Clinical trial NCT03238651
Conditions: Lymphoma, Non-Hodgkin Lymphoma, Follicular, Marginal Zone
Keywords: Drug therapy
Sponsor: Calithera Biosciences, Inc
Start date: 2017-08-01; Completion date: 2020-08-17
Enrollment: 17 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine the safety, tolerability, maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of TAK-659 when administered in East Asian participants with NHL who do not have an effective standard treatment available and to characterize the plasma and urine pharmacokinetic (PK) of TAK-659 in East Asian participants with NHL.

Detailed description:
The drug being tested in this study is called TAK-659. TAK-659 is being tested to treat people who have NHL or people who have relapsed and/or refractory NHL. This study will assess the safety, tolerability, PK, and preliminary efficacy of single-agent TAK-659 in East Asian participants with NHL.

The study will enroll approximately 33 to 47 participants, including at least 6 Japanese at RP2D dose level. Participants will be assigned to one of the following treatment groups:

Dose Escalation Part: TAK-659 Expansion Part: TAK-659 RP2D

This multi-center trial will be conducted in Japan and Republic of Korea. The maximum duration of participation in dose escalation part of the study is up to 12 months, unless in the opinion of the investigator and sponsor the participant would derive benefit from continued therapy beyond 12 months. In expansion part, participants who stop treatment for any other reason other than PD will continue to have PFS follow-up at the site every 2 months from the last dose of study drug up to 6 months or until PD. Participants will be followed 28 days after last dose of study drug or until the start of subsequent antineoplastic therapy, whichever occurs first, for a follow up assessment.

Arms: arm 1: TAK-659, tablet, orally, once daily, in a 28-day treatment cycle for up to 12 months or until disease progression or unacceptable toxicity, with a starting dose of 60 milligram (mg) in Cohort 1. Dose escalation will follow a standard 3+3 schema . If 60 mg, once daily is safe and tolerable, then the dose will be escalated to 80 mg, once daily and subsequently in 20 mg increments until MTD and/or RP2D is determined. Based on emerging safety, tolerability, PK data, a lower dose will be permitted. arm 2: TAK-659, tablet, orally, once daily as 7 days on and 7 days off treatment (dosing on 7 days followed by 7 days of rest) in a 28-day treatment cycle for up to 12 months or until disease progression or unacceptable toxicity, with a starting dose of 80 mg in Cohort 1. Dose escalation will follow a standard 3+3 schema. An alternative intermittent regimen may be evaluated if deemed necessary per the emerging data. arm 3: TAK-659, tablet, orally, once daily, in a 28-day treatment cycle until disease progression or unacceptable toxicity in participants with follicular lymphoma (FL) or marginal zone lymphoma (MZL) who are relapsed and/or refractory. Dose and dosing schedule for this part will be MTD/RP2D determined from results of dose escalation part.
Interventions: intervention 1: TAK-659
Intervention descriptions: intervention 1: TAK-659 Tablets.

Protocol documents:
Prot_000.pdf: 



Title: A Phase 1, Open-label Study of TAK-659 as a Single Agent in Adult East Asian Patients 
with Non-Hodgkin Lymphoma
NCT Number: NCT03238651
Protocol Approve Date: 6 December 2018
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.


PROTOCOL
A Phase 1, Open-label Study of TAK-659 as a Single Agent in Adult East Asian Patients 
With Non-Hodgkin Lymphoma
Sponsor:
Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda 
Pharmaceutical Company Limited
40 Landsdowne Street
Cambridge, MA USA 02139
Telephone: +1 (617) 679-7000
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:
C34007
Compound:
TAK-659
Date:
6 December 2018
Amendment Number:
02
Amendment History:
Date
Amendment Number
Region
7 March 2017
Initial Protocol
Global
24 May 2017
01
Global
6 December 2018
02
Global
Propert
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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.
Takeda sponsored investigators per individual country requirements will be provided with 
emergency medical contact information cards to be carried by each subject.
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site.
Contact Type/Role
Contact
Serious adverse event and 
pregnancy reporting
See Section 10.2
Responsible Medical Officer 
(carries overall responsibility for 
the conduct of the study)
The names and contact information for the medical monitor and responsible medical officer are in 
the study manual.
Property of Takeda: For Non-Commercial Use 
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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 Council for Harmonisation (ICH) E6 Good Clinical Practice (GCP): 
Consolidated Guideline.
!
All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations.
SIGNATURES
The signature of the responsible Takeda medical officer (and other signatories, as applicable) can 
be found on the signature page.
Electronic Signatures may be found on the last page of this document.
Date
Date
Property of Take
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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 subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Council for Harmonisation, E6 Good Clinical Practice: Consolidated Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events (SAEs) defined in Section 10.2
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)
Investigator’s Title
Location of Facility (City, State/Province)
Location of Facility (Country)
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1.3
Protocol Amendment 02 Summary of Changes
This document describes the changes in reference to the Protocol Incorporating Amendment 
No. 02.
The primary purpose of this amendment is to add 2 possible new cohorts (40 mg QD continuous 
and 80 mg QD 7 days on/7 days off intermittent regimen) to the dose escalation part, and to change 
the target tumor type for the expansion part from diffuse large B-cell lymphoma (DLBCL) to 
follicular lymphoma (FL) or marginal zone lymphoma (MZL). Schedule of Events is revised and 
new Tables added for this purpose.
Rationales for these changes made are shown below.
1.3.1
Rationale for Addition of the New Cohorts
While encouraging single-agent TAK-659 clinical benefit has been observed in global clinical 
studies, the durability of the clinical benefit has been limited by toxicities that have led to study 
treatment interruption and/or discontinuation. In Western population studies, the highest dose of 
TAK-659 evaluated in the first in human lymphoma study (C34001) in a 28-day cycle was 
120 mg/day and the MTD was 100 mg QD. A 7 days on/7 days off intermittent dose of TAK-659 
at 60 mg QD in combination with venetoclax at 400 mg QD (study C34008) has been tested 
without dose-limiting toxicity (DLT). Within study C34007, the starting dose of 60 mg QD was 
evaluated and one DLT was observed in 6 subjects within Cycle 1, therefore the dose was 
escalated to 80 mg QD. As of 15 October 2018, 2 patients at 80 mg QD experienced DLTs, one 
case of Grade 3 febrile neutropenia and Grade 3 hypophosphatemia occurred 2 weeks after 
initiation of TAK-659 treatment and one case of prolonged asymptomatic Grade 3 amylase/lipase 
elevations 1 week after dosing TAK-659; therefore 60 mg QD has been considered the MTD for 
the continuous dosing regimen. However, dose interruptions were frequently experienced 
throughout treatment cycles. In order to explore optimal dosing regimen for durable long-term 
tolerability, 2 additional cohorts may open: 40 mg QD continuous (this regimen is considered 
permissible per protocol amendment 01) and 80 mg QD 7 days on/7 days off intermittent regimen. 
An alternative intermittent regimen (eg, 60 mg QD 7 days on/7 days off) may be evaluated if 
deemed necessary per the emerging data. Based on prior experiences, some of the toxicities (eg, 
creatine kinase elevation) seem to be reversible 1 week after treatment interruption. It is therefore 
hypothesized a greater benefit/risk ratio may be derived from an intermittent dosing regimen of 
TAK-659 in patients with lymphoma. This is further supported by the recent approval of 
copanlisib with once weekly dosing regimen that seemed to have presented a favorable benefit/risk 
profile in comparison against idelalisib with a twice daily continuous dosing regimen. It is noted 
that some other B-cell receptor (BCR) inhibitors are also being tested in intermittent dosing 
regimens, suggesting a drug holiday may not necessarily diminish the efficacy of a BCR pathway 
inhibitor. Collectively, the sponsor considers plausible to propose the 2 cohorts in dose escalation 
phase. The recommended phase 2 dose (RP2D) for East Asian patients will be selected among 
60 mg QD, 40 mg QD, and 80 mg QD, 7 days on/7 days off regimens or its alternative regimen, 
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based on the aggregate data of safety, tolerability, pharmacokinetics (PK), pharmacodynamics, 
and clinical efficacy.
1.3.2
Rationale for Changing the Tumor Type in Expansion Cohort
The early signal from TAK-659 studies directed further development in DLBCL, hence the 
expansion cohort of this study was planned to focus on DLBCL. However, the phase 2 data of 
single-agent TAK-659 did not corroborate the early finding in DLBCL. A significant level of 
objective response (82% in response evaluable population) was observed in patients with FL 
treated with TAK-659 single agent in the first in human study. However, the durability of the 
objective response in FL has not been optimal, possibly due to dose modifications associated with 
the toxicities. With the attempt to optimize the dosing regimen, it is hypothesized that a sustainable 
long-term dosing of TAK-659 may offer a potential for clinical success in FL. As an indolent 
disease, FL is a preferred tumor type to test long-term safety profile of TAK-659. Enrollment of 
MZL, another indolent NHL is allowed to mitigate the concern of undue delay of accrual.
A summary of the other major changes made in the amendment are shown below. Minor 
grammatical, editorial, formatting and administrative changes not affecting the conduct of the 
study are included for clarification and administrative purposes only. For specific descriptions of 
text changes and where the changes are located, see Appendix J.
1. Revised the planned number of sites.
2. Updated the diseases under study section to include FL and MZL.
3. Added a sentence to the nonclinical experience section to instruct the reader to refer to the 
TAK-659 IB for detailed discussion of the nonclinical toxicology, metabolism, and 
pharmacology of TAK-659.
4. Updated the clinical experience section with more recent data.
5. Updated the risks and benefits section with more recent data.
6. Revised the rationale for the proposed study.
7. Revised the rationale for dose and dosing schedule.
8. Revised the rationale for PK assessments section.
9.
10. Revised target tumor type description in the secondary objective regarding evaluation of the 
preliminary efficacy of TAK-659.
11.
 
12. Revised the assessment time points for the PK-related primary/additional endpoints.
13. Revised the name of the expansion part, and removed one of the secondary endpoints 
regarding the assessment of time to progression (TTP).
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14. Removed response data collection assessed using the IWG 2014 (Lugano) criteria.
15. R
16. Revised the overview of study design.
17. Revised the number of subjects to be enrolled into this study.
18. Revised the end of study/study completion definition and planned reporting section.
19. Revised maximum time frames for the primary/secondary endpoints.
20. Revised the total study duration.
21. Revised inclusion criterion #3.
22. Revised inclusion criterion #6.
23. Revised exclusion criterion #9.
24. Revised study drug administration section.
25. Clarified the definitions of DLT.
26. Updated the dose escalation rules section.
27. Added a table showing dose reduction levels for TAK-659.
28. Updated the criteria for beginning or delaying a subsequent treatment cycle.
29. Clarified that the use of excluded medications to manage AEs will require appropriate washout 
period before resuming the study drug.
30. Added that females cannot donate ova and males cannot donate sperm for 180 days after the 
last dose of study drug.
31. Added monitoring and prophylaxis procedures for cytomegalovirus (CMV).
32. Added CMV tests to be done at screening and monitored throughout the study.
33. Removed the text describing central reading of radiographic images.
34. Revised the instructions for performing CT scans for disease assessment in the expansion part.
35. Revised the tumor specimen measurements section.
36. Added and reorganized tables indicating the PK, ECG, and pharmacodynamic assessment 
schedules for the dose escalation part and the expansion part in Appendix A.
37. Added description on the blood sample collection time points for PK for subjects on the new 
Dosing Schedule B (7 days on/7 days off intermittent dosing).
38. Added a new section for blood sample collection for assessment of the pharmacodynamic 
effects of TAK-659 on circulating immune cells.
39. Pregnancy was added to the reasons for discontinuation of treatment with study drug.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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40. Pregnancy was added to the reasons for withdrawal of patients from study.
41. Revised the posttreatment follow-up assessments section.
42. Revised the PK analysis section.
43.
44. Revised Table 13.a (Probabilities of Observing the Minimum Number of Responders Given 
True Response Rates, Assuming a Total of 12 Response-Evaluable Patients).
45. Updated the protocol deviations section.
46. Updated the IRB and/or IEC approval section.
47. Revised the list of references.
48. Revised to allow predose ECG to be performed outside the 1 hour window before dosing.
49. Clarified that postdose samples for pharmacodynamic assessment (cytokine/chemokine/serum 
protein) in the dose escalation part and the expansion part, and also the postdose samples for 
pharmacokinetic assessment in the expansion part should be collected either at 2-hour or 
4-hour postdose.
50. Updated the Schedule of Events.
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE.......................................................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 02 Summary of Changes ..........................................................5
1.3.1
Rationale for Addition of the New Cohorts ...................................................5
1.3.2
Rationale for Changing the Tumor Type in Expansion Cohort.......................6
2.0
STUDY SUMMARY ....................................................................................................15
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...........................................................................................23
4.0
INTRODUCTION.........................................................................................................24
4.1
Background .............................................................................................................24
4.1.1
Diseases Under Study .................................................................................24
4.1.2
Study Drug..................................................................................................26
4.1.3
Nonclinical Experience ...............................................................................26
4.1.4
Clinical Experience.....................................................................................27
4.1.5
Risks and Benefits.......................................................................................30
4.2
Rationale for the Proposed Study.............................................................................32
4.2.1
Rationale for Dose and Dosing Schedule.....................................................33
4.2.2
Rationale for PK Assessments.....................................................................33
4.2.3
 
................................34
4.2.4
34
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................36
5.1
Objectives................................................................................................................36
5.1.1
Primary Objectives......................................................................................36
5.1.2
Secondary Objective ...................................................................................36
5.1.3
Exploratory Objectives................................................................................36
5.2
Endpoints.................................................................................................................36
5.2.1
Primary Endpoints.......................................................................................36
5.2.2
Secondary Endpoints...................................................................................37
5.2.3
Additional Endpoints ..................................................................................37
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Commercial Use Only and Subject to the Applicable Terms of Use
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5.2.4
Exploratory Endpoints.................................................................................37
6.0
STUDY DESIGN..........................................................................................................38
6.1
Overview of Study Design.......................................................................................38
6.2
Number of Patients ..................................................................................................40
6.3
Duration of Study ....................................................................................................41
6.3.1
Duration of an Individual Patient’s Study Participation ...............................41
6.3.2
End of Study/Study Completion Definition and Planned Reporting.............41
6.3.3
Timeframes for Primary and Secondary Endpoints to Support Disclosures..41
6.3.4
Total Study Duration...................................................................................43
7.0
STUDY POPULATION................................................................................................44
7.1
Inclusion Criteria .....................................................................................................44
7.2
Exclusion Criteria ....................................................................................................46
8.0
STUDY DRUG .............................................................................................................49
8.1
Study Drug Administration......................................................................................49
8.2
Definitions of DLT ..................................................................................................49
8.3
Dose Escalation Rules..............................................................................................50
8.4
Dose Modification Guidelines..................................................................................53
8.4.1
General Principles.......................................................................................53
8.4.2
Intrapatient Dose Escalation........................................................................54
8.4.3
Criteria for Beginning or Delaying a Subsequent Treatment Cycle..............54
8.4.4
TAK-659 Dose Modification for Hematologic Toxicities............................54
8.4.5
TAK-659 Dose Modification for Nonhematologic Toxicities ......................55
8.5
Concomitant Medications and Procedures................................................................58
8.6
Precautions and Restrictions ....................................................................................59
8.6.1
Pregnancy and Contraception......................................................................60
8.6.2
Patients With Prior Exposure to HBV or HCV ............................................61
8.7
Management of Clinical Events ...............................................................................61
8.7.1
Prophylaxis Against Infections....................................................................61
8.7.2
Pneumonitis ................................................................................................62
8.7.3
Nausea and/or Vomiting..............................................................................62
8.7.4
Diarrhea......................................................................................................63
8.7.5
Edema (Including Periorbital) .....................................................................63
8.7.6
Rash With or Without Pruritus ....................................................................63
8.7.7
Thrombocytopenia ......................................................................................63
8.7.8
Neutropenia ................................................................................................63
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8.7.9
Anemia .......................................................................................................64
8.7.10
Hypophosphatemia......................................................................................64
8.7.11
Enzyme Elevations......................................................................................64
8.7.12
Fluid Deficit................................................................................................64
8.8
Blinding and Unblinding..........................................................................................64
8.9
Description of Investigational Agents ......................................................................64
8.10
Preparation, Reconstitution, and Dispensation..........................................................65
8.11
Packaging and Labeling...........................................................................................65
8.12
Storage, Handling, and Accountability.....................................................................65
9.0
STUDY CONDUCT......................................................................................................66
9.1
Study Personnel and Organizations..........................................................................66
9.2
Arrangements for Recruitment of Patients................................................................66
9.3
Treatment Group Assignments.................................................................................66
9.4
Study Procedures.....................................................................................................66
9.4.1
Informed Consent........................................................................................67
9.4.2
Patient Demographics .................................................................................67
9.4.3
Medical History ..........................................................................................67
9.4.4
Physical Examination..................................................................................67
9.4.5
Patient Height and Weight...........................................................................67
9.4.6
Vital Signs ..................................................................................................67
9.4.7
ECOG Performance Status..........................................................................67
9.4.8
Pregnancy Test............................................................................................68
9.4.9
Concomitant Medications and Procedures...................................................68
9.4.10
AEs.............................................................................................................68
9.4.11
Enrollment ..................................................................................................68
9.4.12
ECG............................................................................................................68
9.4.13
Clinical Laboratory Evaluations ..................................................................69
9.4.14
Ophthalmic Exam .......................................................................................71
9.4.15
Disease Assessment ....................................................................................71
9.4.16
Tumor Specimen Measurements for Biomarkers .........................................73
9.4.17
PK Measurements .......................................................................................74
9.4.18
Pharmacodynamic Measurements ...............................................................75
9.4.19
DNA Measurements....................................................................................75
9.4.20
Sample Retention........................................................................................76
9.5
Completion of Treatment .........................................................................................76
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9.6
Completion of Study................................................................................................76
9.7
Discontinuation of Treatment With Study Drug and Patient Replacement................76
9.8
Withdrawal of Patients From Study .........................................................................77
9.9
Study Compliance....................................................................................................78
9.10
Posttreatment Follow-up Assessments (PFS) (Expansion Part Only)........................78
10.0
ADVERSE EVENTS ....................................................................................................79
10.1
Definitions...............................................................................................................79
10.1.1
Pretreatment Event Definition .....................................................................79
10.1.2
AE Definition..............................................................................................79
10.1.3
SAE Definition ...........................................................................................79
10.2
Procedures for Recording and Reporting AEs and SAEs..........................................80
10.3
Monitoring of AEs and Period of Observation .........................................................81
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) ................................................................................................................82
10.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities...........82
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
Analysis Sets...............................................................................................86
13.1.2
Analysis of Demographics and Other Baseline Characteristics ....................86
13.1.3
Efficacy Analysis ........................................................................................86
13.1.4
PK Analysis ................................................................................................87
13.1.5
Pharmacodynamic Analysis and PK/Pharmacodynamic Analysis................88
13.1.6
Predictive Biomarker Analysis ....................................................................88
13.1.7
Safety Analysis ...........................................................................................88
13.2
Interim Analysis and Criteria for Early Termination ................................................89
13.3
Determination of Sample Size..................................................................................89
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................91
14.1
Study-Site Monitoring Visits ...................................................................................91
14.2
Protocol Deviations..................................................................................................91
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................92
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15.0
ETHICAL ASPECTS OF THE STUDY........................................................................93
15.1
IRB and/or IEC Approval ........................................................................................93
15.2
Subject Information, Informed Consent, and Subject Authorization .........................94
15.3
Subject Confidentiality ............................................................................................95
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................95
15.4.1
Publication..................................................................................................95
15.4.2
Clinical Trial Registration...........................................................................96
15.4.3
Clinical Trial Results Disclosure .................................................................96
15.5
Insurance and Compensation for Injury....................................................................96
16.0
REFERENCES..............................................................................................................97
LIST OF IN-TEXT TABLES
Table 4.a
Overview of TAK-659 Clinical Studies..............................................................28
Table 6.a
Primary and Secondary Endpoints for Disclosures .............................................42
Table 8.a
Planned Dose Levels..........................................................................................52
Table 8.b
Dose Reduction Levels for TAK-659 .................................................................53
Table 8.c
TAK-659 Dose Adjustments for Hematologic Toxicities....................................55
Table 8.d
TAK-659 Dose Adjustments for Nonhematologic Toxicities..............................57
Table 9.a
Clinical Chemistry and Hematology Tests..........................................................70
Table 9.b
Clinical Urinalysis Tests ....................................................................................70
Table 13.a
Probabilities of Observing the Minimum Number of Responders Given True 
Response Rates, Assuming a Total of 12 Response-Evaluable Patients ..............90
LIST OF IN-TEXT FIGURES
Figure 6.a
Overview of Study Design .................................................................................40
Figure 8.a
Dose Escalation Algorithm.................................................................................52
LIST OF APPENDICES
Appendix A
Schedule of Events.............................................................................................99
Appendix B
Responsibilities of the Investigator...................................................................114
Appendix C
Investigator Consent to Use of Personal Information........................................116
Appendix D
International Working Group Response Criteria for Lymphoma.......................117
Appendix E
ECOG Scale for Performance Status................................................................118
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Appendix F
Cockcroft-Gault Equation ................................................................................119
Appendix G
Methods of Contraception Considered to be Effective......................................120
Appendix H
New York Heart Association Classification of Functional Capacity .................121
Appendix I
Medications, Supplements and Food Products that are Strong CYP3A and/or 
P-gp Inhibitors or Inducers...............................................................................122
Appendix J
Detailed Description of Amendments to Text...................................................124
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2.0
STUDY SUMMARY
Clinical Study Sponsor(s):
Millennium Pharmaceuticals, Inc
Compound:
TAK-659
Study Title: A Phase 1, Open-label Study of TAK-659 as a 
Single Agent in Adult East Asian Patients With 
Non-Hodgkin Lymphoma
IND No.:
Not applicable
EudraCT No.:
Not applicable
Study Identifier: C34007
Phase: 1
Study Design:
This is an open-label, multicenter, phase 1 study of TAK-659 including a dose escalation part in adult East Asian 
patients with non-Hodgkin lymphoma (NHL) and an expansion part in adult East Asian patients with relapsed and/or 
refractory follicular lymphoma (FL) or marginal zone lymphoma (MZL).
The dose escalation part of the study will enroll approximately 18 to 32 East Asian patients diagnosed with NHL for 
which no effective standard treatment is available. Assuming a dropout rate of 20%, this will ensure that 16 to 28
dose-limiting toxicity (DLT)-evaluable patients are enrolled in the dose escalation part. TAK-659 will be administered 
continuously, once daily (QD) (Dosing Schedule A), or a 7 days on/7 days off intermittent regimen (Dosing 
Schedule B) in 28-day treatment cycles. Dose escalation will follow a standard 3+3 schema to determine the 
maximum tolerated dose (MTD) and/or the recommended phase 2 dose (RP2D). The initial TAK-659 dose will be 
60 mg QD and will escalate to 80 mg QD, provided that the safety and tolerability of the 60 mg dose has been 
demonstrated. Dose escalation will continue until the MTD is reached or until an RP2D (if different from the MTD) 
for East Asian patients has been identified. More conservative dose escalation, evaluation of intermediate doses or 
regimens, and expansion of an existing dose level are all permissible following written confirmation of discussions 
between the sponsor and the investigators, if such measures are needed for patient safety or for a better understanding 
of the dose-toxicity and dose-exposure relationships of TAK-659. If ≥2 of 6 patients experience a DLT at 60 mg QD, 
depending on the overall safety profile, the type of adverse events (AEs)/DLTs observed, and following the 
examination of the preliminary pharmacokinetic (PK) results in relation to the PK data in the Western population, a 
decision will be made either to de-escalate the dose to 40 mg QD or to terminate the study following discussion the 
investigators and the sponsor. If ≥2 of 6 patients experience a DLT at 80 mg QD, alternate dose regimens between 60 
and 80 mg (ie, 80 mg 7 days on 7 days off [Dosing Schedule B]) will be evaluated as described below. The MTD
and/or RP2D should be evaluated with a total of ≥6 DLT-evaluable patients. The RP2D will be determined on the 
basis of the totality of the safety, tolerability, as well as preliminary PK and efficacy data (if available) observed in 
Cycle 1 and beyond. Intrapatient dose escalation is not allowed in this protocol.
An additional dosing schedule will be tested after implementation of Amendment 02:
Dosing Schedule B: TAK-659 will be administered QD for 7 consecutive days followed by another 7 days of rest and 
repeated again (ie, 7 days "on" and 7 days "off"), for a cycle duration of 28 days. The starting dose of 80 mg QD was 
the maximum administered dose in Dosing Schedule A (2 out of 4 patients presented a DLT in the continuous dosing 
regimen). However, the alternative dose of 60 mg may be tested if the 80 mg intermittent regimen is deemed not 
tolerable per emerging data. Dose escalation will be governed using the same standard 3+3 schema.
The expansion part of this study will begin once the RP2D has been determined. The expansion part will proceed with 
dosing of TAK-659 at the RP2D in 28-day cycles. The patient population will consist of East Asian patients with FL or 
MZL who are relapsed and/or refractory after at least 2 prior lines of chemotherapy and who must be ineligible for or 
refusal to hematopoietic stem cell transplant. It is expected that approximately 12 response-evaluable patients will be 
enrolled. Assuming a 20% dropout rate, a total of approximately 15 patients will be enrolled. The objectives of the 
expansion part are to evaluate the longer-term safety and tolerability of TAK-659 administered at the RP2D, to 
characterize the PK of TAK-659, and to evaluate the preliminary efficacy of TAK-659 in relapsed and/or refractory 
FL or MZL. Disease assessment will be performed according to the International Working Group (IWG) 2007 criteria.
At least 1 Japanese patient will be enrolled in each cohort in the dose escalation part. The total number of Japanese 
patients dosed at the RP2D (either the MTD or a lower dose as determined) will be at least 6 including the dose 
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escalation and expansion parts to ensure adequate characterization of PK and safety in Japanese patients.
Intensive PK samples will be collected during Cycle 1 in all patients in the dose escalation part to permit detailed 
characterization of TAK-659 PK. Sparse PK samples will be collected in expansion patients to contribute to 
population PK and exposure-response analyses. If fewer than 6 Japanese patients are dosed at the RP2D during dose 
escalation, additional intensive PK samples will be collected during Cycle 1 in a subset of Japanese patients in the 
expansion part. In total, intensive PK sampling will be performed in at least 6 Japanese patients dosed at the RP2D. 
On the basis of the geographic distribution of patients enrolled and emerging PK and safety data, additional patients 
may be added, as needed, to further characterize the PK, safety, and tolerability in a particular East Asian geographic 
region. On the basis of emerging efficacy data, additional groups or patients with FL/MZL may be added to further 
explore efficacy.
Primary Objectives:
•
To determine the safety, tolerability, and MTD and/or RP2D of TAK-659 administered orally QD to East Asian 
patients with NHL who do not have an effective standard treatment available.
•
To characterize the plasma and urine PK of TAK-659 in East Asian patients with NHL.
Secondary Objective:
•
To evaluate preliminary efficacy of TAK-659 in patients with relapsed and/or refractory NHL.
Subject Population:
Dose escalation part: East Asian patients with a diagnosis of histologically or cytologically confirmed NHL, for which 
no effective standard treatment is available.
Expansion part: East Asian patients with relapsed and/or refractory FL or MZL after at least 2 prior lines of 
chemotherapy and who must be ineligible for or refusal to hematopoietic stem cell transplant.
Planned Number of Subjects:
Approximately 33 to 47 patients
Dose escalation part: Approximately 18 to 32 patients
Expansion part: Approximately 15 patients
Planned Number of Sites:
Dose escalation part: approximately 3-5 sites
Expansion part: approximately 6-10 sites
Dose Level(s):
The study drug will be dosed continuously, QD, in 28-day 
cycles, with a starting dose of 60 mg.
Dose escalation will follow a standard 3+3 escalation scheme. If 
60 mg QD is safe and tolerable, then the dose will be escalated to 
80 mg QD. Dose escalation will continue until MTD and/or 
RP2D is determined.
After implementation of Amendment 02:
With 80 mg QD having exceeded the MTD and long term 
tolerability concerns of 60 mg QD, the study has planned to test 
Route of Administration:
Oral
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40 mg QD continuous dosing. Further, a 7 days on/7 days off 
intermittent regimen at 80 mg QD is proposed to explore 
potentially improved benefit/risk profile. An alternative 
intermittent regimen (eg, 60 mg QD 7 days on/7 days off) may 
be evaluated if deemed necessary per emerging data.
In the expansion part, TAK-659 will be dosed at the RP2D, QD 
or the intermittent regimen, in 28-day cycles.
Duration of Treatment:
Patients will receive study drug until disease progression, 
unacceptable toxicity, or withdrawal due to other reasons.
Estimated median treatment duration is 6 months.
Period of Evaluation:
Safety follow-up: Patients will be followed for 
safety for approximately 28 days after their last 
dose of study drug or until the start of subsequent 
antineoplastic therapy, whichever occurs first.
Progression-free survival (PFS) follow-up (in 
expansion part only): up to 6 months after the last 
dose of study drug (for patients who discontinue 
for reasons other than disease progression) or until 
progression, whichever occurs first.
It is anticipated that this study will last for 
approximately 52 months.
Main Criteria for Inclusion:
•
Male or female patients of East Asian ethnicity (eg, Japanese, Korean, or Chinese) aged 18 years or older (if local 
regulation requires a minimum age for informed consent of more than 18 years, then patients must be the 
minimum age or older per the local regulation) when written study informed consent is obtained.
•
To be enrolled into the dose escalation part, patients must have:
a)
Histologically or cytologically confirmed diagnosis of NHL for which no effective standard treatment is 
available. However, patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, primary 
central nervous system (CNS) lymphoma, or Waldenström macroglobulinemia will be excluded.
b)
Radiographically or clinically measurable disease with at least 1 target lesion. Radiographically measurable 
disease is determined by IWG 2007 criteria for malignant lymphoma.
•
To be enrolled into the expansion part, patients must meet the following criteria:
a)
Patients must have pathologically confirmed FL (Grade 1, 2, or 3A) or MZL.
b)
Relapsed and/or refractory to ≥2 prior lines of chemotherapy based on standard of care that include at 
least 1 anti-CD20-based regimen, as well as alkylating agents (eg, cyclophosphamide or bendamustine).
c)
Patients must be ineligible for or refusal to hematopoietic stem cell transplant.
d)
For patients who have relapsed or progressed after achieving a response (defined as complete response 
[CR] or partial response [PR]), documented, investigator-assessed relapse or progression after the last 
treatment is required. For patients who are refractory to their last treatment (defined as not having achieved 
a CR or PR before enrollment by investigator assessment), documented progression will not be required.
e)
Must have measurable disease that meets the size criteria per IWG (>1.5 cm in the longest diameter for a 
lymph node or a nodal mass, or >1.0 cm in the longest diameter for an extranodal disease) as assessed on 
cross-sectional imaging by computed tomography (CT) scan/magnetic resonance imaging (MRI). (CT scan 
is to be performed with contrast unless it is medically contraindicated.)
•
Eastern Cooperative Oncology Group performance status score of 0 or 1.
•
Life expectancy of longer than 3 months.
•
Patients must have adequate organ function, including the following:
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a)
Bone marrow reserve: absolute neutrophil count ≥1,000/mm3, platelet count ≥75,000/mm3 (≥50,000/mm3
for patients with bone marrow involvement), and hemoglobin ≥8 g/dL (red blood cell [RBC] and platelet 
transfusion allowed ≥14 days before assessment).
b)
Hepatic function: total bilirubin ≤1.5×the upper limit of the normal range (ULN); alanine aminotransferase 
and aspartate aminotransferase ≤2.5×ULN.
c)
Renal function: creatinine clearance ≥60 mL/min either as estimated by the Cockcroft-Gault equation.
Main Criteria for Exclusion:
•
CNS lymphoma; active brain or leptomeningeal metastases as indicated by positive cytology from lumbar 
puncture or CT/MRI by local assessment.
•
Systemic anticancer treatment (including investigational agents) less than 3 weeks before the first dose of study 
treatment (≤4 weeks for antibody-based therapy including unconjugated antibody, antibody-drug conjugate, and 
bi-specific T-cell engager agent; ≤8 weeks for cell-based therapy or anti-tumor vaccine).
•
Radiotherapy less than 3 weeks before the first dose of study treatment. If prior radiotherapy occurred <4 to 6 
weeks before the study start, as radiated lesions cannot be reliably assessed by FDG-PET, nonradiated target 
lesions are required for eligibility.
•
Prior ASCT within 6 months or prior ASCT at any time without full hematopoietic recovery before Cycle 1 
Day 1, or allogeneic stem cell transplant at any time.
•
Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of 
TAK-659 including difficulty swallowing tablets; diarrhea >Grade 1 despite supportive therapy.
•
Use or consumption of any of the following substances:
‒
Medications or supplements that are known to be inhibitors of P-glycoprotein (P-gp) and/or strong 
reversible inhibitors of cytochrome P450 (CYP)3A within 5 times the inhibitor half-life (if a reasonable 
half-life estimate is known) or within 7 days (if a reasonable half-life estimate is unknown) before the first 
dose of study drug. In general, the use of these agents is not permitted during the study except for AE 
management (see Section 8.5 for details).See Appendix I for a nonexhaustive list of strong CYP3A 
reversible inhibitors and/or P-gp inhibitors based on the United States Food and Drug Administration 
(FDA) Draft Drug-Drug Interaction (DDI) Guidance.
‒
Medications or supplements that are known to be strong CYP3A mechanism-based inhibitors or strong 
CYP3A inducers and/or P-gp inducers within 7 days or within 5 times the inhibitor or inducer half-life 
(whichever is longer) before the first dose of study drug. In general, the use of these agents is not permitted 
during the study except for AE management (see Section 8.5 for details). See Appendix I for a 
nonexhaustive list of strong CYP3A mechanism-based inhibitors or strong CYP3A inducers and/or P-gp 
inducers based on the FDA Draft DDI Guidance.
‒
Grapefruit-containing food or beverages within 5 days before the first dose of study drug. Note that 
grapefruit-containing food and beverage are not permitted during the study.
Main Criteria for Evaluation and Analyses:
Primary:
•
Percentage of patients with treatment-emergent AEs (TEAEs).
•
Percentage of patients with Grade 3 or higher TEAEs.
•
Percentage of patients with serious TEAEs.
•
Percentage of patients with DLTs during Cycle 1 (dose escalation part only).
•
Percentage of patients discontinuing study drug because of TEAEs.
•
Percentage of patients with clinically significant abnormal laboratory values.
•
Percentage of patients with clinically significant abnormal vital sign measurements.
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•
TAK-659 maximum observed concentration (Cmax) on Cycle 1 Days 1 and 7 or 15 by dose.
•
TAK-659 time of first occurrence of Cmax (Tmax) on Cycle 1 Days 1 and 7 or 15 by dose.
•
TAK-659 area under the plasma concentration-time curve during the dosing interval on Cycle 1 Days 1 and 
7 or 15 by dose.
•
Renal clearance (CLR) on Cycle 1 Day 7 or 15 by dose.
Secondary:
•
Overall response rate in the expansion part.
•
CR rate in the expansion part.
•
Duration of response in the expansion part.
•
PFS in the expansion part.
The investigator will perform response assessment using modified IWG 2007 criteria for malignant lymphoma.
Additional:
•
Apparent oral clearance (CL/F), CLR as a percentage of CL/F, peak-trough ratio, accumulation ratio, and 
observed concentration at the end of the dosing interval on Cycle 1 Day 7 or 15 by dose.
•
Plasma concentration-time data contributing to population PK and exposure-response analyses.
Statistical Considerations:
Analysis for primary endpoints will be descriptive using percentages and summary statistics. For the secondary 
efficacy endpoints, percentages will be used for binary endpoints, and Kaplan-Meier analysis will be used for 
time-to-event endpoints.
All statistical analyses will be primarily descriptive in nature. No formal statistical hypothesis testing will be 
performed. A statistical analysis plan will be developed and finalized before database lock.
Sample Size Justification:
No formal statistical power calculations to determine sample size were performed for this study.
This study will use a standard 3+3 design in the dose escalation part. Approximately 4 dose cohorts (3-6 patients per 
cohort) are projected, and approximately 16 to 28 DLT-evaluable patients will be enrolled. The actual number of 
patients may vary depending on the actual doses being tested. Assuming a dropout rate of 20%, the dose escalation 
part will enroll approximately 18 to 32 patients.
The sample size of approximately 12 response-evaluable subjects for the expansion part has been chosen to permit an 
adequate assessment of safety and a preliminary assessment of efficacy. Assuming a dropout rate of 20%, the 
expansion part will enroll approximately 15 patients.
The actual number of patients to be enrolled may increase on the basis of emerging data to allow a sufficient number of 
PK/safety-evaluable patients per country or East Asian race group or to further assess efficacy in a specific subtype or 
group of patients with FL or MZL.
At least 1 Japanese patient will be included in each cohort in the dose escalation part, and at least 6 Japanese patients 
will be evaluated at the RP2D (either the MTD or a lower dose) to ensure adequate characterization of safety and PK in 
Japanese patients.
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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 or equivalent. The identified vendors will perform specific 
study-related activities will perform these activities either in full or in partnership with the sponsor.
3.2
Coordinating Investigator
Takeda will select a signatory coordinating investigator from the investigators who participate in 
the study. Selection criteria for this investigator will include significant knowledge of the study 
protocol, the study medication, their expertise in the therapeutic area and the conduct of clinical 
research as well as study participation. The signatory coordinating investigator will be required to 
review and sign the clinical study report (CSR) and by doing so agrees that it accurately describes 
the results of the study.
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3.3
List of Abbreviations
5-HT3
5-hydroxytryptamine 3 serotonin receptor
ABC
activated B-cell
AE
adverse event
ALC
absolute lymphocyte count
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AML
acute myelogenous leukemia
ANC
absolute neutrophil count
ASCO
American Society of Clinical Oncology
ASCT
autologous stem cell transplant
ASH
American Society of Hematology
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve during the dosing interval
BCR
B-cell receptor
BCRP
breast cancer resistance protein
CL/F
apparent oral clearance
CLL
chronic lymphocytic leukemia
CLR
renal clearance
Cmax
maximum observed concentration
CNS
central nervous system
CR
complete response
CRO
contract research organization
CSR
clinical study report
CT
computed tomography
Ctrough
observed concentration at the end of a dosing interval
CV
coefficient of variation
CYP
cytochrome P450
DDI
drug-drug interactions
DLBCL
diffuse large B-cell lymphoma
DLT
dose-limiting toxicity
DOR
duration of response
EBV
Epstein-Barr virus
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EOT
End of Treatment
FDA
(United States) Food and Drug Administration
FDG
fluoro-2-deoxy-D-glucose
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FFPE
formalin-fixed, paraffin-embedded
FIH
first-in-human
FL
follicular lymphoma
FLT3
FMS-like tyrosine kinase 3
GCB
germinal center B-cell
GCP
Good Clinical Practice
G-CSF
granulocyte colony stimulating factor
GGT
gamma glutamyl transferase
GI
gastrointestinal
GM-CSF
granulocyte macrophage-colony stimulating factor
HBcAb
hepatitis B core antibody
HBsAb
hepatitis B surface antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HCVAb
hepatitis C virus antibody
HIV
human immunodeficiency virus
IC50
concentration producing 50% inhibition
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use
IEC
independent ethics committee
IRB
institutional review board
IV
intravenous; intravenously
IWG
International Working Group
LDH
lactate dehydrogenase
MCL
mantle cell lymphoma
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
MZL
marginal zone lymphoma
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NHL
non-Hodgkin lymphoma
NK
natural killer
OAT
organic anion transporter
OATP
organic anion-transporting polypeptide
OCT
organic cation transporter
ORR
overall response rate
PBMC
Peripheral blood mononuclear cell(s)
PD
progressive disease (disease progression)
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PET
positron emission tomography
PFS
progression-free survival
P-gp
P-glycoprotein
PJP
Pneumocystis jirovecii pneumonia
PK
pharmacokinetic(s)
PMDA
Pharmaceuticals and Medical Devices Agency
PO
per os; by mouth (orally)
PR
partial response
PTR
peak-trough ratio
QD
quaque die; each day; once daily
QTc
rate-corrected QT interval (millisec) of electrocardiograph
QTcB
QT interval with Bazett correction method
QTcF
QT interval with Fridericia correction method
Rac
accumulation ratio
RBC
red blood cell
R-CHOP
rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, prednisone
R-ICE
rituximab, ifosfamide, carboplatin, etoposide
RP2D
recommended phase 2 dose
SAE
serious adverse event
SD
stable disease
SLL
small lymphocytic lymphoma
SUSAR
suspected unexpected serious adverse reaction
SYK
spleen tyrosine kinase
TEAE
treatment-emergent adverse event
Tmax
time of first occurrence of Cmax
TTP
time to progression
ULN
upper limit of the normal range
US
United States
WHO
World Health Organization
3.4
Corporate Identification
Millennium
Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceutical 
Company Limited.
TDC Japan
Takeda Development Center Japan
TDC Asia
Takeda Development Center Asia, Pte Ltd
TDC Europe
Takeda Development Centre Europe Ltd
TDC Americas
Takeda Development Center Americas, Inc
TDC
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable
Takeda
Millennium Pharmaceuticals, Inc, TDC Japan, TDC Asia, TDC Europe and/or TDC 
Americas, as applicable
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4.0
INTRODUCTION
4.1
Background
4.1.1
Diseases Under Study
Non-Hodgkin lymphomas (NHLs) are a heterogeneous group of lymphoproliferative disorders 
originating in B lymphocytes, T lymphocytes, or natural killer (NK) cells. Mature B-cell 
lymphomas account for greater than 85% of NHL cases worldwide. The two most common types 
of NHL are diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) [1]. NHL is 
one of the most common malignancies worldwide, with an estimated 386,000 new cases and 
200,000 deaths in 2012. The incidence of NHL exhibits marked geographic variation and is higher 
in North America and Europe. The East Asia region has one of the lowest incidence rates. While 
the increasing incidence of malignant lymphoma has recently slowed in Western countries, other 
parts of the world, including East Asia, have continued to experience an upward trend. In 2012, an 
estimated 63,000 people in the United States (US), 34,000 people in Western Europe, and 72,000 
people in East Asia (21,000 Japanese; 43,000 Chinese; and 4,700 South Korean) were diagnosed
with NHL [2].
In East Asia, it is the same tendency with the Western countries that B-cell neoplasms are the most 
common followed by T/NK cell neoplasms. The proportion of mature B-cell and T/NK cell 
lymphoma subtypes is different, while the most common subtype is DLBCL in China, Korea and 
Japan. Japan shows a higher proportion of FL and adult T-cell leukemia/lymphoma cases, and 
China has a higher proportion of extranodal NK/T-cell lymphoma, nasal type cases [3]. In Korea, 
precursor cell neoplasms are relatively high and MZL is the second most common subtype among 
mature B-cell lymphoma [4].
4.1.1.1
DLBCL
DLBCL represents about 30% of all NHL. It is estimated that approximately 20,000; 10,000; 
6,400; 12,000; and 1,400 new cases of DLBCL are diagnosed annually in the United States, 
Western Europe, Japan, China, and South Korea, respectively [2]. DLBCL is a form of aggressive 
B-cell NHL that is invariably fatal without treatment.
Treatment guidelines in Asia generally follow the National Comprehensive Cancer Network 
guidelines. Despite slight differences in approved drugs, the systematic therapy pattern for 
DLBCL in Asia is very similar to that in the United States and Western Europe. The 
immunochemotherapy regimen R-CHOP (rituximab, cyclophosphamide, doxorubicin 
hydrochloride, vincristine sulfate, and prednisone) is the standard treatment for patients newly 
diagnosed with DLBCL worldwide. This frontline regimen results in complete response (CR) in 
approximately 60% to 75% of patients with DLBCL as reported in trials with Western patients 
[5,6]. In a key publication in Japan, a CR rate of 78% was reported with the frontline R-CHOP 
regimen in patients with DLBCL [7]. This treatment is considered curative in a subset of patients, 
with a cure rate of >50% [8,9]. However, DLBCL is highly heterogeneous in histology, clinical 
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behavior, and underlying biology and therefore exhibits significant variation in outcome after 
therapy [5,10].
High-dose chemotherapy, including salvage regimens such as R-ICE (rituximab, ifosfamide, 
carboplatin, etoposide), followed by autologous stem cell transplant (ASCT) is the treatment of 
choice for patients with relapsed disease. For patients with disease relapse following transplant or 
for patients not eligible for transplant, there is no clear standard of care; therefore, multiple 
chemotherapy regimens and investigational agents in clinical trials are being used to treat these 
patients. However, clinically meaningful benefit is rarely achieved in patients with progressive 
disease (PD) following multiple regimens.
Consistent with the heterogeneity in underlying biology, it has been reported that DLBCL can be 
molecularly subclassified into 3 categories based on gene expression profiles [11]. One of the 
subtypes, a BCR/proliferation subtype identified in ~40% of DLBCL, has higher expression of 
BCR signaling components such as CD19, IgH, CD79α, BLK, spleen tyrosine kinase (SYK), 
PLCγ2, and MAP4K. BCR signaling has subsequently been shown to be a critical driver of 
tumorigenesis in the BCR subtype of DLBCL. Therefore, inhibition of BCR signaling by a SYK 
inhibitor such as TAK-659 might generate pronounced antitumor effects in DLBCL, particularly 
in the BCR-driven subpopulation.
4.1.1.2
Indolent NHL
Follicular lymphoma (FL) is the most common indolent NHL in the Western hemisphere, 
representing 20% of NHL [12], whereas Asian frequency is different from that of the Western. It 
varies in each Asian country; 2.9%, 1.7%, 21.7% of total lymphoid neoplasms in China, Korea, 
Japan [3]. Randomized clinical trials have demonstrated that the addition of rituximab to standard 
chemotherapy induction has improved overall survival. Maintenance rituximab strategies can 
improve PFS. Bendamustine combined with rituximab has rapidly become a standard frontline 
strategy in North America and parts of Europe. However, several unmet needs remain, including 
the identification of high-risk patients at diagnosis and the development of predictive biomarkers 
for targeted agents [12].
Other common B cell malignancies include Mantle cell lymphoma (MCL) and MZL. These B cell 
lymphoma subtypes comprise about 6% and 10% of all NHL respectively [13]. In Asia, the 
proportion of MCL and MZL is 2.4%, 8.3% in China, 1.8%, 13.5% in Korea and 3.3%, 4.3% in 
Japan of total lymphoid neoplasms [3]. MCL is poor prognostic despite the development of 
therapeutic strategy based on understanding of its biology and is thought to have the worst 
characterstics of both indolent and aggressive NHLs [14]. MZL is heterogeneous and 
clinocopathological subtypes are extranodal MZL of MALT, nodal MZL and splenic MZL[13].
For indolent B-NHL, watchful wait or radiotherapy is frequently used for early stage or low-tumor 
burden lymphoma, while rituximab or rituximab plus cytotoxic agent(s) such as CHOP, 
bendamustine is administered for patients who require chemotherapy [15,16]. In Japan, R-CHOP 
or R-Bendamustine is frequently chosen as the frontline treatment for FL and MZL [17-19]. In 
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relapsed or refractory iNHL, bendamustine as a single agent or rituximab-containing 
chemotherapy regimens can be used.
In Korea, R-CVP (cyclophosphamide, vincristine, prednisolone) is used for MZL [20], and 
R-CVP and R-CHOP are used for FL [21].
4.1.2
Study Drug
TAK-659, created by Takeda Pharmaceutical Company Limited, is an orally (PO) bioavailable, 
potent and reversible inhibitor of SYK and FMS-like tyrosine kinase 3 (FLT3) and is currently 
under development for the treatment of patients with advanced malignancies. Dual SYK/FLT3 
inhibition represents a novel mechanism of action, and currently there are no marketed drugs with 
either a dual SYK/FLT3 or SYK alone mechanism of action.
SYK is a nonreceptor protein tyrosine kinase that is widely expressed in hematopoietic cells. It is 
involved in coupling activated immune receptors to downstream signaling pathways that mediate 
diverse cellular responses, including proliferation, differentiation, and survival. SYK activation 
leads to phosphorylation and subsequent activation of a number of downstream signaling
pathways (eg, PI3K, MAPK, and NF-B). The SYK pathway is implicated in hematologic tumors 
and select solid tumors (eg, Epstein-Barr virus [EBV]-mediated nasopharyngeal tumors).
FLT3 is a receptor tyrosine kinase that plays a role in hematopoiesis. Activating mutations in 
tyrosine kinase genes, including FLT3, are found in approximately 30% of patients with de novo 
acute myelogenous leukemia (AML). Mutations in the FLT3 gene most often involve internal 
tandem duplication of the juxtamembrane domain coding region or point mutations of the tyrosine 
kinase domain, resulting in ligand-independent proliferation due to constitutive activation of the 
FLT3 receptor, conferring poor prognosis for patients.
TAK-659 inhibits SYK purified enzyme with a concentration producing 50% inhibition (IC50) of 
3.2 nM. In cultured human tumor cells, TAK-659 potently inhibited SYK activity in 
hematopoietic-derived cell lines. In a broad kinase panel, TAK-659 demonstrated a more than 
50-fold selectivity for SYK over 290 other protein kinases screened. Subsequent dose response 
analysis independently confirmed the potency of TAK-659 on 4 of these enzymes (FLT-3, 
ZAP-70, JAK3, and vascular endothelial growth factor receptor 2) with potency ranging from 4.6
to 135 nM.
4.1.3
Nonclinical Experience
In vitro and in vivo pharmacology studies demonstrated that TAK-659 is a potent, reversible SYK 
and FLT3 inhibitor. TAK-659 has exhibited significant antitumor activity in a number of mouse 
DLBCL xenograft models, including the OCI-Ly10 model, an activated B-cell-like 
(ABC)-DLBCL model; the OCI-Ly19 model, a germinal center B-cell–like (GCB)-DLBCL 
model; the PHTX-95L model, a primary human DLBCL model; the TMD8 ABC-DLBCL model; 
the RL follicular lymphoma (FL) model; and the MINO mantle cell lymphoma (MCL) model. In 
nonclinical species, TAK-659 has good oral bioavailability, low plasma protein binding, moderate 
to large volumes of distribution, and moderate to high plasma clearance. The TAK-659 nonclinical 
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pharmacokinetic (PK) profile makes it a suitable candidate for clinical development. On the basis 
of results of nonclinical safety pharmacology studies, TAK-659 is not expected to cause 
cardiovascular (CV), respiratory, or central nervous system (CNS) effects in patients. Overall, the 
nonclinical safety profile of TAK-659 has been adequately characterized. The nonclinical 
assessment of TAK-659 supports clinical trials in patients with advanced malignancies such as 
relapsed and/or refractory FL.
A detailed discussion of the nonclinical toxicology, metabolism, and pharmacology of TAK-659
can be found in the TAK-659 IB.
4.1.4
Clinical Experience
4.1.4.1
Clinical Experience with TAK-659
TAK-659 is being investigated in 7 clinical studies involving patients with advanced malignancies 
(Table 4.a) in addition to this study. The status of each study is described below.
Currently, more than 300 patients have been dosed with TAK-659, including 143 patients in
first-in-human (FIH) Study C34001 (single-agent study in advanced solid tumors and lymphomas), 
43 patients in Study C34002 (single-agent study in relapsed or refractory AML), 41 patients in 
Study C34003 (study of TAK-659 in combination of nivolumab in advanced solid tumors), 49 
patients in Study C34004 (single-agent study in DLBCL), 41 patients in Study C34005 (study of 
TAK-659 in different combinations in NHL), 10 patients in Study C34007 (single-agent dose 
escalation study in Japanese patients), and 11 patients in Study C34008 (study of TAK-659 in 
combination with venetoclax in NHL). Further details about safety and efficacy on these clinical 
studies are provided in the current IB.
For detailed clinical study information, please refer to the TAK-659 IB.
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Table 4.a
Overview of TAK-659 Clinical Studies
Protocol No. /
Status
Study Design and Population
Dosing Regimen
C34001/
Closed to 
enrollment
Open-label, multicenter, phase 1, 
dose escalation study of TAK-659 in 
adult patients with advanced solid 
tumors and lymphoma malignancies
Increasing TAK-659 oral doses of 60, 80, 100, and 120 mg 
QD during dose escalation;
MTD of 100 mg QD further explored in patients with 
lymphoma during dose expansion.
C34002/
Closed to 
enrollment
Open-label, multicenter, phase 1b/2, 
dose escalation study of TAK-659 in 
adult patients with relapsed or 
refractory AML
Starting TAK-659 dose of 60 mg QD; additional doses of 
100, 120, 140, and 160 mg QD; 60 mg BID and 80 mg BID 
evaluated;
QD MTD is 160 mg; BID MTD is 60 mg BID.
C34003/
Closed to 
enrollment
Open-label, multicenter, phase 1b, 
dose escalation and dose expansion 
study of TAK- 659 in combination 
with nivolumab in adult patients with 
advanced solid tumors.
TAK-659: starting dose of 60 mg QD; dose has been 
escalated to 100 mg QD.
RP2D will be used in expansion cohorts.
Nivolumab: 3 mg/kg IV dosing over 60 min Q2W (Days 1 
and 15 of each 28-day cycle). If the 240 mg fixed dose cohort 
is evaluated and deemed safe and tolerable, the dosing 
regimen may switch to 240 mg.
MTD of TAK-659 80 mg QD further explored in Triple 
Negative Breast Cancer patients in expansion
C34004/
Ongoing
Open-label, multicenter, phase 2 
study in adult patients with relapsed 
or refractory DLBCL, beginning with 
a lead-in dose exploration phase with 
2 TAK-659 dose regimens
Cohort 1: TAK-659 100 mg QD in 28-day treatment cycles
Cohort 2: TAK-659 increasing dose (every 28 days) 
beginning with 60 mg QD, followed by 80 mg QD, up to 
100 mg QD
C34005/
Ongoing
Open-label, multicenter, phase 1b, 
dose escalation study of TAK-659 in 
combination with 1 of 5 combination 
agents (bendamustine, 
bendamustine + rituximab, 
gemcitabine, lenalidomide, and 
ibrutinib) in adult patients with NHL 
after at least 1 prior line of therapy
TAK-659: starting dose of 60 mg QD; dose will be escalated 
to 100 mg QD until MTD is reached, assuming tolerability at 
the lower doses (60, 80 mg QD).
Combination Agents:
(A) Bendamustine: 90 mg/m2 administered IV over 
10 or 60 min (depending on which formulation is 
used) on Days 1 and 2 of each 21-day cycle, up to 
8 cycles
(B) Bendamustine + rituximab: 90 mg/m2
bendamustine administered IV over 10 or 60 min 
(depending on which formulation is used) on Days 1 
and 2 of each 21-day cycle, up to 8 cycles, and 
375 mg/m2 rituximab IV on Day 1 of each 21-day 
cycle, up to 8 cycles
(C) Gemcitabine: 1000 mg/m2 IV infusion over 30 min 
on Days 1 and 8 of each 21-day cycle
(D) Lenalidomide: 25 mg PO QD for Days 1-21 of each 
28-day cycle
(E) Ibrutinib: 560 mg PO QD of a 28-day cycle
Currently Arms A, C, D, E have been closed. TAK-659 + 
bendamustine +rituximab will be further explored in FL or 
MZL patients only.
Footnotes are on last table page.
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Table 4.a
Overview of TAK-659 Clinical Studies(Continued)
Protocol No. /
Status
Study Design and Population
Dosing Regimen
C34008/
Ongoing
Dose escalation phase: adult patients 
with advanced NHL of any histology.
Patients will be refractory or relapsed 
after at least 1 prior line of therapy 
with no effective standard therapy 
available.
TAK-659: 40 mg, 60 mg, 80 mg or 100 mg PO QD, or 
alternative dosing regimens, as needed, such as intermittent 
TAK-659 for 7 days on followed by 7 days off, or 14 days on 
followed by 7 days off, plus one of the following venetoclax 
regimens administered in 28-day cycles after Cycle 1 
(35 days):
•
50 mg QD increasing to 200 mg QD by Day 16.
•
50 mg QD increasing to 400 mg QD by Day 17.
•
50 mg QD increasing to 800 mg by Day 19.
C34015/
Planned
A phase 1b study of TAK-659 in 
combination with NKTR-214 in 
patients with advanced NHL after 2 
but no more than 3 prior lines of 
therapy
TAK-659: starting dose of 60 mg QD; 80 mg QD or 100 mg 
QD, or alternative dosing regimens, as needed, such as 
intermittent dosing in a 21 day cycle
NKTR-214: 0.003 mg/kg or 0.006 mg/kg IV dosing over 
30 min on Day 1 of each 21 day cycle ).
MTD or RP2D of TAK-659 with NKTR-214 will be 
investigated in expansion.
AML=acute myeloid leukemia, BID=twice daily, DLBCL=diffuse large B-cell lymphoma, IV=intravenous,
MTD=maximum tolerated dose, NHL=non-Hodgkin lymphoma, PO=oral(ly), Q2W=every 2 weeks, QD=once daily,
RP2D=recommended phase 2 dose.
4.1.4.2
Clinical PK of TAK-659
Preliminary plasma pharmacokinetics (PK) results are available from lymphoma, solid tumor, and 
AML patients enrolled in Studies C34001 and C34002. In addition, preliminary urine PK results 
are available from lymphoma and solid tumor patients enrolled in the dose escalation cohorts of 
Study C34001. TAK-659 is characterized by fast absorption (overall median Tmax [time of first 
occurrence of Cmax (maximum observed concentration)] of 2 hours) in patients with hematologic 
and nonhematologic malignancies. Moderate variability is observed among dose-normalized 
steady-state AUC(area under the plasma concentration-time curve during the dosing interval) 
values in lymphoma, solid tumor, and AML patients (coefficient of variation of 20.0%, 43.5%, and 
34.8%, respectively). An approximately dose-proportional increase in steady state AUCwas 
observed over the 60 to 160 mg range in patients with AML. Mean accumulation ratios ranging 
from 1.90-fold to 2.54-fold and mean peak-to-trough ratios ranging from 4.34 to 5.09 were 
observed across the study populations after repeated QD dosing for 15 days. Based on data in 
lymphoma and solid tumor patients, renal clearance accounted for about 30% of TAK-659 
apparent clearance, and therefore at least about 30% of TAK-659 systemic clearance. Active 
tubular secretion appeared to be the predominant component of renal clearance, based on 
comparison of unbound renal clearance to glomerular filtration rate. Geometric mean terminal 
disposition half-life of 34.4 hours was determined in a single dose PK run-in phase of the indolent 
NHL expansion cohort of Study C34001.
Refer to the TAK-659 IB for detailed clinical pharmacology information.
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4.1.5
Risks and Benefits
Because TAK-659 has been administered to limited number of patients, it is not currently possible 
to identify and describe with certainty the adverse effects of the compound.
4.1.5.1
Potential Risks Identified From Nonclinical Studies
Potential risks from nonclinical studies in dogs and rats include:

Lymphoid/hematopoietic effects that include lymphoid depletion and myelosuppression that 
are associated with thrombocytopenia, neutropenia, and reticulocytopenia. These findings may 
be associated with increased susceptibility to infection, bleeding, and/or anemia.

Epithelial effects on the intestinal tract, urinary tract, and lens. Intestinal effects included 
minimal-to-slight mucosal hemorrhaging. Urinary and renal tract effects included hyperplasia 
of transitional epithelium in the kidney and bladder, dilatation and hemorrhage in the renal 
pelvis that led to hematuria and proteinuria, and urolithiasis with possible ureter obstruction. 
Lens effects included epithelium hyperplasia leading to anterior axial opacity.

Reproductive system effects, including decreased spermatozoa and seminiferous tubule 
degeneration in the testis and corpora luteal necrosis in the ovaries.

Possible mutation of DNA.

Growth plate thickening and disorganization (not relevant to adults).
Lymphoid and hematopoietic effects and reproductive system effects are considered important 
potential risks.
4.1.5.2
Potential Risks Based on Clinical Observations
As of the 22 October 2017 data cutoff, following evaluation of the current safety data, 
asymptomatic lipase elevation, pneumonitis, and infections (including pneumonia, CMV 
infections, and sepsis) are recognized as potential risks.
Asymptomatic Lipase Elevation
In clinical studies to date, lipase elevations are reported commonly (≥10%). Patients in study 
C34007 will have frequent monitoring of lipase and amylase as outlined in the Schedule of Events 
(Appendix A).
Pneumonitis
Cases of pneumonitis have been reported in clinical studies with B-cell receptor (BCR) pathway 
kinase inhibitors, including TAK-659, and pneumonitis is considered a potential risk of TAK-659. 
There were 5 SAEs of pneumonitis (4 reported in C34001 and 1 reported in C34002). Pneumonitis 
and other pulmonary toxicities are being closely monitor patients for respiratory signs and 
symptoms throughout TAK-659 treatment. 
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Infections
In an analysis of safety data from 107 patients with lymphoma treated with single-agent TAK-659 
in Study C34001, most patients (72%) experienced at least 1 TEAE of any grade classified under 
the infections and infestations System Organ Class (SOC) as defined by the Medical Dictionary 
for Regulatory Activities (MedDRA). Pneumonia was the most frequently reported infection 
TEAE (26%) and most frequently reported infection SAE (15%). CMV infection (20%) and sepsis 
(17%) were also frequently reported infection TEAEs. Sepsis (17%) and pneumonia (15%) were 
the most frequently reported ≥Grade 3 infection TEAEs. In a heavily pretreated relapsed and/or 
refractory lymphoma patient population, a high rate of infection is expected particularly when 
considering confounding factors such as comorbidities or other immunosuppressive medications. 
The rate of infection, including pneumonia and sepsis, observed in patients with lymphoma who 
received TAK-659 is high and warrants continued monitoring and/or prophylaxis as outlined by
this protocol.
Refer to the TAK-659 IB for detailed information on potential risks.
4.1.5.3
Drug-Drug Interaction Risk Assessment
No formal PK drug-drug interaction (DDI) studies have been conducted with TAK-659 in humans. 
In vitro studies indicate that TAK-659 is a substrate of the efflux transporter P-glycoprotein (P-gp) 
and is metabolized by CYP3A4/5, CYP2D6, and CYP1A2, with relative contributions of 69.1% to 
73.0%, 16.6% to 30.9%, and 0% to 8.4%, respectively. Therefore, there is a potential risk for 
TAK-659 PK to be altered by drugs that are CYP3A inhibitors or inducers or P-gp inhibitors or 
inducers. Consequently, use of strong CYP3A inhibitors or inducers or P-gp inhibitors or inducers 
is not permitted during prespecified periods before the first dose of TAK-659. In general, use of 
these agents is not permitted during the study unless otherwise indicated (see Section 8.5).
TAK-659 was not a potent reversible inhibitor of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5 
in human liver microsomes at concentrations up to 100 M (IC50 values >100 M), nor a 
time-dependent inhibitor of these same CYPs at concentrations up to 50 M. In addition, 
TAK-659 was not an inducer of CYP1A2, 2B6, or 3A activity or messenger RNA expression 
levels in human hepatocytes at concentrations up to 50 M. Furthermore, TAK-659 was not an 
inhibitor of the efflux transporters P-gp or BCRP in Caco-2 cells at concentrations up to 100 µM. 
When these in vitro findings are viewed in context of the maximum observed concentration (Cmax) 
in patients with lymphoma at the single-agent MTD of 100 mg QD, there is low risk for TAK-659 
to cause DDIs via induction or inhibition of CYP enzymes, P-gp, or BCRP.
Additional details on DDI risk are included in TAK-659 IB.
4.1.5.4
Potential Benefits Based on Clinical Observations
The benefits of TAK-659 have not been established; however the clinical benefit of TAK-659 has 
been and continues to be investigated as a single agent or in combination with other agents for the 
treatment of patients with advanced solid tumors, NHL, and AML. Early signs of clinical
antitumor activity were seen.
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Clinical benefit has been observed in First In Human Study C34001 evaluating TAK-659 as a 
single agent. Response data were available for 106 patients (11 solid tumor, 69 DLBCL, 17 iNHL, 
5 Chronic Lymphocytic Leukemia [CLL]), 3 Mantle Cell Lymphoma (MCL), and 1 Post 
Transplant Lymphoproliferative Disorder (PTLD) as of 22 October 2018 in Study C34001. 
Among response-evaluable patients with solid tumors, 1 patient experienced a partial response 
(PR). Among response-evaluable patients with DLBCL, best responses of CR and PR were 
reported for 14 and 12 patients, respectively. Among the 5 response-evaluable patients with CLL, 
3 patients achieved PR. Thirteen patients with indolent lymphomas responded to treatment with 
TAK-659. Four patients achieved a CR and 9 patients achieved PR. These indolent responders 
were made up of both Follicular and Marginal Zone Lymphoma patients. Lastly, 1 out of 3 patients 
with MCL achieved a PR.
Additional single agent activity was observed in Studies C34004, a phase 2 R/R DLBCL study and 
this study, C34007. Of 41 response evaluable DLBCL patients in C34004, 8 responded. Three out 
of 4 DLBCL and 2 out of 2 FL patients responded in C34007.
Responses have also been observed in two additional NHL studies where TAK-659 was combined 
with other agents. Fifteen out of 29 response evaluable NHL patients responded in Study C34005, 
a five-arm combination study with more than half of patients enrolled into the Bendamustine +/-
Rituximab arms. Four out of 5 response evaluable NHL patients responded in Study C34008, a 
Phase 1b study of TAK-659 in combination with venetoclax.
Specific details of the tumor response by cancer type can be found in the TAK-659 IB.
4.2
Rationale for the Proposed Study
This study is intended to evaluate the safety, tolerability, PK, and efficacy of single-agent 
TAK-659 in East Asian patients with NHL and to expand the TAK-659 global clinical 
development program to the East Asian population.
The TAK-659 MTD and RP2D in Western patients with lymphoma were determined in the FIH 
study (C34001) to be 100 mg QD in 28-day treatment cycles. Objective responses have been 
observed in patients with lymphoma (DLBCL, iNHL [FL and MZL], CLL, and MCL) across the 
multiple dose levels evaluated (60-120 mg QD), supporting further evaluation of TAK-659 in 
relapsed and/or refractory FL or MZL after at least 2 prior lines of chemotherapy; a setting that 
represents an unmet medical need in which there is no standard of care available.
In addition, on the basis of the currently available data, TAK-659 administration can lead to 
adverse events (AEs) that are generally manageable and reversible with dose modification and/or 
prophylactic/supportive care. AEs reported in the clinical studies to date are consistent with 
nonclinical toxicology findings of TAK-659, published studies of other BCR pathway inhibitors
[22-24], and the patient population being studied. These events are detectable using standard 
safety monitoring practices and are generally manageable in the clinical setting.
These results support the initiation of an Asian phase 1 study, including a dose escalation part to 
determine the MTD and/or RP2D and PK profile of TAK-659 in East Asian patients with NHL and 
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a dose expansion part to further evaluate the safety and investigate preliminary efficacy in patients 
with relapsed and/or refractory FL/MZL.
4.2.1
Rationale for Dose and Dosing Schedule
Because this is the first clinical study of TAK-659 in Asia, the initial dose and dose increment will 
be determined on the basis of the starting dose and MTD from the FIH study (C34001) conducted 
in Western patients.
Although 100 mg QD TAK-659 has been determined to be the MTD for lymphoma in Study 
C34001, the question whether it is the optimal biological dose is outstanding. While an appreciable 
level of clinical activity was shown at 100 mg QD in Western patients, responses to TAK-659 
were also observed in patients treated with two lower doses evaluated (60 mg and 80 mg) QD, 
suggesting a therapeutic window of TAK-659 extending from 60 mg to 100 mg QD. Plasma PK 
exposure of TAK-659 from that study was found to be approximately dose proportional, and 
higher drug exposure levels were observed at 100 mg QD compared to the lower doses of 60 and 
80 mg QD. However, the level of SYK target inhibition achieved at different dose/exposure levels 
is not understood due to lack of available clinical pharmacodynamic data. Additionally, the degree 
and the temporal profile of the SYK inhibition required to generate clinical efficacy are not known. 
Therefore, it is plausible that the optimal biological dose may not be the Western MTD of 100 mg 
QD and may fall at a QD dose or intermittent schedule below that. It is also possible that there may 
be efficacious doses below 60 mg QD which is why 40 mg QD will also be tested. In this study, 
intermittent dosing schedules of TAK-659 will be also be evaluated such as 7 days on followed by 
7 days off. The rationale for intermittent dosing schedules for TAK-659 is based on the occurrence 
of frequent dose interruptions in Cycle 1 and 2 due to various AEs that was observed in study 
C34001. Most of the AEs that led to drug holds were laboratory changes that returned to ≤Grade 1 
with drug hold. In addition to this, most subjects in C34001 that received more than 6 cycles of 
treatment had multiple dose holds and dose reductions from 100 mg down to 60 mg QD.
Moreover, TAK-659 intermittent regimen has been conducted in Study C34008 and showed 
potential of more tolerability and safety compared to daily administration in combination regimen. 
This study is monotherapy, however, intermittent regimen is worthwhile to explore in this study to 
elucidate monotherapy dose optimization.
The starting dose in this study will be 60 mg QD, which is the same as that in Study C34001, and 
which is 2 dose levels (40%) lower than the MTD determined in the Western patient population. If 
60 mg QD is proven to be safe and tolerable, dose escalation will be conducted in 20 mg 
increments of daily dose. Based on emerging safety, tolerability, PK data, a lower dose (eg, 40 mg 
QD) or alternative dosing regimens (eg, 7 days on followed by 7 days off) will be permitted.
4.2.2
Rationale for PK Assessments
In the dose escalation part, intensive PK samples will be collected from all patients during Cycle 1 
to permit detailed characterization of TAK-659 plasma and urine PK across different dose levels in 
East Asian patients with NHL (refer to Section 9.4.17.1 and Appendix A, Table A and Table B). 
Plasma PK data will be used to characterize single- and repeat-dose concentration-time profiles of 
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TAK-659, calculate PK parameters, evaluate the dose-exposure relationship, and contribute to 
population PK analysis. Urine PK data will be used to determine the percentage of the 
administered TAK-659 dose excreted in urine as unchanged drug, and renal clearance and its 
minimum contribution to systemic clearance.
In the expansion part, blood samples for plasma PK will be collected via a limited (sparse) 
sampling schedule to contribute to population PK and exposure-response analyses (refer to 
Section 9.4.17.2 and Appendix A, Table C and Table D).
Plasma PK data collected in the dose escalation and expansion parts may be used individually or in 
combination with data from other studies to explore the relationship between TAK-659 exposure 
and clinical safety and efficacy parameters. Plasma PK data also may be evaluated in relation to 
pharmacodynamic effects (changes in serum cytokines/chemokines/serum proteins), as permitted 
by the data.
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CCI


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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objectives
The primary objectives are:
!
To determine the safety, tolerability, and MTD and/or RP2D of TAK-659 administered orally 
QD to East Asian patients with NHL who do not have an effective standard treatment 
available.
!
To characterize the plasma and urine PK of TAK-659 in East Asian patients with NHL.
5.1.2
Secondary Objective
The secondary objective is to evaluate preliminary efficacy of TAK-659 in patients with relapsed 
and/or refractory NHL.
5.2
Endpoints
5.2.1
Primary Endpoints
The primary endpoints are:
!
Percentage of patients with treatment-emergent AEs (TEAEs).
!
Percentage of patients with Grade 3 or higher TEAEs.
!
Percentage of patients with serious TEAEs.
!
Percentage of patients with DLTs during Cycle 1 (dose escalation part only).
!
Percentage of patients discontinuing study drug because of TEAEs.
!
Percentage of patients with clinically significant abnormal laboratory values.
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TAK-659
Study No. C34007
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Protocol Incorporating Amendment No.02
6 December 2017
!
Percentage of patients with clinically significant abnormal vital sign measurements.
!
TAK-659 Cmax on Cycle 1 Days 1 and 7 or 15 by dose.
!
TAK-659 Tmax on Cycle 1 Days 1 and 7 or 15 by dose.
!
TAK-659 AUC∀on Cycle 1 Days 1 and 7 or 15 by dose.
!
Renal clearance (CLR) on Cycle 1 Day 7 or 15 by dose.
5.2.2
Secondary Endpoints
The secondary endpoints are:
!
Overall response rate (ORR) in the expansion part.
!
CR rate in the expansion part.
!
Duration of response (DOR) in the expansion part.
!
Progression-free survival (PFS) in the expansion part.
The investigators will perform response assessment using modified International Working Group 
(IWG) 2007 criteria for malignant lymphoma [25], which will be the main analysis for the efficacy 
endpoints.
5.2.3
Additional Endpoints
Additional endpoints are:
!
Apparent oral clearance (CL/F), CLR as a percentage of CL/F, peak-trough ratio (PTR), 
accumulation ratio (Rac), and observed concentration at the end of the dosing interval (Ctrough) 
on Cycle 1 Day 7 or 15 by dose.
!
Plasma concentration-time data contributing to population PK and exposure-response 
analyses.
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Study No. C34007
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Protocol Incorporating Amendment No.02
6 December 2017
6.0
STUDY DESIGN
6.1
Overview of Study Design
This is an open-label, multicenter, phase 1 study of TAK-659 including a dose escalation part in 
adult East Asian patients with NHL and an expansion part in adult East Asian patients with 
relapsed and/or refractory NHL.
The dose escalation part of the study will enroll approximately 18 to 32 East Asian patients 
diagnosed with NHL for which no effective standard treatment is available. Assuming a dropout 
rate of 20%, this will ensure that 16 to 28 DLT-evaluable patients are enrolled in the dose
escalation part. TAK-659 will be administered continuously, QD, in 28-day treatment cycles 
(Dosing Schedule A). Dose escalation will follow a standard 3+3 schema to determine the MTD 
and/or the RP2D. The initial TAK-659 dose will be 60 mg QD and will escalate to 80 mg QD, 
provided that the safety and tolerability of the 60 mg dose has been demonstrated. Dose escalation 
will continue until the MTD is reached or until an RP2D (if different from the MTD) for East 
Asian patients has been identified. More conservative dose escalation, evaluation of intermediate 
doses or regimens, and expansion of an existing dose level are all permissible following written 
confirmation of discussions between the sponsor and the investigators, if such measures are 
needed for patient safety or for a better understanding of the dose-toxicity and dose-exposure 
relationships of TAK-659.
If ≥2 of 6 patients experience a DLT at 60 mg QD, depending on the overall safety profile, the type 
of AEs/DLTs observed, and following the examination of the preliminary PK results in relation to 
the PK data in the Western population, a decision will be made either to de-escalate the dose to 
40 mg QD or to terminate the study following discussion between the investigator and the sponsor. 
If ≥2 of 6 patients experience a DLT at 80 mg QD, alternate dose regimens between 60 and 80 mg 
(ie, 80 mg 7 days on 7 days off [Dosing Schedule B]) will be evaluated as described below. The 
MTD and/or RP2D should be evaluated with a total of ≥6 DLT-evaluable patients. The RP2D will 
be determined on the basis of the totality of the safety, tolerability, and preliminary PK and 
efficacy data (if available) observed in Cycle 1 and beyond. Intrapatient dose escalation is not 
allowed in this protocol.
An additional dosing schedule will be tested after implementation of Amendment 02:

Dosing Schedule B: TAK-659 will be administered QD for 7 consecutive days followed by 
another 7 days of rest and repeated again (ie, 7 days "on" and 7 days "off"), for a cycle duration 
of 28 days. The starting dose of 80 mg QD was the maximum administered dose in Dosing 
Schedule A (2 out of 4 patients presented a DLT in the continuous dosing regimen). However,
the alternative dose of 60 mg may be tested if the 80 mg intermittent regimen is deemed not 
tolerable per emerging data. Dose escalation will be governed using the same standard 3+3 
schema as described in Section 8.3.
The expansion part of this study will begin once the RP2D has been determined. The expansion 
part will proceed with dosing of TAK-659 at the RP2D in 28-day cycles. The patient population 
will consist of East Asian patients with FL or MZL who are relapsed and/or refractory after at least 
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TAK-659
Study No. C34007
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2 prior lines of chemotherapy and who must be ineligible for or refusal to hematopoietic stem cell 
transplant. It is expected that approximately 12 response-evaluable patients will be enrolled. 
Assuming a 20% dropout rate, a total of approximately 15 patients will be enrolled. The objectives 
of the expansion part are to evaluate the longer-term safety and tolerability of TAK-659 
administered at the RP2D, to characterize the PK of TAK-659, and to evaluate the preliminary 
efficacy of TAK-659 in relapsed and/or refractory FL/MZL as measured by ORR and other 
efficacy variables, including CR rate, DOR, TTP, and PFS.
At least 1 Japanese patient will be enrolled in each cohort in the dose escalation part. The total 
number of Japanese patients dosed at the RP2D (either the MTD or a lower dose as determined) 
will be at least 6 including the dose escalation and expansion parts to ensure adequate 
characterization of PK and safety in Japanese patients.
On the basis of the geographic distribution of patients enrolled and emerging PK and safety data, 
additional patients may be added, as needed, to further characterize the PK, safety, and tolerability 
in a particular East Asian geographic region. On the basis of emerging efficacy data, additional 
groups or patients with FL/MZL may be added to further explore efficacy.
Patients will discontinue treatment if they experience an unacceptable TAK-659-related toxicity. 
Patients may discontinue therapy at any time. Patients will attend the End of Treatment (EOT) visit 
28 days (+10 days) after receiving their last dose of TAK-659 or before the start of subsequent 
antineoplastic therapy, whichever occurs first, to permit the detection of any delayed 
treatment-related AEs. AEs will be assessed, and laboratory values, vital signs, ophthalmic exams, 
and electrocardiograms (ECGs) will be obtained to evaluate the safety and tolerability of 
TAK-659. Toxicity will be evaluated according to National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03, effective date 14 June 2010
[26]. DLTs are defined in Section 8.2.
Intensive PK samples (serial blood samples and 2 urine samples) will be collected during Cycle 1 
in all patients in the dose escalation part to permit detailed characterization of TAK-659 plasma 
PK and urine PK across different dose levels. Sparse PK samples will be collected in expansion 
patients to contribute to population PK and exposure-response analyses. If fewer than 6 Japanese 
patients are dosed at the RP2D in the dose escalation part, then additional intensive PK samples 
will be collected during Cycle 1 in a subset of Japanese patients in the expansion part. In total, 
intensive PK sampling will be performed in at least 6 Japanese patients dosed at the RP2D (either 
the MTD or a lower dose) among the dose escalation and expansion parts combined to ensure 
adequate characterization of plasma and urine PK in Japanese patients. Details of the PK 
measurements are described in Section 9.4.17.
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TAK-659
Study No. C34007
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Protocol Incorporating Amendment No.02
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Evaluation of disease response will be performed as described in Section 9.4.15 and the Schedule 
of Events (Appendix A), using the IWG 2007 modified response criteria for malignant lymphoma 
(Appendix D) [25]based on investigator assessment. An imaging modality (eg, computed 
tomography [CT] with contrast and fluoro-2-deoxy-D-glucose [FDG]-positron emission 
tomography [PET] if appropriate) will be used to follow sites of measurable disease during the 
study treatment. Radiographic images will be maintained at the site. Based on efficacy data 
observed, the sponsor can elect to have central collection of disease assessment images. In the 
event of antitumor response, the sponsor may request electronic images for those patients who 
demonstrate tumor reduction.
The study design is detailed in Figure 6.a.
Figure 6.a
Overview of Study Design
FL=follicular lymphoma MTD=maximum tolerated dose, MZL=marginal zone lymphoma, NHL=non-Hodgkin 
lymphoma, QD=once daily, RP2D=recommended phase 2 dose.
*The alternative dose of 60 mg may be tested if the 80 mg intermittent regimen is deemed not tolerable.
6.2
Number of Patients
It is expected that approximately 33 to 47 patients will be enrolled in this study from 
approximately 6 to 10 study sites in East Asia. Enrollment is defined as the time of administration 
of the first dose of study drug.
For the dose escalation part, approximately 16 to 28 DLT-evaluable patients will be enrolled; 
assuming a 20% dropout rate, approximately 18 to 32 patients will be enrolled. For the expansion 
part, approximately 12 response-evaluable patients will be enrolled; assuming a 20% dropout rate, 
approximately 15 patients will be enrolled.
Cohort 2
80 mg QD
Cohort 1
60 mg QD
MTD and/or
RP2D
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Expansion
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refractory FL/MZL planned
Dose Escalation Part
NHL
Expansion Part
FL/MLZ
Cohort 3
40 mg QD
Cohort 4 *
80 mg QD
7 days/7 days off
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6.3
Duration of Study
6.3.1
Duration of an Individual Patient’s Study Participation
Patients, including those who achieve a CR, may receive study drug until they experience PD. 
Patients will discontinue treatment if they have an unacceptable TAK-659-related toxicity.
Patients will be followed for 28 days after the last dose of study drug or until the start of 
subsequent antineoplastic therapy, whichever occurs first, to permit the detection of any delayed 
treatment-related AEs (safety follow-up).
For patients enrolled in the dose escalation part, the maximum duration of treatment will be 12 
months unless in the opinion of the investigator and with the agreement with sponsor the patient 
would derive benefit from continued therapy beyond 12 months.
Patients enrolled in the expansion part who stop treatment for any reason other than PD will 
continue PFS follow-up every 2 months after the last dose of study drug for up to 6 months or until 
PD, whichever occurs first.
6.3.2
End of Study/Study Completion Definition and Planned Reporting
Primary Completion/Study Completion
The primary analysis for safety, PK, and efficacy endpoints and authoring of a CSR may be 
conducted after all patients enrolled in the study have had the opportunity to complete 4-6 cycles 
of treatment with study drug and patients who discontinued study treatment must complete safety 
follow-up. The estimated time frame for primary completion is approximately 47 months. For 
patients enrolled in the expansion part, PFS follow-up will occur every 2 months after the last dose 
of study drug for up to 6 months or until PD, whichever occurs first (for patients who discontinue 
for reasons other than PD). The estimated time frame for study completion is approximately 52
months.
A CSR addendum will be provided to describe additional data not included in the original CSR.
6.3.3
Timeframes for Primary and Secondary Endpoints to Support Disclosures
Please refer to Table 6.a for disclosures information for all primary and secondary endpoints.
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Study No. C34007
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Protocol Incorporating Amendment No.02
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Table 6.a
Primary and Secondary Endpoints for Disclosures
Endpoint
Definition
Maximum Time Frame (a)
Primary:
• Percentage of patients with 
TEAEs (b).
Percentage of patients with TEAEs.
Through study completion, ~52 
months.
• Percentage of patients with Grade 
3 or higher TEAEs.
Percentage of patients with Grade 3 or 
higher TEAEs.
Through study completion, ~52 
months.
• Percentage of patients with 
serious TEAEs.
Percentage of patients with serious 
TEAEs.
Through study completion, ~52 
months.
• Percentage of patients with DLTs 
during Cycle 1 (dose escalation 
part only).
Percentage of patients with DLTs 
during Cycle 1 (dose escalation part
only).
4 weeks after last dose of last 
patient in dose escalation or up to 
6 months, if needed
• Percentage of patients 
discontinuing study drug because 
of TEAEs.
Percentage of patients discontinuing
study drug because of TEAEs.
Through study completion, ~52 
months.
• Percentage of patients with
clinically significant laboratory 
values.
Percentage of patients with clinically 
significant laboratory values, as 
assessed by the investigator or 
identified subinvestigator(s).
Through study completion, ~52 
months.
• Percentage of patients with
clinically significant vital sign 
measurements.
Percentage of patients with clinically 
significant vital sign measurements as 
assessed by the investigator or 
identified subinvestigator(s).
Through study completion, ~52 
months.
• TAK-659 Cmax on Cycle 1 Days 1 
and 7 or 15 by dose.
Geometric mean and CV for Cmax on 
Cycle 1 Days 1 and 7 or 15 by dose in 
the PK-evaluable population.
Up to Cycle 1 Day 16.
• TAK-659 Tmax on Cycle 1 Days 1 
and 7 or 15 by dose.
Median (range) for Tmax on Cycle 1 
Days 1 and 7 or 15 by dose in the 
PK-evaluable population.
Up to Cycle 1 Day 16.
• TAK-659 AUCon Cycle 1 Days 
1 and 7 or 15 by dose.
Geometric mean and CV for AUCon 
Cycle 1 Days 1 and 7 or 15 by dose in 
the PK-evaluable population.
Up to Cycle 1 Day 16.
• CLR on Cycle 1 Day 7 or 15 by 
dose.
Geometric mean and CV for CLR on 
Cycle 1 Day 7 or 15 by dose in the 
PK-evaluable population.
Up to Cycle 1 Day 16.
Footnotes are on last table page.
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Table 6.a
Primary and Secondary Endpoints for Disclosures (continued)
Endpoint
Definition
Maximum Time Frame (a)
Secondary:
• ORR in the expansion part as 
assessed by investigators 
according to modified IWG 
criteria for malignant lymphoma.
The proportion of patients in the 
response-evaluable population of the 
expansion part who achieved either CR 
or PR, as assessed by investigators, 
according to modified IWG criteria for 
malignant lymphoma.
Through study completion, ~52 
months.
• CR rate per investigator in the 
expansion part.
The proportion of patients in the 
response-evaluable population of the 
expansion part who achieved CR, as 
assessed by investigator, according to 
modified IWG criteria for malignant 
lymphoma.
Through study completion, ~52 
months.
• DOR per investigator in the 
expansion part.
The time from first documentation of 
response (CR/PR) to the date of first 
documentation of PD/relapse, as 
assessed by investigator, according to 
modified IWG criteria for malignant 
lymphoma in the response-evaluable 
population of the expansion part.
Through study completion, ~52 
months.
• PFS per investigator in the 
expansion part.
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, in the 
safety population of the expansion part, 
as assessed by the investigator,
according to modified IWG criteria for 
malignant lymphoma.
Through study completion, ~52 
months.
AUC=area under the plasma concentration-time curve during the dosing interval, CLR=renal clearance, 
Cmax=maximum observed concentration, CR=complete response, CV=coefficient of variation, DLT=dose-limiting 
toxicity, DOR=duration of response, IWG=International Working Group, ORR=overall response rate, 
PD=progressive disease, PFS=progression-free survival, PR=partial response, TEAE=treatment-emergent adverse 
event, Tmax=time of first occurrence of Cmax, TTP=time to progression.
(a) Time to last assessment for that endpoint for an individual patient.
(b) TEAEs are defined as AEs that occur after administration of the first dose of study drug until 28 days after the last 
dose of study drug or the start of subsequent antineoplastic therapy, whichever occurs first.
6.3.4
Total Study Duration
It is anticipated that this study will last for approximately 52 months, including approximately 
27 months for the dose escalation part and approximately 25 months for the expansion part
including 6 cycles treatment and 6 months PFS follow-up.
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7.0
STUDY POPULATION
7.1
Inclusion Criteria
Each patient must meet all the following inclusion criteria to be enrolled in the study:
1. Male or female patients of East Asian ethnicity (eg, Japanese, Korean, or Chinese) aged 18 
years or older (if local regulation requires a minimum age for informed consent of more than 
18 years, then patients must be the minimum age or older per the local regulation) when 
written study informed consent is obtained.
2. To be enrolled to the dose escalation part, patients must have:
a)
Histologically or cytologically confirmed diagnosis of NHL for which no effective 
standard treatment is available. However, patients with CLL/small lymphocytic 
lymphoma (SLL), primary CNS lymphoma, or Waldenström macroglobulinemia will be 
excluded.
b)
Radiographically or clinically measurable disease with at least 1 target lesion. 
Radiographically measurable disease is determined by IWG 2007 criteria for malignant 
lymphoma.
3. To be enrolled in the expansion part, patients must meet the following criteria:
a)
Patients must have pathologically confirmed FL (Grade 1, 2, or 3A) or MZL.
b)
Relapsed and/or refractory to ≥2 prior lines of chemotherapy based on standard of care 
that include at least 1 anti-CD20-based regimen, as well as alkylating agents (eg, 
cyclophosphamide or bendamustine).
c)
Patients must be ineligible for or refusal to hematopoietic stem cell transplant.
d)
For patients who have relapsed or progressed after achieving a response (defined as CR or 
PR), documented, investigator-assessed relapse or progression after the last treatment is 
required. For patients who are refractory to their last treatment (defined as not having 
achieved a CR or PR before enrollment by investigator assessment), documented 
progression will not be required.
e)
Must have measurable disease that meets the size criteria per IWG (>1.5 cm in the longest 
diameter for a lymph node or a nodal mass, or >1.0 cm in the longest diameter for an 
extranodal disease) as assessed on cross-sectional imaging by CT scan/magnetic 
resonance imaging (MRI). (CT scan is to be performed with contrast unless it is medically 
contraindicated.)
4. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 (See 
Appendix E for a description of the ECOG performance status scale).
5. Life expectancy longer than 3 months.
6. Patients must have adequate organ function, including the following:
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a)
Bone marrow reserve: absolute neutrophil count (ANC) ≥1,000/mm3, platelet count 
≥75,000/mm3 (≥50,000/mm3 for patients with bone marrow involvement), and 
hemoglobin ≥8 g/dL (red blood cell [RBC] and platelet transfusion allowed ≥14 days 
before assessment).
b)
Hepatic function: total bilirubin ≤1.5×the upper limit of normal range (ULN); alanine 
aminotransferase (ALT) and AST ≤2.5×ULN.
c)
Renal function: creatinine clearance ≥60 mL/min as estimated by the Cockcroft-Gault 
equation (refer to Appendix F).
Others:

Lipase ≤1.5ULN and amylase ≤1.5ULN with no clinical symptoms suggestive of 
pancreatitis or cholecystitis.

Blood pressure ≤Grade 1 (hypertensive patients are permitted if their blood pressure 
is controlled to ≤Grade 1 by hypertensive medications and glycosylated hemoglobin 
[HbA1C] ≤6.5%)
7. Female patients who:
a)
Are postmenopausal (natural amenorrhea, not due to other medical reasons) for at least 1 
year before the screening visit, OR
b)
Are surgically sterile, OR
c)
If they are of childbearing potential, agree to practice 1 highly effective method of 
contraception and 1 additional effective (barrier) method (see Appendix G) at the same 
time, from the time of signing the informed consent through 180 days after the last dose of 
study drug, OR
d)
Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle 
of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], condoms only, withdrawal, spermicides only, and lactational amenorrhea are 
not acceptable methods of contraception.)
Male patients, even if surgically sterilized (ie, status postvasectomy), who:
a)
Agree to practice effective barrier contraception during the entire study treatment period 
and through 180 days after the last dose of study drug, OR
b)
Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle 
of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods for the female partner], condoms only, withdrawal, spermicides only, and 
lactational amenorrhea are not acceptable methods of contraception.)
8. Voluntary written consent must be given before performance of any study-related procedure 
not part of standard medical care, with the understanding that consent may be withdrawn by 
the patient at any time without prejudice to future medical care.
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9. Recovered (ie, ≤Grade 1 toxicity) from the reversible effects of prior anticancer therapy. 
Patients with ongoing toxicities at baseline may be eligible; however, any Grade 2 baseline 
toxicity (except for alopecia) should be discussed with the medical monitor.
7.2
Exclusion Criteria
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
1. CNS lymphoma; active brain or leptomeningeal metastases as indicated by positive cytology 
from lumbar puncture or CT/MRI by local assessment.
2. Known human immunodeficiency virus (HIV)-related malignancy.
3. Any serious medical or psychiatric illness, including drug or alcohol abuse, that could, in the 
investigator’s opinion, potentially interfere with the completion of treatment according to this 
protocol (eg, Grade 2 or greater hypertension or lymphopenia, Grade 2 or higher amylase 
and/or lipase elevations).
4. Life-threatening illness unrelated to cancer that could, in the investigator’s opinion, make the 
patient not appropriate for this study.
5. Female patients who are lactating and breastfeeding or have a positive serum pregnancy test 
during the Screening period or a positive urine pregnancy test on Day 1 before the first dose of 
the study drug.
(Note: Female patients who are in the lactation period, even if they discontinue breastfeeding, 
will be excluded from the study.)
6. Systemic anticancer treatment (including investigational agents) less than 3 weeks before the 
first dose of study treatment (≤4 weeks for antibody-based therapy including unconjugated 
antibody, antibody-drug conjugate, and bi-specific T-cell engager agent; ≤8 weeks for 
cell-based therapy or anti-tumor vaccine).
7. Radiotherapy less than 3 weeks before the first dose of study treatment. If prior radiotherapy 
occurred <4 to 6 weeks before the study start, as radiated lesions cannot be reliably assessed by 
FDG-PET, nonradiated target lesions are required for eligibility.
8. Known HIV positive (testing not required).
9. Known hepatitis B surface antigen (HBsAg) positive, or known or suspected active hepatitis C 
virus (HCV) infection.
Note: Hepatitis testing will be performed as specified in the Schedule of Events (Appendix A). 
Patients who have positive hepatitis B core antibody (HBcAb) or hepatitis B surface antibody 
(HBsAb) can be enrolled but must have an undetectable hepatitis B virus (HBV) viral load. 
Patients who have positive hepatitis C virus antibody (HCVAb) must have an undetectable 
HCV viral load.
10. Prior ASCT within 6 months or prior ASCT at any time without full hematopoietic recovery 
before Cycle 1 Day 1, or allogeneic stem cell transplant at any time.
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11. Any clinically significant comorbidities, such as uncontrolled pulmonary disease (eg, severe 
chronic obstructive pulmonary disease with hypoxemia, interstitial lung disease, radiation 
induced lung injury), known impaired cardiac function or clinically significant cardiac disease 
(specified below), active CNS disease, or any other condition that could, in the opinion of the 
investigator, compromise the patient’s safety and participation in the study per protocol.
12. Patients with any of the following cardiovascular conditions are excluded:

Acute myocardial infarction within 6 months before starting study drug.

Current or history of New York Heart Association Class III or IV heart failure (Appendix 
H).

Evidence of current, uncontrolled cardiovascular conditions including cardiac 
arrhythmias, angina, pulmonary hypertension, or electrocardiographic evidence of acute 
ischemia or active conduction system abnormalities.

QT interval with Fridericia correction method (QTcF) >450 milliseconds (msec) (men) or 
>475 msec (women) on a 12-lead ECG during the Screening period.

Abnormalities on 12-lead ECG including, but not limited to, changes in rhythm and 
intervals that are considered to be clinically significant by the investigator.
13. Major surgery within 14 days before the first dose of study drug or incomplete recovery from 
any complications from surgery.
14. Systemic infection requiring parenteral antibiotic therapy or other serious infection (bacterial, 
fungal, or viral) within 21 days before the first dose of study drug. Patients who are at 
substantial risk of developing an infection may receive prophylaxis at the start of study 
treatment per investigator’s discretion (see Section 8.7.1).
15. Treatment with high-dose corticosteroids for anticancer purposes within 7 days before the first 
dose of TAK-659. Use of corticosteroids at daily dose equivalent to 10 mg oral prednisone or 
less is permitted. Corticosteroids for topical use or in nasal spray or inhalers are allowed.
16. Patient with another malignancy within 2 years of study start. Patients with nonmelanoma skin 
cancer or carcinoma in situ of any type are not excluded if they have undergone complete 
resection and are considered disease-free at the time of study entry.
17. Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral 
absorption or tolerance of TAK-659 including difficulty swallowing tablets; diarrhea >Grade 1 
despite supportive therapy.
18. Lack of suitable venous access for the study-required blood sampling for TAK-659.
19. Use or consumption of any of the following substances:

Medications or supplements that are known to be inhibitors of P-gp and/or strong 
reversible inhibitors of CYP3A within 5 times the inhibitor half-life (if a reasonable 
half-life estimate is known) or within 7 days (if a reasonable half-life estimate is unknown) 
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before the first dose of study drug. In general, the use of these agents is not permitted 
during the study except for AE management (see Section 8.5 for details). See Appendix I
for a nonexhaustive list of strong CYP3A reversible inhibitors and/or P-gp inhibitors 
based on the US Food and Drug Administration (FDA) Draft DDI Guidance.

Medications or supplements that are known to be strong CYP3A mechanism-based 
inhibitors or strong CYP3A inducers and/or P-gp inducers within 7 days or within 5 times 
the inhibitor or inducer half-life (whichever is longer) before the first dose of study drug. 
In general, the use of these agents is not permitted during the study except for AE 
management (see Section 8.5 for details). See Appendix I for a nonexhaustive list of 
strong CYP3A mechanism-based inhibitors or strong CYP3A inducers and/or P-gp 
inducers based on the US FDA Draft DDI Guidance.

Grapefruit-containing food or beverages within 5 days before the first dose of study drug. 
Note that grapefruit-containing food and beverages are not permitted during the study.
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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 before 
drug administration. Study drug will be administered only to eligible patients under the 
supervision of the investigator or identified subinvestigator(s).
If required by local regulations or local clinical guidelines or preferred by the investigator, study 
drugs and protocol assessments may be administered in an in-patient setting during Cycle 1.
The study drug will be administered according to the assigned dosing schedule (ie, Dosing 
Schedule A or B). For Dosing Schedule A, the study drug will be administered continuously, QD, 
in 28-day cycles. For Dosing Schedule B, the study drug will be administered QD for 7 
consecutive days followed by 7 days of rest and repeated again for a 28-day cycle (ie, 7 days “on” 
and 7 days “off”). The study drug should be taken on an empty stomach, at least 1 hour before and 
no sooner than 2 hours after ingestion of food and/or beverages other than water. Each tablet 
should be swallowed separately with a sip of water. A total of approximately 240 mL of water 
should be taken with the prescribed dose. Patients should swallow the study medication whole. 
The study medication should not be chewed, crushed, or manipulated in any way before 
swallowing. Administration of the tablets will be guided by the dosing tables included in the 
Pharmacy Manual.
Patients should be instructed to take their study medication at approximately the same time each 
day and to not take more than the prescribed dose at any time. On visit days, patients should be 
instructed to hold their dose until predose assessments have been performed. If a patient does not 
take the TAK-659 dose at the scheduled dosing time (±6 hours), that dose should be skipped, and 
the patient must not make dose adjustments on that day or subsequent days to account for the 
missed dose (for example, by taking a double dose of TAK-659 the following day). Patients should 
record any skipped doses in their dosing diary (see the Study Manual) and resume dosing at the 
next scheduled time with the prescribed dosage.
If severe emesis prevents the patient from taking a TAK-659 dose, that dose will be skipped. If 
emesis occurs after study medication ingestion, patients should not re-dose following emesis and 
should record the time of the emesis in their dosing diary (see the Study Manual). Patients should 
resume dosing at the next scheduled time with the prescribed dosage.
8.2
Definitions of DLT
Toxicity will be evaluated according to the NCI CTCAE, version 4.03, effective 14 June 2010
[26]. These criteria are provided in the Study Manual. DLT is defined as any of the following 
events occurring during Cycle 1 that are considered by the investigator to be at least possibly 
related to therapy with TAK-659.

Grade 4 neutropenia (ANC <500 cells/mm3) unresolved to ≤Grade 1 (ANC ≥1500 cells/mm3) 
or baseline for more than 7 consecutive days in the absence of growth factor support.
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
≥Grade 3 neutropenia (ANC <1000 cells/mm3) with fever and/or infection, where fever is 
defined as a single temperature of >38.3°C or a sustained temperature of ≥38°C for more than 
1 hour.

Grade 4 thrombocytopenia (PLT <25,000/mm3) unresolved to ≤Grade 1 (PLT ≥75,000/mm3) 
or baseline for more than 7 consecutive days, or PLT <10,000/mm3 at any time.

≥Grade 3 thrombocytopenia (<50,000/mm3) with clinically significant bleeding.

Any Grade 3 or greater nonhematologic toxicity with the following exceptions:
–
≥Grade 3 nausea and/or emesis that resolves to <Grade 3 within 3 days after the use of 
optimal antiemetic treatment based on standard practice. (An optimal antiemetic regimen is 
defined as one that employs both a 5-hydroxytryptamine 3 serotonin receptor [5-HT3] 
antagonist and a corticosteroid given in standard doses and according to standard 
schedules.)
–
≥Grade 3 diarrhea that resolves to <Grade 3 within 3 days after receiving the maximal 
supportive therapy based on standard practice.
–
Grade 3 fatigue that lasts ≤72 hours.
–
Isolated asymptomatic ≥Grade 3 laboratory abnormalities that resolve to ≤Grade 1 or 
baseline in ≤7 days.

Receiving <75% of planned doses of study drug (receiving <21 days for Dosing Schedule A 
and <11 days for Dosing Schedule B) within Cycle 1 because of prolonged treatment 
interruption caused by TAK-659-related toxicities.

Other TAK-659-related Grade 2 or greater nonhematologic toxicities that, in the opinion of the 
investigator, require a dose reduction or discontinuation of TAK-659 therapy.
Although DLT-like toxicities may occur at any time during treatment, only DLTs occurring during 
Cycle 1 of treatment will influence decisions regarding dose escalation, expansion of a dose level, 
or evaluation of intermediate dose levels. Patients will be monitored throughout all cycles of 
therapy for treatment-related toxicities.
8.3
Dose Escalation Rules
Dose escalation will follow a standard 3+3 schema to determine the MTD and/or the RP2D in East 
Asian patients with NHL. The dose escalation plan, as specified in Table 8.a, is based on the 
starting dose of 60 mg, the dose determined to be tolerable in the FIH Study C34001 in the 
Western population. The dose will escalate to 80 mg QD provided that the safety and tolerability 
of the 60 mg dose has been demonstrated. Dose escalation will continue until the MTD is reached 
or until an RP2D (if different from the MTD) for East Asian patients has been identified. More 
conservative dose escalation, evaluation of intermediate doses or regimens, and expansion of an 
existing dose level are all permissible following written confirmation of discussions between the 
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sponsor and the investigators, if such measures are needed for patient safety or for a better 
understanding of the dose-toxicity and dose-exposure relationship of TAK-659.
If ≥2 of 6 patients experience a DLT at 60 mg QD, depending on the overall safety profile, the type 
of AEs/DLTs observed, and following the examination of the preliminary PK results in relation to 
the PK data in the Western population, a decision will be made either to de-escalate the dose to 
40 mg QD or to terminate the study following discussion between the investigator and the sponsor. 
If ≥2 of 6 patients experience a DLT at 80 mg QD, alternate dose regimens between 60 and 80 mg 
(ie, 80 mg 7 days on 7 days off) will be evaluated.
While the primary escalation schema is designed to determine a classic Cycle 1-based MTD, dose 
escalation may be halted at any time after consultation between the sponsor and investigators if 
cumulative toxicity beyond Cycle 1 indicates that a given dose exceeds a tolerable RP2D. The 
MTD and/or RP2D should be evaluated with a total of ≥6 DLT-evaluable patients. The RP2D will 
be determined on the basis of the safety, tolerability, and preliminary PK and efficacy data (if 
available) observed in Cycle 1 and beyond. Intrapatient dose escalation is not allowed in this 
protocol.
Escalation rules based on DLTs include:
1. If 0 of 3 patients experience DLT, dose escalation will proceed to the next higher dose level, at 
which 3 patients will be enrolled.
2. If 1 of 3 patients experiences DLT, 3 more patients will be enrolled at that same dose level.
3. Escalation will continue if 1 of 6 patients experiences DLT.
4. If 2 or more patients in any dose level experience DLT, enrollment at that dose level will stop. 
Following consultation between the sponsor and investigators, either the previous dose level 
will be considered the MTD (if 6 or more patients have been studied at that dose level), the 
previous dose level will be expanded (if fewer than 6 patients have been studied at that dose 
level), or a dose level intermediate between the current and the previous dose level will be 
evaluated.
Figure 8.a is a diagrammatic representation of these rules.
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Figure 8.a
Dose Escalation Algorithm
DLT, dose-limiting toxicity; MTD, maximum tolerated dose.
Table 8.a
Planned Dose Levels
Dose Level
Dose (unit)
1
60 mg QD
2
80 mg QD
3
40 mg QD
4
80 mg QD*, 7 days on/7 days off
*The alternative dose of 60 mg may be tested if the 80 mg intermittent regimen is deemed not tolerable per emerging 
data.
More conservative dose escalation, evaluation of intermediate doses or alternative regimens, and expansion of an 
existing dose level are all permissible following written confirmation of discussions between the sponsor and the 
investigators, if such measures are needed for patient safety or for a better understanding of the dose-toxicity and 
dose-exposure relationship of TAK-659.
DLT-evaluable patients in each dose cohort will consist of patients who have met the minimum 
treatment and safety evaluation requirements of the study or who have experienced a DLT during 
Cycle 1. The minimum treatment and safety evaluation requirements are met if, in Cycle 1, the 
patient has been treated with TAK-659 for ≥21 days for Dosing Schedule A and for ≥11 days for 
Dosing Schedule B (receiving at least 75% of planned doses of TAK-659 in Cycle 1) and observed 
for ≥28 days following the dose on Cycle 1 Day 1, and is considered to have sufficient safety data 
by both the sponsor and investigators to conclude that a DLT did not occur. Patients who do not 
meet these minimum requirements will be regarded as ineligible for inclusion as DLT-evaluable 
patients for the given dose cohort and may be replaced within the same cohort. However, all AEs 
Enter 3 at
same dose
> 1 of 6 DLTs 
Stop
MTD = Previous dose
1 of 6 DLT 
Escalate to
next dose
0 DLTs
Enter 3
1 DLT
2-3 DLTs
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observed in each dose level, including those observed in DLT non-evaluable subjects, will be 
evaluated in concert with DLTs when making dose escalation decisions during the study.
8.4
Dose Modification Guidelines
8.4.1
General Principles
Treatment cycles with TAK-659 will occur in 28-day increments. Patients will be evaluated 
weekly during Cycle 1, every other week during Cycle 2, and then every cycle thereafter for 
possible toxicities that may have occurred after previous doses. Toxicities are to be assessed 
according to the NCI CTCAE, version 4.03. All toxicities that occur during the study will be 
actively managed following the standard of care unless otherwise specified in the protocol. 
Patients experiencing AEs attributed to TAK-659 may continue study treatment and maintain the 
same dose, or have doses of TAK-659 held, or permanently discontinue from the study. Detailed 
dose modification guidelines are provided in Sections 8.4.4 and 8.4.5. Patients who have a 
TAK-659 dose held because of a treatment-related or possibly related AE may resume study drug 
after resolution of the AE, and may either maintain the same dose level or have TAK-659 reduced 
by at least 1 dose level (dose reduction). Dose reduction levels for TAK-659 are presented in Table 
8.b. When a dose reduction occurs, the TAK-659 dose will be reduced to the next lower dose. If 
initial dose adjustment does not provide sufficient relief, the dose of TAK-659 can be further 
reduced if the treating physician believes that the patient is benefiting from study treatment and 
may benefit at a further-reduced dose of TAK-659. When a dose reduction of TAK-659 is required 
because of toxicity, no dose re-escalation will be permitted. If TAK-659 dosing is delayed for >21 
days for TAK-659-related or possibly related toxicities despite supportive treatment per standard 
clinical practice, or more than 2 dose reductions (more than 1 dose reduction for 40 mg QD) are
required in a patient, the patient should be discontinued from study treatment, unless the treating 
physician believes that the patient may benefit from continued study treatment after resolution of 
AEs to ≤Grade 1 or baseline. In this case, consultation with the medical monitor or designee is 
required. Study drug interruption before resolution of AEs to ≤Grade 1 or baseline may be longer 
than 21 days if justified. In such cases, agreement with the medical monitor or designee must be 
documented. Patients who discontinue the study for any reason other than death will continue to be 
followed for AEs for 28 days after the last administration of TAK-659 or until the start of 
subsequent antineoplastic therapy, whichever occurs first.
Table 8.b
Dose Reduction Levels for TAK-659
Dose Reduction Levels
Dose (unit)
Planned dose
40, 60, or 80 mg
(-) 1 dose level
Planned dose minus 20 mg (a)
(-) 2 dose level
Planned dose minus 40 mg (a) (b)
(a) Intermittent regimen (eg, 7 days on/7 days off) may be allowed.
(b) Not applicable to 40 mg QD cohort.
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For AEs that occur during the study but are not related to TAK-659, the dose modification of 
TAK-659, in principle, is not required. However, on the basis of medical conditions and the 
possibility of potential worsening of toxicities from continuous administration of TAK-659, 
investigators can decide to hold the TAK-659 dose until resolution of the AEs to a level that is 
considered clinically appropriate to resume the study drug (nonhematologic AEs with the
exception of asymptomatic laboratory changes must be ≤Grade 2).
Patients who experience a DLT (during escalation part) or DLT-like toxicity (expansion part) 
during the first cycle will, in general, require treatment with TAK-659 to be permanently 
discontinued. The patient will be followed until resolution or stabilization of the event. If, in the 
opinion of the investigator and the sponsor (project clinician or designee), it is in the patient’s best 
interest to continue treatment with TAK-659, then the dose of TAK-659 will be reduced by at least 
1 dose level (for example, reduced to a lower dose that has been evaluated and found to be safe and 
tolerable during dose escalation) when treatment resumes after recovery from the toxicity or 
toxicities in question to ≤Grade 1 or baseline or to a level considered acceptable by the 
investigator. This discussion will be documented in the study file. However, if a patient requires a 
dose delay of >21 days for such an event to resolve despite the best supportive care permissible per 
the protocol, then the patient must be discontinued from the study.
For management of toxicities on study, dose modification guidelines should be closely followed. 
However, on the basis of evolving safety data for TAK-659 and individual patient cases, 
alternative dose modifications may be recommended after discussion between the investigator and 
the sponsor to maximize exposure of study treatment while protecting patient safety. Discussions 
and agreements will be documented.
8.4.2
Intrapatient Dose Escalation
Intrapatient dose escalation is not allowed in this protocol.
8.4.3
Criteria for Beginning or Delaying a Subsequent Treatment Cycle
TAK-659 is administered in continuous cycles; therefore study drug should be administered 
continuously or according to the intermittent dosing regimen, unless AEs occur that meet the dose 
modification criteria outlined below.
Before starting a new treatment cycle, TAK-659-related AEs or laboratory abnormalities must 
have returned to ≤Grade 1 or baseline levels.
8.4.4
TAK-659 Dose Modification for Hematologic Toxicities
Please refer to Table 8.c for dose delay and reduction recommendations for hematologic toxicities. 
When the TAK-659 dose is withheld according to the following criteria (Table 8.c), clinical and 
laboratory re-evaluation should be repeated at least weekly or more frequently until the toxicity 
resolves to ≤Grade 1 or baseline. Upon recovery, TAK-659 may be reinitiated either at the same 
dose level or at a reduced dose level. For transient laboratory value abnormalities that, per 
investigator assessment, are not clinically significant or are related to the disease and not the drug, 
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continuation of therapy without following the dose modification guideline is permissible upon 
discussion with the sponsor. When a dose reduction of TAK-659 is required, no re-escalation of 
dose will be permitted.
Table 8.c
TAK-659 Dose Adjustments for Hematologic Toxicities
Criteria
Action
Neutropenia (ANC)
Grade 1 (ANC <LLN-1500 cells/mm3)
Maintain dose level.
Grade 2 (ANC 1000-1499 cells/mm3)
Maintain dose level.
Grade 3 (ANC 500-999 cells/mm3)
Withhold dose until resolved to ≤Grade 1 (ANC 
≥1500 cells/mm3) or baseline, then:

If resolved in ≤7 days, maintain dose level.

If resolved in >7 days, reduce dose by 1 dose level.

If recurred, reduce dose by 1 dose level.
Grade 4 (ANC 500 cells/mm3)
Withhold dose until resolved to ≤Grade 1 (ANC 
≥1500 cells/mm3) or baseline, then dose reduced by 1 dose 
level.
Febrile neutropenia (ANC <1000 cells/mm3, a 
single temperature of >38.3°C [101°F], or a 
sustained temperature of ≥38°C [100.4°F] for 
more than 1 hour)
Withhold dose until resolved to ≤Grade 1 (ANC 
≥1500 cells/mm3) or baseline and fever/infection have 
recovered, then reduce by 1 dose level.
Thrombocytopenia (PLT)
Grade 1 (PLT <LLN-75,000 cells/mm3)
Maintain dose level.
Grade 2 (PLT 50,000-74,999 cells/mm3)
Maintain dose level.
Grade 3 (PLT 25,000-49,999 cells/mm3)
Withhold dose until resolved to ≤Grade 1 (PLT 
≥75,000 cells/mm3) or baseline, then:

If resolved in ≤7 days, maintain dose level.

If resolved in >7 days, reduce dose by 1 dose level.
Grade 4 (PLT 25,000 cells/mm3)
Withhold dose until resolved to ≤Grade 1 or baseline, then 
reduce by 1 dose level
Grade 3 anemia
Withhold dose until resolved to ≤Grade 1 or baseline, then:

If resolved in ≤7 days, maintain dose level.

If resolved in >7 days, reduce dose by 1 dose level.

If recurred, reduce dose by 1 dose level.
Grade 4 anemia
Withhold dose until resolved to ≤Grade 1 or baseline, then 
reduce by 1 dose level if patient is not discontinued.
ANC=absolute neutrophil count, LLN=lower limit of normal, PLT=platelets.
8.4.5
TAK-659 Dose Modification for Nonhematologic Toxicities
Please refer to Table 8.d for dose holding and dose reduction recommendations for 
nonhematologic toxicities. When the TAK-659 dose is withheld according to the criteria in Table 
8.d, clinical and laboratory re-evaluation should be repeated at least weekly or more frequently 
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until the toxicity resolves to ≤Grade 1 or baseline. Upon recovery, TAK-659 dosing may be 
re-initiated either at the same dose level or at a reduced dose level. For transient laboratory value 
abnormalities that, per investigator assessment, are not clinically significant or are related to the 
disease and not the drug, continuation of therapy without following the dose modification 
guideline is permissible upon discussion with the sponsor.
Grade 4 nonhematologic toxicities, with the exception of asymptomatic laboratory changes that 
are considered clinically manageable, will in general require that treatment with TAK-659 be 
permanently discontinued. If, in the opinion of the investigator and the sponsor (project clinician 
or designee), it is in the patient’s best interest to continue treatment with TAK-659, then the dose 
of TAK-659 will be reduced by at least 1 dose level when treatment resumes after recovery from 
the toxicity or toxicities in question to ≤Grade 1 or baseline. When a dose reduction of TAK-659 is 
required because of Grade 4 nonhematologic toxicities, no re-escalation of dose will be permitted.
For Grade 4 asymptomatic laboratory abnormalities (eg, lipase, amylase, AST, ALT, or creatine 
phosphokinase [CPK]), TAK-659 should be held until resolution to ≤Grade 1 or baseline. When 
the study drug is resumed, TAK-659 can be started at the same or a reduced dose level, depending 
on how quickly the AE resolves. If a dose reduction is required, no dose re-escalation is permitted 
in this situation.
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Table 8.d
TAK-659 Dose Adjustments for Nonhematologic Toxicities
Criteria
Action
All Grade 3 nonhematologic toxicities with the 
exception of:

Grade 3 nausea, vomiting, and diarrhea resolved 
to ≤Grade 1 or baseline within 48 hours with 
optimal antiemetics and antidiarrheals following 
standard of care.

Transient Grade 3 fatigue (lasting <72 hours).

Asymptomatic lipase elevation (<Grade 4) in the 
absence of significant amylase elevation 
(<Grade 3).

Asymptomatic amylase elevation (<Grade 4) in 
the absence of significant lipase elevation 
(<Grade 3).

Asymptomatic Grade 3 elevation of a single 
liver enzyme (AST or ALT) in the absence of 
significant bilirubin elevation (<Grade 3).

Grade 3 hypophosphatemia resolved to 
≤Grade 1 or baseline within 72 hours with 
phosphate repletion.

Other Grade 3 asymptomatic enzyme elevations 
not considered clinically significant following 
agreement between sponsor and investigators.
Hold TAK-659 until resolution to ≤Grade 1 or baseline.

If resolved in ≤7 days, maintain the dose level.

If resolved in >7 days, reduce dose by 1 dose 
level.

If recurs, reduce dose by 1 dose level.
For the 7 exceptions listed, maintain the dose level (no 
dose hold required).
Permanent discontinuation should be considered if the 
toxicities persist as ≥Grade 3 for more than 21 days 
despite temporary disruption of study drug.
Grade 4 nonhematologic toxicities with the exception 
of asymptomatic laboratory change that is considered 
clinically manageable:

Asymptomatic Grade 4 lipase elevation in the 
absence of significant amylase elevation 
(<Grade 3).

Asymptomatic Grade 4 amylase elevation in the 
absence of significant lipase elevation 
(<Grade 3).

Asymptomatic Grade 4 elevation of a single 
liver enzyme (AST or ALT) in the absence of 
significant bilirubin elevation (<Grade 3).

Grade 4 hypophosphatemia resolved to 
≤Grade 1 or baseline within 72 hours with 
phosphate repletion.

Other Grade 4 asymptomatic enzyme elevations 
not considered clinically significant following 
agreement between sponsor and investigators.
Consider permanently discontinuing TAK-659, except 
when the investigator determines that the patient is 
obtaining a clinical benefit and has discussed this with 
the medical monitor or designee. Dose reduction by 
≥1 dose level is required if study treatment resumes after 
resolution to ≤Grade 1 or baseline.
For the exceptions, hold TAK-659 until resolution to 
≤Grade 1 or baseline.

If resolved in ≤7 days, maintain dose level.

If resolved in >7 days, reduce dose by 1 dose 
level.

If recurrence occurs, reduce dose by 1 dose 
level.
ALT=alanine aminotransferase, AST=aspartate aminotransferase.
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8.5
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 non-drug therapies, including physical therapy and blood transfusions, 
should be recorded from signing of the ICF through 28 days after the last dose of study drug or the 
start of subsequent antineoplastic therapy, whichever occurs first.
The following restrictions apply during the study:

Any antineoplastic therapy other than TAK-659 is prohibited on study. If alternative therapy is 
required for treatment of the patient’s tumor, the patient should be removed from this study and 
the reason for removal recorded in the electronic case report form (eCRF).

Radiation therapy (note that, in general, the requirement for local radiation therapy indicates 
disease progression) is not permitted during study. Palliative radiotherapy for local 
pain/symptom control in a pre-existing non-target lesion, if required, may be considered after 
discussion with the medical monitor or designee. Details of the palliative radiotherapy should 
be documented in the source records and eCRF, including dates of treatment, anatomical site, 
dose administered and fractionation schedule, and associated adverse events.

Chronic treatment with systemic steroids at dosages equivalent to prednisone >10 mg/day or 
other immunosuppressive agents is not permitted (except to treat drug-related AEs). Topical, 
ocular, intra-articular, intranasal, and inhaled corticosteroids (with minimal systemic 
absorption) are allowed.

Primary prophylactic use of myeloid growth factors (eg, granulocyte colony stimulating factor 
[G-CSF], granulocyte macrophage-colony stimulating factor [GM-CSF]) is not recommended 
at the study start and in Cycle 1. Patients who experience severe and/or febrile neutropenia 
during the study can be managed with growth factor support if needed, including prophylactic 
use of growth factors, in accordance with American Society of Clinical Oncology (ASCO) 
guidelines.

Concurrent systemic administration of TAK-659 with inhibitors or inducers of P-gp or strong 
inhibitors or inducers of CYP3A should be avoided in this study. In vitro studies indicate that 
TAK-659 is a substrate for P-gp and that, among CYP isozymes, TAK-659 is preferentially 
metabolized by CYP3A4/5. Refer to the list below and Appendix I for a nonexhaustive list of 
medications, supplements, and food products that are inhibitors or inducers of P-gp or strong 
inhibitors or inducers of CYP3A based on the US FDA Draft DDI Guidance.
–
Antifungals: itraconazole, ketoconazole, posaconazole, voriconazole.
–
Antibiotics: azithromycin, clarithromycin, erythromycin, telithromycin.
–
Antimycobacterials: rifabutin, rifampin, rifapentine.
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–
Antiepileptics: carbamazepine, phenobarbital, phenytoin, primidone.
–
Antidepressant: nefazodone.
–
Immunosuppressant: cyclosporine.
–
Calcium channel blockers: diltiazem, felodipine, mibefradil, verapamil.
–
Antiarrhythmics: amiodarone, dronedarone, quinidine.
–
Antiplatelet: ticagrelor.
–
Antilipid: avasimibe.
–
Other cardiovascular: captopril, carvedilol, ranolazine.
–
Vasopressin antagonist: conivaptan.
–
Antivirals for HCV: boceprevir, daclatasvir, simeprevir, telaprevir, danoprevir+ritonavir, 
velpatasvir+sofosbuvir (fixed dose combination), paritaprevir+ritonavir+ombitasvir (fixed 
dose combination), paritaprevir+ritonavir+ombitasvir+dasabuvir (fixed dose 
combination).
–
Foods/herbals/supplements: grapefruit-containing food and beverages, St. John’s wort, 
quercetin.
If a patient experiences an AE on study and TAK-659 dosing is temporarily interrupted due to that 
AE, the medications listed above and in Appendix I may be used for AE management provided 
there is no appropriate alternative treatment available based on the investigator’s judgment and the 
dosing is not concurrent with study drug. Treatment with the study drug may then resume after an 
appropriate washout period for the prohibited concomitant medication (consistent with the 
washout period as specified in the eligibility criteria for the study). Sites are encouraged to discuss 
any such situations with the Medical Monitor or designee. Patients should be closely monitored for 
potential toxicities.
Note that medications used to treat HIV infection are not listed above or in Appendix I because 
patients with known HIV infection are excluded from study participation. In addition, oncology 
medications are not listed because they are prohibited during the study. If a medication, 
supplement, or food/beverage is suspected or known to be a P-gp inhibitor or inducer and/or strong 
CYP3A inhibitor or inducer, but is not on the list above and in Appendix I, then its use must be 
discussed with the medical monitor or designee to assess the relative benefit and risk.
8.6
Precautions and Restrictions
Patients should not drive, operate dangerous tools or machinery, or engage in any other potentially 
hazardous activity that requires full alertness and coordination if they experience sedation while 
enrolled in this study.
Patients are to be instructed to limit the use of alcohol while enrolled in this study.
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8.6.1
Pregnancy and Contraception
No teratogenicity studies were conducted on animals. It is not known what effects TAK-659 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 the reproductive age group and 
male patients should use effective methods of contraception throughout defined periods during 
and after study treatment as specified below:
1) Some examples of effective contraceptive methods include intrauterine devices and hormonal 
contraceptives.
2) Use only contraceptive methods that are locally approved and available in each country.
3) Female patients must meet 1 of the following criteria:

Postmenopausal (natural amenorrhea, not due to other medical reasons) for at least 1 year 
before the Screening visit, or

Surgically sterile, or

If they are of childbearing potential, agree to practice 1 highly effective method of 
contraception and 1 additional effective (barrier) method at the same time, from the time 
of signing of the informed consent form (ICF) through 180 days after the last dose of study 
drug, or

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle 
of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], condoms only, withdrawal, spermicides only, and lactational amenorrhea are 
not acceptable methods of contraception.)
4) 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 180 days after the last dose of study drug, or

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle 
of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods for the female partner], condoms only, withdrawal, spermicides only, and 
lactational amenorrhea are not acceptable methods of contraception.)
5) Female patients should not donate ova from the time of signing the informed consent through 
180 days after the last dose of study drug.
6) Male patients should not donate sperm from the time of signing the informed consent through 
180 days after the last dose of study drug.
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8.6.2
Patients With Prior Exposure to HBV or HCV
Patients who have detectable HBV or HCV viral loads are excluded from study participation (see 
Section 7.2, Exclusion Criterion #8). Patients with prior exposure to HBV or HCV who have 
subsequently cleared the infection (determined by a negative viral load) are allowed in the study,
but should be monitored for reactivation every 2 months. Patients who develop detectable HBV or 
HCV in their blood during the study will have TAK-659 treatment held and will be treated with 
antivirals medication (eg, nucleoside antagonist [NA] lamivudine for HBV) per local institutional 
standard practice; a consultation with a hepatologist should be considered.
Restarting TAK-659 after HBV or HCV is no longer detected may be considered in the setting of 
continued prophylaxis and after a discussion with the sponsor’s medical monitor to review the 
potential benefit versus risk to the patient in the setting of a controlled HBV or HCV infection.
8.7
Management of Clinical Events
Therapies that are required to manage AEs and control cancer symptoms are allowed per standard 
clinical practice, unless specifically excluded. Supportive care agents, such as erythropoietin, 
G-CSF, blood products (RBC and platelet transfusions), and pain medications, are permitted as 
needed per American Society of Hematology (ASH)/ASCO guidelines or local institutional 
practice. However, these agents should not be used in this study in a manner that would either help 
establish eligibility for the study or support escalation of study drug dose during the dose 
escalation part. The said growth factors and blood products cannot be used within 14 days before 
the first dose of the study; and their use is prohibited during Cycle 1. However, the use of these 
agents in Cycle 1 is permissible when it is determined to be necessary in the clinical management 
of the patient following discussions and agreement between the investigator and the sponsor. In 
such a case, depending on the relatedness of the adverse event to the study drug, the patient will 
either be replaced for DLT evaluation or the event will be called a DLT.
8.7.1
Prophylaxis Against Infections
8.7.1.1
Cytomegalovirus Monitoring and Prophylaxis
At screening, all patients must have CMV serology and quantitative polymerase chain reaction 
(PCR) assay performed. CMV monitoring with a quantitative PCR assay will be performed as 
specified in the Schedule of Events. If positive at baseline, CMV monitoring is advised once a 
week with a decrease to a monthly frequency as it becomes negative. Preemptive treatment should 
be initiated based on the local CMV copy number per institutional practice. Prophylactic treatment 
can be initiated per investigators’ discretion based on the risk assessment (even if the CMV test is 
negative at baseline). Interruption of study drug is generally advised if the positive CMV test is 
accompanied by associated clinical symptoms or the copy number reaches a level that treatment is
indicated per institutional standard or the CMV test remains positive despite the antiviral treatment 
for CMV. If the study drug is interrupted, it can be resumed only after the infection has resolved. 
CMV monitoring is advised for the duration of the study as described in Section 9.4.13.3 and in the 
Schedule of Events (Appendix A).
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The following agents could be considered for prophylaxis or pre-emptive treatment against 
cytomegalovirus: ganciclovir (intravenous [IV]), valganciclovir (PO), foscarnet (IV), or cidofovir 
(IV). Duration of antiviral therapy generally is for at least 2 weeks until cytomegalovirus is no 
longer detected.
8.7.1.2
Prophylaxis for Pneumocystis jirovecii Pneumonia
Patients with lymphopenia may also be prone to developing infections, such as respiratory 
infections including pneumonia. Consider a diagnosis of opportunistic infection including 
Pneumocystis jirovecii pneumonia (PJP) in patients presenting with shortness of breath, cough, or 
fever. Prophylaxis for PJP must be initiated (either at baseline or during treatment) if at least 1 of 
the following is present:

Absolute CD4+ T-cell count of <200/mm3.

Percentage of CD4+ T-cells <20%.

Prior episode of PJP in medical history.
For older patients; patients with recent exposure to steroids, rituximab, cyclophosphamide, or 
immunosuppressive agents; or patients who, in the investigator’s opinion, are more susceptible to 
opportunistic infection at baseline, PJP prophylaxis should be considered at the start of the study 
treatment. When steroids and/or any immunosuppressive agents need to be used to manage AEs 
during the study, PJP prophylaxis should be considered when the study treatment resumes or is 
co-administered. Trimethoprim-sulfamethoxazole is recommended as the treatment of choice for 
PJP prophylaxis unless contraindicated; however, investigator discretion in selecting a more 
appropriate prophylaxis regimen is permitted.
Consideration should be given to antibiotic, antifungal, and antiviral prophylaxis during therapy, 
particularly if the patient is prone to developing neutropenia; however, the use of such agents 
should be at the discretion of investigators based on the local standard practice. Patients who 
develop neutropenic fever should be evaluated promptly and treated immediately with parenteral 
antibiotics tailored to the prominent organisms and resistance patterns of the institution.
8.7.2
Pneumonitis
Patients with serious lung events that do not respond to conventional antimicrobial therapy should 
be assessed for drug-induced pneumonitis after ruling out infectious causes and alternative 
etiologies. If pneumonitis is suspected, TAK-659 treatment should be interrupted and the patient 
treated per standard of care. If pneumonitis is moderate/severe, discontinue TAK-659. Patients 
should be monitored for respiratory signs and symptoms throughout treatment and should be 
advised to promptly report respiratory symptoms.
8.7.3
Nausea and/or Vomiting
This study will not initially employ prophylactic antiemetics before the first dose of the study drug 
during dose escalation. However, patients who develop nausea and/or vomiting will be actively 
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managed using optimal antiemetic treatment per local standard practice. Additionally, antiemetics 
could be used prophylactically as clinically indicated following the first occurrence of 
TAK-659-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.
8.7.4
Diarrhea
Prophylactic antidiarrheals will not be used in this study; however, patients should be instructed to 
take loperamide or comparable antidiarrheal medication according to institutional or local 
practice, once infectious causes of diarrhea are ruled out. Adequate fluid intake should be 
maintained to avoid dehydration, and any fluid deficit should be corrected before initiation of 
treatment with study drug and during treatment.
8.7.5
Edema (Including Periorbital)
Peripheral and periorbital edema have been observed in patients treated with TAK-659. 
Management of the event, if it occurs, should follow the standard local practice, and dose 
modification should proceed following the dose modification guidelines in Table 8.d.
8.7.6
Rash With or Without Pruritus
Prophylactic measures should also be considered if a patient develops a rash (eg, using a thick, 
alcohol-free, emollient cream on dry areas of the body). In the case of rash, the use of a topical or 
oral steroid (eg, prednisone ≤10 mg per day or equivalent) is permitted. Treatment with TAK-659 
must be withheld for Grade 3 or 4 rash. Refer to dose modification guidelines in Table 8.d.
8.7.7
Thrombocytopenia
Blood counts should be monitored regularly as outlined in the Schedule of Events (Appendix A), 
with additional testing obtained according to standard clinical practice. Administration of 
TAK-659 should be modified per dose modification guidelines when thrombocytopenia occurs 
(see Table 8.c). Platelet transfusion is allowed to manage severe thrombocytopenia to prevent and 
minimize bleeding according to ASH/ASCO guidelines. In general, platelet transfusion should be 
given prophylactically to patients with platelet counts <10,000/mm3 or to any patients with signs 
of overt bleeding, such as oral purpura. Each transfusion episode, including the type of transfusion 
(platelets), should be recorded.
8.7.8
Neutropenia
Blood counts should be monitored regularly as outlined in the Schedule of Events (Appendix A), 
with additional testing obtained according to standard clinical practice. TAK-659 administration 
should be modified per dose modification guidelines when neutropenia occurs (see Table 8.c). 
Myeloid growth factors (eg, G-CSF, GM-CSF) may be used to treat severe and/or febrile 
neutropenia according to ASCO guidelines; however, it should be noted that prophylactic use of 
myeloid growth factors should be avoided during the first cycle (see Section 8.5).
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8.7.9
Anemia
Hemoglobin should be monitored regularly as outlined in the Schedule of Events (Appendix A), 
with additional testing obtained according to standard clinical practice. Packed RBC transfusion is 
permitted, as necessary, per local institutional practice. In general, RBC transfusion is 
recommended for all symptomatic patients with anemia or any asymptomatic patients with 
hemoglobin <8 g/dL to maintain the hemoglobin between 8 and 10 g/dL, depending on the 
patient’s age, symptoms, and comorbid conditions. Each transfusion episode, including the type of 
transfusion (RBC), should be recorded. Erythropoietic agent use at the investigator’s discretion is 
also allowed if approved locally and should be administered according to institutional practice.
8.7.10 Hypophosphatemia
Hypophosphatemia has been observed in patients treated with TAK-659. Consider prophylaxis; 
otherwise, refer to dose modification guidelines in Table 8.d.
8.7.11 Enzyme Elevations
8.7.11.1 Transaminase, Amylase and Lipase, and CPK Elevations
Elevations of transaminases, amylase, lipase and CPK have been observed. Events are generally 
asymptomatic and reversible with dose interruption and not associated with evidence of 
pathological tissue injuries. See dose modification guidelines in Table 8.d.
8.7.11.2 Lactate dehydrogenase Elevations
Lactate dehydrogenase (LDH) elevations have been observed in the majority of patients exposed 
to TAK-659. These elevations have been asymptomatic, and the clinical significance is unknown. 
No action, such as dose interruption, has been taken as a result of increased LDH; however, LDH 
elevation is reversible based upon experience in patients who had TAK-659 interrupted for other 
reasons.
8.7.12 Fluid Deficit
Fluid deficit should be corrected before initiation of study drug and during treatment.
8.8
Blinding and Unblinding
This is an open-label study.
8.9
Description of Investigational Agents
TAK-659 has been formulated into immediate-release, film-coated tablets via a common 
granulation process. Three different tablet dosage strengths, 20 mg, 60 mg, and 100 mg, have been 
formulated. The formulation contains compendial excipients that include mannitol, 
microcrystalline cellulose, hydroxypropyl cellulose, sodium starch glycolate, and magnesium 
stearate. Tablets are coated with Opadry film coat.
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8.10
Preparation, Reconstitution, and Dispensation
Detailed instructions for dispensing TAK-659 immediate-release, film-coated tablets are provided 
in the Pharmacy Manual.
TAK-659 is an anticancer drug, and as with other potentially toxic compounds, caution should be 
exercised when handling TAK-659.
8.11
Packaging and Labeling
TAK-659 20 mg, 60 mg, and 100 mg tablets are packaged into round, white, high-density 
polyethylene bottles with induction seals, desiccant packs, and polypropylene, child-resistant caps. 
Each bottle of TAK-659 is labeled with either a single-panel or multilanguage label containing 
pertinent study information, country-specific requirements, and a caution statement.
8.12
Storage, Handling, and Accountability
TAK-659 tablets should be stored in the original dispensing bottles at 1°C to 25°C, with 
excursions permitted to 30°C as long as they do not exceed 7 days. All temperature excursions for 
the tablets must be reported back to the sponsor for assessment and determination for continued 
use. Please refer to the Pharmacy Manual for additional information. TAK-659 tablets must be 
used before the retest date indicated on the label and/or accompanying documentation. Throughout 
the clinical trial, the stability of the drug product will be monitored. TAK-659 tablets should 
remain in the original bottle provided to the investigational site and patients. Drug supplies must 
be kept in an appropriate, limited access, secure place until they are dispensed to the enrolled 
patients, returned to sponsor, or forwarded to the sponsor’s designee for destruction. Drug supplies 
received at the clinical sites will be counted and reconciled before being returned to the sponsor.
A drug dispensing log, including records of drug received from the sponsor and drug dispensed to 
the subjects, will be provided and kept at the study site. Storage area temperature conditions must 
be monitored and recorded daily.
Because TAK-659 is an investigational agent, it should be handled with due care. When cleaning 
up broken tablets, raising dust should be avoided. Damaged tablets may be harmful if inhaled, 
ingested, or through skin and/or eye contact. If damaged tablets come in contact with the eyes or 
skin, immediately and thoroughly flush and wash for at least 15 minutes with water (and soap for 
skin). Medical personnel should be notified.
Patients are to be instructed on proper storage, accountability, and administration of TAK-659, 
including that TAK-659 is to be taken as intact tablets. Patients will receive diary cards to record 
dosing compliance of TAK-659. Patients will be instructed to return any unused study drug in the 
original packaging along with their completed diary cards at the appropriate visits.
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9.0
STUDY CONDUCT
This trial will be conducted in compliance with the protocol, GCP, applicable regulatory 
requirements, and ICH guidelines.
9.1
Study Personnel and Organizations
The contact information for the medical monitor for this study, the central laboratory and any 
additional clinical laboratories and the contract research organization (CRO) team and the 
interactive voice/web response system may be found in the Study Manual. A full list of 
investigators is available in the sponsor’s or CRO’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 part and an expansion part at the RP2D 
(either the MTD or a lower dose as determined). In the dose escalation part, patients will be 
assigned to a dose cohort using the dose escalation rules as described in Section 8.3. In the 
expansion part, patients will be assigned as described in Section 6.1.
At least 1 Japanese patient will be enrolled in each cohort in the dose escalation part. The total 
number of Japanese patients dosed at the RP2D (either the MTD or a lower dose as determined) 
will be at least 6 including the dose escalation and expansion parts.
9.4
Study Procedures
Patients will be evaluated at scheduled visits over the following study periods: Screening, 
Treatment, EOT, and PFS follow-up (for patients in the expansion part only). Evaluations during 
the Screening period are to be conducted within 28 days before administration of the first dose of 
study drug. 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.
Unless otherwise noted, evaluations during the Treatment period must occur before study drug 
administration on scheduled visits. Tests and procedures should be performed on schedule for all 
visits. Laboratory assessments and procedures may occur within ±3 days of the scheduled day for 
extenuating circumstances (ie, inclement weather, holidays, vacations, or other administrative 
reasons). However, the timing of PK and pharmacodynamic assessments as specified in the 
Schedule of Events (Appendix A: Table A, Table B, Table C and Table D) is not flexible.
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Refer to the Schedule 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 must provide written informed consent before any study-required procedures are 
conducted, unless those procedures are performed as part of the patient’s standard care.
9.4.2
Patient Demographics
The age, race, ethnicity, and sex of the patient are to be recorded during Screening.
9.4.3
Medical History
During the Screening period, a complete medical history, including smoking history, will be 
compiled for each patient. The history will emphasize the background and progress of the patient’s 
malignancy, including a description of prior therapies. In addition, concomitant medications will 
be recorded as specified in Section 9.4.9. During dose expansion, medical history will also include 
baseline disease characteristics such as staging, risk/prognostic index, and other individual 
prognostic evaluations.
9.4.4
Physical Examination
A physical examination will be conducted per standard of care at the times specified in the 
Schedule of Events (Appendix A). During dose escalation, complete physical examinations will be 
performed at Screening, on Day 1 of each cycle of treatment, and at EOT. Symptom- or 
finding-directed physical examinations will be performed on Days 8, 15, and 22 of Cycle 1 and on 
Day 15 of Cycle 2. During dose expansion, complete physical examinations will be performed at 
Screening only, and post-Screening physical examinations will be symptom- or finding-directed 
examinations.
9.4.5
Patient Height and Weight
Height will be measured during Screening only (within 28 days before the first dose of TAK-659).
Weight will be measured as specified in the Schedule of Events (Appendix A).
9.4.6
Vital Signs
Vital sign measurements include seated position (after the patient has been sitting quietly for 
approximately 5 minutes in this position) measurements of diastolic and systolic blood pressure, 
pulse rate, temperature and O2 saturation will be assessed as specified in the Schedule of Events 
(Appendix A).
9.4.7
ECOG Performance Status
ECOG performance status will be assessed as specified in the Schedule of Events (Appendix A).
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9.4.8
Pregnancy Test
A serum pregnancy test will be performed for women of childbearing potential at Screening and 
again at Cycle 1 Day 1. A urine pregnancy test will be performed predose on Day 1 of all cycles, 
and negative results must be obtained before the first dose of TAK-659 may be administered. If the 
serum pregnancy test is performed within 3 days before the first dose and the result is negative, the 
urine pregnancy test on Cycle 1 Day 1 may be waived.
Women of childbearing potential is defined as any sexually active female patients who meet both 
of the following criteria:

Those who have not undergone hysterectomy or bilateral oophorectomy, AND

Those who have not had natural menopause for 12 consecutive months or longer (eg,
follicle-stimulating hormone >40 IU/L and no menopausal period for at least 12 consecutive 
months; loss of menopausal periods following chemotherapy may not rule out childbearing
potential).
9.4.9
Concomitant Medications and Procedures
Medications used by the patient and therapeutic procedures completed by the patient and their 
outcomes will be recorded in the eCRF from the time of the signing of the ICF through 28 days 
after the last dose of study drug or the start of subsequent antineoplastic therapy, whichever occurs 
first. See Section 8.5 for information on concomitant medications and procedures.
9.4.10 AEs
Monitoring of AEs, serious and nonserious, will be conducted throughout the study as specified in 
the Schedule of Events (Appendix A). Refer to Section 10.0 for details regarding definitions, 
documentation, and reporting of pretreatment events, AEs, and SAEs.
9.4.11
Enrollment
A patient is considered to be enrolled in the study when the first dose of TAK-659 has been 
administered.
Procedures for completing the enrollment information are described in the Study Manual.
9.4.12
ECG
A 12-lead ECG will be performed and interpreted locally at the time points specified in the 
Schedule of Events (Appendix A). The ECG schedule is more intensive for patients enrolled in the 
dose escalation cohorts.
All scheduled ECGs should be performed predose and after the patient has rested quietly for at 
least 5 minutes in a supine position. When the timing of a PK, pharmacodynamic, or safety 
laboratory blood sampling coincides with the timing of ECG measurements, the ECG will be 
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completed before the blood sample collection. In some cases, it may be appropriate to repeat an
ECG to rule out improper lead placement contributing to the ECG abnormality.
Confirmation that the machine-estimates of the rate-corrected QT interval (millisec) of 
electrocardiograph (QTc) are accurate using the appropriate QT correction formula (QTcF, QT 
interval with Bazett correction method [QTcB]) should be performed. Estimates of QTc for study 
eligibility should use QTcF. If a QTc value confirmed by the qualified reader is >475 msec, an 
evaluation to determine etiology should be conducted. If the prolonged QTc finding can be 
corrected by a change in medication and/or correction of electrolyte abnormalities, and a repeat 
ECG meets eligibility requirements, the patient may enroll in the study upon review and agreement 
by the sponsor’s clinician.
Following initiation of treatment, if a QTc value is confirmed by a qualified reader as >500 msec 
for any ECG, the following will occur:

The sponsor’s clinician or designee will be promptly notified.

TAK-659 should be held, and an evaluation should be conducted to correct other possible 
causes (eg, electrolyte disturbance, concomitant medication).

A formal consult by a cardiologist should be considered. Additional ECGs may be performed 
at intervals that the treating physician deems clinically appropriate until repeated QTc 
measurements are below the threshold interval that triggered the repeat measurement.
The decision of whether to reinitiate TAK-659 treatment, with or without dose reduction and 
additional monitoring, in those patients who had asymptomatic prolonged QTc >500 msec 
(Grade 3) that has reverted to an acceptable interval, have previously tolerated TAK-659, and 
appear to have benefited from TAK-659 treatment with either disease control or response will be 
made by the investigator and the sponsor’s clinician on a case-by-case basis.
ECGs should be reviewed by the investigator or delegate before the patient leaves the clinic on 
visit days.
9.4.13
Clinical Laboratory Evaluations
Clinical laboratory evaluations will be performed locally. Handling and shipment of clinical 
laboratory samples will be outlined in the Laboratory Manuals.
Clinical laboratory evaluations will be performed as outlined below.
9.4.13.1 Clinical Chemistry, Hematology, and Urinalysis
Blood samples for analysis of the clinical chemistry and hematological parameters shown in 
Table 9.a and urine samples for analysis of the parameters shown in Table 9.b will be obtained as 
specified in the Schedule of Events (Appendix A).
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Table 9.a
Clinical Chemistry and Hematology Tests
Hematology
Chemistry
Hematocrit
Hemoglobin
Leukocytes with differential
Neutrophils (ANC)
Platelets (count)
Lymphocytes (absolute lymphocyte 
count [ALC])
Lymphocyte subsets (CD4, CD8, 
CD4/CD8)
Albumin
Alkaline phosphatase (ALP)
Alanine aminotransferase (ALT)
Amylase
Aspartate aminotransferase (AST)
Bilirubin (total)
Urea nitrogen
Calcium
Carbon dioxide (CO2)
Creatinine
Creatine kinase (CK)
Chloride
Gamma glutamyl transferase (GGT)
Glucose
Lactate dehydrogenase (LDH) 
(including LDH isozymes)
Lipase
Magnesium
Phosphate
Potassium
Sodium
Protein (total protein)
Urate
Table 9.b
Clinical Urinalysis Tests
Urinalysis
Bilirubin
Glucose
Ketones
Leukocytes
Nitrite
Occult blood
pH
Protein
Specific gravity
Turbidity and color
Urobilinogen
When creatinine clearance is estimated, the Cockcroft-Gault formula will be employed (refer to 
Appendix F).
9.4.13.2 Hepatitis Testing
Hepatitis testing will be performed during the Screening period. HBV testing will include HBsAg, 
HBsAb, and HBcAb. For patients who are HbsAg negative but HBsAb and/or HbcAb positive, 
HBV DNA will also be assessed at Screening. HCV testing will include HCVAb. Patients who test 
positive for HCVAb will also be tested for HCV RNA at Screening.
Note that patients who have negative HBsAg but positive HBcAb and/or HBsAb may be enrolled 
but must have undetectable HBV viral load. Patients who have a positive HCVAb can be enrolled 
but must have undetectable HCV viral load.
Patients who are HBsAg negative but HBsAb and/or HBcAb positive, and/or HCVAb positive 
with a negative viral load at Screening, who are enrolled in this study will be monitored by 
assessment of viral load (DNA titers for HBV, RNA titers for HCV) every 2 months.
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9.4.13.3 CMV Testing
Patients will be tested at screening for CMV. CMV will continue to be monitored throughout the 
study.
Tests at screening include CMV serology (immunoglobulin [Ig]G and IgM) and quantitative PCR 
for CMV. Quantitative PCR for CMV monitoring will be performed as specified in the Schedule 
of Events (Appendix A).
9.4.14 Ophthalmic Exam
A slit lamp eye examination will be performed by an ophthalmologist at Screening, Cycle 2 Day 1, 
Cycle 7 Day 1, every 6 cycles thereafter (±2 weeks), and at EOT. On the basis of nonclinical 
toxicology findings with TAK-659 in rats, slit lamp examinations should focus on detecting any 
posttreatment changes in ocular lenses. Examination and photographing of the retina will be 
performed at Screening but not during the study unless clinically indicated. Additional eye exams 
may also be performed as required. Patients will be carefully monitored for eye complaints at each 
visit and instructed to report visual symptoms as soon as they occur.
9.4.15 Disease Assessment
Response status for all patients will be assessed and reported by the investigators; no independent 
confirmation of the assessment results is planned.
9.4.15.1 Dose Escalation Part
Patients in the dose escalation part will undergo radiographic evaluation and symptom assessment 
to monitor and assess disease response. Response assessment will follow the modified IWG 2007
criteria for malignant lymphoma (Appendix D, [25]). CT scans (with contrast) of the neck (if 
appropriate), chest, abdomen, and pelvis will be performed at Screening (within 28 days before the 
first study drug administration); at the end of Cycles 2, 4, and 6; at the end of every 3 cycles 
thereafter (until PD or the start of alternative therapies); and at the EOT visit. An FDG-PET scan 
extending from the neck through the mid-thighs should be performed only at baseline for tumor 
types for which it represents standard of care for response assessment. If the screening FDG-PET 
scan is positive, FDG-PET scans should be repeated either at the time of assessment for CR or for 
recurrence/progression of disease unless otherwise specified per local standard of care for a given 
lymphoma subtype. If the screening FDG-PET scan is negative, additional FDG-PET scans need
not be performed but could be performed as clinically indicated during the study. PET/CT scans 
may be used as the source of the CT scan, but the CT component should be performed with IV 
contrast. The same imaging modality should be used consistently throughout the study to monitor 
the disease status.
For patients with cutaneous T-cell lymphoma, investigator assessment will be based on a 
composite assessment of total tumor burden including cutaneous disease, lymph node 
involvement, and blood (Sezary cells).
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The sponsor may request clinical sites to forward for review any original data that support the 
response determination made by the sites.
9.4.15.2 Expansion Part
Baseline disease status will be assessed by investigator using the modified IWG 2007 criteria for 
malignant lymphoma (Appendix D, [25]) at Screening (within 28 days before the first study drug 
administration). Efficacy will be assessed using the same criteria at the end of every 2 cycles up to 
Cycle 12, at the end of every 3 cycles thereafter (until PD or start of alternative therapies), and at 
the EOT visit. Response will also continue to be assessed in PFS follow-up every 2 months for 
patients who discontinue treatment for reasons other than PD until 6 months after the last dose or 
occurrence of PD, whichever occurs first.
Response assessments should include radiographic imaging (CT and FDG-PET), evaluation of 
symptoms, and bone marrow aspirate/biopsy if appropriate. The FDG-PET imaging should be 
done minimally at Screening and at the end of Cycles 2, 6, and 12 if positive at baseline or 
clinically indicated.
Two modifications to the IWG 2007 criteria will be instituted in this study:
1. When assessing response, special consideration should be given to a situation where a patient 
may have had study drug held between the 2 scheduled imaging scans for ≥2 weeks because of 
AEs or other circumstances. If at the time of response assessment, metabolic changes are 
observed on a patient’s PET scan (ie, increased or new FDG uptake) that are not consistent 
with lesion changes indicative of PD by CT scan, discontinuation of study treatment is not 
recommended. Rather, it is recommended that the patient receive an additional cycle of 
treatment and that another response assessment be performed at the end of that cycle. If the 
metabolic changes observed on PET scans (ie, increased or new FDG uptake) remain, this 
result would be consistent with PD, and the patient should be discontinued from the study. If 
the previous metabolic changes observed on PET scan resolve and there is no indication of PD 
by CT or other measures, the patient may remain on study.
2. If PET-CT indicates bone marrow involvement at baseline, bone marrow biopsy is not 
required. Negative FDG-PET avidity is adequate to confirm CR in these patients. If FDG-PET 
does not suggest baseline bone marrow involvement, a bone marrow biopsy is required, and if 
infiltrate of lymphoma is shown, a repeat biopsy to confirm CR is also needed.
If a patient has been on study for 2 years (on treatment), response will be assessed every 6 months. 
Patients in PFS follow-up will be assessed for response every 2 months irrespective of duration on 
study.
9.4.15.2.1
CT Scans
CT scans of the chest, abdomen, and pelvis (neck should be included, if appropriate) will be 
performed to assess baseline disease at Screening and to assess disease response per the 
assessment schedule noted above and in the Schedule of Events (Appendix A). All CT scans 
should be performed with IV or oral contrast (unless medically contraindicated). Hybrid PET-CT 
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scanners may be used to acquire the required CT images only if CT produced by the scanner is of 
diagnostic quality, adheres to specified scan parameters, and includes IV/oral contrast (unless 
medically contraindicated). Nondiagnostic CT images acquired for attenuation purposes during 
PET-CT are NOT acceptable as the only CT scan for the time point. Diagnostic CT images with 
contrast (unless medically contraindicated) with a standalone CT scanner must be acquired if 
PET-CT is unable to acquire diagnostic CT images. If the diagnostic CT and PET are acquired on 
the same day, it is strongly recommended that the PET be performed before the CT with IV/oral
contrast to avoid compromising PET results.
9.4.15.2.2
PET Scans
A PET scan with FDG extending from the neck through the mid-thighs will be performed to assess 
baseline disease at Screening. If the screening FDG-PET scan is positive, FDG-PET scans should 
be conducted at the end of Cycles 2, 6, and 12, and repeated either at the time of assessment for CR 
or for recurrence/progression of disease; if the screening FDG-PET scan is negative, additional 
FDG-PET scans do not need to be conducted at these time points (ie, Cycles 2, 6, and 12) but could 
be performed as clinically indicated during the study. Examinations should be consistent across all 
time points, including amount of tracer, location of injection, arm position, and scan delay. Note 
that if a patient achieves CR, PET scans are not required at subsequent assessments. The Deauville 
5-point scale will be used to assess PET avidity.
9.4.15.2.3
Bone Marrow Biopsy and Aspirate
A bone marrow biopsy will be performed at Screening to assess disease only in patients with 
baseline PET-CT indicating negative bone marrow involvement, and will be repeated to confirm 
CR if the screening evaluation was positive and other criteria for CR have been met, or at the time 
of suspected PD per standard practice. If bone marrow involvement is indeterminate by 
morphology, immunohistochemistry evaluation of the biopsy material should be negative for 
assessment as CR. If bone marrow involvement is identified using PET-CT at baseline, PET-CT 
evaluation to rule out FDG-avid disease in bone marrow is sufficient to confirm CR. A biopsy 
could be performed at EOT (optional to patients) if the initial biopsy was positive and a response 
has been achieved but relapse subsequently documented.
Proper
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9.4.17 PK Measurements
The primary aim of PK sampling in this study is to measure the plasma and urine concentrations of 
TAK-659. However, plasma and urine samples collected for TAK-659 PK measurements may 
additionally be used for exploratory measurement of metabolites of TAK-659 if technically 
feasible and considered necessary for further understanding the metabolism and clearance of 
TAK-659.
Details on collecting, processing, storing, and shipping PK samples are provided in the Laboratory 
Manual. On days when predose PK samples are to be collected, patients should be instructed to 
refrain from taking their TAK-659 dose at home so that predose PK samples are collected before 
TAK-659 dosing in the clinic. The timing of the predose PK samples should be encouraged to 
occur at approximately the same time as TAK-659 dosing times on previous days to ensure that 
samples represent trough samples.
The timing, but not the number, of blood or urine PK samples may be changed in the dose 
escalation and/or expansion parts of the study if emerging data indicate that an alteration in 
sampling schedule is needed to optimize the characterization of TAK-659 PK in East Asian 
patients.
9.4.17.1 PK Measurements for the Dose Escalation Part
In all dose escalation patients, blood samples for determination of the plasma concentrations of 
TAK-659 will be collected at the times indicated in Appendix A, Table A (Dosing Schedule A) or
Table B (Dosing Schedule B).
To determine urine concentrations of TAK-659, a spot urine collection will be obtained predose on 
Cycle 1 Day 1, and a urine collection will be obtained in the clinic either on Cycle 1 Day 15 (for 
subjects on Dosing Schedule A) or Cycle 1 Day 7 (for subjects on Dosing Schedule B) at 0 to 
8 hours postdose. For the 0-to-8-hours-postdose urine collection, patients should void the bladder 
immediately before TAK-659 administration. This voided urine will not contribute to the urine PK 
sample collection but may be used for the scheduled urinalysis (safety assessment) as specified in 
the Schedule of Events for Dose Escalation Part (Appendix A). Urine voided subsequently during 
the 0-to-8-hours-postdose time frame will be collected for analysis of TAK-659 concentration. At 
the end of the 8-hour period, patients will void completely to finish the timed urine collection. The 
8-hours-postdose plasma PK sample should be collected immediately before the patient’s final 
urine void.
The dates and exact times of TAK-659 dosing and PK sample collection will be recorded in the 
eCRF on PK sample collection days (Cycle 1 Days 1, 2, 8, 15, 16, and 22 [Dosing Schedule A] or 
Cycle 1 Days 1, 2, 7, 8, 15 and 22 [Dosing Schedule B]). In addition, the dates and exact times of 
TAK-659 dosing (from patient diaries) will be recorded in the eCRF for the 2 doses of TAK-659 
administered before each PK sample collection day. Patients should be reminded to record dosing 
times in their diaries as instructed.
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9.4.17.2 PK Measurements for the Expansion Part
For expansion patients (except for a potential subset of Japanese patients), blood samples for 
determination of TAK-659 plasma concentrations will be collected during Cycles 1 through 4 
according to a sparse sampling schedule at the times indicated in Appendix A, Table C (Dosing 
Schedule A) or Table D (Dosing Schedule B). Specifically, blood samples will be collected on 
Days 1, 15, and 22 of Cycle 1 and on Day 1 of Cycles 2 through 4 (for subjects on Dosing Schedule 
A) or Days 1, 7 and 21 of Cycle 1 and on Day 7 of Cycles 2 through 4 (for subjects on Dosing 
Schedule B). No urine PK samples will be collected in expansion patients designated for sparse PK 
sampling. If fewer than 6 Japanese patients are dosed at the RP2D in the dose escalation part, 
additional intensive PK samples will be collected during Cycle 1 in a subset of Japanese patients in 
the expansion part. For this subset, additional blood samples and 2 urine samples should be 
collected as specified in Appendix A, Table A and Table B.
For all expansion patients, the dates and exact times of TAK-659 dosing and PK sample collection 
will be recorded in the eCRF on PK sample collection days. In addition, the dates and exact times 
of TAK-659 dosing (from patient diaries) will be recorded in the eCRF for the 2 doses of TAK-659 
administered before each PK sample collection day. Patients should be reminded to record dosing 
times in their diaries as instructed.
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9.4.20 Sample Retention
FFPE tumor tissues, 
 
 will be stored at BioStorage Technologies (Indiana USA) up to 15 years from the 
end of study (as defined by the finalization of the CSR). All samples will be destroyed by a 
third-party vendor identified by BioStorage Technologies per company standard operating 
procedures. FFPE tumor tissues will be stored at ambient temperature and serum and buccal 
epithelial cell DNA samples will be stored at -70ºC.
If patients decide to withdraw their informed consent, the samples will be discarded according to 
the local procedure, ie, the procedure relevant to where the sample resides at the time of 
withdrawal. In this case, the investigator is required to inform the sponsor of the patient’s intention 
to withdraw. Test results will not be shared with patients unless required by a local law. The tests 
performed with these samples are not intended to make determinations about a patient’s health or 
the likelihood a patient will develop any disease, so no test results will be provided to the 
investigator or put into patient’s medical record.
9.5
Completion of Treatment
Patients will be considered to have completed the study treatment if they discontinue treatment 
with TAK-659 for any of the reasons outlined in Section 9.7.
9.6
Completion of Study
In the dose escalation part, patients will be considered to have completed the study when they have 
discontinued treatment with TAK-659 for any of the reasons outlined in Section 9.7.
In the expansion part, patients will be considered to have completed the study if:
!
They have discontinued treatment because of PD.
They remain on study treatment free of PD for at least 6 months after their first dose of study 
treatment.
They discontinue study treatment for any reason other than PD and continue on to the PFS 
follow-up and either:
–
Experience PD before the end of the 6-month follow-up period, or
–
Reach the end of the follow-up period.
The sponsor terminates the study.
9.7
Discontinuation of Treatment With Study Drug and Patient Replacement
Treatment with study drug may be discontinued for any of the following reasons:
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicab
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
AE, including patients who experience a DLT (during escalation) or DLT-like toxicity (during 
expansion) during the first cycle, patients with Grade 4 nonhematologic toxicity, and patients 
with Grade 4 anemia.

Protocol deviation.

PD.

Symptomatic deterioration (at investigator’s discretion).

Unsatisfactory therapeutic response.

Initiation of hematopoietic stem cell transplant.

Pregnancy.

Study terminated by sponsor.

Withdrawal by subject.

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 Schedule of Events (Appendix A). The primary reason for study drug 
discontinuation will be recorded on the eCRF.
Patients who receive <75% of planned doses of TAK-659 in Cycle 1 for reasons other than related 
AEs during dose escalation will be replaced. Patients in the expansion part who are not evaluable 
for response will be replaced.
9.8
Withdrawal of Patients From Study
A patient may be withdrawn from the study for any of the following reasons:

AE.

Protocol deviation.

PD.

Symptomatic deterioration (at investigator’s discretion).

Unsatisfactory therapeutic response.

Initiation of hematopoietic stem cell transplant.

Pregnancy.

Study terminated by sponsor.

Withdrawal by subject.
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
Lost to follow-up.

Other.
The consequence of study withdrawal is that no new information will be collected from the 
withdrawn patient and added to the existing data or any database.
9.9
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. Patients will be given a diary to record study drug dosing. 
The dosing diary will provide supporting information, if necessary. The study center staff will 
check the patient drug diary versus the patient’s supply of TAK-659 tablets to assess compliance.
Tests and procedures should be performed on schedule, but unless otherwise specified, occasional 
changes are allowable within a 3-day window for holidays, vacations, and other administrative 
reasons. If extenuating circumstances prevent a patient from beginning treatment or completing a 
planned procedure or assessment within 3 days of the scheduled time, the patient may continue the 
study at the discretion of the investigator and after consultation with the project clinician or 
designee. However, the timing of PK and pharmacodynamic assessments as specified in the 
Schedule of Events (Appendix A: Table A, Table B, Table C and Table D) is not flexible. If a dose 
of TAK-659 is held for up to 21 days for reasons unrelated to toxicity, the patient may be 
discontinued from the study following a discussion between the investigator and the sponsor.
9.10
Posttreatment Follow-up Assessments (PFS) (Expansion Part Only)
Patients enrolled in the expansion part who stop treatment for any reason other than PD will 
continue to have PFS follow-up visits. The PFS follow-up visits should be conducted at the study 
site every 2 months for up to 6 months after the last dose of study drug or until PD, whichever 
occurs first.
If a patient has transitioned to either autologous or allogeneic stem cell transplant during this 
follow-up period, transplant details will also be collected in the eCRF including, but not limited to, 
type of transplant and success of transplant.
NOTE: Related SAEs must be reported to the Takeda 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 is any untoward medical occurrence in a patient or subject who has signed 
informed consent to participate in a study but before administration of any study medication; it 
does not necessarily have to have a causal relationship with study participation.
10.1.2 AE Definition
AE means any untoward medical occurrence in a patient or subject administered a pharmaceutical 
product; the untoward medical occurrence does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product whether or not it is related to the medicinal product. This includes any 
newly occurring event, or a previous condition that has increased in severity or frequency since the 
administration of study drug.
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.
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 
include allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
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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 4.03, effective date 14 June 2010 [26]. Clarification should be made 
between an SAE and an AE that is considered severe in intensity (Grade 3 or 4) because the terms 
serious and severe are NOT synonymous. The general term severe is often used to describe the 
intensity (severity) of a specific event; the event itself, however, may be of relatively minor 
medical significance (such as a Grade 3 headache). This is NOT the same as serious, which is 
based on patient/event outcome or action criteria described above, and is usually associated with 
events that pose a threat to a patient’s life or ability to function. A severe AE (Grade 3 or 4) does 
not necessarily need to be considered serious. For example, a white blood cell count of 1000/mm3
to less than 2000 is considered Grade 3 (severe) but may not be considered serious. Seriousness 
(not intensity) serves as a guide for defining regulatory reporting obligations.
10.2
Procedures for Recording and Reporting AEs and SAEs
All AEs spontaneously reported by the patient 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 a single, comprehensive event.
Regardless of causality, SAEs and serious pretreatment events (as defined in Section 10.1) must be 
reported (see Section 10.3 for the period of observation) by the investigator to the Takeda Global 
Pharmacovigilance department or designee (contact information provided below). This should be 
done by faxing the SAE Form within 24 hours after becoming aware of the event. The SAE Form, 
created specifically by Takeda, will be provided to each clinical study site. A sample of the SAE 
Form may be found in the Study Manual. Follow-up information on the SAE or serious 
pretreatment event may be requested by Takeda. SAE report information must be consistent with 
the data provided on the eCRF.
SAE Reporting Contact Information
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Planned hospital admissions or surgical procedures for an illness or disease that existed before the 
patient was enrolled in the trial 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. For serious 
pretreatment events, the investigator must determine both the severity (toxicity grade) of the event 
and the causality of the event in relation to study procedures.
Severity (toxicity grade) for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE, version 4.03, effective date 14 June 2010 [26]. 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 (not related) to this question: “Is there a reasonable 
possibility that the AE is associated with the study drug?”
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 28 days after 
administration of the last dose of study drug or the start of subsequent antineoplastic therapy, 
whichever occurs first, and recorded in the eCRFs.

SAEs
–
Serious pretreatment events will be reported to the Takeda Global Pharmacovigilance 
department or designee from the time of the signing of the ICF up to first dose of study 
drug, and will also be recorded in the eCRF.
–
Related and unrelated, treatment-emergent SAEs will be reported to the Takeda Global 
Pharmacovigilance department or designee from the first dose of study drug through 
28 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 caused by a patient’s stable or chronic condition or intercurrent 
illness(es).
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events
If a woman becomes pregnant or suspects that she is pregnant while participating in this study, she 
must inform the investigator immediately and permanently discontinue study drug. The sponsor 
must also be contacted immediately by faxing a completed Pregnancy Form to the Takeda Global 
Pharmacovigilance department or designee (see Section 10.2). The pregnancy must be followed 
for the final pregnancy outcome.
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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 faxing a completed Pregnancy Form 
to the Takeda Global Pharmacovigilance department or designee (see Section 10.2). 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 e-mail addresses provided below.
Call center
Phone number
E-mail
Fax
DLSS
Product complaints or medication errors in and of themselves are not AEs. If a product complaint 
or medication error results in an SAE, an SAE form should be completed and sent to 
 
(refer to Section 10.2).
10.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
The sponsor or its designee will be responsible for reporting all suspected unexpected serious 
adverse reactions (SUSARs) and any other applicable SAEs to regulatory authorities, investigators 
and IRBs or IECs or the head of the study site, as applicable, in accordance with national
regulations in the countries where the study is conducted. Relative to the first awareness of the 
event by/or further provision to the sponsor or sponsor’s designee, SUSARs will be submitted to 
the regulatory authorities as 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 or its designee 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.
Property of Takeda: For Non-Commercial 
and Subject to the Applicable Terms of Use
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11.0
STUDY-SPECIFIC COMMITTEES
No steering committee, data safety monitoring committee, or clinical endpoint 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, pretreatment events, medical history, and concurrent conditions will 
be coded using the Medical Dictionary for Regulatory Activities (MedDRA). Drugs will be coded 
using the WHO Drug Dictionary.
12.1
eCRFs
Completed eCRFs are required for each subject who signs an ICF.
The sponsor or its designee will supply investigative sites with access to eCRFs and will make 
arrangements to train appropriate site staff in the use of the eCRF. These forms are used to transmit 
the information collected in the performance of this study to the sponsor, CRO partners, and 
regulatory authorities. Investigative sites must complete eCRFs in English.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designee) and will be answered by the site.
Any change of, modification of, or addition to the data on the eCRFs should be made by the 
investigator or appropriate site personnel. Corrections to eCRFs are recorded in an audit trail that 
captures the old information, the new information, identification of the person making the 
correction, the date the correction was made, and the reason for change.
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the principal investigator must retain 
full responsibility for the accuracy and authenticity of all data entered on the eCRFs.
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed eCRFs 
are the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor.
12.2
Record Retention
The following procedure applies for all countries except Japan. The investigator agrees to keep the 
records stipulated in Section 12.1 and those documents that include (but are not limited to) the 
study-specific documents, the identification log of all participating subjects, medical records, 
temporary media such as thermal-sensitive paper, source worksheets, all original signed and dated 
ICFs, subject authorization forms regarding the use of personal health information (if separate 
from the ICFs), electronic 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 subject’s chart to ensure long-term 
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legibility. Furthermore, ICH E6 Section 4.9.5 requires the investigator to retain essential 
documents specified in ICH E6 (Section 8) until at least 2 years after the last approval of a 
marketing application for a specified drug indication being investigated or, if an application is not 
approved, until at least 2 years after the investigation is discontinued and regulatory authorities are 
notified. In addition, ICH E6 Section 4.9.5 states that the study records should be retained until an 
amount of time specified by applicable regulatory requirements or for a time specified in the 
Clinical Study Site Agreement between the investigator and sponsor.
Refer to the Clinical Study Site Agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of any 
such documents.
The following procedure applies for Japan sites only:
The investigator and the head of the institution agree to keep the records stipulated in Section 12.1
and those documents that include (but are not limited to) the study-specific documents, the 
identification log of all participating subjects, medical records, temporary media such as 
thermal-sensitive paper, source worksheets, all original signed and dated ICFs, subject 
authorization forms regarding the use of personal health information (if separate from the ICFs), 
copies of all paper CRFs and query responses/electronic copy of eCRFs including the audit trails, 
and detailed records of drug disposition to enable evaluations or audits from regulatory authorities, 
and the sponsor (or designees). Any source documentation printed on degradable, 
thermal-sensitive paper should be photocopied by the site and filed with the original in the 
subject’s chart to ensure long-term legibility. Furthermore, ICH E6 Section 4.9.5 requires the 
investigator and the head of the institution to retain essential documents specified in ICH E6 
(Section 8) until at least 3 years after the last approval of a marketing application for a specified 
drug indication being investigated or, if an application is not approved, until at least 3 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/or the head of the institution and sponsor.
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 will be prepared and finalized before database lock. This document will 
provide further details regarding the definition of analysis variables and analysis methodology to 
address all study objectives. No formal statistical hypothesis testing will be performed.
13.1.1 Analysis Sets
Analysis sets will include the following:

Safety analysis set: patients who receive at least 1 dose of study drug. The safety analysis set 
will be used for all safety analyses and for efficacy analyses.

PK analysis set: patients who have sufficient dosing and PK data to reliably estimate 1 or more 
PK parameters will be used for noncompartmental PK analysis.

Response-evaluable set: patients who receive at least 1 dose of study drug, have sites of 
measurable disease at baseline, and have at least 1 postbaseline disease assessment. Analyses 
of responses will use the response-evaluable set.

DLT-evaluable set: patients who have met the minimum treatment and safety evaluation 
requirements of the study or who experience a DLT during Cycle 1. The minimum treatment 
and safety evaluation requirements are met if in Cycle 1, the patient is treated with at least 75% 
of planned doses of TAK-659, is observed for ≥28 days following the dose on Cycle 1 Day 1, 
and is considered to have sufficient safety data by the sponsor and the investigators to conclude 
that a DLT did not occur.
13.1.2 Analysis of Demographics and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized, including sex, age, race, weight, 
height, primary diagnosis, and other parameters as appropriate. No inferential statistics will be 
done.
13.1.3 Efficacy Analysis
Efficacy is not the primary endpoint of this study. Secondary efficacy endpoints are ORR, CR rate, 
DOR, TTP, PFS, in expansion patients. ORR is defined as the proportion of patients who achieved 
CR and PR in the response-evaluable set. CR rate is defined as the proportion of patients who 
achieved CR in the response-evaluable set. DOR is defined as the time from the date of first 
documentation of response to the date of first documentation of PD/relapse. TTP is defined as the 
time from the date of first study drug administration to the date of first documentation of PD by the 
investigator. PFS is defined as the time from the date of first study drug administration to the day 
of first documentation of PD or death due to any cause, whichever occurs first. Analyses of ORR, 
CR, and DOR will use the response-evaluable set. Analyses of TTP and PFS will use the safety 
analysis set.
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Analysis of efficacy measures will be descriptive. Antitumor activity of TAK-659 will be 
determined by the best overall response. Response will be assessed using IWG criteria for 
lymphoma at each time point, and the best overall response for each patient will be derived 
programmatically from among the reported responses. Data listings will present the tumor 
measurements from CT or FDG-PET (including changes from baseline), disease response 
category (eg, CR, PR, stable disease [SD]), DOR, and others as appropriate.
The number and percentage of patients falling into each response category (eg, CR, PR, SD) will 
be tabulated descriptively. Estimates of the CR+PR rate will be presented with 2-sided 95% exact 
binomial confidence intervals. Response rate will also be tabulated by baseline prognostic factors 
if applicable. The prognostic factors will include, but will not be limited to, age, number and types 
of prior therapy, TTP from diagnosis or prior therapy, prior ASCT, and International Prognostic 
Index score. PFS will be analyzed using the standard Kaplan-Meier method for survival analysis.
For all analyses related to response and PFS, investigator assessments per IWG 2007 will be used 
for the primary analysis.
13.1.4 PK Analysis
The plasma and urine concentrations of TAK-659 will be determined by validated liquid 
chromatography tandem mass spectrometry assay methods. For patients who undergo intensive or 
sparse PK sampling in either dose escalation or expansion, plasma TAK-659 concentrations will 
be summarized by descriptive statistics according to nominal (scheduled) time postdose, dose 
level, day and cycle. For patients who undergo intensive PK sampling in either dose escalation or 
expansion, mean and individual plasma TAK-659 concentration data from Cycle 1will be plotted 
over time and grouped according to dose level and day, including a graphical presentation of mean 
and individual concentration-time data in the Japanese patients at the RP2D who undergo intensive 
PK assessments. All plasma and urine concentration data will be listed by patient, dose level, 
dosing cycle and day, and nominal and actual time point.
13.1.4.1 Noncompartmental PK Analysis
Plasma and urine PK parameters for patients with intensive PK sampling will be estimated in the 
PK analysis set using noncompartmental methods. The following PK parameters will be 
determined as permitted by available data: Cmax, Tmax, AUCτ, CL/F, Ctrough, Rac, PTR, CLR, and 
CLR as a percentage of CL/F. PK parameters will be summarized using descriptive statistics 
according to dose level and dosing cycle and day, including descriptive summarization of PK 
parameters in the Japanese patients administered the RP2D who undergo intensive PK 
assessments to permit noncompartmental PK analysis. Individual PK parameters will be listed by 
patient, dose level, and dosing cycle and day.
13.1.4.2 PK Sampling Intended to Support Population PK and Exposure-Response Analyses
The plasma PK data collected in the dose escalation and expansion parts of this study are intended 
to contribute to population PK, exposure-safety, and exposure-efficacy analyses of TAK-659. 
These analyses may include data collected from other TAK-659 clinical studies. As applicable, the 
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specifics of the population PK and exposure-response analyses will be described in separate 
analysis plans, and results will be reported separately from the CSR.
13.1.7 Safety Analysis
The incidence of DLT will be tabulated for each dose group. In addition, to assess the relationship 
between toxicities and TAK-659 dose, the preferred terms for individual toxicities will be 
summarized by their frequency and intensity for each dose group. The DLT-evaluable set will be 
used for the analysis of DLT.
Safety will be evaluated by the frequency 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 analysis 
set. Exposure to study drug and reasons for discontinuation will be tabulated. TEAEs that occur 
after administration of the first dose of study drug and through 28 days after the last dose of study 
drug or the start of subsequent antineoplastic therapy, whichever occurs first, will be tabulated.
AEs will be tabulated according to the MedDRA and will include the following categories:
!
TEAEs.
!
Drug-related TEAEs.
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
Grade 3 or higher TEAEs.

Grade 3 or higher, drug-related TEAEs.

Serious TEAEs.

Drug-related serious TEAEs.

TEAEs leading to study drug discontinuation.
Descriptive statistics for the actual values of clinical laboratory parameters (and/or change from 
baseline in clinical laboratory parameters) will be presented for all scheduled measurements over 
time. Mean laboratory values over time will be plotted for key laboratory parameters.
Descriptive statistics for the actual values (and/or the changes from baseline) of vital signs and 
weight over time will be tabulated by scheduled time point.
Shift tables for laboratory parameters will be generated to show changes in NCI CTCAE grade 
from baseline to the worst postbaseline value. Graphical displays of key safety parameters, such as 
scatter plots of baseline versus worst postbaseline values, may be used to understand the TAK-659 
safety profile.
All concomitant medications collected from Screening through the study period will be classified 
to preferred terms according to the WHO drug dictionary.
Additional safety analyses may be performed to most clearly enumerate rates of toxicities and to 
further define the safety profile of TAK-659.
13.1.7.1 ECG Analysis
A summary of ECG abnormalities will be presented by visit. ECG parameters (QT and QTcB and 
QTcF, PR interval, QRS) and heart rate will be summarized at each scheduled time point, along 
with mean change from baseline to each posttreatment time point.
13.2
Interim Analysis and Criteria for Early Termination
No interim analysis is planned.
13.3
Determination of Sample Size
No formal statistical power calculations to determine sample size were performed for this study.
It is estimated that 16 to 28 DLT-evaluable subjects will be enrolled in the dose escalation part. 
The actual number of patients may vary depending on the actual doses being tested. Assuming a 
20% dropout rate, 18 to 32 patients will be enrolled in the dose escalation part.
For the expansion part, approximately 12 response-evaluable patients will be enrolled to allow 
adequate assessment of safety and a preliminary assessment of efficacy. Assuming a 20% dropout 
rate, approximately 15 patients will be enrolled in the expansion part.
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The actual number of patients enrolled may increase on the basis of emerging data to allow a 
sufficient number of PK/safety-evaluable patients per country or in the East Asian race group or to 
further assess efficacy in a specific subtype or group of patients with FL or MZL.
The probability of observing at least 4 responders in the 12 response-evaluable patients is 0.775 if 
the true TAK-659 response rate is 40% (can be considered the true positive rate); the probability of 
observing at least 4 responses in the 12 response-evaluable patients is 0.205 if the true TAK-659 
response rate is 20% (can be considered the false positive rate). See Table 13.a for more details.
Table 13.a
Probabilities of Observing the Minimum Number of Responders Given True 
Response Rates, Assuming a Total of 12 Response-Evaluable Patients
Number of 
Responders
TAK-659 True Response Rate
0.2
0.4
0.6
0.8
≥2
0.725
0.980
1
1
≥3
0.442
0.917
0.997
1
≥4
0.205
0.775
0.985
1
≥5
0.073
0.562
0.943
0.999
≥6
0.019
0.335
0.842
0.996
≥7
0.004
0.158
0.665
0.981
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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, subject medical records, informed consent documentation, documentation of 
subject authorization to use personal health information (if separate from the ICFs), and review of 
eCRFs and associated source documents. It is important that the investigator and other study 
personnel are available during the monitoring visits and that sufficient time is devoted to the 
process.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
The site should document all protocol deviations in the subject’s source documents. In the event of 
a significant deviation, the site should notify the sponsor or its designee (and IRB or IEC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of the primary study 
assessment.
The sponsor will assess any protocol deviation; if it is likely to affect to a significant degree the 
safety and rights of a subject or the reliability and robustness of the data generated, it may be 
reported to regulatory authorities as a serious breach of GCP and the protocol.
The procedure below applies to Japanese sites only:
The investigator can deviate from and change the protocol for any medically unavoidable reason, 
for example, to eliminate an immediate hazard to study subjects, without prior written agreement 
with the sponsor or a prior approval from the IRB. In the event of a deviation or change, the 
principal investigator should notify the sponsor and the head of the site of the deviation or change 
and its reason in a written form, and then retain a copy of the written form. When necessary, the 
principal investigator may consult and agree with the sponsor on a protocol amendment. If the 
protocol amendment is appropriate, the amendment proposal should be submitted to the head of 
the site as soon as possible, and approval from the IRB should be obtained.
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The investigator should document all protocol deviations.
14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the FDA, the United Kingdom Medicines and Healthcare 
products Regulatory Agency, the Pharmaceuticals and Medical Devices Agency of Japan). If the 
study site is contacted for an inspection by a regulatory body, the sponsor should be notified 
immediately. The investigator and institution guarantee access for quality assurance auditors to all 
study documents as described in Section 14.1.
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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, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the responsibilities of the investigator listed in Appendix B. The 
principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities.
15.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable requirements of each participating 
country. 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.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the investigator’s brochure, a copy of 
the ICF, and, if applicable, subject 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 subject 
informed consent must be obtained and submitted to the sponsor or designee before 
commencement of the study (ie, before shipment of the sponsor-supplied drug or study specific 
screening activity). The IRB or IEC approval must refer to the study by exact protocol title, 
number, and version date; identify versions of other documents (eg, ICF) reviewed; and state the 
approval date. If required by country or regional regulations or procedures, approval from the 
competent regulatory authority will be obtained before commencement of the study or 
implementation of a substantial amendment. The sponsor or its designee will notify site once the 
sponsor or its designee has confirmed the adequacy of site regulatory documentation and, when 
applicable, the sponsor or its designee has received permission from the 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 subjects, local safety reporting requirements, reports and 
updates regarding the ongoing review of the study at intervals specified by the respective IRB or 
IEC, and submission of the investigator’s final status report to IRB or IEC. All IRB and IEC 
approvals and relevant documentation for these items must be provided to the sponsor or its 
designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor.
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15.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The ICF, subject authorization form (if applicable), and subject 
information sheet (if applicable) describe the planned and permitted uses, transfers, and 
disclosures of the subject’s personal and personal health information for purposes of conducting 
the study. The ICF and the subject information sheet (if applicable) further explain the nature of 
the study, its objectives, and potential risks and benefits, 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 subject authorization form. The ICF, subject authorization form (if 
applicable), and subject information sheet (if applicable) must be approved by both the IRB or IEC 
and the sponsor before use.
The ICF, subject authorization form (if applicable), and subject information sheet (if applicable) 
must be written in a language fully comprehensible to the prospective subject. It is the 
responsibility of the investigator to explain the detailed elements of the ICF, subject authorization 
form (if applicable), and subject information sheet (if applicable) to the subject. Information 
should be given in both oral and written form whenever possible and in the manner deemed 
appropriate by the IRB or IEC. If the subject is not capable of rendering adequate written informed 
consent, then the subject’s legally acceptable representative may provide such consent for the 
subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the study and (2) decide whether to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines that he or she will participate 
in the study, then the ICF and subject authorization form (if applicable) must be signed and dated 
by the subject, or the subject’s legally acceptable representative, at the time of consent and before
the subject enters into the study. The subject or the subject’s legally acceptable representative 
should be instructed to sign using their legal names, not nicknames, using a ballpoint pen with 
either blue or black ink. The investigator must also sign and date the ICF and subject authorization 
(if applicable) at the time of consent and before the subject enters into the study; however, the 
sponsor may allow a designee of the investigator to sign to the extent permitted by applicable law.
Once signed, the original ICF, subject authorization form (if applicable), and subject information 
sheet (if applicable) will be stored in the investigator’s site file. The investigator must document 
the date the subject signs the informed consent in the subject’s medical record. Copies of the 
signed ICF, the signed subject authorization form (if applicable), and subject information sheet (if 
applicable) shall be given to the subject.
All revised ICFs must be reviewed and signed by relevant subjects or the relevant subject’s legally 
acceptable representative in the same manner as the original informed consent. The date the 
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revised consent was obtained should be recorded in the subject’s medical record, and the subject 
should receive a copy of the revised ICF.
15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
or its designee may requires the investigator to permit its monitor or designee’s monitor, 
representatives from any regulatory authority (eg, US FDA, UK Medicines and Healthcare 
products Regulatory Agency, Japan Pharmaceuticals and Medical Devices Agency), the sponsor’s 
designated auditors, and the appropriate IRBs and IECs to review the subject’s original medical 
records (source data or documents), including, but not limited to, laboratory test result reports, 
ECG reports, admission and discharge summaries for hospital admissions occurring during a 
subject’s study participation, and autopsy reports. Access to a subject’s original medical records 
requires the specific authorization of the subject as part of the informed consent process (see 
Section 15.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
identifying personal information removed (eg, subject name, address, and other identifier fields 
not collected on the subject’s eCRF).
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1 Publication
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the clinical study site agreement. In the event of any discrepancy between the 
protocol and the clinical study site agreement, the clinical study site agreement will prevail.
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15.4.2 Clinical Trial Registration
To ensure that information on clinical trials reaches the public in a timely manner and to comply 
with applicable laws, regulations and guidance, Takeda will, at a minimum register interventional 
clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other publicly accessible 
websites on or before start of study, as defined by Takeda policy/standards. Takeda contact 
information, along with investigator’s city, state (for Americas investigators), country, and 
recruiting status will be registered and available for public viewing.
As needed, Takeda and investigator/site contact information may be made public to support 
participant access to trials via registries. In certain situations/registries, Takeda may assist 
participants or potential participants finding a clinical trial by helping them locate trial sites closest 
to their homes by providing the investigator name, address, and phone number via email/phone or 
other methods preferred by callers requesting trial information. Once subjects receive investigator 
contact information, they may call the site requesting enrollment into the trial. The investigative 
sites are encouraged to handle the trial inquiries according to their established subject screening 
process. If the caller asks additional questions beyond the topic of trial enrollment, they should be 
referred to the sponsor.
Any investigator who objects to Takeda providing this information to callers must provide Takeda 
with a written notice requesting that their information not be listed on the registry site.
15.4.3 Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites (including the Takeda corporate site) and registries, as required by Takeda 
policy/standards, applicable laws, and/or regulations.
15.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to clinical study subjects. 
Refer to the clinical study site agreement regarding the sponsor’s policy on subject compensation 
and treatment for injury. If the investigator has questions regarding this policy, he or she should 
contact the sponsor or sponsor’s designee.
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16.0
REFERENCES
1.
Roman E, Smith AG. Epidemiology of lymphomas. Histopathology 2011;58(1):4-14.
2.
Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, et al.  GLOBOCAN 
2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 
[Internet]. Published 2013.
3.
Miyoshi H, Ohshima K. Epidemiology of malignant lymphoma and recent progress in 
research on adult T-cell leukemia/lymphoma in Japan. Int J Hematol 2018;107(4):420-7.
4.
Lee H, Park HJ, Park EH, Ju HY, Oh CM, Kong HJ, et al. Nationwide Statistical Analysis 
of Lymphoid Malignancies in Korea. Cancer Res Treat 2018;50(1):222-38.
5.
Smith A, Howell D, Patmore R, Jack A, Roman E. Incidence of haematological 
malignancy by sub-type: a report from the Haematological Malignancy Research Network. 
Br J Cancer 2011;105(11):1684-92.
6.
Kumar V, Abbas A, Fausto N, Aster J. Robbins and Cotran Pathologic Basis of Disease. 8 
ed. Philadelphia: Saunders Elsevier; 2010.
7.
Nishimori H, Matsuo K, Maeda Y, Nawa Y, Sunami K, Togitani K, et al. The effect of 
adding rituximab to CHOP-based therapy on clinical outcomes for Japanese patients with 
diffuse large B-cell lymphoma: a propensity score matching analysis. Int J Hematol 
2009;89(3):326-31.
8.
Maurer MJ, Ghesquieres H, Jais JP, Witzig TE, Haioun C, Thompson CA, et al. Event-free 
survival at 24 months is a robust end point for disease-related outcome in diffuse large 
B-cell lymphoma treated with immunochemotherapy. J Clin Oncol 2014;32(10):1066-73.
9.
Sehn LH, Gascoyne RD. Diffuse large B-cell lymphoma: optimizing outcome in the 
context of clinical and biologic heterogeneity. Blood 2015;125(1):22-32.
10.
Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, et al. Distinct types of 
diffuse large B-cell lymphoma identified by gene expression profiling. Nature 
2000;403(6769):503-11.
11.
Monti S, Savage KJ, Kutok JL, Feuerhake F, Kurtin P, Mihm M, et al. Molecular profiling 
of diffuse large B-cell lymphoma identifies robust subtypes including one characterized by 
host inflammatory response. Blood 2005;105(5):1851-61.
12.
Kahl BS, Yang DT. Follicular lymphoma: evolving therapeutic strategies. Blood 
2016;127(17):2055-63.
13.
NCCN Clinical Practice Guidelines in Oncology (NCCN guidelines ®) B-Cell 
Lymphomas Version 5.2018 – October 2, 2018.
14.
Maddocks K. Update on mantle cell lymphoma. Blood 2018;132(16):1647-56.
15.
Lunning MA, Vose JM. Management of indolent lymphoma: where are we now and where 
are we going. Blood Rev 2012;26(6):279-88.
16.
Tan D, Tan SY, Lim ST, Kim SJ, Kim WS, Advani R, et al. Management of B-cell 
non-Hodgkin lymphoma in Asia: resource-stratified guidelines. Lancet Oncol 
2013;14(12):e548-61.
17.
Nagai H. [Revision of JSH Guideline for Tumors of Hematopoietic and Lymphoid Tissues 
2018: lymphoma]. Rinsho Ketsueki 2018;59(10):2146-52.
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18.
Kato K. [Malignant lymphoma and adult T-cell leukemia-lymphoma]. Rinsho Ketsueki 
2014;55(2):191-200.
19.
Ando K. [Follicular lymphoma: recent advances]. Rinsho Ketsueki 2018;59(10):2104-8.
20.
Yoo KH, Lee H, Suh C. Lymphoma epidemiology in Korea and the real clinical field 
including the Consortium for Improving Survival of Lymphoma (CISL) trial. Int J Hematol 
2018;107(4):395-404.
21.
Cho SH, Suh C, Do YR, Lee JJ, Yun HJ, Oh SY, et al. Clinical Features and Survival of 
Patients With Follicular Lymphoma in Korea. Clin Lymphoma Myeloma Leuk 
2016;16(4):197-202.
22.
Barr PM, Saylors G, Spurgeon SE, Cheson BD, Greenwald DR, O’Brien SM, et al. SYK 
and PI3Kδ pathway inhibition resulted in increased rates of pneumonitis: Implications for 
developing future small molecule combinations. Hematol Oncol 2015;33 (suppl. 1):121-2.
23.
Advani RH, Buggy JJ, Sharman JP, Smith SM, Boyd TE, Grant B, et al. Bruton tyrosine 
kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with 
relapsed/refractory B-cell malignancies. J Clin Oncol 2013;31(1):88-94.
24.
Friedberg JW, Sharman J, Sweetenham J, Johnston PB, Vose JM, Lacasce A, et al. 
Inhibition of Syk with fostamatinib disodium has significant clinical activity in 
non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood 
2010;115(13):2578-85.
25.
Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. Revised 
response criteria for malignant lymphoma. J Clin Oncol 2007;25(5):579-86.
26.
Common Terminology Criteria for Adverse Events (CTCAE). National Cancer Institute, 
National Institutes of Health, U.S. Department of Health and Human Services Series v4.03. 
June 14, 2010. Publication No. 09-5410.
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Appendix A
Schedule of Events
Schedule of Events for Dose Escalation Part (Dosing Schedule A and Dosing Schedule B) (28-Day Cycles)
Screening
(a)
Cycle 1
Cycle 2
Cycles 3 and 
Beyond
EOT (b) 
(+10 days)
Day 1
Day 2
Day 7
Day 8 Day 15 Day 16 Day 22 Day 1 Day 15 Day 22 Day 1 Day 22
Dosing
TAK-659 administration (c)
TAK-659 is dosed orally according to dosing schedule
Study Procedures
Informed consent (d)
X
Inclusion/exclusion criteria
X
Demographics
X
Medical history (e)
X
X
Physical examination (e)
X
X
X
X
X
X
X
X
X
Height
X
Weight (f)
X
X
X
X
X
Vital signs (g)
X
X
X
X
X
X
X
X
X
ECOG performance status
X
X
X
X
X
12-lead ECG (h)
X
Refer toTable A for Dosing Schedule A and 
Table B for Dosing Schedule B
X
X
X
Monitoring of concomitant 
medications and procedures
Recorded from the signing of ICF through 28 days after the last dose of study drug or the start of subsequent antineoplastic 
therapy, whichever occurs first.
AE reporting
Recorded from the signing of ICF through 28 days after the last dose of study drug or the start of subsequent antineoplastic
therapy, whichever occurs first.
SAE reporting
SAEs (i) will be reported from signing of the ICF through 28 days after the last dose of study drug even if the patient starts 
nonprotocol therapy.
Patient diary review (j)
X
X
X
X
X
X
X
X
Imaging/Response Assessments
Tumor assessment by IWG 
(CT/FDG-PET) (k)
X
X (k)
X (k)
X
Footnotes are on last table page.
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Schedule of Events for Dose Escalation Part (Dosing Schedule A and Dosing Schedule B) (28-Day Cycles) (continued)
Screening
(a)
Cycle 1
Cycle 2
Cycles 3 and 
Beyond
EOT (b) 
(+10 days)
Day 1
Day 2
Day 7
Day 8 Day 15 Day 16 Day 22 Day 1 Day 15 Day 22 Day 1 Day 22
Samples/Laboratory Assessments
Pregnancy test (l)
X
X
X
X
HBV and HCV screening (m)
X
CMV testing (n)
X
X
X
X
X
Hematology/chemistry (o) (p)
X
X
X
X
X
X
X
X
X
LDH isozymes (p)
X
X
X
X
X
X (q)
CK testing (p)
X
X
X
X
X
X
X
X
X
Urinalysis (for hematuria and 
proteinuria evaluation) (r) (p)
X
X
X
X
X
Ophthalmic exam (s)
X
X
X (s)
X
Archival (banked) tumor tissue 
sample (u)
X
Fresh tumor tissue biopsy if 
archival banked tumor is not 
available (v)
X
Blood samples for PK (w)
Refer toTable A for Dosing Schedule A and 
Table B for Dosing Schedule B
Urine samples for PK (x)
Refer to Table A for Dosing Schedule A and 
Table B for Dosing Schedule B
CK=creatine kinase, CMV=cytomegalovirus, CT=computed tomography, CYP=cytochrome P450, ECG=electrocardiogram, ECOG=Eastern Cooperative 
Oncology Group, EOT=End of Treatment, FDG=fluoro-2-deoxy-D-glucose, HBV=hepatitis B virus, HCV=hepatitis C virus, ICF=informed consent form, 
IWG=International Working Group, PBMC=peripheral blood mononuclear cell(s), PCR= polymerase chain reaction, PET=positron emission tomography, 
Property of Take
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PK=pharmacokinetic(s).
Evaluations/laboratory assessments performed on visit days must take place before dosing unless otherwise indicated. On these days, patients should be 
instructed to hold dosing until relevant assessments have been completed.
(a) Screening assessments are performed within 28 days before the Cycle 1 Day 1 dose. Screening assessments performed no more than 3 days before Cycle 1 Day 
1 will qualify as baseline assessments and need not be repeated, unless otherwise specified.
(b) End of treatment will occur 28 days (+10 days) after the last dose of study drug or before the start of subsequent anticancer therapy if that occurs sooner.
(c) TAK-659 will be administered orally once daily in 28-day cycles.
(d) Informed consent may be obtained before the Screening period (within 28 days before Cycle 1 Day 1 dosing).
(e) The Cycle 1 Day 1 physical examination and medical history are not required if the screening physical examination was conducted and medical history obtained 
within 3 days before administration of the first dose of study drug (Cycle 1 Day 1). Complete physical examinations will be performed during Screening, on Day 1 
of each cycle, and at the EOT visit. Symptom- or finding-directed physical examinations will be performed on Days 8, 15, and 22 of Cycle 1 and on Day 15 of 
Cycle 2.
(f) Weight should be obtained at Screening, Day 1 predose of each cycle, and at EOT.
(g) Vital signs measurement (blood pressure, pulse rate, temperature, O2 saturation) should be performed before dosing.
(h) In Cycle 1, single 12-lead ECGs will be performed as detailed in Table A (Dose Escalation Part [Dosing Schedule A] PK, ECG, and Pharmacodynamic 
Assessment Schedule) or Table B (Dose Escalation Part [Dosing Schedule B] PK, ECG, and Pharmacodynamic Assessment Schedule). For Cycle 2 and beyond, the 
ECGs will be performed only on Day 1 predose.
(i) All SAEs occurring after consent will be reported to the Takeda Global Pharmacovigilance department or designee (see Section 10.2).
(j) The study center staff will check the patient drug diary versus the patient’s supply of TAK-659 tablets to assess compliance.
(k) Response assessments for lymphoma using the modified IWG 2007 criteria for malignant lymphoma (Appendix D) will be performed at Screening; between 
Days 22 and 29 (predose) of Cycles 2, 4, and 6; between Days 22 and 29 (predose) of every 3 cycles thereafter; and at the EOT visit. At Screening, chest, abdomen, 
and pelvis (neck should be included, if appropriate) should be imaged by CT scan with contrast. FDG-PET scans should be performed at baseline only in tumor 
types for which it represents standard of care for response assessment. If the screening FDG-PET scan is positive, FDG-PET scans should be repeated either at the 
time of assessment for CR or for recurrence/progression of disease unless otherwise specified per local standard of care. If the screening FDG-PET scan is negative, 
additional FDG-PET scans need not be performed but could be performed as clinically indicated during the study. See Section 9.4.15.1. If the patient has had an 
appropriate CT or FDG-PET scan performed within 28 days before Cycle 1 Day 1, the results of that scan may be used for tumor lesion measurements at Screening.
The sponsor may request clinical sites to forward for review any original data that support the response determination made by the sites.
(l) A serum pregnancy test will be performed for women of childbearing potential at Screening and again at Cycle 1 Day 1. A urine pregnancy test must be 
performed predose on Day 1 of all cycles, with negative results available before the first dose of TAK-659 may be administered in that cycle. If a serum pregnancy 
test is performed within 3 days before the first dosing and the result is negative, the urine pregnant test may be waived on Cycle 1 Day 1.
(m) Patients with prior exposure to HBV or HCV who have subsequently cleared the infection (determined by a negative viral load) are allowed in the study, but 
should be monitored for reactivation every 2 months. Patients who develop detectable HBV or HCV in their blood during the study will have TAK-659 treatment 
held and will be treated with antivirals medication (eg, neucleoside antagonist [NA] lamivudine for HBV) per local institutional standard practice; a consultation 
with a hepatologist should be considered.
(n) CMV serology (IgG and IgM) and quantitative PCR assay will be performed during Screening; quantitative PCR will be performed on Day 1 of each cycle; and 
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at the EOT visit.
(o) The hematology and chemistry blood samples for Cycle 1 Day 1 may be collected within 3 days before dosing to ensure patient eligibility. If screening clinical 
laboratory testing was performed within 3 days before the Cycle 1 Day 1 dose, it need not be repeated at Cycle 1 Day 1.
(p) Laboratory assessments can be conducted within ±3 days of the scheduled visit, with the exception of PK/pharmacodynamic assessments or unless otherwise 
noted.
(q) Cycles 3 and 4 only.
(r) Urinalysis samples will be collected predose and analyzed at the site’s local laboratory.
(s) An ophthalmic exam should be performed at Screening, Cycle 2 Day 1, Cycle 7 Day 1, every 6 cycles thereafter (±2 weeks), and at EOT. See Section 9.4.14 for 
details.
(u) Archival (banked) tumor tissue samples should be obtained, if available, from the diagnosis specimens or a previous resection or biopsy that was done as part of 
the patient’s standard care. The archival (banked) tumor tissue samples are to be collected only from enrolled patients and may be sent to the sponsor (or designee) 
after initiation of protocol treatment. Suitable specimens are either a tumor block or a minimum of 10 unstained slides. If archived tumor tissue is not available, an 
optional fresh tumor biopsy may be obtained. See Section 9.4.16 and the Laboratory Manual for details about sample collections and shipment procedures.
(v) An optional fresh tumor biopsy may be obtained in the absence of archived tumor tissue. See Section 9.4.16 and the Laboratory Manual for details about sample 
collections and shipment procedures.
(w) Blood specimens for plasma PK analysis will be collected during Cycle 1 in all dose escalation cohorts at time points specified in Table A (Dose Escalation Part
[Dosing Schedule A] PK, ECG, and Pharmacodynamic Assessment Schedule) or Table B (Dose Escalation Part [Dosing Schedule B] PK, ECG, and 
Pharmacodynamic Assessment Schedule).
(x) Urine specimens for urine PK analysis will be collected during Cycle 1 in all dose escalation cohorts at time points specified in Table A (Dose Escalation Part
[Dosing Schedule A] PK, ECG, and Pharmacodynamic Assessment Schedule) or Table B (Dose Escalation Part [Dosing Schedule B] PK, ECG, and 
Pharmacodynamic Assessment Schedule). The PK samples will consist of a Cycle 1 Day 1 predose spot urine collection and a Cycle 1 Day 15 in-clinic 
0-to-8-hours-postdose urine collection. Note that 2 urine samples will be collected on Cycle 1 Day 15: a predose specimen for urinalysis (safety assessment) and the 
0-to-8-hours-postdose specimen for PK analysis.
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Table A
Dose Escalation Part (Dosing Schedule A) PK, ECG, and Pharmacodynamic Assessment Schedule
Cycle 1
Day 1
Day 2 
(24 h 
After 
Day 1 
Dose 
±1 h)
Day 8
Day 15
Day 16 
(24 h 
After 
Day 15 
Dose 
±1 h)
Day 22
Single 
ECG
PK
PD
PK
PK
PD
Single 
ECG
PK
PD
PK
PK
PD
Plasma Urine Serum PBMC Plasma Plasma Serum PBMC
Plasma Urine
Serum
PBMC
Plasma
Plasma
Serum PBMC
Predose
(within 1 hour before 
dosing on all days) (a)
X (b)
X
X (c)
X
X
X
X
X
X
X (b)
X
X
X
X
X
X
X
0.5 hours postdose
(±10 min)
X
X
X (d)
(0–8 h
[±1 h])
1 hour postdose
(±10 min)
X
X
2 hours postdose
(±20 min)
X
X
X
X
X (e)
(2 h or 
4 h 
postdose)
X(f)
X (e)
(2 h or 
4 h 
postdose)
3 hours postdose
(±30 min)
X
X
4 hours postdose
(±30 min)
X
X
8 hours postdose
(±30 min)
X
X
ECG=electrocardiogram, PBMC=peripheral blood mononuclear cell(s), PD=pharmacodynamic, PK=pharmacokinetic.
When the timing of a PK, pharmacodynamic, or safety laboratory blood sample coincides with the timing of ECG measurements, the ECG will be completed before 
the collection of the blood samples.
The dates and exact times of TAK-659 dosing and PK sample collection will be recorded in the eCRF on days of PK sample collection. In addition, the dates and 
exact times of TAK-659 dosing (from patient diaries) will be recorded in the eCRF for the 2 doses of TAK-659 administered before each day of PK sample 
collection.
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(a) On days when predose samples are collected, patients will be instructed to arrive at the clinic in the morning without taking their TAK-659 dose at home. The 
TAK-659 dose will be administered in the clinic after collection of all predose samples. The timing of the predose samples on Days 2, 8, 15, 16, and 22 should be 
encouraged to occur at approximately the same time as TAK-659 dosing times on previous days to ensure that samples represent trough samples.
(b) Predose ECG may be performed outside the 1 hour window before dosing.
(c) A predose spot urine specimen will be collected at Cycle 1 Day 1 before first study drug dose administration. See the Laboratory Manual for details on urine 
collection methodology.
(d) On Day 15, patients will void the bladder immediately before study drug administration. This voided urine will not contribute to the urine PK sample collection 
but may be used for the scheduled urinalysis (safety assessment) as specified in the Schedule of Events for Dose Escalation Part. Urine voided subsequently during 
the 0-to-8-hours-postdose time frame will be collected for PK analysis. At the end of the 8-hour period, patients will void completely to finish the timed urine 
collection. The 8-hours-postdose plasma PK sample should be collected immediately before the patient’s final urine void. See the Laboratory Manual for details on 
urine collection methodology.
(e) On Cycle 1 Day 15 and Cycle 1 Day 22, serum samples for pharmacodynamic assessment of circulating cytokines/chemokines/serum proteins consist of a 
predose sample and a postdose sample. One postdose sample must be collected when the 2-hour or the 4-hour postdose PK sample is collected.
(f) The postdose PK sample on Cycle 1 Day 22 should be collected between the 2- or 4-hours postdose timeframe (at the same time the 2- or-4 hours postdose 
sample for pharmacodynamic assessment is collected).
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Table B
Dose Escalation Part (Dosing Schedule B) PK, ECG, and Pharmacodynamic Assessment Schedule
Cycle 1
Day 1
Day 2 
(24 h 
After 
Day 1 
Dose 
±1 h)
Day 7
Day 8 (24 h 
After Day 7
Dose ±1 h)
Day 15
Day 22 (24 h After Day 21
Dose ±1 h)
Single 
ECG
PK
PD
PK
Single 
ECG
PK
PD
PK
PD
PK
PD
PK
PD
Plasma Urine Serum PBMC Plasma
Plasma Urine
Serum
Plasma PBMC Plasma Serum PBMC Plasma Serum PBMC
Predose
(within 1 hour before 
dosing on all days) (a)
X (b)
X
X (c)
X
X
X
X (b)
X
X
X
X
X
X
X
X
X
X
0.5 hours postdose
(±10 min)
X
X
X (d)
(0–8 h
[±1 h])
1 hour postdose
(±10 min)
X
X
2 hours postdose
(±20 min)
X
X
X
X
X (e)
(2 h or 
4 h 
postdose)
3 hours postdose
(±30 min)
X
X
4 hours postdose
(±30 min)
X
X
8 hours postdose
(±30 min)
X
X
ECG=electrocardiogram, PBMC= peripheral blood mononuclear cell(s), PD=pharmacodynamic, PK=pharmacokinetic.
When the timing of a PK, pharmacodynamic, or safety laboratory blood sample coincides with the timing of ECG measurements, the ECG will be completed before 
the collection of the blood samples.
The dates and exact times of TAK-659 dosing and PK sample collection will be recorded in the eCRF on days of PK sample collection. In addition, the dates and 
exact times of TAK-659 dosing (from patient diaries) will be recorded in the eCRF for the 2 doses of TAK-659 administered before each day of PK sample 
collection.
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(a) On days when predose samples are collected, patients will be instructed to arrive at the clinic in the morning without taking their TAK-659 dose at home. The 
TAK-659 dose will be administered in the clinic after collection of all predose samples. The timing of the predose samples on Days 2, 7, 8, 15 and 22 should be 
encouraged to occur at approximately the same time as TAK-659 dosing times on previous days to ensure that samples represent trough samples.
(b) Predose ECG may be performed outside the 1 hour window before dosing.
(c) A predose spot urine specimen will be collected at Cycle 1 Day 1 before first study drug dose administration. See the Laboratory Manual for details on urine 
collection methodology.
(d) On Day 7, patients will void the bladder immediately before study drug administration. This voided urine will not contribute to the urine PK sample collection 
but may be used for the scheduled urinalysis (safety assessment) as specified in the Schedule of Events for Dose Escalation Part. Urine voided subsequently during 
the 0-to-8-hours-postdose time frame will be collected for PK analysis. At the end of the 8-hour period, patients will void completely to finish the timed urine 
collection. The 8-hours-postdose plasma PK sample should be collected immediately before the patient’s final urine void. See the Laboratory Manual for details on 
urine collection methodology.
(e) On Cycle 1 Day 7, serum samples for pharmacodynamic assessment consist of a predose sample and a postdose sample. One postdose sample must be collected 
when the 2-hour or the 4-hour postdose PK sample is collected.
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Schedule of Events for Expansion Part (Dosing Schedule A and Dosing Schedule B) (28-Day Cycles)
Screening
(a)
Cycle 1
Cycle 2
Cycles 3 and 
Beyond
EOT (b)
(+10 days)
PFS (c)
Days
Days
Days
1
2
7
8
15
16
21
22
1
7
15
22
1
7
22
Dosing
TAK-659 administration (d)
TAK-659 is dosed orally according to dosing schedule.
Study Procedures
Informed consent (e)
X
Inclusion/exclusion criteria
X
Demographics
X
Medical history (f)
X
X
Physical examination (f)
X
X
X
X
X
X
X
X
X
X
Height
X
Weight (g)
X
X
X
X
X
Vital signs (h)
X
X
X
X
X
X
X
X
X
X
ECOG performance status
X
X
X
X
X
12-lead ECG (i)
X
X
X
X
X
Monitoring of concomitant 
medications and procedures
Recorded from the signing of ICF through 28 days after the last dose of study drug or the start of subsequent antineoplastic therapy, 
whichever occurs first.
AE reporting
Recorded from the signing of ICF through 28 days after the last dose of study drug or the start of subsequent antineoplastic therapy, 
whichever occurs first.
SAE reporting
SAEs (j) will be reported from signing of the ICF through 28 days after the last dose of study drug even if the patient starts 
nonprotocol therapy.
Patient diary review (k)
X
X
X
X
X
X
X
X
Footnotes are on last table page.
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CONFIDENTIAL
Schedule of Events for Expansion Part (Dosing Schedule A and Dosing Schedule B) (28-Day Cycles) (continued)
Screening
(a)
Cycle 1
Cycle 2
Cycles 3 and 
beyond
EOT (b)
(+10 days)
PFS (c)
Days
Days
Days
1
2
7
8
15
16
21
22
1
7
15
22
1
7
22
Imaging/Response Assessments
Tumor assessment for 
lymphoma by IWG 
(CT/FDG-PET) (l)
X
X (l)
X (l)
X
X
Samples/Laboratory Assessments
Pregnancy test (m)
X
X
X
X
HBV and HCV screening (n)
X
CMV testing (o)
X
X
X
X
X
Hematology/chemistry (p)
(q)
X
X
X
X
X
X
X
X
X
LDH isozymes (q)
X
X
X
X
X
X (r)
CK testing (q)
X
X
X
X
X
X
X
X
X
Urinalysis (for hematuria and 
proteinuria evaluation) (q) (s)
X
X
X
X
Ophthalmic exam (t)
X
X
X (t)
X
Footnotes are on last table page.
Property of Taked
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TAK-659
Study No. C34007
Page 109 of 162
Protocol Incorporating Amendment No.02
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CONFIDENTIAL
Schedule of Events for Expansion Part (Dosing Schedule A and Dosing Schedule B) (28-Day Cycles) (continued)
Screening
(a)
Cycle 1
Cycle 2
Cycles 3 and 
beyond
EOT (b)
(+10 days)
PFS (c)
Days
Days
Days
1
2
7
8
15
16
21
22
1
7
15
22
1
7
22
Blood samples for sparse PK
(z)
Refer to Table C for Dosing Schedule A and Table D for Dosing Schedule B
Blood samples for intensive
PK
Samples may be required only in a subset of Japanese patients as specified in Table A and 
in Table B.
Urine samples for PK
Samples may be required only 
in a subset of Japanese patients 
as specified in Table A and in 
Table B.
Bone marrow biopsy and 
aspirate (aa)
X
CK=creatine kinase, CMV=cytomegalovirus, CT=computed tomography, CYP=cytochrome P450, ECG=electrocardiogram, ECOG=Eastern Cooperative 
Oncology Group, EOT=End of Treatment, FDG=fluoro-2-deoxy-D-glucose, HBV=hepatitis B virus, HCV=hepatitis C virus, ICF=informed consent form, 
IWG=International Working Group, MRI=magnetic resonance imaging, MTD=maximum tolerated dose, PBMC=peripheral blood mononuclear cell(s), PCR=
polymerase chain reaction, PET=positron emission tomography, PFS=progression-free survival, PK=pharmacokinetic(s), RP2D=recommended phase 2 dose.
Evaluations/laboratory assessments performed on visit days need to take place before dosing unless otherwise indicated. On these days, patients should be 
instructed to hold dosing until relevant assessments have been completed.
(a) Screening assessments are performed within 28 days before the first dose of study drug. Screening assessments performed no more than 3 days before Cycle 1 
Day 1 will qualify as baseline assessments and need not be repeated, unless otherwise specified.
(b) End of treatment will occur 28 days (+10 days) after the last dose of study drug or before the start of subsequent anticancer therapy if that occurs sooner.
(c) Patients who stop treatment for any reason other than progressive disease (PD) will continue to have PFS follow-up visits. The PFS follow-up visits should be 
conducted at the site every 2 months from last dose of study drug up to 6 months or until PD, whichever occurs first.
Property of Takeda: For Non-Commercial Us
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TAK-659
Study No. C34007
Page 110 of 162
Protocol Incorporating Amendment No.02
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CONFIDENTIAL
(d) TAK-659 will be administered orally once daily on 28-day cycles at the RP2D (the MTD or a lower dose as determined).
(e) Informed consent may be captured before the Screening period (within 28 days before Cycle 1 Day 1 dosing).
(f) The Cycle 1 Day 1 physical examination and medical history are not required if the screening physical examination was conducted and medical history obtained 
within 3 days before administration of the first dose of study drug (Cycle 1 Day 1). A complete physical examination should be performed at Screening. 
Postscreening physical examinations will be symptom directed or finding directed.
(g) Weight should be obtained at Screening, predose on Day 1 of each cycle, and at EOT.
(h) Vital signs measurement (blood pressure, pulse rate, temperature, O2 saturation) should be performed before dosing.
(i) Single 12-lead ECGs will be performed at Screening, predose on Day 1 of each cycle, and at EOT.
(j) SAE reporting will include serious pretreatment events. Only those SAEs that occur after the first dose of study drug will be collected in the eCRF. However, all 
SAEs occurring after consent will be reported to the Takeda Global Pharmacovigilance department or designee (see Section 10.2).
(k) The study center staff will check the patient drug diary versus the patient’s supply of TAK-659 tablets to assess compliance.
(l) Response assessments for follicular lymphoma (FL)/marginal zone lymphoma (MZL) using the modified IWG 2007 criteria for malignant lymphoma, 
(Appendix D), including a CT (with contrast) scan of chest, abdomen, and pelvis (neck should be included, if appropriate) and symptom evaluation, will be 
performed at Screening; between Days 22 and 29 (predose) of every 2 cycles up to Cycle 12; between Days 22 and 29 (predose) of every 3 cycles thereafter (until 
PD, or start of alternative therapies); and at the EOT visit. Response will continue to be assessed in PFS follow-up every 2 months for patients who discontinue 
treatment for reasons other than PD until 6 months after the last dose or occurrence of PD, whichever occurs first. An FDG-PET scan extending from the neck 
through the mid-thighs will be performed at Screening for all patients enrolled. If the screening FDG-PET scan is positive, FDG-PET scans should be conducted at 
the end of Cycles 2, 6 and 12) and repeated either at the time of assessment for complete response (CR) or for recurrence/progression of disease; if the screening 
FDG-PET scan is negative, additional FDG-PET scans need not be performed at these time points (ie, Cycles 2, 6 and 12) but could be performed as clinically 
indicated during the study. If the patient has had an appropriate FDG-PET or CT scan performed within 28 days before Cycle 1 Day 1, the results of that scan may 
be used for tumor lesion measurements at Screening; see Section 9.4.15.2. Central collection of disease assessment images by sponsor or designee is required.
(m) A serum pregnancy test will be performed for women of childbearing potential at Screening and again at Cycle 1 Day 1. A urine pregnancy test must be 
performed predose on Day 1 of all cycles, with negative results available before the first dose of TAK-659 may be administered in that cycle. If a serum pregnancy 
test is performed within 3 days before the first dose and the result is negative, the urine pregnancy test may be waived on Cycle 1 Day 1.
(n) Patients with prior exposure to HBV or HCV who have subsequently cleared the infection (determined by a negative viral load) are allowed in the study, but 
should be monitored for reactivation every 2 months. Patients who develop detectable HBV or HCV in their blood during the study will have TAK-659 treatment 
held and will be treated with antivirals medication (eg, neucleoside antagonist [NA] lamivudine for HBV) per local institutional standard practice; a consultation 
with a hepatologist should be considered.
(o) CMV serology (IgG and IgM) and quantitative PCR assay will be performed during Screening; quantitative PCR will be performedon Day 1 of each cycle; and 
at the EOT visit.
(p) The hematology and chemistry blood samples for Cycle 1 Day 1 may be collected within 3 days before dosing to ensure patient eligibility. If screening clinical 
laboratory testing was performed within 3 days before the Cycle 1 Day 1 dose, it need not be repeated at Cycle 1 Day 1.
(q) Laboratory assessments can be conducted within ±3 days of the scheduled visit, with the exception of PK/pharmacodynamic assessments or unless otherwise 
noted.
(r) Cycles 3 and 4 only.
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CONFIDENTIAL
(s) Urinalysis samples will be collected predose and analyzed at the site’s local laboratory.
(t) An ophthalmic exam should be performed at Screening, Cycle 2 Day 1, Cycle 7 Day 1, every 6 cycles thereafter (±2 weeks), and at EOT. See Section 9.4.14 for 
(x)
 
 
 
(y) An optional fresh tumor biopsy may be obtained in the absence of archived tumor tissue. See Section 9.4.16 and the Laboratory Manual for details about sample 
collections and shipment procedures.
(z) In the expansion patients who undergo sparse PK sampling, blood specimens for plasma PK analysis will be collected at the time points specified in Table C or 
Table D.
(aa) A bone marrow biopsy and aspirate will be collected at Screening and as necessary for confirmation of CR or at the time of suspected PD per standard practice. 
A bone marrow aspirate/biopsy could also be performed at EOT if the initial bone marrow evaluation was positive and a response has been achieved but relapse is 
subsequently documented (optional to patients).
Property of Takeda: For Non-Commercial Use 
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TAK-659
Study No. C34007
Page 112 of 162
Protocol Incorporating Amendment No.02
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CONFIDENTIAL
Table C
Expansion Part (Dosing Schedule A) Sparse PK and Pharmacodynamic Assessments Schedule (a)
Cycle 1
Cycles 
2, 3, and 
4
Day 1
Day 8
Day 15
Day 22
Day 1
PK
PD
PK
PD
PK
PD
PK
PD
PK
Plasma
Serum
PBMC
Plasma
Serum
PBMC
Plasma
Serum
PBMC
Plasma
Serum
PBMC
Plasma
Predose
(within 1 hour 
before dosing) (b)
X
X
X
X
X
X
X
X
X
X
X
X
X
2 or 4 hours 
postdose
X
X
X
X
X
X
X
PD=pharmacodynamic, PBMC=peripheral blood mononuclear cell(s), PD=pharmacodynamic, PK=pharmacokinetic.
When the timing of a PK, pharmacodynamic, or safety laboratory blood sample coincides with the timing of ECG measurements, the ECG will be completed before 
the collection of the blood samples.
The dates and exact times of TAK-659 dosing and PK sample collection will be recorded in the eCRF on PK sample collection days. In addition, the dates and exact 
times of TAK-659 dosing (from patient diaries) will be recorded in the eCRF for the 2 doses of TAK-659 administered before each PK sample collection day.
(a) In the subset of Japanese patients designated for intensive PK sampling, plasma and urine PK samples and pharmacodynamic samples will be collected during
Cycle 1 at time points specified in Table A (Dose Escalation Part [Dosing Schedule A] PK, ECG, and Pharmacodynamic Assessment Schedule). In addition, plasma 
PK samples will be collected predose on Day 1 of Cycles 2, 3, and 4 according to Table C (Expansion Part [Dosing Schedule A] Sparse PK and PD Assessments 
Schedule).
(b) On days when predose samples are collected, patients will be instructed to arrive at the clinic in the morning without taking their TAK-659 dose at home. The 
TAK-659 dose will be administered in the clinic after collection of all predose samples. The timing of the predose samples should be encouraged to occur at 
approximately the same time as TAK-659 dosing times on previous days to ensure that samples represent trough samples.
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TAK-659
Study No. C34007
Page 113 of 162
Protocol Incorporating Amendment No.02
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CONFIDENTIAL
Table D
Expansion Part (Dosing Schedule B) Sparse PK and Pharmacodynamic Assessments Schedule (a)
Cycle 1
Cycles 2, 
3, and 4
Day 1
Day 7
Day 15
Day 21
Day 7
PK
PD
PK
PD
PK
PD
PK
PD
PK
Plasma
Serum
PBMC
Plasma
Serum
PBMC
Plasma
Serum
PBMC
Plasma
Serum
PBMC
Plasma
Predose
(within 1 hour 
before dosing) (b)
X
X
X
X
X
X
X
X
X
X
X
X
X
2 or 4 hours 
postdose
X
X
X
X
X
PD= pharmacodynamic, PBMC=peripheral blood mononuclear cell(s), PD=pharmacodynamic, PK=pharmacokinetic.
When the timing of a PK, pharmacodynamic, or safety laboratory blood sample coincides with the timing of ECG measurements, the ECG will be completed before 
the collection of the blood samples.
The dates and exact times of TAK-659 dosing and PK sample collection will be recorded in the eCRF on PK sample collection days. In addition, the dates and exact 
times of TAK-659 dosing (from patient diaries) will be recorded in the eCRF for the 2 doses of TAK-659 administered before each PK sample collection day.
(a) In the subset of Japanese patients designated for intensive PK sampling, plasma and urine PK samples and pharmacodynamic samples will be collected during 
Cycle 1 at time points specified in Table B (Dose Escalation Part [Dosing Schedule B] PK, ECG, and Pharmacodynamic Assessment Schedule). In addition, plasma 
PK samples will be collected predose on Day 7 of Cycles 2, 3, and 4 according to Table D (Expansion Part [Dosing Schedule B] Sparse PK and PD Assessments 
Schedule).
(b) On days when predose samples are collected, patients will be instructed to arrive at the clinic in the morning without taking their TAK-659 dose at home. The 
TAK-659 dose will be administered in the clinic after collection of all predose samples. The timing of the predose samples should be encouraged to occur at 
approximately the same time as TAK-659 dosing times on previous days to ensure that samples represent trough samples.
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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:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff who will assist in the protocol.
3. If the investigator/institution retains the services of any individual or party to perform 
trial-related duties and functions, the investigator/institution should ensure that this individual 
or party is qualified to perform those trial-related duties and functions and should implement 
procedures to ensure the integrity of the trial-related duties and functions performed and any 
data generated.
4. Ensure that study related procedures, including study specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential subjects, before the receipt of written 
approval from relevant governing bodies/authorities.
5. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
6. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
ICH, and local regulatory requirements.
7. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
8. Ensure that requirements for informed consent, as outlined in ICH and local regulations, are 
met.
9. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each ICF should contain a subject authorization section that 
describes the uses and disclosures of a subject’s personal information (including personal 
health information) that will take place in connection with the study. If an ICF does not include 
such a subject authorization, then the investigator must obtain a separate subject authorization 
form from each subject or the subject’s legally acceptable representative.
10. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents.
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11. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
12. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor. This responsibility lies on 
the appropriate individual, designated by the site in Japan.
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, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
The investigator’s personal information may be retained, processed, and transferred by Takeda 
and these other parties for research purposes including the following:

Assessment of the suitability of the investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
The investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in the investigator’s 
own country.
The investigator acknowledges and consents to the use of his or her personal information by 
Takeda and other parties for the purposes described above.
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Appendix D
International Working Group Response Criteria for Lymphoma
Response
Definition
Nodal Masses
Spleen, Liver
Bone Marrow
CR
Disappearance 
of all evidence 
of disease
(a) FDG avid or PET positive 
before therapy; mass of 
any size permitted if PET 
negative
(b) Variably FDG avid or 
PET negative; regression 
to normal size on CT
Not palpable, 
nodules 
disappeared
Infiltrate cleared on repeat 
biopsy; if indeterminate 
by morphology, 
immunohistochemistry 
should be negative
PR
Regression of 
measurable 
disease and no 
new sites
≥50% decrease in SPD of up 
to 6 largest dominant masses; 
no increase in size of other 
nodes
(a) FDG avid or PET positive 
before therapy; 1 or more 
PET positive at previously 
involved site
(b) Variably FDG avid or 
PET negative; regression 
on CT
≥50% decrease in 
SPD of nodules 
(for single nodule 
in greatest 
transverse 
diameter); no 
increase in size of 
liver or spleen
Irrelevant if positive 
before therapy; cell type 
should be specified
SD
Failure to 
attain CR/PR 
but no PD
(a) FDG avid or PET positive 
before therapy; PET 
positive at prior sites of 
disease and no new sites 
on CT or PET
(b) Variably FDG avid or 
PET negative; no change 
in size of previous lesions 
on CT
Relapsed 
disease or PD
Any new 
lesion or 
increase by 
≥50% of 
previously 
involved sites 
from nadir
Appearance of a new lesion(s) 
>1.5 cm in any axis, 50% 
increase in SPD of more than 
1 node, or ≥50% increase in 
longest diameter of a 
previously identified node 
>1 cm in short axis
Lesions PET positive if 
FDG-avid lymphoma or PET 
positive before therapy
>50% increase 
from nadir in the 
SPD of any 
previous lesions
New or recurrent 
involvement
Source: Cheson BD et al, 2007 [25].
CR=complete remission, FDG=[18F]fluorodeoxyglucose, PET=positron emission tomography, CT=computed 
tomography, PR=partial remission, SPD=sum of the product of the diameters, SD=stable disease, PD=progressive
disease.
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Appendix E
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 et al, 1982.
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Appendix F
Cockcroft-Gault Equation
For male subjects:
Creatinine clearance = (140 age[years]) weight [kg]
72 (serum creatinine [mg/dL]) OR (140 age[years]) weight [kg]
0.81 (serum creatinine [mol/L])
For female subjects:
Creatinine clearance = 0.85 (140 age[years]) weight [kg]
72 (serum creatinine [mg/dL]) OR 0.85 (140 age[years]) weight [kg]
0.81 (serum creatinine [mol/L])
Source: Cockcroft DW and Gault MH, 1976.
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Appendix G
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 1:
– oral
– intravaginal
– transdermal
progestogen-only hormonal contraception associated with inhibition of ovulation 1:
– oral
– injectable
– implantable 2
intrauterine device (IUD) 2
intrauterine hormone-releasing system (IUS) 2
bilateral tubal occlusion 2
vasectomised partner 2,3
sexual abstinence 4
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 5
cap, diaphragm or sponge with spermicide 5
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_Co
ntraception.pdf
(1) Hormonal contraception may be susceptible to interaction with the investigational medicinal product, which may 
reduce the efficacy of the contraception method.
(2) Contraception methods that in the context of this guidance are considered to have low user dependency.
(3) 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.
(4) 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 subject.
(5) 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 H
New York Heart Association Classification of Functional Capacity
Class
Functional Capacity
Objective Assessment
I
Patients with cardiac disease but without resulting limitations of 
physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain.
No objective evidence of 
cardiovascular disease.
II
Patients with cardiac disease resulting in slight limitation of physical 
activity. They are comfortable at rest. Ordinary physical activity 
results in fatigue, palpitation, dyspnea, or anginal pain.
Objective evidence of minimal 
cardiovascular disease.
III
Patients with cardiac disease resulting in marked limitation of 
physical activity. They are comfortable at rest. Less than ordinary 
activity causes fatigue, palpitation, dyspnea, or anginal pain.
Objective evidence of moderately 
severe cardiovascular disease.
IV
Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort. Symptoms of heart failure or 
the anginal syndrome may be present even at rest. If any physical 
activity is undertaken, discomfort is increased.
Objective evidence of severe 
cardiovascular disease.
Source: The Criteria Committee of New York Heart Association, 1994.
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Appendix I
Medications, Supplements and Food Products that are Strong CYP3A and/or 
P-gp Inhibitors or Inducers
Medication, Supplement, or Food Product (a) (b)
Required Washout Period Before First Dose
Strong CYP3A Reversible Inhibitors and/or P-gp 
Inhibitors
amiodarone
azithromycin
boceprevir
captopril
carvedilol
cyclosporine
daclatasvir
diltiazem
dronedarone
erythromycin
felodipine
itraconazole
ketoconazole
nefazodone
posaconazole
quercetin
quinidine
ranolazine
simeprevir
ticagrelor
velpatasvir + sofosbuvir (fixed dose combination)
verapamil 
voriconazole
5 times the inhibitor half-life (if a reasonable half-life 
estimate is known), or 7 days (if a reasonable half-life 
estimate is unknown)
Strong CYP3A Mechanism-Based Inhibitors
clarithromycin (c)
conivaptan (c)
danoprevir + ritonavir (c)
mibefradil (c)
paritaprevir + ritonavir + ombitasvir (fixed dose 
combination) (c) 
paritaprevir + ritonavir + ombitasvir + dasabuvir 
(fixed dose combination) (c)
telaprevir (c)
telithromycin
7 days, or 5 times the inhibitor half-life, whichever is longer
grapefruit and grapefruit-containing foods and 
beverages
5 days
Footnotes are on last table page.
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Appendix I
Medications, Supplements and Food Products that are Strong CYP3A and/or 
P-gp Inhibitors or Inducers (continued)
Medication, Supplement, or Food Product (a) (b)
Required Washout Period Before First Dose
Strong CYP3A Inducers and/or P-gp Inducers
avasimibe
carbamazepine
phenobarbital
phenytoin
primidone
rifabutin
rifampin
rifapentine
St. John’s wort
7 days, or 5 times the inducer half-life, whichever is longer
(a) Note the list of strong CYP3A inhibitors or inducers and/or P-gp inhibitors or inducers is not exhaustive and is 
based on the FDA Draft DDI Guidance (Sources: 
fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM292362.pdf and 
fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm080499.htm) If 
a medication, supplement, or food/beverage is suspected or known to be a or P-gp inhibitor or inducer and/or strong 
CYP3A inhibitor or inducer, but is not on the list, then its use must be discussed on a case by case basis with the 
medical monitor or designee to assess the relative benefit and risk.
(b) Note that medications used to treat HIV infection that are strong CYP3A inhibitors or inducers and/or P-gp 
inhibitors or inducers are not included in this list, as patients with known HIV infection are excluded from study 
participation. The list also does not include oncology medications because they are prohibited during the study.
(c) Also inhibitors of P-gp.
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Appendix J
Detailed Description of Amendments to Text
The primary section(s) of the protocol affected by the major changes in Amendment 02 are 
indicated below. Please note that text in Section 2.0 STUDY SUMMARY has also been amended
accordingly, but is not described in this Appendix.
Change 1: Revised the planned number of sites.
The primary change occurs in Section 2.0 STUDY SUMMARY.
Amended 
text:
Planned Number of Sites:
Dose escalation part: approximately 3-5 sites
DLBCL eExpansion part: approximately 6-10 sites
Rationale for Change:
To add flexibility to the number of sites to take part in this study considering the recruitment 
prediction with addition of new cohorts and change in targeted tumor type in expansion part.
Change 2: Updated the diseases under study section to include FL and MZL.
The primary change occurs in Section 4.1.1 Diseases Under Study. New references are added, and 
reference numbers revised accordingly.
Amended
text:
Non-Hodgkin lymphomas (NHLs) are a heterogeneous group of lymphoproliferative 
disorders originating in B lymphocytes, T lymphocytes, or natural killer (NK) cells. 
Mature B-cell lymphomas account for greater than 85% of NHL cases worldwide, and 
its major subtype is. The two most common types of NHL are diffuse large B-cell 
lymphoma (DLBCL) and follicular lymphoma (FL) [1]. NHL is one of the most 
common malignancies worldwide, with an estimated 386,000 new cases and 200,000 
deaths in 2012. The incidence of NHL exhibits marked geographic variation and is
higher in North America and Europe. The East Asia region has one of the lowest 
incidence rates. While the increasing incidence of malignant lymphoma has recently 
slowed in Western countries, other parts of the world, including East Asia, have 
continued to experience an upward trend. In 2012, an estimated 63,000 people in the 
United States (US), 34,000 people in Western Europe, and 72,000 people in East 
AsianAsia (21,000 Japanese; 43,000 Chinese; and 4,700 South Korean) were 
diagnosed with NHL [2].
In East Asia, it is the same tendency with the Western countries that B-cell 
neoplasms are the most common followed by T/NK cell neoplasms. The 
proportion of mature B-cell and T/NK cell lymphoma subtypes is different, 
while the most common subtype is DLBCL in China, Korea and Japan. Japan 
shows a higher proportion of FL and adult T-cell leukemia/lymphoma cases, and 
China has a higher proportion of extranodal NK/T-cell lymphoma, nasal type 
cases [3]. In Korea, precursor cell neoplasms are relatively high and MZL is the 
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second most common subtype among mature B-cell lymphoma [4].
4.1.1.1 DLBCL
DLBCL represents about 30% of all NHL. It is estimated that approximately 20,000; 
10,000; 6,400; 12,000; and 1,400 new cases of DLBCL are diagnosed annually in the 
United States, Western Europe, Japan, China, and South Korea, respectively [2]. 
DLBCL is a form of aggressive B-cell NHL that is invariably fatal without treatment.
…
4.1.1.2 Indolent NHL
Follicular lymphoma (FL) is the most common indolent NHL in the Western 
hemisphere, representing 20% of NHL [12]. Randomized clinical trials have 
demonstrated that the addition of rituximab to standard chemotherapy 
induction has improved overall survival. Maintenance rituximab strategies can 
improve PFS. Bendamustine combined with rituximab has rapidly become a 
standard frontline strategy in North America and parts of Europe. However, 
several unmet needs remain, including the identification of high-risk patients at 
diagnosis and the development of predictive biomarkers for targeted agents [12].
Other common B cell malignancies include Mantle cell lymphoma (MCL) and 
MZL. These B cell lymphoma subtypes comprise about 6% and 10% of all NHL 
respectively [13]. In Asia, the proportion of MCL and MZL is 2.4%, 8.3% in 
China, 1.8%, 13.5% in Korea and 3.3%, 4.3% in Japan of total lymphoid 
neoplasms [3]. MCL is poor prognostic despite the development of therapeutic 
strategy based on understanding of its biology and is thought to have the worst 
characterstics of both indolent and aggressive NHLs [14]. MZL is heterogeneous 
and clinocopathological subtypes are extranodal MZL of MALT, nodal MZL 
and splenic MZL[13].
For indolent B-NHL, watchful wait or radiotherapy is frequently used for early 
stage or low-tumor burden lymphoma, while rituximab or rituximab plus 
cytotoxic agent(s) such as CHOP, bendamustine is administer for patients who 
require chemotherapy [15][16]. In Japan, R-CHOP or R-Bendamustine is 
frequently chosen as the frontline treatment for FL and MZL [17][18][19]. In 
relapsed or refractory iNHL, bendamustine as a single agent or 
rituximab-containing chemotherapy regimens can be used.
In Korea, R-CVP (cyclophosphamide, vincristine, prednisolone) is used for 
MZL [20], and R-CVP and R-CHOP are used for FL [21].
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Rationale for Change:
To provide information on the new target tumor types for the expansion part.
Change 3: Added a sentence to the nonclinical experience section to instruct the reader to refer to 
the TAK-659 IB for detailed discussion of the nonclinical toxicology, metabolism, and 
pharmacology of TAK-659.
The primary change occurs in Section 4.1.3 Nonclinical Experience.
Amended 
text:
Overall, the nonclinical safety profile of TAK-659 has been adequately characterized. 
The nonclinical assessment of TAK-659 supports clinical trials in patients with 
advanced malignancies such as relapsed and/or refractory DLBCL FL.
A detailed discussion of the nonclinical toxicology, metabolism, and 
pharmacology of TAK-659 can be found in the TAK-659 IB.
Rationale for Change:
To clarify where further information can be found.
Change 4: Updated the clinical experience section with more recent data.
The primary change occurs in Section 4.1.4 Clinical Experience.
Amended 
text:
As of 27 April 2016, 68 patients have been dosed with TAK-659, including 54 
patients in the first-in-human (FIH) Study C34001 and 14 patients in Study C34002.
4.1.4.1 Clinical Safety and Efficacy of Experience with TAK-659
TAK-659 is being investigated in 7 clinical studies involving patients with 
advanced malignancies (Table 4.a) in addition to this study. The status of each 
study is described below.
In Study C34001, an open-label, multicenter, phase 1, dose escalation study of 
TAK-659 in adult patients with advanced solid tumors and lymphoma malignancies, 
the TAK-659 dose was escalated from 60 mg to 120 mg (60 mg [10 patients], 80 mg 
[4 patients], 100 mg [14 patients], and 120 mg [7 patients]). The maximum tolerated 
dose (MTD) for patients with lymphoma and solid tumors has been determined to be 
100 mg once daily (QD). The patients in the expansion phase of the study are treated 
at the MTD/recommended phase 2 dose (RP2D) of 100 mg. Of the 54 patients treated 
in this study (35 lymphoma, 18 solid tumors, and 1 chronic lymphocytic leukemia
[CLL]), 40 patients had discontinued from study by the data cutoff date. The reasons 
for discontinuation included PD (20 patients), adverse events (AEs) (9 patients), 
withdrawal of consent (1 patient), protocol violation (1 patient), symptomatic 
deterioration (3 patients), and other (6 patients).
In Study C34002, an open-label, multicenter, phase 1b/2, dose escalation and 
expansion study of TAK-659 in adult patients with relapsed or refractory AML, the 
TAK-659 dose has been escalated from 60 mg to 100 mg to 120 mg (4 patients, 7 
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patients, and 3 patients, respectively). Of the 14 patients treated in this study, 11 
patients had discontinued from study by the data cutoff date. The reasons for 
discontinuation included AEs (7 patients), PD (2 patients), withdrawal by subject (1 
patient), and other (1 patient).
The reported AEs were generally as expected based on nonclinical toxicology 
findings of TAK-659 and the patient population being studied. In Study C34001, 10 
deaths were reported. The causes of the deaths included sepsis, PD (3 patients each), 
hypoxia, pulmonary embolism, hepatic encephalopathy and pneumonia (1 patient 
each). One of the AEs that led to death (sepsis) was considered treatment related. The 
most common treatment-related AEs reported in Study C34001 (20% of patients) 
have been aspartate aminotransferase (AST) increased (23 patients [43%]), fatigue 
(15 patients [28%]), amylase increased (12 patients [22%]), lipase increased (12 
patients [22%]), and diarrhea (11 patients [20%]). The most common Grade 3 or 
greater treatment-related AEs (5% of patients) have been hypophosphatemia (7 
patients [13%]), amylase increased (6 patients [11%]), anemia (5 patients [9%]), 
neutropenia (5 patients [9%]), lipase increased (4 patients [7%]), and pneumonia (3 
patients [6%]). As noted, Grade 3 or greater treatment-related increased serum lipase 
was observed in 4 patients (7%), and Grade 3 or greater treatment-related increased 
AST was observed in 2 patients (4%). However, patients did not have any related 
symptoms, nor was there evidence of pancreatitis or other tissue injuries. Further 
investigations are required to determine the clinical significance of these 
asymptomatic laboratory abnormalities.
In Study C34001, of the 26 response-evaluable patients with lymphoma, 11 patients 
had responded to treatment according to investigator reports. Five patients with 
DLBCL achieved a partial response (PR) and 3 achieved a CR. Three patients with FL 
achieved PRs.
Currently, more than 300 patients have been dosed with TAK-659, including 143 
patients in first-in-human (FIH) Study C34001 (single-agent study in advanced 
solid tumors and lymphomas), 43 patients in Study C34002 (single-agent study 
in relapsed or refractory AML), 41 patients in Study C34003 (study of TAK-659 
in combination of nivolumab in advanced solid tumors), 49 patients in Study 
C34004 (single-agent study in DLBCL), 41 patients in Study C34005 (study of 
TAK-659 in different combinations in NHL), 10 patients in Study C34007 
(single-agent dose escalation study in Japanese patients), and 11 patients in 
Study C34008 (study of TAK-659 in combination with venetoclax in NHL). 
Further details about safety and efficacy on these clinical studies are provided in 
the current IB.
For detailed clinical study information, please refer to the TAK-659 IB.
[A new table (Table 4.a Overview of TAK-659 Clinical Studies) added]
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…
4.1.4.2 Clinical PK of TAK-659
As of 27 April 2016, clinical PK data include preliminary data from the dose 
escalation portion of Study C34001, an ongoing, phase 1, FIH, dose escalation and 
expansion study in patients with advanced solid tumors or lymphomas. Preliminary 
PK results from Study C34001 are available across the 60 to 120 mg QD dose range in 
patients with solid tumors and lymphoma enrolled at US clinical study sites.
Preliminary plasma PK results are available in 34 patients (17 lymphoma, 17 solid 
tumor) after single dosing and in 25 patients (14 lymphoma, 11 solid tumor) after 
repeated QD dosing for 15 days. Preliminary urine PK results are available from 19 
patients (12 lymphoma, 7 solid tumor). Because Study C34007 will enroll patients 
with NHL only, PK results below are summarized specifically for NHL patients.
Among patients with relapsed/refractory lymphoma, TAK-659 exhibited fast 
absorption after oral administration of an immediate–release tablet formulation 
(Preliminary plasma pharmacokinetics (PK) results are available from 
lymphoma, solid tumor, and AML patients enrolled in Studies C34001 and 
C34002. In addition, preliminary urine PK results are available from lymphoma 
and solid tumor patients enrolled in the dose escalation cohorts of Study C34001. 
TAK-659 is characterized by fast absorption (overall median Tmax [time of first 
occurrence of Cmax (maximum observed concentration])] of 2 hours on Days 1 and 15 
of Cycle 1). Approximate steady-state PK conditions appeared to be achieved by 
Cycle 1 Day 8, as determined by a comparison of predose (trough) concentrations 
available during Cycle 1. Geometric mean values of steady-state dose-normalized ) in 
patients with hematologic and nonhematologic malignancies. Moderate 
variability is observed among dose-normalized steady-state AUC(area under the 
plasma concentration-time curve overduring the dosing interval (AUCτ/Dose) were 
similar across the 60 to 100 mg range, suggesting no obvious deviation from dose 
proportionality. Moderate variability was observed in AUCτ/Dose when pooled across 
the 60 to 120 mg dose range) values in lymphoma, solid tumor, and AML patients
(coefficient of variation [CV] of 30% for Day 1 and 50% for Day 15).
Following repeated QD dosing, TAK-659 was characterized by meanof 20.0%, 
43.5%, and 34.8%, respectively). An approximately dose-proportional increase 
in steady state AUCwas observed over the 60 to 160 mg range in patients with 
AML. Mean accumulation of 2.1-ratios ranging from 1.90-fold. The to 2.54-fold 
and mean peak-to-trough fluctuation over the steady-state dosing interval was 4.2. 
The mean terminal disposition half-life is predicted to be between 24 and 48 hours and 
will be confirmed in the expansion phase of Study C34001.
The mean ratio of TAK-659ratios ranging from 4.34 to 5.09 were observed across 
the study populations after repeated QD dosing for 15 days. Based on data in 
lymphoma and solid tumor patients, renal clearance toaccounted for about 30% 
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of TAK-659 apparent oral clearance was 0.34. Although the exact contribution of 
renal excretion, and therefore at least about 30% of TAK-659 to systemic clearance
is unknown because absolute bioavailability is unknown, the contribution is expected 
to be at least 34% of systemic clearance. On average, unbound renal clearance was 
3.9-fold higher than estimated glomerular filtration rate (based on creatinine clearance 
calculated by the Cockcroft-Gault equation), suggesting that active. Active tubular 
secretion isappeared to be the majorpredominant component of renal clearance, 
based on comparison of unbound renal clearance to glomerular filtration rate.
Preliminary analyses demonstrated a relationship between creatinine clearance and 
both TAK-659 renal clearance and apparent oral clearance, suggesting that renal 
function can affect TAK-659 systemic exposure.
In vitro studies indicated that TAK-659 undergoes metabolism in human liver 
microsomes and hepatocytes. Cytochrome P450 (CYP)3A4/5 contributed to the 
majority (69.1%-73.0%) of TAK-659 metabolism in human liver microsomes, with 
relatively minor contributions by CYP2D6 (16.6%-30.9%) and CYP1A2 (0%-8.4%). 
The relative contribution of hepatic metabolism to systemic clearance is currently 
unknown; however, current in vitro and clinical PK data suggest that both hepatic 
metabolism and renal excretion contribute to TAK-659 elimination. Geometric mean 
terminal disposition half-life of 34.4 hours was determined in a single dose PK 
run-in phase of the indolent NHL expansion cohort of Study C34001.
Refer to the TAK-659 IB for detailed clinical pharmacology information.
Rationale for Change:
To update values on the basis of newer clinical data.
Change 5: Updated the risks and benefits section with more recent data.
The primary change occurs in Section 4.1.5 Risks and Benefits.
Amended 
text:
Because TAK-659 has been administered to a totallimited number of only 68 
patients as of 27 April 2016, it is not currently possible to identify and describe with 
certainty the adverse effects of the compound.
…
4.1.5.2 Potential Risks Based on Clinical Observations
OnAs of the basis of data from Study C34001, 22 October 2017 data cutoff, 
following evaluation of the current safety data, asymptomatic lipase elevation in 
lipase was added, pneumonitis, and infections (including pneumonia, CMV 
infections, and sepsis) are recognized as an important potential risk of TAK-659. In 
nonclinical studies, lipase was sporadically elevated at high doses of TAK-659;
however, there was no evidence of microscopic organ damage. potential risks.
Asymptomatic Lipase Elevation
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In clinical studies to date, asymptomatic lipase or amylase elevations are reported 
commonly (≥10%). Patients in Sstudy C34007 will have frequent monitoring of lipase 
and amylase as outlined in the Schedules of Events (Appendix A).
Pneumonitis
Cases of pneumonitis have been reported in clinical studies with B-cell receptor 
(BCR) pathway kinase inhibitors, including TAK-659, and pneumonitis is considered 
an importanta potential risk of TAK-659. There were 5 SAEs of pneumonitis (4 
reported in C34001 and 1 reported in C34002). Pneumonitis and other pulmonary 
toxicities are being closely monitored in TAK-659 clinical studies and will also be 
closely monitoredmonitor patients for respiratory signs and symptoms 
throughout TAK-659 treatment. 
Infections
In an analysis of safety data from 107 patients with lymphoma treated with 
single-agent TAK-659 in Study C34007C34001, most patients (72%) experienced 
at least 1 TEAE of any grade classified under the infections and infestations 
System Organ Class (SOC) as defined by the Medical Dictionary for Regulatory 
Activities (MedDRA). Pneumonia was the most frequently reported infection 
TEAE (26%) and most frequently reported infection SAE (15%). CMV infection 
(20%) and sepsis (17%) were also frequently reported infection TEAEs. Sepsis 
(17%) and pneumonia (15%) were the most frequently reported ≥ Grade 3 
infection TEAEs. In a heavily pretreated relapsed and/or refractory lymphoma 
patient population, a high rate of infection is expected particularly when 
considering confounding factors such as comorbidities or other 
immunosuppressive medications. The rate of infection, including pneumonia 
and sepsis, observed in patients with lymphoma who received TAK-659 is high 
and warrants continued monitoring and/or prophylaxis as outlined by this 
protocol.
Refer to the TAK-659 IB for detailed information on potential risks.
4.1.5.3 Drug-Drug Interaction Risk Assessment
…
In cell-based assays, TAK-659 was not a substrate of the efflux transporter breast 
cancer resistance protein (BCRP), or the uptake transporters organic anion transporter 
(OAT)1, OAT3, organic cation transporter 2 (OCT2), organic anion-transporting 
polypeptide (OATP)1B1, or OATP1B3. Therefore, there is low risk for inhibitors or 
inducers of these transporters to affect TAK-659 exposure.
…
Additional details on DDI risk are included in TAK-659 IB
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4.1.5.4 Potential Benefits Based on Clinical Observations
The benefits of TAK-659 have not been established; however, early the clinical 
benefit of TAK-659 has been and continues to be investigated as a single agent or 
in combination with other agents for the treatment of patients with advanced 
solid tumors, NHL, and AML. Early signs of clinical antitumor activity were seen. 
In Study C34001, as of the 27 April 2016 data cutoff, 11 of 26 response-evaluable 
patients with lymphoma responded to treatment (8 with DLBCL and 3 with FL). Five 
patients with DLBCL achieved a PR and 3 achieved a CR, and 3 patients with FL 
achieved a PR.
Clinical benefit has been observed in First In Human Study C34001 evaluating 
TAK-659 as a single agent. Response data were available for 106 patients (11 
solid tumor, 69 DLBCL, 17 indolent NHL, 5 Chronic Lymphocytic Leukemia 
[CLL]), 3 Mantle Cell Lymphoma (MCL), and 1 Post Transplant 
Lymphoproliferative Disorder (PTLD) as of 22 October 2018 in Study C34001. 
Among response-evaluable patients with solid tumors, 1 patient (9%) 
experienced a partial response (PR). Among response-evaluable patients with 
DLBCL, best responses of CR and PR were reported for 14 and 12 patients, 
respectively. Among the 5 response-evaluable patients with CLL, 3 patients 
achieved PR. Thirteen patients with indolent lymphomas responded to 
treatment with TAK-659. Four patients achieved a CR and 9 patients achieved 
PR. These indolent responders were made up of both Follicular and Marginal 
Zone Lymphoma patients. Lastly, 1 out of 3 patients with MCL achieved a PR. 
Additional single agent activity was observed in Studies C34004, a phase 2 R/R 
DLBCL study and this study, C34007. Of 41 response evaluable DLBCL patients 
in C34004, 8 responded. Three out of 4 DLBCL and 2 out of 2 FL patients 
responded in C34007.
Responses have also been observed in two additional NHL studies where 
TAK-659 was combined with other agents. Fifteen out of 29 response evaluable 
NHL patients responded in Study C34005, a five-arm combination study with 
more than half of patients enrolled into the Bendamustine +/- Rituximab arms. 
Four of out 5 response evaluable NHL patients responded in Study C34008, a 
Phase 1b study of TAK-659 in combination with venetoclax.
Specific details of the tumor response by cancer type can be found in the 
TAK-659 IB.
Rationale for Change:
To update values on the basis of newer clinical data.
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Change 6: Revised the rationale for the proposed study.
The primary change occurs in Section 4.2 Rationale for the Proposed Study.
Amended 
text:
This study is intended to evaluate the safety, tolerability, PK, and efficacy of 
single-agent TAK-659 in East Asian patients with NHL and to expand the TAK-659 
global clinical development program to the East Asian population.
The TAK-659 MTD and RP2D in Western patients with lymphoma were determined 
in the FIH study (C34001) to be 100 mg QD in 28-day treatment cycles. Objective 
responses have been observed in patients with lymphoma (DLBCL, iNHL [FL and 
FLMZL], CLL, and MCL) across the multiple dose levels evaluated (60-120 mg 
QD), supporting further evaluation of TAK-659 in relapsed and/or refractory 
DLBCLFL or MZL after at least 2 prior lines of chemotherapy; a setting that 
represents an unmet medical need in which there is no standard of care available.
In addition, on the basis of the currently available data, TAK-659 has demonstrated a 
manageable safety and tolerability profile.administration can lead to adverse 
events (AEs) that are generally manageable and reversible with dose 
modification and/or prophylactic/supportive care. AEs reported in the clinical 
studies to date are consistent with nonclinical toxicology findings of TAK-659, 
published studies of other BCR pathway inhibitors [10] [11] [12] [22] [23] [24], and 
the patient population being studied. These events are detectable using standard safety 
monitoring practices and are generally manageable in the clinical setting.
These results support the initiation of an Asian phase 1 study, including a dose 
escalation part to determine the MTD and/or RP2D and PK profile of TAK-659 in 
East Asian patients with NHL and a dose expansion part to further evaluate the safety 
and investigate preliminary efficacy in patients with relapsed and/or refractory 
DLBCLFL/MZL.
Rationale for Change:
To update the target tumor type in the expansion part from DLBCL to FL/MZL in line with the 
rationale described in section 1.3.1.
Change7: Revised the rationale for dose and dosing schedule.
The primary change occurs in Section 4.2.1 Rationale for Dose and Dosing Schedule.
Amended 
text:
4.2.1 Rationale for Dose and Dosing Schedule
Because this is the first clinical study of TAK-659 in Asia, the initial dose and dose 
increment will be determined on the basis of the starting dose and MTD from the FIH 
study (C34001) conducted in Western patients.
As of 27 April 2016, 54 patients had been dosed with TAK-659 in Study C34001. Of 
the 54 patients dosed, 35 were dosed in the escalation part (18 solid tumor, 12 
DLBCL, 4 FL, and 1 MCL), and 19 had been dosed in the expansion part (18 DLBCL 
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and 1 CLL). During the dose escalation part of the study, the TAK-659 dose was 
escalated from 60 to 120 mg QD (60 mg [10 patients], 80 mg [4 patients], 100 mg [14 
patients], and 120 mg [7 patients]). No dose-limiting toxicities (DLTs) were observed 
in the 14 patients (including 8 DLT-evaluable patients) dosed at 100 mg in the dose 
escalation part. The MTD/RP2D for patients with lymphoma was determined to be 
100 mg QD. Nineteen patients in the expansion cohorts had received TAK-659 at the 
100 mg QD dose. In total, 33 patients had been dosed at 100 mg QD. Longer-term 
safety and tolerability data of the 100 mg QD dose is limited at the present time, but 
will be further collected in the ongoing and planned studies. However, based on the 
currently available data, the benefit/risk assessment for the 100 mg QD dose is 
favourable.
Although the metabolic and disposition profiles of TAK-659 remain to be fully 
characterized in humans, the relative contribution for each CYP (CYP3A4, CYP2D6, 
and CYP1A2) to the overall human liver microsomal metabolism was estimated to be 
69.1% to 73.0%, 16.6% to 30.9%, and 0% to 8.4%, respectively, from in vitro data, 
suggesting that TAK-659 is predominantly metabolized by CYP3A, with minor 
contributions by CYP2D6 and CYP1A2. TAK-659 is also a substrate for P-gp but not 
for uptake transporters such as OATP1B1 and OATP1B3. Genetic differences in 
CYP3A and P-gp are not known to be associated with clinically meaningful 
differences in exposure. From the preliminary results in Study C34001, 34% of the 
orally administered TAK-659 dose was excreted into the urine as unchanged 
TAK-659 in patients with lymphoma. These data do not indicate a major contribution 
of enzymes or transporters with clinically significant genetic polymorphisms and/or 
interethnic differences (ie, CYP2C19, CYP2D6, hepatic OATP) to TAK-659 
systemic clearance.
Although 100 mg QD TAK-659 has been determined to be the MTD for 
lymphoma in Study C34001, the question whether it is the optimal biological 
dose is outstanding. While an appreciable level of clinical activity was shown at 
100 mg QD in Western patients, responses to TAK-659 were also observed in 
patients treated with two lower doses evaluated (60 mg and 80 mg) QD, 
suggesting a therapeutic window of TAK-659 extending from 60 mg to 100 mg 
QD. Plasma PK exposure of TAK-659 from that study was found to be 
approximately dose proportional, and higher drug exposure levels were 
observed at 100 mg QD compared to the lower doses of 60 and 80 mg QD. 
However, the level of SYK target inhibition achieved at different dose/exposure 
levels is not understood due to lack of available clinical pharmacodynamic data. 
Additionally, the degree and the temporal profile of the SYK inhibition required 
to generate clinical efficacy are not known. Therefore, it is plausible that the 
optimal biological dose may not be the Western MTD of 100 mg QD and may fall 
at a QD dose or intermittent schedule below that. It is also possible that there 
may be efficacious doses below 60 mg QD which is why 40 mg QD will also be 
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tested. In this study, intermittent dosing schedules of TAK-659 will be also be 
evaluated such as 7 days on followed by 7 days off. The rationale for intermittent 
dosing schedules for TAK-659 is based on the occurrence of frequent dose 
interruptions in Cycle 1 and 2 due to various AEs that was observed in study 
C34001. Most of the AEs that led to drug holds were laboratory changes that 
returned to ≤Grade 1 with drug hold. In addition to this, most subjects in 
C34001 that received more than 6 cycles of treatment had multiple dose holds 
and dose reductions from 100 mg down to 60 mg QD. Moreover, TAK-659 
intermittent regimen has been conducted in Study C34008 and showed potential 
of more tolerability and safety compared to daily administration in combination 
regimen. This study is monotherapy, however, intermittent regimen is 
worthwhile to explore in this study to elucidate monotherapy dose optimization.
The starting dose in this study will be 60 mg QD, which is the same as that in Study 
C34001, and which is 2 dose levels (40%) lower than the MTD determined in the 
Western patient population. If 60 mg QD is proven to be safe and tolerable, dosing 
will increase to 100 mg QD. Subsequent escalations beyond 100 mg QD, as permitted 
by safety/tolerability, dose escalation will be conducted in 20 mg increments of daily 
dose. Based on emerging safety, tolerability, PK data, a lower dose (eg, 40 mg 
QD) or alternative dosing regimens (eg, 7 days on followed by 7 days off) will be 
permitted.
Rationale for Change:
To provide rationale for the addition of 2 possible new cohorts (40 mg QD continuous and 80 mg 
QD 7 days on/7 days off intermittent regimen) to the dose escalation part based on current clinical 
data.
Change 8: Revised the rationale for PK assessments section.
The primary change occurs in Section 4.2.2 Rationale for PK Assessments.
Amended 
text:
In the dose escalation part, intensive PK samples will be collected from all patients 
during Cycle 1 to permit detailed characterization of TAK-659 plasma and urine PK 
across different dose levels in East Asian patients with NHL (refer to Section 9.4.17.1
and Appendix A, Table A and Table B). Plasma PK data will be used to characterize 
single- and repeat-dose concentration-time profiles of TAK-659, calculate PK 
parameters, evaluate the dose-exposure relationship, and contribute to population PK 
analysis. Urine PK data will be used to determine the percentage of the administered 
TAK-659 dose excreted in urine as unchanged drug, and renal clearance and its 
minimum contribution to systemic clearance.
In the DLBCL expansion part, blood samples for plasma PK will be collected via a 
limited (sparse) sampling schedule to contribute to population PK and 
exposure-response analyses (refer to Section 9.4.17.2 and Appendix A, Table B Table 
C and Table D)
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Rationale for Change:
To reflect the addition of new tables (Schedule of Events [Appendix A], Table B and Table D) 
regarding PK sample collection for the new dosing schedule.
Change 10: Revised target tumor type description in the secondary objective regarding evaluation 
of the preliminary efficacy of TAK-659.
The primary change occurs in Section 5.1.2 Secondary Objective.
Amended 
text:
The secondary objective is to evaluate preliminary efficacy of TAK-659 in patients 
with relapsed and/or refractory DLBCLNHL.
Rationale for Change:
To reflect the change in the target tumor type in the expansion part.
The following sections also contain this change:
!
Section 2.0 STUDY SUMMARY
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The following sections also contain this change:
!
Section 2.0 STUDY SUMMARY
!
Section 4.2.2 Rationale for PK Assessments
!
 
!
Section 5.1.3 Exploratory Objectives
!
Section 5.2.4 Exploratory Endpoints
!
Section 6.1 Overview of Study Design
!
Schedule of Events (Appendix A), for Dose Escalation Part, footnote (y)
!
Schedule of Events (Appendix A) for Expansion Part, footnote (v)
Change 12: Revised the assessment time points for the PK-related primary/additional endpoints.
The primary change occurs in Section 5.2.1 Primary Endpoints and Section 5.2.3 Additional 
Endpoints.
Amended 
text:
5.2.1 Primary Endpoints
!
Summary statistics of TAK-659 Cmax on Cycle 1 Days 1 and 7 or 15 by dose.
!
Summary statistics of TAK-659 Tmax on Cycle 1 Days 1 and 7 or 15 by dose.
!
Summary statistics of TAK-659 AUC∀on Cycle 1 Days 1 and 7 or 15 by dose.
Property of T
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
Summary statistics of rRenal clearance (CLR) on Cycle 1 Day 7 or 15 by dose.
5.2.3 Additional Endpoints

Summary statistics of aApparent oral clearance (CL/F), CLR as a percentage of 
CL/F, peak-trough ratio (PTR), accumulation ratio (Rac), and observed 
concentration at the end of the dosing interval (Ctrough) on Cycle 1 Day 7 or 15 by 
dose.
Rationale for Change:
To reflect the PK assessment dates for the new intermittent dosing schedule, and to better define 
the endpoints.
The following sections also contain this change:

Section 2.0 STUDY SUMMARY

Section 6.3.3 Timeframes for Primary and Secondary Endpoints to Support Disclosures, Table 
6.a Primary and Secondary Endpoints for Disclosures
Change 13: Revised the name of the expansion part, and removed one of the secondary endpoints 
regarding the assessment of time to progression (TTP).
The primary change occurs in Section 5.2.2 Secondary Endpoints. The name of the expansion part 
is revised throughout the protocol.
Amended 
text:

Overall response rate (ORR) in the DLBCL expansion part.

CR rate in the DLBCL expansion part.

Duration of response (DOR) in the DLBCL expansion part.

Time to progression (TTP) in the DLBCL expansion part.

Progression-free survival (PFS) in the DLBCL expansion part.
Rationale for Change:

The name of the expansion part was revised to reflect the change in the target tumor type in the 
expansion part.

The endpoint regarding TTP was removed because PFS is a more relevant endpoint in the 
indolent lymphoma subtypes (FL and MZL) under study.
The following sections also contain this change:

Section 2.0 STUDY SUMMARY

Section 6.3.3 Timeframes for Primary and Secondary Endpoints to Support Disclosures, Table 
6.a Primary and Secondary Endpoints for Disclosures
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Change 14: Removed response data collection assessed using the IWG 2014 (Lugano) criteria.
The primary change occurs in Section 5.2.2 Secondary Endpoints.
Amended 
text:
The investigators will perform response assessment using modified International 
Working Group (IWG) 2007 criteria for malignant lymphoma [13] [25], which will be 
the main analysis for the efficacy endpoints. In addition, response might be assessed 
by the investigator following the IWG 2014 (Lugano) criteria [14], and these data 
might be used for sensitivity analyses of efficacy endpoints.
Rationale for Change:
Revised because the IWG 2007 criteria is the most common criteria in Asian clinical practice.
The following sections also contain this change:
!
Section 2.0 STUDY SUMMARY
!
Section 6.1 Overview of Study Design
!
Section 9.4.15 Disease Assessment
!
Section 13.1.3 Efficacy Analysis
!
Schedule of Events (Appendix A) for Dose Escalation Part, footnote (k)
!
Schedule of Events (Appendix A) for Expansion Part, footnote (l)
Propert
e Only and Subject to the Applicable Terms of Use
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will b
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asses
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The following sections also contain this change:

Section 2.0 STUDY SUMMARY

Section 6.3.3 Timeframes for Primary and Secondary Endpoints to Support Disclosures, Table 
6.a Primary and Secondary Endpoints for Disclosures
Change 16: Revised the overview of study design.
The primary change occurs in Section 6.1 Overview of Study Design.
Amended 
text:
This is an open-label, multicenter, phase 1 study of TAK-659 including a dose 
escalation part in adult East Asian patients with NHL and an expansion part in adult 
East Asian patients with relapsed and/or refractory DLBCLNHL.
The dose escalation part of the study will enroll approximately 1218 to 2332 East 
Asian patients diagnosed with NHL for which no effective standard treatment is 
available. Assuming a dropout rate of 20%, this will ensure that 916 to 1828
DLT-evaluable patients are enrolled in the dose escalation part. TAK-659 will be 
administered continuously, QD, in 28-day treatment cycles (Dosing Schedule A). 
Dose escalation will follow a standard 3+3 schema to determine the MTD and/or the 
RP2D. The initial TAK-659 dose will be 60 mg QD and will escalate to 10080 mg
QD, provided that the safety and tolerability of the 60 mg dose has been demonstrated. 
Subsequent escalation (above 100 mg QD) will be in 20 mg increments (eg, 100 mg to 
120 mg). Dose escalation will continue until the MTD is reached or until an RP2D (if 
different from the MTD) for East Asian patients has been identified. More 
conservative dose escalation, evaluation of intermediate doses or regimens, and 
expansion of an existing dose level are all permissible following written confirmation 
of discussions between the sponsor and the investigators, if such measures are needed 
for patient safety or for a better understanding of the dose-toxicity and dose-exposure 
relationships of TAK-659.
If ≥2 of 6 patients experience a DLT at 60 mg QD, depending on the overall safety 
profile, the type of AEs/DLTs observed, and following the examination of the 
preliminary PK results in relation to the PK data in the Western population, a decision 
will be made either to de-escalate the dose to 40 mg QD or to terminate the study 
following discussion between the investigator and the sponsor. If ≥2 of 6 patients 
experience a DLT at 10080 mg QD, intermediatealternate dose levelsregimens
between 60 and 10080 mg (ie, 80 mg 7 days on 7 days off [Dosing Schedule B]) will 
be evaluated as described below. The MTD and/or RP2D should be evaluated with a 
total of ≥6 DLT-evaluable patients. The RP2D will be determined on the basis of the 
totality of the safety, tolerability, and preliminary PK and efficacy data (if available) 
observed in Cycle 1 and beyond. If 100 mg QD dose, which is the Western 
MTD/RP2D, is determined to be tolerable and there is no significant difference in 
systemic exposure between Asian and Western patients, dose escalation could stop at 
100 mg QD without further escalation to 120 mg QD. Intrapatient dose escalation is 
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not allowed in this protocol.
An additional dosing schedule will be tested after implementation of 
Amendment 02:

Dosing Schedule B: TAK-659 will be administered QD for 7 consecutive days
followed by another 7 days of rest and repeated again (ie, 7 days "on" and 7 
days "off"), for a cycle duration of 28 days. The starting dose of 80 mg QD 
was the maximum administered dose in Dosing Schedule A (2 out of 4
patients presented a DLT in the continuous dosing regimen). However, the 
alternative dose of 60 mg may be tested if the 80 mg intermittent regimen is 
deemed not tolerable per emerging data. Dose escalation will be governed 
using the same standard 3+3 schema as described in Section 8.3.
The DLBCL expansion part of this study will begin once the RP2D has been 
determined. The DLBCL expansion part will proceed with continuous QD dosing of 
TAK-659 at the RP2D in 28-day cycles. The patient population will consist of East 
Asian patients with DLBCLFL or MZL who are relapsed and/or refractory after at 
least 2 prior lines and no more than 4 prior lines of chemotherapy and who have 
experienced failure of ASCT or are not eligiblemust be ineligible for ASCTor 
refusal to hematopoietic stem cell transplant. It is expected that a minimum of
approximately 12 response-evaluable patients will be enrolled. Assuming a 20% 
dropout rate, a total of approximately 15 patients will be enrolled. The objectives of 
the DLBCL expansion part are to evaluate the longer-term safety and tolerability of 
TAK-659 administered at the RP2D, to characterize the PK of TAK-659, and to 
evaluate the preliminary efficacy of TAK-659 in relapsed and/or refractory 
DLBCLFL/MZL as measured by ORR and other efficacy variables, including CR 
rate, DOR,TTP, and PFS.
At least 1 Japanese patient will be enrolled in each group of 3 patientscohort in the 
dose escalation part. The total number of Japanese patients dosed at the RP2D (either 
the MTD or a lower dose as determined) will be at least 6 including the dose escalation 
and DLBCL expansion parts to ensure adequate characterization of PK and safety in 
Japanese patients.
On the basis of the geographic distribution of patients enrolled and emerging PK and 
safety data, additional patients may be added, as needed, to further characterize the 
PK, safety, and tolerability in a particular East Asian geographic region. On the basis 
of emerging efficacy data, additional groups or patients with specific subtypes of 
DLBCLFL/MZL may be added to further explore efficacy.
…
SerumBlood samples will be collected pretreatment and posttreatment, and the levels 
of circulating cytokines/chemokines/serum proteins in serum will be measured.
Whole blood samples will be collected pretreatment during Cycle 1, and the 
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levels of circulating immune cells will be measured.
…
Evaluation of disease response will be performed as described in Section 9.4.15 and 
the Schedule of Events (Appendix A), using the IWG 2007 modified response criteria 
for malignant lymphoma (Appendix D) [1320] based on investigator assessment. An 
imaging modality (eg, computed tomography [CT] with contrast and 
fluoro-2-deoxy-D-glucose [FDG]-positron emission tomography [PET] if 
appropriate) will be used to follow sites of measurable disease during the study 
treatment. If investigator assessment of response following the IWG 2014 (Lugano) 
criteria [14] is also available per institute practice, these data will also be collected. 
Central collection of images at imaging time points by the sponsor or designee is 
required for patients in the DLBCL expansion part (optional for patients in the dose 
escalation part).Radiographic images will be maintained at the site. Based on 
efficacy data observed, the sponsor can elect to have central collection of disease 
assessment images. In the event of antitumor response, the sponsor may request 
electronic images for those patients who demonstrate tumor reduction.
The study design is detailed in Figure 6.a.
[Figure 6.a (Overview of Study Design) revised.]
Rationale for Change:
!
To describe the addition of the new cohorts.
!
To describe the change in the target tumor type in the expansion part.
!
To reflect the change in the number of patients to be enrolled.
!
!
To clarify the handling procedures of radiographic/electronic images used for reponse 
assessment.
Change 17: Revised the number of subjects to be enrolled into this study.
The primary change occurs in Section 6.2 Number of Patients.
Amended 
text:
It is expected that approximately 2733 to 3847 patients will be enrolled in this study 
from approximately 6 to 10 study centerssites in East Asia. Enrollment is defined as 
the time of administration of the first dose of study drug.
For the dose escalation part, approximately 916 to 1828 DLT-evaluable patients will 
be enrolled; assuming a 20% dropout rate, approximately 1218 to 2332 patients will 
be enrolled. For the DLBCL expansion part, at leastapproximately 12 
response-evaluable patients will be enrolled; assuming a 20% dropout rate, 
Property of Taked
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ext:
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and 
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approximately 15 patients will be enrolled.
Rationale for Change:
To reflect the change in patient number based on the addition of the new cohorts, and to add 
flexibility to the number of patients to be enrolled into the expansion part.
The following sections also contain this change:

Section 2.0 STUDY SUMMARY

Section 6.1 Overview of Study Design

Section 13.3 Determination of Sample Size
Change 18: Revised the end of study/study completion definition and planned reporting section.
The primary change occurs in Section 6.3.2 End of Study/Study Completion Definition and 
Planned Reporting.
Amended 
text:
Primary Completion/Study Completion
The primary analysis for safety, PK, and efficacy endpoints and authoring of a clinical 
study report (CSR) may be conducted after all patients enrolled in the study have had 
the opportunity to complete 4-6 cycles of treatment with study drug and patients who 
discontinued study treatment must complete safety follow-up. The estimated time 
frame for primary completion is approximately 47 months. For patients enrolled 
in the DLBCL expansion part, PFS follow-up will occur every 2 months after the last 
dose of study drug for up to 6 months or until PD, whichever occurs first (for patients 
who discontinue for reasons other than PD). The estimated time frame for study 
completion is approximately 3952 months.
Completion of the study will be considered when PFS events have occurred in 70% of 
the DLBCL expansion patients, or 24 months after last patient in, whichever occurs 
earlier. The study may be prematurely terminated if, in the opinion of the sponsor, 
there is sufficient reasonable cause. A CSR addendum will be provided to describe 
additional data not included in the original CSR.
Rationale for Change:
To reflect the addition of the new cohorts to the dose escalation part and the change in target tumor 
type in the expansion part. Also, to reflect the change in the study reporting plan.
The following sections also contain this change:

Section 2.0 STUDY SUMMARY
Change 19: Revised maximum time frames for the primary/secondary endpoints.
The primary change occurs in Section 6.3.3 Timeframes for Primary and Secondary Endpoints to 
Support Disclosures.
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Description 
of change:
The maximum time frame shown in Table 6.a (Primary and Secondary Endpoints for 
Disclosures) for safety/efficacy-related primary/secondary endpoints were revised.
Rationale for Change:
Revised for more accuracy.
Change 20: Revised the total study duration.
The primary change occurs in Section 6.3.4 Total Study Duration.
Amended 
text:
It is anticipated that this study will last for approximately 3952 months, including 
approximately 2627 months for the dose escalation part and approximately
1925 months for the DLBCL expansion part including 6 cycles treatment and 6 
months PFS follow-up.
Rationale for Change:
To reflect the addition of new cohorts to the dose escalation part.
The following sections also contain this change:

Section 2.0 STUDY SUMMARY
Change 21: Revised inclusion criterion #3.
The primary change occurs in Section 7.1 Inclusion Criteria.
Amended 
text:
3. To be enrolled in the DLBCL expansion part, patients must meet the following 
criteria:
a) Patients must have pathologically confirmed DLBCL, including de novo or 
transformed disease from indolent NHLFL (Grade 1, 2, or 3A) or MZL.

Patients with transformed DLBCL must meet 2016 World Health 
Organization (WHO) criteria for DLBCL [26] on last biopsy before study 
entry and have ≥1 prior histological diagnosis of FL or other indolent 
disease.

Patients must have pathologically confirmed diagnosis of one of the 
following DLBCL subtypes based on the 2016 WHO classification 
criteria for lymphoid neoplasms:
i.
DLBCL, not otherwise specified (NOS), including GCB and 
ABC/non-GCB subtypes.
1) DLBCL with double expression of MYC and BCL-2 and/or 
BCL-6 protein without gene aberration is eligible under 
DLBCL, NOS.
2) High-grade B-cell lymphoma with MYC and BCL-2 and/or 
BCL-6 translocations (double-hit DLBCL under DLBCL, NOS 
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based on the 2008 WHO classification criteria [27]) is not 
eligible for this study.
ii.
T-cell/histiocyte-rich large B-cell lymphoma.
iii.
DLBCL associated with chronic inflammation.
iv.
EBV+DLBCL, NOS (EBV+DLBCL of the elderly based on the 
2008 WHO classification criteria for lymphoma).
v.
FL Grade 3B.

Local pathology review for histological confirmation:
i.
A formalin-fixed, paraffin-embedded (FFPE) tumor block or 
appropriately stained slides from a fresh biopsy is required. If a 
fresh specimen cannot be obtained without putting the patient at 
unjustifiable risk, slides prepared from the archival specimen 
supporting a prior DLBCL diagnosis may be submitted to local 
pathology review to fulfill this inclusion criterion.
ii.
If the patient requires immediate treatment and the sample cannot 
be evaluated by local pathology review before the start of 
treatment, medical monitor or designee approval for initiation of 
protocol treatment is required; in this case, submission of an 
appropriate sample (either fresh biopsy acquired before Cycle 1 
Day 1 or archival sample) to local pathology review is absolutely 
required, and the DLBCL diagnosis should be confirmed no later 
than 4 weeks after Cycle 1 Day 1.
b) Relapsed and/or refractory to ≥2 prior lines of chemotherapy based on standard 
of care that include at least: 1 anti-CD20-based regimen, as well as 
alkylating agents (eg, cyclophosphamide or bendamustine).

The standard first-line chemotherapy regimen containing rituximab and 
an anthracycline (eg, R-CHOP) or equivalent if anthracycline is 
contraindicated, and

One additional systemic chemotherapy as a second-line salvage therapy 
that may have included ASCT.
i.
Included are ASCT-eligible patients for whom ASCT failed 
following response to a standard salvage regimen, or patients who 
did not respond to salvage therapy and were therefore not 
indicated for ASCT, or patients who did not proceed to ASCT 
after responding to salvage therapy for other reasons, such as 
insufficient CD34+ cell harvest, and then relapsed.
ii.
Also included are ASCT-ineligible patients who were refractory to 
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or relapsed after a second-line systemic, chemotherapy regimen.
c) Patients should not have experienced failure of more than 4 prior lines of 
therapy. Patients must be ineligible for or refusal to hematopoietic stem 
cell transplant.

Pre-induction salvage chemotherapy and ASCT should be considered 1 
therapy.

Antibody therapy (eg, rituximab) given in combination with or as 
consolidation/maintenance therapy after a chemotherapy regimen 
(without intervening relapse) should be considered 1 therapy (ie, 
R-CHOP+rituximab maintenance should be considered as 1 line 
therapy).

Antibody therapy given as a single agent should be considered 1 therapy.

Prior treatment with single-agent BCR in-pathway inhibitors such as 
ibrutinib and idelalisib is permitted and will not count as a prior line of 
therapy.
d) For patients who have relapsed or progressed after achieving a response 
(defined as CR or PR), documented, investigator-assessed relapse or 
progression after the last treatment is required. For patients who are refractory 
to their last treatment (defined as not having achieved a CR or PR before 
enrollment by investigator assessment), documented progression will not be 
required.
e) Must have FDG-PET-avid measurable disease that meets the size criteria per 
IWG (≥(>1.5 cm in the longest diameter for a lymph node or a nodal mass, or 
≥>1.0 cm in the longest diameter for an extranodal disease) as assessed on 
cross-sectional imaging by CT scan/magnetic resonance imaging (MRI). (CT 
scan is to be performed with contrast unless it is medically contraindicated.)
Rationale for Change:

To reflect the change in the target tumor type in the expansion part.

Corrected per the IWG 2007 criteria.
The following sections also contain this change:

Section 2.0 STUDY SUMMARY
Change 22: Revised inclusion criterion #6.
The primary change occurs in Section 7.1 Inclusion Criteria.
Amended 
text:
6. Patients must have adequate organ function, including the following:
a)
Bone marrow reserve: absolute neutrophil count (ANC) ≥1,000/mm3, platelet 
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count ≥75,000/mm3 (≥50,000/mm3 for patients with bone marrow 
involvement), and hemoglobin ≥8 g/dL (red blood cell [RBC] and platelet 
transfusion allowed ≥14 days before assessment).
b)
Hepatic function: total bilirubin ≤1.5×the upper limit of normal range (ULN); 
alanine aminotransferase (ALT) and AST ≤2.5×ULN.
c)
Renal function: creatinine clearance ≥60 mL/min as estimated by the 
Cockcroft-Gault equation (refer to Appendix F) or based on urine collection 
(12 or 24 hours).
Rationale for Change:
To unify the method for measuring renal function. Renal function has been identified as a 
significant factor impacting TAK-659 exposure and there are always slight differences of 
creatinine clearance values based on Cockcroft-Gault equation vs urine collection.
The following sections also contain this change:

Section 2.0 STUDY SUMMARY
Change 23: Revised exclusion criterion #9.
The primary change occurs in Section 7.2 Exclusion Criteria.
Amended 
text:
9. Known hepatitis B surface antigen (HBsAg) positive, or known or suspected active 
hepatitis C virus (HCV) infection.
Note: Hepatitis testing will be performed as specified in the Schedule of Events 
(Appendix A). Patients who have positive hepatitis B core antibody (HBcAb) or 
hepatitis B surface antibody (HBsAb) can be enrolled but must have an 
undetectable hepatitis B virus (HBV) viral load. Patients who have positive 
hepatitis C virus antibody (HCVAb) must have an undetectable HCV viral load.
Rationale for Change:
For clarification.
The following sections also contain this change:

Section 2.0 STUDY SUMMARY
Change 24: Revised study drug administration section.
The primary change occurs in Section 8.1 Study Drug Administration.
Amended 
text:
The study drug will be dosedadministered according to the assigned dosing 
schedule (ie, Dosing Schedule A or B). For Dosing Schedule A, the study drug 
will be administered continuously, QD, in 28-day cycles. For Dosing Schedule B, 
the study drug will be administered QD for 7 consecutive days followed by 7 
days of rest and repeated again for a 28-day cycle (ie, 7 days “on” and 7 days 
“off”). The study drug should be taken on an empty stomach, at least 1 hour before 
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and no sooner than 2 hours after ingestion of food and/or beverages other than water.
Rationale for Change:
To reflect the addition of a new dosing schedule.
Change 25: Clarified the definitions of DLT.
The primary change occurs in Section 8.2 Definitions of DLT.
Amended 
text:
Toxicity will be evaluated according to the NCI CTCAE, version 4.03, effective 14 
June 2010[1728]. These criteria are provided in the Study Manual. DLT is defined as 
any of the following events occurring during Cycle 1 that are considered by the 
investigator to be at least possibly related to therapy with TAK-659 (note that AEs for 
which the relationship to study drug cannot be ruled out should be considered possibly 
related to study drug).
…

Receiving <75% of planned doses of study drug (receiving <21 days for Dosing
Schedule A and <11 days for Dosing Schedule B) within Cycle 1 because of 
prolonged treatment interruption caused by TAK-659-related toxicities.
Although DLTsDLT-like toxicities may occur at any time during treatment, only 
DLTs occurring during Cycle 1 of treatment will influence decisions regarding dose 
escalation, expansion of a dose level, or evaluation of intermediate dose levels. 
Patients will be monitored throughout all cycles of therapy for treatment-related 
toxicities.
Rationale for Change:

To clarify that related AEs which meet the DLT criteria will only be judged as DLTs when 
they occur during Cycle 1. DLT definition is important for the study, but the definition was
unclear in the previous version of the protocol.

Removed the “note” in parenthesis for consistency with the definition of relationship of AEs 
with the study drug in Section 10.2.

To clarify the exact number of days needed for the subject to receive 75% of planned doses in 
both dosing schedules.

To clarify the difference in DLTs and DLT-like toxicities.
Change 26: Updated the dose escalation rules section.
The primary change occurs in Section 8.3 Dose Escalation Rules.
Amended 
text:
Dose escalation will follow a standard 3+3 schema to determine the MTD and/or the 
RP2D in East Asian patients with NHL. The dose escalation plan, as specified in 
Table 8.a, is based on the starting dose of 60 mg, the dose determined to be tolerable in 
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the FIH Study C34001 in the Western population. The dose will escalate to 10080 mg 
QD provided that the safety and tolerability of the 60 mg dose has been demonstrated. 
Subsequent escalation (above 100 mg QD) will follow in 20 mg increments (eg, 
100 mg to 120 mg). Dose escalation will continue until the MTD is reached or until an 
RP2D (if different from the MTD) for East Asian patients has been identified. More 
conservative dose escalation, evaluation of intermediate doses or regimens, and 
expansion of an existing dose level are all permissible following written confirmation 
of discussions between the sponsor and the investigators, if such measures are needed 
for patient safety or for a better understanding of the dose-toxicity and dose-exposure 
relationship of TAK-659. If ≥2 of 6 patients experience a DLT at 60 mg QD, 
depending on the overall safety profile, the type of AEs/DLTs observed, and 
following the examination of the preliminary PK results in relation to the PK data in 
the Western population, a decision will be made either to de-escalate the dose to 
40 mg QD or to terminate the study following discussion between the investigator and 
the sponsor. If ≥2 of 6 patients experience a DLT at 100 mg QD, intermediate dose 
levels between 60 and 100 mg (ie, 80 mg) will be evaluated. If 100 mg QD dose, 
which is the Western MTD/RP2D, is determined to be tolerable and there is no 
significant difference in systemic exposure between Asian and Western patients, dose 
escalation could stop at 100 mg QD without further escalation to 120 mg QD80 mg 
QD, alternate dose regimens between 60 and 80 mg (ie, 80 mg 7 days on 7 days 
off) will be evaluated.
…
Table 8.a Planned Dose Levels
Dose Level
Dose (unit)
1
60 mg QD
2
10080 mg QD
3
12040 mg QD
4
80 mg QD*, 7 days on/7 days off
*The alternative dose of 60 mg may be tested if the 80 mg intermittent regimen is deemed not 
tolerable per emerging data.
More conservative dose escalation, evaluation of intermediate doses or alternative regimens, and 
expansion of an existing dose level are all permissible following written confirmation of discussions 
between the sponsor and the investigators, if such measures are needed for patient safety or for a better 
understanding of the dose-toxicity and dose-exposure relationship of TAK-659.
DLT-evaluable patients in each dose cohort will consist of patients who have met the 
minimum treatment and safety evaluation requirements of the study or who have 
experienced a DLT during Cycle 1. The minimum treatment and safety evaluation 
requirements are met if, in Cycle 1, the patient has been treated with TAK-659 for ≥21 
days for Dosing Schedule A and for ≥11 days for Dosing Schedule B (receiving at 
least 75% of planned doses of TAK-659 in Cycle 1) and observed for ≥28 days 
following the dose on Cycle 1 Day 1, and is considered to have sufficient safety data 
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by both the sponsor and investigators to conclude that a DLT did not occur. …
Rationale for Change:
To reflect the addition of the new cohorts in the dose escalation part and to update based on latest 
clinical experience.
Change 27: Added a table showing dose reduction levels for TAK-659.
The primary change occurs in Section 8.4.1 General Principles. Also, the numbering of the 
original Table 8.b (TAK-659 Dose Adjustments for Hematologic Toxicities) and Table 8.c 
(TAK-659 Dose Adjustments for Nonhematologic Toxicities) have been revised to Table 8c and 
Table 8.d, respectively.
Amended 
text:
…Patients who have a TAK-659 dose held because of a treatment-related or possibly 
related AE may resume study drug after resolution of the AE, and may either maintain 
the same dose level or have TAK-659 reduced by at least 1 dose level (dose 
reduction). Dose reduction levels for TAK-659 are presented in Table 8.b. When a 
dose reduction occurs, the TAK-659 dose will be reduced to the next lower dose. If 
initial dose adjustment does not provide sufficient relief, the dose of TAK-659 can be 
further reduced if the treating physician believes that the patient is benefiting from 
study treatment and may benefit at a further-reduced dose of TAK-659. When a dose 
reduction of TAK-659 is required because of toxicity, no dose re-escalation will be 
permitted. If TAK-659 dosing is delayed for >21 days for TAK-659-related or 
possibly related toxicities despite supportive treatment per standard clinical practice, 
or more than 2 dose reductions (more than 1 dose reduction for 40 mg QD) are
required in a patient, the patient should be discontinued from study treatment, unless 
the treating physician believes that the patient may benefit from continued study 
treatment after resolution of AEs to ≤Grade 1 or baseline. …
Table 8.b Dose Reduction Levels for TAK-659
Dose Reduction Levels
Dose (unit)
Planned dose
40, 60, or 80 mg
(-) 1 dose level
Planned dose minus 20 mg (a)
(-) 2 dose level
Planned dose minus 40 mg (a) (b)
(a) Intermittent regimen (eg, 7 days on/7 days off) may be allowed.
(b) Not applicable to 40 mg QD cohort.
Rationale for Change:
To clarify the dose reduction levels possible for TAK-659.
Change 28: Updated the criteria for beginning or delaying a subsequent treatment cycle.
The primary change occurs in Section 8.4.3 Criteria for Beginning or Delaying a Subsequent 
Treatment Cycle.
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Amended 
text:
TAK-659 is administered in continuous cycles; therefore, study drug should be 
administered continuously or according to the intermittent dosing regimen, unless 
AEs occur that meet the dose modification criteria outlined below.
Before starting a new treatment cycle, TAK-659-related AEs or laboratory 
abnormalities must have returned to ≤Grade 1 or baseline levels.
Rationale for Change:
For clarification of the criteria. Also, minor revision was made to reflect the new dosing regimen.
Change 29: Clarified that the use of excluded medications to manage AEs will require appropriate 
washout period before resuming the study drug.
The primary change occurs in Section 8.5 Concomitant Medications and Procedures.
Amended 
text:
…
If a patient experiences an AE on study and TAK-659 dosing is temporarily 
interrupted due to that AE, the medications listed above and in Appendix I may be 
used for AE management provided there is no appropriate alternative treatment 
available based on the investigator’s judgment and the dosing is not concurrent with 
study drug. This situation requires discussion between the investigator and the 
medical monitor, and the discussion will be documented in the study file.Treatment 
with the study drug may then resume after an appropriate washout period for 
the prohibited concomitant medication (consistent with the washout period as 
specified in the eligibility criteria for the study). Sites are encouraged to discuss 
any such situations with the Medical Monitor or designee. Patients should be 
closely monitored for potential toxicities.
…
Rationale for Change:
To provide clarification on the used of prohibited concomitant medications for management of an 
AE and when TAK-659 could restart.
Change 30:Added that females cannot donate ova and males cannot donate sperm for 180 days 
after the last dose of study drug.
The primary change occurs in Section 8.6.1 Pregnancy and Contraception.
Amended 
text:
…Nonsterilized female patients of the reproductive age group and male patients 
should use effective methods of contraception throughout defined periods during and 
after study treatment as specified below:
…
5) Female patients should not donate ova from the time of signing the informed 
consent through 180 days after the last dose of study drug.
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6) Male patients should not donate sperm from the time of signing the informed 
consent through 180 days after the last dose of study drug.
Rationale for Change:
For consistency with the ICF and other TAK-659 protocols noting restrictions for female donation 
of ova and male donation of sperm through 180 days after last dose of study drug.
Change 31: Added monitoring and prophylaxis procedures for cytomegalovirus (CMV).
The primary change occurs in Section 8.7.1 Prophylaxis Against Infections.
Amended 
text:
8.7.1.1 Cytomegalovirus Monitoring and Prophylaxis
Patients with advanced hematologic malignancies may have an increased risk of 
infection. Prophylactic use of antibiotic, antiviral, or antifungal medication can be 
considered as clinically indicated and per local standard practice. In particular, 
lymphopenia can develop in association with either treatment or with the underlying 
disease. Lymphopenia can be associated with reactivation of herpes zoster, 
cytomegalovirus, herpes simplex, and other viruses. Antiviral therapy such as 
acyclovir, ganciclovir, valacyclovir, or other antiviral agents may be initiated as 
clinically indicated. Testing and monitoring for cytomegalovirus replication and 
prophylactic or preemptive therapy to asymptomatic patients, if indicated, should 
follow the institutional standard practice.
At screening, all patients must have CMV serology and quantitative polymerase 
chain reaction (PCR) assay performed. CMV monitoring with a quantitative 
PCR assay will be performed as specified in the Schedule of Events. If positive at 
baseline, CMV monitoring is advised once a week with a decrease to a monthly 
frequency as it becomes negative. Preemptive treatment should be initiated 
based on the local CMV copy number per institutional practice. Prophylactic 
treatment can be initiated per investigators’ discretion based on the risk 
assessment (even if the CMV test is negative at baseline). Interruption of study 
drug is generally advised if the positive CMV test is accompanied by associated 
clinical symptoms or the copy number reaches a level that treatment is indicated 
per institutional standard or the CMV test remains positive despite the antiviral 
treatment for CMV. If the study drug is interrupted, it can be resumed only after 
the infection has resolved. CMV monitoring is advised for the duration of the 
study as described in Section 9.4.13.3 and in the Schedule of Events (Appendix 
A).
The following agents could be considered for prophylaxis or pre-emptive treatment 
against cytomegalovirus: ganciclovir (intravenous [IV]), valganciclovir (PO), 
foscarnet (IV), or cidofovir (IV). Duration of antiviral therapy generally is for at least 
2 weeks until cytomegalovirus is no longer detected.
8.7.1.2 Prophylaxis for Pneumocystis jiroveci Pneumonia
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Patients with lymphopenia may also be prone to developing infections, such as 
respiratory infections including pneumonia. Consider a diagnosis of opportunistic 
infection including Pneumocystis jiroveci pneumonia (PJP) in patients presenting 
with shortness of breath, cough, or fever. Prophylaxis for PJP must be initiated (either 
at baseline or during treatment) if at least 1 of the following is present:
…
Rationale for Change:
To be able to monitor CMV reactivation, which has frequently occurred across the TAK-659 
program. Monitoring and prophylaxis procedure are added to prevent CMV disease.
Change 32: Added CMV tests to be done at screening and monitored throughout the study.
The primary change occurs in Section 9.4.13 Clinical Laboratory Evaluations.
Added
text:
9.4.13.3 CMV Testing
Patients will be tested at screening for CMV. CMV will continue to be monitored 
throughout the study.
Tests at screening include CMV serology (immunoglobulin [Ig]G and IgM) and 
quantitative PCR for CMV. Quantitative PCR for CMV monitoring will be 
performed as specified in the Schedule of Events (Appendix A).
Rationale for Change:
To reflect the addition of CMV monitoring.
The following sections also contain this change:

Schedule of Events (Appendix A)
Change 33: Removed the text describing central reading of radiographic images.
The primary change occurs in Section 9.4.15 Disease Assessment.
Amended
text:
9.4.15.2 DLBCL Expansion Part
…
Response assessments should include radiographic imaging (CT and FDG-PET), 
evaluation of symptoms, and bone marrow aspirate/biopsy if appropriate. The 
FDG-PET imaging should be done minimally at Screening and at the end of Cycles 2, 
6, and 12 if positive at baseline or clinically indicated. Central collection of images at 
imaging time points by the sponsor or designee is required.
…
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Rationale for Change:
To reflect the current plan for not performing central reading of the radiographic imaging.
Change 34: Revised the instructions for performing CT scans for disease assessment in the 
expansion part.
The primary change occurs in Section 9.4.15 Disease Assessment.
Amended 
text:
9.4.15.2.1 CT Scans
CT scans of the chest, abdomen, and pelvis (neck should be included, if appropriate) 
will be performed to assess baseline disease at Screening and to assess disease 
response per the assessment schedule noted above and in the Schedule of Events 
(Appendix A). All CT scans should be performed with IV contrast, and abdominal and 
pelvic CT scans should also be performed withor oral contrast (unless medically 
contraindicated). Hybrid PET-CT scanners may be used to acquire the required CT 
images only if CT produced by the scanner is of diagnostic quality, adheres to 
specified scan parameters, and includes IV/oral contrast (unless medically 
contraindicated). Nondiagnostic CT images acquired for attenuation purposes during 
PET-CT are NOT acceptable as the only CT scan for the time point. Diagnostic CT 
images with contrast (unless medically contraindicated) with a standalone CT scanner 
must be acquired if PET-CT is unable to acquire diagnostic CT images. If the 
diagnostic CT and PET are acquired on the same day, it is strongly recommended that 
the PET be performed before the CT with IV/oral contrast to avoid compromising 
PET results.
Rationale for Change:
CT with oral contrast may be more appropriate than CT with IV contrast, depending on location of 
the lesion.
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Change 36: Added and reorganized tables indicating the PK, ECG, and pharmacodynamic 
assessment schedules for the dose escalation part and the expansion part in Appendix A.
The primary change occurs in Appendix A. References to these tables are revised throughout the 
protocol accordingly.
Description 
of change:
!
Two new tables were added to show the PK, ECG and pharmacodynamic 
assessment schedules for patients who are on Dosing Schedule B (7 days on/7 
days off intermittent dosing). These tables are now placed in the following order:
‒
Table A: Dose Escalation Part (Dosing Schedule A) PK, ECG, and 
Pharmacodynamic Assessment Schedule
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‒
Table B: Dose Escalation Part (Dosing Schedule B) PK, ECG, and 
Pharmacodynamic Assessment Schedule
‒
Table C: Expansion Part (Dosing Schedule A) Sparse PK and 
Pharmacodynamic Assessments Schedule
‒
Table D: Expansion Part (Dosing Schedule B) Sparse PK and 
Pharmacodynamic Assessments Schedule

Columns for the collection of PBMC were added.
Rationale for Change:

To reflect the addition of the new intermittent dosing schedule.

To reflect the addition of a new pharmacodynamic assessment.
The following sections also contain this change:

Section 9.4.17 PK Measurements

Section 9.9 Study Compliance
Change 37: Added description on the blood sample collection time points for PK for subjects on 
the new Dosing Schedule B (7 days on/7 days off intermittent dosing).
The primary change occurs in Section 9.4.17 PK Measurements and Section 13.1.5 
Pharmacodynamic Analysis and PK/Pharmacodynamic Analysis .
Amended 
text:
9.4.17.1 PK Measurements for the Dose Escalation Part
In all dose escalation patients, blood samples for determination of the plasma 
concentrations of TAK-659 will be collected in Cycle 1 on Days 1, 2, 8, 15, 16, and 22 
at the times indicated in Appendix A, Table A (Dosing Schedule A) or Table B
(Dosing Schedule B).
To determine urine concentrations of TAK-659, a spot urine collection will be 
obtained predose on Cycle 1 Day 1, and a urine collection will be obtained in the clinic 
either on Cycle 1 Day 15 (for patients on Dosing Schedule A) or Cycle 1 Day 7 
(for patients on Dosing Schedule B) at 0 to 8 hours postdose. …
…
The dates and exact times of TAK-659 dosing and PK sample collection will be 
recorded in the eCRF on PK sample collection days (Cycle 1 Days 1, 2, 8, 15, 16, and 
22). [Dosing Schedule A] or Cycle 1 Days 1, 2, 7, 8, 15 and 22 [Dosing Schedule 
B]). …
9.4.17.2 PK Measurements for the DLBCL Expansion Part
For DLBCL expansion patients (except for a potential subset of Japanese patients), 
blood samples for determination of TAK-659 plasma concentrations will be collected 
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during Cycles 1 through 4 according to a sparse sampling schedule at the times 
indicated in Appendix A, Table B.Table C (Dosing Schedule A) or Table D (Dosing 
Schedule B). Specifically, blood samples will be collected on Days 1, 15, and 22 of 
Cycle 1 and on Day 1 of Cycles 2 through 4. (for patients on Dosing Schedule A) or 
Days 1, 7 and 21 of Cycle 1 and on Day 7 of Cycles 2 through 4 (for patients on 
Dosing Schedule B). No urine PK samples will be collected in expansion patients 
designated for sparse PK sampling. If fewer than 6 Japanese patients are dosed at the 
RP2D in the dose escalation part, additional intensive PK samples will be collected 
during Cycle 1 in a subset of Japanese patients in the DLBCL expansion part. For this 
subset, additional blood samples and 2 urine samples should be collected as specified 
in Appendix A, Table A and Table B.
…
Rationale for Change:
To reflect the addition of the new intermittent dosing schedule.
Change 38: Added a new section for blood sample collection for assessment of the 
pharmacodynamic effects of TAK-659 on circulating immune cells.
The primary change occurs in Section 9.4.18 Pharmacodynamic Measurements.
Amended 
text:
9.4.18.1 Serum Samples for Pharmacodynamic Measurements for 
Cytokines/Chemokines/Serum Proteins
Serum samples will be collected from all patients for pharmacodynamic evaluation as 
indicated in the Schedule of Events (Appendix A, Table A, Table B, Table C and 
Table D), and the cytokines/chemokines/proteins in serum will be measured. 
Posttreatment changes in the amount of cytokines/chemokines will be assessed and 
their correlation with clinical response will be analyzed.
9.4.18.2 Blood Samples for Pharmacodynamic Measurements for Circulating 
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Immune Cells by Flow Cytometry
Blood samples will be collected from all patients as indicated in the Schedule of 
Events (Appendix A, Table A, Table B, Table C and Table D). Peripheral blood 
mononuclear cells (PBMCs) isolated and cyropreserved to evaluate the response 
of circulating immune cells to TAK-659 treatment during the different 
treatment regimens. Blood will only be collected during Cycle 1 for 
immunophenotyping.
Rationale for Change:
To reflect the addition of a new pharmacodynamic assessment.
The following sections also contain this change:

Schedule of Events (Appendix A)
Change 39: Pregnancy was added to the reasons for discontinuation of treatment with study drug.
The primary change occurs in Section 9.6 Completion of Study.
Amended 
text:
Treatment with study drug may be discontinued for any of the following reasons:
…

Initiation of hematopoietic stem cell transplant.

Pregnancy.

Study terminated by sponsor.
…
Rationale for Change:
For consistency with other TAK-659 protocols.
Change 40: Pregnancy was added to the reasons for withdrawal of patients from study.
The primary change occurs in Section 9.7 Discontinuation of Treatment With Study Drug and 
Patient Replacement.
Amended 
text:
A patient may be withdrawn from the study for any of the following reasons:
…

Initiation of hematopoietic stem cell transplant.

Pregnancy.

Study terminated by sponsor.
…
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Rationale for Change:
For consistency with other TAK-659 protocols.
Change 41: Revised the posttreatment follow-up assessments section.
The primary change occurs in Section 9.10 Posttreatment Follow-up Assessments (PFS) 
(Expansion Part Only).
Amended 
text:
Patients enrolled in the DLBCL expansion part who stop treatment for any reason 
other than PD will continue to have PFS follow-up visits. The PFS follow-up visits 
should be conducted at the study site every 2 months for up to 6 months after the last 
dose of study drug or until PD, whichever occurs first.
Survivor information and death details may be collected by methods that include, but 
are not limited to, telephone, email, mail, or retrieval from online or other databases 
(eg, social security indexes). In addition, the start of another anticancer therapy for the 
disease under study will be collected.
If a patient has transitioned to either autologous or allogeneic stem cell transplant 
during this follow-up period, transplant details will also be collected in the eCRF 
including, but not limited to, type of transplant and success of transplant.
…
Rationale for Change:
Removed description on the collection of survivor information, since overall survival data is not 
collected in this study.
Change 42: Revised the PK analysis section.
The primary change occurs in Section 13.1.4 PK Analysis.
Amended 
text:
The plasma and urine concentrations of TAK-659 will be determined by validated 
liquid chromatography tandem mass spectrometry assay methods. For patients who 
undergo intensive or sparse PK sampling in either dose escalation or DLBCL 
expansion, plasma TAK-659 concentrations obtained from Cycle 1 will be 
summarized by descriptive statistics according to nominal (scheduled) time postdose
(except for 2-4 hr postdose on Day 22), dose level, and day and cycle.For DLBCL 
expansion patients undergoing sparse PK sampling, only plasma concentrations from 
Cycle 1 predose samples will be summarized by day (plasma concentrations obtained 
from Cycle 1, 2-4 hr postdose samples and from Cycles 2 through 4 predose samples 
will be listed but not summarized). For patients who undergo intensive PK sampling 
in either dose escalation or DLBCL expansion, mean and individual plasma TAK-659 
concentration data from Cycle 1will be plotted over time and grouped according to 
dose level and day, including a graphical presentation of mean and individual 
concentration-time data in the Japanese patients at the RP2D who undergo intensive 
PK assessments. All plasma and urine concentration data will be listed by patient, 
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dose level, dosing cycle and day, and nominal and actual time point.
13.1.4.1 Noncompartmental PK Analysis
Plasma and urine PK parameters for patients with intensive PK sampling will be 
estimated in the PK analysis set using noncompartmental methods. The following PK 
parameters will be determined as permitted by available data: Cmax, Tmax, AUCτ, CL/F, 
Ctrough, Rac, PTR, CLR, and CLR as a percentage of CL/F.
…
Rationale for Change:
To extend the summary of PK concentration in every cycle of the expansion phase, and to clarify 
that the noncompartmental PK analysis is only applicable for patients with intensive PK sampling.
Change 44: Revised Table 13.a (Probabilities of Observing the Minimum Number of Responders 
Given True Response Rates, Assuming a Total of 12 Response-Evaluable Patients).
The primary change occurs in Section 13.3 Determination of Sample Size.
Description 
of change:
The probability of observing a certain number of responders were originally estimated 
on the basis of the true TAK-659 response rate as being 20%, 30%, 40% and 50%, but 
these numbers were re-estimated using true TAK-659 response rates of 20%, 40%, 
60% and 80%.
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Rationale for Change:
To reflect the new target tumor types (FL and MZL) in the expansion part.
Change 45: Updated the protocol deviations section.
The primary change occurs in Section 14.2 Protocol Deviations.
Amended 
text:
…
The site should document all protocol deviations in the subject’s source documents. In 
the event of a significant deviation, the site should notify the sponsor or its designee 
(and IRB or IEC, as required). Significant deviations include, but are not limited to, 
those that involve fraud or misconduct, increase the health risk to the subject, or 
confound interpretation of the primary study assessment. A Protocol Deviation Form 
should be completed by the site and signed by the sponsor or designee for any 
significant deviation from the protocol.
The sponsor will assess any protocol deviation; if it is likely to affect to a 
significant degree the safety and rights of a subject or the reliability and 
robustness of the data generated, it may be reported to regulatory authorities as 
a serious breach of GCP and the protocol.
…
Rationale for Change:
For consistency with the latest protocol template.
Change 46: Updated the IRB and/or IEC approval section.
The primary change occurs in Section 15.1 IRB and/or IEC Approval.
Amended 
text:
… 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. If required by country or regional regulations or procedures, 
approval from the competent regulatory authority will be obtained before 
commencement of the study or implementation of a substantial amendment. The 
sponsor or its designee will notify site once the sponsor or its designee has confirmed 
the adequacy of site regulatory documentation and, when applicable, the sponsor or its 
designee has received permission from the competent authority to begin the trial. 
Until the site receives notification no protocol activities, including screening may
occur.
…
Rationale for Change:
For consistency with the latest protocol template.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-659
Study No. C34007
Page 161 of 162
Protocol Incorporating Amendment No.02
6 December 2017
Change 47: Revised the list of references.
The primary change occurs in 16.0 REFERENCES.
Description 
of change:
Added new references and rearranged the numbering of the references. 
Cross-references are also revised throughout the protocol for consistency.
Rationale for Change:
To reflect the addition of new references.
Change 48: Revised to allow predose ECG to be performed outside the 1 hour window before 
dosing.
The primary change occurs in the Schedule of Events (Appendix A), Table A. The new Table B 
has been prepared with this change incorporated.
Description 
of change:
Added a new footnote (b) to the Schedule of Events, Table A, to indicate this rule.
Rationale for Change:
To allow flexibility to the predose ECG timing for study visits when multiple examination 
procedures coincide. As long as the predose ECG is performed before dosing, the timing is of little 
clinical significance.
The primary change occurs in the Schedule of Events (Appendix A), Table A. The new Table B 
has been prepared with this change incorporated.
Description 
of change:

Added a note in the cells for postdose pharmacodynamic sample collection in 
Schedule of Events, Table A (and the new Table B), to indicate this requirement.

In Schedule of Events, Table C (and the new Table D), the following revision has 
been made:
2 toor 4 hours post dose
Rationale for Change:
To clarify the timing of blood collection for the original and additional dosing schedules.
Change 50: Updated the Schedule of Events.
The primary change occurs in Schedule of Events (Appendix A), including Table A, Table B, 
Table C and Table D.
Property of Takeda: For Non-Comm
Only and Subject to the Applicable Terms of Use
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TAK-659
Study No. C34007
Page 162 of 162
Protocol Incorporating Amendment No.02
6 December 2017
Description 
of change:
For both the dose escalation part and expansion part:

Revised texts for TAK-659 administration to reflect the new dosing schedule.

Added a new row for CMV testing.

Added a new row for the collection of blood samples for flowcytometry.

Added new columns according to the new sample collection time points for PK.
Dose escalation part only:

Revised texts in several rows (12-lead ECG, blood samples for PK, urine samples 
for PK, serum samples for pharmacodynamics) to refer to Table A for subjects on 
Dosing Schedule A and to refer to the new Table B for subjects on Dosing 
Schedule B.
Expansion part only:

Revised texts in several rows (blood samples for sparse PK and blood samples for 
intensive PK) to refer to Table A for subjects on Dosing Schedule A and to refer to 
the new Table B for subjects on Dosing Schedule B.
Rationale for Change:
For consistency with the revisions/updates made to the other sections of this protocol amendment.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


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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: A Phase 1, Open-label Study of TAK-659 as a Single Agent in Adult East Asian Patients 
with Non-Hodgkin Lymphoma
NCT Number: NCT03238651
SAP Approve Date: 20 February 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-659 C34007
A Phase 1, Open-label Study of TAK-659 as a Single Agent in Adult East Asian Patients with 
Non-Hodgkin Lymphoma
PHASE 1
Version: Final
Date: 20 February 2020
Prepared by:
Based on:
Protocol Version: Protocol Amendment No. 02
Protocol Date: 06 December 2018
P
of Takeda: F
mmercial Use Only and Subject to the Applicable Terms of Use
ult East A
East
n: Final
Fin
0 Febru
0 Febr
Versi
Version
olol Date
Da
l
PPD


TAK-659 C34007
Page 2 of 26
Statistical Analysis Plan 
20 February 2020
1.1
Approval Signatures
Electronic signatures can be found on the last page of this document.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-659 C34007
Page 3 of 26
Statistical Analysis Plan 
20 February 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..........................................................................................4
4.0
OBJECTIVES .................................................................................................................7
4.1
Primary Objectives ....................................................................................................7
4.2
Secondary Objectives.................................................................................................7
4.3
Exploratory Objectives ..............................................................................................7
4.4
Study Design .............................................................................................................7
5.0
ANALYSIS ENDPOINTS.............................................................................................11
5.1
Primary Endpoints ...................................................................................................11
5.2
Secondary Endpoints ...............................................................................................11
5.3
Additional Endpoints ...............................................................................................11
5.4
Exploratory Endpoints .............................................................................................12
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................13
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................14
7.1
General Principles....................................................................................................14
7.1.1
Data Presentation ...............................................................................................14
7.1.2
Definition of Study Days....................................................................................15
7.1.3
Conventions for Missing/Partial Dates in Screening Visit...................................15
7.1.4
Conventions for Missing Adverse Event Dates...................................................15
7.1.6 Conventions for Missing Concomitant Medication/Therapy Dates ........................16
7.2
Analysis Sets ...........................................................................................................16
7.3
Disposition of Subjects ............................................................................................17
7.4
Demographic and Other Baseline Characteristics.....................................................17
7.5
Medication History and Concomitant Medications...................................................17
7.6
Study Drug Exposure and Compliance.....................................................................17
7.6.1
Study Treatments ...............................................................................................17
7.6.2
Extent of Exposure.............................................................................................18
7.6.3
Action on Drug ..................................................................................................18
7.7
Efficacy Analysis.....................................................................................................19
7.7.1
Primary Efficacy Endpoint(s).............................................................................19
7.7.2
Secondary Efficacy Endpoint(s).........................................................................19
7.7.3
Additional Efficacy Endpoint(s).........................................................................19
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-659 C34007
Page 4 of 26
Statistical Analysis Plan 
20 February 2020
7.8
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................19
7.8.1
Pharmacokinetic Analysis ..................................................................................19
7.8.2
.......................20
7.8.3
...........................................................................20
7.9
Safety Analysis........................................................................................................21
7.9.1
Adverse Events ..................................................................................................21
7.9.2
Clinical Laboratory Evaluations .........................................................................22
7.9.3
Vital Signs .........................................................................................................23
7.9.4
12-Lead ECGs ...................................................................................................23
7.9.5
Other Observations Related to Safety.................................................................23
7.10
Interim Analysis ......................................................................................................24
7.11
Changes in the Statistical Analysis Plan...................................................................24
8.0
REFERENCES..............................................................................................................25
9.0
DATA LISTINGS .........................................................................................................26
LIST OF IN-TEXT TABLES
Table 6.a
Probabilities of observing the minimum number of responders given true 
response rates, assuming a total of 12 response-evaluable patients .....................13
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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TAK-659 C34007
Page 5 of 26
Statistical Analysis Plan 
20 February 2020
3.0
LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BUN
blood urea nitrogen
CMV
cytomegalovirus
CPK
creatine phosphokinase
CRF
case report form
ECG
electrocardiogram
FAS
full analysis set
GGT
-glutamyl transferase
HIV
human immunodeficiency virus
ICH
International Conference on Harmonisation
LDH
lactate dehydrogenase
MedDRA
Medical Dictionary for Regulatory Activities
PD
pharmacodynamics
PK
pharmacokinetics
SAE
serious adverse event
SAP
statistical analysis plan
SDB
standard database
ULN
upper limit of normal
WHODrug
World Health Organization Drug Dictionary
Ae0-8
amount of TAK-659 present in the urine from time zero to 8 hours postdose 
AUClast
area under the plasma concentration-time curve from time zero to the time of last 
quantifiable concentration
AUCtau
area under the plasma concentration-time curve over the dosing interval 
CL/F
apparent oral clearance after extravascular administration
CLr
renal clearance
Cmax
Maximum observed plasma concentration
Ctrough
trough concentration
fe0-8
fraction of the administered dose present as TAK-659 in the urine from time zero to 
8 hours postdose 
t1/2z
terminal disposition half-life
tmax
first time to reach Cmax
ASCT
autologous stem cell transplant
CLL
chronic lymphocytic leukemia
CR
complete response
CT
Computed tomography
Ctrough
observed concentration at the end of a dosing interval
DLBCL
Diffuse large B-cell lymphoma
DLT
Dose-limiting toxicity
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-659 C34007
Page 6 of 26
Statistical Analysis Plan 
20 February 2020
DOR
Duration of response
ECOG
Eastern Cooperative Oncology Group
FDG
fluoro-2-deoxy-D-glucose
FL
follicular lymphoma
HBV
hepatitis B virus
HCV
hepatitis C virus
IWG
International Working Group
MTD
Maximum tolerated dose
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NHL
Non-Hodgkin lymphoma
ORR
overall response rate
PD
progressive disease (disease progression)
PET
positron emission tomography
PFS
progression-free survival
PR
Partial response
PTR
peak-trough ratio
Rac
accumulation ratio
RP2D
Recommended phase 2 dose
SD
stable disease
SPD
Sum of the product of the diameters
ECOG
Eastern Cooperative Oncology Group
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-659 C34007
Page 7 of 26
Statistical Analysis Plan 
20 February 2020
4.0
OBJECTIVES
4.1
Primary Objectives
The primary objectives are:
∀
To determine the safety, tolerability, and the MTD and/or RP2D of TAK-659 administered 
orally QD to East Asian patients with NHL who do not have an effective standard treatment 
available.
∀
To characterize the plasma and urine PK of TAK-659 in East Asian patients with NHL.
4.2
Secondary Objectives
The secondary objective is to evaluate preliminary efficacy of TAK-659 in patients with relapsed 
and/or refractory NHL.
4.4
Study Design
This is an open-label, multicenter, phase 1 study of TAK-659 including a dose escalation part in 
adult East Asian patients with NHL and an expansion part in adult East Asian patients with 
relapsed and/or refractory NHL.
The dose escalation part of the study will enroll approximately 18 to 32 East Asian patients 
diagnosed with NHL for which no effective standard treatment is available. Assuming a dropout
rate of 20%, this will ensure that 16 to 28 DLT-evaluable patients are enrolled in the dose 
escalation part. TAK-659 will be administered continuously, QD, in 28-day treatment cycles
(Dosing Schedule A).Dose escalation will follow a standard 3+3 schema to determine the MTD 
and/or the RP2D. The initial TAK-659 dose will be 60 mg QD and will escalate to 80 mg QD, 
provided that the safety and tolerability of the 60 mg dose has been demonstrated. Dose 
escalation will continue until the MTD is reached or until an RP2D (if different from the MTD) 
for East Asian patients has been identified. More conservative dose escalation, evaluation of 
intermediate doses or regimens, and expansion of an existing dose level are all permissible 
following written confirmation of discussions between the sponsor and the investigators, if such 
Property of Takeda: For Non-C
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l, multic
patients 
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CCI


TAK-659 C34007
Page 8 of 26
Statistical Analysis Plan 
20 February 2020
measures are needed for patient safety or for a better understanding of the dose-toxicity and 
dose-exposure relationships of TAK-659. 
If ≥2 of 6 patients experience a DLT at 60 mg QD, depending on the overall safety profile, the 
type of AEs/DLTs observed, and following the examination of the preliminary PK results in 
relation to the PK data in the Western population, a decision will be made either to de-escalate 
the dose to 40 mg QD or to terminate the study following discussion between the investigator 
and the sponsor. If ≥2 of 6 patients experience a DLT at 80 mg QD, alternate dose regimens 
between 60 and 80 mg (ie, 80 mg 7 days on 7 days off [Dosing Schedule B]) will be evaluated as 
described below. The MTD and/or RP2D should be evaluated with a total of ≥6 DLT-evaluable 
patients. The RP2D will be determined on the basis of the totality of the safety, tolerability, and 
preliminary PK and efficacy data (if available) observed in Cycle 1 and beyond. Intrapatient dose 
escalation is not allowed in this protocol.

Dosing Schedule B: TAK-659 will be administered QD for 7 consecutive days followed by 
another 7 days of rest and repeated again (ie, 7 days “on” and 7 days “off”), for a cycle 
duration of 28 days. The starting dose of 80 mg QD was the maximum administered dose in 
Dosing Schedule A (2 out of 4 patients presented a DLT in the continuous dosing regimen). 
However, the alternative dose of 60 mg may be tested if the 80 mg intermittent regimen is 
deemed not tolerable per emerging data. 
The expansion part of this study will begin once the RP2D has been determined. The expansion 
part will proceed with dosing of TAK-659 at the RP2D in 28-day cycles. The patient population 
will consist of East Asian patients with FL or MZL who are relapsed and/or refractory after at 
least 2 prior of chemotherapy and who must be ineligible for or refusal to hematopoietic stem 
cell transplant. It is expected that a minimum of 12 response-evaluable patients will be enrolled. 
Assuming a 20% dropout rate, a total of approximately 15 patients will be enrolled. The 
objectives of the expansion part are to evaluate the longer-term safety and tolerability of 
TAK-659 administered at the RP2D, to characterize the PK of TAK-659, and to evaluate the 
preliminary efficacy of TAK-659 in relapsed and/or refractory FL/MZL as measured by ORR 
and other efficacy variables, including CR rate, DOR, and PFS.
At least 1 Japanese patient will be enrolled in each cohort in the dose escalation part. The total 
number of Japanese patients dosed at the RP2D (either the MTD or a lower dose as determined) 
will be at least 6 including the dose escalation and expansion parts to ensure adequate 
characterization of PK and safety in Japanese patients.
On the basis of the geographic distribution of patients enrolled and emerging PK and safety data,
additional patients may be added, as needed, to further characterize the PK, safety, and 
tolerability in a particular East Asian geographic region. On the basis of emerging efficacy data, 
additional groups or patients with FL/MZL may be added to further explore efficacy.
Patients will discontinue treatment if they experience an unacceptable TAK-659-related toxicity.
Patients may discontinue therapy at any time. Patients will attend the End of Treatment (EOT) 
visit 28 days (+10 days) after receiving their last dose of TAK-659 or before the start of 
subsequent antineoplastic therapy, whichever occurs first, to permit the detection of any delayed
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-659 C34007
Page 9 of 26
Statistical Analysis Plan 
20 February 2020
treatment-related AEs. AEs will be assessed, and laboratory values, vital signs, ophthalmic 
exams, and electrocardiograms (ECGs) will be obtained to evaluate the safety and tolerability of
TAK-659. Toxicity will be evaluated according to National Cancer Institute Common
Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03, effective date 14 June 
2010. DLTs are defined in the study protocol.
Intensive PK samples (serial blood samples and 2 urine samples) will be collected during Cycle 
1 in all patients in the dose escalation part to permit detailed characterization of TAK-659 
plasma PK and urine PK across different dose levels. Sparse PK samples will be collected in 
expansion patients to contribute to population PK and exposure-response analyses. If fewer than 
6 Japanese patients are dosed at the RP2D in the dose escalation part, then additional intensive
PK samples will be collected during Cycle 1 in a subset of Japanese patients in the expansion
part. In total, intensive PK sampling will be performed in at least 6 Japanese patients dosed at the
RP2D (either the MTD or a lower dose) among the dose escalation and expansion parts
combined to ensure adequate characterization of plasma and urine PK in Japanese patients. 
Archived and/or freshly biopsied tumor samples may be analyzed to identify potential patient
selection markers or to identify biomarkers of response and resistance to TAK-659.
Serum samples will be collected pretreatment and posttreatment, and the levels of circulating
cytokines/chemokines/serum proteins in serum will be measured. Whole blood samples will be
collected pretreatment during Cycle 1, and the levels of circulating immune cells will be 
measured.
Buccal epithelial cells will be collected, and DNA may be analyzed for germline polymorphisms
in genes encoding drug-metabolizing enzymes and/or transporters involved in the metabolism or
disposition of TAK-659 (e.g., CYP2D6). Germline DNA may also be used as a comparator for
analysis of tumor mutations and genetic changes.
Evaluation of disease response will be performed as described in the protocol, using the IWG 
2007 modified response criteria for malignant lymphoma based on investigator assessment. An 
imaging modality (e.g., computed tomography [CT] with contrast and fluoro-2-deoxy-D-glucose 
[FDG]-positron emission tomography [PET] if appropriate) will be used to follow sites of 
measurable disease during the study treatment. Radiographic images will be maintained at the 
site. Based on efficacy data observed, the sponsor can elect to have central collection of disease 
assessment images. In the event of antitumor response, the sponsor may request electronic 
images for those patients who demonstrate tumor reduction.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-659 C34007
Page 10 of 26
Statistical Analysis Plan 
20 February 2020
The study design is detailed below:
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TAK-659 C34007
Page 11 of 26
Statistical Analysis Plan 
20 February 2020
5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoints
The primary endpoints are:

Percentage of patients with treatment-emergent AEs (TEAEs).

Percentage of patients with Grade 3 or higher TEAEs.

Percentage of patients with serious TEAEs.

Percentage of patients with DLTs during Cycle 1 (dose escalation part only).

Percentage of patients discontinuing study drug because of TEAEs.

Percentage of patients with clinically significant abnormal laboratory values.

Percentage of patients with clinically significant abnormal vital sign measurements.

TAK-659 Cmax on Cycle 1 Days 1 and 7 or 15 by dose.

TAK-659 tmax on Cycle 1 Days 1 and 7 or 15 by dose.

TAK-659 AUCon Cycle 1 Days 1 and 7 or 15 by dose.

Renal clearance (CLR) on Cycle 1 Day 7 or 15 by dose.
5.2
Secondary Endpoints
The secondary endpoints are:

Overall response rate (ORR) in the expansion part.

CR rate in the expansion part.

Duration of response (DOR) in the expansion part.

Progression-free survival (PFS) in the expansion part.
The investigators will perform response assessments using modified International Working 
Group (IWG) 2007 criteria for malignant lymphoma, which will be the main analysis for the 
efficacy endpoints. 
5.3
Additional Endpoints
Additional endpoints are:

Apparent oral clearance (CL/F), CLR as a percentage of CL/F, peak-trough ratio (PTR), 
accumulation ratio (Rac), and observed concentration at trough on Cycle 1 Day 7 or 15 by 
dose.

Plasma concentration-time data contributing to population PK and exposure response 
analyses.
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TAK-659 C34007
Page 12 of 26
Statistical Analysis Plan 
20 February 2020
Property of Takeda: For Non-Commercial Use Only and Subject t
e
CCI


TAK-659 C34007
Page 13 of 26
Statistical Analysis Plan 
20 February 2020
6.0
DETERMINATION OF SAMPLE SIZE
No formal statistical power calculations to determine sample size were performed for this study.
It is estimated that 16 to 28 DLT-evaluable subjects will be enrolled in the dose escalation part. 
The actual number of patients may vary depending on the actual doses being tested. Assuming a 
20% dropout rate, 18 to 32 patients will be enrolled in the dose escalation part.
For the expansion part, a minimum of 12 response-evaluable patients will be enrolled to allow 
adequate assessment of safety and a preliminary assessment of efficacy. Assuming a 20%
dropout rate, approximately 15 patients will be enrolled in the expansion part. The actual number 
of patients enrolled may increase on the basis of emerging data to allow a sufficient number of 
PK/safety-evaluable patients per country or in the East Asian race group or to further assess 
efficacy in a specific subtype or group of patients with FL or MZL. The probability of observing 
at least 4 responders in the 12 response-evaluable patients is 0.775 if the true TAK-659 response 
rate is 40% (can be considered the true positive rate); the probability of observing at least 
4 responses in the 12 response-evaluable patients is 0.205 if the true TAK-659 response rate is 
20% (can be considered the false positive rate). See Table 6.a for more details.
Table 6.a
Probabilities of observing the minimum number of responders given true 
response rates, assuming a total of 12 response-evaluable patients
Number of 
Responders
TAK-659 True Response Rate
0.2
0.3
0.4
0.5
≥2
0.725
0.980
1
1
≥3
0.442
0.917
0.997
1
≥4
0.205
0.775
0.985
1
≥5
0.073
0.562
0.943
0.999
≥6
0.019
0.335
0.842
0.996
≥7
0.004
0.158
0.665
0.981
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TAK-659 C34007
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Statistical Analysis Plan 
20 February 2020
7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
All statistical analyses will be conducted using SAS® Version 9.4.
Unless otherwise specified, the baseline value is defined as the value collected at the time closest 
to, but prior to, the start of the study drug administration. Cycle 1 Day 1 values are considered 
pre-dose. Screening values are used for baseline values if a Cycle 1 Day 1 value is unavailable.In 
general, summary tabulations will display the number of observations, mean, standard deviation, 
median, minimum and maximum for continuous variables, and the number and percent (of non-
missing values) per category for categorical data.
All available efficacy and safety data will be included in data tabulations and listings as needed. 
Data that are potentially spurious or erroneous will be examined under the auspices of standard 
data management operating procedures.
Means, medians, min and max will be presented to 1 more decimal place than the recorded data. 
The standard deviations (SDs) will be presented to 2 or more decimal places than the recorded 
data. Confidence intervals about a parameter estimate will be presented using the same number 
of decimal places as the parameter estimate.
Where appropriate, variables will be summarized descriptively by study visit. For the categorical 
variables, the count and proportions of each possible value will be tabulated by treatment group. 
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.
Screen failure subjects and reasons for screen failure will be grouped. 
A month is operationally defined to be 30.4375 days.
7.1.1
Data Presentation
In general, data will be presented as follows 
TAK-659
40 mg QD
N=xx
TAK-659
60 mg QD
N=xx
TAK-659
80 mg QD
N=xx
TAK-659
QD Total
N=xx
TAK-659
80 mg
7 days off/
7 days on
N=xx
TAK-659
100 mg
7 days 
off/
7 days on
N=xx
TAK-659
Total
7 days off/
7 days on
N=xx
TAK-659
Total
N=xx
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Statistical Analysis Plan 
20 February 2020
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 study 
drug. Other study days are defined relative to the Study Day 1 with Day 1 being Study Day 1 and 
Day -1 being the day prior to Study Day 1.
7.1.3
Conventions for Missing/Partial Dates in Screening Visit
The following rules apply to dates recorded during the screen visits.
1. If only the day-component is missing, the first day of the month will be used if the year and 
the month are the same as those for the first dose of TAK-659. Otherwise, the fifteenth will 
be used. 
2. If only the year is present, and it is the same as the year of the first dose of TAK-659, the 
fifteenth of January will be used unless it is later than the first dose, in which case the date of 
the first of January will be used. 
3. If only the year is present, and it is not the same as the year of the first dose of TAK-659, the 
fifteenth of June will be used, unless other data indicates that the date is earlier.
7.1.4
Conventions for Missing Adverse Event Dates
Adverse events with start dates that are completely or partially missing will be analyzed as 
follows:

If the start date has a month and year but the day is missing, the event will be considered 
treatment emergent if the month and year of the start date of the event are: 
–
On or after the month and year of the date of the first dose of TAK-659.
and 
–
on or before the month and year of the date of the last dose of TAK-659 plus 28 days, or 
the start date of subsequent anticancer therapy, whichever occurs first.

If the start date has a year, but the day and month are missing, the event will be considered 
treatment emergent if the year of the start date of the event is:
–
On or after the year of the date of the first dose of TAK-659.
and 
–
on or before year of the date of the last dose of TAK-659 plus 28 days, or the start date of 
subsequent anticancer therapy, whichever occurs first.

If the start date of an event is completely missing then the event is assumed to be treatment 
emergent.
However, if the end date is complete or partially missing but it is clear that the end date is before 
the first dose of TAK-659, the event will not be considered treatment emergent.
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TAK-659 C34007
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Statistical Analysis Plan 
20 February 2020
7.1.6 Conventions for Missing Concomitant Medication/Therapy Dates
Concomitant medications/therapies with start dates that are completely or partially missing will 
be analyzed as follows:

If the start date has a month and year but the day is missing, the event will be considered 
concomitant if the month and year of the start date of the event are: 
–
On or after the month and year of the date of the first dose of TAK-659.
and 
–
on or before the month and year of the date of the last dose of TAK-659 plus 28 days, or 
the start date of subsequent anticancer therapy, whichever occurs first.

If the start date has a year, but the day and month are missing, the event will be considered 
concomitant if the year of the start date of the event is:
–
On or after the year of the date of the first dose of TAK-659.
and 
–
on or before the year of the date of the last dose of TAK-659 plus 28 days, or the start 
date of subsequent anticancer therapy, whichever occurs first.

If the start date of an event is completely missing then the event is assumed to be 
concomitant. 
However, if the end date is complete or partially missing but it is clear that the end date is before 
the first dose of TAK-659, the event will not be considered concomitant. 
When the start date is complete and is before the first dose, and the concomitant medication is 
not ongoing but the end date is missing completely or partially, a similar algorithm should be 
used to assess whether the end date is before the last dose of TAK-659 plus 28 days to be 
included.
7.2
Analysis Sets
The Analysis Sets (Analysis Populations) will include the following:

Safety analysis set: patients who have received at least 1 dose of study drug will be used for 
all safety analyses and for efficacy analyses.

PK analysis set: patients with sufficient dosing and PK data to reliably estimate 1 or more PK 
parameters will be used for PK analyses.

Response-evaluable analysis set: patients who have received at least 1 dose of study drug, 
have sites of measurable disease at baseline, and have as least 1 post-baseline disease 
assessment will be used for analyses of response.

DLT-evaluable analysis set: patients who have met the minimum treatment and safety 
evaluation requirements of the study or who experience a DLT during Cycle 1. The 
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TAK-659 C34007
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Statistical Analysis Plan 
20 February 2020
minimum treatment and safety evaluation requirements are met if in Cycle 1 the patient is 
treated with at least 75% of planned doses of TAK-659, is observed for 1 cycle following 
the dose on Cycle 1 Day 1, and is considered to have sufficient safety data by both the 
sponsor and the investigators to conclude that a DLT did not occur.
7.3
Disposition of Subjects
The date first subject signed ICF, date of last subject’s last visit/contact, date of last subject’s last
procedure for collection of data for primary endpoint, MedDRA Version, WHO Drug Dictionary
Version, and SAS Version will be generated in a summary table.
The number of patients who were screening failures and reasons for screen failures will be
summarized.
The number of patients in the safety population, in the pharmacokinetics population, in the DLT
evaluable population, and the reason study drug was discontinued will be summarized.
All percentages will be based on the number of patients in the safety set.
7.4
Demographic and Other Baseline Characteristics
Summaries of demographic and baseline characteristics will be presented for subjects in the 
safety set.
The demographic data to be evaluated will include age, sex, race, ethnicity, Asian sub-category, 
baseline height and weight, smoking history, country. Age will be calculated from date of birth 
to date of informed consent. No inferential statistics will be generated.
Baseline characteristics including lymphoma disease subtype, months since initial diagnosis, 
staging, Eastern Cooperative Oncology Group (ECOG) performance status. 
A separate table will summarize the numbers and percentages of patients who received prior 
therapy, including prior anticancer, prior transplant, if the patient received, prior radiation, prior 
surgery, and best response to the last prior anticancer therapy.
7.5
Medication History and Concomitant Medications
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Dictionary. The number and percentage of patients taking concomitant medications will be 
tabulated by WHO drug generic term for the safety population, from the first dose of study 
treatment and through 28 days after the last dose of study treatment, or to the start of subsequent 
anticancer therapy, whichever occurs first. 
7.6
Study Drug Exposure and Compliance
7.6.1
Study Treatments
Cycles consists of 28 days for all treatment arms. In QD arm, TAK-659 will be administered QD 
(every day of a 28-day treatment cycle). In intermittent dosing arm, TAK-659 will be 
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TAK-659 C34007
Page 18 of 26
Statistical Analysis Plan 
20 February 2020
administered QD for 7 consecutive days followed by another 7 days of rest and repeated again 
(ie, 7 days “on” and 7 days “off”), for a cycle duration of 28 days.
7.6.2
Extent of Exposure
The exposure to TAK-659 will be characterized by total amount of dose taken in mg, total 
number of dose taken, relative dose intensity (%), number of treated cycles, numbers and 
percentages of patients who had ≥1, ≥2, …, ≥6, and ≥12 treated cycles in the safety population. 
Relative dose intensity (RDI) (%) will be presented for cycles 1, 2, …, 6 and overall. Overall 
RDI is defined as 100 x (total dose received in mg) / (initial prescribed total dose in mg for
treated days
For TAK-659, the initial prescribed total dose in mg for treated days is defined as below:

For QD dosing regimen: initial prescribed dose per day x number of treated days, where the 
number of treated days is defined as (reference end date for study drug – reference start date 
for study drug) + 1.

For intermittent dosing regimen (7 days on /7 days off, or 14 days on/7 days off): initial 
prescribed dose per “on” day x number of treated “on” days, where an “on” day is defined as 
a day on which a non-zero dose is prescribed, and the number of treated “on” days is defined 
as the total number of “on” days among the number of treated days.
–
For 7 days on/7 days off: let q1 be the quotient and r1 be the remainder after dividing the 
number if treated days by 14. The total number of “on” days=q1*7+r1 if r1<7, otherwise 
the total number of “on” days=(q1+1)*7.
–
For 14 days on/7 days off: let q2 be the quotient and r2 be the remainder after dividing 
the number if treated days by 21. The total number of “on” days=q2*14+r2 if r2<14, 
otherwise the total number of “on” days=(q2+1)*14.
For Relative Dose Intensity by cycle, the same formula is used as overall relative dose intensity, 
but the number of treated days is derived differently. The number of treated days in cycle is 
defined as (last dose date of a cycle – first dose day of cycle) + 1, however, if a patient
discontinues during the cycle then use (date of drug discontinuation – first dose day of 
cycle) + 1.
Prescribed dose is determined by the dose level to which a patient is enrolled at the onset of the 
study. 
7.6.3
Action on Drug 
Action on study drug (eg. Dose reduced due to AE) will be summarized by each of cycle (Cycles 
1- 6), sum of the remainder cycles, and total, summarized by dose. 
The reason for dose modification (omission, delay, reduction) of study drug will be summarized 
by each cycle and overall based on the safety analysis set.
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TAK-659 C34007
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Statistical Analysis Plan 
20 February 2020
7.7
Efficacy Analysis
Analysis of efficacy measures will be descriptive. All efficacy analyses will be based on 
investigator assessments. Investigators will assess responses using the IWG criteria for 
lymphoma.
7.7.1
Primary Efficacy Endpoint(s)
There is no primary efficacy endpoint for the study.
7.7.2
Secondary Efficacy Endpoint(s)
Secondary efficacy endpoints include ORR, CR rate, DOR, and PFS. No formal statistical tests 
will be performed for these secondary endpoints. Analyses for these endpoints will be done for 
expansion patients only. PFS will be summarized using the safety population. All other 
secondary efficacy endpoints will be summarized using the Response-Evaluable population.

ORR is defined as the proportion of patients who achieved Complete Response (CR) and 
Partial Response (PR) (determined by the investigator) in the response-evaluable population.

CR rate is defined as the proportion of patients who achieved Complete Response (CR, 
determined by the investigator) in the response-evaluable population.

DOR is defined as the time from the date of the first documented response to the date of first 
documented Progression of Disease (PD) by the investigator. 

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, by the investigator.
Antitumor activity of TAK-659 will be based on best overall response. Investigators will assess 
responses using the IWG 2007 criteria for lymphoma. 
Response rate will be tabulated by baseline factors if applicable. 
7.7.3
Additional Efficacy Endpoint(s)
Not applicable
7.8
Pharmacokinetic/Pharmacodynamic Analysis
7.8.1
Pharmacokinetic Analysis
The PK population will be used for the description of the plasma PK profile of TAK-659 and for 
the estimation of plasma and urine PK parameters of TAK-659. The plasma and urine 
concentrations of TAK-659 will be determined by validated liquid chromatography tandem mass 
spectrometry assay methods.
Descriptive statistics (number of patients, arithmetic mean, arithmetic standard deviation, 
arithmetic coefficient of variation, geometric mean, median, minimum, and maximum) will be 
used to summarize the plasma concentrations.
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TAK-659 C34007
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Statistical Analysis Plan 
20 February 2020
For dose escalation cohorts, plasma TAK-659 concentrations will be summarized by time 
postdose and grouped by dose cohort and dosing cycle and day. For sparse PK collected in 
expansion, plasma TAK-659 concentrations will be summarized for the predose time points on 
Cycle 1 Days 1, 15 and 22, and Day 1 of Cycle 2, 3 and 4. For dose escalation cohorts, mean and 
individual plasma TAK-659 concentration data will be plotted over time and grouped by dose 
cohort and dosing cycle and day (Cycle 1, Days 1 and 15). Plasma concentration-time data from 
dose escalation cohorts will be used to calculate single-dose (Cycle 1 Day 1) and multiple-dose 
(Cycle 1 Day 15) plasma PK parameters and multiple-dose (Cycle 1, Day 15) urine PK 
parameters of TAK-659 by noncompartmental methods. These parameters will include, but not 
be limited to, Cmax, tmax, Ctrough, AUClast, AUCτ, CL/F, PTR, and Rac. Urine PK parameters to be 
calculated in dose escalation cohorts will include, but not be limited to, Ae0-8, fe0-8, and CLr.
Plasma and urine PK parameters of TAK-659 will be summarized by dose escalation cohort, 
dose expansion cohort, and by dosing cycle and day. Dose proportionality of TAK-659 PK will 
be evaluated by visual inspection of plots of individual PK parameter values versus dose. If data 
permit, regression analysis using a power model will also be used to assess dose proportionality.
TAK-659 plasma PK data from dose escalation and expansion cohorts, along with data from 
other studies, may contribute to population PK analyses and exposure-response analyses for 
pharmacodynamic, safety, and efficacy endpoints. If applicable, the specifics of the population 
PK and exposure-response analyses will be described in separate analysis plans, and results will 
be reported separately from the clinical study report.
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TAK-659 C34007
Page 21 of 26
Statistical Analysis Plan 
20 February 2020
7.9
Safety Analysis
AEs will be summarized using the safety analysis set. 
Safety will be evaluated by the frequency of AEs, severity and types of AEs (whether the AEs 
are related to study drug, and whether they are serious AEs or not), and by changes from 
Baseline in patients’ vital signs, weight, and clinical laboratory results using the safety 
population. Exposure to study drug and reasons for discontinuation will be tabulated.
7.9.1
Adverse Events
The incidence of DLT will be tabulated for each dose group. In addition, to assess the 
relationship between toxicities and TAK-659 dose, the preferred terms for individual toxicities 
will be summarized by their frequency and intensity for each dose group. The DLT-evaluable set 
will be used for the analysis of DLT.
Safety will be evaluated by the frequency 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
analysis set. Exposure to study drug and reasons for discontinuation will be tabulated. TEAEs 
that occur after administration of the first dose of study drug and through 28 days after the last 
dose of study drug or the start of subsequent antineoplastic therapy, whichever occurs first, will 
be tabulated.
AEs will be tabulated according to the MedDRA and will include the following categories: 
∀
Treatment-emergent AEs.
∀
Drug-related treatment-emergent AEs.
∀
Grade 3 or higher treatment-emergent AEs.
∀
Grade 3 or higher drug-related treatment-emergent AEs.
∀
The most commonly reported treatment-emergent AEs (ie, those events reported by more 
than 10% of all patients).
∀
SAEs.
∀
Non-serious treatment-emergent adverse events reported by >5% of patients in any dose 
level. 5% cutoff will be applied before any rounding. 
∀
Treatment-emergent AEs leading to study drug discontinuation.
Descriptive statistics for the actual values of clinical laboratory parameters and/or change from 
baseline in clinical laboratory parameters will be presented for all scheduled measurements over 
time. Mean laboratory values over time will be plotted for key laboratory parameters.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Te
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TAK-659 C34007
Page 22 of 26
Statistical Analysis Plan 
20 February 2020
Descriptive statistics for the actual values and/or change from baseline of vital signs and weight 
over time will be tabulated by scheduled time point.
Shift tables for lab parameters will be generated based on changes in NCI CTCAE grades from 
baseline to the worst post-baseline value. Graphical displays of key safety parameters, such as 
scatter plots of baseline versus worst post-baseline values, may be used to understand the 
TAK-659 safety profile.
All concomitant medications collected from Screening through the study period will be classified 
to preferred terms according to the WHO drug dictionary. 
Additional safety analysis may be performed to most clearly enumerate rates of toxicities to 
further define the safety profile of TAK-659.
Patients with the same AE more than once will have the maximum intensity of that event 
counted within each body system, and once within each preferred term. Drug-related 
treatment-emergent AEs will also be summarized by the National Cancer Institute Common 
Toxicity Criteria for Adverse Event (NCI CTCAE) V4.03 intensity.
All deaths occurring on-study 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 28 days 
of the last dose of study drug.
7.9.2
Clinical Laboratory Evaluations
Whenever available, laboratory values will be assigned toxicity grades using the NCI CTCAE 
v4.03. The number and proportion of patients with shifts in NCI CTCAE toxicity grades from 
baseline to the worst post baseline toxicity grade.
Parameters to be tabulated include:
Hematology
Serum Chemistry
Hematocrit
Hemoglobin
Leukocytes with differential
Neutrophils (ANC)
Platelet (count)
Lymphocytes (absolute lymphocyte 
count [ALC])
Lymphocyte subsets (CD4, CD8, 
CD4:CD8 ratio)
Albumin
Alkaline phosphatase (ALP)
ALT
AST
Amylase
Bilirubin (total)
Blood urea nitrogen (BUN)
Calcium
Carbon dioxide (CO2)
Chloride
Creatinine
Creatine phosphokinase (CPK)
γ-glutamyl transferase (GGT)
Glucose
Lactate dehydrogenase (LDH)
(including LDH isozymes)
Lipase
Magnesium
Phosphate
Potassium
Sodium
Total protein
Urate
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Page 23 of 26
Statistical Analysis Plan 
20 February 2020
Urinalysis
Bilirubin
Glucose
Ketones
Leukocytes
Nitrite
Occult blood
pH
Protein
Specific gravity
Turbidity and color
Urobilinogen
Mean laboratory values over time will be plotted for key lab parameters, including Hgb, WBC, 
lymphocytes, ANC, platelets, and liver function tests (ALT/SGPT, AST/SGOT, alkaline 
phosphatase, total bilirubin), LDH, creatinine, lipase and amylase for all patients.
7.9.3
Vital Signs
Vital sign results (diastolic and systolic blood pressure, pulse, temperature, and oxygen 
saturation and body weight) will be as follows:

Baseline value.

Minimum post-baseline value.

Maximum post-baseline value.
Changes to the minimum and maximum post-baseline values will be calculated relative to the 
baseline value. 
7.9.4
12-Lead ECGs
ECG intervals (QT and Bazette’s and Friderichia’s corrected QT intervals [QTcB and QTcF], 
PR, QRS, and heart rate) will be summarized as follows:

Baseline value.

Minimum post-baseline value.

Maximum post-baseline value.
Changes to the minimum and maximum post-baseline values will be calculated relative to the 
baseline value. 
In addition, the number and percent of patients with increases >30 ms and >60 ms from pre-dose 
in QTcF will also be summarized.
7.9.5
Other Observations Related to Safety
Ophthalmology and CMV
Any ophthalmic and CMV findings that are determined to be abnormal, clinically significant by 
the investigators will be listed.
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Statistical Analysis Plan 
20 February 2020
7.10
Interim Analysis
Not applicable
7.11
Changes in the Statistical Analysis Plan 
None
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TAK-659 C34007
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Statistical Analysis Plan 
20 February 2020
8.0
REFERENCES
None
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TAK-659 C34007
Page 26 of 26
Statistical Analysis Plan 
20 February 2020
9.0
DATA LISTINGS
The below subject-level listings will be generated:

Disposition (date of first dose, date of last dose, number of cycles, reason for discontinuation 
of study treatment).

Populations (can be included with disposition listing).

Demographics.

Baseline characteristics.

Prior therapy. 

Concomitant medications.

Tumor measurements (tumor measurements from imaging, including changes from baseline, 
disease response category, and as appropriate, tumor marker measurements). 

Study drug exposure.

TEAEs.

TEAEs of grade 3 or higher (cycle date information for the AE onset and end dates will be 
included).

TEAEs leading to study drug discontinuation.

TEAEs resulting in dose modifications.

Serious AEs (all SAEs regardless of treatment emergent AE status).

On-study deaths (defined as death that occurs between the first dose of study drug and 
28 days after the last dose of study drug (adverse events with an outcome of death)).

DLTs during Cycle 1. 

Pharmacokinetic concentrations.

Pharmacokinetic parameters.

Best overall response (will include prognostic factors as collected in the baseline 
characteristics: age, number and types of prior therapy, prior autologous transplant, and 
International Prognostic Index score).

Laboratory results and change from baseline.

Ophthalmic findings.

CMV findings.

Significant protocol deviations.
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