Clinical trial NCT03535740
Conditions: ALK-positive Advanced NSCLC
Keywords: Drug Therapy
Sponsor: Ariad Pharmaceuticals
Start date: 2019-01-31; Completion date: 2024-08-21
Enrollment: 103 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary purpose of this study is to determine the efficacy of brigatinib by confirmed objective response rate (ORR) by response evaluation criteria in solid tumors (Response Evaluation Criteria in Solid Tumors \[RECIST\]), in participants with ALK+ locally advanced or metastatic NSCLC whose disease has progressed on therapy with alectinib or ceritinib.

Detailed description:
The drug being tested in this study is called brigatinib (AP26113). Brigatinib is being tested to treat people who have anaplastic lymphoma kinase-positive (ALK+), advanced non-small-cell lung cancer (NSCLC).

The study will enroll approximately 103 patients. Participants will be assigned to the treatment group:

• Brigatinib

All participants will be asked to take brigatinib 90 mg tablet in lead-in period for 7 days, followed by brigatinib 180 mg at the same time each day throughout the study. Participants with progressive disease had an option to receive an escalated dose of brigatinib 240 mg as per investigator's discretion in case no toxicities (greater than grade 2) are experienced.

This multicenter trial will be conducted worldwide. The overall time to participate in this study is approximately 3 years. Participants will make multiple visits to the clinic, and 30 days after last dose of study drug for a follow-up assessment.

Arms: arm 1: Brigatinib 90 mg, tablets, orally, once daily (QD) for 7 days, followed by brigatinib 180 mg, tablets, orally, QD for until objective disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by the investigator, or intolerable toxicity. Participants who experienced progression on the 180 mg dose and had not experienced toxicities greater than Grade 2 had the option to receive brigatinib 240 mg QD based on investigator's discretion, up to 20 months until data cut-off: 30 September 2020. Participants who experienced progression on any doses but judged as still benefiting from the study treatment by the investigator may continue to use the current dose, up to study end.
Interventions: intervention 1: Brigatinib
Intervention descriptions: intervention 1: Brigatinib Tablets

Protocol documents:
Prot_002.pdf: 
For non-commercial use only


 
 
PROTOCOL
Brigatinib in Patients With Anaplastic Lymphoma Kinase-Positive (ALK+), Advanced 
Non–Small-Cell Lung Cancer (NSCLC) Progressed on Alectinib or Ceritinib
Sponsor:
ARIAD Pharmaceuticals, Inc
a wholly owned subsidiary of Takeda
Pharmaceutical Company Limited
40 Landsdowne Street
Cambridge, MA 02139 USA
Telephone: +1 (617) 679-7000
Study Number:
2002
IND Number:
IND 110,935
EudraCT Number:
2018-000635-27
Compound:
Brigatinib (AP26113)
Date:
12 February 2021
Amendment 5
Version Number:
1.0
Amendment History
Date
Amendment Number
Type
Region
12 February 2021
5
Substantial
Global 
24 September 2020
4
Substantial
Global 
27 September 2019
3
Substantial
Global
10 April 2019
2
Substantial
Global
11 December 2018
1 DE v1
Nonsubstantial
Germany
12 October 2018
1 SE v1
Nonsubstantial
Sweden
03 May 2018
1
Nonsubstantial
Global
22 February 2018
Initial Protocol
Not applicable
Global
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement 
by the recipient that no information contained herein will be published or disclosed without written authorization 
from Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her 
staff, and applicable institutional review committee and regulatory agencies to enable conduct of the 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 are presented in Section 10.0, as is 
information on reporting product complaints. 
Investigators will be provided with emergency medical contact information cards to be carried 
by each subject.
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in study manual to the site.
The names and contact information for the medical monitor and responsible medical officer are 
in the study manual.
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1.3
Protocol Amendment 5 Summary and Rationale
This section describes the changes in the protocol incorporating Amendment 5. The primary 
reasons for this amendment are to:

Modify definition of end of study.

Provide posttrial access to brigatinib.

Add language around photosensitivity.

Modify the storage conditions for the study drug.

Clarify that no pharmacokinetic samples should be collected going forward.

Supply information on withdrawal of patients from the study.

Make Independent Review Committee assessment of images optional after the primary 
analysis.
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are not included. 
Protocol Amendment 5
Summary of Changes Since the Last Version of the Approved Protocol
No.
Section(s) Affected by Change
Description of Each Change and Rationale
Location(s)
Description
Rationale
1
Cover page, Amendment History 
table
Date of Amendment 4 corrected 
from 18 to 24 September 2020
Correct typographical error in 
date
2
1.2, Approval
Changed statistical approver
Assignment change
3
Section 6.3.2, End of 
Study/Study Completion 
Definition and Planned 
Reporting
Modified definition of end of 
study to include termination of 
study by sponsor. 
Correct prior omission
4
Section 6.3.5, Posttrial Access
Section added to provide posttrial 
access to brigatinib
Correct prior omission
5
Section 8.4.2, Pulmonary 
Adverse Reactions, 
Photosensitivity, and Other 
Adverse Events
Add language around 
photosensitivity to sunlight
New information available
6
Section 8.12, Storage, Handling, 
and Accountability
Modify storage conditions
New storage conditions
7
Section 9.4.19, Pharmacokinetic 
Measurements
Appendix A, Schedules of 
Events, PK Sampling Schedule
As of Amendment 5, no additional 
pharmacokinetic (PK) samples 
should be collected
Because the primary analysis has 
been conducted, this will help to 
close the study out from a 
bioanalytical perspective
8
Section 9.8, Withdrawal of
Patients From Study
Section added
Correct prior omission
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Protocol Amendment 5
Summary of Changes Since the Last Version of the Approved Protocol
No.
Section(s) Affected by Change
Description of Each Change and Rationale
Location(s)
Description
Rationale
9
Section 11.2, Independent 
Review Committee
Independent Review Committee
assessment of images may be 
discontinued following the 
primary analysis
Optional at sponsor discretion
10
Appendix G, Protocol History
Add summary of Amendment 4 
Takeda template
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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 10.2 of this 
protocol.

Terms outlined in the clinical study site agreement.

Responsibilities of the investigator (Appendix B).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix C of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Province)
Location of Facility (Country)
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE.......................................................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 5 Summary and Rationale ........................................................4
2.0
STUDY SUMMARY ....................................................................................................12
3.0
STUDY REFERENCE INFORMATION ......................................................................16
3.1
Study-Related Responsibilities.................................................................................16
3.2
Principal Investigator...............................................................................................16
3.3
List of Abbreviations ...............................................................................................17
3.4
Corporate Identification...........................................................................................18
4.0
INTRODUCTION.........................................................................................................19
4.1
Background .............................................................................................................19
4.1.1
Epidemiology and Pathology ...........................................................................19
4.1.2
ALK+ NSCLC.................................................................................................19
4.1.3
Current Treatment for ALK+ NSCLC..............................................................20
4.1.4
Unmet Medical Need.......................................................................................21
4.2
Brigatinib.................................................................................................................21
4.3
Rationale for the Proposed Study.............................................................................22
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................23
5.1
Objectives................................................................................................................23
5.1.1
Primary Objective............................................................................................23
5.1.2
Secondary Objectives ......................................................................................23
5.1.3
...................................................................24
5.2
Endpoints.................................................................................................................24
5.2.1
Primary Endpoint.............................................................................................24
5.2.2
Secondary Endpoints .......................................................................................24
5.2.3
....................................................................25
6.0
STUDY DESIGN..........................................................................................................25
6.1
Overview of Study Design.......................................................................................25
6.2
Number of Patients ..................................................................................................27
6.3
Duration of Study ....................................................................................................27
6.3.1
Duration of an Individual Patient’s Study Participation....................................27
6.3.2
End of Study/Study Completion Definition and Planned Reporting..................27
6.3.3
Timeframes for Primary and Secondary Endpoints to Support Disclosures ......27
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6.3.4
Total Study Duration .......................................................................................28
6.3.5
Posttrial Access ...............................................................................................28
7.0
STUDY POPULATION................................................................................................29
7.1
Inclusion Criteria .....................................................................................................29
7.2
Exclusion Criteria ....................................................................................................30
8.0
STUDY DRUG .............................................................................................................32
8.1
Study Drug Administration......................................................................................32
8.2
Reference/Control Therapy......................................................................................33
8.3
Treatment Beyond Radiological Disease Progression...............................................33
8.4
Dose Modification Guidelines..................................................................................33
8.4.1
Dose Modification for Brigatinib-Related Adverse Events...............................34
8.4.2
Pulmonary Adverse Reactions, Photosensitivity, and Other Adverse Events ....38
8.5
Prior and Concomitant Therapies.............................................................................39
8.6
Excluded Concomitant Medications and Procedures ................................................40
8.7
Permitted Concomitant Medications and Procedures................................................41
8.8
Precautions and Restrictions ....................................................................................41
8.8.1
Pregnancy, Breastfeeding, and Contraception ..................................................41
8.9
Blinding and Unblinding..........................................................................................42
8.10
Description of Investigational Agents ......................................................................42
8.11
Packaging and Labeling...........................................................................................42
8.12
Storage, Handling, and Accountability.....................................................................43
8.13
Other Protocol-Specified Materials ..........................................................................43
9.0
STUDY CONDUCT......................................................................................................43
9.1
Study Personnel and Organizations..........................................................................43
9.2
Arrangements for Recruitment of Patients................................................................44
9.3
Treatment Group Assignments.................................................................................44
9.4
Study Procedures.....................................................................................................44
9.4.1
Informed Consent ............................................................................................44
9.4.2
Patient Demographics......................................................................................44
9.4.3
Screening.........................................................................................................45
9.4.4
Enrollment.......................................................................................................45
9.4.5
Medical History...............................................................................................45
9.4.6
Physical Examination ......................................................................................46
9.4.7
Patient Height and Weight ...............................................................................46
9.4.8
Vital Signs.......................................................................................................47
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9.4.9
Concomitant Medications and Procedures........................................................47
9.4.10
AEs .................................................................................................................47
9.4.11
ECG ................................................................................................................47
9.4.12
Clinical Laboratory Evaluations.......................................................................47
9.4.13
Pregnancy Test ................................................................................................48
9.4.14
Disease Assessment.........................................................................................48
9.4.15
End-of-Treatment Visit....................................................................................50
9.4.16
Thirty-Days-After-Last-Dose Visit ..................................................................50
9.4.17
Follow-up Period.............................................................................................50
9.4.18
Biomarker, Pharmacodynamic, and PK Samples..............................................51
9.4.19
Pharmacokinetic Measurements.......................................................................52
9.4.20
QOL Assessment: EORTC QLQ-C30 and QLQ-LC13 ....................................53
9.4.21
..........................................................................53
9.4.22
Health Utilization Data Collection ...................................................................54
9.5
Completion of Study Treatment (for Individual Patients) .........................................54
9.6
Completion of Study (for Individual Patients)..........................................................54
9.7
Discontinuation of Treatment With Study Drug .......................................................54
9.8
Withdrawal of Patients From Study .........................................................................55
9.9
Study Compliance....................................................................................................55
9.10
Overall Survival.......................................................................................................56
10.0
ADVERSE EVENTS ....................................................................................................56
10.1
Definitions...............................................................................................................56
10.1.1
PTE Definition ................................................................................................56
10.1.2
AE Definition ..................................................................................................56
10.1.3
AE Severity .....................................................................................................57
10.1.4
SAE Definition................................................................................................57
10.2
Procedures for Recording and Reporting AEs and SAEs..........................................58
10.3
Monitoring of AEs and Period of Observation .........................................................59
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events.........59
10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose) ................................................................................................................59
10.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities...........60
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................60
11.1
Steering Committee .................................................................................................60
11.2
Independent Review Committee ..............................................................................60
12.0
DATA HANDLING AND RECORDKEEPING............................................................61
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12.1
eCRFs......................................................................................................................61
12.2
Record Retention .....................................................................................................61
13.0
STATISTICAL METHODS..........................................................................................62
13.1
Statistical and Analytical Plans ................................................................................62
13.1.1
Analysis Sets ...................................................................................................62
13.1.2
Analysis of Demographics and Other Baseline Characteristics.........................63
13.1.3
Efficacy Analysis.............................................................................................63
13.1.4
Pharmacokinetic Analysis................................................................................65
13.1.5
Subgroup Analysis in Patients Progressed on Alectinib....................................65
13.1.6
Analysis of Patient-Reported Outcomes and Health Resource Utilization 
Data.................................................................................................................65
13.1.7
Safety Analysis................................................................................................65
13.2
Sample Size Justification .........................................................................................66
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................66
14.1
Study-Site Monitoring Visits ...................................................................................66
14.2
Protocol Deviations..................................................................................................67
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................67
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................67
15.1
Benefit-Risk of the Study.........................................................................................68
15.2
IRB and/or IEC Approval ........................................................................................68
15.3
Subject Information, Informed Consent, and Subject Authorization .........................69
15.4
Subject Confidentiality ............................................................................................70
15.5
Publication, Disclosure, and Clinical Trial Registration Policy.................................71
15.5.1
Publication.......................................................................................................71
15.5.2
Clinical Trial Registration................................................................................71
15.5.3
Clinical Trial Results Disclosure......................................................................71
15.6
Insurance and Compensation for Injury....................................................................72
16.0
REFERENCES..............................................................................................................72
LIST OF IN-TEXT TABLES
Table 6.a
Secondary Endpoints for Disclosure...................................................................28
Table 8.a
Recommended Brigatinib Dose Reduction Levels..............................................34
Table 8.b
Brigatinib Dose Modification Recommendations for Treatment-Related 
Adverse Events ..................................................................................................35
Table 9.a
Clinical Chemistry and Hematology Tests..........................................................48
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Table 9.b
Primary Specimen Collection.............................................................................51
LIST OF IN-TEXT FIGURES
Figure 6.a
Study Design......................................................................................................26
LIST OF APPENDICES
Appendix A
Schedules of Events ...........................................................................................76
Appendix B
Responsibilities of the Investigator.....................................................................83
Appendix C
Investigator Consent to Use of Personal Information..........................................85
Appendix D
Eastern Cooperative Oncology Group Scale for Performance Status ..................86
Appendix E
Response Evaluation Criteria In Solid Tumors (RECIST Version 1.1) ...............87
Appendix F
Modification of Diet in Renal Disease Equation for Estimated Glomerular 
Filtration Rate....................................................................................................90
Appendix G
Protocol History.................................................................................................91
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Main Criteria for Inclusion:
1.
Have histologically or cytologically confirmed stage IIIB (locally advanced or recurrent and not a candidate for 
curative therapy) or stage IV NSCLC.
2.
Must meet both of the following 2 criteria:
a)
Have documentation of ALK rearrangement by a positive result from any laboratory test approved by the 
Food and Drug Administration (FDA) (eg, the Vysis ALK Break Apart FISH [fluorescence in situ 
hybridization] Probe Kit or the Ventana ALK [D5F3] CDx [companion diagnostic] Assay or Foundation 
Medicine’s FoundationOne CDx)
or
Have documented ALK rearrangement by a different test (non–FDA-approved local lab tests) and have 
provided tumor sample to the central laboratory (Note: Central laboratory ALK rearrangement testing 
results are not required to be obtained before randomization.)
b)
The patient had been treated with any 1 of the ALK tyrosine kinase inhibitors (TKIs) (alectinib, ceritinib, 
crizotinib) for at least 12 weeks before progression. 
3.
Had progressive disease while on alectinib or ceritinib (defined as no more than 1 month from last dose of 
alectinib or ceritinib to disease progression, as assessed by the investigator or treating physician). (Number of 
patients not previously treated with alectinib will be capped at 10 for every 30 patients enrolled.)
4.
Had alectinib or ceritinib as the most recent ALK inhibitor therapy. Chemotherapy before or after progression 
on alectinib or ceritinib is allowed. 
5.
Have at least 1 measurable lesion per RECIST version 1.1 as assessed by the investigator. 
6.
Recovered from toxicities related to prior anticancer therapy to National Cancer Institute Common Terminology 
Criteria for Adverse Events version 4.03 Grade ≤1. (Note: Treatment-related alopecia or peripheral neuropathy 
that are Grade >1 are allowed if deemed irreversible.)
7.
Have Eastern Cooperative Oncology Group performance status ≤1.
8.
Have adequate organ and hematologic function.
Main Criteria for Exclusion:
1.
Received any prior ALK-targeted TKI other than crizotinib, alectinib, or ceritinib.
2.
Received both alectinib and ceritinib.
3.
Received crizotinib, alectinib, or ceritinib within 7 days of the first dose of brigatinib. 
4.
Previously received more than 3 regimens of systemic anticancer therapy for locally advanced or metastatic 
disease.
Note: A systemic anticancer therapy regimen will be counted if it is administered for at least 1 complete cycle. A 
new anticancer agent used as maintenance therapy will be counted as a new regimen. Neo-adjuvant or adjuvant 
systemic anticancer therapy will be counted as a prior regimen if disease progression/recurrence occurred within 
12 months upon completion of this (neo-)adjuvant therapy.
1.
Have symptomatic brain metastasis (parenchymal or leptomeningeal). Patients with asymptomatic brain 
metastasis or who have stable symptoms that did not require an increased dose of corticosteroids to control 
symptoms in the past 7 days before the first dose of brigatinib may be enrolled.
Main Criteria for Evaluation and Analyses:
The primary endpoint for this study is confirmed ORR, as assessed by the independent review committee, per 
RECIST version 1.1 in full analysis set.
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Statistical Considerations:
The purpose of this phase 2 study is to determine the confirmed ORR of orally administered brigatinib at current 
clinical doses (≤180 mg QD) in patients with ALK+ NSCLC whose disease progressed after therapy on alectinib or 
ceritinib. The sample size was determined so that it would allow for stating that the true ORR (expected response 
rate) is greater than the threshold response rate of 20% for patients previously treated by alectinib or ceritinib. A 
sample size of 103 patients will be enrolled. This sample size was calculated to provide at least 90% power to rule 
out an uninteresting ORR of 20%, assuming the true ORR is 35%. The calculation is based on an exact binomial test 
with a one-sided alpha level of 0.025 at primary endpoint analysis, allowing for dropout.
The final analysis of the primary endpoint will be conducted approximately 6 months after the last patient is 
enrolled. ORR will be tested at a one-sided alpha of 0.025. If the primary endpoint is achieved in patients previously 
treated with alectinib or ceritinib, then a subgroup analysis of confirmed ORR in patients previously treated with 
alectinib will be performed and tested at a one-sided alpha of 0.025.
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3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities 
The sponsor will perform all study-related activities with the exception of those identified in the 
study manual. The identified vendors in the study manual for specific study-related activities will 
perform these activities in full or in partnership with the sponsor.
3.2
Principal Investigator
Takeda will select a Signatory Coordinating Investigator from the investigators who participate 
in the study. Selection criteria for this investigator will include significant knowledge of the 
study protocol, the study medication, their expertise in the therapeutic area and the conduct of 
clinical research as well as study participation. The Signatory Coordinating Investigator will be 
required to review and sign the clinical study report and by doing so agrees that it accurately 
describes the results of the study.
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3.3
List of Abbreviations
AE
adverse event
ALK
anaplastic lymphoma kinase
ALK+
anaplastic lymphoma kinase-positive
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BCRP
breast cancer resistance protein
CNS
central nervous system
COVID-19
coronavirus disease 2019
CPK
creatine phosphokinase
CR
complete response
CRO
contract research organization
CT
computed tomography
ctDNA
circulating tumor DNA
CYP
cytochrome P-450
DCR
disease control rate
DLT
dose-limiting toxicity
DOR
duration of response
DTP
direct-to-patient
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form 
EDC
electronic data capture
EOPE
early onset pulmonary event
EORTC
European Organization for Research and Treatment of Cancer
EQ VAS
European Quality of Life Scale Visual Analogue Scale
EU
European Union
FDA
Food and Drug Administration
FFPE
formalin-fixed paraffin-embedded
FISH
fluorescence in situ hybridization
GCP
Good Clinical Practice
GI
gastrointestinal
HRQOL
health-related quality of life
HU
health resource utilization
IB
investigator’s brochure
IEC
independent ethics committee
ICF
informed consent form
ICH
International Conference on Harmonisation
ILD
interstitial lung disease
iORR
intracranial objective response rate
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iPFS
intracranial progression-free survival
IRB
institutional review board
IRC
independent review committee
KD
kinase domain
LD
longest diameter(s)
MATE
multidrug and toxin extrusion protein
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NSCLC
non–small-cell lung cancer
OCT1
organic cation transporter 1
ORR
objective response rate
OS
overall survival
PD
progressive disease
PFS
progression-free survival
Pgp
P-glycoprotein
PK
pharmacokinetic(s)
PR
partial response
PRO
patient-reported outcomes
PTE
pretreatment event
QD
once daily
QOL
quality of life
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease
SLD
sum of the longest diameters
SOE
Schedule of Events
SRS
stereotactic radiosurgery
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment-emergent adverse event
TKI
tyrosine kinase inhibitor
TRAE
treatment-related adverse event
ULN
upper limit of normal
US
United States
3.4
Corporate Identification 
ARIAD
ARIAD PHARMACEUTICALS INC, a wholly owned subsidiary of Takeda 
Pharmaceutical Company Limited
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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), 
which was 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) and in the European Union (EU). In the US, an estimated 234,030 new cases 
of lung cancer will be diagnosed by end of 2018, and 154,050 deaths due to the disease are 
estimated to occur [3]. In the EU, lung cancer is ranked as the fourth most frequent cancer; 
approximately 313,000 new cases were diagnosed in 2012 and 268,000 deaths in that year [1]. 
Five-year survival rates remain low: 17.7% and 13% in the US and Europe, respectively [4,5]. 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 (Center for Cancer Control 
and Information Services, National Cancer Center, 2017). Most lung cancer cases are diagnosed 
at advanced stages and about 78% of newly diagnosed patients have regional/distant disease [1]
[5].
Historically, lung cancers have been stratified on the basis of histologic criteria and are generally 
divided into 2 categories: small-cell lung cancer and non–small-cell lung cancer (NSCLC). 
NSCLC is the most prevalent histologic class, accounting for nearly 85% of all lung cancers 
[6,7], and includes a number of subtypes such as adenocarcinoma, squamous-cell carcinoma, 
large-cell carcinoma, and bronchioloalveolar carcinoma [8]. In recent years, attention has turned 
to stratifying lung cancer patients on the basis of molecular alterations since it has become clear 
that histologically identical tumors are driven by different oncogenes and are therefore likely to 
respond differently to therapeutic intervention, such as therapies directed at epithelial growth 
factor receptor (EGFR)-mutant, anaplastic lymphoma kinase-rearranged (ALK+), c-ros oncogene 
1 (ROS1) rearranged, or BRAF V600E mutant NSCLC. The focus herein is on NSCLC that 
contains oncogenic rearrangements in the ALK gene, and the role of brigatinib, a novel 
small-molecule inhibitor, in the treatment of ALK+ NSCLC. 
4.1.2
ALK+ NSCLC
ALK is a tyrosine kinase encoded on chromosome 2 and is primarily involved in developmental 
processes and expressed at low levels in adults [9]. The first genetic rearrangement of ALK seen 
in 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 [10]. 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 [11,12]. 
Estimates of the frequency of ALK rearrangement in the overall population of NSCLC patients 
range from 2% to 7% [13,14], which represent, on the basis of proportionality of total 
populations in the US and EU, approximately 7000 to 25,000 ALK+ NSCLC patients in the US 
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and 5800 to 20,000 patients in the EU in 2016. ALK rearrangements are more common among 
patients with adenocarcinoma histology, patients who have never smoked, and patients who have 
wild-type EGFR and Kirsten rat sarcoma virus oncogene [9]. 
4.1.3
Current Treatment for ALK+ NSCLC
While the standard treatment algorithm for unselected NSCLC patients has historically involved 
frontline treatment with chemotherapy, recent clinical trials have demonstrated that patients with 
ALK+ locally advanced or metastatic NSCLC respond well to treatment with the ALK inhibitors 
(crizotinib, alectinib, and ceritinib).
Crizotinib received accelerated approval from the US Food and Drug Administration (FDA) in 
2011 on the basis of results from 2 single-arm studies [15]. 
The efficacy of crizotinib has been confirmed in a randomized study of crizotinib versus 
chemotherapy [15,16].
ALK-dependent mechanisms of resistance, observed in approximately 30% of patients [17], 
include the acquisition of secondary mutations in ALK that interfere with crizotinib binding, 
and/or amplification of the ALK fusion gene. More than 10 secondary mutations in ALK have 
been associated with crizotinib resistance in patients, with the most common being L1196M and 
G1269A [18,19]. The central nervous system (CNS) is the first site of progression in 
approximately 50% of patients treated with crizotinib [20,21], suggesting inadequate penetration 
of crizotinib into the brain (ie, pharmacologic failure) as the primary cause of resistance in these 
patients. Therefore, an ALK inhibitor that can overcome secondary resistance mutations in ALK, 
has adequate penetration into the CNS, and is less susceptible to pharmacologic failure, may be 
required to overcome resistance.
Recently, 2 other ALK inhibitors, ceritinib [22] and alectinib [23], have become available for 
NSCLC patients with ALK rearrangements. Both drugs are effective in patients previously 
treated with crizotinib. Ceritinib demonstrated significantly improved progression-free survival 
(PFS) versus chemotherapy (hazard ratio 0.55) [24] whereas alectinib demonstrated significantly 
improved PFS versus crizotinib (hazard ratio 0.34-0.47) [25,26] in treatment-naïve ALK+ 
advanced NSCLC. 
ALK secondary mutations associated with clinical resistance to ceritinib and alectinib have also 
been identified, including L1152R and F1174C/V for ceritinib, I1171N/T/S for alectinib, and 
G1202R for both agents [18,27-30].
More recently, the investigational agent lorlatinib has been evaluated in a phase 1/2 trial showing 
responses after ≥1 prior ALK tyrosine kinase inhibitor (TKI) (25% [11 of 44] objective response 
rate (ORR) in patients with 2 prior ALK TKIs and 31% [4 of 13] ORR in patients with 3 prior 
ALK TKIs). The most common treatment-related adverse events (TRAEs) were 
hypercholesterolemia (90%) and hypertriglyceridemia (72%) [31]. 
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4.1.4
Unmet Medical Need
Significant progress has been made with incorporation of ALK TKIs for treatment of ALK+ 
NSCLC, but eventually almost all patients progress on these TKIs. The alternative treatments for 
these patients include chemotherapy and checkpoint inhibitors (PD-1 or PD-L1 antibody). The 
efficacy of platinum doublet chemotherapy seems not to be impacted by prior TKI treatment, but 
the efficacy was limited with a response rate of about 30% and median PFS of about 
4 months [32]. Checkpoint inhibitors have been introduced into the market recently as treatment 
for NSCLC. These agents are particularly effective in patients whose tumors over-express PD-L1 
and have less benefit in patients with EGFR mutation or ALK rearrangements [33], possibly 
related to low mutation burden in this population characterized by nonsmoking status [34]. 
There is still high unmet medical need for these ALK+ NSCLC patients progressed on alectinib 
or ceritinib to have access to an efficacious targeted therapy (evidenced by higher ORR and 
durable responses) and adequate CNS penetration with robust intracranial responses. Such a new 
therapeutic option could prolong disease control and translate into improved long-term outcomes 
including longer PFS. These efficacy attributes of a new therapy, along with a favorable safety 
profile, are needed for this patient population.
4.2
Brigatinib
Brigatinib (AP26113) is a novel, orally administered (PO) 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 ROS1, which play important roles in NSCLC and other cancers. 
A series of in vitro and in vivo studies demonstrated that brigatinib potently inhibited ALK 
activity and proliferation in ALK+ cell lines and exhibited a greater than 100-fold selectivity 
over ALK-negative lines. 
In clinical study, brigatinib has an acceptable safety profile at the recommended dose of 90 mg 
once daily (QD) for 7 days, then 180 mg QD, continuously (hereinafter presented as 90 mg 
QD→180 mg QD). Brigatinib at this dose level exhibited substantial efficacy in patients with 
ALK+ NSCLC who had progressed on crizotinib. In 110 patients, the confirmed response rate 
was 56.4% (62 of 110, 97.5% CI: 45.2, 67.0) by independent review committee (IRC) 
assessment. The IRC-assessed median duration of response (DOR) was 15.7 months (95% CI: 
12.8, 21.8 event rate: 54.8%) and median PFS was 16.7 months (95% CI: 11.6, 21.4, event rate: 
49.1%). High IRC-assessed intracranial objective response rate (iORR) (66.7%, 12 of 18, 95% 
CI: 41.0, 86.7) with a median 16.6 months (95% CI: 3.7, Not Reached) duration of intracranial 
response was also observed in patients with measurable baseline brain metastases by IRC 
(ALTA study, data cut-off: 29 September 2017, data on file). On 28 April 2017, the FDA granted 
accelerated approval to brigatinib (ALUNBRIG) for the treatment of patients with metastatic 
ALK+ NSCLC who have progressed on or are intolerant of crizotinib. 
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4.3
Rationale for the Proposed Study
Second-generation ALK TKIs, including alectinib and ceritinib, have shown efficacy, including 
durable response to intracranial lesions, and have an acceptable safety profile in both ALK TKI 
treatment-naïve and pretreated patients. Both alectinib and ceritinib were approved as first-line 
treatment for ALK+ advanced NSCLC in US and European countries. However, resistance to 
alectinib and ceritinib develops eventually, with emergence of secondary resistant mutations 
detected in approximately 50% of patients [33].
Brigatinib (AP26113) is a novel, synthetic, orally active ALK TKI. A pre-clinical study [35]
revealed that assessed at concentrations relative to the level of exposure achieved in patients at 
the approved or recommended phase 2 doses, brigatinib was the most potent inhibitor compared 
with crizotinib, ceritinib, and alectinib. Brigatinib inhibits 17 clinically and preclinically 
observed crizotinib-, ceritinib- and/or alectinib-resistant ALK mutations. Compared with these 3 
ALK TKIs, brigatinib also exhibited superior preclinical activity when in vitro potencies were 
related to steady-state plasma level of each drug achieved in patients at the approved dose. 
Among the 4 ALK TKIs tested, brigatinib was the only TKI to maintain substantial activity 
against the most recalcitrant G1202R mutant in vivo. Brigatinib also has activity in a mice 
orthotopic brain model metastasis. 
In the ALTA study, the 90 mg QD→180 mg QD treatment regimen was associated with a higher 
confirmed ORR and longer PFS, as well as improved intracranial efficacy, as compared with the 
90 mg QD regimen. Therefore, there appears to be a relationship between dose/exposure and 
efficacy, which suggests that higher brigatinib doses may result in better efficacy. However, 
higher brigatinib doses/exposures were associated with some treatment-related Grade 3 or higher 
adverse events (AEs) (eg, increased creatine phosphokinase [CPK], skin and subcutaneous tissue 
disorders and rash) 
(https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208772Orig1s000TOC.cfm). A 
240 mg QD dose of brigatinib was determined to be the highest acceptably tolerated dose in 
Study AP26113-11-101. As a result, in the present study, patients who progress on brigatinib 
180 mg QD will have the option to receive brigatinib at an increased dose of 240 mg QD in an 
effort to provide better mutational coverage. Patients will be allowed to receive only the 240 mg 
QD brigatinib dose postprogression if they have not experienced toxicities greater than Grade 2 
after the 180 mg brigatinib dose.
The rationale for escalation to 240 mg QD at disease progression is to provide an opportunity at 
progression for treatment at higher exposures of brigatinib that may consequently provide 
clinical benefit through a greater degree of antitumor activity compared to 180 mg and/ or to 
attempt to overcome potential pharmacologic resistance at 180 mg QD brigatinib (ie, to increase 
brigatinib exposure in order to have better activity against a given ALK KD resistance mutation 
or for increased exposure in the CNS).
In study AP26113-11-101, 10 patients were enrolled to receive brigatinib 240 mg QD, of which 
1 patient experienced a dose-limiting toxicity (DLT) of Grade 3 alanine aminotransferase (ALT) 
elevation. Treatment-emergent adverse events (TEAEs) leading to dose interruption, reduction, 
or discontinuation occurred at similar rates for patients dosed at 90 mg QD→180 mg QD (56.3% 
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[18 of 32], 18.8% [6 of 32], and 12.5% [4 of 32], respectively) and 240 mg QD brigatinib (50.0% 
[5 of 10], 20.0% [2 of 10], and 10.0% [1 of 10], respectively). Common TEAEs were similar for 
patients dosed at 90 mg QD→180 mg QD and 240 mg QD brigatinib and included 
gastrointestinal [GI], constitutional, and pulmonary events. Data from studies AP26113-11-101 
and AP26113-13-201 indicate the incidence of early onset pulmonary events (EOPEs) is related 
to the initial dose of brigatinib, but EOPEs have not been observed upon dose escalation 
(ie, 90 mg QD→180 mg QD regimen). Therefore, it is expected that patients who tolerate 
brigatinib at 180 mg QD and then escalate to 240 mg QD will not have an increased risk of 
EOPEs after escalation.
In separate but similar studies, ALK+ patients taking brigatinib after progressing on crizotinib, 
had a longer median PFS as assessed by IRC (15.6 months, 95% CI: 11.1, 21.0, ALTA study, 
data cut: 29 September 2017) than those taking alectinib (8.9 months, [36] and 7.1 months, [37], 
both by IRC assessment) or ceritinib (5.7 months, by investigator assessment, [38]). 
On the basis of nonclinical and clinical data, brigatinib may be efficacious in patients who 
developed resistant mutations to alectinib or ceritinib or those who do not respond to alectinib or 
ceritinib because of pharmacologic resistance. This phase 2 study is designed to assess the 
clinical efficacy and safety of brigatinib in ALK+ advanced NSCLC patients who have 
progressed on alectinib or ceritinib.
5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective
The primary objective of the study is to determine the efficacy of brigatinib, as evidenced by 
confirmed ORR, in patients with ALK+ locally advanced or metastatic NSCLC whose disease 
has progressed on therapy with alectinib or ceritinib. 
5.1.2
Secondary Objectives
The secondary objectives are:
To characterize the durability of efficacy with brigatinib.
1.
To assess intracranial efficacy of brigatinib.
2.
To assess the overall survival (OS) with brigatinib.
3.
To assess the safety and tolerability of brigatinib. 
4.
To collect plasma concentration-time data for brigatinib to contribute to population 
5.
pharmacokinetic (PK) analyses.
To assess patient-reported symptoms and health-related quality of life (HRQOL) assessed by 
6.
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and 
QLQ-LC13.
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Figure 6.a
Study Design
Abbreviations: ALK+, anaplastic lymphoma kinase positive; NSCLC, non–small-cell lung cancer; FDA, Food and 
Drug Administration; TKI, tyrosine kinase inhibitor, PD, progressive disease.
ALK+ by central laboratory is not required before enrollment.
Strongly encourage (but not mandate) re-biopsy at screening and at progression. Plasma sample to be collected at 
screening, Cycle 3 Day 1 and Cycle 5 Day 1 and at progression.
Patients will continue to be treated with brigatinib until they experience objective disease 
progression per RECIST version 1.1, as assessed by the investigator, or intolerable toxicity. 
Upon radiological progression, at the discretion of the investigator, patients who are receiving 
brigatinib 180 mg QD and have experienced toxicities no greater than Grade 2 during treatment 
may elect to increase the brigatinib dose to 240 mg QD, or continue study treatment at their 
current dose if they are still benefiting from treatment at this dose (eg, absence of clinical 
symptoms or signs indicating clinically significant disease progression requiring alternative 
systemic anti-cancer therapy; no decline in performance status; absence of rapid disease 
progression or threat to vital organs or critical anatomical sites [eg, respiratory failure due to 
tumor compression, spinal cord compression] requiring urgent use of alternative anticancer-
therapy; and no significant, unacceptable or irreversible toxicities related to study treatment). In 
both scenarios (increase dose or continue at same dose), the medical monitor shall review and 
approve the case.
AEs will be assessed from the time informed consent is signed till 30 days after last dose. 
Patients’ signs and symptoms, laboratory values, vital signs, electrocardiograms (ECGs), and any 
other relevant special exams as clinically indicated will be obtained to evaluate the safety and 
tolerability of brigatinib.
Sparse PK samples will be collected during the study to measure plasma concentrations of 
brigatinib, as outlined in Appendix A, PK Sampling Schedule.
Toxicity will be evaluated according to National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI CTCAE), version 4.03, effective 14 June 2010 [39]. 
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6.2
Number of Patients
The total number of patients is approximately 103. 
6.3
Duration of Study
6.3.1
Duration of an Individual Patient’s Study Participation
Patients will continue to be treated with brigatinib until they experience objective disease 
progression per RECIST version 1.1, as assessed by the investigator, or intolerable toxicity. With 
medical monitor approval, treatment may be continued at 180 mg QD or may be escalated to 
240 mg QD after initial progression if there is still potential for clinical benefit.
The follow-up period for survival begins after the patient has permanently discontinued study 
drug and continues until patient dies, is lost to follow-up, withdraws consent or the study ends, 
whichever comes first. Patients who discontinue the study drug for reasons other than 
radiological disease progression shall still be followed for tumor assessment according to the 
protocol until radiological disease progression is observed. For patients who qualify and elect to 
receive brigatinib 240 mg QD, the survival follow-up begins after they have discontinued study 
drug.
6.3.2
End of Study/Study Completion Definition and Planned Reporting
The study will end when all patients die or 3 years have passed since the last patient started study 
treatment or the study is terminated by the sponsor, whichever comes first. 
6.3.3
Timeframes for Primary and Secondary Endpoints to Support Disclosures
The study will start enrollment in 2018 and the overall timeframe will be pending on final 
sample size. 
Please refer to Table 6.a for disclosures information for all primary and secondary endpoints.
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Table 6.a
Secondary Endpoints for Disclosure
Endpoint
Primary: Confirmed ORR, as assessed by the IRC.
Secondary: 
1.
Confirmed ORR, as assessed by the investigator (per RECIST version 1.1).
2.
DOR, as assessed by the investigator and IRC.
3.
PFS as assessed by the investigator and IRC.
4.
DCR as assessed by the investigator and IRC.
5.
Time to response as assessed by the investigator and IRC.
6.
Confirmed intracranial ORR in patients with brain metastases at baseline, as assessed by the IRC.
7.
Intracranial DOR in patients with brain metastases at baseline, as assessed by the IRC.
8.
Intracranial PFS in patients with brain metastases at baseline, as assessed by the IRC.
9.
Overall survival.
10. Safety/tolerability (per CTCAE version 4.03).
11. HRQOL assessed with the global health status/quality of life and other function and symptom (per EORTC 
QLQ-C30 version 3.0, and EORTC QLQ-LC13).
Abbreviations: CNS: central nervous system; CTCAE, Common Terminology Criteria for Adverse Events; DCR, 
disease control rate; DOR, duration of response; EORTC, European Organization for Research and Treatment of 
Cancer; HRQOL, health-related quality of life; IRC, independent review committee; ORR, objective response rate; 
PFS, progression-free survival; RECIST, Response Evaluation Criteria in Solid Tumors.
6.3.4
Total Study Duration
The study will end around 5 years after enrollment starts, taking into consideration enrollment 
and follow-up. 
6.3.5
Posttrial Access
Posttrial access to brigatinib may be provided by the sponsor. Continued access to brigatinib for 
participants will be terminated for those individuals who no longer benefit from brigatinib 
(eg, they have completed the recommended course of therapy or their disease has resolved), the 
benefit-risk no longer favors the individual, if brigatinib becomes available either commercially 
or via another access mechanism, or when an alternative appropriate therapy becomes available. 
Posttrial access may be terminated in a country or geographical region where marketing 
authorization has been rejected, the development of brigatinib has been suspended or stopped by 
the sponsor, or the brigatinib can no longer be supplied.
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7.0
STUDY POPULATION
7.1
Inclusion Criteria
Each patient must meet all of the following inclusion criteria to be enrolled in the study:
Have histologically or cytologically confirmed stage IIIB (locally advanced or recurrent and 
1.
not a candidate for curative therapy) or stage IV NSCLC.
Must meet both of the following 2 criteria:
2.
a) Have documentation of ALK rearrangement by a positive result from any laboratory test 
approved by the FDA (eg, the Vysis® ALK Break-Apart fluorescence in situ 
hybridization [FISH] Probe Kit or the Ventana ALK [D5F3] CDx Assay or Foundation
Medicine’s FoundationOne CDx).
or
Have documented ALK rearrangement by a different test (non–FDA-approved local lab 
tests) and have provided tumor sample to the central laboratory. (Note: Central laboratory 
ALK rearrangement testing results are not required to be obtained before randomization.)
b) The patient had been on any one of the ALK TKIs (alectinib, ceritinib, crizotinib) for at 
least 12 weeks before progression. 
Had progressive disease (PD) while on alectinib or ceritinib (defined as no more than 
3.
1 month from last dose of alectinib or ceritinib to disease progression, as assessed by the 
investigator or treating physician). (Number of patients not previously treated with alectinib 
will be capped at 10 for every 30 patients enrolled.)
Had alectinib or ceritinib as the most recent ALK inhibitor therapy. Chemotherapy before or 
4.
after progression on alectinib or ceritinib is allowed. 
Have at least 1 measurable lesion per RECIST version 1.1 as assessed by the investigator. 
5.
Recovered from toxicities related to prior anticancer therapy to NCI CTCAE, version 4.03, 
6.
Grade ≤1. (Note: Treatment-related alopecia or peripheral neuropathy that are Grade >1 are 
allowed if deemed irreversible.)
Male or female, 18 years or older or of local legal adult age. 
7.
Have a life expectancy of ≥3 months.
8.
Have adequate organ and hematologic function as determined by:
9.
a) ALT/aspartate aminotransferase (AST) ≤2.5 × upper limit of normal (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) Estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2, using the modification 
of diet in renal disease (MDRD) equation (Appendix F). 
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d) Serum lipase ≤1.5 × ULN.
e) Absolute neutrophil count ≥1.5 × 109/L. 
f)
Platelet count ≥75 × 109/L.
g) Hemoglobin ≥9 g/dL.
h) Have Eastern Cooperative Oncology Group (ECOG) performance status <1.
For female patients of childbearing potential, have a negative pregnancy test documented 
10.
≤7 days before start of study medication.
Female patients of childbearing potential and male patients with partners of childbearing 
11.
potential must agree to use a highly effective nonhormonal form of contraception with their 
sexual partners during the dosing period and for a period of at least 4 months after the end of 
treatment (Section 8.8.1).
Have the willingness and ability to comply with scheduled visit and study procedures and 
12.
provide a signed and dated informed consent indicating that the patient has been informed of 
all pertinent aspects of the study, including the potential risks, and is willingly participating.
7.2
Exclusion Criteria
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
Received any prior ALK-targeted TKI other than crizotinib, alectinib, or ceritinib.
1.
Received both alectinib and ceritinib.
2.
Received crizotinib, alectinib, or ceritinib within 7 days of the first dose of brigatinib. 
3.
Previously received more than 3 regimens of systemic anticancer therapy for locally 
4.
advanced or metastatic disease.
Note: A systemic anticancer therapy regimen will be counted if it is administered for at least 
1 complete cycle. A new anticancer agent used as maintenance therapy will be counted as a 
new regimen. Neo-adjuvant or adjuvant systemic anticancer therapy will be counted as a 
prior regimen if disease progression/recurrence occurred within 12 months upon completion 
of this (neo-)adjuvant therapy.
Received chemotherapy or radiation within 14 days of first dose of brigatinib, except for 
5.
stereotactic radiosurgery (SRS) or stereotactic body radiation therapy. 
Received anticancer monoclonal antibodies within 30 days of the first dose of brigatinib.
6.
Had major surgery within 30 days of the first dose of brigatinib. Minor surgical procedures 
7.
such as catheter placement or minimally invasive biopsies are allowed. 
Have been diagnosed with another primary malignancy other than NSCLC, except for 
8.
adequately treated nonmelanoma skin cancer or cervical cancer in situ; definitively treated 
nonmetastatic prostate cancer; or patients with another primary malignancy who are 
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definitively relapse-free with at least 3 years elapsed since the diagnosis of the other primary 
malignancy.
Have symptomatic brain metastasis (parenchymal or leptomeningeal). Patients with 
9.
asymptomatic brain metastasis or who have stable symptoms that did not require an 
increased dose of corticosteroids to control symptoms in the past 7 days before the first dose 
of brigatinib may be enrolled. 
Have current spinal cord compression (symptomatic or asymptomatic and detected by 
10.
radiographic imaging). Patients with leptomeningeal disease and without cord compression 
are allowed.
Have significant, uncontrolled, or active cardiovascular disease, specifically including, but 
11.
not restricted to: 
a) Myocardial infarction within 6 months before the first dose of brigatinib.
b) Unstable angina within 6 months before first dose of brigatinib.
c) Congestive heart failure within 6 months before first dose of brigatinib.
d) History of clinically significant atrial arrhythmia (including clinically significant 
bradyarrhythmia), as determined by the treating physician.
e) Any history of clinically significant ventricular arrhythmia.
Had a cerebrovascular accident or transient ischemic attack within 6 months before first dose 
12.
of brigatinib.
Have uncontrolled hypertension. Patients with hypertension should be under treatment on 
13.
study entry to control blood pressure.
Have a history or the presence at baseline of pulmonary interstitial disease, drug-related 
14.
pneumonitis, or radiation pneumonitis. 
Have an ongoing or active infection, including, but not limited to, the requirement for 
15.
intravenous antibiotics.
Have a known history of HIV infection. Testing is not required in the absence of history.
16.
Have malabsorption syndrome or other GI illness that could affect oral absorption of 
17.
brigatinib.
Have a known or suspected hypersensitivity to brigatinib or its excipients.
18.
Are pregnant, planning a pregnancy, or breastfeeding. 
19.
Have any condition or illness that, in the opinion of the investigator, would compromise 
20.
patient safety or interfere with the evaluation of brigatinib.
Received systemic treatment with strong cytochrome P-450 (CYP)3A inhibitors, moderate 
21.
CYP3A inhibitors, strong CYP3A inducers, or moderate CYP3A inducers within 14 days 
before enrollment (refer to Section 8.6 for a list of example medications).
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8.0
STUDY DRUG
8.1
Study Drug Administration
In extenuating circumstances, such as during the COVID-19 public health emergency, additional 
drug supply may be provided to the subjects to cover periods between on-site visits. Additional 
study drug may be dispensed during a scheduled study visit, or study drug may be shipped 
directly from investigational sites to participants’ residences by a contracted logistics provider or 
distributor (direct-to-patient [DTP] shipment) in agreement with Takeda processes and local 
health authorities. 
Before initiation of the DTP process, patients will agree to participate in this process. Patients 
will sign a separate acknowledgment of receipt form permitting this process and agree to share 
limited personal information with the delivery courier. The investigator and courier must ensure 
that no private patient information is shared with the sponsor or other CROs participating in the 
study. The local institutional review board (IRB)/independent ethics committee (IEC) must be 
notified, as applicable per local requirements, that this process is being initiated, and sites must 
clearly document the chain of custody of any study drug dispensed directly to patients. 
Brigatinib will be administered orally at a dose of 90 mg QD for the first 7 days. Patients who 
have tolerated the 90 mg starting dose on Days 1 through 7 will be expected to increase their 
dose to 180 mg QD beginning on Day 8 and continuously every day, with a 28-day study 
procedure execution cycle. The study drug shall be taken approximately at the same time of the 
day each day. It may be taken with or without food. Patients shall be instructed to swallow the 
tablets whole and not crush or chew them. Patients will take the dose with water (recommended 
240 mL). If a dose of brigatinib is missed or vomiting occurs after taking a dose, do not 
administer an additional dose and take the next dose of brigatinib at the scheduled time.
The patient's daily dose of brigatinib should not be increased to 180 mg if any of the following 
adverse reactions are experienced during treatment at 90 mg QD:

Interstitial lung disease (ILD)/pneumonitis (any grade).

Symptomatic bradycardia (Grade 2 or greater).

Grade 2 or higher visual disturbance.

Any other Grade 3 or higher adverse reaction.
A missed dose is defined as a dose not taken within 6 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). If a dose of 
study drug is missed or vomiting occurs after taking a dose, do not administer an additional dose 
and take the next dose of study drug at the scheduled time.
All protocol-specific criteria for administration of study drug must be met and documented 
before drug administration. Study drug will be administered only to eligible patients under the 
supervision of the investigator or identified subinvestigator(s).
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8.2
Reference/Control Therapy
Not applicable.
8.3
Treatment Beyond Radiological Disease Progression
Until radiological disease progression is identified, patients may continue to receive brigatinib at 
current dose, if they are still benefiting from it as determined by investigator (eg, absence of 
clinical symptoms or signs indicating clinically significant disease progression requiring 
alternative systemic anticancer therapy; no decline in performance status; absence of rapid 
disease progression or threat to vital organs or critical anatomical sites [eg, respiratory failure 
due to tumor compression, spinal cord compression] requiring urgent use of alternative 
anticancer-therapy; and no significant, unacceptable or irreversible toxicities related to study 
treatment). Patients will be required to provide consent to receive treatment beyond progression. 
Patients who have progressed on brigatinib 180 mg QD and have had no greater than Grade 2 
brigatinib-related toxicity will be given the option to increase the dose to 240 mg QD until 
radiological disease progression per RECIST, using the tumor assessment before dose escalation 
as the new baseline, is observed or intolerance. Patients will be required to provide consent to 
receive this increased dose of brigatinib.
In either scenario, medical monitor delegated by the sponsor shall review and approve the case 
and an informed consent shall be obtained from the patient. The patient shall continue to receive 
the efficacy, safety, patient report outcome and health resource utilization assessments as in the 
main study treatment phase. 
8.4
Dose Modification Guidelines
The following sections provide recommended dose-modification guidelines for treatment-related 
AEs observed with brigatinib administration.
The allowable daily doses of brigatinib in this study are 240 mg (applicable only for patients 
eligible to increase to 240 mg after disease progression), 180 mg, 120 mg, 90 mg, and 60 mg. 
When patients are intolerant of their current dose they will have the option to reduce their dose in 
accordance with the dose-reduction scheme shown in Table 8.a.
Dose interruptions or reductions should be implemented for patients who experience treatment-
related AEs, upon clinical judgment of the investigator. Study drug administration may be 
delayed for up to 28 days to allow for improvement or resolution of the event. Patients may have 
an interruption in therapy for 14 days should emergency surgery be clinically indicated.
NOTE: If brigatinib treatment interruption lasts ≥14 days, and prior dose was >90 mg QD, 
patients should resume treatment at 90 mg QD for 7 days, before escalating 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.
If an AE does not resolve to Grade 1 or less after dose interruption for more than 28 days, the 
sponsor’s medical monitor must be contacted.
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Re-escalation after dose modification for AEs is discouraged. However, if, in the opinion of the 
treating investigator, re-escalation is warranted, this must be undertaken after consultation with 
the sponsor. To be a candidate for re-escalation, the AE that led to dose modification must not 
have recurred, and no other AEs of Grade 3 or 4 must have been observed during the preceding 
28 days.
Comprehensive assessments of any study drug-related AEs (ie, adverse drug reactions) 
experienced by the patient will be performed throughout the course of the study. The severity of 
the event, as well as clinical judgment, will be utilized to determine appropriate management of 
the patient for any AE experienced while participating in this study.
Any medication, including those administered for therapy of symptoms considered associated 
with study drug administration, should be reported on the appropriate concomitant medication 
page of the patient’s eCRF.
8.4.1
Dose Modification for Brigatinib-Related Adverse Events
The minimum dose for brigatinib is 60 mg QD. If a patient cannot tolerate study drug at this dose 
level, the study drug shall be permanently discontinued. The dose reduction levels of brigatinib 
are listed in Table 8.a. 
Table 8.a
Recommended Brigatinib Dose Reduction Levels
Dose Reduction Levels
Starting Dose
First
Second
Third
Fourth
Fifth
90 mg QD
60 mg QD
Permanently 
discontinue
Not applicable
Not applicable
Not applicable
180 mg QD
120 mg QD
90 mg QD
60 mg QD
Permanently 
discontinue
Not applicable
240 mg QD a
180 mg QD
120 mg QD
90 mg QD
60 mg QD
Permanently 
discontinue
Abbreviation: QD, once daily.
a For patients who tolerated 180 mg dose and had increased dose to 240 mg QD at disease progression.
8.4.1.1
General TRAEs
Guidelines for dose modification of brigatinib treatment-related AEs are outlined in Table 8.b
and are based on the Company Core Data Sheet (CCDS) for brigatinib. Unless otherwise noted, 
reduce dose as shown in Table 8.b if 1 or more dose reduction is necessary because of adverse 
reactions of Grade 3 or 4 severity, as defined by NCI CTCAE version 4.03.
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Table 8.b
Brigatinib Dose Modification Recommendations for Treatment-Related 
Adverse Events
Adverse Reaction
Severity*
Dose Modification
ILD/pneumonitis
Grade 1

If new pulmonary symptoms 
occur during the first 7 days of 
treatment, withhold brigatinib 
until recovery to baseline, then 
resume at same dose and do not 
escalate to 180 mg if 
ILD/pneumonitis is suspected.

If new pulmonary symptoms 
occur after the first 7 days of 
treatment, withhold brigatinib 
until recovery to baseline, then 
resume at same dose.

If ILD/pneumonitis recurs, 
permanently discontinue 
brigatinib.
Grade 2
If new pulmonary symptoms occur 
during the first 7 days of treatment, 
withhold brigatinib until recovery to 
baseline. Resume at next-lower dose 
(Table 8.a) and do not dose-escalate 
if ILD/pneumonitis is suspected.

If new pulmonary symptoms 
occur after the first 7 days of 
treatment, withhold brigatinib 
until recovery to baseline, then 
resume at same dose.

If new ILD/pneumonitis recurs, 
permanently discontinue 
brigatinib.
Grade 3 or 4
Permanently discontinue brigatinib 
for ILD/pneumonitis.
Hypertension 
Grade 3 hypertension (SBP greater than 
or equal to 160 mmHg or DBP greater 
than or equal to 100 mmHg, medical 
intervention indicated, more than one 
antihypertensive drug, or more intensive 
therapy than previously used indicated).

Withhold brigatinib until 
hypertension has recovered to 
baseline or SBP less than 140 
mmHg and DBP less than 90 
mmHg, then resume brigatinib 
at same dose (Table 8.a).

Recurrence: Withhold brigatinib 
until recovery to Grade 1 or less, 
and resume at next-lower dose 
(Table 8.a) or permanently 
discontinue treatment.
Grade 4 hypertension (life-threatening 
consequences, urgent intervention 
indicated).

Withhold brigatinib until 
recovery to Grade 1 (SBP less 
than 140 mmHg and DBP less 
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Table 8.b
Brigatinib Dose Modification Recommendations for Treatment-Related 
Adverse Events
Adverse Reaction
Severity*
Dose Modification
than 90 mmHG), and resume at
next-lower dose (Table 8.a) or
permanently discontinue 
treatment.

Recurrence of Grade 4 
hypertension: Permanently 
discontinue brigatinib.
Bradycardia (HR less than 60 
bpm) 
Symptomatic bradycardia

Withhold 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 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 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 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.
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Table 8.b
Brigatinib Dose Modification Recommendations for Treatment-Related 
Adverse Events
Adverse Reaction
Severity*
Dose Modification
Visual disturbance 
Grade 2 or 3 visual disturbance
Withhold 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.
CPK elevation 
Grade 3 or 4 CPK elevation (greater than 
5.0 × ULN) with Grade ≥2 muscle pain or 
weakness

Withhold brigatinib until 
recovery to Grade 1 or less 
(≤2.5 × ULN) CPK elevation or 
to baseline, then resume 
brigatinib at same dose.

If a Grade 3 or 4 elevation of 
CPK recurs with Grade ≥2 
muscle pain or weakness, 
brigatinib should be withheld 
until recovery to Grade 1 or less 
(≤2.5 × ULN) or to baseline, 
then resume at the next lower 
dose level per Table 8.a.
Lipase/amylase elevation 
Grade 3 (>2.0 × ULN)

Withhold brigatinib until 
recovery to Grade 1 or less 
(≤1.5 × ULN) or to baseline, 
then resume brigatinib at same 
dose.

If Grade 3 elevation of lipase 
and amylase recurs, brigatinib 
should be withheld until 
recovery to Grade 1 or less 
(≤1.5 × ULN) or to baseline, 
then resume at the next lower 
dose level per Table 8.a.
Grade 4 (>5.0 × ULN) 

Withhold brigatinib until 
recovery to Grade 1 or less (less 
than or equal to 1.5 × ULN) or 
to baseline, then resume 
brigatinib at next-lower dose 
(Table 8.a).

If Grade 4 elevation of 
lipase/amylase recurs, 
permanently discontinue 
brigatinib.
Hyperglycemia 
Grade 3 (greater than 250 mg/dL or 13.9 
mmol/L) or greater
If adequate hyperglycemic control 
cannot be achieved with optimal 
medical management, withhold 
brigatinib until adequate 
hyperglycemic control is achieved 
and consider reduction to the next-
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Table 8.b
Brigatinib Dose Modification Recommendations for Treatment-Related 
Adverse Events
Adverse Reaction
Severity*
Dose Modification
lower dose (Table 8.a) or
permanently discontinue brigatinib.
Other 
Grade 3

Withhold brigatinib until 
recovery to baseline, then 
resume at same dose.

Recurrence: Withhold brigatinib 
until recovery to baseline, then 
resume at next-lower dose or 
discontinue brigatinib
(Table 8.a).
Grade 4

First occurrence: Either 
withhold brigatinib until 
recovery to baseline and resume 
at next-lower dose (Table 8.a) or
permanently discontinue.

Permanently discontinue 
brigatinib for recurrence.
Abbreviations: bpm, beats per minute; CPK, creatine phosphokinase; DBP, diastolic blood pressure; HR, heart rate; 
ILD, interstitial lung disease; NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse 
Events; SBP, systolic blood pressure; ULN, upper limit of normal.
*Graded per NCI CTCAE, version 4.03.
8.4.2
Pulmonary Adverse Reactions, Photosensitivity, and Other Adverse Events 
During early clinical development of brigatinib, moderate and severe pulmonary AEs 
(eg, dyspnea, hypoxia, cough, pneumonia, and pneumonitis) were observed shortly after 
initiation of the drug in a subset of patients. These events were termed EOPEs. 
In the ALTA study (Study AP26113-11-201) for brigatinib, as of 21 February 2017, of 
219 treated patients, there were 14 cases of EOPE (total 6.4%, 14 of 219). All cases occurred at a 
dose of 90 mg QD. No EOPEs were identified after escalation to 180 mg QD in the 90 mg 
QD→180 mg QD dose group, or after re-initiation following study treatment interruption. 
Median time of EOPE onset was Day 2 (range: 1-9). Eleven of these 14 cases were reported as 
serious adverse events (SAEs). Seven patients had events that were Grade ≥3, all of whom 
permanently discontinued brigatinib because of these events. One patient had a Grade 5 EOPE 
(pneumonia). 
Pulmonary events occurring within the first 7 days of 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 
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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 no evidence of other etiology is 
identified, a causal relationship to brigatinib should be considered.
The management of new or worsening pulmonary symptoms within the first 7 days of brigatinib 
treatment should include drug interruption, monitoring of oxygen saturation, radiographic 
evaluation of the chest, and appropriate workup for infectious or other etiology, with high-dose 
corticosteroids, supplemental oxygen therapy, and empiric antibiotics as indicated. After drug 
interruption and workup of symptoms, if ILD/pneumonitis is suspected, dose modification 
should be accomplished according to the recommendations in Table 8.b. 
Photosensitivity to sunlight has occurred in patients treated with brigatinib. Patients should be 
advised to avoid prolonged sun exposure while taking brigatinib, and for at least 5 days after 
discontinuation of treatment. When outdoors, patients should be advised to wear a hat and 
protective clothing, and to use a broad-spectrum UVA/UVB sunscreen and lip balm (SPF =30) to 
help protect against potential sunburn. For severe photosensitivity reactions (≥ Grade 3), 
brigatinib should be withheld until recovery to baseline. The dose should be modified according 
to Table 8.b.
See Section 6 of the current version of the investigator’s brochure (IB) for detailed information 
on EOPE, late-onset pneumonitis and other AEs, including bradycardia, hypertension, vision 
impairment, blood CPK increased, pancreatic enzymes elevation, hyperglycemia and other 
adverse drug reactions observed in the clinical studies with brigatinib.
8.5
Prior and Concomitant Therapies
Anticancer Therapy
History of prior cancer therapy will be recorded at screening, and concomitant cancer therapy 
will be recorded during the study on the appropriate eCRF for each patient. Reasonable efforts 
will be made to collect information on all prior cancer therapy received by the patient 
(eg, surgeries, chemotherapy, radiotherapy, immunotherapy, biologics). The information must be 
obtained from the patient’s original source medical document (eg, medical chart for in-hospital 
care and medical record for outpatient clinic care) and recorded on the appropriate eCRF.
Palliative therapy and supportive care are permitted during the study for management of 
symptoms and underlying medical conditions that may develop during the study. Patients with 
brain lesions requiring local radiotherapy such as SRS 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.
New anticancer therapy initiated after radiological PD is observed shall also be collected in 
eCRF. The information to be collected may including name of the therapy, start and end dates, 
best response, and reason for discontinuation. 
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Other Therapy
Concomitant medications for all ongoing medical history conditions or AEs must be reported 
from the date the informed consent is signed until at least the 30 days after last dose, and for all 
concomitant medications related to serious or study drug-related toxicities until the medication is 
no longer taken or until patient contact discontinues.
8.6
Excluded Concomitant Medications and Procedures
Systemic treatment with the following medications should be avoided during the study:

Strong CYP3A inhibitors: boceprevir, clarithromycin, cobicistat, conivaptan, grapefruit-
containing products including grapefruit juice, idelalisib, indinavir, itraconazole, 
ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, 
telithromycin, and voriconazole. If concomitant use of a strong CYP3A inhibitor cannot be 
avoided during the study, reduce the brigatinib once daily dose by approximately 50% 
(ie, from 180 mg to 90 mg, or from 90 mg to 60 mg). After discontinuation of a strong 
CYP3A inhibitor, resume the brigatinib dose that was tolerated before initiating the strong 
CYP3A inhibitor.

Moderate CYP3A inhibitors: aprepitant, cimetidine, ciprofloxacin, clotrimazole, 
cyclosporine, diltiazem, dronedarone, erythromycin, fluconazole, fluvoxamine, imatinib, 
tofisopam, and verapamil. If concomitant use of a moderate CYP3A inhibitor cannot be 
avoided during the study, reduce the brigatinib QD dose by approximately 40% (ie, from 
180 mg to 120 mg, 120 mg to 90 mg, or from 90 mg to 60 mg). After discontinuation of a 
moderate CYP3A inhibitor, resume the brigatinib dose that was tolerated before initiating the 
moderate CYP3A inhibitor.

Strong CYP3A inducers: carbamazepine, enzalutamide, mitotane, phenobarbital, phenytoin, 
primidone, rifampin, rifapentine, rifabutin, and St. John’s wort.

Moderate CYP3A inducers: bosentan, efavirenz, etravirine, modafinil, and nafcillin.
As the above lists are not exhaustive, the investigator should consult the prescribing information 
for any medication under consideration for use to assess if it is a strong CYP3A inhibitor, 
moderate CYP3A inhibitor, strong CYP3A inducer, or moderate CYP3A inducer. 
The following medications and procedures are also prohibited before radiological disease 
progression is observed:

Any illicit substance. Medical use of cannabis is allowed if it is legal where the patient 
resides and no alternative treatment is available, on the base of case-by-case review and 
agreement by the medical monitor. 

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 
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as SRS, used for palliative or symptomatic control of existing lesions, with appropriate 
treatment interruption at the discretion of the investigator).

Use of any other investigational drug or device.
8.7
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. This may 
include blood and blood products and growth factors as clinically needed. 
8.8
Precautions and Restrictions
Brigatinib induces CYP3A in vitro and may decrease concentrations of CYP3A substrates. 
Coadministration of brigatinib with CYP3A substrates, including hormonal contraceptives, can 
result in decreased concentrations and loss of efficacy of CYP3A substrates. Brigatinib may also 
induce other enzymes and transporters (eg, CYP2C, Pgp) via the same mechanism responsible 
for induction of CYP3A (eg, pregnane X receptor activation). Therefore, additional monitoring 
should be considered for patients receiving substrates of these enzymes and transporters with a 
narrow therapeutic index during treatment with brigatinib as their effectiveness may be reduced.
Brigatinib is an in vitro inhibitor of P-glycoprotein (Pgp), breast cancer resistance protein 
(BCRP), organic cation transporter 1 (OCT1), multidrug and toxin extrusion protein 1 (MATE1) 
and 2K (MATE2K). Patients should be closely monitored when brigatinib is coadministered with 
substrates of these transporters with a narrow therapeutic index (eg, digoxin, dabigatran, 
methotrexate) as their plasma concentrations may be increased.
8.8.1
Pregnancy, Breastfeeding, and Contraception
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 
reproductive age group and male patients should use effective methods of contraception through 
defined periods during and after study treatment as specified below.
There are no data regarding the secretion of brigatinib in human milk or its effects on the 
breastfed infant or milk production. Because of the potential for adverse reactions in breastfed 
infants, female patients should not breastfeed during treatment with brigatinib and for 1 week 
following the final dose.
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 nonhormonal method 
(see list below) and 1 additional effective (barrier) method of contraception at the same time, 
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from the time of signing of the informed consent form (ICF) through at least 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 of the ICF through at least 4 months after the 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.)
Highly effective nonhormonal contraceptive methods suitable for patients taking brigatinib 
include:

intrauterine device.

bilateral tubal occlusion.

vasectomised partner.
Because of the potential for genotoxicity, advise males with female partners of reproductive 
potential to use effective contraception during treatment with brigatinib and after the final dose 
for the duration specified in the protocol.
Male patients, even if surgically sterilized (ie, status postvasectomy) must agree to 1 of the 
following:

Agree to practice effective barrier contraception from the time of signing of the ICF through 
at least 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 of the ICF through at least 4 months after the 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.)
8.9
Blinding and Unblinding
This is an open-label study.
8.10
Description of Investigational Agents
Brigatinib drug product is supplied as film-coated tablets, which may contain 30 mg, 90 mg, or 
180 mg of brigatinib active pharmaceutical ingredient. Brigatinib drug product is recommended 
for storage below 30°C. Do not refrigerate or freeze.
8.11
Packaging and Labeling
Brigatinib drug product will be supplied as film-coated tablets, containing 30 mg, 90 mg, or 
180 mg of brigatinib active pharmaceutical ingredient. Other ingredients will include typical 
pharmaceutical excipients (lactose monohydrate, microcrystalline cellulose, sodium starch 
glycolate, colloidal silicon dioxide, and magnesium stearate). The tablet coating is composed of 
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typical pharmaceutical grade coating components (talc, propylene glycol, polyvinyl alcohol, and 
titanium dioxide). The drug product is manufactured under current Good Manufacturing Practice 
in accordance with approved procedures. Brigatinib will be supplied in white high-density 
polyethylene bottles with induction sealed caps or blister packs. Bottle or blister pack 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.
8.12
Storage, Handling, and Accountability
Store brigatinib at controlled room temperature 20°C to 25°C with excursions permitted between 
15°C to 30°C.
The investigator is responsible for ensuring that the study drug provided to the patient and 
returned from the patient are reconciled and noted in source documentation.
All used bottles or blister packs of study drug must be returned to the study sponsor or destroyed 
in an appropriate manner according to the standard practice at each study center. Destruction of 
such supplies will be documented, and a representative of the sponsor 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 use of brigatinib intended for use in this study is authorized by the sponsor. The 
principal investigator or his/her designee will be responsible for the appropriate handling and 
disposition of residual study drug. Each site is responsible for proper and careful destruction of 
study drug returned by patients.
Periodically, throughout and at the conclusion of the study, a representative of the sponsor will 
conduct an inventory of unused study drug. At the completion of the study, a final study drug 
accountability review will be conducted. Any discrepancies must be investigated and all unused 
study drug must be destroyed on site per the standard operating procedures of the investigative 
site.
8.13
Other Protocol-Specified Materials
Details are provided in study manual.
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 project clinician for this study, the central laboratory and any 
additional clinical laboratories, the coordinating investigator for each member state/country, and 
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any additional vendors may be found in the study manual. A full list of investigators is available 
in the sponsor’s investigator database.
9.2
Arrangements for Recruitment of Patients
Recruitment and enrollment strategies for this study may include recruitment from the 
investigator’s local practice or referrals from other physicians. If advertisements become part of 
the recruitment strategy, they will be reviewed by the IRB/IEC. 
9.3
Treatment Group Assignments
This is a single arm study. All patients will be assigned to receive the same treatment.
9.4
Study Procedures
Refer to the Schedules of Events (Appendix A) for timing of assessments, including those for all 
patients, and for patients receive 240 mg brigatinib. Additional details are provided as necessary 
in the sections that follow.
Sites will make every effort to see patients in the clinic to complete all study-specified 
assessments as outlined in the Schedule of Events (SOE) (Appendix A). 
In unavoidable circumstances, such as during the COVID-19 public health emergency, 
exceptions can be made for alternative methods for conducting patient visits and performing 
laboratory and imaging assessments. Remote visits may be performed via telehealth or 
telemedicine as a safety check on subject well-being. Remote visits and telemedicine or 
telehealth must comply with Takeda processes and local health authorities. This will be recorded 
in the eCRF and in the study records.
In extenuating circumstances, such as during the COVID-19 public health emergency, local 
laboratory results and imaging assessment may be used. Assessments that cannot be completed 
during the protocol-specified window will be considered missing data, and such departures will 
be recorded in the study records. Missed clinic visits or subject withdrawals due to COVID-19 
must be recorded in the protocol deviation report and eCRF, as applicable.
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.
Before initiation of the DTP process, patients will agree to participate in this process as described 
in Section 8.1.
9.4.2
Patient Demographics
The date of birth (outside European Economic Area) or age (European Economic Area), race, 
ethnicity (optional depending on country), and sex of the patient are to be recorded during 
screening.
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9.4.3
Screening
Screening assessments must be performed no more than 14 days before Day 1 (the day of the 
first dose). Whenever feasible, baseline imaging should be performed as close as possible to 
Cycle 1 Day 1. Tumor radiological imaging generated for the purpose of regular medical practice 
before patients sign the ICF can be used as baseline disease assessment provided the imaging 
meets the quality and time window required for this study. 
Visit Window
The day the first dose of brigatinib is administered is defined as Day 1. Following visit may be 
arranged ±3 days from the Day 1 of each cycle, with the exception of disease assessment, which 
can be arranged with a ±7-day window. Once radiological disease progression is observed or 
patients have started a new systemic anticancer therapy, the survival follow-up shall be arranged 
with a ±14-day window.
Vital signs should be repeated on Cycle 1 Day 1 before first dose, regardless of the time from 
screening. Insulin, testosterone (male patients) and pregnancy tests (for female with child-
bearing potential) do not need to be repeated on Day 1 if they were performed for screening 
within 7 days before Day 1, and in the opinion of the investigator, there is no reason to believe 
they have substantially changed. Physical examination, ECOG performance status assessments, 
hematology, and chemistry assessments do not need to be repeated on Day 1 if they were 
performed for screening within 3 days before Day 1 and, in the opinion of the investigator, there 
is no reason to believe they have substantially changed. The pregnancy test may be repeated at 
any time during the study if the patient or the investigator has cause to believe that the patient 
may be pregnant. If screening laboratory assessments need to be repeated on Cycle 1 Day 1, they 
should be obtained before starting treatment.
9.4.4
Enrollment
Patients are considered enrolled once the ICF is signed. Patients who signed ICF but did not start 
study treatment will be counted as screening failure. The reason for screening failure shall be 
documented clearly in the source document and the eCRF. Procedures for completion of the 
enrollment information are described in the study manual.
9.4.5
Medical History
A complete medical history, including cancerous and noncancerous disease, will be collected at 
the screening. The type (systemic, surgery, radiotherapy) and intent (neoadjuvant, adjuvant, 
palliative) of prior anticancer therapy to the ALK+ NSCLC, and particularly, the drugs used for
prior systemic anticancer therapy, the start and end date of each of them and the best response, 
shall be captured in the eCRF. The method that ALK+ status was tested shall also be recorded.
Diagnosis and Cancer History
The initial cancer diagnosis, risk factors (such as tobacco and alcohol intake), and the current 
cancer stage at the time of screening, along with tumor histology and all sites of disease, should 
be recorded. The American Joint Committee on Cancer) 7th edition staging 
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(https://www.sciencedirect.com/science/article/pii/S1359634907700186) will be utilized for 
clinical stage at study entry. Any previously identified mutations other than ALK, and the dates 
of identification, must be recorded.
Prior Cancer Therapy
Prior cancer therapy history will be taken at screening and includes cancer-related surgical 
procedures, radiation, and systemic therapies. Surgical procedures include curative and 
palliative, as well as diagnostic procedures (eg, biopsy). Radiation will include both definitive 
and palliative treatment. Systemic therapy should include all regimens given, type of regimen 
(eg, neo-adjuvant, adjuvant, for advanced or metastatic disease), number of cycles administered 
for each regimen, 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 for cancer 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 and other methods including immunohistochemistry, and ALK rearrangements and point 
mutations by Next Generation Sequencing.
Patients entering the study must either have a history of a positive results from FDA-approved 
tests. Otherwise, they must have a history of ALK-positivity by another test and submit tissue 
samples for central laboratory analysis using an FDA-approved test, although confirmed ALK-
positivity by a central laboratory is not required before enrollment. Specifications regarding 
handling and processing of tissue for this test are described in Section 9.4.18.2 and in the study 
manual.
In addition, concomitant medications will be recorded as specified in Section 9.4.9.
9.4.6
Physical Examination
A complete physical examination must be performed at screening, the extent of which should be 
consistent with medical history and the patients’ underlying disease. Subsequent physical 
examinations as described in the Schedules of Events (Appendix A) 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.
The end-of-treatment physical examination should be a complete physical examination. The 
30-days-after-last-dose physical examination may be directed to any relevant findings.
9.4.7
Patient Height and Weight
Height will be measured only during screening. Weight will be measured during screening and at 
every scheduled visit. 
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9.4.8
Vital Signs
Vital signs will include temperature, pulse, respiratory rate, and blood pressure (when patient is 
seated). Vital signs should be repeated on Cycle 1 Day 1, before first dose, regardless of the time 
from screening. Vital signs will also be assessed per the Schedules of Events (Appendix A).
9.4.9
Concomitant Medications and Procedures
Medications used by the patient and therapeutic procedures completed by the patient will be 
recorded in the eCRF from the time informed consent is signed through 30 days after last dose. 
See Section 8.6 and Section 8.7 for a list of medications and therapies that are prohibited and/or 
allowed during the study treatment. 
After 30 days from last dose, follow-up anticancer treatment for the ALK+ NSCLC shall be 
collected during the survival follow-up stage, with the exception of study drug brigatinib being 
used beyond radiological progression. Study drug brigatinib used in these cases, at original or 
increased dose, shall continue to be reported in study medication section in the eCRF. 
In case brigatinib is prescribed again for regular medical practice after study drug brigatinib is 
permanently discontinued, this prescribed brigatinib shall be recorded as follow-up anticancer 
treatment. 
9.4.10
AEs
Monitoring of AEs, serious and nonserious, will be conducted throughout the study as specified 
in the Schedules of Events (Appendix A). Refer to Section 10.0 for details regarding definitions, 
documentation, and reporting of pretreatment events (PTEs), AEs, and SAEs.
9.4.11
ECG
A 12-lead ECG will be administered at the time points specified in the Schedules of Events 
(Appendix A).
All ECGs must be 12-lead ECGs and will be assessed per the Schedules of Events throughout the 
study. The Cycle 1 Day 1 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, during the 
study, been prescribed medication that can prolong the QT interval or medication that can 
potentially alter the QT interval (other than medications explicitly prohibited). 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) intervals.
9.4.12
Clinical Laboratory Evaluations
Clinical laboratory testing for safety evaluations will be performed locally whenever possible; an 
external laboratory may be used if necessary. Clinical laboratory evaluations will be performed 
as outlined in Table 9.a. The frequencies of the laboratory tests are defined in the Schedules of
Events (Appendix A). The results shall be recorded in eCRF. The attending physicians may order 
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additional tests as clinically indicated to follow up on AEs observed during the study. These 
additional results shall also be captured in the eCRF. However, other tests for the purpose of 
regular clinical practice outside of the scope of safety surveillance for brigatinib will not be 
required to enter in the eCRF. The blood sample for Cycle 1 Day 1 clinical laboratory 
assessments should be drawn before the first dose of brigatinib. If the screening blood sample for 
hematology and chemistry was collected within 3 days of the first dose and, in the opinion of the 
investigator, there is no reason to believe that there may be substantial changes, these tests do not 
need to be repeated on Day 1. If the insulin, testosterone (for males only), and pregnancy test (for 
females with child-bearing potential) were performed within 7 days before Day 1 and, in the 
opinion of the investigator, there is no reason to believe that there may be substantial changes or 
that the patient could be pregnant, these assessments do not need to be repeated on Day 1. If the 
tests need to be repeated, the investigator should review the results before instructing the patients 
to take the first dose of brigatinib.
Table 9.a
Clinical Chemistry and Hematology Tests
Hematology
Serum Chemistry
Hematocrit
Hemoglobin
Leukocytes with 
differential
Neutrophils (ANC)
Platelet (count)
Albumin
ALP
ALT
Amylase
AST
Bilirubin (total)
Calcium
CPK
Creatinine 
Chloride
Glucose
LDH
Lipase
Insulin
Magnesium Phosphate
Potassium
Sodium
Testosterone (males)
Abbreviations: ANC, absolute neutrophil count; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, 
aspartate aminotransferase; CPK, creatine phosphokinase; LDH, lactate dehydrogenase.
9.4.13
Pregnancy Test
The pregnancy test must be a beta-human chorionic gonadotropin test, and either urine or serum 
can be used. Women who are not of childbearing potential (status posthysterectomy, status 
post-bilateral oophorectomy, or postmenopausal [defined as amenorrhea for at least 12 months]) 
and men do not need to have the test performed. The test must be known to be negative before 
the study drug administration and be performed within 7 days before the first dose of brigatinib 
(Cycle 1 Day 1). Women of childbearing potential at study start must also complete the 
pregnancy test once every 3 cycles thereafter and at the end-of-treatment visit. Additional 
pregnancy testing should be performed if recommended or required per local guidelines or 
regulations.
9.4.14
Disease Assessment
Tumor response assessments will be determined per RECIST version 1.1 by the investigator and 
an independent radiological review.
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At screening, disease assessment must include imaging of the chest and abdomen (covering 
adrenal glands) using appropriate radiological procedures (computed tomography [CT] scans or 
magnetic resonance imaging [MRI] with contrast medium, unless contraindicated). MRI of the 
brain enhanced by contrast medium (eg, gadolinium) is required at screening for all patients. If 
such medium for MRI is contraindicated, use CT with contrast medium. All radiographic images 
(eg, CT, MRI) performed during the study will be submitted to the imaging core laboratory for 
central review. 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 whole brain radiation therapy 
within 3 months, or 2) previously treated by SRS or surgical resection.
Disease assessment by CT and MRI scans will be performed at screening and at 8-week intervals 
thereafter (on Day 28 [±7 days] of every even-numbered cycle) through 14 cycles after the initial 
dose of brigatinib, and every 3 cycles (12 weeks) thereafter until radiological disease progression 
is observed. Imaging of chest, abdomen, and brain will occur at each assessment for all patients. 
Additional tumor assessment can be performed at any time, if clinically indicated; confirmation 
of CR or PR shall be performed at least 4 weeks after initial response is observed. The same 
imaging modality at the same institution should be used at each assessment, if possible.
For patients who continue study treatment at the same dose beyond documented PD per RECIST 
version 1.1, at the investigator’s discretion and with the sponsor’s medical monitor approval, the 
sponsor does not require further tumor assessment to be collected. The tumor evaluation shall be 
managed according to local medical practice. 
If patients discontinue study treatment due to reasons other than disease progression, tumor 
assessment according to the protocol is strongly encouraged to be continued until radiological 
disease progression is observed. 
For patients who continue the study treatment at 240 mg QD beyond documented PD per 
RECIST version 1.1, at the investigator’s discretion and with the sponsor’s medical monitor 
approval, imaging will continue with the same assessment schedule (Appendix A). If the patient 
experiences symptomatic deterioration in the absence of radiologic progression, it is strongly 
recommended that additional imaging studies be performed to confirm PD. 
The disease assessment that documents progression will serve as the new baseline for the dose 
escalation to 240 mg QD portion of the study. The investigator will reevaluate the patient for 
target and nontarget lesions, according to RECIST criteria, on the basis of the disease assessment 
scans showing the initial progression. The patient need not repeat imaging assessments before 
dose escalation unless the disease assessment is incomplete or occurred >21 days before the first 
dose of brigatinib 240 mg QD, in which case disease assessments must be repeated and will 
serve as the new baseline. If the disease assessment is incomplete, the site will obtain any 
missing radiographic imaging (eg, MRI of the brain) before dose escalation to 240 mg QD. 
Disease assessment by CT and MRI scans will be performed at 8-week intervals thereafter (on 
Day 28 [±7 days] of every even-numbered cycle) for 14 cycles after the initial dose of brigatinib 
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at 240 mg QD, and every 3 cycles (12 weeks, ±7 days) thereafter until radiological disease 
progression is observed, according to the new baseline. The same imaging modality at the same 
institution should be used at each assessment.
All patients will be followed for radiological disease progression. For patients who discontinue 
the study drug for a reason other than objective disease progression, additional tumor assessment 
should be documented, if available, until disease progression or start of another systemic 
anticancer therapy.
9.4.15
End-of-Treatment Visit
The end-of-treatment visit should be performed within 2 weeks (14 days) of the patient’s last 
dose of study drug or the patient/investigator decision to discontinue study drug, whichever 
occurs later. Physical examinations, laboratory tests (hematology, chemistry, insulin and 
testosterone for males), as outlined in Table 9.a. ECGs may be omitted if they had been 
previously performed within 2 weeks since the last assessments and if, in the investigator’s 
judgment, significant change is unlikely. For patients who discontinued the study drug before 
having radiological progression, tumor assessments shall be continued according to the schedule 
in Appendix A until radiological progression is observed. 
9.4.16
Thirty-Days-After-Last-Dose Visit
The 30-days-after-last-dose assessments must be performed 30 days (±7 days) after the last dose 
of study drug. Physical examinations, laboratory tests (hematology, chemistry, insulin and 
testosterone), and ECG can be omitted if the visit occurs within 10 days of the end-of-treatment 
assessment and there have been no clinically significant findings. Any new systemic anticancer 
therapies that the patient has begun receiving since the end of treatment should be reported at this 
visit. For both the end-of-treatment and 30-days-after-last-dose assessments, information may be 
collected from tests performed for the study or as part of the patient’s routine medical care. If the 
day of last dose is more than 30 days before the decision to permanently discontinue from study 
treatment is made, the end-of-treatment visit and 30 days after last dose visit can be combined as 
one visit. If patients permanently discontinued study treatment before radiological disease 
progression is observed, this visit may occur before the end-of-treatment visit.
9.4.17
Follow-up Period
The follow-up period for a patient begins after disease progression or patient starts another 
systemic anticancer therapy and continues until patient contact ceases. If a patient discontinues 
study drug for reasons other than disease progression and has not yet started another systemic 
anticancer therapy, the patient shall continue to be followed for radiological tumor assessment 
and only enters follow-up phase once the radiological tumor progression is observed or another 
systemic anticancer therapy is started. The follow-up assessments (ie, contacting the patient for 
survival and subsequent anticancer therapy) must be performed every 12 weeks (±14 days) after 
the end of treatment for the last study drug administered. The allowable window for follow-up 
assessments is 14 days. All new anticancer therapies should be reported. 
 
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9.4.22
Health Utilization Data Collection
During the treatment and follow-up periods indicated in the Schedules of Events (Appendix A), 
all medical care encounters since the previous collection will be collected from all patients, 
regardless of the reason for the medical care encounter at the schedule visit of each cycle during 
study treatment, end-of-treatment visit, and 30-days-after-last-dose visit. Examples of data to be 
collected are number and duration of medical care encounters such as inpatient/outpatient 
admissions, homecare, and time of work loss.
9.5
Completion of Study Treatment (for Individual Patients)
For the purpose of analysis, patients will be considered to have completed study treatment once 
they have permanently discontinued brigatinib because of disease progression, intolerance, 
investigator discretion, or death while on study treatment. 
For visit purposes, the end-of-treatment visit occurs at the last dose of study drug or when the 
investigator or the patient decide the patient will receive no further study drug, whichever occurs 
later. At 30 days after last dose of study drug, the patient shall complete all posttreatment 
discontinuation assessments. If patient has the last dose equals or more than 30 days before the 
decision of permanent discontinuation from study treatment is made, the end-of-treatment visit 
and 30-days-after-last-dose visit can be combined as 1 visit. 
9.6
Completion of Study (for Individual Patients)
All patients who discontinued study drug shall be followed for survival, regardless of the reason 
for discontinuation. The survival follow-up will continue until patients die or study ends. Patients 
will be considered to have completed the study if they died before or were alive at the time of 
data cut. Patients lost to follow-up or who withdraw consent before study completion are not 
counted in the number of patients who completed the study.
9.7
Discontinuation of Treatment With Study Drug
Study drug must be permanently discontinued for:

Intolerable toxicity as determined by the investigator.

Progression of disease requiring an alternative therapy, in the opinion of the investigator. 
Note: At the discretion of the investigator, treatment of patients with brigatinib may be continued 
at the recommended dose of 180 mg QD, despite investigator-assessed progression per RECIST 
version 1.1, if there is still potential for clinical benefit. Treatment of patients with brigatinib 
may be escalated to 240 mg QD, despite investigator-assessed progression per RECIST 
version 1.1, at the discretion of the investigator and if there is still potential for clinical benefit. 
Treatment beyond progression or escalation to 240 mg brigatinib dose is allowed. In both 
scenarios, the sponsor’s medical monitor shall be contacted to approve these cases. Patients shall 
sign an additional ICF before the treatment continues or increases.
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
Requested by the patient. Note: In cases where patients request to discontinue the study drug, 
the investigator should assess whether this request is due to study drug–related toxicity. This 
election is applicable only if the patients are not having intolerable toxicity in the 
investigators’ medical judgment. Patients who request to permanently discontinue the study 
treatment shall continue to be followed for tumor assessment and survival, unless patients 
withdraw consent to participate in the study. 

Lost to follow-up.

Per investigator discretion, it is in the best interest of the patient to discontinue. If the 
investigator’s determination is made on the basis of intolerable toxicity, the reason of 
discontinuation shall be recorded as intolerable toxicity. In cases where it is reported that 
patient discontinuation is due to investigator discretion, the situation shall be clearly 
documented in the source document and sponsor medical monitor shall be contacted to 
discuss alternative solutions before the discontinuation decision is made.

Significant protocol deviations that will jeopardize safety surveillance and pose a significant 
threat to the safety of the patient.
Once study drug has been discontinued, all study procedures outlined for the end-of-treatment 
visit will be completed as specified in the Schedules of Events (Appendix A). The primary 
reason for study drug discontinuation will be recorded on the eCRF.
9.8
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 consent by subject.

Completed study.

Death.
The consequence of a patient withdrawing consent from further treatment and/or follow-up is 
that no new information will be collected from the withdrawn patient and added to the existing 
data or any database. It is important to be clear what the patient is withdrawing consent from: 
treatment, follow-up or both. However, every effort will be made to follow all patients for safety. 
Data collected during patient consent, however, must be included in the database.
9.9
Study Compliance
Study drug will be administered or dispensed only to eligible patients under the supervision of 
the investigator or identified subinvestigator(s). The appropriate study personnel will maintain 
records of study drug receipt and dispensing.
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In extenuating circumstances, such as during the COVID-19 public health emergency, additional 
drug supply may be provided to the subjects to cover extended periods between on-site visits as 
described in Section 8.1. 
9.10
Overall Survival
After disease progression or starting another systemic anticancer therapy, all patients will be 
followed for OS till death or study termination. The survival follow-up can be conducted by 
remote method (eg, telephone call, etc). At each visit, survival status and information about 
subsequent anticancer therapy (eg, the name, starting and ending time and best known response) 
will be collected. 
If patients discontinue study treatment due to reasons other than disease progression, tumor 
assessment according to the protocol is strongly encouraged to be continued until radiological 
disease progression is observed. 
10.0
ADVERSE EVENTS
10.1
Definitions
10.1.1
PTE Definition
A pretreatment event (PTE) is any untoward medical occurrence in a patient who has signed 
informed consent to participate in a study but before administration of any study medication; it 
does not necessarily have to have a causal relationship with study participation.
10.1.2
AE Definition
AE means any untoward medical occurrence in a patient administered a pharmaceutical product; 
the untoward medical occurrence does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product whether or not it is related to the medicinal product. This includes any 
newly occurring event, or a previous condition that has increased in severity or frequency since 
the administration of study drug.
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is 
considered by the investigator to be a clinically significant change from baseline.
Worsening of signs and symptoms of the malignancy under study should be reported as AEs in 
the appropriate section of the eCRF. Disease progression assessed by measurement of malignant 
lesions on radiographs or other methods should not be reported as an AE.
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10.1.3
AE Severity
The severity of AEs will be assessed according to the CTCAE version 4.03 (see the study 
manual). If the AE is not defined in the CTCAE, the investigator will determine the severity of 
the AE on the basis of the following definitions:

Mild (Grade 1): The AE is noticeable to the patient but does not interfere with routine 
activity.

Moderate (Grade 2): The AE interferes with routine activity but responds to symptomatic 
therapy or rest.

Severe (Grade 3): The AE significantly limits the patient’s ability to perform routine 
activities despite symptomatic therapy.

Life-Threatening (Grade 4): The patient is at immediate risk of death.

Death (Grade 5): The patient dies as a direct result of the complication or condition induced 
by the AE. 
10.1.4
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. (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 1 of the outcomes listed above, or involves suspected 
transmission via a medicinal product of an infectious agent. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
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.)
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In this study, severity for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE, version 4.03, effective date 14 June 2010 [39]. Clarification should be made 
between an SAE and an AE that is considered severe in intensity (Grade 3 or 4), because the 
terms serious and severe are NOT synonymous. The general term severe is often used to describe 
the intensity (severity) of a specific event; the event itself, however, may be of relatively minor 
medical significance (such as a Grade 3 headache). This is NOT the same as serious, which is 
based on patient/event outcome or action criteria described above, and is usually associated with 
events that pose a threat to a patient’s life or ability to function. A severe AE (Grade 3 or 4) does 
not necessarily need to be considered serious. For example, a white blood cell count of 
1000/mm3 to less than 2000 is considered Grade 3 (severe) but may not be considered serious. 
Seriousness (not intensity) serves as a guide for defining regulatory reporting obligations.
10.2
Procedures for Recording and Reporting AEs and SAEs
All AEs spontaneously reported by the patient and/or in response to an open question from study 
personnel or revealed by observation, physical examination, or other diagnostic procedures will 
be recorded on the appropriate page of the eCRF (see Section 10.3 for the period of observation). 
Any clinically relevant deterioration in laboratory assessments or other clinical finding is 
considered an AE. When possible, signs and symptoms indicating a common underlying 
pathology should be noted as 1 comprehensive event.
Regardless of causality, SAEs must be reported (see Section 10.3 for the period of observation) 
by the investigator to the Takeda Global Pharmacovigilance department or designee within 24 
hours of becoming aware of the event. This will be done by transmitting an electronic data 
capture (EDC) SAE report. If transmission of an EDC SAE report is not feasible, then a 
facsimile (fax) of the completed Takeda paper-based SAE form will be sent. A sample of the 
paper-based SAE form and processing directions are in the study manual. Information in the 
SAE report or form must be consistent with the data provided on the eCRF.
If information not available at the time of the first report becomes available at a later date, then 
the investigator will transmit a follow-up EDC SAE report (or a paper-based SAE form if an 
EDC SAE report is not feasible) or provide other documentation immediately within 24 hours of 
receipt. Copies of any relevant data from the hospital notes (eg, ECGs, laboratory tests, discharge 
summary, postmortem results) should be sent to the addressee, if requested.
Planned hospital admissions or surgical procedures for an illness or disease that existed before 
study drug was given 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 
PTEs, 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 [39]. The criteria are provided in the 
study manual.
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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?”
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 and recorded in the eCRFs. 

SAEs.

Serious PTEs will be reported to the Takeda Global Pharmacovigilance department or 
designee from the time of the signing of the ICF up to first dose of study drug, 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 and recorded in the eCRF. After this 
period, only SAEs suspected by the investigator to be related to the study treatment 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.
If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, the sponsor must also be contacted immediately by faxing a completed pregnancy 
form to the Takeda Global Pharmacovigilance department or designee (see Section 10.2). Every 
effort should be made to follow the pregnancy for the final pregnancy outcome.
10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose)
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product. Individuals who 
identify a potential product complaint situation should immediately report this via the phone 
numbers or email addresses provided below.
A medication error is a preventable event that involves an identifiable patient and that leads to 
inappropriate medication use, which may result in patient harm. Whereas overdoses and 
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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.
Product
Call Center
Phone Number
Email
Fax
Brigatinib
Dohmen Life 
Science Services
1-844-662-8532 
Non–toll-free number: 
1-510-740-1273 
GlobalOncologyMedinfo@t
akeda.com
1-800-881-6092
Product complaints in and of themselves are not AEs. If a product complaint results in an SAE, 
the investigator must report the SAE through EDC (refer to Section 10.2).
10.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, including the European 
Medicines Agency, investigators, and IRBs or IECs, as applicable, in accordance with national 
regulations in the countries where the study is conducted. Relative to the first awareness of the 
event by/or further provision to the sponsor or sponsor’s designee, SUSARs will be submitted to 
the regulatory authorities as an expedited report within 7 days for fatal and life-threatening 
events and 15 days for other serious events, unless otherwise required by national regulations. 
The sponsor will also prepare an expedited report for other safety issues where these might 
materially alter the current benefit-risk assessment of an investigational medicinal product or that 
would be sufficient to consider changes in the investigational medicinal product’s administration 
or in the overall conduct of the trial. The investigational site also will forward a copy of all 
expedited reports to his or her IRB or IEC in accordance with national regulations. 
11.0
STUDY-SPECIFIC COMMITTEES
11.1
Steering Committee 
A steering committee composed of external medical experts will be organized to provide 
scientific guidance to study design, conduction, and reporting. The details of the steering 
committee membership and responsibilities will be included in the steering committee charter.
11.2
Independent Review Committee
A central blinded IRC with no knowledge of the patients’ status on study will evaluate all images 
collected during the study for the primary endpoint of confirmed ORR as well as several 
secondary endpoints. An IRC charter defines the procedures used by the committee.
Following the primary analysis, the sponsor reserves the right to discontinue assessment of 
images by the IRC.
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12.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management 
Plan. If selected for coding, AEs, PTEs, medical history, and concurrent conditions will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using 
the World Health Organization Drug Dictionary.
12.1
eCRFs 
Completed eCRFs are required for each patient who signs an ICF.
The sponsor or its designee will supply investigative sites with access to eCRFs and will make 
arrangements to train appropriate site staff in the use of the eCRF. These forms are used to 
transmit the information collected in the performance of this study to the sponsor, 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 patient’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed 
eCRFs are the sole property of the sponsor and should not be made available in any form to third 
parties, except for authorized representatives of appropriate governmental health or regulatory 
authorities, without written permission of the sponsor.
In extenuating circumstances, such as during the COVID-19 public health emergency, direct, 
suitably controlled remote access to patients’ electronic medical records may be used for data 
monitoring. Only pseudonymized documents may be shared through a cloud-based system. 
Videoconferencing may be used for remote site data verification, but copying or recording of the 
video and/or documents (eg, screen captures) is not permitted. These procedures will be 
documented in the Monitoring Plan. 
12.2
Record Retention
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
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participating patients, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated ICFs, subject authorization forms regarding the use of 
personal health information (if separate from the ICFs), electronic copy of eCRFs, including the 
audit trail, and detailed records of drug disposition to enable evaluations or audits from 
regulatory authorities, the sponsor or its designees. Any source documentation printed on 
degradable thermal sensitive paper should be photocopied by the site and filed with the original 
in the patient’s chart to ensure long term legibility. Furthermore, ICH E6 Section 4.9.5 requires 
the investigator to retain essential documents specified in ICH E6 (Section 8) until at least 
2 years after the last approval of a marketing application for a specified drug indication being 
investigated or, if an application is not approved, until at least 2 years after the investigation is 
discontinued and regulatory authorities are notified. In addition, ICH E6 Section 4.9.5 states that 
the study records should be retained until an amount of time specified by applicable regulatory 
requirements or for a time specified in the clinical study site agreement between the investigator 
and sponsor.
Refer to the clinical study site agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of 
any such documents.
13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A SAP will be prepared and finalized before database lock. This document will provide further 
details regarding the definition of analysis variables and analysis methodology to address all 
study objectives.
The final analysis of the primary endpoint (confirmed ORR) will be conducted approximately 
6 months after the last patient is enrolled. The confirmed ORR will be tested at a one-sided alpha 
of 0.025. 
13.1.1
Analysis Sets
13.1.1.1
Full Analysis Set
All patients who receive at least one dose of brigatinib will be included in the full analysis set. 
Primary analyses of safety and efficacy will be performed using the full analysis set.
13.1.1.2
Per-Protocol Population
The per-protocol population will exclude all patients in the full analysis set who do not meet key 
entry criteria, have no measurable disease at baseline, or have no adequate postbaseline response 
assessment unless the reason is death or early discontinuation due to disease progression. In 
particular, patients who have no history of an ALK rearrangement by an FDA approved test at 
study entry and whose protocol-mandated central test is negative for an ALK rearrangement will 
be excluded from the per-protocol analysis.
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Further criteria for the per-protocol population and the sensitivity analyses of the primary 
endpoint and selected secondary efficacy endpoints using this population will be detailed in the 
SAP.
13.1.2
Analysis of Demographics and Other Baseline Characteristics
Demographics and baseline characteristics will be summarized using descriptive statistics. 
Continuous variables will be summarized by means, medians, standard deviations, and ranges; 
categorical variables will be summarized by counts and percentages. Other variables may also be 
included in this analysis by categorizing the continuous variables or recategorizing existing 
categorical variables.
13.1.3
Efficacy Analysis
13.1.3.1
Definitions of Efficacy Endpoints
The primary endpoint (confirmed ORR assessed by the IRC) is defined as the proportion of the 
patients who are confirmed to have achieved CR or PR, per RECIST version 1.1 (confirmed 
≥4 weeks after initial response), out of all patients who have had at least one dose of study drug 
(the full analysis set). 
Secondary efficacy endpoints for this study are defined as follows:

Confirmed ORR assessed by the investigator is defined as 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 in the full analysis set.

DOR is defined as the time interval from the time that the measurement criteria are first met 
for CR/PR (whichever is first recorded) until the first date that the PD is objectively 
documented, or death in patients with a confirmed response.

PFS is defined as the time interval from the date of the first dose of the study treatment until 
the first date at which radiological disease progression is objectively documented, or death 
due to any cause, whichever occurs first, in the full analysis set. PFS will be censored for 
patients without documented disease progression or death.

Disease control rate is defined as the proportion of patients who have achieved CR, PR, or 
SD (in the case of SD, measurements must have met the SD criteria at least once after study 
entry at a minimum interval of 6 weeks) after the initiation of study treatment.

Time to response is defined as the time interval from the date of the first dose of the study 
treatment until the initial observation of CR or PR.

Confirmed iORR is defined as the proportion of the patients who have achieved CR or PR in 
the brain per a modification of RECIST version 1.1, after the initiation of study treatment, in 
patients with intracranial brain metastases at baseline. The criteria of intracranial efficacy 
assessment will be defined in more detail in the SAP. 
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
Duration of intracranial response is defined as the time interval from the time that the 
measurement criteria are first met for CR or PR in the brain (whichever is first recorded) 
until the first date that PD in the brain is objectively documented or death, in patients with 
intracranial metastases at baseline.

iPFS is defined as the time interval from the date of the first dose of the study treatment until 
the first date at which intracranial brain disease progression is objectively documented, or 
death due to any cause, whichever occurs first, in patients with intracranial metastases at 
enrollment. iPFS will be censored for patients without documented intracranial disease 
progression or death. 

OS is defined as the time interval from the date of the first dose of the study treatment until 
death due to any cause in the full analysis set. It will be censored on the date of last contact 
for those patients who are alive.
13.1.3.2
Primary Efficacy Endpoint Analyses
The best response (CR, PR, SD, or PD), according to RECIST version 1.1, will be derived for 
each eligible patient who receives at least 1 dose of study treatment. The ORR is calculated as 
the proportion of patients who are confirmed to have achieved CR or PR after the initiation of 
study treatment. Confirmed responses are those that persist on repeat imaging at least 4 weeks 
after initial response. At the final analysis, exact 2-sided 95% CIs for the ORR will be calculated 
on the basis of the binomial distribution. The primary analysis will be performed on ORR 
assessed by the IRC. Best target lesion response will be displayed using a “waterfall” plot. 
Supportive sensitivity analyses will be performed for ORR assessed by the IRC in the 
per-protocol population. Supportive sensitivity analyses will also be performed in patients 
confirmed to be ALK+ via central assessment and within subgroups defined by age, sex, race, 
geographic region, mutation status, prior anticancer therapies, and other prognostic factors. 
Continuous prognostic factors affecting the ORR may be explored using simple logistic 
regression models.
13.1.3.3
Secondary Efficacy Endpoint Analyses
Confirmed ORR assessed by the investigator in the full analysis set and the per-protocol 
population will be analyzed to assess the robustness of the primary analysis of the primary 
endpoint.
Disease control rate assessed by the investigator in the full analysis set and the per-protocol 
population and the exact 2-sided 95% binomial CIs will be calculated.
For time-to-event efficacy endpoints (PFS, DOR, OS), median values and 2-sided 95% CIs will 
be estimated using Kaplan-Meier method [40] in the full analysis set. The PFS rates and OS rates 
at 12 and 24 months and the associated 2-sided 95% CIs will be computed.
Time to response will be summarized only for confirmed responders using descriptive statistics.
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In patients with CNS metastases at enrollment, iORR assessed by a separate IRC and the exact 
2-sided 95% binomial CIs will be calculated; median intracranial DOR and PFS will be 
estimated using the Kaplan-Meier method.
13.1.4
Pharmacokinetic Analysis
PK data collected in this study will contribute to population PK and exposure/response (safety 
and efficacy) analyses. These analyses may include data from other brigatinib clinical studies. 
The plans for these analyses will be developed and the results reported separately.
13.1.5
Subgroup Analysis in Patients Progressed on Alectinib
If the primary endpoint is achieved in patients previously treated with alectinib or ceritinib, then 
a subgroup analysis of confirmed ORR in patients progressed on alectinib will be performed and 
tested at a one-sided alpha of 0.025.
13.1.6
Analysis of Patient-Reported Outcomes and Health Resource Utilization Data
The analysis will be based on patients with baseline and at least 1 postbaseline measurement. 
The actual value and change from baseline of the summary/subscale scores of EORTC QLQ-C30 
and the subscale scores of EORTC QLQ-LC13 will be summarized using descriptive statistics 
over time. The number and percentage of patients with improved EORTC QLQ-C30 and 
EORTC QLQ-LC13 scores will also be summarized over time, where improvement will be 
defined on the basis of change from baseline scores and a published responder definition 
threshold of 10. Additionally, time to QOL deterioration based on EORTC QLQ-C30 and 
EORTC QLQ-LC13 scores will also be analyzed. Time to QOL deterioration will be defined 
from first dosing date to the date of the first occurrence of QOL scores deterioration of more than 
10 from baseline. 
Published manuals/guidance for the questionnaires will be used for scoring and handling missing 
data. Further investigation about missing data and subsequently sensitivity analysis for missing 
data may be conducted. 
Compliance for EORTC QLQ-C30, EORTC QLQ-LC13, 
 will also be 
summarized over time. 
HU as measured by hospitalizations, outpatient visits, and missed days of work or other activities 
by patients and caregivers will be summarized using descriptive statistics.
13.1.7
Safety Analysis
AEs will be summarized using the safety analysis set. 
Safety assessments will include physical and laboratory examinations, vital signs, and ECGs.
AEs will be graded according to the NCI CTCAE version 4.03.
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All patients who receive at least 1 dose of study treatment will be evaluated for safety. The 
proportion of patients with at least 1 TEAE, TRAE, and serious treatment-emergent adverse 
event (SAE) will be described, as identified with preferred terms and MedDRA system organ 
class. The frequency of occurrence of overall toxicity, categorized by the maximum toxicity 
grades (severity), will also be described. Listings of laboratory test results and CTCAE grades 
will be generated, and descriptive statistics summarizing the changes in laboratory tests over 
time will be presented.
Exploratory analyses will also be performed on other safety parameters, as deemed appropriate, 
and within subgroups defined by age, sex, race, mutation status, prior anticancer therapies, 
medical history, and other prognostic factors.
Exposure to study treatment over time will be summarized with time on treatment, total amount 
of administrated treatment, dose intensity and relative dose intensity.
Safety will be assessed from the first dose of study treatment for all patients and from the date of 
escalation to 240 mg QD in patients who escalate after PD.
13.2
Sample Size Justification
The sample size was determined so that it would allow for stating that the true ORR (expected 
response rate) is greater than the threshold response rate of 20% for patients previously treated 
by alectinib or ceritinib. A total of approximately 103 patients will be enrolled. This sample size 
was calculated to provide at least 90% power to rule out an uninteresting ORR of 20%, assuming 
the true ORR is 35%. The calculation is based on an exact binomial test with a total one-sided 
alpha level of 0.025 at primary endpoint analysis, allowing for dropout.
14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or its 
designee (CRO) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or 
designee (as long as blinding is not jeopardized), including but not limited to the IB, study 
medication, patient medical records, informed consent documentation, documentation of patient 
authorization to use personal health information (if separate from the ICFs), and review of 
eCRFs and associated source documents. It is important that the investigator and other study 
personnel are available during the monitoring visits and that sufficient time is devoted to the 
process.
In extenuating circumstances, such as during the COVID-19 public health emergency, direct, 
suitably controlled remote access to patients’ electronic medical records may be used for data 
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monitoring. Only pseudonymized documents may be shared through a cloud-based system. 
Videoconferencing may be used for remote site data verification, but copying or recording of the 
video and/or documents (eg, screen captures) is not permitted. These procedures will be 
documented in the Monitoring Plan. 
14.2
Protocol Deviations
The sponsor or sponsor delegates cannot grant waiver to the protocol requirement. The 
investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study patients. Should other unexpected circumstances arise that will 
require deviation from protocol-specified procedures, the investigator should consult with the 
sponsor or designee (and IRB or IEC, as required) to determine the appropriate course of action. 
There will be no exemptions (a prospectively approved deviation) from the inclusion or 
exclusion criteria.
The site should document all protocol deviations in the patient’s source documents. In the event 
of a significant deviation, the site should notify the sponsor or its designee (and IRB or EC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the patient, or confound interpretation of primary study 
assessment. A Protocol Deviation Form should be completed by the site and signed by the 
sponsor or designee for any significant deviation from the protocol.
14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, 
including those of foreign governments (eg, the FDA, the United Kingdom Medicines and 
Healthcare products Regulatory Agency, the Pharmaceuticals and Medical Devices Agency of 
Japan). If the study site is contacted for an inspection by a regulatory body, the sponsor should 
be notified immediately. The investigator and institution guarantee access for quality assurance 
auditors to all study documents as described in Section 14.1.
15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, patients) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the responsibilities of the investigator listed in Appendix B. The 
principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities.
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15.1
Benefit-Risk of the Study
The intended study population are patients with refractory disease and those who have limited 
treatment options. 
The study drug brigatinib will be used at the standard 90 mg to 180 mg dose. The safety profile 
of brigatinib at this dose is well established from the previous studies (AP26113-11-101, 
AP26113-13-201, and AP26113-13-301). The safety surveillance procedures in this protocol are 
similar to those used in previous brigatinib studies and are reasonable to ensure proper 
monitoring of patients’ safety. A detailed dose modification guideline is provided in this protocol 
in case treatment-related toxicity emerges. Only patients who tolerated previous doses well and 
have disease progression will be offered the opportunity to escalate to 240 mg, and an additional 
ICF will be provided before dose escalation. This dose level is still below the maximum dose 
studied in humans, and the MTD was not reached in a phase 1 study of brigatinib. Therefore, any 
toxicities are expected to be manageable. 
The mandatory procedures required by this study are similar to the management that these 
patients will receive as part of clinical practice. 
The data collection and reporting plan are standard for such studies. These will ensure the 
collection of high-quality data to report clinically meaningful outcomes. 
Brigatinib may have antitumor effects in ALK+ metastatic NSCLC patients who have already 
progressed on alectinib or ceritinib according to nonclinical studies. Patients enrolled in this 
study may have clinical benefit from the study drug brigatinib. The efficacy and safety from this 
study will serve as important evidence to evaluate the use of brigatinib in this population and 
potentially benefit more patients in the future. 
In summary, the benefit-risk of this study supports the protocol to be implemented. 
15.2
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable state and federal/local 
requirements of each participating region. The sponsor or designee will require documentation 
noting all names and titles of members who make up the respective IRB or IEC. If any member 
of the IRB or IEC has direct participation in this study, written notification regarding his or her 
abstinence from voting must also be obtained. Those American sites unwilling to provide names 
and titles of all members because of privacy and conflict of interest concerns should instead 
provide a Federal Wide Assurance Number or comparable number assigned by the Department 
of Health and Human Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the IB, a copy of the ICF, and, if 
applicable, patient recruitment materials and/or advertisements and other documents required by 
all applicable laws and regulations, must be submitted to a central or local IRB or IEC for 
approval. The IRB’s or IEC’s written approval of the protocol and subject informed consent 
must be obtained and submitted to the sponsor or designee before commencement of the study 
(ie, before shipment of the sponsor-supplied drug or study specific screening activity). The IRB 
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or IEC approval must refer to the study by exact protocol title, number, and version date; identify 
versions of other documents (eg, ICF) reviewed; and state the approval date. The sponsor will 
ship drug/notify site once the sponsor has confirmed the adequacy of site regulatory 
documentation and, when applicable, the sponsor has received permission from competent 
authority to begin the trial. Until the site receives [drug/notification] no protocol activities, 
including screening may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the ICF, recruitment 
materials intended for viewing by patients, local safety reporting requirements, reports and 
updates regarding the ongoing review of the study at intervals specified by the respective IRB or 
IEC, and submission of the investigator’s final status report to IRB or IEC. All IRB and IEC 
approvals and relevant documentation for these items must be provided to the sponsor or its 
designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor.
15.3
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The ICF, subject authorization form (if applicable), and subject 
information sheet (if applicable) describe the planned and permitted uses, transfers, and 
disclosures of the subject’s personal and personal health information for purposes of conducting 
the study. The ICF and the subject information sheet (if applicable) further explain the nature of 
the study, its objectives, and potential risks and benefits, as well as the date informed consent is 
given. The ICF will detail the requirements of the participant and the fact that he or she is free to 
withdraw at any time without giving a reason and without prejudice to his or her further medical 
care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the ICF 
and if applicable, the subject authorization form. The ICF, subject authorization form (if 
applicable), and subject information sheet (if applicable) must be approved by both the IRB or 
IEC and the sponsor before use.
The ICF, subject authorization form (if applicable), and subject information sheet (if applicable) 
must be written in a language fully comprehensible to the prospective subject. It is the 
responsibility of the investigator to explain the detailed elements of the ICF, subject 
authorization form (if applicable), and subject information sheet (if applicable) to the subject. 
Information should be given in both oral and written form whenever possible and in the manner 
deemed appropriate by the IRB or IEC. In the event the subject is not capable of rendering 
adequate written informed consent, then the subject’s legally acceptable representative may 
provide such consent for the subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity 
to: (1) inquire about details of the study and (2) decide whether or not to participate in the study. 
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If the subject, or the subject’s legally acceptable representative, determines he or she will 
participate in the study, then the ICF and subject authorization form (if applicable) must be 
signed and dated by the subject, or the subject’s legally acceptable representative, at the time of 
consent and before the subject entering into the study. The subject or the subject’s legally 
acceptable representative should be instructed to sign using their legal names, not nicknames, 
using blue or black ballpoint ink. The investigator must also sign and date the ICF and subject 
authorization (if applicable) at the time of consent and before subject entering into the study; 
however, the sponsor may allow a designee of the investigator to sign to the extent permitted by 
applicable law.
Once signed, the original ICF, subject authorization form (if applicable), and subject information 
sheet (if applicable) will be stored in the investigator’s site file. The investigator must document 
the date the subject signs the informed consent in the subject’s medical record. Copies of the 
signed ICF, the signed subject authorization form (if applicable), and subject information sheet 
(if applicable) shall be given to the subject.
All revised ICFs must be reviewed and signed by relevant subjects or the relevant subject’s 
legally acceptable representative in the same manner as the original informed consent. The date 
the revised consent was obtained should be recorded in the subject’s medical record, and the 
subject should receive a copy of the revised ICF.
15.4
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or 
date of birth, and subject initials may be used to verify the subject and accuracy of the subject’s 
unique identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
sponsor requires the investigator to permit its monitor or designee’s monitor, representatives 
from any regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the 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 15.3).
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 [e]CRF).
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15.5
Publication, Disclosure, and Clinical Trial Registration Policy
15.5.1
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.
15.5.2
Clinical Trial Registration
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other 
publicly accessible websites on or before start of study, as defined in Takeda Policy/Standard. 
Takeda contact information, along with investigator’s city, state (for Americas investigators), 
country, and recruiting status will be registered and available for public viewing. 
As needed Takeda and Investigator/site contact information may be made public to support 
participant access to trials via registries. In certain situations/registries, Takeda may assist 
participants or potential participants to find a clinical trial by helping them locate trial sites 
closest to their homes by providing the investigator name, address, and phone number via 
email/phone or other methods callers requesting trial information. Once subjects receive 
investigator contact information, they may call the site requesting enrollment into the trial. The 
investigative sites are encouraged to handle the trial inquiries according to their established 
subject screening process. If the caller asks additional questions beyond the topic of trial 
enrollment, they should be referred to the sponsor.
Any investigator who objects to Takeda providing this information to callers must provide 
Takeda with a written notice requesting that their information not be listed on the registry site. 
15.5.3
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. 
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Data Sharing
The sponsor is committed to responsible sharing of clinical data with the goal of advancing 
medical science and improving patient care. Qualified independent researchers will be permitted 
to use data collected from patients during the study to conduct additional scientific research, 
which may be unrelated to the study drug or the patient’s disease. The data provided to external 
researchers will not include information that identifies patients personally.
15.6
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.
16.0
REFERENCES
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Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA 
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Camidge DR, Doebele RC. Treating ALK-positive lung cancer--early successes and future 
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Takeuchi K, Choi YL, Togashi Y, Soda M, Hatano S, Inamura K, et al. KIF5B-ALK, a 
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Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B, Maki RG, et al. Anaplastic 
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Wong DW, Leung EL, So KK, Tam IY, Sihoe AD, Cheng LC, et al. The EML4-ALK 
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Gainor JF, Varghese AM, Ou SH, Kabraji S, Awad MM, Katayama R, et al. ALK 
rearrangements are mutually exclusive with mutations in EGFR or KRAS: an analysis of 
1,683 patients with non-small cell lung cancer. Clin Cancer Res 2013;19(15):4273-81.
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Katayama R, Lovly CM, Shaw AT. Therapeutic targeting of anaplastic lymphoma kinase in 
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Toyokawa G, Inamasu E, Shimamatsu S, Yoshida T, Nosaki K, Hirai F, et al. Identification 
of a Novel ALK G1123S Mutation in a Patient with ALK-rearranged Non-small-cell Lung 
Cancer Exhibiting Resistance to Ceritinib. J Thorac Oncol 2015;10(7):e55-7.
20.
Costa DB, Kobayashi S, Pandya SS, Yeo WL, Shen Z, Tan W, et al. CSF concentration of 
the anaplastic lymphoma kinase inhibitor crizotinib. Journal of Clinical Oncology 
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21.
Weickhardt AJ, Scheier B, Burke JM, Gan G, Lu X, Bunn PA, Jr., et al. Local ablative 
therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in 
oncogene-addicted non-small-cell lung cancer. J Thorac Oncol 2012;7(12):1807-14.
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ZYKADIA (ceritinib) [prescribing information]. East Hanover, NJ, USA: Novartis 
Pharmaceuticals Corporation, 6/2017.
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12 February 2021
CONFIDENTIAL
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ALECENSA (alectinib) [prescribing information]. South San Francisco, CA: Genentech 
USA, Inc., November 2017.
24.
Soria JC, Tan DSW, Chiari R, Wu YL, Paz-Ares L, Wolf J, et al. First-line ceritinib versus 
platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer 
(ASCEND-4): a randomised, open-label, phase 3 study. Lancet 2017;389(10072):917-29.
25.
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.
26.
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.
27.
Friboulet L, Li N, Katayama R, Lee CC, Gainor JF, Crystal AS, et al. The ALK inhibitor 
ceritinib overcomes crizotinib resistance in non-small cell lung cancer. Cancer Discovery 
2014;4(6):662-73.
28.
Ou SH, Greenbowe J, Khan ZU, Azada MC, Ross JS, Stevens PJ, et al. I1171 missense 
mutation (particularly I1171N) is a common resistance mutation in ALK-positive NSCLC 
patients who have progressive disease while on alectinib and is sensitive to ceritinib. Lung 
Cancer 2015;88(2):231-4.
29.
Ou S, Azada M, Hsiang D, Herman J, Kain T, Siwak-Tapp C, et al. Next-generation 
sequencing reveals a Novel NSCLC ALK F1174V mutation and confirms ALK G1202R 
mutation confers high-level resistance to alectinib (CH5424802/RO5424802) in ALK-
rearranged NSCLC patients who progressed on crizotinib. J Thorac Oncol 2014;9(4):549-
53.
30.
Tchekmedyian N, Ali SM, Miller VA, Haura EB. Acquired ALK L1152R Mutation 
Confers Resistance to Ceritinib and Predicts Response to Alectinib. J Thorac Oncol 
2016;11(7):e87-8.
31.
Shaw A, Peters S, Mok T. Alectinib versus crizotinib in treatment-naive advanced ALK-
positive non-small cell lung cancer (NSCLC): Primary results of the global phase III ALEX 
study. J Clin Oncol 2017;35(suppl; abstr 9006).
32.
Mok TS, Wu YL, Ahn MJ, Garassino MC, Kim HR, Ramalingam SS, et al. Osimertinib or
Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer. N Engl J Med 
2017;376(7):629-40.
33.
Gainor JF, Dardaei L, Yoda S, Friboulet L, Leshchiner I, Katayama R, et al. Molecular 
Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in ALK-
Rearranged Lung Cancer. Cancer Discov 2016;6(10):1118-33.
34.
Carbone DP, Reck M, Paz-Ares L, Creelan B, Horn L, Steins M, et al. First-Line 
Nivolumab in Stage IV or Recurrent Non-Small-Cell Lung Cancer. N Engl J Med 
2017;376(25):2415-26.
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35.
Zhang S, Anjum R, Squillace R, Nadworny S, Zhou T, Keats J, et al. The Potent ALK 
Inhibitor Brigatinib (AP26113) Overcomes Mechanisms of Resistance to First- and 
Second-Generation ALK Inhibitors in Preclinical Models. Clin Cancer Res 
2016;22(22):5527-38.
36.
Ou SH, Ahn JS, De Petris L, Govindan R, Yang JC, Hughes B, et al. Alectinib in 
Crizotinib-Refractory ALK-Rearranged Non-Small-Cell Lung Cancer: A Phase II Global 
Study. Journal of Clinical Oncology 2016;34(7):661-8.
37.
Novello S, Mazières J, Oh I, De Castro J, Migliorino M, Helland A, et al. Primary results 
from the Phase III ALUR study of alectinib versus chemotherapy in previously treated 
ALK+ non-small-cell lung cancer (NSCLC). ESMO Congress; Madrid.
38.
Crino L, Ahn MJ, De Marinis F, Groen HJ, Wakelee H, Hida T, et al. Multicenter Phase II 
Study of Whole-Body and Intracranial Activity With Ceritinib in Patients With ALK-
Rearranged Non-Small-Cell Lung Cancer Previously Treated With Chemotherapy and 
Crizotinib: Results From ASCEND-2. J Clin Oncol 2016;34(24):2866-73.
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Common Terminology Criteria for Adverse Events (CTCAE). National Cancer Institute, 
National Institutes of Health, U.S. Department of Health and Human Services Series v4.03. 
June 14, 2010. Publication No. 09-5410.
40.
Kaplan E, Meier P. Nonparametric estimation from incomplete observations. Journal of the 
American Statistical Association 1958;53:457-81.
41.
Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, et al. Using 
standardized serum creatinine values in the modification of diet in renal disease study 
equation for estimating glomerular filtration rate. Ann Intern Med 2006;145(4):247-54.
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Appendix A
Schedules of Events
Schedule of Events: Study Assessments for All Patients
Screening 
Period
Treatment Through 30 Days After Last Dose
Follow-up 
Period
Assessment
Screening
Cycle 1 a
Every Cycle 
(Starting at 
Cycle 2)
Cycle 3 
Day 1 and 
Cycle 5 
Day 1
Every
2 Cycles 
(From 
Cycle 2 to 
Cycle 14)
Every
3 Cycles 
After 
Cycle 14
End of 
Treatment b
30 Days 
After Last 
Dose b
Follow-up c
Day
D -14 to D0
D1
D8
D15
D1
D1
D28
D28
Informed consent (main)
X
Demographics
X
Medical/surgical history
X
Diagnosis and cancer 
history
X
Prior cancer therapy d
X
Prior ALK+ test report 
including test method e
X
Physical examination
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
ECOG performance 
status
X
X
X
X
X
X
Hematology
X f
X f
X
X
X
X
X
Chemistry
X f
X f
X
X
X
X
X
Insulin g
X f
X f
X
X
X
X
Testosterone level (men 
only)
X f
X f
X
X
X
ECG
X
X
X
X
X
AEs
Throughout study h
Concomitant 
medications
Until last dose i
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Screening 
Period
Treatment Through 30 Days After Last Dose
Follow-up 
Period
Assessment
Screening
Cycle 1 a
Every Cycle 
(Starting at 
Cycle 2)
Cycle 3 
Day 1 and 
Cycle 5 
Day 1
Every
2 Cycles 
(From 
Cycle 2 to 
Cycle 14)
Every
3 Cycles 
After 
Cycle 14
End of 
Treatment b
30 Days 
After Last 
Dose b
Follow-up c
Day
D -14 to D0
D1
D8
D15
D1
D1
D28
D28
Pregnancy test (women 
with child bearing 
potential) j
X
X
X
Disease assessment 
X p
X k
X k
X
Plasma sample for 
brigatinib PK
Refer to Appendix A, PK Sampling Schedule
Archival (banked) tumor 
tissue sample
X l
Optional tumor tissue 
rebiopsy sample
X l
X m, q
Plasma sample for 
ctDNA
X
X
X m, q
PRO assessment 
(EORTC QLQ-C30 and 
QLQ-LC-13)
X
X
X
X
X
HU assessment
X
X
X
X
Subsequent anticancer 
therapy/survival o
X
AEs, adverse events; ALK+, anaplastic lymphoma kinase positive; C, Cycle; ctDNA, circulating tumor DNA; D, Day; ECG, electrocardiogram; ECOG, Eastern Cooperative 
Oncology Group; EORTC, European Organization for Research and Treatment of Cancer; HU, health resource utility; NSCLC, non–small-cell lung cancer; PK, 
pharmacokinetics; PRO, patient-reported outcomes; QD, once daily. 
a 1 cycle = 28 days. The allowed visit day window is ±3 days, starting from Cycle 2, with the exception of disease assessment.
b This visit shall be scheduled with a ±7-day window. If patient has the last dose equals or more than 30 days before the decision of permanent discontinuation from study 
treatment is made, the end-of-treatment visit and 30 days after last dose visit can be combined as one visit.
c Survival follow-up shall be scheduled with a ±14-day window.
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Screening 
Period
Treatment Through 30 Days After Last Dose
Follow-up 
Period
Assessment
Screening
Cycle 1 a
Every Cycle 
(Starting at 
Cycle 2)
Cycle 3 
Day 1 and 
Cycle 5 
Day 1
Every
2 Cycles 
(From 
Cycle 2 to 
Cycle 14)
Every
3 Cycles 
After 
Cycle 14
End of 
Treatment b
30 Days 
After Last 
Dose b
Follow-up c
Day
D -14 to D0
D1
D8
D15
D1
D1
D28
D28
d The prior cancer therapy needs to include the detail of prior treatment, starting and ending time, and the best response to each treatment. 
e The assay and sample type of prior ALK test will also be collected.
f If the blood tests are performed within 3 days of first dose, the Cycle 1 Day 1 tests are not required to be repeated, unless clinically indicated. 
g Glucose and insulin will be tested concurrently.
h Assessment for early pulmonary symptoms must be performed during the visit on Day 8. The AEs and SAEs will be reported from the signing of informed consent through 
30 days after administration of the last dose of study drug. After this period, only SAEs suspected by the investigator to be related to the study treatment must be reported.
i Concomitant medications must be reported from the time informed consent is signed until at least the 30-days-after-last-dose assessment, and for all concomitant medications 
related to serious or study drug-related toxicities until the medication is no longer taken or until patient contact discontinues. After study drug is discontinued, only new anticancer 
therapy to the ALK+ NSCLC need to be reported.
j Pregnancy test must be known to be negative before the study drug administration and be performed within 7 days before the first dose of brigatinib (Cycle 1 Day 1) and should 
be repeated every 3rd cycle on treatment (ie, C3D1, C6D1, etc).
k Every 8 weeks ±7 days for 14 cycles, then every 3 cycles (12 weeks) ±7 days. Imaging of chest, abdomen and brain will occur at each assessment for all patients until disease 
progression is observed. If patients continue to receive the study drug beyond progression, the tumor assessment will be managed according to local clinical practice and no need 
to be collected in eCRF. If a patient discontinues study drug for reasons other than disease progression and has not yet started another systemic anticancer therapy, the patient 
shall continue to be followed for radiological tumor assessment and only enters follow-up phase once the radiological tumor progression is observed or another systemic 
anticancer therapy is started.
l Archival tumor sample from recent biopsy after patient progresses on alectinib or ceritinib is highly encouraged. If the original ALK+ was not tested by an FDA-approved 
method, then archived or fresh tumor tissue is mandatory.
m For patients who dose escalate to 240 mg QD, the end-of-treatment, 30-days-after-last-dose, and follow-up assessments will not be performed until after the last dose of 
brigatinib at 240 mg QD. Dose escalation to 240 mg QD can proceed immediately following medical monitor approval with adherence to the Schedule of Events for treatment 
continuation at 240 mg QD after progression on the following page.
 
 
o This refers to other anticancer therapy after brigatinib is discontinued.
p Tumor radiological imaging used as baseline disease assessment before ICF was signed is allowed to be used if they were generated through patients' regular 
medical care and within the required window.
q If study treatment is stopped for a reason other than disease progression, the re-biopsy and ctDNA shall be collected after confirmed disease progression occurs. If study 
treatment is continued beyond progression, the re-biopsy and ctDNA shall only be collected at the initial progression. They are not required to be repeated once these patients 
further progress and stop the treatment entirely.
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Schedule of Events – Treatment Continuation at 240 mg QD After Progression
Treatment Through 30 Days After Last Dose
Follow-up 
Period
Assessment
Before 
Dose 
Escalation
(14 Days) a
Escalation
Cycle 1 b
Every 
Escalation
Cycle 
(Starting at 
Cycle 2)
Cycle 3 
Day 1 and 
Cycle 5 
Day 1
Every 2 
Escalation 
Cycles c (From 
Escalation Cycle 
2 to Cycle 14)
Every 3 
Escalation
Cycles after 
Escalation 
Cycle 14
End of 
Treatment
30 Days 
After Last 
Dose
Follow-up
Day
D1 d
D1
D15
D1
Informed consent 
to 240 mg
X
Physical 
examination
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
ECOG 
performance status
X
X
X
X
X
X
Hematology
X e
X e
X
X
X
X
Chemistry
X e
X e
X
X
X
X
Insulin f
X e
X e
X
X
X
Testosterone level 
(men only)
X e
X e
X
X
X
ECG
X
X
X
X
X
AEs
Throughout study
Concomitant 
medications
Until last dose g
Pregnancy test h
X
X
X
Disease 
assessment
X c
X c
X
Plasma sample for 
brigatinib PK
Refer to Appendix A, PK Sampling Schedule
Plasma sample for 
ctDNA
X
X
X j
Optional tumor 
tissue rebiopsy
X
X I, j
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Treatment Through 30 Days After Last Dose
Follow-up 
Period
Assessment
Before 
Dose 
Escalation
(14 Days) a
Escalation
Cycle 1 b
Every 
Escalation
Cycle 
(Starting at 
Cycle 2)
Cycle 3 
Day 1 and 
Cycle 5 
Day 1
Every 2 
Escalation 
Cycles c (From 
Escalation Cycle 
2 to Cycle 14)
Every 3 
Escalation
Cycles after 
Escalation 
Cycle 14
End of 
Treatment
30 Days 
After Last 
Dose
Follow-up
Day
D1 d
D1
D15
D1
sample at disease 
progression
PRO assessment
X
X
X
X
X
HU assessment
X
Subsequent 
anticancer 
therapy/survival
X
Abbreviations: AEs, adverse events; ALK+, anaplastic lymphoma kinase-positive; C, Cycle; ctDNA, circulating tumor DNA; D, Day; ECG, electrocardiogram; ECOG, Eastern 
Cooperative Oncology Group; EORTC, European Organization for Research and Treatment of Cancer; HU, health resource utility; NSCLC, non–small-cell lung cancer; PK, 
pharmacokinetics; PRO, patient-reported outcomes; QD, once daily.
a Last visit on 180 mg QD can be used as rebaseline assessment before dose escalation.
b 1 cycle = 28 days.
c Every 8 weeks ±7 days for 14 cycles, then every 3 cycles (12 weeks) ±7 days. Imaging of chest, abdomen and brain will occur at each assessment for all patients until disease 
progression is observed. If patients continue to receive the study drug beyond progression, the tumor assessment will be managed according to local clinical practice and no need to 
be collected in eCRF.
d Performed before first dose at 240 mg QD. The week and day listed in this table are counted from the first day of 240 mg dose.
e If the blood tests are performed within 3 days of first dose, the Cycle 1 Day 1 tests are not required to be repeated, unless clinically indicated.
f Glucose and insulin will be tested concurrently.
g Concomitant medications must be reported from the time informed consent is signed until at least the 30-days-after-last-dose assessment, and for all concomitant medications 
related to serious or study drug-related toxicities until the medication is no longer taken or until patient contact discontinues. After study drug is discontinued, only new anticancer 
therapy to the ALK+ NSCLC need to be reported.
h Pregnancy test should be repeated every 3rd cycle on treatment (ie, C3D1, C6D1, etc).
i At disease progression.
J If study treatment is stopped for a reason other than disease progression, the re-biopsy and ctDNA shall be collected after confirmed disease progression occurs. If study treatment 
is continued beyond progression, the re-biopsy and ctDNA shall only be collected at the initial progression; they are not required to be repeated once these patients further progress 
and stop the treatment entirely.
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PK Sampling Schedule
Upon implementation of Amendment 5, no further PK sample collection will be performed as all ongoing patients have completed at 
least 5 cycles of treatment.
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All Patients
The PK samples outlined in the schedule below are to be collected in all patients.
PK Sampling Time
Cycle 1
Day 1
Cycle 1
Day 8
Cycle 2
Day 1
Cycle 3
Day 1
Cycle 4
Day 1
Cycle 5
Day 1
Predose (within 4 h before dosing)
X
X
X
X
X
1 h postdose (±15 min)
X
X
X
4 h postdose (±30 min)
X
X
X
PK, pharmacokinetics.
For Patients Receiving 240 mg Brigatinib Postprogression
The PK samples outlined in the schedule below are to be collected in patients who receive the 240 mg brigatinib dose postprogression.
PK Sampling Time a
Cycle 1
Day 1
Cycle 2
Day 1
Cycle 3
Day 1
Cycle 4
Day 1
Cycle 5
Day 1
Predose (within 4 h before dosing)
X
X
X
X
X
1 h postdose (±15 min)
X
4 h postdose (±30 min)
X
PK, pharmacokinetics.
a Cycle and day listed in this table are counted from the first day of the 240 mg brigatinib dose.
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Appendix B
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this study. 
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572: 
Conduct the study in accordance with the protocol.
1.
Personally conduct or supervise the staff who will assist in the protocol.
2.
Ensure that study related procedures, including study specific (nonroutine/nonstandard panel) 
3.
screening assessments are NOT performed on potential subjects, before the receipt of written 
approval from relevant governing bodies/authorities.
Ensure that all colleagues and employees assisting in the conduct of the study are informed 
4.
of these obligations.
Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform 
5.
to 21 CFR Part 56 ICH, and local regulatory requirements.
Ensure that the IRB/IEC will be responsible for initial review, continuing review, and 
6.
approval of the protocol. Promptly report to the IRB/IEC all changes in research activity and 
all anticipated risks to subjects. Make at least yearly reports on the progress of the study to 
the IRB/IEC, and issue a final report within 3 months of study completion.
Ensure that requirements for informed consent, as outlined in 21 CFR Part 50 ICH and local 
7.
regulations, are met.
Obtain valid informed consent from each subject who participates in the study, and document 
8.
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each ICF should contain a subject authorization Section 
that describes the uses and disclosures of a subject’s personal information (including personal 
health information) that will take place in connection with the study. If an ICF does not 
include such a subject authorization, then the investigator must obtain a separate subject 
authorization form from each subject or the subject’s legally acceptable representative.
Prepare and maintain adequate case histories of all persons entered into the study, including 
9.
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents.
Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
10.
documents.
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CONFIDENTIAL
Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
11.
drugs, and return all unused sponsor-supplied drugs to the sponsor.
Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
12.
within 24 hours.
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Appendix C
Investigator Consent to Use of Personal Information
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, US, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may 
contain the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s 
own country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.
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Appendix D
Eastern Cooperative Oncology Group Scale for Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all predisease performance without restriction.
1
Symptoms but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to 
carry out work of a light or sedentary nature (eg, light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry out any work 
activities. Up and about more than 50% of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more than 50% 
of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair.
5
Dead
Source: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response 
criteria of the Eastern Cooperative Oncology Group. American Journal of Clinical Oncology 1982;5(6):649-55.
For non-commercial use only


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Appendix E
Response Evaluation Criteria In Solid Tumors (RECIST Version 1.1)
Note: These criteria are adapted from Eisenhauer EA, Therasse P, Bogaerts J, et al. New 
response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eu J 
Cancer 2009;45:228-247.
Choosing Target Lesions

Select up to 5 lesions (up to 2 per organ).

Select largest reproducibly measurable lesions.

If the largest lesion cannot be measured reproducibly, select the next largest lesion which can 
be.

Add up longest diameters (LD) of non-nodal lesions (axial plane).

Add short axis diameters of nodes.

This is the sum of the longest diameters (SLD).
Nontarget Lesions

All other sites of disease present at baseline and not classified as target lesions will be 
classified as nontarget lesions, including any measurable lesions that were not chosen as 
target lesions.

It is possible to record multiple nontarget lesions involving the same organ as a single item 
on the eCRF (eg, “multiple enlarged pelvic lymph nodes”).
Determining Response

Assess at baseline and on study with consistent modalities (CT, MRI, PET/CT).
–
Measure target lesions and calculate SLD.
–
Visually assess nontarget lesions.
–
Search for new lesions.
–
Combine these assessments into the overall response.
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Target Lesion Response
Complete response (CR)

Disappearance of all extranodal target lesions.

All pathological lymph nodes must have decreased to <10 mm in short 
axis.
Partial response (PR)

At least a 30% decrease in the SLD of target lesions, taking as reference 
the baseline sum diameters.
Progressive disease (PD)

SLD increased by at least 20% from the smallest value on study 
(including baseline, if that is the smallest).

SLD must also demonstrate an absolute increase of at least 5 mm. (2 
lesions increasing from, for example, 2 mm to 3 mm, does not qualify).
Stable disease (SD)

Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD.
Nonevaluable (NE)

One or more lesions cannot be evaluated because of missing data or poor 
image quality unless a convincing argument can be made that the 
contribution of the individual missing lesion(s) would not change the 
assigned time point response (eg, PD based on other findings).
SLD, sum of the longest diameters.
Nontarget Lesion Response
Complete response (CR)

Disappearance of all extranodal nontarget lesions.

All lymph nodes must be nonpathological in size (<10 mm short axis).

Normalization of tumor marker level.
Non-CR/non-PD

Persistence of 1 or more nontarget lesions(s) and/or maintenance of 
tumor marker level above the normal limits.
Progressive disease (PD)

Unequivocal progression of existing nontarget lesions (subjective 
judgment by experienced reader).
Unable to evaluate (UE)

One or more lesions cannot be evaluated because of missing data or poor 
image quality unless a convincing argument can be made that the 
contribution of the individual missing lesion(s) would not change the 
assigned time point response (eg, PD based on other findings).
New Lesions 

Should be unequivocal and not attributable to differences in scanning technique or findings 
which may not be a tumor (does not have to meet criteria to be “measurable”). 

If a new lesion is equivocal, continue to next time point. If confirmed then, PD is assessed at 
the date when the lesion was first seen. 

Lesions identified in anatomic locations not scanned at baseline are considered new. 

New lesions on ultrasound should be confirmed on CT or MRI.
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CONFIDENTIAL
Evaluation of Overall Time Point Response for Patients With Measurable Disease at 
Baseline
Target Lesions
Nontarget Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
NE
No
PR
PR
Non-PD or NE
No
PR
SD
Non-PD or NE
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or no
PD
Any
PD
Yes or no
PD
Any
Any
Yes
PD
CR, complete response; PR, partial response; PD, progressive disease; SD, stable disease; NE, nonevaluable.
For non-commercial use only


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Appendix F
Modification of Diet in Renal Disease Equation for Estimated Glomerular 
Filtration Rate 
The following is the isotope dilution mass spectrometry (IDMS)-traceable Modification of Diet 
in Renal disease (MDRD) equation (for creatinine methods calibrated to an IDMS reference 
method): 
GFR (mL/min/1.73 m2) = 175 × (Scr)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if 
African American)
GFR, glomerular filtration rate; Scr, serum creatinine. 
Levey et al, 2006 [41]. 
For non-commercial use only


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Appendix G
Protocol History
Date
Amendment Number
Type
Region
12 February 2021
5
Substantial
Global
24 September 2020
4
Substantial
Global
27 September 2019
3
Substantial
Global
10 April 2019
2
Substantial
Global
11 December 2018
1 DE v1
Nonsubstantial
Germany
12 October 2018
1 SE v1
Nonsubstantial
Sweden
03 May 2018
1
Nonsubstantial
Global
22 February 2018
Initial Protocol
Not applicable
Global
Amendment 4
The primary reasons for this amendment are to maintain patient safety, confidentiality, and study 
integrity in the context of healthcare challenges presented by the coronavirus disease 2019 
(COVID-19) public health emergency. This amendment allows investigators and study personnel 
to conduct visits remotely, deliver study drug directly to patients, use local laboratory and 
imaging results if patients are unable to travel to the investigative site, and remotely access 
patient records for data monitoring as necessary during the COVID-19 public health emergency. 
Secondly, the dose modification for Grade 3 and 4 creatine phosphokinase (CPK) elevations 
without concurrent muscular toxicity was deemed no longer warranted.
Protocol Amendment 4
Summary of Changes Since the Last Version of the Approved Protocol
Section(s) Affected by 
Change
Description of Each Change and Rationale
Location(s)
Description
Rationale
Section 8.1
Study Drug 
Administration
Added text: In extenuating 
circumstances, such as during the 
COVID-19 public health emergency, 
additional drug supply may be provided 
to the subjects to cover periods between 
on-site visits. Additional study drug may 
be dispensed during a scheduled study 
visit, or study drug may be shipped 
directly from investigational sites to 
participants’ residences by a contracted 
logistics provider or distributor (direct-
to-patient [DTP] shipment) in agreement 
with Takeda processes and local health 
authorities. 
Before initiation of the DTP process, 
patients will agree to participate in this 
process. Patients will sign a separate 
To maintain patient safety, confidentiality, 
and study integrity in the context of 
healthcare challenges presented by the 
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Protocol Amendment 4
Summary of Changes Since the Last Version of the Approved Protocol
Section(s) Affected by 
Change
Description of Each Change and Rationale
Location(s)
Description
Rationale
acknowledgment of receipt form 
permitting this process and agree to 
share limited personal information with 
the delivery courier. The investigator 
and courier must ensure that no private 
patient information is shared with the 
sponsor or other CROs participating in 
the study. The local independent review 
board (IRB)/independent ethics 
committee (IEC) must be notified, as 
applicable per local requirements, that 
this process is being initiated, and sites 
must clearly document the chain of 
custody of any study drug dispensed 
directly to patients. 
COVID-19 public health emergency. This 
amendment allows investigators and study 
personnel to conduct visits remotely, deliver 
study drug directly to patients, and to use 
local laboratory and imaging results if 
patients are unable to travel to the 
investigative site.
Section 9.4 
Study Procedures
Added text: Sites will make every effort 
to see patients in the clinic to complete 
all study-specified assessments as 
outlined in the Schedule of Events 
(SOE) (Appendix A). In unavoidable 
circumstances, such as during the 
COVID-19 public health emergency, 
exceptions can be made for alternative 
methods for conducting patient visits 
and performing laboratory and imaging 
assessments. Remote visits may be 
performed via telehealth or telemedicine 
as a safety check on subject well-being. 
Remote visits and telemedicine or 
telehealth must comply with Takeda 
processes and local health authorities. 
This will be recorded in the eCRF and in 
the study records.
In extenuating circumstances, such as 
during the COVID-19 public health 
emergency, local laboratory results and 
imaging assessment may be used. 
Assessments that cannot be completed 
during the protocol-specified window 
will be considered missing data, and 
such departures will be recorded in the 
study records. Missed clinic visits or 
subject withdrawals due to COVID-19 
must be recorded in the protocol 
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Protocol Amendment 4
Summary of Changes Since the Last Version of the Approved Protocol
Section(s) Affected by 
Change
Description of Each Change and Rationale
Location(s)
Description
Rationale
deviation report and eCRF, as 
applicable.
Section 9.4.1
Informed Consent
Added text: Before initiation of the DTP 
process, patients will agree to participate 
in this process as described in Section 
8.1.
Section 9.8 
Study Compliance
Added text: In extenuating 
circumstances, such as during the 
COVID-19 public health emergency, 
additional drug supply may be provided 
to the subjects to cover extended periods 
between on-site visits as described in 
Section 8.1.
Section 12.1 eCRFs
Section 14.1 Study-Site 
Monitoring Visits 
In extenuating circumstances, such as 
during the COVID-19 public health 
emergency, direct, suitably controlled 
remote access to patients’ electronic 
medical records may be used for data 
monitoring. Only pseudonymized 
documents may be shared through a 
cloud-based system. Videoconferencing 
may be used for remote site data 
verification, but copying or recording of 
the video and/or documents (eg, screen 
captures) is not permitted. These 
procedures will be documented in the 
Monitoring Plan. 
Table 8.b
Revised:
Grade 4 CPK elevation (greater than 
10.0 × ULN) or recurrence of Grade 3 
elevation 
• Withhold brigatinib until recovery to 
Grade 1 or less (less than or equal to 2.5 
× ULN) or to baseline, then resume 
brigatinib at next-lower dose (Table 8.a).
• If Grade 4 elevation of CPK recurs, 
permanently discontinue brigatinib.
The dose modifications for Grade 4 CPK 
elevation or recurrence of Grade 3 CPK 
elevation were changed to align with the 
Company Core Data Sheet. An analysis of 
data from Studies AP26113-13-301 and 
AP26113-13-201 suggested that CPK 
increases were associated with longer 
duration of treatment and did not seem to be 
associated with the frequency of muscular 
toxicity. In a review of individual patient 
data from these studies, only 1 patient 
reported a Grade 3 CPK elevation as well as 
a Grade 3 muscular toxicity (PT: muscular 
toxicity). Additionally, many of the 49 
patients from these studies with a Grade ≥3 
CPK elevation did not report a muscular 
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Protocol Amendment 4
Summary of Changes Since the Last Version of the Approved Protocol
Section(s) Affected by 
Change
Description of Each Change and Rationale
Location(s)
Description
Rationale
toxicity event (any grade or Grade ≥3). 
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Amendment 3 
Rationale for Amendment 3
The primary reason for this amendment is to remove the interim analysis. 
Additional changes were made for consistency within the protocol and for clarity. Minor 
grammatical, editorial, formatting, and administrative changes not affecting the conduct of the 
study are included for clarification purposes only. 
Changes in Amendment 03
1. Removed interim analysis. 
2. Clarified that the endpoint analyses will be performed using the full analysis set. 
Amendment 2
Rationale for Amendment 2
The primary reason for this amendment is to update the following dose modification tables for 
consistency with the Company Core Data Sheet (CCDS) for brigatinib and provide clarity on
allowed dose levels:

Table 8.a Recommended Brigatinib Dose Reduction Levels.

Table 8.b Brigatinib Dose Modification Recommendations for Treatment-Related Adverse 
Events.
Additional changes were made for consistency within the protocol and for clarity. Minor 
grammatical, editorial, formatting, and administrative changes not affecting the conduct of the 
study are included for clarification purposes only.
Changes in Amendment 2
Update primary objective in the Study Summary (Section 2.0) for consistency with primary 
1.
objective in main protocol (Section 5.1.1).
Delete the redundant Sample Size Justification row from the Study Summary (Section 2.0).
2.
Revise Study Design Figure 6.a to be consistent with the eligibility criteria.
3.
Correct timing of AE assessments (Section 6.1).
4.
Revise minimum age-related inclusion criterion and add clarification regarding patient sex 
5.
(Section 7.1).
Clarify the definition of 1 cycle of prior systemic regimen and replace “antineoplastic” with 
6.
“anticancer” (Section 7.2).
Update Table 8.a (Recommended Brigatinib Dose Reduction Levels).
7.
Update Table 8.b (Brigatinib Dose Modification Recommendations for Treatment-Related 
8.
Adverse Events).
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Amendment 1 DE v1 
Rationale for Amendment 1 DE v 1
The primary reason for this amendment was to address requests about radiation exposure and 
minor technical editing from the Ethikkommission der Med. Fak. HD (Ethics Committee of the 
Medical Faculty of Heidelberg University) during initial assessment.
Changes in Amendment 1 DE v1
1. Clarification of inclusion criteria for brain imaging in Germany to be consistent with 
standard of care and recent changes to the Radiation Protection Act.
2. Clarification of statistical analysis used for the primary endpoint.
3. Clarification of sample size.
4. Clarification of statistical method used for interim analysis.
Amendment 1 SE v 1
Rationale for Amendment 1 SE v 1
The primary reasons for this amendment was to update the dose escalation schedule of events 
and to clarify that patient consent was required to receive treatment beyond progression.
Changes in Amendment 1 SE v 1
Patient consent was required before patients could receive treatment beyond progression. The 
dose escalation schedule was updated.
Amendment 1 (Global)
Rationale for Amendment 1
The primary reasons for this amendment were to update the dose escalation schedule of events 
and clarify that patient consent is required to receive treatment beyond progression. 
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification purposes only.
Changes in Amendment 1
Patients are required to provide consent to receive an increased dose of brigatinib (240 mg 
1.
QD).
Risk factors (such as tobacco and alcohol intake) will be captured during screening.
2.
Updates to the schedule of events for treatment continuation at 240 mg QD after progression.
3.
For non-commercial use only


For non-commercial use only

SAP_001.pdf: 


Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: Brigatinib in Patients With Anaplastic Lymphoma Kinase-Positive (ALK+), Advanced 
Non–Small-Cell Lung Cancer (NSCLC) Progressed on Alectinib or Ceritinib
NCT Number: NCT03535740
SAP Approve Date: 05 June 2020
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information 
or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


1.0
TITLE PAGE
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: 2002
Brigatinib in Patients with Anaplastic Lymphoma Kinase-Positive (ALK+), Advanced
Non–Small-Cell Lung Cancer (NSCLC) Progressed on Alectinib or Ceritinib
PHASE 2
Version: 2.0
Date: 05 June 2020
Prepared by:
Based on:
Protocol Version: 3.0
Protocol Date: 27 September 2019
perty of Takeda: For
Commercial Use Only and Subject to the Applicable Terms of Use
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Brigatinib (AP26113)
Study No. 2002
Page 2 of 40
SAP Amendment 1
5 June 2020
2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
2.0
TABLE OF CONTENTS.................................................................................................2
3.0
LIST OF ABBREVIATIONS..........................................................................................4
4.0
OBJECTIVES .................................................................................................................6
4.1
Primary Objectives ....................................................................................................6
4.2
Secondary Objectives.................................................................................................6
4.3
.............................................................................................6
4.4
Study Design .............................................................................................................6
5.0
ANALYSIS ENDPOINTS...............................................................................................9
5.1
Primary Endpoint.......................................................................................................9
5.2
Secondary Endpoints .................................................................................................9
5.3
..............................................................................9
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................11
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................12
7.1
General Principles....................................................................................................12
7.1.1
Study Definitions ...............................................................................................12
7.1.2
Definition of Study Days....................................................................................14
7.2
Analysis Populations................................................................................................14
7.2.1
Full Analysis Population ....................................................................................14
7.2.2
iCNS Disease Population ...................................................................................14
7.2.3
Per-Protocol Population .....................................................................................15
7.2.4
Safety Analysis Population.................................................................................15
7.3
Patient Disposition...................................................................................................16
7.3.1
Screen Failures...................................................................................................16
7.3.2
Patient Eligibility ...............................................................................................16
7.3.3
Number of Patients Who Were Enrolled.............................................................16
7.3.4
Important Protocol Deviations............................................................................16
7.4
Demographic and Baseline Disease Characteristics..................................................16
7.5
Medical History and Concurrent Medical Conditions...............................................18
7.6
Medication History and Concomitant Medications...................................................19
7.7
Efficacy Analysis.....................................................................................................20
7.7.1
Primary Efficacy Endpoint Analysis...................................................................20
7.7.2
Secondary Efficacy Endpoint Analyses ..............................................................22
7.7.3
Additional Efficacy Endpoint Analyses..............................................................23
akeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Brigatinib (AP26113)
Study No. 2002
Page 3 of 40
SAP Amendment 1
5 June 2020
7.8
Statistical Hypotheses..............................................................................................23
7.9
Statistical Decision Rules.........................................................................................24
7.10
Pharmacokinetic Analysis........................................................................................24
7.10.1 Pharmacokinetic Analysis ..................................................................................24
7.11
Other Outcomes.......................................................................................................24
7.11.1 Subgroup Analyses ............................................................................................24
7.12
Safety Analysis........................................................................................................25
7.12.1 Study Treatment Exposure.................................................................................25
7.12.2 Adverse Events..................................................................................................26
7.12.3 Serious Adverse Events......................................................................................28
7.12.4 Deaths................................................................................................................28
7.12.5 Clinical Laboratory Evaluations .........................................................................30
7.12.6 12-Lead ECGs ...................................................................................................30
7.12.7 Other Observations Related to Safety.................................................................31
7.13
.............................................................................31
7.13.1
31
7.13.2
32
7.14
Changes in the Statistical Analysis Plan...................................................................32
8.0
REFERENCES..............................................................................................................33
9.0
APPENDICES...............................................................................................................34
9.1
Schedules of Events.................................................................................................34
9.2
Adverse Events in Special Categories ......................................................................39
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Brigatinib (AP26113)
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3.0
LIST OF ABBREVIATIONS
AE
adverse event
ALK
anaplastic lymphoma kinase
ALK+
anaplastic lymphoma kinase-positive
ATC
anatomical therapeutic chemical
CDx
companion diagnostic
CNS
central nervous system
CPK
creatine phosphokinase elevation
CR
complete response
ctDNA
circulating tumor DNA
DCR
disease control rate
DLT
dose-limiting toxicity
DOR
duration of response
ECG
electrocardiogram
EORTC
European Organization for Research and Treatment of Cancer
FDA
Food and Drug Administration
FISH
fluorescence in situ hybridization
GI
gastrointestinal
HRQOL
health-related quality of life
HU
health resource utilization
ICF
informed consent form
iCNS
Intracranial Central Nervous System
iDOR
Intracranial duration of response
iORR
intracranial objective response rate
iPFS
intracranial progression-free survival
IRC
independent review committee
MedDRA
Medical Dictionary for Regulatory Activities
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse 
NSCLC
non-small-cell lung cancer
ORR
objective response rate
OS
overall survival
PD
progressive disease
PFS
progression-free survival
PK
pharmacokinetic(s)
PR
partial response
PRO
patient-reported outcomes
PT
preferred term
QD
once daily
QLQ-C30
EORTC core Quality of Life Questionnaire
QLQ-LC13
Quality of Life Questionnaire, Lung Cancer supplementary module 
Non-Commercial Use Only a
bject to the Applicable Terms of Use
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Brigatinib (AP26113)
Study No. 2002
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QOL
quality of life
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease
SOC
system organ class
TEAE
treatment-emergent adverse event
TKI
tyrosine kinase inhibitor
TLF
tables, listings, and figures
TRAE
treatment-related adverse event
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


Brigatinib (AP26113)
Study No. 2002
Page 6 of 40
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4.0
OBJECTIVES
4.1
Primary Objectives
The primary objective of the study is:

To determine the efficacy of brigatinib, as evidenced by confirmed objective response 
rate (ORR), in patients with anaplastic lymphoma kinase-positive (ALK+) locally 
advanced or metastatic non-small-cell lung cancer (NSCLC) whose disease has 
progressed on therapy with alectinib or ceritinib. 
4.2
Secondary Objectives
The secondary objectives are:

To characterize the durability of efficacy with brigatinib.

To assess intracranial efficacy of brigatinib.

To assess the overall survival (OS) with brigatinib.

To assess the safety and tolerability of brigatinib.

To collect plasma concentration-time data for brigatinib to contribute to population 
pharmacokinetic (PK) analyses.

To assess patient-reported symptoms and health-related quality of life (HRQOL) assessed 
by European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 
and QLQ-LC13.
4.4
Study Design
This study is a phase 2, open-label, single-arm, multicenter, international study in patients with 
ALK+ NSCLC whose disease has progressed on prior alectinib or ceritinib (with or without prior 
crizotinib and no more than 3 different systemic regimens as treatment for locally 
advanced/metastatic disease). An estimated 103 patients will be enrolled internationally. Once 
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Brigatinib (AP26113)
Study No. 2002
Page 7 of 40
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enrolled, patients will be treated with brigatinib 180 mg QD with a 7-day lead-in at 90 mg QD. 
The study scheme is outlined in Figure 1.
Figure 1: Study Scheme
Patients will continue to be treated with brigatinib until they experience objective disease
progression per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, as assessed by the 
investigator, or intolerable toxicity. Upon radiological progression, at the discretion of the 
investigator, patients who are receiving brigatinib 180 mg QD and have experienced toxicities no 
greater than Grade 2 during treatment may elect to increase the brigatinib dose to 240 mg QD, or 
continue study treatment at their current dose if they are still benefiting from treatment at this 
dose (e.g. absence of clinical symptoms or signs indicating clinically significant disease 
progression requiring alternative systemic anti-cancer therapy; no decline in performance status; 
absence of rapid disease progression or threat to vital organs or critical anatomical sites [e.g. 
respiratory failure due to tumor compression, spinal cord compression] requiring urgent use of 
alternative anticancer-therapy; and no significant, unacceptable or irreversible toxicities related 
to study treatment). In both scenarios (increase dose or continue at same dose), the medical 
monitor shall review and approve the case.
Adverse events (AEs) will be assessed from the start of the study drug till 30 days after last dose. 
Patients’ signs and symptoms, laboratory values, vital signs, electrocardiograms (ECGs), and any 
other relevant special exams as clinically indicated will be obtained to evaluate the safety and 
tolerability of brigatinib.
Sparse PK samples will be collected during the study to measure plasma concentrations of 
brigatinib, as outlined in Protocol Appendix A, PK Sampling Schedule.
For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Brigatinib (AP26113)
Study No. 2002
Page 8 of 40
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Toxicity will be evaluated according to National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI CTCAE), version 4.03, effective 14 June 2010 [5].
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


Brigatinib (AP26113)
Study No. 2002
Page 9 of 40
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5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoint
The primary endpoint is confirmed ORR, as assessed by the independent review committee 
(IRC), per RECIST v1.1 in the full analysis (see Section 7.2.1) population.
5.2
Secondary Endpoints
The secondary endpoints are:

Confirmed ORR, as assessed by the investigator, per RECIST v1.1.

Duration of response (DOR) as assessed by the IRC.

DOR as assessed by the investigator.

Progression-free survival (PFS) as assessed by the IRC.

PFS as assessed by the investigator.

Disease control rate (DCR) as assessed by the IRC.

DCR as assessed by the investigator.

Time to response as assessed by the IRC.

Time to response as assessed by the investigator.

Confirmed intracranial objective response rate (iORR) in patients with iCNS metastases 
at baseline, as assessed by the IRC.

Duration of intracranial response (iDOR) in patients with iCNS metastases at baseline, as 
assessed by the IRC.

Intracranial progression-free survival (iPFS) in patients with iCNS metastases at baseline, 
as assessed by the IRC.

OS. 

Safety/tolerability (CTCAE version 4.03).

HRQOL assessed with the global health status/quality of life (QOL) and other function 
and symptom from EORTC QLQ-C30 (version 3.0), and EORTC QLQ-LC13.
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Brigatinib (AP26113)
Study No. 2002
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Property of Takeda: For Non-Commercial Use Only and Subject to the Appl
CCI


Brigatinib (AP26113)
Study No. 2002
Page 11 of 40
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6.0
DETERMINATION OF SAMPLE SIZE
The sample size was determined so that it would allow for stating that the true ORR (expected 
response rate) is greater than the threshold response rate of 20% for patients previously treated 
by alectinib or ceritinib. A total of approximately 103 patients will be enrolled. This sample size 
was calculated to provide at least 90% power to rule out an uninteresting ORR of 20%, assuming 
the true ORR is 35%. The calculation is based on an exact binomial test with a total one-sided 
alpha level of 0.025 at primary analysis.
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Brigatinib (AP26113)
Study No. 2002
Page 12 of 40
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7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
Baseline values are defined as the last valid values collected during the time interval from the 
screening visit to the first dose date (time) of the study treatment. 
Descriptive statistics (such as means, medians, standard deviations, and ranges for continuous 
data, and counts/percentages for categorical data) will be used to summarize patient 
characteristics, study treatment administration, efficacy, safety and genetic status of biomarkers. 
Data will also be displayed graphically, where appropriate. 
Means and medians will be presented to 1 more decimal place than the recorded data. The 
standard deviations 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.
For the purpose of reporting efficacy and safety at specific time points, a month will comprise 
30.4375 days.
All the statistical analyses will be performed using SAS Statistical Software v9.4 or higher.
7.1.1
Study Definitions
The primary (and secondary) endpoint, confirmed objective response rate (ORR), is defined as 
the proportion of patients who are confirmed to have achieved CR or PR per RECIST v1.1 after 
the initiation of study treatment. Confirmed responses are those that persist on repeat imaging ≥4 
weeks (allowing a minus 3-day time window) or more after initial response. 
Additional secondary efficacy endpoints for this study are defined as follows: 

Duration of response (DOR) is defined as the time between the first documentation of 
objective tumor response (CR or PR) for patients with a confirmed CR/PR, and the first 
subsequent documentation of objective progressive disease (PD) or death due to any 
cause, whichever occurs first. The detailed scheme of progression and censoring for the 
analysis of DOR is specified in Table 1.

PFS is 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. The detailed scheme of 
progression and censoring for the analysis of PFS is specified in Table 1.

DCR is defined as the proportion of patients who have achieved CR, PR, or SD (in the 
case of SD, measurements must have met the SD criteria at least once after study entry at 
a minimum interval of 6 weeks) after the initiation of study drug, as per RECIST v1.1.

Time to response is 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.

iCNS ORR (iORR) is defined as the proportion of patients who have achieved confirmed 
CR or PR in the iCNS per a modification of RECIST v1.1 as defined in the IRC charter
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Brigatinib (AP26113)
Study No. 2002
Page 13 of 40
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after initiation of study treatment, in patients with any intracranial metastases and in 
patients with at least one measurable intracranial lesion at baseline by the IRC assessment, 
and in patients with only non-measurable intracranial lesions at baseline by the IRC 
assessment.

Duration of intracranial response (iDOR) is defined as the time interval between the first 
documentation of confirmed objective tumor response (CR or PR) in the iCNS and the 
first subsequent documentation of objective PD in the iCNS or death due to any cause, in 
patients with iCNS metastases at enrollment baseline per IRC. The detailed scheme of 
progression and censoring for the analysis of iDOR is specified in Table 1.

iCNS PFS (iPFS) is defined as the time interval from the date of the first dose of study 
treatment until the first date at which iCNS progression is objectively documented by 
IRC, or death due to any cause, whichever occurs first. 
An iPFS event is defined as, regardless of extracranial tumor status, either a new lesion in 
iCNS, or the sum of longest diameters of all measurable iCNS lesions increases by at 
least 20% from the smallest value on study (including baseline). The detailed scheme of 
progression and censoring for the analysis of iPFS is specified in Table 1.

Overall Survival (OS) is defined as the time interval from the date of the first dose of the 
study treatment until death due to any cause. OS will be censored on the date of last 
contact for patients who are still alive.
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Brigatinib (AP26113)
Study No. 2002
Page 14 of 40
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Table 1: The Scheme of Progression and Censoring for PFS. iPFS, DOR, iDOR, PFS240
Situation
Date of progression or censoring
Outcome
1. 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
2. Death or PD within 126 days of last 
evaluable tumor assessment (or first 
treatment date if there are no post-baseline 
tumor assessment)
Date of death or first PD whichever 
occurred first
Progressed
3. Death or PD more than 126 days after 
the last evaluable tumor assessment (or first 
treatment date if there are no post-baseline 
tumor assessment)
Date of last adequate radiological 
assessment prior to the 126-day interval
Censored
4. No progression or death
Date of last adequate radiological 
assessment or the first dose date if no 
valid post-baseline assessment
Censored
7.1.2
Definition of Study Days
Study Day 1 is defined as the date on which a patient is administered their first dose of the 
medication. Other study days are defined relative to the Study Day 1 with Day 1 being Study 
Day 1 and Day -1 being the day prior to Study Day 1.
7.2
Analysis Populations
7.2.1
Full Analysis Population
All patients who receive at least one dose of brigatinib will be included in the full analysis 
population.
The full analysis population will be used for the primary efficacy analysis and analyses on all 
secondary efficacy endpoints, unless otherwise specified. 
7.2.2
iCNS Disease Population
The iCNS disease population will consist of those patients in the full analysis population who 
were determined by the IRC to have iCNS metastases at baseline, regardless of whether they had 
at least one lesion that qualified as a target lesion in their baseline assessment by IRC.
7.2.2.1
Measurable iCNS Disease population 
The measurable iCNS disease population will consist of the patients within the iCNS disease 
population who were determined the IRC to have had at least one iCNS target lesion in their 
baseline assessment.
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Brigatinib (AP26113)
Study No. 2002
Page 15 of 40
SAP Amendment 1
5 June 2020
7.2.2.2
Non-Measurable iCNS Disease population
The non-measurable iCNS Disease population will consist of all patients in the iCNS disease 
population who are not included in the measurable iCNS disease population.
7.2.3
Per-Protocol Population
The per-protocol population will exclude all patients in the full analysis population who do not 
meet key entry criteria, have no measurable disease at baseline, or have no adequate postbaseline 
response assessment unless the reason is death or early discontinuation due to disease 
progression. To specify, the per-protocol population will fulfill the following criteria:

Histologically or cytologically confirmed locally advanced or metastatic NSCLC

Have documentation of ALK rearrangement by either:
o
A positive result from any laboratory test approved by the Food and Drug 
Administration (FDA) (e.g., the Vysis ALK Break Apart FISH [fluorescence in 
situ hybridization] Probe Kit or the Ventana ALK [D5F3] CDx [companion 
diagnostic] Assay or Foundation Medicine’s FoundationOne CDx) 
or
o
A positive result from a non–FDA-approved local lab test and have provided 
tumor sample to the central laboratory

Previously progressed on either alectinib or ceritinib

Did not receive prior treatments of both alectinib and ceritinib

At least one measurable target lesion per RECIST v1.1, as assessed by the investigator

At least two adequate post-baseline radiographic response assessments unless the reason 
for no post-baseline radiographic response assessment is one of the following:
o
Death
o
Discontinuation due to documented disease progression per RECIST v1.1
o
Discontinuation due to AE
The per-protocol population will be used for the sensitivity analyses of the primary endpoint and 
may be used for analyses of selected secondary efficacy endpoints.
7.2.4
Safety Analysis Population
All patients who receive at least one dose of brigatinib will be included in the safety analysis
population; therefore, the safety population is identical to the full analysis population. All safety 
analyses will be performed using the safety population.
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Brigatinib (AP26113)
Study No. 2002
Page 16 of 40
SAP Amendment 1
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7.3
Patient Disposition
The disposition of patients includes the number and percentage of patients for the following 
categories: patients in each analysis population, patients ongoing treatment, patients discontinued 
from study treatment, patients ongoing in the study, and patients discontinued from the study. 
Patients ongoing in the study are defined as patients who are still being followed (either on 
treatment, or in survival follow-up) at the time of data cut. Patients discontinued from the study
are defined as patients who have permanently left the study. 
All percentages will be based on the number of patients in the full analysis population, unless 
otherwise specified below. 
The primary reason for study drug and study discontinuation will also be summarized in this 
table. Frequency distributions will be provided. When calculating percentages for the reasons for
study treatment discontinuation, the total number of patients who had permanently discontinued 
the study treatment will be used as the denominator. When calculating percentages for the 
reasons for study discontinuation, the total number of patients who prematurely discontinued
from the study and are no longer in follow-up will be used as the denominator.
A listing will present data concerning patient disposition.
7.3.1 Screen Failures
Patients who signed an informed consent form (ICF) but did not start study treatment will be 
counted as a screening failure. Frequency distributions and reasons for screen failure will be 
provided. When calculating percentages for reasons for screen failure, the total number of 
patients counted as a screen failure will be used as the denominator.
7.3.2 Patient Eligibility
Frequency distributions will be provided. When calculating percentages for the primary reasons
for patient not being eligible, the total number of ineligible patients will be used as the 
denominator.
7.3.3 Number of Patients Who Were Enrolled 
Frequency distribution of the number of patients enrolled by region, country, and site will be 
provided.
7.3.4
Important Protocol Deviations
Frequency distribution will be provided for each deviation category. A patient who has several 
deviations will be counted once in each appropriate category. A patient who has several
deviations that can be classified into the same category will be counted only once.
7.4
Demographic and Baseline Disease Characteristics
Demographic and baseline characteristics will be analyzed in the full analysis population, as 
listed in Table 2 and Table 3. Continuous prognostic factors will be summarized by means, 
of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Brigatinib (AP26113)
Study No. 2002
Page 17 of 40
SAP Amendment 1
5 June 2020
medians, standard deviations, and ranges; categorical prognostic factors will be summarized by 
counts/percentages. Other prognostic factors (e.g., by categorizing the continuous prognostic 
factors and re-categorizing the categorical prognostic factors) may also be included in the 
analysis.
Table 2: Demographics
Parameters
Categories for categorical parameters
Age (continuous)
Age (categorical)
Grouping 1: 18-64, ≥65 years
Grouping 2: 18-49, 50-64, 65-74, ≥75 years
Sex
Male, Female
Race
White, Black or African American, Asian (Asian Indian, 
Chinese, Japanese, Korean, Not Reported), Other 
(includes American Indian or Alaska Native, Native 
Hawaiian or other Pacific Islander, Not Reported)
Ethnicity
Hispanic or Latino, Not Hispanic or Latino, Not 
reported, Unknown
Geographic Region
Asia Pacific (China, Other), Europe, North America, 
Australia.
Weight (continuous)
Height (continuous)
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Property of Takeda: For Non-Commercial Use Only
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Brigatinib (AP26113)
Study No. 2002
Page 18 of 40
SAP Amendment 1
5 June 2020
Table 3: Baseline Disease Characteristics
Parameters
Categories for categorical parameters
Stage at Initial diagnosis
IA, IB, IIA, IIB, IIIA, IIIB, IV, Unknown or not staged
Stage at study entry
IIIA, IIIB, IV
Time since initial diagnosis (continuous)
Time since advanced stage diagnosis (continuous)
Histopathological classification at study entry
Squamous, Non-squamous (including Adenocarcinoma, 
Adenosquamous Carcinoma, Large cell, Unknown, 
Other)
Lung involvement at study entry
Left, Right, Both, Neither
Sites of cancer involvement at study entry 
All options from eCRF
Metastatic Sites at Baseline
All options from eCRF
Number of sites of cancer involvement at study entry
0, 1, 2, 3+
iCNS metastases as assessed by iCNS IRC
Measurable iCNS metastases as assessed by IRC
Non-measurable only iCNS metastases as assessed by 
IRC
Yes, No
Yes, No
Yes, No
Brain metastases as assessed by investigator
Measurable brain metastases as assessed by 
investigator
Non-measurable only brain metastases as assessed by 
investigator
Yes, No
Yes, No
Yes, No
Tobacco use history
Never, Former, Current
ECOG Performance Status
0, 1, 2+
7.5
Medical History and Concurrent Medical Conditions
Medical history and concurrent medical conditions will be given using the full analysis 
population A general medical history will be listed for all patients, with medical history defined 
as any start date prior to the first dose date. 
Concurrent medical conditions, defined as any medical condition during treatment period, will be 
given by system organ class (SOC) and preferred term (PT), as coded according to the Medical 
Dictionary for Regulatory Activities (MedDRA). Summaries will be provided using SOC and 
PT, where SOC will be sorted alphabetically and PT will be sorted in decreasing frequency. A 
patient with multiple occurrences of medical history or concurrent medical condition with a SOC 
will be counted only once in that SOC. A patient with multiple occurrences of medical history or 
concurrent medication with a PT will be counted only once within that preferred term. Frequency 
distributions will be provided.
Prior cancer therapies will be summarized as given in Table 4.
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Brigatinib (AP26113)
Study No. 2002
Page 19 of 40
SAP Amendment 1
5 June 2020
Table 4: Prior Cancer Therapies
Parameters
Categories for categorical parameters
Type of prior anti-cancer therapy
Target therapy (Alectinib, Ceritinib, Crizotinib), 
Chemotherapy, Immunotherapy, Other 
Number of prior systemic anticancer regimens
1, 2, 3+
Overall best response to prior anti-cancer regimen
Complete or Partial response, Other (include all 
other options from eCRF)
Overall best response to prior TKI therapy

Overall best response to Alectinib

Overall best response to Ceritinib

Overall best response to Crizotinib
Complete or Partial response, Other (include all 
other options from eCRF)
Overall best response to prior Chemotherapy
Complete or Partial response, Other (include all 
other options from eCRF)
Overall best response to prior Immunotherapy
Complete or Partial response, Other (include all 
other options from eCRF)
Reason for stopping prior anti-cancer regimen
Progressive Disease, Other (include all other options 
from eCRF)
Reason for stopping prior TKI

Reason for stopping prior Alectinib

Reason for stooping prior Ceritinib

Reason for stopping prior Crizotinib
Any prior radiotherapy
Yes, No
Prior radiotherapy on the brain
Yes, No
Best response to prior radiotherapy on brain
Complete or Partial response, Other (include all 
other options from eCRF)
Prior radiotherapy on the lung
Yes, No
Best response to prior radiotherapy on lung
Complete or Partial response, Other (include all 
other options from eCRF)
Mutation status will be summarized as given in Table 5. 
Table 5: Mutation status
Parameters
Categories for categorical parameters
ALK rearrangement detected
Yes, No
ALK mutation
List categories from eCRF, including categories from 
‘Other’
Number of ALK mutations
0, 1, 2+
Type of ALK testing used
Vysis ALK Break Apart FISH [fluorescence in situ 
hybridization] Probe Kit, Ventana ALK [D5F3] CDx 
[companion diagnostic] Assay, Foundation Medicine’s 
FoundationOne CDx, All other.
7.6
Medication History and Concomitant Medications
Medication history and concomitant medications will be analyzed in the full analysis population. 
General medication history, defined as any medications with start date prior to the first dose date, 
will be listed for all patients in the full analysis set. Concomitant medications, defined as any 
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Brigatinib (AP26113)
Study No. 2002
Page 20 of 40
SAP Amendment 1
5 June 2020
medication taken during treatment period, will be coded by generic term using the World Health 
Organization (WHO) Drug Dictionary. The number and percentage of patients taking 
concomitant medications from screening through the end of the on-study period will be tabulated 
by Anatomical Therapeutic Chemical (ATC) classification pharmacological subgroup and WHO 
generic drug term and sorted in decreasing frequency based on the number of reports. A patient 
who has been administered several medications with the same preferred medication name will be 
counted only once for that preferred medication name.
The number and percentage of patients with subsequent anti-cancer therapy will be given. 
Subsequent anti-cancer therapies will be categorized as target therapy, chemotherapy, 
immunotherapy, and other (including investigational drugs), all per medical review.
7.7
Efficacy Analysis
7.7.1
Primary Efficacy Endpoint Analysis
The best response (CR, PR, SD, or PD), according to RECIST v1.1, will be derived for each 
patient in the full analysis population (see Section 7.2.1). Patients with no measurable disease at 
baseline as assessed by the IRC or no adequate postbaseline response assessment will be 
included as non-responders, unless their overall response is CR. The primary efficacy endpoint 
confirmed ORR is calculated as the proportion of patients who are confirmed to have achieved 
CR or PR per IRC after the initiation of study treatment, using the following formula: ORR = (# 
IRC-confirmed CR or PR)/(# full analysis patients)*100%. The exact 2-sided 95% binomial 
confidence interval for IRC-confirmed ORR will be calculated along with a p-value from exact 
binomial test.
Confirmed responses are those meet the following criteria: 
1) Part of a pattern leading to confirmed response found in Table 6. 
2) Persist on repeat imaging 4 weeks (allowing a minus 3-day time window) or more after initial 
response. 
3) The date of the first scan with CR/PR must be on or after 6 weeks (allowing a minus 3-day 
time window) relative to the first dose date. 
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Brigatinib (AP26113)
Study No. 2002
Page 21 of 40
SAP Amendment 1
5 June 2020
Table 6: Derivation of confirmed ORR
Overall response
First time point
Overall response
Subsequent time point
Confirmed Response
CR
CR
CR
CR
PR
SD, PD or PRa
CR
SD
SD provided minimum criteriab for 
SD duration met, otherwise PD
CR
PD
SD provided minimum criteriab for 
SD duration met, otherwise PD
CR
NE
SD provided minimum criteriab for 
SD duration met, otherwise NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteriab for 
SD duration met, otherwise PD
PR
NE
SD provided minimum criteriab for 
SD duration met, otherwise NE
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best 
response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be claimed 
when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not CR at the 
first time point. Under these circumstances, the original CR should be changed to PR and the best response is PR.
b Minimum criteria for SD is that measurements must have met the SD criteria at least once after study entry at a 
minimum interval of 6 weeks
A response pattern of PR-SD-PR, PR-NE-PR or CR-NE-CR will be defined as a confirmed 
PR/CR. If the time interval of two PRs/CRs is at least 4 weeks (allowing a minus 3-day time 
window), regardless of how many NE, the first PR will be considered confirmed. 
The best response in target lesions per RECIST v1.1 will be calculated as the maximum 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. The best response will be 
displayed using a waterfall plot in the full analysis population.
Supportive sensitivity analyses will be performed for confirmed ORR assessed by the IRC in the 
per-protocol population. Supportive sensitivity analyses will also be performed in patients 
confirmed to be ALK+ by an FDA approved test via local or central assessment and within 
subgroups defined by age, sex, race, geographic region, prior anticancer therapies (including 
prior alectinib vs prior ceritinib, with/without chemotherapy; with/without prior crizotinib), and 
other prognostic factors. Continuous prognostic factors affecting the ORR may be explored using 
simple logistic regression models.
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Brigatinib (AP26113)
Study No. 2002
Page 22 of 40
SAP Amendment 1
5 June 2020
7.7.2
Secondary Efficacy Endpoint Analyses
Confirmed ORR, as assessed by the investigator (per RECIST v1.1) in both the full analysis and 
per-protocol populations will be used to assess the robustness of the primary analysis of the 
primary endpoint. Investigator-confirmed ORR will be found in the full analysis population and 
per-protocol population, calculated in the same manner as primary endpoint calculation of ORR. 
The exact two-sided 95% binomial confidence intervals will be calculated for investigator-
confirmed ORR in both populations. 
The intracranial ORR (iORR) will be analyzed in all the following populations: iCNS Disease 
population, measurable iCNS disease population, and non-measurable only iCNS disease 
population. Confirmed iORR, as assessed by the IRC, will be calculated in the same manner as 
the primary endpoint of confirmed ORR. The exact two-sided 95% binomial confidence intervals
will be calculated. Derivation of confirmed iORR will follow the patterns as outlined for the 
primary endpoint of confirmed ORR.
The disease control rate (DCR) will be assessed by the investigator and IRC in the full analysis
population, and the exact two-sided 95% binomial confidence intervals will be calculated. The 
calculations of the DCR will be as follows: 

DCR in the full analysis population, per investigator = (# investigator-assessed CR or PR 
or SD)/ (# full analysis patients)*100%; 

DCR in the full analysis population, per IRC= (# IRC-assessed CR or PR or SD)/ (# full 
analysis patients)*100%;
In general, the calculation of time-to-event (in months) efficacy endpoints will be as follows: 

DOR = date of PFS event or censoring – date of first response (CR or PR, whichever is 
first recorded) + 1

PFS = date of progression or death or censoring – date of first study dose + 1

iPFS = date of iCNS disease progression or death due to any cause or censoring – date of 
first study dose + 1

Time to response = date of first confirmed response (CR or PR, whichever occurs first) –
date of first study dose + 1

iDOR = date of iPFS event or censoring – date of first response in the iCNS (CR in the 
iCNS or PR in the iCNS, whichever is first recorded) + 1

OS = date of death or last contact – date of first study dose + 1
For time-to-event efficacy endpoints (DOR, PFS, iPFS, iDOR, OS), median values and the 
associated 2-sided 95% CIs will be estimated using Kaplan-Meier method (Kaplan and Meier, 
1958). The PFS rates, iPFS rates and OS rates will be calculated every 6 months, and the 
associated 2-sided 95% CIs will be computed. Time to event analyses endpoints DOR, and
iDOR, will be analyzed using confirmed responders only. 
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Brigatinib (AP26113)
Study No. 2002
Page 23 of 40
SAP Amendment 1
5 June 2020
Summary statistics for time to response and iCNS response will be provided for confirmed 
responders only. 
The secondary efficacy endpoints of DOR, PFS, OS and time to response will be analyzed in the 
full analysis population and in the subgroup of patients who have progressed on prior alectinib. 
iPFS and iDOR will be analyzed in the iCNS disease population. 
Additionally, a sensitivity analysis will be performed for PFS by removing the censoring rule 
due to more than 1 missing radiological assessment (rule # 3 in Table 1).
7.7.3
Additional Efficacy Endpoint Analyses
Confirmed ORR240, as assessed by the investigator (per RECIST v1.1), will be analyzed in 
patients who dose-escalate to 240 mg QD after initial progression at 180mg QD. The new 
baseline for confirmation of response after escalation to 240 mg QD will be defined as the last 
observed value prior to escalation. The best response (CR, PR, SD, or PD), according to RECIST 
v1.1, will be derived for each patient that dose escalates to 240 mg QD. The ORR240 is 
calculated using the following formula: 

ORR240 = (# investigator-confirmed CR or PR in patients that dose-escalate to 240mg 
QD)/(# patients that dose-escalate to 240 mg QD)*100%. 
The exact 2-sided 95% binomial confidence interval for investigator-confirmed ORR240 will be 
calculated. 
PFS240, as assessed by investigator per RECIST v1.1, will be analyzed in patients who dose 
escalate to 240 mg QD after initial progression at 180 mg QD. The calculation of PFS240 will be 
as follows: PFS240 = date of progression or death or censoring – date of first dose at 240 mg QD 
+ 1. The median value and associated 2-sided 95% CI for PFS240 will be estimated using the 
Kaplan-Meier method. 
7.8
Statistical Hypotheses
The primary null hypothesis to be tested is that the proportion of patients achieving IRC-
confirmed ORR is not different than an uninteresting threshold rate of 20%, i.e., 
H0:  ORR = 20%
The alternative hypothesis is that the confirmed IRC-confirmed ORR is greater than an 
uninteresting threshold rate of 20%, i.e., 
HA:  ORR > 20%
The key subgroup hypothesis to be tested is: 
Confirmed ORR in patients previously treated with alectinib is not different than an uninteresting 
threshold rate of 20%. 
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Brigatinib (AP26113)
Study No. 2002
Page 24 of 40
SAP Amendment 1
5 June 2020
7.9
Statistical Decision Rules
The primary null hypothesis will be tested at a one-sided alpha level of 0.025 using exact 
binomial test. If the primary null hypothesis is rejected, we will conclude that ORR for brigatinib 
treatment in patients previously treated with alectinib or ceritinib is significantly greater than the 
threshold response rate of 20%. 
A fixed sequential testing procedure will be used to test between the primary endpoint and the 
key subgroup hypothesis; that is, the subgroup hypothesis will be tested only if the primary 
efficacy endpoint is statistically significant in the full analysis population. If the primary 
endpoint is achieved in patients previously treated with alectinib or ceritinib, then a subgroup 
analysis of confirmed ORR in patients previously treated with alectinib will be performed and 
tested at a one-sided alpha level of 0.025 using exact binomial test.
7.10
Pharmacokinetic Analysis
7.10.1 Pharmacokinetic Analysis
Plasma concentration-time data will be presented in a by-patient listing. This listing will include 
nominal collection time, actual PK sample collection date/time, and brigatinib concentration. A 
table of plasma concentration-time data for brigatinib will be provided, summarized by time 
point. These analyses will be done using the safety population. 
PK data collected in this study will contribute to population PK and exposure/response (safety 
and efficacy) analyses. These analyses may include data from other brigatinib clinical studies. 
The analysis plan for the population PK and exposure/response analyses will be separately 
defined and the results of these analyses will be reported separately.
7.11
Other Outcomes
7.11.1 Subgroup Analyses
If the primary endpoint is achieved in patients previously treated with alectinib or ceritinib, then 
a subgroup analysis of confirmed ORR in patients progressed on alectinib will be performed and 
tested at a 1-sided alpha of 0.025.
Other subgroups of interest include:

Age (patients ≥ 65 years vs. patients < 65 years) 

Sex (male vs female)

Race (Asian vs. Non-Asian)

Patients with any brain metastases at baseline, per investigator (yes vs. no)
o
Prior radiotherapy status to the brain (yes vs. no)

Region (Asia, China, rest of world)

Smoking status (never vs former/current)
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Brigatinib (AP26113)
Study No. 2002
Page 25 of 40
SAP Amendment 1
5 June 2020

Prior TKI treatments (alectinib vs. ceritinib)

Prior chemotherapy (yes vs. no)

Prior crizotinib treatment (yes vs. no)

Best response to prior ceritinib or alectinib treatment (CR/PR vs. other)

Best response to any ALK TKI (crizotinib, alectinib or ceritinib) (CR/PR vs. other)

Number of prior ALK TKI therapies (1 prior vs. 2 prior)
For the subgroup analysis by region, patients in China is defined as patients enrolled in mainland 
China and Chinese authority accredited sties in Hong Kong (Site 21001, 21003 and 21005).
7.12
Safety Analysis
Safety evaluations will be based on the incidence, severity, type of adverse events, clinically 
significant changes, or abnormalities in the patient’s physical examination, vital signs, and 
clinical laboratory results. 
Exploratory analyses may also be performed on other safety parameters, as deemed appropriate, 
and within subgroups defined by age, sex, race, prior anticancer therapies, medical history, and 
other prognostic factors. These analyses will be based on the Safety Analysis population.
7.12.1 Study Treatment Exposure
Exposure to study treatment over time will be summarized using the following measures: 

Time on treatment (days)

Total amount of administrated treatment (mg)

Dose intensity (mg/day)

Relative dose intensity (%) 

Dose interruption of at least 3 days
o
Number of patients with at least one occurrence
o
Number of patients who resume any dosing after interruption
o
Number of patients who resumed at the original dose prior to interruption
o
Total duration (days) of time off study drug for one interruption episode
o
Longest off study drug duration across all patients (days)

Dose reduction of at least 3 days
o
Number of patients with at least one occurrence
o
Number of patients who returned to dosing after reduction
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Brigatinib (AP26113)
Study No. 2002
Page 26 of 40
SAP Amendment 1
5 June 2020
Time on treatment is defined as the time interval from the first study dose date to the last dosing 
date and is computed using the following formula: Time (days) on treatment = date of last non-
zero dose – date of first dose + 1. 
Total amount of administered treatment is defined as the cumulative dose of study drug (mg), 
measured from the first dose to the last dose of brigatinib.
Dose intensity will be calculated with the following formula: Dose intensity = total amount of 
administered treatment / total # of days received dose. 
Relative dose intensity (%) is defined as the proportion of the expected dose received by patients 
and will be calculated separately for: 90/180 mg QD and 240 mg QD. The expected daily dose 
will be 90mg in the 7-day lead-in period and 180 mg from day 8 onward. If the patient escalates 
to 240 mg, the expected daily dose will be 240 mg from that day onward, unless they de-escalate 
to 180 mg. Relative dose intensity for the three separate dosing groups will be calculated as 
follows: 

Relative Dose Intensity, 90/180 mg QD phase = (Total Dose Administered in 90/180 mg 
QD phase/Total Dose Expected in 90/180 mg QD phase) *100

Relative Dose Intensity, 240 mg QD phase = (Total Dose Administered in 240 mg QD 
phase/Total Dose Expected in 240 mg QD phase) *100
Dose modifications will be summarized by dose interruption and dose reduction. A patient will 
be identified as having a dose interruption if this patient has no exposure to study drug for at 
least 3 consecutive days. A patient will be identified as having dose reduction if this patient had a 
period of reduced dosage of at least 3 consecutive days, as long as the dose received was less 
than the target dose but greater than 0 mg on some of the days in this period. Periods of time in 
which a patient alternates between reduced dosing and dose interruptions will be handled in the 
following manner: 

The entire period of time between the receipt of the target dose and either resumption at 
the target dose or discontinuation of treatment will be considered as a single dose 
reduction period. 

Any period of 3 or more days with no receipt of study drug within that dose reduction 
period will also be treated as a dose interruption. 
Safety will be assessed from the first dose of study treatment for all patients and from the date of 
escalation to 240 mg QD in patients who escalate after PD.
7.12.2 Adverse Events
All AEs entered in the clinical database (including treatment-emergent and non-treatment-
emergent AEs) will be listed in by-patient listings, or available for review in appropriate datasets. 
AEs will be tabulated by 90/180 mg QD (AE data will be truncated at time of starting 240 mg if 
a patient escalates) and 240 mg QD (AE data will start at time of first dose of 240 mg) dose 
groups separately.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Brigatinib (AP26113)
Study No. 2002
Page 27 of 40
SAP Amendment 1
5 June 2020
Treatment-emergent AEs (TEAEs) are defined as any AE that starts/worsens on or after the first 
dose of study treatment and no later than 30 days after the last dose date (or the first dose date of 
brigatinib 240mg if it is within 30 days of the last dose date of brigatinib180mg), and will be 
tabulated by primary SOC and PT. TEAEs also include those with partially or completely 
missing start date since there is not enough evidence that the event started before the first dose of 
study treatment. AEs will be tabulated according to MedDRA by SOC and PT and will include 
the following categories:

TEAEs

Study drug-related TEAEs

Grade 3 or higher

Grade 3 or higher drug-related TEAEs

TEAEs resulting in study drug discontinuation

TEAE resulting in either dose interruption or dose reduction 

Serious AEs (SAEs) including study drug-related SAEs

Fatal SAEs, i.e., death within 30 days of last dose of study drug, or related to study drug 
(if > 30 days)

Summary of Deaths (including Cause of Death)
A summary table of TEAEs will be provided, including the proportion of patients with at least 1 
TEAE, study drug-related TEAE, Grade 3 or 4 TEAE, Grade 3 or 4 study drug-related TEAE, 
SAE, study drug-related SAE, Grade 3 or 4 SAE, Grade 3 or 4 study drug-related SAE, TEAE 
resulting in study drug interruption, dose reduction, or dose discontinuation, SAE leading to 
death and study drug-related. This summary table will be repeated for the safety analysis set in 
following subgroups: 

Age (patients ≥ 65 years vs. patients < 65 years) 

Race (Asian vs. Non-Asian)

Region (Asia, China, rest of world)
For the subgroup analysis by region, patients in China is defined as patients enrolled in mainland 
China and Chinese authority accredited sites in Hong Kong (Site 21001, 21003 and 21005).
The frequency of occurrence of overall toxicity, categorized by the maximum toxicity grades 
(severity), will be described. Listings of laboratory test results and CTCAE grades will be 
generated, and descriptive statistics summarizing the changes in laboratory tests over time will 
be presented.
In addition, TEAEs will be summarized by causal relationship to study treatment (in the opinion 
of the investigator) and action taken on study treatment, including dose modifications, 
interruptions and discontinuation.
Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Brigatinib (AP26113)
Study No. 2002
Page 28 of 40
SAP Amendment 1
5 June 2020
AEs in special categories will also be summarized in terms of number of patients with at least 
one event in the category, and by the number of patients with at least one event for each 
constituent preferred term. The special categories to be analyzed will include at minimum those 
listed in Appendix 9.2, and will align with the risk profile of brigatinib.
7.12.3 Serious Adverse Events
The number and percentage of patients experiencing at least 1 treatment-emergent SAE will be 
summarized by MedDRA primary SOC, and PT.
In addition, a by-patient listing of the SAEs will be presented (the patient listing will contain all 
SAEs regardless of treatment-emergent status).
7.12.4 Deaths
All deaths occurring on-study treatment (including 30 days after last dose) and during follow-up 
will be displayed (regardless of treatment-emergent status). Deaths will be summarized by 
timing (within 30 days after last dose date, more than 30 days after last dose), and reason.
7.12.4.1 Imputation Rule for Missing Causal Relationship of Treatment-Emergent Adverse 
Events
If there is inadequate information regarding the investigator’s assessment of relationship to study 
treatment, the relationship to the study treatment will be imputed as related to study drug for 
treatment-emergent AEs.
7.12.4.2 Imputation Rule for Missing Onset Date and Resolution Date of Adverse Events
In general, the imputation will be conservative such that onset dates will be imputed to be as 
early as possible and resolution dates will be imputed to be as late as possible. Resolution date 
will be imputed first and then used to impute onset date.
Imputation for Resolution Data:

If day is missing but month and year are non-missing (UU-MMM-YYYY), impute as the 
earliest of:
o
Last day of the month (28, 29, 30 or 31 depending on in which month the adverse 
event resolved)
o
Data cutoff date
o
Death date

If day and month are missing (UU-UUU-YYYY), impute as the earliest of:
o
December 31 (31-DEC-YYYY)
o
Data cutoff date
o
Death date

If date is completely missing (e.g., AE is ongoing), impute as earliest of:
o
Data cutoff date
Commercial Use Only and Subject to the Applicable Terms of Use
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


Brigatinib (AP26113)
Study No. 2002
Page 29 of 40
SAP Amendment 1
5 June 2020
o
Treatment discontinuation date + 30 days
o
Death date
Imputation for Onset Data:

If day is missing but month and year are non-missing (UU-MMM-YYYY), impute as the 
earliest of:
o
If year and month are the same as year and month of first dose date:

If resolution date (or imputed resolution date) is on or after first dose 
date, impute as first dose date

If resolution date (or imputed resolution date) is prior to first dose date, 
impute as latest of first day of the month or informed consent date
o
If year is the same as year of first dose date and month is after month of first dose 
date, impute as first date of month
o
If year is the same as year of first dose date and month is before month of first 
dose date, impute as latest of first day of the month or informed consent date
o
If year is after year of first dose date, impute as first day of month
o
If year is before year of first dose date, impute as latest of first day of the month 
or informed consent date

If day and month are missing and year is non-missing (UU-UUU-YYYY), impute as 
follows:
o
If year is the same as year of first dose date:

If resolution date (or imputed resolution date) is on or after first dose date, 
impute as first dose date

If resolution date (or imputed resolution date) is prior to first dose date, 
impute as latest of first day of the month or informed consent date
o
If year is after year of first dose date, impute as January 1 (01-JAN-YYYY)
o
If year is before year of first dose date, impute as latest of first day of the year 
(01-JAN-YYYY) or informed consent date

If date is completely missing:
o
If resolution date (or imputed resolution date) is on or after first dose date, impute
as first dose date
o
If resolution date (or imputed resolution date) is prior to first dose date, impute as
informed consent date.
7.12.4.3 Derivation of Treatment-Emergent Adverse Event Flag
Treatment-emergent AEs are new or worsening AEs with an onset date on or after the first dose 
date and within 30 days of the last dose date of study drug. In the case of missing onset date, 
impute using the rules defined in previous section.
of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Brigatinib (AP26113)
Study No. 2002
Page 30 of 40
SAP Amendment 1
5 June 2020
7.12.4.4 Calculation Specifications for Treatment-Emergent Adverse Events
Time to onset is defined as the time interval from the first dose date until the onset date of a 
treatment-emergent AE. In case of a missing onset date, a date imputed with the rules in Section 
7.12.4.2 will be used. Time to onset will be computed with the following formula: time to onset= 
AE onset date – first dose date + 1.
Time to initial onset of an individual treatment-emergent AE is defined as the time interval from
the first dose date until the earliest onset date of the treatment emergent AEs of the same nature.
In case of a missing onset date, a date imputed with the rules in Section 7.12.4.2 will be used.
Time to initial onset will be computed with the following formula: time to initial onset = earliest
AE onset date – first dose date + 1.
Age at onset (in years) will be computed by the following formula and rounding down to the 
nearest integer: age at onset = floor ((AE start date – birth date + 1)/365.25).
Dose at onset (in mg) will be defined as the dose received by patients on AE onset date, 
regardless of treatment arm. Dose at onset will not be defined if the occurrence of a treatment-
emergent AE is post treatment discontinuation.
Dose by onset will be defined as the last non-zero dose received by AE onset date.
7.12.5 Clinical Laboratory Evaluations
Laboratory and vital signs data in standard units will be summarized using summary statistics 
and graphically at baseline and at each cycle for which adequate data are available. Laboratory 
data will also be graded according to the NCI CTCAE v4.03 when applicable. 
For patients who have escalated to 240 mg, their new baseline will be defined as the last 
observed value prior to escalation. 
Change from baseline to the worst on-study result will also be summarized by shift in CTCAE 
grade for selected laboratories. 
If a laboratory value is reported using a nonnumeric qualifier (e.g., less than (<) or greater than 
(>) a certain value), the given numeric value will be used in the summary statistics, ignoring the 
nonnumeric qualifier.
7.12.6 12-Lead ECGs
For consistency, the Fridericia correction (QTcF = QT interval/(RR)1/3 interval) method will be 
used for all calculations of heart rate-corrected QT (calculated) intervals.
The following Electrocardiogram results will be summarized:

Heart Rate (<60 bpm, <50 bpm, bradycardiac, tachycardiac)

QT Interval >500 ms with baseline <=500 ms

QTcF Maximum Change (No increase, >1-<30 ms, 30-60 ms, >60 ms)
of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Brigatinib (AP26113)
Study No. 2002
Page 31 of 40
SAP Amendment 1
5 June 2020

QTcF (>500 ms & baseline<=500 ms, >480 ms & baseline<=480 ms, >450 ms & 
baseline<=450 ms)
Electrocardiogram results will also be presented in a listing.
7.12.7 Other Observations Related to Safety
{Not applicable} 
e Terms of Use
CCI


Brigatinib (AP26113)
Study No. 2002
Page 32 of 40
SAP Amendment 1
5 June 2020
7.14
Changes in the Statistical Analysis Plan 
The original SAP (v1.0) was finalized on 5 Dec 2019.
The SAP amendment 1 (v.2.0) was finalized on 05 June 2020. Major changes in this SAP 
Amendment 1 include:
1. Medical history is defined as any start date prior to the first dose date instead of informed 
consent date.
2. It is clarified that a p-value will be generated from exact binomial test for the primary 
endpoint in FAS and for patients previously treated with alectinib if the primary objective 
is met.
3. The 126-day restriction for the confirmation of a response is removed so that a 
confirmation scan >126 days after the initial response can be used to confirm the initial 
response.
4. Time to response will be analyzed only for confirmed responders using summary 
statistics. 
5. An additional sensitivity analysis will be performed for PFS by removing the censoring 
rule due to more than 1 missing radiological assessment (rule # 3 in Table 1).
6. Adverse events of special categories are updated based on the current brigatinib project 
standard.
7. A summary table for ECG is added.
Property of Takeda: For Non-Commercial Use O
s Plan
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5 Dec 2
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CCI


Brigatinib (AP26113)
Study No. 2002
Page 33 of 40
SAP Amendment 1
5 June 2020
8.0
REFERENCES
[1] Aaronson NK, Ahmedzai S, Bergman, et al. The European Organization for Research and 
Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials 
in oncology. J Natl Cancer Inst. 1993;85(5):365-376.
[2] Blackhall F, Kim DW, Besse B, Nokihara H, Han JY, Wilner KD, Reisman A, Iyer S, Hirsh 
V, Shaw AT. Patient-reported outcomes and quality of life in PROFILE 1007: A randomized 
trial of crizotinib compared with chemotherapy in previously treated patients with ALK-positive 
advanced non-small-cell lung cancer. J Thorac Oncol. 2014; 9:1625-1633.
[3] Kaplan EL and Meier P. Nonparametric Estimation from Incomplete observations. J Am 
Statistical Assoc. 1958; 53:457-481.
[4] Fayers PM, Aaronson NK, Bjordal K, et al. EORTC Scoring Manual. 3rd edition. Brussels: 
European Organisation for Research and Treatment of Cancer; 2001.
[5] Common Terminology Criteria for Adverse Events (CTCAE). National Cancer Institute, 
National Institutes of Health, U.S. Department of Health and Human Services v4.03. June 14, 
2010. Publication No. 09-5410.
the Applicable Terms of Use
als
o
als
S, Hi
Ter
S, Hirsh
er
rsh
iri
er
iri
do
le
domized
le T
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able
h ALK-
e
bservat
App
bservat
ubject to 
i
p
i
anual. 3r
to th
anual. 3r
001.
ct t
001.
CAE). N
bjec
CAE). N
Property of Takeda: For Non-Commercial Use Only and Su
and Hum
Subj
and Hum


Brigatinib (AP26113)
Study No. 2002
Page 34 of 40
SAP Amendment 1
5 June 2020
9.0
APPENDICES
9.1
Schedules of Events
Schedule of Events: Study Assessments for All Patients
Screening 
Period
Treatment Through 30 Days After Last Dose
Follow-
up 
Period
Assessment
Screening
Cycle 1 a
Every 
Cycle 
(Starting 
at Cycle 
2)
Cycle 
3 Day 
1 and 
Cycle 
5 Day 
1
Every
2 
Cycles 
(From 
Cycle 
2 to 
Cycle 
14)
Every
3 Cycles 
After 
Cycle 14
End of 
Treatment 
b
30 
Days 
After 
Last 
Dose 
b
Follow-
up c
Day
D -14 to 
D0
D1
D8
D15
D1
D1
D28
D28
Informed consent 
(main)
X
Demographics
X
Medical/surgical 
history
X
Diagnosis and 
cancer history
X
Prior cancer 
therapy d
X
Prior ALK+ test 
report including 
test method e
X
Physical 
examination
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
ECOG 
performance 
status
X
X
X
X
X
X
Hematology
X f
X f
X
X
X
X
X
Chemistry
X f
X f
X
X
X
X
X
Insulin g
X f
X f
X
X
X
X
Testosterone 
level (men only)
X f
X f
X
X
X
ECG
X
X
X
X
X
AEs
Throughout study h
Concomitant 
medications
Until last dose i
Footnotes are on last table page.
: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
Follo
Ter
Follo
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Te
es
t
es
er
o
er
ycle
t to
ycle 14
to
14
En
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En
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T
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ubjbjbj
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b
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nd
and
a
On
a
On
On
On
Us
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ciaia
m
ia
X
X
Com
X
X
m
n Co
X
n
X
n-C
on
X
or N
X
No
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Brigatinib (AP26113)
Study No. 2002
Page 35 of 40
SAP Amendment 1
5 June 2020
Schedule of Events: Study Assessments for All Patients (continued)
Screening 
Period
Treatment Through 30 Days After Last Dose
Follow-
up 
Period
Assessment
Screening
Cycle 1 a
Every 
Cycle 
(Starting 
at Cycle 
2)
Cycle 
3 Day 
1 and 
Cycle 
5 Day 
1
Every
2 
Cycles 
(From 
Cycle 
2 to 
Cycle 
14)
Every
3 Cycles 
After 
Cycle 14
End of 
Treatment 
b
30 
Days 
After 
Last 
Dose 
b
Follow-
up c
Day
D -14 to 
D0
D1
D8
D15
D1
D1
D28
D28
Pregnancy test 
(women with 
child bearing 
potential) j
X
X
X
Disease 
assessment 
X p
X k
X k
X
Plasma sample 
for brigatinib PK
Refer to Appendix A, PK Sampling Schedule
Archival 
(banked) tumor 
tissue sample
X l
Optional tumor 
tissue rebiopsy 
sample
X l
X m, q
Plasma sample 
for ctDNA
X
X
X m, q
PRO assessment 
(EORTC QLQ-
C30 and QLQ-
LC-13)
X
X
X
X
X
HU assessment
X
X
X
X
Subsequent 
anticancer 
therapy/survival 
o
X
Footnotes are on the following page.
se Only and Subject to the Applicable Terms of Use
riod
s o
riod
of
f 
i
f 
tment 
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tment 
b
p
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30 
30 
Days
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Days
After
abl
After
La
a
La
ms
ca
T
Ap
th
th
th
th
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th
X
d S
X k
Su
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CCI


Brigatinib (AP26113)
Study No. 2002
Page 36 of 40
SAP Amendment 1
5 June 2020
AEs, adverse events; ALK+, anaplastic lymphoma kinase positive; C, Cycle; ctDNA, circulating tumor DNA; D, Day; ECG, 
electrocardiogram; ECOG, Eastern Cooperative Oncology Group; EORTC, European Organization for Research and Treatment 
of Cancer; HU, health resource utility; NSCLC, non–small-cell lung cancer; PK, pharmacokinetics; PRO, patient-reported 
outcomes; QD, once daily. 
a 1 cycle = 28 days. The allowed visit day window is ±3 days, starting from Cycle 2, with the exception of disease assessment.
b This visit shall be scheduled with a ±7-day window. If patient has the last dose equals or more than 30 days before the decision 
of permanent discontinuation from study treatment is made, the end-of-treatment visit and 30 days after last dose visit can be 
combined as one visit.
c Survival follow-up shall be scheduled with a ±14-day window.
d The prior cancer therapy need to include the detail of prior treatment, starting and ending time, and the best response to each 
treatment. 
e The assay and sample type of prior ALK test will also be collected.
f If the blood tests are performed within 3 days of first dose, the Cycle 1 Day 1 tests are not required to be repeated, unless 
clinically indicated. 
g Glucose and insulin will be tested concurrently.
h Assessment for early pulmonary symptoms must be performed during the visit on Day 8. The AEs and SAEs will be reported 
from the signing of informed consent through 30 days after administration of the last dose of study drug. After this period, only 
SAEs suspected by the investigator to be related to the study treatment must be reported.
i Concomitant medications must be reported from the time informed consent is signed until at least the 30-days-after-last-dose 
assessment, and for all concomitant medications related to serious or study drug-related toxicities until the medication is no 
longer taken or until patient contact discontinues. After study drug is discontinued, only new anticancer therapy to the ALK+ 
NSCLC need to be reported.
j Pregnancy test must be known to be negative before the study drug administration and be performed within 7 days before the 
first dose of brigatinib (Cycle 1 Day 1) and should be repeated every 3rd cycle on treatment (i.e., C3D1, C6D1, etc.).
k Every 8 weeks ±7 days for 14 cycles, then every 3 cycles (12 weeks) ±7 days. Imaging of chest, abdomen and brain will occur 
at each assessment for all patients until disease progression is observed. If patients continue to receive the study drug beyond 
progression, the tumor assessment will be managed according to local clinical practice and no need to be collected in eCRF. If a 
patient discontinues study drug for reasons other than disease progression and has not yet started another systemic anticancer 
therapy, the patient shall continue to be followed for radiological tumor assessment and only enters follow-up phase once the 
radiological tumor progression is observed or another systemic anticancer therapy is started.
l Archival tumor sample from recent biopsy after patient progresses on alectinib or ceritinib is highly encouraged. If the original 
ALK+ was not tested by an FDA-approved method, then archived or fresh tumor tissue is mandatory.
m For patients who dose escalate to 240 mg QD, the end-of-treatment, 30-days-after-last-dose, and follow-up assessments will not 
be performed until after the last dose of brigatinib at 240 mg QD. Dose escalation to 240 mg QD can proceed immediately 
following medical monitor approval with adherence to the Schedule of Events for treatment continuation at 240 mg QD after 
progression on the following page.
n 
 
o This refers to other anticancer therapy after brigatinib is discontinued.
p Tumor radiological imaging used as baseline disease assessment before ICF was signed is allowed to be used if 
they were generated through patients' regular medical care and within the required window.
q If study treatment is stopped for a reason other than disease progression, the re-biopsy and ctDNA shall be collected after 
confirmed disease progression occurs. If study treatment is continued beyond progression, the re-biopsy and ctDNA shall only be 
collected at the initial progression. They are not required to be repeated once these patients further progress and stop the 
treatment entirely. 
a: For No
ommercial Use Only and Subject to the Applicable Terms of Use
nt.
s
nt.
ecision 
ms
ecision 
can be
Term
can be
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able
response t
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and
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Only
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with adhe
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ase progre
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keda
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Property of Tak
entirely. 
ake
entirely. 
CCI


Brigatinib (AP26113)
Study No. 2002
Page 37 of 40
SAP Amendment 1
5 June 2020
Schedule of Events – Treatment Continuation at 240 mg QD After Progression
Treatment Through 30 Days After Last Dose
Follow
-up 
Period
Assessment
Before 
Dose 
Escalat
ion
(14 
Days) a
Escalation
Cycle 1 b
Every 
Escalation
Cycle 
(Starting 
at Cycle 
2)
Cycle 
3 Day 
1 and 
Cycle 
5 Day 
1
Every 2 
Escalation 
Cycles c 
(From 
Escalation 
Cycle 2 to 
Cycle 14)
Every 3 
Escalatio
n
Cycles 
after 
Escalatio
n Cycle 
14
End of 
Treatm
ent
30 Days 
After 
Last 
Dose
Follow
-up
Day
D1 d
D1
D15
D1
Informed 
consent to 
240 mg
X
Physical 
examination
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
ECOG 
performanc
e status
X
X
X
X
X
X
Hematology
X e
X e
X
X
X
X
Chemistry
X e
X e
X
X
X
X
Insulin f
X e
X e
X
X
X
Testosteron
e level (men 
only)
X e
X e
X
X
X
ECG
X
X
X
X
X
AEs
Throughout study
Concomitan
t 
medications
Until last dose g
Pregnancy 
test h
X
X
X
Disease 
assessment
X c
X c
X
Plasma 
sample for 
brigatinib 
PK
Refer to Appendix A, PK Sampling Schedule
Footnotes are on last table page.
y of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
iod
o
iod
of
m
l
m
t
30 Days
ble
30 Days
After
ab
After
La
a
La
s o
pli
Te
o
App
e A
th
t t
bj
ub
S
ly
nl
On
e
Us
 U
X
er
X
er
m
om
No
Fo
o
Fo
Fo
Fo
Fo
or 
Ta
or 
inib 
f T
inib 
da
o
ke
Property 
Footnote
ty o
Footnote


Brigatinib (AP26113)
Study No. 2002
Page 38 of 40
SAP Amendment 1
5 June 2020
Schedule of Events – Treatment Continuation at 240 mg QD After Progression (continued)
Treatment Through 30 Days After Last Dose
Follow
-up 
Period
Assessment
Before 
Dose 
Escalat
ion
(14 
Days) a
Escalation
Cycle 1 b
Every 
Escalation
Cycle 
(Starting 
at Cycle 
2)
Cycle 
3 Day 
1 and 
Cycle 
5 Day 
1
Every 2 
Escalation
Cycles c
Every 3 
Escalatio
n
Cycles
End of 
Treatm
ent
30 Days 
After 
Last 
Dose
Follow
-up
Day
D1 d
D1
D15
D1
Plasma 
sample for 
ctDNA
X
X
X j
Optional 
tumor tissue 
rebiopsy 
sample at 
disease 
progression
X
X I, j
PRO 
assessment
X
X
X
X
X
HU 
assessment
X
Subsequent 
anticancer 
therapy/surv
ival
X
Abbreviations: AEs, adverse events; ALK+, anaplastic lymphoma kinase-positive; C, Cycle; ctDNA, circulating tumor DNA; D, 
Day; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; EORTC, European Organization for Research and 
Treatment of Cancer; HU, health resource utility; NSCLC, non–small-cell lung cancer; PK, pharmacokinetics; PRO, patient-
reported outcomes; QD, once daily.
a Last visit on 180 mg QD can be used as rebaseline assessment before dose escalation.
b 1 cycle = 28 days.
c Every 8 weeks ±7 days for 14 cycles, then every 3 cycles (12 weeks) ±7 days. Imaging of chest, abdomen and brain will occur 
at each assessment for all patients until disease progression is observed. If patients continue to receive the study drug beyond 
progression, the tumor assessment will be managed according to local clinical practice and no need to be collected in eCRF.
d Performed before first dose at 240 mg QD. The week and day listed in this table are counted from the first day of 240 mg dose.
e If the blood tests are performed within 3 days of first dose, the Cycle 1 Day 1 tests are not required to be repeated, unless 
clinically indicated.
f Glucose and insulin will be tested concurrently.
g Concomitant medications must be reported from the time informed consent is signed until at least the 30-days-after-last-dose 
assessment, and for all concomitant medications related to serious or study drug-related toxicities until the medication is no 
longer taken or until patient contact discontinues. After study drug is discontinued, only new anticancer therapy to the ALK+ 
NSCLC need to be reported.
h Pregnancy test should be repeated every 3rd cycle on treatment (ie, C3D1, C6D1, etc).
i At disease progression.
J If study treatment is stopped for a reason other than disease progression, the re-biopsy and ctDNA shall be collected after 
confirmed disease progression occurs. If study treatment is continued beyond progression, the re-biopsy and ctDNA shall only be 
collected at the initial progression; they are not required to be repeated once these patients further progress and stop the treatment 
entirely.
ercial Use Only and Subject to the Applicable Terms of Use
p
riod
s o
riod
of
Days
e T
Days
After
ble
After
Last
abl
Last
Dos
ca
Dos
ms
li
Te
pli
pli
plic
pli
X
A
X j
Ap
j
Ap
th
o
ub
nd
ly
nl
e
erc
 U
Property of Takeda: For Non-Comme
, anaplast
mer
, anaplast
Eastern Co
mme
Eastern Co
urce utilit
omm
urce utilit
C
e used as
n-C
e used as
or 14 cyc
No
or 14 cyc
all patient
or N
all patient
or ass
For
or assessm
or
essm
re first do
a: F
re first do
ests are pe
da:
ests are pe
dicated.
ked
dicated.
e and insu
Take
e and insu
comitant m
f Ta
comitant m
essment, 
of T
essment, 
longer tak
y of
longer tak
NSCLC
rty 
NSCLC
h
ert
h Pr
rt
Pr
i
e
i


Brigatinib (AP26113)
Study No. 2002
Page 39 of 40
SAP Amendment 1
5 June 2020
PK Sampling Schedule
All Patients
The PK samples outlined in the schedule below are to be collected in all patients.
PK Sampling Time
Cycle 1
Day 1
Cycle 1
Day 8
Cycle 2
Day 1
Cycle 3
Day 1
Cycle 4
Day 1
Cycle 5
Day 1
Predose (within 4 h before dosing)
X
X
X
X
X
1 h postdose (±15 min)
X
X
X
4 h postdose (±30 min)
X
X
X
PK, pharmacokinetics.
For Patients Receiving 240 mg Brigatinib Postprogression
The PK samples outlined in the schedule below are to be collected in patients who receive the 240 mg brigatinib 
dose postprogression.
PK Sampling Time a
Cycle 1
Day 1
Cycle 2
Day 1
Cycle 3
Day 1
Cycle 4
Day 1
Cycle 5
Day 1
Predose (within 4 h before dosing)
X
X
X
X
X
1 h postdose (±15 min)
X
4 h postdose (±30 min)
X
PK, pharmacokinetics.
a Cycle and day listed in this table are counted from the first day of the 240 mg brigatinib dose.
9.2
Adverse Events in Special Categories
Selection of AEs for special categories will be performed through the use of Standardized 
MedDRA Queries based on SMQs, Modified MedDRA Queries (MMQs), or Customized 
MedDRA Queries (CMQs). The adverse events in special categories will be listed and updated 
as new events occur and/or MedDRA versions change over the course of the study. 
The following special categories of adverse events will be analyzed: 

Bradycardia events

Hypertension events

Gastrointestinal (GI) Events

Pancreatic Chemical Events

Pancreatic Clinical Events

Elevated Insulin Events

Hepatic Events

Hyperglycemia Events

Creatine Phosphokinase (CPK) Elevation
Use Only and Subject to the Applicable Terms of Use
Cycle 5
Term
Cycle 5
Day
Te
Day
m
e T
e
ab
lic
App
s who rec
ct t
s who rec
Cyc
ub
Cyc
ubj
S
X
a
X
nd
a
Only
e O
e O
Property of Takeda: For Non-Commercial U e O
rom the f
Us
rom the f
al Cate
rcia
al Cate
tegories
mme
tegories
SMQs,
Comm
SMQs,
Qs). The
Co
Qs). The
nd/or M
on-C
nd/or M
ecial cat
or N
ecial cat
cardi
: Fo
cardia e
Fo
a e
y
ke
yperten
keda
perten
yp
y
ke
yp
y
Gastr
Tak
Gastr

of

P


Brigatinib (AP26113)
Study No. 2002
Page 40 of 40
SAP Amendment 1
5 June 2020

Peripheral Neuropathy

Pulmonary Events

Skin and Subcutaneous Events

Vision Impairments Events
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


  
 
 
 
 
 
 
 
 
ELECTRONIC SIGNATURES 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm ‘UTC’) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
090101d680db5fd7
Brig 2002 SAP_v2_Amendment_1_clean
Biostatistics Approval
08-Jun-2020 21:45 UTC
ble Terms of Use
e Te
ate 
T
ate 
ble T
HH:mm ‘U
ble 
HH:mm ‘U
Ter
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable
ble
45 UTC
able
45 UTC
PPD