 
TAK-500 SA cohorts available at that time. The combination dose escalation may begin at a 
dose level of TAK-500 that is below the TAK-500 SA PAD if this is determined to be necessary 
from the evaluation of safety and toxicity data. 
Each combination DL will enroll at least 3 patients initially. A cohort size different from 3 is 
permissible thereafter. There will be a 24-hour dosing delay between the first patient of any new 
combination DL and subsequent patients enrolled at the same DL. The dose escalation/de-
escalation decisions will follow the same BOIN design as the TAK-500 SA arm. If a DL of 
TAK-500 SA is considered to be too toxic in the SA arm, it and any higher DLs will be excluded 
from the explorable dose range of the combination arm. 
Pembrolizumab will be administered at the fixed dose of 200 mg Q3W, to be administered on the 
same day as TAK-500 on a Q3W schedule in a 21-day cycle, or if Q2W dosing of TAK-500 is 
explored, pembrolizumab will be administered on Days 1 and 22 in a 42-day cycle.  
As with the TAK-500 SA arm, dose escalation/de-escalation for the combination arm will 
continue until determination of its minimum PAD. Once the minimum PAD is confirmed in the 
combination arm, additional patients (approximately 3 to 6 additional patients per DL) may be 
enrolled to both the minimum PAD and PAD +1 DLs to establish a more robust statistical basis 
for comparison across DLs. Additional patients may be added to other DLs above the minimum 
PAD, as required, to identify the DL with optimal pharmacodynamic activity and inform 
determination of the RDE. Backfill cohorts may or may not be enriched for specific tumor 
type(s) selected from those included in dose escalation. The criteria for the determination of 
minimum PAD and PAD +1 DLs are the same for both the SA and combination arms (see 
Sections 6.1.1 and 8.4). 
Combination TAK-500 plus pembrolizumab dose escalation may continue in parallel to the 
expansion cohort(s) described in Section 6.1.3. As with the TAK-500 SA arm, dose escalation of 
the combination will occur as dictated by the BOIN statistical design until either (1) the 
combination MTD is determined, (2) peripheral pharmacodynamic biomarkers demonstrate a 
marked decrease in 
 in comparison to prior DLs, or 
(3) the maximum planned DL of 480 μg/kg is completed.  
6.1.2.3 
General Rules for Dose Escalation 
In the dose escalation of both arms (except for the initial 2 accelerated titration SA DLs), 
escalation/de-escalation rules from BOIN with consideration of non-DLT safety and other 
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available clinical, PK, or pharmacodynamic data will be used to inform subsequent DL 
recommendations, dose escalation decisions, and potential MTD estimation for TAK-500. 
Patients not receiving all required doses of TAK-500 or pembrolizumab or not remaining on 
study for reasons other than a DLT for 21 days from first dosing of TAK-500 (C1D21) will not 
be considered DLT-evaluable. While in principle a patient who is not DLT-evaluable may be 
replaced within the same cohort, due to the flexible nature of the BOIN design, this replacement 
may not be mandatory except for the initial BOIN cohort of each arm. Consequently, the need 
for replacement will be determined on the basis of the total number of DLT-evaluable patients in 
the cohort and as agreed on by the sponsor and investigators. Regardless of the need for 
replacement, a patient who is not considered DLT-evaluable may still be allowed to continue on 
study if deemed appropriate by the sponsor and site investigator. 
In the dose escalation of both arms, enrolling additional patients for more conservative dose 
escalation, evaluation of intermediate doses (eg, 60 μg/kg), and alternative dose schedules are 
permissible following discussions between the sponsor and the investigators. In addition, any DL 
not exceeding MTD can be backfilled with additional patients for further evaluation of safety, 
PK, pharmacodynamics, and antitumor activity. 
6.1.3 
TAK-500 Dose Expansion and Randomized Dose Comparison 
In addition to TAK-500 SA and TAK-500 plus pembrolizumab combination dose escalation, the 
preliminary antitumor activity along with the safety, tolerability, PK, and PD of TAK-500 will 
be further evaluated in single-indication expansion cohorts. Dose expansion may proceed with 
both TAK-500 SA and TAK-500 with pembrolizumab and include the opportunity to 
simultaneously explore 2 dose levels of TAK-500 (RDE 1 and RDE 2) to provide additional data 
for identification of the dose for further development. See Figure 6.b for overview of dose 
expansion design. 
As noted in Sections 6.1.2.1 and 6.1.2.2, dose escalation in both the SA and pembrolizumab 
combination arms may proceed beyond identification of PAD until (1) the respective MTD is 
determined, or (2) peripheral pharmacodynamic biomarkers demonstrate a marked decrease in 
 in comparison to prior DLs, or (3) the maximum 
planned DL of 480 μg/kg is completed. Once complete, the totality of data from dose escalation 
will be utilized to identify the RDE(s) and dosing schedule of TAK-500 (Q2W and/or Q3W, both 
in a 42-day cycle) for single-indication dose expansion cohorts. The RDE(s) of TAK-500 may be 
the same as the MTD or may be below the MTD if the totality of data (safety and tolerability, PK 
and PD, and clinical antitumor activity) suggest a lower dose is favorable. Additionally, the 
RDE(s) for dose expansion may or may not be different for the TAK-500 SA versus the 
TAK-500 plus pembrolizumab combination expansion cohorts. For all combination TAK-500 
plus pembrolizumab cohorts, pembrolizumab administration will remain constant at 200 mg IV 
Q3W in a 42-day cycle. 
To accommodate the possible comparison between the Q3W and Q2W schedules, all expansion 
cohorts will be administered in a 42-day cycle. Any Q2W DL evaluated in dose expansion must 
be at or below a Q2W DL previously shown to be tolerated in dose escalation. 
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Figure 6.b 
Schematic of Study Design – Dose Expansion (Phase 2) 
 
2L: second-line; 3L: third-line; length of bar meant to represent relative patient numbers and not time required for a 
given cohort; NSCLC: non–small cell lung cancer; Pancreatic Adeno: pancreatic ductal adenocarcinoma; pts: 
patients; RCC: renal clear cell carcinoma; RDE: recommended dose for expansion; RE: response-evaluable; SA: 
single agent. 
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6.1.3.1 
Expansion Cohort Tumor Type Selection 
Selection of tumor types and line of therapy for single-indication dose expansion cohorts was 
based primarily on scientific rationale for targeting with TAK-500, including 
 
 
 (see Section 4.2.1). High unmet clinical need and 
clinical tractability were also considered. Based on this analysis, 3 tumor types were prioritized 
for initial dose expansion cohorts: nonsquamous NSCLC, pancreatic adenocarcinoma, and 
RCC. These cohorts may begin simultaneously, or one or two indications may be prioritized 
over the other(s). Other single indication expansion cohorts may be explored instead of, or in 
addition to, these indications, if anti-tumor activity is seen during dose escalation in a given 
tumor. 
6.1.3.2 
Dose Expansion in Nonsquamous NSCLC 
The preliminary antitumor activity, safety, tolerability, PK, and PD of TAK-500 SA and/or in 
combination with pembrolizumab will be evaluated in treatment-refractory nonsquamous 
NSCLC patients without driver mutations in both the 2L and 3L setting. 
6.1.3.2.1 
Combination TAK-500 With Pembrolizumab Dose Expansion With Randomized 
Dose Comparison in 2L NSCLC  
Enrollment in 2L NSCLC cohorts will include patients with treatment-refractory nonsquamous 
NSCLC (without targetable driver mutations) with recurrent locally advanced or metastatic 
disease that has previously progressed while on or following 1 prior line of therapy. Patients 
must have had disease progression while on or following at least 6 weeks of 1 prior anti-PD-(L)1 
therapy in the recurrent locally advanced or metastatic setting or must have had disease 
progression/recurrence within 6 months of the completion of anti-PD-(L)1 therapy if 
administered in the adjuvant/neoadjuvant setting. Anti-PD-(L)1 therapy may have been given in 
combination with an anti-CTLA4 antibody or chemotherapy (eg, carboplatin and pemetrexed). 
Patients are eligible to enroll regardless of PD-L1 status. 
The combination TAK-500 plus pembrolizumab dose expansion in 2L NSCLC will proceed as 
outlined below with concurrent start of early randomized dose comparison.  
– Expansion in 2L NSCLC will proceed simultaneously at 2 separate dose levels of TAK-
500 following a 2:1 randomized approach, to RDE 1 and RDE 2, respectively. The 2 dose 
levels will be chosen such that adequate dose/response and exposure/response analyses 
can be performed to support the selection of the dose for further development. RDE 1 and 
RDE 2 selection will be made on the totality of data, including safety, antitumor activity, 
PK and pharmacodynamic analysis, with both doses having a positive benefit-risk ratio 
for further study at the time of selection. Neither RDE 1 nor RDE 2 will be higher than 
the highest dose level assessed in the dose escalation phase or the MTD, whichever is 
lower. 
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– Approximately 59 patients will enroll in this cohort, with up to 39 patients randomized to 
RDE 1 (to achieve an approximate total of 35 response-evaluable patients assuming a 
10% drop-out rate) and up to 20 patients randomized to RDE 2 (to achieve an 
approximate total of 18 response-evaluable patients assuming a 10% drop-out rate). A 
futility analysis will be performed based on ORR at the time when there are 
21 response-evaluable patients in RDE 1 (for definition refer to Section 13.1.1) and each 
of these 21 patients has experienced at least 1 of the following: (1) shown a clinical 
response (cPR or cCR), (2) had at least 2 posttreatment response assessments, or 
(3) documented PD or death. If a partial response or complete response is initially 
observed at the second posttreatment response assessment, a third posttreatment response 
assessment will be performed to confirm the response before the patient may be included 
in the futility analysis. If there are ≥5 responders among the first 21 response-evaluable 
patients treated at RDE 1, then the futility analysis is successful, and the enrollment will 
continue to 35 response-evaluable patients. Enrollment may or may not pause while the 
response assessments needed for the futility analysis are pending.  
– If RDE 1 enrollment is terminated due to failing futility at the stage 1 analysis or fails to 
meet the number of responses needed for proof of concept at final analysis, additional 
patients may be enrolled to RDE 2 in a nonrandomized manner to include 
21 response-evaluable patients (for definition, refer to Section 13.1.1). A futility analysis 
will then be performed based on ORR as described for RDE 1. If there are ≥5 responders 
among the first 21 response-evaluable patients treated at RDE 2, then the futility analysis 
is successful, and the enrollment will continue to 35 response-evaluable patients. 
Otherwise, the cohort will be terminated for futility. Enrollment may or may not pause 
while the response assessments needed for the futility analysis are pending. 
6.1.3.2.2 
TAK-500 SA Dose Expansion With Randomized Dose Comparison in 3L NSCLC 
Enrollment in 3L NSCLC cohorts will include patients with treatment-refractory nonsquamous 
NSCLC (without targetable driver mutations) with recurrent locally advanced or metastatic 
disease that has previously progressed while on or following 2 prior lines of therapy. Patients 
must have had disease progression while on or following at least 6 weeks of 1 prior anti-PD-(L)1 
therapy in the recurrent locally advanced or metastatic setting or must have had disease 
progression/recurrence within 6 months of the completion of anti-PD-(L)1 therapy if 
administered in the adjuvant/neoadjuvant setting. Anti-PD-(L)1 therapy may have been given in 
combination with an anti-CTLA4 antibody or chemotherapy (eg, carboplatin and pemetrexed). 
Patients must have had disease progression while on or after 1 or 2 lines of chemotherapy in the 
recurrent locally advanced or metastatic setting. If the anti-PD-(L)1 therapy is given in 
combination with chemotherapy, the patient must have progressed on an additional line of 
chemotherapy. Patients are eligible to enroll regardless of PD-L1 status.  
– Expansion in 3L NSCLC will proceed simultaneously at 2 separate dose levels of 
TAK-500 following a 1:1 randomized approach, to RDE 1 and RDE 2, respectively. The 
2 dose levels will be chosen such that adequate dose/response and exposure/response 
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analyses can be performed to support the selection of the dose for further development. 
RDE 1 and RDE 2 selection will be made on the totality of data, including safety, 
antitumor activity, PK and pharmacodynamic analysis, with both doses having a positive 
benefit-risk ratio for further study at the time of selection. Neither RDE 1 nor RDE 2 will 
be higher than the highest dose level assessed in the dose escalation phase or the MTD, 
whichever is lower.  
– The 3L nonsquamous NSCLC expansion cohorts will be based on a single-stage design.  
– Approximately 48 patients will be enrolled in this cohort, with 24 patients randomized to 
RDE 1 and RDE 2 each (to achieve an approximate total of 21 response-evaluable 
patients, assuming a 10% drop-out rate in each dose level). 
6.1.3.3 
TAK-500 SA and in Combination With Pembrolizumab Dose Expansion in 2L 
Pancreatic Adenocarcinoma 
The preliminary antitumor activity, safety, tolerability, PK, and PD of TAK-500 SA and in 
combination with pembrolizumab will be evaluated in treatment-refractory pancreatic 
adenocarcinoma with 1 prior line of therapy.  
Enrollment in the 2L pancreatic adenocarcinoma expansion will include patients with treatment-
refractory pancreatic adenocarcinoma with recurrent locally advanced or metastatic disease that 
has previously progressed while on or following 1 prior line of therapy. Patient must have had 
disease progression while on or following 1 prior line of fluorouracil- or gemcitabine-based 
chemotherapy (eg, FOLFIRINOX, FOLFOX, FOLFIRI, gemcitabine/nab-paclitaxel) in the 
metastatic/recurrent locally advanced setting. Prior chemotherapy in the neoadjuvant/adjuvant 
setting does not qualify unless the patient had progression of disease within 6 months of 
completion of neoadjuvant/adjuvant chemotherapy. Patients cannot have had prior exposure to 
anti-PD-(L)1 therapy. Patients are eligible to enroll regardless of PD-(L)1 status. Patients with 
MSI-H/dMMR disease are not eligible. 
– Expansion in 2L pancreatic adenocarcinoma will randomize TAK-500 SA and TAK-500 
in combination with pembrolizumab. Both arms will include TAK-500 at the TAK-500 
RDE 1 identified during combination TAK-500 plus pembrolizumab dose escalation, 
unless the RDE 1 for the combination is below the PAD established during the TAK-500 
SA dose escalation. In this instance, the RDE 1 for TAK-500 SA would be utilized for 
the corresponding arm (see Section 6.1.2.2 and Section 6.1.3).  
– The 2L pancreatic adenocarcinoma expansion cohorts will be based on Simon’s 2-stage 
design with ORR as an endpoint and separate futility analyses for the TAK-500 SA and 
TAK-500 combination cohorts.  
– Approximately 45 patients will be enrolled in each arm to achieve an approximate total of 
40 response-evaluable patients, assuming a 10% drop-out rate per cohort. A futility 
analysis will be performed at the time when there are 25 response-evaluable patients. The 
same futility criteria will be applied for each arm. If there are ≥4 responders among the 
first 25 response-evaluable patients, then the futility analysis is successful, and the 
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enrollment will continue to 40 response-evaluable patients in the respective cohort. 
Otherwise, the cohort will be terminated for futility. Enrollment may or may not pause 
while the response assessments needed for the futility analysis are pending.  
6.1.3.4 
Combination TAK-500 With Pembrolizumab Dose Expansion in 3L RCC 
The preliminary antitumor activity, safety, tolerability, PK, and PD of TAK-500 in combination 
with pembrolizumab will be evaluated in treatment-refractory RCC with 2 prior lines of therapy.  
Enrollment in the 3L RCC cohort will include patients with treatment-refractory RCC with 
recurrent locally advanced or metastatic disease that has previously progressed while on or 
following at least 2 prior lines of therapy. Patients must have had disease progression while on or 
following at least 6 weeks of 1 prior anti-PD-(L)1 therapy in the recurrent locally advanced or 
metastatic setting or must have had disease progression/recurrence within 6 months of the 
completion of anti-PD-(L)1 therapy if administered in the adjuvant/neoadjuvant setting. 
Anti-PD-(L)1 therapy may have been given with or without an anti-CTLA4 antibody and/or an 
anti-VEGFR tyrosine kinase inhibitor (TKI) (eg, cabozantinib). Patients must have had prior 
therapy with 1 or 2 lines of VEGFR TKIs in the metastatic/recurrent locally advanced setting. If 
anti-PD-(L)1 therapy was given in combination with a VEGFR TKI, the patient must have had 
progressive disease on an additional line of therapy (eg, VEGFR TKI or VEGFR TKI-containing 
combination). Patients are eligible to enroll regardless of PD-L1 status. 
– Expansion in 3L RCC will occur at the RDE 1 of TAK-500 identified during combination 
TAK-500 plus pembrolizumab dose escalation (see section 6.1.2.2 and section 6.1.3). 
– The 3L RCC expansion cohorts will be based on a single-stage design, with enrollment of 
up to approximately 34 patients to achieve a total of 30 response-evaluable patients 
(assuming a 10% drop-out rate).  
6.1.4 
Study Assessments 
During dose escalation, all patients will be hospitalized for approximately 24 (±4) hours after the 
first 2 doses of TAK-500 (C1D1 and C2D1 for Q3W TAK-500; C1D1 and C1D15 for Q2W 
TAK-500). Regardless of the treatment cycle, if a Grade ≥2 CRS or infusion-related reaction 
occurs during or after administration of study drug, hospitalization is required for 24 (±4) hours 
after the end of the next 2 TAK-500 infusions. For patients without evidence of grade ≥2 CRS 
after 2 consecutive doses of TAK-500, subsequent administrations of TAK-500 may be 
performed in the outpatient setting with monitoring in clinic for at least 6 hours after infusion. 
Patients who do not experience an infusion-related reaction or Grade ≥2 CRS after 4 consecutive 
administrations of TAK-500 may have their subsequent postinfusion in-clinic monitoring 
reduced to 1 hour. During hospitalization, vital signs will be taken no less frequently than every 
6 hours until discharge (See Appendix A). Before discharge from the hospital and/or clinic, a 
symptom-directed physical examination including assessment of the respiratory and neurologic 
systems and complete set of vital signs will be required. 
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AEs will be assessed, and laboratory values, vital signs, ECGs, and other clinically indicated 
examinations will be obtained to evaluate the safety and tolerability of the study treatment. 
Toxicity will be evaluated according to National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI CTCAE), v5.0. DLTs are defined in Section 8.2. A DLT will be 
defined as any of the TEAEs described in the Section 8.2 that occurs during the first 21 days on 
study (C1D21) and are considered by the investigator to be at least possibly related to TAK-500 
alone or in combination with pembrolizumab. TEAEs meeting DLT definitions occurring in later 
cycles will be considered in the determination of the dose for further development of TAK-500.  
Radiological evaluations (contrast-enhanced computed tomographic [CT] scan and/or magnetic 
resonance imaging [MRI] as clinically indicated) will be used to assess the status of the patient’s 
underlying disease. 
 tumor tissue or a minimum 
number of unstained slides of the tumor tissue will be collected, if available, from all enrolled 
patients to assess baseline features such as 
 
 
t that may emerge from future nonclinical or clinical studies. All patients with a safely 
accessible lesion enrolling at or above DLs where TAK-500 has previously shown 
pharmacodynamic activity will have mandatory tumor biopsies performed per the SOEs 
(Appendix A). 
Serial blood samples will be collected for circulating biomarkers (
 
 
). An evaluation of disease response will 
be performed using the RECIST v1.1 (as determined by the investigator) and per the SOEs 
(Appendix A). Clinically validated peripheral tumor markers will also be collected for patients 
with appropriate tumor types (AFP, CA 27.29, and CA 19-9). Serial blood samples for 
determination of the serum concentration of TAK-500 and related metabolites to understand 
TAK-500 metabolism and excretion mechanisms will be obtained at prespecified time points as 
described in the SOEs (Appendix A). 
See Appendix A for SOEs for TAK-500 Q3W treatment (21-day cycle), TAK-500 Q3W 
treatment (42-day cycle), and TAK-500 Q2W treatment (42-day cycle). 
6.2 
Number of Patients 
Approximately 313 patients in total will be enrolled in this study at approximately 70 sites 
globally. For the phase 1 dose escalation phase, in the SA arm, about 52 patients will be enrolled 
to achieve about 46 DLT-evaluable patients (includes cohorts treated with and without 
premedication); in the combination arm, the number of patients will depend on the starting DL. 
Assuming the starting DL is 80 μg/kg, about 30 patients will be enrolled to achieve a maximum 
of 27 DLT-evaluable patients. Additional patients may be enrolled for the evaluation of the Q2W 
administration of TAK-500 if this schedule is explored in the dose escalation phase. 
For the phase 2 dose expansion phase, assuming only 1 TAK-500 administration schedule is 
expanded, approximately 231 patients will be enrolled to achieve a total of approximately 
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205 response-evaluable patients. This number may increase if more than 1 TAK-500 
administration schedule is explored. 
6.3 
Duration of Study 
6.3.1 
Duration of an Individual Patient’s Study Participation 
Patients may receive TAK-500 for up to 1 year. Patients with demonstrated clinical benefit may 
continue treatment beyond this point if recommended by the investigator and approved by the 
sponsor (see also Section 9.4.13). These patients can continue receiving treatment in this study or 
in any of the poststudy access modalities described in Section 6.3.5. Patients will discontinue 
treatment when they meet any of the discontinuation criteria in Sections 8.5.5 or 9.7.  
Patients in the combination arm who discontinue study treatment (TAK-500) due to PD will be 
discontinued from both TAK-500 and pembrolizumab administration. Patients without evidence 
of PD or clinical progression for whom the investigator decides to discontinue TAK-500 (ie, due 
to safety issues that cannot be managed with dose reductions) will be considered to have ended 
study treatment. These patients will not continue with SA pembrolizumab as part of this study. 
Patients will proceed to the end of treatment (EOT) visit and then continue to be followed until 
disease progression or the initiation of a subsequent systemic anticancer therapy, whichever 
occurs first (See Appendix A).  
Patients receiving TAK-500 SA may be eligible for optional crossover to combination treatment 
with pembrolizumab, after documented disease progression on TAK-500 SA. Eligibility for 
crossover is described in Section 8.5.2. 
Patients without evidence of PD for whom the investigator decides to discontinue 
pembrolizumab due to intolerance, may continue on TAK-500 as an SA at the discretion of the 
investigator and sponsor. This should only occur in instances where the AE is clearly due to 
pembrolizumab and not TAK-500. 
All patients will attend an EOT visit 30 days (+7 days) after receiving their last dose of study 
drug or before the start of subsequent systemic anticancer therapy to permit detection of any 
delayed TEAEs and to resolve any ongoing events. If a patient is not able to return for the EOT 
visit, the EOT assessments may be performed at the time of treatment discontinuation after 
discussion with the sponsor.  
To assess the resolution of any ongoing immune-mediated AEs or to document the occurrence of 
any new treatment-related immune-mediated AEs, patients will be contacted or have the option 
to return for a safety follow-up at 90-days (±3 days) after receiving their last dose of study drug 
or before the start of a subsequent systemic anticancer therapy, whichever occurs first. 
Patients who have discontinued treatment before documented disease progression will continue 
to have imaging assessments after EOT until disease progression or start of a subsequent 
systemic anticancer therapy, whichever occurs first. Subsequent systemic anticancer therapy will 
be documented. An end of study (EOS) case report form will be completed for all patients at last 
study contact. 
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6.3.2 
EOS and Study Completion Definition and Planned Reporting 
It is anticipated that this study will last for approximately 50 months. The final data cutoff for the 
clinical study report will be conducted after all patients have been discontinued from treatment or 
are transferred to a long-term safety study, single-patient and site-initiated Investigational New 
Drug, or a similar program (see Section 6.3.5). 
6.3.3 
Timeframes for Primary and Secondary Endpoints to Support Disclosures 
Refer to Table 6.a for disclosures information for all primary and secondary endpoints. 
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Table 6.a 
Primary and Secondary Endpoints for Disclosures 
Endpoint 
Definition 
Maximum Time 
Frame a 
Primary 
 
 
Frequency and severity of TEAEs 
Standard safety assessments 
Up to ~50 months 
Number of patients with DLTs 
Standard safety assessments 
Up to ~50 months 
Number and percentage of patients with 1 or 
more treatment-emergent SAE 
Standard safety assessments 
Up to ~50 months 
Number and percentage of patients with 1 or 
more TEAEs leading to dose modifications 
and/or treatment discontinuations 
Standard safety assessments 
Up to ~50 months 
Secondary 
 
 
PAD range 
Evaluation of pharmacodynamic 
activity 
Up to ~50 months 
Dose for further development 
Evaluation of pharmacodynamic 
activity 
Up to ~50 months 
PK parameters after administration of TAK-500: 
Cmax, tmax, AUCt, AUC∞, t1/2z, CL, Vss 
Standard PK parameters to allow 
determination of PK profile 
Up to ~50 months 
ORR (cCR + cPR) per RECIST v1.1 
ORR per RECIST v1.1 
Up to ~50 months 
DCR (cCR + cPR + SD) 
DCR 
Up to ~50 months 
DOR 
DOR 
Up to ~50 months 
TTR 
TTR 
Up to ~50 months 
PFS b 
PFS 
Up to ~50 months 
OS b 
OS 
Up to ~50 months 
Intratumoral T-cell infiltration upon TAK-500 
treatment 
Evaluation of pharmacodynamic 
activity 
Up to ~50 months 
Incidence of patients who are ADA-positive and 
acquired immunogenicity 
Immunogenicity 
Up to ~50 months 
ADA: antidrug antibody; AUCt: area under the serum concentration-time curve from time 0 to time t; AUC∞: area 
under the serum concentration-time curve from time 0 to infinity; cCR: confirmed complete response; CL: total 
clearance after intravenous administration; Cmax: maximum observed serum concentration; cPR: confirmed partial 
response; DCR: disease control rate; DLT: dose-limiting toxicity; DOR: duration of response; IFN: interferon; 
ORR: overall response rate; OS: overall survival; PAD: pharmacologically active dose; PFS: progression-free 
survival; PK: pharmacokinetic(s); RECIST: Response Evaluation Criteria in Solid Tumor; SAE: serious adverse 
event; SD: stable disease; STING: Stimulator of Interferon Genes; t1/2z: terminal disposition phase half-life; 
TEAE: treatment-emergent adverse event; tmax: time of first occurrence of Cmax; TTR: time to response; v: 
version; Vss: volume of distribution at steady state after intravenous administration. 
a Maximum time frame to last assessment for that endpoint for the study. 
b For phase 2 expansion cohort only. 
 
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6.3.4 
Total Study Duration 
It is anticipated that this study will last for approximately 50 months. 
Study start is defined as the first patient signing the informed consent form (ICF), and study end 
is defined as the last patient last contact. 
6.3.5 
Poststudy Access 
Patients who are still on study treatment after the estimated study completion time of 
approximately 50 months will be allowed to continue to receive TAK-500 in poststudy access for 
this study, in a separate open-label rollover study, other poststudy access, such as through a 
single-patient Investigational New Drug application or equivalent. The mechanism of access will 
depend on the number of patients who require it. This access will be permitted only when the 
investigator and sponsor confirm that a patient has experienced a clinically important response to 
TAK-500 that outweighs the potential risks of continued treatment. Additionally, these patients 
should have no comparable or satisfactory alternative therapeutic option and would be negatively 
affected without continued access. 
6.3.5.1 
Duration of Poststudy Access 
Continued access to TAK-500 in poststudy access will be terminated for those individuals who 
no longer benefit (eg, they have completed the recommended course of therapy, or their disease 
has progressed), the benefit-risk no longer favors the individual, or when an alternative 
appropriate therapy becomes available. Poststudy access may be terminated in a country or 
geographical region where marketing authorization has been rejected, the development of 
TAK-500 has been suspended or stopped by the sponsor, or TAK-500 is no longer manufactured. 
7.0 
STUDY POPULATION 
7.1 
Inclusion Criteria 
Each patient must meet all the following inclusion criteria to be enrolled in the study: 
1. Male or female patients aged 18 years or older. 
2. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1. 
3. Patients with the following pathologically confirmed (cytological diagnosis is adequate) 
locally advanced or metastatic solid tumors, whose disease has progressed on or are 
intolerant to standard therapy: 
a) For dose escalation with TAK-500 SA and combination TAK-500 with pembrolizumab:  
• Patients with the following pathologically confirmed (cytological diagnosis is 
adequate) locally advanced or metastatic solid tumors, whose disease has 
progressed on or are intolerant to all standard therapy: gastroesophageal 
(esophageal, gastroesophageal junction, and gastric) adenocarcinoma, 
pancreatic adenocarcinoma, HCC, nonsquamous NSCLC, SCCHN, 
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mesothelioma, TNBC, RCC, and NPC. Patients who are intolerant to all 
standard therapies are those who have developed clinical or laboratory 
abnormalities that prevent continued drug administration as evaluated by the 
principal investigator at the time of screening. 
b) For dose expansion in 2L nonsquamous NSCLC (TAK-500 plus pembrolizumab): 
• Patients with pathologically confirmed (cytological diagnosis is adequate) 
locally advanced or metastatic nonsquamous NSCLC.  
• Patients may not have a known targetable driver mutation, rearrangement or 
amplification (eg, EGFR, ALK, MET, ROS1, BRAF, KRASG12C, etc.). 
• Must have had disease progression while on or following 1 prior line of 
therapy:  
1. Disease progression while on or following at least 6 weeks of 1 prior 
anti-PD-(L)1 therapy in the recurrent locally advanced or metastatic 
setting. 
OR 
Disease progression/recurrence within 6 months of the completion of 
anti-PD-(L)1 therapy if administered in the adjuvant/neoadjuvant 
setting.  
Prior anti-PD-(L)1 therapy may have been given with or without an 
anti-CTLA4 antibody and/or chemotherapy (eg, carboplatin and 
pemetrexed). 
• Patients are eligible regardless of PD-L1 status. 
c) For dose expansion in 3L nonsquamous NSCLC (TAK-500 SA): 
• Patients with pathologically confirmed (cytological diagnosis is adequate) 
locally advanced or metastatic nonsquamous NSCLC.  
• Patients may not have a known targetable driver mutation, rearrangement or 
amplification (eg, EGFR, ALK, MET, ROS1, BRAF, KRASG12C, etc.). 
• Must have had disease progression while on or following 2 prior lines of 
therapy:  
1. Disease progression while on or following at least 6 weeks of 1 prior 
anti-PD-(L)1 therapy in the recurrent locally advanced or metastatic 
setting 
OR 
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Disease progression/recurrence within 6 months of the completion of 
1 prior anti-PD-(L)1 therapy if administered in the 
adjuvant/neoadjuvant setting.  
Prior anti-PD-(L)1 therapy may have been given with or without an 
anti-CTLA4 antibody and/or chemotherapy (eg, carboplatin and 
pemetrexed). 
2. Patients must have had disease progression while on or after 1 or 2 lines 
of chemotherapy in the recurrent locally advanced or metastatic setting. 
If the anti-PD-(L)1 therapy is given in combination with chemotherapy, 
patient must have progressed on an additional line of chemotherapy. 
• Patients are eligible regardless of PD-L1 status. 
d) For dose expansion in 2L pancreatic adenocarcinoma (TAK-500 SA and TAK-500 plus 
pembrolizumab): 
• Patients with pathologically confirmed (cytological diagnosis is adequate) 
locally advanced or metastatic pancreatic adenocarcinoma.  
• Must have had disease progression while on or following 1 prior line of 
therapy:  
1. One prior line of fluorouracil- or gemcitabine-based chemotherapy (eg, 
FOLFIRINOX, FOLFOX, FOLFIRI, gemcitabine/nab-paclitaxel) in the 
metastatic/recurrent locally advanced setting. 
Prior chemotherapy in the neoadjuvant/adjuvant setting does not 
qualify unless the patient had progression of disease within 6 months of 
completion of neoadjuvant/adjuvant chemotherapy. 
• Must not have had prior exposure to anti-PD-(L)1 therapy.  
• Patients with MSI-H/dMMR disease are not eligible.  
• Patients are eligible regardless of PD-L1 status. 
e) For dose expansion in 3L RCC (TAK-500 plus pembrolizumab): 
• Patients with pathologically confirmed (cytological diagnosis is adequate) 
locally advanced or metastatic RCC.  
• Must have had disease progression while on or following 2 prior lines of 
therapy:  
1. Disease progression while on or following at least 6 weeks of 1 prior 
anti-PD-(L)1 therapy in the recurrent locally advanced or metastatic 
setting. 
OR 
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Disease progression/recurrence within 6 months of the completion of 
anti-PD-(L)1 therapy if administered in the adjuvant/neoadjuvant 
setting.  
Prior anti-PD-(L)1 therapy may have been given with or without an 
anti-CTLA4 antibody and/or an anti-VEGFR TKI.  
2. Patients must have had prior therapy with 1 or 2 lines of VEGFR TKIs 
in the metastatic/recurrent locally advanced setting. If anti-PD-(L)1 
therapy was given in combination with a VEGFR TKI, the patient must 
have had progressive disease on an additional line of therapy (eg, 
VEGFR TKI or VEGFR TKI-containing combination). 
• Patients are eligible regardless of PD-L1 status. 
4. Patients must have at least 1 RECIST v1.1 measurable lesion. Lesions in previously 
irradiated areas (or other local therapy) should not be selected as measurable/target lesions 
unless there has been demonstrated radiographic progression in that lesion. RECIST v1.1 
target lesions must include at least 1 lesion that was not previously irradiated.  
5. Once a DL is reached where evidence of TAK-500 stimulation of the 
 
 has been observed in the blood and/or a clinical response (PR or CR) 
measured in at least 1 patient, subsequent patients treated at the equivalent or higher DL will 
be required to have 2 biopsies (at screening and on treatment), assuming the potential 
morbidity of the procedures is deemed acceptable by the treating physician. 
6. Adequate bone marrow, renal, and hepatic functions, as determined by the following 
laboratory parameters: 
• Absolute neutrophil count (ANC) ≥1000/μL, platelet count ≥75,000/μL, and hemoglobin 
≥8.0 g/dL without growth factor support for ANC or transfusion support for platelets 
within 14 days before the first study treatment dose. 
• Total bilirubin ≤1.5 times the institutional upper limit of normal (ULN). For patients with 
Gilbert’s disease or HCC, ≤3 mg/dL. 
• Serum ALT and AST ≤3.0 × ULN or ≤5.0 × ULN with liver metastases or HCC. 
• Albumin ≥3.0 g/dL. 
• Calculated creatinine clearance using the Cockcroft-Gault formula (Cockcroft and Gault 
1976) ≥30 mL/minute. 
7. For patients with HCC only: Child-Pugh score less than or equal to 7 (Child-Pugh A or B7). 
8. Left ventricular ejection fraction (LVEF) >50%, as measured by echocardiogram or 
multiple-gated acquisition scan (MUGA) within 4 weeks before receiving the first dose of 
study drug. 
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9. Clinically significant toxic effects of previous therapy have recovered to Grade 1 (per NCI 
CTCAE v5.0) or baseline, except for alopecia, Grade 2 peripheral neuropathy, and/or 
autoimmune endocrinopathies with stable endocrine replacement therapy. 
10. Patients previously treated with fully human/humanized antineoplastic monoclonal 
antibodies must not have received treatment with such antibodies for at least 4 weeks or the 
time period equal to the dosing interval, whichever is shorter. No washout period is required 
for prior treatment with pembrolizumab or other anti–PD-1 antibodies, although the first 
study dose of these drugs must not occur at an interval less than standard of care (ie, 3 weeks 
for 200 mg of IV pembrolizumab). 
11. Suitable venous access for the collection of study-required blood sampling, including PK and 
pharmacodynamic blood samples. 
12. Female patients must be: 
• Postmenopausal (natural amenorrhea and not due to other medical reasons) for at least 
1 year before the screening visit, or 
• Surgically sterile, or 
• If they are of childbearing potential, agree to practice 2 effective methods of 
contraception at the same time, from the time of signing the informed consent through 
180 days after the last dose of study drug(s), or 
• Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the patient. 
– Note: Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation 
methods), withdrawal, spermicides only, and lactational amenorrhea are not 
acceptable methods of contraception. 
13. Male patients, even if surgically sterilized (ie, status postvasectomy), must: 
• Agree to practice effective barrier contraception during the entire study treatment period 
and through 180 days 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. 
– Note: Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation 
methods), withdrawal, spermicides only, and lactational amenorrhea are not 
acceptable methods of contraception. 
14. Voluntary written consent must be given before performance of any study-related procedure 
not part of standard medical care, with the understanding that consent may be withdrawn by 
the patient at any time without prejudice to future medical care. 
15. Patients must be eligible for treatment with pembrolizumab at the dose(s) and schedule(s) 
recommended in the label/prescribing information, where applicable. 
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7.2 
Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not to be enrolled in the study. 
1. History of any of the following ≤6 months before first dose of study drug(s): congestive heart 
failure New York Heart Association Grade III or IV, unstable angina, myocardial infarction, 
persistent hypertension ≥160/100 mm Hg despite optimal medical therapy, ongoing cardiac 
arrhythmias of Grade >2 (including atrial flutter/fibrillation or intermittent ventricular 
tachycardia), other ongoing serious cardiac conditions (eg, Grade 3 pericardial effusion or 
Grade 3 restrictive cardiomyopathy), or symptomatic cerebrovascular events. Chronic, stable 
atrial fibrillation on stable anticoagulation therapy, including low molecular-weight heparin, 
is allowed. 
2. QT interval with Fridericia correction method (QTcF) >450 milliseconds (men) 
or >475 milliseconds (women) on a 12-lead ECG during the screening period. 
3. Grade ≥2 hypotension (ie, hypotension for which nonurgent intervention is required) at 
screening or during C1D1 predose assessment. 
4. Oxygen saturation <92% on room air at screening or during C1D1 predose assessment. 
5. Patients treated with other STING agonists/antagonists, Toll-like receptor agonists, or CCR2 
agonist/antagonist within the past 6 months. 
6. Exclusion criterion removed 
7. Exclusion criterion removed 
8. Active diagnosis of pneumonitis, interstitial lung disease, severe chronic obstructive 
pulmonary disease, idiopathic pulmonary fibrosis, other restrictive lung diseases, acute 
pulmonary embolism, or Grade ≥2 pleural effusion not controlled by tap or requiring 
indwelling catheters. 
9. History of brain metastasis or leptomeningeal disease unless: 
• Brain metastases are stable on cranial imaging (ie, ≥4 weeks) following prior surgery, 
whole-brain radiation, or stereotactic radiosurgery, and 
• Off corticosteroids for brain metastases. 
10. Grade ≥2 fever of malignant origin. 
11. Systemic infection requiring IV antibiotic therapy or other serious infection within 14 days 
before the first dose of study drug. Patients are specifically excluded if they have active, 
severe infections such as tuberculosis (screening per local practice and epidemiology), sepsis, 
cytomegalovirus (including cytomegalovirus colitis), listeriosis, and opportunistic infections 
(including Clostridium difficile) until the infections are controlled. 
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12. Patients with either/both of: 
• Uncontrolled, known or suspected, autoimmune disease. Patients with vitiligo, type I 
diabetes mellitus, residual hypothyroidism due to an autoimmune condition only 
requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions 
not expected to recur in the absence of an external trigger are permitted to enroll. 
• A diagnosis of an identified congenital or acquired immunodeficiency (eg, common 
variable immunodeficiency, uncontrolled HIV infection, organ transplantation). 
13. Chronic, active hepatitis (eg, patients with known hepatitis B surface antigen seropositive 
and/or detectable hepatitis C virus [HCV] RNA). 
• Note: Patients who have positive hepatitis B core antibody can be enrolled but must have 
an undetectable serum hepatitis B virus-DNA. Patients who have positive HCV antibody 
must have an undetectable HCV-RNA serum level. 
14. History of hepatic encephalopathy. 
15. Prior or current clinically significant ascites, as measured by physical examination, that 
requires active paracentesis for control. 
16. Any pre-existing condition or illness, metabolic dysfunction, physical examination finding, 
or clinical laboratory finding that give reasonable suspicion of a disease or condition that 
would contraindicate the use of an investigational drug or that would limit compliance with 
study requirements or compromise ability to provide written informed consent. 
17. Treatment with any investigational products or other anticancer therapy (including 
chemotherapy, targeted agents, and immunotherapy), within 14 days or 5 half-lives, 
whichever is shorter, before C1D1 of study drug(s). 
18. Concurrent chemotherapy, immunotherapy (except for pembrolizumab in the combination 
arm), biologic, or hormonal therapy (except for adjuvant endocrine therapy for a history of 
breast cancer). Concurrent use of hormones for noncancer-related conditions is acceptable 
(except for corticosteroid hormones). 
19. Radiation therapy within 14 days (42 days for radiation to the lungs) and/or systemic 
treatment with radionuclides within 42 days before C1D1 of study drug(s). Patients with 
clinically relevant ongoing pulmonary complications from prior radiation therapy are not 
eligible. 
20. Use of systemic corticosteroids or other immunosuppressive therapy, concurrently or within 
7 days of C1D1 of study drug(s), with the following exceptions: 
• Topical, intranasal, inhaled, ocular, intra-articular, and/or other nonsystemic 
corticosteroids.  
• Physiological doses of replacement steroid therapy (eg, for adrenal insufficiency), not to 
exceed the equivalent of 10 mg prednisone daily. 
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21. Use of medications that are known clinical OATP1B1 and/or OATP1B3 inhibitors, 
concurrently or within 14 days of C1D1 of study drug(s) (see Appendix D). 
22. Receipt of live attenuated vaccine (eg, tuberculosis Bacillus Calmette-Guerin vaccine, oral 
polio vaccine, measles, rotavirus, yellow fever) within 28 days of C1D1 of study drug(s). 
Nonlive, approved vaccines are allowed (eg, coronavirus disease 2019 [COVID-19] vaccine). 
Note: COVID-19 vaccination should not be given ±3 days of systemic study treatments. 
23. Recipients of allogeneic or autologous stem cell transplantation or organ transplantation.  
24. Female patients who are lactating or have a positive serum/urine pregnancy test during the 
screening period or a positive serum/urine pregnancy test on Day 1 before first dose of study 
drug. 
Note: Female patients who are lactating will be eligible if they choose to discontinue 
breastfeeding before the first dose of study drug. 
Additional criteria specific for patients in TAK-500 and pembrolizumab combination arm only: 
25. Contraindication to the administration of pembrolizumab or prior intolerance to 
pembrolizumab or other anti–PD-1 or anti–PD-L1 antibody.  
26. History of intolerance to any component of the study treatment agents or known serious or 
severe hypersensitivity reaction to any of the study drugs or their excipients. (Pembrolizumab 
is formulated with L-histidine, polysorbate 80, and sucrose.) 
8.0 
STUDY DRUG 
Investigational medicinal product(s): TAK-500 drug product. 
Combination product: 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).  
Additional details regarding investigational medicinal product(s) can be found in the pharmacy 
manual. In instances of a discrepancy between the protocol text and the pharmacy manual 
regarding the investigational medicinal product, the pharmacy manual shall supersede the text 
within the protocol.  
8.1.1 
TAK-500 
Route of administration: IV infusion administered as directed in the pharmacy manual. 
DL: To be assigned at time of enrollment. 
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Dose Escalation: TAK-500 will be administered as an IV infusion on a dosing schedule of Q3W 
or Q2W, as assigned at time of enrollment, in a 21-day (Q3W) or 42-day (Q2W) cycle. 
Dose Expansion: TAK-500 will be administered as an IV infusion on a dosing schedule of 
either Q2W or Q3W, as assigned at time of enrollment, in a 42-day cycle. 
Alternate dosing schedules of administration in combination with pembrolizumab may also be 
considered during dose escalation if the collective data including safety, PK, and 
pharmacodynamics support it, without requiring a protocol amendment. TAK-500, 
pembrolizumab and other drugs must not be administered through the same infusion line. 
TAK-500 will be administered by IV infusion at a defined infusion rate. Detailed dosage 
preparation and dose administration instructions are provided in the Directions for Use located in 
the pharmacy manual. Administration should always be performed on schedule; however, if 
extenuating circumstances prevent a patient from beginning treatment on a particular dosing day, 
a ±3-day window may be allowable. On the basis of emerging data (eg, severity of infusion-
related reactions), the infusion time may be adjusted to less than the defined time on agreement 
with the sponsor and investigators. The infusion may be slowed or stopped and restarted for any 
infusion-related reactions. All infusion times must be recorded.  
Due to the risk of developing CRS after administration of TAK-500, 
 
 
 
 
 
 
 
 
 
. 
Enrollment of SA TAK-500 or TAK-500 + pembrolizumab combination dose escalation cohorts 
with premedication may proceed in parallel with cohorts enrolling without premedication or with 
different premedication regimens, with each premedication regimen separately following the 
BOIN design for dose escalation/de-escalation decisions. 
 
 
 
 
.  
For administrations of TAK-500, vital signs will be measured immediately before the start of the 
infusion (within 30 minutes), 30 minutes after start of infusion (±5 minutes), at the EOI 
(±10 minutes), 1 hour after infusion (±10 minutes), any time when clinically indicated, and 
before discharge. For infusion times of less than 30 minutes, vital signs will be measured 
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immediately before the start of the infusion (within 30 minutes), at the EOI (±5 minutes), 
30 minutes after EOI (±5 minutes), and at 1 hour after infusion (±10 minutes). On C1D1 vital 
signs will also be measured at 3 and 6 hours after dosing of TAK-500 (measurement should be 
obtained in a ±30-minute window). Vital signs should be measured and recorded at any time if 
the patient develops symptoms associated with potential risks of TAK-500 and/or 
pembrolizumab. The frequency and timing of vital sign monitoring may be modified on the basis 
of emerging data and agreement between sponsor and investigators. 
TAK-500 administration will occur in facilities with readily available resuscitation equipment, 
diagnostic equipment and supportive care/medications such as oxygen, antihistamines, 
acetaminophen, corticosteroids, epinephrine, anti–IL-6 agents, and bronchodilators. 
As with other potentially toxic compounds, caution should be exercised in handling this drug. 
The use of gloves is recommended. Given the possibility of extravasation, it is advisable to 
closely monitor the infusion site per nursing institutional guidelines for possible infiltration 
during drug administration. Administration through a central port is always preferred versus a 
peripheral line. 
For TAK-500 SA dose escalation, TAK-500 will be administered as described in Section 6.1.1.  
For detailed information on the preparation and administration of TAK-500, refer to the 
pharmacy manual. 
8.1.2 
Pembrolizumab 
Route of administration: IV infusion administered as directed in the most current product 
information available for pembrolizumab (eg, package insert). 
DL: 200 mg. 
Pembrolizumab will be administered on C1D1 at 200 mg IV following the label and on a Q3W 
basis thereafter. Administration will continue until disease progression, intolerance to 
pembrolizumab (defined as the development of a TEAE that is at least possibly related to 
pembrolizumab and for which dose discontinuation is recommended), or withdrawal of consent, 
whichever occurs first. 
For administrations of pembrolizumab, vital signs will be measured immediately before the start 
of the infusion (within 30 minutes) and any time when clinically indicated. 
For preparation, handling, and administration instructions related to pembrolizumab, please 
consult the pharmacy manual and the most current product information available for 
pembrolizumab (eg, package insert). 
8.1.3 
TAK-500 in Combination With Pembrolizumab 
This combination arm will be initiated at a TAK-500 DL of 80 µg/kg, triggered upon safety 
clearance of the 80 µg/kg TAK-500 SA DL. If it is determined during the SA dose escalation 
that the TAK-500 SA minimum PAD is ≤40 µg/kg, the combination TAK-500 plus 
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pembrolizumab dose escalation will begin at a dose no higher than the TAK-500 SA minimum 
PAD DL. The combination dose escalation may begin at a DL of TAK-500 that is below the 
TAK-500 SA PAD if this is determined to be necessary from the evaluation of safety and 
toxicity data. 
For both the dose escalation and dose expansion cohort(s), TAK-500 may be administered in 
either a Q2W or Q3W dosing schedule, as described in Sections 6.1.1 and 6.1.3. TAK-500 will 
be administered on Day 1 of each cycle in combination with 200 mg pembrolizumab 
administered IV Q3W following the label instructions. On days when both drugs are 
administered (ie, Day 1 of each cycle), pembrolizumab should be administered first, followed by 
TAK-500, with a 1-hour interval between completion of pembrolizumab infusion and the 
administration of TAK-500. Alternative schedules of administration of TAK-500 in combination 
with pembrolizumab may be considered if clinical safety, PK, and pharmacodynamics data 
support it. If TAK-500 dosing is delayed for any reason, pembrolizumab dosing should also be 
delayed to coincide with TAK-500 administration. 
The same inpatient and outpatient vital sign monitoring described in Sections 8.1.1 and 8.1.2 will 
be performed for administration of TAK-500 with the pembrolizumab combination. 
For detailed information on the preparation and administration of TAK-500, refer to the 
pharmacy manual. 
8.1.4 
List of European Union Auxiliary Medicinal Products 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
.  
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Table 8.a 
  
 
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8.2 
Definitions of DLT 
Toxicity will be evaluated according to the NCI CTCAE v5.0, effective 27 November 2017. A 
DLT will be defined as any of the following phase 1 TEAEs, that occur during the first 21 days 
on study (through C1D21) and are considered by the investigator to be at least possibly related to 
TAK-500 as an SA or in combination with pembrolizumab. (Note that AEs in which the 
relationship to study drug cannot be ruled out should be considered possibly related to study 
drug.) 
1. Any Grade 5 AE. 
2. Grade 4 anemia. 
3. Grade 4 neutropenia lasting ≥5 days or requiring use of granulocyte colony-stimulating factor 
(G-CSF). 
4. Any febrile neutropenia. 
5. Platelet count <10,000/μL at any time. 
6. Grade 4 thrombocytopenia lasting ≥5 days; or Grade ≥3 thrombocytopenia with clinically 
significant bleeding. 
7. Grade ≥3 CRS. 
8. Grade ≥2 immune-mediated uveitis that does not respond to topical therapy and does not 
improve to Grade ≤1 severity within 2 weeks of the initiation of topical therapy OR requires 
systemic treatment. 
9. Delay in the initiation of Cycle 2 by more than 14 or 21 days (for Q2W and Q3W 
administration schedule of TAK-500, respectively) from the calculated start date due to a 
lack of adequate recovery of treatment-related hematological or nonhematologic toxicities. 
10. Any Grade ≥3 nonhematologic toxicity with the following exceptions:  
• Grade 3 arthralgia/myalgia that responds to nonsteroidal anti-inflammatory drugs within 
1 week. 
• Grade 3 fatigue lasting less than 7 days. 
• Any Grade 3 endocrinopathy that is adequately controlled by hormonal replacement. 
• Grade 3 or 4 inflammatory reaction attributed to a local antitumor response (defined as 
local pain, irritation, or rash localized at sites of known or suspected tumor). 
• Transient (≤48 hours) Grade 3 flu-like symptoms, which resolve spontaneously or are 
controlled with medical management. 
• Grade 3 asymptomatic laboratory changes (other than renal function) that can be 
successfully corrected (reversion of Grade ≤1 or baseline) within 3 days. 
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• The following Grade 4 asymptomatic laboratory changes: creatine kinase increased, 
gamma glutamyl transferase increased, and alkaline phosphatase increased. 
• Grade 3 nausea and/or emesis that can be controlled to Grade ≤1 in ≤3 days with the use 
of antiemetics (such as metoclopramide, prochlorperazine, serotonin type 3 receptor 
[5-HT3] antagonist and/or neurokinin-1 receptor antagonists).  
• Grade 3 rash and pruritis that respond to a standard treatment and resolve or improve to 
Grade <3 within 7 days. 
• Grade 3 diarrhea that can be controlled to Grade ≤2 in ≤3 days with supportive treatment. 
• Alopecia. 
• Transient (< 4-hour) Grade 3 hypertension occurring in association with CRS-related 
rigor, which resolves either spontaneously or with medical management. 
TEAEs meeting DLT definitions occurring after 21 days on study will be considered in the 
determination of the dose for further development of TAK-500, both in the TAK-500 SA and the 
combination with pembrolizumab. 
8.3 
Dose Escalation Rules 
8.3.1 
BOIN Dose Escalation 
Except for the initial 2 TAK-500 SA 1 + 2 + 3 accelerated titration cohorts, dose escalation of 
TAK-500 in both the SA and combination arms will follow the BOIN design to inform dose 
escalation decisions and potential MTD estimation, as described in Appendix F. Each DL of 
TAK-500 following the BOIN dose escalation will enroll 3 patients initially. A cohort size 
different from 3 is permissible thereafter per the escalation/de-escalation guidelines outlined in 
Appendix F, Table F-1. There will be a 24-hour dosing delay between the first patient of any 
new DL and subsequent patients enrolled at the same DL. The target toxicity rate is ϕ = 0.3. To 
guide dose escalation decisions, if the observed DLT rate at the current dose is ≤0.236, the next 
cohort of patients will be treated at the next higher DL; if it is ≥0.358, the next cohort of patients 
will be treated at the next lower DL; if it is within 0.236 and 0.358, additional patients will be 
enrolled in this DL. For the purpose of overdose control, dose j and higher levels will be 
eliminated from further examination if Pr(pj>0.3 | data) >0.95, where pj is the true DLT rate of 
DL j. When the lowest dose is eliminated, the dose escalation will be stopped for safety. Dose 
escalation will continue until either: (1) the maximum sample size is reached, or (2) the number 
of patients treated at the current DL reaches 9 and the recommendation is to retain at the current 
DL.  
In the SA dose escalation, after the BOIN escalation starts, the maximum number of DLT 
evaluable patients to be enrolled is 42 (40 rounded up to the nearest multiple of 3). In the 
combination escalation, the maximum number of DLT-evaluable patients to be enrolled depends 
on the starting DL. In principle, we plan an average of about 5 patients per DL from the starting 
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DL to 480 µg/kg. For example, if the starting DL is 80 µg/kg, the maximum number of 
DLT-evaluable patients to be enrolled is 27 (25 rounded up to the nearest multiple of 3). 
Isotonic regression will be used on the cumulative DLT rate for each DL to determine the MTD, 
defined as the highest TAK-500 dose as an SA or in combination with pembrolizumab that does 
not result in unacceptable toxicity. Note that dose escalation cohorts treated with a specific 
premedication regimen will be analyzed separately from cohorts treated without premedication 
or with other premedication regimens. 
8.3.2 
Stopping Rules 
The sponsor may stop or halt enrollment or treatment of ongoing patients, depending on the 
nature and severity of a safety-related event. A final decision to terminate the study or a protocol 
amendment will be made only after a full review of the safety data by the sponsor’s Safety 
Management Team and the investigators. 
A threshold of fatal AEs related to TAK-500 SA or TAK-500 and pembrolizumab treatment will 
initially be set at 6% per arm. Any rate of fatal events related to TAK-500 SA or TAK-500 + 
pembrolizumab combination therapy that is over 6% with at least an 80% posterior probability 
will result in stopping the study. The study will also be stopped if the rate of TAK-500 
SA-related or TAK-500 + pembrolizumab combination therapy–related Grade ≥4 events in any 
nonhematologic System Organ Class exceeds 25% per arm (with the exception of Grade ≥4 
asymptomatic laboratory abnormalities) with at least an 80% posterior probability. A study stop 
for a safety issue will result in an immediate halt in enrollment and may also necessitate 
cessation of treatment of ongoing patients, depending on the nature and the severity of the safety 
risk. A final decision to terminate the study will be made only after a full review of the safety 
data by the sponsor and the safety management team. 
8.4 
Definition of PAD 
Determination of the PAD dose range for TAK-500 will be used to inform decision-making 
regarding selection of the starting dose for the combination with pembrolizumab dose escalation 
and for dose selection for both the SA and combination dose expansion cohorts. PAD for 
TAK-500 is defined as any dose at which there is evidence of TAK-500–mediated 
pharmacodynamic effects and may include, but is not limited to: 
– Evidence of 
 in peripheral blood. 
– Evidence of 
 in peripheral blood. 
OR 
– Clinical evidence of antitumor activity (eg, PR or CR) as determined by RECIST v1.1 
(Section 9.4.13). 
To enhance and refine PAD and dose selection for expansion cohorts, additional peripheral and 
tumoral pharmacodynamic biomarkers will be assessed. Peripheral pharmacodynamic 
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biomarkers may include 
 
. 
8.5 
Dose Modification Guidelines 
Treatment with TAK-500 as an SA or in combination with pembrolizumab will occur in 21- or 
42-day cycles. Toxicities are to be assessed according to the NCI CTCAE v5.0. All toxicities that 
occur during the study will be actively managed following the System Organ Class unless 
otherwise specified in the protocol. The causal relationship of any reported events (AEs or 
SAEs) should be assessed by the investigator in relation to TAK-500, pembrolizumab, or both. 
Patients experiencing AEs attributed to TAK-500 as an SA or in combination with 
pembrolizumab may continue study treatment and maintain the same dose, have doses held, have 
doses of TAK-500 reduced, or permanently discontinue from the study. Patients who have the 
TAK-500 dose held due to a treatment-related or possibly related AE may resume study drug 
after resolution of the AE, and may either maintain the same DL or have doses of TAK-500 
reduced after consultation with the sponsor. When a dose reduction occurs, the TAK-500 dose 
will be reduced to the next lower dose that has been established as a safe dose during dose 
escalation. If initial dose adjustment does not provide sufficient relief, the dose of TAK-500 can 
be further reduced if the treating physician considers that the patient is benefiting from study 
treatment. If TAK-500 dosing is delayed for more than 14 or 21 days (for Q2W and Q3W 
dosing, respectively) beyond scheduled dosing for TAK-500–related or possibly related 
toxicities, despite maximal supportive treatment per standard clinical practice or if more than 
2 dose reductions are required in a patient, the patient will have study treatment discontinued. 
For AEs that occur during the study but are not related to TAK-500 or pembrolizumab, the dose 
modification of TAK-500 and/or pembrolizumab, in principle, is not required. However, on the 
basis of medical conditions and the possibility of potential worsening of toxicities by the 
continued administration of TAK-500 and/or pembrolizumab, investigators in consultation with 
the sponsor can decide to have the TAK-500 and/or pembrolizumab dose held or reduced (in the 
case of TAK-500) until the resolution of the AE in consultation with the sponsor, as needed. 
Dose modification guidelines for TAK-500 are described in Table 8.b and Table 8.c on the basis 
of the nature and severity of AEs and causality determination by investigators. Further 
clarification can be obtained in consultation with the sponsor. The pembrolizumab dose cannot 
be reduced; it may only be skipped (ie, patient is not dosed), interrupted (ie, dosing is paused 
during infusion), or discontinued. 
8.5.1 
Intrapatient Dose Escalation 
Intrapatient dose escalation will not be permitted as part of the DLT-evaluable dose escalation 
set, but patients treated at TAK-500 SA DLs below minimum PAD (as discussed in Section 8.4) 
will be allowed to escalate to minimum PAD once the minimum PAD DL has been confirmed 
and cleared from a safety perspective. 
For patients to be eligible for intrapatient dose escalation, they must continue on study without 
interruption and without evidence of progressive disease by imaging or clinical deterioration. 
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8.5.2 
Criteria for Crossover From SA to Combination Treatment 
Crossover is optional and at the discretion of the site investigator and sponsor and in agreement 
with the patient. Patients with objective evidence of PD in the TAK-500 SA treatment arm may 
crossover to the TAK-500 + pembrolizumab combination arm into the last DL that is or was 
accruing patients. Crossover to combination treatment will not be possible until the completion 
of the first TAK-500 + pembrolizumab dosing cohort. 
The sponsor will use the SA data from crossover patients in the primary analysis, but after 
crossover will then consider these patients a separate cohort so as to not confound their data with 
the patients originally enrolled into the combination arm. 
Patients who meet the following criteria are eligible for crossover: 
• Documentation of PD on TAK-500 SA regardless of prior exposure to PD-1/PD-L1; no 
evidence of uncontrolled brain metastases or any other uncontrolled CNS disease. 
• Complete an EOT visit for TAK-500 SA (must occur before initiation of combination 
therapy). 
• ECOG Performance Status 0 to 1. 
• No DLT or DLT-like toxicity at the TAK-500 SA DL. 
• Patient has no contraindication for treatment with pembrolizumab. 
Crossover combination therapy must begin within 28 days of documentation (CT or MRI) of PD 
and the full EOT assessments must be completed. Patients will complete procedures as described 
in the SOE starting again at C1D1 with the combination therapy and the data would be entered 
on case report forms for crossover. 
If crossover is approved, TAK-500 SA should continue through the EOT visit and initiation of 
pembrolizumab.  
8.5.3 
Criteria for Administering a Subsequent Dose/Starting a New Treatment Cycle 
Treatment with TAK-500 as an SA or in combination with pembrolizumab will use a cycle 
length of 21 days for Q3W dosing of TAK-500 and 42 days for Q2W dosing of TAK-500 in dose 
escalation. A cycle length of 42 days will be used in dose expansion. For a subsequent dose of 
TAK-500 to be administered, or a new cycle of treatment to begin, the patient must meet the 
following criteria: 
• ANC ≥1000/µL, platelet count ≥75,000/µL, and hemoglobin ≥8.0 g/dL. 
• Total bilirubin ≤1.5 times the institutional ULN. For patients with Gilbert’s disease or HCC, 
≤3 mg/dL. 
• Serum ALT and AST ≤3.0 × ULN or ≤5.0 × ULN with liver metastases or HCC. 
• Estimated creatinine clearance using the Cockcroft-Gault formula ≥30 mL/minute. 
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• Oxygen saturation of ≥92% on room air. 
• Before administering a subsequent dose or starting a new treatment cycle, TAK-500–related 
or pembrolizumab-related AEs and/or clinically significant laboratory abnormalities must 
have returned to Grade ≤1 or baseline, except for alopecia, Grade 2 peripheral neuropathy, 
and/or autoimmune endocrinopathies with stable endocrine replacement therapy. 
If the patient does not meet the above cited criteria for re-treatment, treatment should be delayed 
by 1 week, at the end of which the patient will be re-evaluated to determine whether the criteria 
for re-treatment have been met. If a dose reduction is considered (eg, after 2 dose delays), 
TAK-500 will be reduced by 1 DL. For dose reduction criteria, please see Section 8.5.4. Should 
the start of the following cycle be delayed by more than 14 or 21 days (for Q2W and Q3W 
dosing, respectively), the patient should have study treatment discontinued unless the 
investigator in consultation with the sponsor considers that the patient will receive benefit by 
continuing in the study. For TAK-500 plus pembrolizumab combination cohorts, if dosing of 
TAK-500 is delayed, pembrolizumab dosing should also be delayed by the same period of time. 
This means that for Q3W dosing of TAK-500, TAK-500 and pembrolizumab will always dose 
on the same day.  
8.5.4 
Criteria for Dose Modification 
Dosing of pembrolizumab cannot be reduced, only delayed, skipped, interrupted, or 
discontinued. Refer to the pembrolizumab prescribing information for recommended dose 
modification and/or discontinuation guidelines. 
Dosing of TAK-500 should be reduced according to the dose modification recommendations 
listed in Table 8.b for nonhematologic toxicity and Table 8.c for hematologic toxicities except 
for those AEs that are considered DLTs in Cycle 1 requiring discontinuation. If indicated, 
TAK-500 dose should be reduced by 1 DL (or by 50% if the patient is receiving the first DL). 
For Grade 1 and Grade 2 toxicities, the investigator may consider making a dose adjustment to 
TAK-500. For Grade ≥3 AEs, dose adjustments to TAK-500 must be made as indicated in the 
following tables. During this study, further adjustment to dose reduction guidelines may be made 
following discussion with the sponsor and study investigators. 
If the initial dose adjustment does not provide sufficient relief, the dose of TAK-500 can be 
further reduced by 1 additional DL with agreement by the sponsor if the treating physician 
believes that the patient is receiving benefit. Generally, once a dose is reduced, it will not be 
re-escalated. 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 DL after discussion with the sponsor and 
the treating physician. Additionally, after discussion with the sponsor, patients previously 
dose-reduced for a Grade 2 CRS occurring after dosing of TAK-500 without corticosteroid 
pretreatment (per Protocol Amendment 1), may be re-escalated with the addition of 
corticosteroid pretreatment before TAK-500 administration. If pursued, dose re-escalation for 
these patients should proceed by no more than 1 DL each cycle and may not exceed the initially 
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assigned DL. A patient can have up to 2 DL reductions of TAK-500 as an SA or in combination 
due to AEs, but further reductions are not permitted (the patient should discontinue study drug in 
this case). 
Table 8.b 
Guidelines for TAK-500 Dose Modification and/or Discontinuation for 
Nonhematologic Toxicity 
Refer to the pembrolizumab prescribing information for recommended discontinuation guidelines. 
NCI CTCAE Grade 
TAK-500 Dose Modification 
CRS 
Grade 1: 
Fever with or without constitutional 
symptoms 
• 
Continue TAK-500 at the same DL. 
Grade 2: 
Hypotension responding to fluids; hypoxia 
responding to <40% FiO2 
• 
Hold TAK-500 until recovers to Grade ≤1. 
• 
Once recovered, restart TAK-500 at the same dose. If the 
patient was not previously premedicated with corticosteroids, 
add corticosteroid pretreatment for subsequent doses of 
TAK-500. 
Grade 3: 
Hypotension managed with 1 pressor; 
hypoxia requiring ≥40% O2 
• 
Permanently discontinue TAK-500. 
Grade 4: 
Life-threatening consequences; urgent 
intervention indicated 
• 
Permanently discontinue TAK-500. 
Infusion-related reactions 
Grade 2 
• 
Hold TAK-500 infusion until symptoms resolve to Grade ≤1.  
• 
Resume at a slower rate. 
• 
Consider premedication before the subsequent dose. 
• 
Permanently discontinue if recurrent on re-challenging despite 
premedication use. 
Grade 3 or 4 
• 
Permanently discontinue TAK-500. 
Colitis 
Grade 2 or 3 
• 
Hold TAK-500 until improvement to a Grade ≤1 or baseline. 
• 
Resume at 1 lower DL. 
• 
Permanently discontinue if recurrent on re-challenging. 
Grade 4 
• 
Permanently discontinue TAK-500. 
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Table 8.b 
Guidelines for TAK-500 Dose Modification and/or Discontinuation for 
Nonhematologic Toxicity 
Refer to the pembrolizumab prescribing information for recommended discontinuation guidelines. 
NCI CTCAE Grade 
TAK-500 Dose Modification 
Hepatotoxicity 
AST/ALT <3 × ULN, or ≤5 × ULN in the 
case of known liver metastases 
• 
Continue TAK-500 at the same DL. 
• 
Hepatic laboratory tests, including ALT, AST, ALP, T-Bil, 
D-Bil, PT-INR, more than once a week is recommended until 
improved to AST/ALT ≤1.5 × baseline or ≤5.0 × ULN with 
liver metastases or HCC. 
AST/ALT >3-5 × ULN 
• 
Hold TAK-500 until resolution to AST/ALT ≤3.0 × ULN or 
≤5.0 × ULN with liver metastases or HCC. 
• 
Resume at same DL. 
• 
Permanently discontinue if recurrent on re-challenging. 
• 
Monitoring of hepatic laboratory tests, including ALT, AST, 
ALP, T-Bil, D-Bil, PT-INR is recommended until improved 
AST/ALT ≤1.5 × baseline. 
AST/ALT >5-10 × ULN 
• 
Hold TAK-500 until improvement to AST/ALT ≤3.0 × ULN 
or ≤5.0 × ULN with liver metastases or HCC. 
• 
Resume at 1 lower DL. 
• 
Permanently discontinue if recurrent on re-challenging. 
• 
Monitoring of hepatic laboratory tests, including ALT, AST, 
ALP, T-Bil, D-Bil, and PT-INR is recommended until 
improved AST/ALT ≤1.5 × baseline. 
AST/ALT >10 × ULN or Child-Pugh 
score ≥9 
• 
Permanently discontinue TAK-500. 
Elevated bilirubin 
(Grade 2) 
• 
Hold TAK-500 until resolution to T-Bil ≤1.5 × ULN or 
≤3 mg/dL for patients with Gilbert’s disease or HCC. 
• 
Resume at same DL. 
• 
Reduce by 1 lower DL if recurrent. 
Elevated bilirubin 
(Grade 3 or 4) 
• 
Permanently discontinue TAK-500. 
Endocrinopathies 
Grade 2 
• 
Continue TAK-500 at the same DL.  
• 
Replacement therapy as clinically indicated. 
Grade 3 or 4 
• 
Hold TAK-500 until clinically stable. 
• 
Resume at 1 lower DL. 
• 
Replacement therapy as clinically indicated. 
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Table 8.b 
Guidelines for TAK-500 Dose Modification and/or Discontinuation for 
Nonhematologic Toxicity 
Refer to the pembrolizumab prescribing information for recommended discontinuation guidelines. 
NCI CTCAE Grade 
TAK-500 Dose Modification 
Increased creatinine 
Grade 1 
• 
Continue TAK-500 at the same dose and monitor creatinine 
weekly. 
Grade 2 
• 
Hold TAK-500 until resolution to Grade ≤1 or baseline.  
• 
Resume at 1 lower DL. 
• 
Permanently discontinue if recurrent on re-challenging. 
Grade 3 and 4 
• 
Permanently discontinue TAK-500. 
Pneumonitis 
Grade 2 
• 
Hold TAK-500 until resolution to Grade ≤1 or baseline. 
• 
Resume at 1 lower DL. 
• 
Permanently discontinue if recurrent on re-challenging. 
Grade 3 or 4 
• 
Permanently discontinue TAK-500. 
Rash (skin and subcutaneous tissue disorders) 
Grade 2 
• 
Hold TAK-500 until resolution to Grade ≤1 or baseline. 
• 
Resume TAK-500 at same DL. 
• 
Reduce TAK-500 by 1 DL if recurrent. 
Grade 3 
• 
Hold TAK-500 until resolution to Grade ≤1 or baseline. 
• 
Resume at 1 lower DL. 
• 
Permanently discontinue if recurrent on re-challenging. 
Grade 4 
• 
Permanently discontinue TAK-500. 
Other immune-mediated AEs 
Grade 2  
• 
Hold TAK-500 until resolution to Grade <1. 
• 
Resume at 1 lower DL. 
• 
Permanently discontinue if recurrent on re-challenging. 
Grade 3 or 4 
• 
Permanently discontinue TAK-500. 
Hypertension 
 
Grade 1 and 2 
• 
Continue TAK-500 at the same dose. 
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Table 8.b 
Guidelines for TAK-500 Dose Modification and/or Discontinuation for 
Nonhematologic Toxicity 
Refer to the pembrolizumab prescribing information for recommended discontinuation guidelines. 
NCI CTCAE Grade 
TAK-500 Dose Modification 
Grade 3 
• 
Hold TAK-500 until resolution to Grade ≤2 or baseline. 
• 
If hypertension is associated with rigors and resolves to 
Grade ≤2 or baseline with resolution of the rigors (with or 
without medical intervention, eg, meperidine), continue 
TAK-500 at the same dose and closely monitor blood pressure 
during/post subsequent TAK-500 administration. 
• 
If the patient was not previously premedicated with 
corticosteroids, add corticosteroid pretreatment for subsequent 
doses of TAK-500. 
• 
If hypertension does not resolve with resolution of rigors 
and/or persists continuously >4 hours with or without rigors, 
permanently discontinue TAK-500. 
Grade 4 
• 
Permanently discontinue TAK-500. 
Other nonhematologic toxicities 
All other Grade 3 nonhematologic 
toxicities (except for Grade ≥3 
nonhematological exceptions outlined in 
Section 8.2) 
• 
Hold TAK-500 until resolution to Grade ≤1 or baseline. 
• 
Resume at 1 lower DL. 
• 
Permanently discontinue if recurrent on re-challenging. 
All other Grade 4 nonhematologic 
toxicities (except for Grade ≥4 
nonhematological exceptions outlined in 
Section 8.2) 
• 
Permanently discontinue TAK-500. 
AE: adverse event; ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; 
CRS: cytokine release syndrome; D-Bil: direct bilirubin; DL: dose level; FiO2: fraction of inspired oxygen; NCI 
CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events; HCC: hepatocellular 
carcinoma; PT-INR: prothrombin international normalized ratio; T-Bil: total bilirubin; ULN: upper limit of 
normal. 
 
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Table 8.c 
Guidelines for TAK-500 Dose Modification and/or Discontinuation for 
Hematologic Toxicity 
Refer to the pembrolizumab prescribing information for recommended discontinuation guidelines. 
NCI CTCAE Grade 
TAK-500 Dose Modification 
Neutrophil count (ANC) decreased 
Grade 4 lasting >5 days a 
• 
Hold TAK-500 until resolved to ≥1000/mm3 or baseline, and 
fever/infection resolved. 
• 
Resume at 1 lower DL. 
• 
Permanently discontinue if recurrent on re-challenging. 
Febrile neutropenia a 
• 
Hold TAK-500 until resolved to ≥1500/mm3 or baseline, and 
fever/infection have resolved. 
• 
Resume at 1 lower DL. 
• 
Permanently discontinue if recurrent on re-challenging. 
Platelet count decreased 
Grade 3 without bleeding. 
• 
Hold TAK-500 until resolved to ≥75,000/mm3, then: 
– 
If spontaneously resolved in ≤7 days, resume at same DL. 
– 
If resolved in >7 days, reduce by 1 DL. 
Grade 4 
• 
Hold TAK-500 until resolved to ≥75,000/mm3, then reduce by 
1 DL. 
• 
Permanently discontinue if recurrent on re-challenging. 
Platelets <10,000 cells/μL, or 
thrombocytopenia Grade ≥3 associated 
clinically significant bleeding. 
• 
Permanently discontinue TAK-500. 
Anemia 
Grade 3  
• 
Transfuse PRBCs as clinically indicated. 
• 
Resume at 1 lower DL lower. 
Grade 4 
• 
Permanently discontinue TAK-500. 
ANC: absolute neutrophil count; CxDx: Cycle x Day x; DL: dose level; NCI CTCAE: National Cancer Institute 
Common Terminology Criteria for Adverse Events; PRBC: packed red blood cell. 
a If observed in the DLT-evaluable period (through C1D21), the patient will be discontinued from the study. If 
observed after C1D21, management should proceed as in table. 
 
8.5.5 
Criteria for Discontinuation of TAK-500 
Patients who meet criteria for DLT during the first 21 days after enrollment (C1D21) will be 
discontinued from therapy.  
In addition to the above, the following events should lead to discontinuation of TAK-500:  
• Nonhematological toxicity:  
– Grade >3 nonhematological toxicities that do not meet the DLT exception criteria. 
– Grade ≥3 CRS 
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– Grade ≥3 infusion-related reactions or recurrent Grade 2 infusion-related reactions. 
– Grade ≥3 pneumonitis or recurrent Grade 2 pneumonitis despite 1 TAK-500 dose 
reduction. 
– Grade ≥3 creatinine increase. 
– Grade ≥3 immune-mediated AEs. 
– Grade ≥3 bilirubin increase. 
– ALT and/or AST >10 × ULN or Child-Pugh score ≥9. 
– Grade ≥2 drug-related uveitis. 
• Hematological toxicity: 
– Grade 4 anemia. 
– Recurrent Grade 4 neutropenia lasting >5 days or febrile neutropenia despite 1 TAK-500 
dose reduction. 
– Recurrent Grade 4 thrombocytopenia despite 1 TAK-500 dose reduction. 
– Platelets <10,000 cells/μL or thrombocytopenia Grade ≥3 associated clinically significant 
bleeding. 
If more than 2 dose reductions for other AEs are required, or if the subsequent dose or cycle of 
TAK-500 is delayed for >14 or 21 days (for Q2W or Q3W administration of TAK-500, 
respectively) because of TAK-500–related toxicities, the patient should have study treatment 
discontinued. If treatment discontinuation is decided on, the EOT visit should be completed 
within 30 (+10) days of the last administration of TAK-500 or before the start of subsequent 
anticancer therapy, whichever occurs first. 
8.5.6 
Criteria for Discontinuation of Pembrolizumab 
Patients who discontinue TAK-500 for any reason will also discontinue pembrolizumab. 
Pembrolizumab will also be discontinued if any of the criteria described in the package insert 
have been met. 
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 in Cycle 1 of dose escalation can be managed with growth factor support, if 
needed, in accordance with American Society of Clinical Oncology (ASCO) guidelines 
and/or institutional practices. G-CSF 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. 
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• Any investigational agent other than TAK-500 (except for pembrolizumab in the 
combination arm). 
• Any concurrent anticancer therapy, including but not limited to chemotherapy, 
immunotherapy (except for pembrolizumab in the combination arm), biologic or hormonal 
therapy (except for adjuvant endocrine therapy for a history of breast cancer). 
• Systemic treatment with any known clinical OATP1B1 and/or OATP1B3 inhibitors 
including: 
– Atazanavir. 
– Clarithromycin. 
– Cyclosporine. 
– Erythromycin. 
– Gemfibrozil. 
– Lopinavir. 
– Rifampin (single dose). 
– Ritonavir. 
– Simeprevir. 
– Remdesivir. 
Note: As the above list is not exhaustive, the investigator should consult the prescribed 
information for any medication under consideration for use to assess if it is a potent 
OATP1B1 and/or OATP1B3 inhibitor. These drugs are also listed in Appendix D. 
• Concomitant systemic use of corticosteroids or other immunosuppressive medication, 
 
, concurrent or within 7 days of administration of 
investigational drug with the following exceptions:  
– Topical, intranasal, inhaled, ocular, intra-articular, and/or other nonsystemic 
corticosteroids.  
– Physiological doses of replacement steroid (eg, for adrenal insufficiency), not to exceed 
the equivalent of 10 mg prednisone daily. 
• Any live vaccines while on study.  
• COVID-19 vaccinations given ±3 days of systemic study treatments. COVID-19 
vaccinations outside of this time period are allowed. To the extent possible, administration of 
COVID-19 vaccinations should be avoided during the 21-day DLT window (up to C1D21); 
however, vaccination timing remains at the discretion of the investigator. 
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8.7 
Permitted Concomitant Medications and Procedures 
All concomitant medications (defined as any medication given during the study) including 
prescription and over-the-counter medications, influenza vaccines, and significant nondrug 
therapies, such as physical therapy and blood transfusions, should be recorded in the designated 
electronic case report form (eCRF) from signing of the ICF through 30 days after the last dose of 
study drug or the start of subsequent antineoplastic therapy, whichever occurs first. This also 
includes recording of multivitamins or any folate/folic acid supplementation. 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: 
• Topical, intranasal, inhaled, ocular, intra-articular, and/or other nonsystemic corticosteroids 
are permitted as outlined in Section 8.6.  
• Physiological doses of replacement steroid (eg, for adrenal insufficiency), not to exceed the 
equivalent of 10 mg prednisone daily. 
• Patients should be transfused with red blood cells and platelets as clinically indicated. 
• Patients currently on chronic erythropoietin support for anemia may continue to receive 
erythropoietin. 
• Concomitant treatment with bisphosphonates or denosumab 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. 
• For antiemetics see Section 8.9.5. 
• The cautious use of medications that are known to prolong corrected QT interval (QTc) 
interval is permissible if the patient is taking such medications continuously at the time of 
enrolling in this study and as long as the patient’s baseline QTcF is <450 milliseconds (men) 
or <475 milliseconds (women) on a 12-lead ECG. Patients may not initiate a new treatment 
of such medications on C1D1 until completion of the last triplicate ECG collection. 
• Adjuvant endocrine therapy for a history of breast cancer. 
• Supportive measures consistent with optimal patient care may be given throughout the study. 
8.8 
Precautions and Restrictions 
Precautions and requirements for a safe TAK-500 administration are detailed in Section 8.1. 
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TAK-500 was evaluated in toxicity studies in cynomolgus monkeys (Section 4.1.1.3); however, 
animal studies do not always predict what happens in humans. It is not known if side effects and 
risks observed in animals will occur in patients taking TAK-500, or if the severity of these side 
effects and risks will be the same, less, or greater from what was observed in animal studies. 
It is not known what effects TAK-500 has on human pregnancy or development of the embryo or 
fetus. Female patients participating in this study should avoid becoming pregnant, breastfeeding 
a baby, or donating eggs for 180 days after the last dose of TAK-500. Male patients should avoid 
impregnating a female partner and donating sperm for 180 days after the last dose of TAK-500. 
Female patients of childbearing potential and male patients will be informed as to the potential 
risk of conception while participating in this study and will be advised that they must use 
effective contraception (ie, results in a low failure rate when used consistently and correctly), as 
specified below. A pregnancy test will be performed on each premenopausal female patient of 
childbearing potential at screening, on each day of TAK-500 administration, and again at 
treatment discontinuation during the EOT visit. A negative pregnancy test must be documented 
before the administration of study drug on C1D1. 
Female patients must meet one of the following: 
• Postmenopausal (natural amenorrhea and not due to other medical reasons) for at least 1 year 
before the screening visit. 
• Surgically sterile. 
• If they are of childbearing potential, agree to practice the following 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 180 days after the last dose of study drug. 
Highly Effective Methods 
Other Effective Methods (Barrier Methods) 
Intrauterine device 
Hormonal (birth control pills/oral contraceptives, 
injectable contraceptives, contraceptive patches, or 
contraceptive implants) 
Male condom 
Diaphragm with spermicide; cervical cap; sponge 
 
• 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.) 
Male patients, even if surgically sterilized (ie, status postvasectomy), must agree to one of the 
following: 
• Agree to practice effective barrier contraception (eg, latex condom with a spermicidal agent) 
during the entire study treatment period and through 180 days after the last dose of study 
drug. 
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• Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception.) 
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, if these are desired. 
It is not known whether TAK-500 passes into breast milk. Mothers should not breastfeed during 
the entire study treatment period and for 180 days after the last dose of study drug. 
At the time of discharge from the hospital, patients and their caregivers will be educated about 
potential symptoms including but not limited to fever, edema, lightheadedness, dizziness, 
tachypnea, dyspnea, confusion, aphasia, dysphasia, ataxia, or tremor. If patients develop any of 
these symptoms, they should be instructed to immediately contact the principal investigator, who 
may recommend immediate medical attention.  
As an additional safety measure, each patient will be required to carry a study information card 
detailing treatment site and investigator contact information, and clinical study information. This 
card is intended to provide relevant contact information should a patient be treated by a nonstudy 
health care provider or emergency medical services. It will also alert nonstudy health care 
providers to evaluate patients for the potential risks related to TAK-500 administration and 
provide them with the contact information of the treating site and/or obtain important study 
information relevant to the patient’s care. This card will also remind patients of concerning signs 
or symptoms for which they should seek immediate medical attention. 
8.9 
Management of Clinical Events 
Evidence to support potential risks and effects is provided in Section 4.3. 
There is no known antidote to TAK-500. 
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 G-CSF, 
blood products (red blood cells and platelet transfusions), and pain medications are permitted as 
needed per American Society of Hematology/ASCO guidelines or local institutional practice. 
However, these agents should not be used in this study in a manner that would either help 
establish eligibility for the study or support escalation of study drug dose during dose escalation. 
If dose alterations are necessary because of the events detailed below, please refer to Section 8.5. 
In Sections 8.9.1 to 8.9.9, guidance is provided for the management of some AEs that could be 
expected based on observations in nonclinical toxicology or because of the MOA of TAK-500. 
This guidance is not expected to replace investigator judgment in the management of AEs. 
Notably, for any clinically significant Grade ≥3 AEs, referral to an appropriate subspecialist 
should be considered. 
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8.9.1 
CRS 
Evidence to support the potential risk of CRS is provided in Sections 4.1.2.3 and 4.3.1.1. 
CRS should be graded following NCI CTCAE v5.0. Treatment guidelines are provided below; 
management of CRS requires close collaboration with specialists in neurology, pulmonology, 
cardiology, radiology, and/or critical care medicine, as necessary. Given the potential risk of 
CRS, the on-site pharmacy must confirm that 
 are on site 
and available should they be needed. In circumstances where 
 is not available, 
 will be considered acceptable treatment for CRS, under the condition that this is 
consistent with local institutional guidelines/practice and that the availability of the 
 
 is(are) confirmed with the site investigator before subject enrollment. 
Investigators should differentiate CRS from other critical clinical conditions, including 
infusion-related reactions, sepsis, capillary leak syndrome, and hemophagocytic 
lympho-histiocytosis/macrophage activation syndrome. Fever is an important clinical sign that 
should raise the suspicion of impending CRS. If fever develops, institutional guidelines for 
management should be followed and patients should be frequently reassessed for signs of CRS. 
Strongly consider admission for close observation. For patients experiencing Grade ≥2 CRS, 
ECG telemetry is recommended. Echocardiogram could be obtained as clinically indicated. Early 
administration of IV fluids and tocilizumab is highly recommended for the management of CRS 
of Grade 2 or higher. 
The diagnosis and management of CRS is based on clinical parameters as described in Table 8.d. 
Ferritin, C-reactive protein, and serum cytokine concentrations should NOT be used for clinical 
management decisions. 
To further mitigate the risk of CRS during this study, vital signs will be measured frequently 
during and after infusion of TAK-500. Close monitoring of vital signs and clinical condition will 
continue if the patient experiences symptoms that could be consistent with CRS. During dose 
escalation, all patients will be hospitalized for approximately 24 (±4) hours after the first 2 doses 
of TAK-500 (C1D1 and C2D1 for Q3W TAK-500; C1D1 and C1D15 for Q2W TAK-500). 
Regardless of the treatment cycle, if a Grade 2 CRS or infusion-related reaction occurs during or 
after administration of study drug, hospitalization is required for 24 hours after the end of the 
next 2 TAK-500 infusions. For patients without evidence of Grade 2 CRS after 2 consecutive 
doses of TAK-500, subsequent administrations of TAK-500 may be performed in the outpatient 
setting with monitoring in the clinic for at least 6 hours after infusion. Patients who do not 
experience an infusion-related reaction or Grade 2 CRS after 4 consecutive administrations of 
TAK-500 may have their subsequent postinfusion in-clinic monitoring reduced to 1 hour. Should 
symptoms consistent with CRS develop, see Table 8.b for TAK-500 dose modification. In the 
combination arm, pembrolizumab will be held until TAK-500 is resumed. 
The required hospitalization for the phase 2 dose expansion portion of the study may be 
decreased or removed if an adequate safety profile is demonstrated in the dose escalation phase 
of the study for the DL(s) and premedication regimen(s) included in expansion. If hospitalization 
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is not required for dose expansion, outpatient monitoring will be required as outlined in the 
above paragraph.  
In addition to in-patient and out-patient monitoring, patients will be asked to track oral 
temperature twice daily (first in the morning and last in the evening), and any time the patient 
feels febrile, on a patient diary throughout the first 42 days after initial dosing of TAK-500. If a 
patient experiences a temperature ≥100.4°F (38°C) at any time on study, they will be instructed 
to call the principal investigator immediately. 
Table 8.d 
NCCN Guidelines v1.2021*: Management of CAR T-Cell–Related 
Toxicities 
CYTOKINE RELEASE SYNDROME (CRS) a, b 
Prompt and urgent intervention to prevent progression of CRS is required; however, other causes of systemic 
inflammatory response should be ruled out, including infection and malignancy progression. Empiric treatment 
for infection is warranted in the neutropenic patient. Organ toxicities associated with CRS may be graded 
according to CTCAE v5.0 but they do not influence CRS grading. c 
Fever is defined as temperature >38°C not attributable to any other cause. In patients who have CRS then receive 
antipyretics 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. 
CRS Grade 
Additional Supportive Care 
Grade 1: 
Fever (≥38°C) 
• 
Empiric broad-spectrum 
antibiotics, consider 
G-CSF if neutropenic. g 
• 
Maintenance IV fluids for 
hydration. 
• 
Symptomatic management 
of organ toxicities. 
Grade 2: 
Fever with 
hypotension not 
requiring 
vasopressors 
and/or hypoxia h 
requiring low-flow 
nasal cannula i or 
blow-by. 
• 
IV fluid bolus as needed. 
• 
For persistent refractory 
hypotension after 2 fluid 
boluses 
 
: start vasopressors, 
consider transfer to ICU, 
consider echocardiogram, 
and initiate other methods 
of hemodynamic 
monitoring. 
• 
Manage per Grade 3 if no 
improvement within 
24 hours after starting 
. 
• 
Symptomatic management 
of organ toxicities. 
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Table 8.d 
NCCN Guidelines v1.2021*: Management of CAR T-Cell–Related 
Toxicities 
CYTOKINE RELEASE SYNDROME (CRS) a, b 
Prompt and urgent intervention to prevent progression of CRS is required; however, other causes of systemic 
inflammatory response should be ruled out, including infection and malignancy progression. Empiric treatment 
for infection is warranted in the neutropenic patient. Organ toxicities associated with CRS may be graded 
according to CTCAE v5.0 but they do not influence CRS grading. c 
Fever is defined as temperature >38°C not attributable to any other cause. In patients who have CRS then receive 
antipyretics 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. 
CRS Grade 
Additional Supportive Care 
Grade 3: 
Fever with 
hypotension 
requiring a 
vasopressor with or 
without 
vasopressin and/or 
hypoxia requiring 
high-flow cannula,i 
face mask, 
nonrebreather 
mask, or Venturi 
mask. 
• 
Transfer to ICU, obtain 
echocardiogram, and 
perform hemodynamic 
monitoring. 
• 
Supplemental oxygen. 
• 
IV fluid bolus and 
vasopressors as needed. 
• 
Symptomatic management 
of organ toxicities. 
Grade 4: 
Fever with 
hypotension 
requiring multiple 
vasopressors 
(excluding 
vasopressin) and/or 
hypoxia requiring 
positive pressure 
(eg, CPAP, BiPAP, 
intubation, and 
mechanical 
ventilation). 
• 
ICU care and 
hemodynamic monitoring. 
• 
Mechanical ventilation as 
needed. 
• 
IV fluid bolus and 
vasopressors as needed. 
• 
Symptomatic management 
of organ toxicities. 
BiPAP: bilevel positive airway pressure; CAR: chimeric antigen receptor; CPAP: continuous positive airway 
pressure; CRRT: continuous renal replacement therapy; CRS: cytokine release syndrome; CTCAE: Common 
Terminology Criteria for Adverse Events; G-CSF: granulocyte colony-stimulating factor; GM-CSF: granulocyte-
macrophage colony stimulating factor; HLH/MAS: hemophagocytic lymphohistiocytosis/macrophage activation 
syndrome; ICU: intensive care unit; 
; IT: intrathecal; IV: intravenous; NA: not applicable; 
NCCN: National Comprehensive Cancer Network; NCI: National Cancer Institute. 
All recommendations are category 2A unless otherwise indicated.  
* Note that grading criteria outlined by NCCN for CRS management is different than detailed in this protocol for 
dose-reduction (Table 8.b) and NCI CTCAE v5.0 CRS grading. 
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Table 8.d 
NCCN Guidelines v1.2021*: Management of CAR T-Cell–Related 
Toxicities 
CYTOKINE RELEASE SYNDROME (CRS) a, b 
Prompt and urgent intervention to prevent progression of CRS is required; however, other causes of systemic 
inflammatory response should be ruled out, including infection and malignancy progression. Empiric treatment 
for infection is warranted in the neutropenic patient. Organ toxicities associated with CRS may be graded 
according to CTCAE v5.0 but they do not influence CRS grading. c 
Fever is defined as temperature >38°C not attributable to any other cause. In patients who have CRS then receive 
antipyretics 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. 
CRS Grade 
Additional Supportive Care 
a For HLH/MAS during CRS, treat per CRS with addition of steroids. If symptoms do not improve within 
48 hours, consider etoposide and IT cytarabine for neurotoxicity. 
b With permission from Elsevier (Lee et al. 2019). 
c Organ toxicities should receive a thorough workup and appropriate management. 
 
 
 
 
 
 
  
g GM-CSF is not recommended in the setting of CAR T-cell therapy.  
h CRS grade is determined by the more severe event:
 
 
 
i Low-flow nasal cannula is defined as oxygen delivered at ≤6 L/min. Low flow also includes blow-by oxygen 
delivery, sometimes used in pediatrics. High-flow nasal cannula is defined as oxygen delivered at >6 L/min. 
 
 
 
 
 
 
 
 
. 
 
8.9.2 
Pulmonary Edema 
TAK-500 administration was associated with minimal to mild pulmonary edema in the GLP 
monkey toxicity study (see Section 4.3.1.2 for details).  
To monitor for this potential side effect and minimize the clinical risk to patients, the following 
will occur: 
• Patients will be hospitalized for at least the first 2 doses of TAK-500 or TAK-500 + 
pembrolizumab (C1D1 and C2D1 for Q3W TAK-500; C1D1 and C1D15 for Q2W TAK-
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500), with monitoring for approximately 24 (±4) hours, allowing for close monitoring and 
timely management of symptoms. 
– Vital signs will be collected no less frequently than every 6 hours, and additionally when 
clinically indicated, during hospitalization as specified in Section 8.1.1 and in the SOEs 
(Appendix A). Before discharge, a symptom-directed physical examination including 
assessment of the respiratory system will be required.  
– Oxygenation should be carefully monitored and maintained as clinically indicated. 
Careful diagnosis and aggressive correction of pulmonary symptoms should occur 
quickly. 
– Pulmonary imaging (eg, chest x-ray or chest CT) is recommended and investigators 
should have a low threshold to scan if the patient experiences any pulmonary or vascular 
symptoms.  
As a general approach to established management of pulmonary toxicity, investigators may refer 
to “High dose interleukin-2 (Aldesleukin)-expert consensus on best management practices-2014” 
(see Table 8.e) (Dutcher et al. 2014) or local institution guidelines. 
Table 8.e 
Pulmonary Toxicity Clinical Management Recommendations 
Considerations 
Management 
Tachypnea/dyspnea 
Typical Management 
Diagnose etiology and treat 
Oxygen 2-4 L nasal cannula, increasing up to 35% rebreather 
Hypoxic causes-Fluid overload, capillary 
leak, bronchospasm 
Reassurance or sedative for anxiety, treat bronchospasm or 
acidosis if appropriate 
Nonhypoxic causes 
Hold TAK-500 dose if oxygen saturation <92% 
Anxiety, fever, acidosis 
Variation Management 
Maintain oxygen saturation >92%-95% 
Furosemide 
 
Bronchodilators 
 
Monitor bicarbonate 
 
Investigators should differentiate pulmonary edema from other clinical conditions, including but 
not limited to, COVID-19 and capillary leak syndrome. 
8.9.3 
Skin Conditions/Rash 
It is recommended that for all severity grades of cutaneous events, the diagnostic workup should 
include: 
• Evaluation of a pertinent history and physical examination. 
• Ruling out any other etiology of the skin problem (including infection, another drug side 
effect, a skin condition linked to another systemic disease or unrelated primary skin 
disorder). 
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• Evaluation of laboratory values, including a blood cell count, liver and kidney tests. 
• Directed serologic studies if an autoimmune condition is suspected. 
• Skin biopsy, consultation with dermatologist if indicated. 
• Review full list of patient medications. 
Further management of any noted skin toxicities should follow local management guidelines and 
evolving consensus guidelines for management of potentially immune-mediated skin toxicities 
(Brahmer et al. 2018). 
8.9.4 
Infusion Site Care 
Lesions at the injection site, which may include inflammation or necrosis, represent a potential 
risk. No injection site findings were observed in nonclinical studies with TAK-500. Local 
institutional guidelines must be applied to stress proper administration and prevention of 
accidental extravasation of TAK-500. Usage of an IV port or central access is highly 
recommended. The IV line should be flushed as directed in the pharmacy manual at the end of 
each infusion accordingly to local procedures. Patients should be instructed to report any 
discomfort, pain, or swelling at the infusion site. Monitoring at the beginning and during the 
infusion for any discomfort, pain, or swelling must be ensured. If extravasation occurs, the 
infusion must be discontinued immediately, and supportive measures or institutional guidelines 
applied.  
8.9.5 
Nausea and/or Vomiting 
Nausea and/or vomiting is common in an oncology population; however, there is no evidence 
this is a risk of TAK-500. 
This study will not initially use 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 using optimal antiemetic treatment based on local standard practice. Additionally, 
antiemetics may be used prophylactically as clinically indicated after 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 uses a neuroleptic, a 5-HT3 antagonist, or an NK-1 antagonist may 
be added. Steroid use should be avoided unless it is a clinical necessity. 
8.9.6 
Fluid Deficit 
Fluid deficit is common in an oncology population; however, there is no evidence this is a risk of 
TAK-500. 
Fluid deficit should be corrected before initiation of study drug and during treatment. Patients on 
study should be advised to maintain adequate oral hydration. 
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8.9.7 
Infusion-Related Reactions 
Treatment and monitoring of patients until symptoms resolve should be consistent with 
institutional standards and guidelines, as appropriate. Infusion-related reactions should be 
diagnosed and managed following institutional guidelines and graded following NCI CTCAE 
v5.0. Table 8.b provides indications for dose modifications after an infusion-related reaction 
event. 
The patient should be closely monitored until recovery of symptoms. Patients will be 
hospitalized for at least the first 2 doses of TAK-500 or TAK-500 + pembrolizumab (C1D1 and 
C2D1 for Q3W TAK-500; C1D1 and C1D15 for Q2W TAK-500), with monitoring for 
approximately 24 (±4) hours. The patient will be permanently discontinued from the study in 
case of a Grade 3 or 4 life-threatening reaction (except as noted in Section 8.2). All Grade 3 or 4 
infusion-related reactions should be reported within 24 hours to the medical monitor and 
communicated as an SAE if criteria are met (see Section 10.1.3). Concomitant medications 
administered for infusion-related reaction treatment should be collected in the eCRF. If a patient 
develops signs and symptoms compatible with infusion-related reactions, and at investigator 
discretion, premedication can be instituted for the rest of the treatment.  
Should emergency treatment be required in the event of life-threatening hypersensitivity or other 
acute infusion-related reaction, supportive therapy such as oxygen, bronchodilators, epinephrine, 
and antihistamines should be given according to local institutional guidelines. Corticosteroids 
should be avoided unless clinically indicated (ie, CTCAE Grade 3 or 4). 
Regardless of the treatment cycle, if a Grade ≥2 CRS or infusion-related reaction occurs after the 
administration of study drug, hospitalization is required for 24 hours after the end of the next 
2 TAK-500 infusions. For patients without evidence of Grade ≥2 CRS after 2 consecutive doses 
of TAK-500, subsequent administrations of TAK-500 may be performed in the outpatient setting 
with monitoring in the clinic for at least 6 hours after infusion. Patients who do not experience an 
infusion-related reaction or Grade 2 CRS after 4 consecutive administrations of TAK-500 may 
have their subsequent postinfusion in-clinic monitoring reduced to 1 hour. 
8.9.8 
Management of Pembrolizumab Immune-Mediated AEs 
Potential risks and effects of TAK-500 and pembrolizumab are listed in Section 4.3.2. 
Based on nonclinical safety data for TAK-500 administered as an SA in monkeys, there is a 
potential for synergistic immune-related toxicity when TAK-500 is used in combination with 
pembrolizumab. 
Pembrolizumab can cause immune-mediated reactions, as described in Section 4.3.2. Monitoring 
of these AEs is required through 90 days after the last dose of study drug or the start of 
subsequent anticancer therapy, whichever occurs first (Brahmer et al. 2018). Patients with AEs 
that are suspected to be related to pembrolizumab should be evaluated by appropriate 
methodology, including physical examinations, laboratory tests, and imaging. Dosing of 
pembrolizumab should be interrupted based on the guidance in Section 8.5.6. Treatment of these 
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AEs will be based on standard of care, local institutional guidance, the WARNINGS AND 
PRECAUTIONS section of the package insert, and the proper use guidance of pembrolizumab. 
8.9.9 
Management of COVID-19–Positive Patients 
A consensus plan of action has been developed for the management of patients within the 
context of the COVID-19 pandemic. During the screening period, a patient who exhibits 
symptoms consistent with COVID-19 (eg, fever, shortness of breath, sore throat) will undergo 
COVID-19 testing per institutional guidelines. A patient with a negative test result will undergo 
further diagnostic work-up and management at the discretion of the site investigator. If a patient 
tests positive for COVID-19 during the screening period, enrollment should be paused during 
which time the investigator, in consultation with the sponsor, will determine the appropriate 
course of action for that patient. For patients with symptoms and/or requiring treatment, 
symptoms should have resolved to baseline, and treatment should be completed at least 7 days 
before enrollment. (A negative test result for severe acute respiratory syndrome coronavirus-2 
[SARS CoV-2] by polymerase chain reaction (PCR) may also be documented, if required by 
local institutional guidelines.) Asymptomatic patients who test positive should wait at least 
7 days from the positive test result to ensure they continue to remain asymptomatic before 
enrolling.  
While on study treatment, a patient who exhibits symptoms consistent with COVID-19 
(eg, fever, shortness of breath, sore throat) will undergo COVID-19 testing per institutional 
guidelines, in addition to a work-up for pulmonary toxicity related to the study intervention. A 
patient with a negative test result will undergo further diagnostic work-up and management at the 
discretion of the site investigator. If a patient tests positive for COVID-19 while on study, 
treatment should be withheld (up to 21 days), during which time the sponsor and investigator 
will determine the appropriate course of action for that patient.  
Suggested guidance is as follows: 
• For patients with symptoms and/or requiring treatment, symptoms should have resolved to 
baseline and treatment should be completed at least 7 days before resuming study drug(s) (a 
negative test result for SARS-CoV-2 by PCR may also be documented if required by local 
institutional guidelines). 
• Asymptomatic patients who test positive should wait at least 7 days from the positive test 
result to ensure they continue to remain asymptomatic before resuming study drug(s). 
8.9.10 
CV Toxicity 
Evidence to support potential risks and effects is provided in Section 4.3.  
Patients with medically managed hypertension should continue their antihypertensive medication 
before the administration of TAK-500 or TAK-500 + pembrolizumab. To monitor for potential 
CV toxicity, including transient hypertension of ≥160/100 mm Hg, patients will be hospitalized 
for monitoring after at least the first 2 administrations of TAK-500 or TAK-500 + 
pembrolizumab, with monitoring for approximately 24 (±4) hours. Vital signs will be measured 
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at least every 6 hours during hospitalization. Therapies that are required to manage CV toxicity 
are allowed based on standard clinical practice. Investigators should differentiate 
CRS/rigor-associated transient hypertension from other clinical conditions. 
In all cases, consultation with the medical monitor should also be considered. 
8.10 
Blinding and Unblinding 
This is an open-label study. 
8.11 
Description of Investigational Agents 
8.11.1 
TAK-500 
TAK-500 drug product is provided as a sterile, frozen, liquid formulation contained in a 
single-use 10 mL glass vial with an aluminum seal with a plastic flip off cap. Each vial 
nominally contains 6 mg/3 mL of TAK-500. The excipients are listed in Table 8.f. 
Table 8.f 
TAK-500 Drug Product Excipients 
Excipient 
Function 
TAK-500 (Takeda) 
Active ingredient 
L-histidine (USP, Ph Eur, BP, JP) 
Buffer  
L-histidine monohydrochloride (Ph Eur, JP) 
Buffer  
L-arginine hydrochloride (USP, Ph Eur, BP, JP) 
Stabilizer and tonicity agent 
Polysorbate 80 (NF, JP, Ph Eur) 
Stabilizer 
Water for injection (USP, Ph Eur) 
Solvent 
BP: British Pharmacopoeia; JP: Japanese Pharmacopeia; NF: National Formulary; Ph Eur: European 
Pharmacopeia; USP: United States Pharmacopeia. 
 
Solution stabilizer (Polysorbate 80 IV) is composed of a sterile, aqueous solution consisting of 
excipients (L-histidine, L-arginine monohydrochloride) and polysorbate 80, all of which are also 
present in the TAK-500 drug product formulation. Solution stabilizer is supplied as 10 mL of 
solution filled into a single-use 20 R Type I glass vial. Solution stabilizer will be provided by the 
sponsor. 
For dose preparation, solution stabilizer is added to diluent to obtain consistent levels of 
formulation excipients in the final dosing solution. TAK-500 drug product is then added to the 
diluent containing solution stabilizer. Specific dilution procedures are described in detail in the 
pharmacy manual. 
For additional information, please refer to the pharmacy manual. 
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8.11.2 
Pembrolizumab 
Pembrolizumab will be sourced locally by sites whenever possible. Please refer to the most 
recent prescribing information for guidance on preparation, reconstitution, and administration 
instructions. 
8.12 
Preparation, Reconstitution, and Dispensation 
8.12.1 
TAK-500 
Please refer to the pharmacy manual for preparation, reconstitution, and administration 
instructions. 
In the absence of compatibility studies, this medicinal product must not be mixed with other 
medicinal products. 
TAK-500 is an anticancer drug, and as with other potentially toxic compounds, caution should be 
exercised when handling TAK-500. 
Study drug products should be inspected visually for particulate matter and discoloration before 
administration, whenever solution and container permit. 
8.12.2 
Pembrolizumab 
Please refer to the most recent pembrolizumab prescribing information as applicable to the 
specific country and the pharmacy manual for preparation, reconstitution, and administration 
instructions. 
8.13 
Packaging and Labeling 
8.13.1 
TAK-500 
The TAK-500 drug product is provided in sterile, 10 mL, colorless, Type I borosilicate glass 
vials with a chloro-butyl rubber stopper and an aluminum seal with a plastic flip off cap. The 
TAK-500 drug product is provided as a sterile, frozen, liquid formulation contained in a 
single-use vial; each vial nominally contains 6.0 mg/3 mL of TAK-500 drug product. 
The TAK-500 drug product will be labeled as investigational drug product. All label information 
will fulfill requirements specified by local governing regulations. Additional details are provided 
in the pharmacy manual. 
8.13.2 
Pembrolizumab 
Pembrolizumab, if provided by sponsor, will be labeled as investigational drug product. All label 
information will fulfill requirements specified by local governing regulations. Additional details 
are provided in the pharmacy manual.  
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8.14 
Storage, Handling, and Accountability 
8.14.1 
TAK-500 
TAK-500 must be stored in a secure, limited-access location, according to conditions specified 
on the drug label and in the pharmacy manual. The investigator or designee must confirm that 
appropriate temperature conditions have been maintained and that any excursions are reported 
and resolved before use. Refer to the pharmacy manual for additional details. 
Complete receipt, inventory, accountability, reconciliation, and destruction records will be 
maintained by authorized personnel at the study site 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. For all study sites, the local country sponsor 
personnel or designee will provide appropriate documentation that must be completed for study 
drug accountability, return, and destruction. Instructions are provided in the pharmacy manual. 
8.14.2 
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 excursions are reported and resolved 
before use. Refer to the pharmacy manual and the most recent pembrolizumab prescribing 
information as applicable to the specific country for additional details. 
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 study will be conducted in compliance with the protocol, GCP, applicable regulatory 
requirements, and ICH guidelines. 
9.1 
Study Personnel and Organizations 
The contact information for the project clinician for this study, the central laboratory and any 
additional clinical laboratories, the coordinating investigator, and other vendors participating in 
the study can be found in the study manual. 
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. 
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9.3 
Treatment Group Assignments 
The dose escalation and expansion phases of this study will not be randomized. Details for 
initiation of the SA and combination arms are described in Section 6.1. When TAK-500 SA and 
combination arms are both open to enrollment, patient assignment to a specific arm will be 
decided jointly by the investigator and sponsor with the aim of maximizing enrollment efficiency 
in the study. 
Sites will be notified in advance when a different dosing frequency may be explored 
(eg, TAK-500 Q3W 21-day cycle vs TAK-500 Q3W 42-day cycle vs TAK-500 Q2W 42-day 
cycle dosing) or if certain tumor types are needed to complete an expansion cohort. 
9.4 
Study Procedures 
Refer to the SOEs (Appendix A) for timing of assessments. Additional details are provided as 
necessary in the sections below. Evaluations during the screening period are to be conducted 
within 28 days before administration of the first dose of the study drug. 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 SOEs (Appendix A). 
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, including smoking/vaping 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.  
Available tumor genomic information obtained at the site will be collected. 
9.4.4 
Physical Examination 
Physical examinations will be completed per standard of care at the times specified in the SOEs 
(Appendix A).  
At screening, complete physical examinations will include an assessment of the following: 
height, skin, head, eyes, ears, nose, throat, respiratory system, CV system, gastrointestinal 
system, neurological condition, blood and lymphatic systems, and musculoskeletal system. 
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Symptom-directed physical examination will be conducted on Day 1 and as specified in the SOE 
(Appendix A) of each cycle before administration of the first dose of study treatment and any 
other time point during the 21- or 42-day cycle based on clinical need. This physical examination 
should include assessment of the respiratory system as well as evaluation of weight, and edema. 
Pulse oximetry will be required per Section 9.4.6.2. Evaluation of neurologic condition will also 
be performed on these days. 
Safety follow-up call should be made with the patient as indicated in the SOEs to evaluate for 
overall AEs and general wellbeing. 
9.4.5 
ECOG Performance Status 
Performance status is to be assessed using the ECOG scale (see Appendix G for a description of 
the scale) at the times specified in the SOEs (Appendix A). 
9.4.6 
Vital Signs 
Vital sign measurements, including diastolic and systolic blood pressure while sitting (after 
approximately 5 minutes in this position), heart rate, respiratory rate, oxygen saturation, and 
temperature, as well as height and weight, will be assessed as specified in the SOEs 
(Appendix A).  
For administrations of TAK-500, vital signs will be measured immediately before the start of the 
infusion (within 30 minutes), 30 minutes after start of infusion (±5 minutes), at the EOI 
(±10 minutes), 1 hour after infusion (±10 minutes), any time when clinically indicated, and 
before discharge. For infusion times of less than 30 minutes, vital signs will be measured 
immediately before the start of the infusion (within 30 minutes), at the EOI (±5 minutes), 
30 minutes after EOI (±5 minutes), and at 1 hour after infusion (±10 minutes). On C1D1 vitals 
will also be measured at 3 and 6 hours after dosing of TAK-500 (measurement should be 
obtained in a ±30-minute window). Vital signs should be measured and recorded at any time if 
the patient develops symptoms associated with potential risks of TAK-500 and/or 
pembrolizumab. The frequency and timing of vital sign monitoring may be modified based on 
emerging data and agreement between sponsor and investigators. 
Vital signs should be measured and recorded any time the patient develops symptoms associated 
with potential risks of TAK-500 and/or pembrolizumab. 
9.4.6.1 
Patient Diary 
Patients will be given a diary on which they will record oral temperature twice daily (first in the 
morning and last in the evening), and any time the patient feels febrile during the first 42 days of 
treatment (Cycles 1 and 2 for 21-day cycle and Cycle 1 for 42-day cycle), as specified in the 
SOEs (Appendix A). The diary should be brought to the site at each visit during this period and 
reviewed by study staff. If patients experience a temperature ≥100.4°F (38°C) at any time on 
study, they will be instructed to call the principal investigator. Sites will report clinically 
significant fever as AEs according to NCI CTCAE 5.0 guidelines, if clinically applicable. 
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9.4.6.2 
Pulse Oximetry 
Pulse oximetry should be obtained before each dose of TAK-500 and at any time a patient has 
any new or worsening respiratory symptoms – the requirement for subsequent dosing is based on 
O2 saturation while at rest. A reading at rest and on exertion if clinically indicated should be 
obtained (O2 saturation with exertion is not required to be >92%). Whether to measure O2 
saturation with exertion, should be based on the judgment of the investigator, but should remain 
consistent for each individual patient throughout the study. If O2 saturation is measured with 
exertion, it is meant to (a) ensure that the patient is safe to treat and (b) monitor recovery of 
pulmonary status if decompensation occurred while on study. Instances where measuring O2 
saturation with exertion might be desirable include: 
• Known underlying lung disease (ie, patients that potentially meet criteria described in 
exclusion criterion #8). 
• Recent acute pulmonary injury (eg, from infection, aspiration, thrombosis). 
• Patients who enrolled in the study without the need for supplemental O2, but who 
subsequently had pulmonary decompensation and now require intermittent O2 with exertion 
(monitoring for continued recovery). 
If the patient’s status changes, the investigator can alter the extent of exertion based on their 
medical judgment. If a patient shows changes in pulse oximetry or other pulmonary-related signs 
(eg, hypoxia, fever) or symptoms (eg, dyspnea, cough, fever) consistent with possible pulmonary 
AEs, the patient should be immediately evaluated to rule out pulmonary toxicity. 
9.4.6.3 
 
 
 
 
 
 
 
 
 
9.4.7 
Pregnancy Test 
A serum choriogonadotropin beta pregnancy test will be performed only for patients of 
childbearing potential during screening and again at C1D1 (baseline) if the screening test was 
performed more than 4 days before the first dose of any study drug. Women who are not of 
childbearing potential, surgically sterile, or postmenopausal (defined as amenorrhea for at least 
12 months) and men do not need to have the test performed. The results must be negative within 
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4 days before the first dose of TAK-500 is administered (ie, within the 4 days before C1D1), or 
as otherwise required by local regulations.  
Additional pregnancy testing (serum or urine; urine preferred) should be performed before each 
dose of TAK-500 and at EOT, as scheduled in Appendix A, and may be performed during the 
study at the discretion of the investigator, on request of an independent ethics committee 
(IEC)/institutional review board (IRB), or if required by local regulations. 
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 signature through 30 days after the last 
dose of study drug or the start of subsequent systemic antineoplastic therapy, whichever occurs 
first. See Sections 8.6 and 8.7 for a list of medications and therapies that are prohibited or 
allowed during the study. 
9.4.9 
AEs 
Monitoring of all AEs, including SAEs, will be collected throughout the study as specified in the 
SOEs (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 
9.4.11.1 
Safety 12-Lead ECGs and LVEF 
The 12-lead standard safety ECGs will be performed to assess eligibility and throughout the 
study as specified in the SOEs (Appendix A). Safety ECGs will be compared with baseline 
screening ECGs. ECG assessments are to be performed with the patient supine and rested for 
5 minutes. A qualified person will interpret the ECGs locally. When safety ECG collection times 
coincide with the collection times for triplicate ECGs, the triplicate ECGs may also be used by 
investigators on site for evaluation of safety. An additional safety ECG will not need to be 
performed in this setting. Additional ECGs may be obtained as clinically indicated at any time 
during the study at the discretion of the investigator. When the timing of ECG or vital signs 
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. The frequency and timing of ECG collection for safety may be modified based on 
emerging data and agreement between sponsor and investigators. 
The assessment of LVEF measured by echocardiography or MUGA will be performed at 
screening and as clinically indicated. Any findings from LVEF determinations will be captured 
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as AEs if, in the opinion of the investigator, there has been a clinically significant change from 
baseline.  
9.4.11.2 
Triplicate ECGs (With PK Sampling) 
Triplicate 12-lead ECG recordings matched with PK sampling are required at time points 
specified in the SOEs (Appendix A) for a preliminary assessment of TAK-500 on QTc. The 
triplicate ECG will be stored and centrally read. Triplicate ECGs will be collected before PK 
sample collection. Triplicate 12-lead ECG measurements are performed using standard ECG 
equipment. Patients are required to be in supine position for 15 minutes, which is the ECG 
collection window (ie, at least 5 minutes before and up to 10 minutes during the 3 ECG 
collections for each planned time point). After the patient has been in supine position for at least 
5 minutes, each triplicate ECG is to be collected on the ECG equipment. The actual time of 
triplicate ECG collections for each timepoint will be recorded on the eCRF. 
When safety ECG collection times coincide with the collection times for triplicate ECGs, the 
triplicate ECGs may also be used by investigators on site for evaluation of safety. In these cases, 
the exact date/time and ECG parameters for the safety ECG reading should be recorded by the 
site in the clinical database. Meal consumption is known to alter ECG readings. For this reason, 
on Day 1 patients will abstain from eating food or having anything to drink except water from a 
minimum of 2 hours before the collection of the predose ECGs until after collection of the EOI 
triplicate ECGs. A low calorie and low sodium light meal is permitted immediately after the 
postinfusion ECG has been collected. Similarly, light meals are permissible immediately after 
collection of a scheduled triplicate ECG and approximately 1 hour before the next scheduled 
triplicate ECG collection time point. 
When the timing of ECG or vital signs 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. Handling and shipment of clinical 
laboratory samples will be outlined in the study manual. 
During the COVID-19 public health emergency, if a study participant cannot access a clinical 
study site for unscheduled bloodwork collection as requested by the investigator, alternative 
Clinical Laboratory Improvement Amendments-certified sites may be used for laboratory tests 
that focus on the safety of study participants. Every effort should be made by the treating site to 
ensure laboratory normal ranges are collected from any such alternative locations. 
Troponin I will be measured at screening and repeated on study if clinically indicated. 
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9.4.12.1 
Clinical Chemistry, Hematology, Tumor Markers, Coagulation, and Thyroid 
Function 
Blood samples for analysis of the clinical chemistry, hematology, coagulation, and thyroid 
function shown in Table 9.a will be obtained as specified in the SOEs (Appendix A). 
Table 9.a 
Clinical Chemistry, Hematology, Tumor Markers, Coagulation, and 
Thyroid Function Tests 
Hematology 
Serum Chemistry 
Hematocrit 
Hemoglobin 
Leukocytes with differential 
Neutrophils (ANC) 
Platelets (count) 
Erythrocytes (RBC) 
MCH 
MCV 
MCHC 
Protein (total) 
Albumin 
ALP 
ALT 
AST 
Bilirubin (total) 
Glucose (fasting not required) 
Lactate dehydrogenase 
Calcium 
Bicarbonate (if available as a 
part of blood chemistry panel of 
local laboratory) 
C-reactive protein 
Blood urea nitrogen 
Creatinine 
Magnesium 
Phosphate 
Potassium 
Sodium 
Chloride 
Urate 
Thyroid Function 
Coagulation 
Thyrotropin 
Thyroxine, free 
aPTT 
PT or prothrombin international normalized ratio 
Tumor Markers 
Other 
AFP (HCC)  
CA 27.29 (TNBC) 
Ferritin 
Creatine kinase  
IL-6 
CA 19-9 (pancreatic adenocarcinoma) 
Troponin I 
HbA1c 
ANC: absolute neutrophil count; ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate 
aminotransferase; aPTT: activated partial thromboplastin time; HbA1c: glycosylated hemoglobin; HCC: 
hepatocellular carcinoma; IL-6: interleukin 6; MCH: mean corpuscular hemoglobin; MCHC: mean corpuscular 
hemoglobin concentration; MCV: mean corpuscular volume; PT: prothrombin time; RBC: red blood cell; TNBC: 
triple-negative breast cancer. 
 
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If creatinine clearance is to be estimated, the Cockcroft-Gault formula (see Appendix H) will be 
used as follows: 
Estimated creatinine clearance = [(140 - age [years]) × (weight [kg])] / (72 × serum 
creatinine [mg/dL]). 
For female patients, the result of the formula above should be multiplied by 0.85.  
9.4.13 
Disease Assessment 
For all patients, radiographic assessments of the disease burden will be performed locally at 
screening/baseline (within 28 days before the first study drug administration), then every 
6 weeks (±3 days) for the first 6 months from date of first dose, then every 12 weeks (±3 days) 
thereafter (until PD or the start of subsequent anticancer therapies). Tumor assessments for all 
patients should continue per protocol (scheduled from C1D1) even if dosing is interrupted. 
Patients with an initial CT or MRI scan showing either a PR or CR should have repeat imaging 
in 6 weeks to confirm response. If the patient has had an appropriate CT or MRI scan performed 
within 28 days of C1D1, the results of that scan may be used for tumor lesion measurements at 
screening. If a patient discontinues treatment for a reason other than documented PD, imaging is 
required at EOT if: (1) it has been more than 4 weeks since the most recent imaging, for patients 
within the first 6 months of treatment, or (2) it has been more than 6 weeks since the most recent 
imaging, for patients on study more than 6 months. Patients will undergo CT or MRI with IV 
contrast, as appropriate to monitor and assess response status, using RECIST v1.1 criteria.  
For this study, CT and/or MRI scans should be acquired. CT scans of the chest, abdominal 
cavity, and pelvis will be obtained at screening. For patients with HNSCC or known cervical 
disease, a CT and/or MRI neck should also be obtained. The imaging modalities used for a 
patient should remain consistent throughout the study. If IV contrast is not available or 
contrast-enhanced CT scans are contraindicated for a particular patient, a noncontrast CT of the 
chest, in addition to contrast-enhanced abdomen and pelvis by MRI should be acquired, if 
possible. Anatomical measurements (summed across target lesions) will be collected at baseline 
and each subsequent evaluation. In addition, nonmeasurable disease and new lesions will be 
documented and their statuses evaluated. X-rays and bone scans should be collected as clinically 
indicated. Deidentified copies of all imaging scans (including those from screening and any 
unscheduled scans) will be collected and transferred to the sponsor or designee (eg, central 
imaging vendor/imaging contract research organization) for storage. Determination of disease 
status will be based on local investigator assessment. 
9.4.13.1 
RECIST v1.1 and Treatment Beyond Progression 
When assessing response, special consideration should be given to the tumor response 
characteristics associated with immunotherapy: 
• Measurable tumor size reduction may take longer treatment duration with immunotherapy 
than with a cytotoxic regimen. 
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• Response to immunotherapy may occur after appearance of PD, as assessed per conventional 
RECIST v1.1 (see Appendix I). In particular, small, new lesions may appear in the presence 
of other responsive target lesions (pseudo-progression). 
• Durable SD may represent antitumor activity of immunotherapy. 
Therefore, modifications to RECIST v1.1 will be implemented in this study as described below. 
Accumulating data indicate it is possible that some patients treated with immunotherapy may 
derive clinical benefit beyond initial RECIST-defined PD. The protocol therefore accommodates 
an option to keep patients on treatment beyond such initial progression if specific criteria are 
met. Accordingly, patients treated with TAK-500 as an SA or in combination with 
pembrolizumab will be permitted to continue treatment beyond initial RECIST v1.1–defined PD 
if the following criteria are met: 
• Investigator-assessed overall clinical benefit from continued treatment with pembrolizumab 
and/or TAK-500. The assessment of clinical benefit should consider whether the patient is 
clinically deteriorating and unlikely to receive further benefit from continued treatment. 
• Tolerance of study drug(s). 
• Stable performance status. 
• Treatment beyond apparent progression will not delay an imminent intervention to prevent 
serious complications of PD (eg, CNS metastases). 
• Patient-provided written informed consent describing any reasonably foreseeable risks or 
discomforts, or other alternative treatment options. 
The decision to continue treatment beyond initial RECIST v1.1–defined progression should be 
discussed with the Takeda medical monitor and documented in the study records. Then, the 
patient may remain on the study and continue to receive monitoring according to the 
protocol-defined SOEs. Treatment should be discontinued permanently on documentation of 
further PD. If the patient experiences rapid clinical deterioration as perceived by the investigator 
before radiographic assessment within 6 weeks of original PD, the investigator can discontinue 
the study treatment without objective evidence of disease progression and report it as 
“symptomatic deterioration”. 
Patients who continue study therapy beyond initial RECIST v1.1–defined progression will be 
considered to have investigator-assessed PD at the time of the initial progression event. 
9.4.14 
Biomarker, Pharmacodynamics, and PK Samples 
9.4.14.1 
Primary Specimen Collection 
Blood samples will be collected via venipuncture or indwelling catheter at the time points 
detailed in Appendix A for plasma concentration measurements of TAK-500 and biomarker 
assessments (except for tumor biopsy). These samples must be collected on their own dedicated 
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line, separate from the TAK-500/pembrolizumab administration line. The primary specimen 
collection is presented in Table 9.b. 
If necessary, serum samples collected for PK assessments may also be used for exploration of 
pharmacodynamic biomarkers. These serum PK samples may only be used for this purpose after 
the final PK analysis has been completed. 
Details on sample handling, storage, shipment, and analysis are provided in the laboratory 
manual.  
Table 9.b 
 
 
. 
 
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9.4.14.2 
Tumor Biopsies 
9.4.14.2.1 
 
 
 
 
 
 
 
. 
9.4.14.2.2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
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9.4.15 
PK Measurements 
Details regarding the preparation, handling, and shipping of the PK samples are provided in the 
laboratory manual. Samples for PK will be collected at the time points specified in Appendix A. 
Serum 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 PK 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-500, total antibody, and deconjugated TAK-676. A protocol amendment is not 
necessary for such modifications. 
9.4.16 
Biomarker and Pharmacodynamic Measurements 
In this study, several biomarkers and pharmacodynamic measurements will be assessed to test 
for correlation with safety, PK, and, if possible, with antitumor activity. These biomarkers will 
be used to identify potential pharmacodynamic activity and patients who have a higher 
probability of response or of adverse reactions to TAK-500, including assessment of response or 
resistance to treatment that may emerge from this trial or future nonclinical or clinical trials. The 
biomarker sample analyses will be performed if or when required. Because new techniques 
continue to be developed, the method and laboratory that will be recommended for the biomarker 
analysis cannot be anticipated. 
The biomarker and pharmacodynamic specimen collection time points are displayed in 
Appendix A. Details regarding the preparation, handling, and shipping of samples are provided 
in the laboratory manual. 
The following biomarker and pharmacodynamic measures will be collected and may be tested. 
9.4.16.1 
 
 
 
 
. 
9.4.16.2 
 
 
 
 
. 
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9.4.16.3 
 
 
 
. 
9.4.16.4 
 
 
 
 
. 
9.4.16.5 
 
 
. 
9.4.16.6 
 
 
. 
9.4.16.7 
 
 
. 
9.4.16.8 
 
 
 
 
. 
9.4.17 
DNA Analyses 
 
 
 
 
 
. 
The data resulting from such analyses, if performed, may be pooled with similar data from other 
TAK-500 and TAK-676 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. This 
sample may be collected during the study if the sample cannot be collected at screening. 
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9.4.18 
Immunogenicity Sample Collection  
Serum samples for the assessment of ADA will be collected at time points specified in the SOEs. 
Samples must be collected before study drug is administered on a dosing day, and optionally at 
unscheduled visits for a patient who experiences an AE considered by the investigator to be 
consistent with hypersensitivity/infusion-related reaction. A sample will be assessed for 
neutralizing ADA if a positive ADA is detected. A final sample will be collected at EOT visit. 
9.4.19 
Collection, Storage, and Future Use of Biological Samples From Clinical Trial 
Subjects 
The blood samples for standard clinical tests and PK analysis will be consumed or destroyed at 
or before the end of the study when all the test data have been analyzed. The archival tissue, 
biopsy tissue, and blood samples collected for the biomarker research part of this study will be 
assessed or stored by the sponsor with its long-term storage partners for up to 15 years from the 
end of the study; after that time, the samples will be destroyed. These leftover samples may be 
used for future research, which may be about diseases, conditions, or drugs that may not be 
included in this study, and the efficacy, design, and methods of future studies. These leftover 
samples may also be shared with researchers collaborating with the sponsor. 
9.4.20 
 
 
 
9.4.20.1 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
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9.4.20.2 
 
 
 
 
 
 
 
9.4.20.3 
 
 
 
 
  
 
 
 
 
 
 
 
9.4.20.4 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
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9.5 
Documentation of Patient Screen Failures 
Investigators must account for all patients who sign informed consent. 
If the patient is found to be not eligible before the first dose, the investigator should complete the 
applicable eCRF. 
The primary reason for patient screen failure is recorded in the eCRF using the following 
categories: 
• Pretreatment event. 
• Failed inclusion criteria or did meet exclusion criteria. 
• Protocol deviation. 
• Lost to follow-up. 
• Withdrawal of consent by patient. 
• Study terminated by sponsor. 
Patient identification codes assigned to patients who fail screening should not be reused. Patients 
may be allowed to rescreen within 28 days of initial screening following discussion between 
investigator and sponsor. 
9.6 
Completion of Study Treatment (EOT for Individual Patients), 90-Day Safety 
Check, and Crossover Option 
Patients will be considered to have completed study treatment if they discontinue TAK-500 for 
any of the reasons outlined in Section 9.7. If the patient discontinues TAK-500 they will be 
required to discontinue all study treatment.  
All patients will have a 90-day (±3 days) safety check after receiving last dose of TAK-500. This 
may occur by phone or in the clinic, at the investigator’s discretion, and this contact will focus 
on any treatment-related immune-mediated AEs. If performed over the phone, only AE reporting 
is required. If patients have started on subsequent anticancer or radiation therapy during the 
interval, this will also be documented. 
For patients who discontinue study treatment for reasons other than disease progression, they 
will continue to have imaging according to the following schedule: every 6 weeks (±3 days) for 
the first 6 months from date of first dose, then every 12 weeks (±3 days) thereafter, until PD or 
the start of alternative therapy. Date of disease progression and subsequent anticancer therapies 
will be documented. 
In the setting of disease progression while on TAK-500 SA, crossover to the TAK-500 with 
pembrolizumab combination arm is optional and at the discretion of the investigator, in 
agreement with the sponsor. Patients in the TAK-500 SA treatment arm with objective evidence 
of PD may cross over to the TAK-500 and pembrolizumab combination arm into the last DL that 
is or was accruing patients. Crossover treatment should begin within 28 days of documented 
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disease progression and after the EOT visit; additionally, it is recommended that the first 
pembrolizumab dose be administered on a regularly scheduled TAK-500 dosing day. Crossover 
patients will proceed to a second EOT visit within 30 days of last TAK-500 dose after the 
combination treatment. 
9.7 
Discontinuation of Treatment With Study Drug and Patient Replacement 
Treatment with study drug may be discontinued for any of the following reasons: 
• AE (including patients who experience a DLT during the first 21 days after enrollment 
(C1D21).  
• Protocol deviation (after discussion with sponsor). 
• PD (tumor progression documented as assessed per RECIST v1.1): As noted previously, 
patients who meet the criteria for PD per RECIST v1.1 may continue to stay on study if they 
are clinically benefiting (see Section 9.4.13). In these patients, treatment discontinuation 
should occur when a subsequent scan confirms the initial PD, unless there are earlier clear 
signs of rapid clinical progression (clinical progression is defined as no imaging test 
performed to assess tumor status, but the investigator considers that patient declining is 
caused by tumor progression). 
• Symptomatic deterioration (the patient presents a decline in health that recommends 
terminating treatment, and tumor imaging is performed and does not qualify for PD). 
• Initiation of another systemic anticancer treatment. 
• Pregnancy (patient must be discontinued). 
• Study terminated by sponsor. 
• Withdrawal of consent by patient. 
• Lost to follow-up. 
• Other (after discussion with sponsor). 
Once study drug has been discontinued, all study procedures outlined for the EOT visit will be 
completed as specified in the SOEs (Appendix A) 30 days (+7 days) after last dose, or before 
initiation of any subsequent treatment (if applicable). If a patient is not able to return for the EOT 
visit, the EOT assessments may be performed at the time of treatment discontinuation. The 
primary reason for study drug discontinuation will be recorded on the eCRF.  
Patients are also to be contacted for a safety check 90 days after the last dose. 
During the dose escalation phase, patients not receiving all required doses in the first 21 days 
after initiation of TAK-500 for reasons other than DLT (eg, informed consent withdrawn) may 
be replaced.  
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In the case of study termination by the sponsor, eligible patients may have continued poststudy 
access to TAK-500 as described in Section 6.3.5. 
9.8 
Posttreatment Follow-up Assessments 
Some patients may discontinue study drug for reasons other than PD; these patients will remain 
in the study for follow-up and will be followed every 6 weeks (±3 days) for the first 6 months 
from date of first dose, then every 12 weeks (±3 days) thereafter with imaging until PD or the 
start of alternative therapies. Date of disease progression based on available local data, and 
subsequent anticancer therapies will be collected during this follow-up period. The EOS eCRF is 
to be completed when the patient discontinues from the follow-up period.  
NOTE: Related SAEs must be reported to the Global Pharmacovigilance department or designee. 
This includes deaths or SAEs that the investigator considers related to study drug that occur 
during posttreatment follow-up. Refer to Section 10.0 for details regarding definitions, 
documentation, and reporting of SAEs. 
9.9 
Completion of Study (for Individual Patients)  
Patients will be considered to have completed the study if they discontinue study drug for any of 
the reasons outlined in Section 9.7, including PD, and have also completed the following: 
• EOT visit. 
• Day 90 (±3 days) safety follow-up (visit or telephonic call). 
• For patients without PD at time of discontinuation of therapy: 
– Follow-up imaging as outlined in Section 9.8 to continue until PD or initiation of 
subsequent anticancer therapy, and 
– Documentation of PD or initiation of subsequent anticancer therapy. 
In the dose expansion phase of the study, patients will be considered to have completed the study 
when they complete an EOT visit and posttreatment follow-up (including OS), as applicable, or 
discontinue from the study for any of the reasons outlined in Section 9.7. 
9.10 
Withdrawal of Patients From Study/Early Termination or EOS 
All patients will have an EOS form completed. A patient may end study participation for any of 
the following reasons: 
• Completed study (as defined in Section 9.9). 
• Death. 
• Lost to follow-up. 
• Study terminated by sponsor. 
• Withdrawal by patient. 
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• Study closed and patient continuing with treatment in poststudy access (see Section 6.3.5). 
• Other. 
The consequence of study withdrawal is that no new information will be collected from the 
withdrawn patient and added to the existing data or any database. 
9.11 
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. 
Tests and procedures should be performed on schedule; however, unless otherwise specified, 
occasional changes are allowable within a 3-day window for holidays, vacations, and other 
administrative reasons. If extenuating circumstances prevent a patient from beginning treatment 
or completing a scheduled procedure or assessment within this time, the patient may continue the 
study only with the written permission of the medical monitor. Allowable windows on dosing 
days are described in Section 8.1. 
A maximum of 1 TAK-500 dose can be skipped, otherwise TAK-500 must be permanently 
discontinued. A patient can have up to 2 DL reductions of TAK-500 as an SA or in combination 
due to AEs but further reductions are not permitted (the patient should discontinue study drug in 
this case). 
10.0 
AEs 
10.1 
Definitions 
10.1.1 
Pretreatment Event Definition 
A pretreatment event is any untoward medical occurrence in a patient who has signed informed 
consent to participate in a study but before administration of any study medication; it does not 
necessarily have to have a causal relationship with study participation. 
10.1.2 
AE Definition 
AE means any untoward medical occurrence in a patient 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 
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intervention, or are considered by the investigator to be a clinically significant change from 
baseline will be assessed as AEs. 
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 laboratory abnormality, will be determined 
using the NCI CTCAE v5.0. 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 
Special Situation Report Definition 
A special situation report (SSR) is defined as any of the following events: 
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• Abuse: persistent or sporadic, intentional excessive use of medicinal products that is 
accompanied by harmful or physical or psychological effects. 
• Misuse: situations where the medicinal product is intentionally and inappropriately used not 
in accordance with the prescribed or authorized dose, route of administration, and/or the 
indication(s) or within the legal status of its supply. 
• Medication Error: an unintentional error in the drug treatment process (prescribing, 
dispensing or administration, including incorrect dose or poor quality administration) of a 
medicinal product while in the control of health care provider, patient, or consumer, which 
leads to harm or has the potential to lead to harm. 
• Overdose: the administration of a quantity of medicinal product given per administration or 
per day, which is above the maximal dose according to the protocol. 
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 faxing a paper-based SAE form, site personnel need to confirm successful transmission of all 
pages and include an email address on the fax cover sheet so that an acknowledgment of receipt 
can be returned via email within 1 business day. 
Fax Numbers: 
• US and Canada: + 1-800-963-6290. 
• Rest of World: + 1-202-315-3560. 
Email submission of SAE forms with a PDF attachment should only be used in the case where 
fax is not possible, and EDC is not feasible within 24 hours of receiving the event. If using 
email, site personnel need to confirm successful transmission by awaiting an acknowledgment of 
the receipt via email within 1 business day. 
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Email Address: 
• PVsafetyoncologyAmer@takeda.com. 
If SAEs are reported via fax or by email, EDC/Rave must be updated as soon as possible with 
the appropriate information. 
If information not available at the time of the first report becomes available at a later date, then 
the investigator will transmit a follow-up EDC SAE report (or a paper-based SAE form if an 
EDC SAE report is not feasible) or provide other documentation immediately within 24 hours of 
receipt. Copies of any relevant data from the hospital notes (eg, ECGs, laboratory tests, discharge 
summary, postmortem results) should be sent to the addressee, if requested. 
All SAEs should be followed up until resolution or permanent outcome of the event. The 
timelines and procedure for follow-up reports are the same as those for the initial report. 
Planned hospital admissions or surgical procedures for an illness or disease that existed before 
the patient was enrolled in the study are not to be considered AEs unless the condition 
deteriorated in an unexpected manner during the study; eg, surgery was performed earlier or later 
than planned. 
For both serious and nonserious AEs, the investigator must determine both the severity (toxicity 
grade) of the event and the relationship of the event to study drug and/or the AxMP 
administration. 
Severity (toxicity grade) for each AE, including any laboratory abnormality, will be determined 
using the NCI CTCAE v5.0. The criteria are provided in the study manual. 
Relationship of the event to study drug and/or the AxMP 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/s and/or the AxMP? 
10.2.1 
Recording and Reporting AEs and SAEs Related to AxMPs 
The use of AxMPs is required in this study for both the prevention (premedication before 
TAK-500 dosing; Section 6.1.1) and acute management of CRS (Section 8.9.1, and Table 8.d) 
(Lee et al. 2019). The causality for all AEs must be assessed against the AxMPs. Any SAE 
deemed related to AxMP will follow the SAE reporting procedures described in Section 10.2. All 
non-serious AEs assessed as related to the authorized AxMP should be reported to the sponsor 
within 7 days by transmitting an EDC report. If transmission of the EDC report is not feasible, a 
paper AE/SAE report form must be sent.  
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 time of signing of the informed consent through 30 days after 
the administration of the last dose of study drug(s) (eg, EOT) or before initiation of new 
anticancer therapy (whichever comes first) and recorded in the eCRFs. 
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• AEs ongoing at EOT should be monitored until they are resolved, return to baseline, are 
clearly determined to be due to a patient’s stable or chronic condition or intercurrent 
illness(es), the start of 2L alternative therapy, or 6 months after PD has occurred, whichever 
comes first. 
• AEs that the investigator considers to be immune-mediated will be reported from the time of 
initiation of study drug(s) through 90 days after the administration of the last dose of study 
drug(s) or before initiation of new anticancer therapy (whichever comes first) and recorded in 
the eCRFs. 
• SAEs and AxMP-related AEs and SAEs will be reported to the Takeda Global 
Pharmacovigilance department or designee from the time of signing of informed consent 
through last study visit or before initiation of new anticancer therapy (whichever comes first) 
and recorded in the eCRF. 
• SAEs will be monitored until they have resolved or are clearly determined to be due to a 
patient’s stable or chronic condition or intercurrent illness(es). 
10.4 
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events 
If a woman becomes pregnant or suspects that she is pregnant while participating in this study, 
she must inform the investigator immediately and permanently discontinue study drug. The 
sponsor must also be contacted immediately by sending a completed pregnancy form to the 
Takeda Global Pharmacovigilance department or designee. The pregnancy must be followed for 
the final pregnancy outcome. 
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. 
Pregnancies are to be reported through 180 days after the last dose of study drug. 
10.5 
Procedures for Reporting Product Complaints or SSRs 
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 in the study manual. 
SSRs (see Section 10.1.4) are defined as medication errors and uses outside what is foreseen in 
the protocol, including overdose, misuse, and abuse of the product. SSRs may or may not be 
associated with an AE/SAE. SSRs must be reported to Takeda Global Patient Safety Evaluation, 
using a paper SSR form, within 7 calendar days of awareness via the contact information 
provided in the study manual. If a SSR is associated with an SAE, the SAE must be reported to 
Takeda Global Patient Safety Evaluation within 24 hours of awareness. 
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Product complaints and SSRs in and of themselves are not AEs. If a product complaint or a SSR 
results in an SAE, the SAE should be reported.  
For product complaints related to pembrolizumab sourced locally by the clinical site, use 
standard methods to contact product manufacturer or regulatory agency per standard site process. 
10.6 
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities 
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators, and IRBs and 
IECs, as applicable, in accordance with national regulations in the countries where the study is 
conducted. Relative to the first awareness of the event by/or further provision to the sponsor or 
sponsor’s designee, SUSARs will be submitted to the regulatory authorities as expedited reports 
within 7 days for fatal and life-threatening events and within 15 days for other serious events, 
unless otherwise required by national regulations. The sponsor will also prepare an expedited 
report for other safety issues where these might materially alter the current benefit-risk 
assessment of an investigational medicinal product or that would be sufficient to consider 
changes in the investigational medicinal product’s administration or in the overall conduct of the 
trial. The investigational site also will forward a copy of all expedited reports to his or her IRB or 
IEC in accordance with national regulations. 
11.0 
STUDY-SPECIFIC COMMITTEES 
11.1 
Independent Data Monitoring Committee 
For phase 2 dose expansion only: 
An independent data monitoring committee (IDMC) will review safety data and the interim 
analysis data for futility as detailed in the IDMC charter. The charter of the IDMC will specify 
that this committee is charged with providing periodic reports to the sponsor that contain 
recommendations that include, but are not limited to, (a) continuation of the study, (b) 
continuation with modification, and (c) termination of the study. 
12.0 
DATA HANDLING AND RECORDKEEPING 
The full details of procedures for data handling will be documented in the data management plan. 
If selected for coding, AEs, medical history, and concurrent conditions will be coded using the 
Medical Dictionary for Regulatory Activities (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 
transmit the information collected in the performance of this study to the sponsor, contract 
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research organization partners, and regulatory authorities. Investigative sites must complete 
eCRFs in English. 
After completion of the entry process, computer logic checks will be run to identify items such 
as inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designee) and will be answered by the site. 
Any change of, modification of, or addition to the data on the eCRFs should be made by the 
investigator or appropriate site personnel. Corrections to eCRFs are recorded in an audit trail that 
captures the old information, the new information, identification of the person making the 
correction, the date the correction was made, and the reason for the change. 
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the principal investigator must retain 
full responsibility for the accuracy and authenticity of all data entered on the eCRFs. 
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor (or designee) will be permitted to review the patient’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed 
eCRFs are the sole property of the sponsor and should not be made available in any form to third 
parties, except for authorized representatives of appropriate governmental health or regulatory 
authorities, without written permission of the sponsor. 
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 antitumor activity analyses. 
• PK analysis set: Patients with sufficient dosing and PK data to reliably estimate 1 or more 
PK parameters will be used for PK analyses. 
• DLT-evaluable analysis set: The DLT-evaluable analysis set will include patients who 
receive all required doses of TAK-500 with or without pembrolizumab and remain on study 
for 21 days from first dosing of TAK-500 (through C1D21) without experiencing a DLT or 
who have a DLT during the first 21 days after study drug administration. The DLT-evaluable 
population in the TAK-500 SA and the TAK-500 + pembrolizumab combination dose 
escalation cohorts will be used to determine the MTD (specific premedication regimens to be 
evaluated separately).  
• Response-evaluable analysis set: The response-evaluable analysis set, a subset of the safety 
analysis set including patients with measurable disease at baseline and at least 
1 posttreatment evaluation, will be used for analyses of response. 
• Peripheral pharmacodynamic analysis set: The peripheral pharmacodynamic analysis set 
will include those patients from the safety population who have been on study for at least 
1 week and have baseline and at least 1 postbaseline peripheral sample assessment. 
• Tumor biopsy analysis set: The tumor biopsy analysis set will include those patients from 
the safety population who have baseline and at least 1 postbaseline tumor biopsy sample 
assessments. 
• Immunogenicity analysis set: The immunogenicity analysis set consists of patients who 
receive at least 1 dose of TAK-500 and have an ADA status assessment at baseline, and at 
least 1 postbaseline sample. 
Patients in the SA arm who cross over to the combination arm will be analyzed separately using 
all the post-crossover data, repeating the main analyses as appropriate, to show long-term safety 
and antitumor activity. As described in Section 8.5.2, these crossover patients will still be 
included in the main analyses, in which their post-crossover data will be excluded. 
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Patients treated with a specific premedication regimen will be analyzed separately from cohorts 
treated without premedication or with other premedication regimens. 
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 of 
observations, 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.  
Baseline values for patients who cross over from the SA arm to the combination arm are defined 
as the last valid value before exposure to the combination drug. 
13.1.3 
Efficacy Analysis 
For the dose escalation phase, antitumor activity is not the primary endpoint; secondary 
antitumor activity endpoints include ORR, DCR, DOR, and TTR. In the dose expansion phase, 
ORR is the primary endpoint; secondary antitumor activity endpoints include DCR, DOR, TTR, 
PFS, and OS. No formal statistical tests will be performed for these efficacy endpoints in the 
study. 
ORR is defined as the proportion of patients who achieve cPR or cCR (determined by the 
investigator) during the study in the response-evaluable analysis set. 
DCR is defined as the proportion of patients who achieve SD or better (determined by the 
investigator) >6 weeks during the study in the response-evaluable analysis set. 
DOR is defined as the time from the date of first documentation of a cPR or better to the date of 
first documentation of PD or death for responders (cPR or better) in the response-evaluable 
analysis set. Responders without documentation of PD will be censored at the date of last 
response assessment that is SD or better. 
TTR is defined as the time from the date of first dose administration to the date of first 
documented cPR or better (determined by the investigator) in the response-evaluable analysis 
set. 
PFS is defined as the time from date of study treatment to the first documented disease 
progression based on RECIST v1.1, or death due to any cause, whichever occurs first, in the 
safety analysis set. 
OS is defined as the time from the date of first dose administration to the date of death. 
ORR and DCR will be summarized using descriptive statistics with 95% CI. DOR and TTR will 
be analyzed using Kaplan-Meier method for response-evaluable analysis set. PFS and OS will be 
analyzed using Kaplan-Meier method for the safety analysis set in dose expansion cohorts only. 
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Responses achieved in the crossover patients and long-term durability of response will be 
presented separately from the main study data. 
13.1.4 
PK Analysis 
13.1.4.1 
PK Noncompartmental Analysis 
PK parameters for TAK-500 and total antibody will be estimated using noncompartmental 
methods with WinNonlin software. The PK parameters will be estimated from the 
concentration-time profiles for the PK population.  
The following PK parameters will be determined, as permitted by data: 
• Cmax. 
• tmax. 
• AUCt. 
• AUC∞. 
• t1/2z. 
• CL. 
• Vss. 
PK parameters will be summarized using descriptive statistics. Individual TAK-500 
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. A summary of deconjugated TAK-676 concentration-time data will be 
included (if measurable). 
13.1.4.2 
PK Sampling Intended for Population PK Analysis 
The PK data collected in this study are intended to contribute to future population PK analyses of 
TAK-500. These population PK analyses may additionally include data collected in other 
TAK-500 clinical studies. The plan for the population PK analysis will be defined separately and 
the results reported separately. 
13.1.5 
Immunogenicity Analysis 
Immunogenicity parameters (ADA-negative, transiently and persistently ADA-positive, low or 
high ADA titer) will be analyzed using descriptive statistics in the safety analysis set and 
immunogenicity analysis set. The relationship of immunogenicity responses to PK, antitumor 
activity, and safety may be explored. 
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13.1.6 
Pharmacodynamic Analysis 
The 
 will be evaluated in peripheral blood and/or tumor 
samples collected at baseline and after administration of TAK-500. The change 
 
 will be calculated and used to establish evidence of 
pharmacodynamic modulation. The relationship between 
 
 
 
 may also be explored. The analysis will be performed in 
the pharmacodynamic population. 
13.1.7 
PK/Pharmacodynamic Analysis 
The relationship between TAK-500, total antibody, and/or deconjugated TAK-676 exposure and 
pharmacodynamic response (
 
) will be explored on an ongoing basis as PK and pharmacodynamic 
data become available to understand the PK-pharmacodynamic relationship of TAK-500 and to 
help in estimation of the PAD range. Data permitting, mathematical models may be used to 
describe this relationship and such models may be used to predict the dose/schedule of TAK-500 
that provides the desired exposure and pharmacological response for future evaluation. These 
data may be presented graphically as well as summarized in the clinical study report. The 
analysis will be performed in the pharmacodynamic population. 
13.1.8 
PK/QTc Analysis 
The PK-time matched triplicate ECG data collected in each patient will be pooled to understand 
the PK-QTc relationship of TAK-500. The relationship between TAK-500 serum concentration 
and effects on heart rate and QTcF will be analyzed using mixed effects modeling. These 
population PK-QTc analyses may include data collected in other TAK-500 clinical studies. As 
such, the analysis plan for the population PK-QTc analysis will be separately defined, and the 
results of these analyses will be reported separately and not presented in the clinical study report 
for this study. 
13.1.9 
Safety ECG Analysis 
A summary of ECG abnormalities will be presented by visit. ECG parameters (QT, QTcF, PR 
interval, QRS, and heart rate) will be summarized at each scheduled time point, along with mean 
change from baseline to each posttreatment time point. 
13.1.10 
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. 
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TEAEs that occur after administration of the first dose of study and through 30 days after the last 
dose of study drug will be tabulated. 
Related immune-mediated AEs as determined by the investigator that occur after administration 
of the first dose of study drug and through 90 days after administration of the last dose of study 
drug or before initiation of new anticancer therapy (whichever comes first) will be tabulated. 
AEs will be tabulated according to the MedDRA and will include the following categories: 
• TEAEs. 
• Drug-related TEAEs. 
• Grade 3 or higher TEAEs. 
• Grade 3 or higher drug-related TEAEs. 
• The most commonly reported TEAEs (ie, those reported by ≥10% of all patients). 
• Treatment-emergent SAEs (related and regardless of relationship). 
• TEAEs 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 Status will be summarized 
using a shift table. 
Shift tables for laboratory parameters will be generated for changes in NCI CTCAE grade from 
baseline to worst postbaseline value. Graphical displays of key safety parameters, such as scatter 
plots of baseline vs worst postbaseline values, may be used to understand the TAK-500 safety 
profile. 
All concomitant medications collected from the first dose of study drug throughout the study 
period will be classified to Preferred Terms according to the WHO Drug Dictionary. 
Additional safety analyses may be performed to most clearly enumerate rates of toxicities and to 
further define the safety profile of TAK-500. 
13.1.11 
  
 
 
 
 
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.  
13.1.12 
 
13.1.12.1 
 
 
 
 
 
  
 
 
 
  
13.1.12.2 
 
 
 
 
 
 
 
  
13.2 
Interim Analysis and Criteria for Early Termination 
In the dose escalation phase, although no formal interim analysis is planned, investigators and 
sponsor representatives will review all available data to determine dose escalation and number of 
patients per cohort in the dose escalation phase.  
In the dose expansion phase, an interim futility analysis will be performed, as detailed in 
Sections 6.1.3 and 13.3.  
13.3 
Determination of Sample Size 
Approximately 313 patients will be enrolled in the study, including approximately 82 in the dose 
escalation phase and approximately 231 in the dose expansion phase (assuming only 1 dose 
schedule will be expanded).  
In the phase 1 dose escalation phase, approximately 52 patients will be enrolled to achieve about 
46 DLT-evaluable patients in the SA arm, and approximately 30 patients will be enrolled to 
achieve a maximum of 27 DLT-evaluable patients in the combination arm (assuming a drop-out 
rate of 10%). In the SA arm, a maximum of 42 DLT-evaluable patients is planned for BOIN 
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escalation to cover 8 DLs and additionally 4 DLT-evaluable patients for the two 
1 + 2 + 3 escalation DLs. In the combination arm, the number of patients will depend on the 
starting DL. Assuming the escalation starts at 80 μg/kg, a maximum of 27 DLT-evaluable 
patients will be enrolled. Additional patients may be enrolled for the evaluation of Q2W 
administration of TAK-500 if this schedule is explored in the dose escalation phase (in either the 
SA or combination arm).  
In the phase 2 dose expansion phase, each cohort’s sample size is based on Simon’s 2-stage 
design or an exact binomial 1-stage design with ORR as the endpoint, a 1-sided alpha equal to 
0.1, and an assumed dropout rate of 10%. In the following cohort-specific design specifications, 
H0 represents the “null hypothesis,” HA represents the “alternative hypothesis,” RE represents 
“response-evaluable,” and power represents “statistical power.” Additionally, specific design 
scenarios are dependent on the results from preceding scenarios and may or may not be realized. 
• 2L NSCLC TAK-500 + pembrolizumab RDE 1 versus RDE 2 [2:1 randomization]:  
– Based on Simon’s 2-stage design, approximately 39 patients will be enrolled in the RDE 
1 cohort, allowing for 35 RE patients. H0: ORR ≤ 23%, HA: ORR ≥40%, and power = 
80%. The futility analysis will occur at 21 RE patients, where ≥5 responders are required 
for successfully passing futility.  
– Approximately 20 patients will be enrolled in the RDE 2 cohort, allowing for 18 RE 
patients. If the futility analysis in RDE 1 fails, additional enrollment will be initiated to 
increase the RDE 2 RE sample size to 21 patients and Simon’s 2-stage design will be 
applied in the same manner as planned for RDE 1. Given this, the total number of RE 
patients for RDE 2 may be 18, 21, or 35.  
• 3L NSCLC TAK-500 SA RDE 1 versus RDE 2 [1:1 randomization]: 
– Based on a single-stage exact binomial design, approximately 24 patients will be enrolled 
each in the RDE 1 cohort and the RDE 2 cohort allowing for 21 RE patients per cohort. 
For each cohort, H0: ORR ≤ 5%, HA: ORR ≥20%, and power = 82%. The total RE sample 
size across the 2 cohorts will be 42 patients.  
• 2L pancreatic adenocarcinoma TAK-500 + pembrolizumab RDE 1 versus 2L pancreatic 
adenocarcinoma TAK-500 SA RDE 1 [1:1 randomization]: 
– Based on Simon’s 2-stage design, approximately 45 patients will be enrolled each in the 
combination cohort and the SA cohort, allowing for 40 RE patients per cohort. For each 
cohort, H0: ORR ≤ 16%, HA: ORR ≥30%, and power = 80%. For each cohort, a futility 
analysis will occur at 25 RE patients, where ≥4 responders are required for successfully 
passing futility.  
• 3L RCC TAK-500 + pembrolizumab RDE 1:  
– Based on a single-stage exact binomial design, approximately 34 patients will be enrolled 
allowing for 30 RE patients. H0: ORR ≤ 8%, HA: ORR ≥25%, and power = 90%.  
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14.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
Study-Site Monitoring Visits 
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or its 
designee (contract research organization) and by the IRB or IEC. 
In the event a monitor cannot visit the site in a timely manner due to the COVID-19 pandemic, 
alternative monitoring approaches such as remote source data verification or telephone contact 
may be used to ensure data quality and integrity and maintain patient safety. Alternative 
monitoring approaches should be used only where allowed by the local Health Authority and 
permitted by the IRB/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. 
There will be no exemptions (a prospectively approved deviation) from the inclusion or 
exclusion criteria. 
The site should document all protocol deviations in the patient’s source documents. In the event 
of a significant deviation, the site should notify the sponsor or its designee (and IRB or IEC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the patient, or confound interpretation of the primary 
study assessment. 
The sponsor will assess any protocol deviation; if it is likely to affect to a significant degree the 
safety and rights of a patient or the reliability and robustness of the data generated, it is 
mandatory to be reported to regulatory authorities as a serious breach of GCP and the protocol. 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections 
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
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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, US FDA, the United Kingdom [UK] Medicines and 
Healthcare products Regulatory Agency [MHRA], the Pharmaceuticals and Medical Devices 
Agency [PMDA] of Japan). If the study site is contacted for an inspection by a regulatory body, 
the sponsor should be notified immediately. The investigator and institution guarantee access for 
quality assurance auditors to all study documents as described in Section 14.1. 
15.0 
ETHICAL ASPECTS OF THE STUDY 
This study will be conducted with the highest respect for the individual participants (ie, patients) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the responsibilities of the investigator that are listed in Appendix B. 
The principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities. 
15.1 
IRB and/or IEC Approval 
IRBs and IECs must be constituted according to the applicable requirements of each 
participating region. The sponsor or designee will require documentation noting all names and 
titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC has 
direct participation in this study, written notification regarding his or her abstinence from voting 
must also be obtained. Those American sites unwilling to provide names and titles of all 
members because of privacy and conflict of interest concerns should instead provide a 
Federalwide Assurance number or comparable number assigned by the US Department of Health 
and Human Services. 
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the investigator’s brochure, a copy of 
the ICF, and, if applicable, patient recruitment materials and advertisements and other documents 
required by all applicable laws and regulations must be submitted to a central or local IRB or 
IEC for approval. The IRB’s or IEC’s written approval of the protocol and patient informed 
consent must be obtained and submitted to the sponsor or designee before commencement of the 
study, ie, before shipment of the sponsor-supplied drug or study-specific screening activity. The 
IRB or IEC approval must refer to the study by its exact protocol title, number, and version date; 
identify versions of other documents (eg, ICF) reviewed; and state the approval date. If required 
by country or regional regulations or procedures, approval from the competent regulatory 
authority will be obtained before commencement of the study or implementation of a substantial 
amendment. The sponsor will notify the site once the sponsor has confirmed the adequacy of site 
regulatory documentation and, when applicable, the sponsor has received permission from the 
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competent authority to begin the study. Until the site receives 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 
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 
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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 
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. 
If a serious data breach affecting personal data is detected, the sponsor or its designee and the 
investigator (as applicable) will take appropriate corrective and preventive actions in response. 
These actions will be documented, and the relevant regulatory agency(ies) will be notified as 
appropriate. Where appropriate, the relevant individuals materially affected by the breach would 
also be notified; in the case of study participants, this would be done through the investigator. 
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Takeda applies certain measures to protect participants’ personal data and prevent data breaches, 
detailed in a separate document (Compliance with National Requirements on Data Protection). 
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 
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. 
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15.4.3 
Clinical Trial Results Disclosure 
Takeda will post the results of clinical trials on ClinicalTrials.gov, ClinicalTrialsRegister.eu, and 
other publicly accessible websites (including the Takeda corporate site) and registries, as 
required by Takeda policy/standards, applicable laws, and/or regulations. 
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 SOEs 
The SOEs are provided for: 
• SOE for TAK-500 Q3W treatment (21-day cycle). 
• SOE for TAK-500 Q3W treatment (42-day cycle). 
• SOE for TAK-500 Q2W treatment (42-day cycle). 
 
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SOEs for TAK-500 Q3W Treatment (21-Day Cycle) 
For the SOEs when administered TAK-500 Q3W on a 21-day cycle, as an SA or in combination with pembrolizumab, see: 
• Table A-1 for Cycle 1. 
• Table A-2 for Cycle 2 through EOS. 
• Table A-3 for serial PK and ECG sampling. 
• Table A-4 for pharmacodynamic biomarkers collection. 
 
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Table A-1 
SOE for TAK-500 Q3W Treatment (21-Day Cycle) Cycle 1 
 
Screening a 
Day 1 b 
Day 2 
Day 3 
Day 4 
Day 8 
Day 15 
Tumor markers n 
 
X 
 
 
 
 
 
Thyroid function tests m 
X 
 
 
 
 
 
 
C-reactive protein m 
X 
X 
 
 
 
X 
X 
Creatine kinase  
X 
 
 
 
 
 
 
Ferritin  
X 
X 
 
 
 
X 
X 
Coagulation  
X 
 
 
 
 
 
 
Troponin I  
X 
 
 
 
 
 
 
HbA1c  
X 
 
 
 
 
 
 
IL-6 o 
 
X  
 
 
 
 
 
PK and triplicate ECG sampling schedule for TAK-500 Q3W treatment (21-day cycle): Table A-3 
Biomarker sample collection for TAK-500 Q3W treatment (21-day cycle): Table A-4 
AE: adverse event; ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; cCR: confirmed complete response; CT: computed 
tomography; cPR: confirmed partial response; CTCAE: Common Terminology Criteria for Adverse Events; CxDx: Cycle x Day x; ECG: electrocardiogram; ECHO: 
echocardiogram; ECOG: Eastern Cooperative Oncology Group; EOI: end of infusion; HbA1c: glycosylated hemoglobin; HCC: hepatocellular carcinoma; ICF: informed 
consent form; IEC: independent ethics committee; IL: interleukin; IRB: institutional review board; IV: intravenous; MCH: mean corpuscular hemoglobin; MCHC: mean 
corpuscular hemoglobin concentration; MCV: mean corpuscular volume; MRI: magnetic resonance imaging; MUGA: multiple gated acquisition scan; PD: progressive disease; 
PD-1: programmed cell death protein 1; PK: pharmacokinetic(s); Q2W: once every 2 weeks; Q3W: once every 3 weeks; RECIST: Response Evaluation Criteria in Solid 
Tumors; SA: single agent; SAE: serious adverse event; SOE: schedule of events; TNBC: triple-negative breast cancer; v: Version; WBC: white blood cell. 
Tests and procedures should be performed on schedule, but occasional changes are allowable (±3 days) with permission of the medical monitor for holidays, vacations, and 
other administrative reasons. If extenuating circumstances prevent a patient from beginning treatment or completing a scheduled procedure or assessment within this 
time, the patient may continue the study only with the written permission of the medical monitor. 
All timepoints mentioned are relative to administration of TAK-500 unless otherwise specified.  
a Unless otherwise noted, the screening procedures must occur within 28 days before the day of the first dose of study drug (C1D1). 
b Patients will be hospitalized for at least the first 2 administrations of TAK-500 or TAK-500 + pembrolizumab, with monitoring for approximately 24 (±4) hours. Subsequent 
monitoring will be determined based on the presence of Grade 2 CRS in prior cycles. 
c Medical history will include smoking/vaping history and available baseline disease characteristics, such as disease type, staging, PD-1 expression, etc. Complete physical 
examination (including assessment of the following systems: skin, head, eyes, ears, nose, throat, respiratory, cardiovascular, gastrointestinal, neurological condition, blood and 
lymphatic, and musculoskeletal) and medical history will be collected at screening and the time points indicated. The C1D1 physical examination and medical history are not 
required if the screening physical examination was conducted and medical history obtained within 4 days before administration of the first dose of study drug (C1D1). 
Postscreening physical examinations will be symptom- or finding-directed and will be performed at any time point based on clinical need. Before discharge from the clinic or 
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Table A-1 
SOE for TAK-500 Q3W Treatment (21-Day Cycle) Cycle 1 
 
Screening a 
Day 1 b 
Day 2 
Day 3 
Day 4 
Day 8 
Day 15 
hospital on treatment days, a physical examination will include an assessment of the respiratory and neurologic systems as well as a complete set of vital signs. 
d Vital signs will be measured immediately before the start of the TAK-500 infusion (within 30 minutes), 30 minutes after start of infusion (±5 minutes), at the EOI (±10 
minutes), 1 hour after infusion (±10 minutes), any time when clinically indicated, and before discharge. For infusion times of less than 30 minutes, vital signs will be measured 
immediately before the start of the TAK-500 infusion (within 30 minutes), at the EOI (±5 minutes), 30 minutes after EOI (±5 minutes), and at 1 hour after infusion (±10 
minutes). On C1D1 vital signs will also be measured at 3 and 6 hours after dosing of TAK-500 (measurement should be obtained in a ±30-minute window). Blood pressure 
should be determined with the patient in a seated position after the patient has been sitting quietly for 5 minutes.  
 
 
f Safety ECGs should be performed at screening and C1D1 predose, EOI (+1 hour), and 2 (+1 hour) and 3 (+1 hour) hours postdose. A qualified person will interpret the ECGs 
locally. ECG assessments are to be performed with the patient supine and rested for 5 minutes. Additional ECGs may be obtained as clinically indicated at any time during the 
study at the discretion of the investigator. When the timing of ECG or vital signs 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. The frequency and timing of ECG collection for safety may be modified 
based on emerging data and agreement between sponsor and investigators. 
g Radiological evaluations (contrast-enhanced CT scan or MRI as clinically indicated) will be used to assess the status of the patient’s underlying disease. An evaluation of 
lesions will be performed during screening (within 28 days before the first dose of study drug). For all patients, radiographic assessments of the disease burden will be 
performed locally at screening/baseline (within 28 days before the first study drug administration), then every 6 weeks (±3 days) for the first 6 months from date of first dose, 
then every 12 weeks (±3 days) thereafter (until PD or the start of alternative therapies). Tumor assessments for all patients should continue, scheduled from C1D1, even if 
dosing is interrupted. Patients with an initial CT or MRI scan showing either a PR or CR should have repeat imaging in 6 weeks to confirm response. If the patient has had an 
appropriate CT or MRI scan performed within 28 days of C1D1, the results of that scan may be used for tumor lesion measurements at screening. Patients will undergo CT or 
MRI with IV contrast, as appropriate to monitor and assess response status, using RECIST v1.1 criteria. Refer to Section 9.4.13 for details. 
h For 6 weeks (42 days) after C1D1, on nondosing days or when patient is not hospitalized, patients will be asked to record oral temperature twice daily (first in the morning and 
last in the evening) and any time the patient feels febrile on a patient diary that should be brought to the site at each Cycle 1 and 2 visit. Please report clinically significant fever 
as AEs according to CTCAE v5.0 guidelines. 
i The principal investigator (or appropriate designee, subinvestigator, study nurse) is required to call the patient on the days specified to assess the patient for overall AEs and 
general well-being. 
j For the combination arm only, pembrolizumab will be administered IV with completion of pembrolizumab infusion 1 hour before administration of TAK-500 on Day 1. 
Detailed infusion instructions are provided in the pharmacy manual. 
k For patients in cohorts where premedication with 
 is assigned, 
 will be administered 1 hour (50-120 min) before administration of TAK-500 
in the SA arm and 1 hour (50-120 min) before pembrolizumab in the combination arm. 
 premedication will begin with C1D1 dosing and continue in subsequent 
cycles. 
l A serum choriogonadotropin beta pregnancy test will be performed only for patients of childbearing potential during screening and again at C1D1 (baseline) if the screening 
test was performed more than 4 days before the first dose of any study drug. The results must be negative within 4 days before the first dose of TAK-500 is administered (ie, 
within the 4 days before C1D1), or as otherwise required by local regulations. Additional pregnancy testing (serum or urine; urine preferred) will be performed before each dose 
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Table A-1 
SOE for TAK-500 Q3W Treatment (21-Day Cycle) Cycle 1 
 
Screening a 
Day 1 b 
Day 2 
Day 3 
Day 4 
Day 8 
Day 15 
of TAK-500 and may be performed during the study at the discretion of the investigator, on request of an IEC/IRB, or if required by local regulations. 
m The hematology and chemistry blood samples for C1D1 may be collected within 4 days before dosing to ensure patient eligibility on C1D1. If screening clinical laboratory 
testing was performed within 4 days before the C1D1 dose, it need not be repeated on C1D1. Hematology includes complete blood cell count with differential consisting of the 
following: hemoglobin, hematocrit, leukocytes (WBCs), differential WBC count, platelets, erythrocytes, MCH, MCV, and MCHC. Machine counts are acceptable. The 
chemistry panel consists of the following: protein (total), sodium, potassium, bicarbonate, chloride, blood urea nitrogen, creatinine, bilirubin, ALP, AST, ALT, lactate 
dehydrogenase, albumin, glucose, urate, calcium, phosphate, and magnesium. 
n The following tumor markers for the associated select tumors will be assessed at baseline before treatment on C1D1 and then every 2 cycles (6 weeks) thereafter: TNBC, CA 
27.29; HCC, AFP; pancreatic adenocarcinoma, CA 19-9. 
o IL-6 levels to be measured for the first 2 doses (C1D1 and C2D1) predose and 12 hours postdose (±30 minutes). 
 
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Table A-2 
SOE for TAK-500 Q3W Treatment (21-Day Cycle) Cycle 2 Through EOS 
 
Cycle 2 and Subsequent Cycles 
EOT  
30 (+7) Days After Last Dose or 
Before Subsequent Therapy 
Safety Follow-up  
90 (±3) Days After 
Last Dose c 
Follow-
up c 
Day 1 a 
Day 2 
Day 8 b 
Day 21 
Thyroid function tests p 
X 
 
 
 
 
 
 
C-reactive protein p 
X 
 
X b 
 
 
 
 
Ferritin p 
X 
 
X b 
 
 
 
 
HbA1c p 
X 
 
 
 
 
 
 
IL-6 q  
X  
 
 
 
 
 
 
PK and triplicate ECG sampling schedule for TAK-500 Q3W treatment (21-day cycle): Table A-3 
Biomarker sample collection for TAK-500 Q3W treatment (21-day cycle): Table A-4 
AE: adverse event; ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; cCR: confirmed complete response; cPR: confirmed partial 
response; CRS: cytokine release syndrome; CT: computed tomography; CTCAE: Common Terminology Criteria for Adverse Events; CxDx: Cycle x Day x; ECG: 
electrocardiogram; ECOG: Eastern Cooperative Oncology Group; EOI: end of infusion; EOS: end of study; EOT: end of treatment; HbA1c: glycosylated hemoglobin; HCC: 
hepatocellular carcinoma; ICF: informed consent form; IEC: independent ethics committee; IL: interleukin; IRB: institutional review board; IV: intravenous; MCH: mean 
corpuscular hemoglobin; MCHC: mean corpuscular hemoglobin concentration; MCV: mean corpuscular volume; MRI: magnetic resonance imaging; PD: progressive disease; 
PK: pharmacokinetic(s); Q2W: once every 2 weeks; Q3W: once every 3 weeks; RECIST: Response Evaluation Criteria in Solid Tumors; SA: single agent; SAE: serious 
adverse event; SOE: schedule of events; TNBC: triple-negative breast cancer; v: Version; WBC: white blood cell. 
Tests and procedures should be performed on schedule, but occasional changes are allowable (±3 days) for holidays, vacations, and other administrative reasons. If extenuating 
circumstances prevent a patient from beginning treatment or completing a scheduled procedure or assessment within this time, the patient may continue the study 
only with the written permission of the medical monitor. 
All timepoints mentioned are relative to TAK-500 administration unless otherwise specified.  
a Patients will be hospitalized for at least the first 2 administrations of TAK-500 or TAK-500 plus pembrolizumab, with monitoring for approximately 24 (±4) hours. 
Subsequent monitoring will be determined based on the presence of Grade 2 CRS in prior cycles. If a patient has had 2 consecutive administrations of TAK-500 without Grade 
≥2 CRS, they may be treated as an outpatient with at least 6 hours of in-clinical observation after infusion; patients who do not experience infusion-associated symptoms or 
symptoms consistent with CRS during or after 4 consecutive infusions of TAK-500 may have their postinfusion monitoring reduced to 1 hour for subsequent cycles. 
b Day 8 clinic visit and associated laboratory tests and procedures are only required for Cycle 2. Additional cycles will not require clinic visits and procedures on Day 8. 
c Patients who discontinue study treatment for reasons other than PD will continue follow-up imaging every 6 weeks (±3 days) from first dose for the first 6 months and then 
every 12 weeks (±3 days) thereafter, until the occurrence of PD, loss to follow-up, consent withdrawal, the start of subsequent systemic antineoplastic therapy, study 
termination, or death, whichever occurs first. Date of disease progression and subsequent anticancer therapies will be documented. Ninety days (±3 days) after last dose, all 
patients will have a safety check, which can occur by phone or in the clinic, at the investigator’s discretion and this contact will focus on any treatment-related immune-
mediated AEs. If performed over the phone, only AE reporting is required. An EOS page will be completed for all patients. 
d The symptom-directed physical examination may be performed at additional visits during the treatment cycle at the discretion of the investigator. Before discharge from the 
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Table A-2 
SOE for TAK-500 Q3W Treatment (21-Day Cycle) Cycle 2 Through EOS 
 
Cycle 2 and Subsequent Cycles 
EOT  
30 (+7) Days After Last Dose or 
Before Subsequent Therapy 
Safety Follow-up  
90 (±3) Days After 
Last Dose c 
Follow-
up c 
Day 1 a 
Day 2 
Day 8 b 
Day 21 
clinic or hospital on treatment days, a physical examination will include an assessment of the respiratory and neurologic systems as well as a complete set of vital signs. 
e Vital signs will be measured immediately before the start of the TAK-500 infusion (within 30 minutes), 30 minutes after start of infusion (±5 minutes), at the EOI (±10 
minutes), 1 hour after infusion (±10 minutes), any time when clinically indicated, and before discharge. For infusion times of less than 30 minutes, vital signs will be measured 
immediately before the start of the TAK-500 infusion (within 30 minutes), at the EOI (±5 minutes), 30 minutes after EOI (±5 minutes), and at 1 hour after infusion (±10 
minutes). Blood pressure should be determined with the patient in a seated position after the patient has been sitting quietly for 5 minutes. 
 
 
 
g Single safety ECGs will be collected predose on days of treatment and at EOT as shown. A qualified person will interpret the ECGs locally. Additional ECGs may be obtained 
as clinically indicated at the discretion of the investigator. ECG assessments are to be performed with the patient supine and rested for 5 minutes. 
h Radiological evaluations (contrast-enhanced CT scan or MRI as clinically indicated) will be used to assess the status of the patient’s underlying disease. An evaluation of 
lesions will be performed during screening (within 28 days before the first dose of study drug). For all patients, radiographic assessments of the disease burden will be 
performed locally at screening/baseline (within 28 days before the first study drug administration), then every 6 weeks (±3 days) for the first 6 months from date of first dose, 
then every 12 weeks (±3 days) thereafter (until PD or the start of alternative therapies). Tumor assessments for all patients should continue, scheduled from C1D1, even if 
dosing is interrupted. Patients with an initial CT or MRI scan showing either a PR or CR should have repeat imaging in 6 weeks to confirm response. If the patient has had an 
appropriate CT or MRI scan performed within 28 days of C1D1, the results of that scan may be used for tumor lesion measurements at screening. Patients will undergo CT or 
MRI with IV contrast, as appropriate to monitor and assess response status, using RECIST v1.1 criteria. If a patient is discontinuing treatment for a reason other documented 
PD, imaging is required at EOT if: (1) it has been more than 4 weeks since the most recent imaging, for patients within the first 6 months of treatment, or (2) it has been more 
than 6 weeks since the most recent imaging, for patients on study more than 6 months. Refer to Section 9.4.13 for details. 
i For 6 weeks (42 days) after C1D1, on nondosing days or when patient is not hospitalized, patients will be asked to record oral temperature twice daily (first in the morning and 
last in the evening) and any time the patient feels febrile on a patient diary that should be brought to the site at each Cycle 1 and 2 visit. Please report clinically significant fever 
as AEs according to CTCAE v5.0 guidelines. 
j The principal investigator (or appropriate designee, subinvestigator, study nurse) is required to call the patient on the days specified to assess the patient for overall AEs and 
general well-being. 
k For the combination arm only, pembrolizumab will be administered IV with completion of pembrolizumab infusion 1 hour before administration of TAK-500 on Day 1. 
Detailed infusion instructions are provided in the pharmacy manual. 
l For patients in cohorts where premedication with 
 is assigned, 
 will be administered 1 hour (50-120 min) before administration of TAK-500 in 
the SA arm and 1 hour (50-120 min) before pembrolizumab in the combination arm. 
 premedication will begin with C1D1 dosing and continue in subsequent 
cycles. 
m Pregnancy testing (serum or urine; urine preferred) will be performed before each dose of TAK-500 and at EOT. Additional pregnancy testing (serum or urine; urine 
preferred) may be performed during the study at the discretion of the investigator, on request of an IEC/IRB, or if required by local regulations. 
n Hematology includes complete blood cell count with differential consisting of the following: hemoglobin, hematocrit, leukocytes (WBCs), differential WBC count, platelets, 
For non-commercial use only

TAK-500 
 
Study No. TAK-500-1001 
Page 184 of 243 
Protocol Incorporating Amendment No. 3 
13 June 2023 
 
CONFIDENTIAL 
Table A-2 
SOE for TAK-500 Q3W Treatment (21-Day Cycle) Cycle 2 Through EOS 
 
Cycle 2 and Subsequent Cycles 
EOT  
30 (+7) Days After Last Dose or 
Before Subsequent Therapy 
Safety Follow-up  
90 (±3) Days After 
Last Dose c 
Follow-
up c 
Day 1 a 
Day 2 
Day 8 b 
Day 21 
erythrocytes, MCH, MCV, and MCHC. Machine counts are acceptable. The chemistry panel consists of the following: protein (total), sodium, potassium, bicarbonate, chloride, 
blood urea nitrogen, creatinine, bilirubin, ALP, AST, ALT, lactate dehydrogenase, albumin, glucose, urate, calcium, phosphate, and magnesium. 
o The following tumor markers for the associated select tumors will be assessed at baseline before treatment on C1D1 and then every 2 cycles (6 weeks) thereafter: TNBC, CA 
27.29; HCC, AFP; pancreatic adenocarcinoma, CA 19-9. 
p C-reactive protein and ferritin to be measured every cycle. HbA1c and thyroid function tests to be performed every 12 weeks and if clinically indicated. Additional laboratory, 
including troponin, tests will only be repeated if clinically indicated while on study.  
q IL-6 levels to be measured around the first 2 doses (C1D1 and C2D1) predose and 12 hours postdose (±30 minutes).p For patients in cohorts where premedication with 
 is assigned, 
 will be administered 1 hour before administration of TAK-500 in the SA arm and immediately before pembrolizumab in the 
combination arm. 
 premedication will begin with C1D1 dosing and continue in subsequent cycles. 
 
For non-commercial use only

For non-commercial use only

For non-commercial use only

For non-commercial use only

TAK-500 
 
Study No. TAK-500-1001 
Page 188 of 243 
Protocol Incorporating Amendment No. 3 
13 June 2023 
 
CONFIDENTIAL 
SOEs for TAK-500 Q3W Treatment (42-Day Cycle) 
For the SOEs when administered TAK-500 Q3W on a 42-day cycle, as an SA or in combination with pembrolizumab, see: 
• Table A-5 for Cycle 1. 
• Table A-6 for Cycle 2 through EOS. 
• Table A-7 for serial PK sampling. 
• Table A-8 for pharmacodynamic biomarkers collection. 
For non-commercial use only

For non-commercial use only

TAK-500 
 
Study No. TAK-500-1001 
Page 190 of 243 
Protocol Incorporating Amendment No. 3 
13 June 2023 
 
CONFIDENTIAL 
Table A-5 
SOE for TAK-500 Q3W Treatment (42-Day Cycle) Cycle 1 
 
Screening a 
Day 1 b 
Day 2 
Day 3 
Day 4 
Day 8 
Day 15 
Day 22 b 
Day 29 
Day 42 
Hematology/chemistry m 
X 
X 
 
 
 
X 
X 
X 
X 
 
Tumor markers n 
 
X 
 
 
 
 
 
 
 
 
Thyroid function tests  
X 
 
 
 
 
 
 
 
 
 
C-reactive protein  
X 
X 
 
 
 
X 
 
X 
X 
 
Creatine kinase  
X 
 
 
 
 
 
 
 
 
 
Ferritin  
X 
X 
 
 
 
X 
 
X 
X 
 
Coagulation  
X 
 
 
 
 
 
 
 
 
 
Troponin I  
X 
 
 
 
 
 
 
 
 
 
HbA1c  
X 
 
 
 
 
 
 
 
 
 
IL-6 o 
 
X 
 
 
 
 
 
X 
 
 
PK sampling schedule for TAK-500 Q3W treatment (42-day cycle): Table A-7 
Biomarker sample collection for TAK-500 Q3W treatment (42-day cycle): Table A-8 
AE: adverse event; ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; cCR: confirmed complete response; cPR: confirmed partial 
response; CRS: cytokine release syndrome; CT: computed tomography; CTCAE: Common Terminology Criteria for Adverse Events; CxDx: Cycle x Day x; ECG: 
electrocardiogram; ECHO: echocardiogram; ECOG: Eastern Cooperative Oncology Group; EOI: end of infusion; 
; HbA1c: glycosylated hemoglobin; HCC: hepatocellular carcinoma; ICF: informed consent 
form; IEC: independent ethics committee; IL: interleukin; IRB: institutional review board; IV: intravenous; MCH: mean corpuscular hemoglobin; MCHC: mean corpuscular 
hemoglobin concentration; MCV: mean corpuscular volume; MRI: magnetic resonance imaging; MUGA: multiple gated acquisition scan; PD: progressive disease; PD-1: 
programmed cell death protein 1; PK: pharmacokinetic(s); 
; Q2W: 
once every 2 weeks; Q3W: once every 3 weeks; RECIST: Response Evaluation Criteria in Solid Tumors; SA: single agent; SAE: serious adverse event; SOE: schedule of 
events; TNBC: triple-negative breast cancer; v: Version; WBC: white blood cell. 
Tests and procedures should be performed on schedule, but occasional changes are allowable (±3 days) with permission of the medical monitor for holidays, vacations, and 
other administrative reasons. If extenuating circumstances prevent a patient from beginning treatment or completing a scheduled procedure or assessment within this 
time, the patient may continue the study only with the written permission of the medical monitor. 
All timepoints mentioned are relative to TAK-500 administration unless otherwise specified.  
a Unless otherwise noted, the screening procedures must occur within 28 days before the day of the first dose of study drug (C1D1). 
b Patients will be hospitalized for at least the first 2 administrations of TAK-500 or TAK-500 + pembrolizumab, with monitoring for approximately 24 (±4) hours. Subsequent 
monitoring will be determined based on the presence of Grade 2 CRS in prior cycles. Before discharge from the clinic or hospital on treatment days, a physical examination will 
include an assessment of the respiratory and neurologic systems as well as a complete set of vital signs. 
For non-commercial use only

TAK-500 
 
Study No. TAK-500-1001 
Page 191 of 243 
Protocol Incorporating Amendment No. 3 
13 June 2023 
 
CONFIDENTIAL 
Table A-5 
SOE for TAK-500 Q3W Treatment (42-Day Cycle) Cycle 1 
 
Screening a 
Day 1 b 
Day 2 
Day 3 
Day 4 
Day 8 
Day 15 
Day 22 b 
Day 29 
Day 42 
c Medical history will include smoking/vaping history and available baseline disease characteristics, such as disease type, staging, PD-1 expression, etc. Complete physical 
examination (including assessment of the following systems: skin, head, eyes, ears, nose, throat, respiratory, cardiovascular, gastrointestinal, neurological condition, blood and 
lymphatic, and musculoskeletal) and medical history will be collected at screening and the time points indicated. The C1D1 physical examination and medical history are not 
required if the screening physical examination was conducted and medical history obtained within 4 days before administration of the first dose of study drug (C1D1). 
Postscreening physical examinations will be symptom- or finding-directed and will be performed at any time point based on clinical need. Before discharge from the clinic or 
hospital on treatment days, a physical examination will include an assessment of the respiratory and neurologic systems as well as a complete set of vital signs. 
d Vital signs will be measured immediately before the start of the TAK-500 infusion (within 30 minutes), 30 minutes after start of infusion (±5 minutes), at the EOI (±10 
minutes), 1 hour after infusion (±10 minutes), any time when clinically indicated, and before discharge. For infusion times of less than 30 minutes, vital signs will be measured 
immediately before the start of the TAK-500 infusion (within 30 minutes), at the EOI (±5 minutes), 30 minutes after EOI (±5 minutes), and at 1 hour after infusion (±10 
minutes). On C1D1 vital signs will also be measured at 3 and 6 hours after dosing of TAK-500 (measurement should be obtained in a ±30-minute window). Blood pressure 
should be determined with the patient in a seated position after the patient has been sitting quietly for 5 minutes.  
e Safety ECGs should be performed at screening; C1D1 predose, EOI (+1 hour), and 2 (+1 hour) and 3 (+1 hour) hours postdose; and C1D22 predose. A qualified person will 
interpret the ECGs locally. ECG assessments are to be performed with the patient supine and rested for 5 minutes. Additional ECGs may be obtained as clinically indicated at 
any time during the study at the discretion of the investigator. When the timing of ECG or vital signs 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. The frequency and timing of ECG collection for safety may be 
modified based on emerging data and agreement between sponsor and investigators. 
f Radiological evaluations (contrast-enhanced CT scan or MRI as clinically indicated) will be used to assess the status of the patient’s underlying disease. An evaluation of 
lesions will be performed during screening (within 28 days before the first dose of study drug). For all patients, radiographic assessments of the disease burden will be 
performed locally at screening/baseline (within 28 days before the first study drug administration), then every 6 weeks (±3 days) for the first 6 months from date of first dose, 
then every 12 weeks (±3 days) thereafter (until PD or the start of alternative therapies). Tumor assessments for all patients should continue, scheduled from C1D1, even if 
dosing is interrupted. Patients with an initial CT or MRI scan showing either a PR or CR should have repeat imaging in 6 weeks to confirm response. If the patient has had an 
appropriate CT or MRI scan performed within 28 days of C1D1, the results of that scan may be used for tumor lesion measurements at screening. Patients will undergo CT or 
MRI with IV contrast, as appropriate to monitor and assess response status, using RECIST v1.1 criteria. Refer to Section 9.4.13 for details. 
g For 6 weeks (42 days) after C1D1, on nondosing days or when patient is not hospitalized, patients will be asked to record oral temperature twice daily (first in the morning and 
last in the evening) and any time the patient feels febrile on a patient diary that should be brought to the site at each Cycle 1 visit. Please report clinically significant fever as 
AEs according to CTCAE v5.0 guidelines. 
 
 
 
 
i The principal investigator (or appropriate designee, subinvestigator, study nurse) is required to call the patient on the days specified to assess the patient for overall AEs and 
general well-being. 
j For the combination arm only, pembrolizumab will be administered IV with completion of pembrolizumab infusion 1 hour before the administration of TAK-500 on Day 1 and 
Day 22. Detailed infusion instructions are provided in the pharmacy manual.  
k For patients in cohorts where premedication with 
 is assigned, 
 will be administered 1 hour (50-120 min) before administration of TAK-500 
For non-commercial use only

TAK-500 
 
Study No. TAK-500-1001 
Page 192 of 243 
Protocol Incorporating Amendment No. 3 
13 June 2023 
 
CONFIDENTIAL 
Table A-5 
SOE for TAK-500 Q3W Treatment (42-Day Cycle) Cycle 1 
 
Screening a 
Day 1 b 
Day 2 
Day 3 
Day 4 
Day 8 
Day 15 
Day 22 b 
Day 29 
Day 42 
in the SA arm and 1 hour (50-120 min) before pembrolizumab in the combination arm. 
 premedication will begin with C1D1 dosing and continue in subsequent 
cycles. 
l A serum choriogonadotropin beta pregnancy test will be performed only for patients of childbearing potential during screening and again at C1D1 (baseline) if the screening 
test was performed more than 4 days before the first dose of any study drug. The results must be negative within 4 days before the first dose of TAK-500 is administered (ie, 
within the 4 days before C1D1), or as otherwise required by local regulations. Additional pregnancy testing (serum or urine; urine preferred) will be performed before each dose 
of TAK-500 and may be performed during the study at the discretion of the investigator, on request of an IEC/IRB, or if required by local regulations. 
m The hematology and chemistry blood samples for C1D1 may be collected within 4 days before dosing to ensure patient eligibility on C1D1. If screening clinical laboratory 
testing was performed within 4 days before the C1D1 dose, it need not be repeated on C1D1. Hematology includes complete blood cell count with differential consisting of the 
following: hemoglobin, hematocrit, leukocytes (WBCs), differential WBC count, platelets, erythrocytes, MCH, MCV, and MCHC. Machine counts are acceptable. The 
chemistry panel consists of the following: protein (total), sodium, potassium, bicarbonate, chloride, blood urea nitrogen, creatinine, bilirubin, ALP, AST, ALT, lactate 
dehydrogenase, albumin, glucose, urate, calcium, phosphate, and magnesium. 
n The following tumor markers for the associated select tumors will be assessed at baseline before treatment on C1D1 and then every 6 weeks thereafter: TNBC, CA 27.29; 
HCC, AFP; pancreatic adenocarcinoma, CA 19-9. 
o IL-6 levels to be measured during C1D1 and C1D22 predose and 12 hours postdose (±30 minutes). 
 
For non-commercial use only

For non-commercial use only

TAK-500 
 
Study No. TAK-500-1001 
Page 194 of 243 
Protocol Incorporating Amendment No. 3 
13 June 2023 
 
CONFIDENTIAL 
Table A-6 
SOE for TAK-500 Q3W Treatment (42-Day Cycle) Cycle 2 Through EOS 
 
Cycle 2 and Subsequent Cycles a 
EOT  
30 (+7) Days After 
Last Dose or 
Before Subsequent 
Therapy 
Safety Follow-up  
90 (±3) Days After 
Last Dose 
Follow-up b 
 
Day 1  
Day 22 
Day 42 
C-reactive protein m 
X 
X 
 
 
 
 
Ferritin m 
X 
X 
 
 
 
 
HbA1c m 
X 
 
 
 
 
 
PK sampling schedule for TAK-500 Q3W treatment (42-day cycle): Table A-7 
Biomarker sample collection for TAK-500 Q3W treatment (42-day cycle): Table A-8 
AE: adverse event; ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; cCR: confirmed complete response; cPR: confirmed partial 
response; CRS: cytokine release syndrome; CT: computed tomography; CxDx: Cycle x Day x; ECG: electrocardiogram; ECOG: Eastern Cooperative Oncology Group; EOS: 
end of study; EOT: end of treatment; 
 
; HbA1C: glycosylated hemoglobin; HCC: hepatocellular carcinoma; ICF: informed consent form; IEC: independent ethics committee; IRB: institutional review 
board; IV: intravenous; MCH: mean corpuscular hemoglobin; MCHC: mean corpuscular hemoglobin concentration; MCV: mean corpuscular volume; MRI: magnetic resonance 
imaging; PD: progressive disease; PK: pharmacokinetic(s);
; Q2W: 
once every 2 weeks; Q3W: once every 3 weeks; RECIST: Response Evaluation Criteria in Solid Tumors; SA: single agent; SAE: serious adverse event; SOE: schedule of 
events; TNBC: triple-negative breast cancer; v: Version; WBC: white blood cell. 
Tests and procedures should be performed on schedule, but occasional changes are allowable (±3 days) for holidays, vacations, and other administrative reasons. If extenuating 
circumstances prevent a patient from beginning treatment or completing a scheduled procedure or assessment within this time, the patient may continue the study 
only with the written permission of the medical monitor. 
All timepoints mentioned are relative to TAK-500 administration unless otherwise specified.  
a Patients will be hospitalized for at least the first 2 administrations of TAK-500 or TAK-500 + pembrolizumab, with monitoring for approximately 24 (±4) hours. Subsequent 
monitoring will be determined based on the presence of Grade 2 CRS in prior cycles. If a patient has had 2 consecutive administrations of TAK-500 without Grade ≥2 CRS, 
they may be treated as an outpatient with at least 6 hours of in-clinical observation after infusion; patients who do not experience infusion-associated symptoms or symptoms 
consistent with CRS during or after 4 consecutive infusions of TAK-500 may have their postinfusion monitoring reduced to 1 hour for subsequent cycles. 
b Patients who discontinue study treatment for reasons other than PD will continue follow-up imaging every 6 weeks (±3 days) from first dose for the first 6 months and then 
every 12 weeks (±3 days) thereafter, until the occurrence of PD, loss to follow-up, consent withdrawal, the start of subsequent systemic antineoplastic therapy, study 
termination, or death, whichever occurs first. Date of disease progression and subsequent anticancer therapies will be documented. Ninety days (±3 days) after last dose, patients 
will have a safety check, which can occur by phone or in the clinic, at the investigator’s discretion and this contact will focus on any treatment-related immune-mediated AEs. If 
performed over the phone, only AE reporting is required. An EOS page will be completed for all patients.  
c The symptom-directed physical examination may be performed at additional visits during the treatment cycle at the discretion of the investigator. Before discharge from the 
clinic or hospital on treatment days, a physical examination will include an assessment of the respiratory and neurologic systems as well as a complete set of vital signs. 
For non-commercial use only

TAK-500 
 
Study No. TAK-500-1001 
Page 195 of 243 
Protocol Incorporating Amendment No. 3 
13 June 2023 
 
CONFIDENTIAL 
Table A-6 
SOE for TAK-500 Q3W Treatment (42-Day Cycle) Cycle 2 Through EOS 
 
Cycle 2 and Subsequent Cycles a 
EOT  
30 (+7) Days After 
Last Dose or 
Before Subsequent 
Therapy 
Safety Follow-up  
90 (±3) Days After 
Last Dose 
Follow-up b 
 
Day 1  
Day 22 
Day 42 
d Vital signs will be measured immediately before the start of the TAK-500 infusion (within 30 minutes), 30 minutes after start of infusion (±5 minutes), at the EOI (±10 
minutes), 1 hour after infusion (±10 minutes), any time when clinically indicated, and before discharge. For infusion times of less than 30 minutes, vital signs will be measured 
immediately before the start of the TAK-500 infusion (within 30 minutes), at the EOI (±5 minutes), 30 minutes after EOI (±5 minutes), and at 1 hour after infusion (±10 
minutes). On C1D1 vitals will also be measured at 3 and 6 hours after dosing of TAK-500; measurement should be obtained in a ±30-minute window. Blood pressure should be 
determined with the patient in a seated position after the patient has been sitting quietly for 5 minutes. 
e Single safety ECGs will be collected predose on days of treatment and at EOT as shown. A qualified person will interpret the ECGs locally. Additional ECGs may be obtained 
as clinically indicated at the discretion of the investigator. ECG assessments are to be performed with the patient supine and rested for 5 minutes. 
f Radiological evaluations (contrast-enhanced CT scan or MRI as clinically indicated) will be used to assess the status of the patient’s underlying disease. An evaluation of 
lesions will be performed during screening (within 28 days before the first dose of study drug). For all patients, radiographic assessments of the disease burden will be 
performed locally at screening/baseline (within 28 days before the first study drug administration), then every 6 weeks (±3 days) for the first 6 months from date of first dose, 
then every 12 weeks (±3 days) thereafter (until PD or the start of alternative therapies). Tumor assessments for all patients should continue, scheduled from C1D1, even if 
dosing is interrupted. Patients with an initial CT or MRI scan showing either a PR or CR should have repeat imaging in 6 weeks to confirm response. If the patient has had an 
appropriate CT or MRI scan performed within 28 days of C1D1, the results of that scan may be used for tumor lesion measurements at screening. Patients will undergo CT or 
MRI with IV contrast, as appropriate to monitor and assess response status, using RECIST v1.1 criteria. If a patient is discontinuing treatment for a reason other documented 
PD, imaging is required at EOT if: (1) it has been more than 4 weeks since the most recent imaging, for patients within the first 6 months of treatment, or (2) it has been more 
than 6 weeks since the most recent imaging, for patients on study more than 6 months. Refer to Section 9.4.13 for details. 
 
 
 
h For the combination arm only, pembrolizumab will be administered IV with completion of pembrolizumab infusion 1 hour before the administration of TAK-500 on Day 1 
and Day 22 of each cycle. Detailed infusion instructions are provided in the pharmacy manual. 
i For patients in cohorts where premedication with 
 is assigned, 
 will be administered 1 hour (50-120 min) before administration of TAK-500 in 
the SA arm and 1 hour (50-120 min) before pembrolizumab in the combination arm. 
 premedication will begin with C1D1 dosing and continue in subsequent 
cycles. 
j Pregnancy testing (serum or urine; urine preferred) will be performed before each dose of TAK-500 and at EOT. Additional pregnancy testing (serum or urine; urine preferred) 
may be performed during the study at the discretion of the investigator, on request of an IEC/IRB, or if required by local regulations. 
k Hematology includes complete blood cell count with differential consisting of the following: hemoglobin, hematocrit, leukocytes (WBCs), differential WBC count, platelets, 
erythrocytes, MCH, MCV, and MCHC. Machine counts are acceptable. The chemistry panel consists of the following: protein (total), sodium, potassium, bicarbonate, chloride, 
blood urea nitrogen, creatinine, bilirubin, ALP, AST, ALT, lactate dehydrogenase, albumin, glucose, urate, calcium, phosphate, and magnesium. 
For non-commercial use only

TAK-500 
 
Study No. TAK-500-1001 
Page 196 of 243 
Protocol Incorporating Amendment No. 3 
13 June 2023 
 
CONFIDENTIAL 
Table A-6 
SOE for TAK-500 Q3W Treatment (42-Day Cycle) Cycle 2 Through EOS 
 
Cycle 2 and Subsequent Cycles a 
EOT  
30 (+7) Days After 
Last Dose or 
Before Subsequent 
Therapy 
Safety Follow-up  
90 (±3) Days After 
Last Dose 
Follow-up b 
 
Day 1  
Day 22 
Day 42 
l The following tumor markers for the associated select tumors will be assessed at baseline before treatment on C1D1 and then every 6 weeks hereafter: TNBC, CA 27.29; HCC, 
AFP; pancreatic adenocarcinoma, CA 19-9. 
m C-reactive protein and ferritin to be measured on Day 1 and Day 22 of every cycle. HbA1c and thyroid function tests to be performed every 12 weeks and if clinically 
indicated. Additional laboratory, including troponin, tests will only be repeated if clinically indicated while on study.  
 
For non-commercial use only

For non-commercial use only

For non-commercial use only

For non-commercial use only

TAK-500 
 
Study No. TAK-500-1001 
Page 200 of 243 
Protocol Incorporating Amendment No. 3 
13 June 2023 
 
CONFIDENTIAL 
SOEs for TAK-500 Q2W Treatment (42-Day Cycle) 
For the SOEs when administered TAK-500 Q2W on a 42-day cycle, as an SA or in combination with pembrolizumab, see: 
• Table A-9 for Cycle 1. 
• Table A-10 for Cycle 2 through EOS. 
• Table A-11 for serial PK sampling. 
• Table A-12 for pharmacodynamic biomarkers collection. 
For non-commercial use only

For non-commercial use only

For non-commercial use only

TAK-500 
 
Study No. TAK-500-1001 
Page 203 of 243 
Protocol Incorporating Amendment No. 3 
13 June 2023 
 
CONFIDENTIAL 
Table A-9 
SOE for TAK-500 Q2W Treatment (42-Day Cycle) Cycle 1 
 
Screening a 
Day 1 b 
Day 2 
Day 3 
Day 4 
Day 8 
Day 15 
b 
Day 16 
Day 22 
Day 29 
b 
Day 30 
Day 42 
b Patients will be hospitalized for at least the first 2 administrations of TAK-500 or TAK-500 + pembrolizumab, with monitoring for approximately 24 (±4) hours. Subsequent 
monitoring will be determined based on the presence of Grade 2 CRS in prior cycles. If a patient has had 2 consecutive administrations of TAK-500 without Grade ≥2 CRS, 
they may be treated as an outpatient with at least 6 hours of in-clinical observation after infusion; patients who do not experience infusion-associated symptoms or symptoms 
consistent with CRS during or after 4 consecutive infusions of TAK-500 may have their postinfusion monitoring reduced to 1 hour for subsequent cycles.  
c Medical history will include smoking/vaping history and available baseline disease characteristics, such as disease type, staging, PD-1 expression, etc. Complete physical 
examination (including assessment of the following systems: skin, head, eyes, ears, nose, throat, respiratory, cardiovascular, gastrointestinal, neurological condition, blood and 
lymphatic, and musculoskeletal) and medical history will be collected at screening and the time points indicated. The C1D1 physical examination and medical history are not 
required if the screening physical examination was conducted and medical history obtained within 4 days before administration of the first dose of study drug (C1D1). 
Postscreening physical examinations will be symptom- or finding-directed and will be performed at any time point based on clinical need. Before discharge from the clinic or 
hospital on treatment days, a physical examination will include an assessment of the respiratory and neurologic systems as well as a complete set of vital signs. 
d Vital signs will be measured immediately before the start of the TAK-500 infusion (within 30 minutes), 30 minutes after start of infusion (±5 minutes), at the EOI (±10 
minutes), 1 hour after infusion (±10 minutes), any time when clinically indicated, and before discharge. For infusion times of less than 30 minutes, vital signs will be measured 
immediately before the start of the TAK-500 infusion (within 30 minutes), at the EOI (±5 minutes), 30 minutes after EOI (±5 minutes), and at 1 hours post infusion (±10 
minutes). On C1D1 vital signs will also be measured at 3 and 6 hours after dosing of TAK-500 (measurement should be obtained in a ±30-minute window). Blood pressure 
should be determined with the patient in a seated position after the patient has been sitting quietly for 5 minutes.  
e Safety ECGs should be performed at screening; C1D1 predose, EOI (+1 hour), and 2 (+1 hour) and 3 (+1 hour) hours postdose; C1D15 predose; C!D22 predose and C1D29 
predose. A qualified person will interpret the ECGs locally. ECG assessments are to be performed with the patient supine and rested for 5 minutes. Additional ECGs may be 
obtained as clinically indicated at any time during the study at the discretion of the investigator. When the timing of ECG or vital signs 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. The frequency and timing of 
ECG collection for safety may be modified based on emerging data and agreement between sponsor and investigators. 
f Radiological evaluations (contrast-enhanced CT scan or MRI as clinically indicated) will be used to assess the status of the patient’s underlying disease. An evaluation of 
lesions will be performed during screening (within 28 days before the first dose of study drug). For all patients, radiographic assessments of the disease burden will be 
performed locally at screening/baseline (within 28 days before the first study drug administration), then every 6 weeks (±3 days) for the first 6 months from date of first dose, 
then every 12 weeks (±3 days) thereafter (until PD or the start of alternative therapies). Tumor assessments for all patients should continue, scheduled from C1D1, even if 
dosing is interrupted. Patients with an initial CT or MRI scan showing either a PR or CR should have repeat imaging in 6 weeks to confirm response. If the patient has had an 
appropriate CT or MRI scan performed within 28 days of C1D1, the results of that scan may be used for tumor lesion measurements at screening. Patients will undergo CT or 
MRI with IV contrast, as appropriate to monitor and assess response status, using RECIST v1.1 criteria. Refer to Section 9.4.13 for details. 
g For 6 weeks (42 days) after C1D1, on nondosing days or when patient is not hospitalized, patients will be asked to record oral temperature twice daily (first in the morning and 
last in the evening) and any time the patient feels febrile on a patient diary that should be brought to the site at each Cycle 1 visit. Please report clinically significant fever as 
AEs according to CTCAE v5.0 guidelines. 
 
 
 
For non-commercial use only

TAK-500 
 
Study No. TAK-500-1001 
Page 204 of 243 
Protocol Incorporating Amendment No. 3 
13 June 2023 
 
CONFIDENTIAL 
Table A-9 
SOE for TAK-500 Q2W Treatment (42-Day Cycle) Cycle 1 
 
Screening a 
Day 1 b 
Day 2 
Day 3 
Day 4 
Day 8 
Day 15 
b 
Day 16 
Day 22 
Day 29 
b 
Day 30 
Day 42 
i The principal investigator (or appropriate designee, subinvestigator, study nurse) is required to call the patient on the days specified to assess the patient for overall AEs and 
general well-being. 
j For the combination arm only, pembrolizumab will be administered IV with completion of pembrolizumab infusion 1 hour before the administration of TAK-500 on Day 1. 
Detailed infusion instructions are provided in the pharmacy manual.  
k For patients in cohorts where premedication with 
 is assigned, 
 will be administered 1 hour (50-120 min) before administration of TAK-500 in 
the SA arm and 1 hour (50-120 min) before pembrolizumab in the combination arm. 
 premedication will begin with C1D1 dosing and continue in subsequent 
cycles. 
l A serum choriogonadotropin beta pregnancy test will be performed only for patients of childbearing potential during screening and again at C1D1 (baseline) if the screening 
test was performed more than 4 days before the first dose of any study drug. The results must be negative within 4 days before the first dose of TAK-500 is administered (ie, 
within the 4 days before C1D1), or as otherwise required by local regulations. Additional pregnancy testing (serum or urine; urine preferred) will be performed before each dose 
of TAK-500 and may be performed during the study at the discretion of the investigator, on request of an IEC/IRB, or if required by local regulations. 
m The hematology and chemistry blood samples for C1D1 may be collected within 4 days before dosing to ensure patient eligibility on C1D1. If screening clinical laboratory 
testing was performed within 4 days before the C1D1 dose, it need not be repeated on C1D1. Hematology includes complete blood cell count with differential consisting of the 
following: hemoglobin, hematocrit, leukocytes (WBCs), differential WBC count, platelets, erythrocytes, MCH, MCV, and MCHC. Machine counts are acceptable. The 
chemistry panel consists of the following: protein (total), sodium, potassium, bicarbonate, chloride, blood urea nitrogen, creatinine, bilirubin, ALP, AST, ALT, lactate 
dehydrogenase, albumin, glucose, urate, calcium, phosphate, and magnesium. 
n The following tumor markers for the associated select tumors will be assessed at baseline before treatment on C1D1 and then every 6 weeks thereafter: TNBC, CA 27.29; 
HCC, AFP; Pancreatic adenocarcinoma, CA 19-9. 
o IL-6 levels to be measured during C1D1 and C1D15 predose and 12 hours postdose (±30 minutes).  
 
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Table A-10 
SOE for TAK-500 Q2W Treatment (42-Day Cycle) Cycle 2 Through EOS 
 
Cycle 2 and Subsequent Cycles a 
EOT  
30 (+7) 
Days After 
Last Dose 
or 
Before 
Subsequent 
Therapy 
Safety 
Follow-up  
90 (±3) 
Days 
After 
Last 
Dose b 
Follow-
up b 
Day 1  
Day 15 
Day 22 
Day 29 
Day 42 
a Patients will be hospitalized for at least the first 2 administrations of TAK-500 or TAK-500 + pembrolizumab, with monitoring for approximately 24 (±4) hours. Subsequent 
monitoring will be determined based on the presence of Grade 2 CRS in prior cycles. If a patient has had 2 consecutive administrations of TAK-500 without Grade ≥2 CRS, 
they may be treated as an outpatient with at least 6 hours of in-clinical observation after infusion; patients who do not experience infusion-associated symptoms or symptoms 
consistent with CRS during or after 4 consecutive infusions of TAK-500 may have their postinfusion monitoring reduced to 1 hour for subsequent cycles. 
b Patients who discontinue study treatment for reasons other than PD will continue follow-up imaging every 6 weeks (±3 days) from first dose for the first 6 months and then 
every 12 weeks (±3 days) thereafter, until the occurrence of PD, loss to follow-up, consent withdrawal, the start of subsequent systemic antineoplastic therapy, study 
termination, or death, whichever occurs first. Date of disease progression and subsequent anticancer therapies will be documented. Ninety days (±3 days) after last dose, patients 
will have a safety check, which can occur by phone or in the clinic, at the investigator’s discretion and this contact will focus on any treatment-related immune-mediated AEs. If 
performed over the phone, only AE reporting is required. An EOS page will be completed for all patients. 
c The symptom-directed physical examination may be performed at additional visits during the treatment cycle at the discretion of the investigator. Before discharge from the 
clinic or hospital on treatment days, a physical examination will include an assessment of the respiratory and neurologic systems as well as a complete set of vital signs. 
d Vital signs will be measured immediately before the start of the TAK-500 infusion (within 30 minutes), 30 minutes after start of infusion (±5 minutes), at the EOI (±10 
minutes), 1 hour after infusion (±10 minutes), any time when clinically indicated, and before discharge. For infusion times of less than 30 minutes, vital signs will be measured 
immediately before the start of the infusion (within 30 minutes), at the EOI (±5 minutes), 30 minutes after EOI (±5 minutes), and at 1 hour after infusion (±10 minutes). On 
C1D1 vitals will also be measured at 3 and 6 hours after dosing of TAK-500 (measurement should be obtained in a ±30-minute window). Blood pressure should be determined 
with the patient in a seated position after the patient has been sitting quietly for 5 minutes. 
e Single safety ECGs will be collected predose on days of treatment with TAK-500 and at EOT as shown. A qualified person will interpret the ECGs locally. Additional ECGs 
may be obtained as clinically indicated at the discretion of the investigator. ECG assessments are to be performed with the patient supine and rested for 5 minutes. 
f Radiological evaluations (contrast-enhanced CT scan or MRI as clinically indicated) will be used to assess the status of the patient’s underlying disease. An evaluation of 
lesions will be performed during screening (within 28 days before the first dose of study drug). For all patients, radiographic assessments of the disease burden will be 
performed locally at screening/baseline (within 28 days before the first study drug administration), then every 6 weeks (±3 days) for the first 6 months from date of first dose, 
then every 12 weeks (±3 days) thereafter (until PD or the start of alternative therapies). Tumor assessments for all patients should continue, scheduled from C1D1, even if 
dosing is interrupted. Patients with an initial CT or MRI scan showing either a PR or CR should have repeat imaging in 6 weeks to confirm response. If the patient has had an 
appropriate CT or MRI scan performed within 28 days of C1D1, the results of that scan may be used for tumor lesion measurements at screening. Patients will undergo CT or 
MRI with IV contrast, as appropriate to monitor and assess response status, using RECIST v1.1 criteria. If a patient is discontinuing treatment for a reason other documented 
PD, imaging is required at EOT if: (1) it has been more than 4 weeks since the most recent imaging, for patients within the first 6 months of treatment, or (2) it has been more 
than 6 weeks since the most recent imaging, for patients on study more than 6 months. Refer to Section 9.4.13 for details. 
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Table A-10 
SOE for TAK-500 Q2W Treatment (42-Day Cycle) Cycle 2 Through EOS 
 
Cycle 2 and Subsequent Cycles a 
EOT  
30 (+7) 
Days After 
Last Dose 
or 
Before 
Subsequent 
Therapy 
Safety 
Follow-up  
90 (±3) 
Days 
After 
Last 
Dose b 
Follow-
up b 
Day 1  
Day 15 
Day 22 
Day 29 
Day 42 
 
 
 
h For the combination arm only, pembrolizumab will be administered IV with completion of pembrolizumab infusion 1 hour before the administration of TAK-500 on Day 1. 
Detailed infusion instructions are provided in the pharmacy manual.  
i For patients in cohorts where premedication with 
 is assigned, 
 will be administered 1 hour (50-120 min) before administration of TAK-500 in 
the SA arm and 1 hour (50-120 min) before pembrolizumab in the combination arm. 
 premedication will begin with C1D1 dosing and continue in subsequent 
cycles. 
j Pregnancy testing (serum or urine; urine preferred) will be performed before each dose of TAK-500 and at EOT. Additional pregnancy testing (serum or urine; urine preferred) 
may be performed during the study at the discretion of the investigator, on request of an IEC/IRB, or if required by local regulations 
k Hematology includes complete blood cell count with differential consisting of the following: hemoglobin, hematocrit, leukocytes (WBCs), differential WBC count, platelets, 
erythrocytes, MCH, MCV, and MCHC. Machine counts are acceptable. The chemistry panel consists of the following: protein (total), sodium, potassium, bicarbonate, chloride, 
blood urea nitrogen, creatinine, bilirubin, ALP, AST, ALT, lactate dehydrogenase, albumin, glucose, urate, calcium, phosphate, and magnesium. 
l The following tumor markers for the associated select tumors will be assessed at baseline before treatment on C1D1 and then every 6 weeks thereafter: TNBC, CA 27.29; 
HCC, AFP; pancreatic adenocarcinoma, CA 19-9. 
m C-reactive protein and ferritin to be measured on Day 1 and Day 22 of every cycle. HbA1c and thyroid function tests to be performed every 12 weeks and if clinically 
indicated. Additional laboratory, including troponin, tests will only be repeated if clinically indicated while on study. 
 
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Table A-12 
Pharmacodynamic Biomarkers Collection for TAK-500 Q2W Treatment (42-Day Cycle) 
 
Cycles 2, 3, 4, 9, 15 
EOT 
Day 1 
30 (+7) Days After 
Last Dose 
Predose ≤30 m Before Dose 
0.5 h Post-EOI 
±15 m 
3 h Post-EOI ±30 m 
 
6 h Post-EOI ±1 h 
Serum Sample for Immunogenicity d 
X 
 
 
 
 
X 
ADA: antidrug antibodies; AE: adverse event; CxDx: Cycle x, Day x; DPV: during planned visit; 
; EOI: end of infusion; EOT: end of treatment; 
 
; Q2W: once every 2 weeks; S: screening. 
For the combination arm, the predose sample collections will be conducted before pembrolizumab and TAK-500 administration. All other timeframes within the table should be relative to TAK-500 
administration, not pembrolizumab. 
All timepoints mentioned are relative to TAK-500 administration unless otherwise specified.  
a To coincide with PD biomarker timing, sample should be obtained at least 15 minutes after C1D1 premedication dose, if applicable. 
b While these pharmacodynamic collections will be performed during dose escalation, during dose expansion these pharmacodynamic collections will only be mandated if the patient is hospitalized 
or is seen at the clinic as part of their posttreatment care or at the same time as other blood collections. 
 
 
 
 
 
 
 
 
. 
e Immunogenicity (ADA) samples must be collected before study drug is administered on a dosing day. Additional unscheduled collections should be obtained for a patient who experiences an AE 
considered by the investigator to be consistent with hypersensitivity/infusion-related reaction. A sample will be assessed for neutralizing ADA if a positive ADA is detected.  
 
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Appendix B Responsibilities of the Investigator 
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the Statement of Investigator (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this study. 
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572: 
1. Conduct the study in accordance with the protocol. 
2. Personally conduct or supervise the staff who will assist in the protocol. 
3. If the investigator/institution retains the services of any individual or party to perform 
study-related duties and functions, the investigator/institution should ensure that this 
individual or party is qualified to perform those study-related duties and functions and should 
implement procedures to ensure the integrity of the study-related duties and functions 
performed and any data generated. 
4. Ensure that study-related procedures, including study-specific (nonroutine/nonstandard 
panel) screening assessments, are NOT performed on potential patients before the receipt of 
written approval from relevant governing bodies/authorities. 
5. Ensure that all colleagues and employees assisting in the conduct of the study are informed 
of these obligations. 
6. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform 
to 21 Code of Federal Regulations (CFR) Part 56, ICH and local regulatory requirements. 
7. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and 
approval of the protocol. Promptly report to the IRB/IEC all changes in research activity and 
all anticipated risks to patients. Make at least yearly reports on the progress of the study to 
the IRB/IEC, and issue a final report within 3 months of study completion. 
8. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met. 
9. Obtain valid informed consent from each patient who participates in the study, and document 
the date of consent in the patient’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each ICF should contain a patient authorization section 
that describes the uses and disclosures of a patient’s personal information (including personal 
health information) that will take place in connection with the study. If an ICF does not 
include such a patient authorization, then the investigator must obtain a separate patient 
authorization form from each patient or the patient’s legally acceptable representative. 
10. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
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contact and receive written approval from the sponsor before disposing of any such 
documents. 
11. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents. 
12. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor. This responsibility lies on 
the appropriate individual. 
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 Clinical Inhibitors of OATP1B1 and OATP1B3 
Drug Class 
Medication Name (Brand Name) 
Required 
Washout Period 
Before First 
Dose 
Antiviral 
Atazanavir (Reyataz) 
14 days before 
first dose of study 
drug(s) 
Lopinavir (Kaletra) 
Ritonavir (Norvir) 
Simeprevir (Olysio) 
Remdesivir (Veklury) 
Antibiotic 
Clarithromycin (Biaxin, Biaxin XL) 
Erythromycin (E.E.S. Granules, E.E.S.-400 Filmtab, EryPed 200, 
EryPed 400, Ery-Tab, Erythrocin Lactobionate, Erythrocin Stearate 
Filmtab, PCE Dispertab) 
Rifampin (single dose)/rifampicin (Rifadin, Rifadin IV, Rimactane) 
Immunosuppressant 
Cyclosporine (Gengraf, Neoral, SandIMMUNE) 
Antilipemic/ 
hypercholesterolemia 
Gemfibrozil (Lopid) 
Source: fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-
inhibitors-and-inducers. 
DDI: drug-drug interaction; FDA: Food and Drug Administration; OATP: organic anion transporting polypeptide. 
Note the list of clinical inhibitors of OATP1B1 and OATP1B3 is not exhaustive and is based on the FDA Draft 
DDI Guidance. 
 
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Appendix E Potential Risks of TAK-676 
Several potential risks and target organs were identified in in vitro and in vivo toxicology studies 
with TAK-676 and are discussed below. Increase in pro-inflammatory cytokines were observed 
in an in vitro human whole blood cytokine release assay and in serum from rats and monkeys 
administered TAK-676. The predominant microscopic finding in rats was single-cell necrosis 
across multiple organs that was most consistent with death of lymphocytes and leukocytes. 
Additional targets in rats included bone marrow, lymph nodes, thymus, GIT, hematopoietic 
system (spleen), soleus muscle, and liver. The target organ in the monkey was the lungs. 
Effects on Lung Vasculature 
Administration of TAK-676 resulted in pulmonary changes in monkeys, but not rats, that were 
considered consistent with vascular leak and the cause of the moribundity and/or death observed 
in monkeys at doses ≥0.13 mg/kg (bolus and infusion).  
In the non-GLP single-dose study in monkeys, macroscopic observations at necropsy in the 
monkeys removed early included fluid accumulation in the thoracic cavity and at 0.2 mg/kg only, 
discoloration (diffuse, dark red, mottled) and fluid accumulation in the lungs. Microscopic 
findings in the lung included interstitial/alveolar edema in all monkeys removed early from 
study, with histiocytes in the alveolar space at 0.2 mg/kg only.  
In the 2-week repeat-dose GLP study twice weekly, macroscopic observations were limited to 
monkeys that were found dead or removed moribund on Day 2 at 0.13 mg/kg (infusion) and 
included fluid accumulation in the thoracic cavity and mottled discoloration in the lungs. 
Microscopic findings (limited to lung) were observed in monkeys receiving 0.13 mg/kg 
TAK-676 via bolus or infusion administration that were found dead, removed moribund, or that 
underwent early scheduled euthanasia on Days 4, 8, or 11 and included minimal to moderate 
congestion, minimal to mild alveolar/interstitial edema and histiocytic alveolar infiltration, 
and/or minimal hemorrhage. These findings correlated with the mottled discoloration of the lung 
observed macroscopically, were considered to be consistent with vascular leak, and were 
considered directly related to the poor clinical tolerability and early mortality at this dose. In 
addition, minimal alveolar/interstitial edema was observed in 1 female that survived (with no 
notable clinical observations) to scheduled necropsy on Day 16 at 0.13 mg/kg (slow bolus). 
These findings were not observed in monkeys evaluated after the 2-week postdose period. 
Effects on the Immune and Lymphoid Systems 
TAK-676–related effects on the immune and lymphoid systems were limited to the rat. 
In the exploratory studies in rats, single-cell necrosis of lymphocytes and/or decreases in 
lymphocyte cellularity were observed in the Peyer’s patches and in the cecal, mesenteric, and 
mandibular lymph nodes. These findings correlated with decreases in circulating lymphocytes.  
In the repeat-dose (GLP) study in rats, decreases in thymic and increases in splenic weights were 
observed and correlated with decreased cellularity and necrosis of lymphocytes in the thymus, 
and increased extramedullary hematopoiesis in the spleen (related to decreased red cell mass on 
hematology). In addition, sinus erythrocytosis and congestion/hemorrhage were noted in lymph 
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nodes and thymus that generally correlated with gross observations of discoloration. In animals 
found dead or removed early at ≥20 mg/kg changes in circulating lymphocytes and leukocytes 
included minimal to marked increases in neutrophil counts; moderate to marked decreases in 
lymphocytes; mild increase in monocytes. Additional changes at 40 mg/kg in these animals 
included moderate to marked decreases in eosinophils, increased basophils and decreased large 
unstained cells with low to many pyknotic cells noted on blood smears. In surviving animals at 
≥10 mg/kg, minimal decreases in total white blood cell counts, a minimal to moderate increase in 
neutrophil counts, a moderate to marked decrease in lymphocyte counts, and a minimal increase 
in monocyte counts (20 mg/kg only) were noted. At ≥10 mg/kg, the predominant microscopic 
finding was single cell necrosis most consistent with death of lymphocytes and leukocytes that 
was observed across multiple tissues including: lymph nodes; spleen; gut-associated lymphoid 
tissue; bronchus-associated lymphoid tissue; thymus; in perivascular and interstitial areas in 
skeletal muscle; and in the epididymis. At ≥20 mg/kg, single-cell necrosis of presumptive 
lymphocytes and leukocytes was also observed in the portal interstitium of liver; the lamina 
propria and submucosa of the GIT (stomach, duodenum, jejunum, ileum, colon, cecum, and 
rectum), that was occasionally associated with degeneration of adjacent mucosal cells admixed 
with associated neutrophilic infiltrates; in the bone marrow; and in the perivascular and 
interstitial areas of the lung. At 40 mg/kg, single-cell necrosis of presumptive lymphocytes and 
leukocytes as noted in the cervix. These findings recovered after a 2-week postdose period. 
Effects on the Liver 
In a non-GLP liver microtissue (LiMT) cytotoxicity assay, TAK-676 had no effect on cell 
viability in dog, monkey, or human LiMT (50% inhibitory concentration [IC50] >100 μM), 
suggesting a low drug-induced liver injury (DILI) risk was detected in vitro. In contrast, 
incubation of rat LiMT with 100-μM TAK-676 resulted in a moderate decrease in cell viability 
(60%, IC50 = 88.3 μM), suggesting that rats may have a species-specific DILI hazard. 
In vivo, TAK-676–related effects on the liver were limited to the rat. In the GLP-compliant 
repeat-dose study, bile duct hyperplasia, single-cell hepatocyte necrosis, and increased 
hepatocellular mitosis with corresponding changes in serum chemistry parameters (ALT, AST, 
glutamate dehydrogenase, and gamma glutamyl transferase activities and 
alpha-2-macroglobulin) were observed at ≥20 mg/kg. Except for bile duct hyperplasia associated 
with mild mixed cell infiltrates in the liver of 1 male at 20 mg/kg, findings recovered after a 
2-week postdose period. 
Effects on the Bone Marrow 
TAK-676–related effects on the bone marrow were limited to the rat. In the GLP-compliant 
repeat-dose study, decreased cellularity of mature granulocytes in the bone marrow that was 
associated with increased immature granulocytes and sometimes with the presence of pyknotic 
cells presumed to be granulocytes in the bone marrow were observed microscopically at 
≥20 mg/kg. These findings correlated with increases in neutrophils on hematology. These 
findings recovered after a 2-week postdose period. 
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Effects on the Skeletal Muscle (Soleus) 
TAK-676–related effects on the skeletal muscle (soleus) were limited to the rat. In the 
GLP-compliant repeat-dose study, at ≥10 mg/kg occasional degeneration and necrosis of 
myocytes was associated with single-cell necrosis of presumptive lymphocytes and leukocytes in 
perivascular and interstitial areas and mixed cell infiltrates were noted. These findings recovered 
after a 2-week postdose period. 
Effects on GIT 
TAK-676–related effects on the GIT were limited to the rat. In the GLP-compliant repeat-dose 
study, dose-dependent submucosal edema was noted in the colon, cecum, and rectum at 
≥20 mg/kg. In addition, discoloration of the stomach, jejunum, and ileum were observed at 
≥20 mg/kg and generally correlated with congestion, hemorrhage, and single-cell necrosis of 
presumptive lymphocytes and leukocytes within the lamina propria and submucosa. Feces 
changes (loose, soft, liquid, or mucoid) were observed in moribund animals. In addition, 
decreases in body weight and weight gain were also observed in animals found dead or removed 
from the study early, and correlated with decreases in food consumption, and required food 
supplementation starting on Days 5 for some animals and Day 8 for additional animals at 
40 mg/kg (bolus and infusion). The gross and microscopic findings noted in the GIT could not be 
directly correlated with the clinical observations in the rats. 
Effects at the Injection Site 
There were no injection site findings noted after IV bolus or infusion administration in the 
GLP-compliant repeat-dose toxicity study in rats or in the exploratory or GLP-compliant studies 
in monkeys. In the exploratory repeat-dose toxicity study in rats, microscopic changes at the 
injection site included perivascular minimal to mild hemorrhage and minimal to moderate 
inflammation in all groups (including controls) that had an increased incidence and severity in 
animals administered TAK-676 and was accompanied by minimal to mild vascular degeneration 
and necrosis at ≥2.1 mg/kg twice weekly. 
Potential for CRS 
Increases in pro-inflammatory cytokines were observed in an in vitro human whole blood 
cytokine release assay and suggest a potential TAK-676–related risk for CRS and inflammatory 
and immune-related toxicities in humans. 
There were no clinical signs or increases in body temperature suggestive of a CRS after 
administration of TAK-676 in the GLP-compliant toxicity studies in rats and monkeys. However, 
in rats, increases in TNF-α and IL-6 were observed at ≥10 mg/kg on Days 1, 11, and 15. In 
monkeys, increases in IL-6 were observed at 0.13 mg/kg (bolus and infusion) on Day 1 only. The 
relationship between IL-6 and the toxicity observed at 0.13 mg/kg in the monkey is unclear. In 
addition, there was clinical pathology evidence of an acute phase response in both species. 
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Appendix F BOIN Design 
The BOIN design (Liu and Yuan 2015) will be used to guide the dose escalation decisions and 
MTD estimation. This study was designed and will be conducted using the software BOIN that is 
available at trialdesign.org. 
Target toxicity rate is 0.3. During the study, if the observed DLT rate at the current dose is 
≤0.236, the next cohort of patients will be treated at the next higher DL; if it is ≥0.358, the next 
cohort will be treated at the next lower DL; if it is within 0.236 and 0.358, additional patients 
will be enrolled in this DL. For the purpose of overdose control, a DL and all the DLs above it 
will be eliminated from further examination if its posterior probability of exceeding the target 
toxicity rate is greater than 0.95. If the lowest DL is eliminated, stop the escalation for safety. 
Unless such early stop happens, dose escalation will continue until either: (1) the maximum 
sample size is reached, or (2) the number of patients treated at the current dose reaches 9 and the 
recommendation is to retain at the current DL. 
The dose escalation algorithm is described as the following steps: 
1. Patients in the first cohort are treated at lowest DL. 
2. Decide the DL for the next cohort according to the rule shown in Table F-1, noting the 
following: 
a) “Eliminate” means that the current DL and all higher DLs are eliminated to prevent 
treating any future patients at these overly toxic DLs. 
b) When a DL is eliminated, automatically de-escalate to the next lower DL. When the 
lowest DL is eliminated, stop the dose escalation for safety. In this case, no DL should be 
selected as the MTD. 
c) If none of the actions (ie, escalation, de-escalation or elimination) is triggered, the next 
cohort will be treated with the current dose. 
d) If the current dose is the lowest DL and the rule indicates a de-escalation, treat the next 
cohort at the lowest DL unless the number of DLTs reaches the elimination boundary, at 
which point the dose escalation should be terminated for safety. 
e) If the current dose is the highest dose and the rule indicates an escalation, treat the next 
cohort at the highest dose.  
3. Repeat Step 2 until either: (1) the maximum sample size is reached, or (2) 9 patients have 
been treated with the current DL and the recommendation is to retain at the current DL. 
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Table F-1 
Dose Escalation/De-escalation Rule for the BOIN Design 
Number of patients treated at the 
current dose 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Escalate if number of DLT ≤ 
0 
0 
0 
0 
1 
1 
1 
1 
2 
De-escalate if number of DLT ≥ 
1 
1 
2 
2 
2 
3 
3 
3 
4 
Eliminate if number of DLT ≥ 
NA 
NA 
3 
3 
4 
4 
5 
5 
5 
BOIN: Bayesian Optimal Interval; DLT: dose-limiting toxicity; NA: not applicable. 
Number of DLT is the number of patients with at least 1 DLT. 
 
After the dose escalation is complete, the MTD is selected based on isotonic regression, as 
specified in Liu and Yuan (Liu and Yuan 2015). Specifically, the dose is selected as the MTD for 
which the isotonic estimate of the toxicity rate is closest to the target toxicity rate. If there are 
ties, the higher DL is selected when the isotonic estimate is lower than the target toxicity rate; the 
lower DL is selected when the isotonic estimate is greater than or equal to the target toxicity rate. 
The operating characteristics of the BOIN design are evaluated with simulations assuming 
various distributions of toxicity across DLs shown in Table F-2. 
Table F-2 
Simulation Scenarios 
Dose 
Level 
(TAK-
500) 
True DLT Rate 
Scenario 
1 
Scenario 
2 
Scenario 
3 
Scenario 
4 
Scenario 
5 
Scenario 
6 
Scenario 
7 
Scenario 8 
8 μg/kg 
0.21 
0.15 
0.10 
0.06 
0.04 
0.02 
0.015 
0.01 
16 μg/kg 
0.30 
0.21 
0.15 
0.10 
0.07 
0.05 
0.04 
0.03 
24 μg/kg 
0.42 
0.30 
0.18 
0.13 
0.08 
0.06 
0.05 
0.04 
40 μg/kg 
0.45 
0.40 
0.30 
0.15 
0.10 
0.08 
0.07 
0.05 
80 μg/kg 
0.49 
0.46 
0.45 
0.30 
0.12 
0.11 
0.10 
0.08 
160 
μg/kg 
0.55 
0.53 
0.51 
0.45 
0.30 
0.14 
0.13 
0.10 
240 
μg/kg 
0.62 
0.59 
0.57 
0.51 
0.47 
0.30 
0.15 
0.13 
360 
μg/kg 
0.68 
0.64 
0.62 
0.57 
0.53 
0.48 
0.30 
0.15 
480 
μg/kg 
0.72 
0.68 
0.65 
0.64 
0.59 
0.53 
0.47 
0.30 
DLT: dose-limiting toxicity. 
 
For the SA escalation, we assume the BOIN escalation starts at 16 μg/kg, and a maximum of 
42 DLT-evaluable patients can be enrolled after the BOIN escalation starts. Each cohort enrolls 
3 patients.  
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For the combination escalation, we assume the BOIN escalation starts at 80 μg/kg and a 
maximum of 27 DLT-evaluable patients can be enrolled after the BOIN escalation starts 
(Scenarios 1 and 2 are not included in the simulation because it is unlikely for 24 μg/kg or less to 
be the MTD if 80 μg/kg has been cleared for safety in the SA arm). Each cohort enrolls 
3 patients.  
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Table F-3 
Operating Characteristics for the SA Escalation 
 
Scenario 1 
Scenario 2 
Scenario 3 
Scenario 4 
Scenario 5 
Scenario 6 
Scenario 7 
Scenario 8 
Dose Level 
(TAK-500) 
Selectio
n % 
% Pts 
Treated 
Selection 
% 
% Pts 
Treated 
Selection 
% 
% Pts 
Treated 
Selection 
% 
% Pts 
Treated 
Selection 
% 
% Pts 
Treated 
Selection 
% 
% Pts 
Treated 
Selection 
% 
% Pts 
Treated 
Selection 
% 
% Pts 
Treated 
8 μg/kg 
20.4 
17.0 
5.7 
6.3 
1.6 
2.3 
0.3 
0.6 
0.0 
0.2 
0.0 
0.1 
0.0 
0.0 
0.0 
0.0 
16 μg/kg 
51.4 
47.3 
30.9 
35.2 
11.7 
22.8 
4.1 
16.0 
1.7 
12.4 
0.5 
10.7 
0.3 
9.8 
0.2 
9.4 
24 μg/kg 
20.0 
25.7 
39.8 
33.4 
25.4 
27.2 
8.0 
17.3 
2.0 
12.6 
0.9 
11.1 
0.6 
10.0 
0.3 
9.6 
40 μg/kg 
5.5 
7.7 
18.0 
18.1 
44.6 
29.3 
21.8 
22.4 
3.7 
13.6 
2.6 
11.9 
1.6 
10.9 
0.6 
10.1 
80 μg/kg 
1.1 
2.0 
4.7 
5.7 
13.7 
14.6 
47.5 
26.9 
20.5 
20.0 
5.6 
13.4 
4.4 
12.3 
2.4 
11.2 
160 μg/kg 
0.2 
0.3 
0.6 
1.1 
2.6 
3.1 
15.5 
13.5 
54.4 
26.1 
21.8 
18.2 
7.6 
13.2 
4.2 
12.0 
240 μg/kg 
0.0 
0.0 
0.1 
0.1 
0.3 
0.6 
2.5 
2.7 
15.2 
12.5 
52.5 
22.3 
21.9 
16.0 
7.2 
12.8 
360 μg/kg 
0.0 
0.0 
0.0 
0.0 
0.0 
0.1 
0.3 
0.4 
2.2 
2.2 
13.8 
10.5 
47.2 
18.6 
22.7 
15.7 
480 μg/kg 
0.0 
0.0 
0.0 
0.0 
0.0 
0.0 
0.0 
0.0 
0.2 
0.3 
2.2 
1.8 
16.4 
9.2 
62.4 
19.0 
% Early 
stopping 
1.3 
0.3 
0.0 
0.0 
0.0 
0.0 
0.0 
0.0 
Expected 
no. of pts 
18.6 
21.1 
23.8 
27.4 
30.8 
33.3 
35.2 
35.2 
Pts: patients; SA: single agent. 
 
 
 
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Table F-4 
Operating Characteristics for the Combination Escalation 
 
Scenario 3 
Scenario 4 
Scenario 5 
Scenario 6 
Scenario 7 
Scenario 8 
Dose Level 
(TAK-500) 
Selection % 
% Pts 
Treated 
Selection % 
% Pts 
Treated 
Selection % 
% Pts 
Treated 
Selection % 
% Pts 
Treated 
Selection % 
% Pts 
Treated 
Selection % 
% Pts 
Treated 
8 μg/kg 
0.1 
0.1 
0.0 
0.0 
0.0 
0.0 
0.0 
0.0 
0.0 
0.0 
0.0 
0.0 
16 μg/kg 
1.0 
1.0 
0.0 
0.0 
0.0 
0.0 
0.0 
0.0 
0.0 
0.0 
0.0 
0.0 
24 μg/kg 
13.8 
11.5 
0.7 
1.1 
0.0 
0.0 
0.0 
0.0 
0.0 
0.0 
0.0 
0.0 
40 μg/kg 
47.5 
34.7 
17.4 
16.7 
0.8 
1.6 
0.4 
1.0 
0.2 
0.7 
0.1 
0.4 
80 μg/kg 
32.1 
41.2 
58.8 
49.9 
19.8 
32.2 
5.3 
20.6 
4.2 
18.4 
2.0 
16.5 
160 μg/kg 
5.0 
10.0 
19.1 
25.6 
60.0 
42.0 
22.7 
27.5 
7.7 
19.8 
4.1 
17.7 
240 μg/kg 
0.4 
1.4 
3.5 
5.7 
16.3 
19.6 
53.4 
33.0 
23.4 
23.4 
7.8 
18.9 
360 μg/kg 
0.0 
0.1 
0.3 
0.9 
2.7 
4.1 
15.1 
15.2 
47.2 
25.7 
25.1 
21.5 
480 μg/kg 
0.0 
0.0 
0.0 
0.1 
0.4 
0.5 
3.0 
2.7 
17.4 
12.2 
60.9 
25.0 
% Early 
stopping 
0.0 
0.0 
0.0 
0.0 
0.0 
0.0 
Expected no. 
of pts 
18.2 
17.8 
20.1 
22.2 
23.7 
24.1 
Pts: patients. 
 
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Appendix G 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 H Cockcroft-Gault Equation 
For male patients: 
Creatinine clearance =  
(140 - age [years]) × weight [kg] 
72 × (serum creatinine [mg/dL]) 
 
For female patients: 
Creatinine clearance =  
0.85 (140 - age [years]) × weight [kg] 
72 × (serum creatinine [mg/dL]) 
Source: Cockcroft and Gault, 1976. 
 
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Appendix I 
RECIST v1.1 
All sites of disease, target, and nontarget lesions must be assessed at baseline. Objective disease 
status is to be recorded at each evaluation using the response categories and definitions provided 
in this section. 
All sites of measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, 
representative of all involved organs, should be identified as target lesions at baseline. Target 
lesions should be selected based on size (longest lesions) and suitability for reproducible 
repeated measurements. Measurements must be provided for target site of measurable lesions. 
Table I-1 
Disease Response Criteria for Target and Nontarget Lesions 
Evaluation of target lesions 
CR 
Disappearance of all target lesions. Any pathological lymph nodes (whether target or 
nontarget) must have reduction in short axis to <10 mm. 
PR 
At least a 30% decrease in the sum of the LD of target lesions, taking as reference 
the baseline sum LD. 
PD 
At least a 20% increase in the sum of the LD of target lesions, taking as reference the 
smallest sum LD recorded since the treatment started or the appearance of 1 or more 
new lesions. In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. 
SD 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD, taking as reference the smallest sum LD since the treatment started. 
Evaluation of nontarget lesions 
CR 
Disappearance of all nontarget lesions and normalization of tumor marker level. All 
lymph nodes must be non-pathological in size (<10 mm short axis). 
Non-CR/non-PD 
Persistence of 1 or more nontarget lesion(s) or/and maintenance of tumor marker 
level above the normal limits. 
PD 
Unequivocal progression of existing nontarget lesions. (Note: the appearance of 1 or 
more new lesions is also considered progression). 
Source: (Eisenhauer et al. 2009).  
CR: complete response; LD: longest diameter; PD: progressive disease; PR: partial response; SD: stable disease. 
 
The following table summarizes the overall response status calculation at each time point for 
patients who have measurable disease per RECIST v1.1 at baseline. 
 
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Table I-2 
Disease Time Point Response: Patients With Target (± Nontarget) Disease 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Source: (Eisenhauer et al. 2009). 
CR: complete response; NE: not evaluable; PD: progressive disease; PR: partial response; SD: stable disease. 
 
The following table summarizes the overall response status calculation at each time point for 
patients who have nonmeasurable (therefore nontarget) disease at baseline. 
Table I-3 
Disease Time Point Response: Patients With Nontarget Disease Only 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD a 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
Source: (Eisenhauer et al. 2009). 
CR: complete response; NE: not evaluable; PD: progressive disease; SD: stable disease. 
a Non-CR/non-PD is preferred over SD for nontarget disease because SD is increasingly used as endpoint for 
assessment of antitumor activity in some studies, so to assign this category when no lesions can be measured is 
not advised. 
 
RECIST v1.1 and treatment beyond progression: As described in Section 9.4.13.1, 
accumulating evidence indicates a minority of patients treated with immunotherapy may derive 
clinical benefit despite initial evidence of PD. Patients will be permitted to continue study 
treatment beyond initial RECIST v1.1 defined PD as long as they meet the criteria outlined in 
this section. All decisions to continue treatment beyond initial progression must be discussed 
with the medical monitor and documented in the study records. 
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Appendix N Protocol History 
Date 
Amendment Number 
Region 
13 June 2023 
Amendment 3 
North America, Europe 
25 October 2022 
Amendment 2 
United States 
21 September 2021 
Amendment 1 
United States 
15 July 2021 
Initial Protocol 
United States 
 
Protocol Amendment 2 Summary and Rationale: 
This section describes the changes in reference to the protocol incorporating Amendment 2.  
The primary reasons for this amendment are to: 
• Transition the initiation of the combination TAK-500 plus pembrolizumab dose escalation 
arm to the safety clearance of the 80 µg/kg dose level (DL) or determination of 
pharmacologically active dose (PAD) to be ≤40 µg/kg in the single agent (SA) TAK-500 
dose escalation cohort.  
• Add 2 indications: renal clear cell carcinoma (RCC) and nasopharyngeal carcinoma (NPC). 
• Clarify the number of patients to be enrolled to potentially explore the once every 2 weeks 
(Q2W) TAK-500 dosing schedule in dose escalation. 
• Add a cytokine release syndrome (CRS) mitigation strategy. 
In this amendment, minor grammatical, editorial, formatting, and administrative changes not 
affecting the conduct of the study are included for clarification and administrative purposes 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 4.2 Rationale for the 
Proposed Study  
Section 4.2.1.8 RCC  
Section 4.2.1.9 NPC 
Section 5.1.1 Primary Objectives  
Section 6.1 Overview of Study 
Design  
Section 7.1 Inclusion Criteria  
Included patients with renal 
clear cell carcinoma (RCC) 
and nasopharyngeal carcinoma 
(NPC). 
RCC and NPC are tumors with 
high cysteine-cysteine 
chemokine receptor type 2 
expression in the tumor 
immune microenvironment and 
have high unmet need in later 
lines of therapy.  
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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 
2. 
Section 2.0 STUDY SUMMARY  
Section 4.2.2.4 Dose Range  
Section 4.2.2.5 Dosing Schedule 
of TAK-500 
Section 6.1 Overview of Study 
Design 
Section 6.1.1 TAK-500 Dose 
Escalation 
Section 6.1.1.1 TAK-500 SA 
Dose Escalation 
Section 6.1.1.2 TAK-500 in 
Combination With 
Pembrolizumab Dose Escalation 
Section 6.1.1.3 General Rules for 
Dose Escalation 
Section 6.1.2 TAK-500 in 
Combination With 
Pembrolizumab Dose Expansion 
Section 6.1.3 Study Assessments 
Section 8.1.1 TAK-500 
Section 8.1.3 TAK-500 in 
Combination With 
Pembrolizumab 
Section 8.3.1 BOIN Dose 
Escalation 
Section 8.5.3 Criteria for 
Administering a Subsequent 
Dose/Starting a New Treatment 
Cycle 
Section 8.5.4 Criteria for Dose 
Modification 
Appendix A SOEs 
Adjusted aspects of the study 
design related to dose 
escalation of TAK-500 single 
agent and in combination with 
pembrolizumab.  
The changes optimize the 
approach for balancing 
potential antitumor activity and 
safety. 
3. 
Section 2.0 STUDY SUMMARY 
Section 5.1.2 Secondary 
Objectives 
Section 5.2.2 Secondary 
Endpoints 
Section 6.3.3 Timeframes for 
Primary and Secondary 
Endpoints to Support Disclosures 
Updated language for 
evaluation of dose-responsive 
impact on T-cell infiltration of 
the tumor following TAK-500 
administration. 
Changed in order to more 
accurately represent the 
intended analysis of TAK-500 
on the tumor. 
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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 
4. 
Section 2.0 STUDY SUMMARY 
Section 5.2.2 Secondary 
Endpoints 
Removed pharmacologically 
active dose (PAD) range and 
the dose for further 
development as secondary 
endpoints. 
Endpoints are generally 
subject-level variables, while 
PAD and the dose for further 
development are population 
level. 
5. 
Section 2.0 STUDY SUMMARY 
Section 5.2.2 Secondary 
Endpoints 
Section 6.3.3 Timeframes for 
Primary and Secondary 
Endpoints to Support Disclosures 
Removed the following 
secondary endpoint: “
 
 
 
 
 
.” 
The modified biomarker 
endpoint is of an exploratory 
nature rather than a secondary 
nature. 
6. 
Section 2.0 STUDY SUMMARY 
Section 6.1 Overview of Study 
Design 
Section 6.2 Number of Patients 
Section 13.3 Determination of 
Sample Size 
Increased the number of 
patients to 118.  
Number of patients increased 
to account for additional once-
every-2-weeks cohorts in dose 
escalation. 
7. 
Section 2.0 STUDY SUMMARY 
Section 6.1.1.1 TAK-500 SA 
Dose Escalation 
Changed wording from “2 
subsequent DLs [dose levels]” 
to “2 consecutive DLs” for 
confirmation of minimum 
PAD. 
Changed for clarification. 
8. 
Section 2.0 STUDY SUMMARY 
Section 7.1 Inclusion Criteria 
Changed inclusion criterion #4 
from “evaluable” to 
“measurable” lesion. 
Evaluation of tumor response 
by Response Evaluation 
Criteria in Solid Tumors, 
Version 1.1, requires 
measurement of lesions. 
9. 
Section 2.0 STUDY SUMMARY 
Section 7.1 Inclusion Criteria 
Removed inclusion criterion 
#6. 
While investigators are still 
expected to use their best 
judgment in enrolling patients 
who they expect could remain 
on study reasonably long 
enough to assess safety and 
efficacy of study treatments, it 
was determined performance 
status is a less subjective 
evaluation of overall health. 
10. 
Section 2.0 STUDY SUMMARY 
Section 7.2 Exclusion Criteria 
Added pre-existing conditions 
to exclusion criterion #16. 
A pre-existing condition may 
affect patient safety. 
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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 
11. 
Section 2.0 STUDY SUMMARY 
Section 7.2 Exclusion Criteria 
Changed exclusion criterion 
#20 to reduce the washout 
period from 14 days to 7 days. 
Seven days should be 
sufficient to taper a patient on 
systemic corticosteroids. 
12. 
Section 2.0 STUDY SUMMARY 
Section 7.2 Exclusion Criteria 
Section 8.6 Excluded 
Concomitant Medications and 
Procedures 
Section 8.7 Permitted 
Concomitant Medications and 
Procedures 
Added an exception for 
nonsystemic corticosteroids. 
Nonsystemic corticosteroids 
should not affect the 
pharmacology of TAK-500 or 
present any safety concerns. 
13. 
Section 2.0 STUDY SUMMARY 
Section 6.1.3 Study Assessments 
Section 8.2 Definitions of DLT 
Section 8.5.5 Criteria for 
Discontinuation of TAK-500 
Section 8.6 Excluded 
Concomitant Medications and 
Procedures 
Updated definitions of dose-
limiting toxicity (DLT). 
Updated to clarify and to 
ensure patient safety. 
14. 
Section 2.0 STUDY SUMMARY 
Section 6.1.1.1 TAK-500 SA 
Dose Escalation 
Section 8.4 Definition of PAD 
Updated the definition of PAD. 
The definition was updated to 
reflect the latest understanding 
of what PAD should be for this 
study. 
15. 
Section 2.0 STUDY SUMMARY 
Section 13.1.1 Analysis Sets 
Appendix A SOEs 
Added an option for 
 premedication. 
Specified that patients treated 
with 
 
premedication will be 
evaluated separately from 
those without premedication.  
This change made for 
increased patient safety and 
increased clarity in statistical 
analysis. 
16. 
Section 4.1.2.2 TAK-676 
Updated background 
information about TAK-676. 
This was updated to reflect the 
latest data for TAK-676. 
17. 
Section 4.1.2.3 TAK-500 
Added background information 
about TAK-500. 
This section added to reflect 
the latest data for TAK-500. 
18. 
Section 4.2.2.2 Recommended 
Starting Dose Based on MABEL 
Added clarification regarding 
preclinical models and 
cytokine release syndrome 
(CRS). 
Updated to reflect the latest 
data. 
19. 
Section 4.2.3.1 Tumor Biopsies 
Removed reference to bayesian 
logistic regression modeling. 
This reference is not necessary. 
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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 
20. 
Section 4.3 Potential Risks and 
Benefits 
Updated section to indicate 
that TAK-500 is currently 
being evaluated in a first-in-
human study. 
This section was updated to 
reflect the latest data. 
21. 
Section 4.3.1.1 CRS 
Updated background 
information about CRS. 
This was updated to reflect the 
latest data. 
22. 
Section 6.1.1.1 TAK-500 SA 
Dose Escalation 
Section 6.1.1.2 TAK-500 in 
Combination With 
Pembrolizumab Dose Escalation 
Section 6.1.1.4 Corticosteroid 
Premedication 
Section 8.1.1 TAK-500 
Section 8.5.4 Criteria for Dose 
Modification 
Section 8.9.1 CRS 
Section 8.9.7 Infusion-Related 
Reactions 
Appendix A SOEs 
Updated the study design to 
include a CRS-mitigation 
strategy. 
CRS has been observed in 
patients, and a strategy has 
been developed to mitigate 
CRS for continued dose 
escalation. 
23. 
Section 8.1.1 TAK-500 
Section 9.4.6 Vital Signs 
Appendix A SOEs 
Clarified that measurement of 
vital signs on Cycle 1 Day 1 
should be obtained 3 and 
6 hours after dosing of 
TAK-500, within a ±30-minute 
window. 
This was changed for 
clarification. 
24. 
Section 8.5.3 Criteria for 
Administering a Subsequent 
Dose/Starting a New Treatment 
Cycle 
Removed albumin. 
Patients do not need to have a 
certain level of albumin before 
having a subsequent dose of 
TAK-500 or starting a new 
treatment cycle. 
25. 
Section 8.5.4 Criteria for Dose 
Modification 
Updated dose-modification 
guidelines. 
This was updated to increase 
patient safety. 
26. 
Section 8.9.2 Pulmonary Edema 
Updated guidelines for 
management of pulmonary 
edema. 
This was updated to increase 
patient safety. 
27. 
Section 8.9.7 Infusion-Related 
Reactions 
Updated guidelines for 
management of infusion-
related reactions. 
This was updated to increase 
patient safety. 
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TAK-500 
 
Study No. TAK-500-1001 
Page 240 of 243 
Protocol Incorporating Amendment No. 3 
13 June 2023 
 
CONFIDENTIAL 
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 
28. 
Section 8.9.9 Management of 
COVID-19–Positive Patients 
Updated guidelines for the 
management of coronavirus 
disease 2019 (COVID-19)–
positive patients. 
This was updated to be 
consistent with most recent 
understanding of COVID-19 
risks and management. 
29. 
Section 8.9.10 CV Toxicity 
Added guidelines for 
management of cardiovascular 
toxicity. 
This was added to increase 
patient safety. 
30. 
Section 9.4.4 Physical 
Examination 
Section 9.4.6.2 Pulse Oximetry 
Added clarification regarding 
the assessment of O2 saturation 
using pulse oximetry. 
To harmonize the previous 
contradictions between the 2 
sections. 
31. 
Section 9.4.12.1 Clinical 
Chemistry, Hematology, Tumor 
Markers, Coagulation, and 
Thyroid Function 
Appendix A SOEs 
Added the interleukin-6 test. 
This laboratory test was added 
to increase patient safety. 
32. 
Section 9.4.13 Disease 
Assessment 
Added an option to obtain an 
intravenous (IV) contrast scan. 
IV contrast and contrast-
enhanced computed 
tomography scans (if available) 
are preferable to reduce patient 
burden. 
33. 
Section 9.4.14.2 Tumor Biopsies 
Appendix A SOEs 
Changed PD, biomarker, and 
PK sampling timepoints. 
Increased the biopsy collection 
window to 28 days. 
Specified that biopsy 
collection will be 48 hours 
after dosing. 
The collection window was 
increased to reduce patient 
burden. 
Sampling timepoints changed 
to more appropriately reflect 
PD activity profile.  
34. 
Section 9.7 Discontinuation of 
Treatment With Study Drug and 
Patient Replacement 
Updated the discontinuation 
criteria. 
This was updated for increased 
patient safety. 
35. 
Section 13.1.1 Analysis Sets 
Updated the definition of DLT-
evaluable set. 
The change made for increased 
clarity in statistical analysis. 
36. 
Section 13.1.3 Efficacy Analysis 
Changed antitumor “analysis” 
to antitumor “activity.” 
Change made for increased 
clarity in statistical analysis. 
37. 
Section 13.1.3 Efficacy Analysis 
Added death to the definition 
of duration of response. 
This change was made to 
clarify that all-cause death is 
also considered an event. 
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Study No. TAK-500-1001 
Page 241 of 243 
Protocol Incorporating Amendment No. 3 
13 June 2023 
 
CONFIDENTIAL 
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 
38. 
Section 13.1.3 Efficacy Analysis 
Added “PFS [progression-free 
survival] will be analyzed 
using Kaplan-Meier method 
for the safety analysis set in 
dose expansion cohorts only.” 
This was added for clarity. 
39. 
Section 13.2 Interim Analysis 
and Criteria for Early 
Termination 
Added “In the dose expansion 
phase, an interim futility 
analysis will be performed,” 
To clarify that an interim 
futility analysis for the 
expansion cohort will be 
performed. 
40. 
Appendix A SOEs 
Clarification that ECGs will be 
done on dosing days. 
Update made for clarification. 
41. 
Appendix A SOEs 
Updated footnote “I” in 
Table A-1 SOE for TAK-500 
Q3W Treatment (21-Day 
Cycle) Cycle 1.  
Update made for clarification.  
 
For non-commercial use only

TAK-500 
 
Study No. TAK-500-1001 
Page 242 of 243 
Protocol Incorporating Amendment No. 3 
13 June 2023 
 
CONFIDENTIAL 
Protocol Amendment 1 Summary and Rationale 
This section describes the changes in reference to the protocol incorporating Amendment 1.  
The primary reason for this amendment is to:  
Address the changes requested by United States (US) Food and Drug Administration (FDA) 
during Investigational New Drug (IND) application review. 
In this amendment, minor grammatical, editorial, formatting, and administrative changes not 
affecting the conduct of the study are included for clarification and administrative purposes only. 
Protocol Amendment 1 
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 6.1.1 TAK-500 SA Dose 
Escalation  
Section 6.1.4 Study Assessments 
Section 8.9.1 CRS 
Section 8.9.7 Infusion-Related 
Reactions 
 SOEs 
Increased patient monitoring 
time in the clinic to at least 
4 hours after TAK-500 
infusion during the second 
infusion and beyond. Patients 
who do not experience 
infusion-associated symptoms 
or symptoms consistent with 
cytokine release syndrome 
(CRS) during or after the first 
3 infusions of TAK-500 may 
have their subsequent post-
infusion monitoring reduced to 
1 hour.  
Changes made in response to 
an FDA request for additional 
safety monitoring of patients 
after TAK-500 infusions. 
2. 
Section 2.0 STUDY SUMMARY 
Section 6.1.1 TAK-500 SA Dose 
Escalation 
Section 6.1.2 TAK-500 in 
Combination With 
Pembrolizumab Dose Escalation 
Section 8.3.1 BOIN Dose 
Escalation 
Modified enrollment rule by 
staggering the dosing between 
the first patient of any new 
dose level (DL) and 
subsequent patients enrolled at 
the same DL by 24 hours. 
Changes made in response to 
an FDA request to ensure there 
is a 24-hour gap in dosing 
between the first patient of any 
new DL and subsequent 
patients. 
3. 
Section 2.0 STUDY SUMMARY 
Section 8.1.1 TAK-500 
Section 8.9.1 CRS 
Highlighted the option to use 
other anti–interleukin (IL)-6 
agents for CRS treatment due 
to limited availability of 
tocilizumab.  
Due to the limited supply of 
tocilizumab, which has been 
publicly stated by the 
manufacturer, FDA requested 
that an alternative for 
tocilizumab in treatment of 
CRS be noted.  
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TAK-500 
 
Study No. TAK-500-1001 
Page 243 of 243 
Protocol Incorporating Amendment No. 3 
13 June 2023 
 
CONFIDENTIAL 
Protocol Amendment 1 
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 
4. 
Section 2.0 STUDY SUMMARY 
Section 8.2 Definitions of DLT 
Revised the definitions of 
dose-limiting toxicity (DLT): 
1. Removed the following 
exception: “Isolated 
elevation of alanine 
aminotransferase (ALT) 
and/or aspartate 
aminotransferase (AST), that 
is ≤10 × upper limit of 
normal (ULN) in the absence 
of significant bilirubin 
elevation (Grade <3), 
excluding elevations meeting 
Hy’s Law.”  
2. The following exceptions are 
to be resolved/corrected 
within 3 days instead of 
5 days:  
• 
Grade 3 asymptomatic 
laboratory changes 
(other than renal 
function).  
• 
Grade 3 nausea and/or 
emesis. 
• 
Grade 3 diarrhea. 
Changes made in response to 
FDA request to modify DLT 
definitions. 
5. 
Section 13.1.9 Safety ECG 
Analysis  
Changed the QT interval 
correction method from 
Bazette to Fridericia.  
Changed to correct a 
typographical error. Initial 
intent was only to include QT 
interval with Fridericia 
correction method (QTcF) as 
this is the more established 
standard for QT correction. 
 
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For non-commercial use only