Conditions: Triple-Negative Breast Neoplasms Carcinoma, Non-Small-Cell Lung Head and Neck Carcinoma, Squamous Cell Advanced Solid Tumors
Keywords: Drug Therapy
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 41
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D), safety and efficacy of TAK-659 in combination with nivolumab in participants with advanced solid tumors.

Detailed description:
The drug being tested is TAK-659.This study will look at the determination of the MTD/RP2D and efficacy measured by ORR in participants who take TAK-659 in combination with nivolumab. The study will include a dose escalation phase (Part 1), a potential nivolumab fixed dose cohort, and a dose expansion phase (Part 2).

The study will enroll approximately 120 participants, approximately 9-12 in the dose escalation phase and approximately 36 in each of the 3 dose expansion cohorts. Participants will be assigned to 1 of the 4 treatment groups:

* Part 1: Advanced Solid Tumors
* Potential Nivolumab Fixed Dose Cohort
* Part 2: Metastatic TNBC
* Part 2: Metastatic NSCLC
* Part 2: Metastatic HNSCC

All participants will be asked to take the tablets of TAK-659 at the same time each day throughout the study. Participants will also receive intravenous infusion of nivolumab (within 30 minutes after the TAK-650 dose) once every 2 weeks. This multi-center trial will be conducted globally. The overall time to receive treatment in this study is approximately 12 months. Participants will be assessed for disease response and PD during the PFS follow-up of 6 months (for participants who discontinue due to reasons other than PD) and OS follow-up of 12 months from the last dose of study drug.

Arms:
arm 1: TAK-659 60 milligram (mg), tablets, orally, once daily in each 28-day treatment cycle in combination with nivolumab 3 milligram per kilogram (mg/kg), infusion over 60 minutes, intravenously (IV), on Days 1 and 15 in each 28 day treatment cycle until PD or unacceptable toxicity. Dose escalation of TAK-659 to 100 mg may be done using a 3 + 3 dose escalation design to determine a maximum tolerated dose (MTD) and/or RP2D. arm 2: After RP2D of TAK-659 has been identified, based on evaluation of combination with weight-based dose of nivolumab (3 mg/kg), RP2D may be evaluated in combination with a fixed dose of 240 mg IV nivolumab after discussion between investigator and sponsor for all types of advanced solid tumors. For single-agent nivolumab, fixed dose is expected to have equal exposure, safety, and efficacy as weight-based (3 mg/kg) dose. If nivolumab fixed dose is evaluated with TAK-659 RP2D, 3 participants will be initially enrolled into cohort. Following evaluation of safety, efficacy, and any available PK data, along with discussions between investigator and sponsor, 3 additional participants may be enrolled into cohort for a total of 3 to 6 participants. If \>=1 out of 6 participants experiences dose-limiting toxicity (DLT) in Cycle 1, or significant safety issues are seen in Cycle 2 and beyond, re-evaluation of TAK-659 RP2D when administered with a fixed dose of nivolumab is permitted. arm 3: Participants with metastatic TNBC will receive TAK-659 at the RP2D as determined in Part 1, tablets, orally, once daily in each 28-day treatment cycle in combination with nivolumab 3 mg/kg, infusion over 60 minutes, intravenously, on Day 1 and Day 15 of each 28 day treatment cycle until PD or unacceptable toxicity. A subset of participants will receive two weeks of TAK-659 monotherapy during Cycle 1, and will receive nivolumab beginning on Day 15 of Cycle 1. The dose of nivolumab will be either 3 mg/kg or 240 mg IV, dependent on whether the 240 mg fixed-dose cohort is evaluated and deemed safe and tolerable. If so, the dosing regimen may switch to 240 mg, on the basis of change in clinical practice and discussion between the investigator and sponsor. If the nivolumab fixed-dose evaluation cohort is not run, the dose of nivolumab for all participants in the dose expansion phase will be 3 mg/kg. arm 4: Participants with metastatic NSCLC will receive TAK-659 at the RP2D as determined in Part 1, tablets, orally, once daily in each 28-day treatment cycle in combination with nivolumab 3 mg/kg, infusion over 60 minutes, intravenously, on Day 1 and Day 15 of each 28 day treatment cycle until PD or unacceptable toxicity. A subset of participants will receive two weeks of TAK-659 monotherapy during Cycle 1, and will receive nivolumab beginning on Day 15 of Cycle 1.disease or unacceptable toxicity. The dose of nivolumab will be either 3 mg/kg or 240 mg IV, dependent on whether the 240 mg fixed-dose cohort is evaluated and deemed safe and tolerable. If so, the dosing regimen may switch to 240 mg, on the basis of change in clinical practice and discussion between the investigator and sponsor. If the nivolumab fixed-dose evaluation cohort is not run, the dose of nivolumab for all participants in the dose expansion phase will be 3 mg/kg. arm 5: Participants with Head and Neck Squamous Cell Carcinoma (HNSCC) will receive TAK-659 at the RP2D as determined in Part 1, tablets, orally, once daily in each 28-day treatment cycle in combination with nivolumab 3 mg/kg, infusion over 60 minutes, intravenously, on Day 1 and Day 15 of each 28 day treatment cycle until PD or unacceptable toxicity. A subset of participants will receive two weeks of TAK-659 monotherapy during Cycle 1, and will receive nivolumab beginning on Day 15 of Cycle 1. The dose of nivolumab will be either 3 mg/kg or 240 mg IV, dependent on whether the 240 mg fixed-dose cohort is evaluated and deemed safe and tolerable. If so, the dosing regimen may switch to 240 mg, on the basis of change in clinical practice and discussion between the investigator and sponsor. If the nivolumab fixed-dose evaluation cohort is not run, the dose of nivolumab for all participants in the dose expansion phase will be 3 mg/kg.

Interventions: intervention 1: TAK-659 intervention 2: Nivolumab
Intervention descriptions: intervention 1: TAK-659 Tablets. intervention 2: Nivolumab intravenous infusion.

Protocol document:
Prot_001.pdf: 



Title: A Phase 1b Study to Evaluate TAK-659 in Combination With Nivolumab in Patients With 
Advanced Solid Tumors 
NCT Number: NCT02834247
Protocol Approve Date: 27 April 2017
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.


1.0 TITLE PAGE
PROTOCOL AMENDMENT
A Phase 1b Study to Evaluate TAK-659 in Combination With Nivolumab in Patients With 
Advanced Solid Tumors 
TAK-659 in Combination With Nivolumab in Advanced Solid Tumors
Sponsor:
Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda 
Pharmaceutical Company Limited
40 Landsdowne Street
Cambridge, MA USA 02139
Telephone: +1 (617) 679-7000
Please note: Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda 
Pharmaceutical Company Limited, may be referred to in this protocol as 
“Millennium”, “sponsor”, or “Takeda”
Study Number:
C34003
IND Number:
130,508
EudraCT Number:
2016-000853-10
Compound:
TAK-659
Date:
27 April 2017
Amendment Number:
02
Amendment History:
Date
Amendment Number
Amendment Type
Region
01 April 2016
Initial Protocol
Not applicable
Global
03 May 2016
01
Not applicable
Global
27 April 2017
02
Not applicable
Global
Pro
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1.0
ADMINISTRATIVE
1.1
Contacts 
A separate contact information list will be provided to each site.
Serious adverse event and pregnancy reporting information is presented in Section 11.0, as is 
information on reporting product complaints. 
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site.
Contact Type/Role
North America
Europe
Serious adverse event and pregnancy reporting
See Section 11.2
See Section 11.2
Responsible Medical Officer 
(carries overall responsibility for the conduct of the study)
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o the applicable Terms of Use
, as is
as is
ssigned 
signed
nt guide
t guid
Eur
Eu
he
he
he 
o t
PPD


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 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 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 
subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 11.2 of this 
protocol.

Terms outlined in the Clinical Study Site Agreement.

Appendix B – Responsibilities of the Investigator.
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix C of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Provence)
Location of Facility (Country)
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1.3
Protocol Amendment 02 Summary of Changes 
Rationale for Amendment 02
This document describes the changes in reference to the Protocol Incorporating Amendment 
No. 02. The primary purposes of this amendment are to add the option of a new cohort to evaluate 
a fixed dose of nivolumab, to remove time-bound references to the nivolumab United States 
Prescribing Information (USPI), to clarify how a study cycle is defined in the event of study drug 
interruption due to an adverse event (AE), to update the disease assessment criteria, to provide 
information on treatment after disease progression, and to update the guidelines for TAK-659 and 
nivolumab dose modifications. 
Minor grammatical, editorial, and formatting changes are included for clarification purposes only. 
For specific descriptions of text changes and where those changes are located, see Appendix J.
Changes in Amendment 02
1. Update approved indications for nivolumab.
2. Update information regarding nonclinical studies of TAK-659 in combination with 
anti-programmed cell death protein 1 therapy.
3. Update summaries of TAK-659 clinical experience and risks and benefits.
4. Add an option to conduct a nivolumab fixed-dose evaluation cohort.
5. Identify how a study cycle is defined and the requirement for the start of a new cycle in the 
event of a study drug interruption, and provide a source of further guidance on calculating 
cycle length. 
6. Clarify that the maximum tolerated dose/maximally administered dose/recommended phase 2 
dose will be determined using weight-based nivolumab dosing.
7. Clarify the use of blood samples for biomarker analysis.
8. Update the estimated number of patients in the study.
9. Update the inclusion criterion regarding minimum creatinine clearance laboratory value for 
entry into the study.
10. Update the inclusion criterion regarding minimum hemoglobin laboratory value for entry into 
the study.
11. Update the inclusion criteria regarding permitted lipase and amylase concentrations values for 
entry into the study. 
12. Update the inclusion criterion regarding permissible blood pressure in hypertensives patients 
for entry into the study. 
13. Clarify that patients in the non-small cell lung cancer cohort with epidermal growth factor 
receptor or anaplastic lymphoma kinase genomic alternation should have had progressive 
disease (PD) on United States Food and Drug Administration–approved therapy.
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14. Update exclusion criteria regarding patients with history of autoimmune disease, type I 
diabetes mellitus, childhood asthma, and thyroid disorders.
15. Update the restrictions on corticosteroid-based medication.
16. Clarify exclusion criterion regarding previous anticancer treatments.
17. Update exclusion criterion regarding patients with another malignancy.
18. Update the restrictions on the use of non-oncology vaccine therapies.
19. Update language regarding use of P-glycoprotein and/or strong cytochrome P450 3A 
inhibitors or inducers and clarify exceptions to their use for treatment of an AE requiring a 
TAK-659 hold. 
20. Update the language for dose-expansion patients regarding activated partial thromboplastin 
time or plasma thromboplastin.
21. Provide additional instruction on how to address missed doses of study drug.
22. Update dose-limiting toxicity evaluation period. 
23. Update the guidelines for TAK-659 and nivolumab dose modifications for hematologic and 
nonhematologic toxicity. 
24. Clarify use of concomitant medications and procedures.
25. Add information on the management of diarrhea, edema, rash, hypophosphatemia, and enzyme 
elevations.
26. Clarify that smoking history should be collected with medical history.
27. Include pulse oximetry in the collection of vital signs.
28. Update list of laboratory tests to include creatine phosphokinase and cardiac troponin I and 
troponin T.
29. Update pregnancy testing to include both urine and serum pregnancy testing.
30. Update the disease assessment criteria regarding verification of response and verification of 
progression.
31. Update how pseudo disease progression is defined.
32. Clarify that tumor assessments should be collected for patients who have interruption(s) in 
study drug administration.
33. Indicate that additional exploratory independent review of study imaging data may occur if 
deemed necessary.
34. Add section about treatment beyond disease progression.
35. Clarify timing of tumor biopsy sampling. 
36. Specify that cytokine/chemokine measurements will be taken from serum. 
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37. Clarify study drug dosing instructions on days when predose pharmacokinetic (PK) samples 
are scheduled.
38. Add to the PK measurements section a rationale for conducting PK sampling at any time 
during the clinic visit on Cycle 1 Day 8 during dose expansion.
39. Update reasons for completion of treatment.
40. Indicate that the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, not 
modified RECIST version 1.1, will be used to measure PD.
41. Update procedures for monitoring AEs and the period of observation.
42. Clarify that PK parameters will be summarized using descriptive statistics.
43. Indicate that the relationship between PK and pharmacodynamics changes may be evaluated. 
44. Update language regarding informed consent forms.
45. Clarify language regarding study-site monitoring visits.
46. Remove time-bound references to the nivolumab USPI.
47. Update the Schedule of Events to include additional tests when nivolumab is dosed.
48. Update timing of vital sign measurements for Cycle 1 Day 1.
49. Clarify language regarding disease response assessments to include all relevant sites of 
disease.
50. Clarify language regarding purpose of pharmacodynamic assessments.
51. Update responsibilities of investigator.
52. Add RECIST version 1.1 as appendix.
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE.......................................................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 02 Summary of Changes ..........................................................5
2.0
STUDY SUMMARY ....................................................................................................14
3.0
STUDY REFERENCE INFORMATION ......................................................................20
3.1
Study-Related Responsibilities.................................................................................20
3.2
Coordinating Investigator.........................................................................................20
3.3
List of Abbreviations ...............................................................................................21
3.4
Corporate Identification...........................................................................................24
4.0
INTRODUCTION.........................................................................................................25
4.1
Background .............................................................................................................25
4.1.1
Diseases Under Study ........................................................................................25
4.1.2
Study Drug.........................................................................................................26
4.1.3
Nonclinical Experience ......................................................................................28
4.1.4
Clinical Experience............................................................................................29
4.1.5
Risks and Benefits..............................................................................................31
4.2
Rationale for the Proposed Study.............................................................................33
4.2.1
Rationale for Dose and Schedule Selection ........................................................35
4.2.2
Rationale for PK Assessments............................................................................36
4.2.3
Rationale for Biomarker Analysis (Correlative Science Studies) ........................36
4.2.4
Rationale for Pharmacogenomic Assessments....................................................37
5.0
STUDY OBJECTIVES .................................................................................................39
5.1
Primary Objectives ..................................................................................................39
5.2
Secondary Objectives...............................................................................................39
5.3
Tertiary/Exploratory Objectives...............................................................................39
5.4
Additional Objectives ..............................................................................................39
6.0
STUDY ENDPOINTS...................................................................................................40
6.1
Primary Endpoints ...................................................................................................40
6.2
Secondary Endpoints ...............................................................................................40
6.3
Exploratory Endpoints .............................................................................................40
6.4
Additional Endpoints ...............................................................................................41
7.0
STUDY DESIGN..........................................................................................................42
7.1
Overview of Study Design.......................................................................................42
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7.2
Number of Patients ..................................................................................................46
7.3
Duration of Study ....................................................................................................46
8.0
STUDY POPULATION................................................................................................47
8.1
Inclusion Criteria .....................................................................................................47
8.2
Exclusion Criteria ....................................................................................................50
9.0
STUDY DRUG .............................................................................................................54
9.1
Study Drug Administration......................................................................................54
9.1.1
TAK-659 ...........................................................................................................54
9.1.2
Nivolumab.........................................................................................................54
9.2
Missed Doses and Infusion Delays...........................................................................55
9.3
Definitions of DLT ..................................................................................................55
9.4
Dose Escalation Rules..............................................................................................56
9.5
Dose Modification Guidelines..................................................................................59
9.5.1
Part 1 Intrapatient Dose Escalation.....................................................................61
9.5.2
Dose Modification for Hematologic and Nonhematologic Toxicity: TAK-659 
and Nivolumab...................................................................................................61
9.6
Concomitant Medications and Procedures................................................................67
9.7
Precautions and Restrictions ....................................................................................70
9.8
Management of Clinical Events ...............................................................................70
9.8.1
Nausea and/or Vomiting.....................................................................................71
9.8.2
Anemia, Thrombocytopenia, and/or Neutropenia ...............................................71
9.8.3
Diarrhea.............................................................................................................71
9.8.4
Edema (Including Periorbital) ............................................................................71
9.8.5
Rash With or Without Pruritus ...........................................................................72
9.8.6
Hypophosphatemia ............................................................................................72
9.8.7
Enzyme Elevations.............................................................................................72
9.8.8
Immune-Mediated Adverse Reactions................................................................72
9.8.9
Infusion Reactions .............................................................................................76
9.9
Blinding and Unblinding..........................................................................................77
9.10
Description of Investigational Agents ......................................................................77
9.10.1 TAK-659 ...........................................................................................................77
9.10.2 Nivolumab.........................................................................................................78
9.11
Preparation, Reconstitution, and Dispensation..........................................................78
9.11.1 TAK-659 ...........................................................................................................78
9.11.2 Nivolumab.........................................................................................................78
9.12
Packaging and Labeling...........................................................................................78
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9.12.1 TAK-659 ...........................................................................................................78
9.12.2 Nivolumab.........................................................................................................78
9.13
Storage, Handling, and Accountability.....................................................................78
9.13.1 TAK-659 ...........................................................................................................78
9.13.2 Nivolumab.........................................................................................................79
10.0
STUDY CONDUCT......................................................................................................80
10.1
Study Personnel and Organizations..........................................................................80
10.2
Arrangements for Recruitment of Patients................................................................80
10.3
Treatment Group Assignments.................................................................................80
10.4
Study Procedures.....................................................................................................80
10.4.1 Informed Consent...............................................................................................81
10.4.2 Patient Demographics ........................................................................................81
10.4.3 Medical History .................................................................................................81
10.4.4 Physical Examination.........................................................................................81
10.4.5 Patient Height and Weight .................................................................................81
10.4.6 Vital Signs .........................................................................................................82
10.4.7 ECOG Performance Status.................................................................................82
10.4.8 ECG...................................................................................................................82
10.4.9 Concomitant Medications and Procedures..........................................................83
10.4.10
AEs..............................................................................................................83
10.4.11
Enrollment ...................................................................................................83
10.4.12
Clinical Laboratory Evaluations ...................................................................84
10.4.13
Pregnancy Test.............................................................................................85
10.4.14
Ophthalmic Exam.........................................................................................85
10.4.15
Disease Assessment......................................................................................85
10.4.16
Treatment Beyond Disease Progression........................................................86
10.4.17
Tumor Biopsies............................................................................................88
10.4.18
Banked Tumor Specimen Measurements......................................................88
10.4.19
Analysis of PBMCs......................................................................................88
10.4.20
Cytokine/Chemokine Measurements ............................................................88
10.4.21
Analysis of ctDNA.......................................................................................88
10.4.22
PK Measurements ........................................................................................89
10.4.23
DNA Measurements.....................................................................................90
10.5
Completion of Treatment .........................................................................................90
10.6
Completion of Study................................................................................................90
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10.7
Discontinuation of Treatment With Study Drug and Patient Replacement................90
10.8
Withdrawal of Patients From Study .........................................................................91
10.9
Study Compliance....................................................................................................91
10.10 Posttreatment Follow-up Assessments (PFS and OS)...............................................92
11.0
ADVERSE EVENTS ....................................................................................................93
11.1
Definitions...............................................................................................................93
11.1.1 PTE Definition...................................................................................................93
11.1.2 AE Definition ....................................................................................................93
11.1.3 SAE Definition ..................................................................................................93
11.2
Procedures for Recording and Reporting AEs and SAEs..........................................94
11.3
Monitoring of AEs and Period of Observation .........................................................95
11.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events.........96
11.5
Procedures for Reporting Product Complaints..........................................................96
11.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities...........96
12.0
STUDY-SPECIFIC COMMITTEES .............................................................................98
13.0
DATA HANDLING AND RECORDKEEPING............................................................99
13.1
eCRFs......................................................................................................................99
13.2
Record Retention .....................................................................................................99
14.0
STATISTICAL METHODS........................................................................................101
14.1
Statistical and Analytical Plans ..............................................................................101
14.1.1 Analysis Sets....................................................................................................101
14.1.2 Analysis of Demographics and Other Baseline Characteristics .........................101
14.1.3 Efficacy Analysis.............................................................................................101
14.1.4 PK Analysis .....................................................................................................102
14.1.5 Pharmacodynamic Analysis .............................................................................103
14.1.6 Biomarker Analyses.........................................................................................103
14.1.7 Pharmacogenomic Analyses.............................................................................103
14.1.8 Safety Analyses................................................................................................103
14.2
Interim Analysis and Criteria for Early Termination ..............................................104
14.3
Determination of Sample Size................................................................................105
15.0
QUALITY CONTROL AND QUALITY ASSURANCE.............................................106
15.1
Study-Site Monitoring Visits .................................................................................106
15.2
Protocol Deviations................................................................................................106
15.3
Quality Assurance Audits and Regulatory Agency Inspections ..............................106
16.0
ETHICAL ASPECTS OF THE STUDY......................................................................107
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16.1
IRB and/or IEC Approval ......................................................................................107
16.2
Patient Information, Informed Consent, and Patient Authorization.........................108
16.3
Patient Confidentiality ...........................................................................................109
16.4
Publication, Disclosure, and Clinical Trial Registration Policy...............................109
16.4.1 Publication and Disclosure...............................................................................109
16.4.2 Clinical Trial Registration................................................................................109
16.4.3 Clinical Trial Results Disclosure ......................................................................110
16.5
Insurance and Compensation for Injury..................................................................110
17.0
REFERENCES............................................................................................................111
LIST OF IN-TEXT TABLES
Table 9.a
Planned Dose Levels of TAK-659......................................................................58
Table 9.b
Planned Dose Levels of TAK-659 in the Expansion Phase .................................60
Table 9.c
Guidelines for TAK-659 and Nivolumab Dose Modifications for Hematologic 
Toxicity .............................................................................................................62
Table 9.d
Guidelines for TAK-659 and Nivolumab Dose Modifications for 
Nonhematologic Toxicity...................................................................................64
Table 10.a
Clinical Chemistry and Hematology Tests..........................................................84
Table 10.b
Clinical Urinalysis Tests ....................................................................................84
Table 10.c
Immune Safety Tests..........................................................................................85
LIST OF IN-TEXT FIGURES
Figure 7.a
Study Schema ....................................................................................................43
Figure 9.a
Dose Escalation Algorithm.................................................................................57
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
New York Heart Association Classification of Cardiac Disease........................130
Appendix G
Medications, Supplements, and Food Products that are Strong CYP3A and/or 
P-gp Inhibitors or Inducers...............................................................................131
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Appendix H
Methods of Contraception Considered to be Effective......................................133
Appendix I
Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1)..............134
Appendix J
Detailed Description of Amendments to Text...................................................136
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2.0
STUDY SUMMARY
Name of Sponsor(s):
Millennium Pharmaceuticals, Inc.
Compound:
TAK-659
Title of Protocol: A Phase 1b Study to Evaluate TAK-659 
in Combination With Nivolumab in Patients With 
Advanced Solid Tumors
IND No.: 130,508
EudraCT No.:
Not applicable
Study Number: C34003
Phase: 1b
Study Design:
This is an open-label, multicenter, phase 1b, dose escalation study of TAK-659 in combination with nivolumab in 
patients with advanced solid tumors. The study will include a dose escalation phase (Part 1) and a dose expansion 
phase (Part 2). In the dose escalation phase, the patient population will consist of all-comer patients with advanced 
solid tumors for whom 1 or more prior lines of therapy have failed and who have no effective therapeutic options 
available based on investigator assessment. The dose expansion phase will include 3 cohorts: 1) patients with 
metastatic triple-negative breast cancer (TNBC) who have had ≥1 prior line of chemotherapy; 2) patients with locally 
advanced or metastatic non-small cell lung cancer (NSCLC) that has progressed on or after a prior platinum-based 
chemotherapy; and 3) patients with locally advanced or metastatic head and neck squamous cell carcinoma (HNSCC) 
that has progressed or recurred within 6 months of the last platinum-based chemotherapy.
It is estimated that 126 patients will be enrolled in the study: approximately 9 to 12 patients among the dose escalation 
cohorts evaluating weight-based dosing of nivolumab, 3 to 6 patients in a possible nivolumab fixed-dose evaluation 
cohort (if it is opened), and approximately 36 patients (30 evaluable patients+15% drop off) in each of the 3 dose 
expansion cohorts.
Once enrolled in the study, patients will be administered TAK-659 orally once daily (QD) during each 28-day 
treatment cycle. Patients receiving the combination therapy will also receive nivolumab once every 2 weeks 
intravenously (IV) over 60 minutes on Day 1 and Day 15 of each 28-day treatment cycle (for patients who receive 
2 weeks of TAK-659 monotherapy before starting combination treatment, the first nivolumab infusion will be 
administered on Cycle 1 Day 15). On days when both TAK-659 and nivolumab will be administered, the TAK-659 
dose will be administered first followed by the nivolumab infusion (infusion to begin within 30 minutes after the 
TAK-659 dose). Patients, including those who achieve a complete response, may receive study treatment until they 
experience disease progression (PD) or unacceptable toxicities. 
While the maximum tolerated dose (MTD)/maximally administered dose (MAD)/recommendation phase 2 dose 
(RP2D) of TAK-659 are being determined, the starting dose of nivolumab will be 3 mg/kg IV. 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) may also be 
evaluated, if appropriate. Dose escalation will continue until the MTD is reached, or until 100 mg QD of TAK-659 
(the MAD) is determined to be safe and tolerable, or until a RP2D, if different from the MTD or MAD, has been 
identified on the basis of the safety, tolerability, and preliminary pharmacokinetic (PK) and efficacy data (if available) 
observed in Cycle 1 and beyond. At least 6 patients will be evaluated at the RP2D (the MTD, MAD, or a lower dose as 
determined) before making a decision to advance to further dose expansion.
After the RP2D of TAK-659 has been identified, on the basis of evaluation of the combination with a weight-based 
dose of nivolumab (3 mg/kg), this RP2D of TAK-659 may be evaluated in combination with a fixed dose of 240 mg 
IV nivolumab following discussion between the investigator and sponsor. For single-agent nivolumab, the fixed dose 
is expected to have equivalent exposure, safety, and efficacy as the weight-based (3 mg/kg) dose. If the nivolumab 
fixed dose is evaluated, 3 patients will be initially enrolled into the cohort. Following evaluation of the safety, efficacy, 
and any available PK data, along with discussions between the investigator and sponsor, 3 additional patients may be 
enrolled into the cohort for a total of 3 to 6 patients. Following evaluation of this fixed-dose cohort (if it is run), the 
dose of nivolumab may be switched from the 3 mg/kg weight-based dose to a fixed dose of 240 mg for all patients 
ongoing in the study at the time of the switch and those to be enrolled after the switch. This decision will be made on 
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the basis of an assessment of the change in clinical practice in different regions and upon discussion and agreement 
between the investigators and sponsor. If the nivolumab fixed-dose evaluation cohort is not run, the dose of nivolumab 
for all patients in the dose expansion phase will be 3 mg/kg, unless the direct conversion to a fixed dose of nivolumab 
is justified by other available data. 
After the combination TAK-659 RP2D (the MTD, MAD, or a lower dose) is determined, expansion cohorts are 
planned in patients with TNBC, NSCLC, and HNSCC. Thirty response-evaluable patients will be enrolled in each 
expansion cohort, including approximately 10 patients in each cohort who are able to provide evaluable serial tumor 
biopsies. Additionally, each expansion cohort will include 24 response-evaluable patients who are naïve to 
anti-programmed cell death protein 1 (PD-1)/anti-programmed cell death 1 ligand 1 (PD-L1) therapy and 6 
response-evaluable patients who are relapsed/refractory to prior anti-PD-1/anti-PD-L1 therapy. Ten 
response-evaluable patients in each expansion cohort will first receive single-agent treatment with TAK-659 for 
2 weeks at the RP2D previously determined in combination with nivolumab. Following the 2-week, single-agent 
treatment, TAK-659 treatment will continue (at the same dose) in combination with nivolumab during Week 3 and 
beyond.
The subset of expansion patients who will be treated with single-agent TAK-659 at its combination RP2D during 
Weeks 1 and 2 should have accessible tumors for core or excisional biopsy and provide permission for the biopsies to 
be taken. These patients will undergo mandatory biopsies before single-agent TAK-659 treatment begins, at the end of 
the 2-week treatment window, and after 6 weeks of treatment with TAK-659 in combination with nivolumab; an 
optional biopsy will also be taken at the time of PD. The biopsies will be used for biomarker analysis evaluating the 
effect of TAK-659 on tumor cells and on immune/stromal cells supporting tumor tissue. 
The remaining 20 response-evaluable patients in each expansion cohort will receive TAK-659 at its RP2D in 
combination with nivolumab, starting from Week 1, Day 1. 
During dose escalation, serial blood samples for assessment of TAK-659 plasma PK will be collected for 24 hours 
after TAK-659 dosing on Cycle 1 Days 1 and 15, the days on which both TAK-659 and nivolumab are administered. 
Although the risk of drug-drug interaction between TAK-659 and nivolumab is predicted to be low, TAK-659 plasma 
PK following combination administration in the dose escalation will be compared with historical plasma PK following 
single-agent administration to confirm no clinically meaningful differences in TAK-659 PK between the single-agent 
and combination settings. For purposes of population PK analysis, sparse collection of PK samples will occur in the 
expansion cohorts during both the single-agent and combination administration periods.
All patients in the expansion cohorts will be treated until PD, occurrence of unacceptable toxicities, withdrawal due to 
other reasons, or the study is terminated by the sponsor. The objectives of these expansion cohorts are to evaluate 
efficacy of TAK-659 in combination with nivolumab as measured by overall response rate (ORR) and to determine the 
safety and tolerability of TAK-659 in combination with nivolumab. 
Primary Objectives:

To determine the MTD/RP2D of TAK-659 when administered in combination with nivolumab (dose escalation).

To determine the efficacy of TAK-659 plus nivolumab as measured by ORR (dose expansion).
Secondary Objectives:

To determine the safety and tolerability of TAK-659 when administered in combination with nivolumab.

To evaluate other efficacy measures such as disease control rate (response plus stable disease), duration of 
response (DOR), rate of PD at 6 months, progression-free survival (PFS), and overall survival (OS).

To characterize the plasma PK of TAK-659 when administered in combination with nivolumab.
Patient Population: 
Dose escalation: Patients aged 18 years or older with advanced solid tumors for whom 1 or more prior lines of therapy 
have failed and who have no effective therapeutic options available based on investigator assessment.
Dose expansion: Patients aged 18 years or older with: 

Metastatic TNBC with ≥1 prior line of chemotherapy. 
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
Locally advanced or metastatic NSCLC that has progressed on or after a prior platinum-based chemotherapy.

Locally advanced or metastatic HNSCC that has progressed or recurred within 6 months of the last 
platinum-based chemotherapy.
Number of Patients:
It is estimated that 126 patients will be enrolled in the study: 
approximately 9 to 12 patients among the dose escalation 
cohorts evaluating weight-based dosing of nivolumab, 3 to 
6 patients in the possible nivolumab fixed dose evaluation 
cohort, and approximately 36 patients in each of the 3 dose 
expansion cohorts.
Number of Sites: 
Estimated total: Approximately 25 sites in North 
America and Europe
Dose Level(s): 
TAK-659: oral daily dosing with 3+3 dose escalation 
planned at 60 and 100 mg. The RP2D determined in 
combination with nivolumab during dose escalation will be 
used for the possible fixed-dose evaluation cohort and dose 
expansion cohorts.
Nivolumab: 3 mg/kg IV dosing over 60 minutes every 
2 weeks (Day 1 and Day 15 of each 28-day cycle). If the 
240 mg fixed-dose cohort is evaluated and deemed safe and 
tolerable, the dosing regimen may switch to 240 mg, on the 
basis of change in clinical practice and discussion between 
the investigator and sponsor. For patients participating in 
the 2-week monotherapy run-in with TAK-659, the first 
dose will be on Cycle 1 Day 15.
Route of Administration:
TAK-659: Oral
Nivolumab: IV
Duration of Treatment: 
Treatment will continue until disease progression (PD), 
unacceptable toxicities, completion of the study, or 
withdrawal due to other reasons. The estimated treatment 
duration is 12 months.
Period of Evaluation: 
PFS follow-up of 6 months (for patients who 
discontinue due to reasons other than PD) and OS 
follow-up of 12 months from the last dose of study 
drug are planned.
Main Criteria for Inclusion:
For indication-specific expansion cohorts:
TNBC

Patients with histologically confirmed, metastatic TNBC with measurable disease per Response Evaluation 
Criteria in Solid Tumors (RECIST) version 1.1 [1].

Triple-negative disease (estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2
negativity) confirmed on a histological biopsy of a metastatic tumor lesion (receptor conversion not allowed).

Safely accessible tumor lesions (based on investigator’s assessment) for serial pretreatment and posttreatment 
biopsies are required for patients receiving TAK-659 monotherapy run-in treatment followed by TAK-659 plus 
nivolumab combination treatment (approximately 10/30 response-evaluable patients); adequate, newly obtained, 
core or excisional biopsy of a metastatic tumor lesion not previously irradiated is required. Mandatory biopsies 
will be taken before TAK-659 monotherapy, after the 2 weeks of TAK-659 monotherapy, and after 6 weeks of 
TAK-659 plus nivolumab combination therapy. An optional biopsy may be taken at PD with additional consent 
from the patient.

One, 2, or 3 line(s) of chemotherapy for metastatic disease and with progression of disease on last treatment 
regimen.
–
For the purposes of this study, neoadjuvant and/or adjuvant chemotherapy regimens do not count as a prior 
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line of therapy.
–
Prior treatment must include an anthracycline and/or a taxane in the neoadjuvant, adjuvant, or metastatic 
setting with the exception for patients who are clinically contraindicated for these chemotherapies.
NSCLC

Locally advanced or metastatic (stage IIIB, stage IV, or recurrent) NSCLC with measurable lesions per RECIST 
version 1.1.

PD during or following at least 1 prior treatment. Patients should have received a prior platinum-containing, 
2-drug regimen for locally advanced, unresectable/inoperable or metastatic NSCLC had or disease recurrence 
within 6 months of treatment with a platinum-based adjuvant/neoadjuvant regimen or combined modality (eg, 
chemoradiation) regimen with curative intent.

Patients with epidermal growth factor receptor or anaplastic lymphoma kinase genomic alternations should have 
PD on prior United States Food and Drug Administration-approved therapy for these aberrations.

Safely accessible tumor lesions (based on investigator’s assessment) for serial pretreatment and posttreatment 
biopsies are required for patients receiving TAK-659 monotherapy run-in treatment followed by TAK-659 plus 
nivolumab combination treatment (approximately 10/30 response-evaluable patients); adequate, newly obtained, 
core or excisional biopsy of a metastatic tumor lesion not previously irradiated is required. Mandatory biopsies 
will be taken before TAK-659 monotherapy, after the 2 weeks of TAK-659 monotherapy, and after 6 weeks of 
TAK-659 plus nivolumab combination therapy. An optional biopsy may be taken at PD with additional consent 
from the patient.
HNSCC

Histologically confirmed recurrent or metastatic HNSCC (oral cavity, pharynx, larynx), stage III/IV, and not 
amenable to local therapy with curative intent (surgery or radiation therapy with or without chemotherapy).
–
Histologically confirmed recurrent or metastatic squamous cell carcinoma of unknown primary or 
nonsquamous histologies (eg, mucosal melanoma) are not allowed.
–
Histologically confirmed recurrent or metastatic carcinoma of the nasopharynx is allowed, but these patients 
will not be included as response-evaluable patients for efficacy analysis of HNSCC.

Measurable disease per RECIST 1.1. 

Tumor progression or recurrence within 6 months of the last dose of platinum-based therapy in the adjuvant (ie, 
with radiation after surgery), primary (ie, with radiation), recurrent, or metastatic setting.

Safely accessible tumor lesions (based on investigator’s assessment) for serial pretreatment and posttreatment 
biopsies are required for patients receiving TAK-659 monotherapy run-in treatment followed by TAK-659 plus 
nivolumab combination treatment (approximately 10/30 response-evaluable patients); adequate, newly obtained, 
core or excisional biopsy of a metastatic tumor lesion not previously irradiated is required. Mandatory biopsies 
will be taken before TAK-659 monotherapy, after the 2 weeks of TAK-659 monotherapy, and after 6 weeks of 
TAK-659 plus nivolumab combination therapy. An optional biopsy may be taken at PD with additional consent 
from the patient.
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Main Criteria for Exclusion:

Active brain metastases or leptomeningeal metastases.

Active or a history of known autoimmune disease.

Diagnosis of immunodeficiency or any condition requiring systemic treatment with corticosteroids (>10 mg daily 
prednisone equivalents) or other immunosuppressive medications within 14 days of treatment.

History of pneumonitis requiring treatment with steroids; history of idiopathic pulmonary fibrosis, drug-induced 
pneumonitis, organizing pneumonia, or evidence of active pneumonitis on screening chest computed tomography 
scan; history of radiation pneumonitis in the radiation field (fibrosis) is permitted.

History of interstitial lung disease.

Prior therapy with experimental antitumor vaccines; any T cell co-stimulation agents or inhibitors of checkpoint 
pathways, such as anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody; or other agents 
specifically targeting T cells are also prohibited. However, in each of the expansion cohorts, 6 response-evaluable 
patients with prior exposure to anti-PD-1 or anti-PD-L1 agents will be allowed for enrollment.
Main Criteria for Evaluation and Analyses:
Primary Endpoints: 

MTD or RP2D (dose escalation).

ORR as assessed by the investigator per RECIST version 1.1 (dose expansion).
Secondary Endpoints: 

Percentage of patients with adverse events (AEs), Grade 3 and Grade 4 AEs, serious AEs, and discontinuations 
for AEs, and clinical laboratory values and vital sign measurements outside the normal range that are of clinical 
significance.

Disease control rate. 

DOR.

Rate of PD at 6 months. 

PFS. 

OS.

Summary statistics of TAK-659 maximum (peak) plasma concentration, first time to reach maximum (peak) 
plasma concentration, and area under the plasma concentration versus time curve over the dosing interval on 
Cycle 1, Days 1 and 15, by dose escalation cohort. 
Statistical Considerations:
The MTD/MAD (in combination with 3 mg/kg IV nivolumab) will be estimated by a standard 3+3 method using data 
collected in the dose escalation phase.
AEs will be summarized by treatment group and overall. Categorical variables such as ORR, disease control rate, and 
rate of PD at 6 months will be tabulated by treatment group and overall. Time to event variables such as DOR, PFS, 
and OS will be analyzed using Kaplan-Meier survival curves, and Kaplan-Meier medians (if estimable) will be 
provided. PK parameters will be summarized using descriptive statistics.
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Sample Size Justification: During the dose escalation phase, dose escalation will be conducted according to a 
standard 3+3 dose escalation schema, and approximately 12 to 18 dose-limiting toxicity-evaluable patients will be 
enrolled (including 3 to 6 patients in the possible nivolumab fixed-dose evaluation cohort). The MTD/RP2D cohort 
will have at least 6 patients. 
The sample sizes for each expansion cohort are estimated using a 1-sided exact binomial test at a significance level of 
=0.1 with a power of 80%. Each cohort uses a null hypothesis of response rate ≤20%, versus an alternative 
hypothesis of response rate ≥40% for patients who are naïve to anti-PD/PD-L1 and any other immune-directed 
antitumor therapies. Therefore, approximately 24 response-evaluable patients for each cohort will be needed. In 
addition, 6 response-evaluable patients with prior exposure to a PD-1 or PD-L1 inhibitor will be enrolled in each 
expansion cohort. In total, 30 response-evaluable patients for each cohort and 90 response-evaluable patients in total 
(~108 patients based on a 15% drop-out rate) will be needed for all expansion cohorts.
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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, their expertise in the therapeutic area and the conduct of clinical 
research as well as study participation. The Signatory Coordinating Investigator will be required to 
review and sign the clinical study report and by doing so agrees that it accurately describes the 
results of the study.
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3.3
List of Abbreviations
Abbreviation
Term
5-HT3
5-hydroxytryptamine 3 serotonin receptor
ADL
activities of daily living
AE
adverse event
ALK
anaplastic lymphoma kinase
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AML
acute myelogenous leukemia
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
ASCO
American Society of Clinical Oncology
ASH
American Society of Hematology
AST
aspartate aminotransferase
AUCinf
area under the plasma concentration versus time curve from zero to infinity
AUCτ
area under the plasma concentration versus time curve over the dosing interval
BUN
blood urea nitrogen
CL/F
apparent oral clearance
Cmax
maximum (peak) plasma concentration
CO2
carbon dioxide
CPK
creatine phosphokinase
CR
complete response
CRO
contract research organization
CT
computed tomography
ctDNA
circulating tumor deoxyribonucleic acid
Ctrough
trough concentration
CYP
cytochrome P450
DDI
drug-drug interaction
DLBCL
diffuse large B-cell lymphoma
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid
DOR
duration of response
EBV
Epstein-Barr virus
EC50
concentration producing half-maximal response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EGFR
epidermal growth factor receptor
EOT
end of treatment
EU
European Union
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Abbreviation
Term
FDA
Food and Drug Administration
FIH
first-in-human
FL
follicular lymphoma
GCP
Good Clinical Practice
G-CSF
granulocyte colony stimulating factor
GGT
gamma glutamyl transferase
GI
gastrointestinal
GM-CSF
granulocyte macrophage-colony stimulating factor
HER2
human epidermal growth factor receptor 2
HIV
human immunodeficiency virus
HNSCC
head and neck squamous cell carcinoma
HPV
human papillomavirus
IB
Investigator’s Brochure
IC50
concentration producing 50% inhibition
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
independent ethics committee
IHC
immunohistochemical 
IRB
institutional review board
ITAM
immunoreceptor tyrosine-based activating motif
IV
intravenous(ly)
LDH
lactate dehydrogenase
LMP2A
latent membrane protein 2A
MAD
maximally administered dose
MDSC
myeloid-derived suppressor cells
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NSCLC
non-small cell lung cancer 
ORR
overall response rate
OS
overall survival
PBMC
peripheral blood mononuclear cell
PD
progressive disease (disease progression)
PD-1
programmed cell death protein 1
PD-L1
programmed cell death 1 ligand 1
PD-L2
programmed cell death 1 ligand 2
PE
physical examination
PFS
progression-free survival
P-gp
P-glycoprotein
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Abbreviation
Term
PK
pharmacokinetic(s)
PO
per os; by mouth (orally) 
PR
partial response 
PT
plasma thromboplastin
PTE
pretreatment event
PTR
peaktrough ratio
Q2W
once every 2 weeks
QD
quaque die; each day; once daily
QTc
rate-corrected QT interval (millisec) of electrocardiograph
QTcB
Bazett corrected QT interval
QTcF
Friderichia corrected QT interval
Rac
accumulation ratio
RBC
red blood cell
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
ribonucleic acid
RP2D
recommended phase 2 dose
SAE
serious adverse event
SAP
statistical analysis plan
SCLC
small cell lung cancer
SD
stable disease
SmPC
Summary of Product Characteristics
SUSAR
suspected unexpected serious adverse reactions
SYK
spleen tyrosine kinase
t1/2
terminal disposition half-life
TEAE
treatment-emergent adverse event
TIL
tumor-infiltrating lymphocyte
Tmax
time to reach maximum (peak) plasma concentration
TNBC
triple-negative breast cancer
ULN
upper limit of the normal range
US
United States
USPI
United States Prescribing Information
WHO
World Health Organization
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3.4
Corporate Identification 
Millennium
Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda 
Pharmaceutical Company Limited.
TDC Japan
Takeda Development Center Japan
TDC Asia
Takeda Development Center Asia, Pte Ltd
TDC Europe
Takeda Development Centre Europe Ltd.
TDC Americas
Takeda Development Center Americas, Inc.
TDC
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable
Takeda
Millennium Pharmaceuticals, Inc, TDC Japan, TDC Asia, TDC Europe and/or TDC 
Americas, as applicable
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4.0
INTRODUCTION
4.1
Background
4.1.1
Diseases Under Study
4.1.1.1
Triple-Negative Breast Cancer
Worldwide, breast cancer is the leading type of cancer in women, accounting for 25% of all cases 
[2]. Triple-negative breast cancer (TNBC) represents 10% to 20 % of invasive breast cancers; it is 
an aggressive, heterogeneous subset of breast cancer that demonstrates an absence of estrogen and 
progesterone receptors and no overexpression of human epidermal growth factor receptor 2 
(HER2). TNBC tends to be more prevalent in African-American women, is associated with 
deprivation status, and includes patients with a family history of breast cancer and BRCA1
mutations. At diagnosis, patients with TNBC tend to be younger, and their cancer is generally 
more advanced, at a higher grade, and with higher mitotic indices than patients with hormone- and 
HER2-derived breast cancers [3]. Currently, there is no targeted therapy for TNBC. Patients may 
be offered a lumpectomy with radiation therapy with or without neoadjuvant therapy [4-7]. 
Chemotherapy is also a therapeutic option and would typically either be an anthracycline-based 
regimen combining docetaxel, doxorubicin, and cyclophosphamide, or a non-anthracycline-based 
regimen combining docetaxel and cyclophosphamide [5,8]. Following progression after standard 
chemotherapeutic regimens, patients have a very poor prognosis. Resistance to current standard 
anthracyclines and taxane therapies limits the available options for previously treated patients with 
metastatic TNBC to a small number of non-cross-resistant regimens, and there is currently no 
preferred standard chemotherapy. Duration of response is usually short, rapid relapse is very 
common, and median survival is just 13 months [9].
4.1.1.2
Non-Small Cell Lung Cancer
Lung cancer, classified into small cell lung cancer (SCLC) and non-small cell lung cancer 
(NSCLC), remains the leading cause of cancer-related mortality worldwide. NSCLC, including 
squamous cell carcinoma and nonsquamous cell carcinoma (adenocarcinoma, large cell 
carcinoma, and others), accounts for more than 80% of all lung cancer cases. Treatment of patients 
with NSCLC depends upon the cell type (squamous and nonsquamous), tumor stage, molecular
characteristics, and an assessment of the patient’s overall medical condition. Patients with stage I, 
II, or III NSCLC are generally treated with curative intent using surgery, chemotherapy, radiation 
therapy, or a combined modality approach. Systemic therapy is generally indicated for patients 
who present with advanced disease, including those who present with inoperable, locally advanced 
or metastatic disease (stage IV), or recurring disease following initial definitive treatment. The 
majority of patients with NSCLC are diagnosed at an advanced stage; therefore, the standard 
treatment, which commonly includes a combination of chemotherapy and radiation therapy, 
focuses mainly on disease control and maintenance of quality of life. The platinum-based doublet 
is a standard frontline chemotherapy in this advanced setting for squamous NSCLC and 
nonsquamous NSCLC with no presence of driver mutations such as activating mutations of 
epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK). Following the 
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platinum-based doublet therapy, the standard second-line therapy for NSCLC has been docetaxel. 
Recent approval of immune checkpoint inhibitors, including nivolumab and pembrolizumab, as 
preferred subsequent therapy options for patients with either metastatic nonsquamous or squamous 
cell lung cancer who have progressed on or after platinum-based therapy, was based on improved 
overall survival (OS) when evaluated against docetaxel (median OS of 12.2 vs 9.4 months). 
However, the OS for patients with NSCLC in the advanced setting is still dismal, making it an area 
of highly unmet medical need that attracts extensive research and development efforts [10].
4.1.1.3
Head and Neck Squamous Cell Carcinoma
Head and neck cancers are a heterogeneous group of neoplasms that typically originate from the 
mucosal lining of the lip, oral cavity, nasopharynx, larynx, and hypolarynx. Biologically, they are 
generally similar, with 85% of head and neck cancers being squamous cell carcinomas; they are, 
therefore, called head and neck squamous cell carcinoma (HNSCC) [11,12]. HNSCC is the fifth 
most common cancer diagnosed worldwide and the eighth most common cause of cancer death 
[13]. There are 500,000 new cases each year worldwide [14]. These cancers tend to occur in men 
in their 60s and 70s and are associated with environmental and lifestyle risk factors, including 
smoking, alcohol consumption, exposure to ultraviolet light and certain workplace chemicals, and 
infection with the human papillomavirus [14]. If detected early, HNSCC is highly curable; 
however, these cancers are frequently aggressive and often are first noticed only when they have 
spread to the lymph nodes. Radiation therapy is the most common form of treatment for HNSCC. 
Surgery and carbon dioxide (CO2) laser surgery are also used, often including the removal of 
cervical lymph nodes to reduce the possibility of the disease spreading. Radiotherapy and surgery 
may be used in combination, and the intention of these treatment modalities is curative. 
Chemotherapy is generally used to create a hostile environment for metastasis either as an 
additional or adjuvant treatment. Typically, the chemotherapy will combine a platinum-based 
therapy (carboplatin or cisplatin) with a taxane (taxotere, paclitaxel, or docetaxel), sometimes 
including fluorouracil cetuximab to treat throat cancer. The 5-year survival rate for patients with 
HNSCC is 40% to 50% [14].
4.1.2
Study Drug
4.1.2.1
TAK-659
TAK-659 is a selective, reversible, and potent inhibitor of spleen tyrosine kinase (SYK) and FLT3 
being developed for oncology indications, the pathogenesis of which are either driven by or 
significantly contributed to by SYK- and/or FLT3-mediated signaling. TAK-659 inhibits SYK 
purified enzyme with a concentration producing 50% inhibition (IC50) of 2.0 and 3.2 nM using 
2 methods. In cultured human tumor cells, TAK-659 potently inhibited SYK activity in 
hematopoietic-derived cell lines (Section 4.1.3). In a broad kinase panel, TAK-659 demonstrated a 
more than 50-fold selectivity for SYK over 290 other protein kinases screened. Subsequent dose 
response analysis independently confirmed the potency of TAK-659 on 4 of these enzymes (FLT3, 
ZAP-70, JAK3, and vascular endothelial growth factor receptor 2) with potency ranging from 
4.6 to 135 nM.
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4.1.2.2
Nivolumab
Nivolumab (Opdivo; Bristo-Myers Squibb) is a human immunoglobulin G4 monoclonal antibody 
that blocks the interaction between the programmed cell death protein 1 (PD-1) and its ligands, 
programmed cell death 1 ligand 1 (PD-L1) and programmed cell death 1 ligand 2 (PD-L2). 
Binding of PD-L1 or PD-L2 to the PD-1 receptor, found on the surface of T cells, inhibits T-cell 
proliferation and cytokine production. Up-regulation of PD-L1 and PD-L2 occurs in tumors. The 
cross-talk between tumor and T cells through the PD-1/ligand interaction in the tumor 
microenvironment leads to inhibition of active T-cell immune surveillance of tumors. Inhibition of 
PD-1, therefore, can block this negative regulatory pathway and allow T cells to regain the ability 
to attack tumors [15,16]. Nivolumab, an anti-PD-1 checkpoint inhibitor, is currently approved in 
the United States (US) either as a monotherapy or in combination with ipilimumab in advanced 
melanoma. Nivolumab is approved in the European Union (EU) for advanced melanoma. 
Following initial approval in melanoma, nivolumab was approved in the US for the treatment of 
metastatic NSCLC after prior chemotherapy and in the European Union for the treatment of 
squamous cell NSCLC after prior chemotherapy. It is also approved in the United States for the 
treatment of advanced renal cell carcinoma in patients who have received prior anti-angiogenic 
therapy and for the treatment of patients with metastatic or recurrent HNSCC following 
progression on platinum-based therapy. More recently, the US Food and Drug Administration 
(FDA) granted accelerated approval for nivolumab for treatment of patients with locally advanced 
or metastatic urothelial carcinoma who have disease progression during or following 
platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant 
or adjuvant treatment with a platinum-containing chemotherapy. See the current versions of the 
Opdivo United States Prescribing Information [USPI] [17] and Summary of Product 
Characteristics [SmPC] [18] for further details on indications approved in the United States and 
European Union, respectively. 
While the maximum tolerated dose (MTD)/maximally administered dose (MAD)/recommended 
phase 2 dose (RP2D) of TAK-659 are being determined, nivolumab will be administered at a 
starting dose of 3 mg/kg intravenous (IV) infusion over 60 minutes once every 2 weeks (Q2W). As 
a result of the nivolumab label change to a fixed dose for most indications approved in the United 
States, TAK-659 may be evaluated in combination with fixed-dose nivolumab (240 mg) per USPI 
in this study. If the fixed dose of nivolumab is evaluated, the dose of nivolumab may be switched 
from the 3 mg/kg weight-based dose to a fixed dose of 240 mg for all patients ongoing in the study 
at the time of the switch and those to be enrolled after the switch. This decision will be made on the 
basis of an assessment of the change in clinical practice in different regions and upon discussion 
and agreement between the investigators and sponsor. If the nivolumab fixed-dose evaluation 
cohort is not run, the dose of nivolumab for all patients in the dose expansion phase will be 
3 mg/kg, unless the direct conversion to a fixed dose of nivolumab is justified by other available 
data.
The most common side effects of nivolumab are fatigue, shortness of breath, musculoskeletal pain, 
decreased appetite, cough, nausea, and constipation. A variety of serious immune-mediated 
adverse reactions have also been observed in patients receiving nivolumab, including pneumonitis, 
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colitis, hepatitis, nephritis, hypothyroidism and hyperthyroidism, and other immune-mediated 
adverse reactions [17].
Further details regarding the clinical experience with nivolumab may be found in the current 
versions of the approved Opdivo USPI [17] or SmPC [18].
4.1.3
Nonclinical Experience
TAK-659 potently inhibited SYK activity in hematopoietic malignancy-derived, cultured human 
cell lines, including T-cell lymphoblastoma, megakaryoblastoma, and acute myelogenous 
leukemia (AML), with a concentration producing half-maximal response (EC50) ranging from 11 
to 775 nM in sensitive cell systems. In an additional study in cultured human tumor cells treated 
with TAK-659, the EC50 ranged from 134 to 25,000 nM, with the greatest inhibitory effects 
observed in 2 diffuse large B-cell lymphoma (DLBCL) cell lines (OCI-Ly10 and HBL-1).
TAK-659 demonstrated significant antitumor activity after oral (PO) administration in HBL-1 
(DLBCL cell line model; 120 mg/kg; p0.005); PHTX-95L (primary DLBCL tumor; 30, 60, and 
120 mg/kg; p0.001); OCI-Ly10 (activated B-celllike DLBCL cell line model; 30, 60, and 
90 mg/kg; p0.001); TMD8 (DLBCL cell line model; 60 and 90 mg/kg; p0.001 and 0.01, 
respectively); MV-4-11 (AML cell line model; 30 and 60 mg/kg; p0.001); KG-1 (AML cell line 
model; 60 mg/kg; p0.001); and PHTXM-Ga-32 (gastric cancer model; 60 mg/kg; p<0.001) 
mouse xenograft models. Tumor growth inhibition correlated with markers of SYK pathway 
modulation in the models in which it was analyzed (eg, HBL-1, PHTX-95L, and OCI-Ly10) and 
showed antitumor activity after TAK-659 treatment. Additionally, pharmacodynamic analysis of 
MV-4-11 tumors from mice treated with TAK-659 demonstrated an apparent reduction of SYK 
phosphorylation at tyrosine residues Y525/526 (phosphorylated SYK Y525/526) and an increase 
in terminal biomarker cleaved caspase-3, a critical marker of apoptosis.
Nonclinical studies show that SYK inhibition results in loss of myeloid-derived suppressor cells 
(MDSCs) and activation of T-cell response both in vitro and in vivo. TAK-659 in combination 
with anti-PD-1 therapy has shown regulation of B cells, NK cells, and macrophages in syngeneic 
nonclinical mouse models. The combination effects in immune cells are model and context 
dependent, and combination activity would be greatest in tumors where SYK-mediated MDSC or 
B-cell immunosuppression is active. The nonclinical combination treatment of TAK-659 and 
anti-PD-1 therapy provides therapeutic advantage over single-agent treatment with durable tumor 
growth inhibition, maintained complete responses (CRs), and a vaccinal memory effect. This 
effect could be indirectly attributed to the decrease in CD11b+ MDSC or B220+ B cells in the 
tumor-infiltrating lymphocytes (TILs) of TAK-659-treated tumors.
TAK-659 is a small molecule that inhibits SYK and FLT3 and is currently under development for 
the treatment of patients with advanced malignancies. The compound that will be administered in 
human clinical trials is the citrate salt, and all references to it in this document are expressed as 
TAK-659.
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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 from the 22 October 2016 data cutoff date. 
The most current safety and efficacy data for Study C34001 are provided from the 
07 October 2016 data cutoff date. The most current safety and efficacy data for Study C34002 are 
provided from the 18 September 2016 data cutoff date.
As of 22 October 2016, 111 patients have 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. 
In Study C34001, the TAK-659 dose was escalated from 60 mg to 120 mg (60 mg [10 patients], 
80 mg [4 patients], 100 mg [15 patients], and 120 mg [7 patients]). The MTD for patients with 
lymphoma and solid tumors has been determined to be 100 mg once daily (QD). Expansion 
cohorts for patients with lymphoma were opened in December 2015, and patients in the expansion 
phase of the study are treated at the MTD/RP2D of 100 mg. Of the 82 patients treated in this study 
(60 lymphoma, 19 solid tumors, and 3 chronic lymphocytic leukemia [CLL]), 63 patients had 
discontinued from study by the data cutoff date. The reasons for discontinuation included 
progressive disease (PD) (37 patients), adverse events (AEs) (13 patients), protocol violation (1
patient), symptomatic deterioration (4 patients), and other (8 patients).
In Study C34002, the TAK-659 dose has been escalated from 60 mg 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 the study as of the data cutoff date. The reasons for 
discontinuation included PD (3 patients), AEs (10 patients), withdrawal by patient (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 on the basis of nonclinical toxicology findings of 
TAK-659 and the patient populations being studied. As of 07 October 2016, the most common 
treatment-related AEs reported in Study C34001 (≥20% of patients) 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. 
As of 07 October 2016, there were 20 on-study deaths in Study C34001. Three of the AEs that led 
to death were considered treatment related (multi-organ failure following sepsis, disseminated 
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varicella, and respiratory failure in the presence of Pneumocystis jiroveci pneumonia; 
cytomegalovirus and aspergillus infection; and right pneumothorax and renal failure). The other 
causes of the deaths included PD (8 patients), pneumonia and sepsis (2 patients each), and 
hypoxia, pulmonary embolism, hepatic encephalopathy, 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 mantle cell lymphoma), 17 patients had responded to treatment per 
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 follicular lymphoma (FL) achieved PRs. One patient with CLL achieved a PR, and a 
second achieved a PR after the data cutoff date. 
As of 18 September 2016, there were 7 on-study deaths in Study C34002, none of which was 
deemed treatment related. To date, the safety profile in Study C34002 appears to be similar to that 
of Study C34001. Early signs of antileukemic activity have been observed in a number of patients 
who have demonstrated significant reductions in both peripheral blast and bone marrow blast 
counts; however, no formal responses per IWG 2003 criteria [2] have been reported as of the cutoff 
date.
Additional details on clinical experience with TAK-659 are provided in the TAK-659 
Investigator’s Brochure (IB).
4.1.4.1
Clinical Pharmacokinetics of TAK-659
Preliminary pharmacokinetic (PK) results are available from the dose-escalation portion of 
Study C34001 following single-agent QD administration of 60 to 120 mg TAK-659 to patients 
with advanced solid tumors or lymphomas and from the dose-escalation portion of Study C34002 
following single-agent QD administration of 60 to 160 mg TAK-659 to patients with 
relapsed/refractory AML. For Study C34001, preliminary plasma PK results are available in 
34 patients (17 lymphoma, 17 solid tumor) after single dosing and in 25 patients (14 lymphoma, 
11 solid tumor) after repeated QD dosing for 15 days; preliminary urine PK results are available 
from 19 patients (12 lymphoma, 7 solid tumor). For Study C34002, preliminary plasma PK results 
are available in 21 patients after single dosing and in 13 patients after repeated QD dosing for 
15 days.
Among patients with advanced solid tumors, TAK-659 exhibited fast absorption after oral 
administration of an immediate–release tablet formulation (median Tmax [time of first occurrence 
of Cmax (maximum observed concentration)] of 2-3 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. Moderate variability was 
observed in steady-state dose-normalized area under the plasma concentration versus time curve 
over the dosing interval (AUC) when pooled across the 60 to 120 mg dose range (coefficient of 
variation of approximately 40% on Day 15). Following repeated QD dosing, TAK-659 was 
characterized by mean accumulation of 2.6-fold. The mean peak-to-trough fluctuation over the 
steady-state dosing interval was 3.2. The mean terminal disposition half-life is predicted to be 
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between 24 and 48 hours and will be confirmed in the expansion phase of Study C34001. Because 
of limited sample size at some dose levels, dose proportionality was not evaluated in patients with 
solid tumors. However, among the AML patient population, there was no obvious deviation from 
dose proportionality across the 60 to 160 mg range.
The mean ratio of TAK-659 renal clearance to apparent oral clearance was 0.30 in patients with 
solid tumors. Although the exact contribution of renal clearance to systemic clearance is unknown 
because absolute bioavailability is unknown, the contribution is expected to be at least 30% of 
systemic clearance. On average, unbound renal clearance (based on creatinine clearance calculated 
by the Cockcroft-Gault equation) was 2.7-fold higher than estimated glomerular filtration rate, 
suggesting that active tubular secretion is the major component of renal clearance. Preliminary 
analyses including patients with solid tumors, lymphoma, or AML demonstrated a relationship 
between creatinine clearance and TAK-659 apparent oral clearance, suggesting that renal function 
can affect TAK-659 systemic exposure.
In vitro studies indicated that TAK-659 undergoes metabolism in human liver microsomes and 
hepatocytes. Cytochrome P450 (CYP) 3A4/5 contributed to the majority (69.1%-73.0%) of 
TAK-659 metabolism in human liver microsomes, with relatively minor contributions by 
CYP2D6 (16.6%-30.9%) and CYP1A2 (0%-8.4%). The relative contribution of hepatic 
metabolism to systemic clearance is currently unknown. Current in vitro and clinical PK data 
suggest that hepatic metabolism and renal excretion are pathways of TAK-659 elimination in 
humans. 
Additional details on TAK-659 PK are provided in the TAK-659 IB.
4.1.5
Risks and Benefits
TAK-659 has been administered to a total of 111 patients as of 22 October 2016; thus, it is not 
currently possible to describe with certainty the potential adverse effects of the compound. 
4.1.5.1
Potential Risks from Nonclinical Studies
Potential risks identified from nonclinical studies in dogs and rats include the following:

Lymphoid and hematopoietic effects (including 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 deoxyribonucleic acid.
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
Growth plate thickening and disorganization (not relevant to adults).
Lymphoid and hematopoietic effects and reproductive system effects are considered important 
potential risks.
4.1.5.2
Potential Risks from Clinical Studies
Potential risks based on clinical observations are summarized below.
On the basis of data from Study C34001, asymptomatic elevation in lipase was added as an 
important potential risk of TAK-659. In nonclinical studies, lipase was sporadically elevated at 
high doses of TAK-659; however, there was no evidence of microscopic organ damage. In clinical 
studies to date, asymptomatic lipase or amylase elevations are reported commonly (≥10% of 
patients). Patients in Study C34003 will have frequent monitoring of lipase and amylase as 
outlined in the Schedule of Events (Appendix A). Cases of pneumonitis have been reported in 
clinical studies with BCR pathway kinase inhibitors, including TAK-659, and pneumonitis is 
considered an important potential risk of TAK-659. Pneumonitis and other pulmonary toxicities 
are being closely monitored in TAK-659 clinical studies.
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 mantle cell lymphoma), 17 patients had responded to 
treatment per investigator report as of 07 October 2016. Eight patients with DLBCL achieved a 
CR, and 4 patients 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, and a second achieved a PR after the data 
cutoff date.
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.
Nivolumab is an approved agent for the treatment of HNSCC, melanoma, NSCLC, renal cell 
carcinoma, and urothelial carcinoma (accelerated approval). The risks associated with the 
nivolumab administration should be referenced in accordance with the current USPI [17] or SmPC 
[18].
4.1.5.3
Potential Overlapping Toxicities for the Combination of TAK-659 and Nivolumab
The combination of TAK-659 with nivolumab has been administered to a limited number of 
patients, and at present, there are no identified risks for the combination; hence, all reported AEs 
are considered unexpected for the purpose of regulatory reporting. All the TAK-659 data in this 
section on the occurrence of AEs are from Studies C34001 and C34002 as of the 22 October 2016 
data cutoff from a total 108 patients across these 2 studies.
The potential risks, AEs with occurrence rates equal to or greater than 10%, and the warnings and 
precautions of each drug, including data from nonclinical and clinical studies, have been reviewed. 
Potential overlapping toxicities of the combination include pneumonitis, rash, elevation of AST 
and ALT, diarrhea, and embryofetal toxicity. 
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Severe pneumonitis or interstitial lung disease (2.2%), including fatal cases (0.9%), have occurred 
with nivolumab treatment. Three events of Grade 3 or higher pneumonitis have been reported in 
patients treated with TAK-659. Rash is reported as the most common adverse drug reaction (21%) 
in patients with melanoma treated with nivolumab, with an incidence of Grade 3 or 4 events of 
only 0.4%. Rash has been reported in 18% of patients receiving TAK-659, and 4% of rash events 
were Grade 3 or 4. Per the nivolumab label, the rates of elevated AST and ALT in a melanoma 
clinical trial were 28% and 26%, respectively. The corresponding rates for TAK-659 were 52% 
and 31%, respectively. Immune-mediated colitis occurred in 2.2% of patients receiving nivolumab 
treatment. Diarrhea (32%) has been reported in patients receiving TAK-659 with 3% identified as 
Grade 3 or higher. There is no clinical evidence of embryofetal toxicity for nivolumab or 
TAK-659, which is a potential risk of both drugs when administered to pregnant women based on 
the reproductive effects observed in animal studies. These toxicities are expected to be 
manageable with adequate monitoring and standard of care.
For more detailed information on the adverse reactions associated with nivolumab, please refer to 
the most recent USPI or SmPC for nivolumab.
4.1.5.4
Drug-Drug Interaction Risk Assessment for the Combination of TAK-659 and Nivolumab
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% for these respective CYP enzymes. 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.
Therapeutic proteins like nivolumab are not expected to directly inhibit or induce 
drug-metabolizing enzymes or transporters. In addition, nivolumab is not thought to indirectly 
affect activities of drug-metabolizing enzymes or transporters via modulation of proinflammatory 
cytokines. Therefore, the risk of nivolumab affecting TAK-659 PK is low.
As a therapeutic protein, nivolumab is expected to be catabolized into amino acids by protein 
degradation processes and not expected to be a substrate of drug-metabolizing enzymes and 
transporters. Therefore, there is low risk of TAK-659 affecting nivolumab PK via inhibition or 
induction of drug-metabolizing enzymes or transporters.
4.2
Rationale for the Proposed Study
Although the role of SYK in hematological cancers is well known, the data on the relevance of 
SYK in solid tumors are emerging. Limited data suggest that SYK may play alternate roles in 
carcinogenesis under different circumstances. For example, 6 of 10 HNSCC cell lines found to 
express SYK, and the SYK expression in head and neck tumor cells seems to induce 
chemomigration. Inhibition of SYK in HNSCC cell lines resulted in inhibition of migration, 
haptotaxis, and engagement with matrix proteins [19]. Nasopharyngeal carcinoma, an unusually 
highly metastatic tumor, expresses Epstein-Barr virus (EBV) latent membrane protein 2A 
(LMP2A) in most clinical specimens. LMP2A contains an immunoreceptor tyrosine-based 
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activating motif (ITAM) domain, which is important for SYK activation. This suggests that SYK 
may have a contributing role in the transformation process in this tumor type [20]; as such, an 
inhibitor of SYK may also demonstrate antitumor activity in some solid tumor settings. Such 
EBV-driven subsets of tumors were reported in gastric cancer also [21], and SYK was found to be 
overexpressed in retinoblastoma where SYK inhibition led to myeloid cell leukemia 1 degradation 
and resulted in caspase mediated apoptosis [22]. In H16N-2 breast cancer cells that overexpress 
C35 protein, SYK inhibition either by pharmacological agent or by small interfering ribonucleic 
acid (RNA) knock-down resulted in reduced colony size and numbers upon 3D culture [23]. In 
addition, a subset of breast cancer cell lines (including 28 patient-derived cell lines) enriched for 
basal-like subtype showed viability effects with SYK inhibition, suggesting potential therapeutic 
opportunities for SYK inhibitors in a molecularly defined subset of cancers [24].
Recent studies have shown that MDSCs use CD79A-ITAM signaling that uses SYK as a signaling 
mediator. FLT3 and its ligand have been shown to induce MDSCs in vitro [25]. MDSC-mediated 
immune suppression has been reported in many solid tumors [26]. In addition, a role of B cells in 
tumor immunity has been studied, and the requirement of B cells for tumor growth and metastasis 
has been documented [27]. SYK is known to be essential for development, growth, and 
maintenance of B cells.
Nonclinical studies show that SYK inhibition results in loss of MDSCs and activation of T-cell 
response both in vitro and in vivo. TAK-659 in combination with anti-PD-1 therapy has shown 
regulation of B cells, NK cells, and macrophages in syngeneic nonclinical mouse models. The 
combination effects in immune cells are model and context dependent, and combination activity 
would be greatest in tumors where SYK-mediated MDSC or B-cell immunosuppression is active. 
The nonclinical combination treatment of TAK-659 and anti-PD-1 therapy provides therapeutic 
advantage over single agent treatment with durable tumor growth inhibition, maintained complete 
responses, and a vaccinal memory effect. This effect could be indirectly attributed to the decrease 
in CD11b+ MDSC or B220+ B cells in the TILs of TAK-659-treated tumors.
Therefore, the addition of TAK-659 to an anti-PD-1 agent could improve tumor regression via 
modulation of the tumor-infiltrating immune cells and other immune cells in the tumor 
microenvironment. The make-up of the tumor microenvironment, which differs among different 
tumor types, will drive the choice of diseases to be evaluated in this study. Tumors in which there 
is MDSC or B-cell suppression are of particular interest: nonclinical assessment suggests that 
tumors such as TNBC, NSCLC, and HNSCC show MDSC-mediated tumor immunosuppression. 
This study intends to clinically evaluate the combination effect of TAK-659 and nivolumab in 
3 advanced solid tumor types (TNBC, NSCLC, and HNSCC). With the reference response rate of 
~20% observed with nivolumab monotherapy in each of these indications, added benefit of this 
combination regimen will be assessed by whether a significantly improved overall response rate 
(ORR; target ORR of 40%) is observed, along with assessment of other efficacy measures such as 
duration of response (DOR) and survival benefit. While the majority of the patients in each of the 
cohorts (24/30 response-evaluable patients) should be naïve to anti-PD-1, anti-PD-L1, and any 
other immune-directed antitumor therapies, a small subset of 6/30 response-evaluable patients 
with prior exposure to an anti-PD-1 or anti-PD-L1 agent will be enrolled to observe any 
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combination effect of TAK-659 plus nivolumab in this relapsed/refractory setting with regard to 
the PD-1/PD-L1 blockade. In addition, after determining a safe and tolerable combination dose for 
TAK-659 when co-administered with nivolumab during the initial dose escalation stage of the 
study, a 2-week, single-agent TAK-659 treatment period before combination therapy is planned in 
10 response-evaluable patients in each of the expansion cohorts. Correlative science studies are 
planned in pretreatment and posttreatment tumor biopsies and peripheral blood samples taken 
from these patients with the intent of having more mechanistic understanding of the role of SYK in 
the tumor immunity and direct tumor effect, if any. 
4.2.1
Rationale for Dose and Schedule Selection
TAK-659 has been evaluated as a single-agent given orally 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 were demonstrated 
across all doses evaluated in the escalation phase of the study, including 3 PRs and 1 CR among 
patients with relapsed/refractory DLBCL and 3 PRs among patients with relapsed/refractory FL. 
These responses were observed at doses of 60 (1 PR), 80 (1 PR), 100 (3 PR and 1 CR), 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.
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. The 
TAK-659 dose has been escalated from 60 mg to 160 mg with the MTD/RP2D remaining to be 
determined.
In the dose escalation phase of Study C34003, the starting dose of TAK-659 will be 60 mg QD in 
combination with nivolumab (3 mg/kg IV Q2W). Dose escalation of TAK-659 will follow a 
standard 3+3 escalation scheme. Considering the low risk of DDI between TAK-659 and 
nivolumab, no significant changes in TAK-659 exposure are expected when TAK-659 is given in 
combination with nivolumab versus as a single agent. 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.
After the RP2D of TAK-659 has been identified, on the basis of evaluation of the combination 
with a weight-based dose of nivolumab (3 mg/kg), this RP2D of TAK-659 may be evaluated in 
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combination with a fixed dose of 240 mg IV nivolumab following discussion between the 
investigator and sponsor. For single-agent nivolumab, the fixed dose is expected to have 
equivalent exposure, safety, and efficacy as the weight-based (3 mg/kg) dose. If the nivolumab 
fixed dose is evaluated in combination with the TAK-659 RP2D, 3 patients will be initially 
enrolled into the cohort. Following evaluation of the safety, efficacy, and any available PK data, 
along with discussions between the investigator and sponsor, 3 additional patients may be enrolled 
into the cohort for a total of 3 to 6 patients. Following evaluation of this fixed-dose cohort (if it is 
run), the dose of nivolumab may be switched from the 3 mg/kg weight-based dose to a fixed dose 
of 240 mg for all patients ongoing in the study at the time of the switch and those to be enrolled 
after the switch. This decision will be made on the basis of an assessment of the change in clinical 
practice in different regions and upon discussion and agreement between the investigators and 
sponsor. If the nivolumab fixed-dose evaluation cohort is not run, the dose of nivolumab for all 
patients in the dose expansion phase will be 3 mg/kg, unless the direct conversion to a fixed dose 
of nivolumab is justified by other available data.
4.2.2
Rationale for PK Assessments
During dose escalation, 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 in 
combination with nivolumab. Specifically, serial plasma PK assessments will be used to describe 
single- and repeat-dose concentration-time profiles of TAK-659, calculate PK parameters, and 
contribute to population PK model development. Although the risk of DDI between TAK-659 and 
nivolumab is predicted to be low, TAK-659 plasma PK following combination administration with 
nivolumab will be compared with historical plasma PK from single-agent studies to confirm that 
there are no clinically meaningful differences in TAK-659 PK between the single-agent and 
combination settings.
In dose expansion cohorts, blood samples for plasma PK will be collected during Cycles 1 through 
4 using a limited sampling strategy to contribute to population PK analyses of TAK-659. 
Plasma PK data collected in the dose escalation and expansion 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.
4.2.3
Rationale for Biomarker Analysis (Correlative Science Studies)
4.2.3.1
Tumor Tissue Measurement
Although nonclinical data suggest a role for SYK and/or FLT3 in the induction and maintenance of 
immunosuppressive cells contributing to tumor growth, combination of a SYK or FLT3 inhibitor 
with an immune checkpoint inhibitor has not been tested to date. Therefore, it is important to 
understand the effect of TAK-659 on infiltrating immune cells, tumor microenvironment, and 
differentiation/maintenance of immune cells, and to identify possible patient selection markers for 
the combination of TAK-659 with nivolumab by conducting correlative science studies.
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Immunohistochemical (IHC) studies on tumor samples have been conducted to identify immune 
cell components responsible for antitumor effects and those associated with tumor growth. For 
example, an analysis of TILs in a large cohort of NSCLC patients revealed that an elevated CD3 or 
CD8 signal was statistically significantly associated with longer survival [28]. In addition, levels 
of proteins expressed on tumor cells that can modulate immune cells responsible for antitumor 
activity have been investigated, and IHC measurement of the expression of PD-L1 was developed 
as a companion diagnostic for the immune checkpoint inhibitor pembrolizumab [29]. An 
alternative approach is to deconvolute data of messenger RNA expression based on specific 
signatures identified for subsets of immune cells of interest [30]. This strategy may allow analysis 
of a larger number of immune cell subsets than is possible with the IHC assay. It also may 
potentially improve our understanding of the pharmacological effects of TAK-659, alone or in 
combination with nivolumab, and possibly identify candidate biomarkers of clinical response to 
the combination.
It is known that somatic mutations found in tumors can be recognized by the patient’s own 
immune system [31], and it has been demonstrated recently that efficacy of another PD-1 inhibitor, 
pembrolizumab, was mostly seen in patients with colorectal cancer with high mutation burden 
[32]. Therefore, analysis of somatic mutations in tumors may also help identify biomarkers 
predictive of clinical response to the combination.
These analyses will be performed using serial biopsies taken from a subset of patients who have 
accessible tumors and who consent to sequential tumor biopsies as described above. In addition, 
archival tumor tissue will be collected from the rest of the patients and may be subjected to the 
same analyses.
4.2.3.2
Analysis of Biomarkers Using Peripheral Blood
TILs and other hematopoietic cells that make up the tumor microenvironment may be detected in 
peripheral blood, as those cells are generated and/or mature in host organs such as the bone 
marrow, lymph nodes, and spleen. Peripheral blood mononuclear cells (PBMCs) have been 
profiled to delineate changes in such circulating immune regulatory and effector cells as 
developing prognostic biomarkers, being used as response markers, and supporting proposed 
mechanisms of action from nonclinical studies [33]. As these immune cells produce and/or act on 
cytokines and chemokines in the tumor microenvironment and supporting organs, peripheral 
blood may contain detectable amounts of cytokines and chemokines that could potentially be used 
as a biomarker of response. Circulating tumor DNA (ctDNA) has been used to estimate tumor 
burden and profile mutations in lieu of tumor tissue samples that require obtaining a biopsy [34]. 
Therefore, blood samples will be collected for all patients in the dose expansion cohorts and 
analyzed for biomarkers as described. 
 
4.2.4
Rationale for Pharmacogenomic Assessments
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 of Use
CCI


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5.0
STUDY OBJECTIVES
5.1
Primary Objectives
The primary objectives are:
!
To determine the MTD/RP2D of TAK-659 when administered in combination with nivolumab 
(dose escalation).
!
To determine the efficacy of TAK-659 plus nivolumab as measured by ORR (dose expansion).
5.2
Secondary Objectives
The secondary objectives are:
!
To determine the safety and tolerability of TAK-659 when administered in combination with 
nivolumab.
!
To evaluate other efficacy measures such as disease control rate (response plus stable disease 
[SD]), DOR, rate of PD at 6 months, progression-free survival (PFS), and OS.
!
To characterize the plasma PK of TAK-659 when administered in combination with 
nivolumab.
5.3
Tertiary/Exploratory Objectives
The exploratory objectives are:
5.4
Additional Objectives
The additional objective is to collect TAK-659 plasma concentration data to contribute to 
population PK analyses.
Property of Takeda: 
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6.0
STUDY ENDPOINTS
6.1
Primary Endpoints
The primary endpoints are:
!
MTD (dose escalation).
!
RP2D (dose escalation).
!
ORR as assessed by the investigator per Response Evaluation Criteria in Solid Tumors 
(RECIST) version 1.1 [1] (dose expansion).
6.2
Secondary Endpoints
The secondary endpoints are:
!
Percentage of patients with AEs.
!
Percentage of patients with Grade 3 and Grade 4 AEs.
!
Percentage of patients with serious adverse events (SAEs).
!
Percentage of patients who discontinued due to AEs.
!
Clinically significant laboratory values.
!
Clinically significant vital sign measurements.
!
Disease control rate.
!
DOR.
!
Rate of PD at 6 months.
!
PFS.
!
OS.
!
Summary statistics of TAK-659 maximum (peak) plasma concentration (Cmax) on Cycle 1 
Days 1 and 15, by dose escalation cohort.
!
Summary statistics of TAK-659 Tmax on Cycle 1 Days 1 and 15, by dose escalation cohort.
!
Summary statistics of TAK-659 AUCτ on Cycle 1 Days 1 and 15, by dose escalation cohort.
6.3
Exploratory Endpoints 
The exploratory endpoints are:
Prope ty of Takeda: For non-commercial use only and subject to the applicable Terms of Use
olid Tum
id Tu
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(SAE
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6.4
Additional Endpoints
The additional endpoints are:
!
Summary statistics of TAK-659 apparent oral clearance (CL/F), peak-trough ratio (PTR), 
accumulation ratio (Rac), and trough concentration (Ctrough) on Cycle 1 Day 15 by dose 
escalation cohort.
!
Summary statistics of TAK-659 plasma concentrations on Cycle 1 Days 1 and 15 by dose 
escalation cohort.
!
TAK-659 plasma concentration-time data contributing to population PK analyses.
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7.0
STUDY DESIGN
7.1
Overview of Study Design
This is an open-label, multicenter, phase 1b, dose escalation study of TAK-659 in combination 
with nivolumab in patients with advanced solid tumors. The study will include a dose escalation 
phase (Part 1) and a dose expansion phase (Part 2). In the dose escalation phase, the patient 
population will consist of all-comer patients with advanced solid tumors for whom 1 or more prior 
lines of therapy have failed and who have no effective therapeutic options available based on 
investigator assessment. The dose expansion phase will include 3 cohorts: 1) patients with 
metastatic TNBC who have had ≥1 prior line of chemotherapy; 2) patients with locally advanced 
or metastatic NSCLC that has progressed on or after a prior platinum-based chemotherapy; and 
3) patients with locally advanced or metastatic HNSCC that has progressed or recurred within 
6 months of the last platinum-based chemotherapy.
It is estimated that 126 patients will be enrolled in the study: approximately 9 to 12 patients among
the dose escalation cohorts evaluating weight-based dosing of nivolumab, 3 to 6 patients in the 
nivolumab fixed-dose evaluation cohort (if it is opened), and approximately 36 patients 
(30 evaluable patients+15% drop off) in each of the 3 dose expansion cohorts.
Once enrolled in the study, patients will be administered TAK-659 PO QD during each 28-day 
treatment cycle. Patients receiving the combination therapy will also receive nivolumab Q2W IV 
over 60 minutes on Day 1 and Day 15 of each 28-day treatment cycle (for patients who receive 
2 weeks of TAK-659 monotherapy before starting combination treatment, the first nivolumab 
infusion will be administered on Cycle 1 Day 15). On days when both TAK-659 and nivolumab 
are administered, the TAK-659 dose will be administered first followed by the nivolumab infusion 
(infusion to begin within 30 minutes after the TAK-659 dose). Patients, including those who 
achieve a CR, may receive study treatment until they experience PD or unacceptable toxicities. 
The Study Schema is presented in Figure 7.a.
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Figure 7.a
Study Schema
CXDX=Cycle X Day X, R/R=relapsed/refractory.
While the MTD/MAD/RP2D of TAK-659 are being determined, the starting dose of nivolumab 
will be 3 mg/kg IV. 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 9.4). 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 also evaluated if appropriate. Dose escalation will continue until the MTD is reached, until 
100 mg QD of TAK-659 (the MAD) is determined to be safe and tolerable, or until an RP2D, if 
different from the MTD or MAD, has been identified on the basis of 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, MAD, or a lower dose) before making a decision to 
advance to further dose expansion.
After the RP2D of TAK-659 has been identified, on the basis of evaluation of the combination 
with a weight-based dose of nivolumab (3 mg/kg), this RP2D of TAK-659 may be evaluated in 
combination with a fixed dose of 240 mg IV nivolumab following discussion between the 
investigator and sponsor. For single-agent nivolumab, the fixed dose is expected to have 
equivalent exposure, safety, and efficacy as the weight-based (3 mg/kg) dose. If the nivolumab 
fixed dose is evaluated in combination with the TAK-659 RP2D, 3 patients will be initially 
enrolled into the cohort. Following evaluation of the safety, efficacy, and any available PK data, 
along with discussions between the investigator and sponsor, 3 additional patients may be enrolled 
into the cohort for a total of 3 to 6 patients. If ≥1 out of 6 patients experiences dose-limiting 
toxicity (DLT) during Cycle 1, or significant safety issues are seen in Cycle 2 and beyond, 
1/3 Patients 
in each 
expansion 
cohort
2/3 Patients 
in each 
expansion 
cohort
TAK-659 at the determined RP2D 
+ nivolumab 3 mg/kg
Dose Expansion:
Single Agent TAK-659 
at the determined 
RP2D 
Weeks 1 & 2 
(C1D1 – C1D14)
TAK-659 at the 
determined RP2D +
nivolumab 3 mg/kg
Week 3 Onwards
(C1D15 and Onwards)
60 mg QD +
nivolumab 3 mg/kg
100 mg QD + 
nivolumab 3 mg/kg
Week 1 Onwards (Starting C1D1 and Onwards)
Paired biopsy 
and PBMC
Biopsy and 
PBMC
TNBC 
NSCLC 
HNSCC
24 PD-1/PD-L1 naïve/cohort
6 R/R after PD-1/PD-L1 /cohort
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re-evaluation of the TAK-659 RP2D when administered with a fixed dose of nivolumab is 
permitted 
The dose of nivolumab in the expansion cohorts will be either 3 mg/kg or 240 mg IV, dependent on 
whether the 240 mg fixed-dose cohort is evaluated. If the 240 mg fixed-dose cohort is evaluated 
and deemed safe and tolerable, the dosing regimen may switch to 240 mg, on the basis of change in 
clinical practice and discussion between the investigator and sponsor. If the nivolumab fixed-dose 
evaluation cohort is not run, the dose of nivolumab for all patients in the dose expansion phase will 
be 3 mg/kg.
After the combination TAK-659 RP2D (the MTD, MAD, or a lower dose) is determined, 
expansion cohorts are planned in patients with TNBC, NSCLC, and HNSCC. Thirty 
response-evaluable patients will be enrolled in each expansion cohort. Each expansion cohort will
include 24 patients who are naïve to anti-PD-1/anti-PD-L1 therapy and 6 patients who are 
relapsed/refractory to prior anti-PD-1/anti-PD-L1 therapy. Ten response-evaluable patients in 
each expansion cohort will first receive 2 weeks of single-agent TAK-659 at its RP2D previously 
determined in combination with nivolumab before starting combination therapy and will provide 
paired tumor biopsies during this period; these patients can be either naïve to or relapsed/refractory 
to anti-PD1/anti-PDL1 therapy. Following the 2-week single-agent treatment, TAK-659 treatment 
will continue (at the same dose) in combination with nivolumab during Week 3 and beyond.
During dose escalation, the Cycle 1 DLT-evaluation period typically will be 28 days. However, in 
the event of a nivolumab dosing interruption, a cycle length may be extended. If the second dose of 
nivolumab planned for Cycle 1 Day 15 is held and then dosed within the original 28-day cycle, the 
dose will be considered the second dose of Cycle 1, leading to a cycle with a maximum total of 
42 days. The actual doses of TAK-659 received during this 28- to 42-day DLT-evaluation period 
will be assessed against the planned doses of TAK-659 (daily dose cycle days) to determine 
whether the patient has received at least 75% of planned doses of TAK-659 to be DLT evaluable. 
When the second dose is administered, procedures at the original scheduled visit (ie, Cycle 1 
Day 15) should be performed. If the second dose of nivolumab is interrupted for a period of time 
that extends beyond the original 28-day cycle, this dose will be considered missed. In this case, 
independent of whether the patient has received 75% of the planned doses of TAK-659, the patient 
will receive only one of the 2 nivolumab doses planned for Cycle 1 and, therefore, is not evaluable 
for DLT.
In Cycle 2 and beyond, during escalation and during the expansion phase of the study, if a 
nivolumab dose is delayed because of AEs, when the criteria to resume treatment are met, the 
patient should restart treatment at the next scheduled time point per protocol. However, if 
nivolumab is delayed past the next scheduled time point per protocol and TAK-659 dosing is also 
interrupted, the next scheduled time point will be delayed until dosing with either drug resumes.
The subset of expansion patients who will be treated with single-agent TAK-659 at its 
combination RP2D during Weeks 1 and 2 should have accessible tumors for core or excisional 
biopsy and provide permission for the biopsies to be taken. These patients will undergo mandatory 
biopsies before single-agent TAK-659 treatment begins, at the end of the 2-week treatment 
window, and after 6 weeks of treatment with TAK-659 in combination with nivolumab; an 
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optional biopsy will also be taken at the time of PD. The biopsies will be used for biomarker 
analysis evaluating the effect of TAK-659 on tumor cells and on immune/stromal cells supporting 
tumor tissue.
In addition to analysis of tumor biopsy samples as described above for a subset of patients in each 
expansion cohort, blood samples will be collected from all patients enrolled in the expansion phase 
of the study and analyzed for posttreatment changes in immune cell populations in the course of 
treatment, levels of cytokines and chemokines known for or deemed relevant to tumor growth or 
antitumor activity of TAK-659 or the combination, and ctDNA quantity and characteristics. The 
result will be compared with that obtained from the analysis of paired tumor biopsy samples and 
used to identify a biomarker(s) that would enable monitoring the activity of TAK-659 and the 
combination in future studies using peripheral blood samples. In addition, postdose change of a 
biomarker(s) may be evaluated for its (their) association with clinical responses from treatment 
with TAK-659 in combination with nivolumab. 
A part of the biopsied and archived tumor samples may be used to identify a biomarker(s) 
correlating with the clinical activity of the combination of TAK-659 and nivolumab. Archived 
tumor samples will be collected from patients enrolled both in the dose escalation and in the 
expansion phase, except for those who consent to serial tumor biopsies for pharmacodynamic 
assessment. 
The remaining 20 response-evaluable patients in each expansion cohort will receive TAK-659 at 
its RP2D in combination with nivolumab, starting at Week 1 Day1. 
During dose escalation, 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 in 
combination with nivolumab. Although the risk of DDI between TAK-659 and nivolumab is 
predicted to be low, TAK-659 plasma PK following combination administration with nivolumab 
will be compared with historical plasma PK from single-agent studies to confirm no clinically 
meaningful differences in TAK-659 PK between the single-agent and combination settings. In the 
dose expansion cohorts, blood samples for plasma PK will be collected during Cycles 1 through 4 
using a limited sampling strategy to contribute to population PK analyses of TAK-659. 
All patients in the expansion cohorts will be treated until PD or occurrence of unacceptable 
toxicities. The objectives of these expansion cohorts are to evaluate efficacy of TAK-659 in 
combination with nivolumab as measured by ORR and to determine the safety and tolerability of 
TAK-659 in combination with nivolumab.
Toxicity will be evaluated according to National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI CTCAE) version 4.03, effective 14 June 2010 [35]. DLTs are defined in 
Section 9.3.
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 nivolumab.
Radiological evaluations (computed tomography [CT] scan or magnetic resonance imaging [MRI] 
as clinically indicated) will be employed to assess the status of the patient’s underlying disease. An 
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evaluation of disease response using RECIST version 1.1 [1] will be performed at 
Screening/Baseline (within 28 days before the first study drug administration), predose at the end 
of Cycles 2, 4, and 6 (between Days 22 and 29), and then predose at the end of every 3 cycles 
thereafter (ie, between Days 22 and 29 of Cycles 9, 12, etc).
7.2
Number of Patients
It is estimated that 126 patients will be enrolled in the study from approximately 25 study centers 
in North America and Europe: approximately 9 to 12 patients among the dose escalation cohorts 
evaluating weight-based dosing of nivolumab, 3 to 6 patients in the possible nivolumab fixed-dose 
evaluation cohort (if it is opened), and approximately 36 patients (30 evaluable patients+15% 
dropout) in each of the 3 dose expansion cohorts. Enrollment is defined as the time of the initiation 
of the first dose of study drug.
Patients in the escalation cohorts who are withdrawn from treatment during Cycle 1 for reasons 
other than DLTs will be replaced. Patients in the expansion cohorts who are not evaluable for 
response will be replaced.
7.3
Duration of Study
Patients, including those who achieve a clinical response, may receive TAK-659+nivolumab until 
they experience PD or until completion of the study. Patients will discontinue treatment if they 
have an unacceptable TAK-659+nivolumab-related or possibly related toxicity. For information 
on treatment beyond PD, see Section 10.4.16.
Patients will be followed for 28 days after the last dose of TAK-659+nivolumab to permit the 
detection of any delayed treatment-related AEs. However, immune-mediated toxicities that either 
result in discontinuation of nivolumab or both study treatments or occur during the 28-day AE 
follow-up period (including immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, 
nephritis, rash, and encephalitis as described in nivolumab USPI) will be followed to resolution or 
stabilization, or the start of alternative therapy, or a minimum of 100 days after last dose of study 
treatment, whichever occurs first.
Patients who stop treatment for any reason other than PD will continue to have follow-up visits for 
PFS. The PFS follow-up visit should be conducted at the site every 2 months (up to 6 months after 
the first dose of study drug) or 3 months from the last dose of study drug until PD for a maximum 
of 6 months from the date of the last dose of study drug. After the occurrence of PD, patients will 
continue to have follow-up visits for OS every 2 months until 12 months from the date of the last 
dose of study drug. Patients who discontinue the study, regardless of reasons for discontinuation, 
will be followed for survival every 2 months until death, loss to follow-up, or withdrawal of 
consent to further follow-up for up to 12 months after discontinuation of the study drug. The final 
analyses for the clinical study report will be conducted after all patients enrolled in the study have 
had the opportunity to complete 6 cycles of treatment with TAK-659+nivolumab.
It is anticipated that this study will last for approximately 30 months (6 months escalation, 
18 months expansion, and 6 months treatment after last patient in).
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8.0
STUDY POPULATION
Dose escalation: patients with advanced solid tumors for whom 1 or more prior lines of therapy 
have failed and who have no effective therapeutic options available based on investigator 
assessment.
Dose expansion: 

Metastatic TNBC with ≥1 prior line of chemotherapy. 

Locally advanced or metastatic NSCLC that has progressed on or after a prior platinum-based 
chemotherapy.

Locally advanced or metastatic HNSCC that has progressed or recurred within 6 months of the 
last platinum-based chemotherapy.
8.1
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. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (refer to Appendix D
for a description of the scale). 
3. Female patients who:

Are postmenopausal for at least 1 year before the Screening visit, OR

Are surgically sterile, OR

If they are of childbearing potential, agree to practice one highly effective method of 
contraception and one additional effective (barrier) method, at the same time (see 
Appendix H), from the time of signing the informed consent through 180 days after the last 
dose of study drug, OR

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle 
of the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods] withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.)
Male patients, even if surgically sterilized (ie, status postvasectomy), who:

Agree to practice effective barrier contraception during the entire study treatment period 
and through 180 days after the last dose of study drug, OR

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle 
of the 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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4. 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.
5. Suitable venous access for the study-required blood sampling, including PK and 
pharmacodynamic sampling.
6. Clinical laboratory values and other measures as specified below within 28 days before the 
first dose of study drug:

Total bilirubin must be 1.5the upper limit of normal (ULN).

ALT and AST must be 2.5ULN. 

Creatinine clearance must be ≥60 mL/minute as estimated by the Cockcroft Gault equation 
(see Appendix E) or based on urine collection (12 or 24 hours).

Hemoglobin must be 9 g/dL, absolute neutrophil count (ANC) must be 1500/L, and 
platelet count must be 75,000/L.

Lipase must be ≤1.5ULN and amylase ≤1.5ULN with no clinical symptoms suggestive 
of pancreatitis and cholecystitis.

Blood pressure ≤Grade 1 (hypertensive patients are permitted if their blood pressure is 
controlled to ≤Grade 1 by hypotensive medications and glycosylated HbA1C ≤6.5%). 
7. Recovered (ie, Grade 1 toxicity) from the reversible effects of prior anticancer therapy.
8. To be enrolled in the dose escalation phase of the study, patients must have:

Histologically confirmed diagnosis of advanced solid tumor with a radiographically or 
clinically evaluable disease. Measurable disease as defined by RECIST version 1.1 [1] is 
not required for participation in the dose escalation of the study.

One or more prior lines of therapy and no effective therapeutic options available based on 
investigator assessment. Prior exposure to marketed immune checkpoint inhibitors, such as 
nivolumab and pembrolizumab, is permitted during dose escalation.
9. To be enrolled in the TNBC expansion cohort, patients must have:

Histologically confirmed, metastatic TNBC with measurable disease per RECIST 
version 1.1.

Triple-negative disease (estrogen receptor, progesterone receptor, and HER2 negativity) 
confirmed on a histological biopsy of a metastatic tumor lesion (receptor conversion not 
allowed).

Safely accessible tumor lesions (based on investigator’s assessment) for serial pretreatment 
and posttreatment biopsies are required for patients receiving TAK-659 monotherapy 
run-in treatment for 2 weeks followed by TAK-659 plus nivolumab combination treatment 
(~10/30 response-evaluable patients); adequate, newly obtained, core or excisional biopsy 
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of a metastatic tumor lesion not previously irradiated is required. Mandatory biopsies will 
be taken before TAK-659 monotherapy, after the 2 weeks of TAK-659 monotherapy, and 
after 6 weeks of TAK-659 plus nivolumab combination therapy. An optional biopsy may 
be taken at PD with additional consent from the patient.
One, 2, or 3 prior lines of chemotherapy for metastatic disease and with progression of
disease on last treatment regimen.
–
For the purposes of this study, neoadjuvant and/or adjuvant chemotherapy regimens do 
not count as a prior line of therapy.
–
Prior treatment must include an anthracycline and/or a taxane in the neoadjuvant, 
adjuvant, or metastatic setting with the exception for patients who are clinically 
contraindicated for these chemotherapies.
10. To be enrolled in the NSCLC expansion cohort, patients must have:
Locally advanced or metastatic (stage IIIB, stage IV, or recurrent) NSCLC with 
measurable lesions per RECIST version 1.1.
PD during or following at least 1 prior treatment. Patients should have received a prior 
platinum-based 2-drug regimen for locally advanced, unresectable/inoperable or 
metastatic NSCLC or disease recurrence within 6 months of treatment with a 
platinum-based adjuvant/neoadjuvant regimen or combined modality (eg, chemoradiation) 
regimen with curative intent.

Patients with EGFR or ALK genomic alternations should have PD on prior US 
FDA-approved therapy for these aberrations.

Safely accessible tumor lesions (based on investigator’s assessment) for serial pretreatment 
and posttreatment biopsies are required for patients receiving TAK-659 monotherapy 
run-in treatment for 2 weeks followed by TAK-659 plus nivolumab combination treatment 
(~10/30 response-evaluable patients); adequate, newly obtained, core or excisional biopsy 
of a metastatic tumor lesion not previously irradiated is required. Mandatory biopsies will 
be taken before TAK-659 monotherapy, after the 2 weeks of TAK-659 monotherapy, and 
after 6 weeks of TAK-659 plus nivolumab combination therapy. An optional biopsy may 
be taken at progression with additional consent from the patient.
11. To be enrolled in the HNSCC expansion cohort, patients must have:

Histologically confirmed recurrent or metastatic HNSCC (oral cavity, pharynx, or larynx) 
that is stage III/IV and not amenable to local therapy with curative intent (surgery or 
radiation therapy with or without chemotherapy).
–
Histologically confirmed recurrent or metastatic squamous cell carcinoma of unknown 
primary or nonsquamous histologies (eg, mucosal melanoma) are not allowed.
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–
Histologically confirmed recurrent or metastatic carcinoma of the nasopharynx is 
allowed, but these patients will not be included as response-evaluable patients for 
efficacy analysis of HNSCC.

Measurable disease per RECIST version 1.1.

Tumor progression or recurrence within 6 months of the last dose of platinum-based 
therapy in the adjuvant (ie, with radiation after surgery), primary (ie, with radiation), 
recurrent, or metastatic setting.

Safely accessible tumor lesions (based on investigator’s assessment) for serial pretreatment 
and posttreatment biopsies are required for patients receiving TAK-659 monotherapy 
run-in treatment for 2 weeks followed by TAK-659 plus nivolumab combination treatment 
(~10/30 response-evaluable patients); adequate, newly obtained, core or excisional biopsy 
of a metastatic tumor lesion not previously irradiated is required. Mandatory biopsies will 
be taken before TAK-659 monotherapy, after the 2 weeks of TAK-659 monotherapy, and 
after 6 weeks of TAK-659 plus nivolumab combination therapy. An optional biopsy may 
be taken at progression with additional consent from the patient.
8.2
Exclusion Criteria
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
1. Active brain metastases or leptomeningeal metastases.
2. Active or suspected autoimmune disease or a history of known autoimmune disease, with the 
exception of:

Patients with vitiligo, type I diabetes mellitus, resolved childhood asthma/atopy, residual 
hypothyroidism due to autoimmune condition requiring only hormone replacement, 
psoriasis not requiring systemic treatment, or conditions not expected to recur in the 
absence of an external trigger.
3. Any condition requiring systemic treatment with corticosteroids (>10 mg daily prednisone 
equivalents) or other immunosuppressive medications within 14 days before first dose of study 
drug. 

Corticosteroids for topical use or in nasal spray are allowed, as are inhaled steroids and 
adrenal replacement steroid doses >10 mg daily in the absence of active autoimmune 
disease.
4. History of pneumonitis requiring treatment with steroids; history of idiopathic pulmonary 
fibrosis, drug-induced pneumonitis, organizing pneumonia, or evidence of active pneumonitis 
on the Screening chest CT scan; history of radiation pneumonitis in the radiation field 
(fibrosis) is permitted.
5. History of interstitial lung disease.
6. Prior therapy with experimental antitumor vaccines; any T-cell co-stimulation agents or 
inhibitors of checkpoint pathways, such as anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or 
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anti-CTLA-4 antibody; or other agents specifically targeting T cells are prohibited. However, 
for dose escalation, prior treatment with the marketed inhibitors of the immune checkpoint 
pathway, such as nivolumab and pembrolizumab, is allowed. In addition, in each of the 
expansion cohorts, 6 response-evaluable patients with prior exposure to anti-PD-1 or 
anti-PD-L1 agents (including both marketed and investigational) will be allowed to enroll. 
7. 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.
8. Life-threatening illness unrelated to cancer.
9. 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.
10. Systemic anticancer treatment (including investigational agents) or radiotherapy <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) or have not recovered from acute toxic 
effects from prior chemotherapy and radiotherapy.
11. Prior treatment with investigational agents ≤21 days (≤4 weeks for monoclonal antibodies with 
evidence of PD) or ≤5their half-lives (whichever is shorter) before the first dose of study 
treatment. A minimum of 10 days should elapse from prior therapy to initiating protocol 
therapy. 
12. Major surgery within 14 days before the first dose of study drug and not recovered fully from 
any complications from surgery. 
13. Systemic infection requiring IV antibiotic therapy or other serious infection within 14 days 
before the first dose of study drug. 
14. Known human immunodeficiency virus (HIV) positive (testing not required). 
15. Known hepatitis B surface antigen-positive or known or suspected active hepatitis C infection 
(testing not required). 
16. Patients with another malignancy within 2 years of study start. Patients with nonmelanoma 
skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete 
resection and are considered disease-free at the time of study entry. 
17. Any clinically significant comorbidities, such as uncontrolled pulmonary disease, known 
impaired cardiac function or clinically significant cardiac disease (specified below), active 
central nervous system disease, active infection, or any other condition that could compromise 
the patient’s participation in the study. 
Patients with any of the following cardiovascular conditions are excluded: 

Acute myocardial infarction within 6 months before starting study drug.
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
Current or history of New York Heart Association Class III or IV heart failure (see 
Appendix F).

Evidence of current uncontrolled cardiovascular conditions including cardiac arrhythmias, 
angina, pulmonary hypertension, or electrocardiographic evidence of acute ischemia or 
active conduction system abnormalities.

Fridericia corrected QT interval (QTcF) >450 milliseconds (msec) (men) or >475 msec 
(women) on a 12-lead ECG during the Screening period.

Abnormalities on 12-lead ECG including, but not limited to, changes in rhythm and 
intervals that in the opinion of the investigator are considered to be clinically significant.
18. Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral 
absorption or tolerance of TAK-659 including difficulty swallowing tablets; diarrhea >Grade 1 
despite supportive therapy. 
19. Use or consumption of any of the following substances:

Medications or supplements that are known to be inhibitors of P-gp and/or strong 
reversible inhibitors of CYP3A within 5 times the inhibitor half-life (if a reasonable 
half-life estimate is known) or within 7 days (if a reasonable half-life estimate is unknown) 
before the first dose of study drug. In general, the use of these agents is not permitted 
during the study (see Section 9.6 for details). See Appendix G for a nonexhaustive list of 
strong CYP3A reversible inhibitors and/or P-gp inhibitors based on the US FDA draft DDI 
guidance.

Medications or supplements that are known to be strong CYP3A mechanism-based 
inhibitors or strong CYP3A inducers and/or P-gp inducers within 7 days, or within 5 times 
the inhibitor or inducer half-life (whichever is longer), before the first dose of study drug. 
In general, the use of these agents is not permitted during the study (see Section 9.6 for 
details). See Appendix G 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.

Non-oncology vaccine therapies for prevention of infectious diseases (eg, human 
papillomavirus [HPV] vaccine) within 4 weeks of study drug administration. The 
inactivated seasonal influenza vaccine can be given to patients before treatment and while 
on therapy without restriction. Influenza vaccines containing live virus or other clinically 
indicated vaccinations for infectious diseases (eg, pneumovax, varicella) may be permitted 
but must be discussed with the sponsor’s medical monitor and may require a washout 
period before and after administration of vaccine.

Grapefruit-containing food or beverages within 5 days before the first dose of study drug. 
Note that grapefruit-containing food and beverages are prohibited during the study.
20. For dose expansion patients who will have tumor biopsies collected:

ECOG performance status >1.
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
Activated partial thromboplastin time (aPTT) or plasma thromboplastin (PT) outside the 
institution’s standard of care.

Platelet count <75,000/L.

Known bleeding diathesis or history of abnormal bleeding, or any other known coagulation 
abnormalities that would contraindicate the tumor biopsy procedure.

Ongoing therapy with any anticoagulant or antiplatelet agents (eg, aspirin, clopidogrel, 
coumadin, heparin, or warfarin) that cannot be held to permit tumor biopsy.
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9.0
STUDY DRUG
9.1
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).
9.1.1
TAK-659
TAK-659 will be dosed PO QD in 28-day cycles. TAK-659 should be taken on an empty stomach 
at least 1 hour before and no sooner than 2 hours after ingestion of food and/or beverages other 
than water. Each tablet should be swallowed separately with a sip of water. A total of 
approximately 8 ounces (240 mL) of water should be taken with the prescribed dose. Patients 
should swallow the tablets whole; the tablets should not be chewed, crushed, or manipulated in any 
way before swallowing. Administration of the tablets will be guided by the dosing tables included 
in the Pharmacy Manual.
Patients should be instructed to take TAK-659 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, except for the Cycle 1 Day 8 
visit for patients enrolled in expansion cohorts: for this visit, patients should be instructed to take 
their TAK-659 dose at home before their clinic visit. The intent of this exception is to ensure that 
blood PK samples are collected among different patients at random times after TAK-659 dosing 
for purposes of population PK analyses.
9.1.2
Nivolumab
The previously approved fixed-dose regimen of nivolumab in the United States is 3 mg/kg IV 
Q2W. Recently, the US FDA modified the dosage regimen for nivolumab for the currently 
approved indications for renal cell carcinoma, metastatic melanoma, and NSCLC. The approval 
modifies the Dosage and Administration section of the label by replacing the single-dose regimen 
of nivolumab (3 mg/kg IV Q2W) with the new recommended regimen of 240 mg IV Q2W until 
disease progression or intolerable toxicity for renal cell carcinoma, metastatic melanoma, and 
NSCLC [17]. 
The approval was based on population PK analyses and dose/exposure-response analyses 
demonstrating the comparability of the PK exposure, safety, and efficacy of the proposed new 
dosing regimen with the previously approved regimen. On the basis of simulations by the 
population PK model, the US FDA determined that the overall exposure with the 240 mg Q2W 
fixed dose is similar (<6% difference) to the 3 mg/kg Q2W dose. The difference in exposure is not 
likely to have a clinically meaningful effect on safety and efficacy because dose/exposure response 
relationships appear to be relatively consistent in these 2 indications. (US Food and Drug 
Administration. Modification of the Dosage Regimen for Nivolumab.
fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm520871.htm Accessed 23 March 2017.)
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In this study, patients receiving the combination therapy will receive 3 mg/kg IV dosing over 
60 minutes every 2 weeks (Day 1 and Day 15 of each 28-day cycle). If the 240 mg fixed-dose 
cohort is evaluated and deemed safe and tolerable, the dosing regimen may switch to 240 mg based 
on change in clinical practice and discussion between the investigator and sponsor. On days on 
which both TAK-659 and nivolumab are administered, the TAK-659 dose will be administered 
first followed by the nivolumab infusion (infusion to begin within 30◦minutes after the TAK-659 
dose). For patients participating in the 2-week monotherapy run-in with TAK-659, the first dose 
will be on Cycle 1 Day 15.
9.2
Missed Doses and Infusion Delays
If a patient does not take the TAK-659 dose at his/her scheduled dosing time (6 hours of the 
scheduled dosing time), that dose should be skipped, and the patient must not make dose 
adjustments on that day or subsequent days to account for the missed dose, for example, by taking 
a double dose of TAK-659 on the following day. Patients should record any skipped doses in their 
dosing diaries (see the Study Manual) and resume dosing at the next scheduled time with the 
prescribed dosage. 
If severe emesis prevents the patient from taking a TAK-659 dose, that dose will be skipped. If 
emesis occurs after TAK-659 ingestion, patients should not re-dose following emesis and should 
record the time of the emesis in his/her dosing diary (see the Study Manual). Patients should 
resume dosing at the next scheduled time with the prescribed dosage.
Patients with nivolumab infusion delays of greater than 6 weeks should normally discontinue 
treatment and enter the Follow-up period, with the exception of cases where benefit-risk may 
justify continued study therapy (eg, patient deriving clinical benefit who requires prolonged 
steroid taper for management of non-DLT AEs). These situations require consultation and 
agreement between the investigator and medical monitor. 
9.3
Definitions of DLT
Toxicity will be evaluated according to the NCI CTCAE version 4.03, effective 14 June 2010 
[35]. 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 study 
drug (either TAK-659 or nivolumab or both). 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) unresolved to ≤Grade 1 (ANC >1500 cells/mm3) 
or baseline for more than 7 consecutive days in the absence of growth factor support. 

≥Grade 3 neutropenia (ANC 1000 cells/mm3) with fever and/or infection, where fever is 
defined as an oral temperature 38.5C.

Grade 4 thrombocytopenia (<25,000/mm3) unresolved to ≤Grade 1 (>75,000/mm3) or baseline 
for more than 7 consecutive days or a platelet count 10,000/mm3 at any time.

≥Grade 3 thrombocytopenia (<50,000/mm3) with clinically significant bleeding. 
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
Grade 4 anemia.

Any Grade 3 or greater nonhematological toxicity with the following exceptions:
–
≥Grade 3 nausea and/or vomiting that has not resolved to <Grade 3 within 72 hours upon 
optimal antiemetic and/or antidiarrheal treatment. (All patients should receive optimal 
antiemetic and/or antidiarrheal treatment according to standard of care. An optimal 
antiemetic regimen is defined as one that employs both a 5-hydroxytryptamine 3 serotonin 
receptor [5-HT3] antagonist and a corticosteroid given in standard doses and according to 
standard schedules.)
–
Transient Grade 3 fatigue (≤1 week).
–
Grade 3 arthralgia/myalgia. 
–
Asymptomatic lipase elevation (<Grade 4) in the absence of significant amylase elevation 
(<Grade 3) considered not dose limiting following agreement between the sponsor and 
investigators. 
–
Asymptomatic amylase elevation (<Grade 4) in the absence of significant lipase elevation 
(<Grade 3) considered not dose limiting following agreement between the sponsor and 
investigators.
–
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 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.
The DLT evaluation period is 28 to 42 days during the first cycle of TAK-659 plus nivolumab 
treatment. Although DLT-like events may occur at any point during treatment, only DLTs 
observed during Cycle 1 of treatment will influence dose escalation decisions and MTD 
determination per the 3+3 escalation schema. While the primary escalation schema is designed to 
determine MTD based on Cycle 1 DLTs, cumulative toxicity beyond Cycle 1 will be considered in 
assessing the overall tolerability of a given dose and consequently influence the dose escalation 
decision and selection of the RP2D.
9.4
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 nivolumab. Approximately 9 to 12 patients are 
expected to be enrolled into the TAK-659 escalation cohorts based on the planned 2 dose-level 
escalation for TAK-659 (Table 9.a) when administered with a weight-based dose regimen of 
nivolumab (3 mg/kg IV); the exact number of patients to be enrolled will depend on the actual 
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number of dose-level cohorts required, which may deviate from the dose escalation plan based on 
toxicities and the PK/pharmacodynamic results observed during the initial dose levels. Following 
the determination of the TAK-659 RP2D in combination with 3 mg/kg nivolumab, nivolumab may 
be evaluated at a fixed dose of 240 mg following discussion between the investigator and sponsor 
and administered in combination with TAK-659 at the determined RP2D to approximately 3 to 
6 patients.
The starting dose of nivolumab will be 3 mg/kg IV Q2W on Day 1 and Day 15 of 28-day cycles. 
The starting dose of TAK-659 will be 60 mg QD. Dose escalation will follow a standard 3+3 
escalation scheme (see Figure 9.a), and dosing of TAK-659 will increase to 100 mg QD (Table 
9.a) 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, and the previous dose 
level will be considered the MTD. Following consultation between the sponsor and 
investigators, either the previous dose level will be considered the MTD (if 6 or more patients 
have been studied at that dose level), the previous dose level will be expanded (if fewer than 
6 patients have been studied at that dose level), or a dose level intermediate between the 
current and the previous dose level will be evaluated. 
Figure 9.a is a diagrammatical representation of these rules.
Figure 9.a
Dose Escalation Algorithm
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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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 the intermediate dose (eg, 80 mg QD) or de-escalation at a 
20 mg increment from the starting dose of 60 mg QD of TAK-659 (eg, 40 mg) if determined to be 
not tolerable, expansion of an existing dose level, or an alternative regimen/schedule—is 
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 in combination with nivolumab.
Dose escalation continues until the MTD is reached, or until 100 mg QD of TAK-659 (the MAD) 
is determined to be safe and tolerable, or until an RP2D, if different from the MTD/MAD, has been 
identified on the basis of 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, 
MAD, or at a lower dose as determined) before making a decision to advance further dose 
expansion. 
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 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. In case of immune-related AEs, which often 
occur during nivolumab treatment with a typical onset beyond the first 28 days of treatment, 
evaluation of the incidence, severity, onset, and frequency of associated dose 
modification/discontinuation of nivolumab in Cycle 1 and beyond will contribute to the general 
tolerability assessment for a given dose cohort of TAK-659 plus nivolumab, which consequently 
may influence the dose escalation decision and RP2D determination following discussions 
between investigators and the sponsor.
Table 9.a
Planned Dose Levels of TAK-659
Dose Level
Dose (Unit)
-1
40 mg
1
60 mg
2
100 mg (a)
More conservative dose escalation, including evaluation of intermediate doses, dose de-escalation at a 20 mg 
increment from the starting dose of 60 mg QD, if 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 maximal dose to be assessed is 100 mg QD 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 and/or who experience a DLT during 
Cycle 1. The minimum treatment and safety evaluation requirements are met if in Cycle 1, the 
patient has been treated with 75% of planned doses of TAK-659 in Cycle 1 (depending on cycle 
length) plus 2 doses of nivolumab, and observed for ≥28 to 42 days (unless DLT occurs before the 
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end of the 28- to 42-day evaluation period) following the dose on Cycle 1 Day 1, and is considered 
to have sufficient safety data by both the sponsor and investigators to conclude that a DLT did not 
occur. Patients who do not meet these minimum requirements will be regarded as ineligible for 
DLT evaluation for the given dose cohort and may be replaced within the same cohort.
The dose escalation is planned for TAK-659 only. While the MTD/MAD/RP2D of TAK-659 are 
being determined, the starting dose of nivolumab will be 3 mg/kg IV. The fixed dose of nivolumab 
(240 mg) might be used as an equivalent weight-based dose of nivolumab (3 mg/kg) for further 
evaluation and determination of the TAK-659 MTD/RP2D following discussions between the 
investigators and the sponsor.
9.5
Dose Modification Guidelines
Patients on study drug(s) in both Part 1 (dose escalation) and Part 2 (dose expansion) of the study 
will be evaluated weekly during Cycle 1 (Days 1, 8, 15, and 22); on Day 1 and Day 15 of Cycles 2, 
3, and 4; and on Day 1 of Cycle 5 and beyond. In cases in which either TAK-659 or nivolumab 
monotherapy continues following discontinuation of the other drug due to toxicities, patients will 
be evaluated at monthly visits on Day 1 of each cycle (with the exception of Cycle 1, in which 
weekly visits are required) until PD or discontinuation due to other reasons. 
Toxicities are to be assessed according to the NCI CTCAE version 4.03, effective 14 June 2010 
[35]. The causal relationship of each AE should be assessed in relation to TAK-659, nivolumab, or 
both so that dose modifications can be made accordingly. Administration and dose modification of 
nivolumab will follow prescribing information for nivolumab and also the guidance described in 
this section (see Section 9.8). Dose modification guidelines for hematologic and nonhematologic 
toxicities are described separately below for both study drugs based on the type and severity of 
AEs, causality determination by investigators, and safety and tolerability profiles of each of the
study drugs. Of note, only dose interruption and discontinuation, not dose reductions, are allowed 
for nivolumab. Further clarification can be obtained in consultation with the sponsor project 
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 after resolution of the AE; they 
may either maintain the same dose level or have doses of study drug reduced by at least 1 dose 
level (dose reduction allowed only for TAK-659). 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 
during dose escalation, or at a 20 mg increment (Table 9.a). During Part 2, depending on the 
MTD/RP2D determined during Part 1, TAK-659 dose reduction will follow, in general, an 
increment of 20 mg, or up to a 50% reduction from the previous dose, depending on the RP2D as 
determined in Part 1 (Table 9.b). For example, if 100 mg QD is the RP2D, the first dose reduction 
will lower the dose to 80 mg QD. If initial dose adjustment does not provide sufficient relief, the 
dose of TAK-659 can 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 (eg, 60 mg, 
if 100 mg QD is the RP2D). Based on the data and experience gathered from the Part 1 dose 
escalation, alternative dose reduction levels could be determined if deemed more appropriate 
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following discussions between investigators and the sponsor, and will be communicated via a 
protocol amendment. Up to 2 dose level reductions of TAK-659 due to AEs are generally 
recommended. If more than 2 dose reductions of TAK-659 are needed to manage 
TAK-659-related AEs, discontinuation of treatment should be considered unless the treating 
physician considers that the patient may benefit from continued study treatment, after resolution of 
AEs to <Grade 1 or baseline, and consults with the sponsor.
If 1 study drug is delayed because of toxicity attributed to its use, the other study drug is to be 
administered as scheduled unless otherwise specified. If that study drug is either held or missed 
because of an AE, please refer to the CRF completion guidelines and the SOE for details of cycle 
length and requirements for the start of a new cycle. 
During dose escalation, the Cycle 1 DLT-evaluation period typically will be 28 days. However, in 
the event of a nivolumab dosing interruption, a cycle length may be extended. If the second dose of 
nivolumab planned for Cycle 1 Day 15 is held and then dosed within the original 28-day cycle, the 
dose will be considered the second dose of Cycle 1, leading to a cycle with a maximum total of 
42 days. The actual doses of TAK-659 received during this 28- to 42-day DLT-evaluation period 
will be assessed against the planned doses of TAK-659 (daily dose cycle days) to determine 
whether the patient has received at least 75% of planned doses of TAK-659 to be DLT evaluable. 
When the second dose is administered, procedures at the original scheduled visit (ie, Cycle 1 
Day 15) should be performed. If the second dose of nivolumab is interrupted for a period of time 
that extends beyond the original 28-day cycle, this dose will be considered missed. In this case, 
independent of whether the patient has received 75% planned dose of TAK-659, the patient will 
receive only one of the 2 nivolumab doses planned for Cycle 1 and, therefore, is not evaluable for 
DLT. 
In Cycle 2 and beyond (during both the dose escalation and dose expansion phases of the study), if 
a nivolumab dose is delayed because of AEs, when the criteria to resume treatment are met, the 
patient should restart treatment at the next scheduled time point per protocol. However, if 
nivolumab is delayed past the next scheduled time point per protocol and TAK-659 dosing is also 
interrupted, the next scheduled time point will be delayed until dosing with either drug resumes.
Table 9.b
Planned Dose Levels of TAK-659 in the Expansion Phase
Dose Reduction Levels
TAK-659
TAK-659 (if RP2D=100 mg [c])
RP2D
RP2D TBD (a)
100 mg
(–) 1 dose level
RP2D-20 mg (b)
80 mg
(–) 2 dose level
RP2D-40 mg (b)
60 mg
(a) TBD=to be determined during dose escalation.
(b) TAK-659 dose reduction will follow, in general, a decrement of 20 mg, or up to a 50% reduction from the previous 
dose, depending on the RP2D as determined in dose escalation.
(c) Dose reduction levels are listed if the RP2D for TAK-659 in combination with nivolumab is 100 mg QD.
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9.5.1
Part 1 Intrapatient Dose Escalation
Once the RP2D of TAK-659 is determined when administered in combination with nivolumab, all 
patients in Part 1 actively receiving TAK-659 at a dose lower than the RP2D for a minimum of 
2 cycles, in the absence of PD or unacceptable treatment-related toxicity per the investigator, may 
dose escalate to the RP2D at the investigator’s discretion and with the sponsor’s approval. Patients 
in 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 
(non-hematologic toxicity must be ≤Grade 2).
9.5.2
Dose Modification for Hematologic and Nonhematologic Toxicity: TAK-659 and 
Nivolumab
A decision regarding dose modification of study drug(s) will be dependent upon the toxicity and its 
onset, severity, and time course. The causal relationship of any reported events (AEs or SAEs) 
should be assessed by the investigator in relation to TAK-659, nivolumab, or both. Dose 
modification of study drug(s) is required only when the toxicity is attributed to study drug(s) based 
on the investigator’s assessment. Study drug(s) can be held at the investigator’s discretion for 
high-grade, non-drug-related toxicities if it is viewed to be necessary in the clinical management of 
the event. However, when study drug(s) resumes after resolution of the non-drug-related event, no 
dose reduction of study drug(s) is needed. 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 are presented in Table 9.c and Table 9.d, respectively.
When the dose of study drug(s) is withheld based on the criteria in Table 9.c and Table 9.d, clinical 
and laboratory re-evaluation should be repeated at least weekly or more frequently until the 
toxicity resolves to ≤Grade 1 or baseline, or to an acceptable level according to the investigator’s 
assessment. Upon recovery, study drug(s) may be reinitiated either at the same dose level or at a 
reduced dose level (dose reduction for TAK-659 only). When a dose reduction of TAK-659 is 
required, no re-escalation of dose will be permitted.
For treatment-related, Grade 4, nonhematologic toxicities, dose reduction of TAK-659 by more 
than 2 dose levels or treatment delay for >6 weeks for either or both drugs will, in general, require 
that study treatment 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 study 
treatment, then the study drug(s) can be resumed at a reduced dose of TAK-659 by at least 1 dose 
level and/or at the same dose and schedule of nivolumab after recovery of the toxicity or toxicities 
in question to Grade 1 or baseline. However, no exceptions should be made in the case of adverse 
reactions that result in nivolumab discontinuation as required per the most recent nivolumab USPI 
[17] or SmPC [18]. In particular, the study discontinuation required due to the immune-related 
AEs or infusion reactions associated with the use of nivolumab should not be overridden.
For transient lab value abnormalities that, based on investigator assessment, are not clinically 
significant or are most probably related to disease and not the drug, continuation of therapy 
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without following the dose modification guidelines is permissible upon discussion with the 
sponsor. 
Table 9.c
Guidelines for TAK-659 and Nivolumab Dose Modifications for Hematologic 
Toxicity
NCI CTCAE Grade
TAK-659 Dose Modification
Nivolumab Dose Modification
Neutrophil Count (ANC) Decreased
Grade 1 & 2 (1000/mm3
to <LLN)

Continue TAK-659 at same dose.

Continue nivolumab at same dose 
and schedule.
Grade 3 (500 to 
<999/mm3)

Hold TAK-659 until resolved to 
≥1500/mm3 or baseline: 

If resolved ≤7 days, same dose.

If resolved >7 days, reduce by 1 dose 
level.

If recurrence, reduce by 1 dose level.

Continue nivolumab at same dose 
and schedule.
Grade 4 (<500/mm3)

Hold TAK-659 until resolved to 
≥1500/mm3 or baseline, then reduce by 
1 dose level.

Hold nivolumab until resolution to 
≥1500/mm3 or baseline, then 
resume at same dose and schedule.

If resolved >7 days after start of 
event and the causality is solely 
attributed to nivolumab, 
discontinuation of nivolumab 
should be considered.
Febrile neutropenia 
(<1000/mm3; fever 
≥38.5C)

Hold TAK-659 until resolved to 
≥1500/mm3 or baseline, and fever/infection 
recovered, then reduce by 1 dose level.

Hold nivolumab until resolution to 
≥1500/mm3 or baseline and 
resolution of fever/infection.
Platelet Count Decreased
Grade 1 & 2 
(50,000/mm3 to <LLN)

Continue TAK-659 at same dose.

Continue nivolumab at same dose 
and schedule.
Grade 3 
(25,000-49,999/mm3)

Hold TAK-659 until resolved to ≤Grade 1 
(≥75000/mm3 or baseline, then:
O If resolved ≤7 days, same dose.
O If resolved >7 days, reduce by 1 dose 
level.

Hold nivolumab until resolution to 
≥75000/mm3 or baseline, then 
resume at same dose and schedule. 

If resolved in >7 days and the 
causality is solely attributed to 
nivolumab, discontinuation of 
nivolumab should be considered.
Grade 4 (<25,000/mm3)

Hold TAK-659 until resolved to ≤Grade 1 
or baseline, then reduce by 1 dose level.

Hold nivolumab until resolution to 
≥75000/mm3 or baseline, then 
resume at same dose and schedule.

If resolved in >7 days and the 
causality is solely attributed to 
nivolumab, discontinuation of 
nivolumab should be considered.
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Table 9.c
Guidelines for TAK-659 and Nivolumab Dose Modifications for Hematologic 
Toxicity (continued)
NCI CTCAE Grade
TAK-659 Dose Modification
Nivolumab Dose Modification
Anemia
Grade 3 

Hold TAK-659 until resolved to ≤Grade 1 
or baseline, then:
O If resolved ≤7 days, same dose.
O If resolved >7 days, reduce by 1 dose 
level.

Hold nivolumab until resolution to 
≤Grade 1 or baseline, then resume 
at same dose and schedule.
Grade 4
Consider permanently discontinuing study treatment based on causality determination 
except when the investigator determines that the patient is obtaining clinical benefit and 
has discussed this with the project clinician or designee. If the patient is not discontinued:

Hold TAK-659 until resolved to ≤Grade 1 
or baseline, then reduce by 1 dose level.

Hold nivolumab until resolution to 
≤Grade 1 or baseline, then resume 
at same dose and schedule.

If resolved in >7 days and the 
causality is solely attributed to 
nivolumab, discontinuation of 
nivolumab should be considered
LLN=lower limit of normal.
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Table 9.d
Guidelines for TAK-659 and Nivolumab Dose Modifications for 
Nonhematologic Toxicity
NCI CTCAE Grade (in 
Alphabetic Order)
TAK-659 Dose Modification (a)
Nivolumab Dose Modification
Adrenal Insufficiency
Moderate symptoms; medical 
intervention indicated (Grade 2)

Continue TAK-659 at same 
dose.

Hold nivolumab until Grade 0 or 1, 
then resume nivolumab at the same 
dose and schedule.
Severe symptoms; hospitalization 
indicated; or life threatening
(Grade 3 or 4)

Hold TAK-659 until resolution, 
then resume TAK-659 at the 
same dose and schedule. 

Discontinue nivolumab.
Colitis
With moderate or severe 
symptoms
(Grade 2 or 3 diarrhea)

If Grade 2, optimize 
antidiarrheal therapy and 
continue TAK-659 at same 
dose.

If Grade 3, follow guidelines 
under Other Nonhematologic 
Toxicities.

If Grade 2, hold nivolumab until 
Grade 0 or 1, then resume 
nivolumab at the same dose and 
schedule.

If Grade 3, discontinue nivolumab
With Grade 4 symptoms
(Grade 4 diarrhea)

Follow guidelines under Other 
Nonhematologic Toxicities. 

Discontinue nivolumab.
Encephalitis
Moderate or severe symptoms; 
neurologic signs or symptoms
(Grade 2 or 3)

If unrelated to TAK-659 or 
Grade 2, continue TAK-659 at 
same dose.

If possibly related to TAK-659 
and Grade 3, follow guidelines 
under Other Nonhematologic 
Toxicities.

If Grade 2, hold nivolumab until 
Grade 0 or 1, then resume 
nivolumab at the same dose and 
schedule.

If Grade 3, discontinue nivolumab-
Immune mediated encephalitis 
(Grade 4)

If unrelated to TAK-659, hold 
until resolution to Grade 0 or 1, 
then continue TAK-659 at same 
dose.

If related to TAK-659, follow 
guidelines under Other 
Nonhematologic Toxicities.

Discontinue nivolumab.
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Table 9.d
Guidelines for TAK-659 and Nivolumab Dose Modifications for 
Nonhematologic Toxicity (continued)
NCI CTCAE Grade (in 
Alphabetic Order)
TAK-659 Dose Modification (a)
Nivolumab Dose Modification
Hepatotoxicity/Hepatitis
ALT and/or AST >3ULN to 
≤5×ULN 
(Grade 2)

Continue TAK-659 at the same 
dose.

Hold nivolumab until both ALT 
and AST ≤1.5×ULN, then resume 
nivolumab at the same dose and 
schedule.
ALT and/or AST >5ULN to 
≤20×ULN
(Grade 3)

Follow TAK-659 guidelines 
under Other Nonhematologic 
Toxicities. 

Discontinue nivolumab.
Bilirubin >1.5ULN to 3ULN 
(Grade 2)

Continue TAK-659 at the same 
dose.

Hold nivolumab until Grade 0 or 1, 
then resume nivolumab at the same 
dose and schedule.
Bilirubin >3ULN
(Grade 3)

Follow TAK-659 guidelines 
under Other Nonhematologic 
Toxicities. 

Discontinue nivolumab.
Hypophysitis
Grade 2 or 3

Continue TAK-659 at the same 
dose.

Hold nivolumab until Grade 0 or 1, 
then resume nivolumab at the same 
dose and schedule.
Grade 4

If unrelated to TAK-659, hold 
until resolution to Grade 0 or 1, 
then continue TAK-659 at same 
dose.

If related to TAK-659, follow 
guidelines under Other 
Nonhematologic Toxicities.

Discontinue nivolumab.
Nephritis and Renal Dysfunction
Serum creatinine >1 to 1.5ULN 
to 6.0ULN
(Grades 1-3)

If unrelated to TAK-659, 
continue TAK-659 at same 
dose.

If related to TAK-659, follow 
guidelines under Other 
Nonhematologic Toxicities.

If Grade 1, continue nivolumab but 
monitor creatinine weekly. If Grade 
2-3, hold nivolumab until Grade 1, 
then resume nivolumab at the same 
dose and schedule.
Serum creatinine >6.0ULN
(Grade 4)

If unrelated to TAK-659, hold 
TAK-659 until resolution to 
<Grade 1, then continue 
TAK-659 at same dose.

If related to TAK-659, follow 
guidelines under Other 
Nonhematologic Toxicities.

Discontinue nivolumab.
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Table 9.d
Guidelines for TAK-659 and Nivolumab Dose Modifications for 
Nonhematologic Toxicity (continued)
NCI CTCAE Grade (in 
Alphabetic Order)
TAK-659 Dose Modification (a)
Nivolumab Dose Modification
Pneumonitis
Symptomatic, medical 
intervention, limiting instrumental 
ADL 
(Grade 2)

Hold TAK-659 until resolution 
to ≤Grade 1 or baseline, then 
resume TAK-659 at same dose.

Hold nivolumab until Grade 0 or 1, 
then resume nivolumab at the same 
dose and schedule.
Severe – requiring oxygen 
support; or life threatening 
requiring urgent intervention
(Grade 3 or 4)

Follow TAK-659 guidelines 
under Other Nonhematologic 
Toxicities.

Discontinue nivolumab.
Rash
Rash covering >30% body surface 
area
(Grade 3)

Follow TAK-659 guidelines 
under Other Nonhematologic 
Toxicities.

Hold nivolumab until Grade 0 or 1, 
then resume nivolumab at the same 
dose and schedule.
Rash requiring antibiotics; life 
threatening
(Grade 4)

Follow TAK-659 guidelines 
under Other Nonhematologic 
Toxicities. 

Discontinue nivolumab.
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 2 days with 
optimal antiemetics and 
antidiarrheals following SOC.

Transient Grade 3 fatigue 
(lasting <3 days).

Asymptomatic lipase 
elevation (<Grade 4) in the 
absence of significant 
amylase elevation (<Grade 3) 
considered not dose limiting 
following agreement between 
sponsor and investigators.

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 
sponsor and investigators
Hold TAK-659 until resolution to 
≤Grade 1 or baseline. 
Reduce TAK-659 by 1 dose level. 
For the exceptions, maintain the dose 
level. 
Hold nivolumab if determined to be 
related to nivolumab until resolution to 
Grade 0 or 1, then resume nivolumab at 
same dose.
Permanent discontinuation should be 
considered for: 

Any Grade 2 drug-related uveitis, 
eye pain or blurred vision that does 
not respond to topical therapy and 
does not improve to Grade 1 
severity within the retreatment 
period OR requires systemic 
treatment

Grade 3 drug-related uveitis, 
pneumonitis, bronchospasm, 
hypersensitivity reaction, or 
infusion reaction of any duration 
requires discontinuation

Recurrence of same Grade 3 
toxicity.

Grade 3 toxicities and dose 
interruptions that persist for 
6 weeks.
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Table 9.d
Guidelines for TAK-659 and Nivolumab Dose Modifications for 
Nonhematologic Toxicity (continued)
NCI CTCAE Grade (in 
Alphabetic Order)
TAK-659 Dose Modification (a)
Nivolumab Dose Modification
Other Nonhematologic Toxicities (continued)

Grade 3 hypophosphatemia 
resolved to Grade ≤1 or 
baseline value within 72 hours 
with phosphate repletion.

Other Grade 3 asymptomatic 
enzyme elevations not 
considered clinically 
significant following 
agreement between sponsor 
and investigator.

Toxicities that require 10 mg per 
day or greater prednisone or 
equivalent for >12 weeks.
All other Grade 4 nonhematologic 
toxicities 
Consider permanently discontinuing 
TAK-659 based on causality 
determination except when the 
investigator determines that 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.
Consider permanently discontinuing 
nivolumab based on causality 
determination. 
ADL=activities of daily living, SOC=standard of care.
In general, the study drug(s) will resume only after the resolution of AEs to ≤Grade 1 or baseline or 
as specified in these dose modification guidelines. However, retreatment with study drug(s) could 
start when the AEs are resolved to a level deemed acceptable by the investigator based on 
consideration of the individual patient situation and discussions/agreement with the sponsor 
project clinician.
The recommendations in these dose modification guidelines and in the current nivolumab USPI 
[17] and SmPC [18] should be strictly followed. However, in individual patient cases, following 
discussion and agreement between the investigator and the Millennium project clinician, 
alternative dose modifications may be recommended to maximize exposure to study treatment 
while protecting patient safety. However, nivolumab discontinuation as required per the most 
recent nivolumab USPI [17] or SmPC [18] should not be overridden.
9.6
Concomitant Medications and Procedures
During the course of the study, patients will be instructed not to take any additional medications 
(including over-the-counter products and supplements) without prior consultation with the 
investigator. At each visit, the investigator will ask the patient about any new medications he/she is 
or has taken while on study. All concomitant medications (defined as any medication given during 
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the study) and significant nondrug therapies, including physical therapy and blood transfusions, 
should be recorded from signing of the informed consent form (ICF) through 28 days after the last 
dose of study drug. However, if a patient experiences immune-mediated toxicities that either result 
in discontinuation of nivolumab or both study treatments or occur during the 28-day AE follow-up 
period (including immune-mediated pneumonitis, colitis, hepatitis, endocriopathies, nephritis, 
rash, and encephalitis as described in the nivolumab USPI [17]), they will be followed to 
resolution or stabilization, the start of alternative therapy, or a minimum of 100 days after last dose 
of study treatment, whichever occurs first. During this AE follow-up period, concomitant 
medications and procedures should also be collected. 
The following restrictions apply during the study:

Any antineoplastic therapy other than TAK-659 is prohibited on study. If alternative therapy is 
required for treatment of the patient’s tumor, the patient should be removed from this study and 
the reason for removal recorded in the electronic case report form (eCRF).

Radiation therapy (note that, in general, the requirement for local radiation therapy indicates 
PD) is not permitted during study. Palliative radiotherapy for local pain/symptom control in a 
preexisting nontarget lesion, if required, may be considered after discussion with the sponsor’s 
clinical representative. Details of the palliative radiotherapy should be documented in the 
source records and eCRF, including dates of treatment, anatomical site, dose administered and 
fractionation schedule, and associated AEs. 

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.

Systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) or other 
immunosuppressive medications required as an ongoing therapy is not permitted with the 
following exceptions and clarification:
–
Patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption).
–
Physiologic replacement doses of systemic corticosteroids are permitted, even if 
>10 mg/day prednisone or equivalents.
–
A brief course of corticosteroids for prophylaxis (eg, contrast dye allergy or prevention of 
infusion reactions) or for treatment of non-autoimmune conditions (eg, allergic reaction 
caused by contact allergen or drug-related nausea and/or vomiting) are permitted.

Non-oncology vaccine therapies for prevention of infectious diseases (eg, HPV vaccine) 
within 4 weeks of study drug administration. 
–
The inactivated seasonal influenza vaccine can be given to patients before treatment and 
while on therapy without restriction. 
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–
Influenza vaccines containing live virus or other clinically indicated vaccinations for 
infectious diseases (eg, pneumovax, varicella) may be permitted but must be discussed 
with the sponsor’s medical monitor and may require a washout period before and after 
administration of vaccine.

Concurrent systemic administration of TAK-659 with inhibitors or inducers of P-gp or strong 
inhibitors or inducers of CYP3A should be avoided in this study. In vitro studies indicate that 
TAK-659 is a substrate for P-gp and that, among CYP isozymes, TAK-659 is preferentially 
metabolized by CYP3A4/5. Refer to the list below and Appendix G for a nonexhaustive list of 
medications, supplements, and food products that are inhibitors or inducers of P-gp or strong 
inhibitors or inducers of CYP3A based on the US FDA Draft DDI Guidance.
–
Antifungals: itraconazole, ketoconazole, posaconazole, voriconazole.
–
Antibiotics: azithromycin, clarithromycin, erythromycin, telithromycin.
–
Antimycobacterials: rifabutin, rifampin, rifapentine.
–
Antiepileptics: carbamazepine, phenobarbital, phenytoin, primidone.
–
Antidepressant: nefazodone.
–
Immunosuppressant: cyclosporine.
–
Calcium channel blockers: diltiazem, felodipine, mibefradil, verapamil.
–
Antiarrhythmics: amiodarone, dronedarone, quinidine.
–
Antiplatelet: ticagrelor.
–
Antilipid: avasimibe.
–
Other cardiovascular: captopril, carvedilol, ranolazine.
–
Vasopressin antagonist: conivaptan.
–
Food/Herbals/Supplements: grapefruit-containing food and beverages, St. John’s wort, 
quercetin.
If a patient experiences an AE on study and TAK-659 dosing is temporarily interrupted because of 
that AE, the medications listed above and in Appendix G may be used for AE management 
provided there is no appropriate alternative treatment available per the investigator’s judgment and 
the dosing is not concurrent with TAK-659. This situation requires discussion between the 
investigator and the sponsor’s 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 
G 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 
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list above and in Appendix G, then its use must be discussed with the medical monitor or designee 
to assess the relative benefit and risk.
9.7
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.
It is not known what effects TAK-659 has on human pregnancy or development of the embryo or 
fetus; therefore, female patients participating in this study should avoid becoming pregnant, and 
male patients should avoid impregnating a female partner. Nonsterilized female patients of 
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 one highly effective method of 
contraception and one additional effective (barrier) method (see Appendix H) at the same time, 
from the time of signing of the informed consent form through 180 days after the last dose of 
study drug, or

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.)
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

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods for the female partner], withdrawal, spermicides only, and lactational amenorrhea are 
not acceptable methods of contraception. Female and male condoms should not be used 
together.)
9.8
Management of Clinical Events 
Therapies that are required to manage AEs and control cancer symptoms are allowed based on 
standard clinical practice, unless specifically excluded. Supportive care agents, such as 
erythropoietin, G-CSF, blood products (red blood cell [RBC] and platelet transfusions), and pain 
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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. Nivolumab is associated with immune-related AEs, which may 
be managed per clinical judgment of the investigator in accordance with the institutional guideline 
and the most recent nivolumab USPI [17] and SmPC [18]. 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 9.5.
9.8.1
Nausea and/or Vomiting
This study will not initially employ prophylactic anti-emetics before the first dose of the study 
drug during dose escalation. However, a patient who develops nausea and/or vomiting will be 
actively managed by employing optimal antiemetic treatment based on local standard practice. 
Additionally, anti-emetics may be used prophylactically as clinically indicated following the 
occurrence of a first event of study drug-related or possibly related nausea and/or vomiting. An 
optimal antiemetic regimen is defined as one that employs both a 5-HT3 antagonist and a 
corticosteroid given in standard doses and according to standard schedules. 
9.8.2
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 
nivolumab should be modified per dose modification guidance in the protocol when anemia, 
thrombocytopenia, or neutropenia occur (see Table 9.c). 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 9.6).
9.8.3
Diarrhea
Prophylactic antidiarrheals will not be used in this study; however, patients should be instructed to 
take loperamide or comparable antidiarrheal medication according to institutional or local 
practice, once infectious causes are ruled out. Adequate fluid intake should be maintained to avoid 
dehydration, and any fluid deficit should be corrected before initiation of treatment with study 
drug and during treatment. Refer to Section 9.8.8.2 for management of diarrhea if 
immune-mediated colitis occurs during treatment.
9.8.4
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 following the dose modification guidelines in Table 9.d.
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9.8.5
Rash With or Without Pruritus
Prophylactic measures should be considered if a patient develops a rash (eg, using a thick, 
alcohol-free emollient cream on dry areas of the body). In the case of rash, the use of a topical or 
oral steroid (eg, prednisone ≤10 mg per day or equivalent) is permitted. Refer to dose modification 
guidelines in Table 9.d for occurrence of Grade 3 or 4 rash. Refer to Section 9.8.8.8 for 
management of rash if immune-mediated dermatitis occurs during treatment.
9.8.6
Hypophosphatemia
Hypophosphatemia has been observed in patients treated with TAK-659. Consider prophylaxis; 
otherwise, refer to dose modification guidelines in Table 9.d.
9.8.7
Enzyme Elevations 
9.8.7.1
Transaminase, Amylase, Lipase, and CPK Elevations
Elevations of transaminases, amylase, lipase, and CPK have been observed in patients treated with 
TAK-659. Events are generally asymptomatic and reversible with dose interruption. See dose 
modification guidelines in Table 9.d.
9.8.7.2
Lactate Dehydrogenase Elevations
Lactate dehydrogenase (LDH) elevations have been observed in the majority of patients exposed 
to TAK-659. These elevations have been asymptomatic, and their clinical significance is 
unknown. No action, such as dose interruption, has been taken as a result of increased LDH; 
however, LDH elevation is reversible on the basis of experience in patients who had TAK-659 
interrupted for other reasons.
9.8.8
Immune-Mediated Adverse Reactions
Immune-mediated AEs can occur with nivolumab, both during treatment and following 
discontinuation. For any suspected immune-mediated AEs, other causes should be excluded. 
Based on the severity of the adverse reaction, nivolumab should be permanently discontinued or 
withheld, high-dose corticosteroids should be administered, and if appropriate, 
hormone-replacement therapy should be initiated. Upon improvement to Grade 1 or less, a 
corticosteroid taper should be initiated and continued over at least 1 month. Consideration should 
be given to restarting nivolumab after completion of the corticosteroid taper based on the severity 
of the event. Recommendations for dose modification of TAK-659 during the occurrence of 
immune-mediated AEs are provided in Section 9.5.
9.8.8.1
Immune –Mediated Pneumonitis
Immune-mediated pneumonitis can occur with nivolumab treatment. Patients on study will be 
monitored closely. Oxygen saturation will be monitored and recorded at the frequency specified in 
the Schedule of Events (Appendix A). 
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If immune-mediated pneumonitis occurs, nivolumab should be permanently discontinued for a 
severe (Grade 3) or life-threatening (Grade 4) event and withheld until resolution for a moderate 
(Grade 2) event. Corticosteroids should be administered at a dose of 1 to 2 mg/kg/day prednisone 
equivalents for moderate (Grade 2) or greater pneumonitis. For Grade 3 or Grade 4, 
non-corticosteroid immunosuppressive medication can be added if symptoms do not improve or if 
they worsen after 2 days of corticosteroid treatment. Bronchoscopy, lung biopsy, and prophylactic 
antibiotics for opportunistic infection should be considered. When the event resolves to baseline, 
the corticosteroid should be tapered over at least 1 month. For Grade 2 pneumonitis responsive to 
corticosteroids, nivolumab can be resumed after the taper. However, if Grade 2 pneumonitis does 
not improve after 2 weeks of corticosteroid treatment or worsens, nivolumab should be 
permanently discontinued.
9.8.8.2
Immune-Mediated Colitis
Immune-mediated colitis can occur with nivolumab treatment. Patients on study will be monitored 
for diarrhea and symptoms suggestive of immune-mediated colitis. The severity levels should be 
graded as below based on the NCI CTCAE criteria for diarrhea and colitis:
Grade 1: diarrhea: increase of <4 stools/day over baseline; colitis: asymptomatic and clinical or 
diagnostic observations only, intervention not indicated.
Grade 2: diarrhea: increase of 4-6 stools/day over baseline; IV fluids indicated for <24 hours; not 
interfering with activities of daily living (ADL). Colitis: abdominal pain; mucus or blood in stool.
Grade 3: diarrhea: increase of ≥7 stools/day over baseline; IV fluids indicated for ≥24 hours; 
interfering with ADL. Colitis: severe abdominal pain; medical intervention indicated, peritoneal 
signs.
Grade 4: diarrhea and colitis: life threatening; urgent intervention indicated.
If immune-mediated colitis occurs, nivolumab should be permanently discontinued for a 
life-threatening (Grade 4) event, and withheld until resolution for a moderate (Grade 2) or severe 
(Grade 3) event. Serial stool cultures should be performed to rule out bacterial infections. For 
Grade 2 events, antidiarrheals and other symptomatic treatment should be administered. If 
symptoms persist for >5 days or recur, corticosteroids should be administered at a dose of 0.5 to 
1 mg/kg/day prednisone equivalents; if worsening or no improvement occurs despite initiation of 
corticosteroids, the dose should be increased to 1 to 2 mg/kg/day prednisone equivalents. For 
Grade 3 or Grade 4, corticosteroids should be administered at a dose of 1 to 2 mg/kg/day 
prednisone equivalents. If Grade 4 persists for 3 to 5 days or recurs, non-corticosteroid 
immunosuppressive medication can be added. (Of note, the use of anti-tumor necrosis factor-
therapy should be avoided in the setting of perforation or sepsis.) Lower endoscopy and 
prophylactic antibiotics for opportunistic infection should be considered in the management of the 
event. 
When symptoms improve to ≤Grade 1, study treatment can resume for Grade 2 or Grade 3 after at 
least 1 month of corticosteroid tapering. If Grade 3 persists for >3 to 5 days despite active clinical 
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intervention or if it recurs, nivolumab should be permanently discontinued. Dose modification of 
TAK-659 during the event will follow the guidelines in Section 9.5. 
9.8.8.3
Immune-Mediated Hepatitis
Immune-mediated hepatitis can occur with nivolumab treatment. Patients on study will be 
monitored for immune-mediated hepatitis by liver function tests performed at a frequency 
specified in the Schedule of Events (Appendix A). Severity levels are graded as below based on 
transaminase elevations, with or without concomitant elevation in total bilirubin:
Grade 1: AST or ALT >ULN to 3ULN and/or total bilirubin >ULN to 1.5ULN.
Grade 2: AST or ALT >3 to 5ULN and/or total bilirubin >1.5 to 3ULN.
Grade 3 or 4: AST or ALT >5ULN and/or bilirubin >3ULN; life-threatening consequences for 
Grade 4.
If immune-mediated hepatitis occurs, nivolumab should be withheld for moderate (Grade 2) and 
permanently discontinued for severe (Grade 3) or life-threatening (Grade 4) immune-mediated 
hepatitis. The frequency of the liver function test monitoring should increase to every 3 days for 
Grade 2 and every 1 to 2 days for Grade 3/4 events. Corticosteroids should be administered at a 
dose of 1 to 2 mg/kg/day prednisone equivalents for Grade 3/4 or Grade 2 if it persists for >5 to 7 
days or worsens. Study treatment can resume after at least 1 month of corticosteroid tapering when 
liver function test elevation returns to ≤Grade 1 or baseline. Prophylactic antibiotics should be 
considered for opportunistic infection when retreatment starts. Dose modification of TAK-659 
during the event will follow the guidelines in Section 9.5.
9.8.8.4
Immune-Mediated Hypophysitis
Immune-mediated hypophysitis can occur with nivolumab treatment. If it occurs, corticosteroids 
should be administered at a dose of 1 mg/kg/day prednisone equivalents for moderate (Grade 2) or 
greater hypophysitis. Nivolumab should be withheld for moderate (Grade 2) or severe (Grade 3) 
hypophysitis and permanently discontinued for life-threatening (Grade 4) hypophysitis.
9.8.8.5
Immune-Mediated Thyroid Disorders
Thyroid disorders, including hypothyroidism and hyperthyroidism, can occur with nivolumab 
treatment. If it occurs, hormone-replacement therapy for hypothyroidism should be administered. 
Medical management should be initiated for control of hyperthyroidism. There are no 
recommended dose adjustments of nivolumab for hypothyroidism or hyperthyroidism.
9.8.8.6
Type 1 Diabetes Mellitus
Type 1 diabetes mellitus can occur with nivolumab treatment. If it occurs, insulin should be 
administered, and nivolumab should be withheld in cases of severe (Grade 3) hyperglycemia until 
metabolic control is achieved. Nivolumab should be permanently discontinued for life-threatening 
(Grade 4) hyperglycemia.
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9.8.8.7
Immune-Mediated Nephritis and Renal Dysfunction
Immune-mediated nephritis can occur with nivolumab treatment. Patients on study will be 
monitored for immune-mediated nephritis by serum creatinine test as indicated in the Schedule of 
Events (Appendix A). If it occurs, other causes of creatinine elevation should be excluded. 
Severity levels should be graded as below:
Grade 1: creatinine >ULN and >baseline but ≤1.5baseline.
Grade 2: moderate: creatinine >1.5 to 3baseline; >1.5 to 3ULN.
Grade 3: severe: creatinine >3baseline; >3 to 6ULN.
Grade 4: life threatening: creatinine >6ULN.
Nivolumab should be withheld for moderate (Grade 2) or severe (Grade 3) increased serum 
creatinine, and corticosteroids should be administered at a dose of 0.5 to 1 mg/kg/day prednisone 
equivalents. If the event is resolved to ≤Grade 1 in response to corticosteroids, nivolumab can 
resume after the corticosteroid has been tapered for at least 1 month. If worsening or no 
improvement occurs within 7 days of corticosteroid initiation, the dose of corticosteroids should 
be increased to 1 to 2 mg/kg/day prednisone equivalents, and nivolumab should be permanently 
discontinued. Nivolumab should be permanently discontinued and corticosteroids administered at 
a dose of 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid tapering for 
life-threatening (Grade 4) increased serum creatinine. Renal biopsy and prophylactic antibiotics 
for opportunistic infection should be considered during the management of the event.
9.8.8.8
Immune-Mediated Dermatitis
Immune-mediated dermatitis can occur with nivolumab treatment. Low grade rashes (<Grade 3) 
have also been reported with administration of TAK-659. Patients should avoid excessive 
exposure to sunlight and should use a broad-spectrum sunscreen (containing titanium dioxide or 
zinc oxide) with a sun protection factor >15. Should a Grade 2 or 3 rash occur, photographic 
documentation is recommended. 
For Grade 1 (mild) or Grade 2 (moderate) dermatitis, such as rash (covering ≤30% of body surface 
area) and pruritus, antihistamines and topical steroids should be used as symptomatic treatment. If 
rash persists for >1 to 2 weeks or recurs, nivolumab should be withheld, and corticosteroids at a 
dose of 0.5 to 1 mg/kg/day prednisone equivalents should be considered. For Grade 3 (severe) or 
Grade 4 (life-threatening) dermatitis, corticosteroids should be administered at a dose of 1 to 
2 mg/kg/day prednisone equivalents. Skin biopsy and prophylactic antibiotics for opportunistic 
infection should be considered. Nivolumab should be withheld for severe (Grade 3) rash and 
permanently discontinued for life-threatening (Grade 4) rash. When dermatitis of ≤Grade 3 
resolves to ≤Grade 1, nivolumab treatment can resume after a corticosteroid taper of ≥1 month. 
Dose modification of TAK-659 during the event will follow the guidelines in Section 9.5.
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9.8.8.9
Immune-Mediated Encephalitis
Immune-mediated encephalitis can occur with nivolumab treatment. If it occurs, nivolumab 
should be withheld in patients with new-onset moderate to severe neurologic signs or symptoms, 
and patients should be evaluated to rule out infectious or other causes of moderate to severe 
neurologic deterioration. Evaluation may include, but is not limited to, consultation with a 
neurologist, brain MRI, and lumbar puncture. If other etiologies are ruled out, corticosteroids 
should be administered at a dose of 1 to 2 mg/kg/day prednisone equivalents for patients with 
immune-mediated encephalitis, followed by corticosteroid tapering. Nivolumab should be 
permanently discontinued for immune-mediated encephalitis.
In addition to the immune-mediate toxicities addressed above, the following clinically significant, 
immune-mediated adverse reactions have occurred in less than 1.0% of patients receiving 
nivolumab as a single agent or in combination with ipilimumab in clinical trials (n=1261): uveitis, 
pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, 
autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic inflammatory 
response syndrome, motor dysfunction, vasculitis, and myasthenic syndrome.
9.8.9
Infusion Reactions
Severe infusion reactions have been reported in less than 1.0% of patients in clinical trials of 
nivolumab as a single agent. Although these reactions have been observed at a low incidence, if 
such a reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, 
arthralgias, hypotension or hypertension, bronchospasm, or other symptoms. 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 [35].
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines as appropriate.
For Grade 1 symptoms: mild reaction; infusion interruption not indicated; intervention not 
indicated. 
Bedside monitoring of the patient should be provided until recovery from symptoms. For future 
infusions, prophylactic premedications such as diphenhydramine 50 mg (or equivalent) and/or 
acetaminophen 325 to 1000 mg should be considered at least 30 minutes before additional 
administrations. 
For Grade 2 symptoms: moderate reaction requires therapy or infusion interruption but responds 
promptly to symptomatic treatment (eg, antihistamines, nonsteroidal anti-inflammatory drugs, 
narcotics, corticosteroids, bronchodilators, IV fluids); prophylactic medications indicated for 
≥24 hours. 
Nivolumab infusion should be stopped. The patient should be given IV infusion normal saline, and 
diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen 325 to 1000 mg should be 
administered. Close bedside monitoring should be provided until symptoms resolve. 
Corticosteroid or bronchodilator therapy may also be administered as appropriate. When 
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symptoms resolve, the infusion can be restarted at 50% of the original infusion rate, which can 
then increase to 100% of the original rate if no further complications ensue after 30 minutes. If 
symptoms recur, nivolumab will not be administered at that visit. Diphenhydramine 50 mg IV 
should be re-administered, and the patient should be closely monitored until symptoms resolve. 
The amount of study drug infused must be recorded on the eCRF. For future infusions, 
prophylactic premedications such as diphenhydramine 50 mg (or equivalent) and/or 
acetaminophen 325 to 1000 mg should be considered at least 30 minutes before additional 
administrations. If necessary, corticosteroids (recommended dose: up to 25 mg of IV 
hydrocortisone or equivalent) may be used. 
For Grade 3 or Grade 4 symptoms: severe reaction, Grade 3: prolonged (ie, not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion); recurrence of 
symptoms following initial improvement; hospitalization indicated for other clinical sequelae (eg, 
renal impairment, pulmonary infiltrates). Grade 4: life threatening; pressor or ventilatory support 
indicated. 
Infusion should be discontinued immediately. The patient should be given IV infusion with normal 
saline, and the following medications are recommended: 1) a bronchodilator such as epinephrine 
0.2 to 1 mg of a 1:1000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 
solution injected slowly for IV administration; and/or 2) diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. Investigators should follow their 
institutional guidelines for the treatment of anaphylaxis. The patient should be closely monitored 
until recovery of symptoms. The patient will be permanently discontinued from the trial. In the 
case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or generalized 
pruritus within 1 week after treatment), symptomatic treatment may be given (eg, oral 
antihistamine, or corticosteroids).
9.9
Blinding and Unblinding
This is an open-label study.
9.10
Description of Investigational Agents
9.10.1 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 mg, 
60 mg, and 100 mg, were formulated. The formulation contains compendial excipients that 
include mannitol, microcrystalline cellulose, hydroxypropyl cellulose, sodium starch glycolate, 
and magnesium stearate. Tablets were coated with Opadry® film coat. 
Additional dose strength tablets, either higher or lower than the currently available tablets (20 mg, 
60 mg, 100 mg) may also be developed to appropriately identify an RP2D that offers the maximal 
benefit balancing safety, tolerability, PK, and potential efficacy.
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9.10.2 Nivolumab
Nivolumab 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 
nivolumab USPI [17] or SmPC [18]. 
9.11
Preparation, Reconstitution, and Dispensation
9.11.1 TAK-659
Detailed instructions for the dispensing of TAK-659 immediate-release film-coated tablets are 
provided in the Pharmacy Manual. 
TAK-659 is an anticancer drug, and as with other potentially toxic compounds, caution should be 
exercised when handling TAK-659.
9.11.2 Nivolumab
Nivolumab 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 
nivolumab USPI [17] or SmPC [18].
9.12
Packaging and Labeling
9.12.1 TAK-659
TAK-659 20 mg, 60 mg, 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. 
9.12.2 Nivolumab
Nivolumab will be supplied to the site from commercial sources. Please refer to the most recent 
nivolumab USPI [17] or SmPC [18]. 
9.13
Storage, Handling, and Accountability
9.13.1 TAK-659
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. Please refer to the Pharmacy Manual for additional information. The TAK-659 
tablets must be used before the retest date that is 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 
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site and patients. Drug supply must be kept in an appropriate, limited access, secure place until it is 
dispensed to the enrolled patients.
A drug dispensing log, including records of drug received from the sponsor and drug dispensed to 
the patients, will be provided and kept at the study site. Storage area temperature conditions must 
be monitored and recorded daily. 
Because TAK-659 is an investigational agent, it should be handled with due care. In the case of 
broken tablets, raising dust should be avoided during the clean-up operation. Damaged tablets may 
be harmful by inhalation, ingestion, or skin and/or eye contact. 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 
dosing compliance of TAK-659. Patients will be instructed to return any unused study drug in the 
original packaging along with their completed diary cards at the appropriate visits.
9.13.2 Nivolumab
Nivolumab should be stored according to instructions provided in the manufacturer’s USPI [17] or 
SmPC [18].
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10.0
STUDY CONDUCT
This trial will be conducted in compliance with the protocol, Good Clinical Practice (GCP), 
applicable regulatory requirements, and International Council for Harmonisation (ICH) 
guidelines.
10.1
Study Personnel and Organizations
The contact information for the Millennium 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.
10.2
Arrangements for Recruitment of Patients
Recruitment and enrollment strategies for this study may include recruitment from the 
investigator’s local practice or referrals from other physicians. If advertisements become part of 
the recruitment strategy, they will be reviewed by the institutional review board 
(IRB)/independent ethics committee (IEC). It is not envisioned that prisoners (or other populations 
that might be subject to coercion or exploitation) will be enrolled into this study.
10.3
Treatment Group Assignments
This is a phase 1 study that incorporates a dose escalation phase and a dose expansion phase at the 
MTD/RP2D. In the dose escalation phase, the patient population will consist of all-comer patients 
with advanced solid tumors for whom 1 or more prior lines of therapy have failed and who have no 
effective therapeutic options available based on investigator assessment. The dose expansion 
phase will include 3 cohorts: 1) patients with metastatic TNBC who have had ≥1 prior line of 
chemotherapy; 2) patients with locally advanced or metastatic NSCLC that has progressed on or 
after a prior platinum-based chemotherapy; and 3) patients with locally advanced or metastatic 
HNSCC that has progressed or recurred within 6 months of the last platinum-based chemotherapy. 
Thirty response-evaluable patients will be enrolled in each expansion cohort. Each expansion 
cohort will include 24 patients who are naïve to anti-PD-1/anti-PD-L1 therapy and 6 patients who 
are relapsed/refractory to prior anti-PD-1/anti-PD-L1 therapy. Ten response-evaluable patients in 
each cohort will receive 2 weeks of single-agent TAK-659 at its RP2D before starting combination 
therapy and will provide serial tumor biopsies during this period; these patients can be either naïve 
to or relapsed/refractory to anti-PD1/anti-PDL1 therapy. After completion of 2 weeks of 
single-agent TAK-659, these patients will receive TAK-659 at its RP2D in combination with 
nivolumab from Week 3 onward. Twenty response-evaluable patients in each cohort will receive 
TAK-659 at its RP2D in combination with nivolumab, from Day 1 Week 1. 
10.4
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 
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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) 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 timing of assessments. Additional details are 
provided as necessary in the sections that follow.
10.4.1 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.
Informed consent may be captured before the Screening period (ie, 28 days before Cycle 1 Day 1).
10.4.2 Patient Demographics
The date of birth, race, ethnicity, and sex of the patient are to be recorded during Screening.
10.4.3 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 will include a description of prior therapies for it. In addition, concomitant 
medications will be recorded as specified in Section 10.4.9. During dose expansion, medical 
history will also include baseline disease characteristics such as staging, risk/prognostic index, and 
other individual prognostic evaluations. 
10.4.4 Physical Examination
A physical examination (PE) will be conducted per standard of care and will include a neurological 
examination at the times specified in the Schedule of Events (Appendix A). During dose 
escalation, complete PEs will be performed at Screening, Day 1 of each cycle of treatment, and 
EOT. Symptom- or finding-directed PEs will be performed at Day 8, 15, and 22 of Cycle 1 and 
Day 15 of Cycle 2. During dose expansion, complete PEs will be performed at Screening only, and 
post-Screening PEs will be symptom- or finding-directed PEs.
10.4.5 Patient Height and Weight
Height will be measured only during Screening (within 28 days before the first dose of TAK-659).
Weight will be measured during the times specified in the Schedule of Events (Appendix A).
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10.4.6 Vital Signs
Vital sign measurements include diastolic and systolic blood pressure, heart rate, and temperature, 
and will be assessed as specified in the Schedule of Events (Appendix A). Blood pressure should 
be determined with the patient in a seated position after the patient has been sitting quietly for 
approximately 5 minutes. Oxygen saturation will also be measured when vital signs are taken.
Pulse oximetry should be obtained before each dose of nivolumab and any time a patient has any 
new or worsening respiratory symptoms. A reading at rest and on exertion should be obtained at 
each time point. The extent of the exertion should be based on the judgment of the investigator but 
should remain consistent for each individual patient throughout the study. If the patient’s status 
changes, the investigator can alter the extent of exertion per their medical judgment. If a patient 
shows changes on pulse oximetry or other pulmonary-related signs (hypoxia, fever) or symptoms 
(dyspnea, cough, fever) consistent with possible pulmonary AEs, the patient should be 
immediately evaluated to rule out pulmonary toxicity. 
10.4.7 ECOG Performance Status
ECOG performance status is to be assessed at the times specified in the Schedule of Events 
(Appendix A).
10.4.8 ECG
A 12-lead singlet ECG will be performed and interpreted locally at the time points specified in the 
Schedule of Events (Appendix A). The ECG schedule is more intensive for patients enrolled in the 
dose escalation cohorts. 
All scheduled ECGs should be performed predose, unless otherwise specified in Table A, and after 
the patient has rested quietly for at least 5 minutes in a supine position. When the timing of a PK or 
safety laboratory blood sample coincides with the timing of ECG measurements, the ECG will be 
completed before the 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 or 
Bazett corrected QT interval [QTcB]) 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 with medication and/or correction of electrolyte abnormalities, and a 
repeat ECG meets eligibility requirements, the patient may enroll in the study upon review and 
agreement by the sponsor’s clinician. 
Following initiation of treatment, if a QTc value is confirmed by a qualified reader as >500 msec 
or >60 msec elevated from baseline for any ECG, the following will occur: 

The sponsor’s clinician will be promptly notified.
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
Study treatment should be held, and an evaluation should be conducted to correct other 
possible causes (eg, electrolyte disturbance, concomitant medication).

A formal consult by a cardiologist should be considered. Additional ECGs may be performed 
at intervals that the treating physician deems clinically appropriate until repeated QTc 
measurements 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 will be agreed to by the investigator and the 
sponsor’s clinician on a case-by-case basis. 
The ECGs performed should be reviewed by the investigator or delegate before the patient leaves 
the clinic on visit days.
10.4.9 Concomitant Medications and Procedures
Concomitant medications and procedures will be recorded in the eCRF from the time of signing of 
the ICF through 28 days after the last dose of study drug. However, if a patient experiences 
immune-mediated toxicities that either result in discontinuation of nivolumab or both study 
treatments or occur during the 28-day AE follow-up period (including immune-mediated 
pneumonitis, colitis, hepatitis, endocriopathies, nephritis, rash, and encephalitis as described in the 
nivolumab USPI [17]), they will be followed to resolution or stabilization, the start of alternative 
therapy, or a minimum of 100 days after last dose of study treatment, whichever occurs first. 
During this AE follow-up period, concomitant medications and procedures should also be 
collected.
See Section 9.6 for a list of medications and procedures that should be avoided during the study 
unless otherwise specified. 
10.4.10 AEs
Monitoring of AEs, serious and nonserious, will be conducted throughout the study as specified in 
the Schedule of Events (Appendix A). Refer to Section 11.0 for details regarding definitions, 
documentation, and reporting of pretreatment events (PTEs), AEs, and SAEs.
10.4.11
Enrollment
A patient is considered to be enrolled in the study when the first dose of study drug has been 
administered.
Procedures for completing enrollment information are described in the Study Manual.
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10.4.12
Clinical Laboratory Evaluations
Clinical laboratory evaluations will be performed locally. Handling and shipment of clinical 
laboratory samples will be outlined in the Study and Laboratory Manuals. Clinical laboratory 
evaluations will be performed as outlined in the following sections.
10.4.12.1
Clinical Chemistry, Hematology, and Urinalysis
Blood samples for analysis of the clinical chemistry and hematological parameters shown in Table 
10.a and urine samples for analysis of the parameters shown in Table 10.b will be obtained as 
specified in the Schedule of Events (Appendix A). 
Creatinine clearance should be calculated according to the Cockcroft-Gault equation (Appendix
E).
Table 10.a
Clinical Chemistry and Hematology Tests
Hematology
Serum Chemistry
Hematocrit
Hemoglobin
Leukocytes with differential
Neutrophils (ANC)
Platelet (count)
Albumin
Alkaline phosphatase 
(ALP)
Alanine aminotransferase 
(ALT)
Aspartate 
aminotransferase (AST)
Amylase
Bilirubin (total)
Blood urea nitrogen 
(BUN)
Calcium
CO2
Chloride
Creatine phosphokinase 
(CPK)
Creatinine 
γ-glutamyl transferase (GGT)
Glucose
Lactate dehydrogenase (LDH)
Lipase
Magnesium
Phosphate
Potassium
Sodium
Total protein
Cardiac Troponin I and Troponin T (cTnI and 
cTnT)
Urate
Table 10.b
Clinical Urinalysis Tests
Urinalysis
Bilirubin
Glucose
Ketones
Leukocytes
Nitrite
Occult blood
pH
Protein
Specific gravity
Turbidity and color
Urobilinogen
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10.4.12.2
Immune Safety Tests
Blood samples for immune safety tests will be collected at the time points specified in the 
Schedule of Events (Appendix A) and analyzed for the immune safety parameters shown in 
Table 10.c. Serum for additional immune safety testing (if needed) will be obtained and sent to the 
study sponsor. Refer to the laboratory manual for details on collecting, processing, storage, and 
shipment of serum samples to the study sponsor.
Table 10.c
Immune Safety Tests
Immune Safety Tests
Adrenocorticotropic hormone 
Antinuclear antibody 
C-reactive protein 
Free T4 level
Rheumatoid factor 
Thyroid-stimulating hormone 
Additional tests may be ordered at the investigator’s discretion in case of abnormal immunologic 
or endocrine findings. Additional endocrine testing may require an endocrinologist consult.
10.4.13 Pregnancy Test
A serum pregnancy test will be performed for women of childbearing potential at Screening. A 
urine or serum pregnancy test will be performed predose on Day 1 of all cycles with negative 
results available before the first dose may be administered. If the serum pregnancy test is
performed within 3 days before the first dose and the result is negative, the urine pregnancy test on 
Cycle 1 Day 1 may be waived.
10.4.14 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 the 
nonclinical toxicology findings with TAK-659 in rats, slit lamp examinations should focus on 
detecting any posttreatment changes in the ocular lens. Examination and photographing of the 
retina will be performed at Baseline but not during the study unless it is clinically indicated. 
Additional eye exams may also be performed, as required. Patients will be carefully monitored for 
eye complaints at each visit and instructed to report visual symptoms as soon as they occur.
10.4.15 Disease Assessment
Patients will undergo CT with contrast or MRI, x-ray, and/or bone scanning as appropriate at 
Screening/Baseline (within 28 days before the first study drug administration), the end of Cycles 2, 
4, and 6 (between Days 22 and 29 [predose]), and every 3 cycles thereafter (ie, Cycle 9, 12, etc) to 
monitor and assess response status using RECIST version 1.1 [1]. Follow-up CT scans will 
encompass the known sites of disease. Disease sites that cannot be adequately imaged by CT may 
be documented by MRI. Target and nontarget measurable lesions will be evaluated at Baseline and 
each subsequent evaluation using an imaging modality consistent with that used at Screening. A 
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confirmatory CT/MRI scan should be performed at approximately 4 weeks from the previous scan 
for all patients with an objective response of PR or better. 

Verification of response: To be assigned a status of CR or PR, changes in tumor measurements 
must be confirmed by consecutive repeat assessments that should be performed no sooner than 
28 days after the criteria for response are first met. For this study, the next scheduled tumor 
assessment can meet this requirement.

Verification of progression: Progression of disease should be verified in cases where 
progression is equivocal. If repeat scans confirm PD, then progression should be declared 
using the date of the initial scan. If repeat scans do not confirm PD, then the patient is 
considered to not have PD.
Note that patients with nonmeasurable tumor lesions are also eligible for enrollment to dose 
escalation. 
When assessing response, special consideration should be given to the tumor response 
characteristics associated with immunotherapy: 
1. Measurable tumor size reduction may take longer treatment duration with immunotherapy than 
with a cytotoxic regimen. 
2. Response to immunotherapy may occur after appearance of PD, as assessed per conventional 
RECIST version 1.1. In particular, small, new lesions may appear in the presence of other 
responsive target lesions (pseudo-progression).
3. Durable SD may represent antitumor activity of immunotherapy.
The sponsor may consider an exploratory independent central review of the study imaging data 
using immune-related RECIST if deemed necessary.
Pseudo-progression has been described during treatment with nivolumab in multiple indications. 
Therefore, discontinuation of study treatment is not recommended unless PD (at least 20% 
increase in tumor burden compared with nadir at any single point during study treatment) has been 
confirmed in 2 consecutive imaging assessment 8 weeks apart or more conveniently at the next 
scheduled imaging time point. However, when the objectively assessed PD per imaging is 
accompanied by rapid clinical deterioration, immediate study drug discontinuation is indicated. 
Refer to Section 10.4.16 for details regarding treatment beyond PD.
In the event of antitumor response, the sponsor may request electronic images of scans performed 
on study to be collected for central storage. Determination of disease status will be based on local 
investigator assessment. The collection and central storage of scans are planned in the event that 
more detailed analysis of imaging data, as determined by the sponsor, is needed. 
Tumor assessments for all patients should continue per protocol even if dosing is interrupted.
10.4.16 Treatment Beyond Disease Progression
Contemporary immunotherapy protocols generally allow patients to continue treatment beyond 
initial radiographic evidence of PD following further investigation, as accumulating data indicates 
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it is possible that some patients treated with immunotherapy may derive clinical benefit beyond 
initial RECIST-defined PD, which may not be captured by radiographic assessments. [36,37]In 
this study, patients treated TAK-659 in combination with nivolumab will be permitted to continue 
treatment beyond initial RECIST 1.1-defined PD if the following criteria are met:
1. Investigator-assessed overall clinical benefit from continued treatment with nivolumab and/or 
TAK-659.
2. Tolerance of study drug(s).
3. Stable performance status.
4. Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of PD (eg, CNS metastases).
5. Patient provides written informed consent before receiving additional nivolumab or TAK-659 
treatment, using an ICF describing any reasonably foreseeable risks or discomforts, or other 
alternative treatment options.
The decision to continue treatment beyond initial RECIST 1.1-defined progression should be 
discussed with the Takeda medical monitor and documented in the study records. Then, the patient 
may remain on the study and continue to receive monitoring according to the protocol-defined 
Schedule of Events.
A radiographic assessment/scan should be performed within 8 weeks of original PD to determine 
whether there has been a decrease in the tumor size, or continued PD. 
For the patients who continue study therapy beyond progression, further progression is defined as 
an additional ≥20% increase in tumor burden volume from time of initial PD. This includes an 
increase in the sum of all target lesions or the development of new measurable lesions.
New lesions are considered measureable at the time of initial progression if the longest diameter is 
at least 10 mm (except for pathological lymph nodes, which must have a short axis of at least 
15 mm). Any new lesion considered non-measureable at the time of initial progression may 
become measureable and is therefore included in the tumor burden volume if the longest diameter 
increases to at least 10 mm (except for pathological lymph nodes, which must have a short axis of 
at least 15 mm).
Treatment should be discontinued permanently upon documentation of further PD. If the patient 
experiences rapid PD (such as global deterioration as perceived by the investigator) before 
radiographic assessment within 8 weeks of original PD, the investigator can discontinue the study 
treatment without objective evidence of disease progression and report it as “symptomatic 
deterioration”.
For statistical analyses, patients who continue study therapy beyond initial RECIST 1.1-defined 
progression will be considered to have investigator-assessed PD at the time of the initial 
progression event.
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10.4.17 Tumor Biopsies
Serial tumor biopsies will be obtained from approximately 10 patients enrolled in each expansion 
cohort at Screening, after 2 weeks of TAK-659 single-agent treatment, and after 6 weeks of the 
combination treatment as indicated in the Schedule of Events (Appendix A). An additional,
optional biopsy sample may be taken upon PD if the patient consents. Patients undergoing tumor 
biopsy procedures must have a platelet count >75,000/mm3 and an aPTT and PT based on site’s 
institutional standard; must not have an ECOG performance status >1; must not be receiving any 
anticoagulant therapy or antiplatelet agents; and must not have any other known coagulation 
abnormalities that would contraindicate the tumor biopsy procedure. The tumor biopsy procedure 
will be performed by core needle, under radiological guidance if indicated, or surgically if the site 
of disease is superficial and palpable or visible. 
 
 
 
 
 
10.4.18
Banked Tumor Specimen Measurements
If archival tumor tissue is available, it will be collected for all patients for biomarker analysis at 
any time during the treatment, except for patients who undergo serial biopsies.
 
 
 
 
10.4.19
Analysis of PBMCs
Blood samples will be collected from all patients enrolled in the expansion phase of the study as 
indicated in the Schedule of Events (Appendix A) for immune cell profiling to investigate the 
pharmacodynamic effect of TAK-659 as a single agent and in combination with nivolumab.
10.4.20
Cytokine/Chemokine Measurements
Blood samples will be collected from all patients enrolled in the expansion phase of the study as 
indicated in the Schedule of Events (Appendix A) for analysis of cytokines and chemokines. 
Serum will be extracted from blood samples and subjected to analysis of a panel of cytokines and 
chemokines using a multiplex platform.
10.4.21
Analysis of ctDNA
Blood samples will be collected from all patients enrolled in the expansion phase of study as 
indicated in the Schedule of Events (Appendix A), and plasma will be extracted to obtain ctDNA. 
Changes in the amount of purified ctDNA may be quantified and monitored during the course of 
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treatment. In addition, ctDNA may be subjected to analysis of mutations using an appropriate 
platform such as next-generation sequencing.
10.4.22 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 nivolumab concentrations if an 
investigation into the effect of TAK-659 co-administration on nivolumab PK is warranted based 
on emerging study findings. Details on the collection, storage, processing, handling, and shipping 
of the PK samples are provided in the Laboratory Manual.
Dose Escalation Cohorts
Blood samples for determination of TAK-659 plasma concentrations will be obtained 
during Cycle 1 on Days 1, 2, 15, and 16 at the times indicated in Table A. For clinic visits 
where predose PK samples are scheduled, patients will be instructed to refrain from taking 
their TAK-659 dose at home before the clinic visit. 
The dates and exact times of TAK-659 dosing and PK sample collection will be recorded in 
the eCRF on days of PK sample collection (Days 1, 2, 15, and 16). In addition, the dates and 
exact times of TAK-659 dosing (from patient diaries) will be recorded in the eCRF for the 
2 doses administered before the day of PK sample collection. 
Dose Expansion Cohorts
Blood samples for determination of TAK-659 plasma concentrations will be obtained 
during Cycles 1 through 4 at the times indicated in Table B. For clinic visits where predose 
samples are scheduled, patients should be instructed to refrain from taking their TAK-659 
dose at home before the clinic visit. For the Cycle 1 Day 8 visits, patients should be 
instructed to take their TAK-659 dose at home before the clinic visit; PK samples can be 
collected at any time during this clinic visit. A distribution of clinic visit times during the 
day across patients is to be encouraged to provide a range of postdose sampling times across 
the study population.
The dates and exact times of TAK-659 dosing and PK sample collection will be recorded in 
the eCRF on days of PK sample collection. In addition, the dates and exact times of
TAK-659 dosing (from patient diaries) will be recorded in the eCRF for the 2 doses 
administered before the day of PK sample collection. 
For both the dose escalation and dose expansion cohorts, the timing of blood sampling for plasma 
PK may be changed if emerging data indicate that an alteration in the sampling scheme is needed 
for optimal characterization of TAK-659 PK. However, the number of PK samples collected and 
the volume of blood drawn for these samples will not increase.
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10.4.23
DNA Measurements 
10.5
Completion of Treatment
Patients will be treated until PD, occurrence of unacceptable toxicities, withdrawal due to other 
reasons, or the study is terminated by the sponsor. Study treatment can continue beyond initial 
RECIST 1.1 progression as specified in Section 10.4.16.
10.6
Completion of Study
Patients will be considered to have completed the study if:
!
They are followed until death before the end of the survival follow-up window (up to 
12 months after discontinuation of study drug for any reason).
!
They remain on study treatment free of PD at the close of the study at least 1 year after their 
first dose of study treatment. 
!
They continue on to the follow-up for survival after discontinuation of the study drug and reach 
the end of the 12-month OS follow-up window.
!
They discontinue study treatment while in CR and continue on to the follow-up for progression 
and either experience PD before the end of the 12-month follow-up period or reach the end of 
the follow-up period.
!
The sponsor terminates the study.
10.7
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) or DLT-like toxicity (during 
expansion) during the first cycle, and patients with other drug-related AEs that require study 
drug discontinuation per dose modification guidelines in Section 9.5 and the current USPI [17]
and SmPC [18] for nivolumab. Discontinuation of treatment occurs only when both study 
drugs are required to be discontinued due to AEs. 
!
Protocol violation.
!
PD: as noted previously, PD per RECIST 1.1 should be confirmed in 2 subsequent scans 
8 weeks apart before treatment discontinuation is considered unless there are clear signs of 
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rapid clinical progression. In addition, in rare situations, patients with confirmed PD may 
remain on study, after discussion between the investigator and the sponsor clinician, if it is felt 
that they are deriving a clinical benefit from doing so.

Symptomatic deterioration (at investigator’s discretion). 

Unsatisfactory therapeutic response. 

Study terminated by sponsor.

Withdrawal by patient.

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. During the expansion phase, patients who do not meet the 
response-evaluable criteria will be replaced.
Once study drug has been discontinued, all study procedures outlined for the EOT visit will be 
completed as specified in the Schedule of Events (Appendix A). The primary reason for study drug 
discontinuation will be recorded on the eCRF.
10.8
Withdrawal of Patients From Study
A patient may be withdrawn from the study for any of the following reasons:

AE.

Protocol violation.

PD. 

Symptomatic deterioration (at investigator’s discretion).

Unsatisfactory therapeutic response. 

Study terminated by sponsor.

Withdrawal by patient.

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.
10.9
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 
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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 pharmacodynamic) assessments as specified in the Schedule of 
Events (Appendix A) 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 Millennium 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.
10.10 Posttreatment Follow-up Assessments (PFS and OS) 
Patients who stop treatment for any reason other than PD will continue to have PFS follow-up 
visits. The PFS follow-up visit should be conducted at the site every 2 months (up to 6 months 
after the first dose of study drug) or 3 months from the last dose of study drug until PD for a 
maximum of 6 months from the date of the last dose of study drug. After the occurrence of PD, 
patients will continue to have OS follow-up visits. The OS information will be collected every 2 
months until 12 months from the date of the last dose of study drug. Patients who discontinue the 
study, regardless of reasons for discontinuation, will be followed for survival every 2 months until 
death, loss to follow-up, or withdrawal of consent to further follow-up for up to 12 months after 
discontinuation of the study drug.
Survivor information may be collected by methods that include, but are not limited to, telephone, 
e-mail, mail, or retrieval from online or other databases (eg, social security indexes). In addition, 
the start of another anticancer therapy will be collected.
NOTE: Related SAEs must be reported to the Millennium Department of Pharmacovigilance or 
designee. This includes deaths that the investigator considers related to study drug that occur 
during the posttreatment follow-up. Refer to Section 11.0 for details regarding definitions, 
documentation, and reporting of SAEs.
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11.0
ADVERSE EVENTS
11.1
Definitions
11.1.1 PTE Definition
A PTE is any untoward medical occurrence in a patient or subject who has signed informed 
consent to participate in a study but before administration of any study medication; it does not 
necessarily have to have a causal relationship with study participation.
11.1.2 AE Definition
AE means any untoward medical occurrence in a patient or subject administered a pharmaceutical 
product; the untoward medical occurrence does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product whether or not it is related to the medicinal product. This includes any 
newly occurring event, or a previous condition that has increased in severity or frequency since the 
administration of study drug.
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is considered 
by the investigator to be a clinically significant change from baseline.
11.1.3 SAE Definition
SAE means any untoward medical occurrence that at any dose:

Results in death.

Is life-threatening (refers to an AE in which the patient was at risk of death at the time of the 
event. It does not refer to an event which hypothetically might have caused death if it were 
more severe).

Requires inpatient hospitalization or prolongation of an existing hospitalization (see 
clarification in the paragraph in Section 11.2 on planned hospitalizations).

Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions.)

Is a congenital anomaly/birth defect.

Is a medically important event. This refers to an AE that may not result in death, be 
immediately life threatening, or require hospitalization, but may be considered serious when, 
based on appropriate medical judgment, may jeopardize the patient, require medical or 
surgical intervention to prevent 1 of the outcomes listed above, or involves suspected 
transmission via a medicinal product of an infectious agent. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
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 [35]. Clarification should be made between an 
SAE and an AE that is considered severe in intensity (Grade 3 or 4) because the terms serious and 
severe are NOT synonymous. The general term severe is often used to describe the intensity 
(severity) of a specific event; the event itself, however, may be of relatively minor medical 
significance (such as a Grade 3 headache). This is NOT the same as serious, which is based on 
patient/event outcome or action criteria described above, and is usually associated with events that 
pose a threat to a patient’s life or ability to function. A severe AE (Grade 3 or 4) does not 
necessarily need to be considered serious. For example, a white blood cell count of 1000/mm3 to 
less than 2000 is considered Grade 3 (severe) but may not be considered serious. Seriousness (not 
intensity) serves as a guide for defining regulatory reporting obligations.
11.2
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 11.3 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 11.1) must be reported (see 
Section 11.3 for the period of observation) by the investigator to the Takeda Global 
Pharmacovigilance department or designee (contact information provided below). This should be 
done by faxing the SAE Form within 24 hours after becoming aware of the event. The SAE Form, 
created specifically by Takeda, will be provided to each clinical study site. A sample of the SAE 
Form may be found in the Study Manual. Follow-up information on the SAE or serious PTE may 
be requested by Takeda. SAE report information must be consistent with the data provided on the 
eCRF.
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SAE Reporting Contact Information
Cognizant
US and Canada
Toll-Free Fax #: 1-800-963-6290
E-mail: takedaoncocases@cognizant.com
All Other Countries (Rest of World)
Fax #: 1-202-315-3560
E-mail: takedaoncocases@cognizant.com
Planned hospital admissions or surgical procedures for an illness or disease that existed before the 
patient was enrolled in the trial are not to be considered AEs unless the condition deteriorated in an 
unexpected manner during the trial (eg, surgery was performed earlier or later than planned).
For both serious and nonserious AEs, the investigator must determine both the intensity of the 
event and the relationship of the event to study drug administration. For serious PTEs, the 
investigator must determine both the intensity of the event and the relationship of the event to 
study procedures.
Intensity for each AE, including any lab abnormality, will be determined using the NCI CTCAE 
version 4.03, effective 14 June 2010 [35]. 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?
11.3
Monitoring of AEs and Period of Observation
AEs, both nonserious and serious, will be monitored throughout the study as follows: 

AEs will be reported from signing of the ICF through 28 days after administration of the last 
dose of study drug and recorded in the eCRFs. However, immune-mediated toxicities that 
either result in discontinuation of nivolumab or both study treatments or occur during the 
28-day AE follow-up period (including immune-mediated pneumonitis, colitis, hepatitis, 
endocrinopathies, nephritis, rash, and encephalitis as described in nivolumab USPI) will be 
followed to resolution or stabilization, the start of alternative therapy, or a minimum of 
100 days after last dose of study treatment, whichever occurs first.

Serious PTEs will be reported to the Takeda Global Pharmacovigilance department or 
designee from the time of the signing of the ICF up to the first dose of study drug and will be 
recorded in the eCRF.

Related and unrelated treatment-emergent SAEs will be reported to the Takeda Global 
Pharmacovigilance department or designee from the first dose of study drug through 28 days 
after administration of the last dose of study drug and recorded in the eCRF. After this period, 
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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).
11.4
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 
also must be contacted immediately by faxing a completed Pregnancy Form to the Takeda Global 
Pharmacovigilance department or designee (see Section 11.2). 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 11.2). Every effort 
should be made to follow the pregnancy for the final pregnancy outcome.
11.5
Procedures for Reporting Product Complaints
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 contact the Medical 
Information Call Center/Dohmen Life Science Services and report the complaint. The contact 
information is as follows:
Medical Information Center:
Dohmen Life Science Services
Phone:
1-844-ONC-TDKA (1-844-662-8532)
Fax:
1-800-881-6092
E-mail:
GlobalOncologyMedinfo@takeda.com
Hours:
Monday-Friday, 9 AM–7 PM, ET
Whenever possible, the associated product should be maintained in accordance with the label 
instructions pending further guidance from a Millennium Quality representative.
Product complaints in and of themselves are not AEs. If a product complaint results in an SAE, an 
SAE form should be completed and sent to Cognizant (refer to Section 11.2)
11.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, including the European 
Medicines Agency, investigators and IRBs or IECs, as applicable, in accordance with national 
regulations in the countries where the study is conducted. Relative to the first awareness of the 
event by/or further provision to the sponsor or sponsor’s designee, SUSARs will be submitted to 
the regulatory authorities as an expedited report within 7 calendar days for fatal and 
life-threatening events and 15 calendar days for other serious events, unless otherwise required by 
national regulations. The sponsor will also prepare an expedited report for other safety issues 
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where these might materially alter the current benefit-risk assessment of an investigational 
medicinal product or that would be sufficient to consider changes in the investigational medicinal 
product’s administration or in the overall conduct of the trial. The investigational site 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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12.0
STUDY-SPECIFIC COMMITTEES
No steering committee, data safety monitoring committee, or clinical endpoint committee will be 
used in this study.
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13.0
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.
13.1
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.
13.2
Record Retention
The investigator agrees to keep the records stipulated in Section 13.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating patients, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated ICFs, patient authorization forms regarding the use of 
personal health information (if separate from the ICFs), electronic copy of eCRFs, including the 
audit trail, and detailed records of drug disposition to enable evaluations or audits from regulatory 
authorities, the sponsor or its designees. Any source documentation printed on degradable thermal 
sensitive paper should be photocopied by the site and filed with the original in the patient’s chart to 
ensure long term legibility. Furthermore, ICH E6 Section 4.9.5 requires the investigator to retain 
essential documents specified in ICH E6 (Section 8) until at least 2 years after the last approval of 
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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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14.0
STATISTICAL METHODS
14.1
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.
14.1.1 Analysis Sets
The populations used for analysis will include the following:

Safety population: the Safety population is defined as all patients who receive at least 1 dose of 
study drug. Patients will be analyzed according to the actual treatment they received.

Response-Evaluable population: the Response-Evaluable population is defined as patients 
who receive at least 1 dose of study drug, have measurable disease at Baseline, and have at 
least 1 post-Baseline disease assessment.

PK-Evaluable population: the PK-Evaluable population is defined as patients with sufficient 
concentration-time and dosing data to reliably estimate PK parameters. This population will be 
used for analyses of PK parameters.

DLT-Evaluable population: the DLT-Evaluable population is defined as patients who have 
met the minimum treatment and safety evaluation requirements of the study and/or who 
experience a DLT during Cycle 1. The minimum treatment and safety evaluation requirements 
are met if, in Cycle 1, the patient has been treated with TAK-659 for ≥21 days (receiving at 
least 75% of planned doses of TAK-659 in Cycle 1) plus 2 doses of nivolumab, and observed 
for ≥28 days (unless DLT occurs before the end of the 28- to 42-day evaluation period) 
following the dose on Cycle 1 Day 1, and is considered to have sufficient safety data by both 
the sponsor and investigators to conclude that a DLT did not occur.
14.1.2 Analysis of Demographics and Other Baseline Characteristics
Demographics and baseline characteristics will be summarized descriptively, including sex, age, 
race, weight, height, and other parameters as appropriate. No inferential statistics will be carried 
out.
Throughout this study, baseline assessments are defined as those performed at the closest time 
before the start of study drug administration.
14.1.3 Efficacy Analysis
Summary tabulations will be presented by treatment and will display the number of observations, 
mean, standard deviation, median, minimum, and maximum for continuous variables, and the 
number and percentage per category for categorical data. For time to event data, Kaplan-Meier 
survival curves and Kaplan-Meier medians (if estimable) will also be provided. 
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The SAP will be developed and finalized by the sponsor, or its designee, before final database 
lock. The SAP will outline all data handling conventions and specify all statistical methods to be 
used for safety and efficacy analyses. Deviations from the statistical analyses outlined in this 
protocol will be indicated in the SAP; any further modifications will be noted in the final clinical 
study report.
All efficacy analyses will be based on investigator assessments. Any sensitivity analysis will be 
specified in the SAP.
14.1.3.1 Analyses of Primary Efficacy Endpoints
The primary endpoint for efficacy for the dose expansion phase is ORR. A responder is defined as 
a patient who has either CR or PR. ORR will be summarized using the Response-Evaluable 
population, in the following groups:

By expansion cohort.

Within each expansion cohort, by anti-PD1/PD-L1 naïve and anti-PD1/PD-L1 
relapsed/refractory subgroup. 

Across all expansion cohorts in the anti-PF1/PD-L1 relapsed/refractory patients. 
14.1.3.2 Analyses of Secondary Efficacy Endpoints
Disease control rate is the proportion of patients who had CR, PR, or SD in the 
Response-Evaluable population. Duration of response, PFS, and OS will be analyzed by a 
Kaplan-Meier approach using the Safety population. Rate of PD at 6 months is the proportion of 
patients who progressed by 6 months. All secondary efficacy endpoints will be summarized using 
the Response-Evaluable population, in the following groups:

By expansion cohort.

Within each expansion cohort, by anti-PD1/PD-L1 naïve and anti-PD1/PD-L1 
relapsed/refractory subgroup. 

Across all expansion cohorts in the anti-PF1/PD-L1 relapsed/refractory patients.
14.1.4 PK 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 dose escalation cohorts, plasma TAK-659 concentrations will be summarized by time 
postdose and grouped by dose group and dosing cycle and day. Mean and individual plasma 
TAK-659 concentration data will be plotted over time and grouped by dose group and dosing cycle 
and day. 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, Ctrough, AUCτ, CL/F, 
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PTR, and Rac. Estimation of plasma PK parameters of the terminal disposition phase, such as t1/2
and area under the plasma concentration-time curve from time zero to infinity (AUCinf), will
depend on an adequate representation of the terminal disposition phase during the period of PK 
sampling. Plasma PK parameters of TAK-659 will be summarized using descriptive statistics by 
dose group and by dosing cycle and day. 
For dose expansion cohorts, plasma concentrations of TAK-659 will be listed by cohort, nominal 
and actual time point, and dosing cycle and day.
TAK-659 plasma PK data from dose escalation and expansion cohorts, along with data from other 
studies, may contribute to population PK analyses and exposure-response analyses for 
pharmacodynamic, safety, and efficacy endpoints. If applicable, the specifics of the population PK 
and exposure-response analyses will be described in separate analysis plans, and results will be 
reported separately from the clinical study report. 
14.1.5 Pharmacodynamic Analysis
Individual data at each time point will be summarized in a table describing changes in the course of 
treatment per patient. Individual and summary data also will be presented graphically for each 
marker. If sufficient data are generated, data may be summarized by cohort or by indication as 
appropriate. Descriptive statistics, graphical methods, and statistical modeling will be used as 
appropriate to explore the relationship between response and the levels of various biomarkers. In 
addition, the relationship between PK and pharmacodynamics changes may be evaluated as 
permitted by the data.
14.1.6 Biomarker Analyses
14.1.7 Pharmacogenomic Analyses
14.1.8 Safety Analyses
The Safety population will be used for all safety analyses.
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Safety will be evaluated by the incidence of AEs, severity and type of AEs, and by changes from 
baseline in the patient’s vital signs, weight, ECOG performance status, ECG results, and clinical 
laboratory results. Exposure to study drug and reasons for discontinuation will be tabulated.
All treatment-emergent AEs (TEAEs) will be tabulated. A TEAE for tabulation is defined as: 
1) any AE that occurs after administration of the first dose of study drug and up through 30 days 
after the last dose of study drug; 2) any event that is considered drug related regardless of the start 
date of the event; or 3) any event that is present at the Baseline assessment but worsens in severity 
after the assessment or is subsequently considered drug related by the investigator. AEs will be 
tabulated according to the MedDRA by system organ class, high-level term, and preferred term, 
and will include the following categories:

TEAEs.

Grade 3, 4, and 5 TEAEs (presented by grade and overall).

Drug-related TEAEs.

Drug-related, Grade 3, 4, and 5 TEAEs (presented by grade and overall).

TEAEs resulting in study drug discontinuation.

The most commonly reported TEAEs (ie, those events reported by 10% of all patients).

Treatment-emergent SAEs.

Nonserious TEAEs.
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 changes from baseline) of vital signs and weight 
over time will be tabulated by scheduled time point.
Shift tables for laboratory parameters will be generated based on changes in NCI CTCAE grade 
from baseline to the worst postbaseline value. Graphical displays of key safety parameters, such as 
scatter plots of baseline versus worst postbaseline values, may be used to understand the safety 
profile of TAK-659 in combination with nivolumab.
Descriptive statistics for the actual values and changes from baseline ECGs will be tabulated by 
time point, including any unscheduled measurements.
All concomitant medications collected from Screening through the study period will be classified 
to preferred terms according to the WHO drug dictionary. 
Additional safety analyses may be performed to most clearly enumerate rates of toxicities and 
further define the safety profile of TAK-659 plus nivolumab.
14.2
Interim Analysis and Criteria for Early Termination
No interim analysis is planned.
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14.3
Determination of Sample Size
During the dose escalation phase, dose escalation will be conducted according to a standard 3+3 
dose escalation schema, and approximately 12 to 18 DLT-evaluable patients will be enrolled 
(including a possible 3 to 6 patients in the nivolumab fixed dose evaluation cohort). The 
MTD/RP2D cohort will have at least 6 patients.
The sample sizes for each expansion cohort are estimated using a 1-sided exact binomial test at a 
significance level of =0.1 with a power of 80%. Each cohort uses a null hypothesis of response 
rate ≤20%, versus an alternative hypothesis of response rate ≥40% for patients who are naïve to
anti-PD/PD-L1 and any other immune-directed antitumor therapies. Therefore, approximately 
24 response-evaluable patients for each cohort will be needed. In addition, 6 response-evaluable 
patients with prior exposure to a PD-1 or PD-L1 inhibitor will be enrolled in each expansion 
cohort. In total, 30 response-evaluable patients for each cohort and 90 response-evaluable patients 
in total (~108 patients based on 15% drop out) will be needed.
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15.0
QUALITY CONTROL AND QUALITY ASSURANCE
15.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or its 
designee (CRO) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or designee, 
including but not limited to the Investigator’s Binder, study medication, patient medical records, 
informed consent documentation, documentation of patient authorization to use personal health 
information (if separate from the ICFs), and review of eCRFs and associated source documents. It 
is important that the investigator and other study personnel are available during the monitoring 
visits and that sufficient time is devoted to the process.
15.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study patients. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
The site should document all protocol deviations in the patient’s source documents. In the event of 
a significant deviation, the site should notify the sponsor or its designee (and IRB or EC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the patient, or confound interpretation of primary study 
assessment. A Protocol Deviation Form should be completed by the site and signed by the sponsor 
or designee for any significant deviation from the protocol.
15.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the FDA, the United Kingdom Medicines and Healthcare 
products Regulatory Agency, the Pharmaceuticals and Medical Devices Agency of Japan). If the 
study site is contacted for an inspection by a regulatory body, the sponsor should be notified 
immediately. The investigator and institution guarantee access for quality assurance auditors to all 
study documents as described in Section 15.1.
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16.0
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.
16.1
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 [drug/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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16.2
Patient Information, Informed Consent, and Patient Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The ICF, patient authorization form (if applicable), and patient 
information sheet (if applicable) describe the planned and permitted uses, transfers, and 
disclosures of the patient’s personal and personal health information for purposes of conducting 
the study. The ICF and the patient information sheet (if applicable) further explain the nature of the 
study, its objectives, and potential risks and benefits, as well as the date informed consent is given. 
The ICF will detail the requirements of the participant and the fact that he or she is free to 
withdraw at any time without giving a reason and without prejudice to his or her further medical 
care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the ICF 
and if applicable, the patient authorization form. The ICF, patient authorization form (if 
applicable), and patient information sheet (if applicable) must be approved by both the IRB or IEC 
and the sponsor prior to use.
The ICF, patient authorization form (if applicable), and patient information sheet (if applicable) 
must be written in a language fully comprehensible to the prospective patient. It is the 
responsibility of the investigator to explain the detailed elements of the ICF, patient authorization 
form (if applicable), and patient information sheet (if applicable) to the patient. Information should 
be given in both oral and written form whenever possible and in the manner deemed appropriate by 
the IRB or IEC. 
The patient must be given ample opportunity to: (1) inquire about details of the study and 
(2) decide whether or not to participate in the study. If the patient determines he or she will 
participate in the study, then the ICF and patient authorization form (if applicable) must be signed 
and dated by the patient at the time of consent and prior to the patient entering into the study. 
Patients should be instructed to sign using their legal names, not nicknames, using blue or black 
ballpoint ink. The investigator must also sign and date the ICF and patient authorization (if 
applicable) at the time of consent and prior to patient entering into the study; however, the sponsor 
may allow a designee of the investigator to sign to the extent permitted by applicable law.
Once signed, the original ICF, patient authorization form (if applicable), and patient information 
sheet (if applicable) will be stored in the investigator’s site file. The investigator must document 
the date the patient signs the informed consent in the patient’s medical record. Copies of the signed 
ICF, the signed patient authorization form (if applicable), and patient information sheet (if 
applicable) shall be given to the patient.
All revised ICFs must be reviewed and signed by relevant patients in the same manner as the 
original informed consent. The date the revised consent was obtained should be recorded in the 
patient’s medical record, and the patient should receive a copy of the revised ICF.
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16.3
Patient Confidentiality
The sponsor and designees affirm and uphold the principle of the patient’s right to protection 
against invasion of privacy. Throughout this study, a patient’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited patient attributes, such as sex, age, or date 
of birth, and patient initials may be used to verify the patient and accuracy of the patient’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the patient’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a patient’s study participation, 
and autopsy reports. Access to a patient’s original medical records requires the specific 
authorization of the patient as part of the informed consent process (see Section 16.2).
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).
16.4
Publication, Disclosure, and Clinical Trial Registration Policy
16.4.1 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 discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail.
16.4.2 Clinical Trial Registration
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum, register 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
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contact information, along with investigator’s city, state (for American 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. 
16.4.3 Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws, and/or regulations.
16.5
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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17.0
REFERENCES
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evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 
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2. IARC. The global and regional burden of cancer. In: Stewart BW, Wild CP, editors. World 
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3. Boyle P. Triple-negative breast cancer: epidemiological considerations and recommendations. 
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4. Solin LJ, Hwang WT, Vapiwala N. Outcome after breast conservation treatment with radiation 
for women with triple-negative early-stage invasive breast carcinoma. Clinical Breast Cancer 
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Tilanus-Linthorst MM, Bartels CC, et al. Prophylactic mastectomy in BRCA1/2 mutation 
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Clin Oncol 2006;24(36):5652-7.
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breast cancer after breast-conserving surgery and radiation. Cancer 2009;115(5):946-51.
8. Jones SE, Savin MA, Holmes FA, O'Shaughnessy JA, Blum JL, Vukelja S, et al. Phase III trial 
comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as 
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cancer with currently approved agents. Ann Oncol 2012;23 Suppl 6:vi46-51.
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Pharmaceuticals (Basel) 2012;5(11):1236-64.
11. Joseph AW, D'Souza G. Epidemiology of human papillomavirus-related head and neck 
cancer. Otolaryngol Clin North Am 2012;45(4):739-64.
12. Parfenov M, Pedamallu CS, Gehlenborg N, Freeman SS, Danilova L, Bristow CA, et al. 
Characterization of HPV and host genome interactions in primary head and neck cancers. Proc 
Natl Acad Sci U S A 2014;111(43):15544-9.
13. O'Rorke MA, Ellison MV, Murray LJ, Moran M, James J, Anderson LA. Human 
papillomavirus related head and neck cancer survival: a systematic review and meta-analysis. 
Oral Oncol 2012;48(12):1191-201.
14. Rousseau A, Badoual C. Head and Neck: Squamous cell carcinoma: an overview. Atlas of 
Genetics and Cytogenetics in Oncology and Haematology 2011;16(2):145-55.
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15. Keating GM. Nivolumab: A Review in Advanced Squamous Non-Small Cell Lung Cancer. 
Drugs 2015;75(16):1925-34.
16. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 
2012;12(4):252-64.
17. OPDIVO (nivolumab) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb, 2016.
18. OPDIVO 10 mg/mL concentrate for solution for infusion (nivolumab) [Summary of Product 
Characteristics].
19. Luangdilok S, Box C, Patterson L, Court W, Harrington K, Pitkin L, et al. Syk tyrosine kinase 
is linked to cell motility and progression in squamous cell carcinomas of the head and neck. 
Cancer Res 2007;67(16):7907-16.
20. Dawson CW, Port RJ, Young LS. The role of the EBV-encoded latent membrane proteins 
LMP1 and LMP2 in the pathogenesis of nasopharyngeal carcinoma (NPC). Semin Cancer Biol 
2012;22(2):144-53.
21. Cancer Genome Atlas Research N. Comprehensive molecular characterization of gastric 
adenocarcinoma. Nature 2014;513(7517):202-9.
22. Zhang J, Benavente CA, McEvoy J, Flores-Otero J, Ding L, Chen X, et al. A novel 
retinoblastoma therapy from genomic and epigenetic analyses. Nature 
2012;481(7381):329-34.
23. Katz E, Dubois-Marshall S, Sims AH, Faratian D, Li J, Smith ES, et al. A gene on the HER2 
amplicon, C35, is an oncogene in breast cancer whose actions are prevented by inhibition of 
Syk. Br J Cancer 2010;103(3):401-10.
24. Muellner MK, Mair B, Ibrahim Y, Kerzendorfer C, Lechtermann H, Trefzer C, et al. Targeting 
a cell state common to triple-negative breast cancers. Mol Syst Biol 2015;11(1):789.
25. Lechner MG, Megiel C, Russell SM, Bingham B, Arger N, Woo T, et al. Functional 
characterization of human Cd33+ and Cd11b+ myeloid-derived suppressor cell subsets 
induced from peripheral blood mononuclear cells co-cultured with a diverse set of human 
tumor cell lines. J Transl Med 2011;9:90.
26. Cotechini T, Medler TR, Coussens LM. Myeloid Cells as Targets for Therapy in Solid 
Tumors. Cancer J 2015;21(4):343-50.
27. DiLillo DJ, Yanaba K, Tedder TF. B cells are required for optimal CD4+ and CD8+ T cell 
tumor immunity: therapeutic B cell depletion enhances B16 melanoma growth in mice. J 
Immunol 2010;184(7):4006-16.
28. Schalper KA, Brown J, Carvajal-Hausdorf D, McLaughlin J, Velcheti V, Syrigos KN, et al. 
Objective measurement and clinical significance of TILs in non-small cell lung cancer. J Natl 
Cancer Inst 2015;107(3).
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29. Herbst RS, Baas P, Kim DW, Felip E, Perez-Gracia JL, Han JY, et al. Pembrolizumab versus 
docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer 
(KEYNOTE-010): a randomised controlled trial. Lancet 2015.
30. Gentles AJ, Newman AM, Liu CL, Bratman SV, Feng W, Kim D, et al. The prognostic 
landscape of genes and infiltrating immune cells across human cancers. Nat Med 
2015;21(8):938-45.
31. Segal NH, Parsons DW, Peggs KS, Velculescu V, Kinzler KW, Vogelstein B, et al. Epitope 
landscape in breast and colorectal cancer. Cancer Res 2008;68(3):889-92.
32. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 Blockade in 
Tumors with Mismatch-Repair Deficiency. N Engl J Med 2015;372(26):2509-20.
33. Gebhardt C, Sevko A, Jiang H, Lichtenberger R, Reith M, Tarnanidis K, et al. Myeloid Cells 
and Related Chronic Inflammatory Factors as Novel Predictive Markers in Melanoma 
Treatment with Ipilimumab. Clin Cancer Res 2015;21(24):5453-9.
34. Gray ES RH, Reid AL, Boyd SC, Pereira MR, et al. Circulating tumor DNA to monitor 
treatment response and detect acquired resistance in patients with metastatic melanoma. 
Oncotarget 2015.
35. 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.
36. Weinstock C, Maher V, Zhang L, XU J, Tang S, Sridhara R, et al. FDA analysis of treatment 
beyond progression disease (PD) in patients with metastatic renal cell carcinoma (mRCC) 
treated with nivolumab vs. everolimus. J Clin Oncol (ASCO Annual Meeting Proceedings) 
2016;34(suppl). 4508.
37. Ferris RL, Blumenschein G, Jr., Fayette J, Guigay J, Colevas AD, Licitra L, et al. Nivolumab 
for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med 
2016;375(19):1856-67.
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Appendix A
Schedules of Events
Schedule of Events for Dose Escalation (28-Day Cycle)
Screening 
(a)
Cycle 1
Cycle 2 and Beyond
EOT (b)
(+10 
Days)
Survival
Follow-up
Day 1
Day 2
Day 8
Day 
15
Day 
16
Day 
22
Day 
1
Day 
15
Days 
22-29
PFS (c)
OS (d)
Informed consent (e)
X
Inclusion/exclusion criteria
X
Demographics and disease 
characteristics
X
Complete medical history (f)
X
X
Physical examination (f)
X
X
X
X
X
X
X
X
Height
X
Weight (g)
X
X
X
X
Vital signs (h)
X
X
X
X
X
X
X
X
ECOG performance status
X
X
X
X
12-lead ECG (i) 
X
X
X
X
X
Monitoring of concomitant 
medications and procedures (j)
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 (j)
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
Serious adverse events (k) 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.
Dosing
TAK-659 administration (l)
TAK-659 is dosed PO QD every day.
Nivolumab administration (m)
Nivolumab is dosed every 2 weeks on Days 1 and 15 of each treatment cycle.
Patient diary review (n)
X
X
X
X
X
X
X
X
Footnotes are on last table page.
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Schedule of Events for Dose Escalation (28-Day Cycle) (continued)
Screening 
(a)
Cycle 1
Cycle 2 and Beyond
EOT (b)
(+10 
Days)
Survival
Follow-up
Day 1
Day 2
Day 8
Day 
15
Day 
16
Day 
22
Day 1
Day 
15
Days 
22-29
PFS (c)
OS 
(d)
Imaging/Response Assessments
Tumor assessment for solid 
tumors by RECIST version 
1.1 (CT scan/MRI) (o)
X
X
X (c)
Sample/Laboratory Assessments
Hematology/chemistry (p, q)
X
X
X
X
X
X
X
X
Urinalysis (for hematuria and 
proteinuria evaluation) (q,r)
X
X
X
Immune safety tests (q)
X
X
X
X
X
X
X
X
Pregnancy test (s)
X
X
X
Ophthalmic exam (t)
X
X
X
Blood samples for PK (v)
X
X
X
X
Survival follow-up contact
X (d)
(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.
(c) All patients, including those patients no longer on treatment, will be assessed for survival. Patients who stop treatment for any reason other than PD will continue
to have follow-up visits for PFS. The PFS follow-up visit should be conducted at the site every 2 months from the last dose of study drug until PD for a maximum
of 6 months from the date of the first dose of study drug or 3 months from the last dose of study drug until PD for a maximum of 6 months from the last dose of study
drug. Information on any subsequent anticancer therapies will be collected during the survival follow-up period. For patients who discontinue study treatment
before PD, investigator response assessments based upon available local data will also be collected during the survival follow-up period.
Property of Takeda: For non
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(d) After the occurrence of PD, patients will continue to have follow-up visits for OS. The OS information will be collected every 2 months until 12 months from the 
date of the last dose of study drug.
(e) Informed consent may be captured before the Screening period (28 days before first dose).
(f) The Cycle 1 Day 1 physical examination and medical history are not required if the screening physical examination was conducted and medical history obtained 
within 3 days before administration of the first dose of study drug (Cycle 1 Day 1). Complete physical examinations (including smoking history) will be performed 
during Screening and will include a neurological exam. 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.
(g) Weight should be obtained at Screening, on Day 1 predose of each cycle, and at EOT.
(h) Measure vital signs before dosing. On Cycle 1 Day 1 only, also measure vital signs at 1 and 3 (±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.
(i) 12-lead ECGs will be performed as detailed in Section 10.4.8.
(j) If a patient experiences immune-mediated toxicities that either result in discontinuation of nivolumab or both study treatments or occur during the 28-day AE 
follow-up period (including immune-mediated pneumonitis, colitis, hepatitis, endocriopathies, nephritis, rash, and encephalitis), they will be followed to resolution 
or stabilization, the start of alternative therapy, or a minimum of 100 days after last dose of study treatment, whichever occurs first. During this AE follow-up 
period, concomitant medications and procedures should also be collected.
(k) Including serious PTEs; see Section 11.0.
(l) TAK-659 will be administered PO QD for 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. On days when nivolumab infusions are administered, the dose 
of TAK-659 should be taken first and is to be taken in the clinic.
(m) Nivolumab is to be administered at 3 mg/kg or 240 mg IV as a 60-minute infusion on Days 1 and 15 of each 28-day cycle. Nivolumab should be administered 
after the dose of TAK-659 is taken, and the infusion should start within 30 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 solid tumors, including CT scan with contrast (or MRI if clinically indicated) of the chest, abdomen, pelvis, and other known sites of 
disease (eg, head and neck), relevant tumor markers (eg, CA125, PSA, CA19.9, CEA), and physical assessment of the disease will be performed at Screening, 
between Days 22 and 29 (predose) of Cycles 2, 4, and 6, and between Days 22 and 29 (predose) of every 3 cycles thereafter (ie, Cycle 9, 12, etc). The same imaging 
modality (CT scan with contrast or MRI) and/or the same methods for disease measurement must be used throughout the study. If the patient has had an appropriate 
CT scan or MRI performed within 28 days before Cycle 1 Day 1, the results of that scan may be used for tumor lesion measurements at Screening. See Section 
10.4.15 for details. 
(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 (white blood cell [WBC] count), differential WBC 
count, and platelets. The chemistry panel consists of the following: sodium, potassium, CO2, chloride, BUN, creatinine, bilirubin, ALP, AST, ALT, LDH, GGT, 
albumin, glucose, urate, calcium, phosphate, magnesium, amylase, lipase, total protein, cardiac troponin I and T (cTnI and cTnT), and CPK.
(q) Laboratory assessments can be conducted within -3 days of the scheduled visit, with the exception of PK/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 (ie, inclement weather, holidays, vacations, or other 
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administrative reasons).
(r) Urinalysis samples will be collected predose and analyzed at the site’s local laboratory.
(s) A serum pregnancy test will be performed for women of childbearing potential at Screening. A urine or serum 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 of dosing and the result is negative, the urine pregnancy test may be waived on Cycle 1 Day 1.
(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 10.4.14 for details.
(see Section 10.4.18). Suitable specimens are either a tumor block or a minimum of 10 unstained slides.
(v) Blood samples for plasma PK analysis will be collected as specified in Table A.
Property of Takeda: For non-commercial use on
bj
 the applicable Terms of Use
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Table A
Dose Escalation ECG and PK Schedule: Cycle 1
Cycle 1
Day 1
Day 2 
Day 15
Day 16 
Single ECG
PK
PK
Single ECG
PK
PK
Predose (within 1 
hour before dosing 
on all days) (a,b)
X
X
X
(24 h after Day 1 
dose 1 h)
X
X
X
(24 h after Day 15 dose 
1 h)
0.5 hour postdose 
(10 min)
X
X
1 hours postdose 
(10 min)
X
X
2 hours postdose 
(10 min)
X
X
X
X
4 hours postdose 
(30 min)
X
X
8 hours postdose 
(30 min)
X
X
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.
(a) On days when predose samples are collected, patients will be instructed to arrive at the clinic in the morning 
without taking their TAK-659 dose at home. The TAK-659 dose will be administered in the clinic after collection of 
all predose samples.
(b) The timing of the predose PK sample on Days 2, 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.
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Schedule of Events for Expansion TNBC, HNSCC, and NSCLC (28-Day Cycle)
Screening (a)
Cycle 1
Cycle 2 and Beyond
EOT (b) 
(+10 Days)
Survival
Follow-up
Day 1
Day 8
Day 15
Day 22
Day 1
Day 
15
Days 
22-29
PFS (c)
OS (d)
Informed consent (e)
X
Inclusion/exclusion criteria
X
Demographics and disease 
characteristics
X
Complete medical history (f)
X
X
Physical examination (f)
X
X
X
X
X
X
X
X
Height
X
Weight (g)
X
X
X
X
Vital signs (h)
X
X 
X
X
X
X
X
X
ECOG performance status
X
X
X
X
12-lead ECG (i) 
X
X 
X 
X
Monitoring of concomitant 
medications and procedures (j)
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 (j)
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
Serious adverse events (k) 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.
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Schedule of Events for Expansion TNBC, HNSCC, and NSCLC (28-Day Cycle) (continued)
Screening 
(a)
Cycle 1
Cycle 2 and Beyond
EOT (b) 
(+10 Days)
Survival
Follow-up
Day 1
Day 8
Day 15
Day 22
Day 1
Day 15
Days 
22-29
PFS 
(c)
OS (d)
Dosing
TAK-659 administration 
(l,v)
TAK-659 is dosed PO QD every day beginning on Cycle 1 Day 1.
Nivolumab administration 
(m,v)
TAK-659 
single-agent 
treatment window; no 
nivolumab 
administered
Nivolumab is dosed every 2 weeks, starting on Cycle 1 Day 15, and on Days 1 and 15 for 
every cycle thereafter. 
TAK-659 administration (n)
TAK-659 is dosed PO QD every day.
Nivolumab administration 
(n)
Nivolumab is dosed every 2 weeks on Days 1 and 15 of each treatment cycle.
Patient diary review (m)
X
X
X
X
X
X
X
X
Imaging/Response Assessments
Tumor assessment for solid 
tumors by RECIST version 
1.1 (CT scan/MRI) (p)
X
X
X (c)
Sample/Laboratory Assessments
Hematology/chemistry (q,r)
X
X
X
X
X
X
X
X
Urinalysis (for hematuria and 
proteinuria evaluation) (r,s)
X
X
X
Immune safety tests (r)
X
X
X
X
X
X
X
X
Pregnancy test (t)
X
X
X
Ophthalmic exam (u)
X
X
X
Footnotes are on last table page.
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Schedule of Events for Expansion TNBC, HNSCC, and NSCLC (28-Day Cycle) (continued)
Screening (a)
Cycle 1
Cycle 2 and Beyond
EOT (b) 
(+10 days)
Survival
Follow-up
Day 1
Day 8
Day 15
Day 22
Day 1
Day 15
Days 
22-29
PFS 
(c)
OS 
(d)
Tumor biopsy for 
pharmacodynamic assessment 
(v)
X
X
X (w)
X (y)
Blood sample for PBMCs (z)
X
X
X (w)
X (y)
Blood sample for 
cytokine/chemokine 
measurement (aa)
X
X
X (w)
X (y)
Blood sample for ctDNA (bb)
X
X
X (w)
X (y)
Blood samples for PK (cc)
X
X
X
X
Blood samples for 
pharmacogenetic studies
X (dd)
Survival follow-up contact
X (d)
(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.
(c) All patients, including those patients no longer on treatment, will be assessed for survival. Patients who stop treatment for any reason other than PD will continue 
to have follow-up visits for PFS. The PFS follow-up visit should be conducted at the site every 2 months from the last dose of study drug until PD for a maximum 
of 6 months from the date of the first dose of study drug or 3 months from the last dose of study drug until PD for a maximum of 6 months from the last dose of study 
drug. Information on any subsequent anticancer therapies will be collected during the survival follow-up period. For patients who discontinue study treatment 
before PD, investigator response assessments based upon available local data will also be collected during the survival follow-up period.
(d) After the occurrence of PD, patients will continue to have follow-up visits for OS. The OS information will be collected every 2 months until 12 months from the 
date of the last dose of study drug.
(e) Informed consent may be captured before the Screening period (28 days before the first dose).
(f) The Cycle 1 Day 1 physical examination and medical history are not required if the screening physical examination was conducted and medical history obtained 
within 3 days before administration of the first dose of study drug (Cycle 1 Day 1). Complete physical examinations (including smoking history) will be performed 
Property of Takeda: For non-commercial use only an
ct to the applicable Terms of Use
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during Screening and will include a neurological exam. Complete physical exams will also be performed on Day 1 of each cycle and at the EOT visit. Symptom- or 
finding-directed physical examinations will be performed on Days 8, 15, and 22 of Cycle 1 and on Day 15 of Cycles 2, 3, and 4.
(g) Weight should be obtained at Screening, on Day 1 predose of each cycle, and at EOT.
(h) Measure vital signs before dosing. On Cycle 1 Day 1 only, also measure vital signs at 1 and 3 (±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. 
(i) 12-lead ECGs will be performed as detailed in Section 10.4.8.
(j) If a patient experiences immune-mediated toxicities that either result in discontinuation of nivolumab or both study treatments or occur during the 28-day AE 
follow-up period (including immune-mediated pneumonitis, colitis, hepatitis, endocriopathies, nephritis, rash, and encephalitis), they will be followed to resolution 
or stabilization, the start of alternative therapy, or a minimum of 100 days after last dose of study treatment, whichever occurs first. During this AE follow-up 
period, concomitant medications and procedures should also be collected.
(k) Including serious PTEs; see Section 11.0. 
(l) TAK-659 will be administered PO QD during 28-day cycles commencing on Cycle 1 Day 1 for patients in the single-agent treatment window. On days when 
nivolumab infusions are administered, the dose of TAK-659 should be taken first and is to be taken in the clinic.
(m) Nivolumab is to be administered either at 3 mg/kg or 240 mg IV as a 60-minute infusion starting on Cycle 1 Day 15 and on Days 1 and 15 of each 28-day cycle 
thereafter for patients in the single-agent treatment window. The dose of nivolumab will be consistent for all patients in the expansion cohorts and will be either
3 mg/kg or 240 mg IV. Nivolumab should be administered after the dose of TAK-659 is taken, and the infusion should start within 30 minutes after the dose of 
TAK-659 is administered.
(n) TAK-659 will be administered PO QD during 28-day cycles commencing on Cycle 1 Day 1 for patients not participating in the single-agent treatment window. 
Nivolumab is to be administered at 3 mg/kg or 240 mg IV as a 60-minute infusion on Days 1 and 15 of each 28-day cycle for patients not participating in the 
single-agent treatment window. The dose of nivolumab will be consistent for all patients in the expansion cohorts and will be either 3 mg/kg or 240 mg IV. On days 
when nivolumab infusions are administered, the dose of TAK-659 should be taken first and is to be taken in the clinic. The nivolumab infusion should start within 
30 minutes after the dose of TAK-659 is administered.
(o) The study center staff will check the patient drug diary versus the patient’s supply of TAK-659 tablets to assess compliance.
(p) Response assessments for solid tumors, including CT scan with contrast (or MRI if clinically indicated) of the chest, abdomen, pelvis, and other known sites of 
disease (eg, head and neck), relevant tumor markers (eg, CA125, PSA, CA19.9, CEA) and physical assessment of the disease, will be performed at Screening, 
between Days 22 and 29 (predose) of Cycles 2, 4, and 6, and between Days 22 and 29 (predose) of every 3 cycles thereafter (ie, Cycle 9, 12, etc). The same imaging 
modality (CT scan with contrast or MRI) and/or the same methods for disease measurement must be used throughout the study. If the patient has had an appropriate 
CT scan or MRI performed within 28 days before Cycle 1 Day 1, the results of that scan may be used for tumor lesion measurements at Screening. See 
Section 10.4.15 for details. 
(q) 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 (white blood cell [WBC] count), differential WBC 
count, and platelets. The chemistry panel consists of the following: sodium, potassium, CO2, chloride, BUN, creatinine, bilirubin, ALP, AST, ALT, LDH, GGT, 
albumin, glucose, urate, calcium, phosphate, magnesium, amylase, lipase, total protein, cardiac troponin I and T (cTnI and cTnT), and CPK.
(r) Laboratory assessments can be conducted within -3 days of the scheduled visit, with the exception of PK/pharmacodynamic assessments or unless otherwise 
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noted. Day 1 visits of Cycle 2 and beyond may be modified by up to 3 days for extenuating circumstances (ie, inclement weather, holidays, vacations, or other 
administrative reasons).
(s) Urinalysis samples will be collected predose and analyzed at the site’s local laboratory.
(t) A serum pregnancy test will be performed for women of childbearing potential at Screening. A urine or serum 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 of dosing and the result is negative, the urine pregnancy test may be waived on Cycle 1 Day 1.
(u) 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 10.4.14 for details.
(v) Serial tumor biopsies will be obtained from approximately 10 patients enrolled in each expansion cohort at Screening, after 2 weeks of TAK-659 single-agent 
therapy, and after 6 weeks of the combination treatment. An additional, optional biopsy sample may be taken upon PD if the patient consents. Coagulation testing, 
consisting of PTT and PT, should be performed and assessed in advance of performing any tumor biopsy procedures.
(w) Only on Cycle 3 Day 1.
(y) Optional sample collection at time of relapse.
(z) Peripheral blood samples will be collected from all patients enrolled in the expansion phase at Screening and predose on Cycle 1 Day 15 and Cycle 3 Day 1 for 
pharmacodynamic assessment and their potential association with clinical activity of TAK-659 or in combination with nivolumab. Samples will be subjected to 
flow cytometry analysis to evaluate changes in immune cell populations.
(aa) Peripheral blood samples will be collected at Screening and predose on Cycle 1 Day 15 and Cycle 3 Day 1 for pharmacodynamic assessment and their potential 
association with clinical activity of TAK-659 or in combination with nivolumab. Samples will be assayed to measure a panel of cytokines and chemokines.
(bb) Peripheral blood samples will be collected at Screening and predose on Cycle 1 Day 15 and Cycle 3 Day 1 for identification of candidate biomarker(s) 
predictive of clinical activity of the combination of TAK-659 and nivolumab. ctDNA will be purified from collected samples from analysis including, but not 
limited to, sequencing.
(cc) Blood samples for plasma PK analysis will be collected as specified in Table B during Cycles 1-4.
(dd) 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 clearance of TAK-659 (eg, CYP2D6). This sample may be collected during the course of the study if the sample cannot be collected at 
Screening.
Property of Takeda: For non-commercial us
subject to the applicable Terms of Use
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Table B
Dose Expansion PK Schedule: Cycles 1 through 4
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Day 1
Day 8
Day 15
Day 1
Day 1
Day 1
Predose (within 1 hour before dosing on all days) (a, b)
X
X
X
X
1 hour postdose (10 minutes)
X
2-4 hours postdose
X
X
At time of clinic visit
X (c)
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.
(a) On days on which predose samples are collected, patients will be instructed to arrive at the clinic in the morning 
without taking their TAK-659 dose at home. The TAK-659 dose will be administered in the clinic after collection of 
all predose samples.
(b) The timing of the predose PK samples should be encouraged to occur at approximately the same time as TAK-659 
dosing times on previous days to ensure that samples represent trough samples.
(c) For the Cycle 1 Day 8 visit, patients will be instructed to take their TAK-659 dose at home before their clinic visit. 
The PK sample can be collected at any time during the clinic visit. A distribution of clinic visit times during the day 
across patients is to be encouraged to provide a range of postdose sampling times across the study population.
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Appendix B
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the 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 (non routine/non standard 
panel) screening assessments are NOT performed on potential patients, prior to 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. If trial-related duties and functions are assigned to any individual or party, ensure that this 
individual or party is qualified to perform those trial-related duties and functions, and 
implements procedures to ensure the integrity of the trial-related duties and functions 
performed and any data generated.
6. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
21 CFR Part 56, ICH, and local regulatory requirements.
7. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to patients. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
8. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH. and local 
regulations, are met.
9. Obtain valid informed consent from each patient who participates in the study, and document 
the date of consent in the patient’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each ICF should contain a patient authorization section that 
describes the uses and disclosures of a patient’s personal information (including personal 
health information) that will take place in connection with the study. If an ICF does not include 
such a patient authorization, then the investigator must obtain a separate patient authorization 
form from each patient.
10. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc., and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents.
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11. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
12. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor.
13. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.
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Appendix C
Investigator Consent to Use of Personal Information 
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, US, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.
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Appendix D
ECOG Scale for Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all predisease performance without restriction.
1
Symptoms but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to 
carry out work of a light or sedentary nature (eg, light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry out any work 
activities. Up and about more than 50% of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair.
5
Dead
Source: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response criteria 
of the Eastern Cooperative Oncology Group. American Journal of Clinical Oncology 1982;5(6):649-55.
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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
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 G
Medications, Supplements, and Food Products that are Strong CYP3A and/or 
P-gp Inhibitors or Inducers
Medication, Supplement, or Food Product (a,b)
Required Washout Period Before First Dose
Strong CYP3A Reversible Inhibitors and/or P-gp 
Inhibitors
amiodarone
azithromycin
captopril
carvedilol
cyclosporine
diltiazem
dronedarone
erythromycin
felodipine
ketoconazole
itraconazole
nefazodone
posaconazole
quercetin
quinidine
ranolazine
ticagrelor
verapamil 
voriconazole
5 times the inhibitor half-life (if a reasonable half-life 
estimate is known), or 7 days (if a reasonable 
half-life estimate is unknown) 
Strong CYP3A Mechanism-based Inhibitors 
clarithromycin (c)
conivaptan (c)
mibefradil (c,d)
telithromycin
7 days, or 5 times the inhibitor half-life, whichever is 
longer
grapefruit-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.
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Appendix H
Methods of Contraception Considered to be Effective
Acceptable Methods Considered Highly Effective
Birth control methods that can achieve a failure rate of less than 1% per year when used consistently and 
correctly are considered as highly effective. Such methods include:

combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of 
ovulation 1:
–
oral
–
intravaginal
–
transdermal

progestogen-only hormonal contraception associated with inhibition of ovulation 1:
–
oral
–
injectable
–
implantable 2

intrauterine device (IUD)2

intrauterine hormone-releasing system (IUS)2

bilateral tubal occlusion2

vasectomised partner2,3

sexual abstinence 4
Methods that are Considered Less Highly Effective
Acceptable birth control methods that result in a failure rate of more than 1% per year include:

progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary 
mode of action

male or female condom with or without spermicide5

cap, diaphragm or sponge with spermicide5
__________________________________________________
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 I
Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1)
All sites of disease, target and nontarget lesions must be assessed at Baseline. Objective disease status is to be recorded 
at each evaluation using the response categories and definitions provided in this section.
All sites of measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, representative of all involved 
organs, should be identified as target lesions at Baseline. Target lesions should be selected on the basis of size (longest 
lesions) and suitability for reproducible repeated measurements. Measurements must be provided for target site of 
measurable lesions.
Disease Response Criteria for Target and Nontarget Lesions
Evaluation of Target Lesions
Complete Response (CR):
Disappearance of all target lesions
Partial Response (PR):
At least a 30% decrease in the sum of the LD of target lesions, taking as reference the 
baseline sum LD
Progressive Disease (PD):
At least a 20% increase in the sum of the LD of target lesions, taking as reference the 
smallest sum LD recorded since the treatment started or the appearance of one or more 
new lesions
Stable Disease (SD):
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, 
taking as reference the smallest sum LD since the treatment started
Evaluation of nontarget lesions
Complete Response (CR):
Disappearance of all nontarget lesions and normalization of tumor marker level
Incomplete Response/
Stable Disease (SD): 
Persistence of one or more nontarget lesion(s) or/and maintenance of tumor marker level 
above the normal limits
Progressive Disease (PD):
Appearance of one or more new lesions and/or unequivocal progression of existing 
nontarget lesions 
Source: Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation 
criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45(2):228-47.[39] 
Abbreviation: LD = longest diameter.
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The following table summarizes the overall response status calculation at each time point for patients who have 
measurable disease per RECIST at baseline.
Time Point Response: Patients With Target (Nontarget) Disease
Target Lesions
Nontarget Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Source: Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation 
criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45(2):228-47. [39]
Abbreviations: CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease; NE = 
not evaluable.
The following table summarizes the overall response status calculation at each time point for patients who have 
nonmeasurable (therefore nontarget) disease at baseline.
Time Point Response: Patients with Nontarget Disease Only
Nontarget Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
Source: Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation 
criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45(2):228-47.[34]
Abbreviations: CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease; NE = 
not evaluable.
a ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for nontarget disease because SD is increasingly used as 
endpoint for assessment of efficacy in some trial so to assign this category when no lesions can be measured is not 
advised.
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Appendix J
Detailed Description of Amendments to Text
The primary section(s) of the protocol affected by the changes in Amendment No. 02 are indicated. 
The corresponding text has been revised throughout the protocol. 
Change 1: Update approved indications for nivolumab.
The primary change occurs in Section 4.1.2.2 Nivolumab:
Added text:Nivolumab is approved in the European Union (EU) for advanced melanoma. 
Following initial approval in melanoma, nivolumab was approved the US for the 
treatment of metastatic NSCLC after prior chemotherapy and in the European Union
for the treatment of squamous cell NSCLC after prior chemotherapy. It is also 
approved in the United States for the treatment of advanced renal cell carcinoma in 
patients who have received prior anti-angiogenic therapy and for the treatment of 
patients with metastatic or recurrent HNSCC following progression on 
platinum-based therapy. More recently, the US Food and Drug Administration 
(FDA) granted accelerated approval for nivolumab for treatment of patients 
with locally advanced or metastatic urothelial carcinoma who have disease 
progression during or following platinum-containing chemotherapy or have 
disease progression within 12 months of neoadjuvant or adjuvant treatment with 
a platinum-containing chemotherapy. See the current versions of the Opdivo 
United States Prescribing Information [USPI] [17] and Summary of Product 
Characteristics [SmPC] [18] for further details on indications approved in the 
United States and European Union, respectively.
Rationale for Change:
To provide updated information.
Change 2: Update information regarding nonclinical studies of TAK-659 in combination with 
anti-programmed cell death protein 1 therapy.
The primary change occurs in Section 4.1.3 Nonclinical Experience:
Initial 
wording:
Preclinical studies show that SYKi results in loss of myeloid-derived suppressor cells 
(MDSCs) and activation of T-cell response both in vitro and in vivo. Although 
TAK-659 did not impact T cell function directly, a synergistic activity is expected 
with a PD-1 inhibitor in combination with TAK-659 in tumors where SYK-mediated 
MDSC or B-cell immunosuppression is active. The synergistic benefit of 
administering an anti-PD-1 with TAK-659 has been observed preclinically, and this 
effect could be indirectly attributed to the decrease in CD11b+ MDSC or B220+ B 
cells in the tumor-infiltrating lymphocytes (TILs) of TAK-659-treated tumors.
Amended 
or new 
wording:
PreNonclinical studies show that SYKi SYK inhibition results in loss of 
myeloid-derived suppressor cells (MDSCs) and activation of T-cell response both in 
vitro and in vivo. Although TAK-659 did not impact T cell function directly, a 
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synergistic activity is expected with a PD-1 inhibitor in combination with TAK-659 
TAK-659 in combination with anti-PD-1 therapy has shown regulation of B cells, 
NK cells, and macrophages in syngeneic nonclinical mouse models. The 
combination effects in immune cells are model and context dependent, and 
combination activity would be greatest in tumors where SYK-mediated MDSC or 
B-cell immunosuppression is active. The synergistic benefit of administering an 
anti-PD-1 with TAK-659 has been observed preclinically, and The prenonclinical 
combination treatment of TAK-659 and anti-PD-1 therapy provides therapeutic 
advantage over single-agent treatment with durable tumor growth inhibition, 
maintained complete responses (CRs), and a vaccinal memory effect. tThis effect 
could be indirectly attributed to the decrease in CD11b+ MDSC or B220+ B cells in 
the tumor-infiltrating lymphocytes (TILs) of TAK-659-treated tumors.
Rationale for Change:
To provide updated information.
Section 4.2 Rationale for the Proposed Study also contains this change.
Change 3: Update summaries of TAK-659 clinical experience and risks and benefits.
The primary change occurs in Section 4.1.4 Clinical Experience:
Description 
of Change:
Replaced previous text with updated safety, efficacy, and PK (where available) data 
from Studies C34001, C34002, and C34003.
Rationale for Change:
To provide updated information.
The following sections also contain this change:

Section 4.1.5 Risks and Benefits.

Section 4.2.1 Rationale for Dose and Schedule Selection.
Change 4: Add an option to conduct a nivolumab fixed-dose evaluation cohort.
The primary change occurs in Section 7.1 Overview of Study Design:
Added text:After the RP2D of TAK-659 has been identified, on the basis of evaluation of the 
combination with a weight-based dose of nivolumab (3 mg/kg), this RP2D of 
TAK-659 may be evaluated in combination with a fixed dose of 240 mg IV 
nivolumab following discussion between the investigator and sponsor. For 
single-agent nivolumab, the fixed dose is expected to have equivalent exposure, 
safety, and efficacy as the weight-based (3 mg/kg) dose. If the nivolumab fixed 
dose is evaluated in combination with the TAK-659 RP2D, 3 patients will be 
initially enrolled into the cohort. Following evaluation of the safety, efficacy, and 
any available PK data, along with discussions between the investigator and 
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sponsor, 3 additional patients may be enrolled into the cohort for a total of 3 to 6 
patients. If ≥1 out of 6 patients experiences dose-limiting toxicity (DLT) during 
Cycle 1, or significant safety issues are seen in Cycle 2 and beyond, re-evaluation 
of the TAK-659 RP2D when administered with a fixed dose of nivolumab is 
permitted 
The dose of nivolumab in the expansion cohorts will be either 3 mg/kg or 240 mg 
IV, dependent on whether the 240 mg fixed-dose cohort is evaluated. If the 
240 mg fixed-dose cohort is evaluated and deemed safe and tolerable, the dosing 
regimen may switch to 240 mg, on the basis of change in clinical practice and 
discussion between the investigator and sponsor. If the nivolumab fixed-dose 
evaluation cohort is not run, the dose of nivolumab for all patients in the dose 
expansion phase will be 3 mg/kg.
Rationale for Change:
To evaluate the dose regimen recently approved by the US FDA.
The following sections also contain this change:

Section 2.0 STUDY SUMMARY.

Section 4.1.2.2 Nivolumab.

Section 4.2.1 Rationale for Dose and Schedule Selection.

Section 7.2 Number of Patients.

Section 9.1.2 Nivolumab.

Section 9.4 Dose Escalation Rules.

Appendix A Schedules of Events, Schedule of Events for Expansion TNBC, HNSCC, and 
NSCLC (28-Day Cycle), footnotes m and n.
Change 5: Identify how a study cycle is defined and the requirement for the start of a new cycle in 
the event of a study drug interruption, and provide a source of further guidance on calculating 
cycle length. 
The primary change occurs in Section 7.1 Overview of Study Design:
Added text:During dose escalation, the Cycle 1 DLT-evaluation period typically will be 
28 days. However, in the event of a nivolumab dosing interruption, a cycle length 
may be extended. If the second dose of nivolumab planned for Cycle 1 Day 15 is 
held and then dosed within the original 28-day cycle, the dose will be considered 
the second dose of Cycle 1, leading to a cycle with a maximum total of 42 days. 
The actual doses of TAK-659 received during this 28- to 42-day DLT-evaluation 
period will be assessed against the planned doses of TAK-659 (daily dose cycle 
days) to determine whether the patient has received at least 75% of planned 
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doses of TAK-659 to be DLT evaluable. When the second dose is administered, 
procedures at the original scheduled visit (ie, Cycle 1 Day 15) should be 
performed. If the second dose of nivolumab is interrupted for a period of time 
that extends beyond the original 28-day cycle, this dose will be considered 
missed. In this case, independent of whether the patient has received 75% of the 
planned doses of TAK-659, the patient will receive only one of the 2 nivolumab 
doses planned for Cycle 1 and, therefore, is not evaluable for DLT.
In Cycle 2 and beyond, during escalation and during the expansion phase of the 
study, if a nivolumab dose is delayed because of AEs, when the criteria to resume 
treatment are met, the patient should restart treatment at the next scheduled 
time point per protocol. However, if nivolumab is delayed past the next 
scheduled time point per protocol and TAK-659 dosing is also interrupted, the 
next scheduled time point will be delayed until dosing with either drug resumes.
Rationale for Change:
To ensure that patients receive appropriate monitoring and that treatment cycles are clinically 
meaningful.
Section 9.5 Dose Modification Guidelines also contains this change.
Change 6: Clarify that the maximum tolerated dose/maximally administered dose/recommended 
phase 2 dose will be determined using weight-based nivolumab dosing.
The primary change occurs in Section 7.1 Overview of Study Design:
Initial 
wording:
The dose of nivolumab will be 3 mg/kg IV.
Amended 
or new 
wording:
While the MTD/maximally administered dose (MAD)/RP2D of TAK-659 are 
being determined, Tthe starting dose of nivolumab will be 3 mg/kg IV.
Rationale for Change:
To provide clarification.
The following sections also contain this change:

Section 2.0 STUDY SUMMARY.

Section 4.2.1 Rationale for Dose and Schedule Selection.

Section 9.4 Dose Escalation Rules.
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Change 7: Clarify the use of blood samples for biomarker analysis.
The primary change occurs in Section 7.1 Overview of Study Design:
Initial 
wording:
In addition to analysis of tumor biopsy samples as described above for a subset of 
patients in each expansion cohort, blood samples will be collected from all patients 
enrolled in the expansion phase of the study and analyzed for changes in immune cell 
populations in the course of treatment, levels of cytokines and chemokines known for 
or deemed relevant to tumor growth or antitumor activity of TAK-659 or the 
combination, and ctDNA. The result will be compared with that obtained from the 
analysis of biopsied tumor samples and used to identify a biomarker(s) that would 
enable monitoring the activity of TAK-659 and the combination in future studies 
using peripheral blood samples. In addition, a biomarker(s) or assay may be developed 
for selecting patients who would benefit the most from treatment with the combination 
of TAK-659 and nivolumab. 
Amended 
or new 
wording:
In addition to analysis of tumor biopsy samples as described above for a subset of 
patients in each expansion cohort, blood samples will be collected from all patients 
enrolled in the expansion phase of the study and analyzed for posttreatment changes 
in immune cell populations in the course of treatment, levels of cytokines and 
chemokines known for or deemed relevant to tumor growth or antitumor activity of 
TAK-659 or the combination, and ctDNA quantity and characteristics. The result 
will be compared with that obtained from the analysis of paired biopsied tumor 
biopsy samples and used to identify a biomarker(s) that would enable monitoring the 
activity of TAK-659 and the combination in future studies using peripheral blood 
samples. In addition, postdose change of a biomarker(s) or assay may be developed
evaluated for selecting patients who would benefit the most from treatment with the 
combination of TAK-659 and nivolumab its (their) association with clinical 
responses from treatment with TAK-659 in combination with nivolumab.
Rationale for Change:
Required additional information.
Change 8: Update the estimated number of patients in the study.
The primary change occurs in Section 7.2 Number of Patients:
Initial 
wording:
It is expected that approximately 120 patients will be enrolled in the study from 
approximately 25 study centers in North America and Europe: approximately 9 to 12 
patients in the dose escalation cohort and approximately 36 patients (30 evaluable 
patients+15% dropout) in each of the 3 dose expansion cohorts. Enrollment is defined 
as the time of the initiation of the first dose of study drug.
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Amended 
or new 
wording:
It is expected estimated that approximately 120126 patients will be enrolled in the 
study from approximately 25 study centers in North America and Europe: 
approximately 9 to 12 patients inamong the dose escalation cohorts evaluating 
weight-based dosing of nivolumab, 3 to 6 patients in the possible nivolumab 
fixed-dose evaluation cohort, and approximately 36 patients (30 evaluable 
patients+15% dropout) in each of the 3 dose expansion cohorts. Enrollment is defined 
as the time of the initiation of the first dose of study drug.
Rationale for Change:
To reflect additional patients in the new, optional nivolumab fixed-dose evaluation cohort.
The following sections also contain this change:

Section 2.0 STUDY SUMMARY.

Section 7.1 Overview of Study Design.

Section 14.3 Determination of Sample Size.
Change 9: Update the inclusion criterion regarding minimum creatinine clearance laboratory 
value for entry into the study.
The primary change occurs in Section 8.1 Inclusion Criteria, criterion 6:
Initial 
wording:

Serum creatinine must be ≤1.5×ULN or creatinine clearance or calculated 
creatinine clearance must be >50 mL/minute (See Appendix E).
Amended 
or new 
wording:

Serum cCreatinine clearance must be ≤1.5×ULN or creatinine clearance or 
calculated creatinine clearance must be >50 ≥60 mL/minute as estimated by the 
Cockcroft Gault equation (Ssee Appendix E) or based on urine collection (12 
or 24 hours).
Rationale for Change:
To be consistent with other TAK-659 protocols.
The following sections also contain this change:

Section 4.1.4.1 Clinical Pharmacokinetics of TAK-659

Section 10.4.12.1 Clinical Chemistry, Hematology, and Urinalysis
Change 10: Update the inclusion criterion regarding minimum hemoglobin laboratory value for 
entry into the study.
The primary change occurs in Section 8.1 Inclusion Criteria, criterion 6:
Initial 
wording:

Hemoglobin must be 8 g/dL, absolute neutrophil count (ANC) must be 
1500/L, and platelet count must be 75,000/L.
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Amended 
or new 
wording:

Hemoglobin must be 89 g/dL, absolute neutrophil count (ANC) must be 
1500/L, and platelet count must be 75,000/L.
Rationale for Change:
To be consistent with other TAK-659 protocols.
Change 11: Update the inclusion criteria regarding permitted lipase and amylase concentrations 
values for entry into the study. 
The primary change occurs in Section 8.1 Inclusion Criteria, criterion 6:
Added text: 
Lipase must be ≤1.5ULN and amylase ≤1.5ULN with no clinical symptoms 
suggestive of pancreatitis and cholecystitis.
Rationale for Change:
Required additional information.
Change 12: Update the inclusion criterion regarding permissible blood pressure in hypertensives 
patients for entry into the study. 
The primary change occurs in Section 8.1 Inclusion Criteria, criterion 6:
Added text: 
Blood pressure ≤Grade 1 (hypertensive patients are permitted if their blood 
pressure is controlled to ≤Grade 1 by hypotensive medications and 
glycosylated HbA1C ≤6.5%).
Rationale for Change:
Required additional information.
Change 13: Clarify that patients in the non-small cell lung cancer cohort with epidermal growth 
factor receptor or anaplastic lymphoma kinase genomic alternation should have had progressive 
disease (PD) on United States Food and Drug Administration–approved therapy.
The primary change occurs in Section 8.1 Inclusion Criteria, criterion 10:
Initial 
wording:

Patients with EGFR or ALK genomic alternations should have PD on prior 
therapy for these aberrations.
Amended 
or new 
wording:

Patients with EGFR or ALK genomic alternations should have PD on prior US 
FDA-approved therapy for these aberrations.
Rationale for Change:
Required additional information.
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Change 14: Update exclusion criteria regarding patients with history of autoimmune disease, type 
I diabetes mellitus, childhood asthma, and thyroid disorders.
The primary change occurs in Section 8.2 Exclusion Criteria, criterion 2: 
Initial 
wording:
Active, known, or suspected autoimmune disease.
Amended 
or new 
wording:
Active, known, or suspected autoimmune disease or a history of known 
autoimmune disease, with the exception of:

Patients with vitiligo, type I diabetes mellitus, resolved childhood 
asthma/atopy, residual hypothyroidism due to autoimmune condition 
requiring only hormone replacement, psoriasis not requiring systemic 
treatment, or conditions not expected to recur in the absence of an 
external trigger.
Rationale for Change:
Required additional information.
Section 2.0 STUDY SUMMARY also contains this change.
Change 15: Update the restrictions on corticosteroid-based medication.
The primary change occurs in Section 8.2 Exclusion Criteria, criteria 3 and 14:
Initial 
wording:
3. Diagnosis of immunodeficiency or any condition requiring systemic treatment 
with either corticosteroids (>10 mg daily prednisone equivalents) or other 
immunosuppressive medications within 14 days of treatment.
…
14. 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.
Amended 
or new 
wording:
3. Diagnosis or immunodeficiency or anyAny condition requiring systemic 
treatment with either corticosteroids (>10 mg daily prednisone equivalents) or 
other immunosuppressive medications within 14 days of treatmentbefore first 
dose of study drug.

Corticosteroids for topical use or in nasal spray are allowed, as are inhaled 
steroids and adrenal replacement steroid doses >10 mg daily in the 
absence of active autoimmune disease.
…
14. Treatment with high-dose corticosteroids for anticancer purposes within 14 days 
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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.
Rationale for Change:
Required additional information.
Section 9.6 Concomitant Medications and Procedures also contains this change.
Change 16: Clarify exclusion criterion regarding previous anticancer treatments.
The primary change occurs in Section 8.2 Exclusion Criteria, criterion 10:
Initial 
wording:
Systemic anticancer treatment or radiotherapy less than 2 weeks before the first dose 
of study treatment (≤4 weeks for monoclonal antibodies with evidence of PD) or not 
recovered from acute toxic effects from prior chemotherapy and radiotherapy.
Amended 
or new 
wording:
Systemic anticancer treatment (including investigational agents) or radiotherapy 
less than <2 weeks before the first dose of study treatment (≤4 weeks for monoclonal 
antibodies with evidence of PD 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) or have not recovered from 
acute toxic effects from prior chemotherapy and radiotherapy.
Rationale for Change:
To be consistent with other TAK-659 protocols.
Change 17: Update exclusion criterion regarding patients with another malignancy.
The primary change occurs in Section 8.2 Exclusion Criteria, criterion 16:
Initial 
wording:
Active secondary malignancy that requires treatment. 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.
Amended 
or new 
wording:
Active secondary malignancy that requires treatment. Patients with another 
malignancy within 2 years of study start. Patients with nonmelanoma skin cancer or 
carcinoma in situ of any type are not excluded if they have undergone complete 
resection and are considered disease-free at the time of study entry.
Rationale for Change:
To be consistent with other TAK-659 protocols.
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Change 18: Update the restrictions on the use of non-oncology vaccine therapies.
The primary change occurs in Section 8.2 Exclusion Criteria, criterion 19:
Added text: 
Non-oncology vaccine therapies for prevention of infectious diseases (eg, 
human papillomavirus [HPV] vaccine) within 4 weeks of study drug 
administration. The inactivated seasonal influenza vaccine can be given to 
patients before treatment and while on therapy without restriction. Influenza 
vaccines containing live virus or other clinically indicated vaccinations for 
infectious diseases (eg, pneumovax, varicella) may be permitted but must be 
discussed with the sponsor’s medical monitor and may require a washout 
period before and after administration of vaccine.
Rationale for Change:
Required additional information.
Section 9.6 Concomitant Medications and Procedures also contains this change.
Change 19: Update language regarding use of P-glycoprotein and/or strong cytochrome P450 3A 
inhibitors or inducers and clarify exceptions to their use for treatment of an AE requiring a 
TAK-659 hold. 
The primary change occurs in Section 8.2 Exclusion Criteria, criterion 19:
Initial 
wording:

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. The use of these agents is 
not permitted during the study. See Appendix G for a list of prohibited strong 
CYP3A reversible inhibitors and/or P-gp inhibitors based on the US FDA draft 
DDI guidance.

Medications or supplements that are known to be strong CYP3A 
mechanism-based inhibitors or strong CYP3A inducers and/or P-gp inducers 
within 7 days, or within 5 times the inhibitor or inducer half-life (whichever is 
longer), before the first dose of study drug. The use of these agents is not permitted 
during the study. See Appendix G for a list of prohibited strong CYP3A 
mechanism-based inhibitors or strong CYP3A inducers and/or P-gp inducers 
based on the US FDA draft DDI guidance.
Amended 
or new 
wording:

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, Tthe use of 
these agents is not permitted during the study (see Section 9.6 for details). See 
Appendix G for a nonexhaustive list of prohibited strong CYP3A reversible 
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inhibitors and/or P-gp inhibitors based on the US FDA draft DDI guidance.

Medications or supplements that are known to be strong CYP3A 
mechanism-based inhibitors or strong CYP3A inducers and/or P-gp inducers 
within 7 days, or within 5 times the inhibitor or inducer half-life (whichever is
longer), before the first dose of study drug. In general, Tthe use of these agents is 
not permitted during the study (see Section 9.6 for details). See Appendix G for a 
nonexhaustive list of prohibited strong CYP3A mechanism-based inhibitors or 
strong CYP3A inducers and/or P-gp inducers based on the US FDA draft DDI 
guidance.
Rationale for Change:
To be consistent with other TAK-659 protocols.
The following sections also contain this change:

Section 9.6 Concomitant Medications and Procedures.

Appendix G Medications, Supplements, and Food Products that are Strong CYP3A and/or 
P-gp Inhibitors or Inducers
Change 20: Update the language for dose-expansion patients regarding activated partial 
thromboplastin time or plasma thromboplastin.
The primary change occurs in Section 8.2 Exclusion Criteria, criterion 20:
Initial 
wording:

Activated partial thromboplastin time (aPTT) or plasma thromboplastin (PT) 
outside the normal range.
Amended 
or new 
wording:

Activated partial thromboplastin time (aPTT) or plasma thromboplastin (PT) 
outside the normal rangeinstitution’s standard of care.
Rationale for Change:
Required additional information.
Change 21: Provide additional instruction on how to address missed doses of study drug.
The primary change occurs in Section 9.2 Missed Doses and Infusion Delays:
Added 
text:
9.2
Missed Doses and Infusion Delays
If a patient does not take the TAK-659 dose at his/her scheduled dosing time (6 hours 
of the scheduled dosing time), that dose should be skipped, and the patient must not 
make dose adjustments on that day or subsequent days to account for the missed dose, 
for example, by taking a double dose of TAK-659 on the following day. Patients should 
record any skipped doses in their dosing diaries (see the Study Manual) and resume 
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dosing at the next scheduled time with the prescribed dosage. 
If severe emesis prevents the patient from taking a TAK-659 dose, that dose will be 
skipped. If emesis occurs after TAK-659 ingestion, patients should not re-dose 
following emesis and should record the time of the emesis in his/her dosing diary (see 
the Study Manual). Patients should resume dosing at the next scheduled time with the 
prescribed dosage.
Patients with nivolumab infusion delays of greater than 6 weeks should normally 
discontinue treatment and enter the Follow-up period, with the exception of cases 
where benefit-risk may justify continued study therapy (eg, patient deriving 
clinical benefit who requires prolonged steroid taper for management of non-DLT 
AEs). These situations require consultation and agreement between the 
investigator and medical monitor. 
Rationale for Change:
Required additional information.
Change 22: Update dose-limiting toxicity evaluation period. 
The primary change occurs in Section 9.4 Dose Escalation Rules:
Initial 
wording:
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) plus 2 doses of nivolumab, 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 investigators to conclude that a DLT did not occur.
Amended 
or new 
wording:
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) (depending on cycle length) plus 2 doses of 
nivolumab, and observed for ≥28 to 42 days (unless DLT occurs before the end of the 
28- to 42-day evaluation period) following the dose on Cycle 1 Day 1, and is 
considered to have sufficient safety data by both the sponsor and investigators to 
conclude that a DLT did not occur.
Rationale for Change:
To account for time that may result due to a dose delay.
The following sections also contain this change:

Section 7.1 Overview of Study Design.

Section 9.3 Definitions of DLT.

Section 14.1.1 Analysis Sets.
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Change 23: Update the guidelines for TAK-659 and nivolumab dose modifications for 
hematologic and nonhematologic toxicity. 
The primary change occurs in Section 9.5.2 Dose Modification for Hematologic and 
Nonhematologic Toxicity: TAK-659 and Nivolumab:
Description 
of Change:

Table 9.c: updated or added nivolumab dose modifications for the following:
–
Grade 4 neutrophil count (ANC) decreased.
–
Febrile neutropenia.
–
Grade 3 and 4 platelet count decreased.
–
Grade 3 and 4 anemia.

Table 9.d: updated or added nivolumab dose modifications for the following:
–
Grade 2 or 3 colitis.
–
Grade 2 or 3 encephalitis.
–
Grade 1-3 serum creatinine.
–
Grade 2 or 3 drug-related uveitis.
–
Grade 3 drug-related pneumonitis, bronchospasm, hypersensitivity reaction, or 
infusion reaction.
–
Grade 3 hypophosphatemia.
–
Grade 3 asymptomatic enzyme elevations.
Rationale for Change:
Corrected for accuracy.
Change 24: Clarify use of concomitant medications and procedures.
The primary change occurs in Section 9.6 Concomitant Medications and Procedures (formerly 
Section 9.5 Excluded Concomitant Medications and Procedures):
Initial 
wording:
9.5 Excluded Concomitant Medications and Procedures
The following medications and procedures are prohibited during the study:

Any antineoplastic therapy other than TAK-659. This includes chronic use of 
corticosteroids at daily doses greater than the equivalent of 10 mg of prednisone as 
part of any anticancer treatment regimens. If alternative therapy is required for 
treatment of the patient’s tumor, the patient should be removed from this study and 
the reason for removal recorded in the electronic case report form (eCRF).

Radiation therapy (note that, in general, the requirement for local radiation therapy 
indicates PD). Palliative radiotherapy for pain control in a pre-existing lesion may 
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be considered after discussion with the sponsor’s clinical representative. 

Prophylactic use of myeloid growth factors (eg, granulocyte colony stimulating 
factor [G-CSF], granulocyte macrophage-colony stimulating factor [GM-CSF]) in 
Cycle 1 during dose escalation. Patients who experience severe and/or febrile 
neutropenia can be managed with growth factor support if needed in accordance 
with American Society of Clinical Oncology (ASCO) guidelines.

Systemic treatment with either corticosteroids (>10 mg daily prednisone 
equivalent) or other immunosuppressive medications required as an ongoing 
therapy is not permitted with the following exceptions and clarification:
–
Patients are permitted to use topical, ocular, intra-articular, intranasal, and 
inhalational corticosteroids (with minimal systemic absorption).
–
Physiologic replacement doses of systemic corticosteroids are permitted, even 
if >10 mg/day prednisone or equivalents.
–
A brief course of corticosteroids for prophylaxis (eg, contrast dye allergy or 
prevention of infusion reactions) or for treatment of non-autoimmune 
conditions (eg, allergic reaction caused by contact allergen or drug-related 
nausea and/or vomiting) are permitted.
Systemic treatment with inhibitors or inducers of P-gp or strong inhibitors or inducers 
of CYP3A is not permitted in this study because in vitro studies indicate that TAK-659 
is a substrate for P-gp and that, among CYP isozymes, TAK-659 is preferentially 
metabolized by CYP3A4/5. Refer to the list below and Appendix G for excluded 
medications, supplements, and food products; Appendix G also provides the required 
washout period for these substances before the first dose of study drug. Note that 
medications used to treat HIV or hepatitis C infection are not listed below or in 
Appendix G 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 or P-gp 
inhibitor or inducer and/or strong CYP3A inhibitor or inducer, but is not on the list 
below and in Appendix G, then its use must be approved on a case-by-case basis by 
the medical monitor after consultation with the clinical pharmacologist and 
assessment of the relative benefit and risk.
Amended 
or new 
wording:
9.56 Excluded Concomitant Medications and Procedures
During the course of the study, patients will be instructed not to take any 
additional medications (including over-the-counter products and supplements) 
without prior consultation with the investigator. At each visit, the investigator 
will ask the patient about any new medications he/she is or has taken while on 
study. All concomitant medications (defined as any medication given during the 
study) and significant nondrug therapies, including physical therapy and blood 
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transfusions, should be recorded from signing of the informed consent form 
(ICF) through 28 days after the last dose of study drug. However, if a patient 
experiences immune-mediated toxicities that either result in discontinuation of 
nivolumab or both study treatments or occur during the 28-day AE follow-up 
period (including immune-mediated pneumonitis, colitis, hepatitis, 
endocriopathies, nephritis, rash, and encephalitis as described in the nivolumab 
USPI [17]), they will be followed to resolution or stabilization, the start of 
alternative therapy, or a minimum of 100 days after last dose of study treatment, 
whichever occurs first. During this AE follow-up period, concomitant 
medications and procedures should also be collected.
The following medications and procedures are prohibited restrictions apply during 
the study:

Any antineoplastic therapy other than TAK-659 is prohibited on study. This 
includes chronic use of corticosteroids at daily doses greater than the equivalent of 
10 mg of prednisone as part of any anticancer treatment regimens. If alternative 
therapy is required for treatment of the patient’s tumor, the patient should be 
removed from this study and the reason for removal recorded in the electronic case 
report form (eCRF).

Radiation therapy (note that, in general, the requirement for local radiation therapy 
indicates PD) is not permitted during study. Palliative radiotherapy for local 
pain/symptom control in a preexisting nontarget lesion, if required, may be 
considered after discussion with the sponsor’s clinical representative. Details of 
the palliative radiotherapy should be documented in the source records and 
eCRF, including dates of treatment, anatomical site, dose administered and 
fractionation schedule, and associated AEs.

Prophylactic use of myeloid growth factors (eg, granulocyte colony stimulating 
factor [G-CSF], granulocyte macrophage-colony stimulating factor [GM-CSF]) in 
Cycle 1 during dose escalation 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.

Systemic treatment with either corticosteroids (>10 mg daily prednisone 
equivalent) or other immunosuppressive medications required as an ongoing 
therapy is not permitted with the following exceptions and clarification:
–
SubjectsPatients are permitted to use topical, ocular, intra-articular, 
intranasal, and inhalational corticosteroids (with minimal systemic 
absorption).
–
Physiologic replacement doses of systemic corticosteroids are permitted, even 
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if >10 mg/day prednisone or equivalents.
–
A brief course of corticosteroids for prophylaxis (eg, contrast dye allergy or 
prevention of infusion reactions) or for treatment of non-autoimmune 
conditions (eg, allergic reaction caused by contact allergen or drug-related 
nausea and/or vomiting) are permitted.

Non-oncology vaccine therapies for prevention of infectious diseases (eg, 
HPV vaccine) within 4 weeks of study drug administration. 
–
The inactivated seasonal influenza vaccine can be given to patients before 
treatment and while on therapy without restriction. 
–
Influenza vaccines containing live virus or other clinically indicated 
vaccinations for infectious diseases (eg, pneumovax, varicella) may be 
permitted but must be discussed with the sponsor’s medical monitor and 
may require a washout period before and after administration of vaccine.

Systemic treatment Concurrent systemic administration of TAK-659 with 
inhibitors or inducers of P-gp or strong inhibitors or inducers of CYP3A is not 
permitted should be avoided in this study. because iIn vitro studies indicate that 
TAK-659 is a substrate for P-gp and that, among CYP isozymes, TAK-659 is 
preferentially metabolized by CYP3A4/5. Refer to the list below and Appendix G 
for excluded a nonexhaustive list of medications, supplements, and food 
products; Appendix G also provides the required washout period for these 
substances before the first dose of study drug. 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.
–
Vasopressin antagonist: conivaptan.
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–
Food/Herbals/Supplements: grapefruit-containing food and beverages, St. 
John’s wort, quercetin.
If a patient experiences an AE on study and TAK-659 dosing is temporarily 
interrupted because of that AE, the medications listed above and in Appendix G 
may be used for AE management provided there is no appropriate alternative 
treatment available per the investigator’s judgment and the dosing is not 
concurrent with TAK-659. This situation requires discussion between the 
investigator and the sponsor’s 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 below
above or in Appendix G 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 or
P-gp inhibitor or inducer and/or strong CYP3A inhibitor or inducer, but is not on the 
list below above and in Appendix G, then its use must be approved on a case-by-case 
basis by discussed with the medical monitor or designee after consultation with the 
clinical pharmacologist and assessment of to assess the relative benefit and risk.
Rationale for Change:
Required additional information.
The following sections also contain this change:

Section 10.4.9 Concomitant Medications and Procedures.

Appendix A Schedules of Events, Schedule of Events for Dose Escalation (28-Day Cycle), 
footnote j.

Appendix A Schedules of Events, Schedule of Events for Expansion TNBC, HNSCC, and 
NSCLC (28-Day Cycle), footnote j.

Appendix G Medications, Supplements, and Food Products that are Strong CYP3A and/or 
P-gp Inhibitors or Inducers.
Change 25: Add information on the management of diarrhea, edema, rash, hypophosphatemia, 
and enzyme elevations.
The primary change occurs in new Sections 9.8.3 Diarrhea through 9.8.7 Enzyme Elevations:
Added text:9.8.3
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. 
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Adequate fluid intake should be maintained to avoid dehydration, and any fluid 
deficit should be corrected before initiation of treatment with study drug and 
during treatment. Refer to Section 9.8.8.2 for management of diarrhea if 
immune-mediated colitis occurs during treatment.
9.8.4
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 following the dose modification 
guidelines in Table 9.d.
9.8.5
Rash With or Without Pruritus
Prophylactic measures should be considered if a patient develops a rash (eg, 
using a thick, alcohol-free emollient cream on dry areas of the body). In the case 
of rash, the use of a topical or oral steroid (eg, prednisone ≤10 mg per day or 
equivalent) is permitted. Refer to dose modification guidelines in Table 9.d for 
occurrence of Grade 3 or 4 rash. Refer to Section 9.8.8.8 for management of rash 
if immune-mediated dermatitis occurs during treatment.
9.8.6
Hypophosphatemia
Hypophosphatemia has been observed in patients treated with TAK-659. 
Consider prophylaxis; otherwise, refer to dose modification guidelines in Table 
9.d.
9.8.7
Enzyme Elevations 
9.8.7.1 Transaminase, Amylase, Lipase, and CPK Elevations
Elevations of transaminases, amylase, lipase, and CPK have been observed in 
patients treated with TAK-659. Events are generally asymptomatic and 
reversible with dose interruption. See dose modification guidelines in Table 9.d.
9.8.7.2 Lactate Dehydrogenase Elevations
Lactate dehydrogenase (LDH) elevations have been observed in the majority of 
patients exposed to TAK-659. These elevations have been asymptomatic, and 
their clinical significance is unknown. No action, such as dose interruption, has 
been taken as a result of increased LDH; however, LDH elevation is reversible 
on the basis of experience in patients who had TAK-659 interrupted for other 
reasons.
Rationale for Change:
Required additional information.
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Change 26: Clarify that smoking history should be collected with medical history.
The primary change occurs in Section 10.4.3 Medical History:
Initial 
wording:
During the Screening period, a complete medical history will be compiled for each 
patient.
Amended 
or new 
wording:
During the Screening period, a complete medical history (including smoking 
history) will be compiled for each patient.
Rationale for Change:
Required additional information.
The following sections also contain this change:

Appendix A Schedules of Events, Schedule of Events for Dose Escalation (28-Day Cycle), 
footnote f.

Appendix A Schedules of Events, Schedule of Events for Expansion TNBC, HNSCC, and 
NSCLC (28-Day Cycle), footnote f.
Change 27: Include pulse oximetry in the collection of vital signs.
The primary change occurs in Section 10.4.6 Vital Signs:
Added text:Pulse oximetry should be obtained before each dose of nivolumab and any time a 
patient has any new or worsening respiratory symptoms. A reading at rest and 
on exertion should be obtained at each time point. The extent of the exertion 
should be based on the judgment of the investigator but should remain consistent 
for each individual patient throughout the study. If the patient’s status changes, 
the investigator can alter the extent of exertion per their medical judgment. If a 
patient shows changes on pulse oximetry or other pulmonary-related signs 
(hypoxia, fever) or symptoms (dyspnea, cough, fever) consistent with possible 
pulmonary AEs, the patient should be immediately evaluated to rule out 
pulmonary toxicity.
Rationale for Change:
Required additional information.
Change 28: Update list of laboratory tests to include creatine phosphokinase and cardiac troponin 
I and troponin T.
The primary change occurs in Section 10.4.12.1 Clinical Chemistry, Hematology, and Urinalysis:
Description 
of change:
Added creatine phosphokinase (CPK) and cardiac troponin I and troponin T to Table 
10a. 
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Rationale for Change:
Added because of elevations in CPK observed in patients treated with TAK-659 and elevations of 
troponin observed in patients treated with TAK-659 100 mg cohort in combination with 
nivolumab (3mg/kg) who developed cardiac toxicity.
The following sections also contain this change:

Appendix A Schedules of Events, Schedule of Events for Dose Escalation (28-Day Cycle), 
footnote p.

Appendix A Schedules of Events, Schedule of Events for Expansion TNBC, HNSCC, and 
NSCLC (28-Day Cycle), footnote q.
Change 29: Update pregnancy testing to include both urine and serum pregnancy testing.
The primary change occurs in Section 10.4.13 Pregnancy Test:
Initial 
wording:
A urine pregnancy test will be performed predose on Day 1 of all cycles with negative 
results available before the first dose may be administered.
Amended 
or new 
wording:
A urine or serum pregnancy test will be performed predose on Day 1 of all cycles 
with negative results available before the first dose may be administered.
Rationale for Change:
Required additional information.
The following sections also contain this change:

Appendix A Schedules of Events, Schedule of Events for Dose Escalation (28-Day Cycle), 
footnote s.

Appendix A Schedules of Events, Schedule of Events for Expansion TNBC, HNSCC, and 
NSCLC (28-Day Cycle), footnote t.
Change 30: Update the disease assessment criteria regarding verification of response and 
verification of progression.
The primary change occurs in Section 10.4.15 Disease Assessment:
Added text:
Verification of response: To be assigned a status of CR or PR, changes in 
tumor measurements must be confirmed by consecutive repeat assessments 
that should be performed no sooner than 28 days after the criteria for 
response are first met. For this study, the next scheduled tumor assessment 
can meet this requirement.

Verification of progression: Progression of disease should be verified in cases 
where progression is equivocal. If repeat scans confirm PD, then progression 
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should be declared using the date of the initial scan. If repeat scans do not 
confirm PD, then the patient is considered to not have PD.
Rationale for Change:
Required additional information.
Change 31: Update how pseudo disease progression is defined.
The primary change occurs in Section 10.4.15 Disease Assessment:
Initial 
wording:
Pseudo-progression has been described during treatment with nivolumab in multiple 
indications. Therefore, discontinuation of study treatment is not recommended unless 
PD (at least 25% increase in tumor burden compared with nadir at any single point 
during study treatment) has been confirmed in 2 consecutive imaging assessment at 
least 4 weeks apart. However, when the objectively assessed PD per imaging is 
accompanied by rapid clinical deterioration, immediate study drug discontinuation is 
indicated. 
Amended or 
new 
wording:
Pseudo-progression has been described during treatment with nivolumab in multiple 
indications. Therefore, discontinuation of study treatment is not recommended unless 
PD (at least 25% 20% increase in tumor burden compared with nadir at any single 
point during study treatment) has been confirmed in 2 consecutive imaging 
assessment 4 8 weeks apart or more conveniently at the next scheduled imaging 
time point. However, when the objectively assessed PD per imaging is accompanied 
by rapid clinical deterioration, immediate study drug discontinuation is indicated. 
Refer to Section 10.4.16 for details regarding treatment beyond PD.
Rationale for Change:
Corrected for accuracy.
Change 32: Clarify that tumor assessments should be collected for patients who have 
interruption(s) in study drug administration.
The primary change occurs in Section 10.4.15 Disease Assessment:
Added 
text:
Tumor assessments for all patients should continue per protocol even if dosing is 
interrupted.
Rationale for Change:
Required additional information.
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Change 33: Indicate that additional exploratory independent review of study imaging data may 
occur if deemed necessary.
The primary change occurs in Section 10.4.15 Disease Assessment:
Added text: The sponsor may consider an exploratory independent central review of the 
study imaging data using immune-related RECIST if deemed necessary.
Rationale for Change:
Required additional information.
Change 34: Add section about treatment beyond disease progression.
The primary change occurs in new Section 10.4.16 Treatment Beyond Disease Progression:
Added text:10.4.16 Treatment Beyond Disease Progression
Contemporary immunotherapy protocols generally allow patients to continue 
treatment beyond initial radiographic evidence of PD following further 
investigation, as accumulating data indicates it is possible that some patients 
treated with immunotherapy may derive clinical benefit beyond initial 
RECIST-defined PD, which may not be captured by radiographic assessments. 
[36,37]In this study, patients treated TAK-659 in combination with nivolumab 
will be permitted to continue treatment beyond initial RECIST 1.1-defined PD if 
the following criteria are met:
1. Investigator-assessed overall clinical benefit from continued treatment with 
nivolumab and/or TAK-659.
2. Tolerance of study drug(s).
3. Stable performance status.
4. Treatment beyond progression will not delay an imminent intervention to 
prevent serious complications of PD (eg, CNS metastases).
5. Patient provides written informed consent before receiving additional 
nivolumab or TAK-659 treatment, using an ICF describing any reasonably 
foreseeable risks or discomforts, or other alternative treatment options.
The decision to continue treatment beyond initial RECIST 1.1-defined 
progression should be discussed with the Takeda medical monitor and 
documented in the study records. Then, the patient may remain on the study and 
continue to receive monitoring according to the protocol-defined Schedule of 
Events.
A radiographic assessment/scan should be performed within 8 weeks of original 
PD to determine whether there has been a decrease in the tumor size, or 
continued PD. 
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For the patients who continue study therapy beyond progression, further 
progression is defined as an additional ≥20% increase in tumor burden volume 
from time of initial PD. This includes an increase in the sum of all target lesions 
or the development of new measurable lesions.
New lesions are considered measureable at the time of initial progression if the 
longest diameter is at least 10 mm (except for pathological lymph nodes, which 
must have a short axis of at least 15 mm). Any new lesion considered 
non-measureable at the time of initial progression may become measureable and 
is therefore included in the tumor burden volume if the longest diameter 
increases to at least 10 mm (except for pathological lymph nodes, which must 
have a short axis of at least 15 mm).
Treatment should be discontinued permanently upon documentation of further 
PD. If the patient experiences rapid PD (such as global deterioration as 
perceived by the investigator) before radiographic assessment within 8 weeks of 
original PD, the investigator can discontinue the study treatment without 
objective evidence of disease progression and report it as “symptomatic 
deterioration”.
For statistical analyses, patients who continue study therapy beyond initial 
RECIST 1.1-defined progression will be considered to have investigator-assessed 
PD at the time of the initial progression event.
Rationale for Change:
Required additional information.
Change 35: Clarify timing of tumor biopsy sampling. 
The primary change occurs in Section 10.4.17 Tumor Biopsies:
Initial 
wording:
The biopsy sample at Screening must be obtained at least 2 days after the last dose of 
any prior anticancer therapy and before the first dose of study drug treatment. Patients 
undergoing tumor biopsy procedures must have a platelet count >75,000/mm3 and an
aPTT and PT within the normal range; must not have an ECOG performance status 
>1; must not be receiving any anticoagulant therapy or antiplatelet agents; and must 
not have any other known coagulation abnormalities that would contraindicate the 
tumor biopsy procedure.
Amended 
or new 
wording:
The biopsy sample at Screening must be obtained at least 2 days after the last dose of 
any prior anticancer therapy and before the first dose of study drug treatment. Patients 
undergoing tumor biopsy procedures must have a platelet count >75,000/mm3 and an 
aPTT and PT within the normal rangebased on site’s institutional standard; must 
not have an ECOG performance status >1; must not be receiving any anticoagulant 
therapy or antiplatelet agents; and must not have any other known coagulation 
abnormalities that would contraindicate the tumor biopsy procedure.
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Rationale for Change:
Required additional information.
Appendix A Schedules of Events, Schedule of Events for Expansion TNBC, HNSCC, and NSCLC 
(28-Day Cycle), footnote v, also contains this change.
Change 36: Specify that cytokine/chemokine measurements will be taken from serum. 
The primary change occurs in Section 10.4.20 Cytokine/Chemokine Measurements:
Initial 
wording:
Plasma will be extracted from blood samples and subjected to analysis of a panel of 
cytokines and chemokines using a multiplex platform.
Amended 
or new 
wording:
PlasmaSerum will be extracted from blood samples and subjected to analysis of a 
panel of cytokines and chemokines using a multiplex platform.
Rationale for Change:
Required additional information.
Change 37: Clarify study drug dosing instructions on days when predose pharmacokinetic (PK) 
samples are scheduled.
The primary change occurs in Section 10.4.22 PK Measurements, Dose Escalation Cohorts 
subsection:
Initial 
wording:
Dose Escalation Cohorts
Blood samples for determination of TAK-659 plasma concentrations will be obtained 
during Cycle 1 on Days 1, 2, 15, and 16 at the times indicated in Table A. The samples 
obtained on Days 2 and 16 should be obtained before TAK-659 dosing on those days. 
On those days, patients should be instructed to refrain from taking their TAK-659 dose 
at home before the clinic visit.
Amended 
or new 
wording:
Dose Escalation Cohorts
Blood samples for determination of TAK-659 plasma concentrations will be obtained 
during Cycle 1 on Days 1, 2, 15, and 16 at the times indicated in Table A. The samples 
obtained on Days 2 and 16 should be obtained before TAK-659 dosing on those days. 
On those days, For clinic visits where predose PK samples are scheduled, patients
should will be instructed to refrain from taking their TAK-659 dose at home before the 
clinic visit.
Rationale for Change:
To ensure that patients do not take study drug at home on any day when predose PK samples are 
scheduled.
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Change 38: Add to the PK measurements section a rationale for conducting PK sampling at any 
time during the clinic visit on Cycle 1 Day 8 during dose expansion.
The primary change occurs in Section 10.4.22 PK Measurements, Dose Expansion Cohorts 
subsection:
Added text:A distribution of clinic visit times during the day across patients is to be 
encouraged to provide a range of postdose sampling times across the study 
population.
Rationale for Change:
To ensure consistency of PK-related information between the PK measurements section and 
Table B.
Change 39: Update reasons for completion of treatment.
The primary change occurs in Section 10.5 Completion of Treatment:
Initial 
wording:
Patients will be considered to have completed study treatment if they have an 
opportunity to complete 6 cycles of study treatment, if they achieve a CR, or if they 
experience PD.
Amended 
or new 
wording:
Patients will be considered to have completed study treatment if they have an 
opportunity to complete 6 cycles of study treatment, if they achieve a CR, or if they 
experience PD.Patients will be treated until PD, occurrence of unacceptable 
toxicities, withdrawal due to other reasons, or the study is terminated by the 
sponsor. Study treatment can continue beyond initial RECIST 1.1 progression as 
specified in Section 10.4.16.
Rationale for Change:
To be consistent with other TAK-659 protocols.
Section 2.0 STUDY SUMMARY also contains this change.
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TAK-659
Study No. C34003 
Page 161 of 168
Protocol Incorporating Amendment No. 02
27 April 2017
Change 40: Indicate that the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, 
not modified RECIST version 1.1, will be used to measure PD.
The primary change occurs in Section 10.7 Discontinuation of Treatment With Study Drug and 
Patient Replacement:
Initial 
wording:

PD: as noted previously, PD per RECIST should be confirmed in 2 subsequent 
scans at least 4 weeks apart before treatment discontinuation is considered unless 
there are clear signs of rapid clinical progression. In addition, in rare situations, 
patients with confirmed PD may remain on study, after discussion between the 
investigator and the sponsor clinician, if it is felt that they are deriving a clinical 
benefit from doing so.
Amended 
or new 
wording:

PD: as noted previously, PD per RECIST 1.1 should be confirmed in 2 subsequent 
scans at least 48 weeks apart before treatment discontinuation is considered unless 
there are clear signs of rapid clinical progression. In addition, in rare situations, 
patients with confirmed PD may remain on study, after discussion between the 
investigator and the sponsor clinician, if it is felt that they are deriving a clinical 
benefit from doing so.
Rationale for Change:
To correct for accuracy.
The following sections also contain this change:

Section 2.0 STUDY SUMMARY.

Section 10.4.15 Disease Assessment.
Change 41: Update procedures for monitoring AEs and the period of observation.
The primary change occurs in Section 11.3 Monitoring of AEs and Period of Observation:
Added text:

AEs will be reported from signing of the ICF through 28 days after 
administration of the last dose of study drug and recorded in the eCRFs. 
However, immune-mediated toxicities that either result in 
discontinuation of nivolumab or both study treatments or occur during 
the 28-day AE follow-up period (including immune-mediated 
pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, rash, and 
encephalitis as described in nivolumab USPI) will be followed to 
resolution or stabilization, or the start of alternative therapy, or a 
minimum of 100 days after last dose of study treatment, whichever occurs 
first.
Rationale for Change:
Required additional information.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-659
Study No. C34003 
Page 162 of 168
Protocol Incorporating Amendment No. 02
27 April 2017
The following sections also contain this change:

Section 7.3 Duration of Study. also contains this change.

Appendix A Schedules of Events, Schedule of Events for Dose Escalation (28-Day Cycle), 
footnote j.

Appendix A Schedules of Events, Schedule of Events for Expansion TNBC, HNSCC, and 
NSCLC (28-Day Cycle), footnote j.
Change 42: Clarify that PK parameters will be summarized using descriptive statistics.
The primary change occurs in Section 14.1.4 PK Analysis:
Initial 
wording:
Plasma PK parameters of TAK-659 will be summarized by dose group and by dosing 
cycle and day.
Amended 
or new 
wording:
Plasma PK parameters of TAK-659 will be summarized using descriptive statistics
by dose group and by dosing cycle and day.
Rationale for Change:
Required additional information.
Section 2.0 STUDY SUMMARY also contains this change.
Change 43: Indicate that the relationship between PK and pharmacodynamics changes may be 
evaluated. 
The primary change occurs in Section 14.1.5 Pharmacodynamic Analysis:
Added text:In addition, the relationship between PK and pharmacodynamics changes may 
be evaluated as permitted by the data.
Rationale for Change:
Required additional information.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


TAK-659
Study No. C34003 
Page 163 of 168
Protocol Incorporating Amendment No. 02
27 April 2017
Change 44: Update language regarding informed consent forms.
The primary change occurs in Section 16.2 Patient Information, Informed Consent, and Patient 
Authorization (formerly titled Subject Information, Informed Consent, and Subject 
Authorization):
Initial 
wording:
The ICF, subject authorization form (if applicable), and subject information sheet (if 
applicable) must be written in a language fully comprehensible to the prospective 
subject. It is the responsibility of the investigator to explain the detailed elements of 
the ICF, subject authorization form (if applicable), and subject information sheet (if 
applicable) to the subject. Information should be given in both oral and written form 
whenever possible and in the manner deemed appropriate by the IRB or IEC. In the 
event the subject is not capable of rendering adequate written informed consent, then 
the subject’s legally acceptable representative may provide such consent for the 
subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample 
opportunity to: (1) inquire about details of the study and (2) decide whether or not to 
participate in the study. If the subject, or the subject’s legally acceptable 
representative, determines he or she will participate in the study, then the ICF and 
subject authorization form (if applicable) must be signed and dated by the subject, or 
the subject’s legally acceptable representative, at the time of consent and prior to the 
subject entering into the study. The subject or the subject’s legally acceptable 
representative should be instructed to sign using their legal names, not nicknames, 
using blue or black ballpoint ink.
…
All revised ICFs must be reviewed and signed by relevant subjects or the relevant 
subject’s legally acceptable representative in the same manner as the original 
informed consent.
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TAK-659
Study No. C34003 
Page 164 of 168
Protocol Incorporating Amendment No. 02
27 April 2017
Amended 
or new 
wording:
The ICF, subject patient authorization form (if applicable), and subject patient 
information sheet (if applicable) must be written in a language fully comprehensible to 
the prospective subject patient. It is the responsibility of the investigator to explain 
the detailed elements of the ICF, subject patient authorization form (if applicable), 
and subject patient information sheet (if applicable) to the subject 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 subject is not 
capable of rendering adequate written informed consent, then the subject’s legally 
acceptable representative may provide such consent for the subject in accordance with 
applicable laws and regulations.
The subject patient, or the subject’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 subject patient, or the subject’s legally acceptable 
representative, determines he or she will participate in the study, then the ICF and 
subject patient authorization form (if applicable) must be signed and dated by the 
subject patient, or the subject’s legally acceptable representative, at the time of 
consent and prior to the subject patient entering into the study. The subjectPatients or 
the subject’s legally acceptable representative, should be instructed to sign using their 
legal names, not nicknames, using blue or black ballpoint ink.
…
All revised ICFs must be reviewed and signed by relevant subjects patients or the 
relevant subject’s legally acceptable representative in the same manner as the original 
informed consent.
Rationale for Change:
Added to comply with International Council for Harmonisation (ICH) Section 4.2.6.
Appendix B Responsibilities of the Investigator also contains this change.
Change 45: Clarify language regarding study-site monitoring visits.
The primary change occurs in Section 15.1 Study-Site Monitoring Visits:
Deleted 
text:
All aspects of the study and its documentation will be subject to review by the sponsor 
or designee (as long as blinding is not jeopardized), including but not limited to the 
Investigator’s Binder, study medication, subject medical records, informed consent 
documentation, documentation of subject authorization to use personal health 
information (if separate from the ICFs), and review of eCRFs and associated source 
documents.
Rationale for Change:
Corrected for accuracy.
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TAK-659
Study No. C34003 
Page 165 of 168
Protocol Incorporating Amendment No. 02
27 April 2017
Change 46: Remove time-bound references to the nivolumab USPI.
The primary change occurs in Section 17.0 REFERENCES:
Initial 
wording:
17. OPDIVO (nivolumab) [prescribing information]. Princeton, NJ: Bristol-Myers 
Squibb, 2016.
Amended 
or new 
wording:
17. OPDIVO (nivolumab) [prescribing information]. Princeton, NJ: Bristol-Myers 
Squibb, 2016 dailymed.nlm.nih.gov/dailymed/.
Rationale for Change:
To reflect the latest version of the prescribing information.
The following sections also contain this change:

Section 4.1.5 Risks and Benefits.

Section 9.5.2 Dose Modification for Hematologic and Nonhematologic Toxicity: TAK-659 
and Nivolumab.

Section 10.7 Discontinuation of Treatment With Study Drug and Patient Replacement.
Change 47: Update the Schedule of Events to include additional tests when nivolumab is dosed.
The primary change occurs in Appendix A Schedules of Events:
Description 
of Change:
Removed “Cycle 5, 6, and beyond” column and updated “Cycles 2, 3, and 4” column 
to indicate “Cycle 2 and beyond”.
Rationale for Change:
To ensure appropriate monitoring of laboratory tests prior to nivolumab dosing on Day 15 of study 
cycles.
Appendix A Schedules of Events, Schedule of Events for Expansion TNBC, HNSCC, and NSCLC 
(28-Day Cycle), also contains this change.
Change 48: Update timing of vital sign measurements for Cycle 1 Day 1.
The primary change occurs in Appendix A Schedules of Events, Schedule of Events for Dose 
Escalation (28-Day Cycle), footnote h:
Initial 
wording:
(h) 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.
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TAK-659
Study No. C34003 
Page 166 of 168
Protocol Incorporating Amendment No. 02
27 April 2017
Amended 
or new 
wording:
(h) Measure vital signs before dosing. On Cycle 1 Day 1 only, also measure vital signs 
at 1 and 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.
Rationale for Change:
Reduce unnecessary measurements.
Appendix A Schedules of Events, Schedule of Events for Expansion TNBC, HNSCC, and NSCLC 
(28-Day Cycle), footnote h, also contains this change.
Change 49: Clarify language regarding disease response assessments to include all relevant sites 
of disease.
The primary change occurs in Appendix A Schedules of Events, Schedule of Events for Dose 
Escalation (28-Day Cycle), footnote o:
Initial 
wording:
(n) Response assessments for solid tumors, including CT scan with contrast (or MRI if 
clinically indicated) of the chest, abdomen, and pelvis, relevant tumor markers (eg, 
CA125, PSA, CA19.9, CEA), and physical assessment of the disease will be 
performed at Screening, between Days 22 and 29 (predose) of Cycles 2, 4, and 6, and 
between Days 22 and 29 (predose) of every 3 cycles thereafter (ie, Cycle 9, 12, etc).
Amended 
or new 
wording:
(n) Response assessments for solid tumors, including CT scan with contrast (or MRI if 
clinically indicated) of the chest, abdomen, and pelvis, and other known sites of 
disease (eg, head and neck), relevant tumor markers (eg, CA125, PSA, CA19.9, 
CEA), and physical assessment of the disease will be performed at Screening, between 
Days 22 and 29 (predose) of Cycles 2, 4, and 6, and between Days 22 and 29 (predose) 
of every 3 cycles thereafter (ie, Cycle 9, 12, etc).
Rationale for Change:
Reduce unnecessary measurements.
Appendix A Schedules of Events, Schedule of Events for Expansion TNBC, HNSCC, and NSCLC 
(28-Day Cycle), footnote p, also contains this change.
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TAK-659
Study No. C34003 
Page 167 of 168
Protocol Incorporating Amendment No. 02
27 April 2017
Change 50: Clarify language regarding purpose of pharmacodynamic assessments.
The primary change occurs in Appendix A Schedules of Events, Schedule of Events for Expansion 
TNBC, HNSCC, and NSCLC (28-Day Cycle), footnotes z, aa, and bb:
Initial 
wording:
(y) Peripheral blood samples will be collected at Screening, Cycle 1 Day 15, and 
Cycle 3 Day 1 for pharmacodynamic assessment and development of a biomarker(s) 
predictive of clinical activity of the combination of TAK-659 and nivolumab. Samples 
will be subjected to flow cytometry analysis to evaluate changes in immune cell 
populations.
(z) Peripheral blood samples will be collected at Screening, Cycle 1 Day15, and Cycle 
3 Day 1 for pharmacodynamic assessment and development of a biomarker(s) 
predictive of clinical activity of the combination of TAK-659 and nivolumab. Samples 
will be assayed to measure a panel of cytokines and chemokines known for or deemed 
relevant to tumor growth and antitumor activity of TAK-659 and the combination with 
nivolumab.
Amended 
or new 
wording:
(y) Peripheral blood samples will be collected from all patients enrolled in the 
expansion phase at Screening, and predose on Cycle 1 Day 15, and Cycle 3 Day 1 
for pharmacodynamic assessment and development of a biomarker(s) predictive of 
their potential association with clinical activity of the TAK-659 or in combination 
of TAK-659 andwith nivolumab. Samples will be subjected to flow cytometry 
analysis to evaluate changes in immune cell populations.
(z) Peripheral blood samples will be collected at Screening, and predose on Cycle 1 
Day 15, and Cycle 3 Day 1 for pharmacodynamic assessment and development of a 
biomarker(s) predictive of their potential association with clinical activity of the 
TAK-659 or in combination of TAK-659 andwith nivolumab. Samples will be 
assayed to measure a panel of cytokines and chemokines known for or deemed 
relevant to tumor growth and antitumor activity of TAK-659 and the combination with 
nivolumab.
Rationale for Change:
Required additional information.
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TAK-659
Study No. C34003 
Page 168 of 168
Protocol Incorporating Amendment No. 02
27 April 2017
Change 51: Update responsibilities of investigator.
The primary change occurs in Appendix B Responsibilities of the Investigator:
Added text:5. If trial-related duties and functions are assigned to any individual or party, 
ensure that this individual or party is qualified to perform those trial-related 
duties and functions, and implements procedures to ensure the integrity of the 
trial-related duties and functions performed and any data generated.
Rationale for Change:
Added to comply with International Council for Harmonisation (ICH) Section 4.2.6.
Change 52: Add RECIST version 1.1 as appendix.
The primary change occurs in Appendix I Response Evaluation Criteria in Solid Tumors (RECIST 
Version 1.1):
Description 
of change
Added RECIST Version 1.1 as new appendix.
Rationale for Change:
Required additional information.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


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SAP_000.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 Study to Evaluate TAK-659 in Combination With Nivolumab in Patients With 
Advanced Solid Tumors 
NCT Number: NCT02834247
SAP Approve Date: 22JAN2019
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information 
or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


1.0
TITLE PAGE
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: C34003
A Phase 1b Study to Evaluate TAK-659 in Combination with Nivolumab in Patients with 
Advanced Solid Tumors
TAK-659 in Combination with Nivolumab in Advanced Solid Tumors
Phase: 1b
Version: Final
Date: 22JAN2019
Prepared by:
Based on:
Protocol Version: Amendment 02
Protocol Date: 27APR2017
Proper
of Takeda: For n
ercial use only and subject to the applicable Terms of Use
volumab
lum
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: F
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TAK659 - C34003
Page 2 of 24
Statistical Analysis Plan Final
22 January 2019
1.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
1.0
TABLE OF CONTENTS.................................................................................................2
List of In-Text Tables............................................................................................................3
2.0
LIST OF ABBREVIATIONS..........................................................................................4
3.0
OBJECTIVES .................................................................................................................6
3.1
Primary Objectives ....................................................................................................6
3.2
Secondary Objectives.................................................................................................6
3.3
Exploratory Objectives ..............................................................................................6
3.4
Additional Objectives ................................................................................................6
3.5
Study Design .............................................................................................................6
4.0
ANALYSIS ENDPOINTS...............................................................................................9
4.1
Primary Endpoints .....................................................................................................9
4.2
Secondary Endpoints .................................................................................................9
4.3
Exploratory endpoints................................................................................................9
4.4
Additional Endpoints ...............................................................................................10
5.0
DETERMINATION OF SAMPLE SIZE.......................................................................11
6.0
METHODS OF ANALYSIS AND PRESENTATION...................................................12
6.1
General Principles....................................................................................................12
6.2
Definition of Baseline Values ..................................................................................12
6.3
Definition of Study Days .........................................................................................12
6.4
Conventions for Handling Missing Data ..................................................................12
6.4.1
Conventions for Missing partial dates in Screen Visits .......................................12
6.4.2
Conventions for Missing Adverse Event Dates...................................................13
6.4.3
Conventions for Missing Concomitant Medication/Therapy Dates .....................13
6.5
Analysis Sets ...........................................................................................................14
6.6
Disposition of Subjects ............................................................................................14
6.7
Demographic and Other Baseline Characteristics.....................................................15
6.8
Medication History and Concomitant Medications...................................................15
6.9
Study Drug Exposure and Compliance.....................................................................15
6.10
Efficacy Analysis.....................................................................................................16
6.10.1 Primary Efficacy Endpoint(s).............................................................................16
6.10.2 Secondary Efficacy Endpoint(s).........................................................................16
6.10.3 Additional Efficacy Endpoint(s).........................................................................17
6.11
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................18
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Statistical Analysis Plan Final
22 January 2019
6.11.1 Pharmacokinetic Analysis ..................................................................................18
6.11.2 Pharmacodynamic/Biomarker/Pharmacogenomic Analyses................................18
6.12
Other Outcomes.......................................................................................................19
6.13
Safety Analysis........................................................................................................19
6.13.1 Adverse Events ..................................................................................................19
6.13.2 Clinical Laboratory Evaluations .........................................................................20
6.13.3 Vital Signs .........................................................................................................21
6.13.4 12-Lead ECGs ...................................................................................................21
6.13.5 Other Observations Related to Safety.................................................................22
6.14
Interim Analysis ......................................................................................................22
6.15
Changes in the Statistical Analysis Plan...................................................................22
7.0
REFERENCES..............................................................................................................23
LIST OF IN-TEXT TABLES
Table 6.a
Handling of Missing Response Assessment and Censoring for Progression-
Free Survival Analysis Based on US Food and Drug Administration Guidance..17
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Page 4 of 24
Statistical Analysis Plan Final
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2.0
LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUCtau
area under the plasma concentration versus time curve over the dosing interval
BMI
body mass index
BUN
blood urea nitrogen
CLss/F
apparent oral clearance at steady state
Cmax
maximum plasma concentration
CPK
creatine phosphokinase
CR
complete response
CRF
case report form
DCR
disease control rate
DLT
dose-limiting toxicity
DOR
duration of response
ECG
electrocardiogram
FAS
full analysis set
GGT
-glutamyl transferase
ICH
International Conference on Harmonization
IVRS
Interactive Voice Response System
LDH
lactate dehydrogenase
LLN
lower limit of normal
LOCF
last observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities
MTD
Maximum Tolerated Dose
ORR
overall response rate
OS
overall survival
PD
progressive disease (disease progression)
PFS
progression -free survival
PK
pharmacokinetics
PR
partial response
PTR
peak-through ratio
QOL
quality-of-life
PRO
patient-reported outcome
Rac
accumulation ratio
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
recommended phase 2 dose
SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease
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Statistical Analysis Plan Final
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SDB
standard database
tmax
first time to reach maximum plasma concentration
TLGs
tables, listings, and graphs
ULN
upper limit of normal
WHODrug
World Health Organization Drug Dictionary
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3.0
OBJECTIVES
3.1
Primary Objectives
∀
To determine the Maximum Tolerated Dose/Recommended Phase 2 Dose (MTD/RP2D) of 
TAK-659 when administered in combination with nivolumab (dose escalation phase).
∀
To determine the efficacy of TAK-659 plus nivolumab as measured by Overall Response 
Rate (ORR) (dose expansion phase).
3.2
Secondary Objectives
∀
To determine the safety and tolerability of TAK-659 when administered in combination with 
nivolumab.
∀
To evaluate other efficacy measures such as disease control rate (DCR) Duration of 
Response (DOR), rate of Progression of Disease (PD) at 6 months, progression-free survival 
(PFS), and Overall Survival (OS).
∀
To characterize the plasma pharmacokinetics (PK) of TAK-659 when administered in 
combination with nivolumab.
3.3
Exploratory Objectives
The exploratory objectives are:
3.4
Additional Objectives
The additional objective is to collect TAK-659 plasma concentration data to contribute to
population PK analyses.
3.5
Study Design
This is an open-label, multicenter, phase 1b, dose escalation study of TAK-659 in combination 
with nivolumab in patients with advanced solid tumors. The study will include a dose escalation 
phase (Part 1) and a dose expansion phase (Part 2). In the dose escalation phase, the patient 
population will consist of all-comer patients with advanced solid tumors for whom 1 or more 
prior lines of therapy have failed and who have no effective therapeutic options available based 
on investigator assessment. The dose expansion phase will include 3 cohorts: (1) patients with 
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Statistical Analysis Plan Final
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metastatic triple-negative breast cancer (TNBC) who have had ≥1 prior line of chemotherapy; 
(2) patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that has 
progressed on or after a prior platinum-based chemotherapy; and (3) patients with locally 
advanced or metastatic head and neck squamous cell carcinoma (HNSCC) that has progressed or 
recurred within 6 months of the last platinum-based chemotherapy.
It is expected that approximately 126 patients will be enrolled in the study: approximately 9 to 
12 patients in the dose escalation cohort evaluating weight-based dosing of nivolumab, 3 to 
6 patients in a possible nivolumab fixed-dose evaluation cohort (if it is opened), and 
approximately 36 patients (30 evaluable patients+15% drop off) in each of the 3 dose expansion 
cohorts. Enrollment is defined as the time of the initiation of the first dose of study drug. Once 
enrolled in the study, patients will be administered TAK-659 orally once daily (QD) during each 
28-day treatment cycle. Patients receiving the combination therapy will also receive nivolumab 
once every 2 weeks intravenously (IV) over 60 minutes on Day 1 and Day 15 of each 28-day 
treatment cycle (for patients who receive 2 weeks of TAK-659 monotherapy before starting 
combination treatment, the first nivolumab infusion will be administered on Cycle 1 Day 15). On 
days when both TAK-659 and nivolumab will be administered, the TAK-659 dose will be 
administered first followed by the nivolumab infusion (infusion to begin within 30 minutes after 
the TAK-659 dose). Patients, including those who achieve a complete response (CR), may 
receive study treatment until they experience PD or unacceptable toxicities.
The dose of nivolumab will be 3 mg/kg IV. 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) may be also evaluated if appropriate. Dose escalation will continue 
until the maximum tolerated dose (MTD) is reached, or until 100 mg QD of TAK-659 (the 
maximally administered dose, [MAD]) is determined to be safe and tolerable, or until a 
recommended phase 2 dose (RP2D), if different from the MTD or MAD, has been identified on 
the basis of the safety, tolerability, and preliminary pharmacokinetic (PK) and efficacy data (if 
available) observed in Cycle 1 and beyond. At least 6 patients will be evaluated at the RP2D (the 
MTD, MAD, or a lower dose as determined) before making a decision to advance to further dose 
expansion.
After the combination RP2D (the MTD, MAD, or a lower dose) is determined, expansion 
cohorts are planned in patients with TNBC, NSCLC, and HNSCC. Thirty response-evaluable 
patients will be enrolled in each expansion cohort, including approximately 10 patients in each 
cohort who are able to provide evaluable serial biopsies.
Additionally, each expansion cohort will include 24 response-evaluable patients who are naïve to 
anti-programmed cell death protein 1 (PD-1)/anti-programmed cell death 1 ligand 1 (PD-L1) 
therapy and 6 response-evaluable patients who are relapsed/refractory to prior 
anti-PD-1/anti-PD-L1 therapy. Ten response-evaluable patients in each expansion cohort will 
first receive single-agent treatment with TAK-659 for 2 weeks at the RP2D previously 
determined in combination with nivolumab. Following the 2-week, single-agent treatment, 
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TAK-659 treatment will continue (at the same dose) in combination with nivolumab during 
Week 3 and beyond.
The subset of expansion patients who will be treated with single-agent TAK-659 at its 
combination RP2D during Weeks 1 and 2 should have accessible tumors for core or excisional 
biopsy and provide permission for the biopsies to be taken. These patients will undergo 
mandatory biopsies before single-agent TAK-659 treatment begins, at the end of the 2-week 
treatment window, and after 6 weeks of treatment with TAK-659 in combination with 
nivolumab; an optional biopsy will also be taken at the time of PD. The biopsies will be used for 
biomarker analysis evaluating the effect of TAK-659 on tumor cells and on immune/stromal 
cells supporting tumor tissue.
The remaining 20 response-evaluable patients in each expansion cohort will receive TAK-659 at 
its RP2D in combination with nivolumab, starting from Week 1, Day 1.
During dose escalation, serial blood samples for assessment of TAK-659 plasma PK will be 
collected for 24 hours after TAK-659 dosing on Cycle 1 Days 1 and 15, the days on which both 
TAK-659 and nivolumab are administered. During the expansion phase, sparse PK samples will 
be collected. 
All patients in the expansion cohorts will be treated until either PD or occurrence of 
unacceptable toxicities. The objectives of these expansion cohorts are to evaluate efficacy of 
TAK-659 in combination with nivolumab as measured by overall response rate (ORR) and to 
determine the safety and tolerability of TAK-659 in combination with nivolumab.
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4.0
ANALYSIS ENDPOINTS
4.1
Primary Endpoints
∀
Maximum tolerated dose (MTD) or Recommended phase 2 dose (RP2D) (dose escalation
phase).
∀
ORR as assessed by the investigator per Response Evaluation Criteria in Solid Tumors
(RECIST) version 1.1 [1] (dose expansion phase).
4.2
Secondary Endpoints
∀
Percentage of patients with AEs.
∀
Percentage of patients with Grade 3 and Grade 4 AEs.
∀
Percentage of patients with SAEs.
∀
Percentage of patients who discontinued due to AEs.
∀
Clinically significant laboratory values.
∀
Clinically significant vital sign measurements.
∀
Disease control rate.
∀
DOR.
∀
TAK-659 maximum (peak) plasma concentration (Cmax), first time to reach maximum (peak) 
plasma concentration (tmax), and area under the plasma concentration versus time curve over 
the dosing interval (AUCtau) on Cycle 1, Days 1 and 15, by dose escalation cohort.
∀
Rate of PD at 6 months.
∀
PFS.
∀
OS.
4.3
Exploratory endpoints
Prope
or non-commercial use only and subject to the applicable Terms of Use
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4.4
Additional Endpoints

TAK-659 apparent oral clearance (CLss/F), peak-trough ratio (PTR), accumulation ratio 
(Rac), and trough concentration (Ctrough) on Cycle 1 Day 15 by dose escalation cohort.
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5.0
DETERMINATION OF SAMPLE SIZE
During the dose escalation phase, dose escalation will be conducted according to a standard 3+3 
dose escalation schema, and approximately 9 to 12 dose-limiting toxicity-evaluable patients will 
be enrolled. The MTD/RP2D cohort will have at least 6 patients.
The sample size for the expansion cohort is estimated using a 1-sided exact binomial test at a 
significance level of alpha=0.1 with a power of 80%. Each cohort uses a null hypothesis of 
response rate ≤20%, versus an alternative hypothesis of response rate ≥40% for patients who are 
naïve to anti-PD/PD-L1 and any other immune-directed antitumor therapies. Therefore, 
approximately 24 response-evaluable patients for each cohort will be needed. In addition, 
6 response-evaluable patients with prior exposure to a PD-1 or PD-L1 inhibitor will be enrolled 
in each expansion cohort. In total, 30 response-evaluable patients for each cohort and 
90 response-evaluable patients in total (~108 patients based on a 15% drop-out rate) will be 
needed for all expansion cohorts.
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6.0
METHODS OF ANALYSIS AND PRESENTATION
6.1
General Principles 
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.
All statistical analyses will be conducted using SAS® Version 9.4, 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 each dose group in the escalation cohort, total for dose 
escalation phase, and by expansion cohort and overall for both phases as appropriate.
6.2
Definition of Baseline Values
Unless otherwise specified, baseline value is defined as the last observed value before the first 
dose of study medication. Screening values are considered as baseline values if cycle 1 day 1 
value is unavailable.
6.3
Definition of Study Days
Study Day 1 is defined as the date on which a subject is administered their first dose of the 
medication. Other study days are defined relative to the Study Day 1 with Day 1 being Study 
Day 1 and Day -1 being the day prior to Study Day 1.
6.4
Conventions for Handling Missing Data
6.4.1
Conventions for Missing partial dates in Screen Visits
The following rules apply to dates recorded during the screening visits. 
If only the day-component is missing, the first day of the month will be used if the year and 
1.
the month are the same as those for the first dose of study drug. Otherwise, the fifteenth will 
be used. 
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If only the year is present, and it is the same as the year of the first dose of study drug, the 
2.
fifteenth of January will be used unless it is later than the first dose, in which case the first of 
January will be used. 
If only the year is present, and it is not the same as the year of the first dose of study drug, the 
3.
fifteenth of June will be used, unless other data indicates that the date is earlier.
6.4.2
Conventions for Missing Adverse Event Dates
Adverse events with start dates that are completely or partially missing will be analyzed as 
follows:

If the start date has a month and year but the day is missing, the event will be considered 
treatment emergent if the month and year of the start date of the event are: 
–
on or after the month and year of the date of the first dose of study drug
and 
–
on or before the month and year of the date of the last dose of any study drug plus 28
days, or the start date of subsequent anticancer therapy, whichever occurs first.

If the start date has a year, but the day and month are missing, the event will be considered 
treatment emergent if the year of the start date of the event is:
–
on or after the year of the date of the first dose of study drug
and 
–
on or before year of the date of the last dose of any study drug plus 28 days, or the start 
date of subsequent anticancer therapy, whichever occurs first.

If the start date of an event is completely missing, then the event is assumed to be treatment 
emergent.
However, if it is clear that the end date is before the first dose of study drug, the event will not be 
considered treatment emergent.
6.4.3
Conventions for Missing Concomitant Medication/Therapy Dates
Concomitant medications/therapies with start dates that are completely or partially missing will 
be analyzed as follows:
If the start date has a month and year but the day is missing, the event will be considered 
1.
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, or the start date of subsequent anticancer therapy, whichever occurs first.
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If the start date has a year, but the day and month are missing, the event will be considered 
2.
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, or the 
start date of subsequent anticancer therapy, whichever occurs first.
If the start date of an event is completely missing, then the event is assumed to be 
3.
concomitant. 
However, if it is clear that the end date is before the first dose of study drug, 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.
6.5
Analysis Sets
The Analysis Sets (Analysis Populations) will include the following:

Safety population: Safety population is defined as all patients who receive at least 1 dose of 
study drug. Patients will be analyzed according to the actual treatment they received.

Response-Evaluable population: Response-Evaluable population is defined as patients who 
receive at least 1 dose of study drug, have measurable disease at Baseline, and have at least 
1 post-Baseline disease assessment.

PK-Evaluable population (dose escalation): PK-Evaluable population is defined as patients 
with sufficient concentration-time and dosing data to reliably estimate PK parameters. This 
population will be used for analyses of PK parameters.

DLT-Evaluable population: DLT-Evaluable population is defined as patients who have met 
the minimum treatment and safety evaluation requirements of the study and/or who 
experience a DLT during Cycle 1. The minimum treatment and safety evaluation 
requirements are met if, in Cycle 1, the patient has been treated with TAK-659 for ≥21 days 
(receiving at least 75% of planned doses of TAK-659 in Cycle 1) plus 2 doses of nivolumab, 
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 investigators to conclude that a DLT did not occur.
6.6
Disposition of Subjects
Disposition of patients includes the number and percentage of patients in each dose group in the 
dose escalation phase, total dose escalation phase, safety expansion phase and overall for the 
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escalation and expansion phases, along with a summary of the primary reason for patients’ study 
termination. 
Subjects who failed the screening will be summarized in a separate table by age, age category, 
gender, ethnicity, race. Primary reasons for screen failure will also be summarized.
6.7
Demographic and Other Baseline Characteristics
Demographics will be summarized. Baseline demographic data to be evaluated will include age, 
sex, race, ethnicity, height, and weight. Age will be calculated from date of birth to date of 
informed consent.
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. 
6.8
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 medication drug, or to the start of 
subsequent anticancer therapy, whichever occurs first. 
6.9
Study Drug Exposure and Compliance
The exposure to TAK-659 and Nivolumab will be characterized separately by: Number of 
Treated Cycles, Number of Cumulative Treatment Cycles ((≥1, ≥2, …, ≥6, and ≥12 cycles), 
Duration of Treatment (weeks) and Cumulative Dose (mg). Relative Dose Intensity (%) will be 
summarized for TAK-659.
Relative dose intensity (%) for TAK-659 is defined as 100 x (total dose received in mg) / (initial 
prescribed dose per day x number of treated days). Where number of treated days = (reference 
end date for study drug – reference start date for study drug) + 1. 
Action on study drug will be summarized by cycles (Cycles 1, 2, 3, …6 and post-Cycle 6), and 
total for each dose group in the dose escalation phase, for total of the dose escalation phase, for 
the safety expansion phase and for overall of all the patients in the safety population. 
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6.10
Efficacy Analysis
All efficacy analyses will be based on investigator assessments. Investigators will assess 
response using the RECIST criteria for solid tumors. Efficacy endpoints will be summarized for 
both dose escalation and dose expansion phase. For the dose escalation phase, they will be 
summarized by dose groups as needed. 
6.10.1 Primary Efficacy Endpoint(s)
The primary efficacy endpoint is ORR in the dose expansion phase. A responder is defined as a 
patient who has either CR or PR. In the dose escalation phase, ORR will be summarized using 
the Response-Evaluable population by dose groups and the total escalation cohort. In the dose 
expansion phase, ORR will be summarized for the total expansion cohort and by 
anti-PD1/PD-L1 naïve and anti-PD1/PD-L1 relapsed/refractory subgroup.
Estimates of the ORR will be presented with 2-sided 95% exact binomial confidence intervals 
(CIs) as needed. Antitumor activity of TAK-659 will be based on the best overall response.
ORR will also be tabulated by baseline prognostic factors, if applicable. The prognostic factors 
may include, but will not be limited to, age, number and types of prior therapy. CR and PR needs 
to be confirmed per RECIST 1.1 guidelines to calculate ORR.
6.10.2 Secondary Efficacy Endpoint(s)
The secondary efficacy endpoints are DCR DOR, rate of PD at 6 months, PFS and OS. 
Disease control rate (DCR) is the proportion of patients who had CR, PR, or SD. DCR will be 
summarized using the Response-Evaluable population. The number and percentage of patients 
falling into each response category (e.g., CR, PR, and SD) will be tabulated descriptively.
Rate of PD at 6 months is the proportion of patients who progressed by 6 months.
DOR is defined as the time from the date of first documentation of response to the date of first 
documented PD. DOR will be censored at the last response assessment that is SD or better. DOR 
will be censored when any of these happens: (1) patient dies without PD; (2) patient starts new 
anticancer therapy before PD; (3) patient drops off study due to any reason other than PD.
PFS is defined as the time from date of first study drug administration to the day of first 
documented PD or death due to any cause, whichever occurs first. PFS will be censored at the 
last response assessment that is SD or better. The detailed approach for handling missing 
response assessment and censoring based on US Food and Drug Administration (FDA) guidance 
is presented in Table 6.a.
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Table 6.a
Handling of Missing Response Assessment and Censoring for Progression-
Free Survival Analysis Based on US Food and Drug Administration 
Guidance
Situation
Date of Progression of Censoring
Outcome
No baseline and/or no post baseline assessment
First dose date
Censored
Disease progression documented between 
scheduled visits
Date of disease progression
PFS event
No documented disease progression or death
Date of last adequate assessment*
Censored
Treatment discontinuation for
undocumented disease progression after the last 
adequate assessment
Date of last adequate assessment*
Censored
Alternate anti-cancer therapy started prior to 
disease progression
Date of last adequate assessment* 
prior to the start of subsequent anti-
cancer therapy
Censored
Death before first assessment
Date of death
PFS event
Death between adequate assessment visits
Date of death
PFS event
Abbreviation: PFS = progression-free survival.
* Adequate assessment is defined as there is sufficient radiographic data to evaluate a patient’s disease status.
OS will be calculated from date of patient enrollment to the date of patient death due to any 
cause. Patients without documentation of death at time of the analysis will be censored as of the 
date the patient was last known to be alive, or the data cutoff date, whichever is earlier.
DOR, PFS, and OS will be analyzed by Kaplan-Meier approach. The corresponding 
KaplanMeier curves will also be plotted.
In general, time-to-event data will be analyzed by the Kaplan-Meier method and results will be
summarized by the 25th, 50th, and 75th percentiles with associated 2-sided 95% CIs.
DCR, ORR, rate of PD at 6 months and DOR will be summarized using response-evaluable 
population for both dose escalation and dose expansion cohort, whereas PFS and OS will be 
summarized using safety population. For the dose escalation phase, they will be summarized by 
dose groups and the total escalation cohort. For the dose expansion phase, they will be 
summarized for the total expansion cohort and by anti-PD1/PD-L1 naïve and anti-PD1/PD-L1
relapsed/refractory subgroups.
Responses (CR and PR) need to be confirmed per RECIST 1.1 guideline to calculate any 
efficacy endpoints that involves CR or PR.
They will be summarized in the following groups (1) by expansion cohort (2) within each 
expansion cohort, by anti-PD1/PD-L1 naïve and anti-PD1/PD-L1relapsed/refractory subgroup 
(3) across all expansion cohorts in the anti-PF1/PD-L1 relapsed/refractory patients.
6.10.3 Additional Efficacy Endpoint(s)
{Not applicable}
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6.11
Pharmacokinetic/Pharmacodynamic Analysis
{Not applicable}
6.11.1 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
(LC/MS/MS).
For dose escalation cohorts, plasma TAK-659 concentrations will be summarized by time
postdose and grouped by dose group and dosing cycle and day. Mean and individual plasma
TAK-659 concentration data will be plotted over time and grouped by dose group and dosing 
cycle and day. 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, Ctrough, AUCtau of 
Cycle 1 Day 1 and 15, and CLss/F, PTR, and Racof Cycle 1 Day 15. Plasma PK parameters of 
TAK-659 will be summarized by dose group and by dosing cycle and day. 
For dose expansion cohorts, plasma concentrations of TAK-659 will be listed by cohort, nominal
and actual time point, and dosing cycle and day.
TAK-659 plasma PK data from dose escalation and expansion cohorts, along with data from 
other studies, may contribute to population PK analyses and exposure-response analyses for
pharmacodynamic, safety, and efficacy endpoints. If applicable, the specifics of the population 
PK and exposure-response analyses will be described in separate analysis plans, and results will 
be reported separately from the clinical study report.
6.11.2 Pharmacodynamic/Biomarker/Pharmacogenomic Analyses
Individual data at each time point will be summarized in a table describing changes in the course 
of treatment per patient. Individual and summary data also will be presented graphically for each 
marker. If sufficient data are generated, data may be summarized by cohort or by indication as 
appropriate. Descriptive statistics, graphical methods, and statistical modeling will be used as 
appropriate to explore the relationship between response and the levels of various biomarkers.
The relationship between observed clinical response and candidate biomarkers will be explored 
to identify a biomarker(s) predictive of sensitivity to TAK-659 and the combination of TAK-659 
with nivolumab. Developing such a potential predictive biomarker(s) of TAK-659- and/or 
combination-mediated antitumor activity may require analysis of data from multiple clinical 
studies of TAK-659 in the future. A separate biomarker analysis plan will be written to detail 
such analyses.
Genotyping of polymorphisms in genes encoding proteins involved in metabolism or disposition 
of TAK-659 may be performed, guided by emerging understanding of the PK and clearance 
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mechanisms of TAK-659. Individual germline genotype will be listed for each of the 
polymorphisms evaluated. Descriptive and graphical methods may be used to explore the 
relationship between genotype and selected PK parameters for those related to the metabolism or 
disposition of TAK-659. Pharmacogenomic results from this study may be combined with results 
from future studies. These analyses may be summarized in a separate report.
6.12
Other Outcomes
{Not applicable}
6.13
Safety Analysis
The safety analyses will be performed using the safety population.
6.13.1 Adverse Events
AEs will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA) 
coding dictionary for the purpose of summarization. 
All treatment-emergent AEs (TEAEs) will be tabulated. A TEAE for tabulation is defined as: 
(1) any AE that occurs after administration of the first dose of study drug and up through 28 days 
after the last dose of study drug or the start date of subsequent anticancer therapies, whichever 
comes first. AEs will be tabulated according to the MedDRA by system organ class and 
preferred term, and will include the following categories:
∀
TEAEs.
∀
# Grade 3 TEAEs.
∀
Drug-related TEAEs.
∀
Drug-related, # Grade 3 TEAEs.
∀
TEAEs resulting in study drug discontinuation.
∀
The most commonly reported TEAEs (ie, those events reported by # 10% of all patients).
∀
Treatment-emergent SAEs.
∀
Nonserious TEAEs.
Property of Takeda: For non-commercial use only and subje
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Patients with the same AE more than once will have the maximum intensity of that event 
counted within each system organ class, and once within each preferred term.
An overall summary of AE will include numbers and percentages of patients who had any 
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.
6.13.1.1 Serious Adverse Events
The number and percentage of subjects experiencing at least 1 treatment emergent serious AE 
(SAE) will be summarized by MedDRA primary system organ class, high-level term, and 
preferred term. Drug-related SAEs will be summarized similarly.
6.13.1.2 Deaths
A by-subject listing of the deaths will be presented. All deaths occurring on-study and during 
follow-up will be displayed (regardless of treatment emergent AE status). An on-study death is 
defined as a death that occurs between the first dose of study drug and 28 days of the last dose of 
study drug.
6.13.1.3 Adverse Events Resulting in Discontinuation of Study Drug
Treatment-emergent AEs that resulted in discontinuation of study drugs will be summarized by 
preferred terms. Numbers and percentages of patients in which each of the AEs resulted in study 
drug discontinuation will be also be summarized.
6.13.1.4 Dose Limiting Toxicities (DLTs)
A by-patient listing of DLTs in Cycle 1 will be presented by dose level for patients in the 
DLT-evaluable population. 
6.13.2 Clinical Laboratory Evaluations
For the purposes of summarization in both the tables and listings, all laboratory values will be 
converted to standardized units. If a lab value is reported using a non-numeric qualifier (eg, less 
than (<) a certain value, or greater than (>) a certain value), the given numeric value will be used 
in the summary statistics, ignoring the non-numeric qualifier.
If a patient has repeated laboratory values for a given time point, the value from the last 
evaluation will be used.
The laboratory test results will be summarized for both dose escalation and dose expansion 
cohorts. For the dose escalation phase, they will be summarized by dose groups and by the total 
escalation cohort. For the dose expansion phase, they will be summarized by the total expansion 
cohort.
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In each case, the laboratory test results will be summarized by Baseline, Post-Baseline Minimum 
and Post-Baseline Maximum. Change from Baseline to Post-Baseline Minimum and Change 
from Baseline to Post-Baseline Maximum will also be summarized. 
Mean laboratory values over time will be plotted for key laboratory results. 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 CTC for 
toxicity from baseline to post baseline worst on study CTC grade, if available. Parameters to be 
tabulated will include:
Hematology: 

Hemoglobin

Hematocrit

Platelet (count)

Leukocytes with differential

Neutrophils (ANC)

Lymphocytes (absolute lymphocyte count [ALC])

Lymphocyte subsets
Serum chemistry: 

Creatinine

Bilirubin (total)

Lactate dehydrogenase 
(LDH)(with isozymes)

Phosphate

Alkaline phosphatase 
(ALP)

Aspartate aminotransferase 
(AST)

Alanine aminotransferase 
(ALT)

Amylase

Lipase
Mean laboratory values over time will be plotted for key lab parameters, including Hb, 
leukocytes, ALC, ANC, platelets, and liver function tests (ALT, AST, ALP, total bilirubin), 
LDH (with isozymes), phosphate, creatinine, lipase and amylase).
6.13.3 Vital Signs
The actual values of vital sign parameters including oral temperature, heart rate, systolic and 
diastolic blood pressure, and weight, will be summarized in a similar fashion to laboratory test 
results.
6.13.4 12-Lead ECGs
A summary of ECG abnormalities will be presented by visit. ECG intervals (QT and Fridericia’s 
corrected QT intervals [QTcF], PR, QRS, and heart rate) will be summarized in a similar fashion 
to laboratory test results.
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TAK659 - C34003
Page 22 of 24
Statistical Analysis Plan Final
22 January 2019
6.13.5 Other Observations Related to Safety
Additional safety analyses may be determined at any time without prejudice to enumerate rates 
of toxicities and to further define the safety profile of study drugs.
6.14
Interim Analysis
There is no interim analysis planned.
6.15
Changes in the Statistical Analysis Plan 
Not applicable 
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TAK659 - C34003
Page 23 of 24
Statistical Analysis Plan Final
22 January 2019
7.0
REFERENCES
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
1.
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J 
Cancer 2009;45(2):228-47.
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TAK659 - C34003
Page 24 of 24
Statistical Analysis Plan Final
22 January 2019
Appendix 
By-subject listings will be produced for the following information
Dispositions - dose escalation and dose expansion phases – safety population.
1.
Screen failures.
2.
Demographics and baseline characteristics - dose escalation and dose expansion phases –
3.
safety population.
Prior Therapies – dose escalation and dose expansion phases – safety population.
4.
Concomitant medications – dose escalation and dose expansion phases – safety population.
5.
Medical history – dose escalation and dose expansion phases – safety population.
6.
RECIST response assessment – dose escalation and dose expansion phases – response-
7.
evaluable population (for this listing, a column will be added to indicate whether the subject 
has received treatment beyond initial RECIST-defined PD).
Best overall response based on investigator assessment – dose escalation and dose expansion 
8.
phases – response-evaluable population.
Adverse events resulting in discontinuation of study drug – dose escalation and dose 
9.
expansion phases – safety population.
Serious adverse events – dose escalation and dose expansion phases – safety population.
10.
Deaths and cause of death – dose escalation and dose expansion phases – safety population.
11.
Dose limiting toxicity – dose escalation phase – DLT-evaluable population.
12.
Plasma concentrations of TAK-659 – dose escalation and dose expansion phases – safety 
13.
population.
PK parameters – PK-evaluable population.
14.
Significant protocol deviations.
15.
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