Conditions: Diffuse Large B-cell Lymphoma
Keywords: Drug therapy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 49
Healthy volunteers: no

Brief summary:
The purpose of this study is to assess the efficacy of TAK-659 measured by independent radiologic review committee (IRC)-assessed overall response rate (ORR) in participants with relapsed or refractory DLBCL.

Detailed description:
The drug being tested is TAK-659. This study will evaluate overall response rate (ORR) in participants with relapsed or refractory DLBCL who take TAK-659.

The study will enroll approximately 122 participants. Participants will be assigned to:

• TAK-659 60 mg to 100 mg

All participants will be asked to take the tablets of TAK-659 at the same time each day throughout the study in a 28-day cycle.

This multi-center trial will be conducted in the United States, United Kingdom, Spain, Italy, France, Canada, Germany. The overall time to participate in this study is approximately 48 months. Participants will be assessed for disease response and progression during the PFS follow-up every 3 months after end of treatment (for participants who discontinue due to reasons other than disease progression) and OS follow-up every 3 months from the last dose of study drug until death or conclusion of the study, whichever occurs first.

Arms:
arm 1: TAK-659 100 mg tablet, orally, once daily (QD), during each 28-days cycle (median exposure was 41 days). arm 2: TAK-659 60-100 mg tablet, orally, QD, dose based on safety and tolerability during each 28-days cycle (median exposure was 28 days).

Interventions: intervention 1: TAK-659
Intervention descriptions: intervention 1: TAK-659 Tablets

Protocol document:
Prot_000.pdf: 



Title: Phase 2 Study of TAK-659 in Patients With Relapsed or Refractory Diffuse Large B-Cell 
Lymphoma After at Least 2 Prior Lines of Chemotherapy
NCT Number: NCT03123393
Protocol Approve Date:  24 April 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
Phase 2 Study of TAK-659 in Patients With Relapsed or Refractory Diffuse Large
B-Cell Lymphoma After at Least 2 Prior Lines of Chemotherapy
Sponsor:
Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda 
Pharmaceutical Company Limited
40 Landsdowne Street
Cambridge, MA 02139 USA
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:
C34004
IND Number:
119,231
EudraCT Number:
2016-003716-12
Compound:
TAK-659
Date:
24 April 2018
Version/Amendment 
Number:
02
Amendment History:
Date
Amendment Number
Amendment Type 
(for regional Europe purposes only)
Region
27 February 2017
Initial version
Not applicable
Global
14 November 2017
01
Not applicable
Global
24 April 2018
02
Not applicable
Germany-specific
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1.0
ADMINISTRATIVE 
1.1
Contacts 
A separate contact information list will be provided to each site.
Serious adverse event and pregnancy reporting information is presented in Section 10.0, as is 
information on reporting product complaints. 
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site.
Contact Type/Role
North America
European 
Serious adverse event and pregnancy reporting
See Sections 10.2, 10.4
See Sections 10.2, 10.4
Responsible Medical Officer 
(carries overall responsibility for the conduct of the study)
Property of Takeda: For non-commercial use only
o the applicable Terms of Use
, as is
as is
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1.2
Approval 
REPRESENTATIVES OF TAKEDA 
This study will be conducted with the highest respect for the individual participants in accordance 
with the requirements of this clinical study protocol and also in accordance with the following:
!
The ethical principles that have their origin in the Declaration of Helsinki.
!
International Conference on Harmonisation E6 Good Clinical Practice: Consolidated 
Guideline.
!
All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations.
SIGNATURES
The signature of the responsible Takeda medical officer (and other signatories, as applicable) can 
be found on the signature page.
Electronic Signatures may be found on the last page of this document.
Property of Takeda: For no
d subject to the applicable Terms of Use
ordance
ordance
owing:
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solidate
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1.3
Protocol Amendment 02 Summary of Changes
This section describes the changes in reference to the Protocol Incorporating Amendment 02.
Minor grammatical and editorial changes are included for clarification purposes only. Full details 
on changes of text are given in Appendix J. The following is a summary of the major changes 
made in the amendment:
Changes in Amendment 02
1. The IND number, amendment history, and summary of changes were added to the protocol.
2. The names of the sponsor’s signatories were updated.
3. National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 
version was updated from version 4.03 to version 5.0.
4. Definitions of childbearing potential and highly effective contraception methods for female 
patients of childbearing potential were added to the protocol.
5. Definitions of highly effective contraception methods for male patients who are sexually 
active with partners of childbearing potential were added to the protocol.
6. A new inclusion criterion was added and the precautions and restrictions section was revised to 
state that male patients should not donate sperm from the time of signing the informed consent 
through 180 days after last dose of study drug.
7. One new exclusion criterion was added to exclude patients with known hypersensitivity 
reactions to the active substance or to any of the excipients of the study drug.
8. Suspected pneumonitis was specifically added to all Grade 3 and Grade 4 nonhematologic 
toxicities.
9. A urine pregnancy test for all women of childbearing potential was added to the end of 
treatment visit.
10. Reasons for discontinuation of treatment with study drug were revised.
11. Reasons for withdrawal of patients from the study were revised.
12. Reasons for early discontinuation of the study by the sponsor were added to the protocol.
13. Human immunodeficiency virus (HIV), hepatitis B, and hepatitis C virus tests were added 
during the Screening period.
14. Fresh tumor biopsy criteria were revised.
15. Optional tumor biopsy criteria were revised.
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INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure and any 
other product information provided by the sponsor. I agree to conduct this study in accordance 
with the requirements of this protocol and also to protect the rights, safety, privacy, and well-being 
of study patients in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.2 of this
protocol.

Terms outlined in the Clinical Study Site Agreement.

Appendix B – Responsibilities of the Investigator.
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix C of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Province)
Location of Facility (Country)
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE.......................................................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 02 Summary of Changes ..........................................................4
2.0
STUDY SUMMARY ....................................................................................................12
3.0
STUDY REFERENCE INFORMATION ......................................................................19
3.1
Study-Related Responsibilities.................................................................................19
3.2
Coordinating Investigator.........................................................................................19
3.3
List of Abbreviations ...............................................................................................20
3.4
Corporate Identification...........................................................................................22
4.0
INTRODUCTION.........................................................................................................23
4.1
Background .............................................................................................................23
4.1.1
Diseases Under Study ........................................................................................23
4.1.2
Study Drug.........................................................................................................24
4.1.3
Nonclinical Experience ......................................................................................24
4.1.4
Clinical Experience............................................................................................25
4.1.5
Risks and Benefits..............................................................................................27
4.2
Rationale for the Proposed Study.............................................................................29
4.2.1
Rationale for Dose and Schedule Selection ........................................................29
4.2.2
Rationale for PK Assessments............................................................................32
4.2.3
Rationale for Biomarker Analysis (Pharmacodynamic Biomarkers and 
Correlative Studies to Identify Predictive Biomarkers).......................................32
4.2.4
Rationale for Pharmacogenomic Assessments....................................................33
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................34
5.1
Objectives................................................................................................................34
5.1.1
Primary Objectives.............................................................................................34
5.1.2
Key Secondary Objective...................................................................................34
5.1.3
Secondary Objectives.........................................................................................34
5.1.4
Additional Objectives.........................................................................................34
5.1.5
Exploratory Objectives.......................................................................................35
5.2
Endpoints.................................................................................................................35
5.2.1
Primary Endpoints .............................................................................................35
5.2.2
Key Secondary Endpoint....................................................................................35
5.2.3
Secondary Endpoints..........................................................................................35
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5.2.4
Additional Endpoints .........................................................................................36
5.2.5
Exploratory Endpoints .......................................................................................36
6.0
STUDY DESIGN..........................................................................................................37
6.1
Overview of Study Design.......................................................................................37
6.2
Number of Patients ..................................................................................................41
6.3
Duration of Study ....................................................................................................42
6.3.1
Duration of an Individual Patient’s Study Participation ......................................42
6.3.2
End of Study/Study Completion Definition and Planned Reporting....................42
6.3.3
Time Frames for Primary and Secondary Endpoints to Support Disclosures.......42
6.3.4
Total Study Duration..........................................................................................43
7.0
STUDY POPULATION................................................................................................44
7.1
Inclusion Criteria .....................................................................................................44
7.2
Exclusion Criteria ....................................................................................................47
8.0
STUDY DRUG .............................................................................................................50
8.1
Study Drug Administration......................................................................................50
8.2
Dose Modification Guidelines..................................................................................50
8.2.1
General Principles..............................................................................................50
8.2.2
Intrapatient Dose Re-escalation..........................................................................52
8.2.3
Criteria for Beginning or Delaying a Subsequent Treatment Cycle.....................52
8.2.4
TAK-659 Dose Modification for Hematologic Toxicities...................................52
8.2.5
TAK-659 Dose Modification for Nonhematologic Toxicities .............................53
8.2.6
Criteria for Dose Escalation During Stage 1 Ramp-up........................................55
8.3
Concomitant Medications and Procedures................................................................55
8.4
Precautions and Restrictions ....................................................................................57
8.5
Management of Clinical Events ...............................................................................58
8.5.1
Prophylaxis Against Infection ............................................................................58
8.5.2
Pneumonitis .......................................................................................................59
8.5.3
Nausea and/or Vomiting.....................................................................................59
8.5.4
Diarrhea.............................................................................................................59
8.5.5
Edema (Including Periorbital) ............................................................................60
8.5.6
Rash With or Without Pruritus ...........................................................................60
8.5.7
Thrombocytopenia .............................................................................................60
8.5.8
Neutropenia .......................................................................................................60
8.5.9
Anemia ..............................................................................................................60
8.5.10 Hypophosphatemia ............................................................................................61
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8.5.11 Enzyme Elevations.............................................................................................61
8.6
Blinding and Unblinding..........................................................................................61
8.7
Description of Investigational Agents ......................................................................61
8.8
Preparation, Reconstitution, and Dispensation..........................................................61
8.9
Packaging and Labeling...........................................................................................61
8.10
Storage, Handling, and Accountability.....................................................................62
9.0
STUDY CONDUCT......................................................................................................63
9.1
Study Personnel and Organizations..........................................................................63
9.2
Arrangements for Recruitment of Patients................................................................63
9.3
Treatment Group Assignments.................................................................................63
9.4
Study Procedures.....................................................................................................63
9.4.1
Informed Consent...............................................................................................64
9.4.2
Patient Demographics ........................................................................................64
9.4.3
Medical History .................................................................................................64
9.4.4
Physical Examination.........................................................................................64
9.4.5
Patient Height and Weight .................................................................................64
9.4.6
ECOG Performance Status.................................................................................64
9.4.7
Vital Signs .........................................................................................................64
9.4.8
Pregnancy Test...................................................................................................64
9.4.9
Concomitant Medications and Procedures..........................................................65
9.4.10 Adverse Events ..................................................................................................65
9.4.11 Enrollment .........................................................................................................65
9.4.12 Electrocardiogram..............................................................................................65
9.4.13 Clinical Laboratory Evaluations .........................................................................66
9.4.14 Ophthalmic Exam ..............................................................................................67
9.4.15 Disease Assessment ...........................................................................................67
9.4.16 Tumor Biopsies..................................................................................................69
9.4.17 Analysis of ctDNA.............................................................................................70
9.4.18 Analysis of Cytokines/Chemokines....................................................................71
9.4.19 Analysis of Immune Cells in Peripheral Blood...................................................71
9.4.20 PK Measurements..............................................................................................71
9.4.21 DNA Measurements...........................................................................................72
9.4.22 CMV Testing .....................................................................................................72
9.5
Completion of Study Treatment (for Individual Patients) .........................................73
9.6
Completion of Study (for Individual Patients)..........................................................73
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9.7
Discontinuation of Treatment With Study Drug .......................................................73
9.8
Withdrawal of Patients From Study .........................................................................74
9.9
Early Discontinuation of the Study...........................................................................74
9.10
Study Compliance....................................................................................................74
9.11
Posttreatment Follow-up Assessments (PFS and OS)...............................................75
10.0
ADVERSE EVENTS ....................................................................................................76
10.1
Definitions...............................................................................................................76
10.1.1 PTE Definition...................................................................................................76
10.1.2 AE Definition ....................................................................................................76
10.1.3 SAE Definition ..................................................................................................76
10.2
Procedures for Recording and Reporting AEs and SAEs..........................................77
10.3
Monitoring of AEs and Period of Observation .........................................................78
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events.........79
10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose) ................................................................................................................79
10.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities...........79
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................81
11.1
IRC..........................................................................................................................81
11.2
Steering Committee .................................................................................................81
11.3
Independent Data Monitoring Committee ................................................................81
12.0
DATA HANDLING AND RECORDKEEPING............................................................82
12.1
eCRFs......................................................................................................................82
12.2
Record Retention .....................................................................................................82
13.0
STATISTICAL METHODS..........................................................................................84
13.1
Statistical and Analytical Plans ................................................................................84
13.1.1 Analysis Populations..........................................................................................84
13.1.2 Analysis of Demographics and Other Baseline Characteristics ...........................84
13.1.3 Efficacy Analysis...............................................................................................84
13.1.4 PK Analysis .......................................................................................................86
13.1.5 Biomarker Analyses...........................................................................................86
13.1.6 Pharmacogenomic Analyses...............................................................................87
13.1.7 Safety Analysis ..................................................................................................87
13.1.8 Dose Exploration Analysis.................................................................................88
13.2
Interim Analysis and Criteria for Early Termination ................................................88
13.3
Determination of Sample Size..................................................................................89
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................90
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14.1
Study-Site Monitoring Visits ...................................................................................90
14.2
Protocol Deviations..................................................................................................90
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................90
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................91
15.1
IRB and/or IEC Approval ........................................................................................91
15.2
Patient Information, Informed Consent, and Patient Authorization...........................92
15.3
Patient Confidentiality .............................................................................................92
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................93
15.4.1 Publication.........................................................................................................93
15.4.2 Clinical Trial Registration..................................................................................93
15.4.3 Clinical Trial Results Disclosure ........................................................................94
15.5
Insurance and Compensation for Injury....................................................................94
16.0
REFERENCES..............................................................................................................95
LIST OF IN-TEXT TABLES
Table 6.a
Primary and Secondary Endpoints for Disclosures .............................................43
Table 8.a
Dose Reduction Levels for TAK-659 .................................................................51
Table 8.b
TAK-659 Dose Adjustments for Hematologic Toxicities....................................53
Table 8.c
TAK-659 Dose Adjustments for Nonhematologic Toxicities..............................54
Table 9.a
Clinical Chemistry and Hematology Tests..........................................................66
Table 9.b
Clinical Urinalysis Tests ....................................................................................67
LIST OF IN-TEXT FIGURES
Figure 4.a
Relationship between TAK-659 exposure (AUC) and Grade ≥3 Adverse 
Event in DLBCL Patients (N=37) ......................................................................32
Figure 6.a
Stage 1 Study Schema........................................................................................38
Figure 6.b
Stage 2 Study Schema........................................................................................39
LIST OF APPENDICES
Appendix A
Schedule of Events.............................................................................................97
Appendix B
Responsibilities of the Investigator...................................................................103
Appendix C
Investigator Consent to Use of Personal Information........................................105
Appendix D
IWG Response Criteria for Lymphoma ............................................................106
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Appendix E
ECOG Scale for Performance Status ................................................................107
Appendix F
Cockcroft-Gault Equation ................................................................................108
Appendix G
Methods of Contraception Considered to be Effective......................................109
Appendix H
New York Heart Association Classification of Cardiac Disease........................110
Appendix I
Medications, Supplements, and Food Products that are Strong CYP3A and/or 
P-gp Inhibitors or Inducers...............................................................................111
Appendix J
Detailed Description of Amendments to Text...................................................112
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2.0
STUDY SUMMARY
Name of Sponsor(s):
Millennium Pharmaceuticals, Inc.
Compound:
TAK-659
Title of Protocol: Phase 2 Study of TAK-659 in Patients 
With Relapsed or Refractory Diffuse Large B-Cell 
Lymphoma After at Least 2 Prior Lines of Chemotherapy
IND No.: 119,231
EudraCT No.:
2016-003716-12
Study Number: C34004
Phase: 2
Study Design:
This is an open-label, multicenter, phase 2 study to evaluate the efficacy and safety of TAK-659 as a single agent in 
patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after at least 2 prior lines of 
chemotherapy. Eligible patients will also be ineligible for autologous stem cell transplant (ASCT) or be patients for 
whom ASCT has failed.
This study will start with a lead-in dose exploration phase (Stage 1) during which two TAK-659 dose regimens will be 
evaluated in two patient cohorts (Cohorts A and B). Patients in Cohort A will receive a daily dose of 100 mg TAK-659 
continuously throughout the study. In Cohort B, patients will follow a ramp-up dosing schema leading to a full dose of 
100 mg QD TAK-659. Patients will initially receive 60 mg QD TAK-659 for one cycle of 28 days, and if tolerated 
well, will then receive 80 mg QD TAK-659 for the next cycle, and subsequently 100 mg QD TAK-659 in the 3rd cycle 
and beyond. At the end of each cycle during the ramp-up, patients will be assessed for their suitability to dose-escalate 
to the next level based on safety and tolerability. 
If the patient experiences any drug-related adverse events that require dose modification (inclusive of dose held and 
dose reduction) per protocol in a given dose cycle, dose escalation will not proceed to the next level. If the AE(s) 
resolves, the patient may then restart dose escalation in the next cycle either at the same dose or a reduced dose 
according to the protocol-defined dose reduction criteria. In case dose reduction is not required, when the patient 
resumes the study drug at the same dose, dose escalation to the next dose level and further to the full dose of 100 mg 
QD TAK-659 may be pursued if no recurrence of the same AE(s) or any other AEs leading to dose modification is 
observed in the next cycle of treatment. However, if the same AE(s) or different AE(s) requiring dose modification 
occur in two consecutive cycles at the same dose level, further dose escalation is not allowed. If the patient resumes the 
study drug at a reduced dose per protocol, no dose re-escalation is recommended. Approximately 20 patients are 
expected to be enrolled into each cohort, with a total of ~40 patients planned for Stage 1. 
Upon completion of Stage 1, the dose exploration analysis will occur. Based on the posterior probability of response 
comparison between the 2 cohorts, one TAK-659 dose regimen will be selected to proceed to Stage 2. During this 
analysis, if both Stage 1 regimens are determined to be ineffective, termination of the study without proceeding to 
Stage 2 may be considered. However, other considerations should be taken into account when making this 
development decision including, but not limited to, sample size, relevant data from other TAK-659 trials, and 
applicable patient enrichment or selection strategy that justifies further evaluation of TAK-659 in this setting.
During the Stage 2 efficacy evaluation phase, it is expected that approximately 82 patients will be enrolled. Once 
enrolled, patients will be administered TAK-659 orally in 28-day treatment cycles according to the selected dose 
regimen of TAK-659 from Stage 1. After approximately 40 patients have been enrolled in Stage 2 and have had the 
opportunity to receive at least 3 cycles of study treatment and have at least 1 posttreatment response evaluation, an 
interim analysis will be performed to assess futility. The study may either stop for futility or continue as planned. 
Patients on TAK-659, including those who achieve a complete response (CR), may receive study drug until they 
experience disease progression or unacceptable toxicities. Patients will be followed for progression-free survival 
(PFS) (applies only for patients who discontinue study for reasons other than disease progression) and overall survival 
(OS) after the last dose of study drug. 
Sparse pharmacokinetic (PK) samples to support population PK and exposure–response analyses will be collected 
from all patients, along with blood and tumor tissue samples for biomarker analysis.
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The objectives are to evaluate the efficacy of TAK-659 as measured by overall response rate (ORR) and other efficacy 
variables, including CR rate, ORR at cycles 3, 6 and 9, duration of response (DOR), PFS, and OS, and to determine the 
safety and tolerability of TAK-659. Disease assessments will be performed by central review of radiology by an 
independent radiologic review committee (IRC) according to the modified 2007 and 2014 (Lugano) International 
Working Group (IWG) criteria. ORR by IRC per the 2007 IWG criteria will be used as the primary endpoint for the 
study.
Primary Objective:
The primary objective is to assess the efficacy of TAK-659 as measured by IRC-assessed ORR in patients with 
DLBCL (Stage 2).
Key Secondary Objective:
The key secondary objective is to assess CR rate per IRC in patients with DLBCL (Stage 2).
Secondary Objectives:
!
To select the Stage 2 dose regimen of TAK-659 from the lead-in dose exploration phase (Stage 1) and assess 
efficacy using ORR per IRC (Stage 2). 
!
To assess ORR per IRC at 3, 6, and 9 cycles in patients with DLBCL (Stage 2).
!
To assess DOR and duration of CR per IRC in patients with DLBCL (Stage 2).
!
To assess ORR per IRC in the subgroup of patients with germinal center B-cell (GCB) DLBCL (Stage 2).
!
To assess ORR per IRC in the subgroup of patients with DLBCL transformed from indolent non-Hodgkin 
lymphoma (NHL) (Stage 2).
!
To assess PFS per IRC in patients with DLBCL (Stage 2).
!
To assess OS in patients with DLBCL (Stage 2).
Additional Objectives:
!
To assess the safety and tolerability of TAK-659 in the patient population under study (Stages 1 and 2).
!
To assess the number of responding patients proceeding to ASCT or allogeneic stem cell transplant (Stage 2).
!
To collect TAK-659 plasma concentration–time data to contribute to population PK and exposure–response 
analyses (Stages 1 and 2).
Exploratory Objectives:
Patient Population: Male or female patients aged 18 years or older with histologically confirmed DLBCL, including 
de novo disease or transformed disease from indolent NHL. Patients must also be relapsed or refractory to ≥2 prior 
lines of chemotherapy based on standard of care and may not have failed more than 4 prior lines of therapy. Patients 
must have either failed or not be eligible for ASCT. Patients must have [18F]fluorodeoxyglucose-positron emission 
tomography (FDG-PET)–avid disease measurable by computed tomography (CT)/magnetic resonance imaging 
(MRI), and Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.
Number of Patients:
Approximately 122 patients will be enrolled in the study, 
including 40 patients (20 per dose schedule) in the lead-in 
dose exploration phase (Stage 1) and 82 patients in the 
efficacy evaluation phase (Stage 2).
Number of Sites: 
Approximately 50 sites in North America and Europe
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Dose Levels:
TAK-659: 100 mg QD or a 3-dose-level ramp-up schema 
leading to 100 mg QD (60, 80, 100 mg QD) in 28-day 
treatment cycles.
Route of Administration:
TAK-659: oral
Duration of Treatment:
Treatment will continue until disease progression, 
unacceptable toxicities, or withdrawal for other reasons. 
The estimated median treatment duration is 6 months.
Period of Evaluation:
PFS follow-up: every 3 months after the last dose of 
study drug until progression, the start of alternative 
therapy, or conclusion of the study, whichever occurs 
first (for patients who discontinue for reasons other 
than disease progression). 
OS follow-up: every 3 months after the last dose of 
study drug until death or conclusion of the study, 
whichever occurs first. 
Main Criteria for Inclusion:
1.
Male or female patients aged 18 years or older.
2.
Patients must have histologically confirmed DLBCL, including de novo disease or transformed disease from 
indolent NHL.
a.
Patients with transformed DLBCL must meet 2016 World Health Organization (WHO) criteria for 
DLBCL on last biopsy before study entry and have ≥1 prior histological diagnosis of follicular 
lymphoma (FL) or other indolent disease.
b.
To be enrolled in the study, patients must have a 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 activated B-cell/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, based on the 2008 WHO classification criteria) is not eligible for 
this study. 
ii.
T-cell/histiocyte-rich large B-cell lymphoma.
iii.
DLBCL associated with chronic inflammation.
iv.
Epstein-Barr virus (EBV)+DLBCL, NOS (EBV+DLBCL of the elderly based on the 2008 WHO 
classification criteria for lymphoma).
v.
FL Grade 3B.
c.
Local pathology review for histological confirmation:
i.
A formalin-fixed, paraffin-embedded 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.
3.
Relapsed or refractory to ≥2 prior lines of chemotherapy based on standard of care that include at least:
a.
The standard first-line chemotherapy regimen containing rituximab and an anthracycline (eg, R-CHOP
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[cyclophosphamide+doxorubicin (hydroxydaunomycin)+vincristine (Oncovin)+prednisone with 
rituximab]) or equivalent if anthracycline is contraindicated; included are DLBCL patients transformed 
from indolent lymphoma who may have already received R-CHOP or equivalent as part of their indolent 
lymphoma treatment. Therefore, alternative frontline therapy other than R-CHOP or equivalent used for 
DLBCL post-transformation may be acceptable upon discussions with the sponsor.
and 
b.
One additional systemic chemotherapy as a second-line salvage therapy that may have included ASCT.
i.
Included are ASCT-eligible patients who failed ASCT following response to a standard salvage 
regimen, or who did not respond to salvage therapy and were therefore not indicated for ASCT, or 
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 or relapsed after a second-line 
systemic chemotherapy regimen.
iii.
Also included are patients not indicated for systemic chemotherapy regimens who were refractory 
to or relapsed after an alternative second-line salvage therapy.
4.
Patients should not have failed more than 4 prior lines of therapy.
a.
Pre-induction salvage chemotherapy and ASCT should be considered 1 therapy.
b.
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.
c.
Antibody therapy given as a single agent should be considered 1 therapy.
d.
Prior treatment with single-agent B-cell receptor in-pathway inhibitors such as ibrutinib and idelalisib is 
permitted and will not count as a prior line of therapy.
e.
For patients with DLBCL transformed from indolent lymphoma, any treatment received for the indolent 
disease prior to the transformation to DLBCL will, in general, not count towards the 2 to 4 prior lines of 
therapy required for DLBCL in this study.
5.
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.
6.
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 nodal mass, or ≥1.0 cm in the longest diameter for extranodal disease) as 
assessed on cross-sectional imaging by CT/MRI (CT is to be performed with contrast unless contrast is 
medically contraindicated). 
7.
ECOG performance status score of 0 or 1. 
8.
Life expectancy of >3 months.
9.
Patients must have adequate organ function, including the following:
a.
Bone marrow reserve: absolute neutrophil count 1000/L, platelet count 75,000/L (50,000/L for 
patients with bone marrow involvement), and hemoglobin ≥8 g/dL (red blood cell and platelet 
transfusions allowed ≥14 days before assessment). 
b.
Hepatic: total bilirubin ≤1.5 times the upper limit of the normal range (ULN); alanine aminotransferase 
and aspartate aminotransferase ≤2.5ULN.
c.
Renal: creatinine clearance ≥60 mL/min either as estimated by the Cockcroft-Gault equation or based 
on urine collection (12 or 24 hours).
d.
Other:
i.
Lipase ≤1.5ULN and amylase ≤1.5ULN with no clinical symptoms suggestive of pancreatitis or 
cholecystitis.
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ii.
Blood pressure Grade ≤1 (hypertensive patients are permitted if their blood pressure is controlled to 
Grade ≤1 by hypertensive medications).
iii. Glycosylated hemoglobin is ≤6.5% (hyperglycemic patients permitted if glucose is well controlled 
by hypoglycemic medication).
Main Criteria for Exclusion:
1.
Central nervous system 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–related malignancy.
3.
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 agents; ≤8 weeks for cell-based therapy or anti-tumor vaccine). 
4.
Radiotherapy less than 3 weeks before the first dose of study treatment. If prior radiotherapy occurred <4 to 
6 weeks before study start, as radiated lesions cannot be reliably assessed by FDG-PET, nonradiated target 
lesions are required for eligibility, and prior radiotherapy information must be submitted to the IRC.
5.
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 any time.
6.
Use or consumption of any of the following substances:
a)
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, use of these agents is not permitted during the study except when an 
adverse event (AE) must be managed. 
b)
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, use of these agents is not permitted 
during the study except when an AE must be managed. 
c)
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.
Main Criteria for Evaluation and Analyses:

Primary: ORR as assessed by IRC according to modified 2007 IWG criteria for malignant lymphoma.

Key secondary: CR rate as assessed by IRC according to the modified 2007 IWG criteria.

Secondary:

ORR per IRC according to the 2014 IWG (Lugano) criteria (Stage 2).

CR rate per IRC according to the 2014 IWG (Lugano) criteria (Stage 2).

ORR per IRC to select the Stage 2 dose regimen of TAK-659 from the lead-in dose exploration phase 
(Stage 1).

ORR per IRC at 3, 6, and 9 cycles, respectively (Stage 2). 

DOR and duration of CR per IRC (Stage 2).

ORR per IRC in patients with GCB DLBCL (Stage 2).

ORR per IRC in patients with DLBCL transformed from indolent NHL (Stage 2).

PFS per IRC (Stage 2).

OS (Stage 2).

The IRC will evaluate the assessments above using both the modified 2007 IWG criteria for malignant lymphoma 
and the 2014 IWG (Lugano) criteria. Unless otherwise specified, evaluations using the 2007 IWG criteria will be 
the primary analyses, and evaluations using the 2014 IWG (Lugano) criteria will be the sensitivity analyses.
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!
Additional:
!
Percentage of patients who experience AEs, Grade #3 AEs, serious AEs, discontinuations for AEs, and 
clinical laboratory values and vital sign measurements outside the normal range (Stages 1 and 2).
!
Percentage of patients proceeding to ASCT or allogeneic stem cell transplant out of all patients who achieve 
a best response of PR or CR on study (Stage 2).
!
TAK-659 plasma concentration–time data (Stages 1 and 2).
!
Exploratory:
Statistical Considerations:
For the lead-in dose exploration phase (Stage 1) of the study, assuming a historical control rate of 20% for ORR, at 
least 20 patients per dosing regimen are required to determine the dosing regimen for the phase 2 efficacy evaluation 
phase (Stage 2) of the study. Data from both dosing regimens will be analyzed with a Bayesian model assuming prior 
of Beta(1,1) for each ORR. The dose exploration analysis will occur upon completion of Stage 1 Dosing regimen A 
will be claimed ineffective if the posterior probability of ORRA <20% is greater than the threshold of 0.75, likewise for
dosing regimen B. If both regimens are deemed to be ineffective, termination of the study without proceeding to stage 
2 may be considered. Other considerations for making this decision will be taken into account including, but not 
limited to, sample size limitation, relevant data from other TAK-659 trials, and applicable patient enrichment or 
selection strategy that justifies further evaluation of TAK-659 in this setting. 
If only one dosing regimen is deemed to be ineffective, then the other dosing regimen will be chosen as the dosing 
regimen for the remaining phase of the study. If neither dosing regimen is claimed to be ineffective, then regimen A 
will be chosen if the posterior probability of ORRA>ORRB is greater than the threshold of 0.55, likewise dosing 
regimen B will be chosen if the posterior probability of ORRB>ORRA is greater than 0.55; if both the posterior 
probability of ORRA>ORRB and the posterior probability of ORRB>ORRA are ≤0.55, clinical and safety factors will be 
considered to choose the dosing regimen for Stage 2. 
Consideration of an alternative dose regimen other than the two TAK-659 dose regimens evaluated in Stage 1 is 
permissible if supported by the Stage 1 data. For example, if the ramp-up dose schema (dose regimen B) is chosen 
based on the Bayesian model (see above) but majority of patients treated with dose regimen B fail to dose escalate 
beyond 60 mg QD TAK-659 following the dose escalation criteria, 60 mg QD TAK-659 may be considered as the 
dose for Stage 2. The Stage 1 data, as well as other relevant supportive data from other trials of TAK-659, will be 
reviewed and discussed by the Study Steering Committee (SSC). The Stage 2 dose regimen of TAK-659 will be 
selected based on the recommendation by SSC upon agreement with the sponsor.
For Stage 2, assuming a historical control rate of 20% for ORR and a TAK-659 ORR of 37%, 82 patients are required 
to detect the improvement in ORR with approximately 91% power using a 1-sided exact binomial test at a significance 
level of 0.025. After approximately 40 patients have been enrolled in Stage 2 and have had the opportunity to receive 
at least 3 cycles of treatment and have at least 1 posttreatment response evaluated, an interim analysis will be 
performed. The interim analysis will assess futility, and the study may either stop for futility (if posterior probability of 
ORR <20% is greater than the threshold of 0.75) or continue as planned. 
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Protocol Incorporating Amendment No. 02
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Sample Size Justification: For the lead-in dose exploration phase (Stage 1), assuming a historical control rate of 20% 
for ORR, at least 20 patients per dosing regimen are required to determine if either dosing regimen A or dosing 
regimen B is more effective than the other given a futility threshold of 0.75 and a superiority threshold of 0.55. 
For the phase 2 efficacy evaluation phase (Stage 2) of the study, assuming a historical control rate of 20% for ORR and 
a TAK-659 ORR of 37%, this study will need to enroll at least 82 patients to achieve 91% power at a 1-sided alpha 
level of 0.025, using an exact binomial test in ORR with approximately 91% power using a 1-sided exact binomial test 
at a significance level of 0.025.
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3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities
The sponsor will perform all study-related activities with the exception of those identified in the 
Clinical Study Supplier List. The identified vendors for specific study-related activities will 
perform these activities in full or in partnership with the sponsor.
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 and the study medication, expertise in the therapeutic area and the conduct of clinical 
research, and study participation. The signatory coordinating investigator will be required to 
review and sign the clinical study report and, by doing so, agrees that it accurately describes the 
results of the study. 
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3.3
List of Abbreviations
ABC
activated B-cell
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASCO
American Society of Clinical Oncology
ASCT
autologous stem cell transplant
ASH
American Society of Hematology
AST
aspartate aminotransferase
AUCτ/dose
dose-normalized area under the plasma concentration–time curve during the dosing 
interval 
BCR
B-cell receptor
BCRP
breast cancer resistance protein
BfArM
Bundesinstitut für Arzneimittel und Medizinprodukte
CFR
Code of Federal Regulations
CK
creatine kinase
CLL
chronic lymphocytic leukemia
Cmax
maximum observed concentration
CMV
cytomegalovirus
CNS
central nervous system
CPK
creatine phosphokinase
CR
complete response 
CRO
contract research organization
CSR
clinical study report
CT
computed tomography
ctDNA
circulating tumor DNA
CYP
cytochrome P450
DDI
drug-drug interaction
DLBCL
diffuse large B-cell lymphoma
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-PET
[18F]fluorodeoxyglucose-positron emission tomography
FFPE
formalin-fixed, paraffin-embedded
FIH
first-in-human
FL
follicular lymphoma
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GCB
germinal center B-cell
GCP
Good Clinical Practice
G-CSF
granulocyte colony stimulating factor
GI
gastrointestinal
GM-CSF
granulocyte macrophage-colony stimulating factor
HbAc1
glycosylated hemoglobin
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
IC50
concentration producing 50% inhibition
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IHC
immunohistochemical; immunohistochemistry 
IRB
institutional review board
IRC
independent radiologic review committee
ITAM
immunoreceptor tyrosine-based activating motifs
IV
intravenous; intravenously
IWG
International Working Group
LDH
lactate dehydrogenase
MCL
mantle cell lymphoma
MedDRA
Medical Dictionary for Regulatory Activities
mITT
modified intent-to-treat
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NHL
non-Hodgkin lymphoma
NK
natural killer
NOS
not otherwise specified
ORR
overall response rate
OS
overall survival
PCR
polymerase chain reaction
PD
progressive disease (disease progression)
PET
positron emission tomography
PFS
progression-free survival
P-gp
P-glycoprotein
PJP
Pneumocystis jiroveci pneumonia 
PK
pharmacokinetic(s)
PLT
platelets
PO
per os; by mouth (orally) 
PR
partial response 
PTE
pretreatment events
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QD
once daily
QTc
rate-corrected QT interval (msec) of electrocardiograph
QTcB
Bazett’s corrected QT interval
QTcF
Fridericia’s corrected QT interval
RBC
red blood cell
R-CHOP
cyclophosphamide+doxorubicin (hydroxydaunomycin)+vincristine 
(Oncovin)+prednisone with rituximab
RP2D
recommended phase 2 dose
SAE
serious adverse event
SAP
statistical analysis plan
SSC
study steering committee
SUSAR
suspected unexpected serious adverse reaction
SYK
spleen tyrosine kinase
TEAE
treatment-emergent adverse events
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
Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma 
(NHL), representing about 30% of all NHL. It is estimated that approximately 66,000 new cases of 
NHL, including 20,000 new cases of DLBCL, are diagnosed annually in the United States (US) [1]. 
DLBCL is a form of aggressive B-cell NHL that is invariably fatal without treatment. 
The immunochemotherapy regimen R-CHOP (cyclophosphamide + doxorubicin 
[hydroxydaunomycin] + vincristine [Oncovin] + prednisone with rituximab) is the standard 
treatment for patients newly diagnosed with DLBCL. This regimen results in complete remission 
in approximately 60% to 75% of patients with frontline DLBCL [2,3]. It is considered curative in a 
subset of patients, with both a reported 5-year progression-free survival [4,5] and an overall 
survival (OS) of approximately 50%. However, DLBCL is highly heterogeneous in histology, 
clinical behavior, and underlying biology, and therefore exhibits significant variation in outcome 
after therapy.
High-dose chemotherapy, including salvage regimens such as R-ICE (rituximab, ifosfamide, 
carboplatin, etoposide), and autologous stem cell transplant (ASCT) are 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 such patients. 
Clinically meaningful benefit is rarely achieved, however, in patients with progressive disease 
(PD) following multiple regimens.
The classification of DLBCL continues to evolve on the basis of emerging clinical, pathologic, 
molecular, and genetic data. The World Health Organization (WHO) 2016 classification of 
lymphoid neoplasms [6] recognizes a number of DLBCL subtypes based upon their distinct 
clinical-pathologic characteristics and their molecular cell of origin classification.
Distinct subtypes of DLBCL recognized under the WHO classification are considered separate 
entities and include T-cell/histiocyte-rich large B-cell lymphoma, primary DLBCL of the central 
nervous system (CNS), primary cutaneous DLBCL, leg type, and Epstein-Barr virus 
(EBV)-positive DLBCL of the elderly. However, the overwhelming majority of cases are 
classified as DLBCL, not otherwise specified (NOS). 
By definition, DLBCL, NOS, is dominated by large atypical cells with vesicular chromatin, 
discernible nucleoli, and identifiable mitoses [7]. Although partial involvement of nodes can occur 
and create diagnostic difficulty, the majority of cases demonstrate a diffuse growth pattern. The 
majority of DLBCL, NOS, can be divided into centroblastic, immunoblastic, and anaplastic 
variants and (most recently) plasmablastic subtypes primarily on the basis of morphology [7,8]. 
The morphological distinction between centroblastic and immunoblastic variants is particularly 
prone to poor interobserver concordance [9], and such subdivision appears to have little prognostic 
significance [7]; therefore, morphological subclassification of DLBCL is neither emphasized in 
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the WHO classification nor considered mandatory by most practicing pathologists. In contrast to 
the limited utility of morphological classification of DLBCL, NOS, immunohistochemical (IHC) 
classification is considered part of routine care. 
The molecular pathogenesis of DLBCL is a complex, multistep process that ultimately results in 
the transformation and expansion of a malignant clone of germinal or postgerminal B-cell origin. 
The WHO classification of lymphoid neoplasms describes use of gene expression profiling or IHC 
to subclassify DLBCL, NOS, into tumors of germinal center B-cell (GCB)-like and nongerminal 
center (eg, activated B-cell [ABC]-like and primary mediastinal B-cell lymphoma) origin and 
indicates that these 2 classes of tumor have different prognoses with current therapies [6]. The 
non-GCB and GCB subtypes occur with approximately equal frequencies [2,10]. GCB DLBCL 
tumors express many genes found in normal GCBs, while gene expression in ABC DLBCL 
resembles that of antigen-ABCs. In particular, ABC DLBCL expresses many targets of NF-κB 
signaling [11]. ABC DLBCL has an inferior clinical outcome compared with GCB DLBCL, with 
an OS of approximately 40% [12].
There are other classification systems [13] that have a molecular basis, including one proposed by 
Monti et al [14]. In that categorization system, gene-set enrichment analysis of a large series of 
DLBCL tumors revealed an increased abundance of specific genes within each of 3 subtypes: 
oxidative phosphorylation, B-cell receptor (BCR)/proliferation, or host response. The BCR / 
proliferation subtype has abundant expression of cell-cycle regulatory genes, DNA repair genes, 
and higher levels of many components of the BCR signaling cascade, including spleen tyrosine 
kinase (SYK). It is expected that SYK inhibition can target the BCR/proliferation subtype of 
DLBCL and that a portion of patients in each WHO classification subtype will have tumors that 
are related to the activation of this pathway.
4.1.2
Study Drug
TAK-659 is a potent and reversible inhibitor of SYK being developed for oncology indications, 
the pathogenesis of which are either driven by, or significantly contributed to by, SYK-mediated 
signaling. 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 (Section 4.1.3). 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
TAK-659 is an orally (PO) bioavailable, potent and reversible inhibitor of SYK and FLT3. SYK is 
a nonreceptor tyrosine kinase with SH2-binding domains that bind to phosphorylated 
immunoreceptor tyrosine activation-motifs (ITAMs) located on B and T cells and certain natural 
killer (NK) cells. SYK becomes activated upon ITAM binding and subsequently controls the 
activity of downstream signaling cascades that promote cell survival, growth, and proliferation, 
transcriptional activation, and cytokine release in these cell types. SYK is expressed ubiquitously 
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in hematopoietic cells, and abnormal function of SYK has been implicated in NHL, including 
follicular lymphoma (FL), DLBCL, and mantle cell lymphoma (MCL). TAK-659 inhibits 
SYK-purified enzyme with an IC50 of 3.2 nM and a concentration producing half-maximal 
response ranging from 25 to 400 nM in sensitive cell systems. Nonclinically, TAK-659 has 
exhibited significant antitumor activity in a number of mouse DLBCL xenograft models, including 
the OCI-Ly10 model, an ABC-like-DLBCL model; the OCI-Ly19 model, a GCB-DLBCL model; 
the PHTX-95L model, a primary human DLBCL model; the TMD8 ABC-DLBCL model; the RL 
FL model; and the MINO MCL model.
4.1.4
Clinical Experience
As of 05 September 2017, 181 patients have been dosed with TAK-659 in 4 ongoing studies, 
including 121 patients in the first-in-human (FIH) Study C34001 (advanced solid tumors and 
lymphoma), 32 patients in Study C34002 (R/R AML), 19 patients in Study C34003 (advanced 
solid tumor), and 9 patients in Study C34005 (advanced NHL). Both the C34001 and C34002 
studies are evaluating TAK-659 as a single agent, while the C34003 and C34005 studies are 
evaluating TAK-659 in combination with nivolumab (C34003) and 5 additional combination 
agents (C34005). Different data cutoff dates were used to provide the most current clinical 
information, given that the ongoing studies are in various stages of conduct. The most current 
safety and efficacy data for Study C34001 are from the 02 June 2017 data cutoff date. The most 
current safety and efficacy data for Study C34002 are from the 24 May 2017 data cutoff date. In 
Study C34003, the TAK-659 dose has been evaluated across 3 dose levels of 60 mg, 80 mg, and 
100 mg and the maximum tolerated dose (MTD) determination is pending. In Study C34005, 
TAK-659 is currently being evaluated at 60mg with plans to escalate to 100 mg.
4.1.4.1
Ongoing Studies With TAK-659
As of 05 September 2017, 181 patients have been dosed with TAK-659 in 4 ongoing studies, 
including 121 patients in the first-in-human (FIH) Study C34001, 32 patients in Study C34002, 
19 patients in Study C34003, and 9 patients in Study C34005.
Study C34001: As of 02 June 2017, the TAK-659 dose was escalated from 60 mg to 120 mg 
(60 mg [10 patients], 80 mg [4 patients], 100 mg [90 patients], and 120 mg [7 patients]). The MTD 
for patients with lymphoma and solid tumors has been determined to be 100 mg once daily (QD). 
Expansion cohorts for patients with lymphoma were opened in December 2015, and patients in the 
expansion phase of the study are treated at the MTD/recommended phase 2 dose (RP2D) of 
100 mg. Of the 111 patients treated in this study (92 patients with lymphoma, including 5 patients 
with chronic lymphocytic leukemia [CLL] and 19 patients with solid tumors), 96 patients had 
discontinued from study by the June 2017 data cutoff date. The reasons for discontinuation 
included PD (45 patients), adverse events (AEs) (29 patients), symptomatic deterioration 
(13 patients), initiation of hematopoietic stem cell transplant (2 patients), protocol violation 
(1 patient), withdrawal by subject (1 patient), and other (5 patients).
Study C34002: As of 24 May 2017, 31 patients had enrolled. TAK-659 has been escalated from 
60 mg QD to 160 mg QD, and an additional dose level of 80 mg BID is also being evaluated. The 
MTD/RP2D has not yet been determined. Of the 31 patients treated in this study, 28 patients had 
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discontinued from the study as of the May 2017 data cutoff date. The reasons for discontinuation 
included PD (5 patients), AEs (18 patients), symptomatic deterioration (2 patients), withdrawal by 
subject (1 patient), and other (2 patients).
The reported AEs were generally as expected on the basis of nonclinical toxicology findings of 
TAK-659 and the patient population being studied. As of 02 June 2017, the most common 
treatment-related AEs reported in Study C34001 (20% of patients) have been aspartate 
aminotransferase (AST) increased (49 patients [44%]), amylase increased (39 patients [35%]),
lipase increased (31 patients [28%]), alanine aminotransferase (ALT) increased and diarrhea 
(28 patients each [25%]), blood creatinine phosphokinase (CPK) increased and hypophosphatemia 
(26 patients each [23%]), and fatigue (22 patients [20%]). 
The most common Grade 3 or greater treatment-related AEs (5% of patients) have been amylase 
increased (23 patients [21%]), hypophosphatemia (18 patients [16%]), lipase increased
(15 patients [14%]), neutropenia (14 patients [13%]), CPK increased (13 patients [12%]), anemia
and AST increased (7 patients each [6%]), and pneumonia (5 patients [5%]). Further investigations 
are required to determine the clinical significance of the laboratory abnormalities, many of which 
have been asymptomatic, such as amylase and lipase increased, AST and ALT increased, and 
blood CPK increased. In Study C34001, as of 02 June 2017, there were 35 on-study deaths. Three 
of the AEs that led to death were considered treatment related (multi-organ failure following sepsis, 
disseminated varicella, and respiratory failure in the presence of Pneumocystis jiroveci pneumonia 
[PJP]; cytomegalovirus [CMV] and aspergillus infection; and right pneumothorax and renal 
failure).
In Study C34001, as of 02 June 2017, 9 of 48 response-evaluable patients with DLBCL achieved a 
complete response (CR) and 4 achieved a partial response (PR). Seven of 10 response-evaluable 
patients with indolent lymphomas responded (1 CR and 6 PRs). Two out of 4 response-evaluable 
patients with CLL achieved a response (both PR). 
In Study C34002, as of 24 May 2017, there were 15 on-study deaths (one drug-related, multiple 
organ dysfunction syndrome). To date, the safety profile in Study C34002 appears to be similar to 
that of Study C34001. Early signs of antileukemic activity have been observed in a number of 
patients who have demonstrated significant reductions in both peripheral blast and bone marrow 
blast counts. Three patients have achieved objective response per IWG 2003 criteria (1 CR, 2 CRi) 
[15] as of the cutoff date.
4.1.4.2
Clinical Pharmacokinetics of TAK-659
Preliminary pharmacokinetic (PK) results are available across the 60 to 120 mg dose range 
evaluated in the dose-escalation portion of Study C34001. 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).
Among patients with relapsed/refractory lymphoma, TAK-659 exhibited fast absorption after oral 
administration of an immediate–release tablet formulation (median Tmax [time of first occurrence 
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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 upon 
comparison of predose (trough) concentrations available during Cycle 1. Geometric mean values 
of steady-state, dose-normalized area under the plasma concentration–time curve during the 
dosing interval (AUC/dose) were similar across the 60 to 100 mg dose range, suggesting no 
obvious deviation from dose proportionality. Moderate variability was observed in AUC/Dose 
when pooled across the 60 to 120 mg dose range (coefficient of variation of 30% for Day 1 and 
50% for Day 15).
Following repeated QD dosing, TAK-659 was characterized by a mean 2.1-fold accumulation. 
The 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-659 renal clearance to apparent oral clearance was 0.34. Although the 
exact contribution of renal excretion 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 (based on creatinine clearance calculated by the 
Cockcroft-Gault equation) was 3.9-fold higher than estimated glomerular filtration rate, 
suggesting that active tubular secretion is the major component of renal clearance. 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% to 73.0%) of 
TAK-659 metabolism in human liver microsomes, with relatively minor contributions by 
CYP2D6 (16.6% to 30.9%) and CYP1A2 (0% to 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. 
Additional details about TAK-659 PK and metabolism are provided in the TAK-659 Investigator’s 
Brochure (IB).
4.1.5
Risks and Benefits
Because TAK-659 has been administered to a total of only 181 patients as of 05 September 2017, 
it is not currently possible to describe with certainty the potential adverse effects of the compound. 
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4.1.5.1
Potential Risks From Nonclinical Studies
Potential risks from nonclinical studies in dogs and rats include the following:

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 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 From Clinical Studies
Potential risks based on clinical observations include the following:
On the basis of data from Study C34001, asymptomatic elevation in lipase was added 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. In clinical 
studies to date, asymptomatic lipase or amylase elevations are reported commonly (≥10% of 
patients). Patients in Study C34004 will have frequent monitoring of lipase and amylase as 
outlined in the Schedule of Events (Appendix A).
Cases of pneumonitis have been reported in clinical studies with BCR pathway kinase inhibitors, 
including TAK-659, and pneumonitis is considered an important potential risk of TAK-659. 
Pneumonitis and other pulmonary toxicities are being closely monitored in TAK-659 clinical 
studies.
Further details regarding the benefits and risks associated with TAK-659 may be found in the 
current version of the TAK-659 IB.
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 
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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 specified (see Section 8.2.6).
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 was 
it 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 ribonucleic acid 
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 breast cancer resistance protein (BCRP) in 
Caco-2 cells at concentrations up to 100 μM. When these in vitro findings are viewed in context of 
the Cmax observed 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 the TAK-659 IB.
4.2
Rationale for the Proposed Study
TAK-659 is a selective, reversible, and potent inhibitor of SYK. SYK is a nonreceptor kinase with 
SH2-binding domains that bind to phosphorylated ITAMs. These domains are located in the 
cytoplasmic tails of key surface receptors located on B cells, T cells, and certain NK cells. SYK 
functions normally to mediate ITAM signaling in immune cells by coupling activated 
immunoreceptors to downstream signaling events that mediate diverse cellular responses, 
including proliferation, differentiation, phagocytosis, and survival. The SYK pathway can become 
dysregulated to drive the pathophysiology of various immune disorders and oncogenic processes. 
Abnormal function of SYK has been implicated in several types of hematopoietic malignancies, 
including CLL, DLBCL, and indolent lymphomas, such as FL and MCL, in which dependency on 
BCR-mediated signaling is thought to be important to the survival of tumor cells. 
Nonclinical evaluation of TAK-659 in multiple mouse DLBCL xenograft models demonstrated 
significant antitumor activity. These models, including HBL-1 (DLBCL cell line), PHTX-95L
(primary DLBCL tumor), and OCI-Ly10 (ABClike DLBCL cell line), represent genetic 
heterogeneity underlying the disease. In addition, tumor growth inhibition correlated with markers 
of SYK pathway modulation in the HBL-1 and PHTX-95L mouse xenograft models. In the FIH 
study of TAK-659, 4 of 9 heavily pretreated patients with DLBCL achieved objective responses 
across multiple dose levels of TAK-659 during dose escalation. This study plans to further 
evaluate TAK-659 in relapsed and refractory DLBCL after 2 prior lines of chemotherapy, which 
represents an unmet medical need setting in which there is no standard of care available.
4.2.1
Rationale for Dose and Schedule Selection
TAK-659 has been evaluated as a single agent given PO on a continuous daily dosing schedule in 
its FIH study (C34001) in patients with advanced solid tumors or lymphoma. Four dose levels 
(60, 80, 100, and 120 mg QD) have been evaluated in the dose-escalation portion of Study C34001, 
and the MTD has been determined to be 100 mg QD. Following the safety expansion of the 
100 mg cohort, Study C34001 is currently in the dose-expansion phase, evaluating the efficacy, 
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safety, and tolerability of TAK-659 administered at the 100 mg dose level in 5 different cohorts of 
B-lymphocyte malignancies. Early signs of clinical activity in lymphoma have been demonstrated 
across all doses evaluated. 
In Study C34001, as of 02 June 2017, 9 of 48 response-evaluable patients with DLBCL achieved a 
complete response (CR), and 4 achieved a partial response (PR). Seven of 10 response-evaluable 
patients with indolent lymphomas responded (1 CR and 6 PRs). Two of 4 response-evaluable 
patients with CLL achieved a response (both PRs).
These responses have been observed at doses of 60 (1 CR), 80 (1 PR), 100 (9 CRs and 11 PRs), and 
120 mg QD (1 PR). These data suggest that doses in the tolerable dose range of 60 to 100 mg are 
pharmacologically active. Preliminary data show that TAK-659 exhibits an acceptable PK profile 
across the 60 to 100 mg dose levels that support continuous QD dosing. On the basis of the 
available safety and tolerability data, the AEs observed with TAK-659 treatment overall are 
reversible and manageable. The laboratory abnormalities, such as lipase, amylase, and liver 
function test elevations, were generally asymptomatic.
Although 100 mg QD TAK-659 has been determined to be the MTD and RP2D 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 (20 CR+PR/65 response-evaluable 
lymphoma patients), responses to TAK-659 were also observed in patients treated with two lower 
doses evaluated, 60 mg (1 CR/4 response-evaluable lymphoma patients) and 80 mg (1 PR/2 
response-evaluable lymphoma patients) QD, suggesting a therapeutic window of TAK-659 
extending from 60 mg to 100 mg QD. Plasma PK exposure of TAK-659 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 MTD of 100 mg QD and may fall within the therapeutic range 
between 60 and 100 mg QD. 
By the data cut-off of 02 June 2017, 84 lymphoma patients had been treated with 100 mg QD 
TAK-659 in study C34001. The incidence of high-grade AEs at 100 mg QD was low and the most 
frequent AEs were asymptomatic laboratory changes. Therefore, the 100 mg QD dose overall has 
shown a favorable safety and tolerability profile. The median relative dose intensity for patients 
receiving 100 mg QD was 94.2% (min, max: 13%, 103%) overall but only 80.8% (min, max: 7%, 
100%) for the 1st cycle of study treatment. During the first cycle, although only 6% of patients 
receiving 100 mg QD experienced AEs that led to a dose reduction, 51% of patients had study dose 
held due to AEs. The advanced disease stage associated with the study patient population and the 
aggressive nature of the disease may have contributed to the frequent study drug interruptions 
during the initial therapy. 
Among the lymphoma responders to TAK-659, the initial response was mostly achieved within 
the first two cycles of treatment (median time to response 55 days [min, max: 27,168]). Therefore, 
improved study drug exposure in the initial cycles of treatment may be important for maximizing 
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the patients’ probability of responding to TAK-659. A ramp-up schedule starting from a lower but 
biologically active dose such as 60 mg QD may alleviate the AE burden for patients and therefore 
decrease the probability of drug hold and improve relative dose intensity for the first cycle of 
treatment. Further escalation to 80 mg QD based on the tolerability level and then to the full dose 
of 100 mg QD allows dose titration for patients so that individual variability in PK and 
responsiveness to study drug can be better addressed. The evaluation between the 100 mg QD 
versus a 3-dose ramp-up schema to reach the full dose of 100 mg QD, therefore, is planned in the 
lead-in phase (Stage 1) of this study. The selection of the dose schedule of TAK-659 for Stage 2 of 
the study will be based on the efficacy readout, consistent with the purpose of this dose 
exploration.
Evaluating a ramp-up schema with the potential of dose titration in the lead-in dose exploration 
portion (Stage 1) was further guided by exploratory exposure-response analyses of the efficacy 
and safety data from the DLBCL patients in Study C34001. Limited data from a total of 37 
DLBCL patients with available PK and efficacy/safety information were included in the analyses. 
Data were available with the dose range of 60 to 120 mg (N=4, 2, 30 and 1 for 60, 80, 100 and 
120 mg groups, respectively). The metric of exposure was the area under the plasma concentration 
versus time curve per day (derived from individual clearance values on the basis of population PK) 
for both the exposure/efficacy and exposure/safety analysis.
Logistic regression analysis was performed for efficacy and safety analyses. For efficacy analysis, 
efficacy data were separated into 2 groups: responders (PR or higher) versus non-responders (SD, 
PD). Results from the analysis did not show evidence of a relationship between the probability of 
response (PR or CR) and area under the plasma concentration versus time curve. For the safety 
analysis, AE data were categorized into 2 groups: Patients with Grade ≥3 AE versus patients with 
Grade ≤2 AE as their worst grade of AE. Results of the logistic regression suggested a trend 
between Grade ≥3 AE and exposure (p=0.08) (Figure 4.a). Based on the exposure/safety 
relationship being observed, probability of having Grade ≥3 AE was estimated for 60 mg, 80 mg 
and 100 mg using PopPK model simulated steady state exposure (N=1000 for each dose). As 
shown in Figure 4.a, at the starting dose of 60 mg QD in Cycle 1, which is 60% of the 100 mg QD 
MTD, the logistic regression model predicted the reduction of the probability of having Grade ≥3 
AE from 0.76 to 0.50 when compared to the 100 mg QD dose. While at the dose of 80 mg, the 
probability of Grade ≥3 AE was reduced from 0.76 to 0.64 when compared to 100 mg QD dose.
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Figure 4.a
Relationship between TAK-659 exposure (AUC∀) and Grade ≥3 Adverse 
Event in DLBCL Patients (N=37)
TAK-659 is also being evaluated as a single agent in relapsed/refractory acute myelogenous 
leukemia in Study C34002, which includes phase 1b dose-escalation and phase 2 dose-expansion 
phases. Currently, the 60 to 160 mg QD doses of TAK-659 have been determined to be safe and 
tolerable, and dose escalation is ongoing at the 80 mg BID dose level. 
4.2.2
Rationale for PK Assessments
Blood samples for determination of TAK-659 plasma concentrations will be collected during 
Cycles 1 through 4 via a limited (sparse) sampling strategy to contribute to population PK and 
exposure–response analyses of TAK-659.
 
 
Plasma PK data collected in this study 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.
4.2.3
Rationale for Biomarker Analysis (Pharmacodynamic Biomarkers and Correlative 
Studies to Identify Predictive Biomarkers)
SYK is involved in BCR-independent functions, such as B-cell migration and adhesion. To 
monitor pharmacodynamic effects of TAK-659 in patients with DLBCL, cytokine and chemokine 
levels at Baseline and posttreatment will be measured as alternative pharmacodynamic endpoints. 
In addition, changes in the immune cell population in blood will be examined. Changes in 
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circulating cytokine and chemokine levels and changes in the immune cell profile in each 
individual patient will be assessed to determine if they are regulated by TAK-659 and/or correlated 
with clinical response. PK-pharmacodynamic relationships may be evaluated as permitted by the 
data. Association of the postdose changes of cytokines/chemokines or postdose changes in the 
immune cell population with clinical response may also be assessed. 
Correlative studies will be conducted to identify potential candidate biomarkers (eg, genetic or 
genomic or gene expression signature) in tumor tissue that are significantly associated with 
observed clinical response to TAK-659 in patients with DLBCL. These candidate biomarkers 
include, but are not limited to, BCR-signaling gene expression profiles, cancer-specific somatic 
gene alterations, DLBCL disease biomarkers relevant to diagnosis and prognosis, and known 
subtype classifications such as ABC and GCB types. Similar correlative study efforts are ongoing 
in Study C34001, the FIH study of TAK-659, currently expanding in DLBCL. If any predictive 
biomarkers are identified in Study C34001, further validation of the biomarkers in relation to 
clinical response may be conducted in this trial. Initial validation may be a retrospective study, 
using the clinical efficacy data available for the all-comer population inclusive of both the 
marker-positive and marker-negative patients. Before the retrospective biomarker validation study, 
a validation study protocol and a statistical analysis plan (SAP) will be developed with acceptance 
criteria prespecified for all major parameters under evaluation. If the retrospective validation is 
successful, the candidate biomarkers may further be prospectively validated in an independent 
patient population. Ultimately, this may provide a patient-stratification strategy for TAK-659 in 
the treatment of patients with advanced DLBCL.
4.2.4
Rationale for Pharmacogenomic Assessments
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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objectives
The primary objective is to assess the efficacy of TAK-659 as measured by independent radiologic 
review committee (IRC)-assessed ORR in patients with DLBCL (Stage 2).
5.1.2
Key Secondary Objective
The key secondary objective is to assess CR rate per IRC in patients with DLBCL (Stage 2).
5.1.3
Secondary Objectives
The secondary objectives are:

To select the Stage 2 dose regimen of TAK-659 from the lead-in dose exploration phase 
(Stage 1) and assess efficacy using ORR per IRC (Stage 2). 

To assess ORR per IRC at 3, 6, and 9 cycles in patients with DLBCL (Stage 2).

To assess duration of response (DOR) and duration of CR per IRC in patients with DLBCL 
(Stage 2).

To assess ORR per IRC in the subgroup of patients with GCB DLBCL (Stage 2).

To assess ORR per IRC in the subgroup of patients with DLBCL transformed from indolent 
non-Hodgkin lymphoma (Stage 2).

To assess PFS per IRC in patients with DLBCL (Stage 2).

To assess OS in patients with DLBCL (Stage 2).
5.1.4
Additional Objectives
The additional objectives are:

To assess the safety and tolerability of TAK-659 in the patient population under study 
(Stages 1 and 2).

To assess the number of responding patients proceeding to ASCT or allogeneic stem cell 
transplant (Stage 2).

To collect TAK-659 plasma concentration–time data to contribute to population PK and 
exposure–response analyses (Stages 1 and 2).
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5.1.5
Exploratory Objectives
The exploratory objectives are:
5.2
Endpoints
5.2.1
Primary Endpoints
The primary endpoint is ORR as assessed by IRC according to the modified 2007 International 
Working Group (IWG) criteria for malignant lymphoma [16] (Stage 2).
5.2.2
Key Secondary Endpoint
The key secondary endpoint is CR rate as assessed by IRC according to the modified 2007 IWG 
criteria [16] (Stage 2).
5.2.3
Secondary Endpoints
The secondary endpoints are:
!
ORR per IRC according to the 2014 IWG (Lugano) criteria [15] (Stage 2).
!
CR rate per IRC according to the 2014 IWG (Lugano) criteria [15] (Stage 2).
!
ORR per IRC to select the Stage 2 dose regimen of TAK-659 from the lead-in dose exploration 
phase (Stage 1).
!
ORR per IRC at 3, 6, and 9 cycles, respectively (Stage 2).
!
DOR and duration of CR per IRC (Stage 2).
!
ORR per IRC in patients with GCB DLBCL (Stage 2).
!
ORR per IRC in patients with DLBCL transformed from indolent NHL (Stage 2).
!
PFS per IRC (Stage 2).
!
OS (Stage 2).
!
The IRC will evaluate the assessments above using both the modified 2007 IWG criteria for 
malignant lymphoma [16] and the 2014 IWG (Lugano) criteria [15]. Unless otherwise 
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specified, evaluations using the modified 2007 IWG criteria will be the primary analyses, and 
evaluations using the 2014 IWG (Lugano) criteria will be the sensitivity analyses. 
5.2.4
Additional Endpoints
The additional endpoints are:
!
Percentage of patients who experience AEs, Grade #3 AEs, serious AEs (SAEs), 
discontinuations for AEs, and clinical laboratory values and vital sign measurements outside 
the normal range (Stages 1 and 2).
!
Percentage of patients proceeding to ASCT or allogeneic stem cell transplant out of all patients 
who achieve a best response of PR or CR on study (Stage 2).
!
TAK-659 plasma concentration–time data (Stages 1 and 2).
5.2.5
Exploratory Endpoints
The exploratory endpoints are:
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6.0
STUDY DESIGN
6.1
Overview of Study Design
This is an open-label, multicenter, phase 2 study to evaluate the efficacy and safety of TAK-659 as 
a single agent in patients with relapsed or refractory DLBCL after at least 2 prior lines of 
chemotherapy. Eligible patients will also be ineligible for ASCT or be patients for whom ASCT 
has failed. Approximately 122 patients will be treated in the study. This study will include a 
lead-in dose exploration phase (Stage 1) for dose optimization that is further described below. 
Study schemas are provided in Figure 6.a and Figure 6.b. See Appendix A for the Schedule of 
Events.
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Figure 6.a
Stage 1 Study Schema
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Figure 6.b
Stage 2 Study Schema
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This study will start with a lead-in dose exploration phase (Stage 1) during which two TAK-659 
dose regimens will be evaluated in two patient cohorts (Cohorts A and B). Patients in Cohort A 
will receive a daily dose of 100 mg TAK-659 continuously throughout the study. In Cohort B, 
patients will follow a ramp-up dosing schema leading to a full dose of 100 mg QD TAK-659. 
Patients will initially receive 60 mg QD TAK-659 for one cycle of 28 days, and if tolerated well, 
will then receive 80 mg QD TAK-659 for the next cycle, and subsequently 100 mg QD TAK-659 
in the 3rd cycle and beyond. At the end of each cycle during the ramp-up, patients will be assessed 
for their suitability to dose-escalate to the next level based on safety and tolerability. 
If the patient experiences any drug-related adverse events that require dose modification (inclusive 
of dose held and dose reduction) per protocol in a given dose cycle, dose escalation will not 
proceed to the next level. If the AE(s) resolves, the patient may then restart dose escalation in the 
next cycle either at the same dose or a reduced dose according to the protocol-defined dose 
reduction criteria (Section 8.2). In case dose reduction is not required, when the patient resumes 
the study drug at the same dose, dose escalation to the next dose level and further to the full dose of 
100 mg QD TAK-659 may be pursued if no recurrence of the same AE(s) or any other AEs leading 
to dose modification is observed in the next cycle of treatment. However, if the same AE(s) or 
different AE(s) requiring dose modification occur in two consecutive cycles at the same dose level, 
further dose escalation is not allowed. If the patient resumes the study drug at a reduced dose per 
protocol, no dose re-escalation is recommended. Approximately 20 patients are expected to be 
enrolled into each cohort, with a total of ~40 patients planned for Stage 1. Details around cohort 
assignment will be described in the Study Manual. 
Upon completion of Stage 1, a dose exploration analysis will occur. Based on the posterior 
probability of response comparison between the 2 cohorts, one TAK-659 dose regimen will be 
selected to proceed to Stage 2. During this analysis, if both Stage 1 regimens are deemed to be 
ineffective, termination of the study without proceeding to Stage 2 may be considered. Other 
considerations for making this decision should be taken into account including, but not limited to, 
sample size limitations, relevant data from other TAK-659 studies, and applicable patient 
enrichment or selection strategy that justifies further evaluation of TAK-659 in this setting. 
Otherwise, one of the two TAK-659 regimens will be selected to proceed to Stage 2. 
During the Stage 2 efficacy evaluation phase, it is expected that approximately 82 patients will be 
enrolled. Once enrolled, patients will be administered TAK-659 orally in 28-day treatment cycles 
according to the selected dose regimen of TAK-659 from Stage 1. After approximately 40 patients 
have been enrolled in Stage 2 and have had the opportunity to receive at least 3 cycles of study 
treatment and have at least 1 posttreatment response evaluation, an interim analysis will be 
performed to assess futility. The study may either stop for futility or continue as planned. 
In Stage 2, patients will be administered TAK-659 orally according to the dose regimen selected in 
Stage 1. Efficacy will be assessed using the IWG revised response criteria for malignant 
lymphoma (the modified 2007 IWG criteria [16] and the 2014 [Lugano] criteria [15]). Dedicated 
computed tomography (CT) scans (chest, neck, abdomen, and pelvis) will be performed at 
Baseline; at the end of Cycles 1, 3, and 6; every 3 cycles up to 24 cycles; and every 6 cycles 
thereafter. [18F]Fluorodeoxyglucose-positron emission tomography (FDG-PET) scans will be 
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performed at baseline and at the end of Cycles 1, 3, and 6 if positive at baseline, or when clinically 
indicated during the study (see Appendix A Schedule of Events). The primary endpoint of this 
study is ORR, defined as the proportion of patients with CR or PR as determined by independent 
central review of radiology by an IRC according to the modified 2007 IWG criteria. 
AEs will be assessed, and laboratory values, vital signs, 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 5.0, effective date 27 November 2017 [17].
Patients on TAK-659, including those who achieve a CR, may receive study drug until they 
experience PD or unacceptable toxicities. Patients who discontinue study for reasons other than 
PD will be followed for PFS every 3 months after the last dose of study drug until PD, the start of 
alternative therapy, or conclusion of the study, whichever occurs first. All patients, after the last 
dose of study drug, will be followed for OS every 3 months until death or conclusion of the study, 
whichever occurs first.
Patients may discontinue therapy at any time. Patients will attend the End-of-Treatment (EOT) 
visit 28 days (+10) after receiving their last dose of TAK-659 or before the start of subsequent 
anticancer therapy, whichever occurs first, to permit the detection of any delayed treatment-related 
AEs. 
6.2
Number of Patients
Approximately 122 patients will be enrolled in the study, including 40 patients (20 per dose 
schedule) in the lead-in dose exploration phase (Stage 1) and 82 patients in the efficacy evaluation 
phase (Stage 2) of the study from approximately 50 study centers in North America and Europe. 
Enrollment is defined as the time of the initiation of the first dose of study drug.
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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 clinical response, may receive study drug until they 
experience PD. Patients will discontinue treatment if they have an unacceptable study drug–related 
or possibly related toxicity or withdraw for other reasons. 
Patients will be followed for 28 days (+10) after the last dose of study drug or until the start of 
subsequent anticancer therapy (whichever occurs first) to permit the detection of any delayed 
treatment-related AEs.
PFS follow-up every 3 months after the last dose of study drug or until PD, the start of alternative 
therapy, or conclusion of the study, whichever occurs first (for patients who discontinue for 
reasons other than PD) and OS follow-up every 3 months from the last dose of study drug until 
death or conclusion of study, whichever occurs first, are planned. The primary analysis of the 
efficacy endpoint will be conducted when the last patient has had the opportunity to receive at least 
6 cycles of treatment. 
6.3.2
End of Study/Study Completion Definition and Planned Reporting
Primary Completion/Study Completion 
The primary analysis for the efficacy and safety 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 6 cycles of treatment with study drug. PFS follow-up every 3 months after the last dose 
of study drug until PD, the start of alternative therapy, or conclusion of the study, whichever 
occurs first (for patients who discontinue for reasons other than PD) and OS follow-up every 
3 months from the last dose of study drug until death or conclusion of the study, are planned. The 
estimated time frame for study completion is approximately 41 months. A CSR addendum will be 
provided to describe additional data collected. 
Conclusion of the study will be considered when OS events have occurred in 70% of patients, or 
24 months after last patient in, whichever occurs earlier. Alternatively, at the time of the interim 
analysis, if the prespecified futility boundary is passed, the study will stop; otherwise, the study 
will continue as planned. The study may be prematurely terminated if, in the opinion of the 
sponsor, there is sufficient reasonable cause. 
6.3.3
Time Frames 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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Table 6.a
Primary and Secondary Endpoints for Disclosures
Endpoint
Definition
Maximum Time Frame (a)
Primary:

ORR as assessed by IRC 
according to the modified 2007 
IWG criteria for malignant 
lymphoma [16] (Stage 2).
ORR as assessed by IRC.
Up to 12 months.
Key Secondary

CR rate as assessed by IRC 
according to the modified 2007 
IWG criteria [16] (Stage 2).
Rate of CR as assessed by IRC.
Up to 12 months.
Secondary: 

ORR per IRC according to the 
2014 IWG (Lugano) criteria [15]
(Stage 2).
Rate of ORR as assessed by IRC.
Up to 12 months.

CR rate per IRC according to the 
2014 IWG (Lugano) criteria [15]
(Stage 2).
Rate of CR as assessed by IRC.
Up to 12 months.

ORR per IRC to select the 
Stage 2 dose regimen of 
TAK-659 from the lead-in dose 
exploration phase (Stage 1).
ORR as assessed by IRC.
Up to 12 months.

ORR per IRC at 3, 6, and 
9 cycles (Stage 2).
ORR as assessed by IRC at 3, 6, and 
9 cycles, respectively.
Up to 12 months.

DOR and duration of CR per 
IRC (Stage 2).
DOR and duration of CR per IRC.
Up to 12 months.

ORR per IRC in patients with 
GCB DLBCL (Stage 2).
Rate of ORR as assessed by IRC in a 
subset of patients.
Up to 12 months.

ORR per IRC in patients with 
DLBCL transformed from 
indolent NHL (Stage 2).
Rate of ORR as assessed by IRC in a 
subset of patients.
Up to 12 months.

PFS per IRC (Stage 2).
PFS as assessed by IRC.
Up to 18 months.

OS (Stage 2).
OS.
Up to 24 months.
IRC= independent radiologic review committee; PFS=progression-free survival; ORR=overall response rate. 
(a) Time to last assessment for that endpoint for an individual patient.
6.3.4
Total Study Duration
It is anticipated that this study will last for approximately 41 months. This includes approximately 
23 months of enrollment, estimated median treatment duration of 6 months of treatment, and OS 
follow-up after last dose of study drug. 
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7.0
STUDY POPULATION
Patients must have histologically confirmed DLBCL, including de novo disease or transformed 
disease from indolent NHL. Patients must also be relapsed or refractory to ≥2 prior lines of 
chemotherapy based on standard of care and may not have failed more than 4 prior lines of therapy. 
Patients must have either failed or not be eligible for ASCT. Patients must have FDG-PET–avid 
disease that measurable by CT/magnetic resonance imaging (MRI), and Eastern Cooperative 
Oncology Group (ECOG) performance status score of 0 or 1.
7.1
Inclusion Criteria
Each patient must meet all the following inclusion criteria to be enrolled in the study:
1. Male or female patients aged 18 years or older.
2. Patients must have histologically confirmed DLBCL, including de novo disease or 
transformed disease from indolent NHL.
a.
Patients with transformed DLBCL must meet 2016 WHO criteria for DLBCL [6] on last 
biopsy before study entry and have ≥1 prior histological diagnosis of FL or other indolent 
disease.
b. To be enrolled in the study, patients must have a pathologically confirmed diagnosis of one 
of the following DLBCL subtypes based on the 2016 WHO classification criteria for 
lymphoid neoplasms [6]: 
i.
DLBCL, 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, based on the 2008 WHO classification 
criteria) 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) [18].
v.
FL Grade 3B.
c.
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.
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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.
3. Relapsed or refractory to ≥2 prior lines of chemotherapy based on standard of care that include 
at least:
a.
The standard first-line chemotherapy regimen containing rituximab and an anthracycline 
(eg, R-CHOP) or equivalent if anthracycline is contraindicated; included are DLBCL 
patients transformed from indolent lymphoma who may have already received R-CHOP or 
equivalent as part of their indolent lymphoma treatment. Therefore, alternative frontline 
therapy other than R-CHOP or equivalent used for DLBCL post-transformation may be 
acceptable upon discussion with the sponsor.
and 
b. One additional systemic chemotherapy as a second-line salvage therapy that may have 
included ASCT.
i. Included are ASCT-eligible patients who failed ASCT following response to a standard 
salvage regimen, or who did not respond to salvage therapy and were therefore not 
indicated for ASCT, or 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 or relapsed after a 
second-line systemic chemotherapy regimen.
iii. Also included are patients not indicated for systemic chemotherapy regimens who were 
refractory to or relapsed after an alternative second-line salvage therapy.
4. Patients should not have failed more than 4 prior lines of therapy.
a.
Pre-induction salvage chemotherapy and ASCT should be considered 1 therapy.
b. 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.
c.
Antibody therapy given as a single agent should be considered 1 therapy.
d. 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.
e.
For patients with DLBCL transformed from indolent lymphoma, any treatment received 
for the indolent disease prior to the transformation to DLBCL will, in general, not count 
towards the 2 to 4 prior lines of therapy required for DLBCL in this study.
5. 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 
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PR before enrollment by investigator assessment), documented progression will not be 
required.
6. 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 nodal mass, or 1.0 cm in the longest diameter for 
extranodal disease) as assessed on cross-sectional imaging by CT/MRI (CT is to be performed 
with contrast unless contrast is medically contraindicated).
7. ECOG performance status score of 0 or 1 (refer to Appendix E).
8. Life expectancy of >3 months.
9. Patients must have adequate organ function, including the following:
a.
Bone marrow reserve: absolute neutrophil count (ANC) 1000/L, platelet count 
75,000/L (50,000/L 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: total bilirubin ≤1.5 times the upper limit of the normal range (ULN); ALT and 
AST ≤2.5ULN.
c.
Renal: creatinine clearance ≥60 mL/min either as estimated by the Cockcroft-Gault 
equation (refer to Appendix F) or based on urine collection (12 or 24 hours).
d. 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). 

Glycosylated hemoglobin is ≤6.5% (hyperglycemic patients permitted if glucose is 
well controlled by hypoglycemic medication).
10. Female patients of childbearing potential must:
a.
Agree to practice 1 highly effective method of contraception and 1 additional effective 
(barrier) method (see Appendix G) at the same time, from the signing the informed consent 
form (ICF) 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 patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.)
Childbearing potential is defined as not having undergone surgical sterilization, hysterectomy, 
and/or bilateral oophorectomy, or not being postmenopausal for at least 1 year before 
screening visit (≥12 months of amenorrhea in the absence of other biological or physiological 
causes).
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11. Male patients, even if surgically sterilized (ie, status postvasectomy), who are sexually active 
with partners who are of childbearing potential, must:
a.
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 form (ICF) 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 patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods for the female partner] and withdrawal are not acceptable methods of 
contraception.)
12. Male patients should not donate sperm from the time of signing the ICF through 180 days after 
the last dose of study drug.
13. 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.
14. Recovered (ie, Grade 1 toxicity) from the reversible effects of prior anticancer therapy.
7.2
Exclusion Criteria
Patients meeting any of the following exclusion criteria are not to be enrolled in the study.
1. Central nervous system (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.
4. Known hypersensitivity reactions to the active substance or to any of the excipients of the 
study drug.
5. Life-threatening illness unrelated to cancer that could, in the investigator’s opinion, make the 
patient not appropriate for this study.
6. 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. 
7. 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 agents; ≤8 weeks for 
cell-based therapy or antitumor vaccine). 
8. Radiotherapy less than 3 weeks before the first dose of study treatment. If prior radiotherapy 
occurred <4 to 6 weeks before study start, as radiated lesions cannot be reliably assessed by 
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FDG-PET, nonradiated target lesions are required for eligibility, and prior radiotherapy 
information must be submitted to the IRC.
9. Known HIV positive (testing not required).
10. Known hepatitis B surface antigen positive or known or suspected active hepatitis C infection.
11. 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 any time.
12. Any clinically significant comorbidities, such as uncontrolled pulmonary disease, known 
impaired cardiac function or clinically significant cardiac disease (specified below), active 
CNS disease, active infection, or any other condition that could, in the opinion of the 
investigator, compromise the patient’s participation in the study. 
13. Patients with any of the following cardiovascular conditions are excluded: 
a.
Acute myocardial infarction within 6 months before starting study drug.
b. Current or history of New York Heart Association Class III or IV heart failure 
(Appendix H). 
c.
Evidence of current, uncontrolled cardiovascular conditions including cardiac arrhythmias, 
angina, pulmonary hypertension, or electrocardiographic evidence of acute ischemia or 
active conduction system abnormalities.
d. Fridericia’s corrected QT interval (QTcF) >450 milliseconds (msec) (men) or >475 msec 
(women) on a 12-lead ECG during the Screening period.
e.
Abnormalities on 12-lead ECG including, but not limited to, changes in rhythm and 
intervals that, in the opinion of the investigator, are considered to be clinically significant.
14. Major surgery within 14 days before the first dose of study drug or incomplete recovery from 
any complications from surgery.
15. 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 8.5.1).
16. Treatment with high-dose corticosteroids for anticancer purposes within 7 days before the first 
dose of TAK-659. Daily dose equivalent to 10 mg oral prednisone or less is permitted. 
Corticosteroids for topical use or in nasal spray or inhalers are allowed. 
17. Patients 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.
18. 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.
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19. Lack of suitable venous access for the study-required blood sampling for TAK-659.
20. Use or consumption of any of the following substances:
a.
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) 
before the first dose of study drug. In general, use of these agents is not permitted during 
the study except when an AE must be managed (see Section 8.5 for details). See 
Appendix I for a nonexhaustive list of strong CYP3A reversible inhibitors and P-gp 
inhibitors based on the US Food and Drug Administration (FDA) draft guidance for DDI 
studies (“Drug Interaction Studies — Study Design, Data Analysis, Implications for 
Dosing, and labeling Recommendations”, February 2012).
b. 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, use of these agents is not permitted during the study except when an AE must be 
managed (see Section 8.5 for details). See Appendix I for a nonexhaustive list of strong 
CYP3A mechanism-based inhibitors and strong CYP3A inducers and P-gp inducers based 
on the US FDA draft guidance for DDI studies.
c.
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).
TAK-659 will be dosed PO, QD, in 28-day cycles. 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 8 ounces (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 provided in the Pharmacy Manual.
Patients should be instructed to take their study medication at approximately the same time each 
day and not to take more than the prescribed dose at any time. On clinic visit days, patients should 
be instructed to hold their dose until predose assessments have been performed in the clinic, with 
the exception of the Cycle 1 Day 8 visit: For this visit, patients should be instructed to take their 
TAK-659 dose at home before their clinic visit. The reason for this exception is to ensure a range 
of postdose PK sampling times across the study population for purposes of population PK analyses. 
If a patient fails to take the TAK-659 dose at the scheduled dosing time (6 hours of the scheduled 
dosing time), 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 on the following day. Patients should record any skipped doses in their dosing diary (see 
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 Study Manual). Patients should 
resume dosing at the next scheduled time with the prescribed dosage.
8.2
Dose Modification Guidelines
8.2.1
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 Cycles 2 and 3, 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 5.0. 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 modified, or permanently discontinue from the study. 
Detailed dose-modification guidelines are provided in Section 8.2.4 and 8.2.5. Patients who have 
the TAK-659 dose held because of a treatment-related or possibly related AE may resume study 
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drug after resolution of the AE, either at the same dose level or at a dose of TAK-659 reduced 
(dose reduction) by at least 1 dose level. When a dose reduction occurs, the TAK-659 dose will be 
reduced to the -1 dose level (see Table 8.a). 
If initial dose adjustment does not provide sufficient relief, the dose of TAK-659 can be further 
reduced if the treating physician decides that the patient is benefiting from study treatment and 
may benefit at a further-reduced dose of TAK-659 (-2 dose level in Table 8.a). 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 if more than 2 dose reductions are required in a patient, 
the patient should have study treatment discontinued, unless the treating physician decides that the 
patient may benefit from continued study treatment after resolution of AEs to Grade 1 or to 
baseline values. In this case, consultation with the medical monitor or designee is required. Under 
the latter circumstances, dose reduction to a level below 60 mg QD is not advised; therefore, if a 
patient treated at 60 mg QD experiences AEs that require further dose reduction per guidance 
below (Table 8.b, Table 8.c), the treating investigator may allow the patient to continue on study if, 
in the investigator’s opinion, the patient may be able tolerate the rechallenge of 60 mg after a 
period of study drug interruption, provided the benefit–risk assessment is favorable. 
The study drug interruption before resolution of AEs to Grade ≤1 or baseline values 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 anticancer therapy, whichever occurs first.
Table 8.a
Dose Reduction Levels for TAK-659
Dose Reduction Levels
Dose (Unit)
Planned dose
100 mg
-1 dose level
80 mg
-2 dose levels
60 mg
For AEs that occur during the study but are not related or possibly related to TAK-659, TAK-659 
dose modification, 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 have the TAK-659 dose held until the 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). In these instances, the study 
drug will, in general, be resumed at the same dose.
Patients with study drug-related or possibly related Grade 4 nonhematologic toxicities (with the 
exception of asymptomatic laboratory abnormalities as described in Section 8.2.5) or Grade 4 
anemia will, in general, require that treatment with TAK-659 be permanently discontinued (see 
Section 9.7 for reasons for discontinuation). The patient will be followed until resolution or 
stabilization of the event. If, in the opinion of the investigator and the sponsor (medical monitor or 
designee), it is in the patient’s best interest to continue treatment with TAK-659, then the dose of 
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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 to baseline values. This discussion will be 
documented in the study file. 
Asymptomatic laboratory changes (eg, elevations in serum lipase, amylase, AST, ALT, and CPK) 
have been observed in patients treated with TAK-659. Although their clinical significance needs to 
be further evaluated, on the basis of the available data, these laboratory abnormalities related to
TAK-659 treatment are, in general, reversible and not associated with evidence of pathological 
tissue injury. Specific dose modification guidelines relating to asymptomatic laboratory 
abnormalities are described in detail below. In addition, serum lactate dehydrogenase (LDH) 
elevation has been observed in most of the patients exposed to TAK-659. Although LDH is 
monitored during the study, no clinical consequence has thus far been identified with 
TAK-659–induced LDH elevation; therefore, no TAK-659 dose modification is recommended for 
LDH.
Dose modification guidelines should be closely followed to manage toxicities during the study; 
however, on the basis of evolving safety data for TAK-659 and/or 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. Discussion 
and agreement will be documented. The study steering committee (SSC) may be consulted per the 
SSC charter (see Section 11.2).
8.2.2 Intrapatient Dose Re-escalation 
When a dose reduction of TAK-659 is required because of toxicity, dose re-escalation is not 
advised; however, dose re-escalation may be allowed if, following an AE that requires a dose 
reduction, a patient does not have recurrence of the same event that caused the dose reduction 
within 2 cycles of the start of the lower dose. Dose re-escalation is not permitted when dose 
reduction is for Grade 4 nonhematologic toxicities as required per dose modification guidelines 
below (Table 8.c). 
8.2.3
Criteria for Beginning or Delaying a Subsequent Treatment Cycle
TAK-659 is administered in continuous cycles; therefore, study drug should be administered 
continuously unless AEs occur that meet the dose modification criteria as outlined below 
(Table 8.b, Table 8.c).
8.2.4 TAK-659 Dose Modification for Hematologic Toxicities
Please refer to Table 8.b for dose delay and reduction recommendations for hematologic toxicities. 
When the dose of TAK-659 is withheld on the basis of the criteria in Table 8.b, clinical and 
laboratory re-evaluation should be repeated at least weekly or more frequently until the toxicity 
resolves to Grade ≤1 or baseline values. Upon recovery, TAK-659 may be re-initiated either at the 
same dose level or at a reduced dose level. When there are transient laboratory value abnormalities 
that, per investigator assessment, are not clinically significant or are related to the disease and not 
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the drug, continuation of therapy without following the dose modification guidelines is 
permissible upon discussion with the sponsor. 
Table 8.b
TAK-659 Dose Adjustments for Hematologic Toxicities
Criteria
Action
Neutropenia (ANC)
Grade 1 (ANC 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 value, 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 value, then reduce dose by 1 
dose level.
Febrile neutropenia (ANC 1000 cells/mm3, 
fever ≥38.5°C)
Withhold dose until resolved to Grade ≤1 (ANC 
≥1500 cells/mm3) or baseline value and fever/infection 
recovered, then reduce by 1 dose level.
Thrombocytopenia (PLT)
Grade 1 (PLT 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 value, 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 value, 
then reduce by 1 dose level.
Grade 3 anemia
Withhold dose until resolved to Grade ≤1 or baseline value, 
then:

If resolved in ≤7 days, maintain dose level.

If resolved in >7 days, reduce dose by 1 dose level.
Grade 4 anemia
Withhold dose until resolved to Grade ≤1 or baseline value, 
then reduce by 1 dose level if patient is not discontinued (see 
Section 8.2.1 and Section 9.7 for reasons for discontinuation).
PLT=platelets.
8.2.5
TAK-659 Dose Modification for Nonhematologic Toxicities
Please refer to Table 8.c for dose hold and dose reduction recommendations for nonhematologic 
toxicities. When the dose of TAK-659 is withheld on the basis of the criteria in Table 8.c, clinical 
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and laboratory re-evaluation should be repeated at least weekly or more frequently until the 
toxicity resolves to Grade ≤1 or baseline values. Upon recovery, TAK-659 may be re-initiated 
either at the same dose level or at a reduced dose level. When there are transient laboratory value 
abnormalities that, per investigator assessment, are not clinically significant or are related to 
disease and not the drug, continuation of therapy without following the dose modification 
guidelines is permissible upon discussion with the sponsor. 
Table 8.c
TAK-659 Dose Adjustments for Nonhematologic Toxicities
Criteria
Action
All Grade 3 nonhematologic toxicities, including 
suspected pneumonitis, with the exception of:

Grade 3 nausea, vomiting, and diarrhea resolved 
to Grade ≤1 or baseline values within 48 hours 
with optimal antiemetics and antidiarrheal 
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 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 value within 72 hours with 
phosphate repletion.

Other Grade 3 asymptomatic enzyme elevations 
not considered clinically significant following 
agreement between sponsor and investigator.
Hold TAK-659 until resolution to Grade ≤1 or baseline 
values, then:

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, maintain the dose level (no dose hold 
required).
Grade 4 nonhematologic toxicities, including 
suspected pneumonitis, with the exception of: 

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 value within 72 hours with 
phosphate repletion. 

Other Grade 4 asymptomatic enzyme elevations 
not considered clinically significant following 
agreement between sponsor and investigator.
Consider permanently discontinuing TAK-659 (see Section 
8.2.1 and Section 9.7 for reasons for discontinuation), 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 of ≥1 dose level is 
required if study treatment resumes after resolution to 
Grade ≤1 or baseline values.
For the exceptions, hold TAK-659 until resolution to 
Grade ≤1 or baseline values, then:

If resolved in ≤7 days, maintain dose level.

If resolved in >7 days, reduce dose by 1 dose level.

If recurs, reduce dose by 1 dose level.
ALT=alanine aminotransferase; AST=aspartate aminotransferase.
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Grade 4 nonhematologic toxicities, with the exception of asymptomatic laboratory changes, 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, 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 to 
baseline values. 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 CPK), TAK-659 should be held until 
resolution to Grade ≤1 or baseline values. When 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.
8.2.6
Criteria for Dose Escalation During Stage 1 Ramp-up 
To provide patients the opportunity to derive maximum clinical benefit (without prohibitive 
toxicity), the starting dose of 60 mg QD could be increased to 80 mg QD at Cycle 2 Day 1, then 
increased to 100 mg QD at Cycle 3 Day 1, provided that there have been no drug-related AEs that 
require dose modification per protocol. 
At the end of each cycle during the ramp-up, patients will be assessed for their suitability to 
dose-escalate to the next level based on safety and tolerability. If the patient experiences any 
drug-related AEs that require dose modification (inclusive of dose held and dose reduction) per 
protocol in a given dose cycle, dose escalation will not proceed to the next level. If the AE(s) 
resolves, the patient may then restart dose escalation in the next cycle either at the same dose or a 
reduced dose according to the protocol-defined dose reduction criteria. In case that dose reduction 
is not required, when the patient resumes the study drug at the same dose, dose escalation to the 
next dose level and further to the full dose of 100 mg QD TAK-659 may be pursued if no 
recurrence of the same AE(s) or any other AEs leading to dose modification is observed in the next 
cycle of treatment. However, if the same AE(s) or different AE(s) requiring dose modification 
occur in two consecutive cycles at the same dose level, further dose escalation is not allowed. If the 
patient resumes the study drug at a reduced dose per protocol, no dose re-escalation is 
recommended.
8.3
Concomitant Medications and Procedures
During 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 taking or 
has taken while on study. All concomitant medications (defined as any medication given during 
the study) and significant nondrug therapies, including physical therapy and blood transfusions, 
should be recorded from signing of the 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:
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
Any antineoplastic therapy other than TAK-659 is prohibited during the 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 
PD) is not permitted during study. Palliative radiotherapy for local pain/symptom control in a 
preexisting nontarget lesion, if required, may be considered after discussion with the sponsor’s 
clinical representative. 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 AEs. 

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.

Prophylactic use of myeloid growth factors (eg, granulocyte colony stimulating factor 
[G-CSF], granulocyte macrophage-colony stimulating factor [GM-CSF]) is not recommended 
during the first cycle. 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 factor, 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 guidance for DDI studies.
–
Antifungals: itraconazole, ketoconazole, posaconazole, voriconazole.
–
Antibiotics: azithromycin, clarithromycin, erythromycin, telithromycin.
–
Antimycobacterials: rifabutin, rifampin, rifapentine.
–
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.
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–
Food/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 because of 
that AE, the medications listed above and in Appendix I may be used for AE management if there 
is no appropriate alternative treatment available per the investigator’s judgment 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. Patients should be 
closely monitored for potential toxicities.
Note that medications used to treat HIV or hepatitis C infection are not listed above or in 
Appendix I because patients with known HIV infection or known or suspected active hepatitis C 
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 or in Appendix I, its use must be discussed with the medical monitor or 
designee to assess the relative benefit and risk.
8.4
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.
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 childbearing potential and male patients should use highly 
effective methods of contraception through defined periods during and after study treatment as 
specified below.
Female patients of childbearing potential must: 

Agree to practice 1 highly effective method of contraception and 1 additional effective 
(barrier) method (see Appendix G) at the same time, from the signing of the 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 patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.)
Childbearing potential is defined as not having undergone surgical sterilization, hysterectomy, 
and/or bilateral oophorectomy, or not being postmenopausal for at least 1 year before screening 
visit (≥12 months of amenorrhea in the absence of other biological or physiological causes).
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Male patients, even if surgically sterilized (ie, status postvasectomy), who are sexually active with 
partners who are of childbearing potential, must: 

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

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods for the female partner] and withdrawal are not acceptable methods of contraception.)
Male patients should not donate sperm from the time of signing the ICF through 180 days after the 
last dose of study drug.
8.5
Management of Clinical Events
Therapies that are required to manage AEs and control cancer symptoms per standard clinical 
practice are allowed, 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 help 
establish eligibility for the study.
8.5.1
Prophylaxis Against Infection
Patients with advanced hematological malignancies may be at 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 the underlying disease (DLBCL). Lymphopenia can be associated with 
reactivation of herpes zoster, CMV, herpes simplex, and other viruses. Antiviral therapy such as 
acyclovir, ganciclovir, valacyclovir, or other antiviral agents may be initiated as clinically 
indicated. Testing of CMV replication by a local polymerase chain reaction (PCR) assay will be 
required at Baseline, and further monitoring and prophylactic or preemptive therapy to 
asymptomatic patients, if indicated, should follow the institutional standard practice. The 
following agents should be considered for prophylaxis or preemptive treatment against CMV: 
ganciclovir intravenously (IV), valganciclovir (PO), foscarnet (IV), or cidofovir (IV). Duration of 
antiviral therapy generally is for at least 2 weeks until CMV is no longer detected by PCR. 
Patients with lymphopenia may also be more prone to developing infections, such as respiratory 
tract infections or pneumonia. Consider a diagnosis of opportunistic infection including PJP in 
patients presenting with shortness of breath, cough, or fever. Prophylaxis for PJP must be initiated 
(either at Baseline or during treatment) if the following are present: 

Absolute CD4+ T-cell count of <200/mm3. 

Percentage of CD4+ T cells <20%.

Prior episode of PJP in medical history. 
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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 study 
treatment. When steroids or any immunomodulatory agents need to be used to manage AEs during 
the study, PJP prophylaxis should be considered when the study treatment resumes or is 
co-administered. Trimethoprim-sulfamethoxazole is recommended as the treatment of choice for 
PJP prophylaxis unless contraindicated; however, investigator discretion in selecting a more 
appropriate prophylaxis regimen for their patients is permitted. 
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 and 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.
8.5.2
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 or severe, discontinue TAK-659. Patients 
should be monitored for respiratory signs and symptoms throughout treatment and be advised to 
promptly report respiratory symptoms.
8.5.3
Nausea and/or Vomiting
This study will not initially employ prophylactic antiemetics before the first dose of the study drug 
during dose escalation; however, a patient who develops nausea or vomiting will be actively 
managed by employing 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 or vomiting. An optimal antiemetic regimen is 
defined as one that employs both a 5-hydroxytryptamine 3 serotonin receptor antagonist and a 
corticosteroid given in standard doses and according to standard schedules. 
8.5.4
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 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.
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8.5.5
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 according to the dose modification guidelines in Table 8.c.
8.5.6
Rash With or Without Pruritus
Prophylactic measures should 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.c. 
8.5.7
Thrombocytopenia
Blood counts should be monitored regularly as outlined in Appendix A with additional testing 
obtained according to standard clinical practice. Administration of TAK-659 should be modified 
per dose modification guidance in the protocol when thrombocytopenia occurs (see Table 8.b). 
Platelet transfusion is allowed to manage severe thrombocytopenia and 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/L 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.
8.5.8
Neutropenia
Blood counts should be monitored regularly as outlined in Appendix A with additional testing 
obtained according to standard clinical practice. TAK-659 administration should be modified per 
dose modification recommendations in the protocol when neutropenia occurs (see Table 8.b). 
Myeloid growth factors (eg, G-CSF, GM-CSF) may be used to treat severe 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 8.2.6).
8.5.9
Anemia
Hemoglobin should be monitored regularly as outlined in 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, and any asymptomatic patients with hemoglobin ≤7 to 8 g/dL, 
with the purpose of maintaining 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 and should be administered according to institutional practice.
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8.5.10 Hypophosphatemia
Hypophosphatemia has been observed in patients treated with TAK-659. Consider prophylaxis; 
otherwise, refer to dose modification guidelines in Table 8.c. 
8.5.11 Enzyme Elevations 
8.5.11.1 Transaminase, Amylase, Lipase, and CPK Elevations
Elevations of transaminases, amylase, lipase, and CPK have been observed. Events are generally 
asymptomatic and reversible with dose interruption. See dose modification guidelines in 
Table 8.c.
8.5.11.2 LDH Elevations
LDH elevations have been observed in the majority of patients exposed to TAK-659. These 
elevations have been asymptomatic, and their clinical significance is unknown. No action, such as 
dose interruption, has been taken as a result of increased LDH; however, LDH elevation is 
reversible on the basis of experience in patients who had TAK-659 interrupted for other reasons. 
8.6
Blinding and Unblinding
This is an open-label study.
8.7
Description of Investigational Agents
TAK-659 has been formulated into immediate-release, film-coated tablets via a common 
granulation process. Two different tablet dosage strengths, 20 mg and 100 mg, were formulated. 
The formulation contains compendial excipients that include mannitol, microcrystalline cellulose, 
hydroxypropyl cellulose, sodium starch glycolate, and magnesium stearate. Tablets were coated 
with Opadry film coat. 
8.8
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.
8.9
Packaging and Labeling
TAK-659 20 mg and 100 mg tablets will be packaged into round, white, high-density polyethylene 
bottles with induction seals, desiccant packs, and polypropylene child resistant caps. Each bottle of 
TAK-659 will be labeled with either a single-panel or multilanguage label containing pertinent 
study information, country-specific requirements, and a caution statement. 
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8.10
Storage, Handling, and Accountability
TAK-659 tablets should be stored in the original dispensing bottles at 1°C to 25°C (33.8°F to 
77°F) with excursions permitted to 30°C (86°F) as long as they do not exceed 7 days. All 
temperature excursions of the tablets must be reported back to the sponsor for assessment and 
determination for continued use. Refer to the Pharmacy Manual for additional information. The 
TAK-659 tablets must be used before the retest date indicated on the label or accompanying 
documentation. Throughout the clinical trial, the stability of the drug product will be monitored. 
TAK-659 tablets should remain in the original bottles provided to the investigational sites and 
patients. Drug supply must be kept in an appropriate, limited access, secure place until it is 
dispensed to the enrolled patients.
A drug dispensing log, including records of drug received from the sponsor and drug dispensed to 
the patients, 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. In the case of 
broken tablets, raising dust should be avoided during the clean-up operation. Damaged tablets may 
be harmful by inhalation, ingestion, or skin and/or eye contact. If damaged tablets come in contact 
with the eyes or skin, the area should be immediately and thoroughly flushed and washed 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. 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, Good Clinical Practice (GCP), 
applicable regulatory requirements, and International Conference on Harmonisation (ICH) 
guidelines.
9.1
Study Personnel and Organizations
The contact information for the Millennium Study Monitor or designee for this study, the central 
laboratory and any additional clinical laboratories, the coordinating investigator for each member 
state/country, and the contract research organization (CRO) may be found in the Study Manual. A 
full list of investigators is available in the sponsor’s or CRO’s investigator database.
For 24-hour contact information, please refer to the Study Manual.
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 study is for efficacy evaluation purposes. Details around cohort assignment in Stage 1 will be 
described in the Study Manual. 
9.4
Study Procedures
Patients will be evaluated at scheduled visits over the following study periods: Screening, 
Treatment, EOT, PFS follow-up, and OS follow-up. 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 before 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 (see Section 8.1 and Table A), 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) is not flexible. 
Refer to the Schedule of Events (Appendix A) for timing of assessments. Additional details are 
provided as necessary in the sections that follow. 
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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 or on Cycle 1 Day 1 if the screening visit is >4 days prior, 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 and include a description of 
prior therapies for it. In addition, concomitant medications will be recorded as specified in 
Section 9.4.9.
9.4.4
Physical Examination
A physical examination, either complete or symptom directed, will be completed per standard of 
care at the times specified in the Schedule of Events (Appendix A).
9.4.5
Patient Height and Weight
Height will be measured only during Screening (within 28 days before the first dose of TAK-659).
Weight will be measured during the times specified in the Schedule of Events (Appendix A).
9.4.6
ECOG Performance Status
ECOG performance status is to be assessed at the times specified in the Schedule of Events 
(Appendix A).
9.4.7
Vital Signs
Vital sign measurements include seated (after 3 to 5 minutes in this position) measurements of 
diastolic and systolic blood pressure, heart rate, oxygen saturation, and temperature.
9.4.8
Pregnancy Test
A serum pregnancy test will be performed for women of childbearing potential at Screening. 
A urine pregnancy test will be performed predose on Day 1 of all cycles and at the EOT visit, and 
negative results must be obtained before the first dose of study drug may be administered. If the 
screening serum test is done within 3 days before the first dose of study drug in Cycle 1 and the 
result is negative, the urine pregnancy test on Cycle 1 Day 1 may be waived. Additional pregnancy 
testing may be performed during the study at the discretion of the investigator, upon request by an 
IEC/IRB, or if required by local regulations.
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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 the ICF is signed through 28 days after the 
last dose of study drug or the start of subsequent antineoplastic therapy, whichever occurs first. See 
Section 8.3 for a list of concomitant medications and procedures to be avoided during the study 
unless otherwise specified.
9.4.10 Adverse Events
Monitoring of AEs, serious and nonserious, will be conducted throughout the study as specified in 
the Schedule of Events. Refer to Section 10.0 for details regarding definitions, documentation, and 
reporting of pretreatment events (PTEs), 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
Electrocardiogram
A 12-lead ECG will be administered at the time points specified in the Schedule of Events 
(Appendix A). 
Unless otherwise specified, 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 or safety 
laboratory blood sample coincides with the timing of ECG measurements, the ECG will be 
completed before the blood sample collection. In some cases, it may be appropriate to repeat an 
abnormal ECG to rule out improper lead placement as contributing to the ECG abnormality.
Confirmation that the machine estimates of the rate-corrected QT interval (milliseconds) of 
electrocardiograph (QTc) are accurate using the appropriate QT correction formula (Fridericia’s 
correction [QTcF], Bazett’s corrected QT interval [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 with a change in medication and/or correction of electrolyte abnormalities, and a 
repeat ECG meets eligibility requirements, the patient may enroll to 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).
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
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 fall or 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 
agreed to by the investigator and the sponsor’s clinician on a case-by-case basis. 
The ECGs performed 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 centrally. Handling and shipment of clinical 
laboratory samples are outlined in the Study Manual and Laboratory Manual. Additionally, the 
following safety laboratory tests should be performed locally for dosing decisions: standard 
hematology (with white blood cell differential count), AST, ALT, total bilirubin, creatinine, 
creatinine kinase, amylase, and lipase. Additional local laboratory tests should be considered on 
the basis of the AEs that are being monitored and may influence the dose decision.
Clinical laboratory evaluations will be performed as outlined below:
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).
Table 9.a
Clinical Chemistry and Hematology Tests
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
Amylase
AST
Bilirubin (total)
Blood urea nitrogen (BUN)
Calcium
Carbon dioxide (CO2)
Creatinine
Creatine kinase (CK)
Chloride
γ-Glutamyl transferase (GGT)
Glucose
Glycosylated hemoglobin (HbA1c)
Lactate dehydrogenase (LDH)
(including LDH isozymes)
Lipase
Magnesium
Phosphate
Potassium
Sodium
Total protein
Urate
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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 Cockroft-Gault formula will be employed as follows 
(Appendix F):
	
 
	
 
		
 
= [(140 −
) ∗	() ]/[72 ∗
! 
	
 (/")] 
For female patients, the result of the formula above should be multiplied by 0.85. 
9.4.14
Ophthalmic Exam
A slit lamp eye examination will be performed by an ophthalmologist at Screening; on Cycle 2 
Day 1, Cycle 7 Day 1, and 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 Baseline but not during the study unless clinically indicated. Additional eye 
exams may also be performed as required. Additionally, 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 
Efficacy will be assessed by an IRC. The membership of the IRC and the rules for review will be 
constituted by a protocol-specific charter; response will be assessed using both modified 2007 
IWG criteria for malignant lymphoma (Appendix D) [16] and the 2014 IWG (Lugano) criteria 
[15] at Screening; on Days 22 to 29 (predose) of Cycles 1, 3, and 6; every 3 cycles through 
Cycle 24; and every 6 cycles thereafter (until PD or start of alternative therapies). Patients who 
discontinue treatment and do not have previously documented radiographic PD will undergo an 
imaging assessment at the EOT visit. The ORR assessment based on the modified 2007 IWG 
criteria [16] will support the primary endpoint analysis for the study, and ORR based on the 2014 
IWG (Lugano) criteria [15] will support the secondary endpoint. Response will also continue to be 
assessed in PFS follow-up every 3 months for patients who discontinue treatment for reasons other 
than PD until occurrence of PD, start of alternative therapy, or conclusion of the study, whichever 
occurs first.
Response assessments should include radiographic imaging (CT/MRI and FDG-PET), evaluation 
of symptoms, and bone marrow aspirate/biopsy if appropriate (see details below) [15]. The 
FDG-PET imaging should be done minimally at Screening and at the end of Cycles 1, 3, and 6, or 
if clinically indicated (see Schedule of Events [Appendix A]). Central collection of images at 
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imaging time points by sponsor or designee is required. Investigator assessment of response 
following the modified 2007 IWG criteria will also be collected per the Schedule of Events 
(Appendix A).
Two modifications to the 2007 IWG criteria will be instituted in this study: 

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 positron emission tomography (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. It is recommended that the patient 
instead 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, then the patient may 
remain on study.

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 then required, 
and 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 3 months irrespective of duration on 
study. When patients discontinue for reasons other than PD, PFS follow-up requires disease 
assessment every 3 months, regardless of what the frequency of assessments was at the time of 
discontinuation.
9.4.15.1 CT Scans
CT scans of the chest, abdomen, and pelvis (neck should be included, if appropriate) will be 
performed to assess disease at Screening and 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 with oral contrast, unless contrast is 
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 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 contrast to avoid compromising PET results [15]. MRI may be performed in 
place of CT if CT is contraindicated; however the same modality that is used at baseline should be 
used for subsequent timepoints to maintain consistency.
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9.4.15.2 PET Scans
A PET scan with FDG extending from the neck through the mid thighs will be performed to assess 
disease as noted in the Schedule of Events (Appendix A). Examinations should be consistent 
across all time points, including amount of tracer, location of injection, arm position, and scan 
delay. After Cycle 12, PET scans will be performed only if needed to follow the disease, confirm 
the CR or PD status, or as indicated clinically. 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 
[15].
9.4.15.3 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, IHC 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.
9.4.16
Tumor Biopsies
9.4.16.1 Banked Tumor Specimen Measurements
Archival (banked) tumor tissue samples should be obtained at Screening, if available, for all 
patients enrolled to identify candidate biomarkers predictive of clinical response to TAK-659. 
A tumor pathology block or at least 20 unstained slides is required. Archival FFPE tumor tissue 
obtained at the time of the patient’s original diagnosis or during the course of disease (eg, at the 
time of relapse from last prior therapy), and FFPE tissue from the fresh tumor biopsy performed as 
part of the screening procedure to confirm the DLBCL diagnosis for eligibility, are acceptable 
specimens.
The banked sample collection is to support retrospective analysis of various genomic/genetic 
biomarkers or pathway signatures to identify potential predictive biomarkers significantly 
associated with clinical response to TAK-659 in patients with DLBCL. Biomarkers to be 
investigated include, but are not limited to, BCR/SYK pathway molecules; BCR gene expression 
profiles; tumor-specific somatic gene alterations; other disease-relevant biomarkers such as 
BCL-2, MYC, BCL-6, and Ki-67; and known subtype classifications, such as ABC and GCB types 
for patients with DLBCL.
9.4.16.2 Fresh Tumor Biopsies
All patients will undergo fresh tumor biopsy during Screening unless the patient does not have a 
safely accessible lesion and a fresh biopsy procedure would put the patient at unjustifiable risk. 
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Optional tumor biopsies may be obtained from consenting patients at any time during the study as 
determined by the investigator when patients have responded or responded and relapsed. The 
biopsy material will be submitted for local pathology review to confirm diagnosis of DLBCL to 
support the eligibility evaluation for the patient.
 
. If a patient has had a biopsy that confirms the DLBCL diagnosis for 
eligibility performed within 1 month (≤30 days) before Cycle 1 Day 1 or between the completion 
of previous treatment and the Screening period of this study, no additional biopsy will be required 
pending the availability of a sufficient amount of archival tumor tissue for local pathology 
confirmation and biomarker studies. If the available archival tumor tissue sample is not sufficient, 
additional discussion will need to take place with the sponsor or designee, and a fresh tumor 
biopsy may be requested. If a patient has neither a safely accessible lesion for fresh biopsy nor 
archival biopsy samples obtained between the completion of previous treatment and the Screening 
period, upon approval from the sponsor or designee, the confirmation of a DLBCL diagnosis for
the patient may be based on an archival specimen supporting a prior DLBCL diagnosis for the 
purpose of fulfilling eligibility.
Optional fresh tumor biopsies can be requested during the study (eg, when patients have responded 
or responded and relapsed) for the purpose of exploratory biomarker studies if the patient agrees to 
the procedure and signs an informed consent.
Patients who undergo biopsy of tumor tissue must have adequate platelet function per investigator 
assessment, an activated partial thromboplastin time and a prothrombin time within the normal 
range, and no history of excessive bleeding or recent exposure to antiplatelet or anticoagulant 
therapy (eg, clopidogrel [Plavix] or salicylates [aspirin] in the prior 7 days). The tumor biopsy 
procedure will be performed under radiological guidance if indicated, or surgically if the site of 
disease is superficial and palpable or visible.
9.4.17
Analysis of ctDNA
Plasma samples will be collected from all patients as indicated in the Schedule of Events 
(Appendix A), and plasma will be extracted to obtain ctDNA. Changes in the amount of purified 
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ctDNA may be quantified and monitored during the course of treatment. In addition, ctDNA may 
be subjected to analysis of genetic alterations (mutations, translocations, amplifications) using an 
appropriate platform, such as next-generation sequencing.
9.4.18
Analysis of Cytokines/Chemokines
Serum samples will be collected from all patients for pharmacodynamic evaluation as indicated in 
the Schedule of Events (Appendix A, Table A), and the cytokines/chemokines 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.
9.4.19
Analysis of Immune Cells in Peripheral Blood
 
9.4.20
PK Measurements
Blood samples for the determination of TAK-659 plasma concentrations will be obtained during 
Cycles 1 through 4 at the following time points via a limited (sparse) sampling strategy (refer to 
Appendix A, Table A, for additional details):
!
Cycle 1 Day 1:
predose (within 1 hour before dosing).
!
Cycle 1 Day 1:
2 to 4 hours postdose.
!
Cycle 1 Day 8:
any time during the scheduled clinic visit after TAK-659 administration at 
home.
!
Cycle 1 Day 15:
predose (immediately before dosing).
!
Cycle 1 Day 15:
2 to 4 hours postdose.
!
Cycle 1 Day 22:
predose (immediately before dosing).
!
Cycle 1 Day 22:
2 to 4 hours postdose.
!
Cycle 2 Day 1:
predose (immediately before dosing).
!
Cycle 2 Day 1:
2 to 4 hours postdose (for dose titration patients only).
!
Cycle 2 Day 15
predose (immediately before dosing, for dose titration patients only).
!
Cycle 2 Day 15:
2 to 4 hours postdose (for dose titration patients only).
!
Cycle 3 Day 1:
predose (immediately before dosing).
!
Cycle 3 Day 1:
2 to 4 hours postdose (for dose titration patients only).
!
Cycle 3 Day 15:
predose (immediately before dosing, for dosing titration patients only).
!
Cycle 3 Day 15:
2 to 4 hours postdose (for dose titration patients only).
Property of Takeda: For non-commercial use only and subject o the applicable Terms of Use
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!
Cycle 4 Day 1:
predose (immediately before dosing). 
For clinic visits where predose PK samples are to be collected, patients will be instructed to refrain 
from taking their TAK-659 dose at home before the clinic visit. At these visits, predose PK 
samples will be collected before TAK-659 dosing. For the Cycle 1 Day 8 visit, patients should be 
instructed to take their TAK-659 dose at home before the clinic visit. At this visit, the PK sample 
can be collected at any time during the clinic visit. A distribution of visit times during the day 
across patients is to be encouraged to ensure a range of postdose PK sampling times across the 
study population. 
Details about collecting, processing, storing, and shipping the PK samples are provided in the 
Laboratory Manual.
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.
The primary aim of PK sampling in this study is to measure the plasma concentration of TAK-659; 
however, plasma 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. 
9.4.21
DNA Measurements
At Screening, 3 buccal epithelial cell samples will be obtained from patients. 
 
 
 
 
 
 
9.4.22
CMV Testing
A blood sample will be obtained during Screening for the determination of CMV replication per 
local PCR; however, a sample will also be collected for central testing at this time point. The local 
CMV viral load data will be entered into the eCRF along with the normal range for the local assay. 
Further monitoring and prophylaxis or preemptive treatment against CMV in asymptomatic 
patients, if indicated, will follow the local standard practice.
Property of Takeda: For n
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9.5
Completion of Study Treatment (for Individual Patients)
For the purpose of the primary analysis, patients will be considered to have completed study 
treatment if they have an opportunity to complete 6 cycles of treatment with TAK-659 or if they 
experience PD.
9.6
Completion of Study (for Individual Patients)
Patients will be considered to have completed the study if:

They are followed until death or the conclusion of the study, whichever occurs first.

They remain on study treatment free of PD until the start of alternative therapy or the 
conclusion of the study, whichever occurs first. 

They continue on to the survival follow-up after discontinuation of the study drug.

They discontinue study treatment while in CR and continue on to the follow-up for PD, and 
either:
–
Experience PD, or
–
Reach the end of the follow-up period.

The sponsor terminates the study.
9.7
Discontinuation of Treatment With Study Drug
Treatment with study drug must be discontinued for any of the following reasons: 

Occurrence of drug-related Grade 4 nonhematologic toxicity or Grade 4 anemia, or other 
drug-related AEs that require study drug discontinuation per dose modification guidelines in 
Section 8.2. 

If dosing of TAK-659 is interrupted for >21 days for study drug-related or possibly related 
AEs despite supportive treatment per standard clinical practice. (Exceptions to this criterion 
may be made after discussion and agreement between the investigator and the sponsor based 
on the benefit and risk assessment).

If more than 2 dose reductions are required for a patient.

Occurrence of AEs, resulting in discontinuation of study drug that is desired or considered 
necessary by the investigator and/or the patient (if applicable).

Disease progression per 2007 and/or 2014 IWG criteria as determined by the investigator (see 
Section 9.4.15).

Use of a nonpermitted concomitant drug, as defined in Section 8.3, in which the predefined 
consequence is withdrawal from treatment. (The sponsor should be contacted to discuss 
whether trial treatment must be discontinued.)

Occurrence of pregnancy (if applicable).
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
Symptomatic deterioration (at investigator’s discretion). 

Initiation of hematopoietic stem cell transplant.

Withdrawal of consent by patient.

Patient is lost to follow-up.
Because of medical need, it is permissible per protocol for a patient to start the study treatment 
before pathological confirmation of the DLBCL diagnosis as long as the diagnosis is confirmed 
within 4 weeks after Cycle 1 Day 1 dosing. If the diagnosis of DLBCL is not confirmed, or the 
histological subtype of DLBCL is not confirmed to be an eligible type for the study, the patient 
will be replaced. If a patient, after being enrolled and dosed with the study drug, is found to have 
failed to meet all eligibility criteria at Baseline, the patient will be replaced. 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 do not have a confirmed diagnosis of DLBCL will continue 
to receive treatment until PD, unacceptable toxicity, or withdrawal from the study.
9.8
Withdrawal of Patients From Study
Patients may discontinue the trial at any time without giving a reason(s).
A patient must be withdrawn from the study for any of the following reasons:

Withdrawal of consent by patient.

Participation in any other therapeutic trial during the treatment duration of this trial.

Patient noncompliance with protocol.
9.9
Early Discontinuation of the Study
The sponsor has the right to terminate this study at any time. Reasons for terminating the study 
may include, but are not limited to, the following:

The incidence or severity of AEs in this or other studies indicates a potential health hazard to 
patients.

Poor enrollment of patients, making completion of the trial within an acceptable timeframe 
unlikely.

Plans to modify or discontinue the development of the study drug.
The sponsor will notify the investigator if the sponsor decides to discontinue the study.
9.10
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. 
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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 Millennium clinician or 
designee. The timing of PK and pharmacodynamic assessments, however, as specified in the 
Schedule of Events (Appendix A, Table A) 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.
9.11
Posttreatment Follow-up Assessments (PFS and OS)
Patients who stop treatment for any reason other than PD will continue to have PFS follow-up 
visits. The PFS follow-up visit should be conducted at the site every 3 months after the last dose of 
study drug or until PD, the start of alternative therapy, or the conclusion of the study, whichever 
occurs first. After the occurrence of PD, patients will continue to have OS follow-up visits. The OS 
information will be collected every 3 months after the last dose of study drug until death or the 
conclusion of the study, whichever occurs first. 
Survivor information may be collected by methods that include, but are not limited to, telephone, 
email, mail, or retrieval from online or other databases (eg, social security indexes). In addition, 
data about the start of other anticancer therapies will be collected.
If a patient has transitioned to either ASCT 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 Millennium Department of Pharmacovigilance 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 PTE Definition
A PTE is any untoward medical occurrence in a patient who has signed informed consent to 
participate in a study but before administration of any study medication; it does not necessarily 
have to have a causal relationship with study participation.
10.1.2 AE Definition
AE means any untoward medical occurrence in a patient administered a pharmaceutical product; 
the untoward medical occurrence does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product whether or not it is related to the medicinal product. This includes any 
newly occurring event, or a previous condition that has increased in severity or frequency since the 
administration of study drug.
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 that hypothetically might have caused death if it were more 
severe).

Requires inpatient hospitalization or prolongation of an existing hospitalization
(see clarification in the paragraph in Section 10.2 on planned hospitalizations).

Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions).

Is a congenital anomaly/birth defect.

Is a medically important event. This refers to an AE that may not result in death, be 
immediately life-threatening, or require hospitalization, but may be considered serious when, 
on the basis of appropriate medical judgment, the AE may jeopardize the patient, require 
medical or surgical intervention to prevent the outcomes listed above, or involves suspected 
transmission via a medicinal product of an infectious agent. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
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development of drug dependency or drug abuse; any organism, virus, or infectious particle 
(eg, prion protein disease or transmissible spongiform encephalopathy), pathogenic or 
nonpathogenic, is considered an infectious agent.
In this study, intensity for each AE, including any laboratory abnormality, will be determined 
using the NCI CTCAE, version 5.0, effective date 27 November 2017 [17]. 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 1 comprehensive event.
Regardless of causality, SAEs and serious PTEs (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 PTE may 
be requested by Takeda. SAE report information must be consistent with the data provided on the 
eCRF.
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SAE Reporting Contact Information
Cognizant
US and Canada
Toll-Free Fax #: 1-800-963-6290
E-mail: takedaoncocases@cognizant.com
All Other Countries (Rest of World)
Fax #: 1-202-315-3560
E-mail: takedaoncocases@cognizant.com
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 intensity of the 
event and the relationship of the event to study drug administration. For serious PTEs, the 
investigator must determine both the intensity of the event and the relationship of the event to 
study procedures.
Intensity for each AE, including any laboratory abnormality, will be determined using the NCI 
CTCAE, version 5.0, effective date 27 November 2017 [17]. The criteria are provided in the Study 
Manual.
Relationship to study drug administration will be determined by the investigator responding yes 
or no 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 the ICF through 28 days after administration of the 
last dose of study drug or until the start of subsequent anticancer therapy, whichever occurs 
first, and recorded in the eCRFs. 

Serious PTEs will be reported to the Takeda Global Pharmacovigilance department or 
designee from the signing of the ICF up to the first dose of study drug and will be recorded in 
the eCRFs.

Related and unrelated SAEs will be reported to the Takeda Global Pharmacovigilance 
department or designee from the signing of the ICF through 28 days after administration of the 
last dose of study drug and recorded in the eCRFs. 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).
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10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events
If a woman becomes pregnant or suspects that she is pregnant while participating in this study, she 
must inform the investigator immediately and permanently discontinue study drug. The sponsor 
must also be contacted immediately by 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.
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 email address provided below.
Call Center
Phone Number
Email
Fax
DLSS
1-844-662-8532 
Non-toll-free number: 
1-510-740-1273 
GlobalOncologyMedinfo@takeda.com 
1-800-881-6092
Product complaints 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 Cognizant 
(refer to Section 10.2)
10.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, including the European 
Medicines Agency, investigators, and IRBs or IECs, as applicable, in accordance with national 
regulations in the countries where the study is conducted. Relative to the first awareness of the 
event by/or further provision to the sponsor or sponsor’s designee, SUSARs will be submitted to 
the regulatory authorities as an expedited report within 7 calendar days for fatal and 
life-threatening events and 15 calendar days for other serious events, unless otherwise required by 
national regulations. The sponsor will also prepare an expedited report for other safety issues 
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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 will also 
forward a copy of all expedited reports to its IRB or IEC in accordance with national regulations.
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11.0
STUDY-SPECIFIC COMMITTEES
11.1
IRC
An independent radiologic review committee (IRC) will review all disease evaluation data 
between Screening and PD (including the PFS follow-up period) from the study and determine 
disease status (response and progression). Data from the IRC will not be provided back to the 
investigator during the conduct of the study.
11.2
Steering Committee 
The SSC will comprise a subset of investigators and sponsor personnel involved in the study or 
other external lymphoma key opinion leaders. The SSC will oversee the conduct and reporting of 
the study, ensuring expert clinical guidance and a high standard of scientific quality. The SSC will 
make recommendations of the Stage 2 dose regimen selection upon completion of Stage 1 and any 
necessary modifications to the protocol. The SSC charter will define the responsibilities of the 
committee.
11.3
Independent Data Monitoring Committee 
The study will not have an independent data monitoring committee.
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12.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
If selected for coding, AEs, PTEs, medical history, and concurrent conditions will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the WHO 
Drug Dictionary.
12.1
eCRFs 
Completed eCRFs are required for each patient who signs an ICF.
The sponsor or its designee will supply investigative sites with access to eCRFs and will make 
arrangements to train appropriate site staff in the use of the eCRF. These forms are used to transmit 
the information collected in the performance of this study to the sponsor, CRO partners, and 
regulatory authorities. Investigative sites must complete eCRFs in English.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site. 
Any change of, modification of, or addition to the data on the eCRFs should be made by the 
investigator or appropriate site personnel. Corrections to eCRFs are recorded in an audit trail that 
captures the old information, the new information, identification of the person making the 
correction, the date the correction was made, and the reason for change.
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the principal investigator must retain 
full responsibility for the accuracy and authenticity of all data entered on the eCRFs.
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor or its designee will be permitted to review the patient’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed eCRFs 
are the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor.
12.2
Record Retention
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating patients, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated ICFs, patient authorization forms regarding the use of 
personal health information (if separate from the ICFs), electronic copy of eCRFs including the 
audit trails, and detailed records of drug disposition to enable evaluations or audits from regulatory 
authorities, the sponsor, or its designees. Any source documentation printed on degradable 
thermal-sensitive paper should be photocopied by the site and filed with the original in the 
patient’s chart to ensure long-term legibility. Furthermore, ICH E6 Section 4.9.5 requires the 
investigator to retain essential documents specified in ICH E6 (Section 8) until at least 2 years 
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after the last approval of a marketing application for a specified drug indication being investigated 
or, if an application is not approved, until at least 2 years after the investigation is discontinued and 
regulatory authorities are notified. In addition, ICH E6 Section 4.9.5 states that the study records 
should be retained until an amount of time specified by applicable regulatory requirements or for a 
time specified in the Clinical Study Site Agreement between the investigator and sponsor.
Refer to the Clinical Study Site Agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of any 
such documents.
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13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized before the dose exploration 
analysis. This document will provide further details regarding the definition of analysis variables 
and analysis methodology to address all study objectives.
13.1.1 Analysis Populations
DLBCL Population
The DLBCL population includes all patients who have a confirmed DLBCL diagnosis and who 
receive at least 1 dose of TAK-659. The DLBCL population will be used for primary and 
secondary efficacy analysis, and for additional efficacy analyses.
Modified Intent-to-Treat Population
The modified intent-to-treat (mITT) population includes all patients who receive at least 1 dose of 
TAK-659. The mITT will be used for the sensitivity analyses for the efficacy analyses.
Per-Protocol Population
The per-protocol population includes all patients who receive at least 1 dose of TAK-659 and who 
have measurable disease at Baseline and no other major protocol deviations that could potentially 
affect tumor response.
Safety Population
The safety population includes all patients who receive at least 1 dose of TAK-659. The safety 
population will be used for all baseline characteristics, safety analyses, and exposure analysis.
Response-Evaluable Population
The response-evaluable population includes all patients who receive at least 1 dose of TAK-659 
and have measurable disease at Baseline and least 1 postbaseline disease assessment. The 
response-evaluable analysis set will be used for sensitivity analyses of efficacy endpoints that are 
related to response, such as ORR, CR, and DOR.
13.1.2 Analysis of Demographics and Other Baseline Characteristics
Demographics and baseline characteristics, including age, gender, race, weight, height, and other 
parameters, will be summarized using descriptive statistics. 
13.1.3 Efficacy Analysis
13.1.3.1 Primary Efficacy Analysis
The primary endpoint for this study is ORR as assessed by IRC according to modified 2007 IWG 
criteria for malignant lymphoma [16] (Stage 2). Overall response is defined as a CR or PR. ORR is 
the proportion of patients who have overall responses. This primary efficacy hypothesis will be 
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tested using the null hypothesis that ORR for TAK-659 is <20% versus the alternative hypothesis 
that the ORR for TAK-659 is ≥20%. A 1-sided exact binomial test with a significance level of 
0.025 will be used to test this hypothesis. Its associated 1-sided 97.5% CI will be calculated. For 
ease of interpretation, the 2-sided 95% CI of the ORR will also be calculated. Note that the 1-sided 
97.5% CI and the lower bound of the 2-sided 95% CI will be the same. Also note that the primary 
efficacy analysis will be based on the DLBCL population using data from Stage 2.
Sensitivity analyses may be done for ORR using the mITT population, the 2014 IWG criteria [15], 
investigator-assessed responses, and the response-evaluable and per-protocol populations.
Subgroup analyses of ORR will be carried out using subgroups that will be defined in the SAP.
13.1.3.2 Key Secondary Efficacy Analysis
The key secondary efficacy endpoint is CR rate by IRC. The key secondary efficacy endpoint will 
be tested only if the primary efficacy endpoint of ORR per IRC is statistically significant. The key 
secondary efficacy hypothesis will be tested using the null hypothesis of CR rate less than 15% 
versus the alternative hypothesis of CR rate greater than or equal to 15%. If the primary endpoint is 
statistically significant, the key secondary endpoint will be tested at a 1- sided alpha of 0.025. 
Please note that the primary analysis for the key secondary endpoint is using the DLBCL 
population. Sensitivity analysis that is consistent with the sensitivity analysis for the primary 
endpoint may be done for the key secondary endpoints.
13.1.3.3 Secondary Efficacy Analysis
The secondary efficacy endpoints are:

ORR per IRC according to the 2014 IWG (Lugano) criteria [15] (Stage 2).

CR rate per IRC according to the 2014 IWG (Lugano) criteria [15] (Stage 2).

ORR per IRC to select the Stage 2 dose regimen of TAK-659 from the lead-in dose exploration 
phase (Stage 1).

ORR per IRC at 3, 6, and 9 cycles, respectively (Stage 2).

DOR and duration of CR per IRC (Stage 2).

ORR per IRC in patients with GCB DLBCL (Stage 2).

ORR per IRC in patients with DLBCL transformed from indolent NHL (Stage 2).

PFS per IRC (Stage 2).

OS (Stage 2).
For response rate-related endpoints (such as ORR), main analyses for the rates will be performed 
using the DLBCL population (patient population is essentially the mITT population excluding 
patients without a confirmed DLBCL diagnosis) and data as measured by IRC per modified 2007 
IWG criteria [16], with sensitivity analysis using the responses measured by IRC and 2014 IWG 
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(Lugano) criteria [15], and by the investigator, using the mITT population and the 
response-evaluable population.
Calculation of ORR at Cycle 3 (also 6 and 9) will include patients who are responders at Cycle 3 
(also 6 and 9) as the numerator and the number of patients in the population as the denominator.
For duration of CR and duration of response, a Kaplan-Meier approach will be used.
PFS and OS will be estimated using the Kaplan-Meier approach using the DLBCL population. 
Sensitivity analysis for PFS using investigator responses and the mITT population, respectively, 
may be carried out.
Subgroup analyses of secondary endpoints will be carried out using subgroups that will be defined 
in the SAP.
13.1.4 PK Analysis 
Plasma concentrations of TAK-659 will be listed by patient, dosing cycle and day, and nominal 
and actual time point. Descriptive statistics will be calculated for Ctrough (observed concentration at 
the end of the dosing interval) in Cycle 1 to Cycle 4.
The plasma PK data collected in this study are intended to contribute to population PK and 
exposure–response analyses of TAK-659. These analyses may include data collected from other 
TAK-659 clinical studies. If applicable, the specifics of the population PK and exposure–response 
analyses will be described in separate SAPs, and results will be reported separately from the CSR 
for Study C34004. 
13.1.5 Biomarker Analyses
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13.1.6 Pharmacogenomic Analyses
13.1.7 Safety Analysis
AEs will be summarized using the safety population. No statistical testing or inferential statistics 
will be generated.
All AEs will be coded using the effective version of the MedDRA. Data will be summarized using 
Preferred Term and primary System Organ Class.
Exposure to study drug and reasons for discontinuation will be tabulated using the safety 
population. Safety will be evaluated using frequency of AEs, severity and type of AEs, and by 
changes from Baseline in the patient’s vital signs, weight, ECGs, and clinical laboratory or 
instrumental examination results, using the safety population.
Treatment-emergent AEs (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.
Summaries of AEs will include:
!
TEAEs inclusive of all grades.
!
Drug-related TEAEs inclusive of all grades.
!
Grade 3 or higher TEAEs.
!
Grade 3 or higher, drug-related TEAEs.
!
SAEs.
!
Drug-related SAEs.
!
TEAEs leading to study drug discontinuation.
Descriptive statistics for actual values of clinical laboratory parameters, vital signs, and weight 
(and/or change from baseline values) over time will be calculated. Main laboratory values over 
time will be presented in graphs for key laboratory parameters.
Shift tables for laboratory parameters will be generated to show changes in NCI CTCAE grades 
from Baseline to worse postbaseline value. Graphical displays of key safety parameters may be 
used.
Property of Takeda: For non-commercial use only and subject to the a
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All concomitant medications collected from Screening throughout the study period will be 
classified to preferred terms according to the WHO drug dictionary. 
A summary of ECG abnormalities will be presented by visit. ECG parameters (QT, QTcB, and 
QTcF; PR interval; QRS; and heart rate) will be summarized at each scheduled visit along with the 
mean change from Baseline to each posttreatment visit.
13.1.8 Dose Exploration Analysis
Dose exploration analysis will occur at the end of Stage 1. Assuming a historical control rate of 
20% for ORR, 20 patients per dosing regimen are required to determine the dosing regimen for the 
phase 2 efficacy evaluation (Stage 2) portion of the study. Response data from both dosing 
regimens will be analyzed with a Bayesian model assuming prior of Beta(0.1,0.1) for each ORR. 
Dosing regimen A will be claimed ineffective if the posterior probability of ORRA <20% is greater 
than the threshold of 0.75, likewise for dosing regimen B. If both regimens are deemed to be 
ineffective, termination of the study without proceeding to stage 2 may be considered. Other 
considerations for making this decision should be taken into account, including but not limited to 
sample size limitation, relevant data from other TAK-659 trials, and applicable patient enrichment 
or selection strategy that justifies further evaluation of TAK-659 in this setting. If only one dosing 
regimen is determined to be ineffective, then the other dosing regimen is chosen as the dosing 
regimen for the remaining portion of the study. If neither dosing regimen is claimed to be 
ineffective, then regimen A will be chosen if the posterior probability of ORRA>ORRB is greater 
than the threshold of 0.55, likewise dosing regimen B will be chosen if the posterior probability of 
ORRB>ORRA is greater than 0.55. If both the posterior probability of ORRA>ORRB and the 
posterior probability of ORRB>ORRA are ≤0.55, clinical and safety factors will be considered to 
choose the dosing regimen for Stage 2. 
Consideration of an alternative dose regimen other than the two TAK-659 dose regimens 
evaluated in Stage 1 is permissible if supported by the Stage 1 data. For example, if the ramp-up 
dose schema (dose regimen B) is chosen based on the Bayesian model (see above) but majority of 
patients treated with dose regimen B fail to dose escalate beyond 60 mg QD TAK-659 following 
the dose escalation criteria, 60 mg QD TAK-659 may be considered as the dose for Stage 2. The 
Stage 1 data as well as other relevant supportive data from other trials of TAK-659 will be 
reviewed and discussed by the SSC. The stage 2 dose regimen of TAK-659 will be selected based 
on the recommendation by SSC upon agreement with the sponsor.
13.2
Interim Analysis and Criteria for Early Termination
The interim analysis will occur when approximately 40 patients with confirmed DLBCL are 
enrolled in Stage 2 whose response status can be adequately determined; ie, all 40 patients have 
either at least 1 posttreatment response evaluated or have been taken off study. At the interim 
analysis, if the posterior probability of ORR<20% is greater than the threshold of 0.75, the study 
will stop for futility; otherwise, the study will continue as planned until the final analysis. 
The interim analysis will include only those patients with confirmed DLBCL who have taken at 
least 1 dose of TAK-659, have had the opportunity to receive at least 3 cycles of treatment, and 
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have at least 1 posttreatment response assessment. Patients who do not have a confirmed DLBCL 
diagnosis or patients who have been enrolled but did not have enough follow-up will not be 
included in the interim analysis.
13.3
Determination of Sample Size
For the lead-in dose exploration portion (Stage 1) of the study, assuming a historical control rate of 
20% for ORR, at least 20 patients per dosing regimen are required to determine if either dosing 
regimen A or dosing regimen B is more effective.
For Stage 2 efficacy evaluation phase of the study, assuming a historical control rate of 20% for 
ORR and a TAK-659 ORR of 37%, this study will need to enroll at least 82 patients in Stage 2 to 
achieve 91% power at a 1-sided alpha level of 0.025, using an exact binomial test. After 
approximately 40 patients have been enrolled in Stage 2 and have had the opportunity to receive at 
least 3 cycles of treatment and have at least 1 posttreatment response evaluated, the interim 
analysis will be performed. The interim analysis will assess futility, and the study may either stop 
for futility (if posterior probability of ORR<20% is greater than the threshold of 0.75) or continue 
as planned.
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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, 
including but not limited to the Investigator’s Binder, study medication, patient medical records, 
informed consent documentation, documentation of patient authorization to use personal health 
information (if separate from the ICFs), and review of eCRFs and associated source documents. It 
is important that the investigator and other study personnel are available during the monitoring 
visits and that sufficient time is devoted to the process.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study patients. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation) from the study-related procedures per 
protocol.
The site should document all protocol deviations in the patient’s source documents. In the event of 
a significant deviation, the site should notify the sponsor or its designee (and IRB or IEC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the patient, or confound interpretation of 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.
14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the US FDA, the United Kingdom 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, patients) 
according to the protocol, the ethical principles that have their origin in the Declaration of Helsinki, 
and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct the study 
according to applicable local or regional regulatory requirements and align his or her conduct in 
accordance with the “Responsibilities of the Investigator” that are listed in Appendix B. The 
principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities.
15.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable state and federal/local requirements 
of each participating region. The sponsor or designee will require documentation noting all names 
and titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC 
has direct participation in this study, written notification regarding his or her abstinence from 
voting must also be obtained. Those American sites unwilling to provide names and titles of all 
members because of privacy and conflict of interest concerns should instead provide a Federal 
Wide Assurance Number or comparable number assigned by the Department of Health and 
Human Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the IB, a copy of the ICF, and if 
applicable, patient recruitment materials and/or advertisements and other documents required by 
all applicable laws and regulations, must be submitted to a central or local IRB or IEC for approval. 
The IRB’s or IEC’s written approval of the protocol and patient informed consent must be 
obtained and submitted to the sponsor or designee before commencement of the study (ie, before 
shipment of the sponsor-supplied drug or study-specific screening activity). The IRB or IEC 
approval must refer to the study by exact protocol title, number, and version date; identify versions 
of other documents (eg, ICF) reviewed; and state the approval date. The sponsor will notify site 
once the sponsor has confirmed the adequacy of site regulatory documentation and, when 
applicable, the sponsor has received permission from competent authority to begin the trial. Until 
the site receives notification no protocol activities, including screening, may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the ICF, recruitment 
materials intended for viewing by patients, local safety reporting requirements, reports and 
updates regarding the ongoing review of the study at intervals specified by the respective IRB or 
IEC, and submission of the investigator’s final status report to IRB or IEC. All IRB and IEC 
approvals and relevant documentation for these items must be provided to the sponsor or its 
designee.
Patient incentives should not exert undue influence for participation. Payments to patients must be 
approved by the IRB or IEC and sponsor.
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15.2
Patient Information, Informed Consent, and Patient Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The ICF, patient authorization form (if applicable), and patient 
information sheet (if applicable) describe the planned and permitted uses, transfers, and 
disclosures of the patient’s personal and personal health information for purposes of conducting 
the study. The ICF and the patient information sheet (if applicable) further explain the nature of the
study, its objectives, and potential risks and benefits, and the date informed consent is given. The 
ICF will detail the requirements of the participant and the fact that he or she is free to withdraw at 
any time without giving a reason and without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the ICF 
and if applicable, the patient authorization form. The ICF, patient authorization form (if 
applicable), and patient information sheet (if applicable) must be approved by both the IRB or IEC 
and the sponsor before use.
The ICF, patient authorization form (if applicable), and patient information sheet (if applicable) 
must be written in a language fully comprehensible to the prospective patient. It is the 
responsibility of the investigator to explain the detailed elements of the ICF, patient authorization 
form (if applicable), and patient information sheet (if applicable) to the patient. Information should 
be given in both oral and written form whenever possible and in the manner deemed appropriate by 
the IRB or IEC. 
The patient must be given ample opportunity to (1) inquire about details of the study, and (2) 
decide whether or not to participate in the study. If the patient determines he or she will participate 
in the study, then the ICF and patient authorization form (if applicable) must be signed and dated 
by the patient at the time of consent and before the patient enters into the study. The patients 
should be instructed to sign using their legal names, not nicknames, using blue or black ballpoint 
ink. The investigator must also sign and date the ICF and patient authorization (if applicable) at the 
time of consent and before the patient enters into the study; however, the sponsor may allow a 
designee of the investigator to sign to the extent permitted by applicable law.
Once signed, the original ICF, patient authorization form (if applicable), and patient information 
sheet (if applicable) will be stored in the investigator’s site file. The investigator must document 
the date the patient signs the ICF in the patient’s medical record. Copies of the signed ICF, the 
signed patient authorization form (if applicable), and patient information sheet (if applicable) shall 
be given to the patient.
All revised ICFs must be reviewed and signed by relevant patients in the same manner as the 
original informed consent. The date the revised consent was obtained should be recorded in the 
patient’s medical record, and the patient should receive a copy of the revised ICF.
15.3
Patient Confidentiality
The sponsor and designees affirm and uphold the principle of the patient’s right to protection 
against invasion of privacy. Throughout this study, a patient’s source data will only be linked to 
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the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited patient attributes, such as sex, age, or date 
of birth, and patient initials may be used to verify the patient and accuracy of the patient’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, the US FDA, the Medicines and Healthcare products Regulatory Agency, 
the Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the patient’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a patient’s study participation, 
and autopsy reports. Access to a patient’s original medical records requires the specific 
authorization of the patient as part of the informed consent process (see Section 15.2).
Copies of any patient source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, patient name, address, and other identifier fields 
not collected on the patient’s 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/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail.
15.4.2 Clinical Trial Registration
To ensure that information on clinical trials reaches the public in a timely manner and to comply 
with applicable laws, regulations and guidance, Takeda will, at a minimum, register interventional 
clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other publicly accessible 
websites before start of study, as defined in Takeda Policy/Standard. Takeda contact information, 
along with investigator’s city, state (for Americas’ investigators), country, and recruiting status 
will be registered and available for public viewing. 
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For some registries, Takeda will assist callers in locating trial sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting trial 
information. Once patients receive investigator contact information, they may call the site 
requesting enrollment into the trial. The investigative sites are encouraged to handle the trial 
inquiries according to their established patient screening process. If the caller asks additional 
questions beyond the topic of trial enrollment, they should be referred to the sponsor.
Any investigator who objects to Takeda providing this information to callers must provide Takeda 
with a written notice requesting that their information not be listed on the registry site. 
15.4.3 Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws, and/or regulations.
15.5
Insurance and Compensation for Injury
Each patient in the study must be insured in accordance with the regulations applicable to the site 
where the patient is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to clinical study patients. 
Refer to the Clinical Study Site Agreement regarding the sponsor’s policy on patient compensation 
and treatment for injury. If the investigator has questions regarding this policy, he or she should 
contact the sponsor or sponsor’s designee.
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16.0
REFERENCES
1.
Ferlay J, Shin H, Bray F, Forman D, Mathers C, Parkin D. GLOBOCAN 2008 v1.2, Cancer 
Incidence and Mortality Worldwide: IARC CancerBase No. 10 [Internet]. Published 2010. 
Accessed 25 February 2013.
2.
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.
3.
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. British 
Journal of Cancer 2011;105(11):1684-92.
4.
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. Journal of Clinical Oncology 
2014;32(10):1066-73.
5.
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.
6.
Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, et al. The 2016 revision of 
the World Health Organization classification of lymphoid neoplasms. Blood 
2016;127(20):2375-90.
7.
Schmidt MT, Huang Q, Alkan S. Aggressive B-cell lymphomas: a review and practical 
approach for the practicing pathologist. Advances in Anatomic Pathology 
2015;22(3):168-80.
8.
Stein H, Warnke R, Chan W. Diffuse large B-cell lymphoma, not otherwise specified. In: 
Swerdlow S, editor. WHO Classification of Tumours of the Haematopoietic and Lymphoid 
Tissues. Lyon, France: IARC; 2008, p. 233-7.
9.
Harris NL, Jaffe ES, Stein H, Banks PM, Chan JK, Cleary ML, et al. A revised 
European-American classification of lymphoid neoplasms: a proposal from the International 
Lymphoma Study Group. Blood 1994;84(5):1361-92.
10.
Rosenwald A, Wright G, Chan WC, Connors JM, Campo E, Fisher RI, et al. The use of 
molecular profiling to predict survival after chemotherapy for diffuse large-B-cell 
lymphoma. New England Journal of Medicine 2002;346(25):1937-47.
11.
Davis RE, Brown KD, Siebenlist U, Staudt LM. Constitutive nuclear factor kappaB activity 
is required for survival of activated B cell-like diffuse large B cell lymphoma cells. Journal 
of Experimental Medicine 2001;194(12):1861-74.
12.
Roschewski M, Staudt LM, Wilson WH. Diffuse large B-cell lymphoma-treatment 
approaches in the molecular era. Nature Reviews Clinical Oncology 2014;11(1):12-23.
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13.
Gifford GK, Gill AJ, Stevenson WS. Molecular subtyping of diffuse large B-cell lymphoma: 
update on biology, diagnosis and emerging platforms for practising pathologists. Pathology 
2016;48(1):5-16.
14.
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.
15.
Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, et al. 
Recommendations for initial evaluation, staging, and response assessment of Hodgkin and 
non-Hodgkin lymphoma: the Lugano classification. Journal of Clinical Oncology 
2014;32(27):3059-68.
16.
Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. Revised 
response criteria for malignant lymphoma. Journal of Clinical Oncology 2007;25(5):579-86.
17.
Common Terminology Criteria for Adverse Events (CTCAE). National Cancer Institute, 
National Institutes of Health, U.S. Department of Health and Human Services Series v.5.0. 
27 November 2017.
18.
Campo E, Swerdlow SH, Harris NL, Pileri S, Stein H, Jaffe ES. The 2008 WHO 
classification of lymphoid neoplasms and beyond: evolving concepts and practical 
applications. Blood 2011;117(19):5019-32.
19.
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. American Journal of Clinical 
Oncology 1982;5(6):649-55.
20.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron 1976;16(1):31-41.
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Appendix A
Schedule of Events
Schedule of Events for Treatment 
Screening (a)
Cycle 1
Cycle 2
Cycle 3
Cycles ≥4
EOT
PFS/OS (b)
Day 1
Day 8
Day 15
Day 22
Day 1
Day 15
Day 1
Day 15
Day 1
Informed consent
X
Inclusion/exclusion criteria
X
Demographics
X
Medical and smoking 
history
X
X (c)
Complete physical 
examination
X
Physical examination (either 
complete or 
symptom-directed)
X (c)
X
X
X
X
X
X
X
X
X
X (d)
Height
X
Weight
X
X
X
X
X
X
Vital signs (e)
X
X
X
X
X
X
X
X
X
X
X
X (d)
ECOG performance status
X
X
X
X
X
X
12-Lead ECG (f)
X
X
X
X
X
X
Response assessment for 
lymphoma by IWG 
(CT/FDG-PET) (g)
X
X (g)
X (g)
X (g)
X (g)
X (d)
Monitoring of concomitant 
medications and procedures
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.
AE reporting
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.
SAEs (h) will be reported from signing of the ICF through 28 days after the last dose of study drug.
TAK-659 administration (i)
TAK-659 is dosed PO QD every day.
Patient diary review(j)
X
X
X
X
X
X
X
X
X
X
Footnotes are on last table page. 
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Schedule of Events for Treatment
Screening 
(a)
Cycle 1
Cycle 2
Cycle 3
Cycles ≥4
EOT
PFS/OS 
(b)
Day 1
Day 8
Day 15
Day 22
Day 1
Day 15
Day 1
Day 15
Day 1
Ophthalmic exam (k)
X 
X
X (k)
X
Pregnancy test(l)
X
X
X
X
X
X
Hematology/chemistry(m)
X
X
X
X
X
X
X
X
X
X
X
Urinalysis (for hematuria and 
proteinuria evaluation) (m) (n)
X
X
X
X
X
X
LDH isozymes (m)
X
X
X
X
X
X
X
X (o)
CK testing (m)
X
X
X
X
X
X
X
X
X 
HbA1c (for patients who are 
hyperglycemic only (m)
X
HIV, Hep B, Hep C tests (p)
X
Plasma sample for ctDNA(q)
X
X 
X
Fresh tumor biopsy (r)
X
Archival (banked) tumor tissue 
sample (r)
X
Optional fresh tumor biopsy 
sample
X (s)
Blood samples for PK(u)
X
X
X
X
X
X
X
X
X (v)
CMV testing (z)
X
Footnotes are on the following page.
Property of Tak
Ta
Ta
Ta
Ta
llowing p
llowing
rcial use only and subject to the applicable Terms of Use
le
ycle 3
cle 3
lic
y 1
Da
Da
pp
ap
a
X
the
o
to
t t
b
t
X
bj
sub
X
su
su
su
su
d
y a
y
nly
e o
s
us
ia
CCI
CCI
CCI
CCI


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AE=adverse event; CK=creatine kinase; CMV=cytomegalovirus; CT=computed tomography; ctDNA=circulating tumor DNA; ECG=electrocardiogram; 
ECOG=Eastern Cooperative Oncology Group; FDG-PET=[18F]fluorodeoxyglucose-positron emission tomography; HbA1c=glycosylated hemoglobin; 
Hep B=hepatitis B virus; Hep C=hepatitis C virus; HIV=human immunodeficiency virus; IWG=International Working Group; LDH=lactate dehydrogenase; 
PK=pharmacokinetics. 
Tests and procedures should be performed on schedule, but occasional changes are allowable (±3 days) with permission of the medical monitor or designee for 
holidays, vacations, and other administrative reasons. If extenuating circumstances prevent a patient from beginning treatment or completing a scheduled 
procedure or assessment within this time, the patient may continue the study only with the written permission of the medical monitor or designee.
(a) Unless otherwise noted, the Screening visit must occur within 28 days before the day of the first dose of study drug (Cycle 1 Day 1). The ICF may be signed 
more than 28 days before Cycle 1 Day 1.
(b) Patients who stop treatment for any reason other than PD will continue to have PFS follow-up visits. The PFS follow-up visit should be conducted at the site 
every 3 months from last dose of study drug until PD. Response will also continue to be assessed in PFS follow-up every 3 months for patients who discontinue 
treatment for reasons other than PD until occurrence of PD, start of alternative therapy, or conclusion of the study, whichever occurs first. After the occurrence 
of PD, patients will continue to have OS follow-up visits. The OS information will be collected every 3 months after the last dose of study drug until death or 
the conclusion of the study, whichever occurs first. For details about disease assessment, see footnote (g).
(c) The Cycle 1 Day1 physical examination and medical history are not required if the screening physical examination was conducted and medical history obtained 
within 4 days before administration of the first dose of study drug (Cycle 1 Day 1).
(d) Required for PFS only.
(e) Perform vital signs (blood pressure, heart rate, temperature, and oxygen saturation) measurement before dosing. Vital signs include seated measurements.
(f)
Single 12-lead ECGs will be performed at Screening, predose on Day 1 of each cycle, 2 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1, >Cycle 4, and at EOT. 
ECGs should be performed after the patient has rested quietly for at least 5 minutes in a supine position. When the timing of a PK or safety laboratory blood 
sample coincides with the timing of ECG measurements, the ECG will be completed before the blood sample collection.
(g) Response assessments for DLBCL per both the modified 2007 IWG response criteria for malignant lymphoma [16] and the 2014 IWG (Lugano) criteria [15], 
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; on Days 22-29 (predose) of Cycles 1, 3, and 6; every 3 cycles through Cycle 24; and every 6 cycles thereafter (until PD or the start of alternative 
therapy). Patients who discontinue treatment and do not have previously documented radiographic PD will undergo CT and response evaluation at the EOT 
visit. An FDG-PET scan extending from the neck through the mid thighs will be performed at Screening for all patients enrolled. FDG-PET scans should be 
conducted at the 3 subsequent response assessments (Cycles 1, 3, and 6) and repeated either at the time of assessment for CR or for recurrence/progression of 
disease. If the patient has had an appropriate FDG-PET and CT scan performed within 28 days of Cycle 1 Day 1, the results of that scan may be used for tumor 
lesion measurements at Screening. Central collection of disease assessment images by the sponsor or designee is required for patients.
(h) Including serious PTEs; see Section 10.2.
(i)
TAK-659 will be administered PO QD in 28-day cycles at either 100 mg or a 3-dose-level ramp-up leading to 100 mg QD (60, 80, 100 mg QD) depending on 
which cohort a patient is assigned (A or B). 
(j)
The study center staff will check the patient diary versus the patient’s supply of TAK-659 tablets to assess compliance.
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(k) An ophthalmic exam should be performed at Screening, Cycle 2 Day 1, Cycle 7 Day 1, and every 6 cycles thereafter ((2 weeks), and at EOT. See Section 
9.4.14 for details.
(l)
A serum β-human chorionic gonadotropin pregnancy test will be performed only for women of childbearing potential during Screening. A urine pregnancy test 
will be performed predose on Day 1 of all cycles and at the EOT visit, and negative results must be available before the first dose 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. 
Additional pregnancy testing may be performed during the study at the discretion of the investigator, upon request by an IEC/IRB, or if required by local 
regulations.
(m) Laboratory assessments can be conducted within 3 days before the scheduled visit, with the exception of PK and pharmacodynamic assessments, unless 
otherwise noted. If screening clinical laboratory testing was performed within 3 days before the Cycle 1 Day 1 dose, it does not need to be repeated on Cycle 1 
Day 1. 
(n) Urinalysis samples will be collected predose and analyzed at the site’s local laboratory.
(o) Cycle 4 only. 
(p) HIV, hepatitis B virus, and hepatitis C virus tests will be performed during Screening. Negative results must be available before the first dose of study drug may 
be administered.
(q) A plasma sample will be obtained for evaluation of ctDNA at Screening, Cycle 5 Day 1, and at EOT/relapse.
(r) An FFPE tumor block or appropriately stained slides from a fresh biopsy is required. Subjects who undergo tumor biopsies must have adequate platelet 
function per investigator assessment, an activated partial thromboplastin time and a prothrombin time within the normal range, and no history of excessive 
bleeding or recent exposure to antiplatelet or anticoagulant therapy (eg, clopidogrel [Plavix] or salicylates [aspirin] in the prior 7 days). 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. See Section 9.4.16 for details. These samples will be evaluated for candidate biomarkers predictive of response. Archival 
tumor tissue is to be collected only from enrolled patients and may be collected and sent to the sponsor after initiation of protocol treatment.
(s) Optional tumor biopsies may be obtained from consenting patients at any time during the study as determined by the investigator when patients have responded 
or responded and relapsed. Subjects who undergo optional tumor biopsies must have adequate platelet function per investigator assessment, an activated partial 
thromboplastin time and a prothrombin time within the normal range, and no history of excessive bleeding or recent exposure to antiplatelet or anticoagulant 
therapy (eg, clopidogrel [Plavix] or salicylates [aspirin] in the prior 7 days).
(t)
(u) Blood samples for PK analysis will be collected at time points specified in Table A. 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.
(v) Cycle 4 only.
(w)
 
Property
akeda: 
n-commercial use only and subject to the applicable Terms of Use
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(x)
(y)
(z) This blood sample collected during Screening will be used for local PCR testing of CMV replication; however, a sample will also be collected for central 
testing at this time point. The CMV viral load data will be entered in the eCRF along with the local normal range for the assay. Further monitoring of CMV, if 
indicated, will follow the local standard practice.
Property of Takeda: For non-commercial use only and subject t
on; ho
on; ho
ocal no
al norm
o
able Terms of Use
le
CCI
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Table A
PK and Pharmacodynamic Sample Breakdown: Cycle 1 Through Cycle 4 (Stages 1 and 2)
Cycle 1
Cycles 2
Cycle 3
Cycle 4
Day 1
Day 8
(PK 
Only)
Day 15
Day 22
Day 1
Day 15
Day 1
Day 15
Day 1
PK
Pharmaco-
dynamics (a)
PK
Pharmaco-
dynamics (a)
PK
Pharmaco-
dynamics (a)
PK
PK
PK
PK
PK
Predose (within 1 h 
before dosing on 
Cycle 1 Day 1 and 
immediately before 
dosing on all other 
days) (b) (c)
X
X
X
X
X
X
X
X (d)
X
X (d)
X
2-4 h postdose (e)
X
X
X
X
X
X (d)
X (d)
X (d)
X (d)
At time of clinic visit
X (f)
PK=pharmacokinetics. 
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 blood sample collection.
(a) Pharmacodynamic samples in this table refer to cytokines/chemokines. For peripheral blood immune cell assessments, refer to 
(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.
(c) The timing of the predose samples on Cycle 1 Days 15 and 22, Cycle 2 Days 1 and 15, Cycle 3 Days 1 and 15, and Cycle 4 Day 1 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.
(d) For dose titration patients only. 
(e) The PK and pharmacodynamic samples should be collected at the same time during the 2-4 hours postdose window.
(f) For the Cycle 1 Day 8 visit, patients will be instructed to take their TAK-659 dose at home before their clinic visit. The PK sample can be collected at any time 
during the clinic visit. A distribution of clinic visit times across patients is to be encouraged to provide a range of postdose PK sampling times across the study 
population.
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Appendix B
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the US FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this study.
The investigator agrees to assume the following responsibilities by signing Form FDA 1572:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff who will assist in the protocol.
3. If the investigator/institution retains the services of any individual or party to perform 
trial-related duties and functions, the investigator/institution should ensure that this individual 
or party is qualified to perform those trial-related duties and functions and should implement 
procedures to ensure the integrity of the trial-related duties and functions performed and any 
data generated.
4. Ensure that study-related procedures, including study specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential patients, before the receipt of written 
approval from relevant governing bodies/authorities.
5. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
6. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
21 CFR (Code of Federal Regulations) Part 56, ICH, and local regulatory requirements.
7. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to patients. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
8. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH, and local 
regulations, are met.
9. Obtain valid informed consent from each patient who participates in the study, and document 
the date of consent in the patient’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each ICF should contain a patient authorization section that 
describes the uses and disclosures of a patient’s personal information (including personal 
health information) that will take place in connection with the study. If an ICF does not include 
such a patient authorization, then the investigator must obtain a separate patient authorization 
form from each patient.
10. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc., and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
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contact and receive written approval from the sponsor before disposing of any such 
documents.
11. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
12. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor.
13. Report adverse reactions (drug-related AEs) 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.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance activities relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.
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Appendix D
IWG Response Criteria for Lymphoma
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, IHC 
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; one 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 
or 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 [16].
SD=stable disease, SPD=sum of the product of the diameters.
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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 [19]. 
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Appendix F
Cockcroft-Gault Equation
For men:
Creatinine clearance =
(140-age [years])weight [kg]
72(serum creatinine [mg/dL])
OR
Creatinine clearance =
(140-age [years])weight [kg]
0.81(serum creatinine [µmol/L])
For women:
Creatinine clearance =
0.85 (140-age [years])weight [kg]
72(serum creatinine [mg/dL])
OR
Creatinine clearance =
0.85 (140-age [years])weight [kg]
0.81(serum creatinine [µmol/L])
Source: Cockcroft DW, Gault MH, 1976. [20]
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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 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_Contraception.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 patient.
(5) Male condom combined with either cap, diaphragm, or sponge with spermicide (double-barrier methods) is also 
considered an acceptable, but not highly effective, birth control method.
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Appendix H
New York Heart Association Classification of Cardiac Disease
Class
Functional Capacity
Objective Assessment
I
Patients with cardiac disease but without resulting limitations of 
physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain.
No objective evidence of 
cardiovascular disease.
II
Patients with cardiac disease resulting in slight limitation of physical 
activity. They are comfortable at rest. Ordinary physical activity 
results in fatigue, palpitation, dyspnea, or anginal pain.
Objective evidence of minimal 
cardiovascular disease.
III
Patients with cardiac disease resulting in marked limitation of 
physical activity. They are comfortable at rest. Less than ordinary 
activity causes fatigue, palpitation, dyspnea, or anginal pain.
Objective evidence of moderately 
severe cardiovascular disease.
IV
Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort. Symptoms of heart failure or 
the anginal syndrome may be present even at rest. If any physical 
activity is undertaken, discomfort is increased.
Objective evidence of severe 
cardiovascular disease.
Source: The Criteria Committee of New York Heart Association, 1994 Nomenclature and Criteria for Diagnosis of 
Diseases of the Heart and Great Vessels. Ninth Ed. Boston, MA: Little, Brown & Co; 1994:253-256. 
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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
captopril
carvedilol
cyclosporine
diltiazem
dronedarone
erythromycin
felodipine
ketoconazole
itraconazole
nefazodone
posaconazole
quercetin
quinidine
ranolazine
ticagrelor
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)
mibefradil (c) (d)
telithromycin
7 days, or 5 times the inhibitor half-life, whichever is longer
grapefruit and grapefruit-containing foods and beverages
5 days
Strong CYP3A Inducers and/or P-gp Inducers
avasimibe (e)
carbamazepine
phenobarbital
phenytoin
primidone
rifabutin
rifapentine
rifampin
St. John’s wort
7 days, or 5 times the inducer half-life, whichever is longer
Sources: fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM292362.pdf and 
fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm080499.htm.
(a)
Note that the list of strong CYP3A inhibitors or inducers and/or P-gp inhibitors or inducers is not exhaustive and is based on 
the US FDA draft guidance for DDI studies. 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, 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 or hepatitis C 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 or known or suspected active hepatitis 
C infection are excluded from study participation. The list also does not include oncology medications because they are 
prohibited during the study.
(c)
Also inhibitor of P-gp.
(d) Withdrawn from the US market for safety reasons.
(e)
Not marketed in the United States.
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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 No. 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: The IND number, amendment history, and summary of changes were added to the 
protocol.
Amended or 
new wording 
on the Title 
Page:
Study Number:
C34004
IND Number:
119,231
EudraCT 
Number:
2016-003716-12
Compound:
TAK-659
Date:
14 November 
2017
24 April 2018
Version/Amend
ment Number:
0102
Amendment History:
Date
Amendment 
Number
Amendment Type 
(for regional Europe 
purposes only)
Region
27 February 2017
Initial version
Not applicable
Global
14 November 2017
01
Not applicable
Global
24 April 2018
02
Not applicable
Germany-specific
New wording in Section 1.3 and Appendix J:
1.3
Protocol Amendment 02 Summary of Changes
This section describes the changes in reference to the Protocol 
Incorporating Amendment 02.
Minor grammatical and editorial changes are included for clarification 
purposes only. Full details on changes of text are given in Appendix J. The 
following is a summary of the major changes made in the amendment:
Changes in Amendment 02
1. The IND number, amendment history, and summary of changes were 
added to the protocol.
2. The names of the sponsor’s signatories were updated.
3. National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE) version was updated from version 4.03 to version 
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5.0.
4. Definitions of childbearing potential and highly effective contraception 
methods for female patients of childbearing potential were added to the 
protocol.
5. Definitions of highly effective contraception methods for male patients 
who are sexually active with partners of childbearing potential were 
added to the protocol.
6. A new inclusion criterion was added and the precautions and 
restrictions section was revised to state that male patients should not 
donate sperm from the time of signing the informed consent through 
180 days after last dose of study drug.
7. One new exclusion criterion was added to exclude patients with known 
hypersensitivity reactions to the active substance or to any of the 
excipients of the study drug.
8. Suspected pneumonitis was specifically added to all Grade 3 and Grade 
4 nonhematologic toxicities.
9. A urine pregnancy test for all women of childbearing potential was 
added to the end of treatment visit.
10. Reasons for discontinuation of treatment with study drug were revised.
11. Reasons for withdrawal of patients from the study were revised.
12. Reasons for early discontinuation of the study by the sponsor were 
added to the protocol.
13. Human immunodeficiency virus (HIV), hepatitis B, and hepatitis C 
virus tests were added during the Screening period.
14. Fresh tumor biopsy criteria were revised.
15. Optional tumor biopsy criteria were revised.
Rationale for Change: 
Compliance with Takeda writing guidelines. 
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Change 2: The names of the sponsor’s signatories were updated.
New wording 
in Section 
1.2:
____________________________________________________________
Date
____________________________________________________________
Date
Rationale for Change:
Change was made to reflect the addition of the sponsor’s new Medical Monitor and new Statistical 
Lead.
Change 3: National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI CTCAE) version was updated from version 4.03 to version 5.0.
Amended 
wording 
in Sections 
6.1, 8.2.1, 10.1.3,
10.2:
Toxicity will be evaluated according to National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE), Version 4.03 14 
June 2010 version 5.0, effective date 27 November 2017 [17].
Rationale for Change:
Change was made at the request of the BfArM.
Property of Takeda: For non-commercial 
st of
of
al use only and
ding
ng toto
erse 
rse Ev
nd subject to the applicable Terms of Use
_____
___
D
ble
ical Mon
cal Mo
he
gy Cri
Criter
ter
i
o versio
versio
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ctive da
ive da
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PPD
PPD


TAK-659
Study No. C34004
Page 115 of 123
Protocol Incorporating Amendment No. 02
24 April 2018
Change 4: Definitions of childbearing potential and highly effective contraception methods for 
female patients of childbearing potential were added to the protocol.
Revised wording 
in Section 7.1
(inclusion 
criterion #10):
10.
Female patients who of childbearing potential must:
a) Are postmenopausal for at least 1 year before the screening visit, OR
b) Are surgically sterile, OR
a) If they are of childbearing potential, aAgree 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 form (ICF) through 180 days after the last dose of 
study drug, or OR
b) Agree to practice true abstinence, when this is in line with the preferred 
and usual lifestyle of the patient. (Periodic abstinence [eg, calendar, 
ovulation, symptothermal, postovulation methods], withdrawal, 
spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be 
used together.)
Childbearing potential is defined as not having undergone surgical 
sterilization, hysterectomy, and/or bilateral oophorectomy, or not
being postmenopausal for at least 1 year before screening visit (≥12 
months of amenorrhea in the absence of other biological or 
physiological causes).
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-659
Study No. C34004
Page 116 of 123
Protocol Incorporating Amendment No. 02
24 April 2018
Revised wording 
in Section 8.4:
Nonsterilized female patients of reproductive age childbearing potential and 
male patients should use highly effective methods of contraception through 
defined periods during and after study treatment as specified below.
Female patients of childbearing potential must meet 1 of the following: 

Postmenopausal for at least 1 year before the Screening visit, OR

Surgically sterile, OR

If they are of childbearing potential,aAgree 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 of the 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 patient. (Periodic abstinence [eg, calendar, ovulation, 
symptothermal, postovulation methods], withdrawal, spermicides only, and 
lactational amenorrhea are not acceptable methods of contraception. Female 
and male condoms should not be used together.)
Childbearing potential is defined as not having undergone surgical 
sterilization, hysterectomy, and/or bilateral oophorectomy, or not being 
postmenopausal for at least 1 year before screening visit (≥ 12 months of 
amenorrhea in the absence of other biological or physiological causes).
Rationale for Change:
Change was made at the request of the BfArM.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-659
Study No. C34004
Page 117 of 123
Protocol Incorporating Amendment No. 02
24 April 2018
Change 5: Definitions of highly effective contraception methods for male patients who are 
sexually active with partners of childbearing potential were added to the protocol.
Amended 
wording 
in Section 7.1
(inclusion 
criterion #11):
11. Male patients, even if surgically sterilized (ie, status postvasectomy), 
who: are sexually active with partners who are of childbearing 
potential, must: 
a) Agree to practice effective barrier contraception during the entire 
study treatment period and through 120 days (or if the drug has a very 
long half-life, for 90 days plus 5 half-lives) after the last dose of study 
drug, OR
a) 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 form 
(ICF) 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 patient. (Periodic abstinence [eg, 
calendar, ovulation, symptothermal, postovulation methods], 
withdrawal, spermicides only, and lactational amenorrhea are not 
acceptable methods of contraception. Female and male condoms 
should not be used together.)
Amended 
wording 
in Section 8.4:
Male patients, even if surgically sterilized (ie, status postvasectomy), who are 
sexually active with partners who are of childbearing potential, must: agree 
to 1 of the following:

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 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

Agree to practice true abstinence, when this is in line with the preferred and 
usual lifestyle of the patient. (Periodic abstinence [eg, calendar, ovulation, 
symptothermal, postovulation methods], withdrawal, spermicides only, and 
lactational amenorrhea are not acceptable methods of contraception. Female 
and male condoms should not be used together.)
Rationale for Change:
Change was made at the request of the BfArM.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-659
Study No. C34004
Page 118 of 123
Protocol Incorporating Amendment No. 02
24 April 2018
Change 6: A new inclusion criterion was added and the precautions and restrictions section was 
revised to state that male patients should not donate sperm from the time of signing the informed 
consent through 180 days after last dose of study drug.
New wording 
in Section 7.1
(inclusion 
criterion #12) and 
Section 8.4:
12. Male patients should not donate sperm from the time of signing the 
ICF through 180 days after the last dose of study drug.
Rationale for Change:
Change was made at the request of the BfArM.
Change 7: One new exclusion criterion was added to exclude patients with known 
hypersensitivity reactions to the active substance or to any of the excipients of the study drug.
New wording 
in Section 7.2
(exclusion 
criterion #4)
4. Known hypersensitivity reactions to the active substance or to any of 
the excipients of the study drug.
Rationale for Change:
Change was made at the request of the BfArM.
Change 8: Suspected pneumonitis was specifically added to all Grade 3 and Grade 4 
nonhematologic toxicities.
Amended 
wording 
in Table 8.c.
Criteria
All Grade 3 nonhematologic toxicities, including suspected pneumonitis, 
with the exception of:
…
Criteria
All Grade 4 nonhematologic toxicities, including suspected pneumonitis, 
with the exception of:
…
Rationale for Change:
Change was made at the request of the BfArM.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-659
Study No. C34004
Page 119 of 123
Protocol Incorporating Amendment No. 02
24 April 2018
Change 9: A urine pregnancy test for all women of childbearing potential was added to the end of 
treatment visit.
New wording 
in Section 9.4.8
and Schedule of 
Events, including 
footnote (l)
9.4.8
Pregnancy Test
A serum pregnancy test will be performed for women of childbearing 
potential at Screening. A urine pregnancy test will be performed predose on 
Day 1 of all cycles and at the EOT visit, and negative results must be 
obtained before the first dose of study drug may be administered. If the 
screening serum test is done within 3 days before the first dose of study drug 
in Cycle 1 and the result is negative, the urine pregnancy test on Cycle 1 Day 
1 may be waived. Additional pregnancy testing may be performed during the 
study at the discretion of the investigator, upon request by an IEC/IRB, or if 
required by local regulations.
Schedule of Events
(l)
A serum beta-human chorionic gonadotropin pregnancy test will be performed only for 
women of childbearing potential at Screening. A urine pregnancy test will be performed 
predose on Day 1 of all cycles and at the EOT visit, and negative results must be 
available before the first dose 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. Additional pregnancy testing may be 
performed during the study at the discretion of the investigator, upon request by an 
IEC/IRB, or if required by local regulations.
Rationale for Change:
Change was made at the request of the BfArM.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-659
Study No. C34004
Page 120 of 123
Protocol Incorporating Amendment No. 02
24 April 2018
Change 10: Reasons for discontinuation of treatment with study drug were revised.
Amended 
wording 
in Section 9.7
9.7
Discontinuation of Treatment With Study Drug and Patient 
Replacement
Treatment with study drug may must be discontinued for any of the following 
reasons: 
•
AE, including patients who experience toxicity during the first cycle, 
patients with Grade 4 nonhematologic toxicity, and patients with Grade 4 
anemia. 

Protocol deviation.

Progressive disease.

Symptomatic deterioration (at investigator’s discretion). 

Unsatisfactory therapeutic response. 

Initiation of hematopoietic stem cell transplant. 

Study terminated. 

Withdrawal by patient.

Lost to follow-up.

Other.

Occurrence of drug-related Grade 4 nonhematologic toxicity or 
Grade 4 anemia, or other drug-related AEs that require study drug 
discontinuation per dose modification guidelines in Section 8.2. 

If dosing of TAK-659 is interrupted for >21 days for study 
drug-related or possibly related AEs despite supportive treatment 
per standard clinical practice. (Exceptions to this criterion may be 
made after discussion and agreement between the investigator and 
the sponsor based on the benefit and risk assessment).

If more than 2 dose reductions are required for a patient.

Occurrence of AEs, resulting in discontinuation of study drug that is 
desired or considered necessary by the investigator and/or the patient 
(if applicable).

Disease progression per 2007 and/or 2014 IWG criteria as 
determined by the investigator (see Section 9.4.15).

Use of a nonpermitted concomitant drug, as defined in Section 8.3, in 
which the predefined consequence is withdrawal from treatment. 
(The sponsor should be contacted to discuss whether trial treatment 
must be discontinued.)
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-659
Study No. C34004
Page 121 of 123
Protocol Incorporating Amendment No. 02
24 April 2018

Occurrence of pregnancy (if applicable).

Symptomatic deterioration (at investigator’s discretion). 

Initiation of hematopoietic stem cell transplant.

Withdrawal of consent by patient.

Patient is lost to follow-up.
…
Rationale for Change:
Change was made at the request of the BfArM.
Change 11: Reasons for withdrawal of patients from the study were revised.
Amended 
wording 
in Section 9.8
9.8 Withdrawal of Patients From Study
Patients may discontinue the trial at any time without giving a reason(s).
A patient may must be withdrawn from the study for any of the following 
reasons: 
•
AE.
•
Protocol violation.
•
Progressive Disease. 
•
Symptomatic deterioration (at investigator’s discretion).
•
Unsatisfactory therapeutic response. 
•
Initiation of hematopoietic stem cell transplant
•
Study terminated by sponsor.
•
Withdrawal of consent by patient.
•
Participation in any other therapeutic trial during the treatment 
duration of this trial.
•
Patient noncompliance with protocol.
•
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.
Rationale for Change:
Change was made at the request of the BfArM.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-659
Study No. C34004
Page 122 of 123
Protocol Incorporating Amendment No. 02
24 April 2018
Change 12: Reasons for early discontinuation of the study by the sponsor were added to the 
protocol.
New wording 
in Section 9.9
9.9 Early Discontinuation of the Study
The sponsor has the right to terminate this study at any time. Reasons 
for terminating the study may include, but are not limited to, the 
following:
• The incidence or severity of AEs in this or other studies indicates a 
potential health hazard to patients.
• Poor enrollment of patients, making completion of the trial within an 
acceptable timeframe unlikely.
• Plans to modify or discontinue the development of the study drug.
The sponsor will notify the investigator if the sponsor decides to 
discontinue the study.
Rationale for Change:
Change was made at the request of the BfArM.
Change 13: Human immunodeficiency virus (HIV), hepatitis B, and hepatitis C virus tests were 
added during the Screening period.
New wording 
in Schedule of 
Events, including 
footnote (p)
(p)
HIV, hepatitis B virus, and hepatitis C virus tests will be performed during 
Screening. Negative results must be available before the first dose of study drug 
may be administered.
Rationale for Change:
Change was made at the request of the BfArM.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-659
Study No. C34004
Page 123 of 123
Protocol Incorporating Amendment No. 02
24 April 2018
Change 14: Fresh tumor biopsy criteria were revised.
New wording 
in Schedule of 
Events, including 
footnote (r)
(r)
An FFPE tumor block or appropriately stained slides from a fresh biopsy is required.
Subjects who undergo tumor biopsies must have adequate platelet function per 
investigator assessment, an activated partial thromboplastin time and a 
prothrombin time within the normal range, and no history of excessive bleeding 
or recent exposure to antiplatelet or anticoagulant therapy (eg, clopidogrel 
[Plavix] or salicylates [aspirin] in the prior 7 days). 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. See Section 9.4.16 for details. These samples will be evaluated for 
candidate biomarkers predictive of response. Archival tumor tissue is to be collected 
only from enrolled patients and may be collected and sent to the sponsor after initiation 
of protocol treatment.
Rationale for Change:
Change was made at the request of the BfArM.
Change 15: Optional tumor biopsy criteria were revised.
New wording 
in Schedule of 
Events, including 
footnote (s)
(s)
Optional tumor biopsies may be obtained from consenting patients at any time during 
the study as determined by the investigator when patients have responded or responded 
and relapsed. Subjects who undergo optional tumor biopsies must have adequate 
platelet function per investigator assessment, an activated partial thromboplastin 
time and a prothrombin time within the normal range, and no history of excessive 
bleeding or recent exposure to antiplatelet or anticoagulant therapy (eg, 
clopidogrel [Plavix] or salicylates [aspirin] in the prior 7 days).
Rationale for Change:
Change was made at the request of the BfArM.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


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PPD

SAP_001.pdf: 


Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: Phase 2 Study of TAK-659 in Patients With Relapsed or Refractory Diffuse Large B-Cell 
Lymphoma After at Least 2 Prior Lines of Chemotherapy
NCT Number: NCT03123393
SAP Approve Date: 01 April 2019
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.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


1.0
TITLE PAGE
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: C34004
Phase 2 Study of TAK-659 in Patients With Relapsed or Refractory Diffuse Large
B-Cell Lymphoma After at Least 2 Prior Lines of Chemotherapy
PHASE 2
Version: 1.0
Date: 01 April 2019
Prepared by:
Based on:
Protocol Version: Amendment 02
Protocol Date: 24 April 2018
Proper
Takeda: For no
ercial use only and subject to the applicable Terms of Use
fractory
actor
of Chem
f Che
1.0.0
April
April 20
ocol
col Ver
Ve
l
Protocol
otoco
PPD


C34004
Page 2 of 26
Statistical Analysis Plan Version 1.0
01 April 2019
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


C34004
Page 3 of 26
Statistical Analysis Plan Version 1.0
01 April 2019
2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
1.1
Approval Signatures ..................................................................................................2
2.0
TABLE OF CONTENTS.................................................................................................3
3.0
LIST OF ABBREVIATIONS..........................................................................................5
4.0
OBJECTIVES .................................................................................................................8
4.1
Primary Objectives ....................................................................................................8
4.2
Secondary Objectives.................................................................................................8
4.3
Additional Objectives ................................................................................................8
4.3.1
Exploratory Objectives.........................................................................................8
4.4
Study Design .............................................................................................................9
5.0
ANALYSIS ENDPOINTS.............................................................................................11
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................13
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................14
7.1
General Principles....................................................................................................14
7.1.1
Definition of Study Days....................................................................................14
7.1.2
Conventions for Handling Missing Data.............................................................14
7.1.3
Definition of Baseline Values.............................................................................16
7.1.4
Windowing of Visits ..........................................................................................16
7.1.5
Withdrawals, Dropouts, Loss to Follow-up ........................................................16
7.2
Analysis Sets ...........................................................................................................16
7.3
Disposition of Patients .............................................................................................17
7.3.1
Significant Protocol Deviations..........................................................................17
7.4
Demographic and Other Baseline Characteristics.....................................................18
7.4.1
Baseline Disease Characteristics ........................................................................18
7.5
Medical History and Concurrent Medical Conditions...............................................18
7.6
Medication History and Concomitant Medications...................................................18
7.7
Study Drug Exposure and Compliance.....................................................................18
7.8
Efficacy Analysis.....................................................................................................19
7.8.1
Primary Efficacy Endpoint(s).............................................................................19
7.8.2
Secondary Efficacy Endpoint(s).........................................................................19
7.8.3
Additional Efficacy Endpoint(s).........................................................................20
7.9
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................21
7.9.1
Pharmacokinetic Analysis ..................................................................................21
7.9.2
Pharmacodynamic Analysis ...............................................................................21
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


C34004
Page 4 of 26
Statistical Analysis Plan Version 1.0
01 April 2019
7.10
Safety Analysis........................................................................................................21
7.10.1 Adverse Events ..................................................................................................21
7.10.2 Clinical Laboratory Evaluations .........................................................................22
7.10.3 Vital Signs .........................................................................................................23
7.10.4 12-Lead ECGs ...................................................................................................23
7.11
Dose Exploration Analysis.......................................................................................23
7.12
Interim Analysis ......................................................................................................24
7.13
Changes in the Statistical Analysis Plan...................................................................24
8.0
REFERENCES..............................................................................................................25
9.0
DATA LISTINGS .........................................................................................................26
LIST OF IN-TEXT TABLES
Table 7.a
Handling of Missing Response Assessment and Censoring for Progression-
Free Survival Analysis Based on US Food and Drug Administration Guidance..20
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


C34004
Page 5 of 26
Statistical Analysis Plan Version 1.0
01 April 2019
3.0
LIST OF ABBREVIATIONS
ABC
activated B-cell
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASCO
American Society of Clinical Oncology
ASCT
autologous stem cell transplant
ASH
American Society of Hematology
AST
aspartate aminotransferase
BCR
B-cell receptor
BCRP
breast cancer resistance protein
CFR
Code of Federal Regulations
CK
creatine kinase
CLL
chronic lymphocytic leukemia
CMV
cytomegalovirus
CNS
central nervous system
CPK
creatine phosphokinase
CR
complete response 
CRO
contract research organization
CSR
clinical study report
CT
computed tomography
ctDNA
circulating tumor DNA
CYP
cytochrome P450
DDI
drug-drug interaction
DLBCL
diffuse large B-cell lymphoma
DOR
duration of response
EBV
Epstein-Barr virus
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EOT
end of treatment
FAS
Full analysis set
FDA
United States Food and Drug Administration
FDG-PET
[18F]fluorodeoxyglucose-positron emission tomography
FFPE
formalin-fixed, paraffin-embedded
FIH
first-in-human
FL
follicular lymphoma
GCB
germinal center B-cell
GCP
Good Clinical Practice
G-CSF
granulocyte colony stimulating factor
GI
gastrointestinal
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


C34004
Page 6 of 26
Statistical Analysis Plan Version 1.0
01 April 2019
GM-CSF
granulocyte macrophage-colony stimulating factor
HbAc1
glycosylated hemoglobin
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
IC50
concentration producing 50% inhibition
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IHC
immunohistochemical; immunohistochemistry 
IRB
institutional review board
IRC
independent radiologic review committee
ITAM
immunoreceptor tyrosine-based activating motifs
IV
intravenous; intravenously
IWG
International Working Group
KM
Kaplan Meier 
LDH
lactate dehydrogenase
LLN
Lower limit of normal
LOCF
Last observation carried forward
MCL
mantle cell lymphoma
MedDRA
Medical Dictionary for Regulatory Activities
mITT
modified intent-to-treat
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NHL
non-Hodgkin lymphoma
NOS
not otherwise specified
ORR
overall response rate
OS
overall survival
PCR
polymerase chain reaction
PD
progressive disease (disease progression)
PET
positron emission tomography
PFS
progression-free survival
P-gp
P-glycoprotein
PJP
Pneumocystis jiroveci pneumonia 
PK
pharmacokinetic(s)
PLT
platelets
PO
per os; by mouth (orally) 
PR
partial response 
PTE
pretreatment events
QD
once daily
QTc
rate-corrected QT interval (msec) of electrocardiograph
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


C34004
Page 7 of 26
Statistical Analysis Plan Version 1.0
01 April 2019
QTcB
Bazett’s corrected QT interval
QTcF
Fridericia’s corrected QT interval
RDI
Relative dose intensity 
RBC
red blood cell
R-CHOP
cyclophosphamide+doxorubicin (hydroxydaunomycin)+vincristine 
(Oncovin)+prednisone with rituximab
RP2D
recommended phase 2 dose
SAE
serious adverse event
SAP
statistical analysis plan
SSC
study steering committee
SUSAR
suspected unexpected serious adverse reaction
SYK
spleen tyrosine kinase
TEAE
treatment-emergent adverse events
ULN
upper limit of the normal range
US
United States
WHO
World Health Organization
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


C34004
Page 8 of 26
Statistical Analysis Plan Version 1.0
01 April 2019
4.0
OBJECTIVES
4.1
Primary Objectives
The primary objective is to assess the efficacy of TAK-659 as measured by IRC assessed ORR in 
patients with DLBCL (Stage 2). 
4.2
Secondary Objectives
Key Secondary Objective:
The key secondary objective is to assess CR rate per IRC in patients with DLBCL (Stage 2).
Secondary Objectives:
!
To select the Stage 2 dose regimen of TAK-659 from the lead-in dose exploration phase 
(Stage 1) and assess efficacy using ORR per IRC (Stage 2). 
!
To assess ORR per IRC at 3, 6, and 9 cycles in patients with DLBCL (Stage 2).
!
To assess DOR and duration of CR per IRC in patients with DLBCL (Stage 2).
!
To assess ORR per IRC in the subgroup of patients with germinal center B-cell (GCB) 
DLBCL (Stage 2).
!
To assess ORR per IRC in the subgroup of patients with DLBCL transformed from indolent 
non-Hodgkin lymphoma (NHL) (Stage 2).
!
To assess PFS per IRC in patients with DLBCL (Stage 2).
!
To assess OS in patients with DLBCL (Stage 2).
4.3
Additional Objectives
!
To assess the safety and tolerability of TAK-659 in the patient population under study 
(Stages 1).
!
To assess the number of responding patients proceeding to ASCT or allogeneic stem cell 
transplant.
!
To collect TAK-659 plasma concentration–time data to contribute to population PK and 
exposure–response analyses (Stages 1).
4.3.1
Exploratory Objectives
Proper
 Takeda: For non-commercial use only and subject to the applicable Terms of Use
RR in 
RR in 
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in dose e
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4.3.1
3 1
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4.4
Study Design
This is an open-label, multicenter, phase 2 study to evaluate the efficacy and safety of TAK-659 
as a single agent in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) 
after at least 2 prior lines of chemotherapy. Eligible patients will also be ineligible for autologous 
stem cell transplant (ASCT) or be patients for whom ASCT has failed.
This study will start with a lead-in dose exploration phase (Stage 1) during which two TAK-659 
dose regimens will be evaluated in two patient cohorts (Cohorts A and B). Patients in Cohort A 
will receive a daily dose of 100 mg TAK-659 continuously throughout the study. In Cohort B, 
patients will follow a ramp-up dosing schema leading to a full dose of 100 mg QD TAK-659. 
Patients will initially receive 60 mg QD TAK-659 for one cycle of 28 days, and if tolerated well, 
will then receive 80 mg QD TAK-659 for the next cycle, and subsequently 100 mg QD 
TAK-659 in the 3rd cycle and beyond. At the end of each cycle during the ramp-up, patients will 
be assessed for their suitability to dose-escalate to the next level based on safety and tolerability. 
If the patient experiences any drug-related adverse events that require dose modification 
(inclusive of dose held and dose reduction) per protocol in a given dose cycle, dose escalation 
will not proceed to the next level. If the AE(s) resolves, the patient may then restart dose 
escalation in the next cycle either at the same dose or a reduced dose according to the protocol-
defined dose reduction criteria. In case dose reduction is not required, when the patient resumes 
the study drug at the same dose, dose escalation to the next dose level and further to the full dose 
of 100 mg QD TAK-659 may be pursued if no recurrence of the same AE(s) or any other AEs 
leading to dose modification is observed in the next cycle of treatment. However, if the same 
AE(s) or different AE(s) requiring dose modification occur in two consecutive cycles at the same 
dose level, further dose escalation is not allowed. If the patient resumes the study drug at a 
reduced dose per protocol, no dose re-escalation is recommended. Approximately 20 patients are 
expected to be enrolled into each cohort, with a total of ~40 patients planned for Stage 1. 
Upon completion of Stage 1, the dose exploration analysis will occur. Based on the posterior 
probability of response comparison between the 2 cohorts, one TAK-659 dose regimen will be 
selected to proceed to Stage 2. During this analysis, if both Stage 1 regimens are determined to 
be ineffective, termination of the study without proceeding to Stage 2 may be considered. 
However, other considerations should be taken into account when making this development 
decision including, but not limited to, sample size, relevant data from other TAK-659 trials, and 
applicable patient enrichment or selection strategy that justifies further evaluation of TAK-659 in 
this setting.
During the Stage 2 efficacy evaluation phase, it is expected that approximately 82 patients will 
be enrolled. Once enrolled, patients will be administered TAK-659 orally in 28-day treatment 
cycles according to the selected dose regimen of TAK-659 from Stage 1. After approximately 40 
patients have been enrolled in Stage 2 and have had the opportunity to receive at least 3 cycles of 
Property of Takeda: Fo
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For non-commercial use only and subject to the applicable Term of Use
AK-659 
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CCI


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study treatment and have at least 1 posttreatment response evaluation, an interim analysis will be 
performed to assess futility. The study may either stop for futility or continue as planned. 
In Stage 2, patients will be administered TAK-659 orally according to the dose regimen selected 
in Stage 1. Efficacy will be assessed using the IWG revised response criteria for malignant 
lymphoma (the modified 2007 IWG criteria [1] and the 2014 [Lugano] criteria [2]). Dedicated 
computed tomography (CT) scans (chest, neck, abdomen, and pelvis) will be performed at 
Baseline; at the end of Cycles 1, 3, and 6; every 3 cycles up to 24 cycles; and every 6 cycles
thereafter. Fluorodeoxyglucose-positron emission tomography (FDG-PET) scans will be 
performed at baseline and at the end of Cycles 1, 3, and 6 if positive at baseline, or when 
clinically indicated during the study. The primary endpoint of this study is ORR, defined as the 
proportion of patients with CR or PR as determined by independent central review of radiology 
by an IRC according to the modified 2007 IWG criteria. 
AEs will be assessed, and laboratory values, vital signs, 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 5.0, effective date 27 November 2017 [3].
Patients on TAK-659, including those who achieve a CR, may receive study drug until they 
experience PD or unacceptable toxicities. Patients who discontinue study for reasons other than 
PD will be followed for PFS every 3 months after the last dose of study drug until PD, the start 
of alternative therapy, or conclusion of the study, whichever occurs first. All patients, after the 
last dose of study drug, will be followed for OS every 3 months until death or conclusion of the 
study, whichever occurs first.
Patients may discontinue therapy at any time. Patients will attend the End-of-Treatment (EOT) 
visit 28 days (+10) after receiving their last dose of TAK-659 or before the start of subsequent 
anticancer therapy, whichever occurs first, to permit the detection of any delayed treatment-
related AEs. 
Proper
ommercial use only and subject to the applicable Terms of Use
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5.0
ANALYSIS ENDPOINTS
Primary:
!
ORR as assessed by IRC according to modified 2007 IWG criteria for malignant lymphoma.
Key secondary: CR rate as assessed by IRC according to the modified 2007 IWG criteria.
Secondary:
!
ORR per IRC according to the 2014 IWG (Lugano) criteria (Stage 2).
!
CR rate per IRC according to the 2014 IWG (Lugano) criteria (Stage 2).
!
ORR per IRC to select the Stage 2 dose regimen of TAK-659 from the lead-in dose 
exploration phase (Stage 1).
!
ORR per IRC at 3, 6, and 9 cycles, respectively (Stage 2). 
!
DOR and duration of CR per IRC (Stage 2).
!
ORR per IRC in patients with GCB DLBCL (Stage 2).
!
ORR per IRC in patients with DLBCL transformed from indolent NHL (Stage 2).
!
PFS per IRC (Stage 2).
!
OS (Stage 2).
The IRC will evaluate the assessments above using both the modified 2007 IWG criteria for 
malignant lymphoma and the 2014 IWG (Lugano) criteria. Unless otherwise specified, 
evaluations using the 2007 IWG criteria will be the primary analyses, and evaluations using the 
2014 IWG (Lugano) criteria will be the sensitivity analyses.
Additional:
!
Percentage of patients who experience AEs, Grade ∀3 AEs, serious AEs, discontinuations for 
AEs, and clinical laboratory values and vital sign measurements outside the normal range 
(Stages 1 and 2).
!
Percentage of patients proceeding to ASCT or allogeneic stem cell transplant out of all 
patients who achieve a best response of PR or CR on study.
!
TAK-659 plasma concentration–time data (Stages 1 and 2).
Exploratory:
Propert
 Takeda: For non-commercial use only and subject to the applicable Terms of Use
ma.a.
ia.
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Property of Takeda: For non-commercial use only and subject to the applicable Ter
 Use
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6.0
DETERMINATION OF SAMPLE SIZE
For the lead-in dose exploration portion (Stage 1) of the study, assuming a historical control rate 
of 20% for ORR, at least 20 patients per dosing regimen are required to determine if either 
dosing regimen A or dosing regimen B is more effective.
For Stage 2 efficacy evaluation phase of the study, assuming a historical control rate of 20% for 
ORR and a TAK-659 ORR of 37%, this study will need to enroll at least 82 patients in Stage 2 to 
achieve 91% power at a 1-sided alpha level of 0.025, using an exact binomial test. After 
approximately 40 patients have been enrolled in Stage 2 and have had the opportunity to receive 
at least 3 cycles of treatment and have at least 1 posttreatment response evaluated, the interim 
analysis will be performed. The interim analysis will assess futility, and the study may either 
stop for futility (if posterior probability of ORR<20% is greater than the threshold of 0.75) or 
continue as planned.
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7.0
METHODS OF ANALYSIS AND PRESENTATION
The study was terminated early without entering into the Stage 2 efficacy evaluation phase. The 
analyses described in this section are only for the stage 1 lead-in dose exploration phase.
7.1
General Principles 
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 statistical analyses will be conducted using SAS® Version 9.3, or higher.
All confidence intervals, statistical tests, and resulting P-values will be reported as 2-sided and 
will be assessed at α=0.05 significance level unless otherwise stated. 
Means and medians will be presented to 1 more decimal place than the recorded data. The 
standard deviations (SDs) will be presented to 2 more decimal places than the recorded data. 
Confidence intervals about a parameter estimate will be presented using the same number of 
decimal places as the parameter estimate.
7.1.1
Definition of Study Days
Study Day 1 is defined as the date on which a patient is administered their first dose of the 
medication. 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.
7.1.2
Conventions for Handling Missing Data
All available efficacy and safety data will be included in data listings and tabulations. Data that 
are potentially spurious or erroneous will be examined under the auspices of standard data 
management operating procedures.
7.1.2.1
Missing/Partial Dates in Screening Visit
The following rules apply to dates recorded during the screening 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 study drug. 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 study drug, the 
fifteenth of January will be used unless it is later than the first dose, in which case the date of 
the 15th 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 study drug, the 
fifteenth of June will be used, unless other data indicates that the date is earlier.
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7.1.2.2
Missing/Partial Dates in Adverse Events/Concomitant Therapies/Subsequent Therapies
Every effort will be made to avoid missing/partial dates in on-study data. 
7.1.2.3
Missing/Partial Dates in Adverse Events
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 study drug
and 

on or before the month and year of the date of the last dose of any study drug 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 study drug
and 
–
on or before year of the date of the last dose of any study drug 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 study drug, the event will not be considered treatment emergent.
7.1.2.4
Missing/Partial Dates in Concomitant Therapies
Concomitant therapies with start dates that are completely or partially missing will be analyzed 
as follows:
1. If the start date has a month and year but the day is missing, the therapy will be considered 
concomitant if the month and year of the start date are: 
–
On or after the month and year of the date of the first dose of study drug
and 
–
on or before the month and year of the date of the last dose of any study drug plus 28 
days, or the start date of subsequent anticancer therapy, whichever occurs first.
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2. If the start date has a year, but the day and month are missing, the therapy will be considered 
concomitant if the year of the start date is:
–
On or after the year of the date of the first dose of study drug
and 
–
on or before the year of the date of the last dose of any study drug plus 28 days, or the 
start date of subsequent anticancer therapy, whichever occurs first.
3. If the start date of a therapy is completely missing then the therapy 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 study drug, the therapy 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 study drug plus 28 days to be 
included.
7.1.3
Definition of Baseline Values
Unless otherwise specified, the baseline value is defined as the value collected at the time closest 
to, but prior to, the start of study drug administration. C1D1 (cycle 1 day 1) values are generally 
considered pre-dose, unless explicitly stated values are post-dose, C1D1 values are considered 
baseline values if available. Screening values are considered baseline values if C1D1 value is 
unavailable.
7.1.4
Windowing of Visits
All data will be categorized based on the scheduled visit at which it was collected. These visit 
designators are predefined values that appear as part of the visit tab in the eCRF.
7.1.5
Withdrawals, Dropouts, Loss to Follow-up
Patients who dropout or withdraw for any reason will not be replaced.
Time to event parameters (DOR, PFS, 1-year OS) will be censored if patients withdraw, drop 
out, or are lost to follow-up before documentation of the event of interest (progressive 
disease/death). Rules for censoring are detailed in section 7.8.3.1.
7.2
Analysis Sets
DLBCL Population
The DLBCL population includes all patients who have a confirmed DLBCL diagnosis and who 
receive at least 1 dose of TAK-659. The DLBCL population will be used for primary and 
secondary efficacy analysis, and for additional efficacy analyses.
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Modified Intent-to-Treat Population
The modified intent-to-treat (mITT) population includes all patients who receive at least 1 dose 
of TAK-659. The mITT will be used for the sensitivity analyses for the efficacy analyses.
Per-Protocol Population
The per-protocol population includes all patients who receive at least 1 dose of TAK-659 and 
who have measurable disease at Baseline and no other major protocol deviations that could 
potentially affect tumor response.
Safety Population
The safety population includes all patients who receive at least 1 dose of TAK-659. The safety 
population will be used for all baseline characteristics, safety analyses, and exposure analysis.
Response-Evaluable Population
The response-evaluable population includes all patients who receive at least 1 dose of TAK-659 
and have measurable disease at Baseline and at least 1 postbaseline disease assessment. The 
response-evaluable analysis set will be used for sensitivity analyses of efficacy endpoints that are 
related to response, such as ORR, CR, and DOR.
7.3
Disposition of Patients
Disposition of patients includes the number and percentage of patients in each population, 
presented by dosing regimen (Cohorts A and B) and total. The primary reason for 
discontinuation of study drug as well as study termination will be summarized.
All percentages will be based on the number of patients in the safety population.
Summary of number of patients by region, country, and site (for posting)
7.3.1
Significant Protocol Deviations
Protocol deviations will be identified either through manual lists or using programmed 
algorithms. Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the patient, or confound interpretation of primary study 
assessment. Protocol deviations applicable to all study parts and protocol deviations specific to 
each study part will be identified. A listing will be generated for significant protocol deviations, 
which will include, but will not be limited to, at least 1 of the following:

Any inclusion/exclusion criteria not met by an enrolled patient.

Use of or administration of excluded and/or restricted medications, not in accordance with 
the study protocol. 

Study procedures not performed as per the clinical study protocol that may confound 
interpretation of primary clinical study objectives and/or affect patient safety.

Dispensing of incorrect treatment and/or incorrect dose of clinical study medication.
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
Any occasion that withdrawal criterion is met but the patient is not withdrawn.
7.4
Demographic and Other Baseline Characteristics
Patient demographics will be summarized by dosing regimen (Cohorts A and B) and in total. 
Baseline demographic data to be evaluated will include age, sex, race, ethnicity, height, and 
weight. 
Age will be calculated from date of birth to date of informed consent.
Demographic data will also be presented in a by-patient listing.
No inferential statistics will be generated.
7.4.1
Baseline Disease Characteristics 
Baseline disease primary diagnosis and disease subtype, years since initial diagnosis, Ann Arbor 
staging, and Eastern Cooperative Oncology Group (ECOG) performance status, molecular 
classification (GCB vs. Non-GCB), number of nodal sites, bulky disease (Y/N), extranodal 
involvement, bone marrow involvement, and IPI score will be summarized by dosing regimen 
(Cohorts A and B) and in total.
7.5
Medical History and Concurrent Medical Conditions
Medical history will be presented in a by-patient listing, including the medical and surgical 
history, date of onset and the end date relative to signing Informed consent (whether it is before
or ongoing).
7.6
Medication History and Concomitant Medications
Prior therapies will be summarized by the numbers and percentages of patients who received
prior anticancer therapy, prior radiation, prior transplant, number of lines of prior anticancer 
therapies, and best response to the last prior anticancer therapy and dosing regimen (Cohorts A 
and B) and in total.
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 medication drug, or to the start of 
subsequent anticancer therapy, whichever occurs first.
7.7
Study Drug Exposure and Compliance
The study drug will be dosed continuously, QD, in 28-day cycles.
The exposure to TAK-659 will be characterized by total amount of dose taken in mg, total 
number of doses taken, relative dose intensity (RDI, %), number of treated cycles, numbers and 
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percentages of patients who had ≥1, ≥2, …, ≥6, and ≥12 treated cycles for patients by dosing 
regimen (Cohorts A and B) and total in the safety population. 
RDI (%) will be presented overall, by cycle, and by study days 1-28 and study days 29-56. 
Overall RDI is defined as 100 x (total dose received in mg) / (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 RDI by cycle, the same formula is used as overall RDI, but the number of treated days is 
derived differently. Cycle RDI is defined as 100 x (total dose received in mg in cycle) / (initial 
prescribed dose per day x number of treated days in cycle). Where 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.
RDI by study day will have a slightly different calculation than overall or by cycle. Study days 1-
28 RDI will be defined as 100 x (total dose received in mg up to study day 28) / (initial 
prescribed dose per day x 28). Study days 29-56 RDI will be defined as 100 x (total dose 
received in mg between study days 29 through 56) / (initial prescribed dose per day x 28).
Prescribed dose is determined by the dose level to which a patient is enrolled at the onset of the 
study. Patients in Stage 1 Cohort B will have their prescribed dose determined by the first 
scheduled dose of the relevant cycle. 
The extent of exposure will be summarized by dosing regimen (Cohorts A and B) and in total.
Action on study drug will be summarized by each cycle (Cycles 1- 6), sum of the remainder of 
cycles, and dosing regimen (Cohorts A and B) and in total.
7.8
Efficacy Analysis
7.8.1
Primary Efficacy Endpoint(s)
There is no primary efficacy endpoint for the stage 1 lead-in dose exploration phase of the study
7.8.2
Secondary Efficacy Endpoint(s)
The secondary efficacy endpoints defined for Stage 2 are not applicable due to the early 
termination of the study.
The overall response rate (ORR) and Complete Response Rate from Stage 1 will be summarized 
by dosing regimen (Cohorts A and B) based on the DLBCL population. Overall response is 
defined as a best response of CR or PR. ORR is the percentage of patients who have overall 
responses. The summary will be based upon the investigator response assessment. There was no 
IRC review of the responses. The number and percentage of patients falling into each response 
category (CR, PR, SD, PD) will also be tabulated descriptively. Estimates of the ORR will be 
presented with 2-sided 95% exact binomial confidence intervals (CIs).
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7.8.3
Additional Efficacy Endpoint(s)
Additional time to event data (DOR, PFS, and OS) will be analyzed by the Kaplan-Meier method 
and results will be summarized by the 25th, 50th, and 75th percentiles for survival times with 
associated 2-sided 95% CIs. The corresponding Kaplan-Meier curves will also be plotted.
DOR is defined as the time from the date of first documentation of a response (PR or CR) to the 
date of first documented PD. 
PFS is defined as the time from date of first study drug administration to the day of first 
documented PD or death due to any cause, whichever occurs first.
OS is defined as the time from the first dose date to the date of death. Patients without 
documentation of death at the time of the analysis will be censored at the date when they were 
last known to be alive.
7.8.3.1
Censoring Method for Efficacy Analysis of Progression-Free-Survival
The efficacy analysis for PFS will be based on the DLBCL population. The approach regarding 
handling of missing response assessments and censoring based on US Food and Drug 
Administration (FDA) guidance is presented in Table 7.a.
Table 7.a
Handling of Missing Response Assessment and Censoring for Progression-
Free Survival Analysis Based on US Food and Drug Administration 
Guidance
Situation
Date of Progression or Censoring
Outcome
No baseline and/or no post baseline 
assessment
First dose date
Censored
Disease progression documented between 
scheduled visits 
Date of disease progression
PFS event
No documented disease progression or 
death
Date of last adequate assessment*
Censored
Treatment discontinuation for 
undocumented disease progression after 
the last adequate assessment
Date of last adequate assessment*
Censored
Alternate antineoplastic therapy started 
prior to disease progression 
Date of last adequate assessment* prior to the 
start of subsequent antineoplastic therapy
Censored
Death before first assessment
Date of death
PFS event
Death between adequate assessment visits
Date of death
PFS event
Death or disease progression after more 
than 1 missed visit
Date of last adequate assessment prior to multiple 
missing visits*
Censored
Abbreviation: PFS = progression-free survival.
* Adequate assessment is defined as there is sufficient radiographic data to evaluate a patient’s disease status.
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7.9
Pharmacokinetic/Pharmacodynamic Analysis
7.9.1
Pharmacokinetic Analysis
Plasma concentrations of TAK-659 will be listed by patient, dosing cycle and day, and nominal 
and actual time point for each dosing regimen (Cohorts A and B).
7.9.2
Pharmacodynamic Analysis
Not applicable.
7.10
Safety Analysis
Safety evaluations will be based on the incidence, severity, relatedness, and type of AEs, and by 
changes from baseline in the patient’s clinical laboratory results. These analyses will be 
performed using the safety population.
7.10.1 Adverse Events
AEs will be tabulated according to the Medical Dictionary for Regulatory Activities (MedDRA) 
coding dictionary for the purpose of summarization. All AEs will be summarized by the National 
Cancer Institute Common Toxicity Criteria for Adverse Event (NCI CTCAE).
Treatment-emergent AEs will be tabulated where treatment-emergent is defined as any AE that 
occurs after administration of the first dose of study treatment and up to 28 days after the last 
dose of study medication, or until the start of subsequent antineoplastic therapy, whichever 
occurs first. Treatment-emergent AEs will be tabulated by dosing regimen (Cohorts A and B), 
according to the MedDRA by system organ class (SOC), and preferred terms (PT) and will 
include the following categories, for Stage 1 Cohorts A and B. 

Treatment-emergent AEs (SOC and PT, PT).

Drug-related treatment-emergent AEs (SOC and PT, PT).

Grade 3 or higher treatment-emergent AEs (SOC and PT, PT).

Grade 3 or higher drug-related treatment-emergent AEs (SOC and PT, PT).

The most commonly reported treatment-emergent AEs (i.e., those events reported by 10% 
of all patients in the safety population) (PT).

Treatment-Emergent AEs leading to discontinuation (PT).

Drug-Related Treatment-Emergent AEs leading to discontinuation (PT).

Serious Treatment-emergent AEs (SOC and PT).

Drug-related Serious treatment-emergent AEs (SOC and PT).
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.
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An overall summary treatment-emergent AE table will include numbers and percentages of 
patients who had any treatment-emergent AE, drug-related treatment-emergent AE, grade 3 or 
higher treatment-emergent AE, grade 3 or higher drug-related treatment-emergent AE, serious 
AE (SAE), drug-related SAE, treatment-emergent AE resulting in discontinuation, drug-related 
treatment-emergent AE resulting in discontinuation and on-study deaths.
7.10.2 Clinical Laboratory Evaluations
For the purposes of summarization in both the tables and listings, all laboratory values will be 
converted to standardized units. If a lab value is reported using a non-numeric qualifier (e.g., less 
than (<) a certain value, or greater than (>) a certain value), the given numeric value will be used 
in the summary statistics, ignoring the non-numeric qualifier.
If a patient has repeated laboratory values for a given time point, the value from the last 
evaluation will be used.
The actual values of laboratory test results and percent change from baseline will be summarized 
according to the scheduled sample collection time point by Stage 1 (Cohorts A and B separately), 
Shift tables will be constructed for laboratory parameters to tabulate changes in NCI CTC for 
toxicity from baseline to post baseline worst on study CTC grade, if available. Parameters to be 
tabulated will include:
Hematology:
Hematocrit
Hemoglobin
Leukocytes with differential
Neutrophils (ANC)
Platelet (count)
Lymphocytes (absolute lymphocyte count 
[ALC])
Lymphocyte subsets (CD4, CD8, CD4:CD8 
ratio)
Serum chemistry: 
Albumin
Alkaline phosphatase (ALP)
ALT
Amylase
AST
Bilirubin (total)
Blood urea nitrogen (BUN)
Calcium
Carbon dioxide (CO2)
Creatinine
Creatine kinase (CK)
Chloride
γ-Glutamyl transferase (GGT)
Glucose
Glycosylated hemoglobin (HbA1c)
Lactate dehydrogenase (LDH)
(including LDH isozymes)
Lipase
Magnesium
Phosphate
Potassium
Sodium
Total protein
Urate
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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 Hb, 
leukocytes, ALC, ANC, platelets, and liver function tests (ALT, AST, ALP, total bilirubin), 
LDH (with isozymes), phosphate, creatinine, CK, lipase and amylase.
7.10.3 Vital Signs
The actual values of vital sign parameters including oral temperature, heart rate, systolic and 
diastolic blood pressure, and oxygen saturation, will be summarized over time for each dose 
level and overall. Change of vital signs from baseline values will also be summarized over time.
7.10.4 12-Lead ECGs
A summary of ECG abnormalities will be presented by visit. ECG intervals (QT and Bazette’s 
and Friderichia’s corrected QT intervals [QTcB and QTcF], PR, QRS, and heart rate) will be 
summarized at each scheduled time point, along with mean change from baseline to each post 
treatment time point.
7.11
Dose Exploration Analysis
Dose exploration analysis will occur at the end of Stage 1. Assuming a historical control rate of 
20% for ORR, 20 patients per dosing regimen are required to determine the dosing regimen for 
the phase 2 efficacy evaluation (Stage 2) portion of the study. Response data from both dosing 
regimens will be analyzed with a Bayesian model assuming prior of Beta(0.1,0.1) for each ORR. 
Dosing regimen A will be claimed ineffective if the posterior probability of ORRA <20% is 
greater than the threshold of 0.75, likewise for dosing regimen B. If both regimens are deemed to 
be ineffective, termination of the study without proceeding to stage 2 may be considered. Other 
considerations for making this decision should be taken into account, including but not limited to 
sample size limitation, relevant data from other TAK-659 trials, and applicable patient
enrichment or selection strategy that justifies further evaluation of TAK-659 in this setting. If 
only one dosing regimen is determined to be ineffective, then the other dosing regimen is chosen 
as the dosing regimen for the remaining portion of the study. If neither dosing regimen is 
claimed to be ineffective, then regimen A will be chosen if the posterior probability of 
ORRA>ORRB is greater than the threshold of 0.55, likewise dosing regimen B will be chosen if 
the posterior probability of ORRB>ORRA is greater than 0.55. If both the posterior probability of 
ORRA>ORRB and the posterior probability of ORRB>ORRA are ≤0.55, clinical and safety factors 
will be considered to choose the dosing regimen for Stage 2. 
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Consideration of an alternative dose regimen other than the two TAK-659 dose regimens 
evaluated in Stage 1 is permissible if supported by the Stage 1 data. For example, if the ramp-up 
dose schema (dose regimen B) is chosen based on the Bayesian model (see above) but majority 
of patients treated with dose regimen B fail to dose escalate beyond 60 mg QD TAK-659 
following the dose escalation criteria, 60 mg QD TAK-659 may be considered as the dose for 
Stage 2. The Stage 1 data as well as other relevant supportive data from other trials of TAK-659 
will be reviewed and discussed by the SSC. The stage 2 dose regimen of TAK-659 will be 
selected based on the recommendation by SSC upon agreement with the sponsor.
For tabulation of this analysis, the ORR for Cohorts A and B will be displayed, along with the 
number and percentage of patients falling into each response category (CR, PR, SD, PD) by 
cohort.
7.12
Interim Analysis
Since the study was terminated early without proceeding to Stage 2, the interim analysis is not 
applicable.
7.13
Changes in the Statistical Analysis Plan 
All the planned analyses for Stage 2, including the interim analysis, as described in the protocol 
amendment 2 (dated 24 April, 2018) were removed, since the study was terminated early without 
proceeding to Stage 2.
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8.0
REFERENCES
1. Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. Revised 
response criteria for malignant lymphoma. Journal of Clinical Oncology 2007;25(5):579-86.
2. Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, et al. 
Recommendations for initial evaluation, staging, and response assessment of Hodgkin and 
non-Hodgkin lymphoma: the Lugano classification. Journal of Clinical Oncology 
2014;32(27):3059-68.
3. Common Terminology Criteria for Adverse Events (CTCAE). National Cancer Institute, 
National Institutes of Health, U.S. Department of Health and Human Services  Series v5.0. 
27 November 2017.
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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).

Demographics.

Concomitant Medications.

Medical history.

TAK-659 Exposure and Compliance.

Target Lesions.

Non-Target Lesions.

New Lesions.

Imaging Assessments (CT, FDG-PET, MRI).

Lymphoma Symptoms.

Investigator response assessment.

Best Overall response.

Adverse Events.

TEAEs of grade 3 or higher (including day within each cycle based on the AE onset dates).

TEAEs leading to study drug discontinuation.

Serious AEs (all SAEs regardless of treatment emergent AE status).

Deaths.

All Lab Parameters.

Plasma drug concentration. 

Ophthalmic findings.

Significant protocol deviations.
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