An Open-label, Phase 1, Dose-escalation Study to Evaluate the Safety and Preliminary Antitumor Activity of TAK-676 With Pembrolizumab Following Radiation Therapy in the Treatment of Non-small-cell Lung Cancer, Triple-negative Breast Cancer, or Squamous-cell Carcinoma of the Head and Neck That Has Progressed on Checkpoint Inhibitors
Phase: PHASE1
Conditions: Carcinoma, Non-Small-Cell Lung, Triple Negative Breast Neoplasms, Squamous Cell Carcinoma of Head and Neck
Sponsor: Takeda

NCT Number: NCT04879849
Title: An Open-Label, Phase 1, Dose-Escalation Study to Evaluate the Safety and 
Preliminary Antitumor Activity of TAK-676 With Pembrolizumab Following 
Radiation Therapy in the Treatment of Non–Small-Cell Lung Cancer, Triple-
Negative Breast Cancer, or Squamous-Cell Carcinoma of the Head and Neck that 
Has Progressed on Checkpoint Inhibitors
Study Number: TAK-676-1003
Document Version and Date: Amendment 2.0, 18 February 2022
Certain information within this document has been redacted (ie, specific content is masked 
irreversibly from view) to protect either personally identifiable information or company 
confidential information. 
A summary of changes to previous protocol versions is appended to the end of the 
document.
Clinical Study Protocol
For non-commercial use only

PROTOCOL
An Open-Label, Phase 1, Dose-Escalation Study to Evaluate the Safety and Preliminary 
Antitumor Activity of TAK-676 With Pembrolizumab Following Radiation Therapy in the 
Treatment of Non–Small-Cell Lung Cancer, Triple-Negative Breast Cancer, or 
Squamous-Cell Carcinoma of the Head and Neck that Has Progressed on Checkpoint 
Inhibitors
TAK-676 With Pembrolizumab Following Radiation Therapy in the Treatment of 
Non-Small-Cell Lung Cancer, Triple-Negative Breast Cancer, or Squamous-Cell 
Carcinoma of the Head and Neck
Sponsor:
Takeda Development Center Americas, Inc. (TDC Americas)
95 Hayden Avenue
Lexington, MA 02421
Please note: Takeda Development Center Americas, Inc. (TDC 
Americas) may be referred to in this protocol as “sponsor” or “Takeda”.
Study Number:
TAK-676-1003
EudraCT Number:
Not applicable
Compound:
TAK-676
Date:
18 February 2022
Amendment Number:
2
Amendment History:
Date
Amendment Number
Region
18 February 2022
Amendment 2
North America
31 March 2021
Amendment 1
North America
23 October 2020
Initial protocol
North America
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 will be provided to each site.
Serious adverse event (SAE) and pregnancy reporting information is presented in Section 10.0, as 
is information on reporting product complaints.
Takeda Development Center–sponsored investigators per individual country requirements will be 
provided with emergency medical contact information cards to be carried by each patient.
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site.
The names and contact information for the medical monitor and responsible medical officer are in 
the Study Manual.
For non-commercial use only

For non-commercial use only

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CONFIDENTIAL
INVESTIGATOR AGREEMENT
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure (IB), 
prescribing information, and any other product information provided by the sponsor. I agree to 
conduct this study in accordance with the requirements of this protocol and also to protect the 
rights, safety, privacy, and well-being of study patients in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Council for Harmonisation, E6 Good Clinical Practice: Consolidated Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.0 of this 
protocol.

Terms outlined in the clinical study site agreement.

Responsibilities of the investigator (Appendix B).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix C of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Province)
Location of Facility (Country)
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1.3
Protocol Amendment 2 Summary of Changes
Protocol Amendment 2 Summary and Rationale:
This section describes the changes in reference to the protocol incorporating Amendment 2.
The primary reason for this amendment is to delineate the requirements and statistical 
considerations for paired biopsies.
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 6.1 Overview of Study 
Design
Figure 6.a
Study Design
Section 6.1.1 Dose Escalation of 
TAK-676
Section 6.2 Number of Patients
Section 6.3.1 Duration of an 
Individual Patient’s Study 
Participation
Section 13.3 Determination of 
Sample Size
Increased number of subjects to be 
enrolled and duration of the treatment.
Number of patients 
increased because of the 
addition of higher dose 
levels of TAK-676 to be 
investigated and 
increased duration of 
treatment to more 
closely align with 
pembrolizumab label.
2.
Section 4.5.1.2 TNBC
Updated details about IMPASSION
130 trial to justify selected patient 
population (triple-negative breast 
cancer [TNBC]). Also added 
information about the Keynote-355 
trial, that it has been granted 
accelerated approval.
Updated section with 
current available 
information.
3.
Section 2.0 STUDY SUMMARY
Section 4.5.3.1 Dose Range
Figure 6.a
Study Design
Section 6.1 Overview of Study 
Design
Section 8.1.3 TAK-676
Section 8.3 Dose Escalation Rules
Table 8.d
Planned Dose 
Levels of TAK-676
Section 13.3 Determination of 
Sample Size
Increased the explorable dose range for 
TAK-676, provided justification of 
increase in dose range, and explained 
dose escalation criteria in respective 
sections.
Increased the dose 
range on the basis of the 
preliminary 
safety/tolerability data 
available from 
preplanned interim 
safety data review in the 
first-in-human (FIH)
Study TAK-676-1002 
and allowed for more 
aggressive dose 
escalation on the basis 
of this data.
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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 5.1.2 Secondary Objectives
Section 5.2.2 Secondary Endpoints
Section 5.1.3 Exploratory Endpoints
Table 6.b
Primary and 
Secondary Endpoints for 
Disclosures
Section 13.1.5 Pharmacodynamic 
Analysis
Appendix K Statistical 
Considerations for Paired Biopsies
Added secondary objective and 
respective endpoint for evaluation of 
dose-responsive impact on tumor 
immune cell infiltration and activation 
in nonirradiated tumors after TAK-676 
administration.
To more closely align 
with American Society 
of Clinical Oncology
(ASCO)’s Ethical 
Framework for 
Including Research 
Biopsies in Oncology 
Clinical Trials by 
providing clarity and 
quantification around 
mandatory biopsy 
collection and elevating 
it from exploratory to 
secondary 
objective/endpoint.
5.
Section 4.5.4.1 Tumor Biopsies
Section 9.4.15.2.2 Fresh Paired 
Tumor Biopsy
Appendix K Statistical 
Considerations for Paired Biopsies
Addition of statement for mandatory 
biopsies in all patients with safely 
accessible lesions, on observing 
pharmacodynamic activity.
Addition of appendix to explain 
statistical considerations for paired 
biopsies.
To more closely align 
with ASCO’s Ethical 
Framework for 
Including Research 
Biopsies in Oncology 
Clinical Trials by 
providing clarity and 
quantification around 
mandatory biopsy 
collection and elevating 
it from exploratory to 
secondary 
objective/endpoint.
6.
Appendix A Schedule of Events
Table 1 and Table 2 
Addition of blood sample collection at 
6 hours after the end of infusion of 
TAK-676 in Cycle 1 Day 1 (C1D1) and 
C1D15 for immunophenotyping.
On-treatment blood 
samples are collected to 
look at activation of 
peripheral immune 
cells. 
7.
Section 2.0 STUDY SUMMARY
Section 5.2.2 Secondary Endpoints
Revised response assessments to 
include evaluation using both 
Response Evaluation Criteria in Solid 
Tumors (RECIST) v.1.1 and modified 
intratumoral immunotherapy Response 
Evaluation Criteria in Solid Tumors
(itRECIST).
Clarification.
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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
8.
Section 2.0 STUDY SUMMARY
Section 5.2.2 Secondary Endpoints
Section 9.4.14 Disease Assessment
Section 9.4.14.1.1 Irradiated and 
Nonirradiated Response
Figure 9.a Illustration of Irradiated, 
Nonirradiated, and Overall 
Responses per Modified itRECIST
Addition of use of itRECIST criteria 
for select response assessments.
Per itRECIST: overall response rate 
(confirmed complete response + 
confirmed partial response), duration 
of response, time to response.
Clarify the need to 
assess response both per 
RECIST v.1.1 as well as 
per modified itRECIST 
criteria to allow for 
assessment of irradiated 
and nonirradiated 
lesions.
9.
Section 6.1 Overview of Study 
Design
Section 8.1.1 Radiation Treatment 
Regimen
Section 9.4.14 Disease Assessment
Added a clarifying statement that 
before radiation therapy, the radiology 
oncologist and medical oncologist 
should agree on the target lesions 
identified for irradiation using the
baseline imaging assessments.
Addition made to 
provide more clarity.
10.
Section 2.0 STUDY SUMMARY
Section 7.1 Inclusion Criteria
Section 9.4.14.1.1 Irradiated and 
Nonirradiated Response
Modified Inclusion Criteria #4 to add 
dimensions of measurable tumor 
lesions.
Addition made to 
provide more clarity 
around what is 
considered a 
measurable lesion. 
11.
Section 2.0 STUDY SUMMARY
Section 7.1 Inclusion Criteria
Inclusion criteria #6 on life expectancy 
of the patient made not applicable.
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 that being 
able to quantitate life 
expectancy is quite 
difficult, thus it was 
removed as a specific 
criterion for inclusion.
12.
Section 2.0 STUDY SUMMARY
Section 7.2 Exclusion Criteria
Section 8.5 Excluded Concomitant 
Medications and Procedures
The 14-day period of time off systemic 
steroids before C1D1 start was reduced 
to 7 days.
Because these steroids 
have a short half-life, a 
shorter wash-out period 
is better justified and 
optimal.
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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
13.
Section 8.1.1 Radiation Treatment 
Regimen
Appendix A Schedule of Events
Table 1
Revised the time interval for radiation 
therapy administration to between 
Day -8 to Day -2 instead of between 
Day -8 to Day -1
Revision made to 
ensure minimum 
40 hours of time 
interval between end of 
radiation therapy and 
initiation of 
pembrolizumab 
infusion.
14.
Section 8.1.3 TAK-676
Section 8.8.2 CRS
Highlighted the option to use other 
anti–IL-6 agents for cytokine release 
syndrome (CRS) treatment due to 
limited availability of tocilizumab.
Due to the limited 
supply of tocilizumab, 
which has been publicly 
stated by the 
manufacturer, an 
alternative for 
tocilizumab in 
treatment of CRS is 
noted.
15.
Section 8.1.3 TAK-676
Appendix A Schedule of Events
Table 1 footnotes
Clarified that TAK-676 infusion will 
start 1 hour (+15 minutes) after the end 
of pembrolizumab infusion.
Revised language to 
bring more clarity.
16.
Section 8.8.12 Management of 
COVID-19–Positive Patients
In the text about symptomatic patients 
who test positive for coronavirus 
disease 2019 (COVID-19) during 
screening or enrollment, the language 
was updated to require resolution of 
symptoms and completion of any 
COVID-19 treatments within 7 days of 
enrollment or retreatment with study 
drugs. In the text about asymptomatic 
patients who test positive for 
COVID-19 during screening or 
enrollment, the language was updated 
to require a 7-day waiting period from 
the time of positive test before
enrollment or retreatment. In addition, 
a negative COVID-19 polymerase 
chain reaction test is no longer a 
requirement for enrollment or 
retreatment in symptomatic or 
asymptomatic patients unless required 
per local guidelines. Also included 
consultation with medical monitor.
In response to evolving 
COVID-19 testing 
recommendations and 
treatment options.
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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
17.
Table 8.f
Guidelines for 
TAK-676 Dose Modification and/or 
Discontinuation for 
Nonhematologic Toxicity
Updated dose modification for 
hepatoxicity.
Update made to ensure 
consistency within the 
protocol.
18.
Section 8.6 Permitted Concomitant 
Medications and Procedures
Added oxygen supplementation.
To ensure it gets 
recorded as a 
concomitant 
medication.
19.
Section 8.8.1 Pulmonary 
Vasculature 
Toxicity/Noncardiogenic 
Pulmonary Edema
Table 8.h
Pulmonary 
Toxicity Clinical Management 
Recommendations
Revised dose modification suggestion 
in the setting of pulmonary toxicity.
Update made to ensure 
consistency within the 
protocol and to not 
unnecessarily hold 
study drug based on an 
isolated oxygen 
saturation <95%.
20.
Table 8.iNCCN Guidelines Version 
3.2021: Management of CAR T 
Cell–Related Toxicities
Modified table based on most current 
NCCN guidelines for management of 
chimeric antigen receptor T cell–
related toxicities.
Update made to use 
more current guidance.
21.
Section 8.8.2 CRS
The dose modification due to CRS was 
clarified to indicate that if TAK-676 is 
discontinued, pembrolizumab should 
be held until the CRS event recovers to 
Grade ≤1.
Clarification. 
22.
Section 8.8.6 Nausea and/or 
Vomiting
Section 8.8.7 Diarrhea
Addition of statement to use evolving 
consensus guidelines for management 
of immune mediated toxicity, if 
nausea/vomiting/diarrhea are thought 
to be immune mediated.
Additional references 
added for management 
of clinical events.
23.
Section 8.8.10 Management of 
Pembrolizumab Immune-Mediated 
AEs
Addition of statement to use evolving 
consensus guidelines for management 
of immune-checkpoint inhibitor–
related adverse events, in case of 
immune-mediated reactions due to 
pembrolizumab administration.
Additional references 
added for management 
of clinical events.
24.
Section 9.3 Treatment Group 
Assignments
Changed the following sentence to past 
tense as current study is now ongoing: 
Safety data was to be obtained from at 
least 2 dose cohorts of the FIH 
combination arm before administering 
TAK-676 with pembrolizumab 
following radiation therapy in the 
current study.
Editorial update.
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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
25.
Table 9.b
Clinical 
Urinalysis Tests
Leukocytes was corrected to leukocyte 
esterase.
Correction.
26.
Section 9.4.14 Disease Assessment
The scan of the neck was clarified to be 
done only for patients with head and 
neck squamous cell carcinoma and 
when clinically indicated for patients 
with TNBC and non–small-cell lung 
cancer. The anatomy required at 
follow-up time points was also 
clarified. 
Clarification.
27.
Section 9.4.14.1.2 Treatment 
Beyond Progression
Clarified that treatment beyond 
progression will be based on RECIST 
v.1.1 criteria and not modified 
itRECIST.
Clarification. 
28.
Section 9.4.15.3 Biomarker and 
Pharmacodynamic Measurements
Included expression analysis for blood 
sample RNA and inclusion of 
statements that measurements will 
comply with local regulations.
Clarification.
29.
Section 9.10 Study Compliance
Updated window between radiation 
treatment and start of planned study 
drug(s) administration, in case if AE 
occurs after radiation treatment.
This specified duration 
of delay in treatment 
start defines an upper 
limit of reasonable 
delay, beyond which the 
potential implications 
for patient safety and 
study validity 
necessitate discussion 
with the Medical 
Monitor.
30.
Section 13.1.1 Analysis Sets
Addition of comprehensive 
response-evaluable analysis set as 
subset of safety analysis set and 
conversion of response evaluable 
analysis set as subset of safety and 
comprehensive response-evaluable 
analysis set.
Change made to to have 
an additional way of 
defining the 
denominator when 
calculating the response 
rates.
31.
Section 13.1.7 ECG Analysis
Assessment of QT interval with Bazett 
correction method was removed.
The assessment of QT 
interval by Fridericia 
formula is enough. 
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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
32.
Appendix A Schedule of Events
Table 1
Modified footnotes d and added 
footnote e to clarify that vital signs and 
Eastern Cooperative Oncology Group
performance status should also be 
performed before the first fraction of 
radiation therapy.
Clarification.
33.
Appendix E BOIN Design
Added instructions for when additional 
dose levels are added.
To align with other 
protocol changes that 
allow for investigation 
of higher dose levels.
34.
Appendix J Dose constraints as per 
Task Group-101
Fixed table misalignment.
Correction.
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 2 Summary of Changes............................................................5
2.0
STUDY SUMMARY ....................................................................................................19
3.0
STUDY REFERENCE INFORMATION ......................................................................24
3.1
Study-Related Responsibilities.................................................................................24
3.2
Principal Investigator/Coordinating Investigator ......................................................24
3.3
List of Abbreviations ...............................................................................................25
3.4
Corporate Identification...........................................................................................28
4.0
INTRODUCTION.........................................................................................................29
4.1
STING Signaling and Innate and Adaptive Immune Response.................................29
4.2
Radiation Therapy and the Innate and Adaptive Immune Response..........................29
4.3
Radiation Therapy in Combination With CPI...........................................................32
4.4
TAK-676 Nonclinical Background...........................................................................33
4.4.1
Nonclinical Pharmacology...............................................................................34
4.4.2
Nonclinical Pharmacokinetics..........................................................................37
4.4.3
Nonclinical Toxicology ...................................................................................37
4.5
Rationale for the Proposed Study.............................................................................41
4.5.1
Rationale for the Selected Patient Population...................................................42
4.5.2
Rationale for Dose of Radiation Therapy .........................................................43
4.5.3
Rationale for Proposed Starting Dose of TAK-676...........................................44
4.5.4
Rationale for Paired Biopsies and Blood Draws...............................................45
4.5.5
Rationale for PK Assessments .........................................................................46
4.6
Potential Risks and Benefits.....................................................................................46
4.6.1
Potential Risks and Effects of Radiation in Combination with Pembrolizumab
........................................................................................................................46
4.6.2
Potential Risks and Effects of TAK-676 Based on Nonclinical Studies ............50
4.6.3
Potential Risks and Effects Seen With Other STING Agonists.........................53
4.6.4
Potential Risks and Effects of TAK-676 in Combination With 
Pembrolizumab................................................................................................53
4.6.5
Potential Risks and Effects of TAK-676 in Combination With Radiation and 
Pembrolizumab................................................................................................54
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................56
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5.1
Objectives................................................................................................................56
5.1.1
Primary Objective............................................................................................56
5.1.2
Secondary Objectives ......................................................................................56
5.1.3
Exploratory Objectives ....................................................................................56
5.2
Endpoints.................................................................................................................57
5.2.1
Primary Endpoints ...........................................................................................57
5.2.2
Secondary Endpoints .......................................................................................57
5.2.3
Exploratory Endpoints .....................................................................................58
6.0
STUDY DESIGN..........................................................................................................58
6.1
Overview of Study Design.......................................................................................58
6.1.1
Dose Escalation of TAK-676 ...........................................................................60
6.2
Number of Patients ..................................................................................................62
6.3
Duration of Study ....................................................................................................62
6.3.1
Duration of an Individual Patient’s Study Participation....................................62
6.3.2
End of Study/Study Completion Definition and Planned Reporting..................62
6.3.3
Timeframes for Primary and Secondary Endpoints to Support Disclosures ......62
6.3.4
Total Study Duration .......................................................................................63
6.3.5
Post-trial Access ..............................................................................................63
7.0
STUDY POPULATION................................................................................................64
7.1
Inclusion Criteria .....................................................................................................64
7.2
Exclusion Criteria ....................................................................................................66
8.0
STUDY DRUG .............................................................................................................68
8.1
Study Drug Administration......................................................................................68
8.1.1
Radiation Treatment Regimen..........................................................................68
8.1.2
Pembrolizumab................................................................................................70
8.1.3
TAK-676 .........................................................................................................71
8.2
Definitions of DLT ..................................................................................................72
8.3
Dose Escalation Rules..............................................................................................73
8.4
Dose Modification Guidelines..................................................................................75
8.4.1
Criteria for Administering a Subsequent Dose/Starting a New Cycle ...............76
8.4.2
Criteria for Dose Modification of Radiation.....................................................77
8.4.3
Criteria for Dose Modification of Pembrolizumab............................................77
8.4.4
Criteria for Dose Modification of TAK-676.....................................................77
8.4.5
Criteria for Discontinuation of TAK-676 .........................................................82
8.4.6
Criteria for Discontinuation of Pembrolizumab................................................83
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8.4.7
Stopping Rules ................................................................................................83
8.5
Excluded Concomitant Medications and Procedures ................................................83
8.6
Permitted Concomitant Medications and Procedures................................................85
8.7
Precautions and Restrictions ....................................................................................85
8.8
Management of Clinical Events ...............................................................................87
8.8.1
Pulmonary Vasculature Toxicity/Noncardiogenic Pulmonary Edema...............87
8.8.2
CRS.................................................................................................................88
8.8.3
Infusion-Related Reactions..............................................................................93
8.8.4
Infusion Site Care............................................................................................93
8.8.5
Anemia, Thrombocytopenia, and/or Neutropenia.............................................93
8.8.6
Nausea and/or Vomiting ..................................................................................94
8.8.7
Diarrhea...........................................................................................................94
8.8.8
Skin Conditions/Rash ......................................................................................94
8.8.9
Fluid Deficit ....................................................................................................95
8.8.10
Management of Pembrolizumab Immune-Mediated AEs .................................95
8.8.11
Management of Radiation-Associated AEs ......................................................95
8.8.12
Management of COVID-19–Positive Patients ..................................................95
8.9
Blinding and Unblinding..........................................................................................96
8.10
Description of Investigational Agents ......................................................................96
8.10.1
TAK-676 .........................................................................................................96
8.10.2
Pembrolizumab................................................................................................96
8.10.3
Radiation Therapy ...........................................................................................97
8.11
Preparation, Reconstitution, and Dispensation..........................................................97
8.11.1
TAK-676 .........................................................................................................97
8.11.2
Pembrolizumab................................................................................................97
8.12
Packaging and Labeling...........................................................................................97
8.12.1
TAK-676 .........................................................................................................97
8.12.2
Pembrolizumab................................................................................................97
8.13
Storage, Handling, and Accountability.....................................................................98
8.13.1
TAK-676 .........................................................................................................98
8.13.2
Pembrolizumab................................................................................................98
8.14
Other Protocol-Specified Materials ..........................................................................98
9.0
STUDY CONDUCT......................................................................................................98
9.1
Study Personnel and Organizations..........................................................................98
9.2
Arrangements for Recruitment of Patients................................................................98
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9.3
Treatment Group Assignments.................................................................................99
9.4
Study Procedures.....................................................................................................99
9.4.1
Informed Consent ............................................................................................99
9.4.2
Patient Demographics......................................................................................99
9.4.3
Medical History...............................................................................................99
9.4.4
Physical Examination ....................................................................................100
9.4.5
Patient Height and Weight .............................................................................100
9.4.6
ECOG Performance Status.............................................................................100
9.4.7
Vital Signs.....................................................................................................100
9.4.8
Pregnancy Test ..............................................................................................101
9.4.9
Concomitant Medications and Procedures......................................................101
9.4.10
AEs ...............................................................................................................101
9.4.11
Enrollment.....................................................................................................101
9.4.12
Cardiac Monitoring........................................................................................101
9.4.13
Clinical Laboratory Evaluations.....................................................................102
9.4.14
Disease Assessment.......................................................................................104
9.4.15
Biomarker, Pharmacodynamic, and PK Samples............................................107
9.5
Documentation of Patient Screen Failure ...............................................................111
9.6
Completion of Study Treatment (for Individual Patients) .......................................112
9.7
Discontinuation of Treatment With Study Drug and Patient Replacement..............112
9.8
Posttreatment Follow-up Assessments ...................................................................113
9.9
Completion of Study (for Individual Patients)........................................................113
9.10
Study Compliance..................................................................................................114
10.0
ADVERSE EVENTS ..................................................................................................114
10.1
Definitions.............................................................................................................114
10.1.1
Pretreatment Event Definition........................................................................114
10.1.2
AE Definition ................................................................................................115
10.1.3
SAE Definition..............................................................................................115
10.2
Procedures for Recording and Reporting AEs and SAEs........................................116
10.3
Monitoring of AEs and Period of Observation .......................................................117
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events.......118
10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose) ..............................................................................................................118
10.5.1
TAK-676 .......................................................................................................118
10.5.2
Pembrolizumab..............................................................................................118
10.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities.........119
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11.0
STUDY-SPECIFIC COMMITTEES ...........................................................................119
12.0
DATA HANDLING AND RECORDKEEPING..........................................................119
12.1
eCRFs....................................................................................................................119
12.2
Record Retention ...................................................................................................120
13.0
STATISTICAL METHODS........................................................................................120
13.1
Statistical and Analytical Plans ..............................................................................120
13.1.1
Analysis Sets .................................................................................................121
13.1.2
Analysis of Demographics and Other Baseline Characteristics.......................121
13.1.3
Efficacy Analysis...........................................................................................121
13.1.4
Pharmacokinetic Analysis..............................................................................122
13.1.5
Pharmacodynamic Analysis...........................................................................123
13.1.6
PK/Pharmacodynamic Analysis.....................................................................123
13.1.7
ECG Analysis................................................................................................123
13.1.8
Safety Analysis..............................................................................................124
13.2
Interim Analysis and Criteria for Early Termination ..............................................125
13.3
Determination of Sample Size................................................................................125
14.0
QUALITY CONTROL AND QUALITY ASSURANCE.............................................125
14.1
Study-Site Monitoring Visits .................................................................................125
14.2
Protocol Deviations................................................................................................125
14.3
Quality Assurance Audits and Regulatory Agency Inspections ..............................126
15.0
ETHICAL ASPECTS OF THE STUDY......................................................................126
15.1
IRB and/or IEC Approval ......................................................................................126
15.2
Patient Information, Informed Consent, and Patient Authorization.........................127
15.3
Patient Confidentiality ...........................................................................................128
15.4
Publication, Disclosure, and Clinical Trial Registration Policy...............................129
15.4.1
Publication.....................................................................................................129
15.4.2
Clinical Trial Registration..............................................................................129
15.4.3
Clinical Trial Results Disclosure....................................................................130
15.5
Insurance and Compensation for Injury..................................................................130
16.0
REFERENCES............................................................................................................130
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LIST OF IN-TEXT TABLES
Table 4.a
Radiation Therapy in Combination With CPI: Overall Antitumor Activity and 
Abscopal Responses...........................................................................................33
Table 4.b
Trials Showing Safety and Tolerability of Radiation Therapy in Combination 
With CPI............................................................................................................48
Table 6.a
Dose Escalation/De-escalation Rule for the BOIN Design for 55 
DLT-Evaluable Patients.....................................................................................61
Table 6.b
Primary and Secondary Endpoints for Disclosures .............................................63
Table 8.a
Target Region and Contours...............................................................................70
Table 8.b
Biologically Equivalent Dose for the Radiation Fractionation Scheme Based on 
the Linear-Quadratic Model and Assuming an α/β of 3.......................................70
Table 8.c
Dose Escalation/De-escalation Rule for the BOIN Design..................................74
Table 8.d
Planned Dose Levels of TAK-676......................................................................74
Table 8.e
Dose Modification of Radiation .........................................................................77
Table 8.f
Guidelines for TAK-676 Dose Modification and/or Discontinuation for 
Nonhematologic Toxicity...................................................................................78
Table 8.g
Guidelines for TAK-676 Dose Modification and/or Discontinuation for 
Hematologic Toxicity.........................................................................................81
Table 8.h
Pulmonary Toxicity Clinical Management Recommendations............................88
Table 8.i
NCCN Guidelines Version 3.2021: Management of CAR T Cell–Related 
Toxicities...........................................................................................................90
Table 9.a
Clinical Chemistry, Hematology, Coagulation, and Thyroid Function Tests.....103
Table 9.b
Clinical Urinalysis Tests ..................................................................................104
Table 9.c
Primary Specimen Collection...........................................................................108
LIST OF IN-TEXT FIGURES
Figure 4.a
Radiation and Local Induction of Type I Interferon............................................31
Figure 6.a
Study Design......................................................................................................59
Figure 9.a
Illustration of Irradiated, Nonirradiated, and Overall Responses per Modified 
itRECIST.........................................................................................................105
LIST OF APPENDICES
Appendix A
Schedule of Events...........................................................................................137
Appendix B
Responsibilities of the Investigator...................................................................145
Appendix C
Investigator Consent to Use of Personal Information........................................147
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Appendix D
ECOG Scale for Performance Status ................................................................148
Appendix E
BOIN Design ...................................................................................................149
Appendix F
Cockcroft-Gault Equation ................................................................................152
Appendix G
New York Heart Association Classification of Cardiac Disease........................153
Appendix H
Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1)..............154
Appendix I
Clinical Inhibitors of OATP1B1 and OATP1B3...............................................156
Appendix J
Dose constraints as per Task Group-101...........................................................157
Appendix K
Statistical Considerations for Paired Biopsies...................................................160
Appendix L
Protocol History...............................................................................................161
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2.0
STUDY SUMMARY
Name of Sponsor(s): Takeda Development Center Americas, Inc. 
Compound: TAK-676
Title of Protocol: An Open-Label, Phase 1, Dose-Escalation Study to 
Evaluate the Safety and Preliminary Antitumor Activity of TAK-676 With 
Pembrolizumab Following Radiation Therapy in the Treatment of Non–
Small-Cell Lung Cancer, Triple-Negative Breast Cancer, or Squamous-Cell 
Carcinoma of the Head and Neck that Has Progressed on Checkpoint 
Inhibitors.
EudraCT No.: Not applicable
Study Number: TAK-676-1003
Phase: 1
Study Design:
This is an open-label, 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 checkpoint inhibitors (CPIs).
Approximately 65 patients with metastatic NSCLC, TNBC, or SCCHN will be enrolled in this study, to achieve a 
maximum of 55 dose-limiting toxicity (DLT) evaluable patients. All patients will receive 8 Gy × 3 doses of 
image-guided radiation therapy, followed by intravenous (IV) administration of pembrolizumab and TAK-676. 
Pembrolizumab will be administered at 200 mg IV on Day 1 of every 21-day cycle, with a minimum for 40 hours 
between the last fraction of radiation therapy and the initiation of IV pembrolizumab. TAK-676 will be administered 
in a dose-escalating fashion following the Bayesian Optimal INterval (BOIN) design, with an explorable dose range of 
0.2 to 9.0 mg administered on Days 1, 8, and 15 of every 21-day cycle. Patients will only receive TAK-676 with 
pembrolizumab at dose levels that were previously deemed safe in the dose-finding phase 1 study TAK-676-1002. 
Three patients will be enrolled in the initial cohort at the previously identified starting dose level of TAK-676. 
Subsequent cohorts will enroll 2 to 3 patients per escalation/de-escalation guidelines. Administration of 
pembrolizumab (every 3 weeks) and TAK-676 (weekly) will continue until disease progression, intolerance to 
pembrolizumab or TAK-676 (defined as the development of a treatment-emergent adverse event [TEAE] that is at 
least possibly related to pembrolizumab or TAK-676 and for which dose discontinuation is recommended), or 
withdrawal of consent, whichever occurs first. 
Primary Objective:
The primary objective is:

To determine the safety and tolerability of TAK-676 administered in combination with pembrolizumab following 
radiation therapy in patients with locally advanced or metastatic NSCLC, TNBC or SCCHN.
Secondary Objectives:
The secondary objectives are:

To determine the recommended phase 2 dose (RP2D) of TAK-676 administered in combination with 
pembrolizumab following radiation therapy. RP2D can be equal to or lower than the maximum tolerated dose 
(MTD).

To assess the preliminary antitumor activity of TAK-676 administered in combination with pembrolizumab 
following radiation therapy, both locally (in the radiation field) and systemically (nonirradiated lesions).

To evaluate the dose-responsive impact on T-cell infiltration in nonirradiated tumors following TAK-676 
administered in combination with pembrolizumab following radiation therapy.
Patient Population: Healthy male or female patients aged 18 years or older, with advanced NSCLC, TNBC, or 
SCCHN, who have progressed on CPIs.
Number of Patients:
Approximately 65 patients will be enrolled in this study to achieve a 
Number of Sites: 
Estimated total: Approximately 6 
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maximum of 55 DLT evaluable patients.
sites in North America.
Dose Level(s):
Radiation therapy: Fractionated dose of 8 Gy × 3.
Pembrolizumab: 200 mg.
TAK-676: 0.2, 0.4, 0.8, 1.2, 1.6, 2.0, 2.5, 3.5, 5.0, 7.0, and 9.0 mg.
Route of Administration:
Pembrolizumab: IV infusion over 30 
minutes.
TAK-676: IV infusion over 60±10 
minutes.
Duration of Treatment: 
Approximately 24 months. 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 30 months.
Inclusion Criteria:
1.
Adult male or female patients, aged 18 years or older.
2.
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.
3.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
4.
Patients must have at least 2 measurable lesions (ie, >10 mm longest diameter for extranodal lesions, >15 mm 
short axis for lymph nodes) with at least one inside and at least one other outside of the radiation field. The tumor 
outside the radiation field must be accessible for biopsy, and the patient must consent to tumor biopsy at screening 
and during treatment as described in the SOE.
5.
Patients with pathologically confirmed (cytological diagnosis is adequate) advanced or metastatic NSCLC, 
TNBC, or SCCHN who have:
a)
Received or been offered all established standard of care treatment options for which they are eligible; and
b)
Progressed on checkpoint inhibitors in a prior line of therapy.
6.
Not Applicable. In Protocol Amendment 2, requirement of patient having life expectancy >12 weeks has been 
removed.
7.
Adequate bone marrow, renal, and hepatic functions, as determined by the following laboratory parameters:
a)
Absolute neutrophil count (ANC) ≥1000/µL, platelet count ≥75,000/µL, and hemoglobin ≥8.0 g/dL without 
growth factor support for neutrophils or transfusion support for platelets within 14 days before the first study 
treatment dose.
b)
Total bilirubin ≤1.5 times the institutional ULN. For patients with Gilbert’s disease, ≤3 mg/dL.
c)
Serum ALT and AST ≤3.0 times the ULN (or ≤5.0 times the ULN with presence of liver metastases).
d)
Albumin ≥3.0 g/dL.
e)
Estimated creatinine clearance using the Cockcroft-Gault formula ≥30 mL/min.
8.
Left ventricular ejection fraction (LVEF) >50%, as measured by echocardiogram or multiple-gated acquisition 
(MUGA) 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, Version 5.0) 
or baseline, except for alopecia, Grade 2 peripheral neuropathy, and/or autoimmune endocrinopathies with stable 
endocrine replacement therapy.
10. Female patients must be:
a)
Postmenopausal (natural amenorrhea and not due to other medical reasons) for at least 1 year before the 
screening visit, OR
b)
Surgically sterile, OR
c)
If they are of childbearing potential, agreeable to practicing 2 effective methods of contraception at the same 
time, from the time of signing the informed consent through 120 days after the last dose of study drug(s), OR
d)
Agreeable 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.
11. Male patients, even if surgically sterilized (ie, status postvasectomy), must:
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a)
Agree to practice effective barrier contraception during the entire study treatment period and through 120 
days after the last dose of study drug, OR
b)
Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient.
Note: Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods), withdrawal, spermicides 
only, and lactational amenorrhea are not acceptable methods of contraception.
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.
History of brain metastasis unless:
a)
Clinically stable, (ie, treatment completed ≥4 weeks prior) following prior surgery, whole-brain radiation, or 
stereotactic radiosurgery, AND
b)
Off corticosteroids.
3.
Known history of uncontrolled autoimmune disorders, HIV infection, or other relevant congenital or acquired 
immunodeficiencies. 
4.
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.
5.
Contraindication and/or history of intolerance to the administration of CPI.
6.
Contraindication and/or history of intolerance to the radiation therapy.
7.
Any 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.
8.
Treatment with any investigational products and systemic anticancer drugs (including vascular endothelial 
growth factor inhibitors), within 14 days or 5 half-lives, whichever is shorter, before Cycle 1 Day 1 (C1D1) of 
study drug(s).
9.
Concurrent chemotherapy, immunotherapy (except for pembrolizumab), 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 (eg, corticosteroid replacement use).
10. Prior radiation to lesions chosen for biopsy or response assessment.
11. Prior radiation to lesions other than those chosen for radiation therapy or biopsy in the current protocol within 4 
weeks of C1D1 of study drug(s).
12. Use of systemic corticosteroids or other immunosuppressive therapy, concurrently or within 7 days of start of 
radiation therapy, with the following exceptions:
a)
Topical, intranasal, inhaled, ocular, intra-articular and/or other nonsystemic corticosteroids.
b)
Physiological doses of replacement steroid therapy (eg, for adrenal insufficiency).
13. Receipt of live attenuated vaccine (eg, tuberculosis Bacillus Calmette-Guerin [BCG] vaccine, oral polio vaccine, 
measles, rotavirus, yellow fever) within 28 days of C1D1 of study drug(s).
14. Recipients of allogeneic or autologous stem cell transplantation or organ transplantation.
15. Female patients who are lactating or have a positive serum pregnancy test during the screening period or a 
positive urine pregnancy test on Day 1 before first dose of study drug.
Note: Female patients who are lactating will be eligible if they choose to discontinue breastfeeding before the first 
dose of study drug.
16. Ongoing Grade ≥2 infection or patients with Grade ≥2 fever of malignant origin.
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17. Fridericia’s corrected QT interval (QTcF) >450 milliseconds (msec) (males) or >475 msec (females) on a 12-lead 
ECG during the screening period.
18. Grade ≥2 hypotension (ie, hypotension for which nonurgent intervention is required) at screening or during C1D1 
predose assessment.
19. Oxygen saturation <92% on room air at screening or during C1D1 predose assessment.
20. Use of medications that are known clinical OATP1B1 and/or OATP1B3 inhibitors, concurrently or within 
14 days of C1D1 of study drug(s). 
21. Patients treated with other STING agonists/antagonist and toll-like receptors agonists within the past 6 months.
22. Current smoker. 
23. Vaping within 90 days of C1D1 of study drug(s).
24. Current 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 or ascites not controlled by tap or requiring indwelling catheters.
Main Criteria for Evaluation and Analyses:
The primary endpoints are:

Frequency and severity of treatment-emergent adverse events (TEAEs).

Number of patients with DLTs.

Number/percentage of patients with 1 or more treatment-emergent serious adverse event (TESAE).

Number/percentage of patients with 1 or more TEAE leading to dose modifications and treatment 
discontinuation.
Safety endpoints will be evaluated according to the NCI CTCAE, Version 5.0.
The secondary endpoints are:
Response assessments are per Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 by investigator.

Overall response rate (ORR): confirmed complete response [cCR] + confirmed partial response [cPR].

Duration of response (DOR) for all tumor lesions assessed by RECIST v.1.1. 

Time to response (TTR) for all tumor lesions assessed by RECIST v.1.1
Response assessments are per modified intratumoral immunotherapy Response Evaluation Criteria in Solid Tumors
by investigator.

Overall response rate (ORR): cCR + cPR.

Overall response rate for tumors lying within the radiation field (ORRirradiated): confirmed complete response 
[cCRirradiated] + confirmed partial response [cPRirradiated] of tumor lesions lying within the radiation field.

Overall response rate for tumors lying outside the radiation field (ORRnonirradiated): confirmed complete 
response [cCRnonirradiated] + confirmed partial response [cPRnonirradiated] of tumor lesions lying outside of 
the radiation field.

DOR for tumors lying within the radiation field (DORirradiated), and for those lying outside of the radiation field 
(DORnonirradiated).

TTR for tumors lying within the radiation field (TTRirradiated), and for those lying outside of the radiation field 
(TTRnonirradiated).

The following endpoint will be assessed to evaluate T-cell infiltration into the tumor between pretreatment and 
on-treatment biopsies:
–
Cell infiltration evaluated by immunohistochemistry.
Statistical Considerations:
Dose escalation of TAK-676 will follow BOIN design to inform dose escalation decision and potential MTD 
estimation. Three patients will be enrolled in the initial cohort at the previously identified starting dose level of 
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TAK-676. Subsequent cohorts will enroll 2 to 3 patients per the escalation/de-escalation guidelines. The target toxicity 
rate is ϕ= 0.3. It is generally expected that at least 3 patients will enroll per cohort. However, if no DLTs have been 
identified in the TAK-676 + pembrolizumab dose level that has already been evaluated in the dose-finding phase 1 
TAK-676-1002 study, the sponsor, in agreement with the TAK-676-1003 investigators, may opt to enroll a 2-patient 
cohort at that same [radiation] + TAK-676 + pembrolizumab dose level being evaluated in the TAK-676-1003 study. 
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 dose level; if it is ≥0.358, the next cohort of patients will be treated at the next lower
dose level; if it is within 0.236 and 0.358, additional patients will be enrolled in this dose level. 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 dose level j. When the lowest dose is eliminated, the dose escalation will be stopped for 
safety. Dose escalation will continue until the maximum sample size (55 DLT-evaluable patients) is reached or the 
number of DLT evaluable patients treated at the current dose reaches 9. Isotonic regression method will be used on the 
cumulative DLT rate for each dose level to determine the MTD, defined as the highest TAK-676 dose in combination 
with radiation therapy and pembrolizumab that does not result in unacceptable toxicities.
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
Deescalate 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
Number of DLT is the number of patients with at least 1 DLT.
Other dose escalation decisions, evaluation of intermediate doses, expansion of an existing dose level, and stopping 
the dose escalation early are all permissible following discussions between the sponsor and the investigators, if such 
measures are needed for patient safety, or for a better understanding of the dose-related toxicity, exposure, and/or 
pharmacodynamics. Other non-DLT safety and available clinical, pharmacokinetic, or biomarker data will also be 
considered to inform subsequent dose recommendations, dose escalation decisions, and potential MTD and RP2D 
estimation.
Safety will be evaluated by the frequency of AEs, severity and types of AEs, AEs leading to dose modifications and 
treatment discontinuations, and other safety endpoints using the safety analysis set. The incidence of DLTs will be 
tabulated using the DLT-evaluable analysis set. ORR, ORRirradiated, and ORRnonirradiated will be summarized 
using descriptive statistics with 95% CI for the response-evaluable analysis set. DOR, DORirradiated, 
DORnonirradiated, TTR, TTRirradiated, and TTRnonirradiated will be analyzed descriptively using Kaplan-Meier 
method for response-evaluable analysis set.
Sample Size Justification: Approximately 65 patients with metastatic NSCLC, TNBC, or SCCHN will be enrolled in 
this study, to achieve a maximum of 55 DLT evaluable patients. They will receive pembrolizumab administered at 
200 mg IV on Day 1 of every 21-day cycle, and TAK-676 administered in a dose-escalating fashion following the 
BOIN design, with an explorable dose range of 0.2 to 9.0 mg administered on Days 1, 8, and 15 of every 21-day cycle.
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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
Takeda will select a signatory coordinating investigator from the investigators who participate in 
the study. Selection criteria for this investigator will include significant knowledge of the study 
protocol, the study medication, their expertise in the therapeutic area and the conduct of clinical 
research, and study participation. The signatory coordinating investigator will be required to 
review and sign the clinical study report (CSR) and by doing so agrees that it accurately describes 
the results of the study.
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3.3
List of Abbreviations 
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
anti-PD-1
anti-programmed cell death protein 1
anti-PD-L1
anti-programmed cell death ligand 1
ASCO
American Society of Clinical Oncology
ASH
American Society of Hematology
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
AUC24
area under the concentration-time curve from time 0 to 24 hours
BIW
twice weekly
BOIN
Bayesian Optimal INterval 
BWL
body weight loss
cCR
confirmed complete response
cCRirradiated
confirmed complete response in tumors lying within the radiation field
cCRnonirradiated
confirmed complete response in tumors lying outside the radiation field
CDN
cyclic dinucleotide
CFR
Code of Federal Regulations
cGAMP
cyclic guanosine monophosphate–adenosine monophosphate or cyclic GMP-AMP
cGAS
cyclic GMP-AMP synthase
Cmax
maximum observed concentration
COVID-19
coronavirus disease 2019
CPI
checkpoint inhibitor
CPK
creatine phosphokinase
cPR
confirmed partial response
cPRirradiated
confirmed partial response in tumors lying within the radiation field
cPRnonirradiated
confirmed partial response in tumors lying outside the radiation field
CRO
contract research organization
CRS
cytokine release syndrome
CSR
clinical study report
CT
computed tomography
CTV
clinical tumor volume
CxDx
Cycle x Day x (eg, C1D1: Cycle 1 Day 2)
CYP
cytochrome P-450
DC
dendritic cell
DDI
drug-drug interaction
DLT
dose-limiting toxicity
DOR
duration of response
DORirradiated
duration of response in tumors lying within the radiation field
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DORnonirradiated
duration of response in tumors lying outside the radiation field
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EOS
end of study
EOT
end of treatment
FDA
[United States] Food and Drug Administration
FIH
first-in-human
GCP
Good Clinical Practice
G-CSF
granulocyte colony stimulating factor
GI
gastrointestinal
GIT
gastrointestinal tract
GLP
Good Laboratory Practice
GTV
gross tumor volume
Gy
gray
HCV
hepatitis C virus
hERG
human ether-à-go-go–related gene
HNSTD
highest nonseverely toxic dose
IB
Investigator’s Brochure
ICB
immune checkpoint blockade
ICF
informed consent form
ICH
International Council for Harmonisation
ICU
intensive care unit
IEC
independent ethics committee
IFN
interferon
IL
interleukin
IP-10
interferon gamma inducible protein
IRB
institutional review board
IRF3
interferon regulatory factor 3
itRECIST
intratumoral immunotherapy Response Evaluation Criteria in Solid Tumors
ITV
internal target volume
IV
intravenous(ly)
LVEF
left ventricular ejection fraction
MABEL
minimum anticipated biological effect level
MedDRA
Medical Dictionary for Regulatory Activities
MHRA
[United Kingdom] Medicines and Healthcare products Regulatory Agency
MRI
magnetic resonance imaging
mRNA
messenger RNA
MRSD
maximum recommended starting dose
msec
milliseconds
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MTD
maximum tolerated dose
MUGA
multiple-gated acquisition
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NK
natural killer
NOAEL
no-observed-adverse-effect level
NSCLC
non–small-cell lung cancer
NT-I
nontarget irradiated
NT-NI
nontarget nonirradiated
OAR
organs at risk
OATP
organic anion-transporting polypeptide
ORR
overall response rate
ORRirradiated
overall response rate for tumors lying within the radiation field
ORRnonirradiated
overall response rate for tumors lying outside the radiation field
PCR
polymerase chain reaction
PD
progressive disease
PD-1
programmed cell death protein 1
PD-L1
programmed cell death ligand 1
PFS
progression-free survival
PK
pharmacokinetic(s)
PMDA
Pharmaceuticals and Medical Devices Agency, Japan
PR
partial response
PTV
planning tumor volume
Q3D
once every 3 days
QTcF
QT interval with Fridericia correction method
QW
once per week
RBC
red blood cell
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
recommended phase 2 dose
SAE
serious adverse event
SARS-CoV-2
severe acute respiratory syndrome coronavirus-2
SBRT
stereotactic body radiation therapy
SCCHN
squamous cell carcinoma of head and neck
SD
stable disease
SOC
standard of care
SOE
schedule of events
SRS
stereotactic radiosurgery
STING
Stimulator of Interferon Genes
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment-emergent adverse event
TESAE
treatment-emergent serious adverse event
T-I
target irradiated
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TME
tumor microenvironment
TNBC
triple negative breast cancer
T-NI
target, nonirradiated
TTR
time to response
TTRirradiated
time to response in tumors lying within the radiation field
TTRnonirradiated
time to response in tumors lying outside the radiation field
UK
United Kingdom
ULN
upper limit of normal
US
United States
Vss
volume of distribution at steady state after intravenous administration
WHO
World Health Organization
3.4
Corporate Identification
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
Overcoming T cell inhibition in the tumor microenvironment (TME) with checkpoint inhibitors 
(CPIs) has proven to be a successful strategy to produce long-term benefit in a significant number 
of patients with metastatic solid tumors. 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. Evolving data suggest that reduced interferon (IFN) signaling, 
immune escape through human leukocyte antigen loss, as well as altered antigen presentation may 
contribute to CPI resistance (Jenkins et al. 2018; Minn and Wherry 2016; Sharma et al. 
2017). Furthermore, an emerging consensus acknowledges that CPI resistance (relapse or 
refractory in nature) may also be driven by tumor immunophenotype, specifically those tumors 
harboring an immunosuppressive or “immune desert” phenotype. Accordingly, one possible 
strategy to overcome these elements of resistance is to stimulate innate immune cells (myeloid 
cells, including antigen-presenting dendritic cells [DCs], granulocytes, eosinophils, neutrophils, or 
monocytes/macrophages, as well as lymphoid cells, including gamma/delta T cells, natural killer 
[NK] cells, and NK T Cells) to condition the TME, thus turning immunologically “cold” tumors 
into “hot” tumors in which adaptive immune responses can be effectively activated.
Study TAK-676-1003 intends to evaluate the safety, tolerability, and preliminary efficacy of 
radiation therapy followed by the combination of pembrolizumab and the Stimulator of Interferon 
Genes (STING) agonist TAK-676 as a means to stimulate an immune-mediated antitumor 
response in otherwise immunologically cold tumors.
4.1
STING Signaling and Innate and Adaptive Immune Response
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 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 2′,3′-cyclic 
guanosine monophosphate–adenosine monophosphate (cGAMP), which may subsequently be 
transmitted 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. Downregulation 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).
4.2
Radiation Therapy and the Innate and Adaptive Immune Response
Radiotherapy is a pillar of cancer treatment with approximately 50% of cancer patients receiving 
radiotherapy at some point in the course of their disease (Delaney et al. 2005). In the setting of 
metastatic disease of solid tumors, including non–small-cell lung cancer (NSCLC), triple-negative 
breast cancer (TNBC), and squamous cell carcinoma of head and neck (SCCHN), radiotherapy is 
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often used with palliative intent. Technological advances have allowed radiotherapy to be 
delivered more precisely with such techniques as 3D conformal radiotherapy, image-guided 
intensity-modulated radiotherapy, and stereotactic ablative radiotherapy (Ahmad et al. 2012). 
With the increasing use of CPIs in these patients and the available evidence that radiation may 
enhance the immune response through activation of the STING pathway, there is much enthusiasm 
about combining radiation and CPI with the goal of improving treatment outcomes (Vatner et al. 
2014). Radiotherapy has often been thought of as immunosuppressive due to the large treatment 
fields depleting peripheral lymphocytes through direct cell killing (Yovino et al. 2013). However, 
there is clinical evidence that focal radiation in conjunction with immune checkpoint blockade 
(ICB) can lead not only to reduced tumor size in the radiation field but also to a systemic disease 
response, termed the “abscopal response,” in patients with metastatic disease, including NSCLC 
(Formenti et al. 2018; Vatner et al. 2014). This is thought to be through the release of tumor 
antigens by radiation-induced cell death in the context of endogenous adjuvants that facilitate 
priming of antitumor lymphocytes (Golden et al. 2012). This mechanism of radiation-induced 
immunogenicity involves the facilitation of tumor antigen uptake by DC and cross-presentation on 
major histocompatibility complex I, which is shown to be upregulated by radiotherapy in 
preclinical models (Formenti and Demaria 2013; Reits et al. 2006). This enhanced presentation of 
antigens released by cytotoxic radiotherapy potentiates cross-priming of tumor-specific 
lymphocytes in the lymph nodes, which may potentially prime an exhausted immune system in 
patients who are progressing on immunotherapy.
Local radiotherapy has been demonstrated to stimulate antitumor immune responses by increasing 
both apoptosis of tumor cells and subsequent antigen presentation and corresponding expression 
of immunomodulatory genes (Liao et al. 2004). Local radiation may also work through a different 
mechanism, that of altering the TME to promote greater infiltration by immune effector cells 
(Lugade et al. 2008; Matsumura et al. 2008; Zhang et al. 2007). Several studies have observed that 
the rapid reduction of tumor burden after ablative radiation therapy depends on T cell responses 
(Gupta et al. 2012; Lee et al. 2009). Ablative radiation also increases T cell priming in draining 
lymphoid tissues and reduces both the primary tumor and distant metastasis in a CD8 T cell–
dependent fashion (Figure 4.a).
Preclinical tumor models have demonstrated that the immunogenic consequences of radiation are 
dependent on the cGAS/STING pathway (Deng et al. 2014b). Radiation-induced DNA damage 
leads to the generation of cytosolic DNA, which is sensed by cGAS. cGAS then catalyzes the 
production of cGAMP, which activates STING in tumor cells and nearby DCs, resulting in 
downstream induction of IFN-β (Deng et al. 2014b; Vanpouille-Box et al. 2017). IFN-β leads to 
enhanced antigen uptake by DCs and cross-presentation to T cells (Deng et al. 2014b). This 
recently redefined mechanism has bridged the tumor DNA damage response and host cell 
cytosolic DNA-sensing pathways in the context of radiotherapy (Figure 4.a).
The efficacy of radiotherapy has been shown to depend on the host immune response, particularly 
the adaptive immune response. By inducing apoptosis/necrosis of tumor tissues and subsequent 
release of DNA fragments and other danger signals, local high-dose radiation promotes 
inflammation (Apetoh et al. 2007). The potential role of type I IFN in bridging the inflammation 
induced by radiation has been investigated, demonstrating that type I IFNs result in a 
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tumor-reducing adaptive immune response (Burnette et al. 2011) (Figure 4.a). It has also been 
shown that radiation increases the production of IFNβ in the TME. The implications of this 
increase are significant. The therapeutic effect of radiation is diminished in an IFNα/β receptor 
knockout host (Burnette et al. 2011).
Preclinical work in tumor-bearing mice treated with radiation and intratumoral STING agonists 
injection provides evidence for an immune-mediated combination benefit. Deng et al. 
demonstrated that intratumoral delivery of the STING agonist 2′3′-cGAMP potentiates the 
response of MC38 tumors to radiation, and this combination benefit is dependent on the presence 
of STING in the host mice (Deng et al. 2014b). Similarly, a synthetic STING agonist (RR-CDG) 
delivered intratumorally to Panc02 tumors potentiated the effects of radiation to these tumors, and 
the combination resulted in systemic T cell–mediated tumor suppression, including at distant 
tumor sites (Baird et al. 2016).
Figure 4.a
Radiation and Local Induction of Type I Interferon
Source: Deng et al, 2016 (Deng et al. 2016).
Cytosolic DNA sensing orchestrates tumor immunity during radiotherapy. Radiation results in the 
upregulation of “find-me” and “eat-me” signals from tumor cells. During phagocytosis in myeloid 
cells, the DNA fragments hidden in irradiated tumor cells are released from phagosomes to 
cytoplasm, acting as a danger signal. The cyclase cGAS binds this DNA, becomes catalytically 
active, and generates cGAMP as a second messenger. cGAMP binds to STING, which in turn 
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activates IRF3 to induce type I IFN production. Type I IFN signaling in DCs promotes the 
crosspriming of CD8 T cells, leading to tumor control. 
Because type I IFN is a potent inducer of programmed cell death ligand 1 (PD-L1), it was 
postulated that (i) radiation resistance could be due to the engagement of T cell–negative 
regulatory pathways, especially IFN-induced PD-L1 upregulation inside the tumor tissues; and (ii) 
anti-programmed cell death ligand 1 (anti-PD-L1) treatment could overcome resistance to 
radiation therapy, further helping in eradicating the tumor (Deng et al. 2014a). This has led to 
postulating that programmed cell death protein 1 (PD-1)/PD-L1 inhibitors may be effective in 
potentiating the effect of radiation therapy.
4.3
Radiation Therapy in Combination With CPI 
Multiple trials have studied the combination of varying doses and schedules of radiation therapy 
with CPIs (primarily pembrolizumab, ipilimumab, and nivolumab) in metastatic solid cancers, 
providing a preliminary understanding of the antitumor activity and safety profile of this 
combination. The principal trials in this area are summarized in Table 4.a. The side effect profiles 
of combination radiation therapy and CPIs were generally considered safe and tolerable, and 
mirrored those seen with CPIs alone, although with the addition of anticipated local toxicity from 
radiation (see Section 4.6.1 and Table 4.b for additional details). As detailed in Table 4.a, a wide 
range of stereotactic radiation regimens have been utilized in these studies (20–60 gray [Gy] in 3–
5 fractions, given before or concurrently with CPI), with no clear superiority of one schedule over 
another. The majority of the studies listed in Table 4.a showed a modest overall response rate 
(ORR) (8%-36%), but only two of these trials were randomized prospective trials comparing CPI 
alone to CPI with stereotactic radiation therapy (24 Gy or 27 Gy given over 3 fractions (McBride 
et al. 2018; Theelen et al. 2019)). Unfortunately, neither of these randomized controlled trials 
produced statistically significant results, failing to clarify the optimally immunogenic 
dose/schedule for stereotactic radiation in this setting.
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Table 4.a
Radiation Therapy in Combination With CPI: Overall Antitumor Activity 
and Abscopal Responses
Drug
Tumor
Modality, 
Dose 
(Fractions)
Order Given
ORR
(overall)
ORR
(abscopal)
PFS
(m)
OS
(m)
Reference
PD-1 
(Pembrolizumab)
NSCLC
SBRT,
24 Gy (3)
Sequential
(SBRT->PD-1)
36%
(vs 18%)
-
6.6
vs 
1.9
15.9
vs 
7.6
(Theelen et al. 
2019)
PD-1 
(Pembrolizumab)
Multiple
SBRT,
30-50 Gy 
(3-5)
Sequential
(SBRT->PD-1)
13%
27%
3.1
9.6 (Luke et al. 2018)
PD-1 
(Pembrolizumab)
NSCLC
Radiation, 
multiple
Sequential
(RT->PD-1)
-
-
4.4 
vs 
2.1
10.7 
vs 
5.3
(Shaverdian et al. 
2017)
PD-1 
(Pembrolizumab)
Bladder
SBRT,
24 Gy (3)
Concurrent
(PD-1->SBRT)
-
44%
-
-
(Sundahl et al. 
2019b)
PD-1 
(Pembrolizumab)
TNBC
Radiation, 
30 Gy (5)
Concurrent
18%
-
-
-
McArthur et al, 
2008 (ASCO 
poster)
PD-1 
(Nivolumab)
TNBC
SBRT,
24 Gy (3)
Sequential
(SBRT->PD-1)
-
8%
-
-
(Voorwerk et al. 
2019)
PD-1 
(Nivolumab)
Melanoma
SBRT,
24 Gy (3)
Concurrent
(PD-1->SBRT)
-
45%
-
-
(Sundahl et al. 
2019a)
PD-1 
(Nivolumab)
HNSCC
SBRT,
27 Gy (3)
Concurrent
(PD-1->SBRT)
-
-5%
2.4 
vs 
1.9
10 
vs 
NR
(McBride et al. 
2018)
CTLA4 
(Ipilimumab)
Melanoma
SBRT,
50 Gy (4)
Sequential
(SBRT->CTLA4)
32%
18%
3.8
10.7
(Twyman-Saint 
Victor et al. 2015)
CTLA4 
(Ipilimumab)
Melanoma
SBRT,
20-50 Gy 
(1-15)
Concurrent 
(CTLA4->SBRT)
27%
-
-
-
(Hiniker et al. 
2016)
CTLA4 
(Ipilimumab)
Multiple
SBRT,
50 Gy (4)
Concurrent or 
Sequential 
(CTLA4->SBRT)
-
10%
3.2
10.2 (Tang et al. 2017)
CTLA4 
(Ipilimumab)
NSCLC
SBRT,
30 Gy (3-5)
Concurrent
-
18%
3.8
7.4
(Formenti et al. 
2018)
CPI: checkpoint inhibitor; CTLA-4: cytotoxic T lymphocyte–associated antigen-4; Gy: gray; HNSCC: head and neck 
squamous cell carcinoma; m: month; NSCLC: non-small–cell lung cancer; ORR: overall response rate; OS: overall 
survival; PD-1: programmed cell death protein 1; PFS: progression-free survival; RT: radiation therapy; SBRT: 
stereotactic body radiation therapy; TNBC: triple negative breast cancer.
4.4
TAK-676 Nonclinical Background
TAK-676 is a synthetic CDN exhibiting highly selective binding and activation of STING. 
TAK-676 is thought to modulate the innate immune system within the TME through 
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In vivo antitumor activity of TAK-676 was also assessed in A20 tumors in BALB/c mice 
(syngeneic murine B Cell lymphoma model). TAK-676 exhibited statistically significant 
(p<0.001) antitumor activity against the A20 tumor at both 1 and 2 mg/kg dose levels on a 
Q3D × 3 schedule. In 1 of 10 mice, complete regression was observed at 1 mg/kg, and in 2 of 
10 mice, complete regressions were observed at 2 mg/kg.
The effect of TAK-676 on immune cell populations was evaluated in tumor-draining lymph nodes 
of C57BL/6J mice bearing B16F10 tumors (syngeneic murine melanoma model) by flow 
cytometry. The results demonstrated DC activation within the lymph nodes. In addition to 
DC activation, T cell expansion and acquisition of effector T cell functions were also observed in 
both the TME and local tumor-associated lymphoid tissue.
4.4.1.2
Nonclinical Pharmacology of TAK-676 and CPIs
Compelling nonclinical data also support the potential of a systemic STING agonist when 
administered in combination with systemic CPIs. In the A20 syngeneic model, the combination of 
TAK-676 (0.25 to 0.5 mg/kg; Q3D × 3) and an anti–mouse PD-1 blocking antibody (10 mg/kg; 
Q3D × 3 followed by once per week [QW] × 3) synergistically suppressed tumor growth. 
Nonclinical synergy between STING agonism and CPIs has also been reported for other STING 
agonists (Ager et al. 2017; Ghaffari et al. 2018; Kinkead et al. 2018). The combination of 
TAK-676 with an anti–mouse PD-1 antibody in tumor-bearing mouse models did not result in 
synergistic toxicity, as assessed by increased or mortality enhanced body weight loss (BWL) when 
compared with TAK-676 alone. Additional details about the nonclinical pharmacology of 
TAK-676 can be found in the IB.
4.4.1.3
Nonclinical Pharmacology of TAK-676 With or Without CPI With Radiation Therapy
Nonclinical evidence for the added benefit of STING agonism in combination with radiation has 
been generated in the EMT6 murine breast carcinoma model using 2 distinct regimens of radiation 
treatment: 10 Gy × 1 delivered by focal beam radiation with manual positioning of tumor in the 
radiation field, and 8 Gy × 3 delivered by focal beam radiation with volumetric image guidance 
from computed tomography (CT) scans. 
In the studies utilizing 10 Gy × 1 delivered by focal beam radiation, combination benefit with 
TAK-676 was demonstrated on several treatment schedules in 2 studies. In the first study, 
TAK-676 (1 mg/kg) was administered Q3D × 3, and 10 Gy radiation was delivered in a single 
fraction, starting 2 days before, on the same day, or 2 days after initiation of TAK-676 dosing. In 
each case, the combination of TAK-676 and 10 Gy radiation had an additive effect on growth 
inhibition of irradiated tumors compared with the effect of TAK-676 or radiation alone. A second 
study in EMT6 tumor-bearing mice also demonstrated additive effects of TAK-676 and radiation 
on growth inhibition of irradiated tumors (10 Gy radiation delivered 1 or 2 days before, on the 
same day, or 1 or 2 days after initiation of TAK-676 on a Q3D × 3 schedule). In the first study, the 
combination was well tolerated with no treatment-related mortality, and BWL was within 
acceptable limits for all groups. However, in the second study, 2 of 50 mice receiving 10 Gy × 1 
radiation and 1 mg/kg TAK-676 were removed from the study due to BWL. Compared with these 
studies in EMT6 tumor-bearing mice, a study in A20-tumor bearing mice resulted in more BWL 
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0.13 mg/kg. These findings were not observed in monkeys at ≤0.06 mg/kg and were not observed 
in rats.
4.4.2
Nonclinical Pharmacokinetics
The absorption, distribution, metabolism, and elimination properties of TAK-676 were 
characterized both in vitro and in vivo in BALB/c mice bearing A20 syngeneic tumors, 
Sprague Dawley rats, and cynomolgus monkeys after IV dosing. TAK-676 had high clearance in 
rats and moderate clearance in monkeys. The volume of distribution at steady state after IV 
administration (Vss) of TAK-676 was moderate in rats and monkeys. TAK-676 showed little to no 
partitioning into red blood cells (RBCs). TAK-676 protein binding was low in mouse, dog, 
monkey, and human matrices and was moderate in rat plasma. TAK-676 had low clearance in 
hepatocytes and was stable in serum isolated from mice, rats, dogs, monkeys, and humans. No 
unique human metabolite was observed in the in vitro hepatocytes and serum incubations. 
TAK-676 was mainly eliminated as parent compound in bile duct–cannulated rats and monkeys, 
and the contribution of metabolism to the clearance pathway in bile duct–cannulated monkeys was 
considered minimal. TAK-676 has low cellular permeability in human colonic adenocarcinoma 
cells.
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 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.
The drug-drug interaction (DDI) potential of TAK-676 with cytochrome P-450 (CYP) inhibitors 
or inducers is unlikely because the contribution of metabolism to the clearance pathway is 
anticipated to be minimal. The DDIs of TAK-676 as CYP or transporter inhibitors or inducers is 
unlikely at the currently predicted dose. TAK-676 was projected to have moderate plasma 
clearance (0.562 L/h/kg), moderate Vss (0.376 L/kg), and short plasma half-life (0.85 h) in 
humans based on the allometric scaling from monkeys. Additional details about the nonclinical 
pharmacokinetics (PK) of TAK-676 can be found in the IB.
4.4.3
Nonclinical Toxicology
A battery of nonclinical studies, including in vitro studies for off-target liabilities, genotoxicity, 
cytokine release in human whole blood, species selection, liver toxicity, and phototoxicity; and in 
vivo studies (up to 2 weeks in duration) in rats and monkeys (including safety pharmacology 
endpoints), have been completed to assess the potential toxicologic profile of TAK-676. 
Sprague Dawley rats and cynomolgus monkeys were selected as relevant toxicology species, as 
TAK-676 has been shown to activate the STING pathway in these species. IV bolus administration 
was selected for the toxicology program, as it was considered the best opportunity for observing 
potential toxicities, including cytokine release syndrome (CRS) if it were to occur. In addition, to 
proactively evaluate any potential for injection site findings, which may occur with longer 
exposures of TAK-676 at the injection site (ie, if infusional dosing was used in the clinical 
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studies), an IV infusion arm was added to the GLP-compliant toxicity studies at the highest doses 
tested in both rats (40 mg/kg; approximately 10-minute infusion) and monkeys (0.13 mg/kg; 
approximately 30- and 10-minute infusion in males and approximately 10-minute infusion in 
females). On the basis of toxicity occurring at a lower nominal dose, with corresponding lower 
systemic exposures in monkeys compared with rats, the monkey is considered more sensitive than 
rat as a toxicology species. Pivotal toxicity studies in rats and monkeys (BIW administration for 
2-week duration; 5 total doses) were conducted in compliance with GLP Regulations for 
Nonclinical Laboratory Studies of the United States (US) Food and Drug Administration (FDA) 
Code of Federal Regulation (CFR), Title 21, Part 58 (21 CFR Part 58) and Organisation for 
Economic Cooperation and Development Principles of GLP, where applicable. Several studies 
were exploratory in nature and, although were not conducted in full compliance with all aspects of 
GLP regulations, are considered scientifically reliable, as they follow standard work practices and 
standard operating procedures.
4.4.3.1
Summary of Nonclinical Toxicology 
TAK-676 was not mutagenic, clastogenic, or phototoxic as evaluated in in vitro assays and has a 
low risk for off-target, central nervous system, cardiovascular, or hepatotoxic liabilities. Increases 
in 
 levels were observed in an in vitro human cytokine release assay in whole 
blood and suggest a potential TAK-676–related risk for CRS and inflammatory- and 
immune-related toxicities in humans.
4.4.3.2
Observed Toxicity in Rats
TAK-676 was well tolerated in 2 exploratory single-dose studies in Sprague Dawley rats at doses 
up to 33.6 mg/kg (IV bolus) and in an exploratory intermittent repeat-dose toxicity study in rats 
(BIW for 4 doses or QW for 3 doses) at doses up to 4.1 mg/kg (IV bolus). In the GLP repeat-dose 
toxicity study in rats, TAK-676 was administered IV BIW (5 total doses) at 10, 20, and 40 mg/kg 
via bolus (approximately 1-2 minutes). In addition, IV infusion arms, where rats were 
administered either vehicle (50 mM citrate buffer, 0.5% sodium chloride in sterile water for 
injection) or TAK-676 at 40 mg/kg BIW (over approximately 10 minutes using an indwelling 
catheter), were also included to evaluate the potential for injection site findings, which may occur 
with longer exposures of TAK-676 at the injection site. The tolerability of TAK-676 decreased 
with repeated administration, causing removal of animals earlier at 40 mg/kg (slow bolus and 
infusion) on Days 4 through 11 (animals received 2 to 4 doses) and on Day 15 at 10 and 20 mg/kg 
(after the 5th dose). In dead and/or moribund animals, TAK-676–related decreases in body weight 
and weight gain were observed that correlated with decreases in food consumption and clinical 
observations of feces changes (loose, soft, liquid, or mucoid); other observed signs included 
evidence of poor grooming (yellow and/or brown stained, ungroomed, or erected fur); weakness, 
decreased activity, hunched posture, prostrate and/or lateral recumbency; cold to touch; 
generalized pale skin; bilateral pale eyeballs; and/or partially closed eye(s). Clinical pathology 
evaluation reflected an acute phase response (increases in neutrophil counts, 
alpha-2-macroglobulin, and triglycerides, and decreases in albumin and cholesterol). Additionally, 
decreases in lymphocytes, leukocytes, platelets, and red cell counts, and 
 
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4.5.1
Rationale for the Selected Patient Population
This study will enroll adult patients with histologically confirmed advanced or metastatic solid 
tumors who have received or been offered all established standard of care (SOC) treatment options 
for which they are eligible and whose disease previously progressed while on CPIs in a prior line 
of therapy. 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.
This trial specifically recruits patients who are refractory to or have developed resistance to 
anti-PD-1/anti-PD-L1 therapies. There is 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. Additionally, mouse models of TAK-676 combined with radiation demonstrate an 
added benefit from this combination. Thus, while it is unknown whether the addition of radiation 
therapy to the combination of anti-PD-1 antibody and TAK-676 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-676 and pembrolizumab following radiation therapy for patients in 
which CPI alone is not sufficient to drive or maintain a sustained clinical response.
4.5.1.1
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. 2019). The majority of NSCLC patients present 
with metastatic disease. Recently, immunotherapy with or without chemotherapy (depending on 
PD-L1 expression) has become the proven preferred first or second-line systemic therapy in 
patients without actionable tumor driver mutations (Borghaei et al. 2019; Gandhi et al. 2018; Reck 
et al. 2019). Similarly, radiation therapy plays an important role in the management of advanced 
NSCLC, whether in early or late-stage disease. Unfortunately, despite the overall success of ICB, 
the vast majority of patients eventually develop resistance to immunotherapy and have disease 
progression.
4.5.1.2
TNBC
TNBC represents up to 20% of all breast cancers and is defined by a lack of estrogen and 
progesterone receptor expression and the absence of human epidermal growth factor receptor 2 
overexpression and/or amplification (Foulkes et al. 2010). The lack of hormone expression 
precludes the use of endocrine therapy, the backbone of treatment in metastatic hormone 
receptor-positive breast cancer. Thus, chemotherapy is the traditional mainstay of treatment in 
metastatic TNBC, with short-lived responses and limited prognosis in this patient population (Li et 
al. 2017). There has thus been much excitement about the potential use of ICB in TNBC (Adams et 
al. 2019a). Initial studies have shown objective response rates, many with durability, with ICB 
monotherapy of up to 23% in first-line patients with PD-L1 positive tumors (Adams et al. 2019b). 
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Notably, the IMPASSION 130 phase 3 trial evaluated nab-paclitaxel +/- atezolizumab in 902 
previously untreated metastatic TNBC and showed improved progression-free survival (PFS) of 
7.2 months in the atezolizumab arm compared with 5.5 months in the placebo arm (p <0.002); 
median overall survival was 21.3 months in the atezolizumab arm versus 17.6 months with 
placebo (p = 0.08), and an even greater benefit was seen in the PD-L1-positive population (Schmid 
et al. 2018). Although this study initially received accelerated approval for first-line use in patients 
with metastatic TNBC and positive PD-L1 expression levels, this approval has since been 
withdrawn, further highlighting the challenges in treating this type of breast cancer. In contrast, 
recent results from the phase 3 Keynote-355 trial showed a significant increase in PFS (9.7 vs 5.6 
months; p = 0.0012) for patients with metastatic TNBC and a combined positive score ≥10 who 
were treated with pembrolizumab plus chemotherapy (nab-paclitaxel, paclitaxel, or 
carboplatin/gemcitabine) versus chemotherapy alone. On the basis of this study, pembrolizumab 
in combination with chemotherapy for the treatment of patients with locally recurrent unresectable 
or metastatic TNBC whose tumors express PD-L1 (CPS ≥10) has been granted accelerated 
approval. Currently, once a patient progresses on either atezolizumab plus nab-paclitaxel or 
pembrolizumab plus chemotherapy, they may have the option of being treated in a later line with 
the antibody drug conjugate, sacituzumab govitecan, but beyond this, the treatment options remain 
limited.
4.5.1.3
SCCHN
In 2020, an estimated 53,260 new cancers of the oral cavity and pharynx are expected to be 
diagnosed, and 10,750 people will die of the disease. Key risk factors for SCCHN are smoking, 
alcohol consumption, human papillomavirus, and Epstein-Barr virus. 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. Chemoradiation therapy plays a cornerstone role in the 
treatment of locally advanced SCCHN both in a first-line definitive or postoperative setting 
(National Comprehensive Cancer Network 2020; Quon et al. 2017; Sher et al. 2017). More 
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 second-line setting after progression on a 
platinum-containing agent. Although the role of pembrolizumab combined with radiation therapy 
is currently being studied (Yu and Lee 2019), there is an unmet clinical need for those patients who 
have progressive disease (PD) while on CPI and chemotherapy.
4.5.2
Rationale for Dose of Radiation Therapy
As noted in Section 4.2, multiple studies have evaluated the combination of radiation therapy and 
CPIs in metastatic solid malignancies. Dosing regimens in these studies have ranged from 20 to 60 
Gy given over 3 to 5 fractions. The ORRs seen in nonirradiated lesions (abscopal effect) in these 
studies is generally modest, with rates ranging from 8% to 45%. Only two of these studies included 
randomized controls (McBride et al. 2018; Theelen et al. 2019), and neither of these studies 
showed statistically significant differences in response rates between the CPI monotherapy and 
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combined CPI plus stereotactic radiation cohorts. Consequently, it is impossible to definitively 
state a radiation dose and schedule that is optimally immunogenic in this setting. Nonetheless, 
three of the most promising trials from Table 4.a utilized a common radiation therapy regimen 
with 24 Gy given over 3 equal fractions, either concomitantly with CPI (pembrolizumab (Sundahl 
et al. 2019b) or nivolumab (Sundahl et al. 2019a)) or preceding CPI (pembrolizumab (Theelen et 
al. 2019)). Two studies by Sundahl et al. evaluated the concomitant use of stereotactic body 
radiation therapy (SBRT) of 8 Gy × 3 with either pembrolizumab or nivolumab (RT given before 
the second cycle of CPI) in bladder cancer and melanoma, respectively (Sundahl et al. 2019a; 
Sundahl et al. 2019b). Although small, each of these trials showed an ORR in the nonirradiated 
lesions of approximately 45%. Additionally, the randomized phase 2 PEMBRO-RT trial noted 
above evaluated SBRT at 8 Gy × 3 followed by pembrolizumab in advanced NSCLC. While the 
results of this study did not reach statistical significance, there was an observed improvement in 
ORR in nonirradiated lesions (36% vs 18%, p = 0.07), median PFS (6.6 vs 1.9 months, p = 0.19), 
and mOS (15.9 vs 7.6 months, p = 0.16), suggesting the need for further exploration of this 
approach. These results, as well as the tolerable safety profile seen in these and other studies 
utilizing SBRT at 8 Gy × 3 doses (Table 4.b) (Maity et al. 2018; McBride et al. 2018; Voorwerk et 
al. 2019), support the use of this dosing schedule as a safe and adequately immunogenic regimen.
Additionally, recent preclinical data appear to favor fractionated radiotherapy (8 Gy × 3) over 
20 Gy × 1 due to the ability of the 8 Gy × 3 regimen to generate a level of cytosolic DNA which 
activates cGAS and STING, resulting in upregulation of the type I IFN pathway and consequent 
activation of antigen-presenting DCs in the tumor. In contrast, the 20 Gy × 1 regimen upregulates 
the exonuclease Trex1, leading to cytosolic DNA degradation and preventing the activation of 
cGAS and its downstream effects (Vanpouille-Box et al. 2017).
4.5.3
Rationale for Proposed Starting Dose of TAK-676
To appropriately balance the potential risk of developing acute adverse events (AEs) from immune 
stimulation in the cancer patient population and the potential for pharmacologic activity at the 
starting dose, the maximum recommended starting dose (MRSD) from the GLP-compliant 2-week 
repeat-dose monkey toxicity study (most sensitive species) and the minimum anticipated 
biological effect level (MABEL) were considered in selecting the starting dose of TAK-676. 
Please refer to the IB for additional details.
The dose of 0.2 mg TAK-676 corresponds to the MABEL. Furthermore, the dose of 0.06 mg/kg 
was considered both the HNSTD and NOAEL in the GLP-compliant 2-week toxicity study in 
cynomolgus monkeys. Using this dose, the estimated MRSD in humans was 0.19 mg. This 
estimation was based both on body surface area and AUC calculations and includes the 1/6th 
safety factor calculation per ICH S9 and is quasi-concordant with the MABEL-based dose 
calculation.
4.5.3.1
Dose Range
The proposed dose range for TAK-676 in the dose escalation phase of the study is 0.2 to 9.0 mg 
administered on Days 1, 8, and 15 of every 21-day cycle.
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The ongoing TAK-676-1002 first-in-human (FIH) study, where TAK-676 was administered by IV 
infusion once weekly alone or in combination with pembrolizumab, will provide initial clinical 
data on the safety and tolerability of TAK-676 + pembrolizumab. In the combination arm of the 
FIH study, TAK-676 is administered in a dose-escalating fashion (starting at 0.2 mg IV on Days 1, 
8, and 15 of a 21-day cycle) along with pembrolizumab at the fixed dose of 200 mg IV every 3 
weeks. Safety data was to be obtained from at least 2 dose cohorts of the FIH combination arm 
before administering TAK-676 with pembrolizumab following radiation therapy in this study. The 
dose escalation phase of the TAK-676-1002 FIH study is ongoing and no dose-limiting toxicities 
(DLTs) or preliminary safety/tolerability concerns were observed at the preplanned interim safety 
data review at 1.2 mg TAK-676 or through 0.8 mg TAK-676 in combination with pembrolizumab, 
confirming that it is safe to proceed with enrollment in this study at the proposed starting dose 
level. Dose escalation in the FIH study is ongoing at higher dose levels, and the highest proposed 
dose in this study will not exceed the highest dose level determined to be safe in the FIH study.
4.5.4
Rationale for Paired Biopsies and Blood Draws
Tumor and blood tissues will be collected to assess changes over time in the tumor and the innate 
and adaptive immune response following treatment with radiation, pembrolizumab, and TAK-676.
4.5.4.1
Tumor Biopsies
Tumor biopsies of nonirradiated tumors at baseline and on-treatment will be collected to determine 
modulation of the innate and adaptive immune response in the TME, including evaluation of T cell 
diversity. These samples may also be evaluated for tumor mutational burden and to determine 
treatment effects in cancer cells and immune cells.
Induction of an innate and/or adaptive immune response in the tumor will be assessed by 
measuring levels of mRNA and protein using RNA sequencing and slide-based assays for 
evaluation of levels of tumor infiltrating lymphocytes and activation states of innate and adaptive 
immune cell subsets. Additional analyses related to resistance, response or disease 
characterization may be done on collected biopsies.
To minimize the risk of performing invasive procedures on patients at TAK-676 dose levels with 
no measurable pharmacodynamic activity, paired biopsies of nonirradiated tumors will be required 
only for patients on dose levels of TAK-676 that have demonstrated evidence of 
pharmacodynamic activity in peripheral blood (refer Section 9.4.15.1). Additionally, once the 
tumor biopsies are mandated, safely accessible paired biopsies will be collected from all patients 
during dose escalation and additional patients are expected to be added if an expansion phase is 
supported, to achieve a greater than 0.8 predicted posterior probability of increased immune 
infiltration within the tumor (refer to Appendix K). However, paired biopsies are highly desired 
and strongly encouraged in all patients, regardless of dose level, if the lesions are deemed safely 
accessible. The specific anatomical location of the biopsy before resection must be specified.
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4.5.4.2
Blood
Blood samples will be collected to demonstrate STING pathway activation and activation of an 
innate and/or adaptive immune response. This will be assessed by measuring levels of select 
plasma chemokines and cytokines (eg, IP-10), detection of a STING agonism/type I IFN gene 
signature, changes in the number, percentage, or activation state of immune cell subsets in the 
blood, and changes in T cell clonality.
4.5.5
Rationale for PK Assessments
Serial plasma PK of TAK-676 will be assessed. The PK data collected on these occasions will 
coincide with pharmacodynamic assessments. PK data in conjunction with pharmacodynamic data 
can help in the understanding of the PK-pharmacodynamic relationship of TAK-676. Such data 
may also be useful in building mathematical models to describe the PK-pharmacodynamic and/or 
PK-safety/efficacy relationship of TAK-676 that can eventually be used to predict the time course 
of PK and pharmacodynamic effects of TAK-676. This information may also help provide context 
for safety findings from the study and can be helpful in selecting the recommended phase 2 dose 
(RP2D) and schedule for TAK-676.
4.6
Potential Risks and Benefits
The potential effects listed below are based on publicly available data on the effects of radiation as 
well as other clinical studies that have evaluated radiation in combination with pembrolizumab. 
The potential risks associated with TAK-676 administration are reviewed below and in further 
detail in the IB. 
4.6.1
Potential Risks and Effects of Radiation in Combination with Pembrolizumab
Multiple clinical studies have reported on the safety of the combination of radiation therapy and 
pembrolizumab (Table 4.b). Overall, the combination was found to be safe with AEs similar to 
those commonly associated with pembrolizumab. Most of the observed AEs were of Grade 1 and 
2, including dermatitis reported in 29% of patients in 1 study. AEs of Grade 3 in severity were 
reported infrequently, including fatigue, lymphopenia, infection, pneumonitis, infusion-related 
reaction and weight loss. Rare Grade 4 AEs were observed, including Grade 4 adrenal 
insufficiency in 1 study.
An increased rate of radiation necrosis in patients with brain metastases from melanoma who 
received stereotactic radiosurgery (SRS) and CPI was reported. No reports of radiation necrosis 
were noted in patients with NSCLC, TNBC, or SCCHN receiving radiation therapy in 
combination with pembrolizumab or other CPIs. In 1 study evaluating pembrolizumab and 
multisite stereotactic body radiotherapy in 79 patients with advanced solid tumors, toxicity was 
generally low; however, when toxicity was observed, it appeared to be in the region that was 
irradiated, which made it difficult to distinguish between toxicity of combination therapy versus 
radiation alone (Luke et al. 2018). A retrospective review of 133 patients treated with palliative 
radiotherapy and anti–PD-1 showed a 4% Grade 3 or higher immune-related AE rate, and toxicity 
was not related to anatomic location of RT (Bang et al. 2017). Additional potential AEs related to 
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radiation therapy include pain, inflammation, skin ulceration and/or tissue necrosis in the radiation 
field, and/or localized or systemic infection.
Available data (Table 4.b) indicates that the combination of radiation therapy with various 
immune CPIs is generally well tolerated.
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Table 4.b
Trials Showing Safety and Tolerability of Radiation Therapy in Combination With CPI 
Phase of Trial
Treatment 
Patient Population
Number of 
Patients
CPI Dose and 
Radiation 
Fractionation
Safety
Reference
Phase 1
Pembrolizumab + 
SBRT
Metastatic solid 
tumors
24
Pembrolizumab: 6 w 
before RT
RT: 8 Gy × 3 fractions 
or 17 Gy × 1 fraction
Two irAEs (hypothyroidism and 
pneumonitis) occurred post radiation 
to a lung metastasis in the same 
patient who achieved a CR
(Maity et al. 
2018)
Phase 2
Pembrolizumab vs 
SBRT + 
Pembrolizumab
Metastatic NSCLC
74
RT: 8 Gy × 3 fractions
No Grade 3 or higher toxicities 
related to the addition of SBRT
(Theelen et al. 
2018)
Phase 2
Pembrolizumab + 
RT
Metastatic TNBC
17
Pembrolizumab: 
200 mg 1-3 d after first 
RT fraction, and then 
every 3 weeks until 
disease progression
RT: Total 3000 cGy 
(600 cGy × 5 fractions) 
over 5-7 days
Most common Grade 1 to 2 toxicity: 
dermatitis (29%); Grade 3 
pembrolizumab-related AEs (n = 4): 
fatigue, lymphopenia, and infection
(Ho et al. 2020)
Phase 1
Pembrolizumab + 
RT
Locoregionally 
advanced head and 
neck cancer
8
Pembrolizumab: 200 
mg at Weeks -2, 1, 4, 
and 7 with RT
RT: 70 Gy in 35 daily 
fractions, Weeks 1-7
Grade 4 adrenal insufficiency 
definitely related to pembrolizumab 
(n = 1); Grade 3 infusion-related 
reaction (n = 1); Grade 3 weight loss 
(n = 1)
(Sacco et al. 
2019)
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Table 4.b
Trials Showing Safety and Tolerability of Radiation Therapy in Combination With CPI 
Phase of Trial
Treatment 
Patient Population
Number of 
Patients
CPI Dose and 
Radiation 
Fractionation
Safety
Reference
Phase 1/2
Pembrolizumab 
with and without 
RT
Metastatic NSCLC
124
Pembrolizumab: 
200 mg IV on Day 1 and 
given every 3 w for up 
to 16 cycles
SBRT: 50 Gy in 4 
fractions or 70 Gy in 10 
fractions or traditional 
fractionation: 45 Gy in 
15 fractions
Combined-modality arm: Grade 4 
(n = 2) and Grade 3 (n = 9) 
treatment-related toxicities; 
pembrolizumab arm: no Grade 4 
toxicities and Grade 3 toxicities 
(n = 5)
(Welsh et al. 
2019)
Retrospective 
study to review 
risk of RN
Stereotactic 
radiosurgery and 
CPI (ipilimumab, 
pembrolizumab, or 
both)
Metastatic 
melanoma with 
brain metastases
137
-
Rate of RN in patients with 
metastatic melanoma treated with 
SRS and immunotherapy with either 
CTLA-4 inhibitor, PD-1 inhibitor, or 
both is 27% with a median time to 
RN of 6 months
(Fang et al. 
2017)
Retrospective 
study
Stereotactic 
radiosurgery and 
CPI
Brain metastases 
from melanoma
480
-
Patients who received SRS and CPI 
had higher rates of symptomatic RN 
than those who received SRS alone
(Martin et al. 
2018)
cGy: centigray; CPI: checkpoint inhibitor; CR: complete response; CTLA-4: cytotoxic T lymphocyte–associated antigen-4; Gy: gray; IV: intravenous(ly); NSCLC: 
non-small-cell lung cancer; PD-1: programmed cell death protein 1; RN: radiation necrosis; RT: radiation therapy; SBRT: stereotactic body radiation therapy; SRS: 
stereotactic radiosurgery; TNBC: triple-negative breast cancer.
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Coagulopathy
Nonadverse 
 were 
noted in the GLP repeat dose rat toxicity study and suggest that a coagulopathy could occur in 
patients treated with TAK-676.
To minimize the risk of coagulopathy, patients treated with TAK-676 will have their coagulation 
function monitored according to the study evaluation schedule and on an ad hoc basis as needed.
4.6.3
Potential Risks and Effects Seen With Other STING Agonists
Additional risks have been reported with other STING agonists and are described below. Although 
these risks were not observed in TAK-676 animal studies, they should be carefully monitored.

There were no relevant findings from nonclinical toxicology studies indicating a potential for 
skin-related toxicities. Skin rashes are commonly associated with activation of type I IFN. 
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.

No cardiovascular liabilities were identified for TAK-676 based on in vitro results from a 
hERG or human stem cell–cardiomyocyte calcium transient proarrhythmia assay. In addition, 
there were no changes in qualitative ECG parameters or heart rate in evaluated monkeys 
following repeated administration of TAK-676 at doses up to 0.13 mg/kg. However, literature 
data indicate that CDNs can impact hyperpolarization-activated cyclic nucleotide-modulated 
channels that regulate the rhythmic firing of neurons and cardiac myocytes; thus, potentially 
affecting cardiac repolarization (Lolicato et al. 2014).
4.6.4
Potential Risks and Effects of TAK-676 in Combination With Pembrolizumab
Nonclinical toxicology studies evaluating the combination of TAK-676 and pembrolizumab were 
not conducted and are 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. 
TAK-676 at 0.25, 0.5, or 1 mg/kg was administered to tumor-bearing mice Q3D (Days 2, 5, and 9) 
alone or in combination with 10 mg/kg anti-mouse PD-1 antibody (Q3D×3 followed by QW×3). 
Compared with treatment with TAK-676 alone, synergistic toxicity, as assessed by increased 
mortality or more significant decreases in body weight was not observed in mouse tumor-bearing 
models administered TAK-676 in combination with an anti-mouse PD-1 antibody. TAK-676 and 
pembrolizumab both activate the immune system, so known PD-1 immunotherapy-related 
toxicities (such as pneumonitis, colitis, hepatitis, dermatitis, infusion-related reactions, 
endocrinopathies, and nephritis) observed following the administration of pembrolizumab may be 
enhanced when combined with TAK-676. Details regarding the full safety profile of 
pembrolizumab can be found in the most recent prescribing information.
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4.6.5
Potential Risks and Effects of TAK-676 in Combination With Radiation and 
Pembrolizumab
Radiation-related AEs (including inflammatory reactions, infections and abscess within the 
radiation field) may occur or be enhanced when radiation is combined with TAK-676 and 
pembrolizumab.
Nonclinical toxicology studies evaluating the combination of TAK-676 and radiation were not 
conducted and are not warranted per ICH S9 .
Nonclinical Pharmacology Studies of Antitumor Activity of TAK-676 in Combination With 
Radiation in Syngeneic Mouse Models:
Tolerability, as assessed by enhanced mortality and BWL, was monitored in pharmacology studies 
in tumor-bearing mouse models where focal radiation was administered in combination with 
TAK-676, with or without an anti-PD-1 antibody. A regimen of 10 Gy × 1 radiation was delivered 
with the RS 2000 Small Animal Irradiator using a lead box to provide shielding, with a small hole 
to provide access to the tumor. A regimen of 8 Gy × 3 radiation was delivered with the SARRP 
(Small Animal Radiation Research Platform) with 3D volumetric image guidance for target 
localization and dose delivery, which minimizes exposure to nontargeted tissues and organs and 
allows higher total doses of radiation to be delivered to the tumor.

Tolerability of TAK-676 at 1 mg/kg in combination with a single fraction of 10 Gy was 
assessed in 2 pharmacology studies in the EMT6 mouse breast cancer model and in 1 study in 
the A20 mouse lymphoma model.
–
In 1 study, TAK-676 at 1 mg/kg was administered to EMT6 tumor-bearing mice on a 
Q3D×3 schedule (Days 2, 5, and 8) alone or in combination with 10 Gy radiation on 1 of 5 
different days (Day 0, 1, 2, 3, or 4). A radiation alone arm, where 10 Gy radiation was 
given once on Day 2 was also included. All groups contained 10 mice each. Transient 
BWL was observed in all groups. Maximum mean BWL in single agent groups was 4.1% 
and 2.3% for TAK-676 and radiation respectively, while maximum mean BWL in the 
5 combination groups ranged from 7.0% to 10.1%. BWL resulted in the removal of 2 of 
50 mice receiving TAK-676 in combination with 10 Gy radiation. These mice, which 
received TAK-676 + 10 Gy radiation on Day 4, were removed from the study on Days 11 
and 33.
–
In another study, TAK-676 at 1 mg/kg was administered to EMT6 tumor-bearing mice 
Q3D×3 (Days 2, 5, and 8) alone or in combination with 10 Gy radiation on 1 of 3 different 
days (Day 0, 2, or 4). Radiation alone arms, where 10 Gy radiation was given once on Day 
0, 2, or 4 were also included. All groups contained 10 mice each. Transient BWL was 
observed in all treatment groups but was considered tolerable as mean BWL was <11% in 
all groups and no mice met criteria for removal from study due to BWL. Maximum mean 
BWL in single agent groups was 1.7% and 0.9% to 5.2% for TAK-676 and radiation 
groups respectively, while maximum mean BWL in the 3 combination groups ranged from 
9.4% to 11%.
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–
In the A20 mouse lymphoma model, TAK-676 at 1 mg/kg was administered to mice 
Q3D×3 (Days 2, 5, and 8) alone or in combination with 10 Gy radiation on 1 of 3 different 
days (Day 0, 2, or 4). Radiation alone arms, where 10 Gy radiation was given once on Day 
0, 2, or 4 were also included. Transient BWL was observed in all groups which received 
TAK-676 or radiation as single agents or in combination. Maximum mean BWL in single 
agent groups was 4.9%, 8%, 9.7%, and 9.3% for TAK-676, Day 0 radiation, Day 2 
radiation, and Day 4 radiation respectively. BWL in these single-agent groups resulted in 
the removal of 1 mouse (of 10) on Day 11 that received 10 Gy radiation on Day 4. In 
combination groups, BWL was additive, resulting in a maximum mean BWL of 14.3%, 
13.6%, and 15.6% for TAK-676 + radiation on Day 0, 2, or 4, respectively. In combination 
groups, BWL resulted in the early removal of 5 of 10 mice (on Days 4 and 7) with 
TAK-676 + 10 Gy radiation administered on Day 0, 1 of 10 mice (on Day 9) with TAK-676 
+ 10 Gy radiation administered on Day 2, and 3 of 10 mice (on Days 7 and 9) with 
TAK-676 + 10 Gy radiation administered on Day 4.

Tolerability of TAK-676 in combination with 8 Gy × 3 with or without anti-PD-1 antibody 
treatment was assessed in a study in EMT6 tumor-bearing mice. In this study, radiation was 
administered once daily for 3 consecutive days, followed 48 hours later by TAK-676 dosed at 
0.25 or 1 mg/kg on a Q3D×3 schedule, along with an anti-PD-1 antibody dosed Q3D×3 on the 
same days as TAK-676. The regimen of 8 Gy × 3 followed 48 hours later by TAK-676 at 1 
mg/kg was also evaluated with an isotype control antibody instead of an anti-PD-1 antibody. 
For comparison, the study included groups to test single agent effects of 8 Gy × 3 radiation, 
anti-PD-1 antibody, and TAK-676 at 0.25 mg/kg and 1 mg/kg, and a group which received 
8 Gy × 3 radiation followed by anti-PD-1 antibody. All groups contained 8 mice each. 
Transient BWL was observed in all treatment groups. Maximum mean BWL in single-agent 
groups was 3.7%, 1.6%, 7.8%, and 0.2% for radiation, 0.25 mg/kg TAK-676, 1 mg/kg 
TAK-676, and anti-PD-1 groups, respectively. Maximum mean BWL in the group which 
received radiation and anti-PD-1 was 3.8%. In the groups that received 8 Gy × 3 followed by 
TAK-676 at 1 mg/kg, with anti-PD-1 or isotype control, the maximum mean BWL was 9.0% 
and 9.9%, respectively. Maximum mean BWL of the group receiving 8 Gy × 3 with 
0.25 mg/kg TAK-676 and anti-PD-1 was 1.8%. The combination was considered tolerable as 
no mice were removed for BWL during the study.
Taken together, these results indicate that in EMT6 tumor-bearing mice, TAK-676 at 1 mg/kg was 
well tolerated in combination with 8 Gy × 3 radiation delivered through an advanced image-guided 
system to minimize normal tissue radiation exposure. BWL was <10% and no treatment-related 
mortality was observed. The addition of an anti-PD-1 antibody to this regimen did not result in 
additional BWL or mortality. In EMT6 mice, TAK-676 at 1 mg/kg was also generally well 
tolerated in combination with 10 Gy × 1 radiation delivered without image guidance, with 7% to 
11% maximal mean BWL in 8 combination groups (n = 80 mice total), with the exception of the 
removal of 2 mice due to BWL. In contrast, A20 tumor-bearing mice treated with TAK-676 at 1 
mg/kg and 10 Gy × 1 radiation did not tolerate the regimen, experiencing more BWL than seen in 
the EMT6 breast cancer model and removal of 9/30 mice during the study. This is likely due to the 
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greater sensitivity of A20 lymphoma tumor-bearing mice to radiation as a single agent and the 
additive effect of TAK-676 on BWL.
5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective
The primary objective is:

To determine the safety and tolerability of TAK-676 administered in combination with 
pembrolizumab following radiation therapy in patients with locally advanced or metastatic 
NSCLC, TNBC, or SCCHN.
5.1.2
Secondary Objectives
The secondary objectives are:

To determine the RP2D of TAK-676 administered in combination with pembrolizumab 
following radiation therapy. RP2D can be equal to or lower than the MTD.

To assess the preliminary antitumor activity of TAK-676 administered in combination with 
pembrolizumab following radiation therapy, both locally (in the radiation field) and 
systemically (nonirradiated lesions).

To evaluate the dose-responsive impact on T-cell infiltration in nonirradiated tumors following 
TAK-676 administered in combination with pembrolizumab following radiation therapy.
5.1.3
Exploratory Objectives 
The exploratory objectives are:

To determine whether TAK-676 administered in combination with pembrolizumab following 
radiation therapy results in changes in peripheral blood consistent with activation of the innate 
and/or adaptive immune response.

To characterize mutations or polymorphisms associated with response or resistance to the 
combination of TAK-676 and pembrolizumab following radiation therapy, for example, 
polymorphisms in the STING gene (TMEM173) and drug transporter genes relevant to 
TAK-676, and in immune response or DNA damage repair genes.

To characterize plasma concentration of TAK-676 and explore exposure-response 
relationship.
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5.2
Endpoints
5.2.1
Primary Endpoints
The primary endpoints are:

Frequency and severity of treatment-emergent adverse events (TEAEs).

Number of patients with DLTs.

Number/percentage of patients with 1 or more treatment-emergent serious adverse event 
(TESAE).

Number/percentage of patients with 1 or more TEAE leading to dose modifications and 
treatment discontinuation.
Safety endpoints will be evaluated according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0.
5.2.2
Secondary Endpoints
The secondary endpoints are:
Response assessments are to be made by the investigator per Response Evaluation Criteria in Solid 
Tumors (RECIST) v.1.1 (Eisenhauer et al. 2009) and also per a modified intratumoral 
immunotherapy Response Evaluation Criteria in Solid Tumors (itRECIST) (where intratumoral
therapy references are largely replaced with radiation therapy). To allow for instances of 
pseudoprogression, allowances will be made for patients to continue on treatment after an initial 
assessment of PD, assuming subsequent imaging does not confirm PD. See section 9.4.14.1 for 
details regarding this allowance. 
Response assessments are per RECIST v 1.1 by investigator

ORR: confirmed complete response (cCR) + confirmed partial response (cPR).

Duration of response (DOR) for all tumor lesions assessed by RECIST v.1.1

Time to response (TTR) for all tumor lesions assessed by RECIST v.1.1
Response assessments are per modified itRECIST by investigator

Overall response rate (ORR): cCR + cPR.

Overall response rate for tumors lying within the radiation field (ORRirradiated): confirmed 
complete response [cCRirradiated] + confirmed partial response [cPRirradiated] of tumor 
lesions lying within the radiation field.

Overall response rate for tumors lying outside the radiation field (ORRnonirradiated): 
confirmed complete response [cCRnonirradiated] + confirmed partial response 
[cPRnonirradiated] of tumor lesions lying outside of the radiation field.
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
DOR for tumors lying within the radiation field (DORirradiated), and for those lying outside of 
the radiation field (DORnonirradiated).

TTR for tumors lying within the radiation field (TTRirradiated), and for those lying outside of 
the radiation field (TTRnonirradiated).
The following endpoint will be assessed to evaluate T-cell infiltration into the tumor between 
pretreatment and on-treatment biopsies:

Cell infiltration evaluated by immunohistochemistry.
5.2.3
Exploratory Endpoints
The exploratory endpoints are:

Changes in levels of plasma biomarkers, including cytokines and chemokines.

Changes between pretreatment and on-treatment peripheral blood samples in gene expression, 
including the STING agonism/type I IFN signature.

Plasma concentrations of TAK-676.

Relationship between response and polymorphisms in the STING gene (TMEM173) or drug 
transporter genes relevant to TAK-676.

Relationship between response and mutations or polymorphisms in immune response or DNA 
damage repair genes.
6.0
STUDY DESIGN
6.1
Overview of Study Design 
This is an open-label, 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 NSCLC, TNBC, or SCCHN patients who have progressed on CPIs. The information 
obtained during this study will be used to estimate the MTD and determine the RP2D of this 
combination.
The study design is depicted in Figure 6.a.
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Figure 6.a
Study Design
Approximately 65 patients with metastatic NSCLC, TNBC, or SCCHN will be enrolled in this 
study to achieve a maximum of 55 DLT evaluable patients in TAK-676 dose escalating cohorts. 
They will receive 8 Gy × 3 radiation therapy, followed by IV administration of pembrolizumab 
and TAK-676. Pembrolizumab will be administered at 200 mg IV every 3 weeks, with a minimum 
for 40 hours between the last radiation therapy fraction and the initiation of IV pembrolizumab + 
TAK-676. Three patients will be enrolled in the initial cohort at the previously identified starting 
dose level of TAK-676. Subsequent cohorts may enroll 2 to 3 patients per the 
escalation/de-escalation guidelines outlined in Table 6.a. It is generally expected that at least 3 
patients will enroll per cohort. However, if no DLTs have been identified in the TAK-676 + 
pembrolizumab dose level that has already been evaluated in the dose-finding phase 1 
TAK-676-1002 study, the sponsor, in agreement with the TAK-676-1003 investigators, may opt to 
enroll a 2-patient cohort at that same [radiation] + TAK-676 + pembrolizumab dose level being 
evaluated in the TAK-676-1003 study. Administration of pembrolizumab will continue every 3 
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weeks 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. TAK-676 will be administered 
in a dose-escalating fashion following the Bayesian Optimal INterval (BOIN) design (Liu and 
Yuan 2015), with an explorable dose range of 0.2 to 9.0 mg administered on Days 1, 8, and 15 of 
every 21-day cycle.
Patients will receive TAK-676 with pembrolizumab at dose levels that were previously deemed 
safe in the dose-finding phase 1 study TAK-676-1002.
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 drugs in 
combination with radiation. Toxicity will be evaluated according to NCI CTCAE, Version 5.0. 
DLTs are defined in Section 8.2. A DLT will be defined as any of the treatment-emergent AEs 
(TEAEs) described in the safety evaluation section that occur during Cycle 1 and are considered by 
the investigator to be at least possibly related to TAK-676 in combination with pembrolizumab 
and radiation. TEAEs meeting DLT definitions occurring in later cycles will be considered in the 
determination of RP2D of TAK-676.
Radiological evaluations (CT scan and/or magnetic resonance imaging [MRI] as clinically 
indicated) will be employed to assess the status of the patient’s underlying disease. Before
radiation therapy, the radiology oncologist and medical oncologist should agree on the target 
lesions identified for irradiation using the baseline imaging assessments. Banked formalin fixed 
paraffin-embedded 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 gene 
mutations, gene signatures, tumor mutation burden, immune cell content, or biomarkers of 
response or resistance to treatment that may emerge from future nonclinical or clinical studies. All 
patients with a safely accessible lesion outside the radiation field and in whom a fresh tumor 
biopsy enrolling at dose levels of TAK-676 which have been shown to have pharmacodynamic 
activity will have mandatory tumor biopsy performed as per Schedule of Events (SOE) 
(Appendix A).
Serial blood samples will be collected for circulating biomarkers (peripheral proteins, cytokines, 
and chemokines, including IP-10, an IFN-inducible chemokine), immunophenotyping, mRNA 
expression, receptor sequencing, and cell-free DNA. An evaluation of disease response will be 
performed using the RECIST v.1.1 (as determined by the investigator) and as per SOE 
(Appendix A). Serial blood samples for determination of the plasma concentration of TAK-676 
and related metabolites to understand TAK-676 metabolism and excretion mechanisms will be 
obtained at prespecified time points as described in the SOE (Appendix A).
6.1.1
Dose Escalation of TAK-676
Dose escalation of TAK-676 will follow BOIN design to inform dose escalation decisions and 
potential MTD estimation (Appendix E). Three patients will be enrolled in the initial cohort at the 
previously identified starting dose level of TAK-676. Subsequent cohorts will enroll 2 to 3 patients 
per the escalation/de-escalation guidelines outlined in Table 6.a. The target toxicity rate is ϕ = 0.3. 
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It is generally expected that at least 3 patients will enroll per cohort. However, if no DLTs have 
been identified in the TAK-676 + pembrolizumab dose level that has already been evaluated in the 
dose-finding phase 1 TAK-676-1002 study, the sponsor, in agreement with the TAK-676-1003 
investigators, may opt to enroll a 2-patient cohort at that same [radiation] + TAK-676 + 
pembrolizumab dose level being evaluated in the TAK-676-1003 study. 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 dose level; if it is ≥0.358, the next cohort of patients will be treated at the
next lower dose level; if it is within 0.236 and 0.358, additional patients will be enrolled in this 
dose level. 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 dose level j. When 
the lowest dose is eliminated, dose escalation will be stopped for safety. The trial design is 
illustrated in Table 6.a. Dose escalation will continue until the maximum sample size (55 
DLT-evaluable patients) is reached or the number of DLT-evaluable patients treated at the current 
dose reaches 9. Isotonic regression method will be used on the cumulative DLT rate for each dose 
level to determine the MTD, defined as the highest TAK-676 dose in combination with radiation 
therapy and pembrolizumab that does not result in unacceptable toxicities.
Table 6.a
Dose Escalation/De-escalation Rule for the BOIN Design for 55 
DLT-Evaluable Patients
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 DLTs is the number of patients with at least 1 DLT.
Patients not receiving all required doses of radiation, TAK-676, and pembrolizumab through 
Cycle 1 for reasons other than DLTs will not be considered DLT evaluable but may remain on 
study. If a patient is DLT inevaluable, patient replacement may not be mandatory except for the 
first cohort. In this case, the decision for patient replacement can be determined based on the 
number of DLT-evaluable patients in the cohort, as agreed between the sponsor and investigators.
Other dose escalation decisions, evaluation of intermediate doses, expansion of an existing dose 
level, and stopping the dose escalation early are all permissible following discussions between the 
sponsor and the investigators, if such measures are needed for patient safety, or for a better 
understanding of the dose-related toxicity, exposure, and/or pharmacodynamics. Other non-DLT 
safety and available clinical, PK, or biomarker data will also be considered to inform subsequent 
dose recommendations, dose escalation decisions, and potential MTD estimation.
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6.2
Number of Patients
Approximately 65 patients with metastatic NSCLC, TNBC, or SCCHN will be enrolled in this 
study, to achieve a maximum of 55 DLT evaluable patients for the dose escalation of TAK-676 
administered along with pembrolizumab following radiation therapy. 
6.3
Duration of Study
6.3.1
Duration of an Individual Patient’s Study Participation
Patient participation will include screening, treatment, and follow-up. Screening will last up to 28 
days before the first dose of radiation, during which the patient’s eligibility and baseline 
characteristics will be determined. Treatment with TAK-676 with pembrolizumab will be 
administered for up to 24 months or until patients meet any of the discontinuation criteria in 
Section 8.4.5, Section 8.4.6, or Section 9.7. Patients with demonstrated clinical benefit may 
continue treatment beyond 24 months with the agreement of the sponsor. These patients can 
continue receiving treatment in this study or any of the poststudy access modalities described in 
Section 6.3.5.
All patients will attend an end of treatment (EOT) visit 30 days (+10 days) after receiving their last 
dose of study drug or before the start of subsequent systemic anticancer therapy, whichever occurs 
first, to permit detection of any delayed TEAEs and 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 following discussion with the sponsor. Patients with unresolved TEAEs 
will continue the periodic safety follow-up until complete resolution or stabilization (established 
as sequelae) occurs. Patients who receive at least 1 dose of radiation and discontinue study 
treatment for reasons other than PD will continue follow-up every 12 ±1 weeks from the EOT visit 
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 (Section 9.8).
6.3.2
End of Study/Study Completion Definition and Planned Reporting
The anticipated duration of this study will be approximately 30 months (from first patient first visit 
to last patient last visit). The final data cutoff for the CSR will be conducted after all patients have 
been discontinued from treatment or transferred to a long-term safety study or a similar program 
(Section 6.3.5).
Patients previously discontinued from study treatment will undergo the EOT visit but will continue 
to be followed every 12 ±1 weeks from the EOT visit as described in Section 9.8.
6.3.3
Timeframes for Primary and Secondary Endpoints to Support Disclosures
Refer to Table 6.b for disclosures information for all primary and secondary endpoints.
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Table 6.b
Primary and Secondary Endpoints for Disclosures
Endpoint
Definition
Maximum Time Frame a
Primary: 
Frequency and severity of TEAEs
Standard safety assessments
Up to ~30 months
Number of patients with DLTs
Standard safety assessments
Up to ~30 months
Number/percentage of patients with 1 or more 
treatment-emergent SAE
Standard safety assessments
Up to ~30 months
Number/percentage of patients with 1 or more 
TEAE leading to dose modifications and 
treatment discontinuations
Standard safety assessments
Up to ~30 months
Secondary b:
ORR 
ORR 
Up to ~30 months
ORRnonirradiated
ORRnonirradiated
Up to ~30 months
ORRirradiated
ORRirradiated
Up to ~30 months
DOR
DOR
Up to ~30 months
DORnonirradiated
DORnonirradiated
Up to ~30 months
DORirradiated
DORirradiated
Up to ~30 months
TTR
TTR
Up to ~30 months
TTRnonirradiated
TTRnonirradiated
Up to ~30 months
TTRirradiated
TTRirradiated
Up to ~30 months
T-Cell infiltration into the tumor between 
pretreatment and on-treatment biopsies
Standard pharmacodynamic 
assessment
Up to ~30 months
DLT: dose-limiting toxicity; DOR: duration of response; itRECIST: modified intratumoral immunotherapy Response 
Evaluation Criteria in Solid Tumors; RECIST: Response Evaluation Criteria in Solid Tumor; ORR: overall response 
rate; ORRirradiated: overall response rate for tumors lying within the radiation field; ORRnonirradiated: overall 
response rate for tumors lying outside of the radiation field; SAE: serious adverse event; TEAE: treatment-emergent 
adverse event; TTR: time to response; TTRirradiated: time to response for tumors lying within the radiation field; 
TTRnonirradiated: time to response for tumors lying outside of the radiation field.
a Maximum time frame to last assessment for that endpoint for the study.
b Assessments are per RECIST v.1.1 and itRECIST.
6.3.4
Total Study Duration
It is anticipated duration of this study will be approximately 30 months (from first patient first visit 
to last patient last visit).
6.3.5
Post-trial Access
Patients who are still on study after the estimated study completion time of approximately 
30 months will be allowed to continue pembrolizumab with or without TAK-676 in an extension 
phase of this study, in a separate open-label rollover study, or through a single-patient 
Investigational New Drug application or equivalent. Patients who discontinue TAK-676 for 
reasons other than disease progression will continue to receive pembrolizumab as long as clinical 
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benefit is documented. 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 the combination 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. If pembrolizumab is commercially available and reimbursable for a given indication, 
pembrolizumab can be reimbursed by Takeda (if Takeda reimbursed the site while the patient was 
on study) for up to 12 months after study completion, at which time it should then be sourced 
commercially for continued administration with or without TAK-676 if the patient is still 
benefiting. If there are any issues in obtaining authorization for use of pembrolizumab, these 
should be discussed with Takeda and handled on a case by case basis. If pembrolizumab is not 
commercially available and reimbursable in a given indication, it will continue to be reimbursed 
by Takeda for continued administration with or without TAK-676 until any of the conditions in 
Section 6.3.5.1 are met.
6.3.5.1
Duration of Post-trial Access
Continued access to pembrolizumab with or without TAK-676 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, if pembrolizumab 
with or without TAK-676 becomes available either commercially (see preceding paragraph) or via 
another access mechanism, or when an alternative appropriate therapy becomes available. 
Poststudy access may be terminated in a country or geographical region where marketing 
authorization has been rejected, the development of TAK-676 has been suspended or stopped by 
the sponsor, or TAK-676 in combination with pembrolizumab can no longer be supplied.
7.0
STUDY POPULATION
7.1
Inclusion Criteria
Each patient must meet all the following inclusion criteria to be enrolled in the study:
1. Adult male or female patients, aged 18 years or older.
2. 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.
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
4. Patients must have at least 2 measurable lesions (ie >10 mm longest diameter for extranodal 
lesions, >15 mm short axis for lymph nodes), with at least one inside and at least one other 
outside of the radiation field. The tumor outside the radiation field must be accessible for 
biopsy, and the patient must consent to tumor biopsy at screening and during treatment as 
described in the SOE (Appendix A).
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5. Patients with pathologically confirmed (cytological diagnosis is adequate) advanced or 
metastatic NSCLC, TNBC, or SCCHN who have:
a) Received or been offered all established SOC treatment options for which they are eligible; 
and
b) Progressed on CPIs in a prior line of therapy.
6. Not Applicable. In Protocol Amendment 2, requirement of patient having life expectancy >12 
weeks has been removed.
7. Adequate bone marrow, renal, and hepatic functions, as determined by the following 
laboratory parameters:
a) Absolute neutrophil count (ANC) ≥1000/µL, platelet count ≥75,000/µL, and hemoglobin 
≥8.0 g/dL without growth factor support for neutrophils or transfusion support for platelets 
within 14 days before the first study treatment dose.
b) Total bilirubin ≤1.5 times the institutional ULN. For patients with Gilbert’s disease, 
≤3 mg/dL.
c) Serum ALT and AST ≤3.0 times the ULN (or ≤5.0 times the ULN with presence of liver 
metastases).
d) Albumin ≥3.0 g/dL.
e) Estimated creatinine clearance using the Cockcroft-Gault formula ≥30 mL/min.
8. Left ventricular ejection fraction (LVEF) >50%, as measured by echocardiogram or 
multiple-gated acquisition (MUGA) 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, Version 5.0) or baseline, except for alopecia, Grade 2 peripheral neuropathy, and/or 
autoimmune endocrinopathies with stable endocrine replacement therapy.
10. Female patients must be:
a) Postmenopausal (natural amenorrhea and not due to other medical reasons) for at least 
1 year before the screening visit, OR
b) Surgically sterile, OR
c) If they are of childbearing potential, agreeable to practicing 2 effective methods of 
contraception at the same time, from the time of signing the informed consent through 120 
days after the last dose of study drug(s), OR
d) Agreeable 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.
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11. Male patients, even if surgically sterilized (ie, status postvasectomy), must:
a) Agree to practice effective barrier contraception during the entire study treatment period 
and through 120 days after the last dose of study drug, OR
b) Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle 
of the patient.
Note: Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods), 
withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of 
contraception.
7.2
Exclusion Criteria
Patients having 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 (Appendix G), 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. History of brain metastasis unless:
a) Clinically stable, (ie, treatment completed ≥4 weeks prior) following prior surgery, 
whole-brain radiation, or stereotactic radiosurgery, AND
b) Off corticosteroids.
3. Known history of uncontrolled autoimmune disorders, HIV infection, or other relevant 
congenital or acquired immunodeficiencies.
4. 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.
5. Contraindication and/or history of intolerance to the administration of CPI.
6. Contraindication and/or history of intolerance to the radiation therapy.
7. Any 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.
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8. Treatment with any investigational products and systemic anticancer drugs (including vascular 
endothelial growth factor inhibitors), within 14 days or 5 half-lives, whichever is shorter, 
before Cycle 1 Day 1 (C1D1) of study drug(s).
9. Concurrent chemotherapy, immunotherapy (except for pembrolizumab), 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 (eg, corticosteroid 
replacement use is outlined in Section 8.5).
10. Prior radiation to lesions chosen for biopsy or response assessment.
11. Prior radiation to lesions other than those chosen for radiation therapy or biopsy in the current 
protocol within 4 weeks of C1D1 of study drug(s).
12. Use of systemic corticosteroids or other immunosuppressive therapy, concurrently or within 
7 days of start of radiation therapy, with the following exceptions:
a) Topical, intranasal, inhaled, ocular, intra-articular, and/or other nonsystemic 
corticosteroids.
b) Physiological doses of replacement steroid therapy (eg, for adrenal insufficiency).
13. Receipt of live attenuated vaccine (eg, tuberculosis Bacillus Calmette-Guerin [BCG] vaccine, 
oral polio vaccine, measles, rotavirus, yellow fever) within 28 days of C1D1 of study drug(s).
14. Recipients of allogeneic or autologous stem cell transplantation or organ transplantation.
15. Female patients who are lactating or have a positive serum pregnancy test during the screening 
period or a positive urine pregnancy test on Day 1 before first dose of study drug.
Note: Female patients who are lactating will be eligible if they choose to discontinue 
breastfeeding before the first dose of study drug.
16. Ongoing Grade ≥2 infection or patients with Grade ≥2 fever of malignant origin.
17. Fridericia’s corrected QT interval (QTcF) >450 milliseconds (msec) (males) or >475 msec 
(females) on a 12-lead ECG during the screening period.
18. Grade ≥2 hypotension (ie, hypotension for which nonurgent intervention is required) at 
screening or during C1D1 predose assessment.
19. Oxygen saturation <92% on room air at screening or during C1D1 predose assessment.
20. Use of medications that are known clinical OATP1B1 and/or OATP1B3 inhibitors, 
concurrently or within 14 days of C1D1 of study drug(s) (Appendix I). 
21. Patients treated with other STING agonists/antagonist and toll-like receptors agonists within 
the past 6 months.
22. Current smoker.
23. Vaping within 90 days of C1D1 of study drug(s).
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24. Current 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 or ascites not controlled by tap or requiring 
indwelling catheters.
8.0
STUDY DRUG
All protocol-specific criteria for administration of radiation and study drug(s) must be met and 
documented before drug administration. Radiation therapy and study drug(s) will be administered 
under the supervision of the investigator or identified subinvestigator(s).
Investigational medicinal product(s): radiation therapy, pembrolizumab, TAK-676.
8.1
Study Drug Administration
8.1.1
Radiation Treatment Regimen 
Before radiation therapy, the radiology oncologist and medical oncologist should agree on the 
target lesions identified for irradiation using of the baseline imaging assessments.
Radiation therapy with daily image guidance will be administered using a fractionated dose of 
8 Gy × 3.
All patients will receive radiation therapy and pembrolizumab in addition to an escalating dose of
TAK-676.
The radiation must be administered between Day -8 and Day -2 with a minimum of 40 hours 
between the last fraction of radiation and initiation of IV pembrolizumab and TAK-676. At least 1 
and up to 3 lesions may be radiated, if indicated for palliative reasons. If the initial planned dose of 
8 Gy × 3 results in intolerable local AEs when given in combination with TAK-676 and 
pembrolizumab, the radiation dose may be reduced to 8 Gy × 1 in subsequent cohorts.
The radiation treatment and planning process will proceed as follows:
1. Immobilization.
a) Patients will be positioned in a stable and comfortable position, allowing accurate 
reproducibility of the target position from treatment to treatment.
b) A variety of immobilization systems may be used, including stereotactic frames, 
patient-customized rigid pillows, and thermoplastic masks.
2. Radiation CT simulation.
a) The treatment planning process will include CT based simulation with axial imaging every 
1 to 3 mm to cover the area(s) of interest.
b) IV and/or oral contrast during the planning CT is optional.
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3. Internal motion management.
a) Internal tumor and organ motion (eg, due to breathing) must be accounted for during the 
simulation and planning process.
b) For targets (eg, lung, liver, adrenal and thoracic/upper abdominal lymph node targets) that 
have significant motion, 4D-CT planning is mandatory.
c) Acceptable motion management includes reliable abdominal compression, linear 
accelerator beam gating with the respiratory cycle, tumor tracking, and active 
breath-holding techniques.
4. Daily target localization.
a) Image-guided radiation therapy is mandatory.
b) Contours: Tumor contours will be defined by the physician and radiation oncology staff:
i. Gross tumor volume (GTV): This is the target gross tumor as defined by the treating 
radiation oncologist with the help of positron emission tomography, MRI, and 
diagnostic CT with contrast as appropriate.
ii. Internal target volume (ITV): Delineation of an ITV is mandated when a 4D-CT is 
required.
iii. Clinical tumor volume (CTV): An optional 0- to 1-cm margin on GTV is allowed 
when determining the CTVs at the treating radiation oncologist’s discretion to 
account for any uncertainty or microscopic disease. This margin may be expanded 
based on clinical judgment with permission of the principal investigator.
iv. Planning tumor volume (PTV): A 3 to 5 mm PTV margin will be uniformly added to 
the CTV and will also be included to account for set-up variation, as appropriate to 
each individual lesion.
v. Organs at risk (OARs): For the 8 Gy × 3 dose level, several contours of the OAR will 
be defined by the physician and/or treatment planner if visible within the axial slices 
within 2 cm of the PTV as per institutional guidelines and indicated in Table 8.a or 
unless noted below:

Spinal cord: In cases where the PTV overlaps the vertebral column and the dose 
fractionation is greater than 8 Gy × 1, the spinal cord will be delineated with the 
aid of interventional radiology myelogram or fused MRI. Otherwise, the spinal 
cord will be contoured based on the bony limits of the spinal canal. The spinal 
cord should be contoured starting at least 5 cm above the superior extent of the 
PTV and continuing on every CT slice to at least 5 cm below the inferior extent of 
the PTV.

Heart/pericardium: The heart will be contoured along with the pericardial sac. 
The superior aspect will begin at the level of the inferior aspect of the pulmonary 
artery passing the midline and extend inferiorly to the apex of the heart.
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
Proximal bronchial tree: This structure includes the distal 2 cm of the trachea, the 
carina, the right and left mainstem bronchi, the right and left upper lobe bronchi, 
the intermedius bronchus, the right middle lobe bronchus, the lingular bronchus, 
and the right and left lower lobe bronchi.

Skin: The skin will be defined as the outer 0.5 cm of the body surface. 

Bowel: Loops of large bowel and small bowel will be contoured separately. 
Small bowel will be evaluated using the duodenum constraints in TG-101 as they 
are more conservative.
Table 8.a
Target Region and Contours
Target Region
Minimum OARs to contour if on the same axial slice or within 2 cm craniocaudal of 
PTV 
Head and neck
Larynx, spinal cord, brachial plexus, esophagus, lungs, brainstem, skin
Thoracic
Lungs, brachial plexus, trachea, esophagus, proximal bronchial tree, skin, heart, stomach, 
liver, spinal cord, kidneys, small bowel, large bowel
Abdominopelvic
Lungs, esophagus, skin, heart, stomach, liver, spinal cord, kidneys, small bowel, large 
bowel, rectum, bladder, femoral heads, sacral plexus, cauda equina
OAR: organ at risk; PTV: planning tumor volume.
Dose constraints as per TG-101 (Appendix J) will be prioritized over target coverage.
The table below provides the biologically equivalent dose of the fractionation scheme based on 
linear-quadratic model (Brenner 2008) and assuming and α/β of 3.
Table 8.b
Biologically Equivalent Dose for the Radiation Fractionation Scheme Based 
on the Linear-Quadratic Model and Assuming an α/β of 3
Dose Fractionation Scheme
Biologically Effective Dose 
(BED3)
Biologically Equivalent Dose in 2 
Gy Fractions (EQD2)
8 Gy × 3 fractions
88.0 Gy3
52.8 Gy
Source: (Brenner 2008).
Gy: gray.
This was selected for normal tissue toxicity concerns given this is primarily a safety study.
8.1.2
Pembrolizumab
Route of administration: IV infusion over 30 minutes.
Dose level: 200 mg.
Pembrolizumab will be administered on C1D1 at 200 mg IV following the label instructions at 
least 40 hours after the last fraction of radiation and on an every 3-week basis thereafter. 
Administration will continue until disease progression, intolerance to pembrolizumab (defined as 
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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/or the product information included with pembrolizumab 
(eg, package insert).
8.1.3
TAK-676
Route of administration: IV infusion over 60 ±10 minutes.
Dose level: 0.2, 0.4, 0.8, 1.2, 1.6, 2.0, 2.5, 3.5, 5.0, 7.0, and 9.0 mg.
TAK-676 infusion will start 1 hour (+15 minutes) after the end of pembrolizumab infusion on Day 
1 of each cycle.
TAK-676 will be provided as a solution containing 3 mg/3 mL TAK-676 drug substance as free 
base. TAK-676 injection 3 mg/3 mL as free base solution needs to be diluted for infusion at the 
clinical site (refer to the Pharmacy Manual).
TAK-676 will be administered IV on a dosing schedule of Days 1, 8, and 15 of a 21-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.
Administration should always be performed on schedule; however, if extenuating circumstances 
prevent a patient from beginning treatment on a particular dosing day, a -1/+2-day window will be 
allowable for all cycles except for Cycle 1. During subsequent cycles, if the Day 1 dose schedule is 
altered, it is preferred to also shift the Day 8 and Day 15 doses and maintain a 21-day cycle. If the 
Day 8 or Day 15 dose scheduled is altered, it is preferred to return to the original schedule for the 
subsequent dose. If a patient misses a dose outside of this window, that dose will be considered 
missed and dosing will resume at the next scheduled dosing timepoint. Based on emerging data 
(eg, severity of infusion-related reactions), infusion time may be adjusted to less than or greater 
than 60 minutes upon 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. 
Premedication for infusion is not recommended initially, but also may be added based on emerging 
data and upon agreement with the sponsor and investigators.
For administrations of TAK-676, 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 end of infusion 
(±10 minutes), 2 hours post infusion (±30 minutes), any time when clinically indicated, and before 
discharge (if different from and not overlapping with the timepoints above). Vital signs should be 
measured and recorded at any time if the patient develops symptoms associated with potential 
risks of TAK-676 and/or pembrolizumab. The frequency and timing of vital sign monitoring may 
be modified based on emerging data and agreement between sponsor and investigators.
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TAK-676 administration will occur in facilities with readily available resuscitation equipment, 
diagnostic equipment and supportive care/medications such as oxygen, antihistamines, 
acetaminophen, corticosteroids, epinephrine, tocilizumab or other 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 vs a peripheral line.
For detailed information on the preparation and administration of TAK-676, refer to the Pharmacy 
Manual.
8.2
Definitions of DLT
A DLT will be defined as any of the following TEAEs that occur during Cycle 1 and is considered 
by the investigator to be at least possibly related to TAK-676 in combination with pembrolizumab 
(note that AEs in which the relationship to study drug[s] cannot be ruled out should be considered 
possibly related to study drug[s]):
1. Any Grade 5 TEAE.
2. Grade 4 anemia.
3. Grade ≥4 neutropenia lasting ≥7 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 ≥7 days, or Grade ≥3 thrombocytopenia associated 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 21 days from the calculated start date due to a 
lack of adequate recovery of treatment-related hematological or nonhematologic toxicities.
10. Development of Grade ≥3 myelitis, pneumonitis, gastritis, hepatitis, dermatitis or pain flare in 
the relevant radiation field.
11. Any Grade ≥3 nonhematologic toxicity with the following exceptions:
a) Grade 3 arthralgia/myalgia that responds to nonsteroidal anti-inflammatory drugs within 1 
week.
b) Grade 3 fatigue lasting <7 days.
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c) Any Grade 3 endocrinopathy that is adequately controlled by hormonal replacement.
d) 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).
e) Transient (≤24 hours) Grade 3 flu-like symptoms that resolve spontaneously or are 
controlled with medical management.
f)
Grade 3 or 4 asymptomatic laboratory changes (other than renal and hepatic laboratory 
values) that can be successfully corrected (reversion of Grade ≤1 or baseline) within 
72 hours.
g) Isolated elevation of ALT and/or AST, that is, ≤10 times the ULN in the absence of 
significant bilirubin elevation (Grade <3), excluding elevations meeting Hy’s Law.
h) 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, 5-hydroxytryptamine [serotonin] 
type 3 receptor antagonist, and/or neurokinin-1 receptor antagonists).
i)
Grade 3 rash and pruritis that respond to a standard treatment and resolve or improve to 
Grade <3 within 7 days.
j)
Grade 3 diarrhea that can be controlled to Grade ≤2 in ≤3 days with supportive treatment.
k) Alopecia.
To the extent possible, administration of coronavirus disease 2019 (COVID-19) vaccinations 
should be avoided during the Cycle 1 DLT window; however, vaccination timing remains at the 
discretion of the investigator following the guidance in Section 8.5.
TEAEs meeting DLT definitions occurring in Cycle 2 or later will be considered in the 
determination of the RP2D of TAK-676 (that might be equal to or lower than the MTD).
8.3
Dose Escalation Rules 
Dose escalation of TAK-676 will follow BOIN design to inform dose escalation decisions and 
potential MTD estimation. Three patients will be enrolled in the initial cohort at the previously 
identified starting dose level of TAK-676. Subsequent cohorts will enroll 2 to 3 patients per the 
escalation/de-escalation guidelines outlined in Table 6.a. The target toxicity rate is ϕ = 0.3. It is 
generally expected that at least 3 patients will enroll per cohort. However, if no DLTs have been 
identified in the TAK-676 + pembrolizumab dose level that has already been evaluated in the 
dose-finding phase 1 TAK-676-1002 study, the sponsor, in agreement with the TAK-676-1003 
investigators, may opt to enroll a 2-patient cohort at that same [radiation] + TAK-676 + 
pembrolizumab dose level being evaluated in the TAK-676-1003 study. 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 dose level; if it is ≥ 0.358, the next cohort of patients will be treated at the 
next lower dose level; if it is within 0.236 and 0.358, additional patients will be enrolled in this 
dose level. 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 dose level j. When 
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the lowest dose is eliminated, stop the dose escalation for safety. The trial design is illustrated in 
Table 8.c. Dose escalation will continue until the maximum sample size is reached or the number 
of patients treated at the current dose level reaches 9, and the recommendation is to retain at the 
current dose level. Isotonic regression method will be used on the cumulative DLT rate for each 
dose level to determine the MTD, defined as the highest TAK-676 dose in combination with 
radiation therapy and pembrolizumab that does not result in unacceptable toxicities.
Table 8.c
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 DLTs is the number of patients with at least 1 DLT.
Table 8.d
Planned Dose Levels of TAK-676
Dose Level
Dose (unit)
-2
0.05 mg
-1
0.1 mg
1
0.2 mg
2
0.4 mg
3
0.8 mg
4
1.2 mg
5
1.6 mg
6
2.0 mg
7
2.5 mg
8
3.5 mg
9
5.0 mg
10
7.0 mg
11
9.0 mg
Enrollment into dose levels of TAK-676 in this study may not surpass the highest dose determined 
to be safe in combination with pembrolizumab in Study TAK-676-1002, the FIH dose escalation 
study of TAK-676 with or without pembrolizumab in patients with advanced solid tumors.
Additional cohorts at 3.5 mg (~1.4-fold increase from previous dose level), 5.0 mg (~1.4-fold 
increase), 7.0 mg (~1.4-fold increase), and 9.0 mg (~1.3-fold increase) are proposed. The dose 
escalation increments (~1.4-fold) were based on the preliminary PK results from the 
TAK-676-1002 FIH study, which showed modest intersubject variability in clearance and 
overlapping TAK-676 exposures as measured by area under the concentration-time curve from 
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time 0 to infinity across cohorts from 0.4 to 1.2 mg on C1D1 or C1D8. Because enrollment in this 
study may not surpass the highest TAK-676 dose level determined to be safe in combination with 
pembrolizumab in the FIH study, a more aggressive dose escalation (not to exceed 1 dose level 
below the highest dose level of TAK-676 that has been determined to be safe in combination with 
pembrolizumab from the TAK-676-1002 FIH study) is permissible following discussions between 
the sponsor and the investigators, if supported by evolving safety, tolerability, PK, and 
pharmacodynamic data of TAK-676 (eg, if this study determines that radiation + pembrolizumab + 
0.8 mg TAK-676 is safe and the TAK-676-1002 FIH study has determined that pembrolizumab + 
2.5 mg TAK-676 is safe, escalation from 0.8 mg TAK-676 to 2.0 mg TAK-676 will be permissible 
in this study). Other dose escalation decisions, evaluation of intermediate doses, expansion of an 
existing dose level, and stopping the dose escalation early are all permissible following 
discussions between the sponsor and the investigators, if such measures are needed for patient 
safety, or for a better understanding of the dose-related toxicity, exposure, and/or 
pharmacodynamics. Other non-DLT safety and available clinical, PK, or biomarker data will also 
be considered to inform subsequent dose recommendations, dose escalation decisions, and 
potential MTD/RP2D estimation.
8.4
Dose Modification Guidelines
Decisions regarding which study drug requires dose modification will be dependent upon the 
toxicity, its onset, and its time course. The causal relationship of any reported events (AEs or 
SAEs) should be assessed by the investigator in relation to radiation, TAK-676, and 
pembrolizumab. After discussion between the investigator and the sponsor, alternative dose 
modifications may be recommended to maximize exposure of study treatment while protecting 
patient safety. Discussions and agreements will be documented.
General Principles
Treatment with TAK-676 in combination with pembrolizumab following radiation therapy will 
occur in 21-day cycles. Toxicities are to be assessed according to the NCI CTCAE, Version 5.0. 
All toxicities that occur during the study will be actively managed following the SOC 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 radiation therapy, pembrolizumab, and/or 
TAK-676. Patients experiencing AEs attributed to TAK-676 in combination with pembrolizumab 
may continue study treatment and maintain the same dose, have doses held, have doses of 
TAK-676 reduced, or permanently discontinue from the study. Patients who have the TAK-676 
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 dose level or have doses of TAK-676 reduced after 
consultation with the sponsor. When a dose reduction occurs, the TAK-676 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-676 can be further reduced if the 
treating physician considers that the patient is benefiting from study treatment. If TAK-676 dosing 
is delayed for more than 21 days for TAK-676–related or possibly related toxicities, despite 
supportive treatment per standard clinical practice or more than 2 dose reductions are required in a 
patient, this patient will have study treatment discontinued.
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For AEs that occur during the study but are not related to TAK-676 or pembrolizumab, the dose 
modification of TAK-676 and/or pembrolizumab, in principle, is not required. However, these 
situations should be discussed with the medical monitor. Depending on medical conditions and the 
possibility of potential worsening of toxicities by the continued administration of TAK-676 and/or 
pembrolizumab, investigators can decide to have the TAK-676 and/or pembrolizumab dose held 
or reduced (in the case of TAK-676) until the resolution of the AE in consultation with the sponsor, 
as needed.
Dose modification guidelines for toxicities are described in Table 8.f and Table 8.g for TAK-676 
based on 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.
8.4.1
Criteria for Administering a Subsequent Dose/Starting a New Cycle
Treatment with TAK-676 in combination with pembrolizumab will use a cycle length of 21 days. 
For a subsequent dose of TAK-676 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, ≤3 mg/dL.

Serum ALT and AST ≤3.0 times the ULN (or ≤5.0 times the ULN with presence of liver 
metastases).

Albumin ≥3.0 g/dL.

Estimated creatinine clearance using the Cockcroft-Gault formula ≥30 mL/min.

Oxygen saturation of ≥92% on room air.
Before administering a subsequent dose or starting a new treatment cycle, TAK-676–related 
and/or pembrolizumab-related AEs 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. For clinically 
significant lab values that occur during the study but are not related to TAK-676 or 
pembrolizumab, the dose modification of TAK-676 and/or pembrolizumab, in principle, is not 
required. However, these situations should be discussed and documented with the medical monitor 
before administering a subsequent dose.
If the patient fails to meet the above-cited criteria for retreatment, treatment should be held (in the 
case of a subsequent dose) or delayed (in the case of starting a new cycle) by 1 week, at the end of 
which the patient will be re-evaluated to determine whether the criteria for retreatment have been 
met. If criteria are subsequently met, the previous dose will be considered “missed” within that 
cycle. If a dose reduction is considered, TAK-676 will be reduced by 1 dose level, see Section 8.4.
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8.4.2
Criteria for Dose Modification of Radiation
If radiation-related AEs are observed that require reduction of the planned radiation schedule, the 
dose may be reduced in subsequent cohorts following discussion between the investigator and 
sponsor.
Table 8.e
Dose Modification of Radiation
Dose Reduction 
Levels
Dose Fractionation Scheme
Biologically Effective Dose 
(BED3) a 
Biologically Equivalent 
Dose in 2 Gy Fractions a 
Planned dose
8 Gy × 3 fractions
88.0 Gy3
52.8 Gy
(-) 1 dose level
8 Gy × 1 fraction
29.33 Gy3
17.6 Gy
Source: (Brenner 2008). 
Gy: gray.
a Biologically equivalent dose of each radiation fractionation scheme based on linear-quadratic model and assuming 
and α/β of 3. This was selected for normal tissue toxicity concerns given this is primarily a safety study.
8.4.3
Criteria for Dose Modification of Pembrolizumab
Dosing of pembrolizumab cannot be reduced; it can only be skipped, interrupted, or discontinued. 
Refer to the pembrolizumab prescribing label for recommended dose modification and/or 
discontinuation guidelines.
8.4.4
Criteria for Dose Modification of TAK-676
Dosing of TAK-676 should be reduced according to the dose modification recommendations listed 
in Table 8.f for nonhematologic toxicity and Table 8.g for hematologic toxicities. If indicated, 
TAK-676 dose should be reduced by at least 1 dose level (or by 50% if the patient is receiving the 
first dose level). For Grade 1 and Grade 2 toxicities, the investigator may consider making a dose 
adjustment to TAK-676 or pembrolizumab or both agents as clinically indicated by the nature of 
toxicity. For Grade ≥3 AEs, dose adjustments to both TAK-676 and pembrolizumab must be made 
as indicated in the following tables and/or prescribing information for pembrolizumab. During this 
study, further adjustment to dose modification 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-676 can be further 
reduced by another dose level with agreement by the sponsor if the treating physician believes that 
the patient is receiving benefit. 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 TAK-676 related, or 
there were other circumstances contributing to the AE that are unlikely to recur, the dose may be 
re-escalated to the original dose level after discussion with the sponsor and the treating physician. 
A patient can have up to 2 dose level reductions of TAK-676 as a single agent or in combination 
due to AEs, but further reductions are not permitted (the patient should discontinue study drug in 
this case).
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Table 8.f
Guidelines for TAK-676 Dose Modification and/or Discontinuation for 
Nonhematologic Toxicity
Refer to the pembrolizumab prescribing information for recommended dose modification and/or 
discontinuation guidelines.
NCI CTCAE Grade
TAK-676 Dose Modification
CRS
Grade 1:
Fever with or without constitutional 
symptoms

Continue TAK-676 at the same dose level.
Grade 2:
Hypotension responding to fluids; hypoxia 
responding to <40% O2

Interrupt TAK-676 until recovers to Grade ≤1.

Once recovered, restart TAK-676 with a dose reduction of 1 dose 
level. If a second event occurs, permanently discontinue 
TAK-676. 

A maximum of 2 consecutive TAK-676 doses can be skipped; 
otherwise TAK-676 must be permanently discontinued.
Grade 3:
Hypotension managed with 1 pressor; 
hypoxia requiring ≥40% O2

Permanently discontinue TAK-676.
Grade 4:
Life-threatening consequences; urgent 
intervention indicated

Permanently discontinue TAK-676.
Infusion-Related Reactions
Grade 2

Hold TAK-676 infusion until symptoms resolve to Grade ≤1. 

Resume at a slower rate.

Consider premedication before the subsequent dose.

Permanently discontinue if recurrent on rechallenging despite 
premedication use.
Grade 3 or 4

Permanently discontinue TAK-676.
Colitis
Grade 2 or 3

Hold TAK-676 until improvement to a Grade ≤1 or baseline.

Resume at 1 lower dose level.

Permanently discontinue if recurrent on rechallenging.
Grade 4

Permanently discontinue TAK-676.
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Table 8.f
Guidelines for TAK-676 Dose Modification and/or Discontinuation for 
Nonhematologic Toxicity
Refer to the pembrolizumab prescribing information for recommended dose modification and/or 
discontinuation guidelines.
NCI CTCAE Grade
TAK-676 Dose Modification
Hepatotoxicity
AST/ALT ≤3 × ULN, or ≤5 × ULN in the 
case of known liver metastases

Continue TAK-676 at the same dose level.
AST/ALT >3-5 times the ULN

Hold TAK-676 until resolution to AST/ALT ≤ 3 × ULN, or ≤5 ×
ULN in the case of known liver metastases.

Resume at same dose level.

Permanently discontinue if recurrent on rechallenging or 
concurrent TBILI > 2 × ULN (per Hy’s law).

Monitoring of hepatic laboratory tests, including ALT, AST, 
ALP, TBILI, DBILI, PT-INR is recommended until improved 
AST/ALT ≤3 × ULN, or ≤5 × ULN in the case of known liver 
metastases.
AST/ALT >5-10 times the ULN

Hold TAK-676 until improvement to AST/ALT ≤3 × ULN or 
≤5.0 × ULN in the case of known liver metastases.

Resume at 1 lower dose level.

Permanently discontinue if recurrent on re-challenging, or 
concurrent TBILI > 2 × ULN (per Hy’s law).

Monitoring of hepatic laboratory tests, including ALT, AST, 
ALP, TBILI, DBILI, and PT-INR is recommended until 
improved AST/ALT ≤3 × ULN or ≤5.0 × ULN in the case of 
known liver metastases.
AST/ALT >10 times the ULN or Child-Pugh 
score ≥9

Permanently discontinue TAK-676.
Elevated bilirubin
(Grade 2)

Hold TAK-676 until resolution to T-Bili ≤1.5 times the ULN or 
≤3 mg/dL for patients with Gilbert’s disease.

Resume at same dose level.

Reduce by 1 lower dose level if recurrent.
Elevated bilirubin
(Grade 3 or 4)

Permanently discontinue TAK-676.
Endocrinopathies
Grade 2

Continue TAK-676 at the same dose level.

Replacement therapy as clinically indicated.
Grade 3 or 4

Hold TAK-676 until clinically stable.

Resume at 1 lower dose level.

Replacement therapy as clinically indicated.
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Table 8.f
Guidelines for TAK-676 Dose Modification and/or Discontinuation for 
Nonhematologic Toxicity
Refer to the pembrolizumab prescribing information for recommended dose modification and/or 
discontinuation guidelines.
NCI CTCAE Grade
TAK-676 Dose Modification
Increased Creatinine
Grade 1

Continue TAK-676 at the same dose and monitor creatinine 
weekly.
Grade 2

Hold TAK-676 until resolution to Grade ≤1 or baseline. 

Resume at 1 lower dose level.

Permanently discontinue if recurrent on rechallenging.
Grade 3 and 4

Permanently discontinue TAK-676.
Pneumonitis
Grade 2

Hold TAK-676 until resolution to Grade ≤1 or baseline.

Resume at 1 lower dose level.

Permanently discontinue if recurrent on rechallenging.
Grade 3 or 4

Permanently discontinue TAK-676.
Rash (Skin and Subcutaneous Tissue Disorders)
Grade 2

Hold TAK-676 until resolution to Grade ≤1 or baseline.

Resume TAK-676 at same dose level.

Reduce TAK-676 by 1 dose level if recurrent.
Grade 3

Hold TAK-676 until resolution to Grade ≤1 or baseline.

Resume at 1 lower dose level.

Permanently discontinue if recurrent on rechallenging.
Grade 4

Permanently discontinue TAK-676.
Other Immune Mediated Adverse Events
Grade 2 

Hold TAK-676 until resolution to Grade <1.

Resume at 1 lower dose level.

Permanently discontinue if recurrent on rechallenging.
Grade 3 or 4

Permanently discontinue TAK-676.
Other Nonhematologic Toxicities
All other Grade 3 nonhematologic toxicities 
(except for Grade ≥3 nonhematological 
exceptions outlined in Section 8.2)

Hold TAK-676 until resolution to Grade ≤1 or baseline.

Resume at 1 lower dose level.

Permanently discontinue if recurrent on rechallenging.
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Table 8.f
Guidelines for TAK-676 Dose Modification and/or Discontinuation for 
Nonhematologic Toxicity
Refer to the pembrolizumab prescribing information for recommended dose modification and/or 
discontinuation guidelines.
NCI CTCAE Grade
TAK-676 Dose Modification
All other Grade 4 nonhematologic toxicities 
(except for Grade ≥4 nonhematological 
exceptions outlined in Section 8.2)

Permanently discontinue TAK-676.
ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; CRS: cytokine release 
syndrome; CTCAE: Common Terminology Criteria for Adverse Events; DBILI: direct bilirubin; NCI: National 
Cancer Institute; PT-INR: prothrombin international normalized ratio; TBILI: total bilirubin; ULN: upper limit of 
normal.
Table 8.g
Guidelines for TAK-676 Dose Modification and/or Discontinuation for 
Hematologic Toxicity
Refer to the pembrolizumab Prescribing Information for recommended dose modification and/or 
discontinuation guidelines.
NCI CTCAE Grade
TAK-676 Dose Modification
Neutrophil Count (ANC) Decreased
Grade 4 lasting >5 days

Hold TAK-676 until resolved to ≥1000/mm3 or baseline, in absence of 
fever/evidence of infection.

Resume at 1 lower dose level.

Permanently discontinue if recurrent on rechallenging.
Febrile neutropenia

Hold TAK-676 until resolved to ≥1000/mm3 or baseline, and 
fever/infection have resolved.

Resume at 1 lower dose level.

Permanently discontinue if recurrent on rechallenging.
Platelet Count Decreased
Grade 3 without bleeding

Hold TAK-676 until resolved to ≥75000/mm3, then:

If spontaneously resolved in ≤7 days, resume at same dose level.

If resolved in >7 days, reduce by 1 dose level.
Grade 4

Hold TAK-676 until resolved to ≥75000/mm3, then reduce by 1 dose 
level.

Permanently discontinue if recurrent on rechallenging.
Platelets <10,000 cells/μL, or 
thrombocytopenia Grade ≥3 associated 
clinically significant bleeding

Permanently discontinue TAK-676.
Anemia
Grade 3 

Transfuse PRBCs as clinically indicated.

Resume at 1 lower dose level lower.
Grade 4

Permanently discontinue TAK-676.
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Table 8.g
Guidelines for TAK-676 Dose Modification and/or Discontinuation for 
Hematologic Toxicity
Refer to the pembrolizumab Prescribing Information for recommended dose modification and/or 
discontinuation guidelines.
NCI CTCAE Grade
TAK-676 Dose Modification
ANC: absolute neutrophil count; CTCAE: Common Terminology Criteria for Adverse Events; NCI: National Cancer 
Institute; PRBCs: packed red blood cells.
8.4.5
Criteria for Discontinuation of TAK-676
Patients who meet criteria for DLT during Cycle 1 will be discontinued from therapy unless the 
principal investigator believes the potential risks and benefits of a lower TAK-676 dose justifies a 
rechallenge at a lower dose. 
The following events should lead to discontinuation of TAK-676:
1. Nonhematological toxicity:
a) Grade >3 nonhematological toxicities that do not meet the DLT exception criteria.
b) Grade ≥3 CRS.
c) Grade ≥3 infusion-related reactions or recurrent Grade 2 infusion-related reactions.
d) Grade ≥3 pneumonitis or recurrent Grade 2 pneumonitis despite 1 TAK-676 dose 
reduction.
e) Grade ≥3 creatinine increase.
f)
Grade ≥3 immune-mediated AEs.
g) Grade ≥ 3 bilirubin increase.
h) ALT and/or AST >10 times the ULN or Child-Pugh score ≥9.
i)
Grade ≥2 drug-related uveitis.
2. Hematological toxicity:
a) Grade 4 anemia.
b) Recurrent Grade 4 neutropenia lasting >7 days or febrile neutropenia despite 1 TAK-676
dose reduction.
c) Recurrent Grade 4 thrombocytopenia despite 1 TAK-676 dose reduction.
d) 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-676 is delayed for >21 days because of TAK-676–related toxicities, then the patient should 
have study treatment discontinued unless the investigator considers that the patient will receive 
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benefit by continuing in the study. If treatment discontinuation is determined, the EOT visit should 
be completed within 30 (+10) days of the last administration of TAK-676 or before the start of 
subsequent anticancer therapy, whichever occurs first.
Additionally, the study will not begin until safety and tolerability data is available from the first 
two dose levels in a parallel ongoing dose escalation study (TAK-676-1002) of pembrolizumab 
with escalating doses of TAK-676 (0.2 and 0.4 mg IV). 
8.4.6
Criteria for Discontinuation of Pembrolizumab
Pembrolizumab will be held or discontinued if any of the criteria described in the package insert 
have been met.
8.4.7
Stopping Rules
The study will be stopped if 2 fatal AEs related to TAK-676 occur at the same dose levels in 
Cycles 1 and 2.
The stop will result in an immediate halt in enrollment and may also necessitate the halting of 
treatment of ongoing patients, depending on the nature and severity of the safety risk. 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.
Based on the emerging safety profile, alternative rules may also be considered following 
discussions between the sponsor and the investigators.
8.5
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 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. 

Any investigational agent other than pembrolizumab or TAK-676.

Any concurrent anticancer therapy, including but not limited to chemotherapy, 
immunotherapy (except for pembrolizumab), biologic or hormonal therapy (except for 
endocrine therapy for the treatment of breast cancer).

Concomitant systemic use of corticosteroids or other immunosuppressive medication, current 
or within 7 days of administration of investigational drug with the following exceptions:
–
Topical, intranasal, inhaled, ocular, intraarticular corticosteroids.
–
Physiological doses of replacement steroid (eg, for adrenal insufficiency).
eg,
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
Hydrocortisone: Up to 20 mg daily.

Prednisone: Up to 15 mg daily.

Dexamethasone: Up to 0.75 mg daily.

Fludrocortisone: No limitation on use.

Any live vaccines while on study.

COVID-19 vaccinations (including boosters and/or additional doses) given within ±3 days of 
systemic study treatments. To the extent possible, administration of COVID-19 vaccinations 
should be avoided during the Cycle 1 DLT window; however, vaccination timing remains at 
the discretion of the investigator.

Systemic treatment with any known clinical OATP1B1 and/or OATP1B3 inhibitors including: 
–
Atazanavir and ritonavir.
–
Clarithromycin.
–
Cyclosporine.
–
Erythromycin.
–
Gemfibrozil.
–
Lopinavir and ritonavir.
–
Rifampin (single dose).
–
Simeprevir.
–
Remdesivir.
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. 

Smoking.

Vaping.
If a patient experiences an AE on study and TAK-676 dosing is temporarily interrupted because of 
that AE or there has been an appropriate washout of TAK-676 (ie, 5 times the projected half-life), 
the medications listed above and in Appendix I may be used for AE management if there is no 
appropriate alternative treatment available per the investigator’s judgment. This situation will be 
handled on a case by case basis and requires discussion between the investigator and the medical 
monitor to assess the relative benefit and risk for a given patient. The discussion will be 
documented in the study file. Patients should be closely monitored for potential toxicities.
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8.6
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, blood transfusions, oxygen supplementation, etc, should be 
recorded in the designated electronic case report form (eCRF) from signing of the informed 
consent form (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 steroids (eg, for the treatment of asthma) are permitted in addition 
to physiological doses of replacement steroid in Section 8.5.

Patients should be transfused with RBCs 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 or biopsied lesion.

For antiemetics, see Section 8.8.6.
Supportive measures consistent with optimal patient care may be given throughout the study.
8.7
Precautions and Restrictions
Refer to the pembrolizumab prescribing label for information on precautions and restrictions for 
pembrolizumab administration.
Precautions and requirements for a safe TAK-676 administration are detailed in Section 8.1.3.
TAK-676 was evaluated in different studies with animals, including rats and monkeys. 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-676, 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-676 has on human pregnancy or development of the embryo or 
fetus. Female patients participating in this study should avoid becoming pregnant, breastfeeding a 
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baby, or donating eggs for 120 days after the last dose of TAK-676. Male patients should avoid 
impregnating a female partner and donating sperm for 120 days after the last dose of TAK-676. 
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 Day 1 of each cycle, 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 1 of the following criteria:

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, agreeable to practicing 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 120 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

Agreeable to practicing 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 1 of the 
following:

Agree to practice effective barrier contraception (eg, latex condom with a spermicidal agent) 
during the entire study treatment period and through 120 days after the last dose of study drug.

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-676 passes into breast milk. Mothers should not breastfeed during 
the entire study treatment period and for 120 days after the last dose of study drug.
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Before enrolling patients, patients and their caregivers will be educated on 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. Before study start, principal investigators and patients will agree on a 
health care facility in the event of an emergent situation.
As an additional safety measure, each patient will be provided a patient emergency card detailing 
treatment site and investigator contact information, 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-676 administration and provide them with 
the contact information of the treating site. This card will also remind patients of concerning signs 
or symptoms for which they should seek immediate medical attention.
8.8
Management of Clinical Events 
Therapies that are required to manage AEs and control cancer symptoms are allowed based on 
standard clinical practice, unless specifically excluded. Supportive care agents, such as G-CSF, 
blood products (RBC and platelet transfusions), and pain medications are permitted as needed per 
ASH/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 8.4.
In the sections below, guidance is provided for the management of some AEs that could be 
expected based on observations in nonclinical toxicology or because of the mechanism of action of 
TAK-676, pembrolizumab, or radiation. 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.
8.8.1
Pulmonary Vasculature Toxicity/Noncardiogenic Pulmonary Edema
TAK-676 administration was associated with pulmonary changes in monkeys (please refer to the 
IB for details) that could resemble vascular leak or noncardiogenic pulmonary edema in humans. 
To monitor for this potential side effect and minimize the clinical risk to patients, the following 
will be performed for patients enrolled:

Vital signs will be collected before, during and after administration of TAK-676.

On TAK-676 dosing days in Cycle 1, an additional postdose physical examination will include 
an assessment of the respiratory system. 

Oxygenation should be carefully monitored and maintained as clinically indicated. Careful 
diagnosis and aggressive correction of pulmonary symptoms should occur quickly.
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Pulmonary imaging (eg, 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 could refer 
to “High dose IL-2 (Aldesleukin)-expert consensus on best management practices-2014” with 
slight modification on oxygen saturation regarding dose hold (see Table 8.h) (Dutcher et al. 2014), 
ASCO guidelines on management of ICI-related lung toxicity (Brahmer et al. 2018), or local 
institution guidelines. 
Table 8.h
Pulmonary Toxicity Clinical Management Recommendations
Issue
Considerations
Management
Pulmonary
Tachypnea/dyspnea
Typical
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
Consider holding TAK-676 dose if Grade 2 or higher 
hypoxia is observed in the setting of pulmonary toxicity
Anxiety, fever, acidosis
Maintain oxygen saturation 
>92%-95%
Variation
Furosemide
Bronchodilators
Monitor bicarbonate
Investigators should differentiate pulmonary vasculature toxicity/noncardiogenic pulmonary 
edema from other clinical conditions, including capillary leak syndrome. Capillary leak syndrome 
may be characterized by weight gain, generalized edema, hypotension, and hypoalbuminemia 
(Dutcher et al. 2014). Dyspnea and hypoxia may also reflect capillary leak and could lead to a 
requirement for supplemental oxygen to maintain an oxygen saturation of 92% to 95%.
Monitor patients for weight gain, edema, hypotension (including orthostatic changes), and serum 
albumin levels before TAK-676 treatment and as clinically indicated.
8.8.2
CRS
CRS is a disorder characterized by fever, headache, rash, tachycardia, hypotension, tachypnea, 
and/or hypoxia caused by the release of cytokines. CRS may be associated with cardiac, hepatic 
and/or renal dysfunction. Severe CRS complications are life-threatening and frequently require 
intensive care unit (ICU) care with vasopressor and/or ventilation support.
CRS should be graded following NCI CTCAE, Version 5.0. 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 anti–IL-6 agents, such as 
tocilizumab, are on site and available should they be needed. In circumstances where tocilizumab 
is not available, other anti–IL-6 agents (eg, siltuximab) will be considered acceptable treatment for 
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CRS, under the condition that this is consistent with local institutional guidelines/practice and that 
the availability of the anti–IL-6 agent(s) 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.
The diagnosis and management of CRS is based on clinical parameters as described in Table 8.i. 
Ferritin, C-reactive protein, and serum cytokine levels 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-676. Close monitoring of vital signs and clinical condition will 
continue if the patient experiences symptoms that could be consistent with CRS. 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. 
Should symptoms consistent with CRS develop, see Table 8.f for TAK-676 dose modification. If 
TAK-676 is held, pembrolizumab will also be held until TAK-676 is resumed, or if TAK-676 is 
discontinued, pembrolizumab will be held until the CRS event recovers to Grade ≤1.
Should TAK-676 be discontinued/held for an AE, continued administration of pembrolizumab is 
permitted per investigator’s discretion and with sponsor’s agreement.
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Table 8.i
NCCN Guidelines Version 3.2021: Management of CAR T Cell–Related Toxicities
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 (NCI CTCAE, Version 
5.0). 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
Anti–IL-6 Therapy
Corticosteroids d, e
Additional Supportive Care
Grade 1:
Fever (≥38°C)
For prolonged CRS (>3 days) f in 
patients with significant symptoms 
and/or comorbidities, consider 1 dose of 
tocilizumab 8 mg/kg IV over 1 hour (not 
to exceed 800 mg). g
For idecabtagene and lisocabtagene, 
consider dexamethasone 10 mg IV 
every 24 hours for early-onset CRS 
(<72 hours after infusion).

Empiric broad-spectrum antibiotics, 
consider GCSF if neutropenic. h

Maintenance IV fluids for hydration.

Symptomatic management of organ 
toxicities.
Grade 2:
Fever with hypotension not 
requiring vasopressors 
and/or hypoxia i requiring 
low-flow nasal cannula j or 
blow-by.
Tocilizumab 8 mg/kg IV over 1 hour (not 
to exceed 800 mg/dose). d Repeat in 
8 hours if no improvement; no more than 
3 doses in 24 hours, with a maximum of 
4 doses total.
For persistent refractory hypotension 
after 1-2 doses of anti–IL-6 therapy: 
Dexamethasone 10 mg IV every 
12-24 hours depending on product k, l

IV fluid bolus as needed.

For persistent refractory hypotension after 
2 fluid boluses and anti–IL-6 therapy, 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 anti–IL-6 
therapy.

Symptomatic management of organ 
toxicities.
Grade 3:
Fever with hypotension 
requiring a vasopressor with 
or without vasopressin 
and/or hypoxia requiring 
high-flow cannula,f face 
Anti–IL-6 therapy per Grade 2 d if 
maximum dose not reached within 
24-hour period.
Dexamethasone 10 mg IV every 
6 hours. k If refractory, manage as 
Grade 4.

Transfer to ICU, obtain echocardiogram, 
and perform hemodynamic monitoring.

Supplemental oxygen.

IV fluid bolus and vasopressors as needed.

Symptomatic management of organ 
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Table 8.i
NCCN Guidelines Version 3.2021: Management of CAR T Cell–Related Toxicities
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 (NCI CTCAE, Version 
5.0). 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
Anti–IL-6 Therapy
Corticosteroids d, e
Additional Supportive Care
mask, nonrebreather mask, 
or Venturi mask.
toxicities.
Grade 4:
Fever with hypotension 
requiring multiple 
vasopressors (excluding 
vasopressin) and/or hypoxia 
requiring positive pressure 
(eg, CPAP, BiPAP, 
intubation, and mechanical 
ventilation).
Anti–IL-6 therapy as per Grade 2 d if 
maximum dose not reached within 
24-hour period.
Dexamethasone 10 mg IV every 
6 hours m. If refractory, consider 
3 doses of methylprednisolone 
1000 mg/day IV; if refractory, 
consider dosing every 12 hours. m, n

ICU care and hemodynamic monitoring.

Mechanical ventilation as needed.

IV fluid bolus and vasopressors as needed.

Symptomatic management of organ 
toxicities.
BiPAP: bilevel positive pressure therapy; CAR: chimeric antigen receptor; CPAP: continuous positive pressure therapy; CRS: cytokine release syndrome; CTCAE: 
Common Terminology Criteria for Adverse Events; GCSF: granulocyte colony-stimulating factor; HLH/MAS: hemophagocytic lympho-histiocytosis/macrophage 
activation syndrome; ICU: intensive care unit; IV: intravenous; NA: not applicable; NCCN: National Comprehensive Cancer Network.
a For HLH/MAS during CRS, treat per CRS with addition of steroids. If symptoms do not improve within 48 hours, consider etoposide and intrathecal cytarabine 
for neurotoxicity.
b With permission from Elsevier (Lee et al. 2019).
c Organ toxicities should receive a thorough workup and appropriate management.
d After each dose, assess need for subsequent dosing.
e Antifungal prophylaxis should be strongly considered in patients receiving steroids for the treatment of CRS and/or neurotoxicity.
f For axicabtagene ciloleucel or brexucabtagene autoleucel, can consider tocilizumab if CRS symptoms persist for >24 hours.
g For lisocabtagene maraleucel, consider tocilizumab for Grade 1 CRS that develops <72 hours after infusion and consider adding dexamethasone 10 mg × 1. For 
CRS developing ≥72 hours after infusion, treat symptomatically.
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Table 8.i
NCCN Guidelines Version 3.2021: Management of CAR T Cell–Related Toxicities
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 (NCI CTCAE, Version 
5.0). 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
Anti–IL-6 Therapy
Corticosteroids d, e
Additional Supportive Care
h Granulocyte-macrophage colony-stimulating factor is not recommended in the setting of CAR T-cell therapy. A Food and Drug Administration biosimilar is an 
appropriate substitute for filgrastim.
i CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. For example, a patient with a temperature of 39.5°C, 
hypotension requiring 1 vasopressor, and hypoxia requiring low-flow nasal cannula is classified as Grade 3 CRS.
j 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.
k Alternative steroids at an equivalent dose may be considered.
l For axicabtagene ciloleucel, consider dexamethasone 10 mg IV every 24 hours after initial tocilizumab dosing, regardless of clinical response to tocilizumab. For 
lisocabtagene maraleucel, consider dexamethasone 10 mg IV every 12-24 hours if early-onset CRS. For idecabtagene vicleucel, consider dexamethasone 10 mg IV 
every 12-24 hours.
m For example, methylprednisolone IV 1000 mg/day for 3 days, followed by rapid taper at 250 mg every 12 hours for 2 days, 125 mg every 12 hours for 2 days, and 
60 mg every 12 hours for 2 days.
n Other agents such as anakinra, siltuximab, ruxolitinib, or extracorporeal cytokine adsorption with CRRT might be considered. Reported experience with these 
agents is limited.
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8.8.3
Infusion-Related Reactions
An infusion-related reaction is a disorder characterized by an adverse local or general response 
from exposure to an allergen. An infusion-related reaction typically occurs during the infusion or 
shortly thereafter.
Although TAK-676 is not a biologic agent, its 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.
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, 
Version 5.0. Table 8.f provides indications for dose modifications after an infusion-related 
reaction event.
The patient should be closely monitored until recovery of symptoms. The patient will be 
permanently discontinued from the study in case of a Grade 3 or 4 life-threatening reaction. 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, 
antihistamines, and corticosteroids should be given according to local institutional guidelines.
8.8.4
Infusion Site Care
Lesions at the injection site, which may include inflammation or necrosis, represent a potential risk 
and were observed as microscopic changes only in a non-GLP experiment in rats. Local 
institutional guidelines must be applied to stress proper administration and prevention of 
accidental extravasation of TAK-676. 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. There is no known antidote to TAK-676.
8.8.5
Anemia, Thrombocytopenia, and/or Neutropenia
To monitor for side effects of bone marrow toxicity in patients treated with TAK-676, complete 
blood counts will be monitored regularly for all patients. If anemia, thrombocytopenia, or 
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neutropenia occur, TAK-676 dose will be modified according to Table 8.g. Precautionary 
measures should be taken to prevent bleeding and overwhelming infections. Prophylactic use of 
myeloid growth factors should be avoided during the first cycle of dose escalation. Transfusion 
and use of growth factors as necessary to manage anemia, thrombocytopenia, and neutropenia are 
permitted at the discretion of the investigator, consistent with ASH/ASCO guidelines and 
institutional recommendation. See Section 8.3 for additional guidance.
8.8.6
Nausea and/or Vomiting
This study will not initially employ prophylactic antiemetics before the first dose of the study drug 
during dose escalation. However, a patient who develops nausea or vomiting will be actively 
managed by employing optimal antiemetic treatment based on local standard practice. 
Additionally, antiemetics may be used prophylactically as clinically indicated following the 
occurrence of a first event of study drug–related or possibly related nausea and/or vomiting. An 
optimal antiemetic regimen is defined as one that employs a neuroleptic, a 5-HT3 serotonin 
receptor antagonist, or an NK-1 antagonist may be added. Steroid use should be avoided unless it 
is a clinical necessity. If the nausea/vomiting is thought to be immune mediated, management 
should follow evolving consensus guidelines for management of immune mediated toxicities 
(Brahmer et al. 2021; Brahmer et al. 2018).
8.8.7
Diarrhea
This study will not initially employ prophylactic antidiarrheals. However, there is no prohibition 
against their use in the management of a patient who develops diarrhea. Patients will be instructed 
to take antidiarrheal medication(s) at the physician’s discretion until they are diarrhea-free for at 
least 12 hours. Fluid intake should be maintained to avoid dehydration. If the diarrhea is thought to 
be immune mediated or immune-mediated colitis is suspected, management should follow 
evolving consensus guidelines for management of immune mediated toxicities (Brahmer et al. 
2021; Brahmer et al. 2018).
8.8.8
Skin Conditions/Rash
It is recommended that for all severity grades of cutaneous events, the diagnostic work-up 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).

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.
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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).
8.8.9
Fluid Deficit
Fluid deficit should be corrected before initiation of study drug and during treatment. Patients on 
study should be advised to maintain adequate oral hydration.
8.8.10
Management of Pembrolizumab Immune-Mediated AEs
Pembrolizumab can cause immune-mediated reactions, including pneumonitis, colitis, hepatitis, 
endocrinopathies, nephritis, skin adverse reactions, and infusion-related reactions. 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. 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 8.4. Treatment of these AEs should follow evolving consensus 
guidelines for management of potential immune CPI-related AEs (Brahmer et al. 2018) and will be 
based on SOC, local institutional guidance, the WARNINGS AND PRECAUTIONS section of 
the package insert, and the proper use guidance of pembrolizumab.
8.8.11
Management of Radiation-Associated AEs
There is a potential for synergistic toxicity with combination use of radiation and pembrolizumab 
with or without TAK-676. Increased inflammation or radiation burn in the radiation field will be 
treated with local measures as per institutional guidelines. Antibiotics (local or systemic) may be 
used if there is a clinical suspicion of infection.
8.8.12
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 as 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 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.
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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 as per institutional guidelines, in 
addition to work-up for pulmonary toxicity related to the trial 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 
held (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 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).
In all cases, consultation with the medical monitor should also be considered, as appropriate.
8.9
Blinding and Unblinding
This is an open-label study.
8.10
Description of Investigational Agents
8.10.1
TAK-676
TAK-676 drug substance is a white-to-off white powder and freely soluble in aqueous solution. 
“TAK-676 Injection 3 mg/3 mL, as free base” is supplied as a single-use, 17 cc stoppered glass 
vial with an aluminum flip-off seal, providing 3 mL (3 mg) of TAK-676 drug substance solution as 
free base. The excipients are listed in the table below.
Ingredient
Function
Trisodium citrate dihydrate
Buffer
Citric acid monohydrate
Buffer
Sodium chloride
Tonicity agent
For specific information about the storage and handling of TAK-676 drug product, refer to the 
study or Pharmacy Manual associated with this study protocol.
8.10.2
Pembrolizumab
“Pembrolizumab Injection 100 mg/4 mL (25 mg/mL) solution in a single-dose vial” will be either 
labeled as study material and supplied by the sponsor or sourced locally by the clinical site when 
arrangements have been made and agreed to by sponsor and where regulations allow for clinical 
site sourcing, appropriate labeling, and compliance with local and regional regulations. For 
preparation, handling, and administration instructions related to pembrolizumab, please consult 
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the Pharmacy Manual and/or the product information included with pembrolizumab (eg, package 
insert).
8.10.3
Radiation Therapy
For details on radiation therapy, refer Appendix J.
8.11
Preparation, Reconstitution, and Dispensation
8.11.1
TAK-676
The drug product will be administered by IV infusion over 60 ±10 minutes. After the end of the 
infusion, the IV line should be flushed as directed in the Pharmacy Manual. Detailed dosage 
preparation instructions are provided in the Directions for Use located in the Pharmacy Manual.
In the absence of compatibility studies, this medicinal product must not be mixed with other 
medicinal products.
TAK-676 is an anticancer drug, and as with other potentially toxic compounds, caution should be 
exercised when handling TAK-676.
Study drug products should be inspected visually for particulate matter and discoloration before 
administration, whenever solution and container permit.
8.11.2
Pembrolizumab
Please refer to the Pharmacy Manual and/or the most recent pembrolizumab prescribing 
information as applicable to the specific country for preparation, reconstitution, and administration 
instructions.
8.12
Packaging and Labeling
8.12.1
TAK-676
“TAK-676 Injection 3 mg/3 mL, as free base” 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.
8.12.2
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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8.13
Storage, Handling, and Accountability
8.13.1
TAK-676
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.
TAK-676 must be stored in a secure, limited-access location, according to the conditions specified 
on the drug label and remain in the original carton until dispensed. The investigator or designee 
must confirm that appropriate temperature conditions have been maintained and that any 
temperature excursions are reported and resolved before use. Please refer to the Pharmacy Manual 
for additional instructions.
8.13.2
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/or the most recent pembrolizumab prescribing 
information as applicable to the specific country for additional details.
8.14
Other Protocol-Specified Materials
Information on supplies required by the site for drug administration is provided in the Pharmacy 
Manual. Clinical supplies other than study drug to be provided by the sponsor or designee are 
specified in the Study Manual.
9.0
STUDY CONDUCT
This trial will be conducted in compliance with the protocol, 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. If advertisements become part of 
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the recruitment strategy, they will be reviewed by the institutional review board (IRB)/ 
independent ethics committee (IEC).
9.3
Treatment Group Assignments
This is not a randomized study. Patients will be assigned to a dose cohort based on the dose 
escalation rules described in Section 8.3. The ongoing TAK-676-1002 FIH study will also provide 
clinical data on the safety and tolerability of TAK-676 + pembrolizumab. In the combination arm 
of the FIH study, TAK-676 is administered in a dose escalating fashion (starting at 0.2 mg IV on 
Days 1, 8, and 15 of a 21-day cycle) along with pembrolizumab at the fixed dose of 200 mg IV 
every 3 weeks. Safety data was to be obtained from at least 2 dose cohorts of the FIH combination 
arm before administering TAK-676 with pembrolizumab following radiation therapy in the 
current study.
Enrollment into dose levels of TAK-676 may not surpass the highest dose determined to be safe in 
Study TAK-676-1002, the FIH dose escalation study of TAK-676 with or without pembrolizumab 
in patients with advanced solid tumors.
9.4
Study Procedures
Refer to the SOEs (Appendix A) for timing of assessments. Additional details are provided as 
necessary in the sections that follow. Evaluations during the screening period are to be conducted 
within 28 days before the first dose of radiation unless otherwise specified. Unless otherwise 
noted, evaluations during the treatment period must occur before drug administration on scheduled 
visits. Tests and procedures should be performed on schedule for all visits. The timing of PK and 
pharmacodynamic assessments is specified in the SOE (Appendix A). Refer to the SOE 
(Appendix A) for timing of assessments. Additional details are provided as necessary in the 
sections that follow.
9.4.1
Informed Consent
Each patient must provide written informed consent before any study-required procedures are 
conducted, unless those procedures are performed as part of the patient’s standard care.
9.4.2
Patient Demographics
The date of birth, race, ethnicity, and sex of the patient are to be recorded during screening.
9.4.3
Medical History
During the screening period, a complete medical history, 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. In addition, concomitant medications will be recorded as specified in 
Section 9.4.9.
Available tumor genomic information obtained at the site will be collected.
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9.4.4
Physical Examination
Physical examinations will be completed per SOC at the times specified in the SOE (Appendix A). 
Complete physical examinations will include an assessment of the following: skin, head, eyes, 
ears, nose, throat, respiratory system, cardiovascular system, GI system, neurological condition, 
blood and lymphatic systems, and musculoskeletal system.
Symptom-directed physical examination will be conducted on Day 1 of each cycle before 
administration of the first dose of study treatment and any other time point during the cycle based 
on clinical need.
On dosing days in Cycle 1, an additional post dose physical examination will include an 
assessment of the respiratory and neurologic systems.
9.4.5
Patient Height and Weight
Height will be measured only during screening. Body weight will be measured at the times 
specified in the SOE (Appendix A) and as clinically indicated.
9.4.6
ECOG Performance Status
Performance status is to be assessed using the ECOG scale (see Appendix D for a description of 
the scale) at the times specified in the SOE (Appendix A).
9.4.7
Vital Signs
Vital 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, will be assessed as specified in the SOE (Appendix A). Refer to Section 8.1.3 for 
details on vital sign measurements during and post pembrolizumab and TAK-676 infusions.
Vital signs should be measured and recorded any time the patient develops symptoms associated 
with potential risks of TAK-676 and/or pembrolizumab.
9.4.7.1
Pulse Oximetry
Pulse oximetry should be obtained before each dose of TAK-676 and at any time a patient has any 
new or worsening respiratory symptoms. A reading at rest and on exertion if clinically indicated 
(during waking hours) should be obtained. The extent of the exertion should be based on the 
judgment of the investigator, but should remain consistent for each individual patient throughout 
the study. 
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.
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9.4.8
Pregnancy Test
The pregnancy test must be a beta-human chorionic gonadotropin test, and either urine or serum 
can be used. Women who are not of childbearing potential (status posthysterectomy, status 
post-bilateral oophorectomy, or postmenopausal [defined as amenorrhea for at least 12 months]) 
and men do not need to have the test performed.
Women of childbearing potential must have a confirmed negative pregnancy test at screening 
(serum or urine test) and with negative results available before the first dose may be administered. 
A serum or urine pregnancy test must also be completed before the first dose of radiation, on Day 
1 of each cycle and at the EOT assessment. If a serum pregnancy test is performed within 3 days 
from the first dose of radiation and the result is negative, the pregnancy test on the first day of 
radiation may be waived.
9.4.9
Concomitant Medications and Procedures
Medications used by the patient and therapeutic procedures completed by the patient will be 
recorded in the eCRF from the time of informed consent signature through 30 days after the last 
dose of study drug or the start of subsequent systemic antineoplastic therapy, whichever occurs 
first. See Section 8.5 and Section 8.6 for a list of medications and therapies that are prohibited or 
allowed during the study.
9.4.10
AEs
Monitoring of all AEs, including SAEs, will be collected throughout the study as specified in the 
SOE (Appendix A). Refer to Section 10.0 for details regarding definitions, documentation, and 
reporting of AEs and SAEs.
9.4.11
Enrollment
Enrollment is defined as the time of initiation of the first dose of radiation. Procedures for 
completing enrollment information are described in the Study Manual.
9.4.12
Cardiac Monitoring
9.4.12.1
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 SOE (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. 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.
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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 as 
AEs if, in the opinion of the investigator, there has been a clinically significant change from 
baseline. 
9.4.13
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 trial participant cannot access a clinical trial 
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 trial participants. Every effort should be made by the treating site to ensure 
laboratory normal ranges are collected from any such alternative locations.
9.4.13.1
Clinical Chemistry, Hematology, Coagulation, Thyroid Function, and Urinalysis
Blood samples for analysis of the clinical chemistry, hematology, coagulation, and thyroid 
function shown in Table 9.a and urine samples for analysis of the parameters shown in Table 9.b
will be obtained as specified in the SOE (Appendix A).
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Table 9.a
Clinical Chemistry, Hematology, Coagulation, and Thyroid Function Tests
Hematology
Serum Chemistry
Hematocrit
Hemoglobin
Leukocytes with differential
Neutrophils (ANC)
Platelets (count)
RBC
MCH
MCV
MCHC
Protein (total)
Albumin
Alkaline phosphatase
Alanine aminotransferase
Aspartate aminotransferase
Bilirubin (total)
Bilirubin (direct)
Gamma glutamyl transferase
Glucose (random blood 
glucose)
Lactate dehydrogenase
Amylase
Lipase
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 (T4)
Total or free triiodothyronine (total or free T3)
Activated partial thromboplastin time
Prothrombin time (or prothrombin international normalized ratio)
Other 
Ferritin
Creatine phosphokinase
ANC: absolute neutrophil count; MCH: mean corpuscular hemoglobin; MCHC: mean corpuscular hemoglobin 
concentration; MCV: mean corpuscular volume; RBC: red blood cell.
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Table 9.b
Clinical Urinalysis Tests
Urinalysis
Bilirubin
Glucose
Ketones
Leukocyte esterase
Nitrite
Occult blood
pH
Protein
Specific gravity
Turbidity and color
Urobilinogen
If creatinine clearance is to be estimated, the Cockcroft-Gault formula (see Appendix F) will be 
employed as follows (Cockcroft and Gault 1976):
	
 
	
 
		
 
= [(140 −	
) ∗
ℎ () ] / [72 ∗
! 
	
(/")] 
For female patients, the result of the formula above should be multiplied by 0.85.
9.4.14
Disease Assessment
For all patients, radiographic assessments of the disease will be performed at screening/baseline 
(within 28 days before the first study radiation treatment), once at the end of Cycle 2 (Day 15 to 22 
[predose]), then at the end of every 3 cycles (Day 15 to 22 [predose]) for the first year, and then at 
the end of every 6 cycles (+7 days) thereafter until PD or the start of alternative therapies.
Tumor assessments for all patients will continue as scheduled per protocol even if dosing is 
interrupted. If the patient has had an appropriate CT or MRI scan performed within 28 days of the 
first dose of radiation the results of that scan may be used for tumor lesion measurements at 
screening. Patients will undergo CT with IV contrast or MRI, as appropriate to monitor and assess 
response status, using RECIST (v.1.1) criteria and modified itRECIST criteria (where intratumoral 
therapy references are largely replaced with radiation therapy).
For this study, CT and/or MRI scans should be acquired with IV contrast unless contraindicated. 
CT scans of the neck (required for patients with head and neck squamous cell carcinoma and if 
clinically indicated for patients with TNBC and NSCLC), chest, abdomen, and pelvis will be 
obtained at screening. Before radiation therapy, the radiology oncologist and medical oncologist 
should agree on the target lesions identified for irradiation using the baseline imaging assessments. 
The imaging modalities used and anatomy scanned at baseline should remain consistent 
throughout the study. If contrast enhanced CT scans are contraindicated for a particular patient, a 
noncontrast CT of the chest, in addition to contrast enhanced abdomen and pelvis 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. Radiographic images will be maintained at the site and can be requested by 
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the sponsor for centralized review of the images. Determination of disease status will be based on 
local investigator assessment.
9.4.14.1
Special Allowances to RECIST v.1.1 and Treatment Beyond Progression
9.4.14.1.1
Irradiated and Nonirradiated Response
In order to meet the secondary objective of this study, investigators (or designee) are asked to not 
only assess overall response at each timepoint using RECIST v.1.1, but also to assess both the 
irradiated and nonirradiated response at each timepoint as depicted in Figure 9.a aligning with 
principles akin to those of itRECIST (where intratumoral therapy references are largely replaced 
with radiation therapy) (Goldmacher et al. 2020).
Figure 9.a
Illustration of Irradiated, Nonirradiated, and Overall Responses per Modified 
itRECIST
Source: (Goldmacher et al. 2020).
TI: target irradiated; T-NI: target nonirradiated; NT-I: nontarget irradiated; NT-NI: nontarget nonirradiated
According to the inclusion criteria, patients must have at least 2 measurable lesions (ie, >10 mm 
longest diameter for extranodal lesions, >15 mm short axis for lymph nodes), with at least one 
inside and at least one other outside of the radiation field. As stated in Section 8.1.1, 1 lesion and 
up to 3 lesions may be radiated. For the purposes of response assessment, investigators are asked to 
evaluate response using both RECIST v.1.1 and modified itRECIST. 
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The principles of RECIST v.1.1 still apply whereby selection of target lesions in a previously 
irradiated area or in an area subjected to other loco-regional therapy, unless there has been 
demonstrated progression in the lesion(s), is discouraged; therefore, irradiated lesions in this study 
will not be considered part of the RECIST v.1.1 assessment. No more than 5 target lesions in total 
and no more than 2 per organ may be selected in accordance with RECIST v.1.1. The same lesions 
identified as target and nontarget at screening, before radiation administration, will be followed at 
each subsequent response assessment.
For response assessment using modified itRECIST, lesion measurements should be performed per 
RECIST v.1.1 per guidelines on size and reproducibility, except that it is acceptable to select the 
irradiated lesions as target lesions. Baseline lesions are categorized as target irradiated (T-I), 
target, nonirradiated (T-NI), nontarget irradiated (NT-I), and nontarget nonirradiated (NT-NI) 
according to an algorithm (Figure 9.a). The same target and nontarget lesions selected as part of 
the RECIST v.1.1 assessment at screening may be used for the nonirradiated target or nontarget 
lesions selected under the modified itRECIST assessment. One and up to 3 lesions may be 
irradiated. At least 1 lesion must be T-I, while the remaining 2 may be T-I or NT-I. One to 3
measurable lesions are designated as T-I and are used to evaluate the irradiated lesion response.
One to 5 measurable lesions are designated as T-NI. The irradiated response is based entirely on 
T-I lesions aggregating the sum of the largest diameter for all of the irradiated target lesions, while 
the nonirradiated response is based entirely on T-NI lesions aggregating the sum of the largest 
diameter for all of the nonirradiated target lesions. Overall target lesion response, nontarget lesion 
response, and new lesion appearance are defined as they are for RECIST v.1.1 and combined 
similarly to determine the itRECIST overall response for each visit. The overall response should 
include all lesions classified as target at baseline (sum of diameters of T-I and T-NI combined vs
sum of diameters at baseline and at nadir), all nontarget lesions (NT-I and NT-NI) combined 
(classified as absent, present, or collectively showing unequivocal progression), and new lesions.
9.4.14.1.2
Treatment Beyond Progression
RECIST v.1.1 criteria and not modified itRECIST criteria will be used to evaluate considerations 
for treatment beyond progression. When assessing response, special consideration should be given 
to the tumor response characteristics associated with immunotherapy:
1. Measurable tumor size reduction may take longer with immunotherapy than with a cytotoxic 
regimen.
2. Response to immunotherapy may occur after appearance of PD, as assessed per conventional 
RECIST v.1.1 (see Appendix H). In particular, small, new lesions may appear in the presence 
of other responsive target lesions (pseudo-progression).
3. Durable stable disease (SD) may represent antitumor activity of immunotherapy.
Therefore, allowances to RECIST v.1.1 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. 
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Accordingly, patients will be permitted to continue treatment beyond initial RECIST v.1.1-defined 
PD if the following criteria are met:
1. Investigator-assessed overall clinical benefit from continued treatment with pembrolizumab 
and/or TAK-676. The assessment of clinical benefit should consider whether the patient is 
clinically deteriorating and unlikely to receive further benefit from continued treatment.
2. Tolerance of study drug(s).
3. Stable performance status.
4. Treatment beyond apparent progression will not delay an imminent intervention to prevent 
serious complications of PD (eg, central nervous system metastases).
5. 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 v.1.1-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 upon documentation of further PD. If the 
patient experiences rapid clinical deterioration as perceived by the investigator within 8 weeks of 
original PD and before additional radiographic assessment, 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 v.1.1-defined progression will be 
considered to have investigator-assessed PD at the time of the initial progression event, if the 
progression is confirmed on the subsequent scan as detailed in SOE (Appendix A).
9.4.15
Biomarker, Pharmacodynamic, and PK Samples
9.4.15.1
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-676 (as applicable) and biomarker 
assessments (except for tumor biopsy). These samples must be collected on their own dedicated 
line, separate from the TAK-676/pembrolizumab administration line. The primary specimen 
collection is presented in Table 9.c.
If necessary, plasma samples collected for PK assessments may also be used for exploration of 
pharmacodynamic biomarkers. These plasma 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.
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Table 9.c
Primary Specimen Collection
Specimen Name in 
Schedule of 
Procedures
Primary 
Specimen
Primary 
Specimen 
Derivative 1
Primary Specimen 
Derivative 2
Description of 
Intended Use
Sample 
Collection
Archival (banked) 
tumor tissue sample
FFPE 
block/slides
DNA
RNA
Protein
Biomarker 
measurements
Required, if 
sample is 
available
Fresh tumor tissue 
biopsy sample
Fresh tumor 
tissue
FFPE 
block/slides
DNA/RNA/Protein
Biomarker 
measurements
Mandatory a
Plasma sample for 
circulating biomarkers
Plasma
Proteins
DNA/RNA/Metabolites
Biomarker 
measurements
Mandatory
Blood sample for 
immunophenotyping
Blood
Cells
Biomarker 
measurements
Mandatory
Blood sample for 
RNA
Blood
RNA
Biomarker 
measurements
Mandatory
Blood sample for 
receptor sequencing
Blood
DNA
Biomarker 
measurements
Mandatory
Plasma sample for 
cell-free DNA
Plasma
DNA
Biomarker 
measurements
Mandatory
Buccal epithelial cells 
sample for DNA
Tissue
DNA
Biomarker 
measurements
Mandatory
Blood sample for 
single cell RNA seq
Blood
RNA
Biomarker 
measurements
Mandatory b
Plasma sample for 
TAK-676 PK
Plasma
PK 
measurements
Mandatory
FFPE: formalin-fixed, paraffin-embedded; PK: pharmacokinetic(s).
a Tumor biopsy is mandatory only for patients receiving dose levels of TAK-676 that have previously shown 
pharmacodynamic activity. For patients receiving lower doses of TAK-676, tumor biopsies are optional but highly 
desired. Patients with a tumor biopsy obtained less than or equal to 3 months before initiation of TAK-676 (study Day 
1), will not be required to undergo a repeat pretreatment biopsy, assuming 1) adequate tumor tissue is available for 
analysis (FFPE block preferred) and 2) no additional antineoplastic agents were administered since the time of the 
biopsy. 
b To be collected from patients from select centers.
9.4.15.2
Tumor Biopsies Measurements
9.4.15.2.1
Banked Tumor
Banked formalin fixed paraffin-embedded tumor tissue or a minimum number of unstained slides 
(refer to Laboratory Manual for information on number of slides to be obtained) of the tumor tissue 
(ie, tumor tissue obtained at the time of the patient’s original diagnosis and/or at the time of 
subsequent procedures conducted as part of the patient’s standard care) will be collected, if 
available, from all enrolled patients to assess baseline features such as gene mutations, gene 
signatures, tumor mutation burden, immune cell content, or biomarkers of response or resistance 
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to treatment that may emerge from future nonclinical or clinical studies. See the Laboratory 
Manual for details.
9.4.15.2.2
Fresh Paired Tumor Biopsy
All patients with a safely accessible lesion outside the radiation field who enroll at dose levels of 
TAK-676 that have been shown to have pharmacodynamic activity will have mandatory tumor 
biopsy performed at screening and during Cycle 1 between Days 15 and 21 if, in the opinion of the 
investigator, such a biopsy would not place the patient at an unjustifiable risk. Pharmacodynamic
activity is defined as evidence of TAK-676–mediated stimulation of the innate and/or adaptive 
immune system in the blood (refer to Section 9.4.15.1) and/or clinical response (CR/PR) in at least 
1 patient from ongoing clinical studies. Dosing cohorts may be backfilled, as needed, to achieve 
this objective. Once pharmacodynamic activity is observed, biopsies will be required from all 
patients with safely accessible nonirradiated lesions enrolled in dose escalation. The number of 
patients projected to be needed to support a statistically supported posterior probability is outlined 
in Appendix K. Tumor biopsies are optional, but strongly encouraged, for patients enrolling at 
lower dose levels. 
The tumor tissue biopsy at screening should be performed at least 2 days after the last dose of any 
prior antineoplastic therapy and within 3 weeks before the first dose of radiation. Screening biopsy 
should be performed only when the patient is considered otherwise eligible. The paired tumor 
biopsies should be performed on a lesion not targeted for irradiation and, when possible, collected 
from the same lesion (pre- and post-treatment). Patients with a tumor biopsy obtained less than or 
equal to 3 months before initiation of radiation therapy on trial will not be required to undergo a 
repeat pretreatment biopsy, assuming 1) adequate tumor tissue is available for analysis 
(formalin-fixed, paraffin-embedded block preferred) and 2) no additional antineoplastic agents 
were administered since the time of the biopsy.
Tumor biopsy procedures must be performed according to standard site practice. The accessible 
lesion biopsied should not have been previously irradiated. The tumor biopsy procedure will be 
performed by core needle, under radiological guidance if indicated, or surgically if the site of 
disease is superficial and palpable or visible. For tumor biopsies, at least 3 tissue cores of 1 cm 
each obtained using an 18-gauge end-cut needle are requested. These paired biopsies will be used 
to evaluate changes in biomarkers following treatment with radiation and pembrolizumab in 
combination with TAK-676, including the modulation of the tumor immune cell profile and 
impact on the tumor. The specific anatomical location of the biopsy should be noted upon 
collection. 
9.4.15.3
Biomarker and Pharmacodynamic Measurements
In this study, several biomarkers and pharmacodynamic measurements will be assessed to test for 
correlation with PK, safety and, if possible, with efficacy. These biomarkers will be used to 
evaluate pharmacodynamic activity and patients who have a higher probability of response or of 
adverse reactions to radiation and pembrolizumab in combination with TAK-676. Because new 
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techniques continue to be developed, the methods and laboratories that will be recommended for 
the biomarker analyses are not specified.
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 tested:
Plasma Sample for Circulating Biomarkers 
Plasma samples will be collected to monitor the treatment-induced changes in peripheral 
biomarkers, including cytokines and chemokines (for example IP-10, an IFN-inducible 
chemokine). The changes in cytokines and chemokines will be used to identify potential 
pharmacodynamic activity. Additional analysis may explore whether levels of any of these 
biomarkers correlate with probability of response or of adverse reactions to radiation and 
pembrolizumab in combination with TAK-676.
Blood Sample for Immunophenotyping
Blood samples will be collected for assessment of immunophenotypic changes in circulating 
immune cells induced by radiation and pembrolizumab in combination with TAK-676. These 
blood samples will be analyzed for the presence and changes in immune cell state by 
immunophenotyping; including, but not limited to B and T lymphocytes, monocytes, NK cells, 
and DCs.
Blood Sample for RNA 
Blood samples for RNA will be collected for sequencing or expression analysis to monitor gene 
expression changes as a pharmacodynamic effect of radiation and pembrolizumab in combination 
with TAK-676 where acceptable by law. The induction of the STING agonism/type I IFN gene 
signature will be evaluated as part of this analysis. Additional blood samples collected at select 
centers may be analyzed by single cell RNA sequencing to determine changes in gene expression 
within particular cell types of interest, including T cells, NK cells, and monocytes.
Blood Sample for Receptor Sequencing
To monitor for induction of an adaptive immune response, blood samples will be collected to 
sequence T cell and B cell receptors where acceptable by law. Clonality and diversity of the 
receptors may be evaluated with any significant changes being associated with an expanded or 
contracted cellular population.
Plasma Sample for Cell-Free DNA
Plasma samples will be collected for evaluation of cell-free DNA where acceptable by law. From 
the cell-free DNA, circulating tumor DNA may be evaluated to assess tumor mutations.
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9.4.15.4
PK Measurements
Details regarding the preparation, handling, and shipping of the PK samples are provided in the 
Laboratory Manual. Plasma samples for PK will be collected at the time points specified in 
Appendix A. The peripheral IV line on which PK/pharmacodynamics samples are to be drawn 
should be a dedicated line, separate from the TAK-676/pembrolizumab administration line. 
Ideally, the dedicated line should be contralateral, or at a minimum, distal to where 
TAK-676/pembrolizumab is being infused. 
The timing, but not the total number of plasma samples may be modified during the study based on 
emerging PK data if a change in sampling scheme is considered necessary to better characterize 
the PK and pharmacodynamic relationship of TAK-676. A protocol amendment is not necessary 
for such modifications.
Plasma collected in this study will be used to measure the level of TAK-676. The plasma from 
selected patients may be used for exploratory analysis of TAK-676–related metabolites to 
understand TAK-676 metabolism and excretion mechanisms. The results of such exploratory 
metabolite analyses (qualitative or semiquantitative), if conducted, will be presented in a separate 
report and not in the CSR for this study.
9.4.15.5
DNA Analysis
As detailed in the SOE (Appendix A), a buccal epithelial cell sample will be collected during 
screening to extract DNA as a control sample for DNA mutation analysis from banked tumor 
and/or fresh tumor biopsies. In addition, the extracted DNA from such samples may be used in 
eventual pharmacogenomic evaluation to study the impact of genetic polymorphism, including 
drug metabolizing enzymes and/or transporters that may be implicated in the disposition of 
TAK-676, and polymorphisms in the gene encoding STING protein (TMEM173). The data 
resulting from such analyses, if performed, may be pooled with similar data from other TAK-676 
clinical studies and will be reported separately and not within the CSR for this study. This sample 
may be collected during the study if the sample cannot be collected at screening.
9.5
Documentation of Patient Screen Failure
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:

Death.

AE.

Failed inclusion criteria or did meet exclusion criteria.

Protocol deviation.
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
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 (for Individual Patients)
Patients will be considered to have completed study treatment if they discontinue pembrolizumab 
and/or TAK-676 for any of the reasons outlined in Section 9.7.
9.7
Discontinuation of Treatment With Study Drug and Patient Replacement
Patients will be informed that they have the right to discontinue study treatment at any time for any 
reason, without prejudice to their medical care. A patient’s participation in the study may also be 
discontinued at any time at the discretion of the Investigator. It is possible that 1 study drug is 
permanently discontinued due to treatment-related AEs, while the patient continues to receive the 
other study drug and remains on treatment. Discontinuation of treatment occurs only when both 
study drugs are required to be discontinued due to AEs or upon the occurrence of any of the other 
non-AE criteria.
Treatment with radiation and/or study drugs may be discontinued for any of the following reasons:

AE 

Protocol deviation (after discussion with sponsor).

PD (tumor progression documented as assessed per RECIST v.1.1): as noted previously, 
patients who meet the criteria for PD per RECIST v.1.1 may continue to stay on study if they 
are clinically benefitting (see Section 9.4.14.1). 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 decline 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.
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
Lost to follow-up.

Other (after discussion with sponsor). 
Once both study drugs have been discontinued, all study procedures outlined for the EOT visit will 
be completed as specified in the SOE (Appendix A). 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. If the reason for 
ending treatment is also the reason for end of study (EOS) (for example, death), the EOS eCRF 
should be completed.
Patients not receiving all required doses of radiation, TAK-676, and pembrolizumab through 
Cycle 1 for reasons other than DLTs will not be considered DLT evaluable but may remain on 
study. If a patient is DLT inevaluable, patient replacement may not be mandatory. In this case, the 
decision for patient replacement can be determined based on the number of DLT-evaluable 
patients in the cohort, as agreed between the sponsor and investigators.
In the case of study termination by the sponsor, eligible patients may have continued access to 
TAK-676/pembrolizumab 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 12 weeks (±1 week) from the EOT visit 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. Survival status, date of 
disease progression based on available local data, and subsequent anticancer therapies will be 
collected during this follow-up period. This information may be collected by methods that include, 
but are not limited to, telephone, email, mail, or retrieval from online or other databases (eg, Social 
Security indexes).
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 are discontinued from both study 
drugs and 1 or more of the following situations occur:

Death.

Consent withdrawal.

Study terminated by the sponsor.
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
Lost to follow-up.

Completion of follow-up period and assessments, if applicable.

PD.

Start of new systemic anticancer treatment.

Transfer of patient to a long-term safety study, single-patient investigational new 
drug application, or similar program.
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. 
At this time, the EOS eCRF should be completed.
9.10
Study Compliance
Radiation treatment and study drug(s)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. If an AE occurs after study 
radiation treatment (irrespective of causality) that leads to a delay in the start of planned study 
drug(s) administration on Cycle 1 Day 1, Cycle 1 Day 1 may be delayed for up to 1 week following 
discussion with the Medical Monitor or designee. Any Cycle 1 Day 1 delays beyond this 
timeframe would require additional approval from the Medical Monitor or designee.
Allowable windows on dosing days are described in Section 8.1.3.
If a dose of TAK-676 is held for up to 21 days for reasons unrelated to toxicity, the patient may be 
discontinued from the study following a discussion between the investigator and the sponsor.
10.0
ADVERSE EVENTS
10.1
Definitions
10.1.1
Pretreatment Event Definition
A pretreatment event is any untoward medical occurrence in a patient or subject who has signed 
informed consent to participate in a study but before administration of any study medication; it 
does not necessarily have to have a causal relationship with study participation.
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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 
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, 
based on appropriate medical judgment, it may jeopardize the patient, require medical or 
surgical intervention to prevent 1 of the outcomes listed above, or involves suspected 
transmission via a medicinal product of an infectious agent. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse; any organism, virus, or infectious particle 
(eg, prion protein transmitting transmissible spongiform encephalopathy), pathogenic or 
nonpathogenic, is considered an infectious agent. In addition to the above examples, any event 
that the investigator considers to be medically important will be considered an SAE.
In this study, intensity for each AE, including any laboratory abnormality, will be determined 
using the NCI CTCAE, Version 5.0. 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 
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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.
10.2
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 (as defined in Section 10.1.3) 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 should be done by transmitting 
an electronic data capture (EDC) SAE report. If transmission of an EDC SAE report is not feasible 
within 24 hours of becoming aware of this event, then a Takeda paper-based SAE form should be 
submitted via fax at the fax numbers provided below. The SAE form, created specifically by 
Takeda, will be provided to each clinical study site. A sample of the paper-based SAE form and 
processing directions are found in the Study Manual. Information in the SAE report or form must 
be consistent with the data provided on the eCRF. 
In case of 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:

United States 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. In case of 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:

takedaoncocases@cognizant.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 administration. 
Severity (toxicity grade) for each AE, including any laboratory abnormality, will be determined 
using the NCI CTCAE, Version 5.0. The criteria are provided in the Study Manual.
Relationship of the event to study drug administration (ie, its causality) will be determined by the 
investigator responding yes (related) or no (unrelated) to this question: Is there a reasonable 
possibility that the AE is associated with the study drug/s?
10.3
Monitoring of AEs and Period of Observation
AEs, both nonserious and serious, will be monitored throughout the study as follows:

All 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) or before initiation of new anticancer 
therapy (whichever comes first) and recorded in the eCRFs.
AEs that the investigator considers to be immune-mediated will be reported 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 will be reported to the Takeda Global Pharmacovigilance department or designee from 
the time of signing of informed consent through 30 days after administration of the last dose of 
study drug(s) or before initiation of new anticancer therapy (whichever comes first) and 
recorded in the eCRF. 
Only related SAEs occurring greater than 30 days after the last dose of study drug(s) (until 
patient completes the study or initiates new anticancer therapy) must be reported to the Takeda 
Global Pharmacovigilance department or designee. 
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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 120 days after the last dose of study drug.
10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose)
10.5.1
TAK-676
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.
A medication error is a preventable event that involves an identifiable patient and leads to 
inappropriate medication use, which may result in patient harm. Overdoses and underdoses 
constitute medication errors. Individuals who identify a potential medication error (including 
overdose) situation should immediately report this via the phone numbers or email addresses 
provided in the Study Manual.
Product complaints and medication errors in and of themselves are not AEs. If a product complaint 
or a medication error results in an SAE, the SAE should be reported. 
10.5.2
Pembrolizumab
“Pembrolizumab Injection 100 mg/4 mL (25 mg/mL) solution in a single-dose vial” will be either 
labeled as study material and supplied by the sponsor or sourced locally by the clinical site when 
arrangements have been made and agreed to by sponsor and where regulations allow for clinical 
site sourcing, appropriate labeling, and compliance with local and regional regulations. 
Information on the formulation, packaging, and storage of pembrolizumab is provided in the most 
recent package insert. For product complaints related to pembrolizumab provided by the sponsor, 
please see the Pharmacy Manual. For product complaints related to pembrolizumab sourced 
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locally by the clinical site, utilize standard methods to contact product manufacturer or regulatory 
agency as 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. Relative to the first awareness of the 
event by/or further provision to the sponsor or sponsor’s designee, SUSARs will be submitted to 
the regulatory authorities as expedited reports within 7 days for fatal and life-threatening events 
and within 15 days for other serious events, unless otherwise required by national regulations. The 
sponsor will also prepare an expedited report for other safety issues where these might materially 
alter the current benefit-risk assessment of an investigational medicinal product or that would be 
sufficient to consider changes in the investigational medicinal product’s administration or in the 
overall conduct of the study. The investigational site also will forward a copy of all expedited 
reports to his or her IRB or IEC in accordance with national regulations.
11.0
STUDY-SPECIFIC COMMITTEES
No steering committee, data safety monitoring committee, or clinical endpoint committee will be 
used in this 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 research 
organization (CRO) partners, and regulatory authorities. Investigative sites must complete eCRFs 
in English.
After completion of the entry process, computer logic checks will be run to identify items such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designee) and will be answered by the site.
Any change of, modification of, or addition to the data on the eCRFs should be made by the 
investigator or appropriate site personnel. Corrections to eCRFs are recorded in an audit trail that 
captures the old information, the new information, identification of the person making the 
correction, the date the correction was made, and the reason for the change.
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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.
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.
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13.1.1
Analysis Sets
The analysis sets will include the following:

Safety analysis set: Patients who have received at least 1 dose of radiation will be included in 
all safety analyses.

PK analysis set: Patients dosed with TAK-676 for whom plasma concentration data have been 
collected will be used for PK analyses. 

DLT-evaluable analysis set: The DLT-evaluable analysis set will include patients who 
receive all Cycle 1 doses of TAK-676 in addition to pembrolizumab and radiation without 
experiencing a DLT or who have a DLT during Cycle 1.
Patients who receive only 1 or 2 doses of radiation will not be considered DLT evaluable and 
may or may not be replaced within the same cohort but will be allowed to continue on study.

Comprehensive response-evaluable analysis set: The comprehensive response-evaluable 
analysis set, a subset of the safety analysis set including patients with measurable disease at 
baseline, at least 1 posttreatment evaluation or who discontinued before their first postbaseline 
tumor assessment will be used for analyses of response.
- Response-evaluable analysis subset: The response-evaluable analysis subset, a subset 
of the safety analysis and comprehensive response evaluable analysis set including patients 
with measurable disease at baseline and at least 1 posttreatment evaluation, will be used as 
a subset analysis of response.

Pharmacodynamic analysis set: The pharmacodynamic analysis set will include those 
patients in the safety population who have received at least 1 dose of TAK-676 and who have 
baseline and at least 1 postbaseline pharmacodynamic sample assessment.
13.1.2
Analysis of Demographics and Other Baseline Characteristics
Patient demographic and baseline characteristics will be summarized descriptively. Variables to be 
analyzed include sex, age, race, medical history, prior medications/therapies, ECG findings and 
other parameters as appropriate. For continuous variables, descriptive statistics (number, mean, 
standard deviation, median, minimum, and maximum) will be provided. For categorical variables, 
patient counts and percentages will be provided. Categories for missing data will be presented as 
needed.
13.1.3
Efficacy Analysis
Efficacy is not the primary endpoint for this study. Secondary efficacy endpoints include ORR, 
ORRnonirradiated, ORRirradiated, DOR, DORnonirradiated, DORirradiated, TTR, 
TTRnonirradiated, and TTRirradiated. No formal statistical tests will be performed for these 
secondary endpoints. Response assessments by investigator are based on RECIST v.1.1 
(Eisenhauer et al. 2009) and a modified itRECIST (where intratumoral therapy references are 
largely replaced with radiation therapy) referenced in Section 9.4.14.
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ORR is defined as the proportion of patients who achieve cCR or cPR (determined by the 
investigator) during the study in response-evaluable population.
ORRnonirradiated is defined as the proportion of patients who achieve cCR or cPR (determined 
by the investigator) in the tumor lesions lying outside of the radiation field during the study in 
response-evaluable population.
ORRirradiated is defined as the proportion of patients who achieve cCR or cPR (determined by 
the investigator) in the tumor lesions lying within the radiation field during the study in 
response-evaluable population.
DOR is 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). Responders without documentation of PD 
will be censored at the date of last response assessment that is SD or better.
DORnonirradiated is the time from the date of first documentation of a cPR or better in the tumor 
lesions lying outside of the radiation field to the date of first documentation of nonirradiated PD in 
those lesions for nonirradiated responders (cPR or better). Nonirradiated responders without 
documentation of nonirradiated PD will be censored at the date of last response assessment that is 
nonirradiated SD or better.
DORirradiated is the time from the date of first documentation of a cPR or better in the tumor 
lesions lying within the radiation field to the date of first documentation of irradiated PD in those 
lesions for local responders (cPR or better). Local responders without documentation of local PD 
will be censored at the date of last response assessment that is local 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 by the investigator.
TTRnonirradiated is defined as the time from the date of first dose administration to the date of 
first documented cPR or better in the tumor lesions lying outside of the radiation field by the 
investigator.
TTRirradiated is defined as the time from the date of first dose administration to the date of first 
documented cPR or better in the tumor lesions lying within the radiation field by the investigator.
ORR, ORRnonirradiated, and ORRirradiated will be summarized using descriptive statistics with 
95% CI. DOR, DORnonirradiated, DORirradiated, TTR, TTRirradiated, and TTRirradiated will 
also be analyzed using Kaplan-Meier method for response-evaluable analysis set.
13.1.4
Pharmacokinetic Analysis 
13.1.4.1
PK Analysis
Individual TAK-676 concentration-time data 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.
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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-676. These population PK analyses may additionally include data collected in other 
TAK-676 clinical studies. The plan for the population PK analysis will be defined separately and 
the results reported separately.
13.1.5
Pharmacodynamic Analysis 
Changes in T-cell infiltration levels between the pretreatment and on-treatment tumor biopsies 
will be summarized.
Changes between pretreatment and on-treatment peripheral blood samples in levels of plasma 
biomarkers, including cytokines and chemokines, and gene expression, including the STING 
agonism/type I IFN signature may be summarized.
Relationship between response to combination treatment regimen and mutations or 
polymorphisms in immune response or DNA damage repair genes may be analyzed. Relationship 
between response to combination treatment regimen and polymorphisms in the STING gene 
(TMEM173) and drug transporter genes relevant to TAK-676 may be investigated.
13.1.6
PK/Pharmacodynamic Analysis 
The relationship between TAK-676 plasma exposure and pharmacodynamic response (eg, degree 
of immune activation, changes in cytokines/chemokines, gene expression changes) will be 
explored on an ongoing basis as PK and pharmacodynamic data become available to understand 
the PK/pharmacodynamic relationship of TAK-676. Data permitting, mathematical models may 
be used to describe this relationship, and such models may be used to predict the dose/schedule of 
TAK-676 that provides the desired exposure and pharmacological response for future evaluation. 
These data may be presented graphically as well as summarized in the CSR. The analysis will be 
performed in the pharmacodynamic population.
In addition, the PK/pharmacodynamic data collected in the study during dose escalation may be 
used to inform the quantitative systems pharmacology model that may be used to further refine the 
dose/schedule for TAK-676. Furthermore, the PK/pharmacodynamic data collected in this study 
may be pooled with similar data from other clinical studies for population analysis purposes. The 
results of such PK/pharmacodynamic and population PK/pharmacodynamic analyses and 
quantitative systems pharmacology modeling may not be presented in the CSR for this study but 
will be presented in a separate report.
13.1.7
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.
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13.1.8
Safety Analysis
Safety will be evaluated by the frequency of AEs, severity and types of AEs, and by changes from 
baseline in patients’ vital signs, weight, and clinical laboratory results using the safety analysis set. 
Exposure to study drug and reasons for discontinuation will be tabulated. 
TEAEs that occur after administration of the first dose of study 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).

TESAEs (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 scores will be summarized 
using a shift table. 
Shift tables for laboratory parameters will be generated for changes in NCI CTCAE grade from 
baseline to 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 study drugs’ 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 study drugs.
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13.2
Interim Analysis and Criteria for Early Termination
Although no formal interim analysis is planned, investigators and sponsor representatives will 
review accruing data to determine dose escalation decision and number of patients per cohort in 
the dose escalation phase. 
13.3
Determination of Sample Size
Approximately 65 patients with metastatic NSCLC, TNBC, or SCCHN will be enrolled in this 
study, to achieve a maximum of 55 DLT evaluable patients. They will receive pembrolizumab 
administered at 200 mg IV every 3 weeks, and TAK-676 administered in a dose escalating fashion 
followed by BOIN design, with an explorable dose range of 0.2 to 9.0 mg administered on Days 1, 
8, and 15 of every 21-day cycle. 
The details of dose escalation rules are specified in Section 8.3.
14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study-Site Monitoring Visits
Monitoring visits will be conducted 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 (CRO) 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 
including, but not limited to, the investigator’s binder, study medication, subject medical records, 
informed consent documentation, documentation of subject authorization to use personal health 
information (if separate from the ICFs), and review of eCRFs and associated source documents. It 
is important that the investigator and other study personnel are available during the monitoring 
visits and that sufficient time is devoted to the process.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB 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.
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The site should document all protocol deviations in the subject’s source documents. In the event of 
a significant deviation, the site should notify the sponsor or its designee (and IRB or EC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of the primary study 
assessment.
The sponsor will assess any protocol deviation; if it is likely to affect to a significant degree the 
safety and rights of a subject or the reliability and robustness of the data generated, it may be 
reported to regulatory authorities as a serious breach of GCP and the protocol.
14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the US FDA, the United Kingdom [UK] Medicines and 
Healthcare products Regulatory Agency [MHRA], the Pharmaceuticals and Medical Devices 
Agency of Japan [PMDA]). If the study site is contacted for an inspection by a regulatory body, the 
sponsor should be notified immediately. The investigator and institution guarantee access for 
quality assurance auditors to all study documents as described in Section 14.1.
15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, patients) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the responsibilities of the investigator that are listed in Appendix B. 
The principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities.
15.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable requirements of each participating 
region. The sponsor or designee will require documentation noting all names and titles of members 
who make up the respective IRB or IEC. If any member of the IRB or IEC has direct participation 
in this study, written notification regarding his or her abstinence from voting must also be 
obtained. Those American sites unwilling to provide names and titles of all members because of 
privacy and conflict of interest concerns should instead provide a Federal wide Assurance number 
or comparable number assigned by the US Department of Health and Human Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the IB, a copy of the ICF, and, if 
applicable, subject recruitment materials and advertisements and other documents required by all 
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applicable laws and regulations must be submitted to a central or local IRB or IEC for approval. 
The IRB’s or IEC’s written approval of the protocol and subject informed consent must be 
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 site once the sponsor has confirmed the adequacy of site regulatory 
documentation and, when applicable, the sponsor has received permission from the competent 
authority to begin the study. Until the site receives 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 subjects, local safety reporting requirements, reports and 
updates regarding the ongoing review of the study at intervals specified by the respective IRB or 
IEC, and submission of the investigator’s final status report to IRB or IEC. All IRB and IEC 
approvals and relevant documentation for these items must be provided to the sponsor (or 
designee).
Patients incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor.
15.2
Patient Information, Informed Consent, and Patient Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The ICF describes 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 
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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 (if acceptable at site), must be given 
ample opportunity to (1) inquire about details of the study and (2) decide whether to participate in 
the study. If the patient, or the patient’s legally acceptable representative, determines that he or she 
will participate in the study, then the ICF and patient authorization form (if applicable) must be 
signed and dated by the patient, or the patient’s legally acceptable representative, at the time of 
consent and before the patient enters into the study. The patient or the patient’s legally acceptable 
representative should be instructed to sign using their legal names, not nicknames, using a 
ballpoint pen with either blue or black ink. The investigator must also sign and date the ICF and 
patient authorization (if applicable) at the time of consent and before the patient enters into the 
study; however, the sponsor may allow a designee of the investigator to sign to the extent 
permitted by applicable law.
Once signed, the original ICF, patient authorization form (if applicable), and patient information 
sheet (if applicable) will be stored in the investigator’s site file. The investigator must document 
the date the patient signs the informed consent in the patient’s medical record. Copies of the signed 
ICF, the signed patient authorization form (if applicable), and patient information sheet (if 
applicable) shall be given to the patient.
All revised ICFs must be reviewed and signed by relevant patients or the relevant patient’s legally 
acceptable representative in the same manner as the original informed consent. The date the 
revised consent was obtained should be recorded in the patient’s medical record, and the patient 
should receive a copy of the revised ICF.
15.3
Patient Confidentiality
The sponsor and designees affirm and uphold the principle of the patient’s right to protection 
against invasion of privacy. Throughout this study, a patient’s source data will be linked to the 
sponsor’s clinical study database or documentation only via a unique identification number. As 
permitted by all applicable laws and regulations, limited patient attributes, such as sex, age, or date 
of birth, and patient initials may be used to verify the patient and accuracy of the patient’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, US FDA, UK MHRA, Japan PMDA), the sponsor’s 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).
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Copies of any patient source documents that are provided to the sponsor must have certain 
identifying personal information removed, eg, patient name, address, and other identifier fields not 
collected on the patient’s eCRF.
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1
Publication 
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the clinical study site agreement. In the event of any discrepancy between the 
protocol and the clinical study site agreement, the clinical study site agreement will prevail.
15.4.2
Clinical Trial Registration
To ensure that information on clinical trials reaches the public in a timely manner and to comply 
with applicable laws, regulations, and guidance, Takeda will, at a minimum, register interventional 
clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other publicly accessible 
websites on or before start of study, as defined by Takeda policy/standards. Takeda contact 
information, along with investigator’s city, state (for Americas investigators), country, and 
recruiting status will be registered and available for public viewing. 
As needed, Takeda and investigator/site contact information may be made public to support 
participant access to trials via registries. In certain situations/registries, Takeda may assist 
participants or potential participants in finding a clinical trial by helping them locate trial sites 
closest to their homes by providing the investigator name, address, and phone number via 
email/phone or other methods preferred by callers requesting trial information. Once patients 
receive investigator contact information, they may call the site requesting enrollment into the trial. 
The investigative sites are encouraged to handle the trial inquiries according to their 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, 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.
16.0
REFERENCES
Adams, S., Gatti-Mays, M. E., Kalinsky, K., Korde, L. A., Sharon, E., Amiri-Kordestani, L., et al. 
2019a. Current Landscape of Immunotherapy in Breast Cancer: A Review. JAMA Oncol.
Adams, S., Loi, S., Toppmeyer, D., Cescon, D. W., De Laurentiis, M., Nanda, R., et al. 2019b. 
Pembrolizumab monotherapy for previously untreated, PD-L1-positive, metastatic 
triple-negative breast cancer: cohort B of the phase II KEYNOTE-086 study. Ann Oncol,
30(3), 405-11.
Ager, C. R., Reilley, M. J., Nicholas, C., Bartkowiak, T., Jaiswal, A. R. and Curran, M. A. 2017. 
Intratumoral STING Activation with T-cell Checkpoint Modulation Generates Systemic 
Antitumor Immunity. Cancer Immunol Res, 5(8), 676-84.
Ahmad, S. S., Duke, S., Jena, R., Williams, M. V. and Burnet, N. G. 2012. Advances in 
radiotherapy. BMJ, 345, e7765.
Apetoh, L., Ghiringhelli, F., Tesniere, A., Obeid, M., Ortiz, C., Criollo, A., et al. 2007. Toll-like 
receptor 4-dependent contribution of the immune system to anticancer chemotherapy and 
radiotherapy. Nat Med, 13(9), 1050-9.
Baird, J. R., Friedman, D., Cottam, B., Dubensky, T. W., Jr., Kanne, D. B., Bambina, S., et al. 
2016. Radiotherapy Combined with Novel STING-Targeting Oligonucleotides Results in 
Regression of Established Tumors. Cancer Res, 76(1), 50-61.
Bang, A., Wilhite, T. J., Pike, L. R. G., Cagney, D. N., Aizer, A. A., Taylor, A., et al. 2017. 
Multicenter Evaluation of the Tolerability of Combined Treatment With PD-1 and 
CTLA-4 Immune Checkpoint Inhibitors and Palliative Radiation Therapy. Int J Radiat 
Oncol Biol Phys, 98(2), 344-51.
For non-commercial use only

TAK-676
Study No. TAK-676-1003
Page 131 of 167
Protocol Incorporating Amendment No. 2
18 February 2022
CONFIDENTIAL
Benedict, S. H., Yenice, K. M., Followill, D., Galvin, J. M., Hinson, W., Kavanagh, B., et al. 2010. 
Stereotactic body radiation therapy: the report of AAPM Task Group 101. Med Phys,
37(8), 4078-101.
Borghaei, H., Langer, C. J., Gadgeel, S., Papadimitrakopoulou, V. A., Patnaik, A., Powell, S. F., et 
al. 2019. 24-Month Overall Survival from KEYNOTE-021 Cohort G: Pemetrexed and 
Carboplatin with or without Pembrolizumab as First-Line Therapy for Advanced 
Nonsquamous Non-Small Cell Lung Cancer. J Thorac Oncol, 14(1), 124-9.
Brahmer, J. R., Abu-Sbeih, H., Ascierto, P. A., Brufsky, J., Cappelli, L. C., Cortazar, F. B., et al. 
2021. Society for immunotherapy of cancer (SITC) clinical practice guideline on immune 
checkpoint inhibitor-related adverse events. J Immunother Cancer, 9(6).
Brahmer, J. R., Lacchetti, C., Schneider, B. J., Atkins, M. B., Brassil, K. J., Caterino, J. M., et al. 
2018. Management of immune-related adverse events in patients treated with immune 
checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice 
Guideline. J Clin Oncol, 36(17), 1714-68.
Brenner, D. J. 2008. The linear-quadratic model is an appropriate methodology for determining 
isoeffective doses at large doses per fraction. Semin Radiat Oncol, 18(4), 234-9.
Burnette, B. C., Liang, H., Lee, Y., Chlewicki, L., Khodarev, N. N., Weichselbaum, R. R., et al. 
2011. The efficacy of radiotherapy relies upon induction of type i interferon-dependent 
innate and adaptive immunity. Cancer Res, 71(7), 2488-96.
Chalabi, M., Fanchi, L. F., Dijkstra, K. K., Van den Berg, J. G., Aalbers, A. G., Sikorska, K., et al. 
2020. Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient 
and MMR-deficient early-stage colon cancers. Nature Medicine, 26(4), 566-76.
Cockcroft, D. W. and Gault, M. H. 1976. Prediction of creatinine clearance from serum creatinine. 
Nephron, 16(1), 31-41.
Corrales, L. and Gajewski, T. F. 2015. Molecular Pathways: Targeting the Stimulator of Interferon 
Genes (STING) in the Immunotherapy of Cancer. Clin Cancer Res, 21(21), 4774-9.
Delaney, G., Jacob, S., Featherstone, C. and Barton, M. 2005. The role of radiotherapy in cancer 
treatment: estimating optimal utilization from a review of evidence-based clinical 
guidelines. Cancer, 104(6), 1129-37.
Deng, L., Liang, H., Burnette, B., Beckett, M., Darga, T., Weichselbaum, R. R., et al. 2014a. 
Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. 
J Clin Invest, 124(2), 687-95.
Deng, L., Liang, H., Fu, S., Weichselbaum, R. R. and Fu, Y. X. 2016. From DNA Damage to 
Nucleic Acid Sensing: A Strategy to Enhance Radiation Therapy. Clin Cancer Res, 22(1), 
20-5.
Deng, L., Liang, H., Xu, M., Yang, X., Burnette, B., Arina, A., et al. 2014b. STING-Dependent 
Cytosolic DNA Sensing Promotes Radiation-Induced Type I Interferon-Dependent 
Antitumor Immunity in Immunogenic Tumors. Immunity, 41(5), 843-52.
Dutcher, J. P., Schwartzentruber, D. J., Kaufman, H. L., Agarwala, S. S., Tarhini, A. A., Lowder, J. 
N., et al. 2014. High dose interleukin-2 (Aldesleukin) - expert consensus on best 
management practices-2014. J Immunother Cancer, 2(1), 26.
For non-commercial use only

TAK-676
Study No. TAK-676-1003
Page 132 of 167
Protocol Incorporating Amendment No. 2
18 February 2022
CONFIDENTIAL
Eisenhauer, E. A., Therasse, P., Bogaerts, J., Schwartz, L. H., Sargent, D., Ford, R., et al. 2009. 
New response evaluation criteria in solid tumours: revised RECIST guideline (version 
1.1). Eur J Cancer, 45(2), 228-47.
Fang, P., Jiang, W., Allen, P., Glitza, I., Guha, N., Hwu, P., et al. 2017. Radiation necrosis with 
stereotactic radiosurgery combined with CTLA-4 blockade and PD-1 inhibition for 
treatment of intracranial disease in metastatic melanoma. J Neurooncol, 133(3), 595-602.
Ferrarotto, R., Bell, D., Rubin, M. L., Hutcheson, K. A., Johnson, J. M., Goepfert, R. P., et al. 
2020. Impact of neoadjuvant durvalumab with or without tremelimumab on CD8(+) tumor 
lymphocyte density, safety, and efficacy in patients with oropharynx cancer: CIAO trial 
results. Clin Cancer Res, 26(13), 3211-9.
Formenti, S. C. and Demaria, S. 2013. Combining radiotherapy and cancer immunotherapy: a 
paradigm shift. J Natl Cancer Inst, 105(4), 256-65.
Formenti, S. C., Rudqvist, N. P., Golden, E., Cooper, B., Wennerberg, E., Lhuillier, C., et al. 2018. 
Radiotherapy induces responses of lung cancer to CTLA-4 blockade. Nat Med, 24(12), 
1845-51.
Foulkes, W. D., Smith, I. E. and Reis-Filho, J. S. 2010. Triple-negative breast cancer. N Engl J 
Med, 363(20), 1938-48.
Gandhi, L., Rodriguez-Abreu, D., Gadgeel, S., Esteban, E., Felip, E., De Angelis, F., et al. 2018. 
Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J 
Med, 378(22), 2078-92.
Ghaffari, A., Peterson, N., Khalaj, K., Vitkin, N., Robinson, A., Francis, J. A., et al. 2018. STING 
agonist therapy in combination with PD-1 immune checkpoint blockade enhances response
to carboplatin chemotherapy in high-grade serous ovarian cancer. Br J Cancer, 119(4), 
440-9.
Golden, E. B., Pellicciotta, I., Demaria, S., Barcellos-Hoff, M. H. and Formenti, S. C. 2012. The 
convergence of radiation and immunogenic cell death signaling pathways. Front Oncol, 2, 
88.
Goldmacher, G. V., Khilnani, A. D., Andtbacka, R. H. I., Luke, J. J., Hodi, F. S., Marabelle, A., et 
al. 2020. Response criteria for intratumoral immunotherapy in solid tumors: itRECIST. J 
Clin Oncol, 38(23), 2667-76.
Gupta, A., Probst, H. C., Vuong, V., Landshammer, A., Muth, S., Yagita, H., et al. 2012. 
Radiotherapy promotes tumor-specific effector CD8+ T cells via dendritic cell activation. 
J Immunol, 189(2), 558-66.
Harrington, K. J., Brody, J., Ingham, M., Strauss, J., Cemerski, S., Wang, M., et al. 2018. 
Preliminary results of the first-in-human (FIH) study of MK-1454, an agonist of stimulator 
of interferon genes (STING), as monotherapy or in combination with Pemrolizumab in 
Patients with Advanced Solid Tumors or Lymphomas. ESMO Congress, 2018.
Hiniker, S. M., Reddy, S. A., Maecker, H. T., Subrahmanyam, P. B., Rosenberg-Hasson, Y., 
Swetter, S. M., et al. 2016. A Prospective Clinical Trial Combining Radiation Therapy 
With Systemic Immunotherapy in Metastatic Melanoma. Int J Radiat Oncol Biol Phys,
96(3), 578-88.
For non-commercial use only

TAK-676
Study No. TAK-676-1003
Page 133 of 167
Protocol Incorporating Amendment No. 2
18 February 2022
CONFIDENTIAL
Ho, A. Y., Barker, C. A., Arnold, B. B., Powell, S. N., Hu, Z. I., Gucalp, A., et al. 2020. A phase 2 
clinical trialassessing theefficacy and safety of pembrolizumab and radiotherapy in 
patients with metastatic triple-negative breast cancer. Cancer, 126(4), 850-60.
Ishikawa, H., Ma, Z. and Barber, G. N. 2009. STING regulates intracellular DNA-mediated, type I 
interferon-dependent innate immunity. Nature, 461(7265), 788-92.
Jenkins, R. W., Barbie, D. A. and Flaherty, K. T. 2018. Mechanisms of resistance to immune 
checkpoint inhibitors. Br J Cancer, 118(1), 9-16.
Kinkead, H. L., Hopkins, A., Lutz, E., Wu, A. A., Yarchoan, M., Cruz, K., et al. 2018. Combining 
STING-based neoantigen-targeted vaccine with checkpoint modulators enhances 
antitumor immunity in murine pancreatic cancer. JCI Insight, 3(20).
Konno, H., Yamauchi, S., Berglund, A., Putney, R. M., Mulé, J. J. and Barber, G. N. 2018. 
Suppression of STING Signaling Through Epigenetic Silencing and Missense Mutation 
Impedes DNA Damage Mediated Cytokine Production. Oncogene, 37(15), 2037–51.
Lee, D. W., Santomasso, B. D., Locke, F. L., Ghobadi, A., Turtle, C. J., Brudno, J. N., et al. 2019. 
ASTCT consensus grading for cytokine release syndrome and neurologic toxicity 
associated with immune effector cells. Biol Blood Marrow Transplant, 25(4), 625-38.
Lee, Y., Auh, S. L., Wang, Y., Burnette, B., Wang, Y., Meng, Y., et al. 2009. Therapeutic effects 
of ablative radiation on local tumor require CD8+ T cells: changing strategies for cancer 
treatment. Blood, 114(3), 589-95.
Li, X., Yang, J., Peng, L., Sahin, A. A., Huo, L., Ward, K. C., et al. 2017. Triple-negative breast 
cancer has worse overall survival and cause-specific survival than non-triple-negative 
breast cancer. Breast Cancer Res Treat, 161(2), 279-87.
Liao, Y. P., Wang, C. C., Butterfield, L. H., Economou, J. S., Ribas, A., Meng, W. S., et al. 2004. 
Ionizing radiation affects human MART-1 melanoma antigen processing and presentation 
by dendritic cells. J Immunol, 173(4), 2462-9.
Liu, S. and Yuan, Y. 2015. Bayesian optimal interval designs for phase I clinical trials. J R Stat Soc 
Ser C Appl Stat, 64(3), 507-23.
Lolicato, M., Bucchi, A., Arrigoni, C., Zucca, S., Nardini, M., Schroeder, I., et al. 2014. Cyclic 
dinucleotides bind the C-linker of HCN4 to control channel cAMP responsiveness. Nat 
Chem Biol, 10(6), 457-62.
Lugade, A. A., Sorensen, E. W., Gerber, S. A., Moran, J. P., Frelinger, J. G. and Lord, E. M. 2008. 
Radiation-induced IFN-gamma production within the tumor microenvironment influences 
antitumor immunity. J Immunol, 180(5), 3132-9.
Luke, J. J., Lemons, J. M., Karrison, T. G., Pitroda, S. P., Melotek, J. M., Zha, Y., et al. 2018. 
Safety and Clinical Activity of Pembrolizumab and Multisite Stereotactic Body 
Radiotherapy in Patients With Advanced Solid Tumors. J Clin Oncol, 36(16), 1611-8.
Maity, A., Mick, R., Huang, A. C., George, S. M., Farwell, M. D., Lukens, J. N., et al. 2018. A 
phase I trial of pembrolizumab with hypofractionated radiotherapy in patients with 
metastatic solid tumours. Br J Cancer, 119(10), 1200-7.
Marcus, A., Mao, A. J., Lensink-Vasan, M., Wang, L., Vance, R. E. and Raulet, D. H. 2018. 
Tumor-Derived cGAMP Triggers a STING-Mediated Interferon Response in Non-tumor 
Cells to Activate the NK Cell Response. Immunity, 49(4), 754-63 e4.
For non-commercial use only

TAK-676
Study No. TAK-676-1003
Page 134 of 167
Protocol Incorporating Amendment No. 2
18 February 2022
CONFIDENTIAL
Martin, A. M., Cagney, D. N., Catalano, P. J., Alexander, B. M., Redig, A. J., Schoenfeld, J. D., et 
al. 2018. Immunotherapy and Symptomatic Radiation Necrosis in Patients With Brain 
Metastases Treated With Stereotactic Radiation. JAMA Oncol, 4(8), 1123-4.
Matsumura, S., Wang, B., Kawashima, N., Braunstein, S., Badura, M., Cameron, T. O., et al. 2008. 
Radiation-induced CXCL16 release by breast cancer cells attracts effector T cells. J 
Immunol, 181(5), 3099-107.
McBride, S., Sherman, E., Tsai, C., Baxi, S., Aghalar, J., Eng, J., et al. 2018. A phase II 
randomized trial ofnivolumab with stereotactic bodyradiotherapy (SBRT) 
versusnivolumab alone in metastatic(M1) head and neck squamous cellcarcinoma 
(HNSCC). J Clin Oncol, 36(15), 6009.
Minn, A. J. and Wherry, E. J. 2016. Combination Cancer Therapies with Immune Checkpoint 
Blockade: Convergence on Interferon Signaling. Cell, 165(2), 272-5.
National Comprehensive Cancer Network 2020. NCCN Clinical Practice Guidelines in Oncology 
(NCCN Guidelines): Head and Neck Cancers. Version 1.2020.
Oken, M. M., Creech, R. H., Tormey, D. C., Horton, J., Davis, T. E., McFadden, E. T., et al. 1982. 
Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin 
Oncol, 5(6), 649-55.
Quon, H., Vapiwala, N., Forastiere, A., Kennedy, E. B., Adelstein, D. J., Boykin, H., et al. 2017. 
Radiation Therapy for Oropharyngeal Squamous Cell Carcinoma: American Society of 
Clinical Oncology Endorsement of the American Society for Radiation Oncology
Evidence-Based Clinical Practice Guideline. J Clin Oncol, 35(36), 4078-90.
Reck, M., Rodriguez-Abreu, D., Robinson, A. G., Hui, R., Csoszi, T., Fulop, A., et al. 2019. 
Updated Analysis of KEYNOTE-024: Pembrolizumab Versus Platinum-Based 
Chemotherapy for Advanced Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion 
Score of 50% or Greater. J Clin Oncol, 37(7), 537-46.
Reits, E. A., Hodge, J. W., Herberts, C. A., Groothuis, T. A., Chakraborty, M., Wansley, E. K., et 
al. 2006. Radiation modulates the peptide repertoire, enhances MHC class I expression, 
and induces successful antitumor immunotherapy. J Exp Med, 203(5), 1259-71.
Sacco, A. G., Sharabi, A., Jing, Z., Pittman, E., Gold, K. A., Summer, W., et al. 2019. 
Radiotherapy with Concurrent and Adjuvant Pembrolizumab in Patients with P16-Positive 
Locoregionally Advanced Head and Neck Cancer: KEYCHAIN Trial Lead-In Results. Int 
J Radiat Oncol Biol Phys, 105(1 (supplement)), E363-E4.
Schmid, P., Adams, S., Rugo, H. S., Schneeweiss, A., Barrios, C. H., Iwata, H., et al. 2018. 
Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer. N Engl J 
Med, 379(22), 2108-21.
Sharma, P., Hu-Lieskovan, S., Wargo, J. A. and Ribas, A. 2017. Primary, Adaptive, and Acquired 
Resistance to Cancer Immunotherapy. Cell, 168(4), 707-23.
Shaverdian, N., Lisberg, A. E., Bornazyan, K., Veruttipong, D., Goldman, J. W., Formenti, S. C., 
et al. 2017. Previous radiotherapy and the clinical activity and toxicity of pembrolizumab 
in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 
phase 1 trial. Lancet Oncol, 18(7), 895-903.
For non-commercial use only

TAK-676
Study No. TAK-676-1003
Page 135 of 167
Protocol Incorporating Amendment No. 2
18 February 2022
CONFIDENTIAL
Sher, D. J., Adelstein, D. J., Bajaj, G. K., Brizel, D. M., Cohen, E. E. W., Halthore, A., et al. 2017. 
Radiation therapy for oropharyngeal squamous cell carcinoma: Executive summary of an 
ASTRO Evidence-Based Clinical Practice Guideline. Pract Radiat Oncol, 7(4), 246-53.
Siegel, R. L., Miller, K. D. and Jemal, A. 2019. Cancer statistics, 2019. CA Cancer J Clin, 69(1), 
7-34.
Steele, K. E., Tan, T. H., Korn, R., Dacosta, K., Brown, C., Kuziora, M., et al. 2018. Measuring 
multiple parameters of CD8+ tumor-infiltrating lymphocytes in human cancers by image 
analysis. J Immunother Cancer, 6(1), 20.
Sun, L., Wu, J., Du, F., Chen, X. and Chen, Z. J. 2013. Cyclic GMP-AMP Synthase Is a Cytosolic 
DNA Sensor That Activates the Type I Interferon Pathway. Science, 339(6121), 786–91.
Sundahl, N., Seremet, T., Van Dorpe, J., Neyns, B., Ferdinande, L., Meireson, A., et al. 2019a. 
Phase 2 Trial of Nivolumab Combined With Stereotactic Body Radiation Therapy in 
Patients With Metastatic or Locally Advanced Inoperable Melanoma. Int J Radiat Oncol 
Biol Phys, 104(4), 828-35.
Sundahl, N., Vandekerkhove, G., Decaestecker, K., Meireson, A., De Visschere, P., Fonteyne, V., 
et al. 2019b. Randomized Phase 1 Trial of Pembrolizumab with Sequential Versus 
Concomitant Stereotactic Body Radiotherapy in Metastatic Urothelial Carcinoma. Eur 
Urol, 75(5), 707-11.
Tang, C., Welsh, J. W., de Groot, P., Massarelli, E., Chang, J. Y., Hess, K. R., et al. 2017. 
Ipilimumab with Stereotactic Ablative Radiation Therapy: Phase I Results and 
Immunologic Correlates from Peripheral T Cells. Clin Cancer Res, 23(6), 1388-96.
The Criteria Committee of New York Heart Association 1994. Nomenclature and Criteria for 
Diagnosis of Diseases of the Heart and Great Vessels. 9 ed. Boston, MA: Little, Brown & 
Co.
Theelen, W., Peulen, H. M. U., Lalezari, F., de Vries, J., De Langen, J., Aerts, J., et al. 2018. 
Randomized phase II study of pembrolizumab after stereotactic body radiotherapy (SBRT) 
versus pembrolizumab alone in patients with advanced non-small cell lung cancer: The 
PEMBRO-RT study. J Clin Oncol, 36(15 Suppl), 9023.
Theelen, W., Peulen, H. M. U., Lalezari, F., van der Noort, V., de Vries, J. F., Aerts, J., et al. 2019. 
Effect of Pembrolizumab After Stereotactic Body Radiotherapy vs Pembrolizumab Alone 
on Tumor Response in Patients With Advanced Non-Small Cell Lung Cancer: Results of 
the PEMBRO-RT Phase 2 Randomized Clinical Trial. JAMA Oncol.
Tumeh, P. C., Harview, C. L., Yearley, J. H., Shintaku, I. P., Taylor, E. J., Robert, L., et al. 2014. 
PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature,
515(7528), 568-71.
Twyman-Saint Victor, C., Rech, A. J., Maity, A., Rengan, R., Pauken, K. E., Stelekati, E., et al. 
2015. Radiation and dual checkpoint blockade activate non-redundant immune 
mechanisms in cancer. Nat Med, 520, 373.
Vanpouille-Box, C., Alard, A., Aryankalayil, M. J., Sarfraz, Y., Diamond, J. M., Schneider, R. J., 
et al. 2017. DNA exonuclease Trex1 regulates radiotherapy-induced tumour 
immunogenicity. Nat Commun, 8, 15618.
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Vatner, R. E., Cooper, B. T., Vanpouille-Box, C., Demaria, S. and Formenti, S. C. 2014. 
Combinations of immunotherapy and radiation in cancer therapy. Front Oncol, 4, 325.
Voorwerk, L., Slagter, M., Horlings, H. M., Sikorska, K., van de Vijver, K. K., de Maaker, M., et 
al. 2019. Publisher Correction: Immune induction strategies in metastatic triple-negative 
breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial. Nat Med, 25(7), 
1175.
Welsh, J. W., Menon, H., Tang, C., Verma, V., Altan, M., Hess, K. R., et al. 2019. Randomized 
phase I/II trial of pembrolizumab with and without radiotherapy for metastatic non-small 
cell lung cancer. J Clin Oncol, 37(15 (supplement)), 9104-.
Wu, J., Sun, L., Chen, X., Du, F., Shi, H., Chen, C., et al. 2018. Cyclic GMP-AMP Is an 
Endogenous Second Messenger in Innate Immune Signaling by Cytosolic DNA. Science,
339(6121), 826–30.
Yovino, S., Kleinberg, L., Grossman, S. A., Narayanan, M. and Ford, E. 2013. The etiology of 
treatment-related lymphopenia in patients with malignant gliomas: modeling radiation 
dose to circulating lymphocytes explains clinical observations and suggests methods of 
modifying the impact of radiation on immune cells. Cancer Invest, 31(2), 140-4.
Yu, Y. and Lee, N. Y. 2019. JAVELIN Head and Neck 100: a Phase III trial of avelumab and 
chemoradiation for locally advanced head and neck cancer. Future Oncol, 15(7), 687-94.
Zhang, B., Bowerman, N. A., Salama, J. K., Schmidt, H., Spiotto, M. T., Schietinger, A., et al. 
2007. Induced sensitization of tumor stroma leads to eradication of established cancer by T 
cells. J Exp Med, 204(1), 49-55.
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Table 1
SOE for Treatment With Radiation Therapy + Pembrolizumab + TAK-676 (21-Day Cycle)
Screening 
a
RT
Cycle 1
Cycle 2
Cycle 3
Cycle 4 and Beyond
EoT/ 
EoS
Follow 
Up x
Day -8 
to 
Day -2
Day 1
Day 8 Day 15
Day 
15-21 Day 1 Day 8
Day 
15
Day 1 Day 8
Day 
15
Day 
1
Day 8
Day 
15
immunophenotyping q
only)
Blood sample for RNA r
X
X3
X3
X
X
X (Cycles 
4, 9, 15 
only)
Blood sample for 
receptor sequencing s
X
X
X
X (Cycles 
4, 9, 15 
only)
Plasma sample for 
cell-free DNA t
X
X
X
X
X (Cycles 
4, 9, 15 
only)
Buccal epithelial cells 
sample for DNA u
X
Blood sample for single 
cell RNA sequencing v
X
X2
Plasma sample for 
TAK-676 PK w
X4
X4
AE: adverse event; CR: complete response; CT: computed tomography; CTCAE: Common Terminology Criteria for Adverse Events; CxDx: Cycle x Day x; ECG: 
electrocardiogram; ECOG: Eastern Cooperative Oncology Group; eCRF: electronic case report form; EOI: end of infusion; EoS: End of Study; EoT: End of 
Treatment; FFPE: formalin-fixed, paraffin-embedded; GI: gastrointestinal; ICF: informed consent form; IV: intravenous(ly); RECIST: Response Evaluation 
Criteria in Solid Tumors; MRI: magnetic resonance imaging; MUGA: multiple-gated acquisition; PD: progressive disease; PD-1: programmed cell death protein 1; 
PI: principal investigator; PK: pharmacokinetic(s); PR: partial response; RECIST: Response Evaluation Criteria in Solid Tumors; RT: radiation therapy; SA: single 
agent; SAE: serious adverse event; STING: Stimulator of Interferon Genes; X2: 2 samples on the day; X3: 3 samples on the day; X4: 4 samples on the day.
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.
a Unless otherwise noted, the screening visit (first screening procedure completed) must occur within 28 days before the day of the first dose of radiation. The ICF 
may be signed more than 28 days before the first dose of radiation. Study site must record patient data in IRT.
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Table 1
SOE for Treatment With Radiation Therapy + Pembrolizumab + TAK-676 (21-Day Cycle)
Screening 
a
RT
Cycle 1
Cycle 2
Cycle 3
Cycle 4 and Beyond
EoT/ 
EoS
Follow 
Up x
Day -8 
to 
Day -2
Day 1
Day 8 Day 15
Day 
15-21 Day 1 Day 8
Day 
15
Day 1 Day 8
Day 
15
Day 
1
Day 8
Day 
15
b Medical history will include smoking/vaping history and available baseline disease characteristics, such as disease type, staging, and PD-L1 expression. Complete 
physical examination (including assessment of the following systems: skin, head, eyes, ears, nose, throat, respiratory, cardiovascular, GI, neurological condition, 
blood and lymphatic, and musculoskeletal) will be collected at screening. The -C1D1 physical examination and medical history are not required if the screening 
physical examination was conducted and medical history obtained within 3 days before administration of study drug(s). Postscreening physical examinations will 
be symptom- or finding-directed and will be performed predose and at any time point based on clinical need. On dosing days in Cycle 1, an additional postdose 
physical examination will include an assessment of the respiratory and neurologic systems.
c Weight will be collected at screening and predose on days specified.
d Vital sign measurements (heart rate, blood pressure, temperature, respiratory rate, oxygen saturation) should be performed as specified and should be performed 
before the first fraction of radiation therapy. During Cycle 1, vital signs will be measured immediately before the start of the pembrolizumab infusion and before the 
start of TAK-676 infusion (within 30 minutes), 30 minutes after start of TAK-676 infusion (±5 minutes), at the EOI (±10 minutes), 2 hours postinfusion (±30 
minutes), any time when clinically indicated including if the patient develops any signs or symptoms associated with potential risks of TAK-676 and/or 
pembrolizumab, and before discharge (if different from and not overlapping with the timepoints above). 
e ECOG performance status should be performed before the first fraction of radiation therapy.
f Safety ECGs should be performed at screening and C1D1 predose. A qualified person will interpret the ECGs locally. 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. 
g Radiographic assessments including CT with contrast (or MRI if clinically indicated) of the disease burden will be made at screening/baseline (within 28 days 
before the first dose of radiation) and will be performed to assess disease response using RECIST v.1.1. criteria once at end of Cycle 2 (Day 15 to 22 [predose]), then 
at the end of every 3 cycles (Days 15 to 22 [predose]) up to the end of the first year, and then at the end of every 6 cycles (+7 days) thereafter until PD or the start of 
alternative therapies. If the patient has had an appropriate CT or MRI scan performed within 28 days of the first dose of radiation, the results of that scan may be 
used for tumor lesion measurements at screening.
h The radiation must be administered between Day -8 and Day -2 with a minimum of 40 hours between the last fraction of radiation and initiation of pembrolizumab. 
Note:There is no Day 0. For more information, refer to Section 8.4.2.
i Hematology, chemistry, thyroid function and C-reactive protein, CPK, and ferritin blood samples for C1D1 may be collected within 3 days before dosing to ensure 
patient eligibility on study Day 1. Repeat baseline chemistry and hematology labs should be obtained on the day of first dose of radiation if more than 2 weeks have 
elapsed between screening labs and the first dose of radiation.
j TAK-676 will be administered IV on Days 1, 8, and 15 of a 21-day cycle. On Day 1 of each cycle, TAK-676 will be administered 1 hour (+15 minutes) after the 
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Table 1
SOE for Treatment With Radiation Therapy + Pembrolizumab + TAK-676 (21-Day Cycle)
Screening 
a
RT
Cycle 1
Cycle 2
Cycle 3
Cycle 4 and Beyond
EoT/ 
EoS
Follow 
Up x
Day -8 
to 
Day -2
Day 1
Day 8 Day 15
Day 
15-21 Day 1 Day 8
Day 
15
Day 1 Day 8
Day 
15
Day 
1
Day 8
Day 
15
end of Pembrolizumab IV infusion. The option to modify the schedule of drug administration will be based on review of the available safety and other clinical data 
by the investigators and the sponsor.
k Dosing of pembrolizumab will be a minimum 40 hours after the last fraction of radiation. Note: There is no Day 0. 
l A serum or urine pregnancy test will be performed for women of childbearing potential at screening, on Day 1 of each cycle, and at the EOT assessment. A serum 
or urine pregnancy test must be performed before the first fraction of radiation therapy or predose on C1D1 if no pregnancy test had been performed within the prior 
10 days with negative results available.
m Thyroid function tests will be performed at screening, Cycle 1, every other cycle (eg, C3, 5, 7, 9, 11) and EOT.
n Urinalysis samples will be collected at screening and predose on Day 1 of each cycle and analyzed at the site’s local laboratory.
o Patients enrolling at dose levels of TAK-676 which have been shown to have pharmacodynamic activity in ongoing clinical studies will have mandatory tumor
biopsies performed at screening and on Cycle 1 Days 15 through 21, between 4 and 144 hours post-TAK-676 administration. Tumor biopsies are optional, but 
encouraged from patients enrolling at lower dose levels. The tumor tissue biopsy at screening should be performed at least 2 days after the last dose of any prior 
antineoplastic therapy and within 3 weeks before the first dose of radiation. Screening biopsy should be performed only when the patient is considered otherwise 
eligible. The tumor biopsies should be performed on a nonirradiated site. Patients with a tumor biopsy obtained less than or equal to 3 months before initiation of 
TAK-676 (Day 1), will not be required to undergo a repeat pretreatment biopsy, assuming: 1) adequate tumor tissue is available for analysis (FFPE block preferred) 
and 2) no additional antineoplastic agents were administered since the time of the biopsy.
p Plasma samples to monitor changes in peripheral biomarkers, including cytokines and chemokines should be collected at screening, predose on Day 1 of indicated 
cycles, and during cycle 1 at the additional timepoints specified in Table 2 to monitor effects of TAK-676 on Day 1 and Day 15.
q Blood samples to analyze the presence and changes in immune cell state by immunophenotyping should be collected at screening and predose on Day 1 of 
indicated cycles. In cycle 1 only, there are an additional collections at 6 hours post-EOI of TAK-676 on C1D1 and C1D15 and predose on C1D15.
r Blood samples for RNA to monitor gene expression changes should be collected at screening, predose on Day 1 of indicated cycles, and during cycle 1 at the 
additional timepoints specified in Table 2 to monitor effects of TAK-676 on Day 1 and Day 15.
s Blood samples for T cell receptor and B cell receptor sequencing, to monitor induction of adaptive and humoral immune response, should be collected at screening 
and predose on Day 1 of indicated cycles. 
t Blood samples for evaluation of cell-free DNA will be collected at screening and predose on Day 1 of indicated cycles. Circulating tumor DNA from these samples 
may be evaluated for mutations.
u A buccal epithelial cell sample for DNA will be obtained at screening and may be used to genotype patients for mutations or polymorphisms in genes related to 
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Table 1
SOE for Treatment With Radiation Therapy + Pembrolizumab + TAK-676 (21-Day Cycle)
Screening 
a
RT
Cycle 1
Cycle 2
Cycle 3
Cycle 4 and Beyond
EoT/ 
EoS
Follow 
Up x
Day -8 
to 
Day -2
Day 1
Day 8 Day 15
Day 
15-21 Day 1 Day 8
Day 
15
Day 1 Day 8
Day 
15
Day 
1
Day 8
Day 
15
immune response, DNA damage repair pathways, STING gene (TMEM173), and drug transporters relevant to TAK-676. This sample may be collected during the 
course of the study if the sample cannot be collected at screening.
v To be collected from patients only at select centers. Screening sample should be collected only when the patient is considered otherwise eligible.
w Plasma samples for PK analysis of TAK-676 will be collected as specified in Table 2. The PK collection schedule may be modified based on data from ongoing 
studies of TAK-676, without the need for a protocol amendment.
x Patients who discontinue study treatment for reasons other than PD will continue follow-up every 12 ±1 weeks from the EOT visit 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.
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Table 2
TAK-676 Biomarker Collection and PK Sample Collection
Screening
C1D1
C1D15
C1D15-21
C2D1, 
C3D1, 
C4D1 
C9D1 and 
C15D1
Predose
Within 
30 min
Before
Dose a
EOI of 
TAK-676 
(±10 min)
3 h
Post-EOI 
of 
TAK-676
±30 min
6 h
Post-EOI of 
TAK-676
±1 h
Predose 
Within 30 
min Before 
Dose
EOI of 
TAK-676
(±10 min)
3 h
Post-EOI 
of 
TAK-676
±30 min
6 h
Post-EOI of 
TAK-676
±1 h
Predose
Within 
30 min
Before
Dose
Archival (banked) 
tumor tissue sample
X
Fresh tumor tissue 
biopsy sample b
X
X
Plasma sample for 
circulating biomarkers
X
X
X
X
X
X
X
X
Blood sample for 
immunophenotyping
X
X
X
X
X
X
Blood sample for RNA
X
X
X
X
X
X
X
X
Blood sample for 
receptor sequencing
X
X
Plasma sample for 
cell-free DNA
X
X
X
Buccal epithelial cells 
sample for DNA
X
Blood sample for single 
cell RNA seq c
X
X
X
Plasma sample for 
TAK-676 PK d
X
X
X
X
X
X
X
X
CxDx: Cycle x, Day x; EOI: end of infusion; FFPE: fixed-formalin, paraffin-embedded; PK: pharmacokinetic(s). 
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Table 2
TAK-676 Biomarker Collection and PK Sample Collection
Screening
C1D1
C1D15
C1D15-21
C2D1, 
C3D1, 
C4D1 
C9D1 and 
C15D1
Predose
Within 
30 min
Before
Dose a
EOI of 
TAK-676 
(±10 min)
3 h
Post-EOI 
of 
TAK-676
±30 min
6 h
Post-EOI of 
TAK-676
±1 h
Predose 
Within 30 
min Before 
Dose
EOI of 
TAK-676
(±10 min)
3 h
Post-EOI 
of 
TAK-676
±30 min
6 h
Post-EOI of 
TAK-676
±1 h
Predose
Within 
30 min
Before
Dose
a The predose sample collections will be conducted before pembrolizumab and TAK-676 administration. All other timeframes within the table should be relative to 
TAK-676 administration, not pembrolizumab. The timing of the morning visits should occur at approximately the same time as previous dosing days. The date/time 
of the start and end of infusions should be recorded accurately.
b Patients enrolling at dose levels of TAK-676 which have been shown to have pharmacodynamic activity in ongoing clinical studies will have mandatory tumor 
biopsies performed at screening and on Cycle 1 Days 15 through 21, between 4 and 144 hours post-TAK-676 administration. Tumor biopsies are optional but 
encouraged from patients enrolling at lower dose levels. The tumor tissue biopsy at screening should be performed at least 2 days after the last dose of any prior 
antineoplastic therapy and within 3 weeks before the first dose of radiation. Screening biopsy should be performed only when the patient is considered otherwise 
eligible. The tumor biopsies should be performed on a nonirradiated site. Patients with a tumor biopsy obtained less than or equal to 3 months before initiation of 
TAK-676 (Day 1), will not be required to undergo a repeat pretreatment biopsy, assuming: 1) adequate tumor tissue is available for analysis (FFPE block preferred) 
and 2) no additional antineoplastic agents were administered since the time of the biopsy.
c To be collected from patients only at select centers at screening and on C1D15 predose and C1D15 6 hours post dose. Screening sample should be collected only 
when the patient is considered otherwise eligible.
d PK samples are always collected from the contralateral arm (not the same arm as infusion arm).
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Appendix B
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the Statement of Investigator (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this study.
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff who will assist in the protocol.
3. If the investigator/institution retains the services of any individual or party to perform 
trial-related duties and functions, the investigator/institution should ensure that this individual 
or party is qualified to perform those trial-related duties and functions and should implement 
procedures to ensure the integrity of the trial-related duties and functions performed and any 
data generated.
4. Ensure that study-related procedures, including study-specific (nonroutine/nonstandard panel) 
screening assessments, are NOT performed on potential subjects before the receipt of written 
approval from relevant governing bodies/authorities.
5. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
6. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
21 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 subjects. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
8. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met.
9. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each ICF should contain a subject authorization section that 
describes the uses and disclosures of a subject’s personal information (including personal 
health information) that will take place in connection with the study. If an ICF does not include 
such a subject authorization, then the investigator must obtain a separate subject authorization 
form from each subject or the subject’s legally acceptable representative.
10. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc., and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
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contact and receive written approval from the sponsor before disposing of any such 
documents.
11. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
12. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor.
13. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.
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Appendix C
Investigator Consent to Use of Personal Information 
Takeda will collect and retain personal information of the investigator, including his or her name, 
address, and other identifying personal information. In addition, the investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
UK, US, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
The investigator’s personal information may be retained, processed, and transferred by Takeda 
and these other parties for research purposes including the following:

Assessment of the suitability of the investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details, and results on publicly accessible 
clinical trial registries, databases, and websites.
The investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in the investigator’s 
own country.
The investigator acknowledges and consents to the use of his or her personal information by 
Takeda and other parties for the purposes described above.
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Appendix D
ECOG Scale for Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all predisease performance without restriction.
1
Symptoms but ambulatory. Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature (eg, light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair.
5
Dead.
Source: (Oken et al. 1982).
ECOG: Eastern Cooperative Oncology Group.
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Appendix E
BOIN Design
The Bayesian Optimal INterval (BOIN) design (Liu and Yuan 2015) will be used to guide the dose 
escalation decisions and MTD estimation. This trial was designed and will be conducted using the 
software BOIN that is available at www.trialdesign.org. 
The 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 dose level; if it is ≥0.358, the 
next cohort will be treated at the next lower dose level; if it is within 0.236 and 0.358, additional 
patients will be enrolled in this dose level. For the purpose of overdose control, a dose level and all 
the dose levels 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 dose level is eliminated, stop the 
escalation for safety. Unless such early stop happens, dose escalation will continue until the 
maximum sample size is reached, or escalation will be stopped if the number of patients treated at 
the current dose reaches 9 and the recommendation is to retain at the current dose level. The dose 
escalation algorithm is described as the following steps:
Step 1. Patients in the first cohort are treated at lowest dose level.
Step 2. Decide the dose level for the next cohort according to the rule shown in Table 1. Please 
note the following when using Table 1:
1. “Eliminate” means that the current dose level and all higher dose levels are eliminated to 
prevent treating any future patients at these overly toxic dose levels.
2. When a dose level is eliminated, automatically de-escalate to the next lower level. When the 
lowest dose level is eliminated, stop the dose escalation for safety. In this case, no dose level 
should be selected as the MTD.
3. If none of the actions (ie, escalation, de-escalation, or elimination) is triggered, the next cohort 
will be treated with the current dose.
4. If the current dose is the lowest dose level and the rule indicates a de-escalation, treat the next 
cohort at the lowest dose level unless the number of DLTs reaches the elimination boundary, at 
which point the dose escalation should be terminated for safety.
5. If the current dose is the highest dose and the rule indicates an escalation, treat the next cohort 
at the highest dose. 
Step 3. Repeat Step 2 until the maximum sample size is reached or until a certain number of 
patients (n = 9) have already been treated with the current dose level and the recommendation is to 
retain at the current dose level. 
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Table 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
Deescalate 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
DLT: dose-limiting toxicity; NA: not applicable.
Number of DLTs 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 2015). Specifically, the dose is selected as the MTD for which the 
isotonic estimate of the toxicity rate is closest to the target toxicity rate. If there are ties, the higher 
dose level is selected when the isotonic estimate is lower than the target toxicity rate; the lower 
dose level is selected when the isotonic estimate is greater than or equal to the target toxicity rate.
The operating characteristics of the BOIN design are evaluated with simulations assuming various 
distributions of toxicity across dose levels shown in Table 2.
Table 2
Simulation Scenarios
True DLT rate
Dose Level
Scenario 1
Scenario 2
Scenario 3
Scenario 4
Scenario 5
Scenario 6
0.2 mg
0.3
0.12
0.06
0.05
0.04
0.02
0.4 mg
0.44
0.3
0.15
0.1
0.07
0.05
0.8 mg
0.5
0.44
0.3
0.12
0.1
0.08
1.2 mg
0.55
0.5
0.45
0.3
0.12
0.11
1.6 mg
0.6
0.55
0.51
0.45
0.3
0.14
2.0 mg
0.65
0.6
0.57
0.51
0.47
0.3
2.5 mg
0.7
0.65
0.64
0.62
0.59
0.48
DLT: dose-limiting toxicity.
The combination of the radiation therapy schedule and IV pembrolizumab at 200 mg every 
3 weeks plus TAK-676 at a range of dose levels will be evaluated in a maximum of 
39 DLT-evaluable patients with locally advanced or metastatic NSCLC, TNBC, or SCCHN. For 
simulation purpose, we will consider dose levels from 0.2 mg to 2.5 mg (when additional dose 
levels are explored, they may be evaluated for operating characteristics in the Statistical Analysis 
Plan). Each cohort will have 3 patients. The operating characteristics calculated from the 
simulations are shown in Table 3.
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Table 3
Operating Characteristics
Scenario 1
Scenario 2
Scenario 3
Dose Level 
(TAK-676)
Selection %
% Pts 
Treated
Selection %
% Pts 
Treated
Selection 
%
% Pts 
Treated
0.2 mg
61.8
61.8
20.5
31.8
2.4
16.8
0.4 mg
20.9
20.9
56.4
41.4
26.0
28.5
0.8 mg
3.8
3.8
18.3
20.5
50.8
33.7
1.2 mg
0.4
0.4
4.0
5.4
16.6
16.3
1.6 mg
0.0
0.0
0.4
0.8
3.6
3.9
2.0 mg
0.0
0.0
0.0
0.1
0.6
0.8
2.5 mg
0.0
0.0
0.0
0.0
0.0
0.1
% Early Stopping
13.1
0.4
0.0
Expected # of Pts
14.9
21.4
23.9
Scenario 3
Scenario 4
Scenario 6
Dose Level 
(TAK-676)
Selection %
% Pts 
Treated
Selection %
% Pts 
Treated
Selection 
%
% Pts 
Treated
0.2 mg
0.7
13.2
0.3
11.4
0
10.2
0.4 mg
4.4
15.7
1.4
12.7
0.7
11.2
0.8 mg
18
22.9
4.4
14
2.1
12.4
1.2 mg
57.9
30.6
20.7
20.9
4.4
13.8
1.6 mg
15.7
14.4
55.2
26.5
23.2
19.1
2.0 mg
3
2.7
16.6
12.6
52.5
22.7
2.5 mg
0.2
0.5
1.4
2
17.1
10.5
% Early Stopping
0.0
0.0
0.0
Expected # of Pts
27.5
29.9
31.9
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Appendix F
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 G
New York Heart Association Classification of Cardiac Disease
Class
Functional Capacity
Objective Assessment
I
Patients with cardiac disease but without resulting limitations of 
physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain.
No objective evidence of 
cardiovascular disease.
II
Patients with cardiac disease resulting in slight limitation of physical 
activity. They are comfortable at rest. Ordinary physical activity 
results in fatigue, palpitation, dyspnea, or anginal pain.
Objective evidence of minimal 
cardiovascular disease.
III
Patients with cardiac disease resulting in marked limitation of 
physical activity. They are comfortable at rest. Less than ordinary 
activity causes fatigue, palpitation, dyspnea, or anginal pain.
Objective evidence of moderately 
severe cardiovascular disease.
IV
Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort. Symptoms of heart failure or 
the anginal syndrome may be present even at rest. If any physical 
activity is undertaken, discomfort is increased.
Objective evidence of severe 
cardiovascular disease.
Source: The Criteria Committee of New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases 
of the Heart and Great Vessels. Ninth Ed. Boston, MA: Little, Brown & Co; 1994:253-256 (The Criteria Committee of 
New York Heart Association 1994). 
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Appendix H
Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1)
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.
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 non-target 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 v.1.1 at baseline.
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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; PR: partial response; SD: stable disease; PD: progressive disease; NE: not evaluable.
The following table summarizes the overall response status calculation at each time point for 
patients who have nonmeasurable (therefore nontarget) disease at baseline.
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; PR: partial response; SD: stable disease; PD: progressive disease; NE: not evaluable.
a Non-CR/non-PD is preferred over stable disease for nontarget disease because SD is increasingly used as endpoint 
for assessment of efficacy in some study so to assign this category when no lesions can be measured is not advised.
Special Allowances to RECIST v.1.1: As described in Section 9.4.14.1, 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 v.1.1 defined PD as long as they meet the criteria outlined in Section 9.4.14.1. 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 I
Clinical Inhibitors of OATP1B1 and OATP1B3 
Drug Class
Medication Name (Brand Name) a
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)
Sources: fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM292362.pdf and 
fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm080499.htm.
DDI: drug-drug interaction; FDA: [United States] Food and Drug Administration; OATP: organic anion-transporting 
polypeptide.
a 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 J
Dose constraints as per Task Group-101
One fraction
Three fractions
Five fractions
Threshold 
dose
(Gy)
Max point 
dose
(Gy)a
Threshold dose
(Gy)
Max point dose
(Gy)a
Threshold dose
(Gy)
Max point 
dose
(Gy)a
End point
(>Grade 3)
Serial tissue
Max critical 
volume above 
threshold
Optic pathway
<0.2 cc
8
10
15.3 (5.1 Gy/fx)
17.4 (5.8 Gy/fx)
23 (4.6 Gy/fx)
25 (5 Gy/fx)
Neuritis
Cochlea
9
17.1 (5.7 Gy/fx)
25 (5 Gy/fx)
Hearing loss
Brainstem 
(not medulla)
<0.5 cc
10
15
18 (6 Gy/fx)
23.1 (7.7 Gy/fx)
23 (4.6 Gy/fx)
31 (6.2 Gy/fx)
Cranial 
neuropathy
Spinal cord and 
medulla
<0.35 cc
<1.2 cc
10
7
14
18 (6 Gy/fx)
12.3 (4.1 Gy/fx)
21.9 (7.3 Gy/fx)
23 (4.6 Gy/fx)
14.5 (2.9 Gy/fx)
30 (6 Gy/fx)
Myelitis
Spinal cord 
subvolume (5–6 
mm above and 
below level treated 
per Ryu)
<10% of 
subvolume
10
14
18 (6 Gy/fx)
21.9 (7.3 Gy/fx)
23 (4.6 Gy/fx)
30 (6 Gy/fx)
Myelitis
Cauda equina
<5 cc
14
16
21.9 (7.3 Gy/fx)
24 (8 Gy/fx)
30 (6 Gy/fx)
32 (6.4 Gy/fx)
Neuritis
Sacral plexus
<5 cc
14.4
16
22.5 (7.5 Gy/fx)
24 (8 Gy/fx)
30 (6 Gy/fx)
32 (6.4 Gy/fx)
Neuropathy
Esophagus b
<5 cc
11.9
15.4
17.7 (5.9 Gy/fx)
25.2 (8.4 Gy/fx)
19.5 (3.9 Gy/fx)
35 (7 Gy/fx)
Stenosis/fistula
Brachial plexus
<3 cc
14
17.5
20.4 (6.8 Gy/fx)
24 (8 Gy/fx)
27 (5.4 Gy/fx)
30.5 (6.1 
Gy/fx)
Neuropathy
Heart/pericardium
<15 cc
16
22
24 (8 Gy/fx)
30 (10 Gy/fx)
32 (6.4 Gy/fx)
38 (7.6 Gy/fx)
Pericarditis
Great vessels
<10 cc
31
37
39 (13 Gy/fx)
45 (15 Gy/fx)
47 (9.4 Gy/fx)
53 (10.6 
Gy/fx)
Aneurysm
Trachea and large 
bronchus b
<4 cc
10.5
20.2
15 (5 Gy/fx)
30 (10 Gy/fx)
16.5 (3.3 Gy/fx)
40 (8 Gy/fx)
Stenosis/fistula
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One fraction
Three fractions
Five fractions
Threshold 
dose
(Gy)
Max point 
dose
(Gy)a
Threshold dose
(Gy)
Max point dose
(Gy)a
Threshold dose
(Gy)
Max point 
dose
(Gy)a
End point
(>Grade 3)
Bronchus-smaller 
airways
<0.5 cc
12.4
13.3
18.9 (6.3 Gy/fx)
23.1 (7.7 Gy/fx)
21 (4.2 Gy/fx)
33 (6.6 Gy/fx)
Stenosis with 
atelectasis
Rib
<1 cc
22
30
28.8 (9.6 Gy/fx)
36.9 (12.3 Gy/fx)
35 (7 Gy/fx)
43 (8.6 Gy/fx)
Pain or fracture
<30 cc
30.0 (10.0 Gy/fx)
Skin
<10 cc
23
26
30 (10 Gy/fx)
33 (11 Gy/fx)
36.5 (7.3 Gy/fx)
39.5 (7.9 
Gy/fx)
Ulceration
Stomach
<10 cc
11.2
12.4
16.5 (5.5 Gy/fx)
22.2 (7.4 Gy/fx)
18 (3.6 Gy/fx)
32 (6.4 Gy/fx) Ulceration/fistul
a
Duodenum b
<5 cc
11.2
12.4
16.5 (5.5 Gy/fx)
22.2 (7.4 Gy/fx)
18 (3.6 Gy/fx)
32 (6.4 Gy/fx)
Ulceration
<10 cc
9
11.4 (3.8 Gy/fx)
12.5 (2.5 Gy/fx)
Jejunum/ileum b
<5 cc
11.9
15.4
17.7 (5.9 Gy/fx)
25.2 (8.4 Gy/fx)
19.5 (3.9 Gy/fx)
35 (7 Gy/fx)
Enteritis/
obstruction
Colon b
<20 cc
14.3
18.4
24 (8 Gy/fx)
28.2 (9.4 Gy/fx)
25 (5 Gy/fx)
38 (7.6 Gy/fx)
Colitis/fistula
Rectum b
<20 cc
14.3
18.4
24 (8 Gy/fx)
28.2 (9.4 Gy/fx)
25 (5 Gy/fx)
38 (7.6 Gy/fx)
Proctitis/fistula
Bladder wall
<15 cc
11.4
18.4
16.8 (5.6 Gy/fx)
28.2 (9.4 Gy/fx)
18.3 (3.65 Gy/fx)
38 (7.6 Gy/fx)
Cystitis/fistula
Penile bulb
<3 cc
14
34
21.9 (7.3 Gy/fx)
42 (14 Gy/fx)
30 (6 Gy/fx)
50 (10 Gy/fx)
Impotence
Femoral heads 
(right and left)
<10 cc
14
21.9 (7.3 Gy/fx)
30 (6 Gy/fx)
Necrosis
Renal
hilum/vascular 
trunk
<2 - 3 volume
10.6
18.6 (6.2 
Gy/fx)
23 (4.6 Gy/fx)
Malignant 
hypertension
Parallel tissue
Minimum 
critical volume 
below 
threshold
Lung (right and 
left)
1500 cc
7
NA-Parallel 
tissue
11.6 (2.9 Gy/fx)
NA-Parallel 
tissue
12.5 (2.5 Gy/fx)
NA-Parallel 
tissue
Basic lung 
function
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One fraction
Three fractions
Five fractions
Threshold 
dose
(Gy)
Max point 
dose
(Gy)a
Threshold dose
(Gy)
Max point dose
(Gy)a
Threshold dose
(Gy)
Max point 
dose
(Gy)a
End point
(>Grade 3)
Lung (right and 
left)
1000 cc
7.4
NA-Parallel 
tissue
12.4 (3.1 Gy/fx)
NA-Parallel 
tissue
13.5 (2.7 Gy/fx)
NA-Parallel 
tissue
Pneumonitis
Liver
700 cc
9.1
NA-Parallel 
tissue
19.2 (4.8 Gy/fx)
NA-Parallel 
tissue
21 (4.2 Gy/fx)
NA-Parallel 
tissue
Basic liver 
function
Renal cortex (right 
and left)
200 cc
8.4
NA-Parallel 
tissue
16 (4 Gy/fx)
NA-Parallel 
tissue
17.5 (3.5 Gy/fx)
NA-Parallel 
tissue
Basic renal 
function
Source: (Benedict et al. 2010).
a “Point” deﬁned as 0.035 cc or less. 
b Avoid circumferential irradiation.
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Appendix K
Statistical Considerations for Paired Biopsies
While biopsies are requested of all patients with safely accessible nonirradiated/abscopal lesions 
(in the opinion of the investigator), safely accessible biopsies will become mandatory once 
evidence of peripheral immune activation is observed during dose escalation. Pending successful 
completion of the dose escalation phase of the study, it is anticipated that additional patients will 
be evaluated in future dose expansion. In the future dose expansion cohort, we hope to demonstrate
a biologically and statistically meaningful increase of T-cell infiltration into tumors after treatment 
of TAK-676 + pembrolizumab + radiation. A certain number of paired patient biopsies (from a 
single indication and dose level) in the escalation and expansion cohorts may be needed to achieve 
our desired statistical confidence. To evaluate that, we surveyed the literature for the level of T-cell 
infiltration into tumors treated with immune oncology agents in various tumor types (Chalabi et al. 
2020; Ferrarotto et al. 2020; Steele et al. 2018; Tumeh et al. 2014). Evaluation of published results 
suggest that CPI treatment-mediated T-cell infiltration can result in approximately 1.5- to 3-fold 
increases in CD8 T cells within the tumor microenviroment via the evaluation of pretreatment and 
posttreatment biopsies and yields an estimated coefficient of variation of 80% to 180% in majority 
of the studies. On the basis of these data, we assumed a 2.5-fold increase and a coefficient of 
variation of 130% to project the minimum number of paired biopsies that are needed to achieve a 
0.8 posterior probability of achieving a 1.5-fold increase in T cells after treatment, with a 
probability of success of 80%. On the basis of these assumptions, we projected that 11 pairs of 
high quality and interpretable biopsies are needed. The total number of patients biopsied within an 
indication needed to support this statistical goal is expected to be greater than 11 patients and will 
be based on biopsy quality and interpretability (refer to Statistical Analysis Plan for additional 
details).
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Appendix L
Protocol History 
Date
Amendment Number
Region
18 February 2022
Amendment 2
North America
31 March 2021
Amendment 1
North America
23 October 2020
Initial protocol
North America
Rationale for Amendment 1
This document describes the changes to the protocol incorporating Amendment 1. 
The primary reason for this amendment is to clarify concepts and criteria for treatment as well as 
response assessments. 
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
Secondary Objectives
Section 5.1.2 Secondary Objectives
In the objective describing antitumor 
activity, replaced the term “abscopal 
effect” with “nonirradiated lesions.”
Updated text 
throughout protocol 
from “abscopal” to 
“nonirradiated” and 
from “local” to 
“irradiated” for a more 
accurate description, 
since patients are also 
being treated with 
systemic therapies as 
opposed to just 
radiation therapy. 
2
Section 2.0 STUDY SUMMARY
Inclusion Criteria
Section 4.5.1 Rationale for the Selected 
Patient Population
Section 7.1 Inclusion Criteria
Updated Inclusion Criterion 5 to 
clarify that patients must have 
received or been offered all 
established standard of care (SOC) 
treatment options for which they were 
eligible in addition to having
progressed on checkpoint inhibitors 
in a prior line of therapy. 
Clarification to address 
Central Institutional 
Review Board inquiry.
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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
3
Section 2.0 STUDY SUMMARY
Exclusion Criteria
Section 7.2 Exclusion Criteria
Updated Exclusion Criterion 13 to 
provide examples of live attenuated 
virus.
Clarification with 
examples.
4
Section 2.0 STUDY SUMMARY
Main Criteria for Evaluation and 
Analyses
Statistical Considerations
Section 3.3 List of Abbreviations
Section 5.2.2 Secondary Endpoints
Table 6.b Primary and Secondary 
Endpoints for Disclosures
Renamed response assessments to 
replace “local” or “localized” with 
“irradiated” and to replace “abscopal” 
with “nonirradiated” as follows: 
irradiated response rate 
(ORRirradiated); nonirradiated 
response rate (ORRnonirradiated); 
confirmed complete response 
(cCRirradiated) and confirmed partial 
response (cPRirradiated) of tumor 
lesions lying within the radiation 
field; confirmed complete response 
(cCRnonirradiated) and confirmed 
partial response (cPRnonirradiated) 
of tumor lesions lying outside of the 
radiation field; duration of response 
for tumors lying within the radiation 
field (DORirradiated) and for those 
lying outside of the radiation field 
(DORnonirradiated); and time to 
response for tumors lying within the 
radiation field (TTRirradiated), and 
for those lying outside of the 
radiation field (TTRnonirradiated).
Since patients are 
being treated with 
systemic therapies, 
changed “abscopal” to 
“nonirradiated” and 
“local” to “irradiated” 
for a more accurate 
description.
5
Section 2.0 STUDY SUMMARY
Statistical Considerations
Section 6.1 Overview of Study Design
Section 6.1.1 Dose Escalation of 
TAK-676
Section 8.3 Dose Escalation Rules
Added the following clarifying text:
It is generally expected that at least 
3 patients will enroll per cohort. 
However, if no DLTs have been 
identified in the TAK-676 + 
pembrolizumab dose level that has 
already been evaluated in the 
dose-finding phase 1 TAK-676-1002 
study, the sponsor, in agreement with 
the TAK-676-1003 investigators, 
may opt to enroll a 2-patient cohort at 
that same [radiation] + TAK-676 + 
pembrolizumab dose level being 
evaluated in the TAK-676-1003 
study.
Clarification of dose 
escalation procedures.
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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
6
Section 5.2.3 Exploratory Endpoints
Section 13.1.5 Pharmacodynamic 
Analysis
Added changes in protein expression 
to the exploratory endpoint of 
changes between screening and 
on-treatment tumor biopsies in 
immune contexture and gene 
expression.
Clarification.
7
Section 6.1.1 Dose Escalation of 
TAK-676
Clarified that replacement of
dose-limiting toxicity 
(DLT)-inevaluable patients during 
dose escalation may not be 
mandatory except for the first cohort. 
Replacement may be determined 
based on the number of 
DLT-evaluable patients in the cohort.
Clarification.
8
Section 6.2 Number of Patients
Deleted the following sentence: 
"During the dose escalation phases, 
patients not receiving all required 
doses in Cycle 1 for reasons other 
than DLT will be replaced."
Update for consistency 
with patient 
replacement 
procedures.
9
Section 6.3.5 Post-trial Access
Clarified post-trial reimbursement 
procedures for pembrolizumab.
Clarification.
10
Section 8.1.2 Pembrolizumab
Updated that pembrolizumab dosing 
was to be on an every 3-week basis 
(rather than on a 3-week basis) after 
the last fraction of radiation.
Editorial update.
11
Section 8.1.3 TAK-676
Clarified the allowed interval 
between dosing pembrolizumab and 
TAK-676 and the allowable windows 
for TAK-676 dosing in all cycles 
except Cycle 1. 
Clarified that vital signs were to be 
measured before discharge if 
different from and not overlapping 
with specified timepoints for vital 
signs measurement.
Clarification of timing 
of TAK-676 
administration and 
timing of vital signs 
measurement before 
discharge.
12
Section 8.2 Definitions of DLT
Section 8.5 Excluded Concomitant 
Medications and Procedures
Added that coronavirus disease 2019 
(COVID-19) vaccinations should be 
avoided during the Cycle 1 DLT 
window.
Guidance on allowed 
timing of COVID-19 
vaccination.
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13
Section 8.3 Dose Escalation Rules
Appendix E BOIN Design
Modified text to indicate that dose 
escalation will continue until the 
maximum sample size is reached or 
the number of patients treated at the 
current dose level reaches 9 and the 
recommendation is to retain at the 
current dose level.
Clarification to 
describe the BOIN 
escalation rule more 
accurately.
14
Section 8.4 Dose Modification 
Guidelines
Clarified that discussions and 
agreements regarding dose 
modifications will be documented 
and that possible dose modifications 
due to AEs not related to study drug 
should be discussed with the medical 
monitor.
Clarification.
15
Section 8.4.1 Criteria for 
Administering a Subsequent 
Dose/Starting a New Cycle
Clarified criteria for holding or 
delaying treatment in the event of 
failing to meet retreatment criteria. 
Clarified that dose modifications due 
to clinically significant lab values not 
related to study drug are not required 
but should be discussed and 
documented with the medical monitor 
before the next dose.
Clarification.
16
Table 8.g Guidelines for TAK-676 
Dose Modification and/or 
Discontinuation for Hematologic 
Toxicity
Updated that TAK-676 should be 
held until absolute neutrophil count 
resolved to ≥1000/mm3 (instead of 
≥1500/mm3) in the event of febrile 
neutropenia.
Correction.
17
Section 8.5 Excluded Concomitant 
Medications and Procedures
Added that COVID-19 vaccinations 
were prohibited within ±3 days of 
systemic study treatments and should 
be avoided during the Cycle 1 DLT 
window. 
Added that certain prohibited 
medications may be used to treat 
adverse events during a TAK-676 
dose interruption in which there was a 
sufficient washout of TAK-676; these 
situations were to be handled on a 
case by case basis with discussion 
between the investigator and medical 
monitor.
Guidance on allowed 
timing of COVID-19 
vaccination and on use 
of prohibited 
medications to treat 
AEs during a study 
drug dose interruption. 
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18
Section 8.8.12 Management of 
COVID-19–Positive Patients
Added a section describing 
procedures for managing 
COVID-19-positive patients.
Guidance on 
management of 
patients with positive 
COVID-19 results.
19
Section 8.10.1 TAK-676
Section 8.10.2 Pembrolizumab
Clarified locations other than the 
Pharmacy Manual for information on 
preparation, storage, handling, and 
administration of the drug products.
Clarification.
20
Section 9.4 Study Procedures
Revised text to indicate that screening 
procedures must be completed within 
28 days before the first dose of 
radiation, instead of within 28 days 
before administration of the first dose 
of study drug. 
Clarification.
21
Section 9.4.11 Enrollment
Deleted reference to “Parts A and B” 
of the study.
Correction.
22
Section 9.4.14 Disease Assessment
Revised to indicated that screening 
radiographic disease assessments are 
to be completed within 28 days 
before the first dose of radiation.
Clarification.
23
Section 9.4.14.1 Special Allowances to 
RECIST v.1.1 and Treatment Beyond 
Progression
Section 9.4.14.1.1 Irradiated and 
Nonirradiated Response
Section 9.4.14.1.2 Treatment Beyond 
Progression
Added Section 9.4.14.1.1 to describe 
irradiated and nonirradiated response 
assessment and a heading for 
Section 9.4.14.1.2 on treatment 
beyond progression.
Clarified how 
irradiated and 
nonirradiated response 
should be assessed 
within the context of 
RECIST 1.1. 
24
Table 9.c Primary Specimen Collection
Added protein as a primary specimen 
derivative 2 to be collected from 
archival tumor tissue.
Alignment with 
updated exploratory 
endpoint.
25
Section 9.7 Discontinuation of 
Treatment With Study Drug and 
Patient Replacement
Added text clarifying circumstances 
for discontinuation of study treatment 
or study participation, and 
discontinuation of 1 study drug while 
the other is continued. Clarified that 
replacement of DLT-inevaluable 
patients during dose escalation may 
not be mandatory and may be 
determined based on the number of 
DLT-evaluable patients in the cohort.
Since using the 
Bayesian Optimal 
Interval (BOIN) 
design, which does not 
mandate exact number 
of patients required in 
a given cohort, added 
flexibility re: patient 
replacement within a 
cohort.
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26
Section 9.9 Completion of Study (for 
Individual Patients)
Clarified that patients will be 
considered to have completed the 
study if they are discontinued from 
both study drugs and one of the 
criteria specified in the section are 
met. One criterion was updated as 
completion of follow-up period and 
assessments, if applicable. A 
statement that the end of study 
electronic case report form (eCRF) 
should be completed was added. Text 
from a separate section (Section 9.10 
Withdrawal of Patients From the 
Study) was added to this section and 
the separate section was deleted.
Combination of similar 
sections to reduce 
redundancy and for 
clarification of 
procedures.
27
Section 10.3 Monitoring of AEs and 
Period of Observation
Clarified that all adverse events 
(AEs) were to be reported from the 
signing of the informed consent 
through 30 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.
Clarification.
28
Section 10.6 Safety Reporting to 
Investigators, IRBs or IECs, and 
Regulatory Authorities
Added missing heading.
Added missing 
heading.
29
Section 13.1.1 Analysis Sets
Updated the definition of the 
DLT-evaluable analysis set to clarify 
that patients who receive only 1 or 
2 doses of radiation will not be 
considered DLT-evaluable and may 
or may not be replaced within the 
same cohort and allowed to continue 
on study.
Updated the definitions of the 
response-evaluable and 
pharmacodynamic analysis sets to 
add that patients must have received 
at least 1 dose of TAK-676.
Since using the BOIN 
design, which doesn’t 
mandate exact number 
of patients required in 
a given cohort, added 
flexibility re: patient 
replacement within a 
cohort.
Clarified that patients 
need to have received 
at least 1 dose of 
TAK-676 to be 
included in the 
response evaluable and 
pharmacodynamic 
analysis sets. 
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Description of Each Change and Rationale
Location
Description
Rationale
30
Section 13.1.3 Efficacy Analysis
Updated the efficacy endpoint names 
to ORRnonirradiated, ORRirradiated, 
DORnonirradiated, DORirradiated, 
TTRnonirradiated, and 
TTRirradiated and updated the 
definition of DORnonirradiated to 
use “nonirradiated” instead of 
“abscopal.”
Since patients are 
being treated with 
systemic therapies, 
changed “abscopal” to 
“nonirradiated” and 
“local” to “irradiated” 
for a more accurate 
description.
31
Section 13.3 Determination of Sample 
Size
Deleted the extra word “for” from the 
following: “The details of dose 
escalation rules for are specified in 
Section 8.3.”
Correction.
32
Section 16.0 REFERENCES
Added new reference for Response 
Criteria for Intratumoral Therapy in 
Solid Tumors. 
Update to align with 
added text on 
irradiated and 
nonirradiated response.
33
Appendix A Schedule of Events
Table 1 SOE for Treatment With 
Radiation 
Therapy + Pembrolizumab + TAK-676 
(21-Day Cycle)
Updated footnote d to add that vital 
signs were to be measured before 
discharge if different from and not 
overlapping with specified timepoints 
for vital signs measurement.
Added a cross reference to footnote h 
(formerly footnote k) to radiation 
therapy administration row. Added 
the following text to footnote h: 
“Repeat baseline chemistry and 
hematology labs should be obtained 
on the day of first dose of radiation if 
more than 2 weeks have elapsed 
between screening labs and the first 
dose of radiation.”
Reversed the order of footnotes u and 
v as a correction.
Clarification and 
correction.
34
Appendix I Clinical Inhibitors of 
OATP1B1 and OATP1B3
Added the brand name for remdesivir.
Update for 
completeness.
For non-commercial use only

For non-commercial use only