Clinical trial NCT02954406
Conditions: Lymphoma, Non-Hodgkin
Keywords: Drug Therapy
Sponsor: Millennium Pharmaceuticals, Inc.
Start date: 2017-03-05; Completion date: 2020-07-27
Enrollment: 43 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) of TAK-659 when administered in combination with bendamustine, bendamustine + rituximab, gemcitabine, lenalidomide, or ibrutinib.

Detailed description:
The drug being tested in this study is called TAK-659. TAK-659 is being tested to treat people who have advanced non-Hodgkin lymphoma. This study will determine the MTD or RP2D for TAK-659 in combination with bendamustine, bendamustine + rituximab, gemcitabine, lenalidomide, and ibrutinib. The study will enroll approximately 96 participants.

Participants will be assigned to one of the 5 combination cohorts:

* Dose Escalation Phase Cohort A: TAK-659 + Bendamustine
* Dose Escalation Phase Cohort B: TAK-659 + Bendamustine + Rituximab
* Dose Escalation Phase Cohort C: TAK-659 + Gemcitabine
* Dose Escalation Phase Cohort D: TAK-659 + Lenalidomide
* Dose Escalation Phase Cohort E: TAK-659 + Ibrutinib This study comprises 2 phases: a dose escalation phase and a safety expansion phase. Participants in all 5 cohorts (Cohorts A-E) will participate in the dose escalation phase of the study. Approximately 12 additional participants with advanced follicular lymphoma (FL) or marginal zone lymphoma (MZL) will be added to Cohort B, in the safety expansion phase.

This multi-center trial will be conducted in North America and Europe. The overall time to participate in this study is approximately 30 months. Participants will make multiple visits to the clinic and will be followed up for safety for 28 days after the last dose of study drug.

Arms: arm 1: TAK-659 60 mg, immediate-release tablet, orally, once daily on Days 1 to 21 along with bendamustine 90 mg/m\^2, infusion, intravenously, over 10 or 60 minutes on Days 1 and 2 in a 21-day treatment cycle, for up to 8 cycles. Participants continued to receive TAK-659 monotherapy until they experienced progressive disease (PD) or unacceptable toxicities or up to 39 cycles. arm 2: TAK-659 80 mg, immediate-release tablet, orally, once daily on Days 1 to 21 along with bendamustine 90 mg/m\^2, infusion, intravenously, over 10 or 60 minutes on Days 1 and 2 in a 21-day treatment cycle, for up to 8 cycles. The TAK-659 was escalated to 80 mg once daily after safety and tolerability of 60 mg dose was determined. Participants continued to receive TAK-659 monotherapy until they experienced PD or unacceptable toxicities or up to 39 cycles. arm 3: TAK-659 100 mg, immediate-release tablet, orally, once daily on Days 1 to 21 along with bendamustine mg/m\^2, infusion, intravenously, over 10 or 60 minutes on Days 1 and 2 in a 21-day treatment cycle, for up to 8 cycles. The TAK-659 was escalated to 100 mg once daily after safety and tolerability of 60 mg dose was determined. Participants continued to receive TAK-659 monotherapy until they experienced PD or unacceptable toxicities or up to 39 cycles. arm 4: TAK-659 60 mg, immediate-release tablet, orally, once daily on Days 1 to 21 along with bendamustine 90 mg/m\^2, infusion, intravenously, over 10 or 60 minutes on Days 1 and 2 along with rituximab 375 mg/m\^2, infusion, intravenously, on Day 1 in a 21-day treatment cycle, for up to 8 cycles. Participants continued to receive TAK-659 monotherapy until they experienced PD or unacceptable toxicities or up to 12 cycles. arm 5: TAK-659 80 mg, immediate-release tablet, orally, once daily on Days 1 to 21 along with bendamustine 90 mg/m\^2, infusion, intravenously, over 10 or 60 minutes on Days 1 and 2 along with rituximab 375 mg/m\^2, infusion, intravenously, on Day 1 in a 21-day treatment cycle, for up to 8 cycles. The TAK-659 was escalated to 80 mg once daily after safety and tolerability of 60 mg dose was determined. Participants continued to receive TAK-659 monotherapy until they experienced PD or unacceptable toxicities or up to 12 cycles. arm 6: TAK-659 100 mg, immediate-release tablet, orally, once daily on Days 1 to 21 along with bendamustine 90 mg/m\^2, infusion, intravenously, over 10 or 60 minutes on Days 1 and 2 along with rituximab 375 mg/m\^2, infusion, intravenously, on Day 1 in a 21-day treatment cycle, for up to 8 cycles. The TAK-659 was escalated to 100 mg once daily after safety and tolerability of 60 mg dose was determined. Participants continued to receive TAK-659 monotherapy until they experienced PD or unacceptable toxicities or up to 12 cycles. arm 7: TAK-659 60 mg, immediate-release tablet, orally, once daily on Days 1 to 21 along with gemcitabine 1000 mg/m\^2, infusion, intravenously, over 30 minutes on Days 1 and 8 in a 21-day treatment cycle. Participants continued to receive TAK-659 monotherapy until they experienced PD or unacceptable toxicities or up to 2 cycles. arm 8: TAK-659 40 mg, immediate-release tablet, orally, once daily on Days 1 to 28 along with lenalidomide 25 mg, capsules orally, once daily on Days 1 to 21 in a 28-day treatment cycle. The TAK-659 60 mg dose was de-escalated to 40 mg in case of dose limiting toxicity or if the starting dose was determined to be not tolerable. Participants continued to receive TAK-659 monotherapy until they experienced PD or unacceptable toxicities or up to 26 cycles. arm 9: TAK-659 60 mg, immediate-release tablet, orally, once daily on Days 1 to 28 along with lenalidomide 25 mg, capsules orally, once daily on Days 1 to 21 in a 28-day treatment cycle. Participants continued to receive TAK-659 monotherapy until they experienced PD or unacceptable toxicities or up to 26 cycles. arm 10: TAK-659 60 mg, immediate-release tablet, orally, once daily along with ibrutinib 560 mg capsules, orally, once daily on Days 1 to 28 in a 28-day treatment cycle. Participants continued to receive TAK-659 monotherapy until they experienced PD or unacceptable toxicities or up to 3 cycles. arm 11: TAK-659 immediate-release tablet, at the MTD/maximally administered dose (MAD)/RP2D determined from Dose Escalation Phase, orally, once daily on Days 1 to 21 along with bendamustine 90 mg/m\^2, infusion, intravenously, over 10 or 60 minutes on Days 1 and 2 along with rituximab 375 mg/m\^2, infusion, intravenously, on Day 1 in a 21-day treatment cycle, for up to 8 cycles in participants (who were to be entered in Phase 2) with advanced FL or MZL. Treatment could then be continued until they experienced PD or unacceptable toxicities or up to 12 cycles in participants who were to be enrolled in the Safety Expansion Phase Cohort.
Interventions: intervention 1: TAK-659 intervention 2: Bendamustine intervention 3: Rituximab intervention 4: Gemcitabine intervention 5: Lenalidomide intervention 6: Ibrutinib
Intervention descriptions: intervention 1: TAK-659 immediate release tablet intervention 2: Bendamustine intravenous infusion intervention 3: Rituximab intravenous infusion intervention 4: Gemcitabine intravenous infusion intervention 5: Lenalidomide capsule intervention 6: Ibrutinib capsule

Protocol documents:
Prot_000.pdf: 



Title: A Phase 1b, Dose Escalation Study to Determine the Recommended Phase 2 Dose of 
TAK-659 in Combination With Bendamustine (±Rituximab), Gemcitabine, Lenalidomide, or 
Ibrutinib for the Treatment of Patients With Advanced Non-Hodgkin Lymphoma After At Least 
1 Prior Line of Therapy
NCT Number: NCT02954406
Protocol Approve Date: 15 November 2018
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.


PROTOCOL
A Phase 1b, Dose Escalation Study to Determine the Recommended Phase 2 Dose of 
TAK-659 in Combination With Bendamustine (±Rituximab), Gemcitabine, Lenalidomide, 
or Ibrutinib for the Treatment of Patients With Advanced Non-Hodgkin Lymphoma 
After At Least 1 Prior Line of Therapy
A Phase 1b, Dose Escalation of TAK-659 in Combination With Bendamustine 
(±Rituximab), Gemcitabine, Lenalidomide, or Ibrutinib in Patients With Advanced Non-
Hodgkin Lymphoma
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:
C34005
IND Number: 
119,231
EudraCT Number:
2016-001426-34
Compound:
TAK-659
Date:
15 November 2018
Amendment Number:
03
Amendment History:
Date
Amendment Number
Amendment Type 
(for regional Europe purposes only)
Region
07 June 2016
Initial Protocol
Not applicable
Global
08 February 2017
01
Not applicable
Global
22 May 2018
02
Not applicable
Not applicable a
15 November 2018
03
Not applicable
Global
a Protocol Amendment 02 was not activated.
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1.0
ADMINISTRATIVE INFORMATION
1.1
Contacts 
A separate contact information list will be provided to each site.
Serious adverse event (SAE) and pregnancy reporting information is presented in Section 10.0, 
as is information on reporting product complaints. 
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site.
The names and contact information for the medical monitor and responsible medical officer are 
in the study manual.
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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 (ICH) E6 Good Clinical Practice (GCP): 
Consolidated Guideline.
!
All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations.
SIGNATURES
The signature of the responsible Takeda medical officer (and other signatories, as applicable) can 
be found on the signature page.
Electronic signatures may be found on the last page of this document.
PPD
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure (IB), 
package insert, and any other product information provided by the sponsor. I agree to conduct 
this study in accordance with the requirements of this protocol and also to protect the rights, 
safety, privacy, and well-being of study patients in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

ICH, E6 GCP: Consolidated Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting SAEs defined in Section 10.0 of this protocol.

Terms outlined in the clinical study site agreement.

Responsibilities of the Investigator (Appendix B).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix C of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Province)
Location of Facility (Country)
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1.3
Protocol Amendment 03 Summary of Changes
Rationale for Amendment 03
This document describes the changes in reference to the Protocol Incorporating Amendment 03. 
As Protocol Amendment 02 was not activated, the changes described below are based on a 
comparison with Amendment 01. The overall rationale for Amendment 03 is to close enrollment 
to Cohorts A, C, D, and E and to restrict the study population in the Cohort B expansion phase to 
patients with advanced follicular lymphoma (FL) or marginal zone lymphoma (MZL).
A summary of major revisions is shown below. Minor grammatical, editorial, formatting, and 
administrative changes not affecting the conduct of the study are included for clarification and 
administrative purposes only. For specific descriptions of text changes and where the changes are 
located, see Appendix I.
Changes in Amendment 03 (Compared With Amendment 01)
1. Added Investigational New Drug (IND) number and EudraCT number to title page.
2. Revised background to include information on FL, update description of TAK-659, 
reorganize nonclinical pharmacology information for TAK-659 combination therapy, and 
update clinical data for TAK-659.
3. Reorganized and updated potential benefits and risks of TAK-659.
4. Reorganized and updated study rationale.
5. Revised study design to restrict the expansion phase of the study to Cohort B only, and added 
text to permit evaluation of intermittent once-daily (QD) dosing schedules in Cohort B if 
appropriate.
6. Restricted study population in Cohort B expansion phase to patients with advanced FL or 
MZL.
7. Revised study sample size determination and planned enrollment numbers for each cohort.
8. Revised planned dose levels of TAK-659.
9. Revised duration of an individual patient’s study participation.
10. Extended total study duration.
11. Specified number of prior lines of therapy for patients entering Cohort B expansion phase 
and clarified the definition of lines of therapy.
12. Revised method for measuring renal function.
13. Added requirement for controlled fasting serum glucose levels during screening.
14. Added requirement that women of childbearing potential must have a negative serum 
pregnancy test at screening.
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15. Added requirement that female patients should not donate ova from time of signing informed 
consent through 180 days after last dose of study drug.
16. Added requirement that male patients should not donate sperm from time of signing 
informed consent through 180 days after last dose of study drug.
17. Clarified exclusion criteria related to prior anticancer treatment and prior autologous stem 
cell transplant.
18. Clarified exclusion criterion related to cardiovascular conditions.
19. Updated definitions of dose-limiting toxicity.
20. Revised dose modification guidelines for hematologic and nonhematologic toxicities.
21. Revised retreatment criteria for Cohorts A, B, and C.
22. Reorganized and updated management of TAK-659–related clinical events.
23. Added a section heading for management of combination drug-related clinical events.
24. Added sparse PK sampling schedule for Cohort B expansion phase, and clarified PK and PD 
sampling schedules for Cohort B when intermittent QD dosing schedule is used.
25. Added progression-free survival (PFS) follow-up visits for patients in Cohort B expansion 
phase who discontinue treatment for any reason other than progressive disease.
26. Updated procedures for cytomegalovirus monitoring.
27. Removed residual bone marrow sample collections from study procedures.
28.
29.
30. Revised reasons for discontinuation of treatment with study drug.
31. Revised reasons for withdrawal of patients from study.
32. Added criteria for early discontinuation of study.
33. Added PFS as a secondary endpoint for patients in Cohort B expansion phase.
34. Added a urine pregnancy test for women of childbearing potential at end of treatment for 
each cohort.
35. Added vital sign measurements on Day 15 of Cycle 3 and beyond for Cohorts A, B, and C.
36. Updated reference citations to support background information in protocol and added 
reference citation for a published TAK-659 clinical study.
37. Added a recommendation that prophylaxis for varicella-zoster virus should be administered 
for all patients in Cohort B.
38. Added a recommendation that the prophylaxis for Pneumocystis jiroveci pneumonia should 
be administered for all patients in Cohort B.
CCI
CCI
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 03 Summary of Changes ..........................................................5
2.0
STUDY SUMMARY ....................................................................................................14
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.........................................................................................................23
4.1.3
Nonclinical Experience ......................................................................................25
4.1.4
Clinical Experience............................................................................................26
4.1.5
Benefits and Risks..............................................................................................29
4.2
Rationale for the Proposed Study.............................................................................31
4.2.1
Rationale for the Combination of TAK-659 + Combination Drugs.....................31
4.2.2
Rationale for Dose and Schedule Selection ........................................................33
4.2.3
Rationale for PK Assessments............................................................................33
4.2.4
Rationale for Biomarker Analysis (Correlative Science Studies) ........................34
4.2.5
Rationale for Pharmacogenomic Assessments....................................................34
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................35
5.1
Objectives................................................................................................................35
5.1.1
Primary Objective ..............................................................................................35
5.1.2
Secondary Objectives.........................................................................................35
5.1.3
Additional Objective..........................................................................................35
5.1.4
Exploratory Objectives.......................................................................................35
5.2
Endpoints.................................................................................................................35
5.2.1
Primary Endpoints .............................................................................................35
5.2.2
Secondary Endpoints..........................................................................................36
5.2.3
Additional Endpoints .........................................................................................36
5.2.4
Exploratory Endpoints .......................................................................................36
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6.0
STUDY DESIGN..........................................................................................................37
6.1
Overview of Study Design.......................................................................................37
6.2
Number of Patients ..................................................................................................39
6.3
Duration of Study ....................................................................................................39
6.3.1
Duration of an Individual Patient’s Study Participation ......................................39
6.3.2
End of Study/Study Completion Definition and Planned Reporting....................40
6.3.3
Time Frames for Primary and Secondary Endpoints to Support Disclosures.......40
6.3.4
Total Study Duration..........................................................................................41
7.0
STUDY POPULATION................................................................................................42
7.1
Inclusion Criteria .....................................................................................................42
7.2
Exclusion Criteria ....................................................................................................44
8.0
STUDY DRUG .............................................................................................................48
8.1
Study Drug Administration......................................................................................48
8.1.1
Cohort A (TAK-659 + Bendamustine) Dosing Regimen ....................................48
8.1.2
Cohort B (TAK-659 + Bendamustine/Rituximab) Dosing Regimen ...................48
8.1.3
Cohort C (TAK-659 + Gemcitabine) Dosing Regimen.......................................49
8.1.4
Cohort D (TAK-659 + Lenalidomide) Dosing Regimen .....................................49
8.1.5
Cohort E (TAK-659 + Ibrutinib) Dosing Regimen .............................................50
8.1.6
Oral Drug Administration ..................................................................................50
8.2
Definitions of DLT ..................................................................................................51
8.3
Dose Escalation Rules..............................................................................................52
8.4
Dose Modification Guidelines..................................................................................56
8.4.1
Intrapatient Dose Escalation...............................................................................57
8.4.2
Intrapatient Dose Reduction (Cycle 1)................................................................57
8.4.3
Retreatment Criteria for Cohorts A, B, and C (Bendamustine or Gemcitabine)...58
8.4.4
Dose Modification for Hematologic and Nonhematologic Toxicity....................59
8.5
Excluded Concomitant Medications and Procedures ................................................69
8.5.1
Excluded Concomitant Medications Applicable to Cohorts A and B ..................71
8.5.2
Excluded Concomitant Medications Applicable to Cohort C..............................71
8.5.3
Excluded Concomitant Medications Applicable to Cohort D..............................71
8.5.4
Excluded Concomitant Medications Applicable to Cohort E ..............................71
8.6
Permitted Concomitant Medications and Procedures................................................72
8.6.1
Rituximab Premedication for Cohort B ..............................................................72
8.6.2
Additional Concomitant Medications and Procedures.........................................72
8.7
Precautions and Restrictions ....................................................................................73
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8.8
Management of TAK-659–Related Clinical Events..................................................74
8.8.1
Prophylaxis Against Infection ............................................................................74
8.8.2
Pneumonitis .......................................................................................................75
8.8.3
Nausea and/or Vomiting.....................................................................................76
8.8.4
Edema (Including Periorbital) ............................................................................76
8.8.5
Rash With or Without Pruritus ...........................................................................76
8.8.6
Diarrhea.............................................................................................................76
8.8.7
Anemia, Thrombocytopenia, and/or Neutropenia ...............................................76
8.8.8
Hypophosphatemia ............................................................................................77
8.8.9
Enzyme Elevations.............................................................................................77
8.8.10 Fluid Deficit.......................................................................................................77
8.9
Management of Combination Drug-Related Clinical Events ....................................77
8.9.1
Infusion Reactions .............................................................................................77
8.9.2
Cohorts A and B (Bendamustine-Related) Clinical Events .................................78
8.9.3
Cohort B (Rituximab-Related) Clinical Events...................................................78
8.9.4
Cohort C (Gemcitabine-Related) Clinical Events ...............................................78
8.9.5
Cohort D (Lenalidomide-Related) Clinical Events .............................................78
8.9.6
Cohort E (Ibrutinib-Related) Clinical Events......................................................79
8.10
Blinding and Unblinding..........................................................................................79
8.11
Description of Investigational Agents ......................................................................79
8.11.1 Description of TAK-659 ....................................................................................79
8.11.2 Description of Bendamustine .............................................................................79
8.11.3 Description of Rituximab...................................................................................79
8.11.4 Description of Gemcitabine................................................................................79
8.11.5 Description of Lenalidomide..............................................................................79
8.11.6 Description of Ibrutinib......................................................................................80
8.12
Preparation, Reconstitution, and Dispensation..........................................................80
8.12.1 TAK-659 Preparation, Reconstitution, and Dispensation....................................80
8.12.2 Bendamustine Preparation, Reconstitution, and Dispensation.............................80
8.12.3 Rituximab Preparation, Reconstitution, and Dispensation...................................80
8.12.4 Gemcitabine Preparation, Reconstitution, and Dispensation ...............................80
8.12.5 Lenalidomide Preparation, Reconstitution, and Dispensation .............................80
8.12.6 Ibrutinib Preparation, Reconstitution, and Dispensation .....................................80
8.13
Packaging and Labeling...........................................................................................81
8.13.1 TAK-659 Packaging and Labeling .....................................................................81
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8.13.2 Bendamustine Packaging and Labeling ..............................................................81
8.13.3 Rituximab Packaging and Labeling....................................................................81
8.13.4 Gemcitabine Packaging and Labeling.................................................................81
8.13.5 Lenalidomide Packaging and Labeling...............................................................81
8.13.6 Ibrutinib Packaging and Labeling.......................................................................81
8.14
Storage, Handling, and Accountability.....................................................................81
8.14.1 TAK-659 Storage, Handling, and Accountability ...............................................81
8.14.2 Bendamustine Storage, Handling, and Accountability ........................................82
8.14.3 Rituximab Storage, Handling, and Accountability..............................................82
8.14.4 Gemcitabine Storage, Handling, and Accountability...........................................82
8.14.5 Lenalidomide Storage, Handling, and Accountability.........................................82
8.14.6 Ibrutinib Storage, Handling, and Accountability.................................................82
9.0
STUDY CONDUCT......................................................................................................83
9.1
Study Personnel and Organizations..........................................................................83
9.2
Arrangements for Recruitment of Patients................................................................83
9.3
Treatment Group Assignments.................................................................................83
9.4
Study Procedures.....................................................................................................83
9.4.1
Informed Consent...............................................................................................83
9.4.2
Patient Demographics ........................................................................................84
9.4.3
Medical History .................................................................................................84
9.4.4
Physical Examination.........................................................................................84
9.4.5
Patient Height ....................................................................................................84
9.4.6
Vital Signs .........................................................................................................84
9.4.7
ECOG Performance Status.................................................................................84
9.4.8
ECG...................................................................................................................84
9.4.9
Concomitant Medications and Procedures..........................................................85
9.4.10 Enrollment .........................................................................................................86
9.4.11 Clinical Laboratory Evaluations .........................................................................86
9.4.12 Pregnancy Test...................................................................................................87
9.4.13 Ophthalmic Exam ..............................................................................................87
9.4.14 Disease Assessment ...........................................................................................87
9.4.15 CT Scans............................................................................................................88
9.4.16 PET Scans..........................................................................................................89
9.4.17 Bone Marrow Biopsy and Aspirate.....................................................................89
9.4.18
..................................................................................................89
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9.4.19
...................................................................90
9.4.20
................................................................................90
9.4.21 PK Measurements..............................................................................................90
9.4.22
...........................................................................................91
9.4.23 CMV Testing .....................................................................................................91
9.5
Completion of Study Treatment (for Individual Patients) .........................................91
9.6
Discontinuation of Treatment With Study Drug .......................................................91
9.7
Withdrawal of Patients From Study .........................................................................92
9.8
Early Discontinuation of the Study...........................................................................93
9.9
Study Compliance....................................................................................................93
10.0
ADVERSE EVENTS ....................................................................................................94
10.1
Definitions...............................................................................................................94
10.1.1 PTE Definition...................................................................................................94
10.1.2 AE Definition ....................................................................................................94
10.1.3 SAE Definition ..................................................................................................94
10.2
Procedures for Recording and Reporting AEs and SAEs..........................................95
10.3
Monitoring of AEs and Period of Observation .........................................................96
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events.........97
10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose) ................................................................................................................97
10.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities...........97
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................99
12.0
DATA HANDLING AND RECORDKEEPING..........................................................100
12.1
eCRFs....................................................................................................................100
12.2
Record Retention ...................................................................................................100
13.0
STATISTICAL METHODS........................................................................................102
13.1
Statistical and Analytical Plans ..............................................................................102
13.1.1 Analysis Sets....................................................................................................102
13.1.2 Analysis of Demographics and Other Baseline Characteristics.........................102
13.1.3 Efficacy Analysis.............................................................................................103
13.1.4 PK Analysis .....................................................................................................103
13.1.5
13.1.6
13.1.7 Safety Analysis ................................................................................................104
13.2
Interim Analysis and Criteria for Early Termination ..............................................105
13.3
Determination of Sample Size................................................................................105
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14.0
QUALITY CONTROL AND QUALITY ASSURANCE.............................................107
14.1
Study-Site Monitoring Visits .................................................................................107
14.2
Protocol Deviations................................................................................................107
14.3
Quality Assurance Audits and Regulatory Agency Inspections ..............................107
15.0
ETHICAL ASPECTS OF THE STUDY......................................................................108
15.1
IRB and/or IEC Approval ......................................................................................108
15.2
Patient Information, Informed Consent, and Patient Authorization.........................109
15.3
Patient Confidentiality ...........................................................................................110
15.4
Publication, Disclosure, and Clinical Trial Registration Policy...............................110
15.4.1 Publication and Disclosure...............................................................................110
15.4.2 Clinical Trial Registration................................................................................111
15.4.3 Clinical Trial Results Disclosure ......................................................................111
15.5
Insurance and Compensation for Injury..................................................................111
16.0
REFERENCES............................................................................................................112
8.4.3 Re-treatmentRetreatment Criteria for Cohorts A, B, and C (Bendamustine or 
Gemcitabine (Cohorts A, B, and C)..................................................................176
9.4.14 Disease Assessment ..........................................................................................181
9.4.14 Disease Assessment ..........................................................................................181
LIST OF IN-TEXT TABLES
Table 4.a
Overview of TAK-659 Clinical Studies..............................................................27
Table 6.a
Planned Number of Patients ...............................................................................39
Table 6.b
Primary and Secondary Endpoints for Disclosures .............................................41
Table 8.a
Cohort A (TAK-659 + Bendamustine) Dosing Schedule ....................................48
Table 8.b
Cohort B (TAK-659 + Bendamustine/Rituximab) Dosing Schedule ...................49
Table 8.c
Cohort C (TAK-659 + Gemcitabine) Dosing Schedule.......................................49
Table 8.d
Cohort D (TAK-659 + Lenalidomide) Dosing Schedule.....................................50
Table 8.e
Cohort E (TAK-659 + Ibrutinib) Dosing Schedule .............................................50
Table 8.f
Planned Dose Levels of TAK-659 for Cohorts A to E ........................................55
Table 8.g
Dose Reduction Levels for TAK-659 .................................................................57
Table 8.h
Dose Reduction Levels for TAK-659 Combination Drugs..................................57
Table 8.i
Dose Modification Guidelines for Hematologic Toxicities for Cohort A 
(TAK-659 + Bendamustine) and Cohort B (TAK-
659 + Bendamustine/Rituximab)........................................................................60
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Table 8.j
Dose Modification Guidelines for Nonhematologic Toxicities for Cohort A 
(TAK-659 + Bendamustine) and Cohort B (TAK-659 + Bendamustine/ 
Rituximab).........................................................................................................62
Table 8.k
Dose Modification Guidelines for Hematologic Toxicities for Cohort C 
(TAK-659 + Gemcitabine), Cohort D (TAK-659 + Lenalidomide), and 
Cohort E (TAK-659 + Ibrutinib) ........................................................................65
Table 8.l
Dose Modification Guidelines for Nonhematologic Toxicities for Cohort C 
(TAK-659 + Gemcitabine), Cohort D (TAK-659 + Lenalidomide), and 
Cohort E (TAK-659 + Ibrutinib) ........................................................................67
Table 9.a
Clinical Chemistry and Hematology Tests..........................................................86
Table 9.b
Clinical Urinalysis Tests ....................................................................................87
LIST OF IN-TEXT FIGURES
Figure 8.a
Dose Escalation Algorithm.................................................................................54
LIST OF APPENDICES
Appendix A
Schedules of Events .........................................................................................114
Appendix B
Responsibilities of the Investigator...................................................................125
Appendix C
Investigator Consent to Use of Personal Information........................................127
Appendix D
ECOG Scale for Performance Status ................................................................128
Appendix E
Cockcroft-Gault Equation ................................................................................129
Appendix F
Methods of Contraception Considered to be Effective......................................130
Appendix G
New York Heart Association Classification of Cardiac Disease........................132
Appendix H
Medications, Supplements, and Food Products to be Avoided or Used 
Cautiously........................................................................................................133
Appendix I
Detailed Description of Amendments to Text...................................................136
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2.0
STUDY SUMMARY
Name of Sponsor:
Millennium Pharmaceuticals, Inc.
Compound:
TAK-659
Title of Protocol: A Phase 1b, Dose Escalation Study to Determine the 
Recommended Phase 2 Dose of TAK-659 in Combination With Bendamustine 
(± Rituximab), Gemcitabine, Lenalidomide, or Ibrutinib for the Treatment of 
Patients With Advanced Non-Hodgkin Lymphoma After At Least 1 Prior Line 
of Therapy
IND No.:
119,231
EudraCT No.:
2016-001426-34
Study Number: C34005
Phase: 1b
Study Design:
This is a phase 1b, dose escalation study of TAK-659 in combination with 1 of 5 combination drugs (bendamustine, 
bendamustine + rituximab, gemcitabine, lenalidomide, or ibrutinib) in adult patients with advanced non-Hodgkin 
lymphoma (NHL) after at least 1 prior line of therapy. The primary objective of the study is to determine the 
maximum tolerated dose (MTD) or the recommended phase 2 dose (RP2D) of TAK-659 when administered with 
each of the combination drugs. 
Once enrolled in the study, patients will be assigned to 1 of 5 combination cohorts:

Cohort A (TAK-659 + bendamustine).

Cohort B (TAK-659 + bendamustine + rituximab).

Cohort C (TAK-659 + gemcitabine).

Cohort D (TAK-659 + lenalidomide).

Cohort E (TAK-659 + ibrutinib).
This study comprises 2 phases: a dose escalation phase and a safety expansion phase. Patients in all 5 cohorts 
(Cohorts A-E) will participate in the dose escalation phase of the study.
During the dose escalation phase, the dose of TAK-659 will be escalated (3 planned dose levels of escalation: 
60, 80, and 100 mg) according to a 3 + 3 dose escalation scheme. The dose of oral TAK-659 will increase in 20-mg 
increments to a maximum of 100 mg once daily (QD), provided that the safety and tolerability of the 60 mg dose has 
been demonstrated. Dose levels below the starting dose of 60 mg QD (eg, 40 mg QD) or intermittent QD dosing 
schedules (eg, 7 days on followed by 7 days off or 14 days on followed by 7 days off) also may be evaluated, if 
appropriate, in Cohort B. Dose escalation will continue until the MTD is reached, or until TAK-659 100 mg QD (the
maximally administered dose [MAD]) is determined to be safe and tolerable, or until an RP2D, if different from the 
MTD or MAD, is identified based on the safety, tolerability, and preliminary pharmacokinetic (PK) and efficacy 
data (if available) observed in Cycle 1 and beyond.
The doses of combination drugs will be administered at a fixed dose and regimen.
During the safety expansion phase of the study, approximately 12 additional patients with advanced follicular 
lymphoma (FL) or marginal zone lymphoma (MZL) will be added to Cohort B at the MTD/MAD/RP2D for further 
safety evaluation. No patients from Cohorts A, C, D, or E will enter the safety expansion phase of the study because 
effective 16 March 2018, the sponsor closed recruitment into Cohorts C, D, and E and effective 16 October 2018, 
the sponsor closed recruitment into Cohort A.
During both the dose escalation phase and the safety expansion phase of the study, PK samples will be collected at 
prespecified time points to characterize the PK of TAK-659 when administered with each of the combination drugs. 
Pharmacodynamic and other biomarker analyses will also be performed for TAK-659 in combination with each of 
the combination drugs. Toxicity will be evaluated according to National Cancer Institute Common Terminology 
Criteria for Adverse Events version 4.03 [1].
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Primary Objective: To determine the MTD or RP2D for TAK-659 when administered in combination with each of 
the combination drugs (bendamustine, bendamustine + rituximab, gemcitabine, lenalidomide, and ibrutinib).
Secondary Objectives:
!
To characterize the plasma PK of TAK-659 in each of the 5 cohorts.
!
To observe the preliminary efficacy of different combination drugs with TAK-659 (Cohorts A-E) in patients 
with advanced NHL who have relapsed and/or are refractory after ≥1 prior line of therapy (for patients with FL 
or MZL in Cohort B expansion, ≤1 prior line of therapy).
Additional Objective: To evaluate the safety and tolerability of TAK-659 in each of the 5 cohorts.
Exploratory Objectives:
Patient Population: Patients with advanced NHL of any histology after at least 1 prior line of therapy.
Number of Patients:
Patients will be enrolled and assigned to 1 of 5 combination cohorts as follows:
Number of Sites: 
Estimated total: ~15 sites in 
North America and Europe.
Cohort
Total 
(~N) a
Dose Escalation
(~N)
Safety Expansion
(~N)
A
14
9-12
0 b
B
40
9-24 c
12
C
14
9-12
0 b
D
14
9-12
0 b
E
14
9-12
0 b
a Approximate enrolled number was based on the assumption of a 10% dropout 
rate.
b Effective 16 March 2018, enrollment into Cohorts C, D, and E was closed, and 
effective 16 October 2018, enrollment into Cohort A was closed. No patients 
from these 4 cohorts will enter into the safety expansion phase of this study.
c A dose lower than 60 mg QD or intermittent dosing schedules may be 
evaluated, if appropriate.
Dose Levels and Routes of Administration:
TAK-659 Dosage Regimen: Oral TAK-659 will start at a dose of 60 mg QD and may be increased in 20-mg 
increments to 100 mg QD in combination with each of the following combination drugs:
Cohort
Study Drug(s)
Dosage Regimen(s) of Combination Drug(s)
A
TAK-659 + bendamustine
90 mg/m2 administered IV over 10 or 60 min (depending on 
which formulation is used) on Days 1 and 2 of each 21-day 
cycle, up to 8 cycles
B
TAK-
659 + bendamustine + rituximab
90 mg/m2 bendamustine administered IV over 10 or 60 min 
(depending on which formulation is used) on Days 1 and 2 of 
each 21-day cycle, up to 8 cycles, and 375 mg/m2 rituximab 
administered IV per local guidelines and labeling on Day 1 of 
CCI
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each 21-day cycle, up to 8 cycles
C
TAK-659 + gemcitabine
1000 mg/m2 IV infusion over 30 min on Days 1 and 8 of each 
21-day cycle
D
TAK-659 + lenalidomide
25 mg orally (PO) QD for Days 1-21 of each 28-day cycle
E
TAK-659 + ibrutinib
560 mg PO QD of each 28-day cycle
Duration of Treatment:
Treatment will continue until disease progression, unacceptable 
toxicities, or withdrawal due to other reasons. Estimated treatment 
duration is 12 months.
Period of Evaluation:
Patients will be followed for safety for 
28 days after the last dose of study drug or 
until the start of subsequent anticancer 
therapy, whichever occurs first. 
Main Criteria for Inclusion:

Male or female patients aged 18 years or older.

In the dose escalation phase, histologically or cytologically confirmed diagnosis of advanced NHL of any 
histology (with the exception of patients with Waldenström macroglobulinemia and chronic lymphocytic 
leukemia). In the safety expansion phase for Cohort B, only patients with advanced FL or MZL will be 
included.

Radiographically or clinically measurable disease with at least 1 target lesion per International Working Group 
criteria (IWG) for malignant lymphoma [2].

In the dose escalation phase, patients who are refractory or relapsed after at least 1 prior line of therapy due to 
progression, intolerance, or physician/patient decision and for whom no effective standard therapy is available 
per the investigator’s assessment. In the safety expansion phase for Cohort B in patients with FL or MZL, the 
prior line of therapy is limited to ≤1.

Eastern Cooperative Oncology Group performance status score of 0 or 1 and life expectancy of greater than 
3 months.

Patients must have adequate organ function, including the following:
-
Adequate 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 transfusion allowed ≥14 days before assessment). 
-
Hepatic: total bilirubin ≤1.5 times the upper limit of the normal range (ULN); alanine aminotransferase and 
aspartate aminotransferase ≤2.5 × ULN.
-
Renal: creatinine clearance ≥60 mL/min as estimated by the Cockcroft-Gault equation.
-
Others:
o
Lipase ≤1.5 ULN and amylase ≤1.5 ULN with no clinical symptoms suggestive of pancreatitis or 
cholecystitis. 
o
Blood pressure Grade ≤1 (hypertensive patients are permitted if their blood pressure is controlled to 
Grade ≤1 by antihypertensive medications). 
o
Fasting serum glucose level shall be controlled to 130 mg/dL during screening period.

Both men and women in Cohort D (TAK-659 + lenalidomide) must adhere to the guidelines of the RevAssist 
program (United States participants) or the Lenalidomide Pregnancy Risk Minimisation Plan as outlined in the 
study manual (all other participants who are not using commercial supplies).
Main Criteria for Exclusion:
In addition to the standard exclusion criteria:

Central nervous system lymphoma; active brain or leptomeningeal metastases, as indicated by positive cytology 
from lumbar puncture or computed tomography scan/magnetic resonance imaging. Exceptions include those 
patients who have completed definitive therapy, are not on steroids, have a stable neurologic status for at least 
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2 weeks after completion of the definitive therapy and steroids, and do not have neurologic dysfunction that 
would confound the evaluation of neurologic and other adverse events (AEs).

Known human immunodeficiency virus (HIV)-related malignancy.

Known HIV positive.

Systemic anticancer treatment (including investigational agents) or radiotherapy less than 2 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). 

Prior autologous stem cell transplant (ASCT) within 6 months or prior ASCT at any time without adequate 
hematopoietic recovery, defined by the entry criteria in the study, before Cycle 1 Day 1, or allogeneic stem cell 
transplant any time.

Use or consumption of any of the following substances:
-
Medications or supplements that are known to be inhibitors of P-glycoprotein (P-gp) and/or strong
reversible inhibitors of cytochrome P450 (CYP) 3A within 5 times the inhibitor half-life (if a reasonable 
half-life estimate is known) or within 7 days (if a reasonable half-life estimate is unknown) before the first 
dose of study drug. In general, the use of these agents is not permitted during the study except in cases in 
which an AE must be managed (see Section 8.5). 
-
Medications or supplements that are known to be strong CYP3A mechanism-based inhibitors or strong 
CYP3A inducers and/or P-gp inducers within 7 days or within 5 times the inhibitor or inducer half-life 
(whichever is longer) before the first dose of study drug. In general, the use of these agents is not permitted 
during the study except in cases in which an AE must be managed (see Section 8.5).
-
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.

Additionally, for patients in Cohort E (TAK-659 + ibrutinib), use or consumption of any of the following 
substances:
-
Medications or supplements that are known to be moderate 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 drugs. In general, the use of these agents is not 
permitted during the study for this combination except in cases in which an AE must be managed (see 
Section 8.5).
-
Medications or supplements that are known to be moderate mechanism-based inhibitors or moderate 
inducers of CYP3A within 7 days or within 5 times the inhibitor or inducer half-life (whichever is longer) 
before the first dose of study drugs. In general, the use of these agents is not permitted during the study for 
this combination except in cases in which an AE must be managed (see Section 8.5).
-
Seville oranges within 5 days before the first dose of study drugs and during the study.
Main Criteria for Evaluation and Analyses:

Primary Endpoints: 
–
MTD (dose escalation phase) of TAK-659 when administered with each of the combination drugs.
–
RP2D (dose escalation phase) of TAK-659 when administered with each of the combination drugs.

Secondary Endpoints: 
–
TAK-659 PK parameters, including maximum observed concentration (Cmax), time of first occurrence of 
Cmax (Tmax), and area under the plasma concentration-time curve during a dosing interval (AUCτ) by dose 
escalation cohort. 
–
Objective response rate (ORR) by IWG.
–
Duration of response (DOR). 
–
Time to progression (TTP).
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–
Progression-free survival (PFS) (for patients in the Cohort B expansion phase).
!
Additional Endpoints:
-
Safety parameters, including percentage of patients with AEs, percentage of patients with Grade ∀3 AEs, 
percentage of patients with serious adverse events (SAEs), percentage of patients who discontinued due to 
AEs, clinically significant laboratory values, and clinically significant vital sign measurements.
-
Other TAK-659 PK parameters, including apparent oral clearance, peak-trough ratio, accumulation ratio, 
and trough concentration by dose escalation cohort.
!
Exploratory Endpoints:
Statistical Considerations:
Dose escalation will be conducted according to a standard 3 + 3 dose escalation schema for each of the 5 cohorts. 
Approximately 12 dose-limiting toxicity (DLT)-evaluable patients from each of the 5 cohorts will participate in the 
dose escalation phase of the study. Dose escalation will continue until the TAK-659 MTD is reached or until 
TAK-659 100 mg QD (the MAD) is determined to be safe and tolerable, or until an RP2D, if different from the 
MTD or MAD, is identified based on the safety, tolerability, and preliminary PK and efficacy data (if available) 
observed in Cycle 1 and beyond. The escalation of each of the combination cohorts is independent of the other 
cohorts. 
Sample Size Justification: The dose escalation phase of this study will use a 3 + 3 design. With the exception of 
bendamustine, each combination drug’s dose will be the dose according to the manufacturer’s label. The dose of 
bendamustine will be based on its use in previous combination studies [3,4]. In the dose escalation phase, 9 to 
12 DLT-evaluable patients from each of Cohorts A to E will be recruited based on 2 planned dose levels of TAK-
659. A dose lower than 60 mg QD (eg, 40 mg QD) or intermittent QD dosing schedules (eg, 7 days on followed by 
7 days off or 14 days on followed by 7 days off) may be evaluated in Cohort B, if appropriate. As a result, the actual 
number of patients to be enrolled into Cohort B will be increased accordingly. Twelve additional patients with FL or 
MZL will be recruited into Cohort B for the safety expansion phase; no patients from Cohorts A, C, D, or E will be 
recruited for the safety expansion phase since the sponsor has closed enrollment into these cohorts. Assuming a 10% 
dropout rate, approximately 40 patients in Cohort B, and 14 patients each in Cohorts A, C, D, and E will be 
recruited. The total sample size for this study will be approximately 96 patients.
CCI
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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, the study medication, expertise in the therapeutic area and the conduct of clinical 
research, as well as study participation. The signatory coordinating investigator will be required 
to review and sign the clinical study report (CSR) and, by doing so, agrees that it accurately 
describes the results of the study.
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3.3
List of Abbreviations
Abbreviation
Term
AUC
change in area under the concentration-time curve
5-HT3
5-hydroxytryptamine 3
ABC
activated B-cell
AE
adverse event
ALC
absolute lymphocyte count
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AML
acute myeloid leukemia
ANC
absolute neutrophil count
ASCO
American Society of Clinical Oncology
ASCT
autologous stem cell transplant
ASH
American Society of Hematology
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
AUCτ
area under the concentration-time curve during a dosing interval 
BCR
B-cell receptor
BCRP
breast cancer resistance protein
BID
twice daily
BTK
Bruton’s tyrosine kinase 
BUN
blood urea nitrogen
CFR
Code of Federal Regulations
CLL
chronic lymphocytic leukemia
Cmax
maximum observed concentration
CMV
cytomegalovirus
CNS
central nervous system
CO2
carbon dioxide
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 interactions
DLBCL
diffuse large B-cell lymphoma
DLT
dose-limiting toxicity
DOR
duration of response
EC50
concentration producing half-maximal response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
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Abbreviation
Term
EMA
European Medicines Agency
EOT
end of treatment
FDA
[United States] Food and Drug Administration
FDG
fluoro-2-deoxy-D-glucose
FIH
first-in-human
FL
follicular lymphoma
FLT3
FMS-like tyrosine kinase 3
GCB
germinal center B-cell
GCP
Good Clinical Practice
G-CSF
granulocyte colony stimulating factor
GGT
gamma glutamyl transferase
GI
gastrointestinal
GM-CSF
granulocyte macrophage-colony stimulating factor
hCG
human chorionic gonadotropin
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
IRB
institutional review board
ITAM
immunoreceptor tyrosine-based activating motif
IV
intravenous(ly)
IWG
International Working Group
LDH
lactate dehydrogenase
MAD
maximally administered dose
MCL
mantle cell lymphoma
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
MZL
marginal zone lymphoma
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NHL
non-Hodgkin lymphoma
NK
natural killer
ORR
overall response rate
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) 
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Abbreviation
Term
PR
partial response 
PTE
pretreatment event
Q2W
every 2 weeks (14 days)
QD
quaque die; each day; once daily
QTc
rate-corrected QT interval (millisec) of electrocardiograph
QTcF
Fridericia’s corrected QT interval
RA
rheumatoid arthritis
RBC
red blood cell
RP2D
recommended phase 2 dose
SAE
serious adverse event
SD
stable disease
SOC
System Organ Class
SUSAR
suspected unexpected serious adverse reactions
SUV
standardized uptake value
SYK
spleen tyrosine kinase
TEAE
treatment-emergent adverse event
TGI
tumor growth inhibition
Tmax
time of first occurrence of Cmax
TTP
time to progression
ULN
upper limit of the normal range
US
United States
USPI
United States Package Insert
WBC
white blood cell
WHO
World Health Organization
WM
Waldenström macroglobulinemia
WOCBP
women of childbearing potential
3.4
Corporate Identification 
Millennium
Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceutical 
Company Limited
TDC Japan
Takeda Development Center Japan
TDC Asia
Takeda Development Center Asia, Pte Ltd
TDC Europe
Takeda Development Centre Europe Ltd
TDC Americas
Takeda Development Center Americas, Inc
TDC
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable
Takeda
Millennium Pharmaceuticals, Inc, TDC Japan, TDC Asia, TDC Europe and/or TDC 
Americas, as applicable
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4.0
INTRODUCTION
4.1
Background
4.1.1
Diseases Under Study
Non-Hodgkin lymphoma (NHL), is the most common hematologic malignancy and consists of 
numerous subtypes [5]; it is one of the most common cancers in the United States (US), 
accounting for about 4% of all cancers [6]. In 2018, an estimated 74,680 new cases of NHL are 
expected to be diagnosed in the US, and an estimated 19,910 people will die of this disease [7]. 
The two most common types of NHL are diffuse large B-cell lymphoma (DLBCL) and follicular 
lymphoma (FL). DLBCL accounts for about 1 of every 3 lymphomas, and FL accounts for about 
1 of every 5 lymphomas in the US [8].
The immunochemotherapy regimen R-CHOP (cyclophosphamide, doxorubicin 
[hydroxydaunomycin], vincristine [Oncovin], and prednisone with rituximab) is the standard 
treatment for patients with newly diagnosed DLBCL [5,6]. This regimen results in complete 
remission in approximately 65% to 75% of first-line patients with DLBCL. It is considered 
curative in a subset of patients, with a cure rate of >50% [7,8]. However, DLBCL is highly 
heterogeneous in histology, clinical behavior, and underlying biology, and therefore exhibits 
significant variation with regard to 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 treatments of choice 
for patients with relapsed disease. For patients with disease relapse following transplant or for 
patients not eligible for transplant, there is no clear standard of care; therefore, multiple 
chemotherapy regimens and investigational agents in clinical trials are being used to treat these 
patients. 
Follicular lymphoma (FL) is the most common indolent NHL in the Western hemisphere, 
representing 20% of NHL cases [9]. Randomized clinical trials have demonstrated that the 
addition of rituximab to standard chemotherapy induction has improved overall survival. 
Maintenance rituximab strategies can improve progression-free survival (PFS). Bendamustine 
combined with rituximab has rapidly become a standard frontline strategy in North America and 
parts of Europe. However, several unmet needs remain, including the identification of high-risk 
patients at diagnosis and the development of predictive biomarkers for targeted agents [10].
4.1.2
Study Drug
4.1.2.1
TAK-659
TAK-659 is a small molecule that inhibits spleen tyrosine kinase (SYK) and FMS-like tyrosine 
kinase 3 (FLT3) and is currently under development for the treatment of patients with advanced 
malignancies. TAK-659 inhibits SYK- and FLT3-purified enzymes with a concentration 
producing 50% inhibition (IC50) of 3.2 nM and 4.6 nM, respectively. TAK-659 demonstrated a 
more than 50-fold selectivity for SYK over 290 other protein kinases screened. In cultured 
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human tumor cells, TAK-659 potently inhibited SYK activity in hematopoietic-derived cell lines 
(Section 4.1.3). TAK-659 is currently being investigated as a single agent in trials of patients 
with NHL and acute myelogenous leukemia (AML), as well as a combination agent in patients 
with lymphoma and solid tumors.
4.1.2.2
Bendamustine
Bendamustine is a bifunctional mechlorethamine derivative that forms covalent bonds with 
electron-rich nucleophilic moieties, resulting in intrastrand DNA crosslinks. These crosslinks can 
lead to cell death via several pathways in both quiescent and dividing cells. Bendamustine is 
indicated for the treatment of chronic lymphocytic leukemia (CLL) and indolent B-cell NHL that 
has progressed during or within 6 months after treatment with rituximab or a rituximab-
containing regimen [11]. Bendamustine in combination with rituximab has been used as second-
line (or greater) therapy for patients with DLBCL.
4.1.2.3
Rituximab
Rituximab is a genetically engineered chimeric murine/human monoclonal IgG1 kappa antibody 
directed against the CD20 antigen on the surface of pre-B and mature B lymphocytes. Upon 
binding to CD20, rituximab mediates B-cell lysis. Rituximab is indicated for the treatment of 
NHL; CLL; rheumatoid arthritis (RA) in combination with methotrexate in adult patients with 
moderately to severely active RA who have inadequate response to 1 or more tumor necrosis 
factor antagonist therapies; and granulomatosis with polyangiitis (Wegener granulomatosis) and 
microscopic polyangiitis in adult patients in combination with glucocorticoids [12]. Moreover, 
rituximab is indicated for previously untreated DLBCL in combination with CHOP 
(cyclophosphamide, doxorubicin [hydroxydaunomycin], vincristine [Oncovin], and prednisone) 
or other anthracycline-based regimens.
4.1.2.4
Gemcitabine
Gemcitabine is a nucleoside metabolic inhibitor that kills cells undergoing DNA synthesis and 
blocks progression of the cells through the G1/S-phase boundary. Gemcitabine is indicated in 
combination with carboplatin for the treatment of advanced ovarian cancer that has relapsed at 
least 6 months after completion of platinum-based therapy; in combination with paclitaxel for 
first-line treatment of metastatic breast cancer after failure of prior anthracycline-containing 
adjuvant chemotherapy, unless anthracyclines were clinically contraindicated; in combination 
with cisplatin for the treatment of non-small cell lung cancer; and as a single-agent for the 
treatment of pancreatic cancer [13]. Gemcitabine has been used in second line (or greater) 
chemotherapy regimens for patients with relapsed/refractory DLBCL [14].
4.1.2.5
Lenalidomide
Lenalidomide is an analogue of thalidomide with immunomodulatory, antiangiogenic, and 
antineoplastic properties. Lenalidomide is indicated in the US in combination with 
dexamethasone for the treatment of multiple myeloma, for the treatment of transfusion-
dependent anemia due to low- or intermediate-1–risk myelodysplastic syndromes associated with 
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a deletion 5q abnormality with or without additional cytogenetic abnormalities, and for the 
treatment of mantle cell lymphoma (MCL) that has relapsed or progressed after 2 prior therapies, 
1 of which included bortezomib [15].
4.1.2.6
Ibrutinib
Ibrutinib is a small molecule inhibitor of Bruton’s tyrosine kinase (BTK). Ibrutinib forms a 
covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK 
enzymatic activity. Ibrutinib is indicated for the treatment of MCL and CLL after at least 1 prior 
therapy, CLL with 17p deletion, and Waldenström macroglobulinemia (WM) [16].
4.1.3
Nonclinical Experience
4.1.3.1
Nonclinical Pharmacology Experience With TAK-659
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 binds to phosphorylated 
immunoreceptor tyrosine-based activation-motifs (ITAMs) located within receptors found on 
B and T cells and certain 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 in hematopoietic cells, and abnormal function of SYK has been 
implicated in NHL, including FL, DLBCL, and MCL. 
TAK-659 inhibits SYK-purified enzyme with an IC50 of 3.2 nM and a concentration producing 
half-maximal response (EC50) 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 activated B-cell–like (ABC)-
DLBCL model; the OCI-Ly19 model, a germinal center B-cell–like (GCB)-DLBCL model; the 
PHTX-95L model, a primary human DLBCL model; the TMD8 ABC-DLBCL model; the RL FL 
model; and the MINO MCL model. TAK-659 has been tested in nonclinical DLBCL models in 
combination with a number of agents used in the relapsed/refractory setting, including 
bendamustine, gemcitabine, lenalidomide, and ibrutinib. All combination drugs were given 
concomitantly in nonclinical studies.
Refer to the TAK-659 IB for additional information.
4.1.3.2
Nonclinical Pharmacology Experience With Combination Drugs
Bendamustine is a standard-of-care agent used in combination with rituximab as a second-line 
(or greater) therapy to treat patients with DLBCL. TAK-659 (60 mg/kg once daily [QD]) in 
combination with bendamustine (1 mg/kg twice weekly) in the OCI-Ly10 model resulted in 
significant antitumor activity with tumor growth inhibition (TGI) of 78.6% (change in area under 
the concentration-time curve [ΔAUC], p<0.001) when compared with vehicle. This combination 
resulted in additive antitumor activity in the OCI-Ly19 GCB DLBCL model where TAK-659 
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(60 mg/kg QD) and bendamustine (2 mg/kg twice weekly) resulted in TGI of 52.1% (ΔAUC, 
p<0.01).
Gemcitabine HCl is a nucleoside analogue that primarily kills cells undergoing DNA synthesis 
(S-phase) and also blocks the progression of cells through the G1/S-phase boundary. In DLBCL, 
gemcitabine is used to treat relapsed and refractory patients. TAK-659 has shown synergistic 
antitumor activity when combined with gemcitabine in nonclinical models of DLBCL. In the 
TMD8 model, TAK-659 (60 mg/kg QD) in combination with gemcitabine (5 mg/kg, every 3 
days times 4) achieved significant antitumor activity with TGI of 96.7% (ΔAUC, p<0.001), 
demonstrating enhanced therapeutic potential over single-agent treatment. This combination was 
found to be additive in the OCI-Ly10 model with TGI of 90.6% (ΔAUC, p<0.001). 
Lenalidomide is an immunomodulatory agent that has been shown to modulate different 
components of the immune system by altering cytokine production, regulating T-cell 
costimulation, and augmenting the NK cell cytotoxicity. The immunomodulatory properties of 
lenalidomide are implicated in its clinical efficacy and provide a rationale for combination with 
TAK-659. Combination of these agents in nonclinical studies has shown strongly additive tumor 
inhibition in the OCI-Ly10 DLBCL model. TAK-659 (60 mg/kg QD) in combination with 
lenalidomide (10 mg/kg QD) resulted in TGI of 73.1% (ΔAUC, p<0.001). 
Ibrutinib is an inhibitor of BTK that is approved in CLL, MCL, WM, and marginal zone 
lymphoma and is currently in clinical trials for DLBCL. It is hypothesized that targeting BTK, 
which lies downstream of SYK, in combination with SYK inhibition could lead to a more 
pronounced response in hematologic malignancies. In nonclinical animal models of DLBCL, the 
combination of TAK-659 (60 mg/kg QD) with ibrutinib (6 mg/kg QD) has shown synergistic 
antitumor activity. In the OCI-Ly10 ABC DLBCL model, TAK-659 in combination with 
ibrutinib was found to have significant antitumor activity with TGI of 68.8% (ΔAUC, p<0.001) 
when compared with vehicle, resulting in a statistically significant therapeutic advantage over 
single-agent treatments.
Overall, data from nonclinical sources support the potential for TAK-659 to be an effective agent 
in treating patients with relapsed or refractory DLBCL in combination with bendamustine, 
gemcitabine, lenalidomide, or ibrutinib.
4.1.4
Clinical Experience
4.1.4.1
Clinical Experience With TAK-659
TAK-659 is being investigated in 7 clinical studies involving patients with advanced 
malignancies (Table 4.a). All 7 studies are ongoing. 
For detailed clinical study information, please refer to the TAK-659 IB.
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Table 4.a
Overview of TAK-659 Clinical Studies
Protocol No. /
Status
Study Design and Population
Dosing Regimen
C34001/ 
Ongoing
Open-label, multicenter, phase 1, dose 
escalation study of TAK-659 in adult 
patients with advanced solid tumors and 
lymphoma malignancies
Increasing TAK-659 oral doses of 60, 80, 100, and 
120 mg QD during dose escalation; 
RP2D of 100 mg QD further explored in patients 
with lymphoma during dose expansion.
C34002/ 
Ongoing
Open-label, multicenter, phase 1b/2, dose 
escalation study of TAK-659 in adult 
patients with relapsed or refractory AML
Starting TAK-659 dose of 60 mg QD; additional 
doses of 100, 120, 140, and 160 mg QD; 60 mg 
BID and 80 mg BID evaluated; MTD or RP2D not 
yet defined.
C34003/ 
Ongoing
Open-label, multicenter, phase 1b, dose 
escalation and dose expansion study of 
TAK- 659 in combination with nivolumab 
in adult patients with advanced solid 
tumors
TAK-659: starting dose of 60 mg QD; dose has 
been escalated to 100 mg QD. 
RP2D will be used in expansion cohorts.
Nivolumab: 3 mg/kg IV dosing over 60 min Q2W 
(Days 1 and 15 of each 28-day cycle). If the 
240 mg fixed dose is evaluated and deemed safe 
and tolerable, the dosing regimen may switch to 
240 mg.
For patients participating in the 2-week 
monotherapy run-in with TAK-659, the first dose 
will be on Cycle 1 Day 15.
C34004/ 
Ongoing
Open-label, multicenter, phase 2 study in 
adult patients with relapsed or refractory 
DLBCL, beginning with a lead-in dose 
exploration phase with 2 TAK-659 dose 
regimens
Cohort 1: TAK-659 100 mg QD in 28-day 
treatment cycles.
Cohort 2: TAK-659 increasing dose (every 
28 days) beginning with 60 mg QD, followed by 
80 mg QD, up to 100 mg QD.
C34005/ 
Ongoing
Open-label, multicenter, phase 1b, dose 
escalation study of TAK-659 in 
combination with 1 of 5 combination 
agents (bendamustine, 
bendamustine + rituximab, gemcitabine, 
lenalidomide, and ibrutinib) in adult 
patients with NHL after at least 1 prior line 
of therapy
TAK-659: starting dose of 60 mg QD; dose will be 
escalated to 100 mg QD until MTD is reached.
Combination Agents:
Bendamustine: 90 mg/m2 administered IV over 
10 or 60 min (depending on which formulation is 
used) on Days 1 and 2 of each 21-day cycle, up to 
8 cycles.
Bendamustine + rituximab: 90 mg/m2
bendamustine administered IV over 10 or 60 min 
(depending on which formulation is used) on 
Days 1 and 2 of each 21-day cycle, up to 8 cycles, 
and 375 mg/m2 rituximab IV on Day 1 of each 
21-day cycle, up to 8 cycles.
Gemcitabine: 1000 mg/m2 IV infusion over 30 min 
on Days 1 and 8 of each 21-day cycle.
Lenalidomide: 25 mg PO QD for Days 1-21 of 
each 28-day cycle.
Ibrutinib: 560 mg PO QD of a 28-day cycle.
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Table 4.a
Overview of TAK-659 Clinical Studies (continued)
Protocol No. /
Status
Study Design and Population
Dosing Regimen
C34007/Ongoing
Open-label, multicenter, 2-part, phase 1 
study in East Asian adult patients, 
including a dose escalation in patients with 
NHL and an expansion in patients with 
DLBCL
TAK-659: Starting dose of 60 mg QD; dose will 
be escalated to 100 mg QD and will then follow 
20 mg increments until MTD and/or RP2D is 
reached.
Expansion phase will use RP2D.
C34008/Ongoing
Dose escalation phase: adult patients with 
advanced NHL of any histology; patients 
will be refractory or relapsed after at least 
1 prior line of therapy with no effective 
standard therapy available
TAK-659: planned 60 or 100 mg PO QD, plus one 
of the following venetoclax regimens administered 
in 28-day cycles after Cycle 1 (35 days):
•
50 mg QD increasing to 200 mg QD by 
Day 16.
•
50 mg QD increasing to 400 mg QD by 
Day 17.
•
50 mg QD increasing to 800 mg by Day 19.
AML: acute myeloid leukemia; BID: twice daily; DLBCL: diffuse large B-cell lymphoma; IV: intravenous; MTD: 
maximum tolerated dose; NHL: non-Hodgkin lymphoma; PO: oral(ly); Q2W: every 2 weeks; QD: once daily; 
RP2D: recommended phase 2 dose.
4.1.4.2
Clinical Pharmacokinetics of TAK-659
Preliminary plasma pharmacokinetics (PK) results are available from lymphoma, solid tumor, 
and AML patients enrolled in Studies C34001 and C34002. In addition, preliminary urine PK 
results are available from lymphoma and solid tumor patients enrolled in the dose escalation 
cohorts of Study C34001. TAK-659 is characterized by fast absorption (overall median Tmax
[time of first occurrence of Cmax (maximum observed concentration)] of 2 hours) in patients with 
hematologic and nonhematologic malignancies. Moderate variability is observed among 
dose-normalized steady-state AUC(area under the plasma concentration-time curve during the 
dosing interval) values in lymphoma, solid tumor, and AML patients (coefficient of variation of 
20.0%, 43.5%, and 34.8%, respectively). An approximately dose-proportional increase in steady 
state AUCwas observed over the 60 to 160 mg range in patients with AML. Mean accumulation 
ratios ranging from 1.90-fold to 2.54-fold and mean peak-to-trough ratios ranging from 4.34 to 
5.09 were observed across the study populations after repeated QD dosing for 15 days. Based on 
data in lymphoma and solid tumor patients, renal clearance accounted for about 30% of 
TAK-659 apparent clearance, and therefore at least about 30% of TAK-659 systemic clearance. 
Active tubular secretion appeared to be the predominant component of renal clearance, based on 
comparison of unbound renal clearance to glomerular filtration rate. Geometric mean terminal 
disposition half-life of 34.4 hours was determined in a single dose PK run-in phase of the 
indolent NHL expansion cohort of Study C34001.
Refer to the TAK-659 IB for detailed clinical pharmacology information. 
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4.1.5
Benefits and Risks
4.1.5.1
Potential Benefits and Risks of TAK-659
Potential Benefits of TAK-659
Clinical benefit has been observed in Study C34001. Response data were available for 
85 patients (11 solid tumor, 58 DLBCL, 12 indolent NHL, and 4 CLL) as of 22 October 2017 in 
Study C34001. Among response-evaluable patients with solid tumors, 1 patient (9%) 
experienced a partial response (PR) and 1 patient (9%) had a response of stable disease (SD) at 
the time of the data cutoff. Among response-evaluable patients with lymphoma DLBCL, best 
responses of CR and PR were reported for 11 and 6 patients, respectively. Of the 17 patients with 
DLBCL who responded, 2 had transitioned to stem cell transplant before the data cutoff; 
39 patients with DLBCL were still receiving study drug as of the data cutoff. Ten patients had a 
best response of SD, and 31 patients experienced progressive disease (PD). Among the 
4 response-evaluable patients with CLL, 2 patients achieved PR and 2 had SD. Nine patients 
with indolent lymphomas responded to treatment with TAK-659. Three patients achieved a CR, 
6 patients achieved PR, and 2 patients had SD.
Potential Risks From Nonclinical Studies in Dogs and Rats

Lymphoid/hematopoietic effects that include lymphoid depletion and myelosuppression that 
are associated with thrombocytopenia, neutropenia, and reticulocytopenia. These findings 
may be associated with increased susceptibility to infection, bleeding, and/or anemia.

Epithelial effects on the intestinal tract, urinary tract, and lens. Intestinal effects included 
minimal-to-slight mucosal hemorrhaging. Urinary and renal tract effects included hyperplasia 
of transitional epithelium in the kidney and bladder, dilatation and hemorrhage in the renal 
pelvis that led to hematuria and proteinuria, and urolithiasis with possible ureter obstruction. 
Lens effects included epithelium hyperplasia leading to anterior axial opacity.

Reproductive system effects, including decreased spermatozoa and seminiferous tubule 
degeneration in the testis and corpora luteal necrosis in the ovaries.

Possible mutation of DNA.

Growth plate thickening and disorganization (not relevant to adults).
Lymphoid and hematopoietic effects and reproductive system effects are considered important 
potential risks.
Potential Risks Based on Clinical Observations

Based on data from Study C34001, asymptomatic elevation in lipase was added as an 
important potential risk of TAK-659. In clinical studies to date, asymptomatic lipase 
elevations are reported commonly (≥10%). Patients in Study C34005 will have frequent 
monitoring of lipase and amylase as outlined in the Schedules of Events (Appendix A).
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
Cases of pneumonitis have been reported in clinical studies with B-cell receptor (BCR) 
pathway kinase inhibitors, including TAK-659, and pneumonitis is considered an important 
potential risk of TAK-659. Pneumonitis and other pulmonary toxicities are being closely 
monitored in TAK-659 clinical studies.

There have been occurrences of opportunistic infections, such as Pneumocystis jirovecii
pneumonia (PJP), in some patients who had fever. These patients had other underlying 
conditions that made them prone to infections. 

In an analysis of safety data from 107 patients with lymphoma treated with single agent 
TAK-659 in Study C34001, most patients (72%) experienced at least 1 treatment-emergent 
adverse event (TEAE) of any grade classified under the infections and infestations System 
Organ Class (SOC) as defined by the Medical Dictionary for Regulatory Activities 
(MedDRA). Pneumonia was the most frequently reported TEAE (26%) and the most 
frequently reported SAE (15%). Cytomegalovirus (CMV) infection (20%) and sepsis (17%) 
were also frequently reported TEAEs. Sepsis (17%) and pneumonia (15%) were the most 
frequently reported Grade ≥3 TEAEs.
Further details regarding the benefits and risks associated with TAK-659 may be found in the 
TAK-659 IB.
4.1.5.2
Potential Benefits and Risks of Combination Drugs
The benefits and risks associated with the administration of bendamustine, rituximab, 
gemcitabine, lenalidomide, and ibrutinib should be referenced in accordance with their 
respective US Package Inserts (USPIs) [11-13,15-17] or applicable labeling.
TAK-659 has been investigated in combination with other agents in Studies C34003, C34005, 
and C34008, and preliminary activity has been observed (see TAK-659 IB). The combination of 
TAK-659 and other agents in this study (bendamustine, rituximab, gemcitabine, lenalidomide, 
and ibrutinib) may lead to exacerbation of known toxicities of single-agent administration for 
each agent, and possibly the occurrence of new toxicities that have not been identified with the 
single agents. 
Potential Overlapping Toxicities for the Combination of TAK-659 and Combination Drugs
Because the study is ongoing, and the safety data are limited, no identified risks for each of the 
combination agents in this study have been confirmed. Expectedness will be assessed using the 
respective approved reference safety information (RSI). 
Drug-Drug Interaction Risk Assessment for the Combination of TAK-659 and Combination 
Drugs
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 P-glycoprotein (P-gp) and is 
metabolized by cytochrome P450 (CYP) 3A4/5, CYP2D6, and CYP1A2, with relative 
contributions of 69.1% to 73.0%, 16.6% to 30.9%, and 0% to 8.40%, respectively. Consequently, 
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there is a potential risk for TAK-659 PK to be altered by drugs that are strong CYP3A inhibitors 
or inducers or P-gp inhibitors or inducers.
Assessment of TAK-659 as Victim of DDIs
Based on data included in their respective USPIs [11-13,15-17] or applicable labeling, 
bendamustine, rituximab, gemcitabine, and lenalidomide are not expected to inhibit or induce 
CYP3A or P-gp at clinically relevant doses; therefore, it is unlikely for co-administration of 
these agents to cause alterations in TAK-659 PK. 
However, at clinically relevant doses, ibrutinib has the potential to inhibit the efflux transporter 
P-gp in the gastrointestinal (GI) tract at higher local concentrations that may be achieved after 
PO administration. Thus, the systemic exposures of oral narrow therapeutic index P-gp substrates 
may be increased upon co-administration of ibrutinib because of decreased intestinal efflux and 
increased bioavailability of the oral P-gp substrate. Because in vitro data indicate that TAK-659 
is a P-gp substrate, there is a theoretical risk of increased TAK-659 systemic exposure with 
ibrutinib co-administration (gut P-gp inhibitor) relative to TAK-659 administration alone. Based 
on current literature, the majority of clinical DDIs due to P-gp inhibition are associated with 
approximately 2-fold or lower increases in the exposures of P-gp substrates.
Assessment of TAK-659 as Perpetrator of DDIs
TAK-659 was not a potent reversible inhibitor of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 
3A4/5 in human liver microsomes at concentrations up to 100 M (IC50 values >100 M), nor a 
time-dependent inhibitor of these same CYPs at concentrations up to 50 M. In addition, 
TAK-659 was not an inducer of CYP1A2, 2B6, or 3A activity or messenger RNA expression 
levels in human hepatocytes at concentrations up to 50 M. Furthermore, TAK-659 was not an 
inhibitor of the efflux transporters P-gp or 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 (217 ng/mL or 
0.63 M), there is low risk for TAK-659 to cause DDIs via induction or inhibition of CYP 
enzymes, P-gp, or BCRP. Considering this information and the major determinants of clearance 
for all combination drugs (bendamustine, rituximab, gemcitabine, lenalidomide, and ibrutinib), 
it is unlikely that TAK-659 will affect their PK when administered in combination. 
4.2
Rationale for the Proposed Study
4.2.1
Rationale for the Combination of TAK-659 + Combination Drugs
TAK-659 is an orally bioavailable, potent and reversible inhibitor of SYK and FLT3 and is 
currently under development for the treatment of patients with advanced malignancies 
(eg, NHL). SYK is a nonreceptor tyrosine kinase with SH2-binding domains that bind to 
phosphorylated ITAMs located on B and T cells and certain 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 in hematopoietic cells and abnormal 
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function of SYK has been implicated in NHL, including FL, DLBCL, and MCL. TAK-659 
inhibits SYK purified enzyme with an IC50 of 3.2 nM and an EC50 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-DLBCL model; the 
OCI-Ly19 model, a GCB-DLBCL model; the PHTX-95L model, a primary human DLBCL 
model; the RL FL model; and the MINO MCL model. TAK-659 has been tested in nonclinical 
DLBCL models in combination with a number of agents used in the relapsed/refractory setting, 
including gemcitabine, bendamustine, ibrutinib, and lenalidomide. 
Early signs of clinical activity of TAK-659 have been observed in the first-in-human (FIH) 
Study C34001 in patients with multiple subtypes of NHL. In this study, response data were 
available for 85 patients (11 solid tumor, 58 DLBCL, 12 iNHL, and 4 CLL). Among 
response-evaluable patients with solid tumors, 1 patient (9%) had experienced a PR. Among 
response-evaluable patients with DLBCL, best responses of CR and PR were reported for 11 and 
6 patients, respectively. Clinical activity in responding DLBCL patients was achieved
independent of cell of origin subtype (GCB or non-GCB) or disease history (de novo or 
transformed) [18]. Refer to the TAK-659 IB for detailed clinical information.
Gemcitabine HCl is a nucleoside analogue that primarily kills cells undergoing DNA synthesis 
(S-phase) and also blocks the progression of cells through the G1/S-phase boundary. TAK-659 
has shown synergistic antitumor activity when combined with gemcitabine in nonclinical 
models. Ibrutinib is an inhibitor of BTK that is approved in CLL, MCL, WM, and marginal zone 
lymphoma and is currently in clinical trials for DLBCL. It is hypothesized that targeting BTK, 
which lies downstream of SYK, in combination with SYK inhibition could lead to a more 
pronounced response in hematologic malignancies. In nonclinical animal models, the 
combination of TAK-659 with ibrutinib has shown synergistic antitumor activity. Bendamustine 
is a standard-of-care agent used in combination with rituximab as a second-line therapy to treat 
patients with NHL. Bendamustine has also shown synergistic TGI when combined with 
TAK-659. Lenalidomide is an immunomodulatory agent that has been shown to modulate 
different components of the immune system by altering cytokine production, regulating T-cell 
co-stimulation, and augmenting the NK cell cytotoxicity. The immunomodulatory properties of 
lenalidomide are implicated in its clinical efficacy and provide a rationale for combination with 
TAK-659. 
Nonclinical combination of these agents has shown strongly additive tumor inhibition in mouse 
models. Overall, data from nonclinical sources support the potential for TAK-659 to be an 
effective agent in treating patients with relapsed or refractory NHL in combination with 
bendamustine, gemcitabine, lenalidomide, or ibrutinib.
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4.2.2
Rationale for Dose and Schedule Selection
4.2.2.1
Rationale for the Dose and Schedule of TAK-659
TAK-659 has been evaluated as a single agent given PO on a continuous daily dosing schedule 
in its FIH dose escalation study (C34001) in patients with advanced solid tumors or lymphoma. 
Four dose levels (60, 80, 100, and 120 mg QD) have been evaluated in 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, 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. 
Currently, TAK-659 is being evaluated as in combination with nivolumab (Study C34003) and 
venetoclax (Study C34008). Based on the dose escalation experience with TAK-659 in Studies 
C34001, C34003, and C34008, dosing of TAK-659 will escalate in 20 mg increments up to 
100 mg QD provided that the safety and tolerability of the 60 mg QD dose is demonstrated. 
Alternative dose regimens (eg, intermittent QD dosing of 7 days on followed by 7 days off, or 14 
days on followed by 7 days off), or dose levels below the starting dose of 60 mg (eg, 40 mg) may 
be evaluated based on safety, tolerability, and preliminary PK and efficacy data, if available, 
following agreement between investigators and the sponsor. The dose of TAK-659 cannot be 
escalated beyond 100 mg, which is the MTD for single-agent TAK-659 in solid tumors and 
lymphoma.
In this dose escalation study, the starting dose of TAK-659 will be 60 mg QD in combination 
with a fixed dose regimen of each combination drug. Dose escalation of TAK-659 will follow a 
standard 3 + 3 escalation scheme. 
4.2.2.2
Rationale for the Dose and Schedule of Combination Drugs
The dose and schedule at which bendamustine, rituximab, gemcitabine, lenalidomide, and 
ibrutinib will be administered will be in accordance with their respective USPIs [11-13,15-17] or 
applicable labeling, unless otherwise specified. The dose of bendamustine (90 mg/m2) is based 
on its use in previous combination studies with rituximab in both indolent NHL and DLBCL 
[3,4]. 
4.2.3
Rationale for PK Assessments
The primary aim of PK sampling in this study is to compare exposures of TAK-659 following 
co-administration with each combination drug with exposures observed following single-agent 
administration. Specifically, PK data from this combination study will be compared with 
historical single-agent exposures observed in Study C34001 to determine whether there are 
clinically meaningful differences in TAK-659 PK between the single-agent and combination 
settings in patients with lymphoma. In the dose escalation phase, intensive PK samples will be 
collected from all patients during Cycle 1, as detailed in Appendix A, Table 3. In the safety 
expansion part, sparse PK samples will be collected (refer to Appendix A, Table 4). Plasma PK 
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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.
CCI
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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective
The primary objective is to determine the MTD or RP2D for TAK-659 when administered in 
combination with each of the combination drugs (bendamustine, bendamustine + rituximab, 
gemcitabine, lenalidomide, and ibrutinib).
5.1.2
Secondary Objectives
The secondary objectives are:
!
To characterize the plasma PK of TAK-659 in each of the 5 cohorts.
!
To observe the preliminary efficacy of different combination drugs with TAK 659 
(Cohorts A-E) in patients with advanced NHL who have relapsed and/or are refractory after 
≥1 prior line of therapy (for patients in Cohort B expansion with FL/marginal zone 
lymphoma (MZL), ≤1 prior line of therapy).
5.1.3
Additional Objective
The additional objective is to evaluate the safety and tolerability of TAK-659 in each of the 
5 cohorts.
5.1.4
Exploratory Objectives
5.2
Endpoints
5.2.1
Primary Endpoints
The primary endpoints are:
!
MTD (dose escalation phase) of TAK-659 when administered with each of the combination 
drugs.
!
RP2D (dose escalation phase) of TAK-659 when administered with each of the combination 
drugs.
CCI
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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5.2.2
Secondary Endpoints
The secondary endpoints are:
!
TAK-659 PK parameters, including Cmax, Tmax, and AUCτ by dose escalation cohort.
!
Overall response rate (ORR) by International Working Group (IWG).
!
Duration of response (DOR).
!
Time to progression (TTP).
!
PFS (for patients in the Cohort B expansion phase).
5.2.3
Additional Endpoints 
The additional endpoints are:
!
Safety parameters, including percentage of patients with AEs, percentage of patients with 
Grade ≥3 AEs, percentage of patients with SAEs, percentage of patients who discontinued 
due to AEs, clinically significant laboratory values, and clinically significant vital sign 
measurements.
!
Other TAK-659 PK parameters, including apparent oral clearance, peak-trough ratio, 
accumulation ratio, and trough concentration by dose escalation cohort.
5.2.4
Exploratory Endpoints 
CCI
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
AEs, per
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6.0
STUDY DESIGN
6.1
Overview of Study Design
This is a phase 1b, dose escalation study of TAK-659 in combination with 1 of 5 combination 
drugs (bendamustine, bendamustine + rituximab, gemcitabine, lenalidomide, and ibrutinib) in 
adult patients with advanced NHL after at least 1 prior line of therapy. The primary objective of 
the study is to determine the MTD or the RP2D of TAK-659 when administered with each of the 
combination drugs. Once enrolled in the study, patients will be assigned to 1 of 5 combination 
cohorts: 

Cohort A (TAK-659 + bendamustine).

Cohort B (TAK-659 + bendamustine + rituximab).

Cohort C (TAK-659 + gemcitabine).

Cohort D (TAK-659 + lenalidomide).

Cohort E (TAK-659 + ibrutinib).
This study comprises 2 phases: a dose escalation phase and a safety expansion phase. Patients in 
all 5 cohorts (Cohorts A-E) will participate in the dose escalation phase of the study. 
During the dose escalation phase, the dose of TAK-659 will be escalated (planned 3 dose levels 
of escalation: 60, 80, and 100 mg) according to a 3 + 3 dose escalation scheme. The dose of oral 
TAK-659 will increase in 20 mg increments to a maximum of 100 mg QD, provided that the 
safety and tolerability of the 60 mg dose has been demonstrated. Dose levels below the starting 
dose of 60 mg QD (eg, 40 mg QD) or intermittent QD dosing schedules (eg, 7 days on followed 
by 7 days off, or 14 days on followed by 7 days off) also may be evaluated, if appropriate, in 
Cohort B. Dose escalation will continue until the MTD is reached, or until TAK-659 100 mg QD 
(the MAD) is determined to be safe and tolerable, or until an RP2D, if different from the MTD or 
MAD, is identified based on the safety, tolerability, and preliminary PK and efficacy data (if 
available) observed in Cycle 1 and beyond.
The doses of combination drugs will be administered at a fixed dose and regimen (see 
Section 8.3). 
During the dose escalation phase, DLT-evaluable patients in each dose cohort will consist of 
patients who have met the minimum treatment and safety evaluation requirements of the study 
and/or who experience a DLT during Cycle 1. The dose escalation decision is based on the DLT 
occurrences during Cycle 1 per the 3 + 3 escalation schema. Additionally, toxicity and 
tolerability beyond Cycle 1, available PK and pharmacodynamic data, and early signs of clinical 
activity will be taken into consideration in dose escalation decisions and final determination of 
the MTD and RP2D of TAK-659 with combination drugs in each of the cohorts. Based on the 
evolving data from the trial, an alternative dose escalation plan including dose, schedule, DLT 
evaluation period, and further expansion of a given cohort, may be subject to change following 
discussions and agreement between the investigators and the sponsor medical monitor. 
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During the safety expansion phase of the study, approximately 12 additional patients with 
advanced FL or MZL will be added to Cohort B at the MTD/MAD/RP2D for further safety 
evaluation. PK samples will be collected at prespecified time points to characterize the PK of 
TAK-659 when administered with each of the combination drugs. No patients from Cohorts A, 
C, D, or E will enter the safety expansion phase of the study because effective 16 March 2018, 
the sponsor closed recruitment into Cohorts C, D, and E, and effective 16 October 2018, the 
sponsor closed recruitment into Cohort A. 
Patients, including those who achieve a CR, may receive study treatment, for a maximum of 
12 months, until they experience PD or unacceptable toxicities.
Toxicity will be evaluated according to National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI CTCAE) version 4.03, effective 14 June 2010 [1]. DLTs are defined in 
Section 8.2.
AEs will be assessed, and laboratory values, vital signs, and electrocardiograms (ECGs) will be 
obtained to evaluate the safety and tolerability of TAK-659 when administered in combination 
with each of the 6 combination drugs.
Disease status will be assessed using the IWG [2] revised criteria for patients with malignant 
lymphoma, based on investigator assessment. Computed tomography (CT) scans (with contrast) 
of the chest, abdomen, and pelvis (neck should be included if appropriate) and fluoro-2-deoxy-
D-glucose (FDG)-positron emission tomography (PET) scans extending from neck to mid-thigh 
will be performed in all patients to follow the disease as indicated in the Schedule of Events 
(Appendix A, Table 1 and Table 2). Repeat FDG-PET scans will be performed during the study 
only when the screening FDG-PET scan is positive. For patients with a negative screening 
CCI
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FDG-PET scan, additional scans may be performed on study if clinically indicated for 
occurrence of PD per local standard of care. 
6.2
Number of Patients
It is expected that approximately 96 patients will be enrolled in this study from approximately 
15 study centers in North America and Europe. Approximately 40 patients will be enrolled in 
Cohort B, and approximately 14 patients will be enrolled in each of Cohorts A, C, D, and E 
(Table 6.a). Enrollment is defined as the time of the initiation of the first dose of study drug.
Table 6.a
Planned Number of Patients
Cohort
Total
(~N) a
Dose Escalation
(~N)
Safety Expansion
(~N)
A
14
9-12
0 b
B
40
9-24 c
12
C
14
9-12
0 b
D
14
9-12
0 b
E
14
9-12
0 b
a Approximate enrolled number was based on the assumption of a 10% dropout rate.
b Effective 16 March 2018, enrollment into Cohorts C, D, and E was closed, and effective 16 October 2018, 
enrollment into Cohort A was closed. No patients from these 4 cohorts will enter into the safety expansion phase of 
this study.
c A dose lower than 60 mg QD or intermittent dosing schedules may be evaluated, if appropriate.
Patients who are withdrawn from treatment during Cycle 1 for reasons other than DLTs will be 
replaced.
6.3
Duration of Study
6.3.1
Duration of an Individual Patient’s Study Participation
Patients, including those who achieve a CR, may receive study drug until they experience PD. 
Patients will discontinue treatment if they have an unacceptable study drug-related or possibly 
related toxicity. 
The maximum duration of treatment, however, will be 12 months unless it is determined that a 
patient would derive benefit from continued therapy beyond 12 months.
At the conclusion of the study, participants who continue to demonstrate clinical benefit may be 
eligible to receive Takeda-supplied study drug. Study drug may be provided via an extension of 
the study, a rollover study requiring approval by responsible health authority and ethics 
committee, or through another mechanism at the discretion of Takeda. 
Takeda reserves the right to terminate access to Takeda supplied study drug if any of the 
following occurs: a) the benefit-risk profile is not favorable; b) the marketing application is 
rejected by responsible health authority; c) the study is terminated due to safety concerns;
d) investigational agent(s) becomes commercially available or other access mechanism becomes 
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available; e) development of the drug is suspended or ceased, or sponsor cannot adequately 
supply investigational agent; or f) appropriate therapeutic alternatives become available in the 
local market.
Patients will be followed for 28 days 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. 
6.3.2
End of Study/Study Completion Definition and Planned Reporting
The final analyses for the primary endpoint and authoring of a single, final CSR will be 
conducted after all patients enrolled in the study have had the opportunity to complete 6 cycles of 
treatment with study drug and be followed for 28 days or the start of subsequent anticancer 
therapy, whichever occurs first. In the Cohort B expansion phase, patients who discontinue 
treatment for any reason other than PD will continue to have PFS follow-up visits. PFS 
follow-up will occur every 2 months after the last dose of study drug for up to 6 months or until 
PD, whichever occurs first (for patients who discontinue for reasons other than PD). The 
estimated time frame for study completion is approximately 30 months. 
6.3.3
Time Frames for Primary and Secondary Endpoints to Support Disclosures
Please refer to Table 6.b for disclosures information for all primary and secondary endpoints.
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Table 6.b
Primary and Secondary Endpoints for Disclosures
Endpoint
Definition
Maximum Time Frame a
Primary:

MTD (dose escalation phase) of 
TAK-659 when administered 
with each of the combination 
drugs.
Maximum dose that is determined to 
be safe and tolerable
Up to 6 months.

RP2D (dose escalation phase) 
of TAK-659 when administered 
with each of the combination 
drugs.
The dose recommended for use in 
phase 2 studies based on the safety, 
tolerability, and preliminary PK and 
efficacy data (if available) obtained in 
phase 1 studies
Up to 6 months.
Secondary: 

TAK-659 PK parameters, 
including Cmax, Tmax, and AUCτ
by dose escalation cohort.
Descriptive statistics for Cmax, Tmax, 
and AUCτ for each dose group of each 
cohort in the PK population b
Up to 16 days.

ORR by IWG 
The proportion of patients in the 
response-evaluable population who 
achieved either CR or PR
Up to 6 months.

DOR
The time from first CR/PR to PD or 
relapse in the response-evaluable 
population
Up to 6 months.

TTP
Time from first dose to PD or relapse 
in the response-evaluable population
Up to 6 months.

PFS
The time from the date of first study 
drug administration to the date of first 
documented PD or death due to any 
cause, whichever occurs first.
Up to 6 months.
AUC: area under the concentration-time curve; AUCτ: AUC during a dosing interval; Cmax: maximum observed 
concentration; CR: complete response; DOR: duration of response; MTD: maximum tolerated dose; ORR: objective 
response rate; PD: progressive disease; PFS: progression-free survival; PK: pharmacokinetic(s); PR: partial 
response; RP2D: recommended phase 2 dose; tmax: time of first occurrence of Cmax; TTP: time to progression.
a Time to last assessment for that endpoint for an individual.
b For Cohorts A-E in the dose escalation phase, on Cycle 1 Days 1 and 15.
6.3.4
Total Study Duration
It is anticipated that this study will last approximately 30 months.
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7.0
STUDY POPULATION
Patients must have a histologically or cytologically confirmed diagnosis of advanced NHL of 
any histology (with the exception of patients with WM and CLL), radiographically or clinically 
measurable disease with at least 1 target lesion per IWG criteria for malignant lymphoma [2], 
and must be refractory or relapsed after at least 1 prior line of therapy and have no effective 
standard therapy available per investigator’s assessment. Patients must also be either treatment 
naïve to, relapsed/refractory to, or have experienced treatment failure due to other reasons with 
ibrutinib, idelalisib, or any other investigational BCR pathway inhibitors not directly targeting 
SYK.
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. In the dose escalation phase, histologically or cytologically confirmed diagnosis of advanced 
NHL of any histology (with the exception of patients with WM and CLL). In the safety 
expansion phase for Cohort B, only patients with advanced FL or MZL will be included.
3. Radiographically or clinically measurable disease with at least 1 target lesion per IWG 
criteria for malignant lymphoma [2].
4. In the dose escalation phase, patients who are refractory or relapsed after at least 1 prior line 
of therapy due to progression, intolerance, or physician/patient decision and for whom no 
effective standard therapy is available per the investigator’s assessment. In the safety 
expansion phase for Cohort B in patients with FL or MZL, the prior line of therapy is limited 
to ≤1.
a) Either treatment naïve to, relapsed/refractory to, or experienced treatment failure due to 
other reasons with ibrutinib, idelalisib, or any other investigational BCR pathway 
inhibitors not directly targeting SYK.
b) Preinduction salvage chemotherapy and ASCT should be considered 1 therapy.
c) Any consolidation/maintenance therapy after a chemotherapy regimen (without 
intervening relapse) should be considered 1 line of therapy with the preceding 
combination therapy. Maintenance antibody therapy should not be considered a line of 
therapy.
d) For aggressive NHL (ie, DLBCL), single-agent anti-CD20 monoclonal antibody therapy 
should not be considered a line of therapy. Antibody therapy in patients with indolent 
NHL (ie, FL) given as a single agent after disease progression from a prior treatment 
should be considered a line of therapy.
e) For patients with DLBCL transformed from indolent lymphoma, any treatment received 
for the indolent disease before the transformation to DLBCL will, in general, not count 
toward the 2 to 3 prior lines of therapy required for DLBCL in this study.
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f)
Prior treatment with a regimen that includes the combination drug will not necessarily 
exclude a patient from that cohort if the investigator views treatment with that agent as 
appropriate. However, a patient who has a contraindication for a particular combination 
agent or who has been discontinued from prior therapy with a particular agent for toxicity 
will not be eligible for inclusion in that particular cohort.
5. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 and life 
expectancy of greater than 3 months (see Appendix D). 
6. Patients must have adequate organ function, including the following:
a) Adequate 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); alanine 
aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 ULN.
c) Renal: creatinine clearance ≥60 mL/min as estimated by the Cockcroft-Gault equation 
(see Appendix E).
d) Others:
i.
Lipase ≤1.5 ULN and amylase ≤1.5 ULN with no clinical symptoms suggestive 
of pancreatitis or cholecystitis.
ii.
Blood pressure Grade ≤1 (hypertensive patients are permitted if their blood pressure 
is controlled to Grade ≤1 by antihypertensive medications). 
iii.
Fasting serum glucose level shall be controlled to 130 mg/dL during the screening 
period.
7. Female patients who:
a) Are postmenopausal for at least 1 year before the screening visit, OR
b) Are surgically sterile, OR
c) If they are of childbearing potential, agree to practice 1 highly effective method of 
contraception and 1 additional effective (barrier) method (see Appendix F) at the same 
time, from the time of signing the informed consent through 180 days after the last dose 
of study drug, OR
d) Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the 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.)
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e) Women of childbearing potential (WOCBP) must have a negative serum pregnancy test 
(minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin 
[hCG]) at screening.
Male patients, even if surgically sterilized (ie, status postvasectomy), who:
a) Agree to practice effective barrier contraception during the entire study treatment period 
and through 180 days after the last dose of study drug, OR
b) Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are 
not acceptable methods of contraception. Female and male condoms should not be used 
together.)
8. Female patients should not donate ova from the time of signing the informed consent through 
180 days after the last dose of study drug.
9. Male patients should not donate sperm from the time of signing the informed consent through 
180 days after the last dose of study drug.
10. Both men and women in Cohort B (TAK-659+bendamustine+rituximab) must practice 
contraception as described above from the time of signing of the informed consent form 
(ICF) through 12 months after the last dose of study drug.
11. Both men and women in Cohort D (TAK-659+lenalidomide) must adhere to the guidelines of 
the RevAssist program (US participants) or the Lenalidomide Pregnancy Risk Minimisation 
Plan as outlined in the study manual (all other participants who are not using commercial 
supplies). 
12. 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.
13. Recovered (ie, Grade 1 toxicity) from the clinically significant 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 scan/magnetic resonance imaging 
(MRI). Exceptions include those patients who have completed definitive therapy, are not on 
steroids, have a stable neurologic status for at least 2 weeks after completion of the definitive 
therapy and steroids, and do not have neurologic dysfunction that would confound the 
evaluation of neurologic and other AEs.
2. Known human immunodeficiency virus (HIV)-related malignancy.
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3. Known hypersensitivity (eg, anaphylactic and anaphylactoid reactions) to any particular 
combination drug and/or drug component will result in a patient being ineligible for inclusion 
in that particular cohort.
4. For patients in Cohort D (TAK-659 + lenalidomide), demonstrated hypersensitivity 
(eg, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide.
5. History of drug-induced pneumonitis requiring treatment with steroids; history of idiopathic 
pulmonary fibrosis, organizing pneumonia, or evidence of active pneumonitis on screening 
chest CT scan; history of radiation pneumonitis in the radiation field (fibrosis) is permitted.
6. Life-threatening illness unrelated to cancer that could, in the investigator’s opinion, make the 
patient not appropriate for this study.
7. Female patients who are lactating and breast-feeding or a positive serum pregnancy test 
during the screening period or a positive urine pregnancy test on Day 1 before the first dose 
of study drug.
8. 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.
9. Known HIV positive.
10. Known hepatitis B surface antigen positive, or known or suspected active hepatitis C 
infection.
11. Systemic anticancer treatment (including investigational agents) or radiotherapy less than 
2 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). 
12. Prior ASCT within 6 months or prior ASCT at any time without adequate hematopoietic 
recovery, defined by the entry criteria in the study, before Cycle 1 Day 1, or allogeneic stem 
cell transplant any time. 
13. 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 compromise the patient’s 
participation in the study. 
14. Patients with any of the following cardiovascular conditions are excluded: 
a) Unstable angina or acute myocardial infarction within 12 months before starting study 
drug.
b) Current or history of New York Heart Association Class III or IV heart failure (see 
Appendix G).
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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.
15. Lack of suitable venous access for the study-required blood sampling for TAK-659.
16. 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, the use of these agents is not 
permitted during the study except in cases in which an AE must be managed (see 
Section 8.5). See Appendix H for a nonexhaustive list of strong CYP3A reversible 
inhibitors and/or P-gp inhibitors based on the US Food and Drug Administration (FDA) 
Draft DDI Guidance.
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, the use of these agents is not permitted during the study except in cases in 
which an AE must be managed (see Section 8.5). See Appendix H for a nonexhaustive 
list of strong CYP3A mechanism-based inhibitors or strong CYP3A inducers and/or P-gp 
inducers based on the US FDA Draft DDI Guidance.
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.
17. Additionally, for patients in the ibrutinib combination arm (Cohort E), use or consumption of 
any of the following substances:
a) Medications or supplements that are known to be moderate 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 drugs. In general, the use of these agents is not permitted during the study for this 
combination except in cases in which an AE must be managed (see Section 8.5). See 
Appendix H for a nonexhaustive list of moderate CYP3A reversible inhibitors based on 
the US FDA Draft DDI Guidance.
b) Medications or supplements that are known to be moderate mechanism-based inhibitors 
or moderate inducers of CYP3A within 7 days or within 5 times the inhibitor or inducer 
half-life (whichever is longer) before the first dose of study drugs. In general, the use of 
these agents is not permitted during the study for this combination except in cases in 
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which an AE must be managed (see Section 8.5). See Appendix H for a nonexhaustive 
list of moderate CYP3A mechanism-based inhibitors or moderate CYP3A inducers based 
on the US FDA Draft DDI Guidance.
c) Seville oranges within 5 days before the first dose of study drugs and during the study.
18. Major surgery within 14 days before the first dose of study drug and not recovered fully from 
any complications from surgery. 
19. Systemic infection requiring IV antibiotic therapy or other serious infection within 14 days 
before the first dose of study drug. 
20. 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. 
21. Known GI disease or GI procedure that could interfere with the oral absorption or tolerance 
of TAK-659 including difficulty swallowing tablets or diarrhea Grade >1 despite supportive 
therapy. 
22. Treatment with high-dose corticosteroids for anticancer purposes within 14 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. 
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8.0
STUDY DRUG
8.1
Study Drug Administration
All protocol-specific criteria for administration of study drugs must be met and documented 
before study drug administration. Study drugs will be administered only to eligible patients under 
the supervision of the investigator or identified subinvestigator(s).
The dosing regimen for study drugs in each of the cohorts is outlined in the following sections.
8.1.1
Cohort A (TAK-659 + Bendamustine) Dosing Regimen
TAK-659 will be dosed PO QD in 21-day cycles. Bendamustine will be administered in the 
clinic in accordance with the Treanda USPI [11], Bendeka USPI [17], or applicable local 
bendamustine labeling unless otherwise specified. The dose of bendamustine will be based on its 
use in previous combination studies [3,4]. Patients will receive 90 mg/m2 bendamustine 
administered IV over 10 or 60 minutes (depending on which formulation is used) on Days 1 and 
2 of each 21-day cycle, up to 8 cycles. Monotherapy with TAK-659 is allowed beyond 8 cycles. 
On days on which both TAK-659 and bendamustine are administered, the TAK-659 dose will be 
administered first, followed by the bendamustine infusion (infusion to begin within 15 minutes 
after the TAK-659 dose) to maximize the overlap in exposures between the 2 drugs. 
Please see Table 8.a for further information on the dosing schedule for each cycle in Cohort A.
Table 8.a
Cohort A (TAK-659 + Bendamustine) Dosing Schedule
Cohort A
21-Day Cycle, Bendamustine Up to 8 Cycles, TAK-659 All Cycles 
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
TAK-659
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Bendamustine
X
X
8.1.2
Cohort B (TAK-659 + Bendamustine/Rituximab) Dosing Regimen
TAK-659 will be administered PO QD in each 21-day cycle. Bendamustine will be administered 
in the clinic in accordance with the Treanda USPI [11], Bendeka USPI [17], or applicable local 
bendamustine labeling unless otherwise specified. The dose of bendamustine will be based on its 
use in previous combination studies [3,4]. Patients will receive 90 mg/m2 bendamustine 
administered IV over 10 or 60 minutes (depending on which formulation is used) on Days 1 and 
2 of each 21-day cycle, up to 8 cycles. Rituximab will be administered in the clinic in accordance 
with local guidelines and the rituximab USPI [12] or applicable labeling. Patients will receive 
375 mg/m2 rituximab administered IV on Day 1 of each 21-day cycle, up to 8 cycles. 
Monotherapy with TAK-659 is allowed beyond 8 cycles. On days (ie, Day 1) in which all 
3 agents (TAK-659, bendamustine, and rituximab) are given, TAK-659 should be administered 
first, followed by the bendamustine infusion (infusion to begin within 15 minutes after the 
TAK-659 dose) to maximize the overlap in exposures between the 2 drugs. After completion of 
the bendamustine infusion, the rituximab infusion should be administered. On days (ie, Day 2) in 
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which only TAK-659 and bendamustine are administered, the TAK-659 dose will be 
administered first, followed by the bendamustine infusion (infusion to begin within 15 minutes 
after the TAK-659 dose) to maximize the overlap in exposures between the 2 drugs. 
Please see Table 8.b for further information on dosing schedule for each cycle in Cohort B.
Table 8.b
Cohort B (TAK-659 + Bendamustine/Rituximab) Dosing Schedule
Cohort B
21-Day Cycle, Bendamustine/Rituximab Up to 8 Cycles, TAK-659 All Cycles
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
TAK-659 a, b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Bendamustine
X
X
Rituximab
X
a For the TAK-659 QD continous dosing schedule only.
b The TAK-659 dosing schedule will be consistent with the intermittent QD dosing schedule (eg, skip dosing on 
Days 15 to 21 for the schedule of 14 days on followed by 7 days off).
8.1.3
Cohort C (TAK-659 + Gemcitabine) Dosing Regimen
TAK-659 will be administered PO QD in each 21-day cycle. Gemcitabine will be administered 
in the clinic in accordance with the gemcitabine USPI [13] or applicable labeling. Patients will 
receive 1000 mg/m2 gemcitabine administered IV over 30 minutes on Days 1 and 8 of each 
21-day cycle. On days on which both TAK-659 and gemcitabine are administered, the TAK-659 
dose will be administered first followed by the gemcitabine infusion (infusion to begin within 
15 minutes after the TAK-659 dose) to maximize the overlap in exposures between the 2 drugs.
Please see Table 8.c for further information on dosing schedule for each cycle in Cohort C.
Table 8.c
Cohort C (TAK-659 + Gemcitabine) Dosing Schedule
Cohort C
21-Day Cycle, All Cycles
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
TAK-659
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Gemcitabine
X
X
8.1.4
Cohort D (TAK-659 + Lenalidomide) Dosing Regimen
TAK-659 will be administered PO QD in each 28-day cycle. Lenalidomide will be administered 
in accordance with the lenalidomide USPI [15] or applicable labeling. Patients will receive 
25 mg lenalidomide PO QD for 21 days, followed by a 7-day rest period, during each 28-day 
cycle. On days on which both TAK-659 and lenalidomide are administered, the lenalidomide 
dose should be administered within 15 minutes after the TAK-659 dose to maximize the overlap 
in exposure between the 2 drugs.
Please see Table 8.d for further information on dosing schedule for each cycle in Cohort D.
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Table 8.d
Cohort D (TAK-659 + Lenalidomide) Dosing Schedule
Cohort D
28-Day Cycle, All Cycles
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
TAK-659
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lenalidomide X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.1.5
Cohort E (TAK-659 + Ibrutinib) Dosing Regimen
TAK-659 will be administered PO QD in each 28-day cycle. Ibrutinib will be administered in 
accordance with the ibrutinib USPI [16] or applicable labeling. Patients will receive 560 mg 
ibrutinib PO QD in 28-day cycles. The ibrutinib dose should be administered within 15 minutes 
after the TAK-659 dose to maximize the overlap in exposures between the 2 drugs.
Please see Table 8.e for further information on dosing schedule for each cycle in Cohort E.
Table 8.e
Cohort E (TAK-659 + Ibrutinib) Dosing Schedule
Cohort E
28-Day Cycle, All Cycles
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
TAK-659
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Ibrutinib
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.1.6
Oral Drug Administration
Study drugs administered PO, including TAK-659, lenalidomide, and ibrutinib, 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/capsule 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 doses of both oral drugs. Patients should swallow the tablets/capsules whole; the 
tablets/capsules should not be chewed, crushed, or manipulated in any way before swallowing. 
Administration of the tablets/capsules will be guided by the dosing tables included in the 
pharmacy manual.
Patients should be instructed to take their study medication at approximately the same time each 
day and to not take more than the prescribed dose at any time. On clinic visit days, patients 
should be instructed to hold their dose until predose assessments are performed in the clinic, and 
a particular dosing sequence for the study drugs will be followed by the study staff per protocol. 
If a patient fails to take oral study drug(s) one day, or if a patient does not take the oral study 
drug(s) at their scheduled dosing time (6 hours of the scheduled dosing time), that dose should 
be skipped, and the patient must not make dose adjustments to account for the missed dose on 
subsequent days, for example, by taking a double dose of study drug(s) on the following day. 
Patients should record any skipped doses in their dosing diary (see the study manual) and resume 
dosing at the next scheduled time with the prescribed dosage. 
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If severe emesis prevents the patient from taking a dose of study drug(s), that dose will be 
skipped. If emesis occurs after study medication ingestion, patients should simply adhere to the 
dosing schedule and continue dosing at the next scheduled time with the prescribed dosage. 
Patients should not take a repeat dose following emesis after study medication ingestion. Patients 
should record the time of the emesis in their dosing diary (see the study manual).
In cohorts where both study drugs are administered PO (Cohort D: TAK-659 + lenalidomide and 
Cohort E: TAK-659 + ibrutinib), the combination drug dose should be administered within 
15 minutes after the TAK-659 dose to maximize the overlap in exposures between the 2 drugs.
8.2
Definitions of DLT
Toxicity will be evaluated according to the NCI CTCAE version 4.03, effective 14 June 2010 
[1]. These criteria are provided in the study manual. DLT is defined as any of the following 
events that are considered by the investigator to be at least possibly related to therapy with 
TAK-659 when administered in combination with bendamustine ± rituximab, gemcitabine, 
lenalidomide, and ibrutinib. AEs in which the relationship to study drug cannot be ruled out 
should be considered possibly related to study drug.

Hematologic toxicity: 
–
Grade 4 neutropenia (ANC <500/µL) unresolved to Grade ≤1 (ANC >1500/µL) or 
baseline for more than 7 consecutive days in the absence of growth factor support. 
–
Grade ≥3 neutropenia (ANC <1000/µL) with fever and/or infection, where fever is 
defined as an oral temperature ≥38.5ºC.
–
Grade 4 thrombocytopenia (<25,000/µL) unresolved to Grade ≤1 (>75,000/µL) or 
baseline for more than 7 consecutive days or a platelet count <10,000/µL at any time.
–
Grade ≥3 thrombocytopenia (<50,000/µL) with clinically significant bleeding. 
–
Grade 4 anemia. 

Any Grade 3 or greater nonhematologic toxicity with the following exceptions:
–
Fatigue or arthralgia/myalgia that improve to Grade ≤2 within 7 days. 
–
Grade ≥3 nausea and/or emesis that can be controlled to Grade ≤1 or baseline in 7 days 
with the use of optimal antiemetic prophylaxis (defined as an antiemetic regimen that 
employs both a 5-hydroxytryptamine 3 (5-HT3) antagonist and a corticosteroid given in 
standard doses and according to standard schedules).
–
Grade ≥3 diarrhea that can be controlled to Grade ≤1 or baseline in 7 days with optimal 
supportive therapy.
–
Asymptomatic Grade 3 amylase or lipase elevations that last ≤7 days.
–
Asymptomatic Grade 3 elevation of a single liver enzyme (AST or ALT) in the absence 
of significant bilirubin elevation (Grade <3) considered not dose limiting following 
agreement between the sponsor and investigators.
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–
Isolated Grade ≥3 abnormalities of other laboratory parameters (other than electrolyte 
imbalances/abnormalities) that resolve to Grade ≤1 in ≤7 days without clinical sequelae 
or need for therapeutic intervention considered not dose-limiting following agreement 
between the sponsor and investigators. 
–
Grade 3 rash lasting ≤7 days with optimal treatment that includes topical steroid 
treatment, PO antihistamines, and pulse PO steroids, if necessary.
–
Any other Grade 3 nonhematologic toxicity that can be controlled to Grade ≤1 or baseline 
in 7 days with appropriate treatment. In this setting, a course of action will be determined 
jointly by the investigators and the sponsor medical monitor.

Inability to administer at least 75% of planned doses of TAK-659 within Cycle 1 due to 
treatment-related toxicity.

Delay in the initiation of the subsequent cycle of therapy by more than 7 days due to study 
drug-related hematologic or nonhematologic toxicities.

Other study drug-related nonhematologic toxicities Grade ≥2 that, in the opinion of the 
investigator, require a dose reduction or discontinuation of study treatment. In this setting, a 
course of action will be determined jointly by the investigators and the sponsor medical 
monitor.
Although DLTs may occur at any point during treatment, only DLTs occurring during Cycle 1 of 
treatment in this dose escalation study will necessarily influence decisions regarding dose 
escalation, expansion of a dose level, or evaluation of intermediate dose levels. Patients will be 
monitored through all cycles of therapy for treatment-related toxicities.
Patients experiencing a DLT in Cycle 1 may continue in the study if they are deriving clinical 
benefit, but they will be administered reduced doses of TAK-659 and/or the combination agent 
as appropriate.
8.3
Dose Escalation Rules 
The dose escalation phase of the study is designed to determine the DLTs and MTD and/or 
RP2D of TAK-659 when given in combination with bendamustine (± rituximab), gemcitabine, 
lenalidomide, or ibrutinib. Patients in Cohorts A to E will be dosed based on the planned 3 dose-
level escalation for TAK-659 (Table 8.f) in each of the combination cohorts. The exact number 
of patients to be enrolled will depend on the actual number of dose-level cohorts required, which 
may deviate from the dose escalation plan based on toxicities and the PK results observed during 
the initial dose levels.
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The dose of the combination drugs will be as follows:
Cohort
Combination Study Drug
Dosage and Regimen
A
Bendamustine
90 mg/m2 administered IV over 10 or 60 minutes (depending on which formulation 
is used) on Days 1 and 2 of each 21-day cycle, up to 8 cycles
B
Bendamustine + rituximab
90 mg/m2 bendamustine administered IV over 10 or 60 minutes (depending on 
which formulation is used) on Days 1 and 2 of each 21-day cycle, up to 8 cycles, 
and 375 mg/m2 rituximab administered IV per local guidelines and labeling on Day 
1 of each 21-day cycle, up to 8 cycles
C
Gemcitabine
1000 mg/m2 IV infusion over 30 minutes on Days 1 and 8 of each 21-day cycle
D
Lenalidomide
25 mg PO QD for Days 1-21 of each 28-day cycle
E
Ibrutinib
560 mg PO QD of each 28-day cycle
The starting dose of TAK-659 will be 60 mg QD. Dose escalation will follow a standard 
3 + 3 escalation scheme (see Figure 8.a), and dosing of TAK-659 will increase to 100 mg QD 
(Table 8.f) provided that the safety and tolerability of the 60 mg dose has been demonstrated.
1. If 0 of 3 patients experiences DLT, dose escalation will proceed to the next higher dose level, 
at which 3 patients will be enrolled.
2. If 1 of 3 patients experiences DLT, 3 more patients will be enrolled at that same dose level. 
3. Escalation will continue if 1 of 6 patients experiences DLT.
4. If 2 or more patients at any dose level experience DLT, dosing will stop. Following 
consultation between the sponsor and investigators, either the previous dose level will be 
considered the MTD (if 6 or more patients have been studied at that dose level), the previous 
dose level will be expanded (if fewer than 6 patients have been studied at that dose level), or 
a dose level between the current and the previous dose level will be evaluated. 
Figure 8.a is a diagrammatical representation of these rules.
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Figure 8.a
Dose Escalation Algorithm
DLT: dose-limiting toxicity; MTD: maximum tolerated dose.
During the dose escalation phase, 3 levels of dose escalation are planned for TAK-659: 60, 80, 
and 100 mg (Table 8.f), according to a 3 + 3 dose escalation scheme. The single-agent MTD for 
TAK-659 is 100 mg QD as established in the FIH dose escalation study of TAK-659 (C34001). 
Therefore, dose escalation of TAK-659 will not exceed 100 mg QD in this study. More 
conservative dose escalation, including de-escalation in 20 mg decrements from the starting dose 
of 60 mg QD of TAK-659 (eg, 40 mg QD) if that dose is determined to be not tolerable, 
expansion of an existing dose level, or an alternative regimen/schedule, are all permissible 
following written confirmation of discussions between the sponsor and the investigators, if such 
measures are needed for patient safety, for a better understanding of the dose-related toxicity and 
preliminary PK and efficacy of TAK-659, or for adjustment based on the initial characterization 
of PK of TAK-659 when administered with the combination drugs.
Dose escalation continues until the MTD is reached, or until TAK-659 100 mg QD (the MAD) is 
determined to be safe and tolerable, or until an RP2D, if different from the MTD/MAD, is 
identified based on the safety, tolerability, and preliminary PK and efficacy data (if available) 
observed in Cycle 1 and beyond. At least 6 patients will be evaluated at the RP2D (the MTD or 
MAD or at a lower dose as determined) before making the dose decision. Further safety 
expansion of approximately 6 additional patients at the RP2D (up to 12 in total) is permitted to 
confirm the safety and tolerability of the combination dose of TAK-659 for each cohort. 
Escalation will be based on safety as determined in Cycle 1. While the primary escalation 
schema is designed to determine a classical Cycle 1-based MTD, dose escalation may be halted 
Enter 3
1 DLT
0 DLTs
2-3 DLTs
Escalate to 
next dose
Enter 3 at 
same dose
1 of 6 DLT
>1 of 6 DLTs
Stop
MTD=Previous dose
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at any time after consultation between the sponsor and investigators if cumulative toxicity 
beyond Cycle 1 indicates that a given dose exceeds a tolerable RP2D. 
Table 8.f
Planned Dose Levels of TAK-659 for Cohorts A to E
Dose Level
Dose (Unit)
1
60 mg
2
80 mg
3
100 mg a
a The maximum dose to be assessed is TAK-659 100 mg QD.
More conservative dose escalation, including evaluation of intermediate doses, dose 
de-escalation in 20 mg decrements from the starting dose of 60 mg QD if that is determined to be 
not tolerable, expansion of an existing dose level, and an alternative dose schedule/regimen are 
all permissible following discussions between the sponsor and the investigators, if such measures 
are needed for patient safety or for a better understanding of the dose-related toxicity and 
preliminary PK and efficacy of TAK-659.
DLT-evaluable patients in each dose cohort will consist of patients who have met the minimum 
treatment and safety evaluation requirements of the study during Cycle 1. 

For Cohorts A, B, and C, the minimum treatment and safety evaluation requirements are met 
if in Cycle 1, the patient has been treated with TAK-659 for ≥16 days (receiving at least 75% 
of planned doses of TAK-659 in Cycle 1) plus 1 or 2 doses of the combination drug, and 
observed for ≥21 days following the dose on Cycle 1 Day 1 (unless DLT occurs before the 
end of the 21-day evaluation period), and is considered to have sufficient safety data by both 
the sponsor and investigators to conclude that a DLT did not occur. 

For Cohorts D and E, the minimum treatment and safety evaluation requirements are met if 
in Cycle 1, the patient has been treated with TAK-659 for ≥21 days (receiving at least 75% of 
planned doses of TAK-659 in Cycle 1), and 75% of the planned doses for each of the 
combination drugs (lenalidomide or ibrutinib, respectively), and observed for ≥28 days 
(unless DLT occurs before the end of the 28-day evaluation period) following the dose on 
Cycle 1 Day 1, and is considered to have sufficient safety data by both the sponsor and 
investigator to conclude that a DLT did not occur. 
Patients who do not meet these minimum requirements will be regarded as ineligible for DLT 
evaluation for the given dose cohort and may be replaced within the same cohort.
The decision to explore a lower dose of the combination drug should not solely be based on the 
safety and tolerability data of the combination drug in combination with TAK-659. The 
preliminary efficacy data should also be carefully examined in relation to available nonclinical 
data and knowledge of the clinical therapeutic dose range for the combination agent, and there 
must be some evidence that the effect of lowering the combination drug dose would most likely 
be compensated for by the combination effect with TAK-659, so that the level of single-agent 
combination drug activity most probably would not be compromised. 
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8.4
Dose Modification Guidelines
In this dose escalation study, patients will be evaluated according to the Schedule of Events 
(Appendix A, Table 1 and Table 2) for each of the 5 cohorts for possible toxicities that may have 
occurred after the previous dose(s). Toxicities are to be assessed according to the NCI CTCAE 
version 4.03, effective 14 June 2010 [1]. The causal relationship of each AE should be assessed 
in relation to TAK-659 and to the combination agent(s) in each cohort so that dose modifications 
can be made accordingly. Administration and dose adjustment of bendamustine (Cohort A), 
bendamustine ± rituximab (Cohort B), gemcitabine (Cohort C), lenalidomide (Cohort D), and 
ibrutinib (Cohort E) will follow applicable prescribing information, the guidance on dose 
modification (Section 8.4), and the guidance on the management of clinical events (see 
Section 8.8). Minimum re-treatment requirements described in the bendamustine and 
gemcitabine prescribing information must be met before starting the next cycle or dose of 
bendamustine and gemcitabine treatment in Cohorts A, B, and C, respectively (see 
Section 8.4.3). Dose modification guidelines for hematologic and nonhematologic toxicities are 
described below for study drugs in each of the combination cohorts based on the type and 
severity of AEs, causality determination by investigators, and safety and tolerability profiles of 
each of the study drugs. Further clarification can be obtained in consultation with the sponsor 
clinician (or designee). 
Per the dose modification guidelines, patients who have the study drug held because of 
treatment-related or possibly related AEs may resume study drug treatment after resolution of the 
AE but may either maintain the same dose level or have doses of study drug reduced (dose 
reduction) by at least 1 dose level. Dose reduction levels for TAK-659 are presented in 
Table 8.g. When a dose reduction of TAK-659 occurs, the TAK-659 dose will be reduced to the 
next lower dose that has been established as a safe dose. The dose reduction of TAK-659 will, in 
general, follow a decrement of 20 mg. If initial dose adjustment does not provide sufficient 
relief, the dose of TAK-659 may be further reduced if the treating physician considers that the 
patient is benefiting from study treatment and may benefit at a further reduced dose of TAK-659. 
Up to 2 dose-level reductions of TAK-659 due to AEs are generally recommended. If more than 
2 dose-level reductions of TAK-659 are needed to manage TAK-659-related AEs, 
discontinuation of treatment should be considered unless the treating physician, in consultation 
with the sponsor, feels the patient may benefit from continued study treatment after resolution of 
AEs to Grade <1 or baseline, or a level (must be Grade ≤2) that is determined to be acceptable by 
the investigators based on benefit-risk assessment. Dose reduction for other combination agents 
is allowed per corresponding prescription information and clinical practice guideline. 
Asymptomatic laboratory changes (eg, elevations in serum lipase, amylase, AST, ALT, and 
creatine phosphokinase [CPK]) have been observed in patients treated with TAK-659. Although 
their clinical significance needs to be further evaluated, based on the available data, these 
laboratory abnormalities related to TAK-659 treatment are, in general, reversible and not 
associated with evidence of pathological tissue injuries. 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 and therefore no dose modification of TAK-659 is 
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recommended for LDH. For management of toxicities on study, dose modification guidelines 
should be closely followed. However, based on evolving safety data for TAK-659 and individual 
patient cases, alternative dose modifications may be recommended after discussion between the 
investigator and the sponsor to maximize exposure of study treatment while protecting patient 
safety.
Table 8.g
Dose Reduction Levels for TAK-659
Dose Reduction Levels
Dose (Unit)
Planned dose
60, 80, or 100 mg
(-) 1 dose level
Planned dose minus 20 mg
(-) 2 dose levels
Planned dose minus 40 mg
Dose reduction levels for bendamustine, gemcitabine, lenalidomide, and ibrutinib are described 
in Table 8.h for AEs that are attributed to each of the combination agents. Rituximab will be 
maintained at the same dose in Cohort B.
Table 8.h
Dose Reduction Levels for TAK-659 Combination Drugs
Dose Reduction 
Levels
Bendamustine
Rituximab
Gemcitabine
Lenalidomide
Ibrutinib
Planned dose
90 mg/m2
375 mg/m2
1000 mg/m2
25 mg
560 mg
(–) 1 dose level
60 mg/m2
Not applicable
750 mg/m2
20 mg
420 mg
(–) 2 dose level
30 mg/m2
Not applicable
500 mg/m2
15 mg
280 mg
If the dose of 1 study drug in a combination regimen is delayed because of toxicity attributed to 
its use, the dose of the other study drug in the combination regimen is to be administered as 
scheduled. 
8.4.1
Intrapatient Dose Escalation 
Once the RP2D of TAK-659 is determined, all patients who have received TAK-659 and another 
combination agent at a dose lower than the RP2D of TAK-659 for a minimum of 2 cycles may 
dose escalate to the RP2D of the assigned treatment arm in the absence of PD or unacceptable 
treatment-related toxicity at the investigator’s discretion and with the sponsor’s approval. 
Patients for whom an increase in the dose of TAK-659 is being considered must have treatment-
related AEs resolved to Grade ≤1 or baseline or to a level that is acceptable to the investigators 
(nonhematologic toxicity must be Grade ≤2, and hematologic toxicities must be less than the 
minimum requirement for starting a new cycle of treatment).
8.4.2
Intrapatient Dose Reduction (Cycle 1)
Intrapatient dose reductions of TAK-659 are not permitted in Cycle 1 during dose escalation 
unless the patient experiences a DLT attributed to TAK-659. DLT is defined in Section 8.2. If a 
patient experiences a DLT during Cycle 1, treatment should be held and the event counted 
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toward the assessment of MTD for the given cohort. Patients experiencing a DLT in Cycle 1 may 
continue in the study upon resolution of the toxicity; however, the dose of TAK-659 (in 
combination with other combination agents) will be reduced by at least 1 dose level (or reduced 
by a 20 mg decrement if the patient is receiving the first dose level). Patients who receive a 
reduced dose of TAK-659 during Cycle 1 for reasons other than DLT will be replaced for DLT 
evaluation and dose escalation. Dose delay and dose reduction of any of the combination drugs, 
and dose modification, are allowed in Cycle 1 (see Section 8.4 and Section 8.4.3, which include 
bendamustine and gemcitabine retreatment criteria). Frequency of dose delay and reduction of 
other combination agents will be taken into account in determining the RP2D for TAK-659 when 
administered in combination with these agents.
8.4.3
Retreatment Criteria for Cohorts A, B, and C (Bendamustine or Gemcitabine)
Per the prescribing information for bendamustine and gemcitabine, the patient must meet the 
following retreatment criteria before starting the next dose of bendamustine (Cohorts A and B) or 
gemcitabine (Cohort C): 
a) ANC ≥1000/µL.
b) Platelet count ≥75,000/µL.
For patients treated with bendamustine (±rituximab) in combination with TAK-659 (Cohorts A 
and B), 1 dose of 90 mg/m2 bendamustine is given on Days 1 and 2 in 21-day cycles. If a patient 
does not meet the bendamustine retreatment criteria, the next cycle of bendamustine dosing 
should be delayed for 1 week while supportive care is given based on the local standard practice 
or as specified in Section 8.9.5. The patient should be re-evaluated within 7 days to determine 
whether the criteria for bendamustine re-treatment have been met. If the criteria have not been 
met, further delay of the next cycle of bendamustine and re-evaluation of bendamustine 
retreatment criteria will occur at maximally weekly intervals until all retreatment criteria are 
satisfied. Dose modification guidelines will be followed to determine whether the dose of 
bendamustine will be maintained or reduced when bendamustine dosing is resumed.
For patients treated with TAK-659 + gemcitabine (Cohort C), 2 doses of 1000 mg/m2
gemcitabine will be given on Day 1 and Day 8 in 21-day treatment cycles. If the patient does not 
meet retreatment criteria for gemcitabine before Day 1 dosing in a given cycle, the start of the 
cycle will be delayed. The patient should be re-evaluated within 7 days to determine if 
gemcitabine retreatment criteria are met. If the re-treatment criteria are not met for the Day 8 
dosing of gemcitabine, the Day 8 dose will be delayed to Day 15 (provided that all re-treatment 
criteria are met on Day 15). In this case, there will still be an off week before the start of the next 
cycle. If further delay is needed, the second dose of gemcitabine will be withheld, and 
gemcitabine will be resumed in the next cycle. 
Discontinuation of study treatment should be considered if, because of lack of adequate recovery 
of the toxicities, there is a delay of a new cycle (due to Day 1 dosing delay for Cohorts A, B, or 
C) for ≥21 days (≥3 weeks), or a failure to resume the next cycle due to a delay of Day 8 
gemcitabine dosing (for Cohort C only) for ≥21 days (≥3 weeks) after the initial delay. 
Continued treatment may be considered in the case of investigator-determined clinical benefit 
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and discussion with the sponsor project clinician. However, study treatment may be resumed 
only after the re-treatment criteria are fully met. If a delay of ≥14 days (≥2 weeks) is required for 
resolution of toxicities before meeting the re-treatment criteria, dose reduction of bendamustine 
and gemcitabine to the next lower level should be considered (Table 8.h).
If the toxicities that result in failure to meet the bendamustine or gemcitabine re-treatment 
criteria are determined to be related to bendamustine or gemcitabine and not to TAK-659, 
patients should continue to receive TAK-659 according to the planned dose and regimen. If, in 
the investigator’s opinion, TAK-659 contributes to the toxicities (related or possibly related) that 
lead to not meeting bendamustine or gemcitabine retreatment criteria, dose delay or modification 
of TAK-659 should be considered per the dose modification guidelines in Section 8.4.
8.4.4
Dose Modification for Hematologic and Nonhematologic Toxicity 
Decisions regarding which study drug requires dose modification will be dependent upon the 
toxicity, its onset, and its time course. The causal relationship of any reported events (AEs or 
SAEs) should be assessed by the investigator in relation to TAK-659 and in relation to the 
combination drug (bendamustine ±rituximab, gemcitabine, lenalidomide, or ibrutinib). If 
multiple toxicities are noted, the dose adjustments and/or delays should be made according to the 
most severe toxicity guidelines and the causal relationship to 1 or both study drugs. Guidelines 
for dose modifications for hematologic and nonhematologic toxicity for each study Cohort (A-E) 
are presented in Table 8.i to Table 8.l. After discussion between the investigator and the Takeda 
project clinician, alternative dose modifications may be recommended to maximize exposure of 
study treatment while protecting patient safety.
8.4.4.1
Dose Modification Guidelines for Hematologic Toxicities for Cohort A (TAK-659 + 
Bendamustine) and Cohort B (TAK-659 + Bendamustine/Rituximab)
Dose modifications guidelines for hematologic toxicities for Cohorts A and B are presented in 
Table 8.i.
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Table 8.i
Dose Modification Guidelines for Hematologic Toxicities for Cohort A 
(TAK-659 + Bendamustine) and Cohort B (TAK-659 + Bendamustine/Rituximab)
NCI 
CTCAE 
Grade
Description
Bendamustine Dose Modification
Rituximab Dose Modification
TAK-659 Dose Modification
Neutropenia 
2 or 3
ANC <1500 to 500/mm3; 
<1.5 to 0.5×109/L
Hold dose of bendamustine until ANC 
≥1000/mm3 or baseline, then restart at same 
schedule and dose (90 mg/m2).
Maintain rituximab at same dose and schedule 
(375 mg/m2).
Continue TAK-659 at same dose 
and schedule.
4
ANC <500/mm3; 
<0.5×109/L
Hold bendamustine dose until ANC ≥1000/mm3
or baseline, then restart bendamustine dose at 
90 mg/m2. If resolved in ≤7 days, maintain the 
same dose of bendamustine. If resolved in 
>7 days, reduce dose by 1 level (first 
occurrence) and by 2 levels (repeat occurrence).
Hold rituximab until ANC ≥1000/mm3 or 
baseline, then restart rituximab dose at same 
dose and schedule (375 mg/m2). 
Hold TAK-659 until ANC 
≥1000/mm3 or baseline, then 
restart TAK-659 at same dose 
and schedule. In case of repeat 
occurrence at a reduced dose of 
bendamustine, TAK-659 may be 
reduced by 1 level (first 
occurrence) and by 2 levels if 
needed.
Other
Febrile neutropenia:
ANC <1000/mm3 and fever 
defined as a single 
temperature of >38.3oC 
(101oF) or a sustained 
temperature of ≥38oC 
(100.4oF) for more than 
1 hour), OR ANC <1000/mm3
with systemic infection
Hold bendamustine dose until ANC ≥1000/mm3
or baseline and fever and infection are resolved, 
then restart bendamustine at dose reduced by 1 
level (first occurrence) and by 2 levels (repeat 
occurrence). 
Hold rituximab until ANC ≥1000/mm3 or 
baseline, then restart rituximab dose at same 
dose and schedule (375 mg/m2).
Hold TAK-659 until ANC 
≥1000/mm3 or baseline, then 
restart TAK-659 at same dose 
and schedule. In case of repeat 
occurrence at a reduced dose of 
bendamustine, TAK-659 may be 
reduced by 1 level first and by 
2 levels if needed.
Thrombocytopenia 
1 or 2
PLT < LLN to 50,000/mm3;
<LLN to 50×109/L
Hold bendamustine until PLT ≥75,000/mm3 or 
baseline, then restart at the same dose.
Maintain rituximab at same dose and schedule 
(375 mg/m2).
No change. Continue TAK-659 at 
same dose and schedule.
3
PLT < 50,000-25,000/mm3;
<50 to 25×109/L
Hold bendamustine until PLT 
≥75,000/mm3 or baseline. If resolved in ≤7 
days, maintain the same dose. If resolved in 
>7 days, reduce dose by 1 level (first 
occurrence) and by 2 levels (repeat 
occurrence). 
Hold rituximab until PLT ≥75,000/mm3 or 
baseline, then restart rituximab at same 
dose and schedule (375 mg/m2).
Hold TAK-659 until PLT 
≥75,000/mm3 or baseline, then 
restart TAK-659 at same dose and 
schedule. 
Footnotes are on last table page.
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Table 8.i
Dose Modification Guidelines for Hematologic Toxicities for Cohort A 
(TAK-659 + Bendamustine) and Cohort B (TAK-659 + Bendamustine/ 
Rituximab) (continued)
NCI 
CTCAE 
Grade
Description
Bendamustine Dose Modification
Rituximab Dose Modification
TAK-659 Dose Modification
4
PLT <25,000/mm3; 
<25×109/L
Hold bendamustine until PLT ≥75,000/mm3 or 
baseline. When resolved, reduce bendamustine dose 
by 1 level (first occurrence) and by 2 levels (repeat 
occurrence).
Hold rituximab until PLT ≥75,000/mm3 or baseline, 
then restart rituximab at same dose and schedule 
(375 mg/m2).
Hold TAK-659 until 
PLT ≥75,000/mm3 or baseline; 
restart TAK-659 at same dose. 
In case of recurrence at a reduced 
dose of bendamustine, TAK-659 
may be reduced by 1 level first 
and by 2 levels if needed. 
Other
PLT <10,000/mm3 OR 
clinically significant 
bleeding
Consider permanently discontinuing bendamustine, 
except when the investigator determines that the 
patient is obtaining a clinical benefit and the 
investigator has discussed this with the sponsor. 
If bendamustine is not discontinued, then the 
bendamustine dose will be reduced to at least 1 dose 
level when PLT ≥75,000/mm3 or baseline and/or 
clinically significant bleeding are completely 
resolved. 
Consider permanently discontinuing rituximab, 
except when the investigator determines that the 
patient is obtaining a clinical benefit and the 
investigator has discussed this with the sponsor. 
If rituximab is not discontinued, then maintain the 
starting dose and schedule (375 mg/m2) when PLT 
≥75,000/mm3 or baseline and/or clinically significant 
bleeding are completely resolved.
Consider permanently 
discontinuing TAK-659, except 
when the investigator determines 
that the patient is obtaining 
clinical benefit and has discussed 
this with the sponsor. If the patient 
is not withdrawn from the study, 
the TAK-659 dose will be reduced 
to at least 1 dose level lower when 
PLT ≥75,000/mm3 or baseline 
and/or clinically significant 
bleeding are completely resolved.
Anemia 
3
Hgb <8.0 g/dL; transfusion 
indicated
Hold bendamustine until Hgb ≥9.0 g/dL or baseline. 
If resolved in ≤7 days, maintain the same dose of 
bendamustine. If resolved in >7 days, reduce dose 
by 1 level (first occurrence) and by 2 levels(repeat 
occurrence).
Hold rituximab until Hgb ≥9.0 g/dL or baseline. 
Restart rituximab dose at 375 mg/m2. In case of 
repeat occurrence at a reduced dose of TAK-659, 
rituximab will be maintained at same dose and 
schedule (375 mg/m2).
Hold TAK-659 until Hgb ≥9.0 g/d 
or baseline. If resolved in ≤7 days, 
maintain the same dose of 
TAK-659. If resolved in >7 days, 
reduce dose by 1 level (first 
occurrence) and by 2 levels (repeat 
occurrence). 
4
Life-threatening 
consequences; urgent 
intervention indicated
Hold bendamustine until resolved to Grade ≤1 or 
baseline. Restart at reduced dose by at least 1 level, 
or consider discontinuation. 
Hold rituximab until Hgb ≥9.0 g/dL or baseline. 
Restart rituximab dose at 375 mg/m2. 
Hold TAK-659 until 
Hgb ≥9.0 g/dL or baseline. When 
resolved, reduce dose by at least 
1 level, or consider 
discontinuation.
Hgb: hemoglobin; PLT: platelets.
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8.4.4.2
Dose Modification Guidelines for Nonhematologic Toxicities for Cohort A 
(TAK-659 + Bendamustine) and Cohort B (TAK-659 + Bendamustine/Rituximab) 
Dose modifications guidelines for non-hematologic toxicities for Cohort A and Cohort B are 
presented in Table 8.j.
Table 8.j
Dose Modification Guidelines for Nonhematologic Toxicities for Cohort A 
(TAK-659 + Bendamustine) and Cohort B (TAK-659 + Bendamustine/ 
Rituximab)
NCI CTCAE Grade
Bendamustine Dose Modification
Rituximab Dose Modification
TAK-659 Dose Modification 
Asymptomatic Serum Lipase and/or Amylase Increase
Asymptomatic lipase elevation 
(Grade <4) in the absence of significant 
amylase elevation (Grade <3) 
considered not dose limiting between 
sponsor and investigators.
Maintain the same dose/regimen of 
bendamustine with close monitoring.
Maintain rituximab at same dose and 
schedule with close monitoring.
Maintain the dose of TAK-659 with close
monitoring.
Asymptomatic amylase elevation 
(Grade <4) in the absence of significant 
lipase elevation (Grade <3) considered 
not dose limiting between sponsor and 
investigators.
Maintain the same dose/regimen of 
bendamustine with close monitoring.
Maintain rituximab at same dose and 
schedule with close monitoring.
Maintain the dose of TAK-659 with close
monitoring.
Asymptomatic Grade 3 serum lipase 
increase accompanied by Grade ≥3 serum 
amylase increase; asymptomatic Grade 3 
serum amylase increase accompanied by 
Grade ≥3 serum lipase increase; OR 
asymptomatic Grade 4 serum lipase or 
amylase increase.
Maintain the same dose/regimen of 
bendamustine with close monitoring.
Maintain rituximab at same dose and 
schedule with close monitoring.
Hold TAK-659 until resolution to 
Grade ≤1, baseline, or a level acceptable 
by the investigator (must be Grade ≤2), 
then restart TAK-659 at the same dose if 
resolved within 7 days or reduce by 
1 level if resolution is more than 7 days. 
If recurs, then reduce by 1 level.
AST/ALT
Grade 3 elevation of single enzyme (AST 
or ALT) in the absence of significant 
bilirubin elevation (Grade <3)
Maintain the dose of bendamustine 
with close monitoring.
Maintain rituximab at same dose and 
schedule with close monitoring.
Maintain the dose of TAK-659 with 
close monitoring.
Grade 3 elevation of both AST and ALT
Hold bendamustine until AST and 
ALT decrease to <2.5 × ULN. Restart 
bendamustine at the same dose if 
resolved within 7 days or reduce by 
1 level if resolution is >7 days.
Hold rituximab until AST and ALT 
decrease to <2.5 × ULN, then restart 
rituximab at same dose and schedule 
(375 mg/m2).
Hold TAK-659 until AST and ALT 
decrease to <2.5 × ULN. Restart 
TAK-659 at the same dose if resolved 
within 7 days or reduce by 1 level if 
resolution is more than 7 days.
Grade 4 elevation of AST and/or ALT
Hold bendamustine until AST and ALT 
<2.5 × ULN. Restart bendamustine at a 
dose reduced by 1 level, and if elevation 
recurs, reduce by 2 dose levels.
Hold rituximab until AST and ALT 
decrease to <2.5 × ULN, then restart 
rituximab at same dose and schedule 
(375 mg/m2).
Hold TAK-659 until AST and ALT 
<2.5 × ULN. Restart TAK-659 at the 
same dose if resolved within 7 days or 
reduce by 1 level if resolution is more 
than 7 days. If recurs, then dose reduce 
by 1 level.).
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Table 8.j
Dose Modification Guidelines for Nonhematologic Toxicities for Cohort A 
(TAK-659 + Bendamustine) and Cohort B (TAK-659 + Bendamustine/ 
Rituximab) (continued)
NCI CTCAE
Grade
Bendamustine Dose Modification
Rituximab Dose Modification
TAK-659 Dose Modification 
Other Nonhematologic Toxicities
All other Grade 3 nonhematologic 
toxicities with the exception of:

Grade 3 nausea, vomiting, and 
diarrhea resolved to Grade ≤1 or 
baseline within 1 week with 
optimal antiemetics and 
antidiarrheals following standard 
of care.

Transient Grade 3 fatigue (lasting 
<1 week).

Grade 3 rash lasting ≤7 days with 
optimal treatment.

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 
within 72 hours with phosphate 
repletion. 

Any other Grade 3 nonhematologic 
toxicity that can be controlled to 
Grade ≤1 or baseline in 1 week 
with appropriate treatment.
Hold bendamustine if determined to be 
related to bendamustine until resolution to 
Grade ≤1, baseline, or a level acceptable to 
the investigator (must be Grade ≤2). 
If resolved in ≤7 days, then maintain 
dose level.
If resolved in >7 days, then reduce dose 
by 1 dose level.
If recurs, then reduce dose by 1 dose 
level.
For the exceptions listed, maintain the 
dose level. 
Permanent discontinuation of bendamustine 
should be considered if the toxicities persist 
as Grade ≥3 for more than 21 days despite 
temporary disruption of study drug.
Hold rituximab if determined to be related 
to rituximab until resolution to Grade ≤1, 
baseline, or a level acceptable to the
investigator (must be Grade ≤2). When 
resolved, maintain rituximab dose and 
schedule.
Permanent discontinuation of rituximab 
should be considered if the toxicities persist 
as Grade ≥3 for >21 days despite temporary 
disruption of study drug.
Hold TAK-659 if determined to be 
related to TAK-659 until resolution to 
Grade ≤1, baseline, or a level 
acceptable to the investigator (must be 
Grade ≤2).
If resolved in ≤7 days, then maintain 
dose level.
If resolved in >7 days, then reduce 
dose by 1 dose level.
If recurred, then reduce dose by 
1 dose level.
For the exceptions listed, maintain 
the dose level. 
Permanent discontinuation should be 
considered if the toxicities persist as 
Grade ≥3 for more than 21 days despite 
temporary interruption of study drug.
For exceptions, maintain dose level.
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Table 8.j
Dose Modification Guidelines for Nonhematologic Toxicities for Cohort A 
(TAK-659 + Bendamustine) and Cohort B (TAK-659 + Bendamustine/ 
Rituximab) (continued)
NCI CTCAE
Grade
Bendamustine Dose Modification
Rituximab Dose Modification
TAK-659 Dose Modification 
Grade 4 nonhematologic toxicities with 
the exception of an asymptomatic 
laboratory change that is considered 
clinically manageable.
Permanent discontinuation of 
bendamustine or rituximab should be 
considered based on causality, except in 
the case where the investigator determines 
the patient is obtaining a clinical benefit 
and has discussed this with the project 
clinician or designee. 
If the patient’s treatment is not 
discontinued, the combination agent dose 
(for bendamustine) will be reduced to at 
least 1 dose level lower when toxicity 
resolves to Grade ≤1, baseline, or a level 
acceptable by the investigator (must be 
Grade ≤2) or held (for rituximab) until 
toxicity resolves to Grade ≤1, baseline, or a 
level acceptable by the investigator (must 
be Grade ≤2)
Permanent discontinuation should be 
considered except in the case where the 
investigator determines the patient is 
obtaining a clinical benefit and has 
discussed this with the project clinician 
or designee. If the patient is not 
discontinued, TAK-659 dose will be 
reduced to at least 1 dose level lower 
when toxicity resolves to Grade ≤1 or 
baseline.
For the asymptomatic laboratory change 
exceptions, hold TAK-659 until 
resolution to Grade ≤1 or baseline.
If resolved in ≤7 days, then maintain 
the dose level;
If resolved in >7 days, then reduce 
dose by 1 dose level;
If recurs, then reduce dose by 1 dose 
level.
Grade 4 nonhematologic toxicities will, in general, require that treatment with TAK-659 be 
permanently discontinued. If, in the opinion of the investigator and the sponsor (project clinician 
or designee), it is in the patient’s best interest to continue treatment with TAK-659, then the dose 
of TAK-659 will be reduced by at least 1 dose level when treatment resumes after recovery of 
the toxicity(ies) 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. When the study drug 
is resumed, TAK-659 can be started at the same or a reduced dose level, depending on how 
quickly the AE resolves. If a dose reduction is required, no dose re-escalation is permitted in this 
situation.
8.4.4.3
Dose Modification Guidelines for Hematologic Toxicities for Cohort C (TAK-659 + 
Gemcitabine), Cohort D (TAK-659 + Lenalidomide), and Cohort E 
(TAK-659 + Ibrutinib) 
Dose modifications guidelines for hematologic toxicities for Cohorts C, D, and E are presented 
in Table 8.k.
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Table 8.k
Dose Modification Guidelines for Hematologic Toxicities for Cohort C 
(TAK-659 + Gemcitabine), Cohort D (TAK-659 + Lenalidomide), and 
Cohort E (TAK-659 + Ibrutinib)
NCI 
CTCAE 
Grade
Description
Combination Drug Dose Modification 
(Gemcitabine, Lenalidomide, or 
Ibrutinib)
TAK-659 Dose Modification
Neutropenia 
2 or 3
ANC <1500 to 500/mm3; 
<1.5 to 0.5×109/L
Hold dose of combination agent 
until ANC ≥1000/mm3 or baseline, then 
restart at same schedule and dose.
Continue TAK-659 at same dose and 
schedule.
4
ANC <500/mm3; 
<0.5×109/L
Hold combination agent dose until ANC 
≥1000/mm3 or baseline, then restart 
combination agent. If resolved in 
≤7 days, maintain the same dose of 
combination agent. If resolved in 
>7 days, reduce dose by 1 level (first 
occurrence) and by 2 levels (repeat 
occurrence).
Hold TAK-659 until ANC ≥1000/mm3 or 
baseline, then restart TAK-659 at same 
dose and schedule. In case of repeat 
occurrence at a reduced dose of the 
combination agent, TAK-659 may be 
reduced by 1 level (first occurrence) and by 
2 levelsif needed.
Other
Febrile neutropenia:
ANC <1000/mm3 and 
fever defined as a single 
temperature of >38.3°C 
(101°F) or a sustained 
temperature of ≥38°C 
(100.4°F) for more than 
1 hour), OR ANC <1000/mm3
with systemic infection
Hold combination agent dose until ANC 
≥1000/mm3 or baseline and fever and 
infection are resolved, then restart 
combination agent at dose reduced by 1 
level (first occurrence) and by 2 levels 
(repeat occurrence). 
Hold TAK-659 until ANC ≥1000/mm3 or 
baseline, then restart TAK-659 at same 
dose and schedule. In case of repeat 
occurrence at a reduced dose of 
combination agent, TAK-659 may be 
reduced by 1 level first and by 2 levels if 
needed.
Thrombocytopenia
1 or 2
PLT < LLN to 50,000/mm3; 
<LLN to 50×109/L
Hold combination agent until PLT 
≥75,000/mm3 or baseline, then restart at 
the same dose.
No change. Continue TAK-659 at same 
dose and schedule.
3
PLT <50,000 to 25,000/mm3; 
<50 to 25×109/L
Hold combination agent until PLT 
≥75,000/mm3 or baseline. If resolved in 
≤7 days, maintain the same dose. If 
resolved in >7 days, reduce dose by 1 
level (first occurrence) and by 2 levels 
(repeat occurrence). 
Hold TAK-659 until PLT ≥75,000/mm3 or 
baseline, then restart TAK-659 at same 
dose and schedule. 
4
PLT <25,000/mm3; 
<25×109/L
Hold combination agent until PLT 
≥75,000/mm3 or baseline. When 
resolved, reduce combination agent dose 
by 1 level (first occurrence) and by 2 
levels (repeat occurrence).
Hold TAK-659 until PLT ≥75,000/mm3 or 
baseline, then restart TAK-659 at same 
dose. In case of recurrence at a reduced 
dose of combination agent, TAK-659 may 
be reduced by 1 level first and by 2 levels 
if needed. 
Footnotes are on last table page.
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Table 8.k
Dose Modification Guidelines for Hematologic Toxicities for Cohort C 
(TAK-659 + Gemcitabine), Cohort D (TAK-659 + Lenalidomide), and 
Cohort E (TAK-659 + Ibrutinib) (continued)
NCI 
CTCAE 
Grade
Description
Combination Drug Dose Modification 
(Gemcitabine, Lenalidomide, or 
Ibrutinib)
TAK-659 Dose Modification
Other
PLT <10,000/mm3; OR
clinically significant bleeding
Consider permanently discontinuing 
combination agent, except when the 
investigator determines that the patient is 
obtaining a clinical benefit, and the 
investigator has discussed this with the 
sponsor. If combination agent is not 
discontinued, then the combination agent 
dose will be reduced by at least 1 dose 
level when PLT ≥75,000/mm3 or 
baseline and/or clinically 
significant bleeding are completely 
resolved. 
Consider permanently discontinuing TAK-
659, except when the investigator 
determines that the patient is obtaining 
clinical benefit and has discussed this with 
the sponsor. If the patient is not withdrawn 
from the study, the TAK-659 dose will be 
reduced by at least 1 dose level when PLT 
≥75,000/mm3 or baseline and/or clinically 
significant bleeding are completely 
resolved.
Anemia
3
Hgb <8.0 g/dL; 
transfusion indicated
Hold combination agent until Hgb ≥9.0 
g/dL or baseline. If resolved in ≤7 days, 
maintain the same dose of combination 
agent. If resolved in >7 days, reduce dose 
by 1 level (first occurrence) and by 
2 levels(repeat occurrence). 
Hold TAK-659 until Hgb ≥9.0 g/dL or 
baseline. If resolved in ≤7 days, maintain 
the same dose of TAK-659. If resolved in 
>7 days, reduce dose by 1 level (first 
occurrence) and by 2 levels (repeat 
occurrence). 
4
Life-threatening consequences; 
urgent intervention indicated
Hold combination agent until resolved to 
Grade ≤1 or baseline. Restart 
combination agent at a dose reduced by 
at least 1 level or consider 
discontinuation. 
Hold TAK-659 until Hgb ≥9.0 g/dL or 
baseline. When resolved, reduce dose by at 
least 1 level, or consider discontinuation.
Hgb: hemoglobin; PLT: platelets.
8.4.4.4
Dose Modification Guidelines for Nonhematologic Toxicities for Cohort C (TAK-659 + 
Gemcitabine), Cohort D (TAK-659 + Lenalidomide), and Cohort E 
(TAK-659 + Ibrutinib) 
Dose modifications guidelines for nonhematologic toxicities for Cohorts C, D, and E are 
presented in Table 8.l.
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Table 8.l
Dose Modification Guidelines for Nonhematologic Toxicities for Cohort C 
(TAK-659 + Gemcitabine), Cohort D (TAK-659 + Lenalidomide), and 
Cohort E (TAK-659 + Ibrutinib)
NCI CTCAE
Grade
Combination Drug Dose Modification 
(Gemcitabine, Lenalidomide, or Ibrutinib) TAK-659 Dose Modification 
Asymptomatic Serum Lipase 
and/or Amylase Increase
Asymptomatic lipase elevation (Grade 
<4) in the absence of significant 
amylase elevation (Grade <3) 
considered not dose limiting between 
sponsor and investigators.
Maintain the same dose/regimen of 
bendamustine with close monitoring.
Maintain rituximab at same dose and 
schedule with close monitoring.
Maintain the dose of TAK-659 with close 
monitoring.
Asymptomatic amylase 
elevation (Grade <4) in the absence of 
significant lipase elevation (Grade <3) 
considered not dose limiting between 
sponsor and investigators.
Maintain the same dose/regimen of 
bendamustine with close monitoring.
Maintain rituximab at same dose and 
schedule with close monitoring.
Maintain the dose of TAK-659 with close 
monitoring.
Asymptomatic Grade 3 serum lipase 
increase accompanied by Grade ≥3 
serum amylase 
increase; asymptomatic Grade 3 
serum amylase increase accompanied 
by Grade ≥3 serum lipase increase; 
OR asymptomatic Grade 4 serum 
lipase or amylase increase.
Maintain the same dose/regimen of 
combination agent with close monitoring.
Hold TAK-659 until resolution to Grade ≤1, 
baseline, or a level acceptable to the 
investigator (must be Grade ≤2), then restart 
TAK-659 at the same dose if resolved 
within 7 days, or reduce by 1 level if 
resolution is more than 7 days. If recurs, 
then reduce by 1 dose level.
AST/ALT
Grade 3 elevation of single enzyme 
(AST or ALT) in the absence of 
significant bilirubin elevation 
(Grade <3)
Maintain the dose of combination agent with 
close monitoring.
Maintain the dose of TAK-659 with close 
monitoring.
Grade 3 elevation of both AST and 
ALT
Hold combination agent until AST and ALT 
decrease to <2.5 × ULN. Restart combination 
agent at the same dose if resolved within 7 
days, or reduce by 1 level if resolution is 
>7 days.
Hold TAK-659 until AST and ALT decrease 
to <2.5 × ULN. Restart TAK-659 at the 
same dose if resolved within 7 days or 
reduce by 1 level if resolution is more than 
7 days.
Grade 4 elevation of AST and/or ALT Hold combination agent until AST and 
ALT <2.5 × ULN. Restart combination agent 
at a reduced dose by 1 level; if elevation 
recurs, reduce by 2 dose levels. 
Hold TAK-659 until AST and 
ALT <2.5 × ULN. Restart TAK-659 at the 
same dose if resolved within 7 days, or 
reduce by 1 level if resolution is more than 
7 days. If recurs, then reduce dose by 1 
level.
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Table 8.l
Dose Modification Guidelines for Nonhematologic Toxicities for Cohort C 
(TAK-659 + Gemcitabine), Cohort D (TAK-659 + Lenalidomide), and 
Cohort E (TAK-659 + Ibrutinib) (continued)
NCI CTCAE
Grade
Combination Drug Dose Modification 
(Gemcitabine, Lenalidomide, or Ibrutinib) TAK-659 Dose Modification 
Other Nonhematologic Toxicities
All other Grade 3 nonhematologic 
toxicities with the exception of:

Grade 3 nausea, vomiting, and 
diarrhea resolved to Grade ≤1 
or baseline within 1 week with 
optimal antiemetics and 
antidiarrheals following SOC.

Transient Grade 3 fatigue 
(lasting <1 week).

Grade 3 rash lasting ≤7 days 
with optimal treatment. 

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 
within 72 hours with phosphate 
repletion.

Any other Grade 3 
nonhematologic toxicity that 
can be controlled to Grade ≤1 or 
baseline in 1 week with 
appropriate treatment. 
Hold combination agent if determined to be 
related to combination agent until resolution 
to Grade ≤1, baseline, or a level acceptable to 
the investigator (must be Grade ≤2). 

If resolved in ≤7 days, then 
maintain dose level.

If resolved in >7 days, then reduce dose 
by 1 dose level.

If recurs, then reduce dose by 
1 dose level.

For the exceptions listed, maintain the 
dose level. 
Permanent discontinuation should be 
considered if the toxicities persist as 
Grade ≥3 for more than 21 days 
despite temporary interruption of study drug.
Hold TAK-659 if determined to be related 
to TAK-659 until resolution to Grade ≤1, 
baseline, or a level acceptable to the 
investigator (must be Grade ≤2).

If resolved in ≤7 days, then maintain 
dose level.

If resolved in >7 days, then reduce 
dose by 1 dose level.

If recurred, then reduce dose by 1 dose 
level.

For the exceptions listed, maintain the 
dose level. 
Permanent discontinuation should be 
considered if the toxicities persist as 
Grade ≥3 for more than 21 days despite 
temporary interruption of study drug.
For exceptions, maintain dose level.
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Table 8.l
Dose Modification Guidelines for Nonhematologic Toxicities for Cohort C 
(TAK-659 + Gemcitabine), Cohort D (TAK-659 + Lenalidomide), and 
Cohort E (TAK-659 + Ibrutinib) (continued)
NCI CTCAE
Grade
Combination Drug Dose Modification 
(Gemcitabine, Lenalidomide, or Ibrutinib) TAK-659 Dose Modification 
Grade 4 nonhematologic toxicities 
with the exception of an 
asymptomatic laboratory change that 
is considered clinically manageable.
Permanent discontinuation of combination 
agent should be considered based on 
causality, except in the case where the 
investigator determines the patient is 
obtaining a clinical benefit and has discussed 
this with the project clinician or designee. If 
the patient’s treatment is not discontinued, 
the combination agent dose will be 
reduced to at least 1 dose level lower when 
toxicity resolves to Grade ≤1, baseline, or a 
level acceptable by the investigator (must be 
Grade ≤2).
Permanent discontinuation should be 
considered based on causality except in the 
case where the investigator determines the 
patient is obtaining a clinical benefit and has 
discussed this with the project clinician or 
designee. If the patient’s treatment is not 
discontinued, TAK-659 dose will be 
reduced to at least 1 dose level lower when 
toxicity resolves to Grade ≤1 or baseline.
For the asymptomatic laboratory change 
exceptions, hold TAK-659 until resolution 
to Grade ≤1 or baseline.
If resolved in ≤7 days, then maintain the 
dose level;
If resolved in >7 days, then reduce dose by 
1 dose level;
If recurs, then reduce dose by 1 dose level.
Grade 4 nonhematologic toxicities will, in general, require that treatment with TAK-659 be 
permanently discontinued. If, in the opinion of the investigator and the sponsor (project clinician 
or designee), it is in the patient’s best interest to continue treatment with TAK-659, then the dose 
of TAK-659 will be reduced by at least 1 dose level when treatment resumes after recovery of 
the toxicity or toxicities in question to Grade 1 or to baseline values. When a dose reduction of 
TAK-659 is required due to 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. When the study drug 
is resumed, TAK-659 can be started at the same or a reduced dose level, depending on how 
quickly the AE resolves. If a dose reduction is required, no dose re-escalation is permitted in this 
situation.
8.5
Excluded Concomitant Medications and Procedures
During the course of the study, patients will be instructed not to take any additional medications 
(including over-the-counter products and supplements) without prior consultation with the 
investigator. At each visit, the investigator will ask the patient about any new medications he/she 
is 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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a) Any antineoplastic therapy other than TAK-659 and its combination study drug(s) is 
prohibited on study. If alternative therapy is required for treatment of the patient’s tumor, the 
patient should be removed from this study and the reason for removal recorded in the eCRF.
b) Radiation therapy (note that, in general, the requirement for local radiation therapy indicates 
PD) is not permitted during the 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. 
c) 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 and as 
outlined in Section 8.6). Tropical, ocular, intra-articular, intranasal, and inhaled 
corticosteroids (with minimal systemic absorption) are allowed.
d) Prophylactic use of myeloid growth factors (eg, granulocyte colony stimulating factor 
[G-CSF], granulocyte macrophage-colony stimulating factor [GM-CSF]) is not 
recommended at the study start. 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.
e) 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 for a list of medications, supplements, and 
food products that are inhibitors or inducers of P-gp or strong inhibitors or inducers of 
CYP3A based on the US FDA Draft DDI Guidance.
–
Antifungals: itraconazole, ketoconazole, posaconazole, voriconazole.
–
Antibiotics: azithromycin, clarithromycin, erythromycin, telithromycin.
–
Antimycobacterials: rifabutin, rifampin, rifapentine.
–
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.
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–
Vasopressin antagonist: conivaptan.
–
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 due 
to that AE, the medications listed above and in Appendix H may be used for AE 
management provided there is no appropriate alternative treatment available based on the 
investigator’s judgement and the dosing is not concurrent with TAK-659. 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 H 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 and in Appendix H, 
then its use must be discussed with the medical monitor or designee to assess the relative 
benefit and risk.
8.5.1
Excluded Concomitant Medications Applicable to Cohorts A and B
Cohorts A and B (TAK-659 + bendamustine ±rituximab): Please refer to the most recent 
bendamustine and rituximab USPI [11,12], Bendeka USPI [17], or applicable labeling for 
information on medications that are prohibited in patients receiving bendamustine ±rituximab. 
8.5.2
Excluded Concomitant Medications Applicable to Cohort C
Cohort C (TAK-659 + gemcitabine): Please refer to the most recent gemcitabine USPI [13] or 
applicable labeling for information on medications that are prohibited in patients receiving 
gemcitabine.
8.5.3
Excluded Concomitant Medications Applicable to Cohort D
Cohort D (TAK-659 + lenalidomide): Please refer to the most recent lenalidomide USPI [15] or 
applicable labeling for information on medications that are prohibited in patients receiving 
lenalidomide.
8.5.4
Excluded Concomitant Medications Applicable to Cohort E
Cohort E (TAK-659 + ibrutinib): Please refer to the most recent ibrutinib USPI [16] or 
applicable labeling for information on medications that are prohibited in patients receiving 
ibrutinib.
For patients in the ibrutinib combination arm (Cohort E), concurrent systemic treatment with 
moderate inhibitors or inducers of CYP3A is also not permitted in this study because of the 
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potential risk for clinically relevant DDI with ibrutinib. Refer to the list below and Appendix H
for a list of medications, supplements, and food products that are moderate inhibitors or inducers 
of CYP3A based on the US Food and Drug Administration (FDA) Draft DDI Guidance. 

Antibiotics: ciprofloxacin, nafcillin.

Antiemetic: aprepitant.

Antifungal: fluconazole.

Endothelin receptor antagonist: bosentan.

Food/beverages: Seville oranges (often contained in marmalades).

Stimulant: modafinil.
Note that medications used to treat HIV or hepatitis C infection are not listed above or in 
Appendix H 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 moderate CYP3A inhibitor or 
inducer, but is not listed above or in Appendix H, then its use must be discussed with the 
medical monitor or designee to assess the relative benefit and risk.
If a patient experiences an AE on study and combination drug dosing is temporarily 
interrupted due to that AE, the medications listed above may be used for AE management 
provided there is no appropriate alternative treatment available based on the investigator’s 
judgement and the dosing is not concurrent with the combination 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.
8.6
Permitted Concomitant Medications and Procedures
8.6.1
Rituximab Premedication for Cohort B
For patients in Cohort B receiving rituximab, premedicate with acetaminophen and an 
antihistamine before rituximab infusion in accordance with the rituximab USPI [12] or 
applicable labeling. Appropriate institutional practices consistent with the rituximab label and 
recommendations should be followed. 
8.6.2
Additional Concomitant Medications and Procedures

Additional concomitant medications and procedures are permitted during the course of the 
study (please refer to Section 8.8) to prevent and actively manage AEs related or not related 
to the study drug(s) unless otherwise specified in Section 8.5.
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8.7
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.
For patients in the bendamustine or bendamustine + rituximab combination arms (Cohorts A and 
B), caution should be used or alternative treatments considered if concomitant treatment with 
CYP1A2 inhibitors or inducers is needed (see Appendix H).
It is not known what effects TAK-659 has on human pregnancy or development of the embryo or 
fetus when administered in combination with bendamustine, rituximab, gemcitabine, 
lenalidomide, or ibrutinib; therefore, female patients participating in this study should avoid 
becoming pregnant, and male patients should avoid impregnating a female partner. Nonsterilized 
female patients of reproductive age and male patients should use effective methods of 
contraception throughout defined periods during and after study treatment as specified below.
Female patients must meet 1 of the following: 

Postmenopausal for at least 1 year before the screening visit, OR

Surgically sterile, OR

If they are of childbearing potential, agree to practice 1 highly effective method of 
contraception and 1 additional effective (barrier) method (see Appendix F) at the same time, 
from the time of signing of the ICF through 180 days after the last dose of study drug (or 
12 months after the last dose of study drug for patients in the rituximab combination arm), 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.)
Female patients should not donate ova from the time of signing the informed consent through 
180 days after the last dose of study drug.
Male patients should not donate sperm from the time of signing the informed consent through 
180 days after the last dose of study drug.
Male patients, even if surgically sterilized (ie, status postvasectomy) 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 12 months after the last dose of study drug for 
patients in the rituximab combination arm), 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 
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methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.)

For both men and women in the rituximab combination arm (Cohort B): patients must 
practice contraception as described above from the time of signing of the ICF through 
12 months after the last dose of study drug.

For both men and women in the lenalidomide combination arm (Cohort D): patients must 
adhere to the guidelines of the RevAssist program (US participants) or the Lenalidomide 
Pregnancy Risk Minimisation Plan as outlined in the study manual (all other participants who 
are not using commercial supplies). For additional precautions and restrictions for each of the 
combination arms, please see the applicable USPIs [11-13,15-17] or applicable labeling.
8.8
Management of TAK-659–Related Clinical Events
Therapies that are required to manage AEs and control cancer symptoms are allowed based on 
standard clinical practice, unless specifically excluded. Supportive care agents, such as 
erythropoietin, G-CSF, blood products (RBC and platelet transfusions), and pain medications are 
permitted as needed per American Society of Hematology (ASH)/ASCO guidelines or local 
institutional practice. However, these agents should not be used in this study in a manner that 
would either help establish eligibility for the study or support escalation of study drug dose 
during dose escalation. The combination drugs are associated with various AEs, which may be 
managed per clinical judgment of the investigator in accordance with the institutional guideline 
and the most recent USPI [11-13,15-17] or applicable labeling for each drug. Additional 
treatment algorithms for use in conjunction with clinical judgment are provided below. If dose 
modification of study drug(s) is necessary as a result of the events detailed below, please refer to 
Section 8.4.
8.8.1
Prophylaxis Against Infection
Patients with advanced hematologic 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 or per National Comprehensive Cancer Network 
Prevention and Treatment of Cancer-Related Infections Guidelines. In particular, lymphopenia 
can develop in association with either treatment or with the underlying disease (lymphoma). 
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. It is recommended that prophylaxis for varicella-
zoster virus should be administered for Cohort B [19].
Given their degree of immunosuppression, subjects with posttransplant lymphoproliferative 
disease are often at an increased risk of developing infections. Consideration should be given to 
antibiotic, antifungal, and antiviral prophylaxis during therapy, particularly if the subject is more 
prone to developing neutropenia. Subjects who develop neutropenic fever should be evaluated 
promptly and treated immediately with parental antibiotics tailored to the prominent organisms 
and resistance patterns of the institution.
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8.8.1.1
CMV Monitoring and Prophylaxis
At screening, on Day 1 of each treatment cycle, and at end of treatment (EOT), all subjects 
should have CMV serology and/or quantitative polymerase chain reaction (PCR) assay 
performed. If positive at any timepoint, CMV monitoring is advised once a week with a decrease 
to once every cycle as it becomes negative. Interruption of study drug is generally advised if the 
positive CMV test is accompanied by associated clinical symptoms, if the copy number reaches a 
level indicates a need for treatment per institutional standard, or if the CMV test remains positive 
despite the antiviral treatment for CMV. Further monitoring and prophylactic or preemptive 
therapy for asymptomatic patients, if indicated, should follow the institutional standard practice. 
The following agents should be considered for prophylaxis or pre-emptive treatment against 
CMV: ganciclovir (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 per PCR. 
8.8.1.2
Prophylaxis for Opportunistic Infections
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 is 
present: 

Absolute CD4+ T-cell count of <200/mm3.

Percent CD4+ T-cells <20%.

Prior episode of PJP in medical history. 
It is recommended that the prophylaxis for PJP should be implemented in Cohort B regardless of 
the above-mentioned conditions [19]. 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 coadministered. 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.
8.8.2
Pneumonitis
Patients with serious lung events who do not respond to conventional antimicrobial therapy 
should be assessed for drug-induced pneumonitis after ruling out infectious causes and 
alternative etiologies. If pneumonitis is suspected, TAK-659 treatment should be interrupted, and 
the patient treated per standard of care. If pneumonitis is moderate/severe, discontinue TAK-659. 
Patients should be monitored for respiratory signs and symptoms throughout treatment and be 
advised to promptly report respiratory symptoms.
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8.8.3
Nausea and/or Vomiting
This study will not initially employ prophylactic antiemetics before the first dose of the study 
drug during dose escalation, unless part of the local standard of care for administration of a 
combination agent (eg, bendamustine, gemcitabine). However, a patient who develops nausea 
and/or vomiting will be actively managed by employing optimal antiemetic treatment based on 
local standard practice. Additionally, antiemetics may be used prophylactically as clinically 
indicated following the occurrence of a first event of study drug-related or possibly related 
nausea and/or vomiting. An optimal antiemetic regimen is defined as one that employs both a 
5-HT3 serotonin receptor antagonist and a corticosteroid given in standard doses and according 
to standard schedules. 
8.8.4
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 per the dose modification guidelines in Table 8.j and Table 8.l.
8.8.5
Rash With or Without Pruritus
Prophylactic measures should also be considered if a patient develops a rash (eg, using a thick, 
alcohol-free emollient cream on dry areas of the body). In the case of rash, the use of a topical or 
oral steroid (eg, prednisone ≤10 mg per day or equivalent) is permitted. Treatment with 
TAK-659 must be withheld in the event of Grade 3 or 4 rash. Refer to dose modification 
guidelines in Table 8.j and Table 8.l.
8.8.6
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 drugs and during treatment.
8.8.7
Anemia, Thrombocytopenia, and/or Neutropenia
Hemoglobin and blood counts should be monitored regularly as outlined in Appendix A, with 
additional testing obtained according to standard clinical practice. Administration of TAK-659 
and combination drugs should be modified per dose modification guidance in the protocol when 
anemia, thrombocytopenia, or neutropenia occur (see Table 8.i and Table 8.k). RBC transfusion 
and use of erythropoietin to manage severe anemia, platelet transfusion to prevent and minimize 
bleeding in case of severe thrombocytopenia, and myeloid growth factor (eg, G-CSF, GM-CSF) 
support to treat severe and/or febrile neutropenia are permitted per ASH/ASCO guidelines, as 
necessary. However, it should be noted that prophylactic use of myeloid growth factors should 
be avoided during the first cycle of dose escalation (see Section 8.5).
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8.8.8
Hypophosphatemia
Hypophosphatemia has been observed in patients treated with TAK-659. Consider prophylaxis; 
otherwise, refer to dose modification guidelines in Table 8.j and Appendix H.
8.8.9
Enzyme Elevations
8.8.9.1
Transaminase, Amylase and Lipase, and CPK Elevations
Elevations of the enzymes above have been observed. Events are generally asymptomatic and 
reversible with dose interruption. See dose modification guidelines in Table 8.j.
8.8.9.2
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 doses have 
been interrupted because of increased LDH; however, LDH elevations have been observed to be 
reversible in patients who had TAK-659 interrupted for other reasons. 
8.8.10 Fluid Deficit
Fluid deficit should be corrected before initiation of study drug and during treatment.
8.9
Management of Combination Drug-Related Clinical Events
Clinical characteristics and risk mitigation measures addressing each of the important 
combination drug–related clinical events are summarized below. Refer to the most recent USPI 
[11-13,15-17] or applicable labeling for each drug for further details.
8.9.1
Infusion Reactions
Severe infusion reactions have been reported in clinical trials of bendamustine and rituximab and 
can manifest with a variety of symptoms, including fever, chills, rigors, headache, rash, pruritus, 
arthralgias, hypotension or hypertension, bronchospasm, and others. All Grade 3 or 4 infusion 
reactions should be reported within 24 hours to the medical monitor and reported as an SAE if 
criteria are met. Infusion reactions should be graded according to NCI CTCAE version 4.03 
guidelines [1].Treatment recommendations for all infusion reactions from bendamustine and 
rituximab in accordance with USPI [12] or applicable labeling guidelines are provided below and 
may be modified based on local treatment standards and guidelines as clinically appropriate.
Infusion reaction symptoms for bendamustine include fever, chills, pruritus, and rash. In rare 
instances, severe anaphylactic and anaphylactoid reactions have occurred, particularly in the 
second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe 
reactions. Ask patients about symptoms suggestive of infusion reactions after their first cycle of 
therapy. Patients who experience Grade 3 or worse allergic-type reactions should not be 
rechallenged. Consider measures to prevent severe reactions, including antihistamines, 
antipyretics, and corticosteroids in subsequent cycles in patients who have experienced Grade 1 
or 2 infusion reactions. Discontinue bendamustine for patients with Grade 4 infusion reactions. 
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Consider discontinuation for Grade 3 infusion reactions as clinically appropriate considering 
individual benefits, risks, and supportive care.
Rituximab can cause severe, including fatal, infusion reactions. Severe reactions typically occur 
during the first infusion with a time to onset of 30 to 120 minutes. Rituximab-induced infusion 
reactions and sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, 
pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular 
fibrillation, cardiogenic shock, anaphylactoid events, and death. Premedicate patients with an 
antihistamine and acetaminophen before dosing. Institute medical management 
(eg, glucocorticoids, epinephrine, bronchodilators, oxygen) for infusion reactions as needed. 
Depending on the severity of the infusion reaction and the required interventions, temporarily or 
permanently discontinue rituximab. Resume infusion at a minimum 50% reduction in rate after 
symptoms have resolved. Closely monitor the following patients: those with pre-existing cardiac 
or pulmonary conditions, those who experienced prior cardiopulmonary adverse reactions, and 
those with high numbers of circulating malignant cells (≥25,000/mm). 
8.9.2
Cohorts A and B (Bendamustine-Related) Clinical Events
Please refer to the most recent Treanda USPI [11], Bendeka USPI [17], or applicable local 
bendamustine labeling for more information on bendamustine-related clinical events, such as 
severe skin reactions, extravasation injury, etc, and for the management of clinical events in 
patients receiving bendamustine.
8.9.3
Cohort B (Rituximab-Related) Clinical Events
Please refer to the most recent rituximab USPI [12] or applicable labeling for more information 
on rituximab-related clinical events, such as severe mucocutaneous reactions, hepatitis B virus 
reactivation, progressive multifocal leukoencephalopathy, etc, and for the management of 
clinical events in patients receiving rituximab.
8.9.4
Cohort C (Gemcitabine-Related) Clinical Events
Please refer to the most recent gemcitabine USPI [13] or applicable labeling for more 
information on gemcitabine-related clinical events, such as unexplained dyspnea or other 
evidence of severe pulmonary toxicity, hemolytic-uremic syndrome, capillary leak syndrome, 
etc, and for the management of clinical events in patients receiving gemcitabine.
8.9.5
Cohort D (Lenalidomide-Related) Clinical Events
Please refer to the most recent lenalidomide USPI [15] or applicable labeling for more 
information on lenalidomide-related clinical events, such as venous and arterial thromboembolic 
events, tumor flare reactions, etc, and for the management of clinical events in patients receiving 
lenalidomide.
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8.9.6
Cohort E (Ibrutinib-Related) Clinical Events
Please refer to the most recent ibrutinib USPI [16] or applicable labeling for ibrutinib-related 
clinical events such as hemorrhage, infections, cytopenias, atrial fibrillation, tumor lysis 
syndrome, etc, and for the management of clinical events in patients receiving ibrutinib.
8.10
Blinding and Unblinding
This is an open-label study.
8.11
Description of Investigational Agents
8.11.1 Description of TAK-659
TAK-659 has been formulated into immediate-release, film-coated tablets for use in phase 1 
clinical studies via a common granulation process. Three different tablet dosage strengths, 
20, 60, 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. 
8.11.2 Description of Bendamustine
Bendamustine is a commercially available drug and will be procured or distributed according to 
the pharmacy manual. Bendamustine is supplied as 100 mg/4 mL (25 mg/mL) in a multiple-dose 
vial or 100 mg lyophilized powder in a 20 mL single-dose vial for reconstitution. Only 1 
formulation should be used for each patient, and the formulation used should be consistent with 
local practice guidelines. Please refer to the most recent Treanda USPI [11], Bendeka USPI [17], 
or applicable local bendamustine labeling.
8.11.3 Description of Rituximab
Rituximab is a commercially available drug and will be procured or distributed according to the 
pharmacy manual. Rituximab is provided as 100 mg/10 mL or 500 mg/50 mL solution for 
injection in a single-dose vial. Please refer to the most recent rituximab USPI [12] or applicable 
labeling.
8.11.4 Description of Gemcitabine
Gemcitabine is a commercially available drug and will be procured or distributed according to 
the pharmacy manual. Gemcitabine is provided as 200 mg lyophilized powder in a 10 mL single-
use vial or 1 g lyophilized powder in a 50 mL single-use vial for injection. Please refer to the 
most recent gemcitabine USPI [13] or applicable labeling.
8.11.5 Description of Lenalidomide
Lenalidomide is a commercially available drug supplied as 25 mg capsules and will be procured 
or distributed according to the pharmacy manual. Please refer to the most recent lenalidomide 
USPI [15] or applicable labeling.
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8.11.6 Description of Ibrutinib
Ibrutinib is a commercially available drug supplied as 140 mg capsules and will be procured or 
distributed according to the pharmacy manual. Please refer to the most recent ibrutinib USPI [16]
or applicable labeling.
8.12
Preparation, Reconstitution, and Dispensation
Parenteral drug products should be inspected visually for particulate matter and discoloration 
before administration, whenever solution and container permit.
8.12.1 TAK-659 Preparation, Reconstitution, and Dispensation
Detailed instructions for dispensing TAK-659 immediate-, 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.
8.12.2 Bendamustine Preparation, Reconstitution, and Dispensation
Bendamustine is a commercially available drug supplied as a solution for injection and will be 
procured or distributed according to the pharmacy manual. Please refer to the most recent 
Treanda USPI [11], Bendeka USPI [17], or applicable local bendamustine labeling. 
8.12.3 Rituximab Preparation, Reconstitution, and Dispensation
Rituximab is a commercially available drug supplied as a solution for injection and will be 
procured or distributed according to the pharmacy manual. Please refer to the most recent 
rituximab USPI [12] or applicable labeling. 
8.12.4 Gemcitabine Preparation, Reconstitution, and Dispensation
Gemcitabine is a commercially available drug supplied as a solution for injection and will be 
procured or distributed according to the pharmacy manual. Please refer to the most recent 
gemcitabine USPI [13] or applicable labeling. 
8.12.5 Lenalidomide Preparation, Reconstitution, and Dispensation
Lenalidomide is a commercially available drug supplied as 25 mg capsules and will be procured 
or distributed according to the pharmacy manual. Please refer to the most recent lenalidomide 
USPI [15] or applicable labeling. 
8.12.6 Ibrutinib Preparation, Reconstitution, and Dispensation 
Ibrutinib is a commercially available drug supplied as 140 mg capsules and will be procured or 
distributed according to the pharmacy manual. Please refer to the most recent ibrutinib USPI [16]
or applicable labeling. 
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8.13
Packaging and Labeling
8.13.1 TAK-659 Packaging and Labeling
TAK-659 20, 60, and 100 mg and additional dose strength 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 multi-language label containing pertinent study information, country-specific 
requirements, and a caution statement. 
8.13.2 Bendamustine Packaging and Labeling
Bendamustine will be supplied to the site from commercial sources. Please refer to the most 
recent Treanda USPI [11], Bendeka USPI [17], or applicable local bendamustine labeling. 
8.13.3 Rituximab Packaging and Labeling
Rituximab will be supplied to the site from commercial sources. Please refer to the most recent 
rituximab USPI [12] or applicable labeling. 
8.13.4 Gemcitabine Packaging and Labeling
Gemcitabine will be supplied to the site from commercial sources. Please refer to the most recent 
gemcitabine USPI [13] or applicable labeling. 
8.13.5 Lenalidomide Packaging and Labeling
Lenalidomide will be supplied to the site from commercial sources. Please refer to the most 
recent lenalidomide USPI [15] or applicable labeling. 
8.13.6 Ibrutinib Packaging and Labeling
Ibrutinib will be supplied to the site from commercial sources. Please refer to the most recent 
ibrutinib USPI [16] or applicable labeling. 
8.14
Storage, Handling, and Accountability
8.14.1 TAK-659 Storage, Handling, and Accountability
TAK-659 tablets should be stored in the original dispensing bottles at 1°C to 25°C (33.8°F-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 and/or accompanying 
documentation. Throughout the duration of the clinical trial, the stability of the drug product will 
be monitored. TAK-659 tablets should remain in the original bottle provided to the 
investigational site and patients. Drug supply must be kept in an appropriate, limited access, 
secure place until it is dispensed to the enrolled patients.
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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. In the case of contact of 
damaged tablets with the eyes or skin, there should be immediate and thorough flushing and 
washing 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 
TAK-659 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.
8.14.2 Bendamustine Storage, Handling, and Accountability
Bendamustine should be stored according to instructions provided in the manufacturer’s Treanda 
USPI [11], Bendeka USPI [17], or applicable local bendamustine labeling. 
8.14.3 Rituximab Storage, Handling, and Accountability
Rituximab should be stored according to instructions provided in the manufacturer’s USPI [12]
or applicable labeling. 
8.14.4 Gemcitabine Storage, Handling, and Accountability
Gemcitabine should be stored according to instructions provided in the manufacturer’s USPI [13]
or applicable labeling. 
8.14.5 Lenalidomide Storage, Handling, and Accountability
Lenalidomide should be stored according to instructions provided in the manufacturer’s USPI 
[15] or applicable labeling. 
8.14.6 Ibrutinib Storage, Handling, and Accountability
Ibrutinib should be stored according to instructions provided in the manufacturer’s USPI [16] or 
applicable labeling.
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9.0
STUDY CONDUCT
This trial will be conducted in compliance with the protocol, GCP, applicable regulatory 
requirements, and ICH guidelines.
9.1
Study Personnel and Organizations
The contact information for the sponsor study monitor 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, refer to the study manual.
9.2
Arrangements for Recruitment of Patients
Recruitment and enrolment 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). 
9.3
Treatment Group Assignments
This is a phase 1, dose escalation study. Patients will be assigned to a dose cohort based on the 
dose escalation rules described in Section 8.3.
9.4
Study Procedures
Patients will be evaluated at scheduled visits over the following study periods: screening, 
treatment, and end of treatment (EOT). Evaluations during the screening period are to be 
conducted within 28 days before administration of the first dose of study drug. Procedures 
conducted during the screening period that are performed within 3 days of Cycle 1 Day 1 may 
also be used as the predose evaluation and do not need to be repeated, unless otherwise specified. 
Unless otherwise noted, evaluations during the treatment period must occur before study drug 
administration on scheduled visits. Tests and procedures should be performed on schedule for all 
visits. The timing of PK and pharmacodynamic assessments is specified in the Schedule of 
Events Appendix A, Table 3 and Table 4) and is not flexible. Laboratory assessments and 
procedures may occur up to 3 days before the scheduled day due to extenuating circumstances 
(ie, inclement weather, holidays, vacations, or other administrative reasons).
Refer to the Schedule of Events (Appendix A) for the timing of assessments for 21-Day cycles 
(Cohorts A, B, and C; Appendix A, Table 1) and for 28-Day cycles (Cohorts D and E; 
Appendix A, Table 2). Additional details are provided as necessary in the sections that follow.
9.4.1
Informed Consent
Each patient must provide written informed consent before any study-required procedures are 
conducted, unless those procedures are performed as part of the patient’s standard care.
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9.4.2
Patient Demographics
The age, race, ethnicity, and sex of the patient are to be recorded during screening.
9.4.3
Medical History
During the screening period, a complete medical history, including smoking history, will be 
compiled for each patient. The history will emphasize the background and progress of the 
patient’s malignancy and include a description of prior therapies for it. In addition, concomitant 
medications will be recorded as specified in Section 9.4.9. During dose expansion, medical 
history will also include baseline disease characteristics such as staging, risk/prognostic index, 
and other individual prognostic evaluations.
9.4.4
Physical Examination
A physical examination will be conducted per standard of care at the times specified in the 
Schedule of Events (Appendix A, Table 1 and Table 2). Complete physical examinations will be 
performed at screening, Day 1 of each cycle of treatment, and EOT. Symptom- or 
finding-directed physical examinations will be performed at all other visits specified in the 
Schedule of Events (Appendix A, Table 1 and Table 2).
9.4.5
Patient Height
Height will be measured only during screening (within 28 days before the first dose of study 
drug).
Weight will be measured during the times specified in the Schedule of Events (Appendix A, 
Table 1 and Table 2).
9.4.6
Vital Signs
Vital sign measurements include diastolic and systolic blood pressure, heart rate, temperature, 
and oxygen saturation, and will be assessed as specified in the Schedule of Events (Appendix A, 
Table 1 and Table 2). Blood pressure should be determined with the patient in a seated position 
after the patient has been sitting quietly for approximately 5 minutes.
9.4.7
ECOG Performance Status
ECOG performance status is to be assessed at the times specified in the Schedule of Events 
(Appendix A, Table 1 and Table 2).
9.4.8
ECG
A 12-lead, singlet ECG will be performed and interpreted locally at the time points specified in 
the Schedule of Events (Appendix A, Table 1 and Table 2). 
All scheduled ECGs should be performed predose, unless otherwise specified in Appendix A, 
Table 3 and Table 4 for Cycle 1, 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 
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timing of ECG measurements, the ECG will be completed before the collection of the blood 
sample. 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 (QTcF, 
Bazett’s corrected QT interval) should be performed. Estimates of QTc for study eligibility 
should use QTcF. If a QTcF value confirmed by a qualified reader is >475 msec for a woman or 
>450 msec for a man, an evaluation to determine etiology should be conducted. If the prolonged 
QTc finding can be corrected by changing medication and/or correcting electrolyte 
abnormalities, and a repeat ECG meets eligibility requirements, the patient may enroll in the 
study upon review and agreement by the sponsor’s clinician. 
Following initiation of treatment, if a QTc value is confirmed by a qualified reader as >500 msec 
or >60 msec elevated from baseline for any ECG, the following will occur: 
a) The sponsor’s clinician will be promptly notified.
b) Study treatment should be held, and an evaluation should be conducted to correct other 
possible causes (eg, electrolyte disturbance, concomitant medication).
c) 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 to reinitiate study treatment with or without dose reduction (dose reduction 
applicable to TAK-659 only) and additional monitoring in those patients who had asymptomatic 
prolonged QTc >500 msec or >60 msec from baseline (Grade 3) that has reverted to an 
acceptable interval, have previously tolerated study treatment, and appear to have benefited from 
study treatment with either disease control or response must be agreed upon 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.
9.4.9
Concomitant Medications and Procedures
Concomitant medications and procedures will be recorded in the eCRF from the time of the 
signing of the ICF through 28 days after the last dose of study drug or the start of subsequent 
antineoplastic therapy, whichever occurs first. See Section 8.5 for a list of excluded concomitant 
medications and procedures to be avoided during the study unless otherwise specified.
Concomitant medications and procedures will be recorded in the eCRF from the time of the 
signing of the ICF through 28 days after the last dose of study drug or the start of subsequent 
antineoplastic therapy, whichever occurs first. See Section 8.5 and Section for a list of excluded 
concomitant medications and procedures. 
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AEs
Monitoring of AEs, serious and nonserious, will be conducted throughout the study as specified 
in the Schedule of Events (Appendix A, Table 1 and Table 2). Refer to Section 10.0 for details 
regarding definitions, documentation, and reporting of pretreatment events (PTEs), AEs, and 
SAEs. 
9.4.10 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.
9.4.11 Clinical Laboratory Evaluations
Clinical laboratory evaluations will be performed locally. Handling and shipment of clinical 
laboratory samples are outlined in the study and laboratory manuals. Clinical laboratory 
evaluations will be performed as outlined below:
9.4.11.1 Clinical Chemistry, Hematology, and Urinalysis
Blood samples for analysis of the clinical chemistry and hematological parameters shown in 
Table 9.a and urine samples for analysis of the parameters shown in 
Table 9.b will be obtained as specified in the Schedule of Events Appendix A, Table 1 and 
Table 2).
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
AST
Amylase
Bilirubin (total)
Blood urea nitrogen (BUN)
Calcium
Carbon dioxide (CO2)
Chloride
Creatinine
Creatine phosphokinase (CPK)
γ-glutamyl transferase (GGT)
Glucose (fasting)
Lactate dehydrogenase (LDH)
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 Cockcroft-Gault formula will be employed as 
follows (see also Appendix E):
For female patients, the result of the formula above should be multiplied by 0.85. 
9.4.12 Pregnancy Test
A serum pregnancy test will be performed for WOCBP at screening. For WOCBP, a urine 
pregnancy test must be performed predose on Day 1 of all cycles with negative results available 
before the first dose of TAK-659 is administered for that cycle. If a serum pregnancy test is 
performed within 3 days before dosing and the result is negative, the urine pregnancy test may be 
waived on Cycle 1 Day 1. For WOCBP, a urine pregnancy test also will be performed at EOT.

For men and women both in Cohort D (TAK-659 + lenalidomide), patients must adhere to 
the guidelines of the RevAssist program (US participants) or the Lenalidomide Pregnancy 
Risk Minimisation Plan as outlined in the study manual (all other participants who are not 
using commercial supplies). For additional precautions and restrictions for each of the 
combination arms, please see the applicable USPIs [11-13,15-17] or applicable labeling.
9.4.13 Ophthalmic Exam
A slit lamp eye examination will be performed by an ophthalmologist at screening; on Cycle 2 
Day 1; on Cycle 7 Day 1; every 6 cycles thereafter (2 weeks); and at EOT. Based on 
nonclinical toxicology findings with TAK-659 in rats, slit lamp examinations should focus on 
detecting any posttreatment changes in ocular lens. 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.
9.4.14 Disease Assessment
Patients will undergo radiographic evaluation and symptom assessment to monitor and assess 
disease response. Response assessment will follow revised response criteria for malignant 
lymphoma per IWG 2007 criteria [2]. CT scans (with contrast) of the neck (if appropriate), chest, 
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abdomen, and pelvis will be performed at screening/baseline (within 28 days before the first 
study drug administration), at the end of every other cycle through Cycle 6 and at the end of 
every 3 cycles thereafter (until PD or the start of alternative therapies), and at the EOT visit. For 
patients with FL or MZL in the Cohort B expansion phase, response will continue to be assessed 
during PFS follow-up every 2 months for patients who discontinue treatment for reasons other 
than PD until 6 months after the last dose or occurrence of PD, whichever occurs first. An FDG-
PET scan extending from the neck through the mid thighs will be performed at baseline. If the 
screening FDG-PET scan is positive, FDG-PET scans should be repeated either at the time of 
assessment for CR or for recurrence/progression of disease unless otherwise specified per local 
standard of care for a given lymphoma subtype. If the screening FDG-PET scan is negative, 
additional FDG-PET scans do not need to be conducted but could be performed as clinically 
indicated during the study. PET/CT scans may be used as the source of the CT scan, but the CT 
component should be performed with IV contrast unless contraindicated. The same imaging 
modality should be used consistently throughout the study to monitor the disease status.
For patients with cutaneous T-cell lymphoma, investigator assessment will be based on a 
composite assessment of total tumor burden including cutaneous disease, lymph node 
involvement, and blood (Sézary cells).
Two modifications to the IWG 2007 criteria will be instituted in this study: 1) When assessing 
response, special consideration should be given to a situation where a patient may have had study 
drug held between the 2 scheduled imaging scans for 2 weeks because of an AE or other 
circumstances. If at the time of response assessment, a patient shows metabolic changes by PET 
(ie, increased or new FDG uptake) that are not consistent with lesion changes indicative of 
progression by CT scan, discontinuation of study treatment is not recommended. Rather, it is 
recommended that the patient receive an additional cycle of treatment and that another response 
assessment is performed at the end of that cycle. If the metabolic changes by PET (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 by PET resolve and there is no 
indication of PD by CT or other, then the patient may remain on study; and 2) If PET-CT 
indicates bone marrow involvement at baseline, bone marrow biopsy is not required. Negative 
FDG-PET avidity is adequate to confirm CR in these patients. If FDG-PET does not suggest 
baseline bone marrow involvement, a bone marrow biopsy is then required, and rebiopsy to
confirm CR is also needed.
9.4.15 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, Table 1 and Table 2). All CT scans should be performed with 
IV contrast, and abdominal and pelvic CT scans should also be performed with oral contrast
unless 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 
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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 is 
performed before the CT with IV contrast to avoid compromising the PET results.
9.4.16 PET Scans
A PET scan with FDG extending from the neck through the mid thighs will be performed to 
assess baseline disease at screening and to assess disease response at the end of Cycle 2 and 
Cycle 4. Examinations should be consistent across all time points, including amount of tracer, 
location of injection, arm position, and scan delay. If, however, the screening FDG-PET scan is 
negative, FDG-PET scans need not be performed at Cycles 2 and 4. After Cycle 4, PET scans 
will be performed only if needed to follow the disease, confirm the CR or PD status, or as 
indicated clinically. PET scans will be interpreted locally; central review of radiology will not be 
performed in this study. Note that if a patient achieves CR, PET scans are not required at 
subsequent assessments. The peak standardized uptake value (SUV) will be determined within 
the most FDG-avid metastases by the local nuclear medicine physician after initial qualitative 
assessment of the baseline PET scan and correlation with CT scan to confirm metastasis. 
Site-specific SUV will be accepted, and the highest SUV will be recorded.
9.4.17 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 identified on 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 end of study (optional to patients) if the initial 
biopsy was positive and a response has been achieved but relapse subsequently documented.
All scans and bone marrow test results will be interpreted locally. When possible, the same 
qualified physicians will interpret results to reduce variability. Radiographic images will be 
maintained at the site. Based on efficacy data observed, the sponsor can elect to have central 
collection of disease assessment images for other cohorts. Test results and physician findings 
will be filed in patient source documents. In the event of antitumor response, the sponsor may 
request electronic images for those patients who demonstrate tumor reduction. Objective 
response data collected for the CSR will be based on investigator assessment. 
CCI
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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9.4.21 PK Measurements
The primary aim of PK sampling in this study is to measure the plasma concentrations of 
TAK-659. However, pending technical feasibility, plasma samples for TAK-659 PK assessments 
may additionally be used for exploratory identification and profiling of TAK-659 metabolites to 
increase understanding of TAK-659 metabolism and clearance. If technically feasible, these 
plasma samples also could be used for exploratory measurement of bendamustine, rituximab, 
gemcitabine, lenalidomide, and ibrutinib concentrations if considered appropriate based on 
emerging study findings (eg, if the incidence and severity of toxicity observed with combination 
drug is higher than anticipated). 
Details on the collection, storage, processing, handling, and shipping of the PK samples are 
provided in the laboratory manual.
Blood samples for determination of TAK-659 plasma concentrations in the dose escalation and 
safety expansion phases will be obtained at the times indicated in Appendix A, Table 3 and 
Table 4. PK samples will be collected at prespecified time points relative to the dosing time of 
TAK-659. For example, the 24-hour postdose PK sample should be collected 24 hours (±1 hour) 
after the TAK-659 dose, not 24 hours after the combination drug dose. The samples obtained on 
Days 2 and 16 (approximately 24 hours after the Day 1 and 15 doses, respectively) should be 
obtained before TAK-659 dosing on those days. The predose samples on Day 8 and Day 15 also 
should be obtained before TAK-659 dosing on those days. On days with predose samples (or 
24 hours postdose from the previous samples), patients should be instructed to refrain from 
taking their doses of TAK-659 (and lenalidomide and ibrutinib) at home before the clinic visit. 
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9.4.23 CMV Testing
A blood sample will be obtained during screening, on Day 1 of each cycle, and at the EOT 
visit, as indicated in the Schedule of Events (Appendix A, Table 1 and Table 2) for the 
determination of CMV replication. 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.
9.5
Completion of Study Treatment (for Individual Patients)
Patients will be considered to have completed the study treatment when they have discontinued 
treatment with TAK-659.
9.6
Discontinuation of Treatment With Study Drug 
Treatment with study drug may be discontinued for any of the following reasons: 
!
AE, including patients who experience a DLT (during escalation) during the first cycle, 
patients with Grade 4 nonhematologic toxicity, patients with Grade 4 anemia, and patients 
with other drug-related AEs that require study drug discontinuation per dose modification 
guidelines in Section 8.4 and the USPIs [11-13,15-17] or applicable labeling for the 
combination drugs. Discontinuation of treatment occurs only when both study drugs are 
required to be discontinued due to AEs. 
!
Protocol deviations.
!
PD.
!
Occurrence of pregnancy (if applicable).
!
Symptomatic deterioration (at investigator’s discretion). 
!
Unsatisfactory therapeutic response. 
!
Initiation of hematopoietic stem cell transplant
!
Withdrawal of consent by patient.
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
In the opinion of the investigator, continued use of study drug is no longer in the patient’s 
best interests.

Lost to follow-up.

Study terminated by sponsor.

Other.
During the dose escalation phase, patients who are withdrawn from treatment during Cycle 1 for 
reasons other than DLT will be replaced. 
In the event of pregnancy, female subjects must discontinue use of study drugs. 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, Table 1 and Table 2). The primary reason for 
study drug discontinuation will be recorded on the eCRF. 
9.7
Withdrawal of Patients From Study
A patient may be withdrawn from the study for any of the following reasons:

AE.

Protocol deviation.

Due to pregnancy.

PD. 

Symptomatic deterioration (at investigator’s discretion).

Unsatisfactory therapeutic response. 

Study terminated by sponsor.

Withdrawal of consent by patient.

In the opinion of the investigator, continued participation is no longer in the patient’s best 
interests.

Lost to follow-up.

Other.
In the event of pregnancy, female subjects must be discontinued from the study. 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.
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9.8
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 
subjects.

Poor enrollment of subjects, 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.
9.9
Study Compliance
Study drug will be administered or dispensed only to eligible patients under the supervision of 
the investigator or identified subinvestigator(s). The appropriate study personnel will maintain 
records of study drug receipt and dispensing. Patients will be given a diary to record TAK-659 
dosing. The dosing diary will provide supporting information, if necessary. The study center staff 
will check the patient drug diary versus the patient’s supply of TAK-659 tablets to assess 
compliance.
Tests and procedures should be performed on schedule, but unless otherwise specified, 
occasional changes are allowable within a 3-day window for holidays, vacations, and other 
administrative reasons. The timing of PK and pharmacodynamics assessments as specified in the 
Schedule of Events (Appendix A, Table 3 and Table 4) is not flexible. 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 sponsor clinician or designee.
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.
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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 or patient who has signed informed 
consent to participate in a study but before administration of any study medication; it does not 
necessarily have to have a causal relationship with study participation.
10.1.2 AE Definition
AE means any untoward medical occurrence in a patient or patient administered a 
pharmaceutical product; the untoward medical occurrence does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product whether or not it is related to the medicinal product. 
This includes any newly occurring event, or a previous condition that has increased in severity or 
frequency since the administration of study drug.
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is 
considered by the investigator to be a clinically significant change from baseline.
10.1.3 SAE Definition
SAE means any untoward medical occurrence that at any dose:
a) Results in death.
b) Is life-threatening (refers to an AE in which the patient was at risk of death at the time of the 
event. It does not refer to an event which hypothetically might have caused death if it were 
more severe).
c) Requires inpatient hospitalization or prolongation of an existing hospitalization
(see clarification in the paragraph in Section 10.2 on planned hospitalizations).
d) 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).
e) Is a congenital anomaly/birth defect.
f)
Is a medically important event. This refers to an AE that may not result in death, be 
immediately life-threatening, or require hospitalization, but may be considered serious when, 
based on appropriate medical judgment, may jeopardize the patient, require medical or 
surgical intervention to prevent 1 of the outcomes listed above, or involves suspected 
transmission via a medicinal product of an infectious agent. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, 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 transmitting transmissible spongiform encephalopathy), pathogenic or 
nonpathogenic, is considered an infectious agent.
In this study, intensity for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE version 4.03, effective 14 June 2010 [1]. Clarification should be made between an 
SAE and an AE that is considered severe or life-threatening 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 
or life-threatening 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
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 lab abnormality, will be determined using the NCI CTCAE 
version 4.03, effective 14 June 2010 [1]. 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: 
a) AEs will be reported from the time of signing of the ICF through 28 days after administration 
of the last dose of study drug or to the start of subsequent anticancer therapy, whichever 
occurs first, and recorded in the eCRFs. 
b) Serious PTEs will be reported to the Takeda Global Pharmacovigilance department or 
designee from the time of the signing of the ICF up to first dose of study drug.
c) 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 eCRF. After this period, only related SAEs 
must be reported to the Takeda Global Pharmacovigilance department or designee. SAEs 
should be monitored until they are resolved or are clearly determined to be due to a patient’s 
stable or chronic condition or intercurrent illness(es).
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Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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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 e-mail addresses provided below.
A medication error is a preventable event that involves an identifiable patient and that leads to 
inappropriate medication use, which may result in patient harm. Whereas overdoses and 
underdoses constitute medication errors, doses missed inadvertently by a patient do not. 
Individuals who identify a potential medication error (including overdose) situation should 
immediately report this via the phone numbers or e-mail addresses provided below.
Call Center
Phone number
E-mail
Fax
Product complaints or medication errors in and of themselves are not AEs. If a product complaint 
or a medication error results in an SAE, an SAE form should be completed and sent to 
 
(see 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 (EMA), 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 days for fatal and 
life-threatening events and 15 days for other serious events, unless otherwise required by 
national regulations. The sponsor will also prepare an expedited report for other safety issues 
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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 
also will forward a copy of all expedited reports to his or her IRB or IEC in accordance with 
national regulations. 
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11.0
STUDY-SPECIFIC COMMITTEES
No steering committee, data safety monitoring committee, or clinical endpoint committee will be 
used in this study.
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12.0
DATA HANDLING AND RECORDKEEPING 
The full details of procedures for data handling will be documented in the Data Management 
Plan. If selected for coding, AEs, PTEs, medical history, and concurrent conditions will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using 
the World Health Organization (WHO) Drug Dictionary.
12.1
eCRFs 
Completed eCRFs are required for each patient who signs an ICF.
The sponsor or its designee will supply investigative sites with access to eCRFs and will make 
arrangements to train appropriate site staff in the use of the eCRF. These forms are used to 
transmit the information collected in the performance of this study to the sponsor, CRO partners, 
and regulatory authorities. Investigative sites must complete eCRFs in English.
After completion of the entry process, computer logic checks will be run to identify items, such 
as inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site. 
Any change of, modification of, or addition to the data on the eCRFs should be made by the 
investigator or appropriate site personnel. Corrections to eCRFs are recorded in an audit trail that 
captures the old information, the new information, identification of the person making the 
correction, the date the correction was made, and the reason for change.
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the principal investigator must retain 
full responsibility for the accuracy and authenticity of all data entered on the eCRFs.
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor or its designee will be permitted to review the patient’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed 
eCRFs are the sole property of the sponsor and should not be made available in any form to third 
parties, except for authorized representatives of appropriate governmental health or regulatory 
authorities, without written permission of the sponsor.
12.2
Record Retention
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating patients, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated ICFs, patient authorization forms regarding the use of 
personal health information (if separate from the ICFs), electronic copy of eCRFs, including the 
audit trail, and detailed records of drug disposition to enable evaluations or audits from 
regulatory authorities, the sponsor or its designees. Any source documentation printed on 
degradable thermal sensitive paper should be photocopied by the site and filed with the original 
in the patient’s chart to ensure long term legibility. Furthermore, ICH E6 Section 4.9.5 requires 
the investigator to retain essential documents specified in ICH E6 (Section 8) until at least 
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2 years after the last approval of a marketing application for a specified drug indication being 
investigated or, if an application is not approved, until at least 2 years after the investigation is 
discontinued and regulatory authorities are notified. In addition, ICH E6 Section 4.9.5 states that 
the study records should be retained until an amount of time specified by applicable regulatory 
requirements or for a time specified in the clinical study site agreement between the investigator 
and sponsor.
Refer to the clinical study site agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of 
any such documents.
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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 database lock. This 
document will provide further details regarding the definition of analysis variables and analysis 
methodology to address all study objectives.
A data review will be conducted before database lock. This review will assess the accuracy and 
completeness of the study database, patient evaluability, and appropriateness of the planned 
statistical methods.
Statistical analyses will be performed separately for each combination arm. Within each 
combination arm, analysis will be done by TAK-659 dose and overall.

Cohort A: TAK-659 + bendamustine.

Cohort B: TAK-659 + bendamustine + rituximab.

Cohort C: TAK-659 + gemcitabine.

Cohort D: TAK-659 + lenalidomide.

Cohort E: TAK-659 + ibrutinib.
13.1.1 Analysis Sets
The analysis sets will include the following:

Safety analysis set: patients who have received at least 1 dose of study drug will be used for 
all safety analyses and for some efficacy analyses.

PK analysis set: patients with sufficient dosing and PK data to reliably estimate 1 or more 
PK parameters will be used for PK analyses.

Response-evaluable analysis set: patients who have received at least 1 dose of study drug, 
have sites of measurable disease at baseline, and 1 post-baseline disease assessment will be 
used for analyses of response.

DLT-evaluable analysis set: patients who have met the minimum treatment and safety 
evaluation requirements of the study or who experience a DLT during Cycle 1. The 
minimum treatment and safety evaluation requirements are met if in Cycle 1 the patient is 
treated with at least 75% of planned dose of TAK-659, is observed for 1 cycle following the 
dose on Cycle 1 Day 1 and is considered to have sufficient safety data by both the sponsor 
and the investigators to conclude that a DLT did not occur.
13.1.2 Analysis of Demographics and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized descriptively. Variables to be 
analyzed include gender, age, race, weight, height, primary diagnosis, and other parameters as 
appropriate. No inferential statistics will be carried out.
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13.1.3 Efficacy Analysis
Efficacy is not the primary endpoint for this study. Secondary efficacy endpoints include ORR, 
DOR, TTP, and PFS (for patients in the Cohort B expansion phase). No formal statistical tests 
will be performed for these secondary endpoints. Analyses for these endpoints will be done for 
each of the 5 combination arms (except PFS will be analyzed for the Cohort B expansion phase 
only), separately and by dose level.

ORR is defined as the proportion of patients who achieved CR and PR (determined by the 
investigator) in the response-evaluable population.

DOR is defined as the time from the date of the first documented response to the date of first 
documented PD by the investigator. 

TTP is defined as the time from the date of first study drug administration to the date of first 
documented PD by the investigator.

PFS is defined as the time from the date of first study drug administration to the date of first 
documented PD or death due to any cause, whichever occurs first.
Analyses of efficacy measures will be descriptive. Antitumor activity of TAK-659 will be based 
on best overall response. Investigators will assess responses using the IWG criteria for malignant 
lymphoma. Data listings will present the tumor measurements from imaging, including changes 
from baseline, disease response category, and as appropriate, tumor marker measurements.
The number and percentage of patients falling into each response category will be tabulated 
descriptively. Estimates of CR+PR rate will be presented with 2-sided 95% exact binomial CIs.
Response rate will be tabulated by baseline factors if applicable. The prognostic factors will 
include, but will not be limited to, age, number and types of prior therapy, TTP from diagnosis or 
prior therapy, prior autologous transplant, and International Prognostic Index score. For patients 
with FL or MZL in the Cohort B expansion phase, PFS will be analyzed using the standard 
Kaplan-Meier method for survival analysis.
13.1.4 PK Analysis 
The PK population will be used for the description of the plasma PK profile of TAK-659 
(Cohorts A-E) and for the estimation of plasma PK parameters of TAK-659. Plasma 
concentrations of TAK-659 will be determined by validated liquid chromatography tandem mass 
spectrometry assay methods. 
Plasma TAK-659 concentrations will be summarized by nominal sampling time and grouped by 
dose cohort and dosing cycle and day. Mean and individual plasma TAK-659 concentration data 
will be plotted over time and grouped by dose cohort and dosing cycle and day. Plasma 
concentration-time data will be used to calculate plasma PK parameters for TAK-659 by 
noncompartmental methods. PK parameters for TAK-659 will include, but not be limited to, 
Cmax, Tmax, Ctrough (observed concentration at the end of a dosing interval), AUCτ, CL/F (apparent 
clearance after extravascular administration), PTR (peak-trough ratio during a dosing interval, at 
steady state), and Rac (accumulation ratio). 
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TAK-659 plasma PK data from the study, along with data from other studies, may contribute to 
population PK analyses and exposure-response analyses for pharmacodynamic, safety, and 
efficacy endpoints. If applicable, the specifics of the population PK and exposure-response 
analyses will be described in separate analysis plans, and results will be reported separately from 
the CSR.
13.1.7 Safety Analysis
AEs will be summarized using the safety analysis set. 
The incidence of DLTs will be tabulated for each dose group. In addition, to assess the 
relationship between toxicities and TAK-659 dose, the preferred term of individual toxicities will 
be summarized by frequency and intensity for each dose group. The DLT-evaluable analysis set 
will be used for the analysis of DLT.
Safety will be evaluated by the frequency of AEs, severity and types of AEs, and by changes 
from baseline in patients’ vital signs, weight, and clinical laboratory results using the safety 
population. Exposure to study drug and reasons for discontinuation will be tabulated.
CCI
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Treatment-emergent AEs that occur after administration of the first dose of study drug and 
through 28 days after the last dose of study drug or the start of subsequent antineoplastic therapy, 
whichever occurs first, will be tabulated.
All AEs will be coded using MedDRA. Data will be summarized in the following categories:

Treatment-emergent AEs.

Drug-related treatment-emergent AEs.

Grade 3 or higher treatment-emergent AEs.

Grade 3 or higher drug-related treatment-emergent AEs.

The most commonly reported treatment-emergent AEs (ie, those events reported by more 
than 10% of all patients).

SAEs.

Listing of treatment-emergent AEs resulting in study drug discontinuation.
Descriptive statistics for the actual values of clinical laboratory parameters and/or change from 
baseline in clinical laboratory parameters will be presented for all scheduled measurements over 
time. Mean laboratory values over time will be plotted for key laboratory parameters.
Descriptive statistics for the actual values and/or change from baseline of vital signs and weight 
over time will be tabulated by scheduled time point.
Shift tables for lab parameters will be generated based on changes in NCI CTCAE grades from 
baseline to the worst post-baseline value. Graphical displays of key safety parameters, such as 
scatter plots of baseline versus worst post-baseline values, may be used to understand the 
TAK-659 safety profile.
All concomitant medications collected from screening through the study period will be classified 
to preferred terms according to the WHO drug dictionary. 
Additional safety analysis may be performed to most clearly enumerate rates of toxicities to 
further define the safety profile of TAK-659.
13.2
Interim Analysis and Criteria for Early Termination
No interim analysis is planned.
13.3
Determination of Sample Size
The dose escalation phase of this study will use a 3 + 3 design. With the exception of 
bendamustine, each combination drug’s dose will be the dose according to the manufacturer’s 
label. The dose of bendamustine will be based on its use in previous combination studies [3,4]. 
In the dose escalation phase, 9 to 12 DLT-evaluable patients from each of Cohorts A to E will be 
recruited based on 2 planned dose levels of TAK-659. A dose lower than 60 mg QD (eg, 40 mg 
QD) or intermittent QD dosing schedules (eg, 7 days on followed by 7 days off or 14 days on 
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followed by 7 days off) may be evaluated in Cohort B, if appropriate. As a result, the actual 
number of patients to be enrolled into Cohort B will be increased accordingly. Twelve additional 
patients with FL or MZL will be recruited into Cohort B for the safety expansion phase; no 
patients from Cohorts A, C, D, or E will be recruited for the safety expansion phase since the 
sponsor has closed enrollment into these cohorts. Assuming a 10% dropout rate, 
approximately 40 patients in Cohort B, and 14 patients each in Cohorts A, C, D, and E will be 
recruited. The total sample size for this study will be approximately 96 patients.
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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 patient to review by the sponsor or 
designee (as long as blinding is not jeopardized), including but not limited to the investigator’s 
binder, study medication, patient medical records, informed consent documentation, 
documentation of patient authorization to use personal health information (if separate from the 
ICFs), and review of eCRFs and associated source documents. It is important that the 
investigator and other study personnel are available during the monitoring visits and that 
sufficient time is devoted to the process.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study patients. Should other unexpected circumstances arise that will 
require deviation from protocol-specified procedures, the investigator should consult with the 
sponsor or designee (and IRB or IEC, as required) to determine the appropriate course of action. 
There will be no exemptions (a prospectively approved deviation) from the inclusion or 
exclusion criteria.
The site should document all protocol deviations in the patient’s source documents. In the event 
of a significant deviation, the site should notify the sponsor or its designee (and IRB or IEC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the patient, or confound interpretation of 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 patient 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 due to privacy and conflict of interest concerns should instead provide a 
Federal Wide Assurance Number or comparable number assigned by the Department of Health 
and Human Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the IB, a copy of the ICF, and, if 
applicable, patient recruitment materials and/or advertisements and other documents required by 
all applicable laws and regulations, must be submitted to a central or local IRB or IEC for 
approval. The IRB’s or IEC’s written approval of the protocol and patient informed consent must 
be obtained and submitted to the sponsor or designee before commencement of the study 
(ie, before shipment of the sponsor-supplied drug or study-specific screening activity). The IRB 
or IEC approval must refer to the study by exact protocol title, number, and version date; identify 
versions of other documents (eg, ICF) reviewed; and state the approval date. The sponsor will 
notify site once the sponsor has confirmed the adequacy of site regulatory documentation and, 
when applicable, the sponsor has received permission from competent authority to begin the 
trial. Until the site receives notification no protocol activities, including screening may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the ICF, recruitment 
materials intended for viewing by patients, local safety reporting requirements, reports and 
updates regarding the ongoing review of the study at intervals specified by the respective IRB or 
IEC, and submission of the investigator’s final status report to IRB or IEC. All IRB and IEC 
approvals and relevant documentation for these items must be provided to the sponsor or its 
designee.
Patient incentives should not exert undue influence for participation. Payments to patients must 
be approved by the IRB or IEC and sponsor.
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15.2
Patient Information, Informed Consent, and Patient Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The ICF, patient authorization form (if applicable), and patient 
information sheet (if applicable) describe the planned and permitted uses, transfers, and 
disclosures of the patient’s personal and personal health information for purposes of conducting 
the study. The ICF and the patient information sheet (if applicable) further explain the nature of 
the study, its objectives, and potential risks and benefits, as well as the date informed consent is 
given. The ICF will detail the requirements of the participant and the fact that he or she is free to 
withdraw at any time without giving a reason and without prejudice to his or her further medical 
care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the ICF 
and if applicable, the patient authorization form. The ICF, patient authorization form (if 
applicable), and patient information sheet (if applicable) must be approved by both the IRB or 
IEC and the sponsor 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. In the event the patient is not capable of rendering adequate 
written informed consent, then the patient’s legally acceptable representative may provide such 
consent for the patient in accordance with applicable laws and regulations.
The patient, or the patient’s legally acceptable representative, must be given ample opportunity 
to: (1) inquire about details of the study and (2) decide whether or not to participate in the study. 
If the patient, or the patient’s legally acceptable representative, determines he or she will 
participate in the study, then the ICF and patient authorization form (if applicable) must be 
signed and dated by the patient, or the patient’s legally acceptable representative, at the time of 
consent and before the patient entering into the study. The patient or the patient’s legally 
acceptable representative should be instructed to sign using their legal names, not nicknames, 
using blue or black ballpoint ink. The investigator must also sign and date the ICF and patient 
authorization (if applicable) at the time of consent and before patient entering into the study; 
however, the sponsor may allow a designee of the investigator to sign to the extent permitted by 
applicable law.
Once signed, the original ICF, patient authorization form (if applicable), and patient information 
sheet (if applicable) will be stored in the investigator’s site file. The investigator must document 
the date the patient signs the informed consent in the patient’s medical record. Copies of the 
signed ICF, the signed patient authorization form (if applicable), and patient information sheet (if 
applicable) shall be given to the patient.
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All revised ICFs must be reviewed and signed by relevant patients or the relevant patient’s 
legally acceptable representative in the same manner as the original informed consent. The date 
the revised consent was obtained should be recorded in the patient’s medical record, and the 
patient should receive a copy of the revised ICF.
15.3
Patient Confidentiality
The sponsor and designees affirm and uphold the principle of the patient’s right to protection 
against invasion of privacy. Throughout this study, a patient’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited patient attributes, such as sex, age, or 
date of birth, and patient initials may be used to verify the patient and accuracy of the patient’s 
unique identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
sponsor requires the investigator to permit its monitor or designee’s monitor, representatives 
from any regulatory authority (eg, US FDA, United Kingdom Medicines and Healthcare 
products Regulatory Agency, Pharmaceuticals and Medical Devices Agency of Japan), 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 and Disclosure
The investigator is obliged to provide the sponsor with complete test results and all data derived 
by the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and 
information generated by the investigator) without the consent of the investigator. Manuscript 
authorship for any peer-reviewed publication will appropriately reflect contributions to the 
production and review of the document. All publications and presentations must be prepared in 
accordance with this section and the clinical study site agreement. In the event of any 
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discrepancy between the protocol and the clinical study site agreement, the clinical study site 
agreement will prevail.
15.4.2 Clinical Trial Registration
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 www.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. 
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 www.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.
Common Terminology Criteria for Adverse Events (CTCAE). National Cancer Institute, 
National Institutes of Health, U.S. Department of Health and Human Services  Series 
v4.03. June 14, 2010. Publication No. 09-5410.
2.
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-
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Rummel MJ, Al-Batran SE, Kim SZ, Welslau M, Hecker R, Kofahl-Krause D, et al. 
Bendamustine plus rituximab is effective and has a favorable toxicity profile in the 
treatment of mantle cell and low-grade non-Hodgkin's lymphoma. Journal of Clinical 
Oncology 2005;23(15):3383-9.
4.
Vacirca JL, Acs PI, Tabbara IA, Rosen PJ, Lee P, Lynam E. Bendamustine combined with 
rituximab for patients with relapsed or refractory diffuse large B cell lymphoma. Annals of 
Hematology 2014;93(3):403-9.
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Kumar V, Abbas A, Fausto N, Aster J. Robbins and Cotran Pathologic Basis of Disease. 8 
ed. Philadelphia: Saunders Elsevier; 2010.
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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.
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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.
8.
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.
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Pinter-Brown L, Besa E. Follicular Lymphoma Management Overview. Medscape 
September 15, 2016:1-26.
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Kahl BS, Yang DT. Follicular lymphoma: evolving therapeutic strategies. Blood 
2016;127(17):2055-63.
11.
TREANDA (bendamustine hydrochloride) [prescribing information]. North Wales, PA: 
Teva Pharmaceuticals USA, Inc., 2015.
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RITUXAN (rituximab) [prescribing information]. San Francisco, CA: Genentech, Inc., 
2013.
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GEMCITABINE (gemcitabine hydrochloride) [prescribing information]. Lake Forest, IL: 
Zydus Hospira Oncology Private Ltd., 2015.
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Corazzelli G, Capobianco G, Arcamone M, Ballerini PF, Iannitto E, Russo F, et al. Long-
term results of gemcitabine plus oxaliplatin with and without rituximab as salvage 
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treatment for transplant-ineligible patients with refractory/relapsing B-cell lymphoma. 
Cancer Chemotherapy & Pharmacology 2009;64(5):907-16.
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REVLIMID (lenalidomide) [prescribing information]. Summit, NJ: Celgene Corporation, 
2016.
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IMBRUVICA (ibrutinib) [prescribing information]. Pharmacylics LLC, 2016.
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BENDEKA (bendamustine hydrochloride) [USPI]. North Wales, PA, USA: Teva 
Pharmaceuticals USA, Inc., 06/2016.
18.
Kaplan JB, Gordon LI, Rambaldi A, Gritti G, Popat R, Burris HA, et al. Phase 1 study of 
TAK-659, an investigational reversible dual SYK/FLT-3 inhibitor, in patients with
lymphoma: Updated results from dose-escalation and expansion cohorts. . Poster presented 
at the 59th American Society of Hematology (ASH) Annual Meeting and Expositio; 
Atlanta, GA, USA.
19.
NCCN Clinical Practice Guidelines in Oncology: B-Cell Lymphomas, version 1. February 
15, 2018.
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Study No. C34005
Page 114 of 189
Protocol Incorporating Amendment 03
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CONFIDENTIAL
Appendix A
Schedules of Events 
Table 1.
21-Day Cycle Schedule of Events for Cohorts A, B, and C
Screening a
Cycle 1
Cycle 2
Cycles 3 and
Beyond
EOT b
(+10 days)
PFS c
Day
1
Day 
2
Day
8
Day
15
Day
16
Day
1
Day
8
Day
15
Days
18-21
Day
1
Day
8
Day
15
Informed consent d
X
Inclusion/exclusion criteria
X
Demographics and disease 
characteristics
X
Complete medical history e
X
X
Physical examination e
X
X
X
X
X
X
X
X
X
Height
X
Weight f
X
X
X
X
X
Vital signs g
X
X
X
X
X
X
X
X
X
ECOG performance status
X
X
X
X
X
12-lead ECG h
X
X
X
X
X
X
Monitoring of concomitant 
medications and procedures
Recorded from signing of the ICF through 28 days after the last dose of 
study drug or to the start of subsequent anticancer therapy, whichever occurs first.
AE reporting
Recorded from signing of the ICF through 28 days after the last dose of 
study drug or to the start of subsequent anticancer therapy, whichever occurs first.
SAEs i will be reported from signing of the ICF through 
28 days after the last dose of study drug even if the patient starts nonprotocol therapy.
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TAK-659
Study No. C34005
Page 115 of 189
Protocol Incorporating Amendment 03
15 November 2018
CONFIDENTIAL
Table 1.
21-Day Cycle Schedule of Events for Cohorts A, B, and C (continued)
Screening a
Cycle 1
Cycle 2 
Cycle 3 and
Beyond
EOT b
(+10 days)
PFS c
Day
1
Day
2
Day
8
Day
15
Day
16
Day
1
Day
8
Day
15
Days
18-21
Day
1
Day
8
Day
15
Dosing
TAK-659 administration j
TAK-659 is dosed PO QD.
Bendamustine 
administration k
Bendamustine is dosed on Days 1 and 2 of each 21-day cycle, up to 8 cycles.
Bendamustine + rituximab 
administration l
Bendamustine is dosed on Days 1 and 2 and rituximab is dosed on Day 1 of each 21-day cycle, up to 8 
cycles.
Gemcitabine administration 
m
Gemcitabine is dosed on Days 1 and 8 of each 21-day cycle. 
Patient diary review n
X
X
X
X
X
X
X
Imaging/Response Assessments
Tumor assessment for 
lymphomas by IWG 
(CT/FDG-PET/) o
X
X
X
X
X
Sample/Laboratory Assessments
Hematology/chemistry p,q
X
X
X
X
X
X
X
X
Urinalysis r,s
X
X
X
X
X
Pregnancy test s
X
X
X
X
X
Ophthalmic exam t
X
X
X
X
CCI
Property of Takeda
da
Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Cycle
Cycl
B
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8-21
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TAK-659
Study No. C34005
Page 116 of 189
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15 November 2018
CONFIDENTIAL
Table 1.
21-Day Cycle Schedule of Events for Cohorts A, B, and C (continued)
Screening a
Cycle 1
Cycle 2 
Cycle 3 and
Beyond
EOT b
(+10 days)
PFS c
Day
1
Day
2
Day
8
Day
15
Day
16
Day
1
Day
8
Day
15
Days
18-21
Day
1
Day
8
Day
15
Blood samples for PK v
See Appendix A, Table 3 and Table 4
Bone marrow biopsy and 
aspirate aa
X
X z
CMV testing aa
X
Day 1 of each cycle
X
AE: adverse event; ALC: absolute leukocyte count; ALT: alanine aminotransferase; ALP: alkaline phosphatase; AST: aspartate aminotransferase; BUN: blood urea nitrogen; 
CMV: cytomegalovirus; CO2: carbon dioxide; CPK: creatine phosphokinase; CR: complete response; CT: computed tomography; ECG: electrocardiogram; ECOG: Eastern 
Cooperative Oncology Group; EOT: end of treatment visit; FDG: fluoro-2-deoxy-D-glucose; FL: follicular lymphoma; GGT: gamma glutamyltransferase; ICF: informed consent 
form; IV: intravenous(ly);  IWG: International Working Group; LDH: lactate dehydrogenase; MZL: marginal zone lymphoma; PCR: polymerase chain reaction; PD: 
pharmacodynamic(s); PET: positron emission tomography; PFS: progression-free survival; PK: pharmacokinetic(s); PO: oral(ly); PTE: pretreatment event; QD: once daily; SAE: 
serious adverse event; WBC: white blood cell; WOCBP: women of childbearing potential.
Cohort A: TAK-659 + bendamustine; Cohort B: TAK-659 + bendamustine + rituximab; Cohort C: TAK-659 + gemcitabine.
a Screening assessments are performed within 28 days before the Cycle 1 Day 1 dose. Screening assessments performed no more than 3 days before Day 1 will qualify as baseline 
assessments and need not be repeated, unless otherwise specified. A bone marrow biopsy and aspirate performed within 6 weeks before Cycle 1 Day 1 will qualify as baseline 
assessment.
b The EOT visit will occur 28 days (+10 days) after the last dose of study drug or before the start of subsequent anticancer therapy if that occurs sooner. Subsequent anticancer 
therapy should not be initiated before recovery from all treatment-emergent toxicities associated with TAK-659 and combination drug.
c For patients with FL or MZL who discontinue treatment for any reason other than PD in the Cohort B expansion phase, PFS follow-up will occur every 2 months after the last 
dose of study drug for up to 6 months or until PD, whichever occurs first.
d Informed consent may be captured before the screening period (28 days before first dose).
e The Cycle 1 Day 1 physical examination and medical history are not required if the screening physical examination was conducted and medical history obtained within 3 days 
before administration of the first dose of study drug (Cycle 1 Day 1). Complete physical examinations will be performed during screening and will include a neurological exam and 
smoking history. Complete physical exams will also be performed on Day 1 of each cycle and at EOT. Symptom- or finding-directed physical examinations will be performed on 
Days 8, 15, and 22 of Cycle 1 and on Day 15 of Cycles 2, 3, and 4.
CCI
CCI
CCI
Property of Takeda: For Non-Commercial Use Only 
ly
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Table 4
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TAK-659
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15 November 2018
CONFIDENTIAL
f Weight should be obtained at screening, on Day 1 predose of each cycle, and at EOT.
g Measure vital signs before dosing. On Cycle 1 Day 1 only, also measure vital signs at 1, 3, and 8 (±10 minutes) hours postdose. Blood pressure should be determined with the 
patient in a seated position after the patient has been sitting quietly for 5 minutes. Oxygen saturation will also be measured when vital signs are taken.
h 12-lead ECGs will be performed as detailed in Section 9.4.8. All scheduled ECGs should be performed at predose, unless otherwise specified in Appendix A, Table 3 and Table 4 
for Cycle 1. 
i Including serious PTEs; see Section 10.0.
j TAK-659 will be administered PO QD for 21-day cycles. The option to modify the schedule of drug administration to include alternative schedules will be based on the review of 
the available PK, safety, and other clinical data by the investigators and the sponsor. 
k Bendamustine is to be administered at 90 mg/m2 IV as a 10- or 60-minute infusion (depending on which formulation is used) on Days 1 and 2 of each 21-day cycle, up to 8 
cycles. Bendamustine should be administered after the dose of TAK-659 is taken, and the infusion should start within 15 minutes after the dose of TAK-659 is administered.
l Bendamustine is to be administered at 90 mg/m2 IV as a 10- or 60-minute infusion (depending on which formulation is used) on Days 1 and 2 of each 21-day cycle, up to 8 
cycles, and 375 mg/m2 rituximab is to be administered IV per local guidelines and labeling on Day 1 of each 21-day cycle, up to 8 cycles. On days (ie, Day 1) in which all 3 agents 
(TAK-659, bendamustine, and rituximab) are given, TAK-659 should be administered first, followed by the bendamustine infusion (infusion to begin within 15 minutes after the 
TAK-659 dose). After completion of the bendamustine infusion, the rituximab infusion should be administered. On days (ie, Day 2) in which only TAK-659 and bendamustine are 
administered, the TAK-659 dose will be administered first, followed by the bendamustine infusion (infusion to begin within 15 minutes after the TAK-659 dose). 
m Gemcitabine is to be administered at 1000 mg/m2 IV as a 30-minute infusion on Days 1 and 8 of each 21-day cycle. Gemcitabine should be administered after the dose of TAK-
659 is taken, and the infusion should start within 15 minutes after the dose of TAK-659 is administered.
n The study center staff will check the patient drug diary versus the patient’s supply of TAK-659 tablets to assess compliance.
o Response assessments for lymphoma, including radiographic evaluation and disease symptoms, will be performed at screening, between Days 18 and 21 (predose) in Cycles 2, 4, 
and 6, and between Days 18 and 21 (predose) in every 3 cycles thereafter (until PD or the start of alternative therapies), and at the EOT visit. For patients with FL or MZL in the 
Cohort B expansion phase, response will continue to be assessed during PFS follow-up every 2 months for patients who discontinue treatment for reasons other than PD until 6 
months after the last dose or occurrence of PD, whichever occurs first. At screening, chest, abdomen, and pelvis (neck should be included, if appropriate) should be imaged by CT 
scan with contrast. FDG-PET scan will be performed at baseline. If the screening FDG-PET scan is positive, FDG-PET scans should be repeated either at the time of assessment 
for CR or for recurrence/progression of disease unless otherwise specified per local standard of care. If the screening FDG-PET scan is negative, additional FDG-PET scans do not 
need to be conducted but could be performed as clinically indicated during the study. See Section 9.4.14. If the patient has had an appropriate CT or FDG-PET scan performed 
within 28 days of Cycle 1 Day 1, the results of that scan may be used for tumor lesion measurements at screening. 
p The hematology and chemistry blood samples for Cycle 1 Day 1 may be collected within 3 days before dosing to ensure patient eligibility on study Day 1. If screening clinical 
laboratory testing was performed within 3 days before the Cycle 1 Day 1 dose, it need not be repeated on Cycle 1 Day 1. Hematology includes complete blood cell count with 
differential consisting of the following: hemoglobin, hematocrit, leukocytes (WBC count), lymphocytes (ALC), lymphocyte subsets (CD4, CD8, CD4:CD8 ratio), differential 
WBC count, and platelets. The chemistry panel consists of the following: sodium, potassium, CO2, chloride, BUN, creatinine, CPK, bilirubin, ALP, AST, ALT, LDH, GGT, 
amylase, lipase, total protein, albumin, glucose, urate, calcium, phosphate, and magnesium.
q Laboratory assessments may be conducted within -3 days of the scheduled visit, with the exception of PK and pharmacodynamic assessments or unless otherwise noted. Day 1 
visits in Cycle 2 and beyond may be modified by up to 3 days for extenuating circumstances (eg, inclement weather, holidays, vacations, or other administrative reasons).
r Urinalysis samples will be collected predose and analyzed at the site’s local laboratory.
s For WOCBP only, a serum pregnancy test will be performed at screening, and a urine pregnancy test will be performed predose on Day 1 of all cycles with negative results 
available before the first dose of TAK-659 is administered for that cycle. If a serum pregnancy test is performed within 3 days before dosing and the result is negative, the urine 
pregnancy test may be waived on Cycle 1 Day 1. For WOCBP only, a urine pregnancy test also will be performed at EOT. 
t An ophthalmic exam should be performed at screening, on Cycle 2 Day 1, on Cycle 7 Day 1, every 6 cycles thereafter (±2 weeks), and at EOT. See Section 9.4.13 for details.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-659
Study No. C34005
Page 118 of 189
Protocol Incorporating Amendment 03
15 November 2018
CONFIDENTIAL
u 
 
 
 
Blood samples for plasma PK analysis will be collected as specified in Appendix A, Table 3 and Table 4.
w A peripheral blood sample will be obtained at screening for the purpose of genotyping patients for certain polymorphisms in genes that may be involved in the metabolism and/or 
disposition of TAK-659 (eg, CYP2D6). 
x
y 
z A bone marrow biopsy and aspirate will be collected at screening and as necessary for confirmation of CR or at the time of suspected PD per standard practice. A bone marrow 
aspirate/biopsy could also be performed at EOT if the initial bone marrow evaluation was positive and a response has been achieved but relapse is subsequently documented 
(optional to patients).
aa CMV serology (immunoglobulin [Ig]G and IgM) and quantitative PCR assay will be performed during screening. Quantitative PCR will be performed at Day 1 of each cycle and 
at the EOT visit. 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.
CCI
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Property of Takeda: For Non-Commercial Use Only and Subject to the Applica
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TAK-659
Study No. C34005
Page 119 of 189
Protocol Incorporating Amendment 03
15 November 2018
CONFIDENTIAL
Table 2.
28-Day Schedule of Events for Cohorts D and E 
Screening a
Cycle 1
Cycle 2
Cycle 3 and Beyond
EOT b
(+10 days)
Day
1
Day
2
Day
8
Day
15
Day
16
Day
22
Day
1
Day
15
Days
22
Day
1
Day
15
Informed consent c
X
Inclusion/exclusion criteria
X
Demographics and disease 
characteristics
X
Complete medical history d
X
X
Physical examination d
X
X
X
X
X
X
X
X
X
X
Height
X
Weight e
X
X
X
X
X
X
Vital signs f
X
X
X
X
X
X
X
X
X
X
ECOG performance status
X
X
X
X
X
X
12-lead ECG g 
X
X
X
X
X
X
X
Monitoring of concomitant 
medications and procedures
Recorded from signing of the ICF through 28 days after the last dose of 
study drug or to the start of subsequent anticancer therapy, whichever occurs first
AE reporting
Recorded from signing of the ICF through 28 days after the last dose of 
study drug or to the start of subsequent anticancer therapy, whichever occurs first
SAEs h will be reported from signing of the ICF through 
28 days after the last dose of study drug even if the patient starts nonprotocol therapy
Footnotes are on last table page.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-659
Study No. C34005
Page 120 of 189
Protocol Incorporating Amendment 03
15 November 2018
CONFIDENTIAL
Table 2.
28-Day Cycle Schedule of Events for Cohorts D and E (continued)
Screening a
Cycle 1
Cycle 2 
Cycle 3 and Beyond
EOT b
(+10 days)
Day
1
Day
2
Day
8
Day
15
Day
16
Day
22
Day
1
Day
15
Day
22
Day
1
Day
15
Dosing
TAK-659 administration i
TAK-659 is dosed PO QD every day.
Lenalidomide administration j
Lenalidomide is dosed on Days 1-21 of a 28-day cycle.
Ibrutinib administration k
Ibrutinib is dosed PO QD every day.
Patient diary review l
X
X
X
X
X
X
X
X
Imaging/Response Assessments
Tumor assessment for 
lymphomas by IWG 
(CT/FDG-PET/) m
X
X
X
X
Sample/Laboratory Assessments
Hematology/chemistry n, o
X
X
X
X
X
X
X
X
X
Urinalysis (for hematuria and 
proteinuria evaluation) o, p
X
X
X
X
X
Pregnancy test q
X
X
X
X
X
Ophthalmic exam r
X
X
X
X
Blood samples for PK t
X
X
X
X
X
Footnotes are on last table page.
CCI
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Property of Tak
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Commercial Use Only and Subject to the Applicable Terms of Use
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Takeda: For 


TAK-659
Study No. C34005
Page 121 of 189
Protocol Incorporating Amendment 03
15 November 2018
CONFIDENTIAL
Table 2.
28-Day Cycle Schedule of Events for Cohorts D and E (continued)
Screening a
Cycle 1
Cycle 2 
Cycle 3 and Beyond
EOT b
(+10 days)
Day
1
Day
2
Day
8
Day
15
Day
16
Day
22
Day
1
Day
15
Day
22
Day
1
Day
15
Bone marrow biopsy and 
aspirate x
X
CMV testing y
X
Day 1 of each cycle
X
AE: adverse event; ALC: absolute leukocyte count; ALT: alanine aminotransferase; ALP: alkaline phosphatase; AST: aspartate aminotransferase; BUN: blood urea nitrogen; 
CMV: cytomegalovirus; CO2: carbon dioxide; CPK: creatine phosphokinase; CR: complete response; CT: computed tomography; ECG: electrocardiogram; ECOG: Eastern 
Cooperative Oncology Group; EOT: end of treatment visit; FDG: fluoro-2-deoxy-D-glucose; FL: follicular lymphoma; GGT: gamma glutamyltransferase; ICF: informed consent 
form; IV: intravenous(ly);  IWG: International Working Group; LDH: lactate dehydrogenase; MZL: marginal zone lymphoma; PCR: polymerase chain reaction; PD: 
pharmacodynamic(s); PET: positron emission tomography; PFS: progression-free survival; PK: pharmacokinetic(s); PO: oral(ly); PTE: pretreatment event; QD: once daily; SAE: 
serious adverse event; WBC: white blood cell; WOCBP: women of childbearing potential.
Cohort D: TAK-659 + lenalidomide; Cohort E: TAK-659 + ibrutinib.
a Screening assessments are performed within 28 days before the Cycle 1 Day 1 dose. Screening assessments performed no more than 3 days before Day 1 will qualify as baseline 
assessments and need not be repeated, unless otherwise specified.
b The EOT visit will occur 28 days (+10 days) after the last dose of study drug or before the start of subsequent anticancer therapy if that occurs sooner. Subsequent anticancer 
therapy should not be initiated before recovery from all treatment-emergent toxicities associated with TAK-659 and combination drugs.
c Informed consent may be captured before the screening period (28 days before first dose).
d The Cycle 1 Day 1 physical examination and medical history are not required if the screening physical examination was conducted and medical history obtained within 3 days 
before administration of the first dose of study drug (Cycle 1 Day 1). Complete physical examinations will be performed during screening and will include a neurological exam and 
smoking history. Complete physical exams will also be performed on Day 1 of each cycle and at EOT. Symptom- or finding-directed physical examinations will be performed on
Days 8, 15, and 22 of Cycle 1 and on Day 15 of Cycles 2, 3, and 4.
e Weight should be obtained at screening, on Day 1 predose of each cycle, and at EOT.
f Measure vital signs before dosing. On Cycle 1 Day 1 only, also measure vital signs at 1, 3, and 8 (±10 minutes) hours postdose. Blood pressure should be determined with the 
patient in a seated position after the patient has been sitting quietly for 5 minutes. Oxygen saturation will also be measured when vital signs are taken.
g 12-lead ECGs will be performed as detailed in Section 9.4.8. All scheduled ECGs should be performed at predose, unless otherwise specified in Appendix A, Table 3 and Table 4 
for Cycle 1.
h Including serious PTEs; see Section 10.0.
i TAK-659 will be administered PO QD in 28-day cycles. The option to modify the schedule of drug administration to include alternative schedules will be based on the review of 
the available PK, safety, and other clinical data by the investigators and the sponsor. 
j Lenalidomide is to be administered orally at 25 mg QD on Days 1-21 of a 28-day cycle. Lenalidomide should be administered after the dose of TAK-659 is taken and should be 
taken within 15 minutes after the dose of TAK-659 is administered.
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TAK-659
Study No. C34005
Page 122 of 189
Protocol Incorporating Amendment 03
15 November 2018
CONFIDENTIAL
k Ibrutinib is to be administered PO at 560 mg QD in 28-day cycles. Ibrutinib should be administered after the dose of TAK-659 is taken and should be taken within 15 minutes 
after the dose of TAK-659 is administered.
l The study center staff will check the patient drug diary versus the patient’s supply of TAK-659 tablets to assess compliance.
m Response assessments for lymphoma, including radiographic evaluation and disease symptoms, will be performed at screening, between Days 22 and 29 (predose) of Cycle 2, 4, 
and 6, and between Days 22 and 29 (predose) of every 3 cycles thereafter (until PD or the start of alternative therapies). At screening, chest, abdomen, and pelvis (neck should be 
included, if appropriate) should be imaged by CT scan with contrast. FDG-PET scan should be performed at baseline. If the screening FDG-PET scan is positive, FDG-PET scans 
should be repeated either at the time of assessment for CR or for recurrence/progression of disease unless otherwise specified per local standard of care. If the screening FDG-PET 
scan is negative, additional FDG-PET scans do not need to be conducted but could be performed as clinically indicated during the study. See Section 9.4.14. If the patient has had 
an appropriate CT or FDG-PET scan performed within 28 days of Cycle 1 Day 1, the results of that scan may be used for tumor lesion measurements at screening. 
n The hematology and chemistry blood samples for Cycle 1 Day 1 may be collected within 3 days before dosing to ensure patient eligibility on study Day 1. If screening clinical 
laboratory testing was performed within 3 days before the Cycle 1 Day 1 dose, it need not be repeated on Cycle 1 Day 1. Hematology includes complete blood cell count with 
differential consisting of the following: hemoglobin, hematocrit, leukocytes (WBC count), lymphocytes (ALC), lymphocyte subsets (CD4, CD8, CD4:CD8 ratio), differential 
WBC count, and platelets. The chemistry panel consists of the following: sodium, potassium, CO2, chloride, BUN, creatinine, CPK, bilirubin, ALP, AST, ALT, LDH, GGT, 
amylase, lipase, total protein, albumin, glucose, urate, calcium, phosphate, and magnesium.
o Laboratory assessments may be conducted within -3 days of the scheduled visit, with the exception of PK and pharmacodynamic assessments or unless otherwise noted. Day 1 
visits of Cycle 2 and beyond may be modified by up to 3 days for extenuating circumstances (eg, inclement weather, holidays, vacations, or other administrative reasons).
p Urinalysis samples will be collected predose and analyzed at the site’s local laboratory.
q For WOCBP only, a serum pregnancy test will be performed at screening, and a urine pregnancy test will be performed predose on Day 1 of all cycles with negative results 
available before the first dose of TAK-659 is administered for that cycle. If a serum pregnancy test is performed within 3 days before dosing and the result is negative, the urine 
pregnancy test may be waived on Cycle 1 Day 1. For WOCBP only, a urine pregnancy test also will be performed at EOT.
r An ophthalmic exam should be performed at screening, on Cycle 2 Day 1, on Cycle 7 Day 1, every 6 cycles thereafter (±2 weeks), and at EOT. See Section 9.4.13 for details.
 
w
x A bone marrow biopsy and aspirate will be collected at Screening and as necessary for confirmation of CR or at the time of suspected PD per standard practice. A bone marrow 
aspirate/biopsy could also be performed at EOT if the initial bone marrow evaluation was positive and a response has been achieved but relapse is subsequently documented 
(optional to patients).
y CMV serology (IgG and IgM) and quantitative PCR assay will be performed during screening. Quantitative PCR will be performed at Day 1 of each cycle and at the EOT visit. 
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. 
CCI
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on Cycle
n Cycl
ommercial
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CONFIDENTIAL
Table 3.
Cycle 1 ECG, Pharmacodynamics, and PK Schedule for TAK-659 in Cohorts A to E (Dose Escalation Phase)
Cycle 1
Day 1
Day 2 
Day 8
Day 15
Day 16
Single 
ECG
PD
PK
PK
PD
PK
Single 
ECG
PD a
PK a
PK a
Predose (within 1 hr before 
dosing on all days) b
X
X
X
X
(24 hrs after 
Day 1 dose 
1 hr) c
X
X c
X
X
X c
X
(24 hrs after 
Day 15 dose 
1 hr) c
0.5 hr postdose (10 min)
X
X
1 hr postdose (10 min)
X
X
2 hrs postdose (10 min)
X
X
X
X
2 to 4 hrs postdose
X d
X d
X e
4 hrs postdose (30 min)
X
X
8 hrs postdose (30 min)
X
X
ECG: electrocardiogram; PD: pharmacodynamic(s); PK: pharmacokinetic(s).
When the timing of a PK, pharmacodynamic, or safety laboratory blood sample coincides with the timing of ECG measurements, the ECG will be completed before the collection 
of the blood samples. All prespecified time points for ECG, PK, and pharmacodynamic collection should be relative to the dosing time of TAK-659.
a Scheduled PD and PK measurements on Cycle 1 Day 15 and Day 16 will be skipped when TAK-659 is administered with intermittent dosing of 7 days on followed by 7 days off 
or 14 days on followed by 7 days off.
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 (and ibrutinib and lenalidomide) dose 
at home. The oral study drug doses will be administered in the clinic after collection of all predose samples.
c The timing of the predose PK samples on Days 2, 8, 15, and 16 should be encouraged to occur at approximately the same time as the TAK-659 dosing times on the previous days 
of the cycle to ensure that samples represent trough samples.
d Scheduled PD and PK measurements at 2-4 hrs postdose on Cycle 1 Day 8 will be skipped when TAK-659 is administered with intermittent dosing of 7 days on followed by 7 
days off. 
e On Day 15, samples for PD assessment consist of a predose sample and a 2- to 4-hour postdose sample; the postdose sample should be collected when the 2-hour or the 4-hour 
postdose PK sample is collected.
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CONFIDENTIAL
Table 4.
Cycle 1 ECG, Pharmacodynamics, and PK Schedule for TAK-659 in Cohort B (Safety Expansion Phase)
Cycle 1
Cycle 2 a
Cycle 3 a
Cycle 4 a
Day 1
Day 8 
Day 15 
Day 1 or 8 b
Day 1 or 8 b
Day1 or 8 b
Single 
ECG
PD
PK
PD
PK
Single 
ECG
PD c
PK c
PK
PK
PK
Predose (within 
1 hr before dosing 
on all days) d, e 
X
X
X
X
X
X
X
X
X
X
X
2 hrs postdose 
(10 min)
X
X
2 to 4 hrs postdose
X
X f
X f
X
X
ECG: electrocardiogram; PD: pharmacodynamic(s); PK: pharmacokinetic(s).
Note: When the timing of a PK, PD, or safety laboratory blood sample coincides with the timing of ECG measurements, the ECG will be completed before the collection of the 
blood samples. All prespecified time points for ECG, PK, and PD collections should be relative to the dosing time of TAK-659.
a Refer to Appendix A Table 1 for 12-lead ECG measurements beyond Cycle 1.
b Predose PK samples on Cycle 2 to Cycle 4 will be taken on Day 1 when TAK-659 is administered with continuous dosing. Predose PK samples on Cycle 2 to Cycle 4 will be 
taken on Day 8 when TAK-659 is administered with intermittent dosing of 7 days on followed by 7 days off or 14 days on followed by 7 days off.
c Scheduled PD and PK measurements on Cycle 1 Day 15 and Day 16 will be skipped when TAK-659 is administered with intermittent dosing of 7 days on followed by 7 days off 
or 14 days on followed by 7 days off.
d 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 oral study drug 
dose will be administered in the clinic after collection of all predose samples.
e The timing of the predose PK samples (Cycle 1 Day 8 and Day 15, Cycle 2 to Cycle 4 Day 1) should be encouraged to occur at approximately the same time as the TAK-659 
dosing times on the previous days of the cycle to ensure that samples represent trough samples.
f Scheduled PD and PK measurements at 2 to 4 hours postdose on Cycle 1 Day 8 will be skipped when TAK-659 is administered with intermittent dosing of 7 days on followed by 
7 days off.
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Appendix B
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are patient to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this study.
The investigator agrees to assume the following responsibilities by signing 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. 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.
4. Ensure that all colleagues and employees assisting in the conduct of the study are informed 
of these obligations.
5. 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.
6. 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.
7. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH, and local 
regulations, are met.
8. Obtain valid informed consent from each patient who participates in the study and document 
the date of consent in the patient’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each ICF should contain a patient authorization section 
that describes the uses and disclosures of a patient’s personal information (including personal 
health information) that will take place in connection with the study. If an ICF does not 
include such a patient authorization, then the investigator must obtain a separate patient 
authorization form from each patient or the patient’s legally acceptable representative.
9. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc., and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents.
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
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11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor.
12. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.
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Appendix C
Investigator Consent to Use of Personal Information
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, US, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may 
contain the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s 
own country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.
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Appendix D
ECOG Scale for Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all predisease performance without restriction.
1
Symptoms but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to 
carry out work of a light or sedentary nature (eg, light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry out any work 
activities. Up and about more than 50% of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more than 50% 
of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair.
5
Dead
Source: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response 
criteria of the Eastern Cooperative Oncology Group. American Journal of Clinical Oncology 1982;5(6):649-55.
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Appendix E
Cockcroft-Gault Equation
For male patients:
Creatinine clearance
=
(140 age[years]) weight [kg]
OR
(140 age[years]) weight [kg]
72 (serum creatinine[mg/dL])
0.81 (serum creatinine[mol/L])
For female patients:
Creatinine clearance
=
0.85 (140 age[years]) weight [kg]
OR
0.85 (140 age[years]) weight [kg]
72 (serum creatinine[mg/dL])
0.81 (serum creatinine[mol/L])
Source: Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16(1):31-41. 
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Appendix F
Methods of Contraception Considered to be Effective
Acceptable Methods Considered Highly Effective
Birth control methods that can achieve a failure rate of less than 1% per year when used 
consistently and correctly are considered as highly effective. Such methods include:
a) combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation 1:
–
oral
–
intravaginal
–
transdermal
b) progestogen-only hormonal contraception associated with inhibition of ovulation 1:
–
oral
–
injectable
–
implantable 2
c) intrauterine device (IUD)2
d) intrauterine hormone-releasing system (IUS)2
e) bilateral tubal occlusion2
f)
vasectomised partner2,3
g) 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:
a) progestogen-only oral hormonal contraception, where inhibition of ovulation is not the
primary mode of action
b) male or female condom with or without spermicide5
c) cap, diaphragm or sponge with spermicide5
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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) A combination of male condom with either cap, diaphragm or sponge with spermicide (double-barrier methods)
are also considered acceptable, but not highly effective, birth control methods.
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Appendix G
New York Heart Association Classification of Cardiac Disease
Class
Functional Capacity
Objective Assessment
I
Patients with cardiac disease but without resulting limitations of 
physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain.
No objective evidence of 
cardiovascular disease.
II
Patients with cardiac disease resulting in slight limitation of 
physical activity. They are comfortable at rest. Ordinary physical 
activity results in fatigue, palpitation, dyspnea, or anginal pain.
Objective evidence of minimal 
cardiovascular disease.
III
Patients with cardiac disease resulting in marked limitation of 
physical activity. They are comfortable at rest. Less than ordinary 
activity causes fatigue, palpitation, dyspnea, or anginal pain.
Objective evidence of moderately 
severe cardiovascular disease.
IV
Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort. Symptoms of heart failure or 
the anginal syndrome may be present even at rest. If any physical 
activity is undertaken, discomfort is increased.
Objective evidence of severe 
cardiovascular disease.
Source: The Criteria Committee of New York Heart Association. Nomenclature and Criteria for Diagnosis of 
Diseases of the Heart and Great Vessels. Ninth Ed. Boston, MA: Little, Brown & Co; 1994:253-256. 
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Appendix H
Medications, Supplements, and Food Products to be Avoided or Used 
Cautiously
Table 1.
Strong CYP3A Inhibitors or Inducers and/or P-gp Inhibitors or Inducers 
(Applicable to Combination Arms A-E)
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-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
Footnotes are on the following page.
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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 FDA Draft DDI Guidance (Sources: fda.gov/downloads/Drugs/GuidanceComplianceRegulatory 
Information/Guidances/UCM292362.pdf and fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ 
DrugInteractionsLabeling/ucm080499.htm). If a medication, supplement, or food/beverage is suspected or known to 
be a 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 due to safety reasons.
e Not marketed in the US.
Table 2.
Moderate CYP3A Inhibitors or Inducers (for Ibrutinib Combination Arm 
[Cohort E] Only)
Medication, Supplement, or Food Product a, b
Required Washout Period Before First Dose
Moderate CYP3A Reversible Inhibitors
aprepitant
ciprofloxacin
fluconazole
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)
Moderate CYP3A Mechanism-based Inhibitors 
Diltiazem c
erythromycin c
verapamil c
7 days, or 5 times the inhibitor half-life, whichever is 
longer
Seville oranges
5 days
Moderate CYP3A Inducers
bosentan
modafinil
nafcillin
7 days, or 5 times the inducer half-life, whichever is 
longer
a Note that the list of moderate CYP3A inhibitors or inducers is not exhaustive and is based on the FDA Draft DDI 
Guidance (Sources: fda.gov/downloads/Drugs/GuidanceComplianceRegulatory 
Information/Guidances/UCM292362.pdf and fda.gov/Drugs/DevelopmentApprovalProcess/Development 
Resources/DrugInteractionsLabeling/ucm080499.htm). If a medication, supplement, or food/beverage is suspected 
or known to be a moderate 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 asses the relative benefit and risk.
b Note that medications used to treat HIV or hepatitis C infection that are moderate CYP3A 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 Diltiazem, erythromycin, and verapamil are also P-gp inhibitors. For patients in the ibrutinib combination arm, the 
washout period for moderate CYP3A mechanism-based inhibitors should be followed instead of the washout period 
for P-gp inhibitors.
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Table 3.
CYP1A2 Inhibitors and Inducers to be Used Cautiously (for Bendamustine 
Combination Arms [Cohorts A and B] only) a, b
Strong CYP1A2 Inhibitors
Moderate CYP1A2 Inducers
ciprofloxacin
montelukast
enoxacin
smoking
fluvoxamine
Moderate CYP1A2 Inhibitors
methoxsalen
mexiletine
oral contraceptives
phenylpropanolamine
thiabendazole
zileuton
a Note that the list of CYP1A2 inhibitors and inducers is not exhaustive and is based on the FDA Draft DDI 
Guidance (Sources: fda.gov/downloads/Drugs/GuidanceComplianceRegulatory Information/Guidances/ 
UCM292362.pdf and fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ 
DrugInteractionsLabeling/ucm080499.htm). 
b Note that medications used to treat HIV or hepatitis C infection that are CYP1A2 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.
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Appendix I
Detailed Description of Amendments to Text
The primary section(s) of the protocol affected by the changes in Amendment 03 are indicated. 
The corresponding text has been revised throughout the protocol.
Change 1: Added Investigational New Drug (IND) number and EudraCT number to title page.
The primary change occurs on the title page.
Added text: IND Number:119,231 
EudraCT Number: 2016-001426-34
Rationale for change: To comply with Takeda medical writing guidelines.
Change 2: Revised background to include information on FL, update description of TAK-659, 
reorganize nonclinical pharmacology information for TAK-659 combination therapy, and update 
clinical data for TAK-659.
The primary change occurs in Section 4.1 Background.
Initial text: 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 40% of all NHL. [5] It is estimated that 
approximately 66,000 new cases of NHL, and consequently, approximately 20,000 
new cases of DLBCL, are diagnosed annually in the United States (US) [6]. DLBCL 
is a form of aggressive B-cell NHL and is invariably fatal without treatment. 
The immunochemotherapy regimen R-CHOP (cyclophosphamide, doxorubicin 
[hydroxydaunomycin], vincristine [Oncovin], and prednisone with rituximab) is the 
standard treatment for patients newly diagnosed with DLBCL [7,8]. This regimen 
results in complete remission in approximately 65% to 75% of first-line patients 
with DLBCL. It is considered curative in a subset of patients, with a cure rate of 
>50% [9.10]. However, DLBCL is highly heterogeneous in histology, clinical 
behavior, and underlying biology, and therefore exhibits significant variation with 
regard to 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 treatments of choice for patients with relapsed disease. For patients with disease 
relapse following transplant or for patients not eligible for transplant, there is no 
clear standard of care; therefore, multiple chemotherapy regimens and 
investigational agents in clinical trials are being used to treat these patients. 
However, clinically meaningful benefit is rarely achieved in patients with
progressive disease (PD) following multiple regimens.
4.1.2 Study Drug
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4.1.2.1 TAK-659
TAK-659 is a potent and reversible inhibitor of spleen tyrosine kinase (SYK) being 
developed for oncology indications, the pathogeneses 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. 
TAK-659 demonstrated a more than 50-fold selectivity for SYK over 290 other 
protein kinases screened. In cultured human tumor cells, TAK-659 potently 
inhibited SYK activity in hematopoietic-derived cell lines (Section 4.1.3). TAK-659 
is currently being investigated as a single agent in trials of patients with NHL and 
acute myelogenous leukemia (AML).
…
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-based 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 
in hematopoietic cells, and abnormal function of SYK has been implicated in NHL, 
including follicular lymphoma (FL), DLBCL, and MCL. TAK-659 inhibits SYK-
purified enzyme with an IC50 of 3.2 nM and a concentration producing half-
maximal response (EC50) 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 activated B-
cell-like (ABC)-DLBCL model; the OCI-Ly19 model, a germinal center B-cell–like 
(GCB)-DLBCL model; the PHTX-95L model, a primary human DLBCL model; the 
TMD8 ABC-DLBCL model; the RL FL model; and the MINO MCL model. TAK-
659 has been tested in nonclinical DLBCL models in combination with a number of 
agents used in the relapsed/refractory setting, including gemcitabine, bendamustine, 
ibrutinib, and lenalidomide. All combination drugs were given concomitantly in 
nonclinical studies.
Gemcitabine HCl is a nucleoside analogue that primarily kills cells undergoing 
DNA synthesis (S-phase) and also blocks the progression of cells through the G1/S-
phase boundary. In DLBCL, gemcitabine is used to treat relapsed and refractory 
patients. TAK-659 has shown synergistic antitumor activity when combined with 
gemcitabine in nonclinical models of DLBCL. In the TMD8 model, TAK-659 (60 
mg/kg once daily [QD]) in combination with gemcitabine (5 mg/kg, every 3 days 
times 4) achieved significant antitumor activity with tumor growth inhibition (TGI) 
of 96.7% (change in area under the concentration-time curve [ΔAUC], p<0.001), 
demonstrating enhanced therapeutic potential over single-agent treatment. This 
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combination was found to be additive in the OCI-Ly10 model with TGI of 90.6% 
(ΔAUC, p<0.001). 
Ibrutinib is an inhibitor of BTK that is approved in CLL, MCL, Waldenström's 
Macroglobulinemia and marginal zone lymphoma and is currently in clinical trials 
for DLBCL. It is hypothesized that targeting BTK, which lies downstream of SYK, 
in combination with SYK inhibition could lead to a more pronounced response in 
hematologic malignancies. In nonclinical animal models of DLBCL, the 
combination of TAK-659 (60 mg/kg QD) with ibrutinib (6 mg/kg QD) has shown 
synergistic antitumor activity. In the OCI-Ly10 ABC DLBCL model, TAK-659 in 
combination with ibrutinib was found to have significant antitumor activity with 
TGI of 68.8% (ΔAUC, p<0.001) when compared with vehicle, resulting in a 
statistically significant therapeutic advantage over single-agent treatments.
Bendamustine is a standard-of-care agent used in combination with rituximab as a 
second-line (or greater) therapy to treat patients with DLBCL. TAK-659 (60 mg/kg 
QD) in combination with bendamustine (1 mg/kg twice weekly) in the OCI-Ly10 
model resulted in significant antitumor activity with TGI of 78.6% (ΔAUC, 
p<0.001) when compared with vehicle. This combination resulted in additive 
antitumor activity in the OCI-Ly19 GCB DLBCL model where TAK-659 (60 mg/kg 
QD) and bendamustine (2 mg/kg twice weekly) resulted in TGI of 52.1% (ΔAUC, 
p<0.01).
Lenalidomide is an immunomodulatory agent that has been shown to modulate 
different components of the immune system by altering cytokine production, 
regulating T-cell co-stimulation, and augmenting the NK cell cytotoxicity. The 
immunomodulatory properties of lenalidomide are implicated in its clinical efficacy 
and provide a rationale for combination with TAK-659. Combination of these 
agents in nonclinical studies has shown strongly additive tumor inhibition in the 
OCI-Ly10 DLBCL model. TAK-659 (60 mg/kg QD) in combination with 
lenalidomide (10 mg/kg QD) resulted in TGI of 73.1% (ΔAUC, p<0.001). 
Overall, data from nonclinical sources support the potential for TAK-659 to be an 
effective agent in treating patients with relapsed or refractory DLBCL in 
combination with gemcitabine, bendamustine, ibrutinib, or lenalidomide.
4.1.4 Clinical Experience
Three different data cutoff dates were used to provide the most current clinical 
information given that the ongoing studies are in various stages of execution. The 
most current disposition data for Studies C34001, C34002, and C34003 are 
provided by the 22 October 2016 data cutoff date. The most current safety and 
efficacy data for Study C34001 are provided as of the 07 October 2016 data cutoff 
date. The most current safety and efficacy data for Study C34002 are provided as of 
the 18 September 2016 data cutoff date. 
As of 22 October 2016, 111 patients had been dosed with TAK-659 in 3 ongoing 
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studies, including 82 patients in the first-in-human (FIH) Study C34001, 26 patients 
in Study C34002, and 3 patients in Study C34003. 
In Study C34001, the TAK-659 dose was escalated from 60 to 120 mg (60 mg [10 
patients], 80 mg [4 patients], 100 mg [15 patients], and 120 mg [7 patients]). The 
maximum tolerated dose (MTD) for patients with lymphoma and solid tumors was 
determined to be 100 mg 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 82 
patients treated in this study (60 lymphoma, 19 solid tumors, and 3 CLL), 63 
patients had discontinued from study by the data cutoff date. The reasons for 
discontinuation included PD (37 patients), adverse events (AEs; 13 patients), 
protocol deviation (1 patient), symptomatic deterioration (4 patients), and other (8 
patients).
In Study C34002, the TAK-659 dose had been escalated from 60 to 160 mg across a 
total of 26 patients, and the MTD/RP2D has not yet been determined. Of the 26 
patients treated in this study, 16 patients had discontinued from study by the data 
cutoff date. The reasons for discontinuation included PD (3 patients), AEs (10 
patients), withdrawal by subject (1 patient), and other (2 patients).
In Study C34003, the TAK-659 dose has been evaluated in 3 patients at 60 mg with 
plans to escalate to 100 mg. At the time of the data cutoff, all 3 patients were still on 
study. 
The reported AEs were generally as expected based on preclinical toxicology 
findings with TAK-659 and the patient population being studied. In Study C34001, 
as of 07 October 2016, the most common (reported in 20% of patients) treatment-
related AEs in Study C34001 have been aspartate aminotransferase (AST) increased 
(35 patients [44%]), amylase increased (27 patients [34%]), lipase increased (22 
patients [28%]), alanine aminotransferase (ALT) increased (19 patients [24%]), 
fatigue (18 patients [23%]), and diarrhea (17 patients [21%]). The most common 
Grade 3 or greater treatment-related AEs (5% of patients) have been amylase 
increased (15 patients [19%]), neutropenia (12 patients [15%]), hypophosphatemia 
(9 patients [11%]), lipase increased (8 patients [10%]), anemia (7 patients [9%]), 
blood creatine phosphokinase (CPK) increased (6 patients [8%]), and pyrexia (4 
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. 
There were 20 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 
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renal failure). The other causes of deaths included PD (8 patients), pneumonia and 
sepsis (2 patients each), and hypoxia, pulmonary embolism, hepatic encephalopathy 
due to PD, ascites, and septic shock (1 patient each).
In Study C34001, of the 48 response-evaluable patients with lymphoma (40 
DLBCL, 5 indolent NHL, 2 CLL, and 1 MCL), 17 patients had responded to 
treatment based on investigator report as of 07 October 2016. Eight patients with 
DLBCL achieved a complete response (CR), and 4 achieved a partial response (PR). 
Four patients with indolent lymphomas responded. One patient with mucosa-
associated lymphoid tissue lymphoma achieved a CR, and 3 patients with FL 
achieved PRs. One patient with CLL achieved a PR with a second achieving PR 
after the datacut.
In Study C34002, as of 18 September 2016, there were 7 on-study deaths, none of 
which was deemed treatment related. To date, the safety profile in Study C34002 
appears 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 their peripheral blast and bone marrow blast counts; however, no formal 
responses as per International Working Group (IWG) 2003 criteria [2] have been 
reported as of the cutoff date. 
4.1.4.1 Clinical Pharmacokinetics of TAK-659
Preliminary pharmacokinetic (PK) results are available at the 60 to 120 mg dose 
range evaluated in the dose escalation portion of Study C34001. Preliminary plasma 
PK results are available for 34 patients (17 lymphoma, 17 solid tumor) after single 
dosing and for 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 (Tmax [time of first occurrence of Cmax (maximum observed 
concentration)] of 2 hours on Days 1 and 15 of Cycle 1). Approximate steady-state 
PK conditions appeared to be achieved by Cycle 1 Day 8 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 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. 
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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.
Amended 
text:
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 40% of all NHL.[5] It is estimated that 
approximately 66,000 new cases of NHL, and consequently, approximately 20,000 
new cases of DLBCL, are diagnosed annually in the United States (US) [6]. DLBCL 
is a form of aggressive B-cell NHL and is invariably fatal without treatment. Non-
Hodgkin lymphoma (NHL), is the most common hematologic malignancy and 
consists of numerous subtypes [5]; it is one of the most common cancers in the 
United States (US), accounting for about 4% of all cancers [6]. In 2018, an 
estimated 74,680 new cases of NHL are expected to be diagnosed in the US, and 
an estimated 19,910 people will die of this disease [7]. The two most common 
types of NHL are diffuse large B-cell lymphoma (DLBCL) and follicular 
lymphoma (FL). DLBCL accounts for about 1 of every 3 lymphomas, and FL 
accounts for about 1 of every 5 lymphomas in the US [8].
The immunochemotherapy regimen R-CHOP (cyclophosphamide, doxorubicin 
[hydroxydaunomycin], vincristine [Oncovin], and prednisone with rituximab) is the 
standard treatment for patients with newly diagnosed with DLBCL [7,8][5,6]. This 
regimen results in complete remission in approximately 65% to 75% of first-line 
patients with DLBCL. It is considered curative in a subset of patients, with a cure 
rate of >50% [9,10][7,8]. However, DLBCL is highly heterogeneous in histology, 
clinical behavior, and underlying biology, and therefore exhibits significant 
variation with regard to 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 treatments of choice for patients with relapsed disease. For patients with disease 
relapse following transplant or for patients not eligible for transplant, there is no 
clear standard of care; therefore, multiple chemotherapy regimens and 
investigational agents in clinical trials are being used to treat these patients. 
Follicular lymphoma (FL) is the most common indolent NHL in the Western 
hemisphere, representing 20% of NHL cases [9]. Randomized clinical trials 
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have demonstrated that the addition of rituximab to standard chemotherapy 
induction has improved overall survival. Maintenance rituximab strategies can 
improve progression-free survival (PFS). Bendamustine combined with 
rituximab has rapidly become a standard frontline strategy in North America 
and parts of Europe. However, clinically meaningful benefit is rarely achieved in 
patients with progressive disease (PD) following multiple regimens.several unmet 
needs remain, including the identification of high-risk patients at diagnosis and 
the development of predictive biomarkers for targeted agents [10].
4.1.2 Study Drug
4.1.2.1 TAK-659
TAK-659 is a potent and reversible inhibitor ofsmall molecule that inhibits spleen 
tyrosine kinase (SYK) being developed for oncology indications, the pathogeneses 
of which are either driven by or significantly contributed to by SYK-mediated 
signalingand FMS-like tyrosine kinase 3 (FLT3) and is currently under 
development for the treatment of patients with advanced malignancies. TAK-
659 inhibits SYK- and FLT3-purified enzymeenzymes with a concentration 
producing 50% inhibition (IC50) of 3.2 nM and 4.6 nM, respectively. TAK-659 
demonstrated a more than 50-fold selectivity for SYK over 290 other protein 
kinases screened. In cultured human tumor cells, TAK-659 potently inhibited SYK 
activity in hematopoietic-derived cell lines (Section 4.1.3). TAK-659 is currently 
being investigated as a single agent in trials of patients with NHL and acute 
myelogenous leukemia (AML), as well as a combination agent in patients with 
lymphoma and solid tumors.
…
4.1.3 Nonclinical Experience
4.1.3.1 Nonclinical Pharmacology Experience With TAK-659
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 
bindbinds to phosphorylated immunoreceptor tyrosine-based activation-motifs 
(ITAMs) located within receptors found 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 in hematopoietic cells, and abnormal function of 
SYK has been implicated in NHL, including follicular lymphoma (FL)FL, DLBCL, 
and MCL. 
TAK-659 inhibits SYK-purified enzyme with an IC50 of 3.2 nM and a concentration 
producing half-maximal response (EC50) ranging from 25 to 400 nM in sensitive 
cell systems. Nonclinically, TAK-659 has exhibited significant antitumor activity in 
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a number of mouse DLBCL xenograft models, including the OCI-Ly10 model, an 
activated B-cell-–like (ABC)-DLBCL model; the OCI-Ly19 model, a germinal 
center B-cell–like (GCB)-DLBCL model; the PHTX-95L model, a primary human 
DLBCL model; the TMD8 ABC-DLBCL model; the RL FL model; and the MINO 
MCL model. TAK-659 has been tested in nonclinical DLBCL models in 
combination with a number of agents used in the relapsed/refractory setting, 
including gemcitabine, bendamustine, ibrutinib, andgemcitabine, lenalidomide, and 
ibrutinib. All combination drugs were given concomitantly in nonclinical studies.
Refer to the TAK-659 IB for additional information.
4.1.3.2 Nonclinical Pharmacology Experience With Combination Drugs
Bendamustine is a standard-of-care agent used in combination with rituximab 
as a second-line (or greater) therapy to treat patients with DLBCL. TAK-659 
(60 mg/kg once daily [QD]) in combination with bendamustine (1 mg/kg twice 
weekly) in the OCI-Ly10 model resulted in significant antitumor activity with 
tumor growth inhibition (TGI) of 78.6% (change in area under the 
concentration-time curve [ΔAUC], p<0.001) when compared with vehicle. This 
combination resulted in additive antitumor activity in the OCI-Ly19 GCB 
DLBCL model where TAK-659 (60 mg/kg QD) and bendamustine (2 mg/kg 
twice weekly) resulted in TGI of 52.1% (ΔAUC, p<0.01).
Gemcitabine HCl is a nucleoside analogue that primarily kills cells undergoing 
DNA synthesis (S-phase) and also blocks the progression of cells through the G1/S-
phase boundary. In DLBCL, gemcitabine is used to treat relapsed and refractory 
patients. TAK-659 has shown synergistic antitumor activity when combined with 
gemcitabine in nonclinical models of DLBCL. In the TMD8 model, TAK-659 (60 
mg/kg once daily [QD]) in combination with gemcitabine (5 mg/kg, every 3 days 
times 4) achieved significant antitumor activity with tumor growth inhibition (TGI) 
of 96.7% (change in area under the concentration-time curve [ΔAUC] ΔAUC, 
p<0.001), demonstrating enhanced therapeutic potential over single-agent treatment. 
This combination was found to be additive in the OCI-Ly10 model with TGI of 
90.6% (ΔAUC, p<0.001). 
Lenalidomide is an immunomodulatory agent that has been shown to modulate 
different components of the immune system by altering cytokine production, 
regulating T-cell co-stimulation, and augmenting the NK cell cytotoxicity. The 
immunomodulatory properties of lenalidomide are implicated in its clinical 
efficacy and provide a rationale for combination with TAK-659. Combination 
of these agents in nonclinical studies has shown strongly additive tumor 
inhibition in the OCI-Ly10 DLBCL model. TAK-659 (60 mg/kg QD) in 
combination with lenalidomide (10 mg/kg QD) resulted in TGI of 73.1% 
(ΔAUC, p<0.001). 
Ibrutinib is an inhibitor of BTK that is approved in CLL, MCL, Waldenström's 
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MacroglobulinemiaWM, and marginal zone lymphoma and is currently in clinical 
trials for DLBCL. It is hypothesized that targeting BTK, which lies downstream of 
SYK, in combination with SYK inhibition could lead to a more pronounced 
response in hematologic malignancies. In nonclinical animal models of DLBCL, the 
combination of TAK-659 (60 mg/kg QD) with ibrutinib (6 mg/kg QD) has shown 
synergistic antitumor activity. In the OCI-Ly10 ABC DLBCL model, TAK-659 in 
combination with ibrutinib was found to have significant antitumor activity with 
TGI of 68.8% (ΔAUC, p<0.001) when compared with vehicle, resulting in a 
statistically significant therapeutic advantage over single-agent treatments.
Bendamustine is a standard-of-care agent used in combination with rituximab as a 
second-line (or greater) therapy to treat patients with DLBCL. TAK-659 (60 mg/kg 
QD) in combination with bendamustine (1 mg/kg twice weekly) in the OCI-Ly10 
model resulted in significant antitumor activity with TGI of 78.6% (ÄAUC, 
p<0.001) when compared with vehicle. This combination resulted in additive 
antitumor activity in the OCI-Ly19 GCB DLBCL model where TAK-659 (60 mg/kg 
QD) and bendamustine (2 mg/kg twice weekly) resulted in TGI of 52.1% (ΔAUC, 
p<0.01).
Lenalidomide is an immunomodulatory agent that has been shown to modulate 
different components of the immune system by altering cytokine production, 
regulating T-cell co-stimulation, and augmenting the NK cell cytotoxicity. The 
immunomodulatory properties of lenalidomide are implicated in its clinical efficacy 
and provide a rationale for combination with TAK-659. Combination of these 
agents in nonclinical studies has shown strongly additive tumor inhibition in the 
OCI-Ly10 DLBCL model. TAK-659 (60 mg/kg QD) in combination with 
lenalidomide (10 mg/kg QD) resulted in TGI of 73.1% (ΔAUC, p<0.001). 
Overall, data from nonclinical sources support the potential for TAK-659 to be an 
effective agent in treating patients with relapsed or refractory DLBCL in 
combination with gemcitabine, bendamustine, ibrutinib, orgemcitabine,
lenalidomide, or ibrutinib.
4.1.4 Clinical Experience
Three different data cutoff dates were used to provide the most current clinical 
information given that the ongoing studies are in various stages of execution. The 
most current disposition data for Studies C34001, C34002, and C34003 are 
provided by the 22 October 2016 data cutoff date. The most current safety and 
efficacy data for Study C34001 are provided as of the 07 October 2016 data cutoff 
date. The most current safety and efficacy data for Study C34002 are provided as of 
the 18 September 2016 data cutoff date. 
As of 22 October 2016, 111 patients had been dosed with TAK-659 in 3 ongoing 
studies, including 82 patients in the first-in-human (FIH) Study C34001, 26 patients 
in Study C34002, and 3 patients in Study C34003. 
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In Study C34001, the TAK-659 dose was escalated from 60 to 120 mg (60 mg [10 
patients], 80 mg [4 patients], 100 mg [15 patients], and 120 mg [7 patients]). The 
maximum tolerated dose (MTD) for patients with lymphoma and solid tumors was 
determined to be 100 mg 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 82 
patients treated in this study (60 lymphoma, 19 solid tumors, and 3 CLL), 63 
patients had discontinued from study by the data cutoff date. The reasons for 
discontinuation included PD (37 patients), adverse events (AEs; 13 patients), 
protocol deviation (1 patient), symptomatic deterioration (4 patients), and other (8 
patients).
In Study C34002, the TAK-659 dose had been escalated from 60 to 160 mg across a 
total of 26 patients, and the MTD/RP2D has not yet been determined. Of the 26 
patients treated in this study, 16 patients had discontinued from study by the data 
cutoff date. The reasons for discontinuation included PD (3 patients), AEs (10 
patients), withdrawal by subject (1 patient), and other (2 patients).
In Study C34003, the TAK-659 dose has been evaluated in 3 patients at 60 mg with 
plans to escalate to 100 mg. At the time of the data cutoff, all 3 patients were still on 
study. 
The reported AEs were generally as expected based on preclinical toxicology 
findings with TAK-659 and the patient population being studied. In Study C34001, 
as of 07 October 2016, the most common (reported in 20% of patients) treatment-
related AEs in Study C34001 have been aspartate aminotransferase (AST) increased 
(35 patients [44%]), amylase increased (27 patients [34%]), lipase increased (22 
patients [28%]), alanine aminotransferase (ALT) increased (19 patients [24%]), 
fatigue (18 patients [23%]), and diarrhea (17 patients [21%]). The most common 
Grade 3 or greater treatment-related AEs (5% of patients) have been amylase 
increased (15 patients [19%]), neutropenia (12 patients [15%]), hypophosphatemia 
(9 patients [11%]), lipase increased (8 patients [10%]), anemia (7 patients [9%]), 
blood creatine phosphokinase (CPK) increased (6 patients [8%]), and pyrexia (4 
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. 
There were 20 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). The other causes of deaths included PD (8 patients), pneumonia and 
sepsis (2 patients each), and hypoxia, pulmonary embolism, hepatic encephalopathy 
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due to PD, ascites, and septic shock (1 patient each).
In Study C34001, of the 48 response-evaluable patients with lymphoma (40 
DLBCL, 5 indolent NHL, 2 CLL, and 1 MCL), 17 patients had responded to 
treatment based on investigator report as of 07 October 2016. Eight patients with 
DLBCL achieved a complete response (CR), and 4 achieved a partial response (PR). 
Four patients with indolent lymphomas responded. One patient with mucosa-
associated lymphoid tissue lymphoma achieved a CR, and 3 patients with FL 
achieved PRs. One patient with CLL achieved a PR with a second achieving PR 
after the datacut.
In Study C34002, as of 18 September 2016, there were 7 on-study deaths, none of 
which was deemed treatment related. To date, the safety profile in Study C34002 
appears 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 their peripheral blast and bone marrow blast counts; however, no formal 
responses as per International Working Group (IWG) 2003 criteria [2] have been 
reported as of the cutoff date. 
4.1.4.1 Clinical Experience With TAK-659
TAK-659 is being investigated in 7 clinical studies involving patients with 
advanced malignancies (Table 4.a). All 7 studies are ongoing. 
For detailed clinical study information, please refer to the TAK-659 IB.
New Table 4.a Overview of TAK-659 Clinical Studies
4.1.4.2 4.1.4.1 Clinical Pharmacokinetics of TAK-659
Preliminary pharmacokinetic (PK) results are available at the 60 to 120 mg dose 
range evaluated in the dose escalation portion of Study C34001. Preliminary plasma 
pharmacokinetics (PK) results are available for 34 patients (17from lymphoma, 17 
solid tumor) after single dosing, and for 25AML patients (14 lymphoma, 11 solid 
tumor) after repeated QD dosing for 15 days;enrolled in Studies C34001 and 
C34002. In addition, preliminary urine PK results are available from 19 patients 
(12 lymphoma, 7 and solid tumor). Among patients with relapsed/refractory 
lymphoma, TAK-659 exhibited patients enrolled in the dose escalation cohorts of 
Study C34001. TAK-659 is characterized by fast absorption (overall median 
Tmax [time of first occurrence of Cmax (maximum observed concentration)] of 2 
hours on Days 1 and 15 of Cycle 1). Approximate steady-state PK conditions 
appeared to be achieved by Cycle 1 Day 8 upon comparison of predose (trough) 
concentrations available during Cycle 1. Geometric mean values of steady-state, 
dose-) in patients with hematologic and nonhematologic malignancies. 
Moderate variability is observed among dose-normalized steady-state AUC
(area under the plasma concentration–-time curve during the dosing interval
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(AUC/Dose) were similar across the 60 to 100 mg range, suggesting no obvious 
deviation from dose proportionality. Moderate variability was observed in 
AUC/Dose when pooled across the 60 to 120 mg dose rangevalues in lymphoma, 
solid tumor, and AML patients (coefficient of variation of 30% for Day 1 and 
50% for Day 15).20.0%, 43.5%, and 34.8%, respectively). An approximately 
dose-proportional increase in steady state AUCwas observed over the 60 to 
160 mg range in patients with AML. Mean accumulation ratios ranging from 
1.90-fold to 2.54-fold and mean peak-to-trough ratios ranging from 4.34 to 5.09 
were observed across the study populations after repeated QD dosing for 15 
days. Based on data in lymphoma and solid tumor patients, renal clearance 
accounted for about 30% of TAK-659 apparent clearance, and therefore at 
least about 30% of TAK-659 systemic clearance. Active tubular secretion 
appeared to be the predominant component of renal clearance, based on 
comparison of unbound renal clearance to glomerular filtration rate. 
Geometric mean terminal disposition half-life of 34.4 hours was determined in 
a single dose PK run-in phase of the indolent NHL expansion cohort of Study 
C34001.
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.
Refer to the TAK-659 IB for detailed clinical pharmacology information. 
Rationale for changes: To better describe the prevalence of the types of NHL, including 
DLBCL and FL, and for consistency with TAK-659 IB Edition 5.1.
Change 3: Reorganized and updated potential benefits and risks of TAK-659.
The primary change occurs in Section 4.1.5 Benefits and Risks.
Initial text:
4.1.5 Benefits and Risks
TAK-659 had been administered to a total of only 111 patients as of 22 October 
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2016, and it is not currently possible to identify and describe with certainty the 
adverse effects of the compound. 
Potential risks from nonclinical studies in dogs and rats include:

Lymphoid/hematopoietic effects that include lymphoid depletion and 
myelosuppression that are associated with thrombocytopenia, neutropenia, and 
reticulocytopenia. These findings may be associated with increased 
susceptibility to infection, bleeding, and/or anemia.

Epithelial effects on the intestinal tract, urinary tract, and lens. Intestinal effects 
included minimal-to-slight mucosal hemorrhaging. Urinary and renal tract 
effects included hyperplasia of transitional epithelium in the kidney and 
bladder, dilatation and hemorrhage in the renal pelvis that led to hematuria and 
proteinuria, and urolithiasis with possible ureter obstruction. Lens effects 
included epithelium hyperplasia leading to anterior axial opacity.

Reproductive system effects, including decreased spermatozoa and 
seminiferous tubule degeneration in the testis and corpora luteal necrosis in the 
ovaries.

Possible mutation of DNA.

Growth plate thickening and disorganization (not relevant to adults).
Lymphoid and hematopoietic effects and reproductive system effects are 
considered important potential risks.
Potential risks based on clinical observations:
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 
elevations are reported commonly (≥10%). Patients in Study C34005 will have 
frequent monitoring of amylase as outlined in the Schedules of Events (Appendix 
A).
Cases of pneumonitis have been reported in clinical studies with B-cell receptor 
(BCR) pathway kinase inhibitors, including TAK-659, and pneumonitis is 
considered an important potential risk of TAK-659. Pneumonitis and other 
pulmonary toxicities are being closely monitored in TAK-659 clinical studies.
The benefits of TAK-659 have not been established; however, early signs of 
clinical antitumor activity were seen. In Study C34001, of the 48 response-
evaluable patients with lymphoma (40 DLBCL, 5 indolent NHL, 2 CLL, and 1 
MCL), 17 patients had responded to treatment per investigator report as of 07 
October 2016. Eight patients with DLBCL achieved a CR and 4 achieved a PR. 
Four patients with indolent lymphomas responded. One patient with mucosa-
associated lymphoid tissue lymphoma achieved a CR, and 3 patients with FL 
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TAK-659
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achieved PRs. One patient with CLL achieved a PR with a second achieving PR 
after the datacut.
Further details regarding the benefits and risks associated with TAK-659 may be 
found in the current version of the TAK-659 Investigator’s Brochure (IB).
The risks associated with the administration of bendamustine, rituximab, 
gemcitabine, lenalidomide, and ibrutinib should be referenced in accordance with 
their respective United States Package Inserts (USPIs) [11-13, 15-17] or applicable 
labeling.
TAK-659 has not been administered in combination previously in NHL. The 
combination of TAK-659 and other agents (bendamustine, rituximab, gemcitabine, 
lenalidomide, and ibrutinib) may lead to exacerbation of known toxicities of 
single-agent administration for each agent, and possibly the occurrence of new 
toxicities that have not been identified with the single agents.
4.1.5.1 Potential Overlapping Toxicities for the Combination of TAK-659 and 
Combination Partners
Because the combination of TAK-659 with any of the combination agents 
(bendamustine, rituximab, gemcitibine, lenalidomide, and ibrutinib) has not yet 
been tested in humans, there are no identified risks for each of the combinations, 
and all reported AEs are considered unexpected for the purposes of regulatory 
reporting. 
4.1.5.2 Drug-Drug Interaction Risk Assessment for the Combination of TAK-659 
and Combination Partners
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 P-
glycoprotein (P-gp) and is metabolized by cytochrome P450 (CYP) 3A4/5, 
CYP2D6, and CYP1A2, with relative contributions of 69.1% to 73.0%, 16.6% to 
30.9%, and 0% to 8.40%, respectively. Consequently, there is a potential risk for 
TAK-659 PK to be altered by drugs that are strong CYP3A inhibitorChns or 
inducers or P-gp inhibitors or inducers.
Assessment of TAK-659 as Victim of DDIs
Based on data included in their respective USPIs [11-13,15-17] or applicable 
labeling, bendamustine, rituximab, gemcitabine, and lenalidomide are not expected 
to inhibit or induce CYP3A or P-gp at clinically relevant doses; therefore, it is 
unlikely for co-administration of these agents to cause alterations in TAK-659 PK. 
However, at clinically relevant doses, ibrutinib has the potential to inhibit the 
efflux transporter P-gp in the gastrointestinal (GI) tract at higher local 
concentrations that may be achieved after PO administration. Thus, the systemic 
exposures of oral narrow therapeutic index P-gp substrates may be increased upon 
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TAK-659
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co-administration of ibrutinib because of decreased intestinal efflux and increased 
bioavailability of the oral P-gp substrate. Because in vitro data indicate that TAK-
659 is a P-gp substrate, there is a theoretical risk of increased TAK-659 systemic 
exposure with ibrutinib co-administration (gut P-gp inhibitor) relative to TAK-659 
administration alone. Based on current literature, the majority of clinical DDIs due 
to P-gp inhibition are associated with approximately 2-fold or lower increases in 
the exposures of P-gp substrates.
For all combination arms, the TAK-659 starting dose (60 mg QD) will be less than 
the single-agent MTD of 100 mg QD determined among patients with solid tumors 
and lymphoma. Dose escalation will proceed to 100 mg QD (maximally 
administered dose [MAD]) only if safety and tolerability of the 60 mg dose is 
demonstrated. If appropriate, intermediate dose levels between 60 and 100 mg (eg, 
80 mg) or dose levels below the starting dose of 60 mg (eg, 40 mg) may also be 
evaluated if supported by safety and preliminary TAK-659 PK findings.
Amended 
text:
4.1.5 Benefits and Risks
TAK-659 had been administered to a total of only 111 patients as of 22 October 
2016, and it is not currently possible to identify and describe with certainty the 
adverse effects of the compound. 
4.1.5.1 Potential Benefits and Risks of TAK-659
Potential Benefits of TAK-659
Clinical benefit has been observed in Study C34001. Response data were 
available for 85 patients (11 solid tumor, 58 DLBCL, 12 indolent NHL, and 4 
CLL) as of 22 October 2017 in Study C34001. Among response-evaluable 
patients with solid tumors, 1 patient (9%) experienced a partial response (PR) 
and 1 patient (9%) had a response of stable disease (SD) at the time of the 
data cutoff. Among response-evaluable patients with lymphoma DLBCL, best 
responses of CR and PR were reported for 11 and 6 patients, respectively. Of 
the 17 patients with DLBCL who responded, 2 had transitioned to stem cell 
transplant before the data cutoff; 39 patients with DLBCL were still receiving 
study drug as of the data cutoff. Ten patients had a best response of SD, and 
31 patients experienced progressive disease (PD). Among the 4 response-
evaluable patients with CLL, 2 patients achieved PR and 2 had SD. Nine 
patients with indolent lymphomas responded to treatment with TAK-659. 
Three patients achieved a CR, 6 patients achieved PR, and 2 patients had SD.
Potential risks from nonclinical studiesRisks From Nonclinical Studies in 
dogsDogs and rats include: Rats

Lymphoid/hematopoietic effects that include lymphoid depletion and 
myelosuppression that are associated with thrombocytopenia, neutropenia, and 
reticulocytopenia. These findings may be associated with increased 
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susceptibility to infection, bleeding, and/or anemia.

Epithelial effects on the intestinal tract, urinary tract, and lens. Intestinal effects 
included minimal-to-slight mucosal hemorrhaging. Urinary and renal tract 
effects included hyperplasia of transitional epithelium in the kidney and 
bladder, dilatation and hemorrhage in the renal pelvis that led to hematuria and 
proteinuria, and urolithiasis with possible ureter obstruction. Lens effects 
included epithelium hyperplasia leading to anterior axial opacity.

Reproductive system effects, including decreased spermatozoa and 
seminiferous tubule degeneration in the testis and corpora luteal necrosis in the 
ovaries.

Possible mutation of DNA.

Growth plate thickening and disorganization (not relevant to adults).
Lymphoid and hematopoietic effects and reproductive system effects are 
considered important potential risks.
Potential risks based on clinical observations:Risks Based on Clinical 
Observations

On the basis ofBased on 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 elevations are reported commonly (≥10%). Patients in 
Study C34005 will have frequent monitoring of lipase and amylase as outlined 
in the Schedules of Events (Appendix A).

Cases of pneumonitis have been reported in clinical studies with B-cell 
receptor (BCR) pathway kinase inhibitors, including TAK-659, and 
pneumonitis is considered an important potential risk of TAK-659. 
Pneumonitis and other pulmonary toxicities are being closely monitored in 
TAK-659 clinical studies.
The benefits of TAK-659 have not been established; however, early signs of 
clinical antitumor activity were seen. In Study C34001, of the 48 response-
evaluable patients with lymphoma (40 DLBCL, 5 indolent NHL, 2 CLL, and 1 
MCL), 17 patients had responded to treatment per investigator report as of 07 
October 2016. Eight patients with DLBCL achieved a CR and 4 achieved a PR. 
Four patients with indolent lymphomas responded. One patient with mucosa-
associated lymphoid tissue lymphoma achieved a CR, and 3 patients with FL 
achieved PRs. One patient with CLL achieved a PR with a second achieving PR 
after the datacut.

There have been occurrences of opportunistic infections, such as 
Pneumocystis jirovecii pneumonia (PJP), in some patients who had fever. 
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These patients had other underlying conditions that made them prone to 
infections. 

In an analysis of safety data from 107 patients with lymphoma treated 
with single agent TAK-659 in Study C34001, most patients (72%) 
experienced at least 1 treatment-emergent adverse event (TEAE) of any 
grade classified under the infections and infestations System Organ Class 
(SOC) as defined by the Medical Dictionary for Regulatory Activities 
(MedDRA). Pneumonia was the most frequently reported TEAE (26%) 
and the most frequently reported SAE (15%). Cytomegalovirus (CMV) 
infection (20%) and sepsis (17%) were also frequently reported TEAEs. 
Sepsis (17%) and pneumonia (15%) were the most frequently reported 
Grade ≥3 TEAEs.
Further details regarding the benefits and risks associated with TAK-659 may be 
found in the current version of the TAK-659 Investigator’s Brochure (IB)IB.
4.1.5.2 Potential Benefits and Risks of Combination Drugs
The benefits and risks associated with the administration of bendamustine, 
rituximab, gemcitabine, lenalidomide, and ibrutinib should be referenced in 
accordance with their respective United StatesUS Package Inserts (USPIs) [11-
13,15-17] or applicable labeling.
TAK-659 has not been administeredinvestigated in combination previously in 
NHLwith other agents in Studies C34003, C34005, and C34008, and 
preliminary activity has been observed (see TAK-659 IB). The combination of 
TAK-659 and other agents in this study (bendamustine, rituximab, gemcitabine, 
lenalidomide, and ibrutinib) may lead to exacerbation of known toxicities of 
single-agent administration for each agent, and possibly the occurrence of new 
toxicities that have not been identified with the single agents. 
4.1.5.1
Potential Overlapping Toxicities for the Combination of TAK-659 and
Combination PartnersDrugs
Because the combination of TAK-659 with any of the combination agents 
(bendamustine, rituximab, gemcitibine, lenalidomide, and ibrutinib) has not yet 
been tested in humans, there are no identified risks for each of the combinations, 
and all reported AEs are considered unexpected for the purposes of regulatory 
reporting. study is ongoing, and the safety data are limited, no identified risks 
for each of the combination agents in this study have been confirmed. 
Expectedness will be assessed using the respective approved reference safety 
information (RSI). 
4.1.5.2 Drug-Drug Interaction Risk Assessment for the Combination of TAK-659 
and Combination PartnersDrugs
No formal PK drug-drug interaction (DDI) studies have been conducted with 
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TAK-659
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TAK-659 in humans. In vitro studies indicate that TAK-659 is a substrate of P-
glycoprotein (P-gp) and is metabolized by cytochrome P450 (CYP) 3A4/5, 
CYP2D6, and CYP1A2, with relative contributions of 69.1% to 73.0%, 16.6% to 
30.9%, and 0% to 8.40%, respectively. Consequently, there is a potential risk for 
TAK-659 PK to be altered by drugs that are strong CYP3A inhibitors or inducers 
or P-gp inhibitors or inducers.
Assessment of TAK-659 as Victim of DDIs
Based on data included in their respective USPIs [11-13,15-17] or applicable 
labeling, bendamustine, rituximab, gemcitabine, and lenalidomide are not expected 
to inhibit or induce CYP3A or P-gp at clinically relevant doses; therefore, it is 
unlikely for co-administration of these agents to cause alterations in TAK-659 PK. 
However, at clinically relevant doses, ibrutinib has the potential to inhibit the 
efflux transporter P-gp in the gastrointestinal (GI) tract at higher local 
concentrations that may be achieved after PO administration. Thus, the systemic 
exposures of oral narrow therapeutic index P-gp substrates may be increased upon 
co-administration of ibrutinib because of decreased intestinal efflux and increased 
bioavailability of the oral P-gp substrate. Because in vitro data indicate that TAK-
659 is a P-gp substrate, there is a theoretical risk of increased TAK-659 systemic 
exposure with ibrutinib co-administration (gut P-gp inhibitor) relative to TAK-659 
administration alone. Based on current literature, the majority of clinical DDIs due 
to P-gp inhibition are associated with approximately 2-fold or lower increases in 
the exposures of P-gp substrates.
For all combination arms, the TAK-659 starting dose (60 mg QD) will be less than 
the single-agent MTD of 100 mg QD determined among patients with solid tumors 
and lymphoma. Dose escalation will proceed to 100 mg QD (maximally 
administered dose [MAD]) only if safety and tolerability of the 60 mg dose is 
demonstrated. If appropriate, intermediate dose levels between 60 and 100 mg (eg, 
80 mg) or dose levels below the starting dose of 60 mg (eg, 40 mg) may also be 
evaluated if supported by safety and preliminary TAK-659 PK findings.
Rationale for change: For consistency with TAK-659 IB Edition 5.1.
Change 4: Reorganized and updated study rationale.
The primary change occurs in Section 4.2 Rationale for the Proposed Study.
Initial text:
4.2 Rationale for the Proposed Study
TAK-659 is an orally bioavailable, potent and reversible inhibitor of SYK and 
FLT3. SYK is a nonreceptor tyrosine kinase with SH2-binding domains that bind 
to phosphorylated ITAMs located on B and T cells and certain NK cells. SYK 
becomes activated upon ITAM binding and subsequently controls the activity of 
downstream signaling cascades that promote cell survival, growth, and 
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proliferation, transcriptional activation, and cytokine release in these cell types. 
SYK is expressed ubiquitously in hematopoietic cells and abnormal function of 
SYK has been implicated in NHL, including FL, DLBCL, and MCL. TAK-659 
inhibits SYK purified enzyme with an IC50 of 3.2 nM and an EC50 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-DLBCL model; the OCI-Ly19 model, a 
GCB-DLBCL model; the PHTX-95L model, a primary human DLBCL model; the 
RL FL model; and the MINO MCL model. TAK-659 has been tested in 
nonclinical DLBCL models in combination with a number of agents used in the 
relapsed/refractory setting, including gemcitabine, bendamustine, ibrutinib, and 
lenalidomide. With regard to clinical activity, in Study C34001 as of the data 
cutoff date of 07 October 2016, 17 of the 48 response-evaluable patients responded 
to treatment. Eight patients with DLBCL achieved a CR, and 4 achieved a PR. 
Four patients with indolent lymphomas responded. One patient with mucosa-
associated lymphoid tissue lymphoma achieved a CR, and 3 patients with FL 
achieved PRs. One patient with CLL achieved a PR with a second achieving PR 
after the datacut.
...
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 dose escalation study (C34001) in patients with 
advanced solid tumors or lymphoma. Four dose levels (60, 80, 100, and 120 mg 
QD) have been evaluated in 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, 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. As of the 07 
October 2016 data cutoff, of the 48 response-evaluable patients with lymphoma 
(40 DLBCL, 5 indolent NHL, 2 CLL, and 1 MCL), 17 patients had responded to 
treatment per investigator report. Eight patients with DLBCL achieved a CR, and 4 
achieved a PR. Four patients with indolent lymphomas responded. One patient 
with mucosa-associated lymphoid tissue lymphoma achieved a CR, and 3 patients 
with FL achieved PRs. One patient with CLL achieved a PR with a second 
achieving PR after the datacut. These responses have been observed at doses of 60 
(1 PR), 80 (1 PR), 100 (8 CRs and 7 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 supports 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 
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TAK-659
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laboratory abnormalities, such as lipase, amylase, and liver function test 
elevations, were asymptomatic.
In addition, TAK-659 is being evaluated as a single agent in relapsed/refractory 
AML in Study C34002, which includes phase 1b dose escalation and phase 2 dose 
expansion phases. Currently, the 60 mg starting dose of TAK-659 has been 
determined to be safe and tolerable, and dose escalation is ongoing at the 160 mg 
dose level. 
In this dose escalation study, the starting dose of TAK-659 will be 60 mg QD in 
combination with a fixed dose regimen of each combination drug. Dose escalation 
of TAK-659 will follow a standard 3+3 escalation scheme. On the basis of the 
dose escalation experience with TAK-659 in Studies C34001 and C34002, dosing 
will increase to 100 mg QD provided that the safety and tolerability of the 60 mg 
QD dose is demonstrated. Intermediate dose levels between 60 and 100 mg (eg, 80 
mg) or dose levels below the starting dose of 60 mg (eg, 40 mg) may be evaluated 
on the basis of safety, tolerability, and preliminary PK and efficacy data if 
available following agreement between investigators and the sponsor. However, 
the dose of TAK-659 cannot be escalated beyond 100 mg, which is the MTD for 
single-agent TAK-659 in solid tumors and lymphoma.
The dose and schedule at which bendamustine, rituximab, gemcitabine, 
lenalidomide, and ibrutinib will be administered will be in accordance with their 
respective USPIs [11-13, 15-17] or applicable labeling, unless otherwise specified. 
The dose of bendamustine (90 mg/m2) is based on its use in previous combination 
studies with rituximab in both indolent NHL and DLBCL [3,4].
4.2.2 Rationale for PK Assessments
For all dose escalation cohorts (including the safety expansion in the 
MTD/MAD/RP2D cohorts), serial blood samples will be collected for 24 hours 
after TAK-659 dosing on Cycle 1 Days 1 and 15 to characterize the plasma PK of 
TAK-659 when administered with each of the combination partners. Specifically, 
serial plasma PK assessments will be used to describe single- and repeat-dose 
concentration-time profiles of TAK-659 and calculate PK parameters. In addition, 
blood samples for plasma PK will be collected at the same time points for 
cytokine/chemokine assessments on Cycle 1 Day 8. All plasma PK data may 
additionally contribute to population PK model development for TAK-659. The 
major aim of PK assessments in this study is to compare exposures of TAK-659 
following co-administration with each combination partner with exposures 
observed following single-agent administration. Specifically, PK data from this 
combination study will be compared with historical single-agent exposures 
observed in Study C34001 to determine whether there are clinically meaningful 
differences in TAK-659 PK between the single-agent and combination settings in 
patients with lymphoma. 
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Additionally, plasma PK data collected in the dose escalation cohorts may be used 
individually or in combination with data from other studies to explore the 
relationship between TAK-659 PK and pharmacodynamic effects, 
pharmacogenomics in drug-metabolizing enzymes and/or transporters, safety 
parameters, and clinical response.
Amended 
text:
4.2 Rationale for the Proposed Study
4.2.1 Rationale for the Combination of TAK-659 + Combination Drugs
TAK-659 is an orally bioavailable, potent and reversible inhibitor of SYK and 
FLT3.3 and is currently under development for the treatment of patients with 
advanced malignancies (eg, NHL). SYK is a nonreceptor tyrosine kinase with 
SH2-binding domains that bind to phosphorylated ITAMs located on B and T cells 
and certain 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 in hematopoietic cells 
and abnormal function of SYK has been implicated in NHL, including FL, 
DLBCL, and MCL. TAK--659 inhibits SYK purified enzyme with an IC50 of 3.2 
nM and an EC50 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-
DLBCL model; the OCI--Ly19 model, a GCB-DLBCL model; the PHTX-95L 
model, a primary human DLBCL model; the RL FL model; and the MINO MCL 
model. TAK-659 has been tested in nonclinical DLBCL models in combination 
with a number of agents used in the relapsed/refractory setting, including 
gemcitabine, bendamustine, ibrutinib, and lenalidomide. With regard to clinical 
activity, in Study C34001 as of the data cutoff date of 07 October 2016, 17 of the 
48 response-evaluable patients responded to treatment. Eight patients with DLBCL 
achieved a CR, and 4 achieved a PR. Four patients with indolent lymphomas 
responded. One patient with mucosa-associated lymphoid tissue lymphoma 
achieved a CR, and 3 patients with FL achieved PRs. One patient with CLL 
CCI
Property of Takeda: For Non-Commercial Use Only and 
y
tion of 
on o
able, po
ble, p
nder de
nder d
s (eg, N
(eg, N
s that bi
that b
ls. SYK
 SY
ontrols t
ntrols
growth
grow
these ce
hese 
normal 
orma
BCL, an
CL, a
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Nonc
No
of
d Subject to the Applicable Terms of Use
d Subject to the Applicable Ter


TAK-659
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achieved a PR with a second achieving PR after the datacut.
Early signs of clinical activity of TAK-659 have been observed in the first-in-
human (FIH) Study C34001 in patients with multiple subtypes of NHL. In this 
study, response data were available for 85 patients (11 solid tumor, 58 
DLBCL, 12 iNHL, and 4 CLL). Among response-evaluable patients with solid 
tumors, 1 patient (9%) had experienced a PR. Among response-evaluable 
patients with DLBCL, best responses of CR and PR were reported for 11 and 
6 patients, respectively. Clinical activity in responding DLBCL patients was 
achieved independent of cell of origin subtype (GCB or non-GCB) or disease 
history (de novo or transformed) [18]. Refer to the TAK-659 IB for detailed 
clinical information.
...
4.2.2 4.2.1 Rationale for Dose and Schedule Selection
4.2.2.1 Rationale for the Dose and Schedule of TAK-659
TAK-659 has been evaluated as a single agent given PO on a continuous daily 
dosing schedule in its FIH dose escalation study (C34001) in patients with 
advanced solid tumors or lymphoma. Four dose levels (60, 80, 100, and 120 mg 
QD) have been evaluated in 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, 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. As of the 07 
October 2016 data cutoff, of the 48 response-evaluable patients with lymphoma 
(40 DLBCL, 5 indolent NHL, 2 CLL, and 1 MCL), 17 patients had responded to 
treatment per investigator report. Eight patients with DLBCL achieved a CR, and 4 
achieved a PR. Four patients with indolent lymphomas responded. One patient 
with mucosa-associated lymphoid tissue lymphoma achieved a CR, and 3 patients 
with FL achieved PRs. One patient with CLL achieved a PR with a second 
achieving PR after the datacut. These responses have been observed at doses of 60 
(1 PR), 80 (1 PR), 100 (8 CRs and 7 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 supports 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 asymptomatic.
In additionCurrently, TAK-659 is being evaluated as a single agent in 
relapsed/refractory AML in Study C34002, which includes phase 1b dose 
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TAK-659
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escalation and phase 2 dose expansion phases. Currently, the 60 mg starting dose 
of TAK-659 has been determined to be safe and tolerable, and dose escalation is 
ongoing at the 160 mg dose level. in combination with nivolumab (Study 
C34003) and venetoclax (Study C34008). Based on the dose escalation 
experience with TAK-659 in Studies C34001, C34003, and C34008, dosing of 
TAK-659 will escalate in 20 mg increments up to 100 mg QD provided that 
the safety and tolerability of the 60 mg QD dose is demonstrated. Alternative 
dose regimens (eg, intermittent QD dosing of 7 days on followed by 7 days off, 
or 14 days on followed by 7 days off), or dose levels below the starting dose of 
60 mg (eg, 40 mg) may be evaluated based on safety, tolerability, and 
preliminary PK and efficacy data, if available, following agreement between 
investigators and the sponsor. The dose of TAK-659 cannot be escalated 
beyond 100 mg, which is the MTD for single-agent TAK-659 in solid tumors 
and lymphoma.
In this dose escalation study, the starting dose of TAK-659 will be 60 mg QD in 
combination with a fixed dose regimen of each combination drug. Dose escalation 
of TAK-659 will follow a standard 3 + 3 escalation scheme. On the basis of the 
dose escalation experience with TAK-659 in Studies C34001 and C34002, dosing 
will increase to 100 mg QD provided that the safety and tolerability of the 60 mg 
QD dose is demonstrated. Intermediate dose levels between 60 and 100 mg (eg, 80 
mg) or dose levels below the starting dose of 60 mg (eg, 40 mg) may be evaluated 
on the basis of safety, tolerability, and preliminary PK and efficacy data if 
available following agreement between investigators and the sponsor. However, 
the dose of TAK-659 cannot be escalated beyond 100 mg, which is the MTD for 
single-agent TAK-659 in solid tumors and lymphoma.
4.2.2.2 Rationale for the Dose and Schedule of Combination Drugs
The dose and schedule at which bendamustine, rituximab, gemcitabine, 
lenalidomide, and ibrutinib will be administered will be in accordance with their 
respective USPIs [11-13,15-17] or applicable labeling, unless otherwise specified. 
The dose of bendamustine (90 mg/m2) is based on its use in previous combination 
studies with rituximab in both indolent NHL and DLBCL [3,4].
4.2.3 4.2.2 Rationale for PK Assessments
For all dose escalation cohorts (including the safety expansion in the 
MTD/MAD/RP2D cohorts), serial blood samples will be collected for 24 hours 
after TAK-659 dosing on Cycle 1 Days 1 and 15 to characterize the plasma PK of 
TAK-659 when administered with each of the combination partners. Specifically, 
serial plasma PK assessments will be used to describe single- and repeat-dose 
concentration-time profiles of TAK-659 and calculate PK parameters. In addition, 
blood samples for plasma PK will be collected at the same time points for 
cytokine/chemokine assessments on Cycle 1 Day 8. All plasma PK data may 
additionally contribute to population PK model development for TAK-659. The 
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majorThe primary aim of PK assessmentssampling in this study is to compare 
exposures of TAK-659 following co-administration with each combination 
partnerdrug with exposures observed following single-agent administration. 
Specifically, PK data from this combination study will be compared with historical 
single-agent exposures observed in Study C34001 to determine whether there are 
clinically meaningful differences in TAK-659 PK between the single-agent and 
combination settings in patients with lymphoma. Additionally, plasma PK data 
collected in the dose escalation cohortsIn the dose escalation phase, intensive 
PK samples will be collected from all patients during Cycle 1, as detailed in 
Appendix A, Table 3. In the safety expansion part, sparse PK samples will be 
collected (refer to Appendix A, Table 4). 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 PK and 
pharmacodynamic effects, pharmacogenomics in drug-metabolizing enzymes 
and/or transporters, safety parameters, and clinical responseexposure and clinical 
Rationale for change: For consistency with TAK-659 IB Edition 5.1 and to clarify different PK 
sampling schemes for dose escalation and safety expansion phases.
Change 5: Revised study design to restrict the expansion phase of the study to Cohort B only, 
and added text to permit evaluation of intermittent once-daily (QD) dosing schedules in 
Cohort B if appropriate.
The primary change occurs in Section 6.1 Overview of Study Design.
Initial text:
6.1 Overview of Study Design
This is a phase 1b, dose escalation study of TAK-659 in combination with 1 of 5 
combination partners (bendamustine, bendamustine+rituximab, gemcitabine, 
lenalidomide, and ibrutinib) in adult patients with advanced NHL after at least 1 
prior line of therapy. The primary objective of the study is to determine the MTD 
or the RP2D of TAK-659 when administered with each of the combination 
CCI
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partners.
During dose escalation, the dose of TAK-659 will be escalated (planned 2 dose 
levels of escalation: 60 and 100 mg) according to a 3+3 dose escalation scheme; 
all 5 combination partners will be administered at a fixed dose and regimen. 
It is expected that approximately 100 patients (approximately 20 in each of the 5 
treatment groups) will be enrolled in the study.
Once enrolled in the study, patients will be assigned to one of 5 treatment groups 
comprising TAK-659 in combination with bendamustine, 
bendamustine+rituximab, gemcitabine, lenalidomide, or ibrutinib. The starting 
dose of TAK-659 will be 60 mg QD. Dose escalation will follow a standard 3+3 
escalation scheme, and dosing will increase to 100 mg QD provided that the safety 
and tolerability of the 60 mg dose has been demonstrated (Section 8.3). 
Intermediate dose levels between 60 and 100 mg (eg, 80 mg) or dose levels below 
the starting dose of 60 mg (eg, 40 mg) also may be evaluated if appropriate. Dose 
escalation will continue until the MTD is reached, or until TAK-659 100 mg QD 
(the MAD) is determined to be safe and tolerable, or until an RP2D, if different 
from the MTD or MAD, is identified on the basis of the safety, tolerability, and 
preliminary PK and efficacy data (if available) observed in Cycle 1 and beyond. 
Approximately 6 additional patients will be enrolled at the MTD/MAD/RP2D for 
each combination for further safety evaluation.
The dose of each combination drug will remain constant while the TAK-659 dose 
escalation takes place. The doses of the combination drugs will be as follows:

Bendamustine: 90 mg/m2 administered intravenously (IV) over 10 or 60 
minutes (depending on which formulation is used) on Days 1 and 2 of a 21-day 
cycle, up to 8 cycles.

Bendamustine+rituximab: 90 mg/m2 bendamustine administered IV over 10 or 
60 minutes (depending on which formulation is used) on Days 1 and 2 of a 21-
day cycle, up to 8 cycles, and 375 mg/m2 rituximab administered IV per local 
guidelines and labeling on Day 1 of a 21-day cycle, up to 8 cycles.

Gemcitabine: 1000 mg/m2 IV infusion over 30 minutes on Days 1 and 8 of a 
21-day cycle. 

Lenalidomide: 25 mg PO QD for Days 1 to 21 of a 28-day cycle.

Ibrutinib: 560 mg PO QD of a 28-day cycle.
Amended 
text:
6.1 Overview of Study Design
This is a phase 1b, dose escalation study of TAK-659 in combination with 1 of 5
combination partnersdrugs (bendamustine, bendamustine + rituximab, 
gemcitabine, lenalidomide, and ibrutinib) in adult patients with advanced NHL 
after at least 1 prior line of therapy. The primary objective of the study is to 
determine the MTD or the RP2D of TAK-659 when administered with each of the 
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combination partners.
During dose escalation, the dose of TAK-659 will be escalated (planned 2 dose 
levels of escalation: 60 and 100 mg) according to a 3+3 dose escalation scheme; 
all 5 combination partners will be administered at a fixed dose and regimen. 
It is expected that approximately 100 patients (approximately 20 in each of the 5 
treatment groups) will be enrolled in the study. drugs. Once enrolled in the study, 
patients will be assigned to one1 of 5 treatment groups comprising TAK-659 in
combination withcohorts: 

Cohort A (TAK-659 + bendamustine,).

Cohort B (TAK-659 + bendamustine + rituximab,).

Cohort C (TAK-659 + gemcitabine,).

Cohort D (TAK-659 + lenalidomide, or).

Cohort E (TAK-659 + ibrutinib). The starting
This study comprises 2 phases: a dose escalation phase and a safety expansion 
phase. Patients in all 5 cohorts (Cohorts A-E) will participate in the dose 
escalation phase of the study. 
During the dose escalation phase, the dose of TAK-659 will be 60 mg QD. Dose 
escalation will follow a standard 3escalated (planned 3 dose levels of escalation: 
60, 80, and 100 mg) according to a 3 + 3 dose escalation scheme, and dosing. 
The dose of oral TAK-659 will increase toin 20 mg increments to a maximum 
of 100 mg QD, provided that the safety and tolerability of the 60 mg dose has been 
demonstrated (Section 8.3). Intermediate dose levels between 60 and 100 mg (eg, 
80 mg) or dose. Dose levels below the starting dose of 60 mg (eg, 40 mg QD (eg, 
40 mg QD) or intermittent QD dosing schedules (eg, 7 days on followed by 7 
days off, or 14 days on followed by 7 days off) also may be evaluated, if 
appropriate, in Cohort B. Dose escalation will continue until the MTD is reached, 
or until TAK-659 100 mg QD (the MAD) is determined to be safe and tolerable, or 
until an RP2D, if different from the MTD or MAD, is identified based on the basis 
of the safety, tolerability, and preliminary PK and efficacy data (if available) 
observed in Cycle 1 and beyond. Approximately 6
The doses of combination drugs will be administered at a fixed dose and 
regimen (see Section 8.3). 
During the dose escalation phase, DLT-evaluable patients in each dose cohort 
will consist of patients who have met the minimum treatment and safety 
evaluation requirements of the study and/or who experience a DLT during 
Cycle 1. The dose escalation decision is based on the DLT occurrences during 
Cycle 1 per the 3 + 3 escalation schema. Additionally, toxicity and tolerability 
beyond Cycle 1, available PK and pharmacodynamic data, and early signs of 
clinical activity will be taken into consideration in dose escalation decisions 
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and final determination of the MTD and RP2D of TAK-659 with combination 
drugs in each of the cohorts. Based on the evolving data from the trial, an 
alternative dose escalation plan including dose, schedule, DLT evaluation 
period, and further expansion of a given cohort, may be subject to change 
following discussions and agreement between the investigators and the 
sponsor medical monitor. 
During the safety expansion phase of the study, approximately 12 additional 
patients with advanced FL or MZL will be enrolledadded to Cohort B at the 
MTD/MAD/RP2D for each combination for further safety evaluation. PK samples 
will be collected at prespecified time points to characterize the PK of 
TAK-659 when administered with each of the combination drugs. No patients 
from Cohorts A, C, D, or E will enter the safety expansion phase of the study 
because effective 16 March 2018, the sponsor closed recruitment into Cohorts 
C, D, and E, and effective 16 October 2018, the sponsor closed recruitment 
into Cohort A. 
The dose of each combination drug will remain constant while the TAK-659 dose 
escalation takes place. The doses of the combination drugs will be as follows:

Bendamustine: 90 mg/m2 administered intravenously (IV) over 10 or 60 
minutes (depending on which formulation is used) on Days 1 and 2 of a 
21-day cycle, up to 8 cycles.

Bendamustine+rituximab: 90 mg/m2 bendamustine administered IV over 
10 or 60 minutes (depending on which formulation is used) on Days 1 and 
2 of a 21-day cycle, up to 8 cycles, and 375 mg/m2 rituximab administered 
IV per local guidelines and labeling on Day 1 of a 21-day cycle, up to 8 
cycles.

Gemcitabine: 1000 mg/m2 IV infusion over 30 minutes on Days 1 and 8 of 
a 21-day cycle. 

Lenalidomide: 25 mg PO QD for Days 1 to 21 of a 28-day cycle.

Ibrutinib: 560 mg PO QD of a 28-day cycle.
Rationale for change: To streamline the text due to the closure of Cohorts A, C, D and E, 
clarify the dose escalation rationale, and allow additional dosing regimens to be evaluated in 
Cohort B.
The following sections also contain this change:
Section 2.0 STUDY SUMMARY.
Section 8.1.2 Cohort B (TAK-659 + Bendamustine/Rituximab) Dosing Regimen.
Section 13.3 Determination of Sample Size.
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Appendix A
Schedules of Events Table 3 and Table 4 footnotes.
Change 6: Restricted study population in Cohort B expansion phase to patients with advanced 
FL or MZL.
The primary change occurs in Section 7.1 Inclusion Criteria.
Initial text:
2. Histologically or cytologically confirmed diagnosis of advanced NHL of any 
histology (with the exception of patients with WM and CLL). 
Amended 
text:
2. HistologicallyIn the dose escalation phase, histologically or cytologically 
confirmed diagnosis of advanced NHL of any histology (with the exception of 
patients with WM and CLL). In the safety expansion phase for Cohort B, 
only patients with advanced FL or MZL will be included.
Rationale for change: To align the patient population in the Cohort B expansion phase with the 
TAK-659 clinical development strategy.
Section 2.0 STUDY SUMMARY also contains this change.
Change 7: Revised study sample size determination and planned enrollment numbers for each 
cohort.
The primary change occurs in Section 13.3 Determination of Sample Size.
Initial text:
13.3 Determination of Sample Size
The dose escalation of this study will use a 3+3 design. With the exception of the 
bendamustine combination arm, the combination partner’s dose will be the dose 
according to the manufacturer’s label. The dose of bendamustine will be based on 
its use in previous combination studies [3,4]. The planned doses of TAK-659 are 
60 and 100 mg. For each combination arm, 9 to 12 DLT-evaluable patients will be 
needed for the dose escalation portion. In addition, for each arm, another 6 patients 
will be needed for safety expansion. Assuming a 10% dropout rate, 20 patients will 
be needed for each arm; therefore, the total sample size for this study, including all 
5 arms, will be 100.
Amended 
text:
13.3 Determination of Sample Size
The dose escalation phase of this study will use a 3 + 3 design. With the exception 
of the bendamustine combination arm, the, each combination partnerdrug’s dose 
will be the dose according to the manufacturer’s label. The dose of bendamustine 
will be based on its use in previous combination studies [3,4]. The planned doses 
of TAK-659 are 60 and 100 mg. For each combination armIn the dose escalation 
phase, 9 to 12 DLT-evaluable patients will be needed for the dose escalation 
portion. In addition, for each arm, another 6 patients will be needed for safety 
expansionfrom each of Cohorts A to E will be recruited based on 2 planned 
dose levels of TAK-659. A dose lower than 60 mg QD (eg, 40 mg QD) or 
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intermittent QD dosing schedules (eg, 7 days on followed by 7 days off, or 14 
days on followed by 7 days off) may be evaluated in Cohort B, if appropriate. 
As a result, the actual number of patients to be enrolled into Cohort B will be 
increased accordingly. Twelve additional patients with FL or MZL will be 
recruited into Cohort B for the safety expansion phase; no patients from 
Cohorts A, C, D, or E will be recruited for the safety expansion phase since 
the sponsor has closed enrollment into these cohorts. Assuming a 10% dropout 
rate, 20 patients will be needed for each arm; therefore, theapproximately 40 
patients in Cohort B and 14 patients each in Cohorts A, C, D, and E will be 
recruited. The total sample size for this study, including all 5 arms, will be 
100.approximately 96 patients.
Rationale for change: To update the sample size estimations to account for the additional 
doses/dosing regimens permitted in Cohort B and the closure of Cohorts A, C, D, and E.
The following sections also contain this change:
Section 2.0 STUDY SUMMARY.
Section 6.2 Number of Patients.
Change 8: Revised planned dose levels of TAK-659.
The primary change occurs in Section 8.3 Dose Escalation Rules.
Initial text:
8.3 Dose Escalation Rules 
The dose escalation phase of the study is designed to determine the DLTs and 
MTD and/or RP2D of TAK-659 when given in combination with bendamustine (± 
rituximab), gemcitabine, lenalidomide, or ibrutinib. Approximately 20 patients are 
expected to be enrolled in each of 5 cohorts based on the planned 2 dose-level 
escalation for TAK-659 (Table 8.f) when administered with a fixed-dose regimen 
of the combination drugs; the exact number of patients to be enrolled will depend 
on the actual number of dose-level cohorts required, which may deviate from the 
dose escalation plan based on toxicities and the PK results observed during the 
initial dose levels.
The dose of the combination drugs will be as follows:

Bendamustine: 90 mg/m2 administered IV over 10 or 60 minutes (depending 
on which formulation is used) on Days 1 and 2 of a 21-day cycle, up to 8 
cycles.

Bendamustine+rituximab: 90 mg/m2 bendamustine administered IV over 10 or 
60 minutes (depending on which formulation is used) on Days 1 and 2 of a 21-
day cycle, up to 8 cycles, and 375 mg/m2 rituximab administered IV per local 
guidelines and labeling on Day 1 of a 21-day cycle, up to 8 cycles.

Gemcitabine: 1000 mg/m2 IV infusion over 30 minutes on Days 1 and 8 of a 
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21-day cycle. 

Lenalidomide: 25 mg PO QD for Days 1 to 21 of a 28-day cycle.

Ibrutinib: 560 mg PO QD of a 28-day cycle.
…
Dose escalation of TAK-659 will not exceed 100 mg QD, the single-agent MTD 
for TAK-659, as established in the FIH dose escalation study of TAK-659 
(C34001). More conservative dose escalation, including evaluation of an 
intermediate dose (eg, 80 mg QD) or de-escalation in 20 mg decrements from the 
starting dose of 60 mg QD of TAK-659 (eg, 40 mg) if that dose is determined to 
be not tolerable, expansion of an existing dose level, or an alternative 
regimen/schedule, are all permissible following written confirmation of 
discussions between the sponsor and the investigators, if such measures are needed 
for patient safety, for a better understanding of the dose-related toxicity and 
preliminary PK and efficacy of TAK-659, or for adjustment based on the initial 
characterization of PK of TAK-659 when administered with the combination 
drugs.
… 
Table 8.f
Planned Dose Levels of TAK-659
Dose Level
Dose (Unit)
1
60 mg
2
100 mg (a)
More conservative dose escalation, including evaluation of intermediate doses, dose de-escalation 
in 20 mg decrements from the starting dose of 60 mg QD if that determined to be not tolerable, 
expansion of an existing dose level, and an alternative dose schedule/regimen are all permissible 
following discussions between the sponsor and the investigators, if such measures are needed for 
patient safety or for a better understanding of the dose-related toxicity and preliminary PK and 
efficacy of TAK-659.
(a) The maximum dose to be assessed is TAK-659 100 mg QD.
…
Patients who do not meet these minimum requirements will be regarded as 
ineligible for DLT evaluation for the given dose cohort and may be replaced 
within the same cohort.
Dose escalation is planned for TAK-659 only. While the combination drugs are 
administered with a fixed dose and schedule, in case of frequent occurrences of 
dose modification or discontinuation of the combination drug in Cycle 1 and/or 
Cycle 2 and beyond per dose modification guidelines in Section 8.4, upon 
discussion and agreement between investigators and the sponsor, the fixed dose of 
the combination drug could be reset at a lower dose for the purpose of further 
evaluation and determination of the TAK-659 MTD/RP2D.
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Amended 
text:
8.3 Dose Escalation Rules 
The dose escalation phase of the study is designed to determine the DLTs and 
MTD and/or RP2D of TAK-659 when given in combination with bendamustine (± 
rituximab), gemcitabine, lenalidomide, or ibrutinib. Approximately 20 patients are 
expected to be enrolled in each of 5 cohortsPatients in Cohorts A to E will be 
dosed based on the planned 23 dose-level escalation for TAK-659 (Table 8.f) 
when administered with a fixed-dose regimenin each of the combination drugs; 
thecohorts. The exact number of patients to be enrolled will depend on the actual 
number of dose-level cohorts required, which may deviate from the dose 
escalation plan based on toxicities and the PK results observed during the initial 
dose levels.
The dose of the combination drugs will be as follows:

Bendamustine: 90 mg/m2 administered IV over 10 or 60 minutes 
(depending on which formulation is used) on Days 1 and 2 of a 21-day 
cycle, up to 8 cycles.

Bendamustine+rituximab: 90 mg/m2 bendamustine administered IV over 
10 or 60 minutes (depending on which formulation is used) on Days 1 
and 2 of a 21-day cycle, up to 8 cycles, and 375 mg/m2 rituximab 
administered IV per local guidelines and labeling on Day 1 of a 21-day 
cycle, up to 8 cycles.

Gemcitabine: 1000 mg/m2 IV infusion over 30 minutes on Days 1 and 8 
of a 21-day cycle. 

Lenalidomide: 25 mg PO QD for Days 1 to 21 of a 28-day cycle.

Ibrutinib: 560 mg PO QD of a 28-day cycle.
Cohort
Combination Study 
Drug
Dosage and Regimen
A
Bendamustine
90 mg/m2 administered IV over 10 or 60 minutes (depending on 
which formulation is used) on Days 1 and 2 of each 21-day cycle, 
up to 8 cycles
B
Bendamustine + rituxi
mab
90 mg/m2 bendamustine administered IV over 10 or 60 minutes 
(depending on which formulation is used) on Days 1 and 2 of 
each 21-day cycle, up to 8 cycles, and 375 mg/m2 rituximab 
administered IV per local guidelines and labeling on Day 1 of 
each 21-day cycle, up to 8 cycles
C
Gemcitabine
1000 mg/m2 IV infusion over 30 minutes on Days 1 and 8 of each 
21-day cycle
D
Lenalidomide
25 mg PO QD for Days 1-21 of each 28-day cycle
E
Ibrutinib
560 mg PO QD of each 28-day cycle
...
Dose escalation of TAK-659 will not exceed 100 mg QD, theDuring the dose 
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escalation phase, 3 levels of dose escalation are planned for TAK-659: 60, 80, 
and 100 mg (Table 8.f), according to a 3 + 3 dose escalation scheme. The
single-agent MTD for TAK-659,659 is 100 mg QD as established in the FIH dose 
escalation study of TAK-659 (C34001). Therefore, dose escalation of TAK-659 
will not exceed 100 mg QD in this study. More conservative dose escalation, 
including evaluation of an intermediate dose (eg, 80 mg QD) or de-escalation in 20 
mg decrements from the starting dose of 60 mg QD of TAK-659 (eg, 40 mg QD) 
if that dose is determined to be not tolerable, expansion of an existing dose level, 
or an alternative regimen/schedule, are all permissible following written 
confirmation of discussions between the sponsor and the investigators, if such 
measures are needed for patient safety, for a better understanding of the dose-
related toxicity and preliminary PK and efficacy of TAK-659, or for adjustment 
based on the initial characterization of PK of TAK-659 when administered with 
the combination drugs.
…
Table 8.f
Planned Dose Levels of TAK-659 for Cohorts A to E
Dose Level
Dose (Unit)
1
60 mg
2
10080 mg (a)
3
100 mg a
a The maximum dose to be assessed is TAK-659 100 mg QD.
…
Patients who do not meet these minimum requirements will be regarded as 
ineligible for DLT evaluation for the given dose cohort and may be replaced 
within the same cohort. Dose escalation is planned for TAK-659 only. While the 
combination drugs are administered with a fixed dose and schedule, in case of 
frequent occurrences of dose modification or discontinuation of the combination 
drug in Cycle 1 and/or Cycle 2 and beyond per dose modification guidelines in 
Section 8.4, upon discussion and agreement between investigators and the sponsor, 
the fixed dose of the combination drug could be reset at a lower dose for the 
purpose of further evaluation and determination of the TAK-659 MTD/RP2D. 
Rationale for change: To allow additional doses/dosing regimens to be evaluated in Cohort B.
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The following sections also contain this change:
Section 2.0 STUDY SUMMARY.
Section 6.1 Overview of Study Design.
Section 8.4 Dose Modification Guidelines.
Change 9: Revised duration of an individual patient’s study participation.
The primary change occurs in Section 6.3.1 Duration of an Individual Patient’s Study 
Participation.
Added text:
At the conclusion of the study, participants who continue to demonstrate 
clinical benefit may be eligible to receive Takeda-supplied study drug. Study 
drug may be provided via an extension of the study, a rollover study 
requiring approval by responsible health authority and ethics committee, or 
through another mechanism at the discretion of Takeda. 
Takeda reserves the right to terminate access to Takeda supplied study drug 
if any of the following occurs: a) the benefit-risk profile is not favorable; b) 
the marketing application is rejected by responsible health authority; c) the 
study is terminated due to safety concerns; d) investigational agent(s) 
becomes commercially available or other access mechanism becomes 
available; e) development of the drug is suspended or ceased, or sponsor 
cannot adequately supply investigational agent; or f) appropriate therapeutic 
alternatives become available in the local market.
Rationale for change: To explain how patients who are benefitting from study drugs can 
continue to have access to them after they complete the study.
Change 10: Extended total study duration.
The primary change occurs in Section 6.3.4 Total Study Duration.
Initial text:
6.3.4 Total Study Duration
It is anticipated that this study will last approximately 27 months.
Amended 
text:
6.3.4 Total Study Duration
It is anticipated that this study will last approximately 2730 months.
Rationale for change: To more accurately reflect the anticipated duration of the study.
Section 6.3.2 End of Study/Study Completion Definition and Planned Reporting also contains 
this change.
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Change 11: Specified number of prior lines of therapy for patients entering Cohort B expansion 
phase and clarified the definition of lines of therapy.
The primary change occurs in Section 7.1 Inclusion Criteria.
Initial text:
4. Patients who are refractory or relapsed after at least 1 prior line of therapy and 
for whom no effective standard therapy is available per the investigator’s 
assessment.

Either treatment naïve to, relapsed/refractory to, or experienced treatment 
failure due to other reasons with ibrutinib, idelalisib, or any other 
investigational BCR pathway inhibitors not directly targeting SYK.

Prior treatment with a regimen that includes the combination drug will not 
necessarily exclude a patient from that cohort if the investigator views 
treatment with that agent as appropriate. However, a patient who has a 
contraindication for a particular combination agent or who has been 
discontinued from prior therapy with a particular agent for toxicity will not 
be eligible for inclusion in that particular cohort.
Amended 
text:
4. Patients In the dose escalation phase, patients who are refractory or relapsed 
after at least 1 prior line of therapy due to progression, intolerance, or
physician/patient decision and for whom no effective standard therapy is 
available per the investigator’s assessment. In the safety expansion phase for 
Cohort B in patients with FL or MZL, the prior line of therapy is limited 
to ≤1.
a) Either treatment naïve to, relapsed/refractory to, or experienced treatment 
failure due to other reasons with ibrutinib, idelalisib, or any other 
investigational BCR pathway inhibitors not directly targeting SYK.
b) Preinduction salvage chemotherapy and ASCT should be considered 1 
therapy.
c) Any consolidation/maintenance therapy after a chemotherapy regimen 
(without intervening relapse) should be considered 1 line of therapy with 
the preceding combination therapy. Maintenance antibody therapy should 
not be considered a line of therapy.
d) For aggressive NHL (ie, DLBCL), single-agent anti-CD20 monoclonal 
antibody therapy should not be considered a line of therapy. Antibody 
therapy in patients with indolent NHL (ie, FL) given as a single agent after 
disease progression from a prior treatment should be considered a line of 
therapy.
e) For patients with DLBCL transformed from indolent lymphoma, any 
treatment received for the indolent disease before the transformation to 
DLBCL will, in general, not count toward the 2 to 3 prior lines of therapy 
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required for DLBCL in this study.
f)
Prior treatment with a regimen that includes the combination drug will not 
necessarily exclude a patient from that cohort if the investigator views 
treatment with that agent as appropriate. However, a patient who has a 
contraindication for a particular combination agent or who has been 
discontinued from prior therapy with a particular agent for toxicity will not be 
eligible for inclusion in that particular cohort.
Rationale for change: To clarify that patients in the Cohort B expansion may have had no more 
than 1 prior line of therapy, and to assist in determining the number of lines of prior therapy for 
study eligibility.
The following sections also contain this change:
Section 2.0 STUDY SUMMARY.
Section 5.1.2 Secondary Objectives.
Change 12: Revised method for measuring renal function.
The primary change occurs in Section 7.1 Inclusion Criteria.
Initial text:
6. Patients must have adequate organ function, including the following:
…

Renal: creatinine clearance ≥60 mL/min either as estimated by the Cockcroft-
Gault equation or based on urine collection (12 or 24 hours) (See Appendix E).
Amended 
text:
6. Patients must have adequate organ function, including the following:
…
c) Renal: creatinine clearance ≥60 mL/min either as estimated by the Cockcroft-
Gault equation or based on urine collection (12 or 24 hours) (See(see
Appendix E).
Rationale for change: To simplify the method for measuring renal function.
Section 2.0 STUDY SUMMARY also contains this change.
Change 13: Added requirement for controlled fasting serum glucose levels during screening.
The primary change occurs in Section 7.1 Inclusion Criteria.
Added text:
6.
Patients must have adequate organ function, including the following:
…
iii. Fasting serum glucose level shall be controlled to 130 mg/dL during the 
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screening period.
Rationale for change: Added as an additional measure of adequate organ function to determine 
study eligibility.
Section 2.0 STUDY SUMMARY also contains this change.
Change 14: Added requirement that women of childbearing potential must have a negative 
serum pregnancy test at screening.
The primary change occurs in Section 7.1 Inclusion Criteria.
Added text:
7. Female subjects who:
…
e) Women of childbearing potential (WOCBP) must have a negative serum 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human 
chorionic gonadotropin [hCG]) at screening.
Rationale for change: For consistency with other TAK-659 clinical study protocols.
Change 15: Added requirement that female patients should not donate ova from time of signing 
informed consent through 180 days after last dose of study drug.
The primary change occurs in Section 7.1 Inclusion Criteria.
Added text:
8.
Female patients should not donate ova from the time of signing the 
informed consent through 180 days after the last dose of study drug.
Rationale for change: For consistency with other TAK-659 clinical study protocols.
Section 8.7 Precautions and Restrictions also contains this change.
Change 16: Added requirement that male patients should not donate sperm from time of signing 
informed consent through 180 days after last dose of study drug.
The primary change occurs in Section 7.1 Inclusion Criteria.
Added text:
9. Male patients should not donate sperm from the time of signing the 
informed consent through 180 days after the last dose of study drug.
Rationale for change: For consistency with other TAK-659 clinical study protocols.
Section 8.7 Precautions and Restrictions also contains this change.
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Change 17: Clarified exclusion criteria related to prior anticancer treatment and prior autologous 
stem cell transplant.
The primary change occurs in Section 7.2 Exclusion Criteria.
Initial text:
11. Systemic anticancer treatment (incluing investigational agents) or 
radiotherapy less than 2 weeks before the first dose of study treatment (≤4 
weeks for large molecule agents).
12. 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. 
Amended 
text:
11. Systemic anticancer treatment (incluingincluding investigational agents) or 
radiotherapy less than 2 weeks before the first dose of study treatment (≤4 
weeks for large molecule agents). 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).
12. Prior ASCT within 6 months or prior ASCT at any time without fulladequate
hematopoietic recovery, defined by the entry criteria in the study, before 
Cycle 1 Day 1, or allogeneic stem cell transplant any time. 
Rationale for change: To more accurately describe the intent of these exclusion criteria.
Section 2.0 STUDY SUMMARY also contains this change.
Change 18: Clarified exclusion criterion related to cardiovascular conditions.
The primary change occurs in Section 7.2 Exclusion Criteria.
Initial text:
14. Patients with any of the following cardiovascular conditions are excluded: 

Acute myocardial infarction within 6 months before starting study drug.
Amended 
text:
14. Patients with any of the following cardiovascular conditions are excluded: 
a) AcuteUnstable angina or acute myocardial infarction within 612
months before starting study drug.
Rationale for change: To more accurately describe the intent of this exclusion criterion.
Change 19: Updated definitions of dose-limiting toxicity.
The primary change occurs in Section 8.2 Definitions of DLT.
Initial text:
8.2 Definitions of DLT
Toxicity will be evaluated according to the NCI CTCAE version 4.03, effective 
14 June 2010 [1]. These criteria are provided in the Study Manual. DLT is defined 
as any of the following events that are considered by the investigator to be at least 
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possibly related to therapy with TAK-659 when administered in combination with 
bendamustine±rituximab, gemcitabine, lenalidomide, and ibrutinib. AEs in which 
the relationship to study drug cannot be ruled out should be considered possibly 
related to study drug.

Grade 4 neutropenia (ANC 500 cells/mm3) lasting more than 7 consecutive 
days. 

≥Grade 3 neutropenia (ANC 1000 cells/mm3) with fever and/or infection, 
where fever is defined as a temperature 38.5C.

Grade 4 thrombocytopenia lasting more than 7 consecutive days.

Grade 3 thrombocytopenia of any duration accompanied by clinically 
significant bleeding. 

A platelet count 10,000/mm3 at any time.

Any Grade 3 or greater nonhematologic toxicity with the following exceptions:

Grade 3 fatigue that lasts less than 1 week.

≥Grade 3 nausea and/or emesis that can be controlled to ≤Grade 1 or baseline 
in 7 days with the use of optimal antiemetic prophylaxis (defined as an 
antiemetic regimen that employs both a 5-HT antagonist and a corticosteroid 
given in standard doses and according to standard schedules).

≥Grade 3 diarrhea that can be controlled to ≤Grade 1 or baseline in 7 days with 
optimal supportive therapy.

Any other Grade 3 nonhematologic toxicity that can be controlled to ≤Grade 1 
or baseline in 7 days with appropriate treatment. In this setting, a course of 
action will be determined jointly by the investigators and the sponsor clinician.

Inability to administer at least 75% of planned doses of study drug within 
Cycle 1 due to treatment-related toxicity.

Delay in the initiation of the subsequent cycle of therapy by more than 7 days 
due to treatment-related hematologic or nonhematologic toxicities.

Greater than or equal to Grade 2 nonhematologic toxicities that are considered 
by the investigator to be related to study drug(s). In this setting, a course of 
action will be determined jointly by the investigators and the sponsor clinician.
Although DLTs may occur at any point during treatment, only DLTs occurring 
during Cycle 1 of treatment in this dose escalation study will necessarily influence 
decisions regarding dose escalation, expansion of a dose level, or evaluation of 
intermediate dose levels. Patients will be monitored through all cycles of therapy 
for treatment-related toxicities.
Patients experiencing a DLT in Cycle 1 may continue in the study if they are 
deriving clinical benefit, but they will be administered reduced doses of TAK-659 
and/or the combination agent as appropriate.
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Amended 
text:
8.2 Definitions of DLT
Toxicity will be evaluated according to the NCI CTCAE version 4.03, effective 14 
June 2010 [1]. These criteria are provided in the Study Manualstudy manual. 
DLT is defined as any of the following events that are considered by the 
investigator to be at least possibly related to therapy with TAK--659 when 
administered in combination with bendamustine ± rituximab, gemcitabine, 
lenalidomide, and ibrutinib. AEs in which the relationship to study drug cannot be 
ruled out should be considered possibly related to study drug.

Hematologic toxicity: 
–
Grade 4 neutropenia (ANC <500 cells/mm3) lasting/µL) unresolved to 
Grade ≤1 (ANC >1500/µL) or baseline for more than 7 consecutive days
in the absence of growth factor support. 
–
≥Grade ≥3 neutropenia (ANC <1000 cells/mm3/µL) with fever and/or 
infection, where fever is defined as aan oral temperature ≥38.5ºC.
–
Grade 4 thrombocytopenia lasting(<25,000/µL) unresolved to Grade ≤1 
(>75,000/µL) or baseline for more than 7 consecutive days or a platelet 
count <10,000/µL at any time.
-

–
Grade ≥3 thrombocytopenia of any duration accompanied by(<50,000/µL) 
with clinically significant bleeding. 
-

A platelet count 10,000/mm3 at any time.
–
Grade 4 anemia. 

Any Grade 3 or greater nonhematologic toxicity with the following exceptions:
–
Grade 3 fatigue that lasts less than 1 week.Fatigue or arthralgia/myalgia 
that improve to Grade ≤2 within 7 days. 
–
Grade ≥Grade 3 nausea and/or emesis that can be controlled to ≤Grade ≤1 
or baseline in 7 days with the use of optimal antiemetic prophylaxis 
(defined as an antiemetic regimen that employs both a 5-
HThydroxytryptamine 3 (5-HT3) antagonist and a corticosteroid given in 
standard doses and according to standard schedules).
–
≥Grade ≥3 diarrhea that can be controlled to ≤Grade ≤1 or baseline in 7 
days with optimal supportive therapy.
–
Asymptomatic Grade 3 amylase or lipase elevations that last ≤7 days.
–
Asymptomatic Grade 3 elevation of a single liver enzyme (AST or 
ALT) in the absence of significant bilirubin elevation (Grade <3) 
considered not dose limiting following agreement between the sponsor 
and investigators.
–
Isolated Grade ≥3 abnormalities of other laboratory parameters (other 
than electrolyte imbalances/abnormalities) that resolve to Grade ≤1 in 
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≤7 days without clinical sequelae or need for therapeutic intervention 
considered not dose-limiting following agreement between the sponsor 
and investigators. 
–
Grade 3 rash lasting ≤7 days with optimal treatment that includes 
topical steroid treatment, PO antihistamines, and pulse PO steroids, if 
necessary.
–
Any other Grade 3 nonhematologic toxicity that can be controlled to 
≤Grade ≤1 or baseline in 7 days with appropriate treatment. In this setting, 
a course of action will be determined jointly by the investigators and the 
sponsor clinicianmedical monitor.

– Inability to administer at least 75% of planned doses of study drugTAK-659
within Cycle 1 due to treatment-related toxicity.

Delay in the initiation of the subsequent cycle of therapy by more than 7 days 
due to treatmentstudy drug-related hematologic or nonhematologic toxicities.

Greater than or equal to Grade 2Other study drug-related nonhematologic 
toxicities that are considered byGrade ≥2 that, in the opinion of the 
investigator to be related to study drug(s), require a dose reduction or 
discontinuation of study treatment. In this setting, a course of action will be 
determined jointly by the investigators and the sponsor clinicianmedical 
monitor.
Although DLTs may occur at any point during treatment, only DLTs occurring 
during Cycle 1 of treatment in this dose escalation study will necessarily influence 
decisions regarding dose escalation, expansion of a dose level, or evaluation of 
intermediate dose levels. Patients will be monitored through all cycles of therapy 
for treatment-related toxicities.
Patients experiencing a DLT in Cycle 1 may continue in the study if they are 
deriving clinical benefit, but they will be administered reduced doses of TAK-659 
and/or the combination agent as appropriate.
Rationale for change: For consistency with other TAK-659 clinical study protocols.
Change 20: Revised dose modification guidelines for hematologic and nonhematologic 
toxicities.
The primary change occurs in Section 8.4.4 Dose Modification for Hematologic and 
Nonhematologic Toxicity Table 8.i, Table 8.j, Table 8.k, and Table 8.l.
Description 
of Change:

In Table 8.i Dose Modification Guidelines for Hematologic Toxicities for 
Cohort A (TAK-659 + Bendamustine) and Cohort B (TAK-
659 + Bendamustine/Rituximab, the following changes were made:
― Revised retreatment criteria based on ANC.
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― Revised descriptions for Grades 1-2 and Grade 3 thrombocytopenia.
― Revised retreatment criteria based on PLT count.
― Revised the description of Grade 4 anemia.

In Table 8.j Dose Modification Guidelines for Nonhematologic Toxicities for 
Cohort A (TAK-659 + Bendamustine) and Cohort B 
(TAK-659 + Bendamustine/Rituximab, the following changes were made:
― Revised the list of exceptions under other Grade 3 nonhematogic toxicities.

In Table 8.k Dose Modification Guidelines for Hematologic Toxicities for 
Cohort C (TAK-659 + Gemcitabine), Cohort D (TAK-659 + Lenalidomide), 
and Cohort E (TAK-659 + Ibrutinib), the following changes were made:
― Revised retreatment criteria based on ANC.
― Revised descriptions for Grades 1-2 and Grade 3 thrombocytopenia.
― Revised retreatment criteria based on PLT count.
― Revised the description of Grade 4 anemia.

In Table 8.l Dose Modification Guidelines for Nonhematologic Toxicities for 
Cohort C (TAK-659 + Gemcitabine), Cohort D (TAK-659 + Lenalidomide), 
and Cohort E (TAK-659 + Ibrutinib), the following changes were made:
― Revised the list of exceptions under other Grade 3 nonhematogic toxicities.
Rationale for change: Updated for accuracy.
Change 21: Revised retreatment criteria for Cohorts A, B, and C.
The primary change occurs in Section 8.4.3 Retreatment Criteria for Cohorts A, B, and C 
(Bendamustine or Gemcitabine).
Initial text:
8.4.3 Re-treatment Criteria for Bendamustine or Gemcitabine (Cohorts A, B, 
and C)
Per the prescribing information for bendamustine and gemcitabine, the patient 
must meet the following re-treatment criteria before starting the next dose of 
bendamustine (Cohorts A and B) or gemcitabine (Cohort C): 

ANC ≥1500/mm3.

Platelet count ≥100,000/mm3.

Total bilirubin <ULN, ALT/AST <1.5×ULN.
Amended 
text:
8.4.3 Re-treatmentRetreatment Criteria for Cohorts A, B, and C 
(Bendamustine or Gemcitabine (Cohorts A, B, and C)
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Per the prescribing information for bendamustine and gemcitabine, the patient 
must meet the following re-treatmentretreatment criteria before starting the next 
dose of bendamustine (Cohorts A and B) or gemcitabine (Cohort C): 
a) ANC ≥1500/mm3.1000/µL.
b) Platelet count ≥100,000/mm3.75,000/ µL.

Total bilirubin <ULN, ALT/AST <1.5×ULN.
Rationale for change: To align with standard of care.
Section 8.4.4 Dose Modification for Hematologic and Nonhematologic Toxicity Table 8.i and 
Table 8.k also contain this change.
Change 22: Reorganized and updated management of TAK-659–related clinical events.
The primary change occurs in Section 8.8 Management of TAK-659–Related Clinical Events.
Initial text:
8.8 Management of Clinical Events
…
8.8.1 Prophylaxis Against Infection
Patients with advanced hematologic 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 with the 
underlying disease (lymphoma). Lymphopenia can be associated with reactivation 
of herpes zoster, CMV, herpes simplex, and other viruses. Antiviral therapy, such 
as acyclovir, gancyclovir, 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 for asymptomatic patients, if indicated, should 
follow the institutional standard practice. The following agents could be 
considered for prophylaxis or pre-emptive treatment against CMV: ganciclovir 
(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 per 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 is present: 

Absolute CD4+ T-cell count of <200/mm3.

Percent 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. 
Given their degree of immunosuppression, patients with posttransplant 
lymphoproliferative disease are often at an increased risk of developing infections. 
Consideration should be given to antibiotic, antifungal, and antiviral prophylaxis 
during therapy, particularly if the patient is more prone to developing neutropenia; 
however, the use of such agents should be at the discretion of investigators based 
on the local standard practice. Patients who develop neutropenic fever should be 
evaluated promptly and treated immediately with parental antibiotics tailored to 
the prominent organisms and resistance patterns of the institution.
Amended 
text:
8.8 Management of TAK-659–Related Clinical Events
…
8.8.1 Prophylaxis Against Infection
Patients with advanced hematologic 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 or per National 
Comprehensive Cancer Network Prevention and Treatment of Cancer-
Related Infections Guidelines. In particular, lymphopenia can develop in 
association with either treatment or with the underlying disease (lymphoma). 
Lymphopenia can be associated with reactivation of herpes zoster, CMV, herpes 
simplex, and other viruses. Antiviral therapy, such as acyclovir, 
gancyclovirganciclovir, valacyclovir, or other antiviral agents, may be initiated as 
clinically indicated. Testing of CMV replication by a local It is recommended
that prophylaxis for varicella-zoster virus should be administered for Cohort 
B [19].
Given their degree of immunosuppression, subjects with posttransplant 
lymphoproliferative disease are often at an increased risk of developing 
infections. Consideration should be given to antibiotic, antifungal, and 
antiviral prophylaxis during therapy, particularly if the subject is more prone 
to developing neutropenia. Subjects who develop neutropenic fever should be 
evaluated promptly and treated immediately with parental antibiotics 
tailored to the prominent organisms and resistance patterns of the institution.
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8.8.1.1 CMV Monitoring and Prophylaxis
At screening, on Day 1 of each treatment cycle, and at end of treatment 
(EOT), all subjects should have CMV serology and/or quantitative polymerase 
chain reaction (PCR) assay will be required at Baseline, and furtherperformed. If 
positive at any timepoint, CMV monitoring is advised once a week with a 
decrease to once every cycle as it becomes negative. Interruption of study 
drug is generally advised if the positive CMV test is accompanied by 
associated clinical symptoms, if the copy number reaches a level indicates a 
need for treatment per institutional standard, or if the CMV test remains 
positive despite the antiviral treatment for CMV. Further monitoring and 
prophylactic or preemptive therapy for asymptomatic patients, if indicated, should 
follow the institutional standard practice. The following agents couldshould be 
considered for prophylaxis or pre-emptive treatment against CMV: ganciclovir 
(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 per PCR. 
8.8.1.2 Prophylaxis for Opportunistic Infections
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 Baselinebaseline or during 
treatment) if the following is present: 

Absolute CD4+ T-cell count of <200/mm3.

Percent CD4+ T-cells <20%.

Prior episode of PJP in medical history. 
It is recommended that the prophylaxis for PJP should be implemented in 
Cohort B regardless of the above-mentioned conditions [19]. 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 Baselinebaseline, 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-
administeredcoadministered. 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. 
Given their degree of immunosuppression, patients with posttransplant 
lymphoproliferative disease are often at an increased risk of developing infections. 
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Consideration should be given to antibiotic, antifungal, and antiviral prophylaxis 
during therapy, particularly if the patient is more prone to developing neutropenia; 
however, the use of such agents should be at the discretion of investigators based 
on the local standard practice. Patients who develop neutropenic fever should be 
evaluated promptly and treated immediately with parental antibiotics tailored to 
the prominent organisms and resistance patterns of the institution.
Rationale for change: For consistency with other TAK-659 clinical study protocols.
Change 23: Added a section heading for management of combination drug-related clinical 
events.
The primary change occurs in Section 8.9 Management of Combination Drug-Related Clinical 
Events.
Added text:
8.9 Management of Combination Drug-Related Clinical Events
Clinical characteristics and risk mitigation measures addressing each of the 
important combination drug–related clinical events are summarized below. 
Refer to the most recent USPI [9-11, 13-15] or applicable labeling for each 
drug for further details.
Rationale for change: For consistency with other TAK-659 clinical study protocols.
Change 24: Added sparse PK sampling schedule for Cohort B expansion phase, and clarified 
PK and PD sampling schedules for Cohort B when intermittent QD dosing schedule is used.
The primary change occurs in Appendix A
Schedules of Events Table 3 and Table 4.
Description 
of change:

The following footnotes were added to Table 3:
a Scheduled PD and PK measurements on Cycle 1 Day 15 and Day 16 will 
be skipped when TAK-659 is administered with intermittent dosing of 7 
days on followed by 7 days off or 14 days on followed by 7 days off.
d Scheduled PD and PK measurements at 2-4 hrs postdose on Cycle 1 Day 
8 will be skipped when TAK-659 is administered with intermittent dosing 
of 7 days on followed by 7 days off.
The following table was added:
[New Table 4 Cycle 1 ECG, Pharmacodynamics, and PK Schedule for 
TAK-659 in Cohort B (Safety Expansion Phase)] 
Rationale for change: To have separate PK sampling schedules for Cohort B expansion phase 
and to clarify PK and PD sampling schedules for intermittent dosing regimens.
Section 9.4.21 PK Measurements also contains this change.
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Change 25: Added progression-free survival (PFS) follow-up visits for patients in Cohort B 
expansion phase who discontinue treatment for any reason other than progressive disease.
The primary change occurs in Section 9.4.14 Disease Assessment.
Initial text:
9.4.14 Disease Assessment
Patients will undergo radiographic evaluation and symptom assessment to monitor 
and assess disease response. Response assessment will follow revised response 
criteria for malignant lymphoma per IWG [2]. CT scans (with contrast) of the neck 
(if appropriate), chest, abdomen, and pelvis will be performed at 
Screening/Baseline (within 28 days before the first study drug administration), at 
the end of every other cycle through Cycle 6, and at the end of every 3 cycles 
thereafter (until PD or the start of alternative therapies). An FDG-PET scan 
extending from the neck through the mid thighs should be performed only at 
Baseline for tumor types for which it represents standard of care for response 
assessment. If the screening FDG-PET scan is positive, FDG-PET scans should be 
repeated either at the time of assessment for CR or for recurrence/progression of 
disease unless otherwise specified per local standard of care for a given lymphoma 
subtype. If the screening FDG-PET scan is negative, additional FDG-PET scans do 
not need to be conducted but could be performed as clinically indicated during the 
study. PET/CT scans may be used as the source of the CT scan, but the CT 
component should be performed with IV contrast unless contraindicated. The same 
imaging modality should be used consistently throughout the study to monitor the 
disease status.
Amended 
text:
9.4.14 Disease Assessment
Patients will undergo radiographic evaluation and symptom assessment to monitor 
and assess disease response. Response assessment will follow revised response 
criteria for malignant lymphoma per IWG 2007 criteria [2]. CT scans (with 
contrast) of the neck (if appropriate), chest, abdomen, and pelvis will be performed 
at Screening/Baseline screening/baseline (within 28 days before the first study 
drug administration), at the end of every other cycle through Cycle 6, and at the 
end of every 3 cycles thereafter (until PD or the start of alternative therapies), and 
at the EOT visit. For patients with FL or MZL in the Cohort B expansion 
phase, response will continue to be assessed during PFS follow-up every 2 
months for patients who discontinue treatment for reasons other than PD 
until 6 months after the last dose or occurrence of PD, whichever occurs first. 
An FDG-PET scan extending from the neck through the mid thighs should will be 
performed only at Baseline for tumor types for which it represents standard of care for 
response assessment at baseline. If the screening FDG-PET scan is positive, FDG-
PET scans should be repeated either at the time of assessment for CR or for 
recurrence/progression of disease unless otherwise specified per local standard of 
care for a given lymphoma subtype. If the screening FDG-PET scan is negative, 
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additional FDG-PET scans do not need to be conducted but could be performed as 
clinically indicated during the study. PET/CT scans may be used as the source of 
the CT scan, but the CT component should be performed with IV contrast unless 
contraindicated. The same imaging modality should be used consistently 
throughout the study to monitor the disease status.
Rationale for change: To be consistent with follow-up requirements and to evaluate a clinically 
relevant efficacy endpoint.
The following sections also contain this change:
Section 2.0 STUDY SUMMARY.
Section 6.3.2 End of Study/Study Completion Definition and Planned Reporting.
Appendix A
Schedules of Events Table 1.
Change 26: Updated procedures for cytomegalovirus monitoring.
The primary change occurs in Appendix A
Schedules of Events Tables 1 and 2.
Description 
of Changes:

For the row CMV Testing:
― Testing was added on Day 1 of each cycle and at the EOT visit.
― The following text was added to the associated footnote:
aa CMV serology (immunoglobulin [Ig]G and IgM) and quantitative 
PCR assay will be performed during screening. Quantitative PCR will 
be performed at Day 1 of each cycle and at the EOT visit.
Rationale for change: To include CMV monitoring time points based on input from TAK-659 
investigators and the recommendation from the TAK-659 Lymphoma Steering Committee to the
mitigate potential risk of CMV reactivation.
The following sections also contain this change:
Section 8.8.1.1 CMV Monitoring and Prophylaxis.
Section 9.4.23 CMV Testing.
Change 27: Removed residual bone marrow sample collections from study procedures.
The primary change occurs in Section Appendix A Schedules of Events Table 1 and Table 2.
Description
of change:

The following rows have been removed:
Residual fresh bone marrow aspirate
Residual fresh bone marrow biopsy
Rationale for change: To reduce redundancy in study procedures.
Section 9.4.17 Bone Marrow Biopsy and Aspirate also contains this change.
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Study No. C34005
Page 183 of 189
Protocol Incorporating Amendment 03
15 November 2018
CCI
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TAK-659
Study No. C34005
Page 184 of 189
Protocol Incorporating Amendment 03
15 November 2018
Rationale for change: To enable additional pharmacodynamic analysis.
The following sections also contain this change:
Section 2.0 STUDY SUMMARY.
Appendix A
Schedules of Events Table 1 footnote (y) and Table 2 footnote (w).
Change 30: Revised reasons for discontinuation of treatment with study drug.
The primary change occurs in Section 9.6 Discontinuation of Treatment With Study Drug.
Initial text:
9.6 Discontinuation of Treatment With Study Drug and Patient Replacement
Treatment with study drug may be discontinued for any of the following reasons: 
!
AE, including patients who experience a DLT (during escalation) during the 
first cycle, patients with Grade 4 nonhematologic toxicity, patients with Grade 
4 anemia, and patients with other drug-related AEs that require study drug 
discontinuation per dose modification guidelines in Section 8.4 and the USPIs 
[11-13,15-17] or applicable labeling for the combination drugs. 
Discontinuation of treatment occurs only when both study drugs are required to 
be discontinued due to AEs. 
!
Protocol deviations.
!
PD.
!
Symptomatic deterioration (at investigator’s discretion). 
!
Unsatisfactory therapeutic response. 
!
Initiation of hematopoietic stem cell transplant
!
Study terminated by sponsor.
!
Withdrawal by subject.
!
Lost to follow-up.
!
Other.
During the dose escalation phase, patients who are withdrawn from treatment 
during Cycle 1 for reasons other than DLT will be replaced. 
Once study drug has been discontinued, all study procedures outlined for the EOT 
CCI
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TAK-659
Study No. C34005
Page 185 of 189
Protocol Incorporating Amendment 03
15 November 2018
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.
Amended 
text:
9.6 Discontinuation of Treatment With Study Drug and Patient Replacement
Treatment with study drug may be discontinued for any of the following reasons: 

AE, including patients who experience a DLT (during escalation) during the 
first cycle, patients with Grade 4 nonhematologic toxicity, patients with Grade 
4 anemia, and patients with other drug-related AEs that require study drug 
discontinuation per dose modification guidelines in Section 8.4 and the USPIs 
[11-13,15-17] or applicable labeling for the combination drugs. 
Discontinuation of treatment occurs only when both study drugs are required to 
be discontinued due to AEs. 

Protocol deviations.

PD.

Occurrence of pregnancy (if applicable).

Symptomatic deterioration (at investigator’s discretion). 

Unsatisfactory therapeutic response. 

Initiation of hematopoietic stem cell transplant


Study terminated by sponsor.

Withdrawal of consent by subjectpatient.

In the opinion of the investigator, continued use of study drug is no longer 
in the patient’s best interests.

Lost to follow-up.

Study terminated by sponsor.

Other.
During the dose escalation phase, patients who are withdrawn from treatment 
during Cycle 1 for reasons other than DLT will be replaced. 
In the event of pregnancy, female subjects must discontinue use of study 
drugs. 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, Table 1 and Table 2). The primary reason for study drug discontinuation will 
be recorded on the eCRF. 
Rationale for change: For consistency with other TAK-659 clinical study protocols.
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TAK-659
Study No. C34005
Page 186 of 189
Protocol Incorporating Amendment 03
15 November 2018
Change 31: Revised reasons for withdrawal of patients from study.
The primary change occurs in Section 9.7 Withdrawal of Patients From Study.
Initial text:
9.7 Withdrawal of Patients From Study
A patient may be withdrawn from the study for any of the following reasons:

AE.

Protocol deviation.

PD. 

Symptomatic deterioration (at investigator’s discretion).

Unsatisfactory therapeutic response. 

Study terminated by sponsor.

Withdrawal by subject.

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.
Amended 
text:
9.7 Withdrawal of Patients From Study
A patient may be withdrawn from the study for any of the following reasons:

AE.

Protocol deviation.

Due to pregnancy.

PD. 

Symptomatic deterioration (at investigator’s discretion).

Unsatisfactory therapeutic response. 

Study terminated by sponsor.

Withdrawal of consent by subjectpatient.

In the opinion of the investigator, continued participation is no longer in 
the patient’s best interests.

Lost to follow-up.

Other.
In the event of pregnancy, female subjects must be discontinued from the 
study. 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.
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TAK-659
Study No. C34005
Page 187 of 189
Protocol Incorporating Amendment 03
15 November 2018
Rationale for change: For consistency with other TAK-659 clinical study protocols.
Change 32: Added criteria for early discontinuation of study.
The primary change occurs in Section 9.8 Early Discontinuation of the Study.
Added text:
9.8 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 subjects.

Poor enrollment of subjects, 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: For consistency with other TAK-659 clinical study protocols.
Change 33. Added PFS as a secondary endpoint for patients in Cohort B expansion phase.
The primary change occurs in Section 5.2.2 Secondary Endpoints.
Added text:

PFS (for patients in the Cohort B expansion phase).
Rationale for change: To evaluate a clinically relevant efficacy endpoint.
The following sections also contain this change:
Section 2.0 STUDY SUMMARY.
Section 6.3.3 Time Frames for Primary and Secondary Endpoints to Support Disclosures Table 
6.b.
Section 13.1.3 Efficacy Analysis.
Change 34. Added a urine pregnancy test for women of childbearing potential at end of 
treatment for each cohort.
The primary change occurs in Appendix A
Schedules of Events Tables 1 and 2.
Description 
of change:

In the Pregnancy test row, an “X” has been added to the EOT column.

The following text has been added to the associated footnote:
For WOCBP only, a urine pregnancy test also will be performed at EOT.
Rationale for change: To ensure examination completeness.
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TAK-659
Study No. C34005
Page 188 of 189
Protocol Incorporating Amendment 03
15 November 2018
Section 9.4.12 Pregnancy Test also contains this change.
Change 35. Added vital sign measurements on Day 15 of Cycle 3 and beyond for Cohorts A, B, 
and C.
The primary change occurs in Appendix A
Schedules of Events Table 1.
Description 
of change:

In the Vital signs row, an “X” has been added to the Cycle 3 and beyond Day 
15 column.
Rationale for change: To ensure examination completeness and for consistency with 
Appendix A Schedule of Events Table 2.
Change 36. Updated reference citations to support background information in protocol and 
added reference citation for a published TAK-659 clinical study.
The primary change occurs in Section 4.1.1 Diseases Under Study and Section 4.2.1 Rationale 
for the Combination of TAK-659 + Combination Drugs.
Description 
of change:

The following references have been removed from Section 4.1.1:
― 5. Diffuse Large B-Cell Lymphoma. 2014 Review of Cancer Medicines on 
the WHO List of Essential Medicines: Union for International Cancer 
Control; 2014. p. 1-8.
― 6. 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.

The following references have been added to Section 4.1.1:
― 5. Kumar V, Abbas A, Fausto N, Aster J. Robbins and Cotran Pathologic 
Basis of Disease. 8 ed. Philadelphia: Saunders Elsevier; 2010.
― 6. 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.
― 7. 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.
― 8. 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.
― 9. Pinter-Brown L, Besa E. Follicular Lymphoma Management Overview. 
Medscape September 15, 2016:1-26.
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TAK-659
Study No. C34005
Page 189 of 189
Protocol Incorporating Amendment 03
15 November 2018
― 10.Kahl BS, Yang DT. Follicular lymphoma: evolving therapeutic 
strategies. Blood 2016;127(17):2055-63.

The following reference has been added to Section 4.2.1:
― 18. Kaplan JB, Gordon LI, Rambaldi A, Gritti G, Popat R, Burris HA, et al. 
Phase 1 study of TAK-659, an investigational reversible dual SYK/FLT-3 
inhibitor, in patients with lymphoma: Updated results from dose-escalation 
and expansion cohorts. Poster presented at the 59th American Society of 
Hematology (ASH) Annual Meeting and Expositio. Atlanta, GA, USA; 
2017.
Rationale for change: To provide the most current reference citations to support the 
background information in the protocol.
Change 37. Added a recommendation that prophylaxis for varicella-zoster virus should be 
administered for all patients in Cohort B.
The primary change occurs in Section 8.8.1 Prophylaxis Against Infection.
Added text: It is recommended that prophylaxis for varicella-zoster virus should be 
administered for Cohort B [19].
Rationale for change: To follow NCCN guidelines for B-Cell Lymphomas, version 1, 2018.
Change 38. Added a recommendation that the prophylaxis for Pneumocystis jiroveci pneumonia
should be administered for all patients in Cohort B.
The primary change occurs in Section 8.8.1.2 Prophylaxis for Opportunistic Infections.
Added text: It is recommended that the prophylaxis for PJP should be implemented in 
Cohort B regardless of the above-mentioned conditions [19].
Rationale for change: To follow NCCN guidelines for B-Cell Lymphomas, version 1, 2018.
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SAP_001.pdf: 


Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Phase 1b, Dose Escalation Study to Determine the Recommended Phase 2 Dose of 
TAK-659 in Combination With Bendamustine (±Rituximab), Gemcitabine, Lenalidomide, or 
Ibrutinib for the Treatment of Patients With Advanced Non-Hodgkin Lymphoma After At 
Least 1 Prior Line of Therapy
NCT Number: NCT02954406
SAP Approve Date: 06 September 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.


STATISTICAL ANALYSIS PLAN
STUDY NUMBER: C34005
A Phase 1b, Dose Escalation Study to Determine the Recommended Phase 2 Dose of TAK-659 
in Combination With Bendamustine (±Rituximab), Gemcitabine, Lenalidomide, or Ibrutinib for 
the Treatment of Patients With Advanced Non-Hodgkin Lymphoma After At Least 1 Prior Line 
of Therapy
PHASE 1b
Version: 1.0
Date: 06 September 2019
Prepared by: 
Based on:
Protocol Version: Amendment 03
Protocol Date: 15 November 2018
PPD
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
ose of T
se of 
ide, or I
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At Lea
At Le
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2019
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15 Nov
15 No
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C34005
Page 2 of 24
Statistical Analysis Plan 1.0
06 September 2019
Approval Signatures
Electronic signatures can be found on the last page of this document.
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C34005
Page 3 of 24
Statistical Analysis Plan 1.0
06 September 2019
TABLE OF CONTENTS
1.0
OBJECTIVES .................................................................................................................7
1.1
Primary Objectives ....................................................................................................7
1.2
Secondary Objectives.................................................................................................7
1.3
Additional Objectives ................................................................................................7
1.4
Exploratory Objectives ..............................................................................................7
1.5
Study Design .............................................................................................................7
2.0
ANALYSIS ENDPOINTS.............................................................................................10
2.1
Primary Endpoints: ..................................................................................................10
2.2
Secondary Endpoints: ..............................................................................................10
2.3
Additional Endpoints:..............................................................................................10
2.4
Exploratory Endpoints: ............................................................................................10
3.0
DETERMINATION OF SAMPLE SIZE.......................................................................11
4.0
METHODS OF ANALYSIS AND PRESENTATION...................................................12
4.1
General Principles....................................................................................................12
4.2
Definition of Study Visit Windows ..........................................................................13
4.3
Conventions for Missing/Partial Dates in Screening Visit ........................................13
4.4
Conventions for Missing Adverse Event Dates ........................................................13
4.5
Conventions for Missing Concomitant Medication/Therapy Dates...........................14
4.6
Analysis Sets ...........................................................................................................14
4.7
Disposition of Subjects ............................................................................................15
4.8
Demographic and Other Baseline Characteristics.....................................................15
4.9
Medical History and Concurrent Medical Conditions...............................................15
4.10
Medication History and Concomitant Medications...................................................15
4.11
Study Drug Exposure and Compliance.....................................................................16
4.11.1 Extent of Exposure:............................................................................................16
4.12
Action on Drug:.......................................................................................................16
4.13
Efficacy Analysis.....................................................................................................16
4.14
Primary Efficacy Endpoint(s)...................................................................................17
4.15
Secondary Efficacy Endpoint(s)...............................................................................17
4.16
Additional Efficacy Endpoint(s)...............................................................................17
4.17
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................18
4.17.1 Pharmacokinetic Analysis ..................................................................................18
4.17.2 Pharmacodynamic Analysis ...............................................................................18
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C34005
Page 4 of 24
Statistical Analysis Plan 1.0
06 September 2019
4.18
Other Outcomes.......................................................................................................19
4.18.1 Biomarker Analysis............................................................................................19
4.19
Pharmacogenomic Analysis .....................................................................................19
4.20
Safety Analysis........................................................................................................19
4.21
Adverse Events........................................................................................................19
4.22
Serious Adverse Events ...........................................................................................21
4.23
Deaths .....................................................................................................................21
4.24
Adverse Events Resulting in Discontinuation of Study Drug....................................21
4.25
Dose Limiting Toxicities (DLTs).............................................................................21
4.26
Clinical Laboratory Evaluations...............................................................................21
4.27
Vital Signs...............................................................................................................22
4.28
12-Lead ECGs .........................................................................................................23
4.29
Other Observations Related to Safety.......................................................................23
4.30
Interim Analysis ......................................................................................................23
4.31
Changes in the Statistical Analysis Plan...................................................................23
5.0
REFERENCES..............................................................................................................24
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C34005
Page 5 of 24
Statistical Analysis Plan 1.0
06 September 2019
LIST OF ABBREVIATIONS
Abbreviation
Term
AUC
change in area under the concentration-time curve
AE
adverse event
ALC
absolute lymphocyte count
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
AUCτ
area under the concentration-time curve during a dosing interval 
AUCτ/Dose
steady-state, dose-normalized area under the concentration-time curve during a dosing 
interval 
BCR
B-cell receptor
BCRP
breast cancer resistance protein
CL/F
apparent clearance after extravascular administration, calculated using the observed 
value of the last quantifiable concentration
Cmax
maximum observed concentration
CO2
carbon dioxide
CPK
creatine phosphokinase
CR
complete response 
ctDNA
circulating tumor DNA
Ctrough
observed concentration at the end of a dosing interval
DLBCL
diffuse large B-cell lymphoma
DLT
dose-limiting toxicity
DOR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
FDG
fluoro-2-deoxy-D-glucose
FL
Follicular Lymphoma
GGT
gamma glutamyl transferase
IWG
International Working Group
LDH
lactate dehydrogenase
MAD
maximally administered dose
MedDRA
Medical Dictionary for Regulatory Activities
MTD
maximum tolerated dose
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NHL
non-Hodgkin lymphoma
ORR
Overall response rate
PD
progressive disease (disease progression)
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C34005
Page 6 of 24
Statistical Analysis Plan 1.0
06 September 2019
Abbreviation
Term
PET
positron emission tomography
PK
pharmacokinetic(s)
PR
partial response 
PTR
peak-trough ratio during a dosing interval, at steady state
QD
once daily
Rac
accumulation ratio
SPD
Sum of Product of Diameters
t1/2
terminal disposition half-life
tmax
first time to reach maximum (peak) plasma concentration
TTP
Time-to-progression
WHO
World Health Organization
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C34005
Page 7 of 24
Statistical Analysis Plan 1.0
06 September 2019
1.0
OBJECTIVES
1.1
Primary Objectives
The primary objective is to determine the maximum tolerated dose (MTD) or the recommended 
Phase 2 dose (RP2D) for TAK-659 when administered in combination with each of the 
combination partners (bendamustine, bendamustine + rituximab, gemcitabine, lenalidomide, and 
ibrutinib).
1.2
Secondary Objectives
The secondary objectives are:
∀
To characterize the PK of TAK-659 when administered with each of the combination 
partners. To observe the preliminary efficacy of different combination drugs with TAK 659 
(Cohorts A-E) in patients with advanced NHL who have relapsed and/or are refractory after 
≥1 prior line of therapy (for patients in Cohort B expansion with FL/marginal zone 
lymphoma (MZL), ≤1 prior line of therapy).
1.3
Additional Objectives
The additional objective is to evaluate safety and tolerability of TAK-659 in combination with 
each of the 5 cohorts.
1.4
Exploratory Objectives
1.5
Study Design
This is a phase 1b, dose escalation study of TAK-659 in combination with 1 of 5 combination 
partners (bendamustine, bendamustine+rituximab, gemcitabine, lenalidomide, and ibrutinib) in 
adult patients with advanced NHL after at least 1 prior line of therapy. The primary objective of 
the study is to determine the MTD or the RP2D of TAK-659 when administered with each of the 
combination partners.
During dose escalation, the dose of TAK-659 will be escalated (planned 2 dose levels of 
escalation: 60 and 100 mg) according to a 3+3 dose escalation scheme; all 5 combination 
partners will be administered at a fixed dose and regimen. 
CCI
Property of Takeda
Study D
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C34005
Page 8 of 24
Statistical Analysis Plan 1.0
06 September 2019
It is expected that approximately 100 patients (approximately 20 in each of the 5 treatment 
groups) will be enrolled in the study.
Once enrolled in the study, patients will be assigned to one of 5 treatment groups comprising 
TAK-659 in combination with bendamustine, bendamustine+rituximab, gemcitabine, 
lenalidomide, or ibrutinib. The starting dose of TAK-659 will be 60 mg QD. Dose escalation will 
follow a standard 3+3 escalation scheme, and dosing will increase to 100 mg QD provided that 
the safety and tolerability of the 60 mg dose has been demonstrated. Intermediate dose levels 
between 60 and 100 mg (eg, 80 mg) or dose levels below the starting dose of 60 mg (eg, 40 mg) 
also may be evaluated if appropriate. Dose escalation will continue until the MTD is reached, or 
until TAK-659 100 mg QD (the maximally administered dose [MAD]) is determined to be safe 
and tolerable, or until an RP2D, if different from the MTD or MAD, is identified on the basis of 
the safety, tolerability, and preliminary PK and efficacy data (if available) observed in Cycle 1 
and beyond. Approximately 6 additional patients will be enrolled at the MTD/MAD/RP2D for 
each combination for further safety evaluation.
The dose escalation rule is as below.
The dose of each combination drug will remain constant while the TAK-659 dose escalation 
takes place. The doses of the combination drugs will be as follows:
Bendamustine: 90 mg/m2 administered intravenously (IV) over 10 or 60 minutes (depending on 
which formulation is used) on Days 1 and 2 of a 21-day cycle, up to 8 cycles.
Bendamustine+rituximab: 90 mg/m2 bendamustine administered IV over 10 or 60 minutes 
(depending on which formulation is used) on Days 1 and 2 of a 21-day cycle, up to 8 cycles, and 
375 mg/m2 rituximab administered IV per local guidelines and labeling on Day 1 of a 21-day 
cycle, up to 8 cycles.
Gemcitabine: 1000 mg/m2 IV infusion over 30 minutes on Days 1 and 8 of a 21-day cycle. 
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Lenalidomide: 25 mg PO QD for Days 1 to 21 of a 28-day cycle.
Ibrutinib: 560 mg PO QD of a 28-day cycle.
For all dose escalation cohorts (including the safety expansion in the MTD/MAD/RP2D 
cohorts), serial blood samples will be collected at prespecified time points for up to 24 hours 
after TAK-659 dosing on Cycle 1 Days 1 and 15 to characterize the plasma PK of TAK-659 
when administered with each of the combination partners. In addition, blood samples for plasma 
PK will be collected at the same time points for cytokine/chemokine assessments on Cycle 1 
Day 8. 
Disease status will be assessed using the Internation Working Group (IWG) revised criteria for 
patients with malignant lymphoma, based on investigator assessment. Computerized tomography 
(CT) scans (with contrast) of the chest, abdomen, and pelvis (neck should be included if 
appropriate) and fluorodeoxyglucose (FDG)-positron emission tomography (PET) scans 
extending from neck to mid-thigh will be performed in all patients to follow the disease as 
indicated in the Schedule of Events (Appendix A, Protocol Amendment 3). Repeat FDG-PET 
scans may be performed during the study only when the screening FDG-PET scan is positive. 
For patients with a negative screening FDG-PET scan, additional scans may be performed on 
study if clinically indicated for occurrence of PD per local standard of care. 
As this is a phase I study using a standard 3+3 methodology to allocate patients to the next dose 
level, no randomization is planned for this study. This is an open-label study. No blinding/ 
unblinding methodology is required.
Patients in the dose escalation cohorts who are withdrawn from treatment during Cycle 1 for 
reasons other than DLTs will be replaced. 
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2.0
ANALYSIS ENDPOINTS
2.1
Primary Endpoints:
Maximum tolerated dose (MTD) (dose escalation).
Recommended phase 2 dose (RP2D) (dose escalation).
2.2
Secondary Endpoints:
∀
TAK-659 PK parameters, including maximum observed concentration (Cmax), time of first 
occurrence of Cmax (Tmax), and area under the plasma concentration-time curve during a 
dosing interval (AUCτ) by dose escalation cohort.
∀
Overall response rate (ORR)
∀
Duration of response (DOR)
∀
Time to progression (TTP)
2.3
Additional Endpoints: 
∀
Percentage of patients with AEs and drug related AEs, respectively.
∀
Percentage of patients with #Grade 3 AEs and drug related #Grade 3 AEs, respectively.
∀
Percentage of patients with serious adverse events (SAEs) and drug related SAEs, 
respectively.
∀
Percentage of patients who discontinued due to AEs.
∀
Clinically significant laboratory values.
∀
Clinically significant vital sign measurements.
∀
Other TAK-659 PK parameters, including apparent oral clearance, peak-trough ratio, 
accumulation ratio, and trough concentration by dose escalation cohort.
2.4
Exploratory Endpoints:
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3.0
DETERMINATION OF SAMPLE SIZE
The dose escalation of this study will use a 3+3 design. With the exception of the bendamustine 
combination arm, the combination partner’s dose will be the dose according to the 
manufacturer’s label. The dose of bendamustine will be based on its use in previous combination 
studies [1,2]. The planned doses of TAK-659 are 60 and 100 mg. For each combination arm, 9 to 
12 DLT-evaluable patients will be needed for the dose escalation portion. In addition, for each 
arm, another 6 patients will be needed for safety expansion. Assuming a 10% dropout rate, 20 
patients will be needed for each arm; therefore, the total sample size for this study, including all 
5 arms, will be 100.
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4.0
METHODS OF ANALYSIS AND PRESENTATION
4.1
General Principles 
Statistical analyses will be performed separately for the following five combination arms. Within 
each combination arm (cohort), analysis will be done by TAK-659 dose escalation cohort and 
overall in pooled data across dose escalation levels. In addition, data collected within each cohort 
will be analyzed across NHL subtypes, and for some tables, separately within DLBCL and 
within FL.
The following specifies each combination (cohort):

TAK-659+bendamustine (cohort A).

TAK-659+bendamustine+rituximab (cohort B).

TAK-659+gemcitabine (cohort C).

TAK-659+lenalidomide (cohort D).

TAK-659+ibrutinib (cohort E).
No formal statistical hypothesis testing will be performed. In general, summary tabulations will 
display the number of observations, mean, standard deviation, median, minimum, and maximum 
for continuous variables, and the number and percent (of non-missing values) per category for 
categorical data. 
All available efficacy and safety data will be included in data listings and tabulations as needed. 
Data that are potentially spurious or erroneous will be examined under the auspices of standard 
data management operating procedures. 
Baseline values are defined as the last observed value before the first dose of study medication. 
All statistical analyses will be conducted using SAS® Version 9.2, or higher.
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.
Where appropriate, variables will be summarized descriptively by study visit. For the categorical 
variables, the count and proportions of each possible value will be tabulated by treatment group. 
The denominator for the proportion will be based on the number of subjects who provided non-
missing responses to the categorical variable. For continuous variables, the number of subjects 
with non-missing values, mean, median, SD, minimum, and maximum values will be tabulated. 
The summary tables will include escalation cohort, overall for dose escalation phase, and by 
expansion cohort and overall for expansion phase and overall for both phases as appropriate. 
Screen failure subjects will be grouped and listed at the end.
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4.2
Definition of Study Visit Windows
All data will be categorized based on the scheduled visit at which it was collected unless 
otherwise specified. These visit designators are predefined values that appear as part of the visit 
tab in the eCRF. 
4.3
Conventions for 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 first of January will be used. 
3. If only the year is present, and it is not the same as the year of the first dose of study drug, the 
fifteenth of June will be used, unless other data indicates that the date is earlier.
4.4
Conventions for Missing Adverse Event Dates
Adverse events with start dates that are completely or partially missing will be analyzed as 
follows:
∀
If the start date has a month and year but the day is missing, then 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.
∀
If the start date has a specified year, but the day and month are missing, then 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.
∀
If the start date of an event is completely missing, then the event is assumed to be treatment 
emergent.
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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, then the event will not be considered treatment emergent.
4.5
Conventions for Missing Concomitant Medication/Therapy Dates
Concomitant medications/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, then the event will be considered 
concomitant if the month and year of the start date of the event are: 
–
On or after the month and year of the date of the first dose of study drug
–
and 
–
on or before the month and year of the date of the last dose of any study drug plus 28 
days.
2. If the start date has a year, but the day and month are missing, the event will be considered 
concomitant if the year of the start date of the event is:
–
On or after the year of the date of the first dose of study drug
–
and 
–
on or before the year of the date of the last dose of any study drug plus 28 days.
3. If the start date of an event is completely missing, then the event is assumed to be 
concomitant.
However, if the end date is complete or partially missing, but it is clear that the end date is before 
the first dose of study drug, then the event will not be considered concomitant. 
When the start date is complete and is before the first dose, and the concomitant medication is 
not ongoing but the end date is missing completely or partially, a similar algorithm should be 
used to assess whether the end date is before the last dose of study drug plus 28 days to be 
included. 
4.6
Analysis Sets
The Analysis Sets (Analysis Populations) will include the following:

Safety analysis set: patients who have received at least 1 dose of study drug will be used for 
all safety analyses and for some efficacy analyses.

PK analysis set: patients with sufficient dosing and PK data to reliably estimate 1 or more PK 
parameters will be used for PK analyses.

Response-evaluable analysis set: patients who have received at least one dose of study drug, 
have sites of measurable disease at Baseline, and have one post-Baseline disease assessment 
will be used for analyses of response. Investigators will assess responses using the IWG 
criteria for malignant lymphoma.
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
DLT-evaluable analysis set: patients who have met the minimum treatment and safety 
evaluation requirements of the study or who experience a DLT during Cycle 1. The 
minimum treatment and safety evaluation requirements are met if in Cycle 1 the patient is 
treated with at least 75% of planned dose of TAK-659, and is observed for 1 cycle 
following the dose on Cycle 1 Day 1, and is considered to have sufficient safety data by both 
the sponsor and the investigators to conclude that a DLT did not occur.
4.7
Disposition of Subjects
Dispositions of patients include the number and percentage of patients in each analysis 
population, and will be presented by each combination arm and overall, as well as by escalation 
cohort and overall. The primary reason for study termination will also be summarized similarly 
in this table. All percentages will be based on the number of patients in the safety population. A 
listing will present data concerning patient disposition. Screen failures will be summarized in 
separate tables/listings.
4.8
Demographic and Other Baseline Characteristics
Demographics will be summarized for each escalation cohort andoverall for dose escalation 
phase. Demographic data will also be presented in a by-patient listing. Baseline demographic 
data to be evaluated will include age, sex, race, ethnicity, height, weight, and primary diagnosis. 
Age will be calculated from date of birth to date of informed consent. No inferential statistics 
will be generated.
Throughout this study, baseline assessments are defined as those performed at the closest time 
before the start of study drug administration.
Baseline characteristics including baseline disease primary diagnosis, years since initial 
diagnosis, staging, Eastern Cooperative Oncology Group (ECOG) performance status, will be
summarized. 
A separate table will summarize the numbers and percentages of patients who received prior 
therapy, including prior anticancer, prior radiation, prior surgery, and best response to the last 
prior anticancer therapy. 
4.9
Medical History and Concurrent Medical Conditions
Medical history will be presented in a by-patient listing, including the medical and surgical 
history, date of onset and the status (whether it is resolved or ongoing).
4.10
Medication History and Concomitant Medications
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Dictionary. The number and percentage of patients taking concomitant medications will be 
tabulated by WHO drug generic term for the safety population, from the first dose of study 
treatment and through 28 days after the last dose of study treatment, or to the start of subsequent 
anticancer therapy, whichever occurs first. 
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Concomitant medications will also be presented in a by-patient listing.
Concomitant procedures will not be coded, but will be presented in a by-patient listing.
4.11
Study Drug Exposure and Compliance
4.11.1 Extent of Exposure:
The exposure to TAK-659, and to each of the other study drugs, will be characterized by total 
amount of dose taken in mg, total number of doses taken, relative dose intensity (%), number of 
treated cycles, numbers and percentages of patients who had ≥1, ≥2, …, ≥6, and ≥12 treated 
cycles for patients in the safety population. A treated cycle is defined as a cycle in which the 
patient received any amount of study drug. 
Relative dose intensity (RDI) (%) will be presented overall and by cycle. 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 relative dose intensity, 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 date of cycle) + 1, 
however, if a patient discontinues during the cycle then use (date of drug discontinuation – first 
dose date of cycle) + 1.
Prescribed dose is determined by the dose level to which a patient is enrolled at the onset of the 
study. 
The extent of exposure to TAK-659 and to each of the combination partner study drugs (as 
applicable to the escalation cohort) will be summarized by escalation dose within each cohort 
and overall for the cohort.
Exposure data will also be presented in a by-patient listing.
4.12
Action on Drug:
Action on study drug will be summarized by each of cycle (Cycles 1- 6, post-Cycle 6), sum of 
the remainder cycles, and total, for each dose escalation within each cohort and overall for each 
cohort.
4.13
Efficacy Analysis
Analysis of efficacy measures will be descriptive. All efficacy analyses will be based on 
investigator assessments. Investigators will assess responses using the IWG criteria for 
lymphoma.
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4.14
Primary Efficacy Endpoint(s)
There is no primary efficacy endpoint for the study.
4.15
Secondary Efficacy Endpoint(s)
Secondary efficacy endpoints include ORR, DOR and TTP. No formal statistical tests will be 
performed for these secondary endpoints. Analyses for these endpoints will be done for each of 
the 5 combination arms separately and by dose level. All secondary efficacy endpoints will be 
summarized using the Response-Evaluable population.
ORR is based on the best overall response recorded from the enrollment in the study until 
progression or end of study. The percentage of subjects from the response-evaluable population 
and experiencing objective response (based on investigator confirmed CR or PR) at the time of 
analysis defines ORR. 
DOR is defined as the time from the date of the first documented response to the date of first 
documented Progression of Disease (PD) by the investigator. 
TTP is defined as the time from the date of first study drug administration to the date of first 
documented PD or relapse in the response evaluable population.
Antitumor activity of TAK-659 will be based on best overall response. Investigators will assess 
individual responses using the IWG criteria for lymphoma. Data listings will present the tumor 
measurements from imaging, including changes from Baseline, disease response category, and as 
appropriate, tumor marker measurements. Waterfall plots will visualize the best change from 
baseline in lesion shrinkage across dose cohorts. 
The number and percentage of patients falling into each response category (eg, CR, PR, SD) will 
be tabulated descriptively for each escalation dose within the cohort and overall for each cohort. 
Estimates of the CR+PR rate will be presented with 2-sided 95% exact binomial CIs. 
ORR will be tabulated by baseline factors if applicable. The prognostic factors will include, but 
will not be limited to age, number and types of prior therapy, TTP from diagnosis or prior 
therapy, prior autologous transplant, and International Prognostic Index score. Waterfall plots 
representing the best percent change from baseline of the sum of the product of diameters (SPD) 
across the lesions of patients from each dose escalation cohort will be provided. These will be 
colored by best objective response.
DOR and TTP will be censored at the last response assessment that is SD or better for patients 
who do not experience progression.
4.16
Additional Efficacy Endpoint(s)
Not applicable
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4.17
Pharmacokinetic/Pharmacodynamic Analysis
4.17.1 Pharmacokinetic Analysis
The PK population will be used for the description of the plasma PK profile of TAK-659 and for 
the estimation of plasma PK parameters of TAK-659. Plasma concentrations of TAK-659 will be 
determined by validated liquid chromatography tandem mass spectrometry assay methods.
For each combination arm, plasma TAK-659 concentrations will be summarized by nominal 
(scheduled) time postdose and grouped by dose cohort and dosing cycle and study day (except 
for those 2 to 4 hours postdose PK samples collected on Cycle 1, Day 8). Summary statistics will 
be reported at nominal sampling times with at least 2 patients in the PK evaluable population; 
means will be reported if the number of observations above the lower limit of quantitation 
(NALQ) is ≥ 50% of the number of patients. The summary statistics will consist of: N, mean 
(SD), coefficient of variation (CV), geometric mean, CV of geometric mean, median, min, max. 
Arithmetic mean, geometric mean, median, min, and max will be reported on at least 2 non-
missing values, while the SD and CV will be reported on at least 3 non-missing values. Plasma 
concentrations that are BLQ will be set to zero for calculation of summary statistics, except for 
geometric means, where BLQ values will be considered missing. Mean and individual plasma 
TAK-659 concentration data will be plotted over time and grouped by dose cohort and dosing 
cycle and day (Cycle 1, Days 1 and 15) on both linear and semi-logarithmic scales. 
Plasma concentration-time data will be used to calculate single-dose (Cycle 1 Day 1) and 
multiple-dose (Cycle 1 Day 15) plasma PK parameters of TAK-659 by noncompartmental 
methods. These parameters will include, but not be limited to, Cmax, tmax, AUCτ, Ctrough, CLss/F, 
PTR, and Rac. Plasma PK parameters of TAK-659 will be summarized by dose escalation 
cohort, dose expansion cohort, and by dosing cycle and day. 
TAK-659 plasma PK data from dose escalation cohorts, along with data from other studies, may 
contribute to population PK analyses and exposure-response analyses for pharmacodynamic, 
safety, and efficacy endpoints. If applicable, the specifics of the population PK and exposure-
response analyses will be described in separate analysis plans, and results will be reported 
separately from the clinical study report.
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Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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4.18
Other Outcomes
4.20
Safety Analysis
AEs will be summarized using the safety analysis set. 
The incidence of DLTs will be tabulated for each dose group. In addition, to assess the 
relationship between toxicities and TAK-659 dose, the preferred term of individual toxicities will 
be summarized by frequency and intensity for each dose group. The DLT-evaluable analysis set 
will be used for the analysis of DLT.
Safety will be evaluated by the frequency of AEs, severity and types of AEs, and by changes 
from Baseline in patients’ vital signs, weight, and clinical laboratory results using the safety 
population. Exposure to study drug and reasons for discontinuation will be tabulated.
4.21
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 presented in a by-patient 
listing. Treatment-emergent AEs that occur after administration of the first dose of study drug 
and through 28 days after the last dose of study drug or the start of subsequent antineoplastic 
therapy, whichever occurs first, will be tabulated according to the MedDRA by system organ 
class, high level terms and preferred terms and will include the following categories, for each 
combination arm and overall as well as for escalation cohort, safety expansion and overall. 
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Categories of AEs:

Treatment-emergent AEs

Drug-related treatment-emergent AEs
–
Relatedness to TAK-659 alone
–
Relatedness to each of the combination partners alone
–
Relatedness to TAK-659 and the combination partner  

Grade 3 or higher treatment-emergent AEs

Grade 3 or higher drug-related treatment-emergent AEs

The most commonly reported treatment-emergent AEs (ie, those events reported by more 
than 10% of all patients)

Serious adverse events (SAEs)
Listing of treatment-emergent AEs resulting in study drug discontinuation will be provided.
Descriptive statistics for the actual values of clinical laboratory parameters and/or change from 
Baseline in clinical laboratory parameters will be presented for all scheduled measurements over 
time. Mean laboratory values over time will be plotted for key laboratory parameters.
Descriptive statistics for the actual values and/or change from Baseline of vital signs and weight 
over time will be tabulated by scheduled time point.
Shift tables for lab parameters will be generated based on changes in NCI CTCAE grades from 
Baseline to the worst post-Baseline value. Graphical displays of key safety parameters, such as 
scatter plots of Baseline versus worst post-Baseline values, may be used to understand the TAK-
659 safety profile.
All concomitant medications collected from Screening through the study period will be classified 
to preferred terms according to the WHO drug dictionary. 
Additional safety analysis may be performed to most clearly enumerate rates of toxicities to 
further define the safety profile of TAK-659.
Patients with the same AE more than once will have the maximum intensity of that event 
counted within each body system, once within each high level term, and once within each 
preferred term. Drug-related treatment-emergent AEs will also be summarized by the National 
Cancer Institute Common Toxicity Criteria for Adverse Event (NCI CTCAE) V4.03 intensity.
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, and on-study 
deaths.
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By-patient listing of grade 3 or higher treatment-emergent AE will also be provided, where the 
cycle day information for the AE onset and end dates will be included in the listing.
4.22
Serious Adverse Events
The number and percentage of subjects experiencing at least 1 treatment emergent serious AEs 
(SAEs) will be summarized by MedDRA primary system organ class, high-level term, and 
preferred term. Drug-related SAEs will be summarized similarly.
In addition, a by-subject listing of the SAEs will be presented (the subject listing will contain all 
SAEs regardless of treatment emergent AE status).
4.23
Deaths
A by-subject listing of the deaths will be presented. All deaths occurring on-study and during 
follow-up will be displayed (regardless of treatment-emergent AE status). An on-study death is 
defined as a death that occurs between the first dose of study drug and 28 days of the last dose of 
study drug.
4.24
Adverse Events Resulting in Discontinuation of Study Drug
A by-patient listing of treatment-emergent AEs resulting in discontinuation of study drug will be 
presented. All AEs resulting in discontinuation of study drug occurring on-study and during 
follow-up will be displayed (regardless of treatment-emergent AE status). 
4.25
Dose Limiting Toxicities (DLTs)
A by-patient listing of DLTs in Cycle 1 will be presented by dose level for patients in the 
DLT-evaluable population. 
In addition, to assess the relationship between toxicities and TAK-659 dose, the preferred term of 
individual toxicities will be summarized by their frequency and intensity for each combination 
arm, and by dose level of TAK-659 within each combination arm.
4.26
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.
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Statistical Analysis Plan 1.0
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The actual values of laboratory test results and percent change from baseline will be summarized 
according to the scheduled sample collection time point by dose escalation cohort, overall for 
dose escalation phase, safety expansion cohort and overall. Laboratory data will also be 
presented in listings. Unscheduled laboratory test results will be listed and included in laboratory
shift tables.
Shift tables will be constructed for laboratory parameters to tabulate changes in NCI CTCAE 
v4.03 for toxicity from baseline to post baseline worst on study CTCAE grade, if available. 
Parameters to be tabulated include:
Hematology
Serum Chemistry
Hematocrit
Hemoglobin
Leukocytes with differential
Neutrophils (ANC)
Platelet (count)
Lymphocytes (absolute lymphocyte 
count [ALC])
Lymphocyte subsets (CD4, CD8, 
CD4:CD8 ratio)
Albumin
Alkaline phosphatase (ALP)
ALT
AST
Amylase
Bilirubin (total)
Blood urea nitrogen (BUN)
Calcium
Carbon dioxide (CO2)
Chloride
Creatinine
Creatine phosphokinase (CPK)
γ-glutamyl transferase (GGT)
Glucose
Lactate dehydrogenase (LDH)
Lipase
Magnesium
Phosphate
Potassium
Sodium
Total protein
Urate
Urinalysis
Bilirubin
Glucose
Ketones
Leukocytes
Nitrite
Occult blood
pH
Protein
Specific gravity
Turbidity and color
Urobilinogen
By-patient listings to be presented include hematology, clinical chemistry, urinalysis, clinically 
significant laboratory values and ophthalmology.
Mean laboratory values over time will be plotted for key lab parameters, including Hgb, WBC, 
lymphocytes, ANC, platelets, and liver function tests (ALT/SGPT, AST/SGOT, alkaline 
phosphatase, total bilirubin), LDH, creatinine, lipase and amylase).
4.27
Vital Signs
The actual values of vital sign parameters including diastolic and systolic blood pressure, heart 
rate, temperature, and oxygen saturation, will be summarized over time by each combination arm 
and overall as well as by escalation cohort and overall in dose escalation phase, safety expansion 
and overall. Change of vital signs from baseline values will also be summarized over time. Vital 
sign values will also be presented in a by-patient listing.
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Statistical Analysis Plan 1.0
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4.28
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. ECG data will be presented in a by-patient listing.
4.29
Other Observations Related to Safety
Not applicable
4.30
Interim Analysis
Not applicable
4.31
Changes in the Statistical Analysis Plan 
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5.0
REFERENCES
1. Rummel MJ, Al-Batran SE, Kim SZ, Welslau M, Hecker R, Kofahl-Krause D, et al. 
Bendamustine plus rituximab is effective and has a favorable toxicity profile in the treatment 
of mantle cell and low-grade non-Hodgkin's lymphoma. J Clin Oncol 2005;23(15):3383-9.
2. Vacirca JL, Acs PI, Tabbara IA, Rosen PJ, Lee P, Lynam E. Bendamustine combined with 
rituximab for patients with relapsed or refractory diffuse large B cell lymphoma. Ann 
Hematol 2014;93(3):403-9.
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