Clinical trial NCT03449030
Conditions: Gastrointestinal Neoplasms; Esophageal, Stomach, Pancreas, Colon Neoplasms; Malignant Tumors of Digestive Organ; Advanced Gastrointestinal Malignancies
Keywords: Drug Therapy
Sponsor: Millennium Pharmaceuticals, Inc.
Start date: 2018-04-23; Completion date: 2020-02-27
Enrollment: 31 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this study is to evaluate the safety of TAK-164 and to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) and schedule.

Detailed description:
The drug being tested in this study is a novel antibody-drug conjugate (ADC) called TAK-164. TAK-164 is being evaluated in participants with advanced GCC-positive GI cancer (Part A) or colorectal carcinoma (CRC) and gastric carcinoma (Part B and Part C) to determine safety, tolerability, and pharmacokinetics (PK) and MTD/RP2D of TAK-164, as well as the preliminary efficacy. The study will include approximately 100 evaluable participants.

In Part A (Escalation), approximately 25 participants with GI carcinoma will be enrolled. Those include participants with various GI malignancies such as carcinomas of esophagus, stomach, colon, and pancreas. The starting dose for Arm 1 will be 0.004 mg/kg of TAK-164 administered intravenously on Day 1 Q3W and the maximal dose will not exceed 0.19 mg/kg Q3W.

In Part B (Expansion), approximately 50 participants will be enrolled to receive TAK-164 infusion at determined RP2D in Part A. Participants will follow the Q3W schedule and will be followed until PD, unacceptable toxicity, or until they choose to withdraw consent.

In Part C (Imaging substudy to be conducted in the Netherlands only), approximately 25 participants with GCC-expressing metastatic colorectal carcinoma (mCRC) will be enrolled to receive 89Zr-TAK-164 and unlabeled TAK-164 at determined RP2D in Part A.

This multi-center trial will be conducted in the United States and the Netherlands. The overall time to participate in this study is up to 55 months. Participants will attend an end of study (EOS) visit 30 days after the last dose of TAK-164 or just prior to the start of subsequent antineoplastic therapy, whichever occurs first.

Arms: arm 1: TAK-164 0.004 milligram per kilogram (mg/kg) starting dose, intravenous infusion, until PD, unacceptable toxicity or discontinuation by participant. Dose escalation will be performed to determine the MTD and/or RP2D. arm 2: TAK-164, intravenous infusion, until PD, unacceptable toxicity or discontinuation by participant. TAK-164 RP2D dose to be decided based on safety, PK, pharmacodynamics and antitumor response data observed in Part A escalation stage. arm 3: 89Zr-TAK-164, intravenous infusion, followed by unlabeled TAK-164, intravenous infusion in combination with 89Zr-TAK-164, intravenous infusion, and further followed by unlabeled TAK-164, intravenous infusion, until PD, unacceptable toxicity or discontinuation by participant. TAK-164 recommended imaging dose (RID) or RP2D dose to be decided based on safety, PK, PD and antitumor response data observed in Part A escalation stage.
Interventions: intervention 1: TAK-164 intervention 2: 89Zr-TAK-164
Intervention descriptions: intervention 1: TAK-164 intravenous infusion. intervention 2: 89Zr-TAK-164 intravenous infusion

Protocol documents:
Prot_000.pdf: 



Title: An Open-Label, Dose Escalation, Phase 1, First-in-Human Study of TAK-164, an Antibody-
Drug Conjugate, in Patients with Advanced Gastrointestinal Cancers Expressing Guanylyl 
Cyclase C
NCT Number: NCT03449030
Protocol Approve Date: 04 September2019
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.


1.0 TITLE PAGE
PROTOCOL
An Open-Label, Dose Escalation, Phase 1, First-in-Human Study of TAK-164, an Antibody-
Drug Conjugate, in Patients with Advanced Gastrointestinal Cancers Expressing Guanylyl 
Cyclase C
Sponsor:
Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda 
Pharmaceutical Company Limited
Please note: Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda 
Pharmaceutical Company Limited, may be referred to in this protocol as 
“Millennium,” “sponsor,” or “Takeda”.
Study Number:
TAK-164-1001
Compound:
TAK-164
Date:
04 September2019
Amendment Number:
05
Amendment History:
Date
Amendment Number
Amendment Type
Region
30 November 2017
Initial protocol
Not applicable
Global
26 January 2018
01
Substantial
Global
27 June 2018
02
Nonsubstantial
Global
13 September 2018
03
Substantial
Netherlands
29 March 2019
04
Substantial
Global
04 September2019
05
Substantial
Global
P
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1.0
ADMINISTRATIVE
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.
Information on service providers is given in Section 3.1 and relevant guidelines provided to the 
site.
The names and contact information for the medical monitor and responsible medical officer are 
in the study manual.
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1.2
Approval
REPRESENTATIVES OF TAKEDA
This study will be conducted with the highest respect for the individual participants in 
accordance with the requirements of this clinical study protocol and also in accordance with the 
following:
!
The ethical principles that have their origin in the Declaration of Helsinki.
!
International Conference on Harmonisation E6 Good Clinical Practice: Consolidated 
Guideline.
!
All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations.
SIGNATURES
The signature of the responsible Takeda medical officer (and other signatories, as applicable) can 
be found on the signature page.
Electronic Signatures may be found on the last page of this document.
ith the
h the
onso
nsolida
lid
data pri
data p
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INVESTIGATOR AGREEMENT
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, 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 Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting SAEs defined in Section 10.0 of this protocol.

Terms outlined in the Clinical Study Site Agreement.

Responsibilities of the Investigator (Appendix B).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix C of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Province)
Location of Facility (Country)
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1.3
Protocol Amendment 05 Summary of Changes
Rationale for Amendment 05
This document describes the changes in reference to the protocol incorporating Amendment 05. 
The primary reasons for this amendment are to limit the future maximal TAK-164 dose to 
0.19 mg/kg once every 3 weeks (Q3W), to identify hepatotoxicity as a potential risk and 
implement an enhanced liver safety management plan, to integrate safety/tolerability data beyond 
Cycle 1 into the recommended phase 2 dose (RP2D) determination for the expansion phase, to 
limit the number of prior lines of therapy to 2 or 3 lines in the expansion phase (part B), and to 
enroll patients at the recommended imaging dose (RID) in the imaging substudy (part C).
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification and administrative purposes only.
Changes in Amendment 05
1. The future maximal TAK-164 dose was limited to 0.19 mg/kg Q3W.
2. Hepatotoxicity was added as a potential risk. An enhanced liver safety management plan was 
implemented.
3. Clarified that safety/tolerability data beyond Cycle 1 will be integrated into the RP2D 
determination for the expansion phase.
4. Limited prior lines of therapy to 2 or 3 lines in the expansion phase (part B).
5. Clarified that patients will be enrolled at the RID in the imaging substudy (part C).
6. Clarified that part C will be conducted in The Netherlands only.
7. Clarified that gastric carcinoma patients in part B and colorectal or gastric carcinoma patients 
in part C must express guanylyl cyclase C (GCC) with an H-score of ≥10.
8. Clinical laboratory directives were updated to reflect local capabilities.
9. Clarified protocol for biopsy.
10. Added definition and requirements for monitoring and reporting adverse events of special 
interest (AESIs).
11. Clarified procedure for collection of electrocardiograms (ECGs) at the end of infusion (EOI).
12. Updated Response Evaluation Criteria in Solid Tumors (RECIST) per RECIST version 1.1 
guidelines.
13. Clarified that the specific mass dose of antibody-drug conjugate (ADC) will be determined 
during the dosimetry and imaging optimization (DIO) phase of the imaging substudy.
14. Clarified the timing of disease assessments.
15. Moved a section of text regarding part C from Section 13.1.6 to Section 13.1.3.
For specific descriptions of text changes and where the changes are located, see Appendix H.
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE.......................................................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 05 Summary of Changes ..........................................................5
2.0
STUDY SUMMARY ....................................................................................................13
3.0
STUDY REFERENCE INFORMATION ......................................................................20
3.1
Study-Related Responsibilities.................................................................................20
3.2
Coordinating Investigator.........................................................................................20
3.3
List of Abbreviations ...............................................................................................21
3.4
Corporate Identification...........................................................................................24
4.0
INTRODUCTION.........................................................................................................25
4.1
Background .............................................................................................................25
4.2
Scientific Background..............................................................................................25
4.2.1
Disease Under Treatment ...................................................................................25
4.2.2
Study Drug.........................................................................................................28
4.3
Preclinical Experience .............................................................................................29
4.3.1
Pharmacology....................................................................................................29
4.3.2
Safety Pharmacology .........................................................................................30
4.3.3
PK .....................................................................................................................30
4.3.4
Toxicology.........................................................................................................31
4.4
Clinical Experience..................................................................................................31
4.5
Rationale for the Proposed Study.............................................................................31
4.6
Potential Risks and Benefits.....................................................................................33
4.6.1
Radiation Burden for Patients in the Imaging Substudy (Part C, To Be 
Conducted in The Netherlands Only) .................................................................35
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................37
5.1
Objectives................................................................................................................37
5.1.1
Primary Objective ..............................................................................................37
5.1.2
Secondary Objectives.........................................................................................37
5.1.3
Exploratory Objectives.......................................................................................37
5.2
Endpoints.................................................................................................................38
5.2.1
Primary Endpoints .............................................................................................38
5.2.2
Secondary Endpoints..........................................................................................38
5.2.3
Exploratory Endpoints .......................................................................................39
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6.0
STUDY DESIGN..........................................................................................................40
6.1
Overview of Study Design.......................................................................................40
6.2
Number of Patients ..................................................................................................47
6.3
Duration of Study ....................................................................................................47
6.3.1
Duration of an Individual Patient’s Study Participation ......................................47
6.3.2
End of Study/Study Completion Definition and Planned Reporting....................47
6.3.3
Timeframes for Primary and Secondary Endpoints to Support Disclosures.........48
6.3.4
Total Study Duration..........................................................................................49
7.0
STUDY POPULATION................................................................................................50
7.1
Inclusion Criteria .....................................................................................................50
7.2
Exclusion Criteria ....................................................................................................52
8.0
STUDY DRUG .............................................................................................................54
8.1
Study Drug Administration......................................................................................54
8.2
Definitions of DLT ..................................................................................................55
8.3
Dose Escalation Rules..............................................................................................55
8.4
Dose Modification Guidelines..................................................................................58
8.4.1
Criteria for Retreatment and Dose Delays and Modifications Delaying a 
Subsequent Treatment Cycle..............................................................................58
8.4.2
Criteria for Dose Reduction................................................................................60
8.4.3
Criteria for Discontinuation of TAK-164............................................................61
8.5
Excluded Concomitant Medications and Procedures ................................................62
8.6
Precautions and Restrictions ....................................................................................62
8.7
Management of Clinical Events ...............................................................................63
8.7.1
Nausea- and/or Vomiting ...................................................................................63
8.7.2
Anemia, Thrombocytopenia, and/or Neutropenia ...............................................64
8.7.3
Skin Lesions ......................................................................................................64
8.7.4
Lacrimal Gland Secretion Alteration..................................................................64
8.7.5
Diarrhea.............................................................................................................64
8.7.6
Infusion-related Reactions..................................................................................64
8.7.7
Hepatotoxicity....................................................................................................65
8.8
Blinding and Unblinding..........................................................................................65
8.9
Description of Investigational Agents ......................................................................65
8.10
Preparation, Reconstitution, and Dispensation..........................................................65
8.11
Packaging and Labeling...........................................................................................66
8.12
Storage, Handling, and Accountability.....................................................................66
8.13
Other Protocol-Specified Materials ..........................................................................66
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8.14
Description of 89Zr-TAK-164...................................................................................66
8.15
Preparation of 89Zr-TAK-164...................................................................................66
8.16
89Zr-TAK-164 Administration .................................................................................66
9.0
STUDY CONDUCT......................................................................................................67
9.1
Study Personnel and Organizations..........................................................................67
9.2
Arrangements for Recruitment of Patients................................................................67
9.3
Treatment Group Assignments.................................................................................67
9.4
Study Procedures.....................................................................................................67
9.4.1
Informed Consent...............................................................................................68
9.4.2
Inclusion/Exclusion Review...............................................................................68
9.4.3
Patient Demographics ........................................................................................68
9.4.4
Medical History .................................................................................................68
9.4.5
Physical Examination.........................................................................................68
9.4.6
Height and Weight .............................................................................................68
9.4.7
ECOG Performance Status.................................................................................68
9.4.8
Vital Signs .........................................................................................................69
9.4.9
Pregnancy Test...................................................................................................69
9.4.10 Concomitant Medications and Procedures..........................................................69
9.4.11 AEs....................................................................................................................69
9.4.12 Enrollment .........................................................................................................69
9.4.13 Cardiac Monitoring............................................................................................69
9.4.14 Clinical Laboratory Evaluations .........................................................................70
9.4.15 Disease Assessment ...........................................................................................71
9.4.16 Assessment of 89Zr-TAK-164 PET Imaging (Part C, To Be Conducted in The 
Netherlands Only)..............................................................................................71
9.4.17 Assessment of 18F-FDG-PET Imaging (Part C, To Be Conducted in The 
Netherlands Only)..............................................................................................72
9.4.18 Biomarker, PK, and Pharmacodynamic Samples ................................................72
9.4.19 DNA Measurements...........................................................................................75
9.4.20 Banked Tumor and/or Fresh Tumor Biopsy Specimen Measurements ................75
9.4.21
...................................................................75
9.4.22 Immunogenicity Sample Collection ...................................................................76
9.5
Completion of Study Treatment (for Individual Patients) .........................................76
9.6
Discontinuation of Treatment with Study Drug and Patient Replacement.................76
9.7
Study Compliance....................................................................................................76
9.8
Posttreatment Follow-up Assessments (PFS) ...........................................................77
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66
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10.0
ADVERSE EVENTS ....................................................................................................78
10.1
Definitions...............................................................................................................78
10.1.1 Pretreatment Event Definition............................................................................78
10.1.2 AE Definition ....................................................................................................78
10.1.3 SAE Definition ..................................................................................................78
10.1.4 AESI Definition.................................................................................................79
10.2
Procedures for Recording and Reporting AEs and SAEs..........................................79
10.3
Monitoring of AEs and Period of Observation .........................................................80
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events.........81
10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose) ................................................................................................................81
10.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities...........81
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................83
12.0
DATA HANDLING AND RECORDKEEPING............................................................84
12.1
eCRFs......................................................................................................................84
12.2
Record Retention .....................................................................................................84
13.0
STATISTICAL METHODS..........................................................................................86
13.1
Statistical and Analytical Plans ................................................................................86
13.1.1 Dose Escalation (Part A)....................................................................................86
13.1.2 Dose Expansion (Part B)....................................................................................88
13.1.3 Imaging Substudy (Part C, To Be Conducted in The Netherlands Only).............88
13.1.4 Analysis of Demographics and Other Baseline Characteristics ...........................89
13.1.5 Efficacy Analysis...............................................................................................89
13.1.6 PK Analysis .......................................................................................................90
13.1.7 Biomarker Analysis............................................................................................90
13.1.8 Immunogenicity Analyses..................................................................................91
13.1.9 Safety Analysis ..................................................................................................91
13.2
Interim Analysis and Criteria for Early Termination ................................................91
13.3
Determination of Sample Size..................................................................................92
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................93
14.1
Study-Site Monitoring Visits ...................................................................................93
14.2
Protocol Deviations..................................................................................................93
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................93
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................95
15.1
IRB and/or IEC Approval ........................................................................................95
15.2
Patient Information, Informed Consent, and Patient Authorization...........................96
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15.3
Patient Confidentiality .............................................................................................97
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................97
15.4.1 Publication.........................................................................................................97
15.4.2 Clinical Trial Registration..................................................................................98
15.4.3 Clinical Trial Results Disclosure ........................................................................98
15.4.4 Data Sharing ......................................................................................................98
15.5
Insurance and Compensation for Injury....................................................................98
16.0
REFERENCES..............................................................................................................99
LIST OF IN-TEXT TABLES
Table 6.a
Primary and Secondary Endpoints for Disclosures .............................................48
Table 8.a
TAK-164 Recommended Dose Modification Criteria.........................................59
Table 9.a
TAK-164-1001: Primary Specimen Collection...................................................73
Table 13.a
TAK-164-1001: Scenarios With Simulated True DLT Rate at Each Dose 
Level..................................................................................................................87
Table 13.b
TAK-164-1001: Simulation Results of Scenario 1..............................................87
Table 13.c
TAK-164-1001: Operating Characteristics for Dose Escalation using mTPI.......88
Table A-1
Schedule of Events for Parts A and B – Cycles 1 and 2 ....................................104
Table A-2
Schedule of Events for Parts A and B – Cycles 3+ ...........................................106
Table A-3
Biomarker Sample Collection for Parts A and B...............................................108
Table A-4
Serial PK and ECG Collection Schedule for Part A..........................................110
Table A-5
Part B Sparse PK and ECG Collection .............................................................112
Table A-6
Part C (Imaging Substudy, DIO Patients Only) Schedule of Events for 14-Day 
Run-in Period...................................................................................................113
Table A-7
Part C (Imaging Substudy) Schedule of Events for Cycle 1 ..............................115
Table A-8
Part C (Imaging Substudy) Schedule of Events for Cycle 2 ..............................118
Table A-9
Part C (Imaging Substudy) Schedule of Events for Cycle 3+ (21-Day Cycle)...121
Table A-10
Part C Sparse PK and ECG Collection .............................................................123
Table A-11
Strong CYP3A Inhibitors and Inducers ............................................................129
Table A-12
Disease Response Criteria for Target and Nontarget Lesions............................131
Table A-13
Time Point Response: Patients With Target (Nontarget) Disease...................132
Table A-14
Time Point Response: Patients With Nontarget Disease Only...........................132
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LIST OF IN-TEXT FIGURES
Figure 6.a
Study Design for TAK-164-1001 Phase 1 First-in-Human..................................40
Figure 6.b
Study Flow Diagram for Part C DIO Subgroup ..................................................45
Figure 6.c
Study Flow Diagram Part C Following DIO.......................................................46
Figure 8.a
TAK-164-1001 mTPI Decision Table ................................................................56
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LIST OF APPENDICES
Appendix A
Schedules of Events [21-Day Cycle - Q3W Schedule]......................................104
Appendix B
Responsibilities of the Investigator...................................................................125
Appendix C
Investigator Consent to Use of Personal Information........................................127
Appendix D
ECOG Scale for Performance Status ................................................................128
Appendix E
Inhibitors and Inducers.....................................................................................129
Appendix F
Methods of Contraception Considered to be Effective......................................130
Appendix G
Response Evaluation Criteria in Solid Tumors (version 1.1).............................131
Appendix H
Detailed Description of Amendments to Text...................................................133
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2.0
STUDY SUMMARY
Name of Sponsor(s):
Millennium Pharmaceuticals, Inc
Compound: TAK-164
Title of Protocol: An Open-Label, Dose Escalation, 
Phase 1, First-in-Human Study of TAK-164, an Antibody-
Drug Conjugate, in Patients with Advanced Gastrointestinal 
Cancers Expressing Guanylyl Cyclase C
IND No.: Not Applicable
EudraCT No.: Not 
Applicable
Study Number: TAK-164-1001
Phase: 1
Study Design:
This is a multicenter, nonrandomized, open-label, phase 1 study of TAK-164 in patients with advanced guanylyl 
cyclase C (GCC)-positive gastrointestinal (GI) cancer for whom standard treatment is no longer effective or for 
whom there is no available standard therapy. This study will be the first to administer TAK-164 to humans. For the 
dose escalation portion of the study (part A), the patient population will consist of adults, aged 18 years or older, 
with any various GI malignancies expressing GCC for whom standard treatment is no longer effective or for whom 
there is no available standard therapy. Maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) 
will be estimated in part A. In the expanded cohort (part B), patients with colorectal carcinoma (CRC) and gastric 
carcinoma will be enrolled at RP2D. In the expanded cohort (part C-imaging substudy), patients with CRC and 
gastric carcinoma will be enrolled at the recommended imaging dose (RID).
This study is designed to determine safety, tolerability, and pharmacokinetics (PK) and to determine an MTD and/or 
RP2D of TAK-164 that may be safely administered to patients with advanced GCC-positive GI cancer. The study 
may also help define a therapeutic window of TAK-164 based on pharmacodynamics and systemic exposures 
achieved over the evaluated dose range. It is anticipated that approximately 100 patients could be enrolled, including 
the escalation phase (part A), the expansion phase (part B), and the imaging substudy (part C).
Once enrolled in the study, patients will receive TAK-164 treatment intravenously (IV) on Day 1 of each 21-day 
treatment cycle or every 3 weeks (Q3W).
Dose Escalation (Part A)
The starting TAK-164 dose will be 0.004 mg/kg Q3W and the maximal dose will not exceed 0.19 mg/kg Q3W. To 
determine the MTD and to guide the dose escalation portion of the study, a method based on a Bayesian model of 
modified toxicity probability interval (mTPI), will be used. Although dose escalation and MTD will be estimated 
based on observed dose-limiting toxicities (DLTs) in Cycle 1, safety/tolerability data beyond Cycle 1 will be 
integrated into the RP2D determination for the expansion phase. The DLT rate will be continuously monitored and 
safety analysis conducted during the dose expansion part of the study to allow regular assessments of the 
appropriateness of the dosing level.
Expansion Cohort (Part B)
Once the RP2D is established, the number of patients at that dose will be expanded to further characterize the safety, 
tolerability, and PK of TAK-164 (conjugated and unconjugated) and to evaluate disease response in patients based 
on the expression of GCC as measured by immunohistochemistry (IHC). Up to 25 patients with CRC of high GCC 
expression level (H-score ≥150) will be assessed. In addition, up to 25 patients with gastric carcinoma expressing 
GCC (H-score ≥10) will be included in the study. Patients with CRC GCC high expression level and patients with 
gastric cancer may experience a greater clinical benefit than patients with other GI malignancies, as supported by 
preclinical research. A minimum of approximately 20 patients will be enrolled in either cohort. The DLT rate will be 
continuously monitored and safety analysis conducted during dose expansion part of the study to allow regular 
assessments of the appropriateness of the dosing level.
The objectives are to evaluate the safety and tolerability of TAK-164 and to assess efficacy, as measured by overall 
response rate (ORR) and other efficacy variables, including disease control rate (DCR), duration of response (DOR), 
and progression-free survival (PFS). The evaluation of tumor status will be performed by computed tomography 
(CT) or magnetic resonance imaging (MRI) scans according to modified Response Evaluation Criteria in Solid 
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Tumors (RECIST) (version 1.1) [1] in all patients participating in this study at treatment intervals of 2 cycles. 
Pharmacodynamic evaluation will be performed by assessing 
 on tumor tissue from pre-
and postdose biopsies required to be obtained from a minimum of approximately 5 evaluable patients participating 
in the study.
All patients participating in this study who are judged by the investigator to be receiving clinical benefit may receive 
study drug until they experience progression of disease (PD) or unacceptable toxicity or they choose to withdraw 
from study due to other factors.
Imaging Substudy (Part C, To Be Conducted in The Netherlands Only)
Up to 25 patients with GCC-expressing metastatic colorectal carcinoma (mCRC) and/or gastric carcinoma at up to 2 
investigational sites in The Netherlands will be enrolled to determine the in vivo biodistribution and tumor targeting 
of zirconium 89 (89Zr)-TAK-164 by positron emission tomography (PET) imaging. In addition, the relationship of 
89Zr-TAK-164 tumor targeting with 18-fluorodeoxyglucose (18F-FDG)-PET–determined response and RECIST 
version 1.1 response, and the relationship of 89Zr uptake with GCC expression, in tumor tissues and other 
biomarkers will be investigated. Based on emerging data from the dose escalation phase (part A) and in agreement 
between the site investigator and sponsor, part C will be triggered at a dose that is considered safe and having 
treatment potential (RID).
Initially, approximately 6 patients (including 3 dosimetry patients) will be enrolled for dosimetry and imaging 
optimization (DIO). This DIO subgroup will receive only 89Zr-TAK-164 (mass dose <50% of the RID) 14 days 
before the first regularly scheduled study dose at Cycle 1 Day 1 and a second 89Zr-TAK-164 administration on 
Cycle 1 Day 1 in combination with unlabeled TAK-164 at a maximum mass dose of 100% of the RID. Imaging will 
be performed 1 hour after end of infusion (EOI) of the first 89Zr-TAK-164 administration for dosimetry in the first 3 
patients and for all patients at 2 time points between Day 2 and Day 7 after EOI. Imaging time points and mass dose 
of TAK-164 can be adjusted to optimize imaging conditions. Up to 19 additional patients will be enrolled into part C 
to receive a single dose of 89Zr-TAK-164 at Cycle 1 Day 1 in addition to unlabeled TAK-164 as determined for 
optimal imaging. Once the RP2D of TAK-164 is determined, part C patients who have received TAK-164 at an RID 
lower than the RP2D of TAK-164 may dose-escalate to the RP2D in the absence of PD or unacceptable treatment-
related toxicity at the investigator’s discretion and with the sponsor’s approval. If the full RID/RP2D is not 
administered at Cycle 1 Day 1, the differential will be provided after the second image acquisition. Part C patients 
will continue treatment with the RID/RP2D of TAK-164 at Cycle 2 Day 1 and beyond. 
Primary Objective:
•
To evaluate the safety of TAK-164 and to determine the MTD and/or RP2D.
Secondary Objectives:
Part A and part B secondary objectives are:
•
To characterize the PK of TAK-164.
•
To evaluate immunogenicity of TAK-164.
•
To evaluate efficacy of TAK-164 as measured by overall response rate.
•
To evaluate other efficacy measures such as DCR, which includes response (complete response [CR]+partial 
response [PR]) plus stable disease, DOR, and PFS.
Part C (imaging substudy) secondary objectives are:
•
To determine the biodistribution of 89Zr-TAK-164 in patients with mCRC and/or metastatic gastric carcinomas.
•
To determine the tumor targeting of 89Zr-TAK-164.
•
To determine dosimetry of 89Zr-TAK-164.
Patient Population: Patients with advanced GI cancer expressing GCC who are appropriate candidates for 
experimental therapy for whom standard treatment is no longer effective or for whom there is no available standard 
therapy.
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Number of Patients:
The maximum number of patients in this study is 
expected to be to approximately 100 evaluable 
patients (including up to 25 in the dose escalation 
phase and up to 25 patients in the imaging substudy 
[part C]).
Number of Sites: Up to 5 sites in the United States (US) 
in the dose escalation portion of the study. Additional sites 
will be added, globally, for the expansion portion of the 
study. Substudy part C will be conducted at up to 2 sites in 
The Netherlands including Amsterdam University Medical 
Centre (Amsterdam UMC), location Vrije Universiteit 
Medical Centre (VUMc).
Route of Administration: TAK-164 IV, 89Zr-TAK-164 IV
Dose Level(s):
Part A 
Q3W Schedule and Dose Levels:

TAK-164 is administered on Day 1 of each 21-day cycle.

Up to 3 initial patients per cohort will be enrolled at the starting dose of 0.004 mg/kg. Dose escalation is 
planned to proceed by evaluating patients at respective doses: 0.008 mg/kg, 0.016 mg/kg, 0.032 mg/kg, 0.064 
mg/kg, 0.12 mg/kg, and 0.19 mg/kg.
The adjustments of percent increases between the dose levels is based on further review of the preclinical modeling 
that predicts human TAK-164 exposures for safety and efficacy. Also, currently available clinical experience 
supports the dose escalation scheme. Lower increments between dose levels may be proposed and discussed 
between sponsor and the investigators based on emerging clinical data.
MTD with a target toxicity of 25% is determined by mTPI (dose level of posterior mean toxicity closest to target 
toxicity). Although dose escalation and MTD will be estimated based on observed DLTs in Cycle 1, 
safety/tolerability data beyond Cycle 1 will be integrated into the RP2D determination for the expansion phase.
Approximately 25 patients will be enrolled during the dose escalation phase on the Q3W schedule. The escalation 
may be stopped upon a completion of enrollment of all patients planned to participate in the dose escalation part of 
the study or based on clinical judgment supported by medical observations.
Dose escalation will apply mTPI design. Up to 3 patients will be enrolled in dose cohort 1 and following completion 
of 1 treatment cycle interval reassessment will be performed to assess tolerability of TAK-164 to inform any dose 
adjustments that may be needed for subsequent patients. Decisions regarding dose escalation will be made on the 
basis of DLTs occurring during the first cycle of treatment.
A dose range of TAK-164 that may be safely administered as a single agent to patients will be assessed in the course 
of the dose escalation part of the study and this information will support the dose schedule recommendation for use 
in the expansion phase (part B and part C of the study). Safety/tolerability data beyond Cycle 1 will be integrated 
into the RP2D determination for the expansion phase.
Note that, depending on PK-defined exposure estimates, a dose level between the planned dose levels may be 
explored. In addition, based on safety/tolerability, alternative dosing schedules may be explored after discussion and 
concurrence with all lead investigators and the Takeda study clinician. However, no patients will receive a dose 
above 0.19 mg/kg Q3W.
Patients participating in the escalation stage, estimated to be approximately 25, will be followed until PD, 
unacceptable toxicity, or until they choose to withdraw consent from the trial.
More conservative dose escalation, evaluation of intermediate doses, and expansion of an existing dose level are all 
permissible following discussion between the sponsor and the investigators, if such measures are needed for patient 
safety or for a better understanding of the dose-related toxicity, exposure, or pharmacodynamics of TAK-164.
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Part B
Schedule: One treatment schedule (Q3W schedule) will be evaluated during part B, as informed by the data obtained 
from part A.
Patients participating in part B (expansion stage of the study) will be followed until PD, unacceptable toxicity, or 
until they choose to withdraw consent.
Part C (To Be Conducted in The Netherlands Only)
Schedule: The DIO subgroup will receive 89Zr-TAK-164 (mass dose <50% of the RID) 14 days before the first 
regularly scheduled study dose at Cycle 1 Day 1 and a second 89Zr-TAK-164 administration on Cycle 1 Day 1 in 
combination with unlabeled TAK-164 at a maximum mass dose of 100% of the RID. Imaging will be performed 1 
hour after EOI of the first 89Zr-TAK-164 administration for dosimetry in the first 3 patients and for all patients at 2 
time points between Day 2 and Day 7 after EOI. Imaging time points and mass dose of TAK-164 can be adjusted to 
optimize imaging conditions. Up to 19 additional patients will be enrolled into part C to receive a single dose of 
89Zr-TAK-164 at Cycle 1 Day 1 in addition to unlabeled TAK-164 as determined for optimal imaging. Once the 
RP2D of TAK-164 is determined, part C patients who have received TAK-164 at an RID lower than the RP2D of 
TAK-164 may dose-escalate to the RP2D in the absence of PD or unacceptable treatment-related toxicity at the 
investigator’s discretion and with sponsor’s approval. If the full RID/RP2D is not administered at Cycle 1 Day 1, the 
differential will be provided after the second image acquisition. Part C patients will continue treatment with the 
RID/RP2D of TAK-164 at Cycle 2 Day 1 and beyond. 
Duration of Treatment:
Treatment with TAK-164 can be continued in the 
absence of unacceptable toxicity until the first 
documentation of PD by imaging (physician 
discretion) or consent withdrawal. The maximum 
duration of treatment is 12 cycles. All patients 
participating in this study who are judged by the 
investigator to be receiving clinical benefit will be 
permitted to remain on therapy until PD or they 
choose to withdraw from the study due to toxicity or 
other factors.
Period of Evaluation:
Assessments of disease will be performed at specified time 
points. Radiographic evaluation will be conducted at 
treatment intervals of 2 cycles.
Follow-up visits for PFS, which will evaluate a response, 
will be conducted at the site every 3 months from last dose 
of study drug for patients who discontinue for reasons 
other than PD. Those follow-up visits will continue for up 
to 6 months or until PD, the start of alternative therapy, or 
conclusion of the study (whichever occurs first).
Main Criteria for Inclusion:

Histologically or cytologically confirmed measurable advanced and/or metastatic solid GI tumor that expresses 
GCC protein (H-score ≥10), for which standard treatment is no longer effective or for whom there is no 
available standard therapy. For the escalation part of the study (part A), GI malignancies include, but are not 
limited to, mCRC, gastric carcinoma, esophageal carcinoma, small intestine cancer, and pancreatic cancer. The 
expansion part of the study (part B) is limited to patients with CRC expressing a high-level GCC (H-score 
≥150) and gastric carcinoma expressing GCC (H-score ≥10). Part C includes patients with CRC and gastric 
carcinoma expressing GCC (H-score ≥10).
–
The expansion part of the study (part B) will be limited to patients with 2 or 3 prior lines of systemic 
standard of care therapy.

Voluntary written consent must be obtained from the patient prior to enrollment in the study with the 
understanding that consent may be withdrawn by the patient at any time without consequences on receiving 
future medical care.

Male or female patients 18 years or older.

Adequate bone marrow function, defined as an absolute neutrophil count of ≥1.5 × 10
9/L, platelet count ≥100 × 
10
9/L, and hemoglobin ≥9 g/dL. Receiving transfusions or hematopoietic growth factors to meet enrollment 
criteria are not allowed within 14 days preceding the first dose of study drug.

Adequate hepatic function with:
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–
Total bilirubin ≤1.5 upper limit of normal (ULN).
–
Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) must be ≤2.5 ULN (AST 
and ALT may be elevated up to 3 ULN if the elevation can be reasonably ascribed to the presence of 
metastatic disease in liver).
–
Serum albumin ≥3.0 g/dL.

Adequate renal function as defined by creatinine clearance ≥60 mL/min.

Eastern Cooperative Oncology Group performance score of 0 or 1.

Life expectancy of at least 12 weeks.

Completion of prior chemotherapy, biologic therapy, immunotherapy, or radiation therapy at least 4 weeks prior 
to enrollment.

Resolution of all toxic effects of prior treatments (except alopecia) to Grade ≤1 by National Cancer Institute 
Common Terminology Criteria for Adverse Events, version 5.

A portion of patients should have tumors amendable for serial biopsy and a willingness to provide consent for 
pharmacodynamic assessment.
Additionally, for part C (imaging substudy), patients must fulfill the following criteria:

At least 1 extrahepatic metastatic lesion ≥2 cm in the longest diameter.
Main Criteria for Exclusion:

Female patients who are lactating and breastfeeding or have a positive serum pregnancy test during the 
screening period, or male or female patients of reproductive potential who are not employing an effective 
method of birth control.

Serious preexisting medical or psychiatric conditions that, in the opinion of the investigator, would preclude 
participation in the study.

Chronic or active infection requiring systemic therapy, as well as a history of symptomatic viral infection which 
has not been fully cured (eg, HIV or viral hepatitis B or C).

Symptomatic central nervous system (CNS) malignancy or metastasis. Screening of asymptomatic patients 
without history of CNS metastases is not required.

History of congestive heart failure with New York Heart Association class greater than 2 (Class 1 and 2 are 
eligible), unstable angina (within 3 months prior to study enrollment), recent myocardial infarction (within 
6 months of study enrollment), transient ischemic attacks, stroke, arterial or venous vascular disease, or 
clinically significant symptomatic arrhythmia despite anti-arrhythmic therapy.

Corrected QT by Fridericia method interval >470 msec.

Treatment with anticancer chemotherapy or biologic therapy or with an experimental anticancer agent within 28 
days of the initial dose of study drug.

Patient has a history of severe allergic or anaphylactic reactions to recombinant proteins or excipients used in 
TAK-164 or 89Zr-TAK-164 formulation.

Patient has concurrent alcohol abuse or a history of drug-induced liver injury (DILI).
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Main Criteria for Evaluation and Analyses:
Primary endpoints for this study are:

Number of patients with a DLT.

Percentage of patients with adverse events (AEs).

Percentage of patients with Grade 3 or above AEs.

Percentage of patients with drug-related AEs.

Percentage of patients with drug-related Grade 3 or above AEs.

Percentage of patients with serious adverse events.

Percentage of patients with AEs leading to discontinuation.

Percentage of participants who meet the markedly abnormal criteria for safety laboratory tests at least once 
postdose.

Percentage of participants who meet the markedly abnormal criteria for vital sign measurements at least 
once postdose.

MTD and/or an alternate RP2D of TAK-164.
Secondary endpoints for this study are:

TAK-164 PK parameters: Cmax, tmax, and AUClast during Cycle 1 Day 1 and Cycle 2 Day 1. In addition, 
observed concentration at the end of a dosing interval (Ctrough) may be reported for other dosing days during 
which a single predose PK sample is collected.

ORR as assessed per modified RECIST version 1.1 [1].

DCR.

DOR.

PFS.

Antidrug antibody in serum.
Imaging-specific secondary endpoints (part C only):

Qualitative and quantitative (in terms of standardized uptake value [SUV]) determination of patient-level 
biodistribution of 89Zr-TAK-164 at all 89Zr-TAK-164 imaging time points.

Qualitative and quantitative (SUV) determination of 89Zr-TAK-164 uptake in tumor lesions identified with 
CT/18F-FDG-PET at all 89Zr imaging time points.
Statistical Considerations:
Part A: Dose Escalation
mTPI:
The mTPI study design by Ji [2] will be utilized to determine MTD.
The starting dose of 0.004 mg/kg will be used to treat the first cohort of patients and the dose escalation schema will 
be followed, as planned.
The dose and schedule recommended for the use in part B and part C (expansion) of the study will be based on 
safety, PK, and pharmacodynamics antitumor response data observed in part A.
Part B: Dose Expansion
Approximately 50 patients with CRC, GCC high expression level (H-score ≥150) and patients with gastric 
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carcinoma expressing GCC (H-score ≥10) will be assessed. A minimum of approximately 20 patients will be 
enrolled in either cohort. The DLT rate will be continuously monitored and safety analysis conducted during dose 
expansion part of the study to allow regular assessments of the appropriateness of the dosing level.
Part C: Imaging Substudy (To Be Conducted in The Netherlands Only)
All patients with at least one 89Zr-TAK-164 PET scan will be included in the analyses. All patients who receive any 
amount of 89Zr-TAK-164 will be included in the safety analyses. Imaging outcome data will be summarized and the 
correlation with pathology and clinical outcome data explored.
Sample Size Justification: A total of approximately100 patients will be enrolled in this study including dose 
escalation (part A), dose expansion (part B), and imaging substudy (part C). Part A and part C each will include up 
to 25 patients.
Part B: The sample size was estimated for CRC and gastric cancer separately. For CRC, assuming a targeted ORR of 
16% with a 2-sided exact 80% confidence interval (CI) such that the lower limit is greater than 5%, approximately 
25 response-evaluable patients will provide close to 60% power to observe at least 4 responses, ie, 4/25 = 16%; 
exact 80% CI (7.2%, 29.5%). For gastric cancer, assuming a targeted ORR of 20% with a 2-sided exact 80% CI such 
that the lower limit is greater than 10%, approximately 25 response-evaluable patients will provide close to 60% 
power to observe at least 5 responses, ie, 5/25 = 20%; exact 80% CI (10.1%, 34.0%).
Approximately 50 response-evaluable patients in total need to be enrolled.
Additional patients may be enrolled based on clinical judgment and the totality of clinical outcomes may be 
considered.
Part C: (Imaging Substudy): Up to 25 patients in total will be enrolled. Other Immuno-PET studies using 89Zr that 
explored only biodistribution and tumor targeting collected meaningful data with 6 to 12 patients [3].
 
 
 
Property of Takeda: For Non-Commerci
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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 Study Supplier List. The identified vendors for specific study-related activities will 
perform these activities in full or in partnership with the sponsor.
The study is being funded by Takeda. Payments for the conduct of the study that will be made to 
study sites (and, if applicable, investigators and/or other study staff) will be specified in the 
Clinical Study Site Agreement(s). All investigators and subinvestigators must declare potential 
conflicts of interests to the sponsor. The sponsor will provide a financial disclosure form that 
must be signed by each investigator and subinvestigator before the study starts at their study site; 
in addition, any potential conflicts of interests that are not covered by this financial disclosure 
form should be disclosed separately to the sponsor prior to the start of the study at their site.
All institutional affiliations of the investigator and subinvestigator should be declared on their 
curriculum vitae, which must be provided to the sponsor prior to the start of the study.
3.2
Coordinating Investigator
Takeda will select a signatory coordinating investigator from the investigators who participate in 
the study. Selection criteria for this investigator will include significant knowledge of the study 
protocol, the study medication, their expertise in the therapeutic area and the conduct of clinical 
research as well as study participation. The signatory coordinating investigator will be required 
to review and sign the clinical study report and by doing so agrees that it accurately describes the 
results of the study.
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3.3
List of Abbreviations
Abbreviation
Term
18F-FDG
18-fluorodeoxyglucose
5-FU
5-fluorouracil
5-HT3
5-hydroxytryptamine 3 serotonin receptor
89Zr
zirconium-89
ADA
antidrug antibody
ADC
antibody-drug conjugate
AE
adverse event
AESI
adverse event of special interest
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASCO
American Society of Clinical Oncology
ASH
American Society of Hematology
AST
aspartate aminotransferase
BCRP
breast cancer resistance protein
CI
confidence interval
CL
clearance
Cmax
single-dose maximum (peak) concentration
CNS
central nervous system
CR
complete response
CRC
colorectal cancer/carcinoma
CRO
contract research organization
CT
computed tomography
CYP
cytochrome P450 enzyme
DCR
disease control rate
DDI
drug-drug interaction
DILI
drug-induced liver injury
DIO
dosimetry and imaging optimization
DLT
dose-limiting toxicity
DOR
duration of response
EANM
European Association of Nuclear Medicine
ECG
electrocardiogram
ECHO
echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EOI
end of infusion
Property of Takeda: For No
mmercial Use Only and Subject to the Applicable Terms of Use
concentr
concen
arcinoma
cinom
ch organi
organ
omograph
gra
chrome P
hrom
isease co
sease c
drug
drug d
dr
R
EANM
ANM
ECG
ECG
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Abbreviation
Term
EOT
end-of-treatment
FDA
Food and Drug Administration
FGN849
free payload for TAK-164
GCC
guanylyl cyclase C
GCP
Good Clinical Practice
G-CSF
granulocyte colony stimulating factor
GI
gastrointestinal
GLP
Good Laboratory Practice
GMP
Good Manufacturing Practice
3H
tritium
HEK
human embryonic kidney
HER2
human epidermal growth factor receptor 2
hERG
human ether-à-go-go-related gene
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
ICRP
International Commission on Radiological Protection
IEC
Independent Ethics Committee
IHC
immunohistochemistry
IRB
Institutional Review Board
IV
intravenous; intravenously
ldCT
low-dose computed tomography
LFT
liver function test
LVEF
left ventricular ejection fraction
mAb
monoclonal antibody
mCRC
metastatic colorectal cancer/carcinoma
MRI
magnetic resonance imaging
MSI
microsatellite instability
MTD
maximum tolerated dose
mTPI
modified toxicity probability interval
MTV
metabolic tumor volume
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NCS
Netherlands Commission on Radiation Dosimetry
ORR
overall response rate
OS
overall survival
PD
progression of disease
PERCIST
Positron Emission Tomography Response Criteria in Solid Tumors
PET 
positron emission tomography
PFS
progression-free survival
P-gp
P-glycoprotein
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Abbreviation
Term
pH2A.X
phospho-histone H2A.X
PK
pharmacokinetic(s)
PR
partial response
pT
toxicity probabilities
PTE
pretreatment event
Q2W
once every 2 weeks
Q3W
once every 3 weeks
QTcF
corrected QT by Fridericia method
RBC
red blood cell
RECIST
Response Evaluation Criteria in Solid Tumors
RID
recommended imaging dose
RP2D
recommended phase 2 dose
SAE
serious adverse event
SAP
statistical analysis plan
SCID
severe combined immunodeficiency
SD
stable disease
s-FGN849
sulfonated FGN849
SUL
standardized uptake value corrected for lean body mass
SUSAR
suspected unexpected serious adverse reactions
SUV
standardized uptake value
t½
terminal disposition half-life
TAb
total antibody
TEAE
treatment-emergent adverse event
TLG
total lesion glycolysis
tmax
single-dose first time of occurrence of maximum (peak) concentration
TBL
total bilirubin
ULN
upper limit of normal
UPM
unit probability mass
US
United States
Vd
volume of distribution 
VOI
volume of interest
WBC
white blood cell
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3.4
Corporate Identification
Millennium
Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda 
Pharmaceutical Company Limited
TDC Japan
Takeda Development Center Japan
TDC Asia
Takeda Development Center Asia, Pte Ltd
TDC Europe
Takeda Development Centre Europe Ltd
TDC Americas
Takeda Development Center Americas, Inc
TDC
TDC Japan, TDC Asia, TDC Europe, and/or TDC Americas, as applicable
Takeda
Millennium Pharmaceuticals, Inc, TDC Japan, TDC Asia, TDC Europe, and/or TDC 
Americas, as applicable
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4.0
INTRODUCTION
4.1
Background
4.2
Scientific Background
Antibody-directed cancer chemotherapy in the form of antibody-drug conjugates (ADCs) can 
improve therapeutic indices, with the potential to enhance efficacy and decrease systemic 
toxicity. After the ADC is internalized by the target tumor cell and shuttled to the lysosomal 
compartment, enzymatic cleavage of the chemical linker releases the cytotoxic drug [4]. In an 
effort to further exploit ADC technology to improve treatment of gastrointestinal (GI) 
malignancies, Takeda Pharmaceuticals Inc (Takeda) has developed TAK-164, a new ADC which 
targets guanylyl cyclase C (GCC) and consists of a human monoclonal antibody (mAb) 
specifically targeting GCC, a potent cytotoxic agent, and a linker. Prior and ongoing clinical 
studies evaluating an ADC-based therapy with another cytotoxic agent, monomethylauristatin E 
have shown promising results [5]. The mechanism of action of TAK-164 should result in potent 
target-dependent eradication of GCC-expressing tumor cells.
4.2.1
Disease Under Treatment
TAK-164 is being developed to be a standard of care in the metastatic and adjuvant setting for 
patients with GI cancers that express GCC.
The expression of GCC is maintained throughout the spectrum of adenoma and carcinoma in the 
colorectum [6,7]. Also, GCC expression has been observed in lymph nodes harboring metastatic 
cells and is being studied as a potential marker for more accurate staging of this disease [8]. In 
addition to colorectal carcinoma (CRC), other GI malignancies have been found expressing 
GCC, such as gastric, esophageal, small intestine, and pancreatic carcinomas.
4.2.1.1
CRC
CRC is the fourth most common visceral malignancy (after prostate, breast, and lung cancer) and 
the second leading cause of cancer death in the United States (US). In 2017, there will be an 
estimated 95,520 new cases of colon cancer and 39,910 cases of rectal cancer diagnosed in the 
US. While the numbers for colon cancer are fairly equal in men (47,700) and women (47,820), a 
larger number of men (23,720) than women (16,190) will be diagnosed with rectal cancer. An 
estimated 27,150 men and 23,110 women will die from CRC in 2017 
(Globocan.iarc.fr/Pages/fact_sheets_. Colorectal Cancer: Estimated Incidence, Mortality and 
Prevalence Worldwide in 2012. Accessed 07 August 2017). The estimated incidence of CRC 
worldwide in 2012 for both sexes is 1,361,000, 746,000 men and 614,000 women, with 374,000 
and 320,000 deaths, respectively. The estimated prevalence of people with CRC worldwide is 
3,544,000 (1,953,000 men 1,590,000 women). CRC incidence has been increasing in the US 
among adults younger than 55 years [9,10]. The prognosis of CRC is primarily related to stage, 
histologic and molecular differentiation, lymphovascular invasion, and extent of tumor-free 
surgical resection margins [11].
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Several therapeutic agents have been introduced that have been effective in the treatment of CRC 
as demonstrated by improved response and 5-year survival. Introduced for clinical use over 
40 years ago, 5-fluorouracil (5-FU) remains the cornerstone for management of metastatic 
disease, achieving a response rate of about 20% when given in standard doses [12]. 
Administration of 5-FU as a continuous infusion for protracted periods has been shown to 
improve the therapeutic index in patients with advanced colon cancer with respect to response 
rate and reduced toxicity [13]. Among various pharmacologic strategies undertaken to enhance 
the activity of 5-FU, a combination with leucovorin has been proven most effective. Since 1996, 
3 new cytotoxic drugs (capecitabine, irinotecan, and oxaliplatin) and 3 new mAbs (bevacizumab, 
cetuximab, and panitumumab) have been introduced for the treatment of CRC [14]. Various 
chemotherapeutic agents such as oxaliplatin and irinotecan, when given in combination with 
5-FU (ie, FOLFOX and FOLFIRI regimen), seem to be equivalent in efficacy when 
administrated as first-line therapy [15]. Targeted therapies, primarily inhibitors of vascular 
endothelial growth factor and epidermal growth factor receptors, have shown promise for 
improving treatment outcome in patients with advanced disease [16]. Similarly, treatment with 
the checkpoint inhibitor pembrolizumab has shown remarkable responses in patients with 
deficient mismatch repair gene expression, as evidenced by high microsatellite instability (MSI) 
[17]. Although the introduction of newer drugs has extended survival for patients with metastatic 
CRC (mCRC) by a range of 12 to approximately 27 months [18], the disease remains incurable 
and a need for new and better therapeutic agents persists.
4.2.1.2
Gastric Carcinoma
Gastric carcinoma is the fourth most common cancer worldwide, with an estimated prevalence of 
153,8000 cases in 2012 and incidence of 952,000 (Globocan.iarc.fr/Pages/fact_sheets_ Gastric 
Cancer: Estimated Incidence, Mortality and Prevalence Worldwide in 2012; accessed 7 August 
2017). Gastric carcinoma is the second leading cause of cancer-related death worldwide [19]. 
The incidence is highest in Japan, China, South America, and Eastern Europe. In the US, an 
estimated 21,000 new cases (12,730 men and 8270 women), and about 12,000 deaths (7000 men 
and 5000 women) were expected in 2012 (Globocan.iarc.fr/Pages/fact_sheets_ Gastric Cancer: 
Estimated Incidence, Mortality and Prevalence Worldwide in 2012; accessed 7 August 2017). 
Gastric cancer affects mostly older people (the average age at the time of diagnosis is 71) and the 
risk is approximately 2 times higher in men than in women. Environmental risk factors include 
smoking, high salt intake, and consumption of poorly preserved food, while precursor conditions 
(largely linked to distal gastric carcinoma) include chronic atrophic gastritis, gastric polyps, and 
Helicobacter pylori infection. Pathologic stage remains the most important determinant of 
prognosis in gastric carcinoma.
Several chemotherapeutic drugs, when used as single agents, have been associated with an 
objective response in over 15% of patients (5-FU producing 20%). Combination therapy in 
advanced gastric carcinoma may produce response rates in the range of 50% with a median 
survival barely exceeding 11 months. Recent studies are addressing the role of biologics such as 
trastuzumab and bevacizumab in advanced gastric carcinoma. Herceptin® (trastuzumab), the 
anti-human epidermal growth factor receptor 2 (HER2) mAb, provides the first targeted 
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biological therapy to show a survival benefit in HER2patients with advanced gastric cancer 
[20]. Approximately 15% to 18% of gastric tumors show high levels of HER2 [21,22].
Despite recent advancements in the treatment of gastric carcinoma and the addition of 
ramucirumab [22] to therapeutic modalities which can be offered to patients with gastric 
carcinoma, more effective therapies are required to provide better options for this unmet clinical 
need.
4.2.1.3
Esophageal Carcinoma
Esophageal carcinoma is relatively uncommon, with 456,000 new cases worldwide and 
40,000 deaths. In the US, 16,940 new cases (13,360 in men and 3580 in women) and 
approximately 15,690 deaths (12,720 men and 2970 women) were expected by the American 
Cancer Society in 2016 (cancer.net/cancer-types/esophageal-cancer/statistics, accessed 
17 October 2017). Treatment options for patients with both locoregional and advanced disease 
are limited. Several drugs, when used as single agents, have been associated with a reduction of 
more than 50% of measurable tumor mass in over 15% of patients. Such agents include 5-FU, 
cisplatin, doxorubicin, paclitaxel, docetaxel, and irinotecan [23-27].
4.2.1.4
Small Intestine Cancer
Malignant neoplasms of the small intestine are among the rarest types of cancer, accounting for 
approximately 2% of all GI cancers. In the US, there were 10,190 new cases and approximately 
1390 deaths expected in 2017 (Cancer.org/cancer/small-intestine-cancer/about/what-is-key-
statistics.html. Accessed 7 August 2017). The most common type of small intestine cancer is 
adenocarcinoma. Other types of small intestine cancer include sarcoma, carcinoid tumor, GI 
stromal tumor, and lymphoma [28-31]. As in other GI malignancies, the predominant modality 
of treatment is surgery when resection is possible, and cure relates to the ability to resect the 
cancer completely. Malignant lesions are often discovered when they have metastasized to 
distant sites. The overall 5-year survival rate for resectable adenocarcinoma is only 20%. The 
5-year survival rate for resectable leiomyosarcoma, the most common primary sarcoma of the 
small intestine, is approximately 50%. For unresectable metastatic disease, treatment options 
consist of palliative treatments.
4.2.1.5
Pancreatic Cancer
Pancreatic cancer accounts for about 3% of all cancers in the US and about 7% of all cancer 
deaths. Carcinoma of the pancreas is the fourth leading cause of cancer death in the US. In the 
US, there are 53,670 new cases (27,970 men and 25,700 women) and approximately 
43,090 (22,300 men and 20,790 women) deaths expected in 2017 (Cancer.org/cancer/pancreatic-
cancer/about/key-statistics.html; accessed 7 August 2017). Cancer of the exocrine pancreas is 
rarely curable and has an overall survival (OS) rate of less than 4% [32]. The highest cure rate 
occurs if the tumor is truly localized to the pancreas; however, this stage of the disease accounts 
for fewer than 20% of cases. For patients with localized disease and small cancers (<2 cm) with 
no lymph node metastases and no extension beyond the capsule of the pancreas, complete 
surgical resection can yield actuarial 5-year survival rates of 18% to 24% [33]. For patients with 
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advanced cancers, the OS rate of all stages is less than 1% at 5 years, with most patients dying 
within 1 year [34]. In patients with advanced pancreatic cancer gemcitabine has demonstrated 
activity and is a useful palliative agent [35-37]. As a first-line therapy for patients with metastatic 
adenocarcinoma of the pancreas, gemcitabine shows a significant improvement in survival 
compared to 5-FU (1-year survival observed in 18% patients treated with gemcitabine versus 2% 
with 5-FU) [35]. Erlotinib has been shown to prolong survival modestly when combined with 
gemcitabine [38]. Many phase 2 studies have evaluated a combination regimen with either a 
platinum analogue (cisplatin or oxaliplatin) or fluoropyrimidine versus single-agent gemcitabine, 
but not one of these studies has demonstrated a statistically significant advantage of combination 
chemotherapy [39,40]. However, Nab-paclitaxel in combination with gemcitabine produces a 
significant improvement in OS, when compared to the treatment with gemcitabine alone [41]. 
Similarly, treatment with FOLFIRINOX provides a superior clinical benefit, when compared to 
gemcitabine (median OS 11.1 months vs 6.8 months) [42]. Therefore, FOLFIRINOX is now 
considered a standard treatment option for patients with advanced pancreatic cancer.
Symptoms caused by pancreatic cancer may depend on the site of the tumor within the pancreas 
and the degree of involvement. Palliative surgical or radiologic biliary decompression, relief of 
gastric outlet obstruction, and pain control may improve the quality of life while not affecting OS 
[43,44].
4.2.2
Study Drug
TAK-164, a novel ADC consists of a mAb that specifically targets GCC, linked to a cytotoxic 
DNA-damaging agent by a peptide linker. TAK-164 is designed to internalize into tumor cells 
and to release the cytotoxic agent, which binds to DNA, resulting in DNA damage due to 
alkylation, ultimately leading to apoptosis-driven cell death.
GCC is expressed throughout the GI tract and plays an important role in maintaining fluid ion 
homeostasis and genomic integrity in intestinal cells. GCC binds to the endogenous ligands, 
guanylin and uroguanylin, as well as to the heat-stable enterotoxin [45,46]. In normal epithelial 
cells, GCC is localized on the apical side of intestinal epithelium. This anatomically distinct 
location is accessible from the luminal side but not from the vascular compartment due to the 
presence of the epithelial tight junctions [47]. The anatomically distinct apical localization is 
altered in malignant intestinal cells in which normal tissue architecture and tight junctions are 
disrupted. Therefore, a systemic intravenous (IV) administration of TAK-164 targeting GCC 
should affect both primary and metastatic GI carcinoma without affecting normal epithelia 
(where GCC would not be accessible to the drug). By accessing malignant cells but not normal 
GI cells due to GCC localization and tight junctions, TAK-164 is expected to have improved 
treatment efficacy while minimizing toxicity of the treatment.
In a broad range of GI cancer cells expressing GCC, TAK-164 has demonstrated antitumor 
activity at picomolar range. Based on preclinical studies, TAK-164 is expected to have a 
manageable safety profile (as described in Section 4.6) when administered IV to patients. 
Preclinical studies have been completed to refine the flexibility of the dose and schedule of 
TAK-164 that could be adopted in the clinical setting to support administration of single-agent 
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TAK-164 as part of this study, as well as a subsequent combination study. Several 
pharmacodynamic biomarkers have been found to be modulated in response to single-agent 
TAK-164, as shown by nonclinical studies. These include 
. Robust and
long-lasting increases in both of these markers are observed in human tumor xenografts. The 
increases are sustained for longer than 24 hours in response to various doses of TAK-164. 
Studies which evaluated a range of response across a spectrum of tumor xenografts as well as 
baseline variability of GCC expression in human tumors have suggested that a majority of tumor 
models that responded to TAK-164 treatment generally had a GCC H-score of 
.
4.3
Preclinical Experience
Detailed information regarding the nonclinical pharmacology and toxicology of TAK-164 may 
be found in the Investigator’s Brochure (IB).
4.3.1
Pharmacology
TAK-164 binds to GCC-expressing cells where the ADC is internalized and processed by 
lysosomal enzymes such as cathepsin B or other proteolytic enzymes releasing active catabolites 
that alkylate cellular DNA. Alkylation of the DNA results in DNA damage that can be measured 
by the pharmacodynamic marker 
 TAK-164 shows 
significant anti-proliferative selectivity between human embryonic kidney (HEK)-293 GCC 
Clone 2 and HEK-293 Vector cell lines. Likewise, TAK-164 also demonstrates selective potency 
relative to the nonbinding control ADC, 
.
Significant dose-dependent antitumor activity was demonstrated following a single IV 
administration of TAK-164 (payload concentration) in HEK-293 GCC Clone 2 human kidney 
tumor xenografts at
PHTX-09C primary human colon 
tumor xenografts at
 PHTX-11C human primary colon tumor 
xenografts at
 and PHTX-17C primary human colon xenograft model at 
in female severe combined immunodeficiency (SCID) or nude 
mice.
The pharmacokinetic (PK) and pharmacodynamic properties of TAK-164 were investigated 
following a single IV administration in HEK-293 GCC 2 tumor-bearing female CB17 SCID 
mice. Pharmacodynamic analysis was measured via an immunohistochemistry (IHC) assay used 
to measure
xpression in tumor samples, indicating the presence or absence of double-
stranded DNA breaks before and after TAK-164 treatment. For both total antibody (TAb) and 
conjugated antibody, the mean plasma concentration at 1 hour and mean plasma area under the 
concentration-time from time 0 to the last value in female CB17 SCID mice increased in a 
dose-proportional manner at
 After a single IV administration 
of TAK-164, a dose-dependent relationship between TAK-164 treatment and an increase in 
DNA damage was measured by
IHC.
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4.3.2
Safety Pharmacology
The 50% inhibitory concentration for the in vitro inhibitory effect of FGN849, the primary 
catabolite of TAK-164, on ionic currents in voltage-clamped HEK-293 cells that stably express 
the human ether-à-go-go-related gene (hERG) was estimated to be greater than 1 µM, the 
solubility limit. Consistent with in vitro monkey plasma stability results, plasma levels of 
FGN849 and sulfonated FGN849 (s-FGN849) were below the limit of quantification in monkeys 
in the 4-week Good Laboratory Practice (GLP)-compliant repeat-dose toxicity study at 
1.6 µg/kg, 4.4 µg/kg, and 8.8 µg/kg once every 2 weeks (Q2W). Human and monkey in vitro 
plasma stability was similar and therefore the risk for circulating FGN849 and hERG inhibition 
in patients is low. Additionally, there were no TAK-164-related findings observed in 
cardiovascular, respiratory, or central nervous system (CNS) safety pharmacology parameters in 
the 4-week GLP-compliant repeat-dose toxicity study in cynomolgus monkeys at any dose.
4.3.3
PK
The nonclinical drug metabolism and PK studies performed support the IV administration of 
TAK-164 to achieve pharmacologic effect in humans. The PK properties and catabolism of 
TAK-164 have been studied in a series of comprehensive experiments in vitro and in vivo using 
tumor-bearing female SCID or nude mice, Sprague-Dawley rats, cynomolgus monkeys, and 
humans (in vitro only) with both unlabeled and tritium (3H)-labeled ADC.
Catabolite/metabolite profiling data revealed that the hydrolysis product s-FGN849 and its 
disulfonyl derivative, FGN849, are the major circulating components in tumor-bearing mice after 
IV administration of [3H]TAK-164 at 5 mg/kg. In tumor homogenates, s-FGN849 is a minor 
component and FGN849 is the major component. In vitro incubation of [3H]TAK-164 with rat 
tritosomes and human cathepsin B revealed the formation of s-FGN849 and FGN849 as 
catabolites.
O-dealkylation and O-dealkylation and oxidation are 2 major metabolic pathways of FGN849 in 
rat, monkey, and human liver microsomes and recombinant cytochrome P450 enzyme (CYP) 
3A4. Metabolites of FGN849 observed in human liver microsomes were also found in rat and 
monkey liver microsomes. FGN849 and s-FGN849 showed low apparent permeability in Caco-2 
cells and appear to be P-glycoprotein (P-gp) and/or breast cancer resistance protein (BCRP) 
efflux pump substrates. There is a potential for drug-drug interaction (DDI) of the free payload, 
FGN849, with BCRP, P-gp, and CYP3A4 inhibitors and inducers.
In mice, rats, and monkeys, TAK-164 (both total and conjugated antibodies) had low clearance 
(CL) (<2.5 mL/h/kg) and low volume of distribution (Vd) (<100 mL/kg). Terminal disposition 
half-lives (t1/2) ranged from 2 to 5 days. The exposure increased in a dose-proportional manner in 
the tested tolerable dose range in mice, rats, and monkeys. No marked sex-related differences 
were observed in TAK-164 PK in monkeys. The TAb PK of TAK-164 in mice, rats, and 
monkeys displayed similar PK profiles to the conjugated antibody at the earlier time points, 
indicating that direct release of payload from the antibody in the plasma was minimal. Trace 
amounts of the free payload, FGN849 (also known as IGN-P1-aniline), were detected in only 1 
out of 238 samples at 6 hours post the dose of 4.4 μg/kg of TAK-164, and no s-FGN849 (also 
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known as s-IGN-P1-aniline) was detected in plasma samples in the GLP-compliant monkey 
toxicokineticstudy.
4.3.4
Toxicology
The toxicology studies with TAK-164 and FGN849, the primary catabolite of TAK-164, 
addressed the target tissues for toxicity, dose-limiting toxicity (DLT), noninvasive methods for 
monitoring of clinically relevant toxicities, and the reversibility of adverse effects. DLTs with 
TAK-164 were similar in rats (in which TAK-164 is not cross-reactive for GCC) and monkeys, 
and were consistent with the toxicity profile of FGN849 in rats at equivalent toxin doses 
indicating that the toxicity profile of TAK-164 in nontumor-bearing nonclinical species is driven 
by the payload. Findings in the repeat-dose monkey study on which the safe starting dose is 
based were similar in nature but observed with increased incidence and severity compared to the 
findings at the same dose level in the single-dose study. DLT with TAK-164 was associated with 
test article-related findings in the hematopoietic and lymphoid systems, skin at procedure-related 
sites (IV administration, blood collection, and/or restraint), and GI tract, with additional toxicity 
observed in the female reproductive system and acinar glandular tissues in monkeys. All target 
organ toxicities observed in the repeat-dose studies were generally monitorable and trending 
toward or completely reversible, or expected to be reversible following a 28-day recovery period.
4.4
Clinical Experience
This is the first-in-human study of TAK-164.
Potential safety concerns and/or biological activity could be extrapolated from toxicology 
findings (see Section 4.6) and data available for other ADCs; however, such extrapolation must 
be done with caution. It is important to note that antibody target specificity or selectivity and 
ADC linker activity may result in significantly different safety profiles between ADCs.
During the dose escalation phase of the study, serious and TAK-164-related hepatic toxicity was 
reported at dose of 0.25 mg/kg once every 3 weeks (Q3W); this led to a dose cap at 0.19 mg/kg 
Q3W.
4.5
Rationale for the Proposed Study
TAK-164, a novel ADC consists of a human mAb that specifically targets GCC, linked to a 
cytotoxic DNA-damaging agent by a peptide linker. TAK-164 is designed to internalize into 
tumor cells and to release the cytotoxic agent which binds to DNA, resulting in DNA damage 
due to alkylation, and ultimately leading to apoptosis-driven cell death.
GCC is expressed in a variety of GI tumors. Also, GCC is expressed throughout the GI tract 
where it is localized on the apical side of intestinal epithelium and plays an important role in 
maintaining fluid ion homeostasis. This anatomically distinct localization is accessible from the 
luminal side but not from the vascular compartment due to the presence of the epithelial tight 
junctions [43,44,46,48]. In malignant intestinal cells, the normal tissue architecture and tight 
junctions are disrupted. Therefore, a systemic IV administration of TAK-164 targeting GCC may 
reach this target in both primary and metastatic GI carcinoma without affecting normal epithelia 
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(where GCC would not be accessible to the drug). By accessing malignant cells but not normal 
GI cells due to GCC localization and tight junctions, TAK-164 is expected to have improved 
treatment efficacy while minimizing toxicity of the treatment.
In a broad range of GI cancer cells expressing GCC, TAK-164 has demonstrated antitumor 
activity in the picomolar range. Preclinical studies have been conducted to refine the flexibility 
of the dose and schedule of TAK-164 that could be adopted in the clinical setting to support 
administration of single-agent TAK-164 as part of this study, as well as a subsequent 
combination study. Several pharmacodynamic biomarkers have been found to be modulated in 
response to single-agent TAK-164, as shown by nonclinical studies. Those include 
. Studies which evaluated a range of responses across a spectrum of tumor 
xenografts have suggested that a majority of tumor models responsive to TAK-164 treatment 
generally had a GCC H-score of 
. In human tumors, a variety of GCC expression levels 
have been detected with a broad range of H-scores up to 
The PK of TAK-164 in humans was predicted using an allometric scaling approach from 
TAK-164 PK in cynomolgus monkeys, an approach that has demonstrated success in predicting 
human PK for the TAK-264 program (previous name “MLN0264”) that used the same GCC-
targeted antibody, 
. The predicted human CL, Vd, and plasma t1/2 of TAK-164 using this 
method is approximately 1.02 mL/h/kg, 51.96 mL/kg, and 35 hours, respectively. No 
accumulation in plasma is expected with either a Q2W or a Q3W dosing schedule.
Translational dynamic PK-efficacy modeling (using data from GCC-expressing tumor xenograft 
models) and semi-mechanistic toxicity modeling (using neutrophil count data from cynomolgus 
monkeys) suggested that Q2W administration of TAK-164 would provide pharmacologically 
active exposures (with a projected dose range of 0.1 mg/kg to 0.25 mg/kg) with a clinically 
manageable safety profile (absolute neutrophil count [ANC] above Grade 3 neutropenia cutoff at 
nadir), making it a favorable schedule to evaluate in this study. However, emerging clinical 
safety data supports limiting the maximum dose to 0.19 mg/kg Q3W.
Based on overall nonclinical investigation, TAK-164 is expected to have a manageable safety 
profile when administered IV to patients. Significant findings emerging from preclinical studies 
are considered monitorable, reversible, and/or manageable in patients with GI malignancies.
Inclusively, these findings provide a rationale for clinical development of TAK-164.
Molecular imaging using immuno-PET (positron emission tomography) can be performed as a 
noninvasive assessment of radioisotope-labeled ADCs. Unlike conventional PK, immuno-PET 
gives detailed information on biodistribution and tumor uptake and may provide additional 
insights on relative dosing of a drug. A variety of antibodies and ADCs have been investigated in 
a wide range of different cancers including GI tumors such as colon cancer. Clinical applications 
of immuno-PET include improved staging before therapy [49,50].
Zirconium-89 (89Zr) lends itself to visualizing the localization of ADCs as it resides largely in 
the target tissue following cellular internalization and has a t1/2 (78 hours) that is suitable for 
centralized production and distribution [3]. On the basis of previous studies, we anticipate that 
the optimal time for a PET assessment of 37 MBq (1 mCi) of the 89Zr-labeled antibody is likely 
Property of Takeda: For Non-Commercial Use Only and Subject to the Appli able Terms of Use
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to be 2 to 7 days after injection. The Vrije Universiteit Medical Centre in Amsterdam has 
previously investigated 89Zr-labeled antibodies and ADCs [51].
89Zr-labeled TAK-164 can be used to evaluate GCC expression at a whole-body level and 
provides information about antibody biodistribution and tumor heterogeneity. Given variable 
GCC expression in patients with CRC and gastric cancer, we also anticipate a range of 
89Zr-TAK-164 tumor uptake in the patients enrolled in this study. Evaluating the relationship 
between 89Zr-TAK-164 tumor uptake and 18-fluorodeoxyglucose (18F-FDG)-PET uptake will be 
informative in determining the impact of GCC expression levels on response in these patient 
populations.
4.6
Potential Risks and Benefits
Based on nonclinical safety analyses of TAK-164 and published clinical data that derive from the 
investigation of similar ADCs and mAb therapies in general, potential risks of TAK-164 
treatment include:

Hepatotoxicity.
–
Increased alanine aminotransferase (ALT), aspartate aminotransferase (AST), and
bilirubin.

Hematopoietic and lymphoid toxicity.
–
Decreased cellularity in bone marrow and lymphoid tissues with resultant decreases in 
red blood cell (RBC) mass, decreases in white blood cells (WBCs), and platelets with 
increased coagulation times.

Potential predisposition to anemia, infection, sepsis, and/or spontaneous hemorrhage.

Local skin toxicity, procedure-related sites.
–
Dermal/subcutaneous necrosis with ulceration present at IV administration and blood 
collection sites observed in monkeys, presumably due to accidental extravasation of 
TAK-164.

Skin hyperpigmentation, focal to generalized.
–
Dark/black discoloration of the face, limbs and/or whole body with/without mild erosion 
or ulceration due to epidermal degeneration and increased melanin.

GI toxicity.
–
Decreased appetite and mild body weight loss.
–
Atrophy of the GI mucosa (stomach through rectum) with loose stool.

Reproductive toxicity.
–
Potential for infertility.
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
Decreased acinar gland granulation.
–
Affected the pancreas (females only), salivary, and lacrimal glands of monkeys.
–
Possible association with mild bilateral conjunctivitis (though may also have been a result 
of skin effects in the conjunctiva).

DDI with CYP3A4, P-gp, and BCRP modulators.

Infusion-related reactions including anaphylaxis.
While toxicities potentially induced by TAK-164 could be severe, they will be managed by 
clinical monitoring and intervention to minimize potential risks. Nevertheless, the potential 
toxicities could become life-threatening. The potential risks of TAK-164 are based on findings 
from single- and repeat-dose nonclinical toxicology studies in monkeys and rats (in which TAK-
164 is not cross-reactive for GCC). Adverse events (AEs) associated with TAK-164 may include 
any toxicity, comprised of those that were not observed in or predicted from the studies 
completed in monkeys and rats.
As with other mAb therapies, potential risk for immunogenicity cannot be excluded. Based on 
our TAK-264 (previous name “MLN0264”) experience, where the same antibody was utilized 
(very low immunogenicity positivity), general screening/titer/confirmation/domain specificity 
immunogenicity assays will be performed but not the further antidrug antibody (ADA) 
characterization assay such as neutralization assay. The overall immunogenicity will be
monitored closely in the study and the timing of implementing neutralization assay will be 
assessed at later phase for this product.
Patients will be monitored closely for anticipated DLTs (defined in Section 8.2) and more 
generalized observations as they are receiving this agent.
In order to limit the risks to patients, up to 3 patients will be enrolled at each new dose (although 
larger cohorts will be permissible if eligible patients are available, following discussions between 
the sponsor and the investigators), and observed through completion of the first cycle before 
additional patients are treated. In the dose escalation phase, there will be an interval of at least 
7 days between dosing of the first 2 patients within a cohort; the interval between subsequent 
patients in the same cohort may be less than 7 days, but at least 1 day later. Additionally, a full 
DLT review period will be observed for Cycle 1 during dose escalation, before dosing a new 
(higher dose) cohort. Although therapeutic efficacy is a desired outcome of treatment with 
TAK-164, it is unknown whether patients will benefit from this study.
It is also noted that some patients may receive suboptimal doses of this drug, if it proves to be 
efficacious. In this dose escalation study, dose will be escalated by cohort. Intrapatient dose 
escalation is not planned. Although dose escalation will be based on observed DLTs in Cycle 1, 
safety/tolerability data beyond Cycle 1 will be integrated into the recommended phase 2 dose 
(RP2D) determination for the expansion phase.
Risk mitigation strategies for potential AEs include, but are not limited to strict application of the 
study inclusion and exclusion criteria, frequent monitoring of clinical and laboratory results, 
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guidelines for management and prophylaxis of potential toxicities, criteria for dose modification, 
and regular monitoring of AEs and serious adverse events (SAEs) by the sponsor.
TAK-164-related effects were observed after repeat doses in the ovaries, uterus, cervix, and 
vagina of sexually immature female monkeys. Effects were also observed in the prostate of 
sexually mature male rats (in which TAK-164 is not cross-reactive for GCC) at nontolerated 
dose levels. The effect of TAK-164 was not evaluated in sexually mature monkeys and because 
TAK-164 is a novel ADC cytotoxic agent with no prior human experience, patients considering 
having children in the future should consider autologous gamete cryopreservation prior to 
therapy with TAK-164.
89Zr immuno-PET conjugates have been shown to be safe in more than 15 clinical studies if 
carefully characterized, demonstrated to be stable, and produced under Good Manufacturing 
Practice (GMP) conditions [3]. When considering the justification of application, a benefit-risk 
analysis must be performed. The Netherlands Commission on Radiation Dosimetry (NCS) 
provides a model for this (2016) based on Report 118 of The International Commission on 
Radiological Protection. The risk level according to this model is stated as Category II. The dose 
caused by a single administration of approximately 37 MBq 89Zr-TAK-164 is estimated to be 
around 20 mSv on the basis of available dosimetry data on 89Zr-labeled intact antibodies. 
Dosimetry will be performed to confirm exposure. After the injection, the patient can go home 
immediately without shielding. For 6 months after the study, male and female patients both are 
advised to prevent pregnancy. The risks associated with 89Zr-TAK-164 seem minor, and 
although patients do not directly benefit from the PET imaging, these results will be valuable for 
understanding tumor uptake and biodistribution in relation to response and toxicity and will 
guide further prospective research. The modifications to TAK-164 with the radiolabeling process 
are considered minimal, so the toxicity profile is anticipated to be similar to that of unlabeled 
TAK-164 (internal in vitro data).
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP), and 
the applicable regulatory requirements.
The benefits of this drug have not been established, because the efficacy of TAK-164 has not yet 
been characterized.
4.6.1
Radiation Burden for Patients in the Imaging Substudy (Part C, To Be Conducted 
in The Netherlands Only)
A single injection of approximately 37 to 40 MBq 89Zr-TAK-164 is expected to result in a 
radiation burden of ~20 mSv [52,53]. For an 18F-FDG injection compliant with the European 
Association of Nuclear Medicine (EANM) procedure guidelines [54] a typical dose of 200 MBq 
will result in a radiation burden of 4 mSv. In addition, every low-dose computed tomography 
(ldCT) scan adds 3 mSv to the radiation burden.
The first 6 patients will receive 2 injections of 89Zr-TAK-164 followed by 5 PET scans (3 after 
the first and 2 after the second injection) resulting in a radiation dose of 55 mSv. Subsequent 
patients will receive 1 injection of 89Zr-TAK-164 followed by 2 PET scans, resulting in a 
radiation dose of 26 mSv. After 89Zr-TAK-164 administration, no shielding is required, and the 
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patient can go home immediately. It is recommended that prolonged physical contact with small 
children (hugging, holding for more than a few hours per day) is avoided in the days following 
injection of 89Zr-TAK-164.
In addition, all patients will receive up to 3 injections of 18F-FDG, each followed by a single 
ldCT scan, resulting in up to 21 mSv. In total, the radiation dose for the first 6 patients is 
expected to be approximately 76 mSv. For subsequent patients, the radiation dose is expected to 
be approximately 47 mSv.
The radiation dose is determined by dosimetry and optimized in approximately the first 
6 patients (the dosimetry and imaging optimization [DIO] subgroup). In these patients, the 
optimal imaging parameter, including the optimal dose of ADC (≤RP2D) for imaging will be 
determined. Subsequent patients will be imaged at this optimal dose. 37 MBq of 89Zr is the 
minimum level of activity that can be used per injection to support adequate quantitation. [52]
There are no risk increasing/decreasing factors.
Justification of this study is provided through the intended benefit of mitigating serious diseases 
in the future (category 3b). In conclusion, the radiation burden for this study has been optimized, 
is justified, and falls within the dose limits as discussed in NCS-26/ICRP-62.
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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective
The primary objective is:
!
To evaluate the safety of TAK-164 and to determine the maximum tolerated dose (MTD) 
and/or RP2D.
5.1.2
Secondary Objectives
Part A and part B secondary objectives are:
!
To characterize the PK of TAK-164.
!
To evaluate immunogenicity of TAK-164.
!
To evaluate efficacy of TAK-164 as measured by overall response rate (ORR).
!
To evaluate other efficacy measures such as disease control rate (DCR), which includes 
response (complete response [CR]+partial response [PR]) plus stable disease (SD), duration 
of response (DOR), and progression-free survival (PFS).
Part C (imaging substudy) secondary objectives are:
!
To determine the biodistribution of 89Zr-TAK-164 in patients with mCRC and/or metastatic 
gastric carcinomas.
!
To determine the tumor targeting of 89Zr-TAK-164.
!
To determine dosimetry of 89Zr-TAK-164.
5.1.3
Exploratory Objectives
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5.2
Endpoints
5.2.1
Primary Endpoints
The primary endpoints are:
!
Number of patients with a DLT.
!
Percentage of patients with AEs.
!
Percentage of patients with Grade 3 or above AEs.
!
Percentage of patients with drug-related AEs.
!
Percentage of patients with drug-related Grade 3 or above AEs.
!
Percentage of patients with SAEs.
!
Percentage of patients with AEs leading to discontinuation.
!
Percentage of participants who meet the markedly abnormal criteria for safety laboratory 
tests at least once postdose.
!
Percentage of participants who meet the markedly abnormal criteria for vital sign 
measurements at least once postdose.
!
MTD and/or an alternate RP2D of TAK-164.
5.2.2
Secondary Endpoints
!
TAK-164 PK parameters: single-dose maximum (peak) concentration (Cmax), single-dose 
first time of occurrence of maximum (peak) concentration (tmax), and area under the plasma 
concentration-time curve from time 0 to time of the last quantifiable concentration (AUClast) 
during Cycle 1 Day 1 and Cycle 2 Day 1. In addition, observed concentration at the end of a 
dosing interval (Ctrough) may be reported for other dosing days during which a single predose 
PK sample is collected.
Property of Takeda: For Non-Commercial Use Only and Subjec
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!
ORR as assessed by the investigator per modified RECIST version 1.1 [1].
!
DCR.
!
DOR.
!
PFS.
!
ADA in serum.
Additional imaging-specific secondary endpoints (part C only):
!
Qualitative and quantitative (SUV) determination of patient-level biodistribution of 89Zr-
TAK-164 at all 89Zr imaging time points.
!
Qualitative and quantitative (SUV) determination of 89Zr-TAK-164 uptake in tumor lesions 
identified with computed tomography (CT)/18F-FDG-PET at all 89Zr imaging time points.
5.2.3
Exploratory Endpoints
Property of
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6.0
STUDY DESIGN
6.1
Overview of Study Design
This is a multicenter, nonrandomized, open-label, phase 1 study of TAK-164 in patients with 
advanced GI cancers expressing GCC for whom standard treatment is no longer effective or for 
whom there is no available standard therapy. The overall study design is presented in Figure 6.a. 
Part C is presented in greater detail in Figure 6.b.
Figure 6.a
Study Design for TAK-164-1001 Phase 1 First-in-Human
CRC: colorectal carcinoma; GCC: guanylyl cyclase C; GI: gastrointestinal; RID: recommended imaging dose; 
RP2D: recommended phase 2 dose.
This study will be the first to administer TAK-164 to humans. For the dose escalation portion of 
the study, the patient population will consist of adults, aged 18 years or older, with various GI 
malignancies for whom standard treatment is no longer effective or for whom there is no 
available standard therapy. In the expanded cohort, enrollment will be limited to patients with 
CRC and gastric carcinoma. This study is designed to determine safety, tolerability, and PK and 
to determine an MTD and/or RP2D of TAK-164 that may be safely administered to patients with 
advanced GI cancer. The study will also define a therapeutic window of TAK-164 based on 
pharmacodynamics within the range of therapeutically relevant exposures. It is anticipated that 
approximately 100 patients could be enrolled, including the escalation (part A), the expansion 
phase (part B), and up to 25 patients in the imaging substudy (part C).
Once enrolled in the study, patients will receive TAK-164 IV administration on Day 1 of each 
21-day cycle or Q3W. Note that for patients who continue on study to Cycle 3 and beyond, a 
window of ±3 days will be permitted for all doses.
The proposed schedule is based upon preclinical pharmacology and toxicology predictions of 
exposure-response. Triplicate electrocardiogram (ECG) data will be collected during dose 
escalation to assess the TAK-164 concentration-QT relationship. In the expansion portion of the 
study (part B), one schedule based on escalation results will be used to administer TAK-164 at 
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RP2D as informed by the data derived in the course of the dose escalation, including clinical 
considerations based on safety, PK, pharmacodynamic, antitumor response, and other relevant 
data.
Dose Escalation (Part A)
The starting TAK-164 dose will be 0.004 mg/kg Q3W and the maximal dose will not exceed 
0.19 mg/kg Q3W. To determine the MTD/RP2D and to guide the dose escalation portion of the 
study, a method based on a Bayesian model of modified toxicity probability interval (mTPI) will 
be used. DLTs occurring during the first cycle of treatment (Cycle 1) at a given dose level will 
be evaluated and will affect decisions to dose-escalate. Although dose escalation and MTD will 
be estimated based on observed DLTs in Cycle 1, safety/tolerability data beyond Cycle 1 will be 
integrated into the RP2D determination for the expansion phase.
Expansion Cohorts (Part B)
Once the RP2D is established, up to 50 patients with CRC GCC high expression level (H-score 
≥150) and patients with gastric carcinoma expressing GCC (H-score ≥10) will be included. A 
minimum of approximately 20 patients will be enrolled in each cohort.
The evaluation of tumor burden status will be performed as described in Appendix A. by CT or 
magnetic resonance imaging (MRI) according to modified RECIST, version 1.1 [1] in all 
patients participating in this study at treatment intervals of 2 cycles. Pharmacodynamic 
evaluation will be performed 
 on tumor biopsies 
required to be obtained from a minimum of approximately 5 evaluable patients of the study.
All patients participating in this study who are judged by the investigator to be receiving clinical 
benefit will be permitted to remain on therapy until progression of disease (PD), unacceptable 
toxicity, or they choose to withdraw from the study.
Toxicity will be evaluated according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE), version 5.0, effective date 27 November 2017 [55]. 
DLTs are defined in Section 8.2.
AEs will be assessed, and laboratory values, vital signs, and ECGs will be obtained to evaluate 
the safety and tolerability of TAK-164.
Part A and Part B
Serial blood samples for determination of the plasma concentration of TAK-164 mAb 
(conjugated and unconjugated), conjugated TAK-164 and FGN849 (free payload) will be 
obtained at prespecified time points as described in the Schedules of Events (Appendix A).
Relationships between plasma exposures of TAK-164 and GCC expression 
activation from tumor biopsies and/or blood-based biopsy samples will be assessed to determine 
if exposure-response relationships are estimable for target inhibition in relevant tissues.
To evaluate the presence of ADA, validated assays will be used to analyze blood samples 
collected from patients prior to dosing, as described in the Schedules of Events (Appendix A). 
These assays are capable of detecting binding antibodies to TAK-164; the ADA status for each 
Property of Takeda: For Non-Commercial U
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patient (positivity [transient, persistent], titer, and specificity) may be reported. Based on our 
TAK-264 experience (previous name “MLN0264”) and because this is a phase 1 study, 
neutralizing ADA is not assessed. The impact of ADA on PK, safety, and efficacy will be 
explored in future studies.
Tumor tissue will be analyzed both during the escalation and expansion phases to investigate 
candidate biomarkers associated with tumor sensitivity and resistance to TAK-164. A 
retrospective analysis of GCC protein expression levels in tumor tissue (archival tissue or 
pretreatment biopsy) using a semiquantitative IHC assay will be done to determine correlations 
between protein levels of GCC in the tumor with clinical outcome. This will allow a better 
understanding of to what extent GCC protein expression may impact clinical responses. Tumor 
tissue may also be evaluated for genetic alterations, such as GCC, 
 
 to determine the clinical benefit of TAK-164 in 
genetically-defined subpopulations and to investigate potential determinants of sensitivity or 
resistance to treatment. A buccal epithelial cell sample will be obtained on Cycle 1 Day 1 to 
generate germline DNA, to be used as a control sample for these analyses. Tumor biopsies may 
also be collected posttreatment from consenting patients who achieve at least a PR and then 
subsequently relapse, if considered advisable by the treating physician. Optionally, tumor 
biopsies from consenting patients who do not achieve a response and experience progression 
may also be collected, if considered advisable by the treating physician, to investigate 
correlations of candidate biomarkers associated with acquired resistance to clinical response. In a 
subset of patients, fresh pretreatment and posttreatment biopsies should be obtained to determine 
changes in the target engagement marker 
.
All patients participating in this study who are judged by the investigator to be receiving clinical 
benefit will be permitted to remain on therapy until they experience PD, unacceptable toxicity, or 
they choose to withdraw from the study.
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Imaging Substudy (Part C, To Be Conducted in The Netherlands Only)
Up to 25 patients will be enrolled in the study in The Netherlands to determine the in vivo 
biodistribution and tumor targeting of 89Zr-TAK-164 in patients with GCC-expressing mCRC 
and/or metastatic gastric carcinoma. In addition, the relationship of 89Zr-TAK-164 tumor 
targeting with 18F-FDG-PET–determined response and RECIST version 1.1 response, and the 
relationship of 89Zr uptake with GCC expression in tumor tissues/other biomarkers, will be 
characterized.
Based on emerging data from the dose escalation phase (part A) and in agreement between the 
site investigator and sponsor, part C will be triggered at a dose that is considered safe and has 
treatment potential (recommended imaging dose [RID]).
Approximately 6 patients (including 3 dosimetry patients) will be enrolled for purposes of DIO. 
This DIO subgroup will receive 89Zr-TAK-164 (mass dose <50% of the RID) 14 days before the 
first regularly scheduled study dose at Cycle 1 Day 1 (see Figure 6.b) and a second 89Zr-TAK-
164 administration on Cycle 1 Day 1 in combination with unlabeled TAK-164 at a maximum 
mass dose of 100% of the RID. Imaging will be performed 1 hour after end of infusion (EOI) of 
the first 89Zr-TAK-164 administration for dosimetry in the first 3 patients, and for all patients at 
2 time points between Day 2 and Day 7 after EOI. Imaging time points and mass dose of 
TAK-164 can be adjusted in order to optimize imaging conditions. Up to 19 additional patients 
will be enrolled into part C to receive a single dose of 89Zr-TAK-164 at Cycle 1 Day 1 in 
addition to unlabeled TAK-164 as determined for optimal imaging. Once the RP2D of TAK-164 
is determined, part C patients who have received TAK-164 at an RID lower than the RP2D of 
TAK-164 may dose-escalate to the RP2D in the absence of PD or unacceptable treatment-related 
toxicity at the investigator’s discretion and with sponsor’s approval. If the full RID/RP2D is not 
administered at Cycle 1 Day 1, the differential will be provided after the second image 
acquisition. Part C patients will continue treatment with the RID/RP2D of TAK-164 at Cycle 2 
Day 1 and beyond (see Figure 6.c).
89Zr-TAK-164 PET
Initially, approximately 6 patients (including 3 dosimetry patients) will be enrolled for DIO. This 
DIO subgroup will receive 89Zr-TAK-164 (mass dose <50% of the RID) 14 days before the first 
regularly scheduled study dose at Cycle 1 Day 1 and a second 89Zr-TAK-164 administration on 
Cycle 1 Day 1 in combination with unlabeled TAK-164 at a maximum mass dose of 100% of the 
RID. Imaging will be performed 1 hour after EOI of the first 89Zr-TAK-164 administration for 
dosimetry in the first 3 patients and for all patients at 2 time points between Day 2 and Day 7 
after EOI. Imaging time points and mass dose of TAK-164 can be adjusted to optimize imaging 
conditions. Qualitative and quantitative (SUVmean,max) will be determined for all 89Zr imaging 
time points (for further details, see Appendix A).
The 89Zr-TAK-164 administration on Cycle 1 Day 1 will be in combination with variable 
amounts of unlabeled TAK-164 in the DIO subgroup, never exceeding the RID. This way, 
imaging conditions can be optimized by adding a variable mass dose of unlabeled TAK-164 to 
89Zr-TAK-164 administration to explore the presence of a potential sink, and by changing 
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imaging time points up to 7 days after EOI if required. When unlabeled TAK-164 is 
administered with 89Zr-TAK-164 for imaging purposes, 89Zr-TAK-164 will be administered 
within 2 hours after the EOI of unlabeled TAK-164.
Radiolabeled 89Zr-TAK-164 will be administered IV. Unlabeled TAK-164 will be administered 
according to the Schedule of Assessments (Appendix A).
Subsequent dosing and CT scans for RECIST version 1.1 determination will be performed 
consistent with the expansion cohort regimen. A flow diagram is provided in Figure 6.b. Further 
details are available in the imaging manual.
18F-FDG-PET
18F-FDG-PET will be performed at baseline, on Cycle 2 Day 12, and again in patients who 
achieve SD or response (CR or PR) per RECIST 1.1 at Cycle 4 Day 21 (see Schedule of 
Assessments [Appendix A]). In patients who agree to a biopsy, the second 18F-FDG-PET image 
will be acquired before the biopsy is taken on Cycle 2 Day 12. Evaluation of metabolic activity 
of the disease and scanner calibrations will fully comply with the EANM guidelines [54,56]. 
Briefly, patients will fast 6 hours before the radiotracer injection. Patients will be injected with 
3 MBq/kg (±10%) 18F-FDG. After 60 minutes (±5 minutes), a PET scan will be performed from 
skull base to mid-thigh. The dose of 18F-FDG will be approximately 185 MBq (adapted by 
weight). Residual activity in the syringe will be measured and subtracted from the injected dose 
before calculations are done.
Data analysis will be performed to assess SULmean, SULmax, SULpeak, 70% volume of interest 
(VOI), and 50% VOI, normalized for serum glucose and body weight.
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CONFIDENTIAL
Figure 6.b
Study Flow Diagram for Part C DIO Subgroup
89Zr: zirconium-89; C: Cycle, CT: computed tomography; D: Day; DIO: dosimetry and imaging optimization; EOI: end of infusion; FDG: fluorodeoxyglucose; 
PET: positron emission tomography.
Dosimetry and Imaging Optimization 
N = approximately 6 patients
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CONFIDENTIAL
Figure 6.c
Study Flow Diagram Part C Following DIO
89Zr: zirconium-89; C: Cycle, CR: complete response; CT: computed tomography; D: Day.; DIO: dosimetry and imaging optimization; EOI: end of infusion; 
FDG: fluorodeoxyglucose; PET: positron emission tomography; PR: partial response; RECIST: Response Evaluation Criteria in Solid Tumors.
a Additional FDG-PET scan for patients with stable disease or response (CR or PR) according to RECIST 1.1.
Biodistribution
Tumor Targeting (using optimized imaging parameter)
N = up to 19 patients
a
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6.2
Number of Patients
Approximately 100 patients will be enrolled in this study from approximately 5 study sites in the 
US and up to 2 sites in The Netherlands.
Approximately 25 patients will be enrolled in part A and up to 50 patients in part B which 
includes approximately 25 patients with CRC of high GCC expression level (with H-score ≥150) 
and approximately 25 patients with gastric carcinoma expressing GCC (with H-score ≥10). A 
minimum of approximately 20 patients will be enrolled in either cohort of the expansion portion 
of the study (part B).
Additional patients may be enrolled based on clinical judgment and the totality of clinical 
outcomes may be considered. Additional sites may be added globally for expansion.
Enrollment is defined as the time of initiation of the first dose of study drug.
Patients who are withdrawn from treatment during Cycle 1 for reasons other than DLTs will be 
replaced.
In part C, the imaging substudy, up to 25 patients will be enrolled.
6.3
Duration of Study
6.3.1
Duration of an Individual Patient’s Study Participation
Patients, including those who achieve a clinical response, may receive TAK-164 until they 
experience disease progression. Patients will discontinue treatment if they have an unacceptable 
TAK-164–related toxicity.
Patients will be followed for 30 days for safety. Radiographic evaluation will be conducted at 
treatment intervals of 2 cycles. The maximum duration of treatment is 12 cycles. All patients 
participating in this study who are judged by the investigator to be receiving clinical benefit will 
be permitted to remain on therapy until PD or they choose to withdraw from the study due to 
toxicity or other factors.
Follow-up visits for PFS, which will evaluate a response, will be conducted at the site every 
3 months from last dose of study drug for patients who discontinue for reasons other than PD. 
Those follow-up visits will continue for up to 6 months or until PD, the start of alternative 
therapy, or conclusion of the study (whichever occurs first).
6.3.2
End of Study/Study Completion Definition and Planned Reporting
Primary Completion/Study Completion
The clinical study report analyses will be conducted after all patients enrolled in the study have 
had the opportunity to complete 4 cycles of treatment with TAK-164 or discontinued from study.
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Study Completion
The estimated time frame for study completion is 43 months (18 months enrollment dose 
escalation + 12 months enrollment expansion cohorts + 12 cycles [approximately 12 months] of 
treatment + 1 month of follow-up).
6.3.3
Timeframes for Primary and Secondary Endpoints to Support Disclosures
Refer to Table 6.a for disclosures information for all primary and secondary endpoints.
Table 6.a
Primary and Secondary Endpoints for Disclosures
Endpoint
Definition
Maximum Time Frame
Primary:

Number of patients with a DLT.
Standard safety assessments 
Up to 36 months

Percentage of patients with AEs.
Standard safety assessments
Up to 36 months

Percentage of patients with Grade 3 or above 
AEs.
Standard safety assessments
Up to 36 months

Percentage of patients with drug-related AEs.
Standard safety assessments
Up to 36 months

Percentage of patients with drug-related 
Grade 3 or above AEs.
Standard safety assessments
Up to 36 months

Percentage of patients with SAEs.
Standard safety assessments
Up to 36 months

Percentage of patients with AEs leading to 
discontinuation.
Standard safety assessments
Up to 36 months

Percentage of participants who meet the 
markedly abnormal criteria for safety 
laboratory tests at least once postdose.
Standard safety assessments
Up to 36 months

Percentage of participants who meet the 
markedly abnormal criteria for vital sign 
measurements at least once postdose.
Standard safety assessments
Up to 36 months

MTD or an alternate RP2D of TAK-164.
Standard safety assessments
Up to 36 months
Secondary: 

TAK-164 PK parameters: Cmax, tmax, and 
AUClast during Cycle 1 Day 1 and Cycle 2 
Day 1. In addition, Ctrough may be reported 
for other dosing days during which a single 
predose PK sample is collected.
Standard PK parameters to allow 
determination of PK profile
Up to 36 months

ORR as assessed by the investigator per 
modified RECIST version 1.1 [1].
ORR
Up to 36 months

DCR.
DCR
Up to 36 months

DOR.
DOR
Up to 36 months

PFS.
PFS
Up to 36 months

ADA levels in serum.
ADA levels in serum
Up to 36 months

Qualitative and quantitative (SUV) 
determination of patient-level biodistribution 
Biodistribution
At 1 hour after EOI for 
Dosimetry patients and 
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Table 6.a
Primary and Secondary Endpoints for Disclosures
Endpoint
Definition
Maximum Time Frame
of 89Zr-TAK-164 at all 89Zr imaging time 
points.
2 instances from Day -13 
to Day -9 (all of DIO 
subgroup) and 2 
instances between Day 2 
and Day 7 after EOI of 
89Zr (all patients in part
C)

Qualitative and quantitative (SUV) 
89Zr-TAK-164 uptake in tumor lesions were 
identified with CT/18F-FDG-PET at all 89Zr 
imaging time points.

For qualitative: uptake levels 
in the tumor will be compared 
visually with the background.

For quantitative: mean, max, 
and peak lesions (SUVs).

For quantification in tumor 
lesions: mean, max, and peak 
SUL, TLG.
2 instances Day -13 to -8 
(DIO patients only) and 
to 2 instances between 
Day 2 and Day 7 after 
end of 89Zr infusion (all 
patients part C).
18F-FDG: 18-fluorodeoxyglucose; 89Zr: zirconium-89; ADA: antidrug antibody; AE: adverse event; AUClast: area 
under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration; Cmax: single-
dose maximum (peak) concentration; CT: computed tomography; Ctrough: observed concentration at the end of a 
dosing interval; DCR: disease control rate; DIO: dosimetry and imaging optimization; DLT: dose-limiting toxicity; 
DOR: duration of response; EOI: end of infusion; MTD: maximum tolerated dose; ORR: overall response rate; PET: 
positron emission tomography; PFS: progression-free survival; PK: pharmacokinetic(s); RECIST: Response 
Evaluation Criteria in Solid Tumors; RP2D: recommended phase 2 dose; SAE: serious adverse event; SUL: 
standardized uptake value corrected for lean body mass; SUV: standardized uptake value; TLG: total lesion 
glycolysis; tmax: single-dose first time of occurrence of maximum (peak) concentration.
6.3.4
Total Study Duration
Patients will be evaluated at scheduled visits over the following study periods: screening, 
treatment, and EOT. Patients will discontinue treatment if they experience PD or unacceptable 
toxicities. The maximum duration of treatment, however, will be 12 cycles unless it is 
determined that a patient would derive benefit from continued therapy beyond 12 cycles as 
discussed with investigators and the sponsor. Patients will attend an EOT visit 30 days after the 
last dose of TAK-164 or just prior to the start of subsequent antineoplastic therapy, whichever 
occurs first.
It is anticipated that this study will last for approximately 43 months.
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7.0
STUDY POPULATION
Male or female patients 18 years or older with histologic or cytologic evidence of measurable 
advanced and/or metastatic solid GI tumor that expresses GCC protein, for which standard 
treatment is no longer effective or for whom there is no available standard therapy (part A) or 
primary or metastatic CRC expressing high levels of GCC and gastric carcinoma expressing 
GCC (part B). Patients must have adequate bone marrow, liver, and renal function, Eastern 
Cooperative Oncology Group (ECOG) performance score of 0 or 1, a life expectancy of at least 
12 weeks, and no serious preexisting medical or psychiatric conditions. A portion of patients 
from part A and part B should have tumors amenable for serial biopsy for pharmacodynamic 
assessment.
Inclusion and exclusion criteria for patients participating in part C (imaging substudy) are 
consistent with the criteria for the patients participating in parts A and B of the study as listed in 
Sections 7.1 and 7.2. In this substudy, patients with mCRC and patients with metastatic gastric 
carcinoma for whom standard treatment is no longer effective or for whom there is no available 
standard therapy can be included. A minimum of approximately 3 patients should have tumors 
suitable for biopsy and be willing to provide consent for pharmacodynamic assessment to 
investigate correlations of candidate biomarkers associated with acquired resistance to clinical 
response. In addition, patients will need to have at least 1 extrahepatic metastatic lesion ≥2 cm in 
the longest diameter.
7.1
Inclusion Criteria
Each patient must meet all of the following inclusion criteria to be enrolled in the study:
1. Histologically or cytologically confirmed measurable advanced and/or metastatic solid GI 
tumor that expresses GCC protein (H-score ≥10), for which standard treatment is no longer 
effective or for whom there is no available standard therapy. For the escalation part of the 
study (part A), GI malignancies include, but are not limited to, mCRC, gastric carcinoma, 
esophageal carcinoma, small intestine cancer, and pancreatic cancer. The expansion part of 
the study (part B) is limited to patients with CRC expressing a high-level GCC (H-score 
≥150) and gastric carcinoma (H-score ≥10). Part C includes patients with CRC and gastric 
carcinoma (H-score ≥10 for both indications).

Part B of the study will be limited to patients with 2 or 3 prior lines of systemic standard 
of care therapy.
2. Voluntary written consent must be obtained from the patient prior to enrollment in the study 
with the understanding that consent may be withdrawn by the patient at any time without 
consequences on receiving future medical care.
3. Male or female patients 18 years or older.
4. Adequate bone marrow function, defined as an ANC of ≥1.5 × 109/L, platelet count 
≥100 × 109/L, and hemoglobin ≥9 g/dL. Receiving transfusions or hematopoietic growth 
factors to meet enrollment criteria is not allowed within 14 days preceding the first dose of 
study drug.
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5. Adequate hepatic function with:

Total bilirubin (TBL) ≤1.5 upper limit of normal (ULN).

Serum ALT and AST must be ≤2.5 ULN (AST and ALT may be elevated up to 3 
ULN if the elevation can be reasonably ascribed to the presence of metastatic disease in 
liver).

Serum albumin ≥3.0 g/dL.
6. Adequate renal function as defined by creatinine CL ≥60 mL/min.
7. ECOG performance score of 0 or 1 (refer to Appendix D).
8. Life expectancy of at least 12 weeks.
9. Completion of prior chemotherapy, biologic therapy, immunotherapy, or radiation therapy at 
least 4 weeks prior to enrollment.
10. Resolution of all toxic effects of prior treatments (except alopecia) to Grade ≤1 NCI CTCAE, 
version 5.
11. Female patients who:

Are postmenopausal for at least 1 year before the screening visit, OR

Are surgically sterile, OR

If they are of childbearing potential, agree to practice one highly effective method of 
contraception and one additional effective (barrier) method (see Appendix F) at the same 
time, from the time of signing the informed consent through 90 days after the last dose of 
study drug, OR

Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are 
not acceptable methods of contraception. Female and male condoms should not be used 
together.)
12. Male patients, even if surgically sterilized (ie, status postvasectomy), who:

Agree to practice effective barrier contraception during the entire study treatment period 
and through 120 days after the last dose of study drug, OR

Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are 
not acceptable methods of contraception. Female and male condoms should not be used 
together.)
13. Suitable peripheral venous access for the study drug administration and required blood 
sampling (ie, PK and pharmacodynamic sampling).
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14. A portion of patients should have tumors amenable for biopsy and a willingness to provide 
consent for pharmacodynamic assessment.
Additionally, for part C (imaging substudy), patients must fulfill the following criteria:
15. At least 1 extrahepatic metastatic lesion ≥2 cm in the longest diameter.
7.2
Exclusion Criteria
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
1. Female patients who are lactating and breastfeeding or have a positive serum pregnancy test 
during the screening period.
2. Serious preexisting medical or psychiatric conditions that, in the opinion of the investigator, 
would preclude participation in the study.
3. Chronic or active infection requiring systemic therapy, as well as a history of symptomatic 
viral infection which has not been fully cured (eg, HIV or viral hepatitis B or C).
4. Symptomatic CNS malignancy or metastasis. Screening of asymptomatic patients without 
history of CNS metastases is not required.
5. History of congestive heart failure with New York Heart Association class greater than 2 
(Class 1 and 2 are eligible), unstable angina (within 3 months prior to study enrollment), 
recent myocardial infarction (within 6 months of study enrollment), transient ischemic 
attacks, stroke, arterial or venous vascular disease, or clinically significant symptomatic 
arrhythmia despite anti-arrhythmic therapy.
6. Corrected QT by Fridericia method (QTcF) interval >470 msec.
7. Treatment with anticancer chemotherapy or biologic therapy or with an experimental 
anticancer agent within 28 days of the initial dose of study drug.
8. Diagnosed or treated for another malignancy within 2 years before administration of the first 
dose of study drug, or previously diagnosed with another malignancy and have any evidence 
of residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type 
are not excluded if they have undergone complete resection.
9. Patient has a history of severe allergic or anaphylactic reactions to recombinant proteins or 
excipients used in TAK-164 or 89Zr-TAK-164 formulation.
10. Use of strong CYP3A inhibitors and CYP3A inducers or inhibitors or modulators of P-gp or 
BCRP within 1 week before the first dose of study drug (see Appendix E).
11. For patients enrolled in studies in which tumor biopsies are obtained:

Known bleeding diathesis or history of abnormal bleeding, or any other known 
coagulation abnormalities that would contraindicate the tumor biopsy procedure.

Ongoing therapy with any anticoagulant or antiplatelet agents (eg, aspirin, clopidogrel, 
heparin, or warfarin).
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12. Patient has concurrent alcohol abuse or a history of drug-induced liver injury (DILI).
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8.0
STUDY DRUG
8.1
Study Drug Administration
All protocol-specific criteria for administration of study drug must be met and documented prior 
to drug administration. Study drug will be administered only to eligible patients under the 
supervision of the investigator or identified subinvestigator(s).
All patients in part A and part B will receive TAK-164 as a single infusion (see pharmacy 
manual for additional details). The study will contain a dose escalation phase (part A), an 
expansion cohort phase (part B), and an imaging substudy (part C).
Each 21-day treatment cycle will consist of a single dose on Day 1, followed by a rest period of 
20 days.
Infusion of TAK-164 should occur in an area with resuscitating equipment and medications such 
as antihistamines, acetaminophen, corticosteroids, epinephrine, and bronchodilators readily 
available. Although no infusion-related reactions were observed with TAK-164 in cynomolgus 
monkeys, such a risk cannot be excluded, and in order to reduce potential risk the patients’ vital 
signs must be monitored before, during, and at the end of administration of TAK-164. Treatment 
must be discontinued in patients who develop Grade 4 toxicity to TAK-164, unless in the opinion 
of the investigator and the project clinician treatment is in the patient’s best interest. For all other 
grades of toxicity, based on the severity of infusion-related reactions potentially observed, the 
infusion rate may be decreased by 50% or discontinued, and signs and symptoms promptly 
treated with 1 or more of the medications detailed above (antihistamines, etc). Patients who 
develop mild to moderate infusion reactions or hypersensitivity (Grade 1 or 2) may receive 
premedication with 1 or more of the medications detailed above for subsequent doses as deemed 
appropriate by the investigator.
Routine prophylaxis for infusion-related reactions is not recommended for the first dose.
Patients will be observed at the clinical site for approximately 8 hours after the administration of 
the first dose and 2 hours after the administration of subsequent doses. The patient should be 
considered clinically stable by the investigator or designee before discharge.
The total amount of TAK-164 administered for each patient will be based on actual body weight 
(kg) as measured on Day 1 of Cycle 1. Dose calculations will be repeated at subsequent visits if 
the patient experiences a greater than 5% change in body weight since the last dose calculation.
As with other potentially toxic compounds, caution should be exercised in handling this drug. 
The use of gloves is recommended. Following topical exposure, events could include redness or 
blistering. Given the possibility of extravasation, it is advisable to closely monitor the infusion 
site for possible infiltration during drug administration.
For Patients in the Imaging Substudy (Part C, To Be Conducted in The Netherlands Only):
The dose of unlabeled TAK-164 to be administered to imaging substudy patients before 
89Zr-TAK-164 infusion will be determined by a multidisciplinary team at the clinical site in 
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agreement with the sponsor and the total amount of TAK-164 (labeled and unlabeled) will not 
exceed the RID/RP2D.
8.2
Definitions of DLT
Toxicity will be evaluated according to the NCI CTCAE, version 5, effective 27 November 2017 
[55]. These criteria are provided in the study manual and are available online at 
ctep.cancer.gov/reporting/ctc.html. DLT will be defined as any of the following AEs that occur 
and are considered by the investigator to be related to therapy with TAK-164:
1. Grade 4 neutropenia (ANC <500 cells/mm3).
2. Febrile neutropenia as characterized by an ANC <1000/mm3 and a single temperature of 
>38.3°C (101°F) or a sustained temperature of ≥38°C (100.4°F) for more than 1 hour.
3. Grade 4 thrombocytopenia (platelets <25,000/mm3).
4. Grade 3 or greater thrombocytopenia with clinically meaningful bleeding at any time.
5. Grade 3 or greater nausea and/or emesis that occurs despite the use of optimal anti-emetic 
prophylaxis. Optimal anti-emetic prophylaxis is defined as an anti-emetic regimen that 
employs both a 5-hydroxytryptamine 3 serotonin receptor (5-HT3) antagonist and a 
corticosteroid given in standard doses and according to standard schedules.
6. Grade 3 or greater diarrhea that occurs despite optimal supportive care measures.
7. Any other Grade 3 or greater nonhematologic toxicity with the following exceptions:

Brief (<1 week) Grade 3 fatigue.
8. Inability to start the next cycle of therapy due to treatment delay of more than 2 weeks 
because of a lack of adequate recovery of TAK-164–related hematological or 
nonhematologic toxicities.
9. Other TAK-164–related nonhematologic toxicities Grade 2 or greater that, in the opinion of 
the investigator, require a discontinuation of therapy with TAK-164.
Although DLTs may occur at any point during treatment, only DLTs occurring during Cycle 1 of 
treatment will necessarily influence decisions regarding dose escalation, expansion of a dose, or 
evaluation of intermediate doses. In part A, Cycle 1, toxicities requiring a dose hold for longer 
than 2 weeks or discontinuation will be considered a DLT.
Patients will be monitored through all cycles of therapy for treatment-related toxicities. AEs 
associated with TAK-164 may include any toxicity except those that are definitely attributable to 
another cause, such as disease progression.
8.3
Dose Escalation Rules
A dose escalation of TAK-164 will follow a mTPI study design. Up to 3 patients will be enrolled 
at dose cohort level 1 (0.004 mg/kg) in the first cycle. Thereafter, interval reassessment for dose 
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adjustment will be performed for subsequent patients, as described below per mTPI design. Each 
patient will be followed until PD, DLT, or until they choose to withdraw consent from the trial.
As described in Ji [2], the mTPI design is based on toxicity probabilities (pT) for each dose level. 
These probabilities are sequentially updated with the data generated by tolerability of each 
patient beginning with the initial dose (dose level 1) and each subsequent patient.
Decision rules at each step are based on calculating the unit probability mass (UPM) of 
3 intervals corresponding to underdosing, proper dosing, and overdosing a patient, in terms of 
toxicity. Specifically, the underdosing interval is defined as (0, targeted pT - ε1), the overdosing 
interval as (pT + ε2, 1), and the proper dosing interval as (pT - ε1, pT + ε2), where ε1 and ε2 are 
small fractions to account for the uncertainty around the true target toxicity. In this study, pT is 
targeted at 25%, ε1, ε2 are both 5% to account for uncertainty.
The 3 dosing intervals are associated with 3 different dose escalation decisions. The underdosing 
interval corresponds to a dose escalation (E), overdosing corresponds to a dose de-escalation (D), 
and proper dosing corresponds to staying at the current dose (S). Given an interval and a 
probability distribution, the UPM of that interval is defined as the probability of the interval 
divided by the length of the interval. The mTPI design calculates the UPMs for the 3 dosing 
intervals, and the one with the largest UPM implies the corresponding dose-finding decision. 
That decision provides the dose level to be used for future patients. The mTPI dosing schema 
will maximize patients treated at or near the MTD and the MTD will be determined by using an 
isotonic regression to fit a function of observed probabilities of DLT at each dose level in this 
trial.
The dose escalation design is shown in Figure 8.a.
Figure 8.a
TAK-164-1001 mTPI Decision Table
Top row indicates the number of patients treated, first column indicates the number of patients with DLTs.
E: Escalate to the next higher dose, S: Stay at the same dose, D: De-escalate to the previous lower dose, DLT: dose-
limiting toxicity; DU: De-escalate to the previous lower dose and the current dose or higher will never be used 
again; mTPI: modified toxicity probability interval.
Safety will be assessed throughout the study by monitoring AEs, vital signs, physical 
examinations, and clinical laboratory tests. Prior to escalating to the next dose level, a meeting 
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with the sponsor and investigators will be conducted, and they will review all data based on the 
clinical observations and laboratory tests. Based on medical judgment and the guidance of the 
statistical model, a decision will be made for each patient’s next dose level, including dose 
increases or decrements as appropriate. In addition, the medical monitor and treating physician 
will consult in real time as needed based on clinical findings.
Note that depending on PK-defined exposure estimates, a dose level between the planned dose 
levels may be explored. In addition, based on safety/tolerability, alternative dosing schedules 
may be explored after discussion and concurrence with all lead investigators and the Takeda 
study clinician. However, no patients will receive a dose above 0.19 mg/kg Q3W.
The first cohort of patients is treated at the starting dose level (0.004 mg/kg).

If the first cohort includes 2 patients and none of the patients experiences DLT, the dose level 
is escalated for the next cohort of patient (corresponding to “E” in Column 1 of the table).

If 1 of the patients experiences DLT, the dose level remains the same, more patients will be 
added.

If both patients experience DLT, the dosing at this level will be stopped, additional cohort of 
patients will be dosed at dose level -1 (0.002 mg/kg). If 2 or more DLTs are observed at the 
0.002 mg/kg dose level, the study will be stopped.
When a cohort of patients completes the DLT observation period, the number of DLTs is 
determined, and the action (escalation, de-escalation, or remaining at the same level) for the next 
cohort of patients is determined based on the number of DLTs and number of patients at that 
dose level. For example, at dose level 3, if 1 DLT is observed in the first of 2 treated patients, the 
dose level remains same for additional patients until 7 patients are dosed at this level and only 1 
DLT is observed. As shown in the table, the value in the row labeled “1” and the column labeled 
“7” indicates “E,” corresponding to “Escalation” for the next cohort. This algorithm is followed 
until 25 patients have been accrued. The operating characteristics of this design are described in 
Section 13.1.1. Patients will be observed for 1 cycle at a given dose level for DLTs prior to 
additional patients enrolling at a higher dose in order to ensure safe dose escalation. Within each 
dose level, there will be a 7-day interval between the first and second patient and subsequent 
patients will be staggered by at least 1 day.

Approximately 25 patients will be enrolled in the dose escalation. More patients may be 
enrolled based on clinical judgment. The starting dose of 0.004 mg/kg will be used to treat 
the first cohort of patients and the dose escalation schema will be followed, as planned. Data 
will be collected to determine PK and estimate variability throughout the tested dose range. 
Intrapatient dose escalation will not be allowed.

MTD will be estimated based on observed DLTs using mTPI and clinical judgment.

The investigator and study physician may diverge from the outlined dose escalation plan to 
select a lower dose than indicated as MTD based on tolerability beyond Cycle 1 or 
cumulative toxicity within Cycle 1 of less than DLT-defined toxicities.
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
If Grade 2 toxicity or greater is seen at a defined dose level and the toxicity is considered by 
investigator as related to TAK-164 treatment, the dose escalation plan may be modified to 
allow a dose increase of no more than 25% of the prior dose.
Patients not receiving all doses of TAK-164 in Cycle 1 for reasons other than DLTs will be 
replaced within the cohort.
Q3W Schedule and Dose Levels:

TAK-164 is administered on Day 1 of each 21-day cycle.

Up to 3 initial patients per cohort will be enrolled at the starting dose of 0.004 mg/kg. Dose 
escalation is planned to proceed by evaluating patients at respective dose levels: 
0.008 mg/kg, 0.016 mg/kg, 0.032 mg/kg, 0.064 mg/kg, 0.12 mg/kg, and 0.19 mg/kg.
MTD with a target toxicity of 25% is determined by mTPI (dose level of posterior mean toxicity 
closest to target toxicity, Section 8.3). Although dose escalation and MTD will be estimated 
based on observed DLTs in Cycle 1, safety/tolerability data beyond Cycle 1 will be integrated 
into the RP2D determination for the expansion phase.
In part C, the imaging substudy, the DIO subgroup will receive 89Zr-TAK-164 (mass dose <50% 
of the RID) 14 days before the first regularly scheduled study dose at Cycle 1 Day 1 (see Figure
6.b) and a second 89Zr-TAK-164 administration on Cycle 1 Day 1 in combination with unlabeled 
TAK-164 at a maximum mass dose of 100% of the RID. Imaging will be performed 1 hour after 
EOI of the first 89Zr-TAK-164 administration for dosimetry in the first 3 patients, and for all 
patients at 2 time points between Day 2 and Day 7 after EOI. Imaging time points and mass dose 
of TAK-164 can be adjusted to optimize imaging conditions. Up to 19 additional patients will be 
enrolled into part C to receive a single dose of 89Zr-TAK-164 at Cycle 1 Day 1 in addition to 
unlabeled TAK-164 as determined for optimal imaging. Once the RP2D of TAK-164 is 
determined, part C patients who have received TAK-164 at an RID lower than the RP2D of 
TAK-164 may dose-escalate to the RP2D in the absence of PD or unacceptable treatment-related 
toxicity at the investigator’s discretion and with sponsor’s approval. If the full RID/RP2D is not 
administered at Cycle 1 Day 1, the differential will be provided after the second image 
acquisition. Part C patients will continue treatment with the RID/RP2D of TAK-164 at Cycle 2 
Day 1 and beyond (see Figure 6.c).
8.4
Dose Modification Guidelines
8.4.1
Criteria for Retreatment and Dose Delays and Modifications Delaying a Subsequent 
Treatment Cycle
Treatment with TAK-164 will be repeated each cycle, 21 days (Q3W schedule). Criteria for 
delaying treatment, modifying the dose, or discontinuing treatment in individual patients are 
outlined in Table 8.a and discussed below. Dose modification will apply to patients who 
complete Cycle 1 and are continuing on treatment. When a dose reduction of TAK-164 is 
required, no re-escalation of dose will be permitted. For the next cycle of treatment to begin, the 
patient must meet the following criteria:
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
ANC must be ≥1500/mm3.

Platelet count must be ≥100,000/mm3.

Serum albumin level must be ≥3 g/dL.

In addition, for therapy to resume, toxicity considered to be related to treatment with 
TAK-164 must have resolved to Grade 1, to the patient’s baseline values, or to a level 
considered acceptable by the physician (eg, hypophosphatemia that can be managed by oral 
replacement). Also, the patient’s nutritional status and organ function must be adequate, as 
assessed by the treating physician.
If the patient does not meet the above-cited criteria for retreatment, initiation of the next cycle of 
treatment should be delayed for 1 week. At the end of that time, the patient should be reevaluated 
to determine whether the criteria for retreatment have been met. If observed that the criteria for 
retreatment have been met, the treatment may continue at a reduced dose. If needed, the initiation 
of the next cycle of treatment should be delayed for 1 additional week. At 2 weeks if the 
treatment criteria are met, the dose may be reduced for at least 1 dose level for subsequent 
cycles. If a patient needs to delay treatment for a period greater than 2 weeks, that should trigger 
discontinuation from the study unless the treating physician considers it to be in the patient’s best 
interest to continue study treatment and the sponsor agrees.
Table 8.a
TAK-164 Recommended Dose Modification Criteria
General
Occurrence
Modification
Any Grade >1 toxicity that does not resolve within 2 weeks of 
study drug being withheld.
Discontinuation a
HEMATOLOGIC TOXICITIES
Adverse Event (Severity)
Modification 
Neutropenia 
Grade 4 without fever.
Dose reduction a
Grade 3 or greater with fever (a single oral temperature of 
>38.3°C or a sustained temperature of ≥38°C for more than 1 
hour).
Dose reduction a
Thrombocytopenia
Grade 3 or greater with clinically meaningful bleeding at any 
time.
Dose reduction a
Anemia 
Grade 3 or greater.
Dose reduction a
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Table 8.a
TAK-164 Recommended Dose Modification Criteria
NONHEMATOLOGIC TOXICITIES
Adverse Event (Severity)
Modification 
Peripheral Neuropathy 
Grade 1 with pain or Grade 2.
Dose reduction a
Grade 2 with pain or Grade 3.
Dose interruption 
Grade 4.
Discontinuation 
All Other Grade 3 or Greater Nonhematologic Toxicities
–
Grade 3 nonhematologic toxicities attributed to study 
drug. b,c
Dose interruption with dose reduction a
–
Grade 3 or greater nausea and/or emesis in the absence 
of optimal antiemetic therapy.
No dose modification required 
–
Grade 3 or greater diarrhea in the absence of optimal 
supportive therapy. 
No dose modification required 
–
Grade 3 fatigue with duration <1 week. 
No dose modification required 
–
Grade 4 nonhematologic toxicities. a
Discontinuation or dose interruption with dose 
reduction
–
Grade 3 derangements of liver function tests.
Refer to discontinuation rules in Section 8.4.3
DLT
If, in the opinion of the investigator and the 
medical monitor it is in the patient’s best 
interest to continue treatment with TAK-164, 
then the dose of TAK-164 should be reduced 
by at least 1 dose level with subsequent 
treatment after recovery of the toxicity or 
toxicities in question to Grade 1 or to baseline 
values. When a dose reduction of TAK-164 is 
required, no re-escalation will be permitted.
DLT: dose-limiting toxicity.
a Dose reduction will be dosing 1 level lower. If at scheduled start of next cycle, the toxicity has returned to 
Grade 1 or baseline, administer TAK-164 at a reduced dose. If toxicity has not resolved to Grade 1 or baseline 
within 1 week, delay treatment for an additional week. Once toxicity has recovered to Grade 1 or baseline (at 1 or 2 
weeks), restart treatment at a reduced dose. Discontinue treatment if after 2 weeks the criteria for retreatment have 
not been met, unless the treating physician considers it to be in the patient’s best interest to continue study treatment 
and the sponsor agrees.
b Except Grade 3 or greater nausea, vomiting, or diarrhea in absence of optimal antiemetic or supportive therapy, 
Grade 3 fatigue less than 1-week duration.
c Except Grade 3 derangements of liver function tests.
8.4.2
Criteria for Dose Reduction
The dose of TAK-164 should be reduced by at least 1 dose level (or by 50% if the patient is 
receiving the first dose level) if the patient has any of the following:

Grade 4 neutropenia (ANC <500 cells/mm3) lasting more than 7 consecutive days.
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
Grade 3 or greater neutropenia with fever and/or infection, where a fever is defined as a 
single oral temperature of >38.3°C or a sustained temperature of ≥38°C for more than 1 hour.
Grade 3 thrombocytopenia with clinically meaningful bleeding at any time.

Grade 4 thrombocytopenia (platelet count <25,000/mm3) lasting more than 7 consecutive 
days.

Grade 3 nonhematologic toxicity (except liver function derangements) attributed to TAK-164 
except for the following that do not require dose reduction:
–
Grade 3 or greater nausea and/or emesis in the absence of optimal antiemetic prophylaxis. 
(Optimal antiemetic prophylaxis is defined as an antiemetic regimen that employs both a 
5-HT3 antagonist and a corticosteroid given in standard doses and according to standard 
schedules.)
–
Grade 3 or greater diarrhea that occurs in the absence of optimal supportive therapy.
–
Grade 3 fatigue lasting less than 1 week.

Derangement of liver function tests (LFTs) will follow discontinuation rules in Section 8.4.3.
When a dose reduction of TAK-164 is required, no re-escalation of dose will be permitted.
8.4.3
Criteria for Discontinuation of TAK-164
Grade 4 nonhematologic toxicities will in general require that treatment with TAK-164 be 
permanently discontinued. Treatment delays of greater than 2 weeks for study drug-related 
toxicities require discontinuation from study treatment, unless the treating physician considers it 
to be in the patient’s best interest to continue study treatment and the sponsor agrees.
Treatment with TAK-164 will also be permanently discontinued under the following conditions:

ALT or AST >8 × ULN; OR

ALT or AST >5 × ULN for more than 2 weeks; OR

ALT or AST >3 × ULN and TBL >2 × ULN.
If, in the opinion of the investigator and the project clinician, it is in the patient’s best interest to 
continue treatment with TAK-164, then the dose of TAK-164 should be reduced by at least 
1 dose level (or by 50% if the patient is receiving the first dose level) after recovery of the 
toxicity or toxicities in question to Grade 1 or to baseline values.
If more than 2 dose reductions are required, TAK-164 should be discontinued. If, in the opinion 
of the investigator and the project clinician, it is in the patient’s best interest to continue 
treatment with TAK-164, then the dose of TAK-164 should be reduced by at least 1 dose level 
for subsequent cycles of treatment after recovery of the toxicity or toxicities in question to 
Grade 1 or to baseline values. When a dose reduction of TAK-164 is required, no re-escalation of 
dose will be permitted.
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8.5
Excluded Concomitant Medications and Procedures
During the course of the study, patients will be instructed not to take any additional medications 
(including over-the-counter products and supplements) without prior consultation with the 
investigator. At each visit, the investigator will ask the patient about any new medications he/she 
is or has taken while on study. All concomitant medications (defined as any medication given 
during the study) and significant nondrug therapies, including physical therapy and blood 
transfusions, should be recorded from signing of the informed consent form (ICF) through 
28 days after the last dose of study drug or the start of subsequent antineoplastic therapy, 
whichever occurs first.
The following medications and procedures are prohibited during the study:

All concomitant chemotherapy, immunotherapy, and radiotherapy.

Any investigational agent other than TAK-164, including agents that are commercially 
available for indications other than GI malignancies that are under investigation for the 
treatment of GI malignancies.

Any antineoplastic treatment with activity against GI malignancies other than TAK-164.

Strong CYP3A inhibitors (a list of CYP3A inhibitors and inducers is presented in 
Appendix E). Concurrent systemic administration of TAK-164 with strong inhibitors or 
inducers of CYP3A or inhibitors or modulators of P-gp or BCRP should be avoided in this 
study. Refer to Appendix E for a nonexhaustive list of medications, supplements, and food 
products that are strong inhibitors or inducers of CYP3A based on the US Food and Drug 
Administration (FDA) Draft Drug-Drug Interaction Guidance.

Anticoagulant therapy (eg, aspirin, coumadin, heparin) that cannot be held for patients who 
will require a tumor biopsy.
If a patient experiences an AE, therapies required to manage the AE and control cancer 
symptoms are allowed according to standard clinical practice including palliative radiation (if, in 
the opinion of the investigator, there is no appropriate alternative treatment available). Such 
situations will be managed on a case-by-case basis and require medical monitor approval based 
on the risk/benefit for the patient. The discussion/approval should be documented in the study 
file and the patient should be closely monitored for potential toxicity.
8.6
Precautions and Restrictions
It is not known what effects TAK-164 has on human pregnancy or development of the embryo or 
fetus. Therefore, female patients participating in this study should avoid becoming pregnant, and 
male patients should avoid impregnating a female partner. Nonsterilized female patients of 
reproductive age group and male patients should use effective methods of contraception through 
defined periods during and after study treatment as specified below.
Female patients must meet 1 of the following:

Postmenopausal for at least 1 year before the screening visit, OR
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
Surgically sterile, OR

If they are of childbearing potential, agree to practice 1 highly effective method and 1 
additional effective (barrier) method of contraception at the same time, from the time of 
signing of the ICF through 90 days after the last dose of study drug (whichever is longer), 
OR

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.)
Male patients, even if surgically sterilized (ie, status postvasectomy) must agree to 1 of the 
following:

Agree to practice effective barrier contraception during the entire study treatment period and 
through 120 days after the last dose of study drug, OR

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.)
8.7
Management of Clinical Events
Therapies that are required to manage AEs and control cancer symptoms are allowed based on 
standard clinical practice, unless specifically excluded. Supportive care agents, such as 
erythropoietin, granulocyte colony stimulating factor (G-CSF), blood products (RBC and platelet 
transfusions), and pain medications are permitted as needed per American Society of 
Hematology (ASH)/American Society of Clinical Oncology (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 as a result of the events detailed below, 
refer to Section 8.4.
8.7.1
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 and/or vomiting will be 
actively managed by employing optimal antiemetic treatment based on local standard practice. 
Additionally, antiemetics may be used prophylactically as clinically indicated following the 
occurrence of a first event of study drug-related or possibly related nausea and/or vomiting. An 
optimal antiemetic regimen is defined as one that employs both a 5-HT3 antagonist and a 
corticosteroid given in standard doses and according to standard schedules.
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8.7.2
Anemia, Thrombocytopenia, and/or Neutropenia
Hemoglobin and blood counts should be monitored regularly as outlined in the Schedules of 
Events (Appendix A) with additional testing obtained according to standard clinical practice. 
Administration of TAK-164 should be modified per dose modification guidance in the protocol 
when anemia, thrombocytopenia, or neutropenia occur (see Table 8.a). RBC transfusion and use 
of erythropoietin to manage severe anemia, platelet transfusion to prevent and minimize bleeding 
in case of severe thrombocytopenia, and myeloid growth factor (eg, G-CSF, GM-CSF) support to 
treat severe and/or febrile neutropenia are permitted per ASH/ASCO guidelines, as necessary. 
However, it should be noted that prophylactic use of myeloid growth factors should be avoided 
during the first cycle of dose escalation.
8.7.3
Skin Lesions
Dermal and subcutaneous lesions with ulceration or necrosis represent a potential risk and are 
presumed associated with accidental extravasation. Local institutional guidelines must be applied 
to stress proper administration and prevention of accidental extravasation of TAK-164. Constant 
monitoring at the beginning and during infusion must be ensured. If extravasation occurs, the 
infusion must be discontinued immediately, and institutional guidelines applied. Treatment and 
monitoring of patients until symptoms resolve should be consistent with institutional standards 
and guidelines as appropriate. Patients should be instructed to report any discomfort, pain, or 
swelling at the infusion site.
8.7.4
Lacrimal Gland Secretion Alteration
Patients should be advised to report any discomfort with dry eye, if that should occur. Treatment 
and monitoring should be consistent with institutional standard and guidelines as appropriate.
8.7.5
Diarrhea
This study will not initially employ prophylactic antidiarrheals; however, there is no prohibition 
against their use in the management of a patient who develops diarrhea. Patients will be 
instructed to take antidiarrheal medication(s) at the physician’s discretion until they are diarrhea-
free for at least 12 hours. Fluid intake should be maintained to avoid dehydration.
8.7.6
Infusion-related Reactions
If such a reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, 
pruritus, arthralgias, hypotension or hypertension, bronchospasm, or other symptoms. Treatment 
and monitoring of patients until symptoms resolve should be consistent with institutional 
standards and guidelines as appropriate. If Grade 3 and 4 infusion reactions occur, infusion 
should be discontinued immediately. Investigators should follow their institutional guidelines for 
the treatment of anaphylaxis. The patient should be closely monitored until recovery of 
symptoms. The patient will be permanently discontinued from the trial. All Grade 3 or 4 infusion 
reactions should be reported within 24 hours to the medical monitor and reported as an SAE if 
criteria are met. Infusion reactions should be graded according to NCI CTCAE, version 5.
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As with other mAb therapies, potential risk for immunogenicity cannot be excluded. Based on 
our TAK-264 experience, where the same antibody was utilized (very low immunogenicity 
positivity), general screening/titer/confirmation/domain specificity immunogenicity assays will 
be performed but not the further ADA characterization assay such as neutralization assay. The 
overall immunogenicity will be monitored closely in the study and the timing of implementing 
neutralization assay will be assessed at later phase for this product.
8.7.7
Hepatotoxicity
It is recommended that patients treated with TAK-164 undergo periodic monitoring of LFTs as 
outlined in the Schedules of Events (Appendix A). These liver tests should be monitored closely 
throughout the study, and strict procedures for evaluation and/or discontinuation of patients with 
elevated liver tests that meet predefined criteria should be implemented. Additional testing and 
treatment should be implemented as per institutional standard of care.
If patients experience ALT or AST >3 × ULN or AST > ULN but ≤3 × ULN, and if this 
observation cannot be explained by concomitant disease or another alternative etiology, 
follow-up laboratory tests (at a minimum alkaline phosphatase [ALP], ALT, AST, and TBL) 
should be performed within a maximum of 48 hours.
8.8
Blinding and Unblinding
This is an open-label study.
8.9
Description of Investigational Agents
The drug product is TAK-164 for injection.
TAK-164 for injection is for IV administration only.
Full details are available in the IB.
8.10
Preparation, Reconstitution, and Dispensation
The reconstituted product will be administered by IV infusion over a defined period of time. 
Detailed reconstitution and dosage preparation instructions are provided in the Directions for Use 
located in the pharmacy manual.
In the absence of compatibility studies, this medicinal product must not be mixed with other 
medicinal products.
TAK-164 is an anticancer drug and, as with other potentially toxic compounds, caution should be 
exercised when handling TAK-164.
Parenteral drug products should be inspected visually for particulate matter and discoloration 
prior to administration, whenever solution and container permit.
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8.11
Packaging and Labeling
All label information will fulfill requirements specified by local governing regulations. 
Additional details are provided in the pharmacy manual.
8.12
Storage, Handling, and Accountability
Complete receipt, inventory, accountability, reconciliation, and destruction records will be 
maintained for all used and unused study drug vials. A drug dispensing log, including records of 
drug received from the sponsor and drug dispensed to patients will be provided and kept at the 
study site. Disposal instructions are provided in the pharmacy manual.
8.13
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.
8.14
Description of 89Zr-TAK-164
Radiolabeling of TAK-164 with 89Zr will be performed by the 
 
 according to 
standard operating procedures. The process will be performed according to GMP standards. This
production site has been inspected by the Dutch Health Care Inspectorate and is licensed to 
manufacture tracers for human use according to European Union guidelines.
8.15
Preparation of 89Zr-TAK-164
89Zr-TAK-164 will be prepared as described in the pharmacy manual and administered by IV at 
an anticipated dose of 0.5 to 2 mg at 37±10% MBq. The specific mass dose of ADC will be 
determined during the DIO phase of the imaging substudy.
The product should be used immediately. For specific instructions and information on expiry 
date, see the lead container.
8.16
89Zr-TAK-164 Administration
89Zr-TAK-164 will be administered as an IV infusion over a period of up to 30 minutes with 
careful monitoring of potential infusion-related and all AEs. When unlabeled TAK-164 is to be 
administered on the same day as 89Zr-TAK-164, the patients will receive 37±10% MBq of 
89Zr-TAK-164 (see pharmacy manual for details) within 2 hours after the infusion of unlabeled 
TAK-164 according to the registered label.
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9.0
STUDY CONDUCT
This trial will be conducted in compliance with the protocol, GCP, applicable regulatory 
requirements, and International Conference on Harmonisation (ICH) guidelines.
9.1
Study Personnel and Organizations
The contact information for the Takeda Study Monitor for this study, the central laboratory and 
any additional clinical laboratories, the contract research organization (CRO), and the 
coordinating investigator for each member state/country may be found in the study manual. A 
full list of investigators is available in the sponsor’s investigator database.
9.2
Arrangements for Recruitment of Patients
Recruitment and enrollment strategies for this study may include recruitment from the 
investigator’s local practice or referrals from other physicians. If advertisements become part of 
the recruitment strategy, they will be reviewed by the Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC). It is not envisioned that prisoners (or other 
populations that might be subject to coercion or exploitation) will be enrolled into this study.
9.3
Treatment Group Assignments
This is a phase 1 study that incorporates a dose escalation phase and an expansion cohort phase 
at the MTD/RP2D. In the dose escalation phase, patients will be assigned a dose by cohort based 
on the dose escalation rules as described in Section 8.3. Patients with mCRC enrolled in the 
MTD/RP2D cohort during the dose escalation phase of the study will be counted as part of the 
total of expansion cohort patients. Up to 50 patients with CRC GCC high expression level and 
patients with gastric carcinoma will be assessed. A minimum of approximately 20 patients will 
be enrolled in either cohort. In addition, up to 25 patients will be enrolled in the imaging 
substudy in The Netherlands (part C).
9.4
Study Procedures
Each patient must sign and date an ICF before undergoing any study-specific procedures unless 
those procedures are performed as part of the patient’s standard of care.
A detailed visit-by-visit schedule of study procedures is provided in the Schedules of Events 
(Appendix A).
Patients will be evaluated at scheduled visits over the following study periods: screening, 
treatment, and EOT. Evaluations during the screening period are to be conducted within 21 days 
before the first dose of TAK-164 except for prescreening of GCC, which may be completed prior 
to screening with appropriate patient consent. Procedures conducted during the screening period 
that are performed within 3 days of Cycle 1 Day 1 may also be used as the predose evaluation 
and do not need to be repeated, unless otherwise specified. For patients in the DIO subgroup of 
part C, all screening procedures must be completed before Day -14. It is recommended to 
consider prescreening patients’ GCC expression while on prior treatment. All EOT evaluations 
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should occur approximately 30 days after the last dose of study drug, or prior to the start of 
subsequent antineoplastic therapy. Refer to the Schedules of Events (Appendix A) for timing of 
assessments. Additional details are provided as necessary in the sections that follow.
9.4.1
Informed Consent
Each patient, or the patient’s legal representative, must provide written informed consent before 
any study-required procedures are conducted, unless those procedures are performed as part of 
the patient’s standard medical care. Informed consent may be obtained more than 21 days before 
the first dose of study drug, provided that the patient is confirmed to be eligible per the 
inclusion/exclusion criteria. A separate informed consent may be given by patients for release of 
archived tumor tissue for GCC prescreening. If archival tissue is not available, patients can 
provide tumor biopsy samples after signing the ICF. Unless specifically stated, references to ICF 
or informed consent in this protocol refer to the ICF patients sign when enrolling in the study.
9.4.2
Inclusion/Exclusion Review
Inclusion and exclusion criteria will be reviewed during screening to ensure patient meets 
eligibility requirements.
9.4.3
Patient Demographics
The date of birth, race, ethnicity, and sex of the patient are to be recorded during screening.
9.4.4
Medical History
During the screening period, a complete medical history will be compiled for each patient. The 
history will emphasize the background and progress of the patient’s malignancy and include a 
description of prior therapies for it. In addition, concomitant medications will be recorded as 
specified in Section 9.4.9.
9.4.5
Physical Examination
A physical examination will be completed per standard of care at the times specified in the 
Schedules of Events (Appendix A). Any clinically relevant findings are to be documented.
9.4.6
Height and Weight
Height will be measured only during screening. Body weight will be measured at the times 
specified in the Schedules of Events (Appendix A).
9.4.7
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 Schedules of Events (Appendix A).
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9.4.8
Vital Signs
Vital sign measurements, including diastolic and systolic blood pressure, heart rate, and 
temperature, will be assessed as specified in the Schedules of Events (Appendix A).
9.4.9
Pregnancy Test
A serum pregnancy test will be obtained for women of childbearing potential at screening and at 
EOT. The screening results must be available and negative prior to enrollment. A urine 
pregnancy test will be obtained for women of childbearing potential on Day 1 of every cycle and 
a negative result must be confirmed prior to dosing.
Pregnancy tests may also be repeated during the study if requested by an IEC/IRB or if required 
by local regulations.
9.4.10 Concomitant Medications and Procedures
Medications used by the patient and therapeutic procedures completed by the patient will be 
recorded in the electronic case report form (eCRF) from signing of the ICF through the EOT visit 
or the start of subsequent antineoplastic therapy, whichever occurs first. See Section 8.5 for a list 
of medications and therapies that are prohibited during the study.
9.4.11 AEs
Monitoring of AEs/AESIs, serious and nonserious, will be conducted throughout the study as 
specified in the Schedules of Events (Appendix A). Refer to Section 10.0 for details regarding 
definitions, documentation, and reporting of AEs/AESIs and SAEs.
9.4.12
Enrollment
Enrollment is defined as the time of initiation of the first dose of study drug.
Procedures for completion of the enrollment information are described in the study manual.
9.4.13
Cardiac Monitoring
9.4.13.1 12-Lead ECGs and Left Ventricular Ejection Fraction
Left ventricular ejection fraction (LVEF) will be measured by an echocardiogram (ECHO) at the 
times listed in the Schedules of Events (Appendix A). If a patient develops signs or symptoms of 
congestive heart failure, TAK-164 administration should immediately be discontinued and LVEF 
measurement should be performed. ECHO will be performed for all patients in part A and the 
first 30 patients in part B. After the first 30 patients, if there are no clinical findings, ECHO will 
no longer be required.
Single 12-lead ECGs will be collected at screening (to assess eligibility) and for “safety” within 
1 hour before TAK-164 administration (ie, start of the infusion). All other ECGs require 
triplicate 12-lead ECG recordings. Refer to the Schedules of Events (Appendix A) for the 
specific visits, timepoints, and type (ie, single vs triplicate recording) of ECGs that are required. 
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All ECGs will be centrally read and ECG parameters will include PR, QT, QTcF, QRS, and 
ventricular rate.
Any findings from ECGs collected after study drug administration will be captured as AEs if, in 
the opinion of the investigator, there has been a clinically significant change from baseline.
When the timing of a PK, biomarker, or safety laboratory blood sample coincides with the timing 
of ECG measurements, the ECG will be completed before the collection of the blood sample.
9.4.13.2 Triplicate ECGs
Triplicate 12-lead ECG recordings matched with PK sampling are required at time points 
specified in the Schedules of Events (Appendix A) for a preliminary assessment of TAK-164 on 
QTcF interval. The triplicate ECG will be stored and submitted for central reading.
When triplicate ECGs overlap with safety ECGs, the triplicate ECG may be used for safety 
assessment.
9.4.14
Clinical Laboratory Evaluations
9.4.14.1 Clinical Chemistry, Hematology, and Urinalysis
Clinical laboratory evaluations will be performed locally as per the institutional standard of care.
Blood samples for analysis of the following clinical chemistry and hematological parameters and 
urine samples for urinalysis will be obtained as specified in the Schedules of Events 
(Appendix A).
Hematology

Hemoglobin

Hematocrit

Platelet (count)

Leukocytes with differential

Neutrophils (ANC)
Coagulation

Prothrombin time

Activated partial thromboplastin time
Serum/Plasma Chemistry

Blood urea nitrogen/urea

Serum creatinine

TBL

Urate

Phosphate

Albumin

ALP

AST

ALT

Glucose

Sodium

Potassium

Calcium

Chloride

Carbon dioxide

Magnesium
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Urinalysis

pH

Specific gravity

Protein

Ketones

Bilirubin

Occult blood

Nitrite

Urobilinogen

Glucose

Leukocytes
Hematology and serum chemistry samples may be taken up to 3 days prior to the visit, and 
coagulation testing and urinalysis may be conducted 24 hours prior to the visit. All results must 
be evaluated prior to dosing.
In order for a new cycle of treatment to begin, the patient’s ANC must be ≥1500/mm3, the 
platelet count must be ≥100,000/mm3, and the patient’s serum albumin level must be ≥3.0 g/dL.
Serum creatinine CL is to be estimated by the Cockcroft-Gault formula [57] as follows:
	
 
	
  
= [(140 −
) ∗	() ] / [72 ∗
" 
	
(/)]
For female patients, the result of the formula above should be multiplied by 0.85.
As a backup creatinine CL can be determined based on 12 hours or 24 hours collection of urine 
specimen.
9.4.15
Disease Assessment
At screening, contrast-enhanced CT of thorax, abdomen, and pelvis should be performed. If an 
anatomic region cannot be adequately imaged by CT, MRI may be used instead. The same 
imaging modality utilized at screening for a particular site of disease must be used consistently 
throughout all subsequent disease assessments.
Objective assessments will be performed at screening, every 2 treatment cycles (42 days with a 
window of 3 days in advance), and at the EOT visit, as described in the Schedules of Events 
(Appendix A). Response assessment will be calendar-based regardless of treatment 
delays/interruptions. Objective assessments will be based on the modified RECIST criteria, 
version 1.1 (see Appendix G) [1]. When possible, the same qualified physician will interpret 
results to reduce variability. Radiographic images will be maintained at the site, and test results 
and physician’s findings will be filed in patient source documents. In addition, all study images 
acquired for patients in part B and part C will be collected by a central imaging vendor and 
assessed in a blinded independent central review. The sites will transfer images to a central 
facility consistent with the guidance provided by the sponsor.
If the patient discontinues the study and has had a CT/MRI scan within 2 weeks of the EOT 
study visit, the CT/MRI scan does not need to be repeated.
9.4.16 Assessment of 89Zr-TAK-164 PET Imaging (Part C, To Be Conducted in The 
Netherlands Only)
All PET/CT data will be reconstructed as described by Makris et al [58]. 89Zr PET assessments 
will be performed under the supervision of a qualified nuclear medicine physician. Qualitative 
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uptake of 89Zr-TAK-164 in tumor lesions will be described as present or absent above local 
background. Quantitative analysis will be performed to determine tissue uptake values expressed 
as SUV. The data will be reflective of the amount of TAK-164 administered and organ and 
tumor lesion(s) biodistribution and accumulation over time. SUVmean will be reported for 
biodistribution to the different organs. Tumor target lesions will need to have a minimum 
diameter of 2 cm, to minimize potential partial volume effect, and must have a visual uptake 
above background activity. SUV mean, max, and peak will be reported for tumor lesions, with a 
maximum of 5 tumor lesions per organ/tumor site.
9.4.17 Assessment of 18F-FDG-PET Imaging (Part C, To Be Conducted in The Netherlands 
Only)
Target lesions must have a minimum diameter of 1 cm on CT scan, to minimize potential partial 
volume effect, and must have an uptake above background activity. The background activity will 
be calculated in healthy liver tissue in a 3 × 3 cm VOI (using the following formula [1.5 × 
SULmean liver] + [2 × standard deviation SULmean liver]) or in the descending aorta in a 1 × 1 cm 
VOI (using the following formula (2 × SULmean descending thoracic aorta) + (2 × standard 
deviation SULmean descending thoracic aorta) in case of hepatic metastases according to Positron 
Emission Tomography Response Criteria in Solid Tumors (PERCIST) [59]. Tumor VOIs will be 
created manually and resized semiautomatically using a delineation tool that uses a 50% SULpeak
threshold with background correction.
At least 3 quantification units will be evaluated: SULpeak within the tumor VOI (placed 
automatically to ensure that a sphere of approximately 1.2 cm diameter with the highest mean 
SUL will be captured), SULmax (defined as the voxel with the highest SUL within the tumor 
VOI), metabolic tumor volume (MTV, this volume is defined with an isocontour VOI of 50% of 
SULpeak with background correction), and TLG (defined as SULmean times MTV). Quantitative 
analysis of the PET images will be done for multiple tumor lesions (≤5 tumor lesions, ≤2 per 
organ) and for the metabolically most active target lesions per PET scan, as suggested in 
PERCIST [59].
9.4.18 Biomarker, PK, and Pharmacodynamic Samples
The primary specimen collection procedures are shown in Table 9.a. Additional handling and 
shipment of biomarker, PK, and pharmacodynamic samples are outlined in the laboratory 
manual.
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Table 9.a
TAK-164-1001: Primary Specimen Collection
Specimen Name in 
Schedule of Procedures
Primary 
Specimen
Primary 
Specimen 
Derivative 1
Description of 
Intended Use
Sample Collection
Fresh tumor tissue biopsy 
sample
Fresh tumor 
tissue
FFPE block
FFPE slides
Biomarker measurements
!
Mandatory if 
archival (banked) 
tumor tissue is not 
available.
!
Minimum of 
approximately 5 
biopsy patients 
required for target 
engagement 
biomarker.
Archival (banked) tumor 
tissue sample a
FFPE block
FFPE slides 
(unstained)
--
GCC evaluation and 
biomarker measurements
If not provided, patient 
must provide a fresh 
biopsy sample.
Buccal epithelial cells 
sample for DNA
Buccal DNA 
swab
DNA
Biomarker measurements
Mandatory
Serum sample for 
pharmacodynamics
Serum
--
Biomarker measurements
Mandatory
Plasma sample for TAK-
164 PK
Plasma
--
PK measurements
Mandatory
Plasma sample for 
FGN849 and s-FGN849
Plasma
--
PK measurements
Mandatory
Serum sample for 
immunogenicity
Serum
--
Immunogenicity evaluation
Mandatory
FFPE: formalin-fixed paraffin-embedded; FGN849: free payload for TAK-164; GCC: guanylyl cyclase C; 
PK: pharmacokinetic; s-FGN849: sulfonated FGN849.
a A deidentified pathology report should be sent to the central lab with archival tumor tissue.
b Samples not collected for patients participating in part C.
9.4.18.1 Biomarker Samples
Blood samples will be collected via venipuncture or indwelling catheter at the time points 
detailed in the Schedules of Events (Appendix A) for concentration measurements of TAK-164 
and biomarker assessments. The primary specimen collection is presented in Table 9.a.
Banked formalin-fixed paraffin-embedded tumor tissue or a minimum of 10 unstained slides 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 at screening to assess biomarkers implicated in the sensitivity or resistance to 
Property of Takeda: Fo
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TAK-164. The accompanying pathology report should be sent to the centralized testing lab. The 
tumor pathology block will be returned to the original site by the sponsor or designee. If the 
pathology block is not provided, submission of 10 unstained slides that have been immersed in 
paraffin after sectioning will be accepted. See the laboratory manual for details. Patients who 
cannot provide at least 10 histological slides from their diagnosis biopsy may undergo a new 
fresh tumor biopsy during screening (may be obtained up to 21 days prior to the first dose of 
study drug).
Effort should be made to take an additional optional biopsy when patients have relapsed. These 
samples are to be tested for the expression of GCC and other potential markers of tumor 
resistance.
In this study, several biomarkers will be assessed to test for correlation with safety 
 
 
 
 
 
9.4.18.2 PK Measurements
Serial plasma samples for PK analysis of TAK-164 will be collected during Cycle 1 Day 1 and 
Cycle 2 Day 1 of the 21-day dosing schedule. In addition, trough samples (ie, predose) will be 
collected at prespecified time points as described in the Schedules of Events (Appendix A). The 
primary purpose of collecting these samples is to measure the plasma concentrations of 
TAK-164 (conjugated and unconjugated antibody) and circulating plasma concentrations of 
FGN849 and s-FGN849 to characterize the PK of TAK-164, FGN849, and s-FGN849 after 
single- and multiple-dose administration. This information will also further inform the building 
of PK models to describe TAK-164 and FGN849 PK and such models will be used to predict 
TAK-164 and FGN849 plasma levels under different dosing scenarios to help select an 
appropriate dose/schedule of TAK-164. The dates and exact times of TAK-164 administration 
before collecting PK samples and the dates and exact times of postdose PK sample collections 
will be recorded in the eCRFs. These plasma samples may also be used for additional 
exploratory assessments if needed in the future.
9.4.18.3 Pharmacodynamic Measurements
Serum for Pharmacodynamic Measurement
Serum samples will be collected to monitor different pharmacodynamic biomarkers such as 
immune system response via cytokine/chemokine changes upon treatment. Collection of this 
sample will be at the time points described in the Schedules of Events (Appendix A). Instructions 
for processing and shipping of blood samples for serum pharmacodynamic measurements are 
provided in the laboratory manual.
Property of Takeda: For Non-Commercial Use Only and S
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Serum for Protein (Local) Measurements
Serum samples for protein will not be collected for patients participating in part C. For all other 
patients, samples will be collected to monitor changes in clinically established biomarkers such 
as carcinoembryonic antigen to assess relationship with clinical response. Collection of this
sample will be at baseline (all cycles) and Day 8 (Cycle 2 only). Laboratory tests will be 
performed at the site.
9.4.19 DNA Measurements
Buccal epithelial cells at baseline or at screening will be collected via swab as detailed in the 
Schedules of Events (Appendix A) as a germline control sample for DNA mutation analysis from 
banked tumor and/or fresh tumor biopsies.
9.4.20 Banked Tumor and/or Fresh Tumor Biopsy Specimen Measurements
GCC expression is evaluated by using IHC, as conducted by a central laboratory. An H-score 
will be used for GCC assessment and enrollment. Patients with GCC H-score ≥10 will be eligible 
for enrollment. An H-score ≥ 150 will be used for assigning patients to a GCC high group. In 
addition, status of MSI may be analyzed on banked tumor and/or fresh tumor biopsies. 
Collection of tumor biopsies at baseline and following treatment with TAK-164 is highly 
encouraged to monitor expression of GCC 
. A viable fresh baseline biopsy 
and a viable posttreatment biopsy will be collected during dose escalation in a minimum of 
approximately 5 patients participating in parts A and B, and approximately 3 patients 
participating in part C. A baseline biopsy and posttreatment biopsy will be collected to assess 
target engagement and the tumor microenvironment. The specific anatomical location of the 
biopsy before resection must be specified.
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9.4.22 Immunogenicity Sample Collection
Blood samples will be collected to evaluate immunogenicity as indicated in the Schedules of 
Events (Appendix A). Serum samples will then be prepared and analyzed in the validated ADA 
assays.
9.5
Completion of Study Treatment (for Individual Patients)
Patients will be considered to have completed study treatment if they complete 12 cycles of 
treatment with TAK-164, or if they experience PD. Patients will be considered to have 
completed study treatment if they discontinued study drug for any reason as outlined in 
Section 8.4.3.
9.6
Discontinuation of Treatment with Study Drug and Patient Replacement
Patients will be informed that they have the right to discontinue study treatment at any time for 
any reason, without prejudice to their medical care.
Treatment with study drug may be discontinued for any of the following reasons:

AE.

Protocol deviation.

PD.

Symptomatic deterioration.

Study terminated by sponsor.

Withdrawal by patient.

Lost to follow-up.

Other.
Once study drug has been discontinued, all study procedures outlined for the EOT visit will be 
completed as specified in the Schedules of Events (Appendix A). The primary reason for study 
drug discontinuation will be recorded on the eCRF.
Patients who are withdrawn from treatment during Cycle 1 for reasons other than DLT will be 
replaced.
Note that some patients may discontinue study drug for reasons other than PD before completing 
the full treatment course; these will remain in the study for posttreatment assessments as outlined 
in the Schedules of Events (Appendix A) until PD occurs.
9.7
Study Compliance
Study drug will be administered or dispensed only to eligible patients under the supervision of 
the investigator or identified subinvestigator(s). The appropriate study personnel will maintain 
records of study drug receipt and dispensing.
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9.8
Posttreatment Follow-up Assessments (PFS)
Patients who stop treatment for any reason other than PD will continue to be followed for PFS. 
The PFS follow-up visits, including imaging, should be conducted at the site every 3 months 
from last dose of study drug for up to 6 months or until PD, the start of alternative therapy, or 
conclusion of the study (whichever occurs first).
NOTE: Related SAEs must be reported to the Global Pharmacovigilance department or designee. 
This includes deaths that the investigator considers related to study drug that occur during the 
posttreatment follow-up. Refer to Section 10.0 for details regarding definitions, documentation, 
and reporting of SAEs.
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10.0
ADVERSE EVENTS
10.1
Definitions
10.1.1 Pretreatment Event Definition
A pretreatment event (PTE) is any untoward medical occurrence in a patient or patient who has 
signed informed consent to participate in a study but before administration of any study 
medication; it does not necessarily have to have a causal relationship with study participation.
10.1.2 AE Definition
AE means any untoward medical occurrence in a patient or 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.
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is 
considered by the investigator to be a clinically significant change from baseline.
Disease progression should not be captured as an AE.
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, 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 
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include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse; any organism, virus, or infectious particle 
(eg, prion protein transmitting transmissible spongiform encephalopathy), pathogenic or 
nonpathogenic, is considered an infectious agent.
In this study, intensity for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE, version 5, effective date 27 Nov 2017 [55]. Clarification should be made between 
an SAE and an AE that is considered severe in intensity (Grade 3 or 4), because the terms serious 
and severe are NOT synonymous. The general term severe is often used to describe the intensity 
(severity) of a specific event; the event itself, however, may be of relatively minor medical 
significance (such as a Grade 3 headache). This is NOT the same as serious, which is based on 
patient/event outcome or action criteria described above, and is usually associated with events 
that pose a threat to a patient’s life or ability to function. A severe AE (Grade 3 or 4) does not 
necessarily need to be considered serious. For example, a WBC count of 1000/mm3 to less than 
2000 is considered Grade 3 (severe) but may not be considered serious. Seriousness (not 
intensity) serves as a guide for defining regulatory reporting obligations.
10.1.4 AESI Definition
An AESI is an AE of scientific and medical concern specific to the compound or program for 
which ongoing monitoring and rapid communication by the investigator to Takeda may be 
appropriate. Such events may require further investigation in order to characterize and 
understand them, and instructions regarding how and when AESIs should be reported to Takeda 
are provided in Section 10.2 along with a list of AESIs. 
10.2
Procedures for Recording and Reporting AEs and SAEs
All AEs spontaneously reported by the patient and/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 1 comprehensive event.
Regardless of causality, SAEs must be reported (see Section 10.3 for the period of observation) 
by the investigator to the Takeda Global Pharmacovigilance department or designee within 24 
hours of becoming aware of the event. This will be done by transmitting an electronic data 
capture (EDC) SAE report. If transmission of an EDC SAE report is not feasible, then a 
facsimile of the completed Takeda paper-based SAE form will be sent. A sample of the paper-
based SAE form and processing directions are in the study manual. Information in the SAE 
report or form must be consistent with the data provided on the eCRF.
If information not available at the time of the first report becomes available at a later date, then 
the investigator will transmit a follow-up EDC SAE report (or a paper-based SAE form if an 
EDC SAE report is not feasible) or provide other documentation immediately within 24 hours of 
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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 trial (eg, surgery was performed earlier or later 
than planned).
For both serious and nonserious AEs, the investigator must determine both the severity (toxicity 
grade) of the event and the relationship of the event to study drug administration.
Severity (toxicity grade) for each AE, including any lab abnormality, will be determined using 
the NCI CTCAE, version 5.0. 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?”
AESI Reporting:
The below aminotransferase test results will be treated as AESIs.

ALT or AST >3 × ULN.

ALT or AST >ULN but ≤ 3 × ULN which cannot be explained by concomitant disease or 
another alternative etiology.
All AESIs will be reported to Takeda Global Pharmacovigilance in an expedited manner 
irrespective of the event’s seriousness or causal relationship. Further, patients will be advised to 
promptly report signs and symptoms that may indicate liver injury, including fatigue, anorexia, 
right upper abdominal discomfort, dark urine, or jaundice. The investigator must contact the 
medical monitor within 24 hours to discuss further management of the patient and refer to 
management of hepatotoxicity in Section 8.7.7.
10.3
Monitoring of AEs and Period of Observation
AEs, both nonserious and serious, will be monitored throughout the study as follows:

AEs will be reported from the signing of informed consent through 30 days after 
administration of the last dose of study drug or the start of subsequent anticancer therapy, 
whichever occurs first, and recorded in the eCRFs.

SAEs will be reported to the Takeda Global Pharmacovigilance department or designee from 
the signing of informed consent through 30 days after administration of the last dose of study 
drug and recorded in the eCRF. After this period, only related SAEs must be reported to the 
Takeda Global Pharmacovigilance department or designee. SAEs should be monitored until 
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they are resolved or are clearly determined to be due to a patient’s stable or chronic condition 
or intercurrent illness(es).

AESIs will be reported and monitored in the same way as SAEs (see above).
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.
10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose)
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product. Individuals who 
identify a potential product complaint situation should immediately report this via the phone 
numbers or email addresses provided below.
A medication error is a preventable event that involves an identifiable patient and that leads to 
inappropriate medication use, which may result in patient harm. Whereas overdoses and 
underdoses constitute medication errors, doses missed inadvertently by a patient do not. 
Individuals who identify a potential medication error (including overdose) situation should 
immediately report this via the phone numbers or email addresses provided below.
Call center
Phone number
Email
Fax
DLSS
1-844-662-8532 
Non-toll-free number: 
1-510-740-1273 
GlobalOncologyMedinfo
@takeda.com 
1-800-881-6092
Product complaints and medication errors in and of themselves are not AEs. If a product 
complaint or medication error results in an SAE, the SAE should be reported.
10.6
Safety Reporting to Investigators, IRBs 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, including the European 
Medicines Agency, investigators, and IRBs or IECs, as applicable, in accordance with national 
regulations in the countries where the study is conducted. Relative to the first awareness of the 
event by/or further provision to the sponsor or sponsor’s designee, SUSARs will be submitted to 
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the regulatory authorities as an expedited report within 7 days for fatal and life-threatening 
events and 15 days for other serious events, unless otherwise required by national regulations. 
The sponsor will also prepare an expedited report for other safety issues where these might
materially alter the current benefit-risk assessment of an investigational medicinal product or that 
would be sufficient to consider changes in the investigational medicinal product’s administration 
or in the overall conduct of the trial. The investigational site also will forward a copy of all 
expedited reports to his or her IRB or IEC in accordance with national regulations.
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11.0
STUDY-SPECIFIC COMMITTEES
No steering committee, data safety monitoring committee, clinical endpoint committee, or 
adjudication committee will be used in this study.
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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, PTEs, medical history, and concurrent conditions will be coded 
using the Medical Dictionary for Regulatory Activities. Drugs will be coded using the World 
Health Organization Drug Dictionary.
12.1
eCRFs
Completed eCRFs are required for each 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, 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 designees) 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 change.
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the principal investigator must retain 
full responsibility for the accuracy and authenticity of all data entered on the eCRFs.
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor or its designee will be permitted to review the 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 copy of eCRFs, including the 
audit trail, and detailed records of drug disposition to enable evaluations or audits from 
regulatory authorities, the sponsor or its 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 
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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 on record retention. 
The investigator should contact and receive written approval from the sponsor before disposing 
of any such documents.
Refer to the Clinical Study Site Agreement for the sponsor’s requirements on record retention. 
The investigator and the head of the institution should contact and receive written approval from 
the sponsor before disposing of any such documents.
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13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized prior to database lock for the final 
analysis. This document will provide further details regarding the definition of analysis variables 
and analysis methodology to address all study objectives.
Deviations from the statistical analyses outlined in this protocol will be indicated in the SAP; any 
further modifications will be noted in the final clinical study report (part A and part B). Part C 
analyses will be reported in a clinical study report addendum.
13.1.1 Dose Escalation (Part A)
The mTPI study design by Ji [2] will be utilized to determine MTD. The mTPI design is based 
on pT for each dose level. These probabilities are sequentially updated with the data generated by 
DLT of each cohort beginning with the initial dose (dose level 1) and each subsequent cohort of 
patient.
Decision rules at each step are based on calculating the UPM of 3 intervals corresponding to 
underdosing, proper dosing, and overdosing a patient, in terms of toxicity. Specifically, the 
underdosing interval is defined as (0, pT - ε1), the overdosing interval as (pT + ε2, 1), and the 
proper dosing interval as (pT - ε1, pT + ε2), where ε1 and ε1 are small fractions to account for the 
uncertainty around the true target toxicity. In this study, pT is targeted at 25%, ε1, ε2 are both 5% 
to account for uncertainty.
The 3 dosing intervals are associated with 3 different dose escalation decisions. The underdosing 
interval corresponds to a dose escalation (E), overdosing corresponds to a dose de-escalation (D), 
and proper dosing corresponds to staying at the current dose (S). Given an interval and a 
probability distribution, the UPM of that interval is defined as the probability of the interval 
divided by the length of the interval. The mTPI design calculates the UPMs for the 3 dosing 
intervals, and the one with the largest UPM implies the corresponding dose-finding decision. 
That decision provides the dose level to be used for future patients. Approximately 25 patients 
will be enrolled. The enrollment in part A will be stopped when prespecified sample size of 25 
patients is reached, unless recommended otherwise based on clinical judgment, as discussed with 
the sponsor and the investigators. The mTPI dosing schema will maximize patients treated at or 
near the MTD and the MTD will be determined by using an isotonic regression to fit a function 
of observed probabilities of DLT at each dose level in this trial. Excessive toxicity (probability of 
DLT level exceeds 25% is greater than 95%) will prevent the escalation to next or higher dose 
levels and early termination of part A.
Assumptions upon which the mTPI design will be operating include an acceptable DLT rate of 
25% based on preliminary data of TAK-164 as a single agent. As discussed above, 
approximately 25 patients will be dosed from starting dose using the Q3W schedule. The 
schedule will follow the same dose schema and mTPI table using different starting doses.
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Simulation to evaluate the operating characteristics of mTPI was performed based on the 
proposed dose levels. Four scenarios of the assumed true DLT rates at each dose level were 
included to represent various distributions of toxicity. Average cohort size of 2 was used. 
Simulation was performed 5000 iterations for each scenario. Scenario details are shown in Table 
13.a.
Table 13.a
TAK-164-1001: Scenarios With Simulated True DLT Rate at Each Dose 
Level
Scenario
Proposed Dose Levels (mg/kg)
0.004
0.008
0.016
0.032
0.045
0.060
0.080
0.106
Simulated True DLT Rate Observed at Each Dose Level
1
0.01
0.02
0.03
0.04
0.05
0.25
0.5
0.6
2
0.05
0.15
0.25
0.3
0.35
0.4
0.6
0.8
3
0.15
0.18
0.2
0.23
0.27
0.3
0.3
0.35
4
0.05
0.2
0.3
0.45
0.6
0.8
0.9
0.95
DLT: dose-limiting toxicity.
Simulation results for scenario 1 are shown in Table 13.b for illustrative purposes. Under this 
scenario, MTD is selected at dose level 0.060 mg/kg, with probability of 56.4%.
Table 13.b
TAK-164-1001: Simulation Results of Scenario 1
Target Toxicity Prob. = 0.25
Selection 
Prob.
# of Patients 
Treated
# of Toxicities
Dose Level 
(mg/kg)
True Tox Prob.
mTPI
mTPI
mTPI
0.004
0.01
0
2.1
0
0.008
0.02
0
2.3
0
0.016
0.03
0.3%
2.5
0.1
0.032
0.04
1.1%
2.6
0.1
0.045
0.05
33.5%
4.2
0.2
0.060
0.25
56.4%
8.3
2.1
0.080
0.5
8.3%
3.4
1.7
0.106
0.6
0.4%
0.7
0.4
mTPI: modified toxicity probability interval; Prob: probability; Tox: toxicity.
Individual scenario results are not included further, while summarized simulation results are 
shown in Table 13.c. Probabilities of selecting the true MTD are 49.9% - 82.5%. The 
probabilities of selecting dose-over-MTD or no selection are generally low with 4.5% to 13.1% 
and 0% to 3.9%.
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Table 13.c
TAK-164-1001: Operating Characteristics for Dose Escalation using mTPI
Scenario
MTD Selection 
Prob (%)
Toxicity 
Prob (%)
Select Dose-over-MTD 
Prob (%)
No Selection
Prob (%)
1
56.4
17.8
8.7
0
2
49.9
21.9
13.1
0.1
3
51.5
20.6
8.4
3.9
4
82.5
23.0
4.5
0.1
MTD: maximum tolerated dose; mTPI: modified toxicity probability interval; Prob: probability.
13.1.2 Dose Expansion (Part B)
Up to 50 patients with CRC, which includes GCC high expression level (H-score ≥150) and 
patients with gastric carcinoma (H-score ≥10) will be assessed. A minimum of approximately 20 
patients will be enrolled in either cohort.
Analysis sets that may be used are defined as below:
Safety analysis set: Patients who receive at least 1 dose of TAK-164. The safety analysis set will 
be used for safety analyses.
DLT analysis set: Patients who complete Cycle 1 or experience a DLT in Cycle 1. The DLT 
analysis set will be used to determine the MTD.
Response-Evaluable analysis set: Patients who receive at least 1 dose of TAK-164, have 
measurable disease at baseline based on modified RECIST, version 1.1 [1], and at least 1 
postbaseline response assessment.
Plasma PK analysis set: Patients with sufficient dosing and PK data to reliably estimate PK 
parameters will be used for PK analyses.
Pharmacodynamic analysis set: Patients who receive at least 1 dose of TAK-164 and at least 
1 target engagement biomarker assessment.
Immunogenicity-Evaluable analysis set: Analysis will be based on available data from patients 
with a baseline assessment and at least 1 postbaseline immunogenicity assessment.
13.1.3 Imaging Substudy (Part C, To Be Conducted in The Netherlands Only)
The imaging analysis set includes patients with at least one 89Zr-TAK-164 PET scan. Results of 
89Zr-TAK-164 PET and 18F-FDG-PET scan will be summarized using descriptive statistics for 
the total analysis set or by baseline, dose, and disease characteristics.
All patients who receive any amount of 89Zr-TAK-164 will be included in the safety analyses. 
Safety will be assessed with summaries of AEs, changes in laboratory test results, and changes in 
vital signs. The in vivo biodistribution and tumor targeting of 89Zr-TAK-164 will be evaluated 
using summary statistics of SUV by organ/tumor lesion, TAK-164 dose, and imaging time point. 
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Correlations between imaging variables, pharmacodynamic markers, and clinical response will 
be explored.
Efficacy endpoints will be summarized, and the correlation with imaging outputs may be 
explored. The results of part C will be summarized in a clinical study report addendum.
13.1.4 Analysis of Demographics and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized by dose levels of TAK-164, 
expansion cohorts, and substudy part C. Data to be evaluated will include at least age, sex, race, 
weight, height, GCC score, etc. Components of disease severity assessment in additional to 
relevant patient and disease assessments and laboratory parameters will be presented if 
appropriate.
13.1.5 Efficacy Analysis
Assessment of tumor response will be according to modified RECIST, version 1.1 [1].
Dose Escalation (Part A)
There is no efficacy endpoint in the dose escalation portion of the study.
Patients with overall response in the dose escalation will be presented in a listing.
Dose Expansion (Part B)
Efficacy endpoints for the dose expansion includes ORR, defined as CR + PR. The estimate of 
ORR will be presented with 2-sided 80% exact binomial CIs for overall and patients of each 
cohort. The number and percentage of patients in each response category will be tabulated for 
overall and patients of each cohort. ORR will be analyzed based on the response-evaluable 
analysis set.
Efficacy analyses in part B also include DCR (CR+PR+SD), PFS, and DOR. DCR is defined as 
CR+PR+SD. The estimate of the DCR will be presented with 2-sided 80% exact binomial 
confidence intervals (CIs) for overall and patients of each cohort. The number and percentage of 
patients in each response category will be tabulated for each treatment arm based on RECIST, 
version 1.1 [1]. DCR will be analyzed based on the response-evaluable analysis set.
PFS is defined as the time from the date of the first dose TAK-164 to the date of first 
documentation of PD or death due to any cause, whichever occurs first. The censoring method 
will be described in the SAP. PFS will be tested based on the safety analysis set. The Kaplan-
Meier survival curves, 25th, 50th (median), and 75th percentiles (if estimable), along with their 
2-sided 95% CIs, will also be provided for overall patients or each cohort, if applicable.
DOR is defined as the time from the date of first documentation of a response to the date of first 
documentation of PD or death, whichever is earlier. Patients without documentation of PD or 
death at the time of analysis will be censored at the date of their last response assessment that is 
SD or better.
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DOR will be analyzed using the Kaplan-Meier method for overall and patients of or each cohort, 
if applicable, along with their 2-sided 95% CIs, will also be provided for all patients or each 
cohort, if applicable. DOR will be analyzed based on the responders in the Response-Evaluable 
analysis set.
In the imaging substudy (part C), efficacy endpoints are assessed. Patient efficacy will be 
summarized, and the correlation with imaging outputs may be explored.
Further details of the efficacy analysis can be found in the SAP.
13.1.6 PK Analysis
PK Analysis
Individual and mean plasma concentration data will be plotted over time. Descriptive statistics 
will be presented for plasma PK parameters including (but not limited to) Cmax, tmax, area under 
the plasma concentration versus time curve from time 0 to time t (AUCt), area under the 
concentration-time curve from time 0 to infinity (AUCinf), t1/2, CL, Vd, etc.
PK data collected in this study are intended to additionally contribute to population PK 
modeling. These models may be used to predict TAK-164 PK in different dosing scenarios to 
further support the selection of a recommended phase-2 dose of TAK-164. The population PK 
analyses may include data collected in additional TAK-164 clinical studies. The analysis plan for 
population PK modeling will be separately developed and the results of such modeling will not 
be presented in the clinical study report for this study but will be presented in a separate report.
PK/QTcF Analysis
The relationship between plasma TAK-164 concentration and QTcF interval will be analyzed 
using mixed effects modeling based on centrally over-read ECG interval data. It is expected that 
the relationship between plasma TAK-164 concentrations and change from baseline (predose) 
values of QTcF will be described using a direct linear concentration-effect relationship; however, 
the selection of the final model and mathematical form of the concentration-effect relationship 
will be based on graphical assessment of the data (eg, visual examination of observed 
concentration-effect plots to rule out a hysteresis secondary to time-delayed effects on QTcF) 
and exploration of alternate structural models (eg, maximum effect attributed to the drug 
models). The analysis plan for the PK-QTcF modeling will be developed separately and the 
results of this analysis may not be included in the clinical study report for this study but will be 
presented in a separate report.
13.1.7 Biomarker Analysis
Pro
y of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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13.1.8 Immunogenicity Analyses
The proportion of patients with positive ADA (transient and persistent, titer, and specificity) 
during the study will be summarized. The effect of immunogenicity on PK, and safety will be 
examined.
Analysis will be based on available data from patients with a baseline assessment and at least 
1 postbaseline immunogenicity assessment. Summaries will be provided separately for each 
study phase and by dose, as applicable. The incidence of immunogenicity will be calculated. The 
impact of anti–TAK-164 antibodies on the PK profile, pharmacodynamic profile, and clinical 
safety will be evaluated, if possible.
13.1.9 Safety Analysis
Safety will be evaluated by the incidence of AEs, severity and type of AEs, and by changes from 
baseline in the patient’s vital signs, weight, and clinical laboratory results using the safety 
population. Exposure to study treatment and reasons for discontinuation will be tabulated.
Treatment-emergent adverse events (TEAEs) that occur after administration of the first dose of 
study drug and through 30 days after the last dose of study drug will be tabulated.
AEs will be tabulated according to the Medical Dictionary for Regulatory Activities and will 
include the following categories:

DLTs.

TEAEs.

Grade 3 or higher TEAEs.

Drug-related TEAEs.

Grade 3 or higher, drug-related, TEAEs.

SAEs.

TEAEs leading to dose reduction.

TEAEs leading to discontinuation.

Abnormal laboratory tests.

Abnormal vital sign measurements.
A listing of TEAEs resulting in study drug discontinuation will be provided.
Additional safety analyses may be determined at any time without prejudice to most clearly 
enumerate rates of toxicities and to further define the safety profile of study drugs.
13.2
Interim Analysis and Criteria for Early Termination
No formal interim analysis is planned for this study.
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13.3
Determination of Sample Size
It is anticipated that approximately 100 patients will be enrolled, combining dose escalation for 
determination of MTD and/or RP2D in part A and dose expansion in part B, as well as up to 
25 additional patients will be enrolled in part C imaging substudy.
The mTPI will be used for dose escalation as detailed in Section 8.3. Approximately 25 patients 
with Q3W schedules will be enrolled during part A.
In part B, the sample size is estimated for CRC and gastric cancer separately. For CRC, 
assuming a targeted ORR of 16% with a 2-sided exact 80% CI such that the lower limit is greater 
than 5%, approximately 25 response-evaluable patients will provide close to 60% power to 
observe at least 4 responses, ie, 4/25 = 16%; exact 80% CI (7.2%, 29.5%). For gastric cancer, 
assuming a targeted ORR of 20% with a 2-sided exact 80% CI such that the lower limit is greater 
than 10%, approximately 25 response-evaluable patients will provide close to 60% power to 
observe at least 5 responses, ie, 5/25 = 20%; exact 80% CI (10.1%, 34.0%). Approximately 
50 response-evaluable patients in total need to be enrolled in part B. Additional patients may be 
enrolled based on clinical judgment and the totality of clinical outcomes may be considered.
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ubject to the Applicable Terms of Use
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14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or its 
designee (CRO) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or 
designee (as long as blinding is not jeopardized), including but not limited to the Investigator’s 
Binder, study medication, patient medical records, informed consent documentation, 
documentation of patient authorization to use personal health information (if separate from the 
ICFs), and review of eCRFs and associated source documents. It is important that the 
investigator and other study personnel are available during the monitoring visits and that 
sufficient time is devoted to the process.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study patients. Should other unexpected circumstances arise that will 
require deviation from protocol-specified procedures, the investigator should consult with the 
sponsor or designee (and IRB or IEC, as required) to determine the appropriate course of action. 
There will be no exemptions (a prospectively approved deviation) from the inclusion or 
exclusion criteria.
The site should document all protocol deviations in the patient’s source documents. In the event 
of a significant deviation, the site should notify the sponsor or its designee (and IRB or EC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the patient, or confound interpretation of primary study 
assessment.
The sponsor will assess any protocol deviation; if it is likely to affect to a significant degree the 
safety and rights of a patient or the reliability and robustness of the data generated, it may be 
reported to regulatory authorities as a serious breach of GCP and the protocol.
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 FDA, the United Kingdom Medicines and 
Healthcare products Regulatory Agency, the Pharmaceuticals and Medical Devices Agency of 
Japan). If the study site is contacted for an inspection by a regulatory body, the sponsor should 
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be notified immediately. The investigator and institution guarantee access for quality assurance 
auditors to all study documents as described in Section 14.1.
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15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, patients) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the “Responsibilities of the Investigator” that are listed in 
Appendix B.
The principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities.
15.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable state and federal/local 
requirements of each participating region. The sponsor or designee will require documentation 
noting all names and titles of members who make up the respective IRB or IEC. If any member 
of the IRB or IEC has direct participation in this study, written notification regarding his or her 
abstinence from voting must also be obtained. Those American sites unwilling to provide names 
and titles of all members due to privacy and conflict of interest concerns should instead provide a 
Federal Wide Assurance Number or comparable number assigned by the Department of Health 
and Human Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the IB, a copy of the ICF, and, if 
applicable, patient recruitment materials and/or advertisements and other documents required by 
all applicable laws and regulations, must be submitted to a central or local IRB or IEC for 
approval. The IRB’s or IEC’s written approval of the protocol and patient informed consent must 
be obtained and submitted to the sponsor or designee before commencement of the study (ie, 
before shipment of the sponsor-supplied drug or study-specific screening activity). The IRB or 
IEC approval must refer to the study by exact protocol title, number, and version date; identify 
versions of other documents (eg, ICF) reviewed; and state the approval date. 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 competent authority to begin the 
trial. Until the site receives notification no protocol activities, including screening may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the ICF, recruitment 
materials intended for viewing by patients, local safety reporting requirements, reports and 
updates regarding the ongoing review of the study at intervals specified by the respective IRB or 
IEC, and submission of the investigator’s final status report to IRB or IEC. All IRB and IEC 
approvals and relevant documentation for these items must be provided to the sponsor or its 
designee.
Patient incentives should not exert undue influence for participation. Payments to patients must 
be approved by the IRB or IEC and sponsor.
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15.2
Patient Information, Informed Consent, and Patient Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The ICF, patient authorization form (if applicable), and patient 
information sheet (if applicable) describe the planned and permitted uses, transfers, and 
disclosures of the patient’s personal and personal health information for purposes of conducting 
the study. The ICF and the patient information sheet (if applicable) further explain the nature of 
the study, its objectives, and potential risks and benefits, as well as 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 prior to use.
The ICF, patient authorization form (if applicable), and patient information sheet (if applicable) 
must be written in a language fully comprehensible to the prospective patient. It is the 
responsibility of the investigator to explain the detailed elements of the ICF, patient authorization 
form (if applicable), and patient information sheet (if applicable) to the patient. Information 
should be given in both oral and written form whenever possible and in the manner deemed 
appropriate by the IRB or IEC. In the event the patient is not capable of rendering adequate 
written informed consent, then the patient’s legally acceptable representative may provide such 
consent for the patient in accordance with applicable laws and regulations.
The patient, or the patient’s legally acceptable representative, must be given ample opportunity 
to: (1) inquire about details of the study and (2) decide whether or not to participate in the study. 
If the patient, or the patient’s legally acceptable representative, determines 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 prior to the patient entering into the study. The patient or the patient’s legally 
acceptable representative should be instructed to sign using their legal names, not nicknames, 
using blue or black ballpoint ink. The investigator must also sign and date the ICF and patient 
authorization (if applicable) at the time of consent and prior to patient entering 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.
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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 only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited 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, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the patient’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a patient’s study participation, 
and autopsy reports. Access to a patient’s original medical records requires the specific 
authorization of the patient as part of the informed consent process (see Section 15.2).
Copies of any patient source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, patient name, address, and other identifier fields 
not collected on the patient’s [e]CRF).
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/or 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 
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discrepancy between the protocol and the Clinical Study Site Agreement, the Clinical Study Site 
Agreement will prevail.
15.4.2 Clinical Trial Registration
In order 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 in Takeda Policy/Standard. 
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 to find 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 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.
15.4.3 Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites (including the Takeda corporate site) and registries, as required by Takeda 
Policy/Standard, applicable laws and/or regulations.
15.4.4 Data Sharing
The sponsor is committed to responsible sharing of clinical data with the goal of advancing 
medical science and improving patient care. Qualified independent researchers will be permitted 
to use data collected from patients during the study to conduct additional scientific research, 
which may be unrelated to the study drug or the patient’s disease. The data provided to external 
researchers will not include information that identifies patients personally.
15.5
Insurance and Compensation for Injury
Each patient in the study must be insured in accordance with the regulations applicable to the site 
where the patient is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to clinical study patients. 
Refer to the Clinical Study Site Agreement regarding the sponsor’s policy on patient 
compensation and treatment for injury. If the investigator has questions regarding this policy, he 
or she should contact the sponsor or sponsor’s designee.
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16.0
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infusion in advanced esophageal cancer. Annals of Oncology 2007;18(5):898-902.
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27. Ajani JA. Docetaxel for gastric and esophageal carcinomas. Oncology (Williston Park) 
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bowel. Journal of Surgical Oncology 1992;49(1):29-34.
30. Matsuo S, Eto T, Tsunoda T, Kanematsu T, Shinozaki T. Small bowel tumors: an analysis of 
tumor-like lesions, benign and malignant neoplasms. European Journal of Surgical Oncology 
1994;20(1):47-51.
31. Chow JS, Chen CC, Ahsan H, Neugut AI. A population-based study of the incidence of 
malignant small bowel tumours: SEER, 1973-1990. International Journal of Epidemiology 
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32. Greenlee RT, Murray T, Bolden S, Wingo PA. Cancer statistics, 2000. Ca: a Cancer Journal 
for Clinicians 2000;50(1):7-33.
33. Yeo CJ, Abrams RA, Grochow LB, Sohn TA, Ord SE, Hruban RH, et al. 
Pancreaticoduodenectomy for pancreatic adenocarcinoma: postoperative adjuvant 
chemoradiation improves survival. A prospective, single-institution experience. Annals of 
Surgery 1997;225(5):621-33; discussion 33-6.
34. Yeo CJ. Pancreatic cancer: 1998 update. Journal of the American College of Surgeons 
1998;187(4):429-42.
35. Burris HA, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, et al. 
Improvements in survival and clinical benefit with gemcitabine as first-line therapy for 
patients with advanced pancreas cancer: a randomized trial. Journal of Clinical Oncology 
1997;15(6):2403-13.
36. Rothenberg ML, Moore MJ, Cripps MC, Andersen JS, Portenoy RK, Burris HA, 3rd, et al. A 
phase II trial of gemcitabine in patients with 5-FU-refractory pancreas cancer. Annals of 
Oncology 1996;7(4):347-53.
37. Storniolo AM, Enas NH, Brown CA, Voi M, Rothenberg ML, Schilsky R. An investigational 
new drug treatment program for patients with gemcitabine: results for over 3000 patients 
with pancreatic carcinoma. Cancer 1999;85(6):1261-8.
38. Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, et al. Erlotinib plus 
gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a 
phase III trial of the National Cancer Institute of Canada Clinical Trials Group. Journal of 
Clinical Oncology 2007;25(15):1960-6.
39. Colucci G, Riccardi F, Giuliani F, Lopez M, Gebbia V, Uomo G, et al. Randomized Trial of 
Gemcitabine (GEM) Alone or With Cisplatin (CDDP) in the Treatment of Advanced 
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Pancreatic Cancer (APC): A Phase II Multicenter Study of the Southern Italy Oncology 
Group. Proc Am Soc Clin Oncol; 1999.
40. Poplin E, Feng Y, Berlin J, Rothenberg ML, Hochster H, Mitchell E, et al. Phase III, 
randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate 
infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic 
carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol 
2009;27(23):3778-85.
41. Von Hoff D, Ervin T, Arena F, Chiorean E, Infante J, Moore M, et al. Randomized phase III 
study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with 
metastatic adenocarcinoma of the pancreas (MPACT). J Clin Oncol (ASCO Meeting 
Abstracts) 2013;31(4 suppl):abstr LBA148.
42. Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y, et al. 
FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. New England Journal of 
Medicine 2011;364(19):1817-25.
43. Sohn TA, Lillemoe KD, Cameron JL, Huang JJ, Pitt HA, Yeo CJ. Surgical palliation of 
unresectable periampullary adenocarcinoma in the 1990s. Journal of the American College of 
Surgeons 1999;188(6):658-66; discussion 66-9.
44. Baron TH. Expandable metal stents for the treatment of cancerous obstruction of the 
gastrointestinal tract. New England Journal of Medicine 2001;344(22):1681-7.
45. Li P, Schulz S, Bombonati A, Palazzo JP, Hyslop TM, Xu Y, et al. Guanylyl cyclase C 
suppresses intestinal tumorigenesis by restricting proliferation and maintaining genomic 
integrity. Gastroenterology 2007;133(2):599-607.
46. Vaandrager AB. Structure and function of the heat-stable enterotoxin receptor/guanylyl 
cyclase C. Mol Cell Biochem 2002;230(1-2):73-83.
47. Wolfe HR, Mendizabal M, Lleong E, Cuthbertson A, Desai V, Pullan S, et al. In vivo 
imaging of human colon cancer xenografts in immunodeficient mice using a guanylyl cyclase 
C--specific ligand. J Nucl Med 2002;43(3):392-9.
48. Wolfe HR, Mendizabal M, Lleong E, Cuthbertson A, Desai V, Pullan S, et al. In vivo 
imaging of human colon cancer xenografts in immunodeficient mice using a guanylyl cyclase 
C--specific ligand. Journal of Nuclear Medicine 2002;43(3):392-9.
49. Dijkers EC, Oude Munnink TH, Kosterink JG, Brouwers AH, Jager PL, de Jong JR, et al. 
Biodistribution of 89Zr-trastuzumab and PET imaging of HER2-positive lesions in patients 
with metastatic breast cancer. Clin Pharmacol Ther 2010;87(5):586-92.
50. Gebhart G, Flamen P, De Vries EG, Jhaveri K, Wimana Z. Imaging Diagnostic and 
Therapeutic Targets: Human Epidermal Growth Factor Receptor 2. J Nucl Med 2016;57 
Suppl 1:81s-8s.
51. Deri MA, Zeglis BM, Francesconi LC, Lewis JS. PET imaging with 89Zr: From 
radiochemistry to the clinic. Nuclear Medicine and Biology 2013;40(1):3-14.
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52. Dosimetry NCoR. Nederlandse Commissie voor Stralingsdosimetrie Accessed 09 September
2018. Available at: https://radiationdosimetry.org/ncs/documents/ncs-26-human-exposure-to-
ionising-radiation-for-clinical-and-research-purposes-radiation-dose-risk-.
53. Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0. U.S. Department 
of Health and Human Services National Cancer Institute. 27 Nov 2017.
54. Boellaard R, Delgado-Bolton R, Oyen WJ, Giammarile F, Tatsch K, Eschner W, et al. FDG 
PET/CT: EANM procedure guidelines for tumour imaging: version 2.0. Eur J Nucl Med Mol 
Imaging 2015;42(2):328-54.
55. Common Terminology Criteria for Adverse Events v5. National Institutes of Health, U.S. 
Department of Health and Human Services.
56. Bombardieri E, Giammarile F, Aktolun C, Baum RP, Bischof Delaloye A, Maffioli L, et al. 
131I/123I-metaiodobenzylguanidine (mIBG) scintigraphy: procedure guidelines for tumour 
imaging. Eur J Nucl Med Mol Imaging 2010;37(12):2436-46.
57. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16(1):31-41.
58. E. MN, P. vVFH, C. HM, W. MC, A. LA, R. B. Validation of simplified dosimetry 
approaches in 89 Zr-PET/CT: The use of manual versus semi-automatic delineation methods 
to estimate organ absorbed doses. Medical Physics 2014;41(10):102503.
59. Wahl RL, Jacene H, Kasamon Y, Lodge MA. From RECIST to PERCIST: Evolving 
Considerations for PET response criteria in solid tumors. J Nucl Med 2009;50 Suppl 1:122s-
50s.
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CONFIDENTIAL
Appendix A
Schedules of Events [21-Day Cycle - Q3W Schedule]
Table A-1
Schedule of Events for Parts A and B – Cycles 1 and 2
Screening
Cycles 1 and 2 
Day -21 
to Day -1
Day 1
Predose
Day 1
Postdose
Day 2
Days 3 
and 4
Day 8
Day 15
Day 21
EOT a
Informed Consent b
X
Inclusion/Exclusion Review
X
Demographics
X
Medical History
X
Complete Physical Examination
X
X
Symptom-Directed Physical Examination
X
Height
X
Weight
X
X
X
ECOG Performance Status
X
X
X
X
Vital Signs
X
X
X c
X
X
X
Pregnancy Test d
X
X
X
TAK-164 Administration
X
Concomitant Medications and Procedures
Concomitant medications and procedures will be recorded (eCRF) from signing of the ICF through the EOT visit or 
the start of subsequent antineoplastic therapy, whichever occurs first.
AEs
AEs will be recorded from signing of the ICF through 30 days after last dose of study drug or the start of subsequent 
anticancer therapy, whichever occurs first.
SAEs, AESIs
SAEs and AESIs will be reported from signing of ICF through 30 days after last dose of study drug even if the 
patient starts nonprotocol therapy.
12-Lead ECG e
X
X
X
X
X
X
X
Echocardiography (LVEF)
X f
Continued on next page.
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CONFIDENTIAL
Screening
Cycles 1 and 2 
Day -21 
to Day -1
Day 1
Predose
Day 1
Postdose
Day 2
Days 3 
and 4
Day 8
Day 15
Day 21
EOT a
Samples/Laboratory Assessments
Hematology
X
X g
X g
X g
X
Chemistry
X
X g
X g
X g
X
Coagulation
X
X h
X
X
X
Urinalysis
X
X h
X
Disease Assessment (CT/MRI 
Scan/RECIST)
X
X i
X
AE: adverse event; AESI: adverse event of special interest; ANC: absolute neutrophil count; CT: computed tomography; 
; ECG: electrocardiogram; 
ECOG: Eastern Cooperative Oncology Group; eCRF: electronic case report form; EOT: End-of-Treatment; GCC: guanylyl cyclase C; ICF: informed consent form; LVEF: left 
ventricular ejection fraction; MRI: magnetic resonance imaging; PK: pharmacokinetic; RECIST: Response Evaluation Criteria in Solid Tumors; SAE: serious adverse event.
a The EOT visit will occur approximately 30 days after the last dose of study drug or prior to the start of subsequent antineoplastic therapy.
b Informed consent may be obtained prior to the start of the screening period (Day -21). A separate consent may be obtained for the release of archival tumor tissue for the 
evaluation of GCC expression prior to screening.
c Vital signs will be obtained on Day 1 at 5 and 15 minutes after start of infusion, and upon completion of the infusion for Cycles 1 and 2 (and the following cycles). Every effort 
should be made to obtain vital signs according to these time points. However, a ±3-minute window is acceptable.
d A serum pregnancy test will be obtained for women of childbearing potential at screening and at EOT. The screening results must be available and negative prior to enrollment. A 
urine pregnancy test will be obtained for women of childbearing potential on Day 1 of every cycle and a negative result must be confirmed prior to dosing. Pregnancy tests may 
also be repeated during the study if requested by an IEC/IRB or if required by local regulations.
e A single 12 lead ECG will be collected at screening to assess eligibility. Triplicate 12-lead ECG recordings will be required at the time points specified in Table A-4 and Table A-
5 for part A and B, respectively. See Section 9.4.13 for details.
f LVEFs will be performed during the screening period and every 4 cycles (Cycles 4, 8, and 12, etc).
g Samples may be taken up to 3 days prior to visit. Results must be evaluated prior to dosing. In order for a new cycle of treatment to begin, the patient’s ANC must be ≥1500/mm3
and the platelet count must be ≥100,000/mm3, and the patient’s serum albumin level must be ≥3.0 g/dL.
h May be taken up to 24 hours prior to visit. Results must be evaluated prior to dosing.
I RECIST response assessments will be performed at screening, every 2 treatment cycles (42 days with a window of 3 days in advance), and at the EOT visit. Response assessment 
will be calendar-based regardless of treatment delays/interruptions. If the patient discontinues the study and has had a CT/MRI scan within 2 weeks of the EOT study visit, the 
CT/MRI scan does not need to be repeated. Every effort should be made to maintain the same imaging modality (CT or MRI) throughout the study in each individual patient.
j
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CONFIDENTIAL
Table A-2
Schedule of Events for Parts A and B – Cycles 3+
Subsequent Cycles (Cycles 3+)
Day 1 Predose
Day 1 Postdose
Day 21
(±3 days)
EOT a
PFS FU
Complete Physical Examination
X
X
Symptom-Directed Physical 
Examination
X
Weight
X
ECOG Performance Status
X
X
X
Vital Signs
X
X b
X
X
Pregnancy Test c
X
X
TAK-164 Administration
X d
Concomitant Medications and 
Procedures
Concomitant medications and procedures will be recorded (eCRF) from signing of the ICF through the EOT 
visit or the start of subsequent antineoplastic therapy, whichever occurs first.
AEs
AEs will be recorded from signing of the ICF through 30 days after last dose of study drug or the start of 
subsequent anticancer therapy, whichever occurs first.
SAEs, AESIs
SAEs and AESIs will be reported from signing of ICF through 30 days after last dose of study drug even if the 
patient starts nonprotocol therapy. 
12-Lead ECG e
X
X
Echocardiography (LVEF)
X f
Samples/Laboratory Assessments
Hematology
X g
X
X
Chemistry
X g
X
Coagulation
X h
X
Urinalysis
X h
X
Disease Assessment (CT/MRI 
Scan/RECIST)
X i
X
X
Biomarker/PK Sample 
Collection j
X
X
X
Continued on next page.
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CONFIDENTIAL
AE: adverse event; AESI: adverse event of special interest; ANC: absolute neutrophil count; CT: computed axial tomography; ECG: electrocardiogram; ECOG: Eastern 
Cooperative Oncology Group; eCRF: electronic case report form; EOT: End-of-Treatment; FU: follow-up; ICF: informed consent form; LVEF: left ventricular ejection fraction; 
MRI: magnetic resonance imaging; PFS: Posttreatment Follow-up Assessments; PK: pharmacokinetic; RECIST: Response Evaluation Criteria in Solid Tumors; SAE: serious 
adverse events.
a The EOT visit will occur approximately 30 days after the last dose of study drug or prior to the start of subsequent antineoplastic therapy.
b Vital signs will be obtained on Day 1 at 5 and 15 minutes after start of infusion, and upon completion of the infusion for Cycles 3 and beyond. Every effort should be made to 
obtain vital signs according to these time points. However, a ± 3-minute window is acceptable.
c A serum pregnancy test will be obtained for women of childbearing potential at screening and at EOT. The screening results must be available and negative prior to enrollment. A 
urine pregnancy test will be obtained for women of childbearing potential on Day 1 of every cycle and a negative result must be confirmed prior to dosing. Pregnancy tests may 
also be repeated during the study if requested by an IEC/IRB or if required by local regulations.
d A window of ±3 days will be permitted.
e Triplicate 12-lead ECG recordings will be required at the time points specified in Table A-4 and Table A-5 for part A and B, respectively. Beginning Cycle 6, a single 12-lead 
ECG is required predose. Patients should be in supine rest position for at least 5 minutes before the initiation of the ECG(s).
f LVEFs will be performed during the screening period and every 4 cycles (Cycles 4, 8, and 12, etc.).
g Samples may be taken up to 3 days prior to visit. Results must be evaluated prior to dosing. For a new cycle of treatment to begin, the patient’s ANC must be ≥1500/mm3 and the 
platelet count must be ≥100,000/mm3, and the patient’s serum albumin level must be ≥3.0 g/dL.
h May be taken up to 24 hours prior to visit. Results must be evaluated prior to dosing.
i RECIST response assessments will be performed at screening, every 2 treatment cycles (42 days with a window of 3 days in advance), and at the EOT visit. Response assessment 
will be calendar-based regardless of treatment delays/interruptions. If the patient discontinues the study and has had a CT/MRI scan within 2 weeks of the EOT study visit, the 
CT/MRI scan does not need to be repeated.
j Refer to Table A-3, Table A-4, and Table A-5 for full details on the part A and B Biomarker/ PK sample collection schema.
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CONFIDENTIAL
Table A-3
Biomarker Sample Collection for Parts A and B
Screening
Cycles 1 and 2
Cycles 3+
Day -21 
to Day -1
Day 1
Predose
Day 1
Postdose
Day 2
Day 3
Day 4
Day 8
Day 15
Day 1 
Predose
Day 1 
Postdose
EOT a
Fresh Tumor Tissue 
Biopsy sample b
X c
X c,d
X b
Archival (Banked) 
Tumor Tissue Sample e
X
Buccal Epithelial Cells 
Sample for DNA
X f
Serum Sample for 
Pharmacodynamics
X
X
X g
X
Serum Sample for 
Protein (Local)
X
X h
X i
Plasma Sample for 
TAK-164 PK k
X
X
X l
X l
X l
X
X
X
X
Plasma Sample for 
FGN849 and s-FGN849 
PK k
X
X
X l
X l
X l
X
X
X
X
Serum Sample for 
Immunogenicity
X n
X n
X n
X
Continued on next page.
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-Comme
Only and Subject to the Applicable Terms of Use
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Day 1
Day 1
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CONFIDENTIAL
ADA: antidrug antibody; 
; EOT: end-of-treatment; FGN849: free payload for TAK-164; GCC: guanylyl cyclase C; IHC: immunohistochemistry; PK: 
pharmacokinetics; s FGN849: sulfonated FGN849.
a The EOT visit will occur approximately 30 days after the last dose of study drug or prior to the start of subsequent antineoplastic therapy.
b Fresh tumor biopsies may be collected from consenting patients who achieve at least a partial response and then subsequently relapse, if considered advisable by the treating 
physician. Optionally, tumor biopsies from consenting patients who do not achieve a response and experience progression could be collected also, if considered advisable by the 
treating physician.
c Paired tumor tissue biopsies (pre- and postdose) are required in a minimum of approximately 5 patients. The specific anatomical location of the biopsy before resection must be 
specified.
d Cycle 2 Day 8 (+4 days) only.
e If archival tissue is not available for GCC evaluation by IHC, as assessed by a central laboratory, the patient may consent to provide biopsy tissue.
f Cycle 1 only.
g Cycle 3 only.
h Cycle 2 only.
i To be taken on Cycle 3 and then every other cycle after (Cycle 5, Cycle 7, etc).
j Cycle 5 only.
k PK blood draws will be performed according to the schedule presented in Table A-4 and Table A-5 for part A and B, respectively.
l Applicable to part A, only.
m
 
.
n ADA samples are taken predose on Day 1 of every cycle; an additional Day 15 sample will be taken for Cycle 1 only (no other cycles).
Property of Takeda: For Non-Commercial Use 
 and Subject to the Applicable Terms of Use
Te
lase C; IH
lase C; 
therapy.
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relapse, i
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CCI
CCI


TAK-164
Study No. TAK-164-1001
Page 110 of 150
Protocol Amendment 05
04 September2019
CONFIDENTIAL
Table A-4
Serial PK and ECG Collection Schedule for Part A
Cycle 1 And Cycle 2
Day 1
Day 2
Day 3
Day 4
Day 8
Day 15
Triplicate 
ECG a,b
PK c
Triplicate 
ECG a,b
PK c
Triplicate 
ECG a,b
PK c
Triplicate 
ECG a,b
PK c
Triplicate 
ECG a,b
PK c
Triplicate 
ECG a,b,d
PK c,d
Predose (within 60 min 
before start of infusion)
X3
X1
EOI e
X3
X1
1 hour after EOI (10 min)
X3
X1
2 hours after EOI (20 min)
X3
X1
4 hours after EOI (30 min)
X3
X1
6 hours after EOI (30 min)
X3
X1
24 hours after EOI (2 hour)
X3
X1
48 hours after EOI (2 hour)
X3
X1
72 hours after EOI (4 hour)
X3
X1
168 hours after EOI (6 hour)
X3
X1
336 hours after EOI (6 hour)
X3
X1
Cycle 3 and Beyond
Predose (within 60 min 
before start of infusion)
X3 f
X1
EOI e
X3 f
X1
Continued on next page.
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Study No. TAK-164-1001
Page 111 of 150
Protocol Amendment 05
04 September2019
CONFIDENTIAL
ECG: electrocardiogram; EOI: end of infusion; FGN849: free payload for TAK-164; PK: pharmacokinetic; s-FGN849: sulfonated FGN849.
a Triplicate 12-lead ECG measurements are to be performed with the patient in supine position. Patients should have been in supine rest position for at least 5 minutes prior to 
initiation of ECG collections. Each ECG measurement of the triplicate collection should be recorded at 2- to 3-minute intervals.
When the timing of a PK or safety laboratory blood sample coincides with the timing of ECG measurements, the ECG will be completed before the collection of the blood sample. 
The triplicate ECG measurements should be completed immediately before the corresponding PK blood draw.
b The triplicate ECG collections can also be used as safety ECGs when the collections times for these ECGs coincide.
c Blood samples for plasma sample for TAK-164, FGN849, and s-FGN849 PK should be taken from the contralateral arm to that used for the TAK-164 infusion. Refer to 
laboratory manual for further instructions. 
d Triplicate ECG and PK collections of Cycle 1 Day 15 and Cycle 2 Day 15 correspond to 336 hours after Cycle 1 Day 1 and Cycle 2 Day 1 infusions, respectively.
e At EOI, the collection of triplicate ECG should be initiated within 5 min prior to completion of TAK-164 infusion (i.e. not 5 min prior to EOI line flush). Each triplicate ECG 
should be collected at 2-3 min intervals with all 3 ECGs collected within a total 10 min window (i.e.,5 min prior to completion of TAK-164 infusion and 5 min after completion of 
TAK-164 infusion). The EOI PK sample should be collected immediately after the third ECG has been collected. EOI PK is in relation to TAK-164 infusion and not infusion line 
flush.
f Triplicate ECGs on Cycle 3 and beyond will be collected up to and including Cycle 5.
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Study No. TAK-164-1001
Page 112 of 150
Protocol Amendment 05
04 September2019
CONFIDENTIAL
Table A-5
Part B Sparse PK and ECG Collection
Cycle 1 and Cycle 2
Day 1
Day 8
Day 15
Triplicate ECG a,b
PK c
Triplicate ECG a,b
PK c
Triplicate ECG a,b,d
PK c,d
Predose (within 60 min before start 
of infusion)
X3
X1
EOI e
X3
X1
1-2 hours after EOI
X3
X1
168 hours after EOI (±6 h)
X3
X1
336 hours after EOI (±6 h)
X3
X1
Cycle 3 and Beyond
Predose (within 60 min before start 
of infusion)
X3 f
X1
EOI e
X3 f
X1
ECG: electrocardiogram; EOI: end of infusion; IV: intravenous; PK: pharmacokinetics.
When TAK164 is administered via a peripheral vein, blood samples for PK should be collected from the arm contralateral (ie, opposite) to the arm used for IV infusion.
When the timing of a PK or safety laboratory blood sample coincides with the timing of ECG measurements, the ECG will be completed before the collection of the blood sample. 
The triplicate ECG measurements should be completed immediately before the corresponding PK blood draw.
a Triplicate 12-lead ECG measurements are to be performed with the patient in supine position. Patients should have been in supine rest position for at least 5 min before initiation 
of ECG collections. Each ECG measurement of the triplicate collection should be recorded at 2- to 3-minute intervals.
b The triplicate ECG collections can also be used as safety ECGs when the collections times for these ECGs coincide.
c Blood samples for PK should be taken from the contralateral arm to that used for the TAK-164 infusion. Refer to laboratory manual for further instructions.
d Triplicate ECG and PK collections of Cycle 1 Day 15 and Cycle 2 Day 15 correspond to 336 hours after Cycle 1 Day 1 and Cycle 2 Day 1 infusions, respectively.
e At EOI, the collection of triplicate ECG should be initiated within 5 min prior to completion of TAK-164 infusion (i.e. not 5 min prior to EOI line flush). Each triplicate ECG 
should be collected at 2-3 min intervals with all 3 ECGs collected within a total 10 min window (i.e., 5 min prior to completion of TAK-164 infusion and 5 min after completion of 
TAK-164 infusion). The EOI PK sample should be collected immediately after the third ECG has been collected. EOI PK is in relation to TAK-164 infusion and not infusion line 
flush.
f Triplicate ECGs on Cycle 3 and beyond will be collected up to and including Cycle 5.
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TAK-164
Study No. TAK-164-1001
Page 113 of 150
Protocol Amendment 05
04 September2019
CONFIDENTIAL
Table A-6
Part C (Imaging Substudy, DIO Patients Only) Schedule of Events for 14-Day Run-in Period
Screening
Day -14
Predose
Run-in Period: Day -14 to Day -1
Day -21 
to Day -15
Day -14
Postdose
Day -12
(-13 to -11)
Day -10
(-10 to -8)
Day -7
Informed consent a
X
Inclusion/exclusion review
X
Demographics
X
Medical history
X
Complete physical exam
X
Symptom-directed physical exam 
X
Height
X
Weight 
X
X
ECOG performance status 
X
X
Vital signs 
X
X
X b
X
Pregnancy test c
X
X
89Zr-TAK-164 administration
X d
Concomitant medications and procedures
Concomitant medications and procedures will be recorded (eCRF) from signing of the ICF through the 
EOT visit or the start of subsequent antineoplastic therapy, whichever occurs first.
AEs
AEs will be recorded from signing of the ICF through 30 days after last dose of study drug or the start of 
subsequent anticancer therapy, whichever occurs first.
SAEs, AESIs
SAEs and AESIs will be reported from signing of the ICF through 30 days after last dose of study drug 
even if the patient starts nonprotocol therapy.
12-Lead ECG e
X
X
X
89Zr-TAK-164 PET scan
X f
X g
X g
18F-FDG-PET h
X
Disease assessment (CT/MRI scan/RECIST)
X
Hematology
X
X i
X i
Chemistry
X
X i
X i
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TAK-164
Study No. TAK-164-1001
Page 114 of 150
Protocol Amendment 05
04 September2019
CONFIDENTIAL
Screening
Day -14
Predose
Run-in Period: Day -14 to Day -1
Day -21 
to Day -15
Day -14
Postdose
Day -12
(-13 to -11)
Day -10
(-10 to -8)
Day -7
Coagulation
X
X j
X j
Urinalysis
X
X j
Archival (banked) tumor tissue sample
X k
Fresh Tumor Tissue Biopsy sample
X k
Buccal Epithelial Cells Sample for DNA
X
Serum sample for Pharmacodynamics
X
Plasma sample for TAK-164 PK l
X
X 
X
X
Plasma sample for FGN849 and s-FGN849 PK l
X
X
X
X
18F-FDG: 18-fluorodeoxyglucose; 89Zr: zirconium-89; AE: adverse event; AESI: adverse event of special interest; CT: computed tomography; DIO: dosimetry and imaging 
optimization; ECG: electrocardiogram; ECOG: Eastern Cooperative Oncology Group; eCRF: electronic case report form; EOT: End-of-Treatment; FGN849: free payload for 
TAK-164; GCC: guanylyl cyclase C; ICF: informed consent form; IHC: immunohistochemistry; MRI: magnetic resonance imaging; PET: positron emission tomography; PK: 
pharmacokinetic; RECIST: Response Evaluation Criteria in Solid Tumors; SAE: serious adverse event; s-FGN849; sulfonated free payload for TAK-164.
a Informed consent may be obtained before the start of the screening period (Day -21). A separate consent may be obtained for the release of archival tumor tissue for the 
evaluation of GCC expression before screening.
b Vital signs will be obtained on Day -14 at 5 and 15 minutes after start of infusion, and upon completion of the infusion. Every effort should be made to obtain vital signs 
according to these time points; however, a ±3-minute window is acceptable.
c A serum pregnancy test will be obtained for women of childbearing potential at screening and at EOT. The screening results must be available and negative before enrollment. A 
urine pregnancy test will be obtained for women of childbearing potential on Day -14, and a negative result must be confirmed before dosing. Pregnancy tests may also be repeated 
during the study if requested by an independent ethics committee/institutional review board or if required by local regulations.
d 89Zr-labeled TAK-164. Record infusion start and stop times and amount of administered in eCRF.
e A single 12-lead ECG will be collected at screening to assess eligibility. Triplicate 12-lead ECG recordings will be required at the time points specified in Table A-10.
f 1 hour after the EOI of the 89Zr-labeled TAK-164. Dosimetry patients only.
g Imaging window maybe adjusted for imaging optimization purposes.
h Patients are required to fast for 6 hours before the FDG radiotracer injection.
i Samples may be taken ≤3 days before visit.
j May be taken ≤24 hours before visit. Results must be evaluated before dosing.
k If archival tissue is not available for GCC evaluation by IHC as assessed by a central laboratory, the patient may consent to provide biopsy tissue.
l Refer to Table A-10 for full details on the PK sample collection scheme.
Property of Takeda: For Non-Commercial Use Only a
bject to the Applicable Terms of Use
Te
able 
riod: Da
iod: D
e
icab
Day 
Day -12
1
pplic
(-(-13 to
13 t
ab
App
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A
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to th
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to
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bjbj
a
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Only
X
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Group; eC
Group; e
munohisto
unohis
; SAE: se
SAE: 
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start o
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details
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TAK-164
Study No. TAK-164-1001
Page 115 of 150
Protocol Amendment 05
04 September2019
CONFIDENTIAL
Table A-7
Part C (Imaging Substudy) Schedule of Events for Cycle 1
Screening †
Day 1
Predose
Cycle 1 
EOT a
PFS FU b
Day -21 
to Day -1
Day 1
Postdose
Day 3
(Day 2 to 
Day 4)
Day 5
(Day 5 to 
Day 7)
Day 8
Day 15
Informed consent c
X d
Inclusion/exclusion review
X d
Demographics
X d
Medical history
X d
Complete physical exam
X d
X
X
Symptom-directed physical exam 
X
Height
X d
Weight 
X
X
X
ECOG performance status 
X
X
X
X
X
Vital signs 
X
X
X e
X
X
X
X
X
Pregnancy test f
X
X
X
89Zr-TAK-164 administration
X g
TAK-164 administration
X h
X i
Concomitant medications and 
procedures
Concomitant medications and procedures will be recorded (eCRF) from signing of the ICF through the 
EOT visit or the start of subsequent antineoplastic therapy, whichever occurs first.
AEs
AEs will be recorded from signing of the ICF through 30 days after last dose of study drug or the start of 
subsequent anticancer therapy, whichever occurs first.
SAEs, AESIs
SAEs and AESIs will be reported from signing of ICF through 30 days after last dose of study drug even if 
the patient starts nonprotocol therapy.
12-Lead ECG j
X
X
X
X
X
89Zr-TAK-164 PET scan
X
X
18F-FDG-PET k
X d
Disease assessment (CT/MRI 
scan/RECIST)
X d
X l
X l
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TAK-164
Study No. TAK-164-1001
Page 116 of 150
Protocol Amendment 05
04 September2019
CONFIDENTIAL
Screening †
Day 1
Predose
Cycle 1 
EOT a
PFS FU b
Day -21 
to Day -1
Day 1
Postdose
Day 3
(Day 2 to 
Day 4)
Day 5
(Day 5 to 
Day 7)
Day 8
Day 15
Hematology
X
X m
X m
X m
X
X
Chemistry
X
X m
X m
X m
X
Coagulation
X
X n
X n
X n
X
Urinalysis
X
X n
X
Fresh tumor tissue biopsy sample
X o,d
Archival (banked) tumor tissue sample
X p,d
Buccal Epithelial Cells Sample for 
DNA
X d
Serum samples for pharmacodynamics
X
X
X
Plasma sample for TAK-164 PK 
X
X
X
X
X
X
Plasma sample for FGN849 and 
s-FGN849 PK q
X
X
X
X
X
X
Serum sample for immunogenicity
X
X
X
18F-FDG: 18-fluorodeoxyglucose; 89Zr: zirconium-89; AE: adverse event; AESI: adverse event of special interest; CT: computed tomography; DIO: dosimetry and imaging 
optimization; ECG: electrocardiogram; ECOG: Eastern Cooperative Oncology Group; eCRF: electronic case report form; EOT: End-of-Treatment; FGN849: free payload for 
TAK-164; FU: follow-up; GCC: guanylyl cyclase C; ICF: informed consent form; IHC: immunohistochemistry; MRI: magnetic resonance imaging; PET: positron emission 
tomography; PFS: progression-free survival; PK: pharmacokinetic; RECIST: Response Evaluation Criteria in Solid Tumors; RID: recommended imaging dose; SAE: serious 
adverse event; s-FGN849: sulfonated free payload for TAK-164.
† DIO patients have already completed some screening events or events do not apply to them, as indicated in footnote (d).
a The EOT visit will occur approximately 30 days after the last dose of study drug or before the start of subsequent antineoplastic therapy.
b Performed at 3-month intervals.
c Informed consent may be obtained before the start of the screening period (Day -21). A separate consent may be obtained for the release of archival tumor tissue for the 
evaluation of GCC expression before screening.
d Excluding DIO patients.
e Vital signs will be obtained on Day 1 at 5 and 15 minutes after start of infusion, and upon completion of the infusion. Every effort should be made to obtain vital signs according 
to these time points; however, a ±3-minute window is acceptable.
f A serum pregnancy test will be obtained for women of childbearing potential at screening and at EOT. The screening results must be available and negative before enrollment. A 
Property of Takeda: For Non-Comme
m
al
ly and Subject to the Applicable Terms of Use
Te
able 
e
A plicab
App
Day
Da
b
ab
Ap
b
A
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Ap
Ap
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n Day 
ver, a ±3
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b
CCI


TAK-164
Study No. TAK-164-1001
Page 117 of 150
Protocol Amendment 05
04 September2019
CONFIDENTIAL
urine pregnancy test will be obtained for women of childbearing potential on Day 1 of every cycle, and a negative result must be confirmed before dosing. Pregnancy tests may 
also be repeated during the study if requested by an independent ethics committee/institutional review board or if required by local regulations.
g 89Zr-labeled TAK-164 will be administered within 2 h post end of infusion of unlabeled TAK-164. Record time and amount of administration in eCRF.
h Patients in the DIO group will receive 89Zr-TAK-164 in combination with variable amounts of unlabeled TAK-164 at a maximum dose ≤RID. Subsequent patients receive 
unlabeled TAK-164 as determined for optimal imaging. Record infusion start and stop times and amount of administered in eCRF.
i Administration of additional unlabeled TAK-164, if necessary to achieve a full dose (record time and amount of administration in eCRF), following the 89Zr PET acquisition.
j A single 12-lead ECG will be collected at screening to assess eligibility. Triplicate 12-lead ECG recordings will be required at the time points specified in Table A-10.
k Patients are required to fast for 6 hours before the FDG radiotracer injection.
l Patients who progress will not have further CT (nor EOT or PFS FU).
m To be collected ≤3 days before visit.
n May be taken ≤24 hours before visit. Results must be evaluated before dosing.
o Pre- and post-treatment biopsies required in approximately 3 patients. The predose biopsies may be taken during screening or on Cycle 1 Day 1 predose. The specific anatomical 
location of the biopsy before resection must be specified.
p If archival tissue is not available for GCC evaluation by IHC, as assessed by a central laboratory, the patient may consent to provide biopsy tissue.
q Refer to Table A-10 for full details on the PK sample collection scheme.
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TAK-164
Study No. TAK-164-1001
Page 118 of 150
Protocol Amendment 05
04 September2019
CONFIDENTIAL
Table A-8
Part C (Imaging Substudy) Schedule of Events for Cycle 2
Cycle 2
EOT a
PFS FU b
Day 1
Predose
Day 1
Postdose
Day 8
(±3 days)
Day 12
(±1 Day)
Day 15
(±3 days)
Day 21
(±3 days)
Complete physical 
exam
X
X
Symptom-directed 
physical exam 
X
Weight 
X
X
X
ECOG performance 
status
X
X
X
Vital signs 
X
X c
X
X
X
Pregnancy test d
X
X
TAK-164 
administration
X
Concomitant 
medications and 
procedures
Concomitant medications and procedures will be recorded (eCRF) from signing of the ICF through the EOT visit or the start of 
subsequent antineoplastic therapy, whichever occurs first.
AEs
AEs will be recorded from signing of the ICF through 30 days after last dose of study drug or the start of subsequent anticancer therapy, 
whichever occurs first.
SAEs, AESIs
SAEs and AESIs will be reported from signing of ICF through 30 days after last dose of study drug even if the patient starts nonprotocol 
therapy.
12-Lead ECG e
X
X
X
X
18F-FDG-PET f
X g
Disease assessment 
(CT/MRI 
scan/RECIST)
X h
X h
X h
Hematology
X i
X 
X
X
X
Chemistry
X i
X 
X
X
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TAK-164
Study No. TAK-164-1001
Page 119 of 150
Protocol Amendment 05
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CONFIDENTIAL
Cycle 2
EOT a
PFS FU b
Day 1
Predose
Day 1
Postdose
Day 8
(±3 days)
Day 12
(±1 Day)
Day 15
(±3 days)
Day 21
(±3 days)
Coagulation
X j
X j
X j
X
Urinalysis
X j
X
Fresh tumor tissue 
biopsy sample
X k
Serum sample for 
pharmacodynamics
X
X
X
Plasma sample for 
TAK-164 PK l
X
X
X
X
Plasma sample for 
FGN849 and s-
FGN849 PK l
X
X
X
X
Serum sample for 
immunogenicity
X
X
18F-FDG: 18-fluorodeoxyglucose; AE: adverse event; AESI: adverse event of special interest; CT: computed tomography; DIO: dosimetry and imaging optimization; ECG: 
electrocardiogram; ECOG: Eastern Cooperative Oncology Group; eCRF: electronic case report form; EOT: End-of-Treatment; FGN849: free payload for TAK-164; FU: follow-
up; ICF: informed consent form; MRI: magnetic resonance imaging; PET: positron emission tomography; PFS: progression-free survival; PK: pharmacokinetic; RECIST: 
Response Evaluation Criteria in Solid Tumors; SAE: serious adverse event; s-FGN849: sulfonated free payload for TAK-164.
a The EOT visit will occur approximately 30 days after the last dose of study drug or before the start of subsequent antineoplastic therapy.
b Performed at 3-month intervals.
c Vital signs will be obtained on Day 1 at 5 and 15 minutes after start of infusion, and upon completion of the infusion. Every effort should be made to obtain vital signs according 
to these time points; however, a ±3-minute window is acceptable.
d A serum pregnancy test will be obtained for women of childbearing potential at screening and at EOT. A urine pregnancy test will be obtained for women of childbearing 
potential on Day 1 of every cycle, and a negative result must be confirmed before dosing. Pregnancy tests may also be repeated during the study if requested by an independent 
ethics committee/institutional review board or if required by local regulations.
e Triplicate 12-lead ECG recordings will be required at the time points specified in Table A-10.
f Patients are required to fast for 6 hours before the FDG radiotracer injection.
g For patients who provide a fresh tumor biopsy in Cycle 2, the 18F-FDG-PET image is to be acquired before the biopsy. The specific anatomical location of the biopsy before 
resection must be specified.
Property of Takeda: For Non-Commercial Use Only
bject to the Applicable Terms of Use
Te
e
Day 21
Day 21
(±3 day
(±3 da
ab
pp
A
e A
th
ct
O
se
ia
m
erse even
rse ev
oup; eCR
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imaging;
magin
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ous adv
er the last
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15 minut
15 minu
window is
ndow 
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a fresh tu
fresh
ied.
ed.
CCI


TAK-164
Study No. TAK-164-1001
Page 120 of 150
Protocol Amendment 05
04 September2019
CONFIDENTIAL
h RECIST response assessments will be performed at screening, every 2 treatment cycles (42 days with a window of 3 days in advance), and at the EOT visit. Response assessment 
will be calendar-based regardless of treatment delays/interruptions. If the patient discontinues the study and had a CT/MRI scan within 2 weeks of the EOT study visit, the 
CT/MRI scan does not need to be repeated. Every effort should be made to maintain the same imaging modality (CT or MRI) throughout the study in each individual patient. 
Patients who progress will not have further CT (nor EOT or PFS).
I To be collected ≤3 days before visit.
j May be taken up to 24 hours before visit. Results must be evaluated before dosing.
k Pre- and post-treatment biopsies are required in a minimum of approximately 3 patients, excluding patients in the DIO. The predose biopsies will be requested to be taken on Day 
-21 to Day 1 predose. Also, the postdose biopsies will be requested to be taken after the PET scan scheduled for Cycle 2 Day 12 (±1 day). The specific anatomical location of the 
biopsy before resection must be specified.
l Refer to Table A-10 for full details on the PK sample collection scheme.
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TAK-164
Study No. TAK-164-1001
Page 121 of 150
Protocol Amendment 05
04 September2019
Table A-9
Part C (Imaging Substudy) Schedule of Events for Cycle 3+ (21-Day Cycle)
Cycle 3+ 
EOT a
PFS FU
Day 1
Predose
Day 1
Postdose
Day 21
(±3 days)
Complete physical exam
X
X
Symptom-directed physical 
exam 
X
Weight 
X
ECOG performance status 
X
X
X
Vital signs 
X
X b
X
X
Pregnancy test c
X
X
TAK-164 administration
X
Concomitant medications and 
procedures
Concomitant medications and procedures will be recorded (eCRF) 
from signing of the ICF through the EOT visit or the start of 
subsequent antineoplastic therapy, whichever occurs first.
AEs
AEs will be recorded from signing of the ICF through 30 days 
after last dose of study drug or the start of subsequent anticancer 
therapy, whichever occurs first.
SAEs, AESIs
SAEs and AESIs will be reported from signing of ICF through 30 
days after last dose of study drug even if the patient starts 
nonprotocol therapy.
12-Lead ECG d
X
X
18F-FDG-PET e
X f
Disease assessment 
(CT/MRI scan/RECIST)
X g,h
X h
X h
Hematology
X i
X
X
Chemistry
X i
X
Coagulation
X j
X
Urinalysis
X j
X
Serum sample for 
pharmacodynamics
X k
X
Plasma sample for TAK-164 
PK m
X
X
Plasma sample for FGN849 
and s-FGN849 PK m
X
X
Serum sample for 
immunogenicity
X
X
18F-FDG: 18-fluorodeoxyglucose; AE: adverse event; AESI: adverse event of special interest; CR: complete response; CT: 
computed axial tomography; ECG: electrocardiogram; ECOG: Eastern Cooperative Oncology Group; eCRF: electronic case 
report form; EOT: End-of-Treatment; FGN849: free payload for TAK-164; FU: follow-up; ICF: informed consent form; MRI: 
magnetic resonance imaging; PET: positron emission tomography; PFS: progression-free survival; PK: pharmacokinetic; PR: 
pert
erty 
Plasm
Plas
er
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partial response; RECIST: Response Evaluation Criteria in Solid Tumors; SAE: serious adverse event; s-FGN849: sulfonated 
free payload for TAK-164.
a The EOT visit will occur approximately 30 days after the last dose of study drug or before the start of subsequent antineoplastic 
therapy.
b Vital signs will be obtained on Day 1 at 5 and 15 minutes after start of infusion, and upon completion of the infusion. Every 
effort should be made to obtain vital signs according to these time points; however, a ±3-minute window is acceptable.
c A serum pregnancy test will be obtained for women of childbearing potential at EOT. A urine pregnancy test will be obtained 
for women of childbearing potential on Day 1 of every cycle, and a negative result must be confirmed before dosing. Pregnancy 
tests may also be repeated during the study if requested by an independent ethics committee/institutional review board or if 
required by local regulations.
d Triplicate 12-lead ECG recordings will be required at the time points specified in Table A-10.
e Patients are required to fast for 6 hours before the FDG radiotracer injection.
f For patients with stable disease or response (CR or PR) according to RECIST 1.1 Cycle 4 Day 21 (-3 days).
g RECIST response assessments will be performed at screening, every 2 treatment cycles (42 days with a window of 3 days in 
advance), and at the EOT visit. Response assessment will be calendar-based regardless of treatment delays/interruptions. If the 
patient discontinues the study and had a CT/MRI scan within 2 weeks of the EOT study visit, the CT/MRI scan does not need to 
be repeated. Every effort should be made to maintain the same imaging modality (CT or MRI) throughout the study in each 
individual patient.
h Following documented progression, patients will not have further CT (nor EOT or PFS).
I Samples may be taken up to 3 days before visit.
j May be taken up to 24 hours before visit. Results must be evaluated before dosing.
k Cycle 3 only.
l Cycle 5 only.
m Refer to Table A-10 for full details on the PK sample collection scheme.
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CONFIDENTIAL
Table A-10
Part C Sparse PK and ECG Collection
Run-in Period g
Day -14
Day -12
(-13 to -11)
Day -10
(-10 to -8)
Day 1
Day 3 a
Day 5 b
Day 8 c
Day 15 d
Triplicate 
ECG e
PK f
PK f
PK f
Triplicate 
ECG e
PK f
PK f
PK f
Triplicate 
ECG e
PK f
Triplicate 
ECG e
PK f
Predose (within 60 min 
before start of infusion)
X3
X1
EOI h
X3
X1
Pre-imaging (within 60 
min before start of 
imaging)
X1 i
X1 i
Cycle 1 and Cycle 2
Predose (within 60 min 
before start of infusion)
X3
X1
EOI h
X3
X1
1-2 hours after EOI
X3
X1
Pre-imaging (within 60 
min before start of 
imaging)
X1 i
X1 i
168 hours after EOI j
X3
X1
336 hours after EOI k
X3
X1
Cycle 3 and Beyond
Predose (within 60 min 
before start of infusion)
X3 l
X1
EOI h
X3 l
X1
89Zr: zirconium-89; DIO: dosimetry and imaging optimization; ECG: electrocardiogram; EOI: end of infusion; FGN849: free payload for TAK-164; IV: 
intravenous; PET: positron emission tomography; PK: pharmacokinetics; s-FGN849: sulfonated free payload for TAK-164.
When the timing of a PK or safety laboratory blood sample coincides with the timing of ECG measurements, the ECG will be completed before the collection of 
the blood sample. The triplicate ECG measurements should be completed immediately before the corresponding PK blood draw.
a Day 3 (Days 2 to 4) for Cycle 1 only, no samples collected for Cycle 2.
b Day 5 (Days 5 to 7) for Cycle 1 only; no samples collected for Cycle 2.
c Day 8 for Cycle 1; Day 8 (±3 days), for Cycle 2.
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CONFIDENTIAL
d Day 15 for Cycle 1; Day 15 (±3 days), for Cycle 2.
e Triplicate 12-lead ECG measurements are to be performed with the patient in supine position. Patients should have been in supine rest position for at least 5 min 
before initiation of ECG collections. Each ECG measurement of the triplicate collection should be recorded at 2- to 3-minute intervals. The triplicate ECG 
collections can also be used as safety ECGs when the collections times for these ECGs coincide.
f Blood samples for TAK-164, FGN849, and s-FGN849 PK should be taken from the contralateral arm to that used for the TAK-164 infusion. Refer to laboratory 
manual for further instructions.
g Only applies to DIO patients.
h At EOI, the collection of triplicate ECG should be initiated within 5 min prior to completion of TAK-164 infusion (i.e. not 5 min prior to EOI line flush). Each 
triplicate ECG should be collected at 2-3 min intervals with all 3 ECGs collected within a total 10 min window (i.e., 5 min prior to completion of TAK-164 
infusion and 5 min after completion of TAK-164 infusion). The EOI PK sample should be collected immediately after the third ECG has been collected. EOI PK 
is in relation to TAK-164 infusion and not infusion line flush.
i Within 60 min before start 89Zr-TAK-164 PET scan.
j Day 8 PK sample should be taken at 168 hours after EOI (±6 h) for Cycle 1, and 168 hours after EOI (±72 h) for Cycle 2.
k Day 15 PK sample should be taken at 336 hours after EOI (±6 h) for Cycle 1, and 336 hours after EOI (±72 h) for Cycle 2.
l Triplicate ECGs on Cycle 3 and beyond will be collected up to and including Cycle 5.
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Appendix B
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations.
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff who will assist in the protocol.
3. If the investigator/institution retains the services of any individual or party to perform trial-
related duties and functions, the investigator/institution should ensure that this individual or 
party is qualified to perform those trial-related duties and functions and should implement 
procedures to ensure the integrity of the trial-related duties and functions performed and any 
data generated.
4. Ensure that study-related procedures, including study specific (nonroutine/nonstandard 
panel) screening assessments are NOT performed on potential patients, prior to 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 CFR Part 56, ICH, and local regulatory requirements.
7. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and 
approval of the protocol. Promptly report to the IRB/IEC all changes in research activity and 
all anticipated risks to patients. Make at least yearly reports on the progress of the study to 
the IRB/IEC and issue a final report within 3 months of study completion.
8. Ensure that requirements for informed consent, as outlined in CFR Part 50, ICH and local 
regulations, are met.
9. Obtain valid informed consent from each patient who participates in the study and document 
the date of consent in the patient’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each ICF should contain a patient authorization section 
that describes the uses and disclosures of a patient’s personal information (including personal 
health information) that will take place in connection with the study. If an ICF does not 
include such a patient authorization, then the investigator must obtain a separate patient 
authorization form from each patient or the patient’s legally acceptable representative.
10. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents.
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11. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
12. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor.
13. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.
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Appendix C
Investigator Consent to Use of Personal Information
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, US, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
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 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.
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 investigator’s 
own country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.
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Appendix D
ECOG Scale for Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all predisease performance without restriction.
1
Symptoms but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to 
carry out work of a light or sedentary nature (eg, light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry out any work 
activities. Up and about more than 50% of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more than 50% 
of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair.
5
Dead.
Source: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response 
criteria of the Eastern Cooperative Oncology Group. American Journal of Clinical Oncology 1982;5(6):649-55.
ECOG: Eastern Cooperative Oncology Group.
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Appendix E
Inhibitors and Inducers
Note that the list of strong CYP3A inhibitors or inducers is not exhaustive and is based on the 
FDA Draft DDI Guidance (Sources: fda.gov/downloads/Drugs/Guidance Compliance Regulatory 
Information/Guidances/UCM292362.pdf and fda.gov/Drugs/Development Approval 
Process/Development Resources/ Drug Interactions Labeling/ucm080499.htm). If a medication, 
supplement, or food/beverage is suspected or known to be a strong CYP3A inhibitor or inducer 
but is not on the list, then its use must be approved on a case-by-case basis by the medical 
monitor after consultation with the clinical pharmacologist and assessment of the relative benefit 
and risk.
Table A-11
Strong CYP3A Inhibitors and Inducers
Strong and Moderate CYP3A4 
Inhibitors
Clinically Significant Strong 
Enzyme Inducers
Inhibitors of P-gp and/or BCRP
Strong CYP3A4 Inhibitors:
boceprevir
ketoconazole
ritonavir
clarithromycin
lopinavir/ritonavir
saquinavir
conivaptan
mibefradil
telaprevir
grapefruit juice
nefazodone
telithromycin
indinavir
nelfinavir
voriconazole
itraconazole
posaconazole
Moderate CYP3A4 inhibitors:
amprenavir
aprepitant
atazanavir
ciprofloxacin
crizotinib
darunavir/ritonavir
diltiazem
erythromycin
fluconazole
fosamprenavir
grapefruit juice
imatinib
verapamil 
carbamazepine
rifabutin
St John’s wort
phenobarbital
rifampin
phenytoin
rifapentine
avasimibe
P-gp Inhibitors:
itraconazole
lopinavir/ritonavir
telaprevir
clarithromycin
ritonavir
ketoconazole
indinavir/ritonavir
conivaptan
BCRP Inhibitors:
cyclosporine
elacridar
eltrombopag
gefitinib
BCRP: breast cancer resistance protein; CYP: cytochrome P450; P-gp: P-glycoprotein.
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Appendix F
Methods of Contraception Considered to be Effective
Acceptable Methods Considered Highly Effective
Birth control methods that can achieve a failure rate of less than 1% per year when used consistently and correctly 
are considered as highly effective. Such methods include:

Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of 
ovulation a:
–
Oral
–
Intravaginal
–
Transdermal

Progestogen-only hormonal contraception associated with inhibition of ovulation a:
–
Oral
–
Injectable
–
Implantable b

Intrauterine device (IUD) b

Intrauterine hormone-releasing system b

Bilateral tubal occlusion b

Vasectomised partner b,c

Sexual abstinence d
Methods That Are Considered Less Highly Effective
Acceptable birth control methods that result in a failure rate of more than 1% per year include:

Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary mode of 
action

Male or female condom with or without spermicide e

Cap, diaphragm or sponge with spermicide e
__________________________________________________
Source: European Heads of Medicines Agencies (HMA) Clinical Trial Facilitation Group (CTFG); see 
hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/CTFG/2014_09_HMA_ 
CTFG_Contraception.pdf.
a Hormonal contraception may be susceptible to interaction with the investigational medicinal product, which may 
reduce the efficacy of the contraception method.
b Contraception methods that in the context of this guidance are considered to have low user dependency.
c Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual partner of 
the woman of childbearing potential participant of the study and that the vasectomised partner has received medical 
assessment of the surgical success.
d In the context of this guidance sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred 
and usual lifestyle of the patient.
e A combination of male condom with either cap, diaphragm or sponge with spermicide (double-barrier methods)
are also considered acceptable, but not highly effective, birth control methods.
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Appendix G
Response Evaluation Criteria in Solid Tumors (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 on the basis of size (longest lesions) and suitability for reproducible 
repeated measurements. Measurements must be provided for target site of measurable lesions.
Confirmation of response is not required, as response is not the primary endpoint of this study.
Table A-12
Disease Response Criteria for Target and Nontarget Lesions
Evaluation of Target Lesions
CR:
Disappearance of all target lesions and any pathological lymph nodes 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 and at least 5 mm increase or the 
appearance of 1 or more new lesions
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, all lymph nodes must be nonpathological in 
size (<10 mm short axis), and normalization of tumor marker level
Incomplete Response/
SD: 
Persistence of 1 or more nontarget lesion(s) or/and maintenance of tumor marker level 
above the normal limits
PD:
Appearance of 1 or more new lesions and/or unequivocal progression of existing 
nontarget lesions 
Source: Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation 
criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45(2):228-47.[1]
CR: complete response; LD: longest diameter; PD: progression of disease; PR: partial response; RECIST: Response 
Evaluation Criteria in Solid Tumors; SD: stable disease.
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The following table summarizes the overall response status calculation at each time point for 
patients who have measurable disease per RECIST at baseline.
Table A-13
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 EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation 
criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45(2):228-47.[1]
CR: complete response; NE: not evaluable; PD: progression of disease; PR: partial response; SD: stable disease.
The following table summarizes the overall response status calculation at each time point for 
patients who have nonmeasureable (therefore nontarget) disease at baseline.
Table A-14
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 EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation 
criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45(2):228-47.[1]
CR: complete response; NE: not evaluable PD: progression of disease; SD: stable disease.
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 trial so to assign this category when no lesions can be measured is not 
advised.
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Appendix H
Detailed Description of Amendments to Text
The primary section(s) of the protocol affected by the changes in Amendment 05 are indicated. 
The corresponding text has been revised throughout the protocol.
Change 1: The future maximal TAK-164 dose was limited to 0.19 mg/kg Q3W.
The primary changes occur in Sections 4.5 Rationale for the Proposed Study, 6.1 Overview of 
Study Design, and 8.3 Dose Escalation Rules:
Initial wording:
Section 4.5 Rationale for the Proposed Study
The PK of TAK-164 in humans was predicted using an allometric scaling 
approach from TAK 164 PK in cynomolgus monkeys, an approach that 
has demonstrated success in predicting human PK for the TAK-264 
program (previous name “MLN0264”) that used the same GCC-targeted 
antibody, 5F9. The predicted human CL), volume of distribution (Vd) and 
plasma t1/2 of TAK-164 using this method is approximately 1.02 
mL/h/kg, 51.96 mL/kg, and 35 hours, respectively. No accumulation in 
plasma is expected with either a Q2W or an every 3-week (Q3W) dosing 
schedule. Q3W and Q2W dosing schedules will be evaluated to allow for 
flexibility in combination with other agents that are administered at their 
respective schedules.
Translational dynamic PK-efficacy modeling (using data from GCC-
expressing tumor xenograft models) and semi-mechanistic toxicity 
modeling (using neutrophil count data from cynomolgus monkeys) 
suggested that Q2W administration of TAK-164 would provide 
pharmacologically active exposures (with a projected dose range of 0.1 
mg/kg to 0.25 mg/kg) with a clinically manageable safety profile (absolute 
neutrophil count [ANC] above Grade 3 neutropenia cutoff at nadir), 
making it a favorable schedule to evaluate in this study.
Q3W schedule: administration of TAK-164 on Day 1 of 21-day cycles.
Amended wording:
Section 4.5 Rationale for the Proposed Study
The PK of TAK-164 in humans was predicted using an allometric scaling 
approach from TAK 164 PK in cynomolgus monkeys, an approach that 
has demonstrated success in predicting human PK for the TAK-264 
program (previous name “MLN0264”) that used the same GCC-targeted 
antibody, 5F9. The predicted human clearance (CL), volume of 
distribution (Vd) and plasma t1/2 of TAK-164 using this method is 
approximately 1.02 mL/h/kg, 51.96 mL/kg, and 35 hours, respectively. No 
accumulation in plasma is expected with either a Q2W or an every 3-week 
(a Q3W) dosing schedule. Q3W and Q2W dosing schedules will be 
evaluated to allow for flexibility in combination with other agents that are 
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administered at their respective schedules.
Translational dynamic PK-efficacy modeling (using data from GCC-
expressing tumor xenograft models) and semi-mechanistic toxicity 
modeling (using neutrophil count data from cynomolgus monkeys) 
suggested that Q2W administration of TAK-164 would provide 
pharmacologically active exposures (with a projected dose range of 
0.1 mg/kg to 0.25 mg/kg) with a clinically manageable safety profile 
(absolute neutrophil count [ANC] above Grade 3 neutropenia cutoff at 
nadir), making it a favorable schedule to evaluate in this study. However, 
emerging clinical safety data supports limiting the maximum dose to 
0.19 mg/kg Q3W.
Q3W schedule: administration of TAK-164 on Day 1 of 21-day cycles.
Initial wording:
Section 6.1 Overview of Study Design
Dose Escalation (Part A)
The starting TAK-164 dose will be 0.004 mg/kg.
The evaluation of tumor burden status will be performed as described in 
Appendix A. by CT or magnetic resonance imaging (MRI) according to 
modified RECIST, Version 1.1 [1] in all patients participating in this study 
at treatment intervals of 2 cycles. Pharmacodynamic evaluation will be 
performed by assessing the target marker 
 on tumor 
biopsies required to be obtained from a minimum of approximately 
5 evaluable patients starting at dose level 6 (0.12 mg/kg) of the study.
Amended wording:
Section 6.1 Overview of Study Design
Dose Escalation (Part A)
The starting TAK-164 dose will be 0.004 mg/kg Q3W and the maximal 
dose will not exceed 0.19 mg/kg Q3W.
The evaluation of tumor burden status will be performed as described in 
Appendix A. by CT or magnetic resonance imaging (MRI) according to 
modified RECIST, Vversion 1.1 [1] in all patients participating in this 
study at treatment intervals of 2 cycles. Pharmacodynamic evaluation will 
be performed by assessing the target marker 
 on tumor 
biopsies required to be obtained from a minimum of approximately 
5 evaluable patients starting at dose level 6 (0.12 mg/kg) of the study.
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Initial wording:
Section 8.3 Dose Escalation Rules
Note that depending on PK-defined exposure estimates, a dose level 
between the planned dose levels may be explored. In addition, based on 
safety during the escalation phase, intermediate doses between those 
outlined may be explored after discussion and concurrence with all lead 
investigators and the Takeda study clinician.
Q3W Schedule and Dose Levels:

TAK-164 is administered on Day 1 of each 21-day cycle.

Up to 3 initial patients per cohort will be enrolled at the starting dose 
of 0.004 mg/kg. Dose escalation is planned to proceed by evaluating 
patients at respective dose levels: 0.008 mg/kg, 0.016 mg/kg, 0.032 
mg/kg, 0.064 mg/kg, 0.12 mg/kg, 0.19 mg/kg. Further respective dose 
increments may continue including 0.25 mg/kg and 0.32mg/kg until 
one of the following occurs:
–
Unacceptable toxicity is observed or suggested by mTPI.
–
The escalation may be stopped upon a completion of enrollment of 
all patients planned to participate in the dose escalation part of the 
study or based on clinical judgment supported by medical 
observations.
Amended wording:
Section 8.3 Dose Escalation Rules
Note that depending on PK-defined exposure estimates, a dose level 
between the planned dose levels may be explored. In addition, based on 
safety during the escalation phase, intermediate doses between those 
outlined/tolerability, alternative dosing schedules may be explored after 
discussion and concurrence with all lead investigators and the Takeda 
study clinician. However, no patients will receive a dose above 0.19 
mg/kg Q3W.
Q3W Schedule and Dose Levels:

TAK-164 is administered on Day 1 of each 21-day cycle.

Up to 3 initial patients per cohort will be enrolled at the starting dose 
of 0.004 mg/kg. Dose escalation is planned to proceed by evaluating 
patients at respective dose levels: 0.008 mg/kg, 0.016 mg/kg, 0.032 
mg/kg, 0.064 mg/kg, 0.12 mg/kg, and 0.19 mg/kg. Further respective 
dose increments may continue including 0.25 mg/kg and 0.32mg/kg 
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until one of the following occurs:
–
Unacceptable toxicity is observed or suggested by mTPI. 
–
The escalation may be stopped upon a completion of enrollment of 
all patients planned to participate in the dose escalation part of the 
study or based on clinical judgment supported by medical 
observations.
Rationale for Change: In preliminary clinical data, serious and life-threatening hepatotoxicity 
was reported at a dose level of 0.25 mg/kg Q3W and was considered related to TAK-164 
treatment; therefore, the maximum dose was limited for patient safety.
The following sections also contain this change:
2.0
STUDY SUMMARY
Appendix A Schedules of Events [21-Day Cycle - Q3W Schedule]
Change 2: Hepatotoxicity was added as a potential risk. An enhanced liver safety management 
plan was implemented.
The primary changes occur in Sections 4.6 Potential Risks and Benefits, 7.2 Exclusion Criteria, 
8.4.1 Criteria for Retreatment and Dose Delays and Modifications Delaying a Subsequent 
Treatment Cycle, 8.4.2 Criteria for Dose Reduction, 8.4.3 Criteria for Discontinuation of TAK-
164, and 8.7.7 Hepatotoxicity:
Added text:
Section 4.6 Potential Risks and Benefits

Hepatotoxicity.
–
Increased alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), and bilirubin.
Added text:
Section 7.2 Exclusion Criteria
12. Patient has concurrent alcohol abuse or a history of drug-induced 
liver injury (DILI).
Description of 
change:
Section 8.4.1 Criteria for Retreatment and Dose Delays and Modifications 
Delaying a Subsequent Treatment Cycle
Table 8.a TAK-164 Recommended Dose Modification Criteria was 
modified to recommend following the discontinuation rules in 
Section 8.4.3 for Grade 3 derangements of liver function tests. A footnote 
was also added to Grade 3 nonhematologic toxicities attributed to study 
drug to clarify that dose interruption with dose reductions(s) does not 
apply to Grade 3 derangements of liver function tests.
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Added text:
Section 8.4.2 Criteria for Dose Reduction
The dose of TAK-164 should be reduced by at least 1 dose level (or by 
50% if the patient is receiving the first dose level) if the patient has any of 
the following:

Grade 4 neutropenia (ANC <500 cells/mm3) lasting more than 7 
consecutive days.

Grade 3 or greater neutropenia with fever and/or infection, where a 
fever is defined as a single oral temperature of >38.3°C or a sustained 
temperature of ≥38°C for more than 1 hour. Grade 3 thrombocytopenia 
with clinically meaningful bleeding at any time.

Grade 4 thrombocytopenia (platelet count <25,000/mm3) lasting more 
than 7 consecutive days.

Grade 3 nonhematologic toxicity (except liver function 
derangements) attributed to TAK-164 except for the following that do 
not require dose reduction:

Grade 3 or greater nausea and/or emesis in the absence of optimal 
antiemetic prophylaxis. (Optimal antiemetic prophylaxis is defined as 
an antiemetic regimen that employs both a 5-HT3 antagonist and a 
corticosteroid given in standard doses and according to standard 
schedules.)

Grade 3 or greater diarrhea that occurs in the absence of optimal 
supportive therapy.

Grade 3 fatigue lasting less than 1 week.

Derangement of liver function tests (LFTs) will follow 
discontinuation rules in Section 8.4.3.
When a dose reduction of TAK-164 is required, no re-escalation of dose 
will be permitted.
Added text:
Section 8.4.3 Criteria for Discontinuation of TAK-164
Treatment with TAK-164 will also be discontinued under the 
following conditions:

ALT or AST >8 × ULN; OR

ALT or AST >5 × ULN for more than 2 weeks; OR

ALT or AST >3 × ULN and TBL >2 × ULN.
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Added text:
Section 8.7.7 Hepatotoxicity
It is recommended that patients treated with TAK-164 undergo 
periodic monitoring of LFTs as outlined in the Schedules of Events 
(Appendix A). These liver tests should be monitored closely 
throughout the study, and strict procedures for evaluation and/or 
discontinuation of patients with elevated liver tests that meet 
predefined criteria should be implemented. Additional testing and 
treatment should be implemented as per institutional standard of 
care.
If patients experience ALT or AST >3 × ULN or AST > ULN but ≤3 × 
ULN, and if this observation cannot be explained by concomitant 
disease or another alternative etiology, follow-up laboratory tests (at a 
minimum alkaline phosphatase [ALP], ALT, AST, and TBL) should 
be performed within a maximum of 48 hours.
Rationale for Change: In preliminary clinical data, hepatotoxicity was causally assessed as 
related to TAK-164, which warranted addition of hepatotoxicity as a potential risk with TAK 
164. Concurrent abuse of alcohol or a history of DILI would diminish liver reserve, the ability to 
recover, and potentially worsen the consequences of DILI, and are, therefore, added as an 
exclusion criterion.
The following sections also contain this change:
2.0
STUDY SUMMARY
10.2
Procedures for Recording and Reporting AEs and SAEs
Change 3: Clarified that safety/tolerability data beyond Cycle 1 will be integrated into the RP2D 
determination for the expansion phase.
The primary change occurs in Section 6.1 Overview of Study Design:
Added text: 
Section 6.1 Overview of Study Design
Although dose escalation and MTD will be estimated based on 
observed DLTs in Cycle 1, safety/tolerability data beyond Cycle 1 will 
be integrated into the RP2D determination for the expansion phase.
Rationale for Change: In preliminary clinical data, serious hepatotoxicity occurred after the 
cycle 2 administration of TAK-164; therefore, late-onset safety signals will be integrated for 
tolerability assessment.
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The following sections also contain this change:
2.0
STUDY SUMMARY
4.6
Potential Risks and Benefits
8.3
Dose Escalation Rules
Change 4: Limited prior lines of therapy to 2 or 3 lines in the expansion phase (part B).
The primary change occurs in Section 7.1 Inclusion Criteria, Inclusion criterion #1:
Added Wording:
•
Part B of the study will be limited to patients with 2 or 3 prior 
lines of systemic standard of care therapy.
Rationale for Change: In preliminary data, potential clinical benefit has been observed, with 
some patients being on study treatment for up to 8 cycles with tumor shrinkage. Most of the 
patients who started TAK-164 treatment had previously progressed on multiple prior lines of 
treatment. The ORR assessment of TAK-164 in the previously planned part B can be confounded 
by multiple factors in a heterogenous prior treatment background.
Section 2.0 STUDY SUMMARY also contains this change.
Change 5: Clarified that patients will be enrolled at the RID in the imaging substudy (part C).
The primary change occurs in Section 6.1 Overview of Study Design:
Description of 
change:
Figure 6.a was updated to clarify that the Imaging Study (part C) would be 
dosed at the RID, and part B would be dosed at the RP2D. The red 
timeline at the top of the figure was removed.
Initial wording:
Section 6.1 Overview of Study Design
Imaging Substudy (Part C)
Up to 25 patients will be enrolled in the study in the Netherlands to 
determine the in vivo biodistribution and tumor targeting of 89Zr-TAK-164 
in patients with mCRC and/or metastatic gastric carcinoma. In addition, 
the relationship of 89Zr-TAK-164 tumor targeting with 18F-FDG-PET–
determined response and RECIST version 1.1 response, and the 
relationship of 89Zr uptake with GCC expression in tumor tissues/other 
biomarkers, will be characterized.
Once the MTD/RP2D is established, approximately 6 patients (including 
3 dosimetry patients) will be enrolled for purposes of dosimetry and 
imaging optimization (DIO). This DIO subgroup will receive 89Zr-TAK-
164 (mass dose <50% of the MTD/RP2D) 14 days before the first 
regularly scheduled study dose at Cycle 1 Day 1 (see Figure 6.b) and a 
second 89Zr-TAK-164 administration on Cycle 1 Day 1 in combination 
with unlabeled TAK-164 at a maximum mass dose of 100% of the 
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MTD/RP2D. Imaging will be performed 1 hour after end of infusion 
(EOI) of the first 89Zr-TAK-164 administration for dosimetry in the first 3 
patients, and for all patients at 2 time points between Day 2 and Day 7 
after EOI. Imaging time points and mass dose of TAK-164 can be adjusted 
in order to optimize imaging conditions. Up to 19 additional patients will 
be enrolled into Part C to receive a single dose of 89Zr-TAK-164 at Cycle 
1 Day 1 in addition to unlabeled TAK-164 as determined for optimal 
imaging. If the full MTD/RP2D is not administered at Cycle 1 Day 1, the 
differential will be provided after the second image acquisition. Part C 
patients will continue treatment with the MTD/RP2D of TAK-164 at 
Cycle 2 Day 1 and beyond (see Figure 6.c).
89Zr-TAK-164 PET
Initially, approximately 6 patients (including 3 dosimetry patients) will be 
enrolled for DIO. This DIO subgroup will receive 89Zr-TAK-164 (mass 
dose <50% of the MTD/RP2D) 14 days before the first regularly 
scheduled study dose at Cycle 1 Day 1 and a second 89Zr-TAK-164 
administration on Cycle 1 Day 1 in combination with unlabeled TAK-164 
at a maximum mass dose of 100% of the MTD/RP2D. Imaging will be 
performed 1 hour after EOI of the first 89Zr-TAK-164 administration for 
dosimetry in the first 3 patients and for all patients at 2 time points 
between Day 2 and Day 7 after EOI. Imaging time points and mass dose 
of TAK-164 can be adjusted to optimize imaging conditions. Qualitative 
and quantitative (SUVmean,max) will be determined for all 89Zr imaging time 
points (for further details, see Appendix A).
The 89Zr-TAK-164 administration on Cycle 1 Day 1 will be in 
combination with variable amounts of unlabeled TAK-164 in the DIO 
subgroup, never exceeding the MTD/RP2D. This way, imaging conditions 
can be optimized by adding a variable mass dose of unlabeled TAK-164 to 
89Zr-TAK-164 administration to explore the presence of a potential sink, 
and by changing imaging time points up to 7 days after EOI if required. 
When unlabeled TAK-164 is administered with 89Zr-TAK-164 for 
imaging purposes, 89Zr-TAK-164 will be administered within 2 hours after 
the EOI of unlabeled TAK-164.
Amended wording:
Section 6.1 Overview of Study Design
Imaging Substudy (Part C, To Be Conducted in The Netherlands 
Only)
Up to 25 patients will be enrolled in the study in The Netherlands to 
determine the in vivo biodistribution and tumor targeting of 89Zr-TAK-164 
in patients with GCC-expressing mCRC and/or metastatic gastric 
carcinoma. In addition, the relationship of 89Zr-TAK-164 tumor targeting 
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with 18F-FDG-PET–determined response and RECIST version 1.1 
response, and the relationship of 89Zr uptake with GCC expression in 
tumor tissues/other biomarkers, will be characterized.
Once the MTD/RP2D is establishedBased on emerging data from the 
dose escalation phase (part A) and in agreement between the site 
investigator and sponsor, part C will be triggered at a dose that is 
considered safe and has treatment potential (recommended imaging 
dose [RID]).
, aApproximately 6 patients (including 3 dosimetry patients) will be 
enrolled for purposes of dosimetry and imaging optimization (DIO). This 
DIO subgroup will receive 89Zr-TAK-164 (mass dose <50% of the 
MTD/RP2DRID) 14 days before the first regularly scheduled study dose 
at Cycle 1 Day 1 (see Figure 6.b) and a second 89Zr-TAK-164 
administration on Cycle 1 Day 1 in combination with unlabeled TAK-164 
at a maximum mass dose of 100% of the MTD/RP2DRID. Imaging will 
be performed 1 hour after end of infusion (EOI) of the first 89Zr-TAK-164 
administration for dosimetry in the first 3 patients, and for all patients at 2 
time points between Day 2 and Day 7 after EOI. Imaging time points and 
mass dose of TAK-164 can be adjusted in order to optimize imaging 
conditions. Up to 19 additional patients will be enrolled into part C to 
receive a single dose of 89Zr-TAK-164 at Cycle 1 Day 1 in addition to 
unlabeled TAK-164 as determined for optimal imaging. Once the RP2D 
of TAK-164 is determined, part C patients who have received TAK-
164 at an RID lower than the RP2D of TAK-164 may dose-escalate to 
the RP2D in the absence of PD or unacceptable treatment-related 
toxicity at the investigator’s discretion and with sponsor’s approval. If 
the full MTDRID/RP2D is not administered at Cycle 1 Day 1, the 
differential will be provided after the second image acquisition. Part C 
patients will continue treatment with the MTDRID/RP2D of TAK-164 at 
Cycle 2 Day 1 and beyond (see Figure 6.c).
89Zr-TAK-164 PET
Initially, approximately 6 patients (including 3 dosimetry patients) will be 
enrolled for DIO. This DIO subgroup will receive 89Zr-TAK-164 (mass 
dose <50% of the MTD/RP2DRID) 14 days before the first regularly 
scheduled study dose at Cycle 1 Day 1 and a second 89Zr-TAK-164 
administration on Cycle 1 Day 1 in combination with unlabeled TAK-164 
at a maximum mass dose of 100% of the MTD/RP2DRID. Imaging will 
be performed 1 hour after EOI of the first 89Zr-TAK-164 administration 
for dosimetry in the first 3 patients and for all patients at 2 time points 
between Day 2 and Day 7 after EOI. Imaging time points and mass dose 
of TAK-164 can be adjusted to optimize imaging conditions. Qualitative 
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and quantitative (SUVmean,max) will be determined for all 89Zr imaging time 
points (for further details, see Appendix A).
The 89Zr-TAK-164 administration on Cycle 1 Day 1 will be in 
combination with variable amounts of unlabeled TAK-164 in the DIO 
subgroup, never exceeding the MTD/RP2DRID. This way, imaging 
conditions can be optimized by adding a variable mass dose of unlabeled 
TAK-164 to 89Zr-TAK-164 administration to explore the presence of a 
potential sink, and by changing imaging time points up to 7 days after EOI 
if required. When unlabeled TAK-164 is administered with 89Zr-TAK-164 
for imaging purposes, 89Zr-TAK-164 will be administered within 2 hours 
after the EOI of unlabeled TAK-164.
Rationale for Change: This change allows for the start of the imaging substudy as soon as a 
dose is determined that is considered safe and likely to have a therapeutic effect.
The following sections also contain this change:
2.0
STUDY SUMMARY
8.1
Study Drug Administration
8.3
Dose Escalation Rules
Appendix A Schedules of Events [21-Day Cycle - Q3W Schedule]
Change 6: Clarified that part C will be conducted in The Netherlands only.
The primary change occurs in Section 6.1 Overview of Study Design:
Added text:
Imaging Substudy (Part C, To Be Conducted in The Netherlands Only)
Rationale for Change: The location of part C was specified in additional parts of the document 
for greater clarity.
The following sections also contain this change:
2.0
STUDY SUMMARY
4.6.1
Radiation Burden for Patients in the Imaging Substudy (Part C, To Be Conducted in The 
Netherlands Only)
8.1
Study Drug Administration
9.4.16 Assessment of 89Zr-TAK-164 PET Imaging (Part C, To Be Conducted in The Netherlands 
Only)
9.4.17 Assessment of 18F-FDG-PET Imaging (Part C, To Be Conducted in The Netherlands Only)
13.1.3 Imaging Substudy (Part C, To Be Conducted in The Netherlands Only)
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Change 7: Clarified that gastric carcinoma patients in part B and colorectal or gastric carcinoma 
patients in part C must express guanylyl cyclase C (GCC) with an H-score of ≥10.
The primary change occurs in Section 7.1 Inclusion Criteria, Inclusion criterion #1:
Initial wording:
1. Histologically or cytologically confirmed measurable advanced and/or 
metastatic solid GI tumor that expresses GCC protein (H-score >10), 
for which standard treatment is no longer effective or for whom there 
is no available standard therapy. For the escalation part of the study 
(Part A), GI malignancies include, but are not limited to, mCRC, 
gastric carcinoma, esophageal carcinoma, small intestine cancer, and 
pancreatic cancer. The expansion part of the study (Part B) is limited 
to patients with CRC expressing a high level GCC (H-score 150 and 
higher) and gastric carcinoma. Part C includes patients with CRC and 
gastric carcinoma.
Amended wording:
1. Histologically or cytologically confirmed measurable advanced and/or 
metastatic solid GI tumor that expresses GCC protein (H-score >≥10), 
for which standard treatment is no longer effective or for whom there 
is no available standard therapy. For the escalation part of the study 
(part A), GI malignancies include, but are not limited to, mCRC, 
gastric carcinoma, esophageal carcinoma, small intestine cancer, and 
pancreatic cancer. The expansion part of the study (part B) is limited 
to patients with CRC expressing a high-level GCC (H-score ≥150 and 
higher) and gastric carcinoma (H-score ≥10). Part C includes patients 
with CRC and gastric carcinoma (H-score ≥10 for both indications).
Rationale for Change: This change clarifies the GCC thresholds for patients in parts B and C 
for both CRC and gastric cancer. H-scores were added to the document in several places for 
clarity.
The following sections also contain this change:
2.0
STUDY SUMMARY
6.1
Overview of Study Design
6.2
Number of Patients
9.3
Treatment Group Assignments
13.1.2 Dose Expansion (Part B)
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Change 8: Clinical laboratory directives were updated to reflect local capabilities.
The primary change occurs in Sections 9.4.14.1 Clinical Chemistry, Hematology, and Urinalysis, 
9.4.18 Biomarker, PK, and Pharmacodynamic Samples, and 9.4.18.3 Pharmacodynamic 
Measurements: 
Initial wording:
9.4.14.1 Clinical Chemistry, Hematology, and Urinalysis
Clinical laboratory evaluations will be performed locally. Additional 
handling and shipment of clinical laboratory samples will be outlined in 
the Laboratory Manual.
Amended wording:
9.4.14.1 Clinical Chemistry, Hematology, and Urinalysis
Clinical laboratory evaluations will be performed locally. Additional 
handling and shipment of clinical laboratory samples will be outlined in 
the Laboratory Manual. as per the institutional standard of care.
Added text:
9.4.18 Biomarker, PK, and Pharmacodynamic Samples
The primary specimen collection procedures are shown in Table 9.a. 
Additional handling and shipment of biomarker, PK, and 
pharmacodynamic samples are outlined in the laboratory manual.
Deleted text:
9.4.18.3 Pharmacodynamic Measurements
Serum for Protein (Local) Measurements
Serum samples for protein will not be collected for patients participating 
in part C. For all other patients, samples will be collected to monitor 
changes in clinically established biomarkers such as carcinoembryonic 
antigen to assess relationship with clinical response. Collection of this 
sample will be at baseline (all cycles) and Day 8 (Cycle 2 only). 
Instructions for collection will be detailed in the Laboratory Manual.
Laboratory tests will be performed at the site.
Rationale for Change: Changes were made to clarify that clinical chemistry, hematology, and 
urinalysis assessments are performed locally, and therefore, no instructions for handling and 
shipment will be in the laboratory manual. Biomarkers, PK, and pharmacodynamics assessments 
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are performed centrally and therefore, instructions for handling and shipment are in the 
laboratory manual.
Change 9: Clarified protocol for biopsy.
The primary change occurs in Section 9.4.20 Banked Tumor and/or Fresh Tumor Biopsy 
Specimen Measurements:
Initial wording:
9.4.20 Banked Tumor and/or Fresh Tumor Biopsy Specimen
Measurements GCC expression is evaluated by using IHC, as conducted 
by a central laboratory. An H-score will be used for GCC assessment and 
enrollment. Patients with GCC H-score ≥10 will be eligible for 
enrollment. An H-score ≥ 150 will be used for assigning patients to a GCC 
high group. In addition,
. Collection of tumor biopsies at baseline and 
following treatment with TAK-164 is highly encouraged to monitor 
expression of GCC and 
. A viable fresh baseline biopsy and 
a viable posttreatment biopsy will be collected during dose escalation 
starting at dose level 0.12 mg/kg and beyond in a minimum of
approximately 5 patients and up to 10 patients participating in Parts A and 
B, and approximately 3 patients participating in Part C. A baseline biopsy 
and posttreatment biopsy will be collected to assess target engagement and 
the tumor microenvironment. 
Amended wording:
9.4.20 Banked Tumor and/or Fresh Tumor Biopsy Specimen
Measurements GCC expression is evaluated by using IHC, as conducted 
by a central laboratory. An H-score will be used for GCC assessment and 
enrollment. Patients with GCC H-score ≥10 will be eligible for 
enrollment. An H-score ≥ 150 will be used for assigning patients to a GCC 
high group. In addition, 
 may be analyzed on banked tumor 
and/or fresh tumor biopsies. Collection of tumor biopsies at baseline and 
following treatment with TAK-164 is highly encouraged to monitor 
expression of GCC and 
. A viable fresh baseline biopsy and 
a viable posttreatment biopsy will be collected during dose escalation 
starting at dose level 0.12 mg/kg and beyond in a minimum of 
approximately 5 patients and up to 10 patients participating in parts A and 
B, and approximately 3 patients participating in part C. A baseline biopsy 
and posttreatment biopsy will be collected to assess target engagement and 
the tumor microenvironment. The specific anatomical location of the 
biopsy before resection must be specified.
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Rationale for Change: A requirement to record the location of the biopsy was added because 
annotation of the location of the biopsy is critical for downstream analyses. In addition, the 
number of patients was clarified as a minimum of approximately 5 with no limit on the number 
of patients biopsied to ensure the biopsies could meet study goals.
The following sections also contain this change:
2.0
STUDY SUMMARY
6.1
Overview of Study Design
Appendix A Schedules of Events [21-Day Cycle - Q3W Schedule]Appendix A
Change 10: Added definition and requirements for monitoring and reporting adverse events of 
special interest (AESIs).
The primary change occurs in Sections 10.1.4 AESI Definition, 10.2 Procedures for Recording 
and Reporting AEs and SAEs, 10.3 Monitoring of AEs and Period of Observation:
Added text:
Section 10.1.4 AESI Definition
An AESI is an AE of scientific and medical concern specific to the 
compound or program for which ongoing monitoring and rapid 
communication by the investigator to Takeda may be appropriate. 
Such events may require further investigation in order to characterize 
and understand them, and instructions regarding how and when 
AESIs should be reported to Takeda are provided in Section 10.2 
along with a list of AESIs.
Added text:
Section 10.2 Procedures for Recording and Reporting AEs and SAEs
AESI Reporting:
The below aminotransferase test results will be treated as AESIs.
ALT or AST >3 × ULN.
ALT or AST >ULN but ≤ 3 × ULN, which cannot be explained by 
concomitant disease or another alternative etiology.
All AESIs will be reported to Takeda Global Pharmacovigilance in an 
expedited manner irrespective of the event’s seriousness or causal 
relationship. Further, patients will be advised to promptly report 
signs and symptoms that may indicate liver injury, including fatigue, 
anorexia, right upper abdominal discomfort, dark urine, or jaundice. 
The investigator must contact the medical monitor within 24 hours to 
discuss further management of the patient and refer to management 
of hepatotoxicity in Section 8.7.7.
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Added text:
10.3 Monitoring of AEs and Period of Observation
AEs, both nonserious and serious, will be monitored throughout the study 
as follows:

AEs will be reported from the signing of informed consent through 30 
days after administration of the last dose of study drug or the start of 
subsequent anticancer therapy, whichever occurs first, and recorded in 
the eCRFs.

SAEs will be reported to the Takeda Global Pharmacovigilance 
department or designee from the signing of informed consent through 
30 days after administration of the last dose of study drug and 
recorded in the eCRF. After this period, only related SAEs must be 
reported to the Takeda Global Pharmacovigilance department or 
designee. SAEs should be monitored until they are resolved or are 
clearly determined to be due to a patient’s stable or chronic condition 
or intercurrent illness(es).

AESIs will be reported and monitored in the same way as SAEs 
(see above).
Rationale for Change: Hepatotoxicity is considered an AESI as this event is considered a 
potential risk with TAK-164. Reporting AESIs is critical for safety monitoring of liver toxicity 
and for further characterization of the safety profile of TAK-164.
The following sections also contain this change:
9.4.11 AEs
Appendix A Schedules of Events [21-Day Cycle - Q3W Schedule]Appendix A
Change 11: Clarified procedure for collection of electrocardiograms (ECGs) at the end of 
infusion (EOI).
The primary change occurs in Appendix A Schedules of Events [21-Day Cycle - Q3W 
Schedule]Appendix A:
Description of 
change:
A footnote was added to the tables below:
Table A-4
Serial PK and ECG Collection Schedule for Part A
Table A-5
Part B Sparse PK and ECG Collection
Table A-10
Part C Sparse PK and ECG Collection
At EOI, the collection of triplicate ECG should be initiated within 5 
min prior to completion of TAK-164 infusion (i.e. not 5 min prior to 
EOI line flush). Each triplicate ECG should be collected at 2-3 min 
intervals with all 3 ECGs collected within a total 10 min window (i.e., 
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Study No. TAK-164-1001
Page 148 of 150
Protocol Amendment 05
04 September2019
5 min prior to completion of TAK-164 infusion and 5 min after 
completion of TAK-164 infusion). The EOI PK sample should be 
collected immediately after the third ECG has been collected. EOI PK 
is in relation to TAK-164 infusion and not infusion line flush.
Rationale for Change: Additional details were added to clarify the procedure of collecting
triplicate ECGs at the end of drug infusion to facilitate consistent measurements.
Change 12: Updated Response Evaluation Criteria in Solid Tumors (RECIST) per RECIST 
version 1.1 guidelines.
The primary change occurs in Appendix G Response Evaluation Criteria in Solid Tumors 
(version 1.1):
Description of 
change:
In Table A-12 Disease Response Criteria for Target and Nontarget 
Lesions, the disease response criteria were updated.
For evaluation of target lesions:
CR: Disappearance of all target lesions and any pathological lymph 
nodes must have reduction in short axis to <10 mm
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 and 
at least 5 mm increase or the appearance of 1 or more new lesions
For evaluation of nontarget lesions:
CR: Disappearance of all nontarget lesions, all lymph nodes must be 
nonpathological in size (<10 mm short axis), and normalization of 
tumor marker level
Rationale for Change: Criteria were updated to reflect the disease response criteria per RECIST 
version 1.1 guidance.
Change 13: Clarified that the specific mass dose of antibody-drug conjugate (ADC) will be 
determined during the dosimetry and imaging optimization (DIO) phase of the imaging substudy.
The primary change occurs in Section 8.15 Preparation of 89Zr-TAK-164:
Added text:
89Zr-TAK-164 will be prepared as described in the pharmacy manual and 
administered by IV at an anticipated dose of 0.5 to 2 mg at 37±10% MBq. 
The specific mass dose of ADC will be determined during the DIO 
phase of the imaging substudy.
Rationale for Change: This sentence was added to provide greater clarity into when the ADC 
specific mass dose will be determined.
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Study No. TAK-164-1001
Page 149 of 150
Protocol Amendment 05
04 September2019
Change 14: Clarified the timing of disease assessments.
The primary change occurs in Section 9.4.15 Disease Assessment:
Initial wording:
Objective assessments will be performed at the end of every other cycle 
starting with Cycle 2 (ie, Cycles 2, 4, 6, etc) and at the EOT visit, as 
described in the Schedules of Events (Appendix A). Objective 
assessments will be based on the modified RECIST criteria, Version 1.1 
(see Appendix G) [1]. Imaging and assessment may be conducted up to 3 
days in advance of the regular periodic assessment day. When possible, 
the same qualified physician will interpret results to reduce variability. 
Radiographic images will be maintained at the site, and test results and 
physician’s findings will be filed in patient source documents. In addition, 
all study images acquired for patients in Part B and Part C will be 
collected by a central imaging vendor and assessed in a blinded 
independent central review. The sites will transfer images to a central 
facility consistent with the guidance provided by the Sponsor.
Amended wording:
Objective assessments will be performed at the end of every other cycle 
starting with Cycle 2 (ie, Cycles 2, 4, 6, etc) at screening, every 2 
treatment cycles (42 days with a window of 3 days in advance), and at 
the EOT visit, as described in the Schedules of Events (Appendix A). 
Response assessment will be calendar-based regardless of treatment 
delays/interruptions. Objective assessments will be based on the 
modified RECIST criteria, version 1.1 (see Appendix G) [1]. Imaging and 
assessment may be conducted up to 3 days in advance of the regular 
periodic assessment day. When possible, the same qualified physician will 
interpret results to reduce variability. Radiographic images will be 
maintained at the site, and test results and physician’s findings will be 
filed in patient source documents. In addition, all study images acquired 
for patients in part B and part C will be collected by a central imaging 
vendor and assessed in a blinded independent central review. The sites 
will transfer images to a central facility consistent with the guidance 
provided by the sponsor.
Rationale for Change: The protocol was edited to clarify that disease response assessments will 
be calendar-based, not cycle-based, due to the potential of dosing delays or interruptions.
Appendix A Schedules of Events [21-Day Cycle - Q3W Schedule] also contains this change.
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Study No. TAK-164-1001
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Protocol Amendment 05
04 September2019
Change 15: Moved a section of text regarding part C from Section 13.1.6 to Section 13.1.3.
The primary change occurs in Sections 13.1.3 Imaging Substudy (Part C, To Be Conducted in 
The Netherlands Only) and 13.1.6 PK Analysis:
Description of 
change:
The text below was moved from Section 13.1.6 to Section 13.1.3:
Efficacy endpoints will be summarized, and the correlation with 
imaging outputs may be explored. The results of part C will be 
summarized in a clinical study report addendum.
Rationale for Change: This text was moved into a more appropriate section.
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PPD

SAP_001.pdf: 


Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: An Open-Label, Dose Escalation, Phase 1, First-in-Human Study of TAK-164, an 
Antibody-Drug Conjugate, in Patients with Advanced Gastrointestinal Cancers Expressing 
Guanylyl Cyclase C
NCT Number: NCT03449030
SAP Approve Date: 08 May 2020
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information 
or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


1.0
TITLE PAGE
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: TAK-164-1001
An Open-Label, Dose Escalation, Phase 1, First-in-Human Study of TAK-164, an Antibody-
Drug Conjugate, in Patients with Advanced Gastrointestinal Cancers Expressing Guanylyl 
Cyclase C
PHASE I
Version: 1.0
Date: 08 May 2020
Prepared by:
Based on:
Protocol Version: Amendment 05
Protocol Date: 04 September 2019
Pr perty of Takeda: 
ommercial Use Only and Subject to the Applicable Terms of Use
y of
of
y
TA
TA
f
Cancer
Cance
E I
Versi
ersion
Date
Date: 0
Protoc
Prot
Pr
PPD


TAK-164-1001
Page 2 of 16
Statistical Analysis Plan 1.0
08 May 2020
1.1
Approval Signatures
Electronic signatures can be found on the last page of this document.
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TAK-164-1001
Page 3 of 16
Statistical Analysis Plan 1.0
08 May 2020
2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
1.1
Approval Signatures ..................................................................................................2
2.0
TABLE OF CONTENTS.................................................................................................3
3.0
LIST OF ABBREVIATIONS..........................................................................................5
4.0
OBJECTIVES .................................................................................................................6
4.1
Primary Objectives ....................................................................................................6
4.2
Secondary Objectives.................................................................................................6
4.3
Exploratory Objectives ..............................................................................................6
4.4
Study Design .............................................................................................................6
5.0
ANALYSIS ENDPOINTS...............................................................................................7
5.1
Primary Endpoints .....................................................................................................7
5.2
Secondary Endpoints .................................................................................................7
5.3
Exploratory Endpoints ...............................................................................................8
6.0
DETERMINATION OF SAMPLE SIZE.........................................................................8
7.0
METHODS OF ANALYSIS AND PRESENTATION.....................................................8
7.1
General Principles......................................................................................................8
7.1.1
Study Definitions...............................................................................................9
7.1.2
Definition of Study Days ...................................................................................9
7.1.3
Definition of Study Visit Windows....................................................................9
7.1.4
Conventions for Missing Adverse Event Dates ..................................................9
7.1.5
Conventions for Missing Concomitant Medication Dates.................................10
7.2
Analysis Sets ...........................................................................................................10
7.3
Disposition of Subjects ............................................................................................10
7.4
Demographic and Other Baseline Characteristics.....................................................11
7.5
Medical History and Concurrent Medical Conditions...............................................11
7.6
Medication History and Concomitant Medications...................................................11
7.7
Study Drug Exposure and Compliance.....................................................................11
7.8
Efficacy Analysis.....................................................................................................12
7.8.1
Primary Efficacy Endpoint(s)...........................................................................12
7.8.2
Secondary Efficacy Endpoint(s).......................................................................12
7.8.3
Additional Efficacy Endpoint(s).......................................................................12
7.9
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................13
7.9.1
Pharmacokinetic Analysis................................................................................13
7.9.2
Pharmacodynamic Analysis.............................................................................13
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Statistical Analysis Plan 1.0
08 May 2020
7.10
Other Outcomes.......................................................................................................13
7.10.1
Immunogenicity...............................................................................................13
7.11
Safety Analysis........................................................................................................13
7.11.1
Adverse Events................................................................................................13
7.11.2
Clinical Laboratory Evaluations.......................................................................15
7.11.3
Vital Signs.......................................................................................................15
7.11.4
12-Lead ECGs.................................................................................................15
7.11.5
Pregnancy Test ................................................................................................15
7.11.6
Other Observations Related to Safety...............................................................16
7.12
Interim Analysis ......................................................................................................16
7.13
Changes in the Statistical Analysis Plan...................................................................16
8.0
REFERENCES..............................................................................................................16
LIST OF IN-TEXT TABLES
Table 7.a
Imputation Rules for Missing AE Start Dates.......................................................9
LIST OF IN-TEXT FIGURES
Figure 4.a
Study Design for TAK-164-1001 Phase 1 First-in-Human....................................7
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TAK-164-1001
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Statistical Analysis Plan 1.0
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3.0
LIST OF ABBREVIATIONS
ADA
antidrug antibody
ADC
antibody-drug conjugate
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
Area under the curve
BMI
body mass index
BUN
blood urea nitrogen
CI
confidence interval
CRF
case report form
DCR
disease control rate
DLT
dose-limiting toxicity
DOR
duration of response
ECG
electrocardiogram
EOT
end-of-treatment
GCC
guanylyl cyclase C
KM
Kaplan-Meier
LLN
lower limit of normal
MedDRA
Medical Dictionary for Regulatory Activities
MTD
maximum tolerated dose
mTPI
modified toxicity probability interval
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
ORR
overall response rate
OS
overall survival
PD
progression of disease
PFS
progression-free survival
PK
pharmacokinetics
PT
Preferred term
PRO
patient-reported outcome
Q3wQ3W
once every 3 weeks
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
recommended phase 2 dose
SAE
serious adverse event
SOC
System organ class
TEAE
Treatment-emergent adverse event
ULN
upper limit of normal
WHODrug
World Health Organization Drug Dictionary
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Statistical Analysis Plan 1.0
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4.0
OBJECTIVES
4.1
Primary Objectives
!
To evaluate the safety of TAK-164 and to determine the maximum tolerated dose (MTD) 
and/or RP2D. 
4.2
Secondary Objectives
!
To characterize the PK of TAK-164.
!
To evaluate immunogenicity of TAK-164.
!
To evaluate efficacy of TAK-164 as measured by overall response rate (ORR).
!
To evaluate other efficacy measures such as DCR, DOR, and PFS.
4.3
Exploratory Objectives
4.4
Study Design
This is a multicenter, nonrandomized, open-label, phase 1 study of TAK-164 in patients with 
advanced GI cancers expressing GCC for whom standard treatment is no longer effective or for 
whom there is no available standard therapy. This study is designed to determine safety, 
tolerability, and PK and to determine an MTD and/or RP2D of TAK-164 that may be safely 
administered to patients with advanced GI cancer.
Only Part A of the study has been conducted (Figure 4.a).
Once enrolled in the study, patients will receive TAK-164 IV administration on Day 1 of each 
21-day cycle or Q3W. The starting TAK-164 dose will be 0.004 mg/kg Q3W and the maximal 
dose will not exceed 0.19 mg/kg Q3W following Protocol Amendment 05. To determine the 
MTD/RP2D and to guide the dose escalation portion of the study, a Bayesian model of modified 
toxicity probability interval (mTPI) will be used. DLTs occurring during Cycle 1 at a given dose 
level will be evaluated and will affect decisions to dose-escalate. Although dose escalation and 
MTD will be estimated based on observed DLTs in Cycle 1, safety/tolerability data beyond 
Cycle 1 will be integrated into the RP2D determination for the expansion phase.
All patients participating in this study who are judged by the investigator to be receiving clinical 
benefit will be permitted to remain on therapy until progression of disease (PD), unacceptable 
toxicity, or they choose to withdraw from the study.
Toxicity will be evaluated according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE), version 5.0, effective date 27 November 2017. DLTs 
Property of Takeda: For Non-Commercial Use
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TAK-164-1001
Page 7 of 16
Statistical Analysis Plan 1.0
08 May 2020
are defined in Protocol Section 8.2. AEs will be assessed, and laboratory values, vital signs, and 
ECGs will be obtained to evaluate the safety and tolerability of TAK-164.
Figure 4.a
Study Design for TAK-164-1001 Phase 1 First-in-Human
5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoints

Number of patients with a DLT in Cycle 1.

Percentage of patients with AEs.

Percentage of patients with Grade 3 or above AEs.

Percentage of patients with drug-related AEs.

Percentage of patients with drug-related Grade 3 or above AEs.

Percentage of patients with SAEs.

Percentage of patients with AEs leading to discontinuation.

Percentage of participants who meet the markedly abnormal criteria for safety laboratory 
tests at least once postdose.

Percentage of participants who meet the markedly abnormal criteria for vital sign 
measurements at least once postdose.

MTD or an alternate RP2D of TAK-164.
5.2
Secondary Endpoints

TAK-164 PK parameters: single-dose maximum (peak) concentration (Cmax), single-dose 
first time of occurrence of maximum (peak) concentration (tmax), and area under the plasma 
concentration–time curve from time 0 to time of the last quantifiable concentration (AUClast) 
during Cycle 1 Day 1 and Cycle 2 Day 1. In addition, observed concentration at the end of a 
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Page 8 of 16
Statistical Analysis Plan 1.0
08 May 2020
dosing interval (Ctrough) may be reported for other dosing days during which a single predose 
PK sample is collected.
!
ORR (CR+PR) as assessed by the investigator per modified Response Evaluation Criteria in 
Solid Tumors (RECIST, Version 1.1).
!
DCR (CR+PR+SD).
!
DOR.
!
PFS.
!
ADA in serum.
5.3
Exploratory Endpoints
6.0
DETERMINATION OF SAMPLE SIZE
It is anticipated that approximately 25 patients will be enrolled into Part A (escalation), 
following an mTPI model detailed in Protocol Section 8.3, to allow for dose finding across 7-8 
different dose levels. The mTPI dosing schema will maximize patients treated at or near the 
MTD.
7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
All available efficacy and safety data will be included in data listings and tabulations. Data that 
are potentially spurious or erroneous will be examined under the auspices of standard data 
management operating procedures.
Where appropriate, variables will be summarized descriptively by study visit. For the categorical 
variables, the count and proportion of each possible value will be tabulated. The denominator for 
the proportion will be based on the number of subjects who provided non-missing responses to 
the categorical variable. For continuous variables, the number of subjects with non-missing 
values, mean, median, SD, minimum, and maximum values will be tabulated. 
Means and medians will be presented to 1 more decimal place than the recorded data. The 
standard deviations (SDs) will be presented to 2 more decimal places than the recorded data. 
Property of Takeda: For Non-Commercial 
MPL
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Statistical Analysis Plan 1.0
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Confidence intervals about a parameter estimate will be presented using the same number of 
decimal places as the parameter estimate.
The summary tables will include each dose group and the total in the escalation stage (Part A).
No formal statistical hypothesis testing will be performed. All statistical analyses will be 
conducted using SAS® Version 9.4, or higher.
7.1.1
Study Definitions
7.1.2
Definition of Study Days
Study Day 1 is defined as the date on which a subject is administered their first dose of TAK-164. 
Other study days are defined relative to the Study Day 1, eg, Day 1 being Study Day 1 and Day -
1 being the day prior to Study Day 1.
7.1.3
Definition of Study Visit Windows
All data will be categorized based on the scheduled visit at which it is collected. These visit 
designators are predefined values that appear as part of the visit tab in the eCRF.
7.1.4
Conventions for Missing Adverse Event Dates
Missing or partial AE start dates will be imputed according to the following rules.
Table 7.a
Imputation Rules for Missing AE Start Dates
Non-
missing
Missing
Estimated
Month and 
Year
Day
Day of first dose date of STUDY DRUG, if month and year of onset date are the 
same as month and year of date of first dose.
The last day of the month, if the month and year of onset date are before the 
month and year of date of first dose of STUDY DRUG.
The first day of the month, if the month and year of onset date are after the 
month and year of date of first dose of STUDY DRUG.
Year
Day and Month
Day and month of first dose date of STUDY DRUG, if the year of onset date is 
the same as the year of date of first dose of STUDY DRUG.
December 31st, if the year of onset date is prior to the year of date of first dose of 
STUDY DRUG.
January 1st, if the year of onset date is after the year of date of first dose of 
STUDY DRUG.
Day, Month 
and Year
Date of first dose of STUDY DRUG
Missing or partial AE stop dates will be imputed according to the following rules: if only the day 
is missing, use 15th of the month; if both month and day are missing, use June 30th. For a record 
with a complete start date and a partial stop date, if the estimated stop date would become earlier 
than the start date, the stop date will not be estimated.
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TAK-164-1001
Page 10 of 16
Statistical Analysis Plan 1.0
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If AE stop date is not missing and the AE stop date < estimated start date, let estimated onset 
date = AE stop date.
All dates presented in listings are recorded dates without imputation.
7.1.5
Conventions for Missing Concomitant Medication Dates
If only the day is missing, use 15th of the month; if both month and day are missing, use June 
30th. For a record with a complete start date and a partial stop date, if the imputed stop date 
would become earlier than the start date, the stop date will not be estimated. 
All dates presented in listings are recorded dates without imputation.
7.2
Analysis Sets

Safety analysis set: Patients who receive at least 1 dose of TAK-164. The safety analysis set 
will be used for safety analyses, and for the primary analysis of PFS and OS

DLT analysis set: Patients who complete Cycle 1 or experience a DLT in Cycle 1. The DLT
analysis set will be used to determine the MTD.

Response-Evaluable analysis set: Patients who receive at least 1 dose of TAK-164, have
measurable disease at baseline based on the modified RECIST, version 1.1, and at least 1
postbaseline response assessment. The response-evaluable analysis set will be used for the 
primary analysis of the response-related efficacy endpoints, eg, ORR, DCR, DOR.

PK analysis set: Patients with sufficient dosing and PK data to reliably estimate PK
parameters will be used for PK analyses.

Pharmacodynamic analysis set: Patients who receive at least 1 dose of TAK-164 and at least
1 target engagement biomarker assessment.

Immunogenicity-Evaluable analysis set: Patients with a baseline immunogenicity assessment 
and at least 1 postbaseline immunogenicity assessment.
7.3
Disposition of Subjects
Disposition of patients includes the number and percentage of patients in each dose level, total 
dose escalation stage, along with a summary of the primary reason for discontinuation from
study drug. All percentages will be based on the number of patients in the safety analysis set.
Subjects who failed the screening will be summarized in a separate table by age, gender, 
ethnicity, and race, as appropriate. Primary reasons for screen failure will also be summarized.
Protocol deviations will be identified. A listing will be generated for significant protocol 
deviations.
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7.4
Demographic and Other Baseline Characteristics
Demographics will be summarized. Baseline demographic data to be evaluated will include age, 
sex, race, ethnicity, height, weight, and GCC score. Age will be calculated from date of birth to 
date of informed consent. 
Throughout this study, baseline assessments are defined as those performed at the closest time 
before the start of study drug administration.
Baseline characteristics including baseline disease primary diagnosis, years since initial 
diagnosis, staging, Eastern Cooperative Oncology Group (ECOG) performance status, will be 
summarized.
7.5
Medical History and Concurrent Medical Conditions
Medical history will be presented in a by-patient listing, including the medical and surgical
history, date of onset and the status (resolved or ongoing, if known.)
7.6
Medication History and Concomitant Medications
A summary table will present the numbers and percentages of patients who received prior 
therapy, including prior systemic anticancer therapy, prior radiation, prior surgery, and best 
response to the prior therapy if known.
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Dictionary. The number and percentage of patients taking concomitant medications will be 
tabulated by WHO drug generic term for the safety analysis set, from the first dose of study 
treatment and through 30 days after the last dose of study drug, or to the start of subsequent 
anticancer therapy, whichever occurs first.
7.7
Study Drug Exposure and Compliance
The exposure to TAK-164 will be characterized separately by: Number of Treated Cycles, 
Number of Cumulative Treatment Cycles ((≥1, ≥2, …, ≥6, and ≥10 cycles), Duration of 
Treatment (weeks) and Cumulative Dose. is defined as time from the first study dose to 21 days 
after the last study dose: [(last dose date +21) – first dose date]. after the last study dose, duration 
of treatment is defined as [date of death – first dose date +1]. Cumulative Dose will be 
summarized and listed in mg for TAK-164.
for TAK-164 as:
100% ×
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Relative dose intensity will be summarized by each cycle and overall.
Action on study drug (dose reduced, interrupted, and withdrawn) will be summarized by each 
cycle and total for each dose level, and for overall in the safety analysis set.  
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Statistical Analysis Plan 1.0
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7.8
Efficacy Analysis
All efficacy analyses will be based on investigator assessments. Investigators will assess 
response using the modified RECIST v1.1. The response-evaluable analysis set will be used for 
the primary analysis of ORR, DCR, DOR, whereas the safety analysis set will be used for the 
primary analysis of PFS and OS.
7.8.1
Primary Efficacy Endpoint(s)
Not applicable
7.8.2
Secondary Efficacy Endpoint(s)
ORR is defined as the proportion of patients who have achieved a CR or PR and will be 
summarized using the Response-Evaluable population by dose level and overall. Estimates of the 
ORR will be presented with 2-sided 95% exact binomial confidence intervals (CIs). 
Disease control rate (DCR) is the proportion of patients who have had a best response of CR, PR, 
or SD. DCR will be summarized using the Response-Evaluable population. The number and 
percentage of patients falling into each response category (e.g., CR, PR, and SD) will be 
tabulated descriptively with 2-sided 95% exact CIs. 
DOR is defined as the time from the date of first documentation of a response to the date of first 
documentation of PD or death due to any cause, whichever occurs first. Patients without 
documentation of PD or death at the time of analysis will be censored at the date of their last 
response assessment that is SD or better, prior to receipt of subsequent anticancer therapy, if 
applicable. DOR will be analyzed based on the responders in the Response-Evaluable analysis 
set.
PFS is defined as the time from the date of first study drug administration to the day of first 
documented PD or death due to any cause, whichever occurs first. PFS will be censored at the 
last response assessment that is SD or better, prior to receipt of subsequent anticancer therapy, if 
applicable. The primary analysis of PFS will be based on the safety analysis set.
OS will be calculated from the date of first study drug administration to the date of patient death 
due to any cause. Patients without documentation of death at time of the analysis will be 
censored as of the date the patient was last known to be alive, or the data cutoff date, whichever 
is earlier. The primary analysis of OS will be based on the safety analysis set.
In general, time-to-event endpoints (DOR, PFS, and OS) will be analyzed using the Kaplan-
Meier method and results will be summarized by the 25th, 50th, and 75th percentiles, if 
estimable, with associated 2-sided 95% CIs. KM plots will be generated with regard to the 
respective analysis sets and meaningful subsets.
7.8.3
Additional Efficacy Endpoint(s)
Not applicable.
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Statistical Analysis Plan 1.0
08 May 2020
7.9
Pharmacokinetic/Pharmacodynamic Analysis
7.9.1
Pharmacokinetic Analysis
Individual and mean plasma concentration data will be plotted over time. Descriptive statistics 
will be presented for plasma concentration and the PK parameters including, but not limited to 
Cmax, tmax, area under the plasma concentration from time 0 to time of the last quantifiable 
concentration (AUClast) during C1D1 and C2D1, t1/2, CL, Vd, Ctrough, etc. 
7.9.2
Pharmacodynamic Analysis
Pharmacodynamic evaluation will be performed by assessing the target marker 
on tumor biopsies required to be obtained from a minimum of approximately 5 evaluable patients 
of the study (pre- and postdose paired). Patients with GCC H-score ≥10 will be eligible for 
enrollment with an H-score ≥ 150 deemed GCC High. Baseline expression of GCC protein and 
and the percent change from baseline will be listed for individual patients, and 
also summarized with descriptive statistics based on the pharmacodynamic analysis set. These 
biomarkers may be evaluated in correlation to dose, PK exposure, other pharmacodynamic 
measures, and response as appropriate. Alternatively, the expression of GCC and 
 
 might be used as a surrogate marker. Circulating tumor DNA in 
plasma may be explored in DNA mutation analysis including gene mutation, total mutation 
burden, MSI status, and DNA damage repair gene signatures.
Descriptive statistics, graphical methods, and statistical modeling, as appropriate, will be used to 
explore various biomarkers. The results of pharmacodynamic analysis may or may not be 
completed as part of this study assessment; hence, will be reported separately from the clinical 
study report.
7.10
Other Outcomes
7.10.1
Immunogenicity
The proportion of patients with positive ADA (transient or persistent, ADA titer: high/low) 
during the study will be summarized. Analysis will be based on the immunogenicity-evaluable 
set. Summaries will be provided by dose and overall. The incidence of immunogenicity (ADA 
positive) will be calculated. The impact of anti–TAK-164 antibodies ADA on the PK profile, 
pharmacodynamic profile, and clinical safety may be evaluated.
7.11
Safety Analysis
The safety analyses will be performed based on the safety analysis set.
7.11.1
Adverse Events
AEs will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA) 
coding dictionary for the purpose of summarization. 
Property of Takeda: For Non-Commercial Use Only and Subject to the A
licable Terms of Use
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Page 14 of 16
Statistical Analysis Plan 1.0
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All treatment-emergent AEs (TEAEs) will be tabulated. A TEAE for tabulation is defined as: 
any AE that occurs after administration of the first dose of study drug and up through 30 days 
after the last dose of study drug. AEs will be tabulated according to the MedDRA by system 
organ class (SOC) and preferred term (PT), and will include the following categories:

TEAEs.

Drug-related TEAEs.

Grade 3 or higher TEAEs 

Drug-related, Grade 3 or higher TEAEs.

Treatment-emergent SAEs.

Drug-related Treatment-emergent SAEs.

TEAEs resulting in study drug discontinuation.

The most commonly reported TEAEs (ie, those events reported by ≥10% of all patients).

Nonserious TEAEs (more than 5% in any dose level).
Patients with the same AE more than once will have the maximum intensity of that event 
counted within each system organ class, and once within each preferred term.
An overall summary of AE will include numbers and percentages of patients who had any TEAE, 
drug-related TEAE, grade 3 or higher TEAE, grade 3 or higher drug-related TEAE, SAE, drug-
related SAE, TEAE resulting in discontinuation, and on-study deaths.
7.11.1.1
Serious Adverse Events
The number and percentage of subjects experiencing at least 1 treatment emergent serious AE 
(SAE) will be summarized by MedDRA primary system organ class and preferred term. Drug-
related SAEs will be summarized similarly.
A by-subject listing of the SAEs will be presented (the subject listing will contain all SAEs 
regardless of treatment emergent AE status).
7.11.1.2
Deaths
A by-subject listing of the deaths will be presented. All deaths occurring on-study and during 
follow-up will be displayed (regardless of treatment emergent AE status). An on-study death is 
defined as a death that occurs between the first dose of study drug and 30 days of the last dose of 
study drug.
7.11.1.3
Adverse Events Resulting in Discontinuation of Study Drug
Treatment-emergent AEs that resulted in discontinuation of study drugs will be summarized by 
preferred terms. Numbers and percentages of patients in which each of the AEs resulted in study 
drug discontinuation will be also be summarized.
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Statistical Analysis Plan 1.0
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7.11.1.4
Dose Limiting Toxicities (DLTs)
A by-patient listing of DLTs in Cycle 1 will be presented by dose level for patients in the DLT-
evaluable population. Numbers and percentages of patients who had a DLT will be also be 
summarized by dose level and overall based on the DLT analysis set.
7.11.2
Clinical Laboratory Evaluations
For the purposes of summarization in both the tables and listings, all laboratory values will be 
converted to standardized units. If a lab value is reported using a non-numeric qualifier (e.g., less 
than (<) a certain value, or greater than (>) a certain value), the given numeric value will be used 
in the summary statistics, ignoring the non-numeric qualifier.
If a patient has repeated laboratory values for a given time point, the value from the last 
evaluation will be used.
In each case, the laboratory test results will be summarized by Baseline, Post-Baseline Minimum 
and Post-Baseline Maximum. Change from Baseline to Post-Baseline Minimum and Change 
from Baseline to Post-Baseline Maximum will also be summarized. 
Mean laboratory values over time will be plotted for key laboratory parameters, including Hb, 
leukocytes, ANC, platelets, and liver function tests [ALT, AST, ALP, total bilirubin], phosphate, 
creatinine). Laboratory data will also be presented in listings. Unscheduled laboratory test results 
will be listed and included in laboratory shift tables.
Shift tables will be constructed for laboratory parameters to tabulate changes in NCI CTCAE for 
toxicity from baseline to post baseline worst on study CTC grade, if available. Parameters to be 
tabulated will include:

Hematology: Hemoglobin, hematocrit, platelet (count), leukocytes with differential, 
neutrophils (ANC)

Serum chemistry: Creatinine, Bilirubin (total), BUN, Phosphate, Alkaline phosphatase 
(ALP), Aspartate aminotransferase (AST), Alanine aminotransferase (ALT)
7.11.3
Vital Signs
The actual values of vital sign parameters including temperature, heart rate, systolic and diastolic 
blood pressure, and weight, will be summarized over time for each dose level and overall. 
Change of vital signs from baseline values will also be summarized over time.
7.11.4
12-Lead ECGs
A summary of ECG abnormalities will be presented by visit. ECG intervals (QT and QTcF, PR
interval, QRS duration, and heart rate) will be summarized in a similar fashion to laboratory test 
results, along with mean change from baseline to each post treatment time point.
7.11.5
Pregnancy Test
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Statistical Analysis Plan 1.0
08 May 2020
7.11.6
Other Observations Related to Safety
Not applicable.
7.12
Interim Analysis
Not applicable.
7.13
Changes in the Statistical Analysis Plan 
Parts B and C of the protocol will not be conducted (Figure 4.a); therefore, the endpoints and 
relevant analyses have been removed from the SAP.
8.0
REFERENCES
1. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: Revised RECIST guideline (version 1.1). Eu J Cancer 2009;45:228-247.
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