Clinical trial NCT03410108
Conditions: ALK-positive Advanced NSCLC
Keywords: Drug therapy
Sponsor: Takeda
Start date: 2018-01-29; Completion date: 2021-07-28
Enrollment: 104 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate efficacy and safety of brigatinib in Japanese participants with anaplastic lymphoma kinase (ALK)-positive NSCLC.

Detailed description:
The drug being tested in this study is called brigatinib. Brigatinib is being tested in participants with ALK-positive NSCLC in order to evaluate efficacy and safety of oral doses of brigatinib in Japanese participants with ALK-positive NSCLC.

The study will enroll approximately 110 participants. Participants will be enrolled in non-randomized and opened manner:

\- Brigatinib 90 mg for the first 7 days, followed by Brigatinib 180 mg of Brigatinib tablets, once daily in a 28-days cycle.

All participants will be asked to take tablets of brigatinib once daily with or without food throughout the study.

This multi-center trial will be conducted in Japan. The overall time to participate in this study is approximately 53 months. Participants will make multiple visits to the clinic during the treatment period, and posttreatment period including a follow-up assessment after last dose of study drug.

Arms: arm 1: Brigatinib 90 milligram (mg), tablets, orally, once daily (QD) for first 7 days followed by brigatinib, 180 mg, tablets, orally, QD in Cycle 1 of 28 days followed by brigatinib 180 mg, tablets, orally, QD in Cycle 2 and onward cycles of 28 days until investigator-assessed progressive disease (PD) or intolerable toxicity, withdrawal of consent, or discontinuation for any other reason, whichever comes first up to Cycle 34 of 28-day cycle, until data cut-off date 29 September 2020.
Interventions: intervention 1: Brigatinib
Intervention descriptions: intervention 1: Brigatinib tablet

Protocol documents:
Prot_000.pdf: 
Title: A Single-Arm, Multicenter, Phase 2 Study of Brigatinib in Japanese Patients With 
ALK-Positive Non-Small Cell Lung Cancer (NSCLC) 
NCT Number: NCT03410108 
Protocol Approve Date: 22-Jul-2020 
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 or company confidential information. 
This may include, but is not limited to, redaction of the following: 

Named persons or organizations associated with the study.

Patient identifiers within the text, tables, or figures or in by-patient data listings.

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.
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae). 


 
PROTOCOL 
A Single-Arm, Multicenter, Phase 2 Study of Brigatinib in Japanese Patients With ALK-Positive 
Non-Small Cell Lung Cancer (NSCLC) 
 
 
Sponsor: 
Takeda Pharmaceutical Company Limited. 
4-1-1 Doshomachi, Chuo-ku, Osaka 540-8645 
Study Number: 
Brigatinib-2001 
IND Number: 
Not applicable 
EudraCT Number: 
Not applicable 
Compound: 
Brigatinib (AP26113) 
Date: 
22 July 2020 
Amendment Number: 04 
 
Amendment History: 
Date 
Amendment Number 
Region 
25 October 2017 
Initial Protocol 
All sites 
30 November 2017 
01 
All sites 
30 May 2018 
02 
All sites 
10 December 2018 
03 
All sites 
22 July 2020 
04 
All sites 
Note: After a marketing approval of brigatinib for both first-line and second-line settings is obtained in Japan, this 
study will become a post-marketing clinical study and will be continued until the last patient get access to the 
commercial supply. This protocol will be continuously used for the post-marketing clinical study, and all the term 
“study” in this protocol shall be then deemed as appropriately replaced to “post-marketing clinical study.” 
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1.0 
ADMINISTRATIVE 
1.1 
Contacts 
A separate contact information list will be provided to each site. 
Serious adverse event and pregnancy reporting information is presented in Section 10.0, as is 
information on reporting product complaints. 
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site. 
Contact Type/Role 
Contact 
Serious adverse event and pregnancy reporting 
See Section 10.0. 
Responsible medical officer  
(carries overall responsibility for the conduct of the 
study) 
See protocol annex. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1.2
Approval 
REPRESENTATIVES OF TAKEDA 
This study will be conducted with the highest respect for the individual participants in accordance 
with the requirements of this clinical study protocol and also in accordance with the following: 
x The ethical principles that have their origin in the Declaration of Helsinki. 
x International Conference on Harmonisation E6 Good Clinical Practice: Consolidated 
Guideline. 
x All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations. 
SIGNATURES
The signature of the responsible Takeda medical officer (and other signatories, as applicable) can 
be found on the signature page. 
Electronic signatures may be found on the last page of this document. 
PPD
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INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure and any 
other product information provided by the sponsor. I agree to conduct this study in accordance 
with the requirements of this protocol and also to protect the rights, safety, privacy, and well-being 
of study subjects in accordance with the following: 
• The ethical principles that have their origin in the Declaration of Helsinki. 
• International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline. 
• All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations. 
• Regulatory requirements for reporting serious adverse events defined in Section 10.0 of this 
protocol. 
• Terms outlined in the Clinical Study Site Agreement. 
• Responsibilities of the Investigator (Appendix B). 
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix C of this protocol. 
 
Signature of Investigator 
Date 
Investigator Name (print or type) 
Investigator’s Title 
Location of Facility (City, State/Province) 
Location of Facility (Country) 
 
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1.3 
Protocol Amendment 04 Summary of Changes 
This section describes the changes in reference to the Protocol Incorporating Amendment No. 04. 
The primary purpose of this amendment is to revise the study completion definition. After a 
marketing approval of brigatinib for both first-line and second-line settings is obtained in Japan, 
this study will become a post-marketing clinical study and will be continued until the last patient 
get access to the commercial supply. This protocol will be continuously used for the 
post-marketing clinical study, and all the term “study” in this protocol shall be then deemed as 
appropriately replaced to “post-marketing clinical study.” 
The changes in this amendment are as follows: 
1. To revise the protocol signatory. 
2. To add notes regarding the transition to a post-marketing study on the title page. 
3. To revise study completion definition on Section 6.3.2. 
4. To update Section 2.0 Study Summary according to the revisions in Section 6.3.2. 
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TABLE OF CONTENTS 
1.0
ADMINISTRATIVE ...........................................................................................................2
1.1
Contacts..........................................................................................................................2
1.2
Approval ........................................................................................................................3
1.3
Protocol Amendment 04 Summary of Changes .............................................................5
2.0
STUDY SUMMARY.........................................................................................................11
3.0
STUDY REFERENCE INFORMATION .........................................................................20
3.1
Study-Related Responsibilities ....................................................................................20
3.2
Coordinating Investigator ............................................................................................20
3.3
List of Abbreviations ...................................................................................................21
4.0
INTRODUCTION .............................................................................................................24
4.1
Background ..................................................................................................................24
4.1.1
Epidemiology and Pathology .................................................................................24
4.1.2
Brigatinib ...............................................................................................................24
4.1.3
Nonclinical Summary: Nonclinical Activity Against ALK ...................................25
4.1.4
Brigatinib Clinical Summary .................................................................................25
4.2
Rationale for the Proposed Study ................................................................................29
4.2.1
Rationale for Dose .................................................................................................31
5.0
STUDY OBJECTIVES AND ENDPOINTS .....................................................................32
5.1
Objectives ....................................................................................................................32
5.1.1
Primary Objective ..................................................................................................32
5.1.2
Secondary Objectives .............................................................................................32
5.1.3
Safety Objectives ...................................................................................................32
5.1.4
32
5.2
Endpoints .....................................................................................................................33
5.2.1
Primary Endpoint ...................................................................................................33
5.2.2
Secondary Endpoints .............................................................................................33
5.2.3
Safety Endpoints ....................................................................................................34
5.2.4
34
6.0
STUDY DESIGN...............................................................................................................35
6.1
Overview of Study Design ...........................................................................................35
6.2
Number of Patients ......................................................................................................37
6.3
Duration of Study .........................................................................................................37
6.3.1
Duration of an Individual Patient’s Study Participation ........................................37
6.3.2
End of Study/Study Completion Definition and Planned Reporting .....................38
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6.3.3 Time Frames for Primary and Secondary Endpoints to Support Disclosures .......39 
6.3.4 Total Study Duration..............................................................................................41 
6.4 
Study Discontinuation and Closure .............................................................................41 
7.0 
STUDY POPULATION ....................................................................................................42 
7.1 
Inclusion Criteria .........................................................................................................42 
7.2 
Exclusion Criteria ........................................................................................................44 
8.0 
STUDY DRUG ..................................................................................................................47 
8.1 
Study Drug Administration ..........................................................................................47 
8.2 
Definitions of DLT ......................................................................................................47 
8.3 
Patient Expansion After the Safety Evaluation Lead-in Part .......................................48 
8.4 
Dose Modification Guidelines .....................................................................................49 
8.4.1 Criteria for Dose Interruption During a Cycle .......................................................51 
8.4.2 Criteria for Dose Reduction ...................................................................................51 
8.4.3 Reintroducing Brigatinib After Dose Interruption .................................................51 
8.4.4 Reescalation After Dose Modification ...................................................................51 
8.4.5 Criteria for Discontinuation of Brigatinib ..............................................................51 
8.5 
Excluded Concomitant Medications and Procedures ..................................................52 
8.6 
Permitted Concomitant Medications and Procedures ..................................................52 
8.7 
Precautions and Restrictions ........................................................................................52 
8.8 
Management of Clinical Events ...................................................................................53 
8.8.1 ILD/Pneumonitis ....................................................................................................53 
8.8.2 Hypertension ..........................................................................................................54 
8.8.3 Bradycardia ............................................................................................................55 
8.8.4 Nausea and Emesis ................................................................................................55 
8.8.5 Visual Disturbance .................................................................................................55 
8.8.6 Diarrhea ..................................................................................................................55 
8.9 
Blinding and Unblinding..............................................................................................55 
8.10 
Description of Investigational Agents .........................................................................55 
8.11 
Preparation, Reconstitution, and Dispensation ............................................................56 
8.12 
Packaging and Labeling ...............................................................................................56 
8.13 
Storage, Handling, and Accountability ........................................................................56 
8.14 
Other Protocol-Specified Materials .............................................................................56 
9.0 
STUDY CONDUCT ..........................................................................................................57 
9.1 
Study Personnel and Organizations .............................................................................57 
9.2 
Arrangements for Recruitment of Patients ..................................................................57 
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9.3
Treatment Group Assignments ....................................................................................57
9.4
Study Procedures .........................................................................................................57
9.4.1
Informed Consent...................................................................................................58
9.4.2
Patient Demographics ............................................................................................58
9.4.3
Medical History .....................................................................................................58
9.4.4
Physical Examination.............................................................................................59
9.4.5
Height and Weight .................................................................................................59
9.4.6
Vital Signs ..............................................................................................................59
9.4.7
ECOG Performance Status ....................................................................................59
9.4.8
Chest X-ray ............................................................................................................60
9.4.9
Pregnancy Test .......................................................................................................60
9.4.10 Concomitant Medications and Procedures .............................................................60
9.4.11 AEs .........................................................................................................................60
9.4.12 Study Enrollment ...................................................................................................60
9.4.13 Electrocardiogram ..................................................................................................61
9.4.14 Clinical Laboratory Evaluations ............................................................................61
9.4.15 Hepatitis Testing ....................................................................................................63
9.4.16 Disease Assessment ...............................................................................................63
9.4.17
64
9.4.18 PK Measurements ..................................................................................................65
9.4.19 Patient-Reported Outcomes Questionnaire (Expansion Part Only) .......................65
9.5
Documentation of Subject Failure ...............................................................................65
9.6
Completion of Study Treatment (for Individual Patients) ...........................................66
9.7
Completion of Study (for Individual Patients).............................................................66
9.8
Discontinuation of Treatment With Study Drug and Patient Replacement .................66
9.9
Withdrawal of Patients From Study .............................................................................67
9.10
Study Compliance ........................................................................................................67
9.11
Posttreatment Follow-up Assessments (PFS and OS) .................................................67
10.0
ADVERSE EVENTS .........................................................................................................69
10.1
Definitions....................................................................................................................69
10.1.1 Pretreatment Event Definition ...............................................................................69
10.1.2 AE Definition .........................................................................................................69
10.1.3 SAE Definition.......................................................................................................69
10.2
Procedures for Recording and Reporting AEs and SAEs ............................................70
10.3
Monitoring of AEs and Period of Observation ............................................................71
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10.4 
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events ..........71 
10.5 
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose) .....................................................................................................................72 
10.6 
Safety Reporting to Investigators, IRBs, and Regulatory Authorities .........................72 
11.0 
STUDY-SPECIFIC COMMITTEES .................................................................................73 
11.1 
Steering Committee .....................................................................................................73 
11.2 
IDMC ...........................................................................................................................73 
11.3 
IRC ...............................................................................................................................73 
12.0 
DATA HANDLING AND RECORDKEEPING ..............................................................74 
12.1 
eCRFs ...........................................................................................................................74 
12.2 
Record Retention .........................................................................................................74 
13.0 
STATISTICAL METHODS ..............................................................................................76 
13.1 
Statistical and Analytical Plans ....................................................................................76 
13.1.1 Analysis Sets ..........................................................................................................76 
13.1.2 Analysis of Demographics and Other Baseline Characteristics ............................77 
13.1.3 Efficacy Analysis ...................................................................................................77 
13.1.4 PK Analysis ...........................................................................................................79 
13.1.5 Safety Analysis ......................................................................................................80 
13.2 
Interim Analysis and Criteria for Early Termination ...................................................80 
13.3 
Determination of Sample Size .....................................................................................81 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................83 
14.1 
Study-Site Monitoring Visits .......................................................................................83 
14.2 
Protocol Deviations ......................................................................................................83 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections ..................................83 
15.0 
ETHICAL ASPECTS OF THE STUDY ...........................................................................84 
15.1 
IRB Approval ...............................................................................................................84 
15.2 
Subject Information, Informed Consent, and Subject Authorization ..........................84 
15.3 
Subject Confidentiality ................................................................................................85 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy ..................................86 
15.4.1 Publication .............................................................................................................86 
15.4.2 Clinical Trial Registration ......................................................................................86 
15.4.3 Clinical Trial Results Disclosure ...........................................................................86 
15.5 
Insurance and Compensation for Injury .......................................................................86 
16.0 
REFERENCES ..................................................................................................................87 
 
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LIST OF IN-TEXT TABLES 
Table 6.a
Primary and Secondary Endpoints for Disclosures ...............................................40
Table 8.a
Recommended Brigatinib Dose Reduction Levels ................................................49
Table 8.b
Recommended Brigatinib Dose Modifications for Treatment-Related AEs .........49
Table 9.a
Hematology and Chemistry Tests ..........................................................................62
Table 13.a
Minimum Number of Confirmed ORR at the Primary Analysis ...........................81
LIST OF IN-TEXT FIGURES 
Figure 6.a
Overview of Study Design .....................................................................................36
 
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2.0 
STUDY SUMMARY 
Name of Sponsor(s): 
Takeda Pharmaceutical Company, Ltd. 
Compound: 
Brigatinib (AP26113) 
Title of Protocol: A Single-Arm, Multicenter, Phase 2 
Study of Brigatinib in Japanese Patients With ALK-Positive 
Non-Small Cell Lung Cancer (NSCLC) 
IND No.: 
Not applicable 
EudraCT No.: 
Not applicable 
Study Number: Brigatinib-2001 
Phase: 2 
Study Design: 
This is a nonrandomized, multicenter, phase 2, open-label study with safety evaluation lead-in, to evaluate the efficacy 
and safety of brigatinib in Japanese patients with anaplastic lymphoma kinase (ALK)-positive advanced NSCLC. 
The study consists of the safety evaluation lead-in part and the expansion part. The safety evaluation lead-in part 
allows patients with any line of prior ALK inhibitor which includes treatment-naïve patients; however, ALK 
inhibitor-naïve patients may be enrolled after the confirmation of first 3 dose-limiting toxicity (DLT) evaluable 
patients to have no more than 1 DLT during Cycle 1 by investigator's judgement. The expansion part consists of the 
tyrosine kinase inhibitor (TKI) naïve expansion cohort and the refractory expansion part. The refractory expansion 
part includes the main cohort and a subcohort based on prior ALK inhibitor treatment. The TKI-naïve expansion 
cohort includes the patients who have not received any prior TKI including ALK inhibitor. In this cohort, the efficacy 
will be evaluated, and a total of 32 patients will be enrolled. The main cohort of the refractory expansion part includes 
patients who had previously received alectinib (as their only ALK inhibitor) or both crizotinib and alectinib 
(regardless the sequence of those 2 ALK inhibitors). The main cohort of the refractory expansion part will be used for 
the primary analysis of efficacy, and a total of 47 patients will be enrolled in the main cohort of the refractory 
expansion part. Patients with all other sequences of up to 2 prior ALK inhibitor(s) may be included in the subcohort of 
the refractory expansion part. Such other ALK inhibitors include 1) crizotinib only, 2) ceritinib only, 3) lorlatinib only, 
4) both crizotinib and ceritinib, 5) both alectinib and ceritinib, 6) both crizotinib and lorlatinib, 7) both alectinib and 
lorlatinib, and 8) both ceritinib and lorlatinib. Up to 20 patients will be enrolled in the subcohort of the refractory 
expansion part.  
In this study, brigatinib will be administered at 90 mg once daily (QD) for the first 7 days and then 180 mg QD 
(90 mg QD→180 mg QD). In the safety evaluation lead-in part, patients will be monitored for intensive 
pharmacokinetics (PK), and the tolerability of 90 mg QD→180 mg QD dosing will be confirmed. If the 90 mg 
QD→180 mg QD dosing regimen is considered tolerable, additional patients enrolled in the expansion part will be 
treated with the same dosing schedule (90 mg QD→180 mg QD). 
Patients will be treated until they experience objective progressive disease (PD) per Response Evaluation Criteria in 
Solid Tumors (RECIST) version 1.1, as assessed by the investigator, intolerable toxicity, withdrawal of consent, or 
discontinuation for any other reason. Treatment of patients with brigatinib may be continued at the tolerated dose 
level, despite investigator-assessed PD by RECIST version 1.1, if the patient otherwise has evidence of ongoing 
clinical benefit. In this case, discussions and agreements between the investigator and the sponsor’s project clinician 
(or designee) are required. 
Safety Evaluation Lead-in Part 
Nine DLT–evaluable patients will be enrolled in the safety evaluation lead-in part. The patients in the safety 
evaluation lead-in part will be hospitalized during Cycle 1 in general (hospitalization on Days 1-10 and Days 22-23 is 
mandatory), and their condition will be closely monitored for safety and tolerability. Serial blood samples will be 
collected for the intensive PK profile. The patients in the safety evaluation lead-in part will receive brigatinib 90 mg 
QD→180 mg QD. A cycle of therapy comprises 28 days of treatment. If a patient is NOT considered DLT evaluable 
for any reason, the patient will be replaced. 
Tolerability of the 90 mg QD→180 mg QD schedule will be determined on the basis of the DLTs observed in Cycle 1. 
If a DLT is observed in fewer than 3 of the 9 DLT-evaluable patients in the safety evaluation lead-in part, the 90 mg 
QD→180 mg QD regimen will be used for the patients enrolled in the expansion part. Opening of the expansion part 
will be determined on the basis of the total safety data available at that time, available PK results, and with 
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recommendation from the independent data monitoring committee (IDMC). Regarding the safety data, all AEs 
observed in the safety evaluation lead-in part, including those observed in DLT non-evaluable patients, will be 
evaluated in concert with DLTs when making the decision on opening of the expansion part. 
Expansion Part (Refractory Expansion Part and TKI-Naïve Expansion Cohort) 
For the TKI-naïve expansion cohort and the refractory expansion part, patients may be managed on an outpatient 
basis, and the number of study sites will be increased up to approximately 40. Patients in the refractory expansion part 
and the TKI-naïve expansion cohort will undergo less-intensive PK blood sampling than patients in the safety 
evaluation lead-in part. 
On an outpatient basis, patients will visit the hospital on Days 1, 8, and 15 of Cycle 1, and then on Day 1 of each cycle 
after Cycle 2. Tumor assessment will be performed every 2 cycles from Cycle 3 Day 1 through Cycle 15 Day 1, then 
every 3 cycles thereafter until the last dose of study drug. For patients who discontinue study treatment in the absence 
of PD, additional tumor assessment should continue at the same time points as the study treatment until PD or the start 
of another systemic anticancer therapy. 
Primary Objective: 
To evaluate efficacy of brigatinib in Japanese patients with ALK-positive advanced NSCLC. 
 
The objective response rate (ORR) will be evaluated in the refractory patients. 
 
The progression-free survival (PFS) rate at 12 months in Kaplan-Meier plots (12 months PFS rate) will be 
evaluated in the TKI-naïve patients. 
Secondary Objectives: 
 
To confirm the clinical dose in Japanese patients. 
 
To characterize the efficacy of brigatinib as shown by following parameters. 
For all enrolled patients (including TKI-naïve patients): duration of response (DOR), PFS, disease control rate 
(DCR), time to response, and overall survival (OS). 
For the TKI-naïve patients: ORR 
 
To characterize the intracranial efficacy of brigatinib, as evidenced by intracranial objective response rate (iORR) 
and duration of intracranial response (iDOR), and intracranial PFS (iPFS) in patients with intracranial disease at 
baseline, from  the refractory expansion part and the TKI-naïve expansion cohort. 
 
To assess patient-reported outcomes (PROs) of health-related quality of life (HRQOL) and symptoms of lung 
cancer with the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life 
Questionnaire (QLQ)-C30 (version 3.0), its lung cancer module QLQ-LC13, and the 5-level version of the 
EuroQol 5-dimensional questionnaire (EQ-5D-5L). 
 
To characterize the PK of brigatinib in Japanese patients. 
Safety Objective: 
The safety objective is to assess the safety and tolerability of brigatinib. 
Subject Population: 
Patients with ALK-positive advanced NSCLC. 
Safety evaluation lead-in part: patients with any line of prior ALK inhibitor treatment including treatment naïve. 
Expansion part: 
 
Patients who have progressed on prior treatment with 1 or 2 ALK inhibitors (refractory expansion part) or, 
 
Patients who have not received ALK inhibitors (TKI-naïve expansion cohort) 
Number of Subjects: 
Approximately 110 patients: 
Safety evaluation lead-in part: approximately 9 patients 
Expansion part: 
Number of Sites: 
Estimated total: approximately 40 sites in Japan 
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 
47 patients in the main cohort of the refractory 
expansion part and 
 
Up to 20 patients in the subcohort of the refractory 
expansion part 
 
32 in the TKI-naïve expansion cohort 
Dose Level(s): 
Brigatinib will be administered as an oral single agent at 
180 mg QD with a 7-day lead-in at 90 mg QD in a 28-day 
cycle 
Route of Administration: 
Oral 
Duration of Treatment: 
Patients will be treated until they experience objective PD 
per RECIST version 1.1, as assessed by the investigator, 
intolerable toxicity, withdrawal of consent, or 
discontinuation for any other reason. Treatment of patients 
with brigatinib may be continued at the tolerated dose level, 
despite investigator-assessed PD by RECIST version 1.1, if 
the patient otherwise has evidence of ongoing clinical 
benefit. In this case, discussions and agreements between 
the investigator and the sponsor’s project clinician (or 
designee) are required. 
Period of Evaluation: 
For the safety evaluation lead-in part and the refractory 
expansion part, the follow-up period will be for 24 
months after the last patient was enrolled, or when all 
patients have completed the study treatment, 
whichever comes later. However, in case a marketing 
approval of brigatinib for both first-line and 
second-line settings is obtained in Japan before the 
study completion noted above, this study will become a 
post-marketing clinical study after the marketing 
approval and will be continued until all the patients 
who are continuing study treatment with brigatinib 
have access to the commercial supply. 
For the TKI-naïve expansion cohort, after a marketing 
approval of brigatinib for both first-line and 
second-line settings is obtained in Japan, this study will 
become a post-marketing clinical study and will be 
continued until the last patient have access to the 
commercial supply. 
Main Criteria for Inclusion: 
1. Male or female Japanese patients aged ≥20 years on the day of consent. 
2. 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. 
3. Have histologically or cytologically confirmed stage IIIB, stage IIIC (locally advanced or recurrent and not a 
candidate for definitive multimodality therapy), or stage IV NSCLC. 
4. Have documentation of ALK rearrangement that meets following criteria. 
For the safety evaluation lead-in part and the refractory expansion part, patients must meet 1 of the following 2 
criteria: 
a) Have documentation of ALK rearrangement by a positive result from the Vysis ALK Break Apart FISH 
[fluorescence in situ hybridization] Probe Kit, the Nichirei Histofine ALK iAEP Kit, or the Ventana ALK 
[D5F3] CDx Assay at any time during prior disease course. The sponsor may require an adequate tissue 
available for central laboratory testing by the Vysis ALK Break Apart FISH test if a documented ALK 
rearrangement is confirmed by a positive result from the Nichirei Histofine ALK iAEP Kit "ONLY". 
b) Had a documented ALK rearrangement by a different test at any time during prior disease course, and 
adequate tissue available for central laboratory testing by the Vysis ALK Break Apart FISH test. Central 
confirmation of ALK rearrangement is not required before enrollment. 
For the TKI-naïve expansion cohort, patients must meet the following criteria: 
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Have documentation of ALK rearrangement by a positive result from MHLW-approved tests (e.g. Vysis 
ALK Break Apart FISH Probe Kit, the Nichirei Histofine ALK iAEP Kit, or the Ventana ALK [D5F3] CDx 
Assay) prior to enrollment, and required to submit sufficient tumor tissue for central laboratory testing 
upon request of sponsor. Central confirmation of ALK rearrangement is not required before enrollment. 
5. The refractory expansion part only: had documented PD during treatment or within 30 days after discontinuation 
of treatment with either alectinib, crizotinib, ceritinib, or lorlatinib. 
– 
Note 1: The refractory expansion part consists of the main cohort and a subcohort based on prior ALK 
inhibitor treatment. The main cohort includes patients who had previously received alectinib (as their only 
ALK inhibitor) or both crizotinib and alectinib (regardless the sequence of those 2 ALK inhibitors), and a 
total of 47 patients will be enrolled. Patients with all other sequences of up to 2 prior ALK inhibitor(s) may be 
included in the subcohort, and the number of patients will be limited to 20. 
– 
Note 2: Patients who will be included in the main cohort of the refractory expansion should have documented 
PD during treatment or within 30 days after discontinuation of treatment with alectinib. 
6. Have at least 1 measurable (ie, target) lesion per RECIST version 1.1.  
Note: Previously irradiated lesions may not be used for target lesions, unless there is unambiguous radiological 
progression after radiotherapy. Brain lesions may not be used as target lesions if they were 1) previously treated 
with whole brain radiation therapy (WBRT) within 3 months, or 2) previously treated by stereotactic radiosurgery 
(SRS) or surgical resection. 
7. Recovered from toxicities related to prior anticancer therapy to National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE) version 4.03 Grade ≤1.  
Note: Treatment-related alopecia is allowed. 
8. Have a life expectancy of ≥3 months. 
9. Have adequate organ and hematologic function, as determined by: 
a) Both alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 times the upper limit of the 
normal range (ULN) (≤5×ULN is acceptable if liver metastases are present). 
b) Total serum bilirubin ≤1.5×ULN (<3.0×ULN for patients with Gilbert syndrome). 
c) Serum creatinine <1.5×ULN. For patients with creatinine levels above or equal to 1.5×ULN, the patient is 
eligible if the estimated creatinine clearance using the Cockcroft-Gault formula is ≥30 mL/minute. 
d) Serum lipase ≤1.5×ULN and serum amylase ≤1.5×ULN. 
e) Absolute neutrophil count (ANC) ≥1.5×109/L. 
f) 
Platelet count ≥75×109/L. 
g) Hemoglobin ≥9 g/dL. 
h) Percutaneous oxygen saturation (SpO2) ≥94% without oxygen support. Patients who need oxygen support are 
excluded. 
10. Have an Eastern Cooperative Oncology Group (ECOG) performance status of ≤2. 
11. Must meet the following criteria: 
a) 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 1 highly effective non-hormonal method of 
contraception and 1 additional effective (barrier) method at the same time, from the time of signing the 
informed consent through 4 months 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, from 
the time of signing the informed consent through 4 months after that last dose of study drug. (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 
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not be used together.) 
b) Male patients, even if surgically sterilized (ie, status postvasectomy), who: 
– 
Agree to practice effective barrier contraception during the entire study treatment period and through 4 
months 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, 
during the entire study treatment period and through 4 months after that last dose of study drug. (Periodic 
abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, 
and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should 
not be used together.) 
12. Have the willingness and ability to comply with scheduled visit and study procedures. 
Main Criteria for Exclusion: 
1. Previously received the following treatments. 
The refractory expansion part only: received any prior ALK inhibitor other than alectinib, crizotinib, ceritinib, or 
lorlatinib. 
The TKI-naïve expansion cohort only: received any prior TKI including but not limited to ALK inhibitor and 
vascular endothelial growth factor receptor (VEGFR) TKI. 
2. The refractory expansion part only: received more than 2 prior ALK inhibitors. 
Note: The safety evaluation lead-in part allows patients with any line of prior ALK inhibitor which includes 
treatment-naïve patients; however, ALK inhibitor-naïve patients may be enrolled after the confirmation of first 3 
DLT evaluable patients to have no more than 1 DLT during Cycle 1 by investigator's judgement. 
3. The safety evaluation lead-in part and the refractory expansion part only: received alectinib, crizotinib, ceritinib, 
or lorlatinib within 7 days before the first dose of brigatinib. 
4. Previously received more than 1 regimen (more than 3 regimens in the safety evaluation lead-in part) of systemic 
anticancer therapy (other than ALK inhibitors) for locally advanced or metastatic disease.  
Note: A systemic anticancer therapy regimen will be counted if it is administered over at least 1 cycle. A new 
anticancer agent used as maintenance therapy will be counted as a new regimen unless it was previously used as 
initial anticancer therapy. Neoadjuvant or adjuvant systemic anticancer therapy will be counted as a prior regimen 
if completion of (neo) adjuvant therapy occurred <12 months before the first dose of brigatinib. 
5. Treatment with any investigational products except for lorlatinib within 30 days or 5 half-lives of that 
investigational agent, whichever is longer, before the first dose of brigatinib. 
6. Received chemotherapy or radiation within 14 days before the first dose of brigatinib, except SRS or stereotactic 
body radiation therapy. 
7. Received antineoplastic monoclonal antibodies within 30 days before the first dose of brigatinib. 
8. Received systemic treatment with strong inhibitors or strong and moderate inducers of cytochrome P450 (CYP) 
3A within 7 days before the first dose of brigatinib. 
9. Had major surgery within 30 days before the first dose of brigatinib. Minor surgical procedures such as venous 
catheter placement or minimally invasive biopsies are allowed. 
10. Have been diagnosed with another primary malignancy other than NSCLC, except for the following 
adequately/definitively treated malignancies: nonmelanoma skin cancer, cervical cancer in situ, nonmetastatic 
prostate cancer; or patients with another primary malignancy who are definitively relapse-free with at least 
3 years elapsed since the diagnosis of the other primary malignancy. 
11. Have symptomatic central nervous system (CNS) metastases (parenchymal or leptomeningeal) at screening or 
asymptomatic disease requiring an increasing dose of corticosteroids to control symptoms within 7 days before 
the first dose of brigatinib.  
Note: If a patient has worsening neurological symptoms or signs due to CNS metastasis, the patient needs to 
complete local therapy and be neurologically stable (with no requirement for an increasing dose of corticosteroids 
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or use of anticonvulsants for symptomatic control) for 7 days before the first dose of brigatinib. 
12. Have current spinal cord compression (symptomatic or asymptomatic and detected by radiographic imaging). 
Patients with asymptomatic leptomeningeal disease and without cord compression are allowed. 
13. Have ongoing or history of interstitial lung disease (ILD) (including interstitial pneumonitis, pneumonitis, 
radiation pneumonitis, drug-related pneumonitis, organized pneumonia, and pulmonary alveolitis). 
14. Have significant, uncontrolled, or active cardiovascular disease, specifically including, but not limited to: 
a) Myocardial infarction within 6 months before the first dose of brigatinib. 
b) Unstable angina within 6 months before the first dose of brigatinib. 
c) Congestive heart failure within 6 months before the first dose of brigatinib. 
d) Uncontrolled atrial arrhythmias despite appropriate medical therapy. 
e) History of ventricular arrhythmia, including history of ventricular tachycardia, ventricular fibrillation, or 
torsade de pointes. Patients with premature ventricular contractions are allowed. 
f) 
Cerebrovascular accident or transient ischemic attack within 6 months before the first dose of brigatinib. 
15. Have uncontrolled hypertension. Patients with hypertension should be under treatment at the start of screening 
and demonstrate adequate control of blood pressure. 
16. Have an ongoing or active infection, including, but not limited to, the requirement for intravenous antibiotics. 
17. Have a known history of HIV infection. Testing is not required in the absence of history. 
18. Hepatitis B surface antigen (HBsAg) positive, detectable hepatitis B viral load, or detectable hepatitis C virus 
(HCV) infection viral load.  
Note: Patients who have positive hepatitis B core antibody (HBcAb) or hepatitis B surface antibody (HBsAb) can 
be enrolled but must have an undetectable hepatitis B viral load. Patients who have positive HCV antibody can be 
enrolled but must have an undetectable hepatitis C viral load. 
19. Have malabsorption syndrome or other gastrointestinal illness that could affect oral absorption of brigatinib. 
20. Have a known or suspected hypersensitivity to brigatinib or its excipients. 
21. Female patients who are lactating and breastfeeding or have a positive serum pregnancy test during the screening 
period.  
Note: Female patients who are lactating will be excluded, even if they discontinue breastfeeding. 
22. Have any condition or illness that, in the opinion of the investigator, would compromise patient safety or interfere 
with the evaluation of brigatinib. 
Main Criteria for Evaluation and Analyses: 
Primary endpoint: 
 
Confirmed ORR as assessed by an independent review committee (IRC), per RECIST version 1.1. in the main 
cohort of the refractory expansion part 
 
12 months PFS rate as assessed by an IRC, per RECIST version 1.1 in the TKI-naïve expansion cohort 
Secondary endpoints: 
a) Efficacy endpoint in the TKI-naïve expansion cohort, the overall population of the refractory expansion part, 
and the safety evaluation lead-in part: 
– 
Confirmed ORR, as assessed by an IRC, per RECIST version 1.1. 
b) Efficacy endpoints in the TKI-naïve expansion cohort, the main cohort of the refractory expansion part, the 
overall population of the refractory expansion part: 
– 
DOR, as assessed by an IRC, per RECIST version 1.1. 
– 
PFS, as assessed by an IRC, per RECIST version 1.1. 
– 
DCR, as assessed by an IRC, per RECIST version 1.1. 
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– 
Time to response, as assessed by an IRC, per RECIST version 1.1. 
– 
OS. 
– 
CNS response, as assessed by an IRC, per modified RECIST version 1.1 for assessment of intracranial 
efficacy (iORR and iDOR in patients who had measurable CNS metastases, and iPFS in all patients). 
– 
Time on treatment 
c) Efficacy endpoints in the TKI-naïve expansion cohort, the main cohort of the refractory expansion part, and 
the safety evaluation lead-in part: 
– 
Confirmed ORR, as assessed by the investigator, per RECIST version 1.1. 
– 
PROs of HRQOL scores and symptoms of lung cancer, assessed with the EORTC QLQ-C30 (version 3.0), its 
lung cancer module QLQ-LC13, and the EQ-5D-5L (except for the safety evaluation lead-in part). 
d) PK endpoint in the safety evaluation lead-in part: 
– 
Brigatinib maximum observed plasma concentration (Cmax), time of first occurrence of Cmax (tmax) and area 
under the plasma concentration-time curve (AUC) on Cycle 1 Days 1 and 22. 
Safety endpoints: 
– 
The number and percentage of patients with treatment-emergent adverse events (TEAEs). 
– 
The number and percentage of patients with Grade 3 or higher TEAEs. 
– 
The number and percentage of patients with serious TEAEs. 
– 
The number and percentage of patients discontinuing study drug because of TEAEs. 
– 
The number of patients with DLTs during Cycle 1 in the safety evaluation lead-in part. 
Statistical Considerations: 
The refractory expansion part and safety lead-in part 
For the primary endpoint, confirmed ORR as assessed by an IRC and its 2-sided 95% CI will be provided using full 
analysis set (FAS)-P population, defined as patients previously treated with alectinib alone or patients previously 
treated with both crizotinib and alectinib who have received at least 1 dose of study drug (ie, main cohort of the 
refractory expansion part). 
In this population for the primary analysis, a 2-stage design will be used. The first 29 patients in the main cohort are 
included in Stage 1, and further patients will be continuously enrolled into Stage 2. An interim analysis for both futility 
and efficacy will be conducted in Stage 1, according to H1-minimax design (Englert and Kieser, 2012). The 
proportion of patients achieving an objective response, per IRC, will be used as the endpoint for the interim analysis. 
The interim analysis will be performed when the first 29 patients in the main cohort of the expansion part have had the 
opportunity to complete the Cycle 7 Day 1 disease assessment. Enrollment will not be suspended during evaluation of 
these 29 patients; however, patients enrolled after the 29th patient in the main cohort of the expansion part will NOT 
be included in the interim analysis, even if their ORR results were available on the cutoff date. 
If the number of patients with confirmed ORR is 3 or fewer of the 29 patients, enrollment will be stopped entirely for 
futility. Additionally, if the number of patients with confirmed ORR is 10 or more of the 29 patients, it will be decided 
that brigatinib is efficacious in this population. 
An IDMC will be formed. The IDMC will provide recommendation on the go/no go decision to move from the safety 
CCI
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evaluation lead-in part to the expansion part and on the futility and efficacy assessment at the interim analysis. The 
IDMC will also evaluate cases of ILD reported as serious adverse events and make recommendations as needed. 
For all secondary endpoints, all variables will be summarized descriptively using both the FAS-P population and the 
FAS population for efficacy, the FAS-P population for QOL, and the FAS population for safety and PK. Continuous 
variables will be summarized using the number of patients, mean, standard deviation, median, minimum, and 
maximum, and categorical variables will be summarized using the number and percentage per category. 
Time-to-event variables will be summarized using Kaplan-Meier methodology, and Kaplan-Meier plots will be 
provided. Kaplan-Meier estimates and 95% CI will be calculated for quantiles and some specified time points. 
The TKI-naïve expansion cohort 
For the primary endpoint, 12 months PFS rate as assessed by an IRC and its 2-sided 90% CI will be provided based on 
complementary log-log transformation. 
For all secondary endpoints, all variables will be summarized descriptively for efficacy, QOL and safety. Continuous 
variables will be summarized using the number of patients, mean, standard deviation, median, minimum, and 
maximum, and categorical variables will be summarized using the number and percentage per category. 
Time-to-event variables will be summarized using Kaplan-Meier methodology, and Kaplan-Meier plots will be 
provided. Kaplan-Meier estimates and 95% CI will be calculated for quantiles and some specified time points. 
Safety and PK analysis 
Safety will be analyzed in the population of patients who have received at least 1 dose of brigatinib. 
The PK population will include patients with sufficient dosing and PK data to reliably estimate PK parameters as 
determined by the clinical pharmacologist. The PK population will be used for all PK analyses. 
Sample Size Justification: 
In the safety evaluation lead-in part, 9 DLT-evaluable patients will be enrolled for intensive safety and PK monitoring. 
This number of patients was derived from the following considerations: The meaningful intensive PK characterization 
needs to be conducted with more than 6 patients. It is assumed that 9 patients may be reasonable to secure the number 
of patients needed for intensive PK characterization, even with the potential dropouts, and to evaluate the tolerability 
of the study drug. Also, 9 DLT-evaluable patients is enough to evaluate tolerability before expanding the dose cohort 
to larger a population using a conventional 3+3 design. 
The sample size in the main cohort of the refractory expansion part was determined to allow confirmation that the true 
ORR (expected response rate) is greater than the threshold response rate of 15% for patients previously treated with 
alectinib alone and those treated with both alectinib and crizotinib. The rationale for the 15% response rate for the 
alectinib (with or without crizotinib) pretreated population is based on the consideration that compared with crizotinib, 
patients who have failed alectinib are less likely to respond to subsequent therapy because of alectinib’s greater 
potency and better coverage of ALK mutations compared with crizotinib. 
A sample size of 47 patients in the post-alectinib population of the refractory expansion part with the stopping rule 
mentioned in in the Statistical Considerations section will allow the study to have more than 90% power to rule out a 
threshold response rate when the true ORR is expected or higher than 35% with a 1-sided alpha of 0.025, according to 
the H1-minimax design (Englert and Kieser, 2012). 
The number of patients in the subcohort of the refractory expansion part (ie, patients previously treated with crizotinib 
only, ceritinib only, lorlatinib only, both crizotinib and ceritinib, both alectinib and ceritinib, both crizotinib and 
lorlatinib, both alectinib and lorlatinib, and both ceritinib and lorlatinib) will be limited to 20. 
The sample size in the TKI-naïve expansion cohort was determined to allow confirmation that the true 12 months PFS 
rate (expected response rate) is greater than the threshold of 42.6% (estimated PFS rate at 12 months in Kaplan-Meier 
plots observed in ALTA-1L crizotinib arm) for TKI-naïve patients. 
A sample size of 32 patients in the TKI-naïve expansion cohort will allow the study to have approximately 80% power 
to rule out the threshold rate (42.6%) when the true 12 months PFS rate is expected or higher than 66.5% (estimated 
PFS rate at 12 months in Kaplan-Meier plots observed in ALTA-1L brigatinib arm) with a 1-sided alpha of 0.05, 
considering 10% patients will discontinue the study follow-up before the 12 months milestone due to reasons other 
than disease progression assessed by IRC or death, and 8 months enrollment period. The primary analysis will be 
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performed at around 10 months after the enrollment of the last subject in the TKI-naïve expansion cohort. The sample 
size and evaluation timing may be adjusted based on results of second interim analysis of ALTA-1L study, and actual 
enrollment period of the TKI-naïve expansion cohort. 
Overall, the total number of patients will be approximately 110 patients. 
 
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3.0 
STUDY REFERENCE INFORMATION 
3.1 
Study-Related Responsibilities 
The sponsor will perform all study-related activities with the exception of those identified in the 
protocol annex and the Study Manual. The identified vendors in the protocol annex and the Study 
Manual 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 (CSR) and by doing so agrees that it accurately describes 
the results of the study. 
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3.3 
List of Abbreviations 
AE 
adverse event 
ALK 
anaplastic lymphoma kinase 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
BID 
twice daily 
BUN 
blood urea nitrogen 
CL/F 
oral clearance 
Cmax 
maximum observed plasma concentration 
CNS 
central nervous system 
CPK 
creatine phosphokinase 
CR 
complete response 
CRO 
contract research organization 
CRP 
C-reactive protein 
CSR 
clinical study report 
CT 
computed tomography 
ctDNA 
circulating tumor DNA 
CxDx 
Cycle x Day x 
CYP 
cytochrome P450 
DCR 
disease control rate 
DDI 
drug-drug interaction 
DLSS 
Dohmen Life Science Services 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EGFR 
epidermal growth factor receptor 
EOPE 
early onset pulmonary event 
EORTC 
European Organisation for Research and Treatment of Cancer 
EOT 
end of treatment 
EQ-5D-5L 
the 5-level version of the EuroQol 5-dimensional questionnaire 
EU 
European Union 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed, paraffin-embedded 
FISH 
fluorescence in situ hybridization 
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GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
GM-CSF 
granulocyte macrophage-colony stimulating factor 
HbA1c 
hemoglobin A1c 
HBcAb 
hepatitis B core antibody 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HCVAb 
hepatitis C virus antibody 
HIV 
human immunodeficiency virus 
HR 
hazard ratio 
HRQOL 
health-related quality of life 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IDMC 
independent data monitoring committee 
iDOR 
duration of intracranial response 
IGF1R 
insulin-like growth factor receptor 1 
ILD 
interstitial lung disease 
iORR 
intracranial objective response rate 
iPFS 
intracranial progression-free survival 
IRB 
institutional review board 
IRC 
independent review committee 
IUD 
intrauterine device 
KD 
kinase domain 
KL-6 
Krebs von den Lungen-6 
KRAS 
v-Ki-ras2 Kirsten rat sarcoma viral oncogene homologue 
LDH 
lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHLW 
Ministry of Health, Labour and Welfare 
MHRA 
Medicines and Healthcare products Regulatory Agency 
MRI 
magnetic resonance imaging 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NGS 
next-generation sequencing 
NSCLC 
non-small cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PMDA 
Pharmaceuticals and Medical Devices Agency of Japan 
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PP 
per-protocol 
PR 
partial response 
PRO 
patient-reported outcome 
QD 
once daily 
QLQ 
Quality of Life Questionnaire 
QOL 
quality of life 
QTc 
heart rate-corrected QT interval (calculated) 
QTcF 
corrected QT interval by the Fridericia formula 
RECIST 
Response Evaluation Criteria in Solid Tumors 
ROS1 
c-ros oncogene 1 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease 
SLD 
sum of the longest diameters 
SP-D 
surfactant protein-D 
SpO2 
percutaneous oxygen saturation 
SRS 
stereotactic radiosurgery 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TKI 
tyrosine kinase inhibitor  
tmax 
time of first occurrence of Cmax 
ULN 
upper limit of the normal range 
US 
United States 
VEGFR 
vascular endothelial growth factor receptor 
WBRT 
whole brain radiation therapy 
WHO 
World Health Organization 
 
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4.0 
INTRODUCTION 
4.1 
Background 
4.1.1 Epidemiology and Pathology 
Lung cancer is one of the most common cancers in the world (1.8 million new cases in 2012) 
12.9% of all new cancers worldwide [1]. Globally, lung cancer accounted for 1.6 million cases and 
1.4 million deaths in 2008 [2]. It is the leading cause of cancer death in the United States (US), in 
the European Union (EU), and in Japan. In Japan, lung cancer is ranked as the third most frequent 
cancer; approximately 113,000 new cases were diagnosed in 2012 and approximately 
71,500 deaths in that year [3]. 
Anaplastic lymphoma kinase (ALK) is a tyrosine kinase encoded on chromosome 2 and is 
primarily involved in developmental processes and expressed at low levels in adults [4]. The first 
genetic rearrangement of ALK seen in non-small cell lung cancer (NSCLC) involved a fusion 
between the EML4 gene and the ALK tyrosine kinase domain (KD). EML4-ALK has the capacity 
to transform fibroblasts grown in culture and as subcutaneous xenografts to induce tumor 
formation [5]. Since then, a number of additional ALK fusion partners have been described in 
NSCLC that are believed to result in aberrant signaling and oncogenic transformation [6,7]. ALK 
rearrangements are more common among patients with adenocarcinoma histology, patients who 
have never smoked, and patients who have wild-type epidermal growth factor receptor (EGFR) 
and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homologue (KRAS) [4]. 
Estimates of the frequency of ALK rearrangement in the overall population of NSCLC patients 
range from 2% to 7% [8,9], which represent, based on proportionality of total populations in the 
US, EU, and Japan, approximately 7000 to 25,000 ALK+ NSCLC patients in the US, 11,000 to 
39,000 patients in the EU, and 1900 to 6700 patients in Japan in 2016. 
In Japan, crizotinib, alectinib, ceritinib, and lorlatinib are approved for treatment of ALK-positive 
NSCLC as of September 2018. 
4.1.2 Brigatinib 
Brigatinib (AP26113) is a novel, orally administered tyrosine kinase inhibitor (TKI) discovered 
and developed by ARIAD Pharmaceuticals, Inc. (ARIAD; Cambridge, Massachusetts), a wholly 
owned subsidiary of Takeda Pharmaceutical Company Limited. Primary targets are activated, 
mutant forms of ALK and c-ros oncogene 1 (ROS1), which play important roles in NSCLC and 
other cancers. 
A series of in vitro and in vivo studies has been performed to characterize the pharmacodynamic 
profile of brigatinib. These studies have demonstrated that brigatinib potently inhibits the in vitro 
activity of all tested secondary mutations in the ALK KD that confer resistance to crizotinib, 
ceritinib, and alectinib. No ALK mutations have been identified in in vitro mutagenesis assays that 
confer resistance to brigatinib at clinically achievable concentrations. Brigatinib also potently 
inhibits ROS1 and demonstrates activity against insulin-like growth factor receptor 1 (IGF-1R) 
and certain mutant variants of EGFR. 
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4.1.3
Nonclinical Summary: Nonclinical Activity Against ALK 
In nonclinical studies, brigatinib has been shown to: 
x Inhibit growth of ALK+ human tumor-derived cell lines with potency at least 9-fold greater 
than that of crizotinib. 
x Potently inhibit ALK variants with secondary mutations that confer resistance to crizotinib, 
ceritinib, or alectinib. 
x Suppress the emergence of any resistant ALK mutant in an in vitro mutagenesis assay, at 
concentrations that can be achieved clinically. 
x Induce regressions or inhibit growth of tumor xenografts driven by native ALK or mutant 
variants that confer clinical resistance. 
x
Prolong survival of mice in an ALK-dependent orthotopic brain tumor model.
Refer to the Investigator’s Brochure for a more comprehensive presentation of the nonclinical 
data. 
4.1.4 Brigatinib Clinical Summary 
4.1.4.1 Study AP26113-11-101 (Phase 1/2) 
This is a first-in-human, open-label, multicenter, dose escalation (3+3 design) study to evaluate the 
safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity of brigatinib. 
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4.1.4.2
Study AP26113-13-201 (ALTA) 
This is a pivotal phase 2, randomized, multicenter, international study of brigatinib in patients with 
ALK+ NSCLC who previously progressed on crizotinib. 
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4.1.4.3
Study AP26113-13-301 (ALTA-1L) 
This is a phase 3, randomized, open label, comparative, multicenter, international study in patients 
with advanced ALK+ NSCLC who had not previously received an ALK targeted TKI. 
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4.2
Rationale for the Proposed Study 
Rearrangements of the ALK gene encode an oncogenic fusion protein in several human cancers, 
including NSCLC. Crizotinib, alectinib, and ceritinib are the oral ALK inhibitors approved in 
Japan for treatment of patients with metastatic ALK-positive NSCLC. Despite the high initial 
activity of ALK inhibitors, resistance inevitably develops in most patients. Analysis of tumor 
specimens collected at the time of acquired resistance to the ALK inhibitors has implicated 
multiple resistance mechanisms, including mutations in the ALK KD, increases in copy number of 
the rearranged ALK gene, and activation of ALK-independent bypass signaling pathways. 
Brigatinib is a novel, synthetic, orally active ALK TKI that is being developed to address the 
limitations of currently approved ALK inhibitors by maximizing selective inhibition of 
ALK-positive NSCLC cells through optimal binding to the ALK KD. Brigatinib received 
accelerated approval by the US Food and Drug Administration (FDA) on 28 April 2017 with an 
indication for the treatment of patients with ALK positive metastatic NSCLC who have progressed 
on or are intolerant to crizotinib. 
In Japan, crizotinib, alectinib, ceritinib, and lorlatinib are approved for treatment of ALK-positive 
NSCLC as of September 2018. In the Japanese Guideline [10], alectinib and crizotinib are 
recommended as first-line treatment, and both alectinib and ceritinib are recommended as 
second-line ALK inhibitor treatments after crizotinib failure, as of September 2017. However, 
after becoming refractory to alectinib in both first- and second-line treatment, and refractory to 
ceritinib in second-line treatment, no molecular targeting agent is recommended, and the treatment 
is limited to “1st line treatment for non-squamous cell carcinoma”. 
The current study is planned to evaluate the efficacy and safety of brigatinib in Japanese patients 
with ALK-positive advanced NSCLC that has progressed after prior ALK inhibitor therapy. In 
Japan, after the release of the J-ALEX study results [11] and an amendment to the guideline, the 
first-line treatment of ALK+ positive patients shifted from crizotinib to alectinib rapidly. 
Crizotinib is still recommended in the guideline, and there are several patients who receive 
CCI
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sequential treatment with crizotinib and alectinib. On the basis of Japanese clinical practice, and to 
achieve a homogeneous population to assess the efficacy of brigatinib in patients who have 
progressed on alectinib, the main cohort in this study for efficacy evaluation is defined as patients 
who have progressed after treatment with alectinib (with or without previous treatment with 
crizotinib). Taking the current medical practice in Japan into consideration, there are treatment 
sequences available other than the above (such as the inclusion of ceritinib); therefore, patients 
will also be enrolled in a subcohort to accumulate clinical data for a preliminary assessment of 
efficacy in these populations. The patients in the subcohort will not be included in the main 
efficacy analysis but will be included in a secondary analysis of efficacy and primary safety 
assessments. 
Although treatment for ALK+ NSCLC can be highly effective by implementing the ALK-TKI, 
most patients with ALK+ NSCLC treated with first-line treatment will eventually relapse. Brain 
metastasis to the central nervous system occurs in almost half of patients, which can have a 
negative impact on quality of life of the patients. Patients with ALK+ NSCLC after first-line 
failure are available for other ALK-TKI. However disease progression has been appeared in 
re-treating patients as a second-line treatment within 1 year. Several secondary mutations of ALK 
kinase domain that are associated with clinical tolerance to crizotinib, ceritinib and alectinib have 
been identified, and those mutations lead to treatment failure of ALK-TKI. 
For treatment of 1L, there is a need for a more potent ALK inhibitor that extends the PFS and that 
has adequate CNS penetration with robust intracranial responses compared with existing treatment. 
Although crizotinib is an effective treatment for ALK+ NSCLC, almost half of ALK+ NSCLC 
patients in the pivotal trials that supported its accelerated approval failed to achieve a response. 
PFS was relatively short in the 2 randomized phase 3 trials, with a median duration of 7.7 to 
10.9 months. Chemotherapy is also used although it is not specifically approved for use in ALK+ 
NSCLC patients, with median PFS duration of 7.0 months with first line platinum doublet 
chemotherapy. Building on the strong efficacy results observed in the post-crizotinib setting, 
newer ALK inhibitors have recently been examined in previously untreated ALK+ NSCLC, 
resulting in FDA approval of alectinib [12,13] as first-line treatments in this population, and 
shifting the standard of care. For alectinib, clinically meaningful improvements in PFS were noted 
in the first-line setting when compared with crizotinib in the global, head-to-head ALEX study, 
with a median PFS (by IRC) of 25.7 months versus 10.4 months, respectively (HR = 0.53) [13,14] 
consistent results were also observed in a similar study (J-ALEX) in previously untreated Japanese 
patients [11]. In addition, alectinib was better tolerated than crizotinib, with an improved safety 
profile. Nonetheless, there are risks with alectinib, including severe hepatic and renal toxicity, as 
well as other class effects (ie, interstitial lung disease [ILD] and bradycardia). 
Alectinib is also approved as first line treatment in Japan for ALK+ NSCLC. 
New therapies are needed to improve response rates, provide greater durability of response, and to 
overcome potential mechanisms of resistance to ALK-targeted therapy, including the emergence 
of secondary resistance mutations in ALK and progression in the CNS. Such a new therapeutic 
option could result in significant prognostic improvement in ALK+ NSCLC patients. 
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For the first interim analysis of ALTA-1L, which is a pivotal randomized phase 3 study in patients 
naïve to ALK-TKI treatment, The primary endpoint of BIRC-assessed PFS was met with 
statistical and clinical superiority in favor of brigatinib (Section 4.1.4.3). In order to evaluate 
efficacy and safety of brigatinib in Japanese patients with ALK+ NSCLC who are naïve to 
ALK-TKI therapy, an expansion cohort in patients naïve to ALK-TKI treatment was added to the 
ongoing Brigatinib-2001. 
4.2.1 Rationale for Dose 
In this study, brigatinib will be administered as an oral single agent at 180 mg QD with a 7-day 
lead-in at 90 mg QD (90 mg QD→180 mg QD). This dose/schedule is the same used in the ALTA 
study, and is the approved dosage in the US. The ALTA study showed that the benefit-risk profile 
of the 90 mg QD→180 mg QD regimen was improved over that of 90 mg QD. In a Western 
clinical pharmacology study (AP26113-13-102), Caucasian and Japanese healthy subjects had 
comparable systemic exposure of brigatinib with a single dose of 90 mg, 120 mg, or 180 mg, 
supporting extrapolation of the Western safety and efficacy experience to define the recommended 
phase 2 dose of brigatinib in Japanese patients for evaluation in this study. 
The safety and tolerability of the 90 mg QD→180 mg QD regimen will be confirmed in patients 
enrolled at a limited number of study sites before expanding to all sites in this study. The safety 
evaluation lead-in part is incorporated to confirm the safety and tolerability of this dose regimen. 
Patients will be enrolled in this safety evaluation lead-in part until 9 dose-limiting toxicity 
(DLT)-evaluable patients are accrued. Patients will be hospitalized during Cycle 1 (Days 1-10 and 
Days 22-23), and their condition will be closely monitored for safety and assessment of DLTs. 
Serial blood samples will be also collected for intensive PK evaluation in these patients. 
For patients in the TKI-naïve expansion cohort, the overseas study ALTA-1L in patients untreated 
with TKIs including ALK inhibitors demonstrated a statistically significant increase in the primary 
endpoint PFS assessed by the BIRC in the brigatinib group (90 mg QD→180 mg QD) compared to 
the crizotinib group (250 mg BID) as well as obvious improvements in the following secondary 
endpoints: DOR, iORR and iPFS. ORR assessed by the BIRC was numerically better in the 
brigatinib group than in the crizotinib group. The subgroup analysis in Asians also demonstrated 
consistently clear benefits in the brigatinib group relative to the crizotinib group. 
The efficacy of brigatinib 90 mg QD→180 mg QD in TKI-naïve Japanese patients is expected to 
be comparable to that seen in Study ALTA-1L. 
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5.0
STUDY OBJECTIVES AND ENDPOINTS 
5.1
Objectives
5.1.1
Primary Objective 
The primary objective is to evaluate efficacy of brigatinib in Japanese patients with ALK-positive 
advanced NSCLC. 
x ORR will be evaluated in the refractory patients. 
x PFS rate at 12 months in Kaplan-Meier plots (12 months PFS rate) will be evaluated in the 
TKI-naïve patients. 
5.1.2 Secondary Objectives 
The secondary objectives are: 
x To confirm the clinical dose in Japanese patients. 
x To characterize the efficacy of brigatinib as shown by following parameters 
For all enrolled patients (including TKI-naïve patients): DOR, PFS, disease control rate (DCR), 
time to response, and overall survival (OS). 
For the TKI-naïve patients: ORR 
x To characterize the intracranial efficacy of brigatinib, as evidenced by iORR, duration of 
intracranial response (iDOR), and iPFS in patients with intracranial disease at baseline, from 
refractory and TKI-naïve cohorts. 
x To assess patient-reported outcomes (PROs) of health-related quality of life (HRQOL) and 
symptoms of lung cancer with the European Organization for Research and Treatment of 
Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 (version 3.0), its lung cancer 
module QLQ-LC13, and the 5-level version of the EuroQol 5-dimensional questionnaire 
(EQ-5D-5L). 
x To characterize the PK of brigatinib in Japanese patients. 
5.1.3 Safety Objectives 
The safety objective is to assess the safety and tolerability of brigatinib. 
5.1.4
 
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5.2 
Endpoints 
5.2.1 Primary Endpoint 
The primary endpoints are: 
• Confirmed ORR as assessed by an IRC, per Response Evaluation Criteria in Solid Tumors 
(RECIST) version 1.1 in the main cohort of the refractory expansion part 
• 12 months PFS rate as assessed by an IRC, per RECIST version 1.1 in the TKI-naïve 
expansion cohort 
5.2.2 Secondary Endpoints 
The secondary endpoints are: 
a) Efficacy endpoint in the TKI-naïve expansion cohort, the overall population of the 
refractory expansion part, and the safety evaluation lead-in part: 
– Confirmed ORR, as assessed by an IRC, per RECIST version 1.1. 
b) Efficacy endpoints in the TKI-naïve expansion cohort, the main cohort of the refractory 
expansion part, the overall population of the refractory expansion part: 
– DOR, as assessed by an IRC, per RECIST version 1.1. 
– PFS, as assessed by an IRC, per RECIST version 1.1. 
– DCR, as assessed by an IRC, per RECIST version 1.1. 
– Time to response, as assessed by an IRC, per RECIST version 1.1. 
– OS. 
– CNS response, as assessed by IRC, per modified RECIST version 1.1 for assessment of 
intracranial efficacy (Appendix H) (iORR and iDOR in patients who had measurable CNS 
metastases, and iPFS in all patients). 
– Time on treatment. 
c) Efficacy endpoints in the TKI-naïve expansion cohort, the main cohort of the refractory 
expansion part, and the safety evaluation lead-in part: 
– Confirmed ORR, as assessed by the investigator, per RECIST version 1.1. 
– PROs of HRQOL scores and symptoms of lung cancer, assessed with the EORTC 
QLQ-C30 (version 3.0), its lung cancer module QLQ-LC13, and the EQ-5D-5L (except for 
the safety evaluation lead-in part). 
d) PK endpoint in the safety evaluation lead-in part: 
– Brigatinib maximum observed plasma concentration (Cmax), time of first occurrence of 
Cmax (tmax), and area under the plasma concentration-time curve (AUC) on Cycle 1 Days 1 
and 22. 
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5.2.3
Safety Endpoints 
The safety endpoints are: 
x The number and percentage of patients with TEAEs. 
x The number and percentage of patients with Grade 3 or higher TEAEs. 
x The number and percentage of patients with serious TEAEs. 
x The number and percentage of patients discontinuing study drug because of TEAEs. 
x The number of patients with DLTs during Cycle 1 in the safety evaluation lead-in part. 
5.2.4
 
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6.0 
STUDY DESIGN 
6.1 
Overview of Study Design 
This is a nonrandomized, multicenter, phase 2, open-label study with a safety evaluation lead-in, to 
evaluate the efficacy and safety of brigatinib in Japanese patients with ALK-positive advanced 
NSCLC. 
The study consists of the safety evaluation lead-in part and the expansion part. The safety 
evaluation lead-in part allows patients with any line of prior ALK inhibitor which includes 
treatment-naïve patients; however, ALK inhibitor-naïve patients may be enrolled after the 
confirmation of first 3 DLT evaluable patients to have no more than 1 DLT during Cycle 1 by 
investigator's judgement. The expansion part consists of the TKI-naïve expansion cohort and the 
refractory expansion part, and the refractory expansion part includes the main cohort and a 
subcohort based on prior ALK inhibitor treatment. The TKI-naïve expansion cohort includes the 
patients who have not received any prior TKI including ALK inhibitor. In this cohort, the efficacy 
will be evaluated, and total of 32 patients will be enrolled. The main cohort of the refractory 
expansion part includes patients who had previously received alectinib (as their only ALK 
inhibitor) or both alectinib and crizotinib (regardless the sequence of those 2 ALK inhibitors). The 
main cohort of the refractory expansion part will be used for the primary analysis of efficacy, and 
a total of 47 patients will be enrolled in the main cohort of the refractory expansion part. Patients 
with all other sequences of up to 2 prior ALK inhibitor(s) may be included in the subcohort of the 
refractory expansion part. Such other ALK inhibitors include 1) crizotinib only, 2) ceritinib only, 
3) lorlatinib only, 4) both crizotinib and ceritinib, 5) both alectinib and ceritinib, 6) both crizotinib 
and lorlatinib, 7) both alectinib and lorlatinib, and 8) both ceritinib and lorlatinib. Up to 20 patients 
will be enrolled in the subcohort of the refractory expansion part. 
In this study, brigatinib will be administered at 90 mg QD for the first 7 days and then 180 mg QD 
(90 mg QD→180 mg QD). In the safety evaluation lead-in part, patients will be monitored for 
intensive PK, and the tolerability of 90 mg QD→180 mg QD dosing will be confirmed. If the 
90 mg QD→180 mg QD dosing regimen is considered tolerable, additional patients enrolled in the 
expansion part will be treated with the same dosing schedule (90 mg QD→180 mg QD). 
For the TKI-naïve expansion cohort, 32 patients will be enrolled and12 month PFS rate will be 
evaluated as the primary endpoint. The primary analysis will be performed at around 10 months 
after the enrollment of the last subject in TKI-naïve expansion cohort. The sample size and 
evaluation timing may be adjusted based on results of second interim analysis of ALTA-1L study, 
and actual enrollment period of the TKI-naïve expansion cohort. 
For the main cohort of the refractory expansion part, there are 2 stages: the first 29 patients in the 
main cohort are included in Stage 1, and further patients will be continuously enrolled into Stage 2. 
An interim analysis for futility and efficacy will be performed in the Stage 1 population when the 
first 29 post-alectinib patients have had the opportunity to complete at least 3 postbaseline scans 
(ie, after the Cycle 7 Day 1 disease assessment). Enrollment will not be suspended during 
evaluation of those 29 patients. 
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Following the screening period, eligible patients will be enrolled and treated with brigatinib. A 
patient is considered to be enrolled in the study when the first dose of brigatinib is administered. 
Toxicity will be evaluated according to National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI CTCAE), Version 4.03, effective date 14 June 2010 [15]. 
Response evaluation per RECIST version 1.1 will be done by both the investigator and an IRC. 
The primary analysis will performed on the results from the IRC. 
Patients will be treated until they experience objective progressive disease (PD) per RECIST 
version 1.1, as assessed by the investigator, intolerable toxicity, withdrawal of consent, or 
discontinuation for any other reason. Treatment of patients with brigatinib may be continued at the 
tolerated dose level, despite investigator-assessed PD by RECIST version 1.1, if the patient 
otherwise has evidence of ongoing clinical benefit. In this case, discussions and agreements 
between the investigator and the sponsor’s project clinician (or designee) are required. 
Figure 6.a 
Overview of Study Design 
 
Safety Evaluation Lead-in Part 
Nine DLT-evaluable patients will be enrolled in the safety evaluation lead-in part. The patients in 
the safety evaluation lead-in part will be hospitalized during Cycle 1 in general, and their condition 
will be closely monitored for safety and tolerability. Serial blood samples will be collected for the 
intensive PK profile. If a patient wishes to return home temporarily and the investigator confirms 
that the patient’s symptoms are stable per the available data, then the patient may return home 
temporarily except on Days 1 through 10 and Days 22 and 23, provided this does not interfere with 
the study assessments. The investigator must document the confirmation record for stabilization of 
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the patient’s symptoms per the available data in an appropriate source record (eg, medical records) 
before the patient's temporary leave. 
The patients in the safety evaluation lead-in part will receive brigatinib 90 mg QD→180 mg QD. 
A cycle of therapy comprises 28 days of treatment. If a patient is NOT considered DLT evaluable 
for any reason, the patient will be replaced. 
DLTs are defined in Section 8.2. Tolerability of the 90 mg QD→180 mg QD schedule will be 
determined on the basis of the DLTs observed in Cycle 1. If a DLT is observed in fewer than 3 of 
the 9 DLT-evaluable patients in the safety evaluation lead-in part, the 90 mg QD→180 mg QD 
regimen will be used for the patients enrolled in the expansion part. Further details on the dose 
expansion rules are described in Section 8.3. 
Expansion Part (Refractory Expansion Part and TKI-Naïve Expansion Cohort) 
Patients in the refractory expansion part and the TKI-naïve expansion cohort may be managed on 
an outpatient basis, and the number of study sites will be increased up to approximately 40. 
Patients in the refractory expansion part and the TKI-naïve expansion cohort will undergo 
less-intensive PK blood sampling than patients in the safety evaluation lead-in part. 
On an outpatient basis, patients will visit the hospital on Days 1, 8, and 15 of Cycle 1, and then on 
Day 1 of each cycle after Cycle 2. Tumor assessment will be performed every 2 cycles from 
Cycle 3 Day 1 through Cycle 15 Day 1, then every 3 cycles thereafter until the last dose of study 
drug. For patients who discontinue study treatment in the absence of PD, additional tumor 
assessment should continue at the same time points as the study treatment until PD or the start of 
another systemic anticancer therapy. 
6.2 
Number of Patients 
Approximately 110 patients (approximately 9 patients in the safety evaluation lead-in part, 32 
patients in the TKI-naïve expansion cohort, 47 patients in the main cohort of the refractory 
expansion part and up to 20 in the subcohort of the refractory expansion part) will be enrolled in 
this study at approximately 40 study sites in Japan. A patient is considered to be enrolled in the 
study when the first dose of brigatinib is administered. 
6.3 
Duration of Study 
6.3.1 Duration of an Individual Patient’s Study Participation 
Patients will be treated until they experience objective PD per RECIST version 1.1, as assessed by 
the investigator, intolerable toxicity, withdrawal of consent, or discontinuation for any other 
reason. Treatment of patients with brigatinib may be continued at the tolerated dose level, despite 
investigator-assessed PD by RECIST version 1.1, if the patient otherwise has evidence of ongoing 
clinical benefit. In this case, discussions and agreements between the investigator and the 
sponsor’s project clinician (or designee) are required. 
The follow-up period for a patient begins after the last completed site visit and continues until 
patient contact ceases. The follow-up assessments (ie, contacting the patient for survival and 
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subsequent anticancer therapy) must be performed every 12 weeks after the end of treatment 
(EOT). For patients who discontinue study treatment in the absence of PD, survival should be 
tracked and additional tumor assessment should be performed at the same time points as the study 
treatment (every 8 weeks until Week 57 [equivalent to Cycle 15 Day 1] and every 12 weeks 
thereafter) until PD or the start of another systemic anticancer therapy. After that, survival must be 
tracked every 12 weeks, and subsequent anticancer therapy should be recorded. 
6.3.2 End of Study/Study Completion Definition and Planned Reporting 
6.3.2.1 The Safety Evaluation Lead-In Part and The Refractory Expansion Part 
Primary Completion 
The primary analysis for the primary endpoint, and authoring of a CSR may be conducted after all 
patients that enrolled in the main cohort of the refractory expansion part have had the opportunity 
to complete 6 cycles of treatment with study drug. 
Other Planned Analyses 
A CSR efficacy and safety addendum is planned at study completion. 
Study Completion 
The study will be considered completed when all patients have discontinued study treatment, or 
24 months after enrollment of the last patient, whichever occurs later. The estimated time frame 
for study completion is approximately 53 months. 
However, in case a marketing approval of brigatinib for both first-line and second-line settings is 
obtained in Japan before the study completion noted above, this study will become a 
post-marketing clinical study after the marketing approval and will be continued until all the 
patients who are continuing study treatment with brigatinib have access to the commercial supply. 
In this case, each patient who enters the post-marketing clinical study will complete the study 
participation when the patient get access to the commercial supply. The post-marketing clinical 
study will be conducted in compliance with the GCP and the Good Post-Marketing Study Practice, 
and all the terms “study” in this protocol shall be then deemed as appropriately replaced to 
“post-marketing clinical study.” 
6.3.2.2 The TKI-Naïve Expansion Cohort 
Primary Completion 
The primary analysis for the primary endpoint, and authoring of a CSR may be conducted at 
around 10 months after the enrollment of the last subject in the TKI-naïve expansion cohort. 
Other Planned Analyses 
A CSR efficacy and safety addendum is planned at study completion. 
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Study Completion 
After a marketing approval of brigatinib for both first-line and second-line settings is obtained in 
Japan, this study will become a post-marketing clinical study and will be continued until the last 
patient have access to the commercial supply. Each patient who enters the post-marketing clinical 
study will complete the study participation when the patient get access to the commercial supply. 
The post-marketing clinical study will be conducted in compliance with the GCP and the Good 
Post-Marketing Study Practice, and all the term “study” in this protocol shall be then deemed as 
appropriately replaced to “post-marketing clinical study.” 
6.3.3 Time Frames for Primary and Secondary Endpoints to Support Disclosures 
Refer to Table 6.a for disclosures information for all primary and secondary endpoints. 
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Table 6.a 
Primary and Secondary Endpoints for Disclosures 
Endpoint 
Definition 
Maximum Time 
Frame 
Primary 
 
 
Efficacy endpoint in the main cohort of the refrectory expansion part: 
Confirmed ORR as assessed by an 
IRC, per RECIST version 1.1 
The proportion of the patients who are confirmed to have achieved 
CR or partial response (PR) per IRC using RECIST version 1.1 after 
the initiation of study treatment. 
Up to 23 months 
Efficacy endpoint in the TKI naïve expansion cohort: 
12 months PFS rate as assessed by an 
IRC, per RECIST version 1.1 
The PFS rate in Kaplan-Meier plot at 12 months after the initiation 
of study treatment, assessed by IRC, per RECIST version 1.1. 
Up to 36 months 
Secondary 
 
 
a) 
Efficacy endpoint in the TKI-naïve expansion cohort, the overall population of the refractory expansion part, and the 
safety evaluation lead-in part: 
Confirmed ORR, as assessed by an 
IRC, per RECIST version 1.1 
The proportion of the patients who are confirmed to have achieved 
CR or PR per IRC using RECIST version 1.1 after the initiation of 
study treatment. 
Up to 53 months 
b) 
Efficacy endpoints in the TKI-naïve expansion cohort, the main cohort of the refractory expansion part, and the 
overall population of the refractory expansion part: 
DOR, as assessed by an IRC, per 
RECIST version 1.1 
The time between the first documentation of objective tumor 
response (CR or PR) and the first subsequent documentation of 
objective PD or death due to any cause, whichever occurs first. 
Up to 53 months 
PFS, as assessed by an IRC, per 
RECIST version 1.1 
The time from the start of study treatment to the first documentation 
of objective PD or to death due to any cause, whichever occurs first. 
Up to 53 months 
DCR, as assessed by an IRC, per 
RECIST version 1.1 
The proportion of patients who are confirmed to have achieved CR 
or PR or have a best overall response of stable disease (SD), per 
RECIST version 1.1, for 6 weeks or more after initiation of study 
drug. 
Up to 53 months 
Time to response, as assessed by an 
IRC, per RECIST version 1.1 
The time interval from the date of the first dose of study treatment 
until the initial observation of CR or PR for patients with confirmed 
CR/PR. 
Up to 53 months 
OS 
The time from the start of study treatment to the date of death. 
Up to 53 months 
CNS response, as assessed by an IRC, 
per modified RECIST version 1.1 for 
assessment of intracranial efficacy 
(iORR and iDOR in patients who had 
measurable CNS metastases, and iPFS 
in all patients) 
The proportion of the patients who have achieved CR or PR in the 
intracranial CNS per modified RECIST version 1.1 as evaluated by 
an IRC after the initiation of study treatment. 
Up to 53 months 
Time on treatment 
The time interval from the first dose to the last dose of brigatinib. 
Up to 53 months 
c) 
Efficacy endpoints in the TKI-naïve expansion cohort, the main cohort of the refractory expansion part, and the safety 
evaluation lead-in part: 
Confirmed ORR, as assessed by the 
investigator, per RECIST version 1.1 
The proportion of the patients who are confirmed to have achieved 
CR or PR per investigator using RECIST version 1.1 after the 
initiation of study treatment. 
Up to 53 months 
PROs of HRQOL scores and 
symptoms of lung cancer, assessed 
with the EORTC QLQ-C30 (version 
3.0), its lung cancer module 
QLQ-LC13, and the EQ-5D-5L 
(except for the safety evaluation 
lead-in part) 
PROs of HRQOL scores and symptoms of lung cancer, assessed 
with the EORTC QLQ-C30 (version 3.0), its lung cancer module 
QLQ-LC13, and the EQ-5D-5L. 
Up to 53 months 
d) 
PK endpoint in the safety evaluation lead-in part: 
Brigatinib Cmax, tmax, and AUC on 
Cycle 1 Days 1 and 22 
Cmax, tmax, and AUC are defined as maximum observed plasma 
concentration, time of first occurrence of Cmax, and area under the 
plasma concentration-time curve, respectively. 
Up to Cycle 1 Day 
22 
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6.3.4 Total Study Duration 
It is anticipated that this study will last for approximately 53 months. 
6.4 
Study Discontinuation and Closure 
Study participation by individual sites or the entire study may be prematurely terminated if, in the 
opinion of the investigator or the sponsor, there is sufficient reasonable cause. Written notification 
documenting the reason for study termination will be provided to the investigator or the sponsor by 
the terminating party. 
Circumstances that may warrant termination include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to patients. 
• Failure to enter patients at an acceptable rate. 
• Insufficient adherence to protocol requirements. 
• Insufficient, incomplete, and/or unevaluable data. 
• Determination of futility based on the interim analysis. 
• Plans to modify, suspend, or discontinue the development of the study drug. 
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7.0 
STUDY POPULATION 
7.1 
Inclusion Criteria 
Each patient must meet all the following inclusion criteria to be enrolled in the study: 
1. Male or female Japanese patients aged ≥20 years on the day of consent. 
2. 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. 
3. Have histologically or cytologically confirmed stage IIIB, stage IIIC (locally advanced or 
recurrent and not a candidate for definitive multimodality therapy), or stage IV NSCLC. 
4. Have documentation of ALK rearrangement that meets following criteria. 
For the safety evaluation lead-in part and the refractory expansion part, patients must meet 1 of 
the following 2 criteria: 
a) Have documentation of ALK rearrangement by a positive result from the Vysis ALK 
Break Apart FISH [fluorescence in situ hybridization] Probe Kit, the Nichirei Histofine 
ALK iAEP Kit, or the Ventana ALK (D5F3) CDx Assay at any time during prior disease 
course. The sponsor may require an adequate tissue available for central laboratory testing 
by the Vysis ALK Break Apart FISH test if a documented ALK rearrangement is 
confirmed by a positive result from the Nichirei Histofine ALK iAEP Kit "ONLY". 
b) Had a documented ALK rearrangement by a different test at any time during prior disease 
course, and adequate tissue available for central laboratory testing by the Vysis ALK Break 
Apart FISH test. Central confirmation of ALK rearrangement is not required before 
enrollment. 
For TKI-naïve expansion cohort, patients must meet the following criteria 
Have documentation of ALK rearrangement by a positive result from MHLW Approved 
tests (e.g. Vysis ALK Break Apart FISH [fluorescence in situ hybridization] Probe Kit, the 
Nichirei Histofine ALK iAEP Kit, or the Ventana ALK [D5F3] CDx Assay) prior to 
enrollment, and required to submit sufficient tumor tissue for central laboratory 
testing upon request of sponsor. Central confirmation of ALK rearrangement is not 
required before enrollment 
5. The refractory expansion part only: had documented PD during treatment or within 30 days 
after discontinuation of treatment with either alectinib, crizotinib, ceritinib, or lorlatinib. 
– Note 1: The refractory expansion part consists of the main cohort and a subcohort based on 
prior ALK inhibitor treatment. The main cohort includes patients who had previously 
received alectinib (as their only ALK inhibitor) or both crizotinib and alectinib (regardless 
the sequence of those 2 ALK inhibitors), and a total of 47 patients will be enrolled. Patients 
with all other sequences of up to 2 prior ALK inhibitor(s) may be included in the subcohort, 
and the number of patients will be limited to 20. 
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– Note 2: Patients who will be included in the main cohort of the refractory should have 
documented PD during treatment or within 30 days after discontinuation of treatment with 
alectinib. 
6. Have at least 1 measurable (ie, target) lesion per RECIST version 1.1 (Appendix G).  
Note: Previously irradiated lesions may not be used for target lesions, unless there is 
unambiguous radiological progression after radiotherapy. Brain lesions may not be used as 
target lesions if they were 1) previously treated with whole brain radiation therapy (WBRT) 
within 3 months, or 2) previously treated by stereotactic radiosurgery (SRS) or surgical 
resection. 
7. Recovered from toxicities related to prior anticancer therapy to NCI CTCAE version 4.03 
Grade ≤1.  
Note: Treatment-related alopecia is allowed. 
8. Have a life expectancy of ≥3 months. 
9. Have adequate organ and hematologic function, as determined by: 
a) Both alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 times the 
upper limit of the normal range (ULN) (≤5×ULN is acceptable if liver metastases are 
present). 
b) Total serum bilirubin ≤1.5×ULN (<3.0×ULN for patients with Gilbert syndrome). 
c) Serum creatinine <1.5×ULN. For patients with creatinine levels above or equal to 
1.5×ULN, the patient is eligible if the estimated creatinine clearance using the 
Cockcroft-Gault formula is ≥30 mL/minute. 
d) Serum lipase ≤1.5×ULN and serum amylase ≤1.5×ULN. 
e) Absolute neutrophil count (ANC) ≥1.5×109/L. 
f) Platelet count ≥75×109/L. 
g) Hemoglobin ≥9 g/dL. 
h) Percutaneous oxygen saturation (SpO2) ≥94% without oxygen support. Patients who need 
oxygen support are excluded. 
10. Have an Eastern Cooperative Oncology Group (ECOG) performance status of ≤2. 
11. Must meet the following criteria: 
a) 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 1 highly effective non-hormonal 
method of contraception and 1 additional effective (barrier) method at the same time, from 
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the time of signing the informed consent through 4 months 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, from the time of signing the informed consent through 4 months after that 
last dose of study drug. (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.) 
b) Male patients, even if surgically sterilized (ie, status postvasectomy), who: 
– Agree to practice effective barrier contraception during the entire study treatment period 
and through 4 months 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, during the entire study treatment period and through 4 months after that last 
dose of study drug. (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not 
acceptable methods of contraception. Female and male condoms should not be used 
together.) 
12. Have the willingness and ability to comply with scheduled visit and study procedures. 
7.2 
Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not to be enrolled in the study. 
1. Previously received the following treatments. 
The refractory expansion part only: received any prior ALK inhibitor other than alectinib, 
crizotinib, ceritinib, or lorlatinib. 
TKI-naïve expansion cohort only: received any prior TKI including but not limited to ALK 
inhibitor and VEGFR TKI. 
2. The refractory expansion part only: received more than 2 prior ALK inhibitors. 
Note: The safety evaluation lead-in part allows patients with any line of prior ALK inhibitor 
which includes treatment-naïve patients; however, ALK inhibitor-naïve patients may be 
enrolled after the confirmation of first 3 DLT evaluable patients to have no more than 1 DLT 
during Cycle 1 by investigator's judgement. 
3. The safety evaluation lead-in part and the refractory expansion part only: received alectinib, 
crizotinib, ceritinib, or lorlatinib within 7 days before the first dose of brigatinib. 
4. Previously received more than 1 regimen (more than 3 regimens in the safety evaluation 
lead-in part) of systemic anticancer therapy (other than ALK inhibitors) for locally advanced 
or metastatic disease. 
Note: A systemic anticancer therapy regimen will be counted if it is administered over at least 
1 cycle. A new anticancer agent used as maintenance therapy will be counted as a new regimen 
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unless it was previously used as initial anticancer therapy. Neoadjuvant or adjuvant systemic 
anticancer therapy will be counted as a prior regimen if completion of (neo) adjuvant therapy 
occurred <12 months before the first dose of brigatinib. 
5. Treatment with any investigational products within 30 days or 5 half-lives of that 
investigational agent, whichever is longer, before the first dose of brigatinib. 
6. Received chemotherapy or radiation within 14 days before the first dose of brigatinib, except 
SRS or stereotactic body radiation therapy. 
7. Received antineoplastic monoclonal antibodies within 30 days before the first dose of 
brigatinib. 
8. Received systemic treatment with strong inhibitors or strong and moderate inducers of 
cytochrome P450 (CYP) 3A within 7 days before the first dose of brigatinib. 
9. Had major surgery within 30 days before the first dose of brigatinib. Minor surgical procedures 
such as venous catheter placement or minimally invasive biopsies are allowed. 
10. Have been diagnosed with another primary malignancy other than NSCLC, except for the 
following adequately/definitively treated malignancies: nonmelanoma skin cancer, cervical 
cancer in situ, nonmetastatic prostate cancer; or patients with another primary malignancy who 
are definitively relapse-free with at least 3 years elapsed since the diagnosis of the other 
primary malignancy. 
11. Have symptomatic CNS metastases (parenchymal or leptomeningeal) at screening or 
asymptomatic disease requiring an increasing dose of corticosteroids to control symptoms 
within 7 days before the first dose of brigatinib. 
Note: If a patient has worsening neurological symptoms or signs due to CNS metastasis, the 
patient needs to complete local therapy and be neurologically stable (with no requirement for 
an increasing dose of corticosteroids or use of anticonvulsants for symptomatic control) for 7 
days before the first dose of brigatinib. 
12. Have current spinal cord compression (symptomatic or asymptomatic and detected by 
radiographic imaging). Patients with asymptomatic leptomeningeal disease and without cord 
compression are allowed. 
13. Have ongoing or history of interstitial lung disease (ILD) (including interstitial pneumonitis, 
pneumonitis, radiation pneumonitis, drug-related pneumonitis, organized pneumonia, and 
pulmonary alveolitis). 
14. Have significant, uncontrolled, or active cardiovascular disease, specifically including, but not 
limited to: 
a) Myocardial infarction within 6 months before the first dose of brigatinib. 
b) Unstable angina within 6 months before the first dose of brigatinib. 
c) Congestive heart failure within 6 months before the first dose of brigatinib. 
d) Uncontrolled atrial arrhythmias despite appropriate medical therapy. 
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e) History of ventricular arrhythmia, including history of ventricular tachycardia, ventricular 
fibrillation, or torsade de pointes. Patients with premature ventricular contractions are 
allowed. 
f) Cerebrovascular accident or transient ischemic attack within 6 months before the first dose 
of brigatinib. 
15. Have uncontrolled hypertension. Patients with hypertension should be under treatment at the 
start of screening and demonstrate adequate control of blood pressure. 
16. Have an ongoing or active infection, including, but not limited to, the requirement for 
intravenous antibiotics. 
17. Have a known history of human immunodeficiency virus (HIV) infection. Testing is not 
required in the absence of history. 
18. Hepatitis B surface antigen (HBsAg) positive, detectable hepatitis B viral load, or detectable 
hepatitis C virus (HCV) infection viral load. 
Note: Patients who have positive hepatitis B core antibody (HBcAb) or hepatitis B surface 
antibody (HBsAb) can be enrolled but must have an undetectable hepatitis B viral load. 
Patients who have positive HCV antibody can be enrolled but must have an undetectable 
hepatitis C viral load. 
19. Have malabsorption syndrome or other gastrointestinal illness that could affect oral absorption 
of brigatinib. 
20. Have a known or suspected hypersensitivity to brigatinib or its excipients. 
21. Female patients who are lactating and breastfeeding or have a positive serum pregnancy test 
during the screening period. 
Note: Female patients who are lactating will be excluded, even if they discontinue 
breastfeeding. 
22. Have any condition or illness that, in the opinion of the investigator, would compromise 
patient safety or interfere with the evaluation of brigatinib. 
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8.0 
STUDY DRUG 
8.1 
Study Drug Administration 
Brigatinib will be administered orally at a dose of 90 mg QD for first 7 days followed by 180 mg 
QD continuously at the same time each day (preferably in the morning). A cycle of therapy will 
comprise 28 days of treatment. Patients will take the prescribed dose with water (recommended 
approximately 240 mL). Brigatinib can be administered with or without food. 
Patients who forget to take their scheduled dose of brigatinib should be instructed not to make up 
the missed dose. A missed dose is defined as a dose not taken within 12 hours of the intended 
scheduled administration. Missed doses should be recorded in an appropriate source record 
(eg, clinic chart), patient diary card, and study drug administration electronic case report form 
(eCRF). 
8.2 
Definitions of DLT 
Toxicity will be evaluated according to the NCI CTCAE, version 4.03, effective 14 June 2010 [15]. 
DLT evaluation applies only to the first 9 DLT-evaluable patients in the safety evaluation lead-in 
part. DLTs will be defined as any of the following events occurring within the first 28 days of 
treatment (end of Cycle 1) that are considered by the investigator to be at least possibly related to 
therapy with brigatinib (note that adverse events [AEs] for which the relationship to study drug 
cannot be ruled out should be considered possibly related to study drug): 
• Nonhematologic toxicities include any nonhematologic toxicity Grade ≥3 with the following 
exceptions: 
– Self-limiting or medically controllable toxicities (ie, nausea, vomiting, diarrhea, fatigue, 
and electrolyte disturbances) lasting ≤3 days. 
– Isolated asymptomatic Grade ≥3 laboratory abnormalities that resolve to Grade ≤1 or 
baseline in ≤7 days. 
• Hematologic toxicities: 
– Febrile neutropenia not related to underlying disease (ANC <1000/mm3 with a single 
temperature of >38.3°C or a sustained temperature of ≥38°C for more than 1 hour). 
– Prolonged (>7 days) Grade 4 neutropenia (if granulocyte-colony stimulating factor 
[G-CSF] is used, the event will be considered as DLT irrespective of the duration). 
– Neutropenic infection: Grade ≥3 neutropenia with Grade ≥3 infection. 
– Thrombocytopenia Grade ≥3 with bleeding, Grade ≥3 requiring platelet transfusion, or 
Grade 4 lasting >7 days. 
– Anemia Grade ≥3 requiring blood transfusion. 
Note: Prophylactic transfusions of blood products or any prophylactic use of hematopoietic 
growth factors (such as erythropoietin, thrombopoietin, G-CSF, and granulocyte 
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macrophage-colony stimulating factor [GM-CSF]) is not permitted during the DLT 
evaluation period. 
• Missed >25% of planned cumulative doses (ie, 1102.5 mg) of brigatinib over 28 days because 
of treatment-related AEs (except Grade 1 or 2 ILD/pneumonitis in the first 7 days) in the first 
cycle. 
Note: In case of Grade 1 or 2 ILD/pneumonitis in the first 7 days, before escalation to 180 mg 
QD: 
1) If the event does not resolve within 14 days (ie, the patient misses 14 or more doses of 
brigatinib), then the events will be considered as a DLT. 
2) If the event resolves within 14 days and the administration of brigatinib can be resumed 
before 14 missed doses, then the patient will be considered DLT nonevaluable in condition that 
the patient does not have any other events qualifying as DLTs later. In case that the event 
resolves within 14 days but the patient does not resume brigatinib based on investigator's 
judgment or patient’s request, those patients will also be considered DLT nonevaluable. (See 
Table 8.b for detail of dose modification based on ILD/pneumonitis.) 
Although the above toxicities may occur at any point during treatment, these toxicities are 
considered DLTs only if they occur during Cycle 1 of treatment, in which case, they will influence 
decisions regarding opening the expansion part. Patients will be monitored through all cycles of 
therapy for treatment-related toxicities. 
DLT-evaluable patients must complete at least 75% (ie, 3,307.5 mg of 4,410 mg in 28 days of 
Cycle 1) of their planned cumulative doses, unless missed doses are due to related AEs. 
DLT-nonevaluable patients in the safety evaluation part of the study will be replaced. The timing 
of adding patients for DLT evaluation may be decided with advice from the chairperson of the 
independent data monitoring committee (IDMC), if needed. 
8.3 
Patient Expansion After the Safety Evaluation Lead-in Part 
If a DLT is observed in fewer than 3 patients in the 9 DLT-evaluable patients of the safety 
evaluation lead-in part, the 90 mg QD→180 mg QD regimen will be used in the patients enrolled 
in the expansion part. Opening of the expansion part will be determined on the basis of the total 
safety data available at that time, available PK results, and with recommendation from the IDMC. 
Regarding the safety data, all AEs observed in the safety evaluation lead-in part, including those 
observed in DLT non-evaluable patients, will be evaluated in concert with DLTs when making the 
decision on opening of the expansion part. 
If a DLT is observed in 3 or more patients of the 9 DLT-evaluable patients, the 
90 mg QD→180 mg QD dose regimen will NOT be considered tolerable. If 3 DLT cases are 
confirmed before completion of enrolling 9 DLT-evaluable cases, the enrollment of subsequent 
patients may be halted. If the dose of 90 mg QD→180 mg QD is NOT considered tolerable, the 
dose for subsequent patients will be selected on the basis of the toxicity observed and available PK 
data in the 9 DLT-evaluable patients. This will require a protocol amendment and possibly 
changes to the inclusion/exclusion criteria and/or modification of the dose regimen. If another 
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dose regimen will be used, the safety evaluation part described above with close safety monitoring 
and intensive PK sampling will be repeated for the new dose regimen. 
8.4 
Dose Modification Guidelines 
The following sections provide recommended dose modification guidelines for treatment-related 
AEs observed. 
Brigatinib dose modification levels are summarized in Table 8.a. 
Table 8.a 
Recommended Brigatinib Dose Reduction Levels 
Dose 
Dose Reduction Levels 
First 
Second 
Third 
90 mg QD 
60 mg QD 
Permanently discontinue 
Not applicable 
180 mg QD 
120 mg QD 
90 mg QD 
60 mg QD 
 
Permanently discontinue brigatinib if patients are unable to continue the 60 mg QD dose because 
of treatment related-AEs. 
Recommendations for dose modifications of brigatinib for the management of treatment-related 
AEs are provided in Table 8.b. 
Table 8.b 
Recommended Brigatinib Dose Modifications for Treatment-Related AEs 
Treatment-Related 
AE 
Severity (a) 
Dose Modification 
ILD/pneumonitis 
Grade 1 
• If ILD/pneumonitis occurs (or is suspected) during the first 7 days 
of treatment, interrupt brigatinib until recovery to baseline, then 
resume at same dose and do not escalate to 180 mg if 
ILD/pneumonitis is suspected. 
• If ILD/pneumonitis occurs (or is suspected) after the first 7 days of 
treatment, interrupt brigatinib until recovery to baseline, then 
resume at same dose. 
• If ILD/pneumonitis recurs, permanently discontinue brigatinib. 
Grade 2 
• If ILD/pneumonitis occurs (or is suspected) during the first 7 days 
of treatment, interrupt brigatinib until recovery to baseline. 
Resume at next lower dose (Table 8.a) and do not dose escalate if 
ILD/pneumonitis is suspected. 
• If ILD/pneumonitis occurs (or is suspected) after the first 7 days of 
treatment, interrupt brigatinib until recovery to baseline. If 
ILD/pneumonitis is suspected, resume at next lower dose 
(Table 8.a); otherwise, resume at same dose. 
• If ILD/pneumonitis recurs, permanently discontinue brigatinib. 
Grade 3 or 4 
Permanently discontinue brigatinib for ILD/pneumonitis. 
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Treatment-Related 
AE 
Severity (a) 
Dose Modification 
Hypertension 
Grade 3 hypertension 
(SBP ≥160 mmHg or 
DBP ≥100 mmHg, 
medical intervention 
indicated, more than 1 
antihypertensive drug, 
or more-intensive 
therapy than previously 
used indicated) 
• Interrupt brigatinib until hypertension has recovered to Grade 1 or 
less (SBP <140 mmHg and DBP <90 mmHg), then resume 
brigatinib at next lower dose (Table 8.a). 
• Recurrence: interrupt brigatinib until recovery to Grade 1 or less 
then resume at next lower dose (Table 8.a), or permanently 
discontinue treatment. 
Grade 4 hypertension 
(life-threatening 
consequences, urgent 
intervention indicated) 
• Interrupt brigatinib until recovery to Grade 1 or less then resume at 
next lower dose (Table 8.a), or permanently discontinue treatment. 
• Recurrence: permanently discontinue brigatinib for recurrence of 
Grade 4 hypertension. 
Bradycardia  
(HR <60 bpm) 
Symptomatic 
bradycardia 
• Interrupt brigatinib until recovery to asymptomatic bradycardia or 
to a resting heart rate of 60 bpm or above. 
• If a concomitant medication known to cause bradycardia is 
identified and discontinued or dose adjusted, resume brigatinib at 
the same dose upon recovery to asymptomatic bradycardia or to 
resting heart rate of 60 bpm or above. 
• If no concomitant medication known to cause bradycardia is 
identified, or if contributing concomitant medications are not 
discontinued or dose adjusted, resume brigatinib at the next lower 
dose (Table 8.a) upon recovery to asymptomatic bradycardia or to 
resting heart rate of 60 bpm or above. 
Bradycardia with 
life-threatening 
consequences, urgent 
intervention indicated 
• Permanently discontinue brigatinib if no contributing concomitant 
medication is identified. 
• If contributing concomitant medication is identified and 
discontinued or dose adjusted, resume brigatinib at the next lower 
dose (Table 8.a) upon recovery to asymptomatic bradycardia or to 
a resting heart rate of 60 bpm or above, with frequent monitoring 
as clinically indicated. 
• Recurrence: permanently discontinue brigatinib. 
Visual disturbance 
Grade 2 or 3 visual 
disturbance 
Interrupt brigatinib until recovery to Grade 1 or baseline, then 
resume at the next lower dose (Table 8.a). 
Grade 4 visual 
disturbance 
Permanently discontinue brigatinib. 
Creatine 
phosphokinase 
(CPK) elevation 
Grade 3 CPK elevation 
(>5.0×ULN) 
Interrupt brigatinib until recovery to Grade 1 or less (≤2.5×ULN) or 
to baseline, then resume brigatinib at the same dose. 
Grade 4 CPK elevation 
(>10.0×ULN) or 
recurrence of Grade 3 
elevation 
Interrupt brigatinib until recovery to Grade 1 or less (≤2.5×ULN) or 
to baseline, then resume brigatinib at the next lower dose (Table 8.a). 
Lipase/amylase 
elevation 
Grade 3 lipase or 
amylase elevation 
(>2.0×ULN) 
Interrupt brigatinib until recovery to Grade 1 or less (≤1.5×ULN) or 
to baseline, then resume brigatinib at the same dose. 
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Treatment-Related 
AE 
Severity (a) 
Dose Modification 
Grade 4 lipase or 
amylase elevation 
(>5.0×ULN) or 
recurrence of Grade 3 
elevation 
Interrupt brigatinib until recovery to Grade 1 or less (≤1.5×ULN) or 
to baseline, then resume brigatinib at the next lower dose (Table 8.a). 
Hyperglycemia 
Grade 3 (>250 mg/dL or 
13.9 mmol/L) or greater 
If adequate hyperglycemic control cannot be achieved with optimal 
medical management, interrupt brigatinib until adequate 
hyperglycemic control is achieved and consider reduction to the next 
dose (Table 8.a), or permanently discontinue brigatinib. 
Other 
Grade 3 
• First occurrence: interrupt brigatinib until recovery to baseline, 
then resume at same dose. 
• Recurrence: interrupt brigatinib until recovery to baseline then 
resume at next lower dose, or discontinue brigatinib (Table 8.a). 
Grade 4 
• First occurrence: either interrupt brigatinib until recovery to 
baseline and resume at next lower dose (Table 8.a) or permanently 
discontinue brigatinib. 
• Permanently discontinue brigatinib for recurrence. 
bpm=beats per minute; DBP=diastolic blood pressure; HR=heart rate; SBP=systolic blood pressure. 
(a) Graded per the NCI CTCAE, version 4.03. 
8.4.1 Criteria for Dose Interruption During a Cycle 
See Table 8.b. 
8.4.2 Criteria for Dose Reduction 
See Table 8.b. 
8.4.3 Reintroducing Brigatinib After Dose Interruption 
If brigatinib treatment interruption lasts ≥14 days, and the prior dose was >90 mg QD, patients 
should resume treatment at 90 mg QD for 7 days, before escalating the dose back to 120 mg QD or 
180 mg QD. The dose should not be escalated higher than the prior dose level before treatment 
interruption. 
8.4.4 Reescalation After Dose Modification 
Reescalation after dose modification for AEs is discouraged. However, if in the opinion of the 
investigator reescalation is warranted, this must be undertaken after consultation with the sponsor. 
To be a candidate for reescalation, the AE that led to dose modification must not have recurred, 
and no other AEs of Grade 3 or Grade 4 must have been observed during the preceding 28 days. 
8.4.5 Criteria for Discontinuation of Brigatinib 
See Table 8.b. 
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In addition, the investigator should discontinue brigatinib at any time and for any reason if it is 
determined to be in the best interest of the patient. 
8.5 
Excluded Concomitant Medications and Procedures 
The following concomitant medications and procedures are prohibited during the treatment 
period: 
• Any other systemic anticancer therapy including, but not limited to, chemotherapeutic agents, 
immunotherapy, biological response modifiers (excluding growth factors), radiotherapy, 
and/or systemic hormonal therapy (with the exception of local therapies, such as SRS and 
WBRT, used for palliative or symptomatic control of existing lesions, with appropriate 
treatment interruption at the discretion of the investigator). Hormonal contraception is not 
allowed. 
• Use of any other investigational drug or device. 
• Extensive surgery requiring in-patient care (patients may have an interruption in therapy for 
14 days should emergency surgery be required). 
If a patient’s clinical condition requires treatment with one of the prohibited classes of medications 
specified above, the clinical details of the situation should be discussed with the sponsor’s project 
clinician (or designee) as soon as possible to determine whether it is safe for the patient to continue 
treatment with brigatinib. 
On the basis of the metabolism of brigatinib being primarily via CYP3A and the results of clinical 
drug-drug interaction (DDI) studies in healthy subjects, the following should be followed: 
• Avoid the concomitant use of strong CYP3A inhibitors (see Appendix F). Grapefruit or 
grapefruit juice may also increase plasma concentrations of brigatinib and should be avoided. 
• Avoid the concomitant use of strong and moderate CYP3A inducers with brigatinib (see 
Appendix F). 
8.6 
Permitted Concomitant Medications and Procedures 
Palliative therapy and supportive care are permitted during the study for management of symptoms 
and underlying medical conditions that may develop during the study. Once a patient has begun 
treatment, a condition may arise that requires the initiation of a new concomitant medication or 
therapy. Patients with CNS lesions requiring local radiotherapy such as SRS or WBRT are allowed 
to continue study drug after appropriate interruption, as determined by the investigator with 
sponsor agreement; however, for analysis purposes, these patients will be considered to have PD. 
8.7 
Precautions and Restrictions 
It is not known what effects brigatinib has on human pregnancy or development of the embryo or 
fetus; therefore, female patients participating in this study should avoid becoming pregnant, and 
male patients should avoid impregnating a female partner. Nonsterilized female patients of the 
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reproductive age group and male patients should use effective methods of contraception through 
defined periods during and after study treatment as specified below. 
Female patients must meet 1 of the following: 
• Postmenopausal for at least 1 year before the screening visit, OR 
• Surgically sterile, OR 
• If they are of childbearing potential, agree to practice 1 highly effective non-hormonal method 
(eg, intrauterine device [IUD]) with a condom, which is an effective barrier method of 
contraception, at the same time, from the time of signing of the informed consent form (ICF) 
through 4 months 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, from the time of signing the informed consent through 4 months after that last dose 
of study drug. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.) 
Male patients, even if surgically sterilized (ie, status postvasectomy) must agree to 1 of the 
following: 
• Agree to practice effective barrier contraception during the entire study treatment period and 
through 4 month 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, during the entire study treatment period and through 4 months after that last dose of 
study drug. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.) 
8.8 
Management of Clinical Events 
8.8.1 ILD/Pneumonitis 
During early clinical development of brigatinib, moderate and severe pulmonary AEs (eg, dyspnea, 
hypoxia, cough, pneumonia, and pneumonitis) were observed early after initiation of the drug in a 
subset of patients. To better characterize early pulmonary AEs observed with brigatinib treatment, 
a strategy for systematic analysis of these events according to a case definition for EOPE was 
developed. In Study AP26113-11-101, pulmonary events occurring within the first 7 days of 
treatment with brigatinib, consistent in some cases with pneumonitis, were observed shortly after 
treatment initiation in 2% of patients who had received brigatinib at a starting dose of 90 mg QD 
(including patients who escalated to 180 mg QD after 7 days). No such events were observed in the 
7 days after escalation to 180 mg QD. In Study AP26113-13-201, of 219 treated patients, 4 cases 
were determined to meet the criteria for definite EOPE, and 10 cases met the criteria for possible 
EOPE. In total, 6.4% of patients had an event that was at least possibly an EOPE. All EOPEs 
occurred at a dose of 90 mg QD, regardless of dose group (ie, within the first 7 days of treatment in 
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the 90 mg QD→180 mg QD dose group). No EOPEs were identified after escalation to 180 mg 
QD in the 90 mg QD→180 mg QD dose group. 
Pulmonary symptoms have been observed after a single dose of brigatinib in some patients. The 
pulmonary symptoms are associated in more severe cases with hypoxia and chest CT findings of 
ground glass opacities consistent with pneumonitis. These events have been managed with 
treatment interruption and medical management as clinically indicated (eg, steroids, antibiotics). 
Most events resolved with interruption or discontinuation of brigatinib. Two fatal pulmonary 
events (hypoxia and pneumonia) and 1 fatal pulmonary event (pneumonia) starting within the first 
7 days of treatment were observed in Studies AP26113-11-101 and AP26113-13-201, respectively. 
Upon resumption of dosing, some patients had events recur, and others did not have recurrence 
with continued dosing. As such, investigators and patients must be aware that pneumonitis-like 
events may present as early as 24 to 48 hours after initial dosing. 
Later-onset pneumonitis has also occurred in the brigatinib development program. 
Pulmonary events occurring after initiation of brigatinib treatment including, but not limited to, 
dyspnea, hypoxia, dry cough, chest tightness, and presumptive lung infection (pneumonia) should 
be monitored and reported. 
To reiterate, some events occur after a single dose of brigatinib, and physicians should be aware of 
this possibility and discuss it with patients. Newly developed or worsening of pulmonary 
symptoms in the first week of study drug administration, specifically with hypoxia and ground 
glass opacity on radiographic imaging indicative of ILD or pneumonitis, could suggest a 
relationship to brigatinib. Other etiologies, including pulmonary embolism and infectious 
pneumonia, should be ruled out if possible. If no evidence of other etiology is identified, a causal 
relationship to brigatinib should be considered. 
The management of new or worsening pulmonary symptoms after initiation of brigatinib treatment 
should include drug interruption; monitoring of oxygen saturation and biomarkers (Serum Krebs 
von den Lungen-6 [KL-6] and surfactant protein-D [SP-D]); thoracentesis, bronchoscopy, open 
lung biopsy, chest x-ray, or CT; and appropriate work up for infectious or other etiology, with 
high-dose corticosteroids, supplemental oxygen therapy, and empiric antibiotics as indicated. 
After drug interruption and workup of symptoms, dose modification should be accomplished 
according to the recommendations in Table 8.b. 
8.8.2 Hypertension 
Blood pressure should be monitored and recorded at each visit. Hypertension detected by at least 
2 blood pressure measurements should be graded according to NCI CTCAE, version 4.03, which 
defines hypertension as a disorder characterized by a pathological increase in blood pressure: a 
repeated elevation in the blood pressure exceeding 140 mmHg for systolic and exceeding 
90 mmHg for diastolic. For patients who either develop hypertension or experience worsening 
hypertension during treatment with study drug, at the discretion of the investigator, aggressive 
antihypertensive medication should be initiated or optimized to achieve target blood pressure 
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before interruption or dose reduction of the study drug. If Grade 3 or Grade 4 hypertension 
develops, dose interruption and reduction is recommended according to Table 8.b. 
8.8.3 Bradycardia 
Heart rate should be monitored and recorded at each visit. Brigatinib should be avoided in 
combination with other agents known to cause bradycardia (eg, beta-blockers, nondihydropyridine 
calcium channel blockers, clonidine, and digoxin) to the extent possible. For symptomatic 
bradycardia, dose interruption and reduction is recommended according to Table 8.b. 
8.8.4 Nausea and Emesis 
Nausea should be treated with standard-of-care antiemetics. Prophylactic antiemetics may be used. 
8.8.5 Visual Disturbance 
In patients with new onset or worsening severe (Grade ≥3) visual disturbance, ophthalmological 
evaluation is recommended. Visual disturbance should be managed as described in Table 8.b. 
8.8.6 Diarrhea 
For Grade 1 diarrhea, symptomatic care such as loperamide may be given, or no intervention may 
be undertaken, according to the investigator’s clinical judgment. For Grade 2 diarrhea, administer 
loperamide until the patient is symptom-free for 12 hours. No dose modification is necessary 
unless the patient does not tolerate brigatinib or the symptom recurs. For Grade ≥3 despite 
loperamide, treatment should be interrupted or permanently discontinued according to Table 8.b. 
Secondary prophylaxis in patients who have experienced diarrhea with brigatinib treatment is 
allowed. Other medications and supportive care may be added according to the institution’s 
standard of care. 
8.9 
Blinding and Unblinding 
This is an open-label study. 
8.10 
Description of Investigational Agents 
Brigatinib drug product is supplied as film-coated tablets containing 30, 90, or 180 mg of 
brigatinib active pharmaceutical ingredient. Other ingredients are typical pharmaceutical 
excipients (lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, colloidal 
silica, and magnesium stearate). The tablet coating is composed of typical pharmaceutical grade 
coating components (talc, polyethylene glycol, polyvinyl alcohol, and titanium dioxide). The drug 
product is manufactured under current Good Manufacturing Practice in accordance with approved 
procedures. 
For additional details, refer to the Investigator’s Brochure and Pharmacy Manual. 
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8.11 
Preparation, Reconstitution, and Dispensation 
Detailed instructions for dispensing brigatinib tablets are provided in the Pharmacy Manual. 
Brigatinib is an anticancer drug, and as with other potentially toxic compounds, caution should be 
exercised when handling brigatinib. 
8.12 
Packaging and Labeling 
Brigatinib will be supplied in white high-density polyethylene bottles with induction-sealed caps. 
Bottle labels will bear the appropriate label text as required by governing regulatory agencies. At a 
minimum, such text will include product name, product strength, number of tablets, and lot 
number. 
8.13 
Storage, Handling, and Accountability 
The recommended storage condition for brigatinib is to store at 15°C to 30°C. Do not refrigerate or 
freeze. A daily temperature log of the drug storage area must be maintained each working day. 
Temperature excursions must be reported to the sponsor or designee. 
The investigator is responsible for ensuring that the study drug provided to the patient and returned 
from the patient is reconciled and noted in source documentation. 
All used bottles of study drug must be returned to the study sponsor or destroyed in an appropriate 
manner according to the standard practice at each study site. Destruction of such supplies will be 
documented, and the sponsor or its designee will verify disposition records. 
During the study and at termination, patients must return all unused study drug supplies, and the 
return of these unused study drug supplies must be recorded. Returned supplies must not be 
redispensed. 
No other utilization of brigatinib intended for use in this study is authorized by the sponsor. The 
on-site pharmacist will immediately return unused study drugs to the sponsor after the study is 
closed at the study site. 
Please refer to the Pharmacy Manual for additional instructions. 
8.14 
Other Protocol-Specified Materials 
Not applicable 
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9.0 
STUDY CONDUCT 
This trial will be conducted in compliance with the protocol, Good Clinical Practice (GCP), 
applicable regulatory requirements, and International Conference on Harmonisation (ICH) 
guidelines. 
9.1 
Study Personnel and Organizations 
The contact information for the sponsor’s project clinician (or designee), the central laboratory, 
any additional clinical laboratories or vendors participating in the study, and the list of 
investigators can be found in the protocol annex or the Study Manual. 
9.2 
Arrangements for Recruitment of Patients 
Recruitment and enrollment strategies for this study may include recruitment from the 
investigator’s local practice or referrals from other physicians. If advertisements become part of 
the recruitment strategy, they will be reviewed by the institutional review board (IRB). 
9.3 
Treatment Group Assignments 
After written informed consent has been obtained, the patient will be assigned a patient 
identification code. 
Patient eligibility will be confirmed by the sponsor’s project clinician (or designee) before 
enrollment by the investigator into the study. Reenrollment of the same patient will not be 
permitted. If a patient is discontinued from the study, that patient identification code will not be 
reused. 
The first 9 patients will be enrolled in the safety evaluation lead-in part. Enrollment will be 
interrupted after the ninth potentially DLT-evaluable patient is enrolled until the DLTs are 
assessed. After the decision to open the expansion part, patient enrollment will be resumed. 
Patients in the expansion part will be assigned to the refractory expansion cohort (including the 
main cohort or the subcohort) or TKI-naïve expansion cohort at enrollment on the basis of prior 
ALK inhibitor treatment. 
9.4 
Study Procedures 
Patients will be evaluated at scheduled visits over the following study periods: screening, 
treatment, EOT, and follow-up. This protocol generally presents scheduled timelines for study 
procedures by abbreviated references to cycle (C) and day (D) relative to the date of the first dose 
of study treatment (defined as C1D1). 
The ICF may be signed more than 21 days before C1D1. Screening assessments must be 
performed within 14 days before C1D1, with the exception of tumor imaging assessment, for 
which the allowable window is 21 days before C1D1. However, whenever feasible, baseline 
imaging should be performed as close as possible to C1D1. 
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Vital signs should be repeated on C1D1 before the first dose, regardless of the time from screening. 
Physical examination, ECOG performance status assessments, hematology, chemistry, insulin, 
testosterone (male patients only), and pregnancy test assessments do not need to be repeated on 
C1D1 if they were performed for screening within 7 days before C1D1 and, in the opinion of the 
investigator, there is no reason to believe they have substantially changed. If screening laboratory 
assessments need to be repeated on C1D1, they should be obtained before starting treatment. 
In the safety evaluation lead-in part, patients will be hospitalized during Cycle 1 in general. If a 
patient wishes to return home temporarily and the investigator confirms that the patient’s 
symptoms are stable on the basis of the available data, then the patient may return home 
temporarily except on Days 1 through 10 and Days 22 and 23, provided this does not interfere with 
the study assessments. The investigator must document the confirmation record for stabilization of 
the patient’s symptoms per the available data in an appropriate source record (eg, medical records) 
before the patient’s temporary leave. 
Refer to the Schedule of Events (Appendix A) for the timing of assessments. Refer to Table B for 
Cycle 1 of the safety evaluation lead-in part; for all other cycles of the safety evaluation lead-in 
part, refer to Table A. The timing of PK assessments is specified in Table C (safety evaluation 
lead-in part) and Table D (expansion part). Additional details are provided as necessary in the 
sections that follow. 
9.4.1 Informed Consent 
Each patient must provide written informed consent before any study-required procedures are 
conducted, unless those procedures are performed as part of the patient’s standard care. 
9.4.2 Patient Demographics 
Demographic information will be obtained at screening and will consist of the date of birth, sex, 
race, and smoking history. 
9.4.3 Medical History 
Medical/Surgical History 
A complete medical history will be taken at screening. Information to be documented includes 
relevant past illnesses, including other cancers, ongoing medical conditions, and surgical 
procedures (not related to the primary diagnosis). 
Diagnosis and Cancer History 
The initial cancer diagnosis and the current cancer stage at the time of screening, along with tumor 
histology, and all sites of primary and metastatic disease, should be recorded. 
Prior Cancer Therapy 
Prior cancer therapy history will be taken at screening and will include cancer-related surgical 
procedures, radiation, and systemic therapies. Surgical procedures include curative, palliative, and 
diagnostic procedures (eg, biopsy). Radiation will include both definitive and palliative treatment. 
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Systemic therapy should include all regimens given, each drug name in a regimen, the start and 
stop dates of each drug, the best response to the regimen, and the reason for discontinuation. 
Experimental or investigational therapy history must also be recorded. 
ALK Mutation Status 
Regarding current and past ALK mutation history, any previously identified mutations and the 
dates of identification must be recorded at screening. This includes ALK rearrangements by FISH, 
ALK abnormalities by other methods including immunohistochemistry, and ALK point mutations. 
Patients entering the study either must have a history of a positive result from the Vysis ALK 
Break Apart FISH Probe Kit, the Nichirei Histofine RALK iAEP Kit, the Ventana ALK (D5F3) 
CDx Assay or DNA/RNA sequencing (except for the patients in TKI-naïve expansion cohort), or 
must submit tissue samples for analysis using a local regulatory authority-approved test. 
Specifications for handling and processing of tissue for this test are described in Section 9.4.17.1 
and in the Study Manual. 
9.4.4 Physical Examination 
A complete physical examination must be performed at screening, the extent of which should be 
consistent with medical history and the patient’s underlying disease. Subsequent physical 
examinations as described in the Schedule of Events may be directed to relevant findings. Of note, 
because of adverse reactions reported during treatment with brigatinib, investigators are cautioned 
to monitor patients for signs of vision dysfunction. For new or worsening severe vision disorders, 
an ophthalmological evaluation should be performed. If new or worsening of vision disorder is 
suspected, investigators should consult and ophthalmologist, and ophthalmological evaluation 
should be performed as needed. 
The EOT physical examination should be a complete physical examination. 
9.4.5 Height and Weight 
Height and weight will be measured during screening only (within 14 days before C1D1). 
9.4.6 Vital Signs 
Vital signs include temperature, pulse, respiratory rate, SpO2, and blood pressure (when patient is 
seated). 
Vital signs should be repeated on C1D1, before the first dose, regardless of the time from 
screening. Vital signs will also be assessed per the Schedule of Events throughout the study. 
9.4.7 ECOG Performance Status 
The patient’s performance status must be assessed using the ECOG performance scale during 
screening. ECOG performance status will also be assessed per the Schedule of Events throughout 
the study. The ECOG performance scale is provided in Appendix D. 
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9.4.8 Chest X-ray 
The chest x-ray as referenced for ILD assessment must be performed during screening. See 
Section 8.8.1 for the management of new or worsening pulmonary symptoms. 
9.4.9 Pregnancy Test 
The pregnancy test must be a human chorionic gonadotropin test, and either urine or serum can be 
used. A serum pregnancy test must be performed within 7 days before the first dose of study drug 
in women of childbearing potential at screening. 
Women of childbearing potential will be defined as sexually mature females who meet the 
following criteria: 
• Those who have not undergone hysterectomy or bilateral oophorectomy, and 
• Those who have not had natural menopause for 12 consecutive months or longer. Note that a 
loss of menopausal periods following chemotherapy may not rule out childbearing potential. 
The results from these tests must be available and negative before the first dose of study drug is 
administered. If C1D1 serum pregnancy results will not be available before dosing, a urine 
pregnancy test may be performed. Women of childbearing potential at study start must also 
complete the pregnancy test at the EOT visit. 
Pregnancy test is to be done by the local laboratory. Results or status from this test will be recorded 
on eCRFs. 
9.4.10 Concomitant Medications and Procedures 
Concomitant medications for all ongoing medical history conditions or AEs, and prophylactic 
treatments and supplements must be recorded in the eCRF from the date the informed consent is 
signed until at least 30 days after the last dose of brigatinib or initiation of the subsequent 
anticancer therapies (whichever comes first). 
9.4.11 AEs 
Monitoring of AEs, serious and nonserious, will be conducted throughout the study as specified in 
the Schedule of Events. Refer to Section 10.0 for details regarding definitions, documentation, and 
reporting of pretreatment events, AEs, and serious adverse events (SAEs). 
9.4.12 Study Enrollment 
A patient is considered to be enrolled in the study when the first dose of brigatinib has been 
administered. Procedures for completing the enrollment information are described in the Study 
Manual. 
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9.4.13 Electrocardiogram 
All electrocardiograms (ECGs) must be 12-lead ECGs and will be assessed per the Schedule of 
Events throughout the study. The C1D1 ECG should be performed before the first dose of 
brigatinib. 
Additional ECGs may be performed at the investigator’s discretion to ensure patient safety. In 
particular, ECG monitoring should be performed during the study if a patient has been prescribed 
medication that can prolong the QT interval or medication that can potentially alter the QT interval 
(other than medications explicitly prohibited). 
The uncorrected QT interval and the QT interval corrected by the Fridericia formula (QTcF) will 
be recorded on eCRFs. 
For consistency, the Fridericia correction (QTcF=QT interval/(RR)1/3 interval) method must be 
used for all calculations of heart rate–corrected QT (calculated) (QTc) intervals. 
When the timing of a PK, biomarker, or safety laboratory blood sample collection coincides with 
the timing of ECG measurements, the ECG will be completed before the blood sample collection, 
if possible. In some cases, it may be appropriate to repeat an ECG to rule out improper lead 
placement contributing to the ECG abnormality. ECGs should be reviewed by the investigator or 
delegate before the patient leaves the clinic on visit days. 
9.4.14 Clinical Laboratory Evaluations 
Clinical laboratory evaluations will be performed locally. Handling and shipment of clinical 
laboratory samples will be outlined in the Study Manual. 
Serum insulin, testosterone (male patients only), KL-6, and SP-D are to be performed by a central 
laboratory, including labs obtained at unscheduled visits, whenever possible. All central laboratory 
results will be provided to the investigator. 
Laboratory tests to establish eligibility must be done within 14 days before C1D1 (Appendix A). 
9.4.14.1 Hematology and Chemistry 
Blood samples for analysis of parameters shown in Table 9.a will be obtained as specified in the 
Schedule of Events (Appendix A). 
C1D1 hematology and chemistry blood draws should be performed before the first dose of 
brigatinib. All scheduled chemistry blood draws should be performed in a fasting state. 
To estimate creatinine clearance, the Cockcroft-Gault formula will be employed (Appendix E). 
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Table 9.a 
Hematology and Chemistry Tests 
Hematology 
Serum Chemistry 
White blood cell count with differential (ANC, basophils, 
eosinophils, lymphocytes, monocytes). 
Hematocrit. 
Platelet count. 
Hemoglobin. 
Albumin. 
Alkaline phosphatase (ALP). 
Amylase. 
ALT. 
AST. 
Blood urea nitrogen (BUN). 
Calcium. 
Creatine phosphokinase (CPK). 
Bicarbonate (or total carbon dioxide) (a). 
Chloride. 
Creatinine. 
C-reactive protein (CRP). 
Glucose (fasted). 
Lactate dehydrogenase (LDH). 
Lipase. 
Magnesium. 
Phosphorus. 
Potassium. 
Sodium. 
Bilirubin (total bilirubin, conjugated and unconjugated 
bilirubin). 
Protein (total protein). 
Uric acid. 
HbA1c. 
(a) To be included if the testing is available as part of blood chemistry panel at the local laboratory. 
9.4.14.2 Insulin 
Serum insulin measurement will be performed according to the Schedule of Events throughout the 
study. Serum insulin and glucose should be measured concurrently. C1D1 insulin blood draws 
should be performed before the first dose of brigatinib. All scheduled insulin blood draws should 
be performed in a fasting state (at least 6 hours passed since last meal). 
9.4.14.3 Testosterone (Male Patients Only) 
In male patients, serum testosterone will be performed according to the Schedule of Events 
throughout the study. The C1D1 testosterone blood draw should be performed before the first dose 
of brigatinib. 
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9.4.14.4 KL-6 and SP-D 
KL-6 and SP-D are used for evaluation of ILD. KL-6 and SP-D measurement must be performed 
during screening as referenced for the ILD assessment. All evaluations of KL-6 and SP-D, 
including for new or worsening pulmonary symptoms, must be performed centrally. See 
Section 8.8.1 for the management of new or worsening pulmonary symptoms. 
9.4.15 Hepatitis Testing 
Hepatitis testing will be performed and interpreted locally during the screening period. HBsAg 
should be checked for hepatitis B virus (HBV), and if negative, patients can be enrolled. For 
patients who are HBsAb and/or HBcAb positive, HBV DNA will also be assessed at screening. 
Hepatitis C virus antibody (HCVAb) should be checked for HCV. Patients who test positive for 
HCVAb will also be tested for HCV RNA at screening. 
Note that patients who have negative HBsAg but are known to be HBcAb and/or HBsAb positive 
may be enrolled but must have an undetectable HBV viral load. Patients who have a positive 
HCVAb can be enrolled but must have an undetectable HCV viral load. 
Patients who are HBsAg negative but HBsAb and/or HBcAb positive, and/or HCVAb positive 
with a negative viral load at screening, will be monitored by assessment of viral load (DNA titers 
for HBV, RNA titers for HCV) every 3 months. 
9.4.16 Disease Assessment 
At screening, disease assessment must include imaging of the chest, abdomen (covering adrenal 
glands) and pelvis, using appropriate radiological procedures (CT scans or magnetic resonance 
imaging [MRI] with contrast, unless contrast media is contraindicated). Contrast-enhanced MRI of 
the brain (such as gadolinium) is required at screening for all patients. If contrast for MRI is 
contraindicated, use CT with contrast. All radiographic images (eg, CT scan, MRI) performed 
during the study will be submitted to the IRC. Details regarding the collection and transmission of 
images can be found in the Study Manual. Patients must have at least 1 measurable lesion per 
RECIST version 1.1. Previously irradiated lesions may not be used for target lesions, unless there 
is unambiguous radiological progression after radiotherapy. Brain lesions may be used as target 
lesions provided they are ≥10 mm and have not been 1) previously treated with WBRT within 
3 months, or 2) previously treated by SRS or surgical resection. 
Disease assessment by CT or MRI scans will be performed for all patients at screening, every 
2 cycles (8 weeks) from C3D1 (±7 days) through C15D1, and every 3 cycles (12 weeks) thereafter 
until EOT. Imaging of the chest, abdomen, pelvis and brain will occur at each assessment for all 
patients (with or without brain metastasis at screening in the expansion cohort). More-frequent 
imaging is recommended at any time, if clinically indicated; confirmation of CR or PR can be 
performed at least 4 weeks after initial response. Imaging assessment will also be performed at the 
EOT visit if more than 4 weeks have passed since the last imaging assessment. The same imaging 
modality at the same institution should be used at each assessment, if possible. SD can be 
evaluated at least 8 weeks after initiation of study drug administration (considering the allowance 
of the evaluation, Day 50 since C1D1 as the earliest). 
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For patients who discontinue study treatment in the absence of PD, additional tumor assessment 
should continue at the same time points as study treatment until PD or the start of another systemic 
anticancer therapy. 
9.4.17 
 
9.4.17.1 
 
CCI
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9.4.17.3
 
9.4.17.4 Biomarker Sample Retention 
Biomarker samples will be stored at Takeda-designated laboratories for up to 15 years after the 
date of study completion as identified in the CSR, and then will be discarded. Tumor tissue 
samples will be stored at refrigeration temperature, and other samples will be stored at -70°C. If 
patients withdraw consent, the samples will be discarded. 
9.4.18 PK Measurements 
PK blood samples will be obtained from all patients as described in Appendix A Table C for 
patients in the safety evaluation lead-in part and in Appendix A Table D for patients in the 
expansion part. The dates and exact times of administration of brigatinib before collection of the 
blood sample for PK analysis and the dates and exact times of the postdose PK sample collection 
will be recorded on the eCRF. Plasma will be obtained from each blood sample, and 
concentrations of brigatinib and AP26123 in the plasma will be simultaneously determined by the 
designee using a validated bioanalytical method. Detailed instructions for sample preparation will 
be provided in the Study Manual. 
9.4.19 Patient-Reported Outcomes Questionnaire (Expansion Part Only) 
In the expansion part, the PRO questionnaires (EORTC QLQ-C30, QLQ-LC13, and EQ-5D-5L; 
(Appendix I) will be administered at specified scheduled visits and at the visit 30 days after the last 
dose of brigatinib. The PRO questionnaires should be administered to patients when they arrive for 
their scheduled visits, before any clinical measurements, assessments, evaluations, or procedures 
being performed. 
9.5 
Documentation of Subject Failure 
Investigators must account for all subjects who sign informed consent. 
If the subject is found to be not eligible before the first dose, the investigator should complete the 
eCRF. 
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The primary reason for subject failure is recorded in the eCRF using the following categories: 
• Death. 
• AE. 
• Screen failure (failed inclusion criteria or did meet exclusion criteria). 
• Protocol deviation. 
• Lost to follow-up. 
• Withdrawal by subject. 
• Study terminated by sponsor. 
Patient identification codes assigned to subjects who fail screening should not be reused. 
9.6 
Completion of Study Treatment (for Individual Patients) 
Patients will be considered to have completed study treatment if they receive the study treatment 
until PD or until discontinuation for unacceptable toxicity, withdrawal of consent, or death. 
Patients will attend an EOT visit approximately 30 days after receiving their last dose of the study 
drug and will continue to be followed for other follow-up assessments specified in the Schedule of 
Events (Appendix A). Refer to the Schedule of Events (Appendix A) for EOT visit assessments. 
9.7 
Completion of Study (for Individual Patients) 
Patients will be considered to have completed the study if they are followed until death or until the 
sponsor terminates the study. 
9.8 
Discontinuation of Treatment With Study Drug and Patient Replacement 
Treatment with study drug may be discontinued for any of the following reasons: 
• AE. 
• Protocol deviation. 
• PD. 
• Symptomatic deterioration. 
• Study terminated by sponsor. 
• Withdrawal by patient. 
• Lost to follow-up. 
• Other. 
Once study drug has been discontinued, all study procedures outlined for the EOT visit will be 
completed as specified in the Schedule of Events. Before starting subsequent anticancer therapy, 
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all study procedures outlined for the EOT visit should be completed as specified in the Schedule of 
Events. The primary reason for study drug discontinuation will be recorded on the eCRF. 
Patients in the safety evaluation lead-in part who are withdrawn from treatment during Cycle 1 for 
reasons other than DLT will be replaced. 
Note that some patients may discontinue study drug for reasons other than PD before completing 
the full treatment course; these will remain in the study for posttreatment assessments as outlined 
in the Schedule of Events until PD occurs. 
9.9 
Withdrawal of Patients From Study 
A patient may be withdrawn from the study for any of the following reasons: 
• Lost to follow-up. 
• Study terminated by sponsor. 
• Withdrawal by patient. 
• Death. 
• Other. 
The consequence of study withdrawal is that no new information will be collected from the 
withdrawn patient and added to the existing data or any database. 
9.10 
Study Compliance 
Study drug will be administered or dispensed only to eligible patients under the supervision of the 
investigator or identified subinvestigator(s). The appropriate study personnel will maintain records 
of study drug receipt and dispensing. 
Patients will be provided a diary card or equivalent where the date of study drug administration 
will be recorded. Patients who forget to take their dose should not make up the missed dose. A 
missed dose is defined as a dose not taken within 12 hours of the intended scheduled 
administration. Any missed doses must be recorded in an appropriate source record (eg, clinic 
chart), patient diary card, and study drug administration eCRF. Training of patients should be 
documented in the appropriate source record (eg, clinic chart). When possible, patients should take 
the study drug under observation during scheduled study visits to the clinic where a predose blood 
sample is collected. The investigator is responsible for ensuring that the patient diary cards are 
retained and noted in source documentation. 
9.11 
Posttreatment Follow-up Assessments (PFS and OS) 
Patients who stop treatment for any reason other than PD will continue to have PFS follow-up 
visits. The PFS follow-up visit should be performed every 8 weeks until Week 57 (equivalent to 
Cycle 15 Day 1), and every 12 weeks (±14 days) thereafter, from the EOT visit until the 
occurrence of PD or the start of subsequent anticancer therapy. 
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After the occurrence of PD or the start of subsequent anticancer therapy, patients will continue to 
have OS follow-up visits. The OS follow-up visits should be performed every 12 weeks (±14 days) 
after documented PD until death, loss to follow-up, consent withdrawal, study termination, or any 
of the circumstances described in Section 9.9 occur. For the safety evaluation lead-in part and the 
refractory expansion part, the duration of OS follow-up will be 2 years after enrollment of the last 
patient or until all patients have discontinued study treatment, whichever occurs later. For the TKI 
naïve expansion cohort, the duation of OS follow-up will be until all patients have discontinud 
study treatment, or at the time of commercial brigatinib placing on the market for TKI-naïve 
patients in Japan, whichever occurs first. 
Survivor information and death details may be collected by methods that include, but are not 
limited to, telephone, email, and mail. NOTE: Related SAEs must be reported to the Takeda 
Global Pharmacovigilance department or designee. This includes deaths that the investigator 
considers related to study drug that occur during the posttreatment follow up. Refer to Section 10.0 
for details regarding definitions, documentation, and reporting of SAEs. 
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10.0 
ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 Pretreatment Event Definition 
A pretreatment event is any untoward medical occurrence in a patient or subject who has signed 
informed consent to participate in a study but before administration of any study medication; it 
does not necessarily have to have a causal relationship with study participation. 
10.1.2 AE Definition 
AE means any untoward medical occurrence in a patient or subject administered a pharmaceutical 
product; the untoward medical occurrence does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product whether or not it is related to the medicinal product. This includes any 
newly occurring event, or a previous condition that has increased in severity or frequency since the 
administration of study drug. 
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is considered 
by the investigator to be a clinically significant change from baseline. 
10.1.3 SAE Definition 
SAE means any untoward medical occurrence that at any dose: 
• Results in death. 
• Is life-threatening (refers to an AE in which the patient was at risk of death at the time of the 
event. It does not refer to an event which hypothetically might have caused death if it were 
more severe). 
• Requires inpatient hospitalization or prolongation of an existing hospitalization (see 
clarification in the paragraph in Section 10.2 on planned hospitalizations). 
• Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions.) 
• Is a congenital anomaly/birth defect. 
• Is a medically important event. This refers to an AE that may not result in death, be 
immediately life-threatening, or require hospitalization, but may be considered serious when, 
on the basis of appropriate medical judgment, it may jeopardize the patient, require medical or 
surgical intervention to prevent one 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 date 14 June 2010 [15]. Clarification should be made 
between an SAE and an AE that is considered severe in intensity (Grade 3 or Grade 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 Grade 4) 
does not necessarily need to be considered serious. For example, a white blood cell count of 
1000/mm3 to less than 2000/mm3 is considered Grade 3 (severe) but may not be considered serious. 
Seriousness (not intensity) serves as a guide for defining regulatory reporting obligations. 
10.2
Procedures for Recording and Reporting AEs and SAEs 
All AEs spontaneously reported by the patient or in response to an open question from study 
personnel or revealed by observation, physical examination, or other diagnostic procedures will be 
recorded on the appropriate page of the eCRF (see Section 10.3 for the period of observation). Any 
clinically relevant deterioration in laboratory assessments or other clinical finding is considered an 
AE. When possible, signs and symptoms indicating a common underlying pathology should be 
noted as a single comprehensive event. 
Regardless of causality, SAEs and serious pretreatment events (as defined in Section 10.1) must be 
reported (see Section 10.3 for the period of observation) by the investigator to the Takeda Global 
Pharmacovigilance department or designee (contact information provided below). This should be 
done by faxing the SAE Form within 24 hours after becoming aware of the event. The SAE Form, 
created specifically by Takeda, will be provided to each clinical study site. A sample of the SAE 
Form may be found in the Study Manual. Follow-up information on the SAE or serious 
pretreatment event may be requested by Takeda. SAE report information must be consistent with 
the data provided on the eCRF. 
SAE Reporting Contact Information 
BI Medical, Inc. 
Toll-free fax:
 
Planned hospital admissions or surgical procedures for an illness or disease that existed before the 
patient was enrolled in the trial are not to be considered AEs unless the condition deteriorated in an 
unexpected manner during the trial (eg, surgery was performed earlier or later than planned). 
For both serious and nonserious AEs, the investigator must determine both the severity (toxicity 
grade) of the event and the relationship of the event to study drug administration. For serious 
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pretreatment events, the investigator must determine both the severity (toxicity grade) of the event 
and the causality of the event in relation to study procedures. 
Severity (toxicity grade) for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE, version 4.03, effective date 14 June 2010 [15]. 
Relationship of the event to study drug administration (ie, its causality) will be determined by the 
investigator responding yes (related) or no (unrelated) to this question: Is there a reasonable 
possibility that the AE is associated with the study drug? 
If ILD (regardless of causality and grade) occurs from the first of study drug through 30 days after 
administration of the last dose of study drug, or initiation of the subsequent anticancer therapy 
(whichever comes first), it should be recorded as an SAE. The SAE Form should be completed and 
reported as described above. Images used for evaluating the clinical course of ILD (eg, chest CT, 
chest x-ray) should be submitted to the sponsor promptly. The sponsor may request additional 
images as needed. Refer the Study Manual for instructions for submitting images. 
10.3 
Monitoring of AEs and Period of Observation 
AEs, both nonserious and serious, will be monitored throughout the study as follows: 
• AEs will be reported from the signing of informed consent through 30 days after 
administration of the last dose of study drug or initiation of the subsequent anticancer therapies 
(whichever comes first) and recorded in the eCRFs. 
• SAEs 
– Serious pretreatment events will be reported to the Takeda Global Pharmacovigilance 
department or designee from the time of the signing of the ICF up to first dose of study 
drug, and will also be recorded in the eCRF. 
– Related and unrelated treatment-emergent SAEs will be reported to the Takeda Global 
Pharmacovigilance department or designee from the first dose of study drug through 
30 days after administration of the last dose of study drug or initiation of the subsequent 
anticancer therapy (whichever comes first) and recorded in the eCRF. After this period, 
only related SAEs must be reported to the Takeda Global Pharmacovigilance department 
or designee. 
– SAEs should be monitored until they are resolved or are clearly determined to be due to a 
patient’s stable or chronic condition or intercurrent illness(es). 
10.4 
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events 
If a woman becomes pregnant or suspects that she is pregnant while participating in this study, she 
must inform the investigator immediately and permanently discontinue study drug. The sponsor 
must also be contacted immediately by faxing a completed pregnancy form to the Takeda Global 
Pharmacovigilance department or designee (see Section 10.2). The pregnancy must be followed 
for the final pregnancy outcome. 
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If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, the sponsor must also be contacted immediately by faxing a completed pregnancy form 
to the Takeda Global Pharmacovigilance department or designee (see Section 10.2). Every effort 
should be made to follow the pregnancy for the final pregnancy outcome. 
10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose) 
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product. Individuals who 
identify a potential product complaint situation should immediately report this via the phone 
numbers or email addresses provided below. 
A medication error is a preventable event that involves an identifiable patient and leads to 
inappropriate medication use, which may result in patient harm. Whereas overdoses and 
underdoses constitute medication errors, doses missed inadvertently by a patient do not. 
Individuals who identify a potential medication error (including overdose) situation should 
immediately report this via the phone numbers or email addresses provided below. 
Call center 
Phone number 
Email 
Fax 
Dohmen Life Science 
Services (DLSS) 
 
Non-toll-free number: 
 
 
 
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 BI Medical, Inc (refer to Section 10.2). 
10.6
Safety Reporting to Investigators, IRBs, 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, investigators, IRBs and/or the 
head of each study site, as applicable, in accordance with national regulations in the countries 
where the study is conducted. Relative to the first awareness of the event by/or further provision to 
the sponsor or sponsor’s designee, SUSARs will be submitted to the regulatory authorities as 
expedited reports within 7 days for fatal and life-threatening events and within 15 days for other 
serious events, unless otherwise required by national regulations. The sponsor will also prepare an 
expedited report for other safety issues where these might materially alter the current benefit-risk 
assessment of an investigational medicinal product or that would be sufficient to consider changes 
in the investigational medicinal product’s administration or in the overall conduct of the trial. 
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11.0 
STUDY-SPECIFIC COMMITTEES 
11.1 
Steering Committee 
A steering committee will be formed when the study is initiated. Its purpose is to function in an 
advisory capacity to 1) provide input on study conduct and progress; 2) ensure scientific and 
ethical integrity of the study; and 3) provide ongoing oversight of safety and efficacy in this 
open-label study. The steering committee will include clinician experts in the clinical care and 
investigation of the targeted patient population, and will include sponsor representatives. In 
addition to general study oversight, it will provide input on operational aspects of the study. The 
committee may make recommendations for the sponsor’s consideration based on periodic review. 
The steering committee charter will define the responsibilities of the committee. 
11.2 
IDMC 
An IDMC, consisting of 3 to 5 members not associated with the conduct of the study, will be 
established for this study. 
The IDMC will provide recommendation on the go/no go decision to move from the safety 
evaluation lead-in part to the expansion part and on futility and efficacy assessment at the interim 
analysis. The IDMC will also evaluate cases of ILD reported as SAEs and make recommendations 
as needed. 
The IDMC will communicate the recommendations to the sponsor. The final decision to act on the 
IDMC recommendations will be made by the sponsor. 
Details of the IDMC will be captured in a charter. 
11.3 
IRC 
An IRC will evaluate all images collected during the study for the primary and certain secondary 
endpoints. An IRC charter will define the procedures used by the committee. 
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12.0 
DATA HANDLING AND RECORDKEEPING 
The full details of procedures for data handling will be documented in the data management plan. 
If selected for coding, AEs, pretreatment events, medical history, and concurrent conditions will 
be coded using the Medical Dictionary for Regulatory Activities (MedDRA). Drugs will be coded 
using the World Health Organization (WHO) Drug Dictionary. 
12.1 
eCRFs 
Completed eCRFs are required for each subject who signs an ICF. 
The sponsor or its designee will supply investigative sites with access to eCRFs and will make 
arrangements to train appropriate site staff in the use of the eCRF. These forms are used to transmit 
the information collected in the performance of this study to the sponsor, contract research 
organization (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 subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed eCRFs 
are the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor. 
12.2 
Record Retention 
The investigator and the head of the institution agree to keep the records stipulated in Section 12.1 
and those documents that include (but are not limited to) the study-specific documents, the 
identification log of all participating subjects, medical records, temporary media such as 
thermal-sensitive paper, source worksheets, all original signed and dated ICFs, subject 
authorization forms regarding the use of personal health information (if separate from the ICFs), 
electronic copies of eCRFs, including the audit trails, and detailed records of drug disposition to 
enable evaluations or audits from regulatory authorities, the sponsor or its designees. Any source 
documentation printed on degradable thermal-sensitive paper should be photocopied by the site 
and filed with the original in the subject’s chart to ensure long-term legibility. Furthermore, ICH 
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E6 Section 4.9.5 and J-GCP requires the investigator and the head of the institution to retain 
essential documents specified in ICH E6 (Section 8), or local laws, regulations and guidelines. In 
addition, ICH E6 Section 4.9.5 states that the study records should be retained until an amount of 
time specified by applicable regulatory requirements or for a time specified in the Clinical Study 
Site Agreement between the investigator and/or the head of the institution and sponsor. 
Refer to the Clinical Study Site Agreement for the sponsor’s requirements for record retention. 
The investigator and the head of the institution should contact and receive written approval from 
the sponsor before disposing of any such documents. 
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13.0 
STATISTICAL METHODS 
13.1 
Statistical and Analytical Plans 
A statistical analysis plan (SAP) will be prepared and finalized before each snapshot. This 
document will provide further details regarding the definitions of analysis variables and analysis 
methodology to address all study objectives. 
In general, summary tabulations will be presented 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. The Kaplan-Meier survival curves and 
25th, 50th (median), and 75th percentiles will be provided along with their 2-sided 95% CIs for 
time-to-event data. 
13.1.1 Analysis Sets 
The populations used for analysis will include the following: 
The refractory expansion part and safety evaluation lead-in part: 
• Safety population: patients who receive at least 1 dose of study drug will be used for all safety 
analyses. All patients in the safety population will be analyzed according to the actual 
treatment received. 
• Full analysis set (FAS) population: all patients who receive at least 1 dose of study drug. All 
patients in the FAS population will be analyzed according to the actual treatment received (ie, 
overall population). 
• FAS-P population: a subset of the FAS population consisting of first 47 patients in the main 
cohort of the refractory expansion part. 
• Per-protocol set (PPS) population: a subset of the FAS-P population including patients who do 
not have a major protocol violation as determined by the sponsor’s project clinician (or 
designee). Each decision to exclude patients from the PPS population at interim analysis and at 
the end of the study will be made before respectively the interim analysis and each snapshot. 
• PK population: patients with sufficient dosing and PK data to reliably estimate PK parameters 
as determined by the clinical pharmacologist for safety evaluation lead-in part. Patients who 
receive at least 1 dose of briganitib and have at least 1 plasma concentration data after 
administration of brigatinib will be used for other PK analyses (PK-evaluable patients). 
The TKI-naïve expansion cohort: 
• Safety population: patients who receive at least 1 dose of study drug will be used for all safety 
analyses. All patients in the safety population will be analyzed according to the actual 
treatment received. 
• Full analysis set (FAS) population: all patients who receive at least 1 dose of study drug. All 
patients in the FAS population will be analyzed according to the actual treatment received (ie, 
overall population). 
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• Per-protocol set (PPS) population: a subset of the FAS population including patients who do 
not have a major protocol violation as determined by the sponsor’s project clinician (or 
designee). Each decision to exclude patients from the PPS population at the end of the study 
will be made before snapshot. 
• PK population: patients who receive at least 1 dose of briganitib and have at least 1 plasma 
concentration data after administration of brigatinib will be used (PK-evaluable patients). 
Further criteria for each analysis set will be detailed in a SAP. 
13.1.2 Analysis of Demographics and Other Baseline Characteristics 
The refractory expansion part and safety evaluation lead-in part: 
Demographics and other baseline characteristics will be summarized using the FAS population 
and FAS-P population. 
The TKI-naïve expansion cohort: 
Demographics and other baseline characteristics will be summarized using the FAS population. 
13.1.3 Efficacy Analysis 
13.1.3.1 Primary Endpoint and Analytical Methods 
The refractory expansion part and safety evaluation lead-in part: 
The primary endpoint is confirmed ORR in the main cohort of the refractory expansion part, as 
assessed by an IRC, per RECIST version 1.1, defined as the proportion of the patients who are 
confirmed to have achieved CR or PR per IRC using RECIST version 1.1 after the initiation of 
study treatment. 
Primary Analysis 
For the primary endpoint, confirmed ORR as assessed by an IRC and its 2-sided 95% CI will be 
provided using the FAS-P population. 
Sensitivity Analysis 
Confirmed ORR will be determined using the PPS population. 
The TKI-naïve expansion cohort: 
The primary endpoint is 12 months PFS rate in the TKI-naïve expansion cohort, as assessed by an 
IRC, per RECIST version 1.1, defined as the PFS rate in Kaplan-Meier plot at 12 months after the 
initiation of study treatment, assessed by IRC, per RECIST version 1.1. 
Primary Analysis 
For the primary endpoint, 12 months PFS rate as assessed by an IRC and its 2-sided 90% CI will be 
provided using the FAS population based on the complementary log-log transformation. If the 
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lower bound of confidence interval is above 42.6%, we will show the efficacy of brigatinib in the 
TKI-naïve population. 
Sensitivity Analysis 
12 months PFS rate will be determined using the PPS population. 
13.1.3.2 Secondary Endpoints and Analytical Methods 
The safety evaluation lead-in part, the main cohort of the refractory expansion part, and the TKI 
naïve expansion cohort: 
• Confirmed ORR as assessed by the investigator, per RECIST version 1.1. 
The safety evaluation lead-in part, the overall population of the refractory expansion part, and the 
TKI naïve expansion cohort: 
• Confirmed ORR as assessed by an IRC, per RECIST version 1.1. 
The main cohort of the refractory expansion part, the overall population of the refractory 
expansion part, and the TKI naïve expansion cohort: 
• DOR as assessed by an IRC, per RECIST version 1.1, defined as the time between the first 
documentation of objective tumor response (CR or PR) and the first subsequent documentation 
of objective PD or death due to any cause, whichever occurs first. 
• PFS as assessed by an IRC, per RECIST version 1.1, defined as the time from the start of study 
treatment to the first documentation of objective PD or to death due to any cause, whichever 
occurs first. 
• DCR as assessed by an IRC, per RECIST version 1.1, defined as the proportion of patients who 
are confirmed to have achieved CR or PR or have a best overall response of stable disease (SD), 
per RECIST version 1.1, for 6 weeks or more after initiation of study drug. 
• Time to response as assessed by an IRC, per RECIST version 1.1, defined as the time interval 
from the date of the first dose of study treatment until the initial observation of CR or PR for 
patients with confirmed CR/PR. 
• OS defined as the time from the start of study treatment to the date of death. 
• CNS response as assessed by an IRC, per modified RECIST version 1.1 for assessment of 
intracranial efficacy (iORR and iDOR in patients who had measurable CNS metastases, and 
iPFS in all patients), defined as the proportion of the patients who have achieved CR or PR in 
the intracranial CNS per modified RECIST version 1.1 as evaluated by an IRC after the 
initiation of study treatment. 
• Time on treatment defined as the time interval from the first dose to the last dose of brigatinib. 
The main cohort of the refractory expansion part, and the TKI naïve expansion cohort: 
• PROs of HRQOL scores and symptoms of lung cancer, assessed with the EORTC QLQ-C30 
(version 3.0), its lung cancer module QLQ-LC13, and the EQ-5D-5L. 
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The refractory expansion part and safety evaluation lead-in part: 
Secondary endpoints will be summarized descriptively using the FAS-P population or the FAS 
population. 
The TKI-naïve expansion cohort: 
Secondary endpoints will be summarized descriptively using the FAS population. 
13.1.3.3 Methods of Data Transformation and Handling of Missing Data 
All available efficacy and safety data will be included in data listings and tabulations. The 
relevance of missing sample data will be assessed. Details on any sensitivity analyses and data 
handling details regarding issues such as missing data will be discussed in a SAP. 
13.1.3.4 Significance Level and Confidence Coefficient 
Statistical inference will be performed at a 1-sided 0.025 level of significance or a 2-sided 0.05 
level of significance as appropriate to preserve an overall type I error rate at or below a 1-sided 
0.025 or 2-sided 0.05. 
13.1.4 PK Analysis 
The refractory expansion part and safety evaluation lead-in part: 
Plasma concentrations of brigatinib will be summarized using descriptive statistics according to 
nominal (scheduled) time postdose and day. Mean and individual plasma concentration data of 
brigatinib from Cycle 1 will be plotted over time for each day (Days 1 and 22) in PK population of 
the safety evaluation lead-in part. Mean and individual plasma concentration data of brigatinib 
predose also will be plotted in Cycles 1, 2, 3, 4, and 5 in all PK-evaluable patients. The same 
analyses will be applied for plasma concentration of AP26123. All plasma concentration data of 
brigatinib and AP26123 will be listed. 
PK parameters will be calculated on Cycle 1 Days 1 and 22 for brigatinib by noncompartmental 
analysis as permitted by the data from PK population of the safety evaluation lead-in part. These 
parameters will include, but will not be limited to, Cmax, tmax, and AUC. PK parameters will be 
summarized using descriptive statistics for each day. The PK parameters of AP26123 also will be 
calculated and summarized using the same procedures. Individual PK parameters of brigatinib and 
AP26123 will be listed. 
The TKI-naïve expansion cohort: 
Mean and individual plasma concentration data of brigatinib predose also will be plotted in Cycles 
1, 2, 3, 4, and 5 in PK-evaluable patients. The same plotting will be applied for plasma 
concentration of AP26123. All plasma concentration data of brigatinib and AP26123 will be listed. 
Where appropriate, the plasma concentration data of brigatinib may be analyzed using population 
PK models and/or combined with data from other studies as part of a pooled analysis. The 
influence of exposure on biomarkers, clinical safety parameters (eg, selected AEs), and clinical 
response may also be explored. 
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13.1.5 Safety Analysis 
AEs will be summarized using the safety analysis set in each cohort separately. Safety will be 
evaluated by the incidence of AEs, severity and type of AEs, and by changes from baseline in the 
patient’s vital signs, weight, and clinical laboratory results using the safety population. 
13.1.5.1 AEs (TEAEs) 
TEAEs that occur after administration of the first dose of study drug and through 30 days after the 
last dose or initiation of the subsequent anticancer therapies, whichever comes first will be 
tabulated. 
TEAEs will be coded using the MedDRA dictionary. The frequency distribution will be provided 
by system organ class and preferred term as follows: 
• TEAEs. 
• Drug-related TEAEs. 
• Grade 3 or higher TEAEs. 
• Grade 3 or higher drug-related TEAEs. 
• The most commonly reported TEAEs (ie, those events reported by ≥10% of all patients). 
• SAEs. 
13.1.5.2 Laboratory Test Results, 12-Lead ECGs, and Vital Signs 
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. 
Descriptive statistics for the actual values (and/or the changes from baseline) of vital signs and 
weight over time will be tabulated by scheduled time point. 
Shift tables for laboratory parameters will be generated showing 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 brigatinib. 
13.2 
Interim Analysis and Criteria for Early Termination 
The main cohort of the refractory expansion part 
In this study, a 2-stage design will be used. An interim analysis for both futility and efficacy will be 
conducted in Stage 1, according to H1-minimax design in Englert [16]. The proportion of patients 
achieving a confirmed objective response, per IRC, will be used as the endpoint for the interim 
analysis. The interim analysis will be performed when the first 29 patients in the main cohort of the 
refractory expansion part have had the opportunity to complete the Cycle 7 Day 1 disease 
assessment. Enrollment will not be suspended during evaluation of these 29 patients; however, 
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The sample size in the main cohort of the refractory expansion part was determined to allow 
confirmation that the true ORR (expected response rate) is greater than the threshold response rate 
of 15% for patients previously treated with alectinib alone and those treated with both alectinib and 
crizotinib. The rationale for the 15% response rate for the alectinib (with or without crizotinib) 
pretreated population is based on the consideration that compared with crizotinib, patients who 
have failed alectinib are less likely to respond to subsequent therapy because of alectinib’s greater 
potency and better coverage of ALK mutations compared with crizotinib. 
A sample size of 47 patients in the post-alectinib population of the refractory expansion part with 
the stopping rule mentioned in Section 13.2 will allow the study to have more than 90% power to 
rule out a threshold response rate when the true ORR is expected or higher than 35% with a 1-sided 
alpha of 0.025, according to the H1-minimax design in Englert [16]. 
The number of patients in the subcohort of the refractory expansion part (ie, patients previously 
treated with crizotinib only, ceritinib only, lorlatinib only, both crizotinib and ceritinib, both 
alectinib and ceritinib, both crizotinib and lorlatinib, both alectinib and lorlatinib, or both ceritinib 
and lorlatinib) will be limited to 20. These patients will be included in evaluations of the overall 
population. 
The sample size in the TKI-naïve expansion cohort was determined to allow confirmation that the 
true 12 months PFS rate (expected response rate) is greater than the threshold of 42.6% (estimated 
PFS rate at 12 months in Kaplan-Meier plots observed in ALTA-1L Crizotinib arm) for TKI-naïve 
patients. 
A sample size of 32 patients in the TKI-naïve expansion cohort will allow the study to have 
approximately 80% power to rule out the threshold rate (42.6%) when the true 12 months PFS rate 
is expected or higher than 66.5% (estimated PFS rate at 12 months in Kaplan-Meier plots observed 
in ALTA-1L Brigatinib arm) with a 1-sided alpha of 0.05, considering 10% patients will 
discontinue the study follow-up before the 12 months milestone due to reasons other than disease 
progression assessed by IRC or death, and 8 months enrollment period. The primary analysis will 
be performed at around 10 months after the enrollment of the last subject in the TKI-naïve 
expansion cohort. The sample size and evaluation timing may be adjusted based on results of 
second interim analysis of ALTA-1L study, and actual enrollment period of the TKI-naïve 
expansion cohort. 
Overall, the total number of patients will be approximately 110 patients. 
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14.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
Study-Site Monitoring Visits 
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and the head of the study site guarantee access to source documents by the 
sponsor or its designee (CRO) and by the IRB. 
All aspects of the study and its documentation will be subject to review by the sponsor or designee, 
including the Investigator’s Binder, study medication, subject medical records, informed consent 
documentation, and review of eCRFs and associated source documents. It is important that the 
investigator and other study personnel are available during the monitoring visits and that sufficient 
time is devoted to the process. 
14.2 
Protocol Deviations 
The investigator can deviate and change from the protocol for any medically unavoidable reason, 
for example, to eliminate an immediate hazard to study subjects, without a prior written agreement 
with the sponsor or a prior approval from IRB. In the event of a deviation or change, the principal 
investigator should notify the sponsor and the head of the site of the deviation or change as well as 
its reason in a written form, and then retain a copy of the written form. When necessary, the 
principal investigator may consult and agree with the sponsor on a protocol amendment. If the 
protocol amendment is appropriate, the amendment proposal should be submitted to the head of 
the site as soon as possible and an approval from IRB should be obtained. 
The investigator should document all protocol deviations. 
Significant deviations should be recorded on the eCRFs and then confirmed by the sponsor or its 
designee. Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of primary study 
assessment. 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections 
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the US FDA, the United Kingdom Medicines and Healthcare 
products Regulatory Agency [MHRA], the Pharmaceuticals and Medical Devices Agency of 
Japan [PMDA]). If the study site is contacted for an inspection by a regulatory body, the sponsor 
should be notified immediately. The investigator and the head of the study site guarantee access 
for quality assurance auditors to all study documents as described in Section 14.1. 
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15.0 
ETHICAL ASPECTS OF THE STUDY 
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of Helsinki, 
and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct the study 
according to applicable local or regional regulatory requirements and align his or her conduct in 
accordance with the “Responsibilities of the Investigator” that are listed in Appendix B. The 
principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities. 
15.1 
IRB Approval 
IRBs must be constituted according to the applicable 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. If any member of the IRB has direct participation in this study, 
written notification regarding his or her abstinence from voting must also be obtained. 
The sponsor or designee will supply relevant documents for submission to the respective IRB for 
the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of the ICF, 
and, if applicable, subject recruitment materials and/or advertisements and other documents 
required by all applicable laws and regulations, must be submitted to a central or local IRB for 
approval. The IRB’s written approval of the protocol and subject informed consent must be 
obtained and submitted to the sponsor or designee before commencement of the study (ie, before 
signing a contract for the clinical study). The IRB 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. Until the site receives notification, no protocol 
activities including assignment of patients may occur. 
Study sites must adhere to all requirements stipulated by their respective IRB. This may include 
notification to the IRB regarding protocol amendments, updates to the ICF, recruitment materials 
intended for viewing by subjects, local safety reporting requirements, reports and updates 
regarding the ongoing review of the study at intervals specified by the respective IRB, and 
submission of the investigator’s final status report to IRB. All IRB approvals and relevant 
documentation for these items must be provided to the sponsor or its designee. 
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB and sponsor. 
15.2 
Subject Information, Informed Consent, and Subject Authorization 
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The ICF describes the planned and permitted uses, transfers, and 
disclosures of the subject’s personal and personal health information for purposes of conducting 
the study. The ICF further explains the nature of the study, its objectives, and potential risks and 
benefits, as well as the date that informed consent is given. The ICF will detail the requirements of 
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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 principal investigator is responsible for the preparation, content, and IRB approval of the ICF. 
The ICF must be approved by both the IRB and the sponsor before use. 
The ICF 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 to the subject. 
Information should be given in both oral and written form whenever possible and in the manner 
deemed appropriate by the IRB. 
The subject 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 determines he or she will participate 
in the study, then the ICF must be signed and dated by the subject, at the time of consent and before 
the subject entering into the study. The subject 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 
at the time of consent and before subject entering into the study. 
Once signed, the original ICF will be stored in the investigator’s site file. The investigator must 
document the date the subject signs the informed consent in the subject’s medical record. Copies 
of the signed ICF shall be given to the subject. 
All revised ICFs must be reviewed and signed by relevant subjects in the same manner as the 
original informed consent. The date the revised consent was obtained should be recorded in the 
subject’s medical record, and the subject should receive a copy of the revised ICF. 
15.3 
Subject Confidentiality 
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth may be used to verify the subject and accuracy of the subject’s unique identification 
number. 
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, the US FDA, MHRA, PMDA), the sponsor’s designated auditors, and the 
appropriate IRBs to review the subject’s original medical records (source data or documents), 
including, but not limited to, laboratory test result reports, ECG reports, admission and discharge 
summaries for hospital admissions occurring during a subject’s study participation, and autopsy 
reports. Access to a subject’s original medical records requires the specific authorization of the 
subject as part of the informed consent process (see Section 15.2). 
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF). 
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15.4 
Publication, Disclosure, and Clinical Trial Registration Policy 
15.4.1 Publication 
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the Clinical Study Site Agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor. 
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail. 
15.4.2 Clinical Trial Registration 
To ensure that information on clinical trials reaches the public in a timely manner and to comply 
with applicable laws, regulations and guidance, Takeda will, at a minimum register interventional 
clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other publicly accessible 
websites on or before start of study, as defined in Takeda Policy/Standard. Takeda contact 
information, along with investigator’s city, country, study site name, and recruiting status will be 
registered and available for public viewing. 
15.4.3 Clinical Trial Results Disclosure 
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites (including the Takeda corporate site) and registries, as required by Takeda 
Policy/Standard, applicable laws and/or regulations. 
15.5 
Insurance and Compensation for Injury 
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to clinical study subjects. 
Refer to the Clinical Study Site Agreement regarding the sponsor’s policy on subject 
compensation and treatment for injury. If the investigator has questions regarding this policy, he or 
she should contact the sponsor or sponsor’s designee. 
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16.0 
REFERENCES 
1. 
Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, et al.  GLOBOCAN 
2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 
[Internet]. Published 2013. 
2. 
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA 
Cancer J Clin 2011;61(2):69-90. 
3. 
Cancer Registry and Statistics. Center for Cancer Control and Information Services, 
National Cancer Center, 2017. Cited 2017 1 August. Available at: 
http://ganjoho.jp/med_pro/index.html. 
4. 
Camidge DR, Doebele RC. Treating ALK-positive lung cancer--early successes and future 
challenges. Nat Rev Clin Oncol 2012;9(5):268-77. 
5. 
Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, et al. Identification of 
the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 
2007;448(7153):561-6. 
6. 
Rikova K, Guo A, Zeng Q, Possemato A, Yu J, Haack H, et al. Global survey of 
phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell 
2007;131(6):1190-203. 
7. 
Takeuchi K, Choi YL, Togashi Y, Soda M, Hatano S, Inamura K, et al. KIF5B-ALK, a 
novel fusion oncokinase identified by an immunohistochemistry-based diagnostic system 
for ALK-positive lung cancer. Clin Cancer Res 2009;15(9):3143-9. 
8. 
Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B, Maki RG, et al. Anaplastic 
lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 
2010;363(18):1693-703. 
9. 
Wong DW, Leung EL, So KK, Tam IY, Sihoe AD, Cheng LC, et al. The EML4-ALK 
fusion gene is involved in various histologic types of lung cancers from nonsmokers with 
wild-type EGFR and KRAS. Cancer 2009;115(8):1723-33. 
10. 
The Japan Lung Cancer Society, Clinical Guidelines of Lung Cancer based on EBM, 2016 
edition. KANEHARA & CO., LTD. 2016. 
11. 
Hida T, Nokihara H, Kondo M, Kim YH, Azuma K, Seto T, et al. Alectinib versus 
crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an 
open-label, randomised phase 3 trial. Lancet 2017;390(10089):29-39. 
12. 
ALECENSA (alectinib hydrochloride) 150 mg hard capsules [Summary of Product 
Characteristics]. Emil-Barrell-Strasse 1, D-79639 Grenzach-Wyhlen, Germany: Roche 
Pharma AG, 2017. 
13. 
ALECENSA (alectinib) [prescribing information]. South San Francisco, CA: Genentech 
USA, Inc., November 2017. 
14. 
Peters S, Camidge DR, Shaw AT, Gadgeel S, Ahn JS, Kim DW, et al. Alectinib versus 
Crizotinib in Untreated ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med 
2017;377(9):829-38. 
15. 
Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03. U.S. 
Department of Health and Human Services National Cancer Institute. 14 June 2010. 
16. 
Englert S, Kieser M. Improving the flexibility and efficiency of phase II designs for 
oncology trials. Biometrics 2012;68(3):886-92. 
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SAP_001.pdf: 
Title: A Single-Arm, Multicenter, Phase 2 Study of Brigatinib in Japanese Patients With 
ALK-Positive Non-Small Cell Lung Cancer (NSCLC) 
NCT Number: NCT03410108 
Statistical analysis plan Approve Date: 13-Jul-2020 
Certain information within this statistical analysis plan has been redacted (ie, specific 
content is masked irreversibly from view with a black/blue bar) to protect either 
personally identifiable information or company confidential information. 
This may include, but is not limited to, redaction of the following: 

Named persons or organizations associated with the study.

Patient identifiers within the text, tables, or figures or in by-patient data listings.

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.
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae). 


 
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: Brigatinib-2001
A Single-Arm, Multicenter, Phase 2 Study of Brigatinib in Japanese Patients With ALK-Positive 
Non-Small Cell Lung Cancer (NSCLC)
PHASE 2
Version: Amendment 6
Date: 13 Jul 2021
Prepared by:
Based on:
Protocol Version: Amendment 4
Protocol Date: 22 Jul 2020
PPD
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se Pat
se Patiei
CLC)
LC)
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ndme
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1.1
Approval Signatures
Electronic signatures can be found on the last page of this document.
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7.7
Study Drug Exposure and Compliance.....................................................................30
7.8
Efficacy Analysis.....................................................................................................31
7.8.1
Primary Efficacy Endpoint(s)...........................................................................31
7.8.2
Secondary Efficacy Endpoint(s).......................................................................32
7.8.3
Additional Efficacy Endpoint(s).......................................................................36
7.9
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................38
7.9.1
Pharmacokinetic Analysis................................................................................38
7.9.2
Pharmacodynamic Analysis.............................................................................39
7.10
Other Outcomes.......................................................................................................40
7.11
Safety Analysis........................................................................................................40
7.11.1
Adverse Events................................................................................................40
7.11.2
Clinical Laboratory Evaluations.......................................................................56
7.11.3
Vital Signs.......................................................................................................57
7.11.4
12-Lead ECGs.................................................................................................58
7.11.5
Other Observations Related to Safety...............................................................59
7.12
Interim Analysis ......................................................................................................59
7.12.1
Analysis plan at the Interim Analysis...............................................................60
7.12.2
Analysis plan in safety lead-in part...................................................................60
7.13
Planned Analysis for the Refractory Patients and one for TKI-naïve Patients...........61
7.13.1
Planned Analysis for the Refractory Patients....................................................61
7.13.2
Planned Analysis for TKI-naïve Patients..........................................................61
7.13.3
Planned Final Analysis ....................................................................................61
7.14
Changes in the Statistical Analysis Plan...................................................................61
8.0
REFERENCES..............................................................................................................62
LIST OF IN-TEXT TABLES
Table 7.a
The Scheme of Progression and Censoring for PFS ............................................16
Table 7.c
Minimum Number of Confirmed ORR at the Primary Analysis ..........................60
LIST OF IN-TEXT FIGURES
Figure 4.a
Overview of Study Design .................................................................................11
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LIST OF APPENDICES
Appendix 1
Criteria for Markedly Abnormal Values .............................................................63
Appendix 2
Definition of Adverse Event of GI events, Hepatic events and Visual 
Impairment Events.............................................................................................65
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3.0
LIST OF ABBREVIATIONS
AE
adverse event
ALK
anaplastic lymphoma kinase
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve 
BID
twice daily
BUN
blood urea nitrogen
CL/F
oral clearance
Cmax
maximum observed plasma concentration
CNS
central nervous system
CPK
creatine phosphokinase 
CR
complete response
CRO
contract research organization
CSR
clinical study report
CT
computed tomography
ctDNA
circulating tumor DNA
CxDx
Cycle x Day x
CYP
cytochrome P450
DCR
disease control rate
DDI
drug-drug interaction
DLSS
Dohmen Life Science Services
DLT
dose-limiting toxicity
DOR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EGFR
epidermal growth factor receptor
EOPE
early onset pulmonary event
EORTC
European Organisation for Research and Treatment of Cancer
EOT
end of treatment
EQ-5D-5L
the 5-level version of the EuroQol 5-dimensional questionnaire
EU
European Union
FAS
full analysis set
FDA
Food and Drug Administration
FFPE
formalin-fixed, paraffin-embedded
FISH
fluorescence in situ hybridization
GCP
Good Clinical Practice
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G-CSF
granulocyte colony-stimulating factor
GM-CSF
granulocyte macrophage-colony stimulating factor
HbA1c
hemoglobin A1c
HBcAb
hepatitis B core antibody
HBsAb
hepatitis B surface antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HCVAb
hepatitis C virus antibody
HIV
human immunodeficiency virus
HRQOL
health-related quality of life
ICF
informed consent form
ICH
International Conference on Harmonisation
IDMC
independent data monitoring committee
iDOR
duration of intracranial response
IGF1R
insulin-like growth factor receptor 1
ILD
interstitial lung disease
iORR
intracranial objective response rate
iPFS
intracranial progression-free survival
IRB
institutional review board
IRC
independent review committee
IUD
intrauterine device
KD
kinase domain
KL-6
Krebs von den Lungen-6
KRAS
v-Ki-ras2 Kirsten rat sarcoma viral oncogene homologue
LDH
lactate dehydrogenase
MedDRA
Medical Dictionary for Regulatory Activities
MHLW
Ministry of Health, Labour and Welfare
MHRA
Medicines and Healthcare products Regulatory Agency
MRI
magnetic resonance imaging
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NGS
next-generation sequencing
NSCLC
non-small cell lung cancer
ORR
objective response rate
OS
overall survival
PD
progressive disease
PFS
progression-free survival
PK
pharmacokinetic(s)
PMDA
Pharmaceuticals and Medical Devices Agency of Japan
PP
per-protocol
PR
partial response
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PRO
patient-reported outcome
QD
once daily
QLQ
Quality of Life Questionnaire
QOL
quality of life
QTc
heart rate-corrected QT interval (calculated)
QTcF
corrected QT interval by the Fridericia formula
RECIST
Response Evaluation Criteria in Solid Tumors
ROS1
c-ros oncogene 1
SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease
SLD
sum of the longest diameters
SMQ
symptoms standardized Medical Dictionary for Regulatory Activities query
SP-D
surfactant protein-D 
SpO2
percutaneous oxygen saturation
SRS
stereotactic radiosurgery
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment-emergent adverse event
TKI
tyrosine kinase inhibitor
tmax
time of first occurrence of Cmax
ULN
upper limit of the normal range
US
United States
WBRT
whole brain radiation therapy
WHO
World Health Organization
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The study consists of the safety evaluation lead-in part and the expansion part. The safety 
evaluation lead-in part allows patients with any line of prior ALK inhibitor which includes 
treatment-naïve patients; however, ALK inhibitor-naïve patients may be enrolled after the 
confirmation of first 3 DLT evaluable patients to have no more than 1 DLT during Cycle 1 by 
investigator’s judgement. The expansion part consists of the TKI-naïve expansion cohort and the 
refractory expansion part, and the refractory expansion part includes the main cohort and a 
subcohort based on prior ALK inhibitor treatment. The TKI-naïve expansion cohort includes the 
patients who have not received any prior TKI including ALK inhibitor. In this cohort, the 
efficacy will be evaluated, and total of 32 patients will be enrolled. The main cohort of the 
refractory expansion part includes patients who had previously received alectinib (as their only 
ALK inhibitor) or both alectinib and crizotinib (regardless the sequence of those 2 ALK 
inhibitors). The main cohort of the refractory expansion part will be used for the primary analysis 
of efficacy, and a total of 47 patients will be enrolled in the main cohort of the refractory 
expansion part. Patients with all other sequences of up to 2 prior ALK inhibitor(s) may be 
included in the subcohort of the refractory expansion part. Such other ALK inhibitors include 
(1) crizotinib only, (2) ceritinib only, (3) lorlatinib only, (4) both crizotinib and ceritinib, (5) both 
alectinib and ceritinib, (6) both crizotinib and lorlatinib, (7) both alectinib and lorlatinib, and 
(8) both ceritinib and lorlatinib. Up to 20 patients will be enrolled in the subcohort of the 
refractory expansion part.
In this study, brigatinib will be administered at 90 mg QD for the first 7 days and then 180 mg 
QD (90 mg QD→180 mg QD). In the safety evaluation lead-in part, patients will be monitored 
for intensive PK, and the tolerability of 90 mg QD→180 mg QD dosing will be confirmed. If the 
90 mg QD→180 mg QD dosing regimen is considered tolerable, additional patients enrolled in 
the expansion part will be treated with the same dosing schedule (90 mg QD→180 mg QD).
For the TKI-naïve expansion cohort, 32 patients will be enrolled and12 month PFS rate will be 
evaluated as the primary endpoint. The primary analysis will be performed at around 10 months 
after the enrollment of the last subject in TKI-naïve expansion cohort. The sample size and 
evaluation timing may be adjusted based on results of second interim analysis of ALTA-1L study, 
and actual enrollment period of the TKI-naïve expansion cohort.
For the main cohort of the refractory expansion part, there are 2 stages: the first 29 patients in the 
main cohort are included in Stage 1, and further patients will be continuously enrolled into 
Stage 2. An interim analysis for futility and efficacy will be performed in the Stage 1 population 
when the first 29 post-alectinib patients have had the opportunity to complete at least 3 
postbaseline scans (ie, after the Cycle 7 Day 1 disease assessment). Enrollment will not be 
suspended during evaluation of those 29 patients.
Following the screening period, eligible patients will be enrolled and treated with brigatinib. A 
patient is considered to be enrolled in the study when the first dose of brigatinib is administered.
Toxicity will be evaluated according to National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI CTCAE), Version 4.03, effective date 14 June 2010.
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Response evaluation per RECIST version 1.1 will be done by both the investigator and an IRC. 
The primary analysis will performed on the results from the IRC.
Patients will be treated until they experience objective progressive disease (PD) per RECIST 
version 1.1, as assessed by the investigator, intolerable toxicity, withdrawal of consent, or 
discontinuation for any other reason. Treatment of patients with brigatinib may be continued at 
the tolerated dose level, despite investigator-assessed PD by RECIST version 1.1, if the patient 
otherwise has evidence of ongoing clinical benefit. In this case, discussions and agreements 
between the investigator and the sponsor’s project clinician (or designee) are required.
Figure 4.a
Overview of Study Design
Safety Evaluation Lead-in Part
Nine DLT-evaluable patients will be enrolled in the safety evaluation lead-in part. The patients 
in the safety evaluation lead-in part will be hospitalized during Cycle 1 in general, and their 
condition will be closely monitored for safety and tolerability. Serial blood samples will be 
collected for the intensive PK profile. If a patient wishes to return home temporarily and the 
investigator confirms that the patient’s symptoms are stable per the available data, then the 
patient may return home temporarily except on Days 1 through 10 and Days 22 and 23, provided 
this does not interfere with the study assessments. The investigator must document the 
confirmation record for stabilization of the patient’s symptoms per the available data in an 
appropriate source record (eg, medical records) before the patient’s temporary leave.
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The patients in the safety evaluation lead-in part will receive brigatinib 90 mg QD→180 mg QD. 
A cycle of therapy comprises 28 days of treatment. If a patient is NOT considered DLT 
evaluable for any reason, the patient will be replaced.
DLTs are defined in Section 8.2. Tolerability of the 90 mg QD→180 mg QD schedule will be 
determined on the basis of the DLTs observed in Cycle 1. If a DLT is observed in fewer than 
3 of the 9 DLT-evaluable patients in the safety evaluation lead-in part, the 90 mg QD→180 mg 
QD regimen will be used for the patients enrolled in the expansion part. Further details on the 
dose expansion rules are described in Section 8.3.
Expansion Part (Refractory Expansion Part and TKI-Naïve Expansion Cohort)
Patients in the refractory expansion part and the TKI-naïve expansion cohort may be managed on 
an outpatient basis, and the number of study sites will be increased up to approximately 40. 
Patients in the refractory expansion part and the TKI-naïve expansion cohort will undergo less-
intensive PK blood sampling than patients in the safety evaluation lead-in part.
On an outpatient basis, patients will visit the hospital on Days 1, 8, and 15 of Cycle 1, and then 
on Day 1 of each cycle after Cycle 2. Tumor assessment will be performed every 2 cycles from 
Cycle 3 Day 1 through Cycle 15 Day 1, then every 3 cycles thereafter until the last dose of study 
drug. For patients who discontinue study treatment in the absence of PD, additional tumor 
assessment should continue at the same time points as the study treatment until PD or the start of 
another systemic anticancer therapy.
5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoint
The primary endpoints are:

Confirmed ORR as assessed by an IRC, per Response Evaluation Criteria in Solid Tumors
(RECIST) version 1.1 in the main cohort of the refractory expansion part

12 months PFS rate as assessed by an IRC, per RECIST version 1.1 in the TKI-naïve
expansion cohort
5.2
Secondary Endpoints
The secondary endpoints are:
a) Efficacy endpoint in the TKI-naïve expansion cohort, the overall population of the
refractory expansion part, and the safety evaluation lead-in part:
–
Confirmed ORR, as assessed by an IRC, per RECIST version 1.1.
b) Efficacy endpoints in the TKI-naïve expansion cohort, the main cohort of the refractory
expansion part, the overall population of the refractory expansion part:
–
DOR, as assessed by an IRC, per RECIST version 1.1.
–
PFS, as assessed by an IRC, per RECIST version 1.1.
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analysis will be performed at around 10 months after the enrollment of the last subject in the 
TKI-naïve expansion cohort. The sample size and evaluation timing may be adjusted based on 
results of second interim analysis of ALTA-1L study, and actual enrollment period of the TKI-
naïve expansion cohort.
Overall, the total number of patients will be approximately 110 patients.
7.0 
METHODS OF ANALYSIS AND PRESENTATION
7.1 
General Principles 
All statistical analyses will be conducted using SAS® Version 9.4, or higher.
A statistical test for the primary endpoint will be reported as 1-sided and will be assessed at 
α=0.025 significance level and all confidence intervals will be reported as 2-sided unless 
otherwise stated. P-values will be rounded to 4 decimal places prior to assessment of statistical 
significance.
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. 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.
7.1.1 
Study Definitions
How to convert a time-to-event endpoint unit from day to month:
value (Month)= value (Day)/30.4375
Dose intensity:
Total amount of doses taken/(Last non-zero dose date – First dose date +1)
Relative Dose Intensity:
(Total amount of dose taken /Total amount of dose planned per initial dose)*100
Objective Response Rate(ORR):
The proportion of patients who are confirmed to have achieved CR or PR
Confirmed responses
Responses that persist on repeat imaging 4 weeks (allowing a minus 3-day time window) or 
more after initial response, which will be confirmed by the investigator or IRC.
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Duration of Response(DOR):
The time between the first documentation of objective tumor response (CR or PR) and the first 
subsequent documentation of objective PD or death due to any cause, whichever occurs first
Progression-Free Survival (PFS):
The time from the start of study treatment to the first documentation of objective PD or to death 
due to any cause, whichever occurs first.

Based only on radiological assessments verified by an IRC. Clinical progression is not
considered a progression endpoint.

The date of death when the patient is closely followed. However, deaths occurring after two
or more missed visits are censored at the last visit

The detailed scheme of progression and censoring for the primary analysis of PFS is
specified in Table 7.a.
Table 7.a
The Scheme of Progression and Censoring for PFS
Situation
Date of progression or censoring
Outcome
Documented disease progression or 
death with no baseline disease 
assessment
Earliest of the following:
Date of death
Date of progression
Progressed
New anticancer treatment (including 
palliative radiotherapy and cancer-
related surgery) started prior to 
documented disease progression or 
death
Date of last adequate radiological assessment 
prior to initiation of new anticancer treatment 
(including palliative radiotherapy and cancer-
related surgery)
Censored
Death or PD without more than 1 
missing radiographic assessment
Date of death or first PD whichever occurred 
first
Progressed
Death or PD after two or more missing
radiographic assessments
Date of last adequate radiological assessment 
Censored
No progression or death
Date of last adequate radiological assessment 
Censored
Disease Control Rate (DCR):
The proportion of patients who are confirmed to have achieved CR or PR or have a best overall 
response of stable disease (SD) for 6 weeks or more after initiation of study drug.
Time to response:
The time interval from the date of the first dose of study treatment until the initial observation of 
CR or PR for patients with confirmed CR/PR.
Overall Survival (OS):
The time from the start of study treatment to the date of death.
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Best response in target lesions:
The maximum unsigned decrease (or the minimum increase if no decrease) in percentage in the 
sum of the longest dimensions of the target lesions at a single assessment as compared with 
baseline.
Time on treatment 
Time on treatment is defined as the time interval from the first dose to the last dose of assigned 
study treatment.
ILD/Pneumonitis Events:
The search strategy included manual selection of PTs of Interstitial lung disease and Pneumonitis. 
Bradycardia Events:
The search strategy included manual selection of PTs of Ibradycardia, Central bradycardia, Heart 
rate decreased, Sinus bradycardia, Bradyarrhythmia, Atrioventricular block, Atrioventricular 
block complete, Atrioventricular block first degree and Atrioventricular block second degree.
Hypertension Events:
The search strategy included manual selection of PTs of Accelerated hypertension, Blood 
pressure diastolic increased, Blood pressure increased, Blood pressure systolic increased, 
Diastolic hypertension, Hypertension and Systolic hypertension.
GI Events:
Some PTs were retrieved manualy from SMQ; Gastrointestinal nonspecific symptoms and 
therapeutic procedures. For other GI events, the search strategy included manual selection of PTs 
of Dysphagia, Gastrointestinal tract irritation, Regurgitation, Retching and Vomiting projectile. 
Further details are given in Appendix 2.
Increased Insulin/ Hyperglycemia Events:
Hyperglycemia Events: The search strategy included manual selection of PTs of Blood glucose 
increased, Diabetes mellitus, Glycosylated haemoglobin increased, Hyperglycaemia, Insulin 
resistant diabetes, Insulin-requiring type 2 diabetes mellitus, Type 1 diabetes mellitus, Type 2 
diabetes mellitus and Type 3 diabetes mellitus.
Increased Insulin Events: The search strategy included manual selection of PTs of Blood Insulin 
increased and Hyperinsulinaemia.
Hyperglycemia Events and Increased Insulin Events were analyzed and tabulated together.
Hepatic Events
Some PTs were retrieved manualy from SMQ; Liver related investigations, signs and symptoms, 
Cholestasis and jaundice of hepatic origin, Hepatic failure, fibrosis and cirrhosis and other liver 
damage-related conditions and Hepatitis, non-infectious. Further details are given in Appendix 2.
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Elevated CPK
The search strategy included manual selection of PTs of Blood creatine increased, Blood creatine 
phosphokinase increased, Hypercreatinaemia, Blood creatine phosphokinase MB increased, 
Blood creatine phosphokinase MM increased and Blood creatine phosphokinase BB increased.
Muscle Toxicity
The search strategy included manual selection of PTs of Muscle necrosis, Myoglobin blood 
increased, Myoglobin blood present, Myoglobin urine present, Myoglobinaemia, Myoglobinuria, 
Myopathy, Myopathy toxic, Necrotising myositis, Rhabdomyolysis, Biopsy muscle abnormal, 
Muscle discomfort, Muscle disorder, Muscle fatigue, Muscular weakness, Musculoskeletal 
discomfort, Musculoskeletal disorder, Musculoskeletal pain, Myalgia, Myositis and 
Musculoskeletal chest pain.
Pancreatic Events
Chemical Pancreatitis: The search strategy included manual selection of PTs of Amylase 
abnormal, Amylase increased, Hyperamylasaemia, Hyperlipasaemia, Lipase abnormal, Lipase 
increased, Pancreatic enzyme abnormality, Pancreatic enzymes abnormal, Pancreatic enzymes 
increased and Ultrasound pancreas abnormal.
Clinical Pancreatitis: The search strategy included manual selection of PTs of Haemorrhagic 
necrotic pancreatitis, Ischaemic pancreatitis, Oedematous pancreatitis, Pancreatic abscess, 
Pancreatic haemorrhage, Pancreatic necrosis, Pancreatitis, Pancreatitis acute, Pancreatitis 
haemorrhagic, Pancreatitis necrotising and Pancreatitis relapsing.
Chemical and clinical pancreatic events were analyzed and tabulated together.
Peripheral Neuropathy Events
A broad search strategy was used for the retrieval of all active PTs from the SMQ: Peripheral 
neuropathy.
Skin and Subcutaneous Events
The search strategy was used for the retrieval of all active PTs from the SOC; Skin and 
Subcutaneous Events.
Visual Impairment Events
The search strategy was used for the retrieval of all active PTs from the HLGT; vision disorder, 
some PTs were retrieved from SMQs; retinal disorder, glaucoma, lens disorder. For other Visual 
Impairment events, the search strategy included manual selection of PTs. Further details are 
given in Appendix 2.
Photosensitivity
The search strategy was used for the retrieval of all active PTs from the HLT; photosensitivity 
and photodermatosis conditions. Further details are given in Appendix 2.
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CNS involvement at Screening:
The subjects with Brain and Leptomeningeal Involvement at Screening
Treatment-Emergent Adverse Events leading to study drug dose modification:
TEAE leading to dose discontinuation, dose interruption, or dose reduction
The subject who administrated any Chemo therapy:
The subjects who administrated the medication whose code are matched in the following table as 
prior anticancer therapy
Bevacizumab
Carboplatin
Chemotherapeutics
Cisplatin
Docetaxel
Gimeracil;Oteracil potassium;Tegafur
Gimeracil;Oteracil;Tegafur
Motesanib
Nivolumab
Paclitaxel
Pembrolizumab
Pemetrexed disodium
Tegafur;Uracil
Vinorelbine tartrate
7.1.2
Definition of Study Days
Study Day 1 is defined as the date on which a subject is administered their first dose of the 
medication. Other study days are defined relative to the Study Day 1 with Day 1 being Study 
Day 1 and Day -1 being the day prior to Study Day 1.
7.1.3
Definition of Study Visit Windows
For each visit, observation obtained in the corresponding time interval will be used. If more than 
one observation lies within the same visit window, the observation with the closest Day to the 
scheduled Day will be used. If there are two observations equidistant to the scheduled Day, the 
later observation will be used. 
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HRQOL scores(EORTC QLQ-C30, QLQ-LC13, and EQ-5D-5L), 12-lead ECG, ECOG 
performance status, and Testosterone
Visit
Scheduled Day
(days)
Time Interval (days)
Day*
Follow-up Day
Baseline
Day from first visit in cycle1:
1
-14 - 1
Cycle 2
Day from first visit in cycle2:
1
-3 - 29
Cycle 3
Day from first visit in cycle3:
1
-3 - 29
Cycle 4
Day from first visit in cycle4:
1
-3 - 29
Cycle 5
Day from first visit in cycle5:
1
-3 - 29
Cycle 6 and beyond
Day from first visit in each cycle:
1
-3 - 29
* “Day” indicates day after first visit in cycle which is mentioned in “Scheduled Study Day”.
If the data is in the scope of several visits, the data will be regarded as the candidate data of the latest visit.
Laboratory Assessments except HbA1c and Testosterone
Visit
Scheduled Day
(days)
Time Interval (days)
Day*
Follow-up Day
Baseline
Day from first visit in cycle1:
1
-14 - 1
Cycle 1 Day15
Day from first visit in cycle1:
15
2 - 29
Cycle 2
Day from first visit in cycle2:
1
-3 - 29
Cycle 3
Day from first visit in cycle3:
1
-3 - 29
Cycle 4
Day from first visit in cycle4:
1
-3 - 29
Cycle 5
Day from first visit in cycle5:
1
-3 - 29
Cycle 6 and beyond
Day from first visit in each cycle:
1
-3 - 29
* “Day” indicates day after first visit in cycle which is mentioned in “Scheduled Study Day”.
If the data is in the scope of several visits, the data will be regarded as the candidate data of the latest visit.
Vital signs
Visit
Scheduled Day
(days)
Time Interval (days)
Day*
Follow-up Day
Baseline
Day from first visit in cycle1:
1
-14 - 1
Cycle 1 Day8
Day from first visit in cycle1:
8
2 - 11
Cycle 1 Day15
Day from first visit in cycle1:
15
12 - 29
Cycle 2
Day from first visit in cycle2:
1
-3 - 29
Cycle 3
Day from first visit in cycle3:
1
-3 - 29
Cycle 4
Day from first visit in cycle4:
1
-3 - 29
Cycle 5
Day from first visit in cycle5:
1
-3 - 29
Cycle 6 and beyond
Day from first visit in each cycle:
1
-3 - 29
* “Day” indicates day after first visit in cycle which is mentioned in “Scheduled Study Day”.
If the data is in the scope of several visits, the data will be regarded as the candidate data of the latest visit.
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HbA1c
Visit
Scheduled Day
(days)
Time Interval (days)
Day*
Follow-up Day
Baseline
Day from first visit in cycle1:
1
-14 - 1
Cycle 4 and beyond
Day from first visit in each cycle:
1
-3 - 29
* “Day” indicates day after first visit in cycle which is mentioned in “Scheduled Study Day”.
If the data is in the scope of several visits, the data will be regarded as the candidate data of the latest visit.
7.1.4
Methods for Handling Missing Data and Specific Data
All available efficacy and safety data will be included in data listing and tabulations. No 
imputation of values for missing data will be performed unless otherwise specified. 

For ORR as assessed by an IRC, if any tumor response of post baseline is not assessed or any
tumor response of baseline is not confirmed as measurable disease per the IRC, the patients
will be treated as the one who are not confirmed to have achieved CR or PR

For ORR as assessed by an investigator, if any tumor response of post baseline is not
assessed or any tumor response of baseline is not confirmed as measurable disease per the
investigator, the patients will be treated as the one who are not confirmed to have achieved
CR or PR

For DCR, patients with only non-measurable disease who had a CR or non-CR/non-PD will
be considered as having achieved DCR.

For DOR, if tumor response cannot be confirmed, the patient will not be analyzed.

For EORTC QLQ-C30, QLQ-LC13, published scoring manuals and guidelines will be used
to calculate scores and handle missing data.

For stage at Screening, if no data has been input in CRF, the stage at initial diagnosis will be
used as the stage at screening,

For clinical laboratory tests, values less than the lower limit of quantification will be treated
as value of lower limit when calculating the descriptive statistics.

Disease duration with first diagnosis date of ALK + non small cell lung cancer that are
completely or partially missing will be derived as follows:
–
If the year is missing, then the disease duration will be treated as missing.
–
If the year is present but the month is missing, then the month will be treated as January
for the calculation.
7.2
Analysis Sets
The refractory expansion part and safety evaluation lead-in part:
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Safety population will be defined as patients who receive at least 1 dose of study drug will be
used for all safety analyses.
Full analysis set (FAS) population will be defined as all patients who receive at least 1 dose of 
study drug.
FAS-P population, the main analysis set used for primary efficacy analysis, will be defined a
subset of the FAS population consisting of first 47 patients in the main cohort of the expansion
part.
Per-protocol (PP) population will be defined as a subset of the FAS-P population including
patients who do not have a major protocol violation listed below:

Subjects who did not meet inclusion criteria #3, #4, #6 or, #10.

Subjects who met exclusion criteria #9, #10, #11, #13 or, #14.

Subjects who have violated the following rules specified in section 8.5.
–
Any other systemic anticancer therapy including, but not limited to, chemotherapeutic
agents, immunotherapy, biological response modifiers (excluding growth factors),
radiotherapy, and/or systemic hormonal therapy (with the exception of local therapies,
such as SRS and WBRT, used for palliative or symptomatic control of existing lesions,
with appropriate treatment interruption at the discretion of the investigator). Hormonal
contraception is allowed.
–
Use of any other investigational drug or device.
–
Extensive surgery requiring in-patient care (patients may have an interruption in therapy
for 14 days should emergency surgery be required).
PK population will be defined as patients with sufficient dosing and PK data to reliably estimate
PK parameters as determined by the clinical pharmacologist
DLT population will be a subset of the DLT evaluable subject who completes at least 75% of 
planned cumulative doses in safety evaluation lead-in part.
The TKI-naïve expansion cohort:
Safety population will be defined as patients who receive at least 1 dose of study drug will be
used for all safety analyses.
Full analysis set (FAS) population will be defined as all patients who receive at least 1 dose of 
study drug.
PK population will be defined as patients with sufficient dosing and PK data to reliably estimate
PK parameters as determined by the clinical pharmacologist
Per-protocol (PP) population will be defined as a subset of the FAS population including patients 
who do not have a major protocol violation listed below:

Subjects who did not meet inclusion criteria #3, #4, #6 or, #10.
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
Subjects who met exclusion criteria #1, #9, #10, #11, #13 or, #14.

Subjects who have violated the following rules specified in section 8.5.
–
Any other systemic anticancer therapy including, but not limited to, chemotherapeutic
agents, immunotherapy, biological response modifiers (excluding growth factors),
radiotherapy, and/or systemic hormonal therapy (with the exception of local therapies,
such as SRS and WBRT, used for palliative or symptomatic control of existing lesions,
with appropriate treatment interruption at the discretion of the investigator). Hormonal
contraception is allowed.
–
Use of any other investigational drug or device.
–
Extensive surgery requiring in-patient care (patients may have an interruption in therapy
for 14 days should emergency surgery be required).
7.3
Disposition of Subjects
7.3.1
Study Information
Analysis Set: All Subjects Who Signed the Informed Consent Form
Analysis 
Variable(s) :
Date First Subject Signed Informed Consent Form
Date of Last Subject’s Last Visit
MedDRA Version
WHO Drug Version
SAS Version Used for Creating the Datasets
Analytical 
Method(s) :
(1) Study Information
Study information shown in the analysis variables section will be
provided.
7.3.2
Screen Failures
Analysis Set: All Subjects Who Did Not Enter the Treatment Period
Analysis 
Variable(s) :
Age (years)
[20<= - <65, 65<= - <=Max]
[20<= - <50, 50<= - <65, 65<= -
<75,75<= - <=Max]
Gender
[Male, Female]
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Analytical 
Method(s) :
(1) Screen Failures
Frequency distributions for categorical variables and descriptive
statistics for continuous variables will be provided.
7.3.3
Subject Eligibility
Analysis Set: All Subjects Who Signed the Informed Consent Form
Analysis 
Variable(s) :
Eligibility Status
[Eligible for Entrance into the 
Treatment Period, Not Eligible for 
Entrance into the Treatment 
Period]
Primary Reason for Subject Not 
Being Eligible
[Adverse Event, Death, Lost to 
Follow-up, Protocol Deviation, 
Screen Failure, Study Terminated 
by Sponsor, Withdrawal by 
Subject, Other]
Analytical 
Method(s) :
(1) Eligibility for Entrance into the Treatment Period
Frequency distributions will be provided. When calculating percentages
for the primary reasons for subject not being eligible, the total number of
ineligible subjects will be used as the denominator.
7.3.4
Number of Subjects Who Entered the Treatment Period by Site
Analysis Set: All Subjects Who Entered the Treatment Period
Analysis 
Variable(s) :
Status of Entrance into the
Treatment Period
[Entered]
Stratum:
Site
[Site name and number will be used 
as categories]
Analytical 
Method(s) :
(1) Number of Subjects Who Entered the Treatment Period by Site
Frequency distribution will be provided for each stratum.
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7.3.5
Disposition of Subjects
Analysis Set: All Subjects Who Entered the Treatment Period
All Subjects Who Entered the Treatment Period in the main cohort
Analysis 
Variable(s) :
Subject Status(End of Treatment)
[Completed, Adverse Event, Death,
Lost to Follow-up, Progressive 
Disease, Protocol Deviation, Study 
Terminated by Sponsor, 
Symptomatic Deterioration, 
Withdrawal by Subject, Other, 
Ongoing]
Subject Status(Follow-up)
[Death, Lost to Follow-up, Study 
Terminated by Sponsor, 
Withdrawal by Subject, Other, 
Ongoing]
Analytical 
Method(s) :
(1) Disposition of Subjects
Frequency distributions will be provided. When calculating percentages
for the reasons for not being treated, the total number of subjects not
treated by the study drug will be used as the denominator. When
calculating percentages for the reasons for discontinuation, the total
number of subjects who prematurely discontinued will be used as the
denominator.
7.3.6
Protocol Deviations
Analysis Set: All Subjects Who Entered the Treatment Period
Analysis 
Variable(s) :
Protocol Deviation
[Entry Criteria, Concomitant Medication, 
Procedure Not Performed Per Protocol(Primary 
Endpoint or Safety Related), Study Medication, 
Withdrawal Criteria, Major GCP Violations]
Analytical 
Method(s) :
(1) Protocol Deviations
Frequency distribution will be provided for each deviation category. A
subject who has several deviations will be counted once in each
appropriate category. A subject who has several deviations that can be
classified into the same category will be counted only once.
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7.3.7
Analysis Sets
Analysis Set: All Subjects Who Entered the Treatment Period
All Subjects Who Entered the Treatment Period in the main cohort
(For the refractory patients)
All Subjects Who Entered the Treatment Period in the safety evaluation 
lead-in part.(For the refractory patients)
Analysis 
Variable(s) :
Handling of Subjects
[Categories are based on Subject 
Evaluability List]
Analysis Sets
Full Analysis Set
Full Analysis Set P
(For the refractory patients)
Per Protocol Set
Safety Analysis Set
PK population
DLT population
(For the refractory patients)
[Included]
[Included]
[Included]
[Included]
[Included]
[Included]
Analytical 
Method(s) :
(1) Subjects Excluded from Analysis Sets
(2) Analysis Sets
For DLT population, frequency distributions will be provided for the
subjects in the safety evaluation lead-in part. For other populations, it
will be done in overall population and main cohort. For (1), a subject
who has several reasons for exclusion will be counted once in each
appropriate category for each analysis set. A subject who has several
reasons for exclusion that can be classified into the same category will be
counted only once.
For analysis on Full Analysis Set P, all subjects who entered the 
treatment period in the main cohort will be used as analysis set.
7.4
Demographic and Other Baseline Characteristics
Analysis Set: Safety analysis set
Full Analysis Set
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Vysis ALK Break Apart FISH 
Probe Kit
Nichirei Histofine RALK iAEP 
Kit 
Ventana ALK (D5F3) CDx
Assay 
RT-PCR 
Sequencing 
Unknown 
Other
[Yes]
[Yes]
[Yes]
[Yes]
[Yes]
[Yes]
[Yes]
Was an abnormality detected?
fusion partner
[Yes, No, Unknown]
[EML4, TFG, KIF5B, NPM, 
Fusion partner unknown, Other 
fusion partner]
ALK secondary mutation
T1151Tins
L1152R 
C1156Y 
I1171T 
I1171N 
I1171S 
F1174C 
F1174L 
V1180L 
L1196M 
L1198F 
G1202R 
G1202del 
D1203N 
S1206Y 
[Yes]
[Yes]
[Yes]
[Yes]
[Yes]
[Yes]
[Yes]
[Yes]
[Yes]
[Yes]
[Yes]
[Yes]
[Yes]
[Yes]
[Yes]
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E1210K 
G1269A 
Unknown 
Other
[Yes]
[Yes]
[Yes]
[Yes]
Any Anticancer Therapies
[Yes, No]
Regimen
[Alectinib only, Crizotinib and 
Alectinib, Crizotinib only, 
Ceritinib only, Lorlatinib only, 
Crizotinib and Ceritinib, Alectinib 
and Ceritinib, Crizotinib and 
Lorlatinib, Alectinib and 
Lorlatinib, Ceritinib and Lorlatinib, 
Other]
Any Prior Chemo therapy
[Yes, No]
Any Prior Radiotherapy
[Yes, No]
Anatomic Site
Lung 
Mediastinal Lymph Nodes
Bone
Brain
Other
[Yes]
[Yes]
[Yes]
[Yes]
[Yes]
Analytical 
Method(s) :
(1) Summary of Demographics and Baseline Characteristics
Frequency distributions for categorical variables and descriptive
statistics for continuous variables will be provided.
7.5
Medical History and Concurrent Medical Conditions
Analysis Set: Safety Analysis Set
Analysis 
Variable(s) :
Medical History
Concurrent Medical Conditions
Analytical 
Method(s) :
(1) Medical History by System Organ Class and Preferred Term
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Relative dose intensity (%)
Duration of treatment (month)
Duration of follow-up (month)
Analytical 
Method(s) :
(1) Study Drug Exposure and Compliance
Frequency distributions for categorical variables and descriptive
statistics for continuous variables will be provided.
7.8
Efficacy Analysis
7.8.1
Primary Efficacy Endpoint(s)
7.8.1.1
Primary Analysis
Analysis Set: Full Analysis Set P(For the refractory patients)
Full Analysis Set (For TKI-naïve Patients)
Analysis 
Variable(s):
Confirmed ORR as assessed by an IRC(For the refractory patients)
PFS as assessed by an IRC (For TKI-naïve Patients)
Analytical 
Method(s):
The point estimate and its 2-sided 95% confidence interval will be
summarized. The point estimate will be calculated by the method 
suggested by Kunzmann(2017) with weight function of uniform 
distribution of [0,1], which means that the point estimate will
((x1+x2+1)/49)x100. X1 and x2 represents the number of events at IA 
for the first 29 patients in the main cohort and the number of events at PA 
for the last 18 patients in the main cohort, respectively.
The confidence interval will be done based on the Clopper-Pearson type.
For PFS, the rate at 12 and, 24 months and the associated two-sided 90% 
confidence intervals with complementary log-log link will also be 
provided using the Kaplan-Meier method.
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7.8.1.2
Secondary Analysis
Analysis Set: Per Protocol Set(For the refractory patients) 
Analysis 
Variable(s):
Confirmed ORR as assessed by an IRC
PFS as assessed by an IRC (For TKI-naïve Patients)
Analytical 
Method(s):
The point estimate and its 2-sided 95% confidence interval will be
summarized. The point estimate will be calculated based on maximum 
likelihood estimation. The confidence interval will be done based on the 
Clopper-Pearson type.
For PFS, the rate at 12 and, 24 months and the associated two-sided 90% 
confidence intervals with complementary log-log link will also be 
provided using the Kaplan-Meier method.
7.8.2
Secondary Efficacy Endpoint(s)
7.8.2.1
Confirmed ORR by the investigator
Analysis Set: Full Analysis Set P(For the refractory patients)
Analysis 
Variable(s):
Confirmed ORR as assessed by the investigator
Analytical 
Method(s):
The point estimate and its 2-sided 95% confidence interval will be
summarized. The point estimate will be calculated based on maximum 
likelihood estimation. The confidence interval will be done based on the 
Clopper-Pearson type.
7.8.2.2
Confirmed ORR by an IRC
Analysis Set: Full Analysis Set
Full Analysis Set P(For the refractory patients)
Analysis 
Variable(s):
Confirmed ORR as assessed by an IRC
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Analytical 
Method(s):
The point estimate and its 2-sided 95% confidence interval will be
summarized. The point estimate will be calculated based on maximum 
likelihood estimation. The confidence interval will be done based on the 
Clopper-Pearson type.
7.8.2.3
Other assessment by an IRC
Analysis Set: Full Analysis Set
Full Analysis Set P(For the refractory patients)
Patients who had measurable CNS metastases in Full Analysis Set
Patients who had measurable CNS metastases in Full Analysis Set P
(For the refractory patients)
Analysis 
Variable(s):
DOR as assessed by an IRC
PFS as assessed by an IRC(For the refractory patients)
DCR as assessed by an IRC
Time to response as assessed by an IRC
OS 
CNS response
iORR by an IRC
iDOR by an IRC
iPFS by an IRC
Time to intracranial response as assessed by an IRC
Time on treatment 
Best response in target lesions
Analytical 
Method(s):
For iDOR and DOR, the cumulative incidences and the two-sided 95%
confidence intervals will be provided using the Kaplan-Meier method.
For DOR, Time to response, and Time to intracranial response as 
assessed by an IRC, summary of descriptive analysis will be provided for 
subjects with confirmed CR or PR. 
For Time on treatment, the summary of descriptive analysis will be 
provided and swimmer’s plot will be presented.
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For iPFS, PFS, and OS, the rate at 12 and, 24 months and the associated 
two-sided 95% confidence intervals with complementary log-log link 
will also be provided using the Kaplan-Meier method.
Especially, for iPFS, considering the progression by investigator 
assessment as competing risk and only intracranial progression by IRC 
as event, the cumulative incidence function for event will be provided.
Additionally, for the analysis for TKI-naïve patients, the same analysis 
mentioned above will be performed in Per Protocol Set.
For iORR, DCR, CNS response, the point estimate and its 2-sided 95% 
confidence interval will be summarized. The point estimate will be 
calculated based on maximum likelihood estimation. The confidence 
interval will be done based on the Clopper-Pearson type.
For iDOR and iORR, patients who had measurable CNS metastases in 
Full Analysis Set or in Full Analysis Set P will be used as analysis set.
For best response in target lesions, summary of descriptive analysis will 
be provided with a waterfall plot.
7.8.2.4
EORTC QLQ-C30
Analysis Set: Full Analysis Set in expansion part
Full Analysis Set P (For the refractory patients)
Analysis 
Variable(s):
Global health status
Global health status
Functional scales
Physical functioning
Role functioning
Emotional functioning
Cognitive functioning
Social functioning
Symptom scales
Fatigue
Nausea and vomiting
Pain
Dyspnoea
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Insomnia
Appetite loss
Constipation
Diarrhoea
Financial difficulties
Visit:
Baseline, Cycle 2, Cycle 3, Cycle 4, Cycle 5, Cycle 6, Cycle 7, Cycle 8, 
Cycle 9, Cycle 10, Cycle 11, Cycle 12, Cycle 13, Cycle 14, Cycle 15, 
Cycle 16, Cycle 17, Cycle 18
Analytical 
Method(s):
Descriptive statistics for observed values for each visit and changes from
baseline will be provided.
7.8.2.5
EORTC QLQ-LC13
Analysis Set: Full Analysis Set in expansion part
Full Analysis Set P(For the refractory patients)
Analysis 
Variable(s):
Dyspnoea
Coughing
Haemoptysis
Sore mouth
Dysphagia
Peripheral neuropathy
Alopecia
Pain in chest
Pain in arm or shoulder
Pain in other parts
Visit:
Baseline, Cycle 2, Cycle 3, Cycle 4, Cycle 5, Cycle 6, Cycle 7, Cycle 8, 
Cycle 9, Cycle 10, Cycle 11, Cycle 12, Cycle 13, Cycle 14, Cycle 15, 
Cycle 16, Cycle 17, Cycle 18
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Analytical 
Method(s):
Descriptive statistics for observed values for each visit and changes from
baseline will be provided.
7.8.2.6
EQ-5D-5L
Analysis Set: Full Analysis Set in expansion part
Full Analysis Set P(For the refractory patients)
Analysis 
Variable(s):
Mobility
Selfcare
Activity
Pain
Anxiety
EQ_VAS
Index Value
Visit:
Baseline, Cycle 2, Cycle 3, Cycle 4, Cycle 5, Cycle 6, Cycle 7, Cycle 8, 
Cycle 9, Cycle 10, Cycle 11, Cycle 12, Cycle 13, Cycle 14, Cycle 15, 
Cycle 16, Cycle 17, Cycle 18
Analytical 
Method(s):
For categorical variables, frequency distributions for each visit will be
provided. And for continuous variables, descriptive statistics for 
observed values for each visit and changes from baseline will be 
provided.
7.8.3
Additional Efficacy Endpoint(s)
7.8.3.1
Confirmed ORR by an IRC by the previous ALK inhibitor regimen
Analysis Set: Full Analysis Set
Full Analysis Set-P(For the refractory patients)
Analysis 
Variable(s):
Confirmed ORR as assessed by an IRC (For the refractory patients)
PFS as assessed by an IRC (For TKI-naïve Patients)
Stratified 
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Variable(s):
Age (years)
Gender
CNS involvement at Screening
Previous ALK Inhibitor Regimen
(For the refractory patients)
ALK secondary mutation
Any Prior Chemo Therapy
[20<= - <65, 65<= - <=Max]
[Male, Female]
[Yes, No]
[Alectinib only, Crizotinib and 
Alectinib, Crizotinib only, 
Ceritinib only, Lorlatinib only, 
Crizotinib and Ceritinib, Alectinib 
and Ceritinib, Other]
[Containing G1202R, Not 
containing G1202R but containing 
other, No or unknown somatic 
mutation]
[Yes, No]
Analytical 
Method(s):
The point estimate and its 2-sided 95% confidence interval will be
summarized by stratified variable. The point estimate will be calculated 
based on maximum likelihood estimation. The confidence interval will 
be done based on the Clopper-Pearson type.
For PFS, the rate at 12 and, 24 months and the associated two-sided 90% 
confidence intervals with complementary log-log link will also be 
provided using the Kaplan-Meier method by stratified variable.
7.8.3.2
Proportion of patients with event
Analysis Set: Full Analysis Set P (For the refractory patients)
Full Analysis Set
Analysis 
Variable(s):
Proportion of patients with PFS event
Proportion of patients with iPFS event (For the naive patients)
Proportion of patients with OS event
Proportion of patients with DOR event
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Analytical 
Method(s):
The point estimate and its 2-sided 95% confidence interval will be
summarized. The confidence interval will be done based on the Clopper-
Pearson type.
7.9
Pharmacokinetic/Pharmacodynamic Analysis
7.9.1
Pharmacokinetic Analysis
7.9.1.1
Plasma concentrations of brigatinib and AP26123
Analysis Set: PK population
Analysis 
Variable(s):
Plasma concentrations of brigatinib and AP26123
Time Point:
(Safety Evaluation Lead-in Part)
Visit: Cycle 1 Day 1 and Cycle 1 Day 22
Predose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours postdose (relative to start 
time of morning dose at Day 1 or 22)
Visit: Cycle 1 Day 8, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 3 Day 1, 
Cycle 4 Day 1, Cycle 5 Day 1
Predose
(Expansion Part)
Visit: Cycle 1 Day 1, Cycle 1 Day 8, and Cycle 1 Day 15
Predose and 1-4 hours postdose (relative to start time of morning dose at 
Day 1, 8, or 15)
Visit: Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1
Predose
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Analytical 
Method(s):
The following summaries will be provided for each analyte by analysis
set.
(1) Descriptive statistics (mean, standard deviation, minimum, median
and maximum) for observed values will be provided for each time
point by dose. In addition, %CV, geometric mean, and
geometric %CV will be provided
(2) Observed values will be plotted using individual case plot
(3) Mean of plasma concentrations will be plotted by time point using
linear scale.
(4) Mean of plasma concentrations will be plotted by time point using
common log scale.
7.9.1.2
Plasma PK parameters of brigatinib and AP26123
Analysis Set: PK population
Analysis 
Variable(s):
Plasma Concentrations of brigatinib and AP26123
[Cycle 1 Day 1]
Cmax
tmax
AUClast
AUC24
C24
tlast
[Cycle 1 Day 22]
Cmax
tmax
C24
AUC24
AUClast
R(AUC24)
R(Cmax)
CL/F
tlast
Visit:
Cycle 1 Day 1 and Cycle 1 Day 22 (Safety Evaluation Lead-in Part)
Analytical 
Method(s):
The following summaries will be provided for each analyte by visit.
(1) Descriptive statistics (mean, standard deviation, minimum, median
and maximum) for PK parameters will be provided. In addition,
geometric mean, 1st and 3rd quartiles, %CV, and geometric %CV will
be computed for all PK parameters.
7.9.2
Pharmacodynamic Analysis
Not applicable
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7.10
Other Outcomes
Not applicable
7.11
Safety Analysis
7.11.1
Adverse Events
7.11.1.1
Overview of Treatment-Emergent Adverse Events
Analysis Set: Safety Analysis Set
Analysis 
Variable(s) :
Treatment-emergent adverse event (TEAE)
Categories:
Relationship to Study Drug
[Related, Not Related]
Analytical 
Method(s) :
The following summaries will be provided.
(1) Overview of Treatment-Emergent Adverse Events
1)
All Treatment-Emergent Adverse Events (number of events,
number and percentage of subjects)
2)
Drug-related Treatment-Emergent Adverse Events (number of
events, number and percentage of subjects)
3)
Grade 3 or higher Treatment-Emergent Adverse Events (number
of events, number and percentage of subjects)
4)
Grade 3 or higher Drug-RelatedTreatment-Emergent Adverse
Events (number of events, number and percentage of subjects)
5)
Treatment-Emergent Adverse Events leading to study drug dose
modification (number of events, number and percentage of
subjects)
6)
Treatment-Emergent Adverse Events leading to study drug
discontinuation (number of events, number and percentage of
subjects)
7)
Treatment-Emergent Adverse Events leading to study drug
interruptions (number of events, number and percentage of
subjects)
8)
Treatment-Emergent Adverse Events leading to study drug
reduction (number of events, number and percentage of
subjects)
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9)
Serious Treatment-Emergent Adverse Events (number of
events, number and percentage of subjects)
10) Drug-Related serious Treatment-Emergent Adverse Events
(number of events, number and percentage of subjects)
11) Treatment-Emergent Adverse Events resulting in death (number
of events, number and percentage of subjects)
12) Drug-RelatedTreatment-Emergent Adverse Events resulting in
death (number of events, number and percentage of subjects)
TEAEs will be counted according to the rules below.
Number of subjects

Summaries for 2), 9), and 11)
A subject with occurrences of TEAE in both categories (ie, Related
and Not Related) will be counted once in the Related category.

Summary for 3) and 4)
A subject with multiple occurrences of TEAE will be counted once
for the TEAE with the maximum grade.

Summaries other than 2), 3), 4), 9) and, 11)
A subject with multiple occurrences of TEAE will be counted only
once.
Number of events
For each summary, the total number of events will be calculated.
7.11.1.2 
Frequency of patients with DLTs during Cycle 1 in the safety evaluation lead-in part. 
Analysis Set: DLT population (For the refractory patients)
Analysis 
Variable(s) : Patients with DLTs during Cycle 1 
[Yes, No]
Analytical 
Method(s) : 
Frequency distributions for categorical variables will be provided.
7.11.1.3 
Displays of Treatment-Emergent Adverse Events
Analysis Set: Safety Analysis Set
Analysis 
Variable(s) : TEAE
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Categories:
Time of Onset (day) 
[1<= - <=28, 29<= - <=56, 57<= -
<=84, 85<= - <=112, 113<= -
<=140, 141<= - <=168, 169<= -
<=Max]
Time of Onset for 
ILD/Pneumonitis Treatment-
Emergent Adverse Events (day)
[1<= - <=14, 15<= - <=Max]
Analytical 
Method(s) :
The following summaries will be provided using frequency distribution.
TEAEs will be coded using the MedDRA and will be summarized using 
SOC and PT.
SOC will be sorted alphabetically and PT will be sorted in decreasing 
frequency for tables provided by SOC and PT. SOC and PT will be 
sorted in decreasing frequency for tables provided by System Organ 
Class only or PT only.
(1)
Treatment-Emergent Adverse Events by System Organ Class and
Preferred Term
(2)
Treatment-Emergent Adverse Events by System Organ Class
(3)
Treatment-Emergent Adverse Events by Preferred Term
(4)
Drug-Related Treatment-Emergent Adverse Events by System
Organ Class and Preferred Term
(5)
Grade 3 or higher Treatment-Emergent Adverse Events by System
Organ Class and Preferred Term
(6)
Grade 3 or higher Drug-Related Treatment-Emergent Adverse
Events by System Organ Class, and Preferred Term
(7)
Treatment-Emergent Adverse Events Leading to study drug
modification by System Organ Class and Preferred Term
(8)
Drug-Related Treatment-Emergent Adverse Events Leading to
study drug modification by System Organ Class and Preferred
Term
(9)
Treatment-Emergent Adverse Events leading to study drug dose
discontinuation by System Organ Class and Preferred Term
(10)
Drug-Related Treatment-Emergent Adverse Events Leading to
study drug discontinuation by System Organ Class and Preferred
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Term
(11)
Treatment-Emergent Adverse Events leading to study drug
interruptions by System Organ Class and Preferred Term
(12)
Drug-Related Treatment-Emergent Adverse Events Leading to
study drug interruptions by System Organ Class and Preferred
Term
(13)
Treatment-Emergent Adverse Events leading to study drug
reduction by System Organ Class and Preferred Term
(14)
Drug-Related Treatment-Emergent Adverse Events Leading to
study drug reduction by System Organ Class and Preferred Term
(15)
Serious Treatment-Emergent Adverse Events by System Organ
Class and Preferred Term
(16)
Drug-Related Serious Treatment-Emergent Adverse Events by
System Organ Class and Preferred Term
(17)
Treatment-Emergent Adverse Events resulting in death by System
Organ Class and Preferred Term
(18)
Drug-Related Treatment-Emergent Adverse Events resulting in
death by System Organ Class and Preferred Term
(19)
Treatment-Emergent Adverse Events by System Organ Class and
Preferred Term Over Time
(20)
ILD/Pneumonitis Treatment-Emergent Adverse Events by System
Organ Class and Preferred Term
(21)
ILD/Pneumonitis Treatment-Emergent Adverse Events by System
Organ Class and Preferred Term Over Time
(22)
ILD/Pneumonitis Drug-Related Treatment-Emergent Adverse
Events by System Organ Class and Preferred Term
(23)
ILD/Pneumonitis Grade 3 or higher Treatment-Emergent Adverse
Events by System Organ Class and Preferred Term
(24)
ILD/Pneumonitis Grade 3 or higher Drug-Related Treatment-
Emergent Adverse Events by System Organ Class and Preferred
Term
(25)
ILD/Pneumonitis serious Treatment-Emergent Adverse Events by
System Organ Class and Preferred Term
(26)
ILD/Pneumonitis serious Drug-Related Treatment-Emergent
Adverse Events by System Organ Class and Preferred Term
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(27)
ILD/Pneumonitis Grade 3 or higher serious Treatment-Emergent
Adverse Events by System Organ Class and Preferred Term
(28)
ILD/Pneumonitis Grade 3 or higher serious Drug-Related
Treatment-Emergent Adverse Events by System Organ Class and
Preferred Term
(29)
ILD/Pneumonitis Treatment-Emergent Adverse Events leading to
study drug discontinuation by System Organ Class and Preferred
Term
(30)
ILD/Pneumonitis Treatment-Emergent Adverse Events leading to
study drug interruptions by System Organ Class and Preferred
Term
(31)
ILD/Pneumonitis Treatment-Emergent Adverse Events leading to
study drug reduction by System Organ Class and Preferred Term
(32)
ILD/Pneumonitis Treatment-Emergent Adverse Events resulting
in death by System Organ Class and Preferred Term
(33)
ILD/Pneumonitis Drug-Related Treatment-Emergent Adverse
Events resulting in death by System Organ Class and Preferred
Term
(34)
Hypertension Treatment-Emergent Adverse Events by System
Organ Class and Preferred Term
(35)
Hypertension Drug-Related Treatment-Emergent Adverse Events
by System Organ Class and Preferred Term
(36)
Hypertension Grade 3 or higher Treatment-Emergent Adverse
Events by System Organ Class and Preferred Term
(37)
Hypertension Drug-Related Grade 3 or higher Treatment-
Emergent Adverse Events by System Organ Class and Preferred
Term
(38)
Hypertension serious Treatment-Emergent Adverse Events by
System Organ Class and Preferred Term
(39)
Hypertension serious Drug-Related Treatment-Emergent Adverse
Events by System Organ Class and Preferred Term
(40)
Hypertension Grade 3 or higher serious Treatment-Emergent
Adverse Events by System Organ Class and Preferred Term
(41)
Hypertension Grade 3 or higher serious Drug-Related Treatment-
Emergent Adverse Events by System Organ Class and Preferred
Term
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(42)
Hypertension Treatment-Emergent Adverse Events leading to
study drug discontinuation by System Organ Class and Preferred
Term
(43)
Hypertension Treatment-Emergent Adverse Events leading to
study drug interruptions by System Organ Class and Preferred
Term
(44)
Hypertension Treatment-Emergent Adverse Events leading to
study drug reduction by System Organ Class and Preferred Term
(45)
Hypertension Treatment-Emergent Adverse Events resulting in
death by System Organ Class and Preferred Term
(46)
Hypertension Drug-Related Treatment-Emergent Adverse Events
resulting in death by System Organ Class and Preferred Term
(47)
Bradycardia Treatment-Emergent Adverse Events by System
Organ Class and Preferred Term
(48)
Bradycardia Drug-Related Treatment-Emergent Adverse Events
by System Organ Class and Preferred Term
(49)
Bradycardia Grade 3 or higher Treatment-Emergent Adverse
Events by System Organ Class and Preferred Term
(50)
Bradycardia Drug-Related Grade 3 or higher Treatment-Emergent
Adverse Events by System Organ Class and Preferred Term
(51)
Bradycardia serious Treatment-Emergent Adverse Events by
System Organ Class and Preferred Term
(52)
Bradycardia serious Drug-Related Treatment-Emergent Adverse
Events by System Organ Class and Preferred Term
(53)
Bradycardia Grade 3 or higher serious Treatment-Emergent
Adverse Events by System Organ Class and Preferred Term
(54)
Bradycardia Grade 3 or higher serious Drug-Related Treatment-
Emergent Adverse Events by System Organ Class and Preferred
Term
(55)
Bradycardia Treatment-Emergent Adverse Events leading to study
drug discontinuation by System Organ Class and Preferred Term
(56)
Bradycardia Treatment-Emergent Adverse Events leading to study
drug interruptions by System Organ Class and Preferred Term
(57)
Bradycardia Treatment-Emergent Adverse Events leading to study
drug reduction by System Organ Class and Preferred Term
(58)
Bradycardia Treatment-Emergent Adverse Events resulting in
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death by System Organ Class and Preferred Term
(59)
Bradycardia Drug-Related Treatment-Emergent Adverse Events
resulting in death by System Organ Class and Preferred Term
(60)
GI Treatment-Emergent Adverse Events by System Organ Class
and Preferred Term
(61)
GI Drug-Related Treatment-Emergent Adverse Events by System
Organ Class and Preferred Term
(62)
GI Grade 3 or higher Treatment-Emergent Adverse Events by
System Organ Class and Preferred Term
(63)
GI Drug-Related Grade 3 or higher Treatment-Emergent Adverse
Events by System Organ Class and Preferred Term
(64)
GI serious Treatment-Emergent Adverse Events by System Organ
Class and Preferred Term
(65)
GI serious Drug-Related Treatment-Emergent Adverse Events by
System Organ Class and Preferred Term
(66)
GI Grade 3 or higher serious Treatment-Emergent Adverse Events
by System Organ Class and Preferred Term
(67)
GI Grade 3 or higher serious Drug-Related Treatment-Emergent
Adverse Events by System Organ Class and Preferred Term
(68)
GI Treatment-Emergent Adverse Events leading to study drug
discontinuation by System Organ Class and Preferred Term
(69)
GI Treatment-Emergent Adverse Events leading to study drug
interruptions by System Organ Class and Preferred Term
(70)
GI Treatment-Emergent Adverse Events leading to study drug
reduction by System Organ Class and Preferred Term
(71)
GI Treatment-Emergent Adverse Events resulting in death by
System Organ Class and Preferred Term
(72)
GI Drug-Related Treatment-Emergent Adverse Events resulting in
death by System Organ Class and Preferred Term
(73)
Pancreatic Treatment-Emergent Adverse Events by System Organ
Class and Preferred Term
(74)
Pancreatic Drug-Related Treatment-Emergent Adverse Events by
System Organ Class and Preferred Term
(75)
Pancreatic Grade 3 or higher Treatment-Emergent Adverse Events
by System Organ Class and Preferred Term
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(76)
Pancreatic Drug-Related Grade 3 or higher Treatment-Emergent
Adverse Events by System Organ Class and Preferred Term
(77)
Pancreatic serious Treatment-Emergent Adverse Events by
System Organ Class and Preferred Term
(78)
Pancreatic serious Drug-Related Treatment-Emergent Adverse
Events by System Organ Class and Preferred Term
(79)
Pancreatic Grade 3 or higher serious Treatment-Emergent Adverse
Events by System Organ Class and Preferred Term
(80)
Pancreatic Grade 3 or higher serious Drug-Related Treatment-
Emergent Adverse Events by System Organ Class and Preferred
Term
(81)
Pancreatic Treatment-Emergent Adverse Events leading to study
drug discontinuation by System Organ Class and Preferred Term
(82)
Pancreatic Treatment-Emergent Adverse Events leading to study
drug interruptions by System Organ Class and Preferred Term
(83)
Pancreatic Treatment-Emergent Adverse Events leading to study
drug reduction by System Organ Class and Preferred Term
(84)
Pancreatic Treatment-Emergent Adverse Events resulting in death
by System Organ Class and Preferred Term
(85)
Pancreatic Drug-Related Treatment-Emergent Adverse Events
resulting in death by System Organ Class and Preferred Term
(86)
Increased Insulin/Hyperglycemia Treatment-Emergent Adverse
Events by System Organ Class and Preferred Term
(87)
Increased Insulin/Hyperglycemia Drug-Related Treatment-
Emergent Adverse Events by System Organ Class and Preferred
Term
(88)
Increased Insulin/Hyperglycemia Grade 3 or higher Treatment-
Emergent Adverse Events by System Organ Class and Preferred
Term
(89)
Increased Insulin/Hyperglycemia Drug-Related Grade 3 or higher
Treatment-Emergent Adverse Events by System Organ Class and
Preferred Term
(90)
Increased Insulin/Hyperglycemia serious Treatment-Emergent
Adverse Events by System Organ Class and Preferred Term
(91)
Increased Insulin/Hyperglycemia serious Drug-Related Treatment-
Emergent Adverse Events by System Organ Class and Preferred
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Term
(92)
Increased Insulin/Hyperglycemia Grade 3 or higher serious
Treatment-Emergent Adverse Events by System Organ Class and
Preferred Term
(93)
Increased Insulin/Hyperglycemia Grade 3 or higher serious Drug-
Related Treatment-Emergent Adverse Events by System Organ
Class and Preferred Term
(94)
Increased Insulin/Hyperglycemia Treatment-Emergent Adverse
Events leading to study drug discontinuation by System Organ
Class and Preferred Term
(95)
Increased Insulin/Hyperglycemia Treatment-Emergent Adverse
Events leading to study drug interruptions by System Organ Class
and Preferred Term
(96)
Increased Insulin/Hyperglycemia Treatment-Emergent Adverse
Events leading to study drug reduction by System Organ Class and
Preferred Term
(97)
Increased Insulin/Hyperglycemia Treatment-Emergent Adverse
Events resulting in death by System Organ Class and Preferred
Term
(98)
Increased Insulin/Hyperglycemia Drug-Related Treatment-
Emergent Adverse Events resulting in death by System Organ
Class and Preferred Term
(99)
Hepatic Treatment-Emergent Adverse Events by System Organ
Class and Preferred Term
(100) Hepatic Drug-Related Treatment-Emergent Adverse Events by
System Organ Class and Preferred Term
(101) Hepatic Grade 3 or higher Treatment-Emergent Adverse Events
by System Organ Class and Preferred Term
(102) Hepatic Drug-Related Grade 3 or higher Treatment-Emergent
Adverse Events by System Organ Class and Preferred Term
(103) Hepatic serious Treatment-Emergent Adverse Events by System
Organ Class and Preferred Term
(104) Hepatic serious Drug-Related Treatment-Emergent Adverse
Events by System Organ Class and Preferred Term
(105) Hepatic Grade 3 or higher serious Treatment-Emergent Adverse
Events by System Organ Class and Preferred Term
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(106) Hepatic Grade 3 or higher serious Drug-Related Treatment-
Emergent Adverse Events by System Organ Class and Preferred
Term
(107) Hepatic Treatment-Emergent Adverse Events leading to study
drug discontinuation by System Organ Class and Preferred Term
(108) Hepatic Treatment-Emergent Adverse Events leading to study
drug interruptions by System Organ Class and Preferred Term
(109) Hepatic Treatment-Emergent Adverse Events leading to study
drug reduction by System Organ Class and Preferred Term
(110) Hepatic Treatment-Emergent Adverse Events resulting in death by
System Organ Class and Preferred Term
(111) Hepatic Drug-Related Treatment-Emergent Adverse Events
resulting in death by System Organ Class and Preferred Term
(112) Elevated CPK Treatment-Emergent Adverse Events by System
Organ Class and Preferred Term
(113) Elevated CPK Drug-Related Treatment-Emergent Adverse Events
by System Organ Class and Preferred Term
(114) Elevated CPK Grade 3 or higher Treatment-Emergent Adverse
Events by System Organ Class and Preferred Term
(115) Elevated CPK Drug-Related Grade 3 or higher Treatment-
Emergent Adverse Events by System Organ Class and Preferred
Term
(116) Elevated CPK serious Treatment-Emergent Adverse Events by
System Organ Class and Preferred Term
(117) Elevated CPK serious Drug-Related Treatment-Emergent Adverse
Events by System Organ Class and Preferred Term
(118) Elevated CPK Grade 3 or higher serious Treatment-Emergent
Adverse Events by System Organ Class and Preferred Term
(119) Elevated CPK Grade 3 or higher serious Drug-Related Treatment-
Emergent Adverse Events by System Organ Class and Preferred
Term
(120) Elevated CPK Treatment-Emergent Adverse Events leading to
study drug discontinuation by System Organ Class and Preferred
Term
(121) Elevated CPK Treatment-Emergent Adverse Events leading to
study drug interruptions by System Organ Class and Preferred
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Term
(122) Elevated CPK Treatment-Emergent Adverse Events leading to
study drug reduction by System Organ Class and Preferred Term
(123) Elevated CPK Treatment-Emergent Adverse Events resulting in
death by System Organ Class and Preferred Term
(124) Elevated CPK Drug-Related Treatment-Emergent Adverse Events
resulting in death by System Organ Class and Preferred Term
(125) Visual Impairment Treatment-Emergent Adverse Events by
System Organ Class and Preferred Term
(126) Visual Impairment Drug-Related Treatment-Emergent Adverse
Events by System Organ Class and Preferred Term
(127) Visual Impairment Grade 3 or higher Treatment-Emergent
Adverse Events by System Organ Class and Preferred Term
(128) Visual Impairment Drug-Related Grade 3 or higher Treatment-
Emergent Adverse Events by System Organ Class and Preferred
Term
(129) Visual Impairment serious Treatment-Emergent Adverse Events
by System Organ Class and Preferred Term
(130) Visual Impairment serious Drug-Related Treatment-Emergent
Adverse Events by System Organ Class and Preferred Term
(131) Visual Impairment Grade 3 or higher serious Treatment-Emergent
Adverse Events by System Organ Class and Preferred Term
(132) Visual Impairment Grade 3 or higher serious Drug-Related
Treatment-Emergent Adverse Events by System Organ Class and
Preferred Term
(133) Visual Impairment Treatment-Emergent Adverse Events leading
to study drug discontinuation by System Organ Class and
Preferred Term
(134) Visual Impairment Treatment-Emergent Adverse Events leading
to study drug interruptions by System Organ Class and Preferred
Term
(135) Visual Impairment Treatment-Emergent Adverse Events leading
to study drug reduction by System Organ Class and Preferred
Term
(136) Muscle Toxicity Treatment-Emergent Adverse Events by System
Organ Class and Preferred Term
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(137) Muscle Toxicity Drug-Related Treatment-Emergent Adverse
Events by System Organ Class and Preferred Term
(138) Muscle Toxicity Grade 3 or higher Treatment-Emergent Adverse
Events by System Organ Class and Preferred Term
(139) Muscle Toxicity Drug-Related Grade 3 or higher Treatment-
Emergent Adverse Events by System Organ Class and Preferred
Term
(140) Muscle Toxicity serious Treatment-Emergent Adverse Events by
System Organ Class and Preferred Term
(141) Muscle Toxicity serious Drug-Related Treatment-Emergent
Adverse Events by System Organ Class and Preferred Term
(142) Muscle Toxicity Grade 3 or higher serious Treatment-Emergent
Adverse Events by System Organ Class and Preferred Term
(143) Muscle Toxicity Grade 3 or higher serious Drug-Related
Treatment-Emergent Adverse Events by System Organ Class and
Preferred Term
(144) Muscle Toxicity Treatment-Emergent Adverse Events leading to
study drug discontinuation by System Organ Class and Preferred
Term
(145) Muscle Toxicity Treatment-Emergent Adverse Events leading to
study drug interruptions by System Organ Class and Preferred
Term
(146) Muscle Toxicity Treatment-Emergent Adverse Events leading to
study drug reduction by System Organ Class and Preferred Term
(147) Peripheral Neuropathy Treatment-Emergent Adverse Events by
System Organ Class and Preferred Term
(148) Peripheral Neuropathy Drug-Related Treatment-Emergent
Adverse Events by System Organ Class and Preferred Term
(149) Peripheral Neuropathy Grade 3 or higher Treatment-Emergent
Adverse Events by System Organ Class and Preferred Term
(150) Peripheral Neuropathy Drug-Related Grade 3 or higher
Treatment-Emergent Adverse Events by System Organ Class and
Preferred Term
(151) Peripheral Neuropathy serious Treatment-Emergent Adverse
Events by System Organ Class and Preferred Term
(152) Peripheral Neuropathy serious Drug-Related Treatment-Emergent
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Adverse Events by System Organ Class and Preferred Term
(153) Peripheral Neuropathy Grade 3 or higher serious Treatment-
Emergent Adverse Events by System Organ Class and Preferred
Term
(154) Peripheral Neuropathy Grade 3 or higher serious Drug-Related
Treatment-Emergent Adverse Events by System Organ Class and
Preferred Term
(155) Peripheral Neuropathy Treatment-Emergent Adverse Events
leading to study drug discontinuation by System Organ Class and
Preferred Term
(156) Peripheral Neuropathy Treatment-Emergent Adverse Events
leading to study drug interruptions by System Organ Class and
Preferred Term
(157) Peripheral Neuropathy Treatment-Emergent Adverse Events
leading to study drug reduction by System Organ Class and
Preferred Term
(158) Skin and Subcutaneous Treatment-Emergent Adverse Events by
System Organ Class and Preferred Term
(159) Skin and Subcutaneous Drug-Related Treatment-Emergent
Adverse Events by System Organ Class and Preferred Term
(160) Skin and Subcutaneous Grade 3 or higher Treatment-Emergent
Adverse Events by System Organ Class and Preferred Term
(161) Skin and Subcutaneous Drug-Related Grade 3 or higher
Treatment-Emergent Adverse Events by System Organ Class and
Preferred Term
(162) Skin and Subcutaneous serious Treatment-Emergent Adverse
Events by System Organ Class and Preferred Term
(163) Skin and Subcutaneous serious Drug-Related Treatment-Emergent
Adverse Events by System Organ Class and Preferred Term
(164) Skin and Subcutaneous Grade 3 or higher serious Treatment-
Emergent Adverse Events by System Organ Class and Preferred
Term
(165) Skin and Subcutaneous Grade 3 or higher serious Drug-Related
Treatment-Emergent Adverse Events by System Organ Class and
Preferred Term
(166) Skin and Subcutaneous Treatment-Emergent Adverse Events
leading to study drug discontinuation by System Organ Class and
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Preferred Term
(167) Skin and Subcutaneous Treatment-Emergent Adverse Events
leading to study drug interruptions by System Organ Class and
Preferred Term
(168) Skin and Subcutaneous Treatment-Emergent Adverse Events
leading to study drug reduction by System Organ Class and
Preferred Term
(169) Photosensitivity Treatment-Emergent Adverse Events by System
Organ Class and Preferred Term
(170) Photosensitivity Drug-Related Treatment-Emergent Adverse
Events by System Organ Class and Preferred Term
(171) Photosensitivity Grade 3 or higher Treatment-Emergent Adverse
Events by System Organ Class and Preferred Term
(172) Photosensitivity Drug-Related Grade 3 or higher Treatment-
Emergent Adverse Events by System Organ Class and Preferred
Term
(173) Photosensitivity serious Treatment-Emergent Adverse Events by
System Organ Class and Preferred Term
(174) Photosensitivity serious Drug-Related Treatment-Emergent
Adverse Events by System Organ Class and Preferred Term
(175) Photosensitivity Grade 3 or higher serious Treatment-Emergent
Adverse Events by System Organ Class and Preferred Term
(176) Photosensitivity Grade 3 or higher serious Drug-Related
Treatment-Emergent Adverse Events by System Organ Class and
Preferred Term
(177) Photosensitivity Treatment-Emergent Adverse Events leading to
study drug discontinuation by System Organ Class and Preferred
Term
(178) Photosensitivity Treatment-Emergent Adverse Events leading to
study drug interruptions by System Organ Class and Preferred
Term
(179) Photosensitivity Treatment-Emergent Adverse Events leading to
study drug reduction by System Organ Class and Preferred Term
(180) Most commonly reported Treatment-Emergent Adverse Events by
System Organ Class and Preferred Term
(181) Most commonly reported Grade 3 or higher Treatment-Emergent
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Adverse Events by System Organ Class and Preferred Term
(182) Most commonly reported Non-Serious Treatment-Emergent
Adverse Events by System Organ Class and Preferred Term
The frequency distribution will be provided according to the rules below.
Number of subjects

Summary tables other than the CTCAE grade, (19), and (21)
A subject with multiple occurrences of TEAE within a SOC will be
counted only once in that SOC. A subject with multiple occurrences
of TEAE within a PT will be counted only once in that PT.
Percentages will be based on the number of subjects in the safety
analysis set.

Summary tables for the CTCAE grade
A subject with multiple occurrences of TEAE within a SOC or a PT
will be counted only once for the TEAE with the maximum intensity.
Percentages will be based on the number of subjects in the safety
analysis set.

Summary table for (19) and (21)
A subject with a TEAE that occurs in more than one interval is
counted in all the intervals that the TEAE occurs. For each time
interval, a subject with multiple occurrences of TEAE within a SOC
or a PT will be counted only once in that SOC or PT.
When calculating percentages for each time interval, the number of
subjects at risk (ie, subjects who either have an exposure or have an
occurrence of TEAE, during or after the corresponding time interval)
will be used as the denominator. The number of subjects whose onset
of any one of the TEAEs is within the time interval will be used as
the numerator.

Summary table for (180) and (181)
Most commonly reported TEAEs refer to PTs whose percentages are
at least 10.0% in any one of the treatment groups.

Summary table for (182)
Most commonly reported Non-Serious TEAEs refer to PTs whose
percentages are at least 5.0% in any one of the treatment groups. If
no Non-Serious TEAEs exceed a frequency of 5.0%, the frequency
cutoff of 2.0% will be used instead. Percentages will be based on the
number of subjects in the safety analysis set.
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7.11.1.4
Time to Onset and the Duration of Special Interest Treatment-Emergent Adverse 
Events
Analysis Set: Safety Analysis Set
Analysis 
Variable(s) :
Time to initial onset of ILD/Pneumonitis
Time to initial onset of Bradycardia Even
Time to initial onset of Hypertension Eve 
Time to initial onset of GI Events
Time to initial onset of Pancreatic Events
Time to initial onset of Increased Insulin/Hyperglycemia Events
Time to initial onset of Hepatic Events
Time to initial onset of Elevated CPK Events
Time to initial onset of Visual Impairment Events
Time to initial onset of Muscle Toxicity Events
Time to initial onset of Peripheral Neuropathy Events
Time to initial onset of Skin and Subcutaneous Events
Time to initial onset of Photosensitivity Events
Analytical 
Method(s) :
For each variable, descriptive statistics will be provided.
7.11.1.5
Displays of Pretreatment Events
Analysis Set: All Subjects Who Signed the Informed Consent Form
Analysis 
Variable(s) :
Pretreatment event (PTE)
Analytical 
Method(s) :
The following summaries will be provided using frequency distribution.
PTEs will be coded using the MedDRA and will be summarized using 
SOC and PT. SOC will be sorted alphabetically and PT will be sorted in 
decreasing frequency.
(1) Pretreatment Events by System Organ Class and Preferred Term
(2) Serious Pretreatment Events by System Organ Class and Preferred
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Term
The frequency distribution will be provided according to the rules below.
Number of subjects
A subject with multiple occurrences of PTE within a SOC will be 
counted only once in that SOC. A subject with multiple occurrences of 
PTE within a PT will be counted only once in that PT.
7.11.2
Clinical Laboratory Evaluations
7.11.2.1
Hematology and Serum Chemistry
Analysis Set: Safety Analysis Set
Analysis 
Variable(s) :
Hematology
Hematocrit
Platelet count
Hemoglobin
White blood cell count with differential (ANC, basophils, eosinophils, 
lymphocytes, monocytes)
Serum Chemistry
Albumin
Alkaline phosphatase 
(ALP)
Amylase
ALT
AST
Blood urea nitrogen 
(BUN)
Calcium
Creatine 
Phosphokinase (CPK)
Bicarbonate (or total 
carbon dioxide)
Chloride
Creatinine
Glucose (fasted)
Lactate dehydrogenase 
(LDH)
C-reactive protein
(CRP)
Magnesium
Phosphorus
Potassium
Sodium
Bilirubin (total bilirubin, conjugated and unconjugated bilirubin)
Protein (total protein)
Uric acid
HbA1c
Insulin
Testosterone (Male 
Patients Only)
Lipase
Visit:
Baseline, Cycle 1 Day 15, Cycle 2, Cycle 3, Cycle 4, Cycle 5, Cycle 6, 
Cycle 7, Cycle 8, Cycle 9, Cycle 10, Cycle 11, Cycle 12, Cycle 13, 
Cycle 14, Cycle 15, Cycle 16, Cycle 17, Cycle 18 (except HbA1c and 
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Testosterone)
Baseline, Cycle 4, Cycle 7, Cycle 10, Cycle 13, Cycle 16 (HbA1c)
Baseline, Cycle 2, Cycle 3, Cycle 4, Cycle 5, Cycle 6, Cycle 7, Cycle 8, 
Cycle 9, Cycle 10, Cycle 11, Cycle 12, Cycle 13, Cycle 14, Cycle 15, 
Cycle 16, Cycle 17, Cycle 18 (Testosterone)
Analytical 
Method(s) :
For each variable, summaries (1) to (2) will be provided.
For applicable variables, summaries (3) will be provided.
(1) Summary of Laboratory Test Results and Change from Baseline by
Visit
Descriptive statistics for observed values for each visit and changes
from baseline will be provided.
(2) Case Plots
Plots Over Time for each subject will be presented.
(3) Summary of Shifts of Laboratory Test Results
Shift tables will be generated showing changes in NCI CTCAE
grade from baseline to the worst postbaseline value.
7.11.3
Vital Signs
7.11.3.1
Vital Signs and Weight
Analysis Set: Safety Analysis Set
Analysis 
Variable(s) :
Systolic Blood Pressure
Diastolic Blood Pressure
Pulse
Respiratory rate
SpO2
Body temperature
Weight
Visit:
Baseline, Cycle 1 Day8, Day 15, Cycle 2, Cycle 3, Cycle 4, Cycle 5, 
Cycle 6, Cycle 7, Cycle 8, Cycle 9, Cycle 10, Cycle 11, Cycle 12, Cycle 
13, Cycle 14, Cycle 15, Cycle 16, Cycle 17, Cycle 18
Analytical 
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Method(s) :
For each variable, summaries (1) to (3) will be provided.
For applicable variables, summaries (4) will be provided.
(1) Summary of Vital Signs Parameters and Change from Baseline by
Visit
Descriptive statistics for observed values for each visit and changes
from baseline will be provided.
(2) Case Plots
Plots over time for each subject will be presented.
(3) Summary of Shifts of Vital Signs Parameters
Shift tables will be generated showing changes in NCI CTCAE
grade from baseline to the worst postbaseline value.
7.11.4
12-Lead ECGs
Analysis Set: Safety Analysis Set
Analysis 
Variable(s) :
12-Lead ECG Interpretation
[Within Normal Limits, Abnormal but not
Clinically Significant, Abnormal and 
Clinically Significant]
QT Interval
QTcF Interval
Visit:
Baseline, Cycle 2, Cycle 3, Cycle 4, Cycle 5, Cycle 6, Cycle 7, Cycle 8, 
Cycle 9, Cycle 10, Cycle 11, Cycle 12, Cycle 13, Cycle 14, Cycle 15, 
Cycle 16, Cycle 17, Cycle 18
Analytical 
Method(s) :
For each variable other than 12-lead ECG interpretations, summaries (1)
and (2) will be provided.
For applicable variables, summary (3) will be provided.
For 12-lead ECG interpretation, summary (4) will be provided.
(1) Summary of ECG Parameters and Change from Baseline by Visit
Descriptive statistics for observed values and changes from baseline
will be provided for each visit.
(2) Case Plots
Plots over time for each subject will be presented.
(3) Number and Percentage of Subjects with Markedly Abnormal
Values of ECG Parameters
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Overall frequency distributions of MAV during treatment period
will be provided. If an ECG laboratory parameter has both lower and 
upper MAV criteria, analysis will be performed for each. Further 
details are given in Appendix.
(4) Summary of Shift of 12-lead ECG Interpretation
Shift table showing the number of subjects in each category at
baseline and each post-baseline visit will be provided.
7.11.5 
Other Observations Related to Safety
Not applicable
7.12 
Interim Analysis
In this study, a 2-stage design will be used. An interim analysis for both futility and efficacy will be 
conducted in Stage 1, according to H1-minimax design in Englert. The proportion of patients 
achieving a confirmed objective response, per IRC, will be used as the endpoint for the interim 
analysis. The interim analysis will be performed with the first 29 patients in the main cohort of 
the expansion part at the cycle 6 after entry of the 29th patient. Enrollment will not be suspended 
during evaluation of these 29 patients; however, patients enrolled after the 29th patient in the 
main cohort of the expansion part will not be included in the interim analysis even if their ORR 
results were available on the cutoff date.
If the number of patients with confirmed ORR is 3 or fewer of the 29 patients, enrollment will be 
stopped entirely for futility. Additionally, if the number of patients with confirmed ORR is 10 or 
more of the 29 patients, it will be decided that brigatinib has demonstrated sufficient efficacy to 
reject the null hypothesis and declare superiority to the uninteresting ORR of 15% but the result at 
the timing of primary analysis will be interpreted descriptively. Otherwise, the study will 
continue until the 47 patients have had the opportunity to complete the Cycle 6 disease 
assessment. For the primary analysis, if the number of patients with confirmed ORR at the primary 
analysis is more than the number determined by the number at the interim analysis mentioned in 
Table 7.b, it will be decided that brigatinib has demonstrated sufficient efficacy to reject the null 
hypothesis. Of note, for the first 29 patients, their efficacy evaluation at the interim analysis were 
to be used.
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Table 7.b
Minimum Number of Confirmed ORR at the Primary Analysis
No. ORR at Interim Analysis
No. ORR at Primary Analysis
4/29
13/47
5/29
13/47
6/29
13/47
7/29
13/47
8/29
13/47
9/29
12/47
An IDMC will be formed. The IDMC will provide recommendation on the go/no go decision to 
move from the safety evaluation lead-in part to the expansion part, and on the futility and efficacy
assessments performed at the interim analysis.
Furthermore for the publishment, the analysis only in safety lead-in part will be performed when 
all patients in safety lead-in part have had the oppotunity to complet the cycle 6.
7.12.1
Analysis plan at the Interim Analysis
The analysis plan at interim analysis is based on this document except the following things.
1. The definition of FAS-P is a subset of the FAS population consisting of first 29 patients in
the main cohort of the expansion part.
2. The point estimate mentioned in section 7.8.1.1 will be calculated based on the maximum
likelihood estimation.
3. The interim analysis will be done for the all subjects who enroll the study until first
29 patients in the main cohort of the expansion part enroll the study.
7.12.2
Analysis plan in safety lead-in part
The analysis plan will be done as follows in 9 patients in safety lead-in part instead of analysis 
population specified in SAP.
1. Same analysis as section 7.4, 7.7, 7.8.1.2, 7.8.2.1, 7.9.1.2, 7.11.1.1, and 7.11.1.2 will be
performed.
2. Same analysis as (1) and (3) in section 7.9.1.1 will be performed.
3. Same analysis as (1), (4), (5), (6), (9), (10), (11), (12), (13), (14), (15), (16), and (17) in
section 7.11.1.3 will be performed.
4. The analysis for best response in target lesions in section 7.8.2.3 will be performed.
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7.13
Planned Analysis for the Refractory Patients and one for TKI-naïve Patients
7.13.1
Planned Analysis for the Refractory Patients
The analysis for the refractory patients will be performed when all refractory patients have had 
the opportunity to complete the Cycle 7 Day 1 disease assessment. The data for TKI-naïve
Patients will be excluded from the analysis.
7.13.2
Planned Analysis for TKI-naïve Patients
The analysis for TKI-naïve Patients will be performed after the final database lock at the end of 
the study. For efficacy and pharmacokinetic analysis, the same analysis described in section 7.8
to 7.9 as the one for the refractory patients will be performed only in TKI-naïve Patient. 
Additionally, 12 months PFS rate as assessed by an IRC, per RECIST version 1.1 in the TKI-
naïve expansion cohort will be performed as primary endpoint. For disposition of subjects, 
demographic, compliance, and safety analysis, the same analysis described in section 7.3 to 7.7, 
and 7.11 as the one for the refractory patients will be performed in TKI-naïve Patient and in all 
patients who have been enrolled.
7.13.3
Planned Final Analysis
For efficacy analysis, the analysis described in section 7.8 to 7.9 will be performed in following 
population.

TKI-naïve Patients.

Refractory Patients.
For disposition of subjects, demographic, compliance, and safety analysis, the same analysis 
described in section 7.3 to 7.7, and 7.11 will be performed in following population

TKI-naïve Patients.

Refractory Patients.

All patients who have been enrolled.
7.14
Changes in the Statistical Analysis Plan 
Based on comment from the team members, the following things has been changed.

The analysis for photosensitivity event as special interest AE has been added.

The analysis which was done in adhoc analysis has been added as additional analysis.

Section 7.13.3 has been added.
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8.0
REFERENCES
Englert S, Kieser M. Improving the flexibility and efficiency of phase II designs for oncology 
trials. Biometrics 2012;68(3):886-92.
Kunzmann, K. and Kieser, M. Point estimation and p values in phase II adaptive two-stage 
designs with binary endpoint. Statistics in Medicine 2017; 36, 971–984.
EORTC QLQ-C30 Scoring Manual (3rd edition). Fayers PM, Aaronson NK, Bjordal K, 
Groenvold M, Curran D, Bottomley A, on behalf of the EORTC Quality of Life Group. Brussels: 
EORTC, 2001. ISBN: 2-9300 64-22-6.
Ikeda S, Shiroiwa T, Igarashi A, Noto S, Fukuda T, and Saito S, Shimozuma K. Developing a 
Japanese version of the EQ-5D-5L value set. Journal of the National Institute of Public Health, 
2015 64(1), 47-55.
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